Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[S:6][C:5]([NH:7][C:8](=[O:23])[N:9]([CH:16]2[CH2:21][CH2:20][CH:19]([CH3:22])[CH2:18][CH2:17]2)[CH:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[N:4][CH:3]=1.[C:24]([O:28][CH3:29])(=[O:27])[CH2:25][SH:26]>>[CH3:29][O:28][C:24](=[O:27])[CH2:25][S:26][C:2]1[S:6][C:5]([NH:7][C:8]([N:9]([CH:16]2[CH2:21][CH2:20][CH:19]([CH3:22])[CH2:18][CH2:17]2)[CH:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[O:23])=[N:4][CH:3]=1
Reactant: CC1CCC(N(C(=O)Nc2ncc(Br)s2)C2CCOCC2)CC1
Reactant: COC(=O)CS
Product: COC(=O)CSc1cnc(NC(=O)N(C2CCOCC2)C2CCC(C)CC2)s1

Procedure:
Prepared as described in general procedure (D) using 3-(5-bromo-thiazol-2-yl)-1-(4-methylcyclohexyl)-1-(tetrahydro-pyran-4-yl)-urea (Example 203) and methyl thioglycolate.
Reaction SMILES: [C:1]([O:4][C@H:5]1[O:27][C@@H:26]([CH2:28][O:29][C:30](=[O:37])[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C@H:16]([O:17][C:18](=[O:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C@@H:6]1[O:7]C(=O)C1C=CC=CC=1)(=[O:3])C.Br.O>C(Cl)Cl>[C:1]([O:4][C@@H:5]1[O:27][C@@H:26]([CH2:28][O:29][C:30](=[O:37])[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[C@H:16]([O:17][C:18](=[O:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C@@H:6]1[OH:7])(=[O:3])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CC(=O)O[C@H]1O[C@@H](COC(=O)c2ccccc2)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1
Agent: Br
Solvent: ClCCl
Solvent: O
Product: O=C(OC[C@@H]1O[C@@H](OC(=O)c2ccccc2)[C@@H](O)[C@H]1OC(=O)c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 3.5 h
Yield: 150.3 %

Procedure:
Compound 10 (9 g, 17.84 mmol) was stirred in 100 mL of CH2Cl2 at 0° C. while 70 mL of CH2Cl2 containing HBr (3.2 g, 30.5 mmol) was added in one portion. The mixture was stirred at 0° C. for 3.5 hrs, water (55 ml) was added and the mixture stirred at room temperature for 18 hours. The organic layer was separated, washed with saturated NaHCO3, dried (MgSO4). After evaporation of the solvent, a foam was obtained, which upon recrystallization from CH2Cl2 and n-hexane, gave 11 as a white solid (6.2 g, 75.5%).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH:5]=[CH2:6].Br[C:8]1[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][CH:9]=1>C1COCC1.[Zn+2].[Br-].[Br-]>[CH2:2]([C:8]1[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][CH:9]=1)[CH2:3][CH2:4][CH:5]=[CH2:6]
Reactant: COC(=O)c1ccc(Br)cc1
Reactant: C=CCCCBr
Agent: [Br-]
Agent: [Zn+2]
Solvent: C1CCOC1
Product: C=CCCCc1ccc(C(=O)OC)cc1
Temperature: 56 °C
Reaction time: 24 h

Procedure:
A mixture of dry Mg (900 mg, 37 mmol) and ZnBr2 (5.63 g, 25 mmol) in THF (25 mL) was treated with 5-bromopent-1-ene (4.45 mL, 37.6 mmol) and the subsequent suspension was heated at 56° C. for 18 h. The mixture was cooled to room temperature and methyl 4-bromobenzoate (7.1 g, 33 mmol) and tetrakis-(triphenylphosphine)palladium(0) (1.0 g, 0.865 mmol) were added, and the mixture was stirred at room temperature for 24 h. The mixture was quenched with 3N HCl (aqueous) and extracted with ethyl acetate. The combined organic extracts were dried over anhydrous MgSO4 and evaporated at reduced pressure. The residue was purified by flash chromatography (silica gel, 5% ethyl acetate/hexane) to give the crude title compound which was used without further purification.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[N:9][CH:10]=[C:11]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:12]=2[C:13]([O:15]C)=[O:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:23]O.[OH-].[K+]>O>[CH3:23][C:10]1[N:9]=[N:8][C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[C:12]([C:13]([OH:15])=[O:14])[C:11]=1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: COC(=O)c1c(-c2ccccc2)cnnc1-c1ccccc1
Reactant: CO
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: Cc1nnc(-c2ccccc2)c(C(=O)O)c1-c1ccccc1
Temperature: 100 °C
Yield: 96 %

Procedure:
To a solution of methyl 3,5-diphenylpyridazine-4-carboxylate (300 mg, 1.03 mmol) in 1:1 MeOH:H2O (10 mL), KOH (576 mg, 10.28 mmol) was added and refluxed at 100° C. for 12 h. After the completion of starting material, the reaction mixture was diluted with water (5 mL×1) and washed with ethyl acetate (5 mL×1). The aqueous layer was acidified with 6N HCl (5 mL) solution, solid precipitated out. The solid was filtered and dried to furnish methyl 3, 5-diphenylpyridazine-4-carboxylic acid (compound 6) (275 mg, 96%) as a white solid.
Reaction SMILES: [ClH:1].CO[C:4](=[NH:13])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1.[NH3:14]>CO>[ClH:1].[CH3:12][O:11][C:8]1[CH:9]=[CH:10][C:5]([C:4]([NH2:13])=[NH:14])=[CH:6][CH:7]=1
Reactant: N
Reactant: COC(=N)c1ccc(OC)cc1
Agent: Cl
Solvent: CO
Product: COc1ccc(C(=N)N)cc1
Temperature: 0 °C

Procedure:
35.9 g of 4-methoxybenzimidic acid methylester hydrochloride was dissolved in 300 ml of methanol. After saturation with ammonia gas under cooling in ice-water and stirring, the solution was stirred at room temperature for 15 hours. Then, methanol was evaporated in vacuo. Ethyl acetate was added to the residue. The precipitated crystals were filtered off and dried. Whereby 30.9 g of the desired substance was obtained as white crystals. Melting point is 220° to 221° C.
Reaction SMILES: Br[C:2]1[C:3]([O:22][CH2:23][C:24]([F:27])([F:26])[F:25])=[N:4][C:5]([C:18]([F:21])([F:20])[F:19])=[C:6]([CH:17]=1)[C:7]([NH:9][C@H:10]1[CH2:15][CH2:14][CH2:13][CH2:12][C@@H:11]1[OH:16])=[O:8].[Cl:28][C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1>>[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([C:2]2[C:3]([O:22][CH2:23][C:24]([F:26])([F:27])[F:25])=[N:4][C:5]([C:18]([F:21])([F:20])[F:19])=[C:6]([CH:17]=2)[C:7]([NH:9][C@H:10]2[CH2:15][CH2:14][CH2:13][CH2:12][C@@H:11]2[OH:16])=[O:8])=[CH:31][CH:30]=1
Reactant: O=C(N[C@H]1CCCC[C@@H]1O)c1cc(Br)c(OCC(F)(F)F)nc1C(F)(F)F
Reactant: OB(O)c1ccc(Cl)cc1
Product: O=C(N[C@H]1CCCC[C@@H]1O)c1cc(-c2ccc(Cl)cc2)c(OCC(F)(F)F)nc1C(F)(F)F

Procedure:
The title compound was synthesized in analogy to Example 1d, using 5-bromo-N-((1S,2S)-2-hydroxy-cyclohexyl)-6-(2,2,2-trifluoro-ethoxy)-2-trifluoromethyl-nicotinamide and 4-chlorophenylboronic acid as starting materials, MS (ISP) 497.1 (M+H)+.
Reaction SMILES: [H-].[Na+].C1C=CC=CC=1.[F:9][C:10]([F:30])([F:29])[C:11]1[CH:16]=[CH:15][N:14]=[CH:13][C:12]=1[CH:17]([C:19]1[CH:20]=[N:21][CH:22]=[CH:23][C:24]=1[C:25]([F:28])([F:27])[F:26])[OH:18].[C:31](Cl)(=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33]>CN(C)C=O>[F:28][C:25]([F:27])([F:26])[C:24]1[CH:23]=[CH:22][N:21]=[CH:20][C:19]=1[CH:17]([C:12]1[CH:13]=[N:14][CH:15]=[CH:16][C:11]=1[C:10]([F:9])([F:29])[F:30])[O:18][C:31](=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33]
Reactant: CC(C)(C)C(=O)Cl
Reactant: OC(c1cnccc1C(F)(F)F)c1cnccc1C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CN(C)C=O
Product: CC(C)(C)C(=O)OC(c1cnccc1C(F)(F)F)c1cnccc1C(F)(F)F
Temperature: 50 °C
Yield: 63.4 %

Procedure:
To a mixture of 0.029 g of sodium hydride in 20 ml of a 1:1 solution of benzene and dimethylformamide were added 0.25 grams of 1,1-bis-(4-trifluoromethylpyrid-3-yl)methanol. After the gas evolution had subsided, 0.14 grams of pivaloyl chloride were added. After stirring for an hour at 50° C., the reaction mixture was partitioned between 25 ml of water and 50 ml of ethyl ether. The ethyl ether layer was washed with water, washed with a saturated sodium chloride solution, dried over magnesium sulfate, filtered, and concentrated in vacuo to afford 0.24 g of the crude product as a light brown semisolid. This crude material was then purified via chromatography on a silica gel column using ethyl acetate-hexane (1:3) as the eluant to afford 0.2 g of 1,1-bis-(4-trifluoromethylpyrid-3-yl)-1-trimethylacetoxymethane as a light brown solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]([OH:13])=O)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.CN(C)C=O.CC1(C)C2CCC1(CS(O)(=O)=O)C(=O)C2.[NH:34]1[CH2:38][CH2:37][C@@:36]2([C:42]3[CH:43]=[CH:44][CH:45]=[CH:46][C:41]=3[C:40](=[O:47])[O:39]2)[CH2:35]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:11]([N:34]3[CH2:38][CH2:37][C@@:36]4([C:42]5[CH:43]=[CH:44][CH:45]=[CH:46][C:41]=5[C:40](=[O:47])[O:39]4)[CH2:35]3)=[O:13])[CH2:9][CH2:10]2)=[CH:6][CH:7]=1
Reactant: O=C1O[C@]2(CCNC2)c2ccccc21
Reactant: O=C(O)C1(c2ccc(Br)cc2)CC1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C1O[C@]2(CCN(C(=O)C3(c4ccc(Br)cc4)CC3)C2)c2ccccc21
Reaction time: 17 h
Yield: 89.9 %

Procedure:
To a stirred solution of 1-(4-bromophenyl)cyclopropanecarboxylic acid (1.616 g, 0.006704 mol) in anhydrous N,N-dimethylformamide (12.0 mL, 0.155 mol) at room temperature was added (7,7-dimethyl-2-oxobicyclo[2.2.1]hept-1-yl)methanesulfonic acid -(1R)-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one (1:1) (2.569 g, 0.006095 mol, example 96, steps 1-2), benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (3.057 g, 0.006704 mol), followed by N,N-diisopropylethylamine (4.27 mL, 0.0244 mol). The resulting clear solution was stirred at temperature for 17 hours. LCMS showed that the reaction was complete. The reaction was quenched with saturated aqueous NaHCO3 (50 mL), and the reaction miture was extracted with EtOAc (2×). The combined organic layer was washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by Combiflash with 30-70% EtOAc/hexanes to give the product as a colorless solid (2.258 g, 90% in yield). LC/MS (M+H+)=412.1.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:12]2[C:21]3[C:16](=[C:17]4[CH:25]=[CH:24][CH:23]=[CH:22][C:18]4=[CH:19][CH:20]=3)[O:15][C:14]([NH2:26])=[C:13]2[C:27]2[N:31]=[C:30]([CH2:32]Cl)[O:29][N:28]=2)[CH:5]=[C:6]([O:10][CH3:11])[C:7]=1[O:8][CH3:9].[CH2:34]([N:36](CC)CC)C.CN>C(#N)C.O>[Br:1][C:2]1[CH:3]=[C:4]([CH:12]2[C:21]3[C:16](=[C:17]4[CH:25]=[CH:24][CH:23]=[CH:22][C:18]4=[CH:19][CH:20]=3)[O:15][C:14]([NH2:26])=[C:13]2[C:27]2[N:31]=[C:30]([CH2:32][NH:36][CH3:34])[O:29][N:28]=2)[CH:5]=[C:6]([O:10][CH3:11])[C:7]=1[O:8][CH3:9]
Reactant: CCN(CC)CC
Reactant: COc1cc(C2C(c3noc(CCl)n3)=C(N)Oc3c2ccc2ccccc32)cc(Br)c1OC
Agent: CN
Solvent: CC#N
Solvent: O
Product: CNCc1nc(C2=C(N)Oc3c(ccc4ccccc34)C2c2cc(Br)c(OC)c(OC)c2)no1
Temperature: 25 °C

Procedure:
4-(3-Bromo-4,5-dimethoxy-phenyl)-3-(5-chloromethyl-[1,2,4]oxadiazol-3-yl)-4H-benzo[h]chromen-2-ylamine (24) (528 mg, 1 mmol) and triethylamine (140 μl, 1 mmol) and 2M methanolic solution of methylamine (600 μl, 1.2 mmol) is taken in acetonitril (10 ml) and stirred at room temperature under LC-MS control till the reaction is complete. The reaction mixture is diluted with water to about 50 ml and stirred for 2 h at room temperature. Thus resulting precipitates are separated by filtration, washed well with water and is dried under high vacuum to get solids of the title compound.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:6][S:5](=[O:8])(=[O:7])[CH2:4][C@H:3]1[C:9]([N:11]1[CH2:16][CH2:15][CH2:14][C@@H:13]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[CH2:12]1)=[O:10].C1([O:31][C:32](=O)[NH:33][C:34]2[S:35][C:36]([C:40](=[O:42])[CH3:41])=[C:37]([CH3:39])[N:38]=2)C=CC=CC=1.C(N(CC)CC)C>CN(C)C=O>[C:40]([C:36]1[S:35][C:34]([NH:33][C:32]([NH:1][C@@H:2]2[C@@H:3]([C:9]([N:11]3[CH2:16][CH2:15][CH2:14][C@@H:13]([CH2:17][C:18]4[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=4)[CH2:12]3)=[O:10])[CH2:4][S:5](=[O:7])(=[O:8])[CH2:6]2)=[O:31])=[N:38][C:37]=1[CH3:39])(=[O:42])[CH3:41]
Reactant: CC(=O)c1sc(NC(=O)Oc2ccccc2)nc1C
Reactant: N[C@@H]1CS(=O)(=O)C[C@H]1C(=O)N1CCC[C@@H](Cc2ccc(F)cc2)C1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(=O)c1sc(NC(=O)N[C@H]2CS(=O)(=O)C[C@@H]2C(=O)N2CCC[C@@H](Cc3ccc(F)cc3)C2)nc1C
Temperature: 25 °C
Reaction time: 94 h
Yield: 54.2 %

Procedure:
[(3R,4S)-4-Amino-1,1-dioxo-tetrahydrothiophen-3-yl]-[(S)-3-(4-fluorobenzyl)-piperidin-1-yl]-methanone (50 mg, 141 μmol) and [5-acetyl-4-methylthiazol-2-yl]-carbamic acid phenyl ester (43 mg, 155 μmol) were dissolved in N,N-dimethylformamide (1 mL) and treated with triethylamine (22 μL, 155 μmol). The mixture was stirred at room temperature for 94 h , and then concentrated. The residue was purified by flash column chromatography (4% methanol/dichloromethane containing 0.4% aqueous ammonium hydroxide) to provide a white solid (41 mg, 55%). 1H NMR (300 mHz, CD3OD) δ7.16 (m, 2H), 6.95 (m, 2H), 4.74 (m, 1H), 4.32 (m, 1H), 4.1-3.8 (m, 2H), 3.6-3.5 (m, 2H), 3.4-3.2 (m, 2H), 3.2-2.8 (m, 2H), 2.54 (s, 3H), 2.5 (m, 2H), 2.46+2.44 (2s, 3H), 1.75 (m, 3H), 1.43 (m, 1H), 1.23 (m, 1H), ESI MS: (M+H)+=537.4.
Reaction SMILES: C([O:5][C:6](=[O:46])[CH2:7][NH:8][CH2:9][CH2:10][C:11]1[N:12]=[C:13]([C:39]2[CH:44]=[CH:43][C:42]([CH3:45])=[CH:41][CH:40]=2)[N:14]([CH:16]([C:20]2[N:29]([CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:28](=[O:37])[C:27]3[C:22](=[CH:23][C:24]([Cl:38])=[CH:25][CH:26]=3)[N:21]=2)[CH:17]([CH3:19])[CH3:18])[CH:15]=1)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:30]([N:29]1[C:28](=[O:37])[C:27]2[C:22](=[CH:23][C:24]([Cl:38])=[CH:25][CH:26]=2)[N:21]=[C:20]1[CH:16]([N:14]1[CH:15]=[C:11]([CH2:10][CH2:9][NH:8][CH2:7][C:6]([OH:46])=[O:5])[N:12]=[C:13]1[C:39]1[CH:40]=[CH:41][C:42]([CH3:45])=[CH:43][CH:44]=1)[CH:17]([CH3:19])[CH3:18])[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: Cc1ccc(-c2nc(CCNCC(=O)OC(C)(C)C)cn2C(c2nc3cc(Cl)ccc3c(=O)n2Cc2ccccc2)C(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc(-c2nc(CCNCC(=O)O)cn2C(c2nc3cc(Cl)ccc3c(=O)n2Cc2ccccc2)C(C)C)cc1
Yield: 74 %

Procedure:
A solution of (2-{1-[1-(3-benzyl-7-chloro-4-oxo-3,4-dihydro-quinazolin-2-yl)-2-methyl-propyl]-2-p-tolyl-1H-imidazol-4-yl}-ethylamino)-acetic acid tert-butyl ester (99.6 mg., 0.155 mmol) and trifluoroacetic acid (8 mL) in methylene chloride (4 mL) was stirred at room temperature for 3.0 h. The reaction was concentrated in vacuo and the residue was triturated with diethyl ether and dried to provide the title compound as a white solid (67 mg., 53%). MS(ES+) m/e 584 [M+H]+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][S:5][C:6]1[S:10][C:9]([NH:11][C:12]([N:14]2[C:30]3[C:25](=[CH:26][C:27]([Cl:31])=[CH:28][CH:29]=3)[C:16]3([CH2:20][CH2:19][N:18]([C:21]([O:23][CH3:24])=[O:22])[CH2:17]3)[CH2:15]2)=[O:13])=[N:8][CH:7]=1.[CH3:32][S:33](Cl)(=[O:35])=[O:34]>>[Cl:31][C:27]1[CH:26]=[C:25]2[C:16]3([CH2:20][CH2:19][N:18]([C:21]([O:23][CH3:24])=[O:22])[CH2:17]3)[CH2:15][N:14]([C:12](=[O:13])[NH:11][C:9]3[S:10][C:6]([S:5][CH2:4][CH2:3][CH2:2][NH:1][S:33]([CH3:32])(=[O:35])=[O:34])=[CH:7][N:8]=3)[C:30]2=[CH:29][CH:28]=1
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)N1CCC2(C1)CN(C(=O)Nc1ncc(SCCCN)s1)c1ccc(Cl)cc12
Product: COC(=O)N1CCC2(C1)CN(C(=O)Nc1ncc(SCCCNS(C)(=O)=O)s1)c1ccc(Cl)cc12

Procedure:
The captioned compound was obtained in the form of a white solid by performing the same reactions and/or treatments as those in Example 3, with the exceptions that the methyl 1-((5-((3-aminopropyl)thio)thiazol-2-yl)carbamoyl)-5-chlorospiro[indoline-3,3′-pyrrolidine]-1′-carboxylate obtained in Example 176 was used instead of 5-bromo-N-(5-chlorothiazol-2-yl)spiro[indoline-3,3′-pyrrolidine]-1-carboxamide, and that methanesulfonic acid chloride was used instead of acetyl chloride.
Reaction SMILES: Cl.[NH2:2][N:3]1[CH2:8][CH:7]=[CH:6][CH2:5][CH2:4]1.C(N(CC)CC)C.[F:16][C:17]1[CH:18]=[C:19]([N:23]=[C:24]=[O:25])[CH:20]=[CH:21][CH:22]=1>C(Cl)Cl>[F:16][C:17]1[CH:18]=[C:19]([NH:23][C:24]([NH:2][N:3]2[CH2:4][CH:5]=[CH:6][CH2:7][CH2:8]2)=[O:25])[CH:20]=[CH:21][CH:22]=1
Reactant: NN1CC=CCC1
Reactant: O=C=Nc1cccc(F)c1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1cccc(F)c1)NN1CC=CCC1
Reaction time: 1 h
Yield: 60.8 %

Procedure:
To a solution of N-amino-1,2,3,6-tetrahydropyridine hydrochloride (1.346 g) and triethylamine (1.012 g) in dry methylene chloride (40 ml) was added a solution of 3-fluorophenyl isocyanate (1.37 g) in dry methylene chloride under ice-bath cooling. After stirring for one hour, the reaction mixture was evaporated to dryness. The residue was extracted with ethyl acetate (100 ml). The extract was washed with water, evaporated to dryness and recystallized from ethyl acetate to give N-[[(3-fluorophenyl)carbamoyl]amino]-1,2,3,6-tetrahydropyridine (1.43 g). mp: 136.5°-138.5° C.
Reaction SMILES: Cl[O-].[Na+].[CH:4]1([C@H:7]([O:12][CH2:13][CH:14]=[N:15][OH:16])[CH2:8]/[CH:9]=[CH:10]/[CH3:11])[CH2:6][CH2:5]1.C(N(CC)CC)C>ClCCl>[CH:4]1([C@@H:7]2[O:12][CH2:13][C:14]3=[N:15][O:16][C@@H:10]([CH3:11])[C@@H:9]3[CH2:8]2)[CH2:6][CH2:5]1
Reactant: C/C=C/C[C@@H](OCC=NO)C1CC1
Agent: [Na+]
Agent: [O-]Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@@H]1ON=C2CO[C@@H](C3CC3)C[C@H]21
Reaction time: 1 h

Procedure:
An aqueous solution of sodium hypochlorite (6.15% solution, 0.7 mL, 0.6 mmol) was added drop-wise to a solution of 2-{[(1R,3E)-1-cyclopropylpent-3-en-1-yl]oxy}-N-hydroxyethanimine (C26) (200 mg, 1.09 mmol) in dichloromethane (10 mL), followed by addition of triethylamine (11 μL, 79 μmol). The reaction mixture was stirred for 1 hour, then treated with a drop of triethylamine and additional aqueous sodium hypochlorite solution (6.15%, 0.5 mL, 0.4 mmol). After 20 minutes, the reaction mixture was partitioned between water (10 mL) and dichloromethane (20 mL); the organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. Purification via silica gel chromatography (Gradient: 0% to 100% ethyl acetate in heptane) provided the product as an oil. The indicated relative stereochemistry of compound C27 was assigned based on nuclear Overhauser enhancement studies, which revealed interactions of the methine proton on carbon 3a with both the protons of the methyl group on carbon 3 and the methine proton on carbon 5. Yield: 150 mg, 0.828 mmol, 76%. 1H NMR (400 MHz, CDCl3) δ 4.64 (d, J=13.5 Hz, 1H), 4.17-4.25 (m, 1H), 4.08 (dd, J=13.6, 1.3 Hz, 1H), 2.84-2.93 (m, 1H), 2.76 (ddd, J=11.0, 7.9, 1.9 Hz, 1H), 2.21 (dddd, J=12.9, 6.6, 1.9, 0.5 Hz, 1H), 1.57 (ddd, J=12.9, 11.4, 11.4 Hz, 1H), 1.45 (d, J=6.2 Hz, 3H), 0.86-0.96 (m, 1H), 0.48-0.61 (m, 2H), 0.35-0.42 (m, 1H), 0.19-0.26 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([O:12][CH3:13])=[CH:10][C:9]([S:14](=[O:17])(=[O:16])[NH2:15])=[CH:8][C:4]=1[C:5](O)=[O:6].S(Cl)([Cl:20])=O>CCCCCC>[CH3:1][O:2][C:3]1[C:11]([O:12][CH3:13])=[CH:10][C:9]([S:14](=[O:17])(=[O:16])[NH2:15])=[CH:8][C:4]=1[C:5]([Cl:20])=[O:6]
Reactant: O=S(Cl)Cl
Reactant: COc1cc(S(N)(=O)=O)cc(C(=O)O)c1OC
Solvent: CCCCCC
Product: COc1cc(S(N)(=O)=O)cc(C(=O)Cl)c1OC
Yield: 94.7 %

Procedure:
419 g (1.6 mole) of 2,3-dimethoxy-5-sulphamoyl benzoic acid and 1,351 g (11.35 moles) of thionyl chloride are placed in a 2 liter flask fitted with an agitator, a thermometer and a condenser connected to a soda bubbler. The mixture is brought to reflux for 1 hour, after which the excess thionyl chloride is expelled under vacuum. The residue is dissolved in 1,000 ml of hexane, filtered, washed twice with 500 ml of petroleum ether and dried in a desiccator under vacuum. 424 g (yield 94.8%) of 2,3-dimethoxy-5-sulphamoyl benzoyl chloride is obtained, with a melting point of 153° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:8][CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.Cl[CH2:10][C:11]1[CH:45]=[CH:44][C:14]([C:15]([NH:17][C:18]2[C:19]3[CH:32]=[C:31]([C:33]([NH:35][N:36]([CH3:43])[C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)=[O:34])[S:30][C:20]=3[N:21](C(OC(C)(C)C)=O)[N:22]=2)=[O:16])=[CH:13][CH:12]=1.ClCC1C=CC(C(NC2C3C=C(C(NN(C4C=CC(Cl)=CC=4)C)=O)SC=3N(C(OC(C)(C)C)=O)N=2)=O)=CC=1>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)C=O>[CH3:1][N:2]1[CH2:8][CH2:7][CH2:6][N:5]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:15]([NH:17][C:18]3[C:19]4[CH:32]=[C:31]([C:33]([NH:35][N:36]([CH3:43])[C:37]5[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=5)=[O:34])[S:30][C:20]=4[NH:21][N:22]=3)=[O:16])=[CH:44][CH:45]=2)[CH2:4][CH2:3]1
Reactant: CN(NC(=O)c1cc2c(NC(=O)c3ccc(CCl)cc3)nn(C(=O)OC(C)(C)C)c2s1)c1ccccc1
Reactant: CN1CCCNCC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: CN(NC(=O)c1cc2c(NC(=O)c3ccc(CCl)cc3)nn(C(=O)OC(C)(C)C)c2s1)c1ccc(Cl)cc1
Agent: [I-]
Solvent: CN(C)C=O
Product: CN1CCCN(Cc2ccc(C(=O)Nc3n[nH]c4sc(C(=O)NN(C)c5ccccc5)cc34)cc2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
27 mg (74 μmol) of tetrabutylammonium iodide, followed by 138 μL (1.11 mmol) of N-methyl-homopiperazine, are added to a solution of 200 mg (0.37 mmol) of an approximately 70:30 mixture of tert-butyl 3-(4-chloromethylbenzoylamino)-5-(N′-methyl-N′-phenylhydrazinocarbonyl)thieno[2,3-c]pyrazole-1-carboxylate and tert-butyl 3-(4-chloromethylbenzoylamino)-5-(N′-(4-chlorophenyl)-N′-methylhydrazinocarbonyl)thieno[2,3-c]pyrazole-1-carboxylate in 6 mL of dimethylformamide under argon. The reaction mixture is stirred at a temperature in the region of 25° C. for 16 hours, and then treated with ice. It is then extracted with ethyl acetate and twice with dichloromethane. The organic extracts are combined and then concentrated to dryness under vacuum (2 kPa) at a temperature in the region of 40° C. The residue is dissolved in 3 mL of methanol and the solution is introduced into a microwave oven tube. The tube is stoppered and the reaction mixture is irradiated at a temperature in the region of 100° C. for 30 minutes. The reaction mixture is then concentrated to dryness under vacuum (2 kPa) at a temperature in the region of 40° C. The residue is purified by preparative LC/MS (1 injection: conditions B′; 3 injections: conditions B). 53 mg of 4-(4-methylperhydro-1,4-diazepin-1-ylmethyl)-N-[5-(N′-methyl-N′-phenylhydrazinocarbonyl)-1H-thieno[2,3-c]pyrazol-3-yl]benzamide are thus obtained in the form of a yellow powder. LC-MS-DAD-ELSD: 516(−)=(M−H)(−); 518(+)=(M+H)(+).
Reaction SMILES: Br[C@H:2]1[CH2:7][CH2:6][C@@H:5]([C:8]([NH2:10])=[O:9])[CH2:4][C@H:3]1[OH:11].[N-:12]=[N+:13]=[N-:14].[Na+]>CN(C=O)C>[N:12]([C@@H:2]1[CH2:7][CH2:6][C@@H:5]([C:8]([NH2:10])=[O:9])[CH2:4][C@H:3]1[OH:11])=[N+:13]=[N-:14]
Reactant: NC(=O)[C@@H]1CC[C@H](Br)[C@H](O)C1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=N[C@@H]1CC[C@@H](C(N)=O)C[C@H]1O
Yield: 57 %

Procedure:
(1R,3R,4S)-4-Bromo-3-hydroxy-cyclohexanecarboxylic amide (b) (2.31 g, 10.4 mmol) was treated with sodium azide (1.35 g, 20.8 mmol) in DMF (100 mL) at 60° C. for 15.5 hours. The solvent was removed in vacuo and the residue purified by flash column chromatography (Silica gel, DCM:MeOH 0-10%) to give a white solid (1.09 g, 5.93 mmol, 57%).
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:10][CH2:11][CH2:12][O:13][CH2:14][N:15]1[CH:22]=[C:21]([CH:23]=[CH2:24])[C:19](=[O:20])[NH:18][C:16]1=[O:17]>N1C=CC=CC=1>[C:1]([O:10][CH2:11][CH2:12][O:13][CH2:14][N:15]1[CH:22]=[C:21]([CH:23]=[CH2:24])[C:19](=[O:20])[NH:18][C:16]1=[O:17])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=Cc1cn(COCCO)c(=O)[nH]c1=O
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Product: C=Cc1cn(COCCOC(=O)c2ccccc2)c(=O)[nH]c1=O
Reaction time: 6 h
Yield: 67.3 %

Procedure:
Benzoylchloride (410 mg, 2.9 mmol) was added to a solution of 1 (614 mg, 2.89 mmol) in dry pyridine (30 ml) and the reaction was allowed to proceed at 25° C. with stirring for 6 h. Removal of the solvent in vacuo and purification of the product by elution from a silica gel column using chloroform-methanol (99:1, v/v) as eluent gave 3 as a viscous oil (615 mg, 67.3%) which was used directly in the next reaction step.