Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:32](Cl)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl.Cl.[N:40]1([CH2:46][CH2:47][NH:48][S:49]([CH3:52])(=[O:51])=[O:50])[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:43]3[CH2:44][CH2:45][N:40]([CH2:46][CH2:47][NH:48][S:49]([CH3:52])(=[O:50])=[O:51])[CH2:41][CH2:42]3)=[O:33])[C@@:13]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)([CH3:24])[C@@:14]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH2:36][CH3:37])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOc1cc(C(C)(C)C)ccc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: CS(=O)(=O)NCCN1CCNCC1
Agent: Cl
Product: CCOc1cc(C(C)(C)C)ccc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CCNS(C)(=O)=O)CC1

Procedure:
In a manner analogous to the method described in example 5, (4S,5R)-2-(4-tert-butyl-2-ethoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride (example 4) was reacted with N-(2-piperazin-1-yl-ethyl)-methanesulfonamide dihydrochloride (prepared as described in Fotouhi, N. et al. WO 2005110996) to give the title compound. HR-MS (ES, m/z) calculated for C37H48N5O4SCl2 [(M+H)+] 782.2799, observed 782.2787.
Reaction SMILES: [Mg].Cl[Si:3]([O:10][CH2:11][CH3:12])([O:7][CH2:8][CH3:9])[O:4][CH2:5][CH3:6].Br[C:14]1[C:27]2[S:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[S:19][C:18]=2[CH:17]=[CH:16][CH:15]=1>C1COCC1>[CH2:5]([O:4][Si:3]([O:10][CH2:11][CH3:12])([O:7][CH2:8][CH3:9])[C:16]1[CH:15]=[CH:14][C:27]2[S:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[S:19][C:18]=2[CH:17]=1)[CH3:6]
Reactant: CCO[Si](Cl)(OCC)OCC
Reactant: Brc1cccc2c1Sc1ccccc1S2
Agent: [Mg]
Solvent: C1CCOC1
Product: CCO[Si](OCC)(OCC)c1ccc2c(c1)Sc1ccccc1S2
Yield: 66.9 %

Procedure:
A 3-neck 3 L flask was filled with magnesium turnings (35 g), THF (600 g) and chlorotriethoxysilane (278 g), and heated to reflux. Bromothianthrene solution from Example 4A was added to the flask in small portions. Grignard started instantly. The reaction was allowed to cool for 1 hour, after which magnesium salts were precipitated with heptanes (500 mL). The solution was filtered, followed by evaporation of volatiles by rotary evaporator. The material was distilled twice at <1 mbar, giving colorless 2-(triethoxysilyl)thianthrene (bp. 175 . . . 200° C., 234.2 g, 66.9% overall yield based on thianthrene, purity 99.5% by GC/MS) and bis(triethoxysilyl)thianthrene (bp. 200 . . . 225° C., 26.7 g, purity 94.6% by GC/MS, a mixture of 2,7- and 2,8-isomers, yield 5.3% by GC/MS).
Reaction SMILES: [F:1][C:2]([F:40])([F:39])[C:3]1[CH:4]=[C:5]([CH:32]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:34]=1)[C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16]OS(C)(=O)=O)[CH2:10][C@H:9]1[CH2:22][C:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[NH:25][CH:24]=1)=[O:7].[C:41]1([CH:47]2[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]2)[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>C(#N)C>[F:1][C:2]([F:40])([F:39])[C:3]1[CH:4]=[C:5]([CH:32]=[C:33]([C:35]([F:37])([F:36])[F:38])[CH:34]=1)[C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][N:50]2[CH2:51][CH2:52][CH:47]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[CH2:48][CH2:49]2)[CH2:10][C@H:9]1[CH2:22][C:23]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[NH:25][CH:24]=1)=[O:7]
Reactant: c1ccc(C2CCNCC2)cc1
Reactant: CS(=O)(=O)OCCCN1CCN(C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H](Cc2c[nH]c3ccccc23)C1
Solvent: CC#N
Product: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCN(CCCN2CCC(c3ccccc3)CC2)C[C@H]1Cc1c[nH]c2ccccc12
Yield: 81.1 %

Procedure:
A mixture of (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(1H-indol-3-ylmethyl)-4-(3-methylsulfonyloxypropyl)piperazine (100 mg) and 4-phenylpiperidine (60 mg) in acetonitrile (3 ml) was refluxed for 2 hours. The reaction mixture was concentrated under reduced pressure and the resulting residue was purified by column chromatography on silica gel using ethyl acetate-methanol (5:1) as an eluent to give (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(1H-indol-3-ylmethyl)-4-[3-(4-phenylpiperidino)propyl]piperazine (90 mg).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[C:4](O)([C:20]([F:23])([F:22])[F:21])[C:5]1[C:9](=[O:10])[N:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=2)[NH:7][C:6]=1[CH3:19].S(Cl)(Cl)=O>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:25])[C:4](=[C:5]1[C:9](=[O:10])[N:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=2)[N:7]=[C:6]1[CH3:19])[C:20]([F:23])([F:21])[F:22]
Reactant: COC(=O)C(O)(c1c(C)[nH]n(-c2cccc(OC)c2)c1=O)C(F)(F)F
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: COC(=O)C(=C1C(=O)N(c2cccc(OC)c2)N=C1C)C(F)(F)F

Procedure:
To a toluene solution (5 ml) of 2,5-dihydro-α-hydroxy-1-(3-methoxyphenyl)-3-methyl-5-oxo-α-trifluoromethyl-1H-pyrazole-4-acetic acid methyl ester (180 mg, 0.5 mmol), thionyl chloride (0.365 ml, 5.0 mmol) was added and the mixture was stirred under reflux for 3 hours. After concentrating the liquid reaction mixture under reduced pressure, the title compound was obtained as a reddish brown solid (171 mg).
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[N:4]=[C:3]1[CH2:11][O:12][C:13]1[CH:45]=[CH:44][C:16]([CH2:17][CH:18]2[S:22][C:21](=[O:23])[N:20](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[C:19]2=[O:43])=[CH:15][CH:14]=1>[Pd].CO>[CH3:1][N:2]1[C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[N:4]=[C:3]1[CH2:11][O:12][C:13]1[CH:14]=[CH:15][C:16]([CH2:17][CH:18]2[S:22][C:21](=[O:23])[NH:20][C:19]2=[O:43])=[CH:44][CH:45]=1
Reactant: Cn1c(COc2ccc(CC3SC(=O)N(C(c4ccccc4)(c4ccccc4)c4ccccc4)C3=O)cc2)nc2cccnc21
Agent: [Pd]
Solvent: CO
Product: Cn1c(COc2ccc(CC3SC(=O)NC3=O)cc2)nc2cccnc21
Yield: 25.5 %

Procedure:
A procedure similar to that described in Example 6 was repeated, except that 500 mg of 5-[4-(3-methyl-3H-imidazo[4,5-b]pyridin-2-ylmethoxy)benzyl]-3-triphenylmethylthiazolidine-2,4-dione (prepared as described in Preparation 16), 1 g of 10% w/w palladium-on-charcoal and 100 ml of methanol were used, to give 77 mg of the title compound, melting at 223-225° C.
Reaction SMILES: C(N1CCC(C(O)C)C(C2C=CC(Cl)=CC=2)C1)C1C=CC=CC=1.[CH2:24]([N:31]1[CH2:36][CH2:35][C@H:34]([C:37](=[O:39])[CH3:38])[C@@H:33]([C:40]2[CH:45]=[CH:44][C:43]([F:46])=[C:42]([F:47])[CH:41]=2)[CH2:32]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>>[CH2:24]([N:31]1[CH2:36][CH2:35][C@H:34]([C@@H:37]([OH:39])[CH3:38])[C@@H:33]([C:40]2[CH:45]=[CH:44][C:43]([F:46])=[C:42]([F:47])[CH:41]=2)[CH2:32]1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CC(=O)[C@H]1CCN(Cc2ccccc2)C[C@@H]1c1ccc(F)c(F)c1
Agent: CC(O)C1CCN(Cc2ccccc2)CC1c1ccc(Cl)cc1
Agent: [Al+3]
Agent: [H-]
Product: C[C@H](O)[C@H]1CCN(Cc2ccccc2)C[C@@H]1c1ccc(F)c(F)c1

Procedure:
In analogy to the procedure described for the synthesis of (RS)-1-[(3SR,4SR)-1-Benzyl-3-(4-chloro-phenyl)-piperidin-4-yl]-ethanol (example 5 (d)) the title compounds were synthesized from 1-[(3S,4S)-1-Benzyl-3-(3,4-difluoro-phenyl)-piperidin-4-yl]-ethanone through reduction with LiAlH4. (S)-1-[(3S,4S)-1-Benzyl-3-(3,4-difluoro-phenyl)-piperidin-4-yl]-ethanol was obtained as light yellow waxy solid. MS (m/e): 332.1 [(M+H)+] and (R)-1-[(3S,4S)-1-Benzyl-3-(3,4-difluoro-phenyl)-piperidin-4-yl]-ethanol was obtained as light yellow viscous oil. MS (m/e): 332.1 [(M+H)+].
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=O)[CH3:10])=[C:4]([C:12]([F:15])([F:14])[F:13])[CH:3]=1.C(Cl)Cl.[N-:19]=[N+:20]=[N-:21].[Na+].FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O>C(#N)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:9]([CH3:10])=[N:21][N:20]=[N:19]2)=[C:4]([C:12]([F:15])([F:14])[F:13])[CH:3]=1
Reactant: [N-]=[N+]=[N-]
Reactant: CC(=O)Nc1ccc(Br)cc1C(F)(F)F
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: [Na+]
Solvent: ClCCl
Solvent: CC#N
Product: Cc1nnnn1-c1ccc(Br)cc1C(F)(F)F
Temperature: 0 °C
Reaction time: 8 h
Yield: 70.5 %

Procedure:
A suspension of N-(4-bromo-2-trifluoromethyl-phenyl)-acetamide (2.41 g, 8.54 mmol) in acetonitrile (40 mL) was treated with methylene chloride (5 mL) to obtain a clear solution at 25° C. The resulting solution was treated with sodium azide (1.24 g, 19.1 mmol), and the reaction mixture was then cooled to 0° C. The reaction mixture was then treated with trifluoromethanesulfonic anhydride (3.59 g, 12.7 mmol). The resulting reaction mixture was allowed to warm to 25° C. where it was stirred overnight, at which time, thin layer chromatography analysis of the reaction mixture indicated the absence of starting material. The reaction mixture was then concentrated in vacuo. The resulting residue was diluted with ethyl acetate (50 mL) and water (50 mL). The two layers were separated, and the aqueous layer was extracted with ethyl acetate (1×30 mL). The combined organic extracts were washed with a saturated aqueous sodium chloride solution (1×100 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40M, Silica, 2/1 hexanes/ethyl acetate) afforded 1-(4-bromo-2-trifluoromethyl-phenyl)-5-methyl-1H-tetrazole (1.85 g, 70%) as a white solid: EI-HRMS m/e calcd for C9H6BrF3N4 (M+) 305.9728, found 305.9733.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([CH2:9][CH2:10][C:11]2[NH:20][C:14]3=[N:15][CH:16]=[C:17](I)[CH:18]=[C:13]3[N:12]=2)[CH:4]=1.[OH:21][C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+].[Cl-].[Li+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([CH2:9][CH2:10][C:11]2[NH:20][C:14]3=[N:15][CH:16]=[C:17]([C:25]4[CH:26]=[CH:27][C:22]([OH:21])=[CH:23][CH:24]=4)[CH:18]=[C:13]3[N:12]=2)[CH:4]=1
Reactant: OB(O)c1ccc(O)cc1
Reactant: COc1ccnc(CCc2nc3cc(I)cnc3[nH]2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccnc(CCc2nc3cc(-c4ccc(O)cc4)cnc3[nH]2)c1
Yield: 43.3 %

Procedure:
0.76 g of 2-[2-(4-methoxypyridin-2-yl)ethyl]-6-iodo-3H-imidazo[4,5-b]pyridine (example 7) and 0.55 g of 4-hydroxyphenylboronic acid are dissolved in 30 ml of degassed dioxane. Then a solution of 0.55 g of potassium carbonate and 0.17 g of lithium chloride in 26 ml of degassed water and 0.23 g of tetrakis(triphenylphosphine)palladium(0) are added. The mixture is heated to reflux under N2 for 56 hours and, after cooling, addition of water and adjusting the pH to 7, it is extracted three times with dichloromethane. The combined organic phases are dried over sodium sulfate, concentrated and the residue is chromatographed on a silica gel column (dichloromethane/methanol 30–10:1). Concentration of the chromatographically pure fractions gives 0.30 g of the title compound as a solid of m.p. 206–208° C. The mass spectrum shows the molecular peaks MH+ and 2MNa+ at 347.3 and 714.9 Da.
Reaction SMILES: C([N:9]1[CH2:15][CH2:14][CH2:13][CH2:12][CH:11]([Cl:16])[C:10]1=[O:17])(=O)C1C=CC=CC=1.C.[C:19]1(=[O:26])[NH:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>C1C=CC(Cl)=C(Cl)C=1>[Cl:16][CH:11]1[CH2:12][CH2:13][CH2:14][CH2:15][NH:9][C:10]1=[O:17].[C:19]1(=[O:26])[NH:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: O=C(c1ccccc1)N1CCCCC(Cl)C1=O
Agent: O=C1CCCCCN1
Solvent: Clc1ccccc1Cl
Product: O=C1NCCCCC1Cl

Procedure:
The ODCB solution of N-benzoyl-α-chloro-ε-caprolactam is passed through a charcoal bed to remove tars as impurities. It is then passed into another reaction vessel where 9718 parts (86 mols) of ε-caprolactam are added. The transamidation is conducted by heating and stirring the ODCB solution at 140° C. for 2 hours. The solution is then cooled to 5° C. for 1 hour whereupon 21,000 parts (82 mols) N-benzoyl-α-chloro-ε-caprolactam precipitates out of the solution. The N-benzoyl-α-chloro-ε-caprolactam is filtered off and saved for recycle. The ODCB solution is then extracted with 250,000 parts 8 weight percent aqueous hydrochloric acid to remove α-chloro-ε-caprolactam and residual ε-caprolactam. The aqueous hydrochloric acid is then extracted countercurrently with 250,000 parts chloroform, and the chloroform extract evaporated to yield 10,915 parts (74 mols) of α-chloro-ε-caprolactam and 1356 parts (12 mols) of ε-caprolactam. The ε-caprolactam is separated from the α-chloro-ε-caprolactam by fractional distillation under vacuum and recycled to the transamidation step.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([NH:11][C:12](=[O:15])[CH:13]=[CH2:14])([CH3:10])[CH3:9])=[CH:4][CH:3]=1.[NH:16]1[CH:20]=[C:19]([CH:21]=[O:22])[N:18]=[CH:17]1.[OH-].C([N+](C)(C)C)C1C=CC=CC=1.O1CCOCC1>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([NH:11][C:12](=[O:15])[CH2:13][CH2:14][N:16]2[CH:20]=[C:19]([CH:21]=[O:22])[N:18]=[CH:17]2)([CH3:10])[CH3:9])=[CH:6][CH:7]=1
Reactant: C=CC(=O)NC(C)(C)c1ccc(Cl)cc1
Reactant: O=Cc1c[nH]cn1
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [OH-]
Solvent: CO
Solvent: C1COCCO1
Product: CC(C)(NC(=O)CCn1cnc(C=O)c1)c1ccc(Cl)cc1
Temperature: 95 °C

Procedure:
A mixture of N-[1-(4-chlorophenyl)-1-methylethyl]acrylamide (22.35 g), imidazole-4-carboxaldehyde (9.6 g), benzyltrimethylammonium hydroxide (2.24 ml of a 40% solution in methanol, Triton®B) and 1,4-dioxane (112 ml) was stirred and heated at 95° C. for 6 hours and then worked up as described in Example 19a to give N-[1-(4-chlorophenyl)-1-methylethyl]-3-(4-formylimidazol-1-yl) propionamide, m.p. 151-1530° C.
Reaction SMILES: [N:1]1([C:7]([N:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)[CH2:12][CH:11]([C:25](O)=[O:26])[CH2:10]2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.O[N:29]=[C:30]([C:32]1[CH:33]=[N:34][CH:35]=[CH:36][C:37]=1[CH3:38])[NH2:31]>>[CH3:38][C:37]1[CH:36]=[CH:35][N:34]=[CH:33][C:32]=1[C:30]1[N:31]=[C:25]([CH:11]2[CH2:12][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:23])([F:22])[F:24])=[CH:17][CH:16]=3)[CH2:14][N:9]([C:7]([N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)=[O:8])[CH2:10]2)[O:26][N:29]=1
Reactant: Cc1ccncc1C(N)=NO
Reactant: O=C(O)C1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)N2CCOCC2)C1
Product: Cc1ccncc1-c1noc(C2CC(c3ccc(C(F)(F)F)cc3)CN(C(=O)N3CCOCC3)C2)n1

Procedure:
250 mg (about 0.520 mmol) of the compound from Example 49A and 87 mg (0.580 mmol) of N′-hydroxy-4-methylpyridine-3-carboximidamide (Example 70A) were reacted according to the General Method 1. Yield: 22 mg (8% of theory).
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:33]=[N:34][C:35]([S:38][CH2:39][C:40]5[CH:45]=[CH:44][CH:43]=[CH:42][N:41]=5)=[CH:36][CH:37]=4)=[O:30])=[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+]>C(Cl)Cl>[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][CH:26]([CH3:27])[CH3:28])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:33]=[N:34][C:35]([S:38]([CH2:39][C:40]5[CH:45]=[CH:44][CH:43]=[CH:42][N:41]=5)=[O:55])=[CH:36][CH:37]=4)=[O:30])=[CH:20][C:19]=3[CH:46]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(SCc4ccccn4)nc2)CCN3CC(C)C)cc1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(S(=O)Cc4ccccn4)nc2)CCN3CC(C)C)cc1
Reaction time: 0.25 h
Yield: 53.7 %

Procedure:
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[6-[(2-pyridinylmethyl)sulfanyl]-3-pyridinyl]-2,3-dihydro-1-benzazepine-4-carboxamide (0.50 g) in methylene chloride (15 ml) was added dropwise a solution of m-chloroperbenzoic acid (0.16 g) in methylene chloride (10 ml) at −78° C., and the mixture was stirred for 15 minutes. To the reaction mixture was added an aqueous solution of saturated sodium thiosulfate. The mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by silica gel column chromatography, to give 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[6-[(2-pyridinylmethyl)sulfinyl]-3-pyridinyl]-2,3-dihydro-1-benzazepine-4-carboxamide (Compound 268) (275 mg).
Reaction SMILES: [OH-:1].[Na+].OO.[C:5]([C:7]1([NH:27][C:28](=O)[CH3:29])[CH2:12][CH2:11][CH:10]([NH:13][S:14]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH3:25])=[C:19]([CH3:26])[CH:18]=2)(=[O:16])=[O:15])[CH2:9][CH2:8]1)#[N:6]>C(O)C.O>[CH2:24]([O:23][C:20]1[CH:21]=[CH:22][C:17]([S:14]([NH:13][CH:10]2[CH2:9][CH2:8][C:7]3([N:27]=[C:28]([CH3:29])[NH:6][C:5]3=[O:1])[CH2:12][CH2:11]2)(=[O:15])=[O:16])=[CH:18][C:19]=1[CH3:26])[CH3:25]
Reactant: CCOc1ccc(S(=O)(=O)NC2CCC(C#N)(NC(C)=O)CC2)cc1C
Reactant: [OH-]
Agent: OO
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOc1ccc(S(=O)(=O)NC2CCC3(CC2)N=C(C)NC3=O)cc1C
Temperature: 80 °C
Yield: 48.3 %

Procedure:
5N Sodium hydroxide (320 ul, 1.59 mmol) followed by 50% aqueous hydrogen peroxide (157 ul, 2.55 mmol) were added to solution of N-(1-cyano-4-(4-ethoxy-3-methylphenylsulfonamido)cyclohexyl)acetamide (Intermediate 126, 242 mg, 0.638 mmol) in ethanol (6.4 ml). The reaction was heated to 80° C. for three hours. LCMS indicated approximately 3:1 product:starting material by co-injection. The reaction was diluted with water and extract with four volumes ethyl acetate. The combined organics were dried over sodium sulfate, filtered and concentrate to 226 mg crude. TLC (10% methanol in ethyl acetate): Rf starting material 0.66; major spot Rf=0.25. The crude was chromatographed on Biotage 12M eluting 0-100% ethyl acetate in (10% methanol in ethyl acetate) to give the product as an off-white solid (117 mg, 0.308 mmol). LCMS [M+H]=380.2.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[C:5]([O:7][CH3:8])=[O:6].Cl[C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][N:16]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[CH3:13][O:12][C:11]1[CH:10]=[CH:9][C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:3][C:2]=1[O:1][C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][N:16]=1
Reactant: COC(=O)c1ccc(OC)c(O)c1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(OC)c(Oc2ccc([N+](=O)[O-])cn2)c1
Temperature: 60 °C
Reaction time: 14 h
Yield: 119.8 %

Procedure:
To a solution of methyl 3-hydroxy-4-methoxybenzoate (4.87 g, 26.7 mmol) and 2-chloro-5-nitropyridine (4.24 g, 26.7 mmol) in N,N-dimethylformamide (100 mL) was added potassium carbonate (8.13 g, 58.8 mmol), and the mixture was stirred at 60° C. for 14 hr. The reaction solution was cooled to room temperature, diluted with water, and extracted with a mixed solvent (1:1, 100 mL) of ethyl acetate and hexane. The combined organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure to give the title compound (9.73 g) as an orange syrup substance.
Reaction SMILES: [CH2:1]1[O:12][C:11]2[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][NH2:8])=[CH:4][C:3]=2[O:2]1.Cl[C:14]1[C:15]2[CH:28]=[C:27]([CH3:29])[S:26][C:16]=2[N:17]=[C:18]([C:20]2[CH:25]=[N:24][CH:23]=[CH:22][N:21]=2)[N:19]=1>>[N:21]1[CH:22]=[CH:23][N:24]=[CH:25][C:20]=1[C:18]1[N:19]=[C:14]([NH:8][CH2:7][CH2:6][C:5]2[CH:9]=[CH:10][C:11]3[O:12][CH2:1][O:2][C:3]=3[CH:4]=2)[C:15]2[CH:28]=[C:27]([CH3:29])[S:26][C:16]=2[N:17]=1
Reactant: Cc1cc2c(Cl)nc(-c3cnccn3)nc2s1
Reactant: NCCc1ccc2c(c1)OCO2
Product: Cc1cc2c(NCCc3ccc4c(c3)OCO4)nc(-c3cnccn3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of 3,4-methylenedioxyphenethylamine with 4-chloro-2-(pyrazin-2-yl)-6-methyl-thieno-[2,3-d]-pyrimidine yields 2-(pyrazin-2-yl)-4-(3,4-methylenedioxyphenethylamino)-6-methyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [C:1]([CH2:6][CH2:7][N:8]([CH3:28])[CH2:9][C@H:10]1[O:14][C@@H:13]([N:15]2[C:24]3[N:23]=[CH:22][N:21]=[C:19]([NH2:20])[C:18]=3[N:17]=[C:16]2[CH3:25])[C@H:12]([OH:26])[C@@H:11]1[OH:27])([O:3][CH2:4][CH3:5])=[O:2].[CH3:29]NC[C@H]1O[C@@H](N2C3N=CN=C(N)C=3N=C2CC)[C@H](O)[C@@H]1O.ClCCC(OCC)=O.CCN(C(C)C)C(C)C>CN(C=O)C>[C:1]([CH2:6][CH2:7][N:8]([CH3:28])[CH2:9][C@H:10]1[O:14][C@@H:13]([N:15]2[C:24]3[N:23]=[CH:22][N:21]=[C:19]([NH2:20])[C:18]=3[N:17]=[C:16]2[CH2:25][CH3:29])[C@H:12]([OH:26])[C@@H:11]1[OH:27])([O:3][CH2:4][CH3:5])=[O:2]
Reactant: CCOC(=O)CCN(C)C[C@H]1O[C@@H](n2c(C)nc3c(N)ncnc32)[C@H](O)[C@@H]1O
Reactant: CCc1nc2c(N)ncnc2n1[C@@H]1O[C@H](CNC)[C@@H](O)[C@H]1O
Agent: CCOC(=O)CCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)CCN(C)C[C@H]1O[C@@H](n2c(CC)nc3c(N)ncnc32)[C@H](O)[C@@H]1O

Procedure:
Compound 13b was prepared by the same procedure as described for the preparation of 13a using 4b (260 mg, 0.84 mmol), ethyl 3-chloropropionate (138 mg, 1.0 mmol), DIEA (53 mg, 0.07 mL, 0.41 mmol), and DMF (4 mL). After column chromatography (elution with 7:1:0.1 chloroform:methanol:NH4OH), a glassy sticky solid was obtained: yield 153 mg (44%), MS: m/z 409 (M+H)+; 1HNMR (DMSO-d6) δ 8.08 (s, 1H, H-2), 7.10 (bs, 2H, 6-NH2), 5.71 (d, 1H, H-1′, J1′,2′=5.5 Hz), 5.32 (bd, 1H, OH-2′, J2′-2′OH=5.0 Hz), 5.16 (bd, 1H, OH-3′, J3′-3′OH=5.1 Hz), 5.12 (ddd, 1H, H-2′, J1′,2′=5.5 Hz, J2′,3′=5.7 Hz, J2′-2′OH=5.0 Hz), 4.14 (ddd, 1H, H-3′, J2′,3′=5.7 Hz, J3′,4′=4.1 Hz, J3′-3′OH=5.1 Hz), 4.01 (q, 2H, OCH2CH3), 3.91-3.98 (m, 1H, H-4′), 2.87 (q, 2H, CH2 of 8-Et), 2.71-2.79 (m, 1H, 5′-CH2), 2.51-2.65 (m, 3H, 5′-CH2, CO—CH2), 2.38 (t, 2H, N(CH3)—CH2), 2.16 (bs, 3H, N—CH3), 1.30 (t, 3H, CH3 of 8-Et), 1.15 (t, 3H, OCH2CH3).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][CH:7]=2)[CH2:3][CH2:2]1.[N:15]1([NH2:21])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1>>[N:15]1([NH:21][C:12]([C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([O:5][CH2:4][CH:1]3[CH2:2][CH2:3]3)[N:11]=2)=[O:14])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: NN1CCCCC1
Reactant: O=C(O)c1cccc(OCC2CC2)n1
Product: O=C(NN1CCCCC1)c1cccc(OCC2CC2)n1

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-cyclopropylmethoxy-pyridine-2-carboxylic acid (CAN 1248077-05-5) and 1-piperidinamine (CAN 2213-43-6) as starting materials, MS (LC/MS): 276.1 (M+H).
Reaction SMILES: [CH3:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].C(N(CC)CC)C.[NH2:19][C:20]1[CH:41]=[CH:40][C:23]([C:24]([N:26]2[C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=3[CH2:30][N:29]3[CH:37]=[CH:38][CH:39]=[C:28]3[CH2:27]2)=[O:25])=[CH:22][CH:21]=1>C(Cl)Cl>[CH:39]1[CH:38]=[CH:37][N:29]2[CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[N:26]([C:24]([C:23]3[CH:22]=[CH:21][C:20]([NH:19][C:4](=[O:5])[C:3]4[CH:7]=[CH:8][CH:9]=[C:10]([CH3:11])[C:2]=4[CH3:1])=[CH:41][CH:40]=3)=[O:25])[CH2:27][C:28]=12
Reactant: Cc1cccc(C(=O)Cl)c1C
Reactant: Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cccc(C(=O)Nc2ccc(C(=O)N3Cc4cccn4Cc4ccccc43)cc2)c1C
Reaction time: 0.25 h
Yield: 56 %

Procedure:
To a stirred solution of 0.320 g of 2,3-dimethylbenzoyl chloride in 10 ml of methylene chloride is added 0.33 ml of triethylamine. After stirring for 15 minutes, 0.485 g of 10,11-dihydro-10-(4- aminobenzoyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepine is added and stirring continued for 5 hours. The reaction mixture is washed with water, 1N HCl, NaHCO3, and brine. The reaction mixture is dried with Na2SO4, filtered and evaporated in vacuo to give a solid which is purified by flash chromatography using 1:1 ethyl acetate-hexane to give 0.39 g of solid, m.p. 168-170° C.