Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16](S(C)=O)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:28]=[CH:29][C:30]=3[CH3:31])[C:22]([NH:24][CH:25]([CH3:27])[CH3:26])=[O:23])[C:13]=2[CH2:12][NH:11][C:10]1=[O:35].C(Cl)(Cl)Cl.[CH3:40][N:41]1[CH2:46][CH2:45][N:44]([CH:47]2[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]2)[CH2:43][CH2:42]1.C(N(CC)C(C)C)(C)C>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([N:50]3[CH2:49][CH2:48][CH:47]([N:44]4[CH2:43][CH2:42][N:41]([CH3:40])[CH2:46][CH2:45]4)[CH2:52][CH2:51]3)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:28]=[CH:29][C:30]=3[CH3:31])[C:22]([NH:24][CH:25]([CH3:27])[CH3:26])=[O:23])[C:13]=2[CH2:12][NH:11][C:10]1=[O:35]
Reactant: CN1CCN(C2CCNCC2)CC1
Reactant: Cc1ccc(C(=O)NC(C)C)cc1-c1nc(S(C)=O)nc2c1CNC(=O)N2c1c(F)cccc1F
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(C(=O)NC(C)C)cc1-c1nc(N2CCC(N3CCN(C)CC3)CC2)nc2c1CNC(=O)N2c1c(F)cccc1F
Yield: 85.3 %

Procedure:
To a solution of compound 3-[8-(2,6-difluorophenyl)-2-(methylsulfinyl)-7-oxo-5,6,7,8-tetrahydropyrimido[4,5-d]pyrimidin-4-yl]-4-methyl-N-(1-methylethyl)benzamide (36 mg, 0.072 mmol) in THF (2 mL)/CHCl3 (2 mL) were added 1-methyl-4-(4-piperidinyl)piperazine (40 mg, 0.22 mmol) and N,N-diisopropylethylamine (0.1 mL, 0.5 mmol). The resultant solution was stirred at room temperature over night. The result mixture was concentrated. CombiFlash chromatography (mobile phase DCM/DCM [90]+MeOH[7]+NH4OH[3]) provided the title compound as a white solid (38 mg, 85%). LC-MS m/z 619 (M+H)+; 1H-NMR (MeOD) δ 1.27 (d, 6H), 1.33 (m, 2H), 1.83 (d, 2H), 2.28 (s, 3H), 2.30 (s, 3H), 2.65 (m, 11H), 4.11 (m, 2H), 4.23 (m, 1H), 4.45 (m, 2H), 7.16 (t, 2H), 7.46 (d, 1H), 7.50 (m, 1H), 7.68 (s, 1H), 7.85 (d, 1H).
Reaction SMILES: B(F)(F)F.CCOCC.[C:10]([C:12]1[CH:20]=[CH:19][C:15]([C:16](O)=[O:17])=[CH:14][CH:13]=1)#[N:11]>C1COCC1>[OH:17][CH2:16][C:15]1[CH:19]=[CH:20][C:12]([C:10]#[N:11])=[CH:13][CH:14]=1
Reactant: N#Cc1ccc(C(=O)O)cc1
Agent: FB(F)F
Solvent: CCOCC
Solvent: C1CCOC1
Product: N#Cc1ccc(CO)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.4 %

Procedure:
Boron trifluoride diethyl etherate (0.85 mL, 6.8 mmol) was added to a solution of 4-cyanobenzoic acid (1.0 g, 6.8 mmol) and THF (10 mL). At room temperature, borane-tetrahydrofuran complex (1.0 M, 13.6 mL) was added to the reaction mixture drop-wise with no observed exotherm. The reaction mixture was stirred at room temperature for 2 hours and concentrated in vacuo. The resulting residue was taken up in ethyl acetate (50 mL), washed with saturated NaHCO3 and brine, dried (Na2SO4), filtered and concentrated in vacuo to give the title compound (0.900 g, 95% yield) as a solid.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([NH:13][NH2:14])=[O:12].C(=O)([O-])O.[Na+].[N:20]#[C:21]Br>O1CCOCC1.O.C(O)C>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]1[O:12][C:21]([NH2:20])=[N:14][N:13]=1
Reactant: NNC(=O)c1ccc2ccccc2c1
Reactant: N#CBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Solvent: CCO
Product: Nc1nnc(-c2ccc3ccccc3c2)o1
Reaction time: 0.08 h
Yield: 19.1 %

Procedure:
To a stirred solution of naphthalene-2-carboxylic acid hydrazide (0.6 g, 3.22 mmol, prepared as described in example 1) in dioxane (20 ml) was added a solution of sodium hydrogen carbonate (0.27 g, 3.22 mmol) in water (15 ml) and the resulting mixture was stirred for 5 min. To the reaction mixture was added cyanogen bromide (0.35 g, 3.3 mmol) and the mixture was stirred for 3 h at room temperature. The precipitate was filtered off and washed with diethyl ether (2×15 ml) and dried in vacuo at 50° C. affording 0.4 g of crude product which was suspended in absolute ethanol (15 ml) and stirred at reflux temperature for 0.5 h. The cooled suspension was filtered and the filter cake was dried in vacuo at 50° C. affording 130 mg (20%) of the title compound as a solid.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])C.C(O)=O.[NH2:11][C:12]1[S:13][CH:14]=[C:15]([C:17](=[N:21][O:22][CH:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)[C:18]([OH:20])=[O:19])[N:16]=1>O1CCCC1>[CH:1]([NH:11][C:12]1[S:13][CH:14]=[C:15]([C:17](=[N:21][O:22][CH:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)[C:18]([OH:20])=[O:19])[N:16]=1)=[O:3]
Reactant: Nc1nc(C(=NOC2CCCC2)C(=O)O)cs1
Reactant: CC(=O)OC(C)=O
Solvent: C1CCOC1
Solvent: O=CO
Product: O=CNc1nc(C(=NOC2CCCC2)C(=O)O)cs1
Yield: 40.7 %

Procedure:
To acetic anhydride (32 g.) was added formic acid (14.4 g.) under ice-cooling and stirred at 40° to 45° C. for an hour. 2-(2-Aminothiazol-4-yl)-2-cyclopentyloxyiminoacetic acid (syn isomer, 20 g.) and tetrahydrofuran (100 ml.) were added to the solution under ice-cooling and stirred at 35° C. for 3 hours. After the solution was concentrated in vacuo, the residue was pulverized with diisopropyl ether, and dried over phosphorus pentoxide to give 2-(2-formamidothiazol-4-yl)-2-cyclopentyloxyiminoacetic acid (syn isomer, 9.04 g.), mp. 158° C. (dec.).
Reaction SMILES: [CH2:1](OCC)C.[CH2:6]([Mg]Cl)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[C:15](=[S:17])=[S:16]>O>[C:7]1([CH2:6][CH2:1][C:15]([SH:17])=[S:16])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: Cl[Mg]Cc1ccccc1
Reactant: CCOCC
Reactant: S=C=S
Solvent: O
Product: S=C(S)CCc1ccccc1
Temperature: 0 °C
Reaction time: 4.5 h

Procedure:
The inside of a 100 ml three-necked round-bottom flask, to which a dropping funnel is connected, was replaced with nitrogen, then a 1.0M diethyl ether solution (22 ml) of benzyl magnesium chloride was added and the mixture was cooled in an ice bath to 0° C. To this, carbon disulfide (1.32 ml) was dropped from a dropping funnel over 10 minutes, then the mixture was stirred at 0° C. for 4.5 hours. Thereafter, 30 ml of water was added, the mixture was returned to room temperature, the mixture was then washed with diethyl ether (total 100 ml) 2 times. Diethyl ether (50 ml) and 30% HCl (5 ml) were added and the product was extracted from the organic layer. Thereafter, the product was washed with water (total 150 ml) 3 times. The diethyl ether layer was concentrated to obtain phenylethyl dithiocarboxylic acid (1.86 g).
Reaction SMILES: [C:1]1([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][C:4]([C:7](Cl)=[O:8])=[CH:3][CH:2]=1.Cl.[CH3:17][NH:18][O:19][CH3:20].C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH3:20][O:19][N:18]([CH3:17])[C:7]([C:4]1[CH:5]=[CH:6][C:1]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:2][CH:3]=1)=[O:8]
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Reactant: CNOC
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CON(C)C(=O)c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4-Biphenylcarbonyl chloride (8 g) was suspended in chloroform (30 mL). This was added dropwise to a stirred solution of N,O-dimethyl hydroxylamine hydrochloride (5.2 g) and triethylamine (13.5 mL) in chloroform (80 mL) at 0° C. After addition was complete, the mixture was allowed to warm to room temperature and was stirred for a further 30 minutes. The organic phase was separated, washed with water and dried over MgSO4. Evaporation gave an oil, purified by flash column chromatography (ethyl acetate:light petroleum, 1:1) to give the title compound as a white solid. δC (CDCl3, 62.9 MHz): 33.8, 61.1, 126.7, 127.2, 127.9, 128.9, 132.8, 140.2, 143.4 and 169.7. δH (CDCl3, 250 MHz): 3.38 (3H, s), 3.59 (3H, s), 7.37-7.48 (3H, m), 7.61 (4H, m) and 7.77 (2H, d, J 8.5).
Reaction SMILES: C([C@@H]1[O:5][CH2:4]1)Cl.[CH2:6]([NH:13][CH2:14][CH2:15][OH:16])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.O.[CH:18](O)(C)[CH3:19].[OH-].C([N+](CC)(CC)CC)C>O>[CH2:6]([N:13]1[CH2:19][CH2:18][O:16][C@H:15]([CH2:4][OH:5])[CH2:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CC(C)O
Reactant: ClC[C@H]1CO1
Reactant: OCCNCc1ccccc1
Agent: CC[N+](CC)(CC)CC
Agent: [OH-]
Solvent: O
Product: OC[C@@H]1CN(Cc2ccccc2)CCO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 52 %

Procedure:
(R)-epichlorohydrin (1.7 ml, 21.6 mmol) was added to a solution of N-benzylethanolamine (3.73 ml, 25.7 mmol) in 1:1 water/isopropanol (7 ml), keeping the temperature between 20 and 25° C. After 6 hours the milky suspension was stored at −20° C. overnight. The solution was warmed to room temperature and 40% tetraethylammonium hydroxide (TEAOH) in water (12.3 ml) was added. The mixture was stirred at 20° C. for 1 hour and then quenched with 1M HCl (4 ml), keeping the pH around 10. The suspension was diluted with water (7 ml) and extracted with dichloromethane (DCM; 3×13 ml). The combined organic portions were dried and concentrated. The residue (yellowish oil) was purified by flash chromatography eluting the silica with DCM/MeOH 1:0 to 92:8. The product was isolated from the low Rf (slow-eluting) fraction as a colourless oil (2.3 g; 52% yield).
Reaction SMILES: Cl.Cl.Cl.[F:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]=[C:13]([CH:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[N:14]([CH2:16][CH2:17][N:18]([CH3:20])[CH3:19])[CH:15]=2)=[CH:7][C:6]=1[C:27]([F:30])([F:29])[F:28].CS(C)=O.Cl[C:36]1[C:37]2[CH2:44][C:43](=[O:45])[N:42]([CH2:46][C:47]3[CH:52]=[CH:51][C:50]([O:53][CH3:54])=[CH:49][C:48]=3[O:55][CH3:56])[C:38]=2[N:39]=[CH:40][N:41]=1>O>[CH3:19][N:18]([CH3:20])[CH2:17][CH2:16][N:14]1[CH:15]=[C:11]([C:8]2[CH:9]=[CH:10][C:5]([F:4])=[C:6]([C:27]([F:28])([F:29])[F:30])[CH:7]=2)[N:12]=[C:13]1[CH:21]1[CH2:26][CH2:25][N:24]([C:36]2[C:37]3[CH2:44][C:43](=[O:45])[N:42]([CH2:46][C:47]4[CH:52]=[CH:51][C:50]([O:53][CH3:54])=[CH:49][C:48]=4[O:55][CH3:56])[C:38]=3[N:39]=[CH:40][N:41]=2)[CH2:23][CH2:22]1
Reactant: COc1ccc(CN2C(=O)Cc3c(Cl)ncnc32)c(OC)c1
Reactant: CN(C)CCn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCNCC1
Agent: Cl
Solvent: CS(C)=O
Solvent: O
Product: COc1ccc(CN2C(=O)Cc3c(N4CCC(c5nc(-c6ccc(F)c(C(F)(F)F)c6)cn5CCN(C)C)CC4)ncnc32)c(OC)c1
Temperature: 62.5 °C
Reaction time: 6 h
Yield: 79.75 %

Procedure:
Combine 2-(4-(4-fluoro-3-(trifluoromethyl)phenyl)-2-(piperidin-4-yl)-1H-imidazol-1-yl)-N,N-dimethylethanamine trihydrochloride (98.76 g, 1 eq), DMSO (395 mL) and 4-chloro-7-(2,4-dimethoxybenzyl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one (1.1 eq). Heat the resulting suspension to 60-65° C. then add TEA (6 eq). Stir for 6 hours. Add DMSO (395 mL) and water (150 mL) as a stream and stir the resulting suspension for 1 hour at 45-38° C. Filter the slurry and wash the solids with a mixture of DMSO (1 vol) and water (1 vol) two times. Further wash the solids with water (3×200 mL), methanol (3×200 mL) and heptane (3×200 mL). Dry the cake on the filter to afford the target compound (106.5 g, 79.75% yield) as a tan solid. 1H NMR (400 MHz, DMSO): 8.18 (s, 1H), 7.99-7.95 (m, 2H), 7.71 (s, 1H), 7.43-7.39 (m, 2H), 6.76 (d, J=7.1 Hz, 1H), 6.54 (d, J=2 Hz 1H), 6.38-6.35 (m, 1H), 4.67 (s, 2H), 4.49 (d, J=13.1 Hz, 2H), 4.03 (t, J=6.52, 2H), 3.89 (s, 2H), 3.78 (s, 3H), 3.69 (s, 3H), 3.15-3.09 (m, 3H), 2.57 (t, J=6.6 Hz, 2H), 2.18 (s, 6H), 1.89-1.74 (m, 4H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([NH2:17])[CH:15]=2)[CH:10]=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:18][C:19]1[N:20]=[C:21](Br)[C:22]2[N:23]([CH:25]=[CH:26][N:27]=2)[CH:24]=1.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([NH:17][C:21]3[C:22]4[N:23]([CH:25]=[CH:26][N:27]=4)[CH:24]=[C:19]([Br:18])[N:20]=3)[CH:15]=2)[CH:10]=[CH:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Brc1cn2ccnc2c(Br)n1
Reactant: CC(C)(C)OC(=O)n1ccc2ccc(N)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)n1ccc2ccc(Nc3nc(Br)cn4ccnc34)cc21

Procedure:
A quantity of 0.23 g (1 mmole) of 6-Amino-indole-1-carboxylic acid tert-butyl ester is treated with 0.27 g (1 mmole) of 6,8-Dibromo-imidazo[1,2-a]pyrazine in acetonitrile with 3 eq. of K2CO3 at reflux for 16 hrs. The reaction mixture is cooled partitioned between ethyl acetate and water, the organic extracts are dried over anhydrous MgSO4 and evaporated in vacuo to afford 6-(6-Bromo-imidazo[1,2-a]pyrazin-8-ylamino)-indole-1-carboxylic acid tert-butyl ester. 6-(6-Bromo-imidazo[1,2-a]pyrazin-8-ylamino)-indole-1-carboxylic acid tert-butyl ester is treated with an excess of TFA in dichloromethane at room temperature for 2 hrs. The reaction solution is evaporated in vacuo and partitioned between saturated Na2CO3 and ethyl acetate; the organic extracts are dried over anhydrous MgSO4 and evaporated in vacuo to afford (6-Bromo-imidazo[1,2-a]pyrazin-8-yl)-(1H-indol-6-yl)-amine.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](Cl)=[N:8][C:9]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:14][CH:13]=2)=[N:10][CH:11]=1)=[O:5])[CH3:2].C(N(CC)CC)C>C(OCC)(=O)C.[H][H].[Pd]>[CH2:1]([O:3][C:4]([C:6]1[CH:11]=[N:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:14][CH:13]=2)=[N:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: [H][H]
Reactant: CCCCOc1ccc(-c2ncc(C(=O)OCC)c(Cl)n2)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCCCOc1ccc(-c2ncc(C(=O)OCC)cn2)cc1
Yield: 79.9 %

Procedure:
This compound (V) (3.3 g, 10 mmols) was dissolved in ethyl acetate (30 ml), followed by agitating the solution together with Pd/C (5%) (0.6 g) and triethylamine (1.0 g) in hydrogen atmosphere at room temperature for 3 hours, filtering off Pd/C, adding toluene (100 ml), washing the resulting fluid with 2N-hydrochloric acid (50 ml), washing it with water till the washing water became pH 7, drying the toluene phase over anhydrous magnesium sulfate, filtering off magnesium sulfate, concentrating under reduced pressure to obtain white crystals and recrystallizing the crystals from methanol to obtain ethyl-2-(4-butyloxyphenyl)-5-pyrimidinecarboxylate (VI) (2.4 g) (yield: 80%) having a melting point 99.1° C.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]([C:30]2[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=2)[N:14]2[CH2:17][CH:16]([NH:18][S:19]([C:22]3[CH:27]=[C:26](F)[CH:25]=[C:24]([F:29])[CH:23]=3)(=[O:21])=[O:20])[CH2:15]2)=[CH:9][CH:8]=1>CS(C)=O.ClCCl>[Cl:6][C:7]1[CH:8]=[CH:9][C:10]([CH:13]([C:30]2[CH:31]=[CH:32][C:33]([Cl:36])=[CH:34][CH:35]=2)[N:14]2[CH2:15][CH:16]([NH:18][S:19]([C:22]3[CH:27]=[C:26]([N:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)[CH:25]=[C:24]([F:29])[CH:23]=3)(=[O:20])=[O:21])[CH2:17]2)=[CH:11][CH:12]=1
Reactant: O=S(=O)(NC1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1)c1cc(F)cc(F)c1
Reactant: C1CCNC1
Solvent: CS(C)=O
Solvent: ClCCl
Product: O=S(=O)(NC1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1)c1cc(F)cc(N2CCCC2)c1
Temperature: 90 °C

Procedure:
0.104 cm3 of pyrrolidine is added, at room temperature, to 0.24 g of N-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-(3,5-difluorophenyl)sulfonamide in solution in 6 cm3 of dimethyl sulfoxide and then the mixture is heated for 18 hours at 90° C. The reaction mixture is diluted with 30 cm3 of dichloromethane and washed with three times 30 cm3 of distilled water. The organic phased is dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa). The residue is purified by flash chromatography on silica gel, eluting with dichloromethane. 50 mg of N-{1-[bis(4-chlorophenyl)methyl]azetidin-3-yl}-(3-fluoro-5-pyrrolidin-1-ylphenyl)sulfonamide are thus obtained in the form of a white powder [1H NMR spectrum (600 MHz, CDCl3 with addition of a few drops of CD3COOD d4, δ in ppm): 2.04 (mt: 4H); from 3.20 to 3.35 (mt: 6H); 3.60 (t, J=8.5 Hz: 2H); 4.14 (mt: 1H); 4.57 (s: 1H); 6.31 (broad d, J=11.5 Hz: 1H); 6.70 (broad d, J=8.5 Hz: 1H); 6.72 (broad s: 1H); from 7.20 to 7.35 (mt: 8H)].
Reaction SMILES: [C:1]([OH:12])(=O)/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[S:13]1[CH2:17][CH2:16][NH:15][CH2:14]1>>[C:1]([N:15]1[CH2:16][CH2:17][S:13][CH2:14]1)(=[O:12])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: C1CSCN1
Reactant: CCCCCCC/C=C/C(=O)O
Product: CCCCCCC/C=C/C(=O)N1CCSC1

Procedure:
The same procedures as in Example 1 were carried out using (E)-2-decenoic acid and thiazolidine as starting raw materials, to produce an intended compound.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1Cl.CC[Mg+].[Br-].[C:13]1([CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.ClC1C=CC=CC=1CC1C=CC=CC=1>CCOCC.C1COCC1>[CH2:14]([C:15]1[CH:16]=[CH:17][CH:18]=[CH:13][C:19]=1[CH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(CCc2ccccc2)cc1
Reactant: Clc1ccccc1Cl
Agent: CC[Mg+]
Agent: Clc1ccccc1Cc1ccccc1
Agent: [Br-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: c1ccc(Cc2ccccc2Cc2ccccc2)cc1
Reaction time: 0.5 h
Yield: 38.4 %

Procedure:
This Example illustrates the use of EtMgBr/[NitriphosCl]PF6 as an activator/catalyst to improve yield. To 2.00 g (13.61 mmoles) of o-dichlorobenzene, 0.050 g (0.065 mmoles) of [NitriphosCl]PF6 in 5 mL of ether at 0° C. was added 0.5 mL (1.5 mmoles) of 2.9M EtMgBr in ether. After stirring for 0.5 hrs, 30 mL of ether and 7.0 mL (14 mmoles) of 2M benzylMgCl in THF were added. The mixture was refluxed for 3 days and worked up as usual. After removing the solvent, the residue was distilled at 0.1 mm to initially remove 0.550 g (3.7 mmoles, 27%) of o-dichlorobenzene and then 1.482 g (bp: 68° to 83° C.) of a clear liquid was collected. 1H NMR spectrum in CDCl3 indicated a 10:1 ratio of 1-chloro-2-benzylbenzene to bibenzyl (representing 6.7 mmoles (67 % based on reacted o-dichlorobenzene) of 1-chloro-2-benzylbenzene and 0.67 mmoles of bibenzyl). The material that remained in the pot was chromatographed on silica gel eluted with 10% EtOAc/hexane to give 0.602 g (2.57 mmoles, 19%) of 1,2-dibenzylbenzene (mp: 61° to 67° C.).
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([Br:13])[CH:11]=2)[C:6]([C:14]([C:20]2[CH:21]=[C:22]3[C:26](=[CH:27][CH:28]=2)[N:25]([C:29]2[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=2)[N:24]=[CH:23]3)([OH:19])[C:15]([F:18])([F:17])[F:16])=[CH:5]1)C=C.[O-][Mn](=O)(=O)=O.[K+].[CH3:42][C:43]([CH3:45])=[O:44].[OH2:46]>>[Br:13][C:10]1[CH:11]=[C:12]2[C:7]([C:6]([C:14]([C:20]3[CH:21]=[C:22]4[C:26](=[CH:27][CH:28]=3)[N:25]([C:29]3[CH:30]=[CH:31][C:32]([F:35])=[CH:33][CH:34]=3)[N:24]=[CH:23]4)([OH:19])[C:15]([F:17])([F:16])[F:18])=[CH:5][N:4]2[CH2:42][CH:43]([OH:44])[CH2:45][OH:46])=[CH:8][CH:9]=1
Reactant: CC(C)=O
Reactant: O
Reactant: C=CCn1cc(C(O)(c2ccc3c(cnn3-c3ccc(F)cc3)c2)C(F)(F)F)c2ccc(Br)cc21
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Product: OCC(O)Cn1cc(C(O)(c2ccc3c(cnn3-c3ccc(F)cc3)c2)C(F)(F)F)c2ccc(Br)cc21
Reaction time: 2 h
Yield: 23 %

Procedure:
To a chilled (0° C.) solution of 0.3 g (0.5 mmol) 1-(1-allyl-6-bromo-1H-indol-3-yl)-2,2,2-trifluoro-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]ethanol in acetone-H2O (3:1) was added 93.2 mg (0.6 mmol) of KMnO4 in 5 mL of a 3:1 mixture of acetone-H2O dropwise. After 2 hours, the reaction was filtered and the solvent was concentrated in vacuo. The residue was diluted with water and extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered and the solvent was concentrated in vacuo. The residue was purified by HPLC (5-100% CH3CN-water buffered with TFA). The material from the column was concentrated, in vacuo to remove the acetonitrile. The aqueous layer was made basic and extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate and concentrated in vacuo to afford 60 mg (23%) of the title compound. MS m/z 579.35 (MH+).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][CH:3]=1.[CH3:9][C:10]1([CH3:44])[C:34]2[C:14]([CH:15]=[C:16]3[CH:33]=[C:32]4[C:19]([C:20]5[C:25]([C:26]6[C:31]4=[CH:30][CH:29]=[CH:28][CH:27]=6)=[CH:24][CH:23]=[CH:22][CH:21]=5)=[CH:18][C:17]3=2)=[CH:13][C:12](B2OC(C)(C)C(C)(C)O2)=[CH:11]1.C([O-])([O-])=O.[Na+].[Na+].CCO>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.CO.C1(C)C=CC=CC=1>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([C:12]2[CH:13]=[C:14]3[C:34]([C:10]([CH3:44])([CH3:9])[CH:11]=2)=[C:17]2[C:16]([CH:33]=[C:32]4[C:19](=[CH:18]2)[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:25]=2[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:31]4=2)=[CH:15]3)=[CH:3][CH:4]=1
Reactant: Brc1ccc(Br)cc1
Reactant: CC1(C)C=C(B2OC(C)(C)C(C)(C)O2)C=C2C=c3cc4c5ccccc5c5ccccc5c4cc3=C21
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: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Solvent: CCO
Product: CC1(C)C=C(c2ccc(Br)cc2)C=C2C=c3cc4c5ccccc5c5ccccc5c4cc3=C21
Temperature: 90 °C
Yield: 53 %

Procedure:
A mixture of 6.6 g (28 mmol) of 1,4-dibromobenzene, 15.1 (32 mmol) of 2-(10,10-dimethyl-10H-indeno[1,2-b]triphenylen-12-yl)-4,4,5,5-teramethyl-1,3,2-dioxaborolane, 0.32 g (0.28 mmol) of Tetrakis(triphenylphosphine)palladium, 22 ml of 2M Na2CO3, 60 ml of EtOH and 130 ml toluene was degassed and placed under nitrogen, and then heated at 90° C. for 12 h. After finishing the reaction, the mixture was allowed to cool to room temperature. Than 500 ml MeOH was added, while stirring and the precipitated product was filtered off with suction and the residue was purified by column chromatography on silica (hexane-dichloromethane) to give product 7.4 g (53%) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:27])=[C:6]([C:8]2[CH:17]=[C:16]3[C:11]([CH:12]=[C:13]([NH:18][C:19]([CH:21]4[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]4)=[O:20])[N:14]=[CH:15]3)=[CH:10][CH:9]=2)[CH:7]=1.CN(C)C=O.[CH:33](N(CC)C(C)C)(C)[CH3:34].ICC>>[CH2:33]([N:24]1[CH2:25][CH2:26][CH:21]([C:19]([NH:18][C:13]2[N:14]=[CH:15][C:16]3[C:11]([CH:12]=2)=[CH:10][CH:9]=[C:8]([C:6]2[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=2[CH3:27])[CH:17]=3)=[O:20])[CH2:22][CH2:23]1)[CH3:34]
Reactant: CCN(C(C)C)C(C)C
Reactant: Cc1ccc(F)cc1-c1ccc2cc(NC(=O)C3CCNCC3)ncc2c1
Solvent: CCI
Solvent: CN(C)C=O
Product: CCN1CCC(C(=O)Nc2cc3ccc(-c4cc(F)ccc4C)cc3cn2)CC1
Temperature: 25 °C
Reaction time: 19 h
Yield: 41.4 %

Procedure:
To a solution of N-(7-(5-fluoro-2-methylphenyl)isoquinolin-3-yl)piperidine-4-carboxamide (110.6 mg, 0.1936 mmol) in N,N-dimethylformamide (2.0 mL, 26 mmol) was added N,N-diisopropylethylamine (0.1 mL, 0.574 mmol) and iodoethane (19.0 uL, 0.238 mmol). The reaction was stirred at room temperature for 19 hours, and then N,N-diisopropylethylamine (0.1 mL) and iodoethane (30 uL, 0.375 mmol) were added. After an additional 4 hours, the mixture was evaporated in vacuo. The crude product was purified via reverse phase HPLC and lyophilized to yield 31.4 mg (41%) of 1-ethyl-N-(7-(5-fluoro-2-methylphenyl)isoquinolin-3-yl)piperidine-4-carboxamide. LCMS (ESI): RT (Min)=4.370, M+H=392.1, method=E; 1H NMR (400 MHz, DMSO-d6) δ 10.76 (s, 1H), 9.19 (s, 1H), 8.53 (s, 1H), 8.06 (s, 1H), 7.96 (d, J=8.6 Hz, 1H), 7.73 (d, J=8.5 Hz, 1H), 7.39 (s, 1H), 7.18 (d, J=8.9 Hz, 2H), 3.53 (unresolved, 2H), 3.08 (unresolved, 2H), 2.83 (unresolved, 3H), 2.25 (s, 3H), 2.07 (unresolved, 2H), 1.90 (unresolved, 2H), 1.22 (unresolved, 3H).