Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[NH:24][CH2:23][CH2:22][C:21]([C:25]([O:27][CH3:28])=[O:26])=[CH:20][C:19]=3[CH:29]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].[O:30]1[CH:34]=[CH:33][C:32]([CH:35]=O)=[CH:31]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O>ClCCCl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:35][C:32]4[CH:33]=[CH:34][O:30][CH:31]=4)[CH2:23][CH2:22][C:21]([C:25]([O:27][CH3:28])=[O:26])=[CH:20][C:19]=3[CH:29]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3)cc1
Reactant: O=Cc1ccoc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: O
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3Cc2ccoc2)cc1
Temperature: 25 °C
Reaction time: 120 h
Yield: 85.9 %

Procedure:
To a solution of methyl 7-(4-butoxyethoxyphenyl)-2,3-dihydro-1-benzazepine-4-carboxylate (300 mg) and 3-furaldehyde (365 mg) in 1,2-dichloroethane (10 ml) was added sodium triacetoxyborohydride (402 mg), and the mixture was stirred under nitrogen atmosphere at room temperature for 5 days. Then, water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried with magnesium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was purified with silica gel column chromatography (hexane:ethyl acetate=1:1) to give methyl 7-(4-butoxyethoxyphenyl)-1-(3-furylmethyl)-2,3-dihydro-1-benzazepine-4-carboxylate (310 mg) as yellow oil.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[CH:10]=1)[C:5]([OH:7])=O.C(N(CC)CC)C.[CH2:22]([NH:25][CH2:26][CH2:27][CH3:28])[CH2:23][CH3:24].[I-].ClC1C=CC=C[N+]=1C>C(Cl)Cl>[CH2:22]([N:25]([CH2:26][CH2:27][CH3:28])[C:5]([C:4]1[CH:8]=[C:9]([CH:10]=[C:2]([I:1])[CH:3]=1)[C:11]([O:13][CH3:14])=[O:12])=[O:7])[CH2:23][CH3:24]
Reactant: COC(=O)c1cc(I)cc(C(=O)O)c1
Reactant: CCCNCCC
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCN(CCC)C(=O)c1cc(I)cc(C(=O)OC)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 79.8 %

Procedure:
To a mixture of 3-iodo-5-(methoxycarbonyl)benzoic acid (65.8 g, 0.215 mol), triethylamine (52.2 g, 0.516 mol), and dipropylamine (23.9 g, 0.237 mol) in methylene chloride (950 mL) was added 2-chloro-1-methylpyridinium iodide (65.9 g, 0.258 mol). The reaction mixture was stirred at room temperature for 15 h and then concentrated under reduced pressure. Purification by silica gel plug (3:1 hexanes/ethyl acetate) provided methyl 3-[(dipropylamino)carbonyl]-5-iodobenzoate (66.8 g): 1NMR (300 MHz, CDCl3) δ 8.39 (s, 1H), 7.98 (s, 1H), 7.88 (s, 1H), 3.93 (s, 3H), 3.45 (m, 2H), 3.14 (m, 2H), 1.69 (m, 2H), 1.54 (m, 2H), 0.98 (m, 3H), 0.77 (m, 3H).
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:14]([C:16]3[CH:24]=[CH:23][CH:22]=[CH:21][C:17]=3[C:18]([OH:20])=O)=[O:15])[CH:5]=[CH:4][C:3]1=2.P(Cl)(Cl)Cl.[CH2:30]([NH:34][CH2:35][CH2:36][CH2:37][CH3:38])[CH2:31][CH2:32][CH3:33]>ClCCl>[CH2:30]([N:34]([CH2:35][CH2:36][CH2:37][CH3:38])[C:18](=[O:20])[C:17]1[CH:21]=[CH:22][CH:23]=[CH:24][C:16]=1[C:14]([C:6]1[CH:5]=[CH:4][C:3]2[C:2]([CH3:25])([CH3:1])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]=2[CH:7]=1)=[O:15])[CH2:31][CH2:32][CH3:33]
Reactant: CCCCNCCCC
Reactant: CC1(C)CCC(C)(C)c2cc(C(=O)c3ccccc3C(=O)O)ccc21
Solvent: ClCCl
Solvent: ClP(Cl)Cl
Product: CCCCN(CCCC)C(=O)c1ccccc1C(=O)c1ccc2c(c1)C(C)(C)CCC2(C)C
Yield: 26.8 %

Procedure:
To a solution of 1.68 g (5 mmoles) of 2-[(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl)carbonyl]benzoic acid in 20 cm3 of anhydrous dichloromethane, there is added 0.22cm3 (2.5 mmoles) of phosphorus trichloride. The mixture is heated for 3 hours at reflux. After cooling to +5° C., 2.6 cm3 (15 mmoles) of dibutylamine are added. Stirring is maintained for 30 minutes at +5° C., and then for 1 additional hour so as to permit the reaction mixture to return to ambient temperature. The reaction mixture is then diluted to about 80 cm3 by the addition of dichloromethane. It is then transferred to a decanting ampoule and washed first with diluted HCl and then with water. The dichloromethane phase is dried on sodium sulfate and then concentrated under reduced pressure. The resulting crude product is purified by chromatography on silica 60 gel in a 5/3/2 toluene/dichloromethane/ethyl acetate eluant mixture. After evaporation and drying under a vacuum a 80° C., 0.6 g of N,N-di-n-butyl 2-[(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl) carbonyl]benzamide in the form of a colorless thick oil is obtained. The NMR1H 80 MHz and IR spectra correspond to the expected structure.
Reaction SMILES: [CH2:1]1[O:17][C:4]2([CH2:9][CH2:8][C:7](O)([C:10]3[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=3)[CH2:6][CH2:5]2)[O:3][CH2:2]1.S(Cl)(Cl)=O.[OH-].[Na+]>N1C=CC=CC=1>[CH2:2]1[O:3][C:4]2([CH2:9][CH2:8][C:7]([C:10]3[CH:11]=[CH:12][N:13]=[CH:14][CH:15]=3)=[CH:6][CH2:5]2)[O:17][CH2:1]1
Reactant: OC1(c2ccncc2)CCC2(CC1)OCCO2
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Product: C1=C(c2ccncc2)CCC2(C1)OCCO2
Temperature: 0 °C
Yield: 86.6 %

Procedure:
In 40 ml of pyridine was dissolved 5 g of 4-hydroxy-4-(4-pyridyl)cyclohexanone ethyleneacetal and, 8 ml of thionyl chloride was added to the solution at -10° C. Then, after stirring at 0° C., the reaction solution was poured onto ice. After an excess of a sodium hydroxide aqueous solution was added to the mixture, it was extracted with methylene chloride and the extract was purified to give 4 g of 4-(4-pyridyl)cyclohex-3-enone ethyleneacetal.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:8][CH2:7][CH2:6][CH2:5]1.[CH2:9]([N:27]=[C:28]=[O:29])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]>CC(C)=O>[N:4]1([CH2:3][CH2:2][O:1][C:28](=[O:29])[NH:27][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:8][CH2:7][CH2:6][CH2:5]1
Reactant: CCCCCCCCCCCCCCCCCCN=C=O
Reactant: OCCN1CCCC1
Solvent: CC(C)=O
Product: CCCCCCCCCCCCCCCCCCNC(=O)OCCN1CCCC1
Temperature: 25 °C

Procedure:
10.1 Grams of N-hydroxyethylpyrrolidine, 23.6 g of octadecyl isocyanate and 100 ml of acetone were charged in a flask equipped with a stirrer and a condenser and refluxed with heating for 3 hours under stirring. The reaction mixture was cooled to room temperature, and the precipitated crystal was filtered off under reduced pressure and washed with acetone, followed by recrystallization from n-hexane to obtained 18.5 g of the desired product. m.p. 57° C.
Reaction SMILES: Br[C:2]1[N:7]2[N:8]=[C:9]([NH2:11])[N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.[C:12]1(B(O)O)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[C:12]1([C:2]2[N:7]3[N:8]=[C:9]([NH2:11])[N:10]=[C:6]3[CH:5]=[CH:4][CH:3]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Nc1nc2cccc(Br)n2n1
Reactant: OB(O)c1ccccc1
Product: Nc1nc2cccc(-c3ccccc3)n2n1

Procedure:
5-Phenyl-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine was prepared from 5-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (3.00 g, 14.0 mmol) and phenyl boronic acid (1.8 g, 15.0 mmol), in a manner analogous to Step 73c. The product was isolated as a white powder (0.567 g, 19%) after chromatography on an Isco silica gel column (80 g) using methanol in dichloromethane as the eluent. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 7.94 (d, J=6.9 Hz, 2H), 7.52 (m, 4H), 7.37 (m, 1H), 7.02 (d, J=6.5 Hz, 1H), 6.02 (s, 2H). MS=210 (MH)+.
Reaction SMILES: Br[C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1)=[O:5].Br[C:18]1[CH:26]=CC=C[C:19]=1C([Cl:22])=O.NC1C=NC=CC=1>N1C=CC=CC=1>[ClH:22].[CH2:19]([N:9]1[CH2:10][CH2:11][CH2:12][C:7]2([C:13]3[C:3](=[CH:2][CH:16]=[CH:15][CH:14]=3)[C:4](=[O:5])[NH:6]2)[CH2:8]1)[CH2:18][CH3:26]
Reactant: O=C(Cl)c1ccccc1Br
Reactant: O=C(Nc1cccnc1)c1ccccc1Br
Agent: Nc1cccnc1
Solvent: c1ccncc1
Product: CCCN1CCCC2(C1)NC(=O)c1ccccc12
Product: Cl
Reaction time: 12 h

Procedure:
2-Bromo-N-(3-pyridyl)benzamide. To a solution of 2-bromobenzoylchloride (11.6 g) in dry pyridine (50 ml) at rt., 3-aminopyridine (5.0 g) dissolved in dry pyridine was added. After stirring for 12 hours and extractive work-up 7.77 g of the title product was obtained as white crystals. MS(ESP+) m/z: 279 (M+H+, 98), 277 (M+H+, 100).
Reaction SMILES: Br[CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[NH:10]1[C:18]2[C:13](=[N:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[N:11]1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.C(OCC)(=O)C>[N:10]1([CH2:2][C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4])[C:18]2[C:13](=[N:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[N:11]1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: c1cnc2cn[nH]c2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)Cn1ncc2ncccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 51 %

Procedure:
Tert-butyl bromoacetate (0.55 mL, 3.69 mmol) was added to 1H-pyrazolo[4,3-b]pyridine (220 mg, 1.85 mmol) and Cs2CO3 (723 mg, 2.22 mmol) in anhydrous DMF (7 mL). The mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with ethyl acetate (50 mL), washed with water (3×30 mL), brine (30 mL), dried over sodium sulphate, evaporated in vacuo and purified by column chromatography on silica gel (hexane:EtOAc 80:20) to afford a colourless gum in 51% yield, 220 mg.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N+:4]([O-:27])[CH:5]=[C:6]([Cl:26])[C:7]=1[CH2:8][C@@H:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH:18]([F:20])[F:19])=[C:13]([O:21][CH2:22][CH:23]2[CH2:25][CH2:24]2)[CH:12]=1)[OH:10].C(Cl)CCl.[CH3:32][N:33]([C@H:43]([CH3:47])[C:44](O)=[O:45])[S:34]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)(=[O:36])=[O:35]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[N+:4]([O-:27])[CH:5]=[C:6]([Cl:26])[C:7]=1[CH2:8][C@@H:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH:18]([F:20])[F:19])=[C:13]([O:21][CH2:22][CH:23]2[CH2:25][CH2:24]2)[CH:12]=1)[O:10][C:44](=[O:45])[C@H:43]([N:33]([CH3:32])[S:34]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)(=[O:36])=[O:35])[CH3:47]
Reactant: C[C@H](C(=O)O)N(C)S(=O)(=O)c1ccccc1
Reactant: [O-][n+]1cc(Cl)c(C[C@H](O)c2ccc(OC(F)F)c(OCC3CC3)c2)c(Cl)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: ClCCCl
Product: C[C@H](C(=O)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1)N(C)S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.5 %

Procedure:
A solution of (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-hydroxyethyl)pyridine 1-oxide (397 mg, 0.945 mmol), EDC (362 mg, 1.891 mmol), and DMAP (289 mg, 2.364 mmol) in 10 ml of dry DCM was stirred for 15 minutes at room temperature, then (R)-2-(N-methylphenyl-sulfonamido)propanoic acid (345 mg, 1.418 mmol) was added. After stirring overnight at room temperature, the reaction was complete. The mixture was washed twice with 1N HCl, then with aq. NaHCO3, with brine and finally dried over sodium sulfate and evaporated to dryness. The residue was purified by flash chromatography on silica gel (AcOEt) to obtain 3,5-dichloro-4-((S)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-((R)-2-(N-methylphenylsulfonamido)propanoyloxy)-ethyl)pyridine 1-oxide (430 mg, 0.666 mmol, 70.5% yield, MS/ESI+ 645.05 [MH]+, [αD]=+6.6, c=0.483, DCM).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[C:5]2[CH:11]=[C:10]([C:12]([OH:14])=[O:13])[NH:9][C:6]2=[N:7][CH:8]=1.S(=O)(=O)(O)O.[CH2:22](O)[CH3:23]>>[F:16][C:2]([F:1])([F:15])[C:3]1[CH:4]=[C:5]2[CH:11]=[C:10]([C:12]([O:14][CH2:22][CH3:23])=[O:13])[NH:9][C:6]2=[N:7][CH:8]=1
Reactant: CCO
Reactant: O=C(O)c1cc2cc(C(F)(F)F)cnc2[nH]1
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1cc2cc(C(F)(F)F)cnc2[nH]1

Procedure:
A 100 ml round-bottomed flask equipped with a magnetic stirrer is charged with 0.3 g (1.3 mmol) of 5-trifluoromethyl-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid (Angew Chem Int Ed 2004, 43(34), 4526-4528) and 50 ml of ethanol. This solution is admixed with 0.5 ml of concentrated sulfuric acid. The reaction mixture is then brought to reflux for 18 hours. The cooled solution is concentrated to dryness under reduced pressure. The residue is taken up in dichloromethane (100 ml) and the organic phase is washed successively with normal aqueous sodium hydroxide solution (30 ml), with water (20 ml) and then with saturated aqueous sodium chloride solution. It is dried over sodium sulfate and then concentrated under reduced pressure. This gives 0.29 g (1.12 mmol) of the expected product in the form of a yellow powder.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@:5]12[CH2:14][N:13]([S:15]([C:18]3[CH:19]=[N:20][C:21](Cl)=[CH:22][CH:23]=3)(=[O:17])=[O:16])[CH2:12][CH2:11][C:10]1=[CH:9][C:8]1[N:25]([C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)[N:26]=[CH:27][C:7]=1[CH2:6]2)=[O:4].[NH:35]1[CH2:38][CH2:37][CH2:36]1>>[CH3:1][O:2][C:3]([C@@:5]12[CH2:14][N:13]([S:15]([C:18]3[CH:19]=[N:20][C:21]([N:35]4[CH2:38][CH2:37][CH2:36]4)=[CH:22][CH:23]=3)(=[O:17])=[O:16])[CH2:12][CH2:11][C:10]1=[CH:9][C:8]1[N:25]([C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)[N:26]=[CH:27][C:7]=1[CH2:6]2)=[O:4]
Reactant: C1CNC1
Reactant: COC(=O)[C@]12Cc3cnn(-c4ccc(F)cc4)c3C=C1CCN(S(=O)(=O)c1ccc(Cl)nc1)C2
Product: COC(=O)[C@]12Cc3cnn(-c4ccc(F)cc4)c3C=C1CCN(S(=O)(=O)c1ccc(N3CCC3)nc1)C2

Procedure:
The title compound was prepared by the method of Preparation 4b using (R)-6-(6-chloropyridine-3-sulfonyl)-1-(4-fluorophenyl)-1,4,5,6,7,8-hexahydro-1,2,6-triazacyclopenta[b]na-phthalene-4a-carboxylic acid methyl ester and azetidine. LCMS (Method B): 524 (M+H)+, Retention time 3.5 minutes.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:20][CH2:19][CH:18]([C:21](=[O:38])[NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[O:29][C:30]2[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][C:31]=2[Cl:37])[CH2:17][CH2:16]1)=O)(C)(C)C.C([O-])([O-])=O.[K+].[K+].O>C(Cl)Cl>[Cl:37][C:31]1[CH:32]=[C:33]([Cl:36])[CH:34]=[CH:35][C:30]=1[O:29][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[NH:22][C:21]([CH:18]1[CH2:19][CH2:20][NH:15][CH2:16][CH2:17]1)=[O:38]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)Nc2ccccc2Oc2ccc(Cl)cc2Cl)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: O
Product: O=C(Nc1ccccc1Oc1ccc(Cl)cc1Cl)C1CCNCC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 77.7 %

Procedure:
AMR01036 Trifluoroacetic acid (TFA, 1 mL) was added to a solution of 4-[2-(2,4-dichlorophenoxy)-phenylcarbamoyl]piperidine-1-carboxylic acid tert-butyl ester (AMR01.032, 100 mg, 0.215 mmol) in dry DCM (2 mL) at 0° C. After stirring at 0° C. for 30 min, the mixture was poured into solid K2CO3 (2.8 g) and water (11 mL) was added. The solution was extracted with DCM (3×20 mL) and the organic layer was dried (MgSO4), filtered and evaporated to give piperidine-4-carboxylic acid [2-(2,4-dichlorophenoxy)phenyl]amide (61 mg, 90%) as an oil which was used in the next step without further purification. Rf: 0.175 (DCM/methanol 4:1 plus 3 drops of triethylamine) 1H NMR (270 MHz, CDCl3) δ 1.66 (2H, m, CH2), 1.87 (2H, m, CH2), 2.24 (1H, br s, NH), 2.40 (1H, tt, CH), 2.66 (2H, td, CH2), 3.15 (2H, br d, J=12.6 Hz, CH2), 6.72 (1H, dd, J=8.2, 1.5 Hz, ArH), 6.93 (1H, d, J=8.6 Hz, ArH), 6.99 (1H, td, J=7.9, 1.5 Hz, ArH), 7.12 (1H, td, J=7.9, 1.2 Hz, ArH), 7.20 (1H, dd, J=8.9, 2.5 Hz, ArH), 7.47 (1H, d, J=2.5 Hz, ArH) and 8.41 (1H, dd, J=7.9, 1.2 Hz, ArH).
Reaction SMILES: C[C:2]([O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(C)[C:3]([O:5]CC)=[O:4].[OH-].[Na+].C[CH2:19][OH:20]>>[CH3:19][O:20][C:13]1[CH:12]=[CH:11][C:10]([O:9][CH2:2][C:3]([OH:5])=[O:4])=[CH:15][CH:14]=1
Reactant: CCOC(=O)C(C)(C)Oc1ccccc1
Reactant: CCO
Agent: [Na+]
Agent: [OH-]
Product: COc1ccc(OCC(=O)O)cc1
Reaction time: 0.5 h

Procedure:
To a solution of ethyl 2-methyl-2-phenoxypropanoate (210 mg, 1 mmol) in EtOH (10 ml) was added 10% NaOH aqueous solution (10 mL) at 26° C. The mixture was stirred for 30 min and then concentrated before the addition of water (20 mL) and washing with ethyl acetate (2×20 mL). The aqueous layer was acidified with 2N HCL until pH 3 and extracted with ethyl acetate (2×20 ml). The organic layer was washed with brine (30 mL), dried over Na2SO4 and concentrated to give the title compound which was used in next step without further purification.
Reaction SMILES: [CH3:1][C:2](=O)[CH2:3][C:4](=O)[CH3:5].[NH2:8][C:9]1[N:13]=[C:12]([SH:14])[NH:11][N:10]=1.N1CCCCC1>C(O)(=O)C>[CH3:1][C:2]1[CH:3]=[C:4]([CH3:5])[N:10]2[N:11]=[C:12]([SH:14])[N:13]=[C:9]2[N:8]=1
Reactant: CC(=O)CC(C)=O
Reactant: Nc1n[nH]c(S)n1
Solvent: CC(=O)O
Solvent: C1CCNCC1
Product: Cc1cc(C)n2nc(S)nc2n1
Temperature: 125 °C
Yield: 81.6 %

Procedure:
A mixture of 2,4-pentanedione (6.46 g, 64.6 mmol), 3-amino-5-mercapto-1,2,4-triazole (7.5 g, 64.6 mmol), glacial acetic acid (230 mL), and piperidine (0.58 mL, 5.9 mmol) was added to a 500 mL RBF with a magnetic stirring bar. The flask was fitted with a condenser, and warmed in an oil bath to a gentle reflux at 125° C. The mixture was heated for 45 hours, and solids remained visible in the flask throughout the heating period. Progress of the reaction was monitored by analytical HPLC with UV detection at 215 and 254 nm. The starting material 3-amino-5-mercapto-1,2,4-triazole elutes rapidly with retention time of 1.05 min, and the product elutes with retention time of 1.87 min. The mixture was cooled to room temperature. Solids were isolated by filtration, rinsed with 75 mL of acetic acid, and then dried under reduced pressure to afford the title compound as a pale yellow powder (9.5 g, 82% yield). A sample of 120 mg was recrystallized in warm acetic acid to afford 60 mg (50% recovery) of fine off-white needles, while the crude powder was used in the next step. 1H NMR (DMSO-d6+CDCl3, 400 MHz) δ ppm: 14.05 (br s, 1H), 7.25 (s, 1H), 2.67 (s, 3H), 2.56 (s, 3H). (NMR from crystalline material.)
Reaction SMILES: [CH2:1]([C:3]1[N:4]([CH2:11][CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([CH:20]=[C:21]3[O:25][C:24](=[O:26])[NH:23][C:22]3=[O:27])=[CH:16][CH:15]=2)[C:5](=[O:10])[CH:6]=[C:7]([CH3:9])[N:8]=1)[CH3:2].[H][H]>O1CCOCC1.[Pd]>[CH2:1]([C:3]1[N:4]([CH2:11][CH2:12][O:13][C:14]2[CH:15]=[CH:16][C:17]([CH2:20][CH:21]3[O:25][C:24](=[O:26])[NH:23][C:22]3=[O:27])=[CH:18][CH:19]=2)[C:5](=[O:10])[CH:6]=[C:7]([CH3:9])[N:8]=1)[CH3:2]
Reactant: [H][H]
Reactant: CCc1nc(C)cc(=O)n1CCOc1ccc(C=C2OC(=O)NC2=O)cc1
Agent: [Pd]
Solvent: C1COCCO1
Product: CCc1nc(C)cc(=O)n1CCOc1ccc(CC2OC(=O)NC2=O)cc1
Yield: 89.5 %

Procedure:
A solution of 5-[4-[2-[2-ethyl-4-methyl-6-oxo-1,6-dihydro-1-pyrimidinyl]ethoxy]phenyl methylene]oxazolidine-2,4-dione (100 mg) (obtained from example 26) in 1,4-dioxane (10 ml) was reduced with hydrogen in the presence of 10% palladium on charcoal (20 mg) at 50 psi for 24 h. The mixture was filtered through a bed of celite. The filtrate was evaporated to dryness under reduced pressure, purified by column chromatography (2:1 EtOAc/petroleum ether as eluent) to afford the title compound (90 mg, 90%).
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=2)[O:11][CH2:12][CH2:13][CH2:14][NH2:15])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[C:20]1[C:24]2[CH:25]=[C:26]([CH3:29])[CH:27]=[CH:28][C:23]=2[S:22](=[O:31])(=[O:30])[N:21]=1.CCOCC.[K+].[Br-]>C(Cl)(Cl)Cl>[N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=2)[O:11][CH2:12][CH2:13][CH2:14][NH:15][C:20]2[C:24]3[CH:25]=[C:26]([CH3:29])[CH:27]=[CH:28][C:23]=3[S:22](=[O:30])(=[O:31])[N:21]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1ccc2c(c1)C(Cl)=NS2(=O)=O
Reactant: NCCCOc1cccc(CN2CCCCC2)c1
Agent: [Br-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CCOCC
Product: Cc1ccc2c(c1)C(NCCCOc1cccc(CN3CCCCC3)c1)=NS2(=O)=O
Reaction time: 0.25 h

Procedure:
To a refluxing solution of 3-[3-(1-piperidinylmethyl)phenoxy]propylamine (1.33 g, 5.36 mmoles) in dried chloroform (50 ml) under dry nitrogen is added over 45 minutes a solution of 3-chloro-5-methyl-1,2-benzisothiazole 1,1-dioxide (1.21 g, 5.64 mmoles) in dried chloroform (25 ml) while maintaining reflux. After the addition is complete refluxing is continued for 15 minutes and the clear brown solution is allowed to come to room temperature. Evaporation in vacuo gives a tan solid which cannot be crystallized. Column chromatography on silica gel using methylene chloride/methanol/ammonium hydroxide 95/5/0.5 as eluent gives the free methanol base as a brown foam, 1.22 g. Trituration with ether gives an off-white colored solid, 0.73 g, m.p. 120°-124° C. Recrystallization from ethyl acetate/pentane and finally ethyl acetate gives the pure product, 0.169 tan solid, m.p. 120°-4° C. IR (KBr) 3300, 2938, 1622, 1530 cm-1 ; NMR (in DMSO) 6.8-8.0 (7 H,m), 4.05 (2H,t), 3.76 (2H,t), 1.37 (6H,s), 1.4 (6H,s), 2.0-2.4 (6H,m), 2.5 (3H,s), 3.4 (2H,s), 3.6 (2H,t), 4.1 (2H,t), 6.7-8.0 (7H,m), 9.3 (1H,n).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11](/[CH:13]=[CH:14]/[C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1)=[O:12]>CC(O)=O.CO.C(Cl)Cl.[Pd]>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([CH2:13][CH2:14][C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1)=[O:12]
Reactant: O=C(/C=C/c1cccnc1)c1ccc2ccccc2c1
Agent: [Pd]
Solvent: CO
Solvent: ClCCl
Solvent: CC(=O)O
Product: O=C(CCc1cccnc1)c1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 68.8 %

Procedure:
A mixture of (2-naphthyl) [(E)-2-(3-pyridyl)-1-ethenyl]ketone (5.02 g) and palladium black (0.15 g) in AcOH—MeOH—CH2Cl2 (4 ml/50 ml/20 ml) was stirred under hydrogen atmosphere at room temperature for 3 hours. The catalyst was filtered off and the filtrate was concentrated in vacuo. The residue dissolved in ethyl acetate, washed with saturated aqueous NaHCO3 solution and brine, and dried. After removal of the solvent, the residue was recrystallized from hexane-ethyl acetate to give the titled compound (3.48 g) as colorless prisms.
Reaction SMILES: CC1C=CC(S([O:11][CH2:12][CH2:13][CH2:14][C:15]([CH3:20])([S:17][S:18][CH3:19])[CH3:16])(=O)=O)=CC=1.O[C:22]1[CH:27]=[C:26]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[N:25]=[C:24]([C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH:23]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:20][C:15]([S:17][S:18][CH3:19])([CH3:16])[CH2:14][CH2:13][CH2:12][O:11][C:22]1[CH:23]=[C:24]([C:33]([O:35][CH2:36][CH3:37])=[O:34])[N:25]=[C:26]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH:27]=1
Reactant: CCOC(=O)c1cc(O)cc(C(=O)OCC)n1
Reactant: CSSC(C)(C)CCCOS(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(OCCCC(C)(C)SSC)cc(C(=O)OCC)n1
Temperature: 90 °C
Reaction time: 18 h
Yield: 52.1 %

Procedure:
To a stirred solution of 4-methyl-4-(methyldisulfanyl)pentyl 4-methylbenzenesulfonate (5c) (0.48 g, 1.435 mmol) and diethyl 4-hydroxypyridine-2,6-dicarboxylate (5a)(0.343 g, 1.435 mmol) in anhydrous dimethylformamide (6.5 mL) was added Potassium carbonate (0.297 g, 2.152 mmol). The reaction was stirred at 90° C. for 18 hours. Then allowed to cool to ambient temperature and quenched with saturated ammonium chloride. The mixture was extracted three times with ethyl acetate. The extracts were dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification by silica gel chromatography (30% hexanes/ethyl acetate) yielded diethyl 4-(4-methyl-4-(methyldisulfanyl)pentyloxy)pyridine-2,6-dicarboxylate (5d)(300 mg, 52%); 1H NMR (400 Hz, CDCl3): δ 7.70 (s, 2H), 4.40 (q, 4H, J=7.2, 14.4 Hz), 4.07 (t, 2H, J=6. Hz), 2.35 (s, 3H), 1.86 (m, 2H), 1.70 (m, 2H), 1.38 (t, 6H, J=7.2 Hz), 1.27 (s, 6H); MS (m/z), found 424.1 (M+Na), 440.1 (M+K). See FIG. 5.