Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([C:12]2[C:13]([CH3:42])([CH3:41])[C@H:14]3[C@:27]([CH3:30])([CH2:28][CH:29]=2)[C@@H:26]2[C@:17]([CH3:40])([C@@:18]4([CH3:39])[C@H:23]([CH2:24][CH2:25]2)[C@H:22]2[C@H:31]([C:34]([CH3:36])=[CH2:35])[CH2:32][CH2:33][C@:21]2([CH:37]=O)[CH2:20][CH2:19]4)[CH2:16][CH2:15]3)[CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].Cl.[NH2:44][CH2:45][CH2:46][C:47]([N:49]1[CH2:53][CH2:52][CH2:51][CH2:50]1)=[O:48]>>[F:1][C:2]1[CH:11]=[C:10]([C:12]2[C:13]([CH3:42])([CH3:41])[C@H:14]3[C@:27]([CH3:30])([CH2:28][CH:29]=2)[C@@H:26]2[C@:17]([CH3:40])([C@@:18]4([CH3:39])[C@H:23]([CH2:24][CH2:25]2)[C@H:22]2[C@H:31]([C:34]([CH3:36])=[CH2:35])[CH2:32][CH2:33][C@:21]2([CH2:37][NH:44][CH2:45][CH2:46][C:47](=[O:48])[N:49]2[CH2:53][CH2:52][CH2:51][CH2:50]2)[CH2:20][CH2:19]4)[CH2:16][CH2:15]3)[CH:9]=[CH:8][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: C=C(C)[C@@H]1CC[C@]2(C=O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)c(F)c6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: NCCC(=O)N1CCCC1
Agent: Cl
Product: C=C(C)[C@@H]1CC[C@]2(CNCCC(=O)N3CCCC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)O)c(F)c6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Yield: 67 %

Procedure:
The title compound was prepared in 67% yield following steps 5 and 6, using methyl 2-fluoro-4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-formyl-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate and 3-amino-1-(pyrrolidin-1-yl)propan-1-one hydrochloride as the reactant amine MS: m/e 687.5 (MH+), 1.74 min (method 2). 1H NMR (400 MHz, MeOD) δ ppm 0.96 (s, 3H) 0.98 (s, 3H) 1.02 (s, 3H) 1.08 (s, 3H) 1.16 (s, 3H) 1.73 (s, 3H) 0.90-1.86 (m, 20H) 1.88-1.96 (m, J=6.78, 6.78, 6.65, 6.40 Hz, 2H) 1.97-2.10 (m, 1H) 2.01 (dt, J=13.74, 6.81 Hz, 2H) 2.16 (dd, J=17.19, 6.40 Hz, 1H) 2.47-2.57 (m, 1H) 2.81 (t, J=6.02 Hz, 2H) 2.88 (d, J=12.55 Hz, 1H) 3.33-3.42 (m, 3H) 3.42-3.52 (m, 4H) 4.65 (s, 1H) 4.76 (d, J=1.76 Hz, 1H) 5.35 (dd, J=5.77, 1.00 Hz, 1H) 6.94 (d, J=11.80 Hz, 1H) 7.02 (dd, J=8.03, 1.25 Hz, 1H) 7.83 (t, J=7.91 Hz, 1H). 19F NMR (376 MHz, MeOD) δ ppm −112.76 (s, 1 F).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[C:11]([CH3:27])=[C:12]([C:23]([O:25]C)=[O:24])[CH:13]=[C:14]4[C:22]=3[C:18]3[O:19][CH2:20][O:21][C:17]=3[CH:16]=[CH:15]4)=[CH:9][C:4]=2[O:3][CH2:2]1.[OH-].[Na+].Cl.O>C1COCC1.CO>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[C:11]([CH3:27])=[C:12]([C:23]([OH:25])=[O:24])[CH:13]=[C:14]4[C:22]=3[C:18]3[O:19][CH2:20][O:21][C:17]=3[CH:16]=[CH:15]4)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: COC(=O)c1cc2ccc3c(c2c(-c2ccc4c(c2)OCO4)c1C)OCO3
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(C(=O)O)cc2ccc3c(c2c1-c1ccc2c(c1)OCO2)OCO3
Reaction time: 96 h

Procedure:
Methyl 9-(1,3-benzodioxole-5-yl)-8-methyl-naphtho[1,2-d]-1,3-dioxole-7-carboxylate was dissolved in a mixture of THF (6 ml) and methanol (3 ml). After addition of 1N NaOH (3 ml), the mixture was stirred for 4 days. 1N HCl was added to the reaction mixture, followed by addition of water. The resulting precipitate was collected by filtration to yield the title compound (264 mg). Some portions of the compound was recrystalized from methanol-chloroform to be used for elemental and instrumental analysis.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6][CH2:5]2.Cl[C:14]1[CH:22]=[CH:21][C:17]([C:18]([NH2:20])=[O:19])=[CH:16][N:15]=1.C([O-])([O-])=O.[K+].[K+]>>[O:12]=[C:8]1[CH2:7][CH2:6][CH2:5][C:4]2[CH:3]=[C:2]([O:1][C:14]3[CH:22]=[CH:21][C:17]([C:18]([NH2:20])=[O:19])=[CH:16][N:15]=3)[CH:11]=[CH:10][C:9]1=2
Reactant: NC(=O)c1ccc(Cl)nc1
Reactant: O=C1CCCc2cc(O)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Product: NC(=O)c1ccc(Oc2ccc3c(c2)CCCC3=O)nc1
Yield: 72.1 %

Procedure:
Using a method similar to Intermediate 1, using 6-hydroxy-1-tetralone (5.00 g, 30.8 mmol), 6-chloronicotinamide (4.38 g, 28.0 mmol) and K2CO3 (5.81 g, 42.0 mmol) gives the little compound (5.7 g) as a yellow solid. Mass spectrum (ion spray): m/z=283 (M+1); 1HNMR (DMSO-d6): 8.63 (s, 1H), 8.29 (d, 1H), 8.06 (s, 1H), 7.90 (d, 1H), 7.51 (s, 1H), 7.16 (d, 1H), 7.12 (s, 1H), 7.09 (d, 1H), 2.92 (t, 2H), 2.58 (t, 2H), 2.03 (m, 2H).
Reaction SMILES: CN(C)C=O.[F:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:18][CH2:17][N:16]([C:19]3[N:24]=[CH:23][NH:22][C:21](=[O:25])[N:20]=3)[CH2:15][CH2:14]2)=[CH:9][CH:8]=1.CC1C=CC(S(O[CH2:37][C:38]2[S:39][C:40]([C:43]([F:46])([F:45])[F:44])=[CH:41][CH:42]=2)(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C.O>[F:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:14][CH2:15][N:16]([C:19]3[N:24]=[CH:23][N:22]([CH2:37][C:38]4[S:39][C:40]([C:43]([F:46])([F:45])[F:44])=[CH:41][CH:42]=4)[C:21](=[O:25])[N:20]=3)[CH2:17][CH2:18]2)=[CH:9][CH:8]=1
Reactant: O=c1nc(N2CCN(c3ccc(F)cc3)CC2)nc[nH]1
Reactant: Cc1ccc(S(=O)(=O)OCc2ccc(C(F)(F)F)s2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=c1nc(N2CCN(c3ccc(F)cc3)CC2)ncn1Cc1ccc(C(F)(F)F)s1
Reaction time: 2 h
Yield: 11.9 %

Procedure:
To an N,N-dimethylformamide solution (1 mL) of 4-[4-(4-fluorophenyl)piperazin-1-yl]-1,3,5-triazin-2(1H)-one (50.0 mg, 0.18 mmol) synthesized in Reference Synthesis Example 3, [5-(trifluoromethyl)thiophen-2-yl]methyl 4-methylbenzenesulfonate (121 mg, 0.36 mmol) synthesized in Reference Synthesis Example 51 and potassium carbonate (99 mg, 0.72 mmol) were added and the resultant mixture was stirred at 80° C. for 2 hours. To the reaction solution, [5-(trifluoromethyl)thiophen-2-yl]methyl 4-methylbenzenesulfonate (500 mg, 0.48 mmol) was added and the resultant reaction solution was stirred further for 2 hours. After the completion of the reaction, water was added to the reaction solution and extraction with ethyl acetate from the resultant reaction solution was performed three times. The organic layer was washed with brine, was dried over anhydrous magnesium sulfate, and was concentrated under reduced pressure. The resultant residue was purified by silica gel column chromatography (hexane/ethyl acetate=4/1) to obtain the title compound (9.4 mg, yield: 12%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][P:7](=[O:14])([O:11][CH2:12][CH3:13])[O:8][CH2:9][CH3:10].[O:15]1[CH:20]=[CH:19][CH2:18][CH2:17][CH2:16]1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>ClCCl>[O:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH:16]1[O:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][P:7](=[O:14])([O:8][CH2:9][CH3:10])[O:11][CH2:12][CH3:13]
Reactant: C1=COCCC1
Reactant: CCOP(=O)(CCCCCO)OCC
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CCOP(=O)(CCCCCOC1CCCCO1)OCC

Procedure:
A solution of 66.9 g (0.298 mol) of diethyl 5-hydroxypentylphosphonate, 32.6 g (0.38 mol) of 3,4-dihydropyran and 1 g (0.004 mol) of pyridinium toluene-4-sulfonate in 800 ml of dichloromethane was heated under reflux for 16 hours. The solution was washed with water and saturated sodium hydrogen carbonate solution, dried over sodium sulfate and distilled in a bulb tube.
Reaction SMILES: [CH:1](=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[CH2:10](Br)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.CCCCCC>[CH2:20]([O:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[CH:1]=[O:9])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH3:10]
Reactant: CCCCCCCCCCCBr
Reactant: O=Cc1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: CCCCCCCCCCCOc1ccccc1C=O
Temperature: 100 °C

Procedure:
A mixture of salicylaldehyde (10.15 mmoles), undecylbromide (10.3 mmoles) and potassium carbonate (11.7 mmoles) in dimethylformamide (10 ml) is heated to 100° C. for 1 hour and then is cooled. The reaction mixture is taken up in hexane and is washed with 5 percent sodium hydroxide and brine. After treatment with anhydrous magnesium sulfate and charcoal, the volatiles are removed under vacuum and the residue is purified by flash chromatography to give the desired product.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([F:9])[CH:8]=1)[NH2:5].C(=O)([O-])O.[Na+].Cl[C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17]>CC(C)=O.O>[F:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([F:9])[CH:8]=1)[NH:5][C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: Nc1cc(F)cc(F)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: O=C(Nc1cc(F)cc(F)c1)OCc1ccccc1
Reaction time: 16 h
Yield: 93.8 %

Procedure:
3,5-Difluoroaniline (4.89 g, 37 91 mM) in acetone (130 ml) and water (70 ml) at 0° C. was treated with sodium hydrogen carbonate (6.55 g, 78.0 mM) and then benzyl chloroformate (6.67 g, 5.6 ml, 39.23 mM) over 10 min. The mixture was stirred for 16 h and then poured into ice. The resultant precipitate was collected and washed with water to give the title carbamate (9.35 g, 94%);
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]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].Br[C:21]1[S:22][C:23]2[C:29]([N+:30]([O-:32])=[O:31])=[C:28]([O:33][CH3:34])[CH:27]=[CH:26][C:24]=2[N:25]=1>O.COCCOC>[CH3:34][O:33][C:28]1[CH:27]=[CH:26][C:24]2[N:25]=[C:21]([C:2]3[CH:3]=[CH:4][C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[CH:1]=3)[S:22][C:23]=2[C:29]=1[N+:30]([O-:32])=[O:31]
Reactant: COc1ccc2nc(Br)sc2c1[N+](=O)[O-]
Reactant: OB(O)c1ccc2ccccc2c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COc1ccc2nc(-c3ccc4ccccc4c3)sc2c1[N+](=O)[O-]
Temperature: 85.5 °C
Reaction time: 18 h
Yield: 83.4 %

Procedure:
0.716 g (4.16 mmol; 1.1 equivalent) of 2-naphthalene boronic acid as well as a solution of 1.2 g (11.35 mmol; 3 equivalents) of sodium carbonate in 15 ml of water are added to a suspension of 1.09 g (3.78 mmol) of 2-bromo-6-methoxy-7-nitro-1,3-benzothiazole and 131 mg (0.114 mmol; 0.03 equivalent) of palladium tetrakis-triphenylphosphine in 30 ml of 1,2-dimethoxyethane. The reaction mixture is maintained under stirring at 85.5° C. for 18 hours, then after concentration under reduced pressure, 100 ml of ethyl acetate is added to the medium which is then washed with twice 75 ml of a saturated aqueous solution of sodium chloride. The organic phase is dried over sodium sulphate then the solvents are evaporated off under reduced pressure and the residue is purified by chromatography on a silica column (eluent: ethyl acetate/heptane mixture 1:2). 1.06 g (83% yield) of 6-methoxy-2-(2-naphthyl)-7-nitro-1,3-benzothiazole is obtained in the form of beige powder.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[N:8]([CH:14]1[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]1=[O:21])[C:7]2=[O:22].[Cl:23][C:24]1[CH:32]=[CH:31][C:27]([C:28](Cl)=[O:29])=[CH:26][CH:25]=1.CCN(C(C)C)C(C)C>C1COCC1>[Cl:23][C:24]1[CH:32]=[CH:31][C:27]([C:28]([NH:2][CH2:3][C:4]2[CH:5]=[C:6]3[C:10](=[CH:11][CH:12]=2)[C:9](=[O:13])[N:8]([CH:14]2[CH2:19][CH2:18][C:17](=[O:20])[NH:16][C:15]2=[O:21])[C:7]3=[O:22])=[O:29])=[CH:26][CH:25]=1
Reactant: NCc1ccc2c(c1)C(=O)N(C1CCC(=O)NC1=O)C2=O
Reactant: O=C(Cl)c1ccc(Cl)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=C1CCC(N2C(=O)c3ccc(CNC(=O)c4ccc(Cl)cc4)cc3C2=O)C(=O)N1
Temperature: 40 °C
Yield: 62.6 %

Procedure:
To a stirred mixture of 5-aminomethyl-2-(2,6-dioxo-piperidin-3-yl)-isoindole-1,3-dione hydrochloride (0.97 g, 3.00 mmol) and 4-chlorobenzoyl chloride (0.53 g, 3.30 mmol) in THF (20 mL), was added DIPEA (1.05 mL, 6.00 mmol) at room temperature under nitrogen. The mixture was heated to 40° C. for 18 h then cooled to rt. The solvent was removed in vacuo and the residue was dissolved in EtOAc (100 mL). The organic layer was washed with dil. aq. HCl (2×150 mL), water (100 mL), dried (MgSO4) and then concentrated. The crude product was purified by column chromatography (0-5% MeOH/CH2Cl2). The product fractions were combined, concentrated and triturated in Et2O (50 mL) for 18 h. The product was isolated by filtration and dried in vacuo to give 4-chloro-N-[2-(2,6-dioxo-piperidin-3-yl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-benzamide as a white solid (0.80 g, 63% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 40/60 CH3CN/0.1% H3PO4, 4.97 min (97.05%); mp: 178-180° C.; 1H NMR (DMSO-d6) δ 1.92-2.15 (m, 1H, CHH), 2.54-2.71 (m, 2H, CHH, CHH), 2.77-3.02 (m, 1H, CHH), 4.65 (d, J=5.9 Hz, 2H, CH2), 5.15 (dd, J=5.5, 12.8 Hz, 1H, CH), 7.53-7.63 (m, 2H, Ar), 7.74-7.87 (m, 2H, Ar), 7.87-8.03 (m, 3H, Ar), 9.31 (t, J=5.9 Hz, 1H, NH), 11.13 (s, 1H, NH); 13C NMR (DMSO-d6) δ 21.99, 30.93, 42.67, 48.99, 122.01, 123.55, 128.50, 129.21, 129.84, 131.62, 132.64, 133.47, 136.30, 147.38, 165.40, 166.96, 167.10, 169.80, 172.72; LCMS: MH=426/428; Anal Calcd for C21H16N3O5Cl: C, 58.98; H, 3.82; N, 9.83. Found: C, 58.67; H, 3.67; N, 9.53.
Reaction SMILES: N1C=CC=CC=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:16])=CC=1.[NH2:29][C:30]1[CH:35]=[CH:34][C:33](=O)[N:32]([CH3:37])[N:31]=1.C(Cl)(Cl)Cl>CO>[NH2:29][C:30]1[CH:35]=[CH:34][C:33](=[S:16])[N:32]([CH3:37])[N:31]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: Cn1nc(N)ccc1=O
Solvent: CO
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: Cn1nc(N)ccc1=S
Yield: 64.3 %

Procedure:
Pyridine (5 ml) and a Lawesson's reagent (970 mg, 2.4 mmol) were added to 3-amino-1-methyl-1,6-dihydropyridazin-6-one (500 mg, 4 mmol) as described in Journal of Medicinal Chemistry, 34 (10), 3074 (1991), and the mixture was refluxed under heating for 5 hours. The reaction mixture was concentrated and the residue obtained was subjected to silica gel column chromatography (chloroform:methanol=100:1) to give 218 mg of 3-amino-1-methyl-1,6-dihydropyridazine-6-thione.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:36]=[CH:37][CH:38]=1)[CH2:8][N:9]1[C@@H:17]2[C@H:12]([C@H:13]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([NH:27][C:28](=[O:33])[CH2:29][N:30]([CH3:32])[CH3:31])=[C:23]([F:34])[CH:22]=3)[CH2:14][S:15](=[O:19])(=[O:18])[CH2:16]2)[O:11]C1=O)([CH3:4])([CH3:3])[CH3:2]>C1(C)C=CC=CC=1>[C:1]([C:5]1[CH:6]=[C:7]([CH:36]=[CH:37][CH:38]=1)[CH2:8][NH:9][C@H:17]1[CH2:16][S:15](=[O:19])(=[O:18])[CH2:14][C@@H:13]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([NH:27][C:28](=[O:33])[CH2:29][N:30]([CH3:31])[CH3:32])=[C:23]([F:34])[CH:22]=2)[C@@H:12]1[OH:11])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C)CC(=O)Nc1ccc(C[C@@H]2CS(=O)(=O)C[C@H]3[C@H]2OC(=O)N3Cc2cccc(C(C)(C)C)c2)cc1F
Solvent: Cc1ccccc1
Product: CN(C)CC(=O)Nc1ccc(C[C@@H]2CS(=O)(=O)C[C@H](NCc3cccc(C(C)(C)C)c3)[C@H]2O)cc1F

Procedure:
The title compound was prepared in analogous manner as described for example 1o from N-{4-[(3aR*,7S*,7aS*)-3-(3-tert-butyl-benzyl)-2,5,5-trioxo-octahydro-1-oxa-5lambda*6*-thia-3-aza-inden-7-ylmethyl]-2-fluoro-phenyl}-2-dimethylamino-acetamide to yield an amorphous solid: TLC (toluene-ETA 85:15) Rf=0.34; HPLC RtA=1.47 min; ESIMS [M+H]+=520; 1H NMR (600 MHz, DMSO-d6): δ 9.46 (s, 1H), 7.86 (t, 1H), 7.35 (s, 1H), 7.23 (m, 2H), 7.13 (d, 1H), 7.10 (d, 1H), 6.98 (d, 1H), 5.22 (d, 1H), 3.79 (m, 1H), 3.63 (m, 1H), 3.38 (m, 1H), 3.16 (m, 1H), 3.08 (m, 3H), 2.98 (m, 2H), 2.79 (m, 1H), 2.64 (m, 1H), 2.51 (m, 1H), 2.41 (br, 1H), 2.27 (s, 6H), 2.04 (m, 1H), 1.25 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:18]([O-])=O)[C:5]([O:8][C:9]2[C:14]([O:15][CH3:16])=[CH:13][CH:12]=[CH:11][C:10]=2[F:17])=[N:6][CH:7]=1>CC(O)=O.CCOC(C)=O.[Fe]>[Cl:1][C:2]1[CH:3]=[C:4]([NH2:18])[C:5]([O:8][C:9]2[C:14]([O:15][CH3:16])=[CH:13][CH:12]=[CH:11][C:10]=2[F:17])=[N:6][CH:7]=1
Reactant: COc1cccc(F)c1Oc1ncc(Cl)cc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: COc1cccc(F)c1Oc1ncc(Cl)cc1N
Temperature: 80 °C

Procedure:
AcOH (30 mL) and iron powder (5 g) were charged into a round bottom flask equipped with a magnetic stirring bar and warmed to 80° C. A solution of crude 5-chloro-2-(2-fluoro-6-methoxy-phenoxy)-3-nitro-pyridine in AcOH was added slowly into the mixture, keeping the temperature under 85° C. The reaction mixture was then cooled to room temperature, diluted with EtOAc, and filtered through a pad of Celite. The filtrate was concentrated under reduced pressure and the residue was partitioned between NaHCO3 and EtOAc. The organic portion was separated and the aqueous portion was extracted with EtOAc. The combined extracts were dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to provide 5-chloro-2-(2-fluoro-6-methoxy-phenoxy)-pyridin-3-ylamine (3.56 g) as a colorless powder.
Reaction SMILES: [Mg].[CH2:2]([O:9][C:10]1[CH:15]=[CH:14][C:13](Br)=[CH:12][CH:11]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:17]([CH:21]1[CH2:26][CH2:25][CH:24](C2CCC(=O)CC2)[CH2:23][CH2:22]1)[CH2:18][CH2:19][CH3:20].Cl>C1COCC1>[CH2:17]([CH:21]1[CH2:26][CH2:25][CH:24]([C:12]2[C:11]([C:10]3([OH:9])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]3)=[C:10]([O:9][CH2:2][C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=3)[CH:15]=[CH:14][CH:13]=2)[CH2:23][CH2:22]1)[CH2:18][CH2:19][CH3:20]
Reactant: Brc1ccc(OCc2ccccc2)cc1
Reactant: CCCCC1CCC(C2CCC(=O)CC2)CC1
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Product: CCCCC1CCC(c2cccc(OCc3ccccc3)c2C2(O)CCCCC2)CC1
Reaction time: 12 h

Procedure:
To the Grignard reagent which was prepared from 2.31 g (95.1 mmol) of dried magnesium and 25.0 g (95.0 mmol) of 4-benzyloxy-bromobenzene in 300 ml of THF, was added dropwise 100 ml of solution of 21.0 g (88.8 mmol) of 4-(4-n-butylcyclohexyl)-cyclohexanone in THF at room temperature, and the mixture was stirred at the same temperature for 12 hours. The reaction solution was added to 500 ml of 0.5N hydrochloric acid, the product thus formed was extracted with ether, the extract was washed with saturated aqueous sodium bicarbonate solution and water in this turn, and then the solvent was distilled off. After the residue was purified by column chromatography on silica gel (eluent: toluene), the solvent was distilled off, and the residue was recrystallized from toluene to give 11.8 g (28.1 mmol) of 4-(4-(4-n-butyl-cyclohexyl(-1-hydroxycyclohexyl)-1-benzyloxybenzene. Yield of this compound based on 4-(4-n-butylcyclohexyl)cyclohexanone was 31.6%.
Reaction SMILES: [C:1](=[S:3])=S.[OH-].[K+].C(O)C.[F:9][C:10]1[CH:38]=[CH:37][C:13]([O:14][C:15]2[C:23]3[N:22]=C(C4C=CC=CN=4)[NH:20][C:19]=3[CH:18]=[C:17]([O:30][C:31]3[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=3)[CH:16]=2)=[CH:12][CH:11]=1>C(OCC)(=O)C>[F:9][C:10]1[CH:38]=[CH:37][C:13]([O:14][C:15]2[C:23]3[N:22]=[C:1]([SH:3])[NH:20][C:19]=3[CH:18]=[C:17]([O:30][C:31]3[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=3)[CH:16]=2)=[CH:12][CH:11]=1
Reactant: Fc1ccc(Oc2cc(Oc3cccnc3)cc3[nH]c(-c4ccccn4)nc23)cc1
Reactant: S=C=S
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Fc1ccc(Oc2cc(Oc3cccnc3)cc3[nH]c(S)nc23)cc1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
0.06 ml of carbon disulfide and 54 mg of potassium hydroxide were added to an ethanol (2.0 ml) solution of 273 mg of 3-(4-fluoro-phenoxy)-5-(pyridin-3-yloxy)-benzene-1,2-diamine obtained in Example 68, and the reaction liquid was stirred overnight at 80° C. The reaction liquid was diluted with ethyl acetate, washed with water and saturated saline in order, and dried with anhydrous magnesium sulfate. The solvent was evaporated away under reduced pressure to obtain the entitled compound.
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[CH2:12][O:11][C:10]([CH3:16])([CH3:15])[C@H:9]1[C:17]([OH:19])=[O:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH2:1]([N:8]1[C:13](=[O:14])[CH2:12][O:11][C:10]([CH3:16])([CH3:15])[C@H:9]1[C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1(C)OCC(=O)N(Cc2ccccc2)[C@@H]1C(=O)O
Reactant: BrCc1ccccc1
Product: CC1(C)OCC(=O)N(Cc2ccccc2)[C@@H]1C(=O)OCc1ccccc1
Yield: 54 %

Procedure:
(S)-4-benzyl-2,2-dimethyl-5-oxomorpholine-3-carboxylic acid (11.2 g, 42.5 mmol) was reacted with benzyl bromide (8.72 g, 51 mmol) according to the procedure as described in Example 34, Step A to give the title compound as a white solid (8.11 g, 54%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [CH:1]1([CH2:7][N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[C:15]1[C:24]([CH:25]=[O:26])=[CH:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[CH:1]1([CH2:7][N:8]2[CH2:9][CH2:10][N:11]([C:15]3[C:24]([CH:25]=[O:26])=[CH:23][C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[N:16]=3)[CH2:12][CH2:13]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=Cc1cc2ccccc2nc1Cl
Reactant: C1CCC(CN2CCNCC2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1cc2ccccc2nc1N1CCN(CC2CCCCC2)CC1
Temperature: 110 °C
Reaction time: 0.33 h
Yield: 83 %

Procedure:
1-(Cyclohexylmethyl)piperazine (0.42 mL, 2.2 mmol) was added to a mixture of 2-chloro-3-quinolinecarboxaldehyde (0.383 g, 2.0 mmol) and potassium carbonate (0.7 g, 5.0 mmol) in anhydrous DMF (4 mL) at ambient temperature under a nitrogen atmosphere. After being stirred for 20 minutes, the reaction mixture was heated at 110° C. for 4.5 h. After cooling to room temperature this mixture was diluted with water (40 mL) and extracted with ethyl acetate (3×30 mL). The combined organic extracts were washed with brine, dried over sodium sulfate, filtered, and then concentrated under vacuum to give a pale brown crude product. Purification by silica gel column chromatography and eluting with 2.5% methanol in dichloromethane afforded the title compound (0.56 g), yield: 86%.
Reaction SMILES: [N:1]([O-:3])=O.[Na+].[C:5]1([C:11](=[O:19])[CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.Cl.C(=O)([O-])[O-].[Na+].[Na+]>O>[C:5]1([C:11](=[O:19])[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[N:1][OH:3])[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: O=N[O-]
Reactant: O=C(Cc1ccccn1)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=C(C(=NO)c1ccccn1)c1ccccc1
Reaction time: 2 h

Procedure:
A solution of 8.75 g (127 mmol) of sodium nitrite in water was added dropwise to a solution of 25 g (127 mmol) of 1-phenyl-2-pyridin-2-ylethanone in 250 ml of water/conc. hydrochloric acid (8:1) at room temperature. After 2 h, the solution was neutralized with sodium carbonate. The product crystallized out overnight to result in 25.3 g of 1-phenyl-2-pyridin-2-ylethane-1,2-dione 2-oxime.
Reaction SMILES: CC1NC(C2C=C(C=CC=2C)C(OC)=O)=C(C)N=1.[CH3:19][C:20]1[CH:29]=[C:28]([CH3:30])[C:27](B2OC(C)(C)C(C)(C)O2)=[CH:26][C:21]=1[C:22]([O:24][CH3:25])=[O:23].CC1C=CC(C(OC)=O)=CC=1B1OC(C)(C)C(C)(C)O1.I[C:61]1[NH:65][C:64]([C:66]2([CH3:70])[CH2:69][O:68][CH2:67]2)=[N:63][C:62]=1[CH3:71].IC1NC(C)=NC=1C>>[CH3:19][C:20]1[CH:29]=[C:28]([CH3:30])[C:27]([C:61]2[NH:65][C:64]([C:66]3([CH3:70])[CH2:69][O:68][CH2:67]3)=[N:63][C:62]=2[CH3:71])=[CH:26][C:21]=1[C:22]([O:24][CH3:25])=[O:23]
Reactant: Cc1nc(C2(C)COC2)[nH]c1I
Reactant: COC(=O)c1cc(B2OC(C)(C)C(C)(C)O2)c(C)cc1C
Agent: COC(=O)c1ccc(C)c(-c2[nH]c(C)nc2C)c1
Agent: COC(=O)c1ccc(C)c(B2OC(C)(C)C(C)(C)O2)c1
Agent: Cc1nc(C)c(I)[nH]1
Product: COC(=O)c1cc(-c2[nH]c(C3(C)COC3)nc2C)c(C)cc1C

Procedure:
The title compound was prepared using standard chemical manipulations and procedures similar to those used for the preparation of compound 5.6, except methyl 2,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (compound 160.1) was used in place of methyl 4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (compound 5.4) and 5-iodo-4-methyl-2-(3-methyloxetan-3-yl)-1H-imidazole (compound 175.2) was used in place of 5-iodo-2,4-dimethyl-1H-imidazole (compound 5.5). m/z (ES+) 315 (M+H)+.