Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][N:11]([C:19]1[S:20][C@H:21]2[O:27][C@H:26]([CH2:28][OH:29])[C@@H:25]([OH:30])[C@H:24]([OH:31])[C@H:22]2[N:23]=1)[C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:39]([Si:43](Cl)([CH3:45])[CH3:44])([CH3:42])([CH3:41])[CH3:40]>CN(C1C=CN=CC=1)C.ClCCl>[CH2:1]([O:8][CH2:9][CH2:10][N:11]([C:19]1[S:20][C@H:21]2[O:27][C@H:26]([CH2:28][O:29][Si:43]([C:39]([CH3:42])([CH3:41])[CH3:40])([CH3:45])[CH3:44])[C@@H:25]([OH:30])[C@H:24]([OH:31])[C@H:22]2[N:23]=1)[C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(C)(C)OC(=O)N(CCOCc1ccccc1)C1=N[C@@H]2[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]2S1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N(CCOCc1ccccc1)C1=N[C@@H]2[C@@H](O)[C@H](O)[C@@H](CO[Si](C)(C)C(C)(C)C)O[C@@H]2S1
Temperature: 25 °C
Reaction time: 12 h
Yield: 73.7 %

Procedure:
A mixture of 131 (2.8 g, 6.2 mmol), DMAP (150 mg, 1.2 mmol), triethylamine (930 g, 9.2 mol) and tert-butylchlorodimethylsilane (1.1 g, 7.5 mmol) in dichloromethane (40 mL) was stirred for 12 hours at room temperature, then quenched with saturated aqueous NaHCO3 solution (30 mL). The aqueous layer was extracted with dichloromethane (2×40 mL), and the combined organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was purified by a silica gel column, eluted with 1%-3% methanol in dichloromethane to afford 132 as a white solid (2.6 g, 75%). (ES, m/z) [M+H]+ 569.0; 1H NMR (300 MHz, CDCl3) δ 7.28-7.38 (m, 5H), 6.13 (d, J=6.3 Hz, 1H), 4.49 (s, 2H), 4.34-4.36 (m, 1H), 4.06-4.08 (m, 1H), 3.83-390 (m, 1H), 3.59-3.67 (m, 2H), 3.30-3.55 (m, 5H), 1.58 (s, 9H), 0.98 (s, 9H), 0.15 (s, 3H), 0.08 (s, 3H).
Reaction SMILES: [NH3:1].Cl[C:3]1[C:4]2[C:11]([I:12])=[CH:10][N:9]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:5]=2[N:6]=[CH:7][N:8]=1.C(=O)=O.CC(C)=O>O1CCOCC1.CC(O)C>[I:12][C:11]1[C:4]2[C:3]([NH2:1])=[N:8][CH:7]=[N:6][C:5]=2[N:9]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:10]=1
Reactant: Clc1ncnc2c1c(I)cn2-c1ccccc1
Reactant: N
Agent: O=C=O
Solvent: C1COCCO1
Solvent: CC(C)=O
Solvent: CC(C)O
Product: Nc1ncnc2c1c(I)cn2-c1ccccc1
Temperature: 100 °C

Procedure:
Gaseous ammonia (from a lecture bottle) was condensed into a suspension of 4-chloro-5-iodo-7-phenyl-7H-pyrrolo[2,3-d]pyrimidine (30 mg, 0.084 mmol) in dioxane (2 mL) and iPrOH (2 mL) in a sealable glass tube, cooled by dry ice/acetone, until the volume increased by ≈2 mL, then the tube was sealed and heated to 100° C. overnight. The solvents were evaporated, water was added, the mixture was extracted with CH2Cl2 (3×30 mL), and the combined CH2Cl2 extracts were washed with brine, dried over MgSO4, filtered and concentrated to give the title compound as a white solid. 1H NMR (CDCl3, 400 MHz): δ=5.69 (brs, 2H), 7.36 (s, 1H), 7.36-7.41 (m, 1H), 7.49-7.55 (m, 2H), 7.60-7.64 (m, 2H), 8.33 (s, 1H). MS (ES+): m/z 337.0 (100) [MH+]. HPLC: tR=2.8 min (OpenLynx, polar—5 min).
Reaction SMILES: [CH3:1]C([O-])(C)C.[K+].[CH2:7]([C:12]1([CH:29]=O)[CH2:17][CH2:16][CH:15]([CH:18]2[CH2:23][CH2:22][CH:21]([CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH2:20][CH2:19]2)[CH2:14][CH2:13]1)[CH2:8][CH2:9][CH2:10][CH3:11].O>C1COCC1.[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:7]([C:12]1([CH:29]=[CH2:1])[CH2:17][CH2:16][CH:15]([CH:18]2[CH2:23][CH2:22][CH:21]([CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH2:20][CH2:19]2)[CH2:14][CH2:13]1)[CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CCCCCC1CCC(C2CCC(C=O)(CCCCC)CC2)CC1
Reactant: CC(C)(C)[O-]
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: C=CC1(CCCCC)CCC(C2CCC(CCCCC)CC2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 17.84 g of KOtBu in 100 ml of THF is added dropwise at 0° C. to a suspension of 53.20 g of 4,4′-dipentylbicyclohexyl-4-carbaldehyde and 56.80 g of methyltriphenylphosphonium bromide in 300 ml of THF. The mixture is stirred at RT overnight, water is added, and the mixture is extracted with MTB ether. The combined organic phases are subjected to conventional work-up, giving 4,4′-dipentyl-4-vinylbicyclohexyl.
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][C:5]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=1)([C:8]#[N:9])[C:6]#[N:7].C(N(S(F)(F)[F:27])CC)C>ClCCl>[F:27][CH2:2][CH2:3][CH2:4][C:5]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=1)([C:8]#[N:9])[C:6]#[N:7]
Reactant: N#CC(C#N)(CCCO)Cc1ccc(C(F)(F)F)cc1
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: N#CC(C#N)(CCCF)Cc1ccc(C(F)(F)F)cc1
Yield: 5 %

Procedure:
Using 0.80 g of 2-(3-hydroxypropyl)-2-(4-(trifluoromethyl)benzyl)-malononitrile, 8 ml of dichloromethane and 0.3 ml of Diethylaminosulfur trifluoride, and according to the process described in the Production Example 11, there was obtained 0.05 g of 2-(3-fluoropropyl)-2-(4-(trifluoromethyl)benzyl)malononitrile (the present compound (14)).
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl[C:11]1[C:12]([N+:17]([O-:19])=[O:18])=[N:13][CH:14]=[CH:15][CH:16]=1>>[CH2:3]([N:2]([CH3:1])[C:11]1[C:12]([N+:17]([O-:19])=[O:18])=[N:13][CH:14]=[CH:15][CH:16]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CNCc1ccccc1
Reactant: O=[N+]([O-])c1ncccc1Cl
Product: CN(Cc1ccccc1)c1cccnc1[N+](=O)[O-]
Temperature: 60 °C
Reaction time: 8 h

Procedure:
The mixture of N-methylbenzylamine (6.085 mL), TEA (13.19 mL) and 3-chloro-2-nitropyridine (5 g) was stirred at 60° C. under N2 overnight. The reaction mixture was concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 0%-30% EtOAc in hexane) to give N-benzyl-N-methyl-2-nitropyridin-3-amine (2.6 g) as dark yellow oil.
Reaction SMILES: CC1C=C(SC[C:11](O)=[O:12])C=C(C)C=1.N1C=CC(SCC(O)=O)=CC=1.[C:25]1([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:30]=[CH:29][C:28]([S:31][CH2:32][C:33]([OH:35])=[O:34])=[CH:27][CH:26]=1>>[CH3:11][O:12][C:39]1[CH:38]=[CH:37][C:36]([C:25]2[CH:30]=[CH:29][C:28]([S:31][CH2:32][C:33]([OH:35])=[O:34])=[CH:27][CH:26]=2)=[CH:41][CH:40]=1
Reactant: Cc1cc(C)cc(SCC(=O)O)c1
Reactant: O=C(O)CSc1ccc(-c2ccccc2)cc1
Agent: O=C(O)CSc1ccncc1
Product: COc1ccc(-c2ccc(SCC(=O)O)cc2)cc1

Procedure:
 was acylated with (3,5-dimethyl-phenylsulfanyl)acetic acid, with pyridin-4-ylsulfanyl-acetic acid, with 2-(biphenyl-4-ylsulfanyl)-acetic acid, and with 2-(4′-methoxy-biphenyl-4-ylsulfanyl)-acetic acid, respectively, to give the following compounds as pale-yellow solids:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:28])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=[O:17])[N:9]2[CH2:18][C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=2)=[CH:4][CH:3]=1.[C:29]1([CH2:34]O)([CH2:32][OH:33])[CH2:31][CH2:30]1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([O:28][CH2:34][C:29]3([CH2:32][OH:33])[CH2:31][CH2:30]3)[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=[O:17])[N:9]2[CH2:18][C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=2)=[CH:4][CH:3]=1
Reactant: O=C1c2ccccc2C(O)(c2ccc(Cl)cc2)N1Cc1ccc([N+](=O)[O-])cc1
Reactant: OCC1(CO)CC1
Product: O=C1c2ccccc2C(OCC2(CO)CC2)(c2ccc(Cl)cc2)N1Cc1ccc([N+](=O)[O-])cc1
Yield: 63.1 %

Procedure:
The named compound was synthesised from 3-(4-Chlorophenyl)-3-hydroxy-2-(4-nitrobenzyl)-2,3-dihydroisoindol-1-one (400 mg, 1.01 mmol, 1 equiv.) and cyclopropane dimethanol (516 mg, 5.05 mmol, 5 equiv.) using General Procedure A and obtained as an off-white solid (305 mg, 63%). 1H NMR (300 MHz, CDCl3): 8.01-7.98 (m, 2H, O2N—C—CH), 7.92-7.89 (m, 1H, C(O)═C═CH), 7.55-7.52 (m, 2H, Ar—H), 7.32-7.29 (m, 2H, Ar—H), 7.19-7.12 (m, 5H, Ar—H), 4.49 (s, 2H, N—CH2), 3.51-3.43 (m, 2H, HOCH2), 2.81 (s, 2H, OCH2), 0.43-0.40 (m, 2H, CH2), 0.22-0.12 (m, 2H, CH2). 13C NMR (75 MHz, CDCl3): 168.54, 145.52, 144.95, 137.47, 135.29, 133.45, 131.87, 130.50, 130.21, 128.98, 128.30, 124.16, 123.60, 123.48, 94.96, 67.84, 42.75, 22.68, 8.94, 8.90 Anal.: calc. for C26H23ClN2O5: C, 65.20; H, 4.84; N, 5.85, Found: C, 64.83; H, 4.92; N, 5.63.
Reaction SMILES: [C:1]([NH:4][C:5]1[O:6][C:7]2[CH:13]=[C:12]([CH2:14][CH2:15][C:16]3[N:17]=[C:18]4[CH:23]=[C:22]([CH3:24])[CH:21]=[CH:20][N:19]4[CH:25]=3)[CH:11]=[CH:10][C:8]=2[N:9]=1)(=O)C.P(Cl)(Cl)(Cl)=O.C(=O)([O-])[O-].[K+].[K+].[CH3:37][N:38](C)[CH:39]=O>O>[CH3:37][N:38]([CH:1]=[N:4][C:5]1[O:6][C:7]2[CH:13]=[C:12]([CH2:14][CH2:15][C:16]3[N:17]=[C:18]4[CH:23]=[C:22]([CH3:24])[CH:21]=[CH:20][N:19]4[CH:25]=3)[CH:11]=[CH:10][C:8]=2[N:9]=1)[CH3:39]
Reactant: CN(C)C=O
Reactant: CC(=O)Nc1nc2ccc(CCc3cn4ccc(C)cc4n3)cc2o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1ccn2cc(CCc3ccc4nc(N=CN(C)C)oc4c3)nc2c1

Procedure:
2-Acetamido-6-[2-(7-methylimidazo[1,2-a]pyridin-2-yl)ethyl]benzoxazole (2.20 g) was added in small portions to a solution of phosphorous oxychloride (1.79 ml) in N,N-dimethylformamide (20 ml) at ambient temperature with stirring. After being stirred for 1 hour, the mixture was diluted with water (200 ml) and stirred for an additional 30 minutes. The mixture was made alkaline with aqueous potassium carbonate and extracted with dichloromethane. The extract was washed with water, dried over magnesium sulfate, and evaporated in vacuo to give dark brown amorphous powder. The crude material was chromatographed on silica gel by eluting with chloroform-methanol (50:1, V/V), followed by recrystallization from a mixture of methanol and diisopropyl]ether to give 2-dimethylaminomethyleneamino-6-[2-(7-methylimidazo[1,2-a]pyridin-2-yl)ethyl]benzoxazole (0.31 g).
Reaction SMILES: [C:1](O)(=[O:4])[C:2]#[CH:3].N1(C(N2C=CN=C2)=O)C=CN=C1.[CH2:18]([C:20]1[N:21]=[C:22]([CH2:27][C:28]([C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)=[O:29])[NH:23][C:24]=1[CH2:25][CH3:26])[CH3:19]>>[CH2:25]([C:24]1[NH:23][C:22]2[N:21]([C:20]=1[CH2:18][CH3:19])[C:1](=[O:4])[CH:2]=[CH:3][C:27]=2[C:28](=[O:29])[C:30]1[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=1)[CH3:26]
Reactant: CCc1nc(CC(=O)c2ccc(F)cc2)[nH]c1CC
Reactant: C#CC(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Product: CCc1[nH]c2c(C(=O)c3ccc(F)cc3)ccc(=O)n2c1CC

Procedure:
The compound is prepared as described in example 6 with 122.1 mg (1.67 mmol) of propiolic acid, 325.6 mg (2.01 mmol) of 1-(1H-imidazol-1-ylcarbonyl)-1H-imidazole and 300 mg (1.12 mmol) of 2-(4,5-Diethyl-1H-imidazol-2-yl)-1-(4-fluorophenyl)ethanone (example XXVII).
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.[CH:5]([C:7]1[CH:12]=[CH:11][C:10]([C:13]#[C:14][C:15]2[CH:20]=[CH:19][C:18]([C:21](=[O:33])[N:22]([CH:24]([C:29]([NH:31][CH3:32])=[O:30])[C:25]([O:27][CH3:28])=[O:26])[CH3:23])=[CH:17][CH:16]=2)=[CH:9][CH:8]=1)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl.C(O)(=O)C>[CH:1]1([NH:4][CH2:5][C:7]2[CH:8]=[CH:9][C:10]([C:13]#[C:14][C:15]3[CH:20]=[CH:19][C:18]([C:21](=[O:33])[N:22]([CH:24]([C:29]([NH:31][CH3:32])=[O:30])[C:25]([O:27][CH3:28])=[O:26])[CH3:23])=[CH:17][CH:16]=3)=[CH:11][CH:12]=2)[CH2:3][CH2:2]1
Reactant: NC1CC1
Reactant: CNC(=O)C(C(=O)OC)N(C)C(=O)c1ccc(C#Cc2ccc(C=O)cc2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: CNC(=O)C(C(=O)OC)N(C)C(=O)c1ccc(C#Cc2ccc(CNC3CC3)cc2)cc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 76 %

Procedure:
Cyclopropylamine (0.15 g) and acetic acid (0.16 g) were added to a chloroform (20 mL) solution of 1-formyl-4-[(4-{[1-methoxy-3-(methylamino)-1,3-dioxopropan-2-yl](methyl)carbamoyl}phenyl)ethynyl]benzene (1.0 g) as obtained in Example 10-(5), and the mixture was stirred for 2.5 hours at room temperature. Then, sodium triacetoxyborohydride (0.89 g) was added, and the mixture was stirred for 15 hours at room temperature. A saturated aqueous solution of sodium hydrogen carbonate was added to the reaction mixture, and then the mixture was extracted with chloroform. The organic layer was washed with brine, and dried over anhydrous sodium sulfate. Then, the desiccant was filtered out, and the solvent was distilled off under reduced pressure. The resulting residue was purified by OH type silica gel chromatography (gradient elution with hexane/ethyl acetate=34/66→1/100) to obtain 1-[(cyclopropylamino)methyl]-4-[(4-{[1-methoxy-3-(methylamino)-1,3-dioxopropan-2-yl](methyl)carbamoyl}phenyl)ethynyl]benzene (colorless foam) (0.84 g, 74%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([Cl:11])=[CH:4][C:3]=1[CH2:12][CH:13]=O.C(O)(=O)C.[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[Cl:11][C:5]1[CH:4]=[C:3]([CH2:12][CH2:13][N:29]2[CH2:28][CH2:27][N:26]([C:24]([O:23][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:25])[CH2:31][CH2:30]2)[C:2]([Cl:1])=[CH:7][C:6]=1[N+:8]([O-:10])=[O:9]
Reactant: O=CCc1cc(Cl)c([N+](=O)[O-])cc1Cl
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCN(CCc2cc(Cl)c([N+](=O)[O-])cc2Cl)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A methylene chloride solution of the title compound of Example 10 was stirred at room temperature under nitrogen. Acetic acid (8.8 ml, 153 mmol) was added in one portion followed by t-butylpiperazinecarboxylate (8.4 g, 50 mmol). Sodium triacetoxy-borohydride (16.2 g, 77 mmol) was added in portions as a solid and the reaction mixture stirred at room temperature for three hours. The reaction mixture was washed two times with excess saturated sodium carbonate solution and one time each with water and brine. The organic layer was dried over magnesium sulfate, filtered and evaporated to afford the title product as an oil 15.6 g, (98% crude yield). This was suitable for use in the next reaction without further purification. NMR (CDCl3) δ 7.92 (s, 1), 7.48 (s, 1), 3.43 (m, 4), 2.97 (t, 2), 2.62 (t, 2), 2.49 (m, 4), 1.43 (s, 9).
Reaction SMILES: I[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1.[OH:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH:16]=[O:17]>O1CCOCC1>[C:2]1([O:12][C:13]2[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=2)[CH:16]=[O:17])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: Ic1cccc2ccccc12
Reactant: O=Cc1cccc(O)c1
Solvent: C1COCCO1
Product: O=Cc1cccc(Oc2cccc3ccccc23)c1
Temperature: 90 °C

Procedure:
1-iodonaphthalene (2.000 g) and 3-hydroxybenzaldehyde (1.442 g) were added to dioxane (25 mL). The solution was degassed and flushed with nitrogen three times. Cesium carbonate (5.13 g), N,N-dimethylglycine hydrochloride (82 mg), and copper (I) iodide (30 mg) were added, and the solution was heated at 90° C. overnight. The solution was cooled, added to 1M aqueous HCl, extracted with diethyl ether, dried with brine and anhydrous sodium sulfate. The solution was concentrated and purified by flash column chromatography on silica gel with 10% ethyl acetate in hexanes to provide the title compound.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([S:14][CH3:15])=[C:9]([CH:13]=1)[C:10]([OH:12])=O)(=[O:4])=[O:3].Cl.[F:17][C:18]([F:31])([F:30])[C:19]1[S:23][C:22]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[N:21][CH:20]=1>>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([S:14][CH3:15])=[C:9]([C:10]([N:27]2[CH2:28][CH2:29][N:24]([C:22]3[S:23][C:19]([C:18]([F:31])([F:17])[F:30])=[CH:20][N:21]=3)[CH2:25][CH2:26]2)=[O:12])[CH:13]=1)(=[O:3])=[O:4]
Reactant: FC(F)(F)c1cnc(N2CCNCC2)s1
Reactant: CSc1ccc(S(C)(=O)=O)cc1C(=O)O
Agent: Cl
Product: CSc1ccc(S(C)(=O)=O)cc1C(=O)N1CCN(c2ncc(C(F)(F)F)s2)CC1
Yield: 18 %

Procedure:
Prepared in analogy to example 1 (b) from 5-methanesulfonyl-2-methylsulfanyl-benzoic acid (Example A26) and 1-(5-trifluoromethyl-thiazol-2-yl)-piperazine hydrochloride (Example 58(c)). The crude material was purified by chromatography (SiO2, ethyl acetate/heptane) to yield the title compound as a light brown solid (yield 18%). MS (m/e): 466.0 (M+H+, 100%).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:19]=[CH:20][CH:21]=1)[CH2:7][C:8]1[C:9](=[O:18])[NH:10][C:11]([CH2:15][CH2:16][CH3:17])=[N:12][C:13]=1[CH3:14])(=[O:3])[CH3:2].Br[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:36]2[N:40]=[C:39](C(Cl)(Cl)Cl)[O:38][N:37]=2)=[CH:26][CH:25]=1.C(=O)([O-])[O-:46].[K+].[K+]>C(#N)C.C(OCC)(=O)C>[C:1]([C:4]1[CH:5]=[C:6]([CH:19]=[CH:20][CH:21]=1)[CH2:7][C:8]1[C:9](=[O:18])[N:10]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[C:36]3[NH:40][C:39](=[O:46])[O:38][N:37]=3)=[CH:26][CH:25]=2)[C:11]([CH2:15][CH2:16][CH3:17])=[N:12][C:13]=1[CH3:14])(=[O:3])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CCCc1nc(C)c(Cc2cccc(C(C)=O)c2)c(=O)[nH]1
Reactant: ClC(Cl)(Cl)c1nc(-c2ccccc2-c2ccc(CBr)cc2)no1
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCCc1nc(C)c(Cc2cccc(C(C)=O)c2)c(=O)n1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Reaction time: 12 h
Yield: 21.3 %

Procedure:
To a solution of 5-(3-acetylbenzyl)-6-methyl-2-propylpyrimidin-4(3H)-one (1 g) and 3-[4′-(bromomethyl)biphenyl-2-yl]-5-(trichloromethyl)-1,2,4-oxadiazole (1.68 g) in acetonitrile (30 mL) was added potassium carbonate (0.98 g), and the mixture was stirred for 12 hr. The reaction mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran-ethanol (1:1, 8 mL), 1 M sodium hydroxide (2 mL) was added, and the mixture was stirred for 30 min. The reaction mixture was weakly acidified with 1 M hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (0.40 g, 21%) as a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[Cl:9])[NH2:5].[CH:10](=O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[Cl:9])[N:5]=[CH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=Cc1ccccc1
Reactant: Nc1ccc(Cl)c(Cl)c1
Product: Clc1ccc(N=Cc2ccccc2)cc1Cl

Procedure:
Equimolar amounts of 3,4-dichloroaniline and benzaldehyde are stirred together at room temperature to give a nearly quantitative yield of product that melts at 62°-5° C. upon recrystallization from ethanol.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][C:13]([O:15][C:16]([CH3:26])([CH3:25])[C:17](=O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:14].[H-].[Na+]>CN(C=O)C.CCOC(C)=O.CCOCC.Cl>[CH3:25][C:16]1([CH3:26])[O:15][C:13](=[O:14])[C:12]([N:3]2[C:2](=[O:1])[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[C:4]2=[O:11])=[C:17]1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[NH2:3][C:12]1[C:13](=[O:14])[O:15][C:16]([CH3:26])([CH3:25])[C:17]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC(C)(OC(=O)CN1C(=O)c2ccccc2C1=O)C(=O)c1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC1(C)OC(=O)C(N)=C1c1ccccc1
Product: CC1(C)OC(=O)C(N2C(=O)c3ccccc3C2=O)=C1c1ccccc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a 0° C. suspension of unpurified 1,1-dimethyl-2-oxo-2-phenylethyl 2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)acetate (4.4 g) in DMF (40 mL) was added a suspension of NaH (1.0 g of 60% dispersion, washed with hexanes) in DMF (10 mL). The mixture was stirred at 0° C. for 2 h, then diluted with EtOAc/ether (1:1) and 1 M HCl. The layers were separated and the organic phase was washed with water and brine, dried over MgSO4 and concentrated. The residue was dissolved in toluene (50 mL), treated with PPTS (100 mg) and heated to reflux with a Dean-Stark trap for 3 h. The solution was cooled, diluted with EtOAc (100 mL) and washed with water and brine. The organic phase was dried over MgSO4 and concentrated. Purification by flash chromatography (30–50% EtOAc/hexanes) provided 2-(5,5-dimethyl-2-oxo-4-phenyl-2,5-dihydro-3-furanyl)-1H-isoindole-1,3(2H)-dione, and 3-amino-5,5-dimethyl-4-phenyl-2(5H)-furanone.
Reaction SMILES: [CH3:1][N:2]1[C:6]([Sn](CCCC)(CCCC)CCCC)=[CH:5][CH:4]=[C:3]1[C:20]1[CH:21]=[C:22]2[C:30](=[CH:31][CH:32]=1)[N:29]([CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[C:28]1[CH:27]=[CH:26][C:25]([N:39]([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)[C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)=[CH:24][C:23]2=1.Br[C:53]1[S:57][C:56]([CH:58]=[O:59])=[CH:55][CH:54]=1>>[CH3:1][N:2]1[C:6]([C:53]2[S:57][C:56]([CH:58]=[O:59])=[CH:55][CH:54]=2)=[CH:5][CH:4]=[C:3]1[C:20]1[CH:21]=[C:22]2[C:30](=[CH:31][CH:32]=1)[N:29]([CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[C:28]1[CH:27]=[CH:26][C:25]([N:39]([C:46]3[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=3)[C:40]3[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=3)=[CH:24][C:23]2=1
Reactant: CCCCCCn1c2ccc(-c3ccc([Sn](CCCC)(CCCC)CCCC)n3C)cc2c2cc(N(c3ccccc3)c3ccccc3)ccc21
Reactant: O=Cc1ccc(Br)s1
Product: CCCCCCn1c2ccc(-c3ccc(-c4ccc(C=O)s4)n3C)cc2c2cc(N(c3ccccc3)c3ccccc3)ccc21

Procedure:
As shown in scheme 3, 3,6-dibromo-9-hexyl-9H-carbazole (31) is reacted with 1-methyl-2-(tributylstannyl)-1H-pyrrole by Stille coupling reaction to obtain N-methyl-2-(3-bromo-9-hexyl-9H-carbazol-6-yl)pyrrole (32). Then, in the presence of sodium tert-butoxide, Pd(dba)2, and tri-tert-butyl phosphine, N-methyl-2-(3-bromo-9-hexyl-9H-carbazol-6-yl)pyrrole (32) is reacted with diphenylamine to obtain N-methyl-2-(3-diphenylamino-9-hexyl-9H-carbazol-6-yl)pyrrole (33). n-butyl lithium is reacted with N-methyl-2-(3-diphenylamino-9-hexyl-9H-carbazol-6-yl)pyrrole (33), and then tributylstannylchloride is added thereto to obtain N-methyl-2-(3-diphenylamino-9-hexyl-9H-carbazol-6-yl)-5-tributyl-stannylpyrrole (34). N-methyl-2-(3-diphenylamino-9-hexyl-9H-carbazol-6-yl)-5-tributylstannylpyrrole (34) is reacted with 5-bromo-2-thiophene-carboxaldehyde by Stille coupling reaction to obtain 5-[N-methyl-2-(3-diphenylamino-9-hexyl-9H-carbazol-6-yl)pyrrol-5-yl]thiophene-2-carbaldehyde (35). Finally, 5-[N-methyl-2-(3-diphenylamino-9-hexyl-9y-carbazol-6-yl)pyrrol-5-yl]thiophene-2-carbaldehyde (35) is reacted with cyanoacetic acid in acetic acid by using ammonium acetate as a catalyst, and (E)-2-cyano-3-[5-(N-methyl-2-(3-diphenylamino-9-hexyl-9H-carbazol-6-yl)pyrrol-5-yl)thiophen-2-yl]acrylic acid (36) is obtained.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[Br:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[N:20]=[C:19]([Cl:24])[CH:18]=[C:17]2[Cl:25].Br[CH2:27][C:28]1[CH:35]=[CH:34][C:31]([C:32]#[N:33])=[CH:30][CH:29]=1>C1COCC1>[Br:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][CH:23]=1)[N:20]=[C:19]([Cl:24])[C:18]([CH2:27][C:28]1[CH:35]=[CH:34][C:31]([C:32]#[N:33])=[CH:30][CH:29]=1)=[C:17]2[Cl:25]
Reactant: N#Cc1ccc(CBr)cc1
Reactant: Clc1cc(Cl)c2cc(Br)ccc2n1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: N#Cc1ccc(Cc2c(Cl)nc3ccc(Br)cc3c2Cl)cc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a solution of diisopropylamine (1.40 mL, 9.96 mmol) in THF (12 mL) cooled to 0° C. was added n-butyllithium (2.5 M solution in hexanes, 3.80 mL, 9.50 mmol) dropwise via syringe. The reaction mixture was stirred at 0° C. for 10 minutes then cooled to −78° C. at which time a separate solution of 6-bromo-2,4-dichloroquinoline (1.80 g, 6.51 mmol, Intermediate 44: step b) in THF (29 mL) was added dropwise via syringe. The mixture was stirred at −78° C. for 30 minutes followed by the addition of 4-(bromomethyl)benzonitrile (1.52 g, 7.74 mmol) in THF (5 mL). After an additional 10 minutes of stirring at −78° C., the reaction was transferred to an ice bath and warmed to ambient temperature over 5 hours. The reaction was quenched with water and the aqueous phase was extracted with DCM. The organic phase was dried (Na2SO4), filtered, and concentrated. The crude product was purified by flash column chromatography (silica gel, 0-5% EtOAc-Hexanes) to provide the title compound as a white solid.