Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11](O)[CH2:10][C@H:9]1[C:14]([N:16]1[CH2:20][CH2:19][S:18][CH2:17]1)=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([N:23](CC)CC)C>ClCCl>[NH2:23][C@@H:11]1[CH2:12][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C@H:9]([C:14]([N:16]2[CH2:20][CH2:19][S:18][CH2:17]2)=[O:15])[CH2:10]1
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1C(=O)N1CCSC1
Reactant: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1C[C@@H](N)C[C@H]1C(=O)N1CCSC1

Procedure:
3-((2S,4R)-1-tert-Butoxycarbonyl-4-hydroxy-2-pyrrolidinylcarbonyl)-1,3-thiazolidine (title compound of Reference Example 9, 56.3 g) and triethylamine (28.5 mL) were dissolved in dichloromethane (1.0 l), and methanesulfonyl chloride (15.1 mL) was added thereto under ice-cooling. After stirring under ice-cooling for 1 hr, the reaction mixture was washed with water and dried. The solvent was evaporated under reduced pressure to give 3-((2S,4R)-1-tert-butoxycarbonyl-4-methanesulfonyloxy-2-pyrrolidinylcarbonyl)-1,3-thiazolidine (70.5 g) as. an oil.
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]([CH3:9])[CH2:5][CH2:6][CH2:7][OH:8].[Cl:10][C:11]1[C:16]([C:17]2[C:22]([F:23])=[CH:21][C:20](F)=[CH:19][C:18]=2[F:25])=[C:15]([NH:26][CH2:27][C:28]([F:31])([F:30])[F:29])[N:14]=[C:13]([N:32]([CH3:35])[C:33]#[N:34])[N:12]=1>CS(C)=O.C(OCC)(=O)C>[Cl:10][C:11]1[C:16]([C:17]2[C:18]([F:25])=[CH:19][C:20]([O:8][CH2:7][CH2:6][CH2:5][N:4]([CH3:9])[CH3:3])=[CH:21][C:22]=2[F:23])=[C:15]([NH:26][CH2:27][C:28]([F:31])([F:30])[F:29])[N:14]=[C:13]([N:32]([CH3:35])[C:33]#[N:34])[N:12]=1
Reactant: CN(C)CCCO
Reactant: CN(C#N)c1nc(Cl)c(-c2c(F)cc(F)cc2F)c(NCC(F)(F)F)n1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CN(C)CCCOc1cc(F)c(-c2c(Cl)nc(N(C)C#N)nc2NCC(F)(F)F)c(F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred mixture of sodium hydride (60% in mineral oil, 12 mg, 0.30 mmol) in 2 mL of dimethylsulfoxide is added 3-dimethylamino-1-propanol (27 μL, 0.23 mmol). The mixture is then stirred at room temperature for 1 h. 4-Chloro-6-[(2,2,2-trifluoroethyl)amino]-5-(2,4,6-trifluorophenyl)pyrimidin-2-yl(methyl)cyanamide (60 mg, 0.152 mmol) is then added, and the reaction mixture is heated at 60° C. for 4 h, and diluted with ethyl acetate. The organic layer is washed with water and saturated sodium chloride, dried over magnesium sulfate, and concentrated. The residue is chromatographed over silica gel, eluting with a gradient of ethyl acetate to 50% methyl alcohol in ethyl acetate to methyl alcohol. Concentration provides 4-chloro-5-{4-[3-(dimethylamino)propoxy]-2,6-difluorophenyl}-6-[(2,2,2-trifluoroethyl)amino]pyrimidin-2-yl(methyl)cyanamide as a light yellow semisolid solid (20 mg). MS: m/z 479.3(M+H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[NH:9][CH2:8][C@H:7]([NH:16][C:17](=[O:24])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:6]1=[O:25].C(N(CC)CC)C.[C:34]1([CH2:40][CH2:41][C:42](Cl)=[O:43])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:26])[CH2:4][N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]([C:42](=[O:43])[CH2:41][CH2:40][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH2:8][C@H:7]([NH:16][C:17](=[O:24])[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:6]1=[O:25]
Reactant: COC(=O)CN1C(=O)[C@@H](NC(=O)c2ccccc2)CNc2ccccc21
Reactant: O=C(Cl)CCc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)CN1C(=O)[C@@H](NC(=O)c2ccccc2)CN(C(=O)CCc2ccccc2)c2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86.7 %

Procedure:
A solution of (3S)-2-oxo-3-benzoylamino-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine-1-acetic acid methyl ester (200 mg, 0.57 mmol) in CH2Cl2 (10 ml) was treated with triethylamine (119 mg, 1.13 mmol) and 3-phenylpropionyl chloride (114 mg, 0.68 mmol). The reaction was stirred at RT for 30 min and diluted with CH2Cl2. The solution was washed with aq. 10% HCl, sat. aq. NaHCO3 and sat. aq. NaCl, dried over Na2SO4 and concentrated in vacuo to give 240 mg (87%) of 602a as a white foam.
Reaction SMILES: CC(C)(C)C[P:4]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.CC(C)(C)CCl>O1CCCC1.CCCCCC>[C:11]1([PH:4][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CC(C)(C)CP(c1ccccc1)c1ccccc1
Agent: CC(C)(C)CCl
Solvent: CCCCCC
Solvent: C1CCOC1
Product: c1ccc(Pc2ccccc2)cc1

Procedure:
The known but unavailable 2,2-dimethylpropyl diphenyl phosphine was derived via reacting 2,2-dimethylpropyl chloride with lithium diphenyl phosphide in a refluxing tetrahydrofuran-hexane solvent mixture. After filtering off the lithium chloride by-product, the 2,2-dimethylpropyl, (i.e., neopentyl) diphenyl phosphine was obtained by the fractional distillation of the filtrate between 109° and 110° C. at 0.1 mm.
Reaction SMILES: I([O-])(=O)(=O)=[O:2].[Na+].[C:7]([NH:9][C:10]([NH:21][CH3:22])=[N:11][CH2:12][CH2:13][S:14][CH2:15][C:16]1[S:17][CH:18]=[CH:19][N:20]=1)#[N:8]>O>[C:7]([NH:9][C:10]([NH:21][CH3:22])=[N:11][CH2:12][CH2:13][S:14]([CH2:15][C:16]1[S:17][CH:18]=[CH:19][N:20]=1)=[O:2])#[N:8]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: CNC(=NCCSCc1nccs1)NC#N
Agent: [Na+]
Solvent: O
Product: CNC(=NCCS(=O)Cc1nccs1)NC#N
Reaction time: 1 h
Yield: 100.7 %

Procedure:
Sodium metaperiodate (220 mg, 1.03 m.mol) was added to a stirred solution of N-cyano-N'-methyl-N"-[2-((2-thiazolyl)methylthio)ethyl]guanidine (255 mg, 1.0 m.mol) in water (90 ml). After 1 hour at 25° then 17 hours at 5° t.l.c. indicated the reaction was essentially complete. The solution was evaporated under reduced pressure at 60° to dryness, with azeotroping with n-propanol (2x). The residue was boiled with isopropanol (20 ml) for 3 minutes, filtered hot from 205 mg of inorganic salts, (100%), and evaporated under reduced pressure to a clear glass which was stirred continuously for 4 days under ether to give crude product (273 mg, 100%) m.p. 110° (softens only). Purification was effected by dissolution in acetonitrite (15 ml) and dilution of the filtered warm solution with ether to 210 ml. After 17 hours standing the precipitate had crystallised yielding, after filtration and washing with ether, N-cyano-N'-methyl-N"-[ 2-((2-thiazolyl)methylsulphinyl)ethyl]guanidine, (335 mg), m.p. 112°-113° C. Found: C, 39.62; H, 5.03; N, 25.64%. C9H13N5OS2 requires: C, 39.83; H, 4.83; N, 25.81%.
Reaction SMILES: [CH:1]([S:4][C:5]1[S:6][CH2:7][C:8](=[O:10])[N:9]=1)([CH3:3])[CH3:2].[CH3:11][S:12](Cl)(=[O:14])=[O:13].C(N(CC)CC)C.O>C(Cl)Cl>[CH:1]([S:4][C:5]1[S:6][CH:7]=[C:8]([O:10][S:12]([CH3:11])(=[O:14])=[O:13])[N:9]=1)([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)SC1=NC(=O)CS1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CC(C)Sc1nc(OS(C)(=O)=O)cs1
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.7 %

Procedure:
8 g of 2-isopropylthio-1,3-thiazoline-4-one was dissolved in 100 ml of methylene chloride and cooled below 10° C. Then, 7.8 g of methanesulfonyl chloride and 12.6 ml of triethylamine were added dropwise to the solution below 15° C. with attention to out-break of heat. After that, the reaction was continued with stirring at room temperature for 2 hours. Water was added to the reaction mixture and extracted by ether. The ether layer was washed with water and dried over anhydrous sodium sulfate. The oil obtained by concentration was purified by silica-gel column chromatography to obtain 9.1 g of the objective compound as a pale brown crystal (yield: 78.8%).
Reaction SMILES: N[C@@H:2]([C:10](O)=O)[CH2:3]C1N=CC=CC=1.[NH2:13][C@@H:14]([C:22]([OH:24])=[O:23])[CH2:15][C:16]1[CH:21]=[N:20][CH:19]=[CH:18][CH:17]=1.N[C@@H](C(O)=O)CC1C=CN=CC=1>>[CH:3]1[CH:2]=[CH:10][C:19]2[NH:20][CH:21]=[C:16]([CH2:15][C@@H:14]([NH2:13])[C:22]([OH:24])=[O:23])[C:18]=2[CH:17]=1
Reactant: N[C@H](Cc1ccccn1)C(=O)O
Reactant: N[C@H](Cc1cccnc1)C(=O)O
Agent: N[C@H](Cc1ccncc1)C(=O)O
Product: N[C@H](Cc1c[nH]c2ccccc12)C(=O)O

Procedure:
with at least one of position 3 or 6 being D-2-Pal, D-3-Pal, or D-4-Pal; and
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][C:3]=1[CH3:10].[NH2:11][C:12]1[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[C:17]([O:23][CH3:24])[C:13]=1[C:14]([NH2:16])=[O:15].OS([O-])=O.[Na+].CC1C=CC(S(O)(=O)=O)=CC=1.O>CC(N(C)C)=O.CCOC(C)=O>[OH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]2[NH:16][C:14](=[O:15])[C:13]3[C:12](=[CH:20][C:19]([O:21][CH3:22])=[CH:18][C:17]=3[O:23][CH3:24])[N:11]=2)=[CH:4][C:3]=1[CH3:10]
Reactant: Cc1cc(C=O)ccc1O
Reactant: COc1cc(N)c(C(N)=O)c(OC)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC(=O)N(C)C
Product: COc1cc(OC)c2c(=O)[nH]c(-c3ccc(O)c(C)c3)nc2c1
Yield: 35.1 %

Procedure:
A mixture of 4-hydroxy-3-methylbenzaldehyde (0.200 g, 1.47 mmol), 2-amino-4,6-dimethoxybenzamide (0.288 g, 1.47 mmol), NaHSO3 (94%, 0.163 g, 1.47 mmol), and p-TsOH.H2O (0.028 g, 0.147 mmol) in DMA (18.4 mL) was heated at reflux for 1 h. The mixture was diluted with EtOAc (300 mL), washed with saturated aqueous NH4Cl (2×150 mL) and brine (75 mL), dried over sodium sulfate, filtered and concentrated under vacuum. The residue was triturated with MeOH and filtered off a yellow solid, which was freeze-dried from MeCN/H2O to provide 2-(4-hydroxy-3-methylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one (0.161 g, 35%). Selected data: 1H NMR (300 MHz, DMSO-d6) δ 11.71 (s, 1H), 10.02 (s, 1H), 7.99 (d, J=1.88 Hz, 1H), 7.89 (dd, J=8.47, 2.29 Hz, 1H), 6.86 (d, J=8.50 Hz, 1H), 6.69 (d, J=2.31 Hz, 1H), 6.48 (d, J=2.31 Hz, 1H), 3.88 (s, 3H), 3.86 (s, 3H), 2.18 (s, 3H); MS (APCI) m/z 313 [M+H]+.
Reaction SMILES: O1CCCC1.[Si:6]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][N:18]=[C:17]([F:21])[CH:16]=1)([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7].C([N-]C(C)C)(C)C.[Li+].[Cl:30]C(Cl)(Cl)C(Cl)(Cl)Cl>C(OCC)(=O)C>[Si:6]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][N:18]=[C:17]([F:21])[C:16]=1[Cl:30])([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7]
Reactant: CC(C)(C)[Si](C)(C)OCc1ccnc(F)c1
Reactant: ClC(Cl)(Cl)C(Cl)(Cl)Cl
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)OCc1ccnc(F)c1Cl
Temperature: 0 °C
Yield: 29.5 %

Procedure:
A tetrahydrofuran solution (10 mL) of 4-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-fluoropyridine (469.1 mg, 1.94 mmol) was mixed with lithium diisopropylamide (1.08 M in tetrahydrofuran, 2.16 mL, 2.33 mmol) under cooling with ice. The reaction mixture was stirred at 0° C. for an hour, then added to hexachloroethane (840.0 mg, 3.50 mmol) and warmed slowly to room temperature for 12 hours with stirring. After completion of the reaction, the reaction solution was mixed with ethyl acetate, and the organic layer was washed with saturated aqueous ammonium chloride, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate=9/1 to 5/1) to give the desired product (157.7 mg, 30% yield).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7](B(O)O)[CH:8]=[CH:9][CH:10]=1)(=[O:3])[CH3:2].Cl[C:15]1[CH:20]=[C:19](Cl)[N:18]=[CH:17][N:16]=1.[IH:22]>>[I:22][C:15]1[CH:20]=[C:19]([C:7]2[CH:8]=[CH:9][CH:10]=[C:5]([NH:4][C:1](=[O:3])[CH3:2])[CH:6]=2)[N:18]=[CH:17][N:16]=1
Reactant: I
Reactant: Clc1cc(Cl)ncn1
Reactant: CC(=O)Nc1cccc(B(O)O)c1
Product: CC(=O)Nc1cccc(-c2cc(I)ncn2)c1

Procedure:
The compound was prepared according to Example 1 using 3-acetylaminophenylboronic acid and 4,6-dichloropyrimidine. The resultant chloro compound was converted to iodo with hydroiodic acid as described in the general procedure.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][C:12](=O)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1)#[N:2].[NH2:16][CH2:17][CH2:18][NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23].C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[C:22]([O:21][C:20](=[O:26])[NH:19][CH2:18][CH2:17][NH:16][CH:12]1[CH2:13][CH2:14][N:9]([C:6]2[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)[CH2:10][CH2:11]1)([CH3:25])([CH3:23])[CH3:24]
Reactant: N#Cc1ccc(N2CCC(=O)CC2)cc1
Reactant: CC(C)(C)OC(=O)NCCN
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC(C)(C)OC(=O)NCCNC1CCN(c2ccc(C#N)cc2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 35 (415 mg, 2.07 mmol), 1 (343 mg, 2.14 mmol), and acetic acid (629 mg, 10.48 mmol) in methanol (10 mL) was treated with sodium cyanoborohydride (140 mg, 2.23 mmol) at room temperature. The resulting mixture was stirred at room temperature (3 h). The solvent was removed in vacuo. PCTLC (SiO2, 4 mm, 10% EtOH-90% CHCl3) afforded the title compound (36).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[CH3:13])[C:6]([O:8][CH3:9])=[O:7].BrN1C(=[O:20])CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N.C1N2CN3CN(C2)CN1C3>C1C=CC=CC=1.C(O)(=O)C.O>[CH:13]([C:12]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[O:2][CH3:1])=[O:20]
Reactant: COC(=O)c1ccc(C)c(OC)c1
Reactant: O=C1CCC(=O)N1Br
Agent: C1N2CN3CN1CN(C2)C3
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: c1ccccc1
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)c1ccc(C=O)c(OC)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.6 %

Procedure:
2.50 g of methyl 3-methoxy-4-methylbenzoate was dissolved in 25 mL of benzene, to which 2.72 g of N-bromosuccinimide and 0.23 g of 2,2′-azobisisobutyronitrile were successively added at room temperature, and this solution was stirred for one hour while heating it under reflux. After 3.90 g of hexamethylenetetramine dissolved in 7.8 mL of acetic acid and 7.8 mL of water was added dropwise to the reaction mixture, benzene was distilled out therefrom, and then the mixture was stirred for one hour while heating it under reflux. The reaction mixture, which was cooled to room temperature, was added to a mixture of chloroform and water and then adjusted to pH 7 with a 20% aqueous solution of sodium hydroxide, and the organic phase was separated therefrom. After the resultant organic phase was successively washed with water, a saturated aqueous solution of sodium hydrogen carbonate, and a saturated sodium chloride solution, the washed phase was dried over anhydrous magnesium sulfate, and the solvent was distilled out under reduced pressure. The resultant residue was purified by silica gel column chromatography [eluent; hexane:ethyl acetate=3:1] to yield 1.74 g of methyl 4-formyl-3-methoxybenzoate as white solid.
Reaction SMILES: CN[C:3]([O:5][CH:6]1[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:13][C:12]2[C:7]1=[CH:8][CH:9]=[CH:10][CH:11]=2)=O.[CH3:20][C:21](=C)[CH2:22]O>>[CH:18]1[C:19]2[CH:6]([O:5][CH2:3][C:21]([CH3:22])=[CH2:20])[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[O:13][C:14]=2[CH:15]=[CH:16][CH:17]=1
Reactant: C=C(C)CO
Reactant: CNC(=O)OC1c2ccccc2Oc2ccccc21
Product: C=C(C)COC1c2ccccc2Oc2ccccc21

Procedure:
9-(N-Methylcarbamoyloxy)xanthene (4.0 g., 15.7 mmoles) was stirred with 20 ml. of 2-methyl-2-propen-1-ol for 20 hours at room temperature, and the mixture was then filtered. The filtrate was evaporated in vacuo and the residue was dissolved in ice-cold ether and washed twice with ice-cold portions of 10% aqueous acetic acid, water, and 5% aqueous sodium bicarbonate solution. After drying over potassium carbonate, the solvent was removed in vacuo, and the resulting oil was distilled to give (2-methyl-2-propen-1-yl) 9-xanthenyl ether, b.p. 116°C. at 0.15 mm.
Reaction SMILES: N(OC(C)(C)C)=O.[CH3:8][O:9][C:10](=[O:46])[N:11]([CH2:34][C:35]1[CH:40]=[C:39]([C:41]([F:44])([F:43])[F:42])[CH:38]=[C:37](N)[CH:36]=1)[CH2:12][C:13]1[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[CH:15][C:14]=1[C:23]1[CH:28]=[C:27]([CH:29]([CH3:31])[CH3:30])[CH:26]=[CH:25][C:24]=1[O:32][CH3:33].[ClH:47]>C(#N)C.CCOC(C)=O>[CH3:8][O:9][C:10](=[O:46])[N:11]([CH2:34][C:35]1[CH:40]=[C:39]([C:41]([F:44])([F:43])[F:42])[CH:38]=[C:37]([Cl:47])[CH:36]=1)[CH2:12][C:13]1[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[CH:15][C:14]=1[C:23]1[CH:28]=[C:27]([CH:29]([CH3:31])[CH3:30])[CH:26]=[CH:25][C:24]=1[O:32][CH3:33]
Reactant: COC(=O)N(Cc1cc(N)cc(C(F)(F)F)c1)Cc1cc(C(F)(F)F)ccc1-c1cc(C(C)C)ccc1OC
Reactant: Cl
Agent: CC(C)(C)ON=O
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COC(=O)N(Cc1cc(Cl)cc(C(F)(F)F)c1)Cc1cc(C(F)(F)F)ccc1-c1cc(C(C)C)ccc1OC
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of CuCl2 (11.9 mg, 0.09 mmol) in acetonitrile (1 mL) was added t-butyl nitrite (11 μL, 0.092 mmol). Next, the solution was cooled to 0° C. and methyl[3-amino-5-(trifluoromethyl)benzyl]{[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}carbamate (41 mg, 0.074 mmol) (Example 33) was added as a solution in acetonitrile (1.5 mL). The reaction was slowly warmed to room temperature. After stirring at room temperature for 2 hours, the mixture was diluted with EtOAc (30 mL) and poured into 20% HCl (5 mL). The organic extracts were washed with 20% HCl (2×5 mL), H2O (10 mL), brine (10 mL), dried over Na2SO4, filtered, and concentrated. Purification by flash chromatography with 5% to 80% EtOAc/hexanes afforded methyl[3-chloro-5-(trifluoromethyl)benzyl]{[5′-isopropyl-2′-methoxy-4-(trifluoromethyl)biphenyl-2-yl]methyl}carbamate. Rf=0.65 (15% EtOAc/hexanes). LCMS=574.3 (M+1)+. 1H NMR (C6D6, 500 MHz, 70° C.) δ 7.68 (s, 1H), 7.36 (d, J=7.5 Hz, 1H), 7.30 (s, 1H), 7.08-7.05 (m, 4H), 6.83 (d, J=2.5 Hz, 1H), 6.60 (d, J=8.5 Hz, 1H), 4.35 (broad singlet, 3H), 4.01 (broad singlet, 1H), 3.36 (s, 3H), 3.26 (s, 3H), 2.74 (m, 1H), 1.16 (d, J=7.0 Hz, 6H).
Reaction SMILES: Cl.[NH2:2][CH:3]1[C:24](=[O:25])[N:5]2[C:6]([C:11]([O:13][CH2:14][C:15]3[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=3)=[O:12])=[C:7]([Cl:10])[CH2:8][S:9][C@H:4]12.C[Si](CC(N)=O)(C)C.[S:34]1[CH:39]=[C:38]([C:40](=[N:44][O:45][CH3:46])[C:41](O)=[O:42])[S:37][CH2:36][CH2:35]1.P(Cl)(Cl)(Cl)=O>C(OCC)(=O)C.CN(C)C=O>[S:34]1[CH:39]=[C:38]([C:40](=[N:44][O:45][CH3:46])[C:41]([NH:2][CH:3]2[C:24](=[O:25])[N:5]3[C:6]([C:11]([O:13][CH2:14][C:15]4[CH:16]=[CH:17][C:18]([N+:21]([O-:23])=[O:22])=[CH:19][CH:20]=4)=[O:12])=[C:7]([Cl:10])[CH2:8][S:9][C@H:4]23)=[O:42])[S:37][CH2:36][CH2:35]1
Reactant: CON=C(C(=O)O)C1=CSCCS1
Reactant: NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(Cl)CS[C@H]12
Agent: C[Si](C)(C)CC(N)=O
Agent: Cl
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(Cl)CS[C@H]12)C1=CSCCS1
Yield: 89.4 %

Procedure:
A solution of 4-nitrobenzyl 7-amino-3-chloro-3-cephem-4-carboxylate hydrochloride (4.06 g.) and trimethylsilylacetamide (9.19 g.) in ethyl acetate (40 ml.) and a solution of 2-(2,3-dihydro-1,4-dithiin-5-yl)-2-methoxyiminoacetic acid (syn isomer, 2.2 g.), N,N-dimethylformamide (0.8 g.) and phosphoryl chloride (1.67 g.) in ethyl acetate (24 ml.) were treated in a similar manner to that of Example 19-(1) to give 4-nitrobenzyl 7-[2-(2,3-dihydro-1,4-dithiin-5-yl)-2-methoxyiminoacetamido]-3-chloro-3-cephem-4-carboxylate (syn isomer, 5.1 g.).
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:8][CH2:9][CH3:10])[CH:5]([Cl:7])[Cl:6])[CH3:2].C[C:12]1[CH:17]=[CH:16][C:15](S(O)(=O)=O)=[CH:14][CH:13]=1>C(O)CCCCCCC>[CH2:1]([O:3][CH:4]([O:8][CH2:9][CH2:10][CH2:12][CH2:17][CH2:16][CH2:15][CH2:14][CH3:13])[CH:5]([Cl:7])[Cl:6])[CH2:2][CH2:16][CH2:17][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CCOC(OCC)C(Cl)Cl
Solvent: CCCCCCCCO
Product: CCCCCCCCOC(OCCCCCCCC)C(Cl)Cl

Procedure:
A mixture of 5 g of dichloro-acetaldehyde diethyl-acetal, 25 g of octanol and 0.1 g of 4-methyl-benzene-sulphonic acid is heated on a water-bath for 5 hours, then distilled.
Reaction SMILES: CN(C)C=O.[CH3:6][O:7][C:8]1[CH:17]=[C:16]2[C:11]([C:12]([CH3:19])=[CH:13][C:14](=[O:18])[NH:15]2)=[CH:10][CH:9]=1.[H-].[Na+].CS(O[CH2:27][CH2:28][CH:29]1[CH2:38][CH2:37][C:32]2([O:36][CH2:35][CH2:34][O:33]2)[CH2:31][CH2:30]1)(=O)=O>C(OCC)(=O)C.O>[O:33]1[C:32]2([CH2:31][CH2:30][CH:29]([CH2:28][CH2:27][N:15]3[C:16]4[C:11](=[CH:10][CH:9]=[C:8]([O:7][CH3:6])[CH:17]=4)[C:12]([CH3:19])=[CH:13][C:14]3=[O:18])[CH2:38][CH2:37]2)[O:36][CH2:35][CH2:34]1
Reactant: COc1ccc2c(C)cc(=O)[nH]c2c1
Reactant: CS(=O)(=O)OCCC1CCC2(CC1)OCCO2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccc2c(C)cc(=O)n(CCC3CCC4(CC3)OCCO4)c2c1
Temperature: 62.5 °C
Reaction time: 0.5 h

Procedure:
To 3 mL of an N,N-dimethylformamide solution containing 0.12 g of 7-methoxy-4-methylquinolin-2(1H)-one, 28 mg of a 60% aqueous sodium hydride solution was added at 50° C., and the mixture was stirred at 60 to 65° C. for 30 minutes. Thereto was added 2 mL of an N,N-dimethylformamide solution containing 0.18 g of 2-(1,4-dioxaspiro[4.5]decan-8-yl)ethyl methanesulfonate at 50° C., and the mixture was stirred at 60 to 65° C. for 1 hour and 20 minutes. Thereto was added 14 mg of a 60% aqueous sodium hydride solution at the same temperature, and the mixture was stirred for 1 hour and 45 minutes. The reaction mixture was cooled to room temperature, and then water and ethyl acetate were then added thereto. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract were combined, the resultant solution was washed with an aqueous saturated sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by flash silica gel column chromatography [hexane:gradient elution of ethyl acetate=40:60 to 30:70] to obtain 65 mg of a colorless oily substance, 1-(2-(1,4-dioxaspiro[4.5]decan-8-yl)ethyl)-7-methoxy-4-methylquinolin-2(1H)-one.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][NH:12][C:11](=[O:15])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].CN(C=O)C.[Cl:23][C:24]1[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=1[CH2:26]Cl>ClCCl.O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([CH2:26][C:25]2[CH:28]=[CH:29][CH:30]=[CH:31][C:24]=2[Cl:23])[C:11](=[O:15])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=c1cc(OCc2ccccc2)cc[nH]1
Reactant: ClCc1ccccc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: O
Product: O=c1cc(OCc2ccccc2)ccn1Cc1ccccc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65.9 %

Procedure:
A solution of 4-benzyloxy-1H-pyridone (300 mg, 1.49 mmol) and NaH (60 mg, 1.49 mmol) in solvent of DMF was stirred for 30 min followed by adding 2-chlorobenzyl chloride (240 mg, 1.49 mmol) further stirring for 30 min at room temperature. The resulting solution was worked up with Water and dichloromethane and purified by column chromatography (ethyl acetate/hexane, 1:1) to obtain the titled compound (320 mg, 67%).