Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[CH2:8][C:7](=[O:9])[O:6][C:4](=[O:5])[CH2:3]1.[CH2:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.[C:17]([O:20]CC)(=[O:19])C>O1CCCC1>[O:19]1[C:12]2[CH:13]=[CH:14][C:15]([C:7](=[O:9])[CH2:8][C:2]([CH3:1])([CH3:10])[CH2:3][C:4]([OH:6])=[O:5])=[CH:16][C:11]=2[O:20][CH2:17]1
Reactant: CC1(C)CC(=O)OC(=O)C1
Reactant: C1CCCCC1
Reactant: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(CC(=O)O)CC(=O)c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 19 %

Procedure:
Cool a solution of 3,3-dimethylglutaric anhydride (5.16 g, 36.3 mmol) in tetrahydrofuran to about 0° C. using an ice water bath. Add 3,4-(methlyeneoxy)phenylmagnesium bromide (1M solution in tetrahydrofuran, 40 mL, 40.0 mmol) quickly under a flow of nitrogen gas. Stir for 30 min, then allow to warm to room temperature over a period of 1 h. Quench with saturated ammonium chloride solution. Dilute with water and ethyl acetate, separate the aqueous layer (pH=8-9) and then acidify using 1N HCl (pH=4-5). Extract using ethyl acetate, dry with magnesium sulfate, filter, and concentrate to afford the crude title compound as an orange/yellow oil (5.99 g). Subject the crude residue to flash chromatography (RediSep silica gel columns (120 g), gradient of 100:0 to 75:25 cyclohexane/ethyl acetate) to obtain 1.80 g (19%) of the title compound. 1H NMR (300 MHz, CDCl3): δ 7.58-7.61 (m, 1H), 7.45 (s, 1H), 6.82-6.87 (m, 1H), 6.05 (s, 2H), 3.00 (s, 2H), 2.52 (s, 2H) and 1.15 (s, 6H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([O:10][C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[O:17][CH:16]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:15][CH2:14]3)=[N:8][CH:9]=1)([O-:3])=[O:2].[OH:27]C1C=C(C2CCC3C(=CC=C(O)C=3)O2)C=CC=1.Cl[C:46]1[CH:51]=[CH:50][C:49]([N+:52]([O-:54])=[O:53])=[CH:48][N:47]=1>>[N+:52]([C:49]1[CH:50]=[CH:51][C:46]([O:27][C:25]2[CH:26]=[C:21]([CH:16]3[CH2:15][CH2:14][C:13]4[C:18](=[CH:19][CH:20]=[C:11]([O:10][C:7]5[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][N:8]=5)[CH:12]=4)[O:17]3)[CH:22]=[CH:23][CH:24]=2)=[N:47][CH:48]=1)([O-:54])=[O:53]
Reactant: Oc1cccc(C2CCc3cc(O)ccc3O2)c1
Reactant: O=[N+]([O-])c1ccc(Oc2ccc3c(c2)CCC(c2ccccc2)O3)nc1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Product: O=[N+]([O-])c1ccc(Oc2cccc(C3CCc4cc(Oc5ccc([N+](=O)[O-])cn5)ccc4O3)c2)nc1

Procedure:
2-[2-(3-(5-Nitropyridin-2-yloxy)phenyl)chroman-6-yloxy]-5-nitropyridine was prepared as described for 5-nitro-2-(2-phenylchroman-6-yloxy)pyridine in Example 1 (b) but starting from 2-(3-hydroxyphenyl)chroman-6-ol and using 210 mol-% of 2-chloro-5-nitropyridine. 1H NMR (400 MHz, d6-DMSO) δ: 9.05 (d, 1H, J 2.9 Hz), 9.03 (d, 1H, J 2.9 Hz), 8.64 (dd, 1H, J 2.9, 9.1 Hz), 8.60 (dd, 1H, J 2.9, 9.1 Hz), 7.52 (t, 1H, J 7.8 Hz), 7.41 (d, 1H, J 7.8 Hz), 7.33-7.31 (m, 1H), 7.28 (d, 1H, J 7.8 Hz), 7.23-7.18 (m, 2H) 7.01-6.90 (m, 3H), 5.20 (dd, 1H, J 2.1, 10.1 Hz), 3.07-2.92 (m, 1H), 2.80-2.70 (m, 1H), 2.30-2.18 (m, 1H), 2.10-1.98 (m, 1H).
Reaction SMILES: C(O[C:9]([NH:11][C@H:12]1[CH2:18][CH2:17][CH2:16][N:15]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:14][CH2:13]1)=O)C1C=CC=CC=1.Cl[C:27]1[N:31](C)[N:30]=[CH:29][C:28]=1[N+:33]([O-:35])=[O:34]>>[CH3:29][N:30]1[C:9]([NH:11][C@H:12]2[CH2:18][CH2:17][CH2:16][N:15]([C:19]([O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:20])[CH2:14][CH2:13]2)=[C:28]([N+:33]([O-:35])=[O:34])[CH:27]=[N:31]1
Reactant: Cn1ncc([N+](=O)[O-])c1Cl
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](NC(=O)OCc2ccccc2)CC1
Product: Cn1ncc([N+](=O)[O-])c1N[C@H]1CCCN(C(=O)OC(C)(C)C)CC1
Yield: 49 %

Procedure:
Following the procedure for Example 332 starting with (S)-tert-butyl 4-(benzyloxycarbonylamino)azepane-1-carboxylate and 5-chloro-1-methyl-4-nitro-1H-pyrazole gave (S)-tert-butyl 4-(1-methyl-4-nitro-1H-pyrazol-5-ylamino)azepane-1-carboxylate as a yellow viscous oil (103 mg, 49%). 1H NMR (400 MHz, CDCl3) δ 7.90 (s, 1H), 6.60-6.50 (m, 1H), 3.80 (s, 3H), 3.79-3.67 (m 1H), 3.60-3.52 (m, 1H), 3.49-3.44 (m, 1H), 3.44-3.22 (m, 2H), 2.25-2.10 (m, 1H), 2.05-1.62 (m, 5H), 1.48 (s, 9H)
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([C:13]([N:15]2[CH2:20][CH2:19][C@H:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3Cl)[C@H:17]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:16]2)=[O:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH3:36][O:37][CH2:38][CH2:39][NH2:40].C1(C2C=CC=CC=2)C=CC=CC=1P(C1CCCCC1)C1CCCCC1>>[F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([C:13]([N:15]2[CH2:20][CH2:19][C@H:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[NH:40][CH2:39][CH2:38][O:37][CH3:36])[C@H:17]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:16]2)=[O:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: COCCN
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CC[C@H](c2ccccc2Cl)[C@H](c2ccccc2)C1
Agent: c1ccc(-c2ccccc2P(C2CCCCC2)C2CCCCC2)cc1
Product: COCCNc1ccccc1[C@H]1CCN(C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)C[C@H]1c1ccccc1

Procedure:
The title compound, MS: m/e=551.1 (M+), was prepared in accordance with the general method of example 10 from rac-cis-(3,5-bis-trifluoromethyl-phenyl)-[4-(2-chloro-phenyl)-3-phenyl-piperidin-1-yl]-methanone, 2-methoxy-ethylamine and biphenyl-2-yl-dicyclohexyl-phosphane as ligand.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([O:15][CH3:16])=[CH:13][C:12]([CH:17]([C:19]2[C:27]3[C:22](=[N:23][CH:24]=[C:25]([Cl:28])[CH:26]=3)[NH:21][CH:20]=2)O)=[C:11]([F:29])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC1C(OC)=CC(C(OC)C2C3C(=NC=C(Cl)C=3)NC=2)=C(F)C=1)C1C=CC=CC=1.FC(F)(F)C(O)=O.C([SiH](CC)CC)C>C(#N)C>[CH2:1]([O:8][C:9]1[C:14]([O:15][CH3:16])=[CH:13][C:12]([CH2:17][C:19]2[C:27]3[C:22](=[N:23][CH:24]=[C:25]([Cl:28])[CH:26]=3)[NH:21][CH:20]=2)=[C:11]([F:29])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc(C(O)c2c[nH]c3ncc(Cl)cc23)c(F)cc1OCc1ccccc1
Agent: CC[SiH](CC)CC
Agent: COc1cc(C(OC)c2c[nH]c3ncc(Cl)cc23)c(F)cc1OCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: COc1cc(Cc2c[nH]c3ncc(Cl)cc23)c(F)cc1OCc1ccccc1
Reaction time: 2 h

Procedure:
(4-Benzyloxy-2-fluoro-5-methoxy-phenyl)-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanol 223a and 3-[(4-benzyloxy-2-fluoro-5-methoxy-phenyl)-methoxy-methyl]-5-chloro-1H-pyrrolo[2,3-b]pyridine 223b (48 mmol) were combined with acetonitrile (1.4 L), trifluoroacetic acid (21 mL, 288 mmol) and triethylsilane (31 mL, 192 mmol). The resulting mixture was stirred for two hours at reflux. The solvent was removed under reduced pressure. Ethyl acetate (6 L) was added and the organic layer was washed with aqueous potassium carbonate saturated solution. The layers were separated and the aqueous layer was back-extracted with ethyl acetate (2 L). The combined organic portions were dried over anhydrous sodium sulfate and evaporated under reduced pressure to give the desired compound 224 which was used without further purification.
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:21])=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)=[CH:7][C:6]=2[Cl:20].C1C(=O)N([Cl:29])C(=O)C1>C1COCC1>[Br:1][C:2]1[C:3]([OH:21])=[C:4]([Cl:29])[C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([C:12]1[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=1)=[CH:7][C:6]=2[Cl:20]
Reactant: COc1ccc(-c2cc(Cl)c3cc(O)c(Br)cc3c2)cc1
Reactant: O=C1CCC(=O)N1Cl
Solvent: C1CCOC1
Product: COc1ccc(-c2cc(Cl)c3c(Cl)c(O)c(Br)cc3c2)cc1

Procedure:
The title compound was prepared by reacting 3-bromo-8-chloro-6-(4-methoxyphenyl)-2-naphthol (0.69 g, 1.90 mmol) and NCS (0.31 g, 2.3 mmol) in THF (25 mL) according to method C to yield 0.61 g (81%) of a yellow solid. An analytical sample was further prepared by reverse phase preparative HPLC to yield the title compound as a white solid: mp 176–178° C. (dec.); 1H NMR (DMSO-d6): δ 3.82 (3H, s), 7.08 (2H, d, J=8.77 Hz), 7.77 (2H, d, J=8.75 Hz), 8.00 (1H, d, J=1.84 Hz), 8.19 (1H, d, J=1.84 Hz), 8.39 (1H, s), 10.53 (1H, bs); MS (ESI) m/z 395/397/399 (M−H)−.
Reaction SMILES: C(O[CH:5]([C:17](=O)[CH3:18])[CH2:6][S:7][CH2:8][CH2:9][NH:10][C:11]([NH:14][C:15]#[N:16])=[N:12][CH3:13])(=O)C.C([O-])([O-])OC.C([O-])=O.[NH4+:28].[CH:29]([NH2:31])=O>>[C:15]([NH:14][C:11]([NH:12][CH3:13])=[N:10][CH2:9][CH2:8][S:7][CH2:6][C:5]1[N:28]=[CH:29][NH:31][C:17]=1[CH3:18])#[N:16]
Reactant: CN=C(NC#N)NCCSCC(OC(C)=O)C(C)=O
Reactant: NC=O
Reactant: [NH4+]
Agent: COC([O-])[O-]
Agent: O=C[O-]
Product: CNC(=NCCSCc1nc[nH]c1C)NC#N
Temperature: 100 °C
Reaction time: 2 h
Yield: 26 %

Procedure:
155 mg of N-{2-(2-acetoxy-3-oxobutylthio)ethyl-}-N'-cyano-N"-methylguanidine and 290 mg of methyl orthoformate was dissolved in 2.5 ml of formamide, and 170 mg of ammonium formate was added. The mixture was stirred at 100° C. for 2 hours. The reaction mixture was treated as in Referential Example 1 to give 36 mg (yield 26%) of the desired product as white crystals.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:21]1[CH:26]=[CH:25][C:24]([CH2:27][C:28]2[C:33](=[O:34])[N:32]([C:35]3[CH:48]=[CH:47][C:38]([O:39][C:40]([CH3:46])([CH3:45])[C:41]([O:43][CH3:44])=[O:42])=[CH:37][CH:36]=3)[C:31]([CH3:49])=[N:30][C:29]=2[CH2:50][CH2:51][CH3:52])=[CH:23][CH:22]=1)#[N:14]>O.C(OCC)(=O)C>[CH3:46][C:40]([O:39][C:38]1[CH:37]=[CH:36][C:35]([N:32]2[C:33](=[O:34])[C:28]([CH2:27][C:24]3[CH:23]=[CH:22][C:21]([C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=4[C:13]4[NH:3][C:4](=[O:7])[O:5][N:14]=4)=[CH:26][CH:25]=3)=[C:29]([CH2:50][CH2:51][CH3:52])[N:30]=[C:31]2[CH3:49])=[CH:48][CH:47]=1)([CH3:45])[C:41]([O:43][CH3:44])=[O:42]
Reactant: O=C([O-])O
Reactant: CCCc1nc(C)n(-c2ccc(OC(C)(C)C(=O)OC)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: [NH3+]O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCc1nc(C)n(-c2ccc(OC(C)(C)C(=O)OC)cc2)c(=O)c1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 24.8 %

Procedure:
A mixture of hydroxylammonium chloride (0.67 g), sodium hydrogen carbonate (1.00 g) and dimethyl sulfoxide (5 mL) was stirred at 40° C. for 30 min, methyl 2-{4-[5-[(2′-cyanobiphenyl-4-yl)methyl]-2-methyl-6-oxo-4-propylpyrimidin-1(6H)-yl]phenoxy}-2-methylpropanoate (0.87 g) was added, and the mixture was stirred at 90° C. for 18 hr. The reaction mixture was allowed to cool to room temperature, ethyl acetate and water were added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was dissolved in tetrahydrofuran (5 mL). N,N′-carbonyldiimidazole (0.20 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.20 mL) were added, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.24 g, 41%).
Reaction SMILES: Br[CH2:2][C:3]([NH:5][C:6]1[CH:31]=[CH:30][C:9]([CH2:10][N:11]([S:20]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)(=[O:22])=[O:21])[C@H:12]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:13]([NH2:15])=[O:14])=[CH:8][CH:7]=1)=[O:4].[CH3:32][NH:33][CH3:34]>C(Cl)Cl.C1COCC1>[Cl:29][C:26]1[CH:27]=[CH:28][C:23]([S:20]([N:11]([CH2:10][C:9]2[CH:30]=[CH:31][C:6]([NH:5][C:3](=[O:4])[CH2:2][N:33]([CH3:34])[CH3:32])=[CH:7][CH:8]=2)[C@H:12]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:13]([NH2:15])=[O:14])(=[O:22])=[O:21])=[CH:24][CH:25]=1
Reactant: CNC
Reactant: CC(C)C[C@H](C(N)=O)N(Cc1ccc(NC(=O)CBr)cc1)S(=O)(=O)c1ccc(Cl)cc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(C)C[C@H](C(N)=O)N(Cc1ccc(NC(=O)CN(C)C)cc1)S(=O)(=O)c1ccc(Cl)cc1
Reaction time: 8 h
Yield: 63 %

Procedure:
To a solution of (2R)-2-[[4-(2-bromo-acetylamino)-benzyl]-(4-chlorobenzenesulfonyl)-amino]-4-methyl-pentanoic acid amide (41 mg, 0.77 mmol) in CH2Cl2 (2 mL) was added excess 2.0 M dimethylamine in THF. The reaction mixture was stirred overnight. The solvent was removed in vacuo. Purification by flash chromatography (SiO2, 10% MeOH/CH2Cl2) afforded the title compound (24 mg) in 63% yield. MS (ESI), (M+H)+495.14, 1H NMR (CDCl3, 400 MHz) δ 8.85 (s, 1H), 8.02 (d, 2H, J=8.0), 7.75 (d, 2H, J=8.0), 7.38 (d, 2H, J=8.0), 7.29 (d, 2H, J=8.0), 6.23 (br s, 1H), 5.39 (br s, 1H), 4.62 (m, 4H), 3.25 (t, 1H, J=6.0), 2.95 (s, 6H), 1.95 (m, 1H), 1.60 (m, 2H), 0.98 (d, 3H, J=7.0), 0.94 (d, 3H, J=7.0)
Reaction SMILES: [C:1]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])(=[O:4])[CH:2]=[CH2:3].[CH2:10]1[CH:14]2[CH:15]3C=CC([CH:13]2C=[CH:11]1)C3>C1(C)C=CC=CC=1>[C:6]([O:5][C:1]([CH:2]1[CH2:13][CH:14]2[CH2:15][CH:3]1[CH:11]=[CH:10]2)=[O:4])([CH3:9])([CH3:8])[CH3:7]
Reactant: C1=CC2C3C=CC(C3)C2C1
Reactant: C=CC(=O)OC(C)(C)C
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)C1CC2C=CC1C2
Reaction time: 5 h
Yield: 64.4 %

Procedure:
Into an autoclave with an internal volume of 2 liters, 256.3 g of t-butyl acrylate, 264.4 g of dicyclopentadiene and 1,040 g of toluene were charged, and the reaction was carried out at a temperature of 170° C. or higher for 5 hours. Subsequently, the reaction product was drawn out, and the toluene was evaporated, followed by distillation using a distillation column at 8.0 Torr and 87° C. to obtain 250 g of 5-t-butoxycarbonylbicyclo[2.2.1]hept-2-ene with a purity of 99.9% by weight. Using the same distillation column, the product was distilled at 0.07 Torr and 97 to 102° C. to obtain 100 g of 8-t-butoxycarbonyltetracyclo[4.4.0.12,5.17,10]dodec-3-ene with a purity of 99.9% by weight:
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8](C(=O)C)=[CH:7][C:6]=1[OH:14])([CH3:4])([CH3:3])[CH3:2].[Br-:15].[Br-].[Br-].C[N+](C)(C)C1C=CC=CC=1.C[N+](C1C=CC=CC=1)(C)C.C[N+](C1C=CC=CC=1)(C)C.[O:48]1CC[CH2:50][CH2:49]1.CO>>[Br:15][CH2:50][C:49]([C:9]1[CH:8]=[CH:7][C:6]([OH:14])=[C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])[CH:10]=1)=[O:48]
Reactant: CC(=O)c1ccc(C(C)(C)C)c(O)c1
Reactant: C1CCOC1
Reactant: [Br-]
Agent: C[N+](C)(C)c1ccccc1
Solvent: CO
Product: CC(C)(C)c1cc(C(=O)CBr)ccc1O

Procedure:
A solution of 1-(4-tert-Butyl-3-hydroxy-phenyl)-ethanone (192 mg, 1.0 mmol) and trimethyl-phenyl-ammonium tribromide in (3:1) tetrahydrofuran/methanol (3 mL) was stirred at room temperature 1 h. The resulting mixture was quenched with 5% wt. aq. sodium thiosulfate (500 μL) then water (3.5 mL). DCM added and the organic layer separated, dried over sodium sulfate, filtered and evaporated in vacuo to yield an amber syrup. The syrup was purified via silica gel chromatography eluting with (3:1) EtOAc/heptanes to yield 2-bromo-1-(3-tert-butyl-4-hydroxy-phenyl)-ethanone as a white solid. C12H15BrO2; MS (ESI) m/z 271/273 (MH)+.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[CH:6][C:7]2[N:8]([N:10]=[C:11]([C:13]3[CH:30]=[CH:29][C:16]([O:17][CH2:18][C@@H:19]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH3:20])=[CH:15][CH:14]=3)[CH:12]=2)[CH:9]=1)[CH3:2].CCCCCC.C([Li])CCC.C1C=CC(S(N(S(C2C=CC=CC=2)(=O)=O)[F:52])(=O)=O)=CC=1>C1COCC1.O>[CH2:1]([O:3][C:4]1[CH:5]=[CH:6][C:7]2[N:8]([N:10]=[C:11]([C:13]3[CH:30]=[CH:29][C:16]([O:17][CH2:18][C@@H:19]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:25])([CH3:27])[CH3:26])[CH3:20])=[CH:15][CH:14]=3)[CH:12]=2)[C:9]=1[F:52])[CH3:2]
Reactant: CCOc1ccc2cc(-c3ccc(OC[C@H](C)NC(=O)OC(C)(C)C)cc3)nn2c1
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCOc1ccc2cc(-c3ccc(OC[C@H](C)NC(=O)OC(C)(C)C)cc3)nn2c1F
Reaction time: 1.5 h
Yield: 30.9 %

Procedure:
To a solution of tert-butyl {(1S)-2-[4-(6-ethoxypyrazolo[1,5-a]pyridin-2-yl)phenoxy]-1-methylethyl}carbamate (580 mg) in THF (10 mL) was added dropwise a hexane solution (1.6 M, 2.2 mL) of n-butyllithium at −78° C. under an argon atmosphere, and the mixture was stirred for 1.5 hr. To the reaction mixture was added N-fluorobenzenesulfonimide (578 mg) at −78° C., and the mixture was stirred at room temperature for 1 hr. Water was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The combined organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound as a pale-yellow solid (187 mg).
Reaction SMILES: [OH-].[Na+].O.S([O:9][CH3:10])(OC)(=O)=O.[OH:11][C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[C:14](O)[CH:13]=1.[CH2:23](O)C>>[CH3:23][O:11][C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[C:14]([O:9][CH3:10])[CH:13]=1
Reactant: CCO
Reactant: Oc1cc(O)c2ccccc2c1
Reactant: COS(=O)(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1cc(OC)c2ccccc2c1
Reaction time: 16 h

Procedure:
A solution of 32.1 g. (0.801 mole) of sodium hydroxide in 80.3 ml. of water and 96 g. (0.763 mole) of dimethyl sulfate are simultaneously added over a period of 30-45 minutes to 50 g. (0.312 mole) of 1,3-dihydroxynaphthalene in 250 ml. of absolute ethanol stirred at -5°-0° C., the former being added slightly faster than the latter. The reaction mixture is allowed to gradually warm to 20°-25° C. with stirring over a 16 hour period. Most of the ethanol is evaporated at reduced pressure, water is added, and the mixture is extracted three times with methyl t-butyl ether. The extracts are combined, washed with 2N. aqueous sodium carbonate solution, dried over anhydrous sodium sulfate and evaporated to dryness at reduced pressure to obtain an oil. The oil is chromatographed on a Waters Prep-500 high pressure liquid chromatography apparatus having a silica gel column and utilizing 5% ethyl acetate/n-hexane as the eluant. The fractions containing the product are combined and evaporated at reduced pressure to obtain the product as a yellow oil (24.15 g.).
Reaction SMILES: [C:1]([OH:13])(=O)[CH2:2][C:3]([CH2:8][C:9]([OH:11])=O)([C:5](O)=O)O.[OH2:14]>>[CH3:5][C:3]1[C:2]2[CH:1]=[CH:2][C:3]([OH:14])=[CH:5][C:1]=2[O:13][C:9](=[O:11])[CH:8]=1
Reactant: O
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Product: Cc1cc(=O)oc2cc(O)ccc12

Procedure:
50 μl of the 4-UMO buffer solution and 25 μl of distilled water (or sample solution) were placed in a 96-well microplate and mixed at 25° C., followed by adding 25 μl of the lipase buffer solution to start enzyme reaction. After 30 minutes of reaction, 100 μl of 0.1M citric acid buffer (pH 4.2) was added to terminate the reaction, and the fluorescence of 4-methylumbelliferone (excitation wavelength: 355 nm, fluorescence wavelength: 460 nm) produced by the reaction was measured with a fluorescence plate reader (Labsystems, Fluoroskan Asent CF).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:48]2[CH:53]=[CH:52][C:51]([O:54][CH3:55])=[CH:50][CH:49]=2)[O:10][CH:11]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[CH:12]2[CH2:16][CH:15]([OH:17])[CH2:14][N:13]2[C:18](=[O:41])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][NH:24][C:25]([C:27]2[C:36](=[O:37])[C:35]3[C:30](=[N:31][C:32]([CH3:38])=[CH:33][CH:34]=3)[N:29]([CH2:39][CH3:40])[CH:28]=2)=[O:26])=[CH:5][CH:4]=1.[C:56]1(=[O:62])[O:61][C:59](=[O:60])[CH2:58][CH2:57]1.C(N(CC)CC)C>CN(C1C=CN=CC=1)C.ClCCl>[CH3:55][O:54][C:51]1[CH:50]=[CH:49][C:48]([CH:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[O:10][CH:11]([C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=2)[CH:12]2[N:13]([C:18](=[O:41])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][NH:24][C:25]([C:27]3[C:36](=[O:37])[C:35]4[C:30](=[N:31][C:32]([CH3:38])=[CH:33][CH:34]=4)[N:29]([CH2:39][CH3:40])[CH:28]=3)=[O:26])[CH2:14][CH:15]([O:17][C:56](=[O:62])[CH2:57][CH2:58][C:59]([OH:61])=[O:60])[CH2:16]2)=[CH:53][CH:52]=1
Reactant: CCn1cc(C(=O)NCCCCCC(=O)N2CC(O)CC2C(OC(c2ccc(OC)cc2)c2ccc(OC)cc2)c2ccccc2)c(=O)c2ccc(C)nc21
Reactant: O=C1CCC(=O)O1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCn1cc(C(=O)NCCCCCC(=O)N2CC(OC(=O)CCC(=O)O)CC2C(OC(c2ccc(OC)cc2)c2ccc(OC)cc2)c2ccccc2)c(=O)c2ccc(C)nc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Referring to scheme 27, Compound 99 (1.48 g, 2 mmol) is mixed with succinic anhydride (0.200 g, 2 mmol) and DMAP (0.244 g, 13 mmol) and dried in a vacuum at 40° C. overnight. The mixture is dissolved in anhydrous dichloromethane (5 mL), triethylamine (0.606 g, 0.96 mL, 6 mmol) is added and the solution stirred at room temperature under argon atmosphere for 16 h. It is then diluted with dichloromethane (100 mL) and washed with ice cold aqueous citric acid (5% wt., 100 mL) and water (2×100 mL) The organic phase is dried over anhydrous sodium sulfate and concentrated to dryness. The crude product is purified by column chromatography to afford compound 101.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:5]=1[NH:11][C:12]([NH:14][C:15]([NH:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[N:29]=[CH:28][N:27]([C:30]3[CH:35]=[CH:34][C:33]([O:36][C:37]([F:40])([F:39])[F:38])=[CH:32][CH:31]=3)[N:26]=2)=[CH:21][CH:20]=1)=[O:16])=[S:13])([CH3:3])[CH3:2].C([O-])(=O)C.[Na+].Cl[CH2:47][C:48](=O)[CH3:49].C(#N)C>[Cl-].[Na+].O.ClCCl>[CH:1]([C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:5]=1[N:11]1[C:48]([CH3:49])=[CH:47][S:13]/[C:12]/1=[N:14]\[C:15]([NH:17][CH2:18][C:19]1[CH:20]=[CH:21][C:22]([C:25]2[N:29]=[CH:28][N:27]([C:30]3[CH:31]=[CH:32][C:33]([O:36][C:37]([F:40])([F:39])[F:38])=[CH:34][CH:35]=3)[N:26]=2)=[CH:23][CH:24]=1)=[O:16])([CH3:3])[CH3:2]
Reactant: CC(=O)CCl
Reactant: Cc1ccc(NC(=S)NC(=O)NCc2ccc(-c3ncn(-c4ccc(OC(F)(F)F)cc4)n3)cc2)c(C(C)C)c1
Agent: CC(=O)[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CC#N
Solvent: ClCCl
Solvent: O
Product: Cc1ccc(-n2c(C)cs/c2=N\C(=O)NCc2ccc(-c3ncn(-c4ccc(OC(F)(F)F)cc4)n3)cc2)c(C(C)C)c1
Temperature: 65 °C
Yield: 21.4 %

Procedure:
To a 20 mL vial was added 1-[(2-isopropyl-4-methyl-phenyl)carbamothioyl]-3-[[4-[1-[4-(trifluoromethoxy)phenyl]-1H-1,2,4-triazol-3-yl]phenyl]methyl]urea (PC5) (0.044 g, 0.077 mmol), sodium acetate (0.019 g, 0.23 mmol), 1-chloropropan-2-one (0.0092 mL, 0.12 mmol) and acetonitrile (1.5 mL). The vial was sealed and heated overnight at 65° C. The reaction mixture was diluted with brine solution and dichloromethane and passed through a phase separator. The organic layer was concentrated and the resulting residue was purified by flash column chromatography using 10-80% ethyl acetate/hexanes as eluent providing the title compound as an off-white solid (0.010 g, 21%): 1H NMR (400 MHz, DMSO-d6) δ 9.38 (s, 1H), 8.14-8.01 (m, 4H), 7.70 (s, 1H), 7.62 (dq, J=7.7, 1.0 Hz, 2H), 7.45-7.35 (m, 2H), 7.34-7.27 (m, 1H), 7.15 (t, J=1.3 Hz, 2H), 6.66 (q, J=0.9 Hz, 1H), 4.47-4.28 (m, 2H), 2.73-2.62 (m, 1H), 2.39 (s, 3H), 2.10 (d, J=1.1 Hz, 3H), 1.10 (d, J=6.8 Hz, 3H), 1.00 (d, J=6.8 Hz, 3H); 19F NMR (376 MHz, DMSO-d6) δ −56.96; ESIMS m/z 607 ([M+H]+).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH:12]2[O:24][CH2:25][C:26]2[CH:35]=[CH:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=2)[CH:8]=[CH:9][CH:10]=1)=[O:4].[OH-].[Na+].Cl>CO>[C:20]([O:19][C:17]([N:14]1[CH2:15][CH2:16][CH:11]([C:7]2[CH:6]=[C:5]([CH:10]=[CH:9][CH:8]=2)[C:3]([OH:4])=[O:2])[CH:12]([O:24][CH2:25][C:26]2[CH:35]=[CH:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=2)[CH2:13]1)=[O:18])([CH3:23])([CH3:21])[CH3:22]
Reactant: COC(=O)c1cccc(C2CCN(C(=O)OC(C)(C)C)CC2OCc2ccc3ccccc3c2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(c2cccc(C(=O)O)c2)C(OCc2ccc3ccccc3c2)C1
Yield: 75 %

Procedure:
A solution of 60 mg (0.13 mmol) of tert-butyl (3RS,4RS)-4-(3-methoxycarbonyl-phenyl)-3-naphthalen-2-ylmethoxy-piperidine-1-carboxylate [Example 26(e)] and 0.26 ml (0.26 mmol) of 1N sodium hydroxide solution in 2 ml of methanol was stirred at 30° C. for 18 hours. For the working-up, the reaction mixture was neutralized with 1N hydrochloric acid and extracted twice with 10 ml of methylene chloride each time. The organic phases were combined, dried over sodium sulphate and evaporated under reduced pressure. The residue was crystallized from a mixture of hexane and diethyl ether. There were obtained 45 mg (75% of theory) of (3RS,4RS)-3-(1-tert-butoxycarbonyl-3-naphthalen-2-ylmethoxy-piperidin-4-yl)-benzoic acid as colourless crystals; MS: 462 (M+H)+.