Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2](=O)[C@@H:3]([NH:19][C:20]([C:22]1([NH:28]C(=O)OC(C)(C)C)[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1)=[O:21])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][N:14]=[C:13]([O:17][CH3:18])[CH:12]=2)=[CH:7][CH:6]=1.CC[N+](S(N=C(OC)[O-])(=O)=O)(CC)CC>ClCCl.C(O)=O>[NH2:28][C:22]1([C:20]([NH:19][C@H:3]([C:2]#[N:1])[CH2:4][C:5]2[CH:6]=[CH:7][C:8]([C:11]3[CH:16]=[CH:15][N:14]=[C:13]([O:17][CH3:18])[CH:12]=3)=[CH:9][CH:10]=2)=[O:21])[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1
Reactant: COc1cc(-c2ccc(C[C@H](NC(=O)C3(NC(=O)OC(C)(C)C)CCOCC3)C(N)=O)cc2)ccn1
Agent: CC[N+](CC)(CC)S(=O)(=O)N=C([O-])OC
Solvent: O=CO
Solvent: ClCCl
Product: COc1cc(-c2ccc(C[C@@H](C#N)NC(=O)C3(N)CCOCC3)cc2)ccn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 58.2 %

Procedure:
(S)-tert-Butyl 4-(1-amino-3-(4-(2-methoxypyridin-4-yl)phenyl)-1-oxopropan-2-ylcarbamoyl)tetrahydro-2H-pyran-4-ylcarbamate (Example 26, step (i), 214 mg) in dichloromethane (10 mL) was treated with Burgess' reagent (205 mg) and the mixture was stirred at room temperature for 18 h. The solvent was evaporated to give a residue that was dissolved in formic acid (2 mL) which was heated at 50° C. for 15 min. The mixture was evaporated and then methanol was added and the solvent was evaporated. The product was purified by reversed phase HPLC using methanol in 0.1% aqueous TFA as eluent. The residue was converted to the free base by elution through a PL-HCO3 MP cartridge in dichloromethane/methanol to afford the titled compound (95 mg).
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:5][C:6]=1[C:7](OCC)=[O:8].[CH:18]([NH2:20])=O>CN(C=O)C.C(O)=O>[C:12]1([C:4]2[NH:3][C:2]3[N:1]=[CH:18][N:20]=[C:7]([OH:8])[C:6]=3[CH:5]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: NC=O
Reactant: CCOC(=O)c1cc(-c2ccccc2)[nH]c1N
Solvent: O=CO
Solvent: CN(C)C=O
Product: Oc1ncnc2[nH]c(-c3ccccc3)cc12

Procedure:
Under a protective gas, 2.30 g (10 mmol) of 2-amino-3-ethoxycarbonyl-5-phenyl-1H-pyrrole [for preparation see: Synthesis, 272 (1987)] in 20 ml of formamide, 10 ml of DMF and 5 ml of formic acid are heated at 150° C. for 24 hours. The reaction mixture is cooled and filtered and the residue is washed with isopropanol/hexane. Stirring in hot isopropanol yields the title compound; m.p.>300° C.; FAB-MS: (M+H)+ =212.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[CH:5]([CH3:11])[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].[CH2:13]([O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH2:27][CH2:28]I)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH2:13]([O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[CH2:27][CH2:28][C:5]([CH3:11])([C:4]([O:3][CH2:1][CH3:2])=[O:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CCOC(=O)C(C)C(=O)OCC
Reactant: ICCc1ccccc1OCc1ccccc1
Product: CCOC(=O)C(C)(CCc1ccccc1OCc1ccccc1)C(=O)OCC

Procedure:
2-Methylmalonic acid diethyl ester and 2-(2-benzyloxyphenyl)ethyl iodide were used in the same manner as working example 52 (3) to give the subject compound.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:5]=1[C:11]1[N:15]=[C:14]([C:16]2[CH:21]=[CH:20][C:19]([CH2:22][OH:23])=[C:18]([Cl:24])[CH:17]=2)[N:13]([CH3:25])[N:12]=1.Cl[C:27]1[C:32]([Cl:33])=[CH:31][C:30]([Cl:34])=[CH:29][N:28]=1.O>COCCOC>[Cl:24][C:18]1[CH:17]=[C:16]([C:14]2[N:13]([CH3:25])[N:12]=[C:11]([C:5]3[C:6]([F:10])=[CH:7][CH:8]=[CH:9][C:4]=3[Cl:3])[N:15]=2)[CH:21]=[CH:20][C:19]=1[CH2:22][O:23][C:27]1[C:32]([Cl:33])=[CH:31][C:30]([Cl:34])=[CH:29][N:28]=1
Reactant: Clc1cnc(Cl)c(Cl)c1
Reactant: Cn1nc(-c2c(F)cccc2Cl)nc1-c1ccc(CO)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Cn1nc(-c2c(F)cccc2Cl)nc1-c1ccc(COc2ncc(Cl)cc2Cl)c(Cl)c1
Temperature: -5 °C
Reaction time: 0.33 h
Yield: 28.3 %

Procedure:
Sodium hydride (60%, 0.12 g) is added to 1,2-dimethoxyethane (50 ml) and a solution of 3-(2-chloro-6-fluorophenyl)-5-(3-chloro-4-hydroxymethylphenyl)-1-methyl-1H-1,2,4-triazole (1.00 g) in 1,2-dimethoxyethane (20 ml) is added dropwise thereto at -5° C. and stirred for 20 minutes. The reaction solution is added dropwise with a solution of 2,3,5-trichloropyridine (0.60 g) in 1,2-dimethoxyethane (20 ml) at -5° C. for 10 minutes with stirring. The reaction mixture is warmed to room temperature, poured into water and extracted with ethyl acetate. The organic layer is washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The concentrate is purified by silica gel column chromatography to give 0.40 g of desired compound (melting point: 153.0°-155.0° C.).
Reaction SMILES: [CH3:1][CH2:2][NH:3][C:4]([CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][C@@H:12]1[C@@H:16](/[CH:17]=[CH:18]/[C@@H:19]([OH:28])[CH2:20][CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[C@H:15]([OH:29])[CH2:14][C@@H:13]1[OH:30])=[O:5].B([O-])[O-].N1C=CC=CC=1.Cl[C:41]([O:43][CH2:44][CH2:45][CH2:46][CH2:47][Cl:48])=[O:42]>C1COCC1.CN(C1C=CN=CC=1)C>[C:41](=[O:42])([O:28][C@@H:19]([CH2:20][CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)/[CH:18]=[CH:17]/[C@H:16]1[C@H:15]([OH:29])[CH2:14][C@H:13]([OH:30])[C@@H:12]1[CH2:11]/[CH:10]=[CH:9]\[CH2:8][CH2:7][CH2:6][C:4]([NH:3][CH2:2][CH3:1])=[O:5])[O:43][CH2:44][CH2:45][CH2:46][CH2:47][Cl:48]
Reactant: CCNC(=O)CCC/C=C\C[C@@H]1[C@@H](/C=C/[C@@H](O)CCc2ccccc2)[C@H](O)C[C@@H]1O
Reactant: O=C(Cl)OCCCCCl
Agent: CN(C)c1ccncc1
Agent: [O-]B[O-]
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CCNC(=O)CCC/C=C\C[C@@H]1[C@@H](/C=C/[C@H](CCc2ccccc2)OC(=O)OCCCCCl)[C@H](O)C[C@@H]1O
Temperature: 0 °C
Reaction time: 48 h
Yield: 133.5 %

Procedure:
To a solution of bimatoprost boronate b-1 (529 mg, 1.10 mmol) in THF was added DMAP (6.9 mg, 0.055 mmol). The solution was cooled to 0° C. and successively slowly added pyridine (0.22 mL, 2.75 mmol) and 4-chlorobutyl chloroformate (0.375 mL, 2.75 mmol). Allowed to stir at ambient temperature over 2 days. Added more pyridine (89 uL, 1.11 mmol) and 4-chlorobutyl chloroformate (150 uL, 1.10 mmol) and stirred for another 24 h. The resultant mixture was concentrated under reduced pressure, residue partitioned with ethyl acetate and water. Washed organic layer with brine, dried over sodium sulfate, filtered, and concentrated in vacuo to provide 808 mg (134%) of a crude oil, which was used without further purification.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH:5]([C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1)[C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1.[CH3:20][CH:21]([CH3:37])[C:22]([NH:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([CH:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[N:26]=1)=[O:23]>>[F:12][C:9]1[CH:10]=[CH:11][C:6]([CH:5]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[CH2:4][CH2:3][CH2:2][N:34]2[CH2:35][CH2:36][CH:31]([C:27]3[N:26]=[C:25]([NH:24][C:22](=[O:23])[CH:21]([CH3:20])[CH3:37])[CH:30]=[CH:29][CH:28]=3)[CH2:32][CH2:33]2)=[CH:7][CH:8]=1
Reactant: Fc1ccc(C(CCCCl)c2ccc(F)cc2)cc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)n1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCC(c3ccc(F)cc3)c3ccc(F)cc3)CC2)n1

Procedure:
Prepared by Procedure G and Scheme AI using 1-[4-chloro-1-(4-fluorophenyl)butyl]-4-fluorobenzene and 2-methyl-N-[6-(4-piperidinyl)-2-pyridinyl]propanamide: ESMS m/e: 492.2 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:9]2[CH2:14][C:13]([CH3:16])([CH3:15])[CH2:12][C:11]([CH3:18])([CH3:17])[CH2:10]2)=[CH:4][C:3]=1[O:25][CH2:26][C:27]([O:29]CC)=[O:28].[OH-].[Na+].C(O)C.Cl>O>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[C:9]2[CH2:14][C:13]([CH3:15])([CH3:16])[CH2:12][C:11]([CH3:18])([CH3:17])[CH2:10]2)=[CH:4][C:3]=1[O:25][CH2:26][C:27]([OH:29])=[O:28]
Reactant: CCOC(=O)COc1cc(C(=C2CC(C)(C)CC(C)(C)C2)c2ccccc2)ccc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1ccc(C(=C2CC(C)(C)CC(C)(C)C2)c2ccccc2)cc1OCC(=O)O
Temperature: 100 °C
Yield: 97.7 %

Procedure:
Compound 42 (50 mg, 0.12 mmol), NaOH (50 mg, 1.25 mmol), ethanol (5 mL) and water (500 uL) were combined in a sealed microwave vessel. The mixture was heated at 100° C. for 10 minutes in a Personal Chemistry Emrys Optimizer microwave. The reaction was then acidified with 1 N HCl (5 mL) and extracted with EtOAc (3×10 mL). The combined organic extracts were dried over MgSO4, filtered, and the solvents removed in vacuuo to give 46 mg (98%) of 43 as a purple solid. 1H NMR (400 MHz, CDCl3): δ 0.88 (s, 6H), 0.91 (s, 6H), 1.20-1.25 (m, 5H), 1.75 (s, 2H), 1.90 (s, 2H), 2.23 (s, 3H), 4.61 (s, 2H), 6.74 (d, J=8.3 Hz, 1H), 6.75-7.05 (m, 2H), 7.09-7.15 (m, 3H) 7.25-7.36 (m, 2H).
Reaction SMILES: [NH2:1][CH2:2][C:3]1([CH2:22][C:23]([OH:25])=O)[CH2:7][C@@H:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[N:5]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:4]1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[O:25]=[C:23]1[CH2:22][C:3]2([CH2:4][N:5]([C:15]([O:17][C:18]([CH3:20])([CH3:21])[CH3:19])=[O:16])[C@H:6]([C:8]([O:10][C:11]([CH3:12])([CH3:14])[CH3:13])=[O:9])[CH2:7]2)[CH2:2][NH:1]1
Reactant: CC(C)(C)OC(=O)[C@@H]1CC(CN)(CC(=O)O)CN1C(=O)OC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)[C@@H]1CC2(CNC(=O)C2)CN1C(=O)OC(C)(C)C
Reaction time: 8 h
Yield: 59.9 %

Procedure:
To a solution of amino acid 2-((5S)-3-(aminomethyl)-1,5-bis(tert-butoxycarbonyl)pyrrolidin-3-yl)acetic acid (D6) (1.45 mmol) in CH2Cl2 (32 ml) was added 1-hydroxybenzotriazole (HOBT, 196 mg, 1.45 mmol, 1 eq), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC, 418 mg, 2.2 mmol, 1.5 eq), and N,N-Diisopropylethylamine (DIEA, 756 μl, 4.4 mmol, 3.0 eq). The reaction was aged at room temp. overnight. The solution was diluted with CH2Cl2 (100 ml) and washed with water (100 ml), 1N sodium hydroxide in water (100 ml) and brine (100 ml). The organics were dried over sodium sulfate, filtered, and concentrated with a second extract, to give crude product. This was purified on silica (1% to 20% MeOH/CH2Cl2 gradient) to give spirolactam (3S)-di-tert-butyl 8-oxo-2,7-diazaspiro[4.4]nonane-2,3-dicarboxylate (E6) (295 mg, 868 μmol). 1H NMR (CDCl3) δ1.35 (m, 18H), 1.91 (m, 2H), 2.3 (m, 3H), 3.2 (m, 2H), 3.3-3.5 (m, 2H), 4.10 (m, 1H), 6.21 (m, 1H); LCMS for C17H28N2O5 340.20 [M], found ES+ 341.2 [M+H]+, 285.2 [M+H, minus t-butyl]+, 285.2 [M+H, minus t-butyl, minus BOC]+ at 2.6 minutes retention time, using 10-90% acetonitrile/water (with 0.1% formic acid buffer) gradient over 5 minutes.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([N:15]1[CH2:20][CH2:19][O:18][CH:17]([C:21]([NH:23][C:24]2[CH:25]=[C:26]3[C:30](=[CH:31][CH:32]=2)[N:29](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[N:28]=[C:27]3[C:52]2[CH:57]=[CH:56][N:55]=[CH:54][CH:53]=2)=[O:22])[CH2:16]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C([SiH](CC)CC)C>>[CH2:8]([N:15]1[CH2:20][CH2:19][O:18][CH:17]([C:21]([NH:23][C:24]2[CH:25]=[C:26]3[C:30](=[CH:31][CH:32]=2)[NH:29][N:28]=[C:27]3[C:52]2[CH:53]=[CH:54][N:55]=[CH:56][CH:57]=2)=[O:22])[CH2:16]1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: O=C(Nc1ccc2c(c1)c(-c1ccncc1)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1)C1CN(Cc2ccccc2)CCO1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1ccc2[nH]nc(-c3ccncc3)c2c1)C1CN(Cc2ccccc2)CCO1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Trifluoroacetic acid (1 mL) was added to 4-benzyl-N-(3-(pyridin-4-yl)-1-trityl-1H-indazol-5-yl)morpholine-2-carboxamide (0.0217 g, 0.0332 mmol). The reaction was stirred at room temperature for 30 minutes. Triethylsilane (0.1 mL) was added to the reaction and stirred for an additional 5 minutes. The reaction was concentrated in vacuo and purified using prep LC/MS. LC-MS: 414.26 [M+H]. LC/MS RT=1.99 min.
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([NH2:8])=[CH:4][CH:3]=1.[F:9][C:10]1[CH:11]=[N:12][CH:13]=[C:14]([F:29])[C:15]=1[Sn](CCCC)(CCCC)CCCC>>[F:9][C:10]1[CH:11]=[N:12][CH:13]=[C:14]([F:29])[C:15]=1[C:2]1[CH:3]=[CH:4][C:5]([NH2:8])=[CH:6][N:7]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1c(F)cncc1F
Reactant: Nc1ccc(Br)nc1
Product: Nc1ccc(-c2c(F)cncc2F)nc1
Yield: 50 %

Procedure:
Obtained (50% yield) following the procedure described in example 34 (step A), starting with 6-bromopyridin-3-amine and 3,5-difluoro-4-(tributylstannyl)pyridine.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:15]=[C:16]([NH:20][C:21](=[O:25])[CH:22]([CH3:24])[CH3:23])[CH:17]=[CH:18][CH:19]=2)[CH2:10][CH2:9]1.[CH:26]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:29]=[CH:28][C:27]=1[N:36]=[C:37]=[O:38]>C1COCC1>[CH3:24][CH:22]([CH3:23])[C:21]([NH:20][C:16]1[CH:17]=[CH:18][CH:19]=[C:14]([CH:11]2[CH2:12][CH2:13][N:8]([CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:37]([NH:36][C:27]3[CH:28]=[CH:29][C:30]4[C:35](=[CH:34][CH:33]=[CH:32][CH:31]=4)[CH:26]=3)=[O:38])[CH2:9][CH2:10]2)[CH:15]=1)=[O:25]
Reactant: O=C=Nc1ccc2ccccc2c1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCCCN)CC2)c1
Solvent: C1CCOC1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCCCCNC(=O)Nc3ccc4ccccc4c3)CC2)c1

Procedure:
Prepared by Procedure Q1 (THF) and Scheme AT using N-{3-[1-(6-aminohexyl)-4-piperidinyl]phenyl}-2-methylpropanamide and 2-naphthyl isocyanate: ESMS m/e: 515.3 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([N:8]2[C@@H:15]3[C@@H:10]([CH2:11][CH2:12][NH:13][CH2:14]3)[CH2:9]2)[CH:5]=[N:4][CH:3]=1.CC1C=C(C)N=C(N2[C@@H]3[C@@H](CCNC3)C2)N=1.[F:32][C:33]1[CH:41]=[CH:40][CH:39]=[C:38]([N:42]2[N:46]=[CH:45][CH:44]=[N:43]2)[C:34]=1[C:35](O)=[O:36].S1C=CC=C1C1C=CC=CC=1C(O)=O>C(Cl)Cl>[F:32][C:33]1[CH:41]=[CH:40][CH:39]=[C:38]([N:42]2[N:46]=[CH:45][CH:44]=[N:43]2)[C:34]=1[C:35]([N:13]1[CH2:12][CH2:11][C@@H:10]2[C@@H:15]([N:8]([C:6]3[CH:5]=[N:4][CH:3]=[C:2]([CH3:1])[N:7]=3)[CH2:9]2)[CH2:14]1)=[O:36]
Reactant: Cc1cncc(N2C[C@@H]3CCNC[C@@H]32)n1
Reactant: O=C(O)c1c(F)cccc1-n1nccn1
Agent: Cc1cc(C)nc(N2C[C@@H]3CCNC[C@@H]32)n1
Agent: O=C(O)c1ccccc1-c1cccs1
Solvent: ClCCl
Product: Cc1cncc(N2C[C@@H]3CCN(C(=O)c4c(F)cccc4-n4nccn4)C[C@@H]32)n1

Procedure:
The title compound was prepared in a manner analogous to Example 1, substituting (1R,6S)-8-(6-methylpyrazin-2-yl)-3,8-diazabicyclo[4.2.0]octane (Intermediate 30) for (1R,6S)8-(4,6-dimethyl-pyrimidin-2-yl)-3,8-diaza-bicyclo[4.2.0]octane and 2-fluoro-6-[1,2,3]triazol-2-yl-benzoic acid (Intermediate 15) for 2-thiophen-2-yl-benzoic acid. DCM was used in place of DMF. MS (ESI) mass calcd. For C20H21N7O, 375.44; m/z found 376.1 [M+H]+. 1H NMR (CD3OD): 8.08-7.75 (m, 3H), 7.68-7.37 (m, 4H), 7.33-6.82 (m, 1H), 4.70-3.78 (m, 5H), 3.64-2.97 (m, 3H), 2.43-2.01 (m, 5H). MS (ESI) mass calcd. For C20H20FN7O, 393.43; m/z found 394.1 [M+H]+. 1H NMR (CD3OD): 7.99-7.75 (m, 3H), 7.68-6.92 (m, 4H), 4.71-3.35 (m, 7H), 3.16-2.98 (m, 1H), 2.54-1.85 (m, 5H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[S:8][C:9]([C:18]([O:20][CH3:21])=[O:19])=[C:10]([O:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:5]2=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[Cl:28][C:29]1[CH:36]=[C:35]([Cl:37])[CH:34]=[CH:33][C:30]=1[CH2:31][SH:32]>CS(C)=O>[Cl:28][C:29]1[CH:36]=[C:35]([Cl:37])[CH:34]=[CH:33][C:30]=1[CH2:31][S:32][C:2]1[N:7]=[C:6]2[S:8][C:9]([C:18]([O:20][CH3:21])=[O:19])=[C:10]([O:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:5]2=[CH:4][CH:3]=1
Reactant: SCc1ccc(Cl)cc1Cl
Reactant: CCOC(=O)COc1c(C(=O)OC)sc2nc(Cl)ccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCOC(=O)COc1c(C(=O)OC)sc2nc(SCc3ccc(Cl)cc3Cl)ccc12
Temperature: 80 °C
Reaction time: 3 h

Procedure:
To a mixture of methyl 6-chloro-3-(2-ethoxy-2-oxoethoxy)thieno[2,3-b]pyridine-2-carboxylate (126.4 mg) and DMSO (3.8 mL) were added K2CO3 (63.6 mg) and 2,4-dichlorobenzyl mercaptan (0.065 mL). The mixture was stirred at 80° C. for 3 h. The mixture was quenched with saturated aqueous NaHCO3 and extracted with EtOAc. The combined organic layer was washed successively with water and brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/hexane) to give the title compound (73.9 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]=[C:11]=[O:12])([O-:3])=[O:2].[N:13]1[CH:18]=[CH:17][C:16]([N:19]2[CH2:24][CH2:23][CH:22]([CH2:25][OH:26])[CH2:21][CH2:20]2)=[CH:15][CH:14]=1>ClCCl>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11]([O:26][CH2:25][CH:22]1[CH2:21][CH2:20][N:19]([C:16]2[CH:17]=[CH:18][N:13]=[CH:14][CH:15]=2)[CH2:24][CH2:23]1)=[O:12])([O-:3])=[O:2]
Reactant: OCC1CCN(c2ccncc2)CC1
Reactant: O=C=Nc1ccccc1[N+](=O)[O-]
Solvent: ClCCl
Product: O=C(Nc1ccccc1[N+](=O)[O-])OCC1CCN(c2ccncc2)CC1
Yield: 98.5 %

Procedure:
A solution of 2-nitrophenyl isocyanate (4.25 g, 25.9 mmol) and 1-(4-pyridyl)-4-piperidinemethanol (4.13 g, 21.5 mmol) in dichloromethane (100 mL) was stirred at room temperature overnight (about 18h). The mixture was concentrated and the residue purified by flash chromatography (SiO2; CHCl3 to 5% MeOH/1% Et3N in CHCl3) to yield 7.55 g (96%) of the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[OH:9].[CH3:10][C:11](O)([CH:13]=[CH2:14])[CH3:12]>P(=O)(O)(O)O>[CH3:1][C:2]1[CH:7]=[C:6]([CH2:14][CH:13]=[C:11]([CH3:12])[CH3:10])[CH:5]=[C:4]([CH3:8])[C:3]=1[OH:9]
Reactant: C=CC(C)(C)O
Reactant: Cc1cccc(C)c1O
Agent: O=P(O)(O)O
Product: CC(C)=CCc1cc(C)c(O)c(C)c1
Reaction time: 1 h
Yield: 48.3 %

Procedure:
To a mixture of 2,6-dimethylphenol (122 g, 1 mol) and 85% phosphoric acid (60 mL) was added 2-methyl-3-buten-2-ol (103 g, 1.2 mol) with efficient stirring at 35°-43° C. during 1 h. After stirring for an additional 3.5 h at 25° C., the mixture was quenched into ice and extracted with hexane. The combined hexane extracts were washed successively with 1 N sodium hydroxide (100 mL), 5% sodium bicarbonate (300 mL) and brine (200 mL). The organic layer was dried, the solvent evaporated, and the residue fractionated to yield 92 g of 2,6-dimethyl-4-(3-methyl-2-butenyl)phenol bp 108°-111° C. (1 mm). NMR (CDCl3) δ1.7 (6H, s), 2.2 (6H, s), 3.2 (2H, bd), 4.4 (1H, s, exchanged with D2O), 5.3 (1H, m), 6.8 (2H, s). IR (film) 3500, 1225, 1150, 870 cm-1. MS (m/e) 190 (M+), 175, 160, 135, 91.
Reaction SMILES: [C:1]1([C:7]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[N:8]2[CH:12]=[C:11]([CH2:13][CH2:14][CH2:15][N:16]3[C:20](=[O:21])[C:19]([CH3:32])([C:22]4[C:31]5[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=5)[CH:25]=[CH:24][CH:23]=4)[NH:18][C:17]3=[O:33])[N:10]=[CH:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:47][C:48]([O:50][CH2:51][CH3:52])=[O:49].[H-].[Na+]>CN(C)C=O>[CH2:51]([O:50][C:48](=[O:49])[CH2:47][N:18]1[C:19]([CH3:32])([C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=[CH:24][CH:23]=2)[C:20](=[O:21])[N:16]([CH2:15][CH2:14][CH2:13][C:11]2[N:10]=[CH:9][N:8]([C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)([C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)[C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[CH:12]=2)[C:17]1=[O:33])[CH3:52]
Reactant: CCOC(=O)CBr
Reactant: CC1(c2cccc3ccccc23)NC(=O)N(CCCc2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)C1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CN1C(=O)N(CCCc2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)C(=O)C1(C)c1cccc2ccccc12
Reaction time: 1 h
Yield: 97.1 %

Procedure:
0.082 g(0.14 mmol) of 3-[3-(1-triphenylmethyl-imidazol-4-yl)-propyl]-5-methyl-5-naphthalen-1-yl-imidazolidin-2,4-dione prepared in Example 1-1) and 0.023 ml(0.21 mmol) of ethyl bromoacetate were dissolved in 5 ml of dimethylformamide. 0.017 g(0.21 mmol) of sodium hydride [NaH] was added thereto and the resulting solution was stirred for one hour. Dimethylformamide was removed under reduced pressure and the residue was dissolved in ethyl acetate and then washed with saturated sodium chloride solution. Removal of ethyl acetate under reduced pressure provided 0.092 g(Yield: 99%) of title compound.
Reaction SMILES: [NH2:1][C@H:2]([CH2:6][C:7]1[CH:16]=[CH:15][C:14]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=2[CH:8]=1)[C:3]([OH:5])=[O:4].Cl.[CH3:18][CH2:19]O>>[NH2:1][C@H:2]([CH2:6][C:7]1[CH:16]=[CH:15][C:14]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=2[CH:8]=1)[C:3]([O:5][CH2:18][CH3:19])=[O:4]
Reactant: N[C@H](Cc1ccc2c(c1)CCCC2)C(=O)O
Reactant: CCO
Agent: Cl
Product: CCOC(=O)[C@H](N)Cc1ccc2c(c1)CCCC2

Procedure:
A mixture of 3.7 g (14.5 mmol) (R)-2-amino-3-(5,6,7,8-tetrahydro-naphthalen-2-yl)-propionic acid and 150 mL EtOH was combined with 50 mL ethanolic HCl with stirring. The reaction mixture was stirred for 2 h, evaporated down under reduced pressure and the residue was taken up in DCM. The organic solution washed with 15% K2CO3 solution, dried and evaporated down under reduced pressure.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][CH:6]=1)=O.[CH:13]([NH2:15])=[O:14]>O>[O:14]1[CH:2]=[C:3]([C:5]2[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][CH:6]=2)[N:15]=[CH:13]1
Reactant: NC=O
Reactant: N#Cc1ccc(C(=O)CBr)cc1
Solvent: O
Product: N#Cc1ccc(-c2cocn2)cc1
Temperature: 110 °C
Yield: 17 %

Procedure:
4-(2-Bromo-acetyl)-benzonitrile (1.2 g, 5.4 mmol) was dissolved in formamide (10 mL) and heated to 110° C. for 72 h. The mixture was cooled, diluted with water and extracted five times with methylene chloride. The organics were combined, washed with water, brine, dried over anhydrous MgSO4, filtered and concentrated. Flash chromatography (5%-10% acetone in hexane) afforded 4-(1,3-oxazol-4-yl)benzonitrile (0.16 g, 17%) as a white solid. Analytical HPLC: purity 100% at 270 nm, 6.8 min; 100% at 210-370 nm, 6.8 min; the Xterra® RP18 column, 3.5μ, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. pH=3.5/ACN+MeOH) for 10 min, hold 4 min.
Reaction SMILES: C[C:2]1[C:3](C)=[C:4]([C:11]#[C:12]CO)[CH:5]=[CH:6][C:7]=1[C:8](=[O:10])[CH3:9].[OH-].[Na+]>C1(C)C=CC=CC=1>[C:8]([C:7]1[CH:6]=[CH:5][C:4]([C:11]#[CH:12])=[CH:3][CH:2]=1)(=[O:10])[CH3:9]
Reactant: CC(=O)c1ccc(C#CCO)c(C)c1C
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: C#Cc1ccc(C(C)=O)cc1
Temperature: 120 °C
Yield: 56 %

Procedure:
1.45 g (7.17 mmol) of dimethylhydroxymethyl-4-acetylphenylacetylene and 301 mg (7.53 mmol) of NaOH (KISHIDA CHEMICAL CO., Ltd., 0.7 mm granular, 98%) were placed in a 100 mL two-neck flask equipped with a reflux condenser and the air inside the flask was replaced with Ar. 36 mL of toluene was added thereto and the mixture was refluxed at 120° C. for 15 minutes. Toluene was added to the reaction mixture and the mixture was washed with a saturated aqueous ammonium chloride solution and dried over magnesium sulfate, followed by distilling off of the solvent under reduced pressure by an evaporator. Then, 25 mL of hexane was added to the resulting crude reaction product and the mixture was cooled to give 4-acetylphenylethyne as a yellow solid. (0.74 g, yield: 56%).
Reaction SMILES: Br[CH2:2][CH:3]1[CH2:7][CH2:6][CH:5]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)[O:4]1.[CH3:15][CH:16]1[CH2:21][CH:20]([CH3:22])[CH2:19][NH:18][CH2:17]1>C(OCC)(=O)C>[Cl:14][C:11]1[CH:12]=[CH:13][C:8]([CH:5]2[CH2:6][CH2:7][CH:3]([CH2:2][N:18]3[CH2:19][CH:20]([CH3:22])[CH2:21][CH:16]([CH3:15])[CH2:17]3)[O:4]2)=[CH:9][CH:10]=1
Reactant: CC1CNCC(C)C1
Reactant: Clc1ccc(C2CCC(CBr)O2)cc1
Solvent: CCOC(C)=O
Product: CC1CC(C)CN(CC2CCC(c3ccc(Cl)cc3)O2)C1
Yield: 20 %

Procedure:
20 g (0.073 mole) of 2-bromomethyl-5-(4-chlorophenyl)-tetrahydrofuran and 25 g (0.22 mole) of 3,5-dimethylpiperidine are heated at 120° C. for 16 hours. The cooled reaction mixture is taken up in ethyl acetate and the mixture is washed twice with water, dried over sodium sulphate and concentrated in vacuo. The oily residue is purified by column chromatography (silica gel 60/ligroin-ethyl acetate 2:1/ethyl acetate). 4.5 g (20% of theory) of 2-(4-chlorophenyl)-5-(3,5-dimethylpiperidin-1-ylmethyl)-tetrahydrofuran are obtained as an oil; nD20 =1.5159.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2([C:11]#[N:12])[CH2:10][CH2:9]2)=[CH:6][C:5](F)=[CH:4][N:3]=1.ClC1C(CC#N)=CC=CN=1.ClC1C(CC#N)=CC(F)=CN=1>>[Cl:1][C:2]1[C:7]([C:8]2([C:11]#[N:12])[CH2:9][CH2:10]2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: N#CC1(c2cc(F)cnc2Cl)CC1
Agent: N#CCc1cc(F)cnc1Cl
Agent: N#CCc1cccnc1Cl
Product: N#CC1(c2cccnc2Cl)CC1

Procedure:
1-(2-Chloropyridin-3-yl)cyclopropanecarbonitrile was synthesized analogous to 1-(2-chloro-5-fluoropyridin-3-yl)cyclopropanecarbonitrile (Intermediate 15) using (2-chloropyridin-3-yl)acetonitrile as a reactant in place of 2-(2-chloro-5-fluoropyridin-3-yl)acetonitrile.