Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[CH2:13][N:12]([C:14]([N:16]([C@H:18]2[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][C@H:19]2[F:25])[CH3:17])=[O:15])[C@:11]([CH2:32][OH:33])([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:10]=1.C1C=C(Cl)C=C(C(OO)=[O:42])C=1>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[CH2:13][N:12]([C:14]([N:16]([C@H:18]2[CH2:23][CH2:22][N+:21]([CH3:24])([O-:42])[CH2:20][C@H:19]2[F:25])[CH3:17])=[O:15])[C@:11]([CH2:32][OH:33])([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:10]=1
Reactant: CN1CC[C@H](N(C)C(=O)N2CC(c3cc(F)ccc3F)=C[C@@]2(CO)c2ccccc2)[C@H](F)C1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CN(C(=O)N1CC(c2cc(F)ccc2F)=C[C@@]1(CO)c1ccccc1)[C@H]1CC[N+](C)([O-])C[C@H]1F
Reaction time: 0.5 h

Procedure:
To a solution of 20 mg (0.044 mmol) of 3-1 in 1 mL of CH2Cl2 at 0° C. was added 11 g (˜0.048 mmol) of mCPBA. The ice-bath was removed and the reaction was stirred for 30 min. The mixture was partitioned with EtOAc and saturated aqueous NaHCO3, separated, washed with H2O, brine, dried over Na2SO4 and concentrated by rotary evaporation. The residue was loaded onto a silica gel column and eluted with EtOAc—20:1:1 EtOH/NH4OH/H2O to provide 9-1 as a white foam. Data for 9-1: 1HNMR (500 MHz, CDCl3) δ 7.4-7.2 (m, 5H), 7.1-6.9 (nm, 3H), 6.25 (s, 1H), 5.0-4.9 (m, 2H), 4.7. (m, 1H), 4.5 (m, 1H), 4.3-4.2 (m, 1H), 4.0 (m, 2H), 3.7 (m, 1H), 3.4-3.3 (m, 2H), 3.3 (s, 3H), 3.2 (s, 3H), 2.5-1.9 (bs, 2H), 1.8 (m, 1H) ppm. HRMS (ES) calc'd M+H for C25H28F3N3O3: 476.2156. Found: 476.2165.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[CH3:9])=[CH:4][C:3]=1[F:12].C([Li])CCC.CN([CH:21]=[O:22])C>C1COCC1>[F:10][C:8]([C:5]1[CH:6]=[CH:7][C:2]([CH:21]=[O:22])=[C:3]([F:12])[CH:4]=1)([F:11])[CH3:9]
Reactant: CN(C)C=O
Reactant: CC(F)(F)c1ccc(Br)c(F)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(F)(F)c1ccc(C=O)c(F)c1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 42.3 %

Procedure:
To a solution of 1-bromo-4-(1,1-difluoroethyl)-2-fluorobenzene (2.1 g, 8.79 mmol) in THF (30.3 mL) was added n-butyllithium (1.6M in hexanes, 5.60 mL) over ˜20 min at −78° C. The mixture was stirred for 30 min at −78° C. and DMF (1.02 mL, 13.18 mmol) was added dropwise over ˜4 min. Stirring was continued for 1 hr, the mixture was diluted/quenched with 1N aqueous HCl/MeOH (2/1, 15 mL) and allowed to warm to room temperature. The reaction mixture was diluted further with water (50 mL) and extracted with diethylether (2×50 mL). The combined organic layers were washed with 1N aqueous sodium hydroxide solution (50 mL) and brine (100 mL), dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by column chromatography [SiO2, 40 g, heptane/ethyl acetate] providing 4-(1,1-difluoroethyl)-2-fluorobenzaldehyde (699 mg) as a dark yellow, volatile oil, which was contaminated with 1-bromo-4-(1,1-difluoroethyl)-2-fluorobenzene. 1H NMR (400 Mhz, CDCl3) δ ppm 10.40 (s, 1H), 7.95 (t, J=7.4 Hz, 1H), 7.39-7.47 (m, 2H), 7.35 (d, J=10.6 Hz, 1H), 1.94 (t, J=18.2 Hz, 4H) 7.73 (dd, J=7.2, 8.1 Hz, 1H).
Reaction SMILES: [C:1]([C:4]1[C:5]([O:23][CH3:24])=[C:6]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[C:14]([C:19](OC)=[O:20])[CH:13]=2)[C:7]([CH3:11])=[C:8]([Cl:10])[CH:9]=1)(=[O:3])[CH3:2].[NH3:25].CO>>[C:1]([C:4]1[C:5]([O:23][CH3:24])=[C:6]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[C:14]([C:19]([NH2:25])=[O:20])[CH:13]=2)[C:7]([CH3:11])=[C:8]([Cl:10])[CH:9]=1)(=[O:3])[CH3:2]
Reactant: COC(=O)c1cc(-c2c(C)c(Cl)cc(C(C)=O)c2OC)ccc1F
Reactant: N
Solvent: CO
Product: COc1c(C(C)=O)cc(Cl)c(C)c1-c1ccc(F)c(C(N)=O)c1
Temperature: 90 °C

Procedure:
A mixture of methyl 3′-acetyl-5′-chloro-4-fluoro-2′-methoxy-6′-methylbiphenyl-3-carboxylate (50 mg, 0.1 mmol) and 7.0 M ammonia in methanol (2.0 mL, 14 mmol) was heated at 90° C. in a sealed tube overnight. After evaporating the mixture to dryness, the residue was used directly in next step. LCMS calculated for C17H16ClFNO3 (M+H)+: m/z=336.1. found: 336.0.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1.[Al+3].[Cl-].[Cl-].[Cl-].[C:14]1([CH2:20][C:21](Cl)=[O:22])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O>C(Cl)Cl>[C:14]1([CH2:20][C:21]([C:3]2[C:4]3[C:5](=[N:6][CH:7]=[CH:8][CH:9]=3)[NH:1][CH:2]=2)=[O:22])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: c1cnc2[nH]ccc2c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: O=C(Cc1ccccc1)c1c[nH]c2ncccc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 65 %

Procedure:
Modification of Method A: To a mixture of 1H-pyrrolo[2,3-b]pyridine (1.0 g, 8.46 mmol) and AlCl3 (3.4 g, 25.50 mmol) in dry methylene chloride (20 mL) was added phenyl acetyl chloride (3.27 g, 21.15 mmol) at room temperature. The solution was then stirred at room temperature (RT) for 4 hrs. The mixture was poured into iced water and extracted with methylene chloride (3×20 mL). The combined organic layers were dried over MgSO4, filtered, and evaporated. The residue was then dissolved in MeOH (20 mL) and treated with 6N NaOH (5 mL) at RT for 2 hrs. Evaporated most of the solvent, the residue was acidified with 6N HCl and extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered, and evaporated. The residue was purified by flash column to give desired product (1.3 g, 65%). MS (ES−): m/e=235.2 (M−H); LC/Method A/2.86 min.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9]([S:10][CH2:11][CH3:12])=[C:8]([C:13]([NH2:15])=[O:14])[CH:7]=[N:6][N:5]2[CH:16]=1.[Cu][C:18]#[N:19].CCOC(C)=O>CN1C(=O)CCC1>[C:18]([C:2]1[CH:3]=[C:4]2[C:9]([S:10][CH2:11][CH3:12])=[C:8]([C:13]([NH2:15])=[O:14])[CH:7]=[N:6][N:5]2[CH:16]=1)#[N:19]
Reactant: N#C[Cu]
Reactant: CCSc1c(C(N)=O)cnn2cc(Br)cc12
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: CCSc1c(C(N)=O)cnn2cc(C#N)cc12
Reaction time: 1.5 h
Yield: 85.4 %

Procedure:
A solution of 6-bromo-4-(ethylthio)pyrrolo[1,2-b]pyridazine-3-carboxamide (200 mg, 0.666 mmol) and copper(I) cyanide (119 mg, 1.333 mmol) in NMP (3 mL) was heated to 180° C. for 1.5 hrs, and then 200° C. for 1.5 hrs under microwave oven (CEM). To the reaction mixture was added 50 mL of EtOAc. The mixture was washed with 30 mL of 10% LiCl solution, 30 mL of saturated NH4Cl solution, and 30 mL of brine and dried over Na2SO4. Filtration and concentration yielded 6-cyano-4-(ethylthio)pyrrolo[1,2-b]pyridazine-3-carboxamide (140 mg, 77% yield). MS (ES+) m/z: 247.08 (M+H); HPLC retention time: 1.902 min (analytical HPLC Method F).
Reaction SMILES: CO[C:3]1[CH2:4][CH2:5][CH2:6][CH2:7][N:8]=1.[F:9][C:10]1[CH:11]=[C:12]([C:17]2[O:18][C:19](=[O:22])[CH2:20][N:21]=2)[CH:13]=[CH:14][C:15]=1[F:16].O.[OH-].[Li+]>C1COCC1.O>[F:9][C:10]1[CH:11]=[C:12]([C:17]2[N:8]3[CH2:7][CH2:6][CH2:5][CH2:4][C:3]3=[C:20]([C:19]([OH:22])=[O:18])[N:21]=2)[CH:13]=[CH:14][C:15]=1[F:16]
Reactant: COC1=NCCCC1
Reactant: O=C1CN=C(c2ccc(F)c(F)c2)O1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1nc(-c2ccc(F)c(F)c2)n2c1CCCC2
Temperature: 90 °C
Yield: 70.2 %

Procedure:
6-methoxy-2,3,4,5-tetrahydropyridine (0.431 g, 3.80 mmol) was dissolved in THF (5 mL) in a 40 mL screw-cap vial and 2-(3,4-difluorophenyl)oxazol-5(4H)-one (0.75 g, 3.80 mmol) in THF (5 mL) was added, producing an orange solution. The vial was capped and heated to 90° C. for 3 hours. THF was removed under reduced pressure and the residue was dissolved in MeOH (10 ml) and lithium hydroxide monohydrate (0.479 g, 11.41 mmol) in water (1 mL) was added. The reaction was heated to 90° C. for 3 hours. MeOH was removed by evaporation under reduced pressure. The remaining aqueous solution was diluted with water (5 mL) and acidified to pH 2 with 5M HCl. The solution was extracted with EtOAc (3×5 mL). The combined organic extracts were dried over anhydrous sodium sulfate, filtered and evaporated to yield the desired product as a brown oil (742 mg, 71%) that was used without further purification. LCMS (+ESI) m/z: 279.3 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[CH:10][C:9]=2[O:18][CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[C:4]([Cl:27])[CH:3]=1.C(N(CC)CC)C.Cl[C:36]([O:38][CH3:39])=[O:37]>C(Cl)Cl>[Cl:27][C:4]1[CH:3]=[C:2]([NH:1][C:36]([O:38][CH3:39])=[O:37])[CH:7]=[CH:6][C:5]=1[C:8]1[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:11]=[CH:10][C:9]=1[O:18][CH2:19][C:20]([O:22][C:23]([CH3:24])([CH3:26])[CH3:25])=[O:21]
Reactant: CC(C)(C)OC(=O)COc1ccc(C(F)(F)F)cc1-c1ccc(N)cc1Cl
Reactant: COC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)Nc1ccc(-c2cc(C(F)(F)F)ccc2OCC(=O)OC(C)(C)C)c(Cl)c1
Reaction time: 20 h

Procedure:
The product from step (iii) (0.07 g) was dissolved in DCM (5 ml), triethylamine (0.024 ml) added, followed by methyl chloroformate (0.013 ml) and stirred for 20 h. Further triethylamine (0.024 ml) and methyl chloroformate (0.013 ml) were added three times over to achieve complete reaction. The solvent was removed by evaporation to give the crude product which was carried forward to step (v) without characterisation.
Reaction SMILES: Cl(O)(=O)(=O)=O.[CH3:6][C:7](OC(C)=O)=[O:8].[CH2:13]([O:15][C:16](=[O:32])[CH2:17][O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[O:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH3:14]>C(Cl)Cl>[CH2:30]([O:29][C:27](=[O:28])[CH2:26][O:25][C:20]1[CH:21]=[CH:22][C:23]([C:7](=[O:8])[CH3:6])=[CH:24][C:19]=1[O:18][CH2:17][C:16]([O:15][CH2:13][CH3:14])=[O:32])[CH3:31]
Reactant: CCOC(=O)COc1ccccc1OCC(=O)OCC
Reactant: CC(=O)OC(C)=O
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: ClCCl
Product: CCOC(=O)COc1ccc(C(C)=O)cc1OCC(=O)OCC

Procedure:
Perchloric acid (70% aq.; 1.0 ml) was added slowly to freshly distilled Ac2O (25 ml) at 0° C. The compound of example 20a (31.8 g; 125 mmol) in CH2Cl2 (13 ml) was added drop wise at 10-15° C. The reaction mixture was heated on steam bath for 1 h, concentrated, poured over crushed ice and NaHCO3 (˜25 g) and extracted with ether. The ether layer was washed with brine, dried (Na2SO4), concentrated and purified using flash chromatography (silica gel, 5% CH3CN in CHCl3) to obtain the title compound. Yield, 24.6 g (61.5%), semisolid; analysis: C16H20O7: requires C, 59.25; H, 6.22; found: C, 59.57; H, 6.28%.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.[H-].[Na+].S([O-])(=O)(=O)C.[F:21][C:22]1[CH:23]=[C:24]([CH:29]=[CH:30][CH:31]=1)[O:25][CH2:26][CH2:27]O>CN(C)C=O>[CH3:1][O:2][C:3](=[O:13])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:27][CH2:26][O:25][C:24]2[CH:29]=[CH:30][CH:31]=[C:22]([F:21])[CH:23]=2)=[CH:7][CH:6]=1
Reactant: COC(=O)C(=O)c1ccc(O)cc1
Reactant: OCCOc1cccc(F)c1
Agent: CS(=O)(=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(=O)c1ccc(OCCOc2cccc(F)c2)cc1
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 65.7 %

Procedure:
A stirred mixture of 4-hydroxy-alpha-oxobenzeneacetic acid methyl ester (0.724 g) in dimethylforrnamide (10 mL) under argon was treated with 55% sodium hydride (0.175 g), stirred for 15 minutes and treated with the mesylate of 2-(3-fluorophenoxy)ethanol (1.17 g). The mixture was heated at 60° C. overnight and worked up as in Example 20. The dichloromethane extract was evaporated and the residue was purified by HPLC (dichloromethane-hexane; 4: 1) and the resulting solids were crystallized from diethyl etherhexane to give 0.84 g of 4-[[2-(3-fluorophenoxy)ethyl]oxy]-alpha-oxobenzeneacetic acid methyl ester, mp 68°-69° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[CH:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-:18])=[O:17])[CH:11]=2)=[CH:4][CH:3]=1.O.[O-]S(C(F)(F)F)(=O)=O.[Yb+3].[O-]S(C(F)(F)F)(=O)=O.[O-]S(C(F)(F)F)(=O)=O.[CH:45](=[O:49])[CH:46]([CH3:48])[CH3:47].O>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:6][CH:7]=1)[NH:8][CH:9]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-:18])=[O:17])[CH:11]=1)[C:46]([CH3:48])([CH3:47])[CH:45]2[OH:49]
Reactant: O=[N+]([O-])c1cccc(C=Nc2ccc(Cl)cc2)c1
Reactant: CC(C)C=O
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: C1CCOC1
Solvent: O
Product: CC1(C)C(O)c2cc(Cl)ccc2NC1c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 93.4 %

Procedure:
To a mixture of (4-chloro-phenyl)-(3-nitro-benzylidene)-amine (12 g, 46 mmol) and ytterbium(III) triflate hydrate (2.85 g, 4.6 mmol) in dry tetrahydrofuran (100 mL) at 25° C. was added isobutyraldehyde (4.64 mL, 51 mmol) and water (0.83 mL, 46 mmol) dropwise. The reaction mixture was stirred at 25° C. for 3 h. Then the reaction mixture was concentrated in vacuo and the residue was extracted with ethyl acetate (2×200 mL), washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to afford 6-chloro-3,3-dimethyl-2-(3-nitro-phenyl)-1,2,3,4-tetrahydro-quinolin-4-ol (14.3 g, 93%) as a light yellow oil: LC/MS m/e calcd for C17H17ClN2O3 (M+H)+: 333.79, observed: 315.0.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([N:13]([CH2:15][C:16]2[O:17][CH:18]=[C:19]([C:21](O)=[O:22])[N:20]=2)[CH3:14])(=[O:12])=[O:11])=[C:5]([CH3:24])[CH:4]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.Cl.[CH3:56][NH:57][CH2:58][C:59]1[CH:71]=[CH:70][C:62]([CH2:63][N:64]2[CH2:68][CH2:67][CH:66]([OH:69])[CH2:65]2)=[CH:61][CH:60]=1>C(Cl)Cl>[OH:69][CH:66]1[CH2:67][CH2:68][N:64]([CH2:63][C:62]2[CH:70]=[CH:71][C:59]([CH2:58][N:57]([CH3:56])[C:21]([C:19]3[N:20]=[C:16]([CH2:15][N:13]([S:10]([C:6]4[C:5]([CH3:24])=[CH:4][C:3]([O:2][CH3:1])=[CH:8][C:7]=4[CH3:9])(=[O:12])=[O:11])[CH3:14])[O:17][CH:18]=3)=[O:22])=[CH:60][CH:61]=2)[CH2:65]1
Reactant: CNCc1ccc(CN2CCC(O)C2)cc1
Reactant: COc1cc(C)c(S(=O)(=O)N(C)Cc2nc(C(=O)O)co2)c(C)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cc(C)c(S(=O)(=O)N(C)Cc2nc(C(=O)N(C)Cc3ccc(CN4CCC(O)C4)cc3)co2)c(C)c1

Procedure:
The title compound was prepared according to general procedure BH using 2-{[(4-methoxy-2,6-dimethyl-benzenesulfonyl)-methyl-amino]-methyl}-oxazole-4-carboxylic acid (35 mg, 0.10 mmol), EDCI (26 mg, 0.14 mmol), HOBt (19 mg, 0.15 mmol), DIPEA (0.03 mL, 0.19 mmol), 1-(4-methylaminomethyl-benzyl)-pyrrolidin-3-ol hydrochloride (30 mg, 0.11 mmol) and DCM (10 mL).
Reaction SMILES: [CH2:1]([O:3][CH2:4][N:5]1[CH:9]=[C:8]([CH2:10][OH:11])[N:7]=[CH:6]1)[CH3:2].[CH2:12]([Si:14](Cl)([CH2:17][CH3:18])[CH2:15][CH3:16])[CH3:13]>ClCCl.CN(C1C=CN=CC=1)C.O>[CH2:1]([O:3][CH2:4][N:5]1[CH:9]=[C:8]([CH2:10][O:11][Si:14]([CH2:17][CH3:18])([CH2:15][CH3:16])[CH2:12][CH3:13])[N:7]=[CH:6]1)[CH3:2]
Reactant: CC[Si](Cl)(CC)CC
Reactant: CCOCn1cnc(CO)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: O
Product: CCOCn1cnc(CO[Si](CC)(CC)CC)c1
Reaction time: 17 h

Procedure:
The compound (520 mg) obtained in (2) was dissolved in dichloromethane (30 mL), followed by addition of triethylsilyl chloride (1.12 mL), TEA (1.16 mL) and DMAP (catalytic amount) under stirring, and the stirring was continued for 17 hours. The reaction solution was diluted with water, and extracted with chloroform. The combined extract was washed with saturated brine, dried over anhydrous sodium sulfate, and subsequently the solvent was distilled off under reduced pressure. The resulting residue was purified by flash chromatography (ethyl acetate/hexane=10%→80%) using silica gel column (product name: SNAP Cartridge KP-Sil 50 g, manufactured by Biotage, Ltd.) to afford the title compound (665 mg).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[OH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:15]=[C:16]3[C:21](=[CH:22][CH:23]=2)[N:20]=[C:19]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH:18]=[CH:17]3)=[C:10]([CH3:29])[CH:9]=1.Cl[CH2:31][C:32]1[C:33]([C:40]2[C:45]([Cl:46])=[CH:44][CH:43]=[CH:42][C:41]=2[Cl:47])=[N:34][O:35][C:36]=1[CH:37]([CH3:39])[CH3:38].O>CN(C)C=O>[Cl:46][C:45]1[CH:44]=[CH:43][CH:42]=[C:41]([Cl:47])[C:40]=1[C:33]1[C:32]([CH2:31][O:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]3[CH:15]=[C:16]4[C:21](=[CH:22][CH:23]=3)[N:20]=[C:19]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH:18]=[CH:17]4)=[C:10]([CH3:29])[CH:9]=2)=[C:36]([CH:37]([CH3:39])[CH3:38])[O:35][N:34]=1
Reactant: CCOC(=O)c1ccc2cc(-c3ccc(O)cc3C)ccc2n1
Reactant: CC(C)c1onc(-c2c(Cl)cccc2Cl)c1CCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc2cc(-c3ccc(OCc4c(-c5c(Cl)cccc5Cl)noc4C(C)C)cc3C)ccc2n1
Yield: 67.7 %

Procedure:
Cesium carbonate (55.4 mg, 170.0 μmol) was added to ethyl 6-(4-hydroxy-2-methylphenyl)-2-quinolinecarboxylate (47.5 mg, 154.5 μmol) and 4-(chloromethyl)-3-(2,6-dichlorophenyl)-5-(1-methylethyl)isoxazole (51.8 mg, 170.0 μmol) in N,N-dimethylformamide (3.1 mL) at room temperature. The resulting suspension was stirred for eighteen hours, then water added and the reaction mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, then filtered and concentrated. The residue was purified by silica gel chromatography eluting with 3:7 ethyl acetate:hexanes to give 60.2 mg (68%) of ethyl 6-[4-({[3-(2,6-dichlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)-2-methylphenyl]-2-quinolinecarboxylate as an oil. 1H NMR (400 MHz, d6-DMSO): δ 8.56 (d, J=9 Hz, 1H), 8.16 (d, J=9 Hz, 1H), 8.13 (d, J=9 Hz, 1H), 7.97 (d, J=2 Hz, 1H), 7.80 (dd, J=9, 2 Hz, 1H), 7.66-7.60 (m, 2H), 7.56 (dd, J=9, 7 Hz, 1H), 7.19 (d, J=8 Hz, 1H), 6.78 (d, J=2 Hz, 1H), 6.73 (dd, J=9, 2 Hz, 1H), 4.86 (s, 2H), 4.43 (q, J=7 Hz, 2H), 3.47 (septet, J=7 Hz, 1H), 2.21 (s, 3H), 1.38 (t, J=7 Hz, 3H), 1.35 (d, J=7 Hz, 6H). ESI-LCMS m/z 575 (M+H)+.
Reaction SMILES: Br.[NH2:2][C:3]1[C:11]([OH:12])=[C:10]2[C:6]([CH2:7][CH2:8][C:9]2=[O:13])=[CH:5][CH:4]=1.[CH:14](OCC)(OCC)OCC>O1CCCC1.C(OCC)(=O)C>[O:12]1[C:11]2[C:10]3[C:9](=[O:13])[CH2:8][CH2:7][C:6]=3[CH:5]=[CH:4][C:3]=2[N:2]=[CH:14]1
Reactant: CCOC(OCC)OCC
Reactant: Nc1ccc2c(c1O)C(=O)CC2
Agent: Br
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C1CCc2ccc3ncoc3c21
Yield: 61.7 %

Procedure:
6-Amino-7-hydroxyindan-1-one hydrobromide (50 mg, 0.205 mmol) and triethyl orthoformate (128 μL, 0.769 mmol) were heated under reflux in tetrahydrofuran (2.5 mL) for 0.5 hr. The mixture was diluted with ethyl acetate, washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=30/70→80/20) to give the title compound (21.9 mg, yield from Reference Example 362%).
Reaction SMILES: [F:1][C:2]1[C:3]([NH:13][CH3:14])=[CH:4][C:5]2[O:10][CH2:9][NH:8][C:7](=[O:11])[C:6]=2[CH:12]=1.I[C:16]1[CH:17]=[CH:18][C:19]([NH2:22])=[N:20][CH:21]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O>O1CCOCC1.[Cu]I>[NH2:22][C:19]1[N:20]=[CH:21][C:16]([N:8]2[C:7](=[O:11])[C:6]3[CH:12]=[C:2]([F:1])[C:3]([NH:13][CH3:14])=[CH:4][C:5]=3[O:10][CH2:9]2)=[CH:17][CH:18]=1
Reactant: CNc1cc2c(cc1F)C(=O)NCO2
Reactant: Nc1ccc(I)cn1
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CNc1cc2c(cc1F)C(=O)N(c1ccc(N)nc1)CO2
Temperature: 100 °C
Yield: 23.6 %

Procedure:
To 6-fluoro-7-(methylamino)-2,3-dihydrobenzo[e][1,3]oxazin-4-one (0.05 g, 0.25 mmol) and 5-iodopyridin-2-amine (0.067 g, 0.304 mmol) in dioxane (1 ml) was added potassium phosphate (0.08 g, 0.377 mmol). The reaction mixture was degassed for 5 minutes and to this was added trans-diamino cyclohexane (0.004 g, 0.03 mmol) followed by copper (I) iodide (0.006 g, 0.03 mmol) and the mixture heated to 100° C. for 1 hour. Water was added and the product extracted with ethyl acetate (3×10 ml), dried over anhydrous sodium sulfate and concentrated. The product was further purified by reverse phase HPLC (C18) to yield pure 3-(6-aminopyridin-3-yl)-6-fluoro-7-(methylamino)-2,3-dihydrobenzo[e][1,3]oxazin-4-one (0.017 g, 23%). RP-HPLC: 1.5 min; ES-MS (M+H)+=289.1; 1H-NMR (MeOH-d4) δ (ppm): 2.82 (s, 3), 5.4 (s, 2), 6.2 (d, 1), 6.6 (d, 1), 7.3 (d, 1), 7.4 (dd, 1), 7.8 (s, 1).
Reaction SMILES: [OH:1][C:2]1[C:11]([OH:12])=[C:10]([O:13][CH3:14])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].Br[CH2:16][CH2:17]Br.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:14][O:13][C:10]1[C:11]2[O:12][CH2:16][CH2:17][O:1][C:2]=2[C:3]([C:4]([O:6][CH3:7])=[O:5])=[CH:8][CH:9]=1
Reactant: COC(=O)c1ccc(OC)c(O)c1O
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OC)c2c1OCCO2
Reaction time: 6 h
Yield: 81.3 %

Procedure:
A mixture of methyl 2,3-dihydroxy-4-methoxybenzoate (0.176 mol), 1,2-dibromo-ethane (0.282 mol), K2CO3 (0.444 mol) and CuO (1.4 g) in DMF (1000 ml) was stirred for 6 hours, cooled, filtered and the filtrate was evaporated. Water (300 ml) was added. The mixture was extracted twice with DCM (300 ml). The organic layer was separated, washed with a saturated NaHCO3 solution, dried, filtered and the solvent was evaporated. The residue was triturated in DIPE. The precipitate was filtered off and dried, yielding 32.1 g of methyl 2,3-dihydro-8-methoxy-1,4-benzodioxin-5-carboxylate (intermediate 1, mp. 84° C.).
Reaction SMILES: Cl.NC1C=C(OC2C=CC(NC3N=CC=CC=3C(NC3C=CC(F)=CC=3F)=O)=CC=2F)C=CN=1.[C:35]([C:38]1[CH:43]=[C:42]([O:44][C:45]2[CH:50]=[CH:49][C:48]([NH:51][C:52]3[N:68]=[CH:67][CH:66]=[CH:65][C:53]=3[C:54]([NH:56][C:57]3[CH:62]=[CH:61][C:60](F)=[CH:59][C:58]=3F)=[O:55])=[CH:47][C:46]=2[F:69])[CH:41]=[CH:40][N:39]=1)(=[O:37])[NH2:36].[Cl:70]C1N=CC=CC=1C(NC1C=CC(Cl)=CC=1)=O>>[C:35]([C:38]1[CH:43]=[C:42]([O:44][C:45]2[CH:50]=[CH:49][C:48]([NH:51][C:52]3[N:68]=[CH:67][CH:66]=[CH:65][C:53]=3[C:54]([NH:56][C:57]3[CH:62]=[CH:61][C:60]([Cl:70])=[CH:59][CH:58]=3)=[O:55])=[CH:47][C:46]=2[F:69])[CH:41]=[CH:40][N:39]=1)(=[O:37])[NH2:36]
Reactant: NC(=O)c1cc(Oc2ccc(Nc3ncccc3C(=O)Nc3ccc(F)cc3F)cc2F)ccn1
Reactant: O=C(Nc1ccc(Cl)cc1)c1cccnc1Cl
Agent: Cl
Agent: Nc1cc(Oc2ccc(Nc3ncccc3C(=O)Nc3ccc(F)cc3F)cc2F)ccn1
Product: NC(=O)c1cc(Oc2ccc(Nc3ncccc3C(=O)Nc3ccc(Cl)cc3)cc2F)ccn1
Yield: 47 %

Procedure:
4-(4-Amino-2-fluorophenoxy)picolinamide (0.12 g, 0.50 mmol, Compound C of Example 3) was converted to the desired compound (0.090 g, 47%) in a manner similar to the preparation of 2-(4-(2-carbamoylpyridin-4-yloxy)-3-fluorophenylamino)-N-(2,4-difluorophenyl)-nicotinamide (Step D of Example 3), except that 2-chloro-N-(4-chlorophenyl)nicotinamide (Maybridge, 0.11 g, 0.40 mmol) was used instead of 2-chloro-N-(2,4-difluorophenyl)nicotinamide. HRMS(ESI+), 478.1082 (M+H)+ calc, 478.1059 (M+H)+ found.
Reaction SMILES: C[C:2]1[N:6]2[C:7]([NH2:15])=[C:8]([Cl:14])[CH:9]=[C:10]([C:11]([OH:13])=O)[C:5]2=[N:4][C:3]=1[CH3:16].[NH2:17][CH2:18][CH:19]1[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]1>>[NH2:15][C:7]1[N:6]2[CH:2]=[C:3]([CH3:16])[N:4]=[C:5]2[C:10]([C:11]([NH:17][CH2:18][CH:19]2[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]2)=[O:13])=[CH:9][C:8]=1[Cl:14]
Reactant: Cc1nc2c(C(=O)O)cc(Cl)c(N)n2c1C
Reactant: CC(C)(C)OC(=O)N1CCC(CN)CC1
Product: Cc1cn2c(N)c(Cl)cc(C(=O)NCC3CCN(C(=O)OC(C)(C)C)CC3)c2n1

Procedure:
The title compound was prepared, according to the procedure described in the step 6 of EXAMPLE 1, from 5-amino-6-chloro-2-methylimidazo[1,2-a]pyridine-8-carboxylic acid (EXAMPLE 1, Step 5) and tert-butyl 4-(aminomethyl)piperidine-1-carboxylate (J. Prugh, L. A. Birchenough and M. S. Egbertson, Synth. Commun., 1992, 22, 2357–60).