Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([S:9][CH2:10][C:11]([F:14])([F:13])[F:12])=[CH:4][C:3]=1[OH:15].ClC1C=CC=C(C(OO)=[O:24])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)(Cl)Cl>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([S:9]([CH2:10][C:11]([F:14])([F:13])[F:12])=[O:24])=[CH:4][C:3]=1[OH:15]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1cc(C)c(SCC(F)(F)F)cc1O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: Cc1cc(C)c(S(=O)CC(F)(F)F)cc1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76.8 %

Procedure:
In 30 ml of chloroform was dissolved 2.60 g (11.0 mmol) of 2,4-dimethyl-5-(2,2,2-trifluoroethylthio)phenol. Thereto was added 3.25 g (13.18 mmol) of 3-chloroperbenzoic acid (purity: about 70%) under ice cooling, and the mixture was stirred for 30 minutes at room temperature. Then, saturated aqueous solution of sodium thiosulfate was added to the reaction mixture to decompose excess peroxide. Thereafter, the solvent was distilled off under reduced pressure, and phase separation was conducted by adding ethyl acetate and water. The organic phase obtained was washed by aqueous potassium carbonate solution and saturated aqueous sodium chloride solution, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, to obtain 2.13 g (yield: 77%) of an intended product.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([C@H:12]([C:18]1[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH2:27][CH3:28])[CH:19]=1)[CH2:13][S:14]([CH3:17])(=[O:16])=[O:15])[CH2:7]2.[CH:29]1([C:32](Cl)=[O:33])[CH2:31][CH2:30]1>O1CCCC1>[CH:29]1([C:32]([NH:1][C:2]2[CH:3]=[CH:4][CH:5]=[C:6]3[C:10]=2[C:9](=[O:11])[N:8]([C@H:12]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([O:26][CH2:27][CH3:28])[CH:19]=2)[CH2:13][S:14]([CH3:17])(=[O:15])=[O:16])[CH2:7]3)=[O:33])[CH2:31][CH2:30]1
Reactant: CCOc1cc([C@H](CS(C)(=O)=O)N2Cc3cccc(N)c3C2=O)ccc1OC
Reactant: O=C(Cl)C1CC1
Solvent: C1CCOC1
Product: CCOc1cc([C@H](CS(C)(=O)=O)N2Cc3cccc(NC(=O)C4CC4)c3C2=O)ccc1OC
Yield: 58.7 %

Procedure:
A stirred mixture of 7-amino-2-[(1R)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]isoindolin-1-one (0.91 g, 2.2 mmol) and cyclopropane carbonyl chloride (0.25 mL, 2.8 mmol) in tetrahydrofuran (10 mL) was heated to reflux for 15 min. The solvent was removed in vacuo to give a solid. The solid was recrystallized from ethanol (10 mL) to give cyclopropyl-N-{2-[(1R)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethyl]-3-oxoisoindolin-4-yl}carboxamide as an off-white solid (0.61 g, 56% yield); mp, 173-175° C.; 1H NMR (CDCl3) δ0.86-0.93 (m, 2H, 2CHH), 1.07-1.14 (m, 2H, 2CHH), 1.46 (t, J=6.9 Hz, 3H, CH3), 1.63-1.73 (m, 1H, CH), 2.95 (s, 3H, CH3), 3.68 (dd, J=4.4, 14.3 Hz, 1H, CHH), 3.86 (s, 3H, CH3), 4.07 (q, J=7.1 Hz, 2H, CH2), 4.20 (d, J=16.7 Hz, 1H, CHH), 4.21 (dd, J=9.9, 14.3 Hz, 1H, CHH), 4.44 (d, J=16.7 Hz,1H, CHH), 5.73 (dd, J=4.3, 9.9 Hz, 1H, NCH), 6.84-7.02 (m, 4H, Ar), 7.44 (t, J=7.8 Hz, 1H, Ar), 8.43 (d, J=8.3 Hz, 1H, Ar), 10.46 (s, 1H, NH); 13C NMR (CDCl3) δ8.24, 14.61, 16.10, 41.43, 47.81, 51.55, 55.75, 55.88, 64.56, 111.46, 112.09, 116.69, 116.99, 117.76, 119.17, 129.27, 133.54, 138.06, 141.22, 148.84, 149.67, 169.96, 172.59; Anal Calcd for C24H28N2O6S: C, 61.00; H, 5.97; N, 5.93. Found: C, 60.73; H, 5.91; N, 5.69.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:20]=1.Cl[C:22]1[N:27]=[C:26]([CH3:28])[N:25]=[C:24]([C:29]([C:31]2[CH:40]=[C:39]([CH3:41])[C:34]3[NH:35][C:36](=[O:38])[O:37][C:33]=3[CH:32]=2)=[O:30])[CH:23]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][N:17]([C:22]4[CH:23]=[C:24]([C:29]([C:31]5[CH:40]=[C:39]([CH3:41])[C:34]6[NH:35][C:36](=[O:38])[O:37][C:33]=6[CH:32]=5)=[O:30])[N:25]=[C:26]([CH3:28])[N:27]=4)[CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:20]=1
Reactant: Cc1nc(Cl)cc(C(=O)c2cc(C)c3[nH]c(=O)oc3c2)n1
Reactant: COc1ccc2c(c1)CCN(C1CCNCC1)C(=O)N2
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(C(=O)c4cc(C)c5[nH]c(=O)oc5c4)nc(C)n3)CC1)C(=O)N2

Procedure:
83 mg (0.30 mmol) 7-methoxy-3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one, 91 mg (0.30 mmol) 6-(6-chloro-2-methyl-pyrimidine-4-carbonyl)-4-methyl-3H-benzoxazol-2-one and 0.11 mL (0.60 mmol) DIPEA were stirred together in 3 mL DMF overnight at RT. Then the reaction mixture was purified by preparative HPLC-MS. The fractions containing the product were combined and the organic solvent was evaporated down. The residue was neutralised with 4N aqueous sodium hydroxide solution, the precipitate formed was suction filtered, washed with water and dried i. vac.
Reaction SMILES: [CH2:1]([NH:9][C:10]([C:12]1[C:13]([CH3:24])=[N:14][O:15][C:16]=1[C:17]1[CH:22]=[CH:21][C:20](Br)=[CH:19][CH:18]=1)=[O:11])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:25]([O:27][C:28]([C:30]1([C:33]2[CH:38]=[CH:37][C:36](B3OC(C)(C)C(C)(C)O3)=[CH:35][CH:34]=2)[CH2:32][CH2:31]1)=[O:29])[CH3:26]>>[CH2:25]([O:27][C:28]([C:30]1([C:33]2[CH:38]=[CH:37][C:36]([C:20]3[CH:21]=[CH:22][C:17]([C:16]4[O:15][N:14]=[C:13]([CH3:24])[C:12]=4[C:10](=[O:11])[NH:9][CH2:1][CH2:2][C:3]4[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=4)=[CH:18][CH:19]=3)=[CH:35][CH:34]=2)[CH2:31][CH2:32]1)=[O:29])[CH3:26]
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C(=O)NCCc1ccccc1
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4C(=O)NCCc4ccccc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 3, Step 5, using 5-(4-bromo-phenyl)-3-methyl-isoxazole-4-carboxylic acid phenethyl-amide and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: C([C:4]1[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=1[NH2:6])(C)C.[ClH:11].[CH4:12].CCO[CH2:16][CH3:17]>C(O)C>[ClH:11].[CH:16]([NH:6][C:5]1[CH:4]=[CH:10][CH:9]=[CH:8][CH:7]=1)([CH3:17])[CH3:12]
Reactant: CC(C)c1ccccc1N
Reactant: C
Reactant: CCOCC
Agent: Cl
Solvent: CCO
Product: CC(C)Nc1ccccc1

Procedure:
o-Isopropylaniline (11.2 g, 79.1 mmol) was dissolved in ether (60 ml) and the ether saturated with HCl gas was added dropwise to afford a white precipitate. The precipitate was collected and dried (13.0 g). The precipitate (2.23 g, 13.6 mmol) was dissolved in ethanol (6 ml), activated charcoal (500 mg) was added, and the mixture was filtered through celite filter aid. The resultant clear filtrate was placed in a centrifuge tube and ether (28 ml) was added slowly to give white needles (1.06 g, 6.16 mmol). mp 183-184° C.
Reaction SMILES: [C:1](=[O:6])(OC)OC.C[O-].[Na+].[NH2:10][C:11]1[C:16]([CH2:17][NH:18][CH3:19])=[CH:15][C:14]([Br:20])=[CH:13][N:12]=1>CO.O>[Br:20][C:14]1[CH:13]=[N:12][C:11]2[NH:10][C:1](=[O:6])[N:18]([CH3:19])[CH2:17][C:16]=2[CH:15]=1
Reactant: COC(=O)OC
Reactant: CNCc1cc(Br)cnc1N
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CN1Cc2cc(Br)cnc2NC1=O
Temperature: 50 °C
Yield: 67.1 %

Procedure:
To a solution of dimethyl carbonate (2.14 g, 23.7 mmole) and sodium methoxide (1.0 mL, 4.5 mmole. 25% wt in CH3OH) in CH3OH (25 mL) was added 2-amino-5-bromo-3-(methylaminomethyl)pyridine (1.0 g, 4.62 mmole). The reaction was heated at 50° C. overnight, diluted with H2O (1 mL) and concentrated. Toluene was added to the reaction residue and the contents were heated to reflux for 12 hr under a Dean-Stark apparatus. The reaction was cooled to RT, diluted with EtOAc, and washed with H2O. Purification on Silica gel (9:1 CHCl3/CH3OH containing 5% NH4OH) gave the title compound (0.75 g, 67%) as an off-white solid: MS (ES) m/e 243 (M+H)+.
Reaction SMILES: ClN1C(=O)CCC1=O.N1C=CC=CC=1.[CH3:15][C:16]1[CH:24]=[CH:23][C:19]([CH:20]=[N:21][OH:22])=[CH:18][CH:17]=1.[N+](C1C=C[C:31]([C:32]([O:34][CH:35]=CC(OC)=O)=[O:33])=[CH:30]C=1)([O-])=O.C(N(CC)CC)C.C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl>[C:16]1([CH3:15])[CH:24]=[CH:23][C:19]([C:20]2[C:31]([C:32]([O:34][CH3:35])=[O:33])=[CH:30][O:22][N:21]=2)=[CH:18][CH:17]=1
Reactant: COC(=O)C=COC(=O)c1ccc([N+](=O)[O-])cc1
Reactant: Cc1ccc(C=NO)cc1
Agent: O=C([O-])O
Agent: O=C1CCC(=O)N1Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: COC(=O)c1conc1-c1ccc(C)cc1
Yield: 19.6 %

Procedure:
N-Chlorosuccinimide (9.87 g, 73.4 mmol) and pyridine (175 mg, 2.2 mmol) were dissolved in chloroform (100 ml), 4-methylbenzaldehyde oxime (10 g, 73.4 mmol) was added, and the mixture was stirred until it became clear. A solution of 2-methoxycarbonylvinyl 4-nitrobenzoate (9.22 g, 36.7 mmol) and triethylamine (12.9 g, 128 mmol) in chloroform (180 ml) was slowly added dropwise at 0° C. over 2 hours, and the mixture was stirred overnight at room temperature. Saturated aqueous sodium hydrogencarbonate solution was added, and the mixture was extracted with dichloromethane. The extract was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography (hexane:ethyl acetate=5:95) to give the title compound (1.56 g, 7.19 mmol, 19.6%).
Reaction SMILES: Cl.O1CCOCC1.[F:8][C:9]1([F:30])[CH2:14][CH2:13][CH:12]([CH2:15][N:16]2[CH2:21][CH2:20][CH:19]([NH:22]C(=O)OC(C)(C)C)[CH2:18][CH2:17]2)[CH2:11][CH2:10]1.CO.[OH-].[Na+]>C(OCC)(=O)C>[F:30][C:9]1([F:8])[CH2:10][CH2:11][CH:12]([CH2:15][N:16]2[CH2:17][CH2:18][CH:19]([NH2:22])[CH2:20][CH2:21]2)[CH2:13][CH2:14]1
Reactant: CC(C)(C)OC(=O)NC1CCN(CC2CCC(F)(F)CC2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: C1COCCO1
Product: NC1CCN(CC2CCC(F)(F)CC2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 92 %

Procedure:
A 4 N hydrogen chloride/1,4-dioxane solution (11 ml, 43 mmol) was added to a mixture of tert-butyl N-{1-[(4,4-difluorocyclohexyl)methyl]piperidin-4-yl}carbamate obtained in Example 2c (650 mg, 1.96 mmol) and methanol (11 ml), followed by stirring at room temperature for three hours. After concentrating the reaction liquid, the residue was dissolved in ethyl acetate, a 1N aqueous sodium hydroxide solution was added, and the organic layer was separated. The aqueous layer was further extracted with ethyl acetate twice, the organic layers were dried over sodium sulfate, and the solvent was then distilled off to give the title compound (419 mg, yield 92%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[C:22]([CH3:33])=[CH:23][C:24]([O:31][CH3:32])=[C:25]([CH:30]=4)[C:26]([O:28]C)=[O:27])=[CH:17][C:11]=3[C:12]=2[C:13](=[O:16])[NH:14][CH3:15])=[CH:4][CH:3]=1.[OH-].[Na+]>CO.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[C:22]([CH3:33])=[CH:23][C:24]([O:31][CH3:32])=[C:25]([CH:30]=4)[C:26]([OH:28])=[O:27])=[CH:17][C:11]=3[C:12]=2[C:13](=[O:16])[NH:14][CH3:15])=[CH:6][CH:7]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)OC)c(OC)cc3C)cc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)O)c(OC)cc3C)cc12
Temperature: 50 °C
Reaction time: 10 h

Procedure:
Methyl 5-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-2-methoxy-4-methylbenzoate (0.9 g, 2 mmol, 1 eq) and sodium hydroxide (0.4 g, 10 mmol, 5 eq) were dissolved in methanol/water (20/5 ml) and the reaction was stirred at 50° C. for 10 h. Then the reaction mixture was concentrated and diluted with water and the pH of the solution was brought to 3 by using Conc HCl. The solid obtained was filtered and dried overnight. Yield: 0.72 g (82%). 1H NMR (400 MHz, DMSO-d6): δ 2.29 (s, 3H), 2.87 (d, 3H), 3.87 (s, 3H), 7.09 (s, 1H), 7.40-7.60 (m, 3H), 7.57 (m, 2H), 7.65 (d, 1H, J=8.74 Hz), 7.98-8.01 (m, 2H), 8.46 (q, 1H, J=4.40 Hz), 12.5 (br s, 1H). LCMS: (ES+) m/z=434 (M+H) Method: Mphase A: water; Mphase B: 0.1% acetone in water; Flow: 2 mL/Min.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:14]([NH:16][C:17]([C:19]2[N:20]=[C:21](Cl)[S:22][CH:23]=2)=[O:18])[CH3:15])[CH:5]=[C:6]([F:13])[C:7]=1[NH:8][S:9]([CH3:12])(=[O:11])=[O:10].[CH:25]([C:28]1[CH:29]=[C:30]([OH:34])[CH:31]=[CH:32][CH:33]=1)([CH3:27])[CH3:26]>>[F:1][C:2]1[CH:3]=[C:4]([CH:14]([NH:16][C:17]([C:19]2[N:20]=[C:21]([O:34][C:30]3[CH:31]=[CH:32][CH:33]=[C:28]([CH:25]([CH3:27])[CH3:26])[CH:29]=3)[S:22][CH:23]=2)=[O:18])[CH3:15])[CH:5]=[C:6]([F:13])[C:7]=1[NH:8][S:9]([CH3:12])(=[O:11])=[O:10]
Reactant: CC(NC(=O)c1csc(Cl)n1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Reactant: CC(C)c1cccc(O)c1
Product: CC(C)c1cccc(Oc2nc(C(=O)NC(C)c3cc(F)c(NS(C)(=O)=O)c(F)c3)cs2)c1
Yield: 65.2 %

Procedure:
2-Chloro-thiazole-4-carboxylic acid [1-(3,5-difluoro-4-methanesulfonylamino-phenyl)-ethyl]-amide (50 mg, 0.13 mmol) was reacted with 3-isopropyl phenol (34 mg, 0.25 mmol) to give the title compound (42 mg, 67%) after purification by column chromatography (gradient 12% to 100% EtOAc in n-hexane).
Reaction SMILES: [CH2:1]=[CH:2][C:3]([CH2:6][CH2:7][CH:8]=[C:9]([CH3:11])[CH3:10])([CH3:5])[OH:4].C(N(CC)CC)C.[OH:19][C:20]1[CH:25]=[C:24]([OH:26])[CH:23]=[CH:22][C:21]=1[CH:27]=[CH:28][C:29](O)=[O:30].CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F>C1COCC1.CN(C=O)C>[CH3:5][C:3]([O:4][C:29](=[O:30])[CH:28]=[CH:27][C:21]1[CH:22]=[CH:23][C:24]([OH:26])=[CH:25][C:20]=1[OH:19])([CH:2]=[CH2:1])[CH2:6][CH2:7][CH:8]=[C:9]([CH3:11])[CH3:10]
Reactant: C=CC(C)(O)CCC=C(C)C
Reactant: O=C(O)C=Cc1ccc(O)cc1O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C=CC(C)(CCC=C(C)C)OC(=O)C=Cc1ccc(O)cc1O
Reaction time: 1 h

Procedure:
To a solution of linalool (1.74 g, 11.3 mmol) and triethylamine (2.30 g, 22.6 mmol) in anhydrous THF (150 mL) stirred for 5 min at 22° C. is added 3-(2,4-dihydroxyphenyl)-acrylic acid (2.04 g, 11.3 mmol). To this heterogeneous solution is added BOP Reagent (5.00 g, 11.3 mmol; Aldrich #22,608-4) in DMF (10 mL), and the subsequent homogeneous reaction mixture is stirred for 1 h. The reaction mixture is partitioned between ether (200 mL) and water (400 mL); the organic layer is removed and washed with ether (200 mL). The combined organic layers are washed sequentially with saturated sodium bicarbonate solution (200 mL) and brine (200 mL). The organic layer is dried over anhydrous magnesium sulfate, vacuum filtered and concentrated to give 3-(2,4-dihydroxyphenyl)-acrylic acid 1,5-dimethyl-1-vinyl-hex-4-enyl ester as an oil that is purified by flash chromatography.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].[F:26][C:27]([F:39])([F:38])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[S:34](Cl)(=[O:36])=[O:35]>>[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][N:20]([S:34]([C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=4[C:27]([F:26])([F:38])[F:39])(=[O:36])=[O:35])[CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: O=S(=O)(Cl)c1ccccc1C(F)(F)F
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)cc1OC
Agent: Cl
Product: COc1ccc(C2=NN(C3CCN(S(=O)(=O)c4ccccc4C(F)(F)F)CC3)C(=O)C2(C)C)cc1OC

Procedure:
The title compound is prepared analogously as described for GP1 using 5-(3,4-dimethoxyphenyl)-4,4-dimethyl-2-(piperidin-4-yl)-2,4-dihydro-3H-pyrazol-3-one hydrochloride (compound B1*HCl) and 2-(trifluoromethyl)benzenesulfonyl chloride as starting compounds. The crude product is purified by crystallization from methanol to yield the title compound.
Reaction SMILES: [OH:1][C@@H:2]([CH2:13][O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:3][CH:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:5]#[N:6].N1C=CC=CC=1.[CH3:28][C:29]1[CH:34]=[CH:33][C:32]([S:35](Cl)(=[O:37])=[O:36])=[CH:31][CH:30]=1>C(Cl)(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:28][C:29]1[CH:34]=[CH:33][C:32]([S:35]([O:1][C@@H:2]([CH2:13][O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:3][CH:4]([C:5]#[N:6])[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)(=[O:37])=[O:36])=[CH:31][CH:30]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: N#CC(C[C@@H](O)COCc1ccccc1)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: Cc1ccc(S(=O)(=O)O[C@@H](COCc2ccccc2)CC(C#N)c2ccccc2)cc1
Temperature: 0 °C
Reaction time: 72 h
Yield: 60 %

Procedure:
(4R)-4-hydroxy-2-phenyl-5-[(phenylmethyl)oxy]pentanenitrile (16.0 g, 57 mmol), accessed via the method of preparation 1, was dissolved in 116 mL CHCl3 and 116 mL Pyridine (25 eq) with DMAP (0.70 g, 5.7 mmol, 0.1 eq) and cooled to 0° C. 4-methylbenzenesulfonyl chloride (43.5 g, 228 mmol, 4 eq) was added to the reaction mixture and stirred 3 days at 0° C. The reaction mixture was washed successively with 1N HCl (4×250 mL) and brine, dried over MgSO4, filtered and concentrated to a red oil. The crude material was purified by flash chromatography (SiO2, 10→25% EtOAc/Hexanes) to give the diastereomeric product as a yellow oil (14.88 g, 34.2 mmol, 60%). ES-LCMS m/z 458.36 (M+Na).
Reaction SMILES: [CH2:1]([C:3]([C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[C:23]([CH3:28])[CH:22]=1)([C:6]1[CH:11]=[CH:10][C:9]([C:12]#[C:13][CH:14]([OH:19])[C:15]([CH3:18])([CH3:17])[CH3:16])=[C:8]([CH3:20])[CH:7]=1)[CH2:4][CH3:5])[CH3:2].[H][H]>C(OCC)(=O)C.[Pd]>[CH2:1]([C:3]([C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[C:23]([CH3:28])[CH:22]=1)([C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][CH:14]([OH:19])[C:15]([CH3:17])([CH3:18])[CH3:16])=[C:8]([CH3:20])[CH:7]=1)[CH2:4][CH3:5])[CH3:2]
Reactant: [H][H]
Reactant: CCC(CC)(c1ccc(O)c(C)c1)c1ccc(C#CC(O)C(C)(C)C)c(C)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCC(CC)(c1ccc(O)c(C)c1)c1ccc(CCC(O)C(C)(C)C)c(C)c1
Yield: 98 %

Procedure:
10% Pd—C (0.1 g) was added to a solution of 4-{1-ethyl-1-[4-(3-hydroxy-4,4-dimethyl-1-pentynyl)-3-methyl-phenyl]-propyl}-2-methyl-phenol (Example 3-(2), Enantiomer B; 725 mg, 1.92 mmol) in ethyl acetate (10 mL), and the mixture was stirred in a hydrogen atmosphere for 40 minutes. The reaction mixture was filtered and then concentrated under reduced pressure to give the title compound (720 mg, 98%).
Reaction SMILES: [CH:1]([Mg]Br)=[CH2:2].Cl[Si:6]1(Cl)[CH2:10][CH:9]=[CH:8][CH2:7]1.[Cl-].[NH4+].[CH3:14][CH2:15]OCC>C1COCC1>[CH:14]([Si:6]1([CH:1]=[CH2:2])[CH2:10][CH:9]=[CH:8][CH2:7]1)=[CH2:15]
Reactant: Cl[Si]1(Cl)CC=CC1
Reactant: C=C[Mg]Br
Reactant: CCOCC
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C=C[Si]1(C=C)CC=CC1
Temperature: 0 °C
Yield: 95 %

Procedure:
In a 1 L three neck flask equipped with a Teflon covered magnetic stirring bar, reflux condenser and a pressure equalizing addition funnel. Vinyl magnesium bromide (0.5 mol) in THF 350 mL was placed in the reaction flask. The flask and its contents were cooled to 0° C. in an ice water bath. 1,1-Dichloro-1-silacyclopent-3-ene (Damrauer, R.; Simon, R.; Laporterie, A.; Manuel, G.; Park, Y. T.; Weber, W. P. J. Organomet. Chem., 1990, 391, 7) (11 g, 72 mmol) dissolved in 20 mL of THF was placed in the addition funnel and was added dropwise to reaction flask. The reaction was allowed to slowly warm to room temperature over 6 hours. The reaction mixture was poured into ice cold solution of saturated aqueous ammonium chloride. Ether (200 mL) was added and the organic layer was washed with an equal volume of water (3X). The organic layer was dried over anhydrous calcium chloride, filtered and the volatile organic solvents were removed by distillation through a 15 cm vacuum jacketed Bigreux column at atmospheric pressure. The product was distilled under reduced pressure. A fraction bp 43°-45° C./16 mm Hg, 9.4 g, 95% yield was obtained. 1H NMR: 1.44(d,4H,J=1 Hz), 5.87(t,2H,J=1 Hz), 5.81(dd,2H,J=20 and 3.9 Hz), 6.06(dd,2H,J=14.5 and 3.9 Hz), 6.22(dd,2H,J=20 and 14.5 Hz). 13C NMR: 15.46, 130.71, 134.00, 135.02. 29Si NMR: 1.56. IR: 3040, 3020, 2940, 2885, 1605, 1400, 1200, 1095, 1000., 950, 9430, 815, 795, 725, 690 cm-1. UV nm (): 207 (2.5×103). Anal. Calc. for C8H12Si: C, 70.51; H, 8.88. Found: C, 70.96; H, 9.06.
Reaction SMILES: [N+:1]([C:4]1[C:9]([CH3:10])=[C:8]([N+:11]([O-:13])=[O:12])[CH:7]=C(C)[C:5]=1C([O-])=O)([O-:3])=[O:2].[CH:18](=O)[C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1.N1CCCCC1.[C:34]([O:37][CH2:38]C)(=[O:36])[CH3:35]>>[N+:1]([C:4]1[CH:5]=[C:35]([C:34]([O:37][CH3:38])=[O:36])[CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[C:9]=1[CH:10]=[CH:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1)([O-:3])=[O:2]
Reactant: Cc1cc([N+](=O)[O-])c(C)c([N+](=O)[O-])c1C(=O)[O-]
Reactant: COc1ccc(C=O)cc1
Reactant: CCOC(C)=O
Solvent: C1CCNCC1
Product: COC(=O)c1cc([N+](=O)[O-])c(C=Cc2ccc(OC)cc2)c([N+](=O)[O-])c1

Procedure:
A mixture of 3,5-dinitro-p-methyltoluate (120.08 grams) from Example 1, p-anisaldehyde (68.08 grams), activated basic alumina oxide (150 mesh, 58 angstrom, 70.00 grams), and ethyl acetate (150.0 grams) was heated to reflux. Piperidine (15.3 grams) was added dropwise over 5 hours and the reaction held at reflux for another 6.5 hours. Upon cooling, a yellow crystalline product precipitated and was isolated by filtration. The crude product was recrystallized one time from concentrated ethyl acetate to recover 77.6 grams of bright yellow 2,6-dinitro-4- carbomethoxy-4'-methoxystilbene (4). The product was characterized by NMR and had a melting point of 141.5° to 143° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12](O)=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17].F[C:29]1[C:34]([O:35]C(N(C)C)=[N+](C)C)=[C:33](F)[C:32](F)=C(F)[C:30]=1F.F[P-](F)(F)(F)(F)F.C([N:57](C(C)C)CC)(C)C>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([N:57]1[CH2:32][CH2:33][C:34](=[O:35])[CH2:29][CH2:30]1)=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17]
Reactant: CN(C)C(Oc1c(F)c(F)c(F)c(F)c1F)=[N+](C)C
Reactant: CC(Nc1ncnc2cc(C(=O)O)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1
Reactant: CCN(C(C)C)C(C)C
Agent: F[P-](F)(F)(F)(F)F
Product: CC(Nc1ncnc2cc(C(=O)N3CCC(=O)CC3)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 37a from 6-chloro-4-[1-(5-chloro-1H-benzimidazol-2-yl)-ethylamino]-7-hydroxycarbonyl-quinazoline, pentafluorophenyl-tetramethyluronium-hexafluorophosphate (PFTU), diisopropylethylamine and 4-oxo-piperidinein DMSO at ambient temperature.
Reaction SMILES: [N+:1]([C:4]1[CH:15]=[CH:14][C:7]([O:8][CH:9]([CH3:13])[C:10]([OH:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].O[CH2:17][CH2:18][O:19][C:20](=[O:33])[CH:21]([O:23][C:24]1[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=1)[CH3:22].C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([O:8][CH:9]([CH3:13])[C:10]([O:12][CH2:17][CH2:18][O:19][C:20](=[O:33])[CH:21]([O:23][C:24]2[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=2)[CH3:22])=[O:11])=[CH:14][CH:15]=1)([O-:3])=[O:2]
Reactant: CC(Oc1ccc([N+](=O)[O-])cc1)C(=O)O
Reactant: CC(Oc1ccc([N+](=O)[O-])cc1)C(=O)OCCO
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CC(Oc1ccc([N+](=O)[O-])cc1)C(=O)OCCOC(=O)C(C)Oc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 35.1 %

Procedure:
To a mixture of 2-(4-nitrophenoxy) propionic acid 47 (25 grams, 118.5 mmol) and 2-(4-nitrophenoxy)propionic acid 2-hydroxyethyl ester 48 ( 25 grams, 108 mmol) in anhydrous dichloromethane (625 ml) under nitrogen atm. was added dropwise a solution of 1,3-dicyclohexyl carbodiimide (40 g, 194 mmol) in anhydrous dichloro-methane (250 ml). The reaction mixture was stirred at room temperature for 8 hours. The solids were filtered off and dichloromethane distilled off to get crude 49. The crude 49 was purified by column chromatography on silica gel using hexane as eluant to get pure 49 (17 g, 35.1%) as a white powder.