Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([OH:6])[CH2:2][CH2:3][CH2:4][OH:5].[Cl:7][CH2:8][C:9]([OH:11])=O>C1(C)C=CC(S(O)(=O)=O)=CC=1>[Cl:7][CH2:8][C:9]([O:5][CH2:4][CH2:3][CH2:2][CH2:1][O:6][C:9](=[O:11])[CH2:8][Cl:7])=[O:11]
Reactant: OCCCCO
Reactant: O=C(O)CCl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: O=C(CCl)OCCCCOC(=O)CCl
Temperature: 25 °C

Procedure:
In a 2 liter, 4 neck round bottom flask equipped with a mechanical stirrer, a solution of 75 grams of 1,4-butanediol, 240 grams of chloroacetic acid and 3 grams of para-toluenesulphonic acid 750 ml toluene was refluxed for 6 hours using a Dean-Stark apparatus. The solution was then cooled to room temperature. The toluene layer was washed with water (2×300 ml), 5% sodium bicarbonate solution (3×500 ml), water (2×300 ml), dried over sodium sulfate, and distilled to get crude 21, which was purified by recrystallization in chloroform:hexane (1:7) to get 92 grams of pure 21 as a white fluffy powder. m.p: 74-76.5° C., IH NMR (CDCl3) δ1.78 (t, 2H, CH2), 4.05 (s, 2H, CH2), 4.25 (t, 2H, CH2)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][S:15]([C:18]1[CH:19]=[CH:20][CH:21]=[C:22]2[C:27]=1[CH:26]([CH3:28])[NH:25][CH2:24][CH2:23]2)(=[O:17])=[O:16]>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:25]3[CH2:24][CH2:23][C:22]4[C:27](=[C:18]([S:15]([CH3:14])(=[O:16])=[O:17])[CH:19]=[CH:20][CH:21]=4)[CH:26]3[CH3:28])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Reactant: CC1NCCc2cccc(S(C)(=O)=O)c21
Product: CC1c2c(cccc2S(C)(=O)=O)CCN1C(=O)c1cc2ncc(Br)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 8-Methanesulfonyl-1-methyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH:8]2[NH:13][C:12](=O)[CH2:11][NH:10][C:9]2=O)[CH2:3][CH2:2]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>C1COCC1>[O:1]1[CH2:2][CH2:3][CH:4]([CH2:7][CH:8]2[CH2:9][NH:10][CH2:11][CH2:12][NH:13]2)[CH2:5][CH2:6]1
Reactant: O=C1CNC(=O)C(CC2CCOCC2)N1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: C1CNC(CC2CCOCC2)CN1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76 %

Procedure:
A 250 ml, round-bottomed flask was charged with 3-(tetrahydro-2H-pyran-4-ylmethyl)-2,5-piperazinedione (1.44 g, 6.78 mmol), 50 mL of THF, and lithium aluminum hydride (27.1 mL, 1M in THF, 27.1 mmol). After refluxing for 2 h, the mixture was cooled to room temperature where sodium sulfate decahydrate (10 g) was added. After stirring at room temperature for 1 h, the mixture was filtered and the filtrate was concentrated to give 2-((tetrahydro-2H-pyran-4-yl)methyl)piperazine (0.950 g) as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[CH:7]([OH:8])[C:5](=[O:6])[O:4][CH2:3]1.C([O-])(=O)C.[Na+].ClN1C(=O)N(Cl)C(=O)N(Cl)C1=O>C(Cl)Cl>[CH3:1][C:2]1([CH3:9])[C:7](=[O:8])[C:5](=[O:6])[O:4][CH2:3]1
Reactant: CC1(C)COC(=O)C1O
Agent: CC(=O)[O-]
Agent: O=c1n(Cl)c(=O)n(Cl)c(=O)n1Cl
Agent: [Na+]
Solvent: ClCCl
Product: CC1(C)COC(=O)C1=O
Temperature: 0 °C
Yield: 18.5 %

Procedure:
1.18 g (9.1 mmol) of pantolactone were dissolved in 27 ml of methylene chloride at 22° C. in a 50 ml reaction flask. 777 mg (9.5 mmol) of sodium acetate and 850 mg (3.7 mmol) of trichloroisocyanuric acid were added thereto. The mixture was cooled to 0° C. while stirring. 18.5% of ketopantolactone were obtained after a reaction period of 6 hours at 0° C. After a further reaction period of 20 hours at 22° C. the composition was 22.2% of ketopantolactone and 77.5% of pantolactone (area percent).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]([C:7]([CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][C:16]([OH:18])=O)[CH2:11][CH2:10]2)=[O:8])=[CH:5][CH:4]=1.[NH2:21][CH2:22][C:23]1[NH:32][C:31](=[O:33])[C:30]2[CH2:29][CH2:28][CH2:27][CH2:26][C:25]=2[N:24]=1>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([CH:9]2[CH2:10][CH2:11][N:12]([CH2:15][C:16]([NH:21][CH2:22][C:23]3[NH:32][C:31](=[O:33])[C:30]4[CH2:29][CH2:28][CH2:27][CH2:26][C:25]=4[N:24]=3)=[O:18])[CH2:13][CH2:14]2)=[O:8])=[CH:19][CH:20]=1
Reactant: COc1ccc(C(=O)C2CCN(CC(=O)O)CC2)cc1
Reactant: NCc1nc2c(c(=O)[nH]1)CCCC2
Product: COc1ccc(C(=O)C2CCN(CC(=O)NCc3nc4c(c(=O)[nH]3)CCCC4)CC2)cc1
Yield: 34 %

Procedure:
The title compound (100 mg) was prepared following the general procedure of Example 1 from 2-(4-(4-methoxybenzoyl)piperidin-1-yl)acetic acid (265 mg, 0.67 mmol, 70% purity) and 2-(aminomethyl)-5,6,7,8-tetrahydroquinazolin-4(3H)-one (120 mg, 0.67 mmol). 1H NMR (400 MHz, CDC3) δ 10.91 (br. s., 1H), 7.91 (br. s., 1H), 7.82-7.89 (m, 2H), 6.85-6.91 (m, J=8.6 Hz, 2H), 4.29 (d, J=6.1 Hz, 2H), 3.81 (s, 3H), 3.17 (d, J=6.6 Hz, 1H), 3.07 (br. s., 2H), 2.90 (br. s., 2H), 2.52 (t, J=6.1 Hz, 2H), 2.42 (t, J=6.1 Hz, 4H), 1.80 (br. s., 4H), 1.48-1.77 (m, 4H). HRMS calculated for C24H30N4O4 439.2345. found (ESI, [M+H]+), 439.2352. Retention time=2.84 min.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:15]([OH:17])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH2:3][CH2:2]1.[NH2:18][C@@H:19]([C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1)[C:20]([NH2:22])=[O:21]>>[C:20]([C@@H:19]([NH:18][C:15]([C:7]1[CH:6]=[CH:5][C:4]([CH:1]2[CH2:2][CH2:3]2)=[C:9]([O:10][CH2:11][CH:12]2[CH2:13][CH2:14]2)[N:8]=1)=[O:17])[C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1)(=[O:21])[NH2:22]
Reactant: O=C(O)c1ccc(C2CC2)c(OCC2CC2)n1
Reactant: NC(=O)[C@@H](N)c1ccc(F)cc1
Product: NC(=O)[C@@H](NC(=O)c1ccc(C2CC2)c(OCC2CC2)n1)c1ccc(F)cc1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl-6-cyclopropylmethyloxy-pyridine-2-carboxylic acid (Example 42a) and (αS)-α-amino-4-fluoro-benzeneacetamide (CAN 785041-04-5) as starting materials; LC-MS (UV peak area/ESI) 100%, 384.1716 (M+H)+.
Reaction SMILES: [C:1]([O:5][P:6]([CH:13]([OH:27])[C:14]1[CH:26]=[CH:25][C:17]([CH2:18][CH:19]([C:21]([O:23]C)=[O:22])[NH2:20])=[CH:16][CH:15]=1)([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>O1CCOCC1>[C:9]([O:8][P:6]([CH:13]([OH:27])[C:14]1[CH:26]=[CH:25][C:17]([CH2:18][CH:19]([C:21]([OH:23])=[O:22])[NH2:20])=[CH:16][CH:15]=1)([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:7])([CH3:10])([CH3:11])[CH3:12]
Reactant: COC(=O)C(N)Cc1ccc(C(O)P(=O)(OC(C)(C)C)OC(C)(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(C)(C)OP(=O)(OC(C)(C)C)C(O)c1ccc(CC(N)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of compound 8 (410 mg, 1.02 mmol) in dioxane (10 mL) is treated with 1 N NaOH (5.1 mL, 5 eq.) and stirred at ambient temperature (0.5 h), yielding a solution of crude 4-[bis(tert-Butoxy)phosphorylhydroxymethyl]-D,L-phenylalanine (15), which is not isolated. The pH is adjusted to 8 by bubbling in CO2 gas, Fmoc-OBT (402 mg, 1.12 mmol) is added and the mixture stirred at ambient temperature (3.5 hours). Ice-cold 5% citric acid (25 mL) is added and the resultant solution is extracted with CHCl3 (3×30 mL). The combined extracts are dried (MgSO4) and evaporated under reduced pressure to yield crude 16. Purification by silica gel chromatography affords pure 16 as a colorless foam (277 mg, 44%).
Reaction SMILES: [CH3:1][C:2]1[N:11]=[CH:10][C:9]([CH3:12])=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6](=O)[NH:7]2.P(Br)(Br)([Br:16])=O.C(=O)(O)[O-].[Na+]>>[Br:16][C:6]1[CH:5]=[CH:4][C:3]2[C:8](=[C:9]([CH3:12])[CH:10]=[N:11][C:2]=2[CH3:1])[N:7]=1
Reactant: O=P(Br)(Br)Br
Reactant: Cc1ncc(C)c2[nH]c(=O)ccc12
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1ncc(C)c2nc(Br)ccc12
Temperature: 110 °C
Yield: 22.1 %

Procedure:
A mixture of 5,8-dimethyl-1,6-naphthyridin-2(1H)-one (2.1 g, 12 mmol) and phosphoryl tribromide (5 g) was heated to 110° C. for 1 h, cooled, diluted with ice water, and neutralized with saturated sodium bicarbonate solution. The aqueous phase was extracted with DCM (100 mL×3), and the combined organic layers were dried with sodium sulfate and purified by column chromatography to give 0.63 g of the product as a pale white solid. MS (ESI): m/z 237.0 [M+H]+.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH2:4][S:5][C@@H:6]2[CH:26]([NH:27][C:28](=[O:37])[CH2:29][O:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:25](=[O:38])[N:7]2[C:8]=1[C:9]([O:11][CH:12]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10].[C:39]([C:41]1[CH:46]=[CH:45][C:44](O)=[CH:43][CH:42]=1)#[N:40]>>[C:39]([C:41]1[CH:46]=[CH:45][C:44]([O:1][CH2:2][C:3]2[CH2:4][S:5][C@@H:6]3[CH:26]([NH:27][C:28](=[O:37])[CH2:29][O:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[C:25](=[O:38])[N:7]3[C:8]=2[C:9]([O:11][CH:12]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:10])=[CH:43][CH:42]=1)#[N:40]
Reactant: N#Cc1ccc(O)cc1
Reactant: O=C(COc1ccccc1)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CO)CS[C@H]12
Product: N#Cc1ccc(OCC2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)C(NC(=O)COc4ccccc4)[C@H]3SC2)cc1

Procedure:
The procedure described in Example 1(a) was repeated, but using 2.00 g of diphenylmethyl 3-hydroxymethyl-7-phenoxyacetamido-3-cephem-4-carboxylate and p-cyanophenol, to afford 270 mg of the title compound as a powder.
Reaction SMILES: Cl.Cl.[F:3][C:4]1[CH:12]=[C:11]2[C:7]([CH2:8][CH2:9][CH:10]2[NH:13][C:14]2[C:19]([NH2:20])=[CH:18][CH:17]=[C:16]([NH:21][C:22]3[NH:23][N:24]=[C:25]([CH3:27])[CH:26]=3)[N:15]=2)=[CH:6][CH:5]=1.[CH:28](OC)(OC)OC>C(O)(=O)C>[F:3][C:4]1[CH:12]=[C:11]2[C:7]([CH2:8][CH2:9][C@H:10]2[N:13]2[C:14]3=[N:15][C:16]([NH:21][C:22]4[NH:23][N:24]=[C:25]([CH3:27])[CH:26]=4)=[CH:17][CH:18]=[C:19]3[N:20]=[CH:28]2)=[CH:6][CH:5]=1
Reactant: Cc1cc(Nc2ccc(N)c(NC3CCc4ccc(F)cc43)n2)[nH]n1
Reactant: COC(OC)OC
Agent: Cl
Solvent: CC(=O)O
Product: Cc1cc(Nc2ccc3ncn([C@@H]4CCc5ccc(F)cc54)c3n2)[nH]n1
Reaction time: 0.5 h
Yield: 19 %

Procedure:
Dissolve N2-(6-fluoroindan-1-yl)-N6-(5-methyl-2H-pyrazol-3-yl)-pyridine-2,3,6-triamine dihydrochloride in acetic acid (5 mL) and trimethyl orthoformate (0.68 mL, 6.20 mmol). Stir under nitrogen for 30 minutes. Concentrate in vacuo and purify by reverse phase chromatography, eluting with a gradient of 0.03% aqueous hydrochloric acid in acetonitrile to give the racemate of the title compound (0.124 g, 19%, 2 steps). MS (ES) m/z=349 [M+1]. Separate the racemate with chiral chromatography conditions to give the title compound: (70 mg, 11%. Enantiomer 1 (first eluent at 3.7 min)>99% ee, 100% MeOH, 0.2% DMEA, 1.0 mL/min, 4.6×150 mm, CHIRALPAK® AD-H).
Reaction SMILES: [OH:1][CH2:2][C:3]1([CH3:49])[CH2:11][C:10]2[N:9](COCC[Si](C)(C)C)[N:8]=[C:7]([C:20]3[N:21](COCC[Si](C)(C)C)[C:22]4[C:27]([CH:28]=3)=[CH:26][CH:25]=[C:24]([N:29]([CH3:40])[C:30](=[O:39])[CH2:31][N:32]3[CH2:37][CH2:36][CH2:35][CH2:34][C:33]3=[O:38])[CH:23]=4)[C:6]=2[CH2:5][CH2:4]1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>CN(C)C=O>[OH:1][CH2:2][C:3]1([CH3:49])[CH2:11][C:10]2[NH:9][N:8]=[C:7]([C:20]3[NH:21][C:22]4[C:27]([CH:28]=3)=[CH:26][CH:25]=[C:24]([N:29]([CH3:40])[C:30](=[O:39])[CH2:31][N:32]3[CH2:37][CH2:36][CH2:35][CH2:34][C:33]3=[O:38])[CH:23]=4)[C:6]=2[CH2:5][CH2:4]1
Reactant: CN(C(=O)CN1CCCCC1=O)c1ccc2cc(-c3nn(COCC[Si](C)(C)C)c4c3CCC(C)(CO)C4)n(COCC[Si](C)(C)C)c2c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CN(C)C=O
Product: CN(C(=O)CN1CCCCC1=O)c1ccc2cc(-c3n[nH]c4c3CCC(C)(CO)C4)[nH]c2c1
Temperature: 80 °C
Yield: 13.6 %

Procedure:
A solution of N-(2-{6-hydroxymethyl-6-methyl-1-[2-(trimethylsilyl)ethoxymethyl]-4,5,6,7-tetrahydro-1H-indazol-3-yl}-1-[2-(trimethylsilyl)ethoxymethyl]-1H-indol-6-yl)-N-methyl-2-(2-oxopiperidin-1-yl)acetamide (63 mg, 0.09 mmol) in N,N-dimethylformamide (1.5 ml) was added to tetrabutylammonium fluoride (0.6 ml, 0.6 mmol) concentrated in advance under reduced pressure. Ethylenediamine (0.2 ml) was added, and the mixture was stirred with heating at 80° C. overnight. After cooling, water and ethyl acetate were added, and the organic layer was separated. Then, the organic layer was washed successively with water and saturated brine, and dried over sodium sulfate. Sodium sulfate was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by thin layer silica gel chromatography to give the title compound (5.5 mg, yield 16%).
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:14]=[C:13]2[C:8]([CH2:9][CH2:10][NH:11][CH2:12]2)=[CH:7][CH:6]=1)([O-:4])=[O:3].C(=O)([O-])O.[Na+].Br[CH:21]([CH3:27])[C:22]([O:24][CH2:25][CH3:26])=[O:23].[I-].[K+]>C(O)C>[CH2:25]([O:24][C:22]([CH2:21][CH2:27][N:11]1[CH2:10][CH2:9][C:8]2[C:13](=[CH:14][C:5]([N+:2]([O-:4])=[O:3])=[CH:6][CH:7]=2)[CH2:12]1)=[O:23])[CH3:26]
Reactant: CCOC(=O)C(C)Br
Reactant: O=[N+]([O-])c1ccc2c(c1)CNCC2
Agent: Cl
Agent: O=C([O-])O
Agent: [I-]
Solvent: CCO
Product: CCOC(=O)CCN1CCc2ccc([N+](=O)[O-])cc2C1
Reaction time: 8 h
Yield: 56.6 %

Procedure:
1.5 g of 7-nitro-1,2,3,4-tetrahydroisoquinoline hydrochloride was dissolved in 20 ml of ethanol, and 2.9 g of sodium hydrogencarbonate, 2.3 g of ethyl bromopropionate, and a catalytic amount of potassium iodide were added to the solution. The resulting solution was heated and stirred overnight under reflux. The resulting solution was extracted with ethyl acetate, washed with water and saturated aqueous solution of sodium chloride, and then dried with anhydrous sodium sulfate. After separating the desiccant by filtration, the product was purified by silica gel column chromatography to obtain 1.1 g of 2-(2-(ethoxycarbonyl)ethyl)-7-nitro-1,2,3,4-tetrahydroisoquinoline (yield: 57%, oily product).
Reaction SMILES: O[CH2:2][C:3]#[N:4].[CH:5]([NH:8][CH:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1)([CH3:7])[CH3:6]>O.C(O)C>[CH:9]1([N:8]([CH2:2][C:3]#[N:4])[CH:5]([CH3:7])[CH3:6])[CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: CC(C)NC1CCCC1
Reactant: N#CCO
Solvent: O
Solvent: CCO
Product: CC(C)N(CC#N)C1CCCC1

Procedure:
Hydroxyacetonitrile (8.2 ml of a 70% w/w solution in water, 0.1 mol) was added to a solution of N-isopropylcyclopentanamine (11.43 g, 0.09 mol) (Preparation 47) in ethanol (60 ml). The reaction mixture was heated under reflux for 3 hours, allowed to cool and evaporated under reduced pressure. The residue was purified by chromatography on silica gel eluting with dichloromethane:methanol (98:2, by volume) to give the title compound (14.1 g) as a clear oil.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[CH2:5]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[Br:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][C:25](Cl)=[O:26])=[CH:20][CH:19]=1>Cl>[Br:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][C:25]([C:14]2[CH:13]=[CH:12][C:11]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])=[CH:16][CH:15]=2)=[O:26])=[CH:20][CH:19]=1
Reactant: O=C(Cl)Cc1ccc(Br)cc1
Reactant: CCCCCCc1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: CCCCCCc1ccc(C(=O)Cc2ccc(Br)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 78.6 %

Procedure:
To a 2 L three-necked flask, set up with a mechanical stirring, containing AlCl3 (85.661 g; 642.42 mmol) under N2, 4-hexylbenzene (IVb) (104.25 g; 642.42 mmnol) was added in one portion at room temperature. To this resulting orange suspension (4-bromo-phenyl)-acetyl chloride (IIIa) (125.000 g; 535.35 mmol) was added drop wise during 45 minutes without cooling. Then reaction mixture was stirred for 3 h until temperature cooled down to room temperature, time when no more foaming was observed. The deep brown mixture was then stirred at room temperature overnight. The black thick solution was poured under stirring into a mixture of ice and 1N HCl (800 mL), then the resulting white-orange solid was filtered, and washed successively with water, saturated solution of NaHCO3 and finally with water until pH of the filtrate was 7. The solid was washed with heptane (3×200 mL) and dried under vacuum at room temperature to give the title compound as a white powder (m=151.15 g) in a 79% yield. Melting point: 108° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2[CH:14]=[C:13]([C:15]3[O:19][C:18]([CH3:20])=[N:17][CH:16]=3)[N:12]3[N:21]=[C:22]([NH2:24])[N:23]=[C:11]3[CH:10]=2)=[CH:5][CH:4]=1.[CH2:25]([N:27]=[C:28]=[O:29])[CH3:26].[Sn](OC(C)=O)(OC(C)=O)(CCCC)CCCC.CO.C(Cl)(Cl)Cl>O1CCOCC1.CO.C(Cl)Cl>[CH2:25]([NH:27][C:28]([NH:24][C:22]1[N:23]=[C:11]2[CH:10]=[C:9]([C:6]3[CH:7]=[N:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[CH:14]=[C:13]([C:15]3[O:19][C:18]([CH3:20])=[N:17][CH:16]=3)[N:12]2[N:21]=1)=[O:29])[CH3:26]
Reactant: CCN=C=O
Reactant: COc1ccc(-c2cc(-c3cnc(C)o3)n3nc(N)nc3c2)cn1
Agent: CCCC[Sn](CCCC)(OC(C)=O)OC(C)=O
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: ClC(Cl)Cl
Product: CCNC(=O)Nc1nc2cc(-c3ccc(OC)nc3)cc(-c3cnc(C)o3)n2n1

Procedure:
A mixture of the product of Step 1 (0.14 g, 0.43 mmol), EtNCO (0.15 g, 2.2 mmol) and SnBu2(OAc)2 in dioxane (4 mL) was microwaved at 125° C. for 1 h. The resulting solid was collected by filtration and recrystallized from DMF to give the target compound. Pre-adsorption of a MeOH/CHCl3 solution of this compound onto SiO2 and column chromatography (5% MeOH/DCM) gave the title compound as a solid. MS m/z 394 (M+H+).
Reaction SMILES: C([N:5](CCCC)CCCC)CCC.[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]=[C:23]=[O:24])=[CH:18][CH:17]=1.C(O)(C)C.C([O-])(=O)C.[NH4+]>O.CO.CN(C=O)C>[CH3:14][O:15][C:16]1[CH:17]=[CH:18][C:19]([NH:22][C:23]([NH2:5])=[O:24])=[CH:20][CH:21]=1
Reactant: COc1ccc(N=C=O)cc1
Reactant: CCCCN(CCCC)CCCC
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(C)O
Solvent: O
Solvent: CO
Product: COc1ccc(NC(N)=O)cc1
Yield: 55 %

Procedure:
P1-(cytidine 5′-)tetraphosphate, ditributylammonium salt (50 mg, 0.043 mmol: prepared from the tetraammonium salt by treatment with Dowex 50W×4 H+ in water, followed by mixing the protonated species with an excess of tributylamine in methanol, stripping and lyophilization) was dissolved in dry DMF (1 mL) and tributylamine (10 uL, 0.43 mmol), and p-methoxyphenylisocyanate 8.4 uL, 0.648 mmol) were added in a single portion. The homogeneous reaction mixture was heated overnight at 35° C., whereupon TLC (silica gel, 50% isopropanol/50% ammonium hydroxide) and HPLC (C18) indicated a substantial conversion to a single product. The solvent was removed on a rotary evaporator and the residue dissolved in water (1 mL). The product was isolated by repeated injections onto a semi-preparative HPLC column (Alltech Nucleotide/Nucleoside C18, 7 um, 10 X 250 mm, gradient from 0.1 M ammonium acetate to methanol over 30 minutes, 5 mL/min, monitor at 260 nm). Stripping and lyophilization gave the p-methoxyphenylurea (b 24 mg, 55% yield), as the tetraammonium salt.
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6]([C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]([C:17]2[CH:18]=[N:19][C:20]3[C:25]([CH:26]=2)=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:9]=1)=[O:7]>O1CCCC1.O>[C:6]([C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]([C:17]2[CH:18]=[N:19][C:20]3[C:25]([CH:26]=2)=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:9]=1)([OH:7])=[O:5]
Reactant: COC(=O)c1cn(-c2cnc3ccccc3c2)c2ccccc12
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cn(-c2cnc3ccccc3c2)c2ccccc12
Reaction time: 18 h
Yield: 150.2 %

Procedure:
0.291 g (6.93 mmol) of lithium hydroxide monohydrate and 30 cm3 of water are added at a temperature in the region of 22° C. to 0.7 g (2.31 mmol) of 3-methoxycarbonyl-1-(quinol-3-yl)-1H-indole dissolved in 30 cm3 of tetrahydrofuran. After stirring at the reflux point of the solvent for 18 hours, the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa) to give a residue which is taken up in 15 cm3 of water and then triturated with 7 cm3 of N hydrochloric acid. After filtering off and drying the solid residue under reduced pressure (2.7 kPa) at 40° C., 1 g of 3-carboxy-1-(quinol-3-yl)-1H-indole is obtained in the form of a pale yellow solid. Mass spectrum (EI): m/e 288 (M+·).
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH:4]([O:7][CH2:8][CH3:9])[NH:3]1.C([Li])CCC.[CH:15]([S:23](Cl)(=[O:25])=[O:24])=[CH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>O1CCCC1>[CH:15]([S:23]([N:3]1[CH:4]([O:7][CH2:8][CH3:9])[CH2:5][CH2:6][C:2]1=[O:1])(=[O:25])=[O:24])=[CH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CCOC1CCC(=O)N1
Reactant: O=S(=O)(Cl)C=Cc1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC1CCC(=O)N1S(=O)(=O)C=Cc1ccccc1
Temperature: -5 °C
Reaction time: 4 h
Yield: 22 %

Procedure:
2.6 g of 2-oxo-5-ethoxy pyrrolidine is dissolved in 80 cm3 of anhydrous tetrahydrofuran, then cooled to -5° C., and 12.6 cm3 of butyllithium is added. After 20 minutes under agitation, there is added slowly at the same temperature, 4.05 g of styrene-sulphonyl chloride (CA 47, 3262c (1953)) in 10 cm3 of tetrahydrofuran. After allowing this to return to ambient temperature, after 4 hours, it is concentrated to dryness and the residue is chromatographed on silica. 1.3 g of the expected product is obtained, which is crystallized from a mixture of ethyl ether and hexane. m.p.=61°-63° C.
Reaction SMILES: Cl.[C:2]1([CH:8]([O:15][C:16]([C:18]2[N:23]3[C:24](=[O:27])[C@@H:25]([NH2:26])[C@H:22]3[S:21][CH2:20][C:19]=2[O:28][S:29]([CH3:32])(=[O:31])=[O:30])=[O:17])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:33]([O:37][C:38]([NH:40][C:41]1[S:42][CH:43]=[C:44](/[C:46](=[N:50]/[O:51][CH:52]2[CH2:56][CH2:55][CH2:54][CH2:53]2)/[C:47](O)=[O:48])[N:45]=1)=[O:39])([CH3:36])([CH3:35])[CH3:34].CN1CCOCC1.P(Cl)(Cl)(OC1C=CC=CC=1)=O.Cl>ClCCl.O>[C:2]1([CH:8]([O:15][C:16]([C:18]2[N:23]3[C:24](=[O:27])[C@@H:25]([NH:26][C:47](=[O:48])/[C:46](/[C:44]4[N:45]=[C:41]([NH:40][C:38]([O:37][C:33]([CH3:35])([CH3:34])[CH3:36])=[O:39])[S:42][CH:43]=4)=[N:50]\[O:51][CH:52]4[CH2:56][CH2:55][CH2:54][CH2:53]4)[C@H:22]3[S:21][CH2:20][C:19]=2[O:28][S:29]([CH3:32])(=[O:31])=[O:30])=[O:17])[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)OC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](N)[C@H]2SC1
Reactant: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC2CCCC2)C(=O)O)cs1
Agent: Cl
Agent: O=P(Cl)(Cl)Oc1ccccc1
Solvent: CN1CCOCC1
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC2CCCC2)C(=O)N[C@@H]2C(=O)N3C(C(=O)OC(c4ccccc4)c4ccccc4)=C(OS(C)(=O)=O)CS[C@H]23)cs1
Reaction time: 0.02 h
Yield: 77.7 %

Procedure:
To a suspension of 7β-amino-3-methanesulfonyloxy-3-cephem-4-carboxylic acid diphenylmethyl ester hydrochloride (1.49 g: 3 mMol.) and (Z)-2-(2-t-butoxycarbonylaminothiazol-4-yl)-2-cyclopentyloxyimino-acetic acid (1.23 g: 3.5 mMol.) in dichloromethane (30 ml) at -30° C. are added N-methylmorpholine (1.1 ml: 10 mMol.) and, after 1 minute, phenyl dichlorophosphate (0.49 ml: 3.3 mMol.), and the mixture is stirred at the same temperature for 2 hours. The reaction mixture is mixed with 1N-hydrochloric acid (6 ml) and water (50 ml) and extracted with ethyl acetate. The extract is washed with water, 5% aqueous sodium hydrogen carbonate, and water, dried over sodium sulfate, and purified by silica gel chromatography (toluene: ethyl acetate=5:1, containing 0.5% acetic acid) to give 7β-[(Z)-2-(2-t-butoxycarbonylaminothiazol-4-yl)-2-cyclopentyloxyiminoacetamido]-3-methanesulfonyloxy-3-cephem-4-carboxylic acid diphenylmethyl ester (1.86 g) as white foam. Yield: 78%.