Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[CH3:12][N:13]([CH:15](OC)OC)[CH3:14]>>[CH3:12][N:13]([CH3:15])/[CH:14]=[N:6]/[C:4](=[O:5])[C:3]1[CH:7]=[CH:8][C:9]([F:11])=[CH:10][C:2]=1[F:1]
Reactant: COC(OC)N(C)C
Reactant: NC(=O)c1ccc(F)cc1F
Product: CN(C)/C=N/C(=O)c1ccc(F)cc1F
Temperature: 120 °C
Yield: 91 %

Procedure:
A suspension of 2,4-difluorobenzamide (5 g, 32 mmol) in DMF-DMA (10 mL) was heated at 120° C. for 2.5 h, allowed to cool down to RT and filtered to afford the title compound as a white solid (6.16 g, 91%). 1H NMR (CDCl3): 8.60 (1H, s), 8.19-8.12 (1 H, m), 6.91-6.79 (2 H, m), 3.19 (6 H, m).
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([CH:8]=[C:9](N)[CH:10]=1)[C:5]([OH:7])=[O:6].C(N(CC)C(C)C)(C)C>CN(C=O)C>[C:5]([OH:7])(=[O:6])[C:4]1[CH:8]=[CH:9][CH:10]=[CH:2][CH:3]=1
Reactant: Nc1cc(N)cc(C(=O)O)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3,5-Diaminobenzoic acid (4.3 mg, 0.028 mmol, 0.40 equiv.) was dissolved in 10 mL of anhydrous DMF. To the solution was added H-PEOZ-p-NPC 10K (1.00 gm, 0.0692 mmol, 1.0 equiv.; an active NHS ester can also be used), followed by addition of N,N-Diisopropylethyl amine (DIPEA, 36.2 μL, 0.208 mmol, 3.0 equiv.). Following overnight stirring at room temperature, the solution was evaporated to dryness by rotary evaporation under vacuum at 50° C. The residue was dissolved in dichloromethane, and then precipitated by addition into diethyl ether with stirring. The precipitate was filtered and dried under vacuum. The molecular weight of H-PEOZ2-benzoic acid was verified by GPC.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH2:8])=[CH:5][CH:4]=1.[C:11]([N:14]1[C:23]2[C:18](=[CH:19][C:20]([NH:24][C:25]([CH2:27][C:28](O)=[O:29])=[O:26])=[CH:21][CH:22]=2)[C:17]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)([CH3:31])[CH2:16][C:15]1([CH3:39])[CH3:38])(=[O:13])[CH3:12].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>O1CCCC1>[C:11]([N:14]1[C:23]2[C:18](=[CH:19][C:20]([NH:24][C:25]([CH2:27][C:28]([NH:8][CH2:7][C:6]3[CH:9]=[CH:10][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)=[O:29])=[O:26])=[CH:21][CH:22]=2)[C:17]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)([CH3:31])[CH2:16][C:15]1([CH3:39])[CH3:38])(=[O:13])[CH3:12]
Reactant: CC(=O)N1c2ccc(NC(=O)CC(=O)O)cc2C(C)(c2ccccc2)CC1(C)C
Reactant: COc1ccc(CN)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(CNC(=O)CC(=O)Nc2ccc3c(c2)C(C)(c2ccccc2)CC(C)(C)N3C(C)=O)cc1

Procedure:
Condensation of 4-methoxybenzylamine (5.2 mg) with 1-acetyl-6-(hydroxycarbonylmethylcarbonyl)amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline (10 mg), under the agency of HATU (19 mg) and N,N-diisopropylethylamine (16 μl) in tetrahydrofuran (2 ml) was performed according to the method described in example 11.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([F:9])[CH:3]=1.Cl[CH2:11][C:12]([CH3:14])=[CH2:13].C(=O)([O-])[O-].[K+].[K+].O>CC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:13][C:12]([CH3:14])=[CH2:11])=[C:4]([F:9])[CH:3]=1
Reactant: C=C(C)CCl
Reactant: Oc1ccc(Br)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: C=C(C)COc1ccc(Br)cc1F
Temperature: 70 °C
Reaction time: 15 h

Procedure:
To a solution of 4-bromo-2-fluorophenol (26.8 g) and 3-chloro-2-methylprop-1-ene (13.7 mL) in acetone (420 mL) was added potassium carbonate (29 g), and the mixture was stirred at 70° C. for 15 hr. The reaction mixture was allowed to cool to room temperature, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was purified by silica gel column chromatography to give the title compound as a pale-yellow viscous substance (29.9 g, 87%).
Reaction SMILES: [CH2:1]([C:6]1[CH:38]=[CH:37][C:9]([CH2:10][N:11]([C:23](=[O:36])[CH:24]=[CH:25][C:26]2[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=2)[C@@H:12]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:13]([OH:15])=O)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.[CH:70]([N:72]1[CH2:77][CH2:76][NH:75][CH2:74][CH2:73]1)=[O:71]>C(#N)C>[CH2:16]([C@H:12]([N:11]([CH2:10][C:9]1[CH:37]=[CH:38][C:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])=[CH:7][CH:8]=1)[C:23](=[O:36])[CH:24]=[CH:25][C:26]1[CH:27]=[CH:28][C:29]([C:32]([F:35])([F:33])[F:34])=[CH:30][CH:31]=1)[C:13]([N:75]1[CH2:76][CH2:77][N:72]([CH:70]=[O:71])[CH2:73][CH2:74]1)=[O:15])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=CN1CCNCC1
Reactant: CCCCCc1ccc(CN(C(=O)C=Cc2ccc(C(F)(F)F)cc2)[C@@H](Cc2ccccc2)C(=O)O)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCCCCc1ccc(CN(C(=O)C=Cc2ccc(C(F)(F)F)cc2)[C@@H](Cc2ccccc2)C(=O)N2CCN(C=O)CC2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 54.4 %

Procedure:
2-{(4-pentyl-benzyl)-[3-(4-trifluoromethyl-phenyl)-acryloyl]-amino}-(S)-3-phenyl-propionic acid (50 mg, 0.095 mmol) was dissolved in acetonitrile (1.0 ml), TBTU (37 mg, 0.115 mmol), DIPEA (37 mg, 0.29 mmol) and 1-formylpiperazine (12.23 mg, 0.105 mmol) was added and the mixture was stirred for 16 h at rt, filtered and directly purified by prep. HPLC to give 32 mg of N—[(S)-1-benzyl-2-(4-formyl-piperazin-1-yl)-2-oxo-ethyl]-N-(4-pentyl-benzyl)-3-(4-trifluoromethyl-phenyl)-acrylamide. LC-MS: tR=1.17 min; [M+H]+=620.50.
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH:3]=[CH:2]1.[Br:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][N:13]=[C:12]2[NH2:18]>C1(C)C=CC=CC=1>[Br:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][N:13]=[C:12]2[NH:18][C:1](=[O:7])[CH:2]=[CH:3][C:4]([OH:6])=[O:5]
Reactant: O=C1C=CC(=O)O1
Reactant: Nc1n[nH]c2ccc(Br)cc12
Solvent: Cc1ccccc1
Product: O=C(O)C=CC(=O)Nc1n[nH]c2ccc(Br)cc12
Temperature: 110 °C
Reaction time: 12 h

Procedure:
350 mg of maleic anhydride are added to 500 mg of 5-bromo-1H-indazole-3-amine, prepared as described in U.S. Pat. No. 3,133,081, in 20 cm3 of toluene. The medium is refluxed at about 110° C. for one hour. The heating is then stopped and the mixture is stirred at about 19° C. for 12 hours. The precipitate formed is filtered off on a sinter funnel and rinsed with 20 cm3 of diisopropyl ether, 2 cm3 of ethyl acetate and 2 cm3 of dichloromethane. After drying (90 Pa; 45° C.), 448 mg of 4-[(5-bromo-1H-indazol-3-yl)amino]-4-oxo-2-butenoic acid, Z form, are obtained in the form of a yellow solid melting at 172° C.
Reaction SMILES: Cl.Cl.[F:3][C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[C@@:11]([OH:29])([CH2:23][N:24]1[CH:28]=[N:27][CH:26]=[N:25]1)[C@H:12]([S:14]([N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)(=[O:16])=[O:15])[CH3:13].C(N(CC)CC)C.[F:37][C:38]([F:49])([F:48])[C:39]1[CH:47]=[CH:46][C:42]([C:43](Cl)=[O:44])=[CH:41][CH:40]=1>ClCCl>[CH:39]([O:29][CH:11]([CH3:12])[CH3:23])([CH3:40])[CH3:38].[F:3][C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[C@@:11]([OH:29])([CH2:23][N:24]1[CH:28]=[N:27][CH:26]=[N:25]1)[C@H:12]([S:14]([N:17]1[CH2:22][CH2:21][N:20]([C:43](=[O:44])[C:42]2[CH:46]=[CH:47][C:39]([C:38]([F:37])([F:48])[F:49])=[CH:40][CH:41]=2)[CH2:19][CH2:18]1)(=[O:16])=[O:15])[CH3:13]
Reactant: C[C@H]([C@](O)(Cn1cncn1)c1ccc(F)cc1F)S(=O)(=O)N1CCNCC1
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)OC(C)C
Product: C[C@H]([C@](O)(Cn1cncn1)c1ccc(F)cc1F)S(=O)(=O)N1CCN(C(=O)c2ccc(C(F)(F)F)cc2)CC1
Reaction time: 0.5 h

Procedure:
In dichloromethane (10 ml) was dispersed 1-[(2R,3R)-3-(2,4-difluorophenyl)-3-hydroxy-4-(1H-1,2,4-triazol-1-yl)-2-butylsulfonyl]piperazine.dihydrochloride (Compound 20, 0.20 g) obtained in Working Example 14. To the dispersion were added, under ice-cooling, triethylamine (0.20 ml) and 4-trifluoromethylbenzoyl chloride (0.13 g). The mixture was stirred for 30 minutes at room temperatures. The reaction mixture was then concentrated under reduced pressure. The concentrate was dissolved in ethyl acetate, washed with water, dried and concentrated. The concentrate was subjected to a silica gel chromatography (eluent: hexane/ethyl acetate=1/3) for purification. The object fraction was concentrated which was processed with hydrogen chloride, followed by adding thereto isopropylether to give 1-[(2R,3R)-3-(2,4-difluorophenyl)-3-hydroxy-4-(1H-1,2,4-triazol-1-yl)-2-butylsulfonyl]-4-(4-trifluoromethylbenzoyl)piperazine (Compound 24).hydrochloride (167 mg) as colorless powder.
Reaction SMILES: C[Si](C)(C)N[Si](C)(C)C.C([Li])CCC.[Cl:15][C:16]1[CH:17]=[C:18]([C@@H:26]([CH2:40][CH:41]2[CH2:45]CC[CH2:42]2)[C:27](NC2C=CN(CCC(O)=O)N=2)=[O:28])[CH:19]=[CH:20][C:21]=1[S:22]([CH3:25])(=O)=O.ICC1[CH2:51][O:50]C1.CN1CCCN(C)C1=[O:60]>O1CCCC1.C(OCC)(=O)C>[CH3:51][O:50][C:27](=[O:28])[CH:26]([C:18]1[CH:19]=[CH:20][C:21]([S:22][CH3:25])=[C:16]([Cl:15])[CH:17]=1)[CH2:40][CH:41]1[CH2:42][O:60][CH2:45]1
Reactant: ICC1COC1
Reactant: CN1CCCN(C)C1=O
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2ccn(CCC(=O)O)n2)cc1Cl
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)C(CC1COC1)c1ccc(SC)c(Cl)c1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 69.5 %

Procedure:
In a round bottom flask under argon was placed tetrahydrofuran (15 mL) and 1,1,1,3,3,3-hexamethyldisilazane (0.57 mL, 2.72 mmol) and it was cooled to −78° C. in a dry ice/acetone bath. To this cooled solution was then added n-butyl lithium (2.5 M solution in hexanes, 1.0 mL, 2.55 mmol) and it was stirred for 15 min at −78° C. To this was then dropwise added a solution of (3-chloro-4-methylsulfanyl-phenyl)-acetic acid methyl ester (prepared as in PCT WO 2003/095438 A1, Example 4, 0.56 g, 2.44 mmol) in tetrahydrofuran (5 mL). The reaction was then stirred for 15 min at −78° C. then at 0° C. for 1 h. After such time, it was cooled back to −78° C. and a solution of 3-iodomethyl-oxetane (0.58 g, 2.93 mmol) in tetrahydrofuran (5 ml) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (0.44 mL, 3.64 mmol) was added dropwise at −78° C. The reaction was stirred at 0° C. for 3 h and then it was diluted with ethyl acetate and washed with a saturated aqueous ammonium chloride solution followed by a saturated aqueous sodium chloride solution. The organics were dried over sodium sulfate, filtered and then concentrated in vacuo. Purification on an AnaLogix Intelliflash system (40 g column, 30% ethyl acetate/hexanes to 40% ethyl acetate/hexanes) afforded 2-(3-chloro-4-methylsulfanyl-phenyl)-3-oxetan-3-yl-propionic acid methyl ester (0.51 g, 70%) as a clear oil: 1H NMR (300 MHz, DMSO-d6) δ ppm 1.97-2.13 (m, 1H, CH of CH2), 2.22-2.34 (m, 1H, CH of CH2), 2.46 (s, 3H, SCH3), 2.71-2.87 (m, 1H, CH), 3.54-3.66 (m, 1H, ArCHCO), 3.57 (s, 3H, OCH3), 4.09 (t, J=6.2 Hz, 1H, OCH of OCH2), 4.23 (t, J=6.2 Hz, 1H, OCH of OCH2), 4.40 (dd, J=7.8, 5.9 Hz, 1H, OCH of OCH2), 4.53 (dd, J=7.8, 5.9 Hz, 1H, OCH of OCH2), 7.23-7.26 (m, 2H, Ar), 7.36 (brs, 1H, Ar).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH3:26])[C:5]([CH2:8][N:9]([CH2:16][C:17]2[C:22]([CH:23]([CH3:25])[CH3:24])=[CH:21][CH:20]=[CH:19][N:18]=2)[CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[N:6][CH:7]=1.[O:27]([C:34]([NH:36][OH:37])=O)C1C=CC=CC=1>C1COCC1>[OH:37][NH:36][C:34]([N:13]1[CH2:12][CH2:11][CH:10]([N:9]([CH2:8][C:5]2[C:4]([CH3:26])=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=2)[CH2:16][C:17]2[C:22]([CH:23]([CH3:24])[CH3:25])=[CH:21][CH:20]=[CH:19][N:18]=2)[CH2:15][CH2:14]1)=[O:27]
Reactant: O=C(NO)Oc1ccccc1
Reactant: Cc1cc(Cl)cnc1CN(Cc1ncccc1C(C)C)C1CCNCC1
Solvent: C1CCOC1
Product: Cc1cc(Cl)cnc1CN(Cc1ncccc1C(C)C)C1CCN(C(=O)NO)CC1
Temperature: 25 °C
Yield: 78.6 %

Procedure:
To a solution of (5-Chloro-3-methyl-pyridin-2-ylmethyl)-(3-isopropyl-pyridin-2-ylmethyl)-piperidin-4-yl-amine (0.263 g, 0.71 mmol) in dry THF (7 mL) was added N-(phenoxycarbonyl)hydroxylamine (0.216 g, 1.41 mmol) and the resultant solution was stirred at 60° C. overnight. The mixture was cooled to room temperature and concentrated. Purification of the crude material by column chromatography on silica gel (10:1:1 CH2Cl2-MeOH—NH4OH) provided 241 mg (64%) of COMPOUND 264 as a white solid. 1H NMR (CDCl3) δ 0.99 (d, 6H, J=6.9 Hz), 1.60-1.66 (m, 2H), 1.92 (d, 2H, J=11.1 Hz), 2.14 (s, 3H), 2.66-2.88 (m, 4H), 3.78 (s, 2H), 3.81 (s, 2H), 4.04 (d, 2H, J=12.9 Hz), 6.65 (br s, 1H), 6.81 (br s, 1H), 7.16 (dd, 1H, J=7.8, 4.8 Hz), 7.42 (d, 1H, J=1.5 Hz), 7.52 (dd, 1H, J=7.8, 1.5 Hz), 8.32-8.34 (m, 2H); 13C NMR (CDCl3) δ 19.64, 24.80, 28.47, 28.74, 45.43, 55.31, 58.83, 124.66, 132.29, 135.42, 136.61, 139.11, 145.69, 146.12, 147.20, 156.93, 162.45; ES-MS m/z 432 (35Cl) & 434 (37Cl) (M+H). Anal. Calcd. For C22H30N5O2Cl.0.2CH2Cl2O.0.5H2O: C, 58.22; H, 6.91; N, 15.29; Cl, 10.84. Found: C, 58.51; H, 6.68; N, 15.29; Cl, 10.55.
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:19])[CH2:4][CH2:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16][CH2:17][NH2:18])=[CH:10][N:9]=1.[H-].[Na+]>>[CH3:1][NH:2][C:3](=[O:19])[CH2:4][CH2:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]2[CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:10]=2[N:9]=1
Reactant: CNC(=O)CCCCc1ccc(CCCCN)cn1
Agent: [H-]
Agent: [Na+]
Product: CNC(=O)CCCCc1ccc2c(n1)NCCCC2

Procedure:
A mixture of 11-7 (24 g, 91.2 mmol) and NaH (10.9 g of a 60% weight dispersion in mineral oil, 273 mmol) in xylenes (500 mL) was purged with argon for 30 min, and then heated at reflux for 72 hours. The mixture was cooled, quenched with ethanol, diluted with 10% aqueous potassium carbonate and extracted with ethyl acetate. The organics were dried over MgSO4, and concentrated to an oil. The residue was chromatographed on silica gel (70:25:5 CHCl3/EtOAc/MeOH/H2O) to give 11-8 as a white solid.
Reaction SMILES: O[C@@H:2]1[CH2:7][C@@H:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C@H:5]([CH3:13])[CH2:4][CH2:3]1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N1C=CN=C1.[I:38]I.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N1C(C)=CC=CC=1C.II.[Cl-]>C(Cl)(Cl)(Cl)Cl>[I:38][C@H:2]1[CH2:7][C@@H:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C@H:5]([CH3:13])[CH2:4][CH2:3]1
Reactant: CCOC(=O)[C@@H]1C[C@@H](O)CC[C@H]1C
Reactant: II
Agent: [Cl-]
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: Cc1cccc(C)n1
Product: CCOC(=O)[C@@H]1C[C@H](I)CC[C@H]1C

Procedure:
reacting said ethyl (1R,2R,5S)-5-hydroxy-2-methylcyclohexane-1-carboxylate (12) with Ph3P-imidazole-I2 (or Ph3P-2,6-lutidine-I2) in a carbon tetrachloride/methlylene chloride mixture to produce ethyl (1R,2R,5R)-5-iodo-2-methylcyclohexane-1-carboxylate (4a).
Reaction SMILES: Cl.[CH2:2]([N:4]1[CH2:13][CH2:12][C@@:11]2([C:14]3[CH:19]=[CH:18][CH:17]=[C:16](OC)[CH:15]=3)[C@@H:6]([CH2:7][CH2:8][C:9](=O)[CH2:10]2)[CH2:5]1)[CH3:3].C1(N[N:30]=[C:31]([C:37](=O)[C:38]([F:41])([F:40])[F:39])[C:32]([O:34][CH2:35][CH3:36])=[O:33])C=CC=CC=1.C[C:44](O[Na])=[O:45]>[Zn].C(O)(=O)C>[CH2:2]([N:4]1[CH2:13][CH2:12][C@:11]2([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([O:45][CH3:44])[CH:15]=3)[C@H:6]([CH2:7][C:8]3[C:37]([C:38]([F:39])([F:40])[F:41])=[C:31]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[NH:30][C:9]=3[CH2:10]2)[CH2:5]1)[CH3:3]
Reactant: CCOC(=O)C(=NNc1ccccc1)C(=O)C(F)(F)F
Reactant: CCN1CC[C@]2(c3cccc(OC)c3)CC(=O)CC[C@H]2C1
Reactant: CC(=O)O[Na]
Agent: Cl
Agent: [Zn]
Solvent: CC(=O)O
Product: CCOC(=O)c1[nH]c2c(c1C(F)(F)F)C[C@@H]1CN(CC)CC[C@@]1(c1cccc(OC)c1)C2
Yield: 66.6 %

Procedure:
3.24 g (10 mmol) of (±)-trans-2-ethyl-4a-(3-methoxyphenyl)-6-oxo-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline hydrochloride, 8.65 g (30 mmol) of ethyl 2-phenylhydrazono-4,4,4-trifluoro-3-oxobutyrate, 2.46 g (30 mmol) of CH3COONa, 7.85 g (120 mmol) of zinc dust and 15 ml of glacial acetic acid were treated as described in example 1. The residue was purified by chromatography on silica gel EtOAc/MeOH 0%→10%) yielding 3.0 g of product which was triturated in Et2O yielding 2.5 g of the title compound. M.p. 209°-211° C.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]=C)=[CH2:2].[OH2:11]>C1(C)C=CC=CC=1>[CH2:2]=[CH:1][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:9]([OH:11])[CH2:4][CH2:3][CH2:1][CH3:2]
Reactant: O
Reactant: C=Cc1ccccc1C=C
Solvent: Cc1ccccc1
Product: C=Cc1ccccc1
Product: CCCCCO

Procedure:
The sulfonated porous styrene-divinylbenzene copolymer particles can be produced by a known method. For example, such copolymer particles can be obtained by suspension polymerizing divinylbenzene and a styrene monomer in the presence of a water-insoluble organic solvent such as amyl alcohol, toluene or the like, isolating the produced particles, swelling them with a swelling agent such as dichloroethane, trichloroethane or the like, and adding thereto concentrated sulfuric acid or chlorosulfuric acid to effectuate a sulfonation reaction at room temperature to 120° C. The ion exchange capacity can be adjusted by properly controlling the reaction conditions at the time of reaction with concentrated sulfuric acid or chlorosulfuric acid. The porosity of the column packing material of this invention can be adjusted by properly selecting the reaction conditions, especially the kind and amount of the water-insoluble organic solvent used, at the time of suspension polymerization. The particle size can also be adjusted by properly selecting the suspension polymerization conditions.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[C:10](N)=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.N([O-])=O.[Na+].[S:16](=[O:18])=[O:17].[ClH:19]>O.C(O)(=O)C>[CH3:1][C:2]1[S:3][C:4]2[C:10]([S:16]([Cl:19])(=[O:18])=[O:17])=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: Cc1nc2cccc(N)c2s1
Reactant: Cl
Reactant: O=S=O
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Cc1nc2cccc(S(=O)(=O)Cl)c2s1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A suspension of 8 g of the product from Example 7 in 20 mL of concentrated hydrochloric acid was cooled to 0° C. and treated with a solution of 3.7 g sodium nitrite in 6 mL of water. After completion of the addition, the mixture was stirred at 0°-5° C. for about 15 minutes. This diazonium salt solution was then added all at once to a mixture of liquid sulfur dioxide, 2 g of cupric chloride dihydrate, and 4 mL water in 39 mL of glacial acetic acid at about 10° C.; vigorous gas evolution ensued. This reaction mixture was stirred at room temperature for another 4 hours, and was then poured into 190 mL ice-water. The resulting precipitate was collected by filtration, washed with water, and dried to give 9.2 g of 2-methyl-7-chlorosulfonylbenzothiazole as a yellow powder, m.p. 93°-97° C., dec; IR(KBr): 1380, 1175, 800, 770, 720 cm-1.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:14][CH2:13][C:12]3([CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[C:11]2=[O:20])=[CH:6][CH:5]=1.O=C(Cl)[O:25][C:26](Cl)(Cl)Cl.[NH:31]1[CH2:35][CH2:34][CH2:33][CH2:32]1>>[N:31]1([C:26]([N:17]2[CH2:16][CH2:15][C:12]3([C:11](=[O:20])[N:10]([C:7]4[CH:8]=[CH:9][C:4]([O:3][C:2]([F:1])([F:21])[F:22])=[CH:5][CH:6]=4)[CH2:14][CH2:13]3)[CH2:19][CH2:18]2)=[O:25])[CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: C1CCNC1
Reactant: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCNCC2
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Product: O=C(N1CCCC1)N1CCC2(CC1)CCN(c1ccc(OC(F)(F)F)cc1)C2=O

Procedure:
This material was prepared in analogy to example 251 step B) from 2-(4-trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decan-1-one, diphosgene and pyrrolidine MS (ESI): 412.3 (MH+).
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13](=[O:51])[NH:14][CH:15]([CH2:43][C:44]1[CH:49]=[CH:48][C:47]([F:50])=[CH:46][CH:45]=1)[C:16]([N:18]1C[CH2:22][N:21]([CH:24]([C:36](=[O:39])[NH:37][CH3:38])[CH2:25][C:26]2[CH:35]=[CH:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=2)[CH2:20][CH:19]1COC)=[O:17])=O)(C)(C)C.ClCCCl.FC(F)(F)C([O-])=O.O1[CH2:68][CH2:67][O:66][CH2:65]C1>Cl>[F:50][C:47]1[CH:48]=[CH:49][C:44]([CH2:43][CH:15]([NH:14][C:13]([CH:9]2[CH2:10][CH2:11][CH2:12][NH:8]2)=[O:51])[C:16]([N:18]2[CH2:19][CH2:20][N:21]([CH:24]([C:36](=[O:39])[NH:37][CH3:38])[CH2:25][C:26]3[CH:35]=[CH:34][C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH:27]=3)[CH2:22][C:67]2([CH3:68])[O:66][CH3:65])=[O:17])=[CH:45][CH:46]=1
Reactant: C1COCCO1
Reactant: CNC(=O)C(Cc1ccc2ccccc2c1)N1CCN(C(=O)C(Cc2ccc(F)cc2)NC(=O)C2CCCN2C(=O)OC(C)(C)C)C(COC)C1
Agent: Cl
Agent: O=C([O-])C(F)(F)F
Solvent: ClCCCl
Product: CNC(=O)C(Cc1ccc2ccccc2c1)N1CCN(C(=O)C(Cc2ccc(F)cc2)NC(=O)C2CCCN2)C(C)(OC)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 54 %

Procedure:
Crude 2-{1-(4-fluorobenzyl)-2-[2-methoxymethyl-4-(1-methylcarbamoyl-2-naphthalen-2-yl-ethyl)-piperazin-1-yl]-2-oxo-ethylcarbamoyl)-pyrrolidine-1-carboxylic acid tert-butyl ester, 67, is dissolved in 4M hydrogen chloride in dioxane (10 mL) and stirred at room temperature for 1 hour. 1,2-dichloroethane (10 mL) is added. Removal of solvents in vacuo gives the crude hydrogen chloride salt of product which is then purified by preparative HPLC to afford 0.22 g (54% yield) of the desired product as the trifluoroacetate salt. A small amount of product is converted into free base by treating with NaHCO3 to obtain NMR spectra. 1H NMR (CDCl3, δ): 7.80–7.60 (m, 4H), 7.45–7.25 (m, 3H), 7.18–7.00 (m, 2H), 7.00–6.85 (m, 2H), 6.32–6.28 (m, 0.5H), 5.08–4.92 (m, 1H), 4.78–4.69 (,0.5H), 4.10 (d, J=13.0 Hz, 0.5H), 3.70–3.58 (m, 1H), 3.58–3.15 (m, 8H), 2.98–2.46 (m, 11H), 2.28–2.15 (m, 0.5H), 2.15–1.50 (m, 8H). HRFAB(positive) m/e 604.2399 calculated for C34H42FN5O4 (M+H)+, Found 604.3292.
Reaction SMILES: [CH2:1]([NH:4][C:5]1[CH:12]=[CH:11][C:8]([C:9]#N)=[CH:7][CH:6]=1)[C:2]#[CH:3].[Mg].Cl.[CH2:15]([N:17]([CH2:22][CH3:23])[CH2:18][CH2:19][CH2:20]Cl)[CH3:16].[O:24]1CCCC1>>[CH2:15]([N:17]([CH2:22][CH3:23])[CH2:18][CH2:19][CH2:20][C:9]([C:8]1[CH:11]=[CH:12][C:5]([NH:4][CH2:1][C:2]#[CH:3])=[CH:6][CH:7]=1)=[O:24])[CH3:16]
Reactant: C1CCOC1
Reactant: CCN(CC)CCCCl
Reactant: C#CCNc1ccc(C#N)cc1
Agent: Cl
Agent: [Mg]
Product: C#CCNc1ccc(C(=O)CCCN(CC)CC)cc1

Procedure:
4-(2-Propynylamino)benzonitrile, 5 g (0.032 mol), in tetrahydrofuran is treated with an excess of the Grignard reagent which is prepared from fresh magnesium and 3-diethylaminopropyl chloride hydrochloride, according to the procedure of Sodet, Comptes Rendus, 254, pp. 3105-3107 (1962), to afford the desired product.
Reaction SMILES: Cl.O[CH2:3][CH2:4][CH:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1.P(Br)(Br)[Br:12]>>[BrH:12].[Br:12][CH2:3][CH2:4][CH:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1
Reactant: BrP(Br)Br
Reactant: OCCC1CCNCC1
Agent: Cl
Product: Br
Product: BrCCC1CCNCC1
Yield: 77 %

Procedure:
2-(4-pyridyl)ethanol (70. g, 0.57 M) and platinum oxide (2 g) in water (600 ml) and concentrated aqueous HCl (81 ml) was hydrogenated at the pressure of 1000 psig hydrogen to give 4-(2-hydroxyethyl)piperidine hydrochloride in quantitative yield. Treatment of 4-(2-hydroxyethyl)piperidine hydrochloride (20 g 0.12 M) with phosphorus tribromide (7 ml) at 100° C. for 11/2 hr. followed by trituration with diethyl ether (2×50 ml) and filtration gave 4(2-bromoethyl)piperidine hydrogen bromide (20.76 g, 77% yield). The solution of the 4-(2-bromoethyl)piperidine hydrogen bromide (23 g.0.085 M) in tetrahydrofuran (170 ml) and dimethylformamide (170 ml) was prepared. To this solution was added formic acetic anhydride (12.7 ml) at 0° C., followed by the addition of triethylamine (25 ml) with vigorously stirring. The reaction mixture was stirred overnight. After the reaction, it was filtered and the filtrate was stripped in vacuo to dryness and water (100 ml) was then added to the residue and the mixture was extracted with diethyl ether (3×100 ml). Removal of the solvent and purification on silica gel columns, eluted with ethyl acetate-hexane (9:1 parts by volume) gave 4-(2-bromoethyl)-1-piperidinecarboxaldehyde (12.06 g, 66% yield).