Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:21](=[O:22])[C:12]3=[CH:13][NH:14][C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][C:20]=4[C:11]3=[N:10]2)=[CH:5][CH:4]=1)#[N:2].[OH-:23].[Na+].OO>C(O)C>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:21](=[O:22])[C:12]3=[CH:13][NH:14][C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][C:20]=4[C:11]3=[N:10]2)=[CH:5][CH:4]=1)(=[O:23])[NH2:2]
Reactant: [OH-]
Reactant: N#Cc1ccc(-n2nc3c4ccccc4[nH]cc-3c2=O)cc1
Agent: OO
Agent: [Na+]
Solvent: CCO
Product: NC(=O)c1ccc(-n2nc3c4ccccc4[nH]cc-3c2=O)cc1
Temperature: 25 °C

Procedure:
One gram of 2-(p-cyanophenyl)-pyrazolo[4,3-c]quinolin-3(5H)-one, 3.50 ml of 1 N aqueous sodium hydroxide and 10 ml of ethanol are mixed and stirred at room temperature until the solid has dissolved. The solution is then treated with 1.4 ml of 30% hydrogen peroxide, giving an immediate precipitate. After stirring for 2 hours at room temperature, the mixture is filtered, and the solid is crystallized from dimethylformamide, to yield the 2-(p-carbamoylphenyl)-pyrazolo [4,3-c]quinolin-3(5H)-one, showing peaks in the IR-spectrum at 885, 853, 830, 785, 775, 752 and 732 cm-1.
Reaction SMILES: [H-].[Na+].Cl.[CH:4]([NH2:6])=[NH:5].[F:7][C:8]1[CH:9]=[C:10]([C:15](=[O:38])[C:16](=[C:29]2[NH:33][C:32]3[CH:34]=[CH:35][CH:36]=[CH:37][C:31]=3[NH:30]2)[C:17]([C:19]2[CH:20]=[C:21]([S:25](Cl)(=[O:27])=[O:26])[CH:22]=[CH:23][CH:24]=2)=[O:18])[CH:11]=[C:12]([F:14])[CH:13]=1.[Cl-].[NH4+]>CN(C=O)C>[F:7][C:8]1[CH:9]=[C:10]([C:15](=[O:38])[C:16](=[C:29]2[NH:30][C:31]3[CH:37]=[CH:36][CH:35]=[CH:34][C:32]=3[NH:33]2)[C:17]([C:19]2[CH:20]=[C:21]([S:25]([NH:5][CH:4]=[NH:6])(=[O:26])=[O:27])[CH:22]=[CH:23][CH:24]=2)=[O:18])[CH:11]=[C:12]([F:14])[CH:13]=1
Reactant: N=CN
Reactant: O=C(C(C(=O)c1cccc(S(=O)(=O)Cl)c1)=C1Nc2ccccc2N1)c1cc(F)cc(F)c1
Agent: Cl
Agent: [Cl-]
Agent: [H-]
Solvent: CN(C)C=O
Product: N=CNS(=O)(=O)c1cccc(C(=O)C(C(=O)c2cc(F)cc(F)c2)=C2Nc3ccccc3N2)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
60% Sodium hydride (809 mg) was added to a DMF (30 mL) solution of formamidine hydrochloride (1.92 g), followed by stirring at room temperature for 15 minutes. A DMF (10 mL) solution of 3-[3-(3,5-difluorophenyl)-2-(1,3-dihydro-2H-benzimidazol-2-ylidene)-3-oxopropanoyl]benzenesulfonyl chloride (hereinafter referred to as starting compound A, 1.13 g) was added, followed by stirring at room temperature for 1.5 hours. The reaction mixture was poured into an excess amount of aqueous ammonium chloride solution, followed by extraction with ethyl acetate. The organic layer was washed with water, concentrated under reduced pressure, purified by silica gel column chromatography (chloroform/methanol=10/1), and crystallized from diethyl ether/n-hexane to obtain 3-[3-(3,5-difluorophenyl)-2-(1,3-dihydro-2H-benzimidazol-2-ylidene)-3-oxopropanoyl]-N-(iminomethyl)benzenesulfonamide (81 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:5]([OH:7])=[O:6].S(=O)(=O)(O)O.[CH2:19](O)[CH3:20]>>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:5]([O:7][CH2:19][CH3:20])=[O:6]
Reactant: O=C(O)c1ccc([N+](=O)[O-])c(F)c1
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1ccc([N+](=O)[O-])c(F)c1
Reaction time: 16 h

Procedure:
To the liquid mixture of 3-fluoro-4-nitrobenzoic acid 9.71 g and ethanol 35 mL, cone. sulfuric acid 1.6 mL was added, followed by 16 hours' heating under reflux. After distilling the solvent off, water and tert-butyl methyl ether were added to the residue. The organic layer was extracted, washed with water and dried over magnesium sulfate. Distilling the solvent off, 7.40 g of the title compound was obtained.
Reaction SMILES: C[O-].[Na+].C([O:7][C:8]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[C:13]2[C:9]=1[CH:10]=[C:11]([C:28]([O:30][CH3:31])=[O:29])[N:12]2[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=1)(=O)C>CO>[Cl:27][C:22]1[CH:21]=[C:20]([CH:25]=[CH:24][C:23]=1[Cl:26])[CH2:19][N:12]1[C:13]2[C:9](=[C:8]([OH:7])[C:16]([O:17][CH3:18])=[CH:15][CH:14]=2)[CH:10]=[C:11]1[C:28]([O:30][CH3:31])=[O:29]
Reactant: COC(=O)c1cc2c(OC(C)=O)c(OC)ccc2n1Cc1ccc(Cl)c(Cl)c1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cc2c(O)c(OC)ccc2n1Cc1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.8 %

Procedure:
Sodium methoxide (0.27 g) was added to a stirred solution of methyl 4-acetoxy-N-(3,4-dichlorobenzyl)-5-methoxyindole-2-carboxylate (1.05 g) in methanol (15 ml) under an atmosphere of argon. The reaction was stirred at room temperature for 2 hours, then concentrated in vacuo and the residue partitioned between ethyl acetate and water. Combined organic extracts were washed with water, saturated aqueous sodium chloride solution and dried (MgSO4). The solvent was removed in vacuo and the residue purified by column chromatography using 45% diethyl ether: iso-hexane as eluent to give product as a white solid (0.83 g, 94%); NMR d (CD3SOCD3) 3.75 (s, 3H), 3.80 (s, 3H), 5.72 (s, 2H), 6.87-6.94 (m, 2H), 7.09 (d, 1H), 7.30 (s, 1H), 7.40 (s, 1H), 7.50 (d, 1H), 9.38 (s, 1H); M/z (+) 380 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[C:6]([OH:8])=O.[NH2:14][CH:15]1[CH2:22][CH2:21][CH2:20][NH:19][C:17](=[O:18])[CH2:16]1>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[C:6]([NH:14][CH:15]1[CH2:22][CH2:21][CH2:20][NH:19][C:17](=[O:18])[CH2:16]1)=[O:8]
Reactant: COc1ccc(C(=O)O)cc1OC
Reactant: NC1CCCNC(=O)C1
Solvent: C1CCOC1
Product: COc1ccc(C(=O)NC2CCCNC(=O)C2)cc1OC
Reaction time: 0.5 h
Yield: 53 %

Procedure:
N,N'-Carbonyldiimidazole (9.79 g) was added to a solution of 3,4-dimethoxybenzoic acid (10.0 g) in THF (300 ml) and the whole was stirred for 30 mins. at room temperature. Then, following by addition of 3-amino-ε-caprolactam (7.04 g), the mixture was stirred for 5 hrs. The resultant precipitate was collected by filtration, washed and dried under reduced pressure to give the title compound (8.5 g). This product was used in the following reaction without purification. m.p. 190°-191°.
Reaction SMILES: C(=O)(OC(Cl)(Cl)Cl)[O:2][C:3](Cl)(Cl)[Cl:4].N1C=CC=CC=1.[O:19]1[CH2:24][CH2:23][CH:22]([OH:25])[CH2:21][CH2:20]1>O1CCCC1>[C:3]([Cl:4])(=[O:2])[O:25][CH:22]1[CH2:23][CH2:24][O:19][CH2:20][CH2:21]1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: OC1CCOCC1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: O=C(Cl)OC1CCOCC1
Reaction time: 0.17 h
Yield: 92.9 %

Procedure:
To a solution of bis(trichloromethyl) carbonate (2.97 g) in tetrahydrofuran (40 mL) was added dropwise a solution of pyridine (2.43 mL) in tetrahydrofuran (10 mL) under ice-cooling. The solution was stirred for 10 minutes under ice-cooling, and a solution of tetrahydropyran-4-ol (1.91 g) in tetrahydrofuran (20 mL) was slowly added dropwise. After stirring at room temperature for 2 hrs, the solution was concentrated under reduced pressure, and to the residue were added ethyl acetate (50 mL) and water (50 mL). The ethyl acetate layer was separated, and washed with 0.2 N hydrochloric acid (20 mL), and saturated saline (50 m), followed by drying over anhydrous magnesium sulfate. The solution was concentrated under reduced pressure to give tetrahydropyran-4-yl chlorocarbonate (1.53 g). To a mixture of tert-butyl 2-hydroxyethyl(methyl)carbamate (1.40 g) obtained in Reference Synthetic Example 1 and tetrahydrofuran (20 mL) was added pyridine (0.78 mL), and a solution of tetrahydropyran-4-yl chlorocarbonate (1.53 g) obtained above in tetrahydrofuran (10 mL) was added dropwise thereto, followed by stirring at room temperature overnight. The reaction solution was concentrated under reduced pressure, and to the residue was added water (50 mL), and extracted with ethyl acetate (50 mL). The extract was washed with 5% aqueous solution of citric acid (50 mL), and saturated saline (50 mL), and dried over anhydrous magnesium sulfate. The solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elute with ethyl acetate hexane=4:1, then 3:2). The obtained colorless oil (2.03 g) was dissolved in diethyl ether (2 mL), and added 4N hydrogen chloride-ethyl acetate solution (5 mL). After stirring at room temperature for 30 minutes, diethyl ether (10 mL) was added, followed by stirring overnight. The depositting solid was collected by filtration, and dried under reduced pressure to give title compound as white solid (1.20 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH2:9])[CH:6]=[CH:7][CH:8]=1.Cl.[Cl:11][CH2:12][CH2:13][NH:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[ClH:11].[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:9][CH2:12][CH2:13][NH:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: ClCCNCc1ccccc1
Reactant: COc1cccc(N)c1
Agent: Cl
Product: COc1cccc(NCCNCc2ccccc2)c1

Procedure:
Combine 3-methoxybenzenamine (81.2 g, 0.66 mol) with N-(2-chloroethyl)-benzenemethanamine hydrochloride (45.3 g, 0.22 mol) and heat to 190° C. for 13 h. Add methylene chloride to precipitate a solid. Filter the solid and wash with methylene chloride. Triturate the solid with 100 mL of ethanol, filter the solid and wash with ethanol to give the title compound.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:36])=[C:9]([CH2:11][O:12][C:13]2[CH:33]=[CH:32][C:16]([CH2:17][O:18][C:19]3[C:23]([CH:24]=O)=[CH:22][N:21]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[N:20]=3)=[CH:15][C:14]=2[O:34][CH3:35])[N:10]=1.N1CCNCC1.[C:43](#[N:47])[CH2:44][C:45]#[N:46].C(O)(=O)C1C=CC=CC=1>C(OCC)(=O)C.O.C1(C)C=CC=CC=1>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:36])=[C:9]([CH2:11][O:12][C:13]2[CH:33]=[CH:32][C:16]([CH2:17][O:18][C:19]3[C:23]([CH:24]=[C:44]([C:43]#[N:47])[C:45]#[N:46])=[CH:22][N:21]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[N:20]=3)=[CH:15][C:14]=2[O:34][CH3:35])[N:10]=1
Reactant: N#CCC#N
Reactant: COc1cc(COc2nn(-c3ccccc3)cc2C=O)ccc1OCc1nc(-c2ccco2)oc1C
Agent: C1CNCCN1
Agent: O=C(O)c1ccccc1
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Product: COc1cc(COc2nn(-c3ccccc3)cc2C=C(C#N)C#N)ccc1OCc1nc(-c2ccco2)oc1C
Yield: 79.6 %

Procedure:
A mixture of 3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1-phenyl-1H-pyrazole-4-carbaldehyde (0.40 g), piperazine (0.02 g), malononitrile (0.065 g), benzoic acid (0.020 g) and toluene (30 mL) was heated under reflux for 2 hrs with azeotropic removal of water. Ethyl acetate was added to the reaction mixture. The ethyl acetate layer was washed successively with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give ({3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1-phenyl-1H-pyrazol-4-yl)methylene) malononitrile as yellow crystals (0.35 g, yield 80%) from a fraction eluted with ethyl acetate-hexane (1:2, v/v). Recrystallization from ethyl acetate-hexane gave yellow prism crystals. melting point: 190-191° C.
Reaction SMILES: [O:1]1[C:5]([C:6]2[CH:29]=[CH:28][C:9]3[N:10]([C:13]4[CH:14]=[C:15]([NH:24]C(=O)C)[CH:16]=[C:17]([N:19]5[CH:23]=[CH:22][CH:21]=[CH:20]5)[CH:18]=4)[CH:11]=[N:12][C:8]=3[CH:7]=2)=[CH:4][N:3]=[CH:2]1.[CH:30]1([S:33](Cl)(=[O:35])=[O:34])[CH2:32][CH2:31]1>>[O:1]1[C:5]([C:6]2[CH:29]=[CH:28][C:9]3[N:10]([C:13]4[CH:14]=[C:15]([NH:24][S:33]([CH:30]5[CH2:32][CH2:31]5)(=[O:35])=[O:34])[CH:16]=[C:17]([N:19]5[CH:20]=[CH:21][CH:22]=[CH:23]5)[CH:18]=4)[CH:11]=[N:12][C:8]=3[CH:7]=2)=[CH:4][N:3]=[CH:2]1
Reactant: CC(=O)Nc1cc(-n2cccc2)cc(-n2cnc3cc(-c4cnco4)ccc32)c1
Reactant: O=S(=O)(Cl)C1CC1
Product: O=S(=O)(Nc1cc(-n2cccc2)cc(-n2cnc3cc(-c4cnco4)ccc32)c1)C1CC1

Procedure:
The compound was prepared from the compound of Example 106 using the procedures of Example 107 and cyclopropane sulfonyl chloride. 1H NMR (300 MHz, DMSO-d6): δ 10.35 (s, 1H), 8.87 (s, 1H), 8.52 (s, 1H), 8.22 (s, 1H), 7.82 (d, 3H), 7.74-7.35 (m, 1H), 7.5-7.45 (m, 4H), 6.39 (t, 2H), 3.04-2.95 (m, 1H), 1.08-1.07 (m, 4H); LC-MS (ESI): Calculated mass: 445.49; Observed mass: 446.1 [M+H]+ (rt: 1.43 min).
Reaction SMILES: [C:1]([CH:5]1[CH2:7][O:6]1)([CH3:4])([CH3:3])[CH3:2].[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1.[OH-].[Na+]>O>[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:7][CH:5]([OH:6])[C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:11][CH:10]=1
Reactant: Oc1ccc(Cl)cc1
Reactant: CC(C)(C)C1CO1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)(C)C(O)COc1ccc(Cl)cc1
Temperature: 60 °C
Reaction time: 24 h
Yield: 51.6 %

Procedure:
5 g (0.05 mole) of tert.-butyloxirane were added to 12.8 g (0.1 mole) of 4-chlorophenol and 4 g of sodium hydroxide in 20 ml of water. The reaction mixture was stirred at 60° C. for 24 hours and then diluted with about 100 ml of water. It was extracted three times with 50 ml of methylene chloride each time. The combined organic phases were washed with dilute aqueous sodium hydroxide solution for the purpose of removing unreacted phenol, and were dried over sodium sulpnate and concentrated. The residue was distilled in vacuo. 5.9 g (52% of theory) of 1-(4-chlorophenoxy)-3,3-dimethyl-butan-2-ol of boiling point 105° C./0.5 mm Hg were obtained.
Reaction SMILES: [O:1]=[C:2]1[C:22]2[C:9]3[CH2:10][CH2:11][C:12]4[CH:18]=[CH:17][C:16]([C:19]([OH:21])=[O:20])=[CH:15][C:13]=4[S:14][C:8]=3[CH:7]=[CH:6][C:5]=2[CH2:4][CH2:3]1.O=C1C2C3SC4=CCCC=C4C=C(C(O)=O)C=3C=CC=2CC1>>[OH:1][CH:2]1[C:22]2[C:9]3[CH2:10][CH2:11][C:12]4[CH:18]=[CH:17][C:16]([C:19]([OH:21])=[O:20])=[CH:15][C:13]=4[S:14][C:8]=3[CH:7]=[CH:6][C:5]=2[CH2:4][CH2:3]1
Reactant: O=C(O)c1ccc2c(c1)Sc1ccc3c(c1CC2)C(=O)CC3
Agent: O=C(O)C1=CC2=CCCC=C2Sc2c1ccc1c2C(=O)CC1
Product: O=C(O)c1ccc2c(c1)Sc1ccc3c(c1CC2)C(O)CC3

Procedure:
Substituting an equivalent amount of 1-oxo-2,3,11,12-tetrahydro-1H-benzo[b]indeno[4,5-f]-thiepin-8-carboxylic acid in Example 32 for 1-oxo-2,3,9,10-tetrahydro-1H-benzo[b]indeno[5,4-f]thiepin-6-carboxylic acid provided the title compound.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([O:11][CH2:12][CH2:13][C:14]([F:17])([F:16])[F:15])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.Cl.[NH2:19][CH:20]([CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][C:32]([F:35])([F:34])[F:33])=[CH:27][CH:26]=1)[C:21]([OH:23])=[O:22]>>[F:1][C:2]1[CH:10]=[C:9]([O:11][CH2:12][CH2:13][C:14]([F:17])([F:16])[F:15])[CH:8]=[CH:7][C:3]=1[C:4]([NH:19][CH:20]([CH2:24][C:25]1[CH:26]=[CH:27][C:28]([O:31][C:32]([F:33])([F:34])[F:35])=[CH:29][CH:30]=1)[C:21]([OH:23])=[O:22])=[O:6]
Reactant: O=C(O)c1ccc(OCCC(F)(F)F)cc1F
Reactant: NC(Cc1ccc(OC(F)(F)F)cc1)C(=O)O
Agent: Cl
Product: O=C(NC(Cc1ccc(OC(F)(F)F)cc1)C(=O)O)c1ccc(OCCC(F)(F)F)cc1F
Yield: 93.7 %

Procedure:
A reaction similar to that described in Example 70 (70a) was conducted using 2-fluoro-4-(3,3,3-trifluoropropoxy)benzoic acid (177 mg) prepared in Example 84 (84a) and 2-amino-3-[4-(trifluoromethoxy)phenyl]propanoic acid hydrochloride (200 mg) prepared in Reference Example 2 to give 317 mg of the title compound (white powder).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][NH:4][C:3]1=[O:7].[CH2:8]=[O:9].[OH-].[Na+].CO>CC(C)=O>[CH3:1][N:2]1[CH:6]=[CH:5][N:4]([CH2:8][OH:9])[C:3]1=[O:7]
Reactant: C=O
Reactant: Cn1cc[nH]c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CC(C)=O
Product: Cn1ccn(CO)c1=O
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A mixture of 1-methyl-4-imidazolin-2-one (4 gms, 0.04 mol), 20 ml of formaldehyde (37% aqueous solution), sodium hydroxide (100 mg), and 20 ml of methanol was stirred at room temperature for 20 hours. After removing the solvent using a rotovap at reduced pressure, a liquid residue was obtained and filtered through a column of silica gel using chloroform as the eluent. The residue solidified after left standing overnight and was dissolved in water and then extracted with chloroform. The aqueous phase was concentrated and chromatographed through a column of silica gel G 60. Removal of the solvent afforded a solid which upon addition of acetone became white suspension. The solid was washed twice with acetone and air-dried (1.0 gm, 22%) and sublimed at reduced pressure, m.p. 101.5°-103.5° C. Found: C, 46.70; H, 6.18: N, 21.80. Calc. for C5H8N2O2 : C, 46.87; H, 6.29; N, 21.86%. 1H n.m.r.(CDCl3 ): δ3.15(3H, s, CH3N--); 5.02(2H, s, broad, N-CH2OH); 5.8(1H, s, broad, OH); 6.1 (1H, d, J=3 Hz, HC-CH); 6.3(1H, d, J=3 Hz, HC=CH). νmax (KBr): 3220(OH, broad); 3120, 3100(HC=CH); 1655 cm-1 (C=O). m/e 128, C5H8N2O2 requires 128.
Reaction SMILES: [CH2:1]([O:15][C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][C:24]=1[O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[C:19](O)=[O:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].C(Cl)(=O)C([Cl:43])=O>C(Cl)Cl.CN(C)C=O>[CH2:1]([O:15][C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][C:24]=1[O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[C:19]([Cl:43])=[O:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCCCCCCCCCCOc1ccc(C(=O)O)cc1OCCCCCCCCCCCCCC
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCCCCCCCCCCCCCOc1ccc(C(=O)Cl)cc1OCCCCCCCCCCCCCC
Temperature: 25 °C
Reaction time: 60 h
Yield: 98.7 %

Procedure:
To a room temperature solution of 5.0 g of product from Example 104 in 80 ml of methylene chloride and 5 drops of dimethylformamide is added 1.74 g of oxalyl chloride. The reaction is stirred at room temperature for 2.5 days and concentrated in vacuo. The residue is dissolved in diethyl ether, passed through a pad of diatomaceous earth and concentrated in vacuo to give 5.1 g of the desired product as colorless crystals.
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[CH:16]([NH:18][C:19]1[S:20][CH:21]=[C:22]([C:24](=[N:40][O:41][CH3:42])[C:25]([NH:27][CH:28]2[C:38](=[O:39])[N:30]3[C:31]([C:35]([OH:37])=[O:36])=[CH:32][CH2:33][S:34][C@H:29]23)=[O:26])[N:23]=1)=[O:17].[C:43]([O:53][CH2:54][CH:55]([CH2:57][O:58][C:59](=[O:68])[CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH3:67])O)(=[O:52])[CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51].N1C=CC=CC=1>O1CCCC1>[CH:16]([NH:18][C:19]1[S:20][CH:21]=[C:22]([C:24](=[N:40][O:41][CH3:42])[C:25]([NH:27][CH:28]2[C:38](=[O:39])[N:30]3[C:31]([C:35]([O:37][CH:55]([CH2:54][O:53][C:43](=[O:52])[CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51])[CH2:57][O:58][C:59](=[O:68])[CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH3:67])=[O:36])=[CH:32][CH2:33][S:34][C@H:29]23)=[O:26])[N:23]=1)=[O:17]
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=CCS[C@H]12)c1csc(NC=O)n1
Reactant: CCCCCCCCC(=O)OCC(O)COC(=O)CCCCCCCC
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CCCCCCCCC(=O)OCC(COC(=O)CCCCCCCC)OC(=O)C1=CCS[C@@H]2C(NC(=O)C(=NOC)c3csc(NC=O)n3)C(=O)N12
Temperature: 0 °C
Reaction time: 4 h
Yield: 28.9 %

Procedure:
Dicyclohexylcarbodiimide (6.5 g) was added to a stirred solution of 7-[2-(2-formamidothiazol-4-yl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylic acid (syn isomer, 8.6 g) and 2-n-nonanoyloxy-1-n-nonanoyloxymethylethanol (7.8 g) in a mixture of dry pyridine (80 ml) and dry tetrahydrofuran (25 ml) at 3° C., and then stirred at 0° to 5° C. for 4 hours and allowed to stand at room temperature overnight. The resultant mixture was poured into ice water (450 ml) and extracted with ethyl acetate (450 ml). Water (50 ml) was added to the extract and adjusted to pH 2 to 3 with 20% sulfuric acid. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride (100 ml×2) and an aqueous solution of sodium bicarbonate in turn, and dried over anhydrous magnesium sulfate. After removing the solution in vacuo, the residue was subjected to column chromatography on silica gel (370 g) with a mixture of chloroform and acetone (5:1). The eluate was evaporated in vacuo to give powder (4.62 g) of 2-n-nonanoyloxy-1-n-nonanoyloxymethylethyl 7-[2-(2-formamidothiazol-4-yl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylate (syn isomer).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6](C(O)=O)=[C:5]2[OH:15].C1(OC2C=CC=CC=2)C=CC=CC=1>CO.C(OCC)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2[OH:15]
Reactant: O=C(O)c1cnc2ccc(Br)cc2c1O
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: CCOCC
Solvent: CO
Product: Oc1ccnc2ccc(Br)cc12
Temperature: 25 °C
Yield: 95.7 %

Procedure:
The solid 6-bromo-4-hydroxy-quinoline-3-carboxylic acid (102.59 g, 337.7 mmol) was added to hot diphenyl ether (508 g) and then the mixture was heated to reflux for 9 h to afford a light brown suspension. After cooling to room temperature, the mixture was diluted with methanol (20 mL) and diethyl ether (300 mL). Then, the solids were collected by filtration and washed with diethyl ether. After drying in air, 72.43 g (95% yield) of 6-bromo-quinolin-4-ol was isolated as a white solid: EI-HRMS m/e calcd for C9H6BrNO (M+) 222.9633, found 222.9630.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C@H:4]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=1)[NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].C([NH:39][C@@H:40]([C:48](O)=[O:49])[CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.N1CCCCC1>CN(C=O)C.O>[CH3:1][O:2][C:3](=[O:21])[C@H:4]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:48](=[O:49])[C@H:40]([NH2:39])[CH2:41][C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=2)=[CH:16][CH:15]=1)[NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:10])[CH3:11])=[O:7]
Reactant: COC(=O)[C@H](Cc1ccc(N)cc1)NC(=O)OC(C)(C)C
Reactant: O=C(N[C@H](Cc1ccccc1)C(=O)O)OCC1c2ccccc2-c2ccccc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: C1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@H](Cc1ccc(NC(=O)[C@H](N)Cc2ccccc2)cc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 17.6 %

Procedure:
To the solution of 4-amino-N-[(1,1-dimethylethoxy)carbonyl]-L-phenylalanine methyl ester (5.09 g, 17 mmol) in DMF (60 mL) was added Fmoc-D-Phenylalanine (8.70 g, 22.5 mmol), DIPEA (12 mL, 69 mmol) and HBTU (8.50 g, 22.5 mmol). The mixture was then stirred at room temperature for 4 h. The reaction mixture was diluted with water (150 mL) and the light yellow solid which precipitated was collected by filtration. This solid was then redissolved in 60 mL of acetone and the solution was treated with 100 mL of water. The solid was collected by filtration and was washed with 1N HCl, H2O. After drying at 60° C. under vaccum overnight, a light yellow solid was obtained (13.2 g). A portion of this solid (2.51 g, 3.78 mmol) was dissolved in 15 mL of DMF and to the solution was added 1.5 mL of piperidine. The above solution was stirred at room temperature for 45 min. After removal of the solvent, the residue was recrystillized from ethyl acetate-hexane to give N-[(1,1-dimethylethoxy)carbonyl]-4-[[(2R)-2-amino-1-oxo-3-phenylpropyl]amino]-L-phenylalanine methyl ester (1.36 g, 3.0 mmol) in 81.5% yield. LR MS 442 (M+H).
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[C:8]([N+:10]([O-])=O)[C:7]([CH3:13])=[CH:6][C:3]=1[C:4]#[N:5]>C(O)C.[Pd]>[NH2:10][C:8]1[C:7]([CH3:13])=[CH:6][C:3]([C:4]#[N:5])=[C:2]([CH3:1])[CH:9]=1
Reactant: Cc1cc([N+](=O)[O-])c(C)cc1C#N
Agent: [Pd]
Solvent: CCO
Product: Cc1cc(C#N)c(C)cc1N
Temperature: 25 °C
Reaction time: 3 h
Yield: 84.3 %

Procedure:
2,5-Dimethyl-4-nitrobenzonitrile (500 mg, 2.84 mmol; purchased from Salor) was dissolved in ethanol (20 ml), treated with 10% Pd on carbon catalyst (50 mg) and stirred under a hydrogen atmosphere (10 psi, room temperature, 3 hr). The catalyst was removed by filtration and the solvent evaporated to dryness. The resultant mixture was dissolved in CH2Cl2 and washed with HCl (2N, 4×15 ml), aqueous layer was treated with NaHCO3 then extracted repeatedly with CH2Cl2. Solvent was evaporated from the organic layer to give the desired product (brown solid, 350 mg, 84%). 1H NMR (CD3OD) δ 2.10 (s, 3H), 2.30 (s, 3H), 6.60 (s, 1H), 7.20 (s, 1H). LRMS m/z=147.4 (M+1)+. Found C 72.12, H 6.86, N 18.53%; C9H10N2.0.2H2O requires C 72.16, H 7.00, N 18.70%.