Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:7])([C:3]([F:6])([F:5])[F:4])=[O:2].[CH3:8][O:9][C:10](=[O:29])[C@H:11]([CH:26]([CH3:28])[CH3:27])[NH:12][C:13](=[O:25])[C:14]([CH3:24])([CH3:23])[NH:15]C(OC(C)(C)C)=O>C(Cl)Cl>[F:4][C:3]([F:6])([F:5])[C:1]([OH:7])=[O:2].[CH3:8][O:9][C:10](=[O:29])[C@H:11]([CH:26]([CH3:27])[CH3:28])[NH:12][C:13](=[O:25])[C:14]([CH3:24])([CH3:23])[NH2:15]
Reactant: COC(=O)[C@@H](NC(=O)C(C)(C)NC(=O)OC(C)(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)[C@@H](NC(=O)C(C)(C)N)C(C)C
Reaction time: 2 h
Yield: 82 %

Procedure:
A 50% (v/v) solution of TFA in CH2Cl2 (350 mL) was added to N-tert-butoxycarbonyl α,α-dimethylglycyl L-valine methyl ester (5) (33.50 g, 0.1059 mol) at room temperature and the reaction mixture stirred for 2 hours. The solvent and bulk of excess TFA were removed under reduced pressure. The residue was washed with Et2O (3×200 mL) and dried under reduced pressure affording a clear oil. Dichloromethane (3×200 mL) was added and evaporated under reduced pressure affording a sticky white solid (28.51 g, 82%); δH (300 MHz; d6-DMSO) 8.42 (1H, d, J 8, NH), 8.26 (3H, br s, NH3+), 4.17 (1H, dd, J 8 and 8, CαH(Val)), 3.64 (3H, s, OCH3), 2.16-2.05 (1H, m, CH(CH3)2), 1.52 (3H, s, CH3(Aib)), 1.50 (3H, s, CH3(Aib)), 0.91 (3H, d, J 6, CH3(Val)), 0.88 (3H, d, J 6, CH3(Val)); δC (75 MHz; d6-DMSO) 172.0, 171.6, 158.1 (q, JcF 32), 116.9 (q, JCF 297), 58.3, 56.5, 51.7, 29.5, 23.2, 23.1, 19.0, 18.6; m/z (ESI) 217.1556 (M+; C10H21N2O3 requires 217.1552)
Reaction SMILES: O=C(Cl)[O:3][C:4](Cl)(Cl)Cl.[NH2:9][C:10]1[CH:44]=[CH:43][C:13]([O:14][C:15]2[CH:20]=[CH:19][N:18]=[C:17]3[CH:21]=[C:22]([C:24]4[N:29]=[CH:28][C:27]([CH2:30][N:31]([CH2:39][CH2:40][O:41][CH3:42])[C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[CH:26][CH:25]=4)[S:23][C:16]=23)=[C:12]([F:45])[CH:11]=1.[C:46]1([N:52]2[CH2:56][CH2:55][NH:54][C:53]2=[S:57])[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1.[H-].[Na+]>C1COCC1.CCOC(C)=O>[F:45][C:12]1[CH:11]=[C:10]([NH:9][C:4]([N:54]2[CH2:55][CH2:56][N:52]([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)[C:53]2=[S:57])=[O:3])[CH:44]=[CH:43][C:13]=1[O:14][C:15]1[CH:20]=[CH:19][N:18]=[C:17]2[CH:21]=[C:22]([C:24]3[N:29]=[CH:28][C:27]([CH2:30][N:31]([CH2:39][CH2:40][O:41][CH3:42])[C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[CH:26][CH:25]=3)[S:23][C:16]=12
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: COCCN(Cc1ccc(-c2cc3nccc(Oc4ccc(N)cc4F)c3s2)nc1)C(=O)OC(C)(C)C
Reactant: S=C1NCCN1c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COCCN(Cc1ccc(-c2cc3nccc(Oc4ccc(NC(=O)N5CCN(c6ccccc6)C5=S)cc4F)c3s2)nc1)C(=O)OC(C)(C)C
Reaction time: 2 h
Yield: 48.7 %

Procedure:
Diphosgene (0.023 ml, 0.191 mmol) was added in one portion to a solution of 126 (schemes 6 or 9) (0.200 g, 0.381 mmol) in THF (3.81 ml) and the reaction mixture stirred vigorously for 2 h. 1-Phenylimidazolidine-2-thione (301, 0.102 g, 0.572 mmol) and sodium hydride (60% in mineral oil) (0.046 g, 1.143 mmol) were added sequentially and the mixture was stirred at room temperature for an additional 1 h. The crude mixture was then suspended in EtOAc, washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Luna C18 (2), 5.0 cm ID; gradient: 80% MeOH to 95% MeOH in water, 60 min) affording title compound 302 (0.068 g, 0.093 mmol, 24.5% yield) as creamy solid. m/z: (M+1)+ 729.4 (100%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:26]=[CH:25][C:21]([C:22]([OH:24])=O)=[CH:20][CH:19]=3)=[CH:17][C:9]1=2.[NH2:32][CH:33]1[CH2:38][CH2:37][N:36]([CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH2:35][CH2:34]1>>[CH2:39]([N:36]1[CH2:37][CH2:38][CH:33]([NH:32][C:22](=[O:24])[C:21]2[CH:25]=[CH:26][C:18]([C:16]3[CH:15]=[N:14][C:10]4[NH:11][CH2:12][CH2:13][N:8]([CH2:7][C:6]5[CH:27]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=5[C:28]([F:31])([F:30])[F:29])[C:9]=4[CH:17]=3)=[CH:19][CH:20]=2)[CH2:34][CH2:35]1)[C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1
Reactant: NC1CCN(Cc2ccccc2)CC1
Reactant: O=C(O)c1ccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)cc1
Product: O=C(NC1CCN(Cc2ccccc2)CC1)c1ccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)cc1

Procedure:
4-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid was reacted with 4-amino-1-benzylpiperidine as in General Procedure 10 to give the title compound. LCMS: m/z=619.99 (M+H+); retention time=0.61 minutes.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@@H:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:17][CH:16]=2)[C@H:10]([OH:28])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:31][O:32][CH2:33][CH2:34]Br.O>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@@H:11]([O:14][C:15]2[CH:16]=[CH:17][C:18]([O:21][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)=[CH:19][CH:20]=2)[C@H:10]([O:28][CH2:34][CH2:33][O:32][CH3:31])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COCCBr
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](Oc2ccc(Oc3ccccc3)cc2)[C@H](O)C1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COCCO[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@H]1Oc1ccc(Oc2ccccc2)cc1
Reaction time: 1 h

Procedure:
To a solution of (±)-trans-N-tert-butoxycarbonyl-3-hydroxy-4-(4-phenoxyphenoxy)-piperidine (1.47 g, 3.8 mmol) in dry DMF (30 ml) was added sodium hydride (300 mg 60% suspension in mineral oil, 4.2 mmol). After 1 h, 2-bromoethyl methyl ether (1.7 g, 7.6 mmol) was added. After 6 days water was added and the product was extracted with ethyl acetate (2×30 ml). After drying and evaporation the crude product was obtained as an oil.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH2:9][CH2:10][OH:11])=[CH:6][C:5]([N:12]2[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[N:14]([CH3:23])[C:13]2=[O:24])=[C:4]([F:25])[CH:3]=1.[C:26](Cl)(=[O:28])[CH3:27].N1C=CC=CC=1>C(OCC)C>[C:26]([O:11][CH2:10][CH2:9][O:8][C:7]1[CH:6]=[C:5]([N:12]2[C:17](=[O:18])[CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[N:14]([CH3:23])[C:13]2=[O:24])[C:4]([F:25])=[CH:3][C:2]=1[Cl:1])(=[O:28])[CH3:27]
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(OCCO)c(Cl)cc2F)c1=O
Reactant: CC(=O)Cl
Solvent: CCOCC
Solvent: c1ccncc1
Product: CC(=O)OCCOc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl

Procedure:
using 3-[4-chloro-2-fluoro-5-(2-hydroxyethoxy)-phenyl]-1-methyl-6 -trifluoromethyl-2,4(1H,3H)-pyrimidinedione and acetyl chloride with pyridine in diethyl ether there is obtained 2-{2-chloro-5-[3,6-dihydro-2,6-dioxo-3-methyl-4-trifluoromethyl-1(2H) -pyrimidinyl]-4-fluorophenoxy}-ethyl acetate, m.p. 88°-90° C.;
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:22])[NH:10][CH2:11][CH:12]1[CH2:17][CH:16]2[CH2:18][CH:14]([C:15]2([CH3:20])[CH3:19])[C:13]1=[CH2:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH2:23].[OH2:24].C[N+]([O-])(C)C>C(Cl)Cl.[Os](=O)(=O)(=O)=O>[CH2:1]([O:8][C:9](=[O:22])[NH:10][CH2:11][CH:12]1[CH2:17][CH:16]2[CH2:18][CH:14]([C:15]2([CH3:19])[CH3:20])[C:13]1([OH:24])[CH2:21][OH:23])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O
Reactant: C=C1C(CNC(=O)OCc2ccccc2)CC2CC1C2(C)C
Agent: O=[Os](=O)(=O)=O
Agent: C[N+](C)(C)[O-]
Solvent: ClCCl
Product: CC1(C)C2CC(CNC(=O)OCc3ccccc3)C(O)(CO)C1C2
Temperature: 25 °C
Reaction time: 16 h
Yield: 61.9 %

Procedure:
(6,6-Dimethyl-2-methylene-bicyclo[3.1.1]hept-3-ylmethyl)-carbamic acid benzyl ester (2.19 g, 7.32 mmol), prepared in step B of example 47, was dissolved in CH2Cl2 (50 ml). To this solution was added trimethylamine N-oxide dihydrate (894 mg, 8.79 mmol) and osmium tetroxide (136 mg, 0.535 mmol). The solution was stirred at ambient temperature for 16 hours after which time the reaction was concentrated under vacuum and chromatographed on silica gel using a gradient starting with 30% ethyl acetate in hexanes to 50% ethyl acetate in hexanes to give 1.51 g of the titled compound as a brown oil: C.I. m/z 316 [M+1-H2 0]; 1H NMR (CDCl3)δ 7.31-7.39 (m, 5H), 5.59 (br s, 1H), 5.12 (s, 2H), 3.30-3.58 (m, 4H), 1.93-2.28 (m, 4H), 1.52 (m, 1H), 1.24-1.30 (m, 5H), 0.96 (s, 3H).
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:12]=2)[C:8](O)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)C(Cl)=O.C[Si](C)(C)[NH:30][Si](C)(C)C.CO>C(Cl)Cl.CN(C)C=O>[CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:12]=2)[C:8]([NH2:30])=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C[Si](C)(C)N[Si](C)(C)C
Reactant: O=C(O)C(CC1CCCC1)c1ccc(F)c(C(F)(F)F)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CO
Product: NC(=O)C(CC1CCCC1)c1ccc(F)c(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 109.8 %

Procedure:
A solution 3-cyclopentyl-2-(4-fluoro-3-trifluoromethyl-phenyl)-propionic acid (304 mg, 1.0 mmol) in methylene chloride (10 mL) and N,N-dimethylformamide (1 drop) was cooled to 0° C. and then treated with a 2.0M solution of oxalyl chloride in methylene chloride (1.5 mL, 3.0 mmol). The reaction was stirred for 30 min at 0° C. At this time, 1,1,1,3,3,3-hexamethyldisilazane (2.0 mL, 9.5 mmol) was added to the reaction mixture. The reaction was allowed to slowly warm to 25° C. and then stirred at 25° C. for 16 h. The reaction mixture was then treated with methanol (3 mL) and diluted with methylene chloride (35 mL). The resulting mixture was washed with a 5% aqueous sulfuric acid solution (2×10 mL), water (1×25 mL), and a saturated aqueous sodium chloride solution (3×25 mL). The organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo to afford 3-cyclopentyl-2-(4-fluoro-3-trifluoromethyl-phenyl)-propionamide (333 mg, 92.5%) as a pale yellow oil: EI-HRMS m/e calcd for C15H17F4NO (M+) 303.1246, found 303.1252.
Reaction SMILES: [C:1]12([O:11][CH2:12][C:13]3[NH:17][C:16]([CH:18]4[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]4)=[N:15][C:14]=3[C:24]([NH:26][C:27]3[CH:28]=[C:29]([CH2:33][C:34](O)=[O:35])[CH:30]=[CH:31][CH:32]=3)=[O:25])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.C12(OCC3NC(C4CCCCC4)=[N:51]C=3C(NC3C=C(C=CC=3)C(O)=O)=O)CC3CC(CC(C3)C1)C2.CNC[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O.[OH2:85].O1CCOCC1>>[OH:85][NH:51][C:34]([CH2:33][C:29]1[CH:28]=[C:27]([NH:26][C:24]([C:14]2[N:15]=[C:16]([CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)[NH:17][C:13]=2[CH2:12][O:11][C:1]23[CH2:2][CH:3]4[CH2:9][CH:7]([CH2:6][CH:5]([CH2:4]4)[CH2:10]2)[CH2:8]3)=[O:25])[CH:32]=[CH:31][CH:30]=1)=[O:35]
Reactant: O
Reactant: O=C(O)c1cccc(NC(=O)c2nc(C3CCCCC3)[nH]c2COC23CC4CC(CC(C4)C2)C3)c1
Reactant: O=C(O)Cc1cccc(NC(=O)c2nc(C3CCCCC3)[nH]c2COC23CC4CC(CC(C4)C2)C3)c1
Agent: CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Solvent: C1COCCO1
Product: O=C(Cc1cccc(NC(=O)c2nc(C3CCCCC3)[nH]c2COC23CC4CC(CC(C4)C2)C3)c1)NO

Procedure:
The title compound was prepared according to the procedure of Example 286, with the modification that (3-{[5-(adamantan-1-yloxymethyl)-2-cyclohexyl-1H-imidazole-4-carbonyl]-amino}-phenyl)-acetic acid (Example 219) was used in step a instead of 3-{[5-(adamantan-1-yloxymethyl)-2-cyclohexyl -1H-imidazole-4-carbonyl]-amino}-benzoic acid. 1H NMR (300 MHz, d6-DMSO) 12.15 (1H, s), 10.62 (1H, s), 9.37 (1H, s), 8.80 (1H, s), 7.68 (1H, s), 7.58 (1H, d), 7.21 (1H, t), 6.94 (1H, d), 4.79 (2H, s), 3.25 (2H, s), 2.69 (1H, m), 2.11 (3H, br s), 1.90 (2H, m), 1.75 (8H, m), 1.55 (8H, m), 1.30 (4H, m). The hydroxamic acid was converted to the N-methyl-D-glucamine salt and lyophilised from water/dioxan. Found: C, 59.81; H, 8.06; N, 9.68%; C36H55N5O9.1.1H2O requires: C, 59.87; H, 7.99; N, 9.70%.
Reaction SMILES: [Cl:1][C:2]1[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[C:3]=1[CH2:4][NH:5][CH:6]([CH2:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[N:18]=[C:17]([C:22]1[C:27]([Cl:28])=[CH:26][CH:25]=[CH:24][C:23]=1[Cl:29])[CH:16]=[CH:15]2)[C:7]([O:9][CH3:10])=[O:8].[C:35]([O-])(O)=O.[Na+].CI>CO>[Cl:1][C:2]1[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[C:3]=1[CH2:4][N:5]([CH3:35])[CH:6]([CH2:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[N:18]=[C:17]([C:22]1[C:27]([Cl:28])=[CH:26][CH:25]=[CH:24][C:23]=1[Cl:29])[CH:16]=[CH:15]2)[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)C(Cc1ccc2nc(-c3c(Cl)cccc3Cl)ccc2c1)NCc1c(Cl)cccc1Cl
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: CI
Solvent: CO
Product: COC(=O)C(Cc1ccc2nc(-c3c(Cl)cccc3Cl)ccc2c1)N(C)Cc1c(Cl)cccc1Cl
Temperature: 0 °C
Reaction time: 1 h
Yield: 43 %

Procedure:
To 100 mg of (methyl 2-[(2,6-dichlorobenzyl)amino]-3-[2-(2,6-dichlorophenyl)-6-quinolinyl]propanoate) 41 in CH3OH (2.3 ml) are added, at 0° C., NaHCO3 (1 equ.) and CH3I (1 equ.). The reaction is stirred for 1 h at 0° C., and then at room temperature for 2 days. The solvent is evaporated and CH2Cl2 (10 ml) is added to the residue. The solution is washed with water, brine, again water and dried over MgSO4, filtered and evaporated. Due to an incomplete reaction, the protocol is repeated using a tenfold excess of NaHCO3 and CH3I in MeOH (5 ml). After a similar work-up, the residue is purified by silica gel chromatography using hexane/AcOEt 90/10 as eluent to give methyl 2-[(2,6-dichlorobenzyl)(methyl)amino]-3-[2-(2,6-dichlorophenyl)-6-quinolinyl]propanoate 51.
Reaction SMILES: [Si:1]([O:18][CH2:19][C@@H:20]([N:23]1[C@H:28]([C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=2)[C@@H:27]([C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([Cl:42])[CH:37]=2)[CH2:26][CH:25]([OH:43])[C:24]1=[O:44])[CH2:21][CH3:22])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].I[CH3:48]>C1COCC1>[Si:1]([O:18][CH2:19][C@@H:20]([N:23]1[C@H:28]([C:29]2[CH:30]=[CH:31][C:32]([Cl:35])=[CH:33][CH:34]=2)[C@@H:27]([C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([Cl:42])[CH:37]=2)[CH2:26][CH:25]([O:43][CH3:48])[C:24]1=[O:44])[CH2:21][CH3:22])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC[C@@H](CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)N1C(=O)C(O)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC[C@@H](CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)N1C(=O)C(OC)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Reaction time: 0.5 h

Procedure:
To a 0° C. solution of (5R,6S)-1-((S)-1-(tert-butyldiphenylsilyloxy)butan-2-yl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-hydroxypiperidin-2-one (476 mg, 0.736 mmol; Example 203, Step A) in THF (7.360 mL) was added sodium hydride (58.9 mg, 1.472 mmol). After 30 minutes, iodomethane (0.092 mL, 1.472 mmol) was added. After 5 minutes, the cooling bath was removed. After 2 hours, the mixture was quenched with sat. aq. NH4Cl solution. The mixture was partitioned between ethyl acetate and water. The organic layer was washed with sat. aq. NaCl solution, dried over Na2SO4, and concentrated to afford the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10]2[CH:16]=[C:15]([C:17]([OH:19])=O)[S:14][C:11]=2[NH:12][N:13]=1.Cl.C[N:22](C)CCCN=C=NCC.[OH:32][N:33]1[C:37]2[N:38]=[CH:39][CH:40]=[CH:41][C:36]=2N=N1.CN1CCOCC1>CN(C)C=O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10]2[CH:16]=[C:15]([C:17]([NH:22][C@@H:40]([C:39]3[O:32][N:33]=[C:37]([CH3:36])[N:38]=3)[CH3:41])=[O:19])[S:14][C:11]=2[NH:12][N:13]=1
Reactant: On1nnc2cccnc21
Reactant: O=C(O)c1cc2c(-c3ccc(F)cc3F)n[nH]c2s1
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: Cc1noc([C@@H](C)NC(=O)c2cc3c(-c4ccc(F)cc4F)n[nH]c3s2)n1
Temperature: 50 °C
Reaction time: 0.17 h
Yield: 150 %

Procedure:
3-(2,4-Difluorophenyl)-1H-thieno[2,3-c]pyrazole-5-carboxylic acid (964.9 mg, 1.877 mmol, with 4 equivalents of sodium chloride), L-(1R)-1-(3-methyl-1,2,4-oxadiazol-5-yl)ethanamine bis-hydrochloride (462.3 mg, 2.311 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (725.4 mg, 3.78 mmol), 1-hydroxy-7-azabenzotriazole (129.6 mg, 0.952 mmol), and N-methylmorpholine (0.826 mL, 7.51 mmol) were dissolved in N,N-dimethylformamide (18 mL) at 25° C. The reaction mixture was heated to 50° C. and allowed to stir for 10 min. The reaction was stopped, cooled to room temperature, quenched by addition of saturated aqueous ammonium chloride (15 mL), and extracted with ethyl acetate (3×15 mL). The combined organic phases were washed with saturated aqueous ammonium chloride (2×15 mL) and saturated aqueous sodium chloride (1×15 mL), dried (sodium sulfate), filtered, and the solvent evaporated under reduced pressure. The crude product was purified by flash chromatography (RediSep SiO2, 120 g column) on a CombiFlash purification system eluting with ethyl acetate-hexanes (0-100%). The title compound (556.0 mg, 1.428 mmol, 76% yield) was recovered as a light yellow/white solid. LC-MS [M-1-1]=390.2
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[C:5](=[O:13])[C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1)[CH3:2].[H-].[Na+].Br[CH2:18][CH2:19][CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([C:28](=[O:30])[CH3:29])=[C:24]([O:31][CH3:32])[C:23]=1[CH2:33][CH2:34][CH3:35]>CN(C)C=O>[CH2:1]([O:3][C:4](=[O:14])[C:5](=[O:13])[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[CH:26][C:25]([C:28](=[O:30])[CH3:29])=[C:24]([O:31][CH3:32])[C:23]=2[CH2:33][CH2:34][CH3:35])=[CH:8][CH:7]=1)[CH3:2]
Reactant: CCCc1c(OCCCBr)ccc(C(C)=O)c1OC
Reactant: CCOC(=O)C(=O)c1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCc1c(OCCCOc2ccc(C(=O)C(=O)OCC)cc2)ccc(C(C)=O)c1OC
Temperature: 50 °C
Reaction time: 0.25 h
Yield: 37.3 %

Procedure:
A solution of 4-hydroxy-alpha-oxobenzeneacetic acid ethyl ester (0.471 g) in dimethylformamide (10 mL) was treated with 55% sodium hydride (0.117 g), stirred for 15 minutes and then a solution of with 1-[4-(3-bromopropoxy)-2-methoxy-3propylphenyl]ethanone (0.8 g) in dimethylformamide (5 mL) was added. The mixture was heated at 50° C. for 17 hours and worked up as in Example 20. The residual oil was purified by HPLC (ethyl acetate-hexane; 1:4), followed by flash chromatography over silica gel (ethyl acetate-toluene; 1:19) to yield 0.4 g of 4-[3-[4-acetyl-3-methoxy-2-propylphenoxy)propoxy]-alpha-oxobenzeneacetic acid ethyl ester as an oil.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH2:14][CH2:15][C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([CH2:25][P:26]([O:31][CH2:32][CH3:33])([O:28][CH2:29][CH3:30])=[O:27])=[CH:21][CH:20]=2)=[O:17])=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=2)[N:6]=1.[CH3:34][N:35]([CH:37](OC)OC)[CH3:36].CN(C)C=O>O>[Cl:13][C:10]1[CH:9]=[CH:8][C:7]([C:5]2[N:6]=[C:2](/[N:1]=[CH:34]/[N:35]([CH3:37])[CH3:36])[S:3][C:4]=2[CH2:14][CH2:15][C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([CH2:25][P:26]([O:28][CH2:29][CH3:30])([O:31][CH2:32][CH3:33])=[O:27])=[CH:21][CH:20]=2)=[O:17])=[CH:12][CH:11]=1
Reactant: CCOP(=O)(Cc1ccc(NC(=O)CCc2sc(N)nc2-c2ccc(Cl)cc2)cc1)OCC
Reactant: COC(OC)N(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CCOP(=O)(Cc1ccc(NC(=O)CCc2sc(/N=C/N(C)C)nc2-c2ccc(Cl)cc2)cc1)OCC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 3-[2-amino-4-(4-chlorophenyl)-5-thiazolyl]-N-[4-(diethylphosphonomethyl)phenyl]propionamide (500 mg), N,N-dimethylformamidedimethylacetal (155 mg) and N,N-dimethylformamide (10 ml) was stirred at room temperature for 1 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography and 3-(4-(4-chlorophenyl)-2-{(E)-[(dimethylamino)methylidene]amino}-5-thiazolyl)-N-[4-(diethylphosphonomethyl)phenyl]propionamide was obtained as crystals (510 mg, yield: 92%) from a fraction eluted with 5% methanol-ethyl acetate. Recrystallization from ethyl acetate gave colorless prism crystals. melting point: 150–151° C.
Reaction SMILES: [NH2:1][C:2]1[C:6]([CH3:7])=[CH:5][S:4][C:3]=1[C:8]([O:10]C)=O.[NH2:12][C:13](N)=[O:14]>CN(C=O)C>[CH3:7][C:6]1[C:2]2[NH:1][C:13](=[O:14])[NH:12][C:8](=[O:10])[C:3]=2[S:4][CH:5]=1
Reactant: NC(N)=O
Reactant: COC(=O)c1scc(C)c1N
Solvent: CN(C)C=O
Product: Cc1csc2c(=O)[nH]c(=O)[nH]c12
Temperature: 200 °C
Yield: 86.5 %

Procedure:
To 25.0 g (146 mmol) of methyl 3-amino-4-methylthiophene-2-carboxylate was added 43.5 g (730 mmol) of urea, and the resulting mixture was heated at 200° C. for 1.5 hours. The mixture was allowed to resume room temperature, and DMF (400 ml) was added thereto, followed by heating under reflux for one hour. After completion of the reaction, ice water was added to the reaction mixture, and crystals thus precipitated were filtered to give 23.0 g (yield: 93.7%) of the title compound.
Reaction SMILES: C(OC(=O)[N:7]([CH2:30][C:31]1[CH:40]=[CH:39][C:34]2[O:35][CH2:36][CH2:37][O:38][C:33]=2[CH:32]=1)[CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH3:27])[CH:24]=3)[C:19]([CH3:28])=[CH:18][C:17]2=[O:29])[CH2:10][CH2:9]1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[O:35]1[C:34]2[CH:39]=[CH:40][C:31]([CH2:30][NH:7][CH:8]3[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]4[C:25]5[C:20](=[CH:21][CH:22]=[C:23]([O:26][CH3:27])[CH:24]=5)[C:19]([CH3:28])=[CH:18][C:17]4=[O:29])[CH2:10][CH2:9]3)=[CH:32][C:33]=2[O:38][CH2:37][CH2:36]1
Reactant: COc1ccc2c(C)cc(=O)n(CCN3CCC(N(Cc4ccc5c(c4)OCCO5)C(=O)OC(C)(C)C)CC3)c2c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc2c(C)cc(=O)n(CCN3CCC(NCc4ccc5c(c4)OCCO5)CC3)c2c1
Reaction time: 3 h
Yield: 76.8 %

Procedure:
To 2 mL of a dichloromethane solution containing 95 mg of tert-butyl(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(7-methoxy-4-methyl-2-oxoquinolin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate, 2 mL of trifluoroacetic acid was added and stirred for 3 hours. The solvent was removed under reduced pressure, and aqueous saturated sodium hydrogen carbonate solution and ethyl acetate were added. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layer and extracts were combined, washed with aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [eluent; chloroform:methanol=9:1] to give 60 mg of 1-(2-(4-((2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino)piperidin-1-yl)ethyl)-7-methoxy-4-methylquinolin-2(1H)-one as a white solid.