Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[Cl:5][CH2:6][CH2:7][CH2:8][C:9](Cl)=[O:10].[F:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][CH:17]=[CH:16]2.Cl>ClCCl>[Cl:5][CH2:6][CH2:7][CH2:8][C:9]([C:16]1[C:15]2[C:19](=[CH:20][CH:21]=[C:13]([F:12])[CH:14]=2)[NH:18][CH:17]=1)=[O:10]
Reactant: Fc1ccc2[nH]ccc2c1
Reactant: O=C(Cl)CCCCl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C(CCCCl)c1c[nH]c2ccc(F)cc12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 63.7 %

Procedure:
To a magnetically stirred mixture of AlCl3 (25 g, 0.19 mol) in dichloromethane, 4-chloro-butyryl chloride (21 ml, 0.19 mol) was slowly added at 0° C. The resulting mixture was stirred for 30 minutes and 5-fluoro-1H-indole (25 g, 0.19 mol) was slowly added. After stirring for another 30 minutes the formed orange mixture was poured onto concentrated hydrochloric acid (140 ml) and ice (200 ml) to give a pink precipitate. The precipitate was collected by filtration to give pink 4-chloro-1-(5-fluoro-1H-indol-3-yl)-butan-1-one (29 gram, 65% yield). 1H-NMR (400 MHz, DMSO-d6) δ 2.09 (quintet, J=7, 2H), 3.02 (t, J=7, 2H), 3.70 (t, J=7, 2H), 7.07 (dt, J˜9 and 2, 1H), 7.49 (dd, J˜9 and 4, 1H), 7.85 (dd, J˜9 and 2, 1H), 8.41 (d, J˜3, 1H), 12.21 (br s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH:12]=[CH:13][C:14]3[CH:15]=[C:16]([C@@H:20](OS(C)(=O)=O)[CH2:21][CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[C:29]([O:32]C4CCCCO4)([CH3:31])[CH3:30])[CH:17]=[CH:18][CH:19]=3)=[N:9]2)=[CH:4][CH:3]=1.C([S:47][CH2:48][C:49]1([CH2:52][C:53]([O:55]C)=[O:54])[CH2:51][CH2:50]1)(=O)C>NN.C(=O)([O-])[O-].[Cs+].[Cs+].C(#N)C.O1C=CC=CC1>[CH3:31][C:29]([OH:32])([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[CH2:22][CH2:21][C@@H:20]([S:47][CH2:48][C:49]1([CH2:52][C:53]([OH:55])=[O:54])[CH2:51][CH2:50]1)[C:16]1[CH:17]=[CH:18][CH:19]=[C:14](/[CH:13]=[CH:12]/[C:8]2[CH:7]=[CH:6][C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:11][C:10]=3[N:9]=2)[CH:15]=1)[CH3:30]
Reactant: COC(=O)CC1(CSC(C)=O)CC1
Reactant: CC(C)(OC1CCCCO1)c1ccccc1CC[C@H](OS(C)(=O)=O)c1cccc(C=Cc2ccc3ccc(Cl)cc3n2)c1
Agent: C1=CCOC=C1
Agent: NN
Agent: O=C([O-])[O-]
Solvent: CC#N
Product: CC(C)(O)c1ccccc1CC[C@@H](SCC1(CC(=O)O)CC1)c1cccc(/C=C/c2ccc3ccc(Cl)cc3n2)c1

Procedure:
The process for the preparation comprises of reacting 2-(2-(2-(3(S)-(3-(2-(7-chloro-2-quinolinyl)ethenyl)phenyl)-3-(methanesulfonyloxy)propyl)phenyl)-2-propoxy)tetrahydro pyran with Methyl 1-(acetylthiomethyl)cyclopropane acetate in presence of hydrazine, cesium carbonate in acetonitrile as solvent to get methyl ester of Montelukast in pyran protected form. The protected compound is further reacted with pyridinium p-toluene sulfonate, sodium hydroxide in a mixture of methanol and tetrahydrofuran as a solvent to afford Montelukast sodium of Formula (I).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:4]=[CH:5][C:6]([NH:9][NH2:10])=[N:7][CH:8]=1.[C:13]([C:15](=[C:21](OCC)[CH3:22])[C:16]([O:18][CH2:19][CH3:20])=[O:17])#[N:14].C(O)C.Cl>O>[NH2:14][C:13]1[N:9]([C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:11])[F:12])=[CH:8][N:7]=2)[N:10]=[C:21]([CH3:22])[C:15]=1[C:16]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: CCOC(=O)C(C#N)=C(C)OCC
Reactant: NNc1ccc(C(F)(F)F)cn1
Agent: Cl
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1c(C)nn(-c2ccc(C(F)(F)F)cn2)c1N
Yield: 54.3 %

Procedure:
5-(Trifluoromethyl)pyridin-2-ylhydrazine (10.0 g) described in Reference Example 8 and ethyl 2-cyano-3-ethoxy-3-methylacrylate (10.3 g) were added to a mixed solvent of ethanol (40 ml) and 1N hydrochloric acid aqueous solution (40 ml), and the mixture was stirred at reflux temperature for three hours. Water was added to the reaction solution to give ethyl 5-amino-3-methyl-1-[5-(trifluoromethyl)pyridin-2-yl]-1H-pyrazole-4-carboxylate (9.6 g). Next, the compound was added to tetrahydrofuran (50 ml), isoamyl nitrite (20 g) was added and the mixture was stirred at reflux temperature for five hours. The reaction solution was concentrated, a mixed solvent of ethanol (40 ml) and water (40 ml) and sodium hydroxide (5 g) were added and the mixture was stirred at reflux temperature for two hours. Ethanol was evaporated, diluted hydrochloric acid was added and the precipitated solid was recrystallized from aqueous methanol to give the titled compound.
Reaction SMILES: [CH2:1]([NH:5][S:6]([C:9]([F:12])([F:11])[F:10])(=[O:8])=[O:7])[CH2:2][CH2:3][CH3:4].C(=O)([O-])[O-].[K+].[K+].[CH2:19](Br)[CH:20]=[CH2:21]>CO>[CH2:21]([N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[S:6]([C:9]([F:12])([F:10])[F:11])(=[O:7])=[O:8])[CH:20]=[CH2:19]
Reactant: CCCCNS(=O)(=O)C(F)(F)F
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C=CCN(CCCC)S(=O)(=O)C(F)(F)F
Reaction time: 2 h

Procedure:
A mixture of N-butyltrifluoromethanesulfonamide (62.0 g, 0.302 mole), potassium carbonate (45.54 g, 0.330 mole) and methanol (250 ml) was refluxed with stirring for two hours. Allyl bromide (39.93 g, 0.330 mole) was then added and this mixture stirred under reflux for 24 hours, cooled, filtered, and the solvent evaporated in vacuo. The residue was fractionally distilled yielding 37.0 g (b.p. of 53°-58° C. at 0.07 torr) of the desired compound, N-allyl-N-butyltrifluoromethanesulfonamide.
Reaction SMILES: [I:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:4]2[C:5]([O:7][C:8](=[O:9])[C:3]=12)=[O:6].[CH3:13][CH:14]([NH2:19])[CH2:15][CH2:16][S:17][CH3:18]>C(#N)C>[I:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:4]([C:5]([OH:7])=[O:6])[C:3]=1[C:8]([NH:19][CH:14]([CH3:13])[CH2:15][CH2:16][S:17][CH3:18])=[O:9]
Reactant: O=C1OC(=O)c2c(I)cccc21
Reactant: CSCCC(C)N
Solvent: CC#N
Product: CSCCC(C)NC(=O)c1c(I)cccc1C(=O)O
Reaction time: 3 h
Yield: 89.2 %

Procedure:
To a suspension of 2.74 g of 3-iodophthalic anhydride in 8 ml of acetonitrile cooled with ice was slowly added dropwise a solution of 1.19 g of 1-methyl-3-methylthiopropylamine in 3 ml of acetonitrile. After completion of the dropping, a reaction was carried out at room temperature for 3 hours with stirring. After completion of the reaction, the deposited crystal was collected by filtration and washed with a small quantity of acetonitrile. Thus, 3.5 g of the objective compound was obtained.
Reaction SMILES: N1(S(N[C:9](=O)[C:10]2[CH:15]=C(Cl)C(OCC34CC5CC(CC(CO)(C5)C3)C4)=CC=2F)(=O)=O)CCC1.[C@@H:33]12[CH2:39][C@@H:36]([CH2:37][CH2:38]1)[CH2:35][C@@H:34]2[O:40][C:41]1[C:53](Cl)=[CH:52][C:44]([C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])=[C:43]([F:55])[CH:42]=1>>[C@@H:33]12[CH2:39][C@@H:36]([CH2:37][CH2:38]1)[CH2:35][C@@H:34]2[O:40][C:41]1[C:53]([CH:15]2[CH2:10][CH2:9]2)=[CH:52][C:44]([C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])=[C:43]([F:55])[CH:42]=1
Reactant: CC(C)(C)OC(=O)c1cc(Cl)c(O[C@H]2C[C@@H]3CC[C@H]2C3)cc1F
Reactant: O=C(NS(=O)(=O)N1CCC1)c1cc(Cl)c(OCC23CC4CC(CC(CO)(C4)C2)C3)cc1F
Product: CC(C)(C)OC(=O)c1cc(C2CC2)c(O[C@H]2C[C@@H]3CC[C@H]2C3)cc1F

Procedure:
Following the procedure as described in Example 278 step 7 and making variations as required to replace N-(azetidin-1-ylsulfonyl)-5-chloro-2-fluoro-4-((3-(hydroxymethyl)-adamantan-1-yl)methoxy)benzamide with tert-Butyl 4-((1S,2S,4R)-bicyclo[2.2.1]heptan-2-yloxy)-5-chloro-2-fluorobenzoate. Purification by silica gel column chromatography (10:1 hexanes:ethyl acetate) gave the title compound as a colorless oil (0.77 g, quant): 1H NMR (300 MHz, CDCl3) δ 7.33 (d, J=8.3 Hz, 1H), 6.45 (d, J=13.0 Hz, 1H), 4.20-4.13 (m, 1H), 2.49-2.44 (m, 1H), 2.35-2.29 (m, 1H), 2.01-1.91 (m, 1H), 1.82-1.73 (m, 1H), 1.70-1.63 (m, 1H), 1.61-1.56 (m, 1H), 1.55 (s, 9H), 1.50-1.44 (m, 1H), 1.27-1.09 (m, 4H), 0.88-0.81 (m, 2H), 0.63-0.56 (m, 2H); MS (ES+) m/z 291.2 (M-55).
Reaction SMILES: [C:1]([C:3]1[N:4]=[CH:5][C:6]2[NH:7][C:8]3[C:13]([C:14]=2[CH:15]=1)=[CH:12][CH:11]=[CH:10][CH:9]=3)#[N:2].Cl.[NH2:17][OH:18].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[CH:5]1[C:6]2[NH:7][C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:14]=2[CH:15]=[C:3]([C:1](=[N:17][OH:18])[NH2:2])[N:4]=1
Reactant: N#Cc1cc2c(cn1)[nH]c1ccccc12
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: NC(=NO)c1cc2c(cn1)[nH]c1ccccc12
Reaction time: 22 h
Yield: 85.4 %

Procedure:
A mixture of 2.4 g of 3-cyano-beta-carboline, 1.1 g of hydroxylamine-hydrochloride, 200 ml of 99% ethanol and 5.2 ml of a potassium carbonate solution (2.2 g of potassium carbonate in 10 ml of water) is boiled in an oil bath at 90° C. outside temperature for 22 h at the reflux. The reaction mixture is filtered hot. The filtrate is concentrated. The residue is treated with 100 ml of water. The precipitate is filtered off, washed with water and dried in air. 2.4 g of beta-carboline-3-carboxylic-acid-amide-oxime with a m.p. of 159°-163° C. is obtained.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([OH:12])=[CH:4][N:3]=1.C1C=C(Cl)C=C(C(OO)=O)C=1.COC1C2C(=CC=CC=2)[CH:29]=[N:28][CH:27]=1>>[Cl:1][C:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2[O:12][CH2:29][N:28]=[CH:27][C:4]=2[N:3]=1.[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([OH:12])=[CH:4][N:3]=1
Reactant: COc1cncc2ccccc12
Agent: O=C(OO)c1cccc(Cl)c1
Agent: Oc1cnc(Cl)c2ccccc12
Product: Clc1nc2c(c3ccccc13)OCN=C2

Procedure:
6-Chloro-1,3-Oxazino[5,6-c]isoquinoline was prepared by the procedure of Miyoko Toyama and Hirotaka Otomasu starting from 1-chloro-4-hydroxy isoquinoline. The starting material: 1-chloro-4-hydroxy isoquinoline (Example 226c) was prepared by the synthetic sequence shown above. MCPBA oxidation of 4-methoxy isoquinoline (Example 222a) was carried as usual to give 79.1% of the corresponding N-oxide (Example 226a). The material was converted into the 1-chloro derivative immediately afterward in POCl3 to give the chloride (Example 226b) in essentially quantitative yield. The crude 1-chloro-4-methoxy isoquinoline was de-methylated in BBr3 at room temperature to give the corresponding 1-chloro-4-hydroxy isoquinoline (Example 226c) after treating the crude BBr3 mixture with anhydrous methanol at room temperature, followed by evaporation to get rid of excess of borate residues. The reaction of Miyoko Toyama and Hirotaka Otomasu gave 266 mg of 6-chloro-1,3-oxazino[5,6-c]isoquinoline (Example 226d, 62.3%) overall yield from 300 mg of 4-methoxy isoquinoline in 4 steps. LC/MS Rt-min ([M−HCHO]H+) [method D]: 2.45 (192). 1H NMR (400 MHz, CHLOROFORM-D) δ ppm 5.02 (s, 2H) 5.41 (s, 2H) 7.68 (m, 1H) 7.77 (ddd, J=8.25, 6.91, 1.22 Hz, 1H) 8.10 (d, J=8.31 Hz, 1H) 8.26 (d, J=8.56 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:9]=1)[CH2:7]Br.[CH3:13][O-:14].[Na+]>CO>[N+:10]([C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:9][C:6]=1[CH2:7][O:14][CH3:13])([O-:12])=[O:11]
Reactant: C[O-]
Reactant: O=[N+]([O-])c1ccc(Cl)cc1CBr
Agent: [Na+]
Solvent: CO
Product: COCc1cc(Cl)ccc1[N+](=O)[O-]
Yield: 92.5 %

Procedure:
2.15 g of 5-chloro-2-nitrobenzylbromide is dissolved in approximately 25 ml methanol at room temperature. 1.86 g of 25% sodium methoxide in methanol is added and stirring continued for 0° C. 1 hour after which 10 wt % additional sodium methoxide is added to complete the conversion. The solvent is evaporated and the residue is dissolved in 100 ml dichloromethane and washed with 25 ml water (2×). Evaporation provided 1.6 g of 4-nitro-3-methoxymethylchlorobenzene. 1H-NMR (500 MHz, CDCl3) δ (ppm) 3.527 (s, 3H), 4.838 (s, 2H), 7.399-7.416 (dd, 1H), 7.824-7.826 (d, 1H), 8.066-8.084 (d, 1H).
Reaction SMILES: [NH:1]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C@H:2]([C:11]([O:13][CH3:14])=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.F[C:23]1[CH:36]=[CH:35][C:26]([C:27]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:28])=[CH:25][CH:24]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:18]([O:17][C:15]([NH:1][C@@H:2]([CH2:3][C:4]1[CH:5]=[CH:6][C:7]([O:10][C:32]2[CH:33]=[CH:34][C:29]([C:27](=[O:28])[C:26]3[CH:35]=[CH:36][CH:23]=[CH:24][CH:25]=3)=[CH:30][CH:31]=2)=[CH:8][CH:9]=1)[C:11]([O:13][CH3:14])=[O:12])=[O:16])([CH3:21])([CH3:20])[CH3:19]
Reactant: O=C(c1ccccc1)c1ccc(F)cc1
Reactant: COC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)[C@H](Cc1ccc(Oc2ccc(C(=O)c3ccccc3)cc2)cc1)NC(=O)OC(C)(C)C
Temperature: 100 °C
Reaction time: 42 h
Yield: 102.8 %

Procedure:
A mixture of Boc-Tyr-OMe (0.80 g, 2.7 mmol), 4-fluorobenzophenone (0.80 g, 4.0 mmol) and potassium carbonate (1.11 g, 8.0 mmol) in DMF (30 mL) was heated to 100° C. After 42 h, the reaction mixture was allowed to cool to rt. DMF was removed in vacuo and the remaining material was partitioned between EtOAc (50 mL) and water (50 mL). This gave an emulsion that was allowed to sit overnight. The following day the layers had mostly separated and so the organic layer was concentrated in vacuo to give 1.32 g of material. This material was purified by chromatography (4:1 hexane/ethyl acetate) to give 0.69 g of product. 1H NMR (400 MHz, CDCl3) δ 1.43 (s, 9H), 2.98-3.19 (m, 2H), 3.74 (s, 3H), 4.60 (q, J=6.8 Hz, 1H), 5.03 (br d, J=7.6 Hz, 1H), 6.98-7.05 (m, 4H), 7.14-7.19 (m, 2H), 7.45-7.51 (m, 2H), 7.55-7.61 (m, 1H), 7.75-7.84 (m, 4H).
Reaction SMILES: [OH-].[K+].[NH2:3][C:4]1[C:9]([NH2:10])=[C:8]([CH3:11])[CH:7]=[CH:6][N:5]=1.O.Cl.[C:14](=S)=[S:15]>C(O)C.CO.C(O)(=O)C>[SH:15][C:14]1[NH:3][C:4]2=[N:5][CH:6]=[CH:7][C:8]([CH3:11])=[C:9]2[N:10]=1
Reactant: Cc1ccnc(N)c1N
Reactant: S=C=S
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: CC(=O)O
Solvent: CO
Product: Cc1ccnc2[nH]c(S)nc12

Procedure:
5 g of potassium hydroxide dissolved in 30 ml of ethanol was dropwise added at 20° C. or below to a solution of 15 g of 2,3-diamino-4-methylpyridine in 15 ml of carbon disulfide and 60 ml of methanol, and the mixture was refluxed for 2 hr. Water and 7 ml of concentrated hydrochloric acid were added thereto, and acetic acid was then added thereto to weakly acidify the mixture. The precipitated solid was recovered by filtration. The solid was washed twice with a small amount of methanol and then dried to prepare 12.3 g of 2-mercapto-7-methyl-3H-imidazo[4,5-b]pyridine as a clayish solid.
Reaction SMILES: [OH-].[Na+].[CH3:3]I.[OH:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:15]=1[O:16][CH:17]([CH2:19][CH3:20])[CH3:18])[O:12][C:11]([CH3:22])([CH3:21])[CH2:10][C:9]2=[O:23]>ClCCl.[Cl-].C([N+](CC)(CC)CC1C=CC=CC=1)C>[CH3:3][O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:15]=1[O:16][CH:17]([CH2:19][CH3:20])[CH3:18])[O:12][C:11]([CH3:21])([CH3:22])[CH2:10][C:9]2=[O:23]
Reactant: CI
Reactant: CCC(C)Oc1cc2c(cc1O)C(=O)CC(C)(C)O2
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Product: CCC(C)Oc1cc2c(cc1OC)C(=O)CC(C)(C)O2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96 %

Procedure:
In 40 ml of a 5% sodium hydroxide solution 5.2 g (20 millimoles) of 6-hydroxy-7-sec. butoxy-2,2-dimethyl-4-chromanone are dissolved whereupon 80 ml of dichloro methane and 0.5 g of triethyl benzyl ammonium chloride are added and the mixture is intensively stirred at room temperature for 30 minutes. After the addition of 4.25 g (1.9 ml, 30 millimoles) of methyl iodide the reaction mixture is stirred for further 2 hours. The organic phase is separated, washed twice with 50 ml of water each, dried over sodium sulfate and the solvent is removed. The residue is crystallized from 90% ethanol. Thus 5.34 g of the desired compound are obtained, yield 96%. Mp.: 92.5°-93° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:19]([O:21][CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)=[O:20])[C:7](=[CH:17][CH:18]=1)[C:8]([O:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)=[O:9])([O-])=O.Cl.O.[OH-].[Na+]>C1C=CC=CC=1.[Zn]>[NH2:1][C:4]1[CH:5]=[C:6]([C:19]([O:21][CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)=[O:20])[C:7](=[CH:17][CH:18]=1)[C:8]([O:10][CH:11]1[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]1)=[O:9]
Reactant: O=C(OC1CCCCC1)c1ccc([N+](=O)[O-])cc1C(=O)OC1CCCCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: c1ccccc1
Product: Nc1ccc(C(=O)OC2CCCCC2)c(C(=O)OC2CCCCC2)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 71 %

Procedure:
Compound 405 (2.0 g, 5.3 mmol) was dissolved in 265 ml of benzene, and then 3.2 g of purified zinc dust was added. Concentrated hydrochloric acid (9.3 ml) was added in portions. After 15 minutes of stirring at room temperature, 3.2 g of zinc dust was added and the mixture was stirred at room temperature for 12 hours. Then 320 ml of water was added to the reaction mixture and the mixture was neutralized with 1N NaOH solution. The mixture was transferred to a separatory funnel and the benzene layer was removed. The aqueous layer was extracted with benzene. The combined benzene extracts were washed with water and dried over anhydrous sodium sulfate. After evaporation of the solvent, the residue was purified by silica gel column chromatography (n-hexane: acetic acid =10:1) to give 1.3 g (72.2%) of dicyclohexyl 4-aminophthalate (compound 406).
Reaction SMILES: [N+:1]([C:4]1[S:8][C:7]([S:9]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[N:23]=[CH:22][C:21]([C:24]([OH:33])([C:29]([F:32])([F:31])[F:30])[C:25]([F:28])([F:27])[F:26])=[CH:20][N:19]=3)[C@@H:14]([CH2:34][N:35]3[CH2:40][CH2:39][NH:38][C:37](=[O:41])[C:36]3([CH3:43])[CH3:42])[CH2:13]2)(=[O:11])=[O:10])=[CH:6][CH:5]=1)([O-])=O.C([O-])(O)=O.[Na+]>[Fe].CC(O)=O>[NH2:1][C:4]1[S:8][C:7]([S:9]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[N:19]=[CH:20][C:21]([C:24]([OH:33])([C:25]([F:26])([F:28])[F:27])[C:29]([F:30])([F:31])[F:32])=[CH:22][N:23]=3)[C@@H:14]([CH2:34][N:35]3[CH2:40][CH2:39][NH:38][C:37](=[O:41])[C:36]3([CH3:43])[CH3:42])[CH2:13]2)(=[O:10])=[O:11])=[CH:6][CH:5]=1
Reactant: CC1(C)C(=O)NCCN1C[C@H]1CN(S(=O)(=O)c2ccc([N+](=O)[O-])s2)CCN1c1ncc(C(O)(C(F)(F)F)C(F)(F)F)cn1
Agent: [Fe]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: CC1(C)C(=O)NCCN1C[C@H]1CN(S(=O)(=O)c2ccc(N)s2)CCN1c1ncc(C(O)(C(F)(F)F)C(F)(F)F)cn1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 28 %

Procedure:
A 250-mL round-bottomed flask was charged with 4-(((2S)-4-((5-nitro-2-thiophenyl)sulfonyl)-1-(5-(2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl)-2-pyrimidinyl)-2-piperazinyl)methyl)-3,3-dimethyl-2-piperazinone (0.314 g, 0.475 mmol, step 2), iron filings (0.136 g, 2.43 mmol) and AcOH (10 mL). The reaction mixture was heated at 50° C. for 3 h. An additional 0.052 g of iron filing was added and the heating at 50° C. was continued for 30 min. The mixture was allowed to cool to room temperature and then saturated aqueous NaHCO3 (300 mL) was slowly added. The aqueous phase was extracted with EtOAc (3×100 mL). The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by preparative HPLC (Phenomenex 5 μm, C18 column, 150×30 mm) eluting with 10 to 90% ACN with 0.1% TFA in H2O with 0.1% TFA in 15 min. The fractions were concentrated and basified with saturated aqueous NaHCO3. The resulting solid was collected (0.130 g). The aqueous phase was extracted with 10% iPrOH in CHCl3 containing 1% NH4OH. The combined organic extracts were dried over sodium sulfate, filtered and concentrated to obtain an additional 0.265 g. The combined material was purified by column chromatography (25 g of silica gel, 0 to 10% (2M NH3 in MeOH) in CH2Cl2 to afford 4-(((2S)-4-((5-amino-2-thiophenyl)sulfonyl)-1-(5-(2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl)-2-pyrimidinyl)-2-piperazinyl)methyl)-3,3-dimethyl-2-piperazinone (0.084 g) as an off-white solid.
Reaction SMILES: [C:1]([O:4][C:5](=[O:7])[CH3:6])(=O)[CH3:2].[C:8]1(CCO)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C(Cl)Cl.C/C(/O)=C\C(C)=O.C/C(/O)=C\C(C)=O.O=[V]>[CH3:6][C:5]([O:4][CH2:1][CH2:2][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:7]
Reactant: CC(=O)OC(C)=O
Reactant: OCCc1ccccc1
Agent: O=[V]
Agent: CC(=O)/C=C(\C)O
Solvent: ClCCl
Product: CC(=O)OCCc1ccccc1
Reaction time: 0.17 h
Yield: 84.9 %

Procedure:
In a dry 50-mL, two-necked, round-bottomed flask, vanadyl acetylacetonate (13.7 mg, 0.05 mmol) in 3 mL of anhydrous CH2Cl2 was placed. To the above solution, acetic anhydride (153.1 mg, 141.5 μL, 1.5 mmol) was slowly added at ambient temperature. After about 10 min, a solution of 2-phenylethanol (122 mg, 119.3 μL, 1.0 mmol) in CH2Cl2 (2 mL) was slowly added to the above dark green solution, and the reaction mixture was stirred for 5 hours. After completion of the reaction as monitored by TLC, the reaction mixture was quenched with cold, saturated aqueous NaHCO3 solution (5 mL). The resulting separated organic layer was washed with brine, dried (MgSO4), filtered, and evaporated. The crude product was purified by column chromatography on silica gel to yield 139.4 mg of 2-phenethyl acetate (85%) as colorless oil. The substrate, reaction time, and yield of this test are summarized in Entry 1 of the following Table 1.
Reaction SMILES: C([S:4][CH2:5][S:6][C:7]1[N:8]=[N:9][NH:10][CH:11]=1)(=O)C.C[O-].[Na+].[C:15]1([CH:21]([O:28][C:29]([C:31]2[N:36]3[C:37](=[O:59])[C@@H:38]([NH:39][C:40](=[O:58])/[C:41](/[C:45]4[N:46]=[C:47]([NH:50][C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])[S:48][CH:49]=4)=[CH:42]\[CH2:43][CH3:44])[C@H:35]3[S:34][CH2:33][C:32]=2OS(C)(=O)=O)=[O:30])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CN(C)C=O.CO.Cl.O>[C:15]1([CH:21]([O:28][C:29]([C:31]2[N:36]3[C:37](=[O:59])[C@@H:38]([NH:39][C:40](=[O:58])/[C:41](/[C:45]4[N:46]=[C:47]([NH:50][C:51]([O:53][C:54]([CH3:56])([CH3:57])[CH3:55])=[O:52])[S:48][CH:49]=4)=[CH:42]\[CH2:43][CH3:44])[C@H:35]3[S:34][CH2:33][C:32]=2[S:4][CH2:5][S:6][C:7]2[N:8]=[N:9][NH:10][CH:11]=2)=[O:30])[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CC(=O)SCSc1c[nH]nn1
Reactant: CC/C=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(OS(C)(=O)=O)CS[C@H]12)c1csc(NC(=O)OC(C)(C)C)n1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Solvent: O
Product: CC/C=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(SCSc3c[nH]nn3)CS[C@H]12)c1csc(NC(=O)OC(C)(C)C)n1
Reaction time: 0.33 h
Yield: 69.8 %

Procedure:
To a solution of 4-acetylthiomethylthio-1,2,3-triazole (230 mg: 1.22 mMol.) in dimethylformamide (6 ml) is dropwise added a 1.26N-sodium methoxide in methanol (1.9 ml) at -60° C., and the mixture is stirred for 20 minutes, mixed with a solution of 7β-[(Z)-2-(2-t-butoxycarbonylaminothiazol-4-yl)-2-pentenoylamino]-3-methanesulfonyloxy-3-cephem-4-carboxylic acid diphenylmethyl ester (740 mg: 1 mMol.) in dimethylformamide (3 ml), and stirred at the same temperature for 40 minutes. The reaction mixture is diluted with 10% hydrochloric acid (2 ml) and water (30 ml) and extracted with ethyl acetate. The extract is washed with water, dried over sodium sulfate, and purified by silica gel chromatography (toluene: ethyl acetate=2:1) to give 7β-[(Z)-2-(2-t-butoxycarbonylaminothiazol-4-yl)-2-pentenoylamino]-3-(1,2,3-triazol-4-ylthiomethylthio)-3-cephem-4-carboxylic acid diphenylmethyl ester (553 mg) as colorless foam. Yield: 70%.
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]([OH:8])([CH3:7])[C:4](O)=[O:5].[CH3:11][CH:12]([CH3:30])[CH2:13][CH2:14][NH:15][C:16]([C:18]1[N:19]=[N:20][C:21]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[CH:22][CH:23]=1)=[O:17]>>[CH:12]1([CH2:13][CH2:14][NH:15][C:16]([C:18]2[N:19]=[N:20][C:21]([N:24]3[CH2:29][CH2:28][N:27]([C:4](=[O:5])[C:3]([OH:8])([CH3:7])[C:2]([F:10])([F:9])[F:1])[CH2:26][CH2:25]3)=[CH:22][CH:23]=2)=[O:17])[CH2:30][CH2:11]1
Reactant: CC(O)(C(=O)O)C(F)(F)F
Reactant: CC(C)CCNC(=O)c1ccc(N2CCNCC2)nn1
Product: CC(O)(C(=O)N1CCN(c2ccc(C(=O)NCCC3CC3)nn2)CC1)C(F)(F)F

Procedure:
Following the procedure of Example 14, making variations only as required to use 3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid in place of 4,4,4-trifluoro-2-methylbutyric acid to react with 6-piperazin-1-yl-pyridazine-3-carboxylic acid (3-methylbutyl)amide, the title compound was obtained as a white solid (55% yield). m.p. 181-183° C. 1H NMR (300 MHz, CDCl3) δ8.07, 7.98, 7.01, 4.86, 3.92-3.81, 3.55, 1.74, 1.51, 0.81-0.68, 0.46, 0.09. 13C NMR (75 MHz, CDCl3) δ 167.2, 163.1, 160.0, 145.4, 127.1, 126.3, 122.5, 112.5. 76.8-75.6 (q, J=117 Hz, C—19F), 44.6, 39.7, 35.3, 20.5, 8.5, 4.8. MS (ES+) m/z 416 (M+1).