Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:13])[C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][C:6]=1[Cl:12].CCN(C(C)C)C(C)C.[Cl:23][CH2:24][CH2:25][CH2:26][C:27](Cl)=[O:28]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:2][O:3][C:4](=[O:13])[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:27](=[O:28])[CH2:26][CH2:25][CH2:24][Cl:23])=[CH:7][C:6]=1[Cl:12]
Reactant: O=C(Cl)CCCCl
Reactant: COC(=O)c1ccc(N)cc1Cl
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)c1ccc(NC(=O)CCCCl)cc1Cl
Reaction time: 4 h

Procedure:
To a solution of 4-amino-2-chlorobenzoic acid methyl ester hydrochloride (0.52 g) and DIEA (0.27 mL) in CH2Cl2 (20 mL) at 0° C. under N2 was added 4-chlorobutyryl chloride (0.3 mL) and the mixture was stirred for 4 h at that temperature. DMAP (0.23 mmol) was added and the mixture was stirred at room temperature overnight. 4-Chlorobutyryl chloride (0.3 mL) and DIEA (0.09 mL) were added and the mixture was stirred for 24 h. The mixture was diluted with CH2Cl2 (100 mL) and the solution was washed successively with 1N HCl, std. NaHCO3, brine, dried and evaporated. The residue was purified by column chromatography (silica gel; eluent: hexane/EtOAc 3:1) to yield 4-(4-chlorobutyryl)amino-2-chlorobenzoic acid methyl ester (0.64 g). ESMS: m/z 290 (MH+).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[NH:7][CH2:8][CH2:9][CH2:10][N:11]1[C:19]2[C:14](=[CH:15][C:16]([C:20]([O:22]CC)=[O:21])=[CH:17][CH:18]=2)[CH:13]=[N:12]1.[OH-].[Na+]>C(O)C.O>[N:3]1[CH:4]=[CH:5][CH:6]=[N:1][C:2]=1[NH:7][CH2:8][CH2:9][CH2:10][N:11]1[C:19]2[C:14](=[CH:15][C:16]([C:20]([OH:22])=[O:21])=[CH:17][CH:18]=2)[CH:13]=[N:12]1
Reactant: CCOC(=O)c1ccc2c(cnn2CCCNc2ncccn2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1ccc2c(cnn2CCCNc2ncccn2)c1
Yield: 89.3 %

Procedure:
The product of step A (510 mg, 1.16 mmol) was dissolved in ethanol (50 mL) and sodium hydroxide (6.5 mL of a 1N solution, 6.5 mmol) added. The solution was heated at reflux for 1.5 hours, diluted with water (45 mL), and the ethanol removed under vacuum. The solution was acidified to pH=3 with 1N HCl (˜7 mL) with stirring. The resulting solids were filtered, washed with water, and dried under vacuum to afford the product (308 mg, 89%). LRMS (ES): 298.1 ([M+H]+. HRMS: Calculated for C15H16N5O2: 298.1304; Found: 298.1320. 1HNMR (600.1343 MHz, CDCl3): 12.5 (b, H), 8.42 (s, 1H), 8.26 (d, 2H), 8.19 (s, 1H), 7.90 (d, 1H), 7.67, (d, 1H), 7.45 (m, 1H), 6.58 (s, 1H), 4.50 (t, 2H), 3.29 (m, 2H), 2.13 (t, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([O:15][CH2:16][C:17]1[C:22]([Cl:23])=[CH:21][CH:20]=[CH:19][C:18]=1[Cl:24])=[CH:10][CH:9]=2)=[O:5])[CH3:2].[H-].[Na+].Br[CH2:28][CH2:29][CH2:30][C:31]#[N:32]>CN(C)C=O.C(OCC)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:28][CH2:29][CH2:30][C:31]#[N:32])[C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([O:15][CH2:16][C:17]1[C:22]([Cl:23])=[CH:21][CH:20]=[CH:19][C:18]=1[Cl:24])=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2cc(OCc3c(Cl)cccc3Cl)ccc2[nH]1
Reactant: N#CCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2cc(OCc3c(Cl)cccc3Cl)ccc2n1CCCC#N
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 90 %

Procedure:
To a solution of 5-(2,6-dichlorobenzyloxy)-1H-indole-2-carboxylic acid ethyl ester (1.50 g, 4.12 mmol) in dimethylformamide (15 mL) was added 60% sodium hydride (0.25 g, 6.18 mmol). The reaction mixture was stirred at ambient temperature under argon for 2.5 h. 4-Bromobutyronitrile (0.92 g, 6.14 mmol) was then added and the reaction mixture stirred for another 14 h at ambient temperature. The reaction was diluted with ethyl acetate and washed three times with water. The organic layer was dried over MgSO4, filtered and the solvent removed under reduced pressure. Purification by flash chromatography (silica gel, 25% ethyl acetate/hexane) yielded an off-white solid (1.60 g, 95%). MS(ES) m/e 431.0 [M +H]+.
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH2:9][C:10]2[C:15]([Cl:16])=[CH:14][CH:13]=[CH:12][C:11]=2[F:17])=[CH:6][CH:5]=[CH:4][N:3]=1.[C:18]1([N:24]=[C:25]=[S:26])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C1(C)C=CC=CC=1>C(OCC)C>[F:17][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]([Cl:16])[C:10]=1[CH2:9][O:8][C:7]1[C:2]([NH:1][C:25]([NH:24][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[S:26])=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: S=C=Nc1ccccc1
Reactant: Nc1ncccc1OCc1c(F)cccc1Cl
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: Fc1cccc(Cl)c1COc1cccnc1NC(=S)Nc1ccccc1

Procedure:
A mixture of 2-amino-3-(2-fluoro-6-chlorobenzyloxy)pyridine (7.6 g, 0.03 mol), phenyl isothiocyanate (3.95 ml, 0.033 mol) and toluene (25 ml) was refluxed for 2.5 hours, then cooled and treated with diethyl ether to induce crystallisation of the product. Yield 8.47 g (73%), m.p. 143°-145 ° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][CH:9]=[C:10]2[C:13]#[N:14])=[CH:5][CH:4]=1.[Br:15][Br:16]>C(O)(=O)C>[Br:15][C:12]1[C:3]([O:2][CH3:1])=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10]([C:13]#[N:14])=[CH:9][CH:8]=[CH:7]2.[Br:15][Br:16]
Reactant: COc1ccc2cccc(C#N)c2c1
Agent: BrBr
Solvent: CC(=O)O
Product: COc1ccc2cccc(C#N)c2c1Br

Procedure:
Bromination of 7-methoxy-1-naphthonitrile (4) with bromine in acetic acid is a very temperature sensitive reaction. The compound 8-bromo-7-methoxy-1-naphthonitrile is produced rapidly at room temperature with two equivalent of bromine. It produces many poly-brominated impurities when the temperature is above 70° C. In this process of the present invention, 7-methoxy-1-naphthonitrile (4) is di-brominated at 40-70° C. with 2-6 equivalents of bromine in acetic acid. Upon the completion of the reaction, the reaction mixture is quenched with excess sodium bisulfite to reduce excess bromine and the product precipitates and is isolated with an expected yield on the order of 90-95% with high purity. This dibromide, without further purification, is heated with stannous chloride in a mixture of acetic acid and concentrated HCl at 100° C. The bromine in 8 position is selectively reduced. The product, 3-bromo-7-methoxy-1-naphthonitrile (6) is filtered from the reaction mixture after the reaction is complete. Typically, the yield is 70-80% over 2 steps with 95%+HPLC purity.
Reaction SMILES: [CH2:1]([O:8][C@H:9](C)[C@@H:10]([C:31](OC)=[O:32])[NH:11]C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+].[ClH:44].O1CCOCC1>CCOCC.CO.O.C(OCC)(=O)C>[ClH:44].[NH2:11][C@@H:10]([CH2:9][O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:31][OH:32]
Reactant: COC(=O)[C@@H](NC(c1ccccc1)(c1ccccc1)c1ccccc1)[C@@H](C)OCc1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: CO
Solvent: CCOCC
Solvent: O
Product: N[C@H](CO)COCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Methyl O-benzyl-N-trityl-L-threoninate (137 g, 304 mmol) was dissolved in a minimal amount of Et2O and added dropwise to a mixture of lithium aluminum hydride (12.0 g, 333 mmol) and Et2O (1.5 L) at 0° C. The resulting mixture was stirred for 1 hour at 0° C. Ethyl acetate was then carefully added to the reaction mixture at 0° C. until no further gas evolution was observed and then the reaction mixture was treated with methanol until no further gas evolution was observed. The reaction mixture was then treated sequentially with H2O (12 mL), 6 M aqueous NaOH solution (12 mL), and H2O (36 mL) and stirred for 30 minutes. The resulting slurry was filtered through a pad of CELITE filter agent. The pad was rinsed repeatedly with Et2O and the combined filtrates were dried over MgSO4 and concentrated under reduced pressure to give a colorless oil. The oil was dissolved in 90 mL of methanol and treated with 4M HCl in dioxane (227 mL, 908 mmol). The resulting homogeneous solution was stirred for 2 hours at ambient temperature. The solvent was then removed under reduced pressure to afford a yellow solid. The yellow solid was stirred in Et2O (500 mL) and filtered to give 43 g of (2R)-2-amino-3-(benzyloxy)propan-1-ol hydrochloride as a white crystalline solid.
Reaction SMILES: [O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[C:3]([C:12]([OH:14])=O)=[CH:2]1.S(Cl)([Cl:17])=O>C1CCCCC1>[O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[C:3]([C:12]([Cl:17])=[O:14])=[CH:2]1
Reactant: O=C(O)c1coc2ccccc2c1=O
Reactant: O=S(Cl)Cl
Solvent: C1CCCCC1
Product: O=C(Cl)c1coc2ccccc2c1=O

Procedure:
A mixture of chromone-3-carboxylic acid (1.25 g) and thionyl chloride (6 ml) was heated at reflux for 5 minutes. The reaction mixture was then diluted with cyclohexane (15 ml) and ice-cooled. The crystalline precipitate was collected by filtration, washed with cyclohexane and dried under vacuum to give chromone-3-carbonyl chloride (1.2 g).
Reaction SMILES: [CH2:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([OH:10])[C:4]=2[CH2:3][CH2:2]1.C(NC(C)C)(C)C.S(Cl)([Cl:21])(=O)=O.O>ClCCl>[Cl:21][C:6]1[CH:7]=[CH:8][C:9]2[CH2:1][CH2:2][CH2:3][C:4]=2[C:5]=1[OH:10]
Reactant: Oc1cccc2c1CCC2
Reactant: O=S(=O)(Cl)Cl
Solvent: O
Solvent: CC(C)NC(C)C
Solvent: ClCCl
Product: Oc1c(Cl)ccc2c1CCC2
Temperature: 22.5 °C
Reaction time: 15 h
Yield: 12.7 %

Procedure:
To a clear solution of Indan-4-ol (40.0 gm, 0.297 mole) and Diisopropylamine (4.29 ml, 0.029 mole) in Dichloromethane (140 ml), a solution of Sulfuryl chloride (21.76 ml, 0.267 mole) in Dichloromethane (20 ml) was added at 0-5° C. The reaction mixture was stirred for 15 hours at 20-25° C. and poured into water (200 ml). Further it was extracted with Ethylacetate (2×200 ml). The organic layer was dried over Sodium sulphate, distilled under vacuum to give crude solid which was purified by column chromatography using Ethyl acetate:Hexane (2:98) as mobile phase. The collected fractions were distilled to give 5.7 gm of desired product as a solid.
Reaction SMILES: [CH2:1]([O:5][C:6]1[C:11]([F:12])=[C:10](Cl)[N:9]=[CH:8][N:7]=1)[C:2]#[C:3][CH3:4].[CH3:14][CH:15]1[CH2:20][CH2:19][CH2:18][NH:17][CH2:16]1>C(O)C>[CH2:1]([O:5][C:6]1[C:11]([F:12])=[C:10]([N:17]2[CH2:18][CH2:19][CH2:20][CH:15]([CH3:14])[CH2:16]2)[N:9]=[CH:8][N:7]=1)[C:2]#[C:3][CH3:4]
Reactant: CC1CCCNC1
Reactant: CC#CCOc1ncnc(Cl)c1F
Solvent: CCO
Product: CC#CCOc1ncnc(N2CCCC(C)C2)c1F
Temperature: 25 °C
Reaction time: 10 h
Yield: 94 %

Procedure:
Into 3 ml of ethanol was resolved 0.3 g of 4-(2-butynyloxy)-6-chloro-5-fluoropyrimidine, 0.45 g of 3-methylpiperidine was added therein, and the mixture was stirred for 10 hours under reflux condition. The reaction mixture was cooled to near room temperature, and concentrated. Into the residue was added a saturated ammonium chloride aqueous solution, and the mixture was extracted with tert-butyl methyl ether three times. The organic layers were washed with a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to obtain 0.37 g of 4-(2-butynyloxy)-5-fluoro-6-(3-methylpiperidino) pyrimidine (hereinafter, referred to as Compound (3)).
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[C:19]([F:28])[CH:20]=[C:21]([C:22]4[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=4)[C:15]=3[O:14]2)(=O)=O)=CC=1.[CH3:29][NH2:30]>>[F:28][C:19]1[CH:20]=[C:21]([C:22]2[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=2)[C:15]2[O:14][CH:13]([CH2:12][NH:30][CH3:29])[CH2:17][C:16]=2[CH:18]=1
Reactant: CN
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cc(F)cc(-c4cccnc4)c3O2)cc1
Product: CNCC1Cc2cc(F)cc(-c3cccnc3)c2O1

Procedure:
The title compound was prepared (0.056 g, 34%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-[5-fluoro-7-pyridin-3-yl-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.20 g, 0.50 mmol) and methylamine (0.155 g, 5.0 mmol). mp 255-257° C.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:29])[CH2:6][C@@H:7]([C:27]#[CH:28])[NH:8][C:9]([C@@H:11]1[CH2:16][CH2:15][CH2:14][N:13]([C:17](=[O:26])[CH2:18][CH2:19][CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[CH2:12]1)=[O:10])[CH3:3].C(=O)([O-])[O-].[K+].[K+].Br[CH2:37][C:38]1[O:39][C:40](=[O:44])[O:41][C:42]=1[CH3:43].[Cl-].[NH4+]>CN(C)C=O>[CH2:2]([O:4][C:5](=[O:29])[CH2:6][C@@H:7]([C:27]#[CH:28])[NH:8][C:9]([C@@H:11]1[CH2:16][CH2:15][CH2:14][N:13]([C:17](=[O:26])[CH2:18][CH2:19][CH:20]2[CH2:21][CH2:22][N:23]([CH2:37][C:38]3[O:39][C:40](=[O:44])[O:41][C:42]=3[CH3:43])[CH2:24][CH2:25]2)[CH2:12]1)=[O:10])[CH3:3]
Reactant: C#C[C@H](CC(=O)OCC)NC(=O)[C@@H]1CCCN(C(=O)CCC2CCNCC2)C1
Reactant: Cc1oc(=O)oc1CBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CN(C)C=O
Product: C#C[C@H](CC(=O)OCC)NC(=O)[C@@H]1CCCN(C(=O)CCC2CCN(Cc3oc(=O)oc3C)CC2)C1
Temperature: 0 °C
Yield: 18.2 %

Procedure:
To a solution of N-[(R)-1-{3-(4-piperidyl)propionyl}-3-piperidylcarbonyl]-3(S)-ethynyl-β-alanine ethyl ester hydrochloride (0.47 g) in N,N-dimethylformamide (5 ml) was added potassium carbonate (0.2 g) under stirring at 0° C. After stirring at 0° C. for 15 minutes, a solution of 4-bromomethyl-5-methyl-2-oxo-1,3-dioxole (0.19 g) in N,N-dimethylformamide (1 ml) was added to the mixture. After stirring at ambient temperature for overnight, the mixture was poured into saturated aqueous ammonium chloride, and extracted with ethyl acetate. The extract was washed with water and brine, and dried over MgSO4, and evaporated in vacuo. The residue was purified by column chromatography on silica gel eluting with (CHCl3:MeOH=100:1) to give N-[(R)-1-[3-{1-(5-methyl-2-oxo-1,3-dioxol-4-yl-methyl)-4-piperidyl}propionyl]-3-piperidylcarbonyl]-3(S)-ethynyl-β-alanine ethyl ester (90 mg) as an oil.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6](=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][N:9]=1)(=[O:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C[Si]([N:42]=[N+:43]=[N-:44])(C)C>C1COCC1.CCOC(C)=O>[C:1]([O:4][CH2:5][C:6]1[N:7]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][N:9]=2)[N:44]=[N:43][N:42]=1)(=[O:3])[CH3:2]
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: CC(=O)OCC(=O)Nc1ccc(C(F)(F)F)cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(=O)OCc1nnnn1-c1ccc(C(F)(F)F)cn1
Reaction time: 0.5 h
Yield: 49.7 %

Procedure:
To a solution of 2-oxo-2-{[5-(trifluoromethyl)-2-pyridinyl]amino}ethyl acetate (Intermediate 56, 3.30 g, 12.6 mmol) in THF at 0° C. were added triphenylphosphine (8.24 g, 31.4 mmol) and diisopropyl azodicorboxylate (6.30 g, 31.2 mmol). The reaction mixture was stirred for 30 min and trimethylsilyl azide (3.60 g, 31.2 mmol) was added dropwise at room temperature. The reaction mixture was heated to reflux for 4 hr. The reaction mixture was diluted with EtOAc and washed with ice water, aq. NaHCO3 solution and saturated brine solution, dried over anhydrous Na2SO4, and concentrated under reduced pressure to afford the crude product. This was purified by column chromatography (60-120 mesh silica gel), eluting with 20% ethyl acetate/pet ether, to give the title compound (1.80 g) as a pale yellow liquid.
Reaction SMILES: [C:1]([NH:4][NH:5][C:6](=[O:14])[C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[N:9][CH:8]=1)(=O)[CH3:2]>O1CCCC1.C(OCC)(=O)C>[Cl:13][C:10]1[CH:11]=[CH:12][C:7]([C:6]2[O:14][C:1]([CH3:2])=[N:4][N:5]=2)=[CH:8][N:9]=1
Reactant: CC(=O)NNC(=O)c1ccc(Cl)nc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1nnc(-c2ccc(Cl)nc2)o1
Temperature: 120 °C

Procedure:
N′-Acetyl-6-chloronicotinohydrazide (95 mg, 0.45 mml) and 3,3,3-triethyl-1-(methoxycarbonyl)diazathian-3-ium-1-ide 2,2-dioxide (159 mg, 0.67 mmol) were taken up in tetrahydrofuran (4.5 mL) and heated in a microwave at 120° C. for 30 minutes. The reaction was then diluted with ethyl acetate and washed with saturated aqueous ammonium chloride, water, and brine. The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo to afford the title compound.
Reaction SMILES: [Br-].C1([P+](C2C=CC=CC=2)(C2C=CC=CC=2)[CH2:9][CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])C=CC=CC=1.[CH3:29][C:30]1[O:36][C:33]([CH:34]=O)=[CH:32][CH:31]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>O1CCCC1>[CH3:34][C:33]1[O:36][C:30](/[CH:29]=[CH:9]/[CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:31][CH:32]=1
Reactant: Cc1ccc(C=O)o1
Reactant: CCOC(=O)CCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Br-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)CC/C=C/c1ccc(C)o1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of triphenyl-(3-ethoxycarbonylpropyl)phosphonium bromide (2.27 g, 5 mmol) and 5-methylfurfural (0.55 g, 5 mmol) in 5 mL of dry tetrahydrofuran, a 1 M solution of sodium bis(trimethylsilyl)amide in tetrahydrofuran (5 mL) was added dropwise. The reaction mixture was stirred at room temperature for 2 hours and quenched with 2 N hydrochloric acid solution. The reaction mixture was extracted with ethyl acetate and the combined organic layers were dried over magnesium sulfate, concentrated and chromatographed eluting with 5% ethyl acetate/hexane to yield the title product: 1H NMR (300 MHz, CDCl3) δ 6.16 (d, J=3.05 Hz, 1H), 5.97 (dd, J=3.22, 0.85 Hz, 1H), 5.42 (dt, J=11.44, 7.11 Hz, 1H)), 4.14 (q, J=7.2 Hz, 2H), 2.76 (m, 2H), 2.47 (t, J=7.46 Hz, 2H), 2.31 (s, 3H), 1.25 (t, J=7.12 Hz, 3H); MS (DCI/NH3)(M+H)+ m/z 209.
Reaction SMILES: C[N+]1([O-])CCOCC1.[C:9]([N:12]1[CH2:17][CH2:16][CH2:15][C:14]([CH2:26][OH:27])([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=2)[CH2:13]1)(=[O:11])[CH3:10]>ClCCl.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[C:9]([N:12]1[CH2:17][CH2:16][CH2:15][C:14]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=2)([CH:26]=[O:27])[CH2:13]1)(=[O:11])[CH3:10]
Reactant: CC(=O)N1CCCC(CO)(Cc2ccc(C)cc2)C1
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: ClCCl
Product: CC(=O)N1CCCC(C=O)(Cc2ccc(C)cc2)C1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
N-methyl morpholine-N-oxide (0.19 g, 1.62 mmol) and powdered 4 angstrom molecular sieves (0.5 g) were added to a solution of the product from STEP 4 (0.3 g, 1.08 mmol) in 15 ml dichloromethane. Tetrapropyl-ammonium perruthenate (19 mg, 0.054 mmol) was added at 0° C., and the reaction was allowed to warm to room room temperature. After 1.5 h, the reaction was filtered through a short column of silica gel (2″) and washed with CH2Cl2/MeOH (9/1). The filtrate was concentrated, and the residue was purified by chromatography (SiO2, CH2Cl2/MeOH/NH4OH=95/5/0.1) to give 0.25 g of a viscous. The 1H NMR spectrum of the product was consistent for the proposed structure.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5](Cl)(=[O:7])[CH3:6].[Cl:9][C:10]1[CH:19]=[CH:18][C:17]([CH3:20])=[C:16]2[C:11]=1[C:12]([CH3:22])([CH3:21])[CH2:13][CH2:14][S:15]2>C(Cl)Cl>[C:5]([C:19]1[C:10]([Cl:9])=[C:11]2[C:16](=[C:17]([CH3:20])[CH:18]=1)[S:15][CH2:14][CH2:13][C:12]2([CH3:22])[CH3:21])(=[O:7])[CH3:6]
Reactant: CC(=O)Cl
Reactant: Cc1ccc(Cl)c2c1SCCC2(C)C
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(=O)c1cc(C)c2c(c1Cl)C(C)(C)CCS2
Temperature: 0 °C
Yield: 55.8 %

Procedure:
3.2 Grams (24 mmol) of anhydrous aluminum chloride was suspended in 20 ml of methylene chloride, and a solution of 1.9 g (24 mmol) of acetyl chloride in 10 ml of methylene chloride was dropwise added with cooling with ice. The mixture was stirred until the reaction mixture was homogeneous, and a solution of 4.5 g (20 mmol) of 5-chloro-4,4,8-trimethylthiochroman in 10 ml of methylene chloride was added. The mixture was allowed to react at room temperature for 1 hour. After the completion of the reaction, the reaction mixture was poured into ice water and extracted with methylene chloride. An organic layer was washed with a saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate. The methylene chloride was distilled off under reduced pressure, and the resultant oily substance was purified by silica gel column chromatography to give 3.0 g (yield 56%) of 6-acetyl-5-chloro-4,4,8-trimethylthiochroman.
Reaction SMILES: [CH2:1]([OH:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][OH:10].[OH-].[Na+].S(OC)(O[CH3:18])(=O)=O>CS(C)=O.O>[CH3:18][O:11][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][OH:10]
Reactant: COS(=O)(=O)OC
Reactant: OCCCCCCCCCO
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: COCCCCCCCCCO
Temperature: 40 °C
Yield: 21.9 %

Procedure:
a 500-mL, one-necked, round-bottom flask equipped with a magnetic stirrer and stir bar was charged with 1,9-nonanediol (10.00 g, 62.3 mmol) in dimethyl sulfoxide (100 mL) and H2O (100 mL). To this was added slowly a solution of sodium hydroxide (5.0 g, 125.0 mmol) in H2O (10 mL) at room temperature. During addition of sodium hydroxide the reaction mixture generated heat and the temperature rose to ˜40° C. The mixture was stirred for one hour, and then dimethyl sulfate (16.52 g, 131 mmol) was added in four portions while maintaining the temperature of the reaction mixture at ˜40° C. The reaction mixture was stirred at room temperature overnight. Progress of the reaction was monitored by TLC (Note 1). TLC monitoring indicated that the reaction was 25% conversion. At this stage additional dimethyl sulfate (24.78 g, 196.44 mmol) was added and the resulting mixture was stirred at room temperature for an additional 24 h. After completion of the reaction, sodium hydroxide (10% solution in water) was added to the reaction mixture to adjust the pH of the solution to 11-13. The mixture was stirred at room temperature for 2 h and extracted with dichloromethane (3×100 mL). The combined organic layers were washed with H2O (200 mL), brine (150 mL), dried over anhydrous sodium sulfate (20 g), filtered and concentrated in vacuo to obtain a crude product (14 g). The crude product was purified by column chromatography using 250-400 mesh silica gel. A solvent gradient of ethyl acetate in hexanes (10-50%) was used to elute the product from the column. All fractions containing the desired pure product were combined and concentrated in vacuo to give pure 9-methoxy-1-nonanol (lot D-1027-155, 2.38 g, 21.9%). Completion of the reaction was monitored by thin layer chromatography (TLC) using a thin layer silica gel plate; eluent: 60% ethyl acetate in hexanes.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9](=O)[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][N:12]=1.[NH2:22][OH:23].C(N(CC)CC)C.C(O)C>C(OCC)C.C1CCCCC1>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9](=[N:22][OH:23])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][N:12]=1
Reactant: O=C(Cc1ccc(C(F)(F)F)cn1)c1ccc(F)cc1Cl
Reactant: NO
Solvent: C1CCCCC1
Solvent: CCO
Solvent: CCOCC
Product: ON=C(Cc1ccc(C(F)(F)F)cn1)c1ccc(F)cc1Cl
Temperature: 25 °C
Reaction time: 24 h
Yield: 36.1 %

Procedure:
A reaction vessel was charged with 1-(2-chloro-4-fluorophenyl)-2-(5-trifluoromethyl-2-pyridinyl)ethanone (6 g, 18.9 mmol), hydroxylamine (2.63 g, 37.8 mmol), triethylamine (5.3 m 37.8 mmol) and ethanol (60 ml). The reaction mixture was heated to reflux with stirring for 24 hrs. It was then cooled to room temperature, silica gel (about 25 g) was added and the mixture concentrated to dryness. Purification via column chromatography on silica eluting with diethylether-cyclohexane (3:7) and concentration of the appropriate fractions afforded an oil which solidified on standing. Trituration with cyclohexane containing a little diethylether afforded a solid which was removed by filtration and washed with cyclohexane to provide 2.27 g (28%) of the title compound.