Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[C:9]([F:11])[CH:8]=[N:7][C:6]=1Cl)[CH3:2].[CH3:14][S:15][C:16]1[CH:17]=[C:18]([OH:22])[CH:19]=[CH:20][CH:21]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1>[CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[C:9]([F:11])[CH:8]=[N:7][C:6]=1[O:22][C:18]1[CH:19]=[CH:20][CH:21]=[C:16]([S:15][CH3:14])[CH:17]=1)[CH3:2]
Reactant: CCOC(=O)c1cc(F)cnc1Cl
Reactant: CSc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: CCOC(=O)c1cc(F)cnc1Oc1cccc(SC)c1
Temperature: 100 °C
Reaction time: 48 h

Procedure:
A solution of ethyl-2-chloro-5-fluoro-nicotinoate (50.4 g, 0.247 mol) (prepared according to the method of J. Med. Chem., 1993, 36(18), 2676–88, page 2684, column 2, 3rd example, ethyl-2-chloro-5-fluoropyridine-3-carboxylate) (29 g, 0.143 mol) and 3-methylsulphanyl-phenol (20 g, 0.143 mol) (prepared according to the method of WO 98/45268, page 68, preparation 61) in dioxane (300 mL) was treated with caesium carbonate (46.5 g, 0.143 mol) at room temperature. The reaction mixture was heated to 100° C. and stirred for 48 hours. The reaction mixture was concentrated in vacuo and the residue taken up in water (600 mL) and extracted with ethyl acetate (3×250 mL). The organics were combined, washed with brine (200 mL), dried over magnesium sulphate and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with dichloromethane:toluene (99.75:0.25 to 99.5:0.5) to yield the title product as a yellow oil, 27.1 g (62%).
Reaction SMILES: ClC1C=CC2OC3C=CC=CC=3CN(C(O)=O)C=2C=1.CC(C)(OC([N:26]([CH2:51][C:52]1[O:53][CH:54]=[CH:55][CH:56]=1)[CH2:27][CH2:28][C:29]([NH:31][NH:32][C:33]([N:35]1[CH2:41][C:40]2[CH:42]=[CH:43][CH:44]=[CH:45][C:39]=2[O:38][C:37]2[CH:46]=[CH:47][C:48]([Cl:50])=[CH:49][C:36]1=2)=[O:34])=[O:30])=O)C>>[O:53]1[CH:54]=[CH:55][CH:56]=[C:52]1[CH2:51][NH:26][CH2:27][CH2:28][C:29]([NH:31][NH:32][C:33]([N:35]1[CH2:41][C:40]2[CH:42]=[CH:43][CH:44]=[CH:45][C:39]=2[O:38][C:37]2[CH:46]=[CH:47][C:48]([Cl:50])=[CH:49][C:36]1=2)=[O:34])=[O:30]
Reactant: CC(C)(C)OC(=O)N(CCC(=O)NNC(=O)N1Cc2ccccc2Oc2ccc(Cl)cc21)Cc1ccco1
Agent: O=C(O)N1Cc2ccccc2Oc2ccc(Cl)cc21
Product: O=C(CCNCc1ccco1)NNC(=O)N1Cc2ccccc2Oc2ccc(Cl)cc21

Procedure:
8-chlorodibenz[b,f][1,4]oxazepine-10(11H)-carboxylic acid, 2-[3-[(2-furanylmethyl)amino]-1-oxopropyl]hydrazide (25) was prepared in the same manner as 8-chlorodibenz-[b,f][1,4]-oxazepine-10(11H)-carboxylic acid, 2-[1-oxo-3-[(2-thienylmethyl)amino]propylhydrazide, monohydrochloride (18), as described above in Example 18, on a 0.37 mmol scale from 8-chlorodibenz[b,f][1,4]oxazepine-10(11H)-carboxylic acid, 2-[3-[[(1,1-dimethylethoxy)carbonyl](2-furanylmethyl)amino]-1-oxopropyl]hydrazide (24), prepared as described above in Example 24, to yield 0.14 g (78%) of product. Analysis calculated for C22H21N4O4Cl. HCl 0.25 H2O (M.W. 481.86): C, 54.84; H, 4.71; N, 11.63. Found: C, 54.56; H, 4.60; N, 11.33.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[O:6][C:7]=1[CH3:8].[OH:15][C:16]1[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:23][O:22][C:20](=[O:21])[C:19]1[CH:24]=[CH:25][C:16]([O:15][CH2:2][C:3]2[N:4]=[C:5]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[O:6][C:7]=2[CH3:8])=[CH:17][CH:18]=1
Reactant: Cc1oc(-c2ccccc2)nc1CCl
Reactant: COC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OCc2nc(-c3ccccc3)oc2C)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 4-chloromethyl-5-methyl-2-phenyl-oxazole (3.0 g, 14.4 mmol), methyl 4-hydroxybenzoate (2.64 g, 17.3 mmol), and potassium carbonate (6.0 g, 43.34 mmol) in DMF is stirred at RT overnight. The mixture is then partitioned between EtOAc and water, and the organic phase is washed with brine, dried over magnesium sulfate, and concentrated under vacuum to give the crude product. The material is purified by silica gel chromatography using 15% EtOAc in hexane as the eluent to give 4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy) benzoic acid methyl ester as a white solid.
Reaction SMILES: O[C:2]1[C:3]2[CH2:11][CH2:10][O:9][C:4]=2[N:5]=[C:6]([NH2:8])[N:7]=1.NC1N=C([Cl:19])C(CCCl)=C(Cl)N=1.P(Cl)(Cl)(Cl)=O.[OH-].[Na+]>>[Cl:19][C:2]1[C:3]2[CH2:11][CH2:10][O:9][C:4]=2[N:5]=[C:6]([NH2:8])[N:7]=1
Reactant: Nc1nc(O)c2c(n1)OCC2
Reactant: Nc1nc(Cl)c(CCCl)c(Cl)n1
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: Nc1nc(Cl)c2c(n1)OCC2

Procedure:
5,6-Dihydro-4-hydroxyfuro[2,3-d]pyrimidine-2-amine [Svab, Budesinski and Vavrina, Collection Czech. Chem. Commun. 32, 1582 (1967)] can be converted to 2-amino-5-(2-chloroethyl)-4,6-dichloropyrimidine by heating with phosphorus oxychloride. The product can be subsequently cyclized by treatment with two equivalents of aqueous sodium hydroxide to afford 4-chloro-5,6-dihydrofuro[2,3-d]pyrimidin-2-amine, which is then converted to 5,6-dihydro-4-methoxyfuro[2,3-d]pyrimidin-2-amine by heating with excess sodium methoxide in methanol. ##STR38##
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][CH:8]=[CH:9][CH:10]=1)=[O:5])[CH3:2].[CH:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][C:12]=1[CH2:21][C:22](Cl)=[O:23]>>[CH2:1]([O:3][C:4]([C:6]1[NH:7][CH:8]=[C:9]([C:22](=[O:23])[CH2:21][C:12]2[CH:13]=[CH:14][C:15]3[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:11]=2)[CH:10]=1)=[O:5])[CH3:2]
Reactant: O=C(Cl)Cc1ccc2ccccc2c1
Reactant: CCOC(=O)c1ccc[nH]1
Product: CCOC(=O)c1cc(C(=O)Cc2ccc3ccccc3c2)c[nH]1

Procedure:
4-(2-Naphthalen-2-yl-acetyl)-1H-pyrrole-2-carboxylic acid ethyl ester (141) was synthesized from 1H-pyrrole-2-carboxylic acid ethyl ester and naphthalen-2-yl-acetyl chloride following the procedure described in Example 32. Reaction Conditions: 1,2-dichloromethane/−40° C.→RT. Purification: no purification. LC/MS: 78%.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[NH2:7][C:8]1[N:13]=[C:12]([C:14]2[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=2[Cl:21])[N:11]=[C:10]([N:22]2[CH2:26][C@H:25]([OH:27])[CH2:24][C@H:23]2[C:28](OC)=[O:29])[N:9]=1>O1CCCC1>[NH2:7][C:8]1[N:13]=[C:12]([C:14]2[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=2[Cl:21])[N:11]=[C:10]([N:22]2[CH2:26][C@H:25]([OH:27])[CH2:24][C@H:23]2[CH2:28][OH:29])[N:9]=1
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1c1nc(N)nc(-c2cc(Cl)ccc2Cl)n1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Nc1nc(-c2cc(Cl)ccc2Cl)nc(N2C[C@H](O)C[C@H]2CO)n1
Reaction time: 3 h
Yield: 80.6 %

Procedure:
To a mixture of 20.9 g of lithium aluminum hydride and 1000 ml of tetrahydrofuran under ice-cooling and stirring, a solution of 100 g of the compound obtained in Step 1 in 300 ml of tetrahydrofuran was added gradually dropwise at 0°-5° C. and the reaction was carried out at the same temperature for 3 hours. After the excess lithium aluminum hydride was decomposed, the reaction mixture was filtered and the filtrate was concentrated. The residue was dissolved in ethyl acetate and the solution was washed with water, dried, and concentrated to give a white solid. This solid was recrystallized from ethyl acetate, collected by filtration, and dried to provide 74.7 g of the title compound as white crystals. m.p. 171°-173° C.
Reaction SMILES: [C:1]([C:4]1[S:8][C:7]([C:9]([OH:11])=O)=[CH:6][CH:5]=1)(=[O:3])[CH3:2].S(Cl)(Cl)=O.[NH3:16]>C1C=CC=CC=1.O1CCCC1>[C:1]([C:4]1[S:8][C:7]([C:9]([NH2:16])=[O:11])=[CH:6][CH:5]=1)(=[O:3])[CH3:2]
Reactant: N
Reactant: CC(=O)c1ccc(C(=O)O)s1
Solvent: C1CCOC1
Solvent: c1ccccc1
Solvent: O=S(Cl)Cl
Product: CC(=O)c1ccc(C(N)=O)s1
Reaction time: 1.5 h

Procedure:
A mixture of 5-acetylthiophene-2-carboxylic acid (5.6 g) and thionyl chloride (5.25 ml) in benzene (70 ml) was refluxed for 3 h; a further portion of thionyl chloride (5.3 ml) was added and reflux continued for 1.5 h. The resulting solution was evaporated to leave a white solid which was dissolved in tetrahydrofuran (70 ml). Aqueous ammonia (s.g. 0.88; 6 ml) was added and the reaction mixture was stirred for 1 h. The white precipitate was washed with water, leaving the title amide (3.43 g) mp 231°-233°. TLC SiO2 (EtOAc) Rf 0.28.
Reaction SMILES: [S:1]([NH2:5])([NH2:4])(=[O:3])=[O:2].O.[C:7]1([CH3:17])[CH:12]=[CH:11][C:10]([S:13]([OH:16])(=[O:15])=[O:14])=[CH:9][CH:8]=1.[Cl:18][CH2:19][CH2:20][C:21]#[N:22]>C(Cl)Cl.CC(C)=O>[C:7]1([CH3:17])[CH:8]=[CH:9][C:10]([S:13]([OH:16])(=[O:14])=[O:15])=[CH:11][CH:12]=1.[S:1]([NH:5][C:21](=[NH:22])[CH2:20][CH2:19][Cl:18])(=[O:3])(=[O:2])[NH2:4]
Reactant: N#CCCCl
Reactant: NS(N)(=O)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)=O
Solvent: ClCCl
Solvent: O
Product: N=C(CCCl)NS(N)(=O)=O
Temperature: 57.5 °C

Procedure:
Sulfamide (9.6 g, 0.1 mole) was added to a suspension of p-toluenesulfonic acid monohydrate (38.0 g, 0.2 mole) in 3-chloropropionitrile (51.3 g, 0.6 mole). The suspension was heated at 55-60° C., for 18 hours. At the end of the heating period, the mixture was cooled to room temperature, diluted with methylene chloride (150 ml), and filtered. The solid, thus obtained, was suspended in acetone (50 ml) and the suspension filtered and the product dried.
Reaction SMILES: [CH2:1]([C:3]1[N:7]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[CH:10][CH:9]=2)[N:6]=[C:5]([S:17][CH3:18])[N:4]=1)[CH3:2].[H][H]>[Pd].CO>[CH2:1]([C:3]1[N:7]([C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)[N:6]=[C:5]([S:17][CH3:18])[N:4]=1)[CH3:2]
Reactant: [H][H]
Reactant: CCc1nc(SC)nn1-c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CO
Product: CCc1nc(SC)nn1-c1ccc(N)cc1
Yield: 91 %

Procedure:
A mixture of 41 parts of 5-ethyl-3-(methylthio)-1-(4-nitrophenyl)-1H-1,2,4-triazole and 80 parts of methanol is hydrogenated at normal pressure and at room temperature with 1 part of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen is taken up, the catalyst is filtered off and the filtrate is evaporated. The residue is crystallized from 1,1'-oxybisbutane. The product is filtered off and dried, yielding 33 parts (91%) of 4-[5-ethyl-3-(methylthio)-1H-1,2,4-triazol-1-yl]benzenamine; mp. 131.7° C.
Reaction SMILES: C(O[CH:4](OCC)[CH2:5][N:6]=[C:7]=[NH:8])C.[F:12][C:13]([F:24])([F:23])[C:14]1[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=1)[C:17]([NH2:19])=[O:18].CS(O)(=O)=O>C(O)C>[NH:19]1[CH:17]=[CH:16][N:8]=[C:7]1[NH:6][C:5]1[CH:4]=[C:13]([NH:19][C:17](=[O:18])[C:16]2[CH:20]=[CH:21][CH:22]=[C:14]([C:13]([F:23])([F:24])[F:12])[CH:15]=2)[CH:14]=[CH:22][C:21]=1[CH3:20]
Reactant: NC(=O)c1cccc(C(F)(F)F)c1
Reactant: CCOC(CN=C=N)OCC
Agent: CS(=O)(=O)O
Solvent: CCO
Product: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1Nc1ncc[nH]1
Reaction time: 8 h

Procedure:
A mixture of N-(2,2-diethoxyethyl)carbodiimide (398 mg, 2.51 mmol), 3-amino-4-methyl-phenyl]-3-trifluoromethyl-benzamide (649 mg, 2.20 mmol), methanesulfonic acid (143 μL, 2.20 mmol) in ethanol (25 mL) is heated at reflux for 16 hours. An additional portion of N-(2,2-diethoxyethyl)carbodiimide (525 mg, 3.32 mmol) and methanesulfonic acid (143 μL, 2.20 mmol) are added. After an additional 3 hours refluxing, the reaction mixture is concentrated. The residue is dissolved in HCl (6N, 5 mL) and ethanol (5 mL). After stirring overnight, the reaction mixture is concentrated and basified with 25% NaOH solution to a pH of 14. The mixture is stirred for 30 minutes, extracted with CH2Cl2, dried, concentrated and purified by column chromatography (silica gel, eluting with 7N NH3 in methanol:dichloromethane from 2% to 4%) to give the title compound.
Reaction SMILES: [Br:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([C:10]2[O:11][CH:12]=[CH:13][CH:14]=2)=[CH:4][C:3]=1[O:15][CH3:16].[CH2:17]([O:19][CH:20]([C:27]1[CH:32]=[CH:31][C:30]([C:33]2[O:34][C:35]([CH3:38])=[N:36][N:37]=2)=[CH:29][CH:28]=1)[C:21](N(OC)C)=[O:22])[CH3:18]>>[Br:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([C:10]2[O:11][C:12]([C:21](=[O:22])[CH:20]([O:19][CH2:17][CH3:18])[C:27]3[CH:28]=[CH:29][C:30]([C:33]4[O:34][C:35]([CH3:38])=[N:36][N:37]=4)=[CH:31][CH:32]=3)=[CH:13][CH:14]=2)=[CH:4][C:3]=1[O:15][CH3:16]
Reactant: CCOC(C(=O)N(C)OC)c1ccc(-c2nnc(C)o2)cc1
Reactant: COc1cc(-c2ccco2)cc(OC)c1Br
Product: CCOC(C(=O)c1ccc(-c2cc(OC)c(Br)c(OC)c2)o1)c1ccc(-c2nnc(C)o2)cc1

Procedure:
1-(5-(4-Bromo-3,5-dimethoxyphenyl)furan-2-yl)-2-ethoxy-2-(4-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl)ethanone was prepared from 2-(4-bromo-3,5-dimethoxyphenyl)furan and 2-ethoxy-N-methoxy-N-methyl-2-(4-(5-methyl-1,3,4-oxadiazol-2-yl)phenyl)acetamide according to the procedure used in Example 30. Purification by chromatography (60% EtOAc/hexanes) gave the product as a pale yellow solid (0.070 g, 19% yield). MS: m/z 527.3 [M+H]+.
Reaction SMILES: Br[CH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([CH2:9][NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:5][CH2:4]1.[C:18]1([CH:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(N(CC)CC)C>C(O)C.O>[C:14]([O:13][C:11]([NH:10][CH2:9][C@H:6]1[CH2:7][CH2:8][C@H:3]([CH2:2][N:27]2[CH2:28][CH2:29][CH:24]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:25][CH2:26]2)[CH2:4][CH2:5]1)=[O:12])([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)OC(=O)NC[C@H]1CC[C@H](CBr)CC1
Reactant: c1ccc(C2CCNCC2)cc1
Solvent: CCO
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)(C)OC(=O)NC[C@H]1CC[C@H](CN2CCC(c3ccccc3)CC2)CC1
Temperature: 25 °C

Procedure:
A solution of 2.51 g (8.20 mM) of N-(trans-4-bromomethyl-1-cyclohexylmethyl)-N-(tert-butoxycarbonyl)amine, 1.32 g (8.19 mM) of 4-phenylpiperidine, and 2.3 ml (16.5 mM) of triethylamine in ethanol (10 ml) was refluxed under nitrogen for 64 hours. After cooling to room temperature, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated aqueous solution of sodium chloride and dried over MgSO4. This crude product was purified by column chromatography (methanol-ethyl acetate: 10%) to provide the title compound as light-yellow solid.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][CH:5]=1)=O.Cl.C[O:16][NH2:17]>N1C=CC=CC=1>[F:11][C:10]([F:13])([F:12])[C:7]1[CH:8]=[CH:9][C:4]([C:2](=[N:17][OH:16])[CH3:1])=[CH:5][CH:6]=1
Reactant: CON
Reactant: CC(=O)c1ccc(C(F)(F)F)cc1
Agent: Cl
Solvent: c1ccncc1
Product: CC(=NO)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
4-Trifluoromethylacetophenone (13.6 g, 72.3 mmol) and O-methylhydroxylamine hydrochloride were combined in pyridine (100 mL) and stirred at ambient temperature for 16 hours. The mixture was concentrated under reduced pressure and the residue was suspended in diethyl ether. The suspension was filtered and the filter cake was washed with diethyl ether. The filtrate was washed with water, 1N HCl, and water. The organic phase was concentrated to provide the title compound. 1H NMR (300 MHz, d6-DMSO) 7.90-7.68 (m, 4H), 3.97 and 3.78 (2S, 1H), 2.20 and 2.17 (2s, 3H); MS (DCI/NH3) m/e 218 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:12][C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[NH:18][C:17]([CH3:22])=[CH:16]4)=[N:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:23][CH3:24].O[CH2:26][CH2:27][CH2:28][N:29]1[CH:33]=[CH:32][N:31]=[C:30]1[CH3:34]>>[CH3:24][O:23][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:2]=1[O:1][CH2:26][CH2:27][CH2:28][N:29]1[CH:33]=[CH:32][N:31]=[C:30]1[CH3:34])[N:9]=[CH:8][N:7]=[C:6]2[NH:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17]([CH3:22])=[CH:16]2
Reactant: Cc1nccn1CCCO
Reactant: COc1cc2c(Nc3ccc4[nH]c(C)cc4c3)ncnc2cc1O
Product: COc1cc2c(Nc3ccc4[nH]c(C)cc4c3)ncnc2cc1OCCCn1ccnc1C
Yield: 37.4 %

Procedure:
Using an analogous procedure to that described in Example 224, 7-hydroxy-6-methoxy-4-(2-methylindol-5-ylamino)quinazoline (102 mg, 0.32 mmol), (prepared as described for the starting material in Example 205), was reacted with 1-(3-hydroxypropyl)-2-methylimidazole (67 mg, 0.48 mmol), (EP 0060696 A1), to give 6-methoxy-7-(3-(2-methylimidazol-1-yl)propoxy)-4-(2-methylindol-5-ylamino)quinazoline (53 mg, 37%).
Reaction SMILES: [Br:1][C:2]1C=[CH:13][C:5]([O:6][C@@H:7]2[CH2:11][O:10][CH2:9][C@H:8]2[OH:12])=[CH:4][CH:3]=1.BrC1[N:21]=CC(O)=CC=1>>[Br:1][C:2]1[N:21]=[CH:13][C:5]([O:6][C@@H:7]2[CH2:11][O:10][CH2:9][C@H:8]2[OH:12])=[CH:4][CH:3]=1
Reactant: O[C@@H]1COC[C@H]1Oc1ccc(Br)cc1
Reactant: Oc1ccc(Br)nc1
Product: O[C@@H]1COC[C@H]1Oc1ccc(Br)nc1

Procedure:
The title compound of Step 1 was prepared according to the general procedure for the synthesis of trans-4-(4-bromophenoxy)tetrahydrofuran-3-ol in Example 2, except that 6-bromopyridin-3-ol was used in place of 4-bromophenol, and the crude product was purified by silica gel chromatography (Gradient: 20% to 70% ethyl acetate in heptane). Yield: 5.24 g, 20.2 mmol, 61%. 1H NMR (500 MHz, CDCl3) δ 3.79 (dd, J=9.9, 1.9 Hz, 1H), 3.87 (dd, J=10.4, 1.8 Hz, 1H), 4.00 (dd, J=9.9, 4.3 Hz, 1H), 4.19 (dd, J=10.4, 4.7 Hz, 1H), 4.38 (br m, 1H), 4.59 (br s, 1H), 4.68 (br d, J=4.4 Hz, 1H), 7.14 (dd, J=8.7, 3.2 Hz, 1H), 7.32 (dd, J=8.7, 0.5 Hz, 1H), 8.01 (br d, J=3.1 Hz, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)=[CH:11][N:10]([C:19]3[CH:24]=[CH:23][C:22](=[O:25])[NH:21][N:20]=3)[N:9]=2)=[CH:4][CH:3]=1.[NH2:26]C1C=C(C2C(C3C=CC(F)=CC=3)=NN(C3C=CC(=O)NN=3)C=2)C=CN=1>>[NH2:26][C:23]1[C:22](=[O:25])[NH:21][N:20]=[C:19]([N:10]2[CH:11]=[C:12]([C:13]3[CH:14]=[CH:15][N:16]=[CH:17][CH:18]=3)[C:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)=[N:9]2)[CH:24]=1
Reactant: O=c1ccc(-n2cc(-c3ccncc3)c(-c3ccc(F)cc3)n2)n[nH]1
Reactant: Nc1cc(-c2cn(-c3ccc(=O)[nH]n3)nc2-c2ccc(F)cc2)ccn1
Product: Nc1cc(-n2cc(-c3ccncc3)c(-c3ccc(F)cc3)n2)n[nH]c1=O
Yield: 40 %

Procedure:
The reaction was carried out in the same manner as in Example 4 except for using 213 mg (0.64 mmol) of 3-(4-fluorophenyl)-1-(1,6-dihydro-6-oxopyridazin-3-yl)-4-(pyridin-4-yl)-1H-pyrazole obtained in Example 1-4) in place of 4-(2-aminopyridin-4-yl)-3-(4-fluorophenyl)-1-(1,6-dihydro-6-oxopyridazin-3-yl)-1H-pyrazole to obtain 90.3 mg of the title compound as a white powder. (Yield: 40%)
Reaction SMILES: [C:1]([CH:4]=[CH:5][CH2:6][CH2:7][CH2:8][C:9]1[N:14]2[CH:15]=[N:16][CH:17]=[C:13]2[CH:12]=[CH:11][CH:10]=1)([OH:3])=[O:2]>CO.[Pd]>[C:1]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[N:14]2[CH:15]=[N:16][CH:17]=[C:13]2[CH:12]=[CH:11][CH:10]=1)([OH:3])=[O:2]
Reactant: O=C(O)C=CCCCc1cccc2cncn12
Agent: [Pd]
Solvent: CO
Product: O=C(O)CCCCCc1cccc2cncn12
Reaction time: 3 h

Procedure:
To a solution of 150 mg of 5-(5-carboxypent-4-enyl)-imidazo[1,5-a]pyridine in 7 ml methanol is added 100 mg of 10% palladium on carbon as catalyst. The reaction mixture is hydrogenated at atmospheric pressure for 3 hours. The catalyst is removed by filtration and the solvent evaporated under reduced pressure to yield 5-(5-carboxypentyl)-imidazo[1,5-a]pyridine melting at 144°-7°, and identical to the product of Example 2.
Reaction SMILES: C([O:4][C@H:5]1[C@H:10]([O:11]C(=O)C)[C@@H:9]([O:15]C(=O)C)[C@H:8]([C:19]2[CH:24]=[C:23]([CH2:25][C:26]3[CH:31]=[CH:30][C:29]([CH2:32][CH3:33])=[CH:28][CH:27]=3)[C:22]([Cl:34])=[CH:21][C:20]=2[CH2:35][O:36][CH2:37][CH:38]([OH:41])[CH2:39][OH:40])[O:7][C@@H:6]1[CH2:42][O:43]C(=O)C)(=O)C.[OH-].[Li+]>C1COCC1.CO.O>[Cl:34][C:22]1[C:23]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([CH2:32][CH3:33])=[CH:28][CH:27]=2)=[CH:24][C:19]([C@H:8]2[C@H:9]([OH:15])[C@@H:10]([OH:11])[C@H:5]([OH:4])[C@@H:6]([CH2:42][OH:43])[O:7]2)=[C:20]([CH2:35][O:36][CH2:37][CH:38]([OH:41])[CH2:39][OH:40])[CH:21]=1
Reactant: CCc1ccc(Cc2cc([C@@H]3O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]3OC(C)=O)c(COCC(O)CO)cc2Cl)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CCc1ccc(Cc2cc([C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)c(COCC(O)CO)cc2Cl)cc1
Temperature: 20 °C
Reaction time: 8 h
Yield: 9.3 %

Procedure:
To a stirred solution of (2R,3R,4R,5S,6S)-2-(acetoxymethyl)-6-(4-chloro-2-((2,3-dihydroxypropoxy)methyl)-5-(4-ethylbenzyl)phenyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (50 mg, 0.076 mmol) (prepared from intermediate J using a Sharpless dihydroxylation) in THF:MeOH:H2O (2:3:1, 1.2 mL) was added lithium hydroxide (3.71 mg). The reaction was stirred overnight at 20° C. The volatiles were removed and the residue was dissolved in EtOAc (20 mL), washed 1× with brine, 1× with brine containing 2 mL of 5% aqueous KHSO4 and dried over Na2SO4. Concentration gave 3.5 mg of pure product as a white solid. 1H-NMR (CD3OD, 300 MHz) δ 7.45 (s, 1H), 7.43 (s, 1H), 7.08 (s, 4H), 4.75-4.70 (m, 2H), 4.60-4.45 (m, 2H), 4.10 (d, J=14.8 Hz, 1H), 4.05 (d, J=14.8 Hz, 1H), 3.93-3.83 (m, 2H), 3.87-3.77 (m, 2H), 3.66-3.36 (m, 7H), 2.60 (q, J=7.8 Hz, 2H), 1.21 (t, J=7.8 Hz, 3H), 1.15 (d, J=7.8 Hz, 3H); LC-MS (m/z) 497 [(M+1)+], 541 [(M+45)−].
Reaction SMILES: [F:1][C:2]1[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:3]=1[C:4]([NH:6][C:7]1[CH:29]=[CH:28][C:10]([CH2:11][N:12]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([F:21])[CH:19]=3)[C:14]([CH2:22][C:23]([O:25]CC)=[O:24])=[N:13]2)=[CH:9][CH:8]=1)=[O:5].O.[OH-].[Li+].O.Cl>O1CCCC1>[F:1][C:2]1[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:3]=1[C:4]([NH:6][C:7]1[CH:29]=[CH:28][C:10]([CH2:11][N:12]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([F:21])[CH:19]=3)[C:14]([CH2:22][C:23]([OH:25])=[O:24])=[N:13]2)=[CH:9][CH:8]=1)=[O:5]
Reactant: CCOC(=O)Cc1nn(Cc2ccc(NC(=O)c3ccc(F)cc3F)cc2)c2cc(F)ccc12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)Cc1nn(Cc2ccc(NC(=O)c3ccc(F)cc3F)cc2)c2cc(F)ccc12
Yield: 89.8 %

Procedure:
Ethyl 2-[1-[4-(2,4-difluorobenzamido)benzyl]-6-fluoro-1H-indazol-3-yl]acetate (213 mg, 0.456 mmol) was dissolved in tetrahydrofuran (15 mL), and in an ice bath 10 mL aqueous solution dissolving lithium hydroxide monohydrate (58 mg, 1.38 mmol) was added. It was reacted at room temperature for 3 h, and the reaction was monitored to be complete by TLC. Water was added into the system, and adjusted to pH≈3-4 with diluted hydrochloric acid. A solid precipitated, which was filtered and dried to obtain a white solid 180 mg, at a yield of 89.9%.
Reaction SMILES: O([Si](C)(C)C)[K].[CH3:7][C:8]([C:10]1[CH:15]=[CH:14][C:13](I)=[CH:12][CH:11]=1)=[O:9]>>[CH:7](/[C:13]1[CH:14]=[CH:15][C:10]([C:8](=[O:9])[CH3:7])=[CH:11][CH:12]=1)=[CH:8]/[CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CC(=O)c1ccc(I)cc1
Agent: C[Si](C)(C)O[K]
Product: CCCCC/C=C\c1ccc(C(C)=O)cc1
Temperature: 25 °C
Reaction time: 13 h

Procedure:
Following General Procedure II, a mixture of KOSiMe3 (570 mg, 4.0 mmol, 2.0 equiv), (Z)-21 (379 mg, 2.2 mmol, 1.1 equiv), 4-iodoacetophenone (492 mg, 2.0 mmol) and Pd(dba2) (58 mg, 0.1 mmol, 0.05 equiv) was stirred at room temperature for 13 h, and then was filtered through SiO2. Purification by column chromatography (RP C18, MeOH/H2O, 9/1) and Kugelrohr distillation afforded 360 mg (83%) of (Z)-154c as colorless oil.
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:26][C:27]([O:29]CC)=[O:28])[C:4]2[C:9]([C:10]=1[C:11]1[C:20]3[C:15](=[C:16]([C:21]([F:24])([F:23])[F:22])[CH:17]=[CH:18][CH:19]=3)[N:14]=[CH:13][CH:12]=1)=[CH:8][C:7]([CH3:25])=[CH:6][CH:5]=2.[OH-].[Na+]>C1COCC1.CO>[CH3:1][C:2]1[N:3]([CH2:26][C:27]([OH:29])=[O:28])[C:4]2[C:9]([C:10]=1[C:11]1[C:20]3[C:15](=[C:16]([C:21]([F:22])([F:23])[F:24])[CH:17]=[CH:18][CH:19]=3)[N:14]=[CH:13][CH:12]=1)=[CH:8][C:7]([CH3:25])=[CH:6][CH:5]=2
Reactant: CCOC(=O)Cn1c(C)c(-c2ccnc3c(C(F)(F)F)cccc23)c2cc(C)ccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ccc2c(c1)c(-c1ccnc3c(C(F)(F)F)cccc13)c(C)n2CC(=O)O

Procedure:
A solution of product from step b) (1.46 g) and 1 M sodium hydroxide (3.42 ml) in THF (20 ml) and methanol (2 ml) was stirred for 16 hours. The solvent was removed in vacuo and the residue was dissolved in water (20 ml) and washed with dichloromethane. 1M HCl (3.4 ml) was added slowly to the stirred solution. The precipitate was collected and dried to give the title compound (1.23 g. M.p. 145° C.