Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH2:3][CH:2]1[C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][CH:13]=1)[CH:9]=[O:10].N1C(C)=CC=CC=1C.[H][H]>C1COCC1>[O:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[C:6]1[CH:7]=[C:8]([CH2:9][OH:10])[CH:11]=[CH:12][CH:13]=1
Reactant: O=Cc1cccc(C2CC=CO2)c1
Reactant: [H][H]
Solvent: C1CCOC1
Solvent: Cc1cccc(C)n1
Product: OCc1cccc(C2CCCO2)c1
Yield: 70 %

Procedure:
EX-608C) A THF (15 mL) solution of the aldehyde from EX-608B (0.70 g, 4.0 mmol) and 2,6-lutidine (0.46 mL, 4.0 mmol) was stirred in a hydrogen 4.0 mmol) and 2,6-lutidine (0.46 mL, 4.0 mmol) was stirred in a hydrogen temperature. The slurry was filtered through celite, and the solvent was removed. The residue was taken up in ethyl acetate and washed with 1 N HCl and brine. The organic layer was dried (MgSO4) and evaporated to give 0.50 g (70%) of the desired 3-(tetrahydro-2-furanyl)phenylmethanol product as a yellow oil. The formation of the desired product was monitored by the disappearance of the aldehyde (δ˜10) and olefin peaks in the 1H NMR disappearance of the aldehyde (δ˜10) and olefin peaks in the 1H NMR spectrum. 2.8 mmol) and MnO2 (2.10 g, 24.3 mmol) in dichloromethane (15 mL) was refluxed for 3 h. The slurry was filtered through celite, and the filtrate was evaporated to a yellow oil. Purification by flash chromatography on silica gel eluting with 10% ethyl acetate in hexane gave 0.19 g (45%) of the desired aldehyde product as a pale yellow oil. GCMS: m/z=177 [M+H]+.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6](Cl)(=[O:8])=[O:7].[NH3:10].Cl>C1COCC1>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6]([NH2:10])(=[O:8])=[O:7]
Reactant: N
Reactant: O=S(=O)(Cl)c1cccs1
Agent: Cl
Solvent: C1CCOC1
Product: NS(=O)(=O)c1cccs1
Temperature: 25 °C
Reaction time: 2 h
Yield: 65 %

Procedure:
365.3 mg thiophene-2-sulfonyl chloride was dissolved in 5 ml THF, to which at 0° C. was added 1.7 ml NH3 solution drop wise. The resulting mixture was stirred at r.t. for 2 hrs and acidified with conc. HCl at 0° C. to pH=˜2. The organic solvent was removed via rotavap and the aqueous suspension was extracted with ethyl acetate. The extract was combined and washed with saturated NaHCO3 solution, water and brine. Dried over Na2SO4, the organic phase was filtered and the filtrate was concentrated affording the title compound 212 mg (65%) as a white solid, m.p.: 137-139° C.
Reaction SMILES: [CH3:1][CH:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][CH:15]3[CH2:17][CH2:16]3)=[C:10]([N+:18]([O-])=O)[CH:9]=2)=[N:6][NH:5][C:4](=[O:21])[CH2:3]1.C(O)C.[H][H]>[Pd].C(O)(=O)C>[CH3:1][CH:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][CH:15]3[CH2:16][CH2:17]3)=[C:10]([NH2:18])[CH:9]=2)=[N:6][NH:5][C:4](=[O:21])[CH2:3]1
Reactant: CC1CC(=O)NN=C1c1ccc(NC2CC2)c([N+](=O)[O-])c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: CC(=O)O
Product: CC1CC(=O)NN=C1c1ccc(NC2CC2)c(N)c1

Procedure:
5.8 gm of 5-methyl-6-(3-nitro-4-cyclopropylamino-phenyl)-3-oxo-4,5-dihydro-2H-pyridazine were hydrogenated in a mixture consisting of 100 ml of ethanol and of 20 ml of glacial acetic acid in the presence of 0.5 gm of 10% palladium charcoal at a hydrogen pressure of 5 bar. 120 ml of glacial acetic acid were added, the catalyst was filtered off and the filtrate was evaporated in vacuo. The residue was reacted further without further purification.
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][CH:8]([N:11]3[C:16](=[O:17])[C:15]([CH2:18][C:19]4[CH:24]=[CH:23][C:22]([C:25]5[C:26]([C:31]#[N:32])=[CH:27][CH:28]=[CH:29][CH:30]=5)=[CH:21][CH:20]=4)=[C:14]([CH2:33][CH2:34][CH3:35])[N:13]4[N:36]=[C:37]([CH3:39])[N:38]=[C:12]34)[CH2:7][CH2:6]2)[O:4]CC1.Cl.O1CCCC1>C(OCC)(=O)C>[CH3:39][C:37]1[N:38]=[C:12]2[N:11]([CH:8]3[CH2:7][CH2:6][C:5](=[O:4])[CH2:10][CH2:9]3)[C:16](=[O:17])[C:15]([CH2:18][C:19]3[CH:20]=[CH:21][C:22]([C:25]4[C:26]([C:31]#[N:32])=[CH:27][CH:28]=[CH:29][CH:30]=4)=[CH:23][CH:24]=3)=[C:14]([CH2:33][CH2:34][CH3:35])[N:13]2[N:36]=1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCC3(CC2)OCCO3)c2nc(C)nn12
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCC(=O)CC2)c2nc(C)nn12
Temperature: 70 °C
Reaction time: 16 h
Yield: 80.9 %

Procedure:
A mixture of 4′-{[4-(1,4-dioxaspiro[4.5]dec-8-yl)-2-methyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (27 g), 6N hydrochloric acid (80 mL) and tetrahydrofuran (160 mL) was stirred at 70° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (20 g, 80%).
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([Cl:10])=[N:5][CH:6]=[CH:7][C:8]=1[Cl:9].[SH:11][C:12]1[N:17]=[C:16]([OH:18])[CH:15]=[C:14]([C:19]([F:22])([F:21])[F:20])[N:13]=1.C(N(CC)CC)C>C(O)C>[Cl:10][C:4]1[C:3]([CH2:2][S:11][C:12]2[N:17]=[C:16]([OH:18])[CH:15]=[C:14]([C:19]([F:22])([F:20])[F:21])[N:13]=2)=[C:8]([Cl:9])[CH:7]=[CH:6][N:5]=1
Reactant: Clc1ccnc(Cl)c1CBr
Reactant: Oc1cc(C(F)(F)F)nc(S)n1
Solvent: CCN(CC)CC
Solvent: CCO
Product: Oc1cc(C(F)(F)F)nc(SCc2c(Cl)ccnc2Cl)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 21.9 %

Procedure:
A mixture of 3-(bromomethyl)-2,4-dichloropyridine (2.9 g, 12.3 mmol), 2-sulfanyl-6-(trifluoromethyl)pyrimidin-4-ol (1.2 g, 6.1 mmol), and triethylamine (1.3 mL, 9.3 mmol) in absolute ethanol (25 mL) was stirred at room temperature overnight. The mixture was evaporated to dryness. The residue was dissolved in EtOAc (80 mL). The solution was extracted with water (3×50 mL) and 1 N NaOH (1×50 mL). The organic layer was recovered, dried over MgSO4, filtered, evaporated, and dried in vacuo. The crude product was purified by flash chromatography (0-5% MeOH/DCM), affording the title compound (475 mg, 22% yield); 1H NMR (400 MHz, DMSO-d6): δ 4.75 (s, 2H), 6.72 (s, 1H), 7.69 (d, 1H, J=5.3 Hz), 8.36 (d, 1H, J=5.3 Hz); M+ 357.
Reaction SMILES: CC1N=C(C2C=CC(O)=CC=2)ON=1.[CH3:14][N:15]([CH3:49])[C:16]([C:18]1[CH:19]=[C:20](CCCC(O)=O)[CH:21]=[CH:22][C:23]=1[NH:24][C:25]([C:27]1[C:28]([C:33]2[CH:38]=[CH:37][C:36]([C:39]([F:42])([F:41])[F:40])=[CH:35][CH:34]=2)=[CH:29][CH:30]=[CH:31][CH:32]=1)=[O:26])=[O:17].CCN=C=NCCCN(C)C.[CH3:61][C:62]1[N:66]=[C:65]([C:67]2[CH:72]=[CH:71][C:70]([O:73][C:74](=[O:108])[CH2:75][CH2:76][CH2:77]C3C=CC(NC(C4C(C5C=CC(C(F)(F)F)=CC=5)=CC=CC=4)=O)=C(C(=O)N(C)C)C=3)=[CH:69][CH:68]=2)[O:64][N:63]=1>>[CH3:61][C:62]1[N:66]=[C:65]([C:67]2[CH:72]=[CH:71][C:70]([O:73][C:74](=[O:108])[CH:75]([C:20]3[CH:21]=[CH:22][C:23]([NH:24][C:25]([C:27]4[C:28]([C:33]5[CH:38]=[CH:37][C:36]([C:39]([F:42])([F:40])[F:41])=[CH:35][CH:34]=5)=[CH:29][CH:30]=[CH:31][CH:32]=4)=[O:26])=[C:18]([C:16](=[O:17])[N:15]([CH3:14])[CH3:49])[CH:19]=3)[CH2:76][CH3:77])=[CH:69][CH:68]=2)[O:64][N:63]=1
Reactant: CN(C)C(=O)c1cc(CCCC(=O)O)ccc1NC(=O)c1ccccc1-c1ccc(C(F)(F)F)cc1
Reactant: Cc1noc(-c2ccc(OC(=O)CCCc3ccc(NC(=O)c4ccccc4-c4ccc(C(F)(F)F)cc4)c(C(=O)N(C)C)c3)cc2)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cc1noc(-c2ccc(O)cc2)n1
Product: CCC(C(=O)Oc1ccc(-c2nc(C)no2)cc1)c1ccc(NC(=O)c2ccccc2-c2ccc(C(F)(F)F)cc2)c(C(=O)N(C)C)c1

Procedure:
4-(3-Methyl-[1,2,4]oxadiazol-5-yl)phenol (64 mg) and 4-{3-dimethylcarbamoyl-4-[(4′-trifluoromethylbiphenyl-2-carbonyl)amino]phenyl}butanoic acid (200 mg)(synthesized separately in a similar manner to Working Example 1-1) were treated (WSC condensation) in a similar manner to Step g) of Working Example 1-1 to give the title compound (Compound 1-2) (112 mg).
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[C:8]([C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=2)=[CH:13][CH:12]=1)(=[O:10])[CH3:9].S(=O)(=O)(O)O>[Zn].C1C=CC=CC=1>[CH2:6]([O:5][C:3](=[O:4])[CH2:2][C:8]([C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=2)=[CH:13][CH:12]=1)([OH:10])[CH3:9])[CH3:7]
Reactant: CCOC(=O)CBr
Reactant: CC(=O)c1ccc(-c2ccc(Cl)c(Cl)c2)cc1
Agent: O=S(=O)(O)O
Agent: [Zn]
Solvent: c1ccccc1
Product: CCOC(=O)CC(C)(O)c1ccc(-c2ccc(Cl)c(Cl)c2)cc1

Procedure:
A mixture of 20 g. of ethyl bromoacetate, 26.5 g. of 4-acetyl-3',4'-dichlorobiphenyl and 8 lg. of zinc foil is added to 100 ml. of benzene and the mixture is stirred and heated under reflux for one hour. It is cooled and dilute sulfuric acid is added to decompose the alcoholate obtained. The organic phase is separated off and, after the customary work up, 3-(3',4'-dichloro-4-biphenylyl)-3-hydroxybutyric acid ethyl ester is obtained.
Reaction SMILES: [C:1]12(CN)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.C1(=O)N(C(CC(O)=O)C(O)=O)C(=O)CC1.C1(=O)N(C(CC(O)=O)C(O)=O)C(=O)CC1.C(O)CO.Cl>ClCCl>[CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: NCC12CC3CC(CC(C3)C1)C2
Agent: Cl
Agent: O=C(O)CC(C(=O)O)N1C(=O)CCC1=O
Solvent: OCCO
Solvent: ClCCl
Product: C1C2CC3CC1CC(C2)C3
Temperature: 25 °C
Reaction time: 5 h
Yield: 175.5 %

Procedure:
1-Adamantanemethylamine (0.152 g, 0.92 mmol, Aldrich, Milwaukee, Wis.) was added to Ethylene glycol bis[succinimidylsuccinate] (EGS) (0.2 g, 0.43 mmol, Pierce, Rockford, Ill.) in solution in 10 mL of anhydrous dichloromethane. The resulting solution was stirred for 5 h at room temperature. It was then acidified with 0.1 N HCl and extracted with dichloromethane. The organic phase was dried with MgSO4 and then concentrated to dryness under vacuum. This afforded 0.22 g of solid (yield 90%).
Reaction SMILES: [OH-].[K+].Cl.O.[NH:5]1[CH2:10][CH2:9][C:8](=O)[CH2:7][CH2:6]1.[CH3:12][C:13]1[CH:21]=[C:20]2[C:16]([CH:17]=[CH:18][NH:19]2)=[CH:15][CH:14]=1>CO>[CH3:12][C:13]1[CH:21]=[C:20]2[C:16]([C:17]([C:8]3[CH2:7][CH2:6][NH:5][CH2:10][CH:9]=3)=[CH:18][NH:19]2)=[CH:15][CH:14]=1
Reactant: O=C1CCNCC1
Reactant: Cc1ccc2cc[nH]c2c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1ccc2c(C3=CCNCC3)c[nH]c2c1
Yield: 92.7 %

Procedure:
To a solution of potassium hydroxide (16 g) in methanol were added at 5° C. 4-piperidone hydrate hydrochloride (30 g) and a solution of 6-methyl-1H-indole (10 g) in methanol (50 ml). The mixture was refluxed for 16 hours. After cooling precipitated inorganic salts were filtered off. Methanol was evaporated and the remaining oil was dissolved in ethyl acetate (200 ml) and subsequently washed with brine (2×100 ml). After drying (anh. MgSO4) the solvent was evaporated leaving 15 g of crude 6-methyl-3-(1,2,3,6-tetrahydro-4-pyridyl)-1H-indole, which was used without further purification. The pure tetrahydropyridyl derivative crystallized from diethyl ether. Mp: 150°-152° C. To a solution of 1-(2-chloroethyl)-3-(2-propyl)-2-imidazolidinon (32 g) in MIBK (500 ml) were added 6-methyl-3-(1,2,3,6-tetrahydro-4-pyridyl)-1H-indole (15 g), potassium carbonate (16 g) and potassium iodide (5 g). The mixture was refluxed for 19 hours and finally filtered while still hot. MIBK was evaporated and the resulting oil was dissolved in ethyl acetate (500 ml) and washed with brine (2×100 ml). After drying (anh. Na2SO4) ethyl acetate was evaporated. The remaining oil was stirred with diethyl ether (200 ml) and the precipitated, crystalline 3-[1-[2-[3-(2-propyl)-2-imidazolidinon-1-yl]ethyl]-1,2,3,6-tetrahydro-4-pyridyl]-6-methyl-1H-indole was filtered off. Yield: 14.5 g. Mp: 170°-174° C. To a solution of the thus prepared imidazolidinon derivative (14 g) in acetic acid (300 ml), was added PtO2 (600 mg). This mixture was hydrogenated in a Parr apparatus at 3 atm. for 72 hours. The catalyst was filtered off and most of the acetic acid was evaporated in vacuo. The remaining oil was dissolved in H2O and pH was adjusted to 9-10 by addition of dil. NaOH solution. The title compound 14a was extracted with dichloromethane (2×200 ml) and isolated as above. The crude product was purified by eluting (eluent:ethyl acetate/dichloromethane/ethanol/triethylamine (40:40:20:5) through silica gel. Yield: 4.5 g. Mp: 185° C.
Reaction SMILES: Cl.Cl.[C:3]1([C@H:9]2[C@@H:14]([NH2:15])[CH2:13][CH2:12][CH2:11][NH:10]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:16]([N:19]([C:21]1([C:24]2[CH:25]=[CH:26][C:27]([O:32][CH3:33])=[C:28]([CH:31]=2)[CH:29]=O)[CH2:23][CH2:22]1)[CH3:20])(=[O:18])[CH3:17].C(C1(C2C=CC(OC)=C(C=2)CN[C@H]2CCCN[C@H]2C2C=CC=CC=2)CC1)#N>>[C:16]([N:19]([C:21]1([C:24]2[CH:25]=[CH:26][C:27]([O:32][CH3:33])=[C:28]([CH:31]=2)[CH2:29][NH:15][C@H:14]2[CH2:13][CH2:12][CH2:11][NH:10][C@H:9]2[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:23][CH2:22]1)[CH3:20])(=[O:18])[CH3:17]
Reactant: COc1ccc(C2(N(C)C(C)=O)CC2)cc1C=O
Reactant: N[C@H]1CCCN[C@H]1c1ccccc1
Agent: COc1ccc(C2(C#N)CC2)cc1CN[C@H]1CCCN[C@H]1c1ccccc1
Agent: Cl
Product: COc1ccc(C2(N(C)C(C)=O)CC2)cc1CN[C@H]1CCCN[C@H]1c1ccccc1

Procedure:
This compound was prepared from Compound 3 and Compound 10 in the same manner of Compound 4
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[C:8]1(/[CH:14]=[CH:15]/[C:16]([O:18][CH:19]2[C:36]([CH3:38])([CH3:37])[O:35][C:34]3[C:21](=[C:22]4[C:31](=[C:32]([O:39][CH3:40])[CH:33]=3)[C:30](=[O:41])[C:29]3[C:24](=[CH:25][CH:26]=[C:27]5[CH:45]=[CH:44][CH:43]=[CH:42][C:28]5=3)[N:23]4[CH3:46])[CH:20]2[OH:47])=[O:17])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>N1C=CC=CC=1>[C:8]1(/[CH:14]=[CH:15]/[C:16]([O:18][CH:19]2[C:36]([CH3:38])([CH3:37])[O:35][C:34]3[C:21](=[C:22]4[C:31](=[C:32]([O:39][CH3:40])[CH:33]=3)[C:30](=[O:41])[C:29]3[C:24](=[CH:25][CH:26]=[C:27]5[CH:45]=[CH:44][CH:43]=[CH:42][C:28]5=3)[N:23]4[CH3:46])[CH:20]2[O:47][C:1](=[O:3])[CH3:2])=[O:17])[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CC(=O)OC(C)=O
Reactant: COc1cc2c(c3c1c(=O)c1c4ccccc4ccc1n3C)C(O)C(OC(=O)/C=C/c1ccccc1)C(C)(C)O2
Solvent: c1ccncc1
Product: COc1cc2c(c3c1c(=O)c1c4ccccc4ccc1n3C)C(OC(C)=O)C(OC(=O)/C=C/c1ccccc1)C(C)(C)O2
Temperature: 25 °C
Reaction time: 72 h

Procedure:
31 mmol of acetic anhydride are added to a previously cooled solution of 0.18 mmol of the compound of Example 35 in 3 ml of pyridine. After stirring at ambient temperature for 3 days, the reaction mixture is evaporated under reduced pressure. Chromatography over silica gel (cyclohexane/acetone: 94/6) allows the expected product to be isolated.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8](=[O:26])[CH:9]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:5]=[CH:4][CH:3]=1.Cl.O>C(OCC)C.[BH4-].[Zn+2].[BH4-]>[Cl:1][C:2]1[N:7]=[C:6]([CH:8]([OH:26])[CH:9]([CH2:15][C:16]2[CH:17]=[CH:18][C:19]([C:22]([F:23])([F:24])[F:25])=[CH:20][CH:21]=2)[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(Cc1ccc(C(F)(F)F)cc1)C(=O)c1cccc(Cl)n1
Agent: Cl
Agent: [BH4-]
Agent: [Zn+2]
Solvent: CCOCC
Solvent: O
Product: CCOC(=O)C(Cc1ccc(C(F)(F)F)cc1)C(O)c1cccc(Cl)n1
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 31.9 %

Procedure:
To a solution of zinc chloride (9.0 g, 66.15 mmol) in diethyl ether (200 ml) was added sodium borohydride (5.0 g, 132 mmol), and the mixture was stirred at room temperature for 30 min. The insoluble material was filtered off to give a solution of zinc borohydride in diethyl ether. To a solution of ethyl 3-(6-chloro-2-pyridyl)-3-oxo-2-((4-(trifluoromethyl)phenyl)methyl)propionate (12.7 g, 33.1 mmol) in diethyl ether (100 ml) was dropwise added slowly at −20° C. the solution of zinc borohydride in diethyl ether prepared in advance. The reaction solution was stirred at −20° C. for 30 min., and 1N hydrochloric acid was added to quench the reaction. Water (200 ml) was added and the mixture was extracted with ethyl acetate (300 ml×2). The extract was washed with water and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) to give ethyl 3-(6-chloro-2-pyridyl)-3-hydroxy-2-((4-(trifluoromethyl)phenyl)methyl)propionate (4.1 g, 32%, (2RS,3RS) form: (2RS,3SR)form=1:1, crude) as a colorless oil.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[N:10][C:9]=2[C:17]2[C:18]([F:36])=[C:19]([NH:24][S:25]([C:28]3[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:29]=3[F:35])(=[O:27])=[O:26])[CH:20]=[CH:21][C:22]=2[F:23])[CH:5]=[CH:4][N:3]=1.[OH-].[NH4+:38]>>[NH2:38][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[N:10][C:9]=2[C:17]2[C:18]([F:36])=[C:19]([NH:24][S:25]([C:28]3[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:29]=3[F:35])(=[O:27])=[O:26])[CH:20]=[CH:21][C:22]=2[F:23])[CH:5]=[CH:4][N:3]=1
Reactant: [NH4+]
Reactant: CC(C)(C)c1nc(-c2c(F)ccc(NS(=O)(=O)c3cc(F)ccc3F)c2F)c(-c2ccnc(Cl)n2)s1
Agent: [OH-]
Product: CC(C)(C)c1nc(-c2c(F)ccc(NS(=O)(=O)c3cc(F)ccc3F)c2F)c(-c2ccnc(N)n2)s1

Procedure:
Following a procedure analogous to the procedure described in Example 52, Step B using N-{3-[5-(2-chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2,4-difluorophenyl}-2,5-difluorobenzenesulfonamide (75 mg, 0.135 mmol) and ammonium hydroxide (3 mL), the title compound was obtained as an off-white solid (50 mg, 69% yield). MS (ESI): 538 [M+H]+.
Reaction SMILES: [CH2:1]([C:5]1[C:6]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:7]([OH:17])[C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([O:15][CH3:16])=[CH:10][CH:9]=2)[CH2:2][CH2:3][CH3:4].[H-].[Na+].F[C:27]1[CH:34]=[CH:33][C:30]([CH:31]=[O:32])=[CH:29][CH:28]=1>CN(C=O)C>[CH2:1]([C:5]1[C:6]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:7]([O:17][C:27]2[CH:34]=[CH:33][C:30]([CH:31]=[O:32])=[CH:29][CH:28]=2)[C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([O:15][CH3:16])=[CH:10][CH:9]=2)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1cc2cc(OC)ccc2c(O)c1-c1ccccc1
Reactant: O=Cc1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCc1cc2cc(OC)ccc2c(Oc2ccc(C=O)cc2)c1-c1ccccc1
Yield: 82 %

Procedure:
3-Butyl-6-(methyloxy)-2-phenyl-1-naphthalenol (81) (0.25 g, 0.82 mmol) was treated with NaH in DMF followed by addition of 4-fluorobenzaldehyde to give 0.27 g (82%) of 82 as a light yellow oil. 1H NMR (400 MHz, CDCl3): δ 0.77 (t, J=7.3 Hz, 3H), 1.10-1.25 (m, 2H), 1.40-1.50 (m, 2H), 2.55-2.60 (m, 2H), 3.94 (s, 3H), 6.68 (d, J=8.6 Hz, 2H), 7.05 (dd, J1=9.1 Hz, J2=2.4 Hz, 1H), 7.08-7.13 (m, 2H), 7.17 (d, J=2.6 Hz, 1H), 7.18-7.25 (m, 3H), 7.58-7.64 (m, 3H), 7.67 (d, J=9.1 Hz, 1H), 9.79 (s, 1H). LCMS (ESI): m/z 411 (M+H)+.
Reaction SMILES: Cl.[NH:2]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1)[NH2:3].[CH:14]12[CH2:23][CH:18]3[CH2:19][CH:20]([CH2:22][CH:16]([CH2:17]3)[CH:15]1[NH:24][C:25](=[O:38])/[C:26](/[C:31]([CH:33]1[CH2:37][CH2:36][CH2:35][CH2:34]1)=O)=[CH:27]\N(C)C)[CH2:21]2>C(O)C.C(O)(=O)C>[CH:16]12[CH2:17][CH:18]3[CH2:19][CH:20]([CH2:21][CH:14]([CH2:23]3)[CH:15]1[NH:24][C:25]([C:26]1[CH:27]=[N:3][N:2]([C:4]3[CH:5]=[CH:6][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:12][CH:13]=3)[C:31]=1[CH:33]1[CH2:34][CH2:35][CH2:36][CH2:37]1)=[O:38])[CH2:22]2
Reactant: CN(C)/C=C(\C(=O)NC1C2CC3CC(C2)CC1C3)C(=O)C1CCCC1
Reactant: COC(=O)c1ccc(NN)cc1
Agent: Cl
Solvent: CC(=O)O
Solvent: CCO
Product: COC(=O)c1ccc(-n2ncc(C(=O)NC3C4CC5CC(C4)CC3C5)c2C2CCCC2)cc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 39.4 %

Procedure:
Methyl 4-hydrazinylbenzoate hydrochloride (Intermediate#123) (0.712 g, 3.51 mmol) was added in one portion to (Z)—N-(2-adamantyl)-2-(cyclopentanecarbonyl)-3-dimethylamino-prop-2-enamide (Intermediate#67), 1.21 g, 3.51 mmol) in ethanol (30 mL). 5 drops of acetic acid were added and the resulting solution was stirred at 80° C. for 2 hours and then cooled to ambient giving a precipitate. The reaction mixture was filtered and the product recovered, washed with ethanol (10 mL) and water (10 mL) before being dried under vacuum to give methyl 4-[4-(2-adamantylcarbamoyl)-5-cyclopentyl-pyrazol-1-yl]benzoate (0.620 g, 39.4%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][N:3]=1.P(OCC)(OCC)([S-])=[S:11].O1CCCC1.C(=O)(O)[O-].[Na+]>O>[NH2:1][C:2]1[CH:7]=[C:6]([C:8](=[S:11])[NH2:9])[CH:5]=[CH:4][N:3]=1
Reactant: CCOP(=S)([S-])OCC
Reactant: N#Cc1ccnc(N)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: NC(=S)c1ccnc(N)c1
Temperature: 60 °C
Reaction time: 4 h
Yield: 80.9 %

Procedure:
A mixture of 2-aminopyridine-4-carbonitrile (6.0 g, 50 mmol), O,O′-diethyl dithiophosphate (11 mL, 60 mmol), tetrahydrofuran (25 mL) and water (25 mL) was stirred at 60° C. for 4 hr. To the reaction mixture was added O,O′-diethyl dithiophosphate (2.8 mL, 15 mmol) and the mixture was stirred at 60° C. for 1 day. To the reaction mixture was added aqueous sodium bicarbonate solution, and the mixture was extracted with ethyl acetate. The combined organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the insoluble material was filtered off. The filtrate was concentrated under reduced pressure, and the obtained residue was washed with diisopropyl ether to give the title compound (6.2 g, 81%) as a yellow solid.
Reaction SMILES: [C:1]1([C@H:7]([CH3:13])[CH2:8][NH:9][C:10]([NH2:12])=[S:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH:15]([CH2:19][CH3:20])[C:16](O)=[O:17]>>[CH2:19]([C@@H:15]1[S:11][C:10]([NH:9][CH2:8][C@H:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH3:13])=[N:12][C:16]1=[O:17])[CH3:20]
Reactant: C[C@H](CNC(N)=S)c1ccccc1
Reactant: CCC(Br)C(=O)O
Product: CC[C@@H]1SC(NC[C@@H](C)c2ccccc2)=NC1=O

Procedure:
Synthesis was performed from N-[(2S)-2-phenylpropyl]thiourea and 2-bromo-butyric acid according to Method D3.
Reaction SMILES: Cl[CH2:2][C:3]1[NH:8][C:7]([CH:9]([CH3:11])[CH3:10])=[N:6][C:5](=[O:12])[CH:4]=1.ClCC(=O)CC(OCC)=O.C(N)(=N)C(C)C.[P:29]([S-:35])(=[S:34])([O:32][CH3:33])[O:30][CH3:31].[NH4+]>CO.ClCCl>[P:29]([S:35][CH2:2][C:3]1[N:8]=[C:7]([CH:9]([CH3:11])[CH3:10])[NH:6][C:5](=[O:12])[CH:4]=1)(=[S:34])([O:32][CH3:33])[O:30][CH3:31]
Reactant: CC(C)c1nc(=O)cc(CCl)[nH]1
Reactant: COP(=S)([S-])OC
Agent: CC(C)C(=N)N
Agent: CCOC(=O)CC(=O)CCl
Agent: [NH4+]
Solvent: ClCCl
Solvent: CO
Product: COP(=S)(OC)SCc1cc(=O)[nH]c(C(C)C)n1

Procedure:
The intermediate, 6-(chloromethyl)-2-(1-methylethyl)-4(1H)pyrimidinone, was prepared according to Swiss patent 524617 from ethyl 4-chloroacetoacetate and isobutyramidine. m.p. 123°-125°. The intermediate chloromethyl compound (25 g) was stirred with 50 ml methanol at room temperature. To this mixture was added, dropwise, a solution of 25 g ammonium dimethyl phosphorodithioate dissolved in 500 ml methanol. The mixture was then heated to reflux for 6 hours, then the solvent was evaporated under reduced pressure yielding a solid. The solid was dissolved in dichloromethane and washed with water, separated, dried, and the solvent was evaporated. The remaining solid was recrystallized from toluene; yield: 15.9 g, m.p. 89°-93°.
Reaction SMILES: [C:1](Cl)(=[O:5])[CH:2]([CH3:4])[CH3:3].[CH3:7][O:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:18]=1[CH:17]([NH:19][C:20]1[CH:29]=[CH:28][C:27]3[C:22](=[CH:23][CH:24]=[C:25]([NH2:30])[CH:26]=3)[N:21]=1)[CH2:16][CH2:15][CH2:14]2>C(N(CC)CC)C>[CH3:7][O:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:18]=1[CH:17]([NH:19][C:20]1[CH:29]=[CH:28][C:27]3[C:22](=[CH:23][CH:24]=[C:25]([NH:30][C:1](=[O:5])[CH:2]([CH3:4])[CH3:3])[CH:26]=3)[N:21]=1)[CH2:16][CH2:15][CH2:14]2
Reactant: COc1cccc2c1C(Nc1ccc3cc(N)ccc3n1)CCC2
Reactant: CC(C)C(=O)Cl
Solvent: CCN(CC)CC
Product: COc1cccc2c1C(Nc1ccc3cc(NC(=O)C(C)C)ccc3n1)CCC2

Procedure:
The title compound was prepared in accordance with the general method 9 described in example 116 from isobutyryl chloride, triethylamine and rac-N2-(8-methoxy-1,2,3,4-tetrahydro-naphthalen-1-yl)-quinoline-2,6-diamine; MS: m/e=390.3 (M+H+).