Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C)C=O.Cl[C:7]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:8]=1[C:9]#[N:10].[F:18][C:19]([F:23])([F:22])[CH2:20][OH:21].[H-].[Na+]>O>[N+:15]([C:12]1[CH:13]=[CH:14][C:7]([O:21][CH2:20][C:19]([F:23])([F:22])[F:18])=[C:8]([CH:11]=1)[C:9]#[N:10])([O-:17])=[O:16]
Reactant: N#Cc1cc([N+](=O)[O-])ccc1Cl
Reactant: OCC(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1cc([N+](=O)[O-])ccc1OCC(F)(F)F
Reaction time: 1 h
Yield: 69.7 %

Procedure:
To a dimethylformamide solution (30 ml) containing 2-chloro-5-nitrobenzonitrile (10 g) and 2,2,2-trifluoroethanol (6 g) was added sodium hydride (60% content, 2.65 g) under ice-cooling, and the mixture was stirred for 1 h. The reaction mixture was added to water and extracted with toluene. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, after which the solvent was evaporated under reduced pressure. Diisopropyl ether was added to the residue to allow crystallization. The crystals were recrystallized from a mixed solvent of toluene-diisopropyl ether to give 5-nitro-2-(2,2,2-trifluoroethoxy)benzonitrile (9.4 g), melting point: 94° C.
Reaction SMILES: C1(P(=O)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.[CH3:36][C:37]1[CH:45]=[CH:44][C:43]([NH:46][S:47]([C:50]2[S:51][CH:52]=[CH:53][CH:54]=2)(=[O:49])=[O:48])=[C:42]2[C:38]=1[CH:39]=[C:40]([C:55]([NH:57][CH2:58][CH2:59][S:60]C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=O)[NH:41]2.C(=O)([O-])O.[Na+]>ClCCl>[S:60]1[CH2:59][CH2:58][N:57]=[C:55]1[C:40]1[NH:41][C:42]2[C:38]([CH:39]=1)=[C:37]([CH3:36])[CH:45]=[CH:44][C:43]=2[NH:46][S:47]([C:50]1[S:51][CH:52]=[CH:53][CH:54]=1)(=[O:49])=[O:48]
Reactant: Cc1ccc(NS(=O)(=O)c2cccs2)c2[nH]c(C(=O)NCCSC(c3ccccc3)(c3ccccc3)c3ccccc3)cc12
Agent: O=C([O-])O
Agent: O=P(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc(NS(=O)(=O)c2cccs2)c2[nH]c(C3=NCCS3)cc12
Reaction time: 0.5 h
Yield: 91 %

Procedure:
A mixture of triphenylphosphine oxide (2.1 g), trifluoromethanesulfonic anhydride (0.63 mL) and dichloromethane (35 mL) was stirred for 30 min under ice-cooling. 4-Methyl-7-[(2-thienylsulfonyl)amino]-N-[2-(tritylthio)ethyl]-1H-indole-2-carboxamide (0.80 g) was added, and the mixture was stirred for 90 min under ice-cooling. The reaction mixture was poured into aqueous sodium hydrogencarbonate solution and extracted with dichloromethane. The aqueous layer was extracted with dichloromethane, and the combined dichloromethane layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (ethyl acetate:hexane=3:7-5:5), and the obtained crystals were recrystallized from ethyl acetate-hexane to give the title compound (431 mg, yield 91%) as colorless prism crystals. melting point 198-199° C.
Reaction SMILES: [CH2:1]([N:3]1[C:7]([CH3:8])=[C:6]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH:5]=[N:4]1)[CH3:2].[Li]CCCC.[CH3:22][C@:23]1([CH2:31][N:32]2[C:36]3[CH:37]=[C:38]([C:41]#[N:42])[CH:39]=[CH:40][C:35]=3[N:34]=[CH:33]2)CCC[C@:25]2(OC2)[CH2:24]1.CN1C(=O)CCC1>C1COCC1.O>[CH2:1]([N:3]1[C:7]([CH3:8])=[C:6]([N:9]2[CH2:13][C@@:12]3([CH2:15][CH2:25][CH2:24][C@@:23]([CH2:31][N:32]4[C:36]5[CH:37]=[C:38]([C:41]#[N:42])[CH:39]=[CH:40][C:35]=5[N:34]=[CH:33]4)([CH3:22])[CH2:14]3)[O:11][C:10]2=[O:16])[CH:5]=[N:4]1)[CH3:2]
Reactant: C[C@]1(Cn2cnc3ccc(C#N)cc32)CCC[C@@]2(CO2)C1
Reactant: CCn1ncc(NC(=O)OC(C)(C)C)c1C
Agent: [Li]CCCC
Solvent: CN1CCCC1=O
Solvent: C1CCOC1
Solvent: O
Product: CCn1ncc(N2C[C@@]3(CCC[C@](C)(Cn4cnc5ccc(C#N)cc54)C3)OC2=O)c1C
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 38.9 %

Procedure:
A solution of 1-ethyl-5-methyl-1H-pyrazol-4-amine, 2 hydrochloride (0.5 g, 2.52 mmol), Boc2O (0.703 ml, 3.03 mmol), TEA (1.055 mL, 7.57 mmol) and DMAP (10 mg, 0.082 mmol) in DCM (18.74 mL) was stirred at RT for 16 h. The mixture was then extracted with DCM, dried over Na2SO4 and filtered. The filtrate was concentrated and purified via silica gel chromatography (ISCO, 40 g column; 0-5% MeOH/DCM) to give tert-butyl (1-ethyl-5-methyl-1H-pyrazol-4-yl)carbamate as brown oil (300 mg, 52.8% yield). To a solution of tert-butyl (1-ethyl-5-methyl-1H-pyrazol-4-yl)carbamate (0.162 g, 0.719 mmol) in THF (1 mL) at −78° C. under N2 was added n-BuLi (2.5M in hexane) (0.27 ml, 0.675 mmol) dropwise. The mixture was allowed to warm up to RT and stirred for 20 min. 1-{[(3S,5S)-5-methyl-1-oxaspiro[2.5]oct-5-yl]methyl}-1H-benzimidazole-6-carbonitrile (0.15 g, 0.533 mmol) was then added followed by NMP (0.5 mL). The solution was then heated at 70° C. for 16 h. Water was then added to the reaction mixture and extracted with EtOAc. The organic layer was concentrated and purified via HPLC to give 1-(((5S,7S)-3-(1-ethyl-5-methyl-1H-pyrazol-4-yl)-7-methyl-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile as a white solid (89.6 mg, 38.9% yield). 1H NMR (400 MHz, DMSO-d6) δ 8.47 (s, 1H), 8.38 (s, 1H), 7.83 (d, J=8.28 Hz, 1H), 7.59 (dd, J=1.51, 8.28 Hz, 1H), 7.41 (s, 1H), 4.16 (br. s., 2H), 4.03 (q, J=7.03 Hz, 2H), 3.54 (s, 2H), 2.14 (s, 3H), 1.95 (d, J=14.0 Hz, 1H), 1.86 (d, J=14.31 Hz, 1H), 1.61 (d, J=13.55 Hz, 3H), 1.31-1.51 (m, 3H), 1.28 (t, 3H), 1.06 (s, 3H). MS (m/z) 433.3 (M+H+).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.F[C:10]1[CH:23]=[CH:22][C:13]([C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:15])=[CH:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>C1(C)C=CC=CC=1>[I:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:22]2[CH:23]=[CH:10][CH:11]=[CH:12][C:13]=2[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:15])=[CH:4][CH:3]=1
Reactant: Oc1ccc(I)cc1
Reactant: O=C(c1ccccc1)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: O=C(c1ccccc1)c1ccccc1Oc1ccc(I)cc1
Temperature: 160 °C
Reaction time: 2 h
Yield: 79.1 %

Procedure:
A 1000 mL 3-necked round-bottomed flask fitted with a Dean-Stark trap, condenser, stir-bar and nitrogen gas adaptor was charged with 4-iodophenol (19.0 g, 0.086 mol), 4-fluorobenzophenone (15.72 g, 0.079 mol), potassium carbonate (7.16 g, 0.0518 mol), DMF (157 mL) and toluene (16 mL). The resulting mixture was stirred and refluxed for 2 hours (solution temperature ˜160° C.) under nitrogen atmosphere. Water was collected at the trap during this period of time. After 2 hours, the reaction was cooled to room temperature, and water (400 mL) was added to the reaction mixture and the desired product precipitated out of solution as a cream white solid. The product was further purified by re-crystallization isopropanol (400 mL) to give the desired product as a white crystalline solid (25 g, 87% yield).
Reaction SMILES: [C:1]([C:9]1([CH2:16][CH2:17][C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)=[O:19])[CH2:14]CCC[C:10]1=[O:15])(=O)[C:2]1C=CC=C[CH:3]=1.[OH:30]O>C(O)(C)(C)C.S(=O)(=O)(O)O>[CH3:29][O:28][C:25]1[CH:26]=[CH:27][C:22]([CH2:21][O:20][C:18]([CH2:17][CH2:16][C:9]2([C:10]([OH:30])=[O:15])[CH2:14][CH2:3][CH2:2][CH2:1]2)=[O:19])=[CH:23][CH:24]=1
Reactant: COc1ccc(COC(=O)CCC2(C(=O)c3ccccc3)CCCCC2=O)cc1
Reactant: OO
Agent: O=S(=O)(O)O
Solvent: CC(C)(C)O
Product: COc1ccc(COC(=O)CCC2(C(=O)O)CCCC2)cc1
Reaction time: 48 h
Yield: 44.5 %

Procedure:
To a solution of 2-benzoyl-2-[2-(4-methoxybenzyloxycarbonyl)-ethyl]cyclohexanone (see Preparation 9) (2.16 g, 5.47 mmol) in tert-butanol (4.3 ml) was added, dropwise, a 30% aqueous solution of hydrogen peroxide (0.74 ml, 6.56 mmol) and concentrated sulphuric acid (98% w/w, one drop) at room temperature. The mixture was stirred for 48 hours, partitioned between toluene (25 ml) and 5% aqueous sodium sulphite solution and the layers separated. The toluene layer was washed with dilute aqueous ammonia solution (25 ml of 0.880 ammonia in 200 ml of distilled water, 4×25 ml). The combined aqueous extracts were washed with toluene (25 ml), acidified to pH 2-3 with 5.ON aqueous hydrochloric acid solution and extracted with toluene (3×25 ml). The combined toluene extracts were dried over magnesium sulphate, filtered and concentrated under reduced pressure to give the title compound as an oil, (0.746 g, 44.6%). RF. 0.16 silica, hexane/ethyl acetate 2:1). 1H-NMR (300 MHz, CDCl3):=1.45-1.59 (m, 2H), 1.65-1.78 (m, 4H), 1.98-2.06 (m, 2H), 2.12-2.22 (m, 2H), 2.34-2.46 (m, 2H), 3.84 (s, 3H), 5.06 (s, 2H), 6.91 (d, 2H), 7.31 (d, 2H) ppm. Analysis %: Found: C, 67.05; H, 7.18; C17H22O5 requires: C, 66.65; H, 7.24.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([OH:11])[CH:9]=2)[CH:4]=[CH:3][C:2]=1[OH:12].Cl[C:14]1[C:23]2[C:18](=[CH:19][C:20]([O:26][CH3:27])=[C:21]([O:24][CH3:25])[CH:22]=2)[N:17]=[CH:16][CH:15]=1.[OH-].[K+]>CN1C(=O)CCC1.O.[Cu]>[CH3:25][O:24][C:21]1[CH:22]=[C:23]2[C:18](=[CH:19][C:20]=1[O:26][CH3:27])[N:17]=[CH:16][CH:15]=[C:14]2[O:12][C:2]1[CH:1]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([OH:11])=[CH:9]2)=[CH:4][CH:3]=1
Reactant: Oc1ccc2ccc(O)cc2c1
Reactant: COc1cc2nccc(Cl)c2cc1OC
Agent: [Cu]
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Solvent: O
Product: COc1cc2nccc(Oc3ccc4ccc(O)cc4c3)c2cc1OC
Temperature: 150 °C

Procedure:
To a solution of naphthalene-2,7-diol (8.95 g, 55.88 mmol) in NMP (50 mL) in a sealed tube, was added 4-chloro-6,7-dimethoxyquinoline (5.0 g, 22.35 mmol). KOH (1.40 g, 24.58 mmol) was added, followed by copper powder (0.71 g, 11.18 mmol). The tube was sealed and the solution was stirred and heated to 150° C. for 24 h. The reaction was cooled to RT, diluted with water and extracted with EtOAc 3×. The combined organic layer was washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. The crude material was purified by silica gel chromatography with 50% to 100% (95:5:0.5 EtOAc/MeOH/NH4OH) in Hexanes to give the titled compound. MS (ESI, pos. ion) m/z: 348.2 (M+1).
Reaction SMILES: [C:1]1(=[O:10])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[N+:11]([O-])([O-:13])=[O:12].[K+].[N+](C1C=CC=C2C=1CCC2=O)([O-])=O>OS(O)(=O)=O>[N+:11]([C:7]1[CH:8]=[C:9]2[C:4]([CH2:3][CH2:2][C:1]2=[O:10])=[CH:5][CH:6]=1)([O-:13])=[O:12]
Reactant: O=[N+]([O-])[O-]
Reactant: O=C1CCc2ccccc21
Agent: O=C1CCc2c1cccc2[N+](=O)[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: O=C1CCc2ccc([N+](=O)[O-])cc21
Reaction time: 1 h

Procedure:
A solution of concentrated H2SO4 at 0° C. was treated with 1-indanone (6.00 g, 45.4 mmol) then treated dropwise with KNO3 (5.00 g, 49.94 mmol) in concentrated H2SO4 while maintaining the internal temperature at no more than 15° C. The reaction was stirred for 1 hour after the addition was complete, then poured onto ice. The resulting solids were collected by filtration, washed with water, and dried under vacuum to give a 4:1 mixture of 6-nitro- and 4-nitro-1-indanone (5.04 g, 63%). MS (ESI(+) m/e 178 (M+H)+, 195 (M+NH4)+; MS (ESI(−)) m/e 176 (M−H)−; 1H NMR (300 MHz, DMSO-d6, 6-nitro-1-indanone) δ 8.49 (dd, 1H), 8.29 (d, 1H), 7.87 (d, 1H), 3.25 (m, 2H), 2.78 (m, 2H); 1H NMR (300 MHz, DMSO-d6), 4-nitro-1-indanone) δ 8.51 (dd, 1H), 8.07 (dd, 1H), 7.74 (t, 1H), 3.53 (m, 2H), 2.76 (m, 2H).
Reaction SMILES: [C:1]1([SiH:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O:23][CH2:24][CH:25]=[CH2:26])(=O)C>>[OH:23][CH2:24][CH2:25][CH2:26][Si:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: C=CCOC(C)=O
Reactant: c1ccc([SiH](c2ccccc2)c2ccccc2)cc1
Product: OCCC[Si](c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
The above-mentioned compounds (G-1), (G-2) and (G-3) are prepared by hydrolyzing an adduct (C) of commercially available triphenylsilane (A) and allyl acetate (B) with an alkali to obtain 3-hydroxypropyltriphenylsilane (D) and reacting this compound (D) with acryloyl chloride (E), methacryloyl chloride (E-2) or allyl chloroformate (E-3) in the presence of a dehydrochlorinating agent such as pyridine or triethylamine. ##STR5##
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:24]=[CH:25][C:26]=1[N:27]1[CH2:31][C:30](=[O:32])[N:29](CC[Si](C)(C)C)[S:28]1(=[O:40])=[O:39])[CH2:12][C@@H:13]1[CH2:18][CH2:17][CH2:16][CH2:15][C@H:14]1[NH:19][S:20]([CH3:23])(=[O:22])=[O:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F-].[Cs+].C(OCC)(=O)C>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:24]=[CH:25][C:26]=1[N:27]1[CH2:31][C:30](=[O:32])[NH:29][S:28]1(=[O:39])=[O:40])[CH2:12][C@@H:13]1[CH2:18][CH2:17][CH2:16][CH2:15][C@H:14]1[NH:19][S:20]([CH3:23])(=[O:21])=[O:22])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)CCN1C(=O)CN(c2ccc(C[C@@H]3CCCC[C@H]3NS(C)(=O)=O)cc2OCc2ccccc2)S1(=O)=O
Agent: [Cs+]
Agent: [F-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CS(=O)(=O)N[C@@H]1CCCC[C@H]1Cc1ccc(N2CC(=O)NS2(=O)=O)c(OCc2ccccc2)c1
Temperature: 90 °C
Reaction time: 1 h

Procedure:
To a solution of N-((1R*,2S*)-2-{3-Benzyloxy-4-[1,1,4-trioxo-5-(2-trimethylsilanylethyl)-1,2,5-thiadiazolidin-2-yl]-benzyl}-cyclohexyl)-methanesulfonamide (118 mg, 0.194 mmol) in DMF (3 mL) is added CsF (118 mg, 0.78 mmol) and the mixture is stirred at 90° C. for 1 h. Ethyl acetate is added and the mixture is washed with 1N HCl and brine. The organic phase is dried over magnesium sulfate and the solvent is removed under reduced pressure to give the title compound.
Reaction SMILES: Br[C:2]1[C:11]([O:12][C:13]2[C:22]3[C:17](=[CH:18][C:19]([O:25][CH3:26])=[C:20]([O:23][CH3:24])[CH:21]=3)[N:16]=[CH:15][CH:14]=2)=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[N:27]1[CH:32]=[CH:31][CH:30]=[C:29](B(O)O)[CH:28]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:24][O:23][C:20]1[CH:21]=[C:22]2[C:17](=[CH:18][C:19]=1[O:25][CH3:26])[N:16]=[CH:15][CH:14]=[C:13]2[O:12][C:11]1[C:2]([C:29]2[CH:28]=[N:27][CH:32]=[CH:31][CH:30]=2)=[N:3][C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: COc1cc2nccc(Oc3cc4ccccc4nc3Br)c2cc1OC
Reactant: OB(O)c1cccnc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2nccc(Oc3cc4ccccc4nc3-c3cccnc3)c2cc1OC
Temperature: 25 °C
Yield: 32.1 %

Procedure:
4-(2-Bromo-quinolin-3-yloxy)-6,7-dimethoxy-quinoline (compound 281) (50 mg), tetrakistriphenylphosphine palladium(0) (14 mg), and 3-pyridineboronic acid (42 mg) were suspended in a mixed solvent composed of N,N-dimethylformamide (1 ml) and a 2 N aqueous potassium carbonate solution (1 ml), and the mixture was stirred at 80° C. for 3 hr. The reaction solution was cooled to room temperature, the reaction solution was then filtered, and the solvent was removed from the filtrate by distillation under the reduced pressure. Water was then added to the residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous magnesium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using acetone-chloroform to give the title compound (16 mg, yield 33%).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:23])[C@H:5]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1)[NH:6][C:7]([C:9]1([NH2:14])[CH2:13][CH2:12][CH2:11][CH2:10]1)=[O:8].C(N(CC)CC)C.[C:31]([S:34][C@@H:35]([CH:39]([CH3:41])[CH3:40])[C:36](O)=[O:37])(=[O:33])[CH3:32].C1(N=C=NC2CCCCC2)CCCCC1.ON1C2N=CC=CC=2N=N1>ClCCl>[CH3:2][O:3][C:4](=[O:23])[C@H:5]([CH2:15][C:16]1[CH:17]=[CH:18][C:19]([OH:22])=[CH:20][CH:21]=1)[NH:6][C:7]([C:9]1([NH:14][C:36](=[O:37])[C@@H:35]([S:34][C:31](=[O:33])[CH3:32])[CH:39]([CH3:41])[CH3:40])[CH2:13][CH2:12][CH2:11][CH2:10]1)=[O:8]
Reactant: COC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)C1(N)CCCC1
Reactant: CC(=O)S[C@H](C(=O)O)C(C)C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)C1(NC(=O)[C@@H](SC(C)=O)C(C)C)CCCC1
Reaction time: 0.08 h

Procedure:
To a solution of [(1-amino(1-cyclopentyl)carbonyl]-L-tyrosine methyl ester hydrochloride (1.36 g, 3.97 mmol) in dichloromethane (50 mL) is added triethylamine (0.55 mL, 3.97 mmol). The mixture is stirred for 5 minutes and then (S)-2-acetylthio-3-methylbutanoic acid (0.70 g, 3.97 mmol), 1,3-dicyclohexylcarbodiimide (0.82 g, 3.97 mmol) and 1-hydroxy-7-azabenzotriazole (0.54 g, 3.97 mmol) are added. The mixture is stirred for 16 hours and then the solid precipitate is filtered off. The organic phase is washed with a saturated solution of sodium bicarbonate (30 mL), brine, dried over MgSO4, filtered and concentrated under reduced pressure to give a white foam. The foam is purified by flash chromatography on silica gel, eluting with hexane-ethyl acetate (1:1). The pure fractions are concentrated and the resulting foam is crystallized from ethyl acetate-hexane to afford N-[[1-[(2(S)-acetylmercapto-3-methyl-1-oxobutyl)amino]-1-cyclopentyl]carbonyl]-L-tyrosine methyl ester as a white solid, m.p. 157°-158° C., the compound of formula III wherein R1 is 4-hydroxyphenyl, R2 is methyl, R3 is acetyl and R4 is isopropyl.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[C:5]([CH3:13])[N:4]([C:14]2[N:19]=[CH:18][C:17]([CH2:20][CH2:21][NH:22][C:23](=[O:31])OC3C=CC=CC=3)=[CH:16][CH:15]=2)[N:3]=1.[C:32]1([S:42]([NH2:45])(=[O:44])=[O:43])[CH:37]=[CH:36][CH:35]=[C:34]([S:38]([NH2:41])(=[O:40])=[O:39])[CH:33]=1>>[CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[C:5]([CH3:13])[N:4]([C:14]2[N:19]=[CH:18][C:17]([CH2:20][CH2:21][NH:22][C:23]([NH:45][S:42]([C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([S:38]([NH2:41])(=[O:40])=[O:39])[CH:33]=3)(=[O:44])=[O:43])=[O:31])=[CH:16][CH:15]=2)[N:3]=1
Reactant: NS(=O)(=O)c1cccc(S(N)(=O)=O)c1
Reactant: Cc1nn(-c2ccc(CCNC(=O)Oc3ccccc3)cn2)c(C)c1-c1ccccc1
Product: Cc1nn(-c2ccc(CCNC(=O)NS(=O)(=O)c3cccc(S(N)(=O)=O)c3)cn2)c(C)c1-c1ccccc1

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 42 from phenyl 2-[6-(3,5-dimethyl-4-phenyl-1H-pyrazol-1-yl)pyridin-3-yl]ethylcarbamate (step 5 of Example 83) and 1,3-benzenedisulfonamide: 1H-NMR (CDCl3) δ 8.48-8.43 (1H, m), 8.10-7.76 (3H, m), 7.48-7.20 (8H, m), 6.61 (1H, br.s), 3.43-3.24 (2H, m), 2.73-2.59 (2H, m), 2.37 (3H, s), 2.25 (3H, s).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=2)[C:9]([C:20]([OH:22])=[O:21])=[C:8]([CH3:23])[NH:7][C:6]=1[CH3:24])=[O:4].C1(N=C=NC2CCCCC2)CCCCC1.CN(C1C=CC=CN=1)C.[CH:49]([N:62]1[CH2:67][CH2:66][N:65]([CH2:68][CH2:69]O)[CH2:64][CH2:63]1)([C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1)[C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1>C1(C)C=CC=CC=1>[CH3:24][C:6]1[NH:7][C:8]([CH3:23])=[C:9]([C:20]([O:22][CH2:69][CH2:68][N:65]2[CH2:64][CH2:63][N:62]([CH:49]([C:56]3[CH:57]=[CH:58][CH:59]=[CH:60][CH:61]=3)[C:50]3[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=3)[CH2:67][CH2:66]2)=[O:21])[CH:10]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=2)[C:5]=1[C:3]([O:2][CH3:1])=[O:4]
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)O)C1c1cccc([N+](=O)[O-])c1
Reactant: OCCN1CCN(C(c2ccccc2)c2ccccc2)CC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccccn1
Solvent: Cc1ccccc1
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCN2CCN(C(c3ccccc3)c3ccccc3)CC2)C1c1cccc([N+](=O)[O-])c1
Temperature: 72.5 °C
Yield: 54.4 %

Procedure:
To a suspension of 2,6-dimethyl-4-(3-nitro-phenyl)-1,4-dihydro-pyridine-3,5-dicarboxylic acid monomethyl ester (5 gm), dicyclohexyl carbodiimide (3.08 gm) and dimethylamino pyridine (0.25 gm) in toluene (30 ml) at room temperature was added 2-(4-benzhydryl piperazine-1-yl)ethanol (7.5 gm). Reaction mass was then heated to 70-75° C. for 2 hours. Reaction mass was then cooled to room temperature and filtered. Toluene layer was concentrated under vacuum to get manidipine base (5 gm).
Reaction SMILES: [CH3:1][CH:2]([CH3:18])[CH2:3][CH:4]([NH2:17])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.CO>CC(C)=O>[CH3:1][CH:2]([CH3:18])[CH2:3][C@H:4]([NH2:17])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: CC(C)CC(N)c1ccccc1N1CCCCC1
Solvent: CC(C)=O
Solvent: CO
Product: CC(C)C[C@H](N)c1ccccc1N1CCCCC1

Procedure:
Equimolar quantities of racemic 3-methyl-1-(2-pieridinophenyl)-1-butylamine and of N-acetyl-L-gluatmic acid were refluxed in aceton, whereby methanol was added in such an amount to yield a clear solution.
Reaction SMILES: [Br:1]([O-])(=O)=O.[Na+].[F:6][C:7]([F:21])([F:20])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16].S(=O)(O)[O-].[Na+].S(S([O-])=O)([O-])=O.[Na+].[Na+]>O.C(OCC)(=O)C>[Br:1][CH:14]([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[C:7]([F:20])([F:21])[F:6])[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: [O-][Br+2]([O-])[O-]
Reactant: CCOC(=O)Cc1ccccc1C(F)(F)F
Agent: O=S([O-])O
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)C(Br)c1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 18 h
Yield: 31 %

Procedure:
585 mg (3.89 mmol) of sodium bromate were initially charged in 2 ml of water, and 300 mg (1.29 mmol) of ethyl 2-(trifluoromethyl)phenylacetate, dissolved in 2.5 ml of ethyl acetate, were added at RT. A solution of 403 mg (3.89 mmol) of sodium bisulfite in 3.8 ml of water was then added slowly. The mixture was stirred at RT for 18 h. 5 ml of 10% strength aqueous sodium dithionite solution were then added. The mixture was extracted with 15 ml of ethyl acetate, and the organic phase was washed in each case once with 5 ml of 10% strength sodium dithionite solution and 5 ml of saturated sodium chloride solution. The organic phase was dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 20:1, then 10:1). This gave 186 mg of a mixture consisting of the title compound and the starting material ethyl 2-(trifluoromethyl)phenylacetate (ratio 16:84 according to GC/MS [Method 20]). This mixture was once more reacted with 362 mg (2.40 mmol) of sodium bromate and 250 mg (2.40 mmol) of sodium bisulfite according to the procedure described above. Work-up gave a mixture of 31% title compound and 69% ethyl 2-(trifluoromethyl)phenylacetate, which was reacted further without any further purification.
Reaction SMILES: [C:1]([C:3]1[CH:20]=[CH:19][C:6]([NH:7][C:8]2[C:9]([C:16]([NH2:18])=[O:17])=[CH:10][N:11]([CH3:15])[C:12](=[O:14])[CH:13]=2)=[C:5]([F:21])[CH:4]=1)#[CH:2]>CO.C1COCC1.[Pd]>[CH2:1]([C:3]1[CH:20]=[CH:19][C:6]([NH:7][C:8]2[C:9]([C:16]([NH2:18])=[O:17])=[CH:10][N:11]([CH3:15])[C:12](=[O:14])[CH:13]=2)=[C:5]([F:21])[CH:4]=1)[CH3:2]
Reactant: C#Cc1ccc(Nc2cc(=O)n(C)cc2C(N)=O)c(F)c1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: CCc1ccc(Nc2cc(=O)n(C)cc2C(N)=O)c(F)c1
Yield: 82 %

Procedure:
4-(4-Ethynyl-2-fluoroanilino)-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxamide was hydrogenated in MeOH/THF in the presence of 5% Pd/C as for example 3. Purification of the crude oil was carried out by column chromatography on silica gel (50% acetone/CH2Cl2 as eluant) to give 4-(4-ethyl-2-fluoroanilino)-1-methyl-6-oxo-1,6-dihydro-3-pyridinecarboxamide as a cream solid (82%), m.p. (EtOAc) 268-272° C. 1H NMR [(CD3)2SO, 400 MHz] δ 10.14 (s, 1H), 8.32 (s, 1H), 7.84 (br s, 1H), 7.43 (br s, 1H), 7.33 (t, J=8.4 Hz, 1H), 7.19 (dd, J=11.1, 1.7 Hz, 1H), 7.08 (dd, J=8.2, 1.5 Hz, 1H), 5.39 (d, J=1.1 Hz, 1H), 3.36 (s, 3H), 2.62 (q, J=7.6 Hz, 2H), 1.19 (t, J=7.6 Hz, 3H). Anal. Calcd for C15H16FN3O2: C, 62.3; H, 5.6; N, 14.5. Found: C, 62.5; H, 5.4; N, 14.8.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:11]([I:12])=[CH:10][NH:9][C:4]=2[N:5]=[C:6]([CH3:8])[N:7]=1.ClC1C2C(I)=CN([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])C=2N=CN=1>>[Cl:1][C:2]1[C:3]2[C:11]([I:12])=[CH:10][N:9]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:4]=2[N:5]=[C:6]([CH3:8])[N:7]=1
Reactant: C[Si](C)(C)CCOCn1cc(I)c2c(Cl)ncnc21
Reactant: Cc1nc(Cl)c2c(I)c[nH]c2n1
Product: Cc1nc(Cl)c2c(I)cn(COCC[Si](C)(C)C)c2n1

Procedure:
4-Chloro-5-iodo-2-methyl-7H-pyrrolo[2,3-d]pyrimidine (C22) was converted to the product according to the method used for synthesis of 4-chloro-5-iodo-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine (C1) in Preparation P1. The product was obtained as a yellow oil. Yield: 400 mg, 0.94 mmol, 84%. LCMS m/z 424.0[M+H+].