Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([C:20]([F:23])([F:22])[F:21])=[CH:18][C:17](C=CC(OC)=O)=[CH:16][N:15]=2)[CH2:10][C@H:9]1[CH3:30])=[O:7])([CH3:4])([CH3:3])[CH3:2].C[N+]1([O-])CC[O:35][CH2:34]C1.OS([O-])=O.[Na+]>CC(C)=O.CCCCCC.O=[Os](=O)(=O)=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([C:20]([F:21])([F:23])[F:22])=[CH:18][C:17]([CH:34]=[O:35])=[CH:16][N:15]=2)[CH2:10][C@H:9]1[CH3:30])=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: COC(=O)C=Cc1cnc(N2CCN(C(=O)OC(C)(C)C)[C@H](C)C2)c(C(F)(F)F)c1
Reactant: C[N+]1([O-])CCOCC1
Agent: O=[Os](=O)(=O)=O
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CCCCCC
Solvent: CC(C)=O
Product: C[C@@H]1CN(c2ncc(C=O)cc2C(F)(F)F)CCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A mixture of (2R)-4-[5-(2-methoxycarbonyl-vinyl)-3-trifluoromethyl-pyridin-2-yl]-2-methyl-piperazine-1-carboxylic acid tert-butyl ester from step (d) above (6.02 g, 14 mmol), OsO4 (4.43 mL, 0.7 mmol, 4% in H2O, Aldrich) and N-methylmorpholine N-oxide (1.96 g, 16.8 mmol, Aldrich) in acetone (16 mL) was stirred at room temperature for 5 h. To the mixture was added saturated aqueous solution of NaHSO3 (910 mL) and the mixture was extracted with EtOAc (2×40 mL). The combined organic extracts were washed with brine (20 mL), dried over Na2SO4 and filtered. The filtrate was evaporated in vacuo and the residue was dissolved in dichloromethane (20 mL). To the solution was added Pb(OAc)4 (7.44 g, 16.8 mmol, Aldrich) in one portion and the mixture was stirred at 0° C. for 30 min. The mixture was diluted with hexane (10 mL), filtered through a Celite® pad and the filter cake was washed with 50% EtOAc/hexane. The filtrate was evaporated in vacuo and the residue was purified by silica gel column chromatography, eluting with 30% EtOAc/hexane to give the title compound as a gum. MS (ESI, pos. ion) m/e: 374 (M+1).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C@H:4]1[CH2:8][O:7][C:6]([CH3:10])([CH3:9])[N:5]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].C(N(C(C)C)C(C)C)C.[CH3:27][S:28](Cl)(=[O:30])=[O:29].O>ClCCl>[C:14]([O:13][C:11]([N:5]1[C@@H:4]([CH2:3][CH2:2][O:1][S:28]([CH3:27])(=[O:30])=[O:29])[CH2:8][O:7][C:6]1([CH3:10])[CH3:9])=[O:12])([CH3:17])([CH3:16])[CH3:15]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1[C@@H](CCO)COC1(C)C
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1[C@@H](CCOS(C)(=O)=O)COC1(C)C

Procedure:
To a stirred solution of tert-butyl (S)-4-(2-hydroxyethyl)-2,2-dimethyl-oxazolidine-3-carboxylate (1.0 g) at 0° C. (ice cooling) in dichloromethane (25 ml) under an argon atmosphere were added N-ethyldiisopropylamine (3.5 ml) and methanesulfonyl chloride (0.56 g). The mixture was stirred at 0° C. for 2.5 hours Water was added and the mixture was extracted 3 times with dichloromethane. The combined organic layers were dried (MgSO4) and evaporated to yield crude (S)-4-(2-methanesulfonyloxy-ethyl)-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester. To a stirred solution of this compound (1.4 g) at room temperature in tetrahydrofuran (15 ml) under an argon atmosphere were added 4-fluorothiophenol (1.11 g) and triethylamine (0.88 g). The mixture was stirred at room temperature overnight. The solvent was evaporated and the residue was purified by column chromatography (SiO2; heptane/EtOAc=4:1) to give (S)-4-[2-(4-fluoro-phenylsulfanyl)-ethyl]-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (1.0 g) as a colourless oil which was used for the next step.
Reaction SMILES: O=[C:2]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1)[C@@H:3]([NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9])[CH3:4].[NH2:20][C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=1[C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=1)=O>CC(O)C.O.O.[Na+].Cl[Au-](Cl)(Cl)Cl>[F:27][C:24]1[CH:23]=[C:22]2[C:21](=[CH:26][CH:25]=1)[N:20]=[C:2]([CH:3]([NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9])[CH3:4])[C:13]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1)=[C:28]2[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=1
Reactant: Nc1ccc(F)cc1C(=O)c1ccccn1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)Cc1ccccn1
Agent: Cl[Au-](Cl)(Cl)Cl
Agent: [Na+]
Solvent: O
Solvent: CC(C)O
Product: CC(NC(=O)OC(C)(C)C)c1nc2ccc(F)cc2c(-c2ccccn2)c1-c1ccccn1
Temperature: 25 °C
Reaction time: 71 h
Yield: 58.9 %

Procedure:
A mixture of (S)-tert-butyl 3-oxo-4-(pyridin-2-yl)butan-2-ylcarbamate (0.427 g, 1.615 mmol), (2-amino-5-fluorophenyl)(pyridin-2-yl)methanone (0.384 g, 1.777 mmol), and sodium tetrachloroaurate(III) dihydrate (0.032 g, 0.081 mmol) in 2-propanol (9.50 mL) was heated under reflux. After 71 h, the mixture was cooled to rt and evaporated to dryness. The mixture was dissolved in DCM (50 mL) and washed with brine (1×50 mL), and dried over Na2SO4. The solution was filtered and concentrated in vacuo to give the crude material. The crude material was purified by silica gel column chromatography eluting with a gradient of 0% to 50% EtOAc in hexane, to provide tert-butyl 1-(6-fluoro-3,4-di(pyridin-2-yl)quinolin-2-yl)ethylcarbamate (0.423 g, 0.952 mmol, 58.9% yield) as orange syrupy solid: LC-MS (ESI) m/z 445.1 [M+H]+. The orange syrupy solid was used without further purification. Epimerization occurred during the condensation.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)O)[CH:2]=1.S(Cl)([Cl:17])=O>C(Cl)Cl>[Cl:17][CH:7]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)[C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1
Reactant: OC(c1cccnc1)c1cccnc1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: ClC(c1cccnc1)c1cccnc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 63 %

Procedure:
A round bottom flask was charged with di(pyridin-3-yl)methanol (600 mg, 3.22 mmol) and CH2Cl2 (50 mL). Thionyl chloride (353 μl, 4.83 mmol) was added and the reaction was stirred for 18 h at room temperature. The solution was concentrated under reduced pressure. The residue was chromatographed on a silica gel column (100% CH2Cl2 to 5% 2M NH3 in MeOH) and yielded 3,3′-(chloromethylene)dipyridine (415 mg, 64%). 1H NMR 400 MHz (CDCl3) δ 8.66 (d, J=2.4 Hz, 2H), 8.59 (dd, J=4.7, 1.6 Hz, 2H), 7.76 (m, 2H), 7.34 (m, 2H), 6.17 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[C:4]([N+:16]([O-:18])=[O:17])[CH:3]=1.[H-].[Na+].CC1C=CC(S(O[CH2:32][CH2:33][CH2:34][S:35]([CH3:38])(=[O:37])=[O:36])(=O)=O)=CC=1.O>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH2:32][CH2:33][CH2:34][S:35]([CH3:38])(=[O:37])=[O:36])[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[C:4]([N+:16]([O-:18])=[O:17])[CH:3]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(Cl)cc1[N+](=O)[O-]
Reactant: Cc1ccc(S(=O)(=O)OCCCS(C)(=O)=O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N(CCCS(C)(=O)=O)c1ccc(Cl)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 43.6 %

Procedure:
(4-Chloro-2-nitro-phenyl)-(3-methanesulfonyl-propyl)-carbamic acid tert-butyl ester was prepared according to Scheme 1. To a solution of tert-butyl 4-chloro-2-nitrophenylcarbamate (580 mg, 2.1 mmol) in DMF (5 mL) was added NaH (170 mg, 4.3 mmol, 60 wt %). The mixture was stirred for 30 min at RT, then 3-(methylsulfonyl)propyl 4-methylbenzenesulfonate (0.75 g, 2.56 mmol) was added. The solution was heated to 50° C. and stirred for overnight. After cooled to RT, H2O (30 mL) was added and the solution was extracted with DCM (40 mL×3). The organic layer was dried over anhydrous and concentrated. The residue was purified by prep-TLC (DCM) to give tert-butyl 4-chloro-2-nitrophenyl(3-(methylsulfonyl)propyl)carbamate (360 mg, yield: 69%) as pale oil. MS obsd. (ESI+) [(M+H)+]: 393.0.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[NH:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[N:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[F:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31]Br)=[CH:29][CH:28]=1>CN(C)C=O.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[N:16]([CH2:31][C:30]3[CH:33]=[CH:34][C:27]([F:26])=[CH:28][CH:29]=3)[C:17]3[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=3[N:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Fc1ccc(CBr)cc1
Reactant: CC(C)(C)OC(=O)N1CCCN(c2nc3ccccc3[nH]2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCCN(c2nc3ccccc3n2Cc2ccc(F)cc2)CC1
Temperature: 80 °C
Reaction time: 0.25 h

Procedure:
Combine 1-t-butoxycarbonyl-4-(1H-benzimidazol-2-yl)[1,4]diazepane (0.82 g, 2.6 mmol) in dimethylformamide (20 mL). Add sodium hydride (0.15 g, 60% in oil, 3.75 mmol). After about 15 minutes, when the gas evolution ceases, add 4-fluorobenzyl bromide (0.35 mL, 2.81 mmol). Heat to 80° C. After 18 hours, cool the reaction mixture and dilute with ethyl acetate (100 mL) and extract five times with brine. Dry the organic layer over MgSO4, filter, and evaporate in vacuo to give 1-t-butoxycarbonyl-4-(1-(4-fluorobenzyl)-1H-benzimidazol-2-yl)[1,4]diazepane: Rf =0.42 (silica gel, 50% ethyl acetate/hexane).
Reaction SMILES: C([O:3][C:4]([C:6]1[S:10][C:9]([C:11]2[CH:15]=[CH:14][N:13]([CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[N:12]=2)=[N:8][C:7]=1[CH3:25])=[O:5])C.[OH-].[Na+].Cl>O1CCCC1.O>[F:24][C:21]1[CH:22]=[CH:23][C:18]([CH2:17][CH2:16][N:13]2[CH:14]=[CH:15][C:11]([C:9]3[S:10][C:6]([C:4]([OH:5])=[O:3])=[C:7]([CH3:25])[N:8]=3)=[N:12]2)=[CH:19][CH:20]=1
Reactant: CCOC(=O)c1sc(-c2ccn(CCc3ccc(F)cc3)n2)nc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1nc(-c2ccn(CCc3ccc(F)cc3)n2)sc1C(=O)O
Temperature: 25 °C
Yield: 86.8 %

Procedure:
A mixture of 2-{1-[2-(4-fluoro-phenyl)-ethyl]-1H-pyrazol-3-yl}-4-methyl-thiazole-5-carboxylic acid ethyl ester (0.5 g, 1.39 mmol) and NaOH (0.22 g, 5.57 mmol) in tetrahydrofuran (10 mL) and water (5 mL) was heated to reflux for 16 hr. The reaction mixture was cooled to room temperature, and neutralized with 5% HCl to pH=6. The precipitate was filtered and dried to provide 2-{1-[2-(4-fluoro-phenyl)-ethyl]-1H-pyrazol-3-yl}-4-methyl-thiazole-5-carboxylic acid as a yellow solid (0.40 g, 87%) MS (M+H)+=332; Rt=1.04 min.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7](=[O:22])[C:8](=[CH:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[CH:14]=1)[C:9](=O)[CH3:10].[NH2:23][C:24](=[CH:26][C:27](=[O:29])[CH3:28])[CH3:25]>CO>[C:27]([C:26]1[CH:12]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([N+:19]([O-:21])=[O:20])[CH:14]=2)[C:8]([C:7](=[O:22])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][Br:1])=[C:9]([CH3:10])[NH:23][C:24]=1[CH3:25])(=[O:29])[CH3:28]
Reactant: CC(=O)C(=Cc1cccc([N+](=O)[O-])c1)C(=O)CCCCCBr
Reactant: CC(=O)C=C(C)N
Solvent: CO
Product: CC(=O)C1=C(C)NC(C)=C(C(=O)CCCCCBr)C1c1cccc([N+](=O)[O-])c1

Procedure:
42 g (0.11 mol) 1-bromo-7-(3-nitrophenyl-methylene)-6,8-nonanedione and 22 g (0.22 mmol) 2-amino-2-penten-4-one are boiled under reflux in 270 ml methanol for 20 h. The mixture is concentrated and the residue is chromatographed over silica gel with toluene/acetone=95/5. The title compound is obtained as a yellow oil. Yield: 22 g (44%).
Reaction SMILES: [N:1]1([C:6]2[N:11]=[C:10]([CH2:12][NH:13][C:14]([CH:16]3[CH2:20][CH2:19][CH2:18][NH:17]3)=[O:15])[CH:9]=[C:8]([CH3:21])[N:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[F:22][C:23]([F:33])([F:32])[C:24]1[CH:31]=[CH:30][C:27]([CH:28]=O)=[CH:26][CH:25]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CN(C)C=O>[N:1]1([C:6]2[N:11]=[C:10]([CH2:12][NH:13][C:14]([CH:16]3[CH2:20][CH2:19][CH2:18][N:17]3[CH2:28][C:27]3[CH:26]=[CH:25][C:24]([C:23]([F:22])([F:32])[F:33])=[CH:31][CH:30]=3)=[O:15])[CH:9]=[C:8]([CH3:21])[N:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: Cc1cc(CNC(=O)C2CCCN2)nc(-n2ccnc2)n1
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: Cc1cc(CNC(=O)C2CCCN2Cc2ccc(C(F)(F)F)cc2)nc(-n2ccnc2)n1
Reaction time: 2 h
Yield: 7.5 %

Procedure:
To a solution of pyrrolidine-2-carboxylic acid (2-imidazol-1-yl-6-methyl-pyrimidin-4-ylmethyl)-amide (43 mg, 0.15 mmol) in dimethylformamide (1.5 mL) was added 4-(trifluoromethyl)benzaldehyde (22 μL, 0.16 mmol) and acetic acid (0.075 mL) at r.t. The solution was allowed to stir for 2 hrs. To the solution was added sodium triacetoxyborohydride (107 mg, 0.50 mmol) at r.t. The solution was stirred for 16 hrs then concentrated under vacuum. The residue was diluted with DCM, washed with NaOH (1N, 30 mL) and water (30 mL), dried over MgSO4, filtered and concentrated. The product was purified using mass-triggered LCMS to afford 5 mg of 1-(4-trifluoromethyl-benzyl)-pyrrolidine-2-carboxylic acid (2-imidazol-1-yl-6-methyl-pyrimidin-4-ylmethyl)-amide as a white solid. [M+H]+ 444.96.
Reaction SMILES: [C:1]([C:3]1[C:4]([C:20]([F:23])([F:22])[F:21])=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13](=[NH:16])[NH:14][OH:15])[C:7]([CH2:17][CH2:18][CH3:19])=[CH:6]2)#[N:2].[Cl:24][C:25]1[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][C:26]=1[C:27](Cl)=O.C(N(CC)C(C)C)(C)C>C(#N)C>[Cl:24][C:25]1[CH:33]=[CH:32][C:31]([C:34]([F:35])([F:36])[F:37])=[CH:30][C:26]=1[C:27]1[O:15][N:14]=[C:13]([CH2:12][N:8]2[C:9]3[C:5](=[C:4]([C:20]([F:22])([F:23])[F:21])[C:3]([C:1]#[N:2])=[CH:11][CH:10]=3)[CH:6]=[C:7]2[CH2:17][CH2:18][CH3:19])[N:16]=1
Reactant: CCCc1cc2c(C(F)(F)F)c(C#N)ccc2n1CC(=N)NO
Reactant: O=C(Cl)c1cc(C(F)(F)F)ccc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCCc1cc2c(C(F)(F)F)c(C#N)ccc2n1Cc1noc(-c2cc(C(F)(F)F)ccc2Cl)n1
Temperature: 150 °C
Yield: 9.5 %

Procedure:
To a solution of 2-[5-cyano-2-propyl-4-(trifluoromethyl)-1H-indol-1-yl]-N-hydroxyethanimidamide (Example 275A) (0.100 g, 0.308 mmol) in anhydrous acetonitrile (3.0 mL) under N2, was added 2-chloro-5-(trifluoromethyl)benzoyl chloride (0.299 g, 1.23 mmol) and N,N-diisopropylethylamine (0.50 mL, 5.21 mmol). The mixture was then heated in a microwave at 150° C. for 30 min. Upon cooling, the mixture was poured onto a biotage prepak column and the mixture was purified by flash chromatography (0-25% EtOAc-hexanes gradient) to give 0.015 g (16% yield) of pure product: MS (ES) m/z 512 (M+).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][S:5][C:6]1[N:10]=[CH:9][NH:8][N:7]=1.[OH:11]O>[Pd].C(O)(=O)C>[CH3:1][O:2][CH2:3][CH2:4][S:5]([C:6]1[N:10]=[CH:9][NH:8][N:7]=1)=[O:11]
Reactant: COCCSc1nc[nH]n1
Reactant: OO
Agent: [Pd]
Solvent: CC(=O)O
Product: COCCS(=O)c1nc[nH]n1

Procedure:
A solution of 31.8 g. of 3-(2-methoxyethylthio)-1,2,4-triazole was dissolved in 300 ml. of acetic acid and heated to 80° C. To this solution was added by portions 67.2 ml. of 100 vol. hydrogen peroxide and the temperature was maintained at 80° C. for two hours with cooling as necessary in the early stages. A small amount of 10% palladium/charcoal catalyst was added to destroy excess hydrogen peroxide. After an hour the solution was filtered and sulphur dioxide passed through the mixture as a precaution in case peroxides had been formed. The solution was vacuum evaporated and crystals of the sulphonyl compound were removed. On the addition of further petroleum ether to the liquors, filtration and vacuum distillation, there was obtained an oily liquid, 3-(2-methoxyethylsulphinyl)-1,2,4-triazole. Elemental analysis satisfactory.
Reaction SMILES: C(O[C:6]([NH:8][C@H:9]([CH2:21][OH:22])[CH2:10][C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])=[O:7])(C)(C)C.N1C=CC=CC=1.C1(C)C=CC(S(OS(C2C=CC(C)=CC=2)(=O)=O)(=O)=O)=CC=1>ClCCCl.C(Cl)Cl>[O:7]=[C:6]1[NH:8][C@@H:9]([CH2:10][C:11]([O:13][CH2:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[O:12])[CH2:21][O:22]1
Reactant: CC(C)(C)OC(=O)N[C@H](CO)CC(=O)OCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)OS(=O)(=O)c2ccc(C)cc2)cc1
Solvent: c1ccncc1
Solvent: ClCCCl
Solvent: ClCCl
Product: O=C(C[C@H]1COC(=O)N1)OCc1ccccc1
Temperature: 25 °C
Yield: 80.7 %

Procedure:
To a solution of (S)-benzyl 3-((tert-butoxycarbonyl)amino)-4-hydroxybutanoate (16.3 g, 52.7 mmol) and pyridine (10.65 ml, 132 mmol) in DCE (157 mL) at 0° C. was added p-toluenesulfonic anhydride (17.10 g, 52.4 mmol) in two portions over 5 min. The mixture was stirred for a few minutes, then allowed to warm to room temperature and stirred for 1 hr. The mixture was heated for 6 hr at 92° C. and then allowed to cool to room temperature. The mixture was diluted with DCM (80 mL), washed with 1N aqueous HCl solution (2×200 mL), brine (200 mL), and saturated aqueous sodium bicarbonate solution (100 mL). The organic layer was dried over sodium sulfate, filtered off and concentrated under reduced pressure. The residue was purified by column chromatography [SiO2, 220 g, EtOAc/heptane=5/95 to 75/25] to provide (S)-benzyl 2-(2-oxooxazolidin-4-yl)acetate (10.0 g) as a white solid. MS m/z 236.2 (M+H)+; Rt-0.59 min.
Reaction SMILES: [C:1]1(=[O:16])[CH2:15][CH2:14][CH:13]=[CH:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH:5]=[CH:4][CH2:3][CH2:2]1.[H][H]>[Pd].C(O)C>[C:1]1(=[O:16])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH:5]=[CH:4][CH2:3][CH2:2]1
Reactant: [H][H]
Reactant: O=C1CCC=CCCCCCCC=CCC1
Agent: [Pd]
Agent: O=C1CC/C=C/CCCCCC/C=C/CC1
Agent: O=C1CC/C=C/CCCCCCCCCC1
Solvent: CCO
Product: O=C1CCC=CCCCCCCCCCC1

Procedure:
A flask was charged with cyclopentadeca-4E,12E-dien-1-one (0.10 g, 0.45 mmole), ethanol (5 ml) and 5% palladium-on-carbon (0.010 g). The mixture was stirred at room temperature under 1 atm of hydrogen gas for 30 minutes. The reaction mixture was filtered through celite and concentrated to provide crude cyclopentadec-4E-en-1-one (0.09 g, 88% yield). C15H30O (226.41 g/mole). 13CNMR (125 MHz, CDCl3): 21.65, 21.72, 25.85, 26.12, 27.86, 30.57, 31.02, 31.74, 31.82, 42.30, 42.49, 130.08, 132.00, 210.00 ppm. GC analysis indicates product to be a mixture of cyclopentadec-4E-en-1-one (39%), cyclopentadeca-4E,12E-dien-1-one (37%), and cyclopentadecanone (24%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:5]([C:15]2[CH:20]=[C:19]([OH:21])[C:18]([Cl:22])=[CH:17][C:16]=2[F:23])[C:6](=[O:14])[CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[N:9]=1)[CH3:2].Cl[C:25]([O:27][CH2:28][CH2:29][CH2:30][CH3:31])=[O:26].N1C=CC=CC=1>C(OCC)C>[C:25](=[O:26])([O:21][C:19]1[CH:20]=[C:15]([N:5]2[C:6](=[O:14])[CH:7]=[C:8]([C:10]([F:13])([F:11])[F:12])[N:9]=[C:4]2[O:3][CH2:1][CH3:2])[C:16]([F:23])=[CH:17][C:18]=1[Cl:22])[O:27][CH2:28][CH2:29][CH2:30][CH3:31]
Reactant: CCOc1nc(C(F)(F)F)cc(=O)n1-c1cc(O)c(Cl)cc1F
Reactant: CCCCOC(=O)Cl
Solvent: CCOCC
Solvent: c1ccncc1
Product: CCCCOC(=O)Oc1cc(-n2c(OCC)nc(C(F)(F)F)cc2=O)c(F)cc1Cl

Procedure:
using 2-ethoxy-1-(4-chloro-2-fluoro-5 -hydroxyphenyl)-4-trifluoromethyl-6(1H)-pyrimidinone and n-butyl chloroformate with pyridine in diethyl ether there is obtained n-butyl {5-[2-ethoxy-6-oxo-4 -trifluoromethyl-1(6H) -pyrimidinyl]-2-chloro-4-fluorophenyl} carbonate, m.p. 100°-102° C.;
Reaction SMILES: [Br:1][C:2]1[C:3]([C:7]([CH3:10])([CH3:9])[CH3:8])=[N:4][NH:5][CH:6]=1.[CH2:11]=[O:12]>C(N(CC)CC)C.CC(C)=O>[Br:1][C:2]1[C:3]([C:7]([CH3:10])([CH3:9])[CH3:8])=[N:4][N:5]([CH2:11][OH:12])[CH:6]=1
Reactant: C=O
Reactant: CC(C)(C)c1n[nH]cc1Br
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C)c1nn(CO)cc1Br
Temperature: 130 °C
Reaction time: 7 h
Yield: 105.2 %

Procedure:
The mixture of 3.14 g of 4-bromo-3-t-butyl-1H-pyrazole, 0.93 g of paraformaldehyde and 0.11 g of triethylamine was stirred at 130° C. for 7 hours. After the reaction mixture was cooled to room temperature, acetone was added to the reaction mixture. The mixture was filtered. Hexane was added to the residue obtained by concentration of the filtrate under reduced pressure, as a result, a crystal was formed. The crystal was collected to obtain 3.79 g of 4-bromo-3-t-butyl-1H-pyrazole-1-ylmethanol.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([S:17]([C:20]2[CH:25]=[CH:24][C:23]([NH2:26])=[CH:22][C:21]=2[C:27]([F:30])([F:29])[F:28])(=[O:19])=[O:18])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[C:40](Cl)(=[O:43])[CH:41]=[CH2:42]>C1COCC1>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([S:17]([C:20]2[CH:25]=[CH:24][C:23]([NH:26][C:40](=[O:43])[CH:41]=[CH2:42])=[CH:22][C:21]=2[C:27]([F:30])([F:28])[F:29])(=[O:19])=[O:18])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=CC(=O)Cl
Reactant: Nc1ccc(S(=O)(=O)N2CCN(C(=O)OCc3ccccc3)CC2)c(C(F)(F)F)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: C=CC(=O)Nc1ccc(S(=O)(=O)N2CCN(C(=O)OCc3ccccc3)CC2)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 127.9 %

Procedure:
4-(4-Amino-2-trifluoromethyl-benzensulfonyl)-piperazine-1-carboxylic acid benzyl ester (0.44 g, 0.11 mmol) was dissolved in THF (15 ml). To this solution was added diisopropylethylamine (0.52 ml, 0.33 mmol) in one portion followed by the drop wise addition of acryloyl chloride (0.09 ml, 0.11 mmol) and the mixture was stirred at room temperature under a nitrogen atmosphere for 3 hours. The THF was removed under vacuum and the resulting crude material, was purified by preparative HPLC to give the title compound (70 mg, 14% yield) as a white solid.
Reaction SMILES: [Cl-].[Cl:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH2:5][Zn+].C1COCC1.[O:16]1[C:20]2[CH:21]=[CH:22][C:23]([C:25]3([C:28]([NH:30][C:31]4[CH:36]=[N:35][C:34](Br)=[CH:33][N:32]=4)=[O:29])[CH2:27][CH2:26]3)=[CH:24][C:19]=2[O:18][CH2:17]1>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]>[O:16]1[C:20]2[CH:21]=[CH:22][C:23]([C:25]3([C:28]([NH:30][C:31]4[CH:36]=[N:35][C:34]([CH2:5][C:4]5[CH:7]=[CH:8][CH:9]=[CH:10][C:3]=5[Cl:2])=[CH:33][N:32]=4)=[O:29])[CH2:27][CH2:26]3)=[CH:24][C:19]=2[O:18][CH2:17]1
Reactant: O=C(Nc1cnc(Br)cn1)C1(c2ccc3c(c2)OCO3)CC1
Reactant: Clc1ccccc1C[Zn+]
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Cl-]
Solvent: C1CCOC1
Product: O=C(Nc1cnc(Cc2ccccc2Cl)cn1)C1(c2ccc3c(c2)OCO3)CC1
Reaction time: 0.33 h
Yield: 39 %

Procedure:
To a 0.5 M solution of (2-chlorobenzyl)zinc(II) chloride in THF (0.8 mL, 0.4 mmol) was added [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (8 mg, 0.01 mmol) and the reaction was stirred under nitrogen for 20 minutes. 1-(Benzo[d][1,3]dioxol-5-yl)-N-(5-bromopyrazin-2-yl)cyclopropanecarboxamide (36 mg, 0.10 mmol) was added and the reaction was irradiated in the microwave for 10 minutes at 150° C. The reaction was quenched with a saturated ammonium chloride solution (2 mL) and a saturated ethylenediamine tetraacetic acid disodium salt solution (2 mL). The mixture was stirred for 30 minutes before it was extracted with dichloromethane (3×4 mL). The organics were dried over Na2SO4 and evaporated. The crude product was dissolved in DMSO (1 mL) and purified by reverse-phase preparative liquid chromatography utilizing a gradient of 0-99% acetonitrile in water containing 0.05% trifluoracetic acid to yield the pure product (16 mg, 0.039 mmol, 39%). ESI-MS m/z calc. 407.1, found 408.2 (M+1)+; retention time 3.82 minutes.