Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](NC1C=C(C(ON2C3C=CC=CC=3N=N2)=O)N(C)C=1)=[O:7])(C)(C)C.CN1C=CN=C1.[CH3:33][N:34]1[CH:38]=[CH:37][CH:36]=[CH:35]1.ClC(Cl)(Cl)C(Cl)=O.[N+:46]([O-])([OH:48])=[O:47]>>[CH3:33][N:34]1[CH:38]=[C:37]([N+:46]([O-:48])=[O:47])[CH:36]=[C:35]1[C:6]([O:5][CH3:1])=[O:7]
Reactant: O=[N+]([O-])O
Reactant: Cn1cccc1
Reactant: Cn1cc(NC(=O)OC(C)(C)C)cc1C(=O)On1nnc2ccccc21
Agent: Cn1ccnc1
Agent: O=C(Cl)C(Cl)(Cl)Cl
Product: COC(=O)c1cc([N+](=O)[O-])cn1C

Procedure:
Nitroesters 6 and 10 were synthesized from the inexpensive N-methylpyrrole and N-methylimidazole as outlined in Schemes 10 and 11, respectively. Each of these compounds can be prepared economically on a large scale. Methyl 1-methyl-4-nitropyrrole-2-carboxylate (6) was prepared using a modification of the reported synthesis of pyrrole-2-trichloroketone. (Bailey et al. (1971) Org. Syn. 51:101). Briefly, reaction of the inexpensive N-methylpyrrole (14) with trichloroacetylchloride followed by nitration with nitric acid gave nitropyrrole trichloroketone (15), which was treated with sodium methoxide to yield nitropyrrole (6).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([Br:9])[CH:8]=1)[NH2:5].[C:10]([N:18]=[C:19]=[S:20])(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>CC(C)=O>[C:10]([NH:18][C:19]([NH:5][C:4]1[CH:3]=[C:2]([Br:1])[CH:8]=[C:7]([Br:9])[CH:6]=1)=[S:20])(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Nc1cc(Br)cc(Br)c1
Reactant: O=C(N=C=S)c1ccccc1
Solvent: CC(C)=O
Product: O=C(NC(=S)Nc1cc(Br)cc(Br)c1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89.6 %

Procedure:
To the solution of 3,5-dibromoaniline (65.0 g, 0.26 mol) in anhydrous acetone (1.6 L) was added benzoylisothiocyanate (46.4 g, 0.28 mol) and the reaction mixture was stirred at room temperature for 30 min. Acetone was distilled off and the crude residue was washed with hexane to obtain desired compound as yellow solid (96.5 g, 90%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([CH2:11][CH2:12][CH3:13])[C:5]=1[OH:14].C(Cl)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(=O)(O)[O-].[Na+]>CO.[OH-].[Na+].CN(C)C=O>[C:17]1([CH2:1][O:2][C:3](=[O:15])[C:4]2[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([CH2:11][CH2:12][CH3:13])[C:5]=2[OH:14])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: ClCc1ccccc1
Reactant: CCCc1c(O)ccc(C(=O)OC)c1O
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CO
Product: CCCc1c(O)ccc(C(=O)OCc2ccccc2)c1O
Yield: 70 %

Procedure:
A solution of 37 g (0.18 mol) of 2,4-dihydroxy-3-propylbenzoic acid methyl ester in 750 mL of methanol and 415 mL of 3N sodium hydroxide was stirred at reflux for 3 hours. The methanol was removed under reduced pressure and the residue was treated with water and 6N hydrochloric acid to acidify. The solid product was extracted with ethyl acetate and the extract was dried and concentrated under reduced pressure to a tan solid which was used without purification. This crude acid (35 g, 0.18 mol), 23 mL (0.2 mol) of benzyl chloride and 17 g (0.2 mol) of sodium bicarbonate in 250 mL of anhydrous dimethylformamide was stirred and heated at 60° for 23 hours. The solvent was removed under reduced pressure and the residue was treated with saturated sodium bicarbonate solution and the product was extracted with ethyl acetate. The dried extract was concentrated under reduced pressure and the residual oil was purified by HPLC using 15% ethyl acetate hexane to give 36 g (70% yield), mp 86°-88° of 2,4-dihydroxy-3-propylbenzoic acid phenylmethyl ester.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:24])[C:10]1[CH:15]=[CH:14][C:13]([CH:16]([P:18]([O:22][CH3:23])([O:20][CH3:21])=[O:19])O)=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(S(F)(F)[F:31])CC>>[CH2:1]([O:8][C:9](=[O:24])[C:10]1[CH:15]=[CH:14][C:13]([CH:16]([P:18]([O:22][CH3:23])([O:20][CH3:21])=[O:19])[F:31])=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCN(CC)S(F)(F)F
Reactant: COP(=O)(OC)C(O)c1ccc(C(=O)OCc2ccccc2)cc1
Product: COP(=O)(OC)C(F)c1ccc(C(=O)OCc2ccccc2)cc1
Temperature: -78 °C
Reaction time: 18 h

Procedure:
4-[(Dimethoxy-phosphoryl)-hydroxy-methyl]-benzoic acid benzyl ester (0.20 g, 0.22 mmol) was added over 30 mins to a stirring solution of DAST (1M in CH2Cl2) cooled to −78° C. under a dry nitrogen environment. The mixture was warmed to RT and stirred for 18 hours. The reaction mixture was then quenched with ethanol containing pyridine (pyr: twice volume of DAST). After another 30 mins the mixture was poured into ice cold water and extracted into DCM (3×). The combined organic extracts were washed with dilute aq HCl, water, brine, dried (MgSO4) then concentrated in vacuo. The residue was purified by HPLC (20-85% MeCN in Water w/0.025% TFA) to afford the title compound: MS: cal'd 353 (MH+), exp 353 (MH+)
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[CH:11]=[C:10]([NH:12][C:13](=[O:30])[CH:14]([NH:18][C:19](=[O:29])[CH2:20][C:21]3[CH:26]=[C:25]([F:27])[CH:24]=[C:23]([F:28])[CH:22]=3)[CH2:15][CH2:16][CH3:17])[N:9]=[CH:8]2)[CH2:3][CH2:2]1.ClC(Cl)C.[CH3:35][C:36]([CH3:41])([CH3:40])[CH2:37][CH:38]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(N(CC)CC)C.C1COCC1>[CH3:35][C:36]([CH3:41])([CH3:40])[CH2:37][CH2:38][N:1]1[CH2:6][CH2:5][CH:4]([N:7]2[CH:11]=[C:10]([NH:12][C:13](=[O:30])[CH:14]([NH:18][C:19](=[O:29])[CH2:20][C:21]3[CH:26]=[C:25]([F:27])[CH:24]=[C:23]([F:28])[CH:22]=3)[CH2:15][CH2:16][CH3:17])[N:9]=[CH:8]2)[CH2:3][CH2:2]1
Reactant: CC(C)(C)CC=O
Reactant: CCCC(NC(=O)Cc1cc(F)cc(F)c1)C(=O)Nc1cn(C2CCNCC2)cn1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC(Cl)Cl
Solvent: C1CCOC1
Product: CCCC(NC(=O)Cc1cc(F)cc(F)c1)C(=O)Nc1cn(C2CCN(CCC(C)(C)C)CC2)cn1
Reaction time: 8 h

Procedure:
2-[2-(3,5-Difluoro-phenyl)-acetylamino]-pentanoic acid (1-piperidin-4-yl-1H-imidazol-4-yl)-amide (100 mg, 2.4 mmol) was charged with 1 mL of THF, 1 mL of Dichloroethane, 0.06 mL of triethyamine, 0.03 mL of 3,3-dimethylbutyraldehyde, and 63 mg of sodiumtriacetoxyborohydride. The reaction was stirred overnight, quenched with sodiumbicarbonate, extracted with methylene chloride, and the resultant oil purified by silica gel chromatography to afford the title compound: C13 NMR (100 MHz, CDCl3) 13.9, 18.8, 29.7, 29.9, 33.3, 36.0, 40.9, 43.1, 52.9, 53.1, 54.5, 55.9, 102.8, 103.1, 105.9, 112.3, 112.4, 112.5, 112.6, 131.5, 137.6, 169.2; MS 504.3 m/z (M+1).
Reaction SMILES: [CH:1]1([NH:6][CH:7]([CH3:13])[CH2:8][C:9]([NH:11][CH3:12])=[O:10])[CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:14][C:15]1[C:16](Cl)=[N:17][C:18]([Cl:21])=[N:19][CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Br:14][C:15]1[C:16]([N:6]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)[CH:7]([CH3:13])[CH2:8][C:9]([NH:11][CH3:12])=[O:10])=[N:17][C:18]([Cl:21])=[N:19][CH:20]=1
Reactant: Clc1ncc(Br)c(Cl)n1
Reactant: CNC(=O)CC(C)NC1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CNC(=O)CC(C)N(c1nc(Cl)ncc1Br)C1CCCC1
Reaction time: 16 h
Yield: 6.5 %

Procedure:
A stirred solution of 3-(cyclopentylamino)-N-methyl-butanamide (Intermediate 122; 887 mg, 4.80 mmol), 5-bromo-2,4-dichloropyrimidine (1.15 g, 5.04 mmol) and potassium carbonate (1.34 g, 9.60 mmol) in acetone (20 mL) were heated under reflux conditions to 65° C. for 3 days and then at 75° C. for a further 16 hrs. The solvent was evaporated and the residue taken up in Ethyl Acetate (200 mL) and water (200 mL). The aqueous phase was separated and the organic phase further washed with water (200 mL) and brine (200 mL). The organic phase was evaporated and the residue purified by flash silica chromatography (companion, 40 g, 0-10% MeOH/DCM) followed by base modified preparative HPLC (30-50% gradient) to give the title compound as a yellow solid (117 mg, 6%).
Reaction SMILES: C([Li])CCC.CCCCCC.C(NC(C)C)(C)C.[CH2:19]([PH:23](=[O:27])[O:24][CH2:25][CH3:26])[CH:20]([CH3:22])[CH3:21].C(OP(OCC)([C:33](=[CH2:39])[C:34]([O:36][CH2:37][CH3:38])=[O:35])=O)C.[CH:43](=O)[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1.[Cl-].[NH4+]>O1CCCC1>[CH2:25]([O:24][P:23]([CH2:39]/[C:33](=[CH:43]\[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)/[C:34]([O:36][CH2:37][CH3:38])=[O:35])([CH2:19][CH:20]([CH3:22])[CH3:21])=[O:27])[CH3:26]
Reactant: CCO[PH](=O)CC(C)C
Reactant: C=C(C(=O)OCC)P(=O)(OCC)OCC
Reactant: O=Cc1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCOC(=O)/C(=C/c1ccccc1)CP(=O)(CC(C)C)OCC
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 29.6 %

Procedure:
Under a nitrogen atmosphere, 7.3 ml (11 millimoles) of 1.5 M butyllithium-hexane was added dropwise to a solution of 1.5 ml (11 millimoles) of diisopropylamine in 20 ml of dry tetrahydrofuran. The mixture was cooled to -78° C. in a dry ice-methanol bath, and 1.50 g (10 millimoles) of ethyl isobutylphosphinate and then 2.46 g (10.4 millimoles) of ethyl 2-diethoxyphosphinoylpropenoate were added. The mixture was stirred at 0° C. for 30 minutes. The mixture was cooled to -30 ° C., and 1.1 ml (11 millimoles) of benzaldehyde was added. The mixture was stirred at -30° C. for 3 hours, and ovenight at room temperature. A saturated aqueous solution of ammonium chloride (50 ml) was added to the reaction mixture, and the mixture was extracted three times with 50 ml of ethyl acetate each time. The combined organic layers were washed with 20 ml of a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by medium-pressure liquid chromatography [Lobar column (a product of E. Merck & Co.), size C, Lichroprep SI 60, ethyl acetate]. The first fraction was evaporated to give 1.00 g (yield 30%) of ethyl (Z)-2-(ethoxyisobutylphosphinoyl)methyl-3-phenylpropenoate as a colorless oil.
Reaction SMILES: FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.[CH2:16]([O:18][C:19]1[CH:20]=[C:21]([C@@H:27]2[C@H:32]([NH:33][C:34](=O)[C:35]3[CH:49]=[CH:48][C:38]([C:39]([N:41]([CH:45]([CH3:47])[CH3:46])[CH:42]([CH3:44])[CH3:43])=[O:40])=[CH:37][CH:36]=3)[CH2:31][CH2:30][O:29][CH2:28]2)[CH:22]=[CH:23][C:24]=1[O:25][CH3:26])[CH3:17].CO.C(N(CC)CC)C>ClCCl.CN(C)C1C=CN=CC=1>[CH2:16]([O:18][C:19]1[CH:20]=[C:21]2[C:22](=[CH:23][C:24]=1[O:25][CH3:26])[C:34]([C:35]1[CH:49]=[CH:48][C:38]([C:39]([N:41]([CH:45]([CH3:47])[CH3:46])[CH:42]([CH3:44])[CH3:43])=[O:40])=[CH:37][CH:36]=1)=[N:33][C@H:32]1[C@@H:27]2[CH2:28][O:29][CH2:30][CH2:31]1)[CH3:17]
Reactant: CCOc1cc([C@H]2COCC[C@H]2NC(=O)c2ccc(C(=O)N(C(C)C)C(C)C)cc2)ccc1OC
Agent: CN(C)c1ccncc1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CO
Product: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)N(C(C)C)C(C)C)cc1)=N[C@@H]1CCOC[C@H]21
Temperature: 0 °C

Procedure:
Alternatively a solution of 12.5 mmol of trifluoromethanesulfonic anhydride dissolved in 10 ml dichloromethane is added over a period of 20 min to a cooled (ice-water bath) solution of 2.5 mmol of N-[(3R,4R)-3-(3-Ethoxy-4-methoxy-phenyl)-tetrahydro-pyran-4-yl]-N′,N′-diisopropyl-terephthalamide and 7.5 mmol of 4-dimethylamino-pyridine in 30 ml of dichloromethane. The solution is stirred over night and then added to a cooled (ice-water bath) mixture of 10 ml of methanol, 10 ml of triethyl amine and 20 ml of dichloromethane and the mixture is stirred for 1 h. After concentration under reduced pressure the solid residue is purified by column chromatography on SiO2 (di-isopropylether/methanol/triethyl amine 18/1/1 vol/vol/vol), the main product fraction is separated and concentrated yielding the title compound as grayish solid foam. M.p. 98-102° C. (unsharp, enamel-like shrinking starting at about 88° C.)
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])(OCC)=O)C.[CH2:17]([O:24][C:25]1[CH:26]=[C:27]([CH:42]=[C:43]([O:45][CH2:46][C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)[CH:44]=1)[CH2:28][N:29]1[CH:33]=[C:32]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:31]([CH:40]=O)=[CH:30]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O>O1CCCC1>[CH2:46]([O:45][C:43]1[CH:42]=[C:27]([CH:26]=[C:25]([O:24][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:44]=1)[CH2:28][N:29]1[CH:33]=[C:32]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:31](/[CH:40]=[CH:11]/[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:30]1)[C:47]1[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: O=Cc1cn(Cc2cc(OCc3ccccc3)cc(OCc3ccccc3)c2)cc1-c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)/C=C/c1cn(Cc2cc(OCc3ccccc3)cc(OCc3ccccc3)c2)cc1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84 %

Procedure:
Sodium hydride (60%, oily, 2.11 g) was added to a mixture of ethyl diethylphosphonoacetate (10.5 ml) and tetrahydrofuran (150 ml) at 0° C., which was stirred at room temperature for 30 minutes. A solution of 1-(3,5-dibenzyloxybenzyl)-4-phenylpyrrole-3-carbaldehyde (22.7 g) in tetrahydrofuran (20 ml) was slowly added to the mixture, which was stirred at room temperature for 1 hour. The reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), then concentrated. The residue was subjected to silica gel column chromatography, and ethyl (E)-3-[1-(3,5-dibenzyloxybenzyl)-4-phenyl-3-pyrrolyl]propenoate (21.9 g, yield: 84%) was obtained. This was recrystallized from ethyl acetate-hexane. Melting point: 98–99° C.
Reaction SMILES: [C:1](N)(=[O:3])[CH3:2].C=O.O.Cl.[NH:9]([CH2:14][C:15]([OH:17])=[O:16])[CH2:10][C:11]([OH:13])=[O:12].C(NCC(O)=O)(=O)C>COCCOC>[C:1]([N:9]([CH2:14][C:15]([OH:17])=[O:16])[CH2:10][C:11]([OH:13])=[O:12])(=[O:3])[CH3:2]
Reactant: O=C(O)CNCC(=O)O
Reactant: CC(N)=O
Agent: C=O
Agent: CC(=O)NCC(=O)O
Agent: Cl
Solvent: COCCOC
Solvent: O
Product: CC(=O)N(CC(=O)O)CC(=O)O
Temperature: 110 °C
Yield: 87 %

Procedure:
A 300 mL autoclave was charged with acetamide (VII) (11.8 g, 0.2 mole), 95% paraformaldehyde (13.6 g, 0.43 mole), water (12.9 g, 0.72 mole), 37% HCl (1.8 g, 0.018 mole), DME (90 mL), and Co2 (CO)8 (4.1 g, 0.012 mole) and pressurized to 1500 psi (10,345 kPa) CO at 25° C. This mixture was heated to 110° C. for 30 minutes. HPLC analysis of this stream gave an 87% yield of (XVI), 0.5% iminodiacetic acid (XIV), and 4.0% N-acetylglycine (XVIII).
Reaction SMILES: C(O)(C(F)(F)F)=O.[Cl:8][C:9]1[CH:10]=[C:11]([Cl:39])[C:12]2[C:13]3[CH2:31][CH2:30][N:29](C(OC(C)(C)C)=O)[CH2:28][CH2:27][C:14]=3[N:15]([CH2:18][CH2:19][O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:16]=2[CH:17]=1.[OH-].[Na+]>C(Cl)Cl>[ClH:8].[Cl:8][C:9]1[CH:10]=[C:11]([Cl:39])[C:12]2[C:13]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27][C:14]=3[N:15]([CH2:18][CH2:19][O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:16]=2[CH:17]=1
Reactant: CC(C)(C)OC(=O)N1CCc2c(n(CCOc3ccccc3)c3cc(Cl)cc(Cl)c23)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cl
Product: Clc1cc(Cl)c2c3c(n(CCOc4ccccc4)c2c1)CCNCC3
Reaction time: 5 h
Yield: 65.9 %

Procedure:
TFA (0.65 mL, 8.4 mmol) was added to a solution of tert-butyl 8,10-dichloro-6-(2-phenoxyethyl)-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate (0.20 g, 0.42 mmol) in CH2Cl2 (6 mL). After 5 h, the reaction was made basic with 10% aqueous NaOH and extracted with CH2Cl2 (3×15 mL). The combined organic layers were washed with brine, dried over Na2SO4, decanted, and concentrated to give a crude solid. After the hydrochloride salt was prepared, it was further purified by recrystallization from MeOH/EtOAc to give 57 mg (33%) of a white solid: mp 242.0-243.0° C.; 1H NMR (300 MHz, DMSO) δ 9.13 (br s, 2H), 7.72 (d, J=1.7 Hz, 1H), 7.26 (m, 2H), 7.13 (d, J=1.7 Hz, 1H), 6.92 (t, J=7.4 Hz, 1H), 6.84 (d, J=7.9 Hz, 2H), 4.64 (m, 2H), 4.17 (m, 2H), 3.49 (m, 2H); 13C NMR (300 MHz, DMSO) δ 157.7, 139.8, 136.7, 129.4, 125.2, 124.4, 121.5, 120.8, 120.0, 114.1, 110.4, 109.6, 66.5, 45.2, 43.6, 42.3, 22.3, 21.0; IR (diffuse reflectance) 2843, 2718, 2688, 2666, 2633, 2440, 1601, 1497, 1460, 1244, 1238, 845, 827, 754, 694 cm−1; MS (EI) m/z 376, 374 (M+), 339, 334, 333, 332, 78, 77, 65, 63; Anal. Calcd for C20H20Cl2N2O.HCl: C, 58.34; H, 5.14; N, 6.80; found: C, 58.10; H, 5.20; N, 6.76.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]2[CH2:11][CH2:12][CH2:13][CH:14](O)[C:3]=12.C1(C)C=CC(S([Cl:25])(=O)=O)=CC=1.[NH:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1>N1C=CC=CC=1>[ClH:25].[CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]2[CH2:11][CH2:12][CH2:13][CH:14]([N:27]3[CH2:31][CH2:30][CH2:29][CH2:28]3)[C:3]=12
Reactant: C1CCNC1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1c2n(c3ccccc13)CCCC2O
Solvent: c1ccncc1
Product: Cc1c2n(c3ccccc13)CCCC2N1CCCC1
Product: Cl
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 6,7,8,9-tetrahydro-10-methylpyrido[1,2-a]indol-9-ol (2.01 g, 10 mmol) in dry pyridine (100 mL) was added a solution of p-toluenesulfonyl chloride (7.6 g, 10 mmol) in the same solvent (50 mL) at 5°-10° C. Maintaining this temperature, stirring was continued for 60 minutes, and then, the reaction mixture was treated with distilled pyrrolidine (7.1 g, 100 mmol), and stirred at room temperature for 8 hours. The resultant solution was poured into ice-water, and the product was extracted with methylene chloride. The combined extracts were washed with water, dried (MgSO4), filtered, and evaporated. The residue was chromatographed using methylene chloride/methanol 99:1. The title base 1.8 g (70%) was converted to the hydrochloride salt in acetonitrile with ethereal HCl, and recrystallized from ethanol, m.p. 179°-181° C. (analytical specimen m.p. 182° C.).
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[C:4]([C:7](=[N:25][O:26][CH2:27][C:28]([OH:30])=[O:29])[C:8]([NH:10][C@@H:11]2[C:23](=[O:24])[N:13]3[C:14]([C:20]([OH:22])=[O:21])=[C:15]([CH2:18][Cl:19])[CH2:16][S:17][C@H:12]23)=[O:9])[N:3]=1.[CH3:31][N:32]1[CH2:37][CH2:36][N:35]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:34][CH2:33]1.C(OCC)(=O)C>CN(C)C=O>[ClH:19].[NH2:1][C:2]1[S:6][N:5]=[C:4]([C:7](=[N:25][O:26][CH2:27][C:28]([OH:30])=[O:29])[C:8]([NH:10][C@@H:11]2[C:23](=[O:24])[N:13]3[C:14]([C:20]([O-:22])=[O:21])=[C:15]([CH2:18][N+:32]4([CH3:31])[CH2:33][CH2:34][N:35]([C:38]([O:40][C:41]([CH3:43])([CH3:42])[CH3:44])=[O:39])[CH2:36][CH2:37]4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:3]=1
Reactant: Nc1nc(C(=NOCC(=O)O)C(=O)N[C@@H]2C(=O)N3C(C(=O)O)=C(CCl)CS[C@H]23)ns1
Reactant: CN1CCN(C(=O)OC(C)(C)C)CC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC[N+](C)(CC2=C(C(=O)[O-])N3C(=O)[C@@H](NC(=O)C(=NOCC(=O)O)c4nsc(N)n4)[C@H]3SC2)CC1
Product: Cl
Reaction time: 1.5 h
Yield: 100.5 %

Procedure:
To a solution of 7β-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-carboxymethoxyiminoacetamido]-3-chloromethyl-3-cephem-4-carboxylic acid (syn isomer) (4.0 g) in N,N-dimethylformamide was added dropwise 1-methyl-4-tert-butoxycarbonylpiperazine (6.7 g) at 2° C. under stirring. The stirring was continued for 1.5 hours at 18°-2° C. The reaction mixture was poured into ethyl acetate (200 ml). The resulting precipitates were collected by filtration to give 7β-[2-(5-amino-1,2,4-thiadiazol-3-yl)-2-carboxymethoxyiminoacetamido]-3-(1-methyl-4-tert-butoxycarbonyl-1-piperazinio)methyl-3-cephem-4-carboxylate hydrochloride (syn isomer) (5.71 g) .
Reaction SMILES: [C:1](Cl)(=[O:5])[CH2:2][CH2:3][CH3:4].Cl.[NH2:8][C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:18]=1[OH:19])=[CH:16][CH:15]=[C:14]([O:20][CH3:21])[CH:13]=2.C(N(CC)CC)C>ClCCl>[OH:19][C:18]1[C:17]2[C:12](=[CH:13][C:14]([O:20][CH3:21])=[CH:15][CH:16]=2)[N:11]=[CH:10][C:9]=1[NH:8][C:1](=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)Cl
Reactant: COc1ccc2c(O)c(N)cnc2c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCC(=O)Nc1cnc2cc(OC)ccc2c1O
Temperature: 25 °C
Yield: 62.8 %

Procedure:
Butyryl chloride (0.63 mL, 6.1 mmol) was added dropwise to a solution containing 3-amino-7-methoxyquinolin-4-ol hydrochloride (1.0 g, 5.26 mmol), triethylamine (2.35 mL, 16.8 mmol), dichloromethane (30 mL) and N,N-dimethylfonnamide (10 mL). The reaction mixture was maintained at ambient temperature overnight. The N,N-dimethylformamide was removed under vacuum and the resulting solid was partitioned between dichloromethane (100 mL) and water (100 mL). The organic fraction was washed with water, dried over magnesium sulfate, filtered and then concentrated under vacuum to provide 0.86 g of N-(4-hydroxy-7-methoxyquinolin-3-yl)butanamide as a tan solid.
Reaction SMILES: [Cl:1][C:2]1[C:9]([CH:10]=[O:11])=[C:8]([F:12])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[BH4-].[Na+].O>CO>[Cl:1][C:2]1[C:9]([CH2:10][OH:11])=[C:8]([F:12])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1ccc(F)c(C=O)c1Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: N#Cc1ccc(F)c(CO)c1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67.6 %

Procedure:
To a solution (10 mL) of 2-chloro-4-fluoro-3-formylbenzonitrile (600 mg) in methanol was added sodium borohydride (136 mg) under ice-cooling, and the mixture was stirred at room temperature for 30 min. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was crystallized from hexane-isopropyl ether to give the title compound as a pale-yellow solid (yield: 410 mg).
Reaction SMILES: [CH2:1]([NH:3][CH2:4][C:5]([OH:7])=O)[CH3:2].[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([O:18][CH3:19])=[C:13]([N:15]=[C:16]=[S:17])[CH:14]=1.C(N(CC)CC)C>C(Cl)Cl>[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([O:18][CH3:19])=[C:13]([N:15]2[C:5](=[O:7])[CH2:4][N:3]([CH2:1][CH3:2])[C:16]2=[S:17])[CH:14]=1
Reactant: CCNCC(=O)O
Reactant: COc1ccc(Cl)cc1N=C=S
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCN1CC(=O)N(c2cc(Cl)ccc2OC)C1=S
Yield: 53.3 %

Procedure:
A mixture N-ethyl glycine (9.2 g), 5-chloro-2-methoxyphenyl-isothiocyanate (10 g), triethylamine (10.1 g), methylene chloride (150 mL) was heated at reflux for 3.5 hours. The mixture was evaporated to dryness. The residue collected, washed with hot ethanol and dried. Title compound (7.6 g) was obtained as a creamy solid, m.p. 171°-174° C. Anal. Calcd. for. C12H13Cl N2O2S: C, 50.61; H, 4.60; N, 9.84. Found: C, 50.33; H, 4.50; N, 9.69. Mass spectrum (El, M.+) m/z 284/286.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[C@H:10]([NH2:19])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[C:21]1[C:22](=[O:33])[N:23]([CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH:24]=[CH:25][N:26]=1.CCN(C(C)C)C(C)C>C1(C)C=CC=CC=1.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[C@H:10]([NH:19][C:21]2[C:22](=[O:33])[N:23]([CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH:24]=[CH:25][N:26]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)Cn1ccnc(Br)c1=O
Reactant: CC(C)(C)OC(=O)N1C[C@@H](N)[C@H](c2ccccn2)C1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)Cn1ccnc(N[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]2c2ccccn2)c1=O
Temperature: 25 °C

Procedure:
A stirred solution of 1-tert-butyloxycarbonyl-trans-3-amino-4-(2-pyridyl)pyrrolidine from step 7 above (2.5 g, 9.5 mmol), 3-bromo-1-ethoxycarbonylmethylpyrazinone (2.5 g, 9.5 mmol), and DIEA (1.9 mL, 11 mmol) in toluene (30 mL) was heated to reflux for 24 h. The mixture was cooled to ambient temperature, diluted with EtOAc, and washed with aqueous NaHCO3. The organic phase was separated, dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography using a gradient elution of 60-85% EtOAc:hexanes to give the title compound as an amorphous solid (3.4 g; TLC Rf=0.5, 4:1 EtOAc:hexanes; HPLC RT=5.92 min, method A).