Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1](OCC)(OCC)OCC.[NH2:11][C:12]1[CH:39]=[CH:38][C:37]([Br:40])=[CH:36][C:13]=1[C:14]([NH:16][CH2:17][C:18]([NH:20][CH2:21][CH:22]1[CH2:27][CH2:26][N:25]([CH2:28][C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=2)[CH2:24][CH2:23]1)=[O:19])=[O:15].[BH4-].[Na+].C(O)C>ClCCl>[Br:40][C:37]1[CH:38]=[CH:39][C:12]([NH:11][CH3:1])=[C:13]([CH:36]=1)[C:14]([NH:16][CH2:17][C:18]([NH:20][CH2:21][CH:22]1[CH2:23][CH2:24][N:25]([CH2:28][C:29]2[CH:30]=[CH:31][C:32]([Cl:35])=[CH:33][CH:34]=2)[CH2:26][CH2:27]1)=[O:19])=[O:15]
Reactant: CCOC(OCC)OCC
Reactant: Nc1ccc(Br)cc1C(=O)NCC(=O)NCC1CCN(Cc2ccc(Cl)cc2)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCO
Product: CNc1ccc(Br)cc1C(=O)NCC(=O)NCC1CCN(Cc2ccc(Cl)cc2)CC1
Temperature: 150 °C
Reaction time: 17 h

Procedure:
A triethyl orthoformate (6.5 mL) solution of 4-[N-(2-amino-5-bromobenzoyl)glycyl]aminomethyl-1-(4-chlorobenzyl)piperidine (Compd. No. 1042) (50 mg, 0.10 mmol) was stirred at 150° C. for 17 hours and concentrated to thereby provide a yellow solid. Sodium borohydride (7.6 mg, 0.2 mmol) was added to an ethanol (3 mL) solution of the yellow solid, and the mixture was stirred at room temperature for 14 hours. The resulting white precipitate was dissolved in dichloromethane, and the obtained solution was washed with a 1 M aqueous solution of NaOH (2 mL). The organic layer was separated, dried over K2CO3, filtered and concentrated, and the obtained crude product was purified by column chromatography (SiO2, 20% methanol/chloroform) to provide 4-[N-[5-bromo-2-(methylamino)benzoyl]glycyl]aminomethyl-1-(4-chlorobenzyl)piperidine (Compd. No. 1427) (40 mg, 80%). The purity was determined by RPLC/MS (100%). ESI/MS m/e 505 (M++H, C23H28BrClF6N4O2).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][CH:12]([OH:15])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[H-].[Na+].Cl[C:21]1[N:26]=[CH:25][C:24]([S:27]([NH:30][CH:31]2[CH2:36][CH2:35][N:34]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:33][CH2:32]2)(=[O:29])=[O:28])=[CH:23][CH:22]=1>>[F:17][C:2]([F:1])([F:16])[C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH2:14][CH2:13][CH:12]([O:15][C:21]3[N:26]=[CH:25][C:24]([S:27]([NH:30][CH:31]4[CH2:36][CH2:35][N:34]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:33][CH2:32]4)(=[O:28])=[O:29])=[CH:23][CH:22]=3)[CH2:11][CH2:10]2)=[CH:7][CH:8]=1
Reactant: CC(C)(C)OC(=O)N1CCC(NS(=O)(=O)c2ccc(Cl)nc2)CC1
Reactant: OC1CCN(c2ccc(C(F)(F)F)cc2)CC1
Agent: [H-]
Agent: [Na+]
Product: CC(C)(C)OC(=O)N1CCC(NS(=O)(=O)c2ccc(OC3CCN(c4ccc(C(F)(F)F)cc4)CC3)nc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99 %

Procedure:
To a stirred solution of 1-(4-(trifluoromethyl)phenyl)piperidin-4-ol (1.4 g, 5.71 mmol) in dimethylormamide (10 mL) at room temperature was added sodium hydride slowly (0.5 g, 60%, 12.4 mmol). After effervescence subsided, tert-butyl 4-(6-chloropyridine-3-sulfonamido)piperidine-1-carboxylate (1.03 g, 4.75 mmol) was added slowly. The mixture was stirred at room temperature overnight and then poured into ice-water. The residue was purified by flash chromatography (silica gel, 2% methanol in methylene chloride) to afford the title compound as a yellow solid (2.75 g, 99%). 1H-NMR (CDCl3, 300 MHz): δ 8.64 (s, 1H), 7.97 (dd, 1H), 7.47 (d, 2H), 6.98 (d, 2H), 6.79 (d, 1H), 5.37 (m, 1H), 4.91 (d, 1H), 3.93 (m, 2H), 3.63 (m, 2H), 3.29 (m, 2H), 2.861 (m, 2H), 1.97 (m, 2H), 1.78 (m, 2H), 1.43 (s, 9H), 1.41 (m, 2H); LCMS: MS (m/z): 585 (MH+)
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[C:11]([C:15](=[O:17])[CH3:16])[CH:12]=[CH:13][CH:14]=1.[CH3:18][CH:19]([CH3:35])[C:20]([NH:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[CH:24]=1)=[O:21]>>[C:15]([C:11]1[CH:10]=[C:9]([CH:14]=[CH:13][CH:12]=1)[O:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:32]1[CH2:33][CH2:34][CH:29]([C:25]2[CH:24]=[C:23]([NH:22][C:20](=[O:21])[CH:19]([CH3:18])[CH3:35])[CH:28]=[CH:27][CH:26]=2)[CH2:30][CH2:31]1)(=[O:17])[CH3:16]
Reactant: CC(=O)c1cccc(OCCCCCCCl)c1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Product: CC(=O)c1cccc(OCCCCCCN2CCC(c3cccc(NC(=O)C(C)C)c3)CC2)c1

Procedure:
Prepared by Procedure G and Scheme B1 using 1-{3-[(6-chlorohexyl)oxy]phenyl}ethanone and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 465.3 (M+H)+.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[Cl:11][C:12]1[CH:17]=[CH:16][N:15]=[C:14]([CH:18]([CH:20]2[CH2:22][CH2:21]2)[OH:19])[C:13]=1[O:23][CH:24]([F:26])[F:25].C(N(CC)CC)C>ClCCl.O>[Cl:11][C:12]1[CH:17]=[CH:16][N:15]=[C:14]([C:18]([CH:20]2[CH2:22][CH2:21]2)=[O:19])[C:13]=1[O:23][CH:24]([F:25])[F:26]
Reactant: OC(c1nccc(Cl)c1OC(F)F)C1CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: O
Solvent: ClCCl
Product: O=C(c1nccc(Cl)c1OC(F)F)C1CC1
Temperature: -78 °C
Reaction time: 0.67 h
Yield: 89.4 %

Procedure:
6.44 ml of oxalyl chloride was dissolved in 150 ml of anhydrous dichloromethane, under cooling at −78° C., 75 ml of anhydrous dichloromethane solution of 5.64 ml of anhydrous dimethylsulfoxide was dropped. The resulting mixture was stirred at −78° C. for 40 minutes, and thereafter, 150 ml of anhydrous dichloromethane solution of 14.17 g of (4-chloro-3-difluoromethoxy-2-pyridyl)cyclopropylmethane-1-ol (IX) was dropped thereto. The resulting mixture was stirred at −78° C. for 30 minutes, and thereafter, the reaction temperature was elevated to −45° C., and the resulting mixture was stirred at the same temperature for 1 hour, and thereafter, 39.56 ml of triethylamine was dropped and the temperature of the resulting mixture was elevated to a room temperature. Water was added thereto and the resulting mixture was extracted with chloroform, and the resulting organic layer was washed with water and saturated salt water, and thereafter, dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent; chloroform:ethyl acetate=125:1) to obtain 12.57 g of (4-chloro-3-difluoromethoxy-2-pyridyl)cyclopropylketone (X).
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([C:8]([NH:10][CH2:11][CH2:12][CH:13]([CH3:15])[CH3:14])=[O:9])=[CH:4][CH:3]=1.[C:16]1([CH2:22][CH2:23][CH:24]2[CH2:28][CH2:27][NH:26][CH2:25]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.CCN(CC)CC>CN1CCCC1=O>[CH3:14][CH:13]([CH3:15])[CH2:12][CH2:11][NH:10][C:8]([C:5]1[N:6]=[N:7][C:2]([N:26]2[CH2:27][CH2:28][CH:24]([CH2:23][CH2:22][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:25]2)=[CH:3][CH:4]=1)=[O:9]
Reactant: c1ccc(CCC2CCNC2)cc1
Reactant: CC(C)CCNC(=O)c1ccc(Cl)nn1
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: CC(C)CCNC(=O)c1ccc(N2CCC(CCc3ccccc3)C2)nn1
Temperature: 120 °C
Reaction time: 8 h

Procedure:
To a solution of 6-chloro-N-(3-methylbutyl)pyridazine-3-carboxamide (20 mg, 0.088 mmol) and 3-(2-phenylethyl)pyrrolidine (23 mg, 0.13 mmol) in 1-methyl-2-pyrrolidinone (1 mL) was added Et3N (25 μL, 0.18 mmol) at room temperature. The mixture was stirred at 120° C. overnight. The reaction was then concentrated and the residue purified using a semi-prep HPLC/MS to give the title compound. MS (+ESI) m/z 367 (MH+).
Reaction SMILES: [OH-:1].[Na+].[CH2:3]([Sn:7](Br)(Br)[CH2:8][CH2:9][CH2:10][CH3:11])[CH2:4][CH2:5][CH3:6].C([Sn](Br)(Br)Br)CCC.O>C1CCCCC1>[CH2:3]([Sn:7](=[O:1])[CH2:8][CH2:9][CH2:10][CH3:11])[CH2:4][CH2:5][CH3:6]
Reactant: CCCC[Sn](Br)(Br)CCCC
Reactant: [OH-]
Agent: CCCC[Sn](Br)(Br)Br
Agent: [Na+]
Solvent: C1CCCCC1
Solvent: O
Product: CCCC[Sn](=O)CCCC
Temperature: 70 °C

Procedure:
The same apparatus as used in Example 1 was employed. To the flask were continuously fed 1,075 g of 30% aqueous sodium hydroxide solution and 1,500 g of a cyclohexane solution which had been prepared by dissolving, in 750 g of cyclohexane, 750 g of di-n-butyltin dibromide containing 1.8% tri-n-butyltin bromide and 1.5% mono-n-butyltin tribromide. The above feeding was performed with stirring and heating at 70° C., to conduct hydrolysis for 45 minutes. To the resulting reaction mixture overflowed was added 3,600 g of water, and the mixture was then allowed to stand, whereby it split into three distinct phases. The specific gravities of the upper, intermediate and lower phases were 0.6, 1.1 and 1.3 respectively. The lower phase was separated out, washed with water, and then dried under reduced pressure, thereby obtaining 445 g of a white substance of di-n-butyltin oxide. Acid titration revealed that its purity was 99.8%, and the oxide had an average particle diameter of 50 μm.
Reaction SMILES: [CH3:1][N:2]([CH3:17])[C:3]([C:5]1[CH:6]=[C:7]([OH:16])[C:8]2[N:9]([C:11]([CH3:15])=[C:12]([CH3:14])[N:13]=2)[CH:10]=1)=[O:4].[O:18]1[C@H:20]2[CH2:21][C:22]3[C:27]([C@@H:19]12)=[CH:26][CH:25]=[CH:24][CH:23]=3.C(N(CC)CC)C>C(O)C.O>[OH:18][C@H:20]1[CH2:21][C:22]2[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=2)[C@@H:19]1[O:16][C:7]1[C:8]2[N:9]([C:11]([CH3:15])=[C:12]([CH3:14])[N:13]=2)[CH:10]=[C:5]([C:3]([N:2]([CH3:1])[CH3:17])=[O:4])[CH:6]=1
Reactant: Cc1nc2c(O)cc(C(=O)N(C)C)cn2c1C
Reactant: c1ccc2c(c1)C[C@@H]1O[C@H]21
Solvent: O
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1nc2c(O[C@H]3c4ccccc4C[C@@H]3O)cc(C(=O)N(C)C)cn2c1C
Reaction time: 3 h
Yield: 72.7 %

Procedure:
To a solution of 1.5 g (6.4 mmol) 6-(N,N-dimethylamino-carbonyl)-8-hydroxy-2,3-dimethyl-imidazo[1,2-a]pyridine in 30 ml ethanol and 7.5 ml water are added 1.7 g (12.9 mmol) (1R,2S)-epoxyindane and 1.8 ml triethylamine. After 3 h at 70° C., the mixture is cooled down and partitioned between dichloro-methane and water. The organic layer is separated, dried over anhydrous magnesium sulphate and evaporated. Purification of the residue by column chromatography on silica gel using ethyl acetate:light petroleum ether (1:1) and crystallization from diisopropyl ether yields 1.7 g (74%) of the title compound as a colourless solid (m.p. 122° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][N:9]1[C:13]([CH:14]([CH3:20])[C:15]([O:17]CC)=[O:16])=[CH:12][N:11]=[C:10]1[S:21][CH2:22][CH2:23][CH3:24].C(=O)([O-])[O-].[K+].[K+]>O.CO>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][N:9]1[C:13]([CH:14]([CH3:20])[C:15]([OH:17])=[O:16])=[CH:12][N:11]=[C:10]1[S:21][CH2:22][CH2:23][CH3:24]
Reactant: CCCSc1ncc(C(C)C(=O)OCC)n1Cc1ccccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CCCSc1ncc(C(C)C(=O)O)n1Cc1ccccc1Cl

Procedure:
A solution of ethyl 2-[1-{(2-chlorophenyl)methyl}-2-propylthio-1H-imidazol-5-yl]propionate (0.71 g, 1.94 mmol) in water (10 mL) and methanol (5 mL) was treated with potassium carbonate (0.51 g, 3.7 mmol). The reaction mixture was refluxed on a steam bath for 2 hours, the methanol was evaporated, the aqueous layer was washed with diethyl ether, cooled in ice, and adjusted to pH 3.4 with aqueous hydrochloric acid solution. The resulting gummy solid was extracted into methylene chloride, washed with water, dried, and concentrated. The residue was triturated with diethyl ether to give 2-[1-{(2-chlorophenyl)methyl}-2-propylthio-1H-imidazol-5-yl]propionic acid; mp 170°-172° C.
Reaction SMILES: C(O)(C(F)(F)F)=O.[S:8]([O-:39])([O:11][N:12]1[C:18](=[O:19])[N:17]2[CH2:20][C@H:13]1[CH2:14][CH2:15][C@H:16]2[C:21]1[S:22][C:23]([CH:26]2[CH2:31][CH2:30][N:29](C(OC(C)(C)C)=O)[CH2:28][CH2:27]2)=[N:24][N:25]=1)(=[O:10])=[O:9].[Na+]>C(Cl)Cl.CCOCC>[S:8]([OH:39])([O:11][N:12]1[C:18](=[O:19])[N:17]2[CH2:20][C@H:13]1[CH2:14][CH2:15][C@H:16]2[C:21]1[S:22][C:23]([CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[N:24][N:25]=1)(=[O:9])=[O:10]
Reactant: CC(C)(C)OC(=O)N1CCC(c2nnc([C@@H]3CC[C@@H]4CN3C(=O)N4OS(=O)(=O)[O-])s2)CC1
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOCC
Solvent: O=C(O)C(F)(F)F
Product: O=C1N2C[C@@H](CC[C@H]2c2nnc(C3CCNCC3)s2)N1OS(=O)(=O)O
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 25.7 %

Procedure:
TFA (0.20 mL) was added to a 0° C. mixture of sodium (2S,5R)-2-(5-(1-(tert-butoxycarbonyl)piperidin-4-yl)-1,3,4-thiadiazol-2-yl)-7-oxo-1,6-diaza-bicyclo[3.2.1]octan-6-yl sulfate (50 mg, 0.10 mmol) in dry DCM (0.60 mL). The reaction mixture was stirred at 0° C. for 2-3 hrs and then diluted with ether (−10 mL). The precipitate was collected via centrifugation, washed with ether (3×) and dried under high vacuum to afford (2S,5R)-7-oxo-2-(5-(piperidin-4-yl)-1,3,4-thiadiazol-2-yl)-1,6-diazabicyclo[3.2.1]octan-6-yl hydrogen sulfate (10 mg, 25%) after prep-HPLC using ammonium formate buffer. ESI-MS (EI+, m/z): 390.12.
Reaction SMILES: Cl.[C:2]([CH2:5][CH2:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([N:13]2[CH2:17][CH2:16][N:15]([C:18]3[CH:19]=[N:20][C:21]4[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23][C:22]=4[N:29]=3)[C:14]2=[O:30])[CH2:9][CH2:8]1)([OH:4])=[O:3].[CH2:31](O)[CH3:32]>>[CH2:31]([O:3][C:2]([CH2:5][CH2:6][C@H:7]1[CH2:8][CH2:9][C@H:10]([N:13]2[CH2:17][CH2:16][N:15]([C:18]3[CH:19]=[N:20][C:21]4[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23][C:22]=4[N:29]=3)[C:14]2=[O:30])[CH2:11][CH2:12]1)=[O:4])[CH3:32]
Reactant: CN1CCc2ncc(N3CCN([C@H]4CC[C@H](CCC(=O)O)CC4)C3=O)nc2CC1
Reactant: CCO
Agent: Cl
Product: CCOC(=O)CC[C@H]1CC[C@H](N2CCN(c3cnc4c(n3)CCN(C)CC4)C2=O)CC1
Reaction time: 8 h

Procedure:
Gaseous hydrogen chloride is passed into 1.0 g of 1-[trans-4-(2-carboxyethyl)cyclohexyl]-3-(7-methyl-6,7,8,9-tetrahydro-5H-pyrazino[2,3-d]azepin-2-yl)imidazolidin-2-one in 30 ml of ethanol for 10 minutes and the mixture is subsequently heated under reflux for 1 hour. After standing at room temperature overnight, it is again heated to reflux, cooled and concentrated. The residue is stirred with dilute aqueous sodium carbonate solution. The solid is filtered off with suction, washed with water and dried.
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:10]([NH:12][CH2:13][C:14]([CH2:20][NH:21][C:22]1[CH:30]=[C:29]([CH3:31])[CH:28]=[C:27]2[C:23]=1[CH:24]=[N:25][N:26]2[C:32]1[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=1)([OH:19])[C:15]([F:18])([F:17])[F:16])[CH3:11]>>[CH2:10]([N:12]([CH2:13][C:14]([CH2:20][NH:21][C:22]1[CH:30]=[C:29]([CH3:31])[CH:28]=[C:27]2[C:23]=1[CH:24]=[N:25][N:26]2[C:32]1[CH:33]=[CH:34][C:35]([F:38])=[CH:36][CH:37]=1)([OH:19])[C:15]([F:17])([F:18])[F:16])[C:1](=[O:9])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH3:11]
Reactant: O=C(O)c1ccccc1
Reactant: CCNCC(O)(CNc1cc(C)cc2c1cnn2-c1ccc(F)cc1)C(F)(F)F
Product: CCN(CC(O)(CNc1cc(C)cc2c1cnn2-c1ccc(F)cc1)C(F)(F)F)C(=O)c1ccccc1

Procedure:
Prepared similarly to Example 1 from benzoic acid and 3-(ethylamino)-1,1,1-trifluoro-2-({[1-(4-fluorophenyl)-6-methyl-1H-indazol-4-yl]amino}methyl)-2-propanol.
Reaction SMILES: [CH3:1][N:2]([CH2:12][CH2:13][O:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][CH:16]=1)[C:3]1[O:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1.[S:23]1[CH2:27][C:26](=[O:28])[NH:25][C:24]1=[O:29].C([O-])(=O)C.[NH2+]1CCCCC1>C1(C)C=CC=CC=1>[CH3:1][N:2]([CH2:12][CH2:13][O:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=[C:27]2[S:23][C:24](=[O:29])[NH:25][C:26]2=[O:28])=[CH:17][CH:16]=1)[C:3]1[O:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1
Reactant: CN(CCOc1ccc(C=O)cc1)c1nc2ccccc2o1
Reactant: O=C1CSC(=O)N1
Agent: C1CC[NH2+]CC1
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Product: CN(CCOc1ccc(C=C2SC(=O)NC2=O)cc1)c1nc2ccccc2o1

Procedure:
A solution of 4-[2-(N-methyl-N-(2-benzoxazolyl)amino)ethoxy]benzaldehyde (1.6 g) and 2,4-thiazolidinedione (0.63 g) in toluene (100 ml) containing a catalytic quantity of piperidinium acetate was boiled under reflux in a Dean and Stark apparatus for 2 hours. The mixture was cooled and filtered to give the title compound (mp 227°-9° C.).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Cl:5][C:6]1[CH:37]=[CH:36][C:9]([CH2:10][N:11]2[C:19]3[C:14](=[CH:15][C:16]([O:20]C)=[CH:17][CH:18]=3)[C:13]([S:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[C:12]2[CH2:27][C:28]([CH3:35])([CH3:34])[C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:8][CH:7]=1.Cl>C(S)(C)(C)C.C(Cl)Cl>[Cl:5][C:6]1[CH:7]=[CH:8][C:9]([CH2:10][N:11]2[C:19]3[C:14](=[CH:15][C:16]([OH:20])=[CH:17][CH:18]=3)[C:13]([S:22][C:23]([CH3:24])([CH3:25])[CH3:26])=[C:12]2[CH2:27][C:28]([CH3:35])([CH3:34])[C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:36][CH:37]=1
Reactant: CCOC(=O)C(C)(C)Cc1c(SC(C)(C)C)c2cc(OC)ccc2n1Cc1ccc(Cl)cc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(C)(C)S
Solvent: ClCCl
Product: CCOC(=O)C(C)(C)Cc1c(SC(C)(C)C)c2cc(O)ccc2n1Cc1ccc(Cl)cc1
Yield: 69.7 %

Procedure:
To a suspension of aluminum chloride (26.3 g, 198 mmol) in t-butanethiol (60 ml) at 0° C. was added a solution of ethyl 3-(1-(4-chlorobenzyl)-3-(t-butylthio)-5-methoxyindol-2-yl)-2,2-dimethylpropionate (32 g, 66 mmol), prepared as in step 2, in methylene chloride (90 ml) and the reaction mixture was stirred at 0° C. for 10 min and at ambient temperature for 3 hours. The reaction mixture was then poured into ice and acidified with 10% aqueous hydrochloric acid. The organic layer was washed with water and brine, dried over MgSO4, filtered, and concentrated in vacuo to provide a white solid. The solid was washed with 20% solution of ethyl ether in hexane and dried in vacuo to afford 21.8 g of ethyl 3-(1-(4-chlorobenzyl)-3-(t-butylthio)-5-hydroxyindol-2-yl)-2,2-dimethylpropionate.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([O:11][CH3:12])=[C:7]([CH:10]=1)[C:8]#[N:9].[CH2:13]([OH:15])[CH3:14]>>[CH2:13]([O:15][C:8](=[NH:9])[C:7]1[CH:10]=[C:3]([Cl:2])[CH:4]=[CH:5][C:6]=1[O:11][CH3:12])[CH3:14]
Reactant: COc1ccc(Cl)cc1C#N
Reactant: CCO
Agent: Cl
Product: CCOC(=N)c1cc(Cl)ccc1OC
Reaction time: 48 h
Yield: 56 %

Procedure:
Hydrogen chloride gas (˜200 mmol) was passed into a solution of 5-chloro-2-methoxy-benzonitrile(1.68 g, 10.0 mmol) in ethanol (50 ml). After stirring for 48 hours, the mixture was concentrated under reduced pressure. The residue was treated with ethyl acetate (25 ml) and stirred for 1 hour. Filtration provided 5-chloro-2-methoxy-benzimidic acid ethyl ester (1.20 g, 56% yield) as a white powder.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:14][CH2:13][C@H:12]1[C:15]([OH:17])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:21])=O.CN(C=O)C>ClCCl>[CH2:1]([O:8][C:9]([N:11]1[CH2:14][CH2:13][C@H:12]1[C:15]([Cl:21])=[O:17])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)[C@@H]1CCN1C(=O)OCc1ccccc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)[C@@H]1CCN1C(=O)OCc1ccccc1
Temperature: -5 °C
Reaction time: 3 h

Procedure:
(2S)-1-(benzyloxycarbonyl)azetidine-2-carboxylic acid (729.3 mg, 3.10 mmol, 1.0 eq) was dissolved in dry dichloromethane (15 mL) and cooled to about −5° C. under argon. Oxalyl chloride (380 μL, 4.36 mmol, 1.4 eq) and a drop of DMF were added to the solution. The mixture was warmed to reflux temperature with stirring over about a 3 hour period. After cooling, the mixture was concentrated and used in Reference Example 16.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:13]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][C:16]=2[CH3:22])=[C:12]([F:23])[C:8]2[NH:9][CH:10]=[N:11][C:7]=2[CH:6]=1)=[O:4].[OH-].[Na+]>CO.C(OCC)(=O)C.O>[F:23][C:12]1[C:8]2[NH:9][CH:10]=[N:11][C:7]=2[CH:6]=[C:5]([C:3]([OH:4])=[O:2])[C:13]=1[NH:14][C:15]1[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][C:16]=1[CH3:22]
Reactant: COC(=O)c1cc2nc[nH]c2c(F)c1Nc1ccc(Br)cc1C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1cc(Br)ccc1Nc1c(C(=O)O)cc2nc[nH]c2c1F
Temperature: 0 °C
Reaction time: 16 h
Yield: 95.4 %

Procedure:
7-Fluoro-6-(4-bromo-2-methyl-phenylamino)-1H-benzoimidazole-5-carboxylic acid methyl ester 8a (63 mg, 0.167 mmol) is suspended in MeOH (1.5 mL) and 20% NaOH (400 μl) is added. After 16 hours, the reaction is cooled to 0° C. and 1 N NCl solution is added dropwise until pH is 2 to 3. The reaction mixture is diluted with ethyl acetate and water and the layers separated. The organic layer is washed with brine, dried (Na2SO4) and concentrated under reduced pressure to give 58 mg (95%) of desired product: MS APCI (+) m/z 366, 364 (M+1 Br pattern) detected; MS APCI (−) m/z 364, 362 (M−1 Br pattern) detected.
Reaction SMILES: C([NH:5][S:6]([C:9]1[S:10][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]3[N:25]=[C:24]([CH3:26])[CH:23]=[C:22]([C:27]4[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[C:29]([CH3:37])[CH:28]=4)[N:21]=3)[CH:15]=2)=[CH:12][CH:13]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[CH3:26][C:24]1[CH:23]=[C:22]([C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[C:29]([CH3:37])[CH:28]=2)[N:21]=[C:20]([C:16]2[CH:15]=[C:14]([C:11]3[S:10][C:9]([S:6]([NH2:5])(=[O:7])=[O:8])=[CH:13][CH:12]=3)[CH:19]=[CH:18][CH:17]=2)[N:25]=1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)c(C)c2)nc(-c2cccc(-c3ccc(S(=O)(=O)NC(C)(C)C)s3)c2)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(-c2ccc(C(F)(F)F)c(C)c2)nc(-c2cccc(-c3ccc(S(N)(=O)=O)s3)c2)n1
Temperature: 25 °C
Reaction time: 15 h
Yield: 47.6 %

Procedure:
To a cooled and stirred solution of N-tert-butyl-5-{3-[4-methyl-6-(3-methyl-4-trifluoromethyl-phenyl)-pyrimidin-2-yl]-phenyl}-thiophene-2-sulfonic acid amide (0.15 g) in dichloromethane (3 ml) was added TFA (3 ml) and the reaction mixture was allowed to stir at room temperature for 15 h. The mixture was evaporated to dryness, poured into 2N Na2CO3 solution (25 ml) and extracted with ethyl acetate (3×50 ml). The combined organic layers were washed with brine (50 ml), dried (MgSO4) and evaporated. Further purification by crystallization (ethyl acetate/heptane) yielded the title compound as a light brown solid (0.064 g, 25%). MS (ISP) 490.1 [(M+H)+]; mp 242° C.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][C:9]([NH:11][CH:12]2[N:18]=[C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:16]3[CH:25]=[CH:26][CH:27]=[CH:28][C:15]=3[NH:14][C:13]2=S)=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:30][CH2:31][CH2:32][OH:33].[Cl-]>C1COCC1>[CH:1]1([CH2:7][CH2:8][C:9]([NH:11][CH:12]2[N:18]=[C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:16]3[CH:25]=[CH:26][CH:27]=[CH:28][C:15]=3[NH:14][C:13]2=[N:30][CH2:31][CH2:32][OH:33])=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NCCO
Reactant: O=C(CCC1CCCCC1)NC1N=C(c2ccccc2)c2ccccc2NC1=S
Agent: [Cl-]
Solvent: C1CCOC1
Product: O=C(CCC1CCCCC1)NC1N=C(c2ccccc2)c2ccccc2NC1=NCCO
Temperature: 55 °C
Reaction time: 1 h
Yield: 69.4 %

Procedure:
A mixture of 3-cyclohexyl-N-(2,3-dihydro-5-phenyl-2-thioxo-1H-1,4-benzodiazepin-3-yl)propanamide (162 mg, 0.4 mmol), 2-aminoethanol (96 μL, 98 mg, 1.6 mmol) and mereuric chloride (141 mg, 0.52 mmol) in THF (5 mL) was stirred at 55° C. for 1 h. The solvent was evaporated under reduced pressure and the residue was triturated with EtOAc/Hexane. The solid was collected and dried in vacuo to give 3-cyclohexyl-N-[2,3-dihydro-2-(2-hydroxyethylimino)-5-phenyl-1H-1,4-benzodiazepin-3-yl)propanamide as a solid (120 mg, 69%). A sample (90 mg, 0.2 mmol) was dissolved in dichloromethane (7 mL), cooled to 0° C. and methanesulfonyl chloride (19 μL, 28 mg, 2.4 mmol) and diisopropylethylamine (75 μl, 56 mg, 0.43 mmol) were added. The mixture was stirred at 0° C. for 30 min., then at room temperature for 2 h. The solvent was evaporated under reduced pressure, toluene was added and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with CH2Cl2 /MeOH (98:2) to give 3-cyclohexyl-N-{2,4-dihydro-6-phenyl-1H-imidazo[1,2-a][1,4]benzodiazepin-4-yl}propanamide as a solid (40 mg, 48%), m.p. 202°-208.5° C.
Reaction SMILES: [C:1]([O:7][CH2:8][C@@H:9]([NH:11]C(OC(C)(C)C)=O)[CH3:10])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[ClH:19].O1CCOCC1>CCOC(C)=O>[ClH:19].[NH2:11][C@@H:9]([CH3:10])[CH2:8][O:7][C:1](=[O:6])[C:2]([CH3:4])([CH3:3])[CH3:5]
Reactant: C[C@@H](COC(=O)C(C)(C)C)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: C[C@H](N)COC(=O)C(C)(C)C
Reaction time: 2.5 h

Procedure:
To a solution of (2S)-2-[(tert-butoxycarbonyl)-amino]-propyl pivaloate (1.0 eq.) in EtOAc (0.6 M) was added 4N HCl in dioxane (10 eq.). The reaction mixture was stirred for 2.5 h and then the solvent was evaporated in vacuo to give a solid that was washed with Et2O and dried.