Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(Cl)(=O)=O.[CH3:6][N:7]1[CH2:12][CH2:11][C@@H:10]([C:13]2[C:18]([O:19][CH3:20])=[CH:17][C:16]([O:21][CH3:22])=[CH:15][C:14]=2[O:23][CH3:24])[C@H:9]([OH:25])[CH2:8]1.C(N(CC)CC)C.[C:33]([O-])(=[O:35])[CH3:34].[Na+]>C1COCC1.CC(O)C.CCOC(C)=O.O>[CH3:6][N:7]1[CH2:12][CH2:11][C@@H:10]([C:13]2[C:14]([O:23][CH3:24])=[CH:15][C:16]([O:21][CH3:22])=[CH:17][C:18]=2[O:19][CH3:20])[C@@H:8]1[CH2:9][O:25][C:33](=[O:35])[CH3:34]
Reactant: COc1cc(OC)c([C@@H]2CCN(C)C[C@H]2O)c(OC)c1
Reactant: CC(=O)[O-]
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1cc(OC)c([C@@H]2CCN(C)[C@H]2COC(C)=O)c(OC)c1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
Methanesulfonyl chloride (44.8 g, 0.4 mol) was added dropwise to a cooled and stirred solution of compound of example 2 (100 g, 0.35 mol) and triethylamine (71.88 g, 0.7 mol) in dry THF (1.0 L). The reaction mixture was further stirred for 45 min. at 0° C. The precipitate of triethylamine HCl was filtered and washed with dry THF (2×100 mL). The filtrate was added dropwise to a refluxing suspension of sodium acetate (115 g, 1.42 mol) in 2-propanol (1.0 L). The reaction mixture was refluxed for a further 15 min., diluted with EtOAc (1.0 L) and salts were filtered. The mixture of salts was washed with EtOAc (2×100 mL). The combined filtrate was concentrated to give a gum. Water (50 mL) was added to the gum with stirring to obtain a solid which was filtered and dried to yield the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]([N:14]2[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[N:15]2)[CH2:11][CH2:12][CH3:13])=[CH:6][CH:5]=1.CO.NN>C(OCC)(=O)C.[Ni].O>[CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:5]=[CH:6][C:7]([CH:10]([N:14]2[CH:18]=[CH:17][C:16]([NH2:19])=[N:15]2)[CH2:11][CH2:12][CH3:13])=[CH:8][CH:9]=1
Reactant: CCCC(c1ccc(C(=O)OC)cc1)n1ccc([N+](=O)[O-])n1
Agent: [Ni]
Agent: NN
Solvent: CO
Solvent: CCOC(C)=O
Solvent: O
Product: CCCC(c1ccc(C(=O)OC)cc1)n1ccc(N)n1
Yield: 94.1 %

Procedure:
The 4-[1-(3-nitro-pyrazol-1-yl)-butyl]-benzoic acid methyl ester (127 mg, 0.42 mmol) was dissolved in ethyl acetate (3 mL) and methanol (3 mL) was added. While stirring, a 50% slurry of raney nickel in water (500 μL) was added followed by hydrazine (150 μL). Immediate effervescence was observed. The reaction continued to stir and bubble for 30 min. The reaction was passed through a plug of celite and concentrated in vacuo to afford 4-[1-(3-amino-pyrazol-1-yl)-butyl]-benzoic acid methyl ester (108 mg, 94%) as a clear oil: ESI-LRMS m/e calcd for C15H19N3O2 [M+] 273.15, found 274.29 [M+H+], 547.43 [2M+H+].
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([NH:10][CH:11]2[C:31](=[O:32])[N:13]3[C:14]([C:18]([O:20]CC4C=CC([N+]([O-])=O)=CC=4)=[O:19])=[CH:15][CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.C(O)(=O)C.[H][H]>CO.O1CCCC1.[Pd]>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([NH:10][CH:11]2[C:31](=[O:32])[N:13]3[C:14]([C:18]([OH:20])=[O:19])=[CH:15][CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: Nc1nc(CC(=O)NC2C(=O)N3C(C(=O)OCc4ccc([N+](=O)[O-])cc4)=CCS[C@H]23)cs1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: Nc1nc(CC(=O)NC2C(=O)N3C(C(=O)O)=CCS[C@H]23)cs1
Temperature: 25 °C
Reaction time: 8.5 h
Yield: 18.5 %

Procedure:
A solution of 4-nitrobenzyl 7-[2-(2-amino-4-thiazolyl)acetamido]-3-cephem-4-carboxylate (1.4 g) in a mixture of methanol (25 ml) and tetrahydrofuran (60 ml) was added to a mixture of 10% palladium-on-carbon (1.7 g), glacial acetic acid (7 ml) and methanol (20 ml) in an atmosphere of nitrogen. Hydrogen gas was introduced into the mixture and shaken for 8.5 hours at room temperature. After removing the insoluble substance by filtration, the filtrate was concentrated under reduced pressure. The residue was pulverized with diethyl ether, and the resultant substance was dissolved in an aqueous solution of sodium bicarbonate, washed with ethyl acetate and diethyl ether in turn and then the remaining ether was removed by bubbling with nitrogen gas. The resultant solution was adjusted to pH 4.5 with dilute hydrochloric acid, subjected to column chromatography on macroporous non-ionic adsorption resin "Diaion HP-20" (Trademark, manufactured by Mitsubishi Chemical Industries Ltd.), and eluted with 20% isopropyl alcohol. Isopropyl alcohol was distilled off under reduced pressure and the remaining solution was lyophilized to give 7-[2-(2-amino-4-thiazolyl)acetamido]-3-cephem-4-carboxylic acid (185 mg).
Reaction SMILES: Cl[C:2]1[N:6]([CH3:7])[C:5]2[C:8]([N:12]3[C:16]([CH2:17][CH3:18])=[CH:15][C:14]([CH2:19][CH3:20])=[N:13]3)=[CH:9][CH:10]=[CH:11][C:4]=2[N:3]=1.[Cl:21][C:22]1[CH:27]=[C:26]([Cl:28])[CH:25]=[C:24]([CH3:29])[C:23]=1[OH:30].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[Cl:21][C:22]1[CH:27]=[C:26]([Cl:28])[CH:25]=[C:24]([CH3:29])[C:23]=1[O:30][C:2]1[N:6]([CH3:7])[C:5]2[C:8]([N:12]3[C:16]([CH2:17][CH3:18])=[CH:15][C:14]([CH2:19][CH3:20])=[N:13]3)=[CH:9][CH:10]=[CH:11][C:4]=2[N:3]=1
Reactant: CCc1cc(CC)n(-c2cccc3nc(Cl)n(C)c23)n1
Reactant: Cc1cc(Cl)cc(Cl)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCc1cc(CC)n(-c2cccc3nc(Oc4c(C)cc(Cl)cc4Cl)n(C)c23)n1
Yield: 78.3 %

Procedure:
A suspension of 2-chloro-7-(3,5-diethyl-1H-pyrazol-1-yl)-1-methyl-1H-benzimidazole (92 mg, 0.318 mmol), 2,4-dichloro-6-methylphenol (114 mg, 0.643 mmol), potassium carbonate (89 mg, 0.643 mmol) in N,N-dimethylformamide (1.5 ml) was stirred at 90° C. for 5.5 days (2,4-dichloro-6-methylphenol and potassium carbonate were added in three equal portions each over 5.5 days). After cooling, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with a 10-25% ethyl acetate/n-hexane gradient mixture to give 107 mg (0.249 mmol, 78.3%) of the title compound as an oil. The oil was crystallized from hexane to give 70 mg (51%) as a pale yellow crystal.
Reaction SMILES: CO[C:3]([C:5]1[N:6]([CH3:24])[N:7]=[C:8]([O:10][CH2:11][C:12]2[C:13]([CH:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[N:14][O:15][C:16]=2[CH3:17])[CH:9]=1)=[O:4].COC(C1NN=C(OC[C:36]2[C:37]([C:42]3[CH:47]=CC=CC=3)=[N:38][O:39][C:40]=2C)C=1)=O.NC1CCOCC1>>[O:39]1[CH2:47][CH2:42][CH:37]([NH:38][C:3]([C:5]2[N:6]([CH3:24])[N:7]=[C:8]([O:10][CH2:11][C:12]3[C:13]([CH:18]4[CH2:19][CH2:20][O:21][CH2:22][CH2:23]4)=[N:14][O:15][C:16]=3[CH3:17])[CH:9]=2)=[O:4])[CH2:36][CH2:40]1
Reactant: COC(=O)c1cc(OCc2c(C3CCOCC3)noc2C)nn1C
Reactant: COC(=O)c1cc(OCc2c(-c3ccccc3)noc2C)n[nH]1
Agent: NC1CCOCC1
Product: Cc1onc(C2CCOCC2)c1COc1cc(C(=O)NC2CCOCC2)n(C)n1
Yield: 76 %

Procedure:
As described for example 1b, 2-methyl-5-[5-methyl-3-(tetrahydro-pyran-4-yl)-isoxazol-4-ylmethoxy]-2H-pyrazole-3-carboxylic acid methyl ester (200 mg, 0.6 mmol), instead of 5-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-2H-pyrazole-3-carboxylic acid methyl ester, was converted, using 4-aminotetrahydropyran instead of morpholine, to the title compound (183 mg, 76%) which was obtained as a colorless gum. MS: m/e=403.1 [M−H]−.
Reaction SMILES: [NH2:1][C:2]1[N:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[CH:6][C:3]=1[CH:4]=O.[NH2:18][C:19]1[CH:20]=[C:21]([S:26]([NH2:29])(=[O:28])=[O:27])[CH:22]=[CH:23][C:24]=1[NH2:25].OS([O-])=O.[Na+].CCOC(C)=O>CC(N(C)C)=O>[NH2:1][C:2]1[C:3]([C:4]2[NH:18][C:19]3[CH:20]=[C:21]([S:26]([NH2:29])(=[O:27])=[O:28])[CH:22]=[CH:23][C:24]=3[N:25]=2)=[CH:6][C:7]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)=[CH:8][N:9]=1
Reactant: COc1ccc(-c2cnc(N)c(C=O)c2)cc1
Reactant: Nc1ccc(S(N)(=O)=O)cc1N
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: COc1ccc(-c2cnc(N)c(-c3nc4ccc(S(N)(=O)=O)cc4[nH]3)c2)cc1
Temperature: 200 °C
Reaction time: 1 h
Yield: 15 %

Procedure:
2-amino-5-(4-methoxyphenyl)nicotinaldehyde (61.6 mg, 0.27 mmol), 3,4-diaminobenzene-1-sulphonamide (59.7 mg, 0.32 mmol), and NaHSO3 (29.2 mg, 0.4 mmol) were suspended in 3 ml dimethylacetamide. The reaction mixture was heated to 200° C. for 10 min in the SmithSynthesizer™ microwave instrument. Upon cooling, 5 ml of 4:1H2O/EtOAc was added to afford a slurry which was stirred for 1 h. The solids were collected via vacuum filtration, washed with water and then diethyl ether, and dried under vacuum for 15 hours to yield 2-[2-amino-5-(4-methoxyphenyl)pyridin-3-yl]-1H-benzimidazole-6-sulfonamide (16 mg).
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:2]1.[H-].[Na+].[Si:17]([O:24][CH2:25][CH2:26][C@@H:27]1[CH2:29][N:28]1[S:30]([C:33]1[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=1)(=[O:32])=[O:31])([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18].[Cl-].[NH4+]>CN(C=O)C.C(OCC)(=O)C>[CH3:14][O:13][C:11](=[O:12])[CH2:10][C:3]1[C:4]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[N:1]([CH2:29][C@H:27]([NH:28][S:30]([C:33]2[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=2)(=[O:32])=[O:31])[CH2:26][CH2:25][O:24][Si:17]([C:20]([CH3:23])([CH3:21])[CH3:22])([CH3:18])[CH3:19])[CH:2]=1
Reactant: COC(=O)Cc1c[nH]c2ncccc12
Reactant: CC(C)(C)[Si](C)(C)OCC[C@@H]1CN1S(=O)(=O)c1ccc(F)cc1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)Cc1cn(C[C@@H](CCO[Si](C)(C)C(C)(C)C)NS(=O)(=O)c2ccc(F)cc2)c2ncccc12
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 37.6 %

Procedure:
To a cooled solution at 0° C. of methyl 1H-pyrrolo[2,3-b]pyridin-3-ylacetate (1.1 g, 5.8 mmol) in DMF (12 mL) was added 60% NaH in oil (0.26 g, 6.4 mmol, 1.1 equiv.). After a period of 10 min at room temperature, the reaction mixture was cooled to 0° C. and a DMF solution (12 mL) of (2R)-2-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-1-[(4-fluorophenyl)-sulfonyl]aziridine (2.0 g, 5.8 mmol) was added. The reaction was aged 0.5 h at room temperature and poured over saturated ammonium chloride and ethyl acetate. The organic phase was separated, dried over sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by combiflash (hexane to 50% ethyl acetate in hexane) to provide 1.2 g of the title compound.
Reaction SMILES: [OH-].[K+].[Br:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([N+:11]([O-])=O)[CH:5]=1.S(S([O-])=O)([O-])=O.[Na+].[Na+].C(OCC)(=O)C>O>[NH2:11][C:6]1[CH:5]=[C:4]([Br:3])[CH:9]=[CH:8][C:7]=1[OH:10]
Reactant: O=[N+]([O-])c1cc(Br)ccc1O
Agent: O=S([O-])S(=O)[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: Nc1cc(Br)ccc1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 56.5 %

Procedure:
A solution of KOH (5.14 g, 91.7 mmol) in water (33 mL) was added to 4-bromo-2-nitrophenol (Aldrich, 1.00 g, 4.59 mmol). Sodium hydrosulfite (7.98 g, 45.9 mmol) was added in one portion. The mixture was stirred at RT for 30 min. and poured into ethyl acetate (25 mL). The layers were partitioned and the aqueous layer was extracted with ethyl acetate (4×25 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated to give 488 mg (56%) of the title compound which was used without further purification. 1H NMR (CDCl3, 400 MHz) δ 6.77 (d, 1H, J=2.1 Hz), 6.65 (dd, 1H, J=8.3, 2.5 Hz), 6.52 (d, 1H, J=8.3 Hz); 13C NMR (CDCl3, 100 MHz) δ 144.0, 136.6, 121.7, 118.7, 116.2 112.1; MS (Cl) m/z 188.0 (M+1); HPLC retention time=1.10 min.
Reaction SMILES: [CH3:1][C@H:2]1[N:7]2[C:8]3[N:14]=[C:13]([C:15]([OH:17])=O)[CH:12]=[CH:11][C:9]=3[CH:10]=[C:6]2[C:5](=[O:18])[NH:4][CH2:3]1.[CH:19]1[CH:20]=C[C:22]2[N:27](O)N=[N:25][C:23]=2[CH:24]=1.Cl.C(N=C=NCCCN(C)C)C.NC1C=NC=CC=1>CN(C=O)C.CN(C1C=CN=CC=1)C.CO.CCOCC>[CH3:1][CH:2]1[N:7]2[C:8]3[N:14]=[C:13]([C:15]([NH:25][C:23]4[CH:22]=[N:27][CH:20]=[CH:19][CH:24]=4)=[O:17])[CH:12]=[CH:11][C:9]=3[CH:10]=[C:6]2[C:5](=[O:18])[NH:4][CH2:3]1
Reactant: C[C@@H]1CNC(=O)c2cc3ccc(C(=O)O)nc3n21
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CO
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC1CNC(=O)c2cc3ccc(C(=O)Nc4cccnc4)nc3n21
Temperature: 60 °C
Yield: 34.4 %

Procedure:
To a suspension of 9-methyl-6-oxo-6,7,8,9-tetrahydropyrido[3′,2′:4,5]pyrrolo[1,2-a]pyrazine-2-carboxylic acid (Intermediate J, 47 mg, 0.19 mmol) and HOBt (31 mg, 0.23 mmol) in DMF (0.5 mL) is added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (44 mg, 0.23 mmol), followed by 3-aminopyridine (22 mg, 0.23 mmol) and DMAP (2.8 mg, 0.023 mmol). The mixture is stirred at 60° C. under a continuous stream of nitrogen, which slowly concentrates the solution. After being stirred for 5 h, the mixture was warmed to 80° C. and stirred overnight. The reaction mixture is diluted with methanol (0.5 mL) and ether (1 mL). The resultant precipitate is collected by filtration to afford the title compound as a dark yellow solid (21 mg, 34%).
Reaction SMILES: N.O.O[N:4]1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[Cl:25][C:26]1[CH:27]=[N:28][C:29]2[C:34]([C:35]=1[CH2:36][CH2:37][CH2:38][C:39]1([C:54]([OH:56])=O)[CH2:44][CH2:43][N:42]([CH2:45][CH2:46][CH2:47][C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)[CH2:41][CH2:40]1)=[CH:33][C:32]([O:57][CH3:58])=[CH:31][CH:30]=2.[Na]>O1CCOCC1.ClCCl.O.C(N(CC)CC)C>[Cl:25][C:26]1[CH:27]=[N:28][C:29]2[C:34]([C:35]=1[CH2:36][CH2:37][CH2:38][C:39]1([C:54]([NH2:4])=[O:56])[CH2:44][CH2:43][N:42]([CH2:45][CH2:46][CH2:47][C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)[CH2:41][CH2:40]1)=[CH:33][C:32]([O:57][CH3:58])=[CH:31][CH:30]=2
Reactant: COc1ccc2ncc(Cl)c(CCCC3(C(=O)O)CCN(CCCc4ccccc4)CC3)c2c1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: N
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc2ncc(Cl)c(CCCC3(C(N)=O)CCN(CCCc4ccccc4)CC3)c2c1
Temperature: 20 °C
Reaction time: 17 h
Yield: 29.4 %

Procedure:
15.6 cm3 of a 0.5N solution of aqueous ammonia in dioxane, 0.26 g of 1-hydroxybenzotriazole hydrate, 0.75 g of 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride and 0.55 cm3 of triethylamine were added to a mixture of 0.75 g of 4-[3-(3-chloro-6-methoxyquinolin-4-yl)propyl]-1-(3-phenylpropyl)piperidine-4-carboxylic acid in the form of the sodium salt, in 20 cm3 of dichloromethane. The suspension obtained was stirred for 17 hours at a temperature in the region of 20° C. The reaction mixture was diluted with 25 cm3 of water and stirred, and the phases were then separated by settling. The aqueous phase was extracted with twice 25 cm3 of dichloromethane and the organic extracts were combined, washed with 25 cm3 of brine, dried over magnesium sulfate and then concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. The evaporation residue obtained was purified by chromatography under a pressure of 50 kPa of argon, on a column of silica gel (particle size 20-45μ; diameter 3 cm; height 21 cm), eluting with a mixture of dichloromethane/methanol (90/10 by volume). The fractions containing the product were combined and then concentrated to dryness under the above conditions. 0.22 g of 4-[3-(3-chloro-6-methoxyquinolin-4-yl)propyl]-1-(3-phenylpropyl)piperidine-4-carboxamide was obtained in the form of a white solid melting at 160° C.
Reaction SMILES: [F:1][C:2]1[C:3]([OH:21])=[C:4]([CH:15]=[C:16]([N+:18]([O-:20])=[O:19])[CH:17]=1)[CH2:5][N:6]([CH3:14])[C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10].[O:22]1[CH2:26][CH2:25][C@H:24](O)[CH2:23]1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[F:1][C:2]1[C:3]([O:21][C@@H:24]2[CH2:25][CH2:26][O:22][CH2:23]2)=[C:4]([CH:15]=[C:16]([N+:18]([O-:20])=[O:19])[CH:17]=1)[CH2:5][N:6]([CH3:14])[C:7](=[O:13])[O:8][C:9]([CH3:11])([CH3:12])[CH3:10]
Reactant: CN(Cc1cc([N+](=O)[O-])cc(F)c1O)C(=O)OC(C)(C)C
Reactant: O[C@H]1CCOC1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CN(Cc1cc([N+](=O)[O-])cc(F)c1O[C@@H]1CCOC1)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 100.3 %

Procedure:
To a solution of 17D (566 mg, 1.885 mmol), (S)-tetrahydrofuran-3-ol (365 mg, 4.15 mmol) and PPh3 (1088 mg, 4.15 mmol) in THF (5 mL) was added DIAD (0.822 mL, 4.15 mmol) dropwise. The reaction was stirred at 0° C. for 0.5 h and then at rt for 16 h. The mixture was concentrated and purified by prep HPLC to give 38A (700 mg, 1.890 mmol, 100% yield). MS (ESI) m/z: 371.2 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:11]=[C:10]([F:12])[N:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.FC1N=CC2N=CNC(=O)C=2C=1.C(N(CC)CC)C.[C:32]([O:36][C:37]([N:39]1[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1)=[O:38])([CH3:35])([CH3:34])[CH3:33]>[Cl-].[Na+].O.C(Cl)Cl>[C:32]([O:36][C:37]([N:39]1[CH2:44][CH2:43][N:42]([C:2]2[C:3]3[CH:11]=[C:10]([F:12])[N:9]=[CH:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH2:41][CH2:40]1)=[O:38])([CH3:35])([CH3:33])[CH3:34]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Fc1cc2c(Cl)ncnc2cn1
Agent: O=c1[nH]cnc2cnc(F)cc12
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCN(c2ncnc3cnc(F)cc23)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 58 %

Procedure:
According to the method described in J. Med. Chem., 39:1823-1835 (1996), 4-chloro-6-fluoropyrido[3,4-d]pyrimidine was derived from 6-fluoropyrido[3,4-d]pyrimidine-4(3H)-one (1.48 g, 8.96 mmol). Triethylamine (3.75 mL, 26.9 mmol) and N-tert-butoxycarbonylpiperazine (2.00 g, 10.7 mmol) were added to a methylene chloride solution (25 mL) of this partially purified product, followed by stirring at room temperature overnight. Saturated brine was added to the reaction solution, the mixture ma was extracted with chloroform, the extract was dried over anhydrous sodium sulfate, then the solvent was evaporated and the resulting residue was purified by silica gel column chromatography to give the target compound (1.73 g, 5.20 mmol).
Reaction SMILES: [C:1]([S:4][CH2:5][C@@H:6]([CH3:10])[C:7]([OH:9])=[O:8])(=[O:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.O[C@@H:24]([CH2:28][S:29][CH3:30])[C:25]([OH:27])=[O:26].C(N(CC)CC)C.Cl>O1CCCC1>[C:1]([S:4][CH2:5][C@@H:6]([CH3:10])[C:7](=[O:9])[O:8][C@@H:24]([CH2:28][S:29][CH3:30])[C:25]([OH:27])=[O:26])(=[O:3])[CH3:2]
Reactant: CSC[C@H](O)C(=O)O
Reactant: CC(=O)SC[C@@H](C)C(=O)O
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CSC[C@H](OC(=O)[C@H](C)CSC(C)=O)C(=O)O
Reaction time: 0.5 h
Yield: 15.2 %

Procedure:
(S)-3-(Acetylthio)-2-methylpropanoic acid (0.38 g, 2.35 mmol) and 1,1'-carbonyldiimidazole (0.38 g, 2.35 mmol) were stirred under nitrogen, in tetrahydrofuran (10 ml). After 30 min, a solution of (R)-2-hydroxy-3-(methylthio)propanoic acid (0.32 g, 2.35 mmol), triethylamine (0.33 ml, 2.35 mmol) and tetrahydrofuran (10 ml) was added dropwise. The reaction mixture was stirred at 25° for 18 h before evaporation of the solvent. The residue was acidified with dilute hydrochloric acid and extracted with ethyl acetate. The organic extracts were dried (Na2SO4) and the solvent evaporated. Chromatography on silica with dichloromethane/ethyl acetate as eluant gave the sub-title compound (0.1 g).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:16](=[O:31])[N:17]3[C:22](=[C:23]([C:25](O)=[O:26])[CH:24]=2)[C:21]2[S:28][CH:29]=[CH:30][C:20]=2[CH:19]=[CH:18]3)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O=S(Cl)Cl.CN(C=O)C.[CH3:41][O:42][CH2:43][CH2:44][NH:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1>C1(C)C=CC=CC=1.ClCCl.C(N(CC)CC)C>[CH3:41][O:42][CH2:43][CH2:44][N:45]([C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)[C:25]([C:23]1[CH:24]=[C:15]([C:12]2[CH:11]=[CH:10][C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[CH:14][CH:13]=2)[C:16](=[O:31])[N:17]2[C:22]=1[C:21]1[S:28][CH:29]=[CH:30][C:20]=1[CH:19]=[CH:18]2)=[O:26]
Reactant: COCCNc1ccccc1
Reactant: O=C(O)c1cc(-c2ccc(OCc3ccccc3)cc2)c(=O)n2ccc3ccsc3c12
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: COCCN(C(=O)c1cc(-c2ccc(OCc3ccccc3)cc2)c(=O)n2ccc3ccsc3c12)c1ccccc1

Procedure:
From 8-[p-(benzyloxy)phenyl]-7-oxo-7H-thieno[2,3-a]quinolizine-10-carboxylic acid with SOCl2 and DMF in toluene. Then treatment with triethylamine and (2-methoxy-ethyl)-phenyl-amine in dichloromethane.
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][CH2:11][C:12](O)=[O:13])=O)(C)(C)C.Cl.C[O:17][C:18]([CH:20]1[CH2:29][CH:28]([NH2:30])[C:27]2[C:22](=[CH:23][C:24]([Cl:32])=[CH:25][C:26]=2[Cl:31])[NH:21]1)=[O:19].OC1C2N=NNC=2C=CC=1.Cl.CN(C)CCCN=C=NCC.[OH-].[Na+].Cl>O1CCCC1.CO.C(OCC)(=O)C.C(N(CC)CC)C>[ClH:31].[C:18]([C@H:20]1[CH2:29][C@H:28]([NH:30][C:12]([CH2:11][CH2:10][CH2:9][NH2:8])=[O:13])[C:27]2[C:22](=[CH:23][C:24]([Cl:32])=[CH:25][C:26]=2[Cl:31])[NH:21]1)([OH:17])=[O:19]
Reactant: CC(C)(C)OC(=O)NCCCC(=O)O
Reactant: COC(=O)C1CC(N)c2c(Cl)cc(Cl)cc2N1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(CC)CC
Solvent: CO
Solvent: C1CCOC1
Product: NCCCC(=O)N[C@H]1C[C@H](C(=O)O)Nc2cc(Cl)cc(Cl)c21
Temperature: 25 °C
Reaction time: 14 h

Procedure:
4-(Tertiarybutyloxycarbonylamino)butanoic acid (0.3 g, 1.5 molar equivalents), 2-methoxycarbonyl-5,7-dichloro-4-amino-1,2,3,4-tetrahydroquinoline hydrochloride (Example 9a) (0.3 g, 0.000963M), hydroxybenzotriazole (0.156 g, 1.2 molar equivalents) and triethylamine (0.4 ml, 3 molar equivalents) were dissolved in anhydrous tetrahydrofuran (40 ml) followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.22 g, 1.2 molar equivalents). After stirring at room temperature for 14 h the solvents were evaporated, the residue was dissolved in ethyl acetate (100 ml) and washed with 0.5M citric acid solution (2×50 ml), saturated sodium hydrogen carbonate solution (2×50 ml) and brine (1×50 ml). The organic layer was dried (Na2SO4), filtered and concentrated in vacuo to leave a residue which was dissolved in 50% aqueous methanol and treated with sodium hydroxide (0.5 g). After stirring the solution for 36 h at room temperature the methanol was removed under vacuum and the residual aqueous solution was treated with 1M HCl until a pH of 1 was attained. The precipitated solid was extracted into ethyl acetate (2×20 ml) and the combined organic layers were dried (Na2SO4), filtered and concentrated in vacuo. The residue obtained was treated with 5 molar HCl in ethyl acetate (30 ml) and stirred at room temperature for 60 h. The solvents were evaporated and the residue recrystallised from methanol/diethyl ether/ethyl acetate to give the title compound as a white crystalline solid, m.p. 238°-240° C.; δ (360 MHz, DMSO) 1.63 (1H, ddd, J=13.0, 12.4 and 3.9 Hz, CHACHBHCCHD), 1.80 (2H, m, NHCOCH2CH2CH2NH3+), 2.13-2.21 (3H, m, CHACHBHCCHD and NHCOCH2CH2CH2NH3+), 2.77 (2H, t, J=7.6 Hz, NHCOCH2CHsCH2NH3+), 3.84 (1H, dd, J=12.4 and 2.7 Hz, CHACHBHCCHD), 5.02 (1H, m, CHACHBHCCHD), 6.65 (1H, d, J=1.9 Hz, 6-H or 8-H), 6.83 (1H, s, br, ArNH), 6.88 (1H, d, J=1.9 Hz, 6-H or 8-H), 7.97 (3H, s, br, NH3+), 8.31 (1H, d, J=7.3 Hz, CHDNHCO); Found C, 44.50; H, 4.95; N, 10.12. C14H17N3O3Cl2.HCl.0.25EtoAc requires C, 44.52; H, 4.98; N, 10.38%.