Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]([CH2:37][CH3:38])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[N:9]=[C:10]([C:27]2[CH:28]=[C:29]([CH:33]=[CH:34][C:35]=2[CH3:36])[C:30](O)=[O:31])[C:11]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]3[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=3[F:26])[C:12]=2[N:13]=1)[CH3:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[C:70]1([C@@H:76]([NH2:78])[CH3:77])[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=1>CN(C=O)C>[CH2:37]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[N:9]=[C:10]([C:27]2[CH:28]=[C:29]([CH:33]=[CH:34][C:35]=2[CH3:36])[C:30]([NH:78][C@H:76]([C:70]2[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=2)[CH3:77])=[O:31])[C:11]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]3[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=3[F:26])[C:12]=2[N:13]=1)[CH3:38]
Reactant: CCN(CC)CCCNc1nc(-c2cc(C(=O)O)ccc2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Reactant: C[C@H](N)c1ccccc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCN(CC)CCCNc1nc(-c2cc(C(=O)N[C@@H](C)c3ccccc3)ccc2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 44.8 %

Procedure:
To the compound 3-[2-{[3-(diethylamino)propyl]amino}-8-(2,6-difluorophenyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-4-methylbenzoic acid (26 mg, 0.05 mmol) in DMF (0.5 mL) were added HBTU (28 mg, 0.075 mmol), triethylamine (21.1 uL, 0.15 mmol) and [(1S)-1-phenylethyl]amine (12.9 uL, 0.1 mmol). The mixture was stirred at rt overnight. Separation by HPLC with TFA, followed by neutralization with SPE amine cartridge afforded the title compound (14 mg, 45%). LC-MS m/z 625 (M+H)+.
Reaction SMILES: [O:1]=[C:2]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[C:4]2([CH2:9][CH2:8][CH:7]([NH:10][C:11]([C@H:13]3[CH2:18][CH2:17][CH2:16][NH:15][CH2:14]3)=[O:12])[CH2:6][CH2:5]2)[O:3]1.[Cl:25][C:26]1[C:27]([CH3:36])=[C:28]([S:32](Cl)(=[O:34])=[O:33])[CH:29]=[CH:30][CH:31]=1.C(N(CC)CC)C>C(#N)C>[Cl:25][C:26]1[C:27]([CH3:36])=[C:28]([S:32]([N:15]2[CH2:16][CH2:17][CH2:18][C@H:13]([C:11]([NH:10][CH:7]3[CH2:8][CH2:9][C:4]4([C:19]5[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=5[C:2](=[O:1])[O:3]4)[CH2:5][CH2:6]3)=[O:12])[CH2:14]2)(=[O:34])=[O:33])[CH:29]=[CH:30][CH:31]=1
Reactant: Cc1c(Cl)cccc1S(=O)(=O)Cl
Reactant: O=C1OC2(CCC(NC(=O)[C@H]3CCCNC3)CC2)c2ccccc21
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1c(Cl)cccc1S(=O)(=O)N1CCC[C@H](C(=O)NC2CCC3(CC2)OC(=O)c2ccccc23)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 65.8 %

Procedure:
A mixture of (3S)-N-(3-oxo-3H-spiro[2-benzofuran-1,1′-cyclohexan]-4′-yl)piperidine-3carboxamide (11 mg, 0.03 mmol), 3-chloro-2-methylbenzenesulfonyl chloride (6.8 mg, 0.03 mmol), and triethylamine (10.5 μL, 0.075 mmol) in acetonitrile (0.2 mL) was stirred at r.t. for 2 hours. The mixture was purified by flash column to yield 10.2 mg of final product was obtained. Yield: 65%. LCMS: 517.0 (M+H)+; 539.1 (M+Na)+.
Reaction SMILES: [C:1]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:6]=[CH:5][C:4]([CH2:7][N:8]2[CH:16]=[C:15]3[C:10]([N:11]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:12](=[O:19])[N:13]([CH3:18])[C:14]3=[O:17])=[N:9]2)=[CH:3][CH:2]=1.[Li+].CC([N-]C(C)C)C.[I:38]I>C1COCC1>[C:1]1([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:2]=[CH:3][C:4]([CH2:7][N:8]2[C:16]([I:38])=[C:15]3[C:10]([N:11]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:12](=[O:19])[N:13]([CH3:18])[C:14]3=[O:17])=[N:9]2)=[CH:5][CH:6]=1
Reactant: II
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2cn(Cc3ccc(-c4ccccc4)cc3)nc21
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)Cn1c(=O)n(C)c(=O)c2c(I)n(Cc3ccc(-c4ccccc4)cc3)nc21
Temperature: -78 °C

Procedure:
2-(biphenyl-4-ylmethyl)-7-isobutyl-5-methyl-2H-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione (203 mg, 0.523 mmol) is dissolved in anhydrous THF (5 mL), and then cooled to −78° C. 1.8 M solution of LDA in THF (600 uL) is added dropwise with rigorous stirring at −78° C., followed by the addition of iodine (160 mg, 0.63 mmol) in THF. The reaction mixture is stirred at −78° C. for an hour, and then is allowed to warm up to room temperature before quenching. The mixture is poured into saturated NH4Cl solution, and then extracted with ethyl acetate three times. The combined organic phase is washed with potassium iodide aqueous solution (1 M), water, and then dried over Na2SO4. Solvent is removed under reduced vacuum to give crude product was white solids. MS (ESI) m/z 515.1 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:21][CH3:22])=[CH:5][C:6]2[NH:12][C:11](=[O:13])[CH2:10][N:9]=[C:8]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:7]=2[CH:20]=1.[H-].[Na+].C1(=O)O[CH2:28][CH2:27][O:26]1.O>CN(C=O)C>[CH3:1][O:2][C:3]1[C:4]([O:21][CH3:22])=[CH:5][C:6]2[N:12]([CH2:28][CH2:27][OH:26])[C:11](=[O:13])[CH2:10][N:9]=[C:8]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:7]=2[CH:20]=1
Reactant: O=C1OCCO1
Reactant: COc1cc2c(cc1OC)C(c1ccccc1)=NCC(=O)N2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2c(cc1OC)N(CCO)C(=O)CN=C2c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 40 %

Procedure:
To a solution of 150 mg (0.50 mmol) of 7,8-dimethoxy-5-phenyl-1,3-dihydro-1,4-benzodiazepin-2-one XXIIaa in 5 ml of DMF, add at 0° C. under an inert atmosphere 21 mg (0.52 mmol) of 60% NaH in oil. Stir at room temperature for 1 hour. Add at 0° C., 53 mg (0.60 mmol) of ethylene carbonate. Stir at room temperature overnight. Add 50 ml of H2O and extract three times with 50 ml of AcOEt; dry on MgSO4, evaporate the AcOEt and purify by silica chromatography (AcOEt 3/hexane 1, then AcOEt). Recrystallize in CHCl3/cHexane. Yield: 40%. M: 128–130° C. 1H-NMR (DMSO, 300 MHz): d 3.36–3.52 (m, 2H, HOCH2), 3.60 (s, 3H, OCH3), 3.70–3.86 (m, 5H, NCH2+OCH3), 4.11 (AB system, ? d=0.77, JAB=9.96, 2H, CH2), 4.77 (m, 1H, OH), 6.60 (s, 1H Ar), 7.39 (s, 1H Ar), 7.42–7.58 (m, 4H Ar). Mass: (M+H)+=341.16.
Reaction SMILES: [C:1]([C:4]1[C:5](=[O:15])[O:6][C:7]([OH:14])=[C:8]([C:11](=[O:13])[CH3:12])[C:9]=1[OH:10])(=O)[CH3:2].[NH2:16][C:17]1[CH:22]=[CH:21][C:20]([SH:23])=[CH:19][CH:18]=1>CO>[C:11]([C:8]1[C:7](=[O:14])[O:6][C:5](=[O:15])[C:4](=[C:1]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([SH:23])=[CH:19][CH:18]=2)[CH3:2])[C:9]=1[OH:10])(=[O:13])[CH3:12]
Reactant: CC(=O)c1c(O)oc(=O)c(C(C)=O)c1O
Reactant: Nc1ccc(S)cc1
Solvent: CO
Product: CC(=O)C1=C(O)C(=C(C)Nc2ccc(S)cc2)C(=O)OC1=O

Procedure:
A mixture of 2.12 g. of 3,5-diacetyl-4,6-dihydroxy-2H-pyran-2-one, 1.25 g. of p-aminothiophenol and 75 ml. of methanol is refluxed for two hours, cooled and filtered to yield 5-acetyl-4-hydroxy-3-[1-(p-mercaptophenylamino)ethylidene]-2H-pyran-2,6(3H)-dione, m.p. 207°-210° C.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)[N:5]=[C:4]([C:14]([CH3:17])([CH3:16])[CH3:15])[CH:3]=1.[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][CH:28]([CH2:31][CH2:32]O)[CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:20])[CH3:19].C1CCN(C(N=NC(N2CCCCC2)=O)=O)CC1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][CH:28]([CH2:31][CH2:32][O:13][C:10]2[CH:11]=[CH:12][C:7]([N:6]3[C:2]([NH2:1])=[CH:3][C:4]([C:14]([CH3:17])([CH3:16])[CH3:15])=[N:5]3)=[CH:8][CH:9]=2)[CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)c1cc(N)n(-c2ccc(O)cc2)n1
Reactant: CC(C)(C)OC(=O)N1CCC(CCO)CC1
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(CCOc2ccc(-n3nc(C(C)(C)C)cc3N)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.9 %

Procedure:
To a solution of 4-(5-amino-3-tert-butyl-pyrazol-1-yl)-phenol (550 mg, 2.4 mmol) and 4-(2-hydroxy-ethyl)-piperidine-1-carboxylic acid tert-butyl ester (505 mg, 2.18 mmol) in 50 mL THF was added ADDP (825 mg, 3.28 mmol) and triphenylphosphine (858 mg, 3.28 mmol). The reaction mixture was stirred at room temperature under nitrogen overnight. The solid was removed by filtration, the filtrate was concentrated and the residue was purified by MPLC (80:20 hexane/EtOAc) to give the desired product 4-{2-[4-(5-amino-3-tert-butyl-pyrazol-1-yl)-phenoxy]-ethyl}-piperidine-1-carboxylic acid tert-butyl ester 800 mg (83%). 1H-NMR (DMSO-d6) δ 7.40 (d, 2H), 7.00 (d, 2H), 5.35 (s, 1H), 5.0 (s, 2H), 4.0 (m, 2H), 3.90 (m, 2H), 1.70-1.60 (m, 6H), 1.40 (s, 9H), 1.20 (s, 9H), 1.05 (m, 1H); MS LC-MS [M+H]+=443.3, RT=3.10 min.
Reaction SMILES: [C:1]12([CH:11]([OH:18])[CH2:12][N:13]3[CH:17]=[CH:16][N:15]=[CH:14]3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.CN(C)P(N(C)C)(N(C)C)=O.[H-].[Na+].Cl[CH2:33][C:34]1[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][C:35]=1[Cl:41]>O>[C:1]12([CH:11]([O:18][CH2:33][C:34]3[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][C:35]=3[Cl:41])[CH2:12][N:13]3[CH:17]=[CH:16][N:15]=[CH:14]3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: OC(Cn1ccnc1)C12CC3CC(CC(C3)C1)C2
Reactant: ClCc1ccc(Cl)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: Clc1ccc(COC(Cn2ccnc2)C23CC4CC(CC(C4)C2)C3)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 500 mg. of 1-[2-(1-adamantyl)-2-hydroxyethyl]imidazole in 3 ml. of hexamethylphosphoramide is added 96 mg. of a 56% dispersion of sodium hydride in mineral oil. The addition of base is carried out under a nitrogen atmosphere with continuous stirring. The reaction temperature is then maintained at 25° C. for 1 hour and thereafter at 50° C. After 11/2 hours at 50° C., the reaction mixture is cooled in ice and 450 mg. α,2,4-trichlorotoluene in 3 ml. hexamethylphosphoramide is added dropwise. The temperature is then held at 5° C. for a 1 hour, then raised to 25° C. for 1 hour, and finally held at 50° C. for 2 hours. Thereafter, the resulting solution is poured into 200 ml. water. The aqueous phase is extracted with ether and the extracts washed with water, dried over magnesium sulfate and evaporated to dryness. The resulting residue is chromatographed on silica gel to effect purification. Elution with 5% acetone in dichloromethane yields 1-[2-(1-adamantyl)-2-(2,4-dichlorobenzyloxy)ethyl]imidazole which is then further characterized as the oxalate salt, decomp. 203.5°-205.5° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:11][O:10]2)=[CH:5][CH:4]=1.[CH2:12]([NH2:15])[CH2:13][NH2:14]>CO.O>[OH:10][CH:9]([C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[CH2:11][NH:14][CH2:13][CH2:12][NH2:15]
Reactant: COc1ccc(C2CO2)cc1
Reactant: NCCN
Solvent: O
Solvent: CO
Product: COc1ccc(C(O)CNCCN)cc1

Procedure:
N-[2-Hydroxy-2-(4-methoxyphenyl)ethyl]-ethylenediamine is prepared by reacting 2-(4-methoxyphenyl)oxirane (37.5 g.) dissolved in methanol (52 cc.) with ethylenediamine (30 cc.) dissolved in a mixture of methanol (52 cc.) and water (20 cc.). On distillation under reduced pressure, a product (22.3 g.), b.p. 165°-169° C./0.2 mm.Hg, is obtained, which crystallises on cooling and melts at 68° C.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[F:9].P(Cl)(Cl)Cl.[Cl:14][C:15]1[CH:23]=[C:19]([C:20](O)=[O:21])[C:18]([OH:24])=[CH:17][CH:16]=1.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:20](=[O:21])[C:19]2[CH:23]=[C:15]([Cl:14])[CH:16]=[CH:17][C:18]=2[OH:24])=[CH:4][C:3]=1[F:9]
Reactant: Nc1ccc(Br)c(F)c1
Reactant: O=C(O)c1cc(Cl)ccc1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClP(Cl)Cl
Solvent: Cc1ccccc1
Product: O=C(Nc1ccc(Br)c(F)c1)c1cc(Cl)ccc1O
Yield: 90 %

Procedure:
4-Bromo-3-fluoroaniline (0.570 g, 3.00 mmol) and phosphorus trichloride (0.176 ml, 2.0 mmol) were added to a solution of 5-chlorosalicylic acid (0.690 g, 4.00 mmol) in toluene (30 ml), and the mixture was refluxed for 2 hours. Saturated aqueous sodium hydrogencarbonate was added to the reaction mixture, and the mixture was concentrated under reduced pressure and extracted with tetrahydrofuran. The organic layer was washed with saturated aqueous sodium hydrogencarbonate and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the title compound (0.930 g, 90%) as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[C@@H:5]([NH:13][C:14]([C:16]1S[C:18]([Br:21])=[CH:19][CH:20]=1)=[O:15])[CH2:6][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH3:2].BrC1[O:28]C(C(O)=O)=CC=1>>[CH2:1]([O:3][C:4](=[O:22])[C@@H:5]([NH:13][C:14]([C:16]1[O:28][C:18]([Br:21])=[CH:19][CH:20]=1)=[O:15])[CH2:6][CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH3:2]
Reactant: CCOC(=O)CC[C@H](NC(=O)c1ccc(Br)s1)C(=O)OCC
Reactant: O=C(O)c1ccc(Br)o1
Product: CCOC(=O)CC[C@H](NC(=O)c1ccc(Br)o1)C(=O)OCC
Yield: 72 %

Procedure:
Compound 13 was prepared using the general method described for the preparation of compound 9 and 13, from 12 (1.91 g, 10 mmol) to give 2.71 g (72%) of 13 as yellow oil. 1H NMR (DMSO-d6): δ 1.13-1.19 (m, 6H), 1.88-2.11 (m, 2H), 2.37-2.41 (t, J=7.2 Hz, 2H), 4.00-4.12 (m, 4H), 4.36-4.41 (m, 1H), 6.77-6.78 (d, J=3.6 Hz, 1H), 7.20-7.21 (d, J=3.6 Hz, 1H), 8.72-8.74 (d, J=7.6 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=O)=[C:4]([O:11][CH3:12])[CH:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:22])=CC=1.C(=O)(O)[O-].[Na+]>O1CCCC1>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[S:22])=[C:4]([O:11][CH3:12])[CH:3]=1
Reactant: COc1cc(Cl)ccc1C(N)=O
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc(Cl)ccc1C(N)=S
Yield: 129.9 %

Procedure:
In tetrahydrofuran (100 ml), 4-chloro-2-methoxybenzamide (9.40 g, 50.6 mmol) prepared in the Step 7-1-1 and Lawesson's reagent (10.2 g, 25.3 mmol) were suspended, and the suspension was heated under reflux for 2 hours. After the suspension was allowed to cool, a saturated sodium bicarbonate solution was added to the suspension to stop the reaction. Then the reaction mixture was subjected to extraction with ethyl acetate, and the extract was dried over anhydrous magnesium sulfate and then concentrated. The concentrate was purified by silica gel column chromatography (n-hexane:ethyl acetate=1:1) to give the title compound (6.63 g, 65%) as a yellow powder.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH2:19])[C:7]([C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=2)=[CH:8][CH:9]=1)([O-:3])=[O:2].[C:20](Cl)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CN(C1C=CN=CC=1)C.CN1CCCC1=O>[C:20]([N:19]=[C:6]1[CH2:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=[C:7]1[C:10]1[CH:11]=[CH:12][C:13]([N+:16]([O-:18])=[O:17])=[CH:14][CH:15]=1)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Nc1cc([N+](=O)[O-])ccc1-c1ccc([N+](=O)[O-])cc1
Agent: CN(C)c1ccncc1
Solvent: CN1CCCC1=O
Product: O=C(N=C1CC([N+](=O)[O-])=CC=C1c1ccc([N+](=O)[O-])cc1)c1ccccc1

Procedure:
In the first step, 4,4'-dinitro-2-biphenylamine is reacted with benzoyl chloride in the presence of 4-dimethylamine pyridine in N-methyl-2-pyrrolidinone (NMP) to give 2-(N-benzoylimino)-4,4'-dinitrobiphenyl. The hydrogenation of the latter in N,N-dimethylacetamide (DMAc) at room temperature with 10% Pd/C as a catalyst provides the desired 2-(N-benzoylimino)-4,4'-diaminobiphenyl.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2[CH:8]=[CH:9][C:10](Br)=[CH:11][C:6]=2[N:5]=[C:4]1[CH2:13][C:14]1[N:15]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=2)[N:16]=[CH:17][CH:18]=1)[CH3:2].C([Sn](CCCC)(CCCC)[C:31]([O:33]CC)=[CH2:32])CCC>C1(C)C=CC=CC=1.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>[CH2:1]([N:3]1[C:7]2[CH:8]=[CH:9][C:10]([C:31](=[O:33])[CH3:32])=[CH:11][C:6]=2[N:5]=[C:4]1[CH2:13][C:14]1[N:15]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=2)[N:16]=[CH:17][CH:18]=1)[CH3:2]
Reactant: CCn1c(Cc2ccnn2-c2cccc(F)c2)nc2cc(Br)ccc21
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CCn1c(Cc2ccnn2-c2cccc(F)c2)nc2cc(C(C)=O)ccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 1-Ethyl-2-{[2-(3-fluorophenyl)-pyrazol-3-yl]methyl}-5-bromo-1H-benzimidazole (200 mg, 0.5 mmol), tributyl(1-ethoxyvinyl)tin (0.34 ml, 1.0 mmol), and tetrakis(triphenylphosphine)palladium(0) (29 mg) in toluene (10 mL) is heated at reflux for 1 h under argon. The solvent is removed in vacuo, the residue is then dissolved in 10% HCl (5 mL) and THF (5 mL). The mixture is stirred at room temperature for 0.5 h, then extracted with ethyl acetate. The aqueous layer is adjusted to pH 9, extracted with dichloromethane, and the organic layer dried (Na2SO4), concentrated, and the residue purified by preparative silica gel chromatography to give 1-Ethyl-2-{[2-(3-fluorophenyl)-pyrazol-3-yl]methyl}-5-acetyl-1H-benzimidazole. 1H NMR (CDCl3): δ 8.36 (d, 1H); 7.99 (dd, 1H); 7.645 (d, 1H); 7.25-7.49 (m, 4H); 7.14 (m, 1H); 6.21 (d, 1 h); 4.36 (s, 2H); 4.02 (g, 2H); 2.68 (s, 3H); 1.24 (t, 3H).
Reaction SMILES: Cl[CH:2]([CH:8]([OH:12])[CH2:9][CH2:10][CH3:11])[C:3]([O:5][CH2:6][CH3:7])=[O:4].C(O)C.[O-]CC.[Na+].C(O)C>CCCCCC>[CH2:9]([C@@H:8]1[O:12][C@H:2]1[C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH2:10][CH3:11]
Reactant: CCCC(O)C(Cl)C(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CCO
Product: CCC[C@@H]1O[C@H]1C(=O)OCC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87 %

Procedure:
Ethyl 2-chloro-3-hydroxyhexanoate synthesized in Example 9 (0.8 g, 4 mmol), ethanol (3 ml) and 20% sodium ethoxide/ethanol solution (1.52 g, 1.1 equivalents) were mixed, and the mixture was stirred at room temperature for 30 minutes. Hexane (10 ml) was added, and the mixture was washed with water (10 ml×twice). After the mixture was dried with anhydrous magnesium sulfate, the inorganic salt was separated by filtration. The filtrate was concentrated under reduced pressure. The title compound was obtained as a colorless oil (0.9 g, yield: 87%, (2R,3S) was the main ingredient).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([S:8]([C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH:5]=[C:4]([N:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)[N:3]=1.[CH3:23][C:24]([CH3:28])([CH3:27])[C:25]#[CH:26]>CN(C)C=O.C(NCC)C.[Cu]I.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[CH3:23][C:24]([CH3:28])([CH3:27])[C:25]#[C:26][C:2]1[CH:7]=[C:6]([S:8]([C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH:5]=[C:4]([N:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)[N:3]=1
Reactant: Nc1ccc(S(=O)(=O)c2cc(Br)nc(N3CCCC3)c2)cc1
Reactant: C#CC(C)(C)C
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCNCC
Product: CC(C)(C)C#Cc1cc(S(=O)(=O)c2ccc(N)cc2)cc(N2CCCC2)n1
Yield: 65.2 %

Procedure:
A mixture of 382 mg (1 mmole) 4-(2-bromo-6-pyrrolidine-1-yl-pyridine-4-sulfonyl)-phenylamine, 91 mg (1.1 mmole) 3,3-dimethyl-1-butyne, 38 mg copper(I)-iodide and 35 mg bis(triphenylphosphine)-palladium(II)-chloride is refluxed for 1 hour in 5 ml dimethylformamide and 5 ml diethylamine. The solvents are removed and the residue is diluted with dichloromethane. The dichloromethane solution is washed twice with water, dried over magnesiumsulfate and concentrated in vacuo. Recrystallisation of the residue from ethanol yields 250 mg (65%) pure 4-[2-(3,3-dimethyl-but-1-ynyl)-6-pyrrolidine-1-yl-pyridine-4-sulfonyl]-phenylamine als a light brown solid mp.: 242-244° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH:5][CH2:6][C:7]1[CH:8]=[N:9][CH:10]=[C:11](B2OC(C)(C)C(C)(C)O2)[CH:12]=1.Br[C:23]1[CH:24]=[C:25]2[C:29](=[C:30]([C:32]([NH2:34])=[O:33])[CH:31]=1)[NH:28][CH:27]=[C:26]2[CH:35]1[CH2:40][CH2:39][N:38]([S:41]([CH2:44][CH3:45])(=[O:43])=[O:42])[CH2:37][CH2:36]1.C(=O)([O-])[O-].[K+].[K+]>>[CH2:44]([S:41]([N:38]1[CH2:37][CH2:36][CH:35]([C:26]2[C:25]3[C:29](=[C:30]([C:32]([NH2:34])=[O:33])[CH:31]=[C:23]([C:11]4[CH:10]=[N:9][CH:8]=[C:7]([CH2:6][NH:5][CH2:4][CH2:3][O:2][CH3:1])[CH:12]=4)[CH:24]=3)[NH:28][CH:27]=2)[CH2:40][CH2:39]1)(=[O:43])=[O:42])[CH3:45]
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(Br)cc23)CC1
Reactant: COCCNCc1cncc(B2OC(C)(C)C(C)(C)O2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cncc(CNCCOC)c4)cc23)CC1
Yield: 46 %

Procedure:
Following the general procedure of 5-(5-{[(cyclopropylmethyl)amino]methyl}-3-pyridinyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide, 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinecarbaldehyde (30 mg, 0.129 mmol), [2-(methyloxy)ethyl]amine (0.011 mL, 0.129 mmol), and NaCNBH3 (16 mg, 0.258 mmol) were reacted to give 19 mg of crude [2-(methyloxy)ethyl]{[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinyl]methyl}amine. The crude [2-(methyloxy)ethyl]{[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinyl]methyl}amine was then reacted with 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide (30 mg, 0.0723 mmol), potassium carbonate (60 mg, 0.434 mmol), and chloro-2-(dimethylaminomethyl)-ferrocen-1-yl-(dinorbornylphosphine)palladium(11) (4.4 mg, 0.00723 mmol) to give 15 mg of the title compound (46%).
Reaction SMILES: Br[C:2]1[C:6]2[N:7]=[C:8]([Cl:12])[N:9]=[C:10]([NH2:11])[C:5]=2[S:4][CH:3]=1.[NH2:13][C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[CH:18][CH:19]=1>>[NH2:13][C:14]1[CH:19]=[C:18]([C:2]2[C:6]3[N:7]=[C:8]([Cl:12])[N:9]=[C:10]([NH2:11])[C:5]=3[S:4][CH:3]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: Nc1nc(Cl)nc2c(Br)csc12
Reactant: Nc1cccc(B(O)O)c1
Product: Nc1cccc(-c2csc3c(N)nc(Cl)nc23)c1
Yield: 68.5 %

Procedure:
The target compound (360 mg, 68% yield) was prepared in the same manner as Step 1 of Example 11 using 7-bromo-2-chlorothieno[3,2-d]pyrimidin-4-amine (500 mg, 1.90 mmol) and 3-aminophenylboronic acid (261 mg, 1.90 mmol).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[F:12][C:13]([F:41])([F:40])[C:14]1[CH:15]=[C:16]([CH:37]=[CH:38][CH:39]=1)[CH2:17][NH:18][C:19](=[O:36])[C:20]1[CH:25]=[CH:24][N:23]=[C:22]([C:26]2[CH:31]=[C:30](F)[CH:29]=[CH:28][C:27]=2[N+:33]([O-:35])=[O:34])[CH:21]=1>CN(C)C=O.O>[F:40][C:13]([F:12])([F:41])[C:14]1[CH:15]=[C:16]([CH:37]=[CH:38][CH:39]=1)[CH2:17][NH:18][C:19](=[O:36])[C:20]1[CH:25]=[CH:24][N:23]=[C:22]([C:26]2[CH:31]=[C:30]([N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)[CH:29]=[CH:28][C:27]=2[N+:33]([O-:35])=[O:34])[CH:21]=1
Reactant: C1CCNC1
Reactant: O=C(NCc1cccc(C(F)(F)F)c1)c1ccnc(-c2cc(F)ccc2[N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(NCc1cccc(C(F)(F)F)c1)c1ccnc(-c2cc(N3CCCC3)ccc2[N+](=O)[O-])c1
Temperature: 90 °C
Reaction time: 4 h
Yield: 118.1 %

Procedure:
Into a 10-mL vial, was placed a solution of pyrrolidine (152.5 mg, 2.15 mmol, 3.00 equiv) in N,N-dimethylformamide (5 mL), potassium carbonate (296.2 mg, 2.15 mmol, 3.00 equiv), and N-(3-(trifluoromethyl)benzyl)-2-(5-fluoro-2-nitrophenyl)isonicotinamide 14d (300 mg, 0.72 mmol, 1.00 equiv). The resulting solution was stirred for 4 h at 90° C. in an oil bath. The resulting solution was diluted with 50 mL of water. The resulting solution was extracted with 3×50 mL of ethyl acetate and the organic layers combined. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum to yield 400 mg of crude product as a yellow to green oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:8][CH2:9][CH2:10][OH:11])=[N:4][CH:5]=[CH:6][CH:7]=1.[Br:12]N1C(=O)CCC1=O>ClCCl.C(OCC)(=O)C>[Br:12][C:6]1[CH:7]=[C:2]([Cl:1])[C:3]([NH:8][CH2:9][CH2:10][OH:11])=[N:4][CH:5]=1
Reactant: OCCNc1ncccc1Cl
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: OCCNc1ncc(Br)cc1Cl
Reaction time: 1.5 h
Yield: 103.6 %

Procedure:
2.1 g of 2-(3-chloro-2-pyridinylamino)ethanol was dissolved in 25 mL dichloromethane, and 2.3 g N-bromosuccinimide was added little by little thereto at 0° C. and stirred for 1.5 hours. The reaction mixture was diluted with ethyl acetate and then washed with an aqueous saturated sodium bicarbonate and brine, the organic layer was dried over anhydrous sodium sulfate, and the solvent was removed, whereby 3.17 g of the title compound (yellow oil) was obtained.