Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:19](=[C:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+].[CH2:48]([Cl:50])[Cl:49]>C(O)(=O)C>[NH3:1].[CH2:48]([Cl:50])[Cl:49].[CH:19](=[C:26]1[CH2:31][CH2:30][N:29]([CH2:15][C:14]2[CH:17]=[CH:18][C:11]([O:10][CH2:9][CH2:8][CH2:7][N:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)=[CH:12][CH:13]=2)[CH2:28][CH2:27]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: C(=C1CCNCC1)c1ccccc1
Reactant: O=Cc1ccc(OCCCN2CCCCC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: ClCCl
Product: C(=C1CCN(Cc2ccc(OCCCN3CCCCC3)cc2)CC1)c1ccccc1
Product: N
Reaction time: 16 h

Procedure:
A solution of the product of Example 9 (204 mg), 4-Benzylidene-piperidine (145 mg), and acetic acid (0.05 mL) in DCM (3 mL) was treated with sodium triacetoxyborohydride (300 mg). After 16 h, the resulting mixture was treated with 10% sodium hydroxide (5 mL) and extracted with DCM (3×10 mL). The combined organic phases were dried (magnesium sulfate) and evaporated. Chromatography of the residue (1 to 5% 2 M methanolic ammonia/DCM) gave the title compound as a colorless oil (308 mg). 1H NMR (400 MHz, CDCl3): 7.30 (m, 2H), 7.24-7.16 (m, 4H), 6.84 (m, 2H), 6.26 (s, 1H), 3.99 (t, J=6.3 Hz, 2H), 3.46 (s, 2H), 2.54-2.44 (m, 6H), 2.43-2.35 (m, 6H), 1.97 (m, 2H), 1.74 (br, 1H), 1.63-1.56 (m, 4H), 1.47-1.40 (m, 2H).
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH2:4][S:5][C@@H:6]2[C@H:26]([NH:27][C:28](=[O:35])[CH2:29][C:30]3[S:31][CH:32]=[CH:33][CH:34]=3)[C:25](=[O:36])[N:7]2[C:8]=1[C:9]([O:11][CH:12]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10].[CH2:37]([P:41]([CH2:46][CH2:47][CH2:48][CH3:49])[CH2:42][CH2:43][CH2:44][CH3:45])[CH2:38][CH2:39][CH3:40].C(Cl)(Cl)Cl>C(OCC)(=O)C>[Br-:1].[C:13]1([CH:12]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[O:11][C:9]([C:8]2[N:7]3[C:25](=[O:36])[C@@H:26]([NH:27][C:28](=[O:35])[CH2:29][C:30]4[S:31][CH:32]=[CH:33][CH:34]=4)[C@H:6]3[S:5][CH2:4][C:3]=2[CH2:2][P+:41]([CH2:42][CH2:43][CH2:44][CH3:45])([CH2:46][CH2:47][CH2:48][CH3:49])[CH2:37][CH2:38][CH2:39][CH3:40])=[O:10])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(Cc1cccs1)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CBr)CS[C@H]12
Reactant: CCCCP(CCCC)CCCC
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: CCCC[P+](CCCC)(CCCC)CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](NC(=O)Cc3cccs3)[C@H]2SC1
Product: [Br-]

Procedure:
A solution of diphenylmethyl 3-bromomethyl-7β-(2-thienylacetamido)ceph-3-em-4-carboxylate (583 mg.) in ethyl acetate (5 ml.) was treated with a solution of tri-n-butylphosphine (0.3 ml., ca. 2 equivalents) in ethyl acetate (2 ml.). After 10 minutes at room temperature the mixture was diluted with petroleum ether to give the phosphonium salt (690 ml.) as an amorphous solid, m.p. 65° - 70° [α]D23 - 35° (c 1.0 CHCl3), inflexion at 237 nm. (ε 12,460) and 258 nm. (ε 6,550), νmax 1770 (β-lactam), 1702 (CO2R), 1670 and 1530 (CONH) and 693 (phenyl) cm.-1 ; τ (CDCl3) 4.22 (C(7) -H dd, J 4.5, 9 Hz.), 4.93 (C(6) -H, d, J 4.5 Hz.), 5.5 to 6.1 (C(2) -CH2 and =C--CH2P+, unresolved m), 7.62 (P+CH2CHCH2CH3, m), 8.55 (P+CH2CH2CH2CH3, m) and 9.1 (P+CH2CH2CH2CH3, d, J 6 Hz.).
Reaction SMILES: [O:1]=[C:2]([CH3:9])[CH2:3][CH2:4][CH2:5][C:6](O)=[O:7].S(Cl)([Cl:12])=O>>[O:1]=[C:2]([CH3:9])[CH2:3][CH2:4][CH2:5][C:6]([Cl:12])=[O:7]
Reactant: O=S(Cl)Cl
Reactant: CC(=O)CCCC(=O)O
Product: CC(=O)CCCC(=O)Cl
Yield: 41.7 %

Procedure:
A mixture of 5.50 g of 5-ketohexanoic acid commercially available from Aldrich Chemical Co., Milwaukee, Wisconsin, and 8.83 g of thionyl chloride was stirred for 16 hours at 25° C. under argon. The reaction mixture was distilled to produce 2.62 g of the hexanoylchloride as a light-yellow oil; bp 99°-104° C. (aspirator vacuum), which was contaminated with about 60% of 4-chloro-5-ketohexanoyl chloride. The material had the following spectral chracteristics: nmr δ 1.90 (s, 3, COCH3), 2.0 (s, 3, CHClCOCH3), 5.10 (broad t, 1, CHClCOCH3); no signal for CO2H observed; IR λ max 5.70, 7.50, 8.10, 8.70, 9.45μ.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([OH:12])[C:6](=[CH:10][CH:11]=1)[C:7]([OH:9])=O.[C:13](Cl)(=[O:17])[O:14][CH2:15][CH3:16].[NH2:19][CH2:20][CH2:21][SH:22].Cl>C(Cl)Cl.C(N(CC)CC)C>[CH2:15]([O:14][C:13]([O:12][C:5]1[CH:4]=[C:3]([O:2][CH3:1])[CH:11]=[CH:10][C:6]=1[C:7]([NH:19][CH2:20][CH2:21][SH:22])=[O:9])=[O:17])[CH3:16]
Reactant: COc1ccc(C(=O)O)c(O)c1
Reactant: NCCS
Reactant: CCOC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)Oc1cc(OC)ccc1C(=O)NCCS
Temperature: -15 °C
Reaction time: 1.5 h
Yield: 89 %

Procedure:
Under argon atmosphere, 2.84 g of 4-methoxysalicylic acid was dispersed in 45 ml of methylene chloride, and the dispersion was cooled to -15° C. To the dispersion was added 3.76 g of triethylamine and 3.77 g of ethyl chlorocarbonate, and the mixture was agitated for 1.5 hour. To the mixture was added a solution of 1.56 g of cysteamine in 5 ml of methylene chloride, and the mixture was agitated at -15° C. for 2 hours. The reaction mixture was poured into 1N aqueous hydrochloric acid, and extracted with methylene chloride. The organic layer was washed with saturated aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate. The solvent was distilled off in evacuated atomosphere, and the residue was subjected to column chromatography using silica gel. There was obtained 4.50 g of N-(2-ethoxycarbonyloxy-4-methoxybenzoyl)cysteamine.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH2:8][CH3:9])[CH:5]=[CH:4][C:3]=1[F:10].C([Li])CCC.CCCCCC.C[O:23][B:24](OC)[O:25]C>C1COCC1>[CH2:8]([C:6]1[CH:5]=[CH:4][C:3]([F:10])=[C:2]([B:24]([OH:25])[OH:23])[CH:7]=1)[CH3:9]
Reactant: COB(OC)OC
Reactant: CCc1ccc(F)c(Br)c1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCc1ccc(F)c(B(O)O)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 66 %

Procedure:
To 84B (550 mg, 2.3 mmol) in THF (10 mL) was added 1.6 M n-butyllithium in hexane (2.2 ml, 3.5 mmol) at −78° C. After stirring for 1 h, trimethylborate (0.52 mL, 4.6 mmol) was introduced at −78° C. The reaction mixture was warmed up to rt overnight. It was then quenched by 1.0 N HCl (10 mL) and extracted with EtOAc (3×30 mL). The combined organic layers were washed with brine, dried over MgSO4, and concentrated. The crude product was purified by column chromatography to give 255 mg white solid of 84C. 1H NMR (400 MHz, Methanol-d4) δ ppm 1.15-1.27 (m, 3H) 2.61 (q, J=7.76 Hz, 2H) 6.94 (t, J=8.57 Hz, 1H) 7.17-7.27 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH2:8][C:9]([C:12]2[O:13][CH:14]=[CH:15][C:16]=2[CH3:17])=[N:10]O)[CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O.C(N(CC)CC)C>COCCOC.[Fe](Cl)Cl>[Cl:1][C:2]1[N:7]2[N:10]=[C:9]([C:12]3[O:13][CH:14]=[CH:15][C:16]=3[CH3:17])[CH:8]=[C:6]2[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccoc1C(Cc1cccc(Cl)n1)=NO
Agent: Cl[Fe]Cl
Solvent: CCN(CC)CC
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: COCCOC
Product: Cc1ccoc1-c1cc2cccc(Cl)n2n1
Temperature: 15 °C
Reaction time: 2 h
Yield: 64.2 %

Procedure:
To a solution of 2-(6-chloro-2-pyridinyl)-1-(3-methyl-2-furyl)ethanone oxime (24.5 g, 97.7 mmol) in 1,2-dimethoxyethane (200 mL) at 0° C. was added trifluoroacetic anhydride (14.5 mL, 103 mmol), while keeping the temperature below 10° C. After the addition was complete, the reaction was warmed to 15° C. The solution was then cooled to 0–5° C. and a solution of triethylamine (28.6 mL, 205 mmol) in 1,2-dimethoxyethane (30 mL) was added over 0.5 hours. The reaction mixture was allowed to warm to room temperature and was stirred for 2 hours. To this mixture was added iron(II) chloride (0.62 g, 4.9 mmol) and the reaction was heated at 75° C. for 15 hours. The reaction was concentrated, then ethyl acetate and water were added. The organic phase was separated, washed with water, dried (magnesium sulfate), filtered and concentrated. Purification by silica gel chromatography (9:1 hexanes:ethyl acetate) gave 7-chloro-2-(3-methyl-2-furyl)pyrazolo[1,5-a]pyridine (14.6 g, 640%) as yellow oil. 1H NMR (CDCl3): δ 7.52 (d, 1H), 7.48 (d, 1H), 7.10 (t, 1H), 6.92 (d, 1H), 6.86 (s, 1H), 6.42 (d, 1H), 2.49 (s, 3H). MS m/233 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](Cl)[C:3]=1[Cl:9].[CH3:10][O-:11].[Na+]>CC(N(C)C)=O.CO.O>[Cl:9][C:3]1[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=1[O:11][CH3:10]
Reactant: Clc1cccc(Cl)c1Cl
Reactant: C[O-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Solvent: CO
Product: COc1cccc(Cl)c1Cl

Procedure:
363 g (1 mole) of 1,2,3-trichlorobenzene is dissolved in 600 ml dimethyl acetamide and heated to 125° with stirring. 500 ml of 25% commercial sodium methoxide in methanol is then added at such a rate that the temperature is maintained at 125°-130°. After addition is complete the temperature is maintained at 130° for 30 minutes. The mixture is diluted with water and extracted with toluene. The toluene extracts are washed with brine, dried and the toluene removed by distillation. The residue is fractionated to yield 200 g of the desired isomer 2,3-dichloroanisole bp 140°/29 mm. By appropriate fractionation the minor isomer 2,3-dichloroanisole may also be obtained.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH3:12])=[C:4]([NH2:13])[N:3]=1.[NH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1>O>[N:14]1([C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]([CH3:12])=[C:4]([NH2:13])[N:3]=2)[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1
Reactant: C1COCCN1
Reactant: Cc1c(N)nc(Br)c2ccccc12
Solvent: O
Product: Cc1c(N)nc(N2CCOCC2)c2ccccc12
Yield: 83 %

Procedure:
A mixture of 12 g (0.051 mole) of 1-bromo-3-amino-4-methylisoquinoline and 120 ml of morpholine is refluxed for 6 hours, then diluted with water. 8.5 g (83%) of 1-morpholinyl-3-amino-4-methylisoquinoline are obtained.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH3:19])[CH2:14][CH2:13]2)[C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[C:20](=[O:23])([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.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>[ClH:1].[CH2:18]([N:15]1[CH2:16][CH2:17][N:12]([C:4]2[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:11]=[C:2]([C:5]3[CH:10]=[CH:9][C:8]([CH2:20][OH:23])=[CH:7][CH:6]=3)[N:3]=2)[CH2:13][CH2:14]1)[CH3:19]
Reactant: O=C([O-])[O-]
Reactant: CCN1CCN(c2nc(Cl)cc3ccccc23)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCN1CCN(c2nc(-c3ccc(CO)cc3)cc3ccccc23)CC1
Product: Cl
Yield: 191.3 %

Procedure:
3-Chloro-1-(4-ethylpiperazin-1-yl)isoquinoline (3.5 g) and 4-(1,3,2-dioxaborynan-2-yl)-1-(1,3-dioxolan-2-yl)benzene (5.0 g) were reacted in dimethylformamide (50 ml), in the presence of cesium carbonate (7.3 g) and tetrakistriphenylphosphinepalladium (0.3 g) at 80° C. in a nitrogen stream for 12 hr. The reaction solution was evaporated, and then partitioned between ethyl acetate and water. The resulting organic layer was washed with water, dried and evaporated. The resulting residue was purified by silica gel column chromatography (methylene chloride/methanol system), to give 4.66 g of the title compound as a pale yellow oil.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[C:9]([CH:10]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:8][CH:7]=[C:6]([N+:23]([O-:25])=[O:24])[N:5]=1.[CH3:26]I>CN(C=O)C>[CH3:26][C:10]([C:9]1[C:4]([CH3:3])=[N:5][C:6]([N+:23]([O-:25])=[O:24])=[CH:7][CH:8]=1)([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:11]([O:13][C:14]([CH3:15])([CH3:16])[CH3:17])=[O:12]
Reactant: CCOC(=O)C(C(=O)OC(C)(C)C)c1ccc([N+](=O)[O-])nc1C
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C(=O)OC(C)(C)C)c1ccc([N+](=O)[O-])nc1C
Temperature: 40 °C
Reaction time: 1 h

Procedure:
To a suspension of NaH (60% in oil, 0.8 g, 19 mmol) in DMF (50 mL) was added tert-butyl ethyl (2-methyl-6-nitropyridin-3-yl)propanedioate (4 g, 13 mmol) at room temperature. The mixture was stirred for 1 hour and CH3I (3.7 g, 26 mmol) was added. The mixture was heated to 40° C. for 2 hours. Cooled to ambient temperature, the mixture was poured to ice/water, extracted with EtOAc. The combined organic layer was washed with brine, dried over anhydrous Na2SO4, concentrated and the residue was purified by column chromatograph silica gel to give title compound.
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][S:7][C:8]1[CH2:14][C@H:13]2[N:10]([C:11](=[O:32])[C@@H:12]2[C:15]([CH3:31])([O:17]C(OCC2C=CC([N+]([O-])=O)=CC=2)=O)[CH3:16])[C:9]=1[C:33]([O:35]CC1C=CC([N+]([O-])=O)=CC=1)=[O:34])(=[O:3])[CH3:2].C(=O)([O-])O.[Na+:50]>O.O1CCOCC1.[Pd]>[C:1]([NH:4][CH2:5][CH2:6][S:7][C:8]1[CH2:14][C@H:13]2[N:10]([C:11](=[O:32])[C@@H:12]2[C:15]([OH:17])([CH3:16])[CH3:31])[C:9]=1[C:33]([O-:35])=[O:34])(=[O:3])[CH3:2].[Na+:50]
Reactant: CC(=O)NCCSC1=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)[C@H](C(C)(C)OC(=O)OCc3ccc([N+](=O)[O-])cc3)[C@H]2C1
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC(=O)NCCSC1=C(C(=O)[O-])N2C(=O)[C@H](C(C)(C)O)[C@H]2C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 5% palladium-charcoal (40.0 mg), water (0.96 ml) and dioxane (2.24 ml) was shaken for 30 minutes under hydrogen atmosphere (40 psi) at ambient temperature. The mixture was added to a solution of 4-nitrobenzyl(5R,6S)-3-(2-acetamido-ethylthio)-6-[1-methyl-1-(4-nitrobenzyloxycarbonyloxy)-ethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (40.0 mg) in a mixture of water (0.24 ml) and dioxane (0.56 ml), and shaken for 2 hours under hydrogen atmosphere (40 psi) at ambient temperature. The resulting mixture was added with 1% aqueous sodium hydrogen carbonate (0.522 ml) at 0° C. and filtered by using diatomaceous earth. The filtered cake was washed with water (3×5 ml) and the combined filtrates were concentrated, washed with ethyl acetate (3×20 ml) and evaporated in vacuo. The residue was dissolved in water (25 ml) containing sodium chloride (0.7 g) and chromatographed on a non ionic adsorption resin HP-20 (trademark, made by Mitsubishi Chemical Industries) (1.0×20 cm) eluting with a mixture of water and acetone (100:0 to 7:3, 200 ml). The fractions containing the product were combined and lyophilized to give sodium (5R,6S)-3-(2-acetamido-ethylthio)-6-(1-hydroxy-1-methylethyl)-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (6.9 mg) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.Cl.[CH3:13]O>>[CH3:13][O:10][C:9](=[O:11])[CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=1
Reactant: O=C(O)Cc1cccc(Br)c1
Reactant: CO
Agent: Cl
Product: COC(=O)Cc1cccc(Br)c1
Temperature: 58 °C
Yield: 96 %

Procedure:
3-bromophenylacetic acid (10000 mg, 46.50 mmol) was dissolved in methanol (200 mL) at room temperature and concentrated hydrochloric acid (4 mL) was added. The resulting solution was heated at 58° C. for 2 h then cooled to room temperature at which time the volatiles were removed in vacuo. The crude material was dissolved in ethyl acetate and the solution was carefully poured into a saturated aqueous sodium bicarbonate solution. The phases were separated and the combined organic extracts were dried over magnesium sulfate and concentrated under reduced pressure. The crude product was purified by MPLC (Biotage) with a gradient of 4 to 35%AcOEt/hexanes to give (3-bromo-phenyl)-acetic acid methyl ester as a colorless oil (10250 mg, 96%). GC-MS (MH+230 RT=9.34 min).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C@H:11]2[CH2:16][CH2:15][C@H:14]([O:17][CH2:18][C:19]([N:21]3[CH2:26][CH2:25][N:24]([C:27]4[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=4)[CH2:23][CH2:22]3)=[O:20])[CH2:13][CH2:12]2)=[CH:6][C:5]=1[C:37]([F:40])([F:39])[F:38])([O-:3])=[O:2].[H-].[Na+].[CH3:43]I>O1CCCC1>[CH3:43][N:10]([C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[C:5]([C:37]([F:40])([F:39])[F:38])[CH:6]=1)[C@H:11]1[CH2:16][CH2:15][C@H:14]([O:17][CH2:18][C:19]([N:21]2[CH2:22][CH2:23][N:24]([C:27]3[CH:32]=[CH:31][C:30]([C:33]([F:34])([F:35])[F:36])=[CH:29][CH:28]=3)[CH2:25][CH2:26]2)=[O:20])[CH2:13][CH2:12]1
Reactant: CI
Reactant: O=C(CO[C@H]1CC[C@H](Nc2ccc([N+](=O)[O-])c(C(F)(F)F)c2)CC1)N1CCN(c2ccc(C(F)(F)F)cc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(c1ccc([N+](=O)[O-])c(C(F)(F)F)c1)[C@H]1CC[C@H](OCC(=O)N2CCN(c3ccc(C(F)(F)F)cc3)CC2)CC1

Procedure:
2-[Trans-4-(4-nitro-3-trifluoromethyl-phenylamino)-cyclohexyloxy]-1-[4-(4-trifluoromethyl-phenyl)-piperazin-1-yl]-ethanone (172 mg, 0.30 mmol, prepared in accordance with Example 11) and sodium hydride (12 mg, 0.30 mmol) were placed under an inert atmosphere. Dry tetrahydrofuran (3 mL) was then added. After gas evolution ceased, methyl iodide (20 μL, 0.31 mmol) was added under stirring to the dark orange colored solution. The resulting mixture was stirred at room temperature. After an hour, HPLC-MS monitoring of the reaction showed about 75% conversion to the desired product. More methyl iodide was added (5 μL, 0.08 mmol), and the mixture was stirred for an additional 30 min. HPLC-MS showed 85% conversion. The mixture was quenched with saturated aqueous ammonium chloride (10 mL) and extracted with ethyl acetate (25 mL). The organic layer was separated, washed with water (10 mL), dried over magnesium sulfate, filtered, and concentrated under vacuum. A yellow oil was isolated. The oil was purified by preparative HPLC. Following lyophilization of the fractions of interest, the desired product was isolated as a yellow solid (106 mg, 59% yield). The structure was confirmed using Protocol I-A. Calculated mass=589; observed mass=589; HPLC retention time=4.69 min.
Reaction SMILES: [CH3:1]S(C)(=O)=C.CO[CH:8](OC)[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:10].C[CH2:20][O:21]CC>CS(C)=O.O>[CH3:20][O:21][C:15]1[CH:16]=[C:11]([CH:12]=[CH:13][CH:14]=1)[C:9]1([CH3:8])[O:10][CH2:1]1
Reactant: CCOCC
Reactant: C=S(C)(C)=O
Reactant: COC(OC)C(=O)c1ccccc1
Solvent: CS(C)=O
Solvent: O
Product: COc1cccc(C2(C)CO2)c1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
To a solution of dimethylsulfoxonium methylide (69.4 mmoles) in dimethyl sulfoxide (65 ml.) at room temperature is added solid 3-l -dimethoxyacetophenone (8.33 g., 55.5 mmoles). The reaction mixture is stirred for one hour at 25° C., for one-half hour at 50° C. and is then cooled. The mixture is diluted with water (50 ml.) and added to a mixture of ice water (200 ml.)--ether (250 ml.)--low boiling petroleum ether (25 ml.). The organic extract is washed twice with water (250 ml.), dried (MgSO4) and evaporated to an oil which is fractionally distilled.
Reaction SMILES: [CH:1]([NH:4][CH:5]([CH3:7])[CH3:6])([CH3:3])[CH3:2].C([Li:12])CCC.Br[CH2:14][CH2:15][CH:16]([CH2:21][C:22]([CH3:46])=[CH:23][CH2:24][C:25]1[C:26]([O:38][Si:39]([C:42]([CH3:45])([CH3:44])[CH3:43])([CH3:41])[CH3:40])=[C:27]2[C:31](=[C:32]([CH3:36])[C:33]=1[O:34][CH3:35])[CH2:30][O:29][C:28]2=[O:37])[C:17]([O:19][CH3:20])=[O:18].[Li+].CC([N-]C(C)C)C>C1COCC1>[CH:1]([N-:4][CH:5]([CH3:7])[CH3:6])([CH3:3])[CH3:2].[Li+:12].[CH3:20][O:19][C:17]([C:16]1([CH2:21][C:22]([CH3:46])=[CH:23][CH2:24][C:25]2[C:26]([O:38][Si:39]([C:42]([CH3:45])([CH3:43])[CH3:44])([CH3:41])[CH3:40])=[C:27]3[C:31](=[C:32]([CH3:36])[C:33]=2[O:34][CH3:35])[CH2:30][O:29][C:28]3=[O:37])[CH2:14][CH2:15]1)=[O:18]
Reactant: CC(C)NC(C)C
Reactant: [Li]CCCC
Reactant: COC(=O)C(CCBr)CC(C)=CCc1c(OC)c(C)c2c(c1O[Si](C)(C)C(C)(C)C)C(=O)OC2
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)C1(CC(C)=CCc2c(OC)c(C)c3c(c2O[Si](C)(C)C(C)(C)C)C(=O)OC3)CC1
Temperature: -70 °C
Reaction time: 0.83 h

Procedure:
A solution of lithium diisopropyl amide was prepared from diisopropyl amine (2.24 ml) and n-butyllithium (6.4 ml, 2.5N) in THF (60 ml) and cooled to -70° C. Methyl 2-(2-bromoethyl)-6-(4-t-butyldimethylsiloxy-1,3-dihydro-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl)-4-methyl-hex-4-enoate (2.66 g) in THF (12 ml was added to the LDA solution over 2 min. The reaction mixture was stirred for 50 min at -65° C. to -50° C. and quenched in water. Extraction with ethyl acetate and flash chromatography (silica gel, 20-30% ethyl acetate/hexane) gave 1-[4-(4-t-butyldimethylsiloxy-1,3-dihydro-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl)-2-methyl-but-2-enyl]cyclopropane carboxylic acid methyl ester (1.34 g).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1.[CH:12]1([NH2:15])[CH2:14][CH2:13]1.O>CO>[CH:12]1([NH:15][CH2:2][CH2:3][CH2:4][O:5][C:6]2[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=2)[CH2:14][CH2:13]1
Reactant: NC1CC1
Reactant: ClCCCOc1cccnc1
Solvent: CO
Solvent: O
Product: c1cncc(OCCCNC2CC2)c1
Temperature: 120 °C
Yield: 29.3 %

Procedure:
An Ace Glass pressure tube (185 mL) was charged with 3-chloro-1-(3-pyridyloxy)propane (0.762 g, 4.437 mmol), cyclopropylamine (8.24 g, 194.3 mmol), water (20 mL) and methanol (20 mL). The resulting light-brown solution was heated at 120° C. (oil bath temperature) for 2.5 h and allowed to cool to ambient temperature over 16 h. The solution was concentrated by rotary evaporation to an oily residue that was diluted with saturated NaCl solution (25 mL). The mixture was acidified to pH 1.0 with 10% HCl solution and extracted with CHC3 (2×35 mL) to remove impurities. The aqueous phase was basified to pH 6 with 100% NaOH solution and extracted (4×25 mL) to remove other impurities. The aqueous phase was basified to pH 10 with 100% NaOH solution and extracted with CHCl3 (4×50 mL). The combined CHCl3 extracts were dried (Na2SO4), filtered, concentrated (rotary evaporator) and briefly dried under high vacuum to give 0.250 g of a brown oil. The oil was purified by column chromatography on silica gel (20 g) eluting with CHCl3—CH3OH (100:2) to remove impurities, followed by CHCl3—CH3OH—Et3N (50:50:2) to remove the product. Selected fractions were combined to give 220 mg (25.8%) of a brown semi-solid.
Reaction SMILES: [CH:1]1([C:11]([OH:13])=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[NH2:14][C:15]1[CH:16]=[CH:17][C:18]([CH:21]([CH3:23])[CH3:22])=[N:19][CH:20]=1>>[CH:21]([C:18]1[N:19]=[CH:20][C:15]([NH:14][C:11]([CH:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH2:4][CH2:3][CH2:2]2)=[O:13])=[CH:16][CH:17]=1)([CH3:23])[CH3:22]
Reactant: O=C(O)C1CCCc2ccccc21
Reactant: CC(C)c1ccc(N)cn1
Product: CC(C)c1ccc(NC(=O)C2CCCc3ccccc32)cn1
Yield: 86.4 %

Procedure:
By the reaction and treatment in the same manner as in Preparation Example 11 using 1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (1.51 g) and 5-amino-2-isopropylpyridine (1.17 g) as starting materials, N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (2.18 g) was obtained. melting point: 155.7° C.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[N:8]2[CH:9]=[N:10][C:11]([C:12]#[N:13])=[C:7]2[N:6]=[C:5]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:4]=1.Cl.[NH2:27][OH:28].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[OH:28][NH:27][C:12]([C:11]1[N:10]=[CH:9][N:8]2[C:3]([C:2]([F:24])([F:1])[F:25])=[CH:4][C:5]([C:14]3[CH:15]=[CH:16][C:17]([C:20]([F:23])([F:21])[F:22])=[CH:18][CH:19]=3)=[N:6][C:7]=12)=[NH:13]
Reactant: N#Cc1ncn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: N=C(NO)c1ncn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Yield: 20.3 %

Procedure:
A stirred mixture of 4-trifluoromethyl-2-(4-trifluoromethyl-phenyl)-imidazo[1,5-a]pyrimidine-8-carbonitrile [CAS-No. 851263-42-8] 1.16 g, 3.26 mmol), hydroxylamine hydrochloride (0.46 g, 6.62 mmol) and potassium carbonate (1.35 g, 9.77 mmol) in ethanol (50 ml) was heated under reflux conditions for 3 h. The precipitate was collected by filtration and washed with ethanol, the combined filtrates were evaporated and the crude product purified by column chromatography on silica gel (ethyl acetate/ethanol 95:5) and crystallization from diethyl ether/hexane to yield the title compound (257 mg, 20%) as a red solid. MS (ISN) 388.2 [(M−H)−]; mp 213° C.