Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1.[N:12]1([C:18]2[N:19]=[CH:20][C:21]3[C:26]([CH:27]=2)=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1>N1C=CC=CC=1.O>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([N:15]2[CH2:16][CH2:17][N:12]([C:18]3[N:19]=[CH:20][C:21]4[C:26]([CH:27]=3)=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH2:13][CH2:14]2)=[O:8])=[CH:5][CH:4]=1
Reactant: c1ccc2cc(N3CCNCC3)ncc2c1
Reactant: COc1ccc(C(=O)Cl)cc1
Solvent: O
Solvent: c1ccncc1
Product: COc1ccc(C(=O)N2CCN(c3cc4ccccc4cn3)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
9.38 g of 4-methoxybenzoyl chloride are added dropwise to 10 g of 3-(piperazin-1-yl)-isoquinoline, dissolved in 40 ml of pyridine. After stirring for 1 hour at room temperature, the mixture is diluted with water and extracted with ethyl acetate. The ethyl acetate phase is dried and the solvent is removed by evaporation. 5.8 g, melting point 156°-159° C., can be isolated.
Reaction SMILES: [NH2:1][CH:2]([P:11](=[O:18])([O:15][CH2:16][CH3:17])[O:12][CH2:13][CH3:14])[P:3](=[O:10])([O:7][CH2:8][CH3:9])[O:4][CH2:5][CH3:6].[C:19]1([S:25](Cl)(=[O:27])=[O:26])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>N1C=CC=CC=1.CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[C:19]1([S:25]([NH:1][CH:2]([P:3](=[O:10])([O:7][CH2:8][CH3:9])[O:4][CH2:5][CH3:6])[P:11](=[O:18])([O:12][CH2:13][CH3:14])[O:15][CH2:16][CH3:17])(=[O:27])=[O:26])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CCOP(=O)(OCC)C(N)P(=O)(OCC)OCC
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CCOP(=O)(OCC)C(NS(=O)(=O)c1ccccc1)P(=O)(OCC)OCC
Reaction time: 4 h

Procedure:
To a solution of tetraethyl (aminomethylene)bis(phosphonate) (661 mg) in pyridine (2 ml) were added benzenesulfonyl chloride (0.35 ml) and then 4-(dimethylamino)pyridine (50 mg) at ambient temperature with stirring. After stirring for 4 hours at the same temperature, the reaction mixture was diluted with ethyl acetate (20 ml). The mixture was washed with 1N hydrochloric acid four times, water and saturated aqueous hydrogen bicarbonate solution successively. The organic layer was dried over magnesium sulfate and evaporated under reduced pressure. The residue was subjected to column chromatography on silica gel (20 g) eluted with a mixture of chloroform and methanol (20:1 V/V) to give tetraethyl (phenylsulfonylaminomethylene)bis(phosphonate) as a yellow syrup (364 mg).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([S:14][C:15](=O)[CH3:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CO.C[O-].[Na+].[Br:23][CH2:24][CH2:25][CH2:26][CH2:27]CCBr>C1COCC1.CO>[Br:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:16][CH2:15][S:14][CH:11]1[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][CH2:10]1
Reactant: CC(=O)SC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: BrCCCCCCBr
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(SCCCCCCBr)CC1
Yield: 61.4 %

Procedure:
To a solution of N-t-butyloxycarbonyl-4-acetylthiopiperidine (5.5 g) in a mixture of THF (50 ml) and methanol (50 ml) was added 28% sodium methoxide methanol solution (4.76 ml) with stirring under ice-cooling and stirred at the same temperature for 30 minutes. To the solution was added 1,6-dibromohexane (17.1 g) under ice-cooling, and the mixture was successively stirred at ambient temperature for 30 minutes and then stirred at 45° C. for 2 hours. The reaction mixture was concentrated in vacuo. The resulting residue was chromatographed on silica gel (500 ml) eluting with a mixture of n-hexane and ethyl acetate (6:1 v/v). The fractions containing the desired compound were collected and evaporated under reduced pressure to give 4-(6-bromohexylthio)-N-t-butyloxycarbonylpiperidine (4.95 g).
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:25]([CH2:26][CH:27]([CH3:29])[CH3:28])[CH2:24][CH2:23][CH2:22][C:21]([C:30]([NH:32][C:33]4[CH:38]=[CH:37][C:36]([S:39][CH2:40][C:41]5[N:45]([CH2:46][CH2:47][CH3:48])[CH:44]=[N:43][C:42]=5[CH3:49])=[C:35]([CH3:50])[CH:34]=4)=[O:31])=[CH:20][C:19]=3[CH:51]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:60])C=1>ClCCl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:25]([CH2:26][CH:27]([CH3:28])[CH3:29])[CH2:24][CH2:23][CH2:22][C:21]([C:30]([NH:32][C:33]4[CH:38]=[CH:37][C:36]([S:39]([CH2:40][C:41]5[N:45]([CH2:46][CH2:47][CH3:48])[CH:44]=[N:43][C:42]=5[CH3:49])=[O:60])=[C:35]([CH3:50])[CH:34]=4)=[O:31])=[CH:20][C:19]=3[CH:51]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(SCc4c(C)ncn4CCC)c(C)c2)CCCN3CC(C)C)cc1
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(S(=O)Cc4c(C)ncn4CCC)c(C)c2)CCCN3CC(C)C)cc1
Reaction time: 1 h
Yield: 78.2 %

Procedure:
To a solution of 8-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[3-methyl-4-[[[4-methyl-1-propylimidazol-5-yl]methyl]sulfanyl]phenyl]-1,2,3,4-tetrahydro-1-benzoazocine-5-carboxamide (290 mg) in dichloromethane (10 ml) was added dropwise a 70% solution of 3-chloro-perbenzoic acid (111 mg) in dichloromethane (10 ml) at −78° C. After stirring as such for 1 hour, the dry ice-acetone bath was removed, and an aqueous sodium thiosulfate solution was added under vigorous stirring. The mixture was returned to room temperature and stirred for 30 minutes, after which water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with aqueous saturated sodium bicarbonate solution and saturated brine, and was dried with magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was separated and purified with basic silica gel column chromatography (ethyl acetate→methanol:ethyl acetate=1:30) and recrystallized from hexane-ethyl acetate to give 8-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[3-methyl-4-[[[4-methyl-1-propylimidazol-5-yl]methyl]sulfinyl]phenyl]-1,2,3,4-tetrahydro-1-benzoazocine-5-carboxamide (232 mg) as yellow crystals (Compound 41).
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-])=O.C([O:19][CH2:20][C@@H:21]([OH:24])[CH2:22][F:23])C1C=CC=CC=1>>[NH2:9][C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[O:24][C@@H:21]([CH2:22][F:23])[CH2:20][OH:19]
Reactant: O[C@@H](CF)COCc1ccccc1
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Product: Nc1ccc(F)cc1O[C@H](CO)CF

Procedure:
Is prepared in a similar manner as intermediate III.1 from 2,4-difluoro-1-nitro-benzene and (2R)-1-benzyloxy-3-fluoro-propan-2-ol.
Reaction SMILES: [CH3:1][C:2]1[C:7](=[O:8])[N:6]2[CH2:9][CH2:10][CH2:11][NH:12][C:5]2=[N:4][C:3]=1[C:13]1[CH:18]=[CH:17][N:16]=[CH:15][N:14]=1.[H-].[Na+].[CH2:21](Br)[C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:23].[Cl-].[Na+]>CN(C)C=O>[CH3:1][C:2]1[C:7](=[O:8])[N:6]2[CH2:9][CH2:10][CH2:11][N:12]([CH2:21][C:22](=[O:23])[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:5]2=[N:4][C:3]=1[C:13]1[CH:18]=[CH:17][N:16]=[CH:15][N:14]=1
Reactant: O=C(CBr)c1ccccc1
Reactant: Cc1c(-c2ccncn2)nc2n(c1=O)CCCN2
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1c(-c2ccncn2)nc2n(c1=O)CCCN2CC(=O)c1ccccc1
Temperature: 40 °C
Reaction time: 3 h
Yield: 34.2 %

Procedure:
A solution containing 0.608 g (2.5 mmol) of 3-methyl-2-(pyrimidin-4-yl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one in anhydrous dimethylformamide was treated with 0.11 g (2.5 mmol) of sodium hydride (60% suspension in mineral oil) and the mixture warmed to 40° C. during 1 h. 0.497 g (2.5 mmol) of phenacyl bromide dissolved in 5 ml of dimethylformamide was added dropwise and the resulting solution stirred at room temperature for 3 h. The reaction mixture was treated with a saturated aqueous solution of sodium chloride and then extracted with ethyl acetate. The organic extracts were dried and evaporated to give a crude product, which was purified by chromatography on silica gel eluting with dichloromethane/methanol/ammonia in the proportions 100/0/0 to 98/2/0.2. A pure product was obtained which was triturated in diethylether to give 0.309 g (34%) of yellow solid. Mp.: 184-185° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:11])[C:3]=1[S:12](Cl)(=[O:14])=[O:13].[CH:16]([NH2:19])([CH3:18])[CH3:17].C(N(CC)CC)C>>[CH:16]([NH:19][S:12]([C:3]1[C:4]([Cl:11])=[CH:5][CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]=1[Cl:1])(=[O:14])=[O:13])([CH3:18])[CH3:17]
Reactant: O=[N+]([O-])c1ccc(Cl)c(S(=O)(=O)Cl)c1Cl
Reactant: CC(C)N
Solvent: CCN(CC)CC
Product: CC(C)NS(=O)(=O)c1c(Cl)ccc([N+](=O)[O-])c1Cl
Yield: 80.3 %

Procedure:
Following the general procedure for sulfonamide formation outlined in example 15, 2,6-dichloro-3-nitrobenzenesulfonyl chloride (1.5 g, 5.17 mmol), isopropylamine (0.44 m, 5.17 mmol) and triethylamine (1.08 mL, 7.76 mmol) were reacted to form the desired product (1.3 g, 81 %). EI-MS m/z 312 (M-H)−.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:3]=1.[CH3:28][C@@H:29]1[CH2:33][O:32][C:31](=[O:34])[NH:30]1>>[CH3:22][C:21]1[C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[CH:6]=[CH:7][C:2]([N:30]4[C@H:29]([CH3:28])[CH2:33][O:32][C:31]4=[O:34])=[CH:3][C:4]=3[S:24]([CH3:27])(=[O:26])=[O:25])=[O:9])[CH2:11][CH2:12]2)=[N:17][CH:18]=[C:19]([CH3:23])[CH:20]=1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cc3S(C)(=O)=O)CC2)c(C)c1
Reactant: C[C@@H]1COC(=O)N1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4C(=O)OC[C@H]4C)cc3S(C)(=O)=O)CC2)c(C)c1
Yield: 30.7 %

Procedure:
By reaction and treatment in the same manner as in Example 1 and using (4-bromo-2-methanesulfonylphenyl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (839 mg) described in Preparation Example 61 and (R)-4-methyloxazolidin-2-one (288 mg) described in Preparation Example 25, the title compound (269 mg) was obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[S:14][CH2:13][C:12]3[C:11]([C:15](=[O:28])[CH:16]([C:26]#[N:27])[C:17]([NH:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[O:18])=[N:10][N:9]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[C:8]=3[C:6]=2[CH:7]=1.[C:35]1(=[O:41])[O:40][C:38](=[O:39])[CH2:37][CH2:36]1>O1CCCC1>[C:38]([CH2:37][CH2:36][C:35]([NH:1][C:2]1[CH:3]=[CH:4][C:5]2[S:14][CH2:13][C:12]3[C:11]([C:15](=[O:28])[CH:16]([C:26]#[N:27])[C:17]([NH:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[O:18])=[N:10][N:9]([C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)[C:8]=3[C:6]=2[CH:7]=1)=[O:41])([OH:40])=[O:39]
Reactant: O=C1CCC(=O)O1
Reactant: N#CC(C(=O)Nc1ccccc1)C(=O)c1nn(-c2ccccc2)c2c1CSc1ccc(N)cc1-2
Solvent: C1CCOC1
Product: N#CC(C(=O)Nc1ccccc1)C(=O)c1nn(-c2ccccc2)c2c1CSc1ccc(NC(=O)CCC(=O)O)cc1-2
Temperature: 0 °C
Reaction time: 3 h
Yield: 67.3 %

Procedure:
3-(8-amino-1,4-dihydro-1-phenyl-[1]-benzothiopyrano[4,3-c]pyrazol-3-yl)-2-cyano-3-oxo-N-phenyl-propanamide (1.1 g) dissolved in anhydrous tetrahydrofuran (23 ml) is reacted with succinic anhydride (0.71 g) at the reflux temperature under stirring for 3 hours. After cooling the reaction mixture is diluted with ice water. The precipitate is filtered and washed with water. Crystallization from CHCl3 /methanol yields 0.9 g of 3-[8-(3-carboxy-propanoylamino)-1,4-dihydro-1-phenyl-[1]-benzothiopyrano[4,3-c]pyrazol-3-yl]-2-cyano-3-oxo-N-phenylpropanamide, m.p. 230°-233° C.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH:19][C:20](=[O:22])[CH3:21])[S:5][C:6]=1[C:7]1[CH:12]=[CH:11][N:10]=[C:9](N2CCOCC2)[N:8]=1.Cl.[C:24](N)(=N)[CH:25](C)[CH3:26]>>[CH:25]([C:9]1[N:8]=[C:7]([C:6]2[S:5][C:4]([NH:19][C:20](=[O:22])[CH3:21])=[N:3][C:2]=2[CH3:1])[CH:12]=[CH:11][N:10]=1)([CH3:26])[CH3:24]
Reactant: CC(C)C(=N)N
Reactant: CC(=O)Nc1nc(C)c(-c2ccnc(N3CCOCC3)n2)s1
Agent: Cl
Product: CC(=O)Nc1nc(C)c(-c2ccnc(C(C)C)n2)s1

Procedure:
The titled compound is prepared by an analogous procedure to N-[4-Methyl-5-(2-morpholin-4-yl-pyrimidin-4-yl)-thiazol-2-yl]-acetamide (25e) by replacing morpholinoformamidine hydrobromide (part 25c) with isobutyramidine hydrochloride.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([F:12])[C:9]([N:13]2[C:18](=[O:19])[CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[N:15]([CH3:24])[C:14]2=[O:25])=[CH:8][C:3]=1[NH:4]C(=O)C.Cl>C(O)C.O1CCCC1>[NH2:4][C:3]1[C:2]([Cl:1])=[CH:11][C:10]([F:12])=[C:9]([N:13]2[C:18](=[O:19])[CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[N:15]([CH3:24])[C:14]2=[O:25])[CH:8]=1
Reactant: CC(=O)Nc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: CCO
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(N)c(Cl)cc2F)c1=O
Temperature: 25 °C

Procedure:
A mixture of 2′-chloro-5′-[3,6-dihydro-3-methyl-2,6-dioxo-4-(trifluoromethyl)-1(2H)-pyrimidinyl]-4′-fluoroacetanilide (24.42 g, 64.3 mmol) in ethanol is treated with 2N hydrochloric acid (200 ml), diluted with tetrahydrofuran, refluxed overnight, cooled to room temperature, partially concentrated in vacuo to remove ethanol and tetrahydrofuran, neutralized with 3N sodium hydroxide solution, and extracted with ethyl acetate. The organic extracts are combined, washed sequentially with saturated sodium hydrogen carbonate solution and brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo to give the title product as a light, brown solid (20.3 g, mp 132-135° C.).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH3:9].C([Li])CCC.[C:15](=[O:17])=[O:16]>C1COCC1.[OH-].[Na+]>[F:1][C:2]1[C:3]([O:8][CH3:9])=[CH:4][CH:5]=[CH:6][C:7]=1[C:15]([OH:17])=[O:16]
Reactant: O=C=O
Reactant: COc1ccccc1F
Agent: [Li]CCCC
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COc1cccc(C(=O)O)c1F
Temperature: -78 °C

Procedure:
Pentamethylenediethylenetetramine (31.2 ml) was added to a solution of 2-fluoroanisole (15.0 g) in THF (450 ml). The reaction mixture was cooled to −78° C. and n-butyllithium (59.6 ml, 2.5M solution in hexanes) was added dropwise. Stirring was maintained for 2 h before the solution was added in a dropwise fashion to a flask containing solid carbon dioxide pellets. Upon complete addition (30 min) the mixture was allowed to warm to room temperature before removal of the volatiles in vacuo. The residue was dissolved in 10% sodium hydroxide solution (300 ml) and extracted with Et2O (3×). The aqueous was acidified to pH 1 with concentrated hydrochloric acid before extracting with DCM. The organics were washed with H2O, dried (MgSO4) and concentrated in vacuo to afford the subtitle compound as a yellow solid. Yield: 7.1 g.
Reaction SMILES: [C:1]([C:3]1[C:4]([CH3:14])=[CH:5][C:6]([CH3:13])=[C:7]([CH:12]=1)[C:8]([O:10][CH3:11])=[O:9])#[N:2].[ClH:15].[CH3:16][OH:17]>>[ClH:15].[NH:2]=[C:1]([O:17][CH3:16])[C:3]1[C:4]([CH3:14])=[CH:5][C:6]([CH3:13])=[C:7]([CH:12]=1)[C:8]([O:10][CH3:11])=[O:9]
Reactant: CO
Reactant: COC(=O)c1cc(C#N)c(C)cc1C
Agent: Cl
Product: COC(=N)c1cc(C(=O)OC)c(C)cc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 15 %

Procedure:
Into a 50-mL three neck round-bottom flask, was placed a solution of methyl 5-cyano-2,4-dimethylbenzoate (compound 2.3, 900 mg, 4.28 mmol, 1.00 equiv, 90%) in methanol (20 mL). Hydrogen chloride gas was introduced by bubbling through the solution for 0.5 hr. The reaction mixture was then transferred into a 30-mL sealed tube and stirred overnight at room temperature. The mixture was concentrated under vacuum and the residue was diluted with ethyl acetate (30 mL) and extracted with water (10 mL). The aqueous was concentrated in vacuo to obtain the title compound as a white solid (200 mg, 15%).
Reaction SMILES: [CH3:1][O-:2].[Na+].Cl[CH2:5][C:6]1[CH:7]=[C:8]([CH:24]=[C:25]([C@H:27]2[C@H:32]([OH:33])[C@@H:31]([OH:34])[C@H:30]([OH:35])[C@@H:29]([CH2:36][OH:37])[O:28]2)[CH:26]=1)[CH2:9][C:10]1[CH:19]=[C:18]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=[CH:17]2)[C:11]=1C(OC)=O.[OH-].[Na+].Cl>CO>[CH:19]1[C:18]2[C:12]([CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[CH:11][C:10]=1[CH2:9][C:8]1[CH:24]=[C:25]([C@@H:27]2[O:28][C@H:29]([CH2:36][OH:37])[C@@H:30]([OH:35])[C@H:31]([OH:34])[C@H:32]2[OH:33])[CH:26]=[C:6]([CH2:5][O:2][CH3:1])[CH:7]=1
Reactant: C[O-]
Reactant: COC(=O)c1c(Cc2cc(CCl)cc([C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)c2)cc2cccccc1-2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COCc1cc(Cc2cc3cccccc-3c2)cc([C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
28% methanol solution of sodium methoxide (0.5 ml) was added to a solution of methyl 2-[3-(chloromethyl)-5-[(2S,3R,4R,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl) tetrahydro-2H-pyran-2-yl]benzyl]azulene-1-carboxylate (0.06 g) in methanol (3.0 ml) at room temperature. The mixture was stirred for one hour. 10% aqueous solution of sodium hydroxide (3.0 ml) was further added to the reaction mixture and the mixture was refluxed with heating for one hour. After cooling to room temperature, the reaction mixture was neutralized by adding 10% aqueous solution of hydrochloric acid, extracted with chloroform. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated. The residue was purified by silica gel column chromatography (chloroform-methanol) to obtain (1S)-1,5-anhydro-1-[3-(azulen-2-ylmethyl)-5-(methoxymethyl)phenyl]-D-glucitol (0.02 g).
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:14])[NH:4][CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[CH:7]=1.Br[CH:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1.C(=O)([O-])[O-].[K+].[K+]>>[Br:1][C:2]1[C:3](=[O:14])[N:4]([CH:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[CH:7]=1
Reactant: O=c1[nH]cc(-c2ccccn2)cc1Br
Reactant: BrC1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=c1c(Br)cc(-c2ccccn2)cn1C1CCCC1
Yield: 19.9 %

Procedure:
2.00 g of 3-bromo-5-(2-pyridyl)-1,2-dihydropyridin-2-one as the stock material was N-alkylated by the normal method with 5.94 g of bromocyclopentane and 5.50 g of potassium carbonate, to obtain 506 mg of 3-bromo-1-cyclopentyl-5-(2-pyridyl)-1,2-dihydropyridin-2-one, 150 mg of which was treated in accordance with the method for Example 32, to obtain 120 mg of the subject compound.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][C:3]=1[NH2:4].[CH:10](=O)/[CH:11]=[CH:12]/[CH3:13]>Cl>[CH3:13][C:12]1[CH:11]=[CH:10][C:5]2[C:3](=[C:2]([CH3:1])[CH:8]=[CH:7][C:6]=2[CH3:9])[N:4]=1
Reactant: C/C=C/C=O
Reactant: Cc1ccc(C)c(N)c1
Agent: Cl
Product: Cc1ccc2c(C)ccc(C)c2n1
Temperature: 25 °C

Procedure:
In 50 ml of 6N hydrochloric acid, 10.0 g of 2,5-dimethylaniline were dissolved. To the resulting solution, 6.8 ml of crotonaldehyde were added dropwise under reflux. After the completion of the dropwise addition, the reaction mixture was heated under reflux for further one hour and the reaction was terminated. After the reaction mixture was allowed to cool down to room temperature, 5N sodium hydroxide-was added to neutralize the reaction mixture, followed by extraction with ethyl acetate (200 ml×2). The combined organic layers were washed with saturated saline and dried over anhydrous magnesium sulfate. After filtration, the-filtrate was concentrated and the product so obtained was purified by chromatography on a silica gel column, whereby 5.8 g of 2,5,8-trimethylquinoline were obtained. In 30 ml of ethanol were dissolved 3.6 g of 2,5,8-trimethylquinoline and 2.8 g of selenium dioxide, followed by heating under reflux for 6 hours. The residue obtained by distilling off ethanol was subjected to chromatography oh a silica gel column, whereby 2.3 g of the product were obtained. Since the product was proved to be a mixture of the raw material, aldehyde and a diethylacetal derivative of the aldehyde from the result of 1H-NMR, it was treated with 6N-hydrochloric acid (10 ml)-THF (20 ml) and then, extracted with ethyl acetate (100 ml×2). The combined organic layers were washed with a saturated aqueous solution of sodium bicarbonate and dried over anhydrous magnesium sulfate, followed by filtration. The filtrate so obtained was concentrated and the residue was purified by chromatography on a silica gel column, whereby 1.9 g of the title compound were obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[F:9][C:10]1[N:25]=[CH:24][CH:23]=[CH:22][C:11]=1[C:12](NC1C=CC=CC=1C)=[O:13]>>[Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH:4][C:12](=[O:13])[C:11]1[CH:22]=[CH:23][CH:24]=[N:25][C:10]=1[F:9]
Reactant: Cc1ccccc1NC(=O)c1cccnc1F
Reactant: Nc1ccccc1Cl
Product: O=C(Nc1ccccc1Cl)c1cccnc1F
Yield: 84 %

Procedure:
2-Chloroaniline (Aldrich, 0.17 mL, 1.6 mmol) was converted to the desired compound (0.084 g, 84%) in a manner similar to the preparation of 2-fluoro-N-o-tolylnicotinamide (Step A of Example 8). MS(ESI+) m/z 251 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[I:11])[C:5](O)=[O:6].C(Cl)(=O)C([Cl:15])=O>C(Cl)Cl.CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[I:11])[C:5]([Cl:15])=[O:6]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1ccc(I)c(F)c1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccc(I)c(F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.1 %

Procedure:
To a solution of 3-fluoro-4-iodobenzoic acid (1.3 g, 4.9 mmol) in anhydrous CH2Cl2 (20 mL) at 0° C. was added oxalyl chloride (1.2 mL, 15.0 mmol) followed by catalytic DMF (7 drops). The reaction mixture was allowed to warm to room temperature, stirred for 2 h, and then concentrated in vacuo to provide 1.2 g of 3-fluoro-4-iodobenzoyl chloride as a yellow solid. The acid chloride (600 mg, 2.1 mmol) was dissolved in anhydrous CH2Cl2, and dimethylamine (2.1 mL, 4.2 mmol, 2M in THF) was added followed by triethylamine (0.6 mL, 4.2 mmol). The reaction mixture was stirred at room temperature for 2 h and then diluted with CH2Cl2. The organic layer was washed with water, washed with brine, dried (MgSO4), filtered, and concentrated. The resulting solid was stirred with diethyl ether and filtered to afford 353 mg of the title compound as a white solid. 1H NMR (300 MHz, DMSO-d6): δ 7.91 (dd, 1H), 7.32 (dd, 1H), 7.04 (dd, 1H), 2.97 (s, 3H), 2.89 (s, 3H).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]2[C:11](Br)=[C:10](Br)[S:9][C:8]=2[CH:14]=1)(=[O:3])[CH3:2]>C(O)C.C(OCC)(=O)C>[C:1]([C:4]1[CH:5]=[CH:6][C:7]2[CH:11]=[CH:10][S:9][C:8]=2[CH:14]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc2c(Br)c(Br)sc2c1
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(=O)c1ccc2ccsc2c1
Reaction time: 3 h
Yield: 107.8 %

Procedure:
6-Acetyl-2,3-dibromobenzo[b]thiophene (6.68 g, 20 mmole) was dissolved in a mixture of ethanol and ethyl acetate (100 ml each) and MgO (1.6 g) and (20% Pd(OH2)/C (800 mg) were added under a N2 atmosphere. Hydrogenolysis was carried out at 40 psi of H2 at room temperature for 3 hours. The catalyst was removed by filtration and the solvent was removed in vacuo. The residue was partitioned between CHCl3 (100 ml) and H2O (50 ml). The CHCl3 layer was washed with H2O (50 ml). The aqueous layers were combined and back-extracted with CHCl3 (30 ml). The CHCl3 solutions were combined, dried over Na2SO4 and the solvent evaporated in vacuo to yield 3.8 g of product which was used in the next step without further purification.