Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:28])[NH:10][C@H:11]1[CH2:16][CH2:15][C@H:14]([O:17][CH2:18][C:19](Br)=[CH:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1B(O)O>>[CH2:1]([O:8][C:9](=[O:28])[NH:10][C@H:11]1[CH2:16][CH2:15][C@H:14]([O:17][CH2:18][C:19]([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=2[CH3:29])=[CH:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccccc1B(O)O
Reactant: O=C(N[C@H]1CC[C@H](OCC(Br)=Cc2ccccc2)CC1)OCc1ccccc1
Product: Cc1ccccc1C(=Cc1ccccc1)CO[C@H]1CC[C@H](NC(=O)OCc2ccccc2)CC1

Procedure:
From trans-[4-(2-bromo-3-phenyl-allyloxy)-cyclohexyl]-carbamic acid benzyl ester, and 2-methylphenylboronic acid using the procedure described above for Example 11, Step 4, gave the product as a white crystalline solid: MS (m+1)=456.5; 1H NMR (400 MHz, CDCl3) 7.3 (m, 2H), 7.2 (m, 7H), 7.05 (m, 3H), 6.85 (m, 2H), 6.66 (s 1H), 5.05 (s, 2H), 4.55 (s, 1H), 4.28 (s, 2H), 3.5 (m, 1H), 3.42 (s, 3H), 3.3 (m, 1H), 2.0 (m, 4H), 1.4 (dd, 2H), 1.15 (dd, 2H).
Reaction SMILES: [O:1]([CH2:8][CH2:9][N:10]1[CH2:15][CH2:14][CH2:13][CH2:12][C@@H:11]1[C:16]([NH:18][C@H:19]([C:21]1[CH:30]=[CH:29][C:24]([C:25]([O:27]C)=[O:26])=[CH:23][CH:22]=1)[CH3:20])=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].[ClH:33]>C1COCC1.CO>[ClH:33].[O:1]([CH2:8][CH2:9][N:10]1[CH2:15][CH2:14][CH2:13][CH2:12][C@@H:11]1[C:16]([NH:18][C@H:19]([C:21]1[CH:22]=[CH:23][C:24]([C:25]([OH:27])=[O:26])=[CH:29][CH:30]=1)[CH3:20])=[O:17])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc([C@H](C)NC(=O)[C@H]2CCCCN2CCOc2ccccc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: C[C@H](NC(=O)[C@H]1CCCCN1CCOc1ccccc1)c1ccc(C(=O)O)cc1
Yield: 66.1 %

Procedure:
Dissolve methyl 4-[(1S)-1-[[(2R)-1-(2-phenoxyethyl)piperidine-2-carbonyl]amino]ethyl]benzoate (930 mg, 2.27 mmol) in THF (4.0 mL) and CH3OH (4.0 mL) at room temperature. Add NaOH (1 M aqueous solution, 4.5 mL, 4.5 mmol), then stir the resulting mixture at room temperature for three days. Concentrate the reaction mixture under reduced pressure to furnish a gummy solid. Add hydrogen chloride (4 M solution in dioxane, 2 mL, 8 mmol), and stir vigorously for 10 minutes. Remove the suspended solids by filtration, and concentrate the filtrate under reduced pressure to furnish a white solid. Triturate the solid in boiling diethyl ether (25 mL), and isolate the suspended solids by filtration to furnish the title compound (650 mg, 66% yield) as a white solid. Mass spectrum (m/z): 397 (M+H)+. 1H NMR (400 MHz, DMSO-d6): δ 12.89 (br s, 1H), 10.08 (br s, 1H), 9.41 (d, J=7.6 Hz, 1H), 7.88 (d, J=8.2 Hz, 2H), 7.47 (d, J=8.2 Hz, 2H), 7.26 (dd, J=8.4, 7.6 Hz, 2H), 6.96 (t, J=7.2 Hz, 1H), 6.90 (d, J=7.9 Hz, 2H), 5.02 (app pentet, J=7.1 Hz, 1H), 4.34-4.21 (m, 2H), 4.03 (app t, J=10.2 Hz, 1H), 3.57 (d, J=12.4 Hz, 1H), 3.48-3.39 (m, 1H), 3.37-3.18 (m, 2H), 2.15 (d, J=13.5 Hz, 1H), 1.82-1.66 (m, 4H), 1.50-1.43 (m, 1H), 1.39 (d, J=7.2 Hz, 3H).
Reaction SMILES: [CH:1]1[C:14]2[C:13](=[O:15])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[NH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Cl.Cl[CH2:20][CH2:21][N:22]([CH3:24])[CH3:23]>CN(C)C=O>[CH3:23][N:22]([CH3:24])[CH2:21][CH2:20][N:6]1[C:5]2[C:14](=[CH:1][CH:2]=[CH:3][CH:4]=2)[C:13](=[O:15])[C:12]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]1=2
Reactant: CN(C)CCCl
Reactant: O=c1c2ccccc2[nH]c2ccccc12
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)CCn1c2ccccc2c(=O)c2ccccc21
Reaction time: 0.5 h

Procedure:
A mixture of 3.9 g of acridanone, 1.0 g of sodium hydride and 80 ml of dimethylformamide is stirred for 0.5 hours, then treated with 2.9 g of 1-chloro-2-dimethylaminoethane hydrochloride, stirred at 60° for 18 hours and evaporated. The residue is extracted with methylene chloride. The extract is washed with water, dried over sodium sulfate and evaporated. By crystallization from isopropyl ether there is obtained 10-[2-(dimethylamino)ethyl]-9-acridanone of melting point 145°-146°.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][C:11]2[N:10]([C:14](=[O:17])[CH2:15][CH3:16])[CH2:9][C:8]3[CH:18]=[N:19][NH:20][C:7]=3[C:6]=2[CH:5]=1)([O-])=O>CO.[Pd]>[NH2:1][C:4]1[CH:13]=[CH:12][C:11]2[N:10]([C:14](=[O:17])[CH2:15][CH3:16])[CH2:9][C:8]3[CH:18]=[N:19][NH:20][C:7]=3[C:6]=2[CH:5]=1
Reactant: CCC(=O)N1Cc2cn[nH]c2-c2cc([N+](=O)[O-])ccc21
Agent: [Pd]
Solvent: CO
Product: CCC(=O)N1Cc2cn[nH]c2-c2cc(N)ccc21
Yield: 81.1 %

Procedure:
A solution of 4,5-dihydro-8-nitro-5-propionyl-1H -pyrazolo[4,3-c]quinoline (1.36 g) in methanol (250 ml) was hydrogenated over 5% palladium on carbon (0.4 g) under atmospheric pressure at ambient temperature. After the theoretical amount of hydrogen gas was absorbed, the catalyst was filtered off and the filtrate rated in vacuo. The residual solid was recrystallized from a mixture of methanol and chloroform to give 8-amino-4,5-dihydro-5-propionyl-1H -pyrazolo-[4,3-c]quinoline (0.981 g).
Reaction SMILES: [Cl:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH:12]1([CH2:15][CH:16]([C:19]2[CH:20]=[N:21][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:23][CH:24]=2)[CH2:17][NH2:18])[CH2:14][CH2:13]1>>[Cl:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:18][CH2:17][CH:16]([C:19]1[CH:20]=[N:21][C:22]([C:25]([F:28])([F:26])[F:27])=[CH:23][CH:24]=1)[CH2:15][CH:12]1[CH2:13][CH2:14]1)=[O:6]
Reactant: NCC(CC1CC1)c1ccc(C(F)(F)F)nc1
Reactant: O=C(O)c1cccc(F)c1Cl
Product: O=C(NCC(CC1CC1)c1ccc(C(F)(F)F)nc1)c1cccc(F)c1Cl

Procedure:
From 2-chloro-3-fluorobenzoic acid and 3-cyclopropyl-2-(6-(trifluoromethyl)pyridin-3-yl)propan-1-amine. LCMS (MH+): m/z=401.1, tR (minutes, Method G)=2.51
Reaction SMILES: Br[C:2]1[C:3]([NH2:8])=[N:4][CH:5]=[CH:6][CH:7]=1.[F:9][C:10]1[CH:11]=[C:12]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:13]=[CH:14][C:15]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].O>COCCOC.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>[F:9][C:10]1[CH:11]=[C:12]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:13]=[CH:14][C:15]=1[C:2]1[C:3]([NH2:8])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ncccc1Br
Reactant: OB(O)c1ccc(-c2ccccc2)cc1F
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: COCCOC
Solvent: O
Product: Nc1ncccc1-c1ccc(-c2ccccc2)cc1F
Temperature: 80 °C
Reaction time: 4 h
Yield: 100 %

Procedure:
To a solution of 3-bromopyridin-2-amine (1.0 g) in 1,2-dimethoxyethane (50 mL) were added 3-fluorobiphenyl-4-ylboronic acid (1.623 g), sodium carbonate (1.225 g), tetrakis(triphenylphosphine)palladium(0) (0.334 g), and water (10 mL) at room temperature. The reaction mixture was stirred under a nitrogen atmosphere at 80° C. for 4 hr, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by recrystallization (THF/diisopropyl ether) to give the title compound (1.528 g).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:14][CH2:13][CH2:12][NH:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N+:15]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:24](=[O:44])[CH2:25][N:26]1[C:35](=[O:36])[C:34]2[N:33]([CH2:37][CH:38]=[C:39]([CH3:41])[CH3:40])[C:32](Cl)=[N:31][C:30]=2[N:29]([CH3:43])[C:27]1=[O:28])([O-:17])=[O:16].C(=O)([O-])[O-].[Na+].[Na+].O>CS(C)=O>[N+:15]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:24](=[O:44])[CH2:25][N:26]1[C:35](=[O:36])[C:34]2[N:33]([CH2:37][CH:38]=[C:39]([CH3:40])[CH3:41])[C:32]([N:11]3[CH2:12][CH2:13][CH2:14][CH:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:10]3)=[N:31][C:30]=2[N:29]([CH3:43])[C:27]1=[O:28])([O-:17])=[O:16]
Reactant: CC(C)=CCn1c(Cl)nc2c1c(=O)n(CC(=O)c1ccccc1[N+](=O)[O-])c(=O)n2C
Reactant: CC(C)(C)OC(=O)NC1CCCNC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)=CCn1c(N2CCCC(NC(=O)OC(C)(C)C)C2)nc2c1c(=O)n(CC(=O)c1ccccc1[N+](=O)[O-])c(=O)n2C
Temperature: 65 °C
Reaction time: 16 h

Procedure:
2.20 g of 3-tert-butyloxycarbonylaminopiperidine is added at 65° C. to 4.40 g of 1-[2-(2-nitrophenyl)-2-oxoethyl]-3-methyl-7-(3-methyl-2-buten-1-yl)-8-chloroxanthine and 1.30 g of sodium carbonate in 50 mL of dimethylsulfoxide. The reaction mixture is stirred for approximately 16 hours at 65° C. After cooling to ambient temperature, it is poured onto a mixture of 600 mL of water and 100 g of ice. The precipitate formed is suction filtered and washed with water. The filter cake is dissolved in diethyl ether, and the solution is dried and evaporated down. The brown resinous flask residue is brought to crystallization with diisopropylether. Yield: 3.30 g (54% of theory); Rf value: 0.52 (silica gel, cyclohexane/ethyl acetate (3:7)); mass spectrum (ESI+): m/z=596 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](=[O:11])[CH3:10])=[CH:4][CH:3]=1.[OH:12][C:13]1[CH:14]=[C:15]([CH:18]=[C:19]([N+:22]([O-:24])=[O:23])[C:20]=1[OH:21])[CH:16]=O>>[OH:12][C:13]1[CH:14]=[C:15]([CH:16]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=2)[C:9](=[O:11])[CH3:10])[CH:18]=[C:19]([N+:22]([O-:24])=[O:23])[C:20]=1[OH:21]
Reactant: CC(=O)Cc1ccc(C)cc1
Reactant: O=Cc1cc(O)c(O)c([N+](=O)[O-])c1
Product: CC(=O)C(=Cc1cc(O)c(O)c([N+](=O)[O-])c1)c1ccc(C)cc1

Procedure:
The procedure described in Example 1 was repeated by using 0.81 g of 3-(4-methylphenyl)-2-propanone and 0.92 g of 3,4-dihydroxy-5-nitrobenzaldehyde. Yield 0.82 g, mp 189°-194° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]([CH2:13][CH3:14])[CH2:11][CH3:12])=[O:9])=[CH:4][C:3]=1[NH:15][C:16](=O)[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH3:26])=[CH:20][CH:19]=1.C(O[C:33]([N:35]1[CH2:41][CH2:40][CH2:39][C@@H:36]1[CH:37]=O)=O)(C)(C)C.C([BH3-])#N.[Na+].C(O)(C(F)(F)F)=O>>[CH2:25]([O:24][C:21]1[CH:22]=[CH:23][C:18]([CH2:17][C:16]2[N:1]([CH2:37][C@H:36]3[CH2:39][CH2:40][CH2:41][N:35]3[CH3:33])[C:2]3[CH:7]=[CH:6][C:5]([C:8]([N:10]([CH2:13][CH3:14])[CH2:11][CH3:12])=[O:9])=[CH:4][C:3]=3[N:15]=2)=[CH:19][CH:20]=1)[CH3:26]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1C=O
Reactant: CCOc1ccc(CC(=O)Nc2cc(C(=O)N(CC)CC)ccc2N)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: CCOc1ccc(Cc2nc3cc(C(=O)N(CC)CC)ccc3n2C[C@H]2CCCN2C)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 36 %

Procedure:
N-[2-Amino-5-[(diethylamino)carbonyl]phenyl]-4-ethoxy-benzeneacetamide (85 mg, 0.230 mmol) and N-(tert-butoxycarbonyl)-D-prolinal (0.06 mL, 1.5 eq) were coupled and cyclized following the procedure in example 40E. The solvent was then concentrated. The residue was dissolved in MeOH and 37% formaldehyde in water (formalin) (few drops, excess) was added, followed by sodium cyanoborohydride (43 mg, 3 eq). The solution was then stirred at rt for 1 h. The crude product was directly purified by reversed-phase chromatography (C-18 column) using a gradient of 15–65% CH3CN/H2O and then lyophilized affording the title compound (46 mg, 36% yield) as the corresponding TFA salt; 1H NMR (400 MHz, CD3OD) δ 7.80 (d, J=8.8 Hz, 1H), 7.69 (s, 1H), 7.48 (d, J=8.4 Hz, 1H), 7.22 (d, J=8.8 Hz, 2H), 6.92 (d, J=8.4 Hz, 2H), 4.85 (m, 1H), 4.66 (m, 1H), 4.49 (s, 2H), 4.01 (q, J=7.2 Hz, 2H), 3.78 (br s, 2H), 3.56 (br s, 2H), 3.27 (br s, 3H), 2.95 (s, 3H), 2.02 (m, 3H), 1.85 (m, 1H), 1.35 (t, J=7.2 Hz, 3H), 1.25 (br s, 3H), 1.11 (br s, 3H); MS (ESI) (M+H)+=449.45; Anal. Calcd for C27H36N4O2+2.4 TFA+1.1H2O: C, 51.47; H, 5.51; N, 7.55. Found: C, 51.46; H, 5.43; N, 7.67.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2([CH2:20][C:21](O)=[O:22])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[O:18][CH3:19].[N:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[O:18][CH3:19])[CH2:20][C:21](=[O:22])[N:33]1[CH2:34][CH2:35][N:30]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][N:24]=2)[CH2:31][CH2:32]1
Reactant: c1ccc(N2CCNCC2)nc1
Reactant: COc1ccccc1C1(CC(=O)O)C(=O)Nc2ccc(Cl)cc21
Product: COc1ccccc1C1(CC(=O)N2CCN(c3ccccn3)CC2)C(=O)Nc2ccc(Cl)cc21
Yield: 86.9 %

Procedure:
With 800 mg of [5-chloro-3-(2-methoxyphenyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]acetic acid, which is the compound described in Preparation 1.1 of the brochure Publication No. WO03/008407, and 433 mg of 1-pyridin-2-ylpiperazine as starting materials, 1.00 g of the title compound (colorless solid) was obtained by a similar method to Step 45-1.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:19]=[CH:20][C:21]=1Cl)[C:7]([C:9]1[CH:14]=[CH:13][C:12](Cl)=[C:11]([N+:16]([O-])=O)[CH:10]=1)=[O:8])([O-])=O.[H][H].[OH-].[Na+]>[Pd].O1CCOCC1>[NH2:1][C:4]1[CH:5]=[C:6]([CH:19]=[CH:20][CH:21]=1)[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH2:16])[CH:10]=1)=[O:8]
Reactant: O=C(c1ccc(Cl)c([N+](=O)[O-])c1)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: [H][H]
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: Nc1cccc(C(=O)c2cccc(N)c2)c1

Procedure:
To a closed glass vessel equipped with a thermometer and a stirrer, there are added 102 g (0.3 moles) of 3,3'-dinitro-4,4'-dichloro benzophenone, 5 g of 5% palladium/active carbon catalyst (available from Nihon Engelhardt Co.) and 300 ml of dioxane. While the mixture is being stirred at 70°-80° C., hydrogen is introduced in the vessel so that 41.5 l (1.85 moles) of hydrogen is absorbed into the mixture over 8 hours. After addition of 80 g (0.8 moles) of 40% aqueous sodium hydroxide, hydrogen is again introduced to the vessel with the mixture being stirred at 70°-80° C., so that it is absorbed 13.8 l (0.62 moles) over 3 hours. The reaction solution is filtered at 70°-80° C. to remove the catalyst. On cooling the solution, there is obtained 3,3'-diamino benzophenone, as yellow needle-like crystals. The crystals are filtered, washed with 30 ml of 50% aqueous solution of dioxane and dried. Yield 59.2 g (93%). M.P. 149°-151° C.
Reaction SMILES: [C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[C:8]([C:18]2[S:19][CH:20]=[C:21]([CH2:23][OH:24])[N:22]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].O>CS(C)=O>[C:1]([N:5]1[C:9]([C:10]2[CH:11]=[CH:12][C:13]([O:16][CH3:17])=[CH:14][CH:15]=2)=[C:8]([C:18]2[S:19][CH:20]=[C:21]([CH:23]=[O:24])[N:22]=2)[CH:7]=[N:6]1)([CH3:3])([CH3:4])[CH3:2]
Reactant: COc1ccc(-c2c(-c3nc(CO)cs3)cnn2C(C)(C)C)cc1
Solvent: CS(C)=O
Solvent: O
Product: COc1ccc(-c2c(-c3nc(C=O)cs3)cnn2C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 92.2 %

Procedure:
To a solution of the compound (663 mg, 1.93 mmol) obtained in step 2 and TEA (0.807 mL, 5.79 mmol) in DMSO (14 mL) was added a sulfur trioxide-pyridine complex (922 mg, 5.79 mmol) at room temperature, and the mixture was stirred at room temperature for 14 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent; ethyl acetate) to give 2-(1-(tert-butyl)-5-(4-methoxyphenyl)-1H-pyrazol-4-yl)thiazole-4-carbaldehyde (607.5 mg, 1.779 mmol, 92%) as a white powder.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=[C:11]2[C:19](OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:20][CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:37][O:38][C:39]1[CH:44]=[CH:43][C:42](B(O)O)=[CH:41][N:40]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=[C:11]2[C:19]([C:42]2[CH:41]=[N:40][C:39]([O:38][CH3:37])=[CH:44][CH:43]=2)=[CH:20][CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COc1ccc(B(O)O)cn1
Reactant: Cc1ccc(S(=O)(=O)OC(=CC2CCCC2)c2cc3cccnc3n2S(=O)(=O)c2ccccc2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COc1ccc(C(=CC2CCCC2)c2cc3cccnc3n2S(=O)(=O)c2ccccc2)cn1
Yield: 85.5 %

Procedure:
To a mixture of toluene-4-sulfonic acid-1-(1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-cyclopentyl-vinyl ester (prepared as in Example 43, 0.15 g, 0.28 mmol), 2-methoxy-5-pyridineboronic acid (110 mg, 0.72 mmol) and dichlorobis(triphenylphosphine)palladium (II) (21 mg, 0.03 mmol) in dioxane (3 mL) was added an aqueous sodium carbonate solution (2 M, 0.36 mL). The resulting mixture was subjected to microwave irradiation for 2 h at 100° C. The mixture was diluted with ethyl acetate (100 mL), washed with a saturated aqueous sodium bicarbonate solution (2×30 mL), brine, dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by flash silica gel chromatography (silica gel from QingDao, 200-300 mesh, glass column from Shanghai SD company, 30% ethyl acetate/hexanes) afforded 1-benzenesulfonyl-2-[2-cyclopentyl-1-(6-methoxy-pyridin-3-yl)-vinyl]-1H-pyrrolo[2,3-b]pyridine (110 mg, 83%) as a white solid: LC/MS m/e calcd for C26H25N3O3S [M+H]+ 460.57, observed 460.0.
Reaction SMILES: [CH:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[Li]>O1CCCC1.C(N)CN>[CH2:10]1[C:11]2[CH2:12][C:13]3[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=3)[C:6]=2[CH2:7][CH2:8][CH2:9]1
Reactant: c1ccc2c(c1)Cc1ccccc1-2
Agent: [Li]
Solvent: C1CCOC1
Solvent: NCCN
Product: c1ccc2c(c1)CC1=C2CCCC1
Temperature: 0 °C
Yield: 93.3 %

Procedure:
Fluorene (100 g, 0.6 mole) was dissolved in a mixture of 600 ml tetrahydrofuran (THF) and 600 ml ethylenediamine (1:1 by volume). The fluorene solution was degassed with nitrogen and cooled to 0° C. 4.25 equivalents of lithium metal (17.7 g, 2.55 mole) were added in 2 g portions every 10 minutes and the reaction temperature was maintained at 10° C. The reaction mixture was warmed to room temperature. The reaction mixture was then quenched with degassed water; the separated organic phase was extracted with a mixture of aqueous NaCl (300 ml) and cyclohexane (500 ml). The organic phase was washed with aqueous NaCl (300 ml), the water phase was removed, and the cyclohexane was stripped from the solution leaving 95 g (0.56 moles) of tetrahydrofluorene (93% yield). 9-trimethylsilyl-1,2,3,4-tetrahydro-9H-fluorene. 1,2,3,4-tetrahydro-9H-fluorene (50 grams (g), 0.294 mol) was dissolved in 1 liter (L) of anhydrous THF and cooled to -78 ° C. To this solution 123 ml (0.307 mol) of n-BuLi (2.5M solution in hexane) was added via syringe within 25 minutes (min). The reaction mixture was stirred for few minutes at -78° C. until the lithium salt precipitated from the solution. After precipitation, the cold bath was removed and the reaction mixture was and stirred for 2 hours (hr) at room temperature. The flask was cooled to -78° C. and 40 ml (34.24 g, 0.315 mol) of trimethylsilyl chloride (TMSCI) was added through syringe within 1 hr. After addition was completed the reaction mixture was stirred for 3 hr at -78 ° C. and then it was slowly warmed up to room temperature and stirred overnight. THF solvent was removed in vacuum and the residue was extracted with 150 ml of hexane. The hexane solution was filtered to another flask and hexane was removed leaving 70.39 g of 9-trimethylsilyl-1,2,3,4-tetrahydro-9H-fluorene (about 95% pure). Yield 99%.
Reaction SMILES: [CH2:1]1[CH2:13][O:12][C:11]2[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][NH2:8])=[CH:4][C:3]=2[O:2]1.Cl[C:15]1[C:16]2[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[S:27][C:17]=2[N:18]=[C:19]([C:21]2[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=2)[N:20]=1>>[N:24]1[CH:25]=[CH:26][C:21]([C:19]2[N:20]=[C:15]([NH:8][CH2:7][CH2:6][C:5]3[CH:9]=[CH:10][C:11]4[O:12][CH2:13][CH2:1][O:2][C:3]=4[CH:4]=3)[C:16]3[CH:29]=[C:28]([C:30]([F:32])([F:31])[F:33])[S:27][C:17]=3[N:18]=2)=[CH:22][CH:23]=1
Reactant: FC(F)(F)c1cc2c(Cl)nc(-c3ccncc3)nc2s1
Reactant: NCCc1ccc2c(c1)OCCO2
Product: FC(F)(F)c1cc2c(NCCc3ccc4c(c3)OCCO4)nc(-c3ccncc3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of 3,4-ethylenedioxyphenethylamine with 4-chloro-2-(pyridin-4-yl)-6-trifluoromethyl-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-4-yl)-4-(3,4-ethylenedioxyphenethylamino)-6-trifluoromethyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [P:1](Cl)([O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[O:14][CH3:15])([O:3][CH2:4][CH:5]=[CH2:6])=[O:2].[F:17][C:18]([F:31])([F:30])[C:19]1[CH:27]=[CH:26][C:25]([OH:28])=[C:24]2[C:20]=1[CH2:21][CH2:22][C:23]2=[O:29].C(N(CC)CC)C>C1(C)C=CC=CC=1>[P:1]([O:28][C:25]1[CH:26]=[CH:27][C:19]([C:18]([F:17])([F:30])[F:31])=[C:20]2[C:24]=1[C:23](=[O:29])[CH2:22][CH2:21]2)([O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[O:14][CH3:15])([O:3][CH2:4][CH:5]=[CH2:6])=[O:2]
Reactant: O=C1CCc2c(C(F)(F)F)ccc(O)c21
Reactant: C=CCOP(=O)(Cl)Oc1ccccc1OC
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: C=CCOP(=O)(Oc1ccccc1OC)Oc1ccc(C(F)(F)F)c2c1C(=O)CC2
Temperature: 0 °C
Reaction time: 8 h

Procedure:
O-Allyl O-(2-methoxyphenyl) chlorophosphate (0.015 mole) dissolved in dry toluene (80) is charged into a glass reaction vessel equipped with a stirrer, thermometer and gas inlet tube. The solution is cooled to about 0° C. and a solution of 4-trifluoromethyl-7-hydroxyindan-1-one (0.015 mole) and triethylamine (0.0175 mole) in toluene (20 ml) is slowly added with stirring. After the addition is completed the reaction mixture is allowed to warm to room temperature and stirring is continued for a period of about 8 hours. After this time the reaction mixture is filtered and the filtrate is washed with water. The washed solution is then dried and is stripped of solvent leaving a residue. This residue is chromatographed through a 200 ml clay column using ethyl acetate and hexane mixtures as the eluant. Ten separate fractions each containing increasing percentages of ethyl acetate are collected and analyzed by IR for the product. The appropriate fractions are then combined stripped of solvent and subjected to vacuum to yield the desired product O-allyl O-(2-methoxyphenyl) O-(4-trifluoromethylindan-1-on-7-yl) phosphate.
Reaction SMILES: C[CH:2]([CH:6]1[C:10]2=[C:11]([S:25][C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)[C:12]3[C:13](Br)=[CH:14][C:15]([C:18]4[N:19]=[N:20][N:21]([CH3:23])[N:22]=4)=[CH:16][C:17]=3[N:9]2[CH2:8][CH2:7]1)[C:3]([O-:5])=[O:4].[CH3:33][N:34]1[CH:38]=[CH:37][CH:36]=[C:35]1[Sn](CCCC)(CCCC)CCCC>>[Cl:32][C:29]1[CH:30]=[CH:31][C:26]([S:25][C:11]2[C:12]3[C:13]([C:35]4[N:34]([CH3:33])[CH:38]=[CH:37][CH:36]=4)=[CH:14][C:15]([C:18]4[N:19]=[N:20][N:21]([CH3:23])[N:22]=4)=[CH:16][C:17]=3[N:9]3[CH2:8][CH2:7][CH:6]([CH2:2][C:3]([OH:5])=[O:4])[C:10]=23)=[CH:27][CH:28]=1
Reactant: CC(C(=O)[O-])C1CCn2c1c(Sc1ccc(Cl)cc1)c1c(Br)cc(-c3nnn(C)n3)cc12
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccn1C
Product: Cn1nnc(-c2cc(-c3cccn3C)c3c(Sc4ccc(Cl)cc4)c4n(c3c2)CCC4CC(=O)O)n1

Procedure:
Starting from (+/−)-methyl[8-bromo-9-[(4-chlorophenyl)thio]-6-(2-methyl-2H-tetrazol-5-yl)-2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-yl]acetate (see Example 32) and 1-methyl-2-(tributylstannyl)-1H-pyrrole, the title compound was synthesized following the procedures described in Example 42 and Step 10 of Example 7.