Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH2:16][C:17]1[N:18]=[C:19]([CH3:22])[S:20][CH:21]=1)[C:11]1[CH2:10][CH2:9][C@@H:8]([NH:23][C:24](=[O:28])[CH:25]([CH3:27])[CH3:26])[CH2:7][C:6]2=1)=O.Cl.[CH3:30][O:31][NH2:32]>N1C=CC=CC=1.O.Cl.CCOC(C)=O>[CH3:30][O:31][N:32]=[CH:1][C:3]1[CH:4]=[C:5]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH2:16][C:17]1[N:18]=[C:19]([CH3:22])[S:20][CH:21]=1)[C:11]1[CH2:10][CH2:9][C@@H:8]([NH:23][C:24](=[O:28])[CH:25]([CH3:26])[CH3:27])[CH2:7][C:6]2=1
Reactant: Cc1nc(Cn2c3c(c4cc(C=O)ccc42)C[C@H](NC(=O)C(C)C)CC3)cs1
Reactant: CON
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O
Solvent: c1ccncc1
Product: CON=Cc1ccc2c(c1)c1c(n2Cc2csc(C)n2)CC[C@@H](NC(=O)C(C)C)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 61.6 %

Procedure:
Dissolve (R)-N-[6-formyl-9-(2-methyl-thiazol-4-ylmethyl)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]-isobutyramide (Example 211) (53 mg, 0.13 mmol) and methoxyamine HCl (22 mg, 0.27 mmol) in pyridine (1 mL). Stir the reaction mixture for 18 h at 25° C. Dilute the reaction mixture with water (2 mL), 1N HCl (1 mL), and EtOAc (10 mL). Load the mixture onto a Varian ChemElut CE1005 solid-phase extraction cartridge (Varian part number 12198006), then elute, collect, and concentrate 50 mL EtOAc to give the crude product (59 mg) as a white solid. Purify on 8 g silica gel (50-60% EtOAc/hexanes) to afford 34 mg (62%) of the title compound as a white solid. MS (ES): m/z 425 (M+1), 469 (M+HCO2−); 1H NMR (CDCl3): δ 8.16 (s, 1H), 7.63 (d, 1H, J=1.3 Hz), 7.44 (dd, 1H, J=8.6, 1.5 Hz), 7.24 (d, 1H, J=8.5 Hz), 6.36 (s, 1H), 5.55 (d, 1H, J=7.9 Hz), 5.29 (td, 2H, J=24.7, 9.0 Hz), 4.41 (m, 1H), 3.96 (s, 3H), 3.13 (dd, 1H, J=15.4, 4.8 Hz), 2.80 (m, 2H), 2.68 (s, 3H), 2.62 (dd, 1H, J=15.6, 6.8 Hz), 2.30 (m, 1H), 2.14-1.97 (m, 2H), 1.14 (d, 6H, J=6.6 Hz).
Reaction SMILES: [CH2:1]1[CH2:5][O:4][CH2:3][CH2:2]1.[N+:6]([C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)([O-:8])=[O:7].C(O[CH2:19][CH3:20])C>>[N+:6]([C:9]1[CH:14]=[CH:13][C:12]([O:15][C@H:20]2[CH:19]=[CH:5][C:1]3[C:2](=[CH:5][CH:1]=[CH:2][CH:3]=3)[C@@H:3]2[OH:4])=[CH:11][CH:10]=1)([O-:8])=[O:7]
Reactant: C1CCOC1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: CCOCC
Product: O=[N+]([O-])c1ccc(O[C@H]2C=Cc3ccccc3[C@@H]2O)cc1
Temperature: 80 °C
Yield: 94 %

Procedure:
To a flame dried round-bottomed flask, [Rh(COD)Cl]2 (1.7 mg, 0.0035 mmol), (S)—(R)-PPF-PtBu2 (3.8 mg, 0.0069 mmol) and 1 (100 mg, 0.694 mmol) were added followed by addition of THF (2.5 mL) and 4-nitrophenol (483 mg, 3.47 mmol). The mixture was heated at 80° C. for 45 minutes, then poured into diethyl ether and extracted 3 times with 10% aqueous sodium hydroxide solution. The aqueous extracts were combined and back-extracted three times with diethyl ether. The combined ether extracts were washed with brine and dried with anhydrous sodium sulfate. The solvents were removed in vacuo, yielding a solid which was purified by flash chromatography on silica gel (30% ethyl acetate in hexanes) giving a white crystalline solid 3 (184 mg, 94%). The ee was determined to be 97% by formation of Mosher's ester. Fr=0.43 on silica (30% ethyl acetate:hexanes); mp 123-125° C. (dec.); [α]25D=+169.90 (c=10.3, CHCl3); IR (KBr, cm−1) 3351 (br), 3113 (w), 3071 (w), 2884 (w), 2843 (w), 1591 (s), 1503 (s), 1342 (s), 1295 (m), 1110 (m), 896 (w); 1H NMR (400 MHz, CDCl3): δ 8.18 (2H, d, J=9.2 Hz), 7.62-7.60 (1H, m), 7.31-7.29 (2H, m), 7.15-7.13 (1H, m), 6.99 (2H, d, J=9.2 Hz), 6.57 (1H, d, J=9.9 Hz), 5.94 (1H, d, J=9.9 Hz), 5.20 (2H, s), 2.61 (1H, s); 13C NMR(400 MHz,CDCl3): δ 162.6, 141.8, 135.0, 131.5, 130.2, 128.5, 128.4, 126.8, 126.0, 125.5, 124.1, 115.4, 79.6, 72.0.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[CH:9][C:4]=1[CH2:5][N:6]=[C:7]=[O:8].[N+:13](=[C:15]1[N:19]=[CH:18][N:17]=[C:16]1[C:20]([NH2:22])=[O:21])=[N-:14]>CS(C)=O>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[CH:9][C:4]=1[CH2:5][N:6]1[C:7](=[O:8])[N:19]2[CH:18]=[N:17][C:16]([C:20]([NH2:22])=[O:21])=[C:15]2[N:13]=[N:14]1
Reactant: [N-]=[N+]=C1N=CN=C1C(N)=O
Reactant: COc1ccccc1CN=C=O
Solvent: CS(C)=O
Product: COc1ccccc1Cn1nnc2c(C(N)=O)ncn2c1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Ortho-methoxybenzyl isocyanate (Sigma Aldrich) (0.390 g, 2.4 mmol) was added drop wise to a suspension of 5-diazoimidazole-4-carboxamide (0.274 g, 2 mmol) in dry DMSO (2.5 mL) at room temperature under nitrogen. The resulting mixture was stirred at room temperature overnight. The reaction was quenched by the addition of ice and the solid product (off-white) removed by filtration, washed with water and ethyl acetate then recrystallised from chloroform/hexane. Yield: 0.343 g, 57%. IR vmax/cm−1 3460, 3094, 1728, 1683, 1589, 1454. 1H NMR δH (DMSO-d6) 5.45 (2H, s, CH2Ar), 6.91 (1H, td, J 7.5, 0.8, ArH), 7.06 (1H, d, J 7.8, ArH), 7.27 (1H, d, J 7.5, 1.4, ArH), 7.30-7.33 (1H, m, ArH), 7.69 (1H, br s, NH), 7.81 (1H, br s, NH), 8.84 (1H, s, 6-H). δC 47.9, 56.0, 111.3, 120.7, 123.7, 129.1, 129.4, 129.7, 131.4, 134.9, 139.6, 157.1, 162.0. MS Found 301.1100. Calc for (M+H): 301.1049. Found C, 51.6; H, 3.9; N, 28.0. Calc. for C13H12N6O3C, 52.0; H, 4.0; N, 28.0%.
Reaction SMILES: [C:1]([O:5][C:6](=[O:49])[CH2:7][N:8]([C:18](=[O:48])[C@H:19]([CH3:47])[NH:20][C@H:21]([C:42]([O:44]CC)=[O:43])[CH2:22][CH2:23][CH2:24][CH2:25][CH:26]1[CH2:31][CH2:30][N:29]([C:32]([O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[O:33])[CH2:28][CH2:27]1)[CH:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10]1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].O>CO>[C:1]([O:5][C:6](=[O:49])[CH2:7][N:8]([C:18](=[O:48])[C@H:19]([CH3:47])[NH:20][C@H:21]([C:42]([OH:44])=[O:43])[CH2:22][CH2:23][CH2:24][CH2:25][CH:26]1[CH2:31][CH2:30][N:29]([C:32]([O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[O:33])[CH2:28][CH2:27]1)[CH:9]1[CH2:10][C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:17]1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CCOC(=O)[C@H](CCCCC1CCN(C(=O)OCc2ccccc2)CC1)N[C@@H](C)C(=O)N(CC(=O)OC(C)(C)C)C1Cc2ccccc2C1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: C[C@H](N[C@@H](CCCCC1CCN(C(=O)OCc2ccccc2)CC1)C(=O)O)C(=O)N(CC(=O)OC(C)(C)C)C1Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.8 %

Procedure:
In 20 ml of methanol is dissolved 0.55 g of N-[N-[(S)-5-(1-benzyloxycarbonyl-4-piperidyl)-1-ethoxycarbonylpentyl]-L-alanyl]-N-(indan-2-yl)glycine tert-butyl ester, and 5 ml of 1N aqueous sodium hydroxide is added dropwise to the solution over a period of 5 minutes. After stirring at room temperature for 1 hour, another 2 ml of 1N aqueous sodium hydroxide is added dropwise to the mixture over a period of 5 hours. After 2 ml of water is added dropwise over a period of 2 hours, 10 ml of water is added to the reaction solution, and the mixture is extracted with 10 ml of n-hexane. The aqueous layer is made weakly acidic with 1N hydrochloric acid, and extracted with 50 ml of ethyl acetate. The extract is washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 0.5 g of N-[N-[(S)-5-(1-benzyloxycarbonyl-4-piperidyl)-1-carboxypentyl]-L-alanyl]-N-(indan-2-yl)glycine tert-butyl ester as a colorless oil.
Reaction SMILES: [OH-].[Na+].[NH2:3][C@H:4]([C:8]([OH:10])=[O:9])[CH:5]([CH3:7])[CH3:6].C([O-])([O-])=O.[Na+].[Na+].Cl[C:18]([O:20][CH3:21])=[O:19]>O.C(O)C>[CH3:21][O:20][C:18]([NH:3][C@@H:4]([CH:5]([CH3:7])[CH3:6])[C:8]([OH:10])=[O:9])=[O:19]
Reactant: CC(C)[C@H](N)C(=O)O
Reactant: COC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COC(=O)N[C@H](C(=O)O)C(C)C
Temperature: 0 °C
Reaction time: 15 h
Yield: 65.1 %

Procedure:
1N NaOH in water (1250 mL) was added into to L-Valine (150 g, 1280 mmol) in a 3 L round bottom flask equipped with a magnetic stir bar. To this solution was added Na2CO3 (67.8 g, 640 mmol) and the reaction mixture was cooled to 0° C. in an ice-water bath. Methyl chloroformate (107 mL, 1390 mmol) was added dropwise and the reaction mixture was allowed to warm to room temperature. The reaction mixture was stirred for 15 hours. The reaction mixture was washed with ethyl acetate (3×400 mL). The aqueous layer was cooled over an ice-water bath and acidified by concentrated HCl (aq) to pH=2. The reaction mixture was extracted with CH2Cl2 (3×1000 mL). The combined organic layers were dried over Na2SO4 and the solvent was concentrated to afford the crude product. The crude product was heated at reflux with 150 mL ethanol and 150 mL water for 2 hours. Then the mixture was cooled to room temperature and the crystalline solids were filtered to give (S)-2-(methoxycarbonylamino)-3-methyl-butanoic acid (146 g, 65% yield).
Reaction SMILES: Br.Br.Br.[CH2:4]([C:6]1[C:7]([C:14]2[CH:22]=[C:21]3[C:17]([C:18]([C:23]4[NH:24][C:25]5[CH2:30][CH2:29][NH:28][CH2:27][C:26]=5[N:31]=4)=[N:19][NH:20]3)=[CH:16][CH:15]=2)=[CH:8][C:9]([F:13])=[C:10]([OH:12])[CH:11]=1)[CH3:5].[CH3:32][O:33][C:34]1[CH:35]=[C:36]([CH:39]=[CH:40][CH:41]=1)[CH:37]=O.CCN(C(C)C)C(C)C.C[C:52]([OH:54])=[O:53].C(=O)([O-])O.[Na+]>CN(C=O)C>[CH:52]([OH:54])=[O:53].[CH2:4]([C:6]1[C:7]([C:14]2[CH:22]=[C:21]3[C:17]([C:18]([C:23]4[NH:24][C:25]5[CH2:30][CH2:29][N:28]([CH2:37][C:36]6[CH:39]=[CH:40][CH:41]=[C:34]([O:33][CH3:32])[CH:35]=6)[CH2:27][C:26]=5[N:31]=4)=[N:19][NH:20]3)=[CH:16][CH:15]=2)=[CH:8][C:9]([F:13])=[C:10]([OH:12])[CH:11]=1)[CH3:5]
Reactant: COc1cccc(C=O)c1
Reactant: CC(=O)O
Reactant: CCc1cc(O)c(F)cc1-c1ccc2c(-c3nc4c([nH]3)CCNC4)n[nH]c2c1
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCc1cc(O)c(F)cc1-c1ccc2c(-c3nc4c([nH]3)CCN(Cc3cccc(OC)c3)C4)n[nH]c2c1
Product: O=CO
Temperature: 25 °C
Reaction time: 1 h
Yield: 41.9 %

Procedure:
To a solution of 5-ethyl-2-fluoro-4-[3-(4,5,6,7-tetrahydro-1H-imidazo[4,5-c]pyridin-2-yl)-1H-indazol-6-yl]-phenol trihydrobromide salt (Preparation 25, 50 mg, 132 μmol) in DMF (1 mL), was added 3-methoxy-benzaldehyde (27 mg, 198 μmol), DIPEA (34 mg, 46 μL, 264 μmol) and AcOH (11.8 mg, 11 μL, 198 μmol). The reaction mixture was stirred at room temperature for 1 hour. STAB (42 mg, 198 μmol) was added and stirring was continued for 18 hours. Saturated aqueous sodium hydrogen carbonate solution (5 ml) was added to the reaction mixture. The resulting solid was collected by filtration and washed with further saturated aqueous sodium hydrogen carbonate solution. The crude material was purified by HPLC Method B to afford 30.1 mg of the title compound.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([O:13]C2C=CC=CC=2)=O)[N:7]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:26][O:27][C:28]1[CH:29]=[C:30]2[C:35](=[CH:36][C:37]=1[O:38][CH3:39])[N:34]=[CH:33][N:32]=[C:31]2[S:40][C:41]1[CH:42]=[C:43]([CH:45]=[CH:46][CH:47]=1)[NH2:44].C(N(CC)C(C)C)(C)C>C1COCC1>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:44][C:43]2[CH:45]=[CH:46][CH:47]=[C:41]([S:40][C:31]3[C:30]4[C:35](=[CH:36][C:37]([O:38][CH3:39])=[C:28]([O:27][CH3:26])[CH:29]=4)[N:34]=[CH:33][N:32]=3)[CH:42]=2)=[O:13])[N:7]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[N:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)Cn1nc(C(C)(C)C)cc1NC(=O)Oc1ccccc1
Reactant: COc1cc2ncnc(Sc3cccc(N)c3)c2cc1OC
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)Cn1nc(C(C)(C)C)cc1NC(=O)Nc1cccc(Sc2ncnc3cc(OC)c(OC)cc23)c1
Yield: 59 %

Procedure:
Using the procedure described in Example 159B, using ethyl 2-[3-tert-butyl-5-(phenoxycarbonylamino)-1H-pyrazol-1-yl]acetate described in Example 166A (0.138 g, 0.4 mmol), 3-(6,7-dimethoxyquinazolin-4-ylthio)aniline from Example 115B (0.125 g, 0.4 mmol), and N,N-diisopropylethylamine (0.5 mL) in THF (6 mL) at 50° C. for 7 hours, to afford ethyl 2-(3-tert-butyl-5-{3-[3-(6,7-dimethoxyquinazolin-4-ylthio)phenyl]ureido}-1H-pyrazol-1-yl)acetate as solid (133 mg, 59%). 1H NMR (300 MHz, DMSO-d6) δ 8.98 (s, 1H), 8.70 (s, 1H), 8.60 (m, 1H), 7.83 (s, 1H), 7.51 (d, 1H), 7.43 (t, 1H), 7.35 (s, 1H), 7.34 (s, 1H), 7.25 (d, 1H), 6.12 (s, 1H), 4.85 (s, 2H), 4.15 (q, 2H), 3.99 (s, 6H), 1.20 (s and t, 12H); LC-MS (ESI) m/z 565 (M+H)+.
Reaction SMILES: [CH3:1][CH:2]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:11]([NH2:16])=[N:12][CH:13]=[CH:14][CH:15]=2)=[CH:6][CH:5]=1)[CH3:3].[H-].[Na+].Cl[CH2:20][CH2:21][S:22](Cl)(=[O:24])=[O:23].C(=O)([O-])O.[Na+]>C1COCC1.C(OCC)(=O)C>[CH3:3][CH:2]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[C:11]3=[N:16][S:22](=[O:24])(=[O:23])[CH2:21][CH2:20][N:12]3[CH:13]=[CH:14][CH:15]=2)=[CH:8][CH:9]=1)[CH3:1]
Reactant: CC(C)c1ccc(-c2cccnc2N)cc1
Reactant: O=S(=O)(Cl)CCCl
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)c1ccc(C2=CC=CN3CCS(=O)(=O)N=C23)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74 %

Procedure:
A mixture of 3-[4-(1-methylethyl)phenyl]pyridin-2-amine (700 mg) in dehydrated THF (15 mL) was added to a mixture of sodium hydride (60%, 659 mg) and 2-chloroethanesulfonyl chloride (1613 mg) in dehydrated THF (15 mL) under ice-cooling. The reaction mixture was stirred at room temperature overnight, and saturated aqueous sodium hydrogen carbonate solution and ethyl acetate were added. The resulting precipitate was collected by filtration, and washed with water and ethyl acetate to give the title compound (738 mg) as a white solid. The obtained solid was crystallized from acetonitrile and diisopropyl ether to give a white solid.
Reaction SMILES: [NH2:1][CH2:2][C:3]#[C:4][C:5]1[CH:6]=[C:7]([C:12]2[S:13][C:14]3[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=3[N:16]=2)[C:8]([NH2:11])=[N:9][CH:10]=1.C[Si]([N:25]=[C:26]=[O:27])(C)C.CN(C=O)C.CCN(C(C)C)C(C)C>>[NH2:11][C:8]1[N:9]=[CH:10][C:5]([C:4]#[C:3][CH2:2][NH:1][C:26]([NH2:25])=[O:27])=[CH:6][C:7]=1[C:12]1[S:13][C:14]2[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=2[N:16]=1
Reactant: C[Si](C)(C)N=C=O
Reactant: NCC#Cc1cnc(N)c(-c2nc3ccccc3s2)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: NC(=O)NCC#Cc1cnc(N)c(-c2nc3ccccc3s2)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 5-(3-aminoprop-1-ynyl)-3-benzothiazol-2-ylpyridin-2-ylamine (10.0 mg, 0.0357 mmol), trimethylsilyl isocyanate (5.31 uL, 0.0392 mmol), DMF (1 mL, 0.01 mol) and DIPEA (0.03 mL, 0.2 mmol) was stirred at rt for 3 h. The solution was used directly for HPLC purification. The fractions containing the pure product were concentrated in vacuo to afford the title compound as a yellow solid. 1H NMR (400 MHz, CD3OD): δ=4.14 (s, 2H), 7.39-7.45 (m, 1H), 7.47-7.52 (m, 1H), 7.93 (s, 1H), 8.00 (d, J=7.8 Hz, 1H), 8.06 (d, J=2.0 Hz, 1H). MS (ES+): m/z=324.10 (100) [MH+]. HPLC: tR=2.85 min (ZQ3, polar—5 min).
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([C@@H:6]([C@@H:11]2[CH2:16][CH2:15][CH2:14][CH2:13][C:12]2=[O:17])[CH2:7][N+:8]([O-])=O)=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O1CCCC1.O>O1CCCC1>[NH2:8][CH2:7][C@H:6]([C@@H:11]1[CH2:16][CH2:15][CH2:14][CH2:13][C@@H:12]1[OH:17])[C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:19][CH:18]=1
Reactant: O=C1CCCC[C@H]1[C@@H](C[N+](=O)[O-])c1ccc(Cl)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: NC[C@@H](c1ccc(Cl)cc1)[C@@H]1CCCC[C@@H]1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 4.55 g (16.1 mmol) of (-)-(2S)-[(R)-4-chloro-α-(nitromethyl)benzyl]cyclohexanone [prepared according to Helv. Chim. Acta 65, 1637 (1982)] in 80 ml of dry tetrahydrofuran is added dropwise at room temperature while stirring to a suspension of 1.5 g (40.4 mmol) of lithium aluminium hydride in 50 ml of dry tetrahydrofuran under argon. The reaction mixture is stirred at room temperature overnight, treated with 20 ml of tetrahydrofuran/water (1:1), the separated precipitate is filtered off under suction while washing with methylene chloride and the filtrate is evaporated. The residue is dissolved in ether, the ethereal phase is extracted with 1N hydrochlorid acid, the acidic phase is made alkaline with 3N sodium hydroxide solution and extracted with methylene chloride. The organic phase is washed with water, dried over magnesium sulphate and evaporated. There is obtained (+)-(1S)-cis-2-[(R)-α-(aminomethyl)-4-chlorobenzyl]cyclohexanol in the form of a yellow oil ([α]D20 =+14.7°, c=0.6 in chloroform), which is processed as such.
Reaction SMILES: C([O:3][C:4]([C:6]1([S:20]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)(=[O:22])=[O:21])[CH2:11][CH2:10][N:9]([CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:8][CH2:7]1)=[O:5])C>C1COCC1.CO.[OH-].[Na+]>[CH3:30][O:29][C:26]1[CH:27]=[CH:28][C:23]([S:20]([C:6]2([C:4]([OH:5])=[O:3])[CH2:7][CH2:8][N:9]([CH2:12][CH2:13][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:10][CH2:11]2)(=[O:22])=[O:21])=[CH:24][CH:25]=1
Reactant: CCOC(=O)C1(S(=O)(=O)c2ccc(OC)cc2)CCN(CCc2ccccc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(S(=O)(=O)C2(C(=O)O)CCN(CCc3ccccc3)CC2)cc1

Procedure:
4-(4-methoxy-benzenesulfonyl)-1-(2-phenyl-ethyl)-piperidine-4-carboxylic acid was prepared starting from 4-(4-methoxy-benzenesulfonyl)-1-(2-phenyl-ethyl)-piperidine-4-carboxylic acid ethyl ester (3.0 g, 6.9 mmol) dissolved in THF:methanol 3:1 and 10 N NaOH (40 ml). The resulting reaction mixture was worked up as outlined in example 83. Yield 2.0 g (72%); off white powder; mp 208° C.; MS: 404.5 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH2:10][CH2:11][CH3:12])=[C:4]([F:13])[CH:3]=1.[Li]CCCC.[B:19](OC)([O:22]C)[O:20]C.Cl>C1COCC1>[CH2:9]([O:8][C:5]1[CH:6]=[CH:7][C:2]([B:19]([OH:22])[OH:20])=[CH:3][C:4]=1[F:13])[CH2:10][CH2:11][CH3:12]
Reactant: CCCCOc1ccc(Br)cc1F
Reactant: COB(OC)OC
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCCOc1ccc(B(O)O)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 65.5 %

Procedure:
The compound (T-8) (97.5 g) obtained in the above procedure was dissolved in dried THF (500 ml) and the solution was cooled to −70° C. n-BuLi (241 ml) was added dropwise under an atmosphere of nitrogen, and the stirring was continued at −70° C. for another 2 hours. Then, trimethyl borate (62.4 g) in a dried THF solution was added dropwise slowly at −70° C., and the mixture was warmed up to room temperature. The stirring was continued for another 16 hours. After the completion of the reaction, 2N—HCl (200 ml) was added to the reaction mixture. The mixture was extracted with toluene, and the organic layer was washed with water and brine, and then dried over anhydrous magnesium sulfate. The solution was concentrated under reduced pressure to leave pale brown solids. Recrystallization (heptane:toluene=4:1 by volume) gave the compound (T-9) as colorless powders (54.8 g) in 66% yield.
Reaction SMILES: [C:1]([OH:7])(=O)[CH2:2][CH2:3][CH2:4][CH3:5].C(N(CC)C(C)C)(C)C.[CH3:17][C:18]1[CH:23]=[C:22]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[CH:21]=[C:20]([CH3:30])[C:19]=1[NH2:31].C(OCC)(=O)C>CN(C)C=O>[CH3:17][C:18]1[CH:23]=[C:22]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[CH:21]=[C:20]([CH3:30])[C:19]=1[NH:31][C:1](=[O:7])[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCC(=O)O
Reactant: Cc1cc(N2CCOCC2)cc(C)c1N
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCC(=O)Nc1c(C)cc(N2CCOCC2)cc1C
Reaction time: 0.03 h
Yield: 39.8 %

Procedure:
Pentanoic acid (0.37 g), N,N-diisopropyl-ethylamine (1.51 mL) and N-[(dimethylamino)-1H-1,2,3-triazolo-[4,5-b]pyridin-1-yl-methylene]-N-methyl-methanaminium hexafluoro-phosphate N-oxide (1.66 g) were mixed in dry N,N-dimethylformamide (3 mL) and stirred under argon for 2 minutes. 2,6-Dimethyl-4-morpholin-4-yl-phenylamine (0.50 g) dissolved in dry N,N-dimethylformamide (2 mL) was added to the reaction mixture, which was stirred at 25° C. under argon for 16 hours. Ethyl acetate (20 mL) was added and the organic phase was washed with saturated aqueous ammonium chloride/water (1:1, 20 mL), water (20 mL), brine/water (1:1, 20 mL), dried over magnesium sulfate, concentrated in vacuo and purified by flash chromatography to furnish 0.28 g (40% yield) of the title compound as a white solid. LC-MS (m/z) 291 (MH+); tR=1.61, (UV, ELSD) 99%, 99%. 1H NMR (500 MHz, DMSO-d6): 0.91 (t, 3H), 1.34 (m, 2H), 1.58 (qui, 2H), 2.06 (s, 6H), 2.27 (t, 2H), 3.04 (t, 4H), 3.71 (t, 4H), 6.62 (s, 2H), 8.94 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][Br:13])[C:3]=1[C:4]([O:6][CH3:7])=[O:5].[C:14]1([P:20]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(#N)C>[Br-:13].[Cl:1][C:2]1[C:3]([C:4]([O:6][CH3:7])=[O:5])=[C:8]([CH:9]=[CH:10][CH:11]=1)[CH2:12][P+:20]([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: COC(=O)c1c(Cl)cccc1CBr
Solvent: CC#N
Product: COC(=O)c1c(Cl)cccc1C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Product: [Br-]
Temperature: 80 °C
Reaction time: 3 h

Procedure:
To a mixture of 27.6 g of methyl 2-chloro-6-bromomethylbenzoate and 39.0 g of triphenylphosphine was added 200 ml of acetonitrile, and the mixture was stirred at 80° C. for 3 hours.
Reaction SMILES: S(O)(O)(=O)=O.[NH2:6][OH:7].[OH-].[Na+].[C:10]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(=O)[CH3:11].OS(O)(=O)=O>CO>[C:10](=[N:6][OH:7])([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH3:11]
Reactant: CC(=O)c1ccccc1
Reactant: NO
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(=NO)c1ccccc1
Temperature: 40 °C
Reaction time: 5 h

Procedure:
In a 500 mL 3-neck flask was placed solid hydroxylamine sulfate (28 g; 0.17 mol) and absolute methanol (100 mL) was added to it. The slurry was stirred vigorously using a magnetic bar over a stir plate and a solution of sodium hydroxide pellets (14 g; 0.35 mol) in absolute methanol (175 mL) was then added slowing with cooling in ice bath (<5° C.). At the completion of addition of the solution, acetophenone (40 g; 0.33 mol) was added and stirring in the cold was continued for 5 hours. Concentrated H2SO4 (1.8 g) was added to adjust the pH of the solution to 6.5. Methanol (50 mL) was added to the slurry and the mixture heated (40° C.) for 2 hours and then filtered hot. The clear filtrate (colorless) was concentrated under reduced pressure and crystalline acetophenone oxime was collected after cooling and filtration. Yield, 40.5 g (90.8%). Purity >98% of isomeric mixture.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][C:22]=1[C:23](=[O:26])[NH:24][CH3:25])[CH2:5][C:6]1[C:7]([CH3:19])=[C:8]([CH3:18])[C:9]([CH:16]=C)=[C:10]([CH:15]=1)[C:11]([O:13][CH3:14])=[O:12].CC(C)=[O:29].C(#N)C.I([O-])(=O)(=O)=O.[Na+]>[Os]=O.O>[F:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][C:22]=1[C:23](=[O:26])[NH:24][CH3:25])[CH2:5][C:6]1[C:7]([CH3:19])=[C:8]([CH3:18])[C:9]([CH:16]=[O:29])=[C:10]([CH:15]=1)[C:11]([O:13][CH3:14])=[O:12]
Reactant: C=Cc1c(C(=O)OC)cc(Cc2ccc(C(=O)NC)c(F)c2)c(C)c1C
Reactant: CC(C)=O
Agent: O=[Os]
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: CC#N
Solvent: O
Product: CNC(=O)c1ccc(Cc2cc(C(=O)OC)c(C=O)c(C)c2C)cc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 5-(3-fluoro-4-(methylcarbamoyl)benzyl)-3,4-dimethyl-2-vinylbenzoate (0.19 g) in a mixed solvent of acetone (2.20 mL)-acetonitrile (2.20 mL)-water (2.20 mL) were added osmium oxide (fixed catalyst I) (0.07 g) and sodium periodate (0.56 g), and the mixture was stirred overnight at room temperature. The reaction mixture was filtered, and the filtrate was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (0.19 g) as a crude product. This compound was used in the next step without an additional purification.