Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:22]=[C:5]2[C:6]([C:10]3[CH:11]=[N:12][N:13]([C:15]4[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=4)[CH:14]=3)=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[C:23]([O:27][C:28]([N:30]1[CH2:35][CH2:34][CH:33]([C:36]2[CH:41]=[CH:40][C:39]([NH2:42])=[CH:38][CH:37]=2)[CH2:32][CH2:31]1)=[O:29])([CH3:26])([CH3:25])[CH3:24].C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)CCCCC1>>[C:23]([O:27][C:28]([N:30]1[CH2:35][CH2:34][CH:33]([C:36]2[CH:41]=[CH:40][C:39]([NH:42][C:2]3[N:22]=[C:5]4[C:6]([C:10]5[CH:11]=[N:12][N:13]([C:15]6[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=6)[CH:14]=5)=[CH:7][CH:8]=[CH:9][N:4]4[N:3]=3)=[CH:38][CH:37]=2)[CH2:32][CH2:31]1)=[O:29])([CH3:26])([CH3:24])[CH3:25]
Reactant: Cc1ccc(-n2cc(-c3cccn4nc(Cl)nc34)cn2)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(N)cc2)CC1
Agent: c1ccc(P(C2CCCCC2)C2CCCCC2)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c1
Product: Cc1ccc(-n2cc(-c3cccn4nc(Nc5ccc(C6CCN(C(=O)OC(C)(C)C)CC6)cc5)nc34)cn2)cc1

Procedure:
4-{4-[8-(1-p-Tolyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-2-ylamino]-phenyl}-piperidine-1-carboxylic acid tert-butyl ester was prepared from 2-chloro-8-(1-p-tolyl-1H-pyrazol-4-yl)-[1,2,4]triazolo[1,5-a]pyridine and 4-(4-amino-phenyl)-piperidine-1-carboxylic acid tert-butyl ester with 2,2′-bis-dicyclohexylphosphanyl-biphenyl as the ligand in a manner analogous to Example 2d (0.265 g, 40%). MP=124-125° C. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.60 (s, 1H), 9.24 (s, 1H), 8.68 (d, 1H), 8.64 (s, 1H), 7.98 (m, 1H), 7.77 (m, 2H), 7.66 (m, 2H), 7.40 (m, 2H), 7.21 (m, 2H), 4.08 (m, 2H), 2.80 (m, 2H), 2.62 (m, 1H), 2.38 (s, 3H), 1.73 (m, 2H), 1.48 (m, 2H), 1.41 (s, 3H). MS=550 (MH)+.
Reaction SMILES: [CH2:1]1COCC1.[C:6]1([C:12]2[NH:13][C:14]3[C:19]([CH:20]=2)=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[H-].[Na+].CI>O>[CH3:1][N:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:20]=[C:12]1[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: C1CCOC1
Reactant: c1ccc(-c2cc3ccccc3[nH]2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CI
Product: Cn1c(-c2ccccc2)cc2ccccc21
Temperature: 65 °C
Reaction time: 3 h
Yield: 79 %

Procedure:
A solution of dry THF containing 2-phenylindole (1 mmole) was added NaH (1.1 mmole) and MeI (1.2 mmole, dropwise), and the reaction mixture was stirred at 65° C. for 3 h. After cooling to room temperature, the reaction mixture was poured into water and extracted with ether. The extracts was dried (MgSO4) and evaporated under reduced pressure to give yellow-orange solid. Further purification by column chromatography on silica gel with hexane as an eluent gave a pale yellow solid of 1-methyl-2-phenylindole (79% yield). The solid product (0.7 mmole) was dissolved in DMF (10 ml), a mixture of POCl3(0.09 mmole) and DMF (0.09 mmole) was added dropwise. After stirring at 75° C. for 1 h, the reaction mixture was added into saturate NaHCO3solution. The precipitated solid was collected by filtration and washed with ethanol to give a pale gray solid of 1-methyl-2-phenylindole-3-carboxaldehyde (85% yield). A dry DMF solution of the aldehyde (2 mmole) was added o-aminothiophenol (2.1 mmole) and Ac2O (0.5 ml) at room temperature. The mixture was stirred at 60° C. for 3 h. The reaction mixture was poured into stirred water and the precipitated solid was collected by filtration. The crude solid was washed with MeOH and recrystallized from benzene to afford compound 1-2 (38% yield). 1H-NMR (CDCl3, TMS) δ(ppm)=3.6 (s, 3H, —CH3), 7.3-7.8, 8.1, 8.9 (m, d, m, 13H, aromatic H).
Reaction SMILES: [C:1]1([CH3:13])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[S:9](Cl)(=[O:11])=[O:10].[CH3:14][C:15](=[N:17][OH:18])[CH3:16].O>N1C=CC=CC=1>[CH3:13][C:1]1[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[S:9]([O:18][N:17]=[C:15]([CH3:16])[CH3:14])(=[O:11])=[O:10]
Reactant: CC(C)=NO
Reactant: Cc1cc(C)c(S(=O)(=O)Cl)c(C)c1
Solvent: O
Solvent: c1ccncc1
Product: CC(C)=NOS(=O)(=O)c1c(C)cc(C)cc1C
Reaction time: 16 h

Procedure:
To a solution of mesitylenesulfonyl chloride (2.0 g, 9.05 mmol) in pyridine (30 mL) was added acetone oxime (0.67 g, 9.05 mmol), and the solution was stirred under N2 for 16 hours. It was poured into 500 ml of water and stirred for 1 hour. The precipitate was filtered and dried. Acetone O-(2,4,6-trimethylphenylsulfonyl)oxime was obtained as white powder (57.6%) yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:13]=[CH:12][C:6]([CH:7]=[CH:8][C:9](O)=[O:10])=[CH:5][CH:4]=1.N1C=CC=CC=1.O=S(Cl)[Cl:22]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:13]=[CH:12][C:6]([CH:7]=[CH:8][C:9]([Cl:22])=[O:10])=[CH:5][CH:4]=1
Reactant: COc1ccc(C=CC(=O)O)cc1
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: COc1ccc(C=CC(=O)Cl)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 94.3 %

Procedure:
A first 3 L, 4 necked round bottomed flask (RBF) was equipped with a mechanical stirrer, thermowell, and a condenser with nitrogen adapter. The RBF was charged with 4-methoxycinnamic acid (175 g, 982 mmol) and 0.1 mL dry pyridine in 2 L dry toluene. The addition funnel was charged with 107.2 mL (1.473 mol) SOCl2 which was then added slowly to the reaction mixture at room temperature. The reaction mixture was heated to reflux and monitored by GC analysis (aliquots were withdrawn periodically, quenched with MeOH, and analyzed). After 5 hours, the GC analysis indicated that the reaction was complete and the reaction mixture was allowed to cool to room temperature. Excess SOCl2 and toluene were removed by rotary evaporation and the crude product was purified by distillation to give 182 g of 4-methoxycinnamoyl chloride (94% yield) with 98.9% purity by GC.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([CH:7]=O)=[CH:4][CH:3]=1.C1(P(=[CH:28][C:29]([O:31][CH3:32])=[O:30])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[CH3:32][O:31][C:29](=[O:30])/[CH:28]=[CH:7]/[C:5]1[S:6][C:2]([Cl:1])=[CH:3][CH:4]=1
Reactant: O=Cc1ccc(Cl)s1
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Product: COC(=O)/C=C/c1ccc(Cl)s1
Temperature: 25 °C
Reaction time: 19 h
Yield: 87.9 %

Procedure:
To a solution of 5-chloro-2-thiophene-carboxaldehyde (5.10 g, 34.8 mmol) in 100 mL of dry CH2Cl2 is added methyl (triphenylphosphoranylidene)acetate (11.8 g, 35.3 mmol). The resulting brown-green mixture is stirred for 19 h at room temperature. The mixture is filtered through a Celite pad, concentrated in vacuo and triturated with hexane. The white precipitate (triphenylphosphine oxide) is filtered off and the filtrate is concentrated. The crude residue is purified via flash column chromatography eluting with a gradient of 5% EtOAc/hexanes to 10% EtOAc/hexanes to provide the title compound (6.20 g, 30.6 mmol) as a yellow solid. 1H NMR (CDCl3, 300 MHz) δ7.65 (d, 1H), 7.05 (d, 1H), 6.89 (d, 1H), 6.10 (d, 1H), 3.80 (s, 3H).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][O:4][C:3]2[CH:7]=[C:8]([C:11]([OH:13])=O)[CH:9]=[CH:10][C:2]1=2.C1C=CC2N(O)N=[N:20]C=2C=1.N.CCN=C=NCCCN(C)C.Cl.O>CN(C=O)C>[O:1]1[CH2:6][CH2:5][O:4][C:3]2[CH:7]=[C:8]([C:11]([NH2:20])=[O:13])[CH:9]=[CH:10][C:2]1=2
Reactant: O=C(O)c1ccc2c(c1)OCCO2
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: N
Solvent: CN(C)C=O
Solvent: O
Product: NC(=O)c1ccc2c(c1)OCCO2
Temperature: 25 °C
Reaction time: 72 h
Yield: 31.2 %

Procedure:
To a solution of 2,3-dihydrobenzo[b][1,4]dioxine-6-carboxylic acid (3.54 g) in DMF (80 mL) were added HOBt-NH3 (4.48 g) and EDCI HCl (5.65 g) at room temperature. The reaction mixture was stirred at room temperature for 3 days, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was washed with hexane to give the title compound (1.10 g).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]2[C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=3[O:10][C:4]=2[CH:3]=1.[C:15]1(B(O)O)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(C)C=CC=CC=1>C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.O>[C:15]1([C:2]2[N:7]=[CH:6][C:5]3[C:8]4[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=4[O:10][C:4]=3[CH:3]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Clc1cc2oc3ccccc3c2cn1
Reactant: OB(O)c1ccccc1
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: c1ccc(-c2cc3oc4ccccc4c3cn2)cc1
Temperature: 25 °C
Yield: 80.7 %

Procedure:
3-chlorobenzofuro[3,2-c]pyridine (2.89 g, 14 mmol), phenylboronic acid (2.56 g, 21 mmol), potassium phosphate (9.6 g, 42 mmol), 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (0.45 g, 1.12 mmol) and Pd2(bda)3 (0.256 g, 0.28 mmol) were to toluene (100 mL) and water (10 mL). Nitrogen was bubbled through the solution for 30 minutes and then the solution was refluxed for overnight in an atmosphere of nitrogen. The reaction was then allowed to cool to room temperature and the organic phase was separated from the aqueous phase. The aqueous phase was washed with ethyl acetate and the organic fractions were combined and dried over sodium sulfate and the solvent removed under vacuum. The product was chromatographed using silica gel with ethyl acetate and hexanes as the eluent. The solvent was removed to give 2.77 g of title compound.
Reaction SMILES: C(OC([NH:11][C@H:12]([C:19]([NH:21][C:22]1[CH:23]=[C:24]([CH2:29][CH2:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH:25]=[CH:26][C:27]=1[F:28])=[O:20])[CH:13]([C:15]([F:18])([F:17])[F:16])[CH3:14])=O)C1C=CC=CC=1>C(O)C.C1COCC1.[Pd]>[F:28][C:27]1[CH:26]=[CH:25][C:24]([CH2:29][CH2:30][C:31]([O:33][C:34]([CH3:36])([CH3:37])[CH3:35])=[O:32])=[CH:23][C:22]=1[NH:21][C:19](=[O:20])[C@H:12]([CH:13]([C:15]([F:18])([F:17])[F:16])[CH3:14])[NH2:11]
Reactant: CC([C@H](NC(=O)OCc1ccccc1)C(=O)Nc1cc(CCC(=O)OC(C)(C)C)ccc1F)C(F)(F)F
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CC([C@H](N)C(=O)Nc1cc(CCC(=O)OC(C)(C)C)ccc1F)C(F)(F)F
Reaction time: 8 h

Procedure:
12.29 g (23.3 mmol) of tert-butyl 3-[3-({N-[(benzyloxy)carbonyl]-4,4,4-trifluorovalyl}amino)-4-fluorophenyl]propanoate (Example 33A, racemic diastereomer mixture) were dissolved in a mixture of 80 ml of ethanol and 20 ml of THF. The solution was inertized with argon, and 745 mg of palladium on carbon (10%) were added. The reaction mixture was stirred vigorously at standard pressure under an atmosphere of hydrogen overnight. After filtration through kieselguhr and washing with ethanol/THF, the filtrate was concentrated under reduced pressure. The residue was purified by chromatography on silica gel (mobile phase cyclohexane/ethyl acetate 20:1→4:1) and the diastereomers were separated:
Reaction SMILES: [CH:1]1([S:7][CH2:8][CH2:9][C:10]([C-:12]2[CH:16]=[CH:15][CH:14]=[CH:13]2)=[O:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH-:17]1[CH:21]=[CH:20][CH:19]=[CH:18]1.[Fe+2:22].ClC1C=C(C=CC=1)C(O)=[O:28]>C(Cl)(Cl)Cl>[CH:1]1([S:7]([CH2:8][CH2:9][C:10]([C-:12]2[CH:13]=[CH:14][CH:15]=[CH:16]2)=[O:11])=[O:28])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1.[CH-:17]1[CH:21]=[CH:20][CH:19]=[CH:18]1.[Fe+2:22]
Reactant: O=C(O)c1cccc(Cl)c1
Reactant: O=C(CCSC1CCCCC1)[c-]1cccc1
Agent: [Fe+2]
Agent: c1cc[cH-]c1
Solvent: ClC(Cl)Cl
Product: O=C(CCS(=O)C1CCCCC1)[c-]1cccc1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
3-(Cyclohexylthio)propionylferrocene (1.3g, 0.00366M) was dissolved in chloroform (30 ml) and the solution was cooled in ice/water. m-Chlorobenzoic acid (0.63g, 0.00366M) was then added slowly with stirring. Following the addition, stirring was continued at room temperature for 3 hours, and the resulting solution was washed with dilute sodium bicarbonate solution and water, before being dried over anhydrous sodium sulphate. Removal of the solvent on a rotary evaporator yielded a red oil which subsequently crystallised as orange needles of the title compound (1.15g) mp = 90°-1°.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4]([Cl:11])[N:3]=1.C(=O)([O-])[O-].[K+].[K+].I[CH2:19][CH3:20]>CS(C)=O.C(O)(=O)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:19][CH3:20])=[C:4]([Cl:11])[N:3]=1
Reactant: Clc1nc(Cl)c2[nH]cnc2n1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: CS(C)=O
Product: CCn1cnc2c(Cl)nc(Cl)nc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 64.5 %

Procedure:
2,6-Dichloropurine (378 mg, 2.0 mmol) was dissolved in dimethylsulfoxide (10 mL), and dry potassium carbonate (345 mg, 2.5 mmol), and iodoethane (312 mg, 2.0 mmol) added. The mixture was stirred at room temperature for 16 hours, then the mixture was diluted with ice, acetic acid was added to adjust the pH to 5, and the solution was extracted with ethyl acetate. The combined extracts were washed with water, dried over sodium sulfate, filtered, and the filtrate evaporated in vacuo. The residue was purified by flash chromatography, eluting initially with cyclohexane-EtOAc (75:25) to give 2,6-dichloro-9-ethylpurine (280 mg, 65%), a compound of formula (2). mp 100–103° C.; UV λmax (MeOH) 214 nm (ε 22900), 274 (ε 9500), (pH 1) 213 nm (ε 22800), 273 (ε 9500), (pH 12) 214 nm (ε 17900), 260 (ε 7800), 266 (ε 8100); 1H NMR (Me2SO-d6) δ 1.45 (t, 3H, J=7.2 Hz, CH2CH3), 4.28 (q, 2H, J=7.2 Hz, CH2CH3), 8.77 (s, 1H, H-8). Anal. (C7H6Cl2N4) C, H, N.
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:9]=[C:10]([CH2:14][N:15]([CH3:17])[CH3:16])[CH:11]=[CH:12][CH:13]=1)=[C:2]=[S:3].[NH2:18][CH2:19][CH2:20][CH2:21][NH2:22]>C(#N)C>[CH2:21]([NH:22][C:2]([NH:1][CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][N:15]([CH3:16])[CH3:17])[CH:9]=1)=[S:3])[CH2:20][CH2:19][NH:18][C:2]([NH:1][CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][N:15]([CH3:16])[CH3:17])[CH:9]=1)=[S:3]
Reactant: CN(C)Cc1cccc(OCCCN=C=S)c1
Reactant: NCCCN
Solvent: CC#N
Product: CN(C)Cc1cccc(OCCCNC(=S)NCCCNC(=S)NCCCOc2cccc(CN(C)C)c2)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 17.9 %

Procedure:
A mixture of 3-(3-isothiocyanatopropoxy)-N,N-dimethylbenzenemethanamine (2.24 g) and 1,3-diaminopropane (0.42 g) in acetonitrile (50 ml) was stirred at room temperature for 24 hours. The solvent was evaporated in vacuo and the oily residue chromatographed (silica/methanol) to yield the title compound (0.46 g) as a gum.
Reaction SMILES: [C:1]1([C:7]2[C:11]([C:12]([NH:14][CH3:15])=[O:13])=[C:10]([CH3:16])[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.CCCCCC.[CH:28](=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>O1CCCC1>[C:1]1([C:7]2[C:11]([C:12]([NH:14][CH3:15])=[O:13])=[C:10]([CH2:16][CH:28]([OH:35])[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[O:9][N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=Cc1ccccc1
Reactant: CNC(=O)c1c(-c2ccccc2)noc1C
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CNC(=O)c1c(-c2ccccc2)noc1CC(O)c1ccccc1
Temperature: -30 °C
Reaction time: 2 h

Procedure:
A suspension of 75 g. (0.348 mole) of 3-phenyl-5,N-dimethyl-isoxazole-4-carboxamide and 1 liter of tetrahydrofuran is cooled to -65° C. and 478 ml. of 1.6 M n-butyllithium in hexane (0.765 mole) is added dropwise maintaining the temperature between -60° and -70° C. After the addition is complete, the orange suspension is stirred for 11/2 hours at -60° to -70° C., and then 37.2 g. (0.350 mole) of benzaldehyde in 375 ml. tetrahydrofuran is added dropwise maintaining the temperature between -60° and -70° C. After addition is complete the mixture is stirred 11/2 hours at -60° to -70° C. and then warmed to -30° C. and quenched by the addition of saturated ammonium chloride solution. The mixture is further diluted with tetrahydrofuran and the layers are separated. The tetrahydrofuran layer is washed twice with 50% brine, and once with brine, dried over anhydrous magnesium sulfate, filtered with a 50:50 mixture of ether:petroleum ether, filtered and washed with cold ether to give 3-phenyl-5-(β-hydroxyphenethyl)-N-methyl-isoxazole-4-carboxamide; m.p. 183°-184° C.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][S:4](Cl)(=[O:6])=[O:5].CS(O)(=O)=O.[NH2:13][CH2:14][C:15]1[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=1.N1C=CC=CC=1.C(C1C=CC(CNS(C=C)(=O)=O)=CC=1)#N>ClCCl>[C:14]([C:15]1[CH:22]=[CH:21][C:18]([CH2:19][NH:20][S:4]([CH2:3][CH2:2][Cl:1])(=[O:6])=[O:5])=[CH:17][CH:16]=1)#[N:13]
Reactant: O=S(=O)(Cl)CCCl
Reactant: N#Cc1ccc(CN)cc1
Agent: C=CS(=O)(=O)NCc1ccc(C#N)cc1
Agent: CS(=O)(=O)O
Solvent: ClCCl
Solvent: c1ccncc1
Product: N#Cc1ccc(CNS(=O)(=O)CCCl)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Chloroethane sulfonyl chloride (4.8 g, 0.029 mol) was added drop by drop to solution of 4-aminomethyl benzonitrile methan sulphonic acid salt acid (7 g, 0.029 mol) and pyridine (24 ml) in dry dichloromethane (25 ml) at −5° C. under nitrogen atmosphere. The reaction mixture was stirred at RT for 2 days and then partitioned between water and dichloromethane. The organic layer was washed with water and brine and dried over sodium sulfate. Solvent was evaporated under reduced pressure and the residue was purified by column chromatography over silica gel using 1% methanol in chloroform as eluent to give mixture of the sub-title compound and ethenesulfonic acid 4-cyano-benzylamide (3.4 g) as a solid. This was directly taken for next step without further purification.
Reaction SMILES: [Cu]([C:4]#[N:5])C#N.Br[C:7]1[CH:8]=[CH:9][C:10](/[C:15](/[C:34]2[CH:39]=[CH:38][C:37]([C:40]([CH3:43])([CH3:42])[CH3:41])=[CH:36][CH:35]=2)=[CH:16]/[C@@H:17]2[N:21]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][C:24]=3[O:31][CH3:32])[C:20](=[O:33])[CH2:19][CH2:18]2)=[N:11][C:12]=1[O:13][CH3:14].O>CN(C)C=O>[C:40]([C:37]1[CH:36]=[CH:35][C:34](/[C:15](/[C:10]2[N:11]=[C:12]([O:13][CH3:14])[C:7]([C:4]#[N:5])=[CH:8][CH:9]=2)=[CH:16]\[C@H:17]2[CH2:18][CH2:19][C:20](=[O:33])[N:21]2[CH2:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][C:24]=2[O:31][CH3:32])=[CH:39][CH:38]=1)([CH3:43])([CH3:41])[CH3:42]
Reactant: COc1ccc(CN2C(=O)CC[C@@H]2/C=C(\c2ccc(C(C)(C)C)cc2)c2ccc(Br)c(OC)n2)c(OC)c1
Reactant: N#C[Cu]C#N
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(CN2C(=O)CC[C@@H]2/C=C(\c2ccc(C(C)(C)C)cc2)c2ccc(C#N)c(OC)n2)c(OC)c1
Temperature: 180 °C
Reaction time: 2 h
Yield: 40 %

Procedure:
Copper cyanide (27 mg) was added to a solution of (5R)-5-[(E)-2-(5-bromo-6-methoxypyridin-2-yl)-2-(4-tert-butylphenyl)ethenyl]-1-(2,4-dimethoxybenzyl)pyrrolidin-2-one obtained in Reference Example 4-42(1) (90 mg) in N,N-dimethylformamide (5 mL), and the mixture was stirred at an external temperature of 180° C. for two hours. Water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was washed with saline, dried over magnesium sulfate and filtered. The solvent was then evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1→1:1) to give 6-{(E)-1-(4-tert-butylphenyl)-2-[(2R)-1-(2,4-dimethoxybenzyl)-5-oxopyrrolidin-2-yl]ethenyl}-2-methoxypyridine-3-carbonitrile (32 mg, 40%).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])[C:5]#[N:6].[F:13][C:14]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:15]=1[NH2:16].C(=O)([O-])[O-].[K+].[K+].O>C(OCC)(=O)C>[F:13][C:14]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:15]=1[NH:16][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])[C:5]#[N:6]
Reactant: N#Cc1ccc([N+](=O)[O-])c(Cl)c1
Reactant: Nc1ccc(F)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Product: N#Cc1ccc([N+](=O)[O-])c(Nc2ccc(F)cc2F)c1
Temperature: 200 °C
Reaction time: 5 h
Yield: 46.4 %

Procedure:
A mixture of 3-chloro-4-nitrobenzonitrile (5 g), 2,4-difluoroaniline (17.7 g), cupric oxide (0.5 g) and potassium carbonate (4.5 g) was stirred for 5 hours at 200° C. To the mixture were added water (100 ml) and ethyl acetate (200 ml). The organic layer was separated, washed with 3N hydrochloric acid and water, dried, and evaporated to dryness. The oil (10 g) was purified by column chromatography on silica gel (200 g) eluting with toluene to give red crystals of 3-(2,4-difluorophenylamino)-4-nitrobenzonitrile (3.5 g).
Reaction SMILES: C[O:2][C:3]([C:5]1[S:9][C:8]([CH2:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][N:19]=3)=[N:14][O:15][C:16]=2[CH3:17])=[N:7][CH:6]=1)=[O:4].O.[OH-].[Li+]>C1COCC1.O>[F:24][C:21]1[CH:22]=[CH:23][C:18]([C:13]2[C:12]([CH2:11][CH2:10][C:8]3[S:9][C:5]([C:3]([OH:4])=[O:2])=[CH:6][N:7]=3)=[C:16]([CH3:17])[O:15][N:14]=2)=[N:19][CH:20]=1
Reactant: COC(=O)c1cnc(CCc2c(-c3ccc(F)cn3)noc2C)s1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1onc(-c2ccc(F)cn2)c1CCc1ncc(C(=O)O)s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 58 %

Procedure:
To a solution of 2-{2-[3-(5-fluoro-pyridin-2-yl)-5-methyl-isoxazol-4-yl]-ethyl}-thiazole-5-carboxylic acid methyl ester (1.27 g, 3.66 mmol) in THF (9 mL) was added a solution of lithium hydroxide monohydrate (307 mg, 7.31 mmol) in water (9 mL) and the resulting mixture stirred at room temperature for 2 h. The mixture was then evaporated to half volume and then acidified to pH 1 with HCl (1 N) and cooled to 0° C. for 15 min. A solid precipitated and was filtered off and dried to afford the title compound (707 mg, 58%) which was obtained as an off white solid after recrystallization from ethyl acetate. MS: m/e=332.3 [M−H]−.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][O:14]1)[N:8]=[CH:7]2)([O-])=O>C(OCC)(=O)C.C(O)C.[Pd]>[O:14]1[CH2:15][CH2:16][CH2:17][CH2:18][CH:13]1[N:9]1[C:10]2[C:6](=[CH:5][C:4]([NH2:1])=[CH:12][CH:11]=2)[CH:7]=[N:8]1
Reactant: O=[N+]([O-])c1ccc2c(cnn2C2CCCCO2)c1
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Nc1ccc2c(cnn2C2CCCCO2)c1
Yield: 55.3 %

Procedure:
To a solution of 5-nitro-1-tetrahydro-2H-pyran-2-yl-1H-indazole (3.69 g, 14.9 mmol) in a mixture of ethyl acetate (50 ml) and ethanol (50 ml) was added 10% Pd—C (300 mg), followed by catalytic reduction at ordinary temperature and atmospheric pressure. After completion or the reaction, the catalyst was filtered off, and the filtrate was concentrated under reduced pressure. The resulting residue was suspended in ethyl acetate, and the solid precipitated was collected by filtration and dried under reduced pressure to obtain 1-tetrahydro-2H-pyran-2-yl-1H-indazol-5-amine (1.79 g, 55%).
Reaction SMILES: Br[C:2]1[C:3](=[O:23])[N:4]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:5](=[O:16])[C:6]=1[C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][CH:8]=1.[CH:24]1[C:34]2=[C:35]3[C:30](=[CH:31][CH:32]=[CH:33]2)[CH2:29][CH2:28][CH2:27][N:26]3[CH:25]=1.C[Si](C)(C)[Si](C)(C)C.[Li]>C1(C)C=CC=CC=1.C1(B(O)O)C2=C3C(=CC=C2)CCCN3C=1>[C:24]1([C:2]2[C:3](=[O:23])[N:4]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:5](=[O:16])[C:6]=2[C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][CH:8]=2)[C:34]2=[C:35]3[C:30](=[CH:31][CH:32]=[CH:33]2)[CH2:29][CH2:28][CH2:27][N:26]3[CH:25]=1
Reactant: O=C1C(Br)=C(c2c[nH]c3ccccc23)C(=O)N1c1ccccc1
Reactant: c1cc2c3c(c1)ccn3CCC2
Agent: C[Si](C)(C)[Si](C)(C)C
Agent: OB(O)c1cn2c3c(cccc13)CCC2
Agent: [Li]
Solvent: Cc1ccccc1
Product: O=C1C(c2c[nH]c3ccccc23)=C(c2cn3c4c(cccc24)CCC3)C(=O)N1c1ccccc1

Procedure:
(±)-Trans-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4(1H-indol-3-yl)pyrrolidine-2,5-dione may be prepared by reacting 1H-indole and 3,4-dibromo-1-phenyl-pyrrole-2,5-dione in the presence of methyl magnesium bromide to yield 3-bromo-4-(1H-indol-3-yl)-1-phenyl-pyrrole-2,5-dione. The 3-bromo-4-(1H-indol-3-yl)-1-phenyl-pyrrole-2,5-dione is subsequently reacted with 5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline and LiHMDS (lithium hexamethyldisilane) in toluene or (5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-boranediol and Pd(PPh3)4(tetrakis(triphenylphosphine)palladium) to yield 3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)-1-phenyl-pyrrole-2,5-dione, which is reduced and deprotected by treatment with Mg in methanol, as in Example 2 procedure C, followed by catalytic hydrogenation over palladium on carbon to yield (±)-trans-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4(1H-indol-3-yl)pyrrolidine-2,5-dione. Bnz is benzyl.