Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]([S:13]([C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=1)(=[O:15])=[O:14])[NH:10][CH:11]=O.P(Cl)(Cl)(Cl)=O.N1C(C)=CC=CC=1C>C1COCC1>[C:19]1([CH3:22])[CH:18]=[CH:17][C:16]([S:13]([CH:9]([N+:10]#[C-:11])[C:3]2[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[F:1])(=[O:15])=[O:14])=[CH:21][CH:20]=1
Reactant: Cc1ccc(S(=O)(=O)C(NC=O)c2ccc(F)cc2F)cc1
Solvent: C1CCOC1
Solvent: O=P(Cl)(Cl)Cl
Solvent: Cc1cccc(C)n1
Product: [C-]#[N+]C(c1ccc(F)cc1F)S(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a mixture of N-[(2,4-Difluoro-phenyl)-(toluene-4-sulfonyl)-methyl]-formamide (2.07 g, 6.36 mmol) and THF (15 mL) is added phosphorous oxychloride (POCl3)(1.19 mL, 12.7 mmol) over a period of 5 minutes, and the resulting mixture stirred at room temperature for 10 minutes. The reaction is then cooled to 4° C. using an ice/water bath and 2,6-lutidine (4.45 mL, 38.2 mmol) is added over 30 minutes, maintaining the temperature less than 12° C. The cooling bath is removed and the mixture stirred at room temperature for 18 hours. The reaction mixture is poured into a stirred, ice water cooled, solution of ice and saturated aqueous NaHCO3. The mixture is extracted with ethyl acetate (2×). The combined organic extracts are washed with 1N aqueous hydrochloric acid, saturated aqueous NaHCO3, brine and dried (MgSO4). The solvents are removed in vacuo, and isopropanol (18.0 mL) added to the residual brownish solid. The resulting slurry is stirred at room temperature for 2 hours, then water (9.0 mL) is added and the slurry stirred for an additional 30 minutes at room temperature. The slurry is filtered, the cake washed with 2:1 isopropanol-water (2×) and dried in a vacuum-oven (30° C.) for 48 hours. The title compound may be obtained as a tan solid (1.33 g, 68%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10](I)=[CH:9][CH:8]=[C:7]([CH3:12])[N:6]=1)=[O:4].[C:13]1(B(O)O)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1.CCOC(C)=O.O>[CH3:12][C:7]1[N:6]=[C:5]([C:3]([O:2][CH3:1])=[O:4])[C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:9][CH:8]=1
Reactant: COC(=O)c1nc(C)ccc1I
Reactant: OB(O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)c1nc(C)ccc1-c1ccccc1
Temperature: 120 °C
Yield: 61.8 %

Procedure:
To a suspension of methyl-3-iodo-6-methylpyridine-2-carboxylate (1 g, 3.6 mmol; prepared according to WO2010063663), Phenyl Boronic Acid (440 mg, 3.6 mmol) and Pd Tetrakistriphenylphospine (417 mg; 0.36 mmol) in dry toluene (12 ml) was added K2CO3 1M aq solution (3.6 ml, 3.6 mmol). The mixture was heated in a microwave oven for 5 min at 120° C. (procedure was repeated for 4 times). To promote the reaction further Tetrakistriphenylphospine palladium (208.5 mg; 0.18 mmol)) and phenyl boronic acid (220 mg, 0.18 mmol) were added. The mixture was subject to 2 cycles of microwave heating at 140° C. for 10 min. The reaction mixture was diluted with AcOEt (10 mL) and water (10 mL). The organic layer was separated, washed with brine, dried with Na2SO4 and filtrated. The solvent was evaporated under reduced pressure and the crude mixture purified on silica gel column (Cyclohexane to Cyclohexane/AcOEt 9:1) to obtain 506 mg of the title compound as yellow oil.
Reaction SMILES: [CH2:1]([C:3]1[C:22]([CH3:23])=[CH:21][C:6]2[NH:7][C:8]([C:10]3[C:18]4[C:13](=[CH:14][CH:15]=[C:16]([C:19]#[N:20])[CH:17]=4)[NH:12][N:11]=3)=[N:9][C:5]=2[CH:4]=1)[CH3:2].C(=O)([O-])[O-:25].[Na+].[Na+].[ClH:30]>C(O)(=O)C>[ClH:30].[ClH:30].[CH2:1]([C:3]1[C:22]([CH3:23])=[CH:21][C:6]2[NH:7][C:8]([C:10]3[C:18]4[C:13](=[CH:14][CH:15]=[C:16]([C:19]([NH2:20])=[O:25])[CH:17]=4)[NH:12][N:11]=3)=[N:9][C:5]=2[CH:4]=1)[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CCc1cc2nc(-c3n[nH]c4ccc(C#N)cc34)[nH]c2cc1C
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Product: CCc1cc2nc(-c3n[nH]c4ccc(C(N)=O)cc34)[nH]c2cc1C
Temperature: 80 °C
Reaction time: 4 h

Procedure:
A stirred suspension of 3-(5-ethyl-6-methyl-1H-benzoimidazol-2-yl)-1H-indazole-5-carbonitrile [100 mg, Example 235(an)] in acetic acid (1 ml) and concentrated hydrochloric acid (1 ml) was heated at 80° C. for 30 minutes and then at 100° C. for 4 hours. The reaction was cooled to ambient temperature and stirred for 16 hours. The reaction was then heated at 80° C. for 2.5 hours and then at 100° C. for 2 hours. The reaction mixture was cooled to ambient temperature and neutralized with aqueous sodium carbonate solution. The resulting white precipitate was collected by filtration and the aqueous layer was extracted with ethyl acetate, combined with the precipitate and concentrated in vacuo. The residue was taken up in methanol, transferred to a solid phase cartridge containing MP-carbonate resin (100 mg) and shaken for 16 hours. The reaction was then filtered, the resin washed with methanol and the combined organic layers concentrated in vacuo. The residue was triturated with diethyl ether, taken up in methanol and acidified with 4M hydrogen chloride in 1,4-dioxane. The solvent was removed in vacuo to give 3-(5-ethyl-6-methyl-1H-benzoimidazol-2-yl)-1H-indazole-5-carboxylic acid amide dihydrochloride (58 mg) as a pale brown solid. LC-MS (METHOD M): RT=9.40 minutes, 320 (M+H)+.
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][N:11]([CH:38]([CH3:40])[CH3:39])[C:12]([C:14]1[C:19]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:18]([OH:28])[N:17]=[C:16]([CH2:29][C:30]2[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][C:31]=2[Br:37])[N:15]=1)=[O:13])(C(C)(C)C)(C)C.C(OCC)(=O)C>O1CCCC1.Cl.CCCCCC>[OH:8][CH2:9][CH2:10][N:11]([CH:38]([CH3:40])[CH3:39])[C:12]([C:14]1[C:19]([O:20][CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[C:18]([OH:28])[N:17]=[C:16]([CH2:29][C:30]2[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][C:31]=2[Br:37])[N:15]=1)=[O:13]
Reactant: CC(C)N(CCO[Si](C)(C)C(C)(C)C)C(=O)c1nc(Cc2ccc(Cl)cc2Br)nc(O)c1OCc1ccccc1
Agent: Cl
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)N(CCO)C(=O)c1nc(Cc2ccc(Cl)cc2Br)nc(O)c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.4 %

Procedure:
To a stirred solution of 5-benzyloxy-2-(2-bromo-4-chlorobenzyl)-6-hydroxypyrimidine-4-carboxylic acid [2-(tert-butyl-dimethylsilanyloxy)-ethyl]-isopropylamide (378) (5.7 g, 8.80 mmol) in tetrahydrofuran (50 mL), 1N HCl (15 mL) was added and the reaction mixture was stirred for 1 h at room temperature while silica thin layer chromatography was performed (70% ethyl acetate in hexane; Rf=0.2). After completion of the reaction, volatiles were removed and the residue was diluted with water (30 mL) and adjusted to pH 8 using NaHCO3. The aqueous mixture was extracted with ethyl acetate (2×150 mL) and the combined extracts were dried and concentrated. The resulting residue was purified by column over normal silica gel (100-200) to get 5-benzyloxy-2-(2-bromo-4-chlorobenzyl)-6-hydroxypyrimidine-4-carboxylicacid(2-hydroxyethyl)-isopropylamide (379) (4.02 g, 85.45%) as a white solid.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[O:10]=[C:11]1[N:20]([CH2:21][CH2:22][CH2:23][CH2:24][N:25]2[CH2:30][CH2:29][CH:28]([O:31][CH:32]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH2:27][CH2:26]2)[C:19](=[O:45])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[NH:12]1>>[O:10]=[C:11]1[N:20]([CH2:21][CH2:22][CH2:23][CH2:24][N:25]2[CH2:26][CH2:27][CH:28]([O:31][CH:32]([C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=3)[C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)[CH2:29][CH2:30]2)[C:19](=[O:45])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]1[CH2:2][CH2:3][CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: O=c1[nH]c2ccccc2c(=O)n1CCCCN1CCC(OC(c2ccccc2)c2ccccc2)CC1
Reactant: CCOC(=O)CCCBr
Product: CCOC(=O)CCCn1c(=O)n(CCCCN2CCC(OC(c3ccccc3)c3ccccc3)CC2)c(=O)c2ccccc21

Procedure:
Using the method similar to that in Example 57 and ethyl 4-bromobutyrate instead of 1-bromo-2-phenylethane and starting from 2,4-dioxo-3-[4-(4-diphenylmethoxypiperidino)butyl]-1,2,3,4-tetrahydroquinazoline (1.00 g) obtained in Example 80, the title compound was obtained as a crystal. This product was used in the next reaction without further purification.
Reaction SMILES: [C:1]1([C@@H:7]([N:9]2[CH:13]=[C:12]([C:14]([OH:16])=O)[CH:11]=[N:10]2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)([Cl:19])=O>C1(C)C=CC=CC=1>[C:1]1([C@@H:7]([N:9]2[CH:13]=[C:12]([C:14]([Cl:19])=[O:16])[CH:11]=[N:10]2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C[C@@H](c1ccccc1)n1cc(C(=O)O)cn1
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: C[C@@H](c1ccccc1)n1cc(C(=O)Cl)cn1
Temperature: 90 °C
Reaction time: 3 h

Procedure:
Intermediate (6g), 1-((S)-1-Phenyl-ethyl)-1H-pyrazole-4-carboxylic acid (0.5 g, 2.31 mmol) was stirred in toluene (20 mL) at RT and thionyl chloride (0.34 mL, 4.62 mmol) was added. The reaction mixture was slowly heated to 90° C. and heating continued for 3 hrs. After cooling the reaction was concentrated in vacuo. Toluene was added to the residue and concentrated in vacuo. This was repeated a further three times and the title compound, intermediate (6h), 1-((S)-1-Phenyl-ethyl)-1H-pyrazole-4-carbonyl chloride, was isolated as an oil, 0.544 g, quantitative.
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)[N:7]=[C:8]([Si:10]([CH3:13])([CH3:12])[CH3:11])[CH:9]=1)=[O:4].[OH-].[Na+]>CO>[C:17]1([CH3:20])[CH:16]=[CH:15][C:14]([N:6]2[C:5]([C:3]([OH:4])=[O:2])=[CH:9][C:8]([Si:10]([CH3:13])([CH3:12])[CH3:11])=[N:7]2)=[CH:19][CH:18]=1
Reactant: COC(=O)c1cc([Si](C)(C)C)nn1-c1ccc(C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1ccc(-n2nc([Si](C)(C)C)cc2C(=O)O)cc1
Temperature: 50 °C
Yield: 98.2 %

Procedure:
Place 2-p-tolyl-5-trimethylsilanyl-2H-pyrazole-3-carboxylic acid methyl ester (665 mg, 2.30 mmol) in methanol (25 mL). Add 1 N NaOH (10 mL, 10 mmol) and heat to 50° C. for 4 hours. Cool to room temperature and concentrate under reduced pressure. Add saturated aq. sodium bicarbonate solution and CH2Cl2. Separate organic layer and extract aqueous layer with CH2Cl2 (2×25 mL). Combine organic extracts, dry over Mg2SO4, filter, and concentrate under reduced pressure to yield 620 mg (98%) of 2-p-tolyl-5-trimethylsilanyl-2H-pyrazole-3-carboxylic acid. MS(ES+): m/z=275.3 [M+H].
Reaction SMILES: C(O[C:4](=[O:15])/[CH:5]=[C:6](\[NH:8][C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)/[CH3:7])C>C1(OC2C=CC=CC=2)C=CC=CC=1>[CH3:7][C:6]1[NH:8][C:9]2[C:10]([C:4](=[O:15])[CH:5]=1)=[N:11][CH:12]=[CH:13][CH:14]=2
Reactant: CCOC(=O)/C=C(/C)Nc1cccnc1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: Cc1cc(=O)c2ncccc2[nH]1
Yield: 36.2 %

Procedure:
Ethyl-(Z)-3-(3-pyridylamino)-2-butenoate (8.0 g) (obtained as described in J. Royal Netherlands Chem. Soc., 1976, 95, 220) was added to a refluxing eutectic mixture of 26.5% v/v diphenyl and 73.5% v/v diphenyl oxide (20 ml). The solution was heated under reflux for 1 hour and then cooled. The precipitated solid was collected, washed with hexane (20 ml) and ether (20 ml), and then purified by flash chromatography, eluting initially with methanol/dichloromethane (1:4 v/v). There was thus obtained 2-methyl-1,7-naphthyridin-4-(1H)-one (0.96 g), as an off-white powder, m.p. >250° C. (sublimes); NMR (d6 -DMSO): 2.4(s,3H), 6.2(s,1H), 8.1(d,1H), 8.45(d,1H), 9.0(s,1H). Further elution of the chromatography column with aqueous ammonia/methanol/dichloromethane (2:99:99 v/v) gave the required 2-methyl-1,5-naphthyridin-4(1H)-one (D1) (2.25 g), as an off-white powder, m.p. >280° C. (decomp.); NMR: 2.65(s,3H), 6.65(s,1H), 7.6(dd,1H), 8.4(dd,1H), 8.8(dd,1H).
Reaction SMILES: C(N(C(C)C)C(C)C)C.[CH3:10][O:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[CH:18]=[C:17]([C:22]([OH:24])=O)[CH:16]=[CH:15]2.O.ON1C2C=CC=CC=2N=N1.Cl.[CH3:37][O:38][C:39]([C:41]1[CH:42]=[C:43]2[C:47](=[CH:48][CH:49]=1)[CH2:46][CH2:45][C@H:44]2[NH2:50])=[O:40]>C(Cl)Cl.C(OCC)(=O)C>[CH3:10][O:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[CH:18]=[C:17]([C:22]([NH:50][C@H:44]1[C:43]3[C:47](=[CH:48][CH:49]=[C:41]([C:39]([O:38][CH3:37])=[O:40])[CH:42]=3)[CH2:46][CH2:45]1)=[O:24])[CH:16]=[CH:15]2
Reactant: COc1ccc2cc(C(=O)O)ccc2c1
Reactant: COC(=O)c1ccc2c(c1)[C@H](N)CC2
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc2c(c1)[C@H](NC(=O)c1ccc3cc(OC)ccc3c1)CC2
Temperature: 0 °C
Reaction time: 8 h
Yield: 83 %

Procedure:
N-Ethyl-diisopropylamine (3 eq.) was added to an ice-cold solution of 6-methoxy-2-naphthoic acid (1 eq.) in methylene chloride. The reaction mixture was cooled to 0° C. and N-ethyl-N′-3-(dimethylamino)-propyl-carbodiimide hydrochloride (1.2 eq.) and 1-hydroxybenzotriazole hydrate (0.2 eq.) were then added. The mixture was stirred at this temperature for 15 min, before (3R)-3-amino-2,3-dihydro-1H-indene-5-carboxylic acid methyl ester hydrochloride (A-03 HCl) (0.989 mmol, 1 eq.) was added. The reaction mixture was then stirred at room temperature overnight. The mixture was diluted with ethyl acetate and the organic phase was washed with 10% NH4Cl solution, sat. NaHCO3 solution and sat. NaCl solution. The organic phase was dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by column chromatography (silica, cyclohexane/ethyl acetate 2:1) to obtain the desired compound (B-10). Yield: 83%
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([C:15]2[CH:16]=[CH:17][C:18]3[C:19]4[CH2:28][NH:27][CH2:26][CH2:25][C:20]=4[N:21]([CH3:24])[C:22]=3[CH:23]=2)[C:11](=[O:29])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:30].[Cl:31][CH2:32][CH2:33][N:34]1[CH2:38][CH2:37][CH2:36][CH2:35]1.C(N(C(C)C)C(C)C)C>C(O)C>[ClH:31].[ClH:30].[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([C:15]2[CH:16]=[CH:17][C:18]3[C:19]4[CH2:28][N:27]([CH2:32][CH2:33][N:34]5[CH2:38][CH2:37][CH2:36][CH2:35]5)[CH2:26][CH2:25][C:20]=4[N:21]([CH3:24])[C:22]=3[CH:23]=2)[C:11](=[O:29])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cn1c2c(c3ccc(-n4ccc(OCc5ccccc5)cc4=O)cc31)CNCC2
Reactant: ClCCN1CCCC1
Agent: Cl
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: Cn1c2c(c3ccc(-n4ccc(OCc5ccccc5)cc4=O)cc31)CN(CCN1CCCC1)CC2
Temperature: 60 °C

Procedure:
4-(Benzyloxy)-1-(5-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-7-yl)pyridin-2(1H)-one (180 mg, 0.46 mmol), 1-(2-chloroethyl)pyrrolidine hydrochloride (95 mg, 0.56 mmol), (i-Pr)2EtN (0.25 mL, 1.4 mmol) were combined in ethanol (2 mL) and heated at 60° C. for 2 h. Purification by preparative HPLC and conversion to the dihydrochloride salt using the procedure of Example 30 (step g) provided the title compound as a white solid: mp 285-289° C.; 1H NMR (300 MHz, D2O) δ 7.50 (d, J=8.3 Hz, 1H), 7.46 (d, J=7.7 Hz, 1H), 7.42-7.31 (m, 6H), 6.96 (dd, J=8.3, 1.6 Hz, 1H), 6.27 (dd, J=7.7, 2.6 Hz, 1H), 6.10 (d, J=2.6 Hz, 1H), 5.90 (s, 2H), 4.59 (br s, 2H), 3.81-3.59 (m, 8H), 3.55 (s, 3H), 3.20 (t, J=5.7 Hz, 2H), 3.18-3.05 (br m, 2H), 2.15-1.90 (m, 4H); ESI MS m/z 483 [M+H]+; HPLC (Method B) 98.8% (AUC), tR=11.3 min.
Reaction SMILES: [CH:1]1([NH:7][C:8]([C:10]2O[C:12]([CH3:25])=[CH:13][C:14](=[O:24])[C:15]=2[O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:26][NH2:27]>CO>[CH:1]1([NH:7][C:8]([C:10]2[N:27]([CH3:26])[C:12]([CH3:25])=[CH:13][C:14](=[O:24])[C:15]=2[O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN
Reactant: Cc1cc(=O)c(OCc2ccccc2)c(C(=O)NC2CCCCC2)o1
Solvent: CO
Product: Cc1cc(=O)c(OCc2ccccc2)c(C(=O)NC2CCCCC2)n1C
Temperature: 72.5 °C
Reaction time: 8 h
Yield: 82.6 %

Procedure:
To a solution of 3-benzyloxy-6-methyl-4-oxo-4H-pyran-2-carboxylic acid cyclohexylamide (1.40 g, 4.1 mmol) in 5 ml of methanol, methylamine solution (9 ml of 2M solution in methanol, 16 mmol) was added. The resulting solution was stirred at 70 to 75° C. for overnight under the pressure in a sealed tube. The solvent was removed under reduced pressure gave light yellow solid as a crude product. The material was purified by column chromatography (elution gradient: 100% ethyl acetate to 25% methanol in ethyl acetate) to give the titled compound as white solid (1.20 g, 83.0%). M.p. 258-260° C.; 1H-NMR (CDCl3, 400 MHz) δ 1.26-1.45 (m, 6H, cyclohexyl-H), 1.79 (m, 2H, cyclohexyl-H), 1.95 (m, 2H, cyclohexyl-H), 2.41 (s, 3H, CH3), 3.82 (s, 3H, NCH3), 3.95 (m, 1H, CH), 5.13 (s, 2H, CH2), 7.19 (s, 1H, CH), 7.36 (m, 3H, ArH), 7.43 (m, 2H, ArH), 8.50 (br, 1H, NH); MS (m/z) 355 (M++1).
Reaction SMILES: [CH:1]([Si:4]([CH:35]([CH3:37])[CH3:36])([CH:32]([CH3:34])[CH3:33])[N:5]1[C:13]2[C:8](=[CH:9][C:10]([NH:14][C:15]([C:17]3[S:21][C:20]([C:22]4[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=4)=[N:19][C:18]=3[CH2:29][CH2:30]O)=[O:16])=[CH:11][CH:12]=2)[CH:7]=[CH:6]1)([CH3:3])[CH3:2].CCN(CC)CC>C(Cl)Cl.CCOC(C)=O.CS(Cl)(=O)=O>[Cl:28][C:25]1[CH:26]=[CH:27][C:22]([C:20]2[S:21][C:17]3[C:15](=[O:16])[N:14]([C:10]4[CH:9]=[C:8]5[C:13](=[CH:12][CH:11]=4)[N:5]([Si:4]([CH:35]([CH3:37])[CH3:36])([CH:1]([CH3:2])[CH3:3])[CH:32]([CH3:34])[CH3:33])[CH:6]=[CH:7]5)[CH2:30][CH2:29][C:18]=3[N:19]=2)=[CH:23][CH:24]=1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2cc(NC(=O)c3sc(-c4ccc(Cl)cc4)nc3CCO)ccc21
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(C)[Si](C(C)C)(C(C)C)n1ccc2cc(N3CCc4nc(-c5ccc(Cl)cc5)sc4C3=O)ccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
Dissolve 2-(4-chloro-phenyl)-4-(2-hydroxy-ethyl)-thiazole-5-carboxylic acid (1-triisopropylsilanyl-1H-indol-5-yl)-amide in CH2Cl2 (25 mL) and add Et3N (0.33 mL, 2.36 mmol) and methanesulfonyl chloride (0.16 mmol, 2.13 mmol). Stir the mixture at room temperature for 2 h, then add additional Et3N (0.33 mL, 2.36 mmol) and methanesulfonyl chloride (0.16 mmol, 2.13 mmol). Stir the mixture for an additional 2 h, dilute with EtOAc (50 mL), then wash with water (20 mL) and brine (20 mL). Dry, filter and concentrate the organic solution then and purify the crude material by flash chromatography, using a linear gradient of 100% hexanes to 50% EtOAc/hexanes as eluent, to give the title compound (1.15 g, 100%). MS (ES+) 536.1 (M+1)+. 1H NMR (400 MHz, CDCl3) δ: 7.93 (d, 2H, J=8.3 Hz), 7.56 (d, 1H, J=1.8 Hz), 7.50 (d, 1H, J=8.8 Hz), 7.44 (d, 2H, J=8.3 Hz), 7.27 (d, 1H, J=3.1 Hz), 7.14-7.10 (m, 1H), 6.61 (d, 1H, J=2.6 Hz), 4.16 (t, 2H, J=6.8 Hz), 3.29 (t, 2H, J=7.0 Hz), 1.73-1.65 (m, 3H), 1.14 (d, 18H, J=7.5 Hz).
Reaction SMILES: [C:1]([N:4]1[C:8]([NH2:9])=[N:7][C:6]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[N:5]1)(=[O:3])[CH3:2].[CH:21]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH:30]([CH3:32])[CH3:31])[C:25]=1[N:33]=[C:34]=[O:35])([CH3:23])[CH3:22]>>[CH3:23][CH:21]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH:30]([CH3:31])[CH3:32])[C:25]=1[NH:33][C:34]([NH:9][C:8]1[N:4]([C:1](=[O:3])[CH3:2])[N:5]=[C:6]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[N:7]=1)=[O:35])[CH3:22]
Reactant: CC(C)c1cccc(C(C)C)c1N=C=O
Reactant: CCCCCCCCCCCc1nc(N)n(C(C)=O)n1
Product: CCCCCCCCCCCc1nc(NC(=O)Nc2c(C(C)C)cccc2C(C)C)n(C(C)=O)n1
Temperature: 20 °C
Yield: 66.3 %

Procedure:
A slurry of 1-acetyl-5-amino-3-undecyl-1,2,4-triazole (3.56 g, 12.7 mmol) was warmed until homogeneous. 2,6-Diisopropylphenyl isocyanate (2.71 mL, 12.7 mmol) was added and the resulting solution was heated under reflux for 15 hours. The resulting solution was cooled (20° C.) and the precipitate was removed by filtration. The filtrate was concentrated in vacuo and the resulting oil was chromatographed on silica (85:15 hexane:ethyl acetate) to yield 4.07 g (66.3%) of the title compound as a light yellow oil.
Reaction SMILES: [O:1]=[C:2]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][CH:12]=O)=[CH:10][C:5]=2[CH2:4][O:3]1.[N:14]1([CH:20]2[CH2:29][CH2:28][C:27]3[CH:26]=[C:25]([C:30]#[N:31])[CH:24]=[CH:23][C:22]=3[CH2:21]2)[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1>>[O:1]=[C:2]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][CH2:12][N:17]3[CH2:16][CH2:15][N:14]([CH:20]4[CH2:29][CH2:28][C:27]5[CH:26]=[C:25]([C:30]#[N:31])[CH:24]=[CH:23][C:22]=5[CH2:21]4)[CH2:19][CH2:18]3)=[CH:10][C:5]=2[CH2:4][O:3]1
Reactant: O=CCc1ccc2c(c1)COC2=O
Reactant: N#Cc1ccc2c(c1)CCC(N1CCNCC1)C2
Product: N#Cc1ccc2c(c1)CCC(N1CCN(CCc3ccc4c(c3)COC4=O)CC1)C2

Procedure:
The above product was prepared following similar procedure of EXAMPLE 38 from (1-oxo-1,3-dihydro-2-benzofuran-5-yl)acetaldehyde and 6-piperazin-1-yl-5,6,7,8-tetrahydronaphthalene-2-carbonitrile. LC-MS (IE, m/z): 402 [M+1]+. (0.050 μM)
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10]([CH3:13])([CH3:12])[CH2:9][CH:8](O)[C:7]=2[CH:15]=1)#[N:2].C(N(CC)CC)C.CS([Cl:27])(=O)=O.O>ClCCl>[Cl:27][CH:8]1[C:7]2[CH:15]=[C:3]([C:1]#[N:2])[CH:4]=[CH:5][C:6]=2[O:11][C:10]([CH3:13])([CH3:12])[CH2:9]1
Reactant: CC1(C)CC(O)c2cc(C#N)ccc2O1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CC1(C)CC(Cl)c2cc(C#N)ccc2O1
Reaction time: 18 h

Procedure:
To a solution of 6-cyano-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-4-ol (U.K. Patent Application GB 2 204 868A) (2.93 g) and triethylamine (4.04 ml) in dichloromethane (100 ml) was added methanesulphonylchloride (2.24 ml) over 30 min, under an atmosphere of nitrogen. The reaction mixture was stirred for 18 h, water was added and the organic phase separated, washed with aqueous sodium hydrogencarbonate and dried over anhydrous sodium sulphate. Filtration and evaporation of the solvent in vacuo gave the title compound (3.03g) as a solid, which was used in the next step without further purification.
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[C:22]([C:23]([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[O:24])=[CH:21][CH:20]=[C:19]([Cl:31])[C:5]=1[CH2:6][O:7][C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:17]=1[N:16]=[C:15]([CH3:18])[CH:14]=[CH:13]2.C(N(CC)CC)C.[CH3:39][NH:40][C:41]([C:43]1[CH:48]=[CH:47][C:46]([NH:49][C:50](=O)[O:51]C2C=CC=CC=2)=[CH:45][CH:44]=1)=[O:42].O>CN(C)C=O>[Cl:3][C:4]1[C:22]([C:23]([N:25]2[CH2:26][CH2:27][N:28]([C:50](=[O:51])[NH:49][C:46]3[CH:45]=[CH:44][C:43]([C:41](=[O:42])[NH:40][CH3:39])=[CH:48][CH:47]=3)[CH2:29][CH2:30]2)=[O:24])=[CH:21][CH:20]=[C:19]([Cl:31])[C:5]=1[CH2:6][O:7][C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:17]=1[N:16]=[C:15]([CH3:18])[CH:14]=[CH:13]2
Reactant: CNC(=O)c1ccc(NC(=O)Oc2ccccc2)cc1
Reactant: Cc1ccc2cccc(OCc3c(Cl)ccc(C(=O)N4CCNCC4)c3Cl)c2n1
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CNC(=O)c1ccc(NC(=O)N2CCN(C(=O)c3ccc(Cl)c(COc4cccc5ccc(C)nc45)c3Cl)CC2)cc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 84.4 %

Procedure:
To a solution of 8-[2,6-dichloro-3-(piperazine-1-carbonyl)benzyloxy]-2-methylquinoline dihydrochloride (60 mg) and triethylamine (48.3 mg) in N,N-dimethylformamide (0.6 ml) was added phenyl 4-(methylcarbamoyl)phenylcarbamate (33.8 mg), and the mixture was stirred for 2 hours at 80° C. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with water and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by preparative thin layer chromatography (chloroform:methanol=10:1, V/V) to give 8-[2,6-dichloro-3-[4-(4-(methylcarbamoyl)phenylcarbamoyl]piperazine-1-carbonyl]benzyloxy]-2-methylquinoline (61 mg) as colorless amorphous.
Reaction SMILES: [N:1]1([CH2:6][C:7]2[CH:12]=[CH:11][C:10]([N:13]3[CH2:18][CH2:17][CH:16]([CH:19]=O)[CH2:15][CH2:14]3)=[CH:9][CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[C:22]1([NH:21][CH2:19][CH:16]2[CH2:17][CH2:18][N:13]([C:10]3[CH:11]=[CH:12][C:7]([CH2:6][N:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)=[CH:8][CH:9]=3)[CH2:14][CH2:15]2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=CC1CCN(c2ccc(CN3CCCC3)cc2)CC1
Reactant: Nc1ccccc1
Product: c1ccc(NCC2CCN(c3ccc(CN4CCCC4)cc3)CC2)cc1

Procedure:
Prepared from the product of Example 16 and aniline.