Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([N:8]2[CH2:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[CH2:11][C:10]3[CH:19]=[CH:20][CH:21]=[CH:22][C:9]2=3)=[O:7])=[CH:4][CH:3]=1.[Cl:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[S:32](Cl)(=[O:34])=[O:33].C(N(CC)CC)C>C(Cl)Cl>[Cl:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[S:32]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([N:8]2[CH2:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[CH2:11][C:10]3[CH:19]=[CH:20][CH:21]=[CH:22][C:9]2=3)=[O:7])=[CH:23][CH:24]=1)(=[O:34])=[O:33]
Reactant: O=S(=O)(Cl)c1ccccc1Cl
Reactant: Nc1ccc(C(=O)N2Cc3ccccc3Cc3ccccc32)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(c1ccc(NS(=O)(=O)c2ccccc2Cl)cc1)N1Cc2ccccc2Cc2ccccc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 128.6 %

Procedure:
A mixture of 0.13 g of 5-(4-aminobenzoyl)-6,11-dihydro-5H-dibenz[b,e]azepine, 0.21 g of 2-chlorobenzenesulfonyl chloride, 0.12 g of triethylamine and 5 mg of N,N-dimethylaminopyridine in 2 ml of methylene chloride is stirred at room temperature for 18 hours. The mixture is partitioned between 1N NaOH and ethyl acetate. The organic layer is washed with 50% NH4Cl and brine, dried over Na2SO4 and evaporated to give 0.26 g of the desired product as a yellow solid. MS(CI):663(M+H; C35).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C@@H:10]1[CH2:12][C@H:11]1[CH2:13][NH2:14].CCN(CC)CC.[C:22](Cl)(=[O:26])[CH:23]([CH3:25])[CH3:24]>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C@@H:10]1[CH2:12][C@H:11]1[CH2:13][NH:14][C:22](=[O:26])[CH:23]([CH3:25])[CH3:24]
Reactant: CC(C)C(=O)Cl
Reactant: COc1ccc(F)c([C@@H]2C[C@H]2CN)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(F)c([C@@H]2C[C@H]2CNC(=O)C(C)C)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 46.2 %

Procedure:
To a magnetically stirred solution of (trans)-2-(2-fluoro-5-methoxyphenyl)cyclopropanemethanamine (600 mg, 3.1 mmol), Et3N (909 mg, 9.0 mmol), in dry dichloromethane (15 mL) at 0° C. was added isobutyryl chloride (352 mg, 3.3 mmol) dropwise. The resulting suspension was then allowed to warm to room temperature and stirred for 18 h. The solvents were removed and the residue was taken into EtOAc (100 mL) and washed sequentially with H2O, 5% citric acid, 5% K2CO3, brine, and dried over K2CO3. Concentration by rotary evaporation yielded a crude oil which was then purified by Kugelrohr distillation. Recrystallization of the resultant solid from Et2O/hexane (1:1) gave 380 mg (47% yield) of the title compound: mp 93°-94° C.; 1H NMR (300 MHz, CDCl3) δ0.82-0.88 (m, 1H), 0.97-1.03 (m, 1H), 1.13 (d, J=8.1 Hz, 6H), 1.14-1.24 (m, 1H), 1.85-1.91 (m, 1H), 2.25-2.30 (m, 1H), 2.93-3.02 (m, 1H), 3.52 (dt, I=7.8, 13.8 Hz, 1H), 3.72 (s, 3H), 5.74 (br s, 1H), 6.41-6.44 (m, 1H), 6.59-6.64 (m, 1H), 6.91 (t, J=6.5 Hz, 1H); IR (NaCl Film) 3298, 2962, 1642, 1546, 1502, 1428 cm-1 ; MS (isobutane--DCI) m/e 253; Analysis calc'd for C15H20NO2F: C, 67.90; H, 7.60; N, 5.28; found: C, 68.18; H, 7.77; N, 5.24.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[F:18])[NH:6][C:5]2=O.S(Cl)([Cl:22])=O.CN(C)C=O>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[F:18])[N:6]=[C:5]2[Cl:22]
Reactant: O=c1[nH]c(-c2ccccc2F)nc2ccc(Br)cc12
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: Fc1ccccc1-c1nc(Cl)c2cc(Br)ccc2n1
Temperature: 0 °C
Yield: 90 %

Procedure:
6-Bromo-2-(2-fluoro-phenyl)-3H-quinazolin-4-one from Step C (1.5 g, 4.6 mmol) was suspended in chloroform in a 50 ml round bottomed flask equipped with magnetic stirrer. The flask was cooled to 0° C. and to it was added thionyl chloride (1.6 ml) drop wise followed by N,N-dimethyl formamide (0.01 ml) and the mixture heated to 80° C. for 4 hrs. The solvent was removed by evaporation in a rotary evaporator to leave a title compound as a solid (1.43 g, 90%). MS (ES) 338 (M+H)+
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[CH:13]=[C:14]([S:19]([NH2:22])(=[O:21])=[O:20])[CH:15]=[CH:16][C:17]=1[Cl:18])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:23]([O:30][C:31](=[O:49])[C:32]1[C:33](=[CH:44][C:45]([Cl:48])=[CH:46][CH:47]=1)[NH:34][C:35](OC1C=CC=CC=1)=[O:36])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH2:23]([O:30][C:31](=[O:49])[C:32]1[CH:47]=[CH:46][C:45]([Cl:48])=[CH:44][C:33]=1[NH:34][C:35]([NH:22][S:19]([C:14]1[CH:15]=[CH:16][C:17]([Cl:18])=[C:12]([NH:11][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:10])[CH:13]=1)(=[O:21])=[O:20])=[O:36])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: NS(=O)(=O)c1ccc(Cl)c(NC(=O)OCc2ccccc2)c1
Reactant: O=C(Nc1cc(Cl)ccc1C(=O)OCc1ccccc1)Oc1ccccc1
Product: O=C(Nc1cc(Cl)ccc1C(=O)OCc1ccccc1)NS(=O)(=O)c1ccc(Cl)c(NC(=O)OCc2ccccc2)c1
Yield: 77.7 %

Procedure:
From 1.0 g (2.93 mmol) of 3-benzyloxycarbonylamino-4-chlorobenzenesulfonamide and 1.18 g (2.93 mmol) of 4-chloro-2-N-phenoxycarbonylanthranilic acid benzylester in a similar manner to Preparation Example 1, 1.43 g (yield 78%) of 2-{[(3-benzyloxycarbonylamino-4-chlorobenzenesulfonylamino)carbonyl]amino}-4-chlorobenzoic acid benzylester (property: colorless amorphous, PMR (δppm, DMSO-d6): 5.19 (2H, s), 5.36 (2H, s), 7.21 (1H, dd), 7.34-7.48 (10H, m), 7.72-7.76 (2H, m), 7.97 (1H, d), 8.25 (1H, d), 8.30 (1H, d), 9.53 (1H, s), 10.30 (1H, s)) was obtained.
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH:19]([F:21])[F:20])[CH:13]=2)(=[O:11])=[O:10])=[CH:6][C:5](B2OC(C)(C)C(C)(C)O2)=[CH:4][N:3]=1.[NH2:31][C:32]1[S:33][C:34]2[CH:40]=[C:39](Br)[CH:38]=[CH:37][C:35]=2[N:36]=1.C(=O)([O-])[O-].[Na+].[Na+].O1CCOCC1>O.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>[NH2:31][C:32]1[S:33][C:34]2[CH:40]=[C:39]([C:5]3[CH:6]=[C:7]([NH:8][S:9]([C:12]4[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH:19]([F:20])[F:21])[CH:13]=4)(=[O:10])=[O:11])[C:2]([Cl:1])=[N:3][CH:4]=3)[CH:38]=[CH:37][C:35]=2[N:36]=1
Reactant: Nc1nc2ccc(Br)cc2s1
Reactant: CC1(C)OB(c2cnc(Cl)c(NS(=O)(=O)c3cccc(OC(F)F)c3)c2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: Nc1nc2ccc(-c3cnc(Cl)c(NS(=O)(=O)c4cccc(OC(F)F)c4)c3)cc2s1
Temperature: 100 °C
Reaction time: 5 h
Yield: 46.7 %

Procedure:
To a 50 mL round-bottomed flask was added N-(2-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)-3-(difluoromethoxy)benzenesulfonamide (98 mg, 213 μmol), 2-amino-6-bromobenzothiazole (49 mg, 213 μmol), tetrakis(triphenylphosphine)palladium (25 mg, 21 μmol), sodium carbonate (213 μl, 425 μmol), dioxane (3 mL). The reaction mixture was stirred at 100° C. for 5 h. The mixture was cooled down to room temperature. The reaction mixture was diluted with water (2 mL) and extracted with EtOAc (3×20 mL). The organic extract was washed with saturated NaCl (10 mL), dried over Na2SO4, filtered and concentrated in vacuo and the residue was purified by silica gel chromatography, eluting with 80% EtOAc/hexanes to give N-(5-(2-aminobenzo[d]thiazol-6-yl)-2-chloropyridin-3-yl)-3-(difluoromethoxy)benzenesulfonamide (48 mg, 47% yield) as a white solid. MS (ESI pos. ion) m/z calc'd for C19H13ClF2N4O3S2: 482.0. found 483.0.1H NMR (300 MHz, MeOH) δ ppm 6.88 (t, J=73.08 Hz, 1H) 7.38-7.71 (m, 5H) 7.91 (d, J=1.17 Hz, 1H) 8.17 (d, J=2.19 Hz, 1H) 8.46 (d, J=2.34 Hz, 1H)
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Cl)=[CH:4][CH:3]=1.[NH:10]1[CH2:20][CH2:19][CH2:18][CH:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:11]1>CC#N>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][N:10]2[CH2:20][CH2:19][CH2:18][CH:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:11]2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)C1CCCNC1
Reactant: ClCc1ccc(Cl)cc1
Solvent: CC#N
Product: CCOC(=O)C1CCCN(Cc2ccc(Cl)cc2)C1
Temperature: 70 °C
Reaction time: 1.5 h
Yield: 98.1 %

Procedure:
4-chlorobenzyl chloride (6.42 g, 39.9 mmol) and 1Pr2NEt (7.74 g, 40.0 mmol) were added to a solution of ethyl nipecotate (6.29 g, 40.0 mmol) in CH3CN (15 mL). The reaction mixture was stirred at 70° C. for 1.5 h. The solvent was removed under reduced pressure. Saturated aqueous NaHCO3 (50 mL) was added to the residue and the mixture was extracted with EtOAc (100 mL). The organic phase was washed with saturated aqueous NaHCO3 and brine, and dried over Na2SO4. The solvent was removed under reduced pressure to afford ethyl 1-(4-chlorobenzyl)nipecotate as a red yellow oil (11.025 g, 97.8%) used without further purification. The purity was determined by RPLC/MS (97%); ESI/MS m/e 382.2 (M++H, C15H21ClNO2).
Reaction SMILES: [CH3:1][CH:2]([CH2:7][CH2:8][CH3:9])[CH:3]([OH:6])[C:4]#[CH:5].N1C=CN=C1.[Si:15](Cl)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16].[NH4+].[Cl-]>CN(C=O)C.CCOC(C)=O>[C:18]([Si:15]([CH3:17])([CH3:16])[O:6][CH:3]([CH:2]([CH3:1])[CH2:7][CH2:8][CH3:9])[C:4]#[CH:5])([CH3:21])([CH3:20])[CH3:19]
Reactant: C#CC(O)C(C)CCC
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: [Cl-]
Agent: [NH4+]
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C#CC(O[Si](C)(C)C(C)(C)C)C(C)CCC
Temperature: 25 °C
Reaction time: 18 h
Yield: 96.7 %

Procedure:
To a solution of 4-methyl-hept-1-yn-3-ol (2.53 g, 0.02 mol) in dry DMF (25 mL) were added imidazole (1.63 g, 0.024 mol) and tert-butyldimethylsilyl chloride (3.62 g, 0.024 mol). The resulting solution was stirred at RT for 18 h and then treated with saturated NH4Cl (15 mL) and EtOAc (120 mL). The organic layer was washed with saturated NH4Cl (20 mL), water (4×20 mL), brine (2×20 mL), dried over sodium sulfate, and concentrated in vacuo to afford a crude product (4.65 g, 97%), as a yellow oil, which was used in the next step without further purification. Rf 0.9 (EtOAc/hexanes 1/9); 1H NMR (CDCl3) δ 0.08 (s, 3H), 0.12 (s, 3H), 0.96-0.85 (m, 15H), 1.57-1.10 (m, 4H), 1.69-1.61 (m, 1H), 2.33 (t, J=2.20 Hz, 1H), 4.22-4.18 (m, 1H).
Reaction SMILES: Cl.CO.[CH3:4][O:5][C:6](=[O:22])[C:7]([N+:19]([O-])=O)=[CH:8][C:9]1[C:17]2[C:12](=[CH:13][C:14]([Cl:18])=[CH:15][CH:16]=2)[NH:11][CH:10]=1>CCOCC>[ClH:18].[CH3:4][O:5][C:6](=[O:22])[C:7]([NH2:19])=[CH:8][C:9]1[C:17]2[C:12](=[CH:13][C:14]([Cl:18])=[CH:15][CH:16]=2)[NH:11][CH:10]=1
Reactant: COC(=O)C(=Cc1c[nH]c2cc(Cl)ccc12)[N+](=O)[O-]
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: COC(=O)C(N)=Cc1c[nH]c2cc(Cl)ccc12
Reaction time: 1.5 h
Yield: 180.1 %

Procedure:
A 3-l. three-necked flask, equipped with a thermometer and a mechanical stirrer was charged with 316 g (1.4 moles) of stannous chloride dihydrate and a solution of 111 g (3 moles) of dry hydrogen chloride gas in 1 l. of methyl alcohol. The colorless solution was stirred and cooled to -30° in a dry ice-acetone bath. 112.3 g (0.40 moles) of alphanitro-6-chloro-3-indoleacrylic acid methylester was added in 4 equal portions over 1 hour, maintaining the temperature between -25 and -20°. After the addition was complete, the temperature was allowed to rise to -10° and stirring at this temperature was continued for 90 minutes. Then 500 ml. of ether was added to the yellow suspension, followed by addition of 500 ml of 12N hydrochloric acid (concentrated), the temperature was kept below 5°. The mixture was then filtered through a Buchner funnel. The filter cake was washed with 1000 ml of methyl alcohol-9N aqueous hydrochloric acid 1:1, precooled to -20°, and 400 ml of ether. The tan product was dried at 40°/0.1 mmHg for 8 hours and then at 20°/0.1 mmHg to constant weight to yield 103.4 g (90%) of crude product, m.p. 191° (dec.).
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[CH2:9][C@H:8]([NH:10][C:11]([C:13]2[CH:22]=[CH:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]=2[OH:23])=[O:12])[CH2:7][N:6]1[CH2:24][CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1)=O.[NH:31]1[CH2:35][CH2:34][CH2:33][CH2:32]1>>[CH:25]1([CH2:24][N:6]2[C@H:5]([C:3]([N:31]3[CH2:35][CH2:34][CH2:33][CH2:32]3)=[O:2])[CH2:9][C@H:8]([NH:10][C:11]([C:13]3[CH:22]=[CH:21][C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[C:14]=3[OH:23])=[O:12])[CH2:7]2)[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]1
Reactant: C1CCNC1
Reactant: COC(=O)[C@@H]1C[C@H](NC(=O)c2ccc3ccccc3c2O)CN1CC1CCCCC1
Product: O=C(N[C@H]1C[C@@H](C(=O)N2CCCC2)N(CC2CCCCC2)C1)c1ccc2ccccc2c1O

Procedure:
Hydroxy-naphthalene-2-carboxylic acid [(3S,5S)-1-cyclohexylmethyl-5-(pyrrolidine-1-carbonyl)-pyrrolidin-3-yl]-amide was prepared from (2S,4S)-1-cyclohexylmethyl-4-[(1-hydroxy-naphthalene-2-carbonyl)-amino]-pyrrolidine-2-carboxylic acid methyl ester and pyrrolidine in an analogous manner to example 12. MS calcd. for C27H36N3O3 [(M+H)+] 450.0, obsd. 450.2.
Reaction SMILES: C1(C)C=CC=CC=1.C([Al](CC(C)C)CC(C)C)C(C)C.[CH3:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([NH2:29])=[CH:25][CH:24]=1.[OH:30][C:31]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[N:34]=[CH:33][C:32]=1[C:41](OCC)=[O:42]>C(Cl)Cl>[OH:30][C:31]1[C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[N:34]=[CH:33][C:32]=1[C:41]([NH:29][C:26]1[CH:27]=[CH:28][C:23]([O:22][CH3:21])=[CH:24][CH:25]=1)=[O:42]
Reactant: COc1ccc(N)cc1
Reactant: CCOC(=O)c1cnc2ccccc2c1O
Agent: CC(C)C[Al](CC(C)C)CC(C)C
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COc1ccc(NC(=O)c2cnc3ccccc3c2O)cc1
Reaction time: 6 h

Procedure:
230 ml of a toluene solution of triisobutyl aluminum were added with stirring at 8°-10° C. over 30 minutes to a mixture of 61.5 gof p-anisidine in one liter of anhydrous methylene chloride and then 21.7 gof ethyl 4-hydroxy-3-quinoline-carboxylate [described in J.A.C.S., Vol. 68 (1946), p. 1264] were added to the mixture in small portions. The mixture was refluxed for 20 hours and was evaporated to dryness. The residue was taken up in a mixture of 500 g of ice and 500 ml of aqueous 6 N hydrochloric acid and the mixture was stirred for 6 hours and vacuum filtered. The recovered product was washed with water until there were no chloride ions in the wash water, dried at 100° C. and was crystallized from acetic acid to obtain 23.54 g of 4-hydroxy-N-(4-methoxyphenyl)-3-quinoline-carboxamide melting at >260° C.
Reaction SMILES: C(N(CC)CC)C.[F:8][C:9]1[CH:10]=[C:11]([S:16][C:17]2[CH:18]=[C:19]3[C:25]([NH:26][C:27](=[O:54])[C:28]4[CH:33]=[CH:32][C:31]([N:34]5[CH2:39][CH2:38][N:37]([CH3:40])[CH2:36][CH2:35]5)=[CH:30][C:29]=4[N:41]([CH:48]4[CH2:53][CH2:52][O:51][CH2:50][CH2:49]4)C(=O)C(F)(F)F)=[N:24][NH:23][C:20]3=[N:21][CH:22]=2)[CH:12]=[C:13]([F:15])[CH:14]=1>CO>[F:8][C:9]1[CH:10]=[C:11]([S:16][C:17]2[CH:18]=[C:19]3[C:25]([NH:26][C:27](=[O:54])[C:28]4[CH:33]=[CH:32][C:31]([N:34]5[CH2:39][CH2:38][N:37]([CH3:40])[CH2:36][CH2:35]5)=[CH:30][C:29]=4[NH:41][CH:48]4[CH2:49][CH2:50][O:51][CH2:52][CH2:53]4)=[N:24][NH:23][C:20]3=[N:21][CH:22]=2)[CH:12]=[C:13]([F:15])[CH:14]=1
Reactant: CN1CCN(c2ccc(C(=O)Nc3n[nH]c4ncc(Sc5cc(F)cc(F)c5)cc34)c(N(C(=O)C(F)(F)F)C3CCOCC3)c2)CC1
Solvent: CCN(CC)CC
Solvent: CO
Product: CN1CCN(c2ccc(C(=O)Nc3n[nH]c4ncc(Sc5cc(F)cc(F)c5)cc34)c(NC3CCOCC3)c2)CC1
Temperature: 65 °C

Procedure:
9.08 ml (65.1 mmol) of triethylamine is added to 2 g (2.96 mmol) of a solution of N-(5-(3,5-difluorophenylthio)-1H-pyrazolo[3,4-b]pyridin-3-yl)-4-(4-methylpiperazin-1-yl)-2-(2,2,2-trifluoro-N-(tetrahydro-2H-pyran-4-yl)acetamido)benzamide in 65 ml of methanol. The reaction medium is heated at 65° C. for 2 hours, and then overnight at room temperature. The precipitate formed is filtered, rinsed with pentane, with water and then with diethyl ether, and then is dried under vacuum to yield 0.73 g (43%) of (N-(5-(3,5-difluorophenylthio)-1-H-pyrazolo[3,4-b]pyridine-3-yl)-4-(4-methylpiperazine-1-yl)-2-(tetrahydro-2H-pyran-4-ylamino)benzamide in the form of a white solid.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]=[C:10]([C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[NH:16][CH:15]=2)[CH2:9]1)C1C=CC=CC=1>[Pd].C(O)=O.CO>[NH:8]1[CH2:13][CH2:12][CH2:11][CH:10]([C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[NH:16][CH:15]=2)[CH2:9]1
Reactant: C1=C(c2c[nH]c3ccccc23)CN(Cc2ccccc2)CC1
Agent: [Pd]
Solvent: O=CO
Solvent: CO
Product: c1ccc2c(C3CCCNC3)c[nH]c2c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of the 3-(1-benzyl-1,2,5,6-tetrahydropyridin-3-yl)-1H-indole obtained in Example 28 and 10% palladium on carbon in a mixture of formic acid and methanol is stirred at room temperature for 3 days and filtered through celite. The celite is washed with methanol. The filtrates are combined and concentrated in vacuo to afford the title product, identified by HPLC and mass spectral analyses.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH3:13])[C:11]([C:14]#[N:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH3:16][S:17](Cl)(=[O:19])=[O:18]>>[C:14]([C:11]1[N:12]([CH3:13])[C:8]([C:5]2[CH:6]=[CH:7][C:2]([N:1]([S:17]([CH3:16])(=[O:19])=[O:18])[S:17]([CH3:16])(=[O:19])=[O:18])=[CH:3][CH:4]=2)=[CH:9][CH:10]=1)#[N:15]
Reactant: Cn1c(C#N)ccc1-c1ccc(N)cc1
Reactant: CS(=O)(=O)Cl
Product: Cn1c(C#N)ccc1-c1ccc(N(S(C)(=O)=O)S(C)(=O)=O)cc1

Procedure:
The title compound was prepared according to general procedure for sulfonylation of 5-(4-aminophenyl)-1-methyl-1H-pyrrole-2-carbonitrile using methane sulfonyl chloride (43 μL, 0.55 mmol) to provide N-[4-(5-cyano-1-methyl-1H-pyrrol-2-yl)phenyl]-N-(methylsulfonyl)methanesulfonamide (0.021 g).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[N:11]3[CH:18]=2)=[C:4]([F:19])[CH:3]=1.[C:20]([NH:24][S:25]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1B(O)O)(=[O:27])=[O:26])([CH3:23])([CH3:22])[CH3:21]>>[C:20]([NH:24][S:25]([C:28]1[C:29]([C:2]2[CH:7]=[CH:6][C:5]([C:8]3[N:9]=[C:10]4[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[N:11]4[CH:18]=3)=[C:4]([F:19])[CH:3]=2)=[CH:30][CH:31]=[CH:32][CH:33]=1)(=[O:27])=[O:26])([CH3:23])([CH3:21])[CH3:22]
Reactant: COc1cccc2nc(-c3ccc(Br)cc3F)cn12
Reactant: CC(C)(C)NS(=O)(=O)c1ccccc1B(O)O
Product: COc1cccc2nc(-c3ccc(-c4ccccc4S(=O)(=O)NC(C)(C)C)cc3F)cn12

Procedure:
The title compound was prepared using methods analogous to those described in Example 88 using 2-(4-bromo-2-fluorophenyl)-5-methoxyimidazo[1,2-a]pyridine and 2-(tert-butylamino)sulfonylphenylboronic acid. MS (ESI): mass calcd. for C24H24FN3O3S, 453.15; m/z found, 454.4 [M+H]+. 1H NMR (500 MHz, CDCl3) δ 8.58 (m, 1H), 8.19 (dd, J=8.0, 1.4, 1H), 8.10 (d, J=3.9, 1H), 7.81 (dd, J=6.7, 0.9, 1H), 7.60-7.55 (m, 1H), 7.54-7.48 (m, 1H), 7.43 (dd, J=12.1, 1.7, 1H), 7.38-7.32 (m, 2H), 6.73 (dd, J=7.6, 6.7, 1H), 6.50 (d, J=7.6, 1H), 4.07 (s, 3H), 3.68 (s, 1H), 1.02 (s, 9H).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([N:7]2[CH2:11][CH2:10][N:9]([CH2:12][C:13](=[O:20])[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:8]2=[O:21])[S:4][C:3]=1[C:22]([NH:24][CH2:25][C:26]1[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=1)=[O:23].[BH4-].[Na+]>CO.C(Cl)(Cl)Cl>[OH:20][CH:13]([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[CH2:12][N:9]1[CH2:10][CH2:11][N:7]([C:5]2[S:4][C:3]([C:22]([NH:24][CH2:25][C:26]3[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=3)=[O:23])=[C:2]([CH3:1])[CH:6]=2)[C:8]1=[O:21]
Reactant: Cc1cc(N2CCN(CC(=O)c3ccccc3)C2=O)sc1C(=O)NCc1cccnc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: Cc1cc(N2CCN(CC(O)c3ccccc3)C2=O)sc1C(=O)NCc1cccnc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 92 %

Procedure:
To a stirred solution of 3-methyl-5-(2-oxo-3-(2-oxo-2-phenylethyl)imidazolidin-1-yl)-N-(pyridin-3-ylmethyl)thiophene-2-carboxamide (0.09 g, 0.20 mmol) in methanol (3 mL) and chloroform (1.5 mL) at 0° C. was added sodium borohydride (0.01 g, 0.29 mmol) under nitrogen atmosphere. The resulting mixture was stirred at 0° C. for 1 h, and then quenched with water (25 mL). The aqueous layer was extracted with dichloromethane (2×50 mL), and the combined organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The residue was triturated with dichloromethane in hexanes to afford the title compound as a brownish solid in 92% yield (0.08 g): mp 75° C. (dec.); 1H NMR (300 MHz, CDCl3) δ 8.52 (s, 1H), 8.43 (s, 1H), 7.65 (d, J=7.8 Hz, 1H), 7.39-7.17 (m, 6H), 6.37 (t, J=5.5 Hz, 1H), 5.98 (s, 1H), 4.94 (dd, J=7.7, 3.3 Hz, 1H), 4.52 (d, J=5.5 Hz, 2H), 3.87 (br s, 1H), 3.75-3.35 (m, 6H), 2.43 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 163.6, 156.6, 149.0, 148.5, 142.4, 141.7, 141.6, 135.6, 134.3, 128.5, 127.9, 125.8, 123.6, 119.0, 112.4, 72.8, 52.3, 43.8, 43.1, 41.1, 16.1; MS (ES+) m/z 437.4 (M+1).
Reaction SMILES: [CH2:1]([N:4]1[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:23]=[C:22]3[C:17]([C:18](Cl)=[N:19][CH:20]=[N:21]3)=[CH:16][C:15]=2[O:25][CH3:26])[CH2:6][CH2:5]1)[CH:2]=[CH2:3].[OH:27][C:28]1[CH:29]=[C:30]2[C:34](=[N:35][CH:36]=1)[NH:33][CH:32]=[CH:31]2.C(=O)([O-])[O-].[K+].[K+]>CC(N(C)C)=O>[CH2:1]([N:4]1[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][CH2:12][O:13][C:14]2[CH:23]=[C:22]3[C:17]([C:18]([O:27][C:28]4[CH:29]=[C:30]5[C:34](=[N:35][CH:36]=4)[NH:33][CH:32]=[CH:31]5)=[N:19][CH:20]=[N:21]3)=[CH:16][C:15]=2[O:25][CH3:26])[CH2:6][CH2:5]1)[CH:2]=[CH2:3]
Reactant: C=CCN1CCN(CCCOc2cc3ncnc(Cl)c3cc2OC)CC1
Reactant: Oc1cnc2[nH]ccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: C=CCN1CCN(CCCOc2cc3ncnc(Oc4cnc5[nH]ccc5c4)c3cc2OC)CC1
Temperature: 85 °C
Reaction time: 3 h
Yield: 77.6 %

Procedure:
A mixture of 7-[3-(4-allylpiperazin-1-yl)propoxy]-4-chloro-6-methoxyquinazoline (288 mg, 0.76 mmol), 5-hydroxy-7-azaindole (113 mg, 0.84 mmol), (prepared as described for the starting material in Example 2), and potassium carbonate (116 mg, 0.84 mmol) in DMA (8 ml) was stirred at 85° C. for 3 hours and allowed to cool to ambient temperature. The mixture was filtered, the filtrate evaporated under vacuum and the residue purified by column chromatography eluting with methylene chloride/methanol (saturated with ammonia) (100/8/1). The volatiles were removed under vacuum to give a white solid which was triturated with diethyl ether, filtered and dried to give 7-[3-(4-allylpiperazin-1-yl)propoxy]-4-(7-azaindol-5-yloxy)-6-methoxyquinazoline (280 mg, 77%).
Reaction SMILES: O=[C:2]1[CH2:6][CH2:5][N:4](C(OC(C)(C)C)=O)[CH2:3]1.[CH:14]1[C:23]2[CH:22]=[CH:21][CH:20]=[C:19]([NH2:24])[C:18]=2[CH:17]=[CH:16][N:15]=1>>[NH:4]1[CH2:5][CH2:6][CH:2]([NH:24][C:19]2[C:18]3[CH:17]=[CH:16][N:15]=[CH:14][C:23]=3[CH:22]=[CH:21][CH:20]=2)[CH2:3]1
Reactant: Nc1cccc2cnccc12
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C1
Product: c1cc(NC2CCNC2)c2ccncc2c1

Procedure:
Reaction of tert-butyl 3-oxopyrrolidine-1-carboxylate and isoquinolin-5-amine using the method of Example 3 followed by deprotection using the method of Example 4 afforded the title compound.
Reaction SMILES: Cl[C:2](Cl)([O:4][C:5](=[O:11])OC(Cl)(Cl)Cl)Cl.[Br:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[N:21]=[C:22]([NH:25][C@H:26](C)[CH2:27]O)[S:23][CH:24]=2)=[CH:16][CH:15]=1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[Br:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[N:21]=[C:22]([N:25]3[C@H:26]([CH3:27])[CH2:2][O:4][C:5]3=[O:11])[S:23][CH:24]=2)=[CH:18][CH:19]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: C[C@H](CO)Nc1nc(-c2ccc(Br)cc2)cs1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C[C@@H]1COC(=O)N1c1nc(-c2ccc(Br)cc2)cs1
Reaction time: 3.5 h
Yield: 113 %

Procedure:
Triphosgene (2.62 g, 8.82 mmol) in 60 mL of methylene chloride was added under nitrogen dropwise over 1.75 h to a solution of (2R)-2-{[4-(4-bromophenyl)-1,3-thiazol-2-yl]amino}propan-1-ol (2.30 g, 7.33 mmol), prepared in the previous step, and N,N-diisopropylethylamine in 125 mL of methylene chloride at ice-bath temperature. After the addition, the reaction was stirred at ice-bath temperature for 3.5 h. The ice bath was removed and the stirring continued for 15 h. The reaction was extracted with 2 N HCl, dried (anhydrous MgSO4), filtered and the solvent removed under reduced pressure to give 2.81 g of a yellow solid. Purification of the solid on 500 g of silica gel (230-400 mesh) using 30% methylene chloride-hexane to methylene chloride as the eluents gave the title compound (2.07 g, 83%) as a white solid, mp 197-199° C.; MS (ES) m/z 339.0 [M+H]+; Anal. Calcd for C13H11BrN2O2S: C, 46.03; H, 3.27; N, 8.26. Found: C, 45.80; H, 3.13; N, 8.16.