Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1](=O)[CH3:2].[C:4]1(=[O:11])[CH2:9][CH2:8][CH2:7][C:6](=O)[CH2:5]1.[CH2:12]([O:14][C:15](=[O:20])[CH2:16][C:17](=[NH:19])[NH2:18])[CH3:13]>C(O)C>[CH2:12]([O:14][C:15]([C:16]1[CH:1]([CH3:2])[C:5]2[C:4](=[O:11])[CH2:9][CH2:8][CH2:7][C:6]=2[NH:19][C:17]=1[NH2:18])=[O:20])[CH3:13]
Reactant: CC=O
Reactant: O=C1CCCC(=O)C1
Reactant: CCOC(=O)CC(=N)N
Solvent: CCO
Product: CCOC(=O)C1=C(N)NC2=C(C(=O)CCC2)C1C
Yield: 53 %

Procedure:
Upon boiling a solution of 2.8 g of acetaldehyde, 5.6 g of cyclohexane-1,3-dione and 6.5 g of amidinoacetic acid ethyl ester in 100 ml of ethanol for 2 hours, 2-amino-4-methyl-1,4,5,6,7,8-hexahydro-5-oxoquinoline-3-carboxylic acid ethyl ester of melting point 236°C (ethanol) is obtained.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]#[N:11])[CH:8]=2)[CH:3]=[N:2]1.[H-].[Na+].Cl[C:15]1[CH:20]=[CH:19][N:18]=[C:17]([NH2:21])[N:16]=1>CN(C=O)C>[NH2:21][C:17]1[N:18]=[C:19]([N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[C:7]([C:10]#[N:11])[CH:8]=3)[CH:3]=[N:2]2)[CH:20]=[CH:15][N:16]=1
Reactant: N#Cc1ccc2cn[nH]c2c1
Reactant: Nc1nccc(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1ccc2cnn(-c3ccnc(N)n3)c2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 1H-indazole-6-carbonitrile (200 mg, 1.40 mmol) in DMF (2 mL), was added NaH (60% oil dispersion) (89.4 mg, 2.24 mmol). The reaction mixture was stirred for 10 min at RT before addition of 4-chloropyrimidin-2-amine (362 mg, 2.79 mmol). The reaction mixture was stirred at RT for 1 hr then heated at 50° C. in a sealed tube for 18 hr. LC-MS (Method B) indicated a mixture of desired product and a regiosiomer by-product [21%, Retention time=1.65 min, m/z=237.4 (M+H)+] and [29%, Retention time=1.43 min, m/z=237.4 (M+H)+]. The reaction was quenched by addition of water (1 mL) and EtOAc (3 mL). The precipitated solid was collected by suction filtration: LC-MS (Method B): Retention time=1.65 min.
Reaction SMILES: Cl.Cl.[CH2:3]([N:10]1[CH2:18][CH2:17][C:13]2([CH2:16][NH:15][CH2:14]2)[CH2:12][CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[F:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2([C:36]3[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=3)[CH2:30][CH2:29][N:28]([CH2:31][C:32](O)=[O:33])[C:27]2=[O:35])=[CH:22][CH:21]=1.C(N=C=NCCCN(C)C)C.CN1CCOCC1>ClCCl>[CH2:3]([N:10]1[CH2:11][CH2:12][C:13]2([CH2:16][N:15]([C:32](=[O:33])[CH2:31][N:28]3[CH2:29][CH2:30][C:26]([C:23]4[CH:24]=[CH:25][C:20]([F:19])=[CH:21][CH:22]=4)([C:36]4[CH:37]=[CH:38][C:39]([F:42])=[CH:40][CH:41]=4)[C:27]3=[O:35])[CH2:14]2)[CH2:17][CH2:18]1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=C(O)CN1CCC(c2ccc(F)cc2)(c2ccc(F)cc2)C1=O
Reactant: c1ccc(CN2CCC3(CC2)CNC3)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: O=C(CN1CCC(c2ccc(F)cc2)(c2ccc(F)cc2)C1=O)N1CC2(CCN(Cc3ccccc3)CC2)C1
Reaction time: 8 h

Procedure:
7-Benzyl-2,7-diazaspiro[3.5]nonane dihydrochloride from Example 7F (0.237 g, 0.749 mmol), the product from Example 14D (0.248 g, 0.749 mmol), N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine (0.199 ml, 1.123 mmol) and N-methylmorpholine (0.247 ml, 2.247 mmol) were stirred together in dichloromethane (2 mL). After stirring overnight, the reaction mixture was diluted with dichloromethane (20 mL) and washed with 1 N HCl (10 mL), brine (10 mL), dried over magnesium sulfate and concentrated. The residue was loaded onto a GraceResolv 40 gm silica gel column and the product was eluted with a gradient of 0.4% methanol/dichloromethane containing 0.2 N NH3 to 6% methanol/dichloromethane containing 0.2 N NH3 to yield the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 7.39-7.15 (m, 9H), 6.99 (t, J=8.2, 4H), 3.97 (s, 2H), 3.72 (d, J=20.0, 4H), 3.53 (t, J=6.5, 2H), 3.46 (s, 2H), 2.75 (t, J=6.4, 2H), 2.32 (s, 4H), 1.73 (s, 4H); MS (ESI+) m/z 530.2 (M+H)+.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][OH:11])=[N:7][CH:8]=1)[CH3:2].F[C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=1.[H-].[Na+].O>CN(C=O)C>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][O:11][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=2)=[N:7][CH:8]=1)[CH3:2]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: CCc1ccc(CCO)nc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCc1ccc(CCOc2ccc([N+](=O)[O-])cc2)nc1
Reaction time: 0.5 h
Yield: 68.4 %

Procedure:
To a solution of 2-(5-ethyl-2-pyridyl)ethanol (53.0 g) and 4-fluoronitrobenzene (47.0 g) in DMF (500 ml) was added portionwise under ice-cooling 60% sodium hydride in oil (16.0 g). The mixture was stirred under ice-cooling for one hour, then at room temperature for 30 minutes, poured into water and extracted with ether. The ether layer was washed with water and dried (MgSO4). The solvent was evaporated off to give 4-[2-(5-ethyl-2-pyridyl)ethoxy]nitrobenzene as crystals (62.0 g, 62.9%). Recrystallization from ether-hexane gave colorless prisms, m.p. 53°-54° C.
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH2:8]([O:47][CH:48]1[C@H:52]2[C@H:53](OC3CCCCO3)[N:54](C(OC(C)(C)C)=O)[C:55]3[CH:62]=[CH:61][C:60]([O:63][CH3:64])=[CH:59][C:56]=3[C:57](=[O:58])[N:51]2[CH2:50][CH2:49]1)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][O:15][CH:16]1[C@H:20]2[C@H:21](OC3CCCCO3)[N:22](C(OC(C)(C)C)=O)[C:23]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][C:24]=3[C:25](=[O:26])[N:19]2[CH2:18][CH2:17]1.C([O-])(O)=O.[Na+]>CO.C(Cl)(Cl)Cl>[CH2:8]([O:47][CH:48]1[C@@H:52]2[CH:53]=[N:54][C:55]3[CH:62]=[CH:61][C:60]([O:63][CH3:64])=[CH:59][C:56]=3[C:57](=[O:58])[N:51]2[CH2:50][CH2:49]1)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][O:15][CH:16]1[C@@H:20]2[CH:21]=[N:22][C:23]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][C:24]=3[C:25](=[O:26])[N:19]2[CH2:18][CH2:17]1
Reactant: COc1ccc2c(c1)C(=O)N1CCC(OCCCCCCCOC3CCN4C(=O)c5cc(OC)ccc5N(C(=O)OC(C)(C)C)[C@@H](OC5CCCCO5)[C@H]34)[C@H]1[C@H](OC1CCCCO1)N2C(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc2c(c1)C(=O)N1CCC(OCCCCCCCOC3CCN4C(=O)c5cc(OC)ccc5N=C[C@@H]34)[C@@H]1C=N2
Reaction time: 1 h
Yield: 85 %

Procedure:
95% TFA (3 mL) was added drop-wise to dimer compound 15e (200 mg, 0.2 mmol) at 0° C. This was then stirred for 1 hr and the mixture was poured into saturated NaHCO3 (30 mL) solution to naturalize the reaction mixture. The mixture was extracted with chloroform (3×20 mL). The organic layer was then washed water (20 mL), brine (20 mL) then dried (MgSO4) and filtrated. The excess solvent was removed under reduced pressure to give the crude product, which was subjected to flash column chromatography (SiO2, 2% methanol-chloroform). Removal of excess eluent under reduced pressure without heating afforded the final product 16e (100 mg, 0.17 mmol, 85%) as a solid: [α]20D=+484° (c=0.15, CHCl3); 1H NMR (CDCl3, 400 MHz): δ 1.39-1.56 (m, 6H, 14-H, 14′-H, 15-H), 1.83-1.94 (m, 4H, 13-H, 13′-H), 2.00-2.10 (m, 4H, 2-H, 2′-H), 2.26-2.38 (m, 4H, 1-H, 1′-H), 3.54-3.63 (m, 2H, 3-H, 3′-H), 3.70-3.77 (m, 2H, 11a-H, 11a′-H), 3.79-3.91 (m, 2H, 3-H, 3′-H), 3.93 (s, 6H, 7-OMe, 7′-OMe), 4.00-4.18 (m, 4H, 12-H, 12′-H), 6.79 (s, 2H, 9-H, 9′-H), 7.51 (s, 2H, 6-H, 6′-H), 7.65 (d, 2H, J=4, 11-H, 11′-H); 13C NMR (CDCl3, 400 MHz): δ 24.1, 25.8, 28.8, 29.0, 46.6, 53.7, 56.1, 68.9, 110.4, 111.6, 120.0, 140.6, 147.8, 150.9, 162.3, 164.6; IR (neat): 3317, 2936, 1620, 1599, 1505, 1453, 1430, 1381, 1261, 1216, 1092, 1020 cm−1; MS (FAB) m/z (relative intensity) 653 ([M+2×MeOH]+., 4), 621 ([M+MeOH]+., 3), 589 (M+., 100).
Reaction SMILES: [OH:1][C@@H:2]1[CH2:21][CH2:20][C@@:19]2([CH3:22])[C@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:18]2[CH2:17][CH2:16][C@@:15]2([CH3:23])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C:12](=[O:14])[CH3:13])[CH2:3]1.[Br:24]Br.O>CO>[OH:1][C@@H:2]1[CH2:21][CH2:20][C@@:19]2([CH3:22])[C@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:18]2[CH2:17][CH2:16][C@@:15]2([CH3:23])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C:12](=[O:14])[CH2:13][Br:24])[CH2:3]1
Reactant: CC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@@H]4C[C@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: BrBr
Solvent: CO
Solvent: O
Product: C[C@]12CC[C@@H](O)C[C@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](C(=O)CBr)CC[C@@H]12

Procedure:
To a flask containing a solution of 3α-hydroxy-5β-pregnan-20-one (5.15 g, 16.5 mmol)in methanol (100 mL) was added a solution of bromine (1.1 mL) in methanol (30 mL) dropwise in such a rate to maintain the brown color of the bromine until this color was persistent. Then water (200 mL) was added and the mixture was extracted with CH2Cl2 (3×100 mL). The combined extracts were dried over Na2SO4. Removal of the solvent resulted in the product as a foamy white solid (6.63 g). Other 21-bromo-pregnan-20-ones (3β-ethynyl-3α-hydroxy-21-bromo-5β-pregnan-20-one, 3β-methyl-3α-hydroxy-21-bromo-5α-pregnan-20-one and 3α-hydroxy-3β-trifluoromethyl-12-bromo-5β-19-norpregnan-20-one) were synthesized using the same method.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:22][CH2:23][C:24]#[N:25])=[C:6]2[C:11]=1[N:10]=[C:9]([CH3:12])[C:8]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)=[C:7]2[CH3:21].[N-:26]=[N+:27]=[N-:28].[Na+].[Cl-].[NH4+].CN(C)C=O>C(OCC)(=O)C.[Cl-].[Na+]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:22][CH2:23][C:24]2[NH:28][N:27]=[N:26][N:25]=2)=[C:6]2[C:11]=1[N:10]=[C:9]([CH3:12])[C:8]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)=[C:7]2[CH3:21]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1nc2c(Cl)ccc(OCC#N)c2c(C)c1Cc1ccc(Cl)cc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1nc2c(Cl)ccc(OCc3nnn[nH]3)c2c(C)c1Cc1ccc(Cl)cc1
Temperature: 100 °C

Procedure:
A mixture of [8-chloro-3-(4-chlorobenzyl)-2,4-dimethylquinolin-5-yloxy]acetonitrile (0.10 g), sodium azide (0.026 g), ammonium chloride (0.022 g) and N,N-dimethylformamide (1.5 mL) was heated by microwave irradiation at 100° C. for 45 minutes. The mixture was diluted with ethyl acetate (20 mL) and saturated aqueous sodium chloride solution (20 mL). The resulting precipitate was collected by filtration, washed with water and ethyl acetate and dried to afford title compound as a white solid, 0.14 g.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[NH:7][CH2:6][CH2:5][NH:4][C:3]1=[O:8].[CH3:10][O:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16]Br)=[CH:14][CH:13]=1.C(N(CC)CC)C>C(Cl)Cl>[CH3:10][O:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16][N:7]2[CH2:6][CH2:5][NH:4][C:3](=[O:8])[C:2]2([CH3:9])[CH3:1])=[CH:14][CH:13]=1
Reactant: COc1ccc(CBr)cc1
Reactant: CC1(C)NCCNC1=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(CN2CCNC(=O)C2(C)C)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 55 %

Procedure:
A mixture of 3,3-dimethyl-piperazin-2-one (Step 108.4) (3.7 g, 28.9 mmol), 4-methoxybenzyl bromide (5.4 mL, 37.6 mmol, 1.3 equiv) and triethylamine (5.2 mL, 37.6 mmol, 1.3 equiv) in DCM (60 mL) was stirred for 48 h at rt. Additional 5.0 mL of 4-methoxybenzyl bromide were added and the mixture was stirred for 72 h at rt, then concentrated. The residue was diluted with DCM/saturated aqueous solution of NaHCO3. The aqueous phase was separated and extracted with DCM. The organic phase was washed with H2O and brine, dried (Na2SO4), filtered and concentrated. The residue was triturated in DCM to provide 3.95 g of the title compound as a white solid: ESI-MS: 249.2 [M+H]+; TLC: Rf=0.16 (Hex/EtOAc, 2:3).
Reaction SMILES: [N+]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10])([O-])=O.[C:11]1(=O)[CH2:16]CCC[CH2:12]1.[CH:18]1(O)CCCCC1>C(=O)([O-])[O-].[Zn+2]>[CH3:18][C:4]1[C:5](=[O:10])[CH2:6][C@H:7]([C:11]([CH3:16])=[CH2:12])[CH2:8][CH:9]=1
Reactant: O=[N+]([O-])c1ccccc1O
Reactant: O=C1CCCCC1
Reactant: OC1CCCCC1
Agent: O=C([O-])[O-]
Agent: [Zn+2]
Product: C=C(C)[C@@H]1CC=C(C)C(=O)C1
Temperature: 214.5 °C
Yield: 63 %

Procedure:
A mixture of 600 parts of R-(+)-1,2-limonene oxide, 5.7 parts of 2-nitrophenol and 12 parts of zinc carbonate was refluxed at 202-227° C. for 7 hours in a three-necked flask equipped with agitator, 3-foot distillation column, distillation head, temperature probe, and addition funnel. When the rearrangement step was completed (no 1,2-limonene oxide left in the reaction mixture), 190 parts of cyclohexanone were slowly added to the reaction mixture. The mixture was held at reflux for 2 hours at 195-200° C. and then cooled down to 120° C. The mixture of cyclohexanone and cyclohexanol was removed at 10-15 mm Hg and pot temperature below 120° C. Cyclohexanone addition step followed by reflux and removal of cyclohexanone-cyclohexanol mixture under vacuum was repeated two more times. After the oxidation step was completed, the conversion of R-(−)-carveol to R-(−)-carvone was above 95%. The catalyst was removed by filtration, and the filtrate was distilled to afford 473 parts of 80% pure R-(−)-carvone (theory yield 63% on 1,2-limonene oxide). This material was purified using conventional methods to 99.6% pure flavor grade R-(−)-carvone.
Reaction SMILES: [N:1]([CH2:4][CH:5]([C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[C:9]([S:14][CH3:15])[CH:8]=1)[OH:6])=[N+]=[N-].C(S)CCS.C(N(CC)CC)C>CO>[NH2:1][CH2:4][CH:5]([C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[C:9]([S:14][CH3:15])[CH:8]=1)[OH:6]
Reactant: CSc1cc(C(O)CN=[N+]=[N-])ccc1O
Agent: SCCCS
Solvent: CO
Solvent: CCN(CC)CC
Product: CSc1cc(C(O)CN)ccc1O
Temperature: 0 °C

Procedure:
Stir the product of Step C (49.5 g, 0.22 mole), 1,3-propane dithiol (103.6 g, 0.96 mole) and triethylamine (101.0 g, 1.0 mole) in methanol (1500 ml) for 72 hours. Cool to 0° C., filter and evaporate in vacuo to obtain 2-amino-1-(4-hydroxy-3-methylthiophenyl)ethanol.
Reaction SMILES: [F:1][C:2]1[C:7]([S:8][CH3:9])=[CH:6][CH:5]=[CH:4][C:3]=1[N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.C(N(CC)CC)C.Cl[C:24]([O:26][CH3:27])=[O:25]>C(Cl)Cl>[F:1][C:2]1[C:7]([S:8][CH3:9])=[CH:6][CH:5]=[CH:4][C:3]=1[N:10]1[CH2:15][CH2:14][N:13]([C:24]([O:26][CH3:27])=[O:25])[CH2:12][CH2:11]1
Reactant: CSc1cccc(N2CCNCC2)c1F
Reactant: COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)N1CCN(c2cccc(SC)c2F)CC1

Procedure:
Preparation according to preparation 26: 1-[2-fluoro-3-(methylthio)phenyl]piperazine (1.25 g, 5.53 mmol), triethylamine (1.2 ml, 7.2 mmol), methylen chloride (50 ml), methyl chloroformate (0.49 g, 6.6 mmol). Yield: 1.56 g. MS m/z (rel. intensity, 70 eV) 284 (M+, 99), 196 (bp), 184 (44), 169 (54), 56 (60)
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH2:16][CH2:17][C:18]#[N:19])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl.[NH2:27][OH:28]>>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH2:16][CH2:17][C:18]([NH2:19])=[N:27][OH:28])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#CCCCCC1CCN(Cc2ccccc2)CC1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: NC(CCCCC1CCN(Cc2ccccc2)CC1)=NO
Yield: 62.8 %

Procedure:
A mixture of 1-benzyl-4-(4-cyanobutyl)piperidine (2.20 g), potassium carbonate (3.56 g) and hydroxylamine hydrochloride (2.39 g) was heated under reflux for 20 hours. After cooling, the mixture was filtered and evaporated in vacuo. The residue was dissolved in ether, filtered and recrystallized to afford 5-(1-benzylpiperidin-4-yl)-1-hydroxyiminopentylamine (1.56 g).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH:19][C:20](=[O:40])[CH2:21][C:22](=O)[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29]2[CH:34]=[CH:33][N:32]=[C:31]([C:35]([F:38])([F:37])[F:36])[CH:30]=2)[CH:24]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:14][C:12]1[C:11]([C:15]([F:17])([F:16])[F:18])=[CH:10][C:9]2[NH:19][C:20](=[O:40])[CH2:21][C:22]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]4[CH:34]=[CH:33][N:32]=[C:31]([C:35]([F:37])([F:38])[F:36])[CH:30]=4)[CH:24]=3)=[N:7][C:8]=2[CH:13]=1
Reactant: Cc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3ccnc(C(F)(F)F)c3)c2)cc1C(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-c3ccnc(C(F)(F)F)c3)c1)=N2

Procedure:
The title compound was prepared from (5-methyl-2-{3-oxo-3-[3-(2-trifluoromethyl-pyridin-4-yl)-phenyl]-propionylamino}-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example M245) (0.28 g, 0.48 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as an off-white solid (220 mg, 99%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([SH:9])=[CH:5][CH:4]=1.[Cl:10][C:11]1[C:12](F)=[CH:13][C:14]2[O:19][CH:18]([C:20]([F:23])([F:22])[F:21])[C:17]([C:24]([O:26]CC)=[O:25])=[CH:16][C:15]=2[CH:29]=1>>[Cl:10][C:11]1[C:12]([S:9][C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[CH:13][C:14]2[O:19][CH:18]([C:20]([F:22])([F:21])[F:23])[C:17]([C:24]([OH:26])=[O:25])=[CH:16][C:15]=2[CH:29]=1
Reactant: COc1ccc(S)cc1
Reactant: CCOC(=O)C1=Cc2cc(Cl)c(F)cc2OC1C(F)(F)F
Product: COc1ccc(Sc2cc3c(cc2Cl)C=C(C(=O)O)C(C(F)(F)F)O3)cc1

Procedure:
The title compound was prepared from 4-methoxybenzenethiol and ethyl 6-chloro-7-fluoro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylate (Example 183, Step 2) via a procedure similar to that described in Example 183, Steps 3 and 4: mp 239.4-242.3° C. 1H NMR (acetone-d6/300 MHz) 7.84 (s, 1H), 7.55 (m, 3H), 7.16 (d, 2H, J=8.7 Hz), 6.20 (s, 1H), 5.75 (q, 1H, J=7.0 Hz), 3.90 (s, 3H). 19F NMR (acetone-d6/282 MHz)−79.4 (d, J=6.5 Hz) ESLRMS m/z 415 (M−H). ESHRMS m/z 415.0005 (M−H, Calc'd 415.0019). Anal. Calc'd for C18H12ClF3O4S: C, 51.87; H, 2.90; Cl, 8.51; S, 7.69. Found: C, 51.76; H, 2.83; Cl 8.55; S, 7.77.
Reaction SMILES: [ClH:1].Cl.Cl.[CH2:4]([C:8]1[N:9]=[N:10][C:11]([O:28][CH:29]2[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]2)=[CH:12][C:13]=1[C:14]1[CH:15]=[CH:16][C:17]([O:21][CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)=[C:18]([NH2:20])[CH:19]=1)[CH2:5][CH2:6][CH3:7].[C:36]([Cl:39])(=[O:38])[CH3:37].CCN(C(C)C)C(C)C.Cl>C(Cl)Cl.CN(C1C=CN=CC=1)C.CCOCC>[ClH:39].[ClH:1].[CH2:4]([C:8]1[N:9]=[N:10][C:11]([O:28][CH:29]2[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]2)=[CH:12][C:13]=1[C:14]1[CH:15]=[CH:16][C:17]([O:21][CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)=[C:18]([NH:20][C:36](=[O:38])[CH3:37])[CH:19]=1)[CH2:5][CH2:6][CH3:7]
Reactant: CC(=O)Cl
Reactant: CCCCc1nnc(OC2CCN(C)CC2)cc1-c1ccc(OC2CCCCC2)c(N)c1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CCOCC
Product: CCCCc1nnc(OC2CCN(C)CC2)cc1-c1ccc(OC2CCCCC2)c(NC(C)=O)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 55.1 %

Procedure:
To a solution of 5-[3-butyl-6-(1-methyl-piperidin-4-yloxy)-pyridazin-4-yl]-2-cyclohexyloxy-phenylamine trihydrochloride (0.2 mmol, 110 mg) in DCM (1.0 mL) at 0° C. was added acetyl chloride (0.4 mmol, 29 μL), DIEA (0.4 mmol, 70 μL) and DMAP (5 mg). And the mixture was stirred at room temperature for 1 hour. It was then condensed in vacuo and the residue was purified by silica gel chromatography (DCM to DCM+10% 2N NH3 in MeOH) to give a colorless sticky solid, which was dissolved in DCM (1.0 mL), 2N HCl in ether (1.0 mL) was added, kept at room temperature for 10 min, condensed, triturated with hexanes to provide the title compound (61 mg). LCMS: m/z 482 [M+1]. 1H NMR (400 MHz, CDCl3): δ 8.43 (1 H, s), 7.89 (1 H, s), 6.97 (2 H, s), 6.81 (1 H, s), 5.60 (1 H, bs), 4.37-4.43 (1 H, m), 3.10-3.45 (4 H, m), 2.90-2.95 (2 H, m), 2.81 (3 H, s), 2.35-2.61 (4 H, m), 2.23 (3 H, s), 1.25-1.87 (14 H, m), 0.83 (3 H, t).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[CH3:11][S:12][C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[CH3:11][S:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=2)=[CH:15][CH:14]=1
Reactant: CSc1ccc(O)cc1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CSc1ccc(Oc2ccc([N+](=O)[O-])cc2)cc1
Temperature: 100 °C
Reaction time: 12 h

Procedure:
1-Chloro-4-nitrobenzene (15 g, 95 mmol) and 4-(methylmercapto)phenol (13.3 g, 95 mmol) were dissolved in dimethylsulfoxide (100 mL). Potassium carbonate (15.8 g, 134 mmol) was added thereto, and the mixture was stirred for 12 h at 100° C. After completion of the reaction, excess water was added to precipitate a solid, which was then filtered and dried to give the title compound.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:33]=[CH:32][C:6]([C:7]([N:9]([C@@H:11]2[CH2:16][CH2:15][N:14]([CH2:17][CH:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)[CH2:13][C@H:12]2[C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([Cl:31])[CH:25]=2)[CH3:10])=[O:8])=[CH:5][CH:4]=1.C(N(CC)CC)C.[C:41](Cl)(=[O:43])[CH3:42].O>C1COCC1>[C:41]([N:21]1[CH2:22][CH2:23][CH:18]([CH2:17][N:14]2[CH2:15][CH2:16][C@@H:11]([N:9]([CH3:10])[C:7](=[O:8])[C:6]3[CH:5]=[CH:4][C:3]([Cl:2])=[CH:33][CH:32]=3)[C@H:12]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[C:26]([Cl:31])[CH:25]=3)[CH2:13]2)[CH2:19][CH2:20]1)(=[O:43])[CH3:42]
Reactant: CN(C(=O)c1ccc(Cl)cc1)[C@@H]1CCN(CC2CCNCC2)C[C@H]1c1ccc(Cl)c(Cl)c1
Reactant: CC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)N1CCC(CN2CC[C@@H](N(C)C(=O)c3ccc(Cl)cc3)[C@H](c3ccc(Cl)c(Cl)c3)C2)CC1
Reaction time: 14 h
Yield: 12 %

Procedure:
To a solution of 4-chloro-N-[(3R,4R)-3-(3,4-dichlorophenyl)-1-(piperidin-4-ylmethyl)piperidin-4-yl]-N-methylbenzamide monohydrochloride (100 mg) obtained in Example 463 and triethylamine (78 μL) in THF (3 mL) was added acetyl chloride (40 μL) at room temperature, and the mixture was stirred for 14 hr. To the reaction mixture was added water, and the resultant product was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and brine and dried, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound (12.5 mg, 12%) as a white powder.
Reaction SMILES: [C:1]([C:3]1[CH:22]=[CH:21][C:6]([CH2:7][NH:8][C:9](=[O:20])[CH:10]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)[O:11][CH3:12])=[CH:5][CH:4]=1)#[N:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[CH:43]1[CH2:48][CH2:47][N:46]([CH3:49])[CH2:45][CH2:44]1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:7][NH:8][C:9](=[O:20])[CH:10]([O:11][CH3:12])[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH:43]3[CH2:48][CH2:47][N:46]([CH3:49])[CH2:45][CH2:44]3)=[CH:15][CH:14]=2)=[CH:21][CH:22]=1)#[N:2]
Reactant: CN1CCC(O)CC1
Reactant: COC(C(=O)NCc1ccc(C#N)cc1)c1ccc(O)cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(C(=O)NCc1ccc(C#N)cc1)c1ccc(OC2CCN(C)CC2)cc1
Temperature: 0 °C
Reaction time: 120 h
Yield: 44.7 %

Procedure:
(RS)-N-(4-Cyano-benzyl)-2-(4-hydroxy-phenyl)-2-methoxy-acetamide (example 21.2, 0.406 g) was dissolved in THF (12 ml). Triphenylphosphine (0.539 g) and 4-hydroxy-N-methylpiperidine (0.237 g) were added. The reaction mixture was cooled to 0° C. Slowly, DEAD (0.384 g) was added. The reaction mixture was stirred at 0° C. for 30 min and at rt for 5 days. The solvent was evaporated and the product was purified by chromatography (silicagel, mobile phase: gradient from CH2Cl2 to CH2Cl2/MeOH 4:1) to give (RS)-N-(4-cyano-benzyl)-2-methoxy-2-[4-(1-methyl-piperidin-4-yloxy)-phenyl]-acetamide as a colorless foam (0.241 g). MS 394.4 ([M+H]+)