Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.Cl.[NH2:10][C:11]1[C:16]([CH3:17])=[CH:15][C:14](/[CH:18]=[CH:19]/[C:20]#[N:21])=[CH:13][C:12]=1[CH3:22].C(N(CC)CC)C.C(OCC)(=O)C>O>[Cl:1][C:2]1[N:7]=[C:6]([NH:10][C:11]2[C:16]([CH3:17])=[CH:15][C:14](/[CH:18]=[CH:19]/[C:20]#[N:21])=[CH:13][C:12]=2[CH3:22])[CH:5]=[CH:4][N:3]=1
Reactant: Cc1cc(/C=C/C#N)cc(C)c1N
Reactant: Clc1ccnc(Cl)n1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1cc(/C=C/C#N)cc(C)c1Nc1ccnc(Cl)n1
Temperature: 145 °C
Yield: 68.1 %

Procedure:
To a mixture of 2,4-dichloropyrimidine (25 gm) and (E)-3-(4-amino-3,5-dimethylphenyl)acrylonitrile hydrochloride (28 gm) was added triethylamine (300 ml) under stirring. The mixture was then heated to 140 to 150° C. and stirred for 55 to 60 hours. The solution was then cooled to room temperature and the solvent was distilled off under reduced pressure to provide a residual solid. To the residual solid was added ethyl acetate (1500 ml) and water (1000 ml). The reaction mass was stirred for 30 minutes at room temperature and then the layers were separated. The organic layer was dried with sodium sulfate and then concentrates to provide 26 gm of (E)-3-(4-(2-chloropyrimidin-4-ylamino)-3,5-dimethylphenyl)acrylonitrile.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:13]=[CH:12][C:6]([O:7][CH:8]2[CH2:11][NH:10][CH2:9]2)=[CH:5][CH:4]=1.[N+]([NH:19][C:20](N)=[O:21])([O-])=O.O>CC(C)=O>[F:15][C:2]([F:1])([F:14])[C:3]1[CH:4]=[CH:5][C:6]([O:7][CH:8]2[CH2:9][N:10]([C:20]([NH2:19])=[O:21])[CH2:11]2)=[CH:12][CH:13]=1
Reactant: NC(=O)N[N+](=O)[O-]
Reactant: FC(F)(F)c1ccc(OC2CNC2)cc1
Solvent: CC(C)=O
Solvent: O
Product: NC(=O)N1CC(Oc2ccc(C(F)(F)F)cc2)C1
Temperature: 25 °C
Yield: 55.3 %

Procedure:
A solution of 9.6 g (0.025 mole) of 3-(4-trifluoromethylphenoxy)azetidine 56.66% (contains diphenylmethane) in 50 ml of acetone was treated with 4.22 g (0.045 mole) of nitro urea and 5 ml of water. The mixture washeated on a hot plate until a clear solution was obtained then allowed to cool to ambient temperature during the next 4 hr. The reaction was diluted with 200 ml of ice water and an oil separated (diphenylmethane) which was dissolved in 30/60 petroleum ether and separated. Upon standing, a fine white precipitate formed in the aqueous solution. Filtration yielded 3.6 g of fine white crystals, m.p. 176°-178° C. After drying under 0.5 mmHg vacuum at 80° C., the product weight was reduced to 3.1 g, m.p. 178°-179° C.; yield was 47.7%
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8]CC)=[O:7])=[CH:4][CH:3]=1.Br[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][O:19][CH:20]=[CH2:21].C(=O)([O-])[O-].[K+].[K+].CN(C)C(=O)C>O>[CH:20]([O:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([OH:8])=[O:7])=[CH:11][CH:12]=1)=[CH2:21]
Reactant: C=COCCCCCBr
Reactant: CCOC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: C=COCCCCCOc1ccc(C(=O)O)cc1
Temperature: 120 °C
Reaction time: 5 h
Yield: 128.6 %

Procedure:
Ethyl p-hydroxybenzoate (33.2 g), 5-bromopentylvinyl ether (58.0 g), potassium carbonate (41.5 g) and N,N-dimethylacetamide (200 mL) were put into a 500-mL three-neck flask, and stirred at 120° C. for 5 hours. After cooled, the reaction mixture was poured into water (200 mL), extracted with ethyl acetate (500 mL), and washed two times with water (100 mL). This was dried with anhydrous magnesium sulfate, and filtered. The solvent was removed through concentration under reduced pressure, the residue was dissolved in methanol (100 mL), and a methanol solution (20 mL) of potassium hydroxide (16.8 g) was dropwise and gradually added thereto, and heated under reflux for 2 hours. After cooled, the formed crystal was collected through filtration and dissolved in water (1 L). Concentrated hydrochloric acid (25.7 mL) was added thereto, and the precipitated crystal was collected through filtration under reduced pressure, and washed with water. This was dried to give 4-(5-vinyloxypentyloxy)benzoic acid (TP-29C) (64.3 g, 90%). Production of 2,3,6,7,10,11-hexa(4-(5-vinyloxypentyloxy)benzoyloxy)triphenylene (TP-29):
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:9][S:10]([CH3:13])(=[O:12])=[O:11])=[C:6]([NH2:8])[CH:7]=1.C([O-])(=O)C.[K+].C(OC(=O)C)(=O)C.C1OCCOCCOCCOCCOCCOC1.C(O[N:49]=O)(C)(C)C>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:7]=[C:6]2[C:5]([C:9]([S:10]([CH3:13])(=[O:12])=[O:11])=[N:49][NH:8]2)=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)Cc1ccc(Br)cc1N
Reactant: CC(C)(C)ON=O
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CC(=O)OC(C)=O
Solvent: ClC(Cl)Cl
Product: CS(=O)(=O)c1n[nH]c2cc(Br)ccc12

Procedure:
To a suspension of {5-bromo-2-[(methylsulfonyl)methyl]phenyl}amine (Intermediate 74) (0.26 g) in chloroform (8 ml) was added potassium acetate (0.11 g) and acetic anhydride (0.195 ml). The mixture was heated under nitrogen at reflux for 18 h. 18-Crown-6 (0.26 g) and tert-butylnitrite (0.35 ml) were added and the mixture was stirred at reflux for a further 88 h. The mixture was concentrated under vacuum and the residue was purified by column chromatography on silica eluting with cyclohexane:ethylacetate (4:1 to 1:1) to give the title compound (0.14 g).
Reaction SMILES: [C:1]([O:9][CH2:10][CH:11]1[CH2:13][O:12]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:14][C:15]1[CH:16]=[C:17]([CH2:22][C@H:23]([NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C:24]([OH:26])=[O:25])[CH:18]=[CH:19][C:20]=1[OH:21]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>[OH:14][C:15]1[CH:16]=[C:17]([CH2:22][C@H:23]([NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C:24]([O:26][CH2:13][CH:11]([OH:12])[CH2:10][O:9][C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:8])=[O:25])[CH:18]=[CH:19][C:20]=1[OH:21]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(O)c(O)c1)C(=O)O
Reactant: O=C(OCC1CO1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(O)c(O)c1)C(=O)OCC(O)COC(=O)c1ccccc1
Yield: 25.7 %

Procedure:
A solution of oxiran-2-ylmethyl benzoate (3.0 g, 16.8 mmol), (2S)-3-(3,4-dihydroxyphenyl)-2-[(tert-butoxy)carbonylamino]propanoic acid (6.0 g, 20.2 mmol), and tetrabutylammonium bromide (542 mg, 1.7 mmol) in anhydrous toluene was heated to 90° C. for 18 hrs. The reaction mixture was concentrated to dryness under reduced pressure, diluted with ethyl acetate, and washed with water twice followed by the addition of a saturated NaHCO3 solution and brine. The organic layer was dried through MgSO4 and concentrated under reduced pressure. Chromatography (silica gel, 1:1 ethyl acetate/hexane) of the residue afforded 2.05 g (26%) of 2-Hydroxy-3-phenylcarbonyloxypropyl (2S)-3-(3,4-dihydroxyphenyl)-2-[(tert-butoxy)carbonylamino]propanoate.
Reaction SMILES: Br[CH:2]([CH:5]=[O:6])[CH:3]=O.[Br:7][C:8]1[C:9]([CH3:15])=[CH:10][C:11]([NH2:14])=[N:12][CH:13]=1.C(#N)C>>[Br:7][C:8]1[C:9]([CH3:15])=[CH:10][C:11]2[N:12]([C:2]([CH:5]=[O:6])=[CH:3][N:14]=2)[CH:13]=1
Reactant: Cc1cc(N)ncc1Br
Reactant: O=CC(Br)C=O
Solvent: CC#N
Product: Cc1cc2ncc(C=O)n2cc1Br
Yield: 79.81 %

Procedure:
Bromomalonaldehyde (5000 mg, 26.74 mmol) was added to a solution of 5-bromo-4-methylpyridin-2-amine in acetonitrile (5250 mg, 34.76 mmol). The reaction mixture was refluxed for 2 hours. After completion of the reaction, the reaction mixture was quenched with sodium bicarbonate solution and extracted with ethyl acetate. The organic layer was washed with brine and dried over sodium sulfate. The organic layer was concentrated in vacuum and the product was purified by column chromatography using ethyl acetate-petroleum ether gradient to obtain the title compound. Yield: 79.81%; 1H NMR (DMSO-d6; 300 MHz): δ 9.90 (s, 1H), 9.52 (s, 1H), 8.51 (s, 1H), 7.94 (s, 1H), 2.50 (s, 3H); MS (m/z): 239 (M+1)+.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][C@H:10]2[CH2:15][CH2:14][C@H:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH2:12][CH2:11]2)[CH:5]=[CH:4][C:3]=1[O:21][C:22](=[O:39])[C:23]1[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C@@H:35]([CH3:38])[CH2:36][CH3:37])=[CH:25][CH:24]=1.[Cu][C:41]#[N:42].N>CN1CCCC1=O>[C:41]([C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][C@H:10]2[CH2:15][CH2:14][C@H:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH2:12][CH2:11]2)[CH:5]=[CH:4][C:3]=1[O:21][C:22](=[O:39])[C:23]1[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C@@H:35]([CH3:38])[CH2:36][CH3:37])=[CH:25][CH:24]=1)#[N:42]
Reactant: N#C[Cu]
Reactant: CCCCC[C@H]1CC[C@H](CCc2ccc(OC(=O)c3ccc(OCCCCC[C@@H](C)CC)cc3)c(Br)c2)CC1
Agent: N
Solvent: CN1CCCC1=O
Product: CCCCC[C@H]1CC[C@H](CCc2ccc(OC(=O)c3ccc(OCCCCC[C@@H](C)CC)cc3)c(C#N)c2)CC1
Temperature: 185 °C
Reaction time: 0.5 h
Yield: 5.5 %

Procedure:
A mixture of 2 g of (S)-4-(6-methyloctyloxy)benzoic acid 2-bromo-4-[2-(trans-4-pentylcyclohexyl)ethyl]phenyl ester, 0.5 g of anhydrous copper(I) cyanide and 50 ml of absolute 1-methyl-2-pyrrolidone was heated to 185° C. on a oil-bath for 2 hours. The cooled mixture was subsequently treated with 50 ml of 15% ammonia solution and stirred for 30 minutes. Thereafter, the reaction mixture was extracted three times with 50 ml of diethyl ether each time. The combined organic phases were washed twice with 250 ml of water each time, dried over magnesium sulphate and concentrated. Chromatography of the residue on silica gel with toluene/hexane (vol. 1:1) gave 0.1 g of (S)-4-(6-methyloctyloxy)benzoic acid 2-cyano-4-[2-(trans-4-pentylcyclohexyl)ethyl]phenyl ester; m.p. (C-Ch) 80° C., transition S*C -Ch 50° C. (monotropic), cl.p. (Ch-I) 120° C.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:17]=[CH:16][C:6]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][N+:12]([O-])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.C(OC(=O)C)(=[O:22])C>>[F:1][C:2]([F:19])([F:18])[C:3]1[CH:17]=[CH:16][C:6]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][NH:12][C:11](=[O:22])[CH:10]=2)=[CH:5][CH:4]=1
Reactant: [O-][n+]1ccc(OCc2ccc(C(F)(F)F)cc2)cc1
Reactant: CC(=O)OC(C)=O
Product: O=c1cc(OCc2ccc(C(F)(F)F)cc2)cc[nH]1
Temperature: 80 °C
Yield: 91 %

Procedure:
4-(4-(Trifluoromethyl)benzyloxy)pyridine 1-oxide (600 mg, 2.22 mmol) was heated to 140° C. in acetic anhydride (20 mL) for 2 h. The mixture was concentrated and then heated at 80° C. for 1 h in a mixture of MeOH (10 mL) and aqueous 1 N NaOH (10 mL). The resultant black solution was concentrated to a volume of 10 mL and extracted with CHCl3/EtOH (3:1). The organic layer was removed and concentrated to provide the title compound (550 mg, 91%) as a tan solid: 1H NMR (300 MHz, CD3OD) δ 7.70-7.60 (m, 4H), 7.41 (d, J=7.0 Hz, 1H), 6.17 (dd, J=7.0, 2.5 Hz, 1H), 5.96 (d, J=2.4 Hz, 1H), 5.18 (s, 2H).
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][N:13]([C:16]2[CH:21]=[C:20]([NH:22][S:23]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([O:32][CH:33]([F:35])[F:34])[CH:27]=3)(=[O:25])=[O:24])[CH:19]=[CH:18][C:17]=2[O:36][CH3:37])[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].[CH3:38]I>CN(C)C=O>[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][N:13]([C:16]2[CH:21]=[C:20]([N:22]([S:23]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([O:32][CH:33]([F:34])[F:35])[CH:27]=3)(=[O:25])=[O:24])[CH3:38])[CH:19]=[CH:18][C:17]=2[O:36][CH3:37])[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4]
Reactant: COc1ccc(NS(=O)(=O)c2cccc(OC(F)F)c2)cc1N1CCN(C(=O)OC(C)(C)C)CC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(N(C)S(=O)(=O)c2cccc(OC(F)F)c2)cc1N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 95.1 %

Procedure:
To a suspension of 0.015 g (0.374 mmol) of sodium hydride (60% in paraffin oil) in 2 mL of dimethylformamide 0.16 g of 4-[5-(3-Difluoromethoxy-benzenesulfonylamino)-2-methoxy-phenyl]-piperazine-1-carboxylic acid tert-butyl ester (0.311 mmol) from preparation example 1 were added at room temperature. After stirring for 30 minutes at 60° C., a solution of 0.053 g methyliodide (0.374 mmol) in 1 mL dimethylformamide were added dropwise. Stirring was continued for 16 h at room temperature before the solvent was evaporated. Then, 15 mL of water were added, and the aqueous phase was extracted twice with 10 mL of ethyl acetate each. The organic phases were combined, dried over magnesium sulfate, filtered, and the solvent was evaporated under reduced pressure to yield 0.156 g of crude title product which was further purified via silica gel chromatography.
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5]1[CH:6]=[C:7]([O:19][C:20]2[CH:25]=[CH:24][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:22][N:21]=2)[CH:8]=[C:9]2[C:13]=1[NH:12][C:11]([C:14]([O:16]CC)=[O:15])=[CH:10]2)[CH3:3].[OH-].[Na+].C(O)C.Cl>O.O1CCCC1>[CH3:3][CH:2]([O:4][C:5]1[CH:6]=[C:7]([O:19][C:20]2[CH:25]=[CH:24][C:23]([S:26]([CH3:29])(=[O:28])=[O:27])=[CH:22][N:21]=2)[CH:8]=[C:9]2[C:13]=1[NH:12][C:11]([C:14]([OH:16])=[O:15])=[CH:10]2)[CH3:1]
Reactant: CCOC(=O)c1cc2cc(Oc3ccc(S(C)(=O)=O)cn3)cc(OC(C)C)c2[nH]1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: CC(C)Oc1cc(Oc2ccc(S(C)(=O)=O)cn2)cc2cc(C(=O)O)[nH]c12
Temperature: 50 °C
Reaction time: 2 h
Yield: 63.6 %

Procedure:
A mixture of ethyl 7-(1-methylethoxy)-5-{[5-(methylsulfonyl)pyridin-2-yl]oxy}-1H-indole-2-carboxylate (10.7 g), 1M aqueous sodium hydroxide solution (50 mL), ethanol (50 mL) and tetrahydrofuran (50 mL) was stirred at 50° C. for 2 h. 1M Hydrochloric acid (50 mL) was added to the mixture and the mixture was adjusted to pH=6 by 1M aqueous sodium hydroxide solution and water. The whole was extracted with ethyl acetate. The organic layer was washed with brine, dried (MgSO4), filtered, and concentrated in vacuo to give the title compound (6.35 g, 64%) as a brown amorphous solid. MS 391 (MH+).
Reaction SMILES: [C:1]([C:4]1[CH:8]=[C:7]([C:9]([O:11][CH3:12])=[O:10])[NH:6][N:5]=1)(=O)[CH3:2].BrBr.BrC(Br)C(C1C=C(C(OC)=O)NN=1)=O.[C:29]([NH2:32])(=[S:31])[CH3:30]>C(Cl)(Cl)Cl.CO>[CH3:30][C:29]1[S:31][CH:2]=[C:1]([C:4]2[CH:8]=[C:7]([C:9]([O:11][CH3:12])=[O:10])[NH:6][N:5]=2)[N:32]=1
Reactant: CC(N)=S
Reactant: COC(=O)c1cc(C(C)=O)n[nH]1
Agent: BrBr
Agent: COC(=O)c1cc(C(=O)C(Br)Br)n[nH]1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COC(=O)c1cc(-c2csc(C)n2)n[nH]1
Yield: 101.7 %

Procedure:
Methyl 3-acetyl-1H-pyrazole-5-carboxylate (100 mg, 0.595 mmol) was refluxed with bromine (143 mg, 0.892 mmol) in chloroform. Solvent was evaporated and thus obtained methyl 3-(2,2-dibromoacetyl)-1H-pyrazole-5-carboxylate (191 mg, 0.586 mmol) was treated with thioacetamide (44 mg, 0.586 mmol) in refluxing methanol. Solvent was evaporated and the residue was dissolved in DCM and washed with water. Organic phase was dried over Na2SO4, filtered and evaporated to give 133 mg (102%) of the title compound. 1H-NMR (400 MHz; d6-DMSO): δ 2.71 (s, 3H), 3.83 (s, 3H), 7.10 (s, 1H), 7.90 (s, 1H) 14.0 (broad s, 1H).
Reaction SMILES: N(C(OC(C)C)=O)=NC(OC(C)C)=O.[CH2:15]([N:22]1[CH2:28][CH:27]([CH2:29][OH:30])[CH2:26][O:25][CH2:24][CH:23]1[CH3:31])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[F:32][C:33]1[CH:38]=[CH:37][C:36](O)=[CH:35][C:34]=1[CH3:40]>ClCCl>[CH2:15]([N:22]1[CH2:28][CH:27]([CH2:29][O:30][C:36]2[CH:37]=[CH:38][C:33]([F:32])=[C:34]([CH3:40])[CH:35]=2)[CH2:26][O:25][CH2:24][CH:23]1[CH3:31])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: Cc1cc(O)ccc1F
Reactant: CC1COCC(CO)CN1Cc1ccccc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Solvent: ClCCl
Product: Cc1cc(OCC2COCC(C)N(Cc3ccccc3)C2)ccc1F
Reaction time: 20 h

Procedure:
Diisopropyl azodicarboxylate (40 uL, 0.20 mmol, 1.2 equiv) was added to a suspension of (4-benzyl-3-methyl-1,4-oxazepan-6-yl)methanol (4-5, 40 mg, 0.17 mmol, 1 equiv), 4-fluoro-3-methylphenol (26 mg, 0.20 mmol, 1.2 equiv), and polystyrene-supported triphenylphosphine resin (250 mg, 0.51 mmol, 3.0 equiv) in anhydrous dichloromethane (30 mL) at 23° C. The mixture was stirred for 20 h, then filtered. The filtrate was concentrated and the residue was purified by flash column chromatography (20% EtOAc in hexanes) to provide 4-benzyl-6-[(4-fluoro-3-methylphenoxy)methyl]-3-methyl-1,4-oxazepane (4-6) as a ˜1:1 mixture of diastereomers (colorless oil). 1H NMR (300 MHz, CDCl3, reported for a single diasteromer) δ 7.38-7.19 (m, 5H), 6.85 (ddd, 1H,J=12.5, 9.2, 3.7 Hz), 6.53 (m, 2H), 3.97-3.50 (m, 6H), 3.08 (m, 1H), 3.00 (dd, 1H,J=14.0, 4.0 Hz), 2.90 (d, 1H,J=13.7 Hz), 2.82 (dd, 1H,J=14.0, 3.0 Hz), 2.60 (d, 1H,J=13.7 Hz), 2.44 (m, 1H), 2.21 (s w/small splittings, 3H), 1.08 (d, 3H,J=6.7 Hz). LRMS m/z (M+H) 344.4 found, 344.2 required.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:19])[C:13](=[O:14])[CH2:12][CH2:11][CH:10]([C:15](OC)=[O:16])[CH2:9]2)=[CH:4][C:3]=1[C:20]([F:23])([F:22])[F:21].[BH4-].[Na+]>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:19])[CH2:9][CH:10]([CH2:15][OH:16])[CH2:11][CH2:12][CH:13]2[OH:14])=[CH:4][C:3]=1[C:20]([F:21])([F:22])[F:23]
Reactant: COC(=O)C1CCC(=O)C(C)(c2ccc(Cl)c(C(F)(F)F)c2)C1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC1(c2ccc(Cl)c(C(F)(F)F)c2)CC(CO)CCC1O
Temperature: 60 °C
Reaction time: 28 h
Yield: 77.4 %

Procedure:
A solution of methyl (1RS,3RS)-3-(4-chloro-3-(trifluoromethyl)phenyl)-3-methyl-4-oxocyclohexane-carboxylate (1.348 g, 3.87 mmol) in ethanol (20 mL) was treated with sodium borohydride (0.292 g, 7.73 mmol) and stirred at 60° C. Additional sodium borohydride (100 mg) was added after 7 h and again after 22.75 h. After 28 h, the resulting mixture was concentrated under vacuum and the resulting residue was stirred with ethyl acetate and saturated aqueous sodium bicarbonate for 30 min. The aqueous and organic layers were separated and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over sodium sulfate and concentrated under vacuum to yield a residue. This residue was purified by column chromatography on silica gel, eluting with 30-70% ethyl acetate-hexanes, to provide (1RS,2RS,4RS)-2-(4-chloro-3-(trifluoromethyl)phenyl)-4-(hydroxymethyl)-2-methylcyclohexanol as a white glassy foam (967 mg, 78%). 1H NMR (500 MHz, CDCl3) δ 8.14 (d, J=2.2 Hz, 1 H), 7.82 (dd, J=8.5, 2.2 Hz, 1 H), 7.41 (d, J=8.8 Hz, 1 H), 3.76 (dd, J=12.1, 3.8 Hz, 1 H), 3.45 (ab portion of abx, 2 H), 2.37 (dt, J=14.3, 2.7 Hz, 1 H), 1.92 (br. s, 1 H), 1.82 (m, 1 H), 1.77 (m, 1 H), 1.58 (m, 3 H), 1.35 (s, 3 H), 1.18 (m, J=14.0, 12.4 Hz, 2H).
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[O:10])=[CH:5][CH:4]=1.Br[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20].C(N(CC)CC)C>C(#N)C>[F:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([CH:11]2[CH2:16][CH2:15][N:14]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:13][CH2:12]2)=[O:10])=[CH:5][CH:4]=1
Reactant: CCOC(=O)CBr
Reactant: O=C(c1ccc(F)cc1)C1CCNCC1
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOC(=O)CN1CCC(C(=O)c2ccc(F)cc2)CC1
Yield: 84.3 %

Procedure:
To a solution of (4-fluorophenyl)(piperidin-4-yl)methanone hydrochloride (51.8 g, 213 mmol) in acetonitrile (400 mL) was added ethyl 2-bromoacetate (38.2 mL, 345 mmol) and triethylamine (70 mL, 506 mmol). The mixture was heated at reflux for 5 h, the solvent was evaporated under reduced pressure and purified via flash column chromatography (ethyl acetate:hexane, 10:90 to 100:0) to provide product (52.7 g, 85% yield). 1H NMR (400 MHz, CDC3) δ 7.98 (dd, J=8.5, 5.5 Hz, 2H), 7.16 (t, J=8.5 Hz, 2H), 4.22 (q, J=7.2 Hz, 2H), 3.16-3.27 (m, 1H), 3.03 (d, J=11.5 Hz, 2H), 2.43 (td, J=11.2, 3.3 Hz, 2H), 1.81-2.09 (m, 4H), 1.51-1.73 (m, 2H), 1.30 (t, J=7.3 Hz, 3H). MS m/z 294.4 (M+1), retention time=1.94 min.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][C:5](=O)[CH:4]([CH2:9][C:10](=O)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:3]1.[NH2:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([OH:25])=[O:24])=[CH:21][CH:20]=1>>[CH3:1][CH:2]1[CH2:7][CH2:6][C:5]2[N:18]([C:19]3[CH:27]=[CH:26][C:22]([C:23]([OH:25])=[O:24])=[CH:21][CH:20]=3)[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:9][C:4]=2[CH2:3]1
Reactant: CC1CCC(=O)C(CC(=O)c2ccccc2)C1
Reactant: Nc1ccc(C(=O)O)cc1
Product: CC1CCc2c(cc(-c3ccccc3)n2-c2ccc(C(=O)O)cc2)C1
Yield: 73 %

Procedure:
Following the general methods as outlined under Intermediate 7, starting from 4-methyl-2-(2-oxo-2-phenylethyl)cyclohexanone and 4-aminobenzoic acid, the title compound was isolated in 73% yield (95% purity by HPLC). MS(ESI+): 332.5; MS(ESI−): 330.4.
Reaction SMILES: [F:1][CH2:2][C@@H:3]1[C@@H:7]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[O:18][N:17]=[C:16]([CH2:19]OS(C)(=O)=O)[CH:15]=3)=[CH:10][CH:9]=2)[O:6][C:5]([CH3:26])([CH3:25])[N:4]1[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28].[OH-].[NH4+:35]>O1CCOCC1>[NH2:35][CH2:19][C:16]1[CH:15]=[C:14]([C:11]2[CH:10]=[CH:9][C:8]([C@H:7]3[O:6][C:5]([CH3:26])([CH3:25])[N:4]([C:27]([O:29][C:30]([CH3:32])([CH3:31])[CH3:33])=[O:28])[C@@H:3]3[CH2:2][F:1])=[CH:13][CH:12]=2)[O:18][N:17]=1
Reactant: CC(C)(C)OC(=O)N1[C@H](CF)[C@@H](c2ccc(-c3cc(COS(C)(=O)=O)no3)cc2)OC1(C)C
Reactant: [NH4+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1[C@H](CF)[C@@H](c2ccc(-c3cc(CN)no3)cc2)OC1(C)C
Temperature: 35 °C
Reaction time: 12 h

Procedure:
To a dioxane (10 ml) solution of (4S,5R)-tert-butyl 4-(fluoromethyl)-2,2-dimethyl-5-(4-(3-((methylsulfonyloxy)methyl)isoxazol-5-yl)phenyl)oxazolidine-3-carboxylate (1.0 g, 2.1 mmol) is added 30% aqueous ammonium hydroxide solution (5 ml). The mixture is stirred at 35° C. for 12 hours. The product is partitioned between water (50 ml) and methylene chloride (25 ml). The organic phase is dried (sodium sulfate) and concentrated to give the title compound (685 mg): m/z (CI) 406 ([M+H]+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C([O-])([O-])=O.[K+].[K+].Cl[C:14]1[C:15]([O:20][CH2:21][CH2:22][O:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([Br:30])[CH:25]=2)=[N:16][CH:17]=[CH:18][N:19]=1>C(#N)C>[N:1]1([C:14]2[C:15]([O:20][CH2:21][CH2:22][O:23][C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([Br:30])[CH:25]=3)=[N:16][CH:17]=[CH:18][N:19]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1
Reactant: C1CNCCN1
Reactant: Clc1nccnc1OCCOc1cccc(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Brc1cccc(OCCOc2nccnc2N2CCNCC2)c1
Yield: 84.9 %

Procedure:
Piperazine (1.29 g, 15.0 mmol) and K2CO3 (0.69 g, 5.0 mmol) were added to a solution of 2-(3-bromophenoxy)ethyl 3-chloro-2-pyrazinyl ether (1.65 g, 5.00 mmol) in acetonitrile (25 mL) at room temperature. The mixture was heated at reflux for 21 h, allowed to cool, concentrated and the residue was partitioned between water and EtOAc. The layers were separated and the organic phase was washed with water and brine, and dried over MgSO4. Purification by chromatography on silica gel (gradient: PhMe to PhMe/MeOH/Et3N, 8:1:1) gave 1.61 g (85%) of the title compound as a pale yellow oil that slowly solidified on standing: mp 62-63° C. Anal. (C16H19BrN4O2) C, H, N.
Reaction SMILES: [C:1]([OH:11])(=O)/[CH:2]=[CH:3]/[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[NH2:12][C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1.C1CCC(N=C=NC2CCCCC2)CC1>>[N:16]1[CH:17]=[CH:18][C:13]([NH:12][C:1](=[O:11])[CH:2]=[CH:3][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)=[CH:14][CH:15]=1
Reactant: O=C(O)/C=C/c1ccccc1
Reactant: Nc1ccncc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Product: O=C(C=Cc1ccccc1)Nc1ccncc1
Yield: 67.8 %

Procedure:
Reaction of trans-cinnamic acid (0.74 g, 5.00 mmol) with 4-aminopyridine (0.47 g, 5.00 mmol) was conducted according to the general amide coupling procedure using DCC to obtain the product as a white solid (0.76 g, 68%). EIMS m/z: 225 ([M]+), 223 ([M]−).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:3]=1[O:4][CH2:5][CH:6]=[O:7].[C:13](O)(=[O:16])[CH2:14][SH:15].B(F)(F)F.CCOCC>CCOCC>[Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:3]=1[O:4][CH2:5][CH:6]1[S:15][CH2:14][C:13](=[O:16])[O:7]1
Reactant: O=C(O)CS
Reactant: O=CCOc1ccc(Cl)cc1Cl
Agent: FB(F)F
Solvent: CCOCC
Product: O=C1CSC(COc2ccc(Cl)cc2Cl)O1
Temperature: 25 °C
Reaction time: 2 h
Yield: 40.1 %

Procedure:
A solution containing 10.25g (0.05 mole) of 2,4-dichlorophenoxyacetaldehyde, 5.1g (0.055 mole) of thioglycolic acid and 15g (0.15 mole) of boron trifluoride etherate in 250 ml of ether was stirred at ambient temperature for 2 hours, washed with 5% aqueous sodium carbonate, dried, concentrated, and triturated with hexane to give 5.6g of 2-(2,4-dichlorophenoxymethyl)-1,3-oxathiolan-5-one as an off-white crystalline solid melting at 59°-61°.