Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([NH:7][C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][C:9]=2[NH2:18])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH2:26]([O:28][CH2:29][C:30](Cl)=[O:31])[CH3:27]>C(Cl)Cl.C(Cl)(Cl)Cl>[CH2:26]([O:28][CH2:29][C:30]([NH:18][C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:8]=1[NH:7][N:1]1[CH2:2][CH2:3][O:4][CH2:5][CH2:6]1)=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:31])[CH3:27]
Reactant: CCOCC(=O)Cl
Reactant: Nc1cnc2ccccc2c1NN1CCOCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CCOCC(=O)Nc1cnc2ccccc2c1NN1CCOCC1
Temperature: 0 °C
Reaction time: 48 h
Yield: 97.6 %

Procedure:
A solution of N4-(morpholin-4-yl)quinoline-3,4-diamine (4.06 g, 16.6 mmol) in 50 mL of CH2Cl2 was treated with triethylamine (4.40 mL, 33.2 mmol) and cooled to 0° C. The solution was treated dropwise with ethoxyacetyl chloride (2.40 g, 17.4 mmol) and stirred under an atmosphere of nitrogen. The reaction mixture was allowed to slowly come to room temperature. After 2 d, the reaction mixture was concentrated under reduced pressure to yield a red semi-solid. The material was dissolved in CHCl3 and washed with water, 5% Na2CO3 solution and brine, dried over Na2SO4, filtered and dried to yield 2-ethoxy—N-{4-[(morpholin-4-yl)amino]quinolin-3-yl}acetamide (5.35 g) as a red/orange foam.
Reaction SMILES: [C:1]1([C:7]2[O:11][N:10]=[C:9]([C:12]([NH:14][CH2:15][C:16]([OH:18])=O)=[O:13])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.Cl.[NH:52]1[CH2:57][CH2:56][CH:55]([NH:58][C:59]2[CH:64]=[CH:63][CH:62]=[CH:61][C:60]=2[C:65]([F:68])([F:67])[F:66])[CH2:54][CH2:53]1>CN(C=O)C.O>[O:18]=[C:16]([N:52]1[CH2:53][CH2:54][CH:55]([NH:58][C:59]2[CH:64]=[CH:63][CH:62]=[CH:61][C:60]=2[C:65]([F:66])([F:67])[F:68])[CH2:56][CH2:57]1)[CH2:15][NH:14][C:12]([C:9]1[CH:8]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[O:11][N:10]=1)=[O:13]
Reactant: O=C(O)CNC(=O)c1cc(-c2ccccc2)on1
Reactant: FC(F)(F)c1ccccc1NC1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: O=C(NCC(=O)N1CCC(Nc2ccccc2C(F)(F)F)CC1)c1cc(-c2ccccc2)on1
Reaction time: 8 h
Yield: 60.3 %

Procedure:
To a stirred solution of [(5-phenyl-isoxazole-3-carbonyl)-amino]-acetic acid (0.0685 g, 0.00024 mol) in DMF (2 mL) was added DIPEA (0.173 g, 0.00134 mol), HOBt (0.045 g, 0.00034 mol) and EDCI.HCl (0.064 g, 0.00034 mol) at ambient temperature. After 2 minutes piperidin-4-yl-(2-trifluoromethyl-phenyl)-amine dihydrochloride (0.068 g, 0.00024 mol) was added and the resulting mixture was stirred overnight. The reaction mixture was then diluted with cold water and the product was extracted with ethyl acetate. The ethyl acetate layer was collected and washed with brine solution, dried over sodium sulfate and concentrated. The resulting residue was purified by column chromatography using neutral aluminium oxide (35% ethyl acetate in hexane) to afford 0.0684 g (60%) of 5-phenyl-isoxazole-3-carboxylic acid {2-oxo-2-[4-(2-trifluoromethyl-phenylamino)-piperidin-1-yl]-ethyl}-amide. LCMS: 473.17 (M+1)+, 97.41%, 1H NMR (DMSO-d6): δ 8.62 (t, 1H), 7.94 (m, 2H), 7.52 (m, 3H), 7.38 (m, 3H), 6.98 (d, 1H), 6.7 (t, 1H), 4.7 (d, 1H), 4.3 (d, 1H), 4.2 (d, 2H), 3.9 (d, 1H), 3.7 (m, 1H), 3.2 (m, 1H), 2.8 (m, 1H), 2.0 (m, 2H), 1.4 (m, 2H).
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][C@H:17]([CH2:19][N:20]([C:29]4[CH:33]=[CH:32][O:31][N:30]=4)[C:21]([O:23][CH2:24][C:25]([Cl:28])([Cl:27])[Cl:26])=[O:22])[O:16][C:15]3=[O:34])=[CH:10][C:9]=2[F:35])[CH2:4]1.C(=O)(O)[O-].[Na+].ClCCl.[C:44](OC(=O)C)(=[O:46])[CH3:45]>O>[C:44]([NH:2][C@H:3]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][C@H:17]([CH2:19][N:20]([C:29]4[CH:33]=[CH:32][O:31][N:30]=4)[C:21]([O:23][CH2:24][C:25]([Cl:28])([Cl:26])[Cl:27])=[O:22])[O:16][C:15]3=[O:34])=[CH:10][C:9]=2[F:35])[CH2:4]1)(=[O:46])[CH3:45]
Reactant: CC(=O)OC(C)=O
Reactant: N[C@H]1CCN(c2ccc(N3C[C@H](CN(C(=O)OCC(Cl)(Cl)Cl)c4ccon4)OC3=O)cc2F)C1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CC(=O)N[C@H]1CCN(c2ccc(N3C[C@H](CN(C(=O)OCC(Cl)(Cl)Cl)c4ccon4)OC3=O)cc2F)C1
Reaction time: 18 h
Yield: 83.7 %

Procedure:
3-(4-(3(S)-Aminopyrrolidin-1-yl)-3-fluorophenyl)-5(R)-(N-(2,2,2-trichloroethyloxycarbonyl)isoxazol-3-ylaminomethyl)oxazolidin-2-one hydrochloride salt (400 mg, 0.74 mM) was dissolved in water (5 ml) and treated with aqueous sodium bicarbonate solution (5 ml) and dichloromethane (10 ml) in an ice-bath. Acetic anhydride (216 mg, 2 mM) was added, the mixture stirred 18 hours, allowing the temperature to rise to ambient, followed by addition of a further portion of acetic anhydride (216 mg ), and a further period of 10 hours stirring. The organic phase was separated, washed with aqueous sodium dihydrogen phosphate (2%, 2×15 ml), brine (10 ml), and dried (magnesium sulfate). Evaporation gave the desired product (338 mg ). NMR (DMSO-d6) δ: 1.79 (s overlapping m, 4H); 2.11 (hextet, 1H); 3.11 (m, 1H); 3.26 (m overlapped by H2O, ˜1H); 3.40 (dd, 1H); 3.49 (m, 1H); 3.8.2 (dd, 1H); 4.13 (t overlapping dd, 2H); 4.27 (dd, 1H); 4.35 (dd, 1H); 4.97 (d, 1H); 5.01 (m, 1H); 5.07 (d, 1H); 6.73 (t, 1H); 6.88 (d, 1H); 7.08 (dd, 1H); 7.35 (dd, 1H); 8.08 (d, 1H); 8.89 (d, 1H). MS (ESP): 578 (MH+) for C22H23Cl3FN5O6
Reaction SMILES: [H-].[Na+].[CH2:3]([N:10]1[CH2:15][CH2:14][C:13]([CH2:24][OH:25])([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2F)[CH2:12][CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>CCCCCCC.O1CCCC1>[CH2:3]([N:10]1[CH2:15][CH2:14][C:13]2([CH2:16][C:17]3[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=3)[O:25][CH2:24]2)[CH2:12][CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: OCC1(Cc2ccccc2F)CCN(Cc2ccccc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCCC
Solvent: C1CCOC1
Product: c1ccc(CN2CCC3(CC2)COc2ccccc2C3)cc1
Yield: 88.4 %

Procedure:
Sodium hydride (350 mg, 7.0 mmol, 50% disp in oil) was washed three times with heptane, under nitrogen atmosphere, and then dissolved in tetrahydrofuran (50 mL). A solution of [1-benzyl-4-(2-fluorobenzyl)piperidin-4-yl)methanol (1 g, 3.2 mmol) in tetrahydrofuran (30 mL) was added and the resulting mixture was refluxed for 3 hrs. The cooled solution was partitioned between water and ethyl acetate and the organic layer was dried over magnesium sulphate and concentrated. The crude product was purified on silica (dichloromethane/methanol) to give 0.83 g (89%) of the subtitle compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([NH:16][C:17]3[CH:37]=[CH:36][C:20]([C:21]([CH:23]4[CH2:28][CH2:27][CH2:26][N:25]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:24]4)=[O:22])=[CH:19][CH:18]=3)=[O:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[BH4-].[Na+].C(OCC)(=O)C>CO.O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[CH:10][C:11]([C:14]([NH:16][C:17]3[CH:37]=[CH:36][C:20]([CH:21]([OH:22])[CH:23]4[CH2:28][CH2:27][CH2:26][N:25]([C:29]([O:31][C:32]([CH3:34])([CH3:33])[CH3:35])=[O:30])[CH2:24]4)=[CH:19][CH:18]=3)=[O:15])=[CH:12][CH:13]=2)=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCCC(C(=O)c2ccc(NC(=O)c3ccc(-c4ccc(Cl)cc4)cc3)cc2)C1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCCC(C(O)c2ccc(NC(=O)c3ccc(-c4ccc(Cl)cc4)cc3)cc2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.1 %

Procedure:
tert-Butyl 3-[4-[[(4′-chloro[1,1′-biphenyl]-4-yl)carbonyl]amino]benzoyl]-1-piperidinecarboxylate (506 mg, 0.975 mmol) obtained in Example 127-1) was dissolved in a mixed solution of methanol and tetrahydrofuran (1:1) (10 ml). Sodium borohydride (73.8 mg, 1.95 mmol) was added to the solution under ice-cooling, which was stirred at room temperature for 1 hour. Ethyl acetate was added to the reaction mixture, which was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and then the solvent was distilled out under reduced pressure. Diisopropyl ether was added to the residue, to give the titled compound (488 mg) as a colorless powder.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:20])[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][C:9]2=[O:19])=[CH:4][C:3]=1[O:21]C.B(Br)(Br)Br.CCCCCC>CCOC(C)=O>[OH:21][C:3]1[CH:4]=[C:5]([C:8]2([CH3:20])[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][C:9]2=[O:19])[CH:6]=[CH:7][C:2]=1[OH:1]
Reactant: COc1cc(C2(C)C(=O)Nc3ccccc3C2=O)ccc1O
Agent: BrB(Br)Br
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CC1(c2ccc(O)c(O)c2)C(=O)Nc2ccccc2C1=O
Yield: 62.7 %

Procedure:
The objective compound was prepared by the same procedure for the example 13, using a 3-(4-hydroxy-3-methoxy-phenyl)-3-methyl-1H-quinoline-2,4-dione (120 mg, 0.40 mmol) and BBr3 (1.60 mL, 1.0 M solution in dichloromethane). After normal workup, the pure objective compound (71 mg, 62%) was obtained as pale yellow solid by a flash column chromatography (n-hexane:EtOAc=3:1): 1H NMR (200 MHz, DMSO-d6) δ 1.57 (s, 3H, CH3), 6.42 (dd, J=8.14, 2.03 Hz, 1H, ArH), 6.59-6.63 (m, 2H, ArH), 7.07 (t, J=7.73 Hz, 2H, ArH), 7.55 (t, J=7.32 Hz, 1H, ArH), 7.68 (d, J=7.32 Hz, 1H, ArH), 9.00 (br s, 1H, OH), 10.93 (br s, 1H, NH); m.p. 259-261° C.; MS(EI) m/e 283 [M+], 268, 255, 237; HRMS m/e cacld. for C16H13N1O4 283.0845, found 283.0849.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N+:15]([O-:17])=[O:16])=[C:7]([CH:9]([OH:14])[C:10]([CH3:13])([CH3:12])[CH3:11])[CH:8]=1.[C@:18]12([CH3:30])[C:24]([CH3:26])([CH3:25])[CH:21]([CH2:22][CH2:23]1)[CH2:20][CH:19]2[C:27](Cl)=[O:28]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C@:18]12([CH3:30])[C:24]([CH3:25])([CH3:26])[CH:21]([CH2:22][CH2:23]1)[CH2:20][CH:19]2[C:27]([O:14][CH:9]([C:7]1[CH:8]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=1[N+:15]([O-:17])=[O:16])[C:10]([CH3:13])([CH3:12])[CH3:11])=[O:28]
Reactant: COc1ccc([N+](=O)[O-])c(C(O)C(C)(C)C)c1
Reactant: CC1(C)C2CC[C@@]1(C)C(C(=O)Cl)C2
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COc1ccc([N+](=O)[O-])c(C(OC(=O)C2CC3CC[C@]2(C)C3(C)C)C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85 %

Procedure:
To a solution of racemic (R/S)-1-(5-methoxy-2-nitrophenyl)-2,2-dimethyl-1-propanol (1.75 g, 7.3 mmol) and DMAP (2.92 g, 23.9 mmol) in anhydrous CH2Cl2 (10 mL), (1S)-camphanic chloride (Corrie et al., 1992), which is incorporated by reference) (2.6 g, 12 mmol) was added, and the mixture was stirred overnight at room temperature under a nitrogen atmosphere. The reaction mixture was diluted with CH2Cl2 (50 mL) and washed with saturated NaHCO3 solution (50 mL). The organic phase was dried over Na2SO4, concentrated in vacuo, and the residue was purified by silica gel column chromatography to yield (R/S)-1-(5-methoxy-2-nitrophenyl)-2,2-dimethyl-1-propyl(1S)-camphanate (2.5 g, 85%, 1:1 mixture of diastereomers). The camphanate was dissolved in ethyl acetate (30 mL) followed by slow addition of hexane (120 mL) with stirring. Needle crystals formed gradually from the solution over a two-hour period. The crystals were collected by filtration to yield pure single diastereomer (S)-1-(5-methoxy-2-nitrophenyl)-2,2-dimethyl-1-propyl(1S)-camphanate. The filtrate was concentrated in vacuo, and the crystallization process was repeated twice to provide additional (S)-1-(5-methoxy-2-nitrophenyl)-2,2-dimethyl-1-propyl(1S)-camphanate (total 1.08 g, 43%). 1H NMR (400 MHz, CDCl3): δ 8.04 (d, 1H, J=9.2 Hz, Ph-H), 7.27 (d, 1H, J=2.8 Hz, Ph-H), 6.88 (dd, 1H, J=2.8 and 8.8 Hz, Ph-H), 6.81 (3, 1H, Ph-CH), 3.87 (s, 3H, OCH3), 2.36 (m, 1H, CH), 1.92 (m, 2H, CH2), 1.66 (m, 1H, CH), 1.12 (s, 3H, CH3), 1.06 (s, 3H, CH3), 1.02 (s, 3H, CH3), 0.95 (s, 9H, C(CH3)3).
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:9]([N:16]1[C:24](=[O:25])[C:23]2[C@@H:22]3[C:26]([CH3:28])([CH3:27])[C@@:19]([CH3:29])([CH2:20][CH2:21]3)[C:18]=2[NH:17]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)C=O.ClCCl>[CH2:1]([N:17]1[C:18]2[C@@:19]3([CH3:29])[C:26]([CH3:28])([CH3:27])[C@H:22]([CH2:21][CH2:20]3)[C:23]=2[C:24](=[O:25])[N:16]1[CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1(C)[C@@H]2CC[C@@]1(C)c1[nH]n(Cc3ccccc3)c(=O)c12
Reactant: BrCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC1(C)[C@@H]2CC[C@@]1(C)c1c2c(=O)n(Cc2ccccc2)n1Cc1ccccc1
Temperature: 100 °C
Yield: 42.7 %

Procedure:
A mixture of benzyl bromide (300 μL, 2.5 mmol), (4S,7R)-2-benzyl-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Intermediate 23; 159 mg, 0.56 mmol), and tetra-n-butylammonium iodide (160 mg, 0.43 mmol) in N,N-dimethylformamide (2 mL) was heated in an oil-bath at 100° C. for 17 h. The reaction mixture was cooled to room temperature and diluted with dichloromethane (125 mL). The solution was washed with water (5×25 mL) and sodium thiosulfate solution (25 mL), dried (magnesium sulfate), filtered, and evaporated and the residue was purified on an Isco 40 g column, eluting with 20-100% ethyl acetate/hexanes to give (4S,7R)-1,2-dibenzyl-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (89 mg, 42%) as a yellow gum. ES(+)-MS (M+H) 373.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=1)=O.N1C=CC=CC=1.Cl.[NH2:26][OH:27].C(OCC)(=O)C>CCCCCCC>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=1)=[N:26][OH:27]
Reactant: NO
Reactant: COc1cccc(C(=O)c2ccc(F)cc2F)c1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: CCCCCCC
Product: COc1cccc(C(=NO)c2ccc(F)cc2F)c1
Yield: 99 %

Procedure:
Combine (2,4-difluoro-phenyl)-(3-methoxy-phenyl)-methanone (51.2 g, 0.206 mol) and pyridine (293.4 g, 300 mL). Add hydroxylamine hydrochloride (21.7 g, 0.312 mol) and heat to 100° C., under a nitrogen atmosphere, for 4 hours. TLC (20% ethyl acetate in heptane) shows that the reaction is complete. Concentrate the reaction mixture and dry (vacuum at 50° C.). Distribute the material between ethyl acetate and water. Wash the organic layer with 10% HCl, saturated sodium chloride, dry (MgSO4) and concentrated to obtain the title compound as a white solid (53.66 g, 99% Yield). Use compound in a crude form or recrystallize from heptane and dry (P2O5). NMR and MS are consistent with the final, desired compound, which is a mixture of the Z-isomer (81%) and the E-isomer (19%). mp=122° C.-127° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:39])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:15]=2[CH2:24][N:25]([CH2:37][CH3:38])[C:26](=[N:34][C:35]#[N:36])OC2C=CC=CC=2)[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2].[CH3:40][O:41][C:42]1[CH:49]=[CH:48][C:45]([CH2:46][NH2:47])=[CH:44][CH:43]=1>>[CH2:1]([O:3][C:4](=[O:39])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:21])([F:22])[F:23])=[CH:16][C:15]=2[CH2:24][N:25]([CH2:37][CH3:38])[C:26]([NH:34][C:35]#[N:36])=[N:47][CH2:46][C:45]2[CH:48]=[CH:49][C:42]([O:41][CH3:40])=[CH:43][CH:44]=2)[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2]
Reactant: COc1ccc(CN)cc1
Reactant: CCOC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CN(CC)C(=NC#N)Oc2ccccc2)c1
Product: CCOC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2CN(CC)C(=NCc2ccc(OC)cc2)NC#N)c1

Procedure:
Prepared according to the procedure described in Example 33, Step 6, using the following starting materials: [2′-(3-cyano-1-ethyl-2-phenyl-isoureidomethyl)-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl]-acetic acid ethyl ester and 4-methoxybenzylamine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH2:6][NH2:7].[CH3:13][O:14][C:15](=[O:34])[C:16]1[CH:21]=[CH:20][C:19]([C:22]2[N:23]=[C:24](Cl)[C:25]3[C:30]([CH3:31])=[C:29]([CH3:32])[S:28][C:26]=3[N:27]=2)=[CH:18][CH:17]=1>>[CH3:13][O:14][C:15](=[O:34])[C:16]1[CH:17]=[CH:18][C:19]([C:22]2[N:23]=[C:24]([NH:7][CH2:6][C:5]3[CH:8]=[CH:9][C:10]([O:11][CH3:12])=[C:3]([O:2][CH3:1])[CH:4]=3)[C:25]3[C:30]([CH3:31])=[C:29]([CH3:32])[S:28][C:26]=3[N:27]=2)=[CH:20][CH:21]=1
Reactant: COc1ccc(CN)cc1OC
Reactant: COC(=O)c1ccc(-c2nc(Cl)c3c(C)c(C)sc3n2)cc1
Product: COC(=O)c1ccc(-c2nc(NCc3ccc(OC)c(OC)c3)c3c(C)c(C)sc3n2)cc1

Procedure:
The reaction procedure as above wherein 3,4-dimethoxy-benzylamine is reacted with 4-(4-chloro-5,6-dimethyl-thieno-[2,3-d]-pyrimidin-2-yl)-benzoic acid methylester yields 4-[4-(3,4-dimethoxybenzylamino)-5,6-dimethyl-thieno-[2,3-d]-pyrimidin-2-yl]-benzoic acid methylester.
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:5][C:6]1[CH:10]=[CH:9][O:8][CH:7]=1.CCCCCC.C([Li])CCC.[OH-].[Na+]>O1CCCC1>[CH2:11]([N:4]1[CH2:3][CH2:2][C:7]2[O:8][CH:9]=[CH:10][C:6]=2[CH2:5]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: ClCCN(Cc1ccccc1)Cc1ccoc1
Agent: [Li]CCCC
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: c1ccc(CN2CCc3occc3C2)cc1
Temperature: 0 °C

Procedure:
2-(Benzyl-(3-furylmethyl)amino)ethanol (6.5 g, 28 mmol), triethylamine (5.9 ml, 42 mmol), 4-dimethylaminopyridine (250 mg, 2.1 mmol) and tosyl chloride (6.4 g, 34 mmol) were stirred at room temperature for 17 hours in dichloromethane (260 ml). The reaction solution was mixed with dichloromethane, washed with water and saturated brine and then dried with anhydrous magnesium sulfate. The solvent was removed by evaporation from the organic layer under a reduced pressure, and the thus obtained material was separated and purified by a silica gel column chromatography to obtain 5.4 g of crude 1-chloro-2-(benzyl-(3-furylmethyl)amino)ethane. The crude 1-chloro-2-(benzyl-(3-furylmethyl)amino)ethane (1.8 g) was dissolved in anhydrous tetrahydrofuran (35 ml) and cooled to 0° C. In an atmosphere of argon, n-butyl lithium hexane solution (14 mmol) was added thereto to carry out 2 hours of the reaction at room temperature. The reaction solution was mixed with 1 N sodium hydroxide aqueous solution, the reaction product was extracted with dichloromethane, and then the organic layer was washed with saturated brine and dried with anhydrous magnesium sulfate. The solvent was removed by evaporation from the organic layer under a reduced pressure, and the thus obtained material was separated and purified by a silica gel column chromatography to obtain 1.1 g (5.1 mmol, 73% in yield) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:15]=[CH:16][C:17]=1[O:18][CH3:19])[NH:6][C:7]([CH3:14])=[CH:8][C:9]([O:11][CH2:12][CH3:13])=[O:10]>C(O)(=O)C.C(Cl)(Cl)Cl.[Pt]=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:15]=[CH:16][C:17]=1[O:18][CH3:19])[NH:6][CH:7]([CH3:14])[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: CCOC(=O)C=C(C)Nc1ccc(OC)c(OC)c1
Agent: O=[Pt]
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)CC(C)Nc1ccc(OC)c(OC)c1
Reaction time: 1 h
Yield: 99.2 %

Procedure:
A mixture of 30.0 g of the product of Example 1 (m.p. 59°-60°), and 2.0 g of platinum oxide in 250 ml of acetic acid was hydrogenated in a Paar shaker at 50 p.s.i.; reduction was complete in 1 hr. The mixture was filtered and concentrated under reduced pressure, to give an amber oil which was dissolved in chloroform and washed with sodium bicarbonate solution followed by saturated sodium chloride. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure to give 30.0 g of an amber oil which was used in the next step without further purification. A sample of oil was converted to the hydrochloride salt, m.p. 137.5°-139°. An equivalent sample of the hydrochloride salt (m.p. 138°-139.5°) was analyzed.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1/[CH:10]=[CH:11]/[N:12]1[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=2)[CH2:14][CH2:13]1)[C:5]#[N:6].[BH4-].[Na+]>CO.C(Cl)Cl>[CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[CH2:10][CH2:11][N:12]1[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C:20]2[CH:21]=[CH:22][C:23]([N+:26]([O-:28])=[O:27])=[CH:24][CH:25]=2)[CH2:14][CH2:13]1)[C:5]#[N:6]
Reactant: Cc1cc(C#N)ccc1/C=C/N1CCN(CCc2ccc([N+](=O)[O-])cc2)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: Cc1cc(C#N)ccc1CCN1CCN(CCc2ccc([N+](=O)[O-])cc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 3-methyl-4-((E)-2-{4-[2-(4-nitrophenyl)ethyl]piperazin-1-yl}vinyl)benzonitrile (100 mg, 0.24 mmol) in 15 mL of methanol and 10 mL of DCM was added NaBH4 (508 mg, 2.4 mmol), then stirred at room temperature overnight. The crude product was purified via prepare TLC (methanol/DCM 1:10) to give 3-methyl-4-(2-{4-[2-(4-nitrophenyl)ethyl]piperazin-1-yl}ethyl)benzonitrile. 1H-NMR (300 MHz, CDCl3) δ ppm 8.12 (d, J=8.6 Hz, 2H), 7.23˜7.40 (m, 5H), 3.01˜3.21 (m, 2H), 2.80˜2.92 (m, 4H), 2.50˜2.65 (m, 10H), 2.33 (s, 3H). MS m/z: 379 (M+1)+. (0.062 μM)
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]([OH:6])=O.Cl.[NH:8]1[CH2:13][CH2:12][C:11]([C:14]2[C:19]([F:20])=[CH:18][C:17]([N:21]3[CH2:25][C@H:24]([CH2:26][N:27]([C:35]4[CH:39]=[CH:38][O:37][N:36]=4)[C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[O:23][C:22]3=[O:40])=[CH:16][C:15]=2[F:41])=[CH:10][CH2:9]1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O.O.C(OCC)(=O)C>[OH:1][CH2:2][CH2:3][C:4]([N:8]1[CH2:13][CH2:12][C:11]([C:14]2[C:19]([F:20])=[CH:18][C:17]([N:21]3[CH2:25][C@H:24]([CH2:26][N:27]([C:35]4[CH:39]=[CH:38][O:37][N:36]=4)[C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[O:23][C:22]3=[O:40])=[CH:16][C:15]=2[F:41])=[CH:10][CH2:9]1)=[O:6]
Reactant: CC(C)(C)OC(=O)N(C[C@H]1CN(c2cc(F)c(C3=CCNCC3)c(F)c2)C(=O)O1)c1ccon1
Reactant: O=C(O)CCO
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N(C[C@H]1CN(c2cc(F)c(C3=CCN(C(=O)CCO)CC3)c(F)c2)C(=O)O1)c1ccon1
Reaction time: 18 h
Yield: 74.2 %

Procedure:
To a solution of 3-hydroxypropionic acid (45 mg, 0.5 mM) in N,N dimethylformamide (2 ml) was added 3-(4-(1,2,5,6-tetrahydropyrid-4-yl)-3,5-difluorophenyl)-5(R)(N-(t-butoxy-carbonyl)isoxazol-3-ylaminomethyl)oxazolidin-2-one hydrochloride (256 mg, 0.5 mM, reference example 10), and O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate (190 mg, 0.5 mM). The mixture was cooled to 0°, N,N-diisopropylethylamine (129 mg, 1 mM) added, and the mixture stirred 18 hours, allowing the temperature to rise to ambient. The mixture was poured into a mixture of ethyl acetate (40 ml) and water (40 ml), the organic layer separated and washed with aqueous sodium dihydrogen phosphate (2%, 40 ml), sodium bicarbonate (40 ml) and brine (40 ml). Solvent was removed, and the residue chromatographed on a 10 g silica Mega Bond Elut® column, eluting with a mixture of 2.5% methanol in dichloromethane. Relevant fractions were combined and evaporated to give the title product (203 mg).