Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]([C@H:8]1[CH2:13][CH2:12][C@H:11]([C:14]([O:16][CH3:17])=[O:15])[CH2:10][CH2:9]1)=[O:7].[BH4-].[Na+]>CO.C(OCC)(=O)C.O>[OH:7][CH:6]([C:2]1[S:1][CH:5]=[CH:4][N:3]=1)[C@H:8]1[CH2:13][CH2:12][C@H:11]([C:14]([O:16][CH3:17])=[O:15])[CH2:10][CH2:9]1
Reactant: COC(=O)[C@H]1CC[C@H](C(=O)c2nccs2)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CO
Product: COC(=O)[C@H]1CC[C@H](C(O)c2nccs2)CC1
Reaction time: 1 h

Procedure:
To a solution of methyl trans-4-(1,3-thiazol-2-ylcarbonyl)cyclohexanecarboxylate (500 mg, 1.97 mmol) in methanol (20 mL) was added sodium borohydride (224 mg, 5.92 mmol) and the solution was stirred for one hour. The solution was then diluted with ethyl acetate and water. The organic layer was separated, dried over magnesium sulfate, filtered and concentrated in vacuo. The crude product was purified by silica gel chromatography to afford methyl trans-4-[hydroxy(1,3-thiazol-2-yl)methyl]cyclohexanecarboxylate. MS ESI calc'd. for C12H18NO3S [M+H]+ 256. found 256. 1H NMR (500 MHz, DMSO-d6) δ 7.70 (d, J=3.2 Hz, 1H), 7.58 (d, J=3.2 Hz, 1H), 6.10 (d, J=5.2 Hz, 1H), 4.59 (t, J=5.1 Hz, 1H), 3.54 (s, 3H), 2.21-2.11 (m, 1H), 1.92-1.83 (m, 2H), 1.75-1.64 (m, 1H), 1.64-1.53 (m, 2H), 1.33-1.11 (m, 4H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11](=[O:17])[NH:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[C:5]2[CH2:18][C:19]([O:21]C)=[O:20].[Li+].[OH-].CCOC(C)=O>C1COCC1.O>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11](=[O:17])[NH:12][C:13]([CH3:14])([CH3:15])[CH3:16])=[C:5]2[CH2:18][C:19]([OH:21])=[O:20]
Reactant: COC(=O)Cc1c(C(=O)NC(C)(C)C)[nH]c2ccc(Br)cc12
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)NC(=O)c1[nH]c2ccc(Br)cc2c1CC(=O)O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Step I (2): To a solution of methyl 2-(5-bromo-2-(tert-butylcarbamoyl)-1H-indol-3-yl)acetate (80 mg, 0.22 mmol) in THF (2.0 mL) was added a solution of LiOH (16 mg, 0.66 mmol) in water (0.5 mL). The mixture was stirred at rt for 3 h. 100 mL of EtOAc was added, and the resulting solution was washed with 0.1 N HCl and water. The organic layer was dried over Na2SO4, and the solvents was removed to give the title compound 2-(5-bromo-2-(tert-butylcarbamoyl)-1H-indol-3-yl)acetic acid which was used without further purification. MS (ESI) (M+H)+=355.03.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:13][C:12](=O)[C:11]([C:15]#[N:16])=[CH:10][C:9]=2[C:17]2[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][CH:18]=2)=[CH:4][CH:3]=1.CC1C=CC(C)=CC=1C.[K+].[Br-:37]>O>[Br:37][C:12]1[C:11]([C:15]#[N:16])=[CH:10][C:9]([C:17]2[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][CH:18]=2)=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[N:13]=1
Reactant: [Br-]
Reactant: CS(=O)(=O)c1ccc(-c2cc(C#N)c(=O)[nH]c2-c2ccc(F)cc2)cc1
Agent: Cc1ccc(C)c(C)c1
Agent: [K+]
Solvent: O
Product: CS(=O)(=O)c1ccc(-c2cc(C#N)c(Br)nc2-c2ccc(F)cc2)cc1
Temperature: 80 °C
Yield: 70.5 %

Procedure:
A mixture of 1,2-dihydro-6-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-2-oxo-pyridine-3-carbonitrile (Example 2, Step 3) (0.66 g, 1.81 mMol), 12 ml of 1,2,4-trimethylbenzene, 1.0 g of KBr, and 5 g of PBr5 was heated to 80° C. for 2 hours and then to 180° C. overnight. The reaction mixture was cooled to room temperature and stirred with 75 ml of water for 1 hour. The organic portion was extracted into dichloromethane. The dichloromethane extract was washed once with brine, dried over MgSO4, and evaporated to dryness. The residual oil was purified by HPLC to give 0.55 g (72% yield) of solid: m.p. 229.5°-231.5° C.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([CH3:13])[N:5]=[CH:4][N:3]=1.[Cl:14][C:15]1[CH:21]=[C:20]([O:22][CH3:23])[C:19]([O:24][CH2:25][C:26]2[C:31]([O:32][CH3:33])=[CH:30][CH:29]=[C:28]([F:34])[C:27]=2[F:35])=[CH:18][C:16]=1[NH2:17].C(N(CC)C(C)C)(C)C.O>C(#N)C>[Cl:14][C:15]1[CH:21]=[C:20]([O:22][CH3:23])[C:19]([O:24][CH2:25][C:26]2[C:31]([O:32][CH3:33])=[CH:30][CH:29]=[C:28]([F:34])[C:27]=2[F:35])=[CH:18][C:16]=1[NH:17][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([CH3:13])[N:5]=[CH:4][N:3]=1
Reactant: COc1cc(Cl)c(N)cc1OCc1c(OC)ccc(F)c1F
Reactant: CCOC(=O)c1c(C)ncnc1Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CCOC(=O)c1c(C)ncnc1Nc1cc(OCc2c(OC)ccc(F)c2F)c(OC)cc1Cl
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 96.7 %

Procedure:
A solution of ethyl 4-chloro-6-methylpyrimidine-5-carboxylate (0.3 g), 2-chloro-5-(2,3-difluoro-6-methoxybenzyloxy)-4-methoxyaniline (0.49 g) and N,N-diisopropylethylamine (0.26 mL) in acetonitrile (4.5 mL) was stirred at 130° C. in a reaction vessel equipped with a reflux condenser for 1 day. To the reaction mixture was added water (3 mL), and the resulting mixture was stirred at room temperature for 40 minutes. The insoluble material was collected by filtration. The collected material was washed with water and diethyl ether, and dried under reduced pressure to give ethyl 4-[2-chloro-5-(2,3-difluoro-6-methoxybenzyloxy)-4-methoxyphenylamino]-6-methylpyrimidine-5-carboxylate (0.71 g). The obtained ethyl 4-[2-chloro-5-(2,3-difluoro-6-methoxybenzyloxy)-4-methoxyphenylamino]-6-methylpyrimidine-5-carboxylate (0.2 g) was dissolved in tetrahydrofuran (1.6 mL)−methanol (1.2 mL). To the solution was added 2 mol/L aqueous sodium hydroxide solution (1.2 mL), and the mixture was stirred at 60° C. for 30 minutes. To the reaction mixture was added 1 mol/L hydrochloric acid (3 mL), and the precipitated crystals were collected by filtration. The collected crystals were washed with water, and dried under reduced pressure to give 4-[2-chloro-5-(2,3-difluoro-6-methoxybenzyloxy)-4-methoxyphenylamino]-6-methylpyrimidine-5-carboxylic acid (0.1 g). To this material were added 1,4-dioxane (4.5 mL), triethylamine (0.12 mL) and diphenylphosphoryl azide (0.071 mL), and the mixture was stirred at room temperature for 1 hour, and then heated at reflux for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: ethyl acetate−ethyl acetate/methanol=9/1) to give the title compound (0.1 g).
Reaction SMILES: [CH3:1][N:2]([CH3:16])[C:3]([NH:5][C:6]1[S:10][N:9]=[C:8]([S:11][CH2:12][CH3:13])[C:7]=1[C:14]#[N:15])=[O:4].S(=O)(=O)(O)[OH:18]>>[CH3:16][N:2]([CH3:1])[C:3]([NH:5][C:6]1[S:10][N:9]=[C:8]([S:11][CH2:12][CH3:13])[C:7]=1[C:14](=[O:18])[NH2:15])=[O:4]
Reactant: CCSc1nsc(NC(=O)N(C)C)c1C#N
Reactant: O=S(=O)(O)O
Product: CCSc1nsc(NC(=O)N(C)C)c1C(N)=O

Procedure:
A mixture of 4.0 g of 1,1-dimethyl-3-(4-cyano-3-(ethylthio)-5-isothiazolyl)urea in 6 ml of concentrated sulfuric acid was heated at 100° during one hour. The reaction mixture was treated as described in Example XIII to give, after recrystallization from ethanol, 2.8 g of 1,1-dimethyl-3-(4-carbamoyl-3-(ethylthio)-5-isothiazolyl)urea, m.p. 147°. The nmr spectrum was consistent with the assigned structure.
Reaction SMILES: O1CCCCC1[O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][O:15][CH2:16][C@H:17]1[C@H:22]([OH:23])[CH2:21][CH2:20][CH2:19][O:18]1.[H-].[Na+].[CH2:26](Br)[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41].O>CN(C)C=O>[CH2:41]([O:23][C@@H:22]1[CH2:21][CH2:20][CH2:19][O:18][C@H:17]1[CH2:16][O:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][OH:7])[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH3:26]
Reactant: O[C@@H]1CCCO[C@H]1COCCCCCCCOC1CCCCO1
Reactant: CCCCCCCCCCCCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCCCO[C@@H]1CCCO[C@H]1COCCCCCCCO
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 1.652 g of dl-trans-2-[7-(tetrahydropyran-2-yloxy)heptyloxymethyl]tetrahydropyran-3-ol (prepared as described in Preparation 54) in 5 ml of dimethylformamide was added dropwise at room temperature to a suspension of 0.24 g of sodium hydride (as a 55% w/w dispersion in mineral oil) in 5 ml of dimethylformamide. The reaction mixture was stirred at room temperature for 30 minutes, after which it was heated on an oil bath kept at 60° C. for a further 30 minutes. At the end of this time, 1.83 g of hexadecyl bromide were added at room temperature, after which the mixture was heated on an oil bath kept at 60° C. for 30 minutes, whilst stirring. The mixture was then cooled, and 0.24 g of sodium hydride (as a 55% w/w dispersion in mineral oil) was added to it at room temperature. The mixture was then heated on an oil bath kept at 60° C. for 30 minutes. The reaction mixture was allowed to cool to room temperature and a further 1.83 g of hexadecyl bromide was added to it. The reaction mixture was then heated on an oil bath kept at 60° C. for 30 minutes, whilst stirring, after which it was cooled and poured into water and then extracted three times with methylene chloride. The combined extracts were dried over anhydrous magnesium sulfate and concentrated by evaporation under reduced pressure. 40 ml of methanol and 0.5 ml of concentrated hydrochloric acid were added to a solution of the oil residue (5.74 g) dissolved in 15 ml of tetrahydrofuran, and the mixture was stirred at room temperature for 30 minutes. The solvent was then removed by distillation under reduced pressure, and the residue was diluted with water and then extracted twice with diethyl ether. The combined extracts were washed with a saturated aqueous solution of sodium bicarbonate and with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and concentrated by evaporation under reduced pressure. The oily residue (5.14 g) was subjected to column chromatography through 90 g of silica gel. 2.123 g of the title compound were obtained, as a viscous oil, from those fractions eluted with a 2:1 by volume mixture of hexane and ethyl acetate.
Reaction SMILES: [CH:1]12[NH:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][CH:3]([C:9]1[N:13]=[C:12]([NH:14][C:15]3[C:20]([O:21][C:22]4[C:23]([CH3:28])=[N:24][CH:25]=[CH:26][CH:27]=4)=[CH:19][C:18]([S:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=4)=[CH:17][N:16]=3)[S:11][N:10]=1)[CH2:2]2.C(N(CC)CC)C.[C:43]([O:46][CH2:47][C:48](Cl)=[O:49])(=[O:45])[CH3:44]>C(Cl)Cl>[C:43]([O:46][CH2:47][C:48]([N:8]1[CH:5]2[CH2:6][CH2:7][CH:1]1[CH2:2][CH:3]([C:9]1[N:13]=[C:12]([NH:14][C:15]3[C:20]([O:21][C:22]4[C:23]([CH3:28])=[N:24][CH:25]=[CH:26][CH:27]=4)=[CH:19][C:18]([S:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=4)=[CH:17][N:16]=3)[S:11][N:10]=1)[CH2:4]2)=[O:49])(=[O:45])[CH3:44]
Reactant: Cc1ncccc1Oc1cc(Sc2ccccn2)cnc1Nc1nc(C2CC3CCC(C2)N3)ns1
Reactant: CC(=O)OCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)OCC(=O)N1C2CCC1CC(c1nsc(Nc3ncc(Sc4ccccn4)cc3Oc3cccnc3C)n1)C2
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 100 %

Procedure:
3-(8-Azabicyclo[3.2.1]octan-3-yl)-N-(3-(2-methylpyridin-3-yloxy)-5-(pyridin-2-ylthio)pyridin-2-yl)-1,2,4-thiadiazol-5-amine (80 mg, 0.159 mmol; prepared in Example 174, step C) was dissolved in CH2Cl2, and triethylamine (88.6 μL, 0.635 mmol) and 2-chloro-2-oxoethyl acetate (25.6 μL, 0.238 mmol) were added. The reaction was stirred at ambient temperature for 5 minutes. The reaction was partitioned between CH2Cl2 and saturated aqueous NaHCO3, dried over sodium sulfate, filtered and concentrated to afford 2-(3-(5-(3-(2-methylpyridin-3-yloxy)-5-(pyridin-2-ylthio)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)-8-azabicyclo[3.2.1]octan-8-yl)-2-oxoethyl acetate (95.9 mg, 0.159 mmol, 100% yield) as a crude foam.
Reaction SMILES: C1(C[N:8]2[CH2:12][CH2:11][C@H:10]([NH:13][CH2:14][CH2:15][C:16]#[N:17])[CH2:9]2)C=CC=CC=1.C1CC=CCC=1>[OH-].[OH-].[Pd+2].C(O)C>[NH:8]1[CH2:12][CH2:11][C@H:10]([NH:13][CH2:14][CH2:15][C:16]#[N:17])[CH2:9]1
Reactant: N#CCCN[C@H]1CCN(Cc2ccccc2)C1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Solvent: C1=CCC=CC1
Product: N#CCCN[C@H]1CCNC1
Temperature: 100 °C
Yield: 83.5 %

Procedure:
3-[[(3S)-1-(Phenylmethyl)-3-pyrrolidinyl]amino]-propanenitrile (as described in WO2000075137) (0.6 g), 20% palladium hydroxide on carbon (0.15 g), 1,4 cyclohexadiene (3 mL) and ethanol (2 mL) were loaded into a 10 mL microwave vial, capped and heated at 100° C. for 90 minutes within a single mode microwave. The reaction mixture was filtered and the volatiles removed under vacuum to afford the sub-title compound (0.304 g).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[C:10](=[O:18])[NH:11][C:12]([CH3:17])=[CH:13][C:14]=1[CH2:15][CH3:16])(C)(C)C.[ClH:20]>O1CCOCC1>[ClH:20].[NH2:7][CH2:8][C:9]1[C:10](=[O:18])[NH:11][C:12]([CH3:17])=[CH:13][C:14]=1[CH2:15][CH3:16]
Reactant: CCc1cc(C)[nH]c(=O)c1CNC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CCc1cc(C)[nH]c(=O)c1CN
Reaction time: 2 h
Yield: 77.9 %

Procedure:
Tert-butyl((4-ethyl-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)carbamate (1.00 g, 3.75 mmol) was dissolved in a solution of hydrogen chloride in 1,4-dioxane (20 mL). The mixture was stirred for 2 hr. The reaction mixture was filtered. The residue was washed with dichloromethane, dried to afford 3-(aminomethyl)-4-ethyl-6-methylpyridin-2(1H)-one hydrochloride (593 mg, 77.9%) as a light yellow solid. LRMS (M+H+) m/z: calcd 166.11. found 167.1. 1H NMR (400 MHz, D2O): δ ppm 6.31 (s, 1 H), 4.06 (s, 2 H), 2.57 (q, J=7.86 Hz, 2 H), 2.25 (s, 3 H), 1.10 (t, J=7.53 Hz, 3 H).
Reaction SMILES: [I-].[CH3:2][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[K+].[Cl:28][C:29]1[C:30]([F:43])=[C:31]([C:37](=O)[C:38]([F:41])([F:40])[F:39])[CH:32]=[C:33]([Cl:36])[C:34]=1[F:35]>O1CCCC1.CCCCC.O>[Cl:36][C:33]1[CH:32]=[C:31]([C:37]([C:38]([F:41])([F:40])[F:39])=[CH2:2])[C:30]([F:43])=[C:29]([Cl:28])[C:34]=1[F:35]
Reactant: O=C(c1cc(Cl)c(F)c(Cl)c1F)C(F)(F)F
Reactant: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCCCC
Product: C=C(c1cc(Cl)c(F)c(Cl)c1F)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70.1 %

Procedure:
To the suspension of methyl triphenylphosphonium iodide (1.92 g) in tetrahydrofuran (12 ml) was added potassium tert-butoxide (0.53 g) slowly at argon atomosphere below 0° C. on ice/water bath. The reaction mixture turned to yellow and stirred for 0.5 h. To the mixture was added a solution of 1-(3,5-dichloro-2,4-difluorophenyl)-2,2,2-trifluoroethanone (1.15 g) in tetrahydrofuran (3 ml) dropwise on ice/water bath. After addition, the reaction mixture was warmed to room temperature and stirred over night. The reaction mixture was diluted with pentane and water. The organic phase was separated and washed with water and dried over MgSO4. The crude residue was purified on silica-gel column chromatography (eluent: n-hexane) to give 1,3-dichloro-2,4-difluoro-5-(3,3,3-trifluoroprop-1-en-2-yl)benzene (0.80 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][CH2:11][CH:10]([O:13][C:14]3[C:15](Br)=[N:16][CH:17]=[CH:18][CH:19]=3)[C:9]2=[O:21])=[CH:4][CH:3]=1.[CH3:22][N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1.[I-].[Na+].O1CCOCC1>C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][CH2:11][CH:10]([O:13][C:14]3[C:15]([N:26]4[CH2:27][CH2:28][N:23]([CH3:22])[CH2:24][CH2:25]4)=[N:16][CH:17]=[CH:18][CH:19]=3)[C:9]2=[O:21])=[CH:4][CH:3]=1
Reactant: O=C1C(Oc2cccnc2Br)CCN1c1ccc(Br)cc1
Reactant: CN1CCNCC1
Agent: [I-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CN1CCN(c2ncccc2OC2CCN(c3ccc(Br)cc3)C2=O)CC1
Yield: 35 %

Procedure:
To a 100 mL round-bottomed flask equipped with condenser and N2 inlet were added 1.15 g (2.79 mmol) of 1-(4-bromo-phenyl)-3-(2-bromo-pyridin-3-yloxy)-pyrrolidin-2-one, 1.6 mL (13.96 mmol) 1-methylpiperazine, 0.418 g (2.79 mmol) sodium iodide, and 20 mL dioxane. The reaction was refluxed 5 days, cooled, taken up in ethyl acetate, washed with water, dried over sodium sulfate, and evaporated. The residue was chromatographed on silica gel using methanol/ethyl acetate to afford the desired product in 35% yield as a foam, which was converted to the hydrochloride salt, mp 72–82° C.
Reaction SMILES: [CH3:1][C:2]1[Se:6][C:5]([C:7]([O:9][CH3:10])=[O:8])=[CH:4][CH:3]=1.[N+:11]([O-])([OH:13])=[O:12]>C(OC(=O)C)(=O)C>[CH3:1][C:2]1[Se:6][C:5]([C:7]([O:9][CH3:10])=[O:8])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: O=[N+]([O-])O
Reactant: COC(=O)c1ccc(C)[se]1
Solvent: CC(=O)OC(C)=O
Product: COC(=O)c1cc([N+](=O)[O-])c(C)[se]1
Temperature: 25 °C
Reaction time: 16 h
Yield: 34.9 %

Procedure:
To an ice cold (0-10° C.) solution of methyl 5-methylselenophene-2-carboxylate (5.4 g, 26.6 mmol) in acetic anhydride (15 mL) was added an ice cold mixture of nitric acid (5.5 mL, 61.1 mmol, 70%) and acetic anhydride (10 mL) for 10 min. The reaction mixture was slowly allowed to room temperature (rt) for 1 h and stirred at rt for 16 h. The mixture was poured into ice cold water and stirred for 10 min. The solution was extracted with chloroform (3×100 mL) and the combined organic layer was washed with water, brine and dried over sodium sulfate. The solution was filtered and evaporated the solvent. The residue was chromatographed over silica gel column using hexane-ethyl acetate (90:10) as eluents to give the product as an pale yellow color solid (2.3 g, 35%), mp 90-92° C. 1H NMR (400 MHz, CDCl3): δ 8.54 (1H, s, H-3), 3.90 (3H, s, —COOCH3), 2.90 (3H, s, —CH3).
Reaction SMILES: [H][H].[CH3:3][N:4]([CH2:6][CH2:7][CH:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[OH:9])[CH3:5].F[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH3:23].CN1CCCC1=O>CN1CCN(C)C1=O>[CH3:3][N:4]([CH2:6][CH2:7][CH:8]([O:9][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH3:23])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH3:5]
Reactant: Cc1ccccc1F
Reactant: CN(C)CCC(O)c1ccccc1
Reactant: [H][H]
Solvent: CN1CCCC1=O
Solvent: CN1CCN(C)C1=O
Product: Cc1ccccc1OC(CCN(C)C)c1ccccc1

Procedure:
In Reaction Scheme B, step a, a nucleophilic aromatic displacement, the alkoxide of an alcohol of formula (1) in which G is methyl or hydrogen, N,N-dimethyl-3-phenyl-3-hydroxypropylamine where G is methyl or N-methyl-3-phenyl-3-hydroxypropylamine where G is hydrogen, is contacted with a 2-fluorotoluene (the compound of formula (2)) in 1,3-dimethyl-2-imidazolidinone or N-methylpyrrolidinone to give the compound of formula (3), N,N-dimethyl-3-(2-methylphenoxy)-3-phenylpropylamine, or the compound of formula (4), N-methyl-3-(2-methylphenoxy)-3-phenylpropylamine; respectively.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:4]=C([CH:8]=[CH:9][C:10]=1[N:11]([CH2:15][CH2:16][OH:17])[CH2:12][CH2:13][OH:14])C#N.[OH-:20].[Na+].[CH2:22]([OH:24])[CH3:23]>>[F:1][C:2]([F:19])([F:18])[C:3]1[CH:4]=[C:23]([CH:8]=[CH:9][C:10]=1[N:11]([CH2:15][CH2:16][OH:17])[CH2:12][CH2:13][OH:14])[C:22]([OH:20])=[O:24]
Reactant: N#Cc1ccc(N(CCO)CCO)c(C(F)(F)F)c1
Reactant: [OH-]
Reactant: CCO
Agent: [Na+]
Product: O=C(O)c1ccc(N(CCO)CCO)c(C(F)(F)F)c1

Procedure:
A solution of the 3-trifluoromethyl-4-[bis(2-hydroxyethyl) amino]benzonitrile and NaOH (0.8 g, 0.02 mol) in aqueous ethanol (10 ml, 50%) was refluxed for 2 hours. The solution was partitioned between EtOAc (120 ml) and HCl (50 ml, 0.4 M), the aqueous layer washed with EtOAc (3×25 ml), the combined organic layers dried (MgSO4) and evaporated to dryness. The residue was recrystallized from EtOAc to give 0.39 g of white crystals.
Reaction SMILES: C([O:3][C:4]([C:6]1[S:10][C:9](/[CH:11]=[CH:12]\[S:13][C:14]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:8][CH:7]=1)=O)C.[H-].C([Al+]CC(C)C)C(C)C.C1(C)C=CC=CC=1.O.Cl>C1COCC1>[OH:3][CH2:4][C:6]1[S:10][C:9](/[CH:11]=[CH:12]\[S:13][C:14]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[N:8][CH:7]=1
Reactant: CCOC(=O)c1cnc(/C=C\SC(c2ccccc2)(c2ccccc2)c2ccccc2)s1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Solvent: Cc1ccccc1
Product: OCc1cnc(/C=C\SC(c2ccccc2)(c2ccccc2)c2ccccc2)s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100.3 %

Procedure:
A solution of 257 mg of 5-ethoxycarbonyl-2-((Z)-2-tritylthioethen-1-yl)thiazole in 10 ml of THF was cooled in ice, and 1.69 ml of a 1.0 M diisobutylaluminum hydride/toluene solution was added dropwise to the cooled solution under an argon atmosphere. The mixture was stirred at room temperature for 2 hr. Water was added to the reaction solution, and the mixture was adjusted to pH 2.5 by the addition of 1 N aqueous hydrochloric acid. The insolubles were removed by filtration through Celite, and the filtrate was extracted twice with ethyl acetate. The organic layers were combined, were washed with brine, were dried over anhydrous magnesium sulfate, were filtered, and were concentrated under the reduced pressure to give 234 mg of the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][N:8]=[CH:7]2)([O-:3])=[O:2].[I:13]C1CC(=O)NC1=O.O.C(OCC)C>CN(C)C=O>[I:13][C:7]1[C:6]2[C:10](=[CH:11][CH:12]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[NH:9][N:8]=1
Reactant: O=C1CC(I)C(=O)N1
Reactant: O=[N+]([O-])c1ccc2[nH]ncc2c1
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccc2[nH]nc(I)c2c1

Procedure:
To a solution of 17.0 g of 5-nitroindazole in 100 ml dimethylformamide was added 24.6 g of N-.iodosuccinimide at room temperature, and the mixture was stirred at 80° C. for 7 hours. After standing to cool, to the reaction mixture were added 150 ml of water and 200 ml of diethyl ether, and the resulting crystals were collected by filtration. The crystals were sequentially washed with water, isopropanol and diethyl ether, to give 27.5 g of the title compound as colorless crystals.
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]3[CH:15]=[C:14]([C:16]([O:18]C)=[O:17])[CH:13]=[CH:12][C:10]=3[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li+].[OH-].O.Cl>C1COCC1.CO>[C:1]1([C:7]2[O:8][C:9]3[CH:15]=[C:14]([C:16]([OH:18])=[O:17])[CH:13]=[CH:12][C:10]=3[N:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)c1ccc2nc(-c3ccccc3)oc2c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=C(O)c1ccc2nc(-c3ccccc3)oc2c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 97.3 %

Procedure:
A mixture of methyl 2-phenyl-benzoxazole-6-carboxylate 25c (0.37 g, 1.46 mmol) and LiOH (0.10 g, 4.2 mmol) in THF (4 mL), MeOH (4 mL), and H2O (4 mL) was stirred at room temperature for 6 h. Aqueous 1N HCl solution was added to the mixture to adjust pH to 3˜4. The resulting mixture was extracted with EtOAc (2×). The organic solution was washed with aq. NaCl, dried over Na2SO4 and concentrated to give 25d (0.34 g).
Reaction SMILES: C([O:3][CH:4](OCC)[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([CH2:26][C:27]([NH:29][C:30]2[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=2)=[O:28])([NH:15][C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=2)=[O:17])[C:7]1=[O:37])C.Cl>CC(C)=O>[CH:4]([CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([CH2:26][C:27]([NH:29][C:30]2[CH:31]=[CH:32][C:33]([CH3:36])=[CH:34][CH:35]=2)=[O:28])([NH:15][C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=2)=[O:17])[C:7]1=[O:37])=[O:3]
Reactant: CCOC(CN1C(=O)C(CC(=O)Nc2ccc(C)cc2)(NC(=O)Nc2ccc(C)cc2)c2ccccc21)OCC
Agent: Cl
Solvent: CC(C)=O
Product: Cc1ccc(NC(=O)CC2(NC(=O)Nc3ccc(C)cc3)C(=O)N(CC=O)c3ccccc32)cc1
Yield: 96.4 %

Procedure:
To a solution of 0.227 g of (+)-1-(2,2-diethoxyethyl)-3-(4-methylphenyl)aminocarbonylmethyl-3-(N'-(4-methylphenyl)ureido)indolin-2-one in 5 ml of acetone was added 5 ml of 6N hydrochloric acid, followed by heating under reflux for 10 minutes. The reaction mixture was concentrated, and the residue was diluted with ethyl acetate and washed twice with an aqueous solution of sodium chloride. The organic layer was dried over anhydrous magnesium sulfate and concentrated to give 0.189 g of the title compound as a crude product.