Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]([C:12]([F:15])([F:14])[F:13])[C:6]=2[N:5]=[C:4]2[CH2:16][CH2:17][NH:18][CH2:19][CH2:20][C:3]=12.Cl[C:22]([O:24][CH2:25][CH3:26])=[O:23]>>[CH2:25]([O:24][C:22]([N:18]1[CH2:19][CH2:20][C:3]2[C:4](=[N:5][C:6]3[C:7]([C:12]([F:14])([F:13])[F:15])=[CH:8][CH:9]=[CH:10][C:11]=3[C:2]=2[CH3:1])[CH2:16][CH2:17]1)=[O:23])[CH3:26]
Reactant: Cc1c2c(nc3c(C(F)(F)F)cccc13)CCNCC2
Reactant: CCOC(=O)Cl
Product: CCOC(=O)N1CCc2nc3c(C(F)(F)F)cccc3c(C)c2CC1
Yield: 92 %

Procedure:
1,2,4,5-Tetrahydro-11-methyl-7-trifluoromethyl-3-azepino[4,5-b]quinoline-carboxylic acid ethyl ester was prepared from 1,2,4,5-tetrahydro-11-methyl-7-trifluoromethyl-3H-azepino[4,5-b]quinoline and ethyl chloroformate analogous to Example 155. Yield: 92% of theory; m.p. 136° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[OH:12].O.[N+:14]([O-])([OH:16])=[O:15]>C(Cl)Cl>[Br:1][C:2]1[C:3]([OH:12])=[C:4]([N+:14]([O-:16])=[O:15])[C:5]([N+:9]([O-:11])=[O:10])=[C:6]([F:8])[CH:7]=1
Reactant: O=[N+]([O-])c1cc(O)c(Br)cc1F
Reactant: O=[N+]([O-])O
Solvent: O
Solvent: ClCCl
Product: O=[N+]([O-])c1c(F)cc(Br)c(O)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 2-bromo-4-fluoro-5-nitrophenol (4.0 g, 17 mmol) in methylene chloride (29.5 mL), 2.0 M nitric acid in DCM (25 mL) was added and the mixture was stirred for 15 min at room temperature. The mixture was poured over cold water and extracted with methylene chloride to give the product.
Reaction SMILES: ClC(Cl)(Cl)CO[C:5]([NH:7][C:8]1[N:12]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)[N:11]=[C:10]([C:20]([CH3:23])([CH3:22])[CH3:21])[CH:9]=1)=[O:6].[NH2:26][C:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:30]([C:37]2[CH:38]=[N:39][C:40]([CH2:43][N:44]3[CH2:49][CH2:48][O:47][CH2:46][CH2:45]3)=[CH:41][CH:42]=2)=[CH:29][CH:28]=1.C(N(C(C)C)CC)(C)C.CS(C)=O>C(OCC)(=O)C>[C:20]([C:10]1[CH:9]=[C:8]([NH:7][C:5]([NH:26][C:27]2[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[C:30]([C:37]3[CH:38]=[N:39][C:40]([CH2:43][N:44]4[CH2:45][CH2:46][O:47][CH2:48][CH2:49]4)=[CH:41][CH:42]=3)=[CH:29][CH:28]=2)=[O:6])[N:12]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)[N:11]=1)([CH3:22])([CH3:21])[CH3:23]
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)OCC(Cl)(Cl)Cl)cc1
Reactant: Nc1ccc(-c2ccc(CN3CCOCC3)nc2)c2ccccc12
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(-c3ccc(CN4CCOCC4)nc3)c3ccccc23)cc1
Reaction time: 5 h

Procedure:
A solution of 5-(2,2,2-trichloroethoxycarbonyl)amino-3-t-butyl-1-p-tolylpyrazole (26 mmol), 1-amino-4-[6-(morpholin-4-ylmethyl)pyridin-3-yl]naphthalene (26 mmol), diisopropylethylamine (25 mmol) and DMSO (75 mL) is heated to 55-90° C. and held for 2-8 h. To this solution, ethyl acetate (100 mL) is added. The organic layer is washed with brine (4×50 mL), and dried over MgSO4. The solvent is removed under reduced pressure, and residue is crystallized from a suitable solvent such as acetonitrile (50 mL) at 0° C. The product is collected by filtration and recrystallized from a suitable solvent such as isopropanol and dried in vacuum to constant weight.
Reaction SMILES: [CH2:1]([S:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15](=[O:19])[NH:14][CH:13]=[C:12]2Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cu][C:22]#[N:23].CN1C(=O)CCC1>C(OCC)(=O)C>[CH2:1]([S:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15](=[O:19])[NH:14][CH:13]=[C:12]2[C:22]#[N:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1[nH]cc(Br)c2cc(SCc3ccccc3)ccc12
Reactant: N#C[Cu]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: N#Cc1c[nH]c(=O)c2ccc(SCc3ccccc3)cc12
Temperature: 200 °C
Reaction time: 4 h

Procedure:
A vial was charged with 6-(benzylthio)-4-bromoisoquinolin-1(2H)-one (0.583 g, 1.684 mmol), copper (i) cyanide (0.052 ml, 1.684 mmol), and NMP (8.42 ml). The reaction was heated to 200° C. and stirred for four hours. The reaction was diluted with ethyl acetate and washed with water. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were dried with sodium sulfate, filtered, and concentrated. The material was purified via column chromatography (40 g silica gel column, gradient elution 0 to 10% MeOH:EtOAc) to afford 6-(benzylthio)-1-oxo-1,2-dihydroisoquinoline-4-carbonitrile as a brown solid. m/z (ESI) 293.1 (M+H)+.
Reaction SMILES: [CH:1]1(/[C:4](/[C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)=[CH:5]/[CH:6]=[CH:7]/[C:8]([OH:10])=[O:9])[CH2:3][CH2:2]1.[N+:19]([C:22]1[CH:27]=[CH:26][C:25](O)=[CH:24][CH:23]=1)([O-:21])=[O:20].C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[N+:19]([C:22]1[CH:27]=[CH:26][C:25]([O:9][C:8](=[O:10])/[CH:7]=[CH:6]/[CH:5]=[C:4](/[CH:1]2[CH2:3][CH2:2]2)\[C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)=[CH:24][CH:23]=1)([O-:21])=[O:20]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: COc1ccc(/C(=C\C=C\C(=O)O)C2CC2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: COc1ccc(/C(=C\C=C\C(=O)Oc2ccc([N+](=O)[O-])cc2)C2CC2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 65.1 %

Procedure:
As in Example 115, (2E,4Z)-5-cyclopropyl-5-(4-methoxyphenyl)-2,4-pentadienoic acid (1.95 g) and 4-nitrophenol (1.33 g) in 15mL of dichloromethane was reacted with 1,3-dicyclohexylcarbodiimide (1.66 g) and the mixture was stirred at room temperature for 18 hours. After the work up. the crude ester was crystallized from 2-propanol to furnish 1.9 g of (2E,4Z)-5-cyclopropyl-5-(4-methoxyphenyl)-2,4-pentadienoic acid 4-nitrophenyl ester, mp 115.5°-116.5° C.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[F:29][C:30]1[CH:37]=[CH:36][CH:35]=[CH:34][C:31]=1[CH2:32]Br>O1CCCC1>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([CH2:32][C:31]2[CH:34]=[CH:35][CH:36]=[CH:37][C:30]=2[F:29])([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C1CCN(Cc2ccccc2)CC1
Reactant: Fc1ccccc1CBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C1(Cc2ccccc2F)CCN(Cc2ccccc2)CC1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 76 %

Procedure:
Ethyl 1-benzylpiperidine-4-carboxylate (2.47 g, 10 mmol) was dissolved in tetrahydrofuran (20 mL) and cooled to −78° C. Lithium bis(trimethylsilyl)amide (11 mL, 1.0 M in tetrahydrofuran) was added slowly, and stirred for 30 minutes. 2-fluoro-benzylbromide (1.34 mL, 11 mmol) in 5 mL tetrahydrofuran was added slowly. The resulting solution was allowed to reach room temperature and stirred over night. The reaction was quenched with ammonium chloride (aq, sat) and partitioned between water and ethyl acetate. The organic layer was washed with brine and dried over magnesium sulphate, filtrated and concentrated. The crude material was purified on silica (heptane/ethyl acetate), to give 2.7 g (77%) the subtitle compound as a colourless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[C:5]([OH:7])=[O:6].C(N(CC)CC)C.[C:20](Cl)(=[O:23])[CH2:21][CH3:22]>O1CCCC1>[C:20]([NH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[C:5]([OH:7])=[O:6])(=[O:23])[CH2:21][CH3:22]
Reactant: COc1ccc(C(=O)O)cc1N
Reactant: CCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCC(=O)Nc1cc(C(=O)O)ccc1OC
Temperature: 25 °C
Yield: 97.1 %

Procedure:
0.6 g 3-amino-4-methoxybenzoic acid (1.0 g, 6 mmol) is dissolved in dry THF (tetrahydrofuran) in a 25 ml flask, triethylamine (1.2 ml, 12 mmol) is subsequently added to obtain transparent yellow solution. The mixture is stirred under nitrogen protection, propionyl chloride (0.78 ml, 9 mmol) is added into the flask in an ice-water bath. After finishing addition of propionyl chloride the mixture is naturally raised to room temperature. The reacted mixture is filtered, the filtrate is evaporated to dryness and separated using a silica column to obtain 3-propionamido-4-methoxybenzoic acid 1.3 g (yield: 67%).
Reaction SMILES: [F:1][C:2]([F:16])([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][CH:4]=1.C1C(=O)[N:21](Br)C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[F:1][C:2]([F:16])([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:3]1[CH:4]=[CH:5][C:6]([CH2:9][NH2:21])=[CH:7][CH:8]=1
Reactant: Cc1ccc(C(F)(F)c2ccccc2)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: NCc1ccc(C(F)(F)c2ccccc2)cc1
Temperature: 80 °C
Reaction time: 4.5 h

Procedure:
Combine 4-(difluoro-phenyl-methyl)-toluene (0.29 g, 1.35 mmol, prepared by following the procedure described in Tetrahedron 1996, 52, 9), NBS (0.26 g, 1.48 mmol), and AIBN (6 mg, 0.03 mmol) in carbon tetrachloride (8 mL) and heat at 80° C. for 16 h. Evaporate the mixture and pass the residue through a pad of silica gel washing with hexane and evaporate the filtrate. Dissolve the residue in methanol and add dropwise to 7M ammonia in methanol (100 mL) at 0° C. After 4.5 h, evaporate the mixture and isolate the amine by SCX chromatography (0.1 g, 32%). MS (ES+) m/z: 234 (M+H)+.
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]([C:36]1[S:40][N:39]=[CH:38][N:37]=1)[S:7]([C:10]1[CH:18]=[C:17]2[C:13]([C:14]([C:20]3[CH:25]=[CH:24][C:23](C(F)(F)F)=[CH:22][C:21]=3[C:30]3[N:34]([CH3:35])[N:33]=[CH:32][CH:31]=3)=[CH:15][N:16]2[CH3:19])=[CH:12][CH:11]=1)(=[O:9])=[O:8].[ClH:47]>CO>[Cl:47][C:23]1[CH:24]=[CH:25][C:20]([C:14]2[C:13]3[C:17](=[CH:18][C:10]([S:7]([NH:6][C:36]4[S:40][N:39]=[CH:38][N:37]=4)(=[O:8])=[O:9])=[CH:11][CH:12]=3)[N:16]([CH3:19])[CH:15]=2)=[C:21]([C:30]2[N:34]([CH3:35])[N:33]=[CH:32][CH:31]=2)[CH:22]=1
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc3c(-c4ccc(C(F)(F)F)cc4-c4ccnn4C)cn(C)c3c2)c(OC)c1
Reactant: Cl
Solvent: CO
Product: Cn1nccc1-c1cc(Cl)ccc1-c1cn(C)c2cc(S(=O)(=O)Nc3ncns3)ccc12
Reaction time: 0.75 h
Yield: 44.6 %

Procedure:
A 10-mL round-bottom flask was charged with N-(2,4-dimethoxybenzyl)-1-methyl-3-(2-(1-methyl-1H-pyrazol-5-yl)-4-(trifluoromethyl)phenyl)-N-(1,2,4-thiadiazol-5-yl)-1H-indole-6-sulfonamide (35.79 mg, 0.056 mmol) and methanol (1 mL). Hydrogen chloride (4M in 1,4-dioxane) (141 μl, 0.563 mmol) was added, and the resulting solution was stirred for 45 min. The reaction mixture was loaded onto a 500 mg SCX-2 ion exchange column (Silicycle, Quebec City, Canada). The column was eluted with methanol, then with a solution of 2N ammonia in methanol. The basic fractions were combined and concentrated. The residue was purified further by chromatography on silica gel (0 to 10% MeOH/DCM) to give 3-(4-chloro-2-(1-methyl-1H-pyrazol-5-yl)phenyl)-1-methyl-N-(1,2,4-thiadiazol-5-yl)-1H-indole-6-sulfonamide (12.05 mg, 0.025 mmol, 44.1% yield) as a cream colored solid. 1H NMR (400 MHz, DMSO-d6) δ=8.35 (br. s., 1 H), 7.90 (d, J=1.1 Hz, 1 H), 7.62 (d, J=1.3 Hz, 2 H), 7.56-7.31 (m, 4 H), 7.12 (s, 1 H), 6.27 (d, J=1.9 Hz, 1 H), 3.79 (s, 3 H), 3.23 (s, 3 H). m/z (ESI) 485.1 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([O:13][CH3:14])=[C:5]([CH3:15])[C:4]=1[CH:16]=O.CO[C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)C(OC)=C[C:21]=1/[CH:32]=[C:33](\C)/[C:34]([O:36][CH2:37][CH3:38])=[O:35]>>[CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([O:13][CH3:14])=[C:5]([CH3:15])[C:4]=1/[CH:16]=[C:33](\[CH2:32][CH2:21][CH2:20][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH3:24])/[C:34]([O:36][CH2:37][CH3:38])=[O:35]
Reactant: CCOC(=O)/C(C)=C/c1cc(OC)c2ccccc2c1OC
Reactant: COc1c(C)c(C=O)c(OC)c2ccccc12
Product: CCCCCCCCC/C(=C\c1c(C)c(OC)c2ccccc2c1OC)C(=O)OCC

Procedure:
Compound 98c was prepared from 34 (0.479 g, 2.08 mmol) as described above for 28a to give 0.373 g (0.874 mmol, 41%) of the product as a yellow oil following flash chromatography (1:9 EtOAc:hexanes).
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:7][CH2:6][CH2:5][C@@H:4]1[NH:8][C:9](=[O:20])[C:10]1[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[CH:12][C:11]=1[O:18][CH3:19].N[C@H]1CCC[C@@H]1NC(=O)OC(C)(C)C.COC1C=CC=C(OC)C=1C([Cl:41])=O>>[ClH:41].[NH2:2][C@H:3]1[CH2:7][CH2:6][CH2:5][C@@H:4]1[NH:8][C:9](=[O:20])[C:10]1[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[CH:12][C:11]=1[O:18][CH3:19]
Reactant: COc1cccc(OC)c1C(=O)N[C@H]1CCC[C@H]1N
Reactant: COc1cccc(OC)c1C(=O)Cl
Agent: CC(C)(C)OC(=O)N[C@H]1CCC[C@@H]1N
Agent: Cl
Product: COc1cccc(OC)c1C(=O)N[C@H]1CCC[C@@H]1N

Procedure:
Prepared according to the procedure for N-[(1S,2R)-2-aminocyclopentyl]-2,6-dimethoxybenzamide hydrochloride (Intermediate 3) from tert-butyl N-[(1S,2S)-2-aminocyclopentyl]carbamate (CAS number 586961-34-4; 1.0 g, 4.99 mmol) and 2,6-dimethoxybenzoyl chloride (CAS number 1989-53-3; 1.50 g, 7.99 mmol) except that after the reaction was complete it was partitioned between DCM and a saturated solution of sodium bicarbonate, filtered through a hydrophobic frit and concentrated in vacuo. The Boc protected intermediate was purified by column chromatography (silica, 0-100% ethyl acetate/petrol) to give a white solid. After deprotection with HCl in 1,4-dioxane, azeotropic distillation from toluene afforded the title compound.
Reaction SMILES: Br[C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[C:16]1(=[O:21])[NH:20][CH2:19][CH2:18][CH2:17]1.C([O-])([O-])=O.[K+].[K+].C1(C)C=CC=CC=1.C(OCC)(=O)C>C(OCC)(=O)C>[C:6]([C:5]1[CH:14]=[CH:15][C:2]([N:20]2[CH2:19][CH2:18][CH2:17][C:16]2=[O:21])=[CH:3][CH:4]=1)(=[O:7])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C1CCCN1
Reactant: O=C(c1ccccc1)c1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: O=C(c1ccccc1)c1ccc(N2CCCC2=O)cc1
Temperature: 140 °C
Reaction time: 2 h

Procedure:
2.61 g (0.01 mole) of 4-bromobenzophenone and 1.13 ml of butyrolactam (0.015 mole) are fused together at 180° C., and 1.4 g of K2CO3 and 0.63 g of Cu powder are added. The mixture is stirred at this temperature for 2 h, allowed to cool to 140° C. and then dissolved in ethyl acetate. Chromatography on silica gel eluting with toluene/ethyl acetate provides N-(4-benzoylphenyl)-2-pyrrolidinone of melting point 162°-164° C., which is immediately dissolved in 10 ml of methanol and 10 ml of 5 N NaOH and boiled under reflux for about 2 h. After the methanol has been removed by distillation, the mixture is acidified to pH 5, and the product is filtered off with suction. Melting point: 156°-158° C.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH2:26][CH3:27])[CH2:23][CH2:22][C:21]([C:28]([NH:30][C:31]4[CH:36]=[CH:35][C:34]([S:37][CH2:38][C:39]5[N:43]([CH2:44][CH3:45])[CH:42]=[N:41][N:40]=5)=[CH:33][CH:32]=4)=[O:29])=[CH:20][C:19]=3[CH:46]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:55])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH2:26][CH3:27])[CH2:23][CH2:22][C:21]([C:28]([NH:30][C:31]4[CH:32]=[CH:33][C:34]([S:37]([CH2:38][C:39]5[N:43]([CH2:44][CH3:45])[CH:42]=[N:41][N:40]=5)=[O:55])=[CH:35][CH:36]=4)=[O:29])=[CH:20][C:19]=3[CH:46]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(SCc4nncn4CC)cc2)CCN3CCC)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(S(=O)Cc4nncn4CC)cc2)CCN3CCC)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 72.9 %

Procedure:
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-N-[4-(4-ethyl-4H-1, 2, 4-triazol-3-ylmethylthio) phenyl]-1-propyl-2,3-dihydro-1H-benzazepine-4-carboxamide (0.93 g) in dichloromethane (20 ml) was added dropwise a solution of 3-chloroperbenzoic acid (70%, 0.54 g) in dichloromethane (10 ml) at −78° C., and the mixture was stirred at −78° C. for 1 hour. To the reaction solution was added sodium thiosulfate solution at room temperature and the mixture was stirred for several minutes. The mixture was extracted with ethyl acetate, and the organic layer was washed with sodium bicarbonate solution and saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was separated and purified by column chromatography (ethanol:ethyl acetate 1:5→1:3→1:2), to give 7-[4-(2-butoxyethoxy)phenyl]-N-[4-(4-ethyl-4H-1,2,4-triazol-3-ylmethylsulfinyl)phenyl]-1-propyl-2,3-dihydro-1H-benzazepine-4-carboxamide (Compound 137) (694.7 mg) as yellow amorphous.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=1[O:18][CH3:19])[C:12](O)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:22])=O>>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=1[O:18][CH3:19])[C:12]([Cl:22])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: COc1ccc(C(=O)O)cc1OCc1ccccc1
Product: COc1ccc(C(=O)Cl)cc1OCc1ccccc1
Yield: 98 %

Procedure:
A solution of 3-benzyloxy-4-methoxy-benzoic acid (35.86 g, 0.139 mole), prepared as described in example 53, in thionyl chloride (150 ml) was refluxed for 2 hours under N2, evaporated to dryness and taken up twice in toluene (100 ml) to give 35.01 g of the title compound (yield: 98%).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]([CH3:17])([CH3:16])[C:5]([NH:7][C:8]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=1)=[O:6].[CH3:18]I>CN(C=O)C>[CH3:18][N:7]([C:5](=[O:6])[C:4]([CH3:17])([CH3:16])[CH3:3])[C:8]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=1
Reactant: CC(C)(C)C(=O)Nc1ccc(C#N)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C(=O)C(C)(C)C)c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.7 %

Procedure:
Add sodium hydride (0.21 g, 8.6 mmol, 95%) to a solution of 4-(2,2-dimethyl-propionylamino)-benzonitrile (1.589 g, 7.857 mmol) in anhydrous DMF (16 mL) at 0° C. under nitrogen. Add methyl iodide (0.54 mL, 8.6 mmol) after bubbling ceased (˜20 min) Stir the mixture to room temperature overnight. Partition the reaction mixture between DCM (250 mL) and water (100 mL). Wash the organic phase with water (2×100 mL). Dry over Na2SO4, filter and concentrate in vacuo. Purify the crude mixture by chromatography on silica gel eluting with hexane/EtOAc (1:0 to 1:1 gradient over 71 min; 50 mL/min) to obtain the desired intermediate as a white solid (1.201 g, 71%).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][CH:9]2[CH2:14][C:13]([CH3:16])([CH3:15])[NH:12][C:11]([CH3:18])([CH3:17])[CH2:10]2)[N:3]=1.[CH3:19][C:20]([OH:28])([CH3:27])[CH2:21][C:22]1[S:23][CH:24]=[CH:25][CH:26]=1>>[CH3:19][C:20]([OH:28])([CH3:27])[CH2:21][C:22]1[S:23][C:24]([C:2]2[CH:7]=[CH:6][N:5]=[C:4]([NH:8][CH:9]3[CH2:14][C:13]([CH3:16])([CH3:15])[NH:12][C:11]([CH3:18])([CH3:17])[CH2:10]3)[N:3]=2)=[CH:25][CH:26]=1
Reactant: CC(C)(O)Cc1cccs1
Reactant: CC1(C)CC(Nc2nccc(Cl)n2)CC(C)(C)N1
Product: CC(C)(O)Cc1ccc(-c2ccnc(NC3CC(C)(C)NC(C)(C)C3)n2)s1

Procedure:
The title compound was prepared analogous to Method C, starting from (4-chloro-pyrimidin-2-yl)-(2,2,6,6-tetramethyl-piperidin-4-yl)-amine and 2-methyl-1-thiophen-2-yl-propan-2-ol.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[C:8]([O:10]CC)=[O:9].[OH-].[Na+].Cl>O>[O:1]=[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[C:8]([OH:10])=[O:9]
Reactant: CCOC(=O)C1CCCCC1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)C1CCCCC1=O
Temperature: 0 °C
Reaction time: 16 h

Procedure:
To ethyl 2-oxocyclohexanecarboxylate (2.0 g, 0.01 mmol), 5N NaOH (0.56 g, 0.014 mmol) dissolved in water (3.0 mL) was added at room temperature and stirred for 16 h. The reaction mixture was cooled to 0° C., conc. HCl (1.2 mL) was added and stirred for 45 min. to give 2-oxocyclohexanecarboxylic acid. In another setup, 2,3-dichloroaniline (1.8 g, 11.0 mmol), dissolved in H2O (10 mL) was cooled to 0° C., conc. HCl (6 mL) was added slowly and stirred for 20 min. NaNO2 (0.77 g, 11.0 mmol) in water (5.0 mL) was added and stirred at 0° C. for 30 min., filtered, the filtrate was cooled to 0° C. and 2-oxocyclohexanecarboxylic acid (prepared above) (1.6 g, 11.6 mmol) was added dropwise. The reaction mixture was warmed to room temperature and stirred for 30 min. during which time a yellow solid was precipitated. The solid was filtered and air dried to give the title compound as a yellow solid (1.7 g, 56%). 1H NMR (200 MHz, CDCl3, δ in ppm) 13.87 (bs, 1H), 7.65 (dd, J=8.4, 1.8 Hz, 1H), 7.26-7.04 (m, 2H), 2.77-2.71 (m, 2H), 2.61-2.54 (m, 2H), 1.91-1.85 (m, 4H).
Reaction SMILES: [C:1]1([C:7]2[C:8]([O:10][C:11](=[O:13])[CH:12]=2)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:14][O:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20][NH2:21])=[CH:18][CH:17]=1>C(O)(=O)C.CO>[CH3:14][O:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20][N:21]2[C:8](=[O:10])[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:12][C:11]2=[O:13])=[CH:18][CH:17]=1
Reactant: O=C1C=C(c2ccccc2)C(=O)O1
Reactant: COc1ccc(CN)cc1
Solvent: CO
Solvent: CC(=O)O
Product: COc1ccc(CN2C(=O)C=C(c3ccccc3)C2=O)cc1
Temperature: 25 °C
Yield: 79.1 %

Procedure:
Phenylmaleic anhydride (2.4 g, 13.8 mmol) and 4-methoxybenzylamine (1.8 mL, 13.8 mmol) in 10 mL glacial acetic acid were heated in a 95° C. oil bath for 2 h. The mixture was cooled to room temperature, diluted with methanol and filtered to provide the title compound as a solid (3.2 g, 79%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:17](=O)[C:16]3[C:15]([C:19]([O:21]CC)=O)=[CH:14][CH:13]=[CH:12][C:11]=3[NH:10][CH:9]2[C:24]2[N:25]([CH3:29])[CH:26]=[CH:27][N:28]=2)=[CH:4][CH:3]=1.O.[NH2:31][NH2:32]>CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:17]3=[N:31][NH:32][C:19](=[O:21])[C:15]4[CH:14]=[CH:13][CH:12]=[C:11]([C:16]=43)[NH:10][CH:9]2[C:24]2[N:25]([CH3:29])[CH:26]=[CH:27][N:28]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cccc2c1C(=O)C(c1ccc(F)cc1)C(c1nccn1C)N2
Reactant: NN
Solvent: CO
Solvent: O
Product: Cn1ccnc1C1Nc2cccc3c(=O)[nH]nc(c23)C1c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 14 %

Procedure:
A mixture of ethyl 3-(4-fluorophenyl)-2-(1-methyl-1H-imidazol-2-yl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate (200 mg, 0.5 mmol) in 85% hydrazine monohydrate (1 mL) and methanol (5 mL) was stirred at room temperature for 4 h. The resulting mixture was filtered and washed by water (20 mL) and methanol (5 mL) to obtain a white solid, which was dried in vacuum at 50° C. to obtain the title compound (25 mg, yield 14%). LC-MS (ESI) m/z: 362(M+1)+. 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 3.58 (s, 3H), 4.52-4.54 (d, J=7.2 Hz, 1H), 4.94-4.97 (m, 1H), 6.69-6.70 (m, 1H), 6.96-6.97 (m, 1H), 7.04-7.08 (m, 3H), 7.18-7.22 (m, 2H), 7.36-7.38 (m, 2H), 7.51-7.55 (t, J=8.0 Hz, 1H), 12.2 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][C:3]=1[OH:11].[OH-].[NH4+:13]>O>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:13])=[O:7])=[CH:4][C:3]=1[OH:11]
Reactant: [NH4+]
Reactant: O=C(Cl)c1ccc(Cl)c(O)c1
Agent: [OH-]
Solvent: O
Product: NC(=O)c1ccc(Cl)c(O)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 86 %

Procedure:
4-Chloro-3-hydroxy-benzoyl chloride is cooled to 0° C. and 20 ml of ammonium hydroxide were added within 5 minutes. The mixture is allowed to stir at 0° C. for 30 minutes, then at room temperature for additional 30 minutes. 30 ml of water is added to the mixture and the white precipitate is filtered, the pH of the water layer is adjusted to 3, followed by extraction with ethyl acetate, dried over MgSO4 to give 4-chloro-3-hydroxy-benzamide as a white solid 850 mg (86% yield).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])/[CH:5]=[CH:6]/[C:7]1[CH:12]=[C:11]([F:13])[C:10]([O:14]CC2C=CC=CC=2)=[C:9]([F:22])[CH:8]=1)[CH3:2]>CCO.[Pd]>[CH2:1]([O:3][C:4](=[O:23])[CH2:5][CH2:6][C:7]1[CH:12]=[C:11]([F:13])[C:10]([OH:14])=[C:9]([F:22])[CH:8]=1)[CH3:2]
Reactant: CCOC(=O)/C=C/c1cc(F)c(OCc2ccccc2)c(F)c1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CCc1cc(F)c(O)c(F)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 97.9 %

Procedure:
(E)-3-(4-Benzyloxy-3,5-difluoro-phenyl)-acrylic acid ethyl ester (1.2 g, 3.77 mmol) obtained in Step C was dissolved in EtOH (20 mL), and 10% Pd/C (120 mg) was added to the solution. The mixture was stirred at room temperature under hydrogen atmosphere for 12 hours. The reactant was filtered by using celite and concentrated under reduced pressure to obtain the title compound (0.85 g, 98%).