Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[C:10]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])#[N:11].C(O)(=O)C>C(O)C.C([O-])(=O)C.[NH4+]>[C:10]([C:12](=[CH:6][C:5]1[CH:8]=[CH:9][C:2]([OH:1])=[CH:3][CH:4]=1)[C:13]([O:15][CH2:16][CH3:17])=[O:14])#[N:11]
Reactant: O=Cc1ccc(O)cc1
Reactant: CCOC(=O)CC#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)C(C#N)=Cc1ccc(O)cc1
Temperature: 0 °C
Yield: 121.8 %

Procedure:
30 g of 4-hydroxybenzaldehyde, 31.7 g of ethyl cyanoacetate, 4.5 ml of acetic acid and 1.9 g of ammonium acetate were refluxed in 100 ml of ethyl alcohol for 4 hours with heating. After the reaction, the reaction solution was poured into 500 ml of ice water to separate crystals. The resulting crystals were recrystallized from 400 ml of methyl alcohol to obtain 65 g of ethyl 2-cyano-3-(4-hydroxyphenyl)acrylate having a melting point of 89° to 91° C. 10.9 g of the resulting compound and 4.3 g of pyridine were dissolved in 100 ml of tetrahydrofuran, and 4.5 g of acryloyl chloride was added dropwise thereto. The reaction was carried out for 2 hours while maintaining the reaction temperature below 40° C. After the reaction, the reacting solution was poured into ice water to separate crystals, and the resulting crystals were recrystallized from 100 ml of methyl alcohol to obtain 11 g of the desired compound having a melting point of 82° to 85° C. The identification of the compound was carried out using IR spectrum, NMR spectrum and elemental analysis.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][C:13]=1[O:14][CH3:15])[CH2:5][CH:6]([CH3:10])[C:7]([OH:9])=O>O>[F:1][C:2]1[CH:3]=[C:4]2[C:11](=[CH:12][C:13]=1[O:14][CH3:15])[C:7](=[O:9])[CH:6]([CH3:10])[CH2:5]2
Reactant: COc1ccc(CC(C)C(=O)O)cc1F
Solvent: O
Product: COc1cc2c(cc1F)CC(C)C2=O
Temperature: 95 °C

Procedure:
A mixture of 3-fluoro-α-methyl-4-methoxy dihydrocinnamic acid, (49.3 g, 0.23 mol) in polyphosphoric acid (500 g) is heated at 95° C. on a steam bath with occasional agitation for 75 min. The dark red solution is stirred with water (3.0 l) overnight. The precipitate is collected, and is washed thoroughly with water. Its solution in ether is extracted with aqueous potassium bicarbonate (4×), is diluted with methylene chloride, is dried (MgSO4), and is evaporated. The residue is recrystallized from methylene chloride/hexanes to give 5-fluoro-6-methoxy-2-methylindanone (m.p. 76-78°).
Reaction SMILES: [C:1]([N:8]([CH2:16][C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]([C:27]([O:29]C)=[O:28])=[CH:19][CH:18]=1)[CH2:9][C:10]1[N:11]([CH3:15])[CH:12]=[CH:13][N:14]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[OH-].[Na+].C1COCC1>CO>[C:1]([N:8]([CH2:16][C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]([C:27]([OH:29])=[O:28])=[CH:19][CH:18]=1)[CH2:9][C:10]1[N:11]([CH3:15])[CH:12]=[CH:13][N:14]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: COC(=O)c1ccc(CN(Cc2nccn2C)C(=O)OC(C)(C)C)c2ccccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cn1ccnc1CN(Cc1ccc(C(=O)O)c2ccccc12)C(=O)OC(C)(C)C
Reaction time: 2.5 h
Yield: 84.1 %

Procedure:
The compound obtained in Example 74-2 (1.0526 g) was dissolved in methanol (10 ml), and 1 N aqueous solution of sodium hydroxide (10 ml) and THF (10 ml) were added. The mixture was stirred for 2.5 hours. Part of the solvent was removed by distillation while adding water to the reaction solution. After adjusting the pH to 6, the water layer was extracted with chloroform. The extract was dried over anhydrous magnesium sulfate, the solvent was removed by distillation, and the residue was dried under vacuum to obtain the title compound (0.8551 g) as a pale yellow solid.
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][C:9]1[CH:10]=[C:11]([CH:19]=[CH:20][CH:21]=1)[O:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])(=O)=O.[I-:22].[Na+].CCOC(C)=O>CC(C)=O>[I:22][CH2:6][CH2:7][CH2:8][C:9]1[CH:10]=[C:11]([CH:19]=[CH:20][CH:21]=1)[O:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: CCOC(=O)COc1cccc(CCCOS(C)(=O)=O)c1
Reactant: [I-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: CCOC(=O)COc1cccc(CCCI)c1
Reaction time: 18 h
Yield: 83.2 %

Procedure:
To a solution of ethyl (3-{3-[(methylsulfonyl)oxy]propyl}phenoxy)acetate (155 g) in acetone (1.55 L) was added sodium iodide (293.7 g) at ambient temperature and the mixture was stirred at the same temperature for 18 hours. EtOAc (1 L) was added to the mixture at ambient temperature and the resulting mixture was washed successively with water and brine. The organic layer was dried over anhydrous MgSO4, filtered and evaporated in vacuo to afford ethyl [3-(3-iodopropyl)phenoxy]acetate (142 g) as a red oil.
Reaction SMILES: [OH-].[Na+].[CH3:3][N:4]1[C:10]2[CH:11]=[CH:12][C:13]([C:15]([NH:17][C:18]3[CH:28]=[CH:27][C:21]([C:22]([O:24]CC)=[O:23])=[CH:20][CH:19]=3)=[O:16])=[CH:14][C:9]=2[C:8]([CH3:30])([CH3:29])[CH2:7][CH2:6][C:5]1=[O:31]>C(O)C.O1CCCC1>[CH3:3][N:4]1[C:10]2[CH:11]=[CH:12][C:13]([C:15]([NH:17][C:18]3[CH:19]=[CH:20][C:21]([C:22]([OH:24])=[O:23])=[CH:27][CH:28]=3)=[O:16])=[CH:14][C:9]=2[C:8]([CH3:29])([CH3:30])[CH2:7][CH2:6][C:5]1=[O:31]
Reactant: CCOC(=O)c1ccc(NC(=O)c2ccc3c(c2)C(C)(C)CCC(=O)N3C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CN1C(=O)CCC(C)(C)c2cc(C(=O)Nc3ccc(C(=O)O)cc3)ccc21
Temperature: 25 °C
Reaction time: 72 h
Yield: 87.2 %

Procedure:
1.69 ml of 3N sodium hydroxide solution were added to 1.00 g of ethyl p-(2,3,4,5-tetrahydro-1,5,5-trimethyl-2-oxo-1H-1-benzazepin-7-carboxamido)benzoate in 10 ml of ethanol/tetrahydrofuran (1:1). The reaction mixture was stirred at room temperature for 3 days and thereafter poured on to ice/conc. hydrochloric acid and extracted with ethyl acetate. The extract was washed with saturated sodium chloride solution, dried and evaporated. Recrystallization from ethyl acetate yielded 0.81 g of p-(2,3,4,5-tetrahydro-1,5,5-trimethyl-2-oxo-1H-1-benzazepine-7-carboxamido)benzoic acid, m.p. >275° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]([C:14]2[CH:19]=[C:18]([Cl:20])[CH:17]=[C:16]([Cl:21])[CH:15]=2)([OH:13])[C:9]([F:12])([F:11])[F:10])[CH:5]=[C:4]([Br:22])[C:3]=1[NH:23][C:24](=[O:34])[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([N+:31]([O-])=O)[CH:26]=1.[Sn](Cl)Cl.Cl>C(O)(C)C>[NH2:31][C:27]1[CH:26]=[C:25]([CH:30]=[CH:29][CH:28]=1)[C:24]([NH:23][C:3]1[C:4]([Br:22])=[CH:5][C:6]([C:8]([C:14]2[CH:19]=[C:18]([Cl:20])[CH:17]=[C:16]([Cl:21])[CH:15]=2)([OH:13])[C:9]([F:12])([F:10])[F:11])=[CH:7][C:2]=1[Br:1])=[O:34]
Reactant: O=C(Nc1c(Br)cc(C(O)(c2cc(Cl)cc(Cl)c2)C(F)(F)F)cc1Br)c1cccc([N+](=O)[O-])c1
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: CC(C)O
Product: Nc1cccc(C(=O)Nc2c(Br)cc(C(O)(c3cc(Cl)cc(Cl)c3)C(F)(F)F)cc2Br)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of N-{2,6-dibromo-4-[1-(3,5-dichloro-phenyl)-2,2,2-trifluoro-1-hydroxy-ethyl]-phenyl}-3-nitro-benzamide (Example I7) (0.206 g, 0.32 mmol) in isopropanol (15 ml) was added tin(II) chloride (0.218 g, 1.15 mmol). The mixture was cooled to 0° C. and aqueous hydrochloric acid (concentrated) (0.263 ml) was added slowly. The reaction mixture was stirred at 80° C. for 0.5 hours. ⅓ of the total volume of isopropanol was evaporated. Water (100 ml) was added to the concentrated mixture and aqueous sodium hydroxide (5N) was added to adjust the pH to 9. The aqueous phase was extracted three times with ethyl acetate (3×50 ml). The combined organic extracts were washed with water and brine, dried over sodium sulfate, and then concentrated. The residue was used without further purification. 1H-NMR (400 MHz, CDCl3): 8.22 (s, 1H), 7.72 (m, 3H), 7.47 (s, 2H), 7.12 (m, 3H), 6.77 (d, 1H), 5.35 (s, 2H) ppm.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:9]=[CH:8][O:7][C:6]=1[CH2:10][C:11](OC)=[O:12])=[O:4].[BH4-].[Na+].O>CO>[OH:12][CH2:11][CH2:10][C:6]1[O:7][CH:8]=[CH:9][C:5]=1[C:3]([O:2][CH3:1])=[O:4]
Reactant: COC(=O)Cc1occc1C(=O)OC
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC(=O)c1ccoc1CCO
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 1.287 g (6.494 mmol) of methyl 3-methoxycarbonylfuran-2-ylacetate in 50 ml of methanol, 1.23 g (32.5 mmol) of sodium borohydride was added at room temperature, followed by stirring at room temperature for 1 hour. The reaction mixture was poured into water and extracted with diethyl ether 3 times. The combined organic layer was dried over anhydrous magnesium sulfate; the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (hexane/ethyl acetate=3/1 to 1/1) to yield the desired product.
Reaction SMILES: C([O:3][C:4](=O)[CH:5]([C:11]1[N:12]=[C:13]([NH:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=2)[C:14]2[C:19]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:18][S:17][C:15]=2[N:16]=1)[C:6](OCC)=[O:7])C.[H-].C([Al+]CC(C)C)C(C)C>O1CCCC1>[C:20]1([C:19]2[C:14]3[C:13]([NH:26][CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=4)=[N:12][C:11]([CH:5]([CH2:6][OH:7])[CH2:4][OH:3])=[N:16][C:15]=3[S:17][CH:18]=2)[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CCOC(=O)C(C(=O)OCC)c1nc(NCc2ccccn2)c2c(-c3ccccc3)csc2n1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: C1CCOC1
Product: OCC(CO)c1nc(NCc2ccccn2)c2c(-c3ccccc3)csc2n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 30.3 %

Procedure:
A stirred solution of 2-{5-phenyl-4-[(pyridin-2-ylmethyl)amino]thieno[2,3-d]pyrimidin-2-yl}malonic acid diethyl ester (0.32 g, 0.672 mmol) in anhydrous tetrahydrofuran (10 ml) was cooled in an ice-bath and treated, under a nitrogen atmosphere, with diisobutylaluminium hydride (1M solution in hexane, 5.52 ml, 5.52 mmol) over 15 minutes. The reaction mixture was allowed to warm up and left to stir at ambient temperature for 3 hours. The resultant mixture was then cooled in an ice-bath and quenched by the slow addition of methanol (5 ml) followed by water (10 ml). The mixture was then diluted with 2M sodium hydroxide solution (50 ml) and extracted with ethyl acetate (3×50 ml). The combined organic extracts were dried (MgSO4) and the solvent removed in vacuo to give the crude product. Purification by flash chromatography (silica) eluting with 5% methanol in dichloromethane gave 2-{5-phenyl-4-[(pyridin-2-ylmethyl)amino]thieno[2,3-d]pyrimidin-2-yl}propane-1,3-diol as a pale yellow solid (0.08 g), m.p. 137°-139° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]=[CH:12][C:13]#[N:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[F:15][S:16]([C:19]1[CH:20]=[C:21]([S:25](Cl)(=[O:27])=[O:26])[CH:22]=[CH:23][CH:24]=1)(=[O:18])=[O:17].S(Cl)(Cl)(=O)=O.N12CCN(CC1)CC2>CC(C)=O>[F:15][S:16]([C:19]1[CH:20]=[C:21]([S:25]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([S:8]([CH:11]=[CH:12][C:13]#[N:14])(=[O:10])=[O:9])=[CH:6][CH:7]=2)(=[O:27])=[O:26])[CH:22]=[CH:23][CH:24]=1)(=[O:17])=[O:18]
Reactant: N#CC=CS(=O)(=O)c1ccc(N)cc1
Reactant: O=S(=O)(F)c1cccc(S(=O)(=O)Cl)c1
Agent: C1CN2CCN1CC2
Solvent: O=S(=O)(Cl)Cl
Solvent: CC(C)=O
Product: N#CC=CS(=O)(=O)c1ccc(NS(=O)(=O)c2cccc(S(=O)(=O)F)c2)cc1
Temperature: 25 °C

Procedure:
To an acetone solution of 10.4 g (0.05 mol) 2-cyanovinyl 4-aminophenyl sulfone is added 12.8 g (0.05 mol of 3-fluorosulfonylbenzenesulfonyl chloride at room temperature, with agitation. The sulfonyl chloride dissolves immediately, giving a clear yellow solution. To this mixture is added over a ten minute period an acetone solution of 1,4-diazabicyclo[2.2.2]-octane (11.2 g, 0.05 mol). A light yellow precipitate forms almost at once; the reaction mixture is maintained at about 25° C for 30 minutes with stirring. Precipitation in water and workup affords a bright yellow powder, 2-cyanovinyl 4-(3-fluorosulfonylbenzenesulfonamido)phenyl sulfone: ##SPC44##
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH2:12][N:13]([CH3:15])[CH3:14])=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[CH:6]2.CN(C=O)C.[C:21]([C:23]1[CH:24]=[C:25]([S:29](Cl)(=[O:31])=[O:30])[CH:26]=[CH:27][CH:28]=1)#[N:22]>>[CH3:15][N:13]([CH2:12][C:4]1[C:3]([O:2][CH3:1])=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[CH:7][N:8]2[S:29]([C:25]1[CH:24]=[C:23]([CH:28]=[CH:27][CH:26]=1)[C:21]#[N:22])(=[O:31])=[O:30])[CH3:14]
Reactant: COc1ccc2[nH]ccc2c1CN(C)C
Reactant: N#Cc1cccc(S(=O)(=O)Cl)c1
Solvent: CN(C)C=O
Product: COc1ccc2c(ccn2S(=O)(=O)c2cccc(C#N)c2)c1CN(C)C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 15.5 %

Procedure:
To a solution of 1-(5-methoxy-1H-indol-4-yl)-N,N-dimethylmethanamine (15 mg, 0.07 mmol; Intermediate 97) in DMF (1 mL) NaH (4 mg, 0.15 mmol) was added at rt. The reaction mixture was stirred at rt for 15 min and 3-cyanobenzenesulphonyl chloride (22 mg, 0.11 mmol) was added. The reaction mixture was allowed to stir at rt over night. The reaction was quenched by addition of water. Purification by preparative HPLC/UV (System B) afforded the title product (4 mg, 13%) as a white solid. MS (ESI+) for C19H19N3O3S m/z 370 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:12]2[CH:13]=[CH:14][C:15]([O:18]C)=[C:16]([I:17])[C:11]=2[O:10][N:9]=1.B(Br)(Br)Br.O>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:12]2[CH:13]=[CH:14][C:15]([OH:18])=[C:16]([I:17])[C:11]=2[O:10][N:9]=1
Reactant: COc1ccc2c(-c3ccccc3F)noc2c1I
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: Oc1ccc2c(-c3ccccc3F)noc2c1I

Procedure:
3-(2-fluorophenyl)-7-iodo-6-methoxy-1,2-benzisoxazole (8.2 g) is refluxed 18 hours in 130 ml of CH2Cl2 containing 6.6 ml of BBr3. The reaction mixture is poured into H2O and extracted into ether. Drying and evaporation gives a crystalline product that is triturated well with hexane to yield 3-(2-fluorophenyl)-6-hydroxy-7-iodo-1,2-benzisoxazole, mp 212°-214° C.
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][C:6]2[C:9]([C:20]3[O:24][N:23]=[C:22]([CH3:25])[N:21]=3)=[C:10]([NH:12]C(=O)OC(C)(C)C)[S:11][C:5]=2[CH2:4]1)[CH3:2].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([N:3]1[CH2:8][CH2:7][C:6]2[C:9]([C:20]3[O:24][N:23]=[C:22]([CH3:25])[N:21]=3)=[C:10]([NH2:12])[S:11][C:5]=2[CH2:4]1)[CH3:2]
Reactant: CCN1CCc2c(sc(NC(=O)OC(C)(C)C)c2-c2nc(C)no2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCN1CCc2c(sc(N)c2-c2nc(C)no2)C1
Temperature: 25 °C
Reaction time: 24 h
Yield: 59.9 %

Procedure:
To a solution of compound I2 (87.0 mg, 0.240 mmol) in anhydrous methylene chloride (3 mL) was added trifluoroacetic acid (3 mL) at 0° C. The reaction mixture was warmed to room temperature and stirred for 24 h. After this time, the reaction mixture was concentrated under reduced pressure. The resulting residue was dissolved in methylene chloride (50 mL), washed with saturated aqueous sodium bicarbonate (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography on silica gel eluting with methylene chloride to methanol/methylene chloride (1:19) to afford compound I3 as a yellow solid (38 mg, 60%): 1H NMR (500 MHz, CDCl3) δ 6.17 (bs, 2H), 3.48 (s, 2H), 2.99-2.96 (m, 2H), 2.82-2.79 (m, 2H), 2.62 (q, J=7.0 Hz, 2H), 2.39 (s, 3H), 1.18 (t, J=7.0 Hz, 3H). MS (M+H) 265.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[O:7][C:6]([C:8]2[CH:9]=[C:10]3[C:15](=[CH:16][CH:17]=2)[N:14]=[CH:13][NH:12][C:11]3=O)=[N:5][N:4]=1.P(Cl)(Cl)([Cl:23])=O>C(N(CC)CC)C>[Cl:23][C:11]1[C:10]2[C:15](=[CH:16][CH:17]=[C:8]([C:6]3[O:7][C:3]([C:2]([F:20])([F:19])[F:1])=[N:4][N:5]=3)[CH:9]=2)[N:14]=[CH:13][N:12]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]cnc2ccc(-c3nnc(C(F)(F)F)o3)cc12
Solvent: CCN(CC)CC
Product: FC(F)(F)c1nnc(-c2ccc3ncnc(Cl)c3c2)o1

Procedure:
6-(5-Trifluoromethyl-1,3,4-oxadiazol-2-yl)quinazolin-4-one (0.79 g) was treated with phosphorus oxychloride (18 ml) and triethylamine (8 ml) at reflux under N2 for 2 hours. The mixture was concentrated in vacuo and the residue azeotroped with toluene. This was then taken up in ethyl acetate and washed with 5% sodium bicarbonate and saturated brine, dried over magnesium sulphate and concentrated in vacuo to give the title compound (0.76 g) as an orange solid; δH CDCl3 9.17(1H,s), 9.05 (1H,d), 8.69(1H,dd), 8.30(1H,d).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([NH:10][C:11]2[CH:16]=[C:15]([C:17]([CH3:20])([CH3:19])[CH3:18])[C:14]([OH:21])=[C:13]([C:22]([CH3:25])([CH3:24])[CH3:23])[CH:12]=2)[CH:7]=[CH:8][CH:9]=1)(O)=[O:2].[H-].[H-].[H-].[H-].[Li+].[Al+3].O.[ClH:33]>C1COCC1.C(OCC)C.C(OCC)(=O)C>[ClH:33].[C:22]([C:13]1[CH:12]=[C:11]([NH:10][C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([CH2:1][OH:2])[CH:5]=2)[CH:16]=[C:15]([C:17]([CH3:20])([CH3:19])[CH3:18])[C:14]=1[OH:21])([CH3:25])([CH3:24])[CH3:23]
Reactant: CC(C)(C)c1cc(Nc2cccc(C(=O)O)c2)cc(C(C)(C)C)c1O
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)c1cc(Nc2cccc(CO)c2)cc(C(C)(C)C)c1O

Procedure:
A 1.8 g quantity of the 4-(3-carboxyphenylamino)-2,6-di-tert-butylphenol prepared in Example 24 was dissolved in 30 ml of THF, and the solution was added dropwise at room temperature to a suspension of 1.7 g of LiAlH4 in 150 ml of ethyl ether with stirring. Then the resulting mixture was refluxed for 3.5 hours. After cooling, water-containing ethyl ether and then water were carefully added to the reaction mixture to decompose the excess LiAlH4. Subsequently the organic layer was separated, dried over MgSO4 and concentrated to give a crude product. The crude product was dissolved in 100 ml of ethyl ether, and 6 ml of 4N hydrogen chloride in ethyl acetate was added to the solution. The crystals thus precipitated were filtered, washed with ethyl ether and air-dried, giving 1.5 g of the title compound (Compound 31).
Reaction SMILES: [C:1]([C:5]1[CH:15]=[CH:14][C:8](/[CH:9]=[CH:10]/[C:11]([OH:13])=O)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(Cl)Cl.Cl.CN(C)CCCN=C=NCC.[NH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>CCOC(C)=O>[C:1]([C:5]1[CH:6]=[CH:7][C:8](/[CH:9]=[CH:10]/[C:11]([NH:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[O:13])=[CH:14][CH:15]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: Nc1ccccc1
Reactant: CC(C)(C)c1ccc(/C=C/C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)c1ccc(/C=C/C(=O)Nc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a 10 mL glass vial was added 4-tert-butyl-trans-cinnamic acid (200 mg, 0.98 mmol, EMKA-Chemie) followed by CH2Cl2 (5 mL), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (225 mg, 1.17 mmol, Bachem) and aniline (98 uL, 100 mg, 1.08 mmol, Aldrich). The reaction mixture was magnetically stirred at 25° C. for 24 h. EtOAc was added (60 mL) and the mixture washed successively with 1 N NaOH (2×20 mL), 1 N HCl (20 mL), water (20 mL) and satd NaCl (20 mL), dried over MgSO4, filtered and concentrated. Recrystallization from hexane and CH2Cl2 provided the title product as white crystals. MP 141° C. MS (ESI, pos. ion) m/z: 280 (M+1).
Reaction SMILES: [H-].[Li+].[Al+3].[H-].[H-].[H-].[CH3:7][C:8]1[N:9]=[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]2[C:16]=1[C:17](OCC)=[O:18].[OH-].[Na+].S([O-])([O-])(=O)=O.[Mg+2]>C1COCC1.O>[CH3:7][C:8]1[N:9]=[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]2[C:16]=1[CH2:17][OH:18]
Reactant: CCOC(=O)c1c(C)nc2ccccn12
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1nc2ccccn2c1CO
Temperature: 0 °C
Reaction time: 1 h
Yield: 94.9 %

Procedure:
Under nitrogen atmosphere, to a suspension of aluminum lithium hydride (1.6 g) in THF (100 ml) was added dropwise a solution of ethyl 2-methylimidazo[1,2-a]pyridine-3-carboxylate (8.56 g) in THF (100 ml) at 0° C. under nitrogen atmosphere. The mixture was stirred for 1 hour at 0° C., water (1.6 ml), 15% aqueous solution of sodium hydroxide (1.6 ml) and water (4.8 ml) were sequentially and slowly added dropwise to the solution, and the mixture was stirred for 2 hours at room temperature. To the reaction solution was added magnesium sulfate, and the precipitates were removed by filtration. The mixture was concentrated under reduced pressure, to give 2-methylimidazo[1,2-a]pyridine-3-methanol (6.45 g) as pale yellow amorphous. A mixture of 2-methylimidazo[1,2-a]pyridine-3-methanol (1 g) and 4-aminothiophenol (0.65 g) in concentrated hydrochloric acid (10 ml) was stirred for 18 hours at room temperature. 8N aqueous solution of sodium hydroxide was added to adjust pH to 10 at 0° C. and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was separated and purified by column chromatography (ethanol:ethyl acetate 1:4), to give 3-(4-aminophenylthiomethyl)-2-methylimidazo[1,2-a]pyridine (311 mg) as colorless crystals.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][C@H:2]1[C@@H:6]1[O:14][CH2:13][C:9]2=[N:10][O:11][CH2:12][C@@H:8]2[CH2:7]1.[F:15][C:16]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=1C12COC([C@@H]3C[C@H]3C)CC1CON2>>[F:15][C:16]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=1[C@:9]12[CH2:13][O:14][C@@H:6]([C@@H:2]3[CH2:3][CH2:4][CH2:5][O:1]3)[CH2:7][C@H:8]1[CH2:12][O:11][NH:10]2
Reactant: C1CO[C@H]([C@H]2C[C@H]3CON=C3CO2)C1
Reactant: C[C@@H]1C[C@H]1C1CC2CONC2(c2ccc(F)cc2F)CO1
Product: Fc1ccc([C@]23CO[C@@H]([C@@H]4CCCO4)C[C@H]2CON3)c(F)c1

Procedure:
(3aR,5R)-5-[(2S)-Tetrahydrofuran-2-yl]-3,3a,4,5-tetrahydro-7H-pyrano[3,4-c][1,2]oxazole (C99) was converted to the product using the method described for the synthesis of 7a-(2,4-difluorophenyl)-5-[(1R,2R)-2-methylcyclopropyl]hexahydro-1H-pyrano[3,4-c][1,2]oxazole (C86) in Example 20. Yield: 1.4 g, 4.5 mmol, 36%. LCMS m/z 312.1 [M+H+]. 1H NMR (400 MHz, CDCl3) δ 7.89-7.95 (m, 1H), 6.87-6.91 (m, 1H), 6.77-6.83 (m, 1H), 6.29 (s, 1H), 4.10 (dd, J=12.5, 1.5 Hz, 1H), 3.72-3.92 (m, 5H), 3.53-3.57 (m, 2H), 3.07 (dt, J=11.4, 5.6 Hz, 1H), 1.79-2.03 (m, 5H), 1.46-1.55 (m, 1H).
Reaction SMILES: [I:1][C:2]1[CH:11]=[C:10]([CH3:12])[CH:9]=[C:8]2[C:3]=1[C:4](=[O:18])[CH:5]=[C:6]([C:13]([O:15]CC)=[O:14])[NH:7]2.IC1C=C2C(C(=O)C=C(C(OCC)=O)N2)=C(C)C=1.[OH-].[Na+]>>[I:1][C:2]1[CH:11]=[C:10]([CH3:12])[CH:9]=[C:8]2[C:3]=1[C:4](=[O:18])[CH:5]=[C:6]([C:13]([OH:15])=[O:14])[NH:7]2
Reactant: CCOC(=O)c1cc(=O)c2c(I)cc(C)cc2[nH]1
Agent: CCOC(=O)c1cc(=O)c2c(C)cc(I)cc2[nH]1
Agent: [Na+]
Agent: [OH-]
Product: Cc1cc(I)c2c(=O)cc(C(=O)O)[nH]c2c1

Procedure:
Treatment of a mixture of ethyl 5-iodo-7-methyl-4-oxo-1,4-dihydroquinoline-2-carboxylate and ethyl 7-iodo-5-methyl-4-oxo-1,4-dihydroquinoline-2-carboxylate (0.449 g) with sodium hydroxide (0.20 g) as described in Example 1c gave a mixture of the corresponding carboxylic acids. Chromatography of this mixture (0.220 g) on a reverse phase carbon-18 column gave 5-iodo-7-methyl-4-oxo-1,4-dihydroquinoline-2-carboxylic acid (12 mg), mp 306° C. δ (360 MHz, DMSO-d6) 2.33 (3H, s, CH3), 6.55 (1H, s, 3-H) and 7.75 (2H, bs, 6-H and 8-H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2([C:13]([NH2:15])=[O:14])[CH2:12][CH2:11][CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.Cl.[CH3:17][C:18]1[N:19]([C:23]2[CH:30]=[CH:29][C:26]([CH2:27]Cl)=[CH:25][CH:24]=2)[CH:20]=[CH:21][N:22]=1>>[CH3:17][C:18]1[N:19]([C:23]2[CH:30]=[CH:29][C:26]([CH2:27][O:1][C:2]3[CH:3]=[C:4]([C:8]4([C:13]([NH2:15])=[O:14])[CH2:12][CH2:11][CH2:10][CH2:9]4)[CH:5]=[CH:6][CH:7]=3)=[CH:25][CH:24]=2)[CH:20]=[CH:21][N:22]=1
Reactant: NC(=O)C1(c2cccc(O)c2)CCCC1
Reactant: Cc1nccn1-c1ccc(CCl)cc1
Agent: Cl
Product: Cc1nccn1-c1ccc(COc2cccc(C3(C(N)=O)CCCC3)c2)cc1

Procedure:
1-(3-Hydroxyphenyl)cyclopentane-1-carboxamide was reacted with 4-(2-methyl-imidazol-1-yl)benzyl chloride hydrochloride according to the procedure described in Example 2H to give the titled compound.