Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:13]=2[CH:22](OC)[O:23]C)[CH:6]=1.Cl>C1COCC1>[CH3:1][O:2][C:3](=[O:27])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:19])([F:21])[F:20])=[CH:14][C:13]=2[CH:22]=[O:23])[CH:6]=1
Reactant: COC(=O)Cc1cccc(Oc2ccc(C(F)(F)F)cc2C(OC)OC)c1
Agent: Cl
Solvent: C1CCOC1
Product: COC(=O)Cc1cccc(Oc2ccc(C(F)(F)F)cc2C=O)c1
Temperature: 70 °C
Reaction time: 1.5 h
Yield: 113.3 %

Procedure:
To [3-(2-dimethoxymethyl-4-trifluoromethyl-phenoxy)-phenyl]-acetic acid methyl ester (0.479 g, 1.2 mmol) in THF (4 mL) was added hydrogen chloride (4N in 1,4-dioxane; 1.5 mL), and the reaction was stirred at 70° C. for 1.5 hours. Additional HCl (0.5 mL) was added, and the reaction was stirred for 40 minutes at 70° C. The mixture was partitioned between H2O and EtOAc, and the aqueous layer was extracted twice with EtOAc. The combined organic layers were dried and concentrated to give the desired product (0.46 g).
Reaction SMILES: [N:1]([C:4]1[C:14]([Cl:15])=[CH:13][C:7]([C:8]([NH:10][CH2:11][CH3:12])=[O:9])=[C:6]([O:16][CH3:17])[CH:5]=1)=[N+:2]=[N-:3].O=[C:19]([CH3:26])[CH2:20][C:21]([O:23]CC)=[O:22].[O-]CC.[Na+]>C(O)C>[Cl:15][C:14]1[CH:13]=[C:7]([C:8]([NH:10][CH2:11][CH3:12])=[O:9])[C:6]([O:16][CH3:17])=[CH:5][C:4]=1[N:1]1[C:19]([CH3:26])=[C:20]([C:21]([OH:23])=[O:22])[N:3]=[N:2]1
Reactant: CCNC(=O)c1cc(Cl)c(N=[N+]=[N-])cc1OC
Reactant: CCOC(=O)CC(C)=O
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCNC(=O)c1cc(Cl)c(-n2nnc(C(=O)O)c2C)cc1OC
Temperature: 60 °C
Reaction time: 5 h
Yield: 28 %

Procedure:
To a solution of 4-azido-5-chloro-N-ethyl-2-methoxybenzamide (1.0 g) obtained in Example 73b) and ethyl 3-keto-n-butanoate (0.61 ml) in ethanol (20 ml) was added 20% sodium ethoxide in ethanol solution (1.85 ml) at room temperature, and the mixture was stirred at 60° C. for 5 hr. The reaction mixture was cooled to room temperature, and the solvent was evaporated under reduced pressure. The residue was diluted with water and washed with ethyl acetate. The aqueous layer was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound as a pale-brown solid (0.38 g, 28%). The obtained crude product was used for the next reaction without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[C:18]2[C:13](=[CH:14][N:15]=[C:16]([C:19]3[CH:20]=[N:21][N:22]([CH3:24])[CH:23]=3)[CH:17]=2)[N:12](C2CCCCO2)[N:11]=1.Cl>CO.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[C:18]2[C:13](=[CH:14][N:15]=[C:16]([C:19]3[CH:20]=[N:21][N:22]([CH3:24])[CH:23]=3)[CH:17]=2)[NH:12][N:11]=1
Reactant: COc1ccc(F)c(-c2nn(C3CCCCO3)c3cnc(-c4cnn(C)c4)cc23)c1
Agent: Cl
Solvent: O
Solvent: CO
Product: COc1ccc(F)c(-c2n[nH]c3cnc(-c4cnn(C)c4)cc23)c1
Temperature: 60 °C
Reaction time: 72 h
Yield: 52.6 %

Procedure:
To a stirred mixture of 3-(2-fluoro-5-methoxyphenyl)-5-(1-methyl-1H-pyrazol-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-c]pyridine (37.0 mg, 0.09 mmol) in methanol (5.0 mL) was added 6 M HCl in water (0.66 mL). The reaction mixture was stirred at 60° C. for 3 days. Volatile solvent was evaporated in vacuo, and the crude was diluted into ethyl acetate (˜30 mL). The organic layer was washed with saturated aqueous sodium bicarbonate solution, water and brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. Trituration from ether-heptanes afforded 172 as a solid (15.3 mg, 52.1%). 1H NMR (400 MHz, DMSO) δ 13.88 (s, 1H), 9.06 (s, 1H), 8.25 (s, 1H), 7.97 (s, 1H), 7.88 (s, 1H), 7.36 (t, J=9.6 Hz, 1H), 7.31 (dd, J=5.7, 3.2 Hz, 1H), 7.09 (s, 1H), 3.88 (s, 3H), 3.83 (s, 3H). LC/MS: m/z 324.0 [M+1]
Reaction SMILES: C(OC([P:9]([C:14]([F:19])([F:18])[CH2:15][CH2:16][CH3:17])(=[O:13])[O:10][CH2:11][CH3:12])(OCC)C)C.C(O)C.C[Si](C)(C)Cl>O1CCCC1>[CH2:11]([O:10][P:9]([C:14]([F:19])([F:18])[CH2:15][CH2:16][CH3:17])[OH:13])[CH3:12]
Reactant: CCCC(F)(F)P(=O)(OCC)C(C)(OCC)OCC
Agent: C[Si](C)(C)Cl
Solvent: CCO
Solvent: C1CCOC1
Product: CCCC(F)(F)P(O)OCC
Temperature: 25 °C

Procedure:
To 8.2 g (27.1 mMol) of ethyl 1,1-diethoxyethyl(1,1-difluorobutyl)phosphinate in 81 ml of dry tetrahydrofuran are added, with stirring at room temperature, 9 ml of ethanol and 5.1 ml (40.7 mMol) of trimethylchlorosilane. After 5 hours of stirring the reaction mixture is evaporated and the remaining oil is chromatographed on a silica gel column eluting with ether. The product-containing fractions are collected and the solvent is evaporated leaving 1,1-difluorobutylphosphonous acid ethyl ester as colorless oil, Rf=0.4 (CH2Cl2 /CH3COOH, 95+5).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([CH2:30][O:31][Si:32]([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33])[CH2:13][CH2:14][C:15]([N:17]1[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]1)=[O:16])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I[CH3:40].[H-].[Na+]>CN(C=O)C>[CH2:1]([O:8][C:9]([N:11]([CH3:40])[C@H:12]([CH2:30][O:31][Si:32]([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33])[CH2:13][CH2:14][C:15]([N:17]1[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]1)=[O:16])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)CC[C@@H](CO[Si](C)(C)C(C)(C)C)NC(=O)OCc2ccccc2)CC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C(=O)OCc1ccccc1)[C@@H](CCC(=O)N1CCN(C(=O)OC(C)(C)C)CC1)CO[Si](C)(C)C(C)(C)C
Temperature: 2.5 °C
Reaction time: 0.5 h
Yield: 102.6 %

Procedure:
To a solution of (S)-tert-butyl 4-(4-(benzyloxycarbonylamino)-5-(tert-butyldimethylsilyloxy)pentanoyl)piperazine-1-carboxylate (32.3 g, 58.8 mmol) and iodomethane (7.3 mL, 117.6 mmol) in DMF (450 mL) was added solid sodium hydride (60%, 3.5 g, 88.2 mmol) at 0-5° C. The mixture was stirred at 0-5° C. for 30 min and quenched with saturated NH4Cl solution. The mixture was concentrated to remove most of DMF under high vacuum. The residue was dissolved in EtOAc (700 mL). The organic mixture was washed with water and brine, dried over Na2SO4, filtered, and concentrated to give (S)-tert-butyl 4-(4-((benzyloxycarbonyl)(methyl)amino)-5-(tert-butyldimethylsilyloxy)pentanoyl)piperazine-1-carboxylate (34 g, crude), which was used without further purification. LRMS (M+H) m/z 564.3.
Reaction SMILES: C([Li])CCC.C(O[SiH](OCC)OCC)C.[C:16]1([CH2:22][C:23](OCC)=[O:24])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[OH-].[Na+]>[Cl-].[Cl-].[CH-]1C=CC=C1.[CH-]1C=CC=C1.[Ti+2].O.CCOCC.CCO.O1CCCC1.CCCCCC>[CH2:23]([OH:24])[CH2:22][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CCOC(=O)Cc1ccccc1
Agent: [Ti+2]
Agent: CCO[SiH](OCC)OCC
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCO
Solvent: CCOCC
Product: OCCc1ccccc1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 81.9 %

Procedure:
To a dry Schlenk tube under argon was added 50 mg of titanocene dichloride (0.2 mmol) and 2 mL of tetrahydrofuran. The slurry was cooled to -78° C. in a dry ice/acetone bath and 250 μL of a 1.6M hexane solution of n-butyl lithium. (0.4 mmol) was added. After stirring for 15 minutes, 1.8 mL of triethoxysilane (10 mmol was added, followed by 500 μL ethyl 2-phenylethanoate (3.0 mmol), and the reaction mixture was allowed to warm to room temperature. The reaction mixture bubbled vigorously. When the bubbles subsided, the reaction mixture began to warm rapidly, causing tetrahydrofuran to begin refluxing. When the mixture cooled back to room temperature, the catalyst was quenched by exposure to air until the color changed from dark brown to yellow. Next, 5 mL of tetrahydrofuran, 15 mL of EtOH, and 0.6 g of NaOH (15 mmol) were then added. After stirring for 2 hours, the mixture was added to a water/ether mixture (150 mL each), shaken vigorously, and the layers were then separated. The aqueous layer was extracted with ether (2×50 mL), the combined organic extracts were dried over MgSO4, filtered, and concentrated by rotary evaporation. The crude product was purified by flash Chromatography (ether:hexane=1:1), which afforded 300 mg (82% yield) of phenethyl alcohol.
Reaction SMILES: C(O)(=O)C1C=CC=CC=1.[NH2:10][CH:11]1[CH2:16][CH2:15][CH2:14][N:13]([C:17]2[N:22]([CH2:23][C:24]3[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=3[C:26]#[N:27])[C:21](=[O:32])[N:20](C)[C:19](=[O:34])[CH:18]=2)[CH2:12]1.[ClH:35]>C1COCC1.O1CCOCC1>[NH2:10][C@@H:11]1[CH2:16][CH2:15][CH2:14][N:13]([C:17]2[N:22]([CH2:23][C:24]3[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=3[C:26]#[N:27])[C:21](=[O:32])[NH:20][C:19](=[O:34])[C:18]=2[Cl:35])[CH2:12]1
Reactant: Cn1c(=O)cc(N2CCCC(N)C2)n(Cc2ccccc2C#N)c1=O
Reactant: Cl
Agent: O=C(O)c1ccccc1
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: N#Cc1ccccc1Cn1c(N2CCC[C@@H](N)C2)c(Cl)c(=O)[nH]c1=O

Procedure:
Compound 4 (100 mg) in THF (2 mL) was treated with 4M HCl in dioxane (1 mL) at rt for 1 h, concentrated, and then purified by LC-MS to give the title compound. 1H-NMR (400 MHz, DMSO-D6): 6 ppm 12.0 (s, 1H), 7.88 (d, J=7.6 Hz, 1H), 7.68 (t, J=7.7 Hz, 1H), 7.49 (t, J=7.7 Hz, 1H), 7.36 (d, J=7.8 Hz, 1H), 5.09-5.21 (m, 2H), 3.17 (m, 2H), 2.96 (t, J=11.1 Hz, 1H), 2.86 (d, J=10.6 Hz, 1H), 2.65 (m, 1H), 1.90 (d, J=11.6 Hz, 1H), 1.57 (d, J=13.1 Hz, 1H), 1.19-1.31 (m, 1H), 1.03-1.15 (m, 1H). MS (ES) [m+H] calc'd for C17H19ClN5O2, 360.1; found, 360.1.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][O:11][C:12]2[CH:13]=[C:14]([O:18]C(=O)C3C=CC=CC=3)[CH:15]=[CH:16][CH:17]=2)=[N:7][CH:8]=1)[CH3:2].C1COCC1.CO.[OH-].[Na+].Cl>CCOC(C)=O.O>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][O:11][C:12]2[CH:13]=[C:14]([OH:18])[CH:15]=[CH:16][CH:17]=2)=[N:7][CH:8]=1)[CH3:2]
Reactant: CCc1ccc(CCOc2cccc(OC(=O)c3ccccc3)c2)nc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: CCOC(C)=O
Product: CCc1ccc(CCOc2cccc(O)c2)nc1
Temperature: 5 °C
Reaction time: 0.25 h

Procedure:
To a solution of benzoic acid 3-[2-(5-ethyl-pyridin-2-yl)-ethoxy]-phenyl ester (493 mg, 1.42 mmol, example 70) in 1:1 THF/CH3OH (5 mL) is added 10N NaOH soln. (0.5 mL) and water (50 μL). The reaction mixture is stirred for 15 min then cooled to 5° C., adjusted to pH 7 with 2N HCl soln. and diluted with EtOAc. The organic layer is washed sequentially with brine, sat NaHCO3 soln. then dried over MgSO4 and concentrated. The residue is purified by several triturations with hexane to give the title compound as a crystalline solid. MS (ESI) 244 (M+H)+.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([Cl:15])[CH:14]=1)[NH:11][CH:10]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[CH:17]=1)[C:9]([CH3:29])([CH3:28])[CH2:8]2)=[O:4].[OH-].[Na+].Cl>CO.O1CCCC1.O>[Cl:15][C:13]1[CH:14]=[C:5]([C:3]([OH:4])=[O:2])[CH:6]=[C:7]2[C:12]=1[NH:11][CH:10]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([N:22]3[CH2:23][CH2:24][O:25][CH2:26][CH2:27]3)[CH:17]=1)[C:9]([CH3:28])([CH3:29])[CH2:8]2
Reactant: COC(=O)c1cc(Cl)c2c(c1)CC(C)(C)C(c1cccc(N3CCOCC3)c1)N2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CC1(C)Cc2cc(C(=O)O)cc(Cl)c2NC1c1cccc(N2CCOCC2)c1
Temperature: 70 °C
Reaction time: 6 h
Yield: 87.3 %

Procedure:
To a stirred mixture solution of 8-chloro-3,3-dimethyl-2-(3-morpholin-4-yl-phenyl)-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid methyl ester (700 mg, 1.8 mmol) in methanol (5.0 mL) and tetrahydrofuran (5.0 mL) was added 50% sodium hydroxide in water (1.0 mL). The reaction mixture was stirred at 70° C. for 6 hours. The mixture was neutralized with a 3 N aqueous hydrochloric acid solution and extracted with ethyl acetate (2×100 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded 8-chloro-3,3-dimethyl-2-(3-morpholin-4-yl-phenyl)-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (630 mg, 90%) as a light yellow solid: LC/MS m/e calcd for C22H25ClN2O3 (M+H)+: 401.91, observed: 401.1.
Reaction SMILES: [ClH:1].[CH2:2]([N:4]([CH:12]([CH3:14])[CH3:13])[C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][CH:6]=1)[CH3:3].Cl.Cl.[NH2:17][C:18]1[CH:27]=[C:26]([NH2:28])[CH:25]=[CH:24][C:19]=1[O:20][CH2:21][CH2:22][OH:23].N>O.C(O)C>[ClH:1].[NH2:28][C:26]1[C:25](=[N:11][C:8]2[CH:9]=[CH:10][C:5]([N:4]([CH2:2][CH3:3])[CH:12]([CH3:13])[CH3:14])=[CH:6][CH:7]=2)[CH:24]=[C:19]([O:20][CH2:21][CH2:22][OH:23])[C:18](=[NH:17])[CH:27]=1
Reactant: CCN(c1ccc(N)cc1)C(C)C
Reactant: Nc1ccc(OCCO)c(N)c1
Agent: Cl
Agent: N
Solvent: CCO
Solvent: O
Product: CCN(c1ccc(N=C2C=C(OCCO)C(=N)C=C2N)cc1)C(C)C
Temperature: 25 °C
Reaction time: 6 h
Yield: 13.5 %

Procedure:
To a solution of 2.14 g (0.01 mol) of N-ethyl-N-isopropyl-4-aminoaniline hydrochloride and 2.41 g (0.01 mol) of 2-(2,4-diaminophenoxy)ethanol dihydrochloride in 10 ml of water and 10 ml of ethanol, brought to pH 9.5 with 20% aqueous ammonia, are added dropwise 5.7 g of 30% aqueous peroxide hydrogen solution (0.05 mol). After stirring for 6 hours at room temperature, a gum forms. The supernatant is removed and the residual gum is washed with four times of water and then taken up in dichloromethane in order to perform a chromatography (eluent: dichloromethane/methanol 98/2 v/v). 510 mg of 2-{4-amino-3-[4-(ethylisopropylamino)phenylimino]-6-iminocyclohexa-1,4-dienyloxy}ethanol hydrochloride 66 are thus obtained in the form of a black powder.
Reaction SMILES: C(N(CC)CC)C.[F:8][C:9]1[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:10]=1[CH2:11][OH:12].S(=O)(=O)=O.N1C=CC=CC=1.OS([O-])(=O)=O.[K+]>CS(C)=O>[F:8][C:9]1[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:10]=1[CH:11]=[O:12]
Reactant: COc1ccc(CO)c(F)c1
Agent: O=S(=O)([O-])O
Agent: O=S(=O)=O
Agent: [K+]
Solvent: c1ccncc1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: COc1ccc(C=O)c(F)c1
Reaction time: 0.5 h
Yield: 88 %

Procedure:
Triethylamine (0.92 ml, 6.60 mmol) was added to a solution of 2-fluoro-4-methoxybenzylalcohol (346.9 mg, 2.22 mmol) in DMSO (8 ml). Pyridine sulfur trioxide (1.0501 g, 6.60 mmol) was added portionwise to the mixture checking raise of the temperature. The mixture was stirred for 0.5 hours. The mixture was added to 5% KHSO4 aqueous solution, extracted three times with ethyl acetate and dried over MgSO4. The mixture was concentrated and purified by silica gel chromatography (hexane/ether=5/1) to give the title compound (301 mg; 88%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[O:15][C:14]([CH3:20])([CH3:19])[CH2:13][CH:12]2[NH:21][S:22]([CH3:25])(=[O:24])=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH2:28](I)[CH3:29]>CC(N(C)C)=O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[O:15][C:14]([CH3:20])([CH3:19])[CH2:13][CH:12]2[N:21]([CH2:28][CH3:29])[S:22]([CH3:25])(=[O:23])=[O:24])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCI
Reactant: CC1(C)CC(NS(C)(=O)=O)c2cc(OCc3ccccc3)ccc2O1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CCN(C1CC(C)(C)Oc2ccc(OCc3ccccc3)cc21)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
7.2 g (20 mmol) of 6-benzyloxy-4-(methylsulfonyl)amino-2,2-dimethylchroman were introduced in portions at 10° C. into a suspension of 0.82 g (27 mmol) of sodium hydride (80 per cent dispersion) in 60 ml of DMA. After stirring at RT for 2 h, 2.2 ml (26.5 mmol) of ethyl iodide were added dropwise, the temperature rising to 32° C. The mixture was then heated to 35-40° C. for 2 h, concentrated in vac., treated with water, the resinous product was taken up EA, the solution was dried and concentrated and the residue was chromatographed using n-heptane/EA (2:1) on silica gel. 6 g of product were crystallized from appropriate fractions using petroleum ether/diisopropyl ether (1:1), m.p. 104-106° C.
Reaction SMILES: C([O:3][C:4](=[O:19])[C@@H:5]([O:17][CH3:18])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]#[C:14][CH2:15]Cl)=[CH:9][CH:8]=1)C.[F:20][C:21]1[CH:35]=[CH:34][C:24]([C:25]([C:27]2[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=2)=[O:26])=[CH:23][CH:22]=1>>[F:20][C:21]1[CH:35]=[CH:34][C:24]([C:25]([C:27]2[CH:32]=[CH:31][C:30]([O:33][CH2:15][C:14]#[C:13][C:10]3[CH:9]=[CH:8][C:7]([CH2:6][C@H:5]([O:17][CH3:18])[C:4]([OH:3])=[O:19])=[CH:12][CH:11]=3)=[CH:29][CH:28]=2)=[O:26])=[CH:23][CH:22]=1
Reactant: CCOC(=O)[C@H](Cc1ccc(C#CCCl)cc1)OC
Reactant: O=C(c1ccc(O)cc1)c1ccc(F)cc1
Product: CO[C@@H](Cc1ccc(C#CCOc2ccc(C(=O)c3ccc(F)cc3)cc2)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-[4-(3-Chloro-prop-1-ynyl)-phenyl]-2-methoxy-propionic acid ethyl ester from Example 5, Step A and 4-fluoro-4′-hydroxybenzophenone in a manner analogous to that described for Example 5, Step B. MS(ES) for C26H21FO[M+H]+: 433.2.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([NH2:16])=[C:12]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:11]=1.N[C:26](N)=[O:27]>O>[CH3:1][O:2][C:3](=[O:24])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]2[NH:16][C:26](=[O:27])[N:17]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:12]=2[CH:11]=1
Reactant: NC(N)=O
Reactant: COC(=O)CCCCCOc1ccc(N)c(Nc2ccccc2)c1
Solvent: O
Product: COC(=O)CCCCCOc1ccc2[nH]c(=O)n(-c3ccccc3)c2c1
Temperature: 140 °C

Procedure:
7.5 g of 6-(3-phenylamino-4-aminophenyl)oxyhexanoic acid methyl ester was mixed with 8.23 g of urea, and the mixture was heated to 140° C. for 4 hours. After cooling, it was mixed with water, extracted three times with ethyl acetate, the combined organic phases were washed with saturated sodium chloride solution, dried on sodium sulfate and concentrated by evaporation in a vacuum. The residue was crystallized from diisopropyl ether. 4.27 g was obtained.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C:11]([C:15]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)=[O:16])([OH:14])[CH2:10][CH2:9]1)C1C=CC=CC=1.CO>C(OCC)(=O)C.[Pd]>[F:23][C:20]1[CH:21]=[CH:22][C:17]([C:15]([C:11]2([OH:14])[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[O:16])=[CH:18][CH:19]=1
Reactant: O=C(c1ccc(F)cc1)C1(O)CCN(Cc2ccccc2)CC1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: O=C(c1ccc(F)cc1)C1(O)CCNCC1
Yield: 100 %

Procedure:
(0.550 g, 1.76 mmol) of (1-Benzyl-4-hydroxy-piperidin-4-yl)-(4-fluoro-phenyl)-methanone was hydrogenated in 4 mL of ethyl acetate and 2 mL of methanol using 0.065 g, (0.61 mmol) of Palladium on charcoal to yield 0.392 g of the title compound (1.76 mmol, 100% yield) as a off-white solid after filtration of the catalyst and removal of the solvent under vacuum. MS (m/e): 314.0 (M+H+).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[O:14][CH2:15][CH3:16])(C)(C)C.B1(Cl)OC2C(=CC=CC=2)O1>C(Cl)Cl>[CH2:15]([O:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[NH2:7])[CH3:16]
Reactant: CCOc1ccccc1NC(=O)OC(C)(C)C
Agent: ClB1Oc2ccccc2O1
Solvent: ClCCl
Product: CCOc1ccccc1N
Yield: 520.7 %

Procedure:
The reaction between 1.2 g (1.4 mmol) of tert-butyl-N-(2-ethoxyphenyl)carbamate (˜1.2 mmol/g) bonded on solid support 9 and 0.87 g (5.66 mmol, 4 eq) of 0.2 M B-chlorocatecholborane in anhydrous CH2Cl2 according to the procedure described hereinabove, followed by filtration and washing, gave 1 g of a brown powder (yield: 95%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:8]([F:11])([F:10])[F:9])=[N:4][NH:5][C:6]=1[CH3:7].Br[CH2:13][C:14]([O:16]CC)=[O:15].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[Cl:1][C:2]1[C:3]([C:8]([F:9])([F:11])[F:10])=[N:4][N:5]([CH2:13][C:14]([OH:16])=[O:15])[C:6]=1[CH3:7]
Reactant: CCOC(=O)CBr
Reactant: Cc1[nH]nc(C(F)(F)F)c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(Cl)c(C(F)(F)F)nn1CC(=O)O
Temperature: 55 °C
Yield: 84.1 %

Procedure:
To a solution of 4-chloro-5-methyl-3-(trifluoromethyl)pyrazole (15 g, 81.3 mmol) in DMF (82 mL) was added ethyl 2-bromoacetate (13.6 g, 81.3 mmol) and potassium carbonate (12.4 g, 89.4 mmol). The mixture was heated at 55° C. for 10 hours with stirring. After cooling to room temperature, the reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (3×150 mL). The combined organic layers were washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo. The crude residue was purified by flash chromatography (SiO2, 0-30% ethyl acetate in hexanes) to afford the desired product (18.5 g, 68.4 mmol, 84%).
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=2)[C:6](=[C:17](OCC)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:5]1=[O:27])(=O)C.[CH3:28][N:29]([CH3:44])[CH2:30][CH2:31][N:32]([S:40]([CH3:43])(=[O:42])=[O:41])[C:33]1[CH:38]=[CH:37][C:36]([NH2:39])=[CH:35][CH:34]=1>>[CH3:28][N:29]([CH3:44])[CH2:30][CH2:31][N:32]([C:33]1[CH:34]=[CH:35][C:36]([NH:39]/[C:17](=[C:6]2\[C:5](=[O:27])[NH:4][C:12]3[C:7]\2=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=3)/[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:37][CH:38]=1)[S:40]([CH3:43])(=[O:42])=[O:41]
Reactant: CN(C)CCN(c1ccc(N)cc1)S(C)(=O)=O
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2cc(OC)c(OC)cc21)c1ccccc1
Product: COc1cc2c(cc1OC)/C(=C(/Nc1ccc(N(CCN(C)C)S(C)(=O)=O)cc1)c1ccccc1)C(=O)N2

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-5,6-dimethoxy-2-indolinone and N-(2-dimethylamino-ethyl)-N-methylsulphonyl-p-phenylenediamine
Reaction SMILES: [CH:1]([N:4]([CH3:28])[C:5]1[C:6]([C:19]2[C:20]([C:24]([F:27])([F:26])[F:25])=[N:21][NH:22][CH:23]=2)=[N:7][C:8]2[C:13]([N:14]=1)=[CH:12][C:11]([C:15]([O:17]C)=[O:16])=[CH:10][CH:9]=2)([CH3:3])[CH3:2].[OH-].[Na+].O>CO>[CH:1]([N:4]([CH3:28])[C:5]1[C:6]([C:19]2[C:20]([C:24]([F:25])([F:26])[F:27])=[N:21][NH:22][CH:23]=2)=[N:7][C:8]2[C:13]([N:14]=1)=[CH:12][C:11]([C:15]([OH:17])=[O:16])=[CH:10][CH:9]=2)([CH3:3])[CH3:2]
Reactant: COC(=O)c1ccc2nc(-c3c[nH]nc3C(F)(F)F)c(N(C)C(C)C)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)N(C)c1nc2cc(C(=O)O)ccc2nc1-c1c[nH]nc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.4 %

Procedure:
To solution of methyl 3-(isopropyl(methyl)amino)-2-(3-(trifluoromethyl)-1H-pyrazol-4-yl)quinoxaline-6-carboxylate (80.0 mg, 0.20 mmol) in methanol (30 mL) was added sodium hydroxide (24 mg, 0.60 mmol) and water (1 mL) with stirring overnight at room temperature. The reaction mixture was concentrated under vacuum, dissolved in water (30 mL) and then adjusted to pH 5 with hydrochloric acid (3N). The solids were collected by filtration, dried in an oven under reduced pressure to afford 3-(isopropyl(methyl)amino)-2-(3-(trifluoromethyl)-1H-pyrazol-4-yl)quinoxaline-6-carboxylic acid as a light yellow solid (64.0 mg, 79%).
Reaction SMILES: [F:1][C:2]1[C:11]2[O:10][CH2:9][CH2:8][O:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[Br:12]N1C(=O)CCC1=O>CO>[Br:12][C:4]1[CH:3]=[C:2]([F:1])[C:11]2[O:10][CH2:9][CH2:8][O:7][C:6]=2[CH:5]=1
Reactant: Fc1cccc2c1OCCO2
Reactant: O=C1CCC(=O)N1Br
Solvent: CO
Product: Fc1cc(Br)cc2c1OCCO2
Temperature: 25 °C
Yield: 87.5 %

Procedure:
A solution of 5-fluoro-2,3-dihydrobenzo[b][1,4]dioxine (1.54 g, 10.0 mmol) and 1-bromopyrrolidine-2,5-dione (1.8 g, 10 mmol) in methanol (20 mL) was heated at reflux for 0.5 h, allowed to cool to ambient temperature and concentrated in vacuo. The residue was taken up in dichloromethane (50 mL) and washed with water (50 mL). The organic phase was dried over magnesium sulfate, filtered and concentrated in vacuo. Purification of the residue by column chromatography eluted with a 0% to 30% gradient of ethyl acetate in hexanes afforded 7-bromo-5-fluoro-2,3-dihydrobenzo[b][1,4]dioxine (2.04 g, 87%) as a colorless solid: MS (ES+) m/z 233.6 (M+1).