Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[N:6][C:5]([N:9]2[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][CH2:10]2)=[C:4]([NH:16][NH2:17])[N:3]=1.CC(O)=O.[N:22]([O-])=O.[Na+]>O.C([O-])(O)=O.[Na+]>[Br:1][C:2]1[N:3]2[N:22]=[N:17][N:16]=[C:4]2[C:5]([N:9]2[CH2:10][CH2:11][N:12]([CH3:15])[CH2:13][CH2:14]2)=[N:6][C:7]=1[CH3:8]
Reactant: O=N[O-]
Reactant: Cc1nc(N2CCN(C)CC2)c(NN)nc1Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Cc1nc(N2CCN(C)CC2)c2nnnn2c1Br
Temperature: 10 °C
Reaction time: 1 h
Yield: 76.9 %

Procedure:
A 25 mL round bottom flask was charged with 2-bromo-6-hydrazinyl-3-methyl-5-(4-methylpiperazin-1-yl)pyrazine (0.92 g, 3.0 mmol) and CH3COOH (2 mL). To the above was added dropwise a solution of NaNO2 (0.32 g, 4.6 mmol) in water (2 mL) at 10° C. The resulting mixture was stirred at 10° C. for 1 h. Work-up: the reaction mixture was diluted with saturated aqueous NaHCO3 (100 mL) and then extracted with CH2Cl2 (100 mL×3). The combined organic layers were dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel with 4% MeOH in CH2Cl2, to afford 0.72 g (75%) of the product as a white solid. MS m/z: 312 (M+H+).
Reaction SMILES: [NH2:1][CH:2]([CH2:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3](O)=[O:4].[H-].[H-].[H-].[H-].[Li+].[Al+3]>>[NH2:1][CH:2]([CH2:6][CH2:7][CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[CH2:3][OH:4]
Reactant: NC(CCCc1ccccc1)C(=O)O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: NC(CO)CCCc1ccccc1

Procedure:
The compound from step 40a was reduced with LiAlH4 under standard conditions to give the title compound.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:20])=[C:11]([N:15]4[CH2:19][CH2:18][O:17][CH2:16]4)[C:12]=3[F:14])[C:7](=[O:21])[C:6]([C:22]([O:24]CC)=[O:23])=[CH:5]2)[CH2:3][CH2:2]1.C(O)C.C(=O)([O-])[O-].[Na+].[Na+]>C(O)(=O)C>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:20])=[C:11]([N:15]4[CH2:19][CH2:18][O:17][CH2:16]4)[C:12]=3[F:14])[C:7](=[O:21])[C:6]([C:22]([OH:24])=[O:23])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: CCOC(=O)c1cn(C2CC2)c2c(F)c(N3CCOC3)c(F)cc2c1=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: O=C(O)c1cn(C2CC2)c2c(F)c(N3CCOC3)c(F)cc2c1=O
Reaction time: 1 h
Yield: 66.7 %

Procedure:
A mixture of 182 mg of ethyl 1-cyclopropyl-6,8-difluoro-7-(3-oxazolidinyl)-1,4-dihydro-4-oxoquinoline-3-carboxylate, 5 ml of ethanol and 10 ml of 10% aq. sodium carbonate solution was stirred for 1 hour under reflux. The reaction mixture was allowed to cool down and then acidified with acetic acid. Crystals thus precipitated were collected by filtration. They were washed with water and ethanol and then dried, whereby 112 mg of the title compound was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:35]=[CH:34][C:5]([C:6]([N:8]2[CH2:13][CH2:12][N:11]([CH:14]3[CH2:18][N:17]([C:19]4[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=4[NH:26][C:27]([NH2:29])=[O:28])[CH2:16][CH:15]3[O:30]C(=O)C)[CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+]>CO>[Cl:25][C:22]1[CH:23]=[CH:24][C:19]([N:17]2[CH2:16][CH:15]([OH:30])[CH:14]([N:11]3[CH2:12][CH2:13][N:8]([C:6](=[O:7])[C:5]4[CH:34]=[CH:35][C:2]([Cl:1])=[CH:3][CH:4]=4)[CH2:9][CH2:10]3)[CH2:18]2)=[C:20]([NH:26][C:27]([NH2:29])=[O:28])[CH:21]=1
Reactant: CC(=O)OC1CN(c2ccc(Cl)cc2NC(N)=O)CC1N1CCN(C(=O)c2ccc(Cl)cc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: NC(=O)Nc1cc(Cl)ccc1N1CC(O)C(N2CCN(C(=O)c3ccc(Cl)cc3)CC2)C1
Reaction time: 2 h
Yield: 38 %

Procedure:
To a solution of acetic acid 4-[4-(4-chloro-benzoyl)-piperazin-1-yl]-1-(4-chloro-2-ureido-phenyl)-pyrrolidin-3-yl ester (60 mg, 0.11 mmol) in MeOH (2 mL), was added K2CO3 (30 mg). The mixture was stirred for 2 h. After concentrating, the residue was purified by column chromatography (ethyl acetate:MeOH:Et3N: 10:1:0.1)) to give the desired product (20 mg, 50% yield) as a yellow oil. MS (ESI), M/Z, 478(M+1). Retention time: 1.68 min (FA-polar).
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[F:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH2:22][C:23](Cl)=[O:24]>>[F:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH2:22][C:23]([CH:7]1[C:2](=[O:1])[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6]1)=[O:24]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: O=C(Cl)Cc1ccccc1F
Product: CC(C)(C)OC(=O)N1CCC(=O)C(C(=O)Cc2ccccc2F)C1
Yield: 52 %

Procedure:
tert-Butyl 3-(2-(2-fluorophenyl)acetyl)-4-oxopiperidine-1-carboxylate (295 mg, 52%) was synthesised from tert-butyl 4-oxopiperidine-1-carboxylate and 2-(2-fluorophenyl)acetyl chloride according to the general procedure for the preparation of diketones. MS (ES−) m/z 334.1(M−H)−
Reaction SMILES: [CH2:1]([N:8]1[C:12]2[C:13](=[O:30])[N:14]([CH3:29])[C:15]([C:25]([O:27][CH3:28])=[O:26])=[C:16](OS(C(F)(F)F)(=O)=O)[C:11]=2[CH:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:31][C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([N:8]1[C:12]2[C:13](=[O:30])[N:14]([CH3:29])[C:15]([C:25]([O:27][CH3:28])=[O:26])=[C:16]([C:35]3[CH:36]=[CH:37][C:32]([Cl:31])=[CH:33][CH:34]=3)[C:11]=2[CH:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: COC(=O)c1c(OS(=O)(=O)C(F)(F)F)c2ccn(Cc3ccccc3)c2c(=O)n1C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1c(-c2ccc(Cl)cc2)c2ccn(Cc3ccccc3)c2c(=O)n1C
Temperature: 90 °C
Reaction time: 8 h
Yield: 92.9 %

Procedure:
A mixture of methyl 1-benzyl-6-methyl-7-oxo-4-(((trifluoromethyl)sulfonyl)oxy)-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-5-carboxylate (7.5 g, 16.9 mmol), 4-chlorophenylboronic acid (3.89 g, 23.64 mmol) and Na2CO3 (7.52 g, 70.9 mmol) in 1,4-Dioxane (100 mL) and Water (20 mL) degassed with N2 for 15 minutes. The mixture was treated with palladium tetrakis (1.024 g, 0.887 mmol) and then stirred at 90° C. under N2 atmosphere overnight. The mixture was diluted with water and then extracted with Ethyl acetate. The combined extracts were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified on silica gel (0-40% ethyl acetate/hexanes) to afford methyl 1-benzyl-4-(4-chlorophenyl)-6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridine-5-carboxylate (6.4 g, 15.7 mmol, 93% yield) as a pale yellow solid. 1H NMR (400 MHz, CHLOROFORM-d) ppm 7.40 (s, 2H) 7.31-7.37 (m, 4H) 7.23-7.27 (m, 2H) 7.05 (d, J=2.93 Hz, 1H) 6.12 (d, J=2.93 Hz, 1H) 5.87 (s, 2H) 3.62 (s, 3H) 3.61 (s, 3H); LCMS (m/z) ES+=407 (M+1).
Reaction SMILES: Br[C:2]1[CH2:6][CH2:5][CH2:4][C:3]=1[C:7]1[CH:12]=[CH:11][C:10]([S:13][CH3:14])=[CH:9][CH:8]=1.[OH:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1>>[OH:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:2]2[CH2:6][CH2:5][CH2:4][C:3]=2[C:7]2[CH:12]=[CH:11][C:10]([S:13][CH3:14])=[CH:9][CH:8]=2)=[CH:19][CH:18]=1
Reactant: OCc1ccc(B(O)O)cc1
Reactant: CSc1ccc(C2=C(Br)CCC2)cc1
Product: CSc1ccc(C2=C(c3ccc(CO)cc3)CCC2)cc1
Yield: 92.5 %

Procedure:
Following the synthetic procedure outlined in Step 3 of Example 1, 250 mg (0.93 mmol) of 1-(2-bromocyclopenten-1-yl)-4-(methylthio) benzene (Example 1, Step 2) was reacted with 290 mg (1.9 mmol) of 4-hydroxymethylphenylboronic acid (Step 1). Purification by silica gel chromatography (MPLC) with ethyl acetate/hexane (1:4) gave 255 mg (92%) of 1-[2-(4-hydroxymethylphenyl)cyclopenten-1-yl]-4-(methylthio)benzene as a solid: mp 82°-85° C.; NMR (CDCl3) δ2.04 (m, J=7 Hz, 2H), 2.45 (s, 3H), 2.88 (t, J=7 Hz, 4H), 4.64 (s, 2H), 7.08 (s, 4H), (m, 2H), 7.15-7.25 (m, 4H).
Reaction SMILES: C([O:3][C:4](=[O:37])[CH2:5][C@@H:6]([C:29]1[CH:30]=[N:31][C:32]([O:35][CH3:36])=[CH:33][CH:34]=1)[CH2:7][CH2:8][CH2:9][N:10]1[C@H:14]([CH3:15])[CH2:13][C@H:12]([NH:16][CH2:17][C:18]2[CH:27]=[CH:26][C:25]3[CH2:24][CH2:23][CH2:22][NH:21][C:20]=3[N:19]=2)[C:11]1=[O:28])C.O.[OH-].[Li+]>O1CCCC1.O>[CH3:36][O:35][C:32]1[N:31]=[CH:30][C:29]([C@@H:6]([CH2:7][CH2:8][CH2:9][N:10]2[C@H:14]([CH3:15])[CH2:13][C@H:12]([NH:16][CH2:17][C:18]3[CH:27]=[CH:26][C:25]4[CH2:24][CH2:23][CH2:22][NH:21][C:20]=4[N:19]=3)[C:11]2=[O:28])[CH2:5][C:4]([OH:37])=[O:3])=[CH:34][CH:33]=1
Reactant: CCOC(=O)C[C@H](CCCN1C(=O)[C@@H](NCc2ccc3c(n2)NCCC3)C[C@H]1C)c1ccc(OC)nc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc([C@@H](CCCN2C(=O)[C@@H](NCc3ccc4c(n3)NCCC4)C[C@H]2C)CC(=O)O)cn1
Reaction time: 16 h

Procedure:
To a stirred solution of 4-9 (150 mg) in tetrahydrofuran (6 mL) was added lithium hydroxide monohydrate (60 mg) in water (6 mL) and the mixture was stirred for 16 h. The reaction mixture was then concentrated at reduced pressure and the resulting oil was purified by flash column chromatography (silica gel, 30:3:3 to 50:5:5% ethanol/ammonium hydroxide/water in ethyl acetate) to give 4-10 as a white solid.
Reaction SMILES: [CH2:1]([C@@:4]1([CH3:30])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@@H:24]([CH2:27][CH3:28])[CH2:25][OH:26])[C:5]1=[O:29])[CH:2]=[CH2:3].O>C(Cl)Cl>[CH2:1]([C@@:4]1([CH3:30])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=2)[N:6]([C@@H:24]([CH2:27][CH3:28])[CH:25]=[O:26])[C:5]1=[O:29])[CH:2]=[CH2:3]
Reactant: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)CO)C1=O
Solvent: ClCCl
Solvent: O
Product: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@H](C=O)CC)C1=O

Procedure:
To a solution of 218 mg (0.49 mmol) of (3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-hydroxybutan-2-yl)-3-methylpiperidin-2-one (Example 91, Step B) in a mixture of water (13.20 μL, 0.733 mmol) and DCM (4883 μL) was added 1,1,1,-tris(acetoxy)-1,1-dihydro-1,2-benziodoxol-3-(1H)one (“Dess Martin periodinane”) (311 mg, 0.733 mmol) at ambient temperature. The reaction was monitored by LCMS, and several small portions of additional periodinane were added until the reaction was complete. The reaction was quenched (2 mL, 1 M Na2S2O3), extracted (2×DCM), and the combined organic layers were washed with sat. NaHCO3 solution (2×), sat NaCl solution, dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure. Purification of the residue by flash chromatography on silica gel (eluent: 20 to 35% EtOAc/hexanes, gradient elution) provided the title compound.
Reaction SMILES: [N+](C1C=CC([O:10][C:11](=O)/[CH:12]=[CH:13]/[CH:14]=[C:15]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)=CC=1)([O-])=O.[CH3:33][C:34]([CH3:45])([NH2:44])[CH2:35][CH2:36][CH2:37][C:38]1[CH:39]=[N:40][CH:41]=[CH:42][CH:43]=1>O1CCCC1>[CH3:31][O:30][C:27]1[CH:26]=[CH:25][C:24]([C:15]([C:16]2[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=2)=[CH:14]/[CH:13]=[CH:12]/[C:11]([NH:44][C:34]([CH3:45])([CH3:33])[CH2:35][CH2:36][CH2:37][C:38]2[CH:39]=[N:40][CH:41]=[CH:42][CH:43]=2)=[O:10])=[CH:29][CH:28]=1
Reactant: CC(C)(N)CCCc1cccnc1
Reactant: COc1ccc(C(=C/C=C/C(=O)Oc2ccc([N+](=O)[O-])cc2)c2ccc(OC)cc2)cc1
Solvent: C1CCOC1
Product: COc1ccc(C(=C/C=C/C(=O)NC(C)(C)CCCc2cccnc2)c2ccc(OC)cc2)cc1

Procedure:
As in Example 134, a solution of (E)-5,5-bis(4-methoxyphenyl)-2,4-pentadienoic acid 4-nitrophenyl ester (1.73 g) and alpha,alpha-dimethyl-3-pyridinebutanamine (0.9 mL) in tetrahydrofuran (20 mL) was stirred for 20 hours at room temperature and then at reflux for an additional 24 hours to complete the reaction. After the usual work up, the crude amide was crystallized from ethyl acetate-hexane (2x) to furnish 1.55 g of (E)-5,5-bis(4-methoxyphenyl)-N-[1,1-dimethyl-4-(3-pyridinyl)butyl]-2,4-pentadienamide mp 144°-145° C. Anal. Calculated for C30H34N2O3 : C, 76.57; H, 7.28; N, 5.95 Found: C, 76.70; H, 7.48; N, 6.20.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@@H:18]3[CH2:22][CH2:21][N:20]([C:23](OC(C)(C)C)=[O:24])[CH2:19]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=3)[C:3]=12.[F:30][C:31]([F:42])([F:41])[C:32]1[CH:33]=[C:34]([N:38]=[C:39]=[O:40])[CH:35]=[CH:36][CH:37]=1.C(O)=O.Cl>C(Cl)Cl>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@@H:18]3[CH2:22][CH2:21][N:20]([C:23]([NH:38][C:34]4[CH:35]=[CH:36][CH:37]=[C:32]([C:31]([F:30])([F:41])[F:42])[CH:33]=4)=[O:24])[CH2:19]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:39]([NH:38][C:34]4[CH:35]=[CH:36][CH:37]=[C:32]([C:31]([F:41])([F:42])[F:30])[CH:33]=4)=[O:40])=[CH:13][CH:12]=3)[C:3]=12
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](n2nc(-c3ccc(N)cc3)c3c(N)ncnc32)C1
Agent: Cl
Solvent: O=CO
Solvent: ClCCl
Product: Nc1ncnc2c1c(-c1ccc(NC(=O)Nc3cccc(C(F)(F)F)c3)cc1)nn2[C@@H]1CCN(C(=O)Nc2cccc(C(F)(F)F)c2)C1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A solution of (R)-tert-butyl 3-(4-amino-3-(4-aminophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidine-1-carboxylate (0.090 g, 0.23 mmol) in CH2Cl2 (10 mL) was cooled in an ice-water bath. To this, 3-(trifluoromethyl)phenyl isocyanate (0.032 mL, 0.23 mmol) diluted in CH2Cl2 (5 mL) was added dropwise. The reaction was allowed to warm to room temperature and left stirring for 6 hours. After, formic acid (5 mL) and concentrated HCl (0.5 mL) were added dropwise directly to the reaction mixture. Three major species were observed by LC-MS corresponding to AD73a, AD73b, and AD73c. The reaction mixture was left stirring for 12 hours and then was concentrated in vacuo, resuspended in 50:50 H2O—CH3CN, and purified on a C18 column in CH3CN/H2O/0.1% TFA (1-100% gradient) to afford AD73a (ESI-MS m/z [M+H]+ found 483.5, calculated 483.2), AD73b (ESI-MS m/z [M+H]+ found 483.5, calculated 483.2), and AD73c (ESI-MS m/z [M+H]+ found 670.5, calculated 670.2).
Reaction SMILES: O=C(Cl)[O:3][C:4](Cl)(Cl)Cl.[CH3:9][C:10]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:14][C:11]=1[CH2:12][NH2:13]>C1(C)C=CC=CC=1>[CH3:9][C:10]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:14][C:11]=1[CH2:12][N:13]=[C:4]=[O:3]
Reactant: Cc1ccc(-c2ccccc2)cc1CN
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: Cc1ccc(-c2ccccc2)cc1CN=C=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.8 %

Procedure:
2.5 g (12.6 mmol) of diphosgene, 0.40 g of activated carbon and 30 ml of toluene were mixed, and allowed to left overnight, and to this solution was slowly dropped at room temperature a solution prepared by dissolving 1.00 g (5.07 mmol) of 2-methyl-5-phenylbenzylamine (produced in the same manner as in Intermediate Production Example 6) in 5 ml of toluene. The reaction mixture turned to white suspension directly after the dropping. The white suspension was stirred at room temperature for 1 hour, further stirred for 5 hours under reflux with heating, then, concentrated under reduced pressure to obtain 1.13 g of 2-methyl-5-phenybenzyl isocyanate.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[O:10][C:9]([CH3:13])([CH3:12])[CH2:8][C:7]=2[CH:6]=[C:5]([C:14]([OH:16])=O)[CH:4]=1.CCN=C=NCCCN(C)C.CN1CCOCC1.C1C=CC2N(O)N=NC=2C=1.[CH3:45][N:46]1[CH:50]=[CH:49][C:48]([NH2:51])=[N:47]1>C(Cl)Cl>[CH3:1][O:2][C:3]1[C:11]2[O:10][C:9]([CH3:12])([CH3:13])[CH2:8][C:7]=2[CH:6]=[C:5]([C:14]([NH:51][C:48]2[CH:49]=[CH:50][N:46]([CH3:45])[N:47]=2)=[O:16])[CH:4]=1
Reactant: Cn1ccc(N)n1
Reactant: COc1cc(C(=O)O)cc2c1OC(C)(C)C2
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: COc1cc(C(=O)Nc2ccn(C)n2)cc2c1OC(C)(C)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 29 %

Procedure:
To a solution of 7-methoxy-2,2-dimethyl-2,3-dihydrobenzofuran-5-carboxylic acid (24 g, 0.11 mol) in CH2Cl2(500 mL) were added EDCI (31.6 g, 1.08 mol), NMM (54.5 g, 0.54 mol), HOBt (22 g, 0.16 mol) and 1-methyl-1H-pyrazol-3-ylamine (11 g, 0.11 mol) sequentially. The mixture was stirred at room temperature overnight. TLC (EtOAc/petroleum ether=1/1) showed the reaction was complete. The mixture was washed with water (250 mL), sat. aq. citric acid (250 mL×2), sat. NaHCO3 (250 mL) and brine (250 mL) sequentially. The organic phase was dried over Na2SO4 and concentrated to give a white solid. The crude solid was purified by column chromatography (EtOAc/petroleum ether=1/10˜1/1) to give the title compound (9.6 g, 30%) as a white solid. 1H NMR (400 MHz, DMSO): δ 10.49 (s, 1H), 7.49 (s, 1H), 7.44 (s, 2H), 6.48 (s, 1H), 3.74 (s, 3H), 3.69 (s, 3H), 2.96 (s, 2H), 1.35 (s, 6H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:24][CH2:23][C:10]2([CH2:13][CH:12]([N:14]3[CH2:19][CH2:18][CH:17]([C:20](O)=[O:21])[CH2:16][CH2:15]3)[CH2:11]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:25]([NH2:29])([CH3:28])([CH3:27])[CH3:26].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:24][CH2:23][C:10]2([CH2:13][CH:12]([N:14]3[CH2:15][CH2:16][CH:17]([C:20](=[O:21])[NH:29][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:18][CH2:19]3)[CH2:11]2)[CH2:9]1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)(C)N
Reactant: CC(C)(C)OC(=O)N1CCC2(CC(N3CCC(C(=O)O)CC3)C2)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)NC(=O)C1CCN(C2CC3(CCN(C(=O)OC(C)(C)C)C3)C2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.5 %

Procedure:
1-[6-(tert-Butoxycarbonyl)-6-azaspiro[3.4]oct-2-yl]piperidine-4-carboxylic acid was dissolved in DMF (2 mL) and t-butylamine (0.087 g, 1.20 mmol), HATU (0.227 g, 0.60 mmol) and DIPEA (0.193 g, 1.50 mmol) were added. The reaction mixture was stirred at rt overnight under nitrogen. The solvents were removed in vacuo, and the residue was partitioned between DCM and sat. NaHCO3 sol., organic layer washed with sat. NaCl sol. and dried over MgSO4. The solvents were removed in vacuo, and the residue was purified by column chromatography (normal phase, [Biotage SNAP cartridge KP-sil 10 g, 40-63 μm, 60 A, 12 mL per min, gradient 0% to 10% MeOH in DCM]) to give tert-butyl-2-[4-(tert-butylcarbamoyl)piperidin-1-yl]-6-azaspiro[3.4]octane-6-carboxylate (0.071 g, 60.5%) as a yellow oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[CH:11][C:12]([O:18][CH3:19])=[C:13]([O:16][CH3:17])[CH:14]=2)[C@H:9]([NH2:20])[CH2:8][C@@H:7]1[CH3:21])=[O:5])[CH3:2].[F:22][C:23]([F:39])([F:38])[C:24]1[CH:25]=[C:26]([CH2:34][C:35](O)=[O:36])[CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1.CN(C)CCCN=C=NCC>ClCCl.C(OCC)(=O)C>[CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[CH:11][C:12]([O:18][CH3:19])=[C:13]([O:16][CH3:17])[CH:14]=2)[C@H:9]([NH:20][C:35](=[O:36])[CH2:34][C:26]2[CH:27]=[C:28]([C:30]([F:31])([F:32])[F:33])[CH:29]=[C:24]([C:23]([F:38])([F:22])[F:39])[CH:25]=2)[CH2:8][C@@H:7]1[CH3:21])=[O:5])[CH3:2]
Reactant: CCOC(=O)N1c2cc(OC)c(OC)cc2[C@H](N)C[C@@H]1C
Reactant: O=C(O)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: CCN=C=NCCCN(C)C
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCOC(=O)N1c2cc(OC)c(OC)cc2[C@H](NC(=O)Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C[C@@H]1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of cis-4-amino-6,7-dimethoxy-2-methyl-3,4-dihydro-2H-quinoline-1-carboxylic acid ethyl ester (150 mg, 0.50 mmol) and 3,5-bis-trifluoromethylphenylacetic acid (138 mg, 0.51 mmol) in 1.5 ml anhydrous dichloromethane was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (192 mg, 0.66 mmol) and the resulting solution was stirred at room temperature overnight. The reaction mixture was diluted with 50 ml ethyl acetate and was washed with 0.1N HCl (2×10 mL), 0.1N NaOH (2×10 mL) and brine (1×10 mL). The organic phase was dried (MgSO4), filtered and concentrated, and the the residue was chromatographed using 20:1 hexanes:ethyl acetate. The title compound crystallized out of the combined fractions (129 mg, 46%). Me 157-9° C.; MS m/z 549 (M+ +1); 1H NMR (CDCl3) δ 1.07 (d, 3H), 7.70-7.78 (m, 3H).
Reaction SMILES: Cl[CH:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N+:10]([O-:12])=[O:11])[CH3:3].[CH3:13][CH:14]([S-:16])[CH3:15].[Na+]>C(#N)C>[CH:14]([S:16][CH:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N+:10]([O-:12])=[O:11])[CH3:3])([CH3:15])[CH3:13]
Reactant: CC(Cl)c1ccccc1[N+](=O)[O-]
Reactant: CC(C)[S-]
Agent: [Na+]
Solvent: CC#N
Product: CC(C)SC(C)c1ccccc1[N+](=O)[O-]
Temperature: 40 °C
Reaction time: 16 h
Yield: 63.2 %

Procedure:
In a 1 liter three-necked flask equipped with a stirrer, dropping funnel and thermometer, 63 g 1-(1-chlorethyl)-2-nitrobenzene (VIII-1) (purity 99.4%, 0.337 mols) in 20 ml acetonitrile are added dropwise at 30-40° C. to 34.8 g (0.354 mol) sodium 2-propanethiolate in 450 ml acetonitrile. The suspension is stirred at 40° C. for another 16 hours, then cooled, and the solvent is removed under vacuum. The residue remaining is dissolved in dichloromethane, washed, dried over sodium sulfate, and the solvent is removed under vacuum. The crude product is purified by column chromatography (silica gel, 29:1 hexane/acetone). 48 g (98.8% purity by HPLC, 62.4% theoretical yield) of 1-[1-(isopropylthio)ethyl]-2-nitrobenzene are obtained as a yellow oil [logP (pH 2.3)=3.89].
Reaction SMILES: [NH2:1][CH:2]([CH3:50])[CH:3]([N:5]1[C:9](=[O:10])[N:8]([C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:22][CH2:21][N:20]([C:23]4[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH:31]5[CH2:35][O:34][C:33]([C:42]6[CH:47]=[CH:46][C:45]([F:48])=[CH:44][C:43]=6[F:49])([CH2:36][N:37]6[CH:41]=[N:40][CH:39]=[N:38]6)[O:32]5)=[CH:25][CH:24]=4)[CH2:19][CH2:18]3)=[CH:13][CH:12]=2)[CH:7]=[N:6]1)[CH3:4].[C:51]1([C@H:57]2[CH2:59][O:58]2)[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1>CC(O)C>[F:49][C:43]1[CH:44]=[C:45]([F:48])[CH:46]=[CH:47][C:42]=1[C:33]1([CH2:36][N:37]2[CH:41]=[N:40][CH:39]=[N:38]2)[O:32][CH:31]([CH2:30][O:29][C:26]2[CH:25]=[CH:24][C:23]([N:20]3[CH2:19][CH2:18][N:17]([C:14]4[CH:13]=[CH:12][C:11]([N:8]5[CH:7]=[N:6][N:5]([CH:3]([CH3:4])[CH:2]([NH:1][CH2:59][CH:57]([OH:58])[C:51]6[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=6)[CH3:50])[C:9]5=[O:10])=[CH:16][CH:15]=4)[CH2:22][CH2:21]3)=[CH:28][CH:27]=2)[CH2:35][O:34]1
Reactant: CC(N)C(C)n1ncn(-c2ccc(N3CCN(c4ccc(OCC5COC(Cn6cncn6)(c6ccc(F)cc6F)O5)cc4)CC3)cc2)c1=O
Reactant: c1ccc([C@H]2CO2)cc1
Solvent: CC(C)O
Product: CC(NCC(O)c1ccccc1)C(C)n1ncn(-c2ccc(N3CCN(c4ccc(OCC5COC(Cn6cncn6)(c6ccc(F)cc6F)O5)cc4)CC3)cc2)c1=O

Procedure:
A mixture of compound (37) (0.0043 mol) and (S)-phenyl oxirane (0.005 mol) in 2-propanol (50 ml) was stirred and refluxed overnight. (S)-phenyl oxirane (0.005 mol) was added again. The mixture was stirred and refluxed for 3 hours. The solvent was evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3OH 99/1). The pure fractions were collected and the solvent was evaporated. The residue was triturated in DIPE, filtered off and dried, yielding 1.6 g (47%) of [2S-[2α,4α[(S*,R*)(R*)]]]4-[4-[4-[4-[[2-(2,4-difluorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-1-piperazinyl]phenyl]-2,4-dihydro-2-[2[(2-hydroxy-2-phenylethyl)amino]-1-methylpropyl]-3H-1,2,4-triazol-3-one (compound 81).