Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=2)[C:12]([NH:14][C:15]2[CH:20]=[CH:19][C:18](I)=[CH:17][CH:16]=2)=[O:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].O.[O:33]1[C:37](B(O)O)=[CH:36][C:35]2[CH:41]=[CH:42][CH:43]=[CH:44][C:34]1=2.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C(O)C.CC1C=CC=CC=1[P](C1C=CC=CC=1C)([Pd](Cl)(Cl)[P](C1=C(C)C=CC=C1)(C1C=CC=CC=1C)C1C=CC=CC=1C)C1C=CC=CC=1C>[O:33]1[C:34]2=[CH:44][CH:43]=[CH:42][C:41]2=[CH:35][CH:36]=[C:37]1[C:20]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[NH:14][C:12](=[O:13])[CH:11]([C:8]1[CH:9]=[CH:10][C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])=[CH:6][CH:7]=1)[CH2:22][C:23]1[CH:24]=[CH:25][C:26]([N+:29]([O-:31])=[O:30])=[CH:27][CH:28]=1
Reactant: OB(O)c1cc2ccccc2o1
Reactant: CC(C)(C)c1ccc(C(Cc2ccc([N+](=O)[O-])cc2)C(=O)Nc2ccc(I)cc2)cc1
Agent: Cc1ccccc1[P](c1ccccc1C)(c1ccccc1C)[Pd](Cl)(Cl)[P](c1ccccc1C)(c1ccccc1C)c1ccccc1C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Solvent: CCO
Product: CC(C)(C)c1ccc(C(Cc2ccc([N+](=O)[O-])cc2)C(=O)Nc2ccccc2-c2ccc3cccc-3o2)cc1
Temperature: 125 °C
Reaction time: 0.1 h
Yield: 80 %

Procedure:
To 2-(4-tert-Butyl-phenyl)-N-(4-iodo-phenyl)-3-(4-nitro-phenyl)-propionamide (1056 mg, 2 mmol) in 8 ml 1,2-dimethoxyethane, 4 ml ethanol, and 2 ml water was added benzo[b]furan-2-boronic acid (972 mg, 6 mmol), bis(tri-o-tolylphosphine)palladium(II) dichloride (158 mg, 0.2 mmol), and sodium carbonate (1060 mg, 10 mmol). The reaction mixture was stirred at 125° C. for 6 min, filtered, and concentrated. Chromatography of the residue (20% ethyl acetate in hexane) afforded N-(4-Benzofuran-2-yl-phenyl)-2-(4-tert-butyl-phenyl)-3-(4-nitro-phenyl)-propionamide as a yellow foam (830 mg, 80%).
Reaction SMILES: CS[C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][C:4]=1[N+:12]([O-:14])=[O:13].O[O:16][S:17]([O-:19])=O.[K+].[CH3:21]O>O>[CH3:21][S:17]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][C:4]=1[N+:12]([O-:14])=[O:13])(=[O:19])=[O:16]
Reactant: O=S([O-])OO
Reactant: CSc1ccc(C(=O)O)cc1[N+](=O)[O-]
Reactant: CO
Agent: [K+]
Solvent: O
Product: CS(=O)(=O)c1ccc(C(=O)O)cc1[N+](=O)[O-]
Temperature: 5 °C
Reaction time: 8 h
Yield: 89 %

Procedure:
4-Methylsulfanyl-3-nitro-benzoic acid (1 g, 4.69 mmole) was dissolved in methanol (25 ml) and cooled to 5° C. A solution of Oxone® (5.8 g) in water (20 ml) was added portionwise at the same temperature. The reaction mixture was allowed to stir overnight at ambient temperature, methanol was removed under reduced pressure. The suspension was diluted with water and the solid was filtered off and dried in vacuum to provide 4-Methanesulfonyl-3-nitro-benzoic acid in 89% yield (960 mg). ESI-MS: 246.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[C:11]2[C:6](=[CH:7][C:8]([CH:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:13][OH:14])=[CH:9][CH:10]=2)[O:5][CH2:4][CH2:3]1.C(#N)C.I([O-])(=O)(=O)=[O:25].[Na+].Cl>C(Cl)(Cl)(Cl)Cl.O.[Ru](Cl)(Cl)Cl>[CH3:1][C:2]1([CH3:20])[C:11]2[C:6](=[CH:7][C:8]([CH:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[C:13]([OH:25])=[O:14])=[CH:9][CH:10]=2)[O:5][CH2:4][CH2:3]1
Reactant: CCCCCC(CO)c1ccc2c(c1)OCCC2(C)C
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: Cl[Ru](Cl)Cl
Agent: Cl
Agent: [Na+]
Solvent: ClC(Cl)(Cl)Cl
Solvent: CC#N
Solvent: O
Product: CCCCCC(C(=O)O)c1ccc2c(c1)OCCC2(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 56.2 %

Procedure:
To a solution of 2-(4,4-dimethyl-chroman-7-yl)-heptan-1-ol (0.27 g, 0.98 mmole, from Example 1, step 6) in a mixture of 2 mL of carbon tetrachloride, 2 mL acetonitrile and 3 mL water, containing 3-5 mg of ruthenium chloride, was added 0.85 g of sodium periodate. The mixture was stirred at room temperature for 2 hours, diluted with 10 mL of water, and pH was adjusted to 2 with 10% hydrochloric acid. The mixture was extracted with three 10 mL portions of dichloromethane. The organic phase was dried over MgSO4, filtered and concentrated in vacuo to give a dark oil. The product was purified by flash chromatography (SiO2, gradient from 0 to 20% ethyl acetate in hexanes) to yield 0.16 g of 2-(4,4-dimethyl-chroman-7-yl)-heptanoic acid as a pale yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[N:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].CN(C=O)C.[NH2:16][C:17]1[C:18]([OH:27])=[N:19][CH:20]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:22]=1.C(N(CC)CC)C>O>[Cl:1][C:2]1[CH:10]=[N:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:16][C:17]1[C:18]([OH:27])=[N:19][CH:20]=[C:21]([C:23]([F:26])([F:24])[F:25])[CH:22]=1)=[O:5]
Reactant: O=C(Cl)c1ccncc1Cl
Reactant: Nc1cc(C(F)(F)F)cnc1O
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(Nc1cc(C(F)(F)F)cnc1O)c1ccncc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 0.88 g of 3-chloroisonicotinic acid, 5 ml of thionyl chloride and 20 mg of DMF was heated to reflux for three hours. After the reaction mixture was cooled to room temperature, it was concentrated under reduced pressure to give 3-chloroisonicotinic acid chloride. The resultant 3-chloroisonicotinic acid chloride and 4 ml of DMF was added dropwise to a mixture of 1.0 g of 3-amino-2-hydroxy-5-trifluoromethylpyridine, 1.14 g of triethylamine and 8 ml of DMF while ice-cooling. The reaction mixture was stirred at room temperature for one hour, and then stirred while heating at 50° C. for 30 minutes. The reaction mixture was cooled to room temperature, and then water was added to the reaction mixture, followed by extraction with ethyl acetate twice. The combined organic layers were washed with water and a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.87 g of 3-chloro-N-[2-hydroxy-5-(trifluoromethyl)pyridin-3-yl]isonicotinamide.
Reaction SMILES: [I:1][CH3:2].[F:3][C:4]1[CH:5]=[C:6]([NH:17][C:18]([NH2:20])=[S:19])[CH:7]=[C:8]([F:16])[C:9]=1[N:10]1[CH:14]=[N:13][C:12]([CH3:15])=[N:11]1>C(O)C>[IH:1].[F:3][C:4]1[CH:5]=[C:6]([NH:17][C:18]([S:19][CH3:2])=[NH:20])[CH:7]=[C:8]([F:16])[C:9]=1[N:10]1[CH:14]=[N:13][C:12]([CH3:15])=[N:11]1
Reactant: Cc1ncn(-c2c(F)cc(NC(N)=S)cc2F)n1
Reactant: CI
Solvent: CCO
Product: CSC(=N)Nc1cc(F)c(-n2cnc(C)n2)c(F)c1
Product: I
Temperature: 70 °C
Yield: 92.6 %

Procedure:
Step R (4): Iodomethane (0.413 mL, 6.63 mmol) was added to a solution of 1-(3,5-difluoro-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl)thiourea (1.7 g, 6.31 mmol) in absolute ethanol (50 mL). The resulting mixture was heated at 70° C. for 3 h. After cooling to rt, the reaction was concentrated in vacuo. The residual volatiles were removed under high vacuum to afford methyl 3,5-difluoro-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenylcarbamimidothioate, hydroiodide (2.4 g, 5.84 mmol, 92% yield) as a grey solid. LC-MS (M+H)+ 284.0. 1H NMR (500 MHz, DMSO-d6) δ ppm 8.86 (s, 1 H), 7.50 (d, J=8.9 Hz, 2 H), 2.71 (s, 3 H), 2.38 (s, 3 H).
Reaction SMILES: C1(NCCO)C=CC=CC=1.[CH2:11]([O:13][C@@H:14]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:21][CH:20]=1)[C:15]([OH:17])=[O:16])[CH3:12].O.S(=O)(=O)(O)O>C1(C)C=CC=CC=1>[CH2:11]([O:13][CH:14]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:21][CH:20]=1)[C:15]([OH:17])=[O:16])[CH3:12]
Reactant: CCO[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)O
Agent: O=S(=O)(O)O
Agent: OCCNc1ccccc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(Cc1ccc(OCc2ccccc2)cc1)C(=O)O
Temperature: 12.5 °C
Reaction time: 0.12 h

Procedure:
A mixture of (S)-2-ethoxy-3-(4-benzyloxyphenyl)propanoic acid α-methyl benzyl amino salt of the formula (12) or (S)-2-ethoxy-3-(4-benzyloxyphenyl) propanoic acid phenyl glycinol salt of the formula (18), (6.7 g) water (70 ml) and toluene (35 ml) was taken in a reaction flask and stirred for 5-10 min. The reaction mass was cooled to 10-15° C. and 25% cold sulfuric acid was added slowly to adjust pH of the reaction mass to 2. Aqueous and organic layers were separated. Aqueous layer was extracted with toluene (35 ml). The combined toluene layers were washed with water (20 ml) and evaporated to yield (S) 2-ethoxy-3-(4-benzyloxyphenyl)propanoic acid the formula (9b) (4 g).
Reaction SMILES: [OH:1][C:2]1[N:6]=[CH:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:8]=2[Cl:14])[N:3]=1.C[O-].[Na+].Br[CH:19]([CH3:25])[C:20]([O:22][CH2:23][CH3:24])=[O:21]>CS(C)=O>[CH2:23]([O:22][C:20]([CH:19]([O:1][C:2]1[N:6]=[CH:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:8]=2[Cl:14])[N:3]=1)[CH3:25])=[O:21])[CH3:24]
Reactant: CCOC(=O)C(C)Br
Reactant: Oc1ncn(-c2ccc(Cl)cc2Cl)n1
Agent: C[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCOC(=O)C(C)Oc1ncn(-c2ccc(Cl)cc2Cl)n1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
Thirteen g of 3-hydroxy-1-(2,4-dichlorophenyl)-1,2,4-1H-triazole was added to a solution of sodium methoxide (prepared from 1.3 g of sodium and excess methanol) in 200 ml of dimethylsulfoxide. The solution was heated on a steam bath for 2 hours, and then 10 g of ethyl 2-bromopropionate was added and heating was continued for 1.5 hours more. The mixture was then cooled, poured over ice-water, and extracted with 200 ml of diethyl ether. The ether extract was washed with 1N hydrochloric acid, with saturated aqueous sodium bicarbonate, and finally with saturated brine, and was dried with sodium sulfate and phase separation paper. The solvent was removed under vacuum to obtain 16 g of the desired product, an oil.
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1.[F:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22]O)=[C:18]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)[CH:17]=1>>[F:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][O:1][C:2]2[N:6]([C:7]3[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=3)[N:5]=[CH:4][CH:3]=2)=[C:18]([O:24][CH2:25][C:26]2[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=2)[CH:17]=1
Reactant: N#Cc1ccnc(-n2nccc2O)c1
Reactant: OCc1ccc(F)cc1OCc1ccc(F)cc1
Product: N#Cc1ccnc(-n2nccc2OCc2ccc(F)cc2OCc2ccc(F)cc2)c1

Procedure:
The title compound was prepared from 2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and [4-fluoro-2-[(4-fluorophenyl)methoxy]phenyl]methanol according to the procedure for the preparation of Example 39, part C. [M+H] Calc'd for C23H16F2N4O2, 419. Found, 419.
Reaction SMILES: [CH2:1]1[O:14][C:13]2[CH:12]=[CH:11][C:5]([CH:6]=[CH:7][N+:8]([O-:10])=[O:9])=[CH:4][C:3]=2[O:2]1.[CH3:15][N:16]([CH3:20])[C:17](=[S:19])[S-:18].C[NH2+]C>C(=S)=S>[CH3:15][N:16]([CH3:20])[C:17](=[S:18])[S:19][CH:6]([CH2:7][N+:8]([O-:10])=[O:9])[C:5]1[CH:11]=[CH:12][C:13]2[O:14][CH2:1][O:2][C:3]=2[CH:4]=1
Reactant: CN(C)C(=S)[S-]
Reactant: O=[N+]([O-])C=Cc1ccc2c(c1)OCO2
Agent: C[NH2+]C
Solvent: S=C=S
Product: CN(C)C(=S)SC(C[N+](=O)[O-])c1ccc2c(c1)OCO2

Procedure:
As in Example 17, reaction of 3,4-(methylenedioxy)-β-nitrostyrene with dimethylammonium dimethyldithiocarbamate in the presence of carbon disulfide gave 3,4-(methylenedioxy)-α-(nitromethyl)benzyl dimethyldithiocarbamate melting at 122° C.-124° C. when recrystallized without heating from acetone-ethanol solution.
Reaction SMILES: C[O:2][C:3]([C:5]1([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH2:7][CH2:6]1)=[O:4].[H-].[Na+].[H][H].Br[CH2:20][CH:21]([O:25][CH2:26][CH3:27])[O:22][CH2:23][CH3:24]>CN(C=O)C>[CH2:23]([O:22][CH:21]([O:25][CH2:26][CH3:27])[CH2:20][O:14][C:11]1[CH:12]=[CH:13][C:8]([C:5]2([C:3]([OH:2])=[O:4])[CH2:7][CH2:6]2)=[CH:9][CH:10]=1)[CH3:24]
Reactant: [H][H]
Reactant: COC(=O)C1(c2ccc(O)cc2)CC1
Reactant: CCOC(CBr)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(COc1ccc(C2(C(=O)O)CC2)cc1)OCC
Temperature: 160 °C
Reaction time: 15 h
Yield: 40.3 %

Procedure:
To a stirred solution of 1-(4-hydroxy-phenyl)-cyclopropanecarboxylic acid methyl ester (15.0 g, 84.3 mmol) in DMF (50 mL) was added sodium hydride (6.7 g, 170 mmol, 60% in mineral oil) at 0° C. After hydrogen evolution ceased, 2-bromo-1,1-diethoxy-ethane (16.5 g, 84.3 mmol) was added dropwise to the reaction mixture. The reaction was stirred at 160° C. for 15 hours. The reaction mixture was poured onto ice (100 g) and extracted with CH2Cl2. The combined organics were dried over Na2SO4. The solvent was evaporated under vacuum to give crude 1-[4-(2,2-diethoxy-ethoxy)-phenyl]-cyclopropanecarboxylic acid (10 g), which was used directly in the next step without purification.
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH:7]=[C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([S:15]([CH3:18])(=[O:17])=[O:16])[C:10]=2[F:19])[CH2:5][CH2:4]1)[CH3:2].C(O)=O>[Pd].C(O)(C)C>[CH2:1]([N:3]1[CH2:4][CH2:5][CH:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([S:15]([CH3:18])(=[O:17])=[O:16])[C:10]=2[F:19])[CH2:7][CH2:8]1)[CH3:2]
Reactant: CCN1CC=C(c2cccc(S(C)(=O)=O)c2F)CC1
Agent: [Pd]
Solvent: O=CO
Solvent: CC(C)O
Product: CCN1CCC(c2cccc(S(C)(=O)=O)c2F)CC1
Reaction time: 20 h
Yield: 175.2 %

Procedure:
A mixture of 1-ethyl-4-[2-fluoro-3-(methylsulfonyl)phenyl]-1,2,3,6-tetrahydropyridine (5 g, 17, 7 mmol), formic acid (3.4 ml, 90 mmol) and palladium on carbon (1.1 g) in isopropanol (50 ml) was shaken in a parr apparatus for 20 h. The reaction mixture was filtered through a pad of celite and the filtrate was concentrated and evaporated to dryness. Aqueous sodium carbonate (10%, 200 ml) was added and the mixture was extracted with ethyl acetate (3×100 ml). The combined organic phases was dried (MgSO4) and evaporated to dryness. Flash column chromatography (ethylacetate/methanol, 1:1) gave the title compound (3.5 g, 70%). The amine was converted to the hydrochloric acid salt and recrystallized from ethanol/diethyl ether: M.p. 280.2° C. MS m/z (relative intensity, 70 eV) 285 (M+, 12), 270 (bp), 57 (19), 84 (15) 133 (9).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][N:3]=1.CO[CH:11](OC)[N:12](C)C.NOS(O)(=O)=O>CN(C)C=O.CO.N1C=CC=CC=1>[I:8][C:6]1[CH:5]=[CH:4][N:3]2[N:12]=[CH:11][N:1]=[C:2]2[CH:7]=1
Reactant: COC(OC)N(C)C
Reactant: Nc1cc(I)ccn1
Agent: NOS(=O)(=O)O
Solvent: CN(C)C=O
Solvent: CO
Solvent: c1ccncc1
Product: Ic1ccn2ncnc2c1
Temperature: 130 °C
Reaction time: 8 h

Procedure:
To a stirred solution of the product from Step B above (220 mg, 1.00 mmol) in N,N-dimethylformamide (0.5 mL) was added N,N-dimethylformamide dimethyl acetal (0.37 mL, 2.60 mmol). The reaction mixture was heated to 130° C. overnight. After cooling to room temperature, the volatiles were removed under reduced pressure to afford a red oil, which was dissolved in 2.0 mL of methanol and 0.162 mL of pyridine. The solution was cooled in an ice bath and hydroxylamine-O-sulfonic acid (147 mg, 1.30 mmol) was added in one portion. The reaction mixture was allowed to warm to room temperature and was stirred overnight. The volatiles were removed under reduced pressure, and the residue was partitioned between saturated aqueous brine solution and ethyl acetate. The aqueous layer was further extracted with ethyl acetate, and the combined organic layers were washed with saturated aqueous brine solution (100 mL), dried over magnesium sulfate and concentrated under reduced pressure to afford the title compound as an orange solid. MS 246.1 (M+1).
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][S:9]([C:12]1[CH:33]=[CH:32][C:15]([O:16][C:17]2[N:22]=[CH:21][N:20]=[C:19]3[N:23]([CH:26]4[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]4)[N:24]=[CH:25][C:18]=23)=[CH:14][CH:13]=1)(=[O:11])=[O:10].[CH:34](=O)[C:35]1[C:36](=[CH:38][CH:39]=[CH:40][CH:41]=1)[OH:37].C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH3:8][S:9]([C:12]1[CH:13]=[CH:14][C:15]([O:16][C:17]2[N:22]=[CH:21][N:20]=[C:19]3[N:23]([CH:26]4[CH2:27][CH2:28][N:29]([CH2:34][C:35]5[CH:41]=[CH:40][CH:39]=[CH:38][C:36]=5[OH:37])[CH2:30][CH2:31]4)[N:24]=[CH:25][C:18]=23)=[CH:32][CH:33]=1)(=[O:11])=[O:10]
Reactant: CS(=O)(=O)c1ccc(Oc2ncnc3c2cnn3C2CCNCC2)cc1
Reactant: O=Cc1ccccc1O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)c1ccc(Oc2ncnc3c2cnn3C2CCN(Cc3ccccc3O)CC2)cc1

Procedure:
2-{4-[4-(4-Methanesulfonyl-phenoxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidin-1-ylmethyl}-phenol was prepared according to General Procedure H by the reaction of 4-(4-methanesulfonyl-phenoxy)-1-piperidin-4-yl-1H-pyrazolo[3,4-d]pyrimidine trifluoroacetate salt (Intermediate 27) with salicylaldehyde (available from Aldrich Chemical Company, Inc., Milwaukee, Wis., USA), triethylamine, and sodium triacetoxyborohydride in 1,2-dichloroethane. 1H NMR (400 MHz, DMSO-d6) δ 1.95-2.03 (m, 2H), 2.19-2.28 (m, 4H), 2.32-2.38 (m, 2H), 2.98-3.06 (m, 2H), 3.30 (methyl sulfonyl and water peak), 3.71 (s, 2H), 4.84-4.89 (m, 1H), 6.75-6.79 (m, 2H), 7.08-7.14 (m, 2H), 7.63-7.65 (m, 2H), 8.04-8.07 (m, 2H), 8.40 (s, 1H), 8.56 (s, 1H). Mass spectrum MH+=480.
Reaction SMILES: Br[CH:2]([C:26](=[O:28])[NH2:27])[CH2:3][C:4]1[CH:5]=[CH:6][C:7]([O:24][CH3:25])=[C:8]([CH:23]=1)[C:9]([NH:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=1)=[O:10].[C:29]([O-:32])(=[S:31])[CH3:30].[K+]>O1CCCC1>[C:29]([S:31][CH:2]([C:26](=[O:28])[NH2:27])[CH2:3][C:4]1[CH:5]=[CH:6][C:7]([O:24][CH3:25])=[C:8]([CH:23]=1)[C:9]([NH:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=1)=[O:10])(=[O:32])[CH3:30]
Reactant: CC([O-])=S
Reactant: COc1ccc(CC(Br)C(N)=O)cc1C(=O)NCc1ccc(C(F)(F)F)cc1
Agent: [K+]
Solvent: C1CCOC1
Product: COc1ccc(CC(SC(C)=O)C(N)=O)cc1C(=O)NCc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 91.4 %

Procedure:
To 1.00 g of 5-(2-bromo-2-carbamoylethyl)-2-methoxy-N-(4-trifluoromethylbenzyl)benzamide were added 80 ml of tetrahydrofuran and 368 mg of potassium thioacetate under an atmosphere of argon, and the mixture was stirred for 6 hours at room temperature. Solvent was distilled off under reduced pressure, and ethyl acetate was added to the residue, which was washed with water and saturated brine in sequence and dried over anhydrous sodium sulfate. Solvent was distilled off under reduced pressure, and the residue obtained was crystallized from hexane-ethyl acetate, then the crystals were collected by filtration to obtain 904 mg of 5-(2-acetylthio-2-carbamoylethyl)-2-methoxy-N-(4-trifluoromethylbenzyl)benzamide as light brown crystals.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][CH:10]([CH3:13])[C:9]1=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[N:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1.P(Cl)(Cl)(Cl)=O>C1C=CC=CC=1>[CH2:1]([N:8]1[CH2:12][CH2:11][CH:10]([CH3:13])[C:9]1=[N:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[N:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccccc1N1CCOCC1
Reactant: CC1CCN(Cc2ccccc2)C1=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccccc1
Product: CC1CCN(Cc2ccccc2)C1=Nc1ccccc1N1CCOCC1

Procedure:
In a similar manner to that described in Example 1, 1-benzyl-3-methyl-2-pyrrolidone (14.17 g) in benzene (80 ml) was reacted with 4-(2-aminophenyl)morpholine (8.9 g) in benzene (30 ml) in the presence of phosphorus oxychloride (6.86 ml) for 24 hours at 70° C. to give 4-[2-(1-benzyl-3-methyl-2-pyrrolidinylideneamino)phenyl]morpholine (m.p. 96°-97° C.) which was recrystallised from hexane.
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9](O)(=[O:15])[CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].C1C=C(SSC2N=CC=CC=2)N=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[CH2:1]([O:8][C:9](=[O:15])[CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCCC(=O)O
Reactant: OCc1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: c1ccc(SSc2ccccn2)nc1
Solvent: ClCCl
Product: CCCCCC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture of 1.08 g. of benzylalcohol, 1.16 g. of caproic acid, 2.20 g. of 2,2'-dipyridyl disulfide and 50 ml. of methylene chloride is added dropwise a solution of 2.62 g. of triphenyl phosphine in 20 ml. of methylene chloride while stirring at room temperature. After completion of the addition, the mixture is stirred at room temperature for an additional 3 hours. The reaction mixture is treated with the same procedure as in Example 1 (1) to give 1.9 g. of the desired product boiling at 75°C/0.2 mmHg.
Reaction SMILES: Cl[C:2]([O:4][CH:5]=[CH2:6])=[O:3].C(N(CC)CC)C.[Br:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][CH:19]=[C:18]2[S:24][CH:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>ClCCl>[Br:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][CH:19]=[C:18]2[S:24][CH:25]1[CH2:30][CH2:29][N:28]([C:2]([O:4][CH:5]=[CH2:6])=[O:3])[CH2:27][CH2:26]1
Reactant: C=COC(=O)Cl
Reactant: Brc1ccc2[nH]cc(SC3CCNCC3)c2c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=COC(=O)N1CCC(Sc2c[nH]c3ccc(Br)cc23)CC1
Reaction time: 2 h

Procedure:
Vinyl chloroformate (0.75 ml) is added dropwise to a solution of triethylamine (1.2 ml) and 5-bromo-3-(piperidin-4-ylthio)-1H-indole (2.5 g, prepared in Example 49) in dichloromethane (25 ml) at 0° C. After 2 hours at room temperature, the solution is washed with water. The organic phase is dried over magnesium sulfate and concentrated. Vinyl 4-[(5-bromo-1H-indol-3-yl)thio]piperidine-1-carboxylate (1.8 g) is obtained after chromatography on silica gel (eluent: cyclohexane/AcOEt 70/30).
Reaction SMILES: S(C1C=CC=C[C:6]=1[C:7]([O:9][C:10](=[O:21])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[S:17]([OH:20])(=[O:19])=O)=O)(O)(=O)=O.[CH3:26][O:27][CH2:28]C(O)C.P(Cl)(Cl)([Cl:34])=O>CN(C)C=O>[CH3:26][O:27][CH2:28][CH:7]([O:9][C:10]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[S:17]([Cl:34])(=[O:19])=[O:20])=[O:21])[CH3:6]
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=C(OC(=O)c1ccccc1S(=O)(=O)O)c1ccccc1S(=O)(=O)O
Reactant: COCC(C)O
Solvent: CN(C)C=O
Product: COCC(C)OC(=O)c1ccccc1S(=O)(=O)Cl
Temperature: 25 °C
Yield: 152.1 %

Procedure:
In 15 ml of N,N-dimethylformamide, 9.2 g of o-sulfobenzoic anhydride was dissolved, and 5.0 g of 1-methoxy-2-propanol was added dropwise thereto with stirring at room temperature. After heating at 70° C. for 1 hour and cooling to room temperature, 11.5 g of phosphorus oxychloride was further added dropwise, followed by stirring at room temperature for 6 hours. The reaction mixture was poured on 100 ml of ice water, and extracted with two 50 ml portions of ethyl acetate. After washing with an aqueous solution of sodium chloride, the extract was dried over magnesium sulfate, and concentrated to obtain 10.6 g of an oily product.
Reaction SMILES: [C:1](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].CCN(C(C)C)C(C)C.[OH:24][C:25]([C:27]([F:30])([F:29])[F:28])=[O:26].[F:31][C:32]1[CH:37]=[C:36]([F:38])[CH:35]=[CH:34][C:33]=1[CH:39]([F:60])[CH:40]1[CH2:45][CH2:44][N:43]([C:46]2[N:51]=[C:50]3[CH2:52][NH:53][CH2:54][CH2:55][C:49]3=[N:48][C:47]=2[NH:56][CH:57]([CH3:59])[CH3:58])[CH2:42][CH2:41]1.C=O>CO>[F:31][C:32]1[CH:37]=[C:36]([F:38])[CH:35]=[CH:34][C:33]=1[CH:39]([F:60])[CH:40]1[CH2:45][CH2:44][N:43]([C:46]2[N:51]=[C:50]3[CH2:52][N:53]([CH3:1])[CH2:54][CH2:55][C:49]3=[N:48][C:47]=2[NH:56][CH:57]([CH3:58])[CH3:59])[CH2:42][CH2:41]1.[C:25]([OH:26])([C:27]([F:30])([F:29])[F:28])=[O:24]
Reactant: CC(C)Nc1nc2c(nc1N1CCC(C(F)c3ccc(F)cc3F)CC1)CNCC2
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: CC(C)Nc1nc2c(nc1N1CCC(C(F)c3ccc(F)cc3F)CC1)CN(C)CC2
Reaction time: 0.5 h

Procedure:
Sodium triacetoxyborohydride (15.3 mg, 0.072 mmol) was added to a mixture of DIPEA (9.4 mg, 0.072 mmol), 3-(4-((2,4-difluorophenyl)fluoromethyl)piperidin-1-yl)-N-isopropyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amine TFA salt (19.3 mg, 0.036 mmol) and formaldehyde (3 μL, 0.036 mmol) in MeOH (360 μL) at rt. After 30 min, the mixture was purified by HPLC Method A to give the title compound as a TFA salt (19.3 mg, 97%) as a yellow film. 1H NMR (400 MHz, methanol-d4) δ ppm 1.24 (dd, J=6.4, 2.2 Hz, 6H), 1.40-1.48 (m, 1H), 1.53-1.74 (m, 2H), 1.96-2.14 (m, 2H), 2.60-2.73 (m, 2H), 2.93-3.06 (br m, 2H), 3.06 (s, 3H), 3.39-3.54 (m, 3H), 3.69-3.81 (m, 1H), 4.18 (dt, J=13.1, 6.4 Hz, 2H), 4.16-4.36 (br m, 1H), 5.52 (dd, J=46.2, 7.6 Hz, 1H), 6.97-7.08 (m, 2H), 7.47-7.54 (m, 1H); ESI-MS m/z [M+H]+ 434.4.