Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].[C:3]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[C:12]([CH3:17])([CH3:16])[CH2:11][CH2:10][C:9]2([CH3:19])[CH3:18])(=[O:5])[CH3:4]>CO>[CH3:16][C:12]1([CH3:17])[CH2:11][CH2:10][C:9]([CH3:19])([CH3:18])[C:8]2[CH:7]=[C:6]([C:3](=[O:5])[CH:4]=[CH:3][C:6]3[CH:7]=[CH:8][C:13]([CH3:12])=[CH:14][CH:15]=3)[CH:15]=[CH:14][C:13]1=2
Reactant: CC(=O)c1ccc2c(c1)C(C)(C)CCC2(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1ccc(C=CC(=O)c2ccc3c(c2)C(C)(C)CCC3(C)C)cc1
Reaction time: 8 h
Yield: 191.4 %

Procedure:
10 g of 50% strength sodium hydroxide solution were added dropwise to a solution of 50 g (0.22 mole) of 6-acetyl-1,2,3,4-tetrahydro-1,1,4,4-tetramethylnaphthalene and 26.1 g (0.22 mole) of 4-tolylaldehyde in 250 ml of methanol. The mixture was stirred overnight, after which it was poured onto ice/water and left to stand for several hours. The precipitated crystals were filtered off under suction and dried to give 70 g of 1-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-3-(4-tolyl)-prop-2-en-1-one of melting point 153°-154° C.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[C:20]([F:22])[C:19]([N:23]2[C:28](=[O:29])[CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[NH:25][C:24]2=[O:34])=[CH:18][C:3]=1[O:4][C:5]1[CH:17]=[CH:16][CH:15]=[CH:14][C:6]=1[O:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10].[C:35](=O)([O-])[O-].[K+].[K+].CI.Cl>CN(C)C=O>[Cl:1][C:2]1[CH:21]=[C:20]([F:22])[C:19]([N:23]2[C:28](=[O:29])[CH:27]=[C:26]([C:30]([F:31])([F:32])[F:33])[N:25]([CH3:35])[C:24]2=[O:34])=[CH:18][C:3]=1[O:4][C:5]1[CH:17]=[CH:16][CH:15]=[CH:14][C:6]=1[O:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)COc1ccccc1Oc1cc(-n2c(=O)cc(C(F)(F)F)[nH]c2=O)c(F)cc1Cl
Agent: Cl
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccccc1Oc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl
Temperature: 25 °C

Procedure:
To ethyl [2-{2-chloro-4-fluoro-5-[2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}phenoxy]acetate, are added N,N-dimethylformamide and potassium carbonate, then, methyl iodide is added to the reaction solution, and the mixture is stirred at room temperature. Diluted hydrochloric acid is added to the reaction solution and extracted with ethyl acetate. The organic layer is washed with water and then saturated saline, and dried over anhydrous magnesium sulfate, and concentrated. The residue is subjected to silica gel column chromatography to obtain ethyl [2-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}phenoxy]acetate [compound 3-12 of the present invention].
Reaction SMILES: [CH3:1][N:2]([CH3:24])[S:3]([NH:6][C:7]1[CH:8]=[C:9]([CH:21]=[CH:22][CH:23]=1)[C:10](=[N:19][OH:20])[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)(=[O:5])=[O:4].C(N(CC)CC)C.[C:32](Cl)(=[O:34])[CH3:33].O>C(Cl)Cl>[C:32]([O:20][N:19]=[C:10]([C:11]1[CH:12]=[CH:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=1)[C:9]1[CH:21]=[CH:22][CH:23]=[C:7]([NH:6][S:3]([N:2]([CH3:1])[CH3:24])(=[O:5])=[O:4])[CH:8]=1)(=[O:34])[CH3:33]
Reactant: CC(=O)Cl
Reactant: COc1ccc(C(=NO)c2cccc(NS(=O)(=O)N(C)C)c2)cc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: COc1ccc(C(=NOC(C)=O)c2cccc(NS(=O)(=O)N(C)C)c2)cc1
Yield: 29.8 %

Procedure:
A suspension of 3-[N-(dimethylaminosulfonyl)amino]-4'-methoxybenzophenone oxime (1.5 g) and triethylamine (650 mg) in dry methylene chloride (15 ml) is stirred under icy water cooling. A solution of acetyl chloride (337 mg) in dry methylene chloride (3 ml) is dropwise added to the suspension, and 30 minutes later the reaction mixture is mixed with icy water, washed with water, dried over anhydrous sodium sulfate and concentrated in vacuum. The residue is chromatographed on a column of Lobar Lichroprep Si 60, which is eluted with benzene:ethyl acetate (2:1). The eluates from the fraction No. 5-18 are combined and concentrated to give 3-[N-(dimethylaminosulfonyl)amino]-4'-methoxybenzophenone O-acetyloxime (500 mg) as an oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:26])=[C:4]([CH:20]2[CH2:24][C:23](=[O:25])[NH:22][CH2:21]2)[C:5]([O:18][CH3:19])=[C:6]([CH:8]([NH:10]C(=O)OC(C)(C)C)[CH3:9])[CH:7]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:10][CH:8]([C:6]1[C:5]([O:18][CH3:19])=[C:4]([CH:20]2[CH2:21][NH:22][C:23](=[O:25])[CH2:24]2)[C:3]([CH3:26])=[C:2]([Cl:1])[CH:7]=1)[CH3:9]
Reactant: COc1c(C(C)NC(=O)OC(C)(C)C)cc(Cl)c(C)c1C1CNC(=O)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1c(C(C)N)cc(Cl)c(C)c1C1CNC(=O)C1
Reaction time: 0.5 h

Procedure:
Solutions of the individual diastereoisomers of tert-butyl {1-[5-chloro-2-methoxy-4-methyl-3-(5-oxopyrrolidin-3-yl)phenyl]ethyl}carbamate (75 mg, 0.20 mmol [peak 1 from step 3]; 75 mg, 0.20 mmol [peak 2 from step 3]) in separate reaction flasks in methylene chloride (1 mL) were each treated individually with trifluoroacetic acid (1 mL) dropwise and stirred for 30 minutes. The reaction mixtures were individually concentrated to residues, diluted with saturated sodium bicarbonate, and extracted several times with dichloromethane to give diastereoisomer from peak 1 (60 mg, quantitative) and diastereoisomer from peak 2 (55 mg, quantitative) as colorless residues that were used without further purification. Peak 1: LCMS for C14H17ClNO2 (M−NH2)+: m/z=266.1. Found: 266.1. Peak 2: LCMS for C14H20ClN2O2 (M+H)+: m/z=283.1. Found: 283.1.
Reaction SMILES: C([O:5][C:6](=[O:21])[C@@H:7]([N:10]1[CH:15]=[CH:14][CH:13]=[C:12]([NH:16][C:17](=[O:19])[CH3:18])[C:11]1=[O:20])[CH2:8][CH3:9])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[C:17]([NH:16][C:12]1[C:11](=[O:20])[N:10]([C@@H:7]([CH2:8][CH3:9])[C:6]([OH:21])=[O:5])[CH:15]=[CH:14][CH:13]=1)(=[O:19])[CH3:18]
Reactant: CC[C@@H](C(=O)OC(C)(C)C)n1cccc(NC(C)=O)c1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC[C@@H](C(=O)O)n1cccc(NC(C)=O)c1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 71.1 %

Procedure:
A solution of (S)-2-(3-Acetylamino-2-oxo-2H-pyridin-1-yl)-butyric acid tert-butyl ester (569 mg, 1.93 mmol) in dichloromethane (5 mL) was cooled to 0° C. Trifluoroacetic acid (5 ml) was added and the resulting mixture allowed to warm to room temperature and stir for 2 hours. The mixture was then concentrated under reduced pressure and the residue redissolved in dichloromethane. This process was repeated several times in order to remove excess trifluoroacetic acid. The resulting solid was slurried in diethyl ether, filtered and washed with more diethyl ether. The solid was then dried to constant weight under vacuum. This gave the title product as a white solid (327 mg, 71%); 1H NMR (400 MHz, d6-DMSO) δ 0.78 (3H, t), 2.02-2.17 (5H, m), 4.98 (1H, dd), 6.29 (1H, t), 7.35 (1H, d), 8.21 (1H, d), 9.30 (1H, s), 13.07 (1H, vbr s).
Reaction SMILES: ClC1C=C(NC2C=CC(C(F)(F)F)=CC=2)C=CC=1C(C1C=C([N+]([O-])=O)C=CC=1C)=O.Br[C:32]1[CH:37]=[CH:36][C:35]([C:38]([C:40]2[CH:45]=[C:44]([N+:46]([O-:48])=[O:47])[CH:43]=[CH:42][C:41]=2[CH3:49])=[O:39])=[C:34]([Cl:50])[CH:33]=1.[Cl:51][C:52]1[CH:58]=[C:57]([F:59])[CH:56]=[CH:55][C:53]=1[NH2:54]>>[Cl:50][C:34]1[CH:33]=[C:32]([NH:54][C:53]2[CH:55]=[CH:56][C:57]([F:59])=[CH:58][C:52]=2[Cl:51])[CH:37]=[CH:36][C:35]=1[C:38]([C:40]1[CH:45]=[C:44]([N+:46]([O-:48])=[O:47])[CH:43]=[CH:42][C:41]=1[CH3:49])=[O:39]
Reactant: Cc1ccc([N+](=O)[O-])cc1C(=O)c1ccc(Br)cc1Cl
Reactant: Nc1ccc(F)cc1Cl
Agent: Cc1ccc([N+](=O)[O-])cc1C(=O)c1ccc(Nc2ccc(C(F)(F)F)cc2)cc1Cl
Product: Cc1ccc([N+](=O)[O-])cc1C(=O)c1ccc(Nc2ccc(F)cc2Cl)cc1Cl

Procedure:
The reaction was carried out similarly as described in the preparation of compound 414, using compound 402 (0.28 mmol) and 2-chloro-4-fluoroaniline (0.28 mmol). The crude product was purified by continuous gradient flash chromatography using MeOH/EtOAc 0:100 to 25:75 as the eluent to afford the title compound as yellow foam.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[C:9]1(B(O)O)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:8][C:5]1[CH:4]=[N:3][C:2]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:7][CH:6]=1
Reactant: Brc1ccc(Br)nc1
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Brc1ccc(-c2ccccc2)nc1
Temperature: 75 °C
Reaction time: 16 h

Procedure:
2,5-Dibromopyridine (0.948 g, 4 mmol), phenylboronic acid (0.488 g, 4 mmol) and tetrakis(triphenylphosphine)palladium (0.116 g, 0.1 mmol) were dissolved in anhydrous tetrahydrofuran (6 mL) and a solution of sodium carbonate (0.848 g, 8 mmol) in water (6 mL) was added. The mixture was put under nitrogen and stirred at 75° C. for 16 h. The mixture was concentrated in vacuo. The residue was dissolved in water (10 mL) and extracted with dichloromethane (3×5 mL). The combined organic extracts were dried with anhydrous sodium sulphate. Column chromatography of the residue (silica gel Fluka 60, hexanes/dichloromethane 1:1) afforded 3-bromo-6-phenylpyridine as a white crystalline product.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[C:11]1(B(O)O)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.COCCOC>[C:11]1([C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: COCCOC
Product: O=[N+]([O-])c1ccc(-c2ccccc2)nc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 97.8 %

Procedure:
2-Chloro-5-nitropyridine (3.0 g, 18.9 mmol), phenylboronic acid (2.5 g, 20.8 mmol), and tetrakis(triphenylphosphine)palladium (0.2 g, 0.2 mmol) were added to 1,2-dimethoxyethan (30 ml), then degassed and purged with nitrogen three times under reduced pressure. Under nitrogen atmosphere the mixture was stirred at room temperature for 20 minutes, then 1M aqueous sodium carbonate (40 ml) was poured in, and the temperature was raised to 80° C. After the reaction at 80° C. for 6 hours, the mixture was cooled to room temperature and crystallized with addition of water. The precipitated crystals were filtered to give the title compound (3.7 g, 96.8%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9](=O)[CH2:10][C:11](=O)[C:12]([F:15])([F:14])[F:13])[CH:5]=[CH:6][C:7]=1[Cl:8].[NH2:18][C:19]1[C:23]([C:24]2[CH:29]=[C:28]([CH3:30])[N:27]=[C:26]([CH3:31])[CH:25]=2)=[CH:22][NH:21][N:20]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[C:11]([C:12]([F:15])([F:14])[F:13])[N:20]3[N:21]=[CH:22][C:23]([C:24]4[CH:29]=[C:28]([CH3:30])[N:27]=[C:26]([CH3:31])[CH:25]=4)=[C:19]3[N:18]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: Cc1cc(-c2c[nH]nc2N)cc(C)n1
Reactant: O=C(CC(=O)C(F)(F)F)c1ccc(Cl)c(Cl)c1
Product: Cc1cc(-c2cnn3c(C(F)(F)F)cc(-c4ccc(Cl)c(Cl)c4)nc23)cc(C)n1
Yield: 48.5 %

Procedure:
Reaction of 1-(3,4-dichloro-phenyl)-4,4,4-trifluoro-butane-1,3-dione (143 mg, 0.5 mmol), prepared from commercially available 3,4-dichloro-acetophenone according to general procedure A, and 3-amino-4-(2,6-dimethyl-4-pyridinyl)-pyrazole [prepared from 4-cyanomethyl-2,6-dimethyl-pyridine, CAS No. 130138-46-4, see part synthesis of amino-pyrazole derivatives] (94 mg, 0.5 mmol) according to general procedure B yielded the title compound as a yellow solid (106 mg, 48%). MS (ISP) 437.1 [(M+H)+]; mp 281° C.
Reaction SMILES: O=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][O:5][C:4]2[CH:13]=[CH:14][C:15]([CH2:17][CH2:18][C:19]([OH:21])=[O:20])=[CH:16][C:3]1=2>C(O)(=O)C.[Zn]>[CH:16]1[C:3]2[CH2:2][C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=3[CH2:6][O:5][C:4]=2[CH:13]=[CH:14][C:15]=1[CH2:17][CH2:18][C:19]([OH:21])=[O:20]
Reactant: O=C(O)CCc1ccc2c(c1)C(=O)c1ccccc1CO2
Agent: [Zn]
Solvent: CC(=O)O
Product: O=C(O)CCc1ccc2c(c1)Cc1ccccc1CO2
Yield: 75.4 %

Procedure:
A solution of 3-(6,11-dihydro-11-oxo-dibenz[b,e]oxepin-2-yl)propanoic acid (6.0 g) in 120 ml glacial acetic acid was treated with zinc dust (18.0 g) in portions over 1 minute. This slurry was heated at reflux for 2 hours then filtered while hot through a sintered funnel. The filtrate was evaporated, taken up in ethyl acetate and washed with dilute HCl, then dried and evaporated to a solid. This solid was recrystallized from ethyl acetate to give 4.3 g of crystals, m.p. 181-183° C.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:5][C@H:4]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH2:3]1.[H-].[Na+].I[CH3:17]>C1COCC1>[C:9]([O:8][C:7](=[O:13])[NH:6][C@H:4]1[CH2:3][C@@H:2]([O:1][CH3:17])[CH2:5]1)([CH3:10])([CH3:12])[CH3:11]
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@@H](O)C1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CO[C@H]1C[C@@H](NC(=O)OC(C)(C)C)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 192.1 %

Procedure:
tert-Butyl (cis-3-hydroxycyclobutyl)carbamate (0.8 g, 4.3 mmol) was dissolved in dry THF (25 mL) under a nitrogen atmosphere, and the solution cooled to 0° C. To this clear solution, sodium hydride (60% dispersion in oil, 0.17 g, 4.3 mmol) was added portion wise (evolution of H2 observed). The mixture was stirred at RT for 30 min. then iodomethane (0.40 mL, 1.5 mmol) added dropwise and the resulting yellow suspension stirred at rt for 16 h. The reaction mixture was quenched with saturated aqueous solution of NH4Cl (20 mL) and partitioned between saturated aqueous solution of NaHCO3 (40 mL) and DCM (60 mL). The combined organic fractions were washed with brine (20 mL), dried (MgSO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (gradient 0-70% EtOAc in cyclohexane) to afford the title compound as a white solid (0.58 g, 66%). 1H NMR (CDCl3, 300 MHz): δ 4.66 (1H, br, NH), 3.71-3.62 (1H, m), 3.61-3.50 (1H, m), 2.71 (3H, s), 2.76-1.62 (2H, m), 1.78-1.62 (2H, m), 1.41 (9H, s).
Reaction SMILES: [CH2:1]([NH:8][C@H:9]1[C@@H:15]([F:16])[CH2:14][C@@H:13]2[N:17]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C@@:10]1([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH2:11][C@H:12]2[C:25](OC(C)(C)C)=[O:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([BH-](CC)CC)C.[Li+].[OH-].[Na+]>O1CCCC1>[CH2:1]([NH:8][C@H:9]1[C@@H:15]([F:16])[CH2:14][C@@H:13]2[N:17]([CH2:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[C@@:10]1([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH2:11][C@H:12]2[CH2:25][OH:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)[C@@H]1C[C@@]2(c3ccccc3)[C@@H](NCc3ccccc3)[C@@H](F)C[C@@H]1N2Cc1ccccc1
Agent: CC[BH-](CC)CC
Agent: [Li+]
Agent: [Na+]
Solvent: C1CCOC1
Product: OC[C@@H]1C[C@@]2(c3ccccc3)[C@@H](NCc3ccccc3)[C@@H](F)C[C@@H]1N2Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.6 %

Procedure:
(1R*,2R*,3S*,5S*,6R*)-2-Benzylamino-8-benzyl-3-fluoro-1-phenyl-6-(tert-butoxycarbonyl)-8-azabicyclo[3.2.1]octane (Description 36b; 651 mg, 1.3 mmol) was dissolved in tetrahydrofuran (10 mL) and then treated with a solution of lithium triethylborohydride in tetrahydrofuran (4 mL, 1M, 4 mmol). The solution was stirred at room temperature for 1 hour, then poured into aqueous sodium hydroxide solution (50 mL, 1M). The suspension formed was extracted with ethyl acetate (2×100 mL) and the extracts were dried (MgSO4). Concentration in vacuo gave a gum which was purified by silica chromatography to give the title compound (476 mg, 1.1 mmol).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:14])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[NH2:6].[C:15](=N)([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(Cl)Cl>[CH3:2][O:3][C:4](=[O:14])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[N:6]=[C:15]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Reactant: N=C(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: ClCCl
Product: COC(=O)[C@H](Cc1ccccc1)N=C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.6 %

Procedure:
L-phenylalanine methyl ester hydrochloride (5.95 g) and benzophenonimine (5.00 g) were added to methylene chloride (100 ml), and the mixture was stirred overnight at room temperature. The solid was filtered off from the reaction solution, and the solvent was distilled off under reduced pressure. Then, diethyl ether (100 ml) was added to the residue. The solid was filtered off again, and the ether layer was then washed with water (100 ml), and dried over anhydrous magnesium sulfate. After magnesium sulfate was removed, the ether solution was concentrated to obtain desired N-(diphenylmethylene)-L-phenylalanine methyl ester (9.44 g) in a yield of 99.6%.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]([O:13][CH3:14])=[O:12])=[CH:8][CH:9]=2)[NH:4][CH:3]=1.[CH:15]1([CH2:21]Br)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.[OH-].[K+]>CC(C)=O.[I-].[Na+]>[CH:15]1([CH2:21][N:4]2[C:5]3[C:10](=[CH:9][CH:8]=[C:7]([C:11]([O:13][CH3:14])=[O:12])[CH:6]=3)[C:2]([CH3:1])=[CH:3]2)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: BrCC1CCCCC1
Reactant: COC(=O)c1ccc2c(C)c[nH]c2c1
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Solvent: CC(C)=O
Product: COC(=O)c1ccc2c(C)cn(CC3CCCCC3)c2c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 63 %

Procedure:
A mixture of methyl 3-methyl-1 H-indole-6-carboxylate(10 g, Reference Example 30), cyclohexylmethylbromide (19 g), potassium hydroxide (12 g) and sodium iodide (0.1 g) in acetone (200 ml) was stirred at room temperature for 6 hours. The reaction mixture was evaporated. The residue was partitioned between ethyl acetate (250 ml) and water (250 ml). The aqueous layer was extracted three times with ethyl acetate (250 ml). The total combined organic phases were dried over sodium sulphate then evaporated. The residue was subjected to flash column chromatography on silica eluting with a mixture of ethyl acetate and hexane (gradient elution, 0:10 to 1:9, v/v)to yield the title compound (9.5 g). NMR (CDCl3): δ0.90-1.10(m), 1.10-1.40(m), 1.60-1.90(m), 2.30(s), 3.90-4.00(m), 3.90(s), 7.00(s), 7.50-7.60(m), 7.70-7.80(m), 8.00(s). MH+271.
Reaction SMILES: [N:1]1C=CC=CC=1.Cl[C:8]([O:10][C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=1)=[O:9]>ClCCl>[C:8](=[O:9])([O:10][C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=1)[NH2:1]
Reactant: c1ccncc1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Product: NC(=O)Oc1ccc([N+](=O)[O-])cc1
Reaction time: 8 h
Yield: 70 %

Procedure:
To a stirred, cooled (about 0° C.) solution of methyl-3-amino-4-methoxy benzoate (5.0 g; 27.6 mmol) in dry dichloromethane (175 mL) was added pyridine (2.34 mL; 29 mmol) followed by 4-nitrophenyl chloroformate (5.8 9; 29 mmol) under a nitrogen (N2) atmosphere. After stirring for 8 hours, the, reaction was washed with 2N aqueous hydrochloric acid (2×200 mL), saturated aqueous sodium bicarbonate (2×200 mL), and brine (200 mL), then dried (MgSO4), and filtered. The filtered solution was diluted with ethyl acetate and hexanes (about 800 mL) until a precipitate formed. The solid was collected on a Buchner funnel with suction, and air dried to provide the desired carbamate as a white solid (70% yield).
Reaction SMILES: O.[SH-].[Na+].[CH3:4][C:5]1([CH3:14])[O:9][N:8]=[C:7]([S:10]([CH3:13])(=O)=O)[CH2:6]1.BrC[C:17]1[C:18]([C:29]([F:32])([F:31])[F:30])=[N:19][N:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:21]=1[F:22].O>CN(C)C=O>[CH3:4][C:5]1([CH3:14])[O:9][N:8]=[C:7]([S:10][CH2:13][C:17]2[C:18]([C:29]([F:32])([F:31])[F:30])=[N:19][N:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:21]=2[F:22])[CH2:6]1
Reactant: CC1(C)CC(S(C)(=O)=O)=NO1
Reactant: Fc1c(CBr)c(C(F)(F)F)nn1-c1ccccc1
Agent: [Na+]
Agent: [SH-]
Solvent: CN(C)C=O
Solvent: O
Product: CC1(C)CC(SCc2c(C(F)(F)F)nn(-c3ccccc3)c2F)=NO1
Reaction time: 2 h
Yield: 37.4 %

Procedure:
9.3 g of sodium hydrosulfide hydrate (purity: 70%, 116.3 mmoles) was added to a solution of 18.7 g (105.7 mmoles) of 5,5-dimethyl-3-methylsulfonyl-2-isoxazoline (present compound No. 2-1) dissolved in 300 ml of N,N-dimethylformamide. The mixture was stirred for 2 hours. The reaction system was ice-cooled. Thereto was added a solution of 30.3 g (93.8 mmoles) of 4-bromomethyl-5-fluoro-1-phenyl-3-trifluoromethyl-1H-pyrazole dissolved in 200 ml of N,N-dimethylformamide. The mixture was stirred at 0° C. for 30 minutes to give rise to a reaction. After the completion of the reaction, the reaction mixture was poured into water, followed by extraction with ethyl acetate. The resulting organic layer was washed with an aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein. The residue was purified by silica gel column chromatography (developing solvent: hexane-ethyl acetate mixed solvent) to obtain 13.11 g (yield: 37.4%) of 5,5-dimethyl-3-(5-fluoro-1-phenyl-3-trifluoromethyl-1H-pyrazol-4-ylmethylthio)-2-isoxazoline as a yellow oily substance.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]([CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH:22]([S:27][C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=2)[C:23]([O:25]C)=[O:24])=[CH:17][CH:16]=1)[CH3:11]>C1(C)C=CC=CC=1>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]([CH2:12][CH2:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([CH2:21][CH:22]([S:27][C:28]2[CH:29]=[CH:30][C:31]([Cl:34])=[CH:32][CH:33]=2)[C:23]([OH:25])=[O:24])=[CH:19][CH:20]=1)[CH3:11]
Reactant: COC(=O)C(Cc1ccc(OCCN(C)c2nc3ccccc3o2)cc1)Sc1ccc(Cl)cc1
Solvent: Cc1ccccc1
Product: CN(CCOc1ccc(CC(Sc2ccc(Cl)cc2)C(=O)O)cc1)c1nc2ccccc2o1

Procedure:
The title compound, mp 156.1°-157.4° C. (toluene), was prepared from methyl 3-[4-[2-[N-(2-benzoxazolyl)-N-methylamino)ethoxy]phenyl]-2-(4-chlorophenylthio)propanoate by a procedure similar to that described in Example 24.
Reaction SMILES: [C:1]([C:3]12[CH2:18][C:17]([CH3:22])([C:19](O)=[O:20])[CH:10]([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=31)[C:9]1[C:4]2=[CH:5][CH:6]=[CH:7][CH:8]=1)#[N:2].N1C=CC=CC=1.N1C(F)=NC(F)=NC=1[F:31]>C(Cl)Cl.Cl>[C:1]([C:3]12[CH2:18][C:17]([CH3:22])([C:19]([F:31])=[O:20])[CH:10]([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=31)[C:9]1[C:4]2=[CH:5][CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: CC1(C(=O)O)CC2(C#N)c3ccccc3C1c1ccccc12
Reactant: Fc1nc(F)nc(F)n1
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC1(C(=O)F)CC2(C#N)c3ccccc3C1c1ccccc12
Reaction time: 0.5 h
Yield: 91 %

Procedure:
To a solution of 9-cyano-9,10-dihydro-11-methyl-9,10-ethanoanthracene-11-carboxylic acid (hereafter called Core A) (5.26 g, 18.2 mmol) and pyridine (2.2 mL, 27.0 mmol) in 10 mL of DCM was added a solution of cyanuric fluoride (2.14 g, 27.0 mmol) dropwise. After stirring 30 min, the reaction was diluted with 1N HCl, and extracted 2×DCM. The DCM extracts were dried over MgSO4. The solution was filtered, concentrated by rotary evaporator to give 4.8 g (91%) of 9-cyano-9,10-dihydro-11-methyl-9,10-ethano-anthracene-11-carboxylic acid fluoride, Core B. MS found: (M+H)+=292.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[CH:38]=[CH:37][C:13]([CH2:14][N:15]([C:24]3[CH:36]=[CH:35][C:27]4[O:28]C(C)(C)[O:30][C:31](=[O:32])[C:26]=4[CH:25]=3)[C:16](=[O:23])[CH2:17][C:18]3[S:19][CH:20]=[CH:21][CH:22]=3)=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.[OH-].[Na+]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]#[C:9][C:10]2[CH:11]=[CH:12][C:13]([CH2:14][N:15]([C:16](=[O:23])[CH2:17][C:18]3[S:19][CH:20]=[CH:21][CH:22]=3)[C:24]3[CH:36]=[CH:35][C:27]([OH:28])=[C:26]([CH:25]=3)[C:31]([OH:32])=[O:30])=[CH:37][CH:38]=2)=[CH:6][CH:7]=1
Reactant: CC1(C)OC(=O)c2cc(N(Cc3ccc(C#Cc4ccc(Cl)cc4)cc3)C(=O)Cc3cccs3)ccc2O1
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)c1cc(N(Cc2ccc(C#Cc3ccc(Cl)cc3)cc2)C(=O)Cc2cccs2)ccc1O

Procedure:
The titled compound was prepared following the procedure C using N-{4-[(4-chlorophenyl)ethynyl]benzyl}-N-(2,2-dimethyl-4-oxo-4H-1,3-benzodioxin-6-yl)-2-(2-thienyl)acetamide and NaOH as a brown solid (42%). M− (ESI): 499.7; M+ (ESI): 502.3. HPLC, Rt: 4.92 min (Purity: 88.5%).