Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:11]2[S:15][C:14]([N:16]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:17][C@@H:18]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[CH2:19][C:20]3[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=3)=[N:13][N:12]=2)[CH:5]=[CH:6][C:7]=1[N+:8]([O-])=O.C(O)(=O)C>CO.[Pd]>[OH:1][C:2]1[CH:3]=[C:4]([C:11]2[S:15][C:14]([N:16]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:17][C@@H:18]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:34])([CH3:35])[CH3:36])[CH2:19][C:20]3[CH:21]=[CH:22][C:23]([C:26]([F:27])([F:28])[F:29])=[CH:24][CH:25]=3)=[N:13][N:12]=2)[CH:5]=[CH:6][C:7]=1[NH2:8]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(C(F)(F)F)cc1)CN(C(=O)OC(C)(C)C)c1nnc(-c2ccc([N+](=O)[O-])c(O)c2)s1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(C(F)(F)F)cc1)CN(C(=O)OC(C)(C)C)c1nnc(-c2ccc(N)c(O)c2)s1
Reaction time: 2 h
Yield: 52.5 %

Procedure:
tert-Butyl (S)-1-(5-(3-hydroxy-4-nitrophenyl)-1,3,4-thiadiazol-2-yl-boc-amino)-3-(4-(trifluoromethyl)phenyl)propan-2-ylcarbamate (400 mg, 625 μmol) was dissolved in 100 mL MeOH in a 500 mL round bottom flask. To this flask was added 10% Pd/C (100 mg pre-wet with water) and 1.5 mL acetic acid. The mixture was stirred under an atmosphere of hydrogen under balloon pressure for 2 hours. After filtration through a pad of celite, the solution was evaporated to dryness. The residue was re-dissolved in 150 mL EtOAc. The solution was washed with saturated ammonia chloride twice and dried over sodium sulfate. After removing the solvent, the remaining residue was subjected to silica gel column chromatograph separation using 20% to 40% EtOAc in hexane as the eluant. After removing the solvent, the desired product (200 mg, 53%) was obtained as a tan solid. LCMS (API-ES) m/z (%): 610.0 (100%, M++H); 1H NMR (400 MHz, CD3OD) δ ppm 1.21 (s, 9H) 1.55 (s, 9H) 2.80-2.95 (m, 1H) 2.95-3.06 (m, 1H) 4.00-4.25 (m, 1H) 4.25-4.57 (m, 2H) 6.77 (d, J=8.22 Hz, 1H) 7.18 (dd, J=8.02, 1.96 Hz, 1H) 7.25 (d, J=1.76 Hz, 1H) 7.44-7.53 (m, 2H) 7.60 (d, J=8.02 Hz, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]=[N:10][C:11]([O:13][Si](C)(C)C)=[CH2:12].C(OC([N:25]1[C:33]2[C:28](=[CH:29][CH:30]=[C:31]([Cl:34])[CH:32]=2)/[C:27](=[CH:35]/[C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([Cl:42])[CH:37]=2)/[C:26]1=[O:43])=O)(C)(C)C.CO>C1(C)C=CC=CC=1>[Cl:34][C:31]1[CH:32]=[C:33]2[NH:25][C:26](=[O:43])[C:27]3([CH:35]([C:36]4[CH:41]=[CH:40][CH:39]=[C:38]([Cl:42])[CH:37]=4)[CH2:13][C:11](=[O:12])[NH:10][CH:9]3[C:3]3[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=3[F:1])[C:28]2=[CH:29][CH:30]=1
Reactant: CC(C)(C)OC(=O)N1C(=O)/C(=C\c2cccc(Cl)c2)c2ccc(Cl)cc21
Reactant: C=C(N=Cc1ccc(F)cc1F)O[Si](C)(C)C
Solvent: CO
Solvent: Cc1ccccc1
Product: O=C1CC(c2cccc(Cl)c2)C2(C(=O)Nc3cc(Cl)ccc32)C(c2ccc(F)cc2F)N1
Temperature: 140 °C
Reaction time: 0.5 h
Yield: 63.1 %

Procedure:
To a solution of 1-(2,4-difluorophenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene prepared in example 41a (2.4 g, 9.40 mmol) in toluene (30 mL) was added E/Z-6-chloro-3-(3-chlorobenzylidene)-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester prepared in Example 24a (0.3 g, 0.77 mmol). The reaction mixture was stirred under nitrogen in a sealed tube at 140° C. for 0.5 h. After the solution was cooled to room temperature, methanol (10 mL) was added. The reaction mixture was filtered through a short pad of celite gel and washed with ethyl acetate. The filtrate was concentrated. The residue was dissolved in dichloromethane (20 mL) and trifluoroactic acid (15 mL) was added. After the reaction mixture was stirred at room temperature for 1 h, the mixture was concentrated. The residue was partitioned between saturated NaHCO3 solution and ethyl acetate. The aqueous layer was extracted with ethyl acetate. The combined organic layer was dried over Na2SO4 and concentrated. The residue was purified by chromatography (EtOAc:hexanes=2:1) to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(2,4-difluorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as an off-white solid (Yield 0.23 g, 63.9%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:14][CH2:15][C:16]1([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)=[CH:11][CH:10]=[CH:9][CH:8]=2)([O-])=O>[Pt].C1(C)C=CC=CC=1.C(O)C>[NH2:1][C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:14][CH2:15][C:16]1([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:27])([CH3:26])[CH3:28])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)=[CH:11][CH:10]=[CH:9][CH:8]=2
Reactant: CC(C)(C)OC(=O)NC1(CNc2c([N+](=O)[O-])cnc3ccccc23)CCCCC1
Agent: [Pt]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CC(C)(C)OC(=O)NC1(CNc2c(N)cnc3ccccc23)CCCCC1
Reaction time: 4 h
Yield: 100 %

Procedure:
A mixture of tert-butyl 1-{[(3-nitroquinolin-4-yl)amino]methyl}cyclohexylcarbamate (29.5 g, 73.7 mmol) and 5% platinum on carbon (0.30 g) in toluene (300 mL) was hydrogenated at 50 psi (3.5×105 Pa) for 4 hours (h) on a Parr apparatus. The reaction mixture was diluted with ethanol (200 mL) and was filtered through CELITE filter agent. The filtrate was concentrated to give tert-butyl 1-{[(3-aminoquinolin-4-yl)amino]methyl}cyclohexylcarbamate as a brown solid (27.3 g, 100%).
Reaction SMILES: [F:1][CH:2]([C:6]1[CH:15]=[CH:14][C:13]2[C:12]([CH3:17])([CH3:16])[CH2:11][CH2:10][C:9]([CH3:19])([CH3:18])[C:8]=2[CH:7]=1)[C:3](O)=[O:4].[NH2:20][C:21]1[CH:32]=[CH:31][C:24]([C:25]([O:27][CH2:28][CH:29]=[CH2:30])=[O:26])=[CH:23][CH:22]=1>>[F:1][CH:2]([C:6]1[CH:15]=[CH:14][C:13]2[C:12]([CH3:17])([CH3:16])[CH2:11][CH2:10][C:9]([CH3:19])([CH3:18])[C:8]=2[CH:7]=1)[C:3]([NH:20][C:21]1[CH:22]=[CH:23][C:24]([C:25]([O:27][CH2:28][CH:29]=[CH2:30])=[O:26])=[CH:31][CH:32]=1)=[O:4]
Reactant: C=CCOC(=O)c1ccc(N)cc1
Reactant: CC1(C)CCC(C)(C)c2cc(C(F)C(=O)O)ccc21
Product: C=CCOC(=O)c1ccc(NC(=O)C(F)c2ccc3c(c2)C(C)(C)CCC3(C)C)cc1

Procedure:
In a manner similar to Example 4(c), by reaction of 1.35 g (5.1 mmol) of α-fluoro-5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthylacetic acid with 920 mg (5.1 mmol) of allyl 4-aminobenzoate, 1.7 g (81%) of ester are obtained in the form of an oil.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[C:35]([O:36][CH3:37])=[CH:34][C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][C:7]=2[CH:6]=1)[N:14]=[CH:13][C:12]([C:17]#[N:18])=[C:11]3[NH:19][C:20]1[CH:25]=[CH:24][C:23]([S:26][C:27]2[N:28]([CH3:32])[CH:29]=[CH:30][N:31]=2)=[C:22]([Cl:33])[CH:21]=1.[NH:38]1[CH:42]=[CH:41][N:40]=[N:39]1.[OH-].[Na+]>CN(C)C=O>[Cl:33][C:22]1[CH:21]=[C:20]([NH:19][C:11]2[C:10]3[C:15](=[CH:16][C:7]4[CH:6]=[C:5]([O:4][CH2:3][CH2:2][N:39]5[N:40]=[CH:41][CH:42]=[N:38]5)[C:35]([O:36][CH3:37])=[CH:34][C:8]=4[CH:9]=3)[N:14]=[CH:13][C:12]=2[C:17]#[N:18])[CH:25]=[CH:24][C:23]=1[S:26][C:27]1[N:28]([CH3:32])[CH:29]=[CH:30][N:31]=1
Reactant: c1c[nH]nn1
Reactant: COc1cc2cc3c(Nc4ccc(Sc5nccn5C)c(Cl)c4)c(C#N)cnc3cc2cc1OCCCl
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: COc1cc2cc3c(Nc4ccc(Sc5nccn5C)c(Cl)c4)c(C#N)cnc3cc2cc1OCCn1nccn1
Temperature: 80 °C
Yield: 19.3 %

Procedure:
A mixture of 0.3 g (0.55 mmol) of 8-(2-chloroethoxy)-4-[3-chloro-4-(1-methyl-1H-imidazol-2-ylsulfanyl)phenylamino]-7-methoxybenzo[g]quinoline-3-carbonitrile, 0.32 mL (5.5 mmol) of 1H-1,2,3-triazole and 0.1 g (2.5 mmol) of sodium hydroxide powder in 5 mL of N,N-dimethyl formamide is heated at 80° C. for 4.5 hours, then cooled and poured on to ice. The solid is collected by filtration, washed with water and dried. The two isomers are separated by silica gel chromatography, utilizing a 99:1 to 85:15 gradient of ethyl acetate/methanol. The less polar material, 0.062 g of 4-[3-chloro-4-(1-methyl-1H-imidazol-2-ylsulfanyl)phenylamino]-7-methoxy-8-(2-[1,2,3]triazol-2-yl-ethoxy)benzo[g]quinoline-3-carbonitrile is obtained as yellow solid, mp 235-237° C.
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[CH:16][CH:15]=[CH:14][C:3]=1[C:4]([NH:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5].Br[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:7]([NH:6][C:4]([C:3]1[CH:14]=[CH:15][CH:16]=[CH:17][C:2]=1[NH:1][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[O:5])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: Nc1ccccc1C(=O)NCc1ccccc1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CNc1ccccc1C(=O)NCc1ccccc1
Temperature: 100 °C
Reaction time: 17 h
Yield: 24.8 %

Procedure:
A mixture of 2-amino-N-benzylbenzamide (400 mg), ethyl bromoacetate (295 mg) and potassium carbonate (244 mg) in N,N-dimethylformamide (10 ml) was stirred at 100° C. for 17 hours. After cooling, the reaction mixture was poured into ice-cold water and extracted with diethyl ether. The extract was washed with water and dried. Removal of the solvent gave a residue, which was chromatographed on silica gel. Elution with chloroform gave ethyl 2-[2-(N-benzylcarbamoyl)anilino]-acetate (137 mg).
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][C:5]2[C:6]([CH2:9][O:10][C:11]3[CH:19]=[CH:18][CH:17]=[C:16]4[C:12]=3[CH:13]=[C:14]([C:20](O)=[O:21])[NH:15]4)=[CH:7][O:8][C:4]=2[CH:3]=1.[ClH:25].Cl.Cl.[C@H:28]1([CH2:38][N:39]2[CH2:44][CH2:43][CH:42]([NH2:45])[CH2:41][CH2:40]2)[C@@H:37]2[N:32]([CH2:33][CH2:34][CH2:35][CH2:36]2)[CH2:31][CH2:30][CH2:29]1>>[ClH:25].[ClH:25].[C@H:28]1([CH2:38][N:39]2[CH2:44][CH2:43][CH:42]([NH:45][C:20]([C:14]3[NH:15][C:16]4[C:12]([CH:13]=3)=[C:11]([O:10][CH2:9][C:6]3[C:5]5[CH:23]=[CH:24][C:2]([F:1])=[CH:3][C:4]=5[O:8][CH:7]=3)[CH:19]=[CH:18][CH:17]=4)=[O:21])[CH2:41][CH2:40]2)[C@@H:37]2[N:32]([CH2:33][CH2:34][CH2:35][CH2:36]2)[CH2:31][CH2:30][CH2:29]1
Reactant: O=C(O)c1cc2c(OCc3coc4cc(F)ccc34)cccc2[nH]1
Reactant: NC1CCN(C[C@@H]2CCCN3CCCC[C@H]23)CC1
Agent: Cl
Product: O=C(NC1CCN(C[C@@H]2CCCN3CCCC[C@H]23)CC1)c1cc2c(OCc3coc4cc(F)ccc34)cccc2[nH]1

Procedure:
This compound is synthesized from 4-(6-fluoro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid (106) (preparation see below) and amine 61 analogously to the method described in example 1.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[C:16]([CH3:23])=[N:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=4)[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:24]([OH:27])[CH2:25][CH3:26])=[CH:4][CH:3]=1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C(P(CCCC)CCCC)CCC.[F:59][CH:60]([F:63])[CH2:61]O>O1CCCC1>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[C:16]([CH3:23])=[N:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=4)[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:24]([O:27][CH2:61][CH:60]([F:63])[F:59])[CH2:25][CH3:26])=[CH:4][CH:3]=1
Reactant: CCC(O)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(OC)nc1C
Reactant: OCC(F)F
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: CCC(OCC(F)F)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(OC)nc1C
Temperature: 60 °C
Reaction time: 0.17 h

Procedure:
To a solution of 1-[9-chloro-1-(6-methoxy-2-methylpyridin-3-yl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl]propan-1-ol (111.0 mg, 0.287 mmol) in tetrahydrofuran (2.8 mL) was added 1,1′-(azodicarbonyl)dipiperidine (144.8 mg, 0.574 mmol) and tributylphosphine (143.0 μL, 0.574 mmol). After 10 min, to the mixture was added 2,2-difluoroethanol (209.1 μL, 2.870 mmol). The reaction mixture was stirred at 60° C. for 4 hrs. To the mixture was added 1,1′-(azodicarbonyl)dipiperidine (144.8 mg, 0.574 mmol) and tributylphosphine (143.0 μL, 0.574 mmol). After 30 min, to the mixture was added 2,2-difluoroethanol (209.1 μL, 2.870 mmol). The reaction mixture was stirred at 60° C. for 1.5 hrs. The mixture was concentrated. To the residue was added diethyl ether and the precipitate was removed by filtration. The residue was purified by silica gel column chromatography eluting with a 0-40% ethyl acetate/n-hexane gradient mixture to give the mixture contained the title compound. The residue was purified by preparative HPLC to give the title compound as the trifluoroacetic acid salt. The salt was neutralized with aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to give the title compound. The resulting solid was recrystallized from ethyl acetate/n-hexane to give the title compound as a colorless solid (50.0 mg, 0.111 mmol, 39).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([CH2:18][S:19][CH2:20][C:21](O)=[O:22])[O:15][CH2:14][C:13]([CH3:17])([CH3:16])[CH2:12][O:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.C1(N=C=NC2CCCCC2)CCCCC1.[C:39]1([C@H:45]2[CH2:49][O:48][C:47](=[O:50])[NH:46]2)[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>C(Cl)Cl.CN(C)C1C=CN=CC=1>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([CH2:18][S:19][CH2:20][C:21]([N:46]4[C@@H:45]([C:39]5[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=5)[CH2:49][O:48][C:47]4=[O:50])=[O:22])[O:11][CH2:12][C:13]([CH3:16])([CH3:17])[CH2:14][O:15]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CC1(C)COC(CSCC(=O)O)(c2ccc3c(c2)OCO3)OC1
Reactant: O=C1N[C@@H](c2ccccc2)CO1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC1(C)COC(CSCC(=O)N2C(=O)OC[C@@H]2c2ccccc2)(c2ccc3c(c2)OCO3)OC1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
({[2-(1,3-Benzodioxol-5-yl)-5,5-dimethyl-1,3-dioxan-2-yl]methyl}thio)acetic acid (Method 13) (12.7 g, 37.4 mmol) was dissolved in dry CH2Cl2 (150 ml) and given 0° C. N,N′-Dicyclohexylcarbodiimide (DCC, 8.48 g, 37.4 mmol) and 4-(dimethylamino)pyridine (DMAP, 9.13 g, 74.8 mmol) were added and the mixture was stirred at 0° C. for 20 minutes. (S)-(+)-4-Phenyl-2-oxazolidinone (6.10 g, 37.4 mmol) was added and the mixture was stirred at room temperature for 16 hours. The mixture was filtrated, concentrated under reduced pressure and purified by flash-chromatography (heptane:EtOAc 2:1). This afforded the title compound.
Reaction SMILES: [Cl-].[NH4+].[CH3:3][O:4][C:5]1[C:10]([N+:11]([O-])=O)=[CH:9][C:8]([Br:14])=[CH:7][C:6]=1[C:15]([CH3:18])([CH3:17])[CH3:16]>CO.O.[Fe]>[Br:14][C:8]1[CH:7]=[C:6]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:5]([O:4][CH3:3])=[C:10]([CH:9]=1)[NH2:11]
Reactant: COc1c([N+](=O)[O-])cc(Br)cc1C(C)(C)C
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CO
Product: COc1c(N)cc(Br)cc1C(C)(C)C
Yield: 90.2 %

Procedure:
Ammonium chloride (38 g) was added to a solution of 4-bromo-2-(tert-butyl)-6-nitrophenyl methyl ether (20.6 g) in methanol-water (140 ml-140 ml) and iron (20 g) was gradually added while heating to reflux. The mixture was heated to reflux for 2 hours and then the reaction mixture was filtered through celite. The filtrate was concentrated under reduced pressure, ethyl acetate was added to the residue and the mixture was washed 3 times with brine. The organic layer was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure to yield a crude product of the title compound (16.65 g) as a brown oil.
Reaction SMILES: CC(C)([O-])C.[Na+].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.[CH3:20][N:21]1[CH:25]=[CH:24][CH:23]=[C:22]1[C:26]1[CH:27]=[C:28]2[C:36](=[CH:37][CH:38]=1)[N:35]([CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])[C:34]1[CH:33]=[CH:32][C:31](Br)=[CH:30][C:29]2=1.[C:46]1([NH:52][C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd]>[CH3:20][N:21]1[CH:25]=[CH:24][CH:23]=[C:22]1[C:26]1[CH:27]=[C:28]2[C:36](=[CH:37][CH:38]=1)[N:35]([CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])[C:34]1[CH:33]=[CH:32][C:31]([N:52]([C:53]3[CH:54]=[CH:55][CH:56]=[CH:57][CH:58]=3)[C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)=[CH:30][C:29]2=1
Reactant: c1ccc(Nc2ccccc2)cc1
Reactant: CCCCCCn1c2ccc(Br)cc2c2cc(-c3cccn3C)ccc21
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: CC(C)(C)[O-]
Product: CCCCCCn1c2ccc(-c3cccn3C)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:1]1([S:7]([C:10]2[C:11]([S:23][CH3:24])=[N:12][N:13]3[C:18](Cl)=[C:17]4[CH2:20][CH2:21][CH2:22][C:16]4=[N:15][C:14]=23)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH3:25]>CO>[C:1]1([S:7]([C:10]2[C:11]([S:23][CH3:24])=[N:12][N:13]3[C:18]([NH2:25])=[C:17]4[CH2:20][CH2:21][CH2:22][C:16]4=[N:15][C:14]=23)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N
Reactant: CSc1nn2c(Cl)c3c(nc2c1S(=O)(=O)c1ccccc1)CCC3
Solvent: CO
Product: CSc1nn2c(N)c3c(nc2c1S(=O)(=O)c1ccccc1)CCC3

Procedure:
In an analogous manner to that described in Example 4) from 3-benzenesulphonyl-8-chloro-2-methylsulphanyl-6,7-dihydro-5H-cyclopenta[d]pyrazolo[1,5-a]pyrimidine and NH3 in MeOH there was obtained 3-benzenesulphonyl-2-methylsulphanyl-6,7-dihydro-5H-cyclopenta[d]pyrazolo[1,5-a]pyrimidin-8-ylamine as colorless crystals, m.p.>230°.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:11]([NH2:15])=[N:12][O:13][N:14]=1.CO.[C:18](#[N:21])[CH:19]=[CH2:20]>N1C=CC=CC=1>[NH:3]1[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[N:1]=[C:2]1[C:10]1[C:11]([NH:15][CH2:20][CH2:19][C:18]#[N:21])=[N:12][O:13][N:14]=1
Reactant: Nc1nonc1-c1nc2ccccc2[nH]1
Reactant: C=CC#N
Solvent: c1ccncc1
Solvent: CO
Product: N#CCCNc1nonc1-c1nc2ccccc2[nH]1

Procedure:
To a solution of 4-(1H-benzimidazol-2-yl)-furazan-3-ylamine (0.10 g, 0.497 mmol) in pyridine (5 ml) sodium in methanol (0.02 g, 0.86 mmol in 1 ml) and acrylonitrile (0.03 g, 0.39 mmol) are added sequentially at 0° C. The mixture is stirred over night. Evaporation of the solvent under reduced pressure and partitioning of the resulting residue between water and ethyl acetate followed by drying of the organic solution over sodium sulphate gives the title compound in pure form. 1H-NMR (400 MHz, d6-DMSO): 13.7 (s, 1H); 7.82 (d, 1H); 7.60 (d, 1H); 7.36 (m, 2H); 7.20 (t, 1H); 3.67 (q, 2H); 2.94 (t, 2H).
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([NH:12][C:13]2[NH:14][N:15]=[C:16]([CH:18]3[CH2:20][CH2:19]3)[CH:17]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH2:21]([Mg]Cl)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C1COCC1.Cl[Ni]1(Cl)[P](C2C=CC=CC=2)(C2C=CC=CC=2)CCC[P]1(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:21]([C:2]1[N:11]=[C:10]([NH:12][C:13]2[NH:14][N:15]=[C:16]([CH:18]3[CH2:20][CH2:19]3)[CH:17]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: Cl[Mg]Cc1ccccc1
Reactant: Clc1nc(Nc2cc(C3CC3)n[nH]2)c2ccccc2n1
Agent: Cl[Ni]1(Cl)[P](c2ccccc2)(c2ccccc2)CCC[P]1(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: c1ccc(Cc2nc(Nc3cc(C4CC4)n[nH]3)c3ccccc3n2)cc1
Temperature: 50 °C

Procedure:
To a solution of the above-prepared (2-chloroquinazolin-4-yl)-(5-cyclopropyl-2H-pyrazol-3-yl)-amine (123 mg, 0.43 mmol) in THF (5 mL) is added NiCl2(dppp) (12 mg, 2.1.10−5 mol), followed by 1M benzylmagnesium chloride in THF (2.15 mL, 2.15 mmol). The solution is heated at 50° C. for 20 hours and the reaction mixture is then quenched with aqueous NH4Cl and the product extracted in ethyl acetate. The solvent is evaporated and the residue purified by flash chromatography to yield the desired (2-benzyl-quinazolin-4-yl)-(5-cyclopropyl-2H-pyrazol-3-yl)-amine.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:3][CH2:2]1.Br[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH3:31])[CH:25]=1>>[CH3:31][O:30][C:26]1[CH:25]=[C:24]([CH:29]=[CH:28][CH:27]=1)[CH2:23][N:1]1[CH2:2][CH2:3][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:5][CH2:6]1
Reactant: COc1cccc(CBr)c1
Reactant: O=C1C(=O)c2ccccc2C2=C1SCC1(CCNCC1)O2
Product: COc1cccc(CN2CCC3(CC2)CSC2=C(O3)c3ccccc3C(=O)C2=O)c1

Procedure:
Compound 121 was synthesized using spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione, 1-(bromomethyl)-3-methoxybenzene and conditions outlined in procedure V. M.p.=129-131° C.; 400 MHz 1H NMR (CDCl3) δ: 8.05 (d, 1H), 7.75 (d, 1H), 7.65 (t, 1H), 7.5 (t, 1H), 7.25 (m, 2H), 6.9 (s, 1H), 6.8 (d, 1H), 3.8 (s, 3H), 3.55 (s, 2H), 2.9 (s, 2H), 2.75 (d, 2H), 2.5 (t, 2H), 2.1 (d, 2H), 1.9 (t, 2H); LCMS: 422 [M+H].
Reaction SMILES: [C:1]([C:3]1[CH:15]=[C:14]2[C:6]([C:7]3[C:8](=[O:30])[C:9]4[CH:21]=[CH:20][C:19](OS(C(F)(F)F)(=O)=O)=[CH:18][C:10]=4[C:11]([CH3:17])([CH3:16])[C:12]=3[NH:13]2)=[CH:5][CH:4]=1)#[N:2].Cl.[CH:32]([N:35]([CH:39]([CH3:41])[CH3:40])[CH2:36][CH2:37][SH:38])([CH3:34])[CH3:33]>>[CH:32]([N:35]([CH:39]([CH3:41])[CH3:40])[CH2:36][CH2:37][S:38][C:19]1[CH:20]=[CH:21][C:9]2[C:8](=[O:30])[C:7]3[C:6]4[C:14](=[CH:15][C:3]([C:1]#[N:2])=[CH:4][CH:5]=4)[NH:13][C:12]=3[C:11]([CH3:16])([CH3:17])[C:10]=2[CH:18]=1)([CH3:34])[CH3:33]
Reactant: CC1(C)c2cc(OS(=O)(=O)C(F)(F)F)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21
Reactant: CC(C)N(CCS)C(C)C
Agent: Cl
Product: CC(C)N(CCSc1ccc2c(c1)C(C)(C)c1[nH]c3cc(C#N)ccc3c1C2=O)C(C)C

Procedure:
Under the same conditions as the method for synthesizing Compound B2-17, the title compound was prepared from Compound B1 and 2-diisopropylaminoethanethiol hydrochloric acid salt.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([NH:12][C:13]([O:15][CH3:16])=[O:14])[C:9]([OH:11])=[O:10].NC(C1C=CC=CC=1OC)[C:19](O)=[O:20]>>[CH3:16][O:15][C:13]([NH:12][CH:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[O:20][CH3:19])[C:9]([OH:11])=[O:10])=[O:14]
Reactant: COc1ccccc1C(N)C(=O)O
Reactant: COC(=O)NC(C(=O)O)c1ccccc1F
Product: COC(=O)NC(C(=O)O)c1ccccc1OC

Procedure:
Methoxycarbonylamino-(2-methoxy-phenyl)-acetic acid was prepared using the procedure used to prepare (2-Fluoro-phenyl)-methoxycarbonylamino-acetic acid using Amino-(2-methoxy-phenyl)-acetic acid. LCMS-ESI+: calc'd for C11H13NO5: 239.08 (M+); Found: 239.94 (M+H+).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([N:9]=[N:10][C:11]2[CH:16]=[C:15](Cl)[CH:14]=[C:13](Cl)[CH:12]=2)[CH:5]=[C:6](Cl)[CH:7]=1>[O-2].[O-2].[Mn+4]>[N:9]([C:4]1[CH:3]=[CH:2][CH:7]=[CH:6][CH:5]=1)=[N:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Clc1cc(Cl)cc(N=Nc2cc(Cl)cc(Cl)c2)c1
Agent: [Mn+4]
Agent: [O-2]
Product: c1ccc(N=Nc2ccccc2)cc1
Yield: 10 %

Procedure:
The oxidation of substituted anilines to azobenzenes is a well-known procedure; oxidizing agents of various sorts are employed. Wheeler and Gonzalez (Reference 6) used manganese dioxide as their oxidizing agent; with this reagent they oxidized 3,5-dichloroaniline (II) to the corresponding 3,5,3'5'-tetrachloroazobenzene (VI) in yields above 90%. Wheeler and Gonzalez report their technique gives only a 10% yield of azobenzene when applied to 3,5-dichloro-4-nitroaniline (VII). ##STR3##