Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[OH:11][CH2:12][CH:13]1[CH2:18][CH2:17][CH:16]([C:19]([O:21][CH3:22])=[O:20])[CH2:15][CH2:14]1.C(N(CC)CC)C>ClCCl.O>[CH:12]([CH:13]1[CH2:14][CH2:15][CH:16]([C:19]([O:21][CH3:22])=[O:20])[CH2:17][CH2:18]1)=[O:11]
Reactant: COC(=O)C1CCC(CO)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: COC(=O)C1CCC(C=O)CC1
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 91.7 %

Procedure:
Dimethyl sulphoxide (0.65 ml) in dry dichloromethane (5 ml) was added to a solution of oxalyl chloride (0.363 ml) in dichloromethane (5 ml) at -70° C. under a stream of nitrogen. After 5 minutes stirring a solution of methyl 4-hydroxymethylcyclohexanecarboxylate (0.64 g) in dichloromethane (5 ml) was added dropwise. The reaction mixture was stirred for 30 minutes at -70° C. Triethylamine (2.60 ml) was then added and the reaction mixture allowed to warm to room temperature during a period of 3 hours. After pouring into water (100 ml) the organic phase was washed with dilute hydrochloric acid, sodium bicarbonate solution and brine before drying over magnesium sulphate. Evaporation in vacuo gave methyl 4-formylcyclohexanecarboxylate (0.58 g) as a mixture of cis and trans-isomers.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][CH:9]=[C:10]([C:14]([NH2:16])=[O:15])[C:11]([NH:12][NH2:13])=[C:6]2[CH:5]=[N:4]1)[CH3:2].[CH3:17][C:18]([CH3:20])=O>>[CH2:1]([N:3]1[C:7]2=[N:8][CH:9]=[C:10]([C:14]([NH2:16])=[O:15])[C:11]([NH:12][N:13]=[C:18]([CH3:20])[CH3:17])=[C:6]2[CH:5]=[N:4]1)[CH3:2]
Reactant: CC(C)=O
Reactant: CCn1ncc2c(NN)c(C(N)=O)cnc21
Product: CCn1ncc2c(NN=C(C)C)c(C(N)=O)cnc21
Reaction time: 8 h

Procedure:
14 g. of well pulverized 1-ethyl-4-hydrazino-1H-pyrazolo[3,4-b]pyridine-5-carboxamide (0.0635 mol.) are dissolved in 500ml. of anhydrous acetone and the solution is allowed to stand overnight. Then excess acetone is removed in vacuo and the residual 1-ethyl-4-[2-(1-methylethylidene)hydrazino]-1H-pyrazolo[3,4-b]pyridine-5-carboxamide is recrystallized from ethyl acetate, m.p. 217°-218°, yield 9.75 g. (59%).
Reaction SMILES: O.[C:2]1([C:8]([CH:10]=[O:11])=[O:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1>ClC(Cl)C.[Ti](Cl)(Cl)(Cl)Cl>[CH2:15]([C:16]1[CH:17]=[CH:18][C:19]([CH:10]([OH:11])[C:8](=[O:9])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:20][CH:21]=1)[CH2:14][CH2:13][CH3:12]
Reactant: O=CC(=O)c1ccccc1
Reactant: CCCCc1ccccc1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: CC(Cl)Cl
Solvent: O
Product: CCCCc1ccc(C(O)C(=O)c2ccccc2)cc1

Procedure:
Phenylglyoxal monohydrate (304 mg, 2 mM) and n-butylbenzene (0.62 ml, 4 mM) were dissolved in dichloroethane (4 ml), titanium tetrachloride (0.33 ml, 3 mM) was added, and reacted at room temperature for 1 hour. Using the same procedure as in Example 1, 4'-n-butylbenzoin was obtained as crystal (362.7 mg, 67.2% yield).
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([F:11])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH:12]([CH3:14])[CH3:13].C(N(C(C)C)CC)(C)C.[CH:24]1([NH2:28])[CH2:27][CH2:26][CH2:25]1>C(O)C>[CH:24]1([NH:28][C:2]2[N:10]=[C:9]([F:11])[N:8]=[C:7]3[C:3]=2[N:4]=[CH:5][N:6]3[CH:12]([CH3:14])[CH3:13])[CH2:27][CH2:26][CH2:25]1
Reactant: CC(C)n1cnc2c(Cl)nc(F)nc21
Reactant: NC1CCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CC(C)n1cnc2c(NC3CCC3)nc(F)nc21
Yield: 67.9 %

Procedure:
6-chloro-2-fluoro-9-isopropyl-9H-purine (0.3 g, 1.4 mmol), diisopropylethylamine (0.2 g, 1.55 mmol) and cyclobutylamine (0.2 g, 2.8 mmol) were stirred together in ethanol (30 ml) at room temperature for 6 h. Volatiles were removed and the residue taken up in ethyl acetate, washed with water (50 ml), brine (50 ml), dried (MgSO4) and concentrated. The crude was purified by silica gel flash column chromatography (ethyl acetate:hexane 3:2) to give the pure product (237 mg, 68%) δH (CDCl3, 500 MHz) 1.56 (6H, d, J 7.5, CH[CH3]2), 1.76-1.74 (2 H, m, CH2 of Cyclobutyl), 1.98-1.94 (2 H, m, CH2 of cyclobutyl), 2.45 (2 H, s, br, CH2 of cyclobutyl)) 4.72-4.7 (2 H, m, CH of cyclobutyl and CHMe2), 6.35 (1 H, s, br, NH), 7.75 (1 H, s, ArH); δC (CDCl3, 500 MHz) 160.08 (C), 158.43 (C), 155.34 (C), 155.18 (C), 150.09 (C), 137.44 (CH), 47.26 (CH), 31.56 (2×CH2), 22.38 (2×CH3), 15.09 (CH2); m/z 250.2 (M+H)
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[OH:11]>C1C2C(=CC=CC=2)C=CC=1O.C(Cl)(Cl)(Cl)Cl>[CH:7]1[CH:6]=[C:5]2[CH:4]=[CH:3][C:2]([OH:11])=[C:1]([C:1]3[C:10]4[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=4)[CH:4]=[CH:3][C:2]=3[OH:11])[C:10]2=[CH:9][CH:8]=1
Reactant: Oc1ccc2ccccc2c1
Solvent: ClC(Cl)(Cl)Cl
Product: Oc1ccc2ccccc2c1-c1c(O)ccc2ccccc12
Reaction time: 0.17 h
Yield: 84 %

Procedure:
A two-neck round bottom flask (5 mL) was charged with a solution of catalyst 1c (12.2 mg, 0.02 mmol) in anhydrous CCl4 (1 mL). The solution was stirred for 10 min under an oxygen atmosphere and then treated with a solution of 2-naphthol (29 mg, 0.2 mmol) in anhydrous CCl4 (1 mL). The reaction mixture was stirred at 0° C. until the reaction was complete (monitored by TLC). The crude mixture was concentrated under reduced pressure, and purified by column chromatography (Ethyl acetate/Petroleum ether=⅓) to give (R)-BINOL 3a, Yield 84%. 1HNMR (300 MHz, CDCl3) δ (ppm) 7.98 (d, J=9.0 Hz, 2H, 2×HC (4)), 7.90 (d, J=7.8 Hz, 2H, 2×HC (5)), 7.38 (d, J=9.0 Hz, 2H, 2×HC (8)), 7.41–7.27 (m, 4H, 2×HC (6), 2×HC (7)), 7.16 (d, J=8.4 Hz, 2 H, 2×HC (3)), 5.09 (s, 2H, 2×OH). e.e. 90% and the configuration was R (Kromasil CHI-TBB column, Hexane/propan-2-ol=90: 10; flow rate 1 mL/min; S-isomer, tR 7.78 min and R-isomer, tR 8.79 min).
Reaction SMILES: FC1C(O[C:9](=[O:24])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[NH:16][CH2:17][C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)=C(F)C(F)=C(F)C=1F.[CH3:29][C:30]1[O:34][N:33]=[C:32]([CH2:35][O:36][NH2:37])[CH:31]=1>>[CH3:29][C:30]1[O:34][N:33]=[C:32]([CH2:35][O:36][NH:37][C:9](=[O:24])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[NH:16][CH2:17][C:18]2[CH:19]=[CH:20][N:21]=[CH:22][CH:23]=2)[CH:31]=1
Reactant: Cc1cc(CON)no1
Reactant: O=C(Oc1c(F)c(F)c(F)c(F)c1F)c1ccccc1NCc1ccncc1
Product: Cc1cc(CONC(=O)c2ccccc2NCc2ccncc2)no1

Procedure:
Prepared by the same method as described for example 415. Starting materials: 2-[(Pyridin-4-ylmethyl)-amino]-benzoic acid pentafluorophenyl ester (preparation 7C) and O-(5-Methyl-isoxazol-3-ylmethyl)-hydroxylamine (see preparation 61)
Reaction SMILES: [C:1]([CH:3]=[C:4]1[CH2:7][CH:6]([C:8]#[N:9])[CH2:5]1)#[N:2].[NH:10]1[CH:14]=[C:13]([C:15]2[C:16]3[CH:23]=[CH:22][N:21]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH:12]=[N:11]1.C(#N)C.N12CCCN=C1CCCCC2>>[C:1]([CH2:3][C:4]1([N:10]2[CH:14]=[C:13]([C:15]3[C:16]4[CH:23]=[CH:22][N:21]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:17]=4[N:18]=[CH:19][N:20]=3)[CH:12]=[N:11]2)[CH2:7][CH:6]([C:8]#[N:9])[CH2:5]1)#[N:2]
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cn[nH]c3)ncnc21
Reactant: N#CC=C1CC(C#N)C1
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CC(C#N)C4)c3)ncnc21
Temperature: 25 °C

Procedure:
3-(Cyanomethylene)cyclobutanecarbonitrile (120 mg, 0.0010 mol) was combined with 4-(1H-pyrazol-4-yl)-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidine (0.1 g, 0.0003 mol) in acetonitrile (2 mL, 0.04 mol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (6 μL, 0.00004 mol) under nitrogen. The mixture was stirred at room temperature over the weekend. After evaporation to dryness, the crude mixture was purified by flash column, eluting with 0 to 10% MeOH in dichloromethane, to give the desired product. LCMS (M+H) 434.4.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]=1[CH:15]=O)[CH2:2][CH3:3].[CH3:17][CH:18]([CH3:34])[C:19]([NH:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH:23]=1)=[O:20]>>[CH3:17][CH:18]([CH3:34])[C:19]([NH:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH:28]2[CH2:33][CH2:32][N:31]([CH2:15][C:6]3[C:7]4[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=4)[CH:13]=[CH:14][C:5]=3[O:4][CH2:1][CH2:2][CH3:3])[CH2:30][CH2:29]2)[CH:23]=1)=[O:20]
Reactant: CCCOc1ccc2ccccc2c1C=O
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Product: CCCOc1ccc2ccccc2c1CN1CCC(c2cccc(NC(=O)C(C)C)c2)CC1

Procedure:
Prepared by Procedure F and Scheme R using 2-propoxy-1-naphthaldehyde and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 445.2 (M+H)+.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7]O)=[CH:5][CH:4]=1.S(Cl)([Cl:13])=O>C1C=CC=CC=1>[CH3:1][S:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][Cl:13])=[CH:5][CH:4]=1
Reactant: O=S(Cl)Cl
Reactant: CSc1ccc(CO)cc1
Solvent: c1ccccc1
Product: CSc1ccc(CCl)cc1

Procedure:
To a stirred solution of 154 g (1 mol) of 4-methylmercaptobenzyl alcohol in 1 liter of dry bensene was added dropwise 80 ml 1.1 mol) of thionyl chloride. The mixture immediately turned blue. After the addition of the thionyl chloride was completed, the mixture was heated at reflux for 2 hours. After cooling the benzene and excess thionyl chloride were distilled at ambient pressure. The product was distilled in vacuo at 105° C. (0.5 mm), to yield 160 g (93%) of water clear liquid.
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([Cl:15])=[CH:10][C:9]=2[CH2:16][N:17]([CH3:19])[CH3:18])=[O:5])C.O[Li].O.Cl>C1COCC1.CCO.O>[Cl:15][C:11]1[CH:12]=[C:13]2[C:8](=[C:9]([CH2:16][N:17]([CH3:18])[CH3:19])[CH:10]=1)[NH:7][C:6]([C:4]([OH:5])=[O:3])=[CH:14]2
Reactant: CCOC(=O)c1cc2cc(Cl)cc(CN(C)C)c2[nH]1
Agent: Cl
Agent: [Li]O
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: CN(C)Cc1cc(Cl)cc2cc(C(=O)O)[nH]c12
Temperature: 45 °C
Reaction time: 1 h
Yield: 42 %

Procedure:
To a solution of 90 mg (0.32 mmol) of 5-chloro-7-dimethylaminomethyl-1H-indole-2-carboxylic acid ethyl ester in THF/EtOH/H2O (5 ml) at RT was added 23 mg of LiOH.H2O. The reaction mixture was stirred at 45° C. for one hour and then acidified with aqueous HCl 1M. The product was extracted with EtOAc and concentrated under vacuo to afford 34 mg (42%) of 5-chloro-7-dimethylaminomethyl-1H-indole-2-carboxylic acid as a white solid. ES-MS m/e (%): 251.3 (M−H+).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([O:20][CH2:21][C:22]3[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=3)=[N:18][CH:17]=[CH:16][N:15]=2)[CH:10]([CH3:28])[CH2:9]1)=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O.C(N(CC)CC)C.[N:43]([C:46]1[CH:51]=[C:50]([C:52]([F:55])([F:54])[F:53])[CH:49]=[C:48]([C:56]([F:59])([F:58])[F:57])[CH:47]=1)=C=O>ClCCl>[F:53][C:52]([F:54])([F:55])[C:50]1[CH:51]=[C:46]([NH:43][C:6]([N:8]2[CH2:13][CH2:12][N:11]([C:14]3[C:19]([O:20][CH2:21][C:22]4[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=4)=[N:18][CH:17]=[CH:16][N:15]=3)[CH:10]([CH3:28])[CH2:9]2)=[O:7])[CH:47]=[C:48]([C:56]([F:57])([F:59])[F:58])[CH:49]=1
Reactant: CC1CN(C(=O)OC(C)(C)C)CCN1c1nccnc1OCc1ccncc1
Reactant: O=C=Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1CN(C(=O)Nc2cc(C(F)(F)F)cc(C(F)(F)F)c2)CCN1c1nccnc1OCc1ccncc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.8 %

Procedure:
2-Methyl-3′-(pyridin-4-ylmethoxy)-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-carboxylic acid tert-butyl ester (103 mgs, 0.27 mmol) was dissolved in dichloromethane (1.5 mL) to which was added TFA (2.0 mL) and the mixture stirred at room temperature for 1 hr until Boc removal was complete. The reaction mixture was concentrated in vacuo and redissolved in dichloromethane (1.0 mL) to which was added triethylamine (0.2 mL, 1.43 mmol) and 1-isocyanato-3,5-bis-trifluoromethyl-benzene (0.055 ml, 0.32 mmol). The mixture was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo and the resulting residue purified by column chromatography (1:1 hexanes:EtOAc, followed by 1:3 hexanes:EtOAc) to give 98.9 mgs (69%) of 2-methyl-3′-(pyridin-4-ylmethoxy)-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-carboxylic acid (3,5-bis-trifluoromethyl-phenyl)-amide as a white solid after lyophilization from H2O—AcCN. 1H NMR (CDCl3) 8.77 (d, 2H), 7.94 (s, 2H), 7.82 (d, 1H), 7.71 (d, 2H), 7.52 (d, 1H), 7.49 (s, 1H), 7.23 (s, 1H), 5.62 (s, 2H), 4.60 (m, 1H), 4.01 (m, 1H), 3.97-3.86 (m, 2H), 3.52-3.45 (m, 2H), 3.34 (m, 1H), 1.26 (d, 3H) ppm. LC-MS (MH+)=541.
Reaction SMILES: [Li].C([N:9]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[CH:12]=[CH:11][S:10]1(=[O:20])=[O:19])C1C=CC=CC=1.CCO.N>C1COCC1>[NH:9]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[CH2:12][CH2:11][S:10]1(=[O:19])=[O:20]
Reactant: O=S1(=O)C=Cc2ccccc2N1Cc1ccccc1
Agent: N
Agent: [Li]
Solvent: CCO
Solvent: C1CCOC1
Product: O=S1(=O)CCc2ccccc2N1
Reaction time: 0.5 h
Yield: 34.1 %

Procedure:
Freshly polished lithium flakes (2.0 g, 0.28 mol) were added to a solution of 1-benzyl-1H-benzo[c][1,2]thiazine 2,2-dioxide (6.5 g, 24 mmol) in THF (120 mL)/EtOH (12 mL) and liquid NH3 (150 mL) at −40° C. with stirring over 0.5 h. The reaction was quenched with NH4Cl powder (10 g). Water (200 mL) and EtOAc (200 mL) were added. The two layers were separated and the aqueous phase was extracted with EtOAc (100 mL×3). The combined organic phases were washed with brine (200 mL×3), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by flash column chromatography on silica gel (EtOAc/hexane=1:4) to afford 3,4-dihydro-1H-benzo[c][1,2]thiazine 2,2-dioxide (1.5 g, 34% yield).
Reaction SMILES: CC(C)(C)C[P:4]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.CC(C)(C)CCl>O1CCCC1.CCCCCC>[C:11]1([PH:4][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CC(C)(C)CP(c1ccccc1)c1ccccc1
Agent: CC(C)(C)CCl
Solvent: C1CCOC1
Solvent: CCCCCC
Product: c1ccc(Pc2ccccc2)cc1

Procedure:
The known but unavailable 2,2-dimethylpropyl diphenyl phosphine was derived via reacting 2,2-dimethylpropyl chloride with lithium diphenyl phosphide in a refluxing tetrahydrofuran-hexane solvent mixture. After filtering off the lithium chloride by-product, the 2,2-dimethylpropyl, (i.e., neopentyl) diphenyl phosphine was obtained by the fractional distillation of the filtrate between 109° and 110° C. at 0.1 mm.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@@:8]([NH:25][C:26](=[O:38])[C:27]2[CH:32]=[CH:31][C:30]([F:33])=[C:29]([C:34]([F:37])([F:36])[F:35])[CH:28]=2)([C:16]2[CH:21]=[C:20]([O:22]C)[CH:19]=[C:18]([F:24])[CH:17]=2)[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:6][CH:7]=1.B(Br)(Br)Br>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@@:8]([NH:25][C:26](=[O:38])[C:27]2[CH:32]=[CH:31][C:30]([F:33])=[C:29]([C:34]([F:36])([F:35])[F:37])[CH:28]=2)([C:16]2[CH:21]=[C:20]([OH:22])[CH:19]=[C:18]([F:24])[CH:17]=2)[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:6][CH:7]=1
Reactant: COc1cc(F)cc([C@](Cc2ccccc2)(NC(=O)c2ccc(F)c(C(F)(F)F)c2)c2ccc(Cl)cn2)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=C(N[C@@](Cc1ccccc1)(c1cc(O)cc(F)c1)c1ccc(Cl)cn1)c1ccc(F)c(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a solution of (S)-N-(1-(5-chloropyridin-2-yl)-1-(3-fluoro-5-methoxyphenyl)-2-phenylethyl)-4-fluoro-3-(trifluoromethyl)benzamide (696 mg, 1.27 mmol, prepared according to procedures 5, 6, 7 and 2) in CH2Cl2 at 0° C. was added BBr3 (12.7 mL, 1M, 12.7 mmol). The mixture was stirred at 0° C. for 3 hrs before it was quenched by being carefully poured into cold Na2CO3 solution. The aqueous was extracted with EtOAc. The combined organic layers were washed with brine, dried over MgSO4, concentrated and the crude mixture was purified by ISCO chromatography (40 g column) using hexanes/EtOAc (0-40% over 25 min) to give (S)-N-(1-(5-chloropyridin-2-yl)-1-(3-fluoro-5-hydroxyphenyl)-2-phenylethyl)-4-fluoro-3-(trifluoromethyl)benzamide as an offwhite solid (606 mg, 90% yield). LCMS: 4.07 min [M+1] 533.30 (4 min gradient, MeOH/H2O 0.1% TFA); 1H NMR (400 MHz, CDCl3) δ ppm 3.64 (d, J=13.21 Hz, 1 H), 4.48 (d, J=12.96 Hz, 1 H), 6.21 (dt, J=10.03, 2.20 Hz, 1 H), 6.45-6.55 (m, 3 H), 6.95-7.04 (m, 3 H), 7.11 (t, J=7.46 Hz, 1 H), 7.20-7.30 (m, 3 H), 7.53 (s, 1 H), 7.70 (dd, J=8.68, 2.32 Hz, 1 H), 7.90 (ddd, J=8.50, 4.46, 2.45 Hz, 1 H), 8.03 (dd, J=6.72, 2.08 Hz, 1 H), 8.29-8.32 (m, 1 H), 9.33-9.41 (m, 1 H).
Reaction SMILES: [F:1][C:2]1[CH:31]=[CH:30][C:5]([C:6]([NH:8][CH2:9][C:10]2([C:26]([F:29])([F:28])[F:27])[C:15]3[CH:16]=[C:17]([N:20]4[CH:24]=[CH:23][CH:22]=[N:21]4)[CH:18]=[CH:19][C:14]=3[NH:13][C:12](=[O:25])[O:11]2)=[O:7])=[CH:4][CH:3]=1.CCCCCC>C(O)C>[F:1][C:2]1[CH:31]=[CH:30][C:5]([C:6]([NH:8][CH2:9][C@:10]2([C:26]([F:28])([F:27])[F:29])[C:15]3[CH:16]=[C:17]([N:20]4[CH:24]=[CH:23][CH:22]=[N:21]4)[CH:18]=[CH:19][C:14]=3[NH:13][C:12](=[O:25])[O:11]2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=C1Nc2ccc(-n3cccn3)cc2C(CNC(=O)c2ccc(F)cc2)(C(F)(F)F)O1
Solvent: CCCCCC
Solvent: CCO
Product: O=C1Nc2ccc(-n3cccn3)cc2[C@](CNC(=O)c2ccc(F)cc2)(C(F)(F)F)O1

Procedure:
4-Fluoro-N-{[2-oxo-6-(1H-pyrazol-1-yl)-4-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazin-4-yl]methyl}benzamide was subjected to optical resolution by HPLC (Chiralpack AD-H, n-hexane:ethanol=4:1), and a fraction eluted at a later time was concentrated, whereby the objective compound was obtained.
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[C:11]2[CH:10]=[C:9]([C:12](=[O:14])[CH3:13])[CH:8]=[CH:7][C:6]=2[C:5]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)=[CH:4]C1.BrC1C=C2C(C(C3C=CC(C)=CC=3)=CC2(C)C)=CC=1>>[CH3:1][C:2]1([CH3:22])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12](=[O:14])[CH3:13])[CH:10]=2)[C:5]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)=[CH:4]1
Reactant: CC(=O)c1ccc2c(c1)C(C)(C)CC=C2c1ccc(C)cc1
Agent: Cc1ccc(C2=CC(C)(C)c3cc(Br)ccc32)cc1
Product: CC(=O)c1ccc2c(c1)C(C)(C)C=C2c1ccc(C)cc1
Yield: 78 %

Procedure:
Following a procedure similar to that for the preparation of 1-(8,8-dimethyl-5-p-tolyl-7,8-dihydro-naphthalen-2-yl)-ethanone (Compound 5) while using 6-bromo-1,1-dimethyl-3-p-tolyl-1H-indene (Compound 13, 980 mg, 3.14 mmol) as the starting material afforded the title compound (678 mg, 78% yield) as a yellow solid:
Reaction SMILES: [CH:1]12[CH2:9][CH:5]3[CH2:6][CH:7]([CH2:8]1)[C:3]([NH2:10])([CH2:4]3)[CH2:2]2.C([O-])([O-])=O.[K+].[K+].Cl[CH2:18][C:19]([N:21]1[CH2:25][CH2:24][CH2:23][C@H:22]1[C:26]#[N:27])=[O:20]>CS(C)=O.CCOC(C)=O>[CH:1]12[CH2:9][CH:5]3[CH2:6][CH:7]([CH2:8]1)[C:3]([NH:10][CH2:18][C:19]([N:21]1[CH2:25][CH2:24][CH2:23][C@H:22]1[C:26]#[N:27])=[O:20])([CH2:4]3)[CH2:2]2
Reactant: N#C[C@@H]1CCCN1C(=O)CCl
Reactant: NC12CC3CC(CC1C3)C2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: N#C[C@@H]1CCCN1C(=O)CNC12CC3CC(CC1C3)C2
Temperature: 25 °C
Reaction time: 3 h
Yield: 42.1 %

Procedure:
To a stirred mixture of tricyclo[3.3.1.03,7]nonan-3-amine (0.28 g, 2.0 mmol) and K2CO3 (0.83 g, 6.0 mmol) in DMSO (8 mL) at ice bath temperature under N2 atmosphere was added (S)-1-(2-chloro-acetyl)pyrrolidine-2-carbonitrile (0.34 g, 2.0 mmol). The reaction mixture was gradually warmed to room temperature and stirred for 3 h. Upon completion of the reaction (checked by TLC), the reaction mixture was diluted with EtOAc and washed with water and brine, dried over Na2SO4, and the solvent was removed under reduced pressure. The crude product was purified by column chromatography to obtain (2S)-1-[(tricyclo[3.3.1.03,7]non-3-ylamino)acetyl]pyrrolidine-2-carbonitrile as a viscous liquid (0.23 g) in 42% yield. m/z (M+1) 274; 1H NMR (CDCl3) 300 MHz δ 4.87-4.76 (m, 1H), 3.71-3.40 (m, 2H), 3.41 (s, 2H), 2.35-2.05 (m, 7H), 1.92-1.74 (m, 6H), 1.68-1.48 (m, 4H).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])/[C:3](/[CH3:15])=[CH:4]/[C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11]C)=[O:10])=[CH:7][CH:6]=1.[OH-].[Na+]>C1COCC1.CO>[F:1][C:2]([F:16])([F:17])/[C:3](/[CH3:15])=[CH:4]/[C:5]1[CH:14]=[CH:13][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1
Reactant: COC(=O)c1ccc(/C=C(\C)C(F)(F)F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: C/C(=C\c1ccc(C(=O)O)cc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 10 h

Procedure:
To a stirred mixture of methyl (E)-4-(3,3,3-trifluoro-2-methylprop-1-enyl)benzoate (60 mg, 0.25 mmol) in THF (5 mL) and MeOH (5 mL) was added a 2N NaOH solution (1 mL). The mixture was stirred at room temperature for 10 h. After removal of the organic solvent in vacuo, the mixture was treated with water and acidified with 1N HCl to pH 2-3. The mixture was extracted with EtOAc (20 mL×3). The combined extracts were washed with brine, dried (Na2SO4), and evaporated. The residue was purified with column to give (E)-4-(3,3,3-trifluoro-2-methylprop-1-enyl)benzoic acid as a white solid. LC-MS: tR=3.04 min, m/z=229 (M−1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH3:18])=[CH:12][CH:11]=2)[CH:5]=[C:4]([F:19])[C:3]=1OB(O)O.FC1C=C(C=C(F)C=1)C=O.[I-].C(OC1C=CC(C[P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1)C.C=CC1C=CC=CC=1.Br[C:73]1[CH:78]=[CH:77][C:76]([F:79])=[C:75]([F:80])[CH:74]=1.C([O-])([O-])=O.[Na+].[Na+]>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.C1(C)C=CC=CC=1>[CH2:17]([O:16][C:13]1[CH:14]=[CH:15][C:10]([CH2:9][CH2:8][C:6]2[CH:7]=[C:2]([F:1])[C:3]([C:73]3[CH:78]=[CH:77][C:76]([F:79])=[C:75]([F:80])[CH:74]=3)=[C:4]([F:19])[CH:5]=2)=[CH:11][CH:12]=1)[CH3:18]
Reactant: Fc1ccc(Br)cc1F
Reactant: CCOc1ccc(CCc2cc(F)c(OB(O)O)c(F)c2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CCOc1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Solvent: C=Cc1ccccc1
Solvent: Cc1ccccc1
Product: CCOc1ccc(CCc2cc(F)c(-c3ccc(F)c(F)c3)c(F)c2)cc1

Procedure:
A mixture of 9.2 g of 2,6-difluoro-4-[2-(p-ethoxyphenyl)ethyl]phenylboric acid (prepared by reacting 3,5-difluorobenzaldehyde with p-ethoxybenzyltriphenylphosphonium iodide by the Wittig method and subsequently hydrogenating the resultant styrene derivative on Pd/C), 5.9 g of 1-bromo-3,4-difluorobenzene, 38 ml of 2 molar aqueous Na2CO3 solution, 0.6 g of tetrakis(triphenylphosphine)palladium(0) and 75 ml of toluene is refluxed for two hours. The aqueous phase is extracted twice with toluene and combined with the organic phase. Customary aqueous work-up and chromatographic purification of the residue give 4-[2-(p-ethoxyphenyl)ethyl]-2,6,3′, 4′-tetrafluorobiphenyl, C 92 I, Δε+24.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:13]/[OH:14])/[C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH:22]1[CH2:26][CH2:25][NH:24][C:23]1=[O:27]>CS(C)=O.O>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:13]/[O:14][CH:22]2[CH2:26][CH2:25][NH:24][C:23]2=[O:27])/[C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1
Reactant: O=C1NCCC1Br
Reactant: CCOC(=O)/C(=N\O)c1csc(N)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)/C(=N\OC1CCNC1=O)c1csc(N)n1
Reaction time: 0.33 h
Yield: 86 %

Procedure:
10.9 g of ethyl (Z)-2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetate are dissolved in 25 ml of dimethylsulfoxide, and a solution of 14 g of anhydrous potassium carbonate in 13 ml of water is added thereto at a temperature of 15° to 20° C. The mixture is stirred at the same temperature for 20 minutes. 10 g of 3-bromo-2-pyrrolidone are added to said mixture at room temperature, and the mixture is stirred at the same temperature for 1.5 hours. 120 ml of water are added to the reaction mixture, and the aqueous mixture is stirred with ice-cooling. Crystalline precipitates are collected by filtration, and the crystals are washed with water and then dried at 40° C. 13 g of ethyl (Z)-2-(2-aminothiazol-4-yl)-2-[(2-pyrrolidon-3yl)oxyimino]acetate are obtained. The physico-chemical properties of this product are identical sith those of the product obtained in Example 2-(3).