Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[C:10]([F:13])([F:12])[F:11])[CH2:5][NH2:6].[N:14]([C:17]1[CH:25]=[CH:24][CH:23]=[C:22]2[C:18]=1[CH:19]=[CH:20][NH:21]2)=[C:15]=[O:16]>>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[C:10]([F:11])([F:12])[F:13])[CH2:5][NH:6][C:15]([NH:14][C:17]1[CH:25]=[CH:24][CH:23]=[C:22]2[C:18]=1[CH:19]=[CH:20][NH:21]2)=[O:16]
Reactant: NCc1ccc(C(F)(F)F)c(F)c1
Reactant: O=C=Nc1cccc2[nH]ccc12
Product: O=C(NCc1ccc(C(F)(F)F)c(F)c1)Nc1cccc2[nH]ccc12
Yield: 68.3 %

Procedure:
3-Fluoro-4-(trifluoromethyl)benzylamine (0.22 g, 1.1 mmol) and the product of Example 80A (0.16 g, 1 mmol) were treated as described in Example 80B to provide the title compound (0.24 g). mp 198° C.; 1H NMR (300 MHz, DMSO-d6) δ 4.43 (d, 2H), 6.52 (m, 1H), 6.98 (m, 3H), 7.26 (m, 1H), 7.39 (m, 2H), 7.57 (dd, 1H), 7.77 (t, 1H), 8.40 (s, 1H), 11.05 (s, 1H); MS (DCI+) m/z 349.9 (M+H)+. Anal. Calcd. for C17H13N3F4O: C, 58.12; H, 3.73; N, 11.96. Found C, 58.52; H, 3.99; N, 11.55.
Reaction SMILES: [NH:1]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C@H:2]([C:22]([OH:24])=[O:23])[CH2:3][NH:4]C(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O.[CH2:32]([N-:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH3:58])[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43].C(NCC)C>ClCCl>[NH:1]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C@H:2]([C:22]([OH:24])=[O:23])[CH2:3][NH2:4].[CH2:32]([N-:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH3:58])[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43]
Reactant: CC(C)(C)OC(=O)N[C@@H](CNC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Agent: CCCCCCCCCCCCCC[N-]CCCCCCCCCCCC
Solvent: ClCCl
Solvent: CCNCC
Product: CC(C)(C)OC(=O)N[C@@H](CN)C(=O)O
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 87.1 %

Procedure:
607 mg Boc-Dap(Fmoc)-N-lauryl-N-myristyl amide were dissolved in 8 ml anhydrous dichloromethane in a 50 ml round-bottom flask (FIG. 6). 3 ml diethylamine were added and the reaction stirred at room temperature for 4.5 hours. The volatile constituents were removed using a rotary evaporator and the residue was purified by chromatography using 40 g silica gel 60 (Merck) with hexane/ethylacetate 5:1. The product was eluted by a step gradient consisting of ethylacetate, dichloromethane and dichloromethane/methanol 3:1. 372 mg (0.655 mmol) Boc-Dap-N-lauryl-N-myristyl amide was obtained as yellowish, viscous oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([F:11])[CH:10]=1)[NH:7][C:6]1[CH2:12][CH:13]([CH2:17][C:18]([OH:20])=[O:19])[CH2:14][CH2:15][CH2:16][C:5]2=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].[CH3:31][S:32]([C:35]1[CH:42]=[CH:41][C:38]([CH2:39]Cl)=[CH:37][CH:36]=1)(=[O:34])=[O:33]>O1CCCC1.C1(C)C=CC=CC=1.O>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([F:11])[CH:10]=1)[N:7]([CH2:39][C:38]1[CH:37]=[CH:36][C:35]([S:32]([CH3:31])(=[O:34])=[O:33])=[CH:42][CH:41]=1)[C:6]1[CH2:12][CH:13]([CH2:17][C:18]([OH:20])=[O:19])[CH2:14][CH2:15][CH2:16][C:5]2=1
Reactant: CS(=O)(=O)c1ccc(CCl)cc1
Reactant: O=C(O)CC1CCCc2c([nH]c3c(F)cc(F)cc23)C1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: O
Product: CS(=O)(=O)c1ccc(Cn2c3c(c4cc(F)cc(F)c42)CCCC(CC(=O)O)C3)cc1
Reaction time: 0.17 h

Procedure:
To a cold solution (0° C.) of 3.5 g of acid from Step 2 in 75 mL of tetrahydrofuran was added dropwise 38.7 cc of a solution of KHMDS in toluene (0.684M) and the mixture stirred for 10 minutes. To the resulting cold (0° C.) solution was added dropwise 3.5 g of a solution of p-methylsufonylbenzyl chloride in 10 mL of tetrahydrofuran. The reaction mixture was then stirred at room temperature for 6 hours. The reaction mixture was diluted with water and washed with Et2O. The aqueous layer was acidified with HCl (1N) and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and evaporated to dryness. The residue was triturated with a mixture of hexane/ethyl acetate (7:3) and filtered to yield the title product m.p. 200°-202° C.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH2:9]([O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]1[NH:19][C:20](=[O:30])[C:21]2[CH:26]=[N:25][N:24]([CH2:27][CH2:28][CH3:29])[C:22]=2[N:23]=1)[CH3:10]>CN(C=O)C>[Br:1][C:15]1[CH:16]=[CH:17][C:12]([O:11][CH2:9][CH3:10])=[C:13]([C:18]2[NH:19][C:20](=[O:30])[C:21]3[CH:26]=[N:25][N:24]([CH2:27][CH2:28][CH3:29])[C:22]=3[N:23]=2)[CH:14]=1
Reactant: CCCn1ncc2c(=O)[nH]c(-c3ccccc3OCC)nc21
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Product: CCCn1ncc2c(=O)[nH]c(-c3cc(Br)ccc3OCC)nc21
Reaction time: 20 h
Yield: 76.9 %

Procedure:
A solution of N-bromosuccinimide (1.0 g, 0.0056 mol) in DMF (10 ml) was added dropwise to a stirred solution of 6-(2-ethoxyphenyl)-1-n-propyl-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one (Example 1; 0.84 g, 0.0028 mol) in DMF (10 ml) and the resulting red solution stirred for 20 hours. The solvent was removed by evaporation under vacuum and the residue partitioned between saturated aqueous sodium bicarbonate solution (20 ml) and ethyl acetate (20 ml). The organic phase was removed and the aqueous phase extracted with ethyl acetate (3×30 ml). The combined organic solutions were dried and the solvent removed by evaporation under vacuum to give an orange crystalline solid. Recrystallisation from ethyl acetate-hexane gave the title compound as colourless crystals (0.812 g, 78%), m.p. 172-173° C. Found: C,51.13; H,4.41; N,14.84. C16H17BrN4O2 requires C,50.94; H,4.54; N,14.85%.
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:19])[CH2:15][CH2:16][CH:17]=[CH2:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].Br[CH2:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33]>C1COCC1>[CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14]([C@@H:15]([CH2:16][CH:17]=[CH2:18])[CH2:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])=[O:19])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: C=CCCC(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CC[C@@H](CC(=O)OC(C)(C)C)C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 92.7 %

Procedure:
A dry round bottom flask was charged with 1a (3.2 g, 12.34 mmol) and dry THF (123 mL) and then cooled to −78° C. To this solution NaHMDS (1M in THF, 13.57 mL, 13.57 mmol) was added over a period of 10 minutes. To ensure complete enolization, the reaction mixture was stirred for an additional 20 minutes at −78° C. A solution of tert-butyl bromoacetate (2.74 mL, 18.51 mmol) in THF (6 mL) was then introduced to the reaction flask. The solution was stirred for 1 hour at −78° C. and then warmed to −48° C. while still stirring. The reaction was monitored by TLC (˜3 h) and quenched with saturated aqueous NH4Cl. The reaction mixture was concentrated by the removing the THF under reduced pressure. The residue was then diluted with dichloromethane. This solution was washed successively with water and brine, dried over Na2SO4, and concentrated under reduced pressure to give white crystals of 2a (4.27 g, 93%). 1H NMR (500 MHz, CDCl3): δ ppm 7.32-7.37 (m, 2H) 7.27-7.30 (m, 3H) 5.74-5.85 (m, 1H) 5.05-5.13 (m, 2H) 4.63-4.70 (m, 1H) 4.25-4.32 (m, 1H) 4.16 (d, J=4.9 Hz, 2H) 3.34 (dd, J=13.4, 2.7 Hz, 1H) 2.74-2.87 (m, 2H) 2.39-2.52 (m, 2H) 2.19-2.26 (m, 1H) 1.44 (s, 9H); 13C NMR (126 MHz, CDCl3): δ 175.0, 171.1, 153.0, 135.6, 134.4, 129.4, 128.8, 127.1, 117.7, 80.6, 65.8, 55.4, 39.0, 37.5, 36.6, 36.1, 28.0. HRMS calcd for C21H27NO5 (M+H) m/z 374.1967, found 374.1971.
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][C:7]([O:9]CC)=[O:8])=[N+:2]=[N-:3].[OH-].[K+].O>CO>[N:1]([CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8])=[N+:2]=[N-:3]
Reactant: CCOC(=O)CCCN=[N+]=[N-]
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: [N-]=[N+]=NCCCC(=O)O
Temperature: 0 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
Ethyl 4-azidobutyrate (8.06 g, 51.3 mmol) and KOH (14.4 g, 0.256 mol) were dissolved into a mixture of 100 ml of water and 120 ml of MeOH. The solution was stirred at 0° C. for 2 hrs and then MeOH was removed in vacuo. The aqueous layer was extracted by CHCl3 (50 ml), acidified to pH=1 by 2N aqueous HCl and extracted by Et2O (2×100 ml). The organic layers were combined, washed with water (100 ml) and dried over Na2SO4. After filtration and evaporation of solvent, 4-azidobutyric acid (5.30 g, 80%) was obtained as a colorless oil.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([CH:8]([CH3:10])[CH3:9])=[N:6][CH:7]=1.[CH2:11](C([Sn])=C(CCCC)CCCC)[CH2:12]CC>CN(C=O)C.C1COCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:8]([C:5]1[CH:4]=[CH:3][C:2]([CH:11]=[CH2:12])=[CH:7][N:6]=1)([CH3:10])[CH3:9]
Reactant: CCCCC([Sn])=C(CCCC)CCCC
Reactant: CC(C)c1ccc(Br)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: O
Product: C=Cc1ccc(C(C)C)nc1
Temperature: 100 °C
Yield: 91.8 %

Procedure:
The title compound was prepared by following general procedure 2. 5-Bromo-2-isopropyl-pyridine (0.75 g, 3.7 mmol) was dissolved in DMF:THF (3:1, 6 mL). Tributylvinyltin (1.2 mL, 4.12 mmol) and Pd(PPh3)4 (0.070 g, 0.06 mmol) was added to this solution at RT under nitrogen and was heated at 100° C. for 30 min. The reaction mixture was cooled to RT and diluted with water (60 mL) and extracted with DCM (3×100 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure below 40° C. The crude was purified through column chromatography (90% DCM-Hexane in silica 100-200 mesh, Diameter of column—5.0 cm, Height of silica—approx. 5 inch) to provide 2-isopropyl-5-vinylpyridine as a light yellow liquid (0.5 g, 90% yield).
Reaction SMILES: S1C=C[CH:3]=N1.CSC(=N)N[N+]([O-])=O.[S:14]1[CH:18]=[CH:17][C:16]([CH2:19][S:20][CH2:21][CH2:22][NH:23][C:24]([NH:26][N+:27]([O-:29])=[O:28])=[NH:25])=[N:15]1.CNC(=N[N+]([O-])=O)SC>>[S:14]1[CH:18]=[CH:17][C:16]([CH2:19][S:20][CH2:21][CH2:22][NH:23][C:24]([NH:25][CH3:3])=[N:26][N+:27]([O-:29])=[O:28])=[N:15]1
Reactant: c1cnsc1
Reactant: N=C(NCCSCc1ccsn1)N[N+](=O)[O-]
Agent: CNC(=N[N+](=O)[O-])SC
Agent: CSC(=N)N[N+](=O)[O-]
Product: CNC(=N[N+](=O)[O-])NCCSCc1ccsn1

Procedure:
Reacting 3-[2-aminoethyl)thiomethyl]isothiazole with S-methyl-N-nitroisothiourea by the procedure of Example 2(ii) gives N-[2-(3-isothiazolylmethylthio)ethyl]-N'-nitroguanidine and reaction of the same starting material with N,S-dimethyl-N'-nitroisothiourea by the procedure of Example 2(iii) gives N-[2-(3-isothiazolylmethylthio)ethyl]-N'-methyl-N"-nitroguanidine.
Reaction SMILES: [H-].[Na+].[C:3]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:4][C:5]([CH3:7])=[O:6].[N+:12]([C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH2:18]Br)([O-:14])=[O:13].[NH4+].[Cl-]>C1COCC1>[N+:12]([C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH2:18][CH:4]([C:5]([CH3:7])=[O:6])[C:3]([O:9][CH2:10][CH3:11])=[O:8])([O-:14])=[O:13]
Reactant: CCOC(=O)CC(C)=O
Reactant: O=[N+]([O-])c1cccc(CBr)c1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCOC(=O)C(Cc1cccc([N+](=O)[O-])c1)C(C)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
NaH (1.94 g, 60%) is added to the solution of ethyl acetoacetate (6.029) in THF (100 ml) at 0° C. under nitrogen atmosphere. The reaction mixture is stirred for 15 minutes at the temperature and 3-nitrobenzylbromide (10 g) is added. The reaction mixture is stirred at room temperature overnight. The reaction mixture is poured into saturated NH4Cl aq. and extracted with EtOAc twice. The combined organic extract is washed with brine and dried over MgSO4. Concentration under reduced pressure gives the residue which is purified over column chromatography to afford ethyl 2-(3-nitrobenzyl)-acetoacetate (12 g).
Reaction SMILES: CC(C)([O-])C.[K+].[N+]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-:18])=[O:17])[CH:11]=1)([O-])=O.[CH2:19]([OH:27])[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.CN(C)P(N(C)C)(N(C)C)=O>O>[C:21]1([CH2:20][CH2:19][O:27][C:10]2[CH:11]=[C:12]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:14][CH:15]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: OCCc1ccccc1
Reactant: O=[N+]([O-])c1cccc([N+](=O)[O-])c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: O=[N+]([O-])c1cccc(OCCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 168 h
Yield: 219.9 %

Procedure:
Potassium t-butoxide (11.2 g; 0.1 mol) is added under a nitrogen atmosphere to a stirred mixture of m-dinitrobenzene (16.8 g; 0.1 mol), phenethyl alcohol (12.2 g; 0.1 mol) and hexamethylphosphoramide (HMPA; 200 ml). Almost instantly a dark red color develops and then slowly fades in the course of the reaction and turns black. The reaction mixture is stirred for 7 days at room temperature. It is then drowned in water, and extracted twice with methylene chloride (500 ml). The methylene chloride solution is washed with water (3X), saturated brine (1X), dried over magnesium sulfate and evaporated to yield 53.5 g of a dark oil. Additional solvent (HMPA) and some m-dinitrobenzene is removed from the oil by heating same at about 90° C. under 0.5 mm vacuum. The residual oil (~25 g) is chromatographed on 1 kg silica gel with 3:1 hexane:methylene chloride. Collected fractions, containing the same material by thin layer chromatography, are combined and evaporated to afford 7.4 g (30%) of product, a light yellow oil. On standing, the oil crystallizes, mp. 46.5°-49° C.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:8]([F:11])=[C:7]2[C:3]=1[C:4]([CH2:12][CH:13]([OH:15])[CH3:14])=[CH:5][NH:6]2.[C:16]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])(=O)[CH2:17][CH2:18][CH3:19].B(F)(F)F.CCOCC>C(Cl)Cl>[CH2:25]([O:24][C:22](=[O:23])[CH2:21][C:16]1([CH2:17][CH2:18][CH3:19])[C:5]2[NH:6][C:7]3[C:3]([C:4]=2[CH2:12][CH:13]([CH3:14])[O:15]1)=[C:2]([Br:1])[CH:10]=[CH:9][C:8]=3[F:11])[CH3:26]
Reactant: CCCC(=O)CC(=O)OCC
Reactant: CC(O)Cc1c[nH]c2c(F)ccc(Br)c12
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: CCCC1(CC(=O)OCC)OC(C)Cc2c1[nH]c1c(F)ccc(Br)c21
Reaction time: 3 h

Procedure:
To a solution of 1-(4-bromo-7-fluoro-1H-indol-3-yl)-propan-2-ol (155 mg, 0.570 mmol) and ethyl butyrylacetate (0.137 mL, 0.854 mmol) in CH2Cl2 (3 mL) was added BF3.OEt2 (0.11 mL, 0.854 mmol) dropwise at room temperature. After stirring for 3 hours, the mixture was diluted with CH2Cl2 (15 mL) and then washed with saturated aqueous NaHCO3 (15 mL) and brine (15 mL). The organic phase was dried (Na2SO4) and concentrated. The residue was purified by flash chromatography (silica, 10% EtOAc in hexanes) to give (5-bromo-8-fluoro-3-methyl-1-propyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-acetic acid ethyl ester as a pale yellow solid (this sample contains ethyl butyrylacetate).
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:5]2[N:6]([CH3:14])[C:7](=[O:13])[CH2:8][CH2:9][C:10]([CH3:12])([CH3:11])[C:4]=2[CH:3]=1.Cl[C:18]1[N:23]=[C:22]([NH:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[S:31]([CH:34]([CH3:36])[CH3:35])(=[O:33])=[O:32])[C:21]([Cl:37])=[CH:20][N:19]=1>>[Cl:37][C:21]1[C:22]([NH:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[S:31]([CH:34]([CH3:36])[CH3:35])(=[O:33])=[O:32])=[N:23][C:18]([NH:1][C:2]2[CH:16]=[CH:15][C:5]3[N:6]([CH3:14])[C:7](=[O:13])[CH2:8][CH2:9][C:10]([CH3:12])([CH3:11])[C:4]=3[CH:3]=2)=[N:19][CH:20]=1
Reactant: CN1C(=O)CCC(C)(C)c2cc(N)ccc21
Reactant: CC(C)S(=O)(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Product: CC(C)S(=O)(=O)c1ccccc1Nc1nc(Nc2ccc3c(c2)C(C)(C)CCC(=O)N3C)ncc1Cl
Yield: 28.8 %

Procedure:
Following a procedure analogous to Example 113, 7-Amino-1,5,5-trimethyl-1,3,4,5-tetrahydro-benzo[b]azepin-2-one (35 mgs) and (2,5-Dichloro-pyrimidin-4-yl)-[2-(propane-2-sulfonyl)-phenyl]-amine (50 mgs) gave the title compound as an off-white solid (22 mgs). 1H-NMR (CDCl3, 400 MHz): 9.65 (s, 1H), 8.55 (d, J=8.3 Hz, 1H); 8.19 (s, 2H), 7.94 (d, J=8.1 Hz, 1H), 7.65-7.58 (m, 2H), 7.37 (s, 1H), 7.30-7.26 (m, 1H); 7.14-7.10 (m, 2H); 3.31 (s, 3H); 3.28-3.23 (m, 1H), 2.33-2.30 (m, 2H), 2.03 (broad s, 2H), 1.34 (d, J=7.1 Hz, 6H), 1.27 (s, 6H). LC/MS: found 528.15 (M+H)+; MP:195-197° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[S:12][CH2:13][C:14]#[N:15].[C:16](OC(=O)C)(=[O:18])[CH3:17]>>[C:14]([CH2:13][S:12][C:3]1[CH:4]=[CH:5][C:6]([C:8]([F:9])([F:10])[F:11])=[CH:7][C:2]=1[NH:1][C:16](=[O:18])[CH3:17])#[N:15]
Reactant: CC(=O)OC(C)=O
Reactant: N#CCSc1ccc(C(F)(F)F)cc1N
Product: CC(=O)Nc1cc(C(F)(F)F)ccc1SCC#N

Procedure:
(2-Amino-4-trifluoromethylphenylsulfanyl)acetonitrile (0.66 g) was stirred on an ice bath at 0° C. Acetic acid anhydride (2.5 ml) was added, and the resulting solution was allowed to reach room temperature. After 1 h the mixture was concentrated in vacuo and the solid residue was triturated with petroleum ether (2×2 ml), filtered off and and dried to give the title compound as a white solid. Yield 0.75 g (96%), mp 103-103.3° C.; 1H-NMR(CDCl3) δ (ppm): 8.79 (br, 1H), 8.36 (br, 1H), 7.78 (d, 1H), 7.38 (dd, 1H, J: 8 Hz/2 Hz), 3.50 (s, 2H) 2.29 (s, 3H); 13C-NMR (DMSO-d6) δ (ppm): 169.2 (C═O), 137.1, 134.3, 129.6, 127.7 (q, J=32 Hz), 122.7 (m, 2C), 123.9 (CF3, J=272), 117.6 (CN), 23.2 (H3), 17.6 (CH2); IR (KBr) ν (cm−1): 3249, 2244 (C≡N), 1660, 1530, 1483, 1335, 1170, 1116, 1095.
Reaction SMILES: [K].[OH:2][C:3]1[C:12]([CH2:13][CH2:14][CH3:15])=[C:11]([O:16][CH3:17])[CH:10]=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6].Cl[CH2:19][O:20][CH2:21]Cl.Cl>O1CCCC1>[CH3:19][O:20][CH2:21][O:2][C:3]1[C:12]([CH2:13][CH2:14][CH3:15])=[C:11]([O:16][CH3:17])[CH:10]=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6]
Reactant: CCCc1c(OC)ccc(C(=O)OC)c1O
Reactant: ClCOCCl
Agent: Cl
Agent: [K]
Solvent: C1CCOC1
Product: CCCc1c(OC)ccc(C(=O)OC)c1OCOC
Reaction time: 0.33 h

Procedure:
In argon atmosphere, a solution of potassium t-buthoxide (18.7 g) in tetrahydrofuran (200 ml) was cooled to 0° C., and to this solution was added dropwise a solution of methyl 2-hydroxy-3-n-propyl-4-methoxybenzoate (28 g) in tetrahydrofuran (100 ml) in 10 minutes, and the mixture was agitated for another 20 minutes. Chloromethyl ether (19.0 ml) was added thereto, and the mixture was agitated at 0° C. for 50 minutes. The reaction mixture was poured into 1N aqueous hydrochloric acid, and extracted twice with ethyl acetate. The organic layer was washed with saturated sodium bicarbonate, dried over anhydrous magnesium sulfate, and then concentrated in evacuated atomosphere. The residue was subjected to column chromatography using silica gel, and there was obtained methyl 2-methoxymethoxy-3-n-propyl-4-methoxybenzoate (29.9 g) from fractions eluted with n-hexane-ethyl acetate (10:1 to 5:1).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:23][O:24][CH3:25])[C:8]([NH:10][CH:11]2[C:21](=[O:22])[N:13]3[C:14]([C:18]([OH:20])=[O:19])=[CH:15][CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.[C:26]([O:31][CH2:32]I)(=[O:30])[CH:27]([CH3:29])[CH3:28]>C(N(CC)CC)C>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:23][O:24][CH3:25])[C:8]([NH:10][CH:11]2[C:21](=[O:22])[N:13]3[C:14]([C:18]([O:20][CH2:32][O:31][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])=[O:19])=[CH:15][CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: CC(C)C(=O)OCI
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=CCS[C@H]12)c1csc(N)n1
Solvent: CCN(CC)CC
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)OCOC(=O)C(C)C)=CCS[C@H]12)c1csc(N)n1

Procedure:
In the same manner as Example 8, 7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylic acid (syn-isomer) was reacted with iodomethyl isobutyrate in the presence of triethylamine to give isobutyryloxymethyl 7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylate (syn-isomer), mp 95°-100° C. (decompn.).
Reaction SMILES: [CH3:1][CH:2]([CH2:5][CH:6]([CH3:14])[CH2:7][CH:8]([CH3:13])[CH2:9][CH:10]([CH3:12])[CH3:11])[CH2:3][OH:4].[C:15]12[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=1)[NH:20]C(=O)O[C:16]2=[O:17]>>[CH3:1][CH:2]([CH2:5][CH:6]([CH3:14])[CH2:7][CH:8]([CH3:13])[CH2:9][CH:10]([CH3:12])[CH3:11])[CH2:3][O:4][C:16](=[O:17])[C:15]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[NH2:20]
Reactant: CC(C)CC(C)CC(C)CC(C)CO
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Product: CC(C)CC(C)CC(C)CC(C)COC(=O)c1ccccc1N
Temperature: 120 °C
Reaction time: 1 h
Yield: 93.3 %

Procedure:
A one liter, four necked, round bottom flask, equipped with an overhead stirrer, sub-surface gas inlet tube, thermowell, Dean-Stark trap, and Friedrick's condenser, is charged with 313.4 grams (1.56 moles) of 2,4,6,8-tetramethyl-nonan-1-ol. The flask is purged with nitrogen and warmed to 120 degrees C. 3.7 grams (46 mmoles) of a 50 percent by weight solution of NaOH in water is added drop-wise over 1 minute. The mixture is stirred at 120 degrees C. for 1 hour and water is collected in the Dean-Stark trap. 250 grams of isatoic anhydride (1.53 moles) is added portion-wise, supra-surface, over a period of 50 minutes. The mixture is stirred at 145 degrees C. for 6 hours. 9 grams of Fax-5 filter aid is added to the flask and stirred. The mixture is filtered and cooled to yield 456 grams of the product, in the form of a brown liquid. The product has a TBN, by ASTM D2896, of 150.
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=1.[CH3:13][O:14][P:15]([O:18]C)[O:16][CH3:17]>C1(C)C=CC=CC=1>[CH3:13][O:14][P:15]([CH2:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=1)(=[O:18])[O:16][CH3:17]
Reactant: BrCc1ccc2ccccc2c1
Reactant: COP(OC)OC
Solvent: Cc1ccccc1
Product: COP(=O)(Cc1ccc2ccccc2c1)OC
Yield: 92.6 %

Procedure:
A solution of 2-bromomethylnaphthalene (4.42 g, 0.020 M) and trimethylphosphite (5 mL, 5.26 g, 0.042 M) in dry toluene (100 mL) is heated at reflux temperature for 120 hours The reaction is incomplete, so the volume of the solution is reduced to 25 mL, additional trimethylphosphite (5 mL) is added, and the solution heated to reflux for another 24 hours. Solvent is removed under reduced pressure and the solid white residue is chromatographed over silica gel (40-63 μm, 195 g, ethyl acetate). Elution of the column with ethyl acetate gave title compound (4.63 g) as a white solid which after crystallization from ether-hexane had mp 80°-81° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[CH2:16][C:6]2[N:7]=[C:8]([N:10]3[CH2:15][CH2:14][O:13][CH2:12][CH2:11]3)[S:9][C:5]=2[C:4](=[O:17])[CH2:3]1.[NH2:19]OS(O)(=O)=O>C(O)=O>[CH3:1][C:2]1([CH3:18])[CH2:3][C:4](=[O:17])[NH:19][C:5]2[S:9][C:8]([N:10]3[CH2:15][CH2:14][O:13][CH2:12][CH2:11]3)=[N:7][C:6]=2[CH2:16]1
Reactant: NOS(=O)(=O)O
Reactant: CC1(C)CC(=O)c2sc(N3CCOCC3)nc2C1
Solvent: O=CO
Product: CC1(C)CC(=O)Nc2sc(N3CCOCC3)nc2C1
Yield: 22.6 %

Procedure:
To a stirred solution of Example 48 (1.00 g, 3.77 mmol) in formic acid (40 mL) was added, dropwise, hydroxylamine-O-sulfonic acid (0.64 g, 5.66 mmol). After refluxing overnight the reaction mixture was quenched with ice/water and neutralised with aqueous 5% NaOH and then extracted with DCM (2×40 μL). The organics were combined, dried (MgSO4), filtered and concentrated in vacuo. Purification by column chromatography (SiO2, 3:1 DCM/EtOAc) gave the title compound (0.24 g, 22%) as an off-white solid. δH (DMSO-d6) 10.77 (1H, s), 3.69 (4H, m), 3.42 (4H, m), 2.52 (2H, s), 2.25 (2H, s), 0.98 (6H, s). LCMS (ES+) 282.0 (M+H)+.