Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:28])[N:4]([C:19]2[O:23][C:22]([C:24]([O:26]C)=[O:25])=[CH:21][CH:20]=2)[C:5]([CH3:18])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17].[OH-].[Na+].Cl.C(#N)C.O>C1COCC1.C(OCC)(=O)C>[Br:1][C:2]1[C:3](=[O:28])[N:4]([C:19]2[O:23][C:22]([C:24]([OH:26])=[O:25])=[CH:21][CH:20]=2)[C:5]([CH3:18])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17]
Reactant: COC(=O)c1ccc(-n2c(C)cc(OCc3ccc(F)cc3F)c(Br)c2=O)o1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CC#N
Solvent: CCOC(C)=O
Product: Cc1cc(OCc2ccc(F)cc2F)c(Br)c(=O)n1-c1ccc(C(=O)O)o1
Temperature: 60 °C

Procedure:
To a room temperature solution of methyl 5-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-2-furoate (step 2) (3.00 g, 6.61 mmol) in THF (20 mL) was added dropwise an aqueous solution of sodium hydroxide (3.0 M, 4.00 mL, 12.0 mmol). The reaction was then heated to 60° C. for 12.0 hours. The resulting suspension was then diluted with 800 mL of ethyl acetate and neutralized with an aqueous solution of hydrochloric acid (3.0 N, 4.0 mL, 12 mmol). The resulting biphasic solution was then concentrated in vacuo to a volume of 90 mL. At this time a white solid began to form and the resulting solid suspension was allowed to sit until precipitation appeared to stop (approximately 1.0 hour). The precipitate was collected and dried in vacuo (1.0 mm Hg) to furnish the solid acid as an intermediate (2.27 g, 78%). 1H NMR (400 MHz, d7-DMF) δ 7.79 (app q, J=8.0 Hz, 1H), 7.32 (t, J=9.2 Hz, 1H), 7.20 (app t, J=7.4 Hz, 1H), 6.88 (app d, J=2.5 Hz, 1H), 6.74 (s, 1H), 6.51 (d, J=2.5 Hz, 1H), 5.44 (s, 2H), 2.10 (s, 3H); LC/MS C-18 column, tr=2.77 minutes (5 to 95% acetonitrile/water over 5 minutes at 1 ml/min with detection 254 nm, at 50° C.). ES-MS m/z 440 (M+H). ES-HRMS m/z 439.9959 (M+H calcd for C18H13BrF2NO5 requires 439.9940).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:13]2[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=2)[N:5]2[C:10]=1[CH:9]=[N:8][C:7]([S:11][CH3:12])=[N:6]2.C(Cl)Cl.C1C=C(Cl)C=C(C(OO)=[O:34])C=1>>[Br:1][C:2]1[CH:3]=[C:4]([C:13]2[CH:14]=[CH:15][C:16]([S:19]([CH3:22])(=[O:20])=[O:21])=[CH:17][CH:18]=2)[N:5]2[C:10]=1[CH:9]=[N:8][C:7]([S:11]([CH3:12])=[O:34])=[N:6]2
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1ncc2c(Br)cc(-c3ccc(S(C)(=O)=O)cc3)n2n1
Solvent: ClCCl
Product: CS(=O)c1ncc2c(Br)cc(-c3ccc(S(C)(=O)=O)cc3)n2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.3 %

Procedure:
Into a 30 mL vial, 5-Bromo-7-(4-methanesulfonyl-phenyl)-2-methylsulfanyl-pyrrolo[2,1-f][1,2,4]triazine (0.140 g, 0.000351 mol) and Methylene chloride (4 mL, 0.07 mol). m-CPBA 70-75% (70:30, m-Chloroperbenzoic acid:3-Chlorobenzoic acid, 0.0910 g, 0.000369 mol) was added portion wise over 10 minutes. The reaction was stirred at room temperature for 2 hours. HPLC suggested no starting material. The reaction was partitioned with DCM and NaHCO3. The organic was separated, washed with water, subsequently Brine and dried over Na2SO4. The solid was filtered and washed with DCM. The organic was removed under vacuum to give 5-Bromo-2-methanesulfinyl-7-(4-methanesulfonyl-phenyl)-pyrrolo[2,1-f][1,2,4]triazine as a yellow solid (140 mg, 96%). The solid was used as is without further purification.
Reaction SMILES: [CH2:1]([N:4]1[C:9](=[O:10])[CH:8]=[C:7]([C:11]([F:14])([F:13])[F:12])[N:6]=[C:5]1SC)[CH:2]=[CH2:3].[F:17][C:18]([F:31])([F:30])[C:19]1[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][C:20]=1[NH2:21].[H-].[Na+].[Cl-].[NH4+]>CN(C=O)C.CCOCC>[CH2:1]([N:4]1[C:9](=[O:10])[CH:8]=[C:7]([C:11]([F:14])([F:13])[F:12])[N:6]=[C:5]1[NH:21][C:20]1[CH:22]=[C:23]([C:26]([F:27])([F:28])[F:29])[CH:24]=[CH:25][C:19]=1[C:18]([F:17])([F:30])[F:31])[CH:2]=[CH2:3]
Reactant: Nc1cc(C(F)(F)F)ccc1C(F)(F)F
Reactant: C=CCn1c(SC)nc(C(F)(F)F)cc1=O
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: C=CCn1c(Nc2cc(C(F)(F)F)ccc2C(F)(F)F)nc(C(F)(F)F)cc1=O
Reaction time: 2.5 h
Yield: 89 %

Procedure:
3-Allyl-2-methylthio-6-trifluoromethyl-4(3H)-pyrimidinone (1.14 g, 4.56 mmol) was dissolved in DMF (15 ml), and 2,5-bis(trifluoromethyl)aniline (0.55 ml, 3.52 mmol) was added. Sodium hydride (60% in oil, 0.23 g, 5.75 mmol) was added with stirring under ice-cooling, followed by stirring at room temperature for 1 hour and then at 70° C. for 2.5 hours. After completion of the reaction, ether (30 ml) and saturated ammonium chloride aqueous solution (30 ml) were added to the reaction solution to separate the organic layer, and the resulting aqueous layer was extracted with ether (20 ml×2). The organic layers were combined, washed with saturated brine (20 ml×2) and then dried over anhydrous sodium sulfate. The drying agent was removed by filtration, and the resulting filtrate was concentrated under a reduced pressure. By purifying the thus obtained crude product by a silica gel column chromatography (hexane), 3-allyl-2-{2,5-bis(trifluoromethyl)phenyl}amino-6-trifluoromethyl-4(3H)pyrimidinone [Compound No. 66] was obtained as a white solid.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([NH:14][C@H:15]3[CH2:19][CH2:18][CH2:17][C@@H:16]3[NH:20]C(=O)OC(C)(C)C)=[N:6][CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[N:9]=2)[CH2:3][CH2:2]1.[ClH:28]>O1CCOCC1>[ClH:28].[CH:1]1([C:4]2[C:5]([NH:14][C@H:15]3[CH2:19][CH2:18][CH2:17][C@@H:16]3[NH2:20])=[N:6][CH:7]=[C:8]([C:10]([F:12])([F:13])[F:11])[N:9]=2)[CH2:2][CH2:3]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCC[C@@H]1Nc1ncc(C(F)(F)F)nc1C1CC1
Agent: Cl
Solvent: C1COCCO1
Product: N[C@H]1CCC[C@@H]1Nc1ncc(C(F)(F)F)nc1C1CC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of tert-butyl N-[(1S,2S)-2-{[3-cyclopropyl-5-(trifluoromethyl)pyrazin-2-yl]amino}cyclopentyl]carbamate (1.54 g, 3.99 mmol) in 1,4-dioxane (14 ml) was added HCl in 1,4-dioxane (4M, 10 ml, 40 mmol). The reaction was stirred at room temperature for 20 hours and was then concentrated in vacuo and azeotropically distilled with toluene to afford the title compound.
Reaction SMILES: C([O-])(=O)C(C(C([O-])=O)O)[OH:3].[NH2:11][CH2:12][CH:13]([CH2:22][CH:23]([CH3:25])[CH3:24])[CH2:14][C:15](N(CC)CC)=[O:16].[OH-].[Na+].[OH-].[K+].Cl>O.CO.ClCCl>[CH3:24][CH:23]([CH2:22][C@H:13]([CH2:12][NH2:11])[CH2:14][C:15]([OH:16])=[O:3])[CH3:25]
Reactant: O=C([O-])C(O)C(O)C(=O)[O-]
Reactant: CCN(CC)C(=O)CC(CN)CC(C)C
Agent: Cl
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: CC(C)C[C@H](CN)CC(=O)O
Temperature: 22.5 °C
Reaction time: 0.21 h

Procedure:
The tartarate salt of 3-aminomethyl N,N-diethyl-5-methyl hexanamide (10 grams) was dissolved in water (15 ml) and dichloromethane (25 ml) was added to it. The pH of reaction mixture was adjusted to 9-10 by addition of sodium hydroxide solution (3.0 grams in 3.0 ml of water) and stirred for 10-15 min at 20-25° C. The aqueous and organic layer was separated. The aqueous layer was extracted with dichloromethane. The solvent was distilled off from combined organic layer to obtain a residue. Potassium hydroxide (5.0 gram), water (10 ml) and methanol (10 ml) was added to the obtained residue and heated it to 70-75° C., the reaction was stirred at this temperature for 18 hours. The reaction mixture was cooled to 30° C. and the pH adjusted to 4.0 using concentrated hydrochloric acid. The reaction mixture was heated to 80° C. and stirred for 45 min and filtered. The filtrate was cooled to 5° C. The solid formed was filtered and washed with cool water. The solid was dried at 50-55° C. to yield (S)-Pregabalin.
Reaction SMILES: Br[C:2]12[CH2:9][CH2:8][C:5]([CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])([CH2:6][CH2:7]1)[CH2:4][CH2:3]2.[C:15]1([CH:21]2[CH2:26][CH2:25][C:24](=[O:27])[CH2:23][CH2:22]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.Cl>[N+](C1C=CC=CC=1)([O-])=O.ClCCl.[Fe](Cl)(Cl)Cl>[CH2:10]([C:5]12[CH2:8][CH2:9][C:2]([C:18]3[CH:19]=[CH:20][C:15]([CH:21]4[CH2:26][CH2:25][C:24](=[O:27])[CH2:23][CH2:22]4)=[CH:16][CH:17]=3)([CH2:3][CH2:4]1)[CH2:7][CH2:6]2)[CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCC12CCC(Br)(CC1)CC2
Reactant: O=C1CCC(c2ccccc2)CC1
Agent: Cl[Fe](Cl)Cl
Agent: Cl
Solvent: O=[N+]([O-])c1ccccc1
Solvent: ClCCl
Product: CCCCCC12CCC(c3ccc(C4CCC(=O)CC4)cc3)(CC1)CC2
Temperature: 80 °C
Reaction time: 0.33 h
Yield: 66.6 %

Procedure:
A solution of 1-bromo-4-pentylbicyclo[2.2.2]octane (6 g, 23 mmol) in sieve-dried nitrobenzene (100 cm3) is added dropwise to a stirred solution of 4-phenylcyclohexanone (3.9 g, 23 mmol) and anhydrous iron(III)chloride (1.2 g, 9 mmol) in sieve-dried nitrobenzene (100 cm3) maintained at 80° C. through the addition and overnight. The cooled solution is added to a small volume of hydrochloric acid and stirred for 20 min. The organic layer is separated off and steam-distilled to yield a solid residue. This is taken up in dichloromethane and dried (MgSO4). The raw product is crystallised from ethanol to yield the desired 4-[4-(4-pentylbicyclo[2.2.2]octyl)phenyl]cyclohexanone (5.4 g, 69%).
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[CH2:6][C@H:5]([N:7]2[C:11]3[N:12]=[CH:13][N:14]=[C:15]([NH2:16])[C:10]=3[C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH:18]=3)=[CH:8]2)[CH2:4]1.[O-:31][C:32]#[N:33].[K+]>CO>[NH2:16][C:15]1[C:10]2[C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH:18]=3)=[CH:8][N:7]([C@H:5]3[CH2:4][C@H:3]([CH2:2][NH:1][C:32]([NH2:33])=[O:31])[CH2:6]3)[C:11]=2[N:12]=[CH:13][N:14]=1
Reactant: NC[C@H]1C[C@H](n2cc(-c3cccc(OCc4ccccc4)c3)c3c(N)ncnc32)C1
Reactant: N#C[O-]
Agent: [K+]
Solvent: CO
Product: NC(=O)NC[C@H]1C[C@H](n2cc(-c3cccc(OCc4ccccc4)c3)c3c(N)ncnc32)C1

Procedure:
To a solution of 50 mg (0.125 mmol) of trans-7-(3-aminomethyl-cyclobutyl)-5-(3-benzyloxy-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine in 5 ml of methanol is added 45 mg (0.561 mmol) of potassium cyanate (Aldrich, Buchs, Switzerland). The mixture is refluxed for one week. After concentration to dryness, the residue is purified by flash-chromatography (dichloromethane:methanol=9:1) to provide trans-{3-[4-amino-5-(3-benzyloxy-phenyl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutylmethyl}-urea. Analytical HPLC: tR=6.43 min (Grad 2); ES-MS: m/eo=443.0.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:27](=[O:28])[N:26]([CH3:29])[C:12]2[N:13]([CH3:25])[C:14]3[C:19]([C:11]=2[CH:10]=1)=[CH:18][C:17]([C:20]1[NH:21][N:22]=[CH:23][CH:24]=1)=[CH:16][CH:15]=3.[CH:30]([N:33]=[C:34]=[O:35])([CH3:32])[CH3:31].CCOCC>C(Cl)(Cl)Cl>[CH:30]([NH:33][C:34]([N:22]1[CH:23]=[CH:24][C:20]([C:17]2[CH:18]=[C:19]3[C:14](=[CH:15][CH:16]=2)[N:13]([CH3:25])[C:12]2[N:26]([CH3:29])[C:27](=[O:28])[C:9]([C:3]4[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=4[Cl:1])=[CH:10][C:11]3=2)=[N:21]1)=[O:35])([CH3:32])[CH3:31]
Reactant: Cn1c(=O)c(-c2ccc(Cl)cc2Cl)cc2c3cc(-c4ccn[nH]4)ccc3n(C)c21
Reactant: CC(C)N=C=O
Solvent: ClC(Cl)Cl
Solvent: CCOCC
Product: CC(C)NC(=O)n1ccc(-c2ccc3c(c2)c2cc(-c4ccc(Cl)cc4Cl)c(=O)n(C)c2n3C)n1

Procedure:
100 mg (0.24 mmol) of compound from Example 39, 3-(2,4-dichlorophenyl)-1,9-dimethyl-6-(2H-pyrazol-3-yl)-1,9-dihydropyrido[2,3-b]indol-2-one, are dissolved in 4 ml of chloroform. 232 μl (2.36 mmol) of isopropyl isocyanate are added and the mixture is then refluxed for 16 hours. The reaction medium is left to cool and then Et2O is added, and the mixture is filtered and washed with a minimum amount of Et2O.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[C:7]2[CH2:13][CH:14]([N+:16]([O-:18])=[O:17])[CH3:15])([O-])=O>CCO.O=[Pt]=O>[NH2:1][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[C:7]2[CH2:13][CH:14]([N+:16]([O-:18])=[O:17])[CH3:15]
Reactant: CC(Cc1c[nH]c2ccc([N+](=O)[O-])cc12)[N+](=O)[O-]
Agent: O=[Pt]=O
Solvent: CCO
Product: CC(Cc1c[nH]c2ccc(N)cc12)[N+](=O)[O-]
Yield: 68.4 %

Procedure:
A solution of 1.5 g (0.006 mole) of 5-nitro-3-(2-nitropropyl)indole in 150 ml of EtOH treated with 100 mg of PtO2 was hydrogenated (Parr) for 15 minutes. The catalyst was filtered and solvent removed in vacuo to give a yellow product which solidified on standing. Recrystallization from EtOH afforded 0.9 g (70%) of desired product: m.p. 120°-121.5°.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[NH:5][C:4]2=[CH:9][C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:11][C:3]=12.[NH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH:19]1[CH2:24][N:25]([CH3:27])[CH3:26].C([O-])([O-])=O.[K+].[K+].C(Cl)Cl>O>[CH3:26][N:25]([CH3:27])[CH2:24][CH:19]1[CH2:20][CH2:21][CH2:22][CH2:23][N:18]1[C:2]1[N:7]=[C:6]([CH3:8])[NH:5][C:4]2[C:3]=1[N:11]=[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH:9]=2
Reactant: Cc1nc(Cl)c2nc(-c3ccccc3)cc-2[nH]1
Reactant: CN(C)CC1CCCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: Cc1nc(N2CCCCC2CN(C)C)c2nc(-c3ccccc3)cc-2[nH]1
Temperature: 140 °C
Reaction time: 2.5 h
Yield: 34.2 %

Procedure:
To a mixture of 4-chloro-2-methyl-6-phenylpyrrolo[3,2-d]pyrimidine (Example 1(e)) (88.3 mg, 0.36 mmol) and N-(2-piperidylmethyl)-dimethylamine (Salor Chemical Company) (0.25 g, 1.72 mmol) was added a solution of K2CO3 (0.25 g, 1.60 mmol) in H2O (2.5 mL). This mixture was stirred at 140° C. in a closed-capped Wheaton vial for 2.5 h. After cooling, CH2Cl2 (10 ML) and H2O (10 mL) were added. The organic solution was removed and the aqueous solution was washed with CH2Cl2 (10 mL). The combined organic solutions were washed with saturated NaCl (15 mL), dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography (3% MeOH:CHCl3 on silica gel) to give 43 mg (34%) of the title compound as a yellow oil. MS m/z: 350 (M+1), 305, 214. 1H NMR (DMSO-d6; 400 MHz): δ 1.63 (m, 6), 2.29 (s, 6), 2.40 (s, 3), 2.81 (m, 2), 3.03 (br t, 1, J=11.8), 4.53-4.63 (m, 2), 6.75 (s, 1), 7.37 (m, 1), 7.50 (t, 2, J=7.5), 7.81 (d, 2, J=7.8), 12.47 (s, 1).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[Br:8][CH:9]([CH3:15])[CH2:10][CH2:11][C:12](Cl)=[O:13].O>C(#N)C>[Br:8][CH:9]([CH3:15])[CH2:10][CH2:11][C:12]([N:5]1[CH2:6][CH2:7][CH:2]([CH3:1])[CH2:3][CH2:4]1)=[O:13]
Reactant: CC1CCNCC1
Reactant: CC(Br)CCC(=O)Cl
Solvent: CC#N
Solvent: O
Product: CC(Br)CCC(=O)N1CCC(C)CC1
Reaction time: 2 h
Yield: 74.7 %

Procedure:
1.09 g of 4-methylpiperidine was dissolved in 10 ml of acetonitrile and added dropwise with 1.09 g of 4-bromovaleroyl chloride. The reaction mixture was stirred for 2 hours, then poured into water and extracted with ethyl acetate. The organic layer was washed with wafer and dried over sodium sulfate, and then the solvent was evaporated under reduced pressure to obtain 1.07 g of the title compound (yield: 82%).
Reaction SMILES: [CH2:1]1[C:8]2[C:7]3[CH:9]=[C:10]([NH2:13])[CH:11]=[CH:12][C:6]=3[O:5][C:4]=2[CH2:3][CH2:2]1.[C:14](Cl)(=[O:19])[CH2:15][CH:16]([CH3:18])[CH3:17]>N1C=CC=CC=1>[CH2:1]1[C:8]2[C:7]3[CH:9]=[C:10]([NH:13][C:14](=[O:19])[CH2:15][CH:16]([CH3:18])[CH3:17])[CH:11]=[CH:12][C:6]=3[O:5][C:4]=2[CH2:3][CH2:2]1
Reactant: CC(C)CC(=O)Cl
Reactant: Nc1ccc2oc3c(c2c1)CCC3
Solvent: c1ccncc1
Product: CC(C)CC(=O)Nc1ccc2oc3c(c2c1)CCC3
Yield: 65.1 %

Procedure:
Following the procedure of Example 1, 2,3-dihydro-1H-cyclopenta[b]benzofuran-7-ylamine (0.69 g, 4.0 mmol) and isovaleryl chloride (0.55 mL, 4.4 mmol) in pyridine (10 mL) provided N-(2,3-Dihydro-1 H-cyclopenta[b]benzofuran-7-yl)-3-methyl-butyramide (0.67 g). Mp 162.0-163.0° C.; Anal. Calcd. for C16H19NO2: C, 74.68; H, 7.44; N, 5.44; Found: C, 74.67; H, 7.70; N, 5.39.
Reaction SMILES: [F:1][C:2]1([F:52])[CH2:7][C@@H:6]([O:8][C:9]2[C:14]([CH3:15])=[CH:13][C:12]([S:16]([N:19](CC3C=CC(OC)=CC=3OC)[C:20]3[CH:25]=[CH:24][N:23]=[CH:22][N:21]=3)(=[O:18])=[O:17])=[C:11]([F:37])[CH:10]=2)[C@H:5]([C:38]2[CH:39]=[N:40][N:41](CC3C=CC(OC)=CC=3)[CH:42]=2)[CH2:4][CH2:3]1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[F:52][C:2]1([F:1])[CH2:7][C@@H:6]([O:8][C:9]2[C:14]([CH3:15])=[CH:13][C:12]([S:16]([NH:19][C:20]3[CH:25]=[CH:24][N:23]=[CH:22][N:21]=3)(=[O:17])=[O:18])=[C:11]([F:37])[CH:10]=2)[C@H:5]([C:38]2[CH:42]=[N:41][NH:40][CH:39]=2)[CH2:4][CH2:3]1
Reactant: COc1ccc(Cn2cc([C@@H]3CCC(F)(F)C[C@H]3Oc3cc(F)c(S(=O)(=O)N(Cc4ccc(OC)cc4OC)c4ccncn4)cc3C)cn2)cc1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(S(=O)(=O)Nc2ccncn2)c(F)cc1O[C@@H]1CC(F)(F)CC[C@H]1c1cn[nH]c1
Yield: 64.2 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 143g by using the 4-({(1R,2S)-5,5-difluoro-2-[1-(4-methoxybenzyl)-1H-pyrazol-4-yl]cyclohexyl}oxy)-N-(2,4-dimethoxybenzyl)-2-fluoro-5-methyl-N-(pyrimidin-4-yl)benzenesulfonamide (0.15 g, 0.20 mmol) prepared in Example 144b, triethylsilane (0.16 mL), trifluoroacetic acid (0.20 mL) and dichloromethane (2.0 mL), to yield the title compound (60 mg, 63%) as a colorless solid.
Reaction SMILES: COC(N[C@H](C1C=CC=CC=1)C(O)=O)=O.Cl.C(OC(=O)[C@@H]1CCCN1)C1C=CC=CC=1.[CH2:32]([O:39][C:40]([C@@H:42]1[CH2:46][CH2:45][CH2:44][N:43]1[C:47](=[O:63])[C@H:48]([NH:55][C:56]([O:58][C:59](C)(C)C)=[O:57])[C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)=[O:41])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>>[CH2:32]([O:39][C:40]([C@@H:42]1[CH2:46][CH2:45][CH2:44][N:43]1[C:47](=[O:63])[C@H:48]([NH:55][C:56]([O:58][CH3:59])=[O:57])[C:49]1[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=1)=[O:41])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1)c1ccccc1
Agent: COC(=O)N[C@@H](C(=O)O)c1ccccc1
Agent: Cl
Agent: O=C(OCc1ccccc1)[C@@H]1CCCN1
Product: COC(=O)N[C@@H](C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1)c1ccccc1

Procedure:
Compound 32 was synthesized from compound 31 and L-proline benzyl ester hydrochloride, following the procedure as described for compound 2a, as a white crystallized solid. MS (ESI, EI+) m/z=397 (MH+).
Reaction SMILES: [CH2:1]([C:9]#[N:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].Cl.[NH2:12][OH:13].C(N(CC)CC)C>CCO>[OH:13][NH:12][C:9](=[NH:10])[CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: NO
Reactant: CCCCCCCCC#N
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCCCCCCCC(=N)NO
Yield: 27 %

Procedure:
Octyl cyanide (2 g, 14 mmol) and hydroxylamine hydrochloride (2.495 g, 36 mmol) were dissolved in EtOH (10 mL) and treated with triethylamine (5 mL, 36 mmol) at reflux over night. Extraction: AcOEt/water. Silica gel chromatography: heptane/AcOEt 1:2 afforded a white solid (0.65 g, 26%). MS: m/z=173 (M +H).
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[OH:13][C:14]1[C:22]([N+:23]([O-:25])=[O:24])=[CH:21][C:17]([C:18]([OH:20])=O)=[CH:16][C:15]=1[O:26][CH3:27].[NH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][O:35][C:36](=[O:42])[NH:37][C:38]([CH3:41])([CH3:40])[CH3:39]>O1CCCC1>[OH:13][C:14]1[C:22]([N+:23]([O-:25])=[O:24])=[CH:21][C:17]([C:18]([NH:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][O:35][C:36](=[O:42])[NH:37][C:38]([CH3:40])([CH3:39])[CH3:41])=[O:20])=[CH:16][C:15]=1[O:26][CH3:27]
Reactant: COc1cc(C(=O)O)cc([N+](=O)[O-])c1O
Reactant: CC(C)(C)NC(=O)OCCCCCCN
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: COc1cc(C(=O)NCCCCCCOC(=O)NC(C)(C)C)cc([N+](=O)[O-])c1O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
8.9 g of 1.1'-carbonyldiimidazole are added to a solution of 10.7 g of 4-hydroxy-3-methoxy-5-nitrobenzoic acid in 500 ml of dry tetrahydrofuran and the reaction mixture is subsequently heated to 65°-70° for 5 hours. It is then cooled to room temperature and a solution of 21.6 g of 6-aminohexyl-t-butylcarbamate in 50 ml of dry tetrahydrofuran is added dropwise thereto within 15 minutes. The reaction mixture is then heated to 65°-70° for 18 hours, evaporated, the residue is suspended in ethyl acetate, suction filtered and the suction filtered material is chromatographed on silica gel with acetone/methylene chloride (3:1). There is obtained [6-(4-hydroxy-5-nitro-m-anisamido)hexyl]-t-butylcarbamate of m.p. 145°-147° (from isopropanol).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]([OH:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].FC(F)(F)C(OC(=O)C(F)(F)F)=O.[CH3:25][C:26]([CH3:28])=O>FC(F)(F)C(O)=O>[OH:11][C:9]1[CH:8]=[CH:7][C:3]2[C:4](=[O:6])[O:5][C:26]([CH3:28])([CH3:25])[O:1][C:2]=2[CH:10]=1
Reactant: O=C(O)c1ccc(O)cc1O
Reactant: CC(C)=O
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)OC(=O)c2ccc(O)cc2O1
Reaction time: 24 h

Procedure:
A suspension of 2,4-dihydroxybenzoic acid (85.0 g) in trifluoroacetic acid (800 mL) was cooled in an ice/water bath as trifluoroacetic anhydride (500 mL) followed by the addition of acetone (100 mL). After the addition was complete, the ice/water bath was removed and the reaction mixture stirred for 24 hours before the volatiles were removed under vacuum using a rotary evaporator. The residue was cautiously added to a water/sodium bicarbonate suspension to afford a neutralized mixture. The mixture was extracted with ethyl acetate and the combined organic phases were washed with brine, dried over magnesium sulfate, filtered and evaporated. The residue was triturated with dichloromethane to afford the product (I-1a) as an off-white solid.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:5][CH:4]=1.C(=O)([O-])O.[Na+].Br[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[C:28]#[N:29]>O>[CH3:1][N:2]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[C:28]#[N:29])[C:3]1[CH:4]=[CH:5][C:6]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:7][CH:8]=1
Reactant: CCOC(=O)Cc1ccc(NC)cc1
Reactant: N#Cc1ccccc1CBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CCOC(=O)Cc1ccc(N(C)Cc2ccccc2C#N)cc1
Yield: 112.8 %

Procedure:
N-Methyl-4-ethoxycarbonylmethylaniline (10 g), sodium hydrogencarbonate (5 g), water (5 ml), and 2-bromomethylcyanobenzene (12.2 g) were treated in the same manner as described in Example 1 for the preparation of the starting material. 18 g of N-methyl-N-(2-cyanobenzyl)-4-ethoxycarbonylmethylaniline was obtained as a light-yellow oily material.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:12]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=2)[OH:13])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2]>C(Cl)Cl.O=[Mn]=O>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=2)=[O:13])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2]
Reactant: CCOc1cc(C(O)c2cccc(OC)c2)ccc1OC
Agent: O=[Mn]=O
Solvent: ClCCl
Product: CCOc1cc(C(=O)c2cccc(OC)c2)ccc1OC
Yield: 91.6 %

Procedure:
To a stirred solution of (3-ethoxy-4-methoxy-phenyl)-(3-methoxy-phenyl) -methanol (1.75 g, 6.1 mmol) in CH2Cl2 (20 mL) at room temperature was added activated MnO2 powder (3.5 g, 40 mmol) and kept adding 23 equivalents of MnO2 every 35 h until HPLC showed disappearance of the starting material. The black suspension was filtered through a Celite pad, concentrated in vacuo to give (3-ethoxy-4-methoxy-phenyl)-(3-methoxy-phenyl)-methanone as an off-white solid (1.60 g, 92% yield): 1H NMR (CDCl3) δ 1.53 (t, J=7 Hz, 3H, CH2CH3), 3.86 (s, 3H, OCH3), 3.96 (s, 3H, OCH3), 4.17 (q, J=7 Hz, 2H, CH2CH3), 6.90 (d, J=8 Hz, 1H, Ar), 7.09-7.14 (m, 1H, Ar), 7.29-7.49 (m, 5H, Ar). The product was used in the next step without further purification.