Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[CH:3]([OH:12])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1.[Si:15](Cl)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16].N1C=CN=C1>ClCCl.CN(C)C1C=CN=CC=1>[Si:15]([O:12][CH:3]([C:2]([F:1])([F:13])[F:14])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16]
Reactant: OC(CCc1ccccn1)C(F)(F)F
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OC(CCc1ccccn1)C(F)(F)F
Temperature: 25 °C
Reaction time: 36 h
Yield: 89.3 %

Procedure:
A solution of 700 mg (3.4 mmol) of 1,1,1-trifluoro-4-pyridin-2-ylbutan-2-ol in 10 mL of dichloromethane was treated with 616 mg (4.1 mmol, 1.2 eq.) of tert-butyldimethylsilyl chloride, 697 mg (10.2 mmol, 3.0 eq.) of imidazole and 415 ng (3.4 mmol) of 4-dimethylaminopyridine at 0° C. The resulting mixture was allowed to warm to room temperature and was stirred for 36 hours. Then the mixture was concentrated and the residue was purified by flash chromatography to give 970 mg (89%) of 2-[3-(tert-butyldimethylsilanyloxy)-4,4,4-trifluorobutyl]pyridine as a colorless oil.
Reaction SMILES: Cl[C:2]1[C:3]([O:16][CH2:17][C:18]2([C:24]([F:27])([F:26])[F:25])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)=[CH:4][C:5]([F:15])=[C:6]([CH:14]=1)[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8].[CH:28]1(B(O)O)[CH2:30][CH2:29]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].F[B-](F)(F)F.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>C1(C)C=CC=CC=1.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:28]1([C:2]2[C:3]([O:16][CH2:17][C:18]3([C:24]([F:25])([F:26])[F:27])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]3)=[CH:4][C:5]([F:15])=[C:6]([CH:14]=2)[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:30][CH2:29]1
Reactant: OB(O)C1CC1
Reactant: CC(C)(C)OC(=O)c1cc(Cl)c(OCC2(C(F)(F)F)CCCCC2)cc1F
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)c1cc(C2CC2)c(OCC2(C(F)(F)F)CCCCC2)cc1F
Temperature: 100 °C
Yield: 83.6 %

Procedure:
To a mixture of tert-butyl 5-chloro-2-fluoro-4-((1-(trifluoromethyl)cyclohexyl)-methoxy)benzoate (4.37 g, 10.63 mmol), cyclopropylboronic acid (1.37 g, 15.93 mmol), potassium phosphate (10.15 g, 47.81 mmol) and tricyclohexylphosphine tetrafluoroborate (0.39 g, 1.06 mmol) in toluene (60 mL) and water (3 mL) under a nitrogen atmosphere was added palladium acetate (0.12 g, 0.53 mmol). The reaction mixture was heated at 100° C. for 18 hours and then cooled to ambient temperature. Water (20 mL) was added and the mixture, and extracted with ethyl acetate, the combined organic extracts was washed with brine; dried over anhydrous sodium sulfate and concentrated in vacuo. Purification of the residue by column chromatography (5% ethyl acetate in hexanes) afforded the title compound (3.70 g, 83%): 1H NMR (300 MHz, CDCl3) δ 7.40 (d, J=8.4 Hz, 1H), 6.51 (d, J=12.3 Hz, 1H), 4.07 (s, 2H), 1.99-1.88 (m, 4H), 1.76-1.62 (m, 5H), 1.55 (s, 9H), 1.48-1.24 (m, 2H), 0.91-0.82 (m, 2H), 0.62-0.55 (m, 2H).
Reaction SMILES: CN(C)C=O.[F:6][C:7]1[CH:8]=[C:9]([CH:11]=[CH:12][CH:13]=1)[NH2:10].Br[CH:15]1[CH2:20][CH2:19][O:18][C:16]1=[O:17].C(=O)([O-])[O-].[Na+].[Na+]>O>[F:6][C:7]1[CH:8]=[C:9]([NH:10][CH:15]2[CH2:20][CH2:19][O:18][C:16]2=[O:17])[CH:11]=[CH:12][CH:13]=1
Reactant: Nc1cccc(F)c1
Reactant: O=C1OCCC1Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1OCCC1Nc1cccc(F)c1
Temperature: 80 °C
Reaction time: 15 h

Procedure:
A dimethylformamide solution (20 ml) of 1.93 ml of 3-fluoroaniline, 4.60 ml of α-bromo-γ-butyrolactone and 4.24 g of sodium carbonate was heated with stirring at 80° C. for 15 hours. The reaction liquid was cooled to room temperature, diluted with water and extracted with ether. The ether extract was dried over anhydrous magnesium sulfate, and thereafter the solvent was distilled off to provide 4.64 g of crude 3-[(3-fluorophenyl)amino]-dihydrofuran-2(3H)-one as a pale yellow, oily substance.
Reaction SMILES: Cl[CH2:2][S:3][C:4]1[CH:5]=[C:6]([CH3:10])[CH:7]=[CH:8][CH:9]=1.[F:11][C:12]1[CH:13]=[N:14][C:15](=[O:18])[NH:16][CH:17]=1.C(N(CC)CC)C.[K+].[Br-]>ClCCl>[CH3:10][C:6]1[CH:5]=[C:4]([S:3][CH2:2][N:16]2[CH:17]=[C:12]([F:11])[CH:13]=[N:14][C:15]2=[O:18])[CH:9]=[CH:8][CH:7]=1
Reactant: Cc1cccc(SCCl)c1
Reactant: O=c1ncc(F)c[nH]1
Agent: [Br-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cccc(SCn2cc(F)cnc2=O)c1

Procedure:
3-(Chloromethylthio)toluene (6.5 mmol) was added to a solution of 5-fluoropyrimidin-2-one (6.5 mmol) and triethylamine (6.5 mmol) in dichloromethane (75 ml) and the resultant mixture heated under reflux for 2 days. The solvent was then distilled off, the residue triturated with water and the residual material extracted with CCl4. Evaporation of the extracts and crystallisation of the residue from ethyl acetate gave the pure product; 0.40 g (25%), m.p. 124° C. (Found: C57.42; H4.63. Calc. for C12H11FN2OS: C57.59; H4.43) 1H NMR (DMSO d6); δ 2.28 (Me), 5.17(CH2), 7.2 (Ph), 8.05 (H-4), 8.70 (H-6). IR (KBr): 1670 cm-1 (CO), MS [70 eV, m/z (% rel. int.)]: 250 (8,M), 137(11), 136(36), 135(10), 128(7), 127(100), 100(34), 91(9).
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[CH2:8][C:9]([OH:11])=O.C(N(CC)C(C)C)(C)C.[CH3:21][C:22]1[CH:27]=[C:26]([N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)[CH:25]=[C:24]([C:34]([F:37])([F:36])[F:35])[C:23]=1[NH2:38].C(OCC)(=O)C>CN(C)C=O>[CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[CH2:8][C:9]([NH:38][C:23]1[C:24]([C:34]([F:35])([F:36])[F:37])=[CH:25][C:26]([N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)=[CH:27][C:22]=1[CH3:21])=[O:11]
Reactant: O=C(O)CC1CC2CCC1C2
Reactant: Cc1cc(N2CCOCC2)cc(C(F)(F)F)c1N
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(N2CCOCC2)cc(C(F)(F)F)c1NC(=O)CC1CC2CCC1C2
Reaction time: 0.03 h
Yield: 5.8 %

Procedure:
Bicyclo[2.2.1]hept-2-yl-acetic acid (160 mg), N,N-diisopropyl-ethylamine (0.44 mL) and N-[(dimethylamino)-1H-1,2,3-triazolo-[4,5-b]pyridin-1-yl-methylene]-N-methyl-methanaminium hexafluoro-phosphate N-oxide (0.47 g) were mixed in dry N,N-dimethylformamide (3 mL) and stirred under argon for 2 minutes. 2-Methyl-4-morpholin-4-yl-6-trifluoromethyl-phenylamine (0.18 g) dissolved in dry N,N-dimethylformamide (2 mL) was added to the reaction mixture, which was stirred at 25° C. under argon for 16 hours. Ethyl acetate (20 mL) was added and the organic phase was washed with saturated aqueous ammonium chloride/water (1:1, 20 mL), water (20 mL), brine/water (1:1, 20 mL), dried over magnesium sulfate, concentrated in vacuo and purified by flash chromatography to furnish 16 mg (6% yield) of the title compound as a white solid. LC-MS (m/z) 397 (MH+); tR=3.12, (UV, ELSD) 91%, 98%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11](=[O:19])[C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)[CH:10]=1)[NH:7][C:6](=[O:20])[CH:5]2SC>O1CCCC1.[Ni]>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11](=[O:19])[C:12]3[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=3)[CH:10]=1)[NH:7][C:6](=[O:20])[CH2:5]2
Reactant: CSC1C(=O)Nc2c(C(=O)c3ccc(F)cc3)cc(F)cc21
Agent: [Ni]
Solvent: C1CCOC1
Product: O=C1Cc2cc(F)cc(C(=O)c3ccc(F)cc3)c2N1
Yield: 6.4 %

Procedure:
A slurry of 27.1 g (0.85 mole) of 5-fluoro-7-(4-fluorobenzoyl)-3-methylthioindolin-2-one in 500 ml of tetrahydrofuran was treated with 220 g of wet Raney nickel. The mixture was filtered and the filtrate was concentrated. The residue obtained was crystallized from acetone to give 14.8 g (64%) of the titled compound as light yellow crystals, m.p. 195°-196.5° C.
Reaction SMILES: [C:1]1(=[O:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH2:2]1>O>[C@@H:1]1([OH:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: O=C1CC=Cc2ccccc21
Solvent: O
Product: O[C@H]1CCCc2ccccc21
Reaction time: 24 h

Procedure:
Washed phaseolus aureus L (green grams) 50 g. were taken into a conical flask and allowed to soak in deionised water (400 ml) for a period of 24 hr. 1-naphthalenone (0.500 g; 0.0034 moles) III was added to the soaked phaseolus aureus L (green grams) in the above water, covered and allowed to shake for 46 hr at 15–20° C. Then the green grams were filtered off and washed with deionised water (3×100 ml). The combined filtrate was extracted with chloroform (3×500 ml). The chloroform layer was dried and the crude product obtained (480 mg). Pure (1S)-1,2,3,4-tetrahydro-1-naphthalenol (IV) was obtained after column chromatography with silica gel using chloroform as eluent.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:11](=[O:12])[N:10]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]([F:24])([F:23])[F:22])=[CH:15][CH:14]=3)[C:9]([S:25][CH2:26][CH2:27][CH3:28])=[N:8][C:7]=2[N:29]=1.Cl.N1C=CC=CC=1.CN(C)C=O>O>[CH2:26]([S:25][C:9]1[N:10]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]([F:22])([F:24])[F:23])=[CH:15][CH:14]=2)[C:11](=[O:12])[C:6]2[CH:5]=[CH:4][C:3](=[O:2])[NH:29][C:7]=2[N:8]=1)[CH2:27][CH3:28]
Reactant: CCCSc1nc2nc(OC)ccc2c(=O)n1-c1ccc(OCC(F)(F)F)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Solvent: CN(C)C=O
Product: CCCSc1nc2[nH]c(=O)ccc2c(=O)n1-c1ccc(OCC(F)(F)F)cc1
Temperature: 120 °C
Reaction time: 3 h
Yield: 88.8 %

Procedure:
A mixture of 7-methoxy-2-(propylsulfanyl)-3-[4-(2,2,2-trifluoroethoxy)phenyl]pyrido[2,3-d]pyrimidin-4(3H)-one (213 mg), pyridine hydrochloride (1156 mg) and N,N-dimethylformamide (10 ml) was stirred at 120° C. for 3 hr. The mixture was allowed to be cooled to room temperature, and to the reaction mixture was added water thereto, and the mixture was extracted with ethyl acetate. The extract was washed with aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (183 mg).
Reaction SMILES: CO[C:3]([C:5]1[CH:10]=[N:9][C:8]([O:11][CH2:12][C:13]2[C:14]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)=[N:15][O:16][CH:17]=2)=[CH:7][N:6]=1)=[O:4].[CH:25]([NH2:28])([CH3:27])[CH3:26]>>[CH:25]([NH:28][C:3]([C:5]1[CH:10]=[N:9][C:8]([O:11][CH2:12][C:13]2[C:14]([C:18]3[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=3)=[N:15][O:16][CH:17]=2)=[CH:7][N:6]=1)=[O:4])([CH3:27])[CH3:26]
Reactant: COC(=O)c1cnc(OCc2conc2-c2ccc(F)cc2)cn1
Reactant: CC(C)N
Product: CC(C)NC(=O)c1cnc(OCc2conc2-c2ccc(F)cc2)cn1
Yield: 75 %

Procedure:
As described for example 13 g, 5-[3-(4-fluoro-phenyl)-isoxazol-4-ylmethoxy]-pyrazine-2-carboxylic acid methyl ester (100 mg, 0.3 mmol) was converted, using isopropylamine instead of 2,2,2-trifluoroethylamine, to the title compound (81 mg, 75%) which was obtained as a light yellow solid. MS: m/e=415.1 [M+OAc]+.
Reaction SMILES: [CH2:1]([N:4]1[CH2:8][C@@H:7]([O:9]CC2C=CC=CC=2)[C@H:6]([O:17]CC2C=CC=CC=2)[C@H:5]1[CH2:25][O:26]CC1C=CC=CC=1)[CH:2]=[CH2:3].Cl>[Pd].C(O)C>[OH:17][C@H:6]1[C@H:7]([OH:9])[CH2:8][N:4]([CH2:1][CH2:2][CH3:3])[C@@H:5]1[CH2:25][OH:26]
Reactant: C=CCN1C[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1COCc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CCCN1C[C@@H](O)[C@H](O)[C@H]1CO

Procedure:
The title compound was synthesized as described for compound 9 using (2R,3R,4R)-1-allyl-3,4-dibenzyloxy-2-benzyloxymethylpyrrolidine (compound 14) (0.910 g, 2.1 mmol), ethanol (100 ml), 10% Pd/C (0.2 g) and excess of 1 M hydrochloric acid to convert the amine to the hydrochloride salt. After evaporation of the solvent in vacuo the compound was purified on silica gel (Eluent: 2-propanol/25% ammonium hydroxide (4:1)) and (2R,3R,4R)-3,4-dihydroxy-2-hydrox-ymethyl-1-propylpyrrolidine was obtained as a yellow crystals (0.279 g, yield: 78%). Melting point: 79-80° C.
Reaction SMILES: [OH-].[Na+].C([O:6][C:7]1[CH:12]=[C:11]([NH:13][C:14](=[O:16])[CH3:15])[C:10]([O:17][CH3:18])=[CH:9][C:8]=1[CH3:19])(=O)C.C(O)C>C(O)(=O)C>[CH3:19][C:8]1[CH:9]=[C:10]([O:17][CH3:18])[C:11]([NH:13][C:14](=[O:16])[CH3:15])=[CH:12][C:7]=1[OH:6]
Reactant: COc1cc(C)c(OC(C)=O)cc1NC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCO
Product: COc1cc(C)c(O)cc1NC(C)=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 75 %

Procedure:
To 35 ml of a 0.4N aqueous solution of sodium hydroxide were added 1.70 g (7.17 mmol) of 2-methyl-4-methoxy-5-acetylaminophenyl acetate and 10 ml of ethanol. The mixture was stirred at room temperature for 10 minutes. When crystals were completely dissolved, the stirring was ceased. Then 0.3 ml of acetic acid was added and thus crystals were precipitated. The crystals were collected by filtration, purified by column chromatography (Silica Gel 60, trade name, manufactured by Merck Co., 230-400 mesh, 200 g, eluent: ethyl acetate) and recrystallized from the solvent mixture of ethyl acetate/hexane (2:1). Thus 1.05 g (5.38 mmol) of 2-methyl-4-methoxy-5-acetylaminophenol was obtained. The yield was 75%.
Reaction SMILES: C(OC([CH:11]1[NH:23][CH2:22][C:20]2=[C:21]3[C:16](=[C:17]([C@H:24]4[C@H:28]([C:29]5[C:37]6[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=6)[NH:31][CH:30]=5)[C:27](=[O:38])[NH:26][C:25]4=[O:39])[CH:18]=[CH:19]2)[CH:15]=[CH:14][N:13]3[CH2:12]1)=O)C1C=CC=CC=1.[H][H]>[Pd].CO>[NH:31]1[C:32]2[C:37](=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:29]([C@H:28]2[C@H:24]([C:17]3[CH:18]=[CH:19][C:20]4[CH2:22][NH:23][CH2:11][CH2:12][N:13]5[C:21]=4[C:16]=3[CH:15]=[CH:14]5)[C:25](=[O:39])[NH:26][C:27]2=[O:38])=[CH:30]1
Reactant: [H][H]
Reactant: O=C(OCc1ccccc1)C1Cn2ccc3c([C@@H]4C(=O)NC(=O)[C@H]4c4c[nH]c5ccccc45)ccc(c32)CN1
Agent: [Pd]
Solvent: CO
Product: O=C1NC(=O)[C@@H](c2ccc3c4c2ccn4CCNC3)[C@@H]1c1c[nH]c2ccccc12

Procedure:
(±)-Trans-7-[4-(1H-indol-3-yl)-2,5-dioxo-pyrrolidin-3-yl]-3,4-dihydro-1H-[1,4]diazepino[6,7,1-hi]indole-2-carb oxylic acid benzyl ester (161 mg, 0.31 mmol) and 10% palladium on carbon (100 mg) in anhydrous methanol (15 ml) were stirred under 1 atmosphere of hydrogen for 16 hours. The catalyst was then filtered through a bed of Celite and the filtrate evaporated to dryness to yield (±)-trans-3-(1H-indol-3-yl)-4-(1,2,3,4-tetrahydro-[1,4]diazepino[6,7,1-hi]indol-7-yl)-pyrrolidine-2,5-dione as an off white solid (95 mg). 1H NMR (DMSO-d6) 400 MHz δ: 11.04 (d, 1H, J=1.6 Hz), 7.35-7.42 (m, 4H), 7.24 (dd, 1H, J=2.8 and 5.6 Hz), 7.09 (t, 1H, J=7.2 Hz), 6.89-6.98 (m, 3H), 4.52 (dd, 2H, J=7.2 and 24.8 Hz), 4.11 (s, 2H), 4.07-4.10 (m, 2H), 3.14-3.17 (m, 2H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[O:10][C:3]=12.[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[C:11]1([C:9]2[O:10][C:3]3[C:4](=[N:5][CH:6]=[CH:7][C:2]=3[O:24][C:21]3[CH:22]=[CH:23][C:18]([NH2:17])=[CH:19][CH:20]=3)[CH:8]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Nc1ccc(O)cc1
Reactant: Clc1ccnc2cc(-c3ccccc3)oc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1ccc(Oc2ccnc3cc(-c4ccccc4)oc23)cc1
Temperature: 125 °C
Reaction time: 8 h
Yield: 54.5 %

Procedure:
To a 10 mL sealed tube with stirbar was added 7-chloro-2-phenylfuro[3,2-b]pyridine (300.00 mg; 1.31 mmol; 1.00 eq.), 4-aminophenol (285.09 mg; 2.61 mmol; 2.00 eq.), and caesium carbonate (1 702.45 mg; 5.22 mmol; 4.00 eq.). The mixture was suspended in DMF (7.00 ml) and stirred at 125° C. overnight. The reaction mixture was cooled to room temperature and poured into 150 mL water. Filtered to collect precipitate, washing with water and hexane. The resulting crude material was purified by Biotage chromatography using a KP-NH column (10-50% EtOAc/Hex) to afford the title compound as a beige solid (216 mg, 55%). (HPLC (method F): 99%, RT: 4.73 min); 1H NMR (400 MHz, DMSO-d6) δ [ppm] 8.29 (d, J=5.5, 1H), 7.96 (d, J=7.2, 2H), 7.66 (s, 1H), 7.54 (t, J=7.4, 3H), 7.47 (t, J=7.3, 1H), 6.99 (d, J=8.7, 2H), 6.67 (d, J=8.7, 2H), 6.56 (d, J=5.5, 1H), 5.20 (s, 2H); MS (m/z) 303 [M+H]+, RT: 2.6 min.
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([S:20][C:21](=O)N(C)C)=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.ClC[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([O:35][CH3:36])[N:30]=1>>[ClH:19].[Cl:19][C:16]1[CH:17]=[CH:18][C:11]2[CH2:10][CH2:9][NH:8][CH2:14][CH2:13][C:12]=2[C:15]=1[S:20][CH2:21][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([O:35][CH3:36])[N:30]=1
Reactant: CN(C)C(=O)Sc1c(Cl)ccc2c1CCN(C(=O)OC(C)(C)C)CC2
Reactant: COc1cccc(CCl)n1
Agent: Cl
Product: COc1cccc(CSc2c(Cl)ccc3c2CCNCC3)n1

Procedure:
Use a method similar to the Example 330, using 3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepine and 2-chloromethyl-6-methoxypyridine hydrochloride to give, after deprotection by a method similar to the General Procedure 14, the title compound as a white solid (120 mg). MS (APCI+) m/z: 335 (M+H)+.
Reaction SMILES: [F:1][CH:2]([F:27])[O:3][C:4]1[CH:5]=[C:6]([C:11]2[O:12][CH:13]=[C:14]([CH2:16][CH2:17][C:18]([C:20]3[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][N:21]=3)=[O:19])[N:15]=2)[CH:7]=[CH:8][C:9]=1[OH:10].Br[CH2:29][CH2:30][CH3:31]>>[F:27][CH:2]([F:1])[O:3][C:4]1[CH:5]=[C:6]([C:11]2[O:12][CH:13]=[C:14]([CH2:16][CH2:17][C:18]([C:20]3[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][N:21]=3)=[O:19])[N:15]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH2:29][CH2:30][CH3:31]
Reactant: CCCBr
Reactant: Cc1cccnc1C(=O)CCc1coc(-c2ccc(O)c(OC(F)F)c2)n1
Product: CCCOc1ccc(-c2nc(CCC(=O)c3ncccc3C)co2)cc1OC(F)F

Procedure:
Using the compound obtained in Example 356 and 1-bromopropane, white powdery 3-[2-(3-difluoromethoxy-4-propoxy phenyl)oxazol-4-yl]-1-(3-methylpyridin-2-yl)propan-1-one was obtained following the procedure of Example 3.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][CH:3]=1.C([Li])CCC.[B:14](OC(C)C)([O:19]C(C)C)[O:15]C(C)C>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[C:4]([B:14]([OH:19])[OH:15])[CH:3]=1
Reactant: Fc1ccc(Cl)cc1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OB(O)c1cc(Cl)ccc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 30.0 g (23 mmol) of 1-chloro-4-fluorobenzene in THF at −78° C. was added 14.4 mL (23 mmol) of a n-butyllithium solution (1.6M in hexanes). After stirring for 2.5 h at that temperature, 10.6 mL (46 mmol) of triisopropyl borate was added dropwise, and the reaction was allowed to slowly warm to room temperature and stir overnight. The reaction was carefully quenched with 1M HCl and then extracted three times with Et2O. The combined organic phase was washed with water, dried over MgSO4, and concentrated to provide 20-1 as a white powder. Data for 20-1: 1HNMR (500 MHz, CDCl3) δ 7.8 (m, 1H), 7.4 (m, 1H), 7.0 (m, 1H), 5.2 (m, 2H) ppm.
Reaction SMILES: BrCCBr.C[Si](Cl)(C)C.[CH3:10][O:11][C:12](=[O:18])/[C:13](/I)=[CH:14]\[CH2:15][CH3:16].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:38][S:39]([C:42]1[CH:47]=[CH:46][C:45](Br)=[CH:44][CH:43]=1)(=[O:41])=[O:40].[Cl-].[NH4+]>O1CCCC1.[Zn].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd]>[CH3:10][O:11][C:12](=[O:18])/[C:13](/[C:45]1[CH:46]=[CH:47][C:42]([S:39]([CH3:38])(=[O:41])=[O:40])=[CH:43][CH:44]=1)=[CH:14]/[CH2:15][CH3:16]
Reactant: CS(=O)(=O)c1ccc(Br)cc1
Reactant: CC/C=C(/I)C(=O)OC
Agent: [Pd]
Agent: C[Si](C)(C)Cl
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1CCOC1
Solvent: BrCCBr
Product: CC/C=C(/C(=O)OC)c1ccc(S(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 77.8 %

Procedure:
A mixture of zinc dust (2.36 g, 36 mmol, Aldrich, −325 mesh) and dry tetrahydrofuran (3 mL) under argon was treated with 1,2-dibromoethane (0.28 g, 1.5 mmol). The zinc suspension was then heated with a heat gun to ebullition, allowed to cool, and heated again. This process was repeated three times to make sure the zinc dust was activated. The activated zinc dust suspension was then treated with trimethylsilyl chloride (163 mg, 1.5 mmol), and the suspension was stirred for 15 min at 25° C. The reaction mixture was then treated dropwise with a solution of (E)-2-iodo-pentenoic acid methyl ester (2.9 g, 12 mmol) in dry tetrahydrofuran (3 mL) over 3 min. The reaction mixture was then stirred at 40-45° C. for 1 h and then stirred overnight at 25° C. The reaction mixture was then diluted with dry tetrahydrofuran (10 mL), and the stirring was stopped to allow the excess zinc dust to settle down (˜2 h). In a separate reaction flask, bis(dibenzylideneacetone)palladium(0) (135 mg, 0.25 mmol) and triphenylphosphine (260 mg, 1 mmol) in dry tetrahydrofuran (16 mL) was stirred at 25° C. under argon for 10 min and then treated with 4-bromophenyl methyl sulfone (2.11 g, 9 mmol) and the freshly prepared zinc compound in tetrahydrofuran. The resulting brick red solution was heated at 50° C. for 24 h. The reaction mixture was then cooled to 25° C. and then poured into a saturated aqueous ammonium chloride solution (100 ml.), and the organic compound was extracted into ethyl acetate (3×50 mL). The combined organic extracts were washed with a saturated aqueous sodium chloride solution (1×100 mL), dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40M, Silica, 3/2 hexanes/ethyl acetate) afforded (E)-2-(4-(methanesulfonyl)-phenyl)-pentenoic acid methyl ester (1.88 g, 78%) as a viscous yellow oil: EI-HRMS m/e calcd for C13H16O4S (M+) 268.0769, found 268.0772.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]([C:14]2[N:22](S(C3C=CC=CC=3)(=O)=O)[C:17]3=[N:18][CH:19]=[CH:20][CH:21]=[C:16]3[CH:15]=2)=[CH:10][CH:11]([CH3:13])[CH3:12])[CH:6]=[CH:7][CH:8]=1.[OH-].[Na+]>C(O)C.O1CCCC1.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]([C:14]2[NH:22][C:17]3=[N:18][CH:19]=[CH:20][CH:21]=[C:16]3[CH:15]=2)=[CH:10][CH:11]([CH3:13])[CH3:12])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(C(=CC(C)C)c2cc3cccnc3n2S(=O)(=O)c2ccccc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: COc1cccc(C(=CC(C)C)c2cc3cccnc3[nH]2)c1
Temperature: 70 °C
Reaction time: 18 h
Yield: 83.5 %

Procedure:
A solution of 2-(1-(3-methoxy-phenyl)-3-methyl-but-1-enyl)-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (1.87 g, 4.3 mmol) in ethanol (38.7 mL) and tetrahydrofuran (77.4 mL) was treated with an aqueous sodium hydroxide solution (10%, 14.6 mL). The reaction was stirred at 70° C. for 18 h. After cooling to 25° C., the reaction mixture was diluted with water (70 mL) and extracted with ethyl acetate (3×60 mL). The organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Silica gel column chromatography (30 g, petroleum ether/ethyl acetate 10:1) afforded 2-(1-(3-methoxy-phenyl)-3-methyl-but-1-enyl)-1H-pyrrolo[2,3-b]pyridine (1.05 g, 90%) as a yellow oil: 1H NMR (300 MHz, CDCl3) δ ppm 9.91 (s, 1H), 7.95 (dd, 1H, J1=3.6 Hz, J2=1.2 Hz), 7.89 (dd, 1H, J1=7.8 Hz, J2=1.2 Hz), 7.23 (t, 1H, J=7.8 Hz), 7.02 (s, 1H), 6.92-6.82 (m, 3H), 6.50 (s, 1H), 5.99 (d, 1H, J=9.9 Hz), 3.76 (s, 3H), 2.94-2.91 (m, 1H), 1.11 (s, 3H), 1.09 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]([C:15](=O)[CH3:16])=[CH:5][C:6]1[C:11]2=[N:12][O:13][N:14]=[C:10]2[CH:9]=[CH:8][CH:7]=1.[CH:19]([O:22][C:23](=[O:28])/[CH:24]=[C:25](\[NH2:27])/[CH3:26])([CH3:21])[CH3:20]>C(O)C>[CH3:16][C:15]1[NH:27][C:25]([CH3:26])=[C:24]([C:23]([O:22][CH:19]([CH3:21])[CH3:20])=[O:28])[CH:5]([C:6]2[C:11]3=[N:12][O:13][N:14]=[C:10]3[CH:9]=[CH:8][CH:7]=2)[C:4]=1[C:3]([O:2][CH3:1])=[O:18]
Reactant: C/C(N)=C/C(=O)OC(C)C
Reactant: COC(=O)C(=Cc1cccc2nonc12)C(C)=O
Solvent: CCO
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OC(C)C)C1c1cccc2nonc12

Procedure:
To achieve the afore-mentioned objects, the present invention provides for a process for the manufacture of the Isradipine which, involves two steps. In the first step 2,1,3-benzoxadiazole-4-carboxaldehyde is reacted with methyl acetoacetate in the presence of acetic acid and piperidine in diisopropyl ether. The product 2-acetyl-3-benzofurazan-4-yl-acrylic acid methyl ester is isolated and purified to get substantially high purity product with less than 0.3% 2,1,3-benzoxadiazole-4-carboxaldehyde content present in the purified product. In the second step the purified intermediate 2-acetyl-3-benzofurazan-4-yl-acrylic acid methyl ester is reacted with isopropyl-β-aminocrotonate in ethanol at 25 to 35° C. The crude Isradipine is crystallised from ethanol to get pure Isradipine having substantially higher purity and containing lower amount of the symmetrical ester isomers (III) and (IV).