Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)[S:8][C:9]=1[CH2:10]Cl)[CH2:2][CH2:3][CH3:4].C(=O)([O-])[O-].[Cs+].[Cs+].[OH:28][C:29]1[CH:30]=[C:31]([CH2:35][CH2:36][C:37]([O:39][CH3:40])=[O:38])[CH:32]=[CH:33][CH:34]=1.O>CN(C=O)C>[CH3:40][O:39][C:37](=[O:38])[CH2:36][CH2:35][C:31]1[CH:32]=[CH:33][CH:34]=[C:29]([O:28][CH2:10][C:9]2[S:8][C:7]([C:12]3[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=3)=[N:6][C:5]=2[CH2:1][CH2:2][CH2:3][CH3:4])[CH:30]=1
Reactant: CCCCc1nc(-c2ccc(C(F)(F)F)cc2)sc1CCl
Reactant: COC(=O)CCc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCc1nc(-c2ccc(C(F)(F)F)cc2)sc1COc1cccc(CCC(=O)OC)c1
Reaction time: 8 h
Yield: 67.5 %

Procedure:
To a solution of 4-butyl-5-chloromethyl-2-(4-trifluoromethyl-phenyl)-thiazole (300 mg, 0.90 mmol) in anhydrous DMF (5 mL) add cesium carbonate (586 mg, 1.80 mmol) and methyl 3-(3-hydroxyphenyl)propionate (178 mg, 0.99 mmol). Stir the resulting mixture overnight then pour into water and extract twice with ethyl acetate. Wash the combined extracts with water, dry over MgSO4, filter and concentrate under vacuum. Purify the residue by flash chromatography on silica gel (eluting with 5% ethyl acetate in heptane) to give the title compound (290 mg) as a yellow oil.
Reaction SMILES: [H-].[Na+].C(=N[OH:11])C1C=CC=CC=1.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:29])[C:20]2[CH:25]=[CH:24][C:23]([N+]([O-])=O)=[CH:22][CH:21]=2)=[CH:15][CH:14]=1.O>CS(C)=O>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:29])[C:20]2[CH:25]=[CH:24][C:23]([OH:11])=[CH:22][CH:21]=2)=[CH:15][CH:14]=1
Reactant: O=C(c1ccc(Cl)cc1)c1ccc([N+](=O)[O-])cc1
Reactant: ON=Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: O=C(c1ccc(O)cc1)c1ccc(Cl)cc1
Temperature: 70 °C
Reaction time: 20 h

Procedure:
250 cc of DMSO and 4.8 g sodium hydride are placed in a 500 cc flask and heated at 70° C. for 1 hour, by which time the solution has become clear. A solution of 24.2 g (0.2 mole) of benzaldoxime in 100 cc of DMSO is then added drop by drop. The solution is maintained at 70° C. for 1 hour, then allowed to cool to 15° C. A solution of 26 g (0.1 mole) of 4'-chloro-4-nitrobenzophenone in 150 cc of DMSO is then added. The reaction mixture is stirred for 20 hours at ambient temperature and then poured into acidulated water. The mixture is extracted with ether and then with ether containing 2 N caustic soda. On acidification the product is precipitated. Yield 15 g (65%). Melting point 178° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[OH:13])[N:9]=[CH:8][CH:7]=[C:6]2[O:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22]([NH:24][CH:25]2[CH2:27][CH2:26]2)=[O:23])=[C:17]([Cl:28])[CH:16]=1)#[N:2].[Br:29][CH2:30][CH2:31][CH2:32]Br>>[Br:29][CH2:30][CH2:31][CH2:32][O:13][C:12]1[CH:11]=[C:10]2[C:5]([C:6]([O:14][C:15]3[CH:20]=[CH:19][C:18]([NH:21][C:22]([NH:24][CH:25]4[CH2:26][CH2:27]4)=[O:23])=[C:17]([Cl:28])[CH:16]=3)=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[C:1]#[N:2]
Reactant: BrCCCBr
Reactant: N#Cc1cc2c(Oc3ccc(NC(=O)NC4CC4)c(Cl)c3)ccnc2cc1O
Product: N#Cc1cc2c(Oc3ccc(NC(=O)NC4CC4)c(Cl)c3)ccnc2cc1OCCCBr
Yield: 15.6 %

Procedure:
The title compound (129 mg, 0.250 mmol, 15.6%) was obtained as light brown crystals from an N-(4-(6-cyano-7-hydroxy-4-quinolyl)oxy-2-chlorophenyl)-N′-cyclopropylurea crude product (500 mg, 1.60 mmol) and 1,3-dibromopropane, by the same procedure as in Example 7.
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[C:4]([N:7]2[CH2:11][CH2:10][CH2:9][CH2:8]2)[C:3]=1[C:12]#[N:13].[CH3:14][N:15]=[C:16]=[O:17]>C([O-])(=O)C.C([O-])(=O)C.C([Sn+2]CCCC)CCC.O1CCCC1>[CH3:14][NH:15][C:16]([NH:1][C:2]1[S:6][N:5]=[C:4]([N:7]2[CH2:11][CH2:10][CH2:9][CH2:8]2)[C:3]=1[C:12]#[N:13])=[O:17]
Reactant: N#Cc1c(N2CCCC2)nsc1N
Reactant: CN=C=O
Agent: CC(=O)[O-]
Agent: CCCC[Sn+2]CCCC
Solvent: C1CCOC1
Product: CNC(=O)Nc1snc(N2CCCC2)c1C#N
Yield: 82.1 %

Procedure:
A mixture of 16.0 g of 5-amino-4-cyano-3-(1-pyrrolidinyl)isothiazole, 25 drops of dibutyltin diacetate and 5.4 g of methyl isocyanate in 90 ml of tetrahydrofuran was heated under reflux for about 56 hours. Small increments of methyl isocyanate (3 ml at 27 hours and 2 ml at 40 hours) and dibutyltin diacetate (10 drops at 32 hours and 5 drops at 40 hours) were added during the reflux period. A solid that had formed was isolated by filtration. The filtrate was concentrated under reduced pressure to obtain a second crop. A total of 17.0 g of 1-methyl-3-(4-cyano-3-(1-pyrrolidinyl)-5-isothiazolyl)urea, m.p. 239°, was obtained. The nmr spectrum was consistent with the assigned structure.
Reaction SMILES: [CH:1]([C:3]1[CH:11]=[C:10]([CH3:12])[CH:9]=[C:5]([C:6]([OH:8])=[O:7])[C:4]=1[OH:13])=O.Cl.[NH2:15]O>CN(C)C=O>[C:1]([C:3]1[CH:11]=[C:10]([CH3:12])[CH:9]=[C:5]([C:6]([OH:8])=[O:7])[C:4]=1[OH:13])#[N:15]
Reactant: Cc1cc(C=O)c(O)c(C(=O)O)c1
Reactant: NO
Agent: Cl
Solvent: CN(C)C=O
Product: Cc1cc(C#N)c(O)c(C(=O)O)c1
Yield: 76.3 %

Procedure:
3-Formyl-5-methylsalicylic acid (3.6 g) was dissolved in dimethylformamide (20 ml) and treated with hydroxylamine hydrochloride (1.53 g). The mixture was heated at reflux for 10 minutes and then the solvent was removed in vacuo. The residue was treated with water (20 ml) and hydrochloric acid (2N; 10 ml). The precipitated solid was filtered off and recrystallized from aqueous ethanol to give 3-cyano-5-methylsalicylic acid (2.7 g), m.p. 193°-194° C.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:18]([O:20][CH3:21])=[O:19])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(=O)([O-])[O-].[K+].[K+].F[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[N+:35]([O-:37])=[O:36]>CN(C)C=O.CCOCC>[C:1]([NH:8][C@H:9]([C:18]([O:20][CH3:21])=[O:19])[CH2:10][C:11]1[CH:12]=[CH:13][C:14]([O:17][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[N+:35]([O-:37])=[O:36])=[CH:15][CH:16]=1)([O:3][C:4]([CH3:5])([CH3:7])[CH3:6])=[O:2]
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: COC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: COC(=O)[C@H](Cc1ccc(Oc2ccccc2[N+](=O)[O-])cc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of N-Boc-(L)tyrosine, methyl ester (500 mg) and potassium carbonate (467 mg) in dimethylformamide (5 mL) was added dropwise 1-fluoro-2-nitrobenzene (189 μL). The yellow solution was stirred for 3 days at room temperature. The mixture was diluted with ether which was subsequently washed with 1N hydrochloric acid, water, saturated salt solution and dried over anhydrous magnesium sulfate. After filtration, the solvent was removed by rotoevaporation to yield the title compound (700 mg) which was used in the subsequent reaction without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13](=[O:20])[N:12]([CH3:21])[C:11]=2[C:22]([O:24][CH3:25])=[O:23])[CH:5]=[CH:6][C:7]=1[CH3:8].[H-].[Na+].[CH3:28]I.Cl.O>CN(C=O)C>[CH3:1][C:2]1[CH:3]=[C:4]([N:9]([CH3:28])[C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13](=[O:20])[N:12]([CH3:21])[C:11]=2[C:22]([O:24][CH3:25])=[O:23])[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: COC(=O)c1c(Nc2ccc(C)c(C)c2)c2ccccc2c(=O)n1C
Reactant: CI
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1c(N(C)c2ccc(C)c(C)c2)c2ccccc2c(=O)n1C
Temperature: 25 °C
Reaction time: 18 h
Yield: 94.7 %

Procedure:
To a solution of methyl 4-[(3,4-dimethylphenyl)amino]-2-methyl-1-oxo-1,2-dihydro-3-isoquinolinecarboxylate (2.03 g, 6.03 mmol) in DMF (40 mL) at 0° C. was added sodium hydride (0.362 g, 9.05 mmol) followed by methyl iodide (5.66 mL, 91 mmol). The mixture was stirred at room temperature for 18 hours. 1M HCl/water was added and the mixture was extracted with EtOAc. The organic phase was washed with brine, dried over sodium sulfate and evaporated in vacuo. The crude product was purified on silica using EtOAc/hexanes 30-50% to provide the title compound as an off-white solid (2 g, 95%): 1H NMR (400 MHz, CDCl3) δ ppm 8.56-8.37 (m, 1 H), 8.03 (s, 1 H), 7.62-7.47 (m, 2 H), 6.93 (d, J=8.4 Hz, 1 H), 6.48 (d, J=2.3 Hz, 1 H), 6.40 (dd, J=2.5, 8.2 Hz, 1 H), 3.77 (s, 3 H), 3.57 (s, 3 H), 3.24 (s, 3 H), 3.04-2.95 (m, 2 H), 2.89 (s, 2 H), 2.17 (d, J=8.8 Hz, 6 H);); ES-LCMS: 351.3 (M+1).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][OH:13].[C:14](O)(=[O:18])[C:15]([CH3:17])=[CH2:16].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.ClCCl>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14](=[O:18])[C:15]([CH3:17])=[CH2:16]
Reactant: OCCCCCCCCCCCBr
Reactant: C=C(C)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: C=C(C)C(=O)OCCCCCCCCCCCBr
Temperature: 0 °C
Reaction time: 19 h
Yield: 79.1 %

Procedure:
19.2 g (76.4 mmol) 11-bromo-1-undecanol, 7.2 g (84.1 mmol) methacrylic acid and 1.03 g (8.4 mmol) 4-dimethylaminopyridine were dissolved in 157 ml dichloromethane. The solution was subsequently cooled to 0° C. and then a solution of 17.4 g (84.2 mmol) dicyclohexylcarbodiimide in 80 ml dichloromethane was added dropwise at 0° C. over a period of 45 minutes. The reaction mixture was allowed to warm to room temperature, stirred for 19 hours and filtered. The filtrate was concentrated by evaporation. The residue was purified by chromatography using a silica gel column (170 g) and toluene as eluant to give 19.3 g (98.4%) 2-methylacrylic acid 11-bromoundecyl ester.
Reaction SMILES: Br[C:2]1[C:7]([N:8]([CH2:23][O:24][CH3:25])[S:9]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([C:19]([F:22])([F:21])[F:20])[CH:13]=2)(=[O:11])=[O:10])=[CH:6][C:5]([Cl:26])=[CH:4][N:3]=1.C([Mg]Cl)(C)C.C[O:33][C:34](=[O:43])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[CH:41]=O>C1COCC1>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([S:9]([N:8]([C:7]2[C:2]([CH:41]3[C:36]4[C:35](=[CH:40][CH:39]=[CH:38][CH:37]=4)[C:34](=[O:33])[O:43]3)=[N:3][CH:4]=[C:5]([Cl:26])[CH:6]=2)[CH2:23][O:24][CH3:25])(=[O:11])=[O:10])=[CH:13][C:14]=1[C:19]([F:22])([F:21])[F:20]
Reactant: COCN(c1cc(Cl)cnc1Br)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Reactant: COC(=O)c1ccccc1C=O
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: COCN(c1cc(Cl)cnc1C1OC(=O)c2ccccc21)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of N-(2-bromo-5-chloro-pyridin-3-yl)-4-chloro-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide (250 mg, 0.50 mmol) in THF (3.0 mL) under nitrogen atmosphere at 0° C. was added isopropylmagnesium chloride (0.60 mL, 1.2 mmol, 2 M in THF). The mixture was then stirred for 30 min at 0° C. and 2-formyl-benzoic acid methyl ester (164 mg, 1.0 mmol) was added. The aqueous layer was stirred at room temperature overnight, quenched with saturated aqueous ammonium chloride, and followed by sodium bicarbonate to pH ˜6. The mixture was extracted with ethyl acetate, dried, and concentrated to provide 4-chloro-N-[5-chloro-2-(3-oxo-1,3-dihydro-isobenzofuran-1-yl)-pyridin-3-yl]-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide. The crude residue was used directly in the next step.
Reaction SMILES: [N+:1]([C:4]1[C:5](=O)[C:6]2[C:7](=[CH:10][S:11][CH:12]=2)[NH:8][CH:9]=1)([O-:3])=[O:2].P(Cl)(Cl)([Cl:16])=O>>[Cl:16][C:5]1[C:6]2[C:7](=[CH:10][S:11][CH:12]=2)[N:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: O=c1c([N+](=O)[O-])c[nH]c2cscc12
Reactant: O=P(Cl)(Cl)Cl
Product: O=[N+]([O-])c1cnc2cscc2c1Cl
Temperature: 105 °C
Reaction time: 1 h
Yield: 60 %

Procedure:
A mixture of 3.00 g of 3-nitrothieno[3,4-b]pyridin-4(1H)-one 10 and 9 ml of phosphorous oxychloride is stirred at 105° C. (bath temperature) for 1 hour and evaporated to dryness in vacuo. The residue is taken up in chloroform and washed with aqueous ammonia and water. The organic phase is dried over magnesium sulfate and evaporated. The residue is purified by column chromatography on silica gel. Elution with dichloromethane-ether (50:1 v/v) affords 2.02 g (60%) of Compound 11. Recrystallization from ether-petroleum ether affords colorless crystals melting at 139°-140° C.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11](COCC[Si](C)(C)C)[N:10]=[C:9]2[O:23][CH3:24].C(N)CN.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[O:3]1[CH2:4][CH2:5][O:1][CH:2]1[C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][N:10]=[C:9]2[O:23][CH3:24]
Reactant: COc1nn(COCC[Si](C)(C)C)c2ccc(C3OCCO3)cc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: NCCN
Solvent: C1CCOC1
Product: COc1n[nH]c2ccc(C3OCCO3)cc12
Temperature: 50 °C
Reaction time: 12 h

Procedure:
To 940 mg (2.682 mmol) 5-(1,3-dioxolan-2-yl)-3-methoxy-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-indazole (Example 6A) and 805 mg (13.41 mmol) ethane-1,2-diamine in THF (50 ml) were added 12.98 ml (12.98 mmol) tetrabutylammonium fluoride solution (1.0 M in THF). The reaction mixture was heated to 50° C. for 3 h. After this time, 12.98 ml (12.98 mmol) tetrabutylammonium fluoride solution (1.0 M in THF) were added again, and heating was continued for further 12 h until conversion was complete. The mixture was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution. The layers were separated, and the aqueous layer was washed twice with ethyl acetate. The combined organic layers were washed with brine and dried over sodium sulfate. After filtration, the solvent was evaporated, and the remaining solid was purified by chromatography on silica gel (cyclohexane/ethyl acetate gradient) to afford 556 mg (94% of th.) of the intermediate compound 5-(1,3-dioxolan-2-yl)-3-methoxy-1H-indazole [LC-MS (method 3): Rt=1.44 min; MS (ESIpos): m/z=211 (M+H)+]. This material was dissolved in ethanol (37 ml), treated with 1 N hydrochloric acid (9.4 ml) and heated to 90° C. for 30 minutes. After this time, the mixture was evaporated to dryness, and the crude aldehyde thus obtained was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([Cl:9])=[CH:4][N:3]=1.[NH2:10][CH:11]1[CH2:25][CH:14]2[CH2:15][N:16]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:17][CH:13]2[CH2:12]1.CCN(CC)CC>CCO>[Cl:1][C:2]1[N:7]=[C:6]([NH:10][CH:11]2[CH2:25][CH:14]3[CH2:15][N:16]([C:18]([O:20][C:21]([CH3:23])([CH3:22])[CH3:24])=[O:19])[CH2:17][CH:13]3[CH2:12]2)[C:5]([Cl:9])=[CH:4][N:3]=1
Reactant: Clc1ncc(Cl)c(Cl)n1
Reactant: CC(C)(C)OC(=O)N1CC2CC(N)CC2C1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CC2CC(Nc3nc(Cl)ncc3Cl)CC2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To a solution of 2,4,5-trichloropyrimidine (1.46 g, 7.96 mmol) and tert-butyl 5-aminohexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (3.11 g, 13.74 mmol) in EtOH (60 mL) was added Et3N (2.21 g, 21.84 mmol) and the reaction mixture was stirred at rt overnight and then concentrated in vacuo. The residue was dissolved in a mixture of EtOAc (50 mL) and water (50 mL), and extracted with EtOAc (150 mL×3). The combined organic phases were washed with brine (150 mL), dried over anhydrous Na2SO4, then concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/PE (v/v)=1/5) to give the title compound as a pale yellow solid (2.97 g, 100%).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:11][CH:12]2[CH2:14][CH2:13]2)[C:5]2[O:10][CH:9]=[CH:8][C:6]=2[N:7]=1.[Cl:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][C:22]=1[N:23]1[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]1)[NH2:19].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C([O-])([O-])=O.[K+].[K+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CC(O)(C)C>[Cl:15][C:16]1[CH:17]=[C:18]([NH:19][C:2]2[N:3]=[C:4]([NH:11][CH:12]3[CH2:14][CH2:13]3)[C:5]3[O:10][CH:9]=[CH:8][C:6]=3[N:7]=2)[CH:20]=[CH:21][C:22]=1[N:23]1[CH2:24][CH2:25][N:26]([CH3:29])[CH2:27][CH2:28]1
Reactant: CN1CCN(c2ccc(N)cc2Cl)CC1
Reactant: Clc1nc(NC2CC2)c2occc2n1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CC(C)(C)O
Product: CN1CCN(c2ccc(Nc3nc(NC4CC4)c4occc4n3)cc2Cl)CC1
Temperature: 85 °C
Reaction time: 8 h
Yield: 43.2 %

Procedure:
To a vial was added 2-chloro-N-cyclopropylfuro[3,2-d]pyrimidin-4-amine (0.099 g, 0.476 mmol, Preparation #A.1), 3-chloro-4-(4-methylpiperazin-1-yl)aniline (0.118 g, 0.523 mmol, Art-Chem), X-Phos (0.0136 g, 0.029 mmol), K2CO3 (0.079 g, 0.571 mmol), and Pd2dba3 (0.026 g, 0.029 mmol). t-BuOH (2 mL) was then added and tube was sealed. The tube was evacuated and purged with nitrogen (3×), and stirred overnight at about 85° C. The mixture was filtered, the filter pad was washed with EtOAc and then the solvent was removed in vacuo. The crude material was added to a silica gel column and was eluted with MeOH/DCM (2% to 10%). The sample was further purified by preparative reverse phase HPLC (Table 2, Method b). The collected fractions were dissolved in DCM (10 mL) and washed with saturated aqueous NaHCO3, (10 mL) and separated using a Biotage phase separator column. The filtrate was concentrated to provide N2-(3-chloro-4-(4-methylpiperazin-1-yl)phenyl)-N4-cyclopropylfuro[3,2-d]pyrimidine-2,4-diamine (0.082 g, 43%): LC/MS (Table 2, Method a) Rt=1.04 min; MS m/z 399.2 (M+H)+. Syk IC50=B
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]=[C:9]2[N:12]([CH2:14][CH2:15][CH2:16][CH3:17])[CH3:13])=[CH:4][CH:3]=1.C([Li])(CC)C.[C:23](=[O:25])=[O:24].Cl>C(OCC)C>[CH2:14]([N:12]([CH3:13])[C:9]1[C:10]2[C:5](=[CH:4][CH:3]=[C:2]([C:23]([OH:25])=[O:24])[CH:11]=2)[CH:6]=[CH:7][N:8]=1)[CH2:15][CH2:16][CH3:17]
Reactant: CCCCN(C)c1nccc2ccc(Br)cc12
Reactant: O=C=O
Agent: Cl
Agent: [Li]C(C)CC
Solvent: CCOCC
Product: CCCCN(C)c1nccc2ccc(C(=O)O)cc12
Temperature: -60 °C
Reaction time: 0.33 h

Procedure:
To a −60° C. solution of 7-bromo-N-butyl-N-methylisoquinolin-1-amine (230 mg, 0.78 mmol) in diethyl ether was added sec-butyllithium (1.00 mL of a 1.3 M solution in cyclohexanes, 1.30 mmol). The solution was stirred at −60° C. for 20 min then excess dry ice (CO2) was added and the reaction mixture was allowed to warm to room temperature. The reaction mixture was then acidified with 1 N hydrochloric acid and extracted with ethyl acetate. The aqueous phase was concentrated under reduced pressure to yield a yellow oil. Purification by flash column chromatography (silica, 50:30:15:5 ethyl acetate/chloroform/methanol/ammonium hydroxide) provided 1-[butyl(methyl)amino]isoquinoline-7-carboxylic acid (90 mg): ESI MS m/z 259 [M+H]+.
Reaction SMILES: [CH2:1]([N:5]([CH2:19][CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[S:6]([C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([N+:16]([O-])=O)[CH:10]=1)(=[O:8])=[O:7])[CH2:2][CH2:3][CH3:4].[H][H]>[Pt].C(O)C>[CH2:1]([N:5]([CH2:19][CH2:20][CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[S:6]([C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([NH2:16])[CH:10]=1)(=[O:8])=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN(CCCc1ccccc1)S(=O)(=O)c1ccc(O)c([N+](=O)[O-])c1
Reactant: [H][H]
Agent: [Pt]
Solvent: CCO
Product: CCCCN(CCCc1ccccc1)S(=O)(=O)c1ccc(O)c(N)c1
Temperature: 25 °C
Reaction time: 22 h
Yield: 98.9 %

Procedure:
A mixture of 13.16 g N-butyl-N-(3'-phenylpropyl)-4-hydroxy-3-nitrobenzenesulfonamide, 2 g 1 wt % platinum on alumina, and 200 ml ethanol was stirred for 22 hours at room temperature in a bomb charged with 800 psi of hydrogen. The solution was filtered and concentrated to give 12.02 g N-butyl-N-(3'-phenylpropyl)-3-amino-4-hydroxybenzensulfonamide.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH2:9][C:8](=[CH:13]N(C)C)[C:7](=O)[C:6]=2[CH:18]=1.Cl.[CH:20]1([C:23]([NH2:25])=[NH:24])[CH2:22][CH2:21]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH2:9][C:8]3[CH:13]=[N:24][C:23]([CH:20]4[CH2:22][CH2:21]4)=[N:25][C:7]=3[C:6]=2[CH:18]=1
Reactant: CN(C)C=C1CC(=O)Nc2ccc(Cl)cc2C1=O
Reactant: N=C(N)C1CC1
Agent: Cl
Product: O=C1Cc2cnc(C3CC3)nc2-c2cc(Cl)ccc2N1
Yield: 83 %

Procedure:
Analogous to Scheme 1, from 7-chloro-4-[(dimethylamino)methylene]-3,4-dihydro-1H-benzazepine-2,5-dione and cyclopropancarboxamidine hydrochloride. Yield: 83%.
Reaction SMILES: Cl.[Cl:2][C:3]1[N:4]=[C:5]([C:10]([NH:12][C@H:13]2[CH2:18][CH2:17][NH:16][CH2:15][C@H:14]2[O:19][CH3:20])=[O:11])[NH:6][C:7]=1[CH2:8][CH3:9].F[C:22]1[CH:27]=[C:26]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH:25]=[CH:24][N:23]=1.C(N(C(C)C)CC)(C)C>>[Cl:2][C:3]1[N:4]=[C:5]([C:10]([NH:12][C@H:13]2[CH2:18][CH2:17][N:16]([C:22]3[CH:27]=[C:26]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH:25]=[CH:24][N:23]=3)[CH2:15][C@H:14]2[O:19][CH3:20])=[O:11])[NH:6][C:7]=1[CH2:8][CH3:9]
Reactant: CCc1[nH]c(C(=O)N[C@H]2CCNC[C@H]2OC)nc1Cl
Reactant: CCOC(=O)c1ccnc(F)c1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1ccnc(N2CC[C@H](NC(=O)c3nc(Cl)c(CC)[nH]3)[C@H](OC)C2)c1
Yield: 29.2 %

Procedure:
The same operation as in Example (158a) was performed using cis(±)-4-chloro-5-ethyl-N-(3-methoxypiperidin-4-yl)-1H-imidazole-2-carboxamide hydrochloride obtained in Example (159a) (38.22 mg, 0.12 mmol), ethyl 2-fluoropyridine-4-carboxylate (20 mg, 0.12 mmol) (reference: Journal of Medicinal Chemistry; English; 33; 6; 1990; 1667-1675) and diisopropylethylamine (45.85 mg, 0.35 mmol), to obtain 15.3 mg of the title compound as a yellow oily substance (30%).
Reaction SMILES: [NH2:1][N:2]1[CH2:7][CH2:6][N:5]([S:8]([C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([Cl:21])[CH:17]=3)[CH:12]=2)(=[O:10])=[O:9])[CH2:4][C:3]1=[O:22].[N:23]1[CH:28]=[CH:27][C:26]([N:29]2[CH2:34][CH2:33][C:32](=O)[CH2:31][CH2:30]2)=[CH:25][CH:24]=1>C(O)C>[Cl:21][C:16]1[CH:17]=[C:18]2[C:13](=[CH:14][CH:15]=1)[CH:12]=[C:11]([S:8]([N:5]1[CH2:6][CH2:7][N:2]([N:1]=[C:32]3[CH2:31][CH2:30][N:29]([C:26]4[CH:27]=[CH:28][N:23]=[CH:24][CH:25]=4)[CH2:34][CH2:33]3)[C:3](=[O:22])[CH2:4]1)(=[O:9])=[O:10])[CH:20]=[CH:19]2
Reactant: O=C1CCN(c2ccncc2)CC1
Reactant: NN1CCN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CC1=O
Solvent: CCO
Product: O=C1CN(S(=O)(=O)c2ccc3cc(Cl)ccc3c2)CCN1N=C1CCN(c2ccncc2)CC1

Procedure:
1-(tert-Butoxycarbonylamino)-4-(6-chloronaphthalene-2-sulfonyl)-2-piperazinone (575 mg) was combined with methanol (4 ml) and a 4N solution of hydrochloric-acid in ethyl acetate (4 ml) and stirred at room temperature for 30 minutes. The reaction mixture was concentrated and the residue obtained was combined with aqueous sodium bicarbonate, extracted with dichloromethane, dried and concentrated to obtain 1-amino-4-(6-chloronaphthalene-2-sulfonyl)-2-piperazinone as a colorless solid. A solution of the resultant 1-amino-4-(6-chloronaphthalene-2-sulfonyl)-2-piperazinone and 1-(4-pyridyl)-4-piperidone (237 mg) in ethanol (30 ml) was dehydrated using a Soxlet extractor packed with molecular sieves 4A while refluxing for 24 hours. The reaction mixture was concentrated and the residue was purified by a column chromatography (dichloromethane: 10% aqueous ammonia-containing methanol=20:1) and crystallized from ether to obtain the title compound (265 mg) as colorless crystals.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH:2]1[C:7]([OH:9])=[O:8].[CH2:10]=O>[Pd]>[CH3:10][N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH:2]1[C:7]([OH:9])=[O:8]
Reactant: O=C(O)C1COCCN1
Reactant: C=O
Agent: [Pd]
Product: CN1CCOCC1C(=O)O
Yield: 96.1 %

Procedure:
To the above prepared solution of morpholine-3-carboxylic acid (140 mg, 0.86 mmol, 1 eq) was added aqueous formaldehyde (0.1 g, 1 mmol, 37%, 1.2 equiv), and the solution was stirred under hydrogen atmosphere at room temperature for 24 h in the presence of 10% palladium on carbon (150 mg, 50% water). After completion of the reaction, the catalyst was filtered off and the filtrate was concentrated under vacuum to give 120 mg of the desired 4-methylmorpholine-3-carboxylic acid. The crude material was used in the next step without further purification. 1H NMR (CD3OD, 400 MHz): δ 4.24-4.22 (m, 1H), 4.00-3.99 (m, 1H), 3.74-3.64 (m, 3H), 3.42-3.38 (m, 1H), 3.20-3.19 (m, 1H), 2.95 (s, 3H)