Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2]/[CH:3]=[CH:4]/[C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH:10]([NH2:13])([CH3:12])[CH3:11].C(N(CC)CC)C>C(O)C>[CH:10]([NH:13][CH2:2]/[CH:3]=[CH:4]/[C:5]([O:7][CH2:8][CH3:9])=[O:6])([CH3:12])[CH3:11]
Reactant: CC(C)N
Reactant: CCOC(=O)/C=C/CBr
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOC(=O)/C=C/CNC(C)C
Yield: 65.8 %

Procedure:
Ethyl 4-bromocrotonate (25.0 g) was added dropwise to a solution of isopropylamine (7.7 g) and triethylamine (13.2 g) in ethanol (200 ml) at room temperature under stirring and taking an hour. The mixture was stirred for 5.5 hours at room temperature. After removing the solvent, to the residue was added ethyl acetate, and the mixture was extracted with 1N hydrochloric acid. Ethyl acetate was added to the hydrochloric acid layer, and alkalified by addition of potassium carbonate powder. After removing the separated oily substance, the ethyl acetate layer was taken out, and the aqueous layer was extracted with ethyl acetate. The combined ethyl acetate layers were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate and distilled to remove the solvent to give the title compound (14.6 g) as pale yellow oily substance.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.[Cl:13][C:14]1[CH:15]=[C:16]([NH:20][C:21](=[O:24])[CH2:22]Cl)[CH:17]=[CH:18][CH:19]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O.O>[Cl:13][C:14]1[CH:15]=[C:16]([NH:20][C:21](=[O:24])[CH2:22][N:10]2[CH2:9][CH2:8][N:7]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)[CH2:12][CH2:11]2)[CH:17]=[CH:18][CH:19]=1
Reactant: O=C(CCl)Nc1cccc(Cl)c1
Reactant: c1ccc(N2CCNCC2)nc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(CN1CCN(c2ccccn2)CC1)Nc1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 32.2 %

Procedure:
A mixture of 1-pyridin-2-ylpiperazine (24 mg, 0.15 mmol, Aldrich), N-(3-chloro-phenyl)-2-chloroacetamide (41 mg, 0.20 mmol, Maybridge) and sodium carbonate (50 mg) in N,N-dimethylformamide/water (2:1, 2 mL) was shaken at room temperature for 18 hours. The resulting mixture was decanted, concentrated under reduced pressure and the residue purified by preparative HPLC to provide 16 mg (32%) of the desired product. 1H NMR (500 MHz, DMSO-d6) δ 2.60 (t, J=4 Hz, 4H), 3.20 (s, 2H), 3.58 (t, J=4 Hz, 4H), 6.63 (t, J=5 Hz, 1H), 6.83 (d, J=6 Hz, 1H), 7.13 (d, J=6 Hz, 1H), 7.38 (t, J=6 Hz, 1H), 7.58 (m, 2H), 7.95 (s, 1H), 8.12 (d, J=5 Hz, 1H), 9.95 (s, 1H); MS (ESI/APCI+) m/e 331 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]([N:11]2[C:15](=[O:16])[CH2:14][C@@H:13]([CH:17]=[O:18])[CH2:12]2)[CH3:10])=[CH:5][CH:4]=1.[CH2:19]=[CH:20][CH2:21][Si]1(Cl)N(CC2C=CC(Br)=CC=2)[C@@H]2[C@H](CCCC2)N1CC1C=CC(Br)=CC=1>>[OH:18][C@@H:17]([C@H:13]1[CH2:12][N:11]([C@@H:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[CH3:10])[C:15](=[O:16])[CH2:14]1)[CH2:21][CH:20]=[CH2:19]
Reactant: COc1ccc([C@@H](C)N2C[C@H](C=O)CC2=O)cc1
Reactant: C=CC[Si]1(Cl)N(Cc2ccc(Br)cc2)[C@H]2CCCC[C@@H]2N1Cc1ccc(Br)cc1
Product: C=CC[C@@H](O)[C@@H]1CC(=O)N([C@H](C)c2ccc(OC)cc2)C1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of (R)-1-((R)-1-(4-methoxyphenyl)ethyl)-5-oxopyrrolidine-3-carbaldehyde 1.07 (0.93 g, 3.76 mmol) at rt was added (S,S)-2-allyl-1,3-bis-(4-bromobenzyl)-2-chlorooctahydro-2-1H-1,3,2-benzodiazasilole (3.338 g, 6.02 mmol) followed by Sc(III) triflate (0.093 g, 0.188 mmol). The reaction was stirred at rt for 1.5 hr and the solvent was removed. To the residue was added Et2O (80 mL) and 1M HCl (20 mL). The suspension was stirred for 1 hr and the solids were removed by filtration. The filter cake was washed with ether. The filtrate was transferred to a separatory funnel and the layers were separated. The aqueous layer was further extracted with Et2O (3×40 mL). The combined organics were dried (MgSO4), filtered and concentrated. The residue was purified by flash chromatography to afford (R)-4-((R)-1-hydroxybut-3-enyl)-1-((R)-1-(4-methoxyphenyl)ethyl)pyrrolidin-2-one 1.08.
Reaction SMILES: [CH3:1][C:2]1[CH:22]=[CH:21][C:5]2[N:6]=[C:7]([C:9](=O)[CH2:10][C:11](=O)[C:12]([F:18])([F:17])[C:13]([F:16])([F:15])[F:14])[S:8][C:4]=2[CH:3]=1.Cl.[CH3:24][S:25]([C:28]1[CH:33]=[CH:32][C:31]([NH:34][NH2:35])=[CH:30][CH:29]=1)(=[O:27])=[O:26]>>[CH3:1][C:2]1[CH:22]=[CH:21][C:5]2[N:6]=[C:7]([C:9]3[N:34]([C:31]4[CH:30]=[CH:29][C:28]([S:25]([CH3:24])(=[O:27])=[O:26])=[CH:33][CH:32]=4)[N:35]=[C:11]([C:12]([F:18])([F:17])[C:13]([F:16])([F:15])[F:14])[CH:10]=3)[S:8][C:4]=2[CH:3]=1
Reactant: CS(=O)(=O)c1ccc(NN)cc1
Reactant: Cc1ccc2nc(C(=O)CC(=O)C(F)(F)C(F)(F)F)sc2c1
Agent: Cl
Product: Cc1ccc2nc(-c3cc(C(F)(F)C(F)(F)F)nn3-c3ccc(S(C)(=O)=O)cc3)sc2c1
Yield: 45 %

Procedure:
The procedure of Example 9 was repeated using 1-(6-methylbenzothiazol-2-yl)-4,4,5,5,5-pentafluoropentane-1,3-dione and 4-methylsulfonylphenylhydrazine hydrochloride as the starting materials to obtain 6-methyl-2-[1-(4-methylsulfonylphenyl)-3-pentafluoroethyl-1H-pyrazol-5-yl]benzothiazole (yield, 45%).
Reaction SMILES: C(O)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=CC=1.[Cl:10][C:11]1[CH:19]=[CH:18][C:17]([S:20]([OH:22])=[O:21])=[CH:16][C:12]=1[C:13]([OH:15])=[O:14].BrCC1CC1.II>C1(CO)CC1>[Cl:10][C:11]1[CH:19]=[CH:18][C:17]([S:20]([CH2:5][CH:6]2[CH2:2][CH2:7]2)(=[O:22])=[O:21])=[CH:16][C:12]=1[C:13]([OH:15])=[O:14]
Reactant: O=C(O)c1ccccc1
Reactant: O=C(O)c1cc(S(=O)O)ccc1Cl
Agent: BrCC1CC1
Agent: II
Agent: OCC1CC1
Product: O=C(O)c1cc(S(=O)(=O)CC2CC2)ccc1Cl
Yield: 8 %

Procedure:
The title compound was synthesised according to the procedure described for the synthesis of 2-Chloro-5-methanesulfonyl)-benzoic acid from 2-Chloro-5-sulfino-benzoic acid and Bromomethyl-cyclopropane (+catalytic amount I2) in 20 ml cyclopropyl methanol/20 ml water and obtained in 8% yield. MS (m/e): 273.1 (MH−, 100%).
Reaction SMILES: [CH:1]1([C:4]2[C:5]([CH3:15])=[CH:6][C:7]([CH3:14])=[C:8]([CH2:10][C:11](O)=[O:12])[CH:9]=2)[CH2:3][CH2:2]1.C(Cl)(=O)C([Cl:19])=O.CN(C)C=O>ClCCl>[CH:1]1([C:4]2[C:5]([CH3:15])=[CH:6][C:7]([CH3:14])=[C:8]([CH2:10][C:11]([Cl:19])=[O:12])[CH:9]=2)[CH2:3][CH2:2]1
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cc1cc(C)c(C2CC2)cc1CC(=O)O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1cc(C)c(C2CC2)cc1CC(=O)Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2.3 g of (5-cyclopropyl-2,4-dimethyl-phenyl)-acetic acid in 20 ml of dichloromethane are treated with 2.1 g of oxalyl chloride and a catalytic amount of dimethylformamide. The reaction mixture is stirred at room temperature for 2 hours. The solvent is removed in vacuo and the crude residue of (5-cyclopropyl-2,4-dimethyl-phenyl)-acetyl chloride (2.5 g) is used for the next step.
Reaction SMILES: C([O:8][C:9]1[CH:18]=[C:17]([O:19]CC2C=CC=CC=2)[CH:16]=[C:15]2[C:10]=1[CH:11]=[CH:12][N:13]=[C:14]2[CH2:27][C:28]1[CH:33]=[C:32]([O:34][CH3:35])[C:31]([O:36][CH3:37])=[C:30]([O:38][CH3:39])[CH:29]=1)C1C=CC=CC=1.[ClH:40].C(O)C.Cl.C(O)C>[H][H].[Pt](=O)=O>[ClH:40].[OH:8][C:9]1[CH:18]=[C:17]([OH:19])[CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][NH:13][CH:14]2[CH2:27][C:28]1[CH:33]=[C:32]([O:34][CH3:35])[C:31]([O:36][CH3:37])=[C:30]([O:38][CH3:39])[CH:29]=1
Reactant: [H][H]
Reactant: COc1cc(Cc2nccc3c(OCc4ccccc4)cc(OCc4ccccc4)cc23)cc(OC)c1OC
Agent: O=[Pt]=O
Agent: Cl
Solvent: CCO
Product: COc1cc(CC2NCCc3c(O)cc(O)cc32)cc(OC)c1OC

Procedure:
A mixture of 1.4 g of 5,7-dibenzyloxy-1-(3,4,5-trimethoxybenzyl)-isoquinoline, 0.7 g of platinum dioxide, 100 ml of a hydrochloric acid-ethanol solution (the content of hydrochloric acid: 9%) and 50 ml of ethanol is shaken at 25° C in hydrogen atmosphere. After 150 ml of hydrogen are absorbed, the catalyst is removed by filtration. The filtrate is evaporated to remove solvent, whereby a mixture of 5,7-dihydroxy-1-(3,4,5-trimethoxybenzyl)-isoquinoline hydrochloride and 5,7-dihydroxy-1-(3,4,5-trimethoxybenzyl)-1,2,3,4-tetrahydroisoquinoline hydrochloride is obtained. This mixture is recrystallized 33 times from ethanol, whereby 0.3 g of 5,7-dihydroxy-1-(3,4,5-trimethoxybenzyl)-1,2,3,4-tetrahydrolsoquinoline hydrochloride is obtained. Yield: 40% The physiocochemical properties of this product are identical with those of the compound obtained in Example 1.
Reaction SMILES: [NH:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH3:7].[F:8][C:9]([F:20])([F:19])[C:10]1[CH:11]=[C:12]([N:16]=[C:17]=[O:18])[CH:13]=[CH:14][CH:15]=1>>[CH3:7][N:3]1[CH2:4][CH2:5][CH2:6][C:2]1=[N:1][C:17]([NH:16][C:12]1[CH:13]=[CH:14][CH:15]=[C:10]([C:9]([F:8])([F:19])[F:20])[CH:11]=1)=[O:18]
Reactant: CN1CCCC1=N
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Product: CN1CCCC1=NC(=O)Nc1cccc(C(F)(F)F)c1
Temperature: 25 °C

Procedure:
Conversion of the hydrochloride salt of 2-imino-1-methylpyrrolidine (6.73 g.; 0.05 mole) to the free base (4.9 g. assuming 100% conversion) is carried out in the usual manner. After drying over K2CO3 the benzene layer is stirred at room temperature and 9.36 g. (0.05 mole) of m-trifluoromethylphenylisocyanate is added (some solid precipitates). The reaction mixture is stirred overnight. The resulting solid is collected, m.p. = 155°-156° C. The benzene filtrate, upon removal of the solvent, affords an additional crop of solid material, m.p. 131°-137° C. Recrystallizations of the combined solids from acetone-pet. ether gives the pure product, 1-(1-methyl-2-pyrrolidylidene)-3-(m-trifluoromethylphenyl)urea, m.p. = 155°-156.5° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:8]1[C@@H:13]([OH:14])[CH2:12][CH2:11][N:10]([CH3:15])[CH2:9]1.[F:16][C:17]1[CH:22]=[CH:21][C:20](O)=[CH:19][CH:18]=1>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:8]1[C@H:13]([O:14][C:20]2[CH:21]=[CH:22][C:17]([F:16])=[CH:18][CH:19]=2)[CH2:12][CH2:11][N:10]([CH3:15])[CH2:9]1
Reactant: Oc1ccc(F)cc1
Reactant: CN1CC[C@H](O)[C@H](c2ccccc2F)C1
Product: CN1CC[C@@H](Oc2ccc(F)cc2)[C@H](c2ccccc2F)C1

Procedure:
The procedure of Example 53 is repeated with cis-3-(2-fluorophenyl)-1-methyl-4-piperidinol and 4-fluorophenol to yield trans-3-(2-fluorophenyl)-4-(4-fluorophenoxy)-1-methylpiperidine. This compound is treated with a solution of fumaric acid in ether containing to yield trans-4-(4-fluorophenoxy)-3-(2-fluorophenyl)-1-methylpiperidine fumarate, m.p. 205.5°-206.5° C. The crude salt is recrystallized from isopropanol to afford colorless crystals, m.p. 205.5-206.5.
Reaction SMILES: [F-].[K+].[OH:3][C:4]1[CH:5]=[C:6]([CH:10]2[CH2:19][CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[C:15]([O:20][C:21]4[N:26]=[CH:25][C:24]([NH:27][S:28]([CH3:31])(=[O:30])=[O:29])=[CH:23][CH:22]=4)[CH:16]=3)[O:11]2)[CH:7]=[CH:8][CH:9]=1.Cl[C:33]1[CH:38]=[CH:37][C:36]([N+:39]([O-:41])=[O:40])=[CH:35][N:34]=1.Cl>CN(C=O)C>[N+:39]([C:36]1[CH:37]=[CH:38][C:33]([O:3][C:4]2[CH:5]=[C:6]([CH:10]3[CH2:19][CH2:18][C:17]4[C:12](=[CH:13][CH:14]=[C:15]([O:20][C:21]5[N:26]=[CH:25][C:24]([NH:27][S:28]([CH3:31])(=[O:30])=[O:29])=[CH:23][CH:22]=5)[CH:16]=4)[O:11]3)[CH:7]=[CH:8][CH:9]=2)=[N:34][CH:35]=1)([O-:41])=[O:40]
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: CS(=O)(=O)Nc1ccc(Oc2ccc3c(c2)CCC(c2cccc(O)c2)O3)nc1
Agent: Cl
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)Nc1ccc(Oc2ccc3c(c2)CCC(c2cccc(Oc4ccc([N+](=O)[O-])cn4)c2)O3)nc1
Temperature: 120 °C
Reaction time: 0.5 h

Procedure:
Potassium fluoride (42 mg) was added into a solution of N-{6-[2-(3-hydroxy-phenyl)chroman-6-yloxy]pyridin-3-yl}methanesulfonamide (100 mg) in dry DMF (1 ml). After stirring the resulting mixture at 120° C. for 30 minutes 2-chloro-5-nitropyridine (40 mg) was added. The reaction mixture was stirred for a further 30 minutes at 120° C. After cooling into room temperature 1 M HCl-solution was added and formed precipitate was filtered. N-(6-{2-[3-(5-Nitropyridin-2-yloxy)phenyl]-chroman-6-yloxy}pyridin-3-yl) methanesulfonamide was purified by column chromatography using 1:1 mixture of ethyl acetate and heptane as eluant. 1H NMR (300 MHz, d6-DMSO) δ: 9.64 (s, 1H), 9.04 (d, 1H, J 2.9 Hz), 8.63 (dd, 1H, J 2.9, 9.1 Hz), 7.98 (d, 1H, J 2.7 Hz), 7.66 (dd, 1H, J 2.7, 8.8 Hz), 7.52 (t, 1H, J 7.7 Hz), 7.39 (d, 1H, J 7.7 Hz), 7.31 (s, 1H), 7.27 (d, 1H, J 9.1 Hz), 7.22-7.19 (m, 1H), 6.96 (d, 1H, J 8.8 Hz), 6.89-6.85 (m, 3H), 5.17 (d, 1H, J 7.8 Hz), 2.97 (s, 3H), 2.98-2.92 (m, 1H), 2.76-2.69 (m, 1H) 2.28-2.19 (m, 1H), 2.02-1.97 (m, 1H).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:15])[N:9]2[CH2:12][CH:13]=C)=[CH:4][CH:3]=1.C(Cl)Cl.CSC.C[OH:23]>>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:15])[N:9]2[CH2:12][CH:13]=[O:23])=[CH:4][CH:3]=1
Reactant: CO
Reactant: C=CCn1c(=O)ccc2ccc(F)cc21
Solvent: ClCCl
Solvent: CSC
Product: O=CCn1c(=O)ccc2ccc(F)cc21
Temperature: -70 °C
Reaction time: 1.5 h
Yield: 82 %

Procedure:
A solution of 7-fluoro-1-(2-propen-1-yl)-2(1H)-quinolinone (5.0 g, 0.025 mmol) in 3:1 CH2Cl2:MeOH (500 mL) was cooled to −70° and 03 was bubbled through the solution for 20 min. Dimethyl sulfide (19 mL, 0.25 mol) were added and the reaction was stirred for 90 min at −70° C., then allowed to warm to room temperature overnight. The solvents were removed under reduced pressure yielding a thick orange oil. Purification by column chromatography on silica gel (1% to 100% hexane:ethyl acetate gradient) yielded a dark yellow solid (4.2 g, 82%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[NH:14][CH3:15])=[CH:6][C:5]([F:16])=[CH:4][N:3]=1.CCN(CC)CC.[F:24][C:25]([F:40])([F:39])[C:26]1[CH:27]=[C:28]([CH:32]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:34]=1)[C:29](Cl)=[O:30]>C(Cl)Cl>[Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[N:14]([CH3:15])[C:29](=[O:30])[C:28]2[CH:27]=[C:26]([C:25]([F:40])([F:39])[F:24])[CH:34]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:32]=2)=[CH:6][C:5]([F:16])=[CH:4][N:3]=1
Reactant: CNc1cnccc1-c1cc(F)cnc1Cl
Reactant: O=C(Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnccc1-c1cc(F)cnc1Cl
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of (2-chloro-5-fluoro-[3,4′]bipyridinyl-3′-yl)-methyl-amine (80 mg, 0.34 mmol) in CH2Cl2 (10 mL) were added Et3N (0.187 mL, 1.35 mmol) and 3,5-bis(trifluoromethyl)-benzoyl chloride (0.061 mL, 0.34 mmol, CAS RN 1271-19-8) at 25° C. and the resulting reaction mixture was stirred for 4 hours at 25° C. The mixture was diluted with CH2Cl2 (20 mL), the organic layer was washed with saturated aqueous NaHCO3 solution (2×20 mL) and brine (25 mL), dried over Na2SO4, filtered and concentrated under vacuum to afford the crude product which was purified using preparative HPLC. Off-white solid (22 mg, 14%). MS (ESI): m/z=478.4 [M+H]+.
Reaction SMILES: Cl.[Cl:2][CH2:3][CH2:4][NH:5][CH2:6][CH2:7][Cl:8].C(N(CC)CC)C.[C:16]([NH:19][C:20]1[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1)(=[O:18])[CH3:17]>O1CCOCC1>[Cl:2][CH2:3][CH2:4][N:5]([CH2:6][CH2:7][Cl:8])[S:26]([C:23]1[CH:22]=[CH:21][C:20]([NH:19][C:16](=[O:18])[CH3:17])=[CH:25][CH:24]=1)(=[O:28])=[O:27]
Reactant: ClCCNCCCl
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CC(=O)Nc1ccc(S(=O)(=O)N(CCCl)CCCl)cc1
Temperature: 80 °C
Yield: 40.44 %

Procedure:
Bis(2-chloroethyl)amine hydrochloride (0.0114 mol) and triethylamine (0.0114 mol) are added to a solution of 4-acetamidophenylsulfonyl chloride (1.34 g, 0.0057 mol) in dioxane (5 mL). The mixture is heated for 1 hour at 80° C., then part of the solvent is removed by evaporation at reduced pressure, and water is added until precipitation of the resulting sulfonamide. The product is collected by filtration as a pink solid in 40.44% yield and used without further purification.
Reaction SMILES: [C:1]([C:3]1[CH:15]=[C:14]2[C:6]([C:7]3[C:8](=[O:30])[C:9]4[CH:21]=[CH:20][C:19](OS(C(F)(F)F)(=O)=O)=[CH:18][C:10]=4[C:11]([CH3:17])([CH3:16])[C:12]=3[NH:13]2)=[CH:5][CH:4]=1)#[N:2].[C:31]([O:35][C:36]([N:38]1[CH2:43][CH:42]=[C:41](B2OC(C)(C)C(C)(C)O2)[CH2:40][CH2:39]1)=[O:37])([CH3:34])([CH3:33])[CH3:32].C(=O)([O-])[O-].[Na+].[Na+].COCCOC>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.O>[C:31]([O:35][C:36]([N:38]1[CH2:39][CH:40]=[C:41]([C:19]2[CH:20]=[CH:21][C:9]3[C:8](=[O:30])[C:7]4[C:6]5[C:14](=[CH:15][C:3]([C:1]#[N:2])=[CH:4][CH:5]=5)[NH:13][C:12]=4[C:11]([CH3:17])([CH3:16])[C:10]=3[CH:18]=2)[CH2:42][CH2:43]1)=[O:37])([CH3:34])([CH3:32])[CH3:33]
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: CC1(C)c2cc(OS(=O)(=O)C(F)(F)F)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CC(C)(C)OC(=O)N1CC=C(c2ccc3c(c2)C(C)(C)c2[nH]c4cc(C#N)ccc4c2C3=O)CC1
Temperature: 80 °C
Reaction time: 2 h
Yield: 89.6 %

Procedure:
To trifluoro-methane sulfonic acid 3-cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl ester (Compound B1, 7.80 g, 18.0 mmol), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (6.11 g, 19.8 mmol, 1.1 eq.), Pd(PPh3)2Cl2 (630 mg, 0.898 mmol, 0.05 eq.), and sodium carbonate (5.71 g, 53.9 mmol, 3.0 eq.), DME (125 ml) and water (25 ml) were added. The mixture was subjected to reduced pressure under ultrasonication treatment, followed by filling with nitrogen. This procedure was repeated five times to remove air. After further stirring at 80° C. for 2 hours under nitrogen atmosphere, the mixture was cooled to room temperature, added with water (250 ml), and further stirred for 30 minutes. The precipitates were filtered and washed with water (50 ml). They were further washed with CH3CN (50 ml) to obtain the target compound as a crude product (gray powder, 7.54 g, 90%).
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[C:16]1[N:21]=[C:20]([NH:22][CH2:23][CH2:24][NH2:25])[N:19]2[CH:26]=[CH:27][N:28]=[C:18]2[CH:17]=1.CN1CCCC1.Cl[C:36]1[N:41]=[CH:40][C:39]([C:42](=[O:44])[CH3:43])=[CH:38][CH:37]=1.CCN(C(C)C)C(C)C>>[Cl:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[C:16]1[N:21]=[C:20]([NH:22][CH2:23][CH2:24][NH:25][C:36]2[N:41]=[CH:40][C:39]([C:42](=[O:44])[CH3:43])=[CH:38][CH:37]=2)[N:19]2[CH:26]=[CH:27][N:28]=[C:18]2[CH:17]=1
Reactant: CC(=O)c1ccc(Cl)nc1
Reactant: NCCNc1nc(-c2ccc(Cl)cc2Cl)cc2nccn12
Agent: CN1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)c1ccc(NCCNc2nc(-c3ccc(Cl)cc3Cl)cc3nccn23)nc1
Temperature: 130 °C

Procedure:
50 mg (0.155 mmol) of the amine (Example 8A) are introduced into 3 ml of dry N-methylpyrrolidine, 48.3 mg (0.31 mmol) of 1-(6-chloropyridin-3-yl)ethanone and 40.1 mg (0.31 mmol) of DIPEA are added, and the mixture is heated in a microwave at 130° C. for 1.5 h. Purification by preparative HPLC results in 11 mg (15% of theory) of the product as a solid.
Reaction SMILES: [CH:1]([C:3]1[NH:4][C:5]([C:10]#[N:11])=[C:6]([C:8]#[N:9])[N:7]=1)=[CH2:2].S(OC)(O[CH3:16])(=O)=O>C1COCC1.CCOCC>[CH3:16][N:7]1[C:6]([C:8]#[N:9])=[C:5]([C:10]#[N:11])[N:4]=[C:3]1[CH:1]=[CH2:2]
Reactant: COS(=O)(=O)OC
Reactant: C=Cc1nc(C#N)c(C#N)[nH]1
Solvent: C1CCOC1
Solvent: CCOCC
Product: C=Cc1nc(C#N)c(C#N)n1C
Temperature: 0 °C
Reaction time: 15 h
Yield: 52.4 %

Procedure:
To a solution of 0.602 g (4.17 mmol) of 2-vinyl-4,5-dicyanoimidazole in distilled THF (15 mL) at 0° C. under nitrogen was added slowly while stirring 0.22 mL (2.32 mmol) of dimethyl sulfate and 0.60 mL (4.30 mmol) triethylaminine via syringe. The reaction solution was allowed to come to room temperature and was stirred for 15 hours. The reaction solution was concentrated down under a stream of nitrogen and dissolved in 10 mL CH2Cl2. This solution was washed twice with a 10% solution of NaOH and twice with a saturated solution of NaCl. CH2Cl2 was stripped off, leaving a brown oil. This oil was dissolved in approximately 1 mL of THF and precipitated out in hexane. The precipitate was vacuum filtered and dried to yield 0.345 g (52.4% yield) of a light brown, fluffy powder. This powder was dissolved in 100 mL of ether and vacuum filtered to remove undissolved particles. 20 mL of hexane was added to the ether solution, and the solution was cooled to 0° C. White, needle-shaped crystals were formed and vacuum filtered.
Reaction SMILES: [CH3:1][C:2]1([CH3:29])[O:7][CH2:6][CH2:5][N:4]([C:8]([N:10]2[CH2:15][CH:14]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)[CH2:13][CH:12]([C:26]([OH:28])=O)[CH2:11]2)=[O:9])[CH2:3]1.O[N:31]=[C:32]([NH2:34])[CH3:33]>>[CH3:1][C:2]1([CH3:29])[O:7][CH2:6][CH2:5][N:4]([C:8]([N:10]2[CH2:15][CH:14]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:23])([F:25])[F:24])=[CH:18][CH:17]=3)[CH2:13][CH:12]([C:26]3[O:28][N:34]=[C:32]([CH3:33])[N:31]=3)[CH2:11]2)=[O:9])[CH2:3]1
Reactant: CC(N)=NO
Reactant: CC1(C)CN(C(=O)N2CC(C(=O)O)CC(c3ccc(C(F)(F)F)cc3)C2)CCO1
Product: Cc1noc(C2CC(c3ccc(C(F)(F)F)cc3)CN(C(=O)N3CCOC(C)(C)C3)C2)n1

Procedure:
250 mg (0.410 mmol, 68% pure) of 1-[(2,2-dimethylmorpholin-4-yl)carbonyl]-5-[4-(trifluoromethyl)phenyl]piperidine-3-carboxylic acid and 33.4 mg (0.451 mmol) of N′-hydroxyethanimidamide were reacted according to the General Method 2. Yield: 117 mg (62% of theory).
Reaction SMILES: [OH-].[Na+].[CH3:3][NH:4][C@H:5]([C:10]([OH:12])=[O:11])[CH2:6][CH:7]([CH3:9])[CH3:8].[Cl:13][C:14]1[CH:15]=[CH:16][C:17]2[O:21][C:20](=[O:22])[C:19]([CH2:29][C:30](Cl)=[O:31])([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:18]=2[CH:33]=1.Cl>O.O1CCCC1>[CH3:3][N:4]([C:30](=[O:31])[CH2:29][C:19]1([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:18]2[CH:33]=[C:14]([Cl:13])[CH:15]=[CH:16][C:17]=2[O:21][C:20]1=[O:22])[C@H:5]([C:10]([OH:12])=[O:11])[CH2:6][CH:7]([CH3:9])[CH3:8]
Reactant: CN[C@@H](CC(C)C)C(=O)O
Reactant: O=C(Cl)CC1(c2ccccc2)C(=O)Oc2ccc(Cl)cc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)C[C@@H](C(=O)O)N(C)C(=O)CC1(c2ccccc2)C(=O)Oc2ccc(Cl)cc21
Temperature: 5 °C
Reaction time: 3 h

Procedure:
0.9 g of sodium hydroxide is added to a solution of 3 g of N-methylleucine in 70 ml of water and 40 ml of tetrahydrofuran. The medium is then cooled to 5° C. and a solution of 7.3 g of 2-(5-chloro-2,3-dihydro-2-oxo-3-phenyl-3-benzofuranyl)acetyl chloride in 50 ml of tetrahydrofuran and a solution of 0.9 g of sodium hydroxide in 22.7 ml of water are then added simultaneously in small portions so as to maintain the pH at 12. The mixture is stirred for 3 hours at room temperature and 22.7 ml of N hydrochloric acid are added. The medium is concentrated and the precipitate obtained is filtered off and dissolved hot in an ethanol/methanol (50:50) mixture. The solution is filtered and the filtrate evaporated. A crystalline product is obtained.
Reaction SMILES: [C:1]([O:5][C:6](=[O:12])[NH:7][CH2:8][CH2:9][CH2:10][NH2:11])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[Cl:20][C:21]1[C:30]2[C:25](=[C:26]([S:31](Cl)(=[O:33])=[O:32])[CH:27]=[CH:28][CH:29]=2)[CH:24]=[CH:23][N:22]=1.Cl.ClC1C2C(=C(S(Cl)(=O)=O)C=CC=2)C=CN=1>ClCCl>[C:1]([O:5][C:6]([NH:7][CH2:8][CH2:9][CH2:10][NH:11][S:31]([C:26]1[CH:27]=[CH:28][CH:29]=[C:30]2[C:25]=1[CH:24]=[CH:23][N:22]=[C:21]2[Cl:20])(=[O:33])=[O:32])=[O:12])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCCN
Reactant: O=S(=O)(Cl)c1cccc2c(Cl)nccc12
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCCNS(=O)(=O)c1cccc2c(Cl)nccc12
Temperature: 25 °C
Reaction time: 20 h

Procedure:
According to the method of Example 1, Step A, a solution of N-(3-aminopropyl)carbamic acid tert-butyl ester (383 mg) and triethylamine (335 μl) in dichloromethane (3 ml) was added with a solution of (1-chloro-5-isoquinolyl)sulfonyl chloride (524 mg, prepared from (1-chloro-5-isoquinolyl)sulfonyl chloride hydrochloride according to the method of Japanese Patent Unexamined Publication (Kokai) No. 63-2980) in dichloromethane (3 ml) with stirring and ice cooling and stirred at room temperature for 20 hours. The reaction mixture was successively washed with saturated aqueous sodium hydrogencarbonate twice and with saturated brine. The organic layer was dried over anhydrous sodium sulfate (Wako Pure Chemical Industries), and then the solvent was evaporated under reduced pressure. Then, the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=2:1) to obtain the title compound (640 mg).