Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(Cl)([Cl:3])=O.CN(C)C=O.[F:10][C:11]([F:27])([F:26])[C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:19]=[C:20]([CH2:24]O)[CH:21]=[N:22][CH:23]=2)=[CH:14][CH:13]=1>ClCCl>[Cl:3][CH2:24][C:20]1[CH:21]=[N:22][CH:23]=[C:18]([C:15]2[CH:16]=[CH:17][C:12]([C:11]([F:27])([F:26])[F:10])=[CH:13][CH:14]=2)[CH:19]=1
Reactant: OCc1cncc(-c2ccc(C(F)(F)F)cc2)c1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: FC(F)(F)c1ccc(-c2cncc(CCl)c2)cc1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
177 mg (0.11 ml, 1.49 mmol) thionyl chloride were added drop by drop at 0° C. to a solution of 0.1 ml N,N-dimethylformamide (DMF) and 196 mg (0.74 mmol) [5-(4-Trifluoromethyl-phenyl)-pyridin-3-yl]-methanol in 6 ml dichloromethane and stirred for 1.5 h at 0° C. The mixture was poured on ice/sodium bicarbonate solution and the organic phase separated. The water phase is extracted with dichloromethane. The combined organic phases were washed with water, dried (sodium sulphate), evaporated and the obtained material (174 mg, 81%) used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.FC(F)(F)S(O[C:17]1[CH:22]=[CH:21][C:20]([C@H:23]2[C:28]3=[N:29][S:30](=[O:34])(=[O:33])[CH2:31][CH2:32][N:27]3[CH2:26][CH2:25][CH2:24]2)=[CH:19][CH:18]=1)(=O)=O.C(=O)([O-])[O-].[Na+].[Na+]>CCO.O.CN(C=O)C.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>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:17]2[CH:18]=[CH:19][C:20]([C@H:23]3[C:28]4=[N:29][S:30](=[O:34])(=[O:33])[CH2:31][CH2:32][N:27]4[CH2:26][CH2:25][CH2:24]3)=[CH:21][CH:22]=2)=[CH:4][CH:3]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: O=S1(=O)CCN2CCC[C@@H](c3ccc(OS(=O)(=O)C(F)(F)F)cc3)C2=N1
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: [Na+]
Solvent: CCO
Solvent: O
Solvent: CN(C)C=O
Product: O=S1(=O)CCN2CCC[C@@H](c3ccc(-c4ccc(Cl)cc4)cc3)C2=N1
Temperature: 50 °C
Reaction time: 16 h
Yield: 29.4 %

Procedure:
Tetrakis(triphenylphosphine)palladium(0) (16.0 mg) was added to a mixture of (4-chlorophenyl)boronic acid (76.0 mg), 4-[(9S)-2,2-dioxido-3,4,6,7,8,9-hexahydropyrido[2,1-c][1,2,4]thiadiazin-9-yl]phenyl trifluoromethanesulfonate (100 mg) and sodium carbonate (51.4 mg) in EtOH (3 mL), water (1.5 mL) and DMF (dry) (2 mL). The mixture was stirred at 50° C. under nitrogen for 16 hr. Silica-gel was added and the volatiles were removed in vacuo. The mixture supported on silica-gel was purified by column chromatography (NH silica gel, eluted with MeOH in EtOAc) and crystallized from MeCN-THF/IPE to give the title compound (26.7 mg) as a colorless crystal.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:27]2[C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[N:29]([CH3:36])[CH:28]=2)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[C:13]([N+:15]([O-])=O)[C:12]([N:18]3[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]3)=[CH:11][C:10]=2[O:25][CH3:26])=[N:6][CH:7]=1.[NH4+].[Cl-]>C(O)C.O.[Fe]>[Cl:1][C:2]1[C:3]([C:27]2[C:35]3[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=3)[N:29]([CH3:36])[CH:28]=2)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[C:13]([NH2:15])[C:12]([N:18]3[CH2:19][CH2:20][N:21]([CH3:24])[CH2:22][CH2:23]3)=[CH:11][C:10]=2[O:25][CH3:26])=[N:6][CH:7]=1
Reactant: COc1cc(N2CCN(C)CC2)c([N+](=O)[O-])cc1Nc1ncc(Cl)c(-c2cn(C)c3ccccc23)n1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: COc1cc(N2CCN(C)CC2)c(N)cc1Nc1ncc(Cl)c(-c2cn(C)c3ccccc23)n1
Yield: 51.9 %

Procedure:
A mixture of 5-chloro-N-[2-methoxy-4-(4-methylpiperazin-1-yl)-5-nitrophenyl]-4-(1-methylindol-3-yl)pyrimidin-2-amine (Intermediate 92, 750 mg, 1.48 mmol), iron (495 mg, 8.86 mmol) and NH4Cl (55.3 mg, 1.03 mmol) in ethanol (12 mL) and water (4 mL) was heated at reflux for 4 h. Purification by ion exchange chromatography, using an SCX column and eluting with 7M methanolic ammonia provided part-purified material that was concentrated in vacuo onto silica. Purification by FCC, eluting with 0-4% 7N methanolic ammonia in CH2Cl2 gave the title compound (367 mg, 52%) as a yellow solid. Impure fractions containing desired product were concentrated in vacuo and the resulting residue was triturated with CH2Cl2/diethyl ether to give more of the title compound (230 mg, 33%) as a yellow solid. Total: 597 mg, 85%; 1H NMR: (CDCl3) 2.37 (3H, s), 2.56 (4H, br s), 2.95 (4H, br t), 3.75 (2H, br s), 3.84 (3H, s), 3.90 (3H, s), 6.70 (1H, s), 7.27-7.36 (2H, m), 7.38-7.42 (1H, m), 7.63 (1H, s), 8.13 (1H, s), 8.21 (1H, s), 8.33 (1H, s), 8.63-8.69 (1H, m); m/z: ES+ MH+ 478.55.
Reaction SMILES: O[C:2]1[C:3](=[O:12])[O:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[NH2:13][OH:14]>>[O:14]1[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:10]=2[C:11]([CH2:2][C:3]([OH:12])=[O:4])=[N:13]1
Reactant: NO
Reactant: O=c1oc2ccccc2cc1O
Product: O=C(O)Cc1noc2ccccc12

Procedure:
Hydroxycoumarin (5) is treated with hydroxylamine to obtain benzo[d]isoxazol-3-yl-acetic acid (6) which is brominated at the alpha position to give benzo[d]isoxazol-3-yl-bromoacetic acid (7) from which 3-bromomethyl-benzo[d]isoxazole (8) is obtained by decarboxylation. The development of this process is limited in that the starting intermediate (1) is not commercially available and therefore the preparation of zonisamide is very complex. In fact, Posner reaction for the preparation of acid (6) requires the use of metal sodium. Moreover, when metal sodium is used in alcoholic solution, besides acid (6) also remarkable amounts of O-hydroxy-acetophenone-oxime as by-product are obtained. Furthermore, the decarboxylation reaction to give compound (8) requires drastic conditions, namely the presence of a large excess of 50% sulfuric acid and reflux temperature, and the resulting product is thus difficult to be isolated.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[NH:12][N:11]=[N:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH2:13]([O:17][C:18](=[O:22])[C:19]([O-])=[O:20])[CH2:14][CH2:15][CH3:16]>>[CH3:16][CH2:15][CH2:14][CH2:13][O:17][C:18]([C:19]([NH:1][C:2]1[CH:3]=[C:4]([C:8]2[N:12]=[N:11][NH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1)=[O:20])=[O:22]
Reactant: Nc1cccc(-c2nnn[nH]2)c1
Reactant: CCCCOC(=O)C(=O)[O-]
Product: CCCCOC(=O)C(=O)Nc1cccc(-c2nn[nH]n2)c1
Yield: 75 %

Procedure:
5-(3-Aminophenyl)tetrazole (1.7 g) was added to 12 ml of n-butyloxalate and reacted at a bath temperature of 165° to 175° C. for 1.5 hr while stirring. After cooling, the precipitated crystals were filtered off and recrystallized from acetone-n-hexane, to give 2.3 g (yield: 75%) of 5-(3-n-butyloxalylaminophenyl)tetrazole.
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]3[CH2:10][CH2:11][CH2:12][C:3]([C:4]=23)=[C:2]1[C:13]([O:15][CH2:16][CH3:17])=[O:14].[H-].[Na+].[CH3:20]I>CN(C)C=O>[CH3:20][N:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]3[CH2:10][CH2:11][CH2:12][C:3]([C:4]=23)=[C:2]1[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: CCOC(=O)c1[nH]c2cccc3c2c1CCC3
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1c2c3c(cccc3n1C)CCC2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.1 %

Procedure:
To a solution of ethyl 1,3,4,5-tetrahydro-benz[cd]indole-2-carboxylate (1.00 g , 4.36 mmol) in N,N-dimethylformamide (20 ml) was added 60% sodium hydride (0.19 g, 4.80 mmol), followed by stirring at room temperature for 30 minutes. Then, methyl iodide (1.86 g, 13.1 mmol) was added and the resulting mixture was stirred at room temperature for 2 hours, after which the reaction mixture was poured into ice water, followed by extraction with ethyl acetate (twice). The extract solution was washed with a 5% aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was purified by a silica gel column chromatography (eluent: ethyl acetate/n-hexane=1.5/98.5) to obtain ethyl 1,3,4,5-tetrahydro-1-methyl-benz[cd]indole-2-carboxylate (1.03 g).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[C:6]([NH:9][CH2:10][C:11]([CH3:14])([OH:13])[CH3:12])[C:5]([N+:15]([O-])=O)=[C:4]([O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:3]=1>[Pt].C1(C)C=CC=CC=1.C(O)(C)C>[NH2:15][C:5]1[C:4]([O:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[N:3][C:2]([CH3:1])=[C:7]([CH3:8])[C:6]=1[NH:9][CH2:10][C:11]([CH3:12])([OH:13])[CH3:14]
Reactant: Cc1nc(Oc2ccccc2)c([N+](=O)[O-])c(NCC(C)(C)O)c1C
Agent: [Pt]
Solvent: CC(C)O
Solvent: Cc1ccccc1
Product: Cc1nc(Oc2ccccc2)c(N)c(NCC(C)(C)O)c1C

Procedure:
To a 500 ml Parr hydrogenation flask was added 5% platinum on carbon (1.432 g) and a solution of 1-[(2,3-dimethyl-5-nitro-6-phenoxypyridin-4-yl)amino]-2-methylpropan-2-ol in 90/10 toluene/isopropanol (105 ml). The flask was evacuated until the solvent bubbled, and hydrogen was pressured into the flask at 207 kPa. After three evacuation cycles the flask was pressurized with hydrogen to 345 kPa and mixed on a shaker for about 2 hours. The pressure was released, and thin layer chromatography (TLC) monitoring of the reaction mixture indicated complete reaction. The reaction mixture was filtered, and the solvent was removed under reduced pressure. The resulting product was used in the next step.
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]([NH:7][C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=2)=[N:4][C:3]=1[C:18]([NH2:20])=[O:19].[CH3:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][C:23]=1[N+:31]([O-:33])=[O:32]>N1C=CC=CC=1>[CH3:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([NH:1][C:2]2[S:6][C:5]([NH:7][C:8]3[CH:17]=[CH:16][C:15]4[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=4)[CH:9]=3)=[N:4][C:3]=2[C:18]([NH2:20])=[O:19])=[O:27])=[CH:24][C:23]=1[N+:31]([O-:33])=[O:32]
Reactant: Cc1ccc(C(=O)Cl)cc1[N+](=O)[O-]
Reactant: NC(=O)c1nc(Nc2ccc3ccccc3c2)sc1N
Solvent: c1ccncc1
Product: Cc1ccc(C(=O)Nc2sc(Nc3ccc4ccccc4c3)nc2C(N)=O)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 16 h
Yield: 66 %

Procedure:
To a mixture of 5-amino-2-(naphthalen-2-ylamino)thiazole-4-carboxamide (0.2 g, 0.70 mmol) in pyridine (5 mL) was added a solution of 4-methyl-3-nitrobenzoyl chloride in pyridine (3 mL) at 0° C. under nitrogen atmosphere. The mixture was allowed to warm up to rt, and stirred for 16 hrs at rt. The solvent was evaporated, and the crude residue was suspended into EtOAc (20 mL). The resulting solids were collected by filtration and washed with MeOH (2×5 mL) to give 0.21 g (66% yield) of the titled compound.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][C:13]([OH:15])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:16](N(CC)CC)[CH3:17].C(OC(ON=C(C#N)C(N)=O)=O)C>CN(C)C=O>[CH2:16]([O:14][C:13](=[O:15])[CH2:12][NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10])[CH3:17]
Reactant: CCN(CC)CC
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Agent: CCOC(=O)ON=C(C#N)C(N)=O
Solvent: CN(C)C=O
Product: CCOC(=O)CNC(=O)OCc1ccccc1
Reaction time: 2 h

Procedure:
To a solution of N-benzyloxycarbonylglycine (1.05 g) and triethylamine (0.73 ml) in dimethylformamide (9 ml), 2-ethoxycarbonyloxyimino-2-cyanoacetic acid amide (1.11 g) is added, and the resulting mixture is stirred for 2 hours. The reaction mixture is treated as in Example A to give N-benzyloxycarbonylglycine ethyl ester (0.2 g) as an oil.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:12]([F:13])=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[CH:7][NH:8]2.[CH3:14][C@H:15]1[CH2:17][O:16]1.O>O1CCCC1.CCOCC>[Cl:3][C:4]1[C:12]([F:13])=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[CH:7][N:8]2[CH2:14][C@@H:15]([OH:16])[CH3:17]
Reactant: C[C@H]1CO1
Reactant: Fc1ccc2[nH]ccc2c1Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Solvent: C1CCOC1
Product: C[C@H](O)Cn1ccc2c(Cl)c(F)ccc21
Reaction time: 1 h
Yield: 78.9 %

Procedure:
A suspension of 0.11 g of sodium hydride dispersion in 15 ml of tetrahydrofuran was treated with 0.5 g of 4-chloro-5-fluoroindole at 0° and stirred at this temperature for 1 hour. After the addition of 0.4 ml of (S)-methyloxirane the reaction mixture was stirred at s room temperature for 48 hours and subsequently treated with water. The mixture was diluted with ether, washed with water and with saturated sodium chloride solution and the organic phase was dried over sodium sulfate. After removal of the solvent the residue was chromatographed over 30 g of silica gel with toluene-ethyl acetate (33:1). There was obtained 0.53 g (78.9%) of (S)-1-(4-chloro-5-fluoro-indol-1-yl)-propan-2-ol as a yellow oil.
Reaction SMILES: N1C2C(=CC=CC=2)C=CC=1.[S].[F:12][C:13]([F:28])([F:27])[C:14]1[CH:15]=[C:16]([CH:20]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:22]=1)[C:17](Cl)=[O:18].[H][H]>C1(C)C=CC=CC=1.[Pd].O>[F:12][C:13]([F:27])([F:28])[C:14]1[CH:15]=[C:16]([CH:20]=[C:21]([C:23]([F:26])([F:24])[F:25])[CH:22]=1)[CH:17]=[O:18]
Reactant: [H][H]
Reactant: O=C(Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [Pd]
Agent: [S]
Solvent: c1ccc2ncccc2c1
Solvent: Cc1ccccc1
Solvent: O
Product: O=Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 105 °C
Yield: 86.8 %

Procedure:
60 g of freshly distilled quinoline and 10 g of sulfur were refluxed for 5 hours with stirring. The cooled mixture was diluted with 700 ml of toluene. This gave a solution of a quinoline-sulfur complex containing 100 mg of the complex per ml. 2.5 g of 5% palladium on barium sulfate, 0.25 ml of the solution of the complex and 250 g of 3,5-bis(trifluoromethyl)benzoyl chloride were placed in a reaction vessel at room temperature with exclusion of water. A gentle stream of hydrogen gas was then passed through the mixture at atmospheric pressure. The mixture was subsequently heated to 100-110° C. and hydrogen gas was continuously introduced at atmospheric pressure. After liberation of acidic offgases had ceased (12 hours), the mixture was cooled, the catalyst was separated off by filtration, and the filtrate was distilled at 27 mbar. A yield of 190.0 g of 3,5-bis(trifluoromethyl)benzaldehyde having a boiling point of 79° C. was obtained. This corresponds to a yield of 86% of theory. A small amount of a mixture of toluene and 3,5-bis(trifluoromethyl)benzene was obtained as first fraction during the distillation.
Reaction SMILES: [N:1]1([C:7]2[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH:23]1([C:26](Cl)=[O:27])[CH2:25][CH2:24]1>ClCCl>[CH:23]1([C:26]([N:4]2[CH2:3][CH2:2][N:1]([C:7]3[CH:8]=[CH:9][C:10]([C:11]([OH:13])=[O:12])=[CH:14][CH:15]=3)[CH2:6][CH2:5]2)=[O:27])[CH2:25][CH2:24]1
Reactant: O=C(Cl)C1CC1
Reactant: O=C(O)c1ccc(N2CCNCC2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(O)c1ccc(N2CCN(C(=O)C3CC3)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 51 %

Procedure:
To a mixture of 4-piperazin-1-yl-benzoic acid (20 g, 71.6 mmol) and triethylamine (58 g, 573 mmol) in dichloromethane (500 mL) was added cyclopropanecarbonyl chloride dropwise at 0° C. The reaction mixture was stirred at RT overnight. The solvent was removed by rotary evaporation. The residue was diluted with water, treated with sodium hydroxide, and washed with ethyl acetate and dichloromethane. The aqueous phase was acidified to pH 6 with 5 N HCl. The resulting precipitate was collected by filtration and concentrated to dryness to provide the title compound (10 g, 51% yield) as a white solid. 1H NMR(CH3OD, 400 MHz) δ (ppm) 7.87 (m, 2H), 6.95 (m, 2H), 3.90 (s, 2H), 3.73 (s, 2H), 3.29 (m, 4H), 1.99 (m, 1H), 0.86 (m, 4H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:21]2[C:13](=[CH:14][C:15]3[CH2:16][O:17][CH2:18][C:19]=3[CH:20]=2)[C@@H:12]([NH:22][CH2:23][C:24]2[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[C:26]([C:34]([F:37])([F:36])[F:35])[CH:25]=2)[CH2:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:38]([N:41](C(C)C)CC)(C)C.N#CBr>O1CCCC1.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[C:21]2[C:13](=[CH:14][C:15]3[CH2:16][O:17][CH2:18][C:19]=3[CH:20]=2)[C@@H:12]([N:22]([CH2:23][C:24]2[CH:25]=[C:26]([C:34]([F:36])([F:37])[F:35])[CH:27]=[C:28]([C:30]([F:32])([F:31])[F:33])[CH:29]=2)[C:38]#[N:41])[CH2:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCN(C(C)C)C(C)C
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](NCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2cc3c(cc21)COC3
Agent: N#CBr
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC[C@H](N(C#N)Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2cc3c(cc21)COC3
Temperature: 65 °C
Reaction time: 8 h

Procedure:
To a solution of (S)-9-(3,5-bis-trifluoromethyl-benzylamino)-1,3,6,7,8,9-hexahydro-2-oxa-5-aza-cyclohepta[f]indene-5-carboxylic acid tert-butyl ester (1.75 mmol) in tetrahydrofuran (7 mL) and diisopropyl ethylamine (5.25 mmol), add cyanogenbromide (5.25 mmol) and heat to 65° C. After stirring overnight, cool to room temperature and dilute with ethyl acetate (10 mL). Wash the organic portion with water (10 mL), followed by brine (10 mL). Dry the organic portion over sodium sulfate, filter, and remove solvent under vacuum. Chromatograph the product over silica gel, eluting with ethyl acetate/hexane (5-35%) to afford the title compound as an oil. MS (ES+): 554.2 (M−H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.ClC1C=CC=C(C(OO)=O)C=1.[Br:23]C1C=C(SC)C(Cl)=NC=1.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[Br:23][C:5]1[CH:6]=[C:7]([S:8]([CH3:11])(=[O:10])=[O:9])[C:2]([Cl:1])=[N:3][CH:4]=1
Reactant: CS(=O)(=O)c1cccnc1Cl
Reactant: CSc1cc(Br)cnc1Cl
Agent: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CS(=O)(=O)c1cc(Br)cnc1Cl
Temperature: 25 °C
Reaction time: 20 h
Yield: 73 %

Procedure:
Using an analogous method to that described by Ponticello et al, J. Org. Chem., Vol. 44, No. 17, 1979, for the preparation of 2-chloro-3-methylsulfonylpyridine, a solution of 3-chloroperbenzoic acid (75% pure; 5 g, 22 mmol) in chloroform (50 mL) was added to a stirred solution of 5-bromo-2-chloro-3-methylthiopyridine (2.6 g, 10.9 mmol) in chloroform (50 mL) and the mixture was stirred at room temperature for 20 hours. The resultant solution was poured into a saturated aqueous sodium hydrogen carbonate solution. The organic phase was separated, washed twice with saturated aqueous sodium hydrogen carbonate solution and dried over sodium sulfate. The organic solvent was removed under reduced pressure and the residue was crystallised from a methanolic solution (20 mL). The resultant solid was filtered off and dried to afford 5-bromo-2-chloro-3-methylsulfonylpyridine (2.15 g, 73% yield); 1H NMR Spectrum: (CDCl3) 8.70 (1H, d); 8.59 (1H, d); 3.34 (3H, s); Mass Spectrum: M+H+ 270 and 272.
Reaction SMILES: [C:1]1([O:7][P:8]([CH2:17][NH:18][C@@H:19]([CH2:28][C:29]2[CH:34]=[CH:33][C:32]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[CH:31][CH:30]=2)[C:20]([NH:22][CH2:23][CH2:24][C:25]([OH:27])=[O:26])=[O:21])([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.Cl[CH2:49][C:50]([N:52]([CH2:55][CH3:56])[CH2:53][CH3:54])=[O:51].[I-].[Na+]>C(OCC)(=O)C>[C:1]1([O:7][P:8]([CH2:17][NH:18][C@@H:19]([CH2:28][C:29]2[CH:30]=[CH:31][C:32]([C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)=[CH:33][CH:34]=2)[C:20]([NH:22][CH2:23][CH2:24][C:25]([O:27][CH2:49][C:50](=[O:51])[N:52]([CH2:55][CH3:56])[CH2:53][CH3:54])=[O:26])=[O:21])([O:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)CCNC(=O)[C@H](Cc1ccc(-c2ccccc2)cc1)NCP(=O)(Oc1ccccc1)Oc1ccccc1
Reactant: CCN(CC)C(=O)CCl
Agent: [I-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCN(CC)C(=O)COC(=O)CCNC(=O)[C@H](Cc1ccc(-c2ccccc2)cc1)NCP(=O)(Oc1ccccc1)Oc1ccccc1

Procedure:
To a stirred solution of (S)-N-[2-(diphenylphosphonomethylamino)-3-(4-biphenylyl)-propionyl]-3-aminopropionic acid (0.6 g, 1.07 mmol) in ethyl acetate (9 mL) is added triethylamine (0.19 mL, 1.34 mmol) followed by 2-chloro-N,N-diethylacetamide (0.18 mL, 1.34 mmol) and sodium iodide (20 mg, 0.13 mmol). The solution is heated under nitrogen at 80° for 12 hours. The precipitate is filtered off and the filtrate is treated with water (10 mL) and 2N HCl (0.5 mL). The organic layer is separated, dried over sodium sulfate and filtered. After evaporation of the solvent under reduced pressure, the semi-solid residue is purified by flash chromatography on silica gel, eluting with ethyl acetate. The title compound is finally crystallized from ethyl acetate-hexane to yield N,N-diethylcarbamoylmethyl (S)-N-[2-(diphenylphosphonomethylamino)-3-(4-biphenylyl)-propionyl]-3-aminopropionate, m.p. 68°-74°, [α]D =-20.55 (c=0.84, CHCl3).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1I.C[C:30]1[C:35]([F:36])=[C:34]([O:37][CH3:38])[CH:33]=[CH:32][C:31]=1[SH:39].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C.[Cu]I>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]([C:11]2[N:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:15](=[O:23])[C:14]3=[C:24]([CH3:27])[CH:25]=[CH:26][N:13]3[N:12]=2)[CH3:10])[C:3]=1[S:39][C:31]1[CH:32]=[CH:33][C:34]([O:37][CH3:38])=[C:35]([F:36])[CH:30]=1
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3I)n(-c3ccccc3)c(=O)c12
Reactant: COc1ccc(S)c(C)c1F
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(Sc2c(N)ncnc2N[C@@H](C)c2nn3ccc(C)c3c(=O)n2-c2ccccc2)cc1F
Temperature: 70 °C

Procedure:
(S)-2-(1-((6-Amino-5-iodopyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (220 mg, 0.45 mmol) and methyl 3-fluoro-4-methoxybenzenethiol (107 mg, 0.68 mmol) were dissolved in 10 mL dimethylformamide in a microwave vessel. Potassium carbonate (94 mg, 0.68 mmol) and copper(I) iodide (129 mg, 0.68 mmol) were added and the mixture was heated overnight at 70° C. The reaction mixture was cooled at room temperature and diluted with ethyl acetate. The organic phase was washed with 2N HCl, 4% sodium bicarbonate solution, water and brine and dried over sodium sulphate, filtered and evaporated under reduced pressure. The residue (0.26 g, 87%) was used in the next synthetic step without further purification. Purity 78%.
Reaction SMILES: [CH:1]1([NH:8][NH:9][C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:20][C:21]([CH3:26])([CH3:25])[C:22](Br)=[O:23]>>[Br:20][C:21]([CH3:26])([CH3:25])[C:22]([N:8]([CH:1]1[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[NH:9][C:10]([O:12][CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)=[O:11])=[O:23]
Reactant: O=C(NNC1CCCCCC1)OCc1ccccc1
Reactant: CC(C)(Br)C(=O)Br
Product: CC(C)(Br)C(=O)N(NC(=O)OCc1ccccc1)C1CCCCCC1

Procedure:
Benzyl 2-cycloheptylhydrazinecarboxylate and 2-bromoisobutyryl bromide were used for a similar reaction and treatment as Process 3 of Example 1, and benzyl 2-(2-bromoisobutyryl)-2-cycloheptylhydrazinecarboxylate was obtained as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH3:13])[C:11]([C:14]#[N:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH:16]1([C:22](Cl)=[O:23])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>>[C:14]([C:11]1[N:12]([CH3:13])[C:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:1][C:22]([CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)=[O:23])=[CH:3][CH:4]=2)=[CH:9][CH:10]=1)#[N:15]
Reactant: Cn1c(C#N)ccc1-c1ccc(N)cc1
Reactant: O=C(Cl)C1CCCCC1
Product: Cn1c(C#N)ccc1-c1ccc(NC(=O)C2CCCCC2)cc1

Procedure:
The title compound was prepared according to the general procedure for acylation of 5-(4-aminophenyl)-1-methyl-1H-pyrrole-2-carbonitrile using cyclohexanecarbonyl chloride (67 μL, 0.55 mmol) to provide N-[4-(5-cyano-1-methyl-1H-pyrrol-2-yl)phenyl]cyclohexanecarboxamide (0.039 g).