Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:20])=[C:6]([CH:19]=1)[CH2:7][N:8]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]1=[O:18].Cl.[N:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28]Cl)[CH:23]=1.[H-].[Na+]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:20][CH2:28][C:24]2[CH:23]=[N:22][CH:27]=[CH:26][CH:25]=2)=[C:6]([CH:19]=1)[CH2:7][N:8]1[C:9](=[O:18])[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:16]1=[O:17]
Reactant: ClCc1cccnc1
Reactant: O=C1c2ccccc2C(=O)N1Cc1cc(Cl)ccc1O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1Cc1cc(Cl)ccc1OCc1cccnc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of 2-[5-chloro-2-hydroxy benzyl]isoindole-1,3-dione (300 mg, 1.04 mmol), and 3-picolylchloride hydrochloride (171 mg, 1.04 mmol) in anhydrous N,N-dimethylformamide (10 mL), cooled to 0° C., was added a 60% dispersion of sodium hydride in oil (104 mg, 2.6 mmol). The reaction was stirred at room temperature under anhydrous conditions for 15 h. The reaction was quenched by the addition of H2O (5 mL) and then poured into a separatory funnel, and aqueous saturated NaHCO3 solution (50 mL) was added. The aqueous layer was extracted 3×50 mL with CH2Cl2. The organics were combined and washed with saturated aqueous NaCl solution (100 mL), dried over MgSO4, filtered, and concentrated on a rotary evaporator triturated with ether, filtered and dried to yield the title compound.
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][N:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6]1.[NH3:15]>CCO>[NH2:15][CH2:3][C@H:2]([OH:1])[CH2:4][N:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6]1
Reactant: c1ccc2c(c1)CCN(C[C@@H]1CO1)C2
Reactant: N
Solvent: CCO
Product: NC[C@H](O)CN1CCc2ccccc2C1
Temperature: 80 °C
Yield: 92 %

Procedure:
To a solution of (R)-2-(oxiran-2-ylmethyl)-1,2,3,4-tetrahydroisoquinoline (15 g, 0.08 mol) in EtOH (100 mL) at −78° C. was slowly bubbled NH3 (g). The reaction mixture was then sealed and heated at 80° C. for 3 h. The reaction mixture was concentrated and the crude product was used in next step without further purification (15 g, Yield 92%). LCMS (m/z): 207.1 (M+1).
Reaction SMILES: C[O:2][C:3](=[O:23])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:5]=1[CH2:11][CH2:12][C:13]1[C:21]2[O:20][CH:19]=[CH:18][C:17]=2[CH:16]=[C:15](Br)[CH:14]=1.[C:24]([Cu])#[N:25]>CN(C=O)C.CCOC(C)=O>[C:24]([C:15]1[CH:14]=[C:13]([CH2:12][CH2:11][C:5]2[C:6]([F:10])=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([OH:2])=[O:23])[C:21]2[O:20][CH:19]=[CH:18][C:17]=2[CH:16]=1)#[N:25]
Reactant: COC(=O)c1cccc(F)c1CCc1cc(Br)cc2ccoc12
Reactant: N#C[Cu]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N#Cc1cc(CCc2c(F)cccc2C(=O)O)c2occc2c1
Temperature: 25 °C
Yield: 48.8 %

Procedure:
To a solution of 2-[2-(5-bromo-benzofuran-7-yl)-ethyl]-3-fluoro-benzoic acid methyl ester (1.5 g, 1.0 equiv) in DMF (16 mL) was added CuCN (0.7 g, 2.0 equiv). The resulting reaction mixture was allowed to heat for 16 hr before additional CuCN (0.7 g, 2.0 equiv) was added. After heating for 6 hr, the reaction mixture was allowed to cool to room temperature, diluted with EtOAc and filtered through celite. The filtrate was washed with saturated aqueous NaHCO3 and water and then dried over MgSO4, filtered, and concentrated. Purification of the residue by column chromatography (SiO2, EtOAc/hexane) gave the desired nitrile (0.6 g, 50%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:14][C:15]2[CH:19]=[C:18]([CH3:20])[NH:17][N:16]=2)[N:3]=1.[C:21]([NH:24][C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1)(=[O:23])[CH3:22]>>[CH3:20][C:18]1[NH:17][N:16]=[C:15]([NH:14][C:4]2[N:3]=[C:2]([C:28]3[CH:29]=[CH:30][C:25]([NH:24][C:21](=[O:23])[CH3:22])=[CH:26][CH:27]=3)[C:11]3[C:6]([CH:5]=2)=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=3)[CH:19]=1
Reactant: COc1ccc2c(Cl)nc(Nc3cc(C)[nH]n3)cc2c1
Reactant: CC(=O)Nc1ccc(B(O)O)cc1
Product: COc1ccc2c(-c3ccc(NC(C)=O)cc3)nc(Nc3cc(C)[nH]n3)cc2c1

Procedure:
Similar procedure as described in example 131 was used, starting from (1-chloro-6-methoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine and 4-acetylamino-phenylboronic acid to give N-{4-[3-(5-methyl-1H-pyrazol-3-ylamino)-6-methoxy-isoquinolin-1-yl]-phenyl}-acetamide. LC-MS m/e 388(MH+).
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[C:5]([C:24]2[CH:25]=[C:26]3[C:30](=[CH:31][CH:32]=2)[N:29]([CH2:33][CH2:34][OH:35])[CH:28]=[CH:27]3)=[CH:6][C:7]2[N:11]=[C:10]([O:12][C:13]3[CH:14]=[CH:15][C:16]([CH3:22])=[C:17]([CH:21]=3)[C:18]([OH:20])=[O:19])[NH:9][C:8]=2[CH:23]=1>CC(O)=O>[Cl:3][C:4]1[C:5]([C:24]2[CH:25]=[C:26]3[C:30](=[CH:31][CH:32]=2)[N:29]([CH2:33][CH2:34][OH:35])[CH2:28][CH2:27]3)=[CH:6][C:7]2[N:11]=[C:10]([O:12][C:13]3[CH:14]=[CH:15][C:16]([CH3:22])=[C:17]([CH:21]=3)[C:18]([OH:20])=[O:19])[NH:9][C:8]=2[CH:23]=1
Reactant: Cc1ccc(Oc2nc3cc(-c4ccc5c(ccn5CCO)c4)c(Cl)cc3[nH]2)cc1C(=O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1ccc(Oc2nc3cc(-c4ccc5c(c4)CCN5CCO)c(Cl)cc3[nH]2)cc1C(=O)O
Temperature: 25 °C

Procedure:
NaBH4 (22 mg, 0.585 mmol) was added to a solution of 5-({6-chloro-5-[1-(2-hydroxyethyl)-1H-indol-5-yl]-1H-benzimidazol-2-yl}oxy)-2-methylbenzoic acid (30 mg, 0.065 mmol, Example 263) in AcOH (1 mL). The reaction was maintained overnight at ambient temperature, quenched with 2 N aqueous HCl and concentrated. The residue was partitioned between EtOAc and H2O. The aqueous phase was extracted with EtOAc. The combined organic layers were washed with brine, dried (MgSO4), filtered and concentrated. Purification of the resulting residue by reverse phase HPLC eluting with 35-100% MeCN/water) afforded the title compound. LC-MS: calculated for C25H22ClN3O4 463.91, observed m/e 464.3 (M+H)+ (Rt 1.60 min).
Reaction SMILES: [CH3:1][SH:2].[N:3]1[C:10]([Cl:11])=[N:9][C:7]([Cl:8])=[N:6][C:4]=1Cl.N1C(C)=CC(C)=CC=1C.Cl.N1C(C)=CC(C)=CC=1C>CC(C)=O>[CH3:1][S:2][C:4]1[N:6]=[C:7]([Cl:8])[N:9]=[C:10]([Cl:11])[N:3]=1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: CS
Agent: Cl
Solvent: CC(C)=O
Solvent: Cc1cc(C)nc(C)c1
Product: CSc1nc(Cl)nc(Cl)n1
Reaction time: 1 h

Procedure:
Methanethiol is passed into a solution of 18.5 g of cyanuric chloride in 200 ml of acetone at a temperature of -25° to -30° C. 13.5 ml of collidine are then added slowly at the same temperature, whereupon collidine hydrochloride precipitates. The mixture is left to stand for 1 hour at 0° C. and is then poured onto ice, whereupon a white crystalline substance precipitates. After filtering the mixture, washing the product with water and drying it in a desiccator, 17.5 g of 2-methylthio-4,6-dichloro-1,3,5-triazine with a melting point of 57° to 59° C. are obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9][CH2:10][CH:11]1[NH:15][CH2:14][CH2:13][S:12]1.[C:16]([CH2:19][C:20](Cl)=[S:21])(=[O:18])[CH3:17]>N1C=CC=CC=1.OS(O)(=O)=O>[C:16]([CH2:19][C:20]([N:15]1[CH2:14][CH2:13][S:12][CH:11]1[CH2:10][S:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[O:2][CH3:1])=[S:21])(=[O:18])[CH3:17]
Reactant: CC(=O)CC(=S)Cl
Reactant: COc1ccccc1SCC1NCCS1
Agent: O=S(=O)(O)O
Solvent: c1ccncc1
Product: COc1ccccc1SCC1SCCN1C(=S)CC(C)=O

Procedure:
A solution of 2-(o-methoxyphenylthio)methyl-thiazolidine (5 g) in pyridine (25 ml) is reacted with acetylthioacetylchloride (2.93 g) for a night at room temperature, the reaction mixture is diluted with 2N H2SO4, extracted with ethylether to give after the usual work-up 3α-acetylthioacetyl-2-(o-methoxyphenylthio)methyl-thiazolidine, m.p. 62°-64° C.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]([C:9]2[N:10]=[C:11]([N:14]3[CH2:17][CH:16](OS(C)(=O)=O)[CH2:15]3)[S:12][CH:13]=2)=[O:8])[CH2:3][CH2:2]1.[C:23]([O-:26])(=[S:25])[CH3:24].[K+]>CN(C)C=O>[C:23]([S:25][CH:16]1[CH2:15][N:14]([C:11]2[S:12][CH:13]=[C:9]([C:7]([N:4]3[CH2:3][CH2:2][O:1][CH2:6][CH2:5]3)=[O:8])[N:10]=2)[CH2:17]1)(=[O:26])[CH3:24]
Reactant: CC([O-])=S
Reactant: CS(=O)(=O)OC1CN(c2nc(C(=O)N3CCOCC3)cs2)C1
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)SC1CN(c2nc(C(=O)N3CCOCC3)cs2)C1
Temperature: 80 °C
Reaction time: 18 h
Yield: 64 %

Procedure:
To a solution of 1-(4-morpholinocarbonyl-1,3-thiazol-2-yl)-3-methanesulfonyloxyazetidine (680 mg, 1.96 mmol) (obtained as described in Reference Example 11(3)) in dimethylformamide (20 ml) was added potassium thioacetate (671 mg, 5.87 mmol) at room temperature, and then the reaction mixture was stirred in an oil bath (80° C.) for 18 hours. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and 10% aqueous sodium chloride solution. The obtained organic layer was washed successively with saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using n-hexane:ethyl acetate (1:3)→ethyl acetate as the eluant to afford 3-acetylthio-1-(4-morpholinocarbonyl-1,3-thiazol-2-yl)azetidine (411 mg, yield 64%) as a pale brown solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[CH2:5][N:6]=[C:7]=[S:8].[CH:12]([NH:14][NH2:15])=[O:13]>C(O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[CH2:5][NH:6][C:7](=[S:8])[NH:15][NH:14][CH:12]=[O:13]
Reactant: NNC=O
Reactant: Fc1cccc(CN=C=S)c1
Solvent: CCO
Product: O=CNNC(=S)NCc1cccc(F)c1
Yield: 22.4 %

Procedure:
3-Fluorobenzyl isothiocyanate (4.3 g, 25.5 mmole) and formyl hydrazine (1.7 g, 28.7 mole) were refluxed in ethanol (30 ml) for one hour. The reaction mixture was evaporated to dryness, triturated with hexane:ethyl acetate (1:1), filtered, and recrystallized from ethanol-hexane to yield 1.3 g (22%) of crude 4-(3'-fluorobenzyl)-1-formyl-3-thiosemicarbazide.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[C:8]([C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1)[N:7]=[C:6]2[C:22]([OH:24])=O.Cl.[CH3:26][O:27][C:28]1[CH:29]=[C:30]2[C:35](=[CH:36][CH:37]=1)[CH2:34][NH:33][CH2:32][CH2:31]2>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[C:8]([C:15]1[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=1)[N:7]=[C:6]2[C:22]([N:33]1[CH2:32][CH2:31][C:30]2[C:35](=[CH:36][CH:37]=[C:28]([O:27][CH3:26])[CH:29]=2)[CH2:34]1)=[O:24]
Reactant: COc1cc2nc(-c3ccc(F)cc3)nc(C(=O)O)c2cc1OC
Reactant: COc1ccc2c(c1)CCNC2
Agent: Cl
Product: COc1ccc2c(c1)CCN(C(=O)c1nc(-c3ccc(F)cc3)nc3cc(OC)c(OC)cc13)C2
Yield: 19.2 %

Procedure:
Reaction of 6,7-dimethoxy-2-(4-fluorophenyl)quinazoline-4-carboxylic acid with 6-methoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride gave compound 111 (19.2% yield). 1H NMR (400 MHz, DMSO-d6) δ 2.81 and 3.05 (2t, 2H), 3.48-4.06 (m, 11H), 4.41 and 4.93 (2s, 2H), 6.66-6.92 (m, 3H), 7.14-7.27 (m, 1H), 7.37-7.41 (m, 1H), 7.51 and 7.54 (2s, 1H), 7.59-7.63 (m, 1H), 8.15-8.20 (m, 1H), 8.31-8.35 (m, 1H); 19F (376 MHz, DMSO-d6) δ −113.0; MS (ESI) m/z 474 ([M+H]+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[CH:9][C:10]=2[C:11]([O:13]CC)=[O:12])[CH:7]=1.[OH-].[Li+:17]>O.CO.C1COCC1>[F:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[CH:9][C:10]=2[C:11]([O-:13])=[O:12])[CH:7]=1.[Li+:17]
Reactant: CCOC(=O)c1cnn2cc(F)cnc12
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: O=C([O-])c1cnn2cc(F)cnc12
Yield: 108.4 %

Procedure:
A suspension of ethyl 6-fluoropyrazolo[1,5-a]pyrimidine-3-carboxylate (512 mg, 2.45 mmol) and lithium hydroxide (61.5 mg, 2.57 mmol) in water (1 ml), MeOH (1 ml) and THF (1 ml) was irradiated to 100° C. for 10 min in the microwave. The reaction mixture was concentrated under vacuum, azeotroping with toluene (10 ml) to leave the title compound as a yellow powder (497 mg). This crude material was used directly in the subsequent reactions.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:12]=[CH:11][CH:10]=[C:9]([OH:13])[C:6]=1[CH:7]=[O:8])(=[O:3])[CH3:2].Br[CH2:15][CH2:16][CH2:17][CH2:18][C:19]([O:21]CC)=[O:20].C(=O)([O-])[O-].[K+].[K+].[I-].[Na+]>C(O)C>[C:1]([NH:4][C:5]1[C:6]([CH:7]=[O:8])=[C:9]([CH:10]=[CH:11][CH:12]=1)[O:13][CH2:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20])(=[O:3])[CH3:2]
Reactant: CCOC(=O)CCCCBr
Reactant: CC(=O)Nc1cccc(O)c1C=O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCO
Product: CC(=O)Nc1cccc(OCCCCC(=O)O)c1C=O
Reaction time: 16 h

Procedure:
2-Acetylamino-6-hydroxybenzaldehyde (0.895 g, 0.005 M), ethyl 5-bromopentanoate (1.05 g. 0.005 M), anhydrous potassium carbonate (0.76 g), sodium iodide (50 mg) and 95% ethanol (20 ml) were refluxed with stirring for 16 hr. The cooled reaction mixture was filtered and the solid washed well with ethanol. The filtrate was evaporated to dryness and the residue partitioned between ether and water. The organic layer was separated and washed with 2 M sodium hydroxide solution, water, dried (sodium sulphate) and evaporated. The residue (ethyl 5-(3-acetylamino-2-formylphenoxy)pentanoate) was dissolved in 95% ethanol (20 ml) and treated with stirring over 1 hr with 1 N sodium hydroxide (4.5 ml), and then stirred at room temperature (2 hours). The solution was evaporated to one-third volume, diluted with water (10 ml) and acidified with concentrated hydrochloric acid with cooling. The precipitated solid was filtered off, washed well with water and recrystallised from benzene/petrol (charcoal) to give 5-(3-acetylamino- 2-formylphenoxy)pentanoic acid, m.p. 119°-121° C. (Found: C, 60.55; H, 6.26; N, 4.88%. C14H17NO5 requires C, 60.22; H, 6.09; N, 5.02%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][C:5]([Br:9])=[CH:4][N:3]=1.[Cl:10][C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=1)[C:14](O)=O.[OH-].[Na+]>>[Br:9][C:5]1[CH:6]=[C:7]2[NH:8][C:14]([C:13]3[CH:17]=[CH:18][CH:19]=[C:11]([Cl:10])[CH:12]=3)=[N:1][C:2]2=[N:3][CH:4]=1
Reactant: O=C(O)c1cccc(Cl)c1
Reactant: Nc1cc(Br)cnc1N
Agent: [Na+]
Agent: [OH-]
Product: Clc1cccc(-c2nc3ncc(Br)cc3[nH]2)c1
Temperature: 170 °C
Reaction time: 2 h
Yield: 69.2 %

Procedure:
A mixture of 2,3-diamino-5-bromopyridine (Compound of Reference Example 1) (1.32 g), 3-chlorobenzoic acid (1.10 g) and polyphosphoric acid (30 g) was stirred at 170° C. for 2 hours. The mixture was poured onto ice, neutralized with 8N-sodium hydroxide and extracted with ethyl acetate-tetrahydrofuran (3:1, v/v). The organic layer was washed with water and dried with MgSO4. The solvent was distilled off under reduced pressure, and resulting crystals were collected by filtration to obtain 6-bromo-2-(3-chlorophenyl)-1H-imidazo[4,5-b]pyridine (1.50 g, 69%).
Reaction SMILES: C([Li])CCC.Br[C:7]1[N:12]=[C:11]2[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:10]2=[CH:9][C:8]=1[CH3:18].[Cl:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=1)[CH:23]=[O:24].O>CCCCCC.C1(C)C=CC=CC=1>[Cl:19][C:20]1[CH:21]=[C:22]([CH:23]([C:7]2[N:12]=[C:11]3[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:10]3=[CH:9][C:8]=2[CH3:18])[OH:24])[CH:25]=[CH:26][CH:27]=1
Reactant: Cc1cc2c(nc1Br)CCCCC2
Reactant: O=Cc1cccc(Cl)c1
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Solvent: CCCCCC
Solvent: O
Product: Cc1cc2c(nc1C(O)c1cccc(Cl)c1)CCCCC2
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 57.2 %

Procedure:
To a solution of 1.6M n-butyl lithium in n-hexane (16.5 ml) in toluene (20 ml) at -20° C. under nitrogen was added a solution of 2-bromo-6,7,8,9-tetrahydro-3-methyl -5H-cyclohepta[b]pyridine (6.0 g, 0.025 m) in toluene (30 ml). The reaction mixture was kept at -20° C. for 0.25 hours and then blown over into a cooled solution of 3-chlorobenzaldehyde (3.7 g) in toluene (30 ml) at -20° C., and allowed to warm to room temperature. Water was added and the separated organic phase extracted with 2N hydrochloric acid. This was basified with solid potassium carbonate and extracted with chloroform. The combined chloroform extracts were washed with water, dried (MgSO4) and evaporated. The solid was purified by passing through a short silica column, eluted with chloroform, then re-crystallised from diethyl ether to give the title compound (4.31 g) m.p. 123°-5° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:21]#[N:22])=[C:4]([CH:18]=[CH:19][CH:20]=1)[O:5][CH2:6][C:7]([CH3:17])([CH3:16])[C:8]([NH:10][CH:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1)=[O:9].O=[C:24]([CH3:31])[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27]>>[NH2:22][C:21]1[C:3]2[C:2](=[CH:20][CH:19]=[CH:18][C:4]=2[O:5][CH2:6][C:7]([CH3:17])([CH3:16])[C:8]([NH:10][CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[O:9])[N:1]=[C:24]([CH3:31])[C:25]=1[C:26]([O:28][CH2:29][CH3:30])=[O:27]
Reactant: CC(C)(COc1cccc(N)c1C#N)C(=O)NC1CCCC1
Reactant: CCOC(=O)CC(C)=O
Product: CCOC(=O)c1c(C)nc2cccc(OCC(C)(C)C(=O)NC3CCCC3)c2c1N

Procedure:
Prepared as in Example 2a from 3-(3-amino-2-cyanophenoxy)-N-cyclopentyl-2,2-dimethylpropanamide (Example 29b) and ethyl 3-oxobutanoate as a bright yellow solid (62%). 1H NR (400 MHz, DMSO-d6) δ 1.26 (s, 6H), 1.34 (t, J=8.0 Hz, 3H), 1.40-1.46 (m, 4H), 1.57-1.59 (m, 2H), 1.74-1.77 (m, 2H), 2.57 (s, 3H), 4.09 (q, J=4.0 Hz, 1H), 4.15 (s, 2H), 4.33 (q, J=8.0 Hz, 2H), 6.89 (d, J=4.0 Hz, 1H), 7.26 (dd, J=8.0 Hz, 1H), 7.53 (d, J=8.0 Hz, 1H), 7.56 (s, 1H), 8.09 (brs, 2H). MS 414 (MH+).
Reaction SMILES: [I:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C@H:9]2[C@@H:13]3[O:14][C:15]([CH3:18])([CH3:17])[O:16][C@@H:12]3[C@@H:11]([CH2:19][OH:20])[CH2:10]2)[CH:3]=1.N1C=CN=C1.[Si:26](Cl)([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27]>CN(C=O)C.O>[Si:26]([O:20][CH2:19][C@@H:11]1[C@H:12]2[O:16][C:15]([CH3:17])([CH3:18])[O:14][C@H:13]2[C@H:9]([NH:8][C:4]2[CH:3]=[C:2]([I:1])[N:7]=[CH:6][N:5]=2)[CH2:10]1)([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27]
Reactant: CC1(C)O[C@@H]2[C@@H](CO)C[C@@H](Nc3cc(I)ncn3)[C@@H]2O1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC1(C)O[C@@H]2[C@@H](CO[Si](C)(C)C(C)(C)C)C[C@@H](Nc3cc(I)ncn3)[C@@H]2O1
Reaction time: 8 h
Yield: 85.7 %

Procedure:
To a solution of {(3aR,4R,6R,6aS)-6-[(6-iodopyrimidin-4-yl)amino]-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl}methanol (1.321 g, 3.38 mmol) and 1H-imidazole (0.552 g, 8.10 mmol) in DMF (16.9 mL) was added tert-butyldimethylsilyl chloride (0.534 g, 3.54 mmol) and the reaction was stirred overnight. The solution was diluted with H2O and extracted with EtOAc (3×). The combined organic layers were washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo. The crude mixture was purified by flash chromatography (10 to 40% EtOAc/hexanes) to afford the title compound (1.465 g, 86%). LC/MS: Rt=2.47 min ES+ 506 (FA Standard).
Reaction SMILES: [CH2:1]([N:5]1[CH:9]=[C:8](B2OC(C)(C)C(C)(C)O2)[CH:7]=[N:6]1)[CH:2]([CH3:4])[CH3:3].Br[C:20]1[S:24][C:23]([C:25]([NH:27][CH2:28][C:29]2[CH:34]=[CH:33][N:32]3[CH:35]=[CH:36][N:37]=[C:31]3[CH:30]=2)=[O:26])=[CH:22][CH:21]=1.BrC1C=CC(N)=CC=1>>[N:37]1[CH:36]=[CH:35][N:32]2[CH:33]=[CH:34][C:29]([CH2:28][NH:27][C:25]([C:23]3[S:24][C:20]([C:9]4[N:5]([CH2:1][CH:2]([CH3:3])[CH3:4])[N:6]=[CH:7][CH:8]=4)=[CH:21][CH:22]=3)=[O:26])=[CH:30][C:31]=12
Reactant: O=C(NCc1ccn2ccnc2c1)c1ccc(Br)s1
Reactant: CC(C)Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: Nc1ccc(Br)cc1
Product: CC(C)Cn1nccc1-c1ccc(C(=O)NCc2ccn3ccnc3c2)s1

Procedure:
The title compound was prepared as described in Example 51A, substituting 1-isobutyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole for 1-isobutyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole and 5-bromo-N-(imidazo[1,2-a]pyridin-7-ylmethyl)thiophene-2-carboxamide for 4-bromoaniline. 1H NMR (500 MHz, DMSO-d6) δ ppm 9.24 (t, J=5.9 Hz, 1H), 8.51 (dd, J=7.0, 0.7 Hz, 1H), 7.90 (d, J=0.8 Hz, 1H), 7.87 (d, J=3.9 Hz, 1H), 7.57-7.49 (m, 2H), 7.43 (s, 1H), 7.39 (d, J=3.9 Hz, 1H), 6.87 (dd, J=7.0, 1.6 Hz, 1H), 6.56 (d, J=1.9 Hz, 1H), 4.51 (d, J=5.9 Hz, 2H), 4.08 (d, J=7.4 Hz, 2H), 2.09 (dp, J=13.8, 6.9 Hz, 1H), 0.80 (d, J=6.7 Hz, 6H); MS (ESI(+)) m/e 380 (M+H)+.
Reaction SMILES: [C:1]1([S:7]([CH2:10][C:11]([NH:13][NH2:14])=[O:12])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:15](OC(=O)C)(=[O:17])[CH3:16]>C(O)(=O)C.O>[C:1]1([S:7]([CH2:10][C:11]([NH:13][NH:14][C:15](=[O:17])[CH3:16])=[O:12])(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NNC(=O)CS(=O)(=O)c1ccccc1
Reactant: CC(=O)OC(C)=O
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)NNC(=O)CS(=O)(=O)c1ccccc1
Yield: 78 %

Procedure:
To a stirred solution of 1.50 g (7.0 mmol) of benzenesulfonyl-acetic acid hydrazide in 5 mL of acetic acid, 1.44 g (14.0 mmol, 2 eq) of acetic anhydride were added, and the solution was heated at reflux for 1 hour. The reaction mixture was diluted with water, extracted with EtOAc, the organic phase dried over Na2SO4, filtered and evaporated, to afford 1.40 g (78%) of acetic acid N′-(2-benzenesulfonyl-acetyl)-hydrazide as a white solid, MS: 274 (MNH4+).
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH:12]([CH3:14])[CH3:13])[CH:10]=2)[C:5](=[O:15])[C:4]([S:16][CH3:17])=[CH:3]1.C([OH:20])C>>[CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH:12]([CH3:13])[CH3:14])[CH:10]=2)[C:5](=[O:15])[C:4]([S:16]([CH3:17])=[O:20])=[CH:3]1
Reactant: CSc1cn(C)c2cc(C(C)C)ccc2c1=O
Reactant: CCO
Product: CC(C)c1ccc2c(=O)c(S(C)=O)cn(C)c2c1

Procedure:
Similarly, the compound 1-methyl-3-methylthio-7-isopropyl-4-quinolone of Example 13 was oxidised to give the compound 1-methyl-3-methylsulphinyl-7-isopropyl-4-quinolone, m.p. 214°-215° (from ethanol).
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]([C:39]1[CH:44]=[CH:43][N:42]=[CH:41][N:40]=1)[S:7]([C:10]1[CH:15]=[CH:14][C:13]([O:16][C@H:17]2[CH2:22][CH2:21][CH2:20][CH2:19][C@@H:18]2[C:23]2[C:24]([N+:34]([O-])=O)=[N:25][N:26](C3CCCCO3)[CH:27]=2)=[C:12]([CH2:37][CH3:38])[CH:11]=1)(=[O:9])=[O:8].C([SiH](CC)CC)C.FC(F)(F)C(O)=O.ClCCl>CO>[NH2:34][C:24]1[C:23]([C@H:18]2[CH2:19][CH2:20][CH2:21][CH2:22][C@@H:17]2[O:16][C:13]2[CH:14]=[CH:15][C:10]([S:7]([NH:6][C:39]3[CH:44]=[CH:43][N:42]=[CH:41][N:40]=3)(=[O:9])=[O:8])=[CH:11][C:12]=2[CH2:37][CH3:38])=[CH:27][NH:26][N:25]=1
Reactant: CCc1cc(S(=O)(=O)N(Cc2ccc(OC)cc2OC)c2ccncn2)ccc1O[C@H]1CCCC[C@@H]1c1cn(C2CCCCO2)nc1[N+](=O)[O-]
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CO
Product: CCc1cc(S(=O)(=O)Nc2ccncn2)ccc1O[C@H]1CCCC[C@@H]1c1c[nH]nc1N
Yield: 107.3 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 22c by using the N-(2,4-dimethoxybenzyl)-3-ethyl-4-({(1S*,2R*)-2-[3-nitro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl]cyclohexyl}oxy)-N-(pyrimidin-4-yl)benzenesulfonamide (70 mg, 0.0990 mmol) prepared in Example 89c, triethylsilane (0.10 mL), trifluoroacetic acid (0.5 mL), dichloromethane (2.0 mL) and methanol (1.0 mL), to yield the title compound (47 mg, 99%) as a white solid.
Reaction SMILES: [CH3:1][N:2]1[C:6]([NH2:7])=[CH:5][CH:4]=[N:3]1.N1C=CC=CC=1.Cl[C:15]([O:17][CH2:18][C:19]([Cl:22])([Cl:21])[Cl:20])=[O:16].O>O1CCCC1>[CH3:1][N:2]1[C:6]([NH:7][C:15](=[O:16])[O:17][CH2:18][C:19]([Cl:22])([Cl:21])[Cl:20])=[CH:5][CH:4]=[N:3]1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: Cn1nccc1N
Solvent: O
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: Cn1nccc1NC(=O)OCC(Cl)(Cl)Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 50.9 %

Procedure:
To a solution of 1-methyl-1H-pyrazole-5-amine (1.00 g, 10.3 mmol) and pyridine (1.01 ml, 12.4 mmol) in tetrahydrofuran (34 ml) was added 2,2,2-trichloroethyl chloroformate (1.71 ml, 12.4 mmol) with ice-cooling and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to obtain the desired product (1.43 g, 50.8%) as an oil.