Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[S:3][C:4]([C:7]([F:10])([F:9])[F:8])=[N:5][N:6]=1.[Cl:11][C:12]1[CH:13]=[C:14]([SH:19])[CH:15]=[CH:16][C:17]=1[Cl:18].C(N(CC)CC)C>C(O)C>[Cl:11][C:12]1[CH:13]=[C:14]([S:19][C:2]2[S:3][C:4]([C:7]([F:10])([F:9])[F:8])=[N:5][N:6]=2)[CH:15]=[CH:16][C:17]=1[Cl:18]
Reactant: FC(F)(F)c1nnc(Br)s1
Reactant: Sc1ccc(Cl)c(Cl)c1
Solvent: CCO
Solvent: CCN(CC)CC
Product: FC(F)(F)c1nnc(Sc2ccc(Cl)c(Cl)c2)s1
Reaction time: 2 h
Yield: 67.3 %

Procedure:
130.5 g (0.66 mole) of 2-bromo-5-trifluoromethyl-1,3,4-thiadiazole were added dropwise to a solution of 98.1 g (0.66 mole) of 3,4dichloro-thiophenol and 57.6 g (0.66 mole) of triethylamine in 500 ml of ethanol. An exothermic effect was observed and a white precipitate separated out. The mixture was stirred for a further 2 hours under reflux, concentrated to half in vacuo and introduced into 1 liter of ice water. The white precipitate was filtered off, dried over phosphorus pentoxide and recrystallized from about 300 ml of petroleum ether. 147 g (76% of theory) of 2-(3',4' -dichlorophenylthio)-5-trifluoromethyl-1,3,4-thiadiazole of melting point 46° C were obtained.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[N:12]1[CH2:17][CH2:16][O:15][C:14]2[CH:18]=[C:19]([S:22]([N:25]([CH2:31][C:32]3[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=3)[C:26]3[S:27][CH:28]=[CH:29][N:30]=3)(=[O:24])=[O:23])[CH:20]=[CH:21][C:13]1=2.[CH2:40]([Sn](CCCC)(CCCC)CCCC)[CH:41]=[CH2:42]>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:42]([C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[N:12]1[CH2:17][CH2:16][O:15][C:14]2[CH:18]=[C:19]([S:22]([N:25]([CH2:31][C:32]3[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=3)[C:26]3[S:27][CH:28]=[CH:29][N:30]=3)(=[O:24])=[O:23])[CH:20]=[CH:21][C:13]1=2)[CH:41]=[CH2:40]
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(c2)OCCN3c2ccc(C(F)(F)F)cc2Br)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: C=CCc1cc(C(F)(F)F)ccc1N1CCOc2cc(S(=O)(=O)N(Cc3ccc(OC)cc3)c3nccs3)ccc21
Temperature: 100 °C
Yield: 95.8 %

Procedure:
A reaction vial was charged with 4-(2-bromo-4-(trifluoromethyl)phenyl)-N-(4-methoxybenzyl)-N-(thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (EXAMPLE 53, Step 1; 0.347 g, 0.542 mmol) and Pd(PPh3)4 (0.031 g, 0.027 mmol), and then diluted with DMF (1.084 ml). After purging with nitrogen, allyltributyltin (0.202 ml, 0.650 mmol) was added and the reaction was heated to 100° C. for 30 minutes until completion. The reaction was concentrated in vacuo and purified via silica-gel chromatography (12-g RediSep Gold column), eluting with 0-30% ethyl acetate in heptanes) to yield 4-(2-allyl-4-(trifluoromethyl)phenyl)-N-(4-methoxybenzyl)-N-(thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (0.312 g, 0.519 mmol, 96% yield) as a yellow oil. m/z (ESI) 602.1 (M+H)+.
Reaction SMILES: CS(O[CH2:6][C@@H:7]1[O:11][C:10](=[O:12])[N:9]([C:13]2[CH:18]=[CH:17][C:16]([I:19])=[C:15]([F:20])[CH:14]=2)[CH2:8]1)(=O)=O.[N-:21]=[N+:22]=[N-:23].[Na+].C(=O)(O)[O-].[Na+]>CN(C)C=O>[N:21]([CH2:6][C@@H:7]1[O:11][C:10](=[O:12])[N:9]([C:13]2[CH:18]=[CH:17][C:16]([I:19])=[C:15]([F:20])[CH:14]=2)[CH2:8]1)=[N+:22]=[N-:23]
Reactant: CS(=O)(=O)OC[C@H]1CN(c2ccc(I)c(F)c2)C(=O)O1
Reactant: [N-]=[N+]=[N-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NC[C@H]1CN(c2ccc(I)c(F)c2)C(=O)O1
Temperature: 75 °C
Reaction time: 8 h
Yield: 88.7 %

Procedure:
[(5R)-3-(3-Fluoro-4-iodophenyl)-2-oxo-1,3-oxazolidin-5-yl]methyl methanesulfonate (Intermediate 4, 6.14 g, 14.7 mmol) was dissolved in N,N-dimethylformamide (50 ml). Sodium azide (1.92 g, 29.6 mmol) was added and the reaction was stirred at 75° C. overnight. The yellow mixture was poured into half-saturated sodium bicarbonate and extracted using ethyl acetate. The organic layer was washed three times with water, dried (magnesium sulfate), filtered, and concentrated to give the title compound as a yellow solid (4.72 g).
Reaction SMILES: [CH3:1][O:2][N:3]=C1C2C=CN=NC=2OC1.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][N:18]=[C:17]2[O:21][CH2:22][C:23](=O)[C:16]=12>>[CH3:1][O:2][N:3]=[C:23]1[C:16]2[C:17](=[N:18][CH:19]=[CH:20][C:15]=2[O:14][CH3:13])[O:21][CH2:22]1
Reactant: CON=C1COc2nnccc21
Reactant: COc1ccnc2c1C(=O)CO2
Product: CON=C1COc2nccc(OC)c21

Procedure:
This compound was prepared using a method analogous to that of furo[2,3-c]pyridazin-5(6H)-one O-methyl oxime (A.2.3.3), 4-methoxyfuro[2,3-b]pyridin-3(2H)-one replacing furo[2,3-c]pyridazin-5(6H)-one. Purification by (KP-SIL™ from Biotage) using Hept/EtOAc (1/1) gives the desired product as white solid;
Reaction SMILES: [C:1]1([C@@H:7]([C@H:9]([C:11](N)=[O:12])[OH:10])[NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(=O)(=O)(O)[OH:15].[O-]S([O-])(=O)=O.[Ba+2]>O>[C:1]1([C@@H:7]([C@H:9]([C:11]([OH:12])=[O:15])[OH:10])[NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NC(=O)[C@H](O)[C@@H](N)c1ccccc1
Reactant: O=S(=O)(O)O
Agent: O=S(=O)([O-])[O-]
Agent: [Ba+2]
Solvent: O
Product: N[C@@H](c1ccccc1)[C@@H](O)C(=O)O
Temperature: 80 °C
Yield: 73.6 %

Procedure:
(2R,3S)-3-phenyl-isoserinamide (200 mg, 1.11 mmol), as prepared in Example 32, was combined with 354 mg (1.12 mmol) of Ba(OH)2 ·8H2O and water (2 ml). The resulting suspension was heated to reflux for nine hours. After the reaction mixture was cooled to 80° C., 15 ml of water was added to the solution. The temperature of the solution was maintained at 80° C. for 20 minutes before a solution of 110 mg, 1.11 mmol of concentrated sulfuric acid in 1 ml of water was added. A white precipitate appeared in the solution which was determined to have a pH of between 5 and 7. Heating at 80° C. was maintained for another 20 minutes, and the mixture was then cooled to room temperature. The resulting precipitate (BaSO4) was centrifuged to the bottom of the container, the supernatant was separated, and solvent was removed under vacuum. The resulting white solid was extracted with acetone and collected by filtration to provide 148 mg of the title compound, for a yield of 74%. The material melted with decomposition at 238° C. The 1H NMR (D2O/NaOD) data were as follows: δ 3.94 (d, J=3.9 Hz, 1H), 4.01 (d, J=3.9 Hz, 1H), 7.0-7.5 (aromatic, 5H). Analytical for C9H11NO3 : Calculated: C, 59.66; H, 6.07, N, 7.73. Found: C, 59.10; H, 6.11; N, 7.61.
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[CH:12]=[C:11]([NH:15][CH3:16])[N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:17][CH:18]([C:24]([O:26]CC)=O)[C:19]([O:21]CC)=O.C1(OC2C=CC=CC=2)C=CC=CC=1>C(OCC)C>[CH2:1]([N:8]1[C:13](=[O:14])[C:12]2[C:24]([OH:26])=[C:18]([CH3:17])[C:19](=[O:21])[N:15]([CH3:16])[C:11]=2[N:10]=[CH:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CNc1cc(=O)n(Cc2ccccc2)cn1
Reactant: CCOC(=O)C(C)C(=O)OCC
Solvent: CCOCC
Solvent: c1ccc(Oc2ccccc2)cc1
Product: Cc1c(O)c2c(=O)n(Cc3ccccc3)cnc2n(C)c1=O
Yield: 76 %

Procedure:
3-Benzyl-6-(methylamino)pyrimidin-4(3H)-one (compound 5A) (10 g, 46.5 mmol, 1 eq) and diethyl methylmalonate (16 mL, 93 mmol, 2 eq) were heated in phenyl ether (20 mL, 127 mmol) at 240° C. for 3 hours. The solution was cooled and diethyl ether (100 mL) was added. A precipitate formed which was filtered and washed with ether to give 10.5 g of the title compound as a tan solid (76%). [M+H] calc'd for C16H15N3O3, 298; found, 298.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][CH:14]2[C:19]([NH:21][C:22]1[CH:23]=[N:24][C:25]([CH:28]([CH3:30])[CH3:29])=[CH:26][CH:27]=1)=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:32][C:33]1[N:34]=[C:35]([CH2:38][CH3:39])[S:36][CH:37]=1>>[CH2:1]([O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][CH:14]2[C:19]([N:21]([CH2:32][C:33]1[N:34]=[C:35]([CH2:38][CH3:39])[S:36][CH:37]=1)[C:22]1[CH:23]=[N:24][C:25]([CH:28]([CH3:30])[CH3:29])=[CH:26][CH:27]=1)=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)c1ccc(NC(=O)C2CCCc3c(OCc4ccccc4)cccc32)cn1
Reactant: CCc1nc(CCl)cs1
Product: CCc1nc(CN(C(=O)C2CCCc3c(OCc4ccccc4)cccc32)c2ccc(C(C)C)nc2)cs1
Yield: 82.5 %

Procedure:
By the reaction and treatment in the same manner as in Example 132 using 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (1.20 g) and 4-chloromethyl-2-ethylthiazole (0.49 g) as starting materials, 5-benzyloxy-N-[(2-ethylthiazol-4-yl)methyl]-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (1.30 g) was obtained.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[CH2:12][C:13]#[N:14])=[CH:7][CH:6]=1.[H][H]>[Ni].CO>[CH3:1][O:2][CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([CH:11]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[CH2:12][CH2:13][NH2:14])=[CH:9][CH:10]=1
Reactant: [H][H]
Reactant: COCOc1ccc(C(CC#N)c2cccnc2)cc1
Agent: [Ni]
Solvent: CO
Product: COCOc1ccc(C(CCN)c2cccnc2)cc1
Yield: 89.4 %

Procedure:
An appropriate amount of Raney nickel was suspended in 15 ml of saturated ammonical methanol solution, 0.54 g of 3-(4-methoxymethyloxyphenyl)-3-(3-pyridyl)propionitrile was added to the suspension and the mixture was stirred for 18 hours under 15 atmospheric pressure in an atmosphere of hydrogen. The resulting reaction mixture was filtered and the filtrate was concentrated under a reduced pressure. The thus prepared residue was subjected to silica gel column chromatography to obtain 0.49 g of 3-(4-methoxymethyloxyphenyl)-3-(3-pyridyl)propylamine from ammonia water-methanol-chloroform (1:10:100 v/v) eluate fraction.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:13]([CH:21]([CH3:26])[C:22](OC)=[O:23])[C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)(=[O:12])=[O:11])=[CH:6][CH:5]=1)[CH3:2].O.[NH2:28][NH2:29]>CO>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:13]([CH:21]([CH3:26])[C:22]([NH:28][NH2:29])=[O:23])[C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)(=[O:12])=[O:11])=[CH:6][CH:5]=1)[CH3:2]
Reactant: NN
Reactant: CCOc1ccc(S(=O)(=O)N(c2ccc(C)cc2)C(C)C(=O)OC)cc1
Solvent: O
Solvent: CO
Product: CCOc1ccc(S(=O)(=O)N(c2ccc(C)cc2)C(C)C(=O)NN)cc1
Temperature: 60 °C
Reaction time: 8 h
Yield: 52 %

Procedure:
The crude carboxylic acid methyl ester, e.g. methyl 2-{[(4-ethoxyphenyl)sulfonyl]-4-methylanilino}propanoate (264 mg, 0.70 mmol), was dissolved in MeOH (2 mL). Hydrazine hydrate was added (0.44 mL). The reaction mixture was stirred overnight at 60° C. Solvents were evaporated. The crude mass was redissolved in MeOH and solvents were evaporated again. This process was repeated three times. The desired product, e.g. 4-ethoxy-N-(2-hydrazino-1-methyl-2-oxoethyl)-N-(4-methylphenyl)benzenesulfonamide (138.4 mg, 52%) was isolated as a colorless solid in 91.1% purity by HPLC (MaxPlot detection between 230 and 400 nm).
Reaction SMILES: [CH3:1][O:2][N:3]=[CH:4][C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:6]=1[Cl:12].C([BH3-])#N.[Na+]>C(O)(=O)C>[Cl:12][C:6]1[CH:7]=[C:8]([Cl:11])[CH:9]=[CH:10][C:5]=1[CH2:4][NH:3][O:2][CH3:1]
Reactant: CON=Cc1ccc(Cl)cc1Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Product: CONCc1ccc(Cl)cc1Cl
Temperature: 24 °C
Reaction time: 7 h
Yield: 68.3 %

Procedure:
A solution of 2,4-dichloro-benzaldehyde O-methyl-oxime (1.0 g, 4.9 mmol), prepared as described in example P10a, in acetic acid (7.1 ml) was treated at 10° C. with sodium cyanoborohydride (615 mg, 9.8 mmol) added in small portions over 10 minutes and the resulting solution was stirred at 24° C. for 7 hours. The solvent was evaporated under reduced pressure (co-evaporation with toluene twice) and the residue was slurried with water. The aqueous phase was extracted with dichloromethane (2×20 ml), washed with brine and dried over anhydrous Na2SO4. After removal of the solvent, the residue (1510 mg) was purified by flash chromatography over silica gel (eluent: c-hexane/ethyl acetate 9:1). 690 mg (68.0% of theory) of N-(2,4-dichloro-benzyl)-O-methyl-hydroxylamine was obtained in form of a clear liquid.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:9][CH:8]([N:10](C)[C:11](=O)C(F)(F)F)[CH2:7][N:6]1[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[O:4].C(=O)([O-])[O-].[K+].[K+]>CO>[CH3:1][O:2][C:3]([CH:5]1[CH2:9][CH:8]([NH:10][CH3:11])[CH2:7][N:6]1[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[O:4]
Reactant: COC(=O)C1CC(N(C)C(=O)C(F)(F)F)CN1C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CNC1CC(C(=O)OC)N(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 4-[Methyl-(2,2,2-trifluoro-acetyl)-amino]-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (0.26 g, 0.73 mmol) in methanol (3 mL) was added an aqueous 1.0M solution of potassium carbonate. The reaction mixture was stirred at room temperature for 5 hours and the solvent evaporated in vacuo to yield the title compound which was used directly without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:9][C:10]2[CH:15]=[C:14]([N:16]([CH3:18])[CH3:17])[N:13]=[C:12]([N:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)[N:11]=2)[CH:6]=[CH:7][CH:8]=1.CCN(C(C)C)C(C)C.Cl[CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[C:38]([O:42][CH3:43])[CH:37]=1>O1CCOCC1>[CH3:43][O:42][C:38]1[CH:37]=[C:36]([CH:41]=[CH:40][CH:39]=1)[CH2:35][N:22]1[CH2:23][CH2:24][N:19]([C:12]2[N:11]=[C:10]([NH:9][C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=3)[CH:15]=[C:14]([N:16]([CH3:18])[CH3:17])[N:13]=2)[CH2:20][CH2:21]1
Reactant: COc1cccc(CCl)c1
Reactant: COc1cccc(Nc2cc(N(C)C)nc(N3CCNCC3)n2)c1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: COc1cccc(CN2CCN(c3nc(Nc4cccc(OC)c4)cc(N(C)C)n3)CC2)c1
Yield: 71.3 %

Procedure:
A solution of N4-(3-methoxyphenyl)-N6,N6-dimethyl-2-(1-piperazinyl)-4,6-pyrimidinediamine (36 mg, 0.1 mmol), DIPEA (52 mg, 0.4 mmol), and 1-(chloromethyl)-3-methoxybenzene (20 mg, 0.13 mmol) in 5 mL of dioxane was stirred at 100° C. for 16 h. The crude product was concentrated in vacuo and treated with saturated NaHCO3 (50 mL) and extracted with CH2Cl2 (3×50 mL). The organic layer washed with brine (2×100 mL), dried over Na2SO4, and concentrated in vacuo. The crude product was purified by chromatography on silica using hexane/EtOAc (1:3), giving the desired product (32 mg, 70%).
Reaction SMILES: [OH-].[Na+].C([O:5][C:6]([C:8]1[NH:9][C:10]([CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:11][CH:12]=1)=[O:7])C.CC(O)C>CO>[CH2:13]([C:10]1[NH:9][C:8]([C:6]([OH:7])=[O:5])=[CH:12][CH:11]=1)[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CCOC(=O)c1ccc(CCc2ccccc2)[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CC(C)O
Product: O=C(O)c1ccc(CCc2ccccc2)[nH]1

Procedure:
Freshly prepared aq. NaOH (10 M in H2O, 1.67 mmol) was added to a stirring, room temperature solution of 35 (0.0814 g, 0.333 mmol) in MeOH (0.83 mL, 0.4 M) under N2. 0.4 mL of iPrOH was added to solubilize 35. The reaction was heated to reflux until the reaction was judged complete by HPLC. The product was concentrated and then dissolved in 1.9 mL H2O. 10% aq. HCl was added dropwise until the pH=2. The white solid that precipitated from the reaction was filtered off and washed with cold H2O. The solid was dried under vacuum overnight to obtain 36 as a pale pink solid (Note: An undesired impurity has a retention time of 12.055 min by HPLC. Also, the 13C NMR of 36 at room temperature showed doublets for the peaks corresponding to the pyrrole carbons, benzyl carbon, and acid carbon. When the NMR probe was heated to 28° C., all doubled peaks collapsed into single peaks as reported below. 1H (CD3OD, 400 MHz): δ 10.97 (1H, broad s), 7.25-7.20 (2H, m), 7.18-7.11 (3H, m), 6.76 (1H, d, J=3.4 Hz), 5.90 (1H, d, J=3.4Hz), 2.94-2.84 (4H, m) ppm. 13C (CD3OD, 100 MHz): δ 164.51, 142.68, 139.79, 129.40, 129.30, 126.98, 122.36, 117.47, 108.90, 37.00, 30.67 ppm. DEPT (CDCl3, 100 MHz): CH2 carbons: 37.00, 30.67; CH carbons: 129.40, 129.30, 126.98, 117.47, 108.90 ppm. HPLC: 11.239 min.
Reaction SMILES: [SH:1][C:2]1[N:3]([CH3:15])[C:4]([C:7]2[CH:12]=[CH:11][N:10]([CH3:13])[C:9](=[O:14])[CH:8]=2)=[N:5][N:6]=1.[OH-].[Na+].[CH2:18](O)C.IC>O>[CH3:13][N:10]1[CH:11]=[CH:12][C:7]([C:4]2[N:3]([CH3:15])[C:2]([S:1][CH3:18])=[N:6][N:5]=2)=[CH:8][C:9]1=[O:14]
Reactant: CCO
Reactant: Cn1c(S)nnc1-c1ccn(C)c(=O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CI
Product: CSc1nnc(-c2ccn(C)c(=O)c2)n1C
Temperature: 25 °C
Reaction time: 6 h
Yield: 78 %

Procedure:
The title compound from example 32.1 (600 mg, 2.7 mmol) was dissolved in a solution of sodium hydroxide (216 mg, 5.4 mmol) and water (5 mL). When a clear, uniform solution was observed ethanol (6 mL) was added, followed by iodomethane (268 μL, 4.3 mmol). The reaction was stirred at room temperature for 6 h. The reaction mixture was then diluted with water and extracted four times with chloroform. The organic phase was dried over magnesium sulfate, filtered and concentrated to yield the title compound (yellowish solid, 500 mg, 78%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]([CH3:15])[CH3:14])=[N:10][C:9]=2[C:16]2[CH:17]=[C:18]([NH:22][S:23]([C:26]3[C:31]([F:32])=[CH:30][CH:29]=[CH:28][C:27]=3[F:33])(=[O:25])=[O:24])[CH:19]=[CH:20][CH:21]=2)[CH:5]=[CH:4][N:3]=1.[NH3:34]>CO>[NH2:34][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]([CH3:15])[CH3:14])=[N:10][C:9]=2[C:16]2[CH:17]=[C:18]([NH:22][S:23]([C:26]3[C:31]([F:32])=[CH:30][CH:29]=[CH:28][C:27]=3[F:33])(=[O:25])=[O:24])[CH:19]=[CH:20][CH:21]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CC(C)c1nc(-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2)c(-c2ccnc(Cl)n2)s1
Reactant: N
Solvent: CO
Product: CC(C)c1nc(-c2cccc(NS(=O)(=O)c3c(F)cccc3F)c2)c(-c2ccnc(N)n2)s1

Procedure:
Following a procedure analogous to the procedure described in Example 51, Step B using N-{3-[5-(2-chloro-4-pyrimidinyl)-2-(1-methylethyl)-1,3-thiazol-4-yl]phenyl}-2,6-difluorobenzenesulfonamide (200 mg, 0.39 mmol) in 7N ammonia in MeOH (2 mL) the title compound was obtained as a white powder (0.16 g, 0.328 mmol, 84.2% yield). 1H NMR (400 MHz, DMSO-d6): δ 11.03 (s, 1H), 7.95 (d, J=5.1 Hz, 1H), 7.68-7.72 (m, 1H), 7.35 (t, J=7.7 Hz, 1H), 7.18-7.28 (m, 5H), 6.76 (s, 2H), 6.00 (d, J=5.1 Hz, 1H), 3.25-3.31 (m, 1H), 1.36 (d, J=7.0 Hz, 6H). MS (ESI): 488.1 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:10]([CH3:26])[C:11]3[C:20]4[C:19](=[O:21])[NH:18][C:17]([CH:22]=[O:23])=[C:16]([CH3:24])[C:15]=4[CH:14]=[CH:13][C:12]=3[N:25]=2)=[C:4]([CH3:27])[CH:3]=1.[CH:28]([Mg]Br)=[CH2:29]>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:10]([CH3:26])[C:11]3[C:20]4[C:19](=[O:21])[NH:18][C:17]([CH:22]([OH:23])[CH:28]=[CH2:29])=[C:16]([CH3:24])[C:15]=4[CH:14]=[CH:13][C:12]=3[N:25]=2)=[C:4]([CH3:27])[CH:3]=1
Reactant: Cc1cc(F)ccc1Nc1nc2ccc3c(C)c(C=O)[nH]c(=O)c3c2n1C
Reactant: C=C[Mg]Br
Solvent: C1CCOC1
Product: C=CC(O)c1[nH]c(=O)c2c(ccc3nc(Nc4ccc(F)cc4C)n(C)c32)c1C
Temperature: -78 °C
Reaction time: 2 h
Yield: 91 %

Procedure:
To a 1 L 3-neck round-bottom flask equipped with a magnetic stir-bar was added 2-(4-fluoro-2-methyl-phenylamino)-1,6-dimethyl-9-oxo-8,9-dihydro-1H-imidazo[4,5-h]isoquinoline-7-carbaldehyde (7.96 g, 21.9 mmole) and THF (260 mL). The resulting slurry was cooled to −78° C., and vinylmagnesium bromide (175 mL, 1.0 M in THF) was added dropwise over 30 minutes. The mixture was stirred at −78° C. for 2 hours, then warmed to -10° C. over 30 minutes and maintained at −10° C. for an additional 2 hours. The reaction was then quenched by addition of saturated aqueous ammonium chloride (200 mL), and extracted into EtOAc (2×200 mL). The organic layers were collected, washed with brine (2×100 mL), dried over sodium sulfate, and concentrated in vacuo to provide 2-(4-fluoro-2-methyl-phenylamino)-7-(1-hydroxy-allyl)-1,6-dimethyl-1,8-dihydro-imidazo[4,5-h]isoquinolin-9-one (7.8 g, 91%) as an orange-yellow solid, which was used without further purification. 1H NMR (400 MHz, DMSO-d6+TFA) δ 10.52 (br s, 1H), 10.38 (br s, 1H), 7.71 (app s, 2H), 7.55 (dd, 1H, J1=5.5 Hz, J2=8.6 Hz), 7.35 (dd, 1H, J1=3.1 Hz, J2=9.8 Hz), 7.24 (td, 1H, J1=9.1 Hz, J2=11.7 Hz), 6.02 (ddd, 1H, J1=5.9 Hz, J2=10.6 Hz, J3=17.2 Hz), 5.41 (app d, 1H, J=5.5 Hz), 5.33 (dt, 1H, J1=1.6 Hz, J2=17.2 Hz), 5.17 (dt, 1H, J1=1.2 Hz, J2=10.2 Hz), 4.19 (s, 3H), 2.29 (s, 3H), 2.26 (s, 3H); ESMS (m/z): 393 (M+1)+.
Reaction SMILES: [ClH:1].[CH2:2]1[C:7]2[C:8](=[O:16])[C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=3[S:11][C:6]=2[CH2:5][CH2:4][NH:3]1.Br[CH2:18][CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>>[ClH:1].[CH:19]1([CH2:18][N:3]2[CH2:4][CH2:5][C:6]3[S:11][C:10]4[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=4[C:8](=[O:16])[C:7]=3[CH2:2]2)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: O=c1c2c(sc3ccccc13)CCNC2
Reactant: BrCC1CCCCC1
Agent: Cl
Product: O=c1c2c(sc3ccccc13)CCN(CC1CCCCC1)C2

Procedure:
Using the procedure of Example 19, 1,2,3,4-tetrahydro-10H-(1)-benzothiopyrano[3,2-c]pyridin-10-one hydrochloride and bromomethylcyclohexane were reacted to obtain 2-cyclohexylmethyl-1,2,3,4-tetrahydro-10H-(1)-benzothiopyrano[3,2-c]pyridin-10-one hydrochloride with the melting point and analysis of Table II.
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([C:8]([O:10][CH2:11]C)=[O:9])=[N:6][CH:7]=1.[C:13](=O)([O-])[O-:14].[K+].[K+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C)C=O.CO>[CH3:13][O:14][C:2]1[CH:3]=[CH:4][C:5]([C:8]([O:10][CH3:11])=[O:9])=[N:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)c1ccc(F)cn1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CO
Product: COC(=O)c1ccc(OC)cn1
Temperature: 90 °C
Yield: 47.1 %

Procedure:
100 mg of ethyl 5-fluoropyridine-2-carboxylate obtained from Reference Example 18 (step 2) was dissolved in 1 ml of dimethylformamide and 1 ml of methanol, and 163 mg of potassium carbonate was added to it and stirred under heat at 90° C. for 40 minutes. This was neutralized with aqueous 10% citric acid solution, extracted with chloroform, and the organic layer was washed with saturated saline water. After dried, the solvent was evaporated away under reduced pressure, and the residue was purified through silica gel column chromatography (developing solvent: hexane/ethyl acetate) to obtain 46.5 mg of methyl 5-methoxypyridine-2-carboxylate as a white crystal.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]([CH:19]=[CH:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH:13]2[C:27]([OH:29])=O)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[OH:30][NH:31]C(C1C(COCC2C=CC=CC=2)CCCCN1S(C1C=CC(OC)=CC=1)(=O)=O)=O>>[OH:30][NH:31][C:27]([CH:13]1[CH:14]([CH:19]=[CH:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:15][CH2:16][CH2:17][CH2:18][N:12]1[S:9]([C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)(=[O:11])=[O:10])=[O:29]
Reactant: COc1ccc(S(=O)(=O)N2CCCCC(COCc3ccccc3)C2C(=O)NO)cc1
Reactant: COc1ccc(S(=O)(=O)N2CCCCC(C=Cc3ccccc3)C2C(=O)O)cc1
Product: COc1ccc(S(=O)(=O)N2CCCCC(C=Cc3ccccc3)C2C(=O)NO)cc1

Procedure:
1-(4-Methoxy-benzenesulfonyl)-3-styryl-azepane-2-carboxylic acid hydroxyamide was synthesized from 1-(4-Methoxy-benzenesulfonyl)-3-styryl-azepane-2-carboxylic acid in the same manner as the procedures used for the preparation of 3-Benzyloxymethyl-1-(4-methoxy-benzenesulfonyl)-azepane-2-carboxylic acid hydroxyamide: MS (M+H)+ =431, (M+NH4)+ =448, (M-H)- =429.