Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[C:4]1[CH:9]=[CH:8][C:7]([C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[C:23]([N+:24]([O-])=O)=[CH:22][CH:21]=[CH:20][N:19]=3)[CH2:14][CH2:13]2)=[O:11])=[CH:6][CH:5]=1.[H][H]>CO.C(Cl)Cl.[Ni]>[CH3:1][O:2][C:3](=[O:27])[C:4]1[CH:9]=[CH:8][C:7]([C:10]([N:12]2[CH2:13][CH2:14][N:15]([C:18]3[C:23]([NH2:24])=[CH:22][CH:21]=[CH:20][N:19]=3)[CH2:16][CH2:17]2)=[O:11])=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(C(=O)N2CCN(c3ncccc3[N+](=O)[O-])CC2)cc1
Reactant: [H][H]
Agent: [Ni]
Solvent: CO
Solvent: ClCCl
Product: COC(=O)c1ccc(C(=O)N2CCN(c3ncccc3N)CC2)cc1
Reaction time: 4 h
Yield: 88.1 %

Procedure:
4-[1-(3-Nitro-2-pyridyl)piperazin-4-yl-carbonyl]benzoic acid methyl ester (5 g) was dissolved in a co-solvent of methanol (80 ml) and methylene chloride (60 ml) in a pressurized reactor. With the addition of about 1 g of Raney-nickel (50% slurry in water), the reaction mixture was filled with hydrogen gas and stirred at 50~60 psi for 4 hours. After completion of the reaction, reaction mixture was filtered through celite and filtrate was concentrated under reduced pressure. The concentrated residue was treated with hexane and ether for crystallization, filtered, washed and dried to give 4.05 g (yield: 88%) of the desired compound.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[C:7]([F:12])[C:3]=1[C:4](Cl)=[O:5].[NH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([NH2:20])[N:15]=1.O1CCOCC1>C(Cl)Cl>[NH2:13][C:14]1[N:15]=[C:16]([NH:20][C:4](=[O:5])[C:3]2[C:2]([F:1])=[CH:10][C:9]([F:11])=[CH:8][C:7]=2[F:12])[CH:17]=[CH:18][CH:19]=1
Reactant: Nc1cccc(N)n1
Reactant: O=C(Cl)c1c(F)cc(F)cc1F
Solvent: ClCCl
Solvent: C1COCCO1
Product: Nc1cccc(NC(=O)c2c(F)cc(F)cc2F)n1
Temperature: 40 °C
Yield: 73.9 %

Procedure:
Combine 2,4,6-trifluorobenzoyl chloride (3.891 g, 20 mmol), 2,6-diaminopyridine (6.548 g, 60 mmol) and dioxane (25 mL) and stir for 1 hr. at room temperature followed by heating at 40° C. overnight. Dilute the reaction mixture with CH2Cl2 (100 mL), and wash with 0.1N NaOH solution. Extract the aqueous layer three times with CH2Cl2. Combine the organic layers, dry over Na2SO4, filter, and concentrate to a residue. Chromatography on silica gel, eluting with a gradient of 40-50% ethylacetate in hexanes gives the title intermediate (3.95 g, 74%): mass spectrum (ion spray): m/z=267.9 (M+1); 1H NMR (CDCl3, ppm): 8.28 (s, br, 1H), 7.66 (d, 1H), 7.52 (t, 1H), 6.78 (m, 2H), 6.31 (d, 1H), 4.36 (s, br, 2H).
Reaction SMILES: Cl.Cl.[CH3:3][C@H:4]1[CH2:9][O:8][CH2:7][CH2:6][N:5]1[CH2:10][C@H:11]1[CH2:16][N:15]([S:17]([C:20]2[S:21][CH:22]=[CH:23][CH:24]=2)(=[O:19])=[O:18])[CH2:14][CH2:13][NH:12]1.Br[C:26]1[CH:31]=[CH:30][C:29]([C:32]([OH:41])([C:37]([F:40])([F:39])[F:38])[C:33]([F:36])([F:35])[F:34])=[CH:28][CH:27]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC(C)C)=CC=CC=2OC(C)C)CCCCC1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.O.CCOC(C)=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:34][C:33]([F:35])([F:36])[C:32]([C:29]1[CH:28]=[CH:27][C:26]([N:12]2[CH2:13][CH2:14][N:15]([S:17]([C:20]3[S:21][CH:22]=[CH:23][CH:24]=3)(=[O:18])=[O:19])[CH2:16][C@@H:11]2[CH2:10][N:5]2[CH2:6][CH2:7][O:8][CH2:9][C@@H:4]2[CH3:3])=[CH:31][CH:30]=1)([OH:41])[C:37]([F:38])([F:40])[F:39]
Reactant: OC(c1ccc(Br)cc1)(C(F)(F)F)C(F)(F)F
Reactant: C[C@H]1COCCN1C[C@H]1CN(S(=O)(=O)c2cccs2)CCN1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)Oc1cccc(OC(C)C)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Product: C[C@H]1COCCN1C[C@H]1CN(S(=O)(=O)c2cccs2)CCN1c1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1
Temperature: 100 °C
Yield: 12.3 %

Procedure:
In a pressure tube (3S)-3-methyl-4-(((2S)-4-(2-thiophenylsulfonyl)-2-piperazinyl)methyl)morpholine dihydrochloride (133 mg, 0.318 mmol, Example 82, Step 2), 2-(4-bromophenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol (123 mg, 0.381 mmol, Bioorg. Med. Chem. Lett. 2002, 12, 3009), Pd2(dba)3 (18.28 mg, 0.032 mmol, Strem Chemicals, Newburyport, Mass.), dicyclohexyl(2′,6′-diisopropoxybiphenyl-2-yl)phosphine (RuPhos) (14.83 mg, 0.032 mmol, Strem Chemicals, Newburyport, Mass.), and sodium tert-butoxide (122 mg, 1.272 mmol) were combined and suspended in toluene (5 mL). Nitrogen gas was bubbled through the solution for 5 min. The reaction vial was sealed and heated to 100° C. for 15 h. The reaction mixture was then diluted with water and EtOAc. The aqueous mixture was extracted with EtOAc (2×20 mL). The organic extracts were combined and dried over MgSO4, filtered, and concentrated. The crude material was purified by purified via reverse-phase preparative HPLC using a Phenomenex Gemini C18 column (30×150 mm, 10 μm) eluting with 0.1% TFA in MeCN/H2O (10% to 100% over 15 min) to afford 1,1,1,3,3,3-hexafluoro-2-(4-((2S)-2-(((3S)-3-methyl-4-morpholinyl)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol (23 mg).
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[CH:6][N:5]=[C:4]([O:9][CH2:10][C:11]2[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=2)[C:14]#[N:15])[N:3]=1.[CH2:19]([N:22]=[C:23]=[S:24])[CH2:20][CH3:21].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[NH4+].[Cl-]>CN(C=O)C>[C:14]([C:13]1[CH:12]=[C:11]([CH:18]=[CH:17][CH:16]=1)[CH2:10][O:9][C:4]1[N:3]=[C:2]([NH:1][C:23]([NH:22][CH2:19][CH2:20][CH3:21])=[S:24])[C:7]([F:8])=[CH:6][N:5]=1)#[N:15]
Reactant: N#Cc1cccc(COc2ncc(F)c(N)n2)c1
Reactant: CCCN=C=S
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: CCCNC(=S)Nc1nc(OCc2cccc(C#N)c2)ncc1F
Reaction time: 8 h
Yield: 51.4 %

Procedure:
To a magnetically stirred mixture of 3-(4-amino-5-fluoropyrimidin-2-yloxymethyl)-benzonitrile (0.075 g, 0.31 mmol) and propylisothiocyanate (0.047 mL, 0.46 mmol) in dry DMF (1.5 mL) was added LiHMDS (1.0 M in THF, 0.31 ml, 0.31 mmol). The vial was capped and reaction was stirred for 8 h. Saturated aq NH4Cl (3 ml) was added to the vial and the mixture was stirred for 4 h. The heterogeneous mixture was filtered and the solid was washed with hot water, washed with hexanes, and dried under vacuum to give the title compound (0.055 g, 52%) as a pale-yellow solid: mp 163-165° C.; 1H NMR (400 MHz, DMSO-d6) δ 10.77 (s, 1H), 10.38 (s, 1H), 8.47 (d, J=2.7 Hz, 1H), 7.90 (s, 1H), 7.82 (d, J=7.5 Hz, 1H), 7.78 (d, J=8.1 Hz, 1H), 7.62 (t, J=7.7 Hz, 1H), 5.42 (s, 2H), 3.55 (dd, J=12.4, 6.8 Hz, 2H), 1.65-1.59 (m, 2H), 0.95 (t, J=7.5 Hz, 3H): HPLC-MS (ESI) m/z 346.3 (M+H)+, 344.2 (M−H)−.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:20])[C:5]2[O:10][CH:9]([CH2:11][O:12][CH:13]3[CH2:18][CH2:17][CH2:16][CH2:15][O:14]3)[CH2:8][CH2:7][C:6]=2[CH:19]=1.CO[CH:23]1[CH2:27][CH2:26][CH:25](OC)O1.CC1C=CC(S(O)(=O)=O)=CC=1>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([N:20]2[CH:23]=[CH:27][CH:26]=[CH:25]2)[C:5]2[O:10][CH:9]([CH2:11][O:12][CH:13]3[CH2:18][CH2:17][CH2:16][CH2:15][O:14]3)[CH2:8][CH2:7][C:6]=2[CH:19]=1
Reactant: Nc1cc(F)cc2c1OC(COC1CCCCO1)CC2
Reactant: COC1CCC(OC)O1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CN(C)C=O
Product: Fc1cc2c(c(-n3cccc3)c1)OC(COC1CCCCO1)CC2
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 55.3 %

Procedure:
A mixture of intermediate 16-b (0.036 mol), 2,5-dimethoxytetrahydrofuran (0.22 mol) and PTSA (catalytic quantity) in DMF (140 ml) was stirred for 90 min at 100° C. The solvent was evaporated. The residue was dissolved in CH2Cl2. The organic solution was washed once with water, dried (MgSO4), filtered and the solvent was evaporated The residue was purified by column chromatography over silica gel (eluent: CH2Cl2). The pure fractions were collected and the solvent was evaporated, yielding 6.6 g (55.3%) of (±)-6-fluoro-3,4-dihydro-8-(1H-pyrrol-1-yl)-2-[[(tetrahydro-2H-pyran-2-yl)oxy]-methyl]-2H-1-benzopyran (interm. 17-b).
Reaction SMILES: [OH:1][C:2]1[C:9]([C:10]([F:13])([F:12])[F:11])=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[O:14]C.Cl>B(Br)(Br)Br.ClCCl>[OH:14][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([C:10]([F:11])([F:12])[F:13])[C:2]=1[OH:1])[CH:6]=[O:7]
Reactant: COc1cc(C=O)cc(C(F)(F)F)c1O
Agent: BrB(Br)Br
Agent: Cl
Solvent: ClCCl
Product: O=Cc1cc(O)c(O)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution containing 2.2 g of 4-hydroxy-3-methoxy-5-trifluoromethylbenzaldehyde in 65 ml of 1 molar BBr3 in dichloromethane was stirred for 2 h at room temperature. Hydrochloric acid was added and the organic phase was separated. The solvent was evaporated in vacuo. Yield 1.4 g (68%), m.p. 188-192° C.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[C:9]([S:11][C:12]#N)[CH:8]=[CH:7][C:5]=1[NH2:6])([O-:3])=[O:2].[OH-].[K+].[CH2:16](I)C.O>C(O)C>[NH2:6][C:5]1[CH:7]=[CH:8][C:9]([S:11][CH2:12][CH3:16])=[CH:10][C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: CCI
Reactant: N#CSc1ccc(N)c([N+](=O)[O-])c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCSc1ccc(N)c([N+](=O)[O-])c1
Reaction time: 0.08 h
Yield: 95.4 %

Procedure:
2-Nitro-4-thiocyanatoaniline (17.55 g.; prepared as hereinbefore described in Example 6) was added portionwise to a stirred solution of potassium hydroxide (13.4 g.) in ethanol (210 ml.), keeping the temperature below 20° C. After 5 minutes, ethyl iodide (14.4 g.) was added during five minutes. The stirring was continued for a further hour and the mixture was allowed to stand overnight. The mixture was then poured into water (1100 ml.) and extracted with chloroform (3× 300 ml.). The chloroform layers were combined, washed with water (500 ml.), dried over magnesium sulphate, and evaporated to give 1-amino-4-ethylthio-2-nitrobenzene (17.0 g.), in the form of a red oil.
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[S:3].Br[CH:6]([C:10](=[O:21])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]([F:20])([F:19])[F:18])[C:7]([NH2:9])=[O:8]>C(O)C>[C:2]([S:3][CH:6]([C:10](=[O:21])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]([F:18])([F:19])[F:20])[C:7]([NH2:9])=[O:8])(=[NH:4])[NH2:1]
Reactant: NC(N)=S
Reactant: NC(=O)C(Br)C(=O)c1ccccc1C(F)(F)F
Solvent: CCO
Product: N=C(N)SC(C(N)=O)C(=O)c1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 10.4 %

Procedure:
To a solution of 2.80 g (0.37 mole) of thiourea in 1200 mL of ethanol was added 11.40 g (0.37 mole) of 2-bromo-3-oxo-3-(2-trifluoromethyl-phenyl)-propionamide. After stirring at room temperature overnight, the mixture was concentrated under reduced pressure. Purification of the residue by silica gel chromatography, eluting with dichloromethane-methanol (gradient 100:0-80:20) gave 11.80 g of 2-carbamimidoylsulfanyl-3-oxo-3-(2-trifluoromethyl-phenyl)-propionamide as a yellow solid.
Reaction SMILES: [N+:1]([O-:4])([O-])=[O:2].[NH4+].[CH2:6]([C:8]1[CH:14]=[CH:13][C:11]([NH2:12])=[CH:10][CH:9]=1)[CH3:7]>S(=O)(=O)(O)O>[CH2:6]([C:8]1[CH:14]=[CH:13][C:11]([NH2:12])=[CH:10][C:9]=1[N+:1]([O-:4])=[O:2])[CH3:7]
Reactant: CCc1ccc(N)cc1
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [NH4+]
Product: CCc1ccc(N)cc1[N+](=O)[O-]
Reaction time: 2 h
Yield: 75.2 %

Procedure:
Ammonium nitrate (39.6 g, 0.49 mol) is added portionwise to a chilled (ice-bath) solution of 4-ethylaniline (20 g, 0.16 mol) in concentrated sulfuric acid (100 ml), maintaining the temperature at −10° C. to 0° C. by external cooling. The reaction mixture is stirred for two hours, then poured onto crushed ice, and the precipitate is collected by filtration. The solid is taken up in water, the solution made neutral by addition of dilute aqueous sodium hydroxide solution and extracted with ethyl acetate. The organic extracts are combined, dried over anhydrous sodium sulfate, filtered and the filtrate is evaporated in vacuo to give 4-ethyl-3-nitroaniline (20 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][NH:13][CH2:14][CH2:15][CH2:16][O:17][C:18]2[N:22]=[C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[O:20][N:19]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH2:29](NCC)[CH3:30].C(Br)C>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][N:13]([CH2:14][CH2:15][CH2:16][O:17][C:18]2[N:22]=[C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[O:20][N:19]=2)[CH2:29][CH3:30])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(CCNCCCOc2noc(-c3ccccc3)n2)cc1OC
Reactant: CCNCC
Solvent: CCBr
Solvent: CN(C)C=O
Product: CCN(CCCOc1noc(-c2ccccc2)n1)CCc1ccc(OC)c(OC)c1
Temperature: 50 °C

Procedure:
2 g of 3-{3-[2-(3,4-dimethoxyphenyl)-ethylamino]-propyloxy}-5-phenyl-1,2,4-oxadiazole (for preparation, see Example 69) were dissolved in 20 ml dimethylformamide. 0.9 ml of diethylamine and 0.6 g ethyl bromide were added to the solution and the reaction mixture was heated at 50° C. for 3.5 hours. For workup, the reaction mixture was then concentrated to dryness and the residue dissolved in dichloromethane. A sufficient quantity of water was added to the solution for a clear phase separation to occur. The mixture was shaken and the organic phase separated out, dried with sodium sulfate, filtered, and concentrated. The crude oily title compound obtained was refined by medium-pressure chromatography on fine-grained silica gel using ethyl acetate/methanol/concentrated aqueous ammonia solution, ratio 9:1:0.05, as the eluent. 1.3 g of the title compound were obtained as a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:19]([O:20][CH3:21])=[CH:18][C:6]2[CH:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH2:8][NH:9][CH2:10][CH2:11][C:5]=2[CH:4]=1.[CH2:22]=O>C(O)=O>[CH3:1][O:2][C:3]1[C:19]([O:20][CH3:21])=[CH:18][C:6]2[CH:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH2:8][N:9]([CH3:22])[CH2:10][CH2:11][C:5]=2[CH:4]=1
Reactant: C=O
Reactant: COc1cc2c(cc1OC)C(c1ccccc1)CNCC2
Solvent: O=CO
Product: COc1cc2c(cc1OC)C(c1ccccc1)CN(C)CC2

Procedure:
A solution of 3.58 g. (0.0126 mol) of 7,8-dimethoxy-1-phenyl-2,3,4,5-tetrahydro-1H-3 -benzazepine in 15 ml. of formic acid and 10 ml. of formaldehyde is refluxed for 18 hours. The reaction mixture is evaporated to dryness, 20 ml. of 6N hydrochloric acid is added and the solution is again evaporated to dryness to give a liquid. The latter is treated with 20 ml. of 10% sodium hydroxide solution and the mixture is extracted with ether. The dried extract is evaporated to give the liquid 7,8-dimethoxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[C:7]([F:15])[CH:6]=1)=O.[Br:16][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][C:24]([OH:26])=[O:25])=[CH:19][CH:18]=1>>[Br:16][C:17]1[CH:18]=[CH:19][C:20]([C:23]2[C:24](=[O:26])[O:25][CH2:2][C:3]=2[C:5]2[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[C:7]([F:15])[CH:6]=2)=[CH:21][CH:22]=1
Reactant: CS(=O)(=O)c1ccc(C(=O)CBr)cc1F
Reactant: O=C(O)Cc1ccc(Br)cc1
Product: CS(=O)(=O)c1ccc(C2=C(c3ccc(Br)cc3)C(=O)OC2)cc1F

Procedure:
The title compound was prepared according to the procedure of Example 32 using 2-bromo-1-[3-fluoro-4-(methylsulfonyl)phenyl]ethanone (Lalezari, Iradj et al., J. Chem. Eng. Data, 11, 619 (1966)) instead of 2-bromo-1-[4-(methylsulfonyl)phenyl]ethanone, 4-bromophenylacetic acid instead of 4-(3-thienyl)phenylacetic acid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.Cl[CH:10]([C:16](Cl)=O)[C:11]([O:13][CH2:14][CH3:15])=[O:12]>C(O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:16][N:8]=2)[CH:7]=1
Reactant: CCOC(=O)C(Cl)C(=O)Cl
Reactant: Nc1ccc(F)cn1
Solvent: CCO
Product: CCOC(=O)c1cnc2ccc(F)cn12
Temperature: 25 °C
Reaction time: 8 h
Yield: 5.9 %

Procedure:
5-Fluoropyridine-2-amine (1 g, 8.92 mmol) and ethyl 2,3-dichloro-3-oxopropanoate (39.6 g, 10.7 mmol, 5% in benzene) were added to a flask along with 75 mL of ethanol and stirred overnight at ambient temperature. The material was purified on Silica gel using methanol and ethyl acetate (Rf=0.4 in 5% MeOH/ethyl acetate) to provide 110 mg of the desired compound as a waxy solid, 95% pure by LC. MS (ES+APCI) m/z=209.2 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:12]=O)=[C:6]2[C:10]=1[O:9][C:8]([CH3:11])=[N:7]2.Cl.[NH2:15][OH:16].C(N(CC)CC)C>CO.O.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5](/[CH:12]=[N:15]/[OH:16])=[C:6]2[C:10]=1[O:9][C:8]([CH3:11])=[N:7]2
Reactant: NO
Reactant: Cc1nc2c(C=O)ccc(Br)c2o1
Agent: Cl
Solvent: O
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1nc2c(/C=N/O)ccc(Br)c2o1
Temperature: 25 °C
Reaction time: 1 h
Yield: 105.2 %

Procedure:
To a suspension of 7-bromo-2-methyl-benzo[d]oxazole-4-carbaldehyde (3.23 g) in a mixture of methanol and water (7:3) (60 ml) were added successively hydroxylamine hydrochloride (1.03 g) and triethylamine (2.06 ml) and the reaction mixture was stirred at ambient temperature for 1 hour. The reaction mixture was diluted with ethyl acetate (200 ml) and water (200 ml). The phases were separated and the aqueous phase was extracted with ethyl acetate (150 ml). The combined organic extracts were washed with brine (200 ml), dried over sodium sulfate and concentrated to give (E)-7-bromo-2-methyl-benzo[d]oxazole-4-carbaldehyde oxime (3.61 g) as a brown solid. 1H-NMR (400 MHz, CDCl3): 9.47 (s, 1H) 7.47 (d, 1H), 7.33 (d, 1H), 2.74 (s, 3H) ppm.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:17][CH2:16][CH2:15][N:14]([CH3:18])[CH2:13][CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C([O-])(=O)C.[K+].[CH3:24][O:25][C:26]1[CH:31]=[CH:30][N:29]=[C:28]([CH2:32][CH2:33][C:34]2[NH:43][C:37]3=[N:38][CH:39]=[C:40](I)[CH:41]=[C:36]3[N:35]=2)[CH:27]=1.C(=O)([O-])[O-].[K+].[K+].[Cl-].[Li+]>O1CCOCC1.O.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:24][O:25][C:26]1[CH:31]=[CH:30][N:29]=[C:28]([CH2:32][CH2:33][C:34]2[NH:43][C:37]3=[N:38][CH:39]=[C:40]([C:2]4[CH:7]=[CH:6][C:5]([S:8]([N:11]5[CH2:17][CH2:16][CH2:15][N:14]([CH3:18])[CH2:13][CH2:12]5)(=[O:10])=[O:9])=[CH:4][CH:3]=4)[CH:41]=[C:36]3[N:35]=2)[CH:27]=1
Reactant: COc1ccnc(CCc2nc3cc(I)cnc3[nH]2)c1
Reactant: CN1CCCN(S(=O)(=O)c2ccc(Br)cc2)CC1
Agent: [Fe+2]
Agent: [Pd]
Agent: CC(=O)[O-]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccnc(CCc2nc3cc(-c4ccc(S(=O)(=O)N5CCCN(C)CC5)cc4)cnc3[nH]2)c1
Temperature: 85 °C
Yield: 55.6 %

Procedure:
A mixture of 0.5 g of 1-(4-bromo-benzene-sulfonyl)-4-methyl-[1,4]diazepane, 0.42 g of bis-(pinacoalato)-diboron, 0.025 g of 1,1′-bis-(diphenylphosphino)-ferrocene, 0.033 g of [1,1′-bis(diphenyl-phosphino)ferrocene]palladium-dichloride (complex with CH2Cl2), 0.442 g of potassium acetate in 6 ml of degassed dioxane are heated to 85° C. in a sealed tube under N2 for 17 hours. To the resulting mixture 5 ml of degassed dioxane, 0.371 g of 2-[2-(4-methoxypyridin-2-yl)ethyl]-6-iodo-3H-imidazo[4,5-b]pyridine (starting material A1), 0.113 g of tetrakis(triphenylphosphine)-palladium(0) and a solution of 0.27 g of potassium carbonate and 0.083 g of lithium chloride in 5 ml of degassed water are added under N2. The tube is sealed again, the mixture is heated to 120° under N2 for 7 hours and, after cooling, addition of water and adjusting the pH to 7, f is extracted three times with dichloromethane. The combined organic phases are dried over sodium sulfate, concentrated and the residue is chromatographed on a silica gel column (dichloromethane/methanol 22-15:1+1% NH4OH). Concentration of the chromatographically pure fractions, crystallization of the residue from ethyl acetate and recrystallization from ethylacetate/acetonitril (4:1) gives 0.275 g of the title compound as a solid of m.p. 160-162° C. The mass spectrum shows the molecular peak MH+ at 507.3 Da.
Reaction SMILES: [CH3:1][C:2]1([CH3:28])[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][CH:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:16]2[CH2:21][CH2:20][N:19]([CH2:22][C@@H:23]3[CH2:25][C@H:24]3[CH2:26]O)[CH2:18][CH2:17]2)[CH2:3]1.C(N(S(F)(F)[F:35])CC)C.C(=O)([O-])O.[Na+].C(OCC)(=O)C>ClCCl.O>[F:35][CH2:26][C@@H:24]1[CH2:25][C@H:23]1[CH2:22][N:19]1[CH2:18][CH2:17][N:16]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH:4]2[CH2:3][C:2]([CH3:28])([CH3:1])[CH2:7][C:6]([CH3:8])([CH3:9])[CH2:5]2)[CH2:21][CH2:20]1
Reactant: CC1(C)CC(c2ccccc2N2CCN(C[C@@H]3C[C@H]3CO)CC2)CC(C)(C)C1
Reactant: CCN(CC)S(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC1(C)CC(c2ccccc2N2CCN(C[C@@H]3C[C@H]3CF)CC2)CC(C)(C)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 28.2 %

Procedure:
To a solution of trans-(2-{4-[2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazin-1-ylmethyl}cyclopropyl)methanol (60 mg, 0.156 mmol) produced in Example (92a) in dichloromethane (5 mL) was added diethylaminosulfur trifluoride (DAST) (0.052 mL, 0.394 mmol), followed by stirring for 2 hours at room temperature under a nitrogen atmosphere. The reaction mixture was cooled at an external temperature of 0° C., saturated aqueous solution of sodium hydrogencarbonate was added, and the mixture was stirred. Then, ethyl acetate and water were added thereto and extraction was performed with ethyl acetate. The separated organic layer was washed with brine and then dried over anhydrous sodium sulfate. The desiccant was filtered off and the filtrate was concentrated under reduced pressure. The resultant residue was purified by NH silica gel column chromatography (ethyl acetate/heptane) to give 17 mg of trans-1-(2-fluoromethylcyclopropylmethyl)-4-[2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazine as a colorless oil.
Reaction SMILES: [CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([SH:16])=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18].C(=O)([O-])[O-].[K+].[K+].Cl[C:26]1[S:27][C:28]2[CH:34]=[CH:33][CH:32]=[C:31]([O:35][CH3:36])[C:29]=2[N:30]=1.CN(C)C=O>C(OCC)(=O)C>[CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([S:16][C:26]4[S:27][C:28]5[CH:34]=[CH:33][CH:32]=[C:31]([O:35][CH3:36])[C:29]=5[N:30]=4)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18]
Reactant: CN1C(=O)CC[C@]2(C)c3ccc(S)cc3CC[C@@H]12
Reactant: COc1cccc2sc(Cl)nc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cccc2sc(Sc3ccc4c(c3)CC[C@H]3N(C)C(=O)CC[C@]43C)nc12
Yield: 66.3 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-4-methyl-8-mercapto-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one (100 mg, 0.38 mmol), potassium carbonate (158 mg, 1.14 mmol), 2-chloro-4-methoxybenzothiazole (92 mg, 0.46 mmol) and 1.5 mL of anhydrous dimethylformamide, fitted with a reflux condenser, and the stirred mixture was heated at 60°, under nitrogen, for 18 h. The mixture was cooled, diluted with ethyl acetate (75 mL) and washed with brine (4×25 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (ethyl acetate eluent) to give 107 mg (66%) of the title compound as an off white solid. mp 200°-205°. FDMS: m/e=424. α[D]589 =+60.56 (c=0.96, chloroform).
Reaction SMILES: C(OC([NH:11][CH2:12][C:13]([NH:15][C@@H:16]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH:17]([CH3:19])[CH3:18])=[O:14])=O)C1C=CC=CC=1.CC#N.[ClH:30].N1C=CC=CC=1>CCO.[Pd]>[ClH:30].[NH2:11][CH2:12][C:13]([NH:15][C@@H:16]([C:20]([O:22][C:23]([CH3:25])([CH3:24])[CH3:26])=[O:21])[CH:17]([CH3:19])[CH3:18])=[O:14]
Reactant: CC(C)[C@@H](NC(=O)CNC(=O)OCc1ccccc1)C(=O)OC(C)(C)C
Agent: [Pd]
Agent: Cl
Solvent: c1ccncc1
Solvent: CC#N
Solvent: CCO
Product: CC(C)[C@@H](NC(=O)CN)C(=O)OC(C)(C)C
Reaction time: 2 h
Yield: 80.6 %

Procedure:
tert-Butyl N-[(benzyloxy)carbonyl]glycyl-D-valinate (3.89 g, 10.7 mmol) and Pd on charcoal (95%, 0.3 g) were mixed in EtOH (95%, 80 ml) and stirred under H2-atmosphere for 2 h. The mixture was filtered through Celite 521 and the solvent was evaporated under reduced pressure. MeCN (25 ml) and pyridine hydrochloride (1.25 g, 10.8 mmol) were added. The solvent was evaporated under reduced pressure to give 2.3 g (81%) of the title product. NMR (500 MHz, CD3COOD) 0.96-1.01 (m, 6H), 1.49 (s, 9H), 2.13-2.23 (m 1H), 3.76 (AB, 2H), 4.28-4.33 (m, 1H).