Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]2[S:12][CH2:11][C:10](=[O:13])[NH:9][C:8]=2[CH:14]=1.C(N(CC)CC)C.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>ClCCl>[O:13]=[C:10]1[NH:9][C:8]2[CH:14]=[C:4]([CH2:3][CH2:2][O:1][S:23]([CH3:22])(=[O:25])=[O:24])[CH:5]=[CH:6][C:7]=2[S:12][CH2:11]1
Reactant: CS(=O)(=O)Cl
Reactant: O=C1CSc2ccc(CCO)cc2N1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCc1ccc2c(c1)NC(=O)CS2
Temperature: 25 °C
Reaction time: 15 h
Yield: 73.7 %

Procedure:
A solution of (h) (0.34 g, 1.7 mmol) and triethylamine (0.25 ml, 0.19 g, 1.8 mmol) in dichloromethane (5 ml) was cooled to −15° C. and treated dropwise with methanesulfonyl chloride (0.14 ml, 1.75 mmol). The ice bath was removed and the mixture stirred 15 hours at room temperature. The organic phase was separated, washed with water, dried over magnesium sulfate and evaporated. The crude product was chromatographed on silica gel eluting with ethyl acetate/heptane (2/1) to give a white solid (0.36 g, 75%).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:10](Br)=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[Li]CCCC.[B-](F)(F)(F)[F:18].[B-](F)(F)(F)F.C1[N+]2(O)CC[N+](F)(CC2)C1.C1C=CC(S(N(S(C2C=CC=CC=2)(=O)=O)F)(=O)=O)=CC=1>C1COCC1>[Cl:1][C:2]1[C:3]2[C:10]([F:18])=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Clc1ncnc2[nH]cc(Br)c12
Reactant: F[B-](F)(F)F
Agent: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Agent: O[N+]12CC[N+](F)(CC1)CC2
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Fc1c[nH]c2ncnc(Cl)c12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 4-chloro-5-bromo-7H-pyrrolo[2,3-d]pyrimidine (800 mg, 3.45 mmol) in THF (50 mL) at −78° C. was treated with n-BuLi (1.6 M in hexane, 2.2 eq, 7.6 mmol, 4.7 mL) dropwise, and stirred for 30 minutes at the same temperature. The mixture was treated with a solution of ACCUFLUOR® NFSi (2.0 eq, 7 mmol, 2.2 g) in THF (10 mL). The reaction mixture was allowed to warm to room temperature, was stirred for 10 h, and then concentrated to dryness. The residue was dissolved in EtOAc (100 mL), washed with water (3×15 mL) and brine (15 mL), dried with Na2SO4, and purified by reverse phase HPLC (10×250 mm C18 Luna column, 4.7 mL/min, 10-90% acetonitrile in water over 20 min) to provide intermediate compound 1. ESI-MS m/z=172.1 (MH+).
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[C:5]([N:13]2[CH2:17][CH2:16][CH:15]([S:18][CH2:19][C:20]([OH:22])=[O:21])[CH2:14]2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[OH:25]OS([O-])=O.[K+].S(OOS([O-])(=O)=O)([O-])(=O)=O>CC(C)=O>[F:24][C:2]([F:1])([F:23])[C:3]1[CH:4]=[C:5]([N:13]2[CH2:17][CH2:16][CH:15]([S:18]([CH2:19][C:20]([OH:22])=[O:21])=[O:25])[CH2:14]2)[CH:6]=[C:7]([C:9]([F:11])([F:10])[F:12])[CH:8]=1
Reactant: O=C(O)CSC1CCN(c2cc(C(F)(F)F)cc(C(F)(F)F)c2)C1
Reactant: O=S([O-])OO
Agent: O=S(=O)([O-])OOS(=O)(=O)[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C(O)CS(=O)C1CCN(c2cc(C(F)(F)F)cc(C(F)(F)F)c2)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 93 %

Procedure:
To a solution of optically resolved tR1 (AS, 300 mg) of ({1-[3,5-bis(trifluoromethyl)phenyl]pyrrolidin-3-yl}sulfanyl)acetic acid obtained in Example 10 in acetone (10 mL) was added aqueous solution (5 ml) of Oxone-persulfate compound (500 mg) at 0° C., and the mixture was stirred at 0° C. for 1 hr. The reaction mixture was extracted with ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated to give the title compound (291 mg, yield 93%) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([F:11])[CH:10]=1)[NH:7][C:6]([CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[CH:5]2.S(Cl)(Cl)=O.[CH2:21](O)[CH3:22]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([F:11])[CH:10]=1)[NH:7][C:6]([CH2:12][CH2:13][C:14]([O:16][CH2:21][CH3:22])=[O:15])=[CH:5]2
Reactant: O=C(O)CCc1cc2cc(Br)cc(F)c2[nH]1
Reactant: CCO
Solvent: O=S(Cl)Cl
Product: CCOC(=O)CCc1cc2cc(Br)cc(F)c2[nH]1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of 3-(5-bromo-7-fluoro-1H-indol-2-yl)propanoic acid (D160) (1 g) in ethanol (15 mL) was added thionyl dichloride (0.083 g). The reaction mixture was stirred at room temperature overnight. The solvent was removed in vacuo. The residue was diluted with EtOAc (30 mL). The organic phase was washed with 2 M sodium carbonate solution (25 mL) and water (50 mL), dried over sodium sulphate and evaporated in vacuo to give the crude product ethyl 3-(5-bromo-7-fluoro-1H-indol-2-yl)propanoate (D161) (1.1 g) as a yellow solid. δH (CDCl3, 400 MHz): 1.23 (3H, t), 2.73 (2H, t), 3.06 (2H, t), 4.16 (2H, m), 6.20 (1H, s), 7.05 (1H, d), 7.41 (1H, s), 8.85 (1H, s).
Reaction SMILES: Cl[CH2:2][N:3]1[C:7](=[O:8])[CH:6]([CH2:9][CH2:10][C:11]([CH3:14])([Cl:13])[CH3:12])[N:5]([CH3:15])[S:4]1(=[O:17])=[O:16].[Cl:18][C:19]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:20]=1[C:21]([OH:23])=[O:22].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:18][C:19]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:20]=1[C:21]([O:23][CH2:2][N:3]1[C:7](=[O:8])[CH:6]([CH2:9][CH2:10][C:11]([CH3:14])([Cl:13])[CH3:12])[N:5]([CH3:15])[S:4]1(=[O:17])=[O:16])=[O:22]
Reactant: O=C(O)c1c(Cl)cccc1Cl
Reactant: CN1C(CCC(C)(C)Cl)C(=O)N(CCl)S1(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN1C(CCC(C)(C)Cl)C(=O)N(COC(=O)c2c(Cl)cccc2Cl)S1(=O)=O
Temperature: 0 °C
Yield: 10 %

Procedure:
To a solution of 2-chloromethyl-4-(3-methyl-3-chlorobutyl)-5-methyl-1,2,5-thiadiazolidin-3-one 1,1-dioxide (0.41 g; 1.35 mmol) in DMF was added at room temperature 2,6-dichlorobenzoic acid (0.283 g; 1.48 mmol) and potassium carbonate (0.246 g, 1.78 mmol), and the resulting solution was allowed to react at room temperature for 40 hours. The mixture was poured into ice/water, extracted with ethyl acetate, and the organic layer was washed with water, brine, and dried. The organic solution was concentrated in vacuo and the residue was purified by silica column chromatography to afford 62 mg (10%) of 2-(2,6-dichlorophenylcarbonyloxymethyl) -4- (3-methyl-3-chlorobutyl)-5-methyl-1,2,5-thiadiazolidin-3-one 1,1-dioxide (Formula I: Ar=2, 6-Cl2 -phenyl; R1 =H; R2 =(CH2)2C (Cl) (CH3)2 ; R3 =CH3) as a gum.
Reaction SMILES: C[O:2][C:3](=[O:25])[C:4]1[CH:9]=[CH:8][C:7](=[CH:10][O:11][C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[CH2:6][C:5]=1[O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[OH-].[K+]>CO.O>[N:14]1[CH:15]=[CH:16][CH:17]=[C:12]([O:11][CH2:10][C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:25])=[O:2])=[C:5]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:6]=2)[CH:13]=1
Reactant: COC(=O)C1=C(Oc2ccccc2)CC(=COc2cccnc2)C=C1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1ccc(COc2cccnc2)cc1Oc1ccccc1
Yield: 92.1 %

Procedure:
To a solution in methanol (15 mL) of 4-(3-pyridyloxymethylene)-2-phenoxybenzoic acid methyl ester (2.46 g), prepared as in Example 157E, was added a solution of 5% aqeuous KOH (2.00 g) in water (3 mL). The reaction mixture was heated at reflux for 1.5 hours. The reaction mixture was concentrated in vacuo and the residue was dissolved in water. The aqueous phase was acidified with acetic acid with cooling and stirring. The resulting solid was filtered, washed with water, and dissolved in THF. The THF solution was dried over Na2SO4, filtered, and concentrated in vacuo to give 4-(3-pyridyloxymethyl)-2-phenoxybenzoic acid (2.17 g).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH:19][C:20](=[O:38])[CH2:21][C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]2[CH:31]=[N:32][C:33]([O:36][CH3:37])=[CH:34][CH:35]=2)[CH:25]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:37][O:36][C:33]1[N:32]=[CH:31][C:30]([C:26]2[CH:25]=[C:24]([C:22]3[CH2:21][C:20](=[O:38])[NH:19][C:9]4[CH:10]=[C:11]([C:15]([F:18])([F:17])[F:16])[C:12]([CH3:14])=[CH:13][C:8]=4[N:7]=3)[CH:29]=[CH:28][CH:27]=2)=[CH:35][CH:34]=1
Reactant: COc1ccc(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)c(C)cc3NC(=O)OC(C)(C)C)c2)cn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(-c2cccc(C3=Nc4cc(C)c(C(F)(F)F)cc4NC(=O)C3)c2)cn1

Procedure:
The title compound was prepared from (2-{3-[3-(6-methoxy-pyridin-3-yl)-phenyl]-3-oxo-propionylamino}-5-methyl-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example M150) (232 mg, 0.43 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a white solid (113 mg, 62%).
Reaction SMILES: [Mg].[CH3:2][CH2:3][CH2:4][CH2:5][CH2:6]Br.[CH3:8][C:9](=[CH:12][CH2:13][CH3:14])[CH:10]=[O:11].[Cl-].[NH4+]>CCOCC>[CH3:8][C:9]([CH:10]([OH:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])=[CH:12][CH2:13][CH3:14]
Reactant: CCCCCBr
Reactant: CCC=C(C)C=O
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOCC
Product: CCC=C(C)C(O)CCCCC
Temperature: 10 °C

Procedure:
2.4 g (0.1 g atom) of magnesium in 50 ml of absolute ether are placed in an apparatus which is customary for Grignard reactions. While stirring and under a protective gas atmosphere (nitrogen) there are subsequently added dropwise 15.0 g (0.1 mol) of n-amyl bromide in 50 ml of absolute ether so that, after initiation of the reaction, the ether constantly boils slightly. After completing the addition, the mixture is held at reflux temperature for a further 30 minutes, then cooled to 10° C. and a solution of 7.85 g (0.08 mol) of 2-methyl-2-pentenal in 20 ml of absolute ether is added dropwise. In order to complete the reaction, the mixture is stirred at room temperature for a further 12 hours. After decomposing the Grignard complex with saturated ammonium chloride solution and ice, the supernatant ethereal solution is washed with saturated sodium chloride solution and subsequently dried. After evaporating the solvent, there remain 13.6 g of crude product which are fractionally distilled. There are thus obtained 8.9 g of pure 4-methyl-3-decen-5-ol of boiling point 103° C./12 mm Hg, nD20 =1.4499.
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][C@H:24]([CH2:27][OH:28])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[C:29]([C:31]1[N:36]=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1)#[N:30]>>[C:29]([C:31]1[N:36]=[CH:35][C:34]([C:2]2[C:3]([N:22]3[CH2:26][CH2:25][C@H:24]([CH2:27][OH:28])[CH2:23]3)=[N:4][CH:5]=[C:6]([C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=3)=[O:8])[CH:21]=2)=[CH:33][CH:32]=1)#[N:30]
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC[C@H](CO)C2)c(Br)c1
Reactant: N#Cc1ccc(B(O)O)cn1
Product: N#Cc1ccc(-c2cc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cnc2N2CC[C@H](CO)C2)cn1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 86 using (S)-5-bromo-6-(3-(hydroxymethyl)pyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 78.1) and (6-cyanopyridin-3-yl)boronic acid to afford a light green solid. UPLC-MS (condition 1) tR=2.46 min, m/z=484.1 [M+H]+, m/z=482.1 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.47-1.65 (m, 1H) 1.78-1.93 (m, 1H) 2.17-2.29 (m, 1H) 2.96 (dd, J=10.64, 6.97 Hz, 1H) 3.11-3.23 (m, 2H) 3.24-3.40 (m, 3H in HDO) 4.62 (br. s, 1H) 7.35 (d, J=8.31 Hz, 2H) 7.85 (d, J=8.56 Hz, 2H) 8.02-8.17 (m, 3H) 8.79 (d, J=1.22 Hz, 1H) 8.84 (s, 1H) 10.19 (s, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10](=[O:20])[CH:11]=[CH:12][C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.[CH3:21][NH2:22].O>CN(C)C=O>[CH3:19][C:16]1[CH:15]=[CH:14][C:13]([CH:12]2[CH2:11][C:10](=[O:20])[CH2:9][CH:8]([C:5]3[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=3)[N:22]2[CH3:21])=[CH:18][CH:17]=1
Reactant: CN
Reactant: Cc1ccc(C=CC(=O)C=Cc2ccc(C)cc2)cc1
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(C2CC(=O)CC(c3ccc(C)cc3)N2C)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 73.8 %

Procedure:
1,5-Bis(4-methylphenyl)-1,4-pentadien-3-one (20aa, 0.32 g, 1.2 mmol) was dissolved in dimethyl formamide (9 ml). Methylamine (51, 0.5 ml, 5.8 mmol, 40% in water) was added and the mixture stirred for 72 hr at room temperature. The mixture was poured into water (50 ml) and stirred for 2 hr at room temperature. The resulting mixture was extracted into ethyl acetate, washed with saturated sodium chloride, dried over magnesium sulfate, filtered and evaporated to afford a solid. The crude solid was chromatographed on silica gel with ethyl acetate/hexane to afford a solid that was recrystallized from ethanol to give 0.26 g (75%) of a white solid: mp 120-121° C. [expected mp 105-107° C.]; 1H NMR δ 1.79 (s, 3H), 2.36 (s, 6H), 3.10 (d, 2H, J=14.9 Hz), 2.79 (t, 2H, J=13.1 Hz), 3.35 (dd, 2H, J=11.9, 2.4 Hz), 7.15 (d, 4H, J=8.0 Hz), 7.21 (d, 4H, J=7.9 Hz); 13C NMR: δ 21.2, 40.7, 50.9, 70.0, 126.9, 129.4 137.2, 140.2, 207.1.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][OH:15])[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[H-].[Na+].[Cl:18][C:19]1[N:20]=[N:21][C:22](Cl)=[CH:23][CH:24]=1>CS(C)=O>[Cl:18][C:19]1[N:20]=[N:21][C:22]([O:15][CH2:14][CH:11]2[CH2:12][CH2:13][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:9][CH2:10]2)=[CH:23][CH:24]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Reactant: Clc1ccc(Cl)nn1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCC(COc2ccc(Cl)nn2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 57.6 %

Procedure:
A solution of N-Boc-4-piperidinemethanol (1.0 g, 4.50 mmol) was added dropwise to a suspension of NaH (60% in mineral oil, 0.27 g, 6.76 mmol) in DMSO (2 mL). The mixture was stirred at ambient temperature for 1 h, then 30 minutes at 50° C. The mixture was cooled to ambient temperature and a solution of 3,6-dichloropyridazine (0.73 g, 4.73 mmol) in DMSO (4 mL) was added dropwise, and the reaction mixture was stirred at ambient temperature overnight, poured onto water, then extracted with EtOAc, washed with water and brine, dried over Na2SO4, filtered, and the filtrate was concentrated to give the crude product as a dark reddish brown oil. The crude product was purified by chromatography on ISCO silica gel column eluted with a EtOAc:hexane gradient (0 to 30%) to give 0.85 g (56%) of 1,1-dimethylethyl 4-{[(6-chloro-3-pyridazinyl)oxy]methyl}-1-piperidinecarboxylate as a white solid. 1H NMR (400 MHz, CDCl3): δ 7.36 (d, 1H, J=9.0 Hz), 6.94 (d, 1H, J=9.1 Hz), 4.34 (d, 2H, J=6.6 Hz), 4.20-4.10 (m, 2H), 2.80-2.65 (m, 2H), 2.10-1.95 (m, 1H), 1.85-1.70 (m, 2H), 1.45 (s, 9H), 1.35-1.20 (m, 2H); LRMS (ESI), m/z 328 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1[S:10]([N:13]=[C:14]=[O:15])(=[O:12])=[O:11])=[O:4].[NH2:16][C:17]1[N:22]=[C:21]([O:23][CH:24]([F:26])[F:25])[CH:20]=[C:19]([CH3:27])[N:18]=1>O1CCCC1>[CH3:1][O:2][C:3]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1[S:10]([NH:13][C:14]([NH:16][C:17]1[N:22]=[C:21]([O:23][CH:24]([F:26])[F:25])[CH:20]=[C:19]([CH3:27])[N:18]=1)=[O:15])(=[O:12])=[O:11])=[O:4]
Reactant: Cc1cc(OC(F)F)nc(N)n1
Reactant: COC(=O)c1sccc1S(=O)(=O)N=C=O
Solvent: C1CCOC1
Product: COC(=O)c1sccc1S(=O)(=O)NC(=O)Nc1nc(C)cc(OC(F)F)n1
Yield: 50 %

Procedure:
A solution of 6.2 g of 2-methoxycarbonyl-3-thienylsulfonylisocyanate in 50 ml of absolute tetrahydrofuran is stirred dropwise into a solution of 4.4 g of 2-amino-4-difluoromethoxy-6-methylpyrimidine in 80 ml of absolute tetrahydrofuran. During the course of this addition, the temperature of the reaction mixture rises from 20° to 26° C. After it has been stirred for another hour, the raction mixture is filtered and the filtrate is concentrated. The residue is crystallised from ethyl acetate, affording 5.3 g (50%) of N-(2-methoxycarbonyl-3-thienylsulfonyl)-N'-(4-difluoromethoxy-6-methylpyrimidin-2-yl)urea (compound 2.1) with a melting point of 178°-179° C.
Reaction SMILES: Cl[C:2](=[O:9])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[NH2:10][C:11]1[C:12]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[N:13][CH:14]=[C:15]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[CH:16]=1>ClCCCl>[CH2:7]([O:6][C:4](=[O:5])[CH2:3][C:2]([NH:10][C:11]1[C:12]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[N:13][CH:14]=[C:15]([CH2:17][C:18]2[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=2)[CH:16]=1)=[O:9])[CH3:8]
Reactant: CCOC(=O)c1ncc(Cc2ccc(F)cc2)cc1N
Reactant: CCOC(=O)CC(=O)Cl
Solvent: ClCCCl
Product: CCOC(=O)CC(=O)Nc1cc(Cc2ccc(F)cc2)cnc1C(=O)OCC

Procedure:
Ethyl 3-chloro-3-oxopropionate (1.32 g, 8.75 mmol) was added to a solution of ethyl 3-amino-5-(4-fluorobenzyl)-2-pyridinecarboxylate (2 g, 7.29 mmol) in DCE (20 mL) and the solution was heated at reflux for 1 h. The solvent was removed in vacuo and silica gel chromatography eluting with 0-5% MeOH/CH2Cl2 provide the product as an amber oil: 1H NMR (CDCl3) δ 8.96 (1H, br s), 8.32 (1H, d, J=1.8 Hz), 7.17 (2H, dd, J˜9, 6 Hz), 7.00 (2H, t, J˜9 Hz), 4.53 (2H, t, J=7 Hz), 4.29 (2H, t, J=7 Hz), 4.02 (2H, s), 3.54 (2H, s), 1.48 (3H, t, J=7 Hz), 1.33 (3H, t, J=7 Hz).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:6]=1[OH:15])([CH3:4])([CH3:3])[CH3:2].[CH3:16][S:17][CH2:18][C:19](O)=[O:20].C(OC(C(F)(F)F)=O)(C(F)(F)F)=O.C(=O)(O)[O-]>CCOC(C)=O>[C:11]([C:7]1[CH:8]=[C:9]([C:19](=[O:20])[CH2:18][S:17][CH3:16])[CH:10]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:6]=1[OH:15])([CH3:14])([CH3:13])[CH3:12]
Reactant: CSCC(=O)O
Reactant: CC(C)(C)c1cccc(C(C)(C)C)c1O
Agent: O=C([O-])O
Solvent: CCOC(C)=O
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: CSCC(=O)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reaction time: 5 h

Procedure:
2,6-di-t-butylphenol (1.7680 g, 8.66mmol) is placed in a flame dried RBF, and 2-(methylthio)acetic acid (0.80 mL, 9.19 mmol) is then added. This is then blanketed with argon and TFAA (1.30 mL, 9.20 mmol) is added via syringe at a fast rate. A small amount of CH2C12 is added to aid in mixing. The reaction quickly turns violet and darkens. It is followed by TLC using 10% EtOAc in hexanes. After 5 h, the reaction is carefully poured into 70 mL saturated bicarbonate and extracted with 2 portions of Et2O. The combined organics are washed with brine, filtered through cotton, dried over molecular sieves, then concentrated on a rotavap and dried under vacuum. This gives a white solid which can be crystallized from EtOAc/hexanes to give orange crystals, mp=108.5°-109.5° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1.Cl[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=1>>[F:17][C:16]([F:18])([F:19])[C:13]1[CH:14]=[CH:15][C:10]([CH2:9][N:1]2[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]2)=[CH:11][CH:12]=1
Reactant: FC(F)(F)c1ccc(CCl)cc1
Reactant: O=C1CCNCC1
Product: O=C1CCN(Cc2ccc(C(F)(F)F)cc2)CC1

Procedure:
1-(4-Trifluoromethylbenzyl)-4-piperidone is prepared from 4-piperidone and α′-chloro-α,α,α-trifluoro-p-xylene essentially as described above in Example 38, Scheme C, step a.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][O:12][CH3:13])(=[O:10])=[O:9])=[CH:4][C:3]=1[C:14]([F:17])([F:16])[F:15].[F:18][C:19]1[CH:20]=[C:21]([N+:26]([O-:28])=[O:27])[CH:22]=[CH:23][C:24]=1F.[H-].[Na+].O>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([O:12][CH3:13])[C:24]2[CH:23]=[CH:22][C:21]([N+:26]([O-:28])=[O:27])=[CH:20][C:19]=2[F:18])(=[O:10])=[O:9])=[CH:4][C:3]=1[C:14]([F:17])([F:15])[F:16]
Reactant: CONS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CON(c1ccc([N+](=O)[O-])cc1F)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Temperature: 25 °C
Yield: 37.3 %

Procedure:
To a solution of 4-chloro-N-methoxy-3-(trifluoromethyl)benzenesulfonamide(0.58 g (2.00 mmol)) and 3,4-difluoronitrobenzene (0.66 ml (5.96 mmol)) in 5.0 ml of DMF, sodium hydride (60%, 0.09 g (2.25 mmol)) was added bit by bit with stirring under cooling with ice. The resulting mixture was stirred under cooling with ice for one hour and allowed to warm-up to room temperature. Water was added to the reaction mixture and the resulting mixture was extracted with diethyl ether. The extract was washed with water, and dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 0.32 g (37%) of the title compound as pale yellow crystals.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:10](=O)[CH3:11])=[CH:4][CH:3]=1.C(O)(=O)C.C([BH3-])#[N:24].[Na+]>N.CO>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:10]([NH2:24])[CH3:11])=[CH:4][CH:3]=1
Reactant: [BH3-]C#N
Reactant: CC(=O)C(Cc1ccc(C)cc1)c1ccccc1
Agent: N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: Cc1ccc(CC(c2ccccc2)C(C)N)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of the 4-(4-methylphenyl)-3-phenylbutan-2-one (308 mg, 1.29 mmol) in 7M ammonia in MeOH (5 mL) and acetic acid (3 mL) was added sodium cyanoborohydride (130 mg, 2.06 mmol) and the reaction stirred at room temperature overnight. The reaction was quenched by pouring into 2M sodium carbonate solution and extracted into EtOAc. The aqueous layer was salted and re-extracted. The combined organic extracts were dried over MgSO4 and concentrated to give the title compound as a mixture of 4 isomers which was used without further purification. LC-MS: m/e 240 (M+H)+ (2.22 min).
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Br:11][C:12]1[CH:17]=[C:16](F)[CH:15]=[C:14]([F:19])[CH:13]=1.O>C1COCC1>[Br:11][C:12]1[CH:17]=[C:16]([O:10][CH2:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:15]=[C:14]([F:19])[CH:13]=1
Reactant: Fc1cc(F)cc(Br)c1
Reactant: OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Fc1cc(Br)cc(OCc2ccccc2)c1
Reaction time: 1 h
Yield: 98445.4 %

Procedure:
Sodium hydride (60% dispersion in oil, 24.0 g, 0.48 mol) was added portionwise to a stirred solution of anhydrous benzyl alcohol (64.5 g, 0.60 mol) in THF (1.0 L). After the mixture was stirred for 1 h, a solution of 1-bromo-3,5-difluorobenzene (76.8 g, 0.40 mmol) in THF (100 mL) was added dropwise over a period of 1 h. The reaction was stirred at room temperature for 2 d. Water (400 mL) was added and the THF was removed in vacuo. The aqueous layer was extracted with hexane (3×150 mL). The combined organic extracts were washed with 2N NaOH (2×100 mL) then, dried (Na2SO4), filtered and concentrated in vacuo to afford the sub-title compound (110.7 g, 98%) as a light yellow oil that was used without further purification.
Reaction SMILES: [CH3:1][C:2]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[NH:6][C:5](=[O:7])[N:4]([C:8]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12][CH:11]=2)=[O:9])[C:3]1=[O:20].[H-].[Na+].Br[CH2:30][C:31]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:32].C(OCC)(=O)C>CN(C=O)C>[CH3:1][C:2]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:6]([CH2:30][C:31](=[O:32])[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:5](=[O:7])[N:4]([C:8]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12][CH:11]=2)=[O:9])[C:3]1=[O:20]
Reactant: CC1(c2ccccc2)NC(=O)N(C(=O)c2cccc3ccccc23)C1=O
Reactant: O=C(CBr)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC1(c2ccccc2)C(=O)N(C(=O)c2cccc3ccccc23)C(=O)N1CC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.1 %

Procedure:
5-Methyl-3-naphthylcarbonyl-5-phenylimidazolidine-2,4-dione (43 mg) was dissolved in DMF (0.4 mL), and sodium hydride (60%, in oil) (5 mg) was added. Then, 25 mg of 2-bromoacetophenone was added, and the mixture was stirred at room temperature overnight. Ethyl acetate (9.5 mL) was added to the reaction solution, separated out white precipitates were filtered, and the filtrate was concentrated and purified by silica gel chromatography (hexane:ethyl acetate=2:1) to obtain 33 mg of white crystals.