Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([F:18])[CH:8]=2)[C:3]1=[O:19].[C:20]12([CH2:30][C:31](O)=[O:32])[CH2:29][CH:24]3[CH2:25][CH:26]([CH2:28][CH:22]([CH2:23]3)[CH2:21]1)[CH2:27]2>>[C:20]12([CH2:30][C:31]([NH:1][N:2]3[N:11]=[C:10]([C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)[C:9]4[C:4](=[CH:5][CH:6]=[C:7]([F:18])[CH:8]=4)[C:3]3=[O:19])=[O:32])[CH2:27][CH:26]3[CH2:25][CH:24]([CH2:23][CH:22]([CH2:28]3)[CH2:21]1)[CH2:29]2
Reactant: O=C(O)CC12CC3CC(CC(C3)C1)C2
Reactant: Nn1nc(-c2ccccc2)c2cc(F)ccc2c1=O
Product: O=C(CC12CC3CC(CC(C3)C1)C2)Nn1nc(-c2ccccc2)c2cc(F)ccc2c1=O

Procedure:
The product from Example 35E and 2-(adamant-1-yl)acetic acid were processed using a method similar to that described in Example 17C to afford the title compound. 1H NMR (500 MHz, DMSO-d6) δ ppm 1.49-1.76 (m, 12H) 1.86-1.99 (m, 3H) 2.06 (s, 2H) 7.39 (dd, J=9.46, 2.44 Hz, 1H) 7.52-7.67 (m, 5H) 7.71-7.94 (m, 1H) 8.49 (dd, J=8.85, 5.49 Hz, 1H) 11.29 (s, 1H); MS (ESI) m/z 432 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:12][C:13]2[CH:17]=[C:16]([CH3:18])[NH:15][N:14]=2)[N:3]=1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1>>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:5]=[C:4]([NH:12][C:13]3[CH:17]=[C:16]([CH3:18])[NH:15][N:14]=3)[N:3]=2)=[CH:22][CH:21]=1
Reactant: Cc1cc(Nc2cc3ccccc3c(Cl)n2)n[nH]1
Reactant: OB(O)c1ccc(Cl)cc1
Product: Cc1cc(Nc2cc3ccccc3c(-c3ccc(Cl)cc3)n2)n[nH]1

Procedure:
Similar procedure as described in example 131 was used, starting from (1-chloro-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine and 4-chloro-Phenylboronic acid to give [1-(4-chloro-phenyl)-isoquinolin-3-yl]-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS m/e 335(MH+).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].C(N(CC)CC)C.[C:13]([O:17][C:18](=[O:34])[NH:19][C@H:20]([CH2:32][OH:33])[CH2:21][CH2:22][CH2:23][NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])([CH3:16])([CH3:15])[CH3:14]>ClCCl>[CH3:1][S:2]([O:33][CH2:32][C@@H:20]([NH:19][C:18]([O:17][C:13]([CH3:15])([CH3:14])[CH3:16])=[O:34])[CH2:21][CH2:22][CH2:23][NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])(=[O:4])=[O:3]
Reactant: CC(C)(C)OC(=O)NCCC[C@@H](CO)NC(=O)OC(C)(C)C
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCCC[C@@H](COS(C)(=O)=O)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
103 mg (0.90 mmol) of methanesulfonyl chloride and 0.21 ml (1.5 mmol) of triethylamine are added to a solution of 240 mg (0.75 mmol) of tert-butyl[(1S)-4-[(tert-butoxycarbonyl)amino]-1-(hydroxymethyl)butyl]carbamate (Example 83A) in 20 ml of dichloromethane, and the mixture is stirred at RT for 16 h. The mixture is diluted with dichloromethane and washed twice with 0.1N hydrochloric acid. The organic phase is dried over magnesium sulfate and evaporated to dryness in vacuo. The product is reacted without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:5]=1[F:11])[CH3:2].C([Li])CCC.[CH2:17]([O:21][C:22]1[CH:27]=[CH:26][C:25]([CH:28]2[CH2:33][CH2:32][C:31](=[O:34])[CH2:30][CH2:29]2)=[C:24]([F:35])[C:23]=1[F:36])[CH2:18][CH2:19][CH3:20].[Cl-].[NH4+]>C1COCC1.C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:31]2([OH:34])[CH2:32][CH2:33][CH:28]([C:25]3[CH:26]=[CH:27][C:22]([O:21][CH2:17][CH2:18][CH2:19][CH3:20])=[C:23]([F:36])[C:24]=3[F:35])[CH2:29][CH2:30]2)=[C:6]([F:10])[C:5]=1[F:11])[CH3:2]
Reactant: CCCCOc1ccc(C2CCC(=O)CC2)c(F)c1F
Reactant: CCOc1cccc(F)c1F
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCCCOc1ccc(C2CCC(O)(c3ccc(OCC)c(F)c3F)CC2)c(F)c1F
Temperature: 30 °C
Reaction time: 2 h
Yield: 97.5 %

Procedure:
1-Ethoxy-2,3-difluorobenzene (27) (7.0 g) and THF (200 ml) were added to a reaction vessel under a nitrogen atmosphere, and cooled to −74° C. n-Butyl lithium (1.57 M in n-hexane; 31.0 ml) was added dropwise in the temperature range of −74° C. to −70° C., and the stirring was continued for another 2 hours. Then, 1-(4-butoxy-2,3-difluorophenyl)-cyclohexane-4-one (28) (12.5 g) dissolved in THF (50 ml) was slowly added dropwise in the temperature range of 50° C. to 60° C., and stirring was continued for another 60 minutes. The obtained reaction mixture was cooled to 30° C., and then poured into a vessel containing an aqueous solution of ammonium chloride (3%; 400 ml) and toluene (200 ml) cooled to 0° C., and mixed. Then the mixture was allowed to separate into organic and aqueous phases, and the extraction into an organic phase was carried out. The organic phase obtained was washed sequentially with water, a saturated aqueous solution of sodium hydrogencarbonate and water, and dried over anhydrous magnesium sulfate. Then, the solvent was distilled off under reduced pressure, giving 19.0 g of 1-(4-ethoxy-2,3-difluorophenyl)-4-(4-butoxy-2,3-difluorophenyl)cyclohexan-1-ol (29). The obtained compound (29) was yellow oil.
Reaction SMILES: [CH:1]1([N:4]([CH2:32][C:33]2[CH:34]=[C:35]([CH:46]=[C:47]([CH2:49][CH2:50][CH2:51][O:52][CH3:53])[CH:48]=2)[O:36][CH2:37][C@H:38]2[CH2:40][C@@H:39]2[C:41]([O:43]CC)=[O:42])[C:5]([C@@H:7]2[C@@H:12]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][O:22][C:23]4[C:28]([Cl:29])=[CH:27][C:26]([CH3:30])=[CH:25][C:24]=4[Cl:31])=[CH:15][CH:14]=3)[CH2:11][CH2:10][NH:9][CH2:8]2)=[O:6])[CH2:3][CH2:2]1.[Na]>>[CH:1]1([N:4]([CH2:32][C:33]2[CH:34]=[C:35]([CH:46]=[C:47]([CH2:49][CH2:50][CH2:51][O:52][CH3:53])[CH:48]=2)[O:36][CH2:37][C@H:38]2[CH2:40][C@@H:39]2[C:41]([OH:43])=[O:42])[C:5]([C@@H:7]2[C@@H:12]([C:13]3[CH:14]=[CH:15][C:16]([O:19][CH2:20][CH2:21][O:22][C:23]4[C:28]([Cl:29])=[CH:27][C:26]([CH3:30])=[CH:25][C:24]=4[Cl:31])=[CH:17][CH:18]=3)[CH2:11][CH2:10][NH:9][CH2:8]2)=[O:6])[CH2:3][CH2:2]1
Reactant: CCOC(=O)[C@H]1C[C@@H]1COc1cc(CCCOC)cc(CN(C(=O)[C@H]2CNCC[C@@H]2c2ccc(OCCOc3c(Cl)cc(C)cc3Cl)cc2)C2CC2)c1
Agent: [Na]
Product: COCCCc1cc(CN(C(=O)[C@H]2CNCC[C@@H]2c2ccc(OCCOc3c(Cl)cc(C)cc3Cl)cc2)C2CC2)cc(OC[C@H]2C[C@@H]2C(=O)O)c1

Procedure:
Prepared according to the procedure described in Example 2 but using instead ethyl (1S,2S)-2-{[3-({cyclopropyl[((3R,4S)-4-{4-[2-(2,6-dichloro-4-methylphenoxy)-ethoxy]phenyl}piperidin-3-yl)carbonyl]amino}methyl)-5-(3-methoxypropyl)phen-oxy]methyl}cyclopropanecarboxylate (Example 7) as the starting material. The sodium salt of the title compound was a foam.
Reaction SMILES: [CH2:1]([NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH2:2][CH3:3].Br[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14]>O1CCOCC1.C1(C2CCCCCCCCCC=2)CCCCCCCCNN=1.O>[C:5]1([N:4]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:1][CH2:2][CH3:3])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CCOC(=O)CBr
Reactant: CCCNc1ccccc1
Agent: C1=C(C2=NNCCCCCCCC2)CCCCCCCCC1
Solvent: O
Solvent: C1COCCO1
Product: CCCN(CC(=O)OCC)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
To a solution of N-propylaniline (60 g) and ethyl bromoacetate (83.6 ml) in dioxane (60 ml), diazabicycloundecene (DBU;113 ml) was added dropwise under ice-cooling. After stirring for 1 hour at room temperature, the reaction mixture was diluted with water and extracted three times with ethyl acetate. The combined organic layer was washed with successive, 1N hydrochloric acid, water and saturated sodium chloride in order. After drying over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure to give 87.9 g (90%) of the objective compound.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].O1CCCC1.C1CCCCC1.[CH3:20][O:21][C:22]([CH:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1)=[O:23].[CH2:29]1[O:38][C:32]([CH2:34][CH2:35][CH2:36]I)([CH3:33])[O:31][CH2:30]1>C1COCC1.[Cl-].[Na+].O>[CH3:20][O:21][C:22]([C:24]1([CH2:36][CH2:35][CH2:34][CH:32]2[O:31][CH2:30][CH2:29][O:38][CH2:33]2)[CH2:28][CH2:27][CH2:26][CH2:25]1)=[O:23]
Reactant: COC(=O)C1CCCC1
Reactant: CC1(CCCI)OCCO1
Agent: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCCCC1
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)C1(CCCC2COCCO2)CCCC1
Temperature: -65 °C
Reaction time: 1 h
Yield: 97.5 %

Procedure:
A solution of lithium diisopropylamide-tetrahydrofuran 1.5M solution in cyclohexane (15 mmol, 10 mL) was cooled to −70° C., and a solution of cyclopentane carboxylic acid methyl ester (10 mmol, 1.28 g) in THF (10 mL) was added dropwise over 15 min, maintaining the internal temperature at −60 to −70° C. The yellow solution was stirred 1 h at −70° C. and a solution of 5-iodo-2-pentanone ethylene ketal (10 mmol, 1.28 g) in THF (10 mL) was added over 15 min, while maintaining temperature of −70° C. After srirring for 1 h at −70° C., the reaction mixture was allowed to warm to room temperature overnight. The reaction mixture was poured into brine (150 mL) and the organic layer was separated. The aqueous layer was extracted with ether (20 mL), the combined organic layers were washed with brine (10 mL), dried over anhydrous magnesium sulfate and evaporated to dryness to give 2.5 g (97%) of a pale yellow oil.
Reaction SMILES: C(O)C.[O:4]=[C:5]1[CH:14]=[N:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]1[CH2:15][CH2:16][CH2:17][C:18]1([C:32]([O:34]CC)=[O:33])[CH2:23][CH2:22][N:21]([CH2:24][CH2:25][S:26][C:27]2[S:28][CH:29]=[CH:30][CH:31]=2)[CH2:20][CH2:19]1.[OH-].[Na+]>O>[O:4]=[C:5]1[CH:14]=[N:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]1[CH2:15][CH2:16][CH2:17][C:18]1([C:32]([OH:34])=[O:33])[CH2:23][CH2:22][N:21]([CH2:24][CH2:25][S:26][C:27]2[S:28][CH:29]=[CH:30][CH:31]=2)[CH2:20][CH2:19]1
Reactant: CCOC(=O)C1(CCCn2c(=O)cnc3ccccc32)CCN(CCSc2cccs2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)C1(CCCn2c(=O)cnc3ccccc32)CCN(CCSc2cccs2)CC1
Temperature: 57.5 °C
Reaction time: 5 h
Yield: 41.3 %

Procedure:
To 2 mL of an ethanol solution containing 90 mg of ethyl 4-(3-(2-oxoquinoxalin-1(2H)-yl)propyl)-1-(2-(2-thienylthio)ethyl)piperidine-4-carboxylate, 0.5 mL of 20% aqueous sodium hydroxide solution was added and stirred at 55-60° C. for 5 hours. 0.5 mL of 20% aqueous sodium hydroxide solution and 0.5 mL of water were added at the same temperature, and stirred at 55-60° C. for 1 hour. The mixture was cooled to the room temperature, and left to stand for 2 nights. The solvent was removed under reduced pressure, water was added, adjusted to pH 6.5 with 6.0 mol/L hydrochloric acid, acetonitrile was added, and the solvent was removed under reduced pressure. Water was added, and the resulting solid was filtered to afford 35 mg of 4-(3-(2-oxoquinoxaline-1(2H)-yl)propyl)-1-(2-(2-thienylthio)ethyl)piperidine-4-carboxylic acid as a brown solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([SH:13])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[Hg](C#N)C#N.[C:19]([O:22][C@@H:23]1[C@@H:28]([O:29][C:30](=[O:32])[CH3:31])[C@H:27]([O:33][C:34](=[O:36])[CH3:35])[CH2:26][S:25][C@@H:24]1Br)(=[O:21])[CH3:20]>>[C:19]([O:22][C@@H:23]1[C@@H:28]([O:29][C:30](=[O:32])[CH3:31])[C@H:27]([O:33][C:34](=[O:36])[CH3:35])[CH2:26][S:25][C@H:24]1[S:13][C:5]1[CH:6]=[C:7]([O:11][CH3:12])[C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1)(=[O:21])[CH3:20]
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@@H](Br)SC[C@H]1OC(C)=O
Reactant: COc1cc(S)cc(OC)c1OC
Agent: N#C[Hg]C#N
Product: COc1cc(S[C@@H]2SC[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]2OC(C)=O)cc(OC)c1OC
Yield: 28 %

Procedure:
If the procedure described in Preparation I is followed starting from 11.35 g (57.10-3 mol) of 3,4,5-trimethoxybenzenethiol, 14.32 g (57.10-3 mol) of mercuric cyanide, Hg(CN)2, and 22.15 g (62.10-3 mol) of 2,3,4-tri-O-acetyl-5-thio-α-D-xylopyranosyl bromide, 7.52 g (yield: 28%) of the expected product are obtained.
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:9]2[NH:10][C:11](=[O:13])[NH:12][C:8]=2[CH:7]=1.[F:22][C:23]1[CH:24]=[C:25]([CH:37]=[CH:38][C:39]=1[F:40])[CH2:26][N:27]1[C:32](=[O:33])[C:31]([C:34](O)=[O:35])=[CH:30][N:29]=[CH:28]1.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CC(N(C)C)=O.O.C(#N)C.CS(C)=O>[F:22][C:23]1[CH:24]=[C:25]([CH:37]=[CH:38][C:39]=1[F:40])[CH2:26][N:27]1[C:32](=[O:33])[C:31]([C:34]([NH:2][C@H:3]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:4][O:5][C:6]2[CH:15]=[CH:14][C:9]3[NH:10][C:11](=[O:13])[NH:12][C:8]=3[CH:7]=2)=[O:35])=[CH:30][N:29]=[CH:28]1
Reactant: N[C@@H](COc1ccc2[nH]c(=O)[nH]c2c1)c1ccccc1
Reactant: O=C(O)c1cncn(Cc2ccc(F)c(F)c2)c1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CS(C)=O
Solvent: CC(=O)N(C)C
Product: O=C(N[C@@H](COc1ccc2[nH]c(=O)[nH]c2c1)c1ccccc1)c1cncn(Cc2ccc(F)c(F)c2)c1=O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 5-[(2R)-2-amino-2-phenylethoxy]-1,3-dihydro-2H-benzimidazol-2-one hydrochloride (38 mg, 0.124 mmol), 1-(3,4-difluorobenzyl)-6-oxo-1,6-dihydropyrimidine-5-carboxylic acid (33.1 mg, 0.124 mmol) and N,N-diisopropylethylamine (65.1 μl, 0.373 mmol) in DMA (710 μl), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (54.3 mg, 0.143 mmol) was added. After stirring for 90 minutes at room temperature, the reaction mixture was diluted with water, acetonitrile, and DMSO. This solution was purified by preparative HPLC Reverse phase (C-18), eluting with Acetonitrile/Water+0.05% TFA, to afford 1-(3,4-difluorobenzyl)-6-oxo-N-{(1R)-2-[(2-oxo-2,3-dihydro-1H-benzimidazol-5-yl)oxy]-1-phenylethyl}-1,6-dihydropyrimidine-5-carboxamide as a white solid after neutralization, extraction, and drying of HPLC fractions. 1H NMR (500 MHz, C2D6SO) δ 10.51 (s, 1H), 10.38 (s, 1H), 9.73 (d, 1H), 8.95 (s, 1H), 8.67 (s, 1H), 7.52 (m, 1H), 7.41 (m, 3H), 7.34 (t, 2H), 7.25 (m, 2H), 6.74 (d, 1H), 6.49 (d, 2H), 5.36 (m, 1H), 5.19 (t, 2H), 4.26 (m, 1H), 4.19 (m, 1H). LRMS (ESI) calc'd for (C27H22F2N5O4) [M+H]+, 518.2; found 518.1.
Reaction SMILES: C[O:2][C:3](=[O:32])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C@@H:11]([C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=3)=[CH:18][CH:17]=2)[CH2:12][CH:13]([CH3:15])[CH3:14])=[N:6][CH:5]=1.CO.[OH-].[Na+]>O1CCCC1>[CH3:14][CH:13]([CH3:15])[CH2:12][C@@H:11]([NH:10][C:7]1[CH:8]=[CH:9][C:4]([C:3]([OH:32])=[O:2])=[CH:5][N:6]=1)[C:16]1[CH:17]=[CH:18][C:19]([C:22]2[CH:23]=[CH:24][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:26][CH:27]=2)=[CH:20][CH:21]=1
Reactant: COC(=O)c1ccc(N[C@H](CC(C)C)c2ccc(-c3ccc(C(F)(F)F)cc3)cc2)nc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)C[C@@H](Nc1ccc(C(=O)O)cn1)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Temperature: 50 °C
Reaction time: 3 h
Yield: 90.1 %

Procedure:
A round bottom flask was charged with (R)-methyl-6-(3-methyl-1-(4′-(trifluoromethyl)biphenyl-4-yl)butylamino)nicotinate (41.5 g, 93.8 mmol), methanol (200 mL) and tetrahydrofuran (200 mL). 1.0N NaOH (188 mL) was then added and the resulting solution was stirred at 50° C. for 3 hours. The reaction was cooled to room temperature and the organic solvents removed under reduced pressure. Water (300 mL) was added and the mixture was acidified with 10% citric acid to pH=3. A white precipitate formed and the heterogeneous mixture was stirred for 30 minutes at 0° C. The mixture was then filtered and the solid was dried under reduced pressure to afford (R)-6-(3-methyl-1-(4′-(trifluoromethyl)biphenyl-4-yl)butylamino)nicotinic acid (36.2 g, 90.0%). 1H NMR (400 MHz, CDCl3, δ): 0.98 (d, J=6.46 Hz, 3 H) 1.03 (d, J=6.46 Hz, 3 H) 1.66-1.78 (m, 1 H) 1.78-1.89 (m, 1 H) 1.96-2.05 (m, 1 H) 4.49-4.63 (m, 1 H) 6.44 (d, J=9.00 Hz, 1 H) 7.44-7.50 (m, 2 H) 7.53-7.58 (m, 2 H) 7.63-7.70 (m, 4 H) 8.17 (d, J=9.19 Hz, 1 H) 8.69-8.74 (m, 1 H) 9.44 (br. s., 1 H). MS (M+1): 429.4.
Reaction SMILES: [CH3:1][N:2]1[CH:7]=[C:6]([CH:8]2[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]2)[CH:5]=[C:4]([CH3:15])[C:3]1=[O:16].[NH:17]1[CH2:20][CH:19]([NH:21][C:22]([CH2:24][NH:25][C:26](=[O:37])[C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=2)=[O:23])[CH2:18]1>>[CH3:1][N:2]1[C:3](=[O:16])[C:4]([CH3:15])=[CH:5][C:6]([CH:8]2[CH2:13][CH2:12][CH:11]([N:17]3[CH2:20][CH:19]([NH:21][C:22]([CH2:24][NH:25][C:26](=[O:37])[C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:34])[F:35])[CH:28]=4)=[O:23])[CH2:18]3)[CH2:10][CH2:9]2)=[CH:7]1
Reactant: Cc1cc(C2CCC(=O)CC2)cn(C)c1=O
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Product: Cc1cc(C2CCC(N3CC(NC(=O)CNC(=O)c4cccc(C(F)(F)F)c4)C3)CC2)cn(C)c1=O

Procedure:
The title compounds were prepared as white solids from the reductive amination of 1,3-dimethyl-5-(4-oxo-cyclohexyl)-1H-pyridin-2-one (as prepared in the previous step) and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide using the procedure described in Step F of Example 1.
Reaction SMILES: C[O-].[Na+].CO.[N+](C1C=CC=CC=1S([NH:18][CH:19]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)(=O)=O)([O-])=O.Cl>C(#N)C>[CH:19]([NH2:18])([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)NC(c1ccccc1)c1ccccc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC#N
Solvent: CO
Product: NC(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 27 h
Yield: 77.9 %

Procedure:
A 28% sodium methoxide/methanol solution (0.34 ml; 1.51 molar equivalents) was added to a solution of N-(2-nitrobenzenesulfonyl)benzhydrylamine (402.1 mg) in dry acetonitrile (3 ml) at room temperature in a nitrogen atmosphere, followed by stirring for 27 hours at room temperature. On the way, a 28% sodium methoxide/methanol solution (0.34 ml; 1.51 molar equivalents) was further added after 10 hours. The reaction mixture was cooled with ice, 1 N hydrochloric acid (5 ml) was added, and the reaction solvents were removed by evaporation under reduced pressure. Water (5 ml), 1 N hydrochloric acid (5 ml) and ether (30 ml) were added to the resulting concentrate, followed by extraction and solution separation, and the organic layer was extracted again with water (5 ml). Sodium hydroxide (0.62 g) was added to the resulting aqueous layer, and extraction was conducted three times with ether (20 ml), followed by drying over sodium sulfate, filtration, concentration and drying under vacuum to obtain benzhydrylamine (155.9 mg; yield: 77.9%).
Reaction SMILES: [C:1]([O:6][CH2:7][CH2:8][OH:9])(=[O:5])[C:2]([CH3:4])=[CH2:3].[C:10](OCC)(=[O:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12].C(O)C>C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C=CC(O)=CC=1)O>[C:1]([O:6][CH2:7][CH2:8][O:9][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[O:16])(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: CCOC(=O)C(=O)OCC
Reactant: C=C(C)C(=O)OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Oc1ccc(O)cc1
Solvent: CCO
Product: C=C(C)C(=O)OCCOC(=O)C(=O)OCC
Reaction time: 4 h
Yield: 76.5 %

Procedure:
A 500 ml flask equipped with a decanter, a thermometer, a stirrer and an inlet for nitrogen gas was charged with 65.1 g (0.5 mol) of 2-hydroxyethyl methacrylate and 365.4 g (2.5 mol) of diethyl oxalate, to which 2 g (10 mmol) of p-toluenesulfonic acid (catalyst) and 4 g of hydroquinone (polymerization inhibitor) were added. The mixture was heated to keep 120° C. for 4 hours in nitrogen atmosphere with distilling 14 ml (0.25 mol) of ethanol away. The reaction mixture was evaporated to remove excess diethyl oxalate and then distilled under vacuum to obtain 88.1 g (yield 76.5%) of 2-ethoxalyloxyethyl methacrylate (colorless transparent liquid) (bp 98° C./0.3 mmHg).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[OH:9])[CH3:2].[S-:10][C:11]#[N:12].[Na+].[Br-].[Na+].BrBr.C(=O)(O)[O-].[Na+]>CO>[CH2:1]([C:3]1[CH:8]=[C:7]([S:10][C:11]#[N:12])[CH:6]=[CH:5][C:4]=1[OH:9])[CH3:2]
Reactant: CCc1ccccc1O
Reactant: N#C[S-]
Agent: BrBr
Agent: O=C([O-])O
Agent: [Br-]
Solvent: CO
Product: CCc1cc(SC#N)ccc1O
Temperature: 0 °C
Reaction time: 1 h
Yield: 92.8 %

Procedure:
To a 500 ml three-necked flask were added sequentially o-ethylphenol (5 g, 40.9 mmol), sodium thiocyanate (10 g, 123.3 mmol), sodium bromide (4.3 g, 41.79 mmol) and methanol (100 ml). The mixture was cooled to 0° C. in an ice bath and then a solution of bromine (2.6 ml, 50.6 mmol) in methanol (50 ml) was added dropwise thereinto. After 1 hour of stirring at 0° C., the mixture was allowed to warm up to room temperature and then stirred for another 4 hours at room temperature. A 200 ml saturated aqueous solution of sodium bicarbonate was added slowly to the reaction mixture and stirred for 10 min. The mixture was extracted with ethyl acetate (2×300 ml). The combined organic layer was dried over anhydrous magnesium sulfate, and filtrated. Filtrate was concentrated under reduced pressure to give a reddish-brown sticky liquid. Column chromatography was performed (silica-gel H: 300-400 mesh; petroleum ether/ethyl acetate=5:1 v/v) to obtain 6.8 g of 3-ethyl-4-hydroxy-phenyl thiocyanic acid (reddish-brown sticky liquid, yield: 93%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:11][C:12]([NH:14][C:15]2[CH:16]=[CH:17][C:18]([CH:21]([CH3:27])[CH2:22][C:23]([O:25][CH3:26])=[O:24])=[N:19][CH:20]=2)=[O:13])[CH:5]=[CH:6][C:7]=1[N+:8]([O-])=O.C([O-])=O.[NH4+]>C(O)C.[Pd]>[NH2:8][C:7]1[CH:6]=[CH:5][C:4]([CH2:11][C:12]([NH:14][C:15]2[CH:16]=[CH:17][C:18]([CH:21]([CH3:27])[CH2:22][C:23]([O:25][CH3:26])=[O:24])=[N:19][CH:20]=2)=[O:13])=[CH:3][C:2]=1[OH:1]
Reactant: COC(=O)CC(C)c1ccc(NC(=O)Cc2ccc([N+](=O)[O-])c(O)c2)cn1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: COC(=O)CC(C)c1ccc(NC(=O)Cc2ccc(N)c(O)c2)cn1
Temperature: 60 °C
Reaction time: 1 h
Yield: 74.5 %

Procedure:
A solution of (RS) methyl 3-{5-[2-(3-hydroxy-4-nitrophenyl)-acetylamino]-pyridin-2-yl}-butanoate (2.0 g, Reference Example 25) in ethanol (80 mL), at 60° C., was treated with ammonium formate (4.0 g) and 10% palladium on charcoal (0.5 g). After stirring at 60° C. for 1 hour the reaction mixture was cooled and then filtered. The filtrate was evaporated and the residue was dissolved in ethyl acetate. This solution was washed twice with water, then dried over magnesium sulphate and then evaporated to give the title compound (1.37 g) as an oil.
Reaction SMILES: [N:1]([CH2:4][CH:5]([C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[C:9]([S:14][CH3:15])[CH:8]=1)[OH:6])=[N+]=[N-].C(S)CCS.C(N(CC)CC)C>CO>[NH2:1][CH2:4][CH:5]([C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[C:9]([S:14][CH3:15])[CH:8]=1)[OH:6]
Reactant: CSc1cc(C(O)CN=[N+]=[N-])ccc1O
Agent: SCCCS
Solvent: CCN(CC)CC
Solvent: CO
Product: CSc1cc(C(O)CN)ccc1O
Temperature: 0 °C

Procedure:
Stir the product of Step C (49.5 g, 0.22 mole), 1,3-propane dithiol (103.6 g, 0.96 mole) and triethylamine (101.0 g, 1.0 mole) in methanol (1500 ml) for 72 hours. Cool to 0° C., filter and evaporate in vacuo to obtain 2-amino-1-(4-hydroxy-3-methylthiophenyl)ethanol.
Reaction SMILES: [Cl:1][C:2]1[C:11]([CH:12]=O)=[CH:10][C:9]2[C:4](=[CH:5][C:6]([O:16][CH3:17])=[C:7]([O:14][CH3:15])[CH:8]=2)[N:3]=1.Cl.[NH2:19][OH:20]>N1C=CC=CC=1>[Cl:1][C:2]1[C:11]([CH:12]=[N:19][OH:20])=[CH:10][C:9]2[C:4](=[CH:5][C:6]([O:16][CH3:17])=[C:7]([O:14][CH3:15])[CH:8]=2)[N:3]=1
Reactant: COc1cc2cc(C=O)c(Cl)nc2cc1OC
Reactant: NO
Agent: Cl
Solvent: c1ccncc1
Product: COc1cc2cc(C=NO)c(Cl)nc2cc1OC
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To 50 g of 2-chloro-6,7-dimethoxy-3-quinolinecarboxaldehyde was added 50 g of hydroxylamine hydrochloride in 500 ml of pyridine. The mixture was stirred at room temperature for 16 hours and the solvent was then evaporated to leave a semi-solid material. This was washed with water, filtered and recrystallized from dimethylformamide to give 2-chloro-6,7-dimethoxy-3-quinolinecarboxaldehyde oxime melting at about 237°-237.5° C. with decomposition.