Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH:11]1([NH2:17])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH:11]1([NH:17][C:2]2[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=2)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: NC1CCCCC1
Reactant: O=[N+]([O-])c1cccnc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cccnc1NC1CCCCC1

Procedure:
A mixture composed of 0.1 mol (15.85 g) of 2-chloro-3-nitropyridine and 0.1 mol (11.50 ml) of cyclohexylamine is heated at 120° C. for 4 hours in 250 ml of DMF in the presence of potassium carbonate (13.81 g). The solution is then extracted with 200 ml of ether and the organic phase is washed three times with water. After drying over magnesium sulphate, the ether is evaporated off.
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=3)[CH2:7][CH:6]3[CH2:23][O:24][CH2:25][CH2:26][N:5]3[C:4]=2[N:3]=1.CC1(C)C(C)(C)OB([C:35]2[CH:43]=[CH:42][CH:41]=[C:40]3[C:36]=2[CH:37]=[C:38]([C:44]([F:47])([F:46])[F:45])[NH:39]3)O1>O1CCOCC1.C([O-])(O)=O.[Na+].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]>[CH3:22][S:19]([C:16]1[CH:17]=[CH:18][C:13]([CH2:12][N:8]2[CH2:7][CH:6]3[CH2:23][O:24][CH2:25][CH2:26][N:5]3[C:4]3[N:3]=[C:2]([C:35]4[CH:43]=[CH:42][CH:41]=[C:40]5[C:36]=4[CH:37]=[C:38]([C:44]([F:47])([F:46])[F:45])[NH:39]5)[N:11]=[CH:10][C:9]2=3)=[CH:14][CH:15]=1)(=[O:21])=[O:20]
Reactant: CC1(C)OB(c2cccc3[nH]c(C(F)(F)F)cc23)OC1(C)C
Reactant: CS(=O)(=O)c1ccc(CN2CC3COCCN3c3nc(Cl)ncc32)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])O
Solvent: C1COCCO1
Product: CS(=O)(=O)c1ccc(CN2CC3COCCN3c3nc(-c4cccc5[nH]c(C(F)(F)F)cc45)ncc32)cc1

Procedure:
The title compound was prepared in a manner similar to EXAMPLE 3 using 2-chloro-5-(4-(methylsulfonyl)benzyl)-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridine (PREPARATION x9, 63.5 mg, 0.161 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)-1H-indole (100 mg, 0.321 mmol) and PdCl2(dppf) (5.88 mg, 8.04 mmol) in dioxane (2 mL) and aqueous saturated NaHCO3 (0.4 mL). 1H NMR (400 MHz, DMSO-d6) δ 3.21 (m, 3 H), 3.23-3.34 (m, 3 H), 3.56-3.66 (m, 2 H), 3.88-4.03 (m, 2 H), 4.05-4.16 (m, 1 H), 4.59-4.68 (m, 1 H), 4.71 (s, 2 H), 7.41-7.48 (m, 1 H), 7.56 (s, 2 H), 7.65 (d, J=8.34 Hz, 3 H), 7.79-7.86 (m, 1 H), 7.94 (d, J=8.34 Hz, 2 H), 12.56-12.65 (m, 1 H). ESI-MS m/z [M+H]+ calc'd for C26H24F3N5O3S, 544.16; found 544.5.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][C:7]2=[O:12].Cl[C:14]1[CH:22]=[CH:21][C:17]([C:18]([NH2:20])=[O:19])=[CH:16][N:15]=1.C([O-])([O-])=O.[K+].[K+]>>[O:1]=[C:2]1[CH2:11][CH2:10][CH2:9][C:8]2[C:7]([O:12][C:14]3[CH:22]=[CH:21][C:17]([C:18]([NH2:20])=[O:19])=[CH:16][N:15]=3)=[CH:6][CH:5]=[CH:4][C:3]1=2
Reactant: NC(=O)c1ccc(Cl)nc1
Reactant: O=C1CCCc2c(O)cccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Product: NC(=O)c1ccc(Oc2cccc3c2CCCC3=O)nc1
Yield: 55.3 %

Procedure:
Using a method similar to Intermediate 1, using 5-hydroxy-1-tetralone (2.68 g, 16.5 mmol), 6-chloronicotinamide (2.34 g, 15.0 mmol) and K2CO3 (3.11 g, 22.5 mmol) gives the title compound (2.34 g) as a yellow solid. Mass spectrum (ion spray): m/z=283 (M+1); 1HNMR (DMSO-d6): 8.55 (s, 1H), 8.27 (d, 1H), 8.02 (s, 1H), 7.80 (m, 1H), 7.48 (s, 1H), 7.43-7.37 (m, 1H), 7.14 (d, 1H), 2.66 (t, 2H), 2.58 (t, 2H), 1.96 (m, 2H).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH3:6][O:7][N:8]=[C:9]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([OH:19])[CH:14]=1)[C:10]([OH:12])=O.[NH2:20][CH:21]1[C:39](=[O:40])[N:23]2[C:24]([C:36]([OH:38])=[O:37])=[C:25]([CH2:28][S:29][C:30]3[N:34]([CH3:35])[N:33]=[N:32][N:31]=3)[CH2:26][S:27][C@H:22]12.C[Si](C([Si](C)(C)C)C(N)=O)(C)C.[Cl-].[Na+]>C(OCC)(=O)C.C(Cl)Cl.CN(C)C=O>[CH3:6][O:7][N:8]=[C:9]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([OH:19])[CH:14]=1)[C:10]([NH:20][CH:21]1[C:39](=[O:40])[N:23]2[C:24]([C:36]([OH:38])=[O:37])=[C:25]([CH2:28][S:29][C:30]3[N:34]([CH3:35])[N:33]=[N:32][N:31]=3)[CH2:26][S:27][C@H:22]12)=[O:12]
Reactant: Cn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Reactant: CON=C(C(=O)O)c1cccc(O)c1
Agent: C[Si](C)(C)C(C(N)=O)[Si](C)(C)C
Agent: [Cl-]
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nnnn3C)CS[C@H]12)c1cccc(O)c1
Temperature: 40 °C
Yield: 63.9 %

Procedure:
A mixture of dimethylformamide (2.81 g.) and phosphorus oxychloride (5.36 g.) was warmed at 40° C. for 1 hour. After cooling, methylene chloride (60 ml.) was added thereto and disilled off. To the residue was added dry ethyl acetate (50 ml.). Then, 2-methoxyimino-2-(3-hydroxyphenyl)acetic acid (syn isomer) (6.83 g.) was added thereto at 5° C. with stirring under ice-cooling. The resultant mixture was then stirred for 50 minutes at the same temperature. On the other hand, 7-amino-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (11.5 g.) and bis(trimethylsilyl)acetamide (28.4 g.) were dissolved in dry ethyl acetate (150 ml.) and stirred under cooling, to which was at a time added the above obtained solution at -40° C. After stirring for 2 hours at -30° to -20° C., a saturated sodium chloride aqueous solution (100 ml.) was added at -20° C. to the reaction mixture. The mixture was stirred for 5 minutes. The precipitates were filtered off and ethyl acetate layer in the filtrate was separated. The aqueous layer was extracted twice with ethyl acetate (50 ml.). Ethyl acetate layer separated from the filtrate and the extracts were combined. The combined ethyl acetate solution was washed with a saturated sodium chloride aqueous solution (50 ml.). To the ethyl acetate layer was added activated charcoal and the mixture was stirred for 5 minutes and filtered. Water (100 ml.) was added to the filtrate and the resulting mixture was adjusted to pH 7 with an aqueous solution of sodium bicarbonate. The aqueous layer was separated and washed with methylene chloride. After the aqueous layer was separated, methylene chloride was removed from the aqueous layer by bubbling of nitrogen gas under ice-cooling. After filtration, the aqueous layer was adjusted to pH 2 with 10% hydrochloric acid with stirring and ice-cooling. Precipitating crystals were collected by filtration, washed with water and dried to give 7-[2-methoxyimino-2-(3-hydroxyphenyl)acetamido]-3-(1-methyl-1H-tetrazol-5-yl)thiomethyl-3-cephem-4-carboxylic acid (syn isomer) (11.3 g.).
Reaction SMILES: [CH2:1]([O:4][C:5]1([CH3:48])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[N:17]=[C:18]([CH2:20][N:21]4[CH:25]=[C:24]([C:26]5[CH:31]=[CH:30][CH:29]=[C:28]([O:32][CH2:33]C=C)[CH:27]=5)[N:23]=[N:22]4)[CH:19]=[C:15]3[N:14]=[C:13]([CH3:36])[C:12]=2[C@H:37]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])[C:38]([O:40]CC)=[O:39])[CH2:7][CH2:6]1)[CH:2]=[CH2:3].[OH-].[Na+]>ClCCCl.CC1C=C(C)C(N2C(=[Ru](Cl)(Cl)=CC3C=CC=CC=3OC(C)C)N(C3C(C)=CC(C)=CC=3C)CC2)=C(C)C=1.CO.[Pd]>[C:44]([O:43][C@@H:37]([C:12]1[C:13]([CH3:36])=[N:14][C:15]2=[CH:19][C:18]3=[N:17][N:16]2[C:11]=1[N:8]1[CH2:9][CH2:10][C:5]([CH3:48])([O:4][CH2:1][CH2:2][CH2:3][CH2:33][O:32][C:28]2[CH:27]=[C:26]([C:24]4[N:23]=[N:22][N:21]([CH:25]=4)[CH2:20]3)[CH:31]=[CH:30][CH:29]=2)[CH2:6][CH2:7]1)[C:38]([OH:40])=[O:39])([CH3:45])([CH3:46])[CH3:47]
Reactant: C=CCOc1cccc(-c2cn(Cc3cc4nc(C)c([C@H](OC(C)(C)C)C(=O)OCC)c(N5CCC(C)(OCC=C)CC5)n4n3)nn2)c1
Agent: Cc1cc(C)c(N2CCN(c3c(C)cc(C)cc3C)C2=[Ru](Cl)(Cl)=Cc2ccccc2OC(C)C)c(C)c1
Agent: [Pd]
Agent: [Na+]
Solvent: ClCCCl
Solvent: CO
Product: Cc1nc2cc3nn2c(c1[C@H](OC(C)(C)C)C(=O)O)N1CCC(C)(CC1)OCCCCOc1cccc(c1)-c1cn(nn1)C3
Reaction time: 5 h
Yield: 37.7 %

Procedure:
To a stirred solution of (S)-ethyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-((4-(3-(allyloxy)phenyl)-1H-1,2,3-triazol-1-yl)methyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (0.018 g, 0.027 mmol) in 1,2-dichloroethane (15 mL) was added at once Hoveyda-Grubbs catalyst 2nd generation (0.857 mg, 1.368 μmol) at 70° C. and refluxed for 2 h. Then, cooled, 10% Pd/C (2.91 mg, 2.74 μmol) was added and stirred under balloon H2 atmosphere for 5 h. Then, filtered, concentrated and the dark residue was refluxed with NaOH (0.137 ml, 0.137 mmol) in MeOH (2 mL) for 6 h. Then, cooled and purified by pre-HPLC to afford desired product (0.0064 g, 10.18 μmol, 37.2% yield) as white solid. 1H NMR (500 MHz, CDCl3) δ 8.44 (s, 1H), 7.77 (d, J=7.6 Hz, 1H), 7.38 (t, J=8.0 Hz, 1H), 7.16-7.20 (m, 1H), 6.90-6.95 (m, 1H), 6.61 (s, 1H), 5.73-5.87 (m, 3H), 4.24-4.37 (m, 2H), 4.16-4.23 (m, 1H), 3.73 (t, J=11.4 Hz, 1H), 3.49-3.59 (m, 3H), 3.03 (d, J=11.8 Hz, 1H), 2.59 (s, 3H), 1.88-2.04 (m, 4H), 1.74-1.82 (m, 2H), 1.52-1.72 (m, 2H), 1.26 (s, 3H), 1.25 (s, 9H). LCMS (M+H)=604.6.
Reaction SMILES: [C:1]([S:4]/[CH:5]=[CH:6]\[C:7]([OH:9])=O)(=[O:3])[CH3:2].CN(C)C=O.C(Cl)(=O)C([Cl:18])=O>C1(C)C=CC=CC=1>[C:1]([S:4]/[CH:5]=[CH:6]\[C:7]([Cl:18])=[O:9])(=[O:3])[CH3:2]
Reactant: CC(=O)S/C=C\C(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CC(=O)S/C=C\C(=O)Cl

Procedure:
To a mixture of 2.8 g (0.0162 mol) of cis-3-(acetylthio)propenoic acid and 0.1 ml of N,N-dimethylformamide in 50 ml of toluene under nitrogen was added 2.84 ml (0.0325 mol) of oxalyl chloride. After 3 h the solvents were removed to give cis-3-(acetylthio)propenoyl chloride. This crude product was used in the next step without any further purification.
Reaction SMILES: [Na+].[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]#[C:10][CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([S:19]([O-:22])(=O)=[O:20])=[CH:15][CH:14]=2)=[CH:5][CH:4]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:24]>ClCCl>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]#[C:10][CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([S:19]([Cl:24])(=[O:22])=[O:20])=[CH:15][CH:14]=2)=[CH:5][CH:4]=1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: O=S(=O)([O-])c1ccc(OCC#Cc2ccc(Cl)cc2)cc1
Agent: [Na+]
Solvent: ClCCl
Product: O=S(=O)(Cl)c1ccc(OCC#Cc2ccc(Cl)cc2)cc1
Yield: 16.8 %

Procedure:
To a solution of the crude 4-[3-(4-chloro-phenyl)-prop-2-ynyloxy]-benzenesulfonic acid sodium salt (2.81 g, 8.7 mmol) was added 2.8 g of phosphorous pentachloride and 50 mL of dichloromethane. The reaction warmed to 40° followed by dissolution of the reagents. The reaction was then quenched with ice, extracted with dichloromethane, washed with water, brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The resulting oil was purified via flash chromatograhpy using 20:1 Hex:EtOAc to afford 0.5 g (17%) of 4-[3-(4-chloro-phenyl)-prop-2-ynyloxy]-benzenesulfonyl chloride.
Reaction SMILES: [ClH:1].Cl.[NH2:3][C:4]1[CH:5]=[C:6]([NH:10][C:11]([N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[NH:12])[CH:7]=[CH:8][CH:9]=1.C(=O)([O-])[O-].[Na+].[Na+].[C:24](OC(=O)C)(=[O:26])[CH3:25]>O.O1CCCC1>[ClH:1].[CH3:25][C:24]([NH:3][C:4]1[CH:5]=[C:6]([NH:10][C:11]([N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[NH:12])[CH:7]=[CH:8][CH:9]=1)=[O:26]
Reactant: CC(=O)OC(C)=O
Reactant: N=C(Nc1cccc(N)c1)N1CCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)Nc1cccc(NC(=N)N2CCCC2)c1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A solution of the product of step (b), 1.38 g, 0.0050 moles, was dissolved in 20 ml of water. The solution was gradually treated with sodium carbonate, 0.84 g, 0.0100 moles, and cooled to 0° C. Next a solution of 0.5 ml of acetic anhydride in 10 ml of tetrahydrofuran was added. This was stirred overnight under nitrogen. The mixture was diluted with enough water to bring the volume to 100 ml. and washed with 20 ml of chloroform. The aqueous layer was made basic with 50% sodium hydroxide and extracted with 20 ml of chloroform (twice). The chloroform was dried with potassium carbonate, filtered and evaporated. The oil was dissolved in ml of isopropanol and treated with 1 ml of concentrated hydrochloric acid. This mix was then diluted to 250 ml with ether. The solids were filtered and washed with 10 ml of ether (twice). The sample was allowed to dry overnight to yield N-(3-((methylcarbonyl)amino)phenyl)-1-pyrrolidinecarboximidamide monohydrochloride. Yield: 350 mg, m.p. 193-196° C.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([I:11])=[CH:7][C:3]=1[C:4](Cl)=[O:5].[NH3:12]>CO>[F:1][C:2]1[CH:10]=[CH:9][C:8]([I:11])=[CH:7][C:3]=1[C:4]([NH2:12])=[O:5]
Reactant: O=C(Cl)c1cc(I)ccc1F
Reactant: N
Solvent: CO
Product: NC(=O)c1cc(I)ccc1F
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 92 %

Procedure:
Add slowly 2-fluoro-5-iodobenzoyl chloride (4.0 g, 14.1 mmol) to a 7 N solution of ammonia in methanol (20 mL, 141 mmol) cooled to 0° C. Stir at 0° C. for 45 min then warm to room temperature and stir 5 h. Add an additional amount of the 7 N solution of ammonia in methanol (20 mL) to the reaction mixture and stir for 15 h. Concentrate, dilute with ethyl acetate (300 mL) and wash twice with water (30 mL) and twice with an aqueous saturated solution of sodium chloride (30 mL). Dry (sodium sulfate), filter, and concentrate. Purify by silica gel chromatography, eluting with 60:40 to 40:60 hexanes:ethyl acetate, to give the title compound as a white solid (3.45 g, 92%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([N:11]2[C@@H:15]([CH:16]([CH3:18])[CH3:17])[CH2:14][O:13][C:12]2=[O:19])=[O:10])=[CH:4][CH:3]=1.[CH3:20][Si]([N-][Si](C)(C)C)(C)C.[Na+].CC(O)=O>C1COCC1.CCOCC>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([CH3:20])[C:9]([N:11]2[C@@H:15]([CH:16]([CH3:17])[CH3:18])[CH2:14][O:13][C:12]2=[O:19])=[O:10])=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CC(C)[C@H]1COC(=O)N1C(=O)Cc1ccc(F)cc1
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CC(=O)O
Product: CC(C)[C@H]1COC(=O)N1C(=O)[C@@H](C)c1ccc(F)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 81 %

Procedure:
To a solution of (4S)-3-[(4-fluorophenyl)acetyl]-4-isopropyl-1,3-oxazolidin-2-one (2.81 g, 10.6 mmol) in dry THF (40 mL) at −78° C. under argon, was added dropwise 1.0M solution of NaHMDS in THF (11.7 mL, 11.7 mmol) over a period of 10 min. After stirring at −78° C. for 1 h, Mel (3.30 mL, 53.0 mmol) was added. The resulting reaction mixture was stirred at −78° C. for 1 h and −40° C. for 2 h, quenched with HOAc (32 mmol) in ether (20 mL), filtered over celite. The filtrate was concentrated in vacuo and the residue was dissolved in CH2Cl2 (100 mL) and washed with H2O following by brine, dried over MgSO4, filtered and concentrated in vacuo. The crude material was purified by flash chromatography (5%–10% EtOAc in hexane) to give 2.40 g (8.60 mmol, 81%) of (4S)-3-[(2S)-2-(4-fluorophenyl)propanoyl]-4-isopropyl-1,3-oxazolidin-2-one: 1H NMR (400 MHz, CDCl3) δ 7.34–7.31 (m, 2H), 7.02–6.96 (m, 2H), 5.13 (q, 1H, J=7.7 Hz), 4.38–4.33 (m, 1H), 4.18–4.13 (m, 2H), 2.48–2.37 (m, 1H), 1.49 (d, 3H, J=7.3 Hz), 0.91 (apparent t, 6H, J=6.9 Hz); ESMS m/e: 280.2 (M+H)+.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.O[C:7]1[CH:16]=[C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=1>>[Cl:3][C:7]1[CH:16]=[C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=1
Reactant: Oc1cc(-c2ccccc2)c2ccccc2n1
Reactant: O=P(Cl)(Cl)Cl
Product: Clc1cc(-c2ccccc2)c2ccccc2n1
Temperature: 25 °C

Procedure:
Phosphorus oxychloride (37.4 mL, 402 mmol) was added to 2-hydroxy-4-phenylquinoline and the mixture was heated to reflux for 4 hours. Upon cooling to room temperature, the mixture was added slowly to stirring ice water yielding a white precipitate. The mixture was extracted with methylene chloride, and the organic phases were combined, dried with magnesium sulfate, filtered and concentrated to yield 2-chloro-4-phenylquinoline.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:16][CH2:15][CH:14]([OH:17])[CH2:13][CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.ClCCl.[CH3:28][S:29](Cl)(=[O:31])=[O:30]>O>[CH3:28][S:29]([O:17][CH:14]1[CH2:15][CH2:16][N:11]([S:8]([C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=2)(=[O:10])=[O:9])[CH2:12][CH2:13]1)(=[O:31])=[O:30]
Reactant: Cc1ccc(S(=O)(=O)N2CCC(O)CC2)cc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: Cc1ccc(S(=O)(=O)N2CCC(OS(C)(=O)=O)CC2)cc1
Reaction time: 2 h
Yield: 100 %

Procedure:
To a stirred solution of 90 parts of 1-[(4-methylphenyl)sulfonyl]-4-piperidinol, 37.5 parts of N,N-diethylethanamine and 1300 parts of dichloromethane was added dropwise a solution of 42.3 parts of methanesulfonyl chloride in 130 parts of dichloromethane (exothermic reaction: temperature rose to 35° C.). Upon completion, stirring was continued for 2 hours at room temperature. Water was added and the layers were separated. The organic phase was washed with water, dried, filtered and evaporated. The residue was suspended in 2,2'-oxybispropane. The product was filtered off and dried, yielding 116 parts (100%) of 1-[(4-methylphenyl)sulfonyl]-4-piperidinol methanesulfonate (ester); mp. 168.5°-175.3° C. (5).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[F:11].S(Cl)(Cl)=O.[CH3:16]O>>[CH3:16][O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([Br:1])=[C:3]([F:11])[CH:4]=1
Reactant: CO
Reactant: O=C(O)c1ccc(Br)c(F)c1
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(Br)c(F)c1
Yield: 100 %

Procedure:
To a solution of 4-bromo-3-fluoro-benzoic acid (5.0 g, 22.9 mmol) in MeOH (60 mL) was added thionyl chloride (10 mL), This mixture was heated for about 5 h at 80 degrees Celsius until the starting material had been consumed, and then evaporated in vacuo to give white solid product (5.3 g, 100%).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1.[CH3:7][C:8]1([CH3:16])[C:10]([CH3:12])([CH3:11])[CH:9]1[C:13](Cl)=[O:14].C(N(CC)CC)C>C(Cl)Cl.C(Cl)(Cl)Cl.O>[CH3:7][C:8]1([CH3:16])[C:10]([CH3:12])([CH3:11])[CH:9]1[C:13]([NH:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1)=[O:14]
Reactant: Nc1nccs1
Reactant: CC1(C)C(C(=O)Cl)C1(C)C
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(C)C(C(=O)Nc2nccs2)C1(C)C
Temperature: 35 °C
Reaction time: 7 h
Yield: 14 %

Procedure:
To a solution of 2-aminothiazole (0.39 g, 3.9 mmol) in 10 mL of methylene chloride at 0° C. was added a solution of the product from Example 1A in 8 mL of chloroform, followed by triethylamine (1.0 mL, 7.7 mmol). The mixture was stirred for 7 hours at 35° C., cooled to ambient temperature and diluted with water. The phases were separated and the aqueous phase was extracted with methylene chloride. The combined organic extracts were washed twice with water and then brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. Purification by column chromatography (SiO2, 30-60% ethyl acetate/hexanes gradient) afforded 0.11 g (14%) of the title compound. 1H NMR (CDCl3, 300 MHz) δ ppm 1.18 (s, 1H), 1.25 (s, 6H), 1.35 (s, 6H), 6.92 (d, J=3.4 Hz, 1H), 7.39 (d, J=3.4 Hz, 1H), 10.7 (s, 1H); MS (DCI/NH3) m/z 225 (M+H)+. Anal. Calculated for C11H16N2OS: C, 58.90; H, 7.19; N, 12.49. Found: C, 59.03; H, 7.34; N, 12.34.
Reaction SMILES: [O:1]1[C:3]2[CH:4]=[CH:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:2]1=2>[Pd]>[CH:2]1([OH:1])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: C1=CC2=C(CCCCCCCC1)O2
Agent: [Pd]
Product: OC1CCCCCCCCCCC1
Yield: 5 %

Procedure:
Further, in a Drafted Report, page 68, of the 24th “Progress in Reaction and Synthesis” Sympodium, Nov. 5 to 6, 1998, a hydrogenation reaction of an epoxycyclododecadiene in the presence of a palladium catalyst carried on a carbon material is reported. In this case, the target cyclododecanol was produced at a yield of 5%.
Reaction SMILES: [CH2:1]([CH:3]([O:6][C:7]1[CH:12]=[C:11]([CH3:13])[N:10]=[C:9]([NH:14][C:15]2[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=2[CH3:23])[C:8]=1[NH2:24])[CH2:4][CH3:5])[CH3:2].[CH:25](OC)(OC)OC.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH2:1]([CH:3]([O:6][C:7]1[CH:12]=[C:11]([CH3:13])[N:10]=[C:9]2[N:14]([C:15]3[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=3[CH3:23])[CH:25]=[N:24][C:8]=12)[CH2:4][CH3:5])[CH3:2]
Reactant: CCC(CC)Oc1cc(C)nc(Nc2c(C)cc(C)cc2C)c1N
Reactant: COC(OC)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCC(CC)Oc1cc(C)nc2c1ncn2-c1c(C)cc(C)cc1C

Procedure:
A mixture of 4-(1-ethyl-propoxy)-6-methyl-N2-(2,4,6-trimethyl-phenyl)-pyridine-2,3-diamine, trimethyl orthoformate, p-toluenesulfonic acid monohydrate in toluene was heated at reflux using Dean-Stark apparatus for 24 hours. The mixture was heated at reflux overnight. The mixture was quenched with water, sat. NaHCO3, extracted with ethyl acetate. The organic layer was separated, dried (MgSO4) and concentrated to dryness. After purification, the title compound was isolated. Anal. For C21H29N30. ¼H2O calc. C, 73.76; H, 8.10; N, 12.29; found: C, 73.22; H, 7.96; N, 12.42.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][C:4]([C:7]2[N:8]([S:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)(=[O:20])=[O:19])[C:9]3[C:14]([CH:15]=2)=[CH:13][C:12]([S:16][CH3:17])=[CH:11][CH:10]=3)=[CH:3][CH2:2]1.OOS([O-])=O.[K+].[OH2:33].O1CCCC1.[OH2:39]>>[O:1]1[CH2:6][CH2:5][C:4]([C:7]2[N:8]([S:18]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)(=[O:20])=[O:19])[C:9]3[C:14]([CH:15]=2)=[CH:13][C:12]([S:16]([CH3:17])(=[O:39])=[O:33])=[CH:11][CH:10]=3)=[CH:3][CH2:2]1
Reactant: O
Reactant: CSc1ccc2c(c1)cc(C1=CCOCC1)n2S(=O)(=O)c1ccccc1
Agent: O=S([O-])OO
Agent: [K+]
Solvent: C1CCOC1
Product: CS(=O)(=O)c1ccc2c(c1)cc(C1=CCOCC1)n2S(=O)(=O)c1ccccc1
Reaction time: 15 h

Procedure:
To a solution of the compound obtained in Example 14 (2) (33.7 mg) in a mixture of tetrahydrofuran/water (3:1, 4 ml), OXONE (registered trademark) (134 mg) was added at 15 to 30° C. and the mixture was stirred for 15 hours. The reaction solution was then poured into water, extracted with dichloromethane, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was separated using silica gel preparative thin-layer chromatography (hexane:ethyl acetate=1:1) to obtain 28.8 mg of the desired product as a white powder.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C:3]1=[O:11].[NH:12]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([CH:21]=O)[CH:19]=2)[CH:14]=[N:13]1>>[NH:12]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18](/[CH:21]=[C:4]3/[C:3](=[O:11])[N:2]([CH3:1])[C:10]4[C:5]/3=[CH:6][CH:7]=[CH:8][CH:9]=4)[CH:19]=2)[CH:14]=[N:13]1
Reactant: CN1C(=O)Cc2ccccc21
Reactant: O=Cc1ccc2cn[nH]c2c1
Product: CN1C(=O)/C(=C/c2ccc3cn[nH]c3c2)c2ccccc21
Yield: 17.5 %

Procedure:
The desired product was synthesized according to the method described for Example A11B, except substituting 1-methylindolin-2-one (37 mg, 0.249 mmol) and 1H-indazole-6-carbaldehyde (40 mg, 0.274 mmol) and then purified by preparatory HPLC to obtain the title compound (12 mg, 17%) as a yellow solid. 1H NMR (400 MHz, CD3OD) δ 8.13 (s, 1H), 7.96-7.86 (m, 3H), 7.67 (d, J=7.83 Hz, 1H), 7.46 (d, J=8.08 Hz, 1H), 7.33 (t, J=7.71 Hz, 1H), 7.02 (d, J=7.83 Hz, 1H), 6.93 (t, J=7.71 Hz, 1H), 3.31 (s, 3H); MS ESI 276.1 [M+H]+, calcd for [C17H13N3O+H]+ 276.11.