Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:24])=[C:6]([C:8]2[CH:17]=[C:16]3[C:11]([CH:12]=[C:13]([NH:18][C:19]([CH:21]4[CH2:23][CH2:22]4)=[O:20])[N:14]=[CH:15]3)=[CH:10][CH:9]=2)[CH:7]=1.N1C=CC=CC=1.[CH2:31]([S:33](Cl)(=[O:35])=[O:34])[CH3:32]>ClCCl>[CH2:31]([S:33]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:24])=[C:6]([C:8]2[CH:17]=[C:16]3[C:11]([CH:12]=[C:13]([NH:18][C:19]([CH:21]4[CH2:22][CH2:23]4)=[O:20])[N:14]=[CH:15]3)=[CH:10][CH:9]=2)[CH:7]=1)(=[O:35])=[O:34])[CH3:32]
Reactant: Cc1ccc(N)cc1-c1ccc2cc(NC(=O)C3CC3)ncc2c1
Reactant: CCS(=O)(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCS(=O)(=O)Nc1ccc(C)c(-c2ccc3cc(NC(=O)C4CC4)ncc3c2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 54.5 %

Procedure:
To a solution of N-(7-(5-amino-2-methylphenyl)isoquinolin-3-yl)cyclopropanecarboxamide (56.2 mg, 0.177 mmol) in methylene chloride (2.0 mL, 31 mmol) was added pyridine (0.20 mL, 2.5 mmol) and ethanesulfonyl chloride (23.0 uL, 0.243 mmol). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was then poured into dichloromethane, washed with water, dried over MgSO4, filtered, and evaporated in vacuo. The crude product was purified via reverse phase HPLC and lyophilized to yield 39.5 mg (54%) of N-(7-(5-(ethylsulfonamido)-2-methylphenyl)isoquinolin-3-yl)cyclopropanecarboxamide. LCMS (ESI): RT (min)=4.534, M+H=410.1, method=E; 1H NMR (400 MHz, DMSO-d6) δ 10.90 (s, 1H), 9.73 (s, 1H), 9.18 (s, 1H), 8.49 (s, 1H), 7.98 (s, 1H), 7.92 (d, J=8.6 Hz, 1H), 7.66 (dd, J=8.5, 1.6 Hz, 1H), 7.29 (d, J=8.2 Hz, 1H), 7.18 (dd, J=8.1, 2.3 Hz, 1H), 7.15 (d, J=2.2 Hz, 1H), 3.10 (q, J=7.3 Hz, 2H), 2.21 (s, 3H), 2.12-2.04 (m, 1H), 1.21 (t, J=7.3 Hz, 3H), 0.84 (m, 4H).
Reaction SMILES: [N:1]1([C:7]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:8]=2[C:9]([NH2:18])=[N:10][C:11]([NH2:17])=[N:12]3)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[F:19][C:20]([F:31])([F:30])[O:21][C:22]1[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=1[CH2:24]Br>>[F:19][C:20]([F:30])([F:31])[O:21][C:22]1[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=1[CH2:24][N:4]1[CH2:5][CH2:6][N:1]([C:7]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:8]=2[C:9]([NH2:18])=[N:10][C:11]([NH2:17])=[N:12]3)[CH2:2][CH2:3]1
Reactant: FC(F)(F)Oc1ccccc1CBr
Reactant: Nc1nc(N)c2c(N3CCNCC3)cccc2n1
Product: Nc1nc(N)c2c(N3CCN(Cc4ccccc4OC(F)(F)F)CC3)cccc2n1
Yield: 54 %

Procedure:
Title compound was prepared via Resin Method using 5-piperazin-1-yl-quinazoline-2,4-diamine (50 mg; 0.2 mmol) and 2-(trifluoromethoxy)benzyl bromide (94.4 mg; 0.37 mmol) to obtain 45.5 mg. (54% yield). 1H NMR (400 MHz, DMSO-d6) δ 12.4 (br s, 1H), 10.0 (br s, 1H), 8.94 (br s, 1H), 7.69 (m, 3H), 7.42 (m, 3H), 7.27 (d, J=7.6 Hz, 1H), 7.23 (d, J=8.4 Hz, 1H), 3.65 (s, 2H), 3.04 (d, J=10.4 Hz, 2H), 2.89 (m, 4H), 2.36 (t, J=11.2 Hz, 2H). ESIMS+419.5 m/z
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:18](=[O:23])[CH2:19][CH:20]([CH3:22])[CH3:21])[C:4]2[C:9]([C:10]=1[C:11]([O:13]C(C)(C)C)=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2.FC(F)(F)C(O)=O>ClCCl>[CH3:1][C:2]1[N:3]([C:18](=[O:23])[CH2:19][CH:20]([CH3:21])[CH3:22])[C:4]2[C:9]([C:10]=1[C:11]([OH:13])=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: Cc1c(C(=O)OC(C)(C)C)c2ccccc2n1C(=O)CC(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1c(C(=O)O)c2ccccc2n1C(=O)CC(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 18.2 %

Procedure:
To a solution of tert-butyl 2-methyl-1-(3-methylbutanoyl)-1H-indole-3-carboxylate (200 mg, 634.10 μmol) in dichloromethane (5 mL) was added trifluoroacetic acid (5 mL). The mixture was stirred at room temperature (25° C.) for 1 hour. The mixture was evaporated and partitioned between dichloromethane and water. The aqueous layer was washed with dichloromethane (10 mL×2), combined the organic layers, dried over sodium sulfate, then filtered and concentrated in vacuum afford the title compound (30 mg, yield: 89%).
Reaction SMILES: [C:1]([O:10][CH3:11])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].Br[CH2:13][C:14]1[N:19]=[C:18]([O:20][CH3:21])[CH:17]=[C:16]([O:22][CH3:23])[N:15]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:21][O:20][C:18]1[CH:17]=[C:16]([O:22][CH3:23])[N:15]=[C:14]([CH2:13][O:4][C:3]2[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=2[C:1]([O:10][CH3:11])=[O:9])[N:19]=1
Reactant: COC(=O)c1ccccc1O
Reactant: COc1cc(OC)nc(CBr)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccccc1OCc1nc(OC)cc(OC)n1
Temperature: 0 °C
Yield: 82.2 %

Procedure:
1.52 g of methyl salicylate, 2.33 g of 2-bromomethyl-4,6-dimethoxypyrimidine and 1.6 g of potassium carbonate were stirred in 20 ml of dimethylformamide at 60° C. for 2 hours. The reaction mixture was poured in ice water and extracted with ethyl acetate. The extract was dried over sodium sulfate and, after distilling off the solvent, purified using silica gel chromatography to obtain 2.5 g of methyl 2-(4,6-dimethoxy-2-pyrimidyl)methyloxybenzoate (yield 82%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([S:12](=[O:15])(=[O:14])[NH2:13])=[CH:8][C:4]=1[C:5]([OH:7])=O.C(N(CC)CC)C.CS(ON1C2C=CC=CC=2N=N1)(=O)=O.[CH2:37]([N:39]1[CH2:43][CH2:42][CH2:41][CH:40]1[CH2:44][NH2:45])[CH3:38]>O1CCCC1>[CH2:37]([N:39]1[CH2:43][CH2:42][CH2:41][CH:40]1[CH2:44][NH:45][C:5](=[O:7])[C:4]1[CH:8]=[C:9]([S:12](=[O:15])(=[O:14])[NH2:13])[CH:10]=[CH:11][C:3]=1[O:2][CH3:1])[CH3:38]
Reactant: CCN1CCCC1CN
Reactant: COc1ccc(S(N)(=O)=O)cc1C(=O)O
Agent: CS(=O)(=O)On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCN1CCCC1CNC(=O)c1cc(S(N)(=O)=O)ccc1OC
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 64.8 %

Procedure:
2-Methoxy-5-sulfamoylbenzoic acid (2.3 g) and triethylamine (1.4 ml) are dissolved in anhydrous tetrahydrofuran (20 ml), and therto is added 1-methanesulfonyloxy-1,2,3-benzotriazole (2.2 g). After stirring at room temperature for 20 minutes, to the mixture is added 1-ethyl-2-aminomethylpyrrolidine (1.3 g) to precipitate oily products with exotherm. The mixture is stirred for 1 hour and then the solvent is distilled off. The resulting oily residue is dissolved in 1 N hydrochloric acid and the solution is washed twice with ethyl acetate. The aqueous layer is distilled under a reduced pressure to remove the remaining ethyl acetate and made alkaline with aqueous ammonia. The resulting precipitates are separated by filtration, washed with diluted aqueous ammonia and dried to give 1-ethyl-2-(2-methoxy-5-sulfamoylbenzamidomethyl)pyrrolidine (2.2 g), melting point: 175°-177° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([B:9]([OH:11])[OH:10])[C:5]([F:8])=[N:6][CH:7]=1.[CH3:12][N:13]([CH2:18][C:19](O)=[O:20])[CH2:14][C:15](O)=[O:16].CS(C)=O>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([B:9]2[O:11][C:19](=[O:20])[CH2:18][N:13]([CH3:12])[CH2:14][C:15](=[O:16])[O:10]2)[C:5]([F:8])=[N:6][CH:7]=1
Reactant: CN(CC(=O)O)CC(=O)O
Reactant: OB(O)c1cc(Br)cnc1F
Solvent: Cc1ccccc1
Solvent: CS(C)=O
Product: CN1CC(=O)OB(c2cc(Br)cnc2F)OC(=O)C1
Yield: 82 %

Procedure:
5-Bromo-2-fluoropyridin-3-ylboronic acid (14.87 g, 67.7 mmol) (Frontier Scientific) and 2,2′-(methylazanediyl)diacetic acid (10.95 g, 74.4 mmol) (Aldrich) were dissolved in toluene (242 mL) and DMSO (97 mL) and the resulting mixture was heated at reflux under a Dean Stark trap for 2 h. After water (>2.5 mL) was collected in the trap, the reaction mixture was concentrated in vacuo to remove toluene, and water was slowly added to the resulting solution until the desired product precipitated as a white solid. This solid was collected by vacuum filteration, washed with water, and dried in a vacuum oven to give the title compound (82% yield) as a fluffy white solid. m/z (ESI, +ve ion) 330.8/332.9 (M+H)+.
Reaction SMILES: [CH:1](/[C@H:6]1[CH2:11][CH2:10][C@H:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18](=O)CC)=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)=[CH:2]\[CH2:3][CH2:4][CH3:5].C(C([C@H]1CC[C@H](C2C=CC(C#[N:38])=CC=2)CC1)CC)=C.[BH4-].[Na+].C(C1C=CC=CC=1)(=O)CC>CO>[CH:1](/[C@H:6]1[CH2:11][CH2:10][C@H:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]#[N:38])=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)=[CH:2]\[CH2:3][CH2:4][CH3:5]
Reactant: C=CC(CC)[C@H]1CC[C@H](c2ccc(C#N)cc2)CC1
Reactant: CCC/C=C/[C@H]1CC[C@H](c2ccc(C(=O)CC)cc2)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCC(=O)c1ccccc1
Solvent: CO
Product: CCC/C=C/[C@H]1CC[C@H](c2ccc(C#N)cc2)CC1

Procedure:
A solution of 7.1 mmol of ethylmagnesium bromide (prepared from 172 mg of magnesium and 530 μl of ethyl bromide) in 20 ml of absolute tetrahydrofuran was placed at -78° C. while gassing with argon in a sulphonation flask provided with a thermometer, dropping funnel and serum cap and treated in sequence with 3.6 ml of a 0.48M solution of dilithium tetrachlorocuprate in absolute tetrahydrofuran and with a solution of 500 mg of p-[trans-4-(3-acetoxy-trans-1-propenyl)cyclohexyl]benzonitrile in 10 ml of absolute tetrahydrofuran. After completion of the addition, the mixture was warmed to -15° C., stirred at this temperature for 1.5 hours, subsequently treated with 20 ml of saturated ammonium chloride solution and stirred at room temperature for a further 1 hour. The aqueous phase, which was now deep blue, was separated and extracted twice with 50 ml of diethyl ether each time. The organic phases were washed twice with 50 ml of water each time, dried over magnesium sulphate and concentrated. Low-pressure chromatography (0.5 bar) of the residue (0.4 g) on silica gel with ethyl acetate/petroleum ether (vol. 3:97) gave 375 mg of crude p-[trans-4-(trans-1-pentenyl)cyclohexyl]benzonitrile which, according to analysis by gas chromatography, was contaminated to 8.5% with p-[trans-4-(trans-1-pentenyl)cyclohexyl]propiophenone and to 4.0% with p-[trans-4-(1-vinylpropyl)cyclohexyl]benzonitrile. Treatment of this crude product with an excess of sodium borohydride in methanol at 0° C. (in order to reduce the propiophenone), working-up, low-pressure chromatography (0.5 bar) on silica gel with ethyl acetate/petroleum ether (vol. 1:9) and finally recrystallization from methanol at -78° C. gave p-[trans-4-(trans-1-pentenyl)cyclohexyl]benzonitrile in a purity of 98.6%; m.p. (C-N) 15.5° C., cl.p. (N-I) 57.0° C.
Reaction SMILES: [Cl:1]C1C=CC=C(O)C=1C=O.F[C:12]1[CH:23]=[CH:22][C:15]2[O:16][C:17]([C:19]([OH:21])=[O:20])=[CH:18][C:14]=2[CH:13]=1.ClC1C=CC2C=C(C(O)=O)OC=2C=1>>[Cl:1][C:12]1[CH:23]=[CH:22][C:15]2[O:16][C:17]([C:19]([OH:21])=[O:20])=[CH:18][C:14]=2[CH:13]=1
Reactant: O=Cc1c(O)cccc1Cl
Reactant: O=C(O)c1cc2cc(F)ccc2o1
Agent: O=C(O)c1cc2ccc(Cl)cc2o1
Product: O=C(O)c1cc2cc(Cl)ccc2o1

Procedure:
By the same procedure, 5-fluorosalicyaldehyde and 6-chlorosalicylaldehyde are converted, respectively, to 5-fluorobenzo[b]furan-2-carboxylic acid and 6-chlorobenzo[b]furan-2-carboxylic acid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[NH:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[N:8]=2)[CH2:3][CH2:2]1.[O:16]1[CH2:18][CH:17]1[CH2:19][N:20]1[C:28]2[CH2:27][CH2:26][N:25]([C:29](=[O:31])[CH3:30])[CH2:24][C:23]=2[C:22]([C:32]2[CH:37]=[CH:36][C:35]([C:38]([F:41])([F:40])[F:39])=[CH:34][CH:33]=2)=[N:21]1>CCO>[NH:11]1[C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[N:8]=[C:7]1[CH:4]1[CH2:3][CH2:2][N:1]([CH2:18][CH:17]([OH:16])[CH2:19][N:20]2[C:28]3[CH2:27][CH2:26][N:25]([C:29](=[O:31])[CH3:30])[CH2:24][C:23]=3[C:22]([C:32]3[CH:37]=[CH:36][C:35]([C:38]([F:41])([F:40])[F:39])=[CH:34][CH:33]=3)=[N:21]2)[CH2:6][CH2:5]1
Reactant: CC(=O)N1CCc2c(c(-c3ccc(C(F)(F)F)cc3)nn2CC2CO2)C1
Reactant: c1ccc2[nH]c(C3CCNCC3)nc2c1
Solvent: CCO
Product: CC(=O)N1CCc2c(c(-c3ccc(C(F)(F)F)cc3)nn2CC(O)CN2CCC(c3nc4ccccc4[nH]3)CC2)C1
Temperature: 60 °C
Yield: 36 %

Procedure:
A solution of 83 mg (0.41 mmol) of 2-piperidin-4-yl-1H-benzoimidazole was dissolved in 4 mL EtOH and treated with 100 mg (0.27 mmol) of 1-[1-oxiranylmethyl-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone. The solution was heated to 60° C. overnight. The solvent was then removed by rotary evaporation and the crude product was purified by column chromatography (silica, 0-10% MeOH/EtOAc) to afford 55 mg (36%) of a white solid. MS (electrospray): exact mass calculated for C30H33F3N6O2, 566.26. m/z found, 567.3 [M+H]+. 1H NMR (CDCl3, 400 MHz, a mixture of amide rotamers):10.66 (br s, 0.5H), 10.57 (br s, 0.5H), 7.73 (bd, J=8.41 Hz, 1H), 7.72-7.63 (m, 3H), 7.60 (bd, J=8.41 Hz, 1H), 7.39-7.32 (m, 1H), 7.23-7.13 (m, 2H), 7.02 (br s, 1), 4.86 and 4.75 (A and B of AB quartet, J=15.85 Hz, 1.25H), 4.64 (br s, 1H), 4.21-4.06 (m, 2H), 4.06-3.81 (m, 2H), 3.80-3.63 (m, 1H), 3.80-3.69 (m, 1H), 3.00-2.68 (m, 5H), 2.44-2.36 (m, 2H), 2.39-2.23 (m, 2H), 2.19 (s, 1.6H), 2.15 (s, 1.4H), 2.13-2.00 (m, 4H), 2.00-1.80 (m, 2H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[C:6](O)=[O:7])#[N:2].C1(C)C=CC=CC=1.S(Cl)([Cl:23])=O>CN(C)C=O>[C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[C:6]([Cl:23])=[O:7])#[N:2]
Reactant: COc1ccc(C(=O)O)cc1C#N
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)Cl)cc1C#N
Temperature: 60 °C
Reaction time: 16 h

Procedure:
To 3-cyano-4-methoxybenzoic acid (1.78 g), toluene (20 mL), N,N-dimethylformamide (3 droplets) and thionyl chloride (1.14 mL) were added, and then the mixture was stirred at 60° C. for 16 hours. The solvent was distilled off under reduced pressure and the obtained residue was azeotroped with toluene and used for the synthesis of (d).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]=[C:7]([CH2:10][O:11][C:12]3[CH:20]=[CH:19][CH:18]=[C:17]4[C:13]=3[CH:14]=[C:15]([C:21]([OH:23])=O)[NH:16]4)[C:6]=2[CH:24]=1.[NH2:25][CH:26]1[CH2:31][CH2:30][C:29]([CH2:33][CH2:34][N:35]2[CH2:40][CH2:39][C@H:38]([OH:41])[C@@H:37]([CH3:42])[CH2:36]2)([OH:32])[CH2:28][CH2:27]1>>[OH:32][C:29]1([CH2:33][CH2:34][N:35]2[CH2:40][CH2:39][C@H:38]([OH:41])[C@@H:37]([CH3:42])[CH2:36]2)[CH2:30][CH2:31][CH:26]([NH:25][C:21]([C:15]2[NH:16][C:17]3[C:13]([CH:14]=2)=[C:12]([O:11][CH2:10][C:7]2[C:6]4[CH:24]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=4[O:9][CH:8]=2)[CH:20]=[CH:19][CH:18]=3)=[O:23])[CH2:27][CH2:28]1
Reactant: O=C(O)c1cc2c(OCc3coc4ccc(Cl)cc34)cccc2[nH]1
Reactant: C[C@H]1CN(CCC2(O)CCC(N)CC2)CC[C@@H]1O
Product: C[C@H]1CN(CCC2(O)CCC(NC(=O)c3cc4c(OCc5coc6ccc(Cl)cc56)cccc4[nH]3)CC2)CC[C@@H]1O

Procedure:
This compound is synthesized analogously to example 1 from 4-(5-chloro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid (synthesis described in WO2005077932A2, cmpd 113) and amine 14.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([CH:18]=[C:19]([CH3:21])[CH:20]=1)[O:6][C:7]1[C:12]([CH:13]([CH3:15])[CH3:14])=[C:11]([Cl:16])[N:10]=[C:9]([Cl:17])[N:8]=1.[C:22]([O-:25])(=[O:24])[CH3:23].[Na+]>CN(C=O)C>[Cl:17][C:9]1[N:8]=[C:7]([O:6][C:5]2[CH:4]=[C:3]([CH:20]=[C:19]([CH3:21])[CH:18]=2)[CH2:2][O:25][C:22](=[O:24])[CH3:23])[C:12]([CH:13]([CH3:15])[CH3:14])=[C:11]([Cl:16])[N:10]=1
Reactant: CC(=O)[O-]
Reactant: Cc1cc(CBr)cc(Oc2nc(Cl)nc(Cl)c2C(C)C)c1
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)OCc1cc(C)cc(Oc2nc(Cl)nc(Cl)c2C(C)C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.4 %

Procedure:
To a stirred solution of (3) (14.4 g, 36.9 mmol) in anhydrous DMF (50 ml), was added sodium acetate (6.05 g, 73.8 mmol) and the mixture was stirred in an oil bath (90˜100° C.) for overnight. After cooling to room temperature, the mixture was partitioned between ether and water. The ether layer was taken, washed with water twice, dried with anhydrous magnesium sulfate, filtered, and evaporated in vacuo. The residue was purified by silica gel column chromatography (eluent, ether: hexanes (from 1:9 to 1:4)) to afford 10 g (73%) of a white solid. m.p. 76-77° C.; 1H NMR (200 MHz, CDCl3) δ 1.41 (6H, d, J=7.2 Hz), 2.12 (3H, s), 2.39 (3H, s), 3.58 (1H, m), 5.09 (2H, s), 6.88 (1H, s), 6.93 (1H, s), 7.08 (1H, s).
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5].Br[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH2:24][C:25]([O:27][CH3:28])=[O:26].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[C:4]([C:3]1[CH:12]=[C:13]([CH3:16])[CH:14]=[CH:15][C:2]=1[O:1][CH:24]([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:18]=1)[C:25]([O:27][CH3:28])=[O:26])(=[O:5])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: COC(=O)Cc1ccccc1Br
Reactant: Cc1ccc(O)c(C(=O)c2ccccc2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)C(Oc1ccc(C)cc1C(=O)c1ccccc1)c1ccccc1
Yield: 18.8 %

Procedure:
To a solution of 1.00 g (4.72 mmol) of 2-hydroxy-5-methylbenzophenone and 1.19 g (5.19 mmol) of methyl 2-bromophenylacetate in 10 mL of acetone was added 1.30 g (9.44 mmol) of K2CO3 and the mixture was stirred and refluxed for 14 hours. The mixture was cooled, filtered and evaporated in vacuo and the residue was purified on a silica gel flash chromatography column eluted with 5% ethyl acetate/hexane to afford 0.320 g (19%) of the title compound.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH2:6][CH:5]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[C:4]([C:19](O)=[O:20])=[C:3]1[CH3:22].[NH2:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][C:32]=1[F:33])[NH:29][N:28]=[CH:27]2>>[F:33][C:32]1[CH:31]=[C:30]2[C:26]([CH:27]=[N:28][NH:29]2)=[CH:25][C:24]=1[NH:23][C:19]([C:4]1[CH:5]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:16])([F:18])[F:17])=[CH:11][CH:10]=2)[CH2:6][C:7](=[O:8])[N:2]([CH3:1])[C:3]=1[CH3:22])=[O:20]
Reactant: Nc1cc2cn[nH]c2cc1F
Reactant: CC1=C(C(=O)O)C(c2ccc(C(F)(F)F)cc2)CC(=O)N1C
Product: CC1=C(C(=O)Nc2cc3cn[nH]c3cc2F)C(c2ccc(C(F)(F)F)cc2)CC(=O)N1C

Procedure:
The title compound was prepared from the product of Example 41, Step 2 and 5-amino-6-fluoroindazole using the method described in Example 56, Step 3. MS (ES+) m/e 447 [M+H]+
Reaction SMILES: C[Si](C)(C)[NH:3][C:4]1[C:5](=[CH:10][CH:11]=[CH:12][C:13]=1[CH3:14])[C:6]([O:8][CH3:9])=[O:7].CC#N.Cl[S:21]([C:24]1[N:34]=[C:27]2[N:28]=[C:29]([CH3:33])[CH:30]=[C:31]([CH3:32])[N:26]2[N:25]=1)(=[O:23])=[O:22]>N1C=CC=CC=1>[CH3:9][O:8][C:6]([C:5]1[CH:10]=[CH:11][CH:12]=[C:13]([CH3:14])[C:4]=1[NH:3][S:21]([C:24]1[N:34]=[C:27]2[N:28]=[C:29]([CH3:33])[CH:30]=[C:31]([CH3:32])[N:26]2[N:25]=1)(=[O:22])=[O:23])=[O:7]
Reactant: Cc1cc(C)n2nc(S(=O)(=O)Cl)nc2n1
Reactant: COC(=O)c1cccc(C)c1N[Si](C)(C)C
Solvent: c1ccncc1
Solvent: CC#N
Product: COC(=O)c1cccc(C)c1NS(=O)(=O)c1nc2nc(C)cc(C)n2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92 %

Procedure:
A solution consisting of 145.9 mg (0.615 mmole) of methyl N-trimethylsilyl-3-methylanthranilate, 1 ml of CH3CN, and 80.4 mg (0.326 mmole) of 2-chlorosulfonyl-5,7-dimethyl-1,2,4-triazolo[1,5-a]pyrimidine was stirred at room temperature and the reaction monitored by reverse phase HPLC. The reaction was about 30 percent complete after 4 hours. Pyridine, 29.1 μl (0.360 mmole), was added and the solution stirred for 10 min and again analyzed. Complete reaction had occurred. The solution was allowed to stand overnight. The CH3CN was removed under a nitrogen atmosphere and the residue treated with 2 ml of 1.0N HCl and 2 ml of CH2Cl2. The CH2Cl2 phase was transferred to a column containing 50 g of silica gel and chromatographed to obtain 112.5 mg of N-(2-methoxycarbonyl-6-methylphenyl)-5,7-dimethyl-1,2,4-triazolo[1,5-a]pyrimidine-2-sulfonamide (0.300 mmole, 92.0 percent yield) as a white crystalline solid, m.p. 181°-182° C. The solid was dissolved in CHCl3 and the solvent again removed in vacuo affording the product as a light yellow powder, m.p. 192°-194° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[N:7][C:8]([N:11]2[CH2:30][CH2:29][C:14]3[NH:15][C:16]4[CH:17]=[CH:18][C:19]([C:22]5[S:23][C:24]([CH:27]=O)=[CH:25][CH:26]=5)=[CH:20][C:21]=4[C:13]=3[CH2:12]2)=[N:9][CH:10]=1)=[O:4].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[CH3:45][N:46]1[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]1>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[N:7][C:8]([N:11]2[CH2:30][CH2:29][C:14]3[NH:15][C:16]4[CH:17]=[CH:18][C:19]([C:22]5[S:23][C:24]([CH2:27][N:49]6[CH2:50][CH2:51][N:46]([CH3:45])[CH2:47][CH2:48]6)=[CH:25][CH:26]=5)=[CH:20][C:21]=4[C:13]=3[CH2:12]2)=[N:9][CH:10]=1)=[O:4]
Reactant: CN1CCNCC1
Reactant: COC(=O)c1cnc(N2CCc3[nH]c4ccc(-c5ccc(C=O)s5)cc4c3C2)nc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)c1cnc(N2CCc3[nH]c4ccc(-c5ccc(CN6CCN(C)CC6)s5)cc4c3C2)nc1
Reaction time: 0.17 h
Yield: 75.8 %

Procedure:
To a 0° C. solution of methyl-2-{8-[5-(formyl)-thien-2-yl]-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indol-2-yl}pyrimidine-5-carboxylate (0.09 g, 0.21 mmol) in DCM (50 mL) was added Na(OAc)3BH (0.114 g, 0.53 mmol) and stirred for 10 min. To the reaction mixture was added N-methylpiperazine (0.107 g, 1.07 mmol) under nitrogen atmosphere and the reaction mixture was continued stirring at room temperature for 4 hr. The progress of the reaction was monitored by TLC and upon completion of the reaction the mixture was partitioned between DCM (100 mL) and water (15 mL) and the organic layer was separated, washed with water (2×10 mL), dried over sodium sulphate filtered and the solvent was removed under reduced pressure to give crude residue, which was purified by column chromatography using silica gel to provide methyl-2-{8-[5-((4-methylpiperazin-1-yl)methyl)-thien-2-yl]-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indol-2-yl}pyrimidine-5-carboxylate (0.08 g).
Reaction SMILES: [Li]CCCC.Br[C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][N:8]=1.[N+:14]([C:17]1[C:18]([CH:27]=[O:28])=[CH:19][CH:20]=[C:21]2[C:26]=1[N:25]=[CH:24][CH:23]=[CH:22]2)([O-:16])=[O:15].[NH4+].[Cl-]>C1(C)C=CC=CC=1.C1COCC1>[F:13][C:10]1[CH:11]=[CH:12][C:7]([CH:27]([C:18]2[C:17]([N+:14]([O-:16])=[O:15])=[C:26]3[C:21]([CH:22]=[CH:23][CH:24]=[N:25]3)=[CH:20][CH:19]=2)[OH:28])=[N:8][CH:9]=1
Reactant: O=Cc1ccc2cccnc2c1[N+](=O)[O-]
Reactant: Fc1ccc(Br)nc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: O=[N+]([O-])c1c(C(O)c2ccc(F)cn2)ccc2cccnc12
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 46.8 %

Procedure:
n-BuLi (1.6M in hexane; 5.5 ml, 8.9 mmol) was added to anhydrous toluene (35 ml) at −78° C. under an N2 atmosphere followed by dropwise addition of a solution 2-bromo-5-fluoropyridine (1.56 g, 8.9 mmol) in anhydrous toluene (10 ml). The mixture was stirred at −78° C. for 45 min. The mixture was added to a solution of 8-nitroquinoline-7-carbaldehyde (Intermediate 204) (1 g, 5.0 mmol) in THF (50 ml) at −78° C. over 10 min. The mixture was stirred at −78° C. for a further 1 h. NH4Cl solution (10 ml) was added at −78° C. and the mixture was warmed to room temperature. The solvent was removed in vacuo. The residue was dissolved in DCM (50 ml) and the organic phase was washed with sat. NaHCO3 solution, dried (Na2SO4) and concentrated in vacuo. The crude residue was purified by column chromatography DCM/MeOH (99:1) as the eluent to give the title compound (700 mg, 46%).
Reaction SMILES: [CH:1]1([NH2:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=1>CN(C)C=O.O>[N+:21]([C:18]1[CH:19]=[CH:20][C:15]([CH2:14][N:6]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=2)[CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)=[CH:16][CH:17]=1)([O-:23])=[O:22]
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: NC1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(CN(Cc2ccc([N+](=O)[O-])cc2)C2CCCC2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 103.9 %

Procedure:
To a solution of cyclopentylamine (0.148 mL, 1.5 mmol) in N,N-dimethylformamide (2 mL) was added potassium carbonate (622 mg, 4.50 mmol) followed by 1-(bromomethyl)-4-nitrobenzene (648 mg, 3.00 mmol). The resulting mixture was stirred at rt for 16 hours, more 1-(bromomethyl)-4-nitrobenzene was added (324 mg, 1.5 mmol), and stirring was continued for an additional 2 hours. The mixture was diluted with water, extracted with CH2Cl2, and the organic layer was dried (Na2SO4), filtered and concentrated. The crude product was purified by precipitation from methanol to afford the title compound (554 mg, quant.). MS (ESI) m/z 356.0 (M+H)+.