Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([CH3:7])[CH2:3]B(O)O.[C:8]([C:10]1[CH:11]=[C:12]([CH:17]=[CH:18][C:19]=1OS(C(F)(F)F)(=O)=O)[C:13]([O:15][CH3:16])=[O:14])#[N:9].C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=CC=1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[C:8]([C:10]1[CH:11]=[C:12]([CH:17]=[CH:18][C:19]=1[CH2:1][CH:2]([CH3:7])[CH3:3])[C:13]([O:15][CH3:16])=[O:14])#[N:9]
Reactant: COC(=O)c1ccc(OS(=O)(=O)C(F)(F)F)c(C#N)c1
Reactant: CC(C)CB(O)O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)c1ccc(CC(C)C)c(C#N)c1
Temperature: 100 °C
Reaction time: 12 h
Yield: 81.3 %

Procedure:
To a solution of (2-methylpropyl)boronic acid (0.508 g), methyl 3-cyano-4-{[(trifluoromethyl)sulfonyl]oxy}benzoate (D22) (1.4 g) and Cs2CO3 (4.43 g) in toluene (10 mL) and water (1 mL) stirred under nitrogen at room temperature was added PdCl2(dppf)-CH2Cl2 adduct (0.370 g). The reaction mixture was stirred at 100° C. for 12 h. The solvent was removed under reduced pressure. The residue was dissolved in EA (80 mL) and washed with water and brine, dried over anhydrous Na2SO4. The solution was concentrated and the crude product was purified by column chromatography to afford methyl 3-cyano-4-(2-methylpropyl)benzoate (D23) (800 mg) as a colorless oil. MS (ES): C13H15NO2 requires 217. found 218.1 (M+H+).
Reaction SMILES: Br[C:2]1[CH:23]=[CH:22][C:5]2[O:6][CH2:7][C:8]3[CH:21]=[CH:20][CH:19]=[CH:18][C:9]=3[C:10](=[C:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)[C:4]=2[CH:3]=1.[CH3:24][N:25](C=O)C>[C-]#N.[C-]#N.[Zn+2].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2]>[CH3:17][N:14]1[CH2:13][CH2:12][C:11](=[C:10]2[C:9]3[CH:18]=[CH:19][CH:20]=[CH:21][C:8]=3[CH2:7][O:6][C:5]3[CH:22]=[CH:23][C:2]([C:24]#[N:25])=[CH:3][C:4]2=3)[CH2:16][CH2:15]1
Reactant: CN1CCC(=C2c3ccccc3COc3ccc(Br)cc32)CC1
Reactant: CN(C)C=O
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: CN1CCC(=C2c3ccccc3COc3ccc(C#N)cc32)CC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 72 %

Procedure:
Zn(CN)2 (4.70 g, 40.0 mmol), Pd2(dba)3 (0.23 g, 0.25 mmol), and DPPF (0.30 g, 0.50 mmol) were added to a DMF (100 mL) solution of 4-(2-bromo-6H-dibenz[b,e]oxepin-11-ylidene)-1-methylpiperidine (14.8 g, 40.0 mmol) in an argon atmosphere, and the mixture was stirred overnight at 80° C. Insoluble matters were filtered off, a saturated sodium chloride solution (50 mL) was then added to the filtrate, and the product was extracted with ethyl acetate. The solvent was distilled off under a reduced pressure, and thereafter the residue was purified by silica gel column chromatography (chloroform-methanol=9:1), to give 9.14 g (72%) of the captioned compound in the form of crystals.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[C:7]([CH3:9])[C:5]([NH2:6])=[C:4]([N+:10]([O-])=O)[CH:3]=1>CO.[Pd]>[CH3:9][C:7]1[CH:8]=[C:2]([CH3:1])[CH:3]=[C:4]([NH2:10])[C:5]=1[NH2:6]
Reactant: Cc1cc(C)c(N)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CO
Product: Cc1cc(C)c(N)c(N)c1
Reaction time: 6 h
Yield: 109.5 %

Procedure:
To a solution of 4,6-dimethyl-2-nitroaniline (312 mg) in 5 mL MeOH, was added 10% Pd/C (50 mg). The mixture evacuated and flushed with H2 (3×), then was stirred under an atmosphere of H2 for 6 h. Conc. HCl (2 drops) was added and the mixture was stirred under H2 for an additional 18 h, then was filtered and concentrated to afford 280 mg of Intermediate 179.1, which was used without further purification.
Reaction SMILES: [SH:1][CH2:2][C:3]([NH:6][C:7](=[O:16])[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([CH3:5])[CH3:4].[CH3:17]I>CO>[CH3:4][C:3]([NH:6][C:7](=[O:16])[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([CH3:5])[CH2:2][S:1][CH3:17]
Reactant: CI
Reactant: CC(C)(CS)NC(=O)OCc1ccccc1
Solvent: CO
Product: CSCC(C)(C)NC(=O)OCc1ccccc1
Reaction time: 17 h
Yield: 65 %

Procedure:
To a pressure tube was added a solution of benzyl 1-mercapto-2-methylpropan-2-ylcarbamate in methanol (5 mL), TEA (2.35 mL, 1 equiv) and methyl iodide (1.05 mL, 1 equiv). The tube was sealed and the reaction stirred for 17 h. The solvent was removed in vacuo and the crude material was purified on an ISCO purification system. The desired fractions were pooled and concentrated under reduced pressure to give a pale yellow oil (2.78 g, 65%). 1H NMR (CDCl3, 400 MHz): δ 1.41 (s, 6H), 2.51 (s, 2H), 2.98 (s, 2 H). LRMS (ESI+) for C13H19NO2S (253.1); Found: 254 (MH+).
Reaction SMILES: Cl.Cl[CH2:3][CH2:4][CH:5]([C:10]1[CH:15]=[C:14]([F:16])[C:13]([F:17])=[C:12]([F:18])[CH:11]=1)[C:6]([NH:8][NH2:9])=O.C(N(CC)CC)C.Cl.Cl.[CH3:28][O:29][C:30]1[CH:31]=[C:32](/[CH:42]=[CH:43]/[C:44](=[NH:48])OCC)[CH:33]=[N:34][C:35]=1[N:36]1[CH:40]=[C:39]([CH3:41])[N:38]=[CH:37]1>C(O)C>[CH3:28][O:29][C:30]1[CH:31]=[C:32](/[CH:42]=[CH:43]/[C:44]2[N:48]=[C:6]3[CH:5]([C:10]4[CH:15]=[C:14]([F:16])[C:13]([F:17])=[C:12]([F:18])[CH:11]=4)[CH2:4][CH2:3][N:8]3[N:9]=2)[CH:33]=[N:34][C:35]=1[N:36]1[CH:40]=[C:39]([CH3:41])[N:38]=[CH:37]1
Reactant: CCOC(=N)/C=C/c1cnc(-n2cnc(C)c2)c(OC)c1
Reactant: NNC(=O)C(CCCl)c1cc(F)c(F)c(F)c1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: COc1cc(/C=C/c2nc3n(n2)CCC3c2cc(F)c(F)c(F)c2)cnc1-n1cnc(C)c1
Temperature: 80 °C
Reaction time: 25 h

Procedure:
A solution of 4-chloro-2-(3,4,5-trifluorophenyl)butyric acid hydrazide hydrochloride synthesized in Examples 253 and 254 (565 mg) and triethylamine (1.0 mL) in ethanol (10 mL) was added to a solution of ethyl (E)-3-[5-methoxy-6-(4-methyl-1H-imidazol-1-yl)pyridin-3-yl]acrylimidate dihydrochloride (500 mg) and triethylamine (0.95 mL) in ethanol (10 mL) at room temperature. The reaction solution was stirred at 80° C. for 25 hours. The reaction solution was left to cool to room temperature and then concentrated under reduced pressure. A saturated sodium bicarbonate solution was added to the resulting residue, followed by extraction with chloroform. The resulting extract was dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (carrier: Chromatorex NH; elution solvent: heptane-ethyl acetate system) to obtain 154 mg of the racemic title compound. The racemic title compound (154 mg) was purified by CHIRALPAK™ IA manufactured by Daicel Chemical Industries, Ltd. (2 cm×25 cm; mobile phase: hexane:ethanol=1:1) and then separated by CHIRALPAK™ IB manufactured by Daicel Chemical Industries, Ltd. (2 cm×25 cm; mobile phase: hexane:ethanol=7:3) to obtain the title optically active compound with a retention time of 17 minutes and positive optical rotation (40 mg) and the title optically active compound with a retention time of 23 minutes and negative optical rotation (37 mg).
Reaction SMILES: [C:1]([S:4][CH2:5][CH2:6][C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][C:8]=1[C:16]([O:18][CH3:19])=[O:17])(=[O:3])[CH3:2].[H-].[Na+].Br[CH2:23][C:24]1[CH:25]=[C:26]([CH:31]=[CH:32][CH:33]=1)[C:27]([O:29][CH3:30])=[O:28].O>CN(C=O)C.CCOC(C)=O>[C:1]([S:4][CH2:5][CH2:6][C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]([CH2:23][C:24]2[CH:33]=[CH:32][CH:31]=[C:26]([C:27]([O:29][CH3:30])=[O:28])[CH:25]=2)[C:8]=1[C:16]([O:18][CH3:19])=[O:17])(=[O:3])[CH3:2]
Reactant: COC(=O)c1[nH]c2ccccc2c1CCSC(C)=O
Reactant: COC(=O)c1cccc(CBr)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(Cn2c(C(=O)OC)c(CCSC(C)=O)c3ccccc32)c1
Temperature: -10 °C
Reaction time: 0.25 h
Yield: 91.9 %

Procedure:
To a solution of methyl 3-[2-(acetylthio)ethyl]-1H-indole-2-carboxylate (0.300 g, 1.1 mmol) in DMF (5 mL) was added sodium hydride (60% dispersion in mineral oil, 0.048 g, 1.2 mmol) at −10° C., and the mixture was stirred at −10° C. for 15 minutes. To the mixture was added methyl 3-(bromomethyl)-benzoate (0.273 g, 1.2 mmol) at −15° C., and the reaction mixture was allowed to gradually come to room temperature and stirred overnight. To the mixture were added H2O (20 mL) and EtOAc (20 mL). The organic layer was dried over Na2SO4 and concentrated to give methyl 3-[2-(acetylthio)ethyl]-1-[[3-(methoxycarbonyl)phenyl]-methyl]-1H-indole-2-carboxylate as an oil (0.430 g). This material was used for the next reaction without further purification: 1H NMR (DMSO-d6) 2.32 (s, 3H), 3.10 (t, J=6.52 Hz, 2H), 3.31 (t, J=6.52 Hz, 2H), 3.80 (s, 3H), 3.83 (s, 3H), 5.85 (s, 2H), 7.17–7.23 (m, 2H), 7.34 (t, J=7.7 Hz, 1H), 7.42 (t, J=7.6 Hz, 1H), 7.56 (d, J=8.5 Hz, 1H), 7.66 (s, 1H), 7.80 (d, J=7.8 Hz, 1H), 7.83 (d, J=8.1 Hz, 1H).
Reaction SMILES: [NH2:1][C@H:2]([C:4]1[N:8]([CH:9]2[CH2:14][CH2:13][CH:12]([C:15]#[N:16])[CH2:11][CH2:10]2)[C:7]2[CH:17]=[C:18]([F:21])[CH:19]=[CH:20][C:6]=2[N:5]=1)[CH3:3].Cl[C:23]1[N:31]=[CH:30][N:29]=[C:28]2[C:24]=1[N:25]=[CH:26][N:27]2C1CCCCO1.CCN(C(C)C)C(C)C.Cl>C(O)CCC.O1CCOCC1>[F:21][C:18]1[CH:19]=[CH:20][C:6]2[N:5]=[C:4]([C@@H:2]([NH:1][C:23]3[N:31]=[CH:30][N:29]=[C:28]4[C:24]=3[N:25]=[CH:26][NH:27]4)[CH3:3])[N:8]([CH:9]3[CH2:14][CH2:13][CH:12]([C:15]#[N:16])[CH2:11][CH2:10]3)[C:7]=2[CH:17]=1
Reactant: C[C@H](N)c1nc2ccc(F)cc2n1C1CCC(C#N)CC1
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Nc1ncnc2[nH]cnc12)c1nc2ccc(F)cc2n1C1CCC(C#N)CC1
Temperature: 105 °C
Reaction time: 1 h
Yield: 18.4 %

Procedure:
A mixture of 4-[2-((S)-1-aminoethyl)-6-fluorobenzoimidazol-1-yl]cyclohexanecarbonitrile (100 mg, 0.35 mmol), 6-chloro-9-(tetrahydropyran-2-yl)-9H-purine (91 mg, 0.38 mmol) and DIPEA (0.10 mL, 0.72 mmol) in n-butanol (0.7 mL) was heated for 48 h at 105° C. After cooling to RT, the crude reaction mixture was treated with 4N HCl in dioxane (0.5 mL) and stirred for 1 h at RT. The crude mixture was loaded onto an Isolute® SCX-2 cartridge and washed with MeOH followed by 2M NH3/MeOH. The basic fractions were combined, concentrated in vacuo and the resulting residue purified by column chromatography (Si—PCC, gradient 0-8% MeOH in DCM), then triturated with hot EtOAc and purified by preparative HPLC (Phenomenex Gemini 5 μm C18 on a gradient 0-40%, 0.1% HCO2H in acetonitrile/water) to afford 174 as a white solid (26 mg, 18%). LCMS (Method K): RT 2.93 min [M+H]+ 405.1. 1H NMR (DMSO-d6, 400 MHz): δ 12.45 (1H, s), 8.34-7.94 (3H, m), 7.71-7.56 (2H, m), 7.05-6.96 (1H, m), 5.96 (1H, bs), 4.62-4.59 (1H, m), 3.09-2.95 (1H, m), 2.38-2.25 (1H, m), 2.21-2.07 (2H, m), 1.93 (1H, bd, J=12.75 Hz), 1.84 (1H, bd, J=12.00 Hz), 1.73-1.65 (5H, m), 1.02 (1H, bs). Broad signals due to presence of rotamers/tautomers
Reaction SMILES: [NH2:1][C:2]([C:7]1[CH:12]=[CH:11][C:10]([C:13]#[N:14])=[CH:9][CH:8]=1)([CH3:6])[C:3]([NH2:5])=[O:4].[C:15](=O)(OC)[O:16]C>>[C:13]([C:10]1[CH:9]=[CH:8][C:7]([C:2]2([CH3:6])[C:3](=[O:4])[NH:5][C:15](=[O:16])[NH:1]2)=[CH:12][CH:11]=1)#[N:14]
Reactant: COC(=O)OC
Reactant: CC(N)(C(N)=O)c1ccc(C#N)cc1
Product: CC1(c2ccc(C#N)cc2)NC(=O)NC1=O

Procedure:
(R or S)-4-(4-Cyanophenyl)-4-methyl-2,5-dioxoimidazolidine was prepared from (R or S)-2-amino-2-(4-cyanophenyl)propionamide using dimethyl carbonate analogously to the procedure indicated in EP-A-173522.
Reaction SMILES: OC(C(F)(F)F)=O.[NH:8]1[CH2:11][CH:10]([C:12]2[CH:33]=[CH:32][C:15]3[C:16]4[N:17]=[C:18]([C:24]5[N:25]([CH:29]([CH3:31])[CH3:30])[N:26]=[CH:27][N:28]=5)[S:19][C:20]=4[CH2:21][CH2:22][O:23][C:14]=3[CH:13]=2)[CH2:9]1.C(N(CC)CC)C.[CH:41]([S:43]([CH3:46])(=[O:45])=[O:44])=[CH2:42]>>[CH:29]([N:25]1[C:24]([C:18]2[S:19][C:20]3[CH2:21][CH2:22][O:23][C:14]4[CH:13]=[C:12]([CH:10]5[CH2:11][N:8]([CH2:42][CH2:41][S:43]([CH3:46])(=[O:45])=[O:44])[CH2:9]5)[CH:33]=[CH:32][C:15]=4[C:16]=3[N:17]=2)=[N:28][CH:27]=[N:26]1)([CH3:31])[CH3:30]
Reactant: C=CS(C)(=O)=O
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C3CNC3)ccc1-2
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C3CN(CCS(C)(=O)=O)C3)ccc1-2
Temperature: 25 °C
Reaction time: 18 h
Yield: 67.9 %

Procedure:
To a solution of 8-azetidin-3-yl-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene TFA salt 235 (200 mg, 0.42 mmol) in IMS (industrial methylated spirits, 3 mL) was added triethylamine (0.20 mL, 1.47 mmol) and methyl vinyl sulfone (0.09 mL, 1.05 mmol) and the reaction mixture was stirred at RT (room temperature) for 18 hours. The reaction mixture was concentrated in vacuo and the residue purified by flash chromatography (SiO2, 0-5% MeOH in DCM). Freeze-drying from methanol and water gave 320 as a pale yellow solid (135 mg, 68%). LCMS: RT=3.10 min, [M+H]+=474. 1H NMR δ (ppm) (DMSO-d6): 8.35 (1 H, d, J=8.19 Hz), 8.11 (1 H, s), 7.29 (1 H, d, J=8.27 Hz), 7.20 (1 H, s), 5.85-5.76 (1 H, m), 4.41-4.35 (3 H, m), 4.14 (3 H, d, J=59.98 Hz), 3.68 (2 H, s), 3.53-3.41 (3 H, m), 3.13 (3 H, s), 1.55 (6 H, d, J=6.60 Hz). 2 Protons obscured by water peak
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][N:17]2[CH2:22][CH2:21][C@H:20]([O:23]C(=O)C(C)(C)C)[C@@H:19]([CH3:30])[CH2:18]2)[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C[O-].[Na+]>>[C:1]([O:5][C:6](=[O:7])[NH:8][CH:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][N:17]2[CH2:22][CH2:21][C@H:20]([OH:23])[C@@H:19]([CH3:30])[CH2:18]2)[CH2:11][CH2:10]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: C[C@H]1CN(CCN2CCC(NC(=O)OC(C)(C)C)CC2)CC[C@@H]1OC(=O)C(C)(C)C
Agent: C[O-]
Agent: [Na+]
Product: C[C@H]1CN(CCN2CCC(NC(=O)OC(C)(C)C)CC2)CC[C@@H]1O

Procedure:
Crude 15 (8.2 g, 19.27 mmol) is treated with NaOMe (0.5M in methanol, 77 ml, 38.5 mmol) and heated under reflux for 24 hours. The solvent is then evaporated, the residue taken up in DCM and extracted with 1N-NaOH and brine. Drying and evaporation gave a brown oil which is purified by chromatography on silicagel using DCM (saturated with ammonia) and MeOH (from 1% to 5%).
Reaction SMILES: S(Cl)(Cl)=O.[CH2:5]([S:7]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[S:16]([NH2:19])(=[O:18])=[O:17])(=[O:9])=[O:8])[CH3:6].N1C=CC=CC=1.[C:26](Cl)(Cl)=[O:27]>ClCCCl>[CH2:5]([S:7]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[S:16]([N:19]=[C:26]=[O:27])(=[O:17])=[O:18])(=[O:9])=[O:8])[CH3:6]
Reactant: O=C(Cl)Cl
Reactant: CCS(=O)(=O)c1ccccc1S(N)(=O)=O
Solvent: O=S(Cl)Cl
Solvent: ClCCCl
Solvent: c1ccncc1
Product: CCS(=O)(=O)c1ccccc1S(=O)(=O)N=C=O
Temperature: 50 °C

Procedure:
102.8 g (0.865 mol) of thionyl chloride were added to 71.8 g (0.288 mol) of 2-(ethylsulfonyl)benzenesulfonamide in 500 ml of 1,2-dichloroethane in the course of 30 minutes while stirring at from 70° to 80° C., and the refluxed mixture was stirred for 2.5 hours. After the mixture had been cooled to 50° C., 2 ml of pyridine were added and gaseous phosgene was passed into the refluxed mixture in the course of 5 hours while stirring. Evaporating down gave 84.1 g of the title compound, which was taken up directly in 1,2-dichloroethane for storage.
Reaction SMILES: [CH2:1](O)[CH2:2][CH2:3][CH2:4][C:5]#[CH:6].[CH3:8][O:9][C:10](=[O:20])[CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[OH:19].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH3:8][O:9][C:10](=[O:20])[CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][CH2:6][CH2:5][CH2:4][CH2:3][C:2]#[CH:1]
Reactant: C#CCCCCO
Reactant: COC(=O)CCc1ccccc1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C#CCCCCOc1ccccc1CCC(=O)OC
Temperature: 25 °C
Reaction time: 100 h
Yield: 76.8 %

Procedure:
A mixture of 0.98 g (10 mmol) of 5-hexyn-1-ol, 1.98 g (11 mmol) of 2-hydroxybenzenepropanoic acid methyl ester, 2.88 g (11 mmol) of triphenylphosphine, 1.91 g (11 mmol) of diethyl azodicarboxylate, and 220 mL of dry tetrahydrofuran was stirred at room temperature for 100 hr and then concentrated under reduced pressure. The residue was triturated with 9:1 hexane-ether. The solid was filtered with suction and washed with the same solvent mixture. The filtrate and washes were combined and concentrated in vacuo. Flash chromatography of the residue on silica gel, eluting with 9:1 hexane-ether gave 2 g (77%) of 2-[(5-hexynyl)oxy]benzenepropanoic acid methyl ester as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:19])=[CH:4][C:5]2[C:14]3[C:9](=[C:10]([CH3:15])[N:11]=[CH:12][CH:13]=3)[C:8](=[O:16])[N:7]([CH3:17])[C:6]=2[CH:18]=1.[H-].[Na+].[CH3:22]I>CN(C=O)C.O>[Cl:1][C:2]1[C:3]([O:19][CH3:22])=[CH:4][C:5]2[C:14]3[C:9](=[C:10]([CH3:15])[N:11]=[CH:12][CH:13]=3)[C:8](=[O:16])[N:7]([CH3:17])[C:6]=2[CH:18]=1
Reactant: Cc1nccc2c1c(=O)n(C)c1cc(Cl)c(O)cc21
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2c3ccnc(C)c3c(=O)n(C)c2cc1Cl
Temperature: 25 °C
Reaction time: 10 h
Yield: 38.1 %

Procedure:
To the stirred solution of 8-chloro-9-hydroxy-4,6-dimethylbenzo[c][2,7]naphthyridin-5(6H)-one (0.3 g, 1.092 mmol) in DMF (10 mL) cooled to 0° C., was added NaH (0.052 g, 2.184 mmol) followed by methyl iodide (0.205 mL, 3.28 mmol). The resultant mixture was allowed to stir at ambient temperature for 10 h. The reaction mixture was then diluted with water (50 mL) and extracted with ethyl acetate (2×80 mL). The combined organic layers were separated, washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography using 70% ethyl acetate in petroleum ether to afford 8-chloro-9-methoxy-4,6-dimethylbenzo[c][2,7]naphthyridin-5(6H)-one (0.12 g, 0.416 mmol, 38% yield) as a semi-solid. LC/MS (ESI) m/e 288.4 [(M)+, calcd for C15H13ClN2O2 288.1]; LC/MS retention time (Method A): tR=1.9 min.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[CH2:7][CH2:6][CH2:5][C:4](=[O:8])[CH2:3]1.[Cl:10][C:11]1[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=1.[OH-].[Na+]>O>[Cl:10][C:11]1[CH:18]=[CH:17][C:14]([CH:15]=[C:5]2[CH2:6][CH2:7][C:2]([CH3:9])([CH3:1])[CH2:3][C:4]2=[O:8])=[CH:13][CH:12]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: CC1(C)CCCC(=O)C1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC1(C)CCC(=Cc2ccc(Cl)cc2)C(=O)C1
Yield: 75 %

Procedure:
A mixture of 3,3-dimethylcyclohexanone (34 g, 0.27 mole) and 4-chlorobenzaldehyde (38 g, 0.27 mole) in water (100 ml) containing sodium hydroxide (5.4 g, 0.27 mole) was refluxed for 24 hours. On cooling, the mixture was extracted with toluene and flashed to give 48g 2-(4-chlorobenzylidene)-5,5-dimethylcyclohexanone after crystallisation from methanol. M.pt. 85-6° C. Yield: 75%.
Reaction SMILES: [CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:35][O:36][CH:37]2[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]2)[C:10]([NH:12][CH:13]2[C:33](=[O:34])[N:15]3[C:16]([C:20]([O:22]CC4C=CC([N+]([O-])=O)=CC=4)=[O:21])=[CH:17][CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1)=[O:2].CO.O1CCCC1.C(O)(=O)C>[C].[Pd].O>[CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:35][O:36][CH:37]2[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]2)[C:10]([NH:12][CH:13]2[C:33](=[O:34])[N:15]3[C:16]([C:20]([OH:22])=[O:21])=[CH:17][CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1)=[O:2]
Reactant: O=CNc1nc(C(=NOC2CCCCC2)C(=O)NC2C(=O)N3C(C(=O)OCc4ccc([N+](=O)[O-])cc4)=CCS[C@H]23)cs1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: CO
Product: O=CNc1nc(C(=NOC2CCCCC2)C(=O)NC2C(=O)N3C(C(=O)O)=CCS[C@H]23)cs1
Yield: 49.3 %

Procedure:
4-Nitrobenzyl 7-[2-(2-formamidothiazol-4-yl)-2-cyclohexyloxyiminoacetamido]-3-cephem-4-carboxylate (syn isomer, 2.0 g.), 10% palladium carbon (0.8 g.), methanol (8 ml.), tetrahydrofuran (20 ml.), acetic acid (0.14 ml.) and water (1.4 ml.) were treated in a similar manner to that of Example 15-(2) to give 7-[2-(2-formamidothiazol-4-yl)-2-cyclohexyloxyiminoacetamido]-3-cephem-4-carboxylic acid (syn isomer, 0.77 g.).
Reaction SMILES: [O:1]1[CH:11]2[CH:2]1[CH2:3][O:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:10]=12.[NH:12]1[CH2:17][CH2:16][CH:15]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:14][CH2:13]1>C(#N)C>[OH:1][C@H:2]1[C@H:11]([N:12]2[CH2:13][CH2:14][CH:15]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:23])([CH3:22])[CH3:24])[CH2:16][CH2:17]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[O:4][CH2:3]1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: c1ccc2c(c1)OCC1OC21
Solvent: CC#N
Product: CC(C)(C)OC(=O)NC1CCN([C@@H]2c3ccccc3OC[C@H]2O)CC1

Procedure:
To 3 g of the compound obtained in Step B of Example 4, dissolved in 45 ml of acetonitrile, there are added 4 g of tert-butyl piperidin-4-ylcarbamate (20.2 mmol). The mixture is then heated at reflux for 12 hours and subsequently evaporated to dryness. A yellow oil is obtained which is purified by flash chromatography on silica (eluant: dichloromethane/ethanol 95/5) to yield the expected product in the form of a pale-yellow meringue.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[F:18][C:19]1[CH:27]=[C:26]([F:28])[C:25]([F:29])=[CH:24][C:20]=1[C:21](Cl)=[O:22]>>[F:18][C:19]1[CH:27]=[C:26]([F:28])[C:25]([F:29])=[CH:24][C:20]=1[C:21]([NH:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1)=[O:22]
Reactant: O=C(Cl)c1cc(F)c(F)cc1F
Reactant: CN1CCC(c2c[nH]c3ccc(N)nc23)CC1
Product: CN1CCC(c2c[nH]c3ccc(NC(=O)c4cc(F)c(F)cc4F)nc23)CC1
Yield: 87.8 %

Procedure:
Beginning with 0.010 gm (0.044 mMol) 5-amino-3-(1-methylpiperidin-4-yl)pyrrolo[3,2-b]pyridine and 0.007 mL (0.055 mMol) 2,4,5-trifluorobenzoyl chloride, 0.015 gm (86%) of the title compound was prepared essentially by the procedure described in Example 7.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([N:15]2[CH2:20][CH2:19][S:18][C:17]([CH3:22])([CH3:21])[CH:16]2[C:23]([O-:25])=[O:24])(=[O:14])=[O:13])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4].FC(F)(F)C(O)=O>ClCCl>[CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([N:15]2[CH2:20][CH2:19][S:18][C:17]([CH3:21])([CH3:22])[CH:16]2[C:23]([OH:25])=[O:24])(=[O:13])=[O:14])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4]
Reactant: CC#CCOc1ccc(S(=O)(=O)N2CCSC(C)(C)C2C(=O)[O-])cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC#CCOc1ccc(S(=O)(=O)N2CCSC(C)(C)C2C(=O)O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.6 %

Procedure:
To a solution of tert-butyl 4-({[4-(2-butynyloxy)phenyl]sulfonyl)-2,2-dimethyl-thiomorpholine-3-carboxylate (0.31 g, 0.71 mmol) in dichloromethane (7 mL) was added trifluoroacetic acid (3 mL) and the resulting mixture was stirred at room temperature for 1 hour, after which the solvents were evaporated and toluene was added. The toluene and excess trifloroacetic acid were removed to give 0.25 g of (3S)-4-({[4-(2-butynyloxy)phenyl]sulfonyl)-2,2-dimethyl-thiomorpholine-3-carboxylic acid, which was used for the next step without further purification. Yield:92.6%. mp 129-131° C. %. Electrospray Mass Spec 381.8(M−H)−.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8]([O:13][C:14]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15]1)[CH2:9][CH2:10][CH2:11][CH3:12]>ClCCl>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8]([O:13][C:14]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:17][NH:16][CH2:15]1)[CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCOC1(c2ccccc2)CN(C(=O)OC(C)(C)C)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCCOC1(c2ccccc2)CNC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
5.5 ml of trifluoroacetic acid are added to a solution containing 3.34 g (10 mmol) of 3-pentoxy-3-phenyl-1-(tert-butoxycarbonyl)azetidine dissolved in 10 ml of dichloromethane. The reaction medium is stirred at ambient temperature for 2 hours 30 min and then concentrated. The crude product obtained is purified by silica gel chromatography (eluent 90/10 dichloromethane/methanol). 3.5 g in the form of a pale yellow oil are obtained with a yield of 100%.