Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:7]2[N:8]=[C:9]([S:11][CH2:12][C:13]3[NH:14][CH:15]=[C:16]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[N:17]=3)[N:10]=[C:6]2[CH:5]=[C:4]([CH3:24])[CH:3]=1.[CH2:25](Br)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:25]([SH:11]([CH2:12][C:13]1[NH:14][CH:15]=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:17]=1)[C:9]1[N:10]=[C:6]2[CH:5]=[C:4]([CH3:24])[CH:3]=[C:2]([CH3:1])[N:7]2[N:8]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: Cc1cc(C)n2nc(SCc3nc(-c4ccccc4)c[nH]3)nc2c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(C)n2nc([SH](Cc3ccccc3)Cc3nc(-c4ccccc4)c[nH]3)nc2c1
Temperature: 75 °C
Reaction time: 8 h

Procedure:
To a solution of 5,7-dimethyl-2-(4-phenyl-1H-imidazol-2-ylmethylsulfanyl)-[1,2,4]triazolo[1,5-a]pyridine (15 mg, 0.045 mmol) in DMF (0.5 mL) was added benzyl bromide (5.4 μL, 0.045 mmol) and potassium carbonate (9.3 mg, 0.067 mmol) and the resulting mixture was stirred overnight at 75° C. Volatiles were evaporated and the residue was purified by preparative LC-MS to yield the title compound. LC-MS: m/z 426.3 (MH+), tR=1.06 min, method A.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:17]3[C:16]([O:18][C@H:19]([CH3:23])[C@H:20]([OH:22])[CH3:21])=[N:15][CH:14]=[N:13][C:12]=3[O:11][C:10]=2[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:5][CH:4]=1.[C:30]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])(=[O:33])[CH:31]=[CH2:32].O>C1COCC1>[C:35]([O:34][C:30](=[O:33])[CH2:31][CH2:32][O:22][C@H:20]([CH3:21])[C@H:19]([O:18][C:16]1[C:17]2[C:9]([C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=3)=[C:10]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[O:11][C:12]=2[N:13]=[CH:14][N:15]=1)[CH3:23])([CH3:38])([CH3:37])[CH3:36]
Reactant: C=CC(=O)OC(C)(C)C
Reactant: COc1ccc(-c2c(-c3ccccc3)oc3ncnc(O[C@H](C)[C@@H](C)O)c23)cc1
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(-c2c(-c3ccccc3)oc3ncnc(O[C@H](C)[C@@H](C)OCCC(=O)OC(C)(C)C)c23)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Add 157 mg (1.37 mmol) potassium tert.-butylate to a solution of 535 mg (1.37 mmol) (2R,3R)-3-{[5-(4-methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidin-4-yl]oxy}butan-2-ol in 5 ml THF. After stirring for 15 min at RT, add 1.0 ml (878 mg, 6.65 mmol) tert.-butyl acrylate. After three hours, add 10 ml water, and concentrate the reaction mixture by vacuum evaporation. Purify the residue by preparative RP-HPLC (gradient: water/acetonitrile). 346 mg (47% of theor.) of the desired product is obtained.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([C:26]3[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=3)([C:19]3[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=3)[CH3:18])=[CH:13][CH:12]=2)([CH3:10])[CH3:9])=[CH:4][CH:3]=1.[CH3:33][S:34](Cl)(=[O:36])=[O:35].C(N(CC)CC)C>O1CCOCC1>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([C:19]3[CH:20]=[CH:21][C:22]([OH:25])=[CH:23][CH:24]=3)([C:26]3[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=3)[CH3:18])=[CH:13][CH:12]=2)([CH3:10])[CH3:9])=[CH:4][CH:3]=1.[CH3:33][S:34]([OH:36])(=[O:1])=[O:35]
Reactant: CS(=O)(=O)Cl
Agent: CC(C)(c1ccc(O)cc1)c1ccc(C(C)(c2ccc(O)cc2)c2ccc(O)cc2)cc1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CS(=O)(=O)O

Procedure:
One (1.0) mole of 1-[1-(4-hydroxyphenyl)isopropyl]-4-[1,1-bis(4-hydroxyphenyl)ethyl]benzene, naphthoquinone-1,2-diazido-5-sulfonyl chloride (2.0 moles) and methanesulfonyl chloride (0.5 moles) were dissolved in dioxane (4,000 g). To the resulting solution, dioxane (2,000 g) having triethylamine (500 g) dissolved therein was added dropwise over 10 minutes at a controlled temperature not higher than 30° C. The precipitating salt was separated by filtration and the thus recovered reaction product was washed and dried to yield esters of the 1-[1-(4-hydroxyphenyl)isopropyl]-4-[1,1-bis(4-hydroxyphenyl)ethyl]benzene with naphthoquinone-1,2-diazido-5-sulfonic acid and methanesulfonic acid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH2:11]=O.[C:13]([NH2:16])(=[O:15])[CH3:14]>S(=O)(=O)(O)O>[CH3:10][C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][C:6]=1[CH2:11][NH:16][C:13](=[O:15])[CH3:14]
Reactant: CC(N)=O
Reactant: Cc1ccc([N+](=O)[O-])cc1
Reactant: C=O
Agent: O=S(=O)(O)O
Product: CC(=O)NCc1cc([N+](=O)[O-])ccc1C
Temperature: 25 °C
Reaction time: 18 h
Yield: 75 %

Procedure:
To a solution of p-nitrotoluene (0.85 g; 0.05 mol) and para-formaldehyde (1.6 g; 0.05 mol) in concentrated sulfuric acid is added acetamide (8.85 g; 0.15 mol) in increments. This solution is stirred at room temperature for 18 hours. The reaction mixture is then poured onto ice. A precipitate is obtainined which is removed by filtration. This solid material is then mixed with butyl acetate, heated, and filtered while hot to remove insolubles. After cooling, 7.8 g (i.e., 75% yield) of product crystallizes out of solution. The product has the following characteristics: melting point of 141° to 143° C.; i.r. 3275, 1640 and 1660 cm-1 (sh); mass. spec. m/e 208.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1.[N:10]1([C:16]2[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=2[C:18]#[N:19])[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.[C:24]([O-])(=O)C.[Na+].C=O.[OH-].[Na+]>O.C(O)(=O)C>[NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[C:2]1[CH2:24][N:13]1[CH2:14][CH2:15][N:10]([C:16]2[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=2[C:18]#[N:19])[CH2:11][CH2:12]1
Reactant: c1cnc2[nH]ccc2c1
Reactant: CC(=O)[O-]
Reactant: N#Cc1ccccc1N1CCNCC1
Agent: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: N#Cc1ccccc1N1CCN(Cc2cc3cccnc3[nH]2)CC1

Procedure:
1H-pyrrolo[2,3-b]pyridine (47 mg, 0.40 mmol), 2-(1-piperazinyl)benzonitrile (65 mg, 0.48 mmol), sodium acetate (72 mg, 0.53 mmol), and formaldehyde (0.48 mmol) were combined in water and glacial acetic acid (1:2, 1 mL) and stirred at room temperature for 18 hours. The mixture was treated with a solution of 2M NaOH and concentrated under reduced pressure. The residue was treated with hot methanol. The methanol was filtered and the filter cake was washed with cold methanol to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ 2.62 (m, 4H) 3.14 (m, 4H) 4.03 (s, 2H) 5.60 (s, 1H) 7.09 (m, 3H) 7.61 (m, 2H) 8.06 (dd, J=8.31, 1.53 Hz, 1H) 8.20 (dd, J=4.75, 1.70 Hz, 1H). (ESI) m/z 318 (M+H)+.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[C:6]([C:8]1[CH:17]=[C:16]2[C:11]([C:12](=[O:20])[C:13]([OH:19])=[CH:14][N:15]2[CH3:18])=[CH:10][CH:9]=1)#[N:7].C(N(CC)CC)C>ClCCl>[CH3:1][S:2]([O:19][C:13]1[C:12](=[O:20])[C:11]2[C:16](=[CH:17][C:8]([C:6]#[N:7])=[CH:9][CH:10]=2)[N:15]([CH3:18])[CH:14]=1)(=[O:4])=[O:3]
Reactant: Cn1cc(O)c(=O)c2ccc(C#N)cc21
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cn1cc(OS(C)(=O)=O)c(=O)c2ccc(C#N)cc21

Procedure:
Methanesulphonyl chloride (1.0 ml) was added to a stirred suspension of 7-cyano-3-hydroxy-1-methyl-4quinolone (0.4 g) and triethylamine (2.0 ml) in dry dichloromethane (200 ml) at 0 to 5° and the resultant solution stirred for 2 hours. The solution was washed with water (2×50 ml), dried over magnesium sulphate and the solvent removed by distillation. The residue was purified by flash chromatography on a silica gel column eluted with dichloromethane:methanol (40:1) followed by trituration with diethyl ether (10 ml) to give the novel compound 7-cyano-1-methyl-4-oxo-1,4-dihydroquinol-3-yl methanesulphonate, m.p. 268°.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH2:12][C:13]1[S:14][CH:15]=[CH:16][N:17]=1>N1C=CC=CC=1>[I:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:12][C:13]2[S:14][CH:15]=[CH:16][N:17]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(I)cc1
Reactant: Nc1nccs1
Solvent: c1ccncc1
Product: O=S(=O)(Nc1nccs1)c1ccc(I)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 53.7 %

Procedure:
4-Iodobenzenesulfonyl chloride (1.8 g, 6.0 mmol, 1.0 equiv) was added portion-wise to a 0° C. solution of 2-aminothiazole (654 mg, 6.53 mmol, 1.1 equiv) in 4.91 mL of anhydrous pyridine. After addition was complete, the reaction mixture was warmed to ambient temperature. After 3 d, the reaction mixture was concentrated in vacuo. The residue was treated with methanol and ether to precipitate the product. The solid was collected by filtration, washing with ether, to afford the product as a light brown solid (1.18 g, 49%).
Reaction SMILES: [S:1]([Cl:3])Cl.[CH3:4][NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9].C(N(CC)CC)C>C(Cl)Cl>[Cl:3][S:1][N:5]([CH3:4])[C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9]
Reactant: CNC(=O)OC(C)(C)C
Reactant: ClSCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(SCl)C(=O)OC(C)(C)C
Temperature: 5 °C
Yield: 103.1 %

Procedure:
To a solution of 62 g (0.6 mole) of sulfur dichloride in 200 ml of methylene chloride cooled to 0° C. under a nitrogen atmosphere was added a solution made up of 50.9 g (0.4 mole) of t-butyl N-methylcarbamate, 44.5 g (0.44 mole) of triethylamine and 100 ml of methylene chloride. The temperature was maintained at -2° to 5° C. during the addition. After stirring for one additional hour at 5° C., the mixture was filtered under a positive nitrogen atmosphere, and the filtrate was concentrated. Solid was removed by extracting the product with hexane. After filtration the hexane solution was concentrated to give 81.5 g of t-butyl N-chlorothio-N-methylcarbamate.
Reaction SMILES: [C@@H:1]1([NH2:8])[CH2:6][CH2:5][CH2:4][CH2:3][C@H:2]1[NH2:7].[Cl:9][C:10]1[N:15]=[C:14](Cl)[C:13]([Cl:17])=[CH:12][N:11]=1.C(N(CC)CC)C.[CH3:25][S:26](Cl)(=[O:28])=[O:27]>O1CCCC1>[Cl:9][C:10]1[N:15]=[C:14]([NH:7][C@@H:2]2[CH2:3][CH2:4][CH2:5][CH2:6][C@H:1]2[NH:8][S:26]([CH3:25])(=[O:28])=[O:27])[C:13]([Cl:17])=[CH:12][N:11]=1
Reactant: CS(=O)(=O)Cl
Reactant: Clc1ncc(Cl)c(Cl)n1
Reactant: N[C@@H]1CCCC[C@H]1N
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CS(=O)(=O)N[C@@H]1CCCC[C@H]1Nc1nc(Cl)ncc1Cl
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
(1R,2R)-Cyclohexane-1,2-diamine (4.17 g, 36.5 mmol) was added into a round bottom flask and was dissolved in tetrahydrofuran (200 mL). The flask was cooled at 0° C., then 2,4,5-trichloropyrimidine (6.08 g, 33.1 mmol) was added. A precipitate formed, and the reaction was stirred 5 min before triethylamine (12 mL, 83 mmol) and methanesulfonyl chloride (4.00 mL, 51.7 mmol) were added simultaneously via two syringes. After 5 min, external cooling was removed, and the contents were stirred under an atmosphere of nitrogen. After 45 min, the contents were partitioned between dichloromethane (150 mL) and saturated sodium bicarbonate solution (150 mL). The layers were separated, and the aqueous phase extracted with dichloromethane (100 mL). The organic fractions were washed with brine (100 mL), dried (sodium sulfate) and were concentrated onto 37 g silica gel, and chromatographed on an ISCO cartridge (120 g SiO2, 0-50% EA:Hex). N-[(1R,2R)-2-(2,5-Dichloro-pyrimidin-4-ylamino)-cyclohexyl]-methanesulfonamide was isolated as a white solid (4.8 g, 43%). m.p. 163-166° C.; LCMS (m/e) 339 (M+1); 1H-NMR (CDCl3, 400 MHz) δ 8.04 (s, 1H), 5.91 (d, 1H, J=7.6 Hz), 5.91 (d, 1H, J=7.6 Hz), 5.91 (d, 1H, J=7.6 Hz), 3.32 (m, 1H), 3.91 (m, 1H), 2.92 (s, 3H), 2.25 (d, 1H, J=12 Hz), 2.13 (d, 1H, J=12 Hz), 1.83 (m, 2H), 1.25-1.48 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:3]=1[CH2:4][O:5][C:6]1[CH:18]=[CH:17][C:9]2[CH:10]([C:13]([O:15][CH3:16])=[O:14])[CH2:11][O:12][C:8]=2[CH:7]=1.[H-].[Na+].I[CH3:27]>CN(C=O)C>[Cl:1][C:2]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:3]=1[CH2:4][O:5][C:6]1[CH:18]=[CH:17][C:9]2[C:10]([CH3:27])([C:13]([O:15][CH3:16])=[O:14])[CH2:11][O:12][C:8]=2[CH:7]=1
Reactant: COC(=O)C1COc2cc(OCc3ccc(Cl)cc3Cl)ccc21
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C1(C)COc2cc(OCc3ccc(Cl)cc3Cl)ccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of methyl 6-((2,4-dichlorobenzyl)oxy)-2,3-dihydro-1-benzofuran-3-carboxylate (150 mg) in DMF (dry) (3.0 mL) was added sodium hydride (18.7 mg) at 0° C. After 30 min, to the mixture was added iodomethane (0.034 mL) at 0° C. The mixture was allowed to room temperature and stirred at room temperature overnight. The mixture was quenched with water at 0° C. and extracted with EtOAc. The combined organic layer was washed successively with water and brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/hexane) to give the title compound (103.8 mg).
Reaction SMILES: [C:1]1([C:7]2[C:25]([C:26]3[CH:31]=[CH:30][C:29]([C:32]4([NH:36]C(=O)OC(C)(C)C)[CH2:35][CH2:34][CH2:33]4)=[CH:28][CH:27]=3)=[N:24][C:10]3[O:11][CH2:12][C:13]4[N:14]([C:15]([C:18]5[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=5)=[N:16][N:17]=4)[C:9]=3[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)(C(F)(F)F)=O>ClCCl>[C:1]1([C:7]2[C:25]([C:26]3[CH:27]=[CH:28][C:29]([C:32]4([NH2:36])[CH2:35][CH2:34][CH2:33]4)=[CH:30][CH:31]=3)=[N:24][C:10]3[O:11][CH2:12][C:13]4[N:14]([C:15]([C:18]5[CH:19]=[CH:20][N:21]=[CH:22][CH:23]=5)=[N:16][N:17]=4)[C:9]=3[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)-n3c(nnc3-c3ccncc3)CO4)cc2)CCC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)-n3c(nnc3-c3ccncc3)CO4)cc2)CCC1
Reaction time: 0.01 h
Yield: 88.2 %

Procedure:
Tert-butyl (1-(4-(8-phenyl-1-(pyridin-4-yl)-4H-pyrido[2,3-b][1,2,4]triazolo[4,3-d][1,4]oxazin-7-yl)phenyl)cyclobutyl)carbamate (14 mg, 0.024 mmol) was dissolved in dichloromethane (1 ml); TFA (0.5 ml) was added at room temperature and the resulting mixture was stirred for 30 seconds. The solution was immediately concentrated to dryness under reduced pressure. The residue was dissolved in diethyl ether (˜2 ml) and concentrated to dryness under reduced pressure. This was repeated three times. The residue was then slurred in diethyl ether (2 ml) and after settling the supernatant solvent was removed by pipette. This was repeated three times. The residue was then slurred in n-hexane (2 ml) and after settling the supernatant solvent was removed by pipette. This was repeated three times. The remaining solvent was removed under reduced pressure and dried to give the desired product as an off-white solid (10 mg, 87% yield). LCMS (Method A) RT=3.66 min, M+H+=474. 1H NMR (500 MHz, CDCl3): 8.77 (2H, d), 8.79 (2H, d), 7.41 (2H, d), 7.33 (1H, s), 7.32 (2H, d), 7.18-7.13 (3H, m), 6.96 (2H, dd), 5.66 (2H, s), 2.70-2.61 (2H, m), 2.52-2.43 (2H, m), 2.19-2.08 (1H, m), 1.92-1.82 (1H, m).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:7](Br)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][CH2:25][CH:24]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([O:34][C:35]([C:38]([OH:40])=[O:39])([CH3:37])[CH3:36])[CH:29]=2)[CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16].CN(C)C=O>O>[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][CH2:25][CH:24]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([O:34][C:35]([C:38]([O:40][CH2:7][C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)=[O:39])([CH3:37])[CH3:36])[CH:29]=2)[CH2:23]1)=[O:21])([CH3:18])([CH3:16])[CH3:17]
Reactant: CC(C)(C)OC(=O)N1CCCC(c2cccc(OC(C)(C)C(=O)O)c2)C1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCCC(c2cccc(OC(C)(C)C(=O)OCc3ccccc3)c2)C1
Temperature: 60 °C
Reaction time: 1.5 h

Procedure:
Cesium carbonate (24.00 g, 73.67 mmol) and benzyl bromide (8.03 mL, 67.53 mmol) were added sequentially to a solution of of 3-[3-(1-Carboxy-1-methyl-ethoxy)-phenyl]-piperidine-1-carboxylic acid tert-butyl ester (22.31 g, 61.39 mmol) and dimethylformamide (100 mL) at ambient temperature. The resulting mixture was warmed to 60° C., stirred 1.5 h, cooled to ambient temperature and diluted with water (600 mL). The aqueous solution was extracted with diethyl ether (2×300 mL). The organic extracts were combined and washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resultant oil was purified by flash column chromatography (7:1 hexanes/ethyl acetate) to provide 3-[3-(1-Benzyloxycarbonyl-1-methyl-ethoxy)-phenyl]-piperidine-1-carboxylic acid tert-butyl ester as a pale-yellow oil.
Reaction SMILES: [CH3:1][O:2][C@@H:3]([CH3:11])[C@@H:4]([CH3:10])[C:5]([O:7]CC)=[O:6].Cl.O>O1CCOCC1>[CH3:1][O:2][C@@H:3]([CH3:11])[C@@H:4]([CH3:10])[C:5]([OH:7])=[O:6]
Reactant: CCOC(=O)[C@H](C)[C@H](C)OC
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: CO[C@@H](C)[C@@H](C)C(=O)O
Temperature: 90 °C
Yield: 70.8 %

Procedure:
This methyl ether (2.55 g) was dissolved in dioxane (50 ml) and conc. hydrochloric acid (36 %, 10 ml) and water (50 ml) were added to the solution. The solution was heated at 90° C. for 5 hours. The reaction mixture was poured into water (100 ml) and the mixture was extracted 4 times with ethyl acetate. The combined extract was dehydrated, concentrated and distilled under reduced pressure (b.p. 105° C./1 mmHg) to obtain (2R, 3S)-3-methoxy-2-methylbutyric acid (1.49 g).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][CH2:11][CH:12]=[CH:13][CH2:14][C@@H:15]([CH2:19][C@H:20]([C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=1)[OH:21])[C:16]([OH:18])=[O:17])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:29]I>C1COCC1>[CH2:3]([O:10][CH2:11][CH:12]=[CH:13][CH2:14][C@@H:15]([CH2:19][C@H:20]([C:22]1[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=1)[O:21][CH3:29])[C:16]([OH:18])=[O:17])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=C(O)[C@@H](CC=CCOCc1ccccc1)C[C@@H](O)c1ccc(F)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CO[C@H](C[C@H](CC=CCOCc1ccccc1)C(=O)O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a suspension of NaH (605 mg, 60% oil dispersion) in 30 mL THF was slowly added at room temperature the crude (S)-6-(benzyloxy)-2-((R)-2-(4-fluorophenyl)-2-hydroxyethyl)hex-4-enoic acid isolated above as a solution in 5 mL THF. To this mixture was added dropwise methyl iodide (732 μL, 1.7 g, 11.3 mmol) and the resulting stirred for 3 h at room temperature. The reaction was quenched by the slow addition of 20 mL 1M aqueous HCl and the mixture extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine (2×30 mL) and dried over sodium sulfate. Evaporation of solvent afforded the product as an oil which was used directly in the next reaction without further purification.
Reaction SMILES: [CH:1]1[C:14]2[C:5](=[CH:6][C:7]3[C:12]([C:13]=2[C:15](Cl)=[O:16])=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:3][CH:2]=1.Cl.Cl.[CH2:20]([O:22][C:23]([CH:25]1[CH2:30][CH2:29][CH2:28][N:27]([CH:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[CH2:26]1)=[O:24])[CH3:21].C(N(CC)CC)C.[OH-].[Na+]>ClCCl>[CH2:20]([O:22][C:23]([C@@H:25]1[CH2:30][CH2:29][CH2:28][N:27]([CH:31]2[CH2:32][CH2:33][N:34]([C:15]([C:13]3[C:14]4[C:5]([CH:6]=[C:7]5[C:12]=3[CH:11]=[CH:10][CH:9]=[CH:8]5)=[CH:4][CH:3]=[CH:2][CH:1]=4)=[O:16])[CH2:35][CH2:36]2)[CH2:26]1)=[O:24])[CH3:21]
Reactant: CCOC(=O)C1CCCN(C2CCNCC2)C1
Reactant: O=C(Cl)c1c2ccccc2cc2ccccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)[C@@H]1CCCN(C2CCN(C(=O)c3c4ccccc4cc4ccccc34)CC2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Anthracene-9-carbonyl chloride (62.2 mmol) was suspended in anhydrous dichloromethane (30 mL) and added slowly by pipette to a solution of [1,4′]bipiperidinyl-3-Carboxylic acid ethyl ester bishydrochloride (62.2 mmol) and triethylamine (4 eq., 35 mL) in anhydrous dichloromethane (50 mL) at such a rate that a gentle reflux was maintained. The resulting suspension was stirred overnight at ambient temperature then shaken with ice-cold water containing sodium hydroxide (0.19 mol, 7.6 g). The dichloromethane layer was separated and the aqueous layer was extracted with dichloromethane. The combined dichloromethane solution was washed with water, dried with anhydrous sodium sulfate, diluted with a little xylene and evaporated to dryness to give the title compound (containing a small amount of the corresponding isopropyl ester) as a pale yellow gummy foam (30.8 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:25]=[CH:24][C:6]([CH2:7][O:8][C:9]([CH3:23])([CH3:22])[CH2:10][O:11][C:12]2[N:13]=[CH:14][C:15]([C:18]([O:20]C)=[O:19])=[N:16][CH:17]=2)=[CH:5][CH:4]=1.[OH-].[Na+].CO.C1COCC1>O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][O:8][C:9]([CH3:23])([CH3:22])[CH2:10][O:11][C:12]2[N:13]=[CH:14][C:15]([C:18]([OH:20])=[O:19])=[N:16][CH:17]=2)=[CH:24][CH:25]=1
Reactant: COC(=O)c1cnc(OCC(C)(C)OCc2ccc(OC)cc2)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(COC(C)(C)COc2cnc(C(=O)O)cn2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.4 %

Procedure:
A mixture of methyl 5-{2-[(4-methoxybenzyl)oxy]-2-methylpropoxy}pyrazine-2-carboxylate (3.5 g), 1 M aqueous sodium hydroxide solution (35 mL), methanol (35 mL), and THF (35 mL) was stirred at room temperature for 1 hour. To the reaction mixture was added water, followed by washing with ethyl acetate. To the aqueous layer was added 1 M hydrochloric acid to adjust the pH to 4, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated to obtain 5-{2-[(4-methoxybenzyl)oxy]-2-methylpropoxy}pyrazine-2-carboxylic acid (2.5 g) as a pale yellow solid.
Reaction SMILES: C1(O[C:8](=[O:29])[NH:9][C:10]2[S:14][N:13]=[C:12]([O:15][CH2:16][C:17]3[C:22]([F:23])=[CH:21][C:20]([CH3:24])=[CH:19][C:18]=3[F:25])[C:11]=2[C:26](=[O:28])[NH2:27])C=CC=CC=1.[NH2:30][CH2:31][CH2:32][CH2:33][CH:34]([OH:42])[CH2:35][N:36]1[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1>>[F:23][C:22]1[CH:21]=[C:20]([CH3:24])[CH:19]=[C:18]([F:25])[C:17]=1[CH2:16][O:15][C:12]1[C:11]([C:26]([NH2:27])=[O:28])=[C:10]([NH:9][C:8]([NH:30][CH2:31][CH2:32][CH2:33][CH:34]([OH:42])[CH2:35][N:36]2[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41]2)=[O:29])[S:14][N:13]=1
Reactant: NCCCC(O)CN1CCCCC1
Reactant: Cc1cc(F)c(COc2nsc(NC(=O)Oc3ccccc3)c2C(N)=O)c(F)c1
Product: Cc1cc(F)c(COc2nsc(NC(=O)NCCCC(O)CN3CCCCC3)c2C(N)=O)c(F)c1

Procedure:
The title compound was prepared from [4-carbamoyl-3-(2,6-difluoro-4-methyl-benzyloxy)-isothiazol-5-yl]-carbamic acid phenyl ester and 5-amino-1-piperidin-1-yl-pentan-2-ol by the procedure analogous to Example 1. MS (APCl, m/z): 512 [M+H]+.