Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:7])[CH2:5][SH:6])[CH3:2].[H-].[Na+].F[C:11]1[CH:18]=[CH:17][C:14]([CH:15]=[O:16])=[CH:13][C:12]=1[N+:19]([O-:21])=[O:20]>CN(C=O)C>[CH:15]([C:14]1[CH:17]=[CH:18][C:11]([S:6][CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:7])=[C:12]([N+:19]([O-:21])=[O:20])[CH:13]=1)=[O:16]
Reactant: O=Cc1ccc(F)c([N+](=O)[O-])c1
Reactant: CCOC(=O)CS
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CSc1ccc(C=O)cc1[N+](=O)[O-]
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 24.4 %

Procedure:
To a solution of ethyl-2-mercaptoacetate (0.7 mmol) in dry DMF (2.5 ml), sodium hydride (0.85 mmol) was added 0° C. After 15 minutes, 4-fluoro-3-nitrobenzaldehyde (0.7 mmol) was added and the mixture was heated at 60° C. overnight and monitored by TLC until completion. After cooling, the solvent was removed under reduced pressure. The residue was chromatogaphed on a silica gel column (cyclogexane/ethyl acetate 4/1 as eluent) to give 46 mg of ethyl 2-(4-formyl-2-nitrophenylthio)acetate as yellow compound (yield 24%). 1H NMR, (250 MHz, CDCl3): δ 1.25 (t, J=7.5 Hz, 3H), 3.80 (s, 2H), 4.21 (q, J=7.75, 2H), 7.64 (d, J=9.75, 1H), 8.03 (d, J=9.75, 1H), 8.68 (s, 1H), 10.00 (s, 1H) 13C NMR (126 MHz, CDCl3): δ 15.4, 36.5, 63.8, 128.5, 129.3, 133.9, 145.6, 147.1, 169.5, 190.1.
Reaction SMILES: [CH2:1]([C:5]1[N:14]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH:23]([C:30]([O:32]C)=[O:31])[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[C:18]([Cl:34])[CH:17]=2)[C:13](=[O:35])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([CH3:36])[CH:11]=2)[N:6]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+].Cl>CO>[CH2:1]([C:5]1[N:14]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH:23]([C:30]([OH:32])=[O:31])[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[C:18]([Cl:34])[CH:17]=2)[C:13](=[O:35])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([CH3:36])[CH:11]=2)[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2ccc(C)cc2c(=O)n1Cc1ccc(OC(C(=O)OC)c2ccccc2)c(Cl)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCc1nc2ccc(C)cc2c(=O)n1Cc1ccc(OC(C(=O)O)c2ccccc2)c(Cl)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 71.4 %

Procedure:
To a solution of 72 mg of the product of Step C dissolved in 2 mL of methanol, was added 0.25 mL of a 1N solution of NaOH and the reaction mixture was stirred at room temperature for 3 days. The reaction mixture was then adjusted to pH 7 with 1N HCl, caoncentrated in vacuo, and the residue was applied to a silica gel flash chromatography column and eluted with CHCl3 /MeOH/NH4OH (80:15:1). Evaporation of the purified fractions and drying in vacuo afforded 50 mg (71%) of the title compound.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].[N:26]1[C:35]2[C:30](=[CH:31][CH:32]=[C:33]([C:36](O)=[O:37])[CH:34]=2)[CH:29]=[CH:28][CH:27]=1>>[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][N:20]([C:36]([C:33]4[CH:34]=[C:35]5[C:30]([CH:29]=[CH:28][CH:27]=[N:26]5)=[CH:31][CH:32]=4)=[O:37])[CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: O=C(O)c1ccc2cccnc2c1
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)cc1OC
Agent: Cl
Product: COc1ccc(C2=NN(C3CCN(C(=O)c4ccc5cccnc5c4)CC3)C(=O)C2(C)C)cc1OC

Procedure:
The title compound is prepared analogously as described for GP2-WU2 using 5-(3,4-dimethoxyphenyl)-4,4-dimethyl-2-(piperidin-4-yl)-2,4-dihydro-3H-pyrazol-3-one (compound B1) and quinoline-7-carboxylic acid as starting compounds. The crude product is purified by chromatography (amino phase silica gel and DCM) and by crystallization from DCM and diethyl ether to yield the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[N:11]([CH2:22][C:23]3[CH:32]=[CH:31][C:26]([C:27]([O:29]C)=[O:28])=[CH:25][CH:24]=3)[N:10]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.CO.[OH-].[Na+]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=3)[N:11]([CH2:22][C:23]3[CH:24]=[CH:25][C:26]([C:27]([OH:29])=[O:28])=[CH:31][CH:32]=3)[N:10]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: COC(=O)c1ccc(Cn2nc(-c3cc(Cl)cc(Cl)c3)cc2-c2ccc(OC)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(-c2cc(-c3cc(Cl)cc(Cl)c3)nn2Cc2ccc(C(=O)O)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of the intermediate from step C (Isomer A, 0.99 g, 2.13 mmol) in THF (30 mL) was added methanol (10 mL) followed by sodium hydroxide solution (2N, 2 mL, 4 mmol). The reaction was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo to remove the organic solvents. The residue was acidified with 1N HCl until the pH was less than 2. The resulting solution was extracted with ethyl acetate (3×) dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give the title compound as a white solid. This material was used in the next step without any further purification. 1H NMR (DMSO, 500 MHz): δ 7.89(d, J=8.2 Hz, 2H), 7.88(d, J=1.8 Hz, 2H), 7.55(d, J=1.9 Hz, 1H), 7.38(d, J=8.7 Hz, 2H), 7.15(d, J=8.3 Hz, 2H), 7.11(s, 1H), 7.04(d, J=8.7 Hz, 2H), 5.5(s, 2H), 3.79(s, 3H). LC-MS: 2.69 min. (M+H)=453.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([C:18](O)=[O:19])=[C:13]2[N:12]=[CH:11][C:10]=1[C:21]([N:23]1[CH2:28][CH2:27][C:26]2([C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH:30]=[CH:29]2)[CH2:25][CH2:24]1)=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:37][S:38]([NH2:41])(=[O:40])=[O:39]>>[CH2:1]([NH:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([C:18]([NH:41][S:38]([CH3:37])(=[O:40])=[O:39])=[O:19])=[C:13]2[N:12]=[CH:11][C:10]=1[C:21]([N:23]1[CH2:28][CH2:27][C:26]2([C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH:30]=[CH:29]2)[CH2:25][CH2:24]1)=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1cnn2c(NCc3ccccc3)c(C(=O)N3CCC4(C=Cc5ccccc54)CC3)cnc12
Reactant: CS(N)(=O)=O
Product: CS(=O)(=O)NC(=O)c1cnn2c(NCc3ccccc3)c(C(=O)N3CCC4(C=Cc5ccccc54)CC3)cnc12
Yield: 29.7 %

Procedure:
In the same manner as in Example 1, step 6 and using 7-benzylamino-6-(spiro[inden-1,4′-piperidine]-1′-ylcarbonyl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (0.125 g, 0.260 mmol) obtained in step 2 and methanesulfonamide (0.123 g, 1.30 mmol), the title compound (0.043 g, 29%) was obtained.
Reaction SMILES: [C:1]([OH:24])(=[O:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].[OH:25][CH2:26][C:27]([CH2:32]O)([CH2:30][OH:31])[CH2:28][OH:29]>>[C:1]([O:24][CH2:32][C:27]([CH2:30][OH:31])([CH2:28][OH:29])[CH2:26][OH:25])(=[O:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCCCCCCCCCCCCCCCCCC(=O)O
Reactant: OCC(CO)(CO)CO
Product: CCCCCCCCCCCCCCCCCCCCCC(=O)OCC(CO)(CO)CO
Temperature: 130 °C

Procedure:
A four-necked rounded bottom flask equipped with a stirrer, a thermocouple, and a nitrogen inlet tube was charged with 4 mol of behenic acid per mol of pentaerythritol, and the contents were heated to 130° C. for 5 hours in a nitrogen atmosphere to carry out an esterification reaction. A reaction product was purified with methyl ether to provide pentaerythritol behenate. Here, the acid value was 0.4 mgKOH/g, and the hydroxyl value was 1.6 mgKOH/g.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[N:9][C:10]3[C:15]([N:16]=2)=[CH:14][C:13]([C:17]2[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][CH:18]=2)=[CH:12][CH:11]=3)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH3:24][N:25]([CH3:30])[S:26](Cl)(=[O:28])=[O:27]>N1C=CC=CC=1>[CH3:24][N:25]([CH3:30])[S:26](=[O:28])(=[O:27])[NH:23][C:20]1[CH:21]=[CH:22][C:17]([C:13]2[CH:14]=[C:15]3[C:10](=[CH:11][CH:12]=2)[N:9]=[CH:8][C:7]([N:1]2[CH2:2][CH2:3][O:4][CH2:5][CH2:6]2)=[N:16]3)=[CH:18][CH:19]=1
Reactant: CN(C)S(=O)(=O)Cl
Reactant: Nc1ccc(-c2ccc3ncc(N4CCOCC4)nc3c2)cc1
Solvent: c1ccncc1
Product: CN(C)S(=O)(=O)Nc1ccc(-c2ccc3ncc(N4CCOCC4)nc3c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.6 %

Procedure:
A mixture of 4-(3-morpholin-4-yl-quinoxalin-6-yl)-phenylamine [intermediate example 4.1] (100 mg) and pyridine (0.5 mL) was treated with a solution of dimethylsulfamyl chloride (75 mg, 0.65 mmol) in pyridine (0.6 mL) and stirred at room temperature overnight. The reaction was partitioned between dichloromethane and water, the phases separated and the organic layer concentrated in vacuo. The residue was purified by preparative reverse phase HPLC to give the title compound (71 mg). 1H-NMR (300 MHz, d6-DMSO) δ=10.06 (1H, br s), 8.76 (1H, s), 7.84 (1H, d), 7.66-7.79 (4H, m)), 7.27 (2H, d), 3.72 (8H, s), 2.70 (6H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:13][CH2:12][CH2:11][C:10]2=[O:14])=[CH:5][C:3]=1[NH2:4].[Cl:15][C:16]1[CH:21]=[C:20]([C:22]([O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])=[O:23])[CH:19]=[C:18]([Cl:39])[C:17]=1[N:40]1[C:44](=[O:45])[CH2:43][C:42](OCC)=[N:41]1.CS(O)(=O)=O>C(OCC)(=O)C>[Cl:15][C:16]1[CH:21]=[C:20]([C:22]([O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])=[O:23])[CH:19]=[C:18]([Cl:39])[C:17]=1[N:40]1[C:44](=[O:45])[CH2:43][C:42]([NH:4][C:3]2[CH:5]=[C:6]([N:9]3[CH2:13][CH2:12][CH2:11][C:10]3=[O:14])[CH:7]=[CH:8][C:2]=2[Cl:1])=[N:41]1
Reactant: CCCCCCCCCCCCCCOC(=O)c1cc(Cl)c(N2N=C(OCC)CC2=O)c(Cl)c1
Reactant: Nc1cc(N2CCCC2=O)ccc1Cl
Agent: CS(=O)(=O)O
Solvent: CCOC(C)=O
Product: CCCCCCCCCCCCCCOC(=O)c1cc(Cl)c(N2N=C(Nc3cc(N4CCCC4=O)ccc3Cl)CC2=O)c(Cl)c1
Temperature: 150 °C

Procedure:
A mixture of 4.4 g of 2-chloro-5-(2-oxo-pyrrolidin-1-yl)aniline, 10.2 g of 1-(2,6-dichloro-4-tetradecyloxycarbonylphenyl)-3-ethoxy-2-pyrazolin-5-one and 0.5 g of methanesulfonic acid was stirred with heating at 150° C. under reduced pressure for 12 hours. After cooling, the reaction mixture was dissolved in ethyl acetate and washed three times with water. After distilling off the solvent, the residue was separated by a silica gel chromatography (using a solvent mixture of ethyl acetate and chloroform as a spreading agent) to obtain the desired compound. By recrystallization from acetonitrile 9 g of crystals having a melting point of 143° to 146° C. were obtained.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][CH:8]2[C:20]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[C:14]3[C:9]2=[CH:10][CH:11]=[CH:12][CH:13]=3)=[CH:3][CH:2]=1.C[OH:22]>>[N:1]1[CH:2]=[CH:3][C:4]([CH2:7][C:8]2([OH:22])[C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=3[C:15]3[C:20]2=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:5][CH:6]=1
Reactant: c1ccc2c(c1)-c1ccccc1C2Cc1ccncc1
Reactant: CO
Product: OC1(Cc2ccncc2)c2ccccc2-c2ccccc21

Procedure:
By substituting 9-(4-pyridinylmethyl)-9H-fluorene in Prep 3, the corresponding carbinol was obtained.
Reaction SMILES: O=[C:2]1[CH2:10][CH:9]2[CH2:11][C:5]3([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:6][CH:7]([CH2:12][CH:3]1[CH2:4]3)[CH2:8]2.[NH2:21][OH:22].Cl.[OH-].[Na+]>CCO.O>[OH:22][N:21]=[C:2]1[CH2:10][CH:9]2[CH2:11][C:5]3([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:6][CH:7]([CH2:12][CH:3]1[CH2:4]3)[CH2:8]2
Reactant: NO
Reactant: CC(C)(C)OC(=O)NC12CC3CC(=O)C(CC(C3)C1)C2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)NC12CC3CC(=NO)C(CC(C3)C1)C2
Temperature: 80 °C
Yield: 90 %

Procedure:
The mixture of ketone 1D (10 mmol), NH2OH—HCl (5 mmol), and NaOH (5 mmol) was diluted with EtOH (5 mL) and H2O (1 mL) and the reaction mixture was heated at 80° C. for 16 h. Upon cooling, the reaction mixture was extracted with DCM (10 mL×3) and the combined organic layers were dried (Na2SO4) and concentrated to provide oxime 12A in 90% yield as a solid. The material was used in the next step without further purification. Data: LC/MS (ESR) m/z 295 [M+1]+.
Reaction SMILES: [CH3:1][Li].[C:3]1([CH2:9][O:10][NH:11][C:12]2([CH3:30])[CH2:21][CH2:20][CH2:19][C:18]3[N:17]=[C:16]([O:22][CH2:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH:15]=[CH:14][C:13]2=3)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>O1CCCC1>[C:3]1([CH2:9][O:10][N:11]([CH3:1])[C:12]2([CH3:30])[CH2:21][CH2:20][CH2:19][C:18]3[N:17]=[C:16]([O:22][CH2:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH:15]=[CH:14][C:13]2=3)[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CC1(NOCc2ccccc2)CCCc2nc(OCc3ccccc3)ccc21
Reactant: [Li]C
Solvent: C1CCOC1
Product: CN(OCc1ccccc1)C1(C)CCCc2nc(OCc3ccccc3)ccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 65 %

Procedure:
Methyllithium (1.4M in diethyl ether, 37.7 ml) was added dropwise over 20 min to a solution of N,2-bis(phenylmethoxy)-5,6,7,8-tetrahydro-5-methyl-5-quinolinamine (18.1 g) and tetrahydrofuran (20 ml) at -78° C. The mixture was allowed to warm to room temperature over 2 hrs and was stirred at room temperature for an additional 1 hr. The solution was quenched with saturated ammonium chloride solution and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous potassium carbonate, filtered, and the filtrate was concentrated. The residue was purified by high performance liquid chromatography (silica gel, elution with ethyl acetate-hexanes) to provide 12.3 g (65%) of product.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:4]=[C:5]([CH2:13][CH2:14][CH2:15]O)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C(Br)(Br)(Br)[Br:20].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl.CCCCC.C([O-])(O)=O.[Na+]>[F:1][C:2]([F:18])([F:17])[C:3]1[CH:4]=[C:5]([CH2:13][CH2:14][CH2:15][Br:20])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: OCCCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: BrC(Br)(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCC
Solvent: ClCCl
Product: FC(F)(F)c1cc(CCCBr)cc(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 74 %

Procedure:
3-[3′,5′-bis(trifluoromethyl)phenyl]-1-propanol (0.88 g, 3.2 mmol) and CBr4 (1.3 g, 4.0 mmol) were dissolved in CH2Cl2 (5 mL) and cooled to 0° C. Triphenylphosphine (1.3 g, 4.8 mmol) was added in three portions over 0.5 h. The mixture was stirred at 0° C. for 10 min., then diluted with pentane (30 mL) and sat. NaHCO3 (30 mL). The aqueous layer was separated and washed with ethyl ether, and the combined organic layers were dried (MgSO4) and concentrated. The residue was purified by silica gel flash chromatography (99:1 ethyl ether-hexane) to yield 0.8 g, (74%) of the 3-[3′,5′-bis(trifluoromethyl)phenyl]-1-bromopropane.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:22])=[CH:4][C:5]([OH:21])=[C:6]([CH:20]=1)[C:7]([C:9]1[C:14]([CH:15]2[O:19][CH2:18][CH2:17][O:16]2)=[CH:13][CH:12]=[CH:11][N:10]=1)=O.Cl.[C:24]([O:28][NH2:29])([CH3:27])([CH3:26])[CH3:25].N1CCCC1>C(O)CC>[C:24]([O:28]/[N:29]=[C:7](\[C:9]1[C:14]([CH:15]2[O:19][CH2:18][CH2:17][O:16]2)=[CH:13][CH:12]=[CH:11][N:10]=1)/[C:6]1[CH:20]=[C:2]([Cl:1])[C:3]([F:22])=[CH:4][C:5]=1[OH:21])([CH3:27])([CH3:26])[CH3:25]
Reactant: O=C(c1cc(Cl)c(F)cc1O)c1ncccc1C1OCCO1
Reactant: CC(C)(C)ON
Agent: Cl
Solvent: CCCO
Solvent: C1CCNC1
Product: CC(C)(C)O/N=C(/c1cc(Cl)c(F)cc1O)c1ncccc1C1OCCO1
Yield: 30.5 %

Procedure:
A solution of 2-(5-chloro-4-fluoro-2-hydroxybenzoyl)-3-(1,3-dioxolan-2-yl)pyridine (1.45 g), O-t-butylhydroxylamine hydrochloride (1.69 g) and pyrrolidine (9.56 g) in n-propanol (20 ml) was heated for 1.5 hour under reflux. The reaction mixture was concentrated, to which was added water, followed by extraction with ethyl acetate. The extract solution was washed with a saturated aqueous saline solution, dried (anhydrous sodium sulfate), and concentrated. The concentrate was purified by means of a silica gel column chromatography (eluent: ethyl acetate/hexane) to give a mixture (540 mg) of (Z)-2-(5-chloro-4-fluoro-2-hydroxybenzoyl)-3-(1,3-dioxolan-2-yl)pyridine O-t-butyloxime and (Z)-2-[5-chloro-2-hydroxy-4-(pyrrolidin-1-yl)benzoyl]-3-(1,3-dioxolan-2-yl)pyridine O-t-butyloxime (about 2:1). A mixture of this mixture (470 mg), p-toluenesulfonic acid monohydrate (162 mg), acetone (9.0 ml) and water (3.5 ml) was heated for 14 hours under reflux. The reaction mixture was concentrated, to which was added water, followed by extraction with ethyl acetate. The extract solution was washed with a saturated aqueous saline solution, dried (anhydrous sodium sulfate), and concentrated to leave an oily substance. This oily substance was dissolved in chloroform (2.0 ml), to which was added, at room temperature, 50% m-chloroperbenzoic acid (75 mg). The mixture was stirred for 8 minutes at the same temperature, which was then poured into an aqueous solution of sodium sulfite, followed by extraction with ethyl acetate. The extract solution was washed with a saturated aqueous saline solution, dried (anhydrous sodium sulfate), and concentrated. The concentrate was purified by means of a silica gel column chromatography (eluent: ethyl acetate/hexane) to give (Z)-2-(5-chloro-4-fluoro-2-hydroxybenzoyl)-3-formylpyridine O-t-butyloxime (230 mg) (Compound 155).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=4[O:27][CH2:28][CH:29]4[CH2:31][CH2:30]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1.Cl[C:33]([O:35][CH2:36][CH3:37])=[O:34]>>[CH2:36]([O:35][C:33](=[O:34])[NH:1][C@H:2]1[CH2:7][CH2:6][C@@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=4[O:27][CH2:28][CH:29]4[CH2:30][CH2:31]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1)[CH3:37]
Reactant: CCOC(=O)Cl
Reactant: N[C@H]1CC[C@@H](NC(=O)c2c[nH]c3c(-c4ccc(F)cc4OCC4CC4)ncnc23)CC1
Product: CCOC(=O)N[C@H]1CC[C@@H](NC(=O)c2c[nH]c3c(-c4ccc(F)cc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from cis-4-(2-Cyclopropylmethoxy-4-fluoro-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (4-amino-cyclohexyl)-amide (example A156) and ethyl chloroformate the title compound is obtained as colorless solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([F:9])[CH:8]=1)[NH2:5].Cl.[N+]([O-])([O-])=O.[Na+].[N-:16]=[N+:17]=[N-].[Na+]>O>[F:1][C:2]1[CH:3]=[C:4]([N:5]=[N+:16]=[N-:17])[CH:6]=[C:7]([F:9])[CH:8]=1
Reactant: [N-]=[N+]=[N-]
Reactant: Nc1cc(F)cc(F)c1
Agent: Cl
Agent: O=[N+]([O-])[O-]
Agent: [Na+]
Solvent: O
Product: [N-]=[N+]=Nc1cc(F)cc(F)c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 90.3 %

Procedure:
3,5-Difluoroaniline (64.5 g, 0.5 mol) is added to a solution of water (206 ml) and concentrated hydrochloric acid (116 ml). The resulting solution is stirred for 10 minutes and cooled to 0° C. A solution of sodium nitrate (37.4 g, 0.54 mol) in water (125 ml) is added in a dropwise manner. After being stirred for one hour, the mixture is filtered and the filtrate is cooled to 0° C. A solution of sodium azide (40.2 g, 0.62 mol) in water (125 ml) is added in a dropwise manner, and stirring is allowed to continue for 30 minutes. The reaction mixture is extracted with ether (3×250 ml), and the combined organic extracts are washed with saturated sodium bicarbonate solution (250 ml) and then brine (250 ml), and dried over sodium sulfate. Removal of the volatiles in vacuo affords pure title compound as a yellow liquid (70 g, 90%).
Reaction SMILES: CCN=C=NCCCN(C)C.OC(C(F)(F)F)=O.[NH2:19][CH2:20][C:21]([NH:23][CH:24]1[CH2:27][N:26]([CH:28]2[CH2:33][CH2:32][CH:31]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH2:30][CH2:29]2)[CH2:25]1)=[O:22].[CH3:40][O:41][C:42]1[CH:50]=[CH:49][C:45]([C:46](O)=[O:47])=[CH:44][C:43]=1[C:51]([F:54])([F:53])[F:52]>>[CH3:40][O:41][C:42]1[CH:50]=[CH:49][C:45]([C:46]([NH:19][CH2:20][C:21](=[O:22])[NH:23][CH:24]2[CH2:27][N:26]([CH:28]3[CH2:33][CH2:32][CH:31]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[CH2:30][CH2:29]3)[CH2:25]2)=[O:47])=[CH:44][C:43]=1[C:51]([F:52])([F:53])[F:54]
Reactant: NCC(=O)NC1CN(C2CCC(c3ccccc3)CC2)C1
Reactant: COc1ccc(C(=O)O)cc1C(F)(F)F
Agent: CCN=C=NCCCN(C)C
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(C(=O)NCC(=O)NC2CN(C3CCC(c4ccccc4)CC3)C2)cc1C(F)(F)F

Procedure:
The title compound was prepared as a white solid from EDCI coupling of 2-amino-N-[1-(4-phenyl-cyclohexyl)-azetidin-3-yl]-acetamide TFA salt (as prepared in Step D of Example 66) and 4-methoxy-3-trifluoromethyl-benzoic acid (Aldrich) using the procedure described in Step F of Example 1.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][O:8][C:9](=[O:35])[CH:10]([NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26](=[O:34])[C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=1)[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1.[Br:36][CH2:37][CH2:38]Br>C(#N)C>[CH3:7][O:8][C:9](=[O:35])[CH:10]([NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26](=[O:34])[C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=1)[CH2:11][C:12]1[CH:13]=[CH:14][C:15]([O:18][CH2:38][CH2:37][Br:36])=[CH:16][CH:17]=1
Reactant: BrCCBr
Reactant: COC(=O)C(Cc1ccc(O)cc1)Nc1ccccc1C(=O)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)C(Cc1ccc(OCCBr)cc1)Nc1ccccc1C(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 58 %

Procedure:
To a solution of potassium carbonate (2 kg) in acetonitrile (5000 ml) is added 2-[(2-(4-fluorobenzoyl)phenyl)amino]-3-(4-hydroxyphenyl)-propionic acid methyl ester (581 g, 1.48 mol) and 1,2-dibromoethane (1000 ml). Then the mixture is stirred at room temperature for 24 hours. After that, the reaction mixture is filtered, and then the filtrate is evaporated under a vacuum. The crude product is purified by silica gel chromatography using hexane/EtOAc (4:1) as eluent to give 2-[(2-(4-fluorobenzoyl)phenyl)amino]-3-[4-(2-bromoethoxy)-phenyl]-propionic acid methyl ester (429 g, 58%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][CH:9]=[C:10]2[CH2:13][C:14]([O:16]CC)=[O:15])=[CH:5][CH:4]=1>[OH-].[Na+].C(O)C>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][CH:9]=[C:10]2[CH2:13][C:14]([OH:16])=[O:15])=[CH:5][CH:4]=1
Reactant: CCOC(=O)Cc1cccc2ccc(OC)cc12
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc2cccc(CC(=O)O)c2c1

Procedure:
A mixture of the ethyl 7-methoxynaphth-1-ylacetate obtained above in 250 cm3 of 20% sodium hydroxide in ethanol is refluxed for 3 hours.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8]Cl)=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:12]1([CH3:21])[CH:17]=[CH:16][C:15]([S:18]([O-:20])=[O:19])=[CH:14][CH:13]=1.[Na+].[K+].[Br-]>CN(C=O)C.O>[CH3:21][C:12]1[CH:17]=[CH:16][C:15]([S:18]([CH2:8][C:7]2[CH:10]=[CH:11][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)(=[O:20])=[O:19])=[CH:14][CH:13]=1
Reactant: O=[N+]([O-])c1ccc(CCl)cc1
Reactant: Cc1ccc(S(=O)[O-])cc1
Agent: [Br-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(S(=O)(=O)Cc2ccc([N+](=O)[O-])cc2)cc1
Reaction time: 18 h

Procedure:
4-Nitrobenzyl chloride (5.0 g, 29.1 mmole) and sodium p-toluenesulfinate (6.8 g, 37.9 mmole) were dissolved in 50 mL of dry DMF. The mixture was stirred at about 23° for about 18 hours then diluted with water. The sulfone crystallized from the aqueous mixture and was filtered. The sulfone was purified by recrystallization from ethanol to give a pale yellow crystalline solid, mp 188°-190° (7.6 g, 25.9 mmole, 89%): IR (KBr) 2994, 1598, 1514, 1490, 1342, 1312, 1304, 1148, 824 cm-1 ; 1H NMR (CDCl3) δ 2.44 (s, 3H), 4.38 (s, 2H), 7.27 (m, 4H), 7.53 (d, J=8.3 Hz, 2H), 8.13 (d, J=8.3 Hz, 2H); MS m/e 292 (MH+).