Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[N:10][C:11]([CH:14]3[CH2:18][CH2:17][N:16]([C:19]([O:21][CH:22]4[CH:29]5[CH2:30][C:25]6([C:32](O)=[O:33])[CH2:26][CH:27]([CH2:31][CH:23]4[CH2:24]6)[CH2:28]5)=[O:20])[CH2:15]3)=[N:12][CH:13]=2)=[CH:4][C:3]1=[O:35].C1C=CC2N(O)N=[N:42]C=2C=1.CCN=C=NCCCN(C)C.Cl.CCN(C(C)C)C(C)C>ClCCl>[CH3:1][N:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[N:10][C:11]([CH:14]3[CH2:18][CH2:17][N:16]([C:19]([O:21][CH:22]4[CH:23]5[CH2:24][C:25]6([C:32](=[O:33])[NH2:42])[CH2:26][CH:27]([CH2:28][CH:29]4[CH2:30]6)[CH2:31]5)=[O:20])[CH2:15]3)=[N:12][CH:13]=2)=[CH:4][C:3]1=[O:35]
Reactant: Cn1ccc(-c2cnc(C3CCN(C(=O)OC4C5CC6CC4CC(C(=O)O)(C6)C5)C3)nc2)cc1=O
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cn1ccc(-c2cnc(C3CCN(C(=O)OC4C5CC6CC4CC(C(N)=O)(C6)C5)C3)nc2)cc1=O

Procedure:
A solution of 4-((3-(5-(1-methyl-2-oxo-1,2-dihydropyridin-4-yl)pyrimidin-2-yl)pyrrolidine-1-carbonyl)oxy)adamantane-1-carboxylic acid (20 mg, 0.04 mmol), HOBt (11.3 mg, 0.08 mmol), EDCl (16.5 mg, 0.08 mmol) and i-Pr2NEt (27 mg, 0.21 mmol) in dichloromethane (5 mL) was stirred overnight under ammonia gas. The reaction mixture was concentrated to afford an oil which was purified by basic preparative HPLC to afford two isomers:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11]CC)=[O:10])=[CH:4][C:3]=1[OH:14].[C:15]1([CH3:24])[C:16]([N:21]=[C:22]=S)=[CH:17][CH:18]=[CH:19][CH:20]=1.C1(N=C=NC2CCCCC2)CCCCC1>C(O)C>[C:15]1([CH3:24])[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[NH:21][C:22]1[O:14][C:3]2[CH:4]=[C:5]([CH2:8][C:9]([OH:11])=[O:10])[CH:6]=[CH:7][C:2]=2[N:1]=1
Reactant: CCOC(=O)Cc1ccc(N)c(O)c1
Reactant: Cc1ccccc1N=C=S
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCO
Product: Cc1ccccc1Nc1nc2ccc(CC(=O)O)cc2o1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of ethyl 4-amino-3-hydroxy-phenylacetate (3.3 g, Reference Example 5) and o-tolylisothiocyanate (2.5 mL) in ethanol (150 mL) was stirred at room temperature for about 2 hours. After standing at room temperature overnight the mixture was evaporated and the residue was subjected to flash chromatography (on silica eluting with a mixture of pentane and ethyl acetate, 7:3 v/v) to give a yellow foam. A solution of this material in ethanol (150 mL) was treated with dicyclohexylcarbodiimide (3.0 g) and the mixture was heated at reflux temperature for 2 hours. The mixture was evaporated and the residue subjected to short column chromatography (on silica eluting with a mixture of tert-butyl methyl ether and dichloromethane, 1:19 to 1:9 v/v). The resulting light yellow oil was dissolved in ethanol (100 mL) and the solution was treated with sodium hydroxide solution (15 mL, 1M) then heated at reflux temperature for 2 hours. The reaction mixture was evaporated and the residue was dissolved in water. The solution was washed with ethyl acetate and the aqueous layer was acidified to pH 1 by addition of concentrated hydrochloric acid. The resulting white precipitate was collected by filtration, then washed thoroughly with water, and then dried to give the title compound (1.8 g) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][CH:28]=1)[CH2:5][N:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9](=[O:16])[C:8]([C:17]([C:19]2[CH:20]=[N:21][C:22](Cl)=[CH:23][CH:24]=2)=[O:18])=[CH:7]1.[CH3:29][O-:30].[Na+]>CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][CH:28]=1)[CH2:5][N:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9](=[O:16])[C:8]([C:17]([C:19]2[CH:20]=[N:21][C:22]([O:30][CH3:29])=[CH:23][CH:24]=2)=[O:18])=[CH:7]1
Reactant: O=C(c1ccc(Cl)nc1)c1cn(Cc2cccc(Cl)c2)c2ccccc2c1=O
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc(C(=O)c2cn(Cc3cccc(Cl)c3)c3ccccc3c2=O)cn1
Yield: 89.5 %

Procedure:
Experimental conditions analogous to those described for Step 6 of Example 60, from 151 mg (0.37 mmol) of 1-(3-chloro-benzyl)-3-(6-chloro-pyridine-3-carbonyl)-1H-quinolin-4-one and 170 mg (3.15 mmol) of sodium methoxide were stirred in 2 mL of dry methanol in a sealed vessel at 75° C. for 2 h. The reaction mixture was evaporated and purified by flash chromatography to give 134 mg of a white powder. LC-MSD, m/z for C23H17ClN2O3 [M+H]+=405.1, 407.1; HPLC retention time: 2.3 min.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH:15]=[CH:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH:23]4[CH2:27][CH2:26][CH2:25][CH2:24]4)=[CH:18][CH:17]=3)[C:12]2=[O:28])=[CH:7][CH:6]=1.[CH3:29][NH2:30]>>[CH:23]1([O:22][C:19]2[CH:20]=[CH:21][C:16]([N:13]3[CH:14]=[CH:15][N:11]([C:8]4[CH:7]=[CH:6][C:5]([O:4][CH2:3][CH2:2][NH:30][CH3:29])=[CH:10][CH:9]=4)[C:12]3=[O:28])=[CH:17][CH:18]=2)[CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: O=c1n(-c2ccc(OCCBr)cc2)ccn1-c1ccc(OC2CCCC2)cc1
Reactant: CN
Product: CNCCOc1ccc(-n2ccn(-c3ccc(OC4CCCC4)cc3)c2=O)cc1

Procedure:
1-[4-(2-Bromoethoxy)phenyl]-3-(4-cyclopentyloxyphenyl)-1,3-dihydroimidazol-2-one was reacted with methylamine as described in example 6. The product with the molecular weight of 393.49 (C23H27N3O3); MS (ESI): 394 ([M+H]+) was obtained in this way.
Reaction SMILES: [N+](C1C=C(S(O[CH2:14][C@:15]2([CH3:18])[CH2:17][O:16]2)(=O)=O)C=CC=1)([O-])=O.[C:19]1(=[O:29])[NH:23][C:22](=[O:24])[C:21]2=[CH:25][CH:26]=[CH:27][CH:28]=[C:20]12.[K]>CN(C)C=O>[CH3:14][C@@:15]1([CH2:18][N:23]2[C:19](=[O:29])[C:20]3[C:21](=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:22]2=[O:24])[CH2:17][O:16]1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: C[C@@]1(COS(=O)(=O)c2cccc([N+](=O)[O-])c2)CO1
Agent: [K]
Solvent: CN(C)C=O
Product: C[C@@]1(CN2C(=O)c3ccccc3C2=O)CO1
Temperature: 50 °C
Reaction time: 5 h
Yield: 56.8 %

Procedure:
To a solution of (2S)-(2-methyloxiran-2-yl)methyl 3-nitrobenzenesulphonate (1.913 g, 7 mmoles) in dry dimethylformamide (15 ml), was added potassium phthalimide (1.304 g, 7 mmoles). The mixture was stirred at 50° C. for 5 h and then cooled to room temperature. The resulting mixture was partitioned between ethyl acetate and water. The aqueous phase was washed with ethyl acetate (2×100 ml) and the combined organic extracts were washed with water (3×100 ml), saturated brine solution, dried over sodium sulfate and concentrated in vacuo to leave a crude orange wax. Purification by chromatography (silica, 20% ethyl acetate in iso-hexane) afforded the subtitle compound as a white solid (0.864 g).
Reaction SMILES: [O:1]1[CH:6]=[CH:5][CH2:4][CH2:3][CH2:2]1.[Br:7][CH2:8][CH2:9][OH:10].Cl>>[O:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]1[O:10][CH2:9][CH2:8][Br:7]
Reactant: OCCBr
Reactant: C1=COCCC1
Agent: Cl
Product: BrCCOC1CCCCO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.3 %

Procedure:
3,4-Dihydro-2H-pyran (92.5 g, 1.1 mol) was added dropwise to 2-bromoethanol (125 g, 1.0 mol) on an ice-bath. The temperature was kept between 25°-30° C. during addition. When addition was complete a concentrated hydrochloric acid solution (1 ml) was added and the reaction mixture was stirred overnight at room temperature. The mixture was fractionated in vacuo to give 147 g (70%) of 2-bromoethyl tetrahydropyran-2-yl ether.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][C:10]2[CH:15]=[C:14]([O:16][CH3:17])[C:13]([O:18][CH3:19])=[C:12]([O:20][CH3:21])[CH:11]=2)[CH:5]=[CH:4][C:3]=1[C:22]1[C:23]2[CH:32]=[CH:31][S:30][C:24]=2[NH:25][C:26](=O)[CH2:27][N:28]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:42])=CC=1>C1(C)C=CC=CC=1.C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][C:10]2[CH:15]=[C:14]([O:16][CH3:17])[C:13]([O:18][CH3:19])=[C:12]([O:20][CH3:21])[CH:11]=2)[CH:5]=[CH:4][C:3]=1[C:22]1[C:23]2[CH:32]=[CH:31][S:30][C:24]=2[NH:25][C:26](=[S:42])[CH2:27][N:28]=1
Reactant: COc1cc(CCc2ccc(C3=NCC(=O)Nc4sccc43)c(Cl)c2)cc(OC)c1OC
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COc1cc(CCc2ccc(C3=NCC(=S)Nc4sccc43)c(Cl)c2)cc(OC)c1OC
Temperature: 25 °C

Procedure:
To a solution of 0.25 g (0.53 mmol) of the compound prepared in (e) above in 5 ml of toluene was added 0.13 g (0.32 mmol) of Lawesson's Reagent, and the resultant mixture was heated to 90° C. and maintained at this temperature for 3 hours. After cooling the reaction mixture to 25° C., the solvent it was diluted with 50 ml methylene chloride, washed successively with 1 ml of water and 10 ml of brine, dried over magnesium sulfate and evaporated. The crude residue was pruified by column chromatography on silica gel employing a mixture of ethyl acetate and hexane in 2:1 ratio as the eluent to yield an orange foam.
Reaction SMILES: Cl.[Cl:2][CH2:3][CH2:4][C:5]([NH2:8])([CH3:7])[CH3:6].[OH-].[Na+].[Cl:11][C:12]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:13]=1[CH:14]=O>C(Cl)Cl>[Cl:2][CH2:3][CH2:4][C:5]([N:8]=[CH:14][C:13]1[C:12]([Cl:11])=[CH:19][CH:18]=[CH:17][C:16]=1[Cl:20])([CH3:7])[CH3:6]
Reactant: CC(C)(N)CCCl
Reactant: O=Cc1c(Cl)cccc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CC(C)(CCCl)N=Cc1c(Cl)cccc1Cl
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 98.8 %

Procedure:
13.3 g (84.0 mmol) of 3-chloro-1,1-dimethyl propylamine-hydrochloride were added to 84.0 mL sodium hydroxide solution (1 M) at 0° C. with vigorous stirring. The reaction mixture was stirred for 30 min at 0° C. and then combined with 50 mL methylene chloride. The phases were separated and the aqueous phase was twice extracted with 35 mL methylene chloride. The combined organic phases were dried over magnesium sulphate and at ambient temperature combined with 14.2 g (81.0 mmol) of 2,6-dichlorobenzaldehyde with stirring. The reaction mixture was stirred for 18 h at ambient temperature, dried again with magnesium sulphate and the solvent was removed. 22.3 g (80.0 mmol, 99%) (3-chloro-1,1-dimethylpropyl)-(2,6-dichlorobenzylidene)-amine were obtained as a yellowish oil.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10].CN(C=O)C.[CH3:19][N:20]1[C:29]2[C:24](=[CH:25][C:26]([O:30][CH2:31][CH2:32][CH2:33][NH:34][CH2:35][C:36]3[CH:41]=[CH:40][N:39]=[CH:38][CH:37]=3)=[CH:27][CH:28]=2)[CH:23]=[CH:22][C:21]1=[O:42]>C(OCC)(=O)C>[CH2:12]([O:11][C:9](=[O:10])[CH2:8][N:34]([CH2:33][CH2:32][CH2:31][O:30][C:26]1[CH:25]=[C:24]2[C:29](=[CH:28][CH:27]=1)[N:20]([CH3:19])[C:21](=[O:42])[CH:22]=[CH:23]2)[CH2:35][C:36]1[CH:37]=[CH:38][N:39]=[CH:40][CH:41]=1)[CH3:13]
Reactant: Cn1c(=O)ccc2cc(OCCCNCc3ccncc3)ccc21
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)CN(CCCOc1ccc2c(ccc(=O)n2C)c1)Cc1ccncc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Potassium carbonate (1.66 g) and ethyl bromoacetate (1.16 ml) were added to a DMF solution (50 ml) of 1-methyl-6-{3-[(pyridin-4-ylmethyl)amino]propoxy}-1H-quinolin-2-one (1.5 g), and stirred at room temperature overnight. The reaction mixture was added to ice water, and extraction with ethyl acetate was performed. The organic layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:methanol=100:0→85:15). The purified product was condensed under reduced pressure to give the title compound (1.28 g) as a orange oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:13]([O-])=O)[C:5]([OH:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].C(O)(=O)C.[H][H]>C(OCC)(=O)C.[Pd]>[NH2:13][C:4]1[C:5]([OH:12])=[C:6]([CH:11]=[C:2]([F:1])[CH:3]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1cc(F)cc([N+](=O)[O-])c1O
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: COC(=O)c1cc(F)cc(N)c1O
Yield: 101 %

Procedure:
A suspension of methyl 5-fluoro-2-hydroxy-3-nitrobenzoate (2.3 g, 10.7 mmol), acetic acid (2 mL) and 10% Pd/C (0.23 g) in ethyl acetate (50 mL) was stirred at 25° C. over 1 atm hydrogen for 4 hr. The mixture was filtered and the filtrate was concentrated to give crude product. The crude product was purified by chromatography (silica gel, petroleum ether/ethyl acetate=100:1 to 20:1) to give methyl 3-amino-5-fluoro-2-hydroxybenzoate (2.0 g, yield 100%) as a light yellow solid. 1H-NMR (400 MHz, CDCl3-d) δ 3.95 (s, 3H), 3.98-4.13 (s, br, 2H), 6.60-6.63 (dd, J1=9.4 Hz, J2=2.4 Hz, 1H), 6.86-6.89 (dd, J1=8.8 Hz, J2=2.8 Hz, 1H), 10.70 (s, 1H); LC-MS (ESI) m/z 186 [M+1]+.
Reaction SMILES: C(OC(=O)[NH:10][C:11]1([C:14]2[N:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[O:16][N:15]=2)[CH2:13][CH2:12]1)C1C=CC=CC=1.[BrH:24]>C(O)(=O)C.CCOCC>[BrH:24].[F:22][C:19]([F:20])([F:21])[C:17]1[O:16][N:15]=[C:14]([C:11]2([NH2:10])[CH2:12][CH2:13]2)[N:18]=1
Reactant: O=C(NC1(c2noc(C(F)(F)F)n2)CC1)OCc1ccccc1
Agent: Br
Solvent: CC(=O)O
Solvent: CCOCC
Product: NC1(c2noc(C(F)(F)F)n2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
[1-(5-Trifluoromethyl-1,2,4-oxadiazol-3-yl)-cyclopropyl]-carbamic acid benzyl ester (0.22 g, 0.67 mmol) was dissolved in 33% HBr in acetic acid (0.5 mL) and the reaction allowed to stir for 30 min at RT. The mixture was diluted with Et2O resulting is formation of a white precipitate. The majority of the liquid was decanted off and the residue concentrated under reduce pressure to give 1-(5-trifluoromethyl-1,2,4-oxadiazol-3-yl)-cyclopropylamine hydrobromide (0.19 g, 0.69 mmol) as an orange solid.
Reaction SMILES: [NH2:1][CH2:2][C:3]1([OH:18])[CH2:8][CH2:7][CH:6]([CH2:9][O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:5][CH2:4]1.[OH-].[K+].[C:21](Cl)(Cl)=[O:22]>C1(C)C=CC=CC=1.O>[CH2:11]([O:10][CH2:9][CH:6]1[CH2:5][CH2:4][C:3]2([O:18][C:21](=[O:22])[NH:1][CH2:2]2)[CH2:8][CH2:7]1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=C(Cl)Cl
Reactant: NCC1(O)CCC(COCc2ccccc2)CC1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: O=C1NCC2(CCC(COCc3ccccc3)CC2)O1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of EXAMPLE 385A (475 mg) and potassium hydroxide (641 mg) in toluene (10 mL) and water (25 mL) was cooled in an ice bath and phosgene (20% in toluene, 2.178 mL) was added dropwise maintaining the temperature below 3° C. The reaction was stirred rapidly at ambient temperature for 3 hours while warming to ambient temperature. The reaction mixture was partitioned between brine (100 mL) and ethyl acetate (100 mL). The organics were dried over sodium sulfate, filtered, and concentrated to provide the title compound.
Reaction SMILES: Br[C:2]1[NH:11][C:10]2[C:9](=[O:12])[N:7]([CH3:8])[C:6](=[O:13])[N:5]([CH3:14])[C:4]=2[N:3]=1.[NH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][OH:21]>CC1C=CC(C)=CC=1>[OH:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][NH:15][C:2]1[NH:11][C:10]2[C:9](=[O:12])[N:7]([CH3:8])[C:6](=[O:13])[N:5]([CH3:14])[C:4]=2[N:3]=1
Reactant: Cn1c(=O)c2[nH]c(Br)nc2n(C)c1=O
Reactant: NCCCCCO
Solvent: Cc1ccc(C)cc1
Product: Cn1c(=O)c2[nH]c(NCCCCCO)nc2n(C)c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66.6 %

Procedure:
A solution of 5.16 grams of 8-bromotheophylline and 5.15 grams of 5-amino-1 pentanol in 18 ml of p-xylene was refluxed for 18 hours. The reaction solution was allowed to cool and upon cooling to room temperature formed a solid/liquid mixture. The xylene was decanted and the solid was washed with pentane (3×40 ml). The resulting solid was stirred in 20 ml of water for 30 minutes and filtered to collect the solid material. The collected solid material was washed with water (3×20 ml), and dried to provide 3.73 g of 8-(5-hydroxypentylamino)theophylline. To a solution of 1.12 g of 8-(5-hydroxypentylamino)theophylline in 15 ml of anhydrous N,N-dimethylformamide (DMF) was added 0.516 g of succinic anhydride and 0.2 g of 4-dimethylamino pyridine (DMAP). The mixture was stirred with a magnetic stirrer overnight at room temperature under anhydrous conditions. The colorless solid that precipitated was collected by vacuum filtration, washed with dichloromethane and air dried to provide 1.20 g of theophylline-8-N-(5-hydroxypentylamino)-O-succinic acid ester. This solid was recrystallized from a boiling 1:1 propanol/water mixture and dried over calcium sulfate to provide a colorless solid.
Reaction SMILES: [C:1]([CH2:3][CH2:4][NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9])#[N:2].[NH2:13][OH:14]>CCO>[NH2:2]/[C:1](=[N:13]/[OH:14])/[CH2:3][CH2:4][NH:5][C:6](=[O:12])[O:7][C:8]([CH3:9])([CH3:11])[CH3:10]
Reactant: CC(C)(C)OC(=O)NCCC#N
Reactant: NO
Solvent: CCO
Product: CC(C)(C)OC(=O)NCC/C(N)=N\O
Temperature: 25 °C
Yield: 99.5 %

Procedure:
Tert-butyl N-(2-cyanoethyl)carbamate (40 g; 235 mmol; 1 eq.) and hydroxylamine (41.6 ml; 705 mmol; 3 eq.) are dissolved in EtOH (800 ml). The resulting solution is heated under reflux for 2 hours. The reaction is followed by NMR. The reaction mixture is then cooled down to RT, and concentrated under vacuum, affording the title compound as a white solid (47.5 g, 99%).
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([CH3:7])[CH:3]=1.C(O[CH:11]=[C:12]([C:18](OCC)=O)[C:13]([O:15][CH2:16][CH3:17])=[O:14])C>>[CH3:7][C:4]1[C:3]2[C:2](=[N:1][CH:11]=[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:18]=2)[O:6][N:5]=1
Reactant: Cc1cc(N)on1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Product: CCOC(=O)c1cnc2onc(C)c2c1
Temperature: 120 °C

Procedure:
A mixture of 5-amino-3-methyl-isoxazole (5.26 g) and diethyl ethoxymethylenemalonate (10.9 ml) was heated at 120° C. for 3 hrs. The mixture was cooled to room temperature. The precipitated solid was collected, washed with n-hexane and dried under high vacuum. A portion of this solid (11.37 g) was dissolved in phosphoryl chloride (55 ml), heated at reflux for 11 hrs, and then cooled to room temperature. The mixture was concentrated under reduced pressure and the residue was purified with the column chromatography (ethyl acetate:n-hexane=1:9) to give ethyl 3-methylisoxazolo[5,4-b]pyridine-5-carboxylate as a white solid. Zinc powder (2.75 g) was added to a solution of a portion of the solid (2.43 g) in acetic acid (24 ml), the mixture was stirred at 80° C. for 1.5 hrs, and then filtered. The filtrate was concentrated under reduced pressure. The residue was dissolved in a mixture of 5N NaOH (10 ml) and ethanol (10 ml), the solution was refluxed for 1.5 hrs, cooled to room temperature, and acidified with concentrated HCl. The precipitated solid was collected by the filtration, washed with water, and dried under high vacuum.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]2=[C:9]([Cl:12])[CH:10]=[CH:11][N:4]2[N:3]=1.CCN(C(C)C)C(C)C.[N:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[CH2:28][NH2:29]>C(Cl)Cl>[Cl:1][C:2]1[N:7]=[C:6]([NH:29][CH2:28][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][N:22]=2)[C:5]2=[C:9]([Cl:12])[CH:10]=[CH:11][N:4]2[N:3]=1
Reactant: Clc1nc(Cl)c2c(Cl)ccn2n1
Reactant: NCc1ccccn1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Clc1nc(NCc2ccccn2)c2c(Cl)ccn2n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 57.1 %

Procedure:
To a stirred solution of 2,4,5-trichloropyrrolo[2,1-f][1,2,4]triazine (0.530 g, 2.38 mmol) in CH2Cl2 (20 mL) was added DIPEA (0.832 mL, 4.76 mmol) and pyridin-2-ylmethanamine (0.283 g, 2.62 mmol) and the contents were stirred for 10 min at room temperature. The reaction mixture was washed with water and the organic layer was separated, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a brown solid. The residue was purified by column chromatography using CombiFlash (REDISEP®, silica gel, 24 g, 20% EtOAc/hexanes) to give 2,5-dichloro-N-(pyridin-2-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (0.400 g, 57.0%) as an off-white solid. LCMS Condition B-12: retention time 2.20, [M+1]=294.2. 1H NMR (400 MHz, DMSO-d6) δ ppm 4.87 (d, J=5.7 Hz, 2H), 6.81 (d, J=2.8 Hz, 1H), 7.32 (t, J=1.6 Hz, 1H), 7.42 (d, J=8.0 Hz, 1H), 7.81 (d, J=2.8 Hz, 1H), 7.83 (t, J=1.6 Hz, 1H), 8.48 (t, J=5.2 Hz, 1H), 8.57 (d, J=1.2 Hz, 1H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:10]1[C:18]2[CH:17]=[CH:16][C:15](=[O:19])[N:14]([C:20]3[CH:25]=[CH:24][C:23]([S:26][CH3:27])=[CH:22][CH:21]=3)[C:13]=2[S:12][C:11]=1[C:28]([O:30][CH2:31][CH3:32])=[O:29])#[N:2].ClC1C=CC=C(C(OO)=[O:41])C=1>C(Cl)Cl>[C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:10]1[C:18]2[CH:17]=[CH:16][C:15](=[O:19])[N:14]([C:20]3[CH:21]=[CH:22][C:23]([S:26]([CH3:27])=[O:41])=[CH:24][CH:25]=3)[C:13]=2[S:12][C:11]=1[C:28]([O:30][CH2:31][CH3:32])=[O:29])#[N:2]
Reactant: CCOC(=O)c1sc2c(ccc(=O)n2-c2ccc(SC)cc2)c1Nc1ccccc1C#N
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CCOC(=O)c1sc2c(ccc(=O)n2-c2ccc(S(C)=O)cc2)c1Nc1ccccc1C#N
Yield: 82 %

Procedure:
A mixture of Example 78 (1.0 g, 2.17 mmol) and m-chloroperbenzoic acid (534 mg, 1 eq) in DCM (50 mL) was stirred at r.t. for 2 h. The mixture was diluted with DCM, washed with NaHCO3 aq, dried (MgSO4) and concentrated in vacuo. Purification by column chromatography (silica, 50% EtOAc in DCM) gave the title compound (850 mg, 82%). δH (CDCl3) 8.80 (1H, s), 8.12-7.70 (2H, m), 7.65-7.53 (3H, m), 7.50 (1H, t, J 7.4 Hz), 7.27 (1H, d, J 9.8 Hz), 7.17-7.09 (2H, m), 6.45 (1H, d, J 9.8 Hz), 4.28 (2H, q, J 7.1 Hz), 2.83 (3H, s), 1.30 (3H, t, J 7.1 Hz). LCMS (ES+) RT 3.16 minutes, 478 (M+H)+.
Reaction SMILES: [C:1]1([CH:7]([NH2:22])[CH2:8][CH2:9][O:10][C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]([CH3:21])=[CH:13][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.Cl[C:31]([O:33][CH2:34][CH3:35])=[O:32]>C1COCC1>[CH2:34]([O:33][C:31]([NH:22][CH:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[CH2:8][CH2:9][O:10][C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14]([CH3:21])=[CH:13][CH:12]=1)=[O:32])[CH3:35]
Reactant: CCOC(=O)Cl
Reactant: Cc1ccc(OCCC(N)c2ccccc2)c2ccccc12
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)NC(CCOc1ccc(C)c2ccccc12)c1ccccc1
Temperature: 25 °C
Yield: 103.3 %

Procedure:
A solution of 2.12 g (7.3 mmol) of 1-phenyl-3-(4-methyl-1-naphthalenyloxy)propanamine, 1.12 ml (8.0 mmol) of triethylamine and 100 ml of THF was cooled to approximately 0° C. under a nitrogen atmosphere. To the mixture was added 0.766 ml (8.0 mmol) of ethyl chloroformate dropwise. The resulting mixture was stirred at room temperature for approximately five and one-half hours and concentrated under vacuum. The residue was dissolved in diethyl ether, toluene and water. The mixture was extracted with diethyl ether. The organic extracts were combined, washed with water, 2N hydrochloric acid, water, 1N sodium hydroxide water, and a saturated sodium chloride solution and dried over anhydrous sodium sulfate. The mixture was concentrated under vacuum to provide 2.74 g of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:14]=[CH:13][C:6]2[NH:7]C(=O)O[C:10](=[O:11])[C:5]=2[CH:4]=1.[CH:15]([C:19]1[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=1)([CH2:17][CH3:18])[CH3:16]>CN(C=O)C>[NH2:7][C:6]1[CH:13]=[CH:14][C:3]([O:2][CH3:1])=[CH:4][C:5]=1[C:10]([NH:23][C:22]1[CH:24]=[CH:25][C:19]([CH:15]([CH2:17][CH3:18])[CH3:16])=[CH:20][CH:21]=1)=[O:11]
Reactant: COc1ccc2[nH]c(=O)oc(=O)c2c1
Reactant: CCC(C)c1ccc(N)cc1
Solvent: CN(C)C=O
Product: CCC(C)c1ccc(NC(=O)c2cc(OC)ccc2N)cc1
Temperature: 115 °C
Reaction time: 16 h

Procedure:
To a flask (100 mL) with magnetic stirrer was added 6-methoxy-1H-benzo[d][1,3]oxazine-2,4-dione (1.55 g, 8.00 mmol), 4-sec-butylaniline (1.19 mL, 8.0 mmol) and anhydrous DMF (10 mL). The reaction mixture was stirred at 115° C. for 16 hours under nitrogen. DMF was removed and the residue was mixed with water (100 mL) and ethyl acetate (150 mL). The organic phase was separated and washed with brine (50 mL). The solvent was removed and the residue was purified by column chromatography on silica gel (230-400 mesh) using hexane/ethyl acetate=1:1 to give 2-amino-N-(4-sec-butyl-phenyl)-5-methoxy-benzamide. Yield: 0.90 g (37%).