Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:9]1[C:10](OCC)=[C:11]2[CH:17]=[N:16][N:15]([CH2:18][C:19]3[O:20][CH:21]=[CH:22][CH:23]=3)[C:12]2=[N:13][CH:14]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:27]([NH2:31])([CH2:29][CH3:30])[CH3:28]>>[C:1]([C:9]1[C:10]([NH:31][CH:27]([CH2:29][CH3:30])[CH3:28])=[C:11]2[CH:17]=[N:16][N:15]([CH2:18][C:19]3[O:20][CH:21]=[CH:22][CH:23]=3)[C:12]2=[N:13][CH:14]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOc1c(C(=O)c2ccccc2)cnc2c1cnn2Cc1ccco1
Reactant: CCC(C)N
Product: CCC(C)Nc1c(C(=O)c2ccccc2)cnc2c1cnn2Cc1ccco1

Procedure:
34.7 g. of 5-benzoyl-4-ethoxy-1-(2-furanyl)methyl-1H-pyrazolo[3,4-b]pyridine (0.1 mol.) is refluxed for 10 hours with 50 ml. of sec. butylamine. The excess amine is removed in vacuo and the residue recrystallized from methanol to obtain 5-benzoyl-4-sec.butylamino-1-(2-furanyl)methyl-1H-pyrazolo[3,4-b]pyridine, yield 31 g. (83%), m.p. 112°-114° (methanol).
Reaction SMILES: [H][H].[N+:3]([C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH:13]2[C:18](=[O:19])[CH:17]=[CH:16][CH2:15][C:14]2([CH3:21])[CH3:20])=[CH:8][CH:7]=1)([O-:5])=[O:4]>C1C=CC=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl-].[Rh]>[N+:3]([C:6]1[CH:7]=[CH:8][C:9]([CH2:12][CH:13]2[C:14]([CH3:20])([CH3:21])[CH2:15][CH2:16][CH2:17][C:18]2=[O:19])=[CH:10][CH:11]=1)([O-:5])=[O:4]
Reactant: CC1(C)CC=CC(=O)C1Cc1ccc([N+](=O)[O-])cc1
Reactant: [H][H]
Agent: [Rh]
Agent: [Cl-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Product: CC1(C)CCCC(=O)C1Cc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 48.2 %

Procedure:
An atmosphere of hydrogen was introduced to and maintained by a balloon to an evacuated 50 mL round-bottomed flask containing 6-(4'-nitrophenyl)methyl-5,5-dimethylcyclohex-2-en-1-one (39) (14.0 mg, mmol) and tris(triphenylphosphine)rhodium chloride (Wilkinson's catalyst) (8.0 mg) in 6.5 mL anhydrous benzene. The yellow-orange solution was stirred at room temperature for 24 h, and then passed through a short silica gel column (hexanes/ethyl acetate, 3:1) to afford the 6.8 mg (48%) of the desired ketone as a pale yellow oil (Rf0.43, 2:1 hexanes lethyl acetate). 1H NMR (400MHz, CDCl3) δ0.86 and 1.23 (2s, 2×3H, geminal-CH3 's), 2.50 (d, 1H, J=13.0 Hz, 2-H), 2.66 and 3.17 (d of ABq, 2H, JAB =13.0 Hz, JA =1.6 Hz, JB =9.6 Hz, benzylic-CH2), 7.37 (d, 2H, J=9.6 Hz, 2', 6'-H), 8.09 ppm (d, 2H, J=9.6 Hz, 3',5'-H). [Compound 40 is hereinafter also referred to as COMPOUND "V" or 120211]
Reaction SMILES: C([O:5][C:6](=[O:41])[CH2:7][N:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[CH2:12][CH2:11][C@H:10]([NH:19][C:20]([C:22]2([CH2:27][CH:28]([CH2:32][C:33]([NH:35][CH2:36][CH2:37][CH2:38][OH:39])=[O:34])[C:29]([O-:31])=[O:30])[CH2:26][CH2:25][CH2:24][CH2:23]2)=[O:21])[C:9]1=[O:40])(C)(C)C.[OH-].[Na+]>O.C(O)C>[C:6]([CH2:7][N:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[CH2:12][CH2:11][C@H:10]([NH:19][C:20]([C:22]2([CH2:27][CH:28]([CH2:32][C:33]([NH:35][CH2:36][CH2:37][CH2:38][OH:39])=[O:34])[C:29]([OH:31])=[O:30])[CH2:26][CH2:25][CH2:24][CH2:23]2)=[O:21])[C:9]1=[O:40])([OH:41])=[O:5]
Reactant: CC(C)(C)OC(=O)CN1C(=O)[C@@H](NC(=O)C2(CC(CC(=O)NCCCO)C(=O)[O-])CCCC2)CCc2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)CN1C(=O)[C@@H](NC(=O)C2(CC(CC(=O)NCCCO)C(=O)O)CCCC2)CCc2ccccc21
Reaction time: 15 h

Procedure:
6.43 g ethyl (2“rel1”)-2-{[1-({[(3S)-1-(2-tert. butoxy-2-oxoethyl)-2-oxo-2,3,4,5-tetrahydro-1H-1-benzazepin-3-yl]amino}carbonyl)cyclopentyl]methyl}-4-[(3-hydroxypropyl)amino]-4-oxobutyrate (for preparation see Example 5) was dissolved in 140 ml of a 1:1 (v/v) mixture of water and ethanol, and 4.28 g solid NaOH was added thereto with stirring. After 15 h, the solvent was evaporated at reduced pressure, the residue was taken up in 100 ml EA and washed once with 50 ml aqueous KHSO4 solution. The aqueous phase was extracted twice with 30 ml EA each time. The combined organic phases were washed twice with 30 ml aqueous common salt solution each time and dried over sodium sulfate. Evaporation of the solvent yielded 5.41 g of the title compound.
Reaction SMILES: [O:1]=[C:2]([N:12]1[CH2:17][CH2:16][C:15]2([CH2:26][C:25]3[C:20](=[N:21][CH:22]=[C:23](/[CH:27]=[CH:28]/[C:29](=[O:42])[N:30]4[CH2:35][CH2:34][C:33]([CH2:36][C:37]5[S:38][CH:39]=[CH:40][N:41]=5)=[CH:32][CH2:31]4)[CH:24]=3)[NH:19][C:18]2=[O:43])[CH2:14][CH2:13]1)[CH2:3][NH:4]C(=O)OC(C)(C)C.[ClH:44]>O1CCOCC1.CCOCC>[ClH:44].[NH2:4][CH2:3][C:2]([N:12]1[CH2:13][CH2:14][C:15]2([CH2:26][C:25]3[C:20](=[N:21][CH:22]=[C:23](/[CH:27]=[CH:28]/[C:29](=[O:42])[N:30]4[CH2:35][CH2:34][C:33]([CH2:36][C:37]5[S:38][CH:39]=[CH:40][N:41]=5)=[CH:32][CH2:31]4)[CH:24]=3)[NH:19][C:18]2=[O:43])[CH2:16][CH2:17]1)=[O:1]
Reactant: CC(C)(C)OC(=O)NCC(=O)N1CCC2(CC1)Cc1cc(/C=C/C(=O)N3CC=C(Cc4nccs4)CC3)cnc1NC2=O
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: NCC(=O)N1CCC2(CC1)Cc1cc(/C=C/C(=O)N3CC=C(Cc4nccs4)CC3)cnc1NC2=O
Temperature: 27.5 °C
Reaction time: 3 h

Procedure:
To a stirred solution of (E)-tert-butyl (2-oxo-2-(2-oxo-6-(3-oxo-3-(4-(thiazol-2-ylmethyl)-5,6-dihydropyridin-1(2H)-yl)prop-1-en-1-yl)-2,4-dihydro-1Hspiro[[1,8]naphthyridine-3,4′-piperidin]-1′-yl)ethyl)carbamate (41.1) (20 mg, 0.03 mmol) in 1,4-dioxane (1 mL) was added 2M HCl in ether (0.24 mL) drop wise at 0° C. and the reaction mixture was allowed to stir at 20-35° C. for 3 h. Then the reaction mixture was rotary evaporated under vacuum to get residue which was triturated with diethyl ether to get the desired compound as a brown solid (20 mg); 1H NMR (400 MHz, DMSO-d6) δ 10.79 (s, 1H), 8.41 (d, J=2.0 Hz, 1H), 8.09 (s, 1H), 8.08-8.00 (m, 3H), 7.71 (d, J=3.4 Hz, 1H), 7.61 (d, J=3.4 Hz, 1H), 7.46 (d, J=15.2 Hz, 1H), 7.28-7.14 (m, 1H), 5.68-5.65 (m, 1H), 4.26-4.18 (m, 1H), 4.08-4.02 (m, 1H), 3.92-3.80 (m, 4H), 3.80-3.72 (m, 3H), 3.68-3.60 (m, 1H), 3.54-3.40 (m, 2H), 2.98 (s, 2H), 2.20-2.04 (m, 2H), 1.92-1.83 (m, 1H), 1.82-1.68 (m, 1H), 1.48-1.32 (m, 2H); ES-MS: 507.3 (M+1)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH:25]([CH3:28])[C:26]#[N:27])[O:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.[N-:29]=[N+:30]=[N-:31].[Na+].Cl.C(N(CC)CC)C>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH:25]([C:26]3[NH:31][N:30]=[N:29][N:27]=3)[CH3:28])[O:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)=[CH:6][CH:7]=1
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C#N)CCCCCc1nc(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2)o1
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(CCCCCc1nc(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2)o1)c1nnn[nH]1
Yield: 55 %

Procedure:
4.45 g of (RS)-7-[4,5-bis(4-chlorophenyl)-2-oxazolyl]-2-methylheptanenitrile in 40 cm3 of dimethylformamide are treated with twice 2.1 g of sodium azide and twice 4.4 g of triethylamine hydrochloride under the (time and temperature) conditions defined in Example 1. After treatment, the product of the reaction is chromatographed on a column 2.8 cm in diameter containing 115 g of silica gel (50 to 200μ). The column is eluted with 1.2 liters of diisopropyl ether and then with 2.8 liters of a diisopropyl ether/ethyl acetate (80:20 by volume) mixture, collecting 200 cm3 fractions. The fractions from the last eluent mixture are concentrated to dryness under reduced pressure (0.2 kPa). 2.7 g (55%) of (RS)-5-{7-[4,5-bis(4-chlorophenyl)-2-oxazolyl]-2-heptyl}-1H-tetrazole are obtained in the form of white crystals, melting point 144° C.
Reaction SMILES: [CH:1]1([N:5]2[CH2:10][CH2:9][N:8]([C:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[NH:18][C:17]([C:22]([N:24]3[CH2:29][CH2:28][C:27]([F:31])([F:30])[CH2:26][CH2:25]3)=[O:23])=[CH:16]4)=[O:12])[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.[H-].[Na+].CS(O[CH2:39][C:40]([F:43])([F:42])[F:41])(=O)=O>CN(C)C=O>[CH:1]1([N:5]2[CH2:6][CH2:7][N:8]([C:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[N:18]([CH2:39][C:40]([F:43])([F:42])[F:41])[C:17]([C:22]([N:24]3[CH2:25][CH2:26][C:27]([F:30])([F:31])[CH2:28][CH2:29]3)=[O:23])=[CH:16]4)=[O:12])[CH2:9][CH2:10]2)[CH2:2][CH2:3][CH2:4]1
Reactant: CS(=O)(=O)OCC(F)(F)F
Reactant: O=C(c1ccc2[nH]c(C(=O)N3CCC(F)(F)CC3)cc2c1)N1CCN(C2CCC2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(c1ccc2c(c1)cc(C(=O)N1CCC(F)(F)CC1)n2CC(F)(F)F)N1CCN(C2CCC2)CC1
Yield: 50 %

Procedure:
The title compound was synthesized in analogy to example 51, from [5-(4-cyclobutyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone (example 41), sodium hydride and 2,2,2-trifluoroethyl methanesulfonate in N,N-dimethylformamide, to give the desired product as a colorless foam (50%).
Reaction SMILES: [OH-].[Li+].O.[Cl:4][C:5]1[C:9]([CH2:10][N:11]([S:13]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH3:12])=[CH:8][S:7][C:6]=1[C:23]([O:25]C)=[O:24]>O1CCOCC1>[Cl:4][C:5]1[C:9]([CH2:10][N:11]([S:13]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH3:12])=[CH:8][S:7][C:6]=1[C:23]([OH:25])=[O:24]
Reactant: COC(=O)c1scc(CN(C)S(=O)(=O)c2ccc(Cl)cc2)c1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CN(Cc1csc(C(=O)O)c1Cl)S(=O)(=O)c1ccc(Cl)cc1
Reaction time: 18 h
Yield: 84.2 %

Procedure:
Lithium hydroxide (210 mg, 5.0 mmol) and water (10 ml) were added to a solution of methyl 3-chloro-4-(N-(4-chlorobenzenesulphonyl)-N-methylaminomethyl)thiophene-2-carboxylate (990 mg, 2.5 mmol) in dioxan (20 ml) and the mixture stirred for 18 h. The mixture was evaporated and 0.3N potassium hydrogen sulphate was added. The mixture was extracted with ethyl acetate and the organic extracts were washed with water and brine, dried and reduced to afford 3-chloro-4-(N-(4-chlorobenzenesulphonyl)-N-methylaminomethyl)thiophene-2-carboxylic acid (800 mg, 84%) as a white solid.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.[N:12]1([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:17][CH2:16][CH:15]([CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[CH2:14][CH2:13]1.C(N(CC)CC)C>ClCCl.CC([O-])=O.CC([O-])=O.[Cu+2]>[CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([N:21]2[CH2:20][CH2:19][CH:18]([CH:15]3[CH2:14][CH2:13][N:12]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:17][CH2:16]3)[CH2:23][CH2:22]2)=[CH:5][CH:4]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C2CCNCC2)CC1
Reactant: CSc1ccc(B(O)O)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CSc1ccc(N2CCC(C3CCN(C(=O)OC(C)(C)C)CC3)CC2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A suspension of 4-methylthiophenylboronic acid (240 mg; 1.431 mmol) in dichloromethane (6 mL) was treated with activated powdered 4 Å molecular sieves (1.5 g), Cu(OAc)2 (87 mg; 0.477 mmol), tert-butyl 4,4′-bipiperidine-1-carboxylate (128 mg; 0.477 mmol) and triethylamine (134 μL; 0.954 mmol). The reaction vessel was purged with oxygen and the mixture stirred under an oxygen atmosphere at ambient temperature for 18 hr. The now brown mixture was filtered through Celite. The eluant was adsorbed onto silica gel. The silica gel was exhaustively eluted without fractionation (1:1 hex/MTBE). The eluant was evaporated to a yellow oil and chromatographed (PTLC; 2:1 hex/MTBE). The major band was collected affording the title compound. LRMS calc: 390.2. obs: 391.1 (M+H), 291.1 (M-BOC+H).
Reaction SMILES: C([O-])([O-])=O.[Cs+].[Cs+].[Br:7][C:8]1[C:13]([N+:14]([O-:16])=[O:15])=[CH:12][CH:11]=[CH:10][C:9]=1[OH:17].I[CH:19]([CH3:21])[CH3:20].CCOC(C)=O>CN(C=O)C>[Br:7][C:8]1[C:9]([O:17][CH:19]([CH3:21])[CH3:20])=[CH:10][CH:11]=[CH:12][C:13]=1[N+:14]([O-:16])=[O:15]
Reactant: CC(C)I
Reactant: O=[N+]([O-])c1cccc(O)c1Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)Oc1cccc([N+](=O)[O-])c1Br
Temperature: 0 °C
Reaction time: 17 h
Yield: 97.2 %

Procedure:
Cs2CO3 was added in 3 portions over 15 min to a stirred solution of 2-bromo-3 nitrophenol (3.00 g, 13.8 mmol) and 2-iodopropane (4.79 g, 27.6 mmol) in 50 ml anhydrous DMF cooled to 0° C. under N2. The reaction was allowed to warm to ambient temperature (2 h) and stirred overnight (17 h). EtOAc (250 ml) was added, the reaction mixture washed with water (2×250 ml) and brine (250 ml), dried (Na2SO4) and concentrated in vacuo to an orange oil (3.78 g). Purification by column chromatography (EtOAc/hexane, 5:95) afforded 3.49 g (97%) of 2-bromo-3-isopropoxynitrobenzene as a yellow oil. TLC (EtOAc/hexane 20:80)Rf =0.12; HPLC (Tr =16.1); 1H-NMR (CDCl3) d 1.35 (d, J=6 Hz, 6H), δ 4.56 (m, J=6 Hz, 1H), δ 6.95 (dd, J=8 Hz, J=3 Hz, 1H), δ 7.34 (d, J=3 Hz, 1H), δ 7.57 (d, J=8 Hz, 1H): MS m/z (relative intensity) 260 (MH+, 100), 262 (MH+ +2, 72).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.[CH:12](=O)[C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1.[OH-].[Na+].Cl>CCO.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([C:8](=[O:10])/[CH:9]=[CH:12]/[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)[CH:7]=1
Reactant: O=Cc1ccncc1
Reactant: CC(=O)c1cc(Br)ccc1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(/C=C/c1ccncc1)c1cc(Br)ccc1O
Reaction time: 8 h
Yield: 42.9 %

Procedure:
To a solution of 1-(5-bromo-2-hydroxyphenyl)ethanone (50 g, 0.23 mol) in EtOH (285 mL) and H2O (15 mL) was added isonicotinaldehyde (25 g, 0.23 mol) and NaOH (84 g, 0.23 mol). The reaction mixture was stirred overnight. EtOH was added to the mixture and filtered to give a solid residue. The residue was dissolved in water and acidified by 1 M HCl to give a solid. The solid was collected by filtration to give (E)-1-(5-bromo-2-hydroxyphenyl)-3-(pyridin-4-yl)prop-2-en-1-one (30 g, 40%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:4]=1[NH:5][CH3:6].C(N(CC)CC)C.[Cl:21][CH2:22][C:23](Cl)=[O:24].Cl>C(Cl)(Cl)Cl>[Cl:21][CH2:22][C:23]([N:5]([CH3:6])[C:4]1[CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=[CH:10][C:3]=1[O:2][CH3:1])=[O:24]
Reactant: CNc1cc([N+](=O)[O-])ccc1OC
Reactant: O=C(Cl)CCl
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1ccc([N+](=O)[O-])cc1N(C)C(=O)CCl
Reaction time: 0.5 h
Yield: 105.5 %

Procedure:
2-Methoxy-N-methyl-5-nitroaniline (D85) (0.68 g, 3.7 mmole) and triethylamine (0.68 ml, 4.9 mmole) were stirred in chloroform (10 ml) as chloroacetyl chloride (0.39 ml, 4.9 mmole) was added. The solution was stirred for 30 min, acidified with 2M HCl, and separated. The organic portion was dried (Na2SO4) and evaporated in vacuo to give the crude title compound as a black solid (1.01 g, quantitative).
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:10]([CH2:13][NH:14][C:15](=[O:20])[C:16]([F:19])([F:18])[F:17])=[CH:9][C:3]=1[C:4]([N:6]=[C:7]=[O:8])=O.[Cl:21][C:22]1[CH:23]=[C:24]([NH:29][NH:30]C(OC(C)(C)C)=O)[CH:25]=[CH:26][C:27]=1[F:28].FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:12]=[CH:11][C:10]([CH2:13][NH:14][C:15](=[O:20])[C:16]([F:19])([F:18])[F:17])=[CH:9][C:3]=1[C:4]1[NH:6][C:7](=[O:8])[N:29]([C:24]2[CH:25]=[CH:26][C:27]([F:28])=[C:22]([Cl:21])[CH:23]=2)[N:30]=1
Reactant: O=C=NC(=O)c1cc(CNC(=O)C(F)(F)F)ccc1Cl
Reactant: CC(C)(C)OC(=O)NNc1ccc(F)c(Cl)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(NCc1ccc(Cl)c(-c2nn(-c3ccc(F)c(Cl)c3)c(=O)[nH]2)c1)C(F)(F)F
Yield: 28.7 %

Procedure:
The title compound was prepared according to the procedure described in Example-83 by using 2-chloro-5-((2,2,2-trifluoroacetamido)methyl)benzoyl isocyanate (step-3 of Intermediate-26, 0.500 g, 1.55 mmol), tert-butyl 2-(3-chloro-4-fluorophenyl)hydrazinecarboxylate (Intermediate-85, 0.455 g, 1.55 mmol), DCM (20 mL) and trifluoro acetic acid (5.0 mL) to afford 0.200 g of the desired product.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[N+:6]([C:9]1[CH:10]=[CH:11][C:12]2[CH2:18][CH2:17][C:16](=O)[CH2:15][CH2:14][C:13]=2[CH:20]=1)([O-:8])=[O:7].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].CC(O)=O>ClCCCl>[N+:6]([C:9]1[CH:10]=[CH:11][C:12]2[CH2:18][CH2:17][CH:16]([N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)[CH2:15][CH2:14][C:13]=2[CH:20]=1)([O-:8])=[O:7]
Reactant: C1CCNC1
Reactant: O=C1CCc2ccc([N+](=O)[O-])cc2CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: O=[N+]([O-])c1ccc2c(c1)CCC(N1CCCC1)CC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Pyrrolidine (0.85 g, 12 mmol) and 2-nitro-5,6,8,9-tetrahydro-benzocyclohepten-7-one (2.05 g, 10 mmol) were mixed in 1,2-dichloroethane (35 mL) and then treated with NaBH(OAc)3 (3.18 g, 15 mmol) and AcOH (0.60 g, 10 mmol). The mixture was stirred at ambient temperature under a N2 atmosphere overnight. The reaction mixture was quenched with saturated NaHCO3, and the product was extracted with EtOAc (3×30 mL). The organic layers were combined and dried over NaSO4. The solvent was evaporated and the residue was purified by flash column chromatography eluting with CH2Cl2/DMA=1/1 (DMA=CH2Cl2/MeOH/30% NH3=80/19/1) to afford 1-(2-nitro-6,7,8,9-tetrahydro-5H-benzo[7]annulen-7-yl)pyrrolidine, a yellow oil (2.2 g, 85%); MS (m/e): 261 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([S:9][CH3:10])[CH:6]=[CH:5][C:3]=1[NH2:4].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Cl[C:22]1[N:23]([CH3:34])[C:24](=[O:33])[C:25]([F:32])=[CH:26][C:27]=1[C:28]([O:30][CH3:31])=[O:29]>C1COCC1>[F:32][C:25]1[C:24](=[O:33])[N:23]([CH3:34])[C:22]([NH:4][C:3]2[CH:5]=[CH:6][C:7]([S:9][CH3:10])=[CH:8][C:2]=2[F:1])=[C:27]([C:28]([O:30][CH3:31])=[O:29])[CH:26]=1
Reactant: COC(=O)c1cc(F)c(=O)n(C)c1Cl
Reactant: CSc1ccc(N)c(F)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)c1cc(F)c(=O)n(C)c1Nc1ccc(SC)cc1F
Temperature: -78 °C
Reaction time: 1 h
Yield: 77 %

Procedure:
To a solution of 2-fluoro-4-(methylthio)aniline (0.236 g, 1.50 mmol) in THF (10 mL) at −78° C. under N2 was added lithium bis(trimethylsilyl)amide (3.42 ml, 3.42 mmol, 1 M solution in hexanes) dropwise. The reaction mixture was stirred for one hour at −78° C. after the addition was complete. Methyl 2-chloro-5-fluoro-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylate (0.300 g, 1.37 mmol) was then added dropwise as a solution in THF (5 mL) and the reaction mixture was stirred for 30 minutes at −78° C. The reaction was quenched by the addition of 1 M HCl until the pH of the reaction mixture was 5, and then diluted with EtOAc and saturated NaCl. The organic layer was separated, dried (Na2SO4), and concentrated under reduced pressure. Purification by flash column chromatography (methylene chloride/EtOAc, 15:1) gave pure desired product (0.359 g, 75%) as a white solid.
Reaction SMILES: CS(C)=O.[OH-:5].[K+].Cl[C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=1[C:15]([F:18])([F:17])[F:16]>C(O)(C)(C)C>[Cl:14][C:11]1[CH:12]=[CH:13][C:8]([OH:5])=[C:9]([C:15]([F:18])([F:17])[F:16])[CH:10]=1
Reactant: [OH-]
Reactant: FC(F)(F)c1cc(Cl)ccc1Cl
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: CS(C)=O
Product: Oc1ccc(Cl)cc1C(F)(F)F
Reaction time: 24 h

Procedure:
To a 300 ml, 3-necked flask fitted with a stirrer, condenser, thermometer and drying tube is added dimethylsulfoxide (100 ml), tert-butanol (20 ml), powdered potassium hydroxide (KOH) pellets (85%, 30 g) and 2,5-dichlorobenzotrifluoride (21.5 g, 0.10 mole). The reaction mixture is warmed to 71°-73° C. for 60 hours, then additional KOH (10 g) is added and heating is continued at 73°-75° C. for 24 hours. The reaction mixture is cooled and the solvent partially removed by distillation at 0.9 mm, bp 55° C.). The cooled pot residue is then poured into ice water (1000 g) which had been preacidified to pH 1 with conc. HCl (50 ml). The aqueous mixture is extracted with carbon tetrachloride (CCl4), the CCl4 layer decanted and dried and the solvent removed under vacuum to afford 10.8 g of 4-chloro-2-trifluoromethylphenol, which is sublimed to afford pure product, mp 81°-81.5° C. Elemental Anal. Calcd for C7H4ClF3O: C, 42.75; H, 2.06; Cl, 18.04: Found: C, 42.54; H, 2.36; Cl, 18.16. ##STR14##
Reaction SMILES: [CH3:1][C:2]([CH3:7])([CH3:6])[C@H:3]([NH2:5])[CH3:4].C(N(CC)CC)C.[Cl:15][C:16]1[C:21]([C:22]2[C:27]([F:28])=[CH:26][C:25]([F:29])=[CH:24][C:23]=2[F:30])=[C:20](Cl)[N:19]2[N:32]=[CH:33][N:34]=[C:18]2[N:17]=1>ClCCl>[Cl:15][C:16]1[C:21]([C:22]2[C:23]([F:30])=[CH:24][C:25]([F:29])=[CH:26][C:27]=2[F:28])=[C:20]([NH:5][C@@H:3]([C:2]([CH3:7])([CH3:6])[CH3:1])[CH3:4])[N:19]2[N:32]=[CH:33][N:34]=[C:18]2[N:17]=1
Reactant: C[C@@H](N)C(C)(C)C
Reactant: Fc1cc(F)c(-c2c(Cl)nc3ncnn3c2Cl)c(F)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@@H](Nc1c(-c2c(F)cc(F)cc2F)c(Cl)nc2ncnn12)C(C)(C)C
Yield: 76 %

Procedure:
With stirring, a mixture of 1.4 mmol of (R)-3,3-dimethylbut-2-ylamine, 1.4 mmol of triethylamine and 10 ml of dichloromethane was introduced into a mixture of 1.4 mmol of 5,7-dichloro-6-(2,4,6-trifluorophenyl)-1,2,4-triazolo[1,5-a]-pyrimidine in 30 ml of dichloromethane. The reaction mixture was then stirred at room temperature for 16 hours and finally washed with 1 N hydrochloric acid and water. The organic phase was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The crude product was purified by silica gel column chromatography. This gave the title compound in the form of colorless crystals in a yield of 76% (m.p.: 169-171° C.).
Reaction SMILES: [CH:1]1([C:6]2[CH2:10][CH2:9][C:8](=[N:11][OH:12])[C:7]=2[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19]C)[CH:14]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.B(Br)(Br)Br.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl.CCCCCC>[CH:1]1([C:6]2[CH2:10][CH2:9][C:8](=[N:11][OH:12])[C:7]=2[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([OH:19])[CH:14]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1cccc(C2=C(C3CCCC3)CCC2=NO)c1
Agent: BrB(Br)Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCCCCC
Product: ON=C1CCC(C2CCCC2)=C1c1cccc(O)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 46.9 %

Procedure:
To a stirred solution of 27 mg 3-cyclopentyl-2-(3-methoxyphenyl)-2-cyclopenten-1-one oxime (Example 7) in 5 ml dichloromethane at −78° C., was added 0.5 ml 1.0 M boron tribromide in hexane dropwise under inert atmosphere. The reaction mixture was stirred for 2 hours while being allowed to gradually warm to room temperature. Then the reaction mixture was poured into saturated aqueous sodium carbonate, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure and purified by column chromatography (silica gel, hexane/ethyl acetate=1:1) to yield 12 mg of 3-cyclopentyl-2-(3-hydroxyphenyl)-2-cyclopenten-1-one oxime as a solid. mp=207-209° C.; 1H NMR (CDCl3, 300 MHz): δ 7.26-7.21 (m, 2H), 6.79-6.70 (m, 3H), 2.93 (m, 1H), 2.80 (m, 2H), 2.61 (m, 2H), 1.70 (m, 4H), 1.54 (m, 4H); APCI MS: m/z 258.1 (M+1).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.C(=O)([O-])[O-].[K+].[K+].CN1CCCC1=O.[CH2:19]([NH:24][CH2:25][C:26]1[CH:31]=[C:30](Br)[CH:29]=[CH:28][C:27]=1[O:33][CH3:34])[CH2:20][CH2:21][CH2:22][CH3:23]>C(OCC)(=O)C>[CH2:19]([NH:24][CH2:25][C:26]1[CH:31]=[C:30]([C:2]2[NH:1][CH:5]=[CH:4][N:3]=2)[CH:29]=[CH:28][C:27]=1[O:33][CH3:34])[CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: c1c[nH]cn1
Reactant: CCCCCNCc1cc(Br)ccc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: CCCCCNCc1cc(-c2ncc[nH]2)ccc1OC
Reaction time: 7 h
Yield: 58.6 %

Procedure:
Imidazole (11.8 g, 0.173 mol), potassium carbonate (0.147 mol), cuprous chloride (1.4 g, 0.014 mol), and N-methylpyrrolidone (270 ml) were added to N-pentyl-(5-bromo-2-methoxyphenyl) methylamine (38.0 g, 0.133 mol), and then the mixture was heated with stirring at 178°-182° C. for 7 hours. The reaction mixture was cooled and added with ethyl acetate (200 ml), and then, inorganic salts and the like were removed by filtration and the solvent was evaporated. The residue was extracted with ethyl acetate, and the extract was washed with 10% aqueous ammonia and then with saturated brine. After dryness over anhydrous sodium sulfate, the solvent was evaporated. The residue was purified by silica gel chromatography (Wako Gell C-300: 360 g, eluent: methyl alcohol/ethyl acetate=1/10 to 1/3) to give N-pentyl-(5-imidazolyl-2-methoxyphenyl)methylamine (21.3 g) as oil.