Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[CH:8][NH:9]2)=[CH:5][CH:4]=1.Cl.[NH:13]1[CH2:18][CH2:17][C:16](=O)[CH2:15][CH2:14]1.[OH-].[K+]>O>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([C:16]3[CH2:17][CH2:18][NH:13][CH2:14][CH:15]=3)=[CH:8][NH:9]2)=[CH:5][CH:4]=1
Reactant: COc1ccc2cc[nH]c2c1
Reactant: O=C1CCNCC1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: COc1ccc2c(C3=CCNCC3)c[nH]c2c1
Reaction time: 0.5 h

Procedure:
A mixture of 20 g of 6-methoxy-1H-indole, 41.75 g of the hydrate of 4-piperidone hydrochloride and 205 ml of 2 N methanolic potassium hydroxide solution was refluxed under an inert atmosphere for 81/2 hours and the mixture was slowly diluted with water to a volume of 1.2 liters. Crystallization began and the mixture was stirred for 30 minutes and then was filtered. The recovered product was rinsed with water and dried at 50° C. under reduced pressure over a desiccant to obtain 23.05 g of 6-methoxy-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[N:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=2)[C@@H:9]([NH:18][C:19]2[N:24]=[C:23]([CH2:25][C:26]3[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[C:28]([C:36]([F:39])([F:38])[F:37])[CH:27]=3)[C:22]([NH:40][C:41]([O:43][CH2:44][CH2:45][OH:46])=[O:42])=[CH:21][N:20]=2)[CH2:8][C@H:7]1[CH2:47][CH3:48])=[O:5])[CH3:2].CC(C)=[O:51]>S(=O)(=O)(O)O.[O-2].[Cr+6].[O-2].[O-2]>[CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[N:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=2)[C@@H:9]([NH:18][C:19]2[N:24]=[C:23]([CH2:25][C:26]3[CH:27]=[C:28]([C:36]([F:37])([F:39])[F:38])[CH:29]=[C:30]([C:32]([F:33])([F:34])[F:35])[CH:31]=3)[C:22]([NH:40][C:41]([O:43][CH2:44][C:45]([OH:51])=[O:46])=[O:42])=[CH:21][N:20]=2)[CH2:8][C@H:7]1[CH2:47][CH3:48])=[O:5])[CH3:2]
Reactant: CC(C)=O
Reactant: CCOC(=O)N1c2ccc(OC)nc2[C@@H](Nc2ncc(NC(=O)OCCO)c(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)n2)C[C@H]1CC
Agent: [Cr+6]
Agent: O=S(=O)(O)O
Agent: [O-2]
Product: CCOC(=O)N1c2ccc(OC)nc2[C@@H](Nc2ncc(NC(=O)OCC(=O)O)c(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)n2)C[C@H]1CC
Reaction time: 4.5 h

Procedure:
(2R,4S)-4-{[3,5-Bis(trifluoromethyl)benzyl]-[5-(2-hydroxyethoxy-carbonylamino)pyrimidin-2-yl]}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (192 mg) is dissolved in acetone (5 ml), and thereto is added 2.67M chromium (VI) oxide in dilute sulfuric acid solution (320 μl) under ice-cooling. The mixture is stirred for 4.5 hours, and partitioned by adding sodium bisulfite, water and ethyl acetate. The organic layer is washed with saturated brine and dried over magnesium sulfate, then concentrated under reduced pressure. The resulting residue is purified by column chromatography (silica gel; chloroform:methanol=9:1→7:3) to give (2R,4S)-4-{[3,5-bis(trifluoromethyl)-benzyl]-(5-carboxymethoxycarbonylaminopyrimidin-2-yl)}amino-2-ethyl-6-methoxy-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (78 mg). MS (m/z): 701 [M+H]+.
Reaction SMILES: O[C@H](CC)[C@@H](N([C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:14][CH:13]=1)C(OC)=O)C(O)=O.O[C@@H:27]([CH2:49][CH3:50])[C@@H:28]([N:32]([C:37]1C=CC(C2C=CC=CC=2)=CC=1)[C:33]([O:35]C)=[O:34])[C:29]([OH:31])=[O:30].CCN(CC)CC.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C(Cl)Cl>[C:18]1([C:15]2[CH:14]=[CH:13][C:12]([O:35][C:33](=[O:34])[N:32]([CH3:37])[C@H:28]3[C:29](=[O:31])[O:30][C@@H:27]3[CH2:49][CH3:50])=[CH:17][CH:16]=2)[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CC[C@@H](O)[C@H](C(=O)O)N(C(=O)OC)c1ccc(-c2ccccc2)cc1
Reactant: CC[C@H](O)[C@H](C(=O)O)N(C(=O)OC)c1ccc(-c2ccccc2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC[C@H]1OC(=O)[C@@H]1N(C)C(=O)Oc1ccc(-c2ccccc2)cc1
Temperature: 0 °C
Reaction time: 15 h
Yield: 57 %

Procedure:
Under nitrogen atmosphere, to a stirred mixture of (2R*,3R*)-3-hydroxy-2-[(4-phenylphenyl)-methoxycarbonylamino]-pentanoic acid and (2R*,3S*)-3-hydroxy-2-[(4-phenylphenyl)-methoxycarbonylamino]-pentanoic acid (0.193 g, 0.56 mmol) in dry CH2Cl2 (25.0 mL), at 0° C., Et3N (0.235 mL, 1.69 mmol) and subsequently TBTU (0.217 g, 0.67 mmol) were added. The mixture was left stirring at 0° C. for 1 h and at rt for 15 h. The organics were then removed under reduced pressure, and the resulting crude product purified by column chromatography, using a Teledyne ISCO apparatus, eluting with Cy/AcOEt (from 90:10 to 80:20) to afford the pure title compound (0.089 g, 57%), as pure anti diastereoisomer, as white solid. MS (ESI) m/z: 343 [M−NH4]+; (ESI) m/z: 324 [M−H]−. 1H NMR (DMSO-d6) δ 0.92 (t, J=7.38 Hz, 3H), 1.68-1.94 (m, 2H), 4.49-4.60 (m, 1H), 4.76 (dd, J=4.32, 8.08 Hz, 1H), 5.12 (s, 2H), 7.33-7.42 (m, 1H), 7.42-7.53 (m, 4H), 7.62-7.76 (m, 4H), 8.25 (d, J=8.09 Hz, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9]([CH:11]=[CH:12][C:13](=[O:20])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:8]=[CH:7][C:4]=1[CH:5]=O.C(OP([CH2:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])(OCC)=O)C.[H-].[Na+]>C1COCC1>[C:33]([O:32][C:30](=[O:31])[CH:29]=[CH:5][C:4]1[CH:7]=[CH:8][C:9]([CH:11]=[CH:12][C:13](=[O:20])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:10][C:3]=1[O:2][CH3:1])([CH3:36])([CH3:35])[CH3:34]
Reactant: COc1cc(C=CC(=O)c2ccccc2)ccc1C=O
Reactant: CCOP(=O)(CC(=O)OC(C)(C)C)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc(C=CC(=O)c2ccccc2)ccc1C=CC(=O)OC(C)(C)C
Yield: 84.2 %

Procedure:
2-methoxy-4-(3-oxo-3-phenyl-propenyl)-benzaldehyde (550 mg, 2.07 mmol) was dissolved in THF (5 ml) and the resulting solution was added to a stirring mixture of tert-butyl diethylphosphonoacetate (603 mg, 2.27 mmol) and NaH (107 mg, 2.69 mmol, 60% oil dispersion) in THF (5 ml). After 15 minutes the reaction was quenched by the addition of water and partitioned between water and EtOAc. The organic extract was dried over Na2SO4 and evaporated under vacuo giving a crude that was purified by silica gel chromatography (EtOAc/petroleum ether 1:6). The collected fraction gave 635 mg of 3-[2-methoxy-4-(3-oxo-3-phenyl-propenyl)-phenyl]-acrylic acid tert-butyl ester as a yellow oil.
Reaction SMILES: C(O)(=O)C.C([O:7][C:8]([CH:10]1[CH2:29][C:13]2[NH:14][C:15]3[CH:16]=[CH:17][C:18]([O:21][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[CH:19][C:20]=3[C:12]=2[CH2:11]1)=[O:9])C>O>[C:23]1([CH2:22][O:21][C:18]2[CH:17]=[CH:16][C:15]3[NH:14][C:13]4[CH2:29][CH:10]([C:8]([OH:9])=[O:7])[CH2:11][C:12]=4[C:20]=3[CH:19]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CCOC(=O)C1Cc2[nH]c3ccc(OCc4ccccc4)cc3c2C1
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)C1Cc2[nH]c3ccc(OCc4ccccc4)cc3c2C1
Temperature: 100 °C
Reaction time: 4 h

Procedure:
To 100 ml of 80% acetic acid in water, was added 1,2,3,4-tetrahydro-7-phenylmethoxycyclopent[b]indole-2-carboxylic acid ethyl ester (10 g, 0.03 mole). After stirring at 100° C. for four hours, the mixture was cooled, poured into 500 ml of water, stirred for five minutes, and extracted with ethyl acetate (3×). The organic layer was washed successively with water and saturated sodium chloride solution, and thereafter dried over anhydrous MgSO4. After filtering, the solution was concentrated to a dark oil (~10 g), which was eluted on a silica gel column with 5% ethyl acetate/dichloromethane via HPLC. The desired fractions were combined and concentrated to a tan solid, 1.3 g, m.p. 160°-162° C. This material was recrystallized from ether to give the product as a tan solid, 1.0 g, m.p. 161°-163° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH3:14][C:15]1[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1>>[C:3]1([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1][S:21]([C:18]1[CH:19]=[CH:20][C:15]([CH3:14])=[CH:16][CH:17]=1)(=[O:23])=[O:22]
Reactant: Nc1ccccc1-c1ccccc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Product: Cc1ccc(S(=O)(=O)Nc2ccccc2-c2ccccc2)cc1

Procedure:
The title compound was prepared from 2-aminobiphenyl (Aldrich) and 4-methyl-benzenesulfonyl chloride according to the method described in Example 1b.
Reaction SMILES: [CH:1]([C:4]1[N:5]=[C:6]([CH2:9][CH2:10][C:11]2[CH:31]=[CH:30][N:14]3[C:15](=[O:29])[C:16](/[CH:20]=[CH:21]/[C:22]([O:24]C(C)(C)C)=[O:23])=[C:17]([OH:19])[N:18]=[C:13]3[CH:12]=2)[S:7][CH:8]=1)([CH3:3])[CH3:2].C(O)=O>C1(C)C=CC=CC=1>[CH:1]([C:4]1[N:5]=[C:6]([CH2:9][CH2:10][C:11]2[CH:31]=[CH:30][N:14]3[C:15](=[O:29])[C:16](/[CH:20]=[CH:21]/[C:22]([OH:24])=[O:23])=[C:17]([OH:19])[N:18]=[C:13]3[CH:12]=2)[S:7][CH:8]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1csc(CCc2ccn3c(=O)c(/C=C/C(=O)OC(C)(C)C)c(O)nc3c2)n1
Solvent: O=CO
Solvent: Cc1ccccc1
Product: CC(C)c1csc(CCc2ccn3c(=O)c(/C=C/C(=O)O)c(O)nc3c2)n1
Yield: 168 %

Procedure:
tert-Butyl (E)-3-{8-[2-(4-isopropyl-1,3-thiazol-2-yl)ethyl]-2-hydroxy-4-oxo-4H-pyrido[1,2-a]pyrimidin-3-yl}-2-propenoate (15 mg) was treated with formic acid (1 ml) in the dark for 1 hour, and added with toluene. The solvent was evaporated under reduced pressure to obtain the title compound (22 mg).
Reaction SMILES: C([Li])CCC.[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]([F:15])[CH:8]=1.[C:16](=[O:18])=[O:17]>O1CCCC1>[Cl:6][C:7]1[C:8]([C:16]([OH:18])=[O:17])=[C:9]([F:15])[C:10]([O:13][CH3:14])=[CH:11][CH:12]=1
Reactant: O=C=O
Reactant: COc1ccc(Cl)cc1F
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc(Cl)c(C(=O)O)c1F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
n-Butyllithium (11.7 ml, 18.77 mmol) was added dropwise to a solution of 4-chloro-2-fluoroanisole (2.01 g, 12.52 mmol) in tetrahydrofuran (20 ml) at −78° C. and the reaction was stirred for 30 mins. Crushed solid carbon dioxide was added in one portion and the reaction was then allowed to warm to room temperature. The solvent was evaporated and the residue dissolved in water. Sodium hydroxide (2M to pH˜14) was added and the aqueous layer extracted with ethyl acetate. The aqueous layer was acidified with hydrochloric acid (5M, pH˜1) and the title compound was collected as a colourless solid (2.25 g, 88%). The compound was dried in vacuo.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[CH2:12][CH:11]3[CH2:15][S:16](=[O:23])[C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=4[C:10]3=[N:9]2)=[CH:4][CH:3]=1.[OH:24]O.O>C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[CH2:12][CH:11]3[CH2:15][S:16](=[O:24])(=[O:23])[C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=4[C:10]3=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=C1CC2CS(=O)c3ccccc3C2=NN1c1ccc(Cl)cc1
Reactant: OO
Solvent: O
Solvent: CC(=O)O
Product: O=C1CC2CS(=O)(=O)c3ccccc3C2=NN1c1ccc(Cl)cc1
Temperature: 25 °C

Procedure:
To a mixture of 4.7 g of 2-(4-chlorophenyl)-2,3,4,4a-tetrahydro-5H-(1)benzothiopyrano[4,3-c]pyridazin-3-one 6-oxide in 150 ml of acetic acid is added 55 ml of 35% hydrogen peroxide dropwise with stirring at room temperature. After the completion of addition, the mixture is stirred at 40°-50° C. on a water bath for 4 hours and poured into an excess amount of water. The precipitated crystals are collected by filtration and recrystallized from 50% aqueous solution of acetic acid to give 2.9 g of 2-(4-chlorophenyl)-2,3,4,4a-tetrahydro-5H-(1)benzothiopyrano[4,3-c]pyridazin-3-one 6,6-dioxide, melting at 168°-170° C., as a colorless powder.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][NH:6][N:5]=1.[CH3:13][O:14][C:15]1[CH:16]=[C:17](B(O)O)[CH:18]=[CH:19][CH:20]=1.N1C=CC=CC=1>CN(C)C(=O)C.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:1][O:2][CH2:3][C:4]1[C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][N:6]([C:19]2[CH:18]=[CH:17][CH:16]=[C:15]([O:14][CH3:13])[CH:20]=2)[N:5]=1
Reactant: COc1cccc(B(O)O)c1
Reactant: COCc1n[nH]cc1C(=O)OC
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CC(=O)N(C)C
Solvent: c1ccncc1
Product: COCc1nn(-c2cccc(OC)c2)cc1C(=O)OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 24.2 %

Procedure:
To a solution of methyl 3-(methoxymethyl)-1H-pyrazole-4-carboxylate (2.8 g) synthesized in Example 29 (1) in N,N-dimethylacetamide (50 mL) were added 3-methoxyphenylboronic acid (5.0 g), copper acetate (6.0 g) and pyridine (5.3 mL), and the mixture was stirred at room temperature overnight. The reaction mixture was filtered through celite, 1N hydrochloric acid (50 mL) was added to the filtrate, and the mixture was extracted with diethyl ether. The extract was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:2, volume ratio) to give the title object compound (1.1 g, 23%) as a pale-yellow oil.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[C@H:6]([CH3:13])[NH:5]2.[CH3:14][C:15]([CH3:19])=[CH:16][CH:17]=O.FC(F)(F)C(O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>ClCCCl>[Cl:1][C:2]1[N:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[C@H:6]([CH3:13])[N:5]2[CH2:17][CH:16]=[C:15]([CH3:19])[CH3:14]
Reactant: CC(C)=CC=O
Reactant: C[C@@H]1Nc2nc(Cl)ccc2NC1=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCCl
Product: CC(C)=CCN1c2nc(Cl)ccc2NC(=O)[C@@H]1C
Yield: 48.9 %

Procedure:
The compound of Example 2 (988 mg, 5.0 mmol) was suspended in 40 ml of anhydrous 1,2-dichloroethane. While stirring, 840 mg (10 mmol) of 3,3-dimethylacrolein and subsequently 1.9 ml (25 mmol) of trifluoroacetic acid were added. The mixture was cooled in an ice bath, 2.1 g (10 mmol) of sodium triacetoxyborohydride were introduced in portions, and the mixture was stirred at 0° C. for 1 h and at room temperature for a further 3 h. The reaction mixture was then added to about 150 ml of saturated aqueous sodium bicarbonate solution, the phases were separated, the aqueous was back-extracted three times with dichloromethane, and the combined organic extracts were dried (sodium sulfate) and concentrated. Chromatography on silica gel (ethyl acetate/heptane=1:2) provided 650 mg (49%) of the desired compound as a crystalline solid of melting point 136°-137° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][N:13]2[CH:22]=[C:21]([C:23]([OH:25])=O)[C:20]3[N:19]=[C:18]4[C:26]([CH3:30])=[CH:27][CH:28]=[CH:29][C:17]4=[CH:16][C:15]=3[C:14]2=[O:31])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH:32]1[N:36]=[CH:35][N:34]([C:37](N2C=NC=C2)=O)[CH:33]=1>C(#N)C>[CH3:35][N:34]([CH3:37])[CH2:33][CH2:32][NH:36][C:23]([C:21]1[C:20]2[N:19]=[C:18]3[C:26]([CH3:30])=[CH:27][CH:28]=[CH:29][C:17]3=[CH:16][C:15]=2[C:14](=[O:31])[N:13]([CH2:12][CH2:11][C:5]2[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=2)[CH:22]=1)=[O:25]
Reactant: COc1ccc(CCn2cc(C(=O)O)c3nc4c(C)cccc4cc3c2=O)cc1OC
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CC#N
Product: COc1ccc(CCn2cc(C(=O)NCCN(C)C)c3nc4c(C)cccc4cc3c2=O)cc1OC
Yield: 81 %

Procedure:
From acid 18s with a reflux time of 48 h and a recharge with an equal amount of CDI after 24 h, and obtained as a yellow solid (81%), mp 113-114° C. (from acetonitrile). 1H NMR (CDCl3): δ 2.26 [s, 6H, N(CH3)2], 2.58 (t, J=6.5 Hz, 2H, CH2CH2NMe2), 2.77 (s, 3H, ArCH3), 3.01 (m, 2H, CH2CH2Ph), 3.67 (q, J=6.1 Hz, 2H, CH2CH2NMe2), 3.79 (s, 6H, 2×OCH3), 4.22 (m, 2H, CH2CH2Ph), 6.72-6.75 (m, 3H, H-2′, H-5′ and H-6′), 7.41 (t, J=7.6 Hz, 1H, H-8), 7.64 (d, J=6.8 Hz, 1H, H-7), 7.77 (d, J=8.2 Hz, 1H, H-9), 8.51 (s, 1H, H-3), 9.15 (s, 1H, H-10), 10.83 (br t, J=5.3 Hz, 1H, CONH).
Reaction SMILES: [CH:1](NC(C)C)(C)C.C([Li])CCC.[CH3:13][O:14][C:15](=[O:40])[C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH2:26][C:25]([C:31]3[CH:36]=[C:35]([Cl:37])[CH:34]=[C:33]([Cl:38])[CH:32]=3)([C:27]([F:30])([F:29])[F:28])[O:24][N:23]=2)=[CH:18][C:17]=1[CH3:39].CI>O1CCCC1>[CH3:13][O:14][C:15](=[O:40])[C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:26]([CH3:1])[C:25]([C:31]3[CH:32]=[C:33]([Cl:38])[CH:34]=[C:35]([Cl:37])[CH:36]=3)([C:27]([F:30])([F:28])[F:29])[O:24][N:23]=2)=[CH:18][C:17]=1[CH3:39]
Reactant: CC(C)NC(C)C
Reactant: COC(=O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1C
Agent: [Li]CCCC
Solvent: CI
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2C)cc1C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of N,N-diisopropylamine (0.24 ml) in dry tetrahydrofuran (8 ml) stirred under argon at 0° C., was added n-butyl lithium (“n-BuLi”) (2.5 M in hexane) (0.74 ml). The solution was stirred at 0° C. for 30 minutes then was cooled to −85° C. To this solution was added a solution of 4-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-benzoic acid methyl ester (made as described in EP 1,731,512) (500 mg) in dry tetrahydrofuran (3 ml). The reaction mixture was stirred at −85° C. until deprotonation was completed as monitored by thin layer chromatography. Then, to this solution was added methyl iodide (0.14 ml) and the reaction mixture was stirred at −85° C. for 1 hour. More methyl iodide (0.08 ml) was added and the reaction mixture was stirred at −85° C. for a further 30 minutes. Then the reaction was quenched by addition of aqueous ammonium chloride (saturated) at −85° C. The mixture allowed to warm to ambient temperature and was then extracted with dichloromethane. The combined organic extracts were dried over magnesium sulfate and concentrated. The residue was purified by chromatography on silica gel (eluent: heptane/ethyl acetate 85:15) to give 4-[5-(3,5-dichloro-phenyl)-4-methyl-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-benzoic acid methyl ester (290 mg) as a white foam. 1H-NMR (CDCl3, 400 MHz): 7.98-7.92 (m, 1H), 7.58-7.38 (m, 5H) 4.22-4.05 (m, 1H), 3.90 (s, 3H), 3.89 (s, 3H), 2.63 (s, 3H), 2.60 (s, 3H), 1.58-1.56 (m, 3H), 0.94-0.92 (m, 3H) ppm.
Reaction SMILES: C([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[C:15](=[O:24])[NH:16][C:17]3[C:22]([CH:23]=2)=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:10][CH2:9]1)C1C=CC=CC=1.[H][H]>CO.[Pd]>[NH:8]1[CH2:9][CH2:10][CH:11]([C:14]2[C:15](=[O:24])[NH:16][C:17]3[C:22]([CH:23]=2)=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:12][CH2:13]1
Reactant: O=c1[nH]c2ccccc2cc1C1=CCN(Cc2ccccc2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: O=c1[nH]c2ccccc2cc1C1CCNCC1
Temperature: 50 °C

Procedure:
A solution of 3-(1-benzyl-1,2,3,6-tetrahydropyridin-4-yl)quinolin-2-(1H)-one (4.00 g, 12.6 mmol) in methanol (500 mL) was degassed with argon, and 10% palladium on carbon (1.2 g) added. The reaction was placed under 1 atm hydrogen and heated to 50° C. for 5.5 h. The reaction was cooled and filtered through celite. Concentration provided the title compound, 2.7 g. MS 229 (M+1). 1H NMR (500 MHz, CD3OD) δ 7.80 (s, 1H), 7.67 (d, J=8 Hz, 1H), 7.51 (t, J=8 Hz, 1H), 7.33 (d, J=8 Hz, 1H), 7.25 (t, J=8 Hz, 1H), 3.52 (t, J=12 Hz, 2H), 3.17 (dt, J=3, 13 Hz, 2H), 3.15 (m, overlaps with δ 3.17 peak, 1H), 2.18 (d, J=14 Hz, 2H), 1.91 (dq, J=3, 12 Hz, 2H).
Reaction SMILES: Cl.[O-:2][C:3]#[N:4].[Na+].[CH2:6]([NH:9][C@H:10]([CH:36]1[CH2:45][CH2:44][C:43]2[C:38](=[CH:39][CH:40]=[C:41]([O:54][CH2:55][C:56]3[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=3)[C:42]=2[O:46][CH2:47][C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[CH2:37]1)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][N:16]([C:26]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27])[CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([NH2:25])=[CH:21][CH:20]=1)[CH2:7][CH3:8]>ClC1C=CC=CC=1>[CH2:6]([NH:9][C@H:10]([CH:36]1[CH2:45][CH2:44][C:43]2[C:38](=[CH:39][CH:40]=[C:41]([O:54][CH2:55][C:56]3[CH:57]=[CH:58][CH:59]=[CH:60][CH:61]=3)[C:42]=2[O:46][CH2:47][C:48]2[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=2)[CH2:37]1)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][N:16]([C:26]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27])[CH2:17][CH2:18][C:19]1[CH:20]=[CH:21][C:22]([NH:25][C:3]([NH2:4])=[O:2])=[CH:23][CH:24]=1)[CH2:7][CH3:8]
Reactant: CCCN[C@@H](CCCCCN(CCc1ccc(N)cc1)C(=O)OCc1ccccc1)C1CCc2c(ccc(OCc3ccccc3)c2OCc2ccccc2)C1
Reactant: N#C[O-]
Agent: Cl
Agent: [Na+]
Solvent: Clc1ccccc1
Product: CCCN[C@@H](CCCCCN(CCc1ccc(NC(N)=O)cc1)C(=O)OCc1ccccc1)C1CCc2c(ccc(OCc3ccccc3)c2OCc2ccccc2)C1

Procedure:
Concentrated HCl (0.7 g; 7.1 mmoles) and sodium cyanate (0.38 g; 5.8 mmoles) were added at room temperature to a stirred solution of Intermediate 64 (2.2 g; 2.9 mmoles), prepared as described in example 32, in chlorobenzene (20 ml) under nitrogen.
Reaction SMILES: [C:1]([O:17]C)(=[O:16])[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([O:8][N:9]1[C:13](=[O:14])[CH2:12][CH2:11][C:10]1=[O:15])=[O:7].Cl[Si](C)(C)C.[I-].[Na+]>C(#N)C.C(OCC)(=O)C>[C:10]1(=[O:15])[N:9]([O:8][C:6](=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2][C:1]([OH:17])=[O:16])[C:13](=[O:14])[CH2:12][CH2:11]1
Reactant: COC(=O)CCCCC(=O)ON1C(=O)CCC1=O
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: O=C(O)CCCCC(=O)ON1C(=O)CCC1=O
Temperature: 25 °C
Yield: 75.2 %

Procedure:
A solution of methyl succinimidyl adipate (4.5 g, 17.5 mmol), chlorotrimethylsilane (11.1 ml, 87.5 mmol) and sodium iodide (13.1 g, 87.5 mmol) in 10 ml of acetonitrile was heated at reflux for 12 hours. The mixture was then cooled to room temperature and diluted with ethyl acetate. The reaction mixture was washed repeatedly with 5 percent aqueous sodium bisulfite until the organic solution was colorless. Then it was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated to provide 3.2 g (71 percent yield by weight) of adipic acid monosuccinimidyl ester as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[CH:9])=[CH:4][CH:3]=1.[CH2:10]([SH:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[Na]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]\[CH:10]([S:17][CH:8](/[CH:9]=[CH:8]\[C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=2)[C:5]2[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:4][CH:3]=1
Reactant: C#Cc1ccc(Br)cc1
Reactant: SCc1ccccc1
Agent: [Na]
Product: Brc1ccc(/C=C\C(SC(/C=C\c2ccc(Br)cc2)c2ccccc2)c2ccccc2)cc1

Procedure:
A solution of 4-bromophenylacetylene (0.02 mol) and benzyl mercaptan (0.02 mol) and metallic sodium (0.02 g atom) was subjected to the General Procedure to form Z-4-bromostyryl benzylsulfide. The title compound was obtained in 80% yield following oxidation. 1HNMR (CDCl3) δ 4.52 (2H, s), 6.80 (1H, d, JH,H=11.98), 7.18-7.59 (9H aromatic+1H ethylenic).
Reaction SMILES: [OH-:1].[Li+].[CH2:3]([C@H:10]([CH2:22][C:23]([N:25]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH3:26])=[O:24])[C:11](N1[C@H](C(C)C)COC1=O)=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>O1CCCC1.O>[CH2:3]([C@H:10]([CH2:22][C:23]([N:25]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH3:26])=[O:24])[C:11]([OH:12])=[O:1])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CC(C)[C@@H]1COC(=O)N1C(=O)[C@@H](CC(=O)N(C)Cc1ccccc1)Cc1ccccc1
Reactant: [OH-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CN(Cc1ccccc1)C(=O)C[C@@H](Cc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 5 h
Yield: 28.4 %

Procedure:
80 mg (1.89 mmole) of lithium hydroxide were added to a solution of 400 mg (0.95 mmole) of 3-[2(R)-benzyl-4-(N-benzyl-N-methylamino)-4-oxobutyryl]-4(R)-isopropyl-2-oxazolidinone (prepared as described in Preparation 14) in a mixture of 10 ml of tetrahydrofuran and 4 ml of water, and the mixture was stirred at room temperature for 5 hours. At the end of this time, the solvent was removed by distillation under reduced pressure, and the resulting residue was mixed with methylene chloride. The mixture was then extracted with a 10% w/v aqueous solution of sodium hydroxide. The aqueous layer was adjusted to a pH value of 2.0 by the addition of citric acid and was then extracted with methylene chloride. The methylene chloride extracts were combined, dried over anhydrous magnesium sulfate and concentrated by distillation under reduced pressure, to afford a colorless oil. This oil was triturated with hexane and the powder which deposited was collected by filtration and then recrystallized from diisopropyl ether, to afford 84 mg of the title compound as needles, melting at 119°-121° C.