Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[CH:30]=[CH:29][C:13]([CH2:14][NH:15][C:16]3[CH:28]=[CH:27][C:19]4[O:20][C:21]([CH3:26])([CH3:25])[O:22][C:23](=[O:24])[C:18]=4[CH:17]=3)=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.[O:31]1[C:35]([C:36](Cl)=[O:37])=[CH:34][CH:33]=[N:32]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]#[C:9][C:10]2[CH:30]=[CH:29][C:13]([CH2:14][N:15]([C:16]3[CH:28]=[CH:27][C:19]4[O:20][C:21]([CH3:26])([CH3:25])[O:22][C:23](=[O:24])[C:18]=4[CH:17]=3)[C:36]([C:35]3[O:31][N:32]=[CH:33][CH:34]=3)=[O:37])=[CH:12][CH:11]=2)=[CH:6][CH:7]=1
Reactant: CC1(C)OC(=O)c2cc(NCc3ccc(C#Cc4ccc(Cl)cc4)cc3)ccc2O1
Reactant: O=C(Cl)c1ccno1
Product: CC1(C)OC(=O)c2cc(N(Cc3ccc(C#Cc4ccc(Cl)cc4)cc3)C(=O)c3ccno3)ccc2O1

Procedure:
The titled compound was prepared following the procedure E using 6-({4-[(4-chlorophenyl)ethynyl]benzyl}amino)-2,2-dimethyl-4H-1,3-benzodioxin-4-one and isoxazole-5-carbonyl chloride as a yellow oil (72%). M− (ESI): 511.5; M+ (ESI): 513.1. HPLC, Rt: 5.38 min (Purity: 99.1%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:18])=[C:6]([C@:8]2([CH3:17])[C:13]([F:15])([F:14])[CH2:12][O:11][C:10]([NH2:16])=[N:9]2)[CH:7]=1.[F:19][CH:20]([F:29])[N:21]1[CH:25]=[CH:24][C:23]([C:26](O)=[O:27])=[N:22]1>>[NH2:16][C:10]1[O:11][CH2:12][C:13]([F:14])([F:15])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:26]([C:23]3[CH:24]=[CH:25][N:21]([CH:20]([F:29])[F:19])[N:22]=3)=[O:27])[CH:3]=[CH:4][C:5]=2[F:18])([CH3:17])[N:9]=1
Reactant: O=C(O)c1ccn(C(F)F)n1
Reactant: C[C@]1(c2cc(N)ccc2F)N=C(N)OCC1(F)F
Product: C[C@]1(c2cc(NC(=O)c3ccn(C(F)F)n3)ccc2F)N=C(N)OCC1(F)F

Procedure:
The condensation of (R)-4-(5-amino-2-fluoro-phenyl)-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (intermediate XI-1) and 1-difluoromethyl-1H-pyrazole-3-carboxylic acid following procedure I yielded the title compound as a white solid. MS (ISP): m/z=404.3 [M+H]+.
Reaction SMILES: CC1(C)CCCC(C)(C)N1.[Li]CCCC.[C:16]1([S:22]([N:25]2[CH:29]=[CH:28][CH:27]=[CH:26]2)(=[O:24])=[O:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[CH3:30][C:31]1[N:36]=[C:35]([CH:37]=[O:38])[CH:34]=[CH:33][CH:32]=1>C1COCC1.CCCCCC.O>[C:16]1([S:22]([N:25]2[CH:26]=[CH:27][CH:28]=[C:29]2[CH:37]([C:35]2[CH:34]=[CH:33][CH:32]=[C:31]([CH3:30])[N:36]=2)[OH:38])(=[O:24])=[O:23])[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=S(=O)(c1ccccc1)n1cccc1
Reactant: Cc1cccc(C=O)n1
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: O
Product: Cc1cccc(C(O)c2cccn2S(=O)(=O)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76.7 %

Procedure:
Under nitrogen atmosphere, a solution of 2,2,6,6-tetramethyl-piperidine (5.00 mL) in THF (120 mL) was cooled to −78° C., and thereto was added dropwise a 1.6N solution of BuLi in hexane (18.5 mL), and the mixture was stirred at room temperature for 30 minutes. The mixture was cooled again to −78° C., and thereto was added a solution of N-benzenesulfonylpyrrole (5.58 g) in THF (25 mL). The mixture was stirred for 30 minutes, and thereto was added a solution of 6-methyl-pyridine-2-aldehyde (3.94 g) in THF (20 mL), and the mixture was stirred at −78° C. for 2 hours. Water was added to the mixture, and the mixture was extracted twice with ethyl acetate. The organic layer was washed with a saturated brine and dried over MgSO4. The solvent was evaporated under reduced pressure, and the precipitated solid was suspended in a mixed solvent of hexane/ethyl acetate=5/1, and collected by filtration to give [1-(phenylsulfonyl)-1H-pyrrol-2-yl](6-methylpyridin-2-yl)methanol (6.78 g, 77%).
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:5]=[C:6]([CH:19]=[CH:20][CH:21]=1)[CH2:7][N:8]1[CH:13]=[CH:12][C:11]([O:14]C)=[C:10]([C:16]#[N:17])[C:9]1=[O:18].Cl>CN(C=O)C>[F:3][C:4]1[CH:5]=[C:6]([CH:19]=[CH:20][CH:21]=1)[CH2:7][N:8]1[CH:13]=[CH:12][C:11]([OH:14])=[C:10]([C:16]#[N:17])[C:9]1=[O:18]
Reactant: COc1ccn(Cc2cccc(F)c2)c(=O)c1C#N
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1c(O)ccn(Cc2cccc(F)c2)c1=O
Temperature: 100 °C
Yield: 92 %

Procedure:
To a solution of sodium hydride (92 mg of a 60% dispersion in mineral oil, 2.3 mmol) in DMF (7 mL) was added ethanethio](0.14 g, 2.2 mmol), followed by a solution of 1-(3-fluorobenzyl)-4-methoxy-2-oxo-1,2-dihydropyridine-3-carbonitrile (0.23 g, 0.89 mmol) in DMF (2 mL), and the reaction mixture was heated to 100° C. The reaction mixture was cooled to room temperature, acidified with 3 N HCl, and washed with EtOAc. The organic solution was washed with brine, dried (Na2SO4), filtered and concentrated under reduced pressure to give 1-(3-fluorobenzyl)-4-hydroxy-2-oxo-1,2-dihydro-pyridine-3-carbonitrile as an off-white solid (0.20 g, 91%): 1H NMR (300 MHz, MeOD) δ 8.00 (s, 1H), 7.82 (d, J=8 Hz, 1H), 7.40-7.30 (m, 1H), 7.15-7.00 (m, 2H), 6.13 (d, J=8 Hz, 1H), 5.11 (s, 2H)
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[O:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH:12]=[C:13]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])[N:14]=2)[CH:11]=1.Br[C:25]1[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=1.CC(C)([O-])C.[K+].C1(C)C=CC=CC=1>C(=O)([O-])O.[Na+]>[N:27]1[CH:28]=[CH:29][CH:30]=[C:25]([NH:1][C:2]2[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=2)[O:5][C:6]2[CH:7]=[CH:8][C:9]3[N:10]([CH:12]=[C:13]([NH:15][C:16]([CH:18]4[CH2:20][CH2:19]4)=[O:17])[N:14]=3)[CH:11]=2)[CH:26]=1
Reactant: Brc1cccnc1
Reactant: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3c2)c1
Agent: CC(C)(C)[O-]
Agent: O=C([O-])O
Agent: [K+]
Solvent: Cc1ccccc1
Product: O=C(Nc1cn2cc(Oc3cccc(Nc4cccnc4)c3)ccc2n1)C1CC1
Temperature: 120 °C
Reaction time: 13 h
Yield: 12 %

Procedure:
A mixture of N-[6-(3-aminophenoxy)imidazo[1,2-a]pyridin-2-yl]cyclopropanecarboxamide (20.0 mg, 0.065 mmol), 3-bromopyridine (14.4 mg, 0.091 mmol), tris(dibenzylideneacetone)2 palladium(0) (6.8 mg, 0.0074 mmol), 5-bis(diphenylphosphino)-9,9-dimethylxanthene (4.3 mg, 0.007 mmol), potassium t-butoxide (17.2 mg, 0.153 mmol) and toluene (2.0 mL) was stirred at 120° C. for 13 hr. The reaction mixture was diluted with aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer was concentrated, and the residue was purified by preparative HPLC to give the title compound (3.0 mg, 12%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]3[CH:13]=[C:14]([O:17]C)[CH:15]=[CH:16][C:10]=3[CH:9]=2)=[CH:4][CH:3]=1.B(Br)(Br)Br>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]3[CH:13]=[C:14]([OH:17])[CH:15]=[CH:16][C:10]=3[CH:9]=2)=[CH:4][CH:3]=1
Reactant: COc1ccc2cc(-c3ccc(Br)cc3)sc2c1
Agent: BrB(Br)Br
Product: Oc1ccc2cc(-c3ccc(Br)cc3)sc2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 87.8 %

Procedure:
To a stirred solution of 2-(4-bromo-phenyl)-6-methoxy-benzo[b]thiophene (80 mg, 0.25 mmol) was added BBr3 (0.5 mL of 1 M in DCM, 0.5 mmol) at 0° C. The mixture was stirred for 3 hours at ambient temperature. DCM was removed under vacuum, and the residue was dissolved in ethyl acetate (30 mL). The organic layer was washed with NaHCO3 solution, water and brine, dried over Na2SO4, filtered and concentrated in vacuo. The obtained residue was treated with hexane to give the product (67 mg, 88%). m/z 303.0, 305.0 (M−H)−.
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:14]([O:16]C)=[O:15])[CH:12]=2)[CH2:7][CH2:6]1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+].Cl>CO>[CH2:1]([N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:14]([OH:16])=[O:15])[CH:12]=2)[CH2:7][CH2:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN1CCc2ccc(C(=O)OC)cc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCCN1CCc2ccc(C(=O)O)cc21
Temperature: 60 °C
Yield: 77.1 %

Procedure:
To a mixture of Methyl 1-butylindoline-6-carboxylate (1.6 g) in methanol (20 mL) was added 1N NaOH (5.0 mL). The mixture was heated at 60° C. for 2 h then cooled to room temperature, poured into 1N HCl and extracted into ethyl acetate. The ethyl acetate extract was dried over anhydrous magnesium sulfate and concentrated to give 1.16 g of the title compound: 1H NMR (CDCl3) δ 0.974, 1.43, 1.60, 3.01, 3.11, 3.42, 7.1, 7.43.
Reaction SMILES: [C:1]1([C:7]2([C:20]3[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][CH:25]=3)[C:19]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:13]3[C:8]2=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32](I)[CH:31]=1.C(=O)([O-])[O-].[K+].[K+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.O.C1(C)C=CC=CC=1.C(O)C>[Br:29][C:30]1[CH:31]=[C:32]([C:22]2[CH:21]=[C:20]([C:7]3([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[C:8]4[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=4[C:14]4[C:19]3=[CH:18][CH:17]=[CH:16][CH:15]=4)[CH:25]=[CH:24][CH:23]=2)[CH:33]=[CH:34][CH:35]=1
Reactant: OB(O)c1cccc(C2(c3ccccc3)c3ccccc3-c3ccccc32)c1
Reactant: Brc1cccc(I)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: Brc1cccc(-c2cccc(C3(c4ccccc4)c4ccccc4-c4ccccc43)c2)c1
Yield: 79.2 %

Procedure:
In a 50 mL three-neck flask were put 1.2 g (3.2 mmol) of [3-(9-phenyl-9H-fluoren-9-yl)phenyl]boronic acid and 54.7 mg (0.2 mmol) of tris(2-methylphenyl)phosphine. The air in the flask was replaced with nitrogen. To this mixture were added 12.0 mL of toluene, 4.0 mL of ethanol, 0.5 mL (3.5 mmol) of 1-bromo-3-iodobenzene, and 3.2 mL of an aqueous solution of potassium carbonate (2 mol/L). The temperature of this mixture was set to 60° C., and then 13.9 mg (0.1 mmol) of palladium(II) acetate was added to the mixture. The temperature of this mixture was set to 80° C., followed by reflux for 3.0 hours. After the reflux, toluene and water were added to this mixture, the organic layer and the aqueous layer were separated, and the aqueous layer was extracted three times with toluene. This toluene layer and the organic layer were combined, washed with saturated brine, and dried with magnesium sulfate. The obtained mixture was gravity filtered so that magnesium sulfate was removed, and the obtained filtrate was concentrated to give a solid. Recrystallization of the solid from a mixed solvent of toluene and methanol gave 1.2 g of a white solid in 80% yield, which was the substance to be produced. The synthesis scheme of this Step 2 is shown in (E18-2) given below.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([CH:11]3[CH2:13][CH2:12]3)[N:10]=[C:6]2[N:5]=[C:4]([CH3:14])[CH:3]=1.[NH2:15][C:16]1[CH:21]=[CH:20][C:19]([S:22]([F:27])([F:26])([F:25])([F:24])[F:23])=[CH:18][CH:17]=1>C(O)C>[CH:11]1([C:9]2[N:10]=[C:6]3[N:5]=[C:4]([CH3:14])[CH:3]=[C:2]([NH:15][C:16]4[CH:21]=[CH:20][C:19]([S:22]([F:27])([F:23])([F:24])([F:25])[F:26])=[CH:18][CH:17]=4)[N:7]3[N:8]=2)[CH2:13][CH2:12]1
Reactant: Nc1ccc(S(F)(F)(F)(F)F)cc1
Reactant: Cc1cc(Cl)n2nc(C3CC3)nc2n1
Solvent: CCO
Product: Cc1cc(Nc2ccc(S(F)(F)(F)(F)F)cc2)n2nc(C3CC3)nc2n1

Procedure:
To a suspension of Intermediate 20 (0.04 g, 0.192 mmol) in ethanol (2.5 mL), 4-aminophenylsulfur pentafluoride (MANCHESTER, 0.042 g, 0.192 mmol) was added and the mixture was stirred under reflux overnight. Solvent was removed in vacuo and the crude mixture was purified by preparative HPLC (SunFire 19×150 mm, H2O 0.1% TFA-ACN 0.1% TFA gradient from 10 to 100%) to yield the title compound as a beige solid.
Reaction SMILES: [Cl-].[C:2]([C:4]1[CH:5]=[CH:6][C:7]2[O:11][CH:10]=[C:9]([CH2:12][P+](C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[C:8]=2[CH:32]=1)#[N:3].[CH3:33][O:34][C:35]1[CH:40]=[CH:39][C:38]([CH2:41][CH:42]=O)=[CH:37][CH:36]=1.C1CCN2C(=NCCC2)CC1>O1CCCC1.C(O)C>[CH3:33][O:34][C:35]1[CH:40]=[CH:39][C:38]([CH:41]=[CH:42][CH2:12][C:9]2[C:8]3[CH:32]=[C:4]([C:2]#[N:3])[CH:5]=[CH:6][C:7]=3[O:11][CH:10]=2)=[CH:37][CH:36]=1
Reactant: COc1ccc(CC=O)cc1
Reactant: N#Cc1ccc2occ(C[P+](c3ccccc3)(c3ccccc3)c3ccccc3)c2c1
Agent: [Cl-]
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCO
Solvent: C1CCOC1
Product: COc1ccc(C=CCc2coc3ccc(C#N)cc23)cc1
Reaction time: 24 h

Procedure:
2.14 g of (5-cyano-3-benzofuranyl)methyltriphenylphosphonium chloride and 0.7 g of 4-methoxyphenylacetaldehyde were dissolved in a solvent mixture of 100 ml of tetrahydrofuran and 100 ml of ethanol. The thus prepared solution was mixed with 0.71 g of 1,8-diazabicyclo[5.4.0]-7-undecene and stirred for 24 hours. After distilling off the solvent, the resulting residue was purified by subjecting it to silica gel column chromatography using toluene as an elution solvent, thereby obtaining 0.86 g of yellow and oily 3-[3-(4-methoxyphenyl)allyl]-5-benzofurancarbonitrile as a mixture of E and Z forms. The thus obtained E/Z mixture was dissolved in 100 ml of ethanol, and the solution was subjected to catalytic hydrogenation under normal pressure in the presence of 370 mg of 5% palladium carbon catalyst. Thereafter, the catalyst was removed by filtration, and the solvent was distilled off to obtain 0.6 g of 3-[3-(4-methoxyphenyl)propyl]-5-benzofurancarbonitrile. The thus obtained methoxy compound was dissolved in 20 ml of dichloromethane. With stirring at -40° C., to the resulting solution was added dropwise 10 ml of a dichloromethane solution containing 0.4 ml of boron tribromide. The resulting mixture was warmed up to room temperature and stirred for 2 hours. The resulting reaction solution was poured into cold dilute hydrochloric acid and extracted with chloroform. After drying the resulting organic layer and distilling off the solvent, the thus obtained residue was purified by subjecting it to silica gel column chromatography using toluene as an elution solvent. In this way, 280 mg of 3-[3-(4-hydroxyphenyl)propyl]-5-benzofurancarbonitrile.
Reaction SMILES: C[O:2][C:3](=[O:28])[CH:4]([N:11]1[C:16](=[O:17])[CH:15]=[C:14]([O:18][C:19]2[CH:27]=[CH:26][CH:25]=[C:24]3[C:20]=2[CH:21]=[CH:22][NH:23]3)[CH:13]=[N:12]1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.[OH-].[Na+].Cl>CO.O>[CH:6]1([CH2:5][CH:4]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][C:19]3[CH:27]=[CH:26][CH:25]=[C:24]4[C:20]=3[CH:21]=[CH:22][NH:23]4)[CH:13]=[N:12]2)[C:3]([OH:28])=[O:2])[CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: COC(=O)C(CC1CCCC1)n1ncc(Oc2cccc3[nH]ccc23)cc1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)C(CC1CCCC1)n1ncc(Oc2cccc3[nH]ccc23)cc1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 41.9 %

Procedure:
A solution of 3-cyclopentyl-2-[4-(1H-indol-4-yloxy)-6-oxo-6H-pyridazin-1-yl]-propionic acid methyl ester (500 mg, 1.3 mmol) in methanol (3 mL) was treated with a 4N aqueous sodium hydroxide solution (63 mg, 1.57 mmol). The reaction solution was stirred at 25° C. overnight. At this time, the reaction mixture was diluted with water (10 mL) and was acidified with a 1N aqueous hydrochloric acid solution until pH=2. The aqueous phase was extracted with ethyl acetate (3×20 mL). The combined organics were washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Chromatography afforded 3-cyclopentyl-2-[4-(1H-indol-4-yloxy)-6-oxo-6H-pyridazin-1-yl]-propionic acid as an off-white solid (0.2 g, 42%); LC-MS: 368 [M+1]+, tR=4.21 min. Purity on HPLC: 95.1% (254 nm), 96.6% (214 nm), tR=7.26 min. 1H NMR (300 MHz, CDCl3): δ 13.00 (s, 1H), 11.50 (s, 1H), 8.17 (d, 1H, J=2.4 Hz), 7.42 (d, 2H, J=7.8 Hz), 7.17 (t, 1H, J=7.8 Hz), 6.89 (d, 1H, J=7.8 Hz), 6.26 (s, 1H), 5.63 (d, 1H, J=2.4 Hz), 5.31 (dd, 1H, J1=10.5 Hz, J2=4.2 Hz), 2.23˜2.13 (m, 1H), 2.02˜1.94 (m, 1H), 1.59˜1.44 (m, 7H), 1.18˜1.04 (m, 2H).
Reaction SMILES: [CH3:1][C@H:2]1[O:7][CH2:6][C@@H:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:4]([CH2:14][C:15]([O:17]CC)=[O:16])[C:3]1=[O:20].[Li+:21].[OH-].Cl>C1COCC1.O>[CH3:1][C@@H:2]1[O:7][CH2:6][C@@H:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:4]([CH2:14][C:15]([O-:17])=[O:16])[C:3]1=[O:20].[Li+:21]
Reactant: CCOC(=O)CN1C(=O)[C@@H](C)OC[C@H]1c1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: C[C@@H]1OC[C@@H](c2ccccc2)N(CC(=O)[O-])C1=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of ethyl [(2R,5R)-2-methyl-3-oxo-5-phenylmorpholin-4-yl]acetate from Step C (590 mg, 2.13 mmol) in THF (5 mL) and H2O (5 mL) was added 1 N aqueous LiOH (2.55 mL, 2.55 mmol) and the resulting mixture was stirred at ambient temperature for 18 h. The mixture was adjusted to pH 6 by addition of 1 N HCl and concentrated to dryness in vacuo to give the title compound. MS: m/z=250 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:11][CH3:12])[CH:10]=1)[CH:6]=O.C(O)(=O)[CH2:14][C:15]([OH:17])=[O:16].N1CCCCC1.Cl>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]=[CH:14][C:15]([OH:17])=[O:16])[CH:8]=[C:9]([O:11][CH3:12])[CH:10]=1
Reactant: O=C(O)CC(=O)O
Reactant: COc1cc(C=O)cc(OC)c1
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: COc1cc(C=CC(=O)O)cc(OC)c1
Temperature: 100 °C
Yield: 70.7 %

Procedure:
To a solution of 3,5-dimethoxybenzaldehyde (12.5 g) in pyridine (20 ml) was added malonic acid (8.61 g) and piperidine (1 ml). The resulting solution was heated at 100° C. for 16 hours, cooled to room temperature, poured onto ice and acidified using conc. HCl. The resulting precipitate was collected, extracted into sodium bicarbonate solution and washed with isohexane. The aqueous phase was acidified using conc. HCl to yield a white precipitate which was filtered off, washed with water and dried to afford the subtitle compound (11.07 g).
Reaction SMILES: [NH2:1][C@H:2]([C:4]1[N:13]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH2:21][C:22]([F:25])([F:24])[F:23])[CH:15]=2)[C:12](=[O:26])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[F:27])[N:5]=1)[CH3:3].Cl[C:29]1[C:30]2[C:37]([F:38])=[CH:36][NH:35][C:31]=2[N:32]=[CH:33][N:34]=1.C(N(C(C)C)CC)(C)C>CC(O)(C)C>[F:27][C:10]1[CH:9]=[CH:8][CH:7]=[C:6]2[C:11]=1[C:12](=[O:26])[N:13]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH2:21][C:22]([F:23])([F:25])[F:24])[CH:15]=1)[C:4]([C@@H:2]([NH:1][C:29]1[C:30]3[C:37]([F:38])=[CH:36][NH:35][C:31]=3[N:32]=[CH:33][N:34]=1)[CH3:3])=[N:5]2
Reactant: Fc1c[nH]c2ncnc(Cl)c12
Reactant: C[C@H](N)c1nc2cccc(F)c2c(=O)n1-c1cccc(OCC(F)(F)F)c1
Solvent: CC(C)(C)O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Nc1ncnc2[nH]cc(F)c12)c1nc2cccc(F)c2c(=O)n1-c1cccc(OCC(F)(F)F)c1
Temperature: 120 °C
Reaction time: 16 h
Yield: 41.6 %

Procedure:
Under nitrogen, to (S)-2-(1-aminoethyl)-5-fluoro-3-(3-(2,2,2-trifluoroethoxy)phenyl)quinazolin-4(3H)-one (76 mg, 0.20 mmol, 1.0 equiv) in t-BuOH (0.4 mL) at 23° C. was added 4-chloro-5-fluoro-7H-pyrrolo[2,3-d]pyrimidine (38 mg, 0.22 mmol, 1.1 equiv) and diisopropylethylamine (70 μL, 0.40 mmol, 2.0 equiv). After stirring for 16 hr at 120° C. in a sealed tube, the reaction mixture was concentrated in vacuo and the residue was purified by preparative TLC eluting with CH2Cl2/MeOH to afford 43 mg of the title compound (42% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][C:5]2[C:6]([O:11][CH2:12][CH3:13])=[N:7][S:8](=[O:10])(=[O:9])[C:4]=2[CH:3]=1.[CH3:16][N:17]=[C:18]=[O:19]>>[CH3:16][NH:17][C:18]([NH:1][C:2]1[CH:15]=[CH:14][C:5]2[C:6]([O:11][CH2:12][CH3:13])=[N:7][S:8](=[O:10])(=[O:9])[C:4]=2[CH:3]=1)=[O:19]
Reactant: CN=C=O
Reactant: CCOC1=NS(=O)(=O)c2cc(N)ccc21
Product: CCOC1=NS(=O)(=O)c2cc(NC(=O)NC)ccc21

Procedure:
Following the procedures outlined in Description 4a, 6-amino-3-ethoxy-benzoisothiazole-1,1-dioxide (0.23 g) was reacted with methyl isocyanate for 3 days to give the title compound.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].Cl.[CH2:16]([O:18][C:19](=[O:23])[CH2:20][CH2:21][NH2:22])[CH3:17].C(N(CC)CC)C>ClCCl>[N+:12]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:2]=1[NH:22][CH2:21][CH2:20][C:19]([O:18][CH2:16][CH3:17])=[O:23])=[CH:10][CH:9]=[CH:8][CH:7]=2)([O-:14])=[O:13]
Reactant: O=[N+]([O-])c1cnc2ccccc2c1Cl
Reactant: CCOC(=O)CCN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)CCNc1c([N+](=O)[O-])cnc2ccccc12
Yield: 98.8 %

Procedure:
The general method described in Step 1 of Example 1 was used to react 4-chloro-3-nitroquinoline (45.3 g, 217 mmol), β-alanine ethyl ester hydrochloride (40.0 g, 240 mmol), and triethylamine (54.8 g, 542 mmol) in dichloromethane for 15 hours to provide ethyl 3-(3-nitroquinolin-4-ylamino)propionate (62.0 g) as a yellow solid.
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:4][C:3]=2[O:2]1.[C:15]1([CH3:24])[CH:20]=[CH:19][C:18]([C:21](Cl)=[O:22])=[CH:17][CH:16]=1>C(Cl)Cl.Cl[Sn](Cl)(Cl)Cl>[CH3:24][C:15]1[CH:20]=[CH:19][C:18]([C:21]([C:6]2[CH:7]=[C:8]3[O:9][CH2:1][O:2][C:3]3=[CH:4][C:5]=2[CH2:10][C:11]([O:13][CH3:14])=[O:12])=[O:22])=[CH:17][CH:16]=1
Reactant: COC(=O)Cc1ccc2c(c1)OCO2
Reactant: Cc1ccc(C(=O)Cl)cc1
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: ClCCl
Product: COC(=O)Cc1cc2c(cc1C(=O)c1ccc(C)cc1)OCO2

Procedure:
The title compound was prepared from methyl 3,4-methylenedioxyphenylacetate (319 mg, 1.64 mmol) in CH2Cl2 (5 mL), SnCl4 (1.0M solution in CH2Cl2 ; 3.5 mL mmol) and 4-toluoyl chloride (260 μL, 1.97 mmol) as an oily solid (90 mg, 18%). 1H NMR (CDCl3) 7.69 (d, 2H, J=8.0), 7.24 (d, 2H, J=8.0), 6.88 (s, 1H), 6.83 (s, (s, 2H), 3.78 (s, 2H), 3.60 (s, 3H), 2.43 (s, 3H).
Reaction SMILES: C(O[C:6](=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14](=[O:30])[NH:15][CH2:16][C:17]2[S:18][C:19]([O:22][C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=3)=[CH:20][CH:21]=2)=[CH:10][N:9]=1)(C)(C)C.NC1N=C(N)C=CC=1C(NCC1SC(CC2SC3C=CC=CC=3C=2)=CC=1)=O.[CH3:59][O:60][CH2:61]CBr.[H-].[Na+].Cl>CS(C)=O.C(OCC)(=O)C.O>[F:29][C:25]1[CH:24]=[C:23]([CH:28]=[CH:27][CH:26]=1)[O:22][C:19]1[S:18][C:17]([CH2:16][NH:15][C:14](=[O:30])[C:11]2[CH:12]=[CH:13][C:8]([NH:7][CH2:6][CH2:59][O:60][CH3:61])=[N:9][CH:10]=2)=[CH:21][CH:20]=1
Reactant: COCCBr
Reactant: CC(C)(C)OC(=O)Nc1ccc(C(=O)NCc2ccc(Oc3cccc(F)c3)s2)cn1
Agent: Cl
Agent: Nc1ccc(C(=O)NCc2ccc(Cc3cc4ccccc4s3)s2)c(N)n1
Agent: [H-]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: O
Product: COCCNc1ccc(C(=O)NCc2ccc(Oc3cccc(F)c3)s2)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 42.8 %

Procedure:
To a solution of (5-((5-(3-fluoro-phenoxy)-thiophen-2-ylmethyl)-carbamoyl)-pyridin-2-yl)-carbamic acid tert-butyl ester described in Preparation Example A+−2 (100 mg, 0.227 mmol) and methoxyethyl bromide (38 mg, 0.272 mmol) in dimethylsulfoxide (5 mL) was added sodium hydride (11 mg, 0.272 mmol, 60% in oil), and the solution was stirred at room temperature for 1 hour. 5N Hydrochloric acid was added to the reaction solution, which was then stirred for 5 minutes at 80° C. Water and ethyl acetate were added to the reaction solution, which was then partitioned, the organic layer was washed with water twice, then, silica gel was added, the solvent was evaporated in vacuo for adsorption, purification was carried out by silica gel column chromatography (hexane:ethyl acetate=1:1, then ethyl acetate), and the title compound (39 mg, 0.097 mmol, 42.8%) was obtained as a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:9][C:10]1[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=1[CH2:12]Cl>CCCCCCCC[N+](CCCCCCCC)(CCCCCCCC)C.[Cl-].[OH-].[Na+].C(Cl)Cl>[NH2:1][C:2]1[C:7]([O:8][CH2:9][C:10]2[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=2[CH3:12])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Cc1ccccc1CCl
Reactant: Nc1ncccc1O
Agent: CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Product: Cc1ccccc1COc1cccnc1N
Reaction time: 24 h

Procedure:
To a mixture of 2-amino-3-hydroxypyridine (7 g) and Adogen 464 (Trademark: prepared by Aldrich Chemical Co.) (0.4 g) in 40% aqueous sodium hydroxide (32 ml) and methylene chloride (32 ml) was added 2-methylbenzyl chloride (8.42 ml) at ambient temperature. After being stirred for 24 hours, the organic layer was separated and the aqueous layer was extracted with methylene chloride. The combined extracts were washed with saturated sodium chloride aqueous solution, dried over magnesium sulfate, and evaporated in vacuo. The crystalline residue was recrystallized from ethyl acetate to give 2-amino-3-(2-methylbenzyloxy)pyridine (7.56 g).