Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([CH:20]3[CH2:22][CH2:21]3)=[CH:18][C:17]([CH:23]3[CH2:25][CH2:24]3)=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:26].C(OCC)(=O)C.[OH-].[Na+]>C(Cl)(Cl)Cl>[ClH:26].[CH:20]1([C:19]2[C:14]([N:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)=[N:15][CH:16]=[C:17]([CH:23]3[CH2:25][CH2:24]3)[CH:18]=2)[CH2:21][CH2:22]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncc(C3CC3)cc2C2CC2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Product: c1nc(N2CCNCC2)c(C2CC2)cc1C1CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 2,3,5-tribromopyridine (10 g), 1-Boc-piperazine (6 g) and potassium carbonate (20 g) was added 2-butanone (80 mL), and the mixture was refluxed for 8 hr. After cooling, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated to give 4-(3,5-dibromopyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (13 g). To a mixture of 4-(3,5-dibromopyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (13 g), bis(tricyclohexylphosphine)palladium (II) dichloride (1.3 g), tripotassium phosphate (38 g) and cyclopropylboronic acid (8.4 g) were added toluene (100 mL) and water (5 mL), and the mixture was refluxed for 8 hr. After cooling, the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated. The residue was purified by column chromatography (hexane:ethyl acetate) to give 4-(3,5-dicyclopropylpyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (7 g). 4-(3,5-Dicyclopropylpyridin-2-yl)piperazine-1-carboxylic acid tert-butyl ester (7 g) was dissolved in chloroform (25 mL), 4N hydrogen chloride/ethyl acetate (25 mL) was added, and the mixture was stirred at room temperature overnight. To the reaction mixture was added 1N aqueous sodium hydroxide solution (100 mL), and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, and the solvent was evaporated. The residue was dissolved in ethyl acetate (50 mL), 4N hydrogen chloride/ethyl acetate (8 mL) was added, and the mixture was filtered to give the title compound (3.2 g).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C@@H:14]([NH2:16])[CH3:15])[N:5]=[C:4]([CH3:17])[C:3]=1[C:18]([O:20][CH2:21][CH3:22])=[O:19].[OH:23][CH2:24][CH2:25][O:26][C:27]1[CH:35]=[CH:34][C:30]([C:31](O)=[O:32])=[CH:29][C:28]=1[O:36][CH3:37]>>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C@@H:14]([NH:16][C:31](=[O:32])[C:30]2[CH:34]=[CH:35][C:27]([O:26][CH2:25][CH2:24][OH:23])=[C:28]([O:36][CH3:37])[CH:29]=2)[CH3:15])[N:5]=[C:4]([CH3:17])[C:3]=1[C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: CCOC(=O)c1c(C)nc2cccc(OC[C@H](C)N)c2c1N
Reactant: COc1cc(C(=O)O)ccc1OCCO
Product: CCOC(=O)c1c(C)nc2cccc(OC[C@H](C)NC(=O)c3ccc(OCCO)c(OC)c3)c2c1N

Procedure:
Prepared as in Example 24a from (S)-ethyl 4-amino-5-(2-aminopropoxy)-2-methylquinoline-3-carboxylate (Example 26b) and 4-(2-hydroxyethoxy)-3-methoxybenzoic acid (Uto, Y. et al. Bioorg. Med. Chem. Lett. 2009, 19, 4151) as a brown solid. MS 498 (MH+).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][O:8][CH2:9][CH:10]1[CH2:14][CH2:13][CH2:12][N:11]1[C:15]1[C:23]([CH3:24])=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=1.[F:25][C:26]1[CH:27]=[CH:28][C:29]([O:36][CH3:37])=[C:30]([C:32](=[N:34]O)[NH2:33])[CH:31]=1.CCN(C(C)C)C(C)C>>[F:25][C:26]1[CH:27]=[CH:28][C:29]([O:36][CH3:37])=[C:30]([C:32]2[N:33]=[C:19]([C:18]3[CH:22]=[C:23]([CH3:24])[C:15]([N:11]4[CH2:12][CH2:13][CH2:14][CH:10]4[CH2:9][O:8][CH3:7])=[N:16][CH:17]=3)[O:21][N:34]=2)[CH:31]=1
Reactant: COc1ccc(F)cc1C(N)=NO
Reactant: COCC1CCCN1c1ncc(C(=O)O)cc1C
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Product: COCC1CCCN1c1ncc(-c2nc(-c3cc(F)ccc3OC)no2)cc1C

Procedure:
Oxalyl chloride (122 μL; 1.44 mmol; 3 eq.), Intermediate 40 (120 mg; 0.48 mmol; 1 eq.), Intermediate 23 (88 mg; 0.48 mmol, 1 eq.) and DIEA (245 μL; 1.44 mmol; 3 eq.) were reacted according to general procedure 2. Purification by column chromatography (c-hexane/ethyl acetate, 50/50) afforded the title compound as a yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:10])[C:5]([NH2:9])=[C:6]([CH3:8])[CH:7]=1.[C:11](O)(=[O:15])[C:12](O)=[O:13]>Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:5]([NH:9][C:11](=[O:15])[C:12](=[O:13])[NH:10]2)=[C:6]([CH3:8])[CH:7]=1
Reactant: Cc1cc(Br)cc(N)c1N
Reactant: O=C(O)C(=O)O
Agent: Cl
Product: Cc1cc(Br)cc2[nH]c(=O)c(=O)[nH]c12

Procedure:
13.05 g (64.9 mmol) of 5-bromo-2,3-diamino-toluene and 6.42 g (1.1 equiv.) of oxalic acid are stirred at reflux for 16 hours in 2N hydrochloric acid. The mixture is cooled and the solid is filtered off and washed with water. The title compound is obtained in the form of a brown solid.
Reaction SMILES: [CH3:1][C:2](=[N:14]O)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]>[Pd].C(O)C>[NH2:14][CH:2]([CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[CH3:1]
Reactant: CCCCCCCCCCCC(C)=NO
Agent: [Pd]
Solvent: CCO
Product: CCCCCCCCCCCC(C)N
Yield: 85.6 %

Procedure:
20 g of 2-tridecanone oxime are reduced in 200 ml of abs. ethanol with 2 g of 5% palladium on charcoal, affording 16 g of 2-aminotridecane. Boiling point: 82°-87° C./0.01.
Reaction SMILES: [C:1]([C:5]1[C:6]([NH2:14])=[N:7][N:8]2[CH:13]=[CH:12][CH:11]=[N:10][C:9]=12)([CH3:4])([CH3:3])[CH3:2].[CH:15]1([CH2:21][C:22](Cl)=[O:23])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1>>[C:1]([C:5]1[C:6]([NH:14][C:22](=[O:23])[CH2:21][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)=[N:7][N:8]2[CH:13]=[CH:12][CH:11]=[N:10][C:9]=12)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)CC1CCCCC1
Reactant: CC(C)(C)c1c(N)nn2cccnc12
Product: CC(C)(C)c1c(NC(=O)CC2CCCCC2)nn2cccnc12

Procedure:
The product from Example 105B and 2-cyclohexylacetyl chloride were processed using the method analogous to that described in Example 105C to afford the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.92-1.03 (m, 2H), 1.11-1.29 (m, 3H), 1.44 (s, 9H), 1.59-1.81 (m, 6H), 2.18 (d, J=6.1 Hz, 2H), 6.99 (dd, J=7.1, 4.1 Hz, 1H), 8.47 (dd, J=4.1, 1.7 Hz, 1H), 8.92 (dd, J=7.1, 1.7 Hz, 1H), 9.64 (s, 1H); MS (DCI) m/z 315 (M+H)+.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:30])[C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([C:20]34[CH2:29][CH:24]5[CH2:25][CH:26]([CH2:28][CH:22]([CH2:23]5)[CH2:21]3)[CH2:27]4)[CH:13]=2)=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[BH4-].[Na+].O>CO>[OH:3][CH:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:30])[C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([C:20]34[CH2:29][CH:24]5[CH2:25][CH:26]([CH2:28][CH:22]([CH2:23]5)[CH2:21]3)[CH2:27]4)[CH:13]=2)=[CH:6][CH:5]=1)[CH3:2]
Reactant: COc1ccc(C(=O)Nc2ccc(C(C)=O)cc2)cc1C12CC3CC(CC(C3)C1)C2
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1ccc(C(=O)Nc2ccc(C(C)O)cc2)cc1C12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Reaction time: 48 h
Yield: 66 %

Procedure:
The amide obtained in Example 23, above, (0.9 g, 2 mmoles) is dissolved in methanol (25 ml) and treated with 0.12 g (3 mmoles) of sodium borohydride. The mixture is stirred at ambient temperature for 2 days, poured into water and extracted with ether. The extracts are dried on magnesium sulfate, then the solvent is evaporated. The resulting residue is recrystallized in ethyl acetate to give N[4-[1-hydroxyethyl)phenyl]-3-(1-adamantyl)-4-methoxy benzamide (0.5 g, 66% yield) having a melting point of 207°-209° C.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[CH3:13][N:14]([CH2:16][CH:17]1[CH2:26][CH2:25][C:24]2[C:19](=[CH:20][CH:21]=[C:22]([OH:27])[CH:23]=2)[CH2:18]1)[CH3:15].[CH3:28][O:29][C:30]1[CH:46]=[CH:45][C:33]([C:34]([O:36][C:37]2[CH:42]=[CH:41][C:40]([CH2:43]O)=[CH:39][CH:38]=2)=[O:35])=[CH:32][CH:31]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[CH3:15][N:14]([CH2:16][CH:17]1[CH2:26][CH2:25][C:24]2[C:19](=[CH:20][CH:21]=[C:22]([O:27][CH2:43][C:40]3[CH:39]=[CH:38][C:37]([O:36][C:34]([C:33]4[CH:32]=[CH:31][C:30]([O:29][CH3:28])=[CH:46][CH:45]=4)=[O:35])=[CH:42][CH:41]=3)[CH:23]=2)[CH2:18]1)[CH3:13]
Reactant: COc1ccc(C(=O)Oc2ccc(CO)cc2)cc1
Reactant: CN(C)CC1CCc2cc(O)ccc2C1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccc(C(=O)Oc2ccc(COc3ccc4c(c3)CCC(CN(C)C)C4)cc2)cc1
Reaction time: 3 h
Yield: 53.8 %

Procedure:
Diethyl azodicarboxylate (40% toluene solution, 950 mg) was added dropwise to THF solution (3 ml) of 2-[(N,N-dimethylamino)methyl]-6-hydroxytetralin (150 mg), 4-(hydroxymethyl)phenyl 4-methoxybenzoate (570 mg) and triphenylphosphine (574 mg) at room temperature, which was stirred for 3 hours. The reaction mixture was concentrated, and the residue was purified using alumina column chromatography (development solvent; hexane˜hexane:ethyl acetate=6:1), and recrystallized (ethyl acetate-hexane) to give the titled compound (175 mg).
Reaction SMILES: [CH2:1]([N:5]([CH2:24][CH2:25][CH2:26][CH3:27])[C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[CH:13][C:14]2[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][CH:15]=2)=[C:8]([O:22][CH3:23])[CH:7]=1)[CH2:2][CH2:3][CH3:4].[C:28]([C:30]1[C:31](=[C:46]([C:49]#[N:50])[C:47]#[N:48])[O:32][C:33]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)([C:36]([F:39])([F:38])[F:37])[C:34]=1[CH3:35])#[N:29]>C(O)C.O1CCCC1>[CH2:24]([N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[CH:13][C:14]2[CH:21]=[CH:20][C:17]([CH:18]=[CH:35][C:34]3[C:33]([C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)([C:36]([F:39])([F:37])[F:38])[O:32][C:31](=[C:46]([C:49]#[N:50])[C:47]#[N:48])[C:30]=3[C:28]#[N:29])=[CH:16][CH:15]=2)=[C:8]([O:22][CH3:23])[CH:7]=1)[CH2:25][CH2:26][CH3:27]
Reactant: CC1=C(C#N)C(=C(C#N)C#N)OC1(c1ccccc1)C(F)(F)F
Reactant: CCCCN(CCCC)c1ccc(C=Cc2ccc(C=O)cc2)c(OC)c1
Solvent: C1CCOC1
Solvent: CCO
Product: CCCCN(CCCC)c1ccc(C=Cc2ccc(C=CC3=C(C#N)C(=C(C#N)C#N)OC3(c3ccccc3)C(F)(F)F)cc2)c(OC)c1
Temperature: 50 °C
Reaction time: 4 h
Yield: 16.3 %

Procedure:
In 15 ml of ethanol and 5 ml of tetrahydrofuran were dissolved 540 mg (1.48 mmol) of 4-[2-(4-dibutylamino-2-methoxyphenyl)vinyl]benzaldehyde and 500 mg (1.59 mmol) of 2-(3-cyano-4-methyl-5-phenyl-5-trifluoromethyl-2(5H)-furanylidene)propanedinitrile. The mixture was stirred at 50° C. for 4 hours. The solvent was evaporated off and the residue was washed with ethanol. The residue was purified by silica gel column chromatography and washed with ethanol to give 160 mg of a black powder (yield: 17.7%; mp: 176-178° C.)
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6](=[O:14])[C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)[CH3:4].[Br:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]Br>CN(C=O)C>[CH2:3]([O:5][C:6](=[O:14])[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][Br:15])=[CH:9][CH:8]=1)[CH3:4]
Reactant: CCOC(=O)c1ccc(O)cc1
Reactant: BrCCCCCCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(OCCCCCCCCCCBr)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 63.7 %

Procedure:
Sodium hydride (1.55 g, 61 mmol) was suspended in DMF (150 mL) under an atmosphere of nitrogen. Ethyl-4-hydroxybenzoate (11) (5.06 g, 30 mmol) was added as a solution in DMF (30 mL) via syringe which was then washed with DMF (2×5 mL). The reaction mixture was then stirred at room temperature under an atmosphere of nitrogen for 2 hours. After this time, 1,10-dibromodecane (30.84 g, 103 mmol) was added as a solution in DMF (50 mL) via syringe which was then washed with DMF (2×5 mL). The reaction mixture was then stirred at room temperature under nitrogen for 19 hours. The reaction was quenched with water (200 mL) and the organic fragments extracted with diethyl ether (4×150 mL), dried over MgSO4, and excess solvent removed in vacuo to form a colorless oil. This was purified by flash column chromatography using CH2Cl2 /hexane (1:1) to CH2Cl2 /hexane (3:1) as eluting solvents to form a white crystalline solid. This was recrystallized from ethanol to form 4-(10-bromo-decyloxy)-benzoic acid ethyl ester (7.38 g, 19.1 mmol, 63%).
Reaction SMILES: [CH3:1][Li].[CH3:3][C:4]([CH3:32])([CH3:31])[CH2:5][C:6]1[N:7]=[C:8]([C:17](=[O:30])[CH2:18][C:19]2[CH:24]=[CH:23][C:22]([N:25]3[CH:29]=[CH:28][CH:27]=[N:26]3)=[CH:21][CH:20]=2)[N:9]([S:11]([N:14]([CH3:16])[CH3:15])(=[O:13])=[O:12])[CH:10]=1>O1CCCC1>[CH3:3][C:4]([CH3:32])([CH3:31])[CH2:5][C:6]1[N:7]=[C:8]([C:17]([OH:30])([CH3:1])[CH2:18][C:19]2[CH:24]=[CH:23][C:22]([N:25]3[CH:29]=[CH:28][CH:27]=[N:26]3)=[CH:21][CH:20]=2)[N:9]([S:11]([N:14]([CH3:16])[CH3:15])(=[O:12])=[O:13])[CH:10]=1
Reactant: [Li]C
Reactant: CN(C)S(=O)(=O)n1cc(CC(C)(C)C)nc1C(=O)Cc1ccc(-n2cccn2)cc1
Solvent: C1CCOC1
Product: CN(C)S(=O)(=O)n1cc(CC(C)(C)C)nc1C(C)(O)Cc1ccc(-n2cccn2)cc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
Methyllithium (1.6 M in diethyl ether) (0.327 mL, 0.524 mmol) was added to a −78° C. solution of 4-(2,2-dimethylpropyl)-N,N-dimethyl-2-{[4-(1H-pyrazol-1-yl)phenyl]acetyl}-1H-imidazole-1-sulfonamide (75 mg, 0.175 mmol) in tetrahydrofuran (2 mL). After stirring at −78° C. for 30 min, the reaction mixture was quenched with saturated aqueous ammonium chloride and extracted with methylene chloride. The combined organic extracts were dried (sodium sulfate) and concentrated in vacuo. Chromatography over silica eluting with 0-50% EtOAc/hexane afforded 4-(2,2-dimethylpropyl)-2-{1-hydroxy-1-methyl-2-[4-(1H-pyrazol-1-yl)phenyl]ethyl}-N,N-dimethyl-1H-imidazole-1-sulfonamide.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]23[O:15][C@@:12]([CH2:16][OH:17])([CH2:13][O:14]2)[C@@H:11]([OH:18])[C@H:10]([OH:19])[C@H:9]3[OH:20])=[CH:4][C:3]=1[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH3:30])=[CH:24][CH:23]=1.CO[CH:33](OC)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[Na]>C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]23[O:15][C@@:12]4([CH2:16][O:17][CH:33]([C:34]5[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=5)[O:18][C@H:11]4[C@H:10]([OH:19])[C@H:9]2[OH:20])[CH2:13][O:14]3)=[CH:4][C:3]=1[CH2:21][C:22]1[CH:23]=[CH:24][C:25]([O:28][CH2:29][CH3:30])=[CH:26][CH:27]=1
Reactant: CCOc1ccc(Cc2cc([C@]34OC[C@](CO)(O3)[C@@H](O)[C@H](O)[C@H]4O)ccc2Cl)cc1
Reactant: COC(OC)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na]
Solvent: CC#N
Solvent: O
Product: CCOc1ccc(Cc2cc([C@@]34OC[C@]5(COC(c6ccccc6)O[C@H]5[C@H](O)[C@H]3O)O4)ccc2Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99.8 %

Procedure:
To a solution of (1S,2S,3S,4R,5S)-5-(4-chloro-3-(4-ethoxybenzyl)phenyl)-1-(hydroxymethyl)-6,8-dioxabicyclo[3.2.1]octane-2,3,4-triol 28a (11.93 g, 27.3 mmol, purchased from Shanghai Caerulum Pharma Discovery Co., Ltd) in acetonitrile (40 mL) were added benzaldehyde dimethyl acetal (12.3 mL, 81.9 mmol) and p-toluenesulfonic acid monohydrate (4.7 g, 27.3 mmol) at room temperature. The mixture was stirred at room temperature for 30 min and adjusted with saturated aqueous sodium bicarnonate till pH becomes 7. The resulting mixture was extracted with ethyl actate (50 mL×2). The combined organic phases were washed with saturated aqueous sodium chloride (30 mL×2), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was purified by silica gel chromatography eluted with PE/EtOAc(v/v)=5/1 to give the title compound 28b as a white solid (14.3 g, 100%).
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([N:8]2[CH2:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[CH2:11][C:10]3[CH:19]=[CH:20][CH:21]=[CH:22][C:9]2=3)=[O:7])=[CH:4][CH:3]=1.Cl.[C:26](Cl)(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[N:29][CH:28]=1.C(N(CC)CC)C>CN(C)C1C=CN=CC=1.ClCCl>[CH:19]1[C:10]2[CH2:11][C:12]3[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=3[CH2:14][N:8]([C:6]([C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:26]([C:27]4[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=4)=[O:33])=[CH:24][CH:23]=3)=[O:7])[C:9]=2[CH:22]=[CH:21][CH:20]=1
Reactant: O=C(Cl)c1cccnc1
Reactant: Nc1ccc(C(=O)N2Cc3ccccc3Cc3ccccc32)cc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(C(=O)N2Cc3ccccc3Cc3ccccc32)cc1)c1cccnc1
Yield: 14.3 %

Procedure:
A mixture of 0.628 g (2 mmol) of 5-(4-aminobenzoyl)-6,11-dihydro-5H-dibenz[b,e]azepine, 0.551 g (3 mmol) of nicotinoyl chloride, hydrochloride, 0.606 g (6 mmol) of triethylamine and 15 mg of 4-(dimethylamino)pyridine in 17 ml of dichloromethane is refluxed for 7 hours. The mixture is washed with H2O, 2N citric acid, H2O, 1N NaHCO3, brine and dried (Na2SO4). The solvent is removed and the solid recrystallized from hexane-dichloromethane to give 0.12 g of crystals,. m.p. 217°-220° C. Anal Calc'd for C27H21N3O2H2O: C,74.1; H,5.3; N,9.6. Found: 73.6; H,4.7; N,9.8.
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][CH:26]([CH3:28])[CH3:27])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([S:38][CH2:39][C:40]5[N:41]([CH3:45])[CH:42]=[CH:43][N:44]=5)=[C:34]([CH3:46])[CH:33]=4)=[O:30])=[CH:20][C:19]=3[CH:47]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:56])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[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][CH:26]([CH3:27])[CH3:28])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([S:38]([CH2:39][C:40]5[N:41]([CH3:45])[CH:42]=[CH:43][N:44]=5)=[O:56])=[C:34]([CH3:46])[CH:33]=4)=[O:30])=[CH:20][C:19]=3[CH:47]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(SCc4nccn4C)c(C)c2)CCN3CC(C)C)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)Cc4nccn4C)c(C)c2)CCN3CC(C)C)cc1
Reaction time: 1 h
Yield: 50.8 %

Procedure:
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[3-methyl-4-[[(1-methylimidazol-2-yl)methyl]sulfanyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (200 mg) in dichloromethane (10 ml) was added dropwise 70% solution of 3-chloroperbenzoic acid (113 mg) in dichloromethane (10 ml) at −78° C. After finishing the dropping, the mixture was stirred for 1 hour at −10° C. to −25° C. To the mixture was added an aqueous solution of sodium thiosulfate, and the mixture was allowed to be at room temperature, stirred for 30 minutes, and extracted with ethyl acetate. The organic layer was washed with an aqueous solution of saturated sodium bicarbonate, and saturated brine, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure. The obtained residue was separated and purified by silica gel column chromatography (ethyl acetate→methanol:ethyl acetate=1:8), and was recrystallized from hexane-ethyl acetate to give 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[3-methyl-4-[[(1-methylimidazol-2-yl)methyl]sulfinyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (104 mg) (Compound 356) as yellow crystals, and was recrystallized from hexane-ethyl acetate to give 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[3-methyl-4-[[(1-methylimidazol-2-yl)methyl]sulfonyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (10 mg) (Compound 357) as yellow crystals.
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[C:11]([NH:13][C:14]2[CH:23]=[CH:22][C:17]([C:18]([O:20]C)=[O:19])=[CH:16][CH:15]=2)[C:10]([C:24](=[O:32])[NH:25][C:26]2[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=2)=[CH:9][N:8]=1)=[O:5])[CH3:2].O.[OH-].[Na+].Cl>C(#N)C>[CH2:1]([NH:3][C:4](=[O:5])[NH:6][C:7]1[CH:12]=[C:11]([NH:13][C:14]2[CH:15]=[CH:16][C:17]([C:18]([OH:20])=[O:19])=[CH:22][CH:23]=2)[C:10]([C:24](=[O:32])[NH:25][C:26]2[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=2)=[CH:9][N:8]=1)[CH3:2]
Reactant: CCNC(=O)Nc1cc(Nc2ccc(C(=O)OC)cc2)c(C(=O)Nc2cccnc2)cn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Product: CCNC(=O)Nc1cc(Nc2ccc(C(=O)O)cc2)c(C(=O)Nc2cccnc2)cn1
Temperature: 40 °C

Procedure:
Methyl 4-[[2-(ethylcarbamoylamino)-5-(3-pyridylcarbamoyl)-4-pyridyl]amino]benzoate (35 mg, 0.07 mmol) was suspended in acetonitrile (3 mL) and water (3 mL) and treated with NaOH (1 mL, 1 M). The mixture was heated to 40° C. for 40 minutes. The mixture was adjusted to pH ˜6 by addition of dilute aqueous HCl. The mixture was then freeze-dried. The crude product was dissolved in DMSO/water and purified by reverse phase chromatography (12 g Reveleris C18 cartridge, eluting with 0-100% acetonitrile in 0.1% aqueous formic acid). Compound 16 was isolated as a white solid (23 mg, 68%). 1H NMR (400 MHz, DMSO-d6): δ 10.53 (s, 1H), 10.04 (s, 1H), 9.24 (s, 1H), 8.86 (d, J=2.1 Hz, 1H), 8.64 (s, 1H), 8.32 (dd, J=4.7, 1.5 Hz, 1H), 8.12 (ddd, J=8.4, 2.5, 1.5 Hz, 1H), 7.93 (d. J=8.7 Hz, 2H), 7.87 (s, 1H), 7.51 (s, 1H), 7.40 (ddd, J=8.4, 4.7, 0.6 Hz, 1H), 7.36 (d. J=8.8 Hz, 2H), 3.20-3.12 (m, 2H), 1.07 (t, J=7.2 Hz, 3H). [M+H]+ m/z=421.14.
Reaction SMILES: [H-].[Na+].[C:3]([O:12][CH:13]([CH3:15])[CH3:14])(=[O:11])[CH2:4][C:5]([O:7][CH:8]([CH3:10])[CH3:9])=[O:6].[C:16]1([CH2:32]C2C=C(C)C=CC=2S([O-])(=O)=O)([CH2:20]C2C=C(C)C=CC=2S([O-])(=O)=O)[CH2:19][CH2:18][CH2:17]1>CN(C=O)C>[CH2:20]1[C:16]2([CH2:19][CH2:18][CH2:17]2)[CH2:32][C:4]1([C:5]([O:7][CH:8]([CH3:9])[CH3:10])=[O:6])[C:3]([O:12][CH:13]([CH3:15])[CH3:14])=[O:11]
Reactant: CC(C)OC(=O)CC(=O)OC(C)C
Reactant: Cc1ccc(S(=O)(=O)[O-])c(CC2(Cc3cc(C)ccc3S(=O)(=O)[O-])CCC2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)OC(=O)C1(C(=O)OC(C)C)CC2(CCC2)C1
Temperature: 140 °C
Yield: 138.2 %

Procedure:
A suspension of NaH (60% in mineral oil, 1.394 g, 34.9 mmol) in DMF (35 mL) was treated drop-wise with diisopropyl malonate (5.30 mL, 27.9 mmol) followed by cyclobutane-1,1-diylbis(methylene)bis(4-methylbenzenesulfonate) (5.92 g, 13.94 mmol) and KI (0.231 g, 1.394 mmol) and heated at 140° C. overnight. The mixture was cooled to RT, poured on satd. NH4Cl, extracted with hexane (2×) and the combined organics were washed with H2O, dried over MgSO4 and concentrated to dryness to afford crude diisopropyl spiro[3.3]heptane-2,2-dicarboxylate (5.17 g, 138%) which was carried on without purification.
Reaction SMILES: F[C:2]1[CH:16]=[CH:15][C:5]([C:6]([C:8]2[CH:13]=[C:12]([CH3:14])[CH:11]=[CH:10][N:9]=2)=[O:7])=[C:4]([C:17]([F:20])([F:19])[F:18])[CH:3]=1.[N-:21]=[N+]=[N-].[Na+].O>CS(C)=O>[NH2:21][C:2]1[CH:16]=[CH:15][C:5]([CH:6]([C:8]2[CH:13]=[C:12]([CH3:14])[CH:11]=[CH:10][N:9]=2)[OH:7])=[C:4]([C:17]([F:20])([F:19])[F:18])[CH:3]=1
Reactant: Cc1ccnc(C(=O)c2ccc(F)cc2C(F)(F)F)c1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: Cc1ccnc(C(O)c2ccc(N)cc2C(F)(F)F)c1
Temperature: 90 °C
Reaction time: 8 h
Yield: 80.3 %

Procedure:
2-(4-fluoro-2-trifluoromethylbenzoyl)-4-methylpyridine (4.5 g) and sodium azide (1.3 g) were suspended in dimethylsulfoxide (30 ml), and the mixture was heated with stirring overnight under nitrogen atmosphere at 90° C. The mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and then, the solvent was evaporated. The residue was dissolved in tetrahydrofuran (30 ml), and to the solution was added aluminum lithium hydride (1.2 g) under ice-cooling, and the mixture was stirred for 1 hour under nitrogen atmosphere under ice-cooling. Water (1.2 ml), 15% aqueous solution of sodium hydroxide (1.2 ml) and water (3.6 ml) were added to the mixture, and the mixture was stirred, dried over anhydrous magnesium sulfate, and filtrated. The solvent of the filtrate was distilled off, to give (4-amino-2-trifluoromethylphenyl)(4-methylpyridin-2-yl)methanol (3.6 g) as colorless crystals.