Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:25])[CH2:15][CH2:16][C:17]1[CH:22]=[C:21]([F:23])[CH:20]=[C:19]([F:24])[CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B(OS(C(F)(F)F)(=O)=O)(CCCC)CCCC.CCN(C(C)C)C(C)C.[C:52]([O:56][C:57]([N:59]1[C@@H:68]([C:69](O)=[O:70])[CH2:67][C:66]2[C:61](=[CH:62][CH:63]=[CH:64][CH:65]=2)[CH2:60]1)=[O:58])([CH3:55])([CH3:54])[CH3:53]>C(Cl)Cl.CO>[F:24][C:19]1[CH:18]=[C:17]([CH:22]=[C:21]([F:23])[CH:20]=1)[CH2:16][C@H:15]([C:14]([N:9]1[C@@H:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:12][O:11][C:10]1=[O:13])=[O:25])[C@@H:69]([C@H:68]1[CH2:67][C:66]2[C:61](=[CH:62][CH:63]=[CH:64][CH:65]=2)[CH2:60][N:59]1[C:57]([O:56][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:58])[OH:70]
Reactant: CC(C)(C)OC(=O)N1Cc2ccccc2C[C@@H]1C(=O)O
Reactant: O=C(CCc1cc(F)cc(F)c1)N1C(=O)OC[C@@H]1Cc1ccccc1
Agent: CCCCB(CCCC)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1Cc2ccccc2C[C@@H]1[C@@H](O)[C@H](Cc1cc(F)cc(F)c1)C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 77.8 %

Procedure:
To a solution of (S)-4-benzyl-3-(3-(3,5-difluorophenyl)propanoyl)oxazolidin-2-one (preparation D, 1.3 g, 3.77 mmol) in CH2Cl2 (50 mL) at −78° C. was added Bu2BOTf (4.90 ml, 4.90 mmol, 1M in CH2Cl2) and Hunig's base (972 mg, 7.54 mmol). The resulting mixture was brought up to 0° C. and stirred for 20 min. The mixture was cooled back to −78° C. and a solution of (R)-tert-butyl 3-formyl-3,4-dihydroisoquinoline-2(1H)-carboxylate (Step A (3), 1.10 g, 4.20 mmol) in CH2Cl2 (50 mL) was added dropwise. When the addition was complete, the mixture was allowed to warm to rt. After stirring at rt for 1 h, MeOH was added and the mixture was concentrated in vacuo. The crude mixture was purified by silica gel Flash chromatography to give 1.78 g (78% yield) of the title compound. MS (ESI)(M+H)+ 607.20.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]([OH:29])[CH:17]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C1C=CC=CN=1)C.[C:39]1([CH3:49])[CH:44]=[CH:43][C:42]([S:45](Cl)(=[O:47])=[O:46])=[CH:41][CH:40]=1>N1C=CC=CC=1>[CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]([O:29][S:45]([C:42]1[CH:43]=[CH:44][C:39]([CH3:49])=[CH:40][CH:41]=1)(=[O:47])=[O:46])[CH:17]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCOC(=O)C(c1ccccc1)C(O)CCCCNC(=O)OCc1ccccc1
Agent: CN(C)c1ccccn1
Solvent: c1ccncc1
Product: CCOC(=O)C(c1ccccc1)C(CCCCNC(=O)OCc1ccccc1)OS(=O)(=O)c1ccc(C)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 47.6 %

Procedure:
3.5 g (8.6 mmol) of ethyl 7-(N-benzyloxycarbonylamino)-3-hydroxy-2-phenylheptanoate obtained in Example 9 was dissolved in 28 ml of pyridine. 240 mg (1.96 mmol) of dimethylaminopyridine was added to the mixture. The mixture was cooled at 0° C. in an ice bath. 2.5 g (13 mmol) of p-toluenesulfonyl chloride was added for 5 minutes, which was stirred for one hour at a same temperature and further stirred at room temperature for 48 hours. After the consumption of the raw material was confirmed by means of HPLC, 100 ml of ethylacetate was added and 2N hydrochloric acid were further added to the reaction mixture to adjust the pH to 4 to extract. A saturated sodium bicarbonate solution was added to the organic layer prepared to neutralize. The neutralized organic layer was washed with saturated brine and then deied with magnesium sulfate anhydride. After the organic layer was concentrated under reduced pressure, the residue was purified by means of SGIC (eluent: hexane/ethylacetate=3/1) to obtain the target compound as a pale yellow oil in an amount 2.3 g at a yield of 47.6%. The analytical results on the target compound are given below.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:26]=[CH:25][CH:24]=[C:23]4[C:18]=3[CH:19]=[CH:20][N:21]=[C:22]4[N:27]3[CH2:32][CH2:31][CH:30]([C:33]([O:35]CC)=[O:34])[CH2:29][CH2:28]3)[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].O1CCCC1.CO.[OH-].[Li+:46]>O>[Li+:46].[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:26]=[CH:25][CH:24]=[C:23]4[C:18]=3[CH:19]=[CH:20][N:21]=[C:22]4[N:27]3[CH2:32][CH2:31][CH:30]([C:33]([O-:35])=[O:34])[CH2:29][CH2:28]3)[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10]
Reactant: CCOC(=O)C1CCN(c2nccc3c(-c4noc(-c5ccc(OC(C)C)c(Cl)c5)n4)cccc23)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c(N5CCC(C(=O)[O-])CC5)nccc34)no2)cc1Cl
Temperature: 80 °C
Reaction time: 3 h
Yield: 59.8 %

Procedure:
A mixture of ethyl 1-[5-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1-isoquinolinyl]-4-piperidinecarboxylate (D14; 35 mg, 0.067 mmol), tetrahydrofuran (THF) (2.0 ml), methanol (2.0 ml), water (1 ml) and lithium hydroxide (1.61 mg, 0.067 mmol) was left to stir at 80° C. for 3 h. The solvent was removed in vacuo and the residue was triturated with diethyl ether. The mixture was filtered to give the title compound as a pale peach coloured solid (20 mg).
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.C1OC1C.C(N(C(C)C)CC)(C)C.[Cl:25]Cl>C(Cl)Cl>[Cl:25][N:5]1[C:1](=[O:11])[C:2]2=[CH:10][CH:9]=[CH:8][CH:7]=[C:3]2[C:4]1=[O:6]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: ClCl
Agent: CC1CO1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C1c2ccccc2C(=O)N1Cl
Reaction time: 24 h

Procedure:
To 150 ml. of dry methylene chloride were added 7.35 g. (0.05 mole) of phthalimide followed by 17.5 ml. (5 equiv.) of propylene oxide and 0.065 g. (0.5 mmoles) of diisopropylethylamine. The mixture was cooled to 0° C. and saturated with chlorine. The mixture was stirred for about 24 hours to provide approximately 50% conversion to N-chlorophthalimide.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][OH:15])[CH2:10][CH2:9]1)=O)(C)(C)C.[Cl:16][C:17]1[C:22]([NH:23][C:24]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][C:32]=3F)[N:27]=[CH:26][N:25]=2)=[C:21]2[O:35][CH2:36][O:37][C:20]2=[CH:19][CH:18]=1>Cl.C(OCC)C>[ClH:16].[ClH:16].[Cl:16][C:17]1[C:22]([NH:23][C:24]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][C:32]=3[O:15][CH2:14][CH:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)[N:27]=[CH:26][N:25]=2)=[C:21]2[O:35][CH2:36][O:37][C:20]2=[CH:19][CH:18]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Reactant: Fc1cccc2ncnc(Nc3c(Cl)ccc4c3OCO4)c12
Agent: Cl
Solvent: CCOCC
Product: Clc1ccc2c(c1Nc1ncnc3cccc(OCC4CCNCC4)c13)OCO2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Using an analogous procedure to that described in Example 37, N-(tert-butoxycarbonyl)piperidin-4-ylmethanol was reacted with 4-(6-chloro-2,3-methylenedioxyanilino)-5-fluoroquinazoline (0.1 g). The product so obtained was dissolved in a 2M solution of hydrogen chloride in diethyl ether (20 ml) and stirred at ambient temperature for 3 hours. The mixture was evaporated and the residue was triturated under diethyl ether. The solid so obtained was washed with diethyl ether and dried under vacuum. There was thus obtained the title compound (0.121 g); NMR Spectrum: (DMSOd6) 1.5–1.6 (m, 2H), 1.9–2.0 (m, 2H), 2.3–2.4 (m, 1H), 2.8–2.9 (m, 2H), 3.3 (d, 2H), 4.42 (d, 2H), 6.15 (s, 2H), 7.07 (d, 1H), 7.15 (d, 1H), 7.53 (m, 2H), 8.06 (m, 1H), 8.87 (s, 1H), 10.57 (br s, 1H); Mass Spectrum: M+H+ 413 and 415.
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]([N:15]1[CH2:20][CH2:19][CH2:18][CH:17]([CH2:21][N:22]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:23](=[O:26])[CH2:24][CH3:25])[CH2:16]1)(OC(C)(C)C)=O.[N:33]1[CH:38]=[CH:37][CH:36]=[C:35](C=O)[CH:34]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[N:33]1[CH:38]=[CH:37][CH:36]=[C:35]([CH2:8][N:15]2[CH2:20][CH2:19][CH2:18][CH:17]([CH2:21][N:22]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:23](=[O:26])[CH2:24][CH3:25])[CH2:16]2)[CH:34]=1
Reactant: O=Cc1cccnc1
Reactant: CCC(=O)N(CC1CCCN(C(=O)OC(C)(C)C)C1)c1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCC(=O)N(CC1CCCN(Cc2cccnc2)C1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76 %

Procedure:
Trifluoroacetic acid (0.5 mL) was added dropwise to a solution of N-(1-Boc-piperidin-3-ylmethyl)-N-phenyl-propionamide 5 (21 mg, 0.061 mmol) in 0.5 mL of dry CH2Cl2 at 0° C. (ice-water). The reaction mixture was stirred at room temperature for 30 minutes. TLC showed the reaction was complete. After removal of the solvents, the residue was dried under vacuum for 3 hrs. The crude compound was dissolved in DMF (0.5 mL) and 3-pyridine carboxaldehyde (8.6 μL, 1.5 eq.) was added. The mixture was stirred at room temperature for 30 min. NaB(OAc)3H (95%, 20.3 mg, 1.5 eq.) was introduced in one portion, and the mixture was shaken at room temperature overnight. The mixture was quenched with 5 mL of aqueous potassium carbonate (sat.), then extracted with ethyl acetate (3×10 mL). The extracts were combined and washed with aqueous NaHCO3 (sat., 2×5 mL), brine (10 mL), and dried over anhydrous sodium sulfate. After the solvent was removed, the remaining oily residue was purified by preparative thin layer chromatography (EtOAc/MeOH, 9:1) to afford N-[1-(Pyridin-3-ylmethyl)-piperidin-3-ylmethyl]-N-phenyl-propionamide 12 as a colorless oil (15.6 mg, 76%). LRMS 338.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9](Cl)=[O:10])[CH:4]=1.[NH3:12]>>[Cl:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9]([NH2:12])=[O:10])[CH:4]=1
Reactant: O=C(Cl)c1cc(Cl)ccn1
Reactant: N
Agent: Cl
Product: NC(=O)c1cc(Cl)ccn1

Procedure:
Entry 44: 4-Chloropyridine-2-carbonyl chloride HCl salt was reacted with ammonia according to Method A2, Step 3b to form 4-chloro-2-pyridinecarboxamide. 4-Chloro-2-pyridinecarboxamide was reacted with 3-aminophenol according to Method A1, Step 4 to form 3-(2-carbamoyl-4-pyridyloxy)aniline. According to Method C1a, 4-chloro-3-(trifluoromethylphenyl isocyanate was reacted with 3-(2-carbamoyl-4-pyridyloxy)aniline to afford the urea.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2([CH2:21][CH2:22][CH2:23][N:24]3[CH2:28][CH2:27][CH2:26][CH2:25]3)[CH2:13][CH2:12][N:11]([C:14](OC(C)(C)C)=[O:15])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.C(O)(C(F)(F)F)=O.[Cl:36][C:37]1[CH:42]=[CH:41][CH:40]=[C:39]([CH3:43])[C:38]=1[S:44]([N:47]([CH2:51][CH2:52][O:53][CH2:54]C(O)=O)[CH:48]1[CH2:50][CH2:49]1)(=[O:46])=[O:45].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>ClCCl>[Cl:36][C:37]1[CH:42]=[CH:41][CH:40]=[C:39]([CH3:43])[C:38]=1[S:44]([N:47]([CH:48]1[CH2:50][CH2:49]1)[CH2:51][CH2:52][O:53][CH2:54][C:14]([N:11]1[CH2:10][CH2:9][C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)([CH2:21][CH2:22][CH2:23][N:24]2[CH2:25][CH2:26][CH2:27][CH2:28]2)[CH2:13][CH2:12]1)=[O:15])(=[O:46])=[O:45]
Reactant: CC(C)(C)OC(=O)N1CCC(CCCN2CCCC2)(c2cccc(F)c2)CC1
Reactant: Cc1cccc(Cl)c1S(=O)(=O)N(CCOCC(=O)O)C1CC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: Cc1cccc(Cl)c1S(=O)(=O)N(CCOCC(=O)N1CCC(CCCN2CCCC2)(c2cccc(F)c2)CC1)C1CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 30 %

Procedure:
A solution of tert-butyl 4-(3-fluorophenyl)-4-(3-(pyrrolidin-1-yl)propyl)piperidine-1-carboxylate (0.2379 mmol, 1.0 eq.) in dichloromethane (3 ml) was Boc-deprotected using standard reaction conditions (see step (vi)/example 25; TFA (3-13 eq.)) and added dropwise to a solution containing 2-(2-(2-chloro-N-cyclopropyl-6-methylphenylsulfonamido)ethoxy)acetic acid [carboxylic acid 2] (1 eq.), EDCI (1.5 eq), HOBt (1.0 eq.) and DIPEA (6.0 eq.) in dichloromethane (5 ml) at 0° C. The mixture was then stirred at room temperature for 16 hrs. The reaction mixture was diluted with dichloromethane and extracted with aq. ammonium chloride, aq. sodium hydrogen carbonate and water respectively. The organic layer was dried over sodium sulfate, concentrated in vacuo and the crude product purified by column chromatography (silica). Yield: 30%
Reaction SMILES: O=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])O)O)O)O.S([O-])([O-])(=O)=[O:14].[NH4+:18].[NH4+:19]>>[NH2:18][C@H:9]([C:11]([OH:12])=[O:14])[CH2:7][CH2:5][CH2:3][CH2:2][NH2:19]
Reactant: [NH4+]
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: O=S(=O)([O-])[O-]
Product: NCCCC[C@H](N)C(=O)O
Temperature: 31.5 °C
Reaction time: 70 h

Procedure:
Brevibacterium flavum AJ 11275 (NRRL B-11474) was inoculated into a medium (pH 7.2) containing glucose 100 g/L, ammonium sulfate 8.0 g/L, Yeast Extract (Basco) 1.05 g/L, KH2PO4 1.0 g/L, MgSO4.7H2O 0.4 g/L, FeSO4.7H2O 10 mg/L, MnSO4.4H2O 10 mg/L, vitamin B, hydrochloride 0.2 mg/L, biotin 0.05 mg/L, and Surfactant GD-113 (Nippon Jushi) 0.05 mg/L, and culture with stirring at 31.5° C. for 70 hours to obtain L-lysine fermentation broth. The L-lysine content of the obtained broth was 3.46 wt %.
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][CH2:12][NH:11][CH:10]([CH2:15][CH3:16])[CH2:9]1)=O)(C)(C)C.[Cl:17][S:18]([C:21]1[CH:30]=[CH:29][CH:28]=[C:27]2[C:22]=1[C:23]([CH3:31])=[CH:24][N:25]=[CH:26]2)(=[O:20])=[O:19]>>[ClH:17].[CH2:15]([CH:10]1[CH2:9][NH:8][CH2:14][CH2:13][CH2:12][N:11]1[S:18]([C:21]1[CH:30]=[CH:29][CH:28]=[C:27]2[C:22]=1[C:23]([CH3:31])=[CH:24][N:25]=[CH:26]2)(=[O:19])=[O:20])[CH3:16]
Reactant: Cc1cncc2cccc(S(=O)(=O)Cl)c12
Reactant: CCC1CN(C(=O)OC(C)(C)C)CCCN1
Product: CCC1CNCCCN1S(=O)(=O)c1cccc2cncc(C)c12
Product: Cl
Yield: 34.5 %

Procedure:
Using 0.68 g of 1-(tert-butoxycarbonyl)-3-ethyl-hexahydro-1H-1,4-diazepine and 0.72 g of 5-chlorosulfonyl-4-methylisoquinoline, the procedure of Example 1 was otherwise repeated to provide 0.38 g of the objective compound (white crystals).
Reaction SMILES: [CH3:1][C:2]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[C:6](=[O:18])[C:5]([C:19]([OH:21])=O)=[CH:4][C:3]=1[C:22]1[N:23]([CH3:27])[N:24]=[CH:25][CH:26]=1.CN(C(O[N:36]1N=[N:43][C:38]2C=CC=C[C:37]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.Cl.NCC#N>O1CCOCC1>[C:37]([CH2:38][NH:43][C:19]([C:5]1[C:6](=[O:18])[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:15])[F:16])[CH:9]=2)[C:2]([CH3:1])=[C:3]([C:22]2[N:23]([CH3:27])[N:24]=[CH:25][CH:26]=2)[CH:4]=1)=[O:21])#[N:36]
Reactant: Cc1c(-c2ccnn2C)cc(C(=O)O)c(=O)n1-c1cccc(C(F)(F)F)c1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: N#CCN
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: Cc1c(-c2ccnn2C)cc(C(=O)NCC#N)c(=O)n1-c1cccc(C(F)(F)F)c1
Reaction time: 0.17 h
Yield: 72.2 %

Procedure:
The compound obtained in step (a) (0.2 g, 0.53 mmol) was dissolved in 1,4-dioxane (5 ml), HBTU (0.19 g, 0.5 mmol) and DIEA (0.32 g, 2.5 mmol). The mixture was stirred for 10 minutes and aminoacetonitrile hydrochloride (0.55 g, 0.6 mmol) was added. After 1 h the mixture was evaporated and the residue purified by chromatography on silica to give the amide (0.15 g, 72%) as a white solid.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:10]1[N:20]2[C:21]3[C:16]([CH2:17][CH2:18][CH:19]2[CH3:22])=[C:15]([F:23])[CH:14]=[CH:13][C:12]=3[N:11]=1)[CH3:9])(C)(C)C.C(O)(C(F)(F)F)=O.C1(C)C=CC=CC=1>C(Cl)Cl>[F:23][C:15]1[CH:14]=[CH:13][C:12]2[N:11]=[C:10]([C@@H:8]([NH2:7])[CH3:9])[N:20]3[C:21]=2[C:16]=1[CH2:17][CH2:18][CH:19]3[CH3:22]
Reactant: CC1CCc2c(F)ccc3nc([C@H](C)NC(=O)OC(C)(C)C)n1c23
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1CCc2c(F)ccc3nc([C@H](C)N)n1c23
Temperature: 25 °C
Reaction time: 16 h
Yield: 93.3 %

Procedure:
To an ice-cooled solution of [(S)-1-(7-fluoro-4-methyl-5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-2-yl)ethyl]carbamic acid tert-butyl ester (24.2 mg, 0.0726 mmol) in DCM (4 mL) was added TFA (0.8 mL) and the mixture was stirred at RT for 16 h. Toluene was added and volatiles were removed under reduced pressure, the resulting residue was dissolved in MeOH and loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH and the product was eluted with 0.5M NH3/MeOH. The product containing fractions were combined and concentrated in vacuo affording the title compound as a colourless gum (15.8 mg, 93%). LCMS (Method B): RT 1.98 min [M+H]+ 234
Reaction SMILES: [C:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9]([N:11]2[CH2:16][CH:15]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=3)[CH2:14][CH:13]([C:27]([OH:29])=O)[CH2:12]2)=[O:10])[CH2:5][CH2:4]1)#[N:2].[F:30][C:31]1[CH:36]=[CH:35][C:34]([F:37])=[CH:33][C:32]=1[C:38](=[N:40]O)[NH2:39]>>[F:30][C:31]1[CH:36]=[CH:35][C:34]([F:37])=[CH:33][C:32]=1[C:38]1[N:40]=[C:27]([CH:13]2[CH2:14][CH:15]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=3)[CH2:16][N:11]([C:9]([N:6]3[CH2:5][CH2:4][CH:3]([C:1]#[N:2])[CH2:8][CH2:7]3)=[O:10])[CH2:12]2)[O:29][N:39]=1
Reactant: N#CC1CCN(C(=O)N2CC(C(=O)O)CC(c3ccc(C(F)(F)F)cc3)C2)CC1
Reactant: NC(=NO)c1cc(F)ccc1F
Product: N#CC1CCN(C(=O)N2CC(c3ccc(C(F)(F)F)cc3)CC(c3nc(-c4cc(F)ccc4F)no3)C2)CC1

Procedure:
100 mg (0.244 mmol) of 1-[(4-cyanopiperidin-1-yl)carbonyl]-5-[4-(trifluoromethyl)phenyl]piperidine-3-carboxylic acid (Example 100A) and 46.2 mg (0.269 mmol) of 2,5-difluoro-N′-hydroxybenzenecarboximidamide (Example 74A) were reacted according to the General Method 1. Yield: 72.5 mg (54% of theory).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]([CH:19]=O)=[C:9]([CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:10]=1[CH3:11])=[O:5])[CH3:2].[Cl:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[NH:27][C:26](=[O:31])[CH2:25]2>N1CCCCC1.C(O)C>[CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]([CH:19]=[C:25]2[C:24]3[C:28](=[CH:29][CH:30]=[C:22]([Cl:21])[CH:23]=3)[NH:27][C:26]2=[O:31])=[C:9]([CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: O=C1Cc2cc(Cl)ccc2N1
Reactant: CCOC(=O)CCc1c(C=O)[nH]c(C(=O)OCC)c1C
Solvent: CCO
Solvent: C1CCNCC1
Product: CCOC(=O)CCc1c(C=C2C(=O)Nc3ccc(Cl)cc32)[nH]c(C(=O)OCC)c1C
Yield: 85.7 %

Procedure:
5-Formyl-4-(2-ethoxycarbonylethyl)-3-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (281 mg), 5-chloro-2-oxindole (168 mg), and piperidine (2 drops) in ethanol (2 mL) were refluxed for 2 hours. The reaction mixture was cooled and the precipitate that formed was filtered, washed with ethanol and hexanes, and dried to give 369 mg (86%) of 4-(2-ethoxycarbonylethyl)-3-methyl-5-(5-chloro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-1H-pyrrole-2-carboxylic acid ethyl ester as a light yellow needle crystals.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH3:7])=[CH:3][C:2]=1[CH3:8].[O-:9][Mn](=O)(=O)=O.[K+].Cl.[OH2:16]>>[CH3:8][C:2]1[CH:3]=[C:4]([C:7]([OH:9])=[O:16])[CH:5]=[CH:6][N:1]=1
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: Cc1ccnc(C)c1
Reactant: O
Agent: Cl
Agent: [K+]
Product: Cc1cc(C(=O)O)ccn1
Temperature: 80 °C
Reaction time: 8 h
Yield: 30 %

Procedure:
To a mechanically (overhead) stirred solution of 2,4-lutidine (140 g, 1.31 mol) in water (1500 mL) was added KMnO4 (412 g, 2.61 mol) portion-wise at 80° C. over a period of 3 h, taking care to allow each portion to react before adding the next. The reaction mixture was then stirred at 80° C. for overnight. The solution was allowed to settle and the aqueous layer separated from the precipitated MnO2. The water was then removed under reduced pressure to produce a volume of approximately 400 mL. Remaining water was chilled in an ice bath and acidified to pH 3.0 with dilute HCl. Solid was allowed to precipitate for an addition hour, then filtered and dried under high vacuum at 50° C. for 48 h to give white solid product (54.9 g, 30% yield).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[C@H:14]([OH:25])[CH2:15][S:16]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:17])=[CH:4][CH:3]=1.[CH2:26]([O:28][C:29]([C:31]1([C:34]2[CH:39]=[CH:38][C:37](B3OC(C)(C)C(C)(C)O3)=[CH:36][CH:35]=2)[CH2:33][CH2:32]1)=[O:30])[CH3:27]>>[CH2:26]([O:28][C:29]([C:31]1([C:34]2[CH:39]=[CH:38][C:37]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[C@H:14]([OH:25])[CH2:15][S:16]([CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[O:17])=[CH:4][CH:3]=3)=[CH:36][CH:35]=2)[CH2:32][CH2:33]1)=[O:30])[CH3:27]
Reactant: Cc1noc(-c2ccc(Br)cc2)c1[C@H](O)CS(=O)Cc1ccccc1
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4[C@H](O)CS(=O)Cc4ccccc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 110, Step 3, using (S)-1-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-2-phenylmethanesulfinyl-ethanol and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH2:22]([CH:24]1[C:28]2[S:29][CH:30]=[CH:31][C:27]=2[C:26](=O)[O:25]1)[CH3:23].Cl>C1COCC1>[CH2:22]([CH:24]1[C:28]2[S:29][CH:30]=[CH:31][C:27]=2[C:26](=[C:5]2[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=3)[NH:7][C:6]2=[O:11])[O:25]1)[CH3:23]
Reactant: O=C1Cc2cc(F)ccc2N1
Reactant: CCC1OC(=O)c2ccsc21
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: CCC1OC(=C2C(=O)Nc3ccc(F)cc32)c2ccsc21
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 32.5 %

Procedure:
A solution of 5-fluoro-1,3-dihydro-indol-2-one (440 mg, 2.9 mmol.) in THF (3 mL) is cooled to 0° C. under an Argon atmosphere and treated with a solution of lithium bis(trimethylsilyl)amide (5.8 mL of a 1 M solution in THF, 5.8 mmol) dropwise. The resulting solution is stirred at 0° C. for 10 min and warmed to room temperature. A solution of 6-ethyl-6H-thieno[2,3-c]furan-4-one, (328 mg, 1.94 mmol) in THF (4 mL) and added dropwise to the reaction mixture. The resulting solution is stirred for 4 h. The reaction mixture is poured into aqueous 10% HCl solution (100 mL). The resulting mixture is heated to 90° C. for 45 min and stirred at room temperature for 36 h. The precipitate which formed is collected by filtration and dried. The solid obtained is purified by chromatography (30% EtOAc/hexane). The product containing fractions are concentrated to give the title compound as a yellow solid (190 mg, 33%).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:19]([CH3:20])[C:18]([C:21]34[CH2:28][CH2:27][C:24]([C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)([CH2:25][CH2:26]3)[CH2:23][CH2:22]4)=[N:17][N:16]=2)=[C:11]([C:35]([F:38])([F:37])[F:36])[CH:10]=1)C1C=CC=CC=1>C(OCC)(=O)C.CO.[Pd]>[CH3:20][N:19]1[C:18]([C:21]23[CH2:22][CH2:23][C:24]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)([CH2:25][CH2:26]2)[CH2:27][CH2:28]3)=[N:17][N:16]=[C:15]1[C:12]1[CH:13]=[CH:14][C:9]([OH:8])=[CH:10][C:11]=1[C:35]([F:37])([F:36])[F:38]
Reactant: Cn1c(-c2ccc(OCc3ccccc3)cc2C(F)(F)F)nnc1C12CCC(c3ccccc3)(CC1)CC2
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: Cn1c(-c2ccc(O)cc2C(F)(F)F)nnc1C12CCC(c3ccccc3)(CC1)CC2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
The 3-[4-(Benzyloxy)-2-(trifluoromethyl)phenyl]-4-methyl-5-(4-phenylbicyclo[2.2.2]oct-1-yl)-4H-1,2,4-triazole (8-E) (27 mg, 0.05 mmol) was dissolved in ethyl acetate/methanol (1:1, 4 mL) to which 10% palladium-on-carbon (4 mg) was added. The reaction was then placed under hydrogen atmosphere and stirred for 3 h at room temperature and pressure. After appropriate evacuation of the hydrogen atmosphere, the palladium was filtered through a filter aid with methanol (40 mL). The filtrate was collected and the solvent removed in vacuo to afford 4-[4-methyl-5-(4-phenylbicyclo[2.2.2]oct-1-yl)-4H-1,2,4-triazol-3-yl]-3-(trifluoromethyl)phenol (8-F). MS: m/z 428 (M+1); 1H NMR (500 MHz, CDCl3): δ 1.92 (6H, m), 2.11 (6H, m), 3.41 (3H, s), 7.17 (2H, m), 7.24 (1H, m), 7.31 (2H, m), 7.38 (3H, m) ppm.