Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C)C=O.[F:6][C:7]1[CH:8]=[C:9]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[OH:29])[CH:10]=[CH:11][C:12]=1[C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14].Br[CH2:31][C@H:32]([CH3:52])[CH2:33][O:34][Si:35]([C:48]([CH3:51])([CH3:50])[CH3:49])([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O.C(OCC)(=O)C>[Si:35]([O:34][CH2:33][C@@H:32]([CH3:52])[CH2:31][O:29][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[C:9]1[CH:10]=[CH:11][C:12]([C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:14])=[C:7]([F:6])[CH:8]=1)([C:48]([CH3:49])([CH3:50])[CH3:51])([C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: O=C(OCc1ccccc1)c1ccc(-c2ccccc2O)cc1F
Reactant: C[C@@H](CBr)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: C[C@@H](COc1ccccc1-c1ccc(C(=O)OCc2ccccc2)c(F)c1)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 60 °C
Reaction time: 1 h
Yield: 76.4 %

Procedure:
To an N,N-dimethylformamide solution (30 ml) of benzyl 3-fluoro-2′-hydroxybiphenyl-4-carboxylate (Example 1-3) (1.0 g) and {[(2R)-3-bromo-2-methylpropyl]oxy}(tert-butyl)diphenylsilane (1.5 g) was added at room temperature cesium carbonate (2.4 g), followed by stirring at 60° C. for 1 hour. Ethyl acetate and water were added to the reaction solution, and the solution was separated. The organic layer was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to afford benzyl 2′-{[(2S)-3-{[tert-butyl(diphenyl)silyl]oxy}-2-methylpropyl]oxy}-3-fluorobiphenyl-4-carboxylate (1.5 g).
Reaction SMILES: O[C:2]1[C:3](C)=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](O)=[O:6].O[N:13]1C2C=CC=CC=2N=N1.C(Cl)CCl.C(OCC)(=O)C>CN(C)C=O>[C:5]([NH2:13])(=[O:6])[C:4]1[CH:8]=[CH:9][CH:10]=[CH:2][CH:3]=1
Reactant: On1nnc2ccccc21
Reactant: Cc1c(O)cccc1C(=O)O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: NC(=O)c1ccccc1
Reaction time: 0.33 h
Yield: 261.7 %

Procedure:
To a solution of 187 mg (1.23 mmol) of 3-hydroxy-2-methylbenzoic acid and 217 mg (1.61 mmol) of N-hydroxybenzotriazole in 6 mL of anhydrous N,N-dimethylformamide at 0° C., was added 236 mg (1.23 mmol) of EDC. After 20 minutes of activation at 0° C. and 1 hour at is room temperature, 450 mg (1.07 mmol) of 2R-hydroxy-3-[[(1,3-benzodioxol-5-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propylamine was added. After 15 hours at room temperature, ethyl acetate was added, washed with 5% citric acid, saturated sodium bicarbonate, brine, dried, filtered and concentrated to afford 650 mg of crude material. This was chromatographed on silica gel using 0-25% ethyl acetate/methylene chloride as eluent to afford 390 mg of pure benzamide, N-[2R-hydroxy-3-[[(1,3-benzodioxol-5-yl)sulfonyl](2-methylpropyl)amino]-1S-(phenylmethyl)propyl]-3-hydroxy-2-methyl, m/e=561(M+Li).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:4]=1[C:5]#N.OS(O)(=O)=O.O.[C:23]([OH:26])(=[O:25])C>>[F:1][C:2]([F:16])([F:15])[C:3]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:4]=1[CH2:5][C:23]([OH:26])=[O:25]
Reactant: N#Cc1ccc(C(F)(F)F)cc1C(F)(F)F
Reactant: CC(=O)O
Agent: O=S(=O)(O)O
Solvent: O
Product: O=C(O)Cc1ccc(C(F)(F)F)cc1C(F)(F)F
Temperature: 120 °C

Procedure:
2,4-Bis(trifluoromethyl)benzonitrile (41.5 mmol, 10.51 g) was taken up in 100 mL acetic acid, 50 mL conc. H2SO4, and 20 mL water. This was heated to 120° C. for 3 h. The reaction was then diluted with 1 L ice water, and extracted with 2×300 mL ethyl acetate. The combined organics were washed with 2×200 mL water, dried with brine and Na2SO4, and evaporated under reduced pressure. The residue was taken up in a minimum of diethyl ether and crystallized by adding sufficient hexane to precipatate the product. The solid was collected to give 7.74 g of 2,4-bis(trifluoromethyl) phenyl acetic acid as white crystals, 68.5%.NMR 1H (CDCl3) δ7.93 (s,1H), 7.80 (d, J=7.9 Hz,1H), 7.55 (d, J=7.9 Hz,1H), 3.94 (s,2H).
Reaction SMILES: [C:1]([C:3]1[C:4]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=2[Cl:28])=[C:5]([C:15](N(OC)C)=[O:16])[S:6][C:7]=1[C:8]1[CH:13]=[CH:12][N:11]=[C:10]([F:14])[CH:9]=1)#[N:2].O1CCCC1.[H-].C([Al+]CC(C)C)C(C)C>>[Cl:28][C:22]1[CH:23]=[C:24]([Cl:27])[CH:25]=[CH:26][C:21]=1[C:4]1[C:3]([C:1]#[N:2])=[C:7]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([F:14])[CH:9]=2)[S:6][C:5]=1[CH:15]=[O:16]
Reactant: CON(C)C(=O)c1sc(-c2ccnc(F)c2)c(C#N)c1-c1ccc(Cl)cc1Cl
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: C1CCOC1
Product: N#Cc1c(-c2ccnc(F)c2)sc(C=O)c1-c1ccc(Cl)cc1Cl
Temperature: -78 °C
Reaction time: 1 h
Yield: 74.3 %

Procedure:
To a dried flask were added 4-cyano-3-(2,4-dichlorophenyl)-5-(2-fluoropyridin-4-yl)-N-methoxy-N-methylthiophene-2-carboxamide (1.511 g, 3.463 mmol) and Tetrahydrofuran (91 mmol, 91 mmol). The mixture was cooled to −78° C. and Diisobutylaluminum hydride (17.3 mmol, 17.3 mmol) in hexanes was added. The mixture was stirred at the same temperature for 1 h and then raised to at 0° C. for 15 min. The reaction was quenched by ammonium chloride solution and the mixture was extracted with EtOAc. The organic layer was collected and dried. After evaporation, the residue was purified by column chromatography to afford the title compound (0.97 g, 67%). LC/MS (FA) ES+ 377, 379.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[CH:12]=[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[N:9]3[C:10]=2[C:5]([C:6](=[O:19])[CH2:7][CH2:8]3)=[CH:4][CH:3]=1.O1CCCC1.[BH4-].[Na+]>C(O)C>[OH:19][CH:6]1[C:5]2[C:10]3=[C:11]([CH:12]=[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[N:9]3[CH2:8][CH2:7]1)[C:2]([CH3:1])=[CH:3][CH:4]=2
Reactant: CCOC(=O)c1cc2c(C)ccc3c2n1CCC3=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)c1cc2c(C)ccc3c2n1CCC3O
Temperature: 0 °C
Reaction time: 1 h
Yield: 79.1 %

Procedure:
Ethyl 5,6-dihydro-9-methyl-6-oxo-4H-pyrrolo[3,2,1-ij]quinoline-2-carboxylate (3.00 g, 11.7 mmol) was added to a mixture of tetrahydrofuran (20 ml) and ethanol (80 ml), and the reaction mixture was cooled to 0° C. Then, sodium borohydride (0.44 g, 11.7 mmol) was added and the resulting mixture was stirred at 0° C. for 1 hour. The reaction mixture was concentrated under reduced pressure, and ethyl acetate and then a 5% aqueous sodium hydroxide solution were added to the residue. After being separated, the aqueous layer was further extracted twice with ethyl acetate, and the combined organic layer was washed with a 5% aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the resulting residue was purified by a silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/9) to obtain 2.40 g of ethyl 5,6-dihydro-6-hydroxy-9-methyl-4H-pyrrolo-[3,2,1-ij]-quinoline-2-carboxylate.
Reaction SMILES: [Na].[CH3:2][O:3][CH:4]([O:12]C)[C:5](=[CH:10]O)[C:6](OC)=O.C(O)C.Cl.Cl.[CH2:19]([NH:26][NH2:27])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>O>[CH2:19]([N:26]1[CH:10]=[C:5]([C:4]([O:3][CH3:2])=[O:12])[CH:6]=[N:27]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: COC(=O)C(=CO)C(OC)OC
Reactant: NNCc1ccccc1
Agent: Cl
Agent: [Na]
Solvent: O
Solvent: CCO
Product: COC(=O)c1cnn(Cc2ccccc2)c1
Temperature: 70 °C
Reaction time: 7 h
Yield: 36.4 %

Procedure:
18.68 g of methyl 2-(dimethoxymethyl)-3-hydroxyacrylate sodium salt was added to 80 ml of ethanol, and 18.39 g of benzylhydrazine dihydrochloride was added. The mixture was stirred at 70° C. for 7 hours and then cooled to room temperature. After 100 ml of water was added, the mixture was concentrated to 100 ml under reduced pressure. The concentrated solution was extracted with ethyl acetate. The organic layer was washed with aqueous saturated sodium chloride, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 7.39 g of methyl 1-benzyl-1H-pyrazole-4-carboxylate.
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].[CH3:7][O:8][C:9](=[O:30])[C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[C:12]([NH:17][S:18]([C:21]2[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=2[O:28][CH3:29])(=[O:20])=[O:19])[CH:11]=1.BrCBr>CN(C)C=O>[CH3:7][O:8][C:9]([C:10]1[CH:15]=[CH:14][C:13]2[O:16][CH2:1][N:17]([S:18]([C:21]3[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=3[O:28][CH3:29])(=[O:19])=[O:20])[C:12]=2[CH:11]=1)=[O:30]
Reactant: COC(=O)c1ccc(O)c(NS(=O)(=O)c2cc(Cl)ccc2OC)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: BrCBr
Product: COC(=O)c1ccc2c(c1)N(S(=O)(=O)c1cc(Cl)ccc1OC)CO2
Temperature: 80 °C
Yield: 99.3 %

Procedure:
Potassium carbonate (3.87 g, 28.0 mmol) was added to a solution of 3-(5-chloro-2-methoxy-benzenesulfonylamino)-4-hydroxy-benzoic acid methyl ester (2.08 g, 5.59 mmol) and dibromomethane (2.92 g, 16.5 mmol) in N,N-dimethylformamide (35 mL), and the suspension was heated at 80° C. for 48 h, then the reaction mixture was partitioned between water and dichloromethane. The organic layer was washed with brine, dried (MgSO4), and evaporated. Chromatography (SiO2, heptane-ethyl acetate gradient) produced 3-(5-chloro-2-methoxy-benzenesulfonyl)-2,3-dihydro-benzooxazole-5-carboxylic acid methyl ester (2.13 g, 99%). White solid, MS (ISP)=384.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:10]3[CH:17]=[C:16]([C:18]4[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH2:27][N:28]([CH2:31][CH3:32])[CH2:29][CH3:30])=[CH:20][CH:19]=4)[N:15]([CH2:33][O:34][CH2:35][CH2:36][Si:37]([CH3:40])([CH3:39])[CH3:38])[C:11]=3[N:12]=[CH:13][N:14]=2)[CH:5]=[CH:4][C:3]=1[NH2:41].[CH:42]1([NH:45][C:46](=O)[O:47]C2C=CC=CC=2)[CH2:44][CH2:43]1.O>CS(C)=O>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:10]3[CH:17]=[C:16]([C:18]4[CH:19]=[CH:20][C:21]([O:24][CH2:25][CH2:26][CH2:27][N:28]([CH2:29][CH3:30])[CH2:31][CH3:32])=[CH:22][CH:23]=4)[N:15]([CH2:33][O:34][CH2:35][CH2:36][Si:37]([CH3:38])([CH3:39])[CH3:40])[C:11]=3[N:12]=[CH:13][N:14]=2)[CH:5]=[CH:4][C:3]=1[NH:41][C:46]([NH:45][CH:42]1[CH2:44][CH2:43]1)=[O:47]
Reactant: CCN(CC)CCCOc1ccc(-c2cc3c(Oc4ccc(N)c(Cl)c4)ncnc3n2COCC[Si](C)(C)C)cc1
Reactant: O=C(NC1CC1)Oc1ccccc1
Solvent: O
Solvent: CS(C)=O
Product: CCN(CC)CCCOc1ccc(-c2cc3c(Oc4ccc(NC(=O)NC5CC5)c(Cl)c4)ncnc3n2COCC[Si](C)(C)C)cc1
Temperature: 80 °C
Reaction time: 1.5 h

Procedure:
After dissolving the 2-chloro-4-[6-[4-(3-diethylaminopropoxy)phenyl]-7-(2-trimethylsilanylethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yloxy]phenylamine synthesized in Production Example 160-2 in 0.6 ml of dimethylsulfoxide, 23 mg of phenyl cyclopropylcarbamate was added and the mixture was stirred at 80° C. for 1.5 hours. After further adding 75 mg of phenyl N-cyclopropylcarbamate and stirring at 100° C. for 5 hours, 70 mg of the same reagent was added prior to stirring overnight. The mixture was then returned to room temperature, water was added, and liquid separation and extraction were performed with an ethyl acetate: tetrahydrofuran (5:1) mixed solvent. The organic layer was dried over sodium sulfate, concentrated and subjected to NH silica gel column chromatography (hexane-ethyl acetate) to obtain 18 mg of the title compound.
Reaction SMILES: [NH2:1][C@H:2]([CH2:22][CH3:23])[C:3]([NH:5][C:6]1[CH:7]=[N:8][C:9]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH:19]([CH3:21])[CH3:20])[CH:14]=2)=[CH:10][CH:11]=1)=[O:4].C(N(CC)CC)C.Cl[C:32](Cl)([O:34]C(=O)OC(Cl)(Cl)Cl)Cl.C([O-])(O)=O.[Na+]>ClCCl>[CH2:22]([C@H:2]1[NH:1][C:32](=[O:34])[N:5]([C:6]2[CH:7]=[N:8][C:9]([O:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([CH:19]([CH3:20])[CH3:21])[CH:14]=3)=[CH:10][CH:11]=2)[C:3]1=[O:4])[CH3:23]
Reactant: CC[C@@H](N)C(=O)Nc1ccc(Oc2cccc(C(C)C)c2)nc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC[C@H]1NC(=O)N(c2ccc(Oc3cccc(C(C)C)c3)nc2)C1=O
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
(2R)-2-amino-N-(6-{[3-(1-methylethyl)phenyl]oxy}-3-pyridinyl)butanamide (Intermediate 70, 930 mg) was dissolved in dry dichloromethane (100 mL). The reaction mixture, under argon, was cooled down in an ice bath. Triethylamine (2.482 mL, 17.81 mmol) was added. Then a solution of triphosgene in dry dichloromethane (352 mg, 1.187 mmol dissolved in 40 mL of dichloromethane) was added dropwise. The reaction mixture was stirred at 0° C., under argon, during 10 min. A saturated aqueous solution of NaHCO3 was added (100 mL) and the aqueous layer was extracted with dichloromethane 4 times (4×80 mL). After drying over sodium sulphate, the solvent was removed under vacuum. The residue obtained was purified by silica gel chromatography (Companion system, 120 g silica cartridge), with a gradient cyclohexane/ethyl acetate 100/0 to 55/45. The title compound (5R)-5-ethyl-3-(6-{[3-(1-methylethyl)phenyl]oxy}-3-pyridinyl)-2,4-imidazolidinedione was obtained as a beige powder (768 mg).
Reaction SMILES: [Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[Na+].[Na+].[F:12][C:13]1[CH:18]=[C:17]([I:19])[CH:16]=[CH:15]C=1C.OS(O)(=O)=O.[C:26]([OH:29])(=[O:28])[CH3:27]>>[F:12][C:13]1[CH:18]=[C:17]([I:19])[CH:16]=[CH:15][C:27]=1[C:26]([OH:29])=[O:28]
Reactant: Cc1ccc(I)cc1F
Reactant: CC(=O)O
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: O=C(O)c1ccc(I)cc1F
Reaction time: 0.08 h

Procedure:
A solution of sodium dichromate (25.2 g, 84.0 mmol) in acetic acid (100 mL) was stirred for 10 min, followed by addition of 2-fluoro-4-iodo-1-methylbenzene (10.0 g, 42 mmol). The reaction mixture was stirred for 5 min followed by slow addition of conc.H2SO4 (60 mL) for 1-2 h. The reaction mixture stirred at 90-100° C. for 7-8 h. The reaction mixture was cooled and quenched with ice water. The reaction mass was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulphate and concentrated to afford 5.0 g of the desired product. 1H NMR (300 MHz, DMSO d6): δ 7.58 (t, J=8.4 Hz, 1H), 7.67 (d, J=7.5 Hz, 1H), 7.75 (d, J=8.4 Hz, 1H), 13 (br s, 1H); MS (m/z): 264.99 (M−H)−.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:12]([O:13][C:14]([F:17])([F:16])[F:15])=[CH:11][CH:10]=[CH:9][C:5]=1[CH2:6]CN)[CH3:2].[C:18](Cl)(=[O:21])[CH:19]=[CH2:20].[CH2:23]([N:25](CC)CC)C>C(Cl)Cl>[CH2:1]([O:3][C:4]1[C:12]([O:13][C:14]([F:15])([F:16])[F:17])=[CH:11][CH:10]=[CH:9][C:5]=1[CH2:6][N:25]([CH3:23])[C:18](=[O:21])[CH:19]=[CH2:20])[CH3:2]
Reactant: CCN(CC)CC
Reactant: CCOc1c(CCN)cccc1OC(F)(F)F
Reactant: C=CC(=O)Cl
Solvent: ClCCl
Product: C=CC(=O)N(C)Cc1cccc(OC(F)(F)F)c1OCC
Reaction time: 0.08 h
Yield: 118.3 %

Procedure:
To a solution of (2-ethoxy-3-trifluoromethoxybenzyl)methylamine (0.720 g, 2.08 mmol) in CH2Cl2 (25 mL), was added acryloyl chloride (0.25 mL, 3.15 mmol) drop-wise. After stirring for five minutes, triethylamine (0.43 mL, 3.15 mmol) was added. The solution was allowed to stir under N2 for 3 h. The solution was diluted with CH2Cl2 (30 mL) and then washed with H2O (3×50 mL) and brine (2×100 mL), dried (Na2SO4) and concentrated to yield the title compound (0.746 g, 86%) as a yellow oil and as a mixture of amide rotamers: 1H NMR (500 MHz, CDCl3) δ 7.21-7.02 (m, 3H), 6.67-6.50 (m, 1H), 6.41-6.36 (m, 1H), 5.75-5.58 (m, 1H), 4.75-4.65 (m, 2H), 4.14-4.05 (m, 2H), 3.03-2.99 (m, 3H), 1.43-141 (m, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:31]=[CH:30][CH:29]=[CH:28][C:5]=1[O:6][CH2:7][CH2:8][NH:9][C@H:10]([CH3:27])[CH2:11][C:12]1[CH:13]=[C:14]2[C:18](=[C:19]([C:21]#[N:22])[CH:20]=1)[N:17]([CH2:23][CH2:24][CH2:25][OH:26])[CH2:16][CH2:15]2)[CH3:2].[OH-].[Na+].OO.S([O-])([O-])=[O:37].[Na+].[Na+]>CS(C)=O.O>[CH2:1]([O:3][C:4]1[CH:31]=[CH:30][CH:29]=[CH:28][C:5]=1[O:6][CH2:7][CH2:8][NH:9][C@H:10]([CH3:27])[CH2:11][C:12]1[CH:13]=[C:14]2[C:18](=[C:19]([C:21]([NH2:22])=[O:37])[CH:20]=1)[N:17]([CH2:23][CH2:24][CH2:25][OH:26])[CH2:16][CH2:15]2)[CH3:2]
Reactant: O=S([O-])[O-]
Reactant: CCOc1ccccc1OCCN[C@H](C)Cc1cc(C#N)c2c(c1)CCN2CCCO
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: CCOc1ccccc1OCCN[C@H](C)Cc1cc2c(c(C(N)=O)c1)N(CCCO)CC2
Temperature: 27.5 °C
Reaction time: 8 h
Yield: 76.1 %

Procedure:
(R)-5-[2-[[2-(2-Ethoxyphenoxy)ethyl]amino]propyl]-1-(3-hydroxypropyl)-2,3-dihydro-1H-indole-7-carbonitrile (5.95 g) was dissolved in dimethylsulfoxide (16.4 ml), and 5N sodium hydroxide solution (0.25 ml) was added to the solution. To the mixture was added 30% hydrogen peroxide (1.55 ml) keeping inner temperature below 25° C., and the mixture was stirred overnight at an inner temperature of 25-30° C. A solution of sodium sulfite (2.39 g) in distilled water (82 ml) was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated aqueous sodium bicarbonate solution, distilled water and brine subsequently, and dried over anhydrous sodium sulfate. The solvent was removed in vacuo, the residue was recrystallized from ethyl acetate to give (R)-5-[2-[[2-(2-ethoxyphenoxy)-ethyl]amino]propyl]-1-(3-hydroxypropyl)-2,3-dihydro-1H-indole-7-carboxamide (4.72 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[CH2:15][CH:14]([CH2:16][CH2:17][CH:18]=O)[O:13][N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].Cl.[CH3:21][O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[CH2:15][CH:14]([CH2:16][CH2:17][CH2:18][N:32]3[CH2:31][CH2:30][N:29]([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=4[O:22][CH3:21])[CH2:34][CH2:33]3)[O:13][N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(C2=NOC(CCC=O)C2)cc1OC
Reactant: COc1ccccc1N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(C2=NOC(CCCN3CCN(c4ccccc4OC)CC3)C2)cc1OC
Yield: 59.4 %

Procedure:
3-[3-(3,4-Dimethoxyphenyl)-4,5-dihydroisoxazol-5-yl]propanal (25.8 mg, 0.096 mmol), 1-(2-methoxyphenyl)piperazine hydrochloride (20.0 mg, 0.087 mmol), molecular sieve (5 beads), NaBH(OAc)3 (55.5 mg, 0.262 mmol) and diisopropylethylamine (26.9 L, 0.087 mmol) were reacted in 3 mL of methylene chloride for about 12 hr. With the following processes the same as in Example 1, 22.7 mg (60.0%) of the target compound was obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]2[C:8](=[O:24])[NH:9][C:10]3[C:15]([C:16]=2[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:14][C:13]([Cl:23])=[CH:12][CH:11]=3)[O:4][N:3]=1.[C:25](OC(=O)C)(=[O:27])[CH3:26].N1C(C)=CC=CC=1C>CN(C1C=CN=CC=1)C.CN(C=O)C>[Cl:23][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=[O:24])[C:7]([C:5]1[O:4][N:3]=[C:2]([NH:1][C:25](=[O:27])[CH3:26])[CH:6]=1)=[C:16]2[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1cc(-c2c(-c3ccccc3)c3cc(Cl)ccc3[nH]c2=O)on1
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: Cc1cccc(C)n1
Product: CC(=O)Nc1cc(-c2c(-c3ccccc3)c3cc(Cl)ccc3[nH]c2=O)on1
Temperature: 50 °C

Procedure:
A flask charged with 3-(3-amino-isoxazol-5-yl)-6-chloro-4-phenyl-1H-quinolin-2-one (example 59)(22 mg, 0.063 mmol), acetic anhydride (9 mg, 0.082 mmol), 2,6-lutidine (11 mg, 0.10 mmol), DMAP (10 mg, 0.082 mmol) and DMF (0.5 mL) was heated at 50° C. for 2 hrs. The reaction was concentrated and the title compound was purified by RP-HPLC, eluting with 40-100% CH3CN in 0.1% TFA/H2O over 30 mins to give 15 mg (60%) the title cpd. 1H NMR (400 MHz, DMSO-d6) δ 12.54 (s, 1H), 10.80 (s, 1H), 7.68 (m, 1H), 7.46 (m, 4H), 7.30 (m, 2H), 6.96 (m, 2H), 2.04 (s, 3H). Mass spectrum (ESI, m/z) calcd. for C20H14ClN3O3 379.1, found 380.0 (M+H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[N:5]=[CH:4][N:3]=1.[OH:18][C:19]1[CH:28]=[C:27]2[C:22]([CH:23]=[CH:24][C:25](=[O:29])[NH:26]2)=[CH:21][CH:20]=1.N12CCCN=C1CCCCC2>CC#N>[F:15][C:14]([F:17])([F:16])[C:11]1[CH:12]=[CH:13][C:8]([C:6]2[N:5]=[CH:4][N:3]=[C:2]([O:18][C:19]3[CH:28]=[C:27]4[C:22]([CH:23]=[CH:24][C:25](=[O:29])[NH:26]4)=[CH:21][CH:20]=3)[CH:7]=2)=[CH:9][CH:10]=1
Reactant: FC(F)(F)c1ccc(-c2cc(Cl)ncn2)cc1
Reactant: O=c1ccc2ccc(O)cc2[nH]1
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: O=c1ccc2ccc(Oc3cc(-c4ccc(C(F)(F)F)cc4)ncn3)cc2[nH]1

Procedure:
The title compound was prepared analogous to the methods used in Example 32(e) using 4-chloro-6-(4-trifluoromethyl-phenyl)-pyrimidine, (Example 2(a), Method A), (0.50 g, 1.9 mmol), 7-hydroxy-1H-quinolin-2-one (0.37 g, 2.3 mmol, prepared according to Synthesis 1997, 87–90) and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.35 mL, 2.3 mmol, Aldrich) in CH3CN (40 mL). Purification by flash chromatography (0→2.5% MeOH/CH2Cl2) afforded the title compound as an off-white powder. Mp 288° C. MS (ESI, pos. ion) m/z: 384 (M+1).
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[O:18][C:17]3[CH:19]=[C:20]([S:23]([CH3:26])(=[O:25])=[O:24])[CH:21]=[CH:22][C:16]=3[O:15][CH2:14]2)(=O)=O)=CC=1.[NH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1>C(#N)C>[CH3:26][S:23]([C:20]1[CH:21]=[CH:22][C:16]2[O:15][CH2:14][CH:13]([CH2:12][N:27]3[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]3)[O:18][C:17]=2[CH:19]=1)(=[O:24])=[O:25]
Reactant: C1CCNCC1
Reactant: Cc1ccc(S(=O)(=O)OCC2COc3ccc(S(C)(=O)=O)cc3O2)cc1
Solvent: CC#N
Product: CS(=O)(=O)c1ccc2c(c1)OC(CN1CCCCC1)CO2
Temperature: 120 °C

Procedure:
A mixture of [7-(methylsulfonyl)-2,3-dihydro-1,4-benzodioxin-2-yl]methyl 4-methylbenzenesulfonate (0.6 g, 1.5 mmol), piperidine (1 ml) and ACN (3 ml) was heated under microwave radiation at 120° C. for 20 min. Purification on SCX-3 column (TEA/MeOH) and by flash chromatography through a small plug of silica (DCM/MeOH, 5:95). Yield: 0.4 g, 85%. The amine was converted to the hydrochloric acid salt and crystallized from MeOH/Et2O. M.p. 248° C. MS m/z (rel. intensity, 70 eV) 311 (M+, 1), 310 (M+, 2), 207 (3), 99 (7), 98 (bp).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:14][CH2:13][CH2:12][CH:11]2[CH2:15][N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)=[O:9])=[CH:4][CH:3]=1.[N:21]1([CH2:26][CH2:27][NH2:28])[CH2:25][CH2:24][CH2:23][CH2:22]1>CS(C)=O>[N:21]1([CH2:26][CH2:27][NH:28][C:2]2[CH:7]=[CH:6][C:5]([C:8]([N:10]3[CH2:14][CH2:13][CH2:12][CH:11]3[CH2:15][N:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)=[O:9])=[CH:4][CH:3]=2)[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: NCCN1CCCC1
Reactant: O=C(c1ccc(F)cc1)N1CCCC1CN1CCCC1
Solvent: CS(C)=O
Product: O=C(c1ccc(NCCN2CCCC2)cc1)N1CCCC1CN1CCCC1

Procedure:
For example, (4-fluoro-phenyl)-(2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone (where Y═F) is treated with a suitable nucleophile, in this case, 2-pyrrolidin-1-yl-ethylamine in a suitable solvent such as DMSO and 33% KF/Al2O3 and the reaction is heated for 1-3 days to yield [4-(2-pyrrolidin-1-yl-ethylamino)-phenyl]-(2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][C:10]([O:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:9][CH:8]=2)[C:3]=1[C:20]([NH2:22])=[O:21].Br[CH2:24][C:25]([C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([N+:33]([O-:35])=[O:34])[CH:28]=1)=O>CCO>[N+:33]([C:29]1[CH:28]=[C:27]([C:25]2[NH:1][C:2]3[N:6]([CH:24]=2)[N:5]=[C:4]([C:7]2[CH:8]=[CH:9][C:10]([O:13][C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)=[CH:11][CH:12]=2)[C:3]=3[C:20]([NH2:22])=[O:21])[CH:32]=[CH:31][CH:30]=1)([O-:35])=[O:34]
Reactant: NC(=O)c1c(-c2ccc(Oc3ccccc3)cc2)n[nH]c1N
Reactant: O=C(CBr)c1cccc([N+](=O)[O-])c1
Solvent: CCO
Product: NC(=O)c1c(-c2ccc(Oc3ccccc3)cc2)nn2cc(-c3cccc([N+](=O)[O-])c3)[nH]c12
Temperature: 80 °C
Reaction time: 16 h
Yield: 11.4 %

Procedure:
A mixture of 5-amino-3-(4-phenoxyphenyl)-1H-pyrazole-4-carboxamide (29.4 mg, 0.1 mmol) and 2-bromo-1-(3-nitrophenyl)ethanone (24.4 mg, 0.1 mmol) in EtOH (2 mL) was stirred at 80° C. for 16 hr. The mixture was filtered to afford 5 mg of crude 2-(3-nitrophenyl)-6-(4-phenoxyphenyl)-1H-imidazo[1,2-b]pyrazole-7-carboxamide as a yellow solid. MS (ESI) m/e [M+1]+ 440.0.