Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:6]([NH:7][NH2:8])=[C:5]([N+:9]([O-:11])=[O:10])[C:4]([CH3:12])=[N:3]1.[CH3:13][O:14][C:15]1[C:16]([O:28][CH3:29])=[CH:17][C:18]2[NH:24][C:23](=[O:25])[CH2:22][CH2:21][C:20](=O)[C:19]=2[CH:27]=1.O>C(O)(=O)C>[CH3:1][N:2]1[C:6]([NH:7][N:8]=[C:20]2[CH2:21][CH2:22][C:23](=[O:25])[NH:24][C:18]3[CH:17]=[C:16]([O:28][CH3:29])[C:15]([O:14][CH3:13])=[CH:27][C:19]2=3)=[C:5]([N+:9]([O-:11])=[O:10])[C:4]([CH3:12])=[N:3]1
Reactant: Cc1nn(C)c(NN)c1[N+](=O)[O-]
Reactant: COc1cc2c(cc1OC)C(=O)CCC(=O)N2
Solvent: O
Solvent: CC(=O)O
Product: COc1cc2c(cc1OC)C(=NNc1c([N+](=O)[O-])c(C)nn1C)CCC(=O)N2
Temperature: 70 °C
Yield: 12.2 %

Procedure:
1,3-Dimethyl-4-nitro-1H-pyrazol-5-yl-hydrazine (0.073 g, 0.4 mmol) was added to a suspension of 7,8-dimethoxy-1H-[1]benzazepin-2,5(3H, 4H)-dione (0.100 g, 0.4 mmol) in acetic acid (5 ml) with stirring under argon. The mixture was heated at 70° C. for 2 days, cooled and water (5 ml) added. The precipitate was then filtered off to give the title compound as a yellow solid (0.019 g, yield 11.5%); 1H-NMR (DMSO-d6, 300 MHz): δ (ppm)=12.8 (v br s; 1 H), 9.59 (s; 1H), 7.2 (s; 1H), 6.63 (s; 1H), 3.96 (s; 3H), 3.75-3.77 (s, 6H), 3.05 (br t, 2H), 2.57 (br t, 2H), 2.35 (s, 3H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][N:3]=1.[C:11]([N:18]1[CH2:24][CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12]>>[NH2:8][C:5]1[CH:6]=[CH:7][C:2]([N:21]2[CH2:22][CH2:23][CH2:24][N:18]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:19][CH2:20]2)=[N:3][CH:4]=1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: CC(C)(C)OC(=O)N1CCCNCC1
Product: CC(C)(C)OC(=O)N1CCCN(c2ccc(N)cn2)CC1

Procedure:
Intermediate B-21 was prepared by the general procedure for intermediate B-2, by using 2-chloro-5-nitropyridine and 1-BOC-homopiperazine as starting materials. MS (M+1): 293.
Reaction SMILES: Cl[C:2]1[O:3][C:4]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=2)=[CH:5][N:6]=1.[NH2:17][C:18]1[CH:19]=[C:20]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])[CH:21]=[CH:22][CH:23]=1>CC(O)C>[F:14][C:13]([F:16])([F:15])[C:10]1[CH:11]=[CH:12][C:7]([C:4]2[O:3][C:2]([NH:17][C:18]3[CH:19]=[C:20]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])[CH:21]=[CH:22][CH:23]=3)=[N:6][CH:5]=2)=[CH:8][CH:9]=1
Reactant: CS(=O)(=O)Nc1cccc(N)c1
Reactant: FC(F)(F)c1ccc(-c2cnc(Cl)o2)cc1
Solvent: CC(C)O
Product: CS(=O)(=O)Nc1cccc(Nc2ncc(-c3ccc(C(F)(F)F)cc3)o2)c1
Temperature: 80 °C
Yield: 40.9 %

Procedure:
A mixture of 2-chloro-5-(4-(trifluoromethyl)phenyl)oxazole 31 (0.599 g, 2.42 mmol) and commercially available N-(3-aminophenyl)methanesulfonamide 6 (0.451 g, 2.42 mmol) in 2-propanol (20 mL) was heated to 80° C. for 14 h with stirring. Upon cooling, solvent was evaporated and silica column purified (Biotage) (Acetone/hexane as an eluent) to provide N-(3-((5-(4-(trifluoromethyl)phenyl)oxazol-2-yl)amino)phenyl) methane sulfonamide 33 (0.393 g, 41% yield) as a solid. MS (ES) m/z 398 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:20]2[C:28](=[O:29])[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]2=[O:30])[CH:5]=[C:6]([Cl:19])[C:7]=1[CH2:8][C:9]1[CH:14]=[C:13]([CH:15]([CH3:17])[CH3:16])[C:12](=[O:18])[NH:11][N:10]=1.[CH3:31]OC(OC)N(C)C>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([N:20]2[C:28](=[O:29])[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]2=[O:30])[CH:5]=[C:6]([Cl:19])[C:7]=1[CH2:8][C:9]1[CH:14]=[C:13]([CH:15]([CH3:17])[CH3:16])[C:12](=[O:18])[N:11]([CH3:31])[N:10]=1
Reactant: CC(C)c1cc(Cc2c(Cl)cc(N3C(=O)c4ccccc4C3=O)cc2Cl)n[nH]c1=O
Reactant: COC(OC)N(C)C
Solvent: ClCCl
Product: CC(C)c1cc(Cc2c(Cl)cc(N3C(=O)c4ccccc4C3=O)cc2Cl)nn(C)c1=O
Temperature: 105 °C
Yield: 52 %

Procedure:
A mixture of 2-[3,5-dichloro-4-(5-isopropyl-6-oxo-1,6-dihydro-pyridazin-3-ylmethyl)-phenyl]-isoindole-1,3-dione (92) (570 mg, 1.29 mmol) and N,N-dimethylformamide dimethyl acetal (12 mL) was heated to 105° C. for 4.5 h. At this time, the reaction was cooled to 25° C. and diluted with methylene chloride. This solution was washed with water (1×50 mL) and a saturated aqueous sodium chloride solution (1×50 mL), dried with magnesium sulfate, filtered and concentrated under vacuum. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 95:5 methylene chloride/methanol) afforded 2-[3,5-dichloro-4-(5-isopropyl-1-methyl-6-oxo-1,6-dihydro-pyridazin-3-ylmethyl)-phenyl]-isoindole-1,3-dione (93) (310 mg, 52%) as an off-white solid; ES_HRMS m/e calcd for C23H19Cl2N3O3 (M+H)+ 456.0876, found 456.0876. Exact Mass=455.0803; Molecular Weight=456.3322.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][OH:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>ClCCl>[CH3:19][S:20]([O:11][CH2:10][CH2:9][CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)(=[O:22])=[O:21]
Reactant: CS(=O)(=O)Cl
Reactant: OCCCCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCCCCc1ccccc1
Temperature: 10 °C
Reaction time: 1 h

Procedure:
To an ice cooled solution of 4-phenyl-1-butanol (20 g) and triethyl amine (15 g) in 200 ml of dichloromethane, a solution of methanesulfonyl chloride (12 ml) in 50 ml of dichloromethane was added dropwise. After stirring for 1 h at 10° C. the reaction mixture was washed with water. Extraction of the water phase with dichloromethane, drying of the combined organic phases over MgSO4 followed by removal of the volatile components in vacuo, gave 29 g of a slightly yellow oil, 4-phenyl-1-butyl methanesulfonate, which was sufficiently pure for use in the next step. A mixture of spiro[isobenzofuran-1(3H),4'-piperidine] (2 g), 4-phenyl-1-butyl methanesulfonate (6 g) and potassium carbonate (14 g) in 75 ml of 4-methyl-2-pentanone was refluxed for 20 h. After cooling the reaction mixture was filtered and concentrated in vacuo. The remaining viscous oil was applied to a silica gel column (eluent:ether/methanol/triethyl amine=93:5:2) giving a colorless oil which crystallized as the fumarate salt, 2a, from acetone by addition of fumaric acid. Yield: 0.7 g, mp: 197°-99° C.
Reaction SMILES: [NH2:1][CH2:2][C:3]([N:5]([C:7]1[C:8]([Cl:32])=[C:9]([C:28]([Cl:31])=[CH:29][CH:30]=1)[CH2:10][O:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[N:20]=[C:19]([CH3:22])[CH:18]=[C:17]2[N:23]1[CH:27]=[CH:26][N:25]=[CH:24]1)[CH3:6])=[O:4].C(N(CC)CC)C.[C:40](Cl)(=[O:44])[CH:41]([CH3:43])[CH3:42]>ClCCl>[C:40]([NH:1][CH2:2][C:3]([N:5]([C:7]1[C:8]([Cl:32])=[C:9]([C:28]([Cl:31])=[CH:29][CH:30]=1)[CH2:10][O:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[N:20]=[C:19]([CH3:22])[CH:18]=[C:17]2[N:23]1[CH:27]=[CH:26][N:25]=[CH:24]1)[CH3:6])=[O:4])(=[O:44])[CH:41]([CH3:43])[CH3:42]
Reactant: CC(C)C(=O)Cl
Reactant: Cc1cc(-n2ccnc2)c2cccc(OCc3c(Cl)ccc(N(C)C(=O)CN)c3Cl)c2n1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(-n2ccnc2)c2cccc(OCc3c(Cl)ccc(N(C)C(=O)CNC(=O)C(C)C)c3Cl)c2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.1 %

Procedure:
To a stirred solution of 8-[3-(N-glycyl-N-methylamino)-2,6-dichlorobenzyloxy]-4-(imidazol-1-yl)-2-methylquinoline (80 mg) and triethylamine (22.4 mg) in dichloromethane (1 ml) was dropwise added isobutyryl chloride (19.9 mg) under ice-cooling, and the mixture was stirred for 15 minutes at the same temperature and for 2 hours at ambient temperature. The mixture was washed with saturated sodium bicarbonate solution, water and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by preparative thin layer chromatography (chloroform:methanol, 10:1, v/v) to give 8-[3-[N-(isobutyrylglycyl)-N-methylamino]-2,6-dichlorobenzyloxy]-4-(imidazol-1-yl)-2-methylquinoline (69 mg) as colorless amorphous.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6](=[O:17])[NH:7][N:8]2[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:4][CH:3]=1.[C:18](=O)([O-])[O-].[K+].[K+].CI>CN(C)C=O>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([O:17][CH3:18])=[N:7][N:8]2[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:4][CH:3]=1
Reactant: O=c1[nH]n(-c2ccccc2)c2cc(Br)ccc12
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COc1nn(-c2ccccc2)c2cc(Br)ccc12
Temperature: 80 °C
Reaction time: 3 h

Procedure:
Into a 100-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 6-bromo-1-phenyl-1,2-dihydroindazol-3-one (5 g, 17.30 mmol, 1.00 equiv) in N,N-dimethylformamide (50 mL), potassium carbonate (3.7 g, 34.91 mmol, 2.00 equiv), CH3I (2.7 g, 19.01 mmol, 1.10 equiv). The resulting solution was stirred for 3 h at 80° C. in an oil bath. The reaction was then quenched by the addition of water (100 mL). The resulting solution was extracted with ethyl acetate (3×150 mL) and the organic layers combined, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:40) to yield 6-bromo-3-methoxy-1-phenyl-1H-indazole as a yellow solid.
Reaction SMILES: [CH2:1]([N:8]1[C:14](=O)[C:13]2[C:16]([F:21])=[CH:17][CH:18]=[C:19]([Br:20])[C:12]=2[O:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O1CCCC1.B.CO.[OH-].[Na+]>O1CCCC1>[CH2:1]([N:8]1[CH2:14][C:13]2[C:16]([F:21])=[CH:17][CH:18]=[C:19]([Br:20])[C:12]=2[O:11][CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1c2c(F)ccc(Br)c2OCCN1Cc1ccccc1
Agent: B
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Fc1ccc(Br)c2c1CN(Cc1ccccc1)CCO2
Temperature: 60 °C
Reaction time: 3 h
Yield: 26 %

Procedure:
To a solution of 4-benzyl-9-bromo-6-fluoro-3,4-dihydro-1,4-benzoxazepine-5 (2H)-one (1.40 g, 4.00 mmol) in tetrahydrofuran (30 ml) was added under ice-cooling 1M borane tetrahydrofuran solution (16.0 ml, 16.0 mmol), and the mixture was stirred at 60° C. for 3 hr. Under ice-cooling, methanol (20 ml) and sodium hydroxide (1.60 g, 40.0 mmol) were added, and the mixture was stirred at room temperature for 1 hr. The solvent was evaporated under reduced pressure. The residue was added to water, and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to give the desired product (350 mg, 26.1%) as an oily substance.
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([CH2:20][S:21][C:22]3[S:26][C:25]([NH:27][CH2:28][CH:29]4[CH2:31][CH2:30]4)=[N:24][CH:23]=3)=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:19][C:16]1[CH:17]=[CH:18][C:11]2[CH2:10][CH2:9][NH:8][CH2:14][CH2:13][C:12]=2[C:15]=1[CH2:20][S:21][C:22]1[S:26][C:25]([NH:27][CH2:28][CH:29]2[CH2:31][CH2:30]2)=[N:24][CH:23]=1
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(CSc3cnc(NCC4CC4)s3)c2CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Clc1ccc2c(c1CSc1cnc(NCC3CC3)s1)CCNCC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.3 %

Procedure:
To a solution of 3-tert-butoxycarbonyl-7-chloro-6-[2-(cyclopropylmethyl-amino)-thiazol-5-ylthiomethyl]-2,3,4,5-tetrahydro-1H-benzo[d]azepine (0.113 g, 0.237 mmol) in anhydrous DCM (4.9 mL) at room temperature add trifluoroacetic acid (4.9 mL) and stir the solution at room temperature overnight. Concentrate in vacuo and elute the residue through a SCX column (20 g). Dissolve the residue in DCM, load the solution on to an Analogix® column (40 g) and purify the crude mixture by preparative liquid chromatography (100:0 to 90:10 DCM/2M ammonia in methanol over 30 min; 90:10 DCM/2M ammonia in methanol over 33 min; 35 mL/min) to afford 7-chloro-6-[2-(cyclopropylmethyl-amino)-thiazol-5-ylthiomethyl]-2,3,4,5-tetrahydro-1H-benzo[d]azepine (0.075 g, 83%). MS (ES+) m/z: 380.1 (M+H)+.
Reaction SMILES: [NH:1]1[C:5]([CH2:6][CH2:7][C:8]2[N:9]([C:21]3[CH:29]=[CH:28][C:24]([C:25](O)=[O:26])=[CH:23][C:22]=3[CH3:30])[C:10]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)=[CH:11][CH:12]=2)=[N:4][N:3]=[N:2]1.C1N=C[N:33](C(N2C=NC=C2)=O)C=1.O.[NH4+]>C1COCC1>[NH:4]1[C:5]([CH2:6][CH2:7][C:8]2[N:9]([C:21]3[CH:29]=[CH:28][C:24]([C:25]([NH2:33])=[O:26])=[CH:23][C:22]=3[CH3:30])[C:10]([C:13]3[CH:14]=[CH:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=3)=[CH:11][CH:12]=2)=[N:1][N:2]=[N:3]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: COc1ccc(-c2ccc(CCc3nnn[nH]3)n2-c2ccc(C(=O)O)cc2C)cc1
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(-c2ccc(CCc3nnn[nH]3)n2-c2ccc(C(N)=O)cc2C)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-(2-(2-(1H-tetrazol-5-yl)ethyl)-5-(4-methoxyphenyl)-1H-pyrrol-1-yl)-3-methylbenzoic acid (130 mg, 0.332 mmol) was dissolved in anhydrous THF (3 mL). CDI (68 mg, 0.419 mmol) was added in three portions at room temperature and stirred at this temperature for 1 h. The resultant yellow solution was added dropwise to 25% ammonium hydrate (3 mL) at 0° C. After the addition was complete, the mixture was allowed to warm to room temperature and stirred for 2 h. The mixture was evaporated in vacuo and the residue was purified by prep-HPLC to afford 2H, R2=4-methoxyphenyl as a yellow solid (7 mg, 5.4%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([CH3:15])[CH:13]=2)[N:8]([C:16](=[O:18])[CH3:17])[C:7]=1[C:19]([F:22])([F:21])[F:20])[CH3:2].CC(N=NC(C#N)(C)C)(C#N)C.[Br:36]N1C(=O)CCC1=O>ClC(Cl)(Cl)Cl>[CH2:1]([O:3][C:4](=[O:23])[CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([CH2:15][Br:36])[CH:13]=2)[N:8]([C:16](=[O:18])[CH3:17])[C:7]=1[C:19]([F:20])([F:21])[F:22])[CH3:2]
Reactant: CCOC(=O)Cc1c(C(F)(F)F)n(C(C)=O)c2ccc(C)cc12
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)Cc1c(C(F)(F)F)n(C(C)=O)c2ccc(CBr)cc12
Temperature: 80 °C
Yield: 60.6 %

Procedure:
A mixture of (1-acetyl-5-methyl-2-trifluoromethyl-1H-indol-3-yl)-acetic acid ethyl ester (3.25 g, 9.94 mmol), AIBN (408 mg, 2.49 mmol) and N-bromosuccinimide (1.77 g, 9.94 mmol) in tetrachloromethane (50 mL) is heated to 80° C. for 2 h. After cooling to room temperature, the reaction mixture is filtered and the filtrate concentrated in vacuo. The crude product is purified by flash column chromatography (silica gel, cyclohexane/EtOAc 9:1) to afford the title compound as a yellow solid (2.44 g, 6.02 mmol, 61%). 1H NMR (400 MHz, CDCl3, 298 K): δ=7.88 (s, J=8.8 Hz, 1H), 7.64 (s, 1H), 7.50 (d, J=8.8 Hz, 1H), 4.62 (s, 2H), 4.18 (q, J=7.1 Hz, 2H), 3.93 (s, 2H), 2.76 (s, 3H), 1.25 (t, J=7.1 Hz, 3H). MS (ES+): 423 (M(C16H1579BrF3NO3)+H2O)+.
Reaction SMILES: [CH2:1]([O:4][C:5]1[C:10]([Cl:11])=[CH:9][C:8]([N+:12]([O-:14])=[O:13])=[C:7](Cl)[CH:6]=1)[CH:2]=[CH2:3].[N-:16]=[N+]=[N-].[Na+].[N-]=[N+]=[N-].[BH4-].[Na+]>CN(C=O)C>[N+:12]([C:8]1[CH:9]=[C:10]([Cl:11])[C:5]([O:4][CH2:1][CH:2]=[CH2:3])=[CH:6][C:7]=1[NH2:16])([O-:14])=[O:13]
Reactant: [N-]=[N+]=[N-]
Reactant: C=CCOc1cc(Cl)c([N+](=O)[O-])cc1Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCOc1cc(N)c([N+](=O)[O-])cc1Cl
Temperature: 0 °C
Yield: 82.7 %

Procedure:
The product of step (b) (66.1 g, 267 mmol) was dissolved in 600 ml DMF at ambient temperature. Sodium azide (19.1 g, 267 mmol) was added and the mixture allowed to stir over a 4-day weekend, after which another 2 g (30.8 mmol) of the azide were added. Sodium borohydride (2.77 g, 73.5 mmol) was added in small portions while cooling in an ice bath. The mixture was stirred over night and then another 0.85 g (0.015 m) of sodium borohydride were added portionwise to the cold mixture. When the reaction appeared complete, the mixture was poured over ice water, the product filtered and dried to yield 50.5 g of 2-nitro-4-chloro-5-allyloxyaniline.
Reaction SMILES: O[CH2:2][C:3]1[N:4]=[N:5][S:6][C:7]=1[CH3:8].[NH2:9][CH2:10][CH2:11][SH:12]>>[NH2:9][CH2:10][CH2:11][S:12][CH2:2][C:3]1[N:4]=[N:5][S:6][C:7]=1[CH3:8]
Reactant: Cc1snnc1CO
Reactant: NCCS
Product: Cc1snnc1CSCCN

Procedure:
Reacting 4-hydroxymethyl-5-methyl-1,2,3-thiadiazole with cysteamine by the procedure of Example 1 gives 4-[ (2-aminoethyl)thiomethyl]-5-methyl-1,2,3-thiadiazole.
Reaction SMILES: [F:1][C@H:2]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Br:11])[CH:6]=1)[CH2:3][OH:4].[C:12]1([CH3:22])[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=1.N1C=CC=CC=1>C(Cl)Cl>[Br:11][C:7]1[CH:6]=[C:5]([C@H:2]([F:1])[CH2:3][O:4][S:18]([C:15]2[CH:16]=[CH:17][C:12]([CH3:22])=[CH:13][CH:14]=2)(=[O:20])=[O:19])[CH:10]=[CH:9][CH:8]=1
Reactant: OC[C@H](F)c1cccc(Br)c1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OC[C@@H](F)c2cccc(Br)c2)cc1
Temperature: 25 °C

Procedure:
A solution of (R)-2-fluro-2-(3-bromophenyl)-1-ethanol (5 mmol) and p-toluenesulfonyl chloride (5.1 mmol) in CH2Cl2 at ice bath temperatures is treated with stirring with pyridine. The reaction mixture is heated at reflux temperature under a nitrogen atmosphere for 16 h, cooled to room temperature, washed with 10% HCl, saturated NaHCO3 and brine, dried over MgSO4 and concentrated in vacuo to give toluene4-sulfonic acid (S)-2-(3-bromophenyl)-2-fluoro-ethyl ester.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[Cl:10]NC(=O)CCC(N)=O.S(=O)(O)[O-].[Na+]>CN(C)C=O>[Cl:10][C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][CH:2]=1
Reactant: c1ccc2[nH]ccc2c1
Reactant: NC(=O)CCC(=O)NCl
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: Clc1c[nH]c2ccccc12
Temperature: 10 °C
Reaction time: 0.25 h
Yield: 110.2 %

Procedure:
To a 3 L round bottom flask equipped with a mechanical stirrer, thermometer and a Gooch tube was added sieve-dried dimethylformamide (1.2 L) and indole (200 g). The solution was stirred under an atmosphere of nitrogen and cooled to about 10° C. N-Chlorosuccinamide (216.6 g) was added via the Gooch tube at a rate such as to maintain a reaction temperature of 10° -18° C. After the addition was complete, a second charge of N-chlorosuccinamide (34.2 g) was added. When the reaction was found to be >97% complete by high performance liquid chromatography, the reaction mixture was poured into a well-stirred, cold solution of aqueous sodium bisulfite (5.2 L of 0.1% sodium bisulfite in water and 640 g of ice). After about 15 min, the precipitate was collected and washed with water (2×1 L). The filtrate was partitioned between dichloromethane (1.3 L) and 0.1% aqueous sodium bisulfite solution (1 L). The phases were separated and the aqueous solution was extracted with dichloromethane (300 ml). The organic fractions were combined, washed with water (800 mL), dried over anhydrous magnesium sulfate, filtered and the filtrate was concentrated (at about 25° C. and about 50 mm Hg). The residue was dried in a vacuum oven at 25° C. and about 125 mm Hg for 2 to 4 hrs to yield 240.3 g (92.9%) of product, 3-chloroindole (91.6% pure).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]([C:16]2[CH:28]=[CH:27][C:19]([C:20]([N:22]([CH2:25][CH3:26])[CH2:23][CH3:24])=[O:21])=[CH:18][CH:17]=2)[N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH:6]=[CH:7][CH:8]=1)#[N:2].[CH:29](=O)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.ClCCl>[CH2:25]([N:22]([CH2:23][CH3:24])[C:20]([C:19]1[CH:27]=[CH:28][C:16]([CH:9]([N:10]2[CH2:11][CH2:12][N:13]([CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH2:14][CH2:15]2)[C:5]2[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=2)[C:1]#[N:2])=[CH:17][CH:18]=1)=[O:21])[CH3:26]
Reactant: CCN(CC)C(=O)c1ccc(C(c2cccc(C#N)c2)N2CCNCC2)cc1
Reactant: O=Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: ClCCCl
Product: CCN(CC)C(=O)c1ccc(C(c2cccc(C#N)c2)N2CCN(Cc3ccccc3)CC2)cc1
Yield: 57 %

Procedure:
To a solution of INTERMEDIATE 3 (606 mg) in 1,2-dichloroethane (15 mL) was added benzaldehyde (220 μL, 1.3 eq) and sodium triacetoxyborohydride (480 mg, 1.4 eq). After 3 days the reaction was diluted with dichloromethane (50 mL) and washed with saturated aqueous sodium bicarbonate. The aqueous layer was washed with dichloromethane (2×25 mL) and the combined organic extracts were dried (MgSO4), filtered and concentrated. The residue was purified by flash chromatography, eluting 5% methanol in dichloromethane to yield INTERMEDIATE 4a as a colorless foam (428mg, 57%).
Reaction SMILES: [C:1]([C:3]1[C:4]([Cl:14])=[N:5][C:6]([Cl:13])=[CH:7][C:8]=1[C:9]([F:12])([F:11])[F:10])#[N:2].S(=O)(=O)(O)[OH:16]>>[Cl:14][C:4]1[C:3]([C:1]([NH2:2])=[O:16])=[C:8]([C:9]([F:10])([F:12])[F:11])[CH:7]=[C:6]([Cl:13])[N:5]=1
Reactant: N#Cc1c(C(F)(F)F)cc(Cl)nc1Cl
Reactant: O=S(=O)(O)O
Product: NC(=O)c1c(C(F)(F)F)cc(Cl)nc1Cl
Temperature: 0 °C

Procedure:
11.3 g of 3-cyano-2,6-dichloro-4-trifluoromethylpyridine was gradually added to 22.6 ml of concentrated sulfuric acid, and then the mixture was heated and reacted at 100° C. for one hour. After completion of the reaction, the mixture was poured into ice water, whereupon white precipitates formed. The precipitates were collected by filtration, and the filtrate was extracted with methylene chloride. The organic layer was dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure to obtain a white solid. This solid and the precipitates previously obtained, were put together to obtain 9.2 g of 2,6-dichloro-4-trifluoromethyl-3-pyridine carboxamide.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4](I)[CH:3]=1.[Cl:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]#[CH:18].C(NCC)C>CN(C)C=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([C:18]#[C:17][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[Cl:10])[CH:3]=1
Reactant: C#Cc1ccccc1Cl
Reactant: Nc1ccc(Cl)cc1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCNCC
Product: Nc1ccc(Cl)cc1C#Cc1ccccc1Cl
Temperature: 50 °C
Yield: 62 %

Procedure:
To a stirred solution of 4-chloro-2-iodo-phenylamine (500 mg, 1.97 mmol) in dimethylformamide (4 ml) was added PdCl2(PPh3)2 (7 mg, 0.02 mmol) followed by copper(I)iodide (3.7 mg, 0.02 mmol), 1-chloro-2-ethynyl-benzene (0.28 ml, 2.36 mmol) and diethylamine (1.65 ml, 15.78 mmol) under nitrogen at RT. The resulting reaction mixture was purged with nitrogen and then heated to 50° C. for 5 h. After cooling to room temperature, the mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated in vacuo to give a crude residue which was purified by flash column chromatography (elution with 4% EtOAc in hexane) to yield 4-chloro-2-(2-chloro-phenylethynyl)-phenylamine (320 mg, 62% yield) as an off white solid. LC-MS: 262 (M+H)+.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[C:6]([I:22])=[C:7]([C:16]([I:21])=[C:17]([NH2:20])[C:18]=1[I:19])[C:8]([NH:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14])=[O:9])=[O:4].[CH3:23][C:24](N(C)C)=[O:25]>>[CH3:1][NH:2][C:3]([C:5]1[C:6]([I:22])=[C:7]([C:16]([I:21])=[C:17]([NH:20][C:24](=[O:25])[CH3:23])[C:18]=1[I:19])[C:8]([NH:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14])=[O:9])=[O:4]
Reactant: CNC(=O)c1c(I)c(N)c(I)c(C(=O)NCCC(=O)O)c1I
Reactant: CC(=O)N(C)C
Product: CNC(=O)c1c(I)c(NC(C)=O)c(I)c(C(=O)NCCC(=O)O)c1I
Yield: 66 %

Procedure:
From 100.0 g. (0.155 mole) of N-(3-methylaminocarbonyl-5-amino-2,4,6-triiodobenzoyl)-β-alanine (IX c), m.p. about 190° C., in 190 ml. of dimethylacetamide, 70.1 g. (66.0%) of the above product, m.p. 295°-297° C. (under decomposition) is obtained with the addition of 28.7 ml. of acetyl chloride analogously to Example 14 and after reprecipitation from aqueous ammonia with hydrochloric acid.