Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(P(=O)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.[CH3:36][C:37]1[C:45]([CH3:46])=[CH:44][C:43]([NH:47][S:48]([C:51]2[S:52][CH:53]=[CH:54][CH:55]=2)(=[O:50])=[O:49])=[C:42]2[C:38]=1[CH:39]=[C:40]([C:56]([NH:58][CH2:59][CH2:60][S:61]C(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=O)[NH:41]2.C(=O)([O-])O.[Na+]>ClCCl>[S:61]1[CH2:60][CH2:59][N:58]=[C:56]1[C:40]1[NH:41][C:42]2[C:38]([CH:39]=1)=[C:37]([CH3:36])[C:45]([CH3:46])=[CH:44][C:43]=2[NH:47][S:48]([C:51]1[S:52][CH:53]=[CH:54][CH:55]=1)(=[O:49])=[O:50]
Reactant: Cc1cc(NS(=O)(=O)c2cccs2)c2[nH]c(C(=O)NCCSC(c3ccccc3)(c3ccccc3)c3ccccc3)cc2c1C
Agent: O=C([O-])O
Agent: O=P(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(NS(=O)(=O)c2cccs2)c2[nH]c(C3=NCCS3)cc2c1C
Reaction time: 0.17 h
Yield: 83.7 %

Procedure:
A mixture of triphenylphosphine oxide (1.1 g), trifluoromethanesulfonic anhydride (0.31 mL) and dichloromethane (20 mL) was stirred for 10 min under ice-cooling. 4,5-Dimethyl-7-[(2-thienylsulfonyl)amino]-N-[2-(tritylthio)ethyl]-1H-indole-2-carboxamide (0.40 g) was added, and the mixture was stirred for 3 hr under ice-cooling. The reaction mixture was poured into aqueous sodium hydrogencarbonate solution and extracted with dichloromethane. The aqueous layer was extracted with dichloromethane, and the combined dichloromethane layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (ethyl acetate:hexane=3:7-5:5), and the obtained crystals were recrystallized from ethyl acetate-hexane to give the title compound (201 mg, yield 84%) as colorless prism crystals. melting point 201-202° C.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]([CH3:12])[C:4](=[O:13])[CH:3]=1.[N+:14]([O-])([OH:16])=[O:15]>C(O)(=O)C>[OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]([CH3:12])[C:4](=[O:13])[C:3]=1[N+:14]([O-:16])=[O:15]
Reactant: O=[N+]([O-])O
Reactant: Cn1c(=O)cc(O)c2ccccc21
Solvent: CC(=O)O
Product: Cn1c(=O)c([N+](=O)[O-])c(O)c2ccccc21

Procedure:
A suspension of 4-hydroxy-1-methyl carbostyril (1.63g; 0.009 mole) in glacial acetic acid (10 ml) was stirred during the addition of concentrated nitric acid (2.5 ml; d, 1.42) and the mixture heated for a few minutes on a steam bath. On cooling the clear red solution deposited yellow crystals of the title compound which were diluted with ethanol, filtered, and washed well with ethanol, m.p. 159°-161° C (Found: C, 54.20; H 3.71; N, 12.42; C10H8N2O4 requires; C, 54.55 H, 3.66; N, 12.72%).
Reaction SMILES: Cl[CH2:2][C:3]([CH3:17])([CH3:16])[C:4]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][CH3:15])[CH:7]=1)=O.O.[NH2:19][NH2:20]>CCO>[CH3:15][O:14][C:8]1[CH:7]=[C:6]([C:4]2[C:3]([CH3:17])([CH3:16])[CH2:2][NH:20][N:19]=2)[CH:11]=[CH:10][C:9]=1[O:12][CH3:13]
Reactant: COc1ccc(C(=O)C(C)(C)CCl)cc1OC
Reactant: NN
Solvent: O
Solvent: CCO
Product: COc1ccc(C2=NNCC2(C)C)cc1OC
Temperature: 80 °C
Yield: 100 %

Procedure:
A 100 mL round bottom flask equipped with a stir bar, Vigreux column and nitrogen inlet was charged with 3-chloro-1-(3,4-dimethoxy-phenyl)-2,2-dimethyl-propan-1-one (1.3 g, 5 mmol), EtOH (20 mL) and hydrazine monohydrate (0.3 mL, 6 mmol). The mixture was heated at 80° C. for 2 h. LC-MS and TLC analysis showed consumption of SM. The solvent was evaporated under reduced pressure and trace hydrazine and EtOH was removed under high vacuum for 30 min. The material was used as in the next step. Amount obtained: 1170 mg, 5 mmol, 100% yield. LC-MS (ESI) m/e 235 (M+H). Step 3
Reaction SMILES: [CH2:1]([N:3]([CH2:7][CH3:8])[CH2:4][CH2:5][NH2:6])[CH3:2].Cl[C:10]1[N:11]=[N+:12]([O-:23])[C:13]2[CH:22]=[C:21]3[C:17]([CH2:18][CH2:19][CH2:20]3)=[CH:16][C:14]=2[N:15]=1>COCCOC>[O-:23][N+:12]1[C:13]2[CH:22]=[C:21]3[C:17](=[CH:16][C:14]=2[N:15]=[C:10]([NH:6][CH2:5][CH2:4][N:3]([CH2:7][CH3:8])[CH2:1][CH3:2])[N:11]=1)[CH2:18][CH2:19][CH2:20]3
Reactant: [O-][n+]1nc(Cl)nc2cc3c(cc21)CCC3
Reactant: CCN(CC)CCN
Solvent: COCCOC
Product: CCN(CC)CCNc1nc2cc3c(cc2[n+]([O-])n1)CCC3
Yield: 96.2 %

Procedure:
N1,N1-Diethyl-1,2-ethanediamine (0.50 mL, 3.5 mmol) was added to a stirred solution of chloride 21 (314 mg, 1.4 mmol) in DME (50 mL) and the solution stirred at reflux temperature for 2 h. The solvent was evaporated and the residue partitioned between DCM (100 mL) and dilute aqueous NH3 solution (50 mL). The organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-10%) of MeOH/DCM, to give 1-oxide 26 (406 mg, 95%) as a yellow solid: mp (MeOH/EtOAc) 109-112° C.; 1H NMR δ 7.93 (s, 1H, H-9), 7.31 (s, 1H, H-5), 7.14 (br s, 1H, NH), 3.97-4.03 (m, 2H, CH2N), 3.42-3.46 (m, 2H, CH2N), 3.25-3.33 (m, 4H, 2×CH2N), 2.19-2.29 (m, 4H, H-6, H-8), 2.08-2.14 (m, 2H, H-7), 1.45 (t, J=7.3 Hz, 6H, 2×CH3); 13C NMR δ 158.2, 154.6, 148.4, 143.7, 129.8, 120.7, 114.4, 50.8, 47.7 (2), 36.3, 33.1, 32.3, 25.7, 8.8 (2). Anal. calcd for C16H23N5O: C, 63.8; H, 7.7; N, 23.2. Found: C, 63.9; H, 7.7; N, 23.3%.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:4]=[C:5]([CH:13]=[CH:14][C:15]=1[O:16]C)[CH2:6][N:7]1[CH:11]=[CH:10][N:9]=[C:8]1[SH:12].Cl.N1C=CC=CC=1.C1COCC1.CCOCC>O.CCCCCC>[F:18][C:2]([F:1])([F:19])[C:3]1[CH:4]=[C:5]([CH:13]=[CH:14][C:15]=1[OH:16])[CH2:6][N:7]1[CH:11]=[CH:10][N:9]=[C:8]1[SH:12]
Reactant: COc1ccc(Cn2ccnc2S)cc1C(F)(F)F
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOCC
Solvent: CCCCCC
Product: Oc1ccc(Cn2ccnc2S)cc1C(F)(F)F

Procedure:
A mixture of 1-(3'-trifluoromethyl-4'-methoxy- benzyl)-2-mercaptoimidazole (2.0 g) and pyridine hydrochloride (15 g) was melted at 210° for 30 minutes, cooled, diluted with water and extracted with ethyl acetate. The ethyl acetate extracts were treated with charcoal, dried over sodium sulfate and concentrated to give a thick oil. Addition of THF (3 ml), ether (6 ml), and hexane (15 ml) produced yellow crystals. Recrystallization from ethyl acetate/hexane yielded 0.7 g (37%) of cream colored crystals: mp 220° (dec).
Reaction SMILES: OO.[F:3][C:4]1[CH:5]=[C:6]([N:17]2[CH2:21][C@H:20]([CH2:22][NH:23][C:24](=[O:26])[CH3:25])[O:19][C:18]2=[O:27])[CH:7]=[CH:8][C:9]=1[C:10]1[S:11][CH2:12][C:13](=[O:16])[NH:14][N:15]=1.[C:28]([OH:31])(=[O:30])[CH3:29]>>[C:24]([NH:23][CH2:22][C@@H:20]1[O:19][C:18](=[O:27])[N:17]([C:6]2[CH:7]=[CH:8][C:9]([C:10]3[S:11][CH:12]([O:31][C:28](=[O:30])[CH3:29])[C:13](=[O:16])[NH:14][N:15]=3)=[C:4]([F:3])[CH:5]=2)[CH2:21]1)(=[O:26])[CH3:25]
Reactant: CC(=O)NC[C@H]1CN(c2ccc(C3=NNC(=O)CS3)c(F)c2)C(=O)O1
Reactant: CC(=O)O
Agent: OO
Product: CC(=O)NC[C@H]1CN(c2ccc(C3=NNC(=O)C(OC(C)=O)S3)c(F)c2)C(=O)O1
Temperature: 65 °C
Yield: 82 %

Procedure:
Hydrogen peroxide (30% aqueous sol, 0.0558 ml, 0.546 mmol) is added to N-{3-[3-Fluoro-4-(5-oxo-5,6-dihydro-4H-[1,3,4]thiadiazin-2-yl)-phenyl]-2-oxo-oxazolidin-5(S)-ylmethyl}-acetamide (0.100 g, 0.273 mmol) in acetic acid (2 ml) and is heated at 65° C. overnight. The reaction mixture is evaporated to dryness and the residue is purified by PTLC (10% MeOH/DCM) to give white solid (0.089 g, 82%); 1HNMR (300 MHz, DMSO-d6) δ 1.82 (s, 3H), 2.09 (s, 3H), 3.41 (t, J=5.5 Hz, 2H), 3.56 (dd, J=6.6, 9.1 Hz, 1H), 4.14 (t, J=9.1 Hz, 1H), 4.70-4.80 (m, 1H), 7.42 (dd, J=2.2, 8.8 Hz, 1H), 7.59 (dd, J=2.2, 14 Hz, 1H), 7.65 (t, J=8.5 Hz, 1H), 8.25 (t, J=5.8 Hz, 1H); mp 174-7; MS (m/z): [M+H]+=425.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[OH:11].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:31](Cl)([Cl:33])=[O:32]>>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[O:11][C:31]([Cl:33])=[O:32]
Reactant: O=C(Cl)Cl
Reactant: Oc1ccc2ccccc2c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: O=C(Cl)Oc1ccc2ccccc2c1
Reaction time: 1 h
Yield: 75 %

Procedure:
433 g (3.0 mols) of 2-naphthol and 15.7 g of triphenylphosphine are initially introduced into an apparatus as described in Example 1. The mixture is heated to 120° to 125° C. and 325 g of COCl2 are introduced in the course of 12 hours. The reaction mixture is stirred for a further 1 hour, excess phosgene is drawn off in vacuo and crude chloroformic acid 2-naphthyl ester is obtained in a yield of 75% of the theoretical yield.
Reaction SMILES: [Cl-].[Cl-].[CH-:3]1[CH:7]=[CH:6][CH:5]=[CH:4]1.[CH-:8]1[CH:12]=[CH:11][CH:10]=[CH:9]1.[Ti+2:13].[CH3:14][Mg]Cl.C1COCC1>C1(C)C=CC=CC=1>[CH3:8][C-:3]1[CH:7]=[CH:6][CH:5]=[CH:4]1.[C-:8]1([CH3:14])[CH:12]=[CH:11][CH:10]=[CH:9]1.[Ti+2:13]
Reactant: C[Mg]Cl
Reactant: c1cc[cH-]c1
Agent: Cl[Ti]Cl
Agent: [Ti+2]
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: C[c-]1cccc1
Temperature: 2.5 °C
Reaction time: 1 h

Procedure:
To a well stirred slurry of titanocene dichloride (CP2TiCl2) (249 g, 1.00 mol) in toluene (2.75 L) chilled to −5° C. (internal temp) was added methyl magnesium chloride (CH3MgCl) (750 mL, 3.0M in THF, 2.25 mol) over 1 h, maintaining the temperature below 8° C. The resulting orange slurry is aged at 0-5° C. for 1 h, or until the insoluble purple Cp2TiCl2 has dissolved. A NMR was taken to confirm reaction completion (see below), then the reaction was quenched into a solution of 6% aqueous ammonium chloride (700 mL), maintained at 0-5° C. The layers were separated and the organic phase was washed with cold water (3×575 mL) and brine (575 mL), then was dried with Na2SO4 (220 g). The filtered organic layer was evaporated to 1.5 Kg (maintaining an internal temperature of 25° or less). Weight % assay by 1H NMR showed the solution to contain 187 g product (90%, 12.5 wt % solution in toluene/THF). Typically, the material was greater than 95% pure, with only traces of the starting material and monomethyl intermediate. The solution may be further concentrated to 1.0 Kg, giving a 18 wt % solution in toluene, allowing for an easier assay. However, the presence of a small amount of THF increases the stability of the compound. The material was stored under nitrogen in a sealed carboy at 0° C. 1H NMR Cp2Ti(CH3)2: δ 6.05 (s, 10H), −0.05 (s, 6H). Cp2TiCl(CH3): δ 6.22 (s, 10H), 0.80 (s, 3H). Cp2TiCl2: δ 6.56 (s, 10H). 13C NMR Cp2Ti(CH3)2: δ 113.20 (Cp2), 45.77 ((CH3)2). Cp2TiClCH3: δ 115.86 (Cp2), 50.37 (CH3). Cp2TiCl2: δ 120.18.
Reaction SMILES: O[C:2]1([CH3:21])[C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][C:6]=2[C:5](O)([CH3:15])[C:4]2[CH:17]=[N:18][CH:19]=[CH:20][C:3]1=2.[BH4-].[Na+]>C(O)C>[CH3:21][C:2]1[C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][C:6]=2[C:5]([CH3:15])=[C:4]2[CH:17]=[N:18][CH:19]=[CH:20][C:3]=12
Reactant: CC1(O)c2cnccc2C(C)(O)c2c1[nH]c1ccccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: Cc1c2cnccc2c(C)c2c1[nH]c1ccccc12

Procedure:
A similar reaction to that described above starting from the compounds of formulae XXVII and XXVIII appears in J. Org. Chem. 48, pp. 2690-2695 (1983) in which an equivalent of 5,11-dihydroxy 5,11-dimethyl 10,11-dihydro 5H-pyrido[3,4-b]carbazole is made to react with about 40 equivalents of sodium borohydride for 20 hours in refluxing ethanol to give rise to 5,11 dimethyl 10H-pyrido[3,4-b]carbazole.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[CH:10][C:11]([N+:18]([O-:20])=[O:19])=[C:12]([CH2:14][C:15]([NH2:17])=[O:16])[CH:13]=2)[CH2:4][CH2:3]1.C[O:22][C:23](=O)[C:24]([C:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[NH:28][CH:27]=1)=O.CC([O-])(C)C.[K+]>C1COCC1>[NH:28]1[C:29]2[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:26]([C:24]2[C:23](=[O:22])[NH:17][C:15](=[O:16])[C:14]=2[C:12]2[CH:13]=[C:8]([N:5]3[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]3)[CH:9]=[CH:10][C:11]=2[N+:18]([O-:20])=[O:19])=[CH:27]1
Reactant: CN1CCN(c2ccc([N+](=O)[O-])c(CC(N)=O)c2)CC1
Reactant: COC(=O)C(=O)c1c[nH]c2ccccc12
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CN1CCN(c2ccc([N+](=O)[O-])c(C3=C(c4c[nH]c5ccccc45)C(=O)NC3=O)c2)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 2-[5-(4-methyl-piperazin-1-yl)-2-nitro-phenyl]-acetamide (278 mg, 1.00 mmol) and (1H-indol-3-yl)-oxo-acetic acid methyl ester (366 mg, 1.80 mmol) in dry THF (8.0 mL) is added a solution of 1.0 M t-BuOK in THF (4.0 mL, 4.0 mmol) at 0° C. under argon. After stirring for 30 min at 0° C. and 1 h at RT, TLC indicates the complete consumption of the acetamide. The purple reaction mixture is partitioned between EtOAc (50 mL) and brine (50 mL), the layers are separated, and the aqueous layer is extracted with EtOAc (50 mL). The combined organic layers are dried over Na2SO4 and concentrated at reduced pressure. The crude product is purified by FCC (EtOAc/AcOH/H2O 7:1:1) to afford the title compound as its water soluble acetate salt. Orange solid. 1H NMR (DMSO-de, 400 MHz): δ 1.84 (s, 6H, CH3COO−), 1.97-2.15 (m, 4H), 2.03 (s, 3H), 2.95-3.21° (m, 4H), 6.51 (d, J=7.8 Hz, 1H), 6.54 (d, J=2.7 Hz, 1H), 6.73 (t, J=7.8 Hz, 1H), 7.01-7.07 (m, 2H), 7.41 (d, J=8.1 Hz, 1H), 8.00 (s, 1H), 8.13 (d, J=9.4 Hz, 1H), 10.8-11.4 (br, 1H), 11.95 (bs, 1H). ES+-MS: 431 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:10][C:11]2[C:16]([Cl:17])=[CH:15][N:14]=[C:13](Cl)[CH:12]=2)=[C:6]([CH:9]=1)[C:7]#[N:8].[CH3:19][C:20]1[CH:24]=[C:23]([NH2:25])[N:22]([CH:26]([CH3:28])[CH3:27])[N:21]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C1C=CC(P(C2C(OC3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=CC=3)=CC=CC=2)C2C=CC=CC=2)=CC=1>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:10][C:11]2[C:16]([Cl:17])=[CH:15][N:14]=[C:13]([NH:25][C:23]3[N:22]([CH:26]([CH3:28])[CH3:27])[N:21]=[C:20]([CH3:19])[CH:24]=3)[CH:12]=2)=[C:6]([CH:9]=1)[C:7]#[N:8]
Reactant: N#Cc1cc(Cl)ccc1Nc1cc(Cl)ncc1Cl
Reactant: Cc1cc(N)n(C(C)C)n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: Cc1cc(Nc2cc(Nc3ccc(Cl)cc3C#N)c(Cl)cn2)n(C(C)C)n1
Yield: 35.1 %

Procedure:
To a solution of 5-chloro-2-[(2,5-dichloro-4-pyridinyl)amino]benzonitrile (1.8 g, 6.03 mmol) and 3-methyl-1-(1-methylethyl)-1H-pyrazol-5-amine (0.839 g, 6.03 mmol) in 1,4-dioxane (40 mL) was added cesium carbonate (5.89 g, 18.09 mmol) and the reaction mixture was degassed. DPEPhos (0.260 g, 0.482 mmol) was added followed by palladium acetate (0.054 g, 0.241 mmol) and the reaction mixture was heated to reflux overnight. The suspension was then filtered. The dioxane was evaporated. Solid was partitioned between 1 M HCl and ethyl acetate. Layers were separated, and organic layer discarded. The HCl-containing layer was neutralized and extracted with 2×50 mL of ethyl acetate. Organic layers were combined, washed with brine, dried over MgSO4, filtered and evaporated. 5-Chloro-2-[(5-chloro-2-{[3-methyl-1-(1-methylethyl)-1H-pyrazol-5-yl]amino}-4-pyridinyl)amino]benzonitrile (850 mg, 2.118 mmol, 35.1% yield) was isolated as a yellow solid. 1H NMR (400 MHz, DMSO-d6) ppm 1.25 (d, J=6.57 Hz, 6 H) 2.09 (s, 3 H) 4.35 (quin, J=6.57 Hz, 1 H) 5.89 (s, 1 H) 6.03 (s, 1 H) 7.46 (d, J=8.84 Hz, 1 H) 7.81 (dd, J=8.72, 2.65 Hz, 1 H) 7.96 (s, 1 H) 8.11 (d, J=2.53 Hz, 1 H) 8.42 (s, 1 H) 8.54 (s, 1 H) HPLC Rt=2.60 min, MS (ESI): 400.8, 403.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=2)[CH:11]=O)[CH:5]=[CH:4][N:3]=1.[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][NH:26][CH:25]([CH2:29][CH2:30][CH3:31])[CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17]>>[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][N:26]([CH2:11][C:10]2[CH:13]=[CH:14][CH:15]=[C:8]([C:6]3[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=3)[CH:9]=2)[CH:25]([CH2:29][CH2:30][CH3:31])[CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17]
Reactant: CCCC1CN(C(=O)OC(C)(C)C)CCN1
Reactant: O=Cc1cccc(-c2ccnc(Cl)n2)c1
Product: CCCC1CN(C(=O)OC(C)(C)C)CCN1Cc1cccc(-c2ccnc(Cl)n2)c1

Procedure:
Intermediate 1 was coupled with 3-propyl-piperazine-1-carboxylic acid tert-butyl ester following procedure B. LC-MS showed the product had the expected M+H+ of 431.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[C:18]([C:20](=[O:22])[CH3:21])[CH:17]=[CH:16][C:15]=2[CH:23]2[CH2:28][C:27]([CH3:30])([CH3:29])[CH2:26][C:25]([CH3:32])([CH3:31])[CH2:24]2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.C(OCC)(=O)C.C(=O)([O-])O.[Na+]>C(OCC)C.CCCCCCC>[N:11]1([C:14]2[CH:19]=[C:18]([C:20](=[O:22])[CH3:21])[CH:17]=[CH:16][C:15]=2[CH:23]2[CH2:24][C:25]([CH3:31])([CH3:32])[CH2:26][C:27]([CH3:30])([CH3:29])[CH2:28]2)[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: CC(=O)c1ccc(C2CC(C)(C)CC(C)(C)C2)c(N2CCN(C(=O)OC(C)(C)C)CC2)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CC(=O)c1ccc(C2CC(C)(C)CC(C)(C)C2)c(N2CCNCC2)c1
Temperature: 25 °C
Yield: 46 %

Procedure:
A mixture of 4-[5-acetyl-2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazine-1-carboxylic acid t-butyl ester (163 mg, 0.368 mmol) produced in Example (82a), diethyl ether (2 mL) and heptane (2 mL) was stirred at room temperature. A 4N solution of hydrogen chloride in ethyl acetate (2 mL, 8 mmol) was added thereto, and the mixture was stirred for 18 hours and 30 minutes. Saturated aqueous solution of sodium hydrogencarbonate was added to the reaction mixture and extraction was performed with diethyl ether. The separated organic layer was washed with water and brine in that order. The mixture was then filtered through Celite, and the filtrate was concentrated under reduced pressure. The resultant residue was purified by NH silica gel column chromatography (ethyl acetate/heptane) to give 58 mg of the title compound as a light yellow oil.
Reaction SMILES: C(O[C:6]([N:8](C(OC(C)(C)C)=O)[C:9](=[O:40])[C:10]1[CH:15]=[C:14]([N:16]2[CH2:20][CH2:19][CH2:18][S:17]2(=[O:22])=[O:21])[CH:13]=[CH:12][C:11]=1[C:23]([N:25]1[CH2:30][CH2:29][N:28]([C:31]2[C:36]([CH3:37])=[CH:35][C:34]([CH2:38][CH3:39])=[CH:33][N:32]=2)[CH2:27][CH2:26]1)=[O:24])=O)(C)(C)C>O1CCCC1.CN>[O:22]=[S:17]1(=[O:21])[CH2:18][CH2:19][CH2:20][N:16]1[C:14]1[CH:13]=[CH:12][C:11]([C:23]([N:25]2[CH2:26][CH2:27][N:28]([C:31]3[C:36]([CH3:37])=[CH:35][C:34]([CH2:38][CH3:39])=[CH:33][N:32]=3)[CH2:29][CH2:30]2)=[O:24])=[C:10]([CH:15]=1)[C:9]([NH:8][CH3:6])=[O:40]
Reactant: CCc1cnc(N2CCN(C(=O)c3ccc(N4CCCS4(=O)=O)cc3C(=O)N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)CC2)c(C)c1
Agent: CN
Solvent: C1CCOC1
Product: CCc1cnc(N2CCN(C(=O)c3ccc(N4CCCS4(=O)=O)cc3C(=O)NC)CC2)c(C)c1
Yield: 65.7 %

Procedure:
Using N,N-di-tert-butyloxycarbonyl-5-(1,1-dioxo-1λ6-isothiazolidin-2-yl)-2-[4-(5-ethyl-3-methylpyridin-2-yl)piperazine-1-carbonyl]benzamide (202 mg) described in Example 785 and 2 mol/L methylamine tetrahydrofuran solution (180 μL) and by the reaction and treatment in the same manner as in Example 770, the title compound (96 mg) was obtained.
Reaction SMILES: F[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([OH:11])[CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+].O1CCC[CH2:22]1>>[OH:8][CH2:6][C:5]1[CH:9]=[C:10]([CH3:22])[CH:2]=[CH:3][C:4]=1[OH:11]
Reactant: O=C(O)c1ccc(F)cc1O
Reactant: C1CCOC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Product: Cc1ccc(O)c(CO)c1
Reaction time: 2 h

Procedure:
A solution of 4.80 g of 4-fluoro-2-hydroxybenzoic acid in 100 ml of tetrahydrofuran is added dropwise at 0° C. to the suspension of 5.29 g of lithium aluminium hydride in 150 ml of tetrahydrofuran and stirred over 2 hours. The reaction mixture is admixed dropwise successively with 6 ml of water, 6 ml of 15% NaOH and 24 ml of water, and stirred over 1 hour. The mixture is filtered and the filtrate is concentrated by evaporation. The crude title compound is obtained as a red-orange oil from the residue. Rf=0.20 (1:1 EtOAc-heptane); Rt=2.47.
Reaction SMILES: [C:1]([N:9]1[CH:14]=[CH:13][C:12](=[O:15])[CH2:11][CH:10]1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18](Cl)[CH:17]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C2C3C(=CC=CC=3)C=CC=2)C2C(=CC=CC=2)C=CC=1.C(PC(C)(C)C)(C)(C)C.C[C:53]([N:55](C)C)=O>[Zn].[C-]#N.[Zn+2].[C-]#N>[C:1]([N:9]1[CH:14]=[CH:13][C:12](=[O:15])[CH2:11][CH:10]1[C:16]1[CH:17]=[C:18]([CH:19]=[CH:20][CH:21]=1)[C:53]#[N:55])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1C=CN(C(=O)c2ccccc2)C(c2cccc(Cl)c2)C1
Reactant: CC(=O)N(C)C
Agent: CC(C)(C)PC(C)(C)C
Agent: [C-]#N
Agent: [Zn+2]
Product: N#Cc1cccc(C2CC(=O)C=CN2C(=O)c2ccccc2)c1
Temperature: 90 °C

Procedure:
1-Benzoyl-2-(3-chlorophenyl)-2,3-dihydro-pyridin-4-one (910 mg) was placed in an argon filled flask together with 42 mg Pd(II) TFA2, 108 mg binaphthyl-di-tert-butyl phosphine, 39 mg zinc powder, 203.4 mg zinc cyanide and 45 ml dimethylacetamide. The solution was degassed with argon and heated at 90° C. for eight hours. After cooling to room temperature, the mixture was filtered through glass fiber filter paper. The supernatant was basified with ammonium hydroxide and the resulting mixture was extracted with diethyl ether. The combined ether extracts were dried over sodium sulfate, filtered, and concentrated in vacuo. Chromatography of the residue gave 350 mg 3-(1-benzoyl-4-oxo-1,2,3,4-tetrahydro-pyridin-2-yl)-benzonitrile.
Reaction SMILES: F[C:2]1[CH:16]=[CH:15][C:5]([C:6]([C:8]2[NH:9][C:10](=[O:14])[NH:11][C:12]=2[CH3:13])=[O:7])=[CH:4][CH:3]=1.[CH3:17][C:18]1[NH:19][C:20]([CH3:24])=[C:21]([CH3:23])[N:22]=1>>[CH3:13][C:12]1[NH:11][C:10](=[O:14])[NH:9][C:8]=1[C:6](=[O:7])[C:5]1[CH:15]=[CH:16][C:2]([N:19]2[C:20]([CH3:24])=[C:21]([CH3:23])[N:22]=[C:18]2[CH3:17])=[CH:3][CH:4]=1
Reactant: Cc1[nH]c(=O)[nH]c1C(=O)c1ccc(F)cc1
Reactant: Cc1nc(C)c(C)[nH]1
Product: Cc1nc(C)n(-c2ccc(C(=O)c3[nH]c(=O)[nH]c3C)cc2)c1C

Procedure:
In a manner similar to Example IV react 4-(4-fluorobenzoyl)-1,3-dihydro-5-methyl-2H-imidazol-2-one with 2,4,5-trimethyl-1H-imidazole to produce the title compound.
Reaction SMILES: [CH:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[OH:14]N1C(=O)C2=CC=CC=C2C1=O.O=O>C(O)(=O)C>[C:1]1(=[O:14])[C:13]2[C:5]([C:6]3[C:11]([CH:12]=2)=[CH:10][CH:9]=[CH:8][CH:7]=3)=[CH:4][CH:3]=[CH:2]1
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: c1ccc2c(c1)Cc1ccccc1-2
Agent: O=O
Solvent: CC(=O)O
Product: O=C1C=CC=C2C1=Cc1ccccc12
Yield: 799.1 %

Procedure:
A mixture containing 166 g (1 mol) of fluorene, 16 g (0.1 mol) of N-hydroxyphthalimide, and 1000 mL of acetic acid was allowed to react at 100° C. for 10 hours in an atmosphere of oxygen to obtain a reaction mixture containing 144 g of fluorenone (yield 80%). From the reaction mixture, acetic acid was distilled off, and to the reaction mixture were added 1000 mL of dibutyl ether and 1000 mL of 0.4N (0.4 mol/L) sodium hydroxide aqueous solution. After stirring at 97° C. for 1 hour, an aqueous phase and an organic phase were separated. To the resulting organic phase were further added sodium hydroxide aqueous solution, and mixed completely at 97° C. to liquid-separate to the aqueous phase and the organic phase. The resulting aqueous and organic phases were analyzed by gas chromatography and liquid chromatography, and, as a result, the extraction ratio of fluorenone into the organic phase was 98%, the extraction ratio of the oxidation catalyst and/or the deactivated oxidation catalyst (conversion into sodium phthalate) (on basis of the amount of N-hydroxyphthalimide used in the reaction) into the aqueous phase was 80%.
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[NH2:8][C:9]1[C:18]2[CH2:17][CH2:16][CH2:15][CH2:14][C:13]=2[CH:12]=[CH:11][CH:10]=1.C([O-])(=O)C.[Na+]>O>[C:5]([NH:8][C:9]1[C:18]2[CH2:17][CH2:16][CH2:15][CH2:14][C:13]=2[CH:12]=[CH:11][CH:10]=1)(=[O:7])[CH3:6]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1cccc2c1CCCC2
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Product: CC(=O)Nc1cccc2c1CCCC2
Reaction time: 0.25 h

Procedure:
Acetic acid anhydride (20 ml) was added to a mixture of 1-amino-5,6,7,8-tetrahydronaphthalene (10 g, 68 mmol), sodium acetate (20 g, 245 mmol) and water (100 ml) at 5° C. The mixture was stirred at room-temperature for 15 minutes. The mixture was cooled on ice for 1 hour followed by filtration. The crystals were washed with water. Yield 13.0 g (100%).