Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[S:29][C:6]2[N:7]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]4[C:22]([C:27]#[N:28])=[CH:23][CH:24]=[CH:25][CH:26]=4)=[CH:17][CH:16]=3)[C:8](=[O:13])[CH2:9][NH:10][C:11](=[O:12])[C:5]=2[CH:4]=1)[CH3:2].Br[CH2:31][C:32]1[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=1.CN(C)C=O.[H-].[Na+]>C(OCC)(=O)C>[CH2:1]([C:3]1[S:29][C:6]2[N:7]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]4[C:22]([C:27]#[N:28])=[CH:23][CH:24]=[CH:25][CH:26]=4)=[CH:17][CH:16]=3)[C:8](=[O:13])[CH2:9][N:10]([CH2:31][C:32]3[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=3)[C:11](=[O:12])[C:5]=2[CH:4]=1)[CH3:2]
Reactant: CCc1cc2c(s1)N(Cc1ccc(-c3ccccc3C#N)cc1)C(=O)CNC2=O
Reactant: Fc1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCc1cc2c(s1)N(Cc1ccc(-c3ccccc3C#N)cc1)C(=O)CN(Cc1ccc(F)cc1)C2=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 58 %

Procedure:
To a mixture of 4′-[(7-ethyl-2,5-dioxo-2,3,4,5-tetrahydro-1H-thieno[2,3-e][1,4]diazepin-1-yl)methyl]biphenyl-2-carbonitrile (0.52 g), 1-(bromomethyl)-4-fluorobenzene (0.24 mL) and N,N-dimethylformamide (15 mL) was added 60% sodium hydride (0.078 g), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed successively with 5% aqueous potassium hydrogensulfate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.38 g, 58%).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([F:8])[C:5]([CH3:9])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][CH:23]([NH2:26])[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14].CCN(C(C)C)C(C)C>C(Cl)Cl>[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][CH:23]([NH:26][C:2]2[CH:7]=[C:6]([F:8])[C:5]([CH3:9])=[CH:4][C:3]=2[N+:10]([O-:12])=[O:11])[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:14])[CH3:15]
Reactant: Cc1cc([N+](=O)[O-])c(Cl)cc1F
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc([N+](=O)[O-])c(NC2CCN(C(=O)OC(C)(C)C)CC2)cc1F
Temperature: 180 °C
Yield: 18.2 %

Procedure:
A mixture of 1-chloro-5-fluoro-4-methyl-2-nitro-benzene (2 g, 10.55 mmol), 4-amino-piperidine-1-carboxylic acid tert-butyl ester (2.32 g, 11.58 mmol), and iPr2NEt (3.8 mL) was heated for 2 hours at 180° C. by microwave heating. After cooling, the reaction mixture was diluted with CH2Cl2 and then filtered. The volatiles were removed under reduced pressure and the residue was purified by flash chromatography (25% ethyl acetate in hexanes) to afford 4-(5-fluoro-4-methyl-2-nitro-phenylamino)piperidine-1-carboxylic acid tert-butyl ester (0.68 g, 18%) as a brown solid.
Reaction SMILES: [OH-].[NH4+].C([O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([CH:22]=[O:23])=[CH:18][CH:17]=2)=[CH:9][CH:8]=1)(=O)C>CO>[OH:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][O:15][C:16]2[CH:17]=[CH:18][C:19]([CH:22]=[O:23])=[CH:20][CH:21]=2)=[CH:9][CH:8]=1
Reactant: CC(=O)Oc1ccc(CCOc2ccc(C=O)cc2)cc1
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Product: O=Cc1ccc(OCCc2ccc(O)cc2)cc1
Yield: 94.3 %

Procedure:
Ammonium hydroxide was added to a solution of 2.0 g (7 mmole) 4-[2-(4-formylphenoxy)ethyl]phenyl acetate in methanol. When the starting material was consumed the solvent was evaporated in vacuo. 0.5 M hydrochloric acid was added and the product was extracted with diethyl ether and dichloromethane, dried, filtered and evaporated to give 1.6 g (yield 93%) of 4-[2-(4-hydroxyphenyl)ethoxy]benzaldehyde
Reaction SMILES: ClC(Cl)(Cl)[C:3]([C:5]1[N:14]2[C:8]([CH2:9][N:10]([C:19](=[O:29])[CH2:20][O:21][C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13]2)=[CH:7][CH:6]=1)=[O:4].[CH3:32][C:33]1[CH:40]=[CH:39][C:36]([CH2:37][NH2:38])=[CH:35][CH:34]=1>>[Cl:28][C:25]1[CH:24]=[CH:23][C:22]([O:21][CH2:20][C:19]([N:10]2[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13][N:14]3[C:5]([C:3]([NH:38][CH2:37][C:36]4[CH:39]=[CH:40][C:33]([CH3:32])=[CH:34][CH:35]=4)=[O:4])=[CH:6][CH:7]=[C:8]3[CH2:9]2)=[O:29])=[CH:27][CH:26]=1
Reactant: Cc1ccc(CN)cc1
Reactant: O=C(COc1ccc(Cl)cc1)N1Cc2ccc(C(=O)C(Cl)(Cl)Cl)n2Cc2ccccc21
Product: Cc1ccc(CNC(=O)c2ccc3n2Cc2ccccc2N(C(=O)COc2ccc(Cl)cc2)C3)cc1

Procedure:
The title compound was synthesized from 2,2,2-trichloro-1-{10-[(4-chlorophenoxy) acetyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}ethanone of Example 67 (0.3 mmol) and 4-methylbenzylamine (2.2 eq.) in the manner of Example 68, m.p. 174-176° C. MS [(+)ESI, m/z]: 500 [M+H]+ Anal. Calcd for C29H26CIN3O3: C, 69.66; H, 5.24; N, 8.40. Found: C, 69.56; H, 5.35; N, 8.37.
Reaction SMILES: O=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+].C(#N)C.[CH3:31][N:32]([CH3:63])[C:33](=[O:62])[C:34]1[CH:39]=[CH:38][C:37]([O:40][CH2:41][CH2:42][CH2:43][CH2:44][CH:45]2[CH2:53][C:52]3[C:47](=[C:48]([O:60]C)[C:49]([O:58][CH3:59])=[C:50]([O:56][CH3:57])[C:51]=3[O:54]C)[CH2:46]2)=[CH:36][CH:35]=1>O>[CH3:63][N:32]([CH3:31])[C:33](=[O:62])[C:34]1[CH:39]=[CH:38][C:37]([O:40][CH2:41][CH2:42][CH2:43][CH2:44][CH:45]2[CH2:53][C:52]3[C:51](=[O:54])[C:50]([O:56][CH3:57])=[C:49]([O:58][CH3:59])[C:48](=[O:60])[C:47]=3[CH2:46]2)=[CH:36][CH:35]=1
Reactant: COc1c2c(c(OC)c(OC)c1OC)CC(CCCCOc1ccc(C(=O)N(C)C)cc1)C2
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Solvent: CC#N
Solvent: O
Product: COC1=C(OC)C(=O)C2=C(CC(CCCCOc3ccc(C(=O)N(C)C)cc3)C2)C1=O
Reaction time: 0.25 h
Yield: 45.8 %

Procedure:
A water (1.0 ml) solution of CAN (1.07 g, 1.96 mmols) was dropwise added to an acetonitrile (8.0 ml) solution of N,N-dimethyl-4-[4-(4,5,6,7-tetramethoxyindan-2-yl)butoxy]benzamide (358 mg, 0.782 mmols), with cooling with ice, and stirred for 15 minutes. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous sodium chloride solution, and then dried. The solvent was evaporated out in vacuo, and the resulting crude product was purified by silica gel column chromatography (hexane:ethyl acetate=4:1 to 1:2) followed by recrystallization (from diisopropyl ether-ethyl acetate) to obtain the entitled compound (153 mg) as crystals.
Reaction SMILES: C([Li])CCC.[CH:6]1([O:11][C:12]2[CH:13]=[C:14](Br)[CH:15]=[CH:16][C:17]=2[O:18][CH3:19])[CH2:10][CH2:9][CH2:8][CH2:7]1.[Cl:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=1[CH2:29][CH:30]=[O:31].[Cl-].[NH4+]>CCCCCC.O1CCCC1>[CH:6]1([O:11][C:12]2[CH:13]=[C:14]([CH:30]([OH:31])[CH2:29][C:23]3[C:22]([Cl:21])=[CH:27][CH:26]=[CH:25][C:24]=3[Cl:28])[CH:15]=[CH:16][C:17]=2[O:18][CH3:19])[CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: O=CCc1c(Cl)cccc1Cl
Reactant: COc1ccc(Br)cc1OC1CCCC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1ccc(C(O)Cc2c(Cl)cccc2Cl)cc1OC1CCCC1
Temperature: -70 °C
Reaction time: 1 h
Yield: 33.1 %

Procedure:
A solution of butyl lithium in hexane (5.1 mL; 2.5 M) is treated with a solution of 3-cyclopentyloxy-4-methoxyphenyl bromide (3.45 g) in dry tetrahydrofuran (30 mL) at −70° C. and the solution is then stirred at −70° C. for 1 hour. It is then treated dropwise with 2,6-dichlorophenylacetaldehyde (2.4 g), while keeping the temperature below −60° C. When the addition is complete the temperature is allowed to rise to room temperature and the solution is stirred for a further 2 hours. The reaction mixture is treated with aqueous ammonium chloride solution (50 mL) and the solution is extracted with diethyl ether (2×200 mL). The combined extracts are dried and concentrated, to give a yellow oil, which is subjected to flash chromatography, eluting with a mixture of diethyl ether and pentane (1:8 v/v), to give 1-(3-cyclopentyloxy-4-methoxyphenyl)-2-(2,6-dichlorophenyl)ethanol (1.6 g), in the form of a white solid, m.p. 87-89° C.
Reaction SMILES: [CH2:1]([C:5]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([CH2:10]/[CH:11]=[CH:12]/[CH3:13])[C:6]([O:8][CH3:9])=[O:7])/[CH:2]=[CH:3]/[CH3:4].[H][H]>CO.O=[Pt]=O>[CH2:1]([C:5]([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)([CH2:10][CH2:11][CH2:12][CH3:13])[C:6]([O:8][CH3:9])=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: [H][H]
Reactant: C/C=C/CC(C/C=C/C)(C(=O)OC)c1ccccc1
Agent: O=[Pt]=O
Solvent: CO
Product: CCCCC(CCCC)(C(=O)OC)c1ccccc1
Yield: 95.9 %

Procedure:
A solution of the product of Example 4A (7.78 g, 30.16 mmol) in methanol (70 mL) was treated with Adams' catalyst (PtO2, 790 mg) and hydrogenated under 60 psi hydrogen pressure for 16 hours at 25° C. The catalyst was removed by filtration and the filtrate concentrated in vacuo to give the title compound (7.59 g, 96%). 1H NMR (300 MHz, CDCl3): δ 7.27 (m, 5 H), 3.64 (s, 3 H), 1.99 (m, 4 H), 1.29 (m, 4 H), 1.03 (m, 4 H), 0.86 (t, J=7.17 Hz, 6 H).
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]2[C:9]([C:10]([CH2:17]Cl)=[C:11]3[C:16]=1[CH:15]=[CH:14][CH:13]=[CH:12]3)=[CH:8][CH:7]=[CH:6][CH:5]=2.[CH3:19][N:20]([CH3:24])[CH2:21][CH2:22][NH2:23]>O>[CH3:19][N:20]([CH3:24])[CH2:21][CH2:22][NH:23][CH2:2][C:3]1[C:4]2[C:9]([C:10]([CH2:17][NH:23][CH2:22][CH2:21][N:20]([CH3:24])[CH3:19])=[C:11]3[C:16]=1[CH:15]=[CH:14][CH:13]=[CH:12]3)=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: CN(C)CCN
Reactant: ClCc1c2ccccc2c(CCl)c2ccccc12
Solvent: O
Product: CN(C)CCNCc1c2ccccc2c(CNCCN(C)C)c2ccccc12
Yield: 36.7 %

Procedure:
1.0 g (0.0036 mol) of 9,10-dichloromethylanthracene (0.0036 mol) is refluxed for 20 minutes with 15 g of 2-dimethylaminoethylamine. The reaction mixture is added to water and the precipitate collected by filtration. The dried solid is then recrystallised from ethyl acetate to yield 0.5 g of the title compound as yellow crystals, m.p. 58°-60° C.; λmax (distilled water) (E/cm/M) 248 nm (51760), 372 nm (9030), 392 nm (8305).
Reaction SMILES: Cl[CH:2]=[CH:3][C:4](=O)[CH:5]([CH3:7])[CH3:6].[NH2:9][C:10]1[N:14]=[CH:13][NH:12][N:11]=1>C(O)(=O)C>[CH3:6][CH:5]([C:4]1[N:11]2[N:12]=[CH:13][N:14]=[C:10]2[N:9]=[CH:2][CH:3]=1)[CH3:7]
Reactant: Nc1nc[nH]n1
Reactant: CC(C)C(=O)C=CCl
Solvent: CC(=O)O
Product: CC(C)c1ccnc2ncnn12

Procedure:
A mixture of 1-chloro-4-methyl-1-penten-3-one (5.83 g), 3-amino-1,2,4-triazole (3.69 g) and glacial acetic acid was heated under reflux for 1 hour and 30 minutes. The reaction mixture was poured onto ice and extracted with dichloromethane. The organic layer was dried over magnesium sulphate and the solvent was evaporated to give a product which was recrystallised from petroleum ether (b.p. 100°-140° C.), to give 7-(1-methylethyl)-1,2,4-triazolo[1,5-a]pyrimidine. Yield 4.18 g.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[NH:7][C:6]2[CH:8]=[CH:9][CH:10]=[CH:11][C:5]=2[N:4]=1.Br[CH2:15][C:16]1[CH:35]=[CH:34][C:19]2/[C:20](=[C:30](/[CH3:33])\[C:31]#[N:32])/[C:21]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:22]=3[O:23][CH2:24][C:18]=2[CH:17]=1>>[F:29][C:26]1[CH:27]=[CH:28][C:21]2=[C:22]([CH:25]=1)[O:23][CH2:24][C:18]1[CH:17]=[C:16]([CH2:15][N:7]3[C:6]4[CH:8]=[CH:9][CH:10]=[CH:11][C:5]=4[N:4]=[C:3]3[C:2]([F:1])([F:12])[F:13])[CH:35]=[CH:34][C:19]=1/[C:20]/2=[C:30](/[CH3:33])\[C:31]#[N:32]
Reactant: C/C(C#N)=C1/c2ccc(CBr)cc2COc2cc(F)ccc21
Reactant: FC(F)(F)c1nc2ccccc2[nH]1
Product: C/C(C#N)=C1/c2ccc(Cn3c(C(F)(F)F)nc4ccccc43)cc2COc2cc(F)ccc21
Yield: 88.9 %

Procedure:
Using 2-(trifluoromethyl)-1H-benzo[d]imidazole (62 mg, 0.335 mmol) and (E)-2-[8-(bromomethyl)-3-fluorodibenzo[b,e]oxepin-11(6H)-ylidene]propanenitrile (120 mg, 0.335 mmol) obtained in Reference Example 1, and in the same manner as in Reference Example 1A, the title compound (138 mg, 88%) was obtained.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[C:8]1[N:13]=[C:12]([O:14][CH3:15])[N:11]=[C:10]([O:16][CH3:17])[CH:9]=1>C(#N)C>[CH3:15][O:14][C:12]1[N:11]=[C:10]([O:16][CH3:17])[CH:9]=[C:8]([N:1]2[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]2)[N:13]=1
Reactant: COc1cc(Cl)nc(OC)n1
Reactant: C1CNCCN1
Solvent: CC#N
Product: COc1cc(N2CCNCC2)nc(OC)n1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
piperazine (1.23 g, 14.32 mmol) was treated with 6-chloro-2,4-dimethoxy pyrimidine (0.5 g, 2.86 mmol) in acetonitrile (5 mL) and the reaction mixture was stirred at room temperature for 6 hours. Subsequently the reaction mixture was poured onto ice-cold water (25 ml) and extracted with ethyl acetate (25 ml). The organic layer was washed with aqueous sodium bicarbonate solution and evaporated to furnish the required compound.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([C:10]2[N:14](C3CCCCO3)[N:13]=[CH:12][CH:11]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[Cl:21][O-].[Na+]>C(O)(=O)C>[Cl:1][C:2]1[CH:9]=[C:8]([C:10]2[NH:14][N:13]=[CH:12][C:11]=2[Cl:21])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: [O-]Cl
Reactant: N#Cc1ccc(-c2ccnn2C2CCCCO2)cc1Cl
Agent: [Na+]
Solvent: CC(=O)O
Product: N#Cc1ccc(-c2[nH]ncc2Cl)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.4 %

Procedure:
2-chloro-4-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)benzonitrile (12.0 g, 41.7 mmol) was dissolved in acetic acid (20 ml) and sodium hypochlorite solution (29.0 ml, 416 mmol) was added. The reaction mixture was stirred at RT overnight. Further again, acetic acid (120 ml) and sodium hypochlorite solution (14 ml) were added and the mixture was stirred at RT overnight. The precipitate was filtrated and washed with water and DCM. The precipitate was dried in vacuum 40° C. overnight to yield 5.8 grams of 2-chloro-4-(4-chloro-1H-pyrazol-5-yl)benzonitrile. The mixture of 2-chloro-4-(4-chloro-1H-pyrazol-5-yl)benzonitrile (5.8 g, 24.36 mmol) and 10% HCl/ethanol solution (167 ml, 365 mmol) was stirred for 2 h at RT and the precipitate was filtrated and washed with water. The precipitate was silted up with ethanol to yield 4.0 g of the raw material. The product was purified with Flash-chromatography to yield total 18% of the title compound. 1H NMR (400 MHz; d6-DMSO): δ 8.05 (m, 2H), 8.16 (m, 2H).
Reaction SMILES: Br[C:2]1[C:3]([NH2:8])=[N:4][CH:5]=[CH:6][CH:7]=1.[F:9][C:10]1[CH:11]=[C:12]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:13]=[CH:14][C:15]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].O>COCCOC>[F:9][C:10]1[CH:11]=[C:12]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:13]=[CH:14][C:15]=1[C:2]1[C:3]([NH2:8])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ncccc1Br
Reactant: OB(O)c1ccc(-c2ccccc2)cc1F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Nc1ncccc1-c1ccc(-c2ccccc2)cc1F
Temperature: 80 °C
Reaction time: 4 h
Yield: 100 %

Procedure:
To a solution of 3-bromopyridin-2-amine (1.0 g) in 1,2-dimethoxyethane (50 mL) were added 3-fluorobiphenyl-4-ylboronic acid (1.623 g), sodium carbonate (1.225 g), tetrakis(triphenylphosphine)palladium(D) (0.334 g), and water (10 mL) at room temperature. The reaction mixture was stirred under a nitrogen atmosphere at 80° C. for 4 hr, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by recrystallization (THF/diisopropyl ether) to give the title compound (1.528 g).
Reaction SMILES: [OH-].[K+].[C:3]1([CH:9]=[CH:10][C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=O)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:19]1([NH:25][NH2:26])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(O)C>[C:19]1([N:25]2[CH:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:10]=[C:9]([C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=3)[NH:26]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: NNc1ccccc1
Reactant: O=C(C=Cc1ccccc1)c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: C1=C(c2ccccc2)NN(c2ccccc2)C1c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 77.6 %

Procedure:
In a 2000-ml four-necked flask were placed 13.0 g (0.23 mole) of potassium hydroxide and 1004.5 g of ethanol. The mixture was stirred at room temperature until the potassium hydroxide dissolved and 25.8 g (0.12 mole) of chalcone and 26.4 g (0.24 mole) of phenylhydrazine were added at room temperature. After the addition, the mixture was heated under reflux with stirring for three hours. Upon completion of the reaction, the reaction mixture was cooled to room temperature and a solid was recovered by filtration. The solid was washed with hexane and dried under reduced pressure to give 27.8 g of 1,3,5-triphenylpyrazoline as a white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20](SCC)=[N:19][C:18]4=[O:25])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:28]([F:31])([F:30])[F:29])[CH:3]=1.[CH3:32][C:33]1([C:39]([OH:41])=[O:40])[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1>>[Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20]([N:36]5[CH2:37][CH2:38][C:33]([CH3:32])([C:39]([OH:41])=[O:40])[CH2:34][CH2:35]5)=[N:19][C:18]4=[O:25])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:28]([F:29])([F:30])[F:31])[CH:3]=1
Reactant: CCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Reactant: CC1(C(=O)O)CCNCC1
Product: CC1(C(=O)O)CCN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(Cl)cc4C(F)(F)F)c3)S2)CC1

Procedure:
1-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-4-methyl-piperidine-4-carboxylic acid was prepared from 5-[1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-one and 4-methyl-piperidine-4-carboxylic acid following General Procedure C.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([F:13])([F:12])[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].Cl[CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30]>CN(C=O)C.C1COCC1>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([F:13])([F:12])[C:7](=[O:11])[N:8]2[CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])=[CH:4][CH:3]=1
Reactant: O=C1Nc2cc(Br)ccc2C1(F)F
Reactant: C[Si](C)(C)CCOCCl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCN1C(=O)C(F)(F)c2ccc(Br)cc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Into the solution of 6-bromo-3,3-difluoroindolin-2-one in DMF (5 mL), was added 1M of NaHMDS solution in THF (1.6 mL), after 30 min., (2-(chloromethoxy)ethyl)trimethylsilane (269 mg) was added. After being stirred at rt for 4 h, the reaction mixture was extracted with ethyl acetate and washed with brine, dried and the solvent was removed, the residue was purified by silica gel chromatography to provide 0.46 g of 6-bromo-3,3-difluoro-1-((2-(trimethylsilyl)ethoxy)methyl)indolin-2-one 7.35. 1H NMR (400 MHz, Chloroform-d) δ 7.43 (s, 1H), 7.37 (d, J=8.2 Hz, 1H), 7.33 (d, J=8.1 Hz, 1H), 5.12 (s, 2H), 3.58 (m, 2H), 1.21 (m, 2H), 0.00 (s, 9H).
Reaction SMILES: [C:1]1([C@@H:7]2[NH:11][C@H:10]([CH2:12][O:13][C:14]3[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][CH:15]=3)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[NH:31][C:32](=[O:46])[NH:33][C:34]1[CH:39]=[CH:38][C:37]([CH2:40][C:41](O)=[O:42])=[CH:36][C:35]=1[O:44][CH3:45].CCN=C=NCCCN(C)C.Cl.O>CN(C=O)C>[Br:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[NH:31][C:32](=[O:46])[NH:33][C:34]1[CH:39]=[CH:38][C:37]([CH2:40][C:41]([N:11]2[C@@H:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH2:8][CH2:9][C@H:10]2[CH2:12][O:13][C:14]2[CH:15]=[CH:16][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:22][CH:23]=2)=[O:42])=[CH:36][C:35]=1[O:44][CH3:45]
Reactant: COc1cc(CC(=O)O)ccc1NC(=O)Nc1ccccc1Br
Reactant: COC(=O)c1ccc(OC[C@@H]2CC[C@H](c3ccccc3)N2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(OC[C@@H]2CC[C@H](c3ccccc3)N2C(=O)Cc2ccc(NC(=O)Nc3ccccc3Br)c(OC)c2)cc1
Reaction time: 8 h
Yield: 91.1 %

Procedure:
To a stirred solution of methyl 4-[5-(R)-phenyl-2-(S)-pirrolidinylmethoxy]benzoate (146 mg, 0.47 mmol), 4-[N′-(2-bromophenyl)ureido]-3-methoxyphenylacetic acid (178 mg, 0.47 mmol) and N,N-dimethylaminopyridine (57.4 mg, 0.47 mmol) in DMF (10 ml) was added EDC.HCl (99.0 mg, 0.52 mmol) at rt, and the resulting mixture was stirred overnight. The reaction mixture was poured into water and extracted with EtOAc. The organic layer was washed with brine, drying over anhydrous Na2SO4, then concentrated in vacuo. The residue was chromatographed on silica gel with hexane-EtOAc (1:5) as eluent to give methyl 4-[1-[4-[N′-(2-bromophenyl)ureido]-3-methoxyphenylacetyl]-5-(R)-phenyl-2-(S)-pyrrolidinylmethoxy]benzoate (288 mg, 91%) as a colorless amorphous solid. 1H-NMR (CDCl3) δ2.00-2.20 (m, 3 H), 2.34-2.43 (m, 1 H), 3.35 (s, 2 H), 3.72 (s, 3 H), 3.89 (s, 3 H), 4.38-4.49 (m, 2 H), 4.62 (brs, 1 H), 4.94 (t, J=7.2 Hz, 1 H), 6.54 (d, J=8.4 Hz, 1 H), 6.67 (s, 1 H), 6.91-7.05 (m, 4 H), 7.28-7.42 (series of m, 7 H), 7.51 (d, J=8.0 Hz, 2 H), 7.87 (d, J=8.4 Hz, 1 H), 7.99 (d, J=8.8 Hz, 2 H), 8.14 (d, J=8.4 Hz, 2H); MS (ESI) m/z, 672 (M+), 674 (M++2).
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][CH:3]1[C:7]1[CH:14]=[CH:13][C:10]([CH:11]=O)=[CH:9][CH:8]=1.[NH2:15][C:16]1[CH:24]=[CH:23][CH:22]=[C:21]2[C:17]=1[CH2:18][O:19][C:20]2=[O:25].[O-]S([O-])(=O)=O.[Mg+2]>CC#N>[CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][CH:3]1[C:7]1[CH:14]=[CH:13][C:10](/[CH:11]=[N:15]/[C:16]2[CH:24]=[CH:23][CH:22]=[C:21]3[C:17]=2[CH2:18][O:19][C:20]3=[O:25])=[CH:9][CH:8]=1
Reactant: CN1CCCC1c1ccc(C=O)cc1
Reactant: Nc1cccc2c1COC2=O
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CC#N
Product: CN1CCCC1c1ccc(/C=N/c2cccc3c2COC3=O)cc1
Temperature: 120 °C
Yield: 41 %

Procedure:
A mixture of 4-(1-methylpyrrolidin-2-yl)benzaldehyde (1.89 g, 10 mmol), 4-aminoisobenzofuran-1(3H)-one (1.49 g, 10 mmol) and MgSO4(12 g, 100 mmol) in CH3CN (60 mL) was refluxed at 120° C. for 4 days. After a hot filtration, CH3CN was partially removed under reduced pressure and a white precipitate was appeared, the title compound was obtained by a direct filtration (1.3 g, yield 41%) as a white solid. LC-MS (ESI) m/z: 440 (M+1)+.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:9]([C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1)([CH3:11])=[CH2:10]>>[OH:18][C:15]1[CH:16]=[CH:17][C:12]([C:9]([C:6]2[CH:7]=[CH:8][C:3]([NH2:2])=[CH:4][CH:5]=2)([CH3:11])[CH3:10])=[CH:13][CH:14]=1
Reactant: C=C(C)c1ccc(O)cc1
Reactant: Nc1ccccc1
Agent: Cl
Product: CC(C)(c1ccc(N)cc1)c1ccc(O)cc1
Yield: 76 %

Procedure:
Example 11 was repeated except that the amount of the aniline hydrochloride was changed to 0.26 g (0.02 mole of catalyst per mole of the p-isopropenyl phenol monomeric unit). After the reaction, the reaction mixture was analyzed by gas chromatography. It was found that 17.3 g (yield 76%) of 2-(4'-hydroxyphenyl)-2-(4'-aminophenyl)-propane and 1.4 g of bisphenol A were formed.
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[C:7]1([S:13][CH2:14][N:15]2[C:19](=[O:20])[CH:18]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[NH:17][S:16]2(=[O:29])=[O:28])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.CI>C1COCC1>[C:7]1([S:13][CH2:14][N:15]2[C:19](=[O:20])[CH:18]([CH2:21][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[N:17]([CH3:1])[S:16]2(=[O:28])=[O:29])[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: O=C1C(Cc2ccccc2)NS(=O)(=O)N1CSc1ccccc1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CI
Solvent: C1CCOC1
Product: CN1C(Cc2ccccc2)C(=O)N(CSc2ccccc2)S1(=O)=O
Reaction time: 0.5 h
Yield: 82.4 %

Procedure:
Potassium t-butoxide (5.65 g, 50.35 mmol) was added to a solution of 2-phenylthiomethyl-4-phenylmethyl-1,2,5-thiadiazolidin-3-one 1,1-dioxide (14.61 g, 41.93 mmol) in 250 ml of THF at 0° C. and the mixture was stirred at this temperature for 1/2 hour. To the above mixture was added methyl iodide (35.69 g, 251.58 mmol) at 0° C. and the resulting mixture was allowed to stir for 4.5 hours at room temperature. The resulting mixture was quenched with saturated ammonium chloride solution, extracted with ethyl acetate and the organic layer was washed with brine. The organic layer was dried, concentrated in vacuo, and the residue was purified by flash chromatography to afford 12.53 g (82.4%) of 2-phenylthiomethyl-4-phenylmethyl-5-methyl-1,2,5-thiadiazolidin-3-one 1,1-dioxide as a yellow solid.