Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([NH2:11])[C:3]=1[C:4]([NH2:6])=[O:5].[CH3:12]OC(OC)OC.S(=O)(=O)(O)O.N>CN(C)C(=O)C.CO>[NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:5])[NH:6][CH:12]=[N:11]2
Reactant: COC(OC)OC
Reactant: NC(=O)c1c(N)cccc1N
Agent: N
Agent: O=S(=O)(O)O
Solvent: CC(=O)N(C)C
Solvent: CO
Product: Nc1cccc2nc[nH]c(=O)c12

Procedure:
900 mg (5.958 mmol) 2,6-diaminobenzamide are dissolved in 3.6 ml N,N-dimethylacetamide and combined with 6.3 ml (57.01 mmol) trimethylorthoformate and 792 μl (8.865 mmol) 98% sulphuric acid. After 16 h at 25° C. the reaction mixture is taken up with 20 ml of methanol and the solvent is eliminated in vacuo. The residue is again taken up in 20 ml of methanol, neutralised with concentrated ammonia. The solvent is eliminated in vacuo and the residue purified by chromatography. The carrier used is silica gel and the eluant used is dichloromethane, to which 7% of a mixture of 90% methanol and 10% saturated aqueous ammonia solution are added.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]([C:13]2[CH:17]=[C:16]([NH2:18])[O:15][N:14]=2)[CH3:12])=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3].[C:19]([N:27]=[C:28]=[S:29])(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(Cl)CCl>[C:19]([NH:27][C:28]([NH:18][C:16]1[O:15][N:14]=[C:13]([CH:11]([C:8]2[CH:7]=[CH:6][C:5]([CH2:1][CH:2]([CH3:4])[CH3:3])=[CH:10][CH:9]=2)[CH3:12])[CH:17]=1)=[S:29])(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(N=C=S)c1ccccc1
Reactant: CC(C)Cc1ccc(C(C)c2cc(N)on2)cc1
Solvent: ClCCCl
Product: CC(C)Cc1ccc(C(C)c2cc(NC(=S)NC(=O)c3ccccc3)on2)cc1
Temperature: 60 °C
Reaction time: 5 h

Procedure:
This isoxazol (11.35 g) was dissolved in ethylene dichloride (200 ml) and then benzoyl isothiocyanate (11.9 ml) was added, after which the resulting mixture was stirred at 60° C. for 5 hours. The reaction mixture was concentrated under reduced pressure and a small amount of water was added, after which the resulting mixture was subjected to extraction with ethyl acetate. The organic layer was dried over sodium sulfate and then concentrated under reduced pressure. The residue was isolated by a silica gel column chromatography (hexane/ethyl acetate=2/1) and then purified by a recrystallization method from toluene, to obtain 1-benzoyl-3-{3-[1-(4-isobutyl-phenyl)-ethyl]-isoxazol-5-yl}-thiourea (4.65 g).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([NH2:17])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[N:6][CH:7]=1.Cl[C:19]1[C:24]([NH:25][C:26](=O)[O:27]C(C)(C)C)=[CH:23][CH:22]=[CH:21][N:20]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.CC(C)([O-])C.[Na+]>CC(O)C.C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([N:17]4[C:19]5=[N:20][CH:21]=[CH:22][CH:23]=[C:24]5[NH:25][C:26]4=[O:27])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[N:6][CH:7]=1
Reactant: Cc1ccc(-n2ncc3cc(N)ccc32)nc1
Reactant: CC(C)(C)OC(=O)Nc1cccnc1Cl
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: Cc1ccccc1
Solvent: O
Solvent: CC(C)O
Product: Cc1ccc(-n2ncc3cc(-n4c(=O)[nH]c5cccnc54)ccc32)nc1
Temperature: 90 °C
Reaction time: 24 h
Yield: 64.6 %

Procedure:
Under argon atmosphere, a mixture of 1-(5-methylpyridin-2-yl)-1H-indazol-5-amine (71 mg), tert-butyl 2-chloropyridin-3-ylcarbamate (80 mg), Pd2(dba)3 (29.0 mg), Xantphos (36.6 mg) and sodium tert-butoxide (33.5 mg) in 2-propanol (2 mL) and toluene (0.5 mL) was stirred at 90° C. for 24 h, treated with water and extracted with EtOAc. The organic layer was separated, dried over MgSO4 and concentrated in vacuo. The residue was chromatographed on silica gel eluting with AcOEt/Hexane to give the title compound as white crystals (70.0 mg).
Reaction SMILES: [O:1]1[CH:6]=[CH:5][CH2:4][CH2:3][CH:2]1[NH2:7].[H][H]>CO>[O:1]1[CH:6]=[CH:5][CH2:4][CH2:3][CH:2]1[NH2:7].[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[NH2:7]
Reactant: [H][H]
Agent: NC1CCC=CO1
Solvent: CO
Product: NC1CCCCO1

Procedure:
For example, hydrogenation of the dihydropyran-ene-amine to form the dihydropyran-amine may be accomplished in methanol, at 25° C., using about 88-110 psi hydrogen pressure, using 1-2 mol % of a catalyst generated from [Rh(nbd)2]BF4 and SL-M004-1 (SL-M004-1: (αR,αR)-2,2′-bis(α-N,N-dimethyl-aminophenylmethyl)-(S,S)-1,1′-bis[di(3,5-dimethyl-4-methoxyphenyl)phosphino]ferrocene, available from Solvias, Inc. Fort Lee, N.J.). Hydrogenation of the dihydropyran-amine to form the tetrahydropyran-amine may be accomplished at 50° C., using about 80 bar hydrogen pressure and 4 mol % catalyst loading of a catalyst generated from [Rh(COD)2]O3SCF3 and SL-A109-2 (solvent: THF) or [Rh(nbd)2]BF4 and SL-A109-2 (solvent: methanol) (SL-A109-2: (S)-(6,6′-dimethoxybiphenyl-2,2′-diyl)-bis[bis(3,5-di-tert-butyl-4-methoxyphenyl)phosphine], available from Solvias, Inc. Fort Lee, N.J.).
Reaction SMILES: C(O[C@H:5]1[NH:8][C:7](=[O:9])[C@@H:6]1[C@H:10]([O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])[CH3:11])(=O)C.C(N1CCCCC1)C.FC(F)(F)S(O[Si](C)(C)C)(=O)=O.[CH2:40]([O:43][C:44]([N:46]1[CH2:50][C@H:49]([O:51][C:52](=[O:55])[NH:53][CH3:54])[CH2:48][C@H:47]1[CH:56]=[C:57]([CH3:61])[C:58](=[O:60])[CH3:59])=[O:45])[CH:41]=[CH2:42].C(=O)([O-])O.[Na+]>ClCCl.O.C(OCC)(=O)C>[CH2:40]([O:43][C:44]([N:46]1[CH2:50][C@H:49]([O:51][C:52](=[O:55])[NH:53][CH3:54])[CH2:48][C@H:47]1[CH:56]=[C:57]([CH3:61])[C:58](=[O:60])[CH2:59][C@H:5]1[NH:8][C:7](=[O:9])[C@@H:6]1[C@H:10]([O:12][Si:13]([C:16]([CH3:17])([CH3:18])[CH3:19])([CH3:14])[CH3:15])[CH3:11])=[O:45])[CH:41]=[CH2:42]
Reactant: C=CCOC(=O)N1C[C@H](OC(=O)NC)C[C@H]1C=C(C)C(C)=O
Reactant: CC(=O)O[C@H]1NC(=O)[C@@H]1[C@@H](C)O[Si](C)(C)C(C)(C)C
Agent: CCN1CCCCC1
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: O=C([O-])O
Solvent: O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: C=CCOC(=O)N1C[C@H](OC(=O)NC)C[C@H]1C=C(C)C(=O)C[C@H]1NC(=O)[C@@H]1[C@@H](C)O[Si](C)(C)C(C)(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 72.2 %

Procedure:
To a solution of (3R,4R)-4-acetoxy-3-[(1R)-1-t-butyldimethylsilyloxyethyl]-2-oxoazetidine (1.48 g) and N-ethylpiperidine (0.69 ml) in dichloromethane (10 ml) was added trimethylsilyl trifluoromethanesulfonate (1.0 ml) at -20° C., and the resulting mixture was stirred at 0° C. for 1 hour (Solution A). To a solution of (2S,4R)-1-allyloxycarbonyl-4-(methylcarbamoyloxy)-2-(2-methyl-3-oxo-1-butenyl)pyrrolidine (1.60 g) and N-ethylpiperidine (1.50 ml) in dichloromethane (20 ml) was added trimethylsilyl trifluoromethanesulfonate (2.5 ml) at -20° C. and the resulting mixture was stirred at 0° C. for 1 hour. To this mixture was added dropwise the above obtained Solution A at 0° C. and the resulting mixture was stirred for another 1 hour at 0° C. The resulting mixture was taken up into a mixture of ethyl acetate (150 ml) and water (150 ml) and the mixture was stirred at ambient temperature for 2 hours. After adjusting pH to around 6.5 with aqueous sodium hydrogen carbonate, the organic layer was separated, washed with brine, dried over magnesium sulfate and evaporated in vacuo. The residue was chromatographed on silica gel (75 ml) eluting with a mixture of n-hexane and ethyl acetate (7:3-0.10 V/V) to give (3S,4R)-4-[4-{(2S,4R)-1-allyloxycarbonyl-4-(methylcarbamoyloxy)pyrrolidin-2-yl}-3-methyl-2-oxo-3-butenyl]-3-[(1R)-1-t-butyldimethylsilyloxyethyl]-2-oxoazetidine (2.00 g).
Reaction SMILES: [CH:1]([C:3]1([OH:11])[CH:8]2[CH2:9][CH2:10][N:5]([CH2:6][CH2:7]2)[CH2:4]1)=[CH2:2].Br[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)=[CH:15][CH:14]=1>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu]I.CN(C)C=O>[N:21]1[CH:22]=[CH:23][CH:24]=[C:19]([C:16]2[CH:15]=[CH:14][C:13]([CH:2]=[CH:1][C:3]3([OH:11])[CH:8]4[CH2:9][CH2:10][N:5]([CH2:6][CH2:7]4)[CH2:4]3)=[CH:18][CH:17]=2)[CH:20]=1
Reactant: Brc1ccc(-c2cccnc2)cc1
Reactant: C=CC1(O)CN2CCC1CC2
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: OC1(C=Cc2ccc(-c3cccnc3)cc2)CN2CCC1CC2
Temperature: 130 °C
Reaction time: 4 h
Yield: 29.7 %

Procedure:
A mixture of 3-ethenyl-3-hydroxyquinuclidine (673 mg), 3-(4-bromophenyl)pyridine (1.08 g), bis-(triphenylphosphine)-palladium (II) chloride (140 mg), copper (I) iodide (70 mg), and dimethylformamide (10 ml) was stirred at 130° C. under an atmosphere of argon for 4 hours. The mixture was evaporated and the residue was paritioned between aqueous 2M sodium hydroxide solution (10 ml) and dichloromethane (10 ml). The organic layer was separated, washed with dichloromethane (2×10 ml), dried (MgSO4) and evaporated. The residue was crystallised from acetonitrile to give 3-[2-(4-[3-pyridyl]phenyl)ethenyl]-3-hydroxyquinuclidine (400 mg) as a solid, m.p. 195°-198° C.; microanalysis, found: C, 76.4; H, 7.2; N, 8.6%; C20H22N2O.0.5H2O requires: C, 76.2; H, 7.3; N, 8.9%; NMR (DMSO-d6 +CD3COOD): 1.7-2.15(4H, m), 2.35(1H, m), 3.15-3.4(5H, m), 3.5(1H, d), 6.7(1H, d), 6.9(1H, d), 7.5-7.8(7H, m), 8.15(1H, d); m/Z 307 (M+H).
Reaction SMILES: [OH:1][C:2]1[C:3]([OH:18])=[CH:4][C:5]2[O:9][N:8]=[C:7]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[CH3:16])[C:6]=2[CH:17]=1.C(=O)([O-])[O-].[K+:23].[K+].Cl[CH:26](Cl)[C:27]([O:29]C)=[O:28].O>CN(C)C=O>[K+:23].[C:11]1([CH3:16])[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[C:7]1[C:6]2[CH:17]=[C:2]3[O:1][CH:26]([C:27]([O-:29])=[O:28])[O:18][C:3]3=[CH:4][C:5]=2[O:9][N:8]=1
Reactant: Cc1ccccc1-c1noc2cc(O)c(O)cc12
Reactant: COC(=O)C(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccccc1-c1noc2cc3c(cc12)OC(C(=O)[O-])O3
Reaction time: 1.5 h
Yield: 47.4 %

Procedure:
A mixture of 5,6-dihydroxy-3-(o-tolyl)-1,2-benzisoxazole (4.7 g), potassium carbonate (12.1 g), methyl dichloroacetate (4.2 g) in N,N-dimethylformamide (40 ml) was stirred at 90°-95° C. for 1.5 hours. After cooling, water (10 ml) was added to the mixture followed by stirring at 80°-90° C. for 10 minutes. After cooling the mixture was extracted with ether, and then the ether layer was washed with water, dried and evaporated to remove the solvent. The residue was dissolved in a potassium bicarbonate aqueous solution, and then ethanol was added to the solution. The resulting precipitate was collected by filtration, washed with ethanol and dried in air to give 3.1 g of 3-(o-tolyl)-1,3-dioxolo [4,5-f]-1,2-benzisoxazole-6-carboxylic acid potassium salt. The resulting potassium salt was dissolved in a small amount of water, and after acidifying it with hydrochloric acid, was extracted with ether. The ether layer was washed with water, dried and evaporated to remove the solvent. The residue was recrystallized from acetonitrile to give 1.9 g of 3-(o-tolyl)-1,3-dioxolo[4,5-f]-1,2-benzisoxazole-6-carboxylic acid. m.p.: 166-170 (decomposition)
Reaction SMILES: [C:1]([OH:6])(=O)[CH2:2][CH2:3][CH3:4].C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:40][C:41]1[C:42]([NH:59][CH:60]2[CH2:65][CH2:64][N:63]([CH2:66][CH2:67][C:68]#[N:69])[CH2:62][CH2:61]2)=[C:43]2[CH:49]=[CH:48][N:47]([S:50]([C:53]3[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=3)(=[O:52])=[O:51])[C:44]2=[N:45][CH:46]=1>CN(C=O)C.C(Cl)Cl>[C:53]1([S:50]([N:47]2[C:44]3=[N:45][CH:46]=[C:41]([NH:40][C:1](=[O:6])[CH2:2][CH2:3][CH3:4])[C:42]([NH:59][CH:60]4[CH2:61][CH2:62][N:63]([CH2:66][CH2:67][C:68]#[N:69])[CH2:64][CH2:65]4)=[C:43]3[CH:49]=[CH:48]2)(=[O:51])=[O:52])[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1
Reactant: N#CCCN1CCC(Nc2c(N)cnc3c2ccn3S(=O)(=O)c2ccccc2)CC1
Reactant: CCCC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCC(=O)Nc1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1NC1CCN(CCC#N)CC1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
Butyric acid (0.029 ml, 0.321 mmol), diisopropylethylamine (0.065 ml, 0.375 mmol), and HATU (0.122 g, 0.321 mmol) were added sequentially to a solution of 3-[4-(5-amino-1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-4-ylamino)-piperidin-1-yl]-propionitrile (0.130 g, 0.306 mmol, prepared as described in Example 118) in a 4:1 mixture of CH2Cl2 and DMF (5 ml) at 25° C. The reaction mixture was stirred for 15 h at 25° C., then was partitioned between saturated NaHCO3 (6 ml) and CH2Cl2 (2 ml). The phases were separated using a phase separation column (Biotage) and the organic layer was concentrated under reduced pressure to give crude N-{1-benzenesulfonyl-4-[1-(2-cyano-ethyl)-piperidin-4-ylamino]-1H-pyrrolo[2,3-b]pyridin-5-yl}-butyramide as a brown oil. LCMS (Method G, ESI): RT=0.59 min, m+H=495.3. This material was used in the next step below without additional purification or characterization.
Reaction SMILES: [OH:1][NH:2][C:3](=[NH:5])[CH3:4].[H-].[Na+].CO[C:10]([C:12]1[N:13]([CH:17]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:19][C:18]2([CH3:27])[CH3:26])[CH:14]=[N:15][CH:16]=1)=O>C1COCC1>[CH3:26][C:18]1([CH3:27])[CH2:19][C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:17]1[N:13]1[C:12]([C:10]2[O:1][N:2]=[C:3]([CH3:4])[N:5]=2)=[CH:16][N:15]=[CH:14]1
Reactant: CC(=N)NO
Reactant: COC(=O)c1cncn1C1c2ccccc2CC1(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1noc(-c2cncn2C2c3ccccc3CC2(C)C)n1
Temperature: 0 °C

Procedure:
To a solution N-hydroxy-acetamidine (137 mg, 1.85 mmol) in THF (5 mL) is added 4 angstrom molecular sieves (500 mg) followed by a 60% oil dispersion of NaH (80 mg, 2.0 mmol). The heterogeneous mixture is heated at 60° C. for 1 hour at which time a solution of 3-(2,2-dimethyl-indan-1-yl)-3H-imidazole-4-carboxylic acid methyl ester, which can be prepared as described in Example 10, (200 mg, 0.74 mmol) in THF (5 mL) is added. The reaction is heated at reflux for 1.5 hours, at which time the reaction is cooled to 0° C. and quenched with water. The reaction is diluted with dichloromethane and filtered. The layers are separated and the aqueous layer is extracted three times with dichloromethane. The organic layers are combined, dried with Na2SO4, filtered, and concentrated. The resulting residue is purified by silica gel flash chromatography (ethyl acetate-dichloromethane, 0:1 to 1:9) to afford 5-[3-(2,2-Dimethyl-indan-1-yl)-3H-imidazol-4-yl]-3-methyl-[1,2,4]oxadiazole; HRMS: (ESI) m/z 259.1566 [(M+H)+: Calcd for C17H19N4O: 295.1559]; 1H NMR (400 MHz, CDCl3) δ ppm 0.75 (s, 3 H), 1.27 (s, 3 H), 2.50 (s, 3 H), 2.71-3.10 (m, 2 H), 6.37 (s, 1 H), 7.17 (s, 1 H), 7.23-7.43 (m, 4 H), 7.98 (s, 1 H).
Reaction SMILES: Cl.[NH2:2][CH:3]([C:5]1[NH:6][C:7]([C:13]2[CH:22]=[CH:21][CH:20]=[C:19]3[C:14]=2[N:15]=[C:16]([NH:24][C:25]([CH3:28])([CH3:27])[CH3:26])[C:17]([CH3:23])=[N:18]3)=[CH:8][C:9]=1[C:10]([OH:12])=O)[CH3:4].CCN(C(C)C)C(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1.N1(P(=O)(N2CCCC2)N2CCCC2)CCCC1.C(=O)=O>CN(C=O)C.C(Cl)Cl.CO>[C:25]([NH:24][C:16]1[C:17]([CH3:23])=[N:18][C:19]2[C:14]([N:15]=1)=[C:13]([C:7]1[NH:6][C:5]3[C@@H:3]([CH3:4])[NH:2][C:10](=[O:12])[C:9]=3[CH:8]=1)[CH:22]=[CH:21][CH:20]=2)([CH3:27])([CH3:28])[CH3:26]
Reactant: Cc1nc2cccc(-c3cc(C(=O)O)c(C(C)N)[nH]3)c2nc1NC(C)(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C=O
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CO
Product: Cc1nc2cccc(-c3cc4c([nH]3)[C@@H](C)NC4=O)c2nc1NC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 25 %

Procedure:
To a mixture of 2-(1-aminoethyl)-5-(3-(tert-butylamino)-2-methylquinoxalin-5-yl)-1H-pyrrole-3-carboxylic acid hydrochloride (326c) (⅔ of the crude material from previous step, estimated to be 9.4 mmol) in 30 mL of DMF and 25 mL of DCM at 0° C. was added DIEA (0.98 mL, 56.4 mmol) and (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (Sigma-Aldrich Chemical Company, Inc.) (6.11 g, 11.75 mmol). The resulting homogeneous solution was stirred at RT for 8 h. It was diluted with 300 mL of DCM, washed sequentially with 15 mL of water, 2×10 mL of 1 N NaOH, and 10 mL of brine. The organic solution was concentrated and the residue was purified on a silica gel column (eluted with a gradient of 1-5% MeOH in DCM) to provide a brown amorphous solid containing 2-(3-(tert-butylamino)-2-methylquinoxalin-5-yl)-6-methyl-5,6-dihydropyrrolo[3,4-b]pyrrolo-4(1H)-one (326d), m/z (ESI, +ve) 350.0 (M+H)+; and a significant amount of undesired side product, tri(pyrrolidin-1-yl)phosphine oxide, m/z (ESI, +ve) 258.0 (M+H)+. The individual enantiomers of Example 326d were obtained by chiral SFC (Column: Chiralcel OJH (250×20 mm, 5μ); Mobile Phase: 85:15 (A:B); A: Liquid CO2; B: MeOH (20 mM NH3); Flow Rate: 70 mL/min; Oven Temp: 40° C.; Inlet Pressure: 100 bar; Wavelength: 278 nm) to give Example 326 (first eluting product) and Example 327 (second eluting product). Example 326: (6R)-2-(3-(tert-butylamino)-2-methyl-5-quinoxalinyl)-6-methyl-5,6-dihydropyrrolo[3,4-b]pyrrol-4(1H)-one (810 mg, 25% yield, >99% ee) as a yellow crystalline solid was obtained. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.00 (1H, br.), 7.83 (1H, dd, J=7.4, 1.2 Hz), 7.64 (2H, m), 7.37 (1H, t, J=7.7 Hz), 6.85 (1H, d, J=1.4 Hz), 6.02 (1H, s), 4.57 (1H, q, J=6.6 Hz), 2.58 (3H, s), 1.56 (9H, s), 1.40 (3H, d, J=6.7 Hz). m/z (ESI, +ve) 350.0 (M+H)+. Example 327: (65)-2-(3-(tert-butylamino)-2-methyl-5-quinoxalinyl)-6-methyl-5,6-dihydropyrrolo[3,4-b]pyrrol-4(1H)-one (85 mg, 2.6% yield, >99% ee) as a brown crystalline solid was obtained. m/z (ESI, +ve) 350.0 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([O:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[C:18]([F:23])[CH:17]=2)=[C:8]([CH:14]=1)[C:9]([O:11][CH2:12][CH3:13])=[O:10])([O-])=O.NC1C=CC=CC=1>C(O)C>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([O:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[C:18]([F:23])[CH:17]=2)=[C:8]([CH:14]=1)[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: CCOC(=O)c1cc([N+](=O)[O-])ccc1Oc1ccc(F)c(F)c1
Solvent: CCO
Solvent: Nc1ccccc1
Product: CCOC(=O)c1cc(N)ccc1Oc1ccc(F)c(F)c1
Yield: 97.2 %

Procedure:
Using the method of Example 17.3, ethyl 5-nitro-2-(3,4-difluorophenoxy)benzoate (0.76 g) in ethanol (8 mL) was converted to the corresponding aniline derivative which was obtained as an oil (0.67 g).
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH2:6][CH2:7][CH3:8])=[O:3].[NH2:9][C:10]1[CH:11]=[C:12]([CH:21]=[CH:22][CH:23]=1)[NH:13][C:14](=[O:20])/[CH:15]=[C:16](\[O:18][CH3:19])/[CH3:17].O1CCCC1>C(N(CC)CC)C>[CH2:5]([O:4][C:2]([NH:9][C:10]1[CH:11]=[C:12]([CH:21]=[CH:22][CH:23]=1)[NH:13][C:14](=[O:20])/[CH:15]=[C:16](\[O:18][CH3:19])/[CH3:17])=[O:3])[CH2:6][CH2:7][CH3:8]
Reactant: CCCCOC(=O)Cl
Reactant: CO/C(C)=C\C(=O)Nc1cccc(N)c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCCOC(=O)Nc1cccc(NC(=O)/C=C(/C)OC)c1
Temperature: 5 °C
Reaction time: 16 h
Yield: 89.8 %

Procedure:
12 g of n-butyl chloroformate were slowly added to a mixture of 16.5 g of m-amino-3-methoxy-crotonanilide, 320 ml of tetrahydrofuran and 8.9 g of triethylamine cooled to 5° C. and the mixture was stirred for 16 hours and then vacuum filtered. The residue was chromatographed over silica gel and was eluted with an 8- 2 methylene chloride-acetone mixture to obtain 22 g of m-(n-butoxycarbonylamino)-3-methoxy-crotonanilide melting at 100° C.
Reaction SMILES: [CH3:1][C:2]([S@@:5]([NH2:7])=[O:6])([CH3:4])[CH3:3].[CH2:8]([O:10][C:11](=[O:22])[C:12]([C:14]1[CH:19]=[C:18]([Br:20])[CH:17]=[CH:16][C:15]=1[F:21])=O)[CH3:9]>O1CCCC1.C(OCC)(=O)C.[O-]CC.[Ti+4].[O-]CC.[O-]CC.[O-]CC>[CH2:8]([O:10][C:11](=[O:22])/[C:12](/[C:14]1[CH:19]=[C:18]([Br:20])[CH:17]=[CH:16][C:15]=1[F:21])=[N:7]\[S@:5]([C:2]([CH3:4])([CH3:3])[CH3:1])=[O:6])[CH3:9]
Reactant: CC(C)(C)[S@@](N)=O
Reactant: CCOC(=O)C(=O)c1cc(Br)ccc1F
Agent: [Ti+4]
Agent: CC[O-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)/C(=N\[S@@](=O)C(C)(C)C)c1cc(Br)ccc1F
Temperature: 70 °C
Reaction time: 3.5 h

Procedure:
A solution of (S)-(−)-2-methyl-2-propanesulfinamide (2.35 g, 19.4 mmol) and (5-bromo-2-fluoro-phenyl)-oxo-acetic acid ethyl ester (5.33 g, 19.4 mmol) in tetrahydrofuran (80 ml) was treated at room temperature with titanium(IV) ethoxide (8.04 ml, 38.8 mmol). The light brown solution was stirred at 70° C. for 3.5 hours. For the workup, the cooled reaction mixture was poured into ice water, diluted with ethyl acetate, and filtered through a pad of Dicalite. The organic layer was separated, washed with brine, dried over sodium sulfate, and finally evaporated at reduced pressure. The crude product (6.7 g) was purified by chromatography on silica gel using a gradient of cyclohexane and dichloromethane=100/0 to 0/100 as the eluent. (S)-(5-bromo-2-fluoro-phenyl)-[(Z)-2-methyl-propane-2-sulfinylimino]-acetic acid ethyl ester was obtained as a yellow oil (4.9 g, 66% of theory). Mass (calculated) C14H17BrFNO3S [378.260]; (found) [M+H]+=378, [M+2-H]+=380.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:16])=[C:4]([C:9]([O:12][CH2:13][CH2:14][OH:15])=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[Br:1][C:2]1[C:3]([CH3:16])=[C:4]([C:9]([O:12][CH2:13][CH:14]=[O:15])=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1c(OCCO)ccc(Br)c1C
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: COC(=O)c1c(OCC=O)ccc(Br)c1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.7 %

Procedure:
To a solution of methyl 3-bromo-6-(2-hydroxyethoxy)-2-methylbenzoate (126a, 126 mg, 0.436 mmol) in DCM (5 mL) was added Dess-Martin periodinane (192 mg, 0.429 mmol). The solution was stirred at room temperature for 2 hours. The solution was purified directly by column chromatography (silica gel, heptanes/EtOAc) to give methyl 3-bromo-2-methyl-6-(2-oxoethoxy)benzoate (126b, 111 mg, 90% yield) as a clear oil.
Reaction SMILES: [CH3:1][Mg+].[Br-].CON(C)[C:7]([C:9]1[C:14]([O:15][CH3:16])=[CH:13][C:12](=[O:17])[N:11]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=2)[N:10]=1)=[O:8]>C1COCC1>[C:7]([C:9]1[C:14]([O:15][CH3:16])=[CH:13][C:12](=[O:17])[N:11]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:26])([F:27])[F:25])[CH:19]=2)[N:10]=1)(=[O:8])[CH3:1]
Reactant: COc1cc(=O)n(-c2cccc(C(F)(F)F)c2)nc1C(=O)N(C)OC
Reactant: C[Mg+]
Agent: [Br-]
Solvent: C1CCOC1
Product: COc1cc(=O)n(-c2cccc(C(F)(F)F)c2)nc1C(C)=O
Reaction time: 1 h
Yield: 45.3 %

Procedure:
MeMgBr (1 M solution in THF, 4 mL, 12 mmol) was added dropwise at −78° C. to a solution of N,4-dimethoxy-N-methyl-6-oxo-1-[3-(trifluoromethyl)phenyl]-1,6-dihydropyridazine-3-carboxamide (1.43 g, 4 mmol) in THF (15 mL). After stirring for 1 h, the reaction mixture was quenched with saturated NH4Cl aqueous solution and extracted with AcOEt. The extract was washed with brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with hexane/AcOEt (1/1) and recrystallized from hexane/AcOEt to give the title compound (566 mg, 45% yield) as a white solid: mp 136-138° C.; NMR (300 MHz, CDCl3): δ ppm 2.57 (3H, s), 3.93 (3H, s), 6.31 (1H, s), 7.63 (1H, t, J=7.9 Hz), 7.69 (1H, d, J=7.9 Hz), 7.84-7.88 (1H, m), 7.91 (1H, s). Anal. Calcd for C14H11F3N2O3: C, 53.85; H, 3.55; N, 8.97. Found: C, 53.96; H, 3.57; N, 8.96.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][N:16]=3)[CH:11]=[C:10]([CH2:18][CH2:19][CH2:20][C:21]3[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=3)[C:9]2=[O:27])[CH:5]=[CH:6][CH:7]=1.N1C=CC=CC=1.[C:34](OC(=O)C)(=[O:36])[CH3:35]>>[C:34]([NH:1][C:2]1[CH:3]=[C:4]([N:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][N:16]=3)[CH:11]=[C:10]([CH2:18][CH2:19][CH2:20][C:21]3[CH:22]=[CH:23][N:24]=[CH:25][CH:26]=3)[C:9]2=[O:27])[CH:5]=[CH:6][CH:7]=1)(=[O:36])[CH3:35]
Reactant: Nc1cccc(-n2c(=O)c(CCCc3ccncc3)cc3cccnc32)c1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)Nc1cccc(-n2c(=O)c(CCCc3ccncc3)cc3cccnc32)c1
Yield: 82 %

Procedure:
1-(3-Aminophenyl)-3-[3-(pyridin-4-yl)propyl]-1,8-naphthyridin-2(1H)-one (100 mg, 0.28 mmol; prepared in Synthetic Example 7) was heated in acetic anhydride (0.5 ml) and pyridine (0.5 ml) at 100° C. for 20 min, concentrated, neutralized with saturated aqueous sodium hydrogen carbonate, and extracted with chloroform. The extract was treated according to conventional techniques. Recrystallization from DMF yielded 1-(3-acetylaminophenyl)-3-[3-(pyridin-4-yl)propyl]-1,8-naphthyridin-2(1H)-one (91.3 mg, 82%; mp 200–202° C./DMF).