Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:4][CH:5]1[CH2:14][CH2:13][C:8]2(OCC[O:9]2)[CH2:7][CH2:6]1)[CH:2]=[CH2:3].Cl.C(=O)([O-])O.[Na+]>CCOCC>[CH2:1]([O:4][CH:5]1[CH2:14][CH2:13][C:8](=[O:9])[CH2:7][CH2:6]1)[CH:2]=[CH2:3]
Reactant: C=CCOC1CCC2(CC1)OCCO2
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Product: C=CCOC1CCC(=O)CC1
Yield: 98569.3 %

Procedure:
19.8 g of compound (11) (0.1 mmole) were stirred for 2 hours at room temperature with 120 ml ether and 40 ml of 6N hydrochloric acid. The mixture was then neutralised with sodium hydrogen carbonate, extracted three times with ether, and the ether solution was dried over sodium sulphate. After removing the solvent by distillation, 15.2 g of crude product were obtained; the product was purified with 3:1 diisopropyl ether/n-hexane via a silica gel column.
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][C:5]([O:6][C:7]([CH3:12])([CH3:11])[C:8]([OH:10])=[O:9])=[CH:4][CH:3]=1.C[Mg]I.[C:18](#N)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.Cl>C1COCC1>[CH2:18]([C:2]1[CH:14]=[CH:13][C:5]([O:6][C:7]([CH3:12])([CH3:11])[C:8]([OH:10])=[O:9])=[CH:4][CH:3]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: N#Cc1ccccc1
Reactant: CC(C)(Oc1ccc(Br)cc1)C(=O)O
Agent: C[Mg]I
Agent: Cl
Solvent: C1CCOC1
Product: CC(C)(Oc1ccc(Cc2ccccc2)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 77 %

Procedure:
26 g (0.1 mole) of 2-[(para-bromo)-phenoxy]-2-methyl-propionic acid is dissolved in 200 cc of anhydrous THF and placed in a 500 cc flask. The mixture is cooled in an ice bath and 0.2 mole of methylmagnesium iodide (prepared in solution of THF) is added slowly. After this addition, the temperature is allowed to rise and the mixture stirred at ambient temperature for 11/2 hours. Then slowly and drop by drop a solution of 4.1 g (0.1 mole) of benzonitrile in 20 cc of THF is added and the mixture is stirred for 2 hours 30 minutes at ambient temperature. The reaction mixture is poured on to 500 cc of 10% hydrochloric acid, cooled by 500 g of ice, and vigorously stirred. The reaction mixture is extracted with ether and the ethereal phases are washed, dried and decolorised. The ether solvent is evaporated under vacuum and the oily residue placed in a desiccator under vacuum. 2-[(para-benzoyl)-phenoxy]-2-methylpropionic acid slowly crystallises (22 g). The yield is 77% and the melting point 130° C.
Reaction SMILES: CO[C:3]1[C:12]2[N:11]=[CH:10][CH:9]=[CH:8][C:7]=2[C:6]([C:13]([OH:15])=O)=[CH:5][CH:4]=1.C(Cl)(=O)[C:17]([Cl:19])=[O:18].[Cl:22]CCl>CN(C=O)C>[ClH:19].[CH3:17][O:18][C:9]1[CH:10]=[N:11][C:12]2[CH:3]=[CH:4][CH:5]=[C:6]([C:13]([Cl:22])=[O:15])[C:7]=2[CH:8]=1
Reactant: ClCCl
Reactant: COc1ccc(C(=O)O)c2cccnc12
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Product: COc1cnc2cccc(C(=O)Cl)c2c1
Product: Cl
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A suspension of 8-methoxyquinoline-5-carboxylic acid (1.5 g) in dichloromethane (12 ml) was cooled to 0° C. and treated with oxalyl chloride (1.3 ml) followed by DMF (8 drops). The reaction was allowed to warm to room temperature and stirred overnight. The solvent was removed in vacuo and the residue azeotroped with toluene (2×10 ml) to yield the desired product (1.61 g) as an off-white powder.
Reaction SMILES: [SH:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.[NH2:7][C:8]1[CH:13]=[N:12][C:11]([CH3:14])=[CH:10][N:9]=1.Cl[C:16]1[C:17]2[N:25]=[C:24](Cl)[CH:23]=[CH:22][C:18]=2[N:19]=[CH:20][N:21]=1>>[NH:3]1[CH:4]=[CH:5][N:6]=[C:2]1[S:1][C:24]1[CH:23]=[CH:22][C:18]2[N:19]=[CH:20][N:21]=[C:16]([NH:7][C:8]3[CH:13]=[N:12][C:11]([CH3:14])=[CH:10][N:9]=3)[C:17]=2[N:25]=1
Reactant: Sc1ncc[nH]1
Reactant: Cc1cnc(N)cn1
Reactant: Clc1ccc2ncnc(Cl)c2n1
Product: Cc1cnc(Nc2ncnc3ccc(Sc4ncc[nH]4)nc23)cn1

Procedure:
The compound of Example 44 was manufactured by the same method as in Example 31, by a similar method thereto or by a combination of such a method with a conventional method using 2-mercaptoimidazole, 2-amino-5-methylpyrazine and 4,6-dichloropyrido-[3,2-d]pyrimidine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1.ClC(Cl)(O[C:27](=[O:33])OC(Cl)(Cl)Cl)Cl.[C:35]([C:39]1[CH:44]=[CH:43][C:42]([CH2:45][NH2:46])=[CH:41][CH:40]=1)([CH3:38])([CH3:37])[CH3:36].C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1.C(N(CC)CC)C>[C:35]([C:39]1[CH:40]=[CH:41][C:42]([CH2:45][NH:46][C:27]([NH:22][C:19]2[CH:18]=[CH:17][C:16]([O:15][C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][CH:7]=3)=[CH:21][CH:20]=2)=[O:33])=[CH:43][CH:44]=1)([CH3:38])([CH3:36])[CH3:37]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC(C)(C)c1ccc(CN)cc1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COc1cc2nccc(Oc3ccc(NC(=O)NCc4ccc(C(C)(C)C)cc4)cc3)c2cc1OC
Yield: 28 %

Procedure:
6,7-Dimethoxy-4-(4-aminophenoxy)quinoline (50 mg) was dissolved in toluene (5 ml) with heat, after the addition of triethylamine (1 ml), triphosgene (55 mg) was added, and the admixture was refluxed with heat for 2 minutes. (4-tert-Butylphenyl)methylamine (0.05 ml) was added to the reaction mixture, and the admixture was refluxed with heat for 12 minutes. After the addition of aqueous sodium hydrogen carbonate, the reaction mixture was extracted 2 times with ethyl acetate, and the organic layer was then washed with brine and dried with anhydrous sodium sulfate. The solvent was removed by reduced-pressure distillation, and the resulting residue was purified by column chromatography on silica gel eluting with chloroform/acetone (10/1) to obtain 23 mg of the title compound (yield: 28%).
Reaction SMILES: [Br-].[CH3:2][C:3]1[C:28]([CH3:29])=[CH:27][CH:26]=[CH:25][C:4]=1[CH2:5][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[K+].[O:36]=[C:37]1[C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[C:39](=[O:46])[N:38]1[CH2:47][CH2:48][CH2:49][C:50]1[CH:51]=[C:52]([CH:55]=[CH:56][CH:57]=1)[CH:53]=O>C(Cl)Cl.C1COCC1>[CH3:2][C:3]1[C:28]([CH3:29])=[CH:27][CH:26]=[CH:25][C:4]=1/[CH:5]=[CH:53]\[C:52]1[CH:51]=[C:50]([CH2:49][CH2:48][CH2:47][N:38]2[C:39](=[O:46])[C:40]3[C:45](=[CH:44][CH:43]=[CH:42][CH:41]=3)[C:37]2=[O:36])[CH:57]=[CH:56][CH:55]=1
Reactant: O=Cc1cccc(CCCN2C(=O)c3ccccc3C2=O)c1
Reactant: Cc1cccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c1C
Agent: CC(C)(C)[O-]
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: Cc1cccc(/C=C\c2cccc(CCCN3C(=O)c4ccccc4C3=O)c2)c1C
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To an ice cold solution of 2,3-dimethylbenzyltriphenylphosphonium bromide (1.1197 g, 2.43 mmol) in CH2Cl2 (10 mL) was added a solution of potassium tert-butoxide (2.5 mL of a 1 M solution in THF, 2.5 mmol). The mixture was stirred for 5 min, then a solution of phthalimide 29 (0.3380 g, 1.15 mmol) in CH2Cl2 (10 mL) was added. The mixture was warmed to room temperature, stirred for 20 min then concentrated under reduced pressure. 10% EtOAc-heptane was added and the solids were removed by filtration. The filtrate was concentrated under reduced pressure. Purification by repeated flash chromatography (6 to 40% EtOAc-hexanes gradient then 10% EtOAc-hexanes) gave (Z)-2-(3-(3-(2,3-dimethylstyryl)phenyl)propyl)isoindoline-1,3-dione as an oil. Yield (0.1871 g, 41%), trans-/cis-isomer ratio 1:11.7. Cis-isomer: 1H NMR (400 MHz, CDCl3) δ 7.85 (dd, J=5.6, 2.8 Hz, 2H), 7.72 (dd, J=5.2, 3.2 Hz, 2H), 7.04 (t, J=7.6 Hz, 1H), 6.88-6.98 (m, 6H), 6.68 (d, J=12.0 Hz, 1H), 6.56 (d, J=12.0 Hz, 1H), 3.64 (t, J=7.2 Hz, 2H), 2.52 (t, J=7.6 Hz, 2H), 2.52 (s, 3H), 2.17 (s, 3H), 1.80-1.88 (m, 2H).
Reaction SMILES: [F:1][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13]([N:16]([CH2:26][C:27]([OH:29])=O)[CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)(=[O:15])=[O:14])=[CH:9][CH:8]=1.[CH:30]1C=CC2N(O)N=NC=2C=1.[CH3:40][O:41][C:42]([O:45][NH2:46])([CH3:44])[CH3:43]>CN(C=O)C.O>[F:1][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13]([N:16]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)[CH2:26][C:27]([NH:46][O:45][C:42]([O:41][CH2:40][CH3:30])([CH3:44])[CH3:43])=[O:29])(=[O:15])=[O:14])=[CH:9][CH:8]=1
Reactant: COc1ccc(CN(CC(=O)O)S(=O)(=O)c2ccc(OCCCCF)cc2)cc1
Reactant: COC(C)(C)ON
Reactant: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(C)(C)ONC(=O)CN(Cc1ccc(OC)cc1)S(=O)(=O)c1ccc(OCCCCF)cc1
Reaction time: 1 h

Procedure:
To a solution of 0.425 g (1 mmol) of desired ([4-(4-fluorobutoxy)-benzenesulfonyl]-(4-methoxy-benzyl)-amino)-acetic acid and 0.27 g (2 mmol) of HOBT in 4 ml of DMF, a solution of 0.116 g of O-(1-methoxy-1-methyl-ethyl)-hydroxylamine in 1 ml of DMF and 0.23 g of WSCD were successively added at 0-5° C. and the mixture was stirred for 1 h. After stirring for additional 2 h at r.t., the mixture is diluted with H2O and extracted with AcOEt. The combined extracts are dried over MgSO4 and concentrated under reduced pressure. The residue is purified by column chromatography on silica gel (eluent; AcOEt:n-hexane=1:1) to give 2-([4-(4-fluorobutoxy)-benzenesulfonyl](4-methoxy-benzyl)amino)-N-(1-ethoxy-1-methyl ethoxy)acetamide; NMR (CDCl3): 1.35 (s, 6H), 1.83-2.0 (m, 4H), 3.29 (s, 3H), 3.70 (s, 2H), 3.78 (s, 3H), 4.08-4.11 (m, 2H), 4.32 (s, 2H), 4.47-4.49 (m, 1H), 4.60 (br s, 1H), 6.80-6.90 (m, 2H), 6.95-7.05 (m, 2H), 7.10-7.25 (m, 2H), 7.79 (d, 2H, J=9.06 Hz), 8.46 (br s, 1H).
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH:8]=[N:7]2>C(O)C>[Cl:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH2:8][NH:7]2
Reactant: O=c1cnc2cc(Cl)ccc2[nH]1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: O=C1CNc2cc(Cl)ccc2N1

Procedure:
Sodium borohydride (5.10 g) is added to a mixture of 6-chloro-1,2-dihydroquinoxalin-2-one (5.60 g), and ethanol (200 ml). The resultant solution is stirred for 2.5 hr at 20°-25°. The material is partitioned between water and ethyl acetate, the phases are separated, the organic phase is dried over magnesium sulfate and concentrated under reduced pressure to give a solid which is recrystallized from ethyl acetate/hexane to give the title compound, mp 171°-174°; IR (mineral oil) 2953, 2925, 1687, 1517, 1408, 1307 and 1299 cm-1 ; NMR (CDCl3 -MeOD) 6.6-6.8 and 3.95 δ; MS (m/z) 182, 153.
Reaction SMILES: C(N[CH:5]([CH3:7])[CH3:6])(C)C.[Li]CCCC.[C:13]([O:18][CH2:19][CH3:20])(=[O:17])C(C)C.[C:21](Cl)(=[O:33])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]>CCOCC>[CH2:19]([O:18][C:13](=[O:17])[C:5]([CH3:6])([CH3:7])[C:21](=[O:33])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH3:20]
Reactant: CC(C)NC(C)C
Reactant: CCCCCCCCCCCC(=O)Cl
Reactant: CCOC(=O)C(C)C
Agent: [Li]CCCC
Solvent: CCOCC
Product: CCCCCCCCCCCC(=O)C(C)(C)C(=O)OCC
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 95.5 %

Procedure:
To a cooled solution (-78° C.) of diisopropylamine (2.22 g, 0.022 mol) in 25 mL ether, n-BuLi (0.022 mol) was added dropwise and stirred for 20 minutes under a nitrogen atmosphere. Ethyl isobutyrate (2.65 g, 0.022 mol) was then added dropwise and the mixture was stirred for 20 minutes. In a separate flask, lauroyl chloride (5.0 g, 0.022 mol) was stirred in 10 mL ether and cooled to 0° C. The ethyl isobutyrate enolate solution was added dropwise to the lauroyl chloride solution over a 5-minute period. The reaction mixture was allowed to gradually warm to room temperature and stir for 16 hours (M. W. Rathke, et al, Tet. Lett., 2953 (1971)). The mixture was quenched with saturated ammonium chloride solution and extracted with ether two times. The combined organic layers were washed with brine, dried (MgSO4), and concentrated in vacuo (30° C.) to yield 6.5 g (0.021 mol, 98.9%) of the title compound.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH3:13][O:14][C:15]1[CH:47]=[CH:46][C:18]([O:19][C:20]2[C:25](=[O:26])[N:24]([CH2:27][C:28]3[CH:33]=[CH:32][C:31]([C:34]4[C:35]([C:40]#[N:41])=[CH:36][CH:37]=[CH:38][CH:39]=4)=[CH:30][CH:29]=3)[C:23]([CH2:42][CH2:43][CH3:44])=[N:22][C:21]=2[CH3:45])=[CH:17][CH:16]=1>C(OCC)(=O)C>[CH3:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([O:19][C:20]2[C:25](=[O:26])[N:24]([CH2:27][C:28]3[CH:33]=[CH:32][C:31]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=4[C:40]4[NH:3][C:4](=[O:7])[O:5][N:41]=4)=[CH:30][CH:29]=3)[C:23]([CH2:42][CH2:43][CH3:44])=[N:22][C:21]=2[CH3:45])=[CH:46][CH:47]=1
Reactant: [NH3+]O
Reactant: CCCc1nc(C)c(Oc2ccc(OC)cc2)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCCc1nc(C)c(Oc2ccc(OC)cc2)c(=O)n1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 59.2 %

Procedure:
A mixture of hydroxylammonium chloride (0.16 g), sodium hydrogen carbonate (0.22 g) and dimethyl sulfoxide (3 mL) was stirred at 40° C. for 30 min, 4′-{[5-(4-methoxyphenoxy)-4-methyl-6-oxo-2-propylpyrimidin-1(6H)-yl]methyl}biphenyl-2-carbonitrile (0.12 g) was added, and the mixture was stirred at 90° C. for 12 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in tetrahydrofuran (5 mL). N,N′-carbonyldiimidazole (0.06 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.06 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.08 g, 56%).
Reaction SMILES: ClC1C=CC2[N:8]=C(C)C=CC=2C=1C(O)=O.[Cl:16][C:17]1[C:18]([NH:34][C:35](=[O:43])[CH2:36][CH:37]2[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]2)=[C:19]2[C:24](=[CH:25][CH:26]=1)[N:23]=[C:22]([N:27]1[CH2:31][CH2:30][C@@H:29]([C:32]#[N:33])[CH2:28]1)[CH:21]=[CH:20]2.C([Sn](=O)CCCC)CCC.[N:54]([Si](C)(C)C)=[N+:55]=[N-:56]>>[NH3:8].[Cl:16][C:17]1[C:18]([NH:34][C:35](=[O:43])[CH2:36][CH:37]2[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]2)=[C:19]2[C:24](=[CH:25][CH:26]=1)[N:23]=[C:22]([N:27]1[CH2:31][CH2:30][C@@H:29]([C:32]3[NH:56][N:55]=[N:54][N:33]=3)[CH2:28]1)[CH:21]=[CH:20]2
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: N#C[C@@H]1CCN(c2ccc3c(NC(=O)CC4CCCCC4)c(Cl)ccc3n2)C1
Reactant: Cc1ccc2c(C(=O)O)c(Cl)ccc2n1
Agent: CCCC[Sn](=O)CCCC
Product: N
Product: O=C(CC1CCCCC1)Nc1c(Cl)ccc2nc(N3CC[C@@H](c4nnn[nH]4)C3)ccc12

Procedure:
Prepared according to the method of example 98 (b), using N-[6-chloro-2-[(3R)-3-cyano-1-pyrrolidinyl]-5-quinolinyl]-cyclohexaneacetamide (example 100 (a)) (66 mg), dibutyltin oxide (9 mg) and azidotrimethylsilane (0.06 mL). The residue was purified by ion exchange column (Varian NH2 cartridge, methanol then 3% acetic acid in methanol as eluant). Further purification by ion exchange column (Varian SCX cartridge, methanol then 7N ammonia in methanol as eluant) gave the title compound as a solid (11 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[OH:10][S:11](O)(=[O:13])=[O:12].O=S(=O)=O>>[Cl:1][C:2]1[CH:9]=[CH:8][C:7]([S:11]([OH:13])(=[O:12])=[O:10])=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: O=S(=O)(O)O
Reactant: O=Cc1ccccc1Cl
Agent: O=S(=O)=O
Product: O=Cc1cc(S(=O)(=O)O)ccc1Cl
Temperature: 2.5 °C
Reaction time: 2.5 h

Procedure:
2-chlorobenzaldehyde 500 g (3.35 moles) was added to 23% oleum 1050 g (1.35 moles), and the contents were cooled to 0 to 5° C. The reaction mixture was stirred for 2.5 hours between 0-15° C. To this stirred solution, 660 g of 65% oleum (2.41 moles) was added over a period of 2.5 hours, maintaining the temperature below 15° C. The reaction mass was stirred and allowed to come to a temperature of 25-30° C.
Reaction SMILES: SC1([CH:13](Br)[C:14](=O)/[C:15](=[N:19]/[O:20][CH3:21])/[C:16]([O-:18])=O)NN=C(C2C=CC=CC=2)O1.[NH2:24][C:25]([NH2:27])=[S:26].C([O-])(=O)C.[Na+:32].[NH2:33][CH:34]1[C:55](=[O:56])[N:36]2[C:37]([C:52]([OH:54])=[O:53])=[C:38]([CH2:41][S:42][C:43]3[N:44]([CH3:51])[N:45]=[C:46]([OH:50])[C:47](=[O:49])[N:48]=3)[CH2:39][S:40][C@H:35]12>O.C(N(CC)CC)C.C1COCC1>[CH3:51][N:44]1[N:45]=[C:46]([OH:50])[C:47](=[O:49])[N:48]=[C:43]1[S:42][CH2:41][C:38]1[CH2:39][S:40][C@@H:35]2[C@H:34]([NH:33][C:16](/[C:15](/[C:14]3[N:24]=[C:25]([NH2:27])[S:26][CH:13]=3)=[N:19]\[O:20][CH3:21])=[O:18])[C:55](=[O:56])[N:36]2[C:37]=1[C:52]([O-:54])=[O:53].[Na+:32]
Reactant: NC(N)=S
Reactant: CO/N=C(\C(=O)[O-])C(=O)C(Br)C1(S)NN=C(c2ccccc2)O1
Reactant: Cn1nc(O)c(=O)nc1SCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)[O-])=C(CSc3nc(=O)c(O)nn3C)CS[C@H]12)c1csc(N)n1
Reaction time: 2.5 h
Yield: 170.7 %

Procedure:
2-mercapto-5-phenyl-1,3,4-oxadiazolyl-(Z)-4-bromo-2-methoxyimino-3-oxo-butyrate (27.0 g) was taken in mixture of THF (250 ml) and water (125 ml). Thiourea (10.6 g) and sodium acetate (2.0 g) were added to this at 10-15° C. after 45 to 60 min. 7-Amino-3-[[(2, 5-dihydro-6-hydroxy-2-methyl-5-oxo-1,2,4-triazin-3yl)thio]methyl]3-cephem-4-carboxylic acid (20.0 g) was suspended in the reaction mixture. The suspension was stirred for 2-3 hours at a pH of 7.0-8.5 maintained by triethylamine to get clear solution. The reaction mixture was monitored by HPLC. After completion of reaction, 200 ml water was added and pH was adjusted to 7.0. The aqueous layer was separated, charcoalized and treated with sodium-2-ethylhexanoate (30.5 g) in acetone, reaction was proceeded by same method as mentioned in Method -I to get crude ceftriaxone sodium (24.0 g).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[NH:13][N:12]=[C:11]([C:14]([OH:16])=[O:15])[CH:10]=1.[C:17](=S)=[S:18].N1C=CC=CC=1.O>CO>[S:18]=[C:17]1[N:13]2[N:12]=[C:11]([C:14]([OH:16])=[O:15])[CH:10]=[C:9]2[C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[NH:2]1
Reactant: Nc1ccccc1-c1cc(C(=O)O)n[nH]1
Reactant: S=C=S
Agent: Cl
Solvent: CO
Solvent: c1ccncc1
Solvent: O
Product: O=C(O)c1cc2c3ccccc3[nH]c(=S)n2n1

Procedure:
A mixture of 600 mg (0.0025 mole) of 5-(2-aminophenyl)-1H-pyrazole-3-carboxylic acid hydrochloride, 1.98 ml of carbon disulfide, 3.2 ml of pyridine and 0.16 ml of water are refluxed under N2 for 40 hours. The reaction mixture is stripped to dryness and the solid obtained is taken up in 175 ml methanol and filtered while hot. The clear light-yellow filtrate is concentrated down to a volume of 80 ml and cooled. The cotton-like precipitates are filtered and dried in vacuo over a 72 hour period at 80°. Yield: 394.8 mg, m.p. 272°-273°, 64.4% recryst. yield.
Reaction SMILES: O[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]#[N:18])[CH:15]=3)[N:10](C3CCCCO3)[N:9]=2)=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:44][N:45]([CH3:49])[CH2:46][CH2:47][OH:48].N(C(OCC)=O)=NC(OCC)=[O:53]>CCOC(C)=O>[CH3:44][N:45]([CH3:49])[CH2:46][CH2:47][O:48][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]([NH2:18])=[O:53])[CH:15]=3)[NH:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: N#Cc1ccc2c(c1)c(-c1ccc(O)cc1)nn2C1CCCCO1
Reactant: CCOC(=O)N=NC(=O)OCC
Reactant: CN(C)CCO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Product: CN(C)CCOc1ccc(-c2n[nH]c3ccc(C(N)=O)cc23)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 21.4 %

Procedure:
A mixture of 3-(4-hydroxyphenyl)-1-perhydro-2H-pyran-2-yl-1H-indazole-5-carbonitrile (400 mg, 1.25 mmol), triphenylphosphine (Ph3P, 656 mg, 2.50 mmol, 2.00 equiv.), 4.00 mL EtOAc, N,N-dimethylethanolamine (223 mg, 2.50 mmol, 2.00 equiv.), and diethyl azodicarboxylate (DEAD, 436 mg, 2.50 mmol, 2.00 equiv.) Was stirred at room temperature for 24 h. The mixture was diluted with EtOAc and washed with 6.0 N aq. HCl. The aqueous layer was extracted with 3×EtOAc and then added to enough 6.0 N aq. NaOH so that the final pH=14.0. This mixture was extracted with 3×EtOAc, and the combined organics were dried (Na2SO4), filtered, and concentrated. To the crude residue was added 6.00 mL of concentrated aq. HCl. The mixture was heated at 45° C. for 1.25 h. This mixture was then added to 25 mL of 6.0 N aq. NaOH that was stirred and cooled on a water bath. The mixture was extracted with 2×EtOAc, and the combined organics dried (Na2SO4). Purification by silica gel chromatography using 0.5% triethylamine (TEA) in CH2Cl2 containing 5–15% MeOH as eluent afforded the title compound (86.6 mg, 21.4% yield): 1H NMR (DMSO-d6) δ 13.34 (br s, 1H), 8.59 (s, 1H), 8.17 (br s, 1H), 8.00–7.85 (m, 3H), 7.58 (d, 2H), 7.35 (br s, 1H), 7.10 (d, 2H), 4.13 (t, 2H), 2.66 (t, 2H), 2.24 (s, 6H); ES-MS (m/z) 325 [M+1]+.
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[S:10][C:11]3[CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([CH:23]5[CH2:26][N:25]([CH2:27][CH2:28][O:29]C6CCCCO6)[CH2:24]5)[CH:20]=[CH:19][C:16]=4[C:17]=3[N:18]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2]>CO>[CH:1]([N:4]1[C:8]([C:9]2[S:10][C:11]3[CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([CH:23]5[CH2:24][N:25]([CH2:27][CH2:28][OH:29])[CH2:26]5)[CH:20]=[CH:19][C:16]=4[C:17]=3[N:18]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C3CN(CCOC4CCCCO4)C3)ccc1-2
Solvent: CO
Product: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C3CN(CCO)C3)ccc1-2
Temperature: 30 °C

Procedure:
Following the procedure for 376, 2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-8-{1-[2-(tetrahydro-pyran-2-yloxy)-ethyl]-azetidin-3-yl}-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene was reacted with MeOH as the solvent and the reaction mixture was warmed to 30° C. The crude product was triturated with diethyl ether to give 322 as a yellow solid (92 mg, quant.) LCMS: RT=3.03 min, [M+H]+=412. 1H NMR δ (ppm) (DMSO-d6): 10.65 (1H, s), 8.34-8.25 (1H, m), 8.06 (1H, s), 7.27-7.20 (1H, m), 7.15 (1H, dd, J=14.90, 1.71 Hz), 5.80-5.71 (1H, m), 4.41-4.21 (5H, m), 4.20-4.08 (1H, m), 3.67-3.56 (2H, m), 3.45-3.30 (2H, m), 3.26 (1H, dd, J=10.12, 5.06 Hz), 1.51-1.46 (6H, m). 2 Protons obscured by water peak and 1 exchangeable not observed
Reaction SMILES: [C:1]([N:4]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH2:19][C:20]([OH:22])=O)[C:5]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:6]=1[Cl:12])(=[O:3])[CH3:2].P(Cl)(Cl)(Cl)(Cl)[Cl:24]>C(OCC)C>[C:1]([N:4]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH2:19][C:20]([Cl:24])=[O:22])[C:5]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:6]=1[Cl:12])(=[O:3])[CH3:2]
Reactant: CC(=O)N(c1ccccc1CC(=O)O)c1c(Cl)cccc1Cl
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: CCOCC
Product: CC(=O)N(c1ccccc1CC(=O)Cl)c1c(Cl)cccc1Cl

Procedure:
2-[N-Acetyl-N-(2,6-dichlorophenyl)amino]phenylacetic acid is reacted with phosphorus pentachloride in diethyl ether to obtain 2-[N-acetyl-N-(2,6-dichlorophenyl)amino]phenylacetic acid chloride. The acid chloride is then reacted with trimethyl phosphite under the conditions described in Example 2, thus producing 2-[N-acetyl-N-(2,6-dichlorophenyl)amino]phenyl-1-hydroxyethene-1-phosphonic acid dimethyl ester; this compound is converted, under the conditions of Example 1, with dimethyl phosphite into 2-[2-(2,6-dichlorophenylamino)phenyl]-1-hydroxyethane-1,1-bis(phosphonic acid dimethyl ester).
Reaction SMILES: [Na].[NH2:2][C:3]1[C:11]2[C:6](=[N:7][CH:8]=[C:9](Cl)[CH:10]=2)[S:5][C:4]=1[C:13]([O:15][CH3:16])=[O:14].[CH3:17][OH:18]>>[NH2:2][C:3]1[C:11]2[C:6](=[N:7][CH:8]=[C:9]([O:18][CH3:17])[CH:10]=2)[S:5][C:4]=1[C:13]([O:15][CH3:16])=[O:14]
Reactant: COC(=O)c1sc2ncc(Cl)cc2c1N
Reactant: CO
Agent: [Na]
Product: COC(=O)c1sc2ncc(OC)cc2c1N
Yield: 86 %

Procedure:
Sodium metal (0.46 g, 20 mmol) was added to methanol (20 mL) and allowed to react until metallic sodium was consumed. To the solution was added the product from Example 32A (0.485 g, 2.0 mmol) and the reaction was heated to reflux for 2 h. The reaction was quenched in sat. aq. NH4Cl and extracted with ethyl acetate. The organic phase was dried (MgSO4) and evaporated to yield 0.410 g (86%) of the title compound: 1H NMR (300 MHz, CDCl3) δ 3.88(s, 3H), 4.02 (s, 3H), 6.74 (d, 1H), 7.77 (d, 1H).