Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][N:29]([C:32]([C:34]2[N:42]3[C:37]([CH:38]=[CH:39][CH:40]=[CH:41]3)=[C:36]([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[C:35]=2[CH2:49][C:50]2[CH:55]=[CH:54][CH:53]=[C:52]([F:56])[C:51]=2[CH3:57])=[O:33])[CH2:28][C@@H:27]1[CH2:58][CH2:59][O:60][Si](C(C)(C)C)(C)C)=[O:25])([CH3:22])([CH3:21])[CH3:20].[Cl-].[NH4+]>C1COCC1>[C:19]([O:23][C:24]([N:26]1[CH2:31][CH2:30][N:29]([C:32]([C:34]2[N:42]3[C:37]([CH:38]=[CH:39][CH:40]=[CH:41]3)=[C:36]([C:43]3[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=3)[C:35]=2[CH2:49][C:50]2[CH:55]=[CH:54][CH:53]=[C:52]([F:56])[C:51]=2[CH3:57])=[O:33])[CH2:28][C@@H:27]1[CH2:58][CH2:59][OH:60])=[O:25])([CH3:21])([CH3:22])[CH3:20]
Reactant: Cc1c(F)cccc1Cc1c(-c2ccccc2)c2ccccn2c1C(=O)N1CCN(C(=O)OC(C)(C)C)[C@@H](CCO[Si](C)(C)C(C)(C)C)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: C1CCOC1
Product: Cc1c(F)cccc1Cc1c(-c2ccccc2)c2ccccn2c1C(=O)N1CCN(C(=O)OC(C)(C)C)[C@@H](CCO)C1
Temperature: 0 °C
Reaction time: 2 h
Yield: 99.5 %

Procedure:
A 1 M solution of tetrabutylammonium fluoride in THF (2.82 ml, 2.82 mmol) was added to a solution of the compound of step 4 (1.29 g, 1.88 mmol) in 7.5 ml of THF cooled to 0° C. under argon. The mixture was stirred at room temperature for 2 h and then 100 ml of a saturated solution of ammonium chloride were added. The solution was extracted twice with 50 ml each of EA, and the combined organic phases were washed with brine, dried over sodium sulfate, filtered and evaporated to dryness under reduced pressure. The residue was purified by chromatography on silica gel (DCM/MOH, 100:0, then 98:2) to give 1.069 g of the title compound as an off-white powder melting at 85° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][C:12]1[CH:17]=[C:16]([C:18]2[NH:19][C:20]([C:23]3[S:24][CH:25]=[CH:26][N:27]=3)=[CH:21][CH:22]=2)[CH:15]=[C:14]([O:28][C@@H:29]([CH3:33])[CH2:30][O:31][CH3:32])[CH:13]=1)[C:5]([OH:7])=O.N.CC[N:37]=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.O>ClCCl.O>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][C:12]1[CH:17]=[C:16]([C:18]2[NH:19][C:20]([C:23]3[S:24][CH:25]=[CH:26][N:27]=3)=[CH:21][CH:22]=2)[CH:15]=[C:14]([O:28][C@@H:29]([CH3:33])[CH2:30][O:31][CH3:32])[CH:13]=1)[C:5]([NH2:37])=[O:7]
Reactant: CCN=C=NCCCN(C)C
Reactant: COC[C@H](C)Oc1cc(Oc2ccc(C(=O)O)cc2F)cc(-c2ccc(-c3nccs3)[nH]2)c1
Agent: Cl
Agent: N
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Product: COC[C@H](C)Oc1cc(Oc2ccc(C(N)=O)cc2F)cc(-c2ccc(-c3nccs3)[nH]2)c1
Temperature: 25 °C
Reaction time: 7 h
Yield: 23.7 %

Procedure:
3-Fluoro-4-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[5-(1,3-thiazol-2-yl)-1H-pyrrol-2-yl]phenoxyl}benzoic acid (40.0 mg, 0.163 mmol) synthesized in Example (44a) was dissolved in dichloromethane (5 mL), and 28% aqueous ammonia solution (0.50 mL), WSCI•HCl (19.6 mg, 0.102 mmol) and HOBt•H2O (13.1 mg, 0.086 mmol) were added, followed by stirring at room temperature for 7 hours under nitrogen atmosphere. To the reaction solution, water (10 mL) was added, and extraction was carried out with ethyl acetate (20 mL). The organic layer was washed with saturated brine, and subsequently dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=0%-75%) to afford the desired compound (11.3 mg, yield 28%) as a white solid.
Reaction SMILES: C(Br)CCC.FC1C=CC=CC=1C1C2C=C([N+]([O-])=O)C=CC=2N(C)C(=O)C(C)(C)N=1.C([N:35]1[C:41]2[CH:42]=[CH:43][C:44]([N+:46]([O-:48])=[O:47])=[CH:45][C:40]=2[C:39]([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][C:50]=2[Cl:55])=[N:38][C:37]([CH3:57])([CH3:56])[C:36]1=[O:58])CCC>CCOCC.CCCCCC>[Cl:55][C:50]1[CH:51]=[CH:52][CH:53]=[CH:54][C:49]=1[C:39]1[C:40]2[CH:45]=[C:44]([N+:46]([O-:48])=[O:47])[CH:43]=[CH:42][C:41]=2[NH:35][C:36](=[O:58])[C:37]([CH3:57])([CH3:56])[N:38]=1
Reactant: CCCCN1C(=O)C(C)(C)N=C(c2ccccc2Cl)c2cc([N+](=O)[O-])ccc21
Agent: CN1C(=O)C(C)(C)N=C(c2ccccc2F)c2cc([N+](=O)[O-])ccc21
Solvent: CCCCCC
Solvent: CCCCBr
Solvent: CCOCC
Product: CC1(C)N=C(c2ccccc2Cl)c2cc([N+](=O)[O-])ccc2NC1=O

Procedure:
From 25 g (0.073 mol) of 5-(o-chlorophenyl)-1,3-dihydro-3,3-dimethyl-7-nitro-2H-1,4-benzodiazepin-2-one and n-butyl bromide there is obtained, in analogy to the details in paragraph (c) of Example 1, with a reaction period of 4 days, 1-butyl-5-(o-chlorophenyl)-1,3-dihydro-3,3-dimethyl-7-nitro-2H-1,4-benzodiazepin-2-one of melting point 129° (ether/n-hexane).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][N:3]=1.O.[NH2:11][NH2:12]>>[NH:11]([C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][N:3]=1)[NH2:12]
Reactant: COc1ccc(Cl)nc1
Reactant: NN
Solvent: O
Product: COc1ccc(NN)nc1

Procedure:
The above-obtained 2-chloro-5-methoxypyridine (4.0 g) in hydrazine monohydrate (30 mL) was stirred at 100° C. for 24 hours, and then cooled in air. The reaction solvent was removed under reduced pressure, and the residue was partitioned by use of chloroform and aqueous 1N sodium hydroxide. The organic layer was dried over magnesium sulfate anhydrate, followed by filtration. The solvent was removed under reduced pressure, to thereby give 2-hydrazino-5-methoxypyridine as an oily product (705 mg, 18%).
Reaction SMILES: [C:1]([C:4]1[N:5]=[C:6]([C:28]2[C:33]([F:34])=[CH:32][CH:31]=[CH:30][C:29]=2[F:35])[O:7][C:8]=1[C:9]1[CH:10]=[CH:11][C:12]([N:15]2[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH2:16]2)=[N:13][CH:14]=1)(=[O:3])[NH2:2].O1CCOCC1.C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl>C(Cl)Cl.Cl>[F:35][C:29]1[CH:30]=[CH:31][CH:32]=[C:33]([F:34])[C:28]=1[C:6]1[O:7][C:8]([C:9]2[CH:14]=[N:13][C:12]([N:15]3[CH2:16][CH2:17][NH:18][CH2:19][CH2:20]3)=[CH:11][CH:10]=2)=[C:4]([C:1]([NH2:2])=[O:3])[N:5]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3oc(-c4c(F)cccc4F)nc3C(N)=O)cn2)CC1
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Solvent: ClCCl
Solvent: C1COCCO1
Product: NC(=O)c1nc(-c2c(F)cccc2F)oc1-c1ccc(N2CCNCC2)nc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 97.9 %

Procedure:
A mixture of tert-butyl 4-(5-(4-carbamoyl-2-(2,6-difluorophenyl)oxazol-5-yl)pyridin-2-yl)piperazine-1-carboxylate (0.227 g, 0.47 mmol) in DCM (3 mL) and 4N HCl in dioxane (2 mL, 8.0 mmol) was stirred at room temperature for 48 hours. The solvent was removed in vacuo to give 2-(2,6-difluorophenyl)-5-(6-(piperazin-1-yl)pyridin-3-yl)oxazole-4-carboxamide (0.211 g, 0.46 mmol, 98%) as a white solid as the dihydrochloride salt. 1H NMR (DMSO) 3.20 (4H, m), 3.90 (4H, t), 7.11 (1H, d), 7.39 (2H, t), 7.73 (3H, m), 8.44 (1H, dd), 9.0 (1H, d), 9.24 (1H, br. s), 9.30 (1H, br. s). LCMS (2) Rt: 2.38 min; m/z (ES+) 386.
Reaction SMILES: S(=O)(=O)(O)O.[C:6]([O-:11])(=[O:10])[C:7]([CH3:9])=[O:8].[Na+].[C:13]([O-:17])(=[O:16])[CH:14]=[O:15].[Na+]>>[OH:8][CH:7]([C:6]([OH:11])=[O:10])[CH2:9][C:14](=[O:15])[C:13]([OH:17])=[O:16]
Reactant: CC(=O)C(=O)[O-]
Reactant: O=CC(=O)[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: O=C(O)C(=O)CC(O)C(=O)O
Reaction time: 16 h

Procedure:
Pseudomonas putida ATCC 795 strain was inoculated into 9 ml of L medium and cultured for 16 hours at 30° C. with shaking. Whole amount of this culture was then inoculated into 300 ml of GMS medium in 2 liter volume Erlenmeyer flask and cultured for 20 hours at 30° C. with shaking. The resulting culture was centrifuged, the collected cells were resuspended in 60 ml of the reactant solution (b), and the suspension was stirred in 300-ml beaker while maintaining pH at 6.5 with 1N sulfuric acid. After 6 hours, 3 ml of 2M sodium pyruvate and 3 ml of 2M sodium glyoxylate were added. After 24 hours from the starting point of this reaction, the cells were removed from the suspension by centrifugation, and the amount of 4-hydroxy-2-ketoglutaric acid formed in the supernatant was determined by HPLC. The amount of L-4-hydroxy-2-ketoglutaric acid was determined to be 150 mM and D-form was not detected.
Reaction SMILES: C([O:4][CH2:5][C:6]1[CH:22]=[CH:21][CH:20]=[CH:19][C:7]=1[CH2:8][O:9][C:10]1[C:11]([N+:16]([O-:18])=[O:17])=[N:12][CH:13]=[CH:14][CH:15]=1)(=O)C.O>CO.[OH-].[Na+]>[OH:4][CH2:5][C:6]1[CH:22]=[CH:21][CH:20]=[CH:19][C:7]=1[CH2:8][O:9][C:10]1[C:11]([N+:16]([O-:18])=[O:17])=[N:12][CH:13]=[CH:14][CH:15]=1
Reactant: CC(=O)OCc1ccccc1COc1cccnc1[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=[N+]([O-])c1ncccc1OCc1ccccc1CO
Yield: 62.2 %

Procedure:
A solution of 3-(2-acetoxymethylbenzyloxy)-2nitropyridine (7.8 g) in methanol (39 ml) and 1N aqueous sodium hydroxide (23 ml) was stirred at room temperature for 0.5 hours. To the mixture was added water (50 ml) and the precipitates were collected by filtration to give 3-(2-hydroxymethylbenzyloxy)-2-nitropyridine (4.18 g).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][C:5]=1[C:14]1[NH:19][C:18](=[O:20])[C:17]2=[C:21]([CH3:25])[N:22]=[C:23]([CH3:24])[N:16]2[N:15]=1)[CH3:2].[OH:26][CH2:27][CH:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1.C(OC1C=CC(S(N2CCC(O)CC2C)(=O)=O)=CC=1C1NC(=O)C2=C(C)N=C(C)N2N=1)C>>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:31]2[CH2:32][CH2:33][CH:28]([CH2:27][OH:26])[CH2:29][CH2:30]2)(=[O:12])=[O:11])=[CH:6][C:5]=1[C:14]1[NH:19][C:18](=[O:20])[C:17]2=[C:21]([CH3:25])[N:22]=[C:23]([CH3:24])[N:16]2[N:15]=1)[CH3:2]
Reactant: CCOc1ccc(S(=O)(=O)Cl)cc1-c1nn2c(C)nc(C)c2c(=O)[nH]1
Reactant: OCC1CCNCC1
Agent: CCOc1ccc(S(=O)(=O)N2CCC(O)CC2C)cc1-c1nn2c(C)nc(C)c2c(=O)[nH]1
Product: CCOc1ccc(S(=O)(=O)N2CCC(CO)CC2)cc1-c1nn2c(C)nc(C)c2c(=O)[nH]1

Procedure:
By the same method, starting with 100 mg (0.261 mmol) of 4-ethoxy-3-(5,7-dimethyl-4-oxo-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl)-benzenesulphonyl chloride and 90 mg (0.784 mmol) of 4-hydroxymethylpiperidine, 22 mg (18% of theory) of 2-[2-ethoxy-5-(4-hydroxy-methylpiperidine-1-sulphonyl)-phenyl]-5,7-dimethyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one are obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:4]=1[CH2:5][N:6]1[C@@:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[F:22])([CH3:15])[C@@H:13]2[C@@H:9]([CH2:10][O:11][CH2:12]2)[O:8][S:7]1=[O:23].I([O-])(=O)(=O)=[O:31].[Na+].C(#N)C.O>C(OCC)(=O)C.[Ru](Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:4]=1[CH2:5][N:6]1[C@@:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[F:22])([CH3:15])[C@@H:13]2[C@@H:9]([CH2:10][O:11][CH2:12]2)[O:8][S:7]1(=[O:31])=[O:23]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: COc1ccc(CN2S(=O)O[C@@H]3COC[C@@H]3[C@@]2(C)c2ccccc2F)c(OC)c1
Agent: Cl[Ru](Cl)Cl
Agent: [Na+]
Solvent: CC#N
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ccc(CN2[C@](C)(c3ccccc3F)[C@H]3COC[C@H]3OS2(=O)=O)c(OC)c1
Temperature: 23 °C
Reaction time: 0.5 h
Yield: 54.5 %

Procedure:
A solution of (3aS,7S,7aS)-rel-6-(2,4-dimethoxy-benzyl)-7-(2-fluoro-phenyl)-7-methyl-hexahydro-2,4-dioxa-5-thia-6-aza-indene 5-oxide (7.24 g, 17.2 mmol) and sodium periodate (4.04 g, 18.9 mmol) in a mixture of ethyl acetate (60 ml), acetonitrile (60 ml) and cold water (99.6 ml) was treated with ruthenium(III) chloride (35.6 mg, 172 μmol). The reaction mixture was stirred at 23° C. for 30 minutes. For the workup, the reaction mixture was extracted with a saturated solution of sodium hydrogencarbonate, the aqueous layer re-extracted with ethyl acetate, and the combined organic layers were dried over sodium sulphate and evaporated. The residue was purified by flash chromatography on silica gel using a gradient of heptane and ethyl acetate=100:0 to 0:100 as the eluent. The (3aS,7S,7aS)-rel-6-(2,4-dimethoxy-benzyl)-7-(2-fluoro-phenyl)-7-methyl-hexahydro-2,4-dioxa-5-thia-6-aza-indene 5,5-dioxide (4.1 g, 55% yield) was obtained as a light yellow solid. MS (ISP): m/z=460.2 [M+Na]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2([OH:14])[CH2:13][CH2:12][NH:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[F:8].C=O.[C:17](O)(=O)/C=C/C(O)=O>C(O)=O>[F:1][C:2]1[CH:3]=[C:4]([C:9]2([OH:14])[CH2:13][CH2:12][N:11]([CH3:17])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=C(O)/C=C/C(=O)O
Reactant: OC1(c2ccc(F)c(F)c2)CCNC1
Agent: C=O
Solvent: O=CO
Product: CN1CCC(O)(c2ccc(F)c(F)c2)C1
Reaction time: 24 h

Procedure:
Preparation according to Example 26: 3-(3,4-difluorophenyl)-pyrrolidin-3-ol (1.32 g, 6.63 mmol), formic acid (19.2 mL), aqueous formaldehyde (40%, 17.2 mL). 60° C. for 24 h. Yield: 0.83 g. The amine was converted to the fumaric acid salt and recrystallized from methanol/diethyl ether/diisopropyl ether: M.p. 164-166° C.; MS m/z (relative intensity, 70 eV) 213 (M+, 7), 141 (10), 113 (10), 58 (43), 57 (bp).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])/[CH:5]=[CH:6]/[O:7][C@H:8]1[C@H:13]2[CH2:14][C@H:10]([C@@H:11]([C:22]([O:24]CC3C=CC=CC=3)=[O:23])[N:12]2[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:9]1)[CH3:2].[H][H]>C(O)C.[Pd]>[C:18]([O:17][C:15]([N:12]1[C@H:11]([C:22]([OH:24])=[O:23])[C@H:10]2[CH2:14][C@@H:13]1[C@H:8]([O:7][CH2:6][CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:32])[CH2:9]2)=[O:16])([CH3:21])([CH3:20])[CH3:19]
Reactant: [H][H]
Reactant: CCOC(=O)/C=C/O[C@@H]1C[C@@H]2C[C@H]1N(C(=O)OC(C)(C)C)[C@@H]2C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CCO[C@@H]1C[C@@H]2C[C@H]1N(C(=O)OC(C)(C)C)[C@@H]2C(=O)O
Yield: 82.8 %

Procedure:
To a solution of 3-benzyl 2-tert-butyl (1R,3S,4S,6R)-6-{[(1E)-3-ethoxy-3-oxo-1-propen-1-yl]oxy}-2-azabicyclo[2.2.1]heptane-2,3-dicarboxylate obtained in Example 30-2 (316 mg) in ethanol (8 mL), was added 10% palladium on carbon (60 mg). The mixture was stirred under 4 atm of hydrogen for 1 hr at room temperature. The resulting mixture was filtered through celite and washed with ethanol. The filtrate and washings were evaporated in vacuo and the residue was chromatographed on silica gel eluting with chloroform and methanol (19:1) to give the target compound (210 mg).
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9]2[CH:14]=[C:13]([O:15][CH3:16])[C:12]([O:17][CH3:18])=[C:11]([O:19][CH3:20])[CH:10]=2)[CH:4]=1.S(Cl)([Cl:23])=O>C(Cl)(Cl)Cl>[Cl:23][CH2:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9]2[CH:14]=[C:13]([O:15][CH3:16])[C:12]([O:17][CH3:18])=[C:11]([O:19][CH3:20])[CH:10]=2)[CH:4]=1
Reactant: O=S(Cl)Cl
Reactant: COc1cc(-c2cc(CO)ccn2)cc(OC)c1OC
Solvent: ClC(Cl)Cl
Product: COc1cc(-c2cc(CCl)ccn2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4-Hydroxymethyl-2-(3,4,5-trimethoxyphenyl)pyridine (18.15 g) was dissolved in chloroform (300 mL), and to the solution thionyl chloride (19.2 mL) was added at 0° C. After 30 minutes, the mixture was warmed to room temperature and stirred for 4 hours. The reaction mixture was washed with a saturated aqueous solution of sodium hydrogencarbonate and saturated brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was then recrystallized from chloroform-hexane to obtain the title compound.
Reaction SMILES: [OH-].[Na+].[Si]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([CH:18]([CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH2:19][C:20]([O:22]CC)=[O:21])=[C:14]([O:30][CH3:31])[CH:13]=1)(C(C)(C)C)(C)C>C(O)C>[OH:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([CH:18]([CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH2:19][C:20]([OH:22])=[O:21])=[C:14]([O:30][CH3:31])[CH:13]=1
Reactant: CCCCCC(CC(=O)OCC)c1ccc(CO[Si](C)(C)C(C)(C)C)cc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCCC(CC(=O)O)c1ccc(CO)cc1OC

Procedure:
80 ml of a 2 N aqueous solution of sodium hydroxide were added to a solution of 32.64 g (77.2 mmol) of ethyl 3-(4-t-butyldimethylsilyloxymethyl-2-methoxyphenyl)octanoate [prepared as described in step (iv) above] in 80 ml of ethanol, and the resulting mixture was heated under reflux for 1 hour and 40 minutes. At the end of this time, the reaction mixture was freed from the solvent by distillation under reduced pressure, and the resulting residue was acidified with 2 N aqueous hydrochloric acid and then extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride, and then the solvent was removed by distillation under reduced pressure, to give 22.09 g (a quantitative yield) of the title compound as an oily substance.
Reaction SMILES: [OH:1][CH:2]1[CH:8]2[CH:9]=[CH:10][CH:3]1[CH:4]1[CH:7]2[N:6]=[N:5]1.[C:11](OC(=O)C)(=[O:13])[CH3:12].C(N(CC)CC)C>CCOCC>[C:11]([O:1][CH:2]1[CH:8]2[CH:9]=[CH:10][CH:3]1[CH:4]1[CH:7]2[N:6]=[N:5]1)(=[O:13])[CH3:12]
Reactant: OC1C2C=CC1C1N=NC21
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CC(=O)OC1C2C=CC1C1N=NC21

Procedure:
5 parts of 9-hydroxy-3,4-diazatricyclo[4,2,1,02,5 ]nona-3,7-diene, 5 parts of acetic anhydride, 1 part of triethylamine and 100 parts of ether were refluxed for 24 hours, after which the reaction mixture was extracted twice with 50 parts of water, and the organic phase was dried with MgSO4 and evaporated down in a rotary evaporator to give 6.2 parts (95 mole %) of 9-acetoxy-3,4-diazatricyclo[4,2,1,02,5 ]nona-3,7-diene of melting point 58° C.
Reaction SMILES: C([O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=[C:11]([CH2:19][O:20][C:21]2[CH:26]=[C:25]([O:27][CH2:28][CH2:29][C:30]([CH3:33])([OH:32])[CH3:31])[CH:24]=[CH:23][N:22]=2)[C:10]=1[CH3:34])C1C=CC=CC=1>C(O)C.C1COCC1.[Pd]>[OH:32][C:30]([CH3:33])([CH3:31])[CH2:29][CH2:28][O:27][C:25]1[CH:24]=[CH:23][N:22]=[C:21]([O:20][CH2:19][C:11]2[NH:12][C:13]3[C:18]([C:9](=[O:8])[C:10]=2[CH3:34])=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:26]=1
Reactant: Cc1c(COc2cc(OCCC(C)(C)O)ccn2)nc2ccccc2c1OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1c(COc2cc(OCCC(C)(C)O)ccn2)[nH]c2ccccc2c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.3 %

Procedure:
To a solution of 4-[(2-{[4-(benzyloxy)-3-methylquinolin-2-yl]methoxy}pyridin-4-yl)oxy]-2-methyl butan-2-ol (1.33 g) in ethanol-THF (1:4, 45 mL) was added 10% palladium-activated carbon (300 mg) under nitrogen atmosphere. The mixture was placed under hydrogen atmosphere, and then stirred at room temperature for 1 hour. The catalyst was removed by filtration, and then the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: chloroform/methanol=97/3) to obtain 2-({[4-(3-hydroxy-3-methylbutoxy)pyridin-2-yl]oxy}methyl)-3-methylquinolin-4(1H)-one (783 mg) as a crystal.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:16]=[CH:15][C:10]([C:11]([O:13]C)=[O:12])=[CH:9][CH:8]=2)=[CH:5][N:4]=[N:3]1.[OH-].[Na+]>O1CCCC1>[CH3:1][N:2]1[C:6]([C:7]2[CH:16]=[CH:15][C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=2)=[CH:5][N:4]=[N:3]1
Reactant: COC(=O)c1ccc(-c2cnnn2C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cn1nncc1-c1ccc(C(=O)O)cc1
Temperature: 70 °C

Procedure:
A mixture of methyl 4-(1-methyl-1H-1,2,3-triazol-5-yl)benzoate (0.5 g, 2.30 mmol) and Sodium hydroxide (4.60 ml, 9.21 mmol, 2N aqueous solution) in tetrahydrofuran (THF) was heated at 70° C. for 1 hr. The organic layer was washed with H2O 3× and discarded. The combined aqueous layers were acidified with 2N HCl aqueous solution. The product precipitated and was filtered, rinsed with H2O and dried under vacuum to give 0.3 g (74%) as a tan solid. LC-MS (ES) m/z=204 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[C:15]([F:16])=[CH:14][C:13]2[O:12][C:11]3[C:6](=[CH:7][C:8]([O:18][CH3:19])=[CH:9][C:10]=3[F:17])[C:5](=[O:20])[C:4]=2[CH:3]=1.[CH3:21][Mg]Cl>C1COCC1>[Br:1][C:2]1[C:15]([F:16])=[CH:14][C:13]2[O:12][C:11]3[C:6](=[CH:7][C:8]([O:18][CH3:19])=[CH:9][C:10]=3[F:17])[C:5]([CH3:21])([OH:20])[C:4]=2[CH:3]=1
Reactant: C[Mg]Cl
Reactant: COc1cc(F)c2oc3cc(F)c(Br)cc3c(=O)c2c1
Solvent: C1CCOC1
Product: COc1cc(F)c2c(c1)C(C)(O)c1cc(Br)c(F)cc1O2
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
A mixture of 2-bromo-3,5-difluoro-7-methoxy-9H-xanthen-9-one (40 g, 117 mmol) and THF (300 mL) was cooled to 0° C. and treated with methylmagnesium chloride (58.6 mL, 176 mmol) (3M in THF). After stirring at this temperature for 20 minutes, the reaction was quenched by the addition of sataturated NH4Cl (500 mL). Brine was added and the mixture was extracted with EtOAc (3×100 mL). The combined organic extracts were dried with sodium sulfate, filtered and concentrated in vacuo to afford crude 2-bromo-3,5-difluoro-7-methoxy-9-methyl-9H-xanthen-9-ol as a brown solid that was carried on without further purification. MS m/z=339.0 [M+1−H2O].
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:8][NH:9][C:10]([CH:12]2[CH2:20][CH2:19][CH2:18][C:17]3[N:16]([CH3:21])[N:15]=[CH:14][C:13]2=3)=O)=[N:4][CH:5]=[CH:6][N:7]=1.O=P(Cl)(Cl)Cl.CN(C=O)C>CC#N>[Cl:1][C:2]1[C:3]2[N:4]([C:10]([CH:12]3[CH2:20][CH2:19][CH2:18][C:17]4[N:16]([CH3:21])[N:15]=[CH:14][C:13]3=4)=[N:9][CH:8]=2)[CH:5]=[CH:6][N:7]=1
Reactant: Cn1ncc2c1CCCC2C(=O)NCc1nccnc1Cl
Solvent: CC#N
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: Cn1ncc2c1CCCC2c1ncc2c(Cl)nccn12
Temperature: 60 °C
Reaction time: 4 h
Yield: 70.9 %

Procedure:
To a solution of N-((3-chloropyrazin-2-yl)methyl)-1-methyl-4,5,6,7-tetrahydro-1H-indazole-4-carboxamide (1.5 g, 4.9 mmol) in MeCN (50 mL) was added POCl3 (1.2 g, 7.9 mmol) dropwise and DMF (0.1 mL). The mixture was stirred at 60° C. for 4 hours. After cooling, the mixture was poured into ice-water and extracted with EA three times. The EA layer was washed with brine and dried over Na2SO4. The solvent was removed and the residue was purified by column chromatography on silica gel (DCM/methanol=40/1 v/v %) to afford 8-chloro-3-(1-methyl-4,5,6,7-tetrahydro-1H-indazol-4-yl)imidazo[1,5-a]pyrazine (1.0 g, 70.4%). MS-ESI (m/z): 288 (M+1)+ (Acq Method: 10-80AB_2 min_220 &254.1 cm; Rt: 0.85 min)
Reaction SMILES: [CH3:1][CH:2]([CH2:23][CH2:24][CH:25]=[C:26]([CH3:28])[CH3:27])[CH2:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([CH2:15][CH2:16][CH2:17][C:18]([O:20]CC)=[O:19])[CH:7]=1)=[O:5].C(C1C=CC(C(CCC)CCCCCCC(C2C3C(=CC=CC=3)N(CCCC(OCC)=O)C=2)=O)=CC=1)C(C)C>>[CH3:1][CH:2]([CH2:23][CH2:24][CH:25]=[C:26]([CH3:27])[CH3:28])[CH2:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19])[CH:7]=1)=[O:5]
Reactant: CCOC(=O)CCCn1cc(C(=O)CC(C)CCC=C(C)C)c2ccccc21
Agent: CCCC(CCCCCCC(=O)c1cn(CCCC(=O)OCC)c2ccccc12)c1ccc(CC(C)C)cc1
Product: CC(C)=CCCC(C)CC(=O)c1cn(CCCC(=O)O)c2ccccc12

Procedure:
The procedure of Ex. 16 was repeated except that ethyl 4-[3-(3,7-dimethyl-6-octenoyl)-1-indolyl]butyrate obtained in Ex. 29 was used in place of ethyl 4-[3-[8-(4-isobutylphenyl)undecanoyl]-1-indolyl]butyrate to give 4-[3-(3,7-dimethyl-6-octenoyl)-1-indolyl]butyric acid as an oil.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[C@@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[N:13]=[C:14]([CH3:24])[S:15][C:16]=1[C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1)=[O:11].Cl[C:26]1[N:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][N:27]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC([O-])(C)C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:33][O:32][C:29]1[CH:28]=[N:27][C:26]([NH:1][CH2:2][C@H:3]2[C@@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]2[C:10]([C:12]2[N:13]=[C:14]([CH3:24])[S:15][C:16]=2[C:17]2[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=2)=[O:11])=[N:31][CH:30]=1
Reactant: Cc1nc(C(=O)N2CCC[C@H](C)[C@@H]2CN)c(-c2ccc(F)cc2)s1
Reactant: COc1cnc(Cl)nc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: COc1cnc(NC[C@H]2[C@@H](C)CCCN2C(=O)c2nc(C)sc2-c2ccc(F)cc2)nc1
Temperature: 70 °C
Reaction time: 72 h

Procedure:
A mixture of rac-cis-(2-(aminomethyl)-3-methylpiperidin-1-yl)(5-(4-fluorophenyl)-2-methylthiazol-4-yl)methanone, 2-chloro-5-methoxypyrimidine, Pd2dba3, BINAP, and NaOtBu in toluene was purged with argon, and then stirred at 70° C. for 72 h. The reaction was cooled, filtered through a pad of silica gel and concentrated in vacuo. The crude reaction mixture was purified by reverse-phase preparative HPLC to afford the title compound. MS (ESI) 456.2 (M+H).