Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH2:23][NH2:24])[CH:7]=1)[CH3:2].[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([S:33](Cl)(=[O:35])=[O:34])=[CH:29][CH:28]=1.C(N(CC)CC)C>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:25])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:20])([F:21])[F:22])=[CH:15][C:14]=2[CH2:23][NH:24][S:33]([C:30]2[CH:31]=[CH:32][C:27]([Cl:26])=[CH:28][CH:29]=2)(=[O:35])=[O:34])[CH:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1cccc(Oc2ccc(C(F)(F)F)cc2CN)c1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)Cc1cccc(Oc2ccc(C(F)(F)F)cc2CNS(=O)(=O)c2ccc(Cl)cc2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
[3-(2-Aminomethyl-4-trifluoromethyl-phenoxy)-phenyl]acetic acid ethyl ester (0.084 g, 0.24 mmol) and 4-chlorobenzenesulfonyl chloride (0.060 g, 0.29 mmol) were combined in CH2Cl2 (3 mL). Triethylamine (0.05 mL, 0.36 mmol) was added, and the reaction was stirred at room temperature for 1 hour. The mixture was concentrated, and the residue was purified by silica gel chromatography (10-20% EtOAc in hexanes) to give the title compound.
Reaction SMILES: [CH3:1][C:2]([CH3:34])([CH3:33])[C:3](=[O:32])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([C:17]2[O:18][C:19]3[CH:25]=[C:24]([O:26][S:27]([CH3:30])(=[O:29])=[O:28])[CH:23]=[CH:22][C:20]=3[CH:21]=2)([CH2:15][CH3:16])[CH2:13][CH3:14])=[CH:8][C:7]=1[CH3:31].[BH4-].[Na+]>C1COCC1>[CH2:13]([C:12]([C:17]1[O:18][C:19]2[CH:25]=[C:24]([O:26][S:27]([CH3:30])(=[O:29])=[O:28])[CH:23]=[CH:22][C:20]=2[CH:21]=1)([C:9]1[CH:10]=[CH:11][C:6]([O:5][CH2:4][CH:3]([OH:32])[C:2]([CH3:33])([CH3:34])[CH3:1])=[C:7]([CH3:31])[CH:8]=1)[CH2:15][CH3:16])[CH3:14]
Reactant: CCC(CC)(c1ccc(OCC(=O)C(C)(C)C)c(C)c1)c1cc2ccc(OS(C)(=O)=O)cc2o1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCC(CC)(c1ccc(OCC(O)C(C)(C)C)c(C)c1)c1cc2ccc(OS(C)(=O)=O)cc2o1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87.9 %

Procedure:
A solution of methanesulfonic acid 2-{1-[4-(3,3-dimethyl-2-oxo-butoxy)-3-methyl-phenyl]-1-ethyl-propyl}-benzofuran-6-yl ester (34 mg, 0.069) in THF (5.0 mL) at 0° C. is treated with NaBH4 (13 mg, 0.349 mmol). The resulting mixture is stirred for 30 min at RT and quenched with HCl (1.0 N, 2.0 mL) and extracted with EtOAc (2×10 mL). The organic layer is dried over Na2SO4, concentrated to afford the title compound (30 mg, 88%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[O:21][CH3:22])[CH2:5][O:6][C:7]1[C:12]([C:13]([OH:15])=O)=[CH:11][N:10]=[C:9]([S:16][CH3:17])[N:8]=1.[CH2:23]([NH2:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C1COCC1.O>[CH2:23]([NH:30][C:13]([C:12]1[C:7]([O:6][CH2:5][C:4]2[CH:18]=[CH:19][C:20]([O:21][CH3:22])=[C:2]([Cl:1])[CH:3]=2)=[N:8][C:9]([S:16][CH3:17])=[N:10][CH:11]=1)=[O:15])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: COc1ccc(COc2nc(SC)ncc2C(=O)O)cc1Cl
Reactant: NCc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COc1ccc(COc2nc(SC)ncc2C(=O)NCc2ccccc2)cc1Cl
Yield: 21.6 %

Procedure:
4-(3-chloro-4-methoxybenzyloxy)-2-(methylmercapto)pyrimidine-5-carboxylic acid (2.2 g, 6.47 mmol), benzylamine (1.0 g, 9.34 mmol) and HATU (2.95 g, 7.76 mmol) were dissolved in 60 mL of THF, DIEA (N,N-diiso-propylethylamine, 3.36 mL, 19.41 mmol) was added dropwise, reacted at room temperature for 8 h. To the reaction solution was added 100 mL of water and then extracted with dichloromethane (50 mL×3), dried with anhydrous sodium sulfate, dried by rotation, the solid was separated with silica gel column (dichloromethane:methanol=100:1) to obtain a white solid N-benzyl-4-(3-chloro-4-methoxybenzyloxy)-2-(methylmercapto)pyrimidine-5-carboxamide 600 mg, 22% yield.
Reaction SMILES: C(O)(C(F)(F)F)=O.[NH2:8][C:9]1[N:14]=[C:13]([NH:15][CH2:16][CH2:17][CH2:18][N:19]2[CH:23]=[C:22]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=3[Cl:31])[C:21]([C:32]([O:34]C(C)(C)C)=[O:33])=[CH:20]2)[CH:12]=[CH:11][C:10]=1[N+:39]([O-:41])=[O:40].O>C(Cl)Cl>[NH2:8][C:9]1[N:14]=[C:13]([NH:15][CH2:16][CH2:17][CH2:18][N:19]2[CH:23]=[C:22]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=3[Cl:31])[C:21]([C:32]([OH:34])=[O:33])=[CH:20]2)[CH:12]=[CH:11][C:10]=1[N+:39]([O-:41])=[O:40]
Reactant: CC(C)(C)OC(=O)c1cn(CCCNc2ccc([N+](=O)[O-])c(N)n2)cc1-c1ccc(Cl)cc1Cl
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1nc(NCCCn2cc(C(=O)O)c(-c3ccc(Cl)cc3Cl)c2)ccc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
In a vial, TFA (catalytic amount) was added to a stirred mixture of tert-butyl ester pyrrole 7 (1 eq), water (.1%), and CH2Cl2 at rt. The vial stirred at room temperature until done (˜12 h. The reaction was then concentrated under reduced pressure at room temperature and dried in vacuo. The crude residue was dissolved again in CH2Cl2 and concentrated under reduced pressure at rt. The material was used in the final coupling step without further purification as the TFA salt.
Reaction SMILES: [H-].[Na+].[I-].C[S+](C)C.[CH3:8][O:9][C:10]1[CH:50]=[CH:49][C:13]([CH2:14][N:15]2[C:42](=[O:43])[C:18]3=[C:19]([CH:40]=[O:41])[CH:20]=[C:21]([N:24]([CH2:31][C:32]4[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=4)[C:25]4[CH:30]=[CH:29][N:28]=[CH:27][N:26]=4)[C:22](=[O:23])[N:17]3[C:16]32[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]3)=[CH:12][CH:11]=1.O1CCC[CH2:52]1>CS(C)=O.O>[CH3:8][O:9][C:10]1[CH:50]=[CH:49][C:13]([CH2:14][N:15]2[C:42](=[O:43])[C:18]3=[C:19]([CH:40]4[CH2:52][O:41]4)[CH:20]=[C:21]([N:24]([CH2:31][C:32]4[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=4)[C:25]4[CH:30]=[CH:29][N:28]=[CH:27][N:26]=4)[C:22](=[O:23])[N:17]3[C:16]32[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]3)=[CH:12][CH:11]=1
Reactant: C1CCOC1
Reactant: COc1ccc(CN(c2ccncn2)c2cc(C=O)c3n(c2=O)C2(CCCCC2)N(Cc2ccc(OC)cc2)C3=O)cc1
Agent: C[S+](C)C
Agent: [H-]
Agent: [I-]
Solvent: CS(C)=O
Solvent: O
Product: COc1ccc(CN(c2ccncn2)c2cc(C3CO3)c3n(c2=O)C2(CCCCC2)N(Cc2ccc(OC)cc2)C3=O)cc1
Temperature: 65 °C
Reaction time: 8 h

Procedure:
A suspension of sodium hydride (50% dispersion washed free of mineral oil, 90 mg, 1.87 mmol) in dimethylsulfoxide (2 mL) is heated to 65° C. under argon for 1 h. The oil bath is removed and to the clear solution is added tetrahydrofuran (2 mL). The solution is cooled to −15° C. and treated with a solution of trimethylsulfonium iodide (0.35 g, 1.72 mmol) in dimethylsulfoxide (2 mL). After 3 min a solution of 2′-(4-methoxybenzyl)-6′-((4-methoxybenzyl)(pyrimidin-4-yl)amino)-1′,5′-dioxo-1′,5′-dihydro-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-8′-carbaldehyde (4, 1 g, 1.72 mmol) in 3 ml. of tetrahydrofuran is added. The reaction is stirred overnight. The resulting mixture is poured into water and extracted with ethyl acetate. The extracts are washed with water, dried and evaporated to afford 2′-(4-methoxybenzyl)-6′-((4-methoxybenzyl)(pyrimidin-4-yl)amino)-8′-(oxiran-2-yl)-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione (5).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][C:9]=2[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:23])[CH:5]=[CH:6][CH:7]=1.C[Si]([N:34]=[C:35]=[O:36])(C)C>>[C:22]([C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:8]=1[C:4]1[CH:3]=[C:2]([NH:1][C:35]([NH2:34])=[O:36])[CH:7]=[CH:6][CH:5]=1)=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]([F:21])([F:19])[F:20])(=[O:23])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: C[Si](C)(C)N=C=O
Reactant: Nc1cccc(-c2c(C(=O)c3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Product: NC(=O)Nc1cccc(-c2c(C(=O)c3ccccc3)cnc3c(C(F)(F)F)cccc23)c1

Procedure:
The title compound was prepared from [4-(3-amino-phenyl)-8-trifluoromethyl-quinolin-3-yl]-phenyl-methanone and trimethylsilyl isocyanate according to the procedure of Example 65. HRMS: calcd for C24H16F3N3O2, 435.1195; found (ESI, [M+H]+), 436.1258.
Reaction SMILES: [CH3:1][NH:2][S:3]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][CH:8]=1)(=[O:5])=[O:4].[H][H].[ClH:18]>C(O)C.O.[Pd]=O>[ClH:18].[NH2:13][C:10]1[CH:11]=[CH:12][C:7]([CH2:6][S:3]([NH:2][CH3:1])(=[O:5])=[O:4])=[CH:8][CH:9]=1
Reactant: CNS(=O)(=O)Cc1ccc([N+](=O)[O-])cc1
Reactant: [H][H]
Agent: O=[Pd]
Agent: Cl
Solvent: CCO
Solvent: O
Product: CNS(=O)(=O)Cc1ccc(N)cc1

Procedure:
A suspension of N-methyl-4-nitrobenzenemethanesulphonamide (30 g) in ethanol (150 ml), water (300 ml) and hydrochloric acid (2N, 65 ml) was hydrogenated over 10% palladium oxide on charcoal (7.5 g, 50% paste with water) until hydrogen uptake ceased (9.75 l). The catalyst was removed by filtration through "hyflo" and the filter pad was washed with water (30 ml). The filtrate was evaporated under reduced pressure to give the title compound as a pale yellow powder (28.2 g) m.p. 143°-144° C.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:15]=[CH:14][C:10]([CH2:11][CH2:12][OH:13])=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.C(N(C(C)C)CC)(C)C.[CH3:25][S:26](Cl)(=[O:28])=[O:27].C(=O)([O-])O.[Na+]>ClCCl>[S:26]([O:13][CH2:12][CH2:11][C:10]1[CH:9]=[CH:8][C:7]([N:4]2[CH2:3][CH2:2][O:1][CH2:6][CH2:5]2)=[CH:15][CH:14]=1)(=[O:28])(=[O:27])[CH3:25]
Reactant: CS(=O)(=O)Cl
Reactant: OCCc1ccc(N2CCOCC2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)OCCc1ccc(N2CCOCC2)cc1
Reaction time: 4 h

Procedure:
4-Morpholinophenethyl alcohol (2.35 g, 11.3 mmol) was dissolved in dichloromethane (20 ml). Diisopropylethylamine (2.60 ml, 14.8 mmol) and methanesulfonyl chloride (1.11 ml, 14.8 mmol) were added to the obtained solution at 0° C., and they were stirred for 4 hours. The reaction mixture was distributed into 5% aqueous sodium hydrogencarbonate solution and dichloromethane. The organic layer was dried and the solvent was evaporated under reduced pressure. The residue was subjected to the silica gel column chromatography. After the elution with hexane and ethyl acetate (3:1) and then with them (1:1) as the eluents, suitable fractions were collected and the solvent was evaporated under reduced pressure to obtain 4-morpholinophenethyl mesylate in the form of a white solid (2.60 g, 81%).
Reaction SMILES: C(OC(C1C=C2SCCN2N=1)=O)C.C([O:16][C:17]([C:19]1[CH:20]=[N:21][N:22]2[CH2:26][CH2:25][S:24][C:23]=12)=O)C.[H-].[H-].[H-].[H-].[Li+].[Al+3]>O1CCCC1>[S:24]1[CH2:25][CH2:26][N:22]2[N:21]=[CH:20][C:19]([CH2:17][OH:16])=[C:23]12
Reactant: CCOC(=O)c1cnn2c1SCC2
Agent: CCOC(=O)c1cc2n(n1)CCS2
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: OCc1cnn2c1SCC2
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To the mixture [21.2 g (0.11 mol)] of 2,3-dihydropyrazolo[5,1-b]thiazol-6-carboxylic acid ethyl ester and 2,3-dihydropyrazolo[5,1-b]thiazol-7-carboxylic acid ethyl ester in 540 ml of dry tetrahydrofuran was added LiAlH4 (4.05 g, 0.11 mol) under a nitrogen atmosphere at 0° C., and then stirred for 2.5 hours at room temperature. The mixture was quenched with water (15 ml) and the precipitate was filtered through a pad of Celite. The pad was washed with water (100 ml) and tetrahydrofuran (500 ml). The filtrate was concentrated under reduced pressure, and then water (150 ml) was added. The aqueous layer was extracted with dichloromethane (15×250 ml). The combined organic layers were dried (MgSO4) and filtered. The filtrate was concentrated under reduced pressure and a mixture of (2,3-dihydropyrazolo[5,1-b]thiazol-6-yl) methanol and (2,3-dihydropyrazolo[5,1-b]thiazol-7-yl) methanol was obtained as pale brown oil (15.5 g).
Reaction SMILES: [OH:1][CH:2]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:3][CH2:4][CH2:5][C:6]([N:8]1[CH:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:11][O:10][C:9]1=[O:19])=[O:7].N1C=CN=C1.[C:31]([Si:35](Cl)([CH3:37])[CH3:36])([CH3:34])([CH3:33])[CH3:32]>CN(C=O)C>[C:31]([Si:35]([CH3:37])([CH3:36])[O:1][CH:2]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:3][CH2:4][CH2:5][C:6]([N:8]1[CH:12]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:11][O:10][C:9]1=[O:19])=[O:7])([CH3:34])([CH3:33])[CH3:32]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=C(CCCC(O)c1ccccc1)N1C(=O)OCC1c1ccccc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OC(CCCC(=O)N1C(=O)OCC1c1ccccc1)c1ccccc1
Temperature: 25 °C

Procedure:
30 g of 3-(5-Hydroxy-5-phenyl-pentanoyl)-4-phenyl-oxazolidin-2-on are solved in 50 ml of DMF. After addition of 14.3 g of imidazol and 19 g of tert.-Butyl-dimethylsilylchlorid in 25 ml of DMF the reaction is stirred at room temperature until all components are dissolved (2-4 h). The reaction solution is evaporated, and after water was added extracted by acetic acid ethylester. After drying of the organic phase by magnesium sulfate and evaporation compound 1 is obtained: C26H35NO4Si (453.6) MS (ESI+) 476 (M+Na+).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([CH:7]=O)[N:4]=[N:3]1.[CH3:9][O:10][C:11]([CH:13]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:12]>ClCCl>[CH3:9][O:10][C:11](=[O:12])/[CH:13]=[CH:7]/[C:5]1[N:4]=[N:3][N:2]([CH3:1])[CH:6]=1
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cn1cc(C=O)nn1
Solvent: ClCCl
Product: COC(=O)/C=C/c1cn(C)nn1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 212.7 %

Procedure:
1-Methyl-1,2,3-triazol-4-carboxaldehyde (1 g, 9 mmol) was added to a solution of methoxycarbonylmethylene triphenylphosphorane (4.5 g, 13.5 mmol) in dichloromethane (50 ml) and stirred at room temperature for 3.5 hours. The solvent was removed and the residue purified by silica gel chromatography to afford the title compound, (3.2 g).
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][C:15]=1[F:16])[CH2:11][OH:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:17][C:18]1([CH3:34])[CH:20]([CH:21]=[C:22]([CH3:30])[C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)[CH:19]1[C:31](Cl)=[O:32].N1C=CC=CC=1.Cl>C1(C)C=CC=CC=1.O>[O:1]([C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][C:15]=1[F:16])[CH2:11][O:12][C:31]([CH:19]1[CH:20]([CH:21]=[C:22]([CH3:30])[C:23]2[CH:24]=[CH:25][C:26]([Cl:29])=[CH:27][CH:28]=2)[C:18]1([CH3:34])[CH3:17])=[O:32])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=CC1C(C(=O)Cl)C1(C)C)c1ccc(Cl)cc1
Reactant: OCc1ccc(F)c(Oc2ccccc2)c1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: O
Solvent: c1ccncc1
Product: CC(=CC1C(C(=O)OCc2ccc(F)c(Oc3ccccc3)c2)C1(C)C)c1ccc(Cl)cc1
Reaction time: 3 h
Yield: 74.8 %

Procedure:
5.4 g (0.025 mol) of 3-phenoxy-4-fluoro-benzyl alcohol and 7 g (0.025 mol) of 2,2-dimethyl-3-(2-methyl-2-(4-chlorophenyl)-vinyl)-cyclopropanecarboxylic acid chloride were dissolved in 100 ml of anhydrous toluene, and 2.5 g of pyridine, dissolved in 50 ml of anhydrous toluene, were added dropwise at 20°-25° C., while stirring. Stirring was then continued at 25°-35° C. for a further 3 hours. The reaction mixture was poured into 150 ml of water, to which 5 ml of concentrated hydrochloric acid were added, and the organic phase was separated off and washed again with 100 ml of water. The toluene phase was then dried over sodium sulphate and the solvent was distilled off under a waterpump vacuum. Last residues of solvent were removed by brief incipient distillation at a bath temperature of 60° C./1 mm Hg. 8.7 g (74.9% of theory) of 2,2-dimethyl-3-(2-methyl-2-(4-chlorophenyl)-vinyl)-cyclopropane-carboxylic acid 3-phenoxy-4-fluoro-benzyl ester were obtained as a yellow viscous oil with the refractive index nD23 : 1.5735.
Reaction SMILES: [Br:1][C:2]1[N:3]=[CH:4][NH:5][CH:6]=1.[H-].[Na+].[N+:9]([C:12]1[CH:13]=[C:14](F)[CH:15]=[CH:16][CH:17]=1)([O-:11])=[O:10]>CN(C=O)C>[Br:1][C:2]1[N:3]=[CH:4][N:5]([C:16]2[CH:15]=[CH:14][CH:13]=[C:12]([N+:9]([O-:11])=[O:10])[CH:17]=2)[CH:6]=1
Reactant: O=[N+]([O-])c1cccc(F)c1
Reactant: Brc1c[nH]cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cccc(-n2cnc(Br)c2)c1
Temperature: 150 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-bromo-imidazole (32 g; 217.7 mmol) in DMF (300 mL) was carefully added NaH (60% dispension; 10.8 g; 270 mmol) such that the temperature did not exceed 30° C. The slurry was stirred for 20 min after which 3-nitro-fluorobenzene 35 mL; 329 mmol) was added. The reaction mixture was stirred for another 30 min, heated to 150° C. and left with stirring overnight. The reaction mixture was poured onto 750 mL of ice-water under stirring. The precipitate was isolated by filtration, washed with H2O, air-dried and trituated with a diethyl ether-petrol ether (bp=80-100° C.) mixture (100 mL+100 mL) to give after filtration and drying of the solid 70 g crude product.
Reaction SMILES: I[C:2]1[C:3]([NH:17][CH3:18])=[N:4][C:5]([NH:8][C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=2)=[N:6][CH:7]=1.[CH3:19][N:20]([C@@H:28]([CH3:37])[C:29](=[O:36])[NH:30][CH2:31][CH2:32][CH2:33][C:34]#[CH:35])[C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24]>>[C:13]([C:12]1[CH:15]=[CH:16][C:9]([NH:8][C:5]2[N:4]=[C:3]([NH:17][CH3:18])[C:2]([C:35]#[C:34][CH2:33][CH2:32][CH2:31][NH:30][C:29](=[O:36])[C@@H:28]([N:20]([CH3:19])[C:21](=[O:27])[O:22][C:23]([CH3:24])([CH3:26])[CH3:25])[CH3:37])=[CH:7][N:6]=2)=[CH:10][CH:11]=1)#[N:14]
Reactant: C#CCCCNC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C
Reactant: CNc1nc(Nc2ccc(C#N)cc2)ncc1I
Product: CNc1nc(Nc2ccc(C#N)cc2)ncc1C#CCCCNC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C

Procedure:
By using 4-((5-iodo-4-(methylamino)pyrimidin-2-yl)amino)benzonitrile (F224) and (S)-tert-butyl methyl(1-oxo-1-(4-pentyn-1-ylamino)propan-2-yl)carbamate (U4), (S)-tert-butyl (1-((5-(2-((4-cyanophenyl)amino)-4-(methylamino)pyrimidin-5-yl)-4-pentyn-1-yl)amino)-1-oxopropan-2-yl)(methyl)carbamate (J17) was obtained in the same manner as that of Example 38, (2).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:12]3[C:21]4[C:16](=[CH:17][CH:18]=[C:19]([O:22][CH2:23][CH2:24][CH2:25][S:26]([NH:29][CH2:30][CH2:31][CH3:32])(=[O:28])=[O:27])[CH:20]=4)[CH2:15][CH2:14][N:13]=3)[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[BH4-].[Na+].Cl>CO.O.C(O)(C)C>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH:12]3[C:21]4[C:16](=[CH:17][CH:18]=[C:19]([O:22][CH2:23][CH2:24][CH2:25][S:26]([NH:29][CH2:30][CH2:31][CH3:32])(=[O:27])=[O:28])[CH:20]=4)[CH2:15][CH2:14][NH:13]3)[CH2:9][CH2:10][CH2:11]2)=[CH:4][CH:3]=1
Reactant: CCCNS(=O)(=O)CCCOc1ccc2c(c1)C(C1(c3ccc(Cl)cc3)CCC1)=NCC2
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: CC(C)O
Product: CCCNS(=O)(=O)CCCOc1ccc2c(c1)C(C1(c3ccc(Cl)cc3)CCC1)NCC2
Reaction time: 0.5 h

Procedure:
3-({1-[1-(4-Chlorophenyl)cyclobutyl]-3,4-dihydroisoquinolin-7-yl}oxy)-N-propylpropane-1-sulfonamide (260 mg, 0.547 mmol) was dissolved in methanol (5 mL) and water (0.2 mL). Sodiumborohydride (41.4 mg, 1.095 mmol) was added in small portions at room temperature and the reaction mixture was stirred over night. 5N Hydrochloric acid in isopropanol was added until the reaction mixture became acidic. Stirring was continued for 30 min at room temperature. The reaction mixture was concentrated in vacuo. The crude product was dissolved in dichloromethane. Aqueous saturated NaHCO3 solution (10 mL) and water (10 mL) were added and the aqueous layer was extracted with dichloromethane (2×). The combined organic layers were dried (MgSO4) and concentrated in vacuo. The crude product was purified by flash chromatography (silica, first dichloromethane, then dichloromethane:methanol=80:1). The purified product was treated with 2N hydrochloric acid in diethylether. The diethylether was removed by destillation. Yield: 120 mg (0.234 mmol, 42.7%, colorless foam).
Reaction SMILES: [CH2:1]([O:8][NH:9][C:10]([C:12]1[C:13](Cl)=[N:14][C:15]([Cl:19])=[C:16]([F:18])[CH:17]=1)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[F:23][C:24]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:25]=1[N:31]=[C:32]=[O:33]>CC(N(C)C)=O>[CH2:1]([O:8][N:9]1[C:10](=[O:11])[C:12]2[CH:17]=[C:16]([F:18])[C:15]([Cl:19])=[N:14][C:13]=2[N:31]([C:25]2[CH:26]=[CH:27][C:28]([F:30])=[CH:29][C:24]=2[F:23])[C:32]1=[O:33])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C=Nc1ccc(F)cc1F
Reactant: O=C(NOCc1ccccc1)c1cc(F)c(Cl)nc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: O=c1c2cc(F)c(Cl)nc2n(-c2ccc(F)cc2F)c(=O)n1OCc1ccccc1
Yield: 82.9 %

Procedure:
Using the General Method 5, the reaction of N-benzyloxy-2,6-dichloro-5-fluoro-3-pyridinecarboxamide (Example M-2, 2.00 g, 6.34 mmol) and 60% NaH in oil (300 mg, 7.52 mmol) with 2,4-difluorophenyl isocyanate (1.13 mL, 9.51 mmol) in DMA afforded 2.28 g of the title compound as a solid, mp 215-216° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:18])[CH2:17][CH2:16][C:11]3(OCC[O:12]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.Cl>CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([OH:18])[CH2:9][CH2:10][C:11](=[O:12])[CH2:16][CH2:17]2)=[CH:6][CH:7]=1
Reactant: OC1(c2ccc(F)cc2)CCC2(CC1)OCCO2
Agent: Cl
Solvent: CO
Product: O=C1CCC(O)(c2ccc(F)cc2)CC1
Reaction time: 78 h
Yield: 80 %

Procedure:
A solution of 8-(4-fluorophenyl)-1,4-dioxaspiro[4.5]decan-8-ol (8.6 g, 36 mmole) in a mixture of 50% aqueous methanol and concentrated HCl (3 ml) was stirred for 78 hr. The methanol was removed in vacuo without heating and the residue extracted with ether. The extracts were dried with Na2SO4 and the solvent removed in vacuo to give the product (6.0 g, 86%, mp: 118-119° C.). Calc'd for C12H13FO2 : C, 69.22%; H, 6.30%. Found: C, 69.32%; H, 6.34%.
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:51])[NH:5][C:6]1[N:11]=[CH:10][C:9]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[N:18]([CH2:22][CH:23]2[CH2:27][CH2:26][N:25]([CH2:28][CH2:29][N:30]4[CH2:35][CH2:34][O:33][CH2:32][CH2:31]4)[CH2:24]2)[CH:17]=[C:16]([C:36]([O:38]CC)=[O:37])[C:15]3=[O:41])=[C:8]([C:42]2[S:43][CH:44]=[C:45]([C:47]([F:50])([F:49])[F:48])[N:46]=2)[CH:7]=1)[CH3:2].[OH-].[Na+]>CO.O1CCCC1>[CH2:1]([NH:3][C:4](=[O:51])[NH:5][C:6]1[N:11]=[CH:10][C:9]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[N:18]([CH2:22][CH:23]2[CH2:27][CH2:26][N:25]([CH2:28][CH2:29][N:30]4[CH2:35][CH2:34][O:33][CH2:32][CH2:31]4)[CH2:24]2)[CH:17]=[C:16]([C:36]([OH:38])=[O:37])[C:15]3=[O:41])=[C:8]([C:42]2[S:43][CH:44]=[C:45]([C:47]([F:50])([F:48])[F:49])[N:46]=2)[CH:7]=1)[CH3:2]
Reactant: CCNC(=O)Nc1cc(-c2nc(C(F)(F)F)cs2)c(-c2ccc3c(c2)c(=O)c(C(=O)OCC)cn3CC2CCN(CCN3CCOCC3)C2)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCNC(=O)Nc1cc(-c2nc(C(F)(F)F)cs2)c(-c2ccc3c(c2)c(=O)c(C(=O)O)cn3CC2CCN(CCN3CCOCC3)C2)cn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 82.6 %

Procedure:
Ethyl 6-(6-(3-ethylureido)-4-(4-(trifluoromethyl)thiazol-2-yl)pyridin-3-yl)-1-((1-(2-morpholinoethyl)pyrrolidin-3-yl)methyl)-4-oxo-1,4-dihydroquinoline-3-carboxylate (Example 240, 340 mg) was dissolved in methanol (3 mL) and tetrahydrofuran (3 mL). To this solution was added 24 wt % sodium hydroxide (1 mL) and the reaction mixture was stirred at room temperature for 3 h. The solution was concentrated under reduced pressure to remove the organics. Water (7 mL) was added and the aqueous layer was carefully acidified to pH˜3 with 1N hydrochloric acid. A solid precipitated, and the mixture was centrifuged to help collect the solid which was then washed with cold water once and dried to give a light yellow solid (270 mg, 81.2%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([S:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=2)=[C:7]([CH:9]=1)[NH2:8].[O:21]1[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=2[CH:23]=[C:22]1[S:30](Cl)(=[O:32])=[O:31]>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([S:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=2)=[C:7]([NH:8][S:30]([C:22]2[O:21][C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=3[CH:23]=2)(=[O:31])=[O:32])[CH:9]=1
Reactant: O=S(=O)(Cl)c1cc2ccccc2o1
Reactant: COc1ccc(SCc2cccc([N+](=O)[O-])c2)c(N)c1
Solvent: c1ccncc1
Product: COc1ccc(SCc2cccc([N+](=O)[O-])c2)c(NS(=O)(=O)c2cc3ccccc3o2)c1
Yield: 55.6 %

Procedure:
Following General Procedure B, the title compound (406 mg, 56%) was prepared from 5-methoxy-2-((3-nitrobenzyl)thio)aniline (450 mg, 1.552 mmol) and benzofuran-2-sulfonyl chloride (335 mg, 1.552 mmol) in pyridine (5 ml).