Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)CCl.C1C=NC2N(O)N=NC=2C=1.[C:15]([O:19][C:20]([NH:22][C@H:23]([CH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1)[C:24]([N:26]1[CH2:33][CH2:32][CH2:31][C@H:27]1[C:28](O)=[O:29])=[O:25])=[O:21])([CH3:18])([CH3:17])[CH3:16].[Cl:40][C:41]1[CH:42]=[CH:43][C:44]([C:49]2[N:50]=[N:51][S:52][CH:53]=2)=[C:45]([CH2:47][NH2:48])[CH:46]=1>CN(C=O)C>[C:15]([O:19][C:20]([NH:22][C@H:23]([CH:34]1[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39]1)[C:24]([N:26]1[CH2:33][CH2:32][CH2:31][C@H:27]1[C:28]([NH:48][CH2:47][C:45]1[CH:46]=[C:41]([Cl:40])[CH:42]=[CH:43][C:44]=1[C:49]1[N:50]=[N:51][S:52][CH:53]=1)=[O:29])=[O:25])=[O:21])([CH3:18])([CH3:16])[CH3:17]
Reactant: NCc1cc(Cl)ccc1-c1csnn1
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)N1CCC[C@H]1C(=O)O)C1CCCCC1
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](C(=O)N1CCC[C@H]1C(=O)NCc1cc(Cl)ccc1-c1csnn1)C1CCCCC1

Procedure:
EDC (0.388 g, 2.02 mmol), HOAt (0.275 g, 2.02 mmol), and 1-{(2R)-2-[(tert-butoxycarbonyl)amino]-2-cyclohexylethanoyl}-L-proline (prepared by standard peptide coupling protocols, 0.551 g, 1.55 mol) were added to a stirred solution of 1-[5-Chloro-2-(1,2,3-thiadiazol-4-yl)phenyl]methanamine (0.351 g, 1.555 mmol) in DMF (7.8 mL). After 16 h the mixture was partitioned between EtOAc and water. The organic layer was washed with brine, dried (Na2SO4) and concentrated in vacuo. The product was purified by flash chromatography on silica (eluting with an EtOAc/hexanes gradient, 1–100% EtOAc). 1-{(2R)-2-[(tert-Butoxycarbonyl)amino]-2-cyclohexylethanoyl}-N-[5-chloro-2-(1,2,3-thiadiazol-4-yl)benzyl]-L-prolinamide was obtained as a solid. MS m/z=562.6.
Reaction SMILES: Br[CH:2]=[C:3]1[C:9]2[CH:10]=[C:11]([F:14])[CH:12]=[CH:13][C:8]=2[CH2:7][CH2:6][C:5]2[CH:15]=[CH:16][CH:17]=[CH:18][C:4]1=2.[OH:19][C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][CH:25]=1>>[F:14][C:11]1[CH:12]=[CH:13][C:8]2[CH2:7][CH2:6][C:5]3[CH:15]=[CH:16][CH:17]=[CH:18][C:4]=3[C:3](=[CH:2][C:22]3[CH:21]=[C:20]([OH:19])[CH:25]=[CH:24][CH:23]=3)[C:9]=2[CH:10]=1
Reactant: OB(O)c1cccc(O)c1
Reactant: Fc1ccc2c(c1)C(=CBr)c1ccccc1CC2
Product: Oc1cccc(C=C2c3ccccc3CCc3ccc(F)cc32)c1

Procedure:
Following the procedures essentially as described in Example 219, below, and using 5-bromomethylene-3-fluoro-10,11-dihydro-5H-dibenzo[a,d]cycloheptene (200 mg, 0.660 mmol) and 3-hydroxyphenylboronic acid (100 mg, 0.726 mmol), affords 192 mg (92%) of a mixture of geometric isomers of the title compound as a yellow oil. MS (ES) 339 (M+Na), 315 (M−H); HPLC shows 95% purity.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH:8]([NH2:10])[CH3:9])=[N:4][CH:5]=[CH:6][CH:7]=1.[O:11]=[C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14](=[O:21])[N:13]1[CH2:22][CH2:23][CH2:24][CH:25]=O.[BH-](O[C:37]([CH3:39])=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl.C([O-])(O)=O.[Na+]>[CH3:1][C:2]1[C:3]([CH:8]([N:10]([CH:39]2[C:37]3[N:4]=[CH:5][CH:6]=[CH:7][C:2]=3[CH2:3][CH2:8][CH2:9]2)[CH2:25][CH2:24][CH2:23][CH2:22][N:13]2[C:14](=[O:21])[C:15]3[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:12]2=[O:11])[CH3:9])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccnc1C(C)N
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: O=CCCCN1C(=O)c2ccccc2C1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cccnc1C(C)N(CCCCN1C(=O)c2ccccc2C1=O)C1CCCc2cccnc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of the above amine and 4-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-butyraldehyde (127 mg, 0.58 mmol) in CH2Cl2 (2.5 mL) was added NaBH(OAc)3 (117 mg, 0.55 mmol) and the reaction was stirred at room temperature under N2 for 16 hours. The mixture was diluted with saturated aqueous NaHCO3 (10 mL) and was extracted with CH2Cl2 (10 mL×3). The combined organic solution was dried (MgSO4), filtered and concentrated under reduced pressure. Purification by flash column chromatography on silica (CH2Cl2/MeOH, 9:1) gave 2-{4-[[1-(3-methyl-pyridin-2-yl)-ethyl]-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-butyl}-isoindole-1,3-dione as a 1:1 mixture of two diastereomers (72 mg, 0.15 mmol, 43%) along with some single diastereomer (33 mg, 0.07 mmol, 20%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[CH:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH:19]([F:21])[F:20])=[CH:14][CH:13]=2)=[CH:6][CH:5]=1)[CH3:2]>C1COCC1.[Pd]>[CH2:1]([O:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH:19]([F:20])[F:21])=[CH:14][CH:13]=2)=[CH:8][CH:9]=1)[CH3:2]
Reactant: CCOc1ccc(C=Cc2ccc(OC(F)F)cc2)cc1
Agent: [Pd]
Solvent: C1CCOC1
Product: CCOc1ccc(CCc2ccc(OC(F)F)cc2)cc1

Procedure:
19.7 g of 1-(4-ethoxyphenyl)-2-(4'-difluoromethoxyphenyl)-ethene are hydrogenated in 150 ml of THF analogously to Example 6b, using 6 g of Pd/C (5% Pd) as catalyst. m.p.: 37° C., Δn=0.103, viscosity: 8
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([O:19][CH3:20])[CH:17]=3)[CH:12]=[C:11]2[Sn](CCCC)(CCCC)CCCC)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:35]1[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][C:36]=1[N+:43]([O-:45])=[O:44]>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.[Cu]I.C1(C)C=CC=CC=1>[C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([O:19][CH3:20])[CH:17]=3)[CH:12]=[C:11]2[C:35]2[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][C:36]=2[N+:43]([O-:45])=[O:44])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COc1ccc(Br)c([N+](=O)[O-])c1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cc2ccc(OC)cc2n1S(=O)(=O)c1ccccc1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: COc1ccc(-c2cc3ccc(OC)cc3n2S(=O)(=O)c2ccccc2)c([N+](=O)[O-])c1
Temperature: 100 °C
Reaction time: 1 h
Yield: 56.4 %

Procedure:
The title compound was synthesized by referring to Tetrahedron, 1994, 50 (6), 1899. A mixture of 1-benzenesulfonyl-6-methoxy-2-tributylstannyl-1H-indole (12.1 g), 4-bromo-3-nitroanisole (4.6 g), tetrakis(triphenylphosphine)palladium(0) (1.1 g), copper(I) iodide (760 mg) and toluene (90 ml) was stirred for 1 hour at 100° C. The reaction mixture was cooled to room temperature, NH silica gel (20 g) was added thereto, the solution was concentrated in vacuo, and the resulting residue was purified by NH silica gel column chromatography (hexane-ethyl acetate system) to provide the title compound (4.9 g).
Reaction SMILES: [C:1]1([C:7]2([C:13]([OH:15])=O)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)(=O)C([Cl:19])=O>ClCCl.CN(C)C=O>[C:1]1([C:7]2([C:13]([Cl:19])=[O:15])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)C1(c2ccccc2)CCCCC1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)C1(c2ccccc2)CCCCC1
Temperature: 40 °C
Reaction time: 1 h
Yield: 102.5 %

Procedure:
To a solution of 1-phenylcyclohexanecarboxylic acid (E7) (0.095 g, 0.46 mmol) in dry dichloromethane (3 ml) under argon atmosphere at ice bath temperature oxalyl chloride (0.468 g, 3.68 mmol) and one drop of dimethylformamide were added. The reaction mixture was stirred at room temperature for 15 minutes and at 40° C. for one hour, then concentrated under reduced pressure to give crude title compound (0.105 g, ca. 100%). The crude product was immediately utilized in the next step of the synthesis without further purification.
Reaction SMILES: Cl[CH2:2][CH2:3][CH:4]1[CH2:12][C:11]2[C:6](=[C:7]([Cl:16])[C:8]([Cl:15])=[C:9]([O:13][CH3:14])[CH:10]=2)[C:5]1=[O:17].[C:18]([OH:21])(=[O:20])[CH3:19].O>CCOCC.C([O-])(=O)C.[Ag+]>[C:18]([O:21][CH2:2][CH2:3][CH:4]1[CH2:12][C:11]2[C:6](=[C:7]([Cl:16])[C:8]([Cl:15])=[C:9]([O:13][CH3:14])[CH:10]=2)[C:5]1=[O:17])(=[O:20])[CH3:19]
Reactant: COc1cc2c(c(Cl)c1Cl)C(=O)C(CCCl)C2
Reactant: CC(=O)O
Agent: [Ag+]
Agent: CC(=O)[O-]
Solvent: O
Solvent: CCOCC
Product: COc1cc2c(c(Cl)c1Cl)C(=O)C(CCOC(C)=O)C2
Temperature: 105 °C
Reaction time: 16 h

Procedure:
2-(2-Chloroethyl)-6,7-dichloro-2,3-dihydro-5-methoxy-1H-inden-1-one (18.14 gm, 0.0619 mole), silver acetate (22.74 gm, 0.136 mole), acetic acid (225 ml) and water (2 ml) was stirred and heated at 105° C. internal temperature for 9 hours, then at ambient temperature for 16 hours. The mixture was diluted with ether, filtered and the solid washed with ethyl acetate. The combined filtrate and washing was evaporated in vacuo and the reside suspended in water then extracted first with a mixture of ether and tetrahydrofuran, then with methylene chloride and finally with ethyl acetate. The combined organic extracts were washed with water, then with brine and finally dried over MgSO4. The solvents were removed by evaporation in vacuo to give 12.9 g of residual solid. The solid was recrystallized from a mixture of ethyl acetate and tetrahydrofuran to give 8.1 g of product, m.p. 134°-136° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([C:11]2[CH:16]=[CH:15][C:14]([CH2:17]O)=[CH:13][CH:12]=2)[CH:8]=[CH:9][CH:10]=1)=[O:4].[C:19]1(=[O:29])[NH:23][C:22](=[O:24])[C:21]2=[CH:25][CH:26]=[CH:27][CH:28]=[C:20]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>O1CCCC1.C(OCC)C.O>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([C:11]2[CH:12]=[CH:13][C:14]([CH2:17][N:23]3[C:19](=[O:29])[C:20]4[C:21](=[CH:25][CH:26]=[CH:27][CH:28]=4)[C:22]3=[O:24])=[CH:15][CH:16]=2)[CH:8]=[CH:9][CH:10]=1)=[O:4]
Reactant: COC(=O)c1cccc(-c2ccc(CO)cc2)c1
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Solvent: CCOCC
Product: COC(=O)c1cccc(-c2ccc(CN3C(=O)c4ccccc4C3=O)cc2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 139.3 %

Procedure:
To a stirred mixture of 1.4 g (5.8 mmol.) 4′-hydroxymethyl-biphenyl-3-carboxylic acid methyl ester, 1.0 g (6.9 mmol.) phthalimide, and 1.8 g (6.9 mmol.) triphenylphosphine in 25 mL tetrahydrofuran at 0° C. was added 1.2 ml (7.5 mmol.) diethylazodicarboxylate. The mixture was warmed to ambient temperature and stirred for 18 hours. The mixture was poured into water and extracted with ethyl acetate. The ethyl acetate extracts were combined then washed successively with 1N NaOH, 1N HCl, water, brine then dried (MgSO4) and concentrated in vacuo to give a solid. Trituration with diethyl ether gave 3.0 g 4′-[1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl]-biphenyl-3-carboxylic acid methyl ester as a solid.
Reaction SMILES: [CH2:1]([O:8][CH2:9][N:10]1[C:14]2[CH:15]=[N:16][NH:17][C:18](=[O:19])[C:13]=2[CH:12]=[C:11]1Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C)C=CC=CC=1.C(N(CC)C(C)C)(C)C.[H][H]>[Pd].O1CCCC1>[CH2:1]([O:8][CH2:9][N:10]1[C:14]2[CH:15]=[N:16][NH:17][C:18](=[O:19])[C:13]=2[CH:12]=[CH:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [H][H]
Reactant: O=c1[nH]ncc2c1cc(Br)n2COCc1ccccc1
Agent: [Pd]
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: O=c1[nH]ncc2c1ccn2COCc1ccccc1
Yield: 95.2 %

Procedure:
To 33.4 g (100 mmol) of 1-benzyloxymethyl-2-bromo-1,5-dihydropyrrolo[2,3-d]pyridazin-4-one obtained in Reference example 17-(d) were added 4.5 g of 5% palladium-active carbon, 330 ml of toluene, 330 ml of tetrahydrofuran and 21 ml (121 mmol) of N,N-diisopropylethylamine, and the mixture was stirred under 1 atm hydrogen atmosphere at 60° C. for 1 hour. After completion of the reaction, the insoluble material in the reaction suspension was removed by filtration, followed by washing with 300 ml of a mixed solution (chloroform/methanol=1/1 (V/V)), and the filtrate and the washing solution were combined, then concentrated under reduced pressure. To the obtained concentrate was added 400 ml of water, and the mixture was extracted with a mixed solvent comprising 500 ml of chloroform and 30 ml of ethanol. The organic layer after separation was washed successively with water and a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to obtain 24.3 g of the title compound as a yellowish brown solid. (Yield: 95%)
Reaction SMILES: [Br:1][CH2:2][C:3](=[N:9][OH:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5].[Cl:11][C:12]1[CH:20]=[CH:19][C:15]([C:16](Cl)=[O:17])=[CH:14][CH:13]=1.N1C=CC=CC=1>C(Cl)Cl>[Br:1][CH2:2][C:3](=[N:9][O:10][C:16](=[O:17])[C:15]1[CH:19]=[CH:20][C:12]([Cl:11])=[CH:13][CH:14]=1)[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: CCOC(=O)C(CBr)=NO
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)C(CBr)=NOC(=O)c1ccc(Cl)cc1
Yield: 100.3 %

Procedure:
To the mixture of ethyl 3-bromo-2-(hydorxyimino)propanoate (3 g, 14.3 mmole) and 4-chlorobenzoyl chloride (2.75 g, 15.71 mmole) in dry methylene chloride (100 ml) at 0° to 5° C. with stirring, was slowly added dry pyridine (1.2 g, 15.18 mmole). After addition, the reaction mixture was stirred at room temperature for one hour. The reaction mixture was diluted with 50 ml of methylene chloride and washed with water and brine. The organic layer was dried with magnesium sulfate and the solvent evaporated to afford 5.0 g (99% yield) of ethyl 3-bromo-2-(4-chlorobenzoyloximino)propanoate as a white solid, m.p. 82°-84.5° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][NH:14][C:15]([NH2:17])=[S:16])[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH:19]([CH:22]=O)[CH:20]=[O:21]>C1COCC1.C(O)(=O)C.O>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][NH:14][C:15]1[S:16][C:19]([CH:20]=[O:21])=[CH:22][N:17]=1)[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H](CNC(N)=S)C(=O)O
Reactant: O=CC(Br)C=O
Solvent: O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N[C@@H](CNc1ncc(C=O)s1)C(=O)O
Temperature: 25 °C
Reaction time: 60 h
Yield: 39 %

Procedure:
To a solution of material from Example 112 (3.21 g, 12.19 mmol) in a mixture of THF (107 mL) and acetic acid (29 mL) is added 2-bromomalonaldehyde (3.29 g, 21.79 mmol). The resulting solution is stirred at room temp for 60 h. The reaction is diluted with water (71 mL) and the resulting slurry is stirred at room temp for 1.5 h. The slurry is extracted with EtOAc (3×300 mL), the organic layers combined, washed with brine (1×50 mL), dried over Na2SO4, filtered and evaporated to dryness. The resulting residue is purified by BIOTAGE® Silica gel chromatography on a 80 g Thompson Single Step silica cartridge using a linear gradient from 100% CHCl3 to 25% MeOH/CHCl3 over 9 column volumes to give 1.5 g (39%) of the title compound as an orange/yellow film, 1H NMR (500 MHz, methanol-d4) δ 9.65 (s, 1H), 7.97 (s, 1H), 4.49-4.37 (m, 1H), 3.93 (dd, J=13.9, 4.4 Hz, 1H), 3.72 (dd, J=14.0, 7.7 Hz, 1H), 1.45 (s, 914). LC/MS (Condition A): ret. T=2.46 min, (M+Na) 338.
Reaction SMILES: O=[CH:2][CH:3]([NH:6][C:7](=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH:4]=O.Cl.[Cl:16][C:17]1[CH:18]=[C:19]([NH:23][NH2:24])[CH:20]=[CH:21][CH:22]=1.Cl>C(O)C>[Cl:16][C:17]1[CH:18]=[C:19]([N:23]2[CH:4]=[C:3]([NH:6][C:7](=[O:14])[C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH:2]=[N:24]2)[CH:20]=[CH:21][CH:22]=1
Reactant: O=CC(C=O)NC(=O)c1ccccc1
Reactant: NNc1cccc(Cl)c1
Agent: Cl
Solvent: CCO
Product: O=C(Nc1cnn(-c2cccc(Cl)c2)c1)c1ccccc1
Reaction time: 0.17 h
Yield: 86.5 %

Procedure:
N-(1,3-dioxopropan-2-yl)benzamide (1 g, 5.2 mmol) and (3-chlorophenyl)hydrazine hydrochloride (0.94 g, 5.2 mmol) were mixed with 1N HCl (5 mL), ethanol (40 mL) and concentrated HCl was added (1 mL). The reaction was heated to boiling for 10 minutes and then allowed to cool. The solvent was removed by rotary evaporation. To the resulting residue was added water (20 mL) and dilute ammonium hydroxide (10%) to pH 11. The solids were collected by filtration and washed with water, then dried under vacuum to provide the title compound (1.34 g, 88%).
Reaction SMILES: C([O:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=[O:17])[C:13]([CH3:16])([CH3:15])[CH3:14])=[CH:8][CH:7]=1)(=O)C.[OH-].[K+]>C(O)C.O>[C:12]([C:9]1[CH:8]=[CH:7][C:6]([CH2:5][OH:4])=[CH:11][CH:10]=1)(=[O:17])[C:13]([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(=O)OCc1ccc(C(=O)C(C)(C)C)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)(C)C(=O)c1ccc(CO)cc1

Procedure:
A mixture of 15 grams (0.064 mole) of α-acetoxy-p-pivaloyl toluene and 15 grams (0.278 mole) of potassium hydroxide in 150 milliliters of ethanol and 50 milliliters of water is refluxed for four hours. The solvent is removed in vacuo, and the residue is treated with ether and water. The ether is separated and the water is again extracted with ether. The ether layers are combined, decolorized with charcoal, dried over magnesium sulfate, filtered and evaporated. The resulting yellow oil is distilled in vacuo to give p-pivaloyl benzyl alcohol (b.p. 100°-105° C./0.1 mm).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1F)[O:8][CH:7]([C:13]([F:16])([F:15])[F:14])[C:6]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:5]2.[Cl:22][C:23]1[CH:28]=[C:27]([CH3:29])[C:26]([CH3:30])=[CH:25][C:24]=1[OH:31].C(=O)([O-])[O-].[K+].[K+].[Al]>CN(C=O)C.C(OCC)C.O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:31][C:24]1[CH:25]=[C:26]([CH3:30])[C:27]([CH3:29])=[CH:28][C:23]=1[Cl:22])[O:8][CH:7]([C:13]([F:16])([F:15])[F:14])[C:6]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:5]2
Reactant: Cc1cc(O)c(Cl)cc1C
Reactant: CCOC(=O)C1=Cc2cc(Cl)c(F)cc2OC1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Al]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOCC
Product: CCOC(=O)C1=Cc2cc(Cl)c(Oc3cc(C)c(C)cc3Cl)cc2OC1C(F)(F)F

Procedure:
To 325 mg (1.0 mmole) of ethyl 6-chloro-7-fluoro-2-(trifluoromethyl)-2H-chromene-3-carboxylate in 2.5 mL of DMF was added 172 mg (1.1 mmole) of 2-chloro-4,5-dimethylphenol and 193.5 mg (1.4 mmole) of potassium carbonate. The suspension was prepared in a capped vial and placed in an aluminum heating block equipped with a shaker. The aluminum block was heated to 110° C. for 16 h. After allowing the vial to cool, the mixture was treated with 10 mL of water and 2 mL of diethyl ether. The organic layer was removed and the aqueous layer extracted two times with diethyl ether. Combined organic extracts were filtered through 5 g of silica and the silica washed with 10 mL of diethyl ether. The filtrates were concentrated under a stream of N2 to afford an off-white solid, which was used in the next step without further purification: 1H NMR (CDCl3/300 MHz) 1.36 (t, 3H, J=7.2 Hz), 2.25, (s, 3H), 2.27 (s, 3H), 4.32 (m, 2H), 5.66 (q, 1H, J=6.8 Hz), 6.27 (s, 1H), 6.93 (2, 1H), 7.25 (s, 1H), 7.33 (s, 1H), 7.66 (s, 1H); 19F NMR (CDCl3/300 MHz) −78.9 (d, 3F, J=6.2 Hz).
Reaction SMILES: [C:1]1([CH3:13])[CH:6]=[CH:5][C:4]([C:7]23[CH2:12][CH:11]2[CH2:10][NH:9][CH2:8]3)=[CH:3][CH:2]=1.[CH2:14](I)[CH3:15].C(=O)([O-])[O-].[Na+].[Na+].[ClH:23]>CCOCC.C1(C)C=CC=CC=1>[ClH:23].[CH2:14]([N:9]1[CH2:10][CH:11]2[C:7]([C:4]3[CH:3]=[CH:2][C:1]([CH3:13])=[CH:6][CH:5]=3)([CH2:12]2)[CH2:8]1)[CH3:15]
Reactant: CCI
Reactant: Cc1ccc(C23CNCC2C3)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CCN1CC2CC2(c2ccc(C)cc2)C1

Procedure:
A mixture of 7.4 g. of 1-(p-tolyl)-3-azabicyclo[3.1.0]hexane (Example 32), 7.3 g. of ethyl iodide and 8.9 g. of sodium carbonate in 60 ml. of toluene is heated at reflux for 18 hrs. Filtration and evaporation of this mixture gives a residue which is dissolved in ether. Addition of ethanolic hydrogen chloride gives a precipitate which is recrystallized from acetonitrile to give the desired product as colorless crystals, m.p. 175°-176° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[S:10](Cl)(=[O:12])=[O:11].[OH:14][NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19].C(N(CC)CC)C>C(OC)(C)(C)C>[C:18]([O:17][C:16](=[O:22])[NH:15][O:14][S:10]([C:3]1[C:4]([CH3:9])=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=1[CH3:1])(=[O:12])=[O:11])([CH3:21])([CH3:20])[CH3:19]
Reactant: Cc1cc(C)c(S(=O)(=O)Cl)c(C)c1
Reactant: CC(C)(C)OC(=O)NO
Solvent: CCN(CC)CC
Solvent: COC(C)(C)C
Product: Cc1cc(C)c(S(=O)(=O)ONC(=O)OC(C)(C)C)c(C)c1
Reaction time: 2 h

Procedure:
2,4,6-trimethylbenzenesulfonyl chloride (5 g, 0.022 mol) was added to a solution of methyl tertiary-butyl ether (50 mL) under nitrogen atmosphere at 0° C., followed by the addition of tert-butyl hydroxycarbamate (3.04 g, 0.22 mol) at 0° C. Next, triethylamine (3.24 mL, 0.023 mol) was added drop wise to the reaction mixture, which was then it was allowed to stir for 2 h. The reaction product was filtered through sintered funnel and the filtrate was concentrated under vacuum up to ¾ volume. Hexane (50 mL) was added to the concentrated filtrate, which was then stirred for 20 min wherein a precipitate formed. The participate was collected by filtration and the solid dried to afford tert-butyl(mesitylsulfonyl)oxycarbamate. 1H NMR (400 MHz, CDCl3) δ 8.49 (s, 1H), 8.31 (s, 1H), 2.38 (s, 9H). MS (M+1): 316.3.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8](F)([F:10])F)=C[CH:5]=[CH:4][C:3]=1[C:12]([N:14]1[CH2:19][CH2:18][N:17]2[CH:20]=[C:21]([C:23]([F:26])([F:25])[F:24])[N:22]=[C:16]2[CH2:15]1)=O.C1C(=O)N([Br:34])C(=O)C1.[OH2:35].S([O-])([O-])=O.[Na+].[Na+]>CN(C)C=O.C(OCC)(=O)C>[Br:34][C:20]1[N:17]2[CH2:18][CH2:19][N:14]([C:12]([C:3]3[CH:4]=[CH:5][C:8]([F:10])=[CH:7][C:2]=3[Cl:1])=[O:35])[CH2:15][C:16]2=[N:22][C:21]=1[C:23]([F:25])([F:26])[F:24]
Reactant: O=C(c1cccc(C(F)(F)F)c1Cl)N1CCn2cc(C(F)(F)F)nc2C1
Reactant: O=C1CCC(=O)N1Br
Reactant: O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(c1ccc(F)cc1Cl)N1CCn2c(nc(C(F)(F)F)c2Br)C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
7-{[2-Chloro-3-(trifluoromethyl)phenyl]carbonyl}-2-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine (I22) (181 mg, 0.455 mmol) was dissolved in N,N-dimethylformamide (DMF) (2 mL) and treated with NBS (97 mg, 0.546 mmol). The solution was stirred at RT for 16 h. The mixture was poured on to water (100 ml) containing 1% sodium sulfite (w/w) and extrated in to ethyl acetate (3×50 ml). Combined extracts were washed with brine (50 ml), dried over anhydrous sodium sulfate and concentrated to afford crude product. The crude product was purified by MDAP to afford desired product in 135 mg.