Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1(CC(O)=O)CCNCC1.[CH2:11]([NH:18][CH2:19][CH2:20][NH:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.CCN(CC)CC.Br[CH2:37]/[CH:38]=[CH:39]/[C:40]([O:42][CH3:43])=[O:41]>C1(C)C=CC=CC=1>[CH2:11]([N:18]1[CH2:19][CH2:20][N:21]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:37][CH:38]1[CH2:39][C:40]([O:42][CH3:43])=[O:41])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: c1ccc(CNCCNCc2ccccc2)cc1
Reactant: COC(=O)/C=C/CBr
Agent: O=C(O)CN1CCNCC1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COC(=O)CC1CN(Cc2ccccc2)CCN1Cc1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 81 %

Procedure:
The piperazineacetic acid compound of formula (XXIV) employed in the synthesis above and many others in this application was synthesized as follows: Twelve milliliters (50 mmol) of N,N′-dibenzylethylene-diamine, 14 mL (100 mmol) of Et3N and 250 mL toluene were combined at 0° C., and 7 mL (50 mmol) of methyl 4-bromocrotonate (7 mL, 50 mmol) was added. The reaction was slowly warmed to room temperature, stirred for 24 hours, filtered, concentrated in vacuo to a residue and treated with 10% aqueous HCl (300 mL). The mixture was filtered again and the filtrate washed with ethyl acetate (2×100 mL). The filtrate was made basic with K2CO3 and extracted with ethyl acetate (3×150 mL). The combined extracts were washed with brine, dried over MgSO4 and concentrated in vacuo to give 13.7 g of methyl 1,4-dibenzylpiperazine-2-acetate. 1H NMR (CDCl3) δ2.28-2.50 (m,4), 2.5-2.75 (m,4), 3.1 (bs, 1), 3.42 (d,2), 3.52 (d,1), 3.6 (s,3), 3.75 (d,1), 7.15-7.35 (m,1).
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[C:9]([O:14][CH2:15][CH3:16])(=[O:13])[CH:10]([CH3:12])[CH3:11].Br[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][Br:25]>C1COCC1>[Br:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][C:10]([CH3:12])([CH3:11])[C:9]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)C(C)C
Reactant: BrCCCCCCCBr
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C(C)(C)CCCCCCCBr
Temperature: 0 °C
Reaction time: 3 h
Yield: 45 %

Procedure:
Under N2 atmosphere at 0° C., LDA (2 M solution in THF/heptane/ethylbenzene, 13.0 mL, 26.0 mmol) was added dropwise to a mixture of ethyl isobutyrate (3.5 mL, 3.0 g, 25.9 mmol) and 1,7-dibromoheptane (9.84 g, 38.2 mmol) in dry THF (50 mL) over 1.5 h, while keeping the temperature below 5° C. After 3 h, the mixture was poured into ice-cold saturated aqueous NH4Cl solution (150 mL). The layers were separated and the aqueous phase was extracted with Et2O (3×100 mL). The combined organic layers were washed with aqueous HCl (1 M, 100 mL), saturated aqueous NaHCO3 solution (100 mL) and brine (100 mL), dried over anhydrous Na2SO4 and concentrated in vacuo. The residue (12.4 g) was purified twice by column chromatography (heptane:ethyl acetate=40:1) to give 205j (3.42 g, 45%) as a colorless liquid. 1H NMR (CDCl3): δ (ppm): 4.11 (q, J=7.2, 2 H), 3.40 (t, J=6.9, 2 H), 1.85 (quintet, J=6.9, 2 H), 1.52-1.47 (m, 2H), 1.45-1.36 (m, 2H), 1.35-1.20 (m, 6H), 1.24 (t, J=7.2, 3 H), 1.15 (s, 6H). 13C-NMR (CDCl3): δ (ppm): 177.8, 60.0, 42.0, 40.5, 33.7, 32.7, 29.7, 28.5, 28.0, 25.0 (2×), 24.7, 14.1. HRMS: Calcd for C13H25BrO2 (M+): 292.1038, found: 292.1034.
Reaction SMILES: [CH:1]([O-:3])=O.[Na+].C(Br)[C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:7]>C(O)C>[CH2:1]([OH:3])[C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:7]
Reactant: O=C[O-]
Reactant: O=C(CBr)c1ccccc1
Agent: [Na+]
Solvent: CCO
Product: O=C(CO)c1ccccc1
Temperature: 105 °C

Procedure:
This procedure was adapted from the one developed by Pirkle and Simmons (Pirkle, W. H. and Simmons, K A., J. Org. Chem. 48:2520-2527 (1983)). 11.62 g (0.1706 moles) sodium formate was stirred in 50 ml ethanol for about 15 minutes. 5.31 g (26.7 mmol) phenacyl bromide was added to it and the mixture was refluxed under nitrogen at 105° C. for nearly 20 h. The reaction mixture was cooled and complete conversion of the starting material was confirmed by TLC. The solvent was evaporated and about 50 ml of boiling water was added and the solution was filtered hot. The filtrate was then cooled to precipitate out the alcohol. Yield 3.11 g (86%) from 5.31 g phenacyl bromide, white crystalline solid: mp 82-84° C. (lit. mp 84-85° C. (Pirkle, W. H. and Simmons, K A., J. Org. Chem. 48:2520-2527 (1983)); 1H NMR (CDCl3) δ6 3.49 (t, J=4.5), 4.87 (d, J=4.5), 7.44-7.65 (m, 3H), 7.91 (dd, J1=8, J21.3, 2H); 13C NMR (CDCl3) δ198.4, 134.3, 133.5, 129.0, 127.7, 65.5; EI-MS, m/z (rel. intensity) 136 (M+, 6), 105 (100), 77 (81), 52 (29).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[NH:11][C:12]1[N:17]=[C:16]([C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)[CH:15]=[CH:14][N:13]=1>C(OCC)(=O)C.C(O)C>[NH2:8][C:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[C:3]([NH:11][C:12]2[N:17]=[C:16]([C:18]3[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=3)[CH:15]=[CH:14][N:13]=2)[CH:4]=1
Reactant: Cc1ccc([N+](=O)[O-])cc1Nc1nccc(-c2cccnc2)n1
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cc1ccc(N)cc1Nc1nccc(-c2cccnc2)n1
Temperature: 25 °C
Yield: 110.7 %

Procedure:
N-(2-methyl-5-nitrophenyl)-4-(3-pyridyl)-2-pyrimidine-amine (35 g, 0.114 mol) and stannous chloride dihydrate (128.5 g, 0.569 mol) were dissolved in a solvent mixture of ethyl acetate and ethanol (250 ml, 10/1, v/v), and the reaction solution was refluxed for 4 hours. The solution was cooled to room temperature, washed with 10% aqueous sodium hydroxide solution, and concentrated to give N-(5-amino-2-methylphenyl)-4-(3-pyridyl)-2-pyrimidine-amine (35 g).
Reaction SMILES: [OH-].[Na+].[CH2:3]([O:5][N:6]=[C:7]([C:10]1[C:11](=[O:26])[CH2:12][CH:13]([C:17]2[C:22]([CH3:23])=[CH:21][C:20]([CH3:24])=[CH:19][C:18]=2[CH3:25])[CH2:14][C:15]=1[OH:16])[CH2:8][CH3:9])[CH3:4].[C:27](Cl)(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>CC(C)=O>[C:27]([O:26][C:11]1[CH2:12][CH:13]([C:17]2[C:18]([CH3:25])=[CH:19][C:20]([CH3:24])=[CH:21][C:22]=2[CH3:23])[CH2:14][C:15](=[O:16])[C:10]=1[C:7](=[N:6][O:5][CH2:3][CH3:4])[CH2:8][CH3:9])(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CCON=C(CC)C1=C(O)CC(c2c(C)cc(C)cc2C)CC1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: CCON=C(CC)C1=C(OC(=O)c2ccccc2)CC(c2c(C)cc(C)cc2C)CC1=O
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 68.5 %

Procedure:
Aqueous 1% sodium hydroxide solution (6 ml) was added to a solution of 2-[1-(ethoxyimino)propyl]-3-hydroxy-5-mesitylcyclohex-2-en-1-one (0.42 g; 1.28 mmole) in acetone (50 ml). The mixture was stirred at room temperature for a period of 5 minutes and then benzoyl chloride (0.2 g) was added dropwise. The mixture was stirred for a further period of 15 minutes and then the solvent was removed by evaporation under reduced pressure using a rotary evaporator. The product was purified by chromatography over silica gel (eluant dichloromethane) to give 3-benzoyloxy-2-[1-(ethoxyimino)propyl]-5-mesitylcyclohex-2-en-1-one (0.38 g; 68.6%) as a pale yellow oil.
Reaction SMILES: Br[C:2]1[CH:18]=[CH:17][C:5]([O:6][Si:7]([CH:14]([CH3:16])[CH3:15])([CH:11]([CH3:13])[CH3:12])[CH:8]([CH3:10])[CH3:9])=[CH:4][C:3]=1[C:19]([CH3:22])([CH3:21])[CH3:20].C([Li])(C)(C)C.CCCCC.Cl[C:34]([O:36][CH2:37][CH3:38])=[O:35]>CCOCC>[C:19]([C:3]1[CH:4]=[C:5]([O:6][Si:7]([CH:14]([CH3:16])[CH3:15])([CH:11]([CH3:12])[CH3:13])[CH:8]([CH3:9])[CH3:10])[CH:17]=[CH:18][C:2]=1[C:34]([O:36][CH2:37][CH3:38])=[O:35])([CH3:22])([CH3:20])[CH3:21]
Reactant: CCOC(=O)Cl
Reactant: CC(C)[Si](Oc1ccc(Br)c(C(C)(C)C)c1)(C(C)C)C(C)C
Agent: [Li]C(C)(C)C
Solvent: CCCCC
Solvent: CCOCC
Product: CCOC(=O)c1ccc(O[Si](C(C)C)(C(C)C)C(C)C)cc1C(C)(C)C
Temperature: 25 °C
Yield: 124.9 %

Procedure:
To a solution of (4-bromo-3-tert-butyl-phenoxy)-triisopropyi-silane (Intermediate 105, 1.00 g, 2.60 mmols) in 15 mL Et2O cooled to −78° C. was added 3.6 mL of tert-butyllithium, 1.7 M in pentane (395.0 mg, 6.2 mmols). After stirring for 30 minutes ethyl chloroformate (607.6 mg, 5.6 mmols) was added. The resulting solution was warmed to room temperature and quenched by the addition of saturated aqueous NH4Cl. The mixture was extracted with EtOAc and the combined organic layers dried (MgSO4) concentrated under reduced pressure The residue was chromatographed (2-5% EtOAc—hexanes) to give 1.23 g (88%) of the title compound as a colorless oil.
Reaction SMILES: Cl[CH2:2][C:3]1[O:7][N:6]=[C:5]([CH3:8])[CH:4]=1.[P:9]([O:16]CC)([O:13][CH2:14][CH3:15])[O:10][CH2:11][CH3:12]>>[CH2:11]([O:10][P:9]([CH2:2][C:3]1[O:7][N:6]=[C:5]([CH3:8])[CH:4]=1)([O:13][CH2:14][CH3:15])=[O:16])[CH3:12]
Reactant: Cc1cc(CCl)on1
Reactant: CCOP(OCC)OCC
Product: CCOP(=O)(Cc1cc(C)no1)OCC
Yield: 74 %

Procedure:
5-Chloromethyl-3-methylisoxazole (1.12 g) was dissolved in triethyl phosphite (2.0 ml) and heated at reflux for 1 h. The residue was then distilled under reduced pressure to give 5-diethylphosphonomethyl-3-methylisoxazole (1.47 g, 74%); bp 122°-5° C. at 0.5 mm; νmax (film) 2980, 2930, 2910, 1605, 1440, 1420, 1390, 1255, 1160, 1060-1010, 980, 900 cm-1 ; δH (CDCl3) 1.35(3H, t, J=7 Hz, OCH2CH3), 2.30(3H, s, CH3 -het), 3.30(1H, d, JH-P =24 Hz, CH2 -P), 4.10(2H, m, OCH2CH3), 6.05(1H, d, J=3 Hz, CH-Het); δC (CDCl3) 11.4 (C5), 16.3, 16.4(OCH2CH3), 24.6, 26.8 (C1), 62.7, 62.8(OCH2CH3), 104.1, 104.2 (C3 ), 160.1 (C4), 163.5, 163.6 (C2); m/e (relative intensity) 233(M+, 18%), 192(47), 177(41), 136(50), 109(100), 97(82), 96(35), 81(76), 43(32) (Found: 233.0831. C9H16NO4P requires 233.0816).
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH2:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:11]1([CH2:17][CH:18]=[O:19])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>ClCCl.C1(C)C=CC=CC=1.C[Si](OS(C(F)(F)F)(=O)=O)(C)C>[C:1]1([CH2:7][CH:8]([NH:10][C:18](=[O:19])[CH2:17][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[NH:10][C:8](=[O:9])[CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=CCc1ccccc1
Reactant: NC(=O)Cc1ccccc1
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: O=C(Cc1ccccc1)NC(Cc1ccccc1)NC(=O)Cc1ccccc1
Yield: 75.2 %

Procedure:
To a well stirred suspension of 2-phenylacetamide (540 mg, 4 mmol) in dry dichloromethane (2 mL) was added the 2-phenylacetaldehyde (240 mg, 2 mmol) and trimethylsilyltrifluoromethanesulfonate (22 mg, 0.1 mmol). The mixture was vigorously stirred for 12 h at room temperature, diluted with toluene (4 mL), and filtered. The precipitate was washed several times with toluene which was recrystallized with methanol and hexane to give the final product (560 mg, 76%). 1H NMR (400 MHz, DMSO-d6) δ 8.45 (d, J=7.6 Hz, 2H), 7.14-7.28 (m, 15H), 5.55 (t, J=7.6 Hz, 1H), 3.39 (s, 4H), 2.93 (d, J=7.2 Hz, 2H). HPLC-MS (ESI): m/z 373.2 (M+H)+.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]([O:20][CH3:21])([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.C(OCC)(=O)C.C(OC(C)C)(C)C.[OH-].[Na+]>C(OCC)(=O)C>[CH3:21][O:20][C:11]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1
Reactant: COC1(c2ccccc2)CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CC(C)OC(C)C
Product: COC1(c2ccccc2)CCNCC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 81.3 %

Procedure:
To a solution of 4-methoxy-4-phenylpiperidine-1-carboxylic acid tert-butyl ester (6.5 g) in ethyl acetate (65 ml) was added dropwise 4N-HCl/ethyl acetate (56 ml) at ambient temperature. The reaction mixture was stirred for 1.5 hours at ambient temperature. To the reaction mixture was added diisopropyl ether. The precipitate was collected by filtration to give powder. The powder was adjusted to pH 11 with 1N-NaOH, and extracted with ethyl acetate. The organic layer was separated, washed with brine, dried over magnesium sulfate. The magnesium sulfate was filtered off, and the filtrate was evaporated under reduced pressure to give 4-methoxy-4-phenylpiperidine (3.47 g).
Reaction SMILES: CS(O[C:6]1[CH:11]=[CH:10][C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:8][C:7]=1[C:16]([CH3:19])([CH3:18])[CH3:17])(=O)=O.C([O-])=O.[Li+].CO>[Pd].[C].O>[C:12]([C:9]1[CH:10]=[CH:11][CH:6]=[C:7]([C:16]([CH3:19])([CH3:18])[CH3:17])[CH:8]=1)([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)c1ccc(OS(C)(=O)=O)c(C(C)(C)C)c1
Agent: [Pd]
Agent: O=C[O-]
Agent: [Li+]
Solvent: O
Solvent: CO
Product: CC(C)(C)c1cccc(C(C)(C)C)c1
Yield: 75.1 %

Procedure:
Using the thus-obtained, regenerated Pd/carbon (10 g), the same reaction as in Example II-1 was carried out in a nitrogen atmosphere under normal pressure at 25° C., in which, however, 2,4-di-tert-butylphenyl methanesulfonate (100 g, 0.35 mols), lithium formate (37 g, 0.70 mols) and methanol (600 g) were used. Water (20 mL) was added to the reaction liquid and Pd/carbon was collected through filtration, and heptane (100 g) was added to the filtrate. The organic layer obtained after extraction was concentrated under reduced pressure to give crude 1,3-di-tert-butylbenzene (50 g, yield 75% by mass).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][C@@H:6]([OH:8])[C@H:5]([CH:9]([CH3:11])[CH3:10])[CH2:4][CH2:3]1.O[C@@H](C)CC(OC1(C)CCC(C(C)C)CC1)=O>>[CH:2]1([CH3:1])[CH2:3][CH2:4][CH:5]([CH:9]([CH3:10])[CH3:11])[CH:6]([OH:8])[CH2:7]1
Reactant: CC(C)[C@@H]1CC[C@@H](C)C[C@H]1O
Agent: CC(C)C1CCC(C)(OC(=O)C[C@H](C)O)CC1
Product: CC1CCC(C(C)C)C(O)C1

Procedure:
A sensate composition was prepared by mixing 1-menthol and the (3S)-1-menthyl 3-hydroxybutyrate obtained in Example 1 at a ratio of 95:5 (weight ratio). Oral sensory evaluation was carried out by preparing 1,000 ml of a 20 ppm aqueous solution of the thus obtained sensate composition, and the oral sensory evaluation was carried out also on a 20 ppm aqueous solution of 1-menthol alone as a comparison.
Reaction SMILES: O.[NH2:2][NH2:3].[F:4][C:5]([F:21])([C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[N:17]=[CH:16][CH:15]=[CH:14]2)[C:6](OCC)=[O:7].NN>CC(O)(CC)C>[F:4][C:5]([F:21])([C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[N:17]=[CH:16][CH:15]=[CH:14]2)[C:6]([NH:2][NH2:3])=[O:7]
Reactant: NN
Reactant: CCOC(=O)C(F)(F)c1ccc2ncccc2c1
Solvent: O
Solvent: CCC(C)(C)O
Product: NNC(=O)C(F)(F)c1ccc2ncccc2c1
Yield: 92.1 %

Procedure:
To a reactor under inert atmosphere was added 31.05 mL 2-methyl-2-butanol and 12.58 mL (0.259 mol) hydrazine hydrate. Then a solution of 26 g (0.103 mol) ethyl difluoro(quinolin-6-yl)acetate in 125 mL 2-methyl-2-butanol was dosed to the hydrazine solution at room temperature. The precipitate was filtered off from the reaction mixture and was washed with water and dried at 50° C. 22.51 g 2,2-difluoro-2-quinolin-6-ylacetohydrazide was obtained in 90% yield.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:12])[CH3:11])=[CH:5][C:4]=1[C:13]1[N:14]([CH3:18])[N:15]=[CH:16][CH:17]=1.[Cl-].[Al+3].[Cl-].[Cl-].C(OCC)(=O)C>ClCCCl>[OH:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:12])[CH3:11])=[CH:5][C:4]=1[C:13]1[N:14]([CH3:18])[N:15]=[CH:16][CH:17]=1
Reactant: COc1ccc(NC(C)=O)cc1-c1ccnn1C
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Solvent: CCOC(C)=O
Product: CC(=O)Nc1ccc(O)c(-c2ccnn2C)c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 70 %

Procedure:
A mixture of N-[4-methoxy-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-acetamide (2.0 g, 8.15 mmol) in anhydrous 1,2-dichloroethane (60 mL) was cooled at 0° C. on an ice bath and stirred for 10 minutes. Anhydrous aluminium chloride (4.35 g, 32.6 mmol) was added and the reaction mixture stirred at 0° C. for 20 minutes, then moved to an oil bath and stirred at 80° C. for 1 hour. Ethyl acetate was added and washed with potassium sodium tartrate (10%) twice. Organic layer was separated, dried over anhydrous Na2SO4, filtered and concentrated to give a crude product that was purified via preparative HPLC. The corresponding fractions were collected and lyophilized to afford N-[4-hydroxy-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-acetamide as a white solid in 70.0% yield. LCMS m/z (%)=232 (M+H, 100). 1H NMR (400 MHz, DMSO-d6) δ: 7.39 (s, 1H), 6.86 (d, J=8.74 Hz, 1H), 6.62 (d, J=8.70 Hz, 1H), 6.47 (s, 1H), 6.15 (s, 1H), 4.80 (bs, 2H), 3.87 (t, J=5.80 Hz, 2H), 3.63 (s, 3H), 2.44 (t, J=5.80 Hz, 2H), 2.08 (s, 6H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[C:6]([OH:8])=O.C1(=O)NC(=O)CC1.[N:21]1([C:27]([C:29]2[CH:30]=[C:31]3[C:36](=[CH:37][CH:38]=2)[NH:35][C:34](=[O:39])[CH2:33][CH2:32]3)=[O:28])[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.O>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[C:6]([N:24]1[CH2:25][CH2:26][N:21]([C:27]([C:29]2[CH:30]=[C:31]3[C:36](=[CH:37][CH:38]=2)[NH:35][C:34](=[O:39])[CH2:33][CH2:32]3)=[O:28])[CH2:22][CH2:23]1)=[O:8]
Reactant: COc1ccc(C(=O)O)cc1OC
Reactant: O=C1CCc2cc(C(=O)N3CCNCC3)ccc2N1
Agent: O=C1CCC(=O)N1
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)N2CCN(C(=O)c3ccc4c(c3)CCC(=O)N4)CC2)cc1OC
Reaction time: 24 h

Procedure:
123 Grams of succinimide 3,4-dimethoxybenzoate and 137 mg of 6-(1-piperazinylcarbonyl)-3,4-dihydrocarbostyril were dissolved in 2 ml of dimethylformamide and stirred for 24 hours. The water was added to the reaction mixture and extracted with chloroform, the chloroform extract was washed with water and a saturated sodium chloride aqueous solution and dried with anhydrous sodium sulfate. The solvent was removed by distillation and the residue was recrystallized from ethanol-chloroform to obtain 100 mg of 6-[4-(3,4-dimethoxybenzoyl)-1-piperazinylcarbonyl]-3,4-dihydrocarbostyril. Colorless granular crystals. Melting point: 238°-239.5° C.
Reaction SMILES: [F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([F:12])[C:3]=1[C:13]1[N:18]=[C:17]2[NH:19][N:20]=[C:21](I)[C:16]2=[CH:15][N:14]=1.[CH3:23][N:24]([CH3:45])[C:25]([CH:27]1[CH2:31][C:30]2[CH:32]=[C:33](B3OC(C)(C)C(C)(C)O3)[CH:34]=[CH:35][C:29]=2[O:28]1)=[O:26].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.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:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([F:12])[C:3]=1[C:13]1[N:18]=[C:17]2[NH:19][N:20]=[C:21]([C:33]3[CH:34]=[CH:35][C:29]4[O:28][CH:27]([C:25]([N:24]([CH3:23])[CH3:45])=[O:26])[CH2:31][C:30]=4[CH:32]=3)[C:16]2=[CH:15][N:14]=1
Reactant: COc1cc(OC)c(F)c(-c2ncc3c(I)n[nH]c3n2)c1F
Reactant: CN(C)C(=O)C1Cc2cc(B3OC(C)(C)C(C)(C)O3)ccc2O1
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: C1COCCO1
Product: COc1cc(OC)c(F)c(-c2ncc3c(-c4ccc5c(c4)CC(C(=O)N(C)C)O5)n[nH]c3n2)c1F
Temperature: 115 °C
Reaction time: 5 h

Procedure:
A mixture of 6-(2,6-difluoro-3,5-dimethoxyphenyl)-3-iodo-1H-pyrazolo[3,4-d]pyrimidine (16.7 mg, 0.0400 mmol), N,N-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1-benzofuran-2-carboxamide (19.0 mg, 0.0600 mmol) (Example 1, Step 2), tetrakis(triphenylphosphine)palladium(0) (2.77 mg, 0.00240 mmol) and sodium carbonate (12.7 mg, 0.120 mmol) in 1,4-dioxane (0.42 mL) and water (0.14 mL) in a reaction vial was sealed, and degassed and recharged with nitrogen for three times. The mixture was stirred at 115° C. for 5 h. After cooling, the mixture was diluted with methanol, and purified by RP-HPLC (pH=10) to afford the desired product. LCMS (M+H)+=482.0.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[CH:6]2.[NH:12]1[CH2:17][CH2:16][C:15](=O)[CH2:14][CH2:13]1>[Pt](=O)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH:15]1[CH2:16][CH2:17][NH:12][CH2:13][CH2:14]1
Reactant: COc1ccc2[nH]ccc2c1
Reactant: O=C1CCNCC1
Agent: O=[Pt]=O
Product: COc1ccc2[nH]cc(C3CCNCC3)c2c1
Yield: 73.8 %

Procedure:
This compound was prepared following the procedure described in example 1 (parts A and B) starting with 5.9 g (40 mmol) of 5-methoxyindol and 15.5 g (100 mmol) of 4-piperidone. In this case the hydrogenation took place for 24 hours at 30 psi and the catalyst used was platinum (IV) oxide. 6.8 g (74% of yield) of 5-methoxy-3-piperidin-4-yl-1H-indole were obtained.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:8]=2)[CH:3]=[C:2]1[C:15]([O:17][CH2:18][CH3:19])=[O:16].C([O-])([O-])=O.[K+].[K+].Br[CH2:27][C:28]#[N:29]>CN(C=O)C.CCOC(C)=O>[C:28]([CH2:27][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:8]=2)[CH:3]=[C:2]1[C:15]([O:17][CH2:18][CH3:19])=[O:16])#[N:29]
Reactant: N#CCBr
Reactant: CCOC(=O)c1ccc2cc(C(=O)OCC)[nH]c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc2cc(C(=O)OCC)n(CC#N)c2c1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 84.9 %

Procedure:
To a solution of diethyl 1H-indole-2,6-dicarboxylate (Intermediate A, 4.0 g, 15.3 mmol) in dry DMF (50 mL) is added K2CO3 (6.3 g, 45.9 mmol). The reaction mixture is stirred under N2 for 30 min. Bromoacetonitrile (2.1 mL, 30.6 mmol) is added and the reaction mixture is heated to 80° C. for 4 h. After cooling, the reaction mixture is taken up in EtOAc (300 mL) and washed with water, then brine, dried (Na2SO4) and concentrated. The residue is recrystallized from ethanol to afford the title compound (3.9 g, 84%) as fine off-white needles.
Reaction SMILES: [C@H]1(NCC2C=C(C(C)(C)C)C=C(C(C)(C)C)C=2O)CCCC[C@@H]1NCC1C=C(C(C)(C)C)C=C(C(C)(C)C)C=1[OH:23].[Cl:41][C:42]1[CH:43]=[C:44]2[C:48](=[CH:49][CH:50]=1)[C:47](=[O:51])[CH:46]([C:52]([O:54][CH3:55])=[O:53])[CH2:45]2.C(OO)(C)(C)C>C1(C)C=CC=CC=1.CC(C)[O-].[Zr+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[Cl:41][C:42]1[CH:43]=[C:44]2[C:48](=[CH:49][CH:50]=1)[C:47](=[O:51])[C:46]([OH:23])([C:52]([O:54][CH3:55])=[O:53])[CH2:45]2
Reactant: CC(C)(C)c1cc(CN[C@H]2CCCC[C@@H]2NCc2cc(C(C)(C)C)cc(C(C)(C)C)c2O)c(O)c(C(C)(C)C)c1
Reactant: COC(=O)C1Cc2cc(Cl)ccc2C1=O
Agent: [Zr+4]
Agent: CC(C)(C)OO
Agent: CC(C)[O-]
Solvent: Cc1ccccc1
Product: COC(=O)C1(O)Cc2cc(Cl)ccc2C1=O
Temperature: 55 °C

Procedure:
A chiral zirconium complex was prepared by stirring zirconium(IV) isopropoxide (0.560 g, 1.44 mmol) with 2,2′-[(1S,2S)-1,2-cyclohexanediylbis(iminomethylene)]bis[4,6-bis(1,1-dimethylethyl)phenol] (Formula IIIa wherein R6 is C(CH3)3, 1.00 g, 1.82 mmol) for 30 minutes in toluene (25 mL) at ambient temperature. The homogeneous solution was evaporated to dryness in vacuo, and the residue redissolved in toluene (8.70 g, 10 mL). A toluene solution of methyl 5-chloro-2,3-dihydro-1-oxo-1H-indene-2-carboxylate (1.53 g of a 21.55% by weight toluene solution, 1.47 mmol of methyl 5-chloro-2,3-dihydro-1-oxo-1H-indene-2-carboxylate) was added to the toluene solution of the chiral zirconium complex and the reaction mixture was heated to 55° C. Over the next 47 minutes, a toluene solution of methyl 5-chloro-2,3-dihydro-1-oxo-1H-indene-2-carboxylate (36.71 g of a 21.55% by weight toluene solution, 35.2 mmol of methyl 5-chloro-2,3-dihydro-1-oxo-1H-indene-2-carboxylate) and, simultaneously, an aqueous solution of tert-butyl hydroperoxide (70%, 4.69 g, 36.4 mmol) were co-fed to the reaction mixture at 55° C. After the two solutions were added, the reaction mixture was heated at 55° C. for an additional 6 hours, cooled to 25° C., and then filtered. After drying, 4.64 g (52.5%) of the S-enantiomer of methyl 5-chloro-2,3-dihydro-2-hydroxy-1-oxo-1H-indene-2-carboxylate was obtained as a white solid in 98% enantiomeric excess. Quantitative HPLC analysis of the filtrate and solids showed that the overall reaction proceeded with 85% conversion of methyl 5-chloro-2,3-dihydro-1-oxo-1H-indene-2-carboxylate, forming methyl 5-chloro-2,3-dihydro-2-hydroxy-1-oxo-1H-indene-2-carboxylate in 74% yield (87% chemoselectivity) and 75% enantiomeric excess of the S-enantiomer.