Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[C:4]([O:11][CH3:12])[CH:3]=1.[S:13]1[CH:17]=[CH:16][CH:15]=[C:14]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>[CH3:12][O:11][C:4]1[CH:3]=[C:2]([C:14]2[S:13][CH:17]=[CH:16][CH:15]=2)[CH:7]=[CH:6][C:5]=1[C:8](=[O:10])[CH3:9]
Reactant: COc1cc(I)ccc1C(C)=O
Reactant: OB(O)c1cccs1
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: O
Solvent: COCCOC
Product: COc1cc(-c2cccs2)ccc1C(C)=O
Temperature: 25 °C
Yield: 97.1 %

Procedure:
Ex-57a: 4′-iodo-2′-methoxyacetophenone (1.08 g, 3.9 mmol) in ethylene glycol dimethyl ether (50 ml) was degassed for 15 minutes. Tetrakis(triphenylphosphine)palladium(0) (0.456 g, 0.39 mmol), thiophene-2-boronic acid (0.75 g, 5.9 mmol), and sodium carbonate solution (2 m, 4 ml, 8 mmol) were added. The mixture was stirred at reflux under nitrogen for 24 hours. Upon cooling to room temperature, it was poured into water and extracted with dichloromethane. The organic phase was dried over sodium sulfate and evaporated. Silica gel chromatography (hexane/ethyl acetate, 3:1) gave 0.88 g (98%) of the desired 2′-methoxy-4′-(thien-2-yl)acetophenone.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]1)=O)CCC.[Br:15]Br>C(Cl)(Cl)Cl>[BrH:15].[Br:15][CH:10]1[C:11](=[O:14])[CH2:12][CH2:13][NH:8][CH2:9]1
Reactant: BrBr
Reactant: CCCCOC(=O)N1CCC(=O)CC1
Solvent: ClC(Cl)Cl
Product: Br
Product: O=C1CCNCC1Br
Reaction time: 2 h
Yield: 163.8 %

Procedure:
About 2.6 g of N-butoxycarbonyl-4-piperdone (FIG. 10b) was dissolved in about 70 ml of chloroform; to this solution was added about 2.08 g Br2 over a period of about 30 minutes. The reaction was continued for about 2 hours at room temperature during which a white precipitate of the compound of FIG. 10c was formed. The reaction mixture was filtered and washed with chloroform ether to yield about 2.76 g of the compound of FIG. 10c.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]=[C:10]=[O:11].[CH3:12][CH:13]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH:21]([CH3:23])[CH3:22])[C:16]=1[NH:24][C:25](=[O:41])[CH2:26][NH:27][CH:28]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH3:14].CC(C1C=CC=C(C(C)C)C=1NC(=O)CNCC(C1C=CC=CC=1)C1C=CC=CC=1)C>>[CH3:14][CH:13]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH:21]([CH3:22])[CH3:23])[C:16]=1[NH:24][C:25](=[O:41])[CH2:26][N:27]([CH:28]([C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[C:10]([NH:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[O:2][CH3:1])=[O:11])[CH3:12]
Reactant: COc1ccccc1N=C=O
Reactant: CC(C)c1cccc(C(C)C)c1NC(=O)CNC(c1ccccc1)c1ccccc1
Agent: CC(C)c1cccc(C(C)C)c1NC(=O)CNCC(c1ccccc1)c1ccccc1
Product: COc1ccccc1NC(=O)N(CC(=O)Nc1c(C(C)C)cccc1C(C)C)C(c1ccccc1)c1ccccc1

Procedure:
When in the procedure of Example 80 an appropriate amount of 2-methoxyphenylisocyanate was substituted for ethyl isocyanato acetate and an appropriate amount of the product of Example 4 was substituted for the product of Example 70 and the general procedure of Example 80 was followed the title compound was obtained. Total yield, 1.56 g (76%).
Reaction SMILES: B(F)(F)[F:2].CCOCC.[Cl:10][C:11]12O[CH:16]1[CH2:15][CH2:14][C:13]([Cl:19])([F:18])[CH2:12]2.[OH2:20]>ClCCCl>[Cl:10][C:11]1([F:2])[CH2:16][CH2:15][CH2:14][C:13]([Cl:19])([F:18])[CH:12]1[OH:20]
Reactant: FB(F)F
Reactant: FC1(Cl)CCC2OC2(Cl)C1
Reactant: O
Solvent: CCOCC
Solvent: ClCCCl
Product: OC1C(F)(Cl)CCCC1(F)Cl

Procedure:
0.47 cm3 (0.55 eq.) of BF3.Et2O were added to 1.89 g (7.03 mmol) of epoxide 2e in solution in 20 cm3 of 1,2-dichloroethane. The reaction mixture was heated to reflux under argon atmosphere for 1 h 45 min and then hydrolyzed hot with 30 cm3 of distilled water (stirring was continued for 10 min). It was extracted with dichloromethane (4×15 cm3) and then dried over MgSO4, filtered and evaporated down. 1.43 g of alcohol 1g were obtained, the macrobore GC purity of which was higher than 97%. The yield of alcohol 1g was 98%.
Reaction SMILES: [C:1]([OH:5])(=[O:4])[CH2:2][OH:3].[C:6](Cl)(=[O:15])[CH:7]=[CH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.Cl>N1C=CC=CC=1.C(=O)(O)[O-].[Na+]>[C:6]([O:3][CH2:2][C:1]([OH:5])=[O:4])(=[O:15])[CH:7]=[CH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C(O)CO
Reactant: O=C(Cl)C=Cc1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: O=C(O)COC(=O)C=Cc1ccccc1
Yield: 25.2 %

Procedure:
To a solution of glycolic acid (15.2 g.) in pyridine (100ml.) was added cinnamoyl chloride (33.4 g.) with stirring under cooling. The reaction mixture was stirred at room temperature for 5 hours and concentrated under reduced pressure at 50° to 60° C. The residue was adjusted to pH 1 with concentrated hydrochloric acid and extracted with ether. The extract was washed with water and a sodium chloride aqueous solution, in turn and concentrated under reduced pressure to give colorless crystals (45 g.). These crystals were dissolved in a sodium bicarbonate aqueous solution and adjusted to pH 3 to 3.5 with aqueous hydrochloric acid and extracted with ether. The extract was treated with a conventional manner to give crude product (16.5 g.). The product was recrystallized from benzene to give a product of 2-cinnamoyloxyacetic acid (10.4 g.), m.p. 116° to 121° C.
Reaction SMILES: [O:1]=[C:2]1[N:14]([CH:15]2[CH2:20][CH2:19][N:18]([C:21]([O:23][C@@H:24]([C:42]([OH:44])=[O:43])[CH2:25][C:26]3[CH:31]=[C:30]([CH3:32])[C:29]([O:33]CC4C=CC=CC=4)=[C:28]([CH3:41])[CH:27]=3)=[O:22])[CH2:17][CH2:16]2)[C:5]2[CH:6]=[N:7][C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[C:4]=2[NH:3]1.[H][H]>C1COCC1.CO.[Pd]>[O:1]=[C:2]1[N:14]([CH:15]2[CH2:16][CH2:17][N:18]([C:21]([O:23][C@@H:24]([C:42]([OH:44])=[O:43])[CH2:25][C:26]3[CH:27]=[C:28]([CH3:41])[C:29]([OH:33])=[C:30]([CH3:32])[CH:31]=3)=[O:22])[CH2:19][CH2:20]2)[C:5]2[CH:6]=[N:7][C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[C:4]=2[NH:3]1
Reactant: [H][H]
Reactant: Cc1cc(C[C@@H](OC(=O)N2CCC(n3c(=O)[nH]c4c5ccccc5ncc43)CC2)C(=O)O)cc(C)c1OCc1ccccc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc(C[C@@H](OC(=O)N2CCC(n3c(=O)[nH]c4c5ccccc5ncc43)CC2)C(=O)O)cc(C)c1O

Procedure:
A suspension of 1.80 g (3.03 mmol) (R)-1-carboxy-2-(4-benzyloxy-3,5-dimethyl-phenyl)-ethyl 4-(2-oxo-1,2-dihydro-imidazo[4,5-c]quinolin-3-yl)-piperidine-1-carboxylate and 300 mg 10% Pd/C in 30 mL THF and 30 mL MeOH was hydrogenated at 3000 hPa hydrogen pressure and RT for 48 h. The catalyst was suction filtered, the filtrate was evaporated down and the residue was purified by HPLC; the fractions containing the product were combined and lyophilised.
Reaction SMILES: [CH2:1]([Sn:5](Cl)([CH2:10][CH2:11][CH2:12][CH3:13])[CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][CH2:3][CH3:4].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C1COCC1.[CH3:30][O:31][C:32]([CH:34]=[CH:35][C:36]1[N:37]=[CH:38][N:39]2[CH:43]=[CH:42][S:41][C:40]=12)=[O:33].O>C1COCC1>[CH3:30][O:31][C:32]([CH:34]=[CH:35][C:36]1[N:37]=[CH:38][N:39]2[CH:43]=[C:42]([Sn:5]([CH2:10][CH2:11][CH2:12][CH3:13])([CH2:6][CH2:7][CH2:8][CH3:9])[CH2:1][CH2:2][CH2:3][CH3:4])[S:41][C:40]=12)=[O:33]
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: COC(=O)C=Cc1ncn2ccsc12
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1cn2cnc(C=CC(=O)OC)c2s1
Reaction time: 0.25 h

Procedure:
Tri-n-butylstannyl chloride (250 μl) and 2.1 ml of a 1.0 N lithiumbis(trimethylsilyl)amide/THF solution were added in that order to a solution of 7-(2-methoxycarbonylvinyl)imidazo[5,1-b]thiazole (a mixture of geometrical isomers) in dry THF in an argon atmosphere at −78° C. The mixture was stirred at the same temperature for 15 min. Water was added thereto. The mixture was extracted with ethyl acetate, followed by washing with saturated brine. The extract was dried over anhydrous magnesium sulfate and then filtered. The solvent was removed by distillation under the reduced pressure. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=4:1) to give 408 mg of the title compound.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH2:13]([C:17]1[N:18]=[C:19]([CH3:45])[N:20]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:21](=[O:38])[C:22]=1[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[C:31]([C:36]#[N:37])=[CH:32][CH:33]=[CH:34][CH:35]=2)=[CH:26][CH:25]=1)[CH2:14][CH2:15][CH3:16]>O.C(OCC)(=O)C>[CH2:13]([C:17]1[N:18]=[C:19]([CH3:45])[N:20]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:21](=[O:38])[C:22]=1[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:36]2[NH:3][C:4](=[O:7])[O:5][N:37]=2)=[CH:26][CH:25]=1)[CH2:14][CH2:15][CH3:16]
Reactant: O=C([O-])O
Reactant: [NH3+]O
Reactant: CCCCc1nc(C)n(-c2ccccc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CS(C)=O
Product: CCCCc1nc(C)n(-c2ccccc2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 40.9 %

Procedure:
A mixture of hydroxylammonium chloride (0.36 g), sodium hydrogen carbonate (0.55 g) and dimethyl sulfoxide (5 mL) was stirred at 40° C. for 30 min, 4′-[(4-butyl-2-methyl-6-oxo-1-phenyl-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (0.28 g) was added, and the mixture was stirred at 90° C. for 18 hr. The reaction mixture was allowed to cool to room temperature, ethyl acetate and water were added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was dissolved in tetrahydrofuran (5 mL), N,N′-carbonyldiimidazole (0.11 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.104 mL) were added, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.13 g, 41%).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([S:14]([NH2:17])(=[O:16])=[O:15])=[CH:10][C:9]=1[OH:18])=[O:7])([CH3:4])([CH3:3])[CH3:2].[O:19]([C:26]([NH:28][C:29]1[C:30](=[CH:35][CH:36]=[CH:37][CH:38]=1)[C:31]([O:33][CH3:34])=[O:32])=O)C1C=CC=CC=1>>[C:1]([O:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([S:14]([NH:17][C:26]([NH:28][C:29]2[CH:38]=[CH:37][CH:36]=[CH:35][C:30]=2[C:31]([O:33][CH3:34])=[O:32])=[O:19])(=[O:16])=[O:15])=[CH:10][C:9]=1[OH:18])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)c1ccc(S(N)(=O)=O)cc1O
Reactant: COC(=O)c1ccccc1NC(=O)Oc1ccccc1
Product: COC(=O)c1ccccc1NC(=O)NS(=O)(=O)c1ccc(C(=O)OC(C)(C)C)c(O)c1
Yield: 77.8 %

Procedure:
618 mg (2.26 mmol) of 4-t-butoxycarbonyl-3-hydroxybenzenesulfonamide and 613 mg (2.26 mmol) of methyl 2-N-phenoxycarbonylanthranilate were treated in the same way as in Preparation Example 17 to obtain 792 mg (yield 78%) of methyl 2-{[(4-t-butoxycarbonyl-3-hydroxybenzene-sulfonylamino)carbonyl]amino}benzoate. Properties: colorless amorphous, PMR (δ ppm, CDCl3): 1.60 (9H, s), 3.97 (3H, s), 7.09 (1H, t), 7.49-7.52 (2H, m), 7.65 (1H, d), 7.90 (1H, d), 8.01 (1H, dd), 8.33 (1H, d), 10.98 (1H, s), 11.18 (1H, s).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:11]=[C:10]2[C:6]([N:7]=[CH:8][N:9]2[C@H:12]2[C@@H:16]3[O:17]C(C)(C)[O:19][C@@H:15]3[C@@H:14]([C:22]([NH:24][CH2:25][CH3:26])=[O:23])[O:13]2)=[C:5]([NH:27][CH2:28][CH:29]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[N:4]=1.C(N(CC)CC)C.[C:49]1([S:55](Cl)(=[O:57])=[O:56])[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1>ClCCl>[C:36]1([CH:29]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:28][NH:27][C:5]2[N:4]=[C:3]([CH2:2][NH:1][S:55]([C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=3)(=[O:57])=[O:56])[N:11]=[C:10]3[C:6]=2[N:7]=[CH:8][N:9]3[C@@H:12]2[O:13][C@H:14]([C:22]([NH:24][CH2:25][CH3:26])=[O:23])[C@@H:15]([OH:19])[C@H:16]2[OH:17])[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CN)nc32)[C@@H]2OC(C)(C)O[C@@H]21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(CNS(=O)(=O)c4ccccc4)nc32)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 18 h
Yield: 51.7 %

Procedure:
A solution of (3aS,4S,6R,6aR)-6-{2-(aminomethyl)-6-[(2,2-diphenylethyl)amino]-9H-purin-9-yl}-N-ethyl-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxole-4-carboxamide (Preparation 10) (140 mg, 0.25 mmol) and triethylamine (0.05 ml, 0.36 mmol) in anhydrous dichloromethane (1 ml) was treated with a solution of benzenesulphonyl chloride (50 mg, 0.28 mmol) in anhydrous dichloromethane (1 ml). The mixture was stirred at room temperature for 18 hours during which time the solvent was allowed to evaporate off freely. The residue was dissolved in ethanol (1 ml), treated with hydrochloric acid (1M, 1 ml) and heated at 60° C. for 8 hours. The solvent was removed under reduced pressure and the residue was azeotroped with ethanol (×2). The residue was then purified by column chromatography on silica gel eluting with a gradient system of dichloromethane:methanol (95:5 by volume) gradually changing to dichloromethane:methanol (90:10 by volume) to give a solid which was triturated with diethyl ether/pentane, filtered and dried to afford the title compound as a solid (85 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1.ClC(Cl)(O[C:27](=[O:33])OC(Cl)(Cl)Cl)Cl.[F:35][C:36]1[CH:42]=[C:41]([F:43])[CH:40]=[C:39]([F:44])[C:37]=1[NH2:38].C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1.C(N(CC)CC)C>[F:35][C:36]1[CH:42]=[C:41]([F:43])[CH:40]=[C:39]([F:44])[C:37]=1[NH:38][C:27]([NH:22][C:19]1[CH:18]=[CH:17][C:16]([O:15][C:6]2[C:5]3[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=3)[N:9]=[CH:8][CH:7]=2)=[CH:21][CH:20]=1)=[O:33]
Reactant: Nc1c(F)cc(F)cc1F
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=O)Nc4c(F)cc(F)cc4F)cc3)c2cc1OC
Yield: 47 %

Procedure:
6,7-Dimethoxy-4-(4-aminophenoxy)quinoline (50 mg) was dissolved in toluene (5 ml) with heat, after the addition of triethylamine (1 ml), triphosgene (55 mg) was added, and the admixture was refluxed with heat for 3 minutes. 2,4,6-Trifluoroaniline. (75 mg) was added to the reaction mixture, and the admixture was refluxed with heat for 20 minutes. After the addition of aqueous sodium hydrogen carbonate, the reaction mixture was extracted 2 times with ethyl acetate, and the organic layer was then washed with brine and dried with anhydrous sodium sulfate. The solvent was removed by reduced-pressure distillation, and the resulting residue was purified by column chromatography on silica gel eluting with chloroform/acetone (10/1) to obtain 37 mg of the title compound (yield: 47%).
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH:15]([CH2:18][CH3:19])[CH2:16]O)[CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.[C:22]1(=[O:32])[NH:26][C:25](=[O:27])[C:24]2=[CH:28][CH:29]=[CH:30][CH:31]=[C:23]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.CCOCC>[F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH:15]([CH2:18][CH3:19])[CH2:16][N:26]4[C:25](=[O:27])[C:24]5=[CH:28][CH:29]=[CH:30][CH:31]=[C:23]5[C:22]4=[O:32])[CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CCC(CO)N1CCC(c2noc3cc(F)ccc23)CC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCC(CN1C(=O)c2ccccc2C1=O)N1CCC(c2noc3cc(F)ccc23)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 7.6 %

Procedure:
A solution of diethyl azodicarhoxylate (DEAD, 4.9 g, 28.3 mmol) in THF (50 ml) was added dropwise to a solution of 2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]butanol (6.9 g, 23.6 mmol), phthalimide (4.16 g, 1.2 eq), and triphenylphosphine (7.4 g, 28.3 mmol) in THF (200 ml) at room temperature. The solution was stirred at room temperature for 24 hours. After the reaction, the solvent was stripped to dryness. The residue was stirred in ether (200 ml) and the insolubles were removed by filtration. The oily residue from concentration of the ether solution was purified by two flash chromatography (SiO2, 75 g, eluted with dichloromethane, DCM, and 1-2% CH3OH in DCM) and (100 g of SiO2, eluted with DCM, 11, and 1% CH3OH in DCM, 1.2 l). Two close compounds were separated and the top compound on TLC (1.6 g) was recrystallized from isopropyl ether to yield 0.76 g of white crystals, m.p. 86-88° C.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][C:11]([OH:13])=O.C(Cl)(=O)C(Cl)=O.[Al+3].[Cl-].[Cl-].[Cl-]>C(Cl)Cl.CN(C=O)C>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]2[C:3]=1[CH2:9][CH2:10][C:11]2=[O:13]
Reactant: O=C(O)CCc1cccc(F)c1F
Agent: O=C(Cl)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C1CCc2c1ccc(F)c2F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 2,3-difluorocinnamic acid (2.8 g, 15.2 mol) (commercially available from Lancaster) (Intermediate TWENTY-1) in ethanol (100 mL) was hydrogenated with H2 (balloon) and 10% Pd/C (0.3 g) at rt for 16 h. The mixture was filtered through Celite® and the solvent was evaporated to give 3-(2,3-difluoro-phenyl)-propionic acid as a solid, 2.68 g (98%). A mixture of 3-(2,3-difluoro-phenyl)-propionic acid (2.7 g, 14.4 mmol) in CH2Cl2 at 0° C. was treated with oxalyl chloride (8.7 mL, 2 M in CH2Cl2) and a few drops of DMF. The reaction mixture was stirred for 2 h at rt. The solution was decanted from the dark colored residues and the solvent was removed under vacuum. The residue was dissolved in CH2Cl2 (20 mL) and added to a mixture of AlCl3 (1.92 g, 14.4 mmol) in CH2Cl2 (25 mL). The mixture was heated at 50° C. for 16 h. The entire mixture was poured into ice water. The aqueous phase was removed and extracted with CH2Cl2. The organic layers were combined, washed with sat. NaHCO3 solution, brine, and dried over Na2SO4, filtered, and evaporated to dryness. The residue was purified by chromatography on silica gel with 20% EtOAc:hexane to give 4,5-difluoro-indan-1-one (Intermediate TWENTY-2), 1.65 g (68%).
Reaction SMILES: [N:1]1[CH:6]=[C:5]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]Cl)[CH:4]=[N:3][CH:2]=1.[C:14]1(=[O:24])[NH:18][C:17](=[O:19])[C:16]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:15]12.[K].[I-].[K+]>CN(C)C=O.O>[N:1]1[CH:6]=[C:5]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:18]2[C:14](=[O:24])[C:15]3[C:16](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:17]2=[O:19])[CH:4]=[N:3][CH:2]=1
Reactant: ClCCCCCCc1cncnc1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [I-]
Agent: [K+]
Agent: [K]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CCCCCCc1cncnc1
Yield: 71.1 %

Procedure:
A solution of 22.3 g of 6-(5-pyrimidinyl)hexyl chloride, 41.6 g of potassium phthalimide, and 1.8 g of potassium iodide in 180 ml of dimethylformamide was heated to a bath temperature of 130° C. for 1 hour. The mixture was diluted with water and was extracted with dichloromethane. The combined organic layers were washed with water and were dried over potassium carbonate. The residue obtained after evaporation was crystallized from ethyl acetate-hexane to give 24.7 g (71%) of 2-[6-(5-pyrimidinyl)hexyl]-1H-isoindole-1,3-(2H)-dione, mp 124°-126.5° C.
Reaction SMILES: FC(F)(F)C(O)=O.ClCCl.[NH2:11][C:12]1[N:17]=[CH:16][N:15]=[C:14]2[N:18]([CH:37]3[CH2:42][CH2:41][N:40]([CH2:43][C:44]4[NH:45][CH:46]=[CH:47][N:48]=4)[CH2:39][CH2:38]3)[N:19]=[C:20]([C:21]3[CH:26]=[CH:25][C:24]([NH:27]C(=O)OC(C)(C)C)=[C:23]([O:35][CH3:36])[CH:22]=3)[C:13]=12>ClCCl>[NH2:27][C:24]1[CH:25]=[CH:26][C:21]([C:20]2[C:13]3[C:14](=[N:15][CH:16]=[N:17][C:12]=3[NH2:11])[N:18]([CH:37]3[CH2:42][CH2:41][N:40]([CH2:43][C:44]4[NH:45][CH:46]=[CH:47][N:48]=4)[CH2:39][CH2:38]3)[N:19]=2)=[CH:22][C:23]=1[O:35][CH3:36]
Reactant: COc1cc(-c2nn(C3CCN(Cc4ncc[nH]4)CC3)c3ncnc(N)c23)ccc1NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc(-c2nn(C3CCN(Cc4ncc[nH]4)CC3)c3ncnc(N)c23)ccc1N
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 67.5 %

Procedure:
A mixture of trifluoroacetic acid/dichloromethane (20:80, 2 mL) was added to a solution of tert-butyl N-(4-{4-amino-1-[1-(1H-2-imidazolylmethyl)-4-piperidyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-methoxyphenyl)carbamate (55 mg, 0.106 mmol) in dichloromethane (0.5 mL) at 0° C. After 15 minutes, the ice-bath was removed and the reaction mixture was stirred at room temperature for 5 hours. Solvents were then evaporated and the residue was dissolved in dichloromethane. Saturated sodium bicarbonate was added to adjust the PH to about 8. The layers were separated and the aqueous layer was extracted with dichloromethane. The combined organic layer was washed with brine, dried over MgSO4, filtered and evaporated give 3-(4-amino-3-methoxyphenyl)-1-[1-(1H-2-imidazolylmethyl)-4-piperidyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (30 mg, 68%). 1H NMR (CDCl3-d) δ 2.20 (m, 2H), 2.44 (m, 2H), 3.04 (m, 2H), 3.75 (s, 2H), 3.93 (s, 3H), 4.01 (s, 2H), 4.80 (m, 1H), 5.58 (bs, 2H), 6.82 (m, 1H), 7.01 (m, 4H), 8.34 (s, 1H).
Reaction SMILES: Br[C:2]1[CH:22]=[CH:21][C:5]2[NH:6][C:7]([CH2:9][O:10][C:11]3[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=3)=[N:8][C:4]=2[CH:3]=1.[C:23]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1B(O)O)(=[O:25])[CH3:24].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O>[F:18][C:17]([F:20])([F:19])[C:14]1[CH:15]=[CH:16][C:11]([O:10][CH2:9][C:7]2[NH:6][C:5]3[CH:21]=[CH:22][C:2]([C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=4[C:23](=[O:25])[CH3:24])=[CH:3][C:4]=3[N:8]=2)=[CH:12][CH:13]=1
Reactant: CC(=O)c1ccccc1B(O)O
Reactant: FC(F)(F)c1ccc(OCc2nc3cc(Br)ccc3[nH]2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CC(=O)c1ccccc1-c1ccc2[nH]c(COc3ccc(C(F)(F)F)cc3)nc2c1
Temperature: 90 °C
Yield: 87.2 %

Procedure:
A mixture of 5-bromo-2-(4-trifluoromethyl-phenoxymethyl)-1H-benzoimidazole (0.450 g, 1.21 mmol), 2-acetylphenylboronic acid (0.298 g, 1.82 mmol), sodium carbonate (0.771 g, 7.26 mmol), and 1,1′-[bis(di-tert-butylphosphino)ferrocene]-palladium dichloride (0.079 g, 0.121 mmol) in DME (10 mL) and H2O (2.5 mL) was heated at 90° C. for 12 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by chromatography (silica, hexanes: EtOAc, 1:1) to afford the product as a yellow oil (0.433 g, 87%).
Reaction SMILES: I[C:2]1[CH:3]=[N:4][N:5]([CH2:7][C:8]([F:11])([F:10])[F:9])[CH:6]=1.[Br:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]#[CH:20])[CH:14]=1>C(N(CC)CC)C.C(#N)C.[Cu](I)I>[Br:12][C:13]1[CH:14]=[C:15]([C:19]#[C:20][C:2]2[CH:3]=[N:4][N:5]([CH2:7][C:8]([F:11])([F:10])[F:9])[CH:6]=2)[CH:16]=[CH:17][CH:18]=1
Reactant: C#Cc1cccc(Br)c1
Reactant: FC(F)(F)Cn1cc(I)cn1
Agent: I[Cu]I
Solvent: CC#N
Solvent: CCN(CC)CC
Product: FC(F)(F)Cn1cc(C#Cc2cccc(Br)c2)cn1
Temperature: 80 °C
Yield: 99.5 %

Procedure:
To a solution of 4-iodo-1-(2,2,2-trifluoroethyl)-1H-pyrazole (4.14 g, 15 mmol) in triethylamine (53 mL) is added tetrakis(triphenylphosphine)paddadium (1.20 g, 1.04 mmol), copper iodide (0.28 g, 1.46 mmol) and a solution of 1-bromo-3-ethynylbenzene (2.78 g, 15 mmol) in acetonitrile (15 mL) at room temperature. After heating for 1 hour at 80° C., the reaction mixture is cooled and concentrated. The crude material is purified by chromatography (silica gel, EtOAc/hexane: 5/95) to give the title compound as a solid (4.91 g, 99%). mp: 107-109° C. MS (+) EI: 328 M+.