Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].N1C=CC=CC=1.Cl[C:19](Cl)([O:21]C(=O)OC(Cl)(Cl)Cl)Cl>C(#N)C.C(Cl)Cl>[F:11][C:9]1[CH:8]=[CH:7][C:3]2[C:4](=[O:6])[O:5][C:19](=[O:21])[NH:1][C:2]=2[CH:10]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Nc1cc(F)ccc1C(=O)O
Solvent: ClCCl
Solvent: CC#N
Solvent: c1ccncc1
Product: O=c1[nH]c2cc(F)ccc2c(=O)o1
Temperature: 55 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 2-amino-4-fluoro benzoic acid (L) (1.15 g, 7.40 mmol) in anhydrous acetonitrile (8 mL) at 55° C. were simultaneously added anhydrous pyridine (1.2 mL, 15 mmol) and a solution of triphosgene (0.73 g, 2.5 mmol) in anhydrous CH2Cl2 (5 mL) via syringe over a period of 15-20 minutes. After the addition was completed, the reaction mixture was stirred at 55° C. for another 2 hours. Much solid precipitated out. The solvent was distilled off. After cooling down to room temperature, water was added and the solid was filtered off, washed with water, followed by chilled CH2Cl2. The solid was dried under vacuum to give 7-fluoro-1H-benzo[d][1,3]oxazine-2,4-dione (M) as grayish solid. Yield: 1.02 g (76%).
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]([CH2:11][CH3:12])=[C:9]([CH3:13])[Se:8][C:4]=2[N:5]=[CH:6][N:7]=1.[NH2:14][C:15]1[CH:19]=[C:18]([C:20]([CH3:23])([CH3:22])[CH3:21])[Se:17][C:16]=1[C:24]([NH2:26])=[O:25].CN(C=O)C.[OH-].[Na+]>>[CH2:11]([C:10]1[C:3]2[C:2]([NH:14][C:15]3[CH:19]=[C:18]([C:20]([CH3:23])([CH3:21])[CH3:22])[Se:17][C:16]=3[C:24]([NH2:26])=[O:25])=[N:7][CH:6]=[N:5][C:4]=2[Se:8][C:9]=1[CH3:13])[CH3:12]
Reactant: CC(C)(C)c1cc(N)c(C(N)=O)[se]1
Reactant: CCc1c(C)[se]c2ncnc(Cl)c12
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CCc1c(C)[se]c2ncnc(Nc3cc(C(C)(C)C)[se]c3C(N)=O)c12

Procedure:
The reaction of 4-chloro-5-ethyl-6-methylselenopheno[2,3-d]pyrimidine with 3-amino-5-tert-butylselenophene-2-carboxamide in the presence of DMF/NaOH as described in Example 1 gave title compound as a pale yellow color solid, mp 258-260° C. IR (KBr) vmax 3321, 3149, 2960, 1666, 1582, 1384, 1356, 1224, 1187, 1129, 1042, 1020, 925, 838, 810 cm−1; 1H NMR (400 MHz, CDCl3): δ 10.96 (1H, s, exchangeable with D2O), 8.51 (1H, s), 8.49 (1H, s), 5.44 (2H, br s, exchangeable with D2O), 3.13 (2H, q, J=7.6 Hz), 2.57 (3H, s), 1.44 (9H, s), 1.24 (3H, t, J=7.6 Hz); 13C NMR (100 MHz, CDCl3): δ 172.1, 167.9, 167.1, 153.4, 151.2, 146.9, 135.6, 133.4, 122.8, 120.8, 110.6, 37.0, 32.6, 21.8, 15.8, 15.3; LC-MS (negative ion mode): m/z 465, 467, 469 (M−H)−.
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][CH:6]=1.CCN(CC)CC.CS(Cl)(=O)=O.Cl.[Na+].[I-:27]>C(Cl)Cl>[I:27][CH2:2][CH2:3][CH2:4][C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][CH:6]=1
Reactant: [I-]
Reactant: N#Cc1ccc(CCCO)cc1
Agent: CS(=O)(=O)Cl
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: N#Cc1ccc(CCCI)cc1

Procedure:
To a solution of 4-(3-hydroxypropyl)benzonitrile (1.8 g, 11.2 mmol) in CH2Cl2 (50 mL) at 0° C., Et3N (1.06 mL, 13.4 mmol) and then MsCl (0.95 mL, 12.5 mmol) were added. Upon completion, the reaction mixture was poured into 0.5M HCl and extracted with EtOAc. The crude mesylate was dissolved in acetone and treated with NaI (3.0 g, 20.0 mmol) in the dark at room temperature. When complete, the reaction was purified by flash chromatography on silica gel eluting with 15% EtOAc in Hexanes to afford the title compound.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][CH2:6][CH:5]([CH2:9]N)[CH2:4]1.[C:11]1([CH2:19]N)[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][NH2:18])[CH:12]=1>C1(C)C=CC=C(C)C=1>[NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][CH2:6][CH:5]([CH3:9])[CH2:4]1.[CH3:19][C:11]1[CH:12]=[C:13]([CH:14]=[CH:15][CH:16]=1)[CH2:17][NH2:18]
Reactant: NCc1cccc(CN)c1
Reactant: NCC1CCCC(CN)C1
Solvent: Cc1cccc(C)c1
Product: CC1CCCC(CN)C1
Product: Cc1cccc(CN)c1

Procedure:
As a result of analysis by gaschromatography, it was found the yield of 1,3-bis(aminomethyl)cyclohexane was 33.3 mol % and as other products 0.3 mol % of metaxylene, 0.6 mol % of 3-aminomethyl-1-methylcyclohexane, 4.7 mol of 3-methylbenzylamine and 61.1 mol % of unreacted metaxylylenediamine were obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([NH:17][C:18]([CH:20]3[CH2:24][CH2:23][N:22]([CH2:25][C:26](=[O:45])[N:27]4[CH2:32][CH2:31][N:30]([C:33]5[CH:38]=[CH:37][C:36]([C:39]6[N:44]=[CH:43][CH:42]=[CH:41][N:40]=6)=[CH:35][CH:34]=5)[CH2:29][CH2:28]4)[CH2:21]3)=[O:19])=[CH:14][CH:15]=2)[C:10]([NH2:46])=[N:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:47](Cl)(=[O:49])[CH3:48]>C(Cl)Cl.N1C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([NH:17][C:18]([CH:20]3[CH2:24][CH2:23][N:22]([CH2:25][C:26](=[O:45])[N:27]4[CH2:28][CH2:29][N:30]([C:33]5[CH:34]=[CH:35][C:36]([C:39]6[N:40]=[CH:41][CH:42]=[CH:43][N:44]=6)=[CH:37][CH:38]=5)[CH2:31][CH2:32]4)[CH2:21]3)=[O:19])=[CH:14][CH:15]=2)[C:10]([NH:46][C:47](=[O:49])[CH3:48])=[N:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)Cl
Reactant: CC(C)(C)OC(=O)n1nc(N)c2cc(NC(=O)C3CCN(CC(=O)N4CCN(c5ccc(-c6ncccn6)cc5)CC4)C3)ccc21
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)Nc1nn(C(=O)OC(C)(C)C)c2ccc(NC(=O)C3CCN(CC(=O)N4CCN(c5ccc(-c6ncccn6)cc5)CC4)C3)cc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 36 from Step 1 in CH2Cl2 (0.3 mL) and pyridine (0.3 mL) was added acetyl chloride (50 ul, 0.7 mmol) at rt. The crude was stirred at rt for 30 mins. The crude was quenched with sat. NaHCO3 at rt. The crude was partitioned between EtOAc and H2O. The organic layer was washed with H2O, brine, dried over MgSO4, filtered, and evaporated. The crude was chromatographed to give 20 mg of the product.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C:13]([CH2:19][CH2:20][CH2:21][OH:22])([CH:16]([CH3:18])[CH3:17])[O:12][C:11]2=[O:23])[CH3:9])=[CH:4][CH:3]=1.CC(C)=[O:26].OS(O)(=O)=O.O=[Cr](=O)=O>CC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C:13]([CH2:19][CH2:20][C:21]([OH:26])=[O:22])([CH:16]([CH3:17])[CH3:18])[O:12][C:11]2=[O:23])[CH3:9])=[CH:4][CH:3]=1
Reactant: CC(C)=O
Reactant: CC(C)C1(CCCO)CCN([C@@H](C)c2ccc(Br)cc2)C(=O)O1
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Product: CC(C)C1(CCC(=O)O)CCN([C@@H](C)c2ccc(Br)cc2)C(=O)O1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
To a mixture of 3-((S)-1-(4-bromophenyl)ethyl)-6-(3-hydroxypropyl)-6-isopropyl-1,3-oxazinan-2-one. (41 mg, 0.1 mmol) in acetone (10 mL) was added Jones reagent (2.5 M, 1 mL) at 0° C. The mixture was stirred at room temperature for 1 h, concentrated, and extracted with EtOAc. The organic layer was concentrated to give the crude product 3-(3-((S)-1-(4-bromophenyl)ethyl)-6-isopropyl-2-oxo-1,3-oxazinan-6-yl)propanoic acid (51 mg, 95% yield), which was used for the next step without further purification.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2([OH:14])[CH2:13][CH2:12][CH2:11]2)=[CH:6][C:5]=1[F:15].Br[CH2:17][C:18]([OH:20])=[O:19]>CN(C)C=O>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2([O:14][CH2:17][C:18]([OH:20])=[O:19])[CH2:11][CH2:12][CH2:13]2)=[CH:6][C:5]=1[F:15]
Reactant: OC1(c2ccc(Cl)c(F)c2)CCC1
Reactant: O=C(O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(O)COC1(c2ccc(Cl)c(F)c2)CCC1
Reaction time: 0.5 h

Procedure:
TO an ambient suspension of NaH (0.341 g, 8.52 mmol, 60% dispersion in mineral oil) in N,N-dimethylformamide (7 mL) was added a solution of Example 56A (0.342 g, 1.71 mmol) in N,N-dimethylformamide (1 mL) dropwise. The reaction was stirred for 0.5 h, and 2-bromoacetic acid (0.474 g, 3.41 mmol) was added as a solution in N,N-dimethylformamide (2 mL) dropwise. The reaction was stirred at room temperature for 24 h and was then quenched by the slow addition of H2O (10 mL) and diethyl ether (15 mL). The layers were separated, and the organic discarded. The aqueous was acidified to pH ˜4-5 with 10% HCl and was extracted with diethyl ether (3×15 mL). The combined organics were dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give a yellow oil, which was used without further purification in the subsequent step, MS (ESI)m/z 2.59 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:13]2[CH2:18][C:17]([CH3:20])([CH3:19])[N:16]([O:21][CH3:22])[C:15]([CH3:24])([CH3:23])[CH2:14]2)[N:5]=[C:4]([NH:25][CH2:26][CH2:27][CH2:28][CH2:29][CH:30]2[CH2:35][C:34]([CH3:37])([CH3:36])[N:33]([O:38][CH3:39])[C:32]([CH3:41])([CH3:40])[CH2:31]2)[N:3]=1.[CH2:42]1[O:45][CH:43]1[CH3:44]>>[OH:45][CH:43]([CH3:44])[CH2:42][NH:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:13]2[CH2:18][C:17]([CH3:19])([CH3:20])[N:16]([O:21][CH3:22])[C:15]([CH3:24])([CH3:23])[CH2:14]2)[N:5]=[C:4]([NH:25][CH2:26][CH2:27][CH2:28][CH2:29][CH:30]2[CH2:31][C:32]([CH3:41])([CH3:40])[N:33]([O:38][CH3:39])[C:34]([CH3:37])([CH3:36])[CH2:35]2)[N:3]=1
Reactant: CON1C(C)(C)CC(CCCCNc2nc(N)nc(NCCCCC3CC(C)(C)N(OC)C(C)(C)C3)n2)CC1(C)C
Reactant: CC1CO1
Product: CON1C(C)(C)CC(CCCCNc2nc(NCCCCC3CC(C)(C)N(OC)C(C)(C)C3)nc(NCC(C)O)n2)CC1(C)C

Procedure:
The title compound is prepared from the reaction of the compound prepared in Example 20 with propylene oxide.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:12]=[CH:13][CH:14]=1)[CH:7]=[CH:8][C:9]([OH:11])=[O:10])(=[O:3])[CH3:2].[Cl:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][CH:17]=1.Cl.[CH2:25](O)[CH3:26]>>[Cl:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=[CH:2][C:1]([C:4]2[CH:5]=[C:6]([CH:12]=[CH:13][CH:14]=2)[CH:7]=[CH:8][C:9]([O:11][CH2:25][CH3:26])=[O:10])=[O:3])=[CH:18][CH:17]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: CC(=O)c1cccc(C=CC(=O)O)c1
Reactant: CCO
Agent: Cl
Product: CCOC(=O)C=Cc1cccc(C(=O)C=Cc2ccc(Cl)cc2)c1
Reaction time: 10 h

Procedure:
12 g (0.055 mole) of the ethyl ester of 3-acetyl-cinnamic acid are dissolved in 120 ml of ethanol. 8 g (0.057 mole) of para-chlorobenzaldehyde are added then 35 ml of anhydrous ethanol saturated with gaseous hydrochloric acid. The reaction medium is stirred for 10 hours.
Reaction SMILES: C1COCC1.[NH2:6][C:7]1[CH:16]=[CH:15][C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:9][C:8]=1[S:17]([CH3:20])(=[O:19])=[O:18].[H-].[Na+].[Cl:23][C:24]1[CH:37]=[CH:36][C:27]2[S:28][C:29]([S:32](Cl)(=[O:34])=[O:33])=[C:30]([CH3:31])[C:26]=2[CH:25]=1>CN(C=O)C>[Cl:23][C:24]1[CH:37]=[CH:36][C:27]2[S:28][C:29]([S:32]([NH:6][C:7]3[CH:16]=[CH:15][C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:9][C:8]=3[S:17]([CH3:20])(=[O:19])=[O:18])(=[O:33])=[O:34])=[C:30]([CH3:31])[C:26]=2[CH:25]=1
Reactant: COC(=O)c1ccc(N)c(S(C)(=O)=O)c1
Reactant: Cc1c(S(=O)(=O)Cl)sc2ccc(Cl)cc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COC(=O)c1ccc(NS(=O)(=O)c2sc3ccc(Cl)cc3c2C)c(S(C)(=O)=O)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 44.7 %

Procedure:
Into a mixed solvent of 20 mL of THF and 3 mL of DMF was dissolved 985 mg of methyl 4-amino-3-methanesulfonylbenzoate, followed by addition of 170 mg of sodium hydride (oily, 60%) at 0° C. After 20 minutes of stirring at the same temperature, 1.28 g of 5-chloro-2-chlorosulfonyl-3-methylbenzo[b]thiophene was added at 0° C., followed by 1 hour of stirring at room temperature. Further, 150 mg of sodium hydride (oily, 60%) was added at room temperature and the mixture was stirred for 2 hours at the same temperature. After confirmation of disappearance of the starting material, the reaction was terminated by adding saturated aqueous ammonium chloride solution at 0° C., followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate. The solvent was removed by evaporation and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=3/1) to obtain 911 mg of the title compound as colorless powder.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][C:3]=1[C:11]#[N:12].[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][SH:21])=[CH:16][CH:15]=1>CN(C)C=O>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][S:21][C:2]2[N:7]=[C:6]([C:8]([OH:10])=[O:9])[CH:5]=[CH:4][C:3]=2[C:11]#[N:12])=[CH:16][CH:15]=1
Reactant: SCc1ccc(Cl)cc1
Reactant: N#Cc1ccc(C(=O)O)nc1Cl
Solvent: CN(C)C=O
Product: N#Cc1ccc(C(=O)O)nc1SCc1ccc(Cl)cc1
Temperature: 45 °C
Yield: 82 %

Procedure:
A mixture of 6-chloro-5-cyanopicolinic acid (30 mg, 0.16 mmol), 4-chlorophenyl methanethiol (24 ul, 0.18 mmol), and CsCO3 (156 mg, 0.48 mmol) in dimethylformamide (2 ml) was heated for 16 hrs at 45° C. After removal of the solvent, the residue was treated with water (2 ml) and acidified with 1N-HCl to pH2. The precipitate was collected by filtration and dried under vacuum to afford 40 mg (82%) of the desired product 52. 1H NMR (600 MHz, DMSO-d6) δ 13.6 (br s, 1H), 8.46 (d, 1H, J=7.8 Hz), 8.15 (d, 1H, J=7.8 Hz), 7.55 (d, 2H, J=9 Hz), 7.47 (d, 2H, J=9 Hz). MS: m/z Calcd 304.8 Found MH+ 305.0
Reaction SMILES: CO[C:3](=[O:34])[C:4]1[C:5](=[CH:10][C:11]([N:24]([CH2:31][CH:32]=[CH2:33])[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[C:12]([N:14]([CH2:21][CH:22]=[CH2:23])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:13]=1)[C:6]([O:8]C)=[O:7].[NH3:35]>CO>[CH2:31]([N:24]([C:11]1[CH:10]=[C:5]([C:6]([OH:8])=[O:7])[C:4](=[CH:13][C:12]=1[N:14]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:21][CH:22]=[CH2:23])[C:3]([NH2:35])=[O:34])[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[CH:32]=[CH2:33]
Reactant: C=CCN(c1ccccc1)c1cc(C(=O)OC)c(C(=O)OC)cc1N(CC=C)c1ccccc1
Reactant: N
Solvent: CO
Product: C=CCN(c1ccccc1)c1cc(C(N)=O)c(C(=O)O)cc1N(CC=C)c1ccccc1
Temperature: 120 °C

Procedure:
In an autoclave, 457 mg (1 mmol) of 4,5-bis(N-allylanilino)phthalic acid dimethyl ester are dissolved in 5 ml of methanol, and 15 ml of ammonia areused for the purpose of amide formation. The autoclave is closed and then heated at 120° C. for 24 hours, then cooled and opened, and the ammonia is driven off with nitrogen. The residue is rinsed out with ethyl acetate and filtered, and the filtrate is chromatographed on silica gel with hexane/ethyl acetate 3:1. The product fractions are concentrated by evaporation and crystallized from hexane/ethyl acetate, yielding the titlecompound in the form of yellow crystals, FAB-MS: 410 [M+ +H], m.p. 122°-127° C. As by product of the reaction, 4,5-Bis-(N-allyl-N-phenylamino)phthalic acid monoamide was isolated and recrystallized from hexane/ethyl acetate to yield yellow crystalIs, FAB-MS: 428 [M+ +H], m.p. 114°-116° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]([N:8]=[C:9]=[S:10])[CH:7]=1.[CH2:12]([NH2:14])[CH3:13]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]([NH:8][C:9]([NH:14][CH2:12][CH3:13])=[S:10])[CH:7]=1
Reactant: Cc1ccc(F)cc1N=C=S
Reactant: CCN
Product: CCNC(=S)Nc1cc(F)ccc1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
5-Fluoro-2-methylphenyl isothiocyanate (16.7 g; 0.1 mol) was added dropwise to aqueous ethylamine (120 mL of 70% solution). The mixture was stirred for 2 hour at ambient temperature. Excess ethylamine was removed under a stream of nitrogen. The residue was diluted with water. The solids were collected by filtration, washed with water and dried. The solid was dissolved in ether and washed with water. The organic phase was dried over anhydrous magnesium sulfate then evaporated to dryness to give N-(5-fluoro-2-methylphenyl)-N′-ethylthiourea (18.5 g), m.p. 93–95° C. Mass spectrum; (El, M.+) m/z 212. 1H-NMR (DMSO-d6; 300 MHz): δ 9.01 (br s, 1H), 7.66 (br s, 1H), 7.25–7.18 (m, 2H), 6.96 (m, 1H), 3.45 (m, 2H), 2.13 (s, 3H), and 1.09 ppm (t, 3H).
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]=[C:14]([CH3:22])[N:13]=2)=[CH:7][CH:6]=1)([CH3:3])[CH3:2].[CH3:23]I>>[CH:1]([O:4][C:5]1[CH:6]=[CH:7][C:8]([N:11]([C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]=[C:14]([CH3:22])[N:13]=2)[CH3:23])=[CH:9][CH:10]=1)([CH3:3])[CH3:2]
Reactant: CI
Reactant: Cc1nc(Nc2ccc(OC(C)C)cc2)c2ccccc2n1
Product: Cc1nc(N(C)c2ccc(OC(C)C)cc2)c2ccccc2n1

Procedure:
The title compound was prepared from (4-isopropoxy-phenyl)-(2-methyl-quinazolin-4-yl)-amine (164.3 mg, 0.56 mmol) and methyl iodide (0.25 ml, 3.92 mmol) by a procedure similar to example 7. 1H NMR (CDCl3): 7.73 (d, J=7.8 Hz, 1H), 7.54-7.49 (m, 1H), 7.10-6.86 (m, 6H), 4.57-4.52 (m, 1H), 3.58 (s, 3H), 2.72 (s, 3H), 1.36 (d, J=6 Hz, 6H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[C:17]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:18]([CH:23]=O)=[CH:19][CH:20]=[CH:21][CH:22]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C1(C2C=CC=CC=2)C=CC=CC=1CN1CCN(C2C=CC=CC=2)CC1>>[C:17]1([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH2:23][N:14]1[CH2:13][CH2:12][N:11]([C:5]2[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=2)[CH2:16][CH2:15]1
Reactant: O=Cc1ccccc1-c1ccccc1
Reactant: COc1ccc(N2CCNCC2)cc1OC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: c1ccc(-c2ccccc2CN2CCN(c3ccccc3)CC2)cc1
Product: COc1ccc(N2CCN(Cc3ccccc3-c3ccccc3)CC2)cc1OC

Procedure:
167.9 mg of the target compound (0.43 mmol, 78.6%) was obtained using 1-(3,4-dimethoxyphenyl)piperazine (245 mg, 1.10 mmol), biphenyl-2-carbaldehyde (100 mg, 0.55 mmol) and NaBH(OAc)3 (355 mg, 1.65 mmol) according to the synthesis method of Compound 1.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH2:12]([CH2:14][NH2:15])[OH:13]>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:15][CH2:14][CH2:12][OH:13])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Reactant: NCCO
Solvent: ClCCl
Product: O=S(=O)(NCCO)c1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 4-bromo-benzenesulfonyl chloride (1.00 g, 3.92 mmol) in methylene chloride (25 mL) was added N,N-dimethylaminopyridine (0.608 g, 4.98 mmol). The reaction mixture was cooled to 0° C., and ethanolamine (0.287 g, 4.70 mmol) was added dropwise. After stirring for 30 minutes, the reaction mixture was quenched with water (15 mL). The resulting mixture was extracted with methylene chloride (3×25 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude product. Purification using silica gel chromatography (100-200 mesh, 10-15% ethyl acetate-hexane) provided 4-bromo-N-(2-hydroxy-ethyl)-benzenesulfonamide. MS calcd. for C8H11BrNO3S [(M+H)+] 281, obsd. 282.2.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[S:9][CH:10]=[CH:11][N:12]=1.[CH3:13][C:14]1[CH:19]=[CH:18][C:17]([Sn](C)(C)C)=[CH:16][CH:15]=1.O>CN(C)C=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:13][C:14]1[CH:19]=[CH:18][C:17]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[C:8]2[S:9][CH:10]=[CH:11][N:12]=2)=[CH:16][CH:15]=1
Reactant: Brc1ccccc1-c1nccs1
Reactant: Cc1ccc([Sn](C)(C)C)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(-c2ccccc2-c2nccs2)cc1
Temperature: 150 °C
Yield: 30.8 %

Procedure:
A solution of 1.18 g (4.92 mmol) of 1-bromo-2-(thiazol-2-yl)benzene and 1.67 g (6.55 mmol) of 4-metylphenyltrimethylstannane in 20 mL of dimethylformamide was treated with 621 mg of bis(triphenylphosphine)palladium(II) chloride. The reaction mixture was heated at 150° C. for 6 hours, cooled and poured into 300 mL of water. The resultant mixture was extracted with ether (3×100 mL). The combined ether extracts were washed with water (4×), dried over magnesium sulfate and evaporated under vacuum. The residue was purified by chromatography on silica gel, eluting with hexane/ether (100:10) to give 381 mg of the product. EI-MS: calculated for C16H13NS 251; found 250. 1H NMR (200 MHz, CDCl3): 2.36 (s, 3H), 7.14 (s, 4H), 7.24 (d, 1H), 7.40 (m, 1H), 7.42 (m, 2H), 7.73 (d, 1H), 8.20 (dt, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]([CH2:21][O:22][CH2:23][CH2:24][O:25][CH3:26])[S:9]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[CH:18][CH:19]=3)[S:14][CH:13]=2)(=[O:11])=[O:10])=[N:4][O:5][C:6]=1[CH3:7].[Li]C(C)(C)C.[CH3:32][C:33]1[CH:40]=[C:39]2[O:41][CH2:42][O:43][C:38]2=[CH:37][C:34]=1[CH:35]=[O:36]>C1COCC1>[Cl:1][C:2]1[C:3]([N:8]([CH2:21][O:22][CH2:23][CH2:24][O:25][CH3:26])[S:9]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[CH:18][CH:19]=3)[S:14][C:13]=2[CH:35]([OH:36])[C:34]2[CH:37]=[C:38]3[O:43][CH2:42][O:41][C:39]3=[CH:40][C:33]=2[CH3:32])(=[O:11])=[O:10])=[N:4][O:5][C:6]=1[CH3:7]
Reactant: COCCOCN(c1noc(C)c1Cl)S(=O)(=O)c1csc2ncccc12
Reactant: Cc1cc2c(cc1C=O)OCO2
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: COCCOCN(c1noc(C)c1Cl)S(=O)(=O)c1c(C(O)c2cc3c(cc2C)OCO3)sc2ncccc12
Yield: 35 %

Procedure:
The title compound was prepared by the method of Example 4(B) using N-(4-chloro-5-methyl-3-isoxazolyl)-N-(methoxyeth-oxymethyl)thieno[2,3-b]pyridine-3-sulfonamide (0.23 g, 0.54 mmoles), THF (5 ml), t-BuLi (1.7 M, 0.41 ml, 0.70 mmoles) and 2-methyl-4,5-(methylenedioxy)benzaldehyde (0.13 g, 0.81 mmoles)[Example 6(A)]. Flash chromatography (40% EtOAc/hexanes) provided 0.11 g (36%) of the title compound as a light orange oil.
Reaction SMILES: [N+:1]([CH:4]=[CH:5][C:6]1[CH:15]=[CH:14][C:9]([C:10]([O:12][CH3:13])=[O:11])=[CH:8][CH:7]=1)([O-])=[O:2].C=O.CO.[H][H]>[Pd].O1CCCC1>[OH:2][N:1]=[CH:4][CH2:5][C:6]1[CH:15]=[CH:14][C:9]([C:10]([O:12][CH3:13])=[O:11])=[CH:8][CH:7]=1
Reactant: COC(=O)c1ccc(C=C[N+](=O)[O-])cc1
Reactant: [H][H]
Agent: [Pd]
Agent: C=O
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1ccc(CC=NO)cc1
Yield: 20.7 %

Procedure:
A mixture of methyl 4-(2-nitrovinyl)benzoate (18.6 g, 90 mmol), paraformaldehyde (3.2 g, 108 mmol) and 10% Pd/C (0.9 g) in the mixture of methanol (220 mL) and tetrahydrofuran (220 mL) was stirred at room temperature over 1 atm of hydrogen for 3 h. Then the mixture was filtered and evaporated, purified by column chromatography (silica gel, petroleum ether/ethyl acetate 15:1 to 8:1) to obtain methyl 4-(2-(hydroxyimino)ethyl)benzoate (3.6 g, yield 21%) as yellow solid. 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 3.55-3.56 (d, J=6.0 Hz, 0.5H), 3.69-3.71 (d, J=5.2 Hz, 1.5H), 3.84 (s, 3H), 6.84-6.87 (t, J=5.6 Hz, 0.75H), 7.45-7.47 (t, J=6.2 Hz, 0.25H), 7.37-7.41 (m, 2H), 7.90-7.91 (m, 2H), 10.68 (s, 0.25H), 11.14 (s, 0.75H); LC-MS (ESI) m/z: 194 (M+1)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][C:14](=O)[CH:13]([C:18]([O:20]CC)=O)[CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[C:23]1([NH:29][NH2:30])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.CC[O-].[Na+].CCO>CCO.[Cl-].[Na+].O>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]2[CH2:16][CH2:15][C:14]3[NH:30][N:29]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[C:18](=[O:20])[C:13]=3[CH2:12]2)(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: NNc1ccccc1
Reactant: CCOC(=O)C1CN(S(=O)(=O)c2ccc(C)cc2)CCC1=O
Agent: CC[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)N2CCc3[nH]n(-c4ccccc4)c(=O)c3C2)cc1
Temperature: 25 °C
Yield: 25 %

Procedure:
In a three-necked flask, under a N2 atmosphere, 0.300 g (0.92 mmol) of ethyl 1-[(4-methyl phenyl)sulfonyl]-4-oxopiperidine-3-carboxylate and 0.099 g (0.92 mmol) of phenyl hydrazine were stirred in 3 mL of EtOH for 1 h at 50° C. HPLC and UPLC-MS analysis revealed the formation of the hydrazone intermediate. After having cooled to room temperature, a solution of EtONa/EtOH—prepared by dissolution of 42 mg (1.84 mmol) of Na in 2 mL of EtOH—was added to the reaction mixture and it was stirred for 1 additional hour at room temperature (reaction monitored by HPLC and UPLC-MS). The reaction mixture was diluted with brine (10 mL) and extracted with ethylacetate (50 mL×3). The combined organic phases were dried over Na2SO4 and evaporated. The crude (400 mg) was purified by silica flash chromatography using ethylacetate/petroleum ether (80/20, gradient to 100% ethylacetate) yielding 84 mg of a white solid as the desired 5-[(4-methylphenyl)sulfonyl]-2-phenyl-1,2,4,5,6,7-hexahydro-3H-pyrazolo[4,3-c]pyridin-3-one (25% yield). 1HNMR (500 MHz, DMSO-d6): 3.95 (s, 3H); 2.64 (t, J=5.5 Hz, 2H); 3.17 (d, J=5 Hz, 2H); 3.30 (m, 2H, hidden by H2O); 7.20 (t, J=7.25 Hz, 1H); 7.40-7.45 (m, 4H); 7.65-7.7 (m, 4H); 11.36 (bs, NH); 370.