Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:7][CH:8]1[CH2:11][CH:10]([O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])[CH2:9]1)(=O)C(C)(C)C.[H-].C([Al+]CC(C)C)C(C)C>C1COCC1>[Si:13]([O:12][CH:10]1[CH2:11][CH:8]([OH:7])[CH2:9]1)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]
Reactant: CC(C)(C)C(=O)OC1CC(O[Si](C)(C)C(C)(C)C)C1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OC1CC(O)C1
Reaction time: 1 h

Procedure:
To a stirred solution of 3-(tert-butyldimethylsilyloxy)cyclobutyl pivalate (4.32 g, 15 mmol) in THF (20 ml) at 0° C. was added diisobutylaluminum hydride, 1.0m solution in hexanes (48 ml, 48 mmol) dropwise. The reaction was stirred in 1 h, then slowly quenched with Rochelle's salt. The quenched mixture was stirred and layers were separated. The organic layer was dried over MgSO4 and concentrated to give the title compound as a colorless oil.
Reaction SMILES: [H+].[B-](F)(F)(F)F.O=O.[Br:9]/[C:10](=[CH:14]\[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])/[C:11]([OH:13])=[O:12]>CO>[Br:9][C@H:10]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[C:11]([OH:13])=[O:12]
Reactant: CCCCC/C=C(\Br)C(=O)O
Agent: F[B-](F)(F)F
Agent: O=O
Agent: [H+]
Solvent: CO
Product: CCCCCC[C@@H](Br)C(=O)O
Reaction time: 1.5 h
Yield: 59.5 %

Procedure:
A catalyst solution was prepared by dissolving 0.035 g (0.0045 mmol) of Ru(OAc)2 [(R)-BIPHEMP] and 17.2 mg (0.0905 mmol) of an 85 percent ethereal HBF4 solution in 20 ml of methanol in a glove box (O2 content <1 ppm) and was stirred at 20° for 1.5 hours. Then, 1.0 g (4.52 mmol) of (Z)-2-bromo-2-octenoic acid and 105 ml of methanol were placed in a 185 ml autoclave and the above-prepared catalyst solution was added. The autoclave was sealed and the hydrogenation was carried out at 50° while stirring and under a constant pressure of 50 bar. After 21 hours the conversion was 98%. The hydrogenation solution was evaporated at 50°/20 mbar and the residue was distilled at 115°/0.2 mbar in a bulb tube oven. There was obtained 0.6 g of (R)-2-bromo-octanoic acid as a colourless oil; chem. purity 97.3 GC area%; 86.0% ee.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]4[CH2:21][C:20](=[O:22])[CH2:19][CH2:18][CH2:17][C:14]=4[CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH:33](=O)[CH3:34]>C1COCC1>[CH:33](=[C:21]1/[C:20](=[O:22])[CH2:19][CH2:18][CH2:17][C:14]2[CH:15]=[C:16]3[C:11]([CH:10]=[N:9][N:8]3[C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)=[CH:12][C:13]/1=2)\[CH3:34]
Reactant: O=C1CCCc2cc3c(cnn3-c3ccc(F)cc3)cc2C1
Reactant: CC=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C/C=C1/C(=O)CCCc2cc3c(cnn3-c3ccc(F)cc3)cc21
Temperature: -70 °C
Yield: 79.1 %

Procedure:
A three necked round bottom flask with septum, nitrogen line, thermometer and stir bar was charged with the 1-(4-fluorophenyl)-5,7,8,9-tetrahydrocyclohepta[f]indazol-6(1H)-one (6, R1=4-Fluorophenyl) (3.75 g, 12.74 mmol) and THF (50 mL). The solution was cooled to about −70° C. then LiHMDS (12.74 mL, 12.74 mmol) was added keeping the internal temp below about −60° C. The mixture was warmed to about 0° C. over about 5 min then cooled to about −70° C. Acetaldehyde (0.786 g, 17.84 mmol) was added in one portion. The mixture was stirred for about 2 h at about −78° C. then the cold bath was removed and the mixture was allowed to warm to about 10° C. Brine (25 mL), water (25 mL) and EtOAc (100 mL) were added and the layers were separated. The aqueous layer was extracted with EtOAc (50 mL) then the organic solutions were combined, extracted with brine (50 mL), dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified on silica gel (120 g) using a gradient of 0-50% EtOAc in heptane. Product fractions were combined and concentrated under reduced pressure to yield (E)-5-ethylidene-1-(4-fluorophenyl)-5,7,8,9-tetrahydrocyclohepta[f]indazol-6(1H)-one (3.23 g, 79%); LC/MS, method 3, Rt=2.68 min, MS m/z 321 (M+H)+. 1H NMR (400 MHz, DMSO) δ 8.36 (d, J=0.8 Hz, 1H), 7.87-7.80 (m, 2H), 7.75 (s, 1H), 7.70 (s, 1H), 7.50-7.40 (m, 2H), 7.12 (q, J=7.4 Hz, 1H), 2.82 (t, J=7.0 Hz, 2H), 2.28 (t, J=7.1 Hz, 2H), 2.01-1.91 (m, 2H), 1.87 (d, J=7.4 Hz, 3H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][OH:8].[CH:9]1[C:14]([C:15]([OH:17])=[O:16])=[CH:13][C:12]2[C:18]([O:20][C:21](=[O:22])[C:11]=2[CH:10]=1)=O>O>[O:22]=[C:21]1[C:11]2[C:12](=[CH:13][C:14]([C:15]([OH:17])=[O:16])=[CH:9][CH:10]=2)[C:18](=[O:20])[N:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][OH:8]
Reactant: NCCCCCCO
Reactant: O=C(O)c1ccc2c(c1)C(=O)OC2=O
Solvent: O
Product: O=C(O)c1ccc2c(c1)C(=O)N(CCCCCCO)C2=O

Procedure:
A mixture of 6-aminohexan-1-ol (11.7 g, 10 mmol) and 1,2,4-benzenetricarboxylic anhydride (7.68 g, 4 mmol) was heated to 175°-225° C. for 15 min or until evolution of H2O vapor stops. The melt was poured into water to give a white crystalline solid. The solid was collected by vacuum filtration and dried overnight in vacuo to give 9.1 g (78%) of analytically pure 27.
Reaction SMILES: C(O)(C(F)(F)F)=O.C([O:12][N:13]1[C:22](=[O:23])[C:21]2[CH:24]=[C:25]([O:40][CH3:41])[C:26]([N:27]3[CH2:31][CH2:30][CH:29]([NH:32]C(=O)OC(C)(C)C)[CH2:28]3)=[C:19]3[C:20]=2[C:15](=[CH:16][CH:17]=[CH:18]3)[C:14]1=[O:42])(C)(C)C>>[NH2:32][CH:29]1[CH2:30][CH2:31][N:27]([C:26]2[C:25]([O:40][CH3:41])=[CH:24][C:21]3[C:22](=[O:23])[N:13]([OH:12])[C:14](=[O:42])[C:15]4[C:20]=3[C:19]=2[CH:18]=[CH:17][CH:16]=4)[CH2:28]1
Reactant: COc1cc2c3c(cccc3c1N1CCC(NC(=O)OC(C)(C)C)C1)C(=O)N(OC(C)(C)C)C2=O
Solvent: O=C(O)C(F)(F)F
Product: COc1cc2c3c(cccc3c1N1CCC(N)C1)C(=O)N(O)C2=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 15.3 %

Procedure:
Following the procedure from Example 62, TFA (1.0 mL) and [1-(2-tert-butyloxy-1,3-dioxo-2,3-dihydro-5-methoxy-1H-benzo[de]isoquinolin-6-yl)-pyrrolidin-3-yl]-carbamic acid, tert-butyl ester (0.2 g, 0.4 mmol, from Example N2) was stirred at room temperature overnight, concentrated, and the solid recrystalillized from ethanol/ether to give 0.02 g of the title compound, mp 217-222° C.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][CH:7]=[C:8]([CH2:10][CH2:11][C:12]2[CH:30]=[CH:29][C:15]([CH2:16][NH:17][C:18]([NH:20][NH:21]C(OC(C)(C)C)=O)=[O:19])=[CH:14][CH:13]=2)[N:9]=1)(=[O:3])[CH3:2].O1CCOCC1.[ClH:37]>ClCCl>[ClH:37].[C:1]([NH:4][C:5]1[S:6][CH:7]=[C:8]([CH2:10][CH2:11][C:12]2[CH:30]=[CH:29][C:15]([CH2:16][NH:17][C:18]([NH:20][NH2:21])=[O:19])=[CH:14][CH:13]=2)[N:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1nc(CCc2ccc(CNC(=O)NNC(=O)OC(C)(C)C)cc2)cs1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC(=O)Nc1nc(CCc2ccc(CNC(=O)NN)cc2)cs1
Temperature: 25 °C
Reaction time: 1 h
Yield: 101.9 %

Procedure:
To a suspension of tert-butyl 2-[(4-{2-[2-(acetylamino)-1,3-thiazol-4-yl]ethyl}benzyl)carbamoyl]hydrazinecarboxylate (281.8 mg, 0.65 mmol) in anhydrous dichloromethane (3.25 ml) was added 4M-hydrogen chloride dioxane solution (3.25 ml, 13.0 mmol). After stirring at room temperature for 1 hr, the reaction mixture was concentrated under reduced pressure. Ethyl acetate was added to the residue, and the mixture was concentrated again under reduced pressure. The operation was performed 3 times to remove hydrogen chloride gas azeotropically. The residue was suspended in ethyl acetate and filtered. The filtered product was washed with ethyl acetate, and dried under reduced pressure to give the title compound (245.1 mg, quantitative) as a white solid.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[N:13]3[N:20]=[CH:21][C:22]([C:23]([OH:25])=O)=[C:12]3[N:11]=2)=[CH:6][CH:5]=1.[S:28]([C:32]1[CH:33]=[C:34]([NH2:38])[CH:35]=[CH:36][CH:37]=1)(=[O:31])(=[O:30])[NH2:29]>>[S:28]([C:32]1[CH:33]=[C:34]([NH:38][C:23]([C:22]2[CH:21]=[N:20][N:13]3[C:14]([C:16]([F:17])([F:19])[F:18])=[CH:15][C:10]([C:7]4[CH:6]=[CH:5][C:4]([O:3][C:2]([F:26])([F:27])[F:1])=[CH:9][CH:8]=4)=[N:11][C:12]=23)=[O:25])[CH:35]=[CH:36][CH:37]=1)(=[O:30])(=[O:31])[NH2:29]
Reactant: O=C(O)c1cnn2c(C(F)(F)F)cc(-c3ccc(OC(F)(F)F)cc3)nc12
Reactant: Nc1cccc(S(N)(=O)=O)c1
Product: NS(=O)(=O)c1cccc(NC(=O)c2cnn3c(C(F)(F)F)cc(-c4ccc(OC(F)(F)F)cc4)nc23)c1

Procedure:
The title compound was prepared from 5-(4-trifluoromethoxy-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.19) and 3-sulfamoyl-phenylamine [commercially available] according to general procedure II. Yellow solid. MS (ISP) 544.2 [(M−H)−]; mp 257° C.
Reaction SMILES: [CH2:1]([N:3]([CH2:18][CH3:19])[CH2:4][CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[CH:12]2)[CH3:2].[Br:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23](F)[CH:22]=1>>[Br:20][C:21]1[CH:22]=[C:23]([N:14]2[C:15]3[C:11](=[CH:10][C:9]([O:8][CH2:7][CH2:6][CH2:5][CH2:4][N:3]([CH2:1][CH3:2])[CH2:18][CH3:19])=[CH:17][CH:16]=3)[CH:12]=[CH:13]2)[CH:24]=[CH:25][CH:26]=1
Reactant: CCN(CC)CCCCOc1ccc2[nH]ccc2c1
Reactant: Fc1cccc(Br)c1
Product: CCN(CC)CCCCOc1ccc2c(ccn2-c2cccc(Br)c2)c1

Procedure:
In analogy to example 4.6, Diethyl-[4-(1H-indol-5-yloxy)-butyl]-amine and 1-bromo-3-fluoro-benzene were converted to yield {4-[1-(3-Bromo-phenyl)-1H-indol-5-yloxy]-butyl}-diethyl-amine as light yellow oil, MS: 415 (MH+, 1Br).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]([F:16])([F:15])[F:14])=[C:11]([C:17](Cl)=[O:18])[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[NH2:20][C:21]1[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=1.N1C=CC=CC=1>C(#N)C>[N:24]1[CH:25]=[CH:26][C:21]([NH:20][C:17]([C:11]2[CH:10]=[N:9][N:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[C:12]=2[C:13]([F:16])([F:15])[F:14])=[O:18])=[CH:22][CH:23]=1
Reactant: O=C(Cl)c1cnn(-c2ccc(Cl)cc2)c1C(F)(F)F
Reactant: Nc1ccncc1
Solvent: c1ccncc1
Solvent: CC#N
Product: O=C(Nc1ccncc1)c1cnn(-c2ccc(Cl)cc2)c1C(F)(F)F
Temperature: 60 °C

Procedure:
1-(4-Chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4-carbonyl chloride (0.100 g, 0.324 mmol) was added to a solution of 4-aminopyridine (0.036 g, 0.387 mmol) and pyridine (0.078 mL, 0.969 mmol) in acetonitrile (10 mL). The reaction mixture was heated at 60° C. for 12 h, concentrated and the crude product was purified by column chromatography on silica gel to give 1-(4-chloro-phenyl)-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid pyridine-4-ylamide. LCMS m/z=366.9 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH:9]([C:20]2[C:25]([F:26])=[CH:24][CH:23]=[C:22]([F:27])[C:21]=2[F:28])[C:10]2[C:11]([CH3:19])=[CH:12][C:13]([C:16]([NH2:18])=[O:17])=[N:14][CH:15]=2)=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:37])C=1>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:9]([C:20]2[C:25]([F:26])=[CH:24][CH:23]=[C:22]([F:27])[C:21]=2[F:28])[C:10]2[C:11]([CH3:19])=[CH:12][C:13]([C:16]([NH2:18])=[O:17])=[N:14][CH:15]=2)=[O:37])=[CH:4][CH:3]=1
Reactant: Cc1cc(C(N)=O)ncc1C(Sc1ccc(F)cc1)c1c(F)ccc(F)c1F
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: Cc1cc(C(N)=O)ncc1C(c1c(F)ccc(F)c1F)S(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 312 h
Yield: 18.8 %

Procedure:
To a solution of 5-[[(4-fluorophenyl)thio](2,3,6-trifluorophenyl)methyl]-4-m ethylpyridine-2-carboxamide (389 mg, 0.96 mmol) in methylene chloride (10 ml), 3-chloroperbenzoic acid (254 mg, 0.96 mmol) was added at 0° C. After stirring for 13 days at room temperature, the reaction mixture was washed with 1 N aqueous sodium hydroxide. The organic layer was dried over anhydrous sodium sulfate and filtered, then the filtrate was concentrated under reduced pressure, and the resulting residue was subjected to preparative thin-layer chromatography (developed with hexane:ethyl acetate=1:2, eluted with methylene chloride:methanol=4:1). The obtained fraction was concentrated under reduced pressure, and the resulting residue was washed with a mixed solvent of ethanol and diethyl ether, and was collected by filtration, to obtain the title compound (78 mg, 0.18 mmol, 19%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH2:6][CH:7]=[CH:8][CH:9]=1.Cl>CO>[CH3:1][O:2][C:3]1[CH2:4][CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: COC1=CC=CCC=C1
Agent: Cl
Solvent: CO
Product: COC1=CC=CC=CC1

Procedure:
In the first step of the above synthesis, warm water is used to dissolve the cycloheptatrienyl tetrafluoborate (tropylium tetrafluoborate) (I) salt under a nitrogen atmosphere. Methanol is added to the resulting aqueous solution of (I), followed by the addition of solid sodium bicarbonate to give the reaction product 7-methoxycycloheptatriene (II). The 7-methoxycycloheptatriene (II) is isomerized by heating at 150° C. for two hours to produce 3-methoxycycloheptatriene (III). In the third step, 3-methoxycycloheptatriene (III) is isomerized in an acid catalyzed rearrangement utilizing hydrogen chloride in methanol at room temperature for two hours, followed by neutralization with sodium bicarbonate, filtration and fractional distillation to give the product 1-methoxycycloheptatriene (IV).
Reaction SMILES: [C:1]([N:5]1[C:9]([NH2:10])=[CH:8][C:7]([CH:11]2[CH2:14][CH2:13][CH2:12]2)=[N:6]1)([CH3:4])([CH3:3])[CH3:2].CO[C:17](OC)([CH3:22])[C:18](OC)=[O:19]>CC(O)=O>[C:1]([N:5]1[C:9]2[NH:10][C:18](=[O:19])[CH:17]=[CH:22][C:8]=2[C:7]([CH:11]2[CH2:14][CH2:13][CH2:12]2)=[N:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)C(C)(OC)OC
Reactant: CC(C)(C)n1nc(C2CCC2)cc1N
Solvent: CC(=O)O
Product: CC(C)(C)n1nc(C2CCC2)c2ccc(=O)[nH]c21
Temperature: 110 °C
Reaction time: 24 h
Yield: 31.5 %

Procedure:
To 2-tert-butyl-5-cyclobutyl-2H-pyrazol-3-ylamine (5.0 g, 25.9 mmol) in AcOH (25 mL) was added methyl dimethoxypropionate (7.4 mL, 51.8 mmol), and then the reaction was heated to 110° C. After 24 hr, the reaction mixture was cooled to room temperature, and concentrated to a viscous oil that was treated with EtOAc. The organic layer was washed with aqueous NaHCO3 dried over MgSO4, filtered, and concentrated under reduced pressure. Purification of this material was accomplished by MPLC using a 45L Biotage® column eluting with 20% EtOAc/hexanes. The product-containing fractions were collected and concentrated under reduced pressure, and the resulting solid was washed with hexanes and dried to afford the title compound (2.0 g, 32% yield) as a colorless solid. Rf=0.33 (10% MeOH/CH2Cl2); 500 MHz 1H NMR (CDCl3) d 7.72 (d, J=9.1 Hz, 1H), 6.26 (d, J=9.1 Hz, 1H), 3.68 (dddd, J=8.7, 8.7, 8.7, 8.7 Hz, 1H), 2.46-2.32 (m, 4H), 2.14-1.89 (m, 2H), 1.71 (s, 9H); LRMS m/z (APCl+) 246 (M+1).
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13][CH2:12]1.CCN(CC)CC>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:1]1([S:7]([N:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13][CH2:12]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc2c(c1)CCN2
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=S(=O)(c1ccccc1)N1CCc2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 96093.7 %

Procedure:
To a mixture of DMAP (1.5 g), benzenesulfonyl chloride (24.0 g, 136 mmol) and indoline (14.7 g, 0.124 mmol) in CH2Cl2 (200 mL) was added dropwise Et3N (19.0 g, 186 mmol) at 0° C. The mixture was stirred at room temperature overnight. The organic layer washed with water (2×), dried over Na2SO4 and concentrated to dryness under reduced pressure to obtain 1-(phenylsulfonyl)indoline (30.9 g, 96%).
Reaction SMILES: [CH3:1][C:2]([Si:5]([CH3:23])([CH3:22])[O:6][C@H:7]1[CH2:12][NH:11][CH2:10][C@@H:9]([CH2:13][NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:8]1)([CH3:4])[CH3:3].[F:24][C:25]1[CH:34]=[C:33]2[C:28]([CH:29]=[CH:30][C:31](=[O:38])[N:32]2[CH2:35][CH:36]=O)=[CH:27][CH:26]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>CO.C(Cl)(Cl)Cl>[CH3:4][C:2]([Si:5]([CH3:23])([CH3:22])[O:6][C@H:7]1[CH2:12][N:11]([CH2:36][CH2:35][N:32]2[C:33]3[C:28](=[CH:27][CH:26]=[C:25]([F:24])[CH:34]=3)[CH:29]=[CH:30][C:31]2=[O:38])[CH2:10][C@@H:9]([CH2:13][NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:8]1)([CH3:1])[CH3:3]
Reactant: O=CCn1c(=O)ccc2ccc(F)cc21
Reactant: CC(C)(C)OC(=O)NC[C@@H]1CNC[C@H](O[Si](C)(C)C(C)(C)C)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)NC[C@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CN(CCn2c(=O)ccc3ccc(F)cc32)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78 %

Procedure:
To cis-1,1-dimethylethyl [((3RS,5RS)-5-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}-3-piperidinyl)methyl]carbamate (350 mg; 1.0 mmol) in MeOH (2 ml) and CHCl3 (8 ml) was added (7-fluoro-2-oxo-1(2H)-quinolinyl)acetaldehyde (for a preparation see Example 2(d) (200 mg; 1.0 mmol) and the reaction was allowed to stir at room temperature under N2 for 8 hours. Na(OAc)3BH (530 mg; 2.5 mmol) was added and the reaction was allowed to stir at room temperature under nitrogen for an additional 14 hours. The solvents were removed and the crude residue was purified by chromatography on silica gel using a 0-10% MeOH/DCM gradient to provide the desired compound (415 mg; 78%) as a colorless oil.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][C@@H:8]1[CH2:12][CH2:11][CH2:10][N:9]1[C:13]([C:15]1[CH:20]=[CH:19][C:18](B2OC(C)(C)C(C)(C)O2)=[CH:17][CH:16]=1)=[O:14].Br[C:31]1[S:35][C:34]([C:36]([N:38]2[CH2:42][CH2:41][CH2:40][CH2:39]2)=[O:37])=[CH:33][CH:32]=1>>[CH3:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][C@@H:8]1[CH2:12][CH2:11][CH2:10][N:9]1[C:13]([C:15]1[CH:20]=[CH:19][C:18]([C:31]2[S:35][C:34]([C:36]([N:38]3[CH2:42][CH2:41][CH2:40][CH2:39]3)=[O:37])=[CH:33][CH:32]=2)=[CH:17][CH:16]=1)=[O:14]
Reactant: O=C(c1ccc(Br)s1)N1CCCC1
Reactant: C[C@@H]1CCCN1C[C@@H]1CCCN1C(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Product: C[C@@H]1CCCN1C[C@@H]1CCCN1C(=O)c1ccc(-c2ccc(C(=O)N3CCCC3)s2)cc1
Yield: 34 %

Procedure:
The title compound is prepared in a manner substantially analogous to General Procedure A using [2-(S)-(2-(R)-methyl-pyrrolidin-1-ylmethyl)-pyrrolidin-1-yl]-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-methanone (398 mg, 1.0 mmol) and (5-Bromo-thiophen-2-yl)-pyrrolidin-1-yl-methanone (CAS 326875-64-3) 261 mg, 1.0 mmol) to give 150 mg (34% yield). MS (ES+) 452.2 (M+H)+
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([C:12]([O:14][CH3:15])=[O:13])[CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=O.[CH3:16][CH:17]([CH3:21])[CH2:18][C:19]#[N:20].Cl.O>O1CCOCC1>[CH2:18]([C:19]1[NH:20][C:4](=[O:6])[C:3]2[C:2](=[CH:11][C:10]([C:12]([O:14][CH3:15])=[O:13])=[CH:9][CH:8]=2)[N:1]=1)[CH:17]([CH3:21])[CH3:16]
Reactant: COC(=O)c1ccc(C(=O)OC)c(N)c1
Reactant: CC(C)CC#N
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1ccc2c(=O)[nH]c(CC(C)C)nc2c1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
A mixture of dimethyl 2-aminoterephthalate (3.0 g, 14.4 mmol), 3-methylbutanenitrile (1.2 g, 14.4 mmol), and saturated HCl solution in dioxane (20 mL) in sealed tube was stirred at 100° C. overnight. After it was cooled to room temperature, the reaction mixture was poured into water (50 mL) and extracted with ethyl acetate (3×20 mL). The combined organic layer was concentrated and the residue was purified by silica gel chromatography give the desired product. MS (ESI): 260 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]#[C:10][CH:11]=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8].[CH2:13]([Mg]Br)[CH:14]=[CH2:15]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]#[C:10][CH:11]([OH:12])[CH2:15][CH:14]=[CH2:13])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=CC#Cc1ccc(Cl)c(Cl)c1
Reactant: C=CC[Mg]Br
Solvent: C1CCOC1
Product: C=CCC(O)C#Cc1ccc(Cl)c(Cl)c1
Reaction time: 2 h
Yield: 75 %

Procedure:
A solution of 3-(3,4-dichlorophenyl)prop-2-yn-1-al (6.46 g; 32.4 mmol; 1 eq) in THF was added to a solution of allylmagnesium bromide (48.5 mL; 1M in Et20, 1.5 eq) at 0° C. over 25 minutes. Stirring was continued for an additional 2 h, and the reaction was carefully quenched with water (50 mL) at 0° C. MTBE (100 mL) was added, and the layers were stirred and allowed to separate. The aqueous phase was re-extracted with MTBE (50 mL) and the combined organic layers were dried over sodium sulfate and filtered. The filtrate was concentrated using a rotary evaporator, and purification of the residue by flash chromatography (4:1→1:1 heptane/EtOAc) afforded the desired homoallylic alcohol (5.86 g; 24.3 mmol; 75%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.56 (t, 2 H) 4.63 (t, 1H) 5.21-5.29 (m, 2H) 5.85-5.97 (m, 1H) 7.21 (d, 1H) 7.37 (d, 1H) 7.51 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[O:9][CH3:10].[C:11](Cl)(=[O:17])[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]>>[C:11]([C:6]1[CH:5]=[C:4]([CH3:8])[C:3]([O:9][CH3:10])=[C:2]([CH3:1])[CH:7]=1)(=[O:17])[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCC(=O)Cl
Reactant: COc1c(C)cccc1C
Product: CCCCCC(=O)c1cc(C)c(OC)c(C)c1

Procedure:
2,6-Dimethylanisole and n-hexanoyl chloride were treated in the same way as in step (a) of Example 30 to give 4-n-hexanoyl-2,6-dimethylanisole.
Reaction SMILES: [C:1]([C:3]1[CH:23]=[CH:22][C:6]([O:7][CH:8]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:5][CH:4]=1)#[N:2].CS(O[CH2:29][CH2:30][NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])(=O)=O.C(=O)([O-])[O-].[K+].[K+]>>[C:34]([O:33][C:32]([NH:31][CH2:30][CH2:29][O:21][C:18]1[CH:17]=[CH:16][C:15]([CH2:14][CH:8]([O:7][C:6]2[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:23][CH:22]=2)[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:20][CH:19]=1)=[O:38])([CH3:37])([CH3:36])[CH3:35]
Reactant: CC(C)(C)OC(=O)NCCOS(C)(=O)=O
Reactant: CCOC(=O)C(Cc1ccc(O)cc1)Oc1ccc(C#N)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOC(=O)C(Cc1ccc(OCCNC(=O)OC(C)(C)C)cc1)Oc1ccc(C#N)cc1
Yield: 57.3 %

Procedure:
In a similar manner to that described in Reference example 25, a reaction was carried out using ethyl 2-(4-cyanophenoxy)-3-(4-hydroxyphenyl)propionate (293 mg), t-butyl 2-methanesulfonyloxyethylcarbamate (560 mg) and potassium carbonate (520 mg) and the reaction mixture was treated to afford the title compound (245 mg) as a colorless oil.
Reaction SMILES: [Na].C[Si](C)(C)N[Si](C)(C)C.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][C:19]([OH:21])=O)=[CH:14][CH:13]=1.[Cl:22][C:23]1[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:24]=1C(OC)=O.Cl>C1COCC1>[Cl:11][C:12]1[CH:13]=[CH:14][C:15]([CH2:18][C:19]([C:30]2[CH:29]=[CH:24][C:23]([Cl:22])=[CH:32][C:31]=2[Cl:33])=[O:21])=[CH:16][CH:17]=1
Reactant: COC(=O)c1ccc(Cl)cc1Cl
Reactant: O=C(O)Cc1ccc(Cl)cc1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: Cl
Agent: [Na]
Solvent: C1CCOC1
Product: O=C(Cc1ccc(Cl)cc1)c1ccc(Cl)cc1Cl
Temperature: -60 °C
Reaction time: 0.67 h
Yield: 62.2 %

Procedure:
420 ml of a 2M solution of the sodium salt of hexamethyldisilazane in THF are cooled to −60° C., under a nitrogen atmosphere, 350 ml of THF are added, and then, dropwise, a solution of 57.6 g of 4-chlorophenylacetic acid in 70 ml of THF and the mixture is kept stirred for 1 hour at −60° C. 66 g of methyl 2,4-dichlorobenzoate are then added, dropwise and at −60° C., the mixture is kept stirred for 40 minutes at −60° C. and then the temperature is allowed to rise to 0° C. The reaction mixture is poured over an ice/1 liter of 2N HCl mixture, extracted with ether, the organic phase is washed with a saturated NaHCO3 solution, with water, the organic phase is dried over Na2SO4, the solvent is concentrated under vacuum to a volume of 150 ml, 200 ml of pentane are added and the crystallized product formed is drained. 60 g of the expected compound are obtained.