Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6](Cl)=[O:7])#[N:2].C(N(CC)CC)C.[N+:19]([C:22]1[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=1[NH2:24])([O-:21])=[O:20]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([NH:24][C:23]1[CH:25]=[CH:26][CH:27]=[CH:28][C:22]=1[N+:19]([O-:21])=[O:20])=[O:7])#[N:2]
Reactant: N#Cc1cccc(C(=O)Cl)c1
Reactant: Nc1ccccc1[N+](=O)[O-]
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: N#Cc1cccc(C(=O)Nc2ccccc2[N+](=O)[O-])c1
Reaction time: 24 h
Yield: 105.9 %

Procedure:
To a mixture of 3-cyanobenzoyl chloride (10.0 g, 60.4 mmol), triethylamine (12.6 mL, 90.6 mmol), and methylene chloride (120 mL) was added 2-nitroaniline (8.30 g, 60.4 mmol) followed by 4-(dimethylamino)pyridine (738 mg, 6.04 mmol). After stirring for 24 h, the reaction mixture was concentrated in vacuo. Chromatography (silica gel, 30% ethyl acetate/70% hexanes to 50% ethyl acetate/50% hexanes) yielded 17.1 g (99%) of the title compound as a yellow solid.
Reaction SMILES: [F:1][C:2]1[C:3]([CH2:23][N:24](C)[C:25](=O)OC(C)(C)C)=[CH:4][N:5]([S:14]([C:17]2[CH:21]=[CH:20][O:19][C:18]=2[CH3:22])(=[O:16])=[O:15])[C:6]=1[C:7]1[C:8]([F:13])=[N:9][CH:10]=[CH:11][CH:12]=1.C(OCC)(=O)C.[ClH:39]>C(OCC)(=O)C.C(O)C>[ClH:39].[F:1][C:2]1[C:3]([CH2:23][NH:24][CH3:25])=[CH:4][N:5]([S:14]([C:17]2[CH:21]=[CH:20][O:19][C:18]=2[CH3:22])(=[O:16])=[O:15])[C:6]=1[C:7]1[C:8]([F:13])=[N:9][CH:10]=[CH:11][CH:12]=1
Reactant: Cc1occc1S(=O)(=O)n1cc(CN(C)C(=O)OC(C)(C)C)c(F)c1-c1cccnc1F
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCO
Product: CNCc1cn(S(=O)(=O)c2ccoc2C)c(-c2cccnc2F)c1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 78 %

Procedure:
tert-Butyl ({4-fluoro-5-(2-fluoropyridin-3-yl)-1-[(2-methyl-3-furyl)sulfonyl]-1H-pyrrol-3-yl}methyl)methylcarbamate (187 mg) was dissolved in ethyl acetate (1 mL) and ethanol (1 mL), and 4 mol/L hydrogen chloride-ethyl acetate solution (2 mL) was added. The mixture was stirred at room temperature for 2 hr, and the reaction mixture was concentrated under reduced pressure. The residue was recrystallized from a mixed solvent of ethyl acetate-ethanol=3:1 to give the title compound as colorless crystals (yield 125 mg, 78%).
Reaction SMILES: [CH:1]1([CH2:7][C@@H:8]([NH2:25])[CH2:9][N:10]2[CH2:15][CH2:14][N:13]([C:16]3[S:17][C:18]4[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=4[N:20]=3)[CH2:12][CH2:11]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH:33]1([C:39](Cl)=[O:40])[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1>ClCCl>[CH:1]1([CH2:7][C@@H:8]([NH:25][C:39]([CH:33]2[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]2)=[O:40])[CH2:9][N:10]2[CH2:11][CH2:12][N:13]([C:16]3[S:17][C:18]4[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=4[N:20]=3)[CH2:14][CH2:15]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: N[C@H](CC1CCCCC1)CN1CCN(c2nc3ccccc3s2)CC1
Reactant: O=C(Cl)C1CCCCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(N[C@H](CC1CCCCC1)CN1CCN(c2nc3ccccc3s2)CC1)C1CCCCC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 0.2 g (0.56 mmol) of {(1R)-1-cyclohexylmethyl-2-[4-(benzothiazol-2-yl)-piperazin-1-yl]-ethyl}-amine and 0.16 mL (1.12 mmol) of triethylamine in 10 mL of dichloromethane at 0° C. was added dropwise 0.086 g (0.59 mmol) of cyclohexanecarboxylic acid chloride in dichloromethane (2 mL). The reaction mixture was allowed to stir under nitrogen for one hour at 0° C. and was then concentrated on a rotary evaporator, diluted with ethyl acetate and washed with H2O and brine. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated on a rotary evaporator to yield the crude product, which was purified by flash chromatography on silica gel (dichloromethane/methanol) and converted to the hydrochloride salt of the title compound with ethereal HCl to yield 0.20 g (70%) as a white solid; mp=229-232° C.; MS (+) ESI m/z=469 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[C:6]=2[N:7]=1.[OH:19][CH2:20][CH2:21][CH2:22][NH2:23]>>[Cl:1][C:2]1[N:3]=[C:4]([NH:23][CH2:22][CH2:21][CH2:20][OH:19])[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[C:6]=2[N:7]=1
Reactant: Fc1ccc(C2CCc3c(Cl)nc(Cl)nc32)cc1
Reactant: NCCCO
Product: OCCCNc1nc(Cl)nc2c1CCC2c1ccc(F)cc1

Procedure:
2,4-dichloro-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine (Preparation H) was reacted as described in Preparation Hr with 3-hydroxypropan-1-amine to afford 3-(2-chloro-7-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-ylamino)propan-1-ol (Preparation Hv). LC-MS (M+H)+=322.1. 1H NMR (500 MHz, CDCl3) δ ppm 7.08 (2H, dd, J=8.55, 5.49 Hz), 6.97 (2H, t, J=8.70 Hz), 5.18 (1H, br. s.), 4.22-4.27 (1H, m), 3.66-3.75 (4H, m), 3.18 (1H, br. s.), 2.60-2.77 (3H, m), 2.02-2.12 (1H, m), 1.78-1.86 (2H, m)
Reaction SMILES: [OH:1][C:2]1[C:3]([C:16]2[CH:17]=[C:18]([CH:24]=[CH:25][C:26]([O:28]CC)=[O:27])[CH:19]=[CH:20][C:21]=2[O:22][CH3:23])=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:13])([CH3:12])[C:10]=2[CH:11]=1.Cl.Cl[CH2:33][CH2:34][N:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1>>[CH3:23][O:22][C:21]1[CH:20]=[CH:19][C:18]([CH:24]=[CH:25][C:26]([OH:28])=[O:27])=[CH:17][C:16]=1[C:3]1[C:2]([O:1][CH2:33][CH2:34][N:35]2[CH2:40][CH2:39][O:38][CH2:37][CH2:36]2)=[CH:11][C:10]2[C:9]([CH3:13])([CH3:12])[CH2:8][CH2:7][C:6]([CH3:15])([CH3:14])[C:5]=2[CH:4]=1
Reactant: CCOC(=O)C=Cc1ccc(OC)c(-c2cc3c(cc2O)C(C)(C)CCC3(C)C)c1
Reactant: ClCCN1CCOCC1
Agent: Cl
Product: COc1ccc(C=CC(=O)O)cc1-c1cc2c(cc1OCCN1CCOCC1)C(C)(C)CCC2(C)C
Yield: 89.4 %

Procedure:
In a manner similar to that of Example 16(a), by reaction of 1.4 g (3.4 mmol) of ethyl 3-[3-(3-hydroxy-5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)-4-methoxyphenyl]acrylate obtained in Example 13(f) with 760 mg (4.08 mmol) of 4-(2-chloroethyl)-morpholine hydrochloride, 1.5 g (85%) of the expected compound was obtained in the form of a yellow oil.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[CH2:3][O:4][C:5]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:6]=1CC#N.Cl.[C:18]([OH:21])(=[O:20])[CH3:19]>>[F:16][C:2]([F:1])([F:15])[CH2:3][O:4][C:5]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:6]=1[CH2:19][C:18]([OH:21])=[O:20]
Reactant: N#CCc1ccc(F)cc1OCC(F)(F)F
Reactant: CC(=O)O
Agent: Cl
Product: O=C(O)Cc1ccc(F)cc1OCC(F)(F)F

Procedure:
To a stirred solution of 2-(2,2,2-trifluoroethoxy)-4-fluorophenylacetonitrile (0.60 g, 2.7 mmol) from Step 4 above in acetic acid (10 mL) was added 12 N aqueous HCl (5 mL). The mixture was refluxed for 4 h. The solvents were removed under reduced pressure and the residue was partitioned between EtOAc (100 mL) and water (2×50 mL). The organic phase was dried (MgSO4), filtered, and the solvent was removed under reduced pressure to give 2-(2,2,2-trifluoroethoxy)-4-fluorophenylacetic acid as an amorphous solid (HPLC retention time=7.5 min (method A)).
Reaction SMILES: Cl.[NH2:2][CH:3]([CH2:8][NH:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C:4]([O:6][CH3:7])=[O:5].CCN(CC)CC.[C:24](Cl)(=[O:34])[O:25][CH2:26][C:27]([CH3:33])([CH3:32])[CH2:28][CH2:29][CH:30]=[CH2:31]>C1COCC1>[CH3:14][C:13]([CH3:16])([O:12][C:10](=[O:11])[NH:9][CH2:8][CH:3]([C:4]([O:6][CH3:7])=[O:5])[NH:2][C:24](=[O:34])[O:25][CH2:26][C:27]([CH3:33])([CH3:32])[CH2:28][CH2:29][CH:30]=[CH2:31])[CH3:15]
Reactant: COC(=O)C(N)CNC(=O)OC(C)(C)C
Reactant: C=CCCC(C)(C)COC(=O)Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C=CCCC(C)(C)COC(=O)NC(CNC(=O)OC(C)(C)C)C(=O)OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.7 %

Procedure:
To a stirring solution of 381 mg of methyl 2-amino-3-(tert-butoxycarbonylamino)propanoate hydrochloride, and 1 mL of Et3N in 10 mL of anhydrous THF, was added 1.5 mmol of 2,2-dimethylhex-5-enyl carbonochloridate. The resulting mixture was stirred at rt overnight, then concentrated. The residue was subject to column chromatography on silica gel with heptanes/EtOAc (v/v 7/1) as eluent, giving 500 mg colorless oil (90%). 1HNMR (400 MHz, CDCl3) d 5.82 (m, 1H), 5.64 (br s, 1H), 5.02 (dd, 1H, J=13.2, 1.8 Hz), 4.95 (d, 1H, J=8.2 Hz), 4.83 (br s, 1H), 4.39 (br d, 1H, J=6.0 Hz), 3.83 (br s, 2H), 3.80 (s, 3H), 2.55 (m, 2H), 2.02 (m, 2H), 1.43 (s, 9H), 1.35 (m, 2H), 0.91 (s, 6H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:23]=[C:11]3[N:12]=[C:13]([CH3:22])[C:14]([CH2:17][C:18]([O:20][CH3:21])=[O:19])=[C:15](Cl)[N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[Na+].[I-:25]>C(#N)C.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:23]=[C:11]3[N:12]=[C:13]([CH3:22])[C:14]([CH2:17][C:18]([O:20][CH3:21])=[O:19])=[C:15]([I:25])[N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: [I-]
Reactant: COC(=O)Cc1c(C)nc2cc(-c3cccc(Br)c3)nn2c1Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COC(=O)Cc1c(C)nc2cc(-c3cccc(Br)c3)nn2c1I
Temperature: 80 °C
Yield: 81.3 %

Procedure:
Methyl 2-(2-(3-bromophenyl)-7-chloro-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)acetate (1 g, 2.53 mmol) and NaI (1.519 g, 10.14 mmol) were suspended in acetonitrile (10 mL) and the resulting mixture was heated at 80° C. for 5 h. After cooling to room temp, mixture was diluted with ethyl acetate (50 mL) and washed with water (25 mL) and aqueous Na2S2O3 (25 mL), dried (Na2SO4), filtered and concentrated. Crude was then triturated with ethyl acetate/hexane to afford methyl 2-(2-(3-bromophenyl)-7-iodo-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)acetate (1 g, 2.057 mmol, 81% yield) as off white solid. 1H NMR (400 MHz, CDCl3) δ: 8.20 (t, J=1.8 Hz, 1H), 7.95 (dt, J=7.8, 1.3 Hz, 1H), 7.55 (ddd, J=8.0, 2.0, 1.0 Hz, 1H), 7.36 (t, J=7.9 Hz, 1H), 7.08 (s, 1H), 4.02 (s, 2H), 3.79 (s, 3H), 2.66 (s, 3H). LCMS (M+H)=486.1.
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH:5]1[CH2:11][CH2:10][CH:9]2[CH:7]([CH2:8]2)[C:6]1([C:13]1[CH:18]=[C:17]([OH:19])[CH:16]=[C:15]([F:20])[CH:14]=1)[OH:12])[CH3:3].[CH3:21][C:22]([CH3:27])([CH3:26])[C:23](Cl)=[O:24].C(N(CC)CC)C>C(Cl)Cl>[CH3:3][N:2]([CH2:4][CH:5]1[CH2:11][CH2:10][CH:9]2[CH:7]([CH2:8]2)[C:6]1([C:13]1[CH:18]=[C:17]([O:19][C:23](=[O:24])[C:22]([CH3:27])([CH3:26])[CH3:21])[CH:16]=[C:15]([F:20])[CH:14]=1)[OH:12])[CH3:1]
Reactant: CN(C)CC1CCC2CC2C1(O)c1cc(O)cc(F)c1
Reactant: CC(C)(C)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)CC1CCC2CC2C1(O)c1cc(F)cc(OC(=O)C(C)(C)C)c1
Yield: 59.2 %

Procedure:
Stir a mixture of 3-dimethylaminomethyl-2-(3-fluoro-5-hydroxy-phenyl)-bicyclo[4.1.0]heptan-2-ol (295 mg, 1.06 mmol), 2,2-dimethyl-propionyl chloride (153 mg, 1.27 mmol) and triethyl-amine (321 mg, 3.18 mmol) in CH2Cl2 (40 mL) at ambient temperature for 5 hours. Quench the mixture with 10 mL of H2O, Separate the aqueous layer off, and concentrate the organic layer under reduced pressure. Purify the residue by preparative TLC to give 2,2-dimethyl-propionic acid 3-(3-dimethylaminomethyl-2-hydroxy-bicyclo[4.1.0]hept-2-yl)-5-fluoro-phenyl ester as white solid (228 mg, Yield: 59.2%). MS (m/z): 364 (M+1). 1H NMR (400 MHz, Methanol-d4) δ 7.25-7.28 (d, J1=10.4, J2=1.6, 1H), 7.14 (s, 1H), 6.76-6.78 (d, J1=9.2, J2=2.4, 1H), 2.37-2.46 (m, 1H), 2.15-2.19 (m, 7H), 1.99-2.03 (d, J=13.2, 1H), 1.82 (m, 2H), 1.53-1.68 (m, 2H), 1.37 (s, 9H), 1.17 (m, 1H), 1.01-1.06 (m, 1H), 0.75-0.81 (m, 1H), 0.48-0.50 (m, 1H).
Reaction SMILES: C[Al](C)C.CO[C:7]([C:9]1[S:13][C:12]([N:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]2)=[CH:11][CH:10]=1)=[O:8].[CH3:27][O:28][C:29]1[CH:30]=[C:31]([CH2:37][CH2:38][C:39]2[CH:40]=[C:41]([NH2:44])[NH:42][N:43]=2)[CH:32]=[C:33]([O:35][CH3:36])[CH:34]=1>C1(C)C=CC=CC=1.CC(C)=O>[CH3:36][O:35][C:33]1[CH:32]=[C:31]([CH2:37][CH2:38][C:39]2[CH:40]=[C:41]([NH:44][C:7]([C:9]3[S:13][C:12]([N:14]4[CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:24])([CH3:25])[CH3:26])=[O:21])[CH2:18][CH2:19]4)=[CH:11][CH:10]=3)=[O:8])[NH:42][N:43]=2)[CH:30]=[C:29]([O:28][CH3:27])[CH:34]=1
Reactant: COc1cc(CCc2cc(N)[nH]n2)cc(OC)c1
Reactant: COC(=O)c1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)s1
Agent: C[Al](C)C
Solvent: CC(C)=O
Solvent: Cc1ccccc1
Product: COc1cc(CCc2cc(NC(=O)c3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)s3)[nH]n2)cc(OC)c1
Temperature: 20 °C
Reaction time: 20 h
Yield: 50.2 %

Procedure:
2M Trimethylaluminium (1.250 ml, 2.50 mmol) in toluene, was added dropwise to a stirred solution of tert-butyl 4-(5-(methoxycarbonyl)thiophen-2-yl)piperazine-1-carboxylate (0.326 g, 1 mmol) and 5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-amine (0.247 g, 1.00 mmol) in toluene (7.14 ml) at 20° C. under nitrogen. The reaction mixture was stirred at 20° C. for 20 h. The temperature was increased to 60° C. and the reaction mixture was stirred for 20 h and then allowed to cool. The reaction mixture was diluted with acetone (10 ml) and quenched with damp solid sodium sulphite. The mixture was stirred for 30 mins, and then a solution of 10% methanol in DCM (10 mL) was added and the mixture stirred for a further 30 mins. The suspension was filtered and the solid washed with 10% methanol in DCM (20 mL); the combined filtrates were evaporated to give a yellow foam. The crude product was purified by silica column chromatography, eluting with a gradient of 1 to 10% 2M ammonia/methanol in DCM. Pure fractions were evaporated to dryness to afford the crude product. This was further purified by preparative HPLC, using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford tert-butyl 4-[5-[[5-[2-(3,5-dimethoxyphenyl)ethyl]-2H-pyrazol-3-yl]carbamoyl]thiophen-2-yl]piperazine-1-carboxylate (0.272 g, 50.2%) as a white dry film. 1H NMR (500.13 MHz, DMSO-d6) δ 1.46 (9H, s), 2.89-2.90 (6H, m), 3.22 (4H, t), 3.52 (4H, t), 3.75 (6H, s), 6.18 (1H, d), 6.27 (1H, s), 6.34 (1H, t), 6.42-6.42 (2H, m), 7.72 (1H, d), 9.81 (1H, s), 11.71 (1H, s); MS: m/z 542 (MH+)
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([N:9]2[C:13]3=[C:14]4[S:20][CH:19]=[CH:18][C:15]4=[N:16][CH:17]=[C:12]3[N:11]=[C:10]2[CH2:21][C:22]#[N:23])[CH2:5][CH2:4]1.C(N(CC)CC)C.Cl[C:32]([O:34][CH3:35])=[O:33]>C(Cl)Cl>[C:22]([CH2:21][C:10]1[N:9]([C@H:6]2[CH2:7][CH2:8][C@H:3]([CH2:2][NH:1][C:32](=[O:33])[O:34][CH3:35])[CH2:4][CH2:5]2)[C:13]2=[C:14]3[S:20][CH:19]=[CH:18][C:15]3=[N:16][CH:17]=[C:12]2[N:11]=1)#[N:23]
Reactant: N#CCc1nc2cnc3ccsc3c2n1[C@H]1CC[C@H](CN)CC1
Reactant: COC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)NC[C@H]1CC[C@H](n2c(CC#N)nc3cnc4ccsc4c32)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of {1-[trans-4-(aminomethyl)cyclohexyl]-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-2-yl}acetonitrile (9.5 mg, 0.029 mmol) and triethylamine (20 μL, 0.14 mmol) in methylene chloride (1 mL) was added methyl chloroformate (2.7 μL, 0.035 mmol). The mixture was stirred at room temperature for 1 h, then stripped to dryness and purified on prep-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 60 mL/min) to give the desired product (1.4 mg, 12%). LCMS calculated for C19H22N5O2S (M+H)+: m/z=384.1. Found: 384.0.
Reaction SMILES: C[Mg]Cl.[S:4]([N:14]1[C:18]2=[N:19][CH:20]=[C:21]([CH:23]=[O:24])[N:22]=[C:17]2[CH:16]=[CH:15]1)([C:7]1[CH:13]=[CH:12][C:10]([CH3:11])=[CH:9][CH:8]=1)(=[O:6])=[O:5].[NH4+].[Cl-].[CH3:27]COC(C)=O>C1COCC1.C(Cl)Cl>[S:4]([N:14]1[C:18]2=[N:19][CH:20]=[C:21]([CH:23]([OH:24])[CH3:27])[N:22]=[C:17]2[CH:16]=[CH:15]1)([C:7]1[CH:8]=[CH:9][C:10]([CH3:11])=[CH:12][CH:13]=1)(=[O:5])=[O:6]
Reactant: Cc1ccc(S(=O)(=O)n2ccc3nc(C=O)cnc32)cc1
Reactant: CCOC(C)=O
Agent: C[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)n2ccc3nc(C(C)O)cnc32)cc1
Temperature: 25 °C
Yield: 23 %

Procedure:
To a solution of methylmagnesium chloride (0.232 mL, 0.697 mmol) in THF (10 mL) at about −78° C. was added a solution of 5-tosyl-5H-pyrrolo[2,3-b]pyrazine-2-carbaldehyde (0.210 g, 0.697 mmol, Example #10, Step B) in DCM (10.0 mL). After about 10 min saturated aqueous NH4Cl was added to the reaction mixture. After warming to room temperature, EtOAc (30 mL) was added to the reaction mixture and the organic layer was separated, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude material was purified by silica gel chromatography eluting with 20-80% EtOAc/heptane to provide 1-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-yl)ethanol (0.050 g, 23%) as a yellow oil. LC/MS (Table 2, Method a) Rt=2.04 min; MS m/z: 318 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:10]=1[NH2:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:18][C:19]([O:21][CH3:22])=[O:20].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:10]=1[NH:11][CH2:18][C:19]([O:21][CH3:22])=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)CBr
Reactant: Nc1c(F)cccc1OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)CNc1c(F)cccc1OCc1ccccc1
Temperature: 60 °C

Procedure:
A mixture of 2-benzyloxy-6-fluoroaniline (950 mg, 4.37 mmol), methyl bromoacetate (456 μL, 737 mg, 4.82 mmol), and potassium carbonate (1.21 g, 8.76 mmols) in DMF (10 mL) is heated at 60° C. for 18 h. The mixture is poured into ethyl acetate and extracted once with water and five times with brine. The organic layer is dried, filtered, and the solvent removed under reduced pressure to afford a crude oil that is chromatographed on an Isco Companion (80 g silica gel, 0-30% gradient of hexane/ethyl acetate) to afford methyl 2-(2-benzyloxy-6-fluoroanilino)-acetate as an oil. MS (M+1)+=290; NMR (CDCl3): δ 7.39 (m, 5H), 6.67 (m, 3H), 5.10 (s, 2H), 4.57 (br s, 1H), 4.11 (m, 2H), 3.72 (s, 3H).
Reaction SMILES: [C:1]([CH2:4][C:5](=[O:7])[CH3:6])(=[O:3])[CH3:2].[H-].[Na+].[C:10]([O:14][C:15]([N:17]1[C:21]2=[N:22][CH:23]=[CH:24][CH:25]=[C:20]2[C:19]([CH2:26]Cl)=[CH:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11].O>CS(C)=O>[C:10]([O:14][C:15]([N:17]1[C:21]2=[N:22][CH:23]=[CH:24][CH:25]=[C:20]2[C:19]([CH2:26][CH:4]([C:5](=[O:7])[CH3:6])[C:1](=[O:3])[CH3:2])=[CH:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11]
Reactant: CC(=O)CC(C)=O
Reactant: CC(C)(C)OC(=O)n1cc(CCl)c2cccnc21
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CC(=O)C(Cc1cn(C(=O)OC(C)(C)C)c2ncccc12)C(C)=O
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To acetylacetone (0.563 g, 5.62 mmol) in dimethyl sulfoxide (29.0 mL) was added sodium hydride (0.225 g, 60% in mineral oil, 5.62 mmol). After 20 minutes, 3-chloromethyl-pyrrolo[2,3-b]pyridine-1-carboxylic acid tert-butyl ester (512, 1.00 g, 3.75 mmol) was added to the reaction. The reaction was stirred at room temperature for 2 hours. The reaction was poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 40% ethyl acetate in hexane to give a colorless oil (513, 0.59 g, 48.0%). MS (ESI) [M+H+]+=331.4.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:16]2[C:20]3[CH:21]=[CH:22][C:23]([C:25]4[CH:26]=[N:27][N:28]([CH2:30][CH2:31][C:32]([CH3:35])([OH:34])[CH3:33])[CH:29]=4)=[CH:24][C:19]=3[N:18]=[CH:17]2)[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:9]=2[F:15])[CH:7]=1.[CH2:36]([S:38](Cl)(=[O:40])=[O:39])[CH3:37]>>[F:15][C:9]1[CH:10]=[C:11]([F:14])[CH:12]=[CH:13][C:8]=1[C:6]1[CH:5]=[C:4]([N:16]2[C:20]3[CH:21]=[CH:22][C:23]([C:25]4[CH:26]=[N:27][N:28]([CH2:30][CH2:31][C:32]([OH:34])([CH3:35])[CH3:33])[CH:29]=4)=[CH:24][C:19]=3[N:18]=[CH:17]2)[CH:3]=[C:2]([NH:1][S:38]([CH2:36][CH3:37])(=[O:40])=[O:39])[CH:7]=1
Reactant: CC(C)(O)CCn1cc(-c2ccc3c(c2)ncn3-c2cc(N)cc(-c3ccc(F)cc3F)c2)cn1
Reactant: CCS(=O)(=O)Cl
Product: CCS(=O)(=O)Nc1cc(-c2ccc(F)cc2F)cc(-n2cnc3cc(-c4cnn(CCC(C)(C)O)c4)ccc32)c1
Yield: 33.6 %

Procedure:
The compound was prepared from 4-(4-(1-(5-amino-2′,4′-difluoro-[1,1′-biphenyl]-3-yl)-1H-benzo[d]imidazol-5-yl)-1H-pyrazol-1-yl)-2-methylbutan-2-ol (88 mg, 0.185 mmol) using the procedure of Example 2(b) and ethanesulfonyl chloride (28.6 mg, 0.370 mmol, 1.2 eq.) to give the product in 33.6% yield (35 mg)1H NMR (300 MHz, DMSO-d6): δ 10.42 (s, 1H), 8.92 (s, 1H), 8.30 (s, 1H), 8.01-7.97 (d, 2H), 7.69 (m, 3H), 7.59 (d, 2H), 7.56 (m, 2H), 7.32 (m, 1H), 4.30 (m, 2H), 3.31-3.28 (m, 4H), 1.8 (m, 2H), 1.28-1.24 (t, 3H), 1.15 (s, 6H), Calculated mass: 565.63; Observed mass: 566.2 [M+H]+ (rt: 1.40 min).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[OH:12].[C:13](Cl)(=O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>O1CCOCC1.C(Cl)Cl>[C:14]1([C:13]2[O:12][C:3]3[CH:4]=[C:5]([C:6]([O:8][CH3:9])=[O:7])[CH:10]=[CH:11][C:2]=3[N:1]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: COC(=O)c1ccc(N)c(O)c1
Solvent: C1COCCO1
Solvent: ClCCl
Product: COC(=O)c1ccc2nc(-c3ccccc3)oc2c1
Temperature: 210 °C

Procedure:
A mixture of methyl 4-amino-3-hydroxy-benzoate is (0.3 g, 1.8 mmol) and benzoyl chloride It (0.23 mL, 2.0 mmol) in dioxane (2.5 mL) was heated at 210° C. under microwave for 15 min. The reaction mixture was diluted with CH2Cl2 and washed with aq. NaHCO3. The organic solution was dried over Na2SO4, concentrated and purified by flash column chromatography (silica gel, 20% EtOAc/heptane) to give 1u (0.39 g).
Reaction SMILES: [NH2:1][C:2]1[C:3]([OH:13])=[C:4]([S:9]([NH2:12])(=[O:11])=[O:10])[C:5]([Cl:8])=[CH:6][CH:7]=1.[CH2:14]([N:17]=[C:18]=[O:19])[CH2:15][CH3:16]>CN(C)C=O.C(OCC)(=O)C>[NH2:12][S:9]([C:4]1[C:3]([OH:13])=[C:2]([NH:1][C:18]([NH:17][CH2:14][CH2:15][CH3:16])=[O:19])[CH:7]=[CH:6][C:5]=1[Cl:8])(=[O:11])=[O:10]
Reactant: CCCN=C=O
Reactant: Nc1ccc(Cl)c(S(N)(=O)=O)c1O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCNC(=O)Nc1ccc(Cl)c(S(N)(=O)=O)c1O
Yield: 44.6 %

Procedure:
A solution of 3-amino-6-chloro-2-hydroxybenzenesulfonamide (150 mg, 0.67 mmol) and propyl isocyanate (76 μL, 0.81 mmol) in 1 mL of N,N-dimethyl-formamide was stirred at room temperature for 20 hours. The mixture was diluted with ethyl acetate and washed with water to give the crude. Purification upon column chromatograph on silica gel, eluting with ethyl acetate/hexane (50/50, v/v), followed by recrystallization from acetone and hexane, gave the desired product (92 mg, 44%). LC-MS (m/z) 308.2 (M+).
Reaction SMILES: [C:1]([C:4]1[C:13]([N:14]2[CH2:18][CH2:17][C@H:16]([NH:19][C:20](=[O:22])[CH3:21])[CH2:15]2)=[C:12]2[C:7]([CH:8]=[CH:9][CH:10]=[N:11]2)=[C:6]([Cl:23])[CH:5]=1)(=O)[CH3:2].C([O-])(=O)C.[NH4+].C([BH3-])#[N:30].[Na+]>CO.C(#N)C>[NH2:30][CH:1]([C:4]1[C:13]([N:14]2[CH2:18][CH2:17][C@H:16]([NH:19][C:20](=[O:22])[CH3:21])[CH2:15]2)=[C:12]2[C:7]([CH:8]=[CH:9][CH:10]=[N:11]2)=[C:6]([Cl:23])[CH:5]=1)[CH3:2]
Reactant: [BH3-]C#N
Reactant: CC(=O)N[C@H]1CCN(c2c(C(C)=O)cc(Cl)c3cccnc23)C1
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Solvent: CC#N
Product: CC(=O)N[C@H]1CCN(c2c(C(C)N)cc(Cl)c3cccnc23)C1
Temperature: 65 °C

Procedure:
A mixture of N-[(3S)-1-(7-acetyl-5-chloroquinolin-8-yl)pyrrolidin-3-yl]acetamide (22 mg, 0.066 mmol) and ammonium acetate (51.1 mg, 0.663 mmol) in methanol (0.37 mL) and acetonitrile (0.38 mL) was heated at 65° C. in a sealed tube for 30 minutes. After cooling, sodium cyanoborohydride (8.33 mg, 0.133 mmol) was added to the resultant mixture. The reaction was heated at 65° C. for another 4 hours, then cooled to room temperature, quenched with saturated sodium bicarbonate, and extracted with dichloromethane. The combined extracts were dried over magnesium sulfate and evaporated to dryness (17 mg, 77%). The residue was used directly in the next step. LCMS calculated for C17H22ClN4O(M+H)+: m/z=333.1; found: 333.1.