Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:31][CH2:30][CH2:29][C@H:2]1[C:3]([NH:5][C@H:6]([C:14]([NH:16][C@H:17]([C:25]([NH:27]N)=[O:26])[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:15])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:4].N[C@@H:40]([C:42]([NH:44][C@H:45]([C:50]([NH:52][C@H:53]([C:58]([NH2:60])=[O:59])[CH2:54][CH2:55][S:56][CH3:57])=[O:51])[CH2:46][CH:47]([CH3:49])[CH3:48])=[O:43])[CH3:41]>>[N:1]1([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:31][CH2:30][CH2:29][C@H:2]1[C:3]([NH:5][C@H:6]([C:14]([NH:16][C@H:17]([C:25]([NH:27][C@@H:40]([C:42]([NH:44][C@H:45]([C:50]([NH:52][C@H:53]([C:58]([NH2:60])=[O:59])[CH2:54][CH2:55][S:56][CH3:57])=[O:51])[CH2:46][CH:47]([CH3:49])[CH3:48])=[O:43])[CH3:41])=[O:26])[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:15])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:4]
Reactant: CSCC[C@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](C)N)C(N)=O
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1ccccc1)C(=O)NN
Product: CSCC[C@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](C)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C)C(N)=O
Yield: 66 %

Procedure:
Condensation of BocPro-Phe-PheNHNH2 (1.31 g.) and HDAla-Leu-MetNH2 (0.85 g.) by the acyl azide method (Yajima et al., Chem. Pharm. Bull., vol. 19, p. 1900, 1971) gave BocPro-Phe-Phe-DAla-Leu-MetNH2 in 66% yield. De-t-butoxycarbonylation of BocPro-Phe-Phe-DAla-Leu-MetNH2 (1.10 g.) using hydrogen chloride in acetic acid gave HPro-Phe-Phe-DAla-Leu-MetNH2, which was isolated as the amorphous white solid phosphate (1:1) salt sesquihydrate in 66% yield.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:10])=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5]Br.[N-:11]=[C:12]=[S:13].[K+].[Na+].[I-]>CN(C)C=O>[Cl:1][C:2]1[C:3]([F:10])=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][N:11]=[C:12]=[S:13]
Reactant: Fc1c(Cl)cccc1CBr
Reactant: [N-]=C=S
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Fc1c(Cl)cccc1CN=C=S

Procedure:
One molar equivalent of 3-chloro-2-fluoro-benzyl bromide (commercially available from e.g., Lancaster Synthesis, Ltd.) is permitted to react with 2 molar equivalents of potassium isothiocyanate in dimethylformamide (DMF) containing 0.5 molar equivalent of NaI at 90° C. for 5 hours with stirring to yield 3-chloro-2-fluorobenzyl isothiocyanate. The reaction mixture is permitted to cool to room temperature, and the solution is diluted with H20 and extracted with ether. The ether phase containing the product is removed and the reaction mixture extracted twice more with fresh ether. The ether phases are combined and the product is concentrated in a Speed Vac® vacuum centrifuge (using house vacuum) set in a water bath at about 45° C. When the ether has evaporated, the unpurified 3-chloro-2-fluorobenzyl isothiocyanate is a viscous liquid.
Reaction SMILES: Cl[CH2:2][C:3]1[C:8]([CH2:9]Cl)=[CH:7][N:6]=[C:5]([C:11]([F:14])([F:13])[F:12])[CH:4]=1.[C:15]1([C:21]([NH2:34])([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[F:12][C:11]([F:14])([F:13])[C:5]1[N:6]=[CH:7][C:8]2[CH2:9][N:34]([C:21]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH2:2][C:3]=2[CH:4]=1
Reactant: FC(F)(F)c1cc(CCl)c(CCl)cn1
Reactant: NC(c1ccccc1)(c1ccccc1)c1ccccc1
Product: FC(F)(F)c1cc2c(cn1)CN(C(c1ccccc1)(c1ccccc1)c1ccccc1)C2

Procedure:
Prepared in analogy to Example A2(b) from 4,5-Bis-chloromethyl-2-trifluoromethyl-pyridine and triphenylmethylamine. White solid.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([C:9]([F:12])([F:11])[F:10])[C:5]([F:13])=[C:4]([F:14])[C:3]=1[NH:15][NH2:16].C(O[CH:20]=[C:21]([C:27]#[N:28])[C:22]([O:24][CH2:25][CH3:26])=[O:23])C>C(O)C>[NH2:28][C:27]1[N:15]([C:3]2[C:2]([F:1])=[C:7]([F:8])[C:6]([C:9]([F:12])([F:11])[F:10])=[C:5]([F:13])[C:4]=2[F:14])[N:16]=[CH:20][C:21]=1[C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: NNc1c(F)c(F)c(C(F)(F)F)c(F)c1F
Reactant: CCOC=C(C#N)C(=O)OCC
Solvent: CCO
Product: CCOC(=O)c1cnn(-c2c(F)c(F)c(C(F)(F)F)c(F)c2F)c1N
Yield: 87.3 %

Procedure:
40 g (0.161 mol) of 2,3,5,6-tetrafluoro-4-trifluoromethylphenylhydrazine and 27.8 g (0.161 mol) of ethyl ethoxymethylenecyanoacetate are dissolved in 70 ml of ethanol and the solution is warmed under reflux for 10 hours. The solvent is distilled off in vacuo, the residue is suspended in 100 ml of diethyl ether, the suspension is filtered and the solid is dried. 52.2 g (87.4% of theory) of 5-amino-4-ethoxycarbonyl-1-(2,3,5,6-tetrafluoro-4-trifluoromethyl-phenyl)-pyrazole of melting point 175° C.-176° C. are obtained.
Reaction SMILES: [OH-].[Na+].[CH2:3]([O:5][C:6](=[O:13])[CH2:7][C:8](=[O:12])[CH:9]([CH3:11])[CH3:10])[CH3:4].Cl[CH:15](OCC)[CH2:16]Cl>O.C(OCC)C>[CH2:3]([O:5][C:6]([C:7]1[CH:16]=[CH:15][O:12][C:8]=1[CH:9]([CH3:10])[CH3:11])=[O:13])[CH3:4]
Reactant: CCOC(Cl)CCl
Reactant: CCOC(=O)CC(=O)C(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Product: CCOC(=O)c1ccoc1C(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 69.5 %

Procedure:
An ice-chilled solution of sodium hydroxide (1.9 g) in water (25 ml) was added, during 40 minutes, to a stirred solution of 4-methyl-3-oxo-pentanoic acid ethyl ester (3 g, 18.96 mmoles) and 1,2-dichloro-1-ethoxy-ethane (3.3 g, 35.19 mmole) in diethyl ether (15 ml) with ice bath cooling. When the addition was complete the mixture was stirred rapidly for 1 hour, then the ethereal layer was separated, washed with water and dried. Evaporation of the solvent gave a yellow oil, which was purified by flash chromatography using a gradient elution from neat pentane to pentane/diethyl ether 9:1 v/v as eluent, to afford compound 82 as an oil (2.4 g)
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3]1.[Cl-].[CH:12](=[N+:19]([CH3:21])[CH3:20])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH3:20][N:19]([CH3:21])[CH:12]([C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:2]([CH3:1])[CH:3]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Cn1ccc2ccccc21
Reactant: C[N+](C)=Cc1ccccc1
Agent: [Cl-]
Product: CN(C)C(c1ccccc1)c1cn(C)c2ccccc12

Procedure:
The preparation was carried out in accordance with general synthesis instructions 4 from 1-methyl-1H-indole and benzylidene-dimethyl-ammonium chloride, which had been prepared in accordance with example 1.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C(O)(=O)C.[O-:13][C:14]#[N:15].[Na+]>O>[OH:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:14]([NH2:15])=[O:13])=[CH:3][CH:4]=1
Reactant: N#C[O-]
Reactant: Nc1ccc(O)cc1
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: NC(=O)Nc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 76.5 %

Procedure:
4-aminophenol (45 g, 0.4123 mol) was charged in water and acetic acid mixture (9:1) (450 vol) to obtain a clear solution. To this clear solution was added drop wise previously prepared solution of sodium cyanate (29.48 g, 0.45358 mol) in water over a period of 1 hour. The reaction mass obtained was stirred for 6 hours at ambient temperature and filtered to obtain solid. The solid was washed with water and vacuum dried to obtain the desired product, i.e., 1-(4-hydroxyphenyl)urea (48 g).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:32]3[CH2:36][CH2:35][NH:34][CH2:33]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)[C:3]=12.[CH:37]([C:39]1[N:40]=[CH:41][NH:42][CH:43]=1)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>ClC(Cl)C>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:32]3[CH2:36][CH2:35][N:34]([CH2:37][C:39]4[N:40]=[CH:41][NH:42][CH:43]=4)[CH2:33]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)[C:3]=12
Reactant: COc1cc(-c2nn(C3CCNC3)c3ncnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Reactant: O=Cc1c[nH]cn1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(Cl)Cl
Product: COc1cc(-c2nn(C3CCN(Cc4c[nH]cn4)C3)c3ncnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Temperature: 25 °C
Reaction time: 24 h
Yield: 31.7 %

Procedure:
A suspension of N2-[4-(4-amino-1-tetrahydro-1H-3-pyrrolyl-1H-pyrazolo [3,4-d]pyrimidin-3-yl)-2-methoxyphenyl]-1-methyl-1H-2-indolecarboxamide (0.200 g, 0.415 mmol) in dichloroethane (5 mL) was treated with 4-formylimidazole (0.08 g, 0.83 mmol) and sodium triacetoxy borohydride (0.176 g, 0.83 mmol). The reaction mixture was stirred at room temperature for 24 h under a nitrogen atmosphere. Sodium hydroxide (1N, 15 mL) was added to the reaction mixture and was stirred for 1 h. The organic layer was removed under reduced pressure and dichloromethane was added. The layers were partitioned and the aqueous layer was extracted with dichloromethane (200 mL). The combined organic layers were dried over magnesium sulfate, filtered and evaporated under reduced pressure. The crude material was purified by flash chromatography on silica gel using 10% methanol in dichloromethane (20 min), 15% methanol in dichloromethane (10 min), 20% methanol in dichloromethane (10 min) and 50% methanol in dichloromethane (8 min) as the eluent. The column afforded 0.074 g (25%) of pure N2-(4-{4-amino-1-[1-(1H-4-imidazolylmethyl)tetrahydro-1H-3-pyrrolyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-methoxyphenyl)-1-methyl-1H-2-indolecarboxamide. 1H NMR (DMSO-d6, 400 MHz) 69.446 (s, 1H), 8.252 (s, 1H), 8.126-8.1082 (d, 1H, J=8.16 Hz), 7.7198-7.7 (d, 1H, J=7.92 Hz), 7.6-7.569 (m, 2H), 7.35-7.298 (m, 4H), 7.171-7.134 (m, 1H), 6.946 (s, 1H), 5.422-5.385 (m, 1H), 4.043 (s, 3H), 3.961 (s, 3H), 3.691 (s, 2H), 3.175-3.162 (m, 2H), 2.9-2.883 (m, 3H), 2.385-2.332 (m, 2H); LCMS (Thermoquest AQA single-quad MS, Genesis C18 column, 3 μm particle size, 33×4.6 mm; 70% 50 mM ammonium acetate in water to 95% acetonitrile over 6 min, 0.8 to 0.5 mL/min) Rt 2.13 min (100%), MH+ 563.3.
Reaction SMILES: [CH2:1]([SH:3])[CH3:2].[H-].[Na+].Cl[C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=1.O>CN(C)C=O>[CH2:1]([S:3][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=1)[CH3:2]
Reactant: CCS
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCSc1ccc([N+](=O)[O-])cc1
Temperature: 60 °C
Reaction time: 24 h

Procedure:
Ethanethiol (6.11 ml, 0.082 mol) was added slowly to a suspension of sodium hydride (3.3 g, 60% dispersion) in dry dimethylformamide (225 ml) at room temperature under a nitrogen atmosphere. The reaction mixture was stirred for 15 min before the addition of 1-chloro-4-nitrobenzene (10 g, 0.063 mol) dissolved in dry dimethylformamide (25 ml). After addition, the resultant mixture was allowed to warm to 60° C. and was stirred for 24 hr. The mixture was then concentrated in vacuo to yield a yellow oil. Ice and water were added and a yellow solid was precipitated and filtered off. The solid was then dissolved in methanol (100 ml) and insoluble by-products were isolated by filtration. The filtrate was then concentrated in vacuo. The residue was dissolved in ethyl acetate (50 ml) and washed with water (2×50 ml). The organic layer was then dried (MgSO4) and concentrated in vacuo to afford 1-(ethylthio)-4-nitrobenzene as a yellow solid. δ(1H NMR, DMSO, ppm): 1.15 (3H, t), 3.05 (2H, q) 7.45 (2H, d), 8.10 (2H, d)
Reaction SMILES: ClC1C=CC(N)=CC=1.C([CH:11]([C:17]([CH3:19])=O)[C:12]([O:14][CH2:15][CH3:16])=[O:13])C.Cl.C([OH:23])C>>[O:23]=[C:11]([CH2:17][CH3:19])[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCO
Reactant: CCOC(=O)C(CC)C(C)=O
Agent: Cl
Agent: Nc1ccc(Cl)cc1
Product: CCOC(=O)C(=O)CC

Procedure:
The p-chlorophenylhydrazone of ethyl 2-oxobutanoate was prepared by adaptation of the Japp-Klingemann reaction as described by lions and Hughes (J. Proc. Roy. Soc. N. S. Wales 1939, 71: 445) to p-chloroaniline and ethyl 2-ethylacetoacetate. This phenylhydrazone was treated with HCl-ethanol according to the procedure of lions and Hughes (J. Proc. Roy. Soc. N. S. Wales 1939, 71: 445) as applied therein to the corresponding bromophenylhydrazone. The title substance was collected by filtration as an orange solid after suspending the concentrated residue in water.
Reaction SMILES: Cl.[NH2:2][C:3]1[NH:4][CH:5]=[CH:6][N:7]=1.N1C=CC=CC=1.[C:14](Cl)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>O>[C:15]1([C:14]([NH:2][C:3]2[NH:4][CH:5]=[CH:6][N:7]=2)=[O:21])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Nc1ncc[nH]1
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: O=C(Nc1ncc[nH]1)c1ccccc1
Temperature: 25 °C

Procedure:
To a suspension of 6.8 g. of 2-aminoimidazole hydrochloride in 100 ml. of pyridine at -20°C. there is added 6.8 ml. of benzoyl chloride. The thus-obtained reaction mixture is allowed to warm slowly to between 20°-30°C. (room temperature), and maintained at this temperature for 12 hours, diluted with water and filtered to give a residue which is recrystallized from methanol to yield 2-phenylcarbonylaminoimidazole [(III), R = phenyl].
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([S:18][C:19]([F:24])([F:23])[CH:20]([F:22])[F:21])[NH:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[CH2:26][O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:28]([O:27][CH2:26][N:10]1[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]=[C:9]1[S:18][C:19]([F:23])([F:24])[CH:20]([F:22])[F:21])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: ClCOCc1ccccc1
Reactant: FC(F)C(F)(F)Sc1nc(-c2ccccc2)c(-c2ccccc2)[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: FC(F)C(F)(F)Sc1nc(-c2ccccc2)c(-c2ccccc2)n1COCc1ccccc1
Temperature: 0 °C
Reaction time: 24 h

Procedure:
A mixture of 3.5 g (0.01 mole) of 4,5-diphenyl-2-(1,1,2,2-tetrafluoroethylthio)imidazole, 2.1 g (0.013 mole) benzyl chloromethyl ether, 3.6 g (0.026 mole) potassium carbonate in 25 ml DMF was stirred for 24 hours. TLC showed some starting material, so an additional 0.5 g (0.003 mole) of benzyl chloromethyl ether was added and stirring continued for another 24 hours. The mixture was poured into ice water, extracted three times with ether and the ether layers backwashed three times with water. The ether solution was dried and concentrated on a rotary evaporator. The residue was chromatographed on 200 g SilicAR CC-7, eluting with toluene to give, after recrystallization from hexane, 3.6 g (76.6%) of white product, mp 70°-70.5°.
Reaction SMILES: Cl[C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[C:5]2=[N:12][CH:13]=[CH:14][N:4]2[N:3]=1.[NH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.CC(C)=O>C(Cl)Cl>[N:15]1([C:2]2[C:11]3[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=3[C:5]3=[N:12][CH:13]=[CH:14][N:4]3[N:3]=2)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: C1CCNCC1
Reactant: Clc1nn2ccnc2c2c1CCCC2
Solvent: CC(C)=O
Solvent: ClCCl
Product: c1cn2nc(N3CCCCC3)c3c(c2n1)CCCC3

Procedure:
A mixture was prepared by adding 15 g of 6-chloro-7,8,9,10-tetrahydroimidazo[2,1-a]phthalazine to 30.5 g of piperidine and the mixture was heated at reflux for 72 hours. The mixture was subjected to preparative liquid chromatography using 15% acetone in methylene chloride to separate the desired product from the impurities. The appropriate fractions from the chromatography were combined and the solvent was evaporated under reduced pressure. The resulting solid was collected by filtration and dried to give 6-(1-piperidinyl)-7,8,9,10-tetrahydroimidazo[2,1-a]phthalazine melting at about 95° C. This compound has the following structural formula ##STR2##
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][C:16]([C:21]([N:23]2[CH2:28][CH2:27][CH:26]([O:29][CH3:30])[CH2:25][CH2:24]2)=[O:22])=[CH:15]3)=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[F:31][C:32]([F:43])([F:42])[C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][CH:38]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[N:17]([C:37]2[CH:36]=[CH:35][CH:34]=[C:33]([C:32]([F:43])([F:42])[F:31])[CH:38]=2)[C:16]([C:21]([N:23]2[CH2:28][CH2:27][CH:26]([O:29][CH3:30])[CH2:25][CH2:24]2)=[O:22])=[CH:15]3)=[O:11])[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Reactant: COC1CCN(C(=O)c2cc3cc(C(=O)N4CCN(C(C)C)CC4)ccc3[nH]2)CC1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC1CCN(C(=O)c2cc3cc(C(=O)N4CCN(C(C)C)CC4)ccc3n2-c2cccc(C(F)(F)F)c2)CC1
Yield: 65 %

Procedure:
The title compound was synthesized in analogy to example 66, from [5-(4-isopropyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(4-methoxy-piperidin-1-yl)-methanone (example 21), 3-(trifluoromethyl)phenylboronic acid, copper(II) acetate and pyridine in dichloromethane, to give the desired product as a colorless foam (65%).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][O:5][C:6]=1[C:7]1[CH:15]=[CH:14][C:10]([C:11](Cl)=[O:12])=[CH:9][CH:8]=1.[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][CH:26]([NH:29][CH:30]2[CH2:32][CH2:31]2)[CH2:25][CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17].C(N(C(C)C)C(C)C)C>ClCCl>[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][CH:26]([N:29]([CH:30]2[CH2:31][CH2:32]2)[C:11](=[O:12])[C:10]2[CH:14]=[CH:15][C:7]([C:6]3[O:5][CH:4]=[N:3][C:2]=3[CH3:1])=[CH:8][CH:9]=2)[CH2:25][CH2:24]1)=[O:22])([CH3:19])([CH3:17])[CH3:18]
Reactant: CC(C)(C)OC(=O)N1CCC(NC2CC2)CC1
Reactant: Cc1ncoc1-c1ccc(C(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ncoc1-c1ccc(C(=O)N(C2CC2)C2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-(4-Methyl-oxazol-5-yl)-benzoyl chloride (340 mg) is added portionwise to a mixture of 4-cyclopropylamino-piperidine-1-carboxylic acid tert-butyl ester (369 mg) and ethyldiisopropylamine (274 μL) in dichloromethane (10 mL). The mixture is stirred for 1 h at room temperature, washed with water, aqueous citric acid solution and 0.5 M NaOH, dried over Na2SO4 and concentrated in vacuo. The residue is chromatographed on silica gel (dichloromethane/methanol 50:1) to afford the title compound. Mass spectrum (ESI+): m/z=426 [M+H]+.
Reaction SMILES: Br[C:2]1[C:10]2[CH:11]=[C:12]3[C:20]([C:21]([CH3:23])([CH3:22])[C:9]=2[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH:7]=2)=[C:19]1[C:14]([CH:15]=[CH:16][CH:17]=[CH:18]1)=[N:13]3.[C:30]1(C2C=CC=CC=2)[CH:35]=[CH:34][C:33]([N:36](C2C=CC(B3OC(C)(C)C(C)(C)O3)=CC=2)[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[CH:32][CH:31]=1.C(=O)([O-])[O-].[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1.C(O)C>[C:6]1([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:7]=[CH:8][C:3]([N:36]([C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[C:33]2[CH:32]=[CH:31][C:30]([C:2]3[C:10]4[CH:11]=[C:12]5[C:20]([C:21]([CH3:23])([CH3:22])[C:9]=4[C:8]4[C:3]=3[CH:4]=[CH:5][CH:6]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:7]=4)=[C:19]3[C:14]([CH:15]=[CH:16][CH:17]=[CH:18]3)=[N:13]5)=[CH:35][CH:34]=2)=[CH:4][CH:5]=1
Reactant: CC1(C)C2=C(C=C3N=c4ccccc4=C31)C(Br)=C1C=CC(c3ccccc3)C=C12
Reactant: CC1(C)OB(c2ccc(N(c3ccccc3)c3ccc(-c4ccccc4)cc3)cc2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CC1(C)C2=C(C=C3N=c4ccccc4=C31)C(c1ccc(N(c3ccccc3)c3ccc(-c4ccccc4)cc3)cc1)=C1C=CC(c3ccccc3)C=C12
Temperature: 73 °C
Reaction time: 8 h
Yield: 116.2 %

Procedure:
7-Bromo-12,12-dimethyl-10-phenyl-10,12-dihydro-indeno[2,1-b]carbazole synthesized in Example 1 (3.0 g), (biphenyl-4-yl)-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]-phenylamine (3.7 g), a toluene/ethanol (4/1, v/v) mixed solvent (50 ml), and a 2M potassium carbonate aqueous solution (10 ml) were added to a nitrogen-substituted reaction vessel and aerated with nitrogen gas for 30 min under ultrasonic irradiation. The mixture was heated after adding tetrakis(triphenylphosphine)palladium (0.4 g), and stirred at 73° C. for 8 hours. After the mixture was cooled to a room temperature, a precipitated crude product was collected by filtration. 1,2-Dichlorobenzene (140 ml) was added to the crude product, and the crude product was dissolved while being heated, and after removing insoluble matter by filtration, a filtrate was concentrated under reduced pressure. Purification by recrystallization using 1,2-dichlorobenzene (100 ml) was performed to obtain a white powder of 7-[4-{(biphenyl-4-yl)-phenylamino}-phenyl]-12,12-dimethyl-10-phenyl-10,12-dihydroindeno[2,1-b]carbazole (2.7 g; yield 57.8%).
Reaction SMILES: [C:1]([C:4]12[CH2:11][CH2:10][C:7]([NH:12][CH2:13][C:14]([N:16]3[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]3[C:22]#[N:23])=[O:15])([CH2:8][CH2:9]1)[CH2:6][CH2:5]2)(O)=[O:2].[NH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([CH3:31])[CH:26]=1>>[F:21][C@@H:19]1[CH2:20][N:16]([C:14](=[O:15])[CH2:13][NH:12][C:7]23[CH2:6][CH2:5][C:4]([C:1]([NH:24][C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([CH3:31])[CH:26]=4)=[O:2])([CH2:9][CH2:8]2)[CH2:11][CH2:10]3)[C@H:17]([C:22]#[N:23])[CH2:18]1
Reactant: Cc1cccc(N)c1
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)O)(CC1)CC2
Product: Cc1cccc(NC(=O)C23CCC(NCC(=O)N4C[C@@H](F)C[C@H]4C#N)(CC2)CC3)c1

Procedure:
In a similar manner to Example 63, (2S,4S)-1-[[N-(4-carboxybicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (50.0 mg) and m-toluidine (25.8 μL) were used to obtain (2S,4S)-4-fluoro-1-[[N-[4-[N-(3-methylphenyl)amino]carbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]pyrrolidine-2-carbonitrile (18.3 mg).
Reaction SMILES: [N:1]1[C:5]2[C:6]3[C:11]([C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=4[C:4]=2[NH:3][CH:2]=1)=[CH:10][CH:9]=[CH:8][CH:7]=3.[S].[S:19]1(CCCC1)(=O)=O>>[NH:1]1[C:5]2[C:6]3[C:11]([C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=4[C:4]=2[N:3]=[C:2]1[SH:19])=[CH:10][CH:9]=[CH:8][CH:7]=3
Reactant: c1ccc2c(c1)c1ccccc1c1[nH]cnc21
Reactant: O=S1(=O)CCCC1
Agent: [S]
Product: Sc1nc2c3ccccc3c3ccccc3c2[nH]1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
Ten grams of the imidazole was suspended in 100 ml of sulfolane (tetramethylene sulfone) and 3 gms of powdered sulfur was added; the resulting mixture was heated in an atmosphere of nitrogen at 200°-205° with thorough stirring for eight hours. The reaction mixture was then cooled, and diluted with 500 ml of ice-cold water. The dark brown mass that separated was collected by filtration and thoroughly washed with water and dried in a vacuum oven at 100° for ten hours. The crude product was purified by column chromatography using basic alumina (Woelm grade 1) and dimethylformamide as the eluent. The purified product was triturated with boiling acetonitrile, melting point above 375°.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([O:14][CH3:15])=[O:13])[CH:10]=2)[NH:5][CH:4]=[CH:3]1.C(O)(=O)C.[I:20]N1C(=O)CCC1=O>O>[I:20][C:3]1[C:2](=[O:1])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]([O:14][CH3:15])=[O:13])[CH:10]=2)[NH:5][CH:4]=1
Reactant: O=C1CCC(=O)N1I
Reactant: COC(=O)c1ccc2[nH]ccc(=O)c2c1
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)c1ccc2[nH]cc(I)c(=O)c2c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 111.9 %

Procedure:
To a mixture of methyl 4-oxo-1,4-dihydroquinoline-6-carboxylate (1.1 g) and acetic acid (30 mL) was added N-iodosuccinimide (1.1 g), followed by stirring at room temperature for one day. The reaction mixture was diluted with water, and the precipitate was collected by filtration to obtain methyl 3-iodo-4-oxo-1,4-dihydroquinoline-6-carboxylate (1.8 g).