Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:10])=[C:6]([CH:9]=1)[CH:7]=O.[C:11]([Si:15]([CH3:30])([CH3:29])[O:16][CH2:17][CH2:18]OC1C=CC(I)=CC=1C=O)(C)(C)C.C[Si]([NH:35][Si](C)(C)C)(C)C.C([Li])CCC.C[Si](Cl)(C)C.C(N(CC)CC)C.C(Cl)(=O)C>>[I:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:10])=[C:6]([CH:7]=[N:35][C:17]([O:16][Si:15]([CH3:30])([CH3:29])[CH3:11])=[CH2:18])[CH:9]=1
Reactant: Cc1ccc(I)cc1C=O
Reactant: CC(C)(C)[Si](C)(C)OCCOc1ccc(I)cc1C=O
Reactant: C[Si](C)(C)N[Si](C)(C)C
Agent: C[Si](C)(C)Cl
Agent: [Li]CCCC
Solvent: CCN(CC)CC
Solvent: CC(=O)Cl
Product: C=C(N=Cc1cc(I)ccc1C)O[Si](C)(C)C

Procedure:
In a manner similar to the method described in example 190b, 5-iodo-2-methylbenzaldehyde prepared in example 198a (5.4 g, 22 mmol) was used as the starting material in place of 2-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-5-iodo-benzaldehyde to react with 1,1,3,3,3-hexamethyldisilazane (3.53 g, 22 mmol), n-butyllithium (2.5 M, 8.8 mL, 22 mmol), trimethylsilyl chloride (2.22 g, 22 mmol), triethylamine (3 mL, 30 mmol) and acetyl chloride (2.34 g, 30 mmol) to give crude 1-(5-iodo-2-methylphenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene as a yellow gum and used for the next step without further purification.
Reaction SMILES: Cl[S:2]([N:5]=[C:6]=[O:7])(=[O:4])=[O:3].[CH2:8]([OH:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.Cl.[NH2:17][C:18]1[CH:47]=[CH:46][C:21]2[NH:22][C:23]([C:28]3[C:29](=[O:45])[C:30]([CH3:44])([CH2:39][CH2:40][CH:41]([CH3:43])[CH3:42])[C:31]4[C:36]([C:37]=3[OH:38])=[CH:35][CH:34]=[CH:33][CH:32]=4)=[N:24][S:25](=[O:27])(=[O:26])[C:20]=2[CH:19]=1.C(N(CC)CC)C>ClCCl>[CH2:8]([O:15][C:6](=[O:7])[NH:5][S:2]([NH:17][C:18]1[CH:47]=[CH:46][C:21]2[NH:22][C:23]([C:28]3[C:29](=[O:45])[C:30]([CH3:44])([CH2:39][CH2:40][CH:41]([CH3:43])[CH3:42])[C:31]4[C:36](=[CH:35][CH:34]=[CH:33][CH:32]=4)[C:37]=3[OH:38])=[N:24][S:25](=[O:27])(=[O:26])[C:20]=2[CH:19]=1)(=[O:4])=[O:3])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: OCc1ccccc1
Reactant: O=C=NS(=O)(=O)Cl
Reactant: CC(C)CCC1(C)C(=O)C(C2=NS(=O)(=O)c3cc(N)ccc3N2)=C(O)c2ccccc21
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)CCC1(C)C(=O)C(C2=NS(=O)(=O)c3cc(NS(=O)(=O)NC(=O)OCc4ccccc4)ccc3N2)=C(O)c2ccccc21
Reaction time: 1 h
Yield: 68.9 %

Procedure:
A solution of chlorosulfonyl isocyanate (60 μL, 0.6 mmol) in 4 mL anhydrous dichloromethane at room temperature was treated drop wise with benzyl alcohol (60 uL, 0.6 mmol). After one hour, a solution of Example 34B (238 mg, 0.5 mmol), triethyl amine (300 μL, 2 mmol) in 2 mL dichloromethane, was added drop wise. The reaction was diluted with dichloromethane and extracted with 1 N HCl. The aqueous layer was extracted with dichloromethane and the combined organic layers dried with anhydrous MgSO4, concentrated and purified by chromatography to give the desired product (225 mg, 69%). 1H NMR (300 MHz, DMSO-d6) δ ppm 0.42 (m, 1H) 0.69 (d, J=6.62 Hz, 3H) 0.72 (d, J=6.62 Hz, 3H) 0.81 (m, 1H) 1.32 (m, 1H) 1.58 (s, 3H) 2.08 (m, 1H) 2.23 (m, 1H) 5.11 (s, 2H) 7.30 (m, 6H) 7.47 (dd, J=9.01, 2.39 Hz, 1H) 7.54 (m, 1H) 7.62 (d, J=2.57 Hz, 1H) 7.70 (d, J=9.19 Hz, 1H) 7.77 (d, J=3.68 Hz, 2H) 8.17 (d, J=8.09 Hz, 1H) 11.12 (s, 1H) 12.15 (s, 1H) 13.78 (s, 1H). MS (ESI−) m/z=651 (M−H)−.
Reaction SMILES: [O:1]([CH2:8][CH2:9]Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[O:1]([CH2:8][CH2:9][N:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCCOc1ccccc1
Reactant: C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: c1ccc(OCCN2CCCCC2)cc1
Temperature: 100 °C
Reaction time: 6 h
Yield: 96.4 %

Procedure:
A mixture of 20 g of 2-phenoxyethyl bromide thus obtained, 7.92 g of piperidine and 12.86 g of potassium carbonate was added into 100 ml of ethyl alcohol and stirred for 6 hours at 100° C. The reaction mixture was filtered and condensed under reduced pressure to give 18.4 g of 1-(2-phenoxyethyl)piperidine having a boiling point of 111° C. to 112° C. at 7 mmHg in a yield of 90%.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].C([O:13][B:14](OC(C)C)[O:15]C(C)C)(C)C.C([Li])CCCCC.O>C1COCC1>[C:4]([C:3]1[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=1[B:14]([OH:15])[OH:13])#[N:5]
Reactant: N#Cc1ccccc1Br
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]CCCCCC
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1ccccc1B(O)O
Temperature: -78 °C
Reaction time: 1 h
Yield: 55.1 %

Procedure:
Dissolve 2-bromobenzonitrile (melt in water bath at 65° C. before use, 6.733 kg, 37.0 mol, 1 eq) in THF (52.5 L) in a cryogenic reactor and cool to −78° C. Add triisopropylborate (13.96 kg, 74 mol, 2 eq). Allow the mixture to cool to −78° C. again. Add hexyllithium (2.5M in hexane, 15.38 kg, 55.5 mol, 1.5 eq) over a period of 2 h (max internal temp=69° C.). After the addition, stir for 1 h at −75° C. Add the mixture (−74° C.) to water (48 L, 5° C.) over a period of 15 min with stirring to give a slightly yellow emulsion (−1° C.). Warm the mixture to 23° C. and stir at this temperature for 90 min. Separate the layers. Extract the aqueous layer with isopropyl acetate (24 L). Combine the organic layers and re-extract with brine (22 L). Combine the aqueous layers and acidify to pH 1 with 1M sulfuric acid (31 L). Extract the product twice with isopropyl acetate (41 L and 39 L). Combine the organic layers and stir overnight with brine (21 L) at 2° C. Collect the organic solution (90 L) and distill under reduced pressure at 50-60° C. to reduce the volume to 10 L. Strip the suspension with isopropyl acetate (11 L). Add methylcyclohexane (20 L) at 25° C. Cool the suspension to -7° C. Collect the precipitated product by filtration. Wash the filter cake with a mixture of isopropyl acetate (2 L) and methylcyclohexane (4 L). Dry the filter cake on the rotovap at reduced pressure at 50° C. to obtain 2.997 kg of title compound as a white powder; 55% yield (poor yield due to some material sticking to the reactor wall). 1H NMR (solvent-dx): § 7.53 (dt, 1H, J=1.5 Hz, 7.5 Hz), 7.62 (dt, 1H, J=1.5 Hz, 7.5 Hz), 7.73 (m, 2H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([CH3:10])[CH3:9].[Li]CCCC.CN([CH:19]=[O:20])C>C1COCC1.[Cl-].[NH4+]>[CH:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[CH:19]=[O:20])([CH3:10])[CH3:9]
Reactant: CC(C)c1ccccc1Br
Reactant: CN(C)C=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)c1ccccc1C=O
Reaction time: 1 h
Yield: 94.5 %

Procedure:
To a solution of 2-bromoisopropyl benzene (2.0 g, 10.0 mmole) in dry THF (20 mL), nBuLi (1.6 M in hexanes) (6.9 mL, 11.05 mmole) was added at −78° C. and the mixture was stirred at same temperature for one hour. DMF (0.9 g, 12.0 mmole) was added and the mixture was stirred at −78° C. for an additional half an hour, then allowed to stir at 0° C. for 15 min. The reaction mixture was diluted with saturated aqueous ammonium chloride (10 mL) and extracted with ethyl acetate (3×30 mL). The combined organic layers were washed with brine and dried over sodium sulfate. The solvent was evaporated to yield 2-isopropyl benzaldehyde (1.4 g).
Reaction SMILES: [CH2:1]([C:8]1[C:9]([NH:20][CH:21]([CH2:25][CH3:26])[C:22]([OH:24])=O)=[N:10][CH:11]=[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl>[CH2:1]([C:8]1[NH:13][C:12]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[CH:11][N:10]2[C:22](=[O:24])[C:21]([CH2:25][CH3:26])=[N:20][C:9]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCC(Nc1ncc(-c2ccccc2)nc1Cc1ccccc1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCc1nc2c(Cc3ccccc3)[nH]c(-c3ccccc3)cn-2c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 89 %

Procedure:
2-((3-benzyl-5-phenylpyrazin-2-yl)amino)butanoic acid was dissolved in DCM (10 mL). Pyridine (0.5 mL) was added followed by N,N′-Dicyclohexylcarbodiimide (137 mg, 0.67 mmol). The reaction mixture was slowly stirred at room temperature for 1 hr. The solvent was evaporated, and the residue purified by flash chromatography (eluting solvent: EtOAc to DCM to 10% methanol in DCM) to give the product as a yellow powder (110 mg, 89%). 1H NMR (300 MHz, CD3OD, δ): 7.26 (m, 3H), 6.84-7:07 (m, 8H), 4.03 (s, 2H), 2.47 (q, J=9.0 Hz, 2H), 0.96 (t, J=9.0 Hz, 3H); MS (ESI): m/z 330.2 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:15](=O)[CH3:16])[CH:5]=[N:6][C:7]=1[CH2:8][O:9][CH2:10][C:11]([F:14])([F:13])[F:12].[CH3:18][C:19]([S@:22]([NH2:24])=[O:23])([CH3:21])[CH3:20]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:15]([NH:24][S@@:22]([C:19]([CH3:21])([CH3:20])[CH3:18])=[O:23])[CH3:16])[CH:5]=[N:6][C:7]=1[CH2:8][O:9][CH2:10][C:11]([F:14])([F:13])[F:12]
Reactant: CC(C)(C)[S@](N)=O
Reactant: CC(=O)c1cnc(COCC(F)(F)F)c(Cl)c1
Product: CC(N[S@](=O)C(C)(C)C)c1cnc(COCC(F)(F)F)c(Cl)c1
Yield: 82 %

Procedure:
The title compound is prepared in 82% yield (827 mg, yellows oil) from 1-(5-chloro-6-((2,2,2-trifluoroethoxy)methyl)pyridin-3-yl)ethanone (720 mg, 2.69 mmol, Step-6) and (R)-2-methylpropane-2-sulfinamide (489 mg, 4.04 mmol) in a similar manner to Step-4 of Amine-1.
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:18])[NH:4][C:5](=[O:17])[N:6]([C:8]([NH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[O:9])[CH:7]=1.Cl[C:20]([O:22][CH2:23][CH:24]([CH3:26])[CH3:25])=[O:21]>N1C=CC=CC=1>[Br:1][C:2]1[C:3](=[O:18])[N:4]([C:20]([O:22][CH2:23][CH:24]([CH3:26])[CH3:25])=[O:21])[C:5](=[O:17])[N:6]([C:8](=[O:9])[NH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH:7]=1
Reactant: CCCCCCNC(=O)n1cc(Br)c(=O)[nH]c1=O
Reactant: CC(C)COC(=O)Cl
Solvent: c1ccncc1
Product: CCCCCCNC(=O)n1cc(Br)c(=O)n(C(=O)OCC(C)C)c1=O
Temperature: 25 °C
Reaction time: 15 h
Yield: 132.8 %

Procedure:
5-Bromo-N-hexyl-2,4-dioxo-pyrimidine-1-carboxamide (Example 5) (0.06 g, 0.18 mmol) was dissolved in dry pyridine (1.5 mL), and isobutyl chloroformate (0.03 mL, 0.21 mmol) was added at 0° C. The reaction was stirred at room temperature for 15 hrs, and the solvent was removed under reduced pressure. The crude was purified by column chromatography using a Teledyne ISCO apparatus (cyclohexane:EtOAc 85:15) to afford the title compound (0.10 g, 48%) as a clear, colorless oil. 1H, NMR (400 MHz, CDCl3): δ 0.89 (t, J=6.8 Hz, 3H), 1.01 (d, J=6.7 Hz, 6H), 1.28-1.38 (m, 6H), 1.57-1.64 (m, 2H), 2.11 (h, J=6.7 Hz, 1H), 3.39 (td, J=7.1, 5.7, 2H), 4.25 (d, J=6.6, 2H), 8.74 (s, 1H), 8.80 (t, J=4.6 Hz, 1H). 13C NMR (101 MHz, CDCl3): δ 14.12, 18.90, 22.63, 26.58, 27.81, 29.18, 31.47, 41.76, 76.84, 98.78, 137.72, 148.46, 148.55, 149.44, 156.04. MS (ESI) m/z: 289 [M-CONH(CH2)5CH3]−.
Reaction SMILES: [CH2:1]([O:6][CH:7]([CH3:11])[CH2:8][CH2:9][OH:10])[CH2:2][CH2:3][CH2:4][CH3:5].CN(C)C1C=CC=CC=1.CCOCC.[C:26]([O:29][C:30]1[CH:38]=[CH:37][C:33]([C:34](Cl)=[O:35])=[CH:32][CH:31]=1)(=[O:28])[CH3:27]>O>[C:26]([O:29][C:30]1[CH:38]=[CH:37][C:33]([C:34]([O:10][CH2:9][CH2:8][CH:7]([O:6][CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[CH3:11])=[O:35])=[CH:32][CH:31]=1)(=[O:28])[CH3:27]
Reactant: CCCCCOC(C)CCO
Reactant: CC(=O)Oc1ccc(C(=O)Cl)cc1
Solvent: CCOCC
Solvent: CN(C)c1ccccc1
Solvent: O
Product: CCCCCOC(C)CCOC(=O)c1ccc(OC(C)=O)cc1
Temperature: 25 °C
Yield: 96.7 %

Procedure:
Separately, 9.0 g of 3-pentyloxybutanol and 6.82 g of N,N-dimethylaniline were added to 20 ml of ether, and under stirring at room temperature, 11.5 g p-acetyloxybenzoic acid chloride was added thereto dropwise. Then, the mixture was heat-refluxed for 3.5 hours. The crystal was dissolved by adding 50 ml of water and extracted with ether. The ether layer was washed successively with 10% H2SO4 aqueous solution and water and dried with anhydrous Na2SO4, followed by distilling-off of the solvent to obtain 17.5 g of 4-(3-pentyloxybutoxycarbonyl)phenyl acetate.
Reaction SMILES: [F:1][C@H:2]1[C@@H:8]([O:9]S(C2C=CC([N+]([O-])=O)=CC=2)(=O)=O)[CH2:7][CH2:6][N:5]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:4][CH2:3]1.[N:29]1[N:30]=[C:31]([C:38]2[CH:47]=[CH:46][C:45]3[C:40](=[C:41](O)[CH:42]=[C:43]([F:48])[CH:44]=3)[N:39]=2)[N:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=12.C(N=C(N(C)C)N(C)C)(C)(C)C>CC#N.O>[N:29]1[N:30]=[C:31]([C:38]2[CH:47]=[CH:46][C:45]3[C:40](=[C:41]([O:9][C@H:8]4[C@H:2]([F:1])[CH2:3][CH2:4][N:5]([C:22]([O:24][C:25]([CH3:26])([CH3:27])[CH3:28])=[O:23])[CH2:6][CH2:7]4)[CH:42]=[C:43]([F:48])[CH:44]=3)[N:39]=2)[N:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=12
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](F)[C@@H](OS(=O)(=O)c2ccc([N+](=O)[O-])cc2)CC1
Reactant: Oc1cc(F)cc2ccc(-c3nnc4ccccn34)nc12
Agent: CN(C)C(=NC(C)(C)C)N(C)C
Solvent: O
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CC[C@@H](F)[C@H](Oc2cc(F)cc3ccc(-c4nnc5ccccn45)nc23)CC1
Temperature: 40 °C
Reaction time: 8 h

Procedure:
cis-tert-butyl 4-fluoro-5-(4-nitrophenylsulfonyloxy)azepane-1-carboxylate (0.484 g, 1.16 mmol) and 2-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-6-fluoroquinolin-8-ol (0.300 g, 1.07 mmol) were slurried in CH3CN (5.0 mL). To this mixture was added 2-tert-butyl-1,1,3,3-tetramethylguanidine (0.259 mL, 1.28 mmol) dropwise. The dark solution was warmed to 40° C. and stirred overnight. The mixture was cooled to ambient temperature and diluted with water (10 mL) and stirred for 15 minutes, then filtered. The solid was washed with water and hexanes and dried in vacuo. The product was purified via column chromatography (10 to 50% Acetone/CH2Cl2) to provide the product as off-white solid. MS ESI (+) m/z 496.0 (M+1) detected.
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Cl[CH2:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH3:23]>CN(C=O)C>[CH3:23][O:22][CH2:21][CH2:20][O:19][CH2:18][CH2:17][N:12]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2[C:13]1=[CH:1][CH:2]=[CH:3][CH:4]=2
Reactant: COCCOCCCl
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCCOCCn1c2ccccc2c2ccccc21
Temperature: 80 °C
Reaction time: 8 h
Yield: 82.8 %

Procedure:
To a solution of carbazole (3.34 g, 20 mmol) in DMF (80 mL) at 0° C. was added NaH (0.72 g, 30 mmol). After heating to 80° C. for 1.5 h, 1-chloro-2-(2-methoxyethoxy)ethane (3.31 g, 24 mmol) was added dropwise. The resulting mixture was kept at 80° C. overnight. After cooling down to 0° C., the reaction mixture was carefully quenched with water and extracted with ethyl acetate three times. The combined organic phase was washed with water and brine. Then the organic layer was dried over anhydrous sodium sulfate and the solvent was removed. The residue was purified by silica gel chromatography using petroleum ether and ethyl acetate as eluent (EA:PE=1:3) to afford alkylated carbazole 1a (4.46 g) as brown oil in 83% yield. 1H NMR (400 MHz, CDCl3) δ 8.09 (d, J=7.6 Hz, 2H), 7.46 (m, 4H), 7.23 (m, 2H), 4.51 (t, J=6.4 Hz, 2H), 3.86 (t, J=6.4 Hz, 2H), 3.52 (m, 2H), 3.42 (m, 2H), 3.31 (s, 3H). 13C NMR (400 MHz, CDCl3) δ 140.5, 125.6, 122.8, 120.2, 118.9, 108.7, 71.8, 70.7, 69.1, 59.0, 43.0. MS (FAB) m/z Calcd for C17H19NO2 269.1. Found 269.2 [M]+.
Reaction SMILES: Br[CH2:2][C:3]#[C:4][C@H:5]([O:11][C:12](=[O:14])[CH3:13])[CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].Br[CH2:16][C:17]#CC(OC(=O)C)(CCC)CCC.C([O:33][C:34]([CH2:57][CH2:58][CH3:59])([CH2:54][CH2:55][CH3:56])[C:35]#[C:36][CH2:37][N:38]([CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][C:49]([O:51]CC)=[O:50])[S:39]([CH3:42])(=[O:41])=[O:40])(=O)C>>[CH2:16]([CH:48]([CH2:47][CH2:46][CH2:45][CH2:44][CH2:43][N:38]([CH2:2]/[CH:3]=[CH:4]/[CH:5]([O:11][C:12](=[O:14])[CH3:13])[CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[S:39]([CH3:42])(=[O:40])=[O:41])[C:49]([OH:51])=[O:50])[CH3:17].[OH:33][C:34]1([CH2:35][CH2:36][CH2:37][N:38]([CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][C:49]([OH:51])=[O:50])[S:39]([CH3:42])(=[O:40])=[O:41])[CH2:54][CH2:55][CH2:56][CH2:2][CH2:59][CH2:58][CH2:57]1
Reactant: CCCCC[C@H](C#CCBr)OC(C)=O
Reactant: CCCC(C#CCBr)(CCC)OC(C)=O
Reactant: CCCC(C#CCN(CCCCCCC(=O)OCC)S(C)(=O)=O)(CCC)OC(C)=O
Product: CCCCCC(/C=C/CN(CCCCCC(CC)C(=O)O)S(C)(=O)=O)OC(C)=O
Product: CS(=O)(=O)N(CCCCCCC(=O)O)CCCC1(O)CCCCCCC1

Procedure:
The synthesis of this compound is carried out as described in Example 3, except that, in Step A, the 1-bromo-4(R)-acetoxy-2-nonyne is replaced by an equimolar amount of 1-bromo-4-acetoxy-4-propyl-2-heptyne (Example W). The product of Step A is thus ethyl 7-[N-(4-acetoxy-4-propyl-2-heptynyl)methanesulfonamido]heptanoate. The subsequent steps yield 7-[N-(4-hydroxy-4-propyl-2-heptynyl)methanesulfonamido]heptanoic acid (B) and 7-[N-(4-hydroxy-4-propyhexyl)methanesulfonamido]heptanoic acid (C).
Reaction SMILES: CS(Cl)(=O)=O.O[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][C:9]=1[CH2:17][CH2:18]O.C([N:22](CC)CC)C.N>C(Cl)Cl.C1COCC1.C1(C)C=CC=CC=1>[N+:14]([C:11]1[CH:10]=[C:9]2[C:8](=[CH:13][CH:12]=1)[CH2:7][NH:22][CH2:18][CH2:17]2)([O-:16])=[O:15]
Reactant: O=[N+]([O-])c1ccc(CO)c(CCO)c1
Reactant: CCN(CC)CC
Agent: CS(=O)(=O)Cl
Agent: N
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc2c(c1)CCNC2
Temperature: 24 °C
Yield: 79.8 %

Procedure:
Methanesulfonyl chloride (0.9 mL, 11.63 mmol) was added dropwise over 10 min to a solution of 2-(2-hydroxymethyl-5-nitrophenyl)-ethanol (1.0 g, 5.07 mmol), triethyl amine (1.8 mL, 12.91 mmol), in methylene chloride (20 mL). TLC showed complete reaction after 30 min. 1H NMR (CD3Cl) δ 8.17-11 (m, 2H), 7.65 (d, J=9 Hz, 1H), (s, 2H), 4.49 (t, J=6 Hz, 2H), 3.25 (t, J=6 Hz, 2H), 3.08 (s, 3H), 2.98 (s, 3H). reaction mixture was washed with 10% aqueous HCL, saturated aqueous sodium bicarbonate, and brine. The organic layer was dried with magnesium sulfate, methylene chloride removed under vacuum and chased with THF (3×100 mL). The product 1.9 g was employed directly in the next reaction without further purification. Ammonia (50 mL) was added to the dimesylate (1.9 g) in THF (30 mL) at -78° C. The contents were warmed to 24° C. for 60 hrs, ammonia distilled out, and solvent removed under vacuum to give the crude product (786 mg, 82%). Toluene was added and the solution was filtered through magnesium sulfate, and solvent removed under vacuum to yield 721 mg (75%) of an amber oil.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8](=[N:39][O:40][CH2:41][C:42]([O:44]C(C)(C)C)=[O:43])[C:9]([NH:11][CH:12]2[C:37](=[O:38])[N:14]3[C:15]([C:21]([O:23]C(C4C=CC=CC=4)C4C=CC=CC=4)=[O:22])=[C:16]([CH:19]=[CH2:20])[CH2:17][S:18][C@H:13]23)=[O:10])[CH:5]=[CH:4][CH:3]=1.C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>C(OC(C)C)(C)C>[NH2:1][C:2]1[N:7]=[C:6]([C:8](=[N:39][O:40][CH2:41][C:42]([OH:44])=[O:43])[C:9]([NH:11][CH:12]2[C:37](=[O:38])[N:14]3[C:15]([C:21]([OH:23])=[O:22])=[C:16]([CH:19]=[CH2:20])[CH2:17][S:18][C@H:13]23)=[O:10])[CH:5]=[CH:4][CH:3]=1
Reactant: C=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)C(=NOCC(=O)OC(C)(C)C)c3cccc(N)n3)[C@H]2SC1
Solvent: CC(C)OC(C)C
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: C=CC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOCC(=O)O)c3cccc(N)n3)[C@H]2SC1
Temperature: 25 °C
Yield: 59.9 %

Procedure:
A mixture of benzhydryl 7-[2-(6-aminopyridin-2-yl)-2-tert-butoxycarbonylmethoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylate (syn isomer) (6.0 g), anisole (10 ml) and trifluoroacetic acid (60 ml) was stirred at ambient temperature for an hour. The reaction mixture was poured into diisopropyl ether (600 ml) with stirring, and the precipitated substance was collected by filtration, washed with diisopropyl ether and then dissolved in water (100 ml), followed by adjusting to pH 7.5 with 5% aqueous sodium bicarbonate and washing with ethyl acetate (50 ml). The resultant aqueous solution was adjusted to pH 2.5 with conc. hydrochloric acid, and extracted with ethyl acetate (200 ml) and tetrahydrofuran (200 ml). The remaining aqueous solution was further adjusted to pH 1.5 with conc. hydrochloride acid and extracted with tetrahydrofuran (100 ml). The combined extracts were washed with a saturated aqueous sodium chloride and then dried over magnesium sulfate. Removal of the solvent gave a residue, which was washed with acetone and diisopropyl ether to obtain 7-[2-(6-aminopyridin-2-yl)-2-carboxymethoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylic acid (syn isomer) (2.4 g), mp 173°-178° C. (dec.).
Reaction SMILES: [CH2:1]([C:4]1[C:13]([O:14][CH3:15])=[C:12]([O:16][CH3:17])[CH:11]=[C:10]2[C:5]=1[C:6]([NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[N:7][CH:8]=[N:9]2)[CH:2]=C.[O:25]=[O+][O-]>CO>[CH3:15][O:14][C:13]1[C:12]([O:16][CH3:17])=[CH:11][C:10]2=[C:5]3[C:4]=1[CH2:1][CH:2]([OH:25])[N:18]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:6]3=[N:7][CH:8]=[N:9]2
Reactant: O=[O+][O-]
Reactant: C=CCc1c(OC)c(OC)cc2ncnc(Nc3ccccc3)c12
Solvent: CO
Product: COc1cc2ncnc3c2c(c1OC)CC(O)N3c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (5-allyl-6,7-dimethoxy-quinazolin-4-yl)-phenyl-amine (0.35 g, 1.09 mmol) (from Example 15, Step E ,supra) in methanol (50 mL) at −78° C. was passed a continuous stream of O3 until the color of the solution became blue. The reaction solution was then purged with argon, and methyl sulfide (5 mL) (Aldrich) was added. The reaction mixture was slowly warmed to room temperature and stirred overnight. The solution was concentrated, the residue was dried in vacuo to give the desired 7,8-dimethoxy-4-phenyl-5,6-dihydro-4H-1,3,4-triaza-phenalen-5-ol as a crude yellow solid. (Yield 0.17 g, 48%).
Reaction SMILES: O=[C:2]([C:11]1[CH:16]=[CH:15][C:14]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:13][CH:12]=1)[CH2:3][C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].CC(OC([N:33]([CH3:35])C)N(C)C)(C)C.O.[NH2:37]N>O1CCCC1>[O:17]([C:14]1[CH:15]=[CH:16][C:11]([C:2]2[C:3]([C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5])=[CH:35][NH:33][N:37]=2)=[CH:12][CH:13]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: NN
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Reactant: CC(C)(C)OC(=O)CC(=O)c1ccc(Oc2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)c1c[nH]nc1-c1ccc(Oc2ccccc2)cc1
Reaction time: 6 h
Yield: 48.1 %

Procedure:
To tert-Butyl 3-oxo-3-(4-phenoxyphenyl)propanoate (559 mg, 1.80 mmol) in tetrahydrofuran, was added Bredereck's reagent (1.18 mL, 5.70 mmol). The reaction mixture was stirred for 6 hours under nitrogen at reflux. The reaction mixture was concentrated in vacuo and taken up in EtOH (5 mL). Hydrazine monohydrate (79 μL, 1.63 mmol) was added and the reaction mixture was heated at reflux for 16 hours. The crude mixture was concentrated in vacuo, taken up in EtOAc, washed with water, a saturated aqueous solution of NaHCO3 and brine. The organic phase was dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (eluting with 40% EtOAc in petroleum ether) to afford the title compound (264 mg, 48% yield). MS (ES+) m/e=337. 1H NMR (CDCl3) δH 1.52 (9H, s), 7.04 (2H, d), 7.06 (2H, d), 7.16 (1H, t), 7.38 (2H, t), 7.66 (2H, d), 7.95 (1H, s), 10.90 (1H, br s).
Reaction SMILES: [C:1]([C:5]1[CH:17]=[CH:16][C:8]([O:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7][CH:6]=1)(=O)[CH2:2][CH3:3].Cl.[NH2:19][OH:20].C([O-])(=O)C.[Na+]>CO.O>[OH:20][N:19]=[C:1]([C:5]1[CH:17]=[CH:16][C:8]([O:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7][CH:6]=1)[CH2:2][CH3:3]
Reactant: CCOC(=O)COc1ccc(C(=O)CC)cc1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCOC(=O)COc1ccc(C(CC)=NO)cc1
Yield: 76.7 %

Procedure:
To a solution of the product of step 1 (49 g, 0.2076 moles) in methanol (343 ml), hydroxylamine hydrochloride (28.6 g, 0.4152 moles) and a solution of sodium acetate (34 g, 0.4152 moles) in water (147 ml) were added and the reaction mixture was refluxed for 1 hour. The solvents were evaporated under reduced pressure. The residue was dissolved in water and extracted with ethyl acetate. The combined ethyl acetate extract was washed with water & brine, dried over sodium sulphate and evapourated under reduced pressure to yield 40 gm (76%) of product as solid.