Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=1.[C:16](O)(=[O:19])[CH:17]=[CH2:18].C1(C=CC(O)=CC=1)O.C1(C)C=CC(S(O)(=O)=O)=CC=1>ClC(Cl)(Cl)C>[C:16]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=1)(=[O:19])[CH:17]=[CH2:18]
Reactant: C=CC(=O)O
Reactant: O=C(O)c1ccc(OCCCCO)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Oc1ccc(O)cc1
Solvent: CC(Cl)(Cl)Cl
Product: C=CC(=O)OCCCCOc1ccc(C(=O)O)cc1

Procedure:
A solution of (1) (282 g; 1.34 mol), freshly distilled acrylic acid (230 ml; 3.35 mol), hydroquinone (1.9 g) and p-toluenesulfonic acid (23.7 g) in 1,1,1-trichloroethane (1.1 l) is refluxed for 10 hours. The reaction mixture is cooled to from 60° to 70° C. and stirred into 2.5 l of petroleum ether, and the precipitate is filtered off, washed with petroleum ether and dried at room temperature under reduced pressure for 24 hours.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH3:14])=[CH:8][CH:7]=1)[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:28][S:29]([C:32]1[CH:40]=[CH:39][C:35]([C:36](O)=[O:37])=[CH:34][CH:33]=1)(=[O:31])=[O:30].[H-].[Na+]>CN(C)C=O.O>[CH2:1]([O:3][C:4](=[O:15])[CH:5]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH3:14])=[CH:8][CH:7]=1)[C:36](=[O:37])[C:35]1[CH:34]=[CH:33][C:32]([S:29]([CH3:28])(=[O:31])=[O:30])=[CH:40][CH:39]=1)[CH3:2]
Reactant: CCOC(=O)Cc1ccc(OCC)cc1
Reactant: CS(=O)(=O)c1ccc(C(=O)O)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(C(=O)c1ccc(S(C)(=O)=O)cc1)c1ccc(OCC)cc1
Yield: 96.2 %

Procedure:
499 mg of 4-ethoxyphenylacetic acid ethyl ester, 480 mg of carbonyldiimidazole, and 0.5 g of 4-methanesulfonyl benzoic acid were dissolved in 10 ml of dimethy formamide, and 119 mg of sodium hydride were slowly added dropwise to the solution and the mixture was reacted at the room temperature for 12 hours. Afterwards, water was added to dilute the resultant, followed by extraction with ethyl acetate. The obtained organic layer was dried over anhydrous magnesium sulfate to give 0.9 g of the titled compound as a light yellow liquid (yield 92%).
Reaction SMILES: [C-:1]#[N:2].[K+].CS(O[CH2:9][CH2:10][CH:11]([C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:26]=1[CH3:32])[C:12]1[C:20]2[C:15](=[C:16]([CH2:21][S:22][CH2:23][CH3:24])[CH:17]=[CH:18][CH:19]=2)[NH:14][CH:13]=1)(=O)=O.O.C(OCC)(=O)C>CN(C=O)C>[Cl:31][C:28]1[CH:29]=[CH:30][C:25]([CH:11]([C:12]2[C:20]3[C:15](=[C:16]([CH2:21][S:22][CH2:23][CH3:24])[CH:17]=[CH:18][CH:19]=3)[NH:14][CH:13]=2)[CH2:10][CH2:9][C:1]#[N:2])=[C:26]([CH3:32])[CH:27]=1
Reactant: [C-]#N
Reactant: CCSCc1cccc2c(C(CCOS(C)(=O)=O)c3ccc(Cl)cc3C)c[nH]c12
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CCSCc1cccc2c(C(CCC#N)c3ccc(Cl)cc3C)c[nH]c12
Temperature: 80 °C
Reaction time: 2 h

Procedure:
86.4 mg (1.33 mmol) of potassium cyanide were added to 300 mg (0.66 mmol) of the compound from Example 60A in 4 ml of DMF. Stirring at 80° C. for 2 h was followed by addition of water, extraction with ethyl acetate, washing of the combined organic phases with saturated aqueous sodium bicarbonate solution, drying over magnesium sulfate, filtration and concentration. The crude product was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% formic acid) to result in 207 mg (81% of theory) of the title compound.
Reaction SMILES: C(S([NH:7][C@H:8]([C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[C:20]([F:25])[CH:19]=1)[CH2:9][S:10][C:11]([CH3:17])([CH3:16])[C:12](OC)=[O:13])=O)(C)(C)C.Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>CO>[F:25][C:20]1[CH:19]=[C:18]([C@H:8]2[NH:7][C:12](=[O:13])[C:11]([CH3:17])([CH3:16])[S:10][CH2:9]2)[CH:23]=[C:22]([F:24])[CH:21]=1
Reactant: COC(=O)C(C)(C)SC[C@H](NS(=O)C(C)(C)C)c1cc(F)cc(F)c1
Agent: Cl
Solvent: CO
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC1(C)SC[C@@H](c2cc(F)cc(F)c2)NC1=O
Temperature: 115 °C

Procedure:
To a solution of methyl 2-{[(2R)-2-[(tert-butylsulfinyl)amino]-2-(3,5-difluorophenyl)ethyl]thio}-2-methylpropanoate from Step C (428 mg, 1.09 mmol) in MeOH (20 mL), cooled to 0° C., was added anhydrous HCl gas for 1 minute. The reaction was sealed and allowed to sit at 0° C. for fifteen minutes, after which nitrogen was bubbled through the reaction for twenty minutes. The reaction was concentrated in vacuo. Additional MeOH (30 mL) was added and it was again concentrated in vacuo. This was repeated with another addition of MeOH and triethylamine (440. mg, 4.35 mmol). To the resulting residue was added toluene (10 mL) and triethylamine (440. mg, 4.35 mmol). A reflux condenser was attached and the mixture stirred at 115° C. After one week of stirring, the reaction was judged to be 90% complete by LCMS. The mixture was cooled to ambient temperature and concentrated in vacuo. The residue was diluted with diethyl ether (50 mL) and washed individually with 20 mL of each of the following aqueous solutions: 1 M HCl (twice), water, and saturated brine. The organic layer was then dried over sodium sulfate, filtered, and concentrated in vacuo to give a residue that was purified by silica gel chromatography, eluting with a gradient of MeOH:CH2Cl2-1:99 to 5:95, to give the title compound. MS: m/z=258 (M+1).
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[CH:7][C:6]=2[CH:5]=[C:4]([C:16]#[N:17])[CH:3]=1.[F:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1>>[F:18][C:19]1[CH:24]=[CH:23][C:22]([C:2]2[C:10]3[N:9]4[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]4=[CH:7][C:6]=3[CH:5]=[C:4]([C:16]#[N:17])[CH:3]=2)=[CH:21][CH:20]=1
Reactant: N#Cc1cc(Br)c2c(c1)cc1n2CCNC1=O
Reactant: OB(O)c1ccc(F)cc1
Product: N#Cc1cc(-c2ccc(F)cc2)c2c(c1)cc1n2CCNC1=O

Procedure:
The title compound, off-white solid (65 mg, 85%), MS (ISP) m/z=306.4 [(M+H)+], mp 297.5° C., was prepared in accordance with the general method of example 1 from 6-bromo-1-oxo-1,2,3,4-tetrahydro-pyrazino[1,2-a]indole-8-carbonitrile (intermediate 15) (72.5 mg, 0.25 mmol) and commercially available 4-fluoro-phenylboronic acid (45.5 mg, 0.325 mmol).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[C:4]([OH:11])[CH:3]=1.[F:12][CH:13]([F:17])[C:14]([CH3:16])=O.N1CCCC1>CO>[Cl:1][C:2]1[CH:3]=[C:4]2[C:5]([C:8](=[O:10])[CH2:9][C:14]([CH:13]([F:17])[F:12])([CH3:16])[O:11]2)=[CH:6][CH:7]=1
Reactant: CC(=O)C(F)F
Reactant: CC(=O)c1ccc(Cl)cc1O
Solvent: CO
Solvent: C1CCNC1
Product: CC1(C(F)F)CC(=O)c2ccc(Cl)cc2O1
Reaction time: 3 h
Yield: 83.9 %

Procedure:
1-(4-Chloro-2-hydroxyphenyl)ethanone (8.07 g, 47.3 mmol), MeOH (81 mL), 1,1-difluoroacetone (4.89 g, 52.0 mmol), and pyrrolidine (4.30 ml, 52.0 mmol) were stirred at ambient temperature for 45 hours, at 35° C. for 7 hours, then at 50° C. for 3 hours. The reaction mixture was concentrated, diluted with MTBE (75 mL), then washed with water (40 mL), 2N HCl (2×25 mL), brine (20 mL), 2N NaOH (2×20 mL), and brine (2×20 mL). The organic portion was dried (Na2SO4), filtered, and concentrated to give the title compound (9.78 g, 39.7 mmol, 84% yield) as a brown oil. MS (DCI/NH3) m/z 264 (M+NH4)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][OH:8])=[CH:5][CH:4]=1.[H-].[Na+].[H][H].[CH2:15]([CH:17]1[O:19][CH2:18]1)Br>O1CCCC1>[O:19]1[CH2:18][CH:17]1[CH2:15][CH:7]([O:8][CH:7]([CH2:15][CH:17]1[O:19][CH2:18]1)[C:6]1[CH:9]=[CH:10][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[C:6]1[CH:9]=[CH:10][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1
Reactant: [H][H]
Reactant: COc1ccc(CO)cc1
Reactant: BrCC1CO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(C(CC2CO2)OC(CC2CO2)c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of 4-methoxybenzyl alcohol (800 g, 5.8 mol) in dry tetrahydrofuran (1200 ml) was added dropwise to a stirred slurry of sodium hydride (280 g of a 60% dispersion in oil, 7.0 mol) in dry tetrahydrofuran (600 ml) at -5° C. and under a gentle stream of dry nitrogen. The resulting slurry was allowed to warm up to room temperature and stirred until hydrogen evolution ceased. The resulting slurry containing sodium alkoxide was cooled to -5° C., and treated with epibromohydrin (860 g, 6.3 mol) at a rate so as to maintain the temperature of the reaction mixture below 5° C. The reaction mixture was allowed to warm gradually to room temperature and was stirred for an additional 12 hours. The reaction mixture was filtered and washed with methanol. The filtrate and washings were combined and evaporated to dryness under reduced pressure to yield a crude product (250 g). The crude product was purified by column chromatography (silica gel, chloroform) to yield 2,3-epoxypropyl-4-methoxybenzyl ether as a pale yellow oil having the following structural characteristics:
Reaction SMILES: [CH3:1][CH:2]([CH2:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:3][OH:4].[H][H]>>[CH:8]1([CH2:7][CH2:6][CH2:5][CH:2]([CH3:1])[CH2:3][OH:4])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: [H][H]
Reactant: CC(CO)CCCc1ccccc1
Product: CC(CO)CCCC1CCCCC1
Reaction time: 15.5 h
Yield: 97.3 %

Procedure:
3415 g of 2-Methyl-5-phenyl-pentanol (Rosaphen™, supplier: Symrise) combined with 33 g Ru on activated carbon (Ru content: 5 wt. %) were hydrogenated at a hydrogen pressure of 20 bar and at a temperature of 100° C. After 14-17 hours the reaction was finished. The catalyst was removed and the product distilled. 3437 g (content: 99.9%) of 5-cyclohexyl-2-methyl-pentanol were obtained. Yield: 97% of theoretical.
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[C:11]2[C:6](=[CH:7][CH:8]=[C:9](/[C:12](/[CH3:24])=[CH:13]/[C:14]3[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][CH:15]=3)[CH:10]=2)[NH:5][CH2:4][CH2:3]1.[CH2:26]=O.Cl>C(O)=O>[CH3:26][N:5]1[C:6]2[C:11](=[CH:10][C:9](/[C:12](/[CH3:24])=[CH:13]/[C:14]3[CH:15]=[CH:16][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:22][CH:23]=3)=[CH:8][CH:7]=2)[C:2]([CH3:25])([CH3:1])[CH2:3][CH2:4]1
Reactant: C=O
Reactant: COC(=O)c1ccc(/C=C(\C)c2ccc3c(c2)C(C)(C)CCN3)cc1
Agent: Cl
Solvent: O=CO
Product: COC(=O)c1ccc(/C=C(\C)c2ccc3c(c2)C(C)(C)CCN3C)cc1
Temperature: 95 °C

Procedure:
A mixture of 3.64 g of methyl 4-[(E)-2-(4,4-dimethyl-1,2,3,4-tetrahydro-6-quinolinyl)-2-methylvinyl]benzoate, 5 ml of 90% formic acid and 5 ml of 40% aqueous formaldehyde is heated at 95° C. for 12 hours. The reaction medium is then cooled and 1.5 ml of concentrated hydrochloric acid is added. The formic acid and excess formaldehyde are removed by evaporation in vacuo. The resulting mixture is then made strongly basic and extracted with dichloromethane. The dichloromethane extracts are combined, dried (MgSO4) and evaporated in vacuo to give the title compound.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([NH2:8])=[O:7].[CH2:14]([CH:17]1[C:22](=O)[CH2:21][CH2:20][O:19][CH2:18]1)[CH:15]=[CH2:16].C[O:25][C:26]1[N:31]=[CH:30][C:29]([N:32]2[CH2:37][CH2:36]C(=O)CC2)=C[CH:27]=1>>[CH2:14]([CH:17]1[CH:22]([N:32]2[CH2:37][CH2:36][C@@H:30]([NH:31][C:26](=[O:25])[CH2:27][NH:8][C:6](=[O:7])[C:5]3[CH:9]=[CH:10][CH:11]=[C:3]([C:2]([F:12])([F:13])[F:1])[CH:4]=3)[CH2:29]2)[CH2:21][CH2:20][O:19][CH2:18]1)[CH:15]=[CH2:16]
Reactant: C=CCC1COCCC1=O
Reactant: COc1ccc(N2CCC(=O)CC2)cn1
Reactant: NC(=O)c1cccc(C(F)(F)F)c1
Product: C=CCC1COCCC1N1CC[C@@H](NC(=O)CNC(=O)c2cccc(C(F)(F)F)c2)C1

Procedure:
The title compound was synthesized in similar fashion to N-[2-{(3R)-1-[1-(6-methoxypyridin-3-yl)piperidin-4-yl]pyrrolidin-3-yl}amino)-2-oxoethyl]-3-(trifluoromethyl)benzamide, whereby 3-allyltetrahydro-4H-pyran-4-one (prepared according to WO2004041161-A2) was substituted for 1-(6-methoxypyridin-3-yl)piperidin-4-one, and was isolated as a white solid. 1H-NMR (CDCl3) δ: 1.46-1.64 (m, 4H), 2.17-2.29 (m, 5H), 2.53-2.59 (m, 2H), 2.74-2.82 (m, 1H), 3.21-3.33 (m, 2H), 3.80-3.91 (m, 2H), 4.07 (d, J=4.8 Hz, 2H), 4.39-4.41 (m, 1H), 4.90-5.02 (m, 2H), 5.59-5.74 (m, 1H), 6.96-7.04 (m, 1H), 7.45-7.50 (m, 1H), 7.68 (d, J=7.5 Hz, 1H), 7.71-7.75 (m, 1H), 7.95 (d, J=7.5 Hz, 1H), 8.05 (s, 1H). MS m/z: 440 (M+1).
Reaction SMILES: Cl[C:2]1[N:3]([CH3:19])[C:4](=[O:18])[C:5]2[C:10]([NH:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:9][NH:8][C:6]=2[N:7]=1.Cl.[NH2:21][C@@H:22]1[CH2:26][CH2:25][CH2:24][C@H:23]1[OH:27].CCN(C(C)C)C(C)C>CN(C=O)C>[OH:27][C@@H:23]1[CH2:24][CH2:25][CH2:26][C@H:22]1[NH:21][C:2]1[N:3]([CH3:19])[C:4](=[O:18])[C:5]2[C:6](=[N:8][NH:9][C:10]=2[NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:7]=1
Reactant: Cn1c(Cl)nc2[nH]nc(Nc3ccccc3)c2c1=O
Reactant: N[C@@H]1CCC[C@H]1O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cn1c(N[C@@H]2CCC[C@H]2O)nc2n[nH]c(Nc3ccccc3)c2c1=O
Yield: 85.7 %

Procedure:
A solution of 6-chloro-5-methyl-3-(phenylamino)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one (3.3 g, 12 mmol), (1R,2R)-2-aminocyclopentanol hydrochloride (2 g, 14.4 mmol) and DIPEA (4.6 mL, 27 mmol) in DMF (25 mL) is heated at 120° C. for 5 hours. Solvent is removed under reduced pressure. The residue is dissolved in CH2Cl2 and MeOH (10:1, v/v), and then washed with water three times. The solution is dried over MgSO4 and evaporated to dryness to give 3.5 g of crude product MS (ESI) m/z 341.2 [M+H]+.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:16]=[CH:15][C:7]([CH2:8][C@@H:9]([C:11]([O:13][CH3:14])=[O:12])[NH2:10])=[CH:6][CH:5]=1.C(N(CC)CC)C.[F:24][C:25]1[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[C:26]=1[CH:27]=[CH:28][C:29](O)=[O:30].CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[F:24][C:25]1[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[C:26]=1[CH:27]=[CH:28][C:29]([NH:10][C@H:9]([C:11]([O:13][CH3:14])=[O:12])[CH2:8][C:7]1[CH:6]=[CH:5][C:4]([O:3][CH3:2])=[CH:16][CH:15]=1)=[O:30]
Reactant: COC(=O)[C@@H](N)Cc1ccc(OC)cc1
Reactant: O=C(O)C=Cc1c(F)cccc1F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@H](Cc1ccc(OC)cc1)NC(=O)C=Cc1c(F)cccc1F
Yield: 81.2 %

Procedure:
The same procedures as in Example 2 were carried out from the compound obtained in Example 33 (2.5 g), triethylamine (1.7 mL), 2,6-difluorocinnamic acid (2.2 g), WSC.HCl (2.3 g), and methylene chloride (70 mL), to give the captioned compound (3.1 g, 82%) as crystals.
Reaction SMILES: C[O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[C:8]([C:14]3[N:15]=[C:16]([CH2:19][S:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)(=[O:22])=[O:21])[S:17][CH:18]=3)[C:9](=[O:13])[NH:10]2)=[CH:5][CH:4]=1.[Al](Br)(Br)Br>CCS>[OH:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[C:8]([C:14]3[N:15]=[C:16]([CH2:19][S:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)(=[O:22])=[O:21])[S:17][CH:18]=3)[C:9](=[O:13])[NH:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc2cc(-c3csc(CS(=O)(=O)c4ccccc4)n3)c(=O)[nH]c2c1
Agent: Br[Al](Br)Br
Solvent: CCS
Product: O=c1[nH]c2cc(O)ccc2cc1-c1csc(CS(=O)(=O)c2ccccc2)n1
Reaction time: 14 h

Procedure:
To a stirred suspension of 7-(methoxy)-3-(2-((phenylsulfonyl)methyl)-1,3-thiazol-4-yl)-2(1h)-quinolinone (Example 8735) (0.1 g, 0.24 mmole) in EtSH (1 mL) was added AlBr3. Stirring was continued in 14 h. The mixture was poured onto ice water and the solid was filtered. The solid was purified by RP-HPLC to give a tan solid. MS (m/z): 399.50 (m+1).
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH3:13][O:14][CH:15]1[CH2:20][CH2:19][CH:18]([N:21]2[C:26](=[O:27])[C:25]([CH2:28][C:29]3[CH:34]=[CH:33][C:32]([C:35]4[C:36]([C:41]#[N:42])=[CH:37][CH:38]=[CH:39][CH:40]=4)=[CH:31][CH:30]=3)=[C:24]([CH2:43][CH2:44][CH3:45])[N:23]3[N:46]=[CH:47][N:48]=[C:22]23)[CH2:17][CH2:16]1>C(OCC)(=O)C>[CH3:13][O:14][CH:15]1[CH2:16][CH2:17][CH:18]([N:21]2[C:26](=[O:27])[C:25]([CH2:28][C:29]3[CH:34]=[CH:33][C:32]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=4[C:41]4[NH:3][C:4](=[O:7])[O:5][N:42]=4)=[CH:31][CH:30]=3)=[C:24]([CH2:43][CH2:44][CH3:45])[N:23]3[N:46]=[CH:47][N:48]=[C:22]23)[CH2:19][CH2:20]1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCC(OC)CC2)c2ncnn12
Reactant: O=C([O-])O
Reactant: [NH3+]O
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n(C2CCC(OC)CC2)c2ncnn12
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 20.8 %

Procedure:
A mixture of hydroxylammonium chloride (0.38 g), sodium hydrogen carbonate (0.61 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C. for 30 min, 4′-{[4-(4-methoxycyclohexyl)-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (0.21 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in tetrahydrofuran (10 mL). N,N′-Carbonyldiimidazole (0.07 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.059 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous potassium hydrogensulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless amorphous solid (0.049 g, 25%).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][CH:7]([NH:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]([N:29]([CH3:37])[CH2:30][CH2:31][C:32]([O:34]CC)=[O:33])=[O:28])=[CH:23][CH:22]=1)[C:8]1[O:9][C:10]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:11]=2[C:12]=1[CH3:13].O1CCCC1.[OH-].[Na+]>C(O)C>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][CH:7]([NH:20][C:21]1[CH:22]=[CH:23][C:24]([C:27]([N:29]([CH3:37])[CH2:30][CH2:31][C:32]([OH:34])=[O:33])=[O:28])=[CH:25][CH:26]=1)[C:8]1[O:9][C:10]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:11]=2[C:12]=1[CH3:13]
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(NC(CCCCOC)c2oc3ccc(OC)cc3c2C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: COCCCCC(Nc1ccc(C(=O)N(C)CCC(=O)O)cc1)c1oc2ccc(OC)cc2c1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.5 %

Procedure:
To a mixture of ethyl 3-{[(4-{[5-methoxy-1-(5-methoxy-3-methyl-1-benzofuran-2-yl)pentyl]amino}phenyl)carbonyl](methyl)amino}propanoate (460 mg) synthesized above, tetrahydrofuran (5 mL) and ethanol (5 mL) was added 1N aqueous sodium hydroxide solution (2.00 mL), and the mixture was stirred overnight at room temperature, and concentrated under reduced pressure. The residue was dissolved in water (10 mL), and 1N hydrochloric acid (2.00 mL) was added at 0° C. The resulting precipitate was collected by filtration to give the title object compound (428 mg, 99%) as a pale-yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[Cl:9].[CH3:10][N:11]1[CH2:16][CH2:15][N:14]([CH2:17][CH2:18]O)[CH2:13][CH2:12]1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:18][CH2:17][N:14]2[CH2:15][CH2:16][N:11]([CH3:10])[CH2:12][CH2:13]2)=[CH:4][C:3]=1[Cl:9]
Reactant: CN1CCN(CCO)CC1
Reactant: Oc1ccc(Br)c(Cl)c1
Product: CN1CCN(CCOc2ccc(Br)c(Cl)c2)CC1

Procedure:
4-Bromo-3-chlorophenol was reacted with 1-methyl-4-(2-hydroxyethyl)piperazine under the Mitsunobu conditions to provide 1-[2-(4-bromo-3-chlorophenoxy)ethyl]-4-methyl-piperazine.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:12][C:13]3[C:21]([F:22])=[CH:20][C:19]([F:23])=[C:18]([NH2:24])[C:14]=3[C:15](=[O:17])[CH:16]=2)=[CH:7][C:6]=1[F:25])(=[O:3])[CH3:2].[CH3:26][S:27][CH2:28][CH2:29]Cl.CC(C)([O-])C.[K+].O>CN(C)C=O>[C:1]([N:4]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:12][C:13]3[C:21]([F:22])=[CH:20][C:19]([F:23])=[C:18]([NH2:24])[C:14]=3[C:15](=[O:17])[CH:16]=2)=[CH:7][C:6]=1[F:25])[CH2:29][CH2:28][S:27][CH3:26])(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(-c2cc(=O)c3c(N)c(F)cc(F)c3o2)cc1F
Reactant: CSCCCl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CSCCN(C(C)=O)c1ccc(-c2cc(=O)c3c(N)c(F)cc(F)c3o2)cc1F
Reaction time: 1 h
Yield: 32 %

Procedure:
1.00 g (2.87 mmol) of Compound 27 obtained in Example 27 was dissolved in 30 ml of dimethylformamide under argon atmosphere, 1.43 ml of chloroethyl methyl sulfide and 354 mg of potassium tert-butoxide were added under ice-cooling and the mixture was stirred at 50° to 60 ° C. for 1 hour. Additional 0.29 ml of chloroethyl methyl sulfide and 322 mg of potassium tert-butoxide were added and the mixture was stirred at the same temperature for 17 hours. The reaction solution was cooled on ice, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with an aqueous solution of sodium chloride and dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol=30:1) to give 380 mg (32%) of 2-[4-[N-acetyl-N-(2-methylthioethyl)amino]-3-fluorophenyl]-5-amino-6,8-difluoro-4H-1-benzopyran-4-one.
Reaction SMILES: [CH3:1][C:2]1([CH3:31])[CH2:11][CH2:10][C:9]2[N:8]=[CH:7][N:6]=[C:5]([N:12]3[CH2:18][C:17]4[CH:19]=[C:20]([C:23]5[CH:24]=[C:25]([NH2:30])[C:26]([NH2:29])=[N:27][CH:28]=5)[CH:21]=[CH:22][C:16]=4[O:15][CH2:14][CH2:13]3)[C:4]=2[CH2:3]1.C(N(CC)CC)C.[C:39](Cl)(=[O:43])[CH2:40][CH2:41][CH3:42]>O1CCCC1>[NH2:29][C:26]1[C:25]([NH:30][C:39](=[O:43])[CH2:40][CH2:41][CH3:42])=[CH:24][C:23]([C:20]2[CH:21]=[CH:22][C:16]3[O:15][CH2:14][CH2:13][N:12]([C:5]4[C:4]5[CH2:3][C:2]([CH3:31])([CH3:1])[CH2:11][CH2:10][C:9]=5[N:8]=[CH:7][N:6]=4)[CH2:18][C:17]=3[CH:19]=2)=[CH:28][N:27]=1
Reactant: CCCC(=O)Cl
Reactant: CC1(C)CCc2ncnc(N3CCOc4ccc(-c5cnc(N)c(N)c5)cc4C3)c2C1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCC(=O)Nc1cc(-c2ccc3c(c2)CN(c2ncnc4c2CC(C)(C)CC4)CCO3)cnc1N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 5-[4-(6,6-dimethyl-5,6,7,8-tetrahydroquinazolin-4-yl)-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]pyridine-2,3-diamine (32 mg, 0.077 mmol) and triethylamine (11 uL, 0.077 mmol) in tetrahydrofuran (1 mL) was add butyryl chloride (7.0 uL, 0.077 mmol), and the resulting mixture was stirred at room temperature for one hour. The reaction mixture was concentrated to give N-{2-amino-5-[4-(6,6-dimethyl-5,6,7,8-tetrahydroquinazolin-4-yl)-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]pyridin-3-yl}butanamide crude product (50 mg). MS (EI) for C28H34N6O2: 487 (MH+).
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:8]=C(N)C(NC)=[C:11]([I:13])[CH:12]=2)=[C:5]([CH3:17])[O:4][N:3]=1.C1N=CN([C:23]([N:25]2[CH:29]=[N:28][CH:27]=[CH:26]2)=O)C=1.C1C[O:33]CC1>>[CH3:1][C:2]1[C:6]([C:7]2[CH:12]=[C:11]([I:13])[C:26]3[N:25]([CH3:23])[C:29](=[O:33])[NH:28][C:27]=3[CH:8]=2)=[C:5]([CH3:17])[O:4][N:3]=1
Reactant: C1CCOC1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CNc1c(N)cc(-c2c(C)noc2C)cc1I
Product: Cc1noc(C)c1-c1cc(I)c2c(c1)[nH]c(=O)n2C
Temperature: 120 °C

Procedure:
To a mixture of 4-(3,5-dimethylisoxazol-4-yl)-6-iodo-N1-methylbenzene-1,2-diamine (1.89 g, 5.5 mmol, 1 equiv.) in a pressure tube was added THF (5 mL) and CDI (2.67 g, 18.5 mmol, 3 equiv.). The mixture was heated to 120° C. for 30 minutes in a microwave reactor. The reaction was concentrated in vacuo and purified by HPLC to provide 5-(3,5-dimethylisoxazol-4-yl)-7-iodo-1-methyl-1H-benzo[d]imidazol-2(3H)-one.