Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]=[CH:7][N:8]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([CH2:17][N:18]3[CH:22]=[CH:21][CH:20]=[N:19]3)=[CH:13][CH:12]=2)[CH:9]=1)=[O:4]>CO.O>[N:18]1([CH2:17][C:14]2[CH:15]=[CH:16][C:11]([CH2:10][N:8]3[CH:9]=[C:5]([C:3]([OH:4])=[O:2])[N:6]=[CH:7]3)=[CH:12][CH:13]=2)[CH:22]=[CH:21][CH:20]=[N:19]1
Reactant: COC(=O)c1cn(Cc2ccc(Cn3cccn3)cc2)cn1
Solvent: O
Solvent: CO
Product: O=C(O)c1cn(Cc2ccc(Cn3cccn3)cc2)cn1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 1-(4-Pyrazol-1-ylmethyl-benzyl)-1H-imidazole-4-carboxylic acid methyl ester (730 mg, 2.5 mmol) and lithiumhydroxyde-hydrate (210 mg, 4.9 mmol) in 10 mL MeOH and 5 mL water was stirred at room temperature for 3 h. The mixture was evaporated in vacuo, the residue was acidified with 1 N aq. HCl and lyophilised to yield the crude product which was used in the next step without further purification. LCMS (method A) RtA=0.412 min; [M+H]+=283.0.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH2:23]([O:30][C:31](=[O:37])[C@@H:32]1[CH2:36][CH2:35][CH2:34][NH:33]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH2:23]([O:30][C:31]([C@@H:32]1[CH2:36][CH2:35][CH2:34][N:33]1[C:10](=[O:12])[C@H:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)=[O:37])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCN1
Reactant: COc1ccc(C[C@@H](NC(=O)OC(C)(C)C)C(=O)O)cc1
Agent: Cl
Product: COc1ccc(C[C@@H](NC(=O)OC(C)(C)C)C(=O)N2CCC[C@H]2C(=O)OCc2ccccc2)cc1
Yield: 52.5 %

Procedure:
Reaction of 3.5 g of N-tert.-Butoxycarbonyl-2-(R)-amino-3-(4-methoxyphenyl)-propionic acid and 2.9 g of (L)-proline benzyl ester hydrochloride according to the procedure described for example 91b gave 3.0 g (52%) of the title compound as a yellow oil. (+)-APCI-MS: 505 (MNa+).
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([C:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[O:10][N:9]=2)[CH2:4][CH2:3]1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:24][CH2:25][CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([C:34](=[O:36])[CH3:35])=[CH:30][C:29]=1[O:37][CH3:38].CN(C)C=O>O>[O:10]1[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:8]([CH:5]2[CH2:4][CH2:3][N:2]([CH2:24][CH2:25][CH2:26][O:27][C:28]3[CH:33]=[CH:32][C:31]([C:34](=[O:36])[CH3:35])=[CH:30][C:29]=3[O:37][CH3:38])[CH2:7][CH2:6]2)=[N:9]1
Reactant: c1ccc2c(C3CCNCC3)noc2c1
Reactant: COc1cc(C(C)=O)ccc1OCCCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(C(C)=O)ccc1OCCCN1CCC(c2noc3ccccc23)CC1
Reaction time: 16 h
Yield: 47.7 %

Procedure:
A mixture of 3-(4-piperidinyl)-1,2-benzisoxazole hydrochloride (4.8 g, 20 mmol), K2CO3 (5.2 g, 40 mmol), 1-[4-(3-chloropropoxy)-3-methoxyphenyl]ethanone (5.3 g, 22 mmol), a few crystals of KI and dimethylformamide (60 ml) was stirred at 90 C. for 16 hours. The reaction was poured into water and the aqueous mixture was extracted with ethyl acetate. The extract was washed (water), dried (MgSO4) and concentrated to afford a brown oil. The oil was chromatographed on a Waters Prep 500 utilizing silica gel columns and ethyl acetate-diethylamine (2%), as eluent. Concentration of the appropriate fractions afforded 3.9 g of product as an off-white solid. Recrystallization from absolute ethyl alcohol afforded 2.6 g (33%) of 1-[4-[3-[4-(1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxypehenyl]ethanone, m.p.=102°-104° C., as colorless needles.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[CH2:5][C:6]1[CH:7]=[C:8]([CH:13]=[CH:14][N:15]=1)[C:9]([O:11][CH3:12])=[O:10]>C(O)(=O)C.[Pt](=O)=O>[F:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[CH2:5][CH:6]1[CH2:7][CH:8]([C:9]([O:11][CH3:12])=[O:10])[CH2:13][CH2:14][NH:15]1
Reactant: COC(=O)c1ccnc(Cc2cccc(F)c2)c1
Agent: O=[Pt]=O
Solvent: CC(=O)O
Product: COC(=O)C1CCNC(Cc2cccc(F)c2)C1
Reaction time: 4.5 h
Yield: 109.6 %

Procedure:
Methyl 2-(3-fluorobenzyl)isonicotinate (6.766 g, 27.59 mmol) was dissolved in acetic acid (70 mL) and platinum(IV) oxide (0.313 g, 1.38 mmol) added. The resulting mixture was hydrogenated in a Büchi hydrogenator at room temperature and 5 bar for 4.5 h. More platinum(IV) oxide (0.313 g, 1.38 mmol) was added and the hydrogenation continued at 5 bar for 2 h 40 min. The catalyst was filtered off, washed with MeOH and the eluate evaporated. DCM and 10% K2CO3 were added and the phases separated. The water phase was extracted with DCM and the combined organic phase washed with brine, passed through a phase separator and evaporated to yield crude methyl 2-(3-fluorobenzyl)piperidine-4-carboxylate (7.6 g, 110%) as a brown oil. MS m/z 252 (M+H)+
Reaction SMILES: [O:1]=[C:2]1[CH2:6][S:5][C:4](=[S:7])[N:3]1[CH2:8][CH2:9][C:10]([OH:12])=[O:11].[CH3:13][O:14][C:15]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][C:16]=1[CH:17]=O.N1CCCCC1>C(O)C>[CH3:13][O:14][C:15]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][C:16]=1/[CH:17]=[C:6]1/[C:2](=[O:1])[N:3]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])[C:4](=[S:7])[S:5]/1
Reactant: COc1ccc(OC)c(C=O)c1
Reactant: O=C(O)CCN1C(=O)CSC1=S
Solvent: C1CCNCC1
Solvent: CCO
Product: COc1ccc(OC)c(/C=C2\SC(=S)N(CCC(=O)O)C2=O)c1
Yield: 87.4 %

Procedure:
3-(4-oxo-2-thioxothiazolidin-3-yl)propanoic acid (200 mg, 1 mmol), 2,5-dimethoxy benzaldehyde (168 mg, 1 mmol) and piperidine (0.3 mL) were combined in ethanol (3 mL) and irradiated in the microwave at 100° C. for 10 minutes. The reaction was cooled, the solid was collected by filtration, washed with ethyl acetate/hexanes (1/1) and recrystallized from ethanol to afford 85% yield of the title compound (309 mg, brown-orange solid). MS (M+H, 284); 1H NMR (400 MHz, DMSO-d6): δ, ppm: 2.57 (t, 2H)), 3.74 (s, J=6.8 Hz, 3H), 3.84 (s, 3H), 4.19 (t, 2H), 6.90 (s, 1H), 7.10 (s, 2H), 7.86 (s, 1H).
Reaction SMILES: [ClH:1].Cl.[NH2:3][C@@H:4]([CH2:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)[CH:5]([OH:9])[C:6]([OH:8])=[O:7].[CH:17](O)([CH3:19])[CH3:18]>>[ClH:1].[CH:17]([O:7][C:6](=[O:8])[CH:5]([OH:9])[C@@H:4]([NH2:3])[CH2:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)([CH3:19])[CH3:18]
Reactant: N[C@@H](CC1CCCCC1)C(O)C(=O)O
Reactant: CC(C)O
Agent: Cl
Product: CC(C)OC(=O)C(O)[C@@H](N)CC1CCCCC1

Procedure:
Hydrogen chloride was passed into a solution of 100 mg of (2RS, 3S)-3-amino-4-cyclohexyl-2-hydroxybutyric acid hydrochloride in 12 ml of isopropyl alcohol with stirring under ice-cooling, and the mixture was heated under reflux for 2 hours. The reaction mixture was evaporated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: chloroform/methanol =15/1 by volume), and the eluate was acidified by adding hydrochloric acid. The mixture was evaporated to dryness under reduced pressure to obtain 108 mg of (2RS, 3S)-3-amino-4-cyclohexyl-2hydroxybutyric acid isopropyl ester hydrochloride as a white powder.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([S:14][C:15]2[C:23]3[C:22]([NH2:24])=[N:21][CH:20]=[N:19][C:18]=3[N:17]([CH:25]3[CH2:29][CH2:28][CH2:27][CH2:26]3)[CH:16]=2)[CH:9]=1)(C)(C)C>CO.C(Cl)Cl>[NH2:7][C:8]1[CH:9]=[C:10]([S:14][C:15]2[C:23]3[C:22]([NH2:24])=[N:21][CH:20]=[N:19][C:18]=3[N:17]([CH:25]3[CH2:29][CH2:28][CH2:27][CH2:26]3)[CH:16]=2)[CH:11]=[CH:12][CH:13]=1
Reactant: CC(C)(C)OC(=O)Nc1cccc(Sc2cn(C3CCCC3)c3ncnc(N)c23)c1
Solvent: CO
Solvent: ClCCl
Product: Nc1cccc(Sc2cn(C3CCCC3)c3ncnc(N)c23)c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of [3-(4-Amino-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidin-5-ylsulfanyl)-phenyl]-carbamic acid tert-butyl ester (108 mg, 0.25 mmole) in a mixture of MeOH and Methylene Chloride (4 mL/2 mL) was bubbled through HCl gas for 20 minutes. The resulting solution was stirred for 20 minutes at room temperature. Then the reaction mixture was extracted with EtOAc (50 mL) and saturated sodium bicarbonate solution (50 mL). The organic layer was washed with brine, dried over sodium sulfate and concentrated. The title compound was obtained as a yellow solid (79 mg, 96%). MS: 326.2 (MH+); HPLC Rf: 5.332 min.; HPLC purity: 90%.
Reaction SMILES: [F:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][N:7]2[C@@H:12]([CH3:13])[CH2:11][N:10]([C:14](=[O:29])[CH2:15][O:16][C:17]3[C:18]([CH2:24][CH2:25][C:26](O)=[O:27])=[N:19][C:20]([CH3:23])=[CH:21][CH:22]=3)[C@H:9]([CH3:30])[CH2:8]2)=[CH:4][CH:3]=1.Cl.CN(C)CCCN=C=NCC.[CH3:45][S:46]([NH2:49])(=[O:48])=[O:47].C(N(CC)CC)C>C(Cl)Cl.CN(C)C1C=CN=CC=1>[F:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][N:7]2[C@@H:12]([CH3:13])[CH2:11][N:10]([C:14](=[O:29])[CH2:15][O:16][C:17]3[C:18]([CH2:24][CH2:25][C:26]([NH:49][S:46]([CH3:45])(=[O:48])=[O:47])=[O:27])=[N:19][C:20]([CH3:23])=[CH:21][CH:22]=3)[C@H:9]([CH3:30])[CH2:8]2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(OCC(=O)N2C[C@H](C)N(Cc3ccc(F)cc3)C[C@H]2C)c(CCC(=O)O)n1
Reactant: CS(N)(=O)=O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(OCC(=O)N2C[C@H](C)N(Cc3ccc(F)cc3)C[C@H]2C)c(CCC(=O)NS(C)(=O)=O)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 42.6 %

Procedure:
To a solution of 3-(3-{2-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1-yl]-2-oxo-ethoxy}-6-methyl-pyridin-2-yl)-propionic acid (0.10 g, 0.23 mmol) in methylene chloride (2 mL) was added 4-dimethylaminopyridine (0.032 g, 0.27 mmol), (3-(dimethylamino)propyl)ethyl carbodiimide hydrochloride (0.051 g, 0.27 mmol), methanesulfonamide (0.025 g, 0.27 mmol) and triethylamine (0.037 mL, 0.27 mmol). The reaction was stirred at ambient temperature for 18 hours. The reaction mixture was then diluted with dichloromethane and washed with 0.2 M hydrochloric acid. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The crude product was purified by chromatography on silica gel to give the title compound (0.051 g, LRMS: 521.5).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=2[N+:22]([O-])=O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C1COCC1.CO.[Pt]>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=2[NH2:22])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1cc(F)ccc1NC1CCN(Cc2ccccc2)CC1
Agent: [Pt]
Solvent: C1CCOC1
Solvent: CO
Product: Nc1cc(F)ccc1NC1CCN(Cc2ccccc2)CC1
Yield: 99.1 %

Procedure:
1-Benzyl-4-(4-fluoro-2-nitrophenylamino)-piperidine (10.1 g) were dissolved in 1:1 THF-methanol (150 ml) and hydrogenated with Pt/C (1.5 g, 10%) at room temperature for 1.5 h. The catalyst was then removed by filtration, and the filtrate evaporated to yield 9.1 g of the title compound as an oil. The compound was used without further purification.
Reaction SMILES: C(O[C:4](=[O:35])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH:11][C:12]1[C:17]([Cl:18])=[CH:16][N:15]=[C:14]([NH:19][C:20]2[CH:34]=[CH:33][C:23]3[CH2:24][CH2:25][N:26]([CH2:29][CH2:30][O:31][CH3:32])[CH2:27][CH2:28][C:22]=3[CH:21]=2)[N:13]=1)C.[CH3:36][O:37][CH2:38][CH2:39][CH2:40][NH2:41]>>[Cl:18][C:17]1[C:12]([NH:11][C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:4]([NH:41][CH2:40][CH2:39][CH2:38][O:37][CH3:36])=[O:35])=[N:13][C:14]([NH:19][C:20]2[CH:34]=[CH:33][C:23]3[CH2:24][CH2:25][N:26]([CH2:29][CH2:30][O:31][CH3:32])[CH2:27][CH2:28][C:22]=3[CH:21]=2)=[N:15][CH:16]=1
Reactant: COCCCN
Reactant: CCOC(=O)c1ccccc1Nc1nc(Nc2ccc3c(c2)CCN(CCOC)CC3)ncc1Cl
Product: COCCCNC(=O)c1ccccc1Nc1nc(Nc2ccc3c(c2)CCN(CCOC)CC3)ncc1Cl

Procedure:
2-{5-Chloro-2-[3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino]-pyrimidin-4-ylamino}-N-(3-methoxy-propyl)-benzamide was prepared from 2-{5-chloro-2-[3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino]-pyrimidin-4-ylamino}-benzoic acid ethyl ester and 3-methoxy-propylamine in an analogous manner to Example 1396. Product isolated as a white solid (21 mg, 36%). m.p.=154-156° C.; LCMS (m/e) 539 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 11.25 (s, 1H), 8.69 (d, 1H, J=8.5 Hz), 8.10 (s, 1H), 7.49 (d, 1H, J=7.8 Hz), 7.47-7.40 (m, 1H), 7.36 (s, 1H), 7.30-7.23 (m, 1H), 7.15-7.00 (m, 3H), 6.93 (s, 1H), 3.65-3.58 (m, 4H), 3.56 (t, 2H, J=5.7 Hz), 3.41 (s, 3H), 3.39 (s, 3H), 2.97-2.87 (m, 4H), 2.82-2.69 (m, 6H), 1.97-1.88 (m, 2H).
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[S:13]1[CH:17]=[CH:16][CH:15]=[C:14]1[C:18]1[O:19][CH:20]=[C:21]([CH2:23][CH2:24][OH:25])[N:22]=1.O[C:27]1[CH:32]=[CH:31][C:30]([CH2:33][CH2:34][CH2:35][N:36]2[CH:40]=[CH:39][N:38]=[CH:37]2)=[CH:29][CH:28]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[N:36]1([CH2:35][CH2:34][CH2:33][C:30]2[CH:31]=[CH:32][C:27]([O:25][CH2:24][CH2:23][C:21]3[N:22]=[C:18]([C:14]4[S:13][CH:17]=[CH:16][CH:15]=4)[O:19][CH:20]=3)=[CH:28][CH:29]=2)[CH:40]=[CH:39][N:38]=[CH:37]1
Reactant: Oc1ccc(CCCn2ccnc2)cc1
Reactant: OCCc1coc(-c2cccs2)n1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: c1csc(-c2nc(CCOc3ccc(CCCn4ccnc4)cc3)co2)c1
Yield: 54.9 %

Procedure:
Diethyl azodicarboxylate (1.20 g) was added dropwise to a stirred mixture of 2-(2-thienyl-4-oxazolyl)ethanol (700 mg). 1-[3-(4-hydroxyphenyl)propyl]imidazole (670 mg), triphenylphosphine (1.73 g), and tetrahydrofuran (50 ml) at room temperature. After refluxing for 3 h, the reaction mixture was concentrated. The residue was purified by silica gel column chromatography. From the fraction eluted with ethyl acetate-methanol (100:1, v/v) 4-[2-[4-[3-(1-imidazolyl)propyl]phenoxy]ethyl]-2-(2-thienyl)oxazole (690 mg, 55%) was obtained. Recrystallization from ethyl acetate-hexane gave colorless prisms, mp 77-78° C.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(=O)(=O)(O)O.O.[C:17]([O-])(O)=O.[Na+]>CO>[Cl:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH3:17])=[O:5]
Reactant: O=C([O-])O
Reactant: O=C(O)c1cccnc1Cl
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC(=O)c1cccnc1Cl
Yield: 40 %

Procedure:
A solution of 2-chloronicotinic acid (1.61 g, 10.2 mmol) and sulfuric acid (0.5 mL) in methanol (30 mL) was stirred at reflux overnight. The solution was poured into water (100 mL) and neutralised with NaHCO3 (s) before being extracted with 1:1 hexane/ethyl acetate (3×40 mL). The solvents were dried (MgSO4) and evaporated and the residue was purified by flash column chromatography (SiO2, 25% ethyl acetate/hexane eluent) to afford the ester as a colourless oil (700 mg, 40%).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([OH:13])=O.C(OC([NH:21][CH2:22][C:23]1[CH:24]=[C:25]([CH2:31][CH:32]([O:38][CH:39]([CH3:41])[CH3:40])[C:33]([O:35]CC)=[O:34])[CH:26]=[CH:27][C:28]=1[O:29][CH3:30])=O)(C)(C)C>>[CH:39]([O:38][CH:32]([CH2:31][C:25]1[CH:26]=[CH:27][C:28]([O:29][CH3:30])=[C:23]([CH2:22][NH:21][C:11]([C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:1]=2)=[O:13])[CH:24]=1)[C:33]([OH:35])=[O:34])([CH3:41])[CH3:40]
Reactant: CCOC(=O)C(Cc1ccc(OC)c(CNC(=O)OC(C)(C)C)c1)OC(C)C
Reactant: O=C(O)c1ccc2ccccc2c1
Product: COc1ccc(CC(OC(C)C)C(=O)O)cc1CNC(=O)c1ccc2ccccc2c1

Procedure:
Using 2-naphthalene carboxylic acid and ethyl 3-[3-([(tert-butoxycarbonyl)amino]methyl)-4-methoxyphenyl]-2-isopropoxypropanoate, 2-isopropoxy-3-(4-methoxy-3-[(2-naphthylcarbonyl)amino]methylphenyl]propanoic acid was obtained in the same method as in Example 38).
Reaction SMILES: [H-].[Na+].CN(C)C=O.[Cl:8][C:9]1[CH:25]=[CH:24][C:23]([N:26]2[C:31](=[O:32])[CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[NH:28][C:27]2=[O:37])=[CH:22][C:10]=1[C:11]([O:13][C:14]([CH3:21])([CH3:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:12].[CH2:38](Br)[CH:39]=[CH2:40]>O>[Cl:8][C:9]1[CH:25]=[CH:24][C:23]([N:26]2[C:31](=[O:32])[CH:30]=[C:29]([C:33]([F:35])([F:34])[F:36])[N:28]([CH2:40][CH:39]=[CH2:38])[C:27]2=[O:37])=[CH:22][C:10]=1[C:11]([O:13][C:14]([CH3:20])([CH3:21])[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:12]
Reactant: CCOC(=O)C(C)(C)OC(=O)c1cc(-n2c(=O)cc(C(F)(F)F)[nH]c2=O)ccc1Cl
Reactant: C=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCn1c(C(F)(F)F)cc(=O)n(-c2ccc(Cl)c(C(=O)OC(C)(C)C(=O)OCC)c2)c1=O

Procedure:
0.35 g of sodium hydride (50% dispersion in white oil) is added to 40 ml of dimethylformamide while stirring. 2.9 g of ethyl 2-{2-chloro-5-[3,6-dihydro-2,6-dioxo-4-trifluoromethyl-1(2H)-pyrimidinyl]-benzoyloxy}-2-methyl-propionate [sic] are added portionwise as the solid. After completion of the addition the mixture is stirred at room temperature for a further hour. 1.2 g of allyl bromide are now added in one portion. The reaction mixture is stirred at room temperature for 18 hours and thereafter introduced into 100 ml of water at 0° C. The mixture is extracted twice with 150 ml of ethyl acetate each time. The organic phases are washed once with 100 ml of saturated sodium chloride solution, dried over anhydrous sodium sulphate and concentrated under reduced pressure. The residue is purified by chromatography over silica gel with ethyl acetate/n-hexane (1:4). There is obtained ethyl 2-{2-chloro-5-[3,6-dihydro-2,6-dioxo-3-(2-propenyl)-4 -trifluoromethyl-1(2H)-pyrimidinyl]-benzoyloxy}-2-methyl-propionate as an oil;
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([OH:8])=O.[N+]([O-])(O)=O.[O:13]([CH2:17][CH2:18][NH2:19])[N+:14]([O-:16])=[O:15].C(OC(C)C)(C)C>>[O:13]([CH2:17][CH2:18][NH:19][C:6]([C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)=[O:8])[N+:14]([O-:16])=[O:15]
Reactant: O=C(O)c1cccs1
Reactant: NCCO[N+](=O)[O-]
Solvent: O=[N+]([O-])O
Solvent: CC(C)OC(C)C
Product: O=C(NCCO[N+](=O)[O-])c1cccs1
Yield: 42.2 %

Procedure:
Following a similar treatment to that in Example 33 and using 0.38 g of 2-thiophenecarboxylic acid and 0.50 g of nitroxyethylamine nitrate, 0.27 g of the title compound was obtained as colorless plates (solvent for recrystallization; diisopropyl ether).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:7][C:8]2[CH:14]=[C:13]([C:15]([CH3:30])([C:23]([O:25]C(C)(C)C)=[O:24])[C:16]([O:18]C(C)(C)C)=[O:17])[CH:12]=[CH:11][C:9]=2[CH:10]=1)=[O:5])[CH3:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1[S:7][C:8]2[CH:14]=[C:13]([C:15]([CH3:30])([C:23]([OH:25])=[O:24])[C:16]([OH:18])=[O:17])[CH:12]=[CH:11][C:9]=2[CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2ccc(C(C)(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)cc2s1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1cc2ccc(C(C)(C(=O)O)C(=O)O)cc2s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100.1 %

Procedure:
Di-tert-butyl [2-(ethoxycarbonyl)-1-benzothien-6-yl](methyl)malonate (0.26 g, 0.598 mmol) was dissolved in DCM (1.5 mL) and TFA (1.5 mL) was added. The solution was stirred at room temperature for 2 hours. The solvent was removed in vacuo and the residue partitioned between saturated NaHCO3-EtOAc. The aqueous phase was acidified with 2N HCl and extracted with EtOAc. The combined organic extracts were dried over MgSO4 and concentrated in vacuo to give 0.193 g of product (pale yellow solid, 100%). 1H NMR (DMSO-d6) δ 13.12 (br s, 2H), 8.14 (s, 1H), 8.03 (d, J=1.8 Hz, 1H), 7.95 (d, J=8.4 Hz, 1H), 7.47 (dd, J=8.4, 1.8 Hz, 1H), 4.32 (q, J=7.2 Hz, 2H), 1.77 (s, 3H), 1.31 (t, J=7.2 Hz, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15]Br)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:17][C:18]1([CH3:30])[C:22]([CH3:24])([CH3:23])[O:21][B:20]([C:25]2[CH:26]=[N:27][NH:28][CH:29]=2)[O:19]1.[H-].[Na+]>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][N:28]2[CH:29]=[C:25]([B:20]3[O:19][C:18]([CH3:30])([CH3:17])[C:22]([CH3:24])([CH3:23])[O:21]3)[CH:26]=[N:27]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCc1ccc(OCc2ccccc2)cc1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(C)OB(c2cnn(Cc3ccc(OCc4ccccc4)cc3)c2)OC1(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of EXAMPLE 4A (0.54 g) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.377 g) in N,N-dimethylformamide (5 mL) was cooled to 0° C. To this solution was added 60% sodium hydride (0.096 g). The solution was stirred at room temperature overnight. The reaction mixture was partitioned between water and ethyl acetate. The aqueous layer was extracted with additional ethyl acetate twice. The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel eluting with 25% ethyl acetate in hexanes to provide the title compound.
Reaction SMILES: Br[C:2]1[C:3]([O:10][CH3:11])=[N:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1.[N:12]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[N:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15]>C1COCC1>[CH3:9][O:8][C:5]1[N:4]=[C:3]([O:10][CH3:11])[C:2]([N:12]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[NH:13][C:14]([O:16][C:17]([CH3:18])([CH3:19])[CH3:20])=[O:15])=[CH:7][N:6]=1
Reactant: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Reactant: COc1ncc(Br)c(OC)n1
Solvent: C1CCOC1
Product: COc1ncc(N(NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c(OC)n1
Temperature: 0 °C
Yield: 75 %

Procedure:
To a stirred solution of 5-bromo-2,4-dimethoxypyrimidine (400 g, 1.826 mol) in anhydrous THF (3 L) under argon and cooled down to 0° C. was added dropwise TurboGrignard (1.821 L, 2.367 mol). The resulting mixture was stirred at 0° C. until exothermic ceased then, allowed to warm up and stir at RT for 30 min. A solution of di-tert-butyl azodicarboxylate in anhydrous THF (1 L) was added dropwise to the mixture and the reaction was stirred at RT for 1 hr. The reaction was slowly quenched with a saturated aq. NH4Cl solution (2 L), diluted with EtOAc (2 L) and water (2 L) and both phases separated. The aq. phase was extracted with EtOAc (3 L), combined organic layers were washed with brine (3 L), dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting yellow oil was dissolved in Hexane (3 L) and the suspension was stirred at 0° C. for 3 hr, filtrated off and dried to afford a first batch of white crystals. The mother liquor was concentrated under reduced pressure and purified to afford a second batch of white crystals. The two batches were combined to afford the title product (507 g, 1.369 mol, 75% yield) as white crystals. tR: 1.03 min (LC-MS 1); ESI-MS: 371 [M+H]+, ESI-MS: 369 [M−H]− (LC-MS 1).
Reaction SMILES: [H-].[Na+].[C:3]([SH:11])(=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:12]([CH2:15][S:16][CH2:17][C@@H:18]1[CH2:22][C@@H:21](OS(C)(=O)=O)[CH2:20][N:19]1[C:28]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][C:35]([N+:38]([O-:40])=[O:39])=[CH:34][CH:33]=1)=[O:29])(=[O:14])[NH2:13]>CN(C)C=O>[C:3]([S:11][C@@H:21]1[CH2:20][N:19]([C:28]([O:30][CH2:31][C:32]2[CH:33]=[CH:34][C:35]([N+:38]([O-:40])=[O:39])=[CH:36][CH:37]=2)=[O:29])[C@H:18]([CH2:17][S:16][CH2:15][C:12](=[O:14])[NH2:13])[CH2:22]1)(=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=C(S)c1ccccc1
Reactant: CS(=O)(=O)O[C@@H]1C[C@@H](CSCC(N)=O)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: NC(=O)CSC[C@@H]1C[C@H](SC(=O)c2ccccc2)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a suspension of sodium hydride (62.8% in oil) (0.22 g) in N,N-dimethylformamide (5 ml) was added dropwise thiobenzoic S-acid (0.66 ml) under ice-cooling. After stirring under the same condition for 30 minutes, this solution was added to a solution of (2S,4R)-2-(carbamoylmethyl)thiomethyl-4-methanesulfonyloxy-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (1.68 g) in N,N-dimethylformamide (20 ml) at ambient temperature. The mixture was stirred at 70°-80° C. for 1 hour. The reaction mixture was poured into ice-water (50 ml) and extracted twice with ethyl acetate (50 ml). The organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and evaporated in vacuo to give a residue. The residue was chromatographed on silica gel (100 g) eluting with a mixture of dichloromethane and acetone (5:1, V/V). The fractions containing the desired compound were collected and evaporated in vacuo to give (2S,4S)-4-benzoylthio-2-(carbamoylmethyl)thiomethyl-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (0.87 g).