Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC(=O)[NH:4][C:5]1[CH:10]=[CH:9][C:8]([F:11])=[C:7]([CH:12]([OH:23])[C:13]2[C:21]3[C:20]([OH:22])=[N:19][CH:18]=[N:17][C:16]=3[NH:15][CH:14]=2)[C:6]=1[F:24].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C(=O)(O)[O-].[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>O1CCCC1.C(OCC)(=O)C>[NH2:4][C:5]1[C:6]([F:24])=[C:7]([C:12]([C:13]2[C:21]3[C:20]([OH:22])=[N:19][CH:18]=[N:17][C:16]=3[NH:15][CH:14]=2)=[O:23])[C:8]([F:11])=[CH:9][CH:10]=1
Reactant: COC(=O)Nc1ccc(F)c(C(O)c2c[nH]c3ncnc(O)c23)c1F
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Nc1ccc(F)c(C(=O)c2c[nH]c3ncnc(O)c23)c1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 50.2 %

Procedure:
In a reaction vessel, {2,4-difluoro-3-[hydroxy-(4-hydroxy-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-methyl]-phenyl}-carbamic acid methyl ester (38, 690 mg, 1.97 mmol) is dissolved in 200 mL of tetrahydrofuran and Dess-Martin periodinane (877.3 mg, 2.068 mmol) is added. The resulting mixture is stirred at room temperature for 3 hours, then 20 mL of saturated aqueous sodium bicarbonate, 5 mL of saturated aqueous sodium thiosulfate, and 100 mL of ethyl acetate are added for extraction. The organic layer is isolated and the aqueous layer extracted with 50 mL of ethyl acetate. The organic fractions are combined and washed with water, then brine, dried with magnesium sulfate, filtered and the filtrate is concentrated under vacuum. The resulting material is suspended in acetonitrile, sonicated for 1 hour, then filtered to collect the solid material, which is then washed with acetonitrile. The resulting material is suspended in 15 mL of dioxane, and combined with 15 mL of 10N aqueous sodium hydroxide, and heated to reflux for 5 hours. The reaction mixture is adjusted to approximately pH 6 with 6N hydrochloric acid and extracted with ethyl acetate. The organic layer is concentrated under vacuum and the resulting material purified by silica gel chromatography eluting with methanol and dichloromethane. Appropriate fractions are combined and concentrated under vacuum to provide the desired compound (39, 287 mg). MS (ESI) [M−H+]−=289.1.
Reaction SMILES: [Cl:1]Cl.[CH2:3]([O:10][C:11]1[CH:20]=[CH:19][C:14]([C:15]([O:17]C)=[O:16])=[C:13]([O:21][CH3:22])[CH:12]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>C(O)(=O)C>[CH2:3]([O:10][C:11]1[C:20]([Cl:1])=[CH:19][C:14]([C:15]([OH:17])=[O:16])=[C:13]([O:21][CH3:22])[CH:12]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(OCc2ccccc2)cc1OC
Reactant: ClCl
Solvent: CC(=O)O
Product: COc1cc(OCc2ccccc2)c(Cl)cc1C(=O)O
Temperature: 22.5 °C
Yield: 58.6 %

Procedure:
A solution of chlorine (5.1 g) in acetic acid (100 ml) was added dropwise to a solution of methyl 4-benzyloxy-2-methoxybenzoate (10 g) in acetic acid (40 ml) whilst maintaining the temperature at 20-25° C. The mixture was poured into ice-water and extracted with dichloromethane. The organic extract was dried over sodium sulfate and concentrated in vacuo. The resulting crude material was suspended in ethanol (500 ml) and treated with 10% aqueous sodium hydroxide (16 ml). The mixture was heated at reflux overnight and then concentrated in vacuo. The residue was treated with excess 5M HCl and extracted into dichloromethane. The extract was dried (sodium sulfate) and concentrated in vacuo to afford a white solid which was crystallised from ethanol to give the title compound (6.3 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([C:28](=O)[C:29]#[C:30][CH3:31])[CH:26]=3)[N:21]=[CH:20][N:19]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1.[O:33]([CH2:35][C@H:36]1[O:41][CH2:40][CH2:39][N:38](C([O-])=O)[CH2:37]1)[NH2:34].CS(O)(=O)=O>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:17][C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[C:25]([C:28](=[N:34][O:33][CH2:35][C@H:36]4[O:41][CH2:40][CH2:39][NH:38][CH2:37]4)[C:29]#[C:30][CH3:31])[CH:26]=3)[N:21]=[CH:20][N:19]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1
Reactant: CC#CC(=O)c1ccc2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c2c1
Reactant: NOC[C@@H]1CN(C(=O)[O-])CCO1
Agent: CS(=O)(=O)O
Solvent: C1COCCO1
Product: CC#CC(=NOC[C@@H]1CNCCO1)c1ccc2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c2c1
Temperature: 80 °C
Reaction time: 22 h

Procedure:
To a suspension of 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(1-oxo-2-butyn-1-yl)quinazoline (IV) (786 mg) and tert-buthyl (S)-2-aminoxymethyl-morpholine-4-carboxylate (614 mg) in 1,4-dioxane (31 mL) was added 2 mol/L methanesulfonic acid aq. solution (2.21 mL) and stirred for 22 hr at 80° C. 2 mol/L methanesulfonic acid aq. solution (1.32 mL) was added and stirred for additional 5.5 hr. After the reaction was completed, the mixture was poured into ice-sodium hydrogen carbonate aq. solution and extracted with ethyl acetate. After the aqueous layer was extracted again with ethylacetate, all the organic layers were combined, washed with water and dried over anhydrous magnesium sulfate. The filtrate was concentrated and the residue was purified by silicagel column chromatography (eluted with chloroform:methanol=9:1) to give yellow oil. A solution of this oil in ethyl acetate (50 mL) was filtered and 4 mol/L hydrochloric acid-ethyl acetate (0.95 mL) was added under stirring and stirred for 1 hr at room temperature. The precipitate was filtered and washed with ethyl acetate and then hexane. The precipitate was recrystallized from methanol-ethyl acetate to give 4-(3-chloro-4-(3-fluorobenzyloxy)phenylamino)-6-(1-((S)-morpholine-2-yl-methoxyimino)-2-butyn-1-yl)quinazoline.2HCl (VI-1) (839 mg) as yellow crystalline.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([NH:13][C:14](=[O:18])OCC)=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH3:19])[CH:9]=2)[N:4]=1.[N:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>>[CH3:1][O:2][C:3]1[C:12]([NH:13][C:14]([N:29]2[CH2:30][CH2:31][N:26]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][N:20]=3)[CH2:27][CH2:28]2)=[O:18])=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH3:19])[CH:9]=2)[N:4]=1
Reactant: CCOC(=O)Nc1nc2cc(C)ccc2nc1OC
Reactant: c1ccc(N2CCNCC2)nc1
Product: COc1nc2ccc(C)cc2nc1NC(=O)N1CCN(c2ccccn2)CC1
Yield: 83 %

Procedure:
Ethyl N-(2-methoxy-6-methylquinoxalin-3-yl)carbamate and 1-(2-pyridyl) piperazine were reacted by the same way with the example 43 to obtain the titled compound (yield, 83%). 1H NMR (300 MHz, CDCl3): δ 2.43-2.47 (m, 3H), 3.63-3.73 (m, 7H), 4.13 (s, 4H), 6.67 (d, J=8.4 Hz, 2H), 7.01-7.12 (m, 1H), 7.30-7.33 (m, 1H), 7.48-7.62 (m, 3H), 8.21 (dd, J=4.8 and 1.5 Hz, 1H).
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.[OH-].[K+].Br[C:15]1[S:19][C:18]([S:20]([NH2:23])(=[O:22])=[O:21])=[CH:17][CH:16]=1>CN(C)C=O.O>[C:9]([CH2:8][C:5]1[CH:4]=[CH:3][C:2]([S:1][C:15]2[S:19][C:18]([S:20]([NH2:23])(=[O:22])=[O:21])=[CH:17][CH:16]=2)=[CH:7][CH:6]=1)([OH:11])=[O:10]
Reactant: O=C(O)Cc1ccc(S)cc1
Reactant: NS(=O)(=O)c1ccc(Br)s1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: NS(=O)(=O)c1ccc(Sc2ccc(CC(=O)O)cc2)s1
Temperature: 120 °C

Procedure:
4-Mercaptophenylacetic acid (2.3 g) was dissolved in dimethylformamide under a nitrogen atmosphere and 1.8 g of potassium hydroxide dissolved in a minimum amount of water was added. 5-bromothiophene-2-sulfonamide (3.3 g) dissolved in dimethylformamide was added and the mixture heated at 120° C. for 2 hours. After cooling to room temperature water was added to the reaction mixture, the pH was adjusted to 8.6 and the mixture was extracted with ethyl acetate. The aqueous phase was separated and acidified, causing a solid to precipitate. The solid was collected by filtration and dried under vacuum to a weight of 3.25 g.
Reaction SMILES: [F:1][C:2]1[C:11]([O:12][CH3:13])=[C:10]([O:14][CH3:15])[CH:9]=[C:8]2[C:3]=1[C:4](=[O:21])[C:5]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:6][NH:7]2.F[C:23]1C=C2C(C(=O)C(C(OCC)=O)=CN2)=C(OC)[C:24]=1OC.C(=O)([O-])[O-].[K+].[K+].P(OCC)(OCC)(OCC)=O>O>[CH2:23]([N:7]1[C:8]2[C:3](=[C:2]([F:1])[C:11]([O:12][CH3:13])=[C:10]([O:14][CH3:15])[CH:9]=2)[C:4](=[O:21])[C:5]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:6]1)[CH3:24]
Reactant: CCOC(=O)c1c[nH]c2cc(OC)c(OC)c(F)c2c1=O
Reactant: CCOC(=O)c1c[nH]c2cc(F)c(OC)c(OC)c2c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOP(=O)(OCC)OCC
Solvent: O
Product: CCOC(=O)c1cn(CC)c2cc(OC)c(OC)c(F)c2c1=O
Temperature: 120 °C
Reaction time: 8 h
Yield: 57.6 %

Procedure:
A mixture of ethyl 5-fluoro-6,7-dimethoxy-4-oxo-1,4-dihydroquinoline-3-carboxylate and ethyl 7-fluoro-5,6-dimethoxy-4-oxo-1,4-dihydroquinoline-3-carboxylate (103 g, 349 mmol), and potassium carbonate (72.3 g, 523 mmol) in triethyl phosphate (297 ml, 1744 mmol) was stirred at 120° C. for 8 h. LCMS indicated completion of the reaction. The reaction mixture was cooled down to rt and diluted with water, extracted with DCM, dried over sodium sulfate and concentrated in vacuo. The crude material was recrystallized in EtOH, the precipitate was collected by filtration and washed by cold EtOH and dried in air. Another recrystallization afforded pure ethyl 1-ethyl-5-fluoro-6,7-dimethoxy-4-oxo-1,4-dihydroquinoline-3-carboxylate (65 g, 201 mmol, 57.6% yield) as a brown solid. LCMS: (M+H)+: 324.1.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][N:11]=1)[C:5]([O:7][CH3:8])=[O:6].Cl[CH2:13][CH2:14][N:15]=[C:16]=[O:17].C(N(CC)CC)C.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1>[O:17]=[C:16]1[NH:15][CH2:14][CH2:13][N:1]1[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][N:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1ccnc(N)c1
Reactant: O=C=NCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)c1ccnc(N2CCNC2=O)c1
Temperature: 25 °C
Yield: 58 %

Procedure:
A solution of methyl 2-aminoisonicotinate (5.00 g, 32.9 mmol) and 2-chloroethyl isocyanate (4.51 g, 42.7 mmol) in anhydrous tetrahydrofuran (85 mL) was stirred at ambient temperature for 17 hours and refluxed for 3 hours, followed by the addition of triethylamine (10 mL) and potassium carbonate (9.60 g, 69.50 mmol). The reaction mixture was refluxed for 23 hours, cooled to ambient temperature and filtered. The solid residue was washed with water (2×20 mL hexanes (2×20 mL) and dried in vacuo to give methyl 2-(2-oxoimidazolidin-1-yl)isonicotinate as a colorless solid (4.22 g, 58%): 1H NMR (300 MHz, DMSO-d6) δ 8.67 (s, 1H), 8.40 (d, J=5.1 Hz, 1H), 7.35-7.33 (m, 2H), 2.97 (t, J=7.5 Hz, 2H), 3.85 (s, 3H), 3.41-3.36 (m, 2H); MS (ES+) m/z 222.1.
Reaction SMILES: [BrH:1].[CH2:2]1[C:4]2([CH2:9][CH2:8][CH2:7][N:6](C(OCC3C=CC=CC=3)=O)[CH2:5]2)[CH2:3]1>CCCCCC>[BrH:1].[CH2:3]1[C:4]2([CH2:9][CH2:8][CH2:7][NH:6][CH2:5]2)[CH2:2]1
Reactant: O=C(OCc1ccccc1)N1CCCC2(CC2)C1
Agent: Br
Solvent: CCCCCC
Product: C1CNCC2(C1)CC2
Temperature: 25 °C
Reaction time: 3 h
Yield: 84.9 %

Procedure:
HBr (6.16 g, 4.13 ml, 30% solution in glacial acetic acid, 22.83 mmol) was added to a benzyl 5-azaspiro[2.5]octane-5-carboxylate (step 1 of intermediate 3, 2.8 g, 11.41 mmol) at 0° C. Reaction mixture was stirred at 25° C. for 3 hr. The progress of reaction was monitored by TLC. Reaction mixture was diluted with hexane (25 ml) and stirred for 15 min at 25° C. Organic layer was separated and solid was again stirred with diethyl ether (25 ml). Solvent layer was removed by decanting and solid was dried to obtain the title compound (1.86 g, 85%). MS: m/z 112 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[N:7][C:8]([Cl:12])=[C:9](Br)[CH:10]=1)=[O:4].[Cl:13][C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1.C(=O)([O-])[O-].[Na+].[Na+].O>C1(C)C=CC=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[CH3:1][O:2][C:3](=[O:4])[C:5]1[CH:10]=[C:9]([C:17]2[CH:18]=[CH:19][C:14]([Cl:13])=[CH:15][CH:16]=2)[C:8]([Cl:12])=[N:7][CH:6]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: COC(=O)c1cnc(Cl)c(Br)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COC(=O)c1cnc(Cl)c(-c2ccc(Cl)cc2)c1
Temperature: 90 °C
Yield: 64.8 %

Procedure:
5-Bromo-6-chloro-3-pyridinecarboxylic acid methyl ester (42.2 g, 0.169 mol, CA 78686-77-8) was dissolved in toluene (840 mL). To this solution was added with stirring [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) CH2Cl2 (6.9 g, 8.4 mmol), 4-chlorophenylboronic acid (27.2 g, 0.169 mol) and sodium carbonate solution (2M, 170 mL). This mixture was heated to 90° C. for 1 h and cooled to room temperature. Water (400 mL) was added, the phases were separated and the water mixture was extracted with ethylacetate. Organic phases were pooled, dried with MgSO4 and the volatiles removed in vacuo. The residue was purified by flash chromatography (SiO2, heptane/CH2Cl2) to give the title compound (30.9 g) as a white solid; MS (EI) 281.1, 283.0 (M)+.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8](=[O:12])[NH:9]2)=[CH:4][C:3]=1[N+:13]([O-])=O.[H-].[Na+].[CH3:18]I.O>CN(C)C=O>[NH2:13][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:2]=1[CH3:1])[N:9]([CH3:18])[C:8](=[O:12])[CH2:7][CH2:6]2
Reactant: CI
Reactant: Cc1cc2c(cc1[N+](=O)[O-])CCC(=O)N2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc2c(cc1N)CCC(=O)N2C
Yield: 60.9 %

Procedure:
The compound (3.14 g, 15.2 mmol) obtained in step A was dissolved in N,N-dimethylformamide (30 ml), 60% sodium hydride (730 mg, 18.2 mmol) was added under ice-cooling with stirring, and thereafter the mixture was stirred at room temperature for 30 min. The reaction mixture was ice-cooled again, methyl iodide (1.9 ml, 30.4 mmol) was added with stirring, and the mixture was stirred at room temperature for 1 hr. To the reaction mixture was added water, and the precipitated solid was collected by filtration, washed with water, and dried under reduced pressure to give a bistered solid. Using this solid and according to the method of Reference Example 116, step B, the title compound (1.76 g, yield 61%) was obtained as a pale-bistered solid.
Reaction SMILES: [CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[C:6](=[CH:16][C:17]3[CH:18]=[C:19]([NH2:23])[CH:20]=[CH:21][CH:22]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH3:24][CH:25]([CH3:31])[CH2:26][S:27](Cl)(=[O:29])=[O:28]>>[CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[C:6](=[CH:16][C:17]3[CH:18]=[C:19]([NH:23][S:27]([CH2:26][CH:25]([CH3:31])[CH3:24])(=[O:29])=[O:28])[CH:20]=[CH:21][CH:22]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)CS(=O)(=O)Cl
Reactant: Nc1cccc(C=C2c3ccccc3CCc3ccccc32)c1
Product: CC(C)CS(=O)(=O)Nc1cccc(C=C2c3ccccc3CCc3ccccc32)c1
Yield: 21.4 %

Procedure:
Following procedures essentially as described in Example 90, 3-(10,11-dihydro-dibenzo[a,d]cyclohepten-5-ylidenemethyl)-phenylamine (50 mg, 0.168 mmol) and 2-methyl-propane-1-sulfonyl chloride (53 mg, 0.336 mmol) (prepared as described in Quast, H., Synthesis (1974), (7), 489-90) affords 15 mg (21%) of the title compound as a brown oil. MS (ES) 435 (M+NH4), 416 (M−H); HPLC shows 100% purity.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:14]([NH:16][C:17]([C:19]2[N:20]=[C:21](Cl)[O:22][CH:23]=2)=[O:18])[CH3:15])[CH:5]=[C:6]([F:13])[C:7]=1[NH:8][S:9]([CH3:12])(=[O:11])=[O:10].[F:25][C:26]([F:37])([F:36])[CH:27]([C:29]1[CH:30]=[C:31]([OH:35])[CH:32]=[CH:33][CH:34]=1)[CH3:28]>>[F:1][C:2]1[CH:3]=[C:4]([CH:14]([NH:16][C:17]([C:19]2[N:20]=[C:21]([O:35][C:31]3[CH:32]=[CH:33][CH:34]=[C:29]([CH:27]([CH3:28])[C:26]([F:25])([F:36])[F:37])[CH:30]=3)[O:22][CH:23]=2)=[O:18])[CH3:15])[CH:5]=[C:6]([F:13])[C:7]=1[NH:8][S:9]([CH3:12])(=[O:11])=[O:10]
Reactant: CC(c1cccc(O)c1)C(F)(F)F
Reactant: CC(NC(=O)c1coc(Cl)n1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Product: CC(NC(=O)c1coc(Oc2cccc(C(C)C(F)(F)F)c2)n1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Yield: 86.7 %

Procedure:
2-Chloro-oxazole-4-carboxylic acid [1-(3,5-difluoro-4-methanesulfonylamino-phenyl)-ethyl]-amide (30 mg, 0.08 mmol) was reacted with 3-(1-trifluoromethylethyl)phenol (20 mg, 0.11 mmol) to give the title compound (37 mg, 88%) after purification by flash chromatography on silica gel (gradient 12% to 100% EtOAc in n-hexane).
Reaction SMILES: COC1C=C(N2CCC(N3CCP(C)(=O)CC3)CC2)C=CC=1N.ClC1N=C(Cl)C(Cl)=CN=1.Cl[C:34]1[N:39]=[C:38]([NH:40][C:41]2[CH:46]=[CH:45][C:44]([N:47]3[CH2:52][CH2:51][CH:50]([N:53]4[CH2:58][CH2:57][P:56]([CH3:60])(=[O:59])[CH2:55][CH2:54]4)[CH2:49][CH2:48]3)=[CH:43][C:42]=2[O:61][CH3:62])[C:37]([Cl:63])=[CH:36][N:35]=1.[CH:64]1([C:67]2[O:71][C:70]([NH2:72])=[N:69][CH:68]=2)[CH2:66][CH2:65]1>>[Cl:63][C:37]1[C:38]([NH:40][C:41]2[CH:46]=[CH:45][C:44]([N:47]3[CH2:48][CH2:49][CH:50]([N:53]4[CH2:58][CH2:57][P:56]([CH3:60])(=[O:59])[CH2:55][CH2:54]4)[CH2:51][CH2:52]3)=[CH:43][C:42]=2[O:61][CH3:62])=[N:39][C:34]([NH:72][C:70]2[O:71][C:67]([CH:64]3[CH2:66][CH2:65]3)=[CH:68][N:69]=2)=[N:35][CH:36]=1
Reactant: Nc1ncc(C2CC2)o1
Reactant: COc1cc(N2CCC(N3CCP(C)(=O)CC3)CC2)ccc1Nc1nc(Cl)ncc1Cl
Agent: COc1cc(N2CCC(N3CCP(C)(=O)CC3)CC2)ccc1N
Agent: Clc1ncc(Cl)c(Cl)n1
Product: COc1cc(N2CCC(N3CCP(C)(=O)CC3)CC2)ccc1Nc1nc(Nc2ncc(C3CC3)o2)ncc1Cl

Procedure:
This compound can be prepared as in Example 32 by reacting 2-methoxy-4-[4-(4-methyl-4-oxido-1,4-azaphosphinan-1-yl)piperidin-1-yl]aniline with 2,4,5-trichloropyrimidine to generate 2,5-dichloro-N-{2-methoxy-4-[4-(4-methyl-4-oxido-1,4-azaphosphinan-1-yl)piperidin-1-yl]phenyl}pyrimidin-4-amine. 2,5-dichloro-N-{2-methoxy-4-[4-(4-methyl-4-oxido-1,4-azaphosphinan-1-yl)piperidin-1-yl]phenyl}pyrimidin-4-amine is then reacted with 5-cyclopropyl-1,3-oxazol-2-amine according to the procedure described in Example 32.
Reaction SMILES: Cl[CH2:2][CH:3]([C:5]1[N:10]=[CH:9][CH:8]=[CH:7][N:6]=1)[OH:4].[I-].[Na+].[CH3:13][NH2:14]>CO>[CH3:13][NH:14][CH2:2][CH:3]([C:5]1[N:10]=[CH:9][CH:8]=[CH:7][N:6]=1)[OH:4]
Reactant: OC(CCl)c1ncccn1
Reactant: CN
Agent: [I-]
Agent: [Na+]
Solvent: CO
Product: CNCC(O)c1ncccn1
Yield: 47.7 %

Procedure:
In a pressure bottle was placed 2-chloro-1-pyrimidin-2-ylethanol (3.525 g, 22.24 mmol), sodium iodide (0.344 g, 2.29 mmol) and a 2M. methylamine solution (160 ml, 320 mmol) in methanol. The bottle was sealed and heated at 62° for 17 hr. The solvent was evaporated and the residue stirred with 10% MeOH—CHCl3. Filtration and evaporation gave a dark oil that was chromatographed over silica gel (90 g) eluting with 5-10% MeOH—CH2Cl2 containing 1% triethylamine The product was obtained as an amber oil (1.625 g).
Reaction SMILES: Cl[C:2]1[C:15]2[O:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH3:16][CH:17]1[NH:21][C:20](=O)[CH2:19][CH2:18]1>>[CH2:16]([CH:17]1[N:21]([C:20]2[CH2:19][CH2:18][CH:17]([CH2:16][CH2:4][CH2:5][CH3:6])[N:21]=2)[C:20]([N:7]2[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[O:14][C:15]3[C:6]2=[CH:5][CH:4]=[CH:3][CH:2]=3)=[CH:19][CH2:18]1)[CH2:3][CH2:2][CH3:15]
Reactant: CC1CCC(=O)N1
Reactant: Clc1cccc2c1Oc1ccccc1N2
Product: CCCCC1CCC(N2C(N3c4ccccc4Oc4ccccc43)=CCC2CCCC)=N1

Procedure:
reaction of 4-chlorophenoxazine with 5-methyl-2-pyrrolidinone according to the procedure of Example 4 provides
Reaction SMILES: [CH3:1][O:2][C:3]1[N:4]=[CH:5][C:6]([C:9]([OH:11])=O)=[N:7][CH:8]=1.S(Cl)(Cl)=O.[NH2:16][C:17]1[CH:18]=[C:19]([F:36])[C:20]([F:35])=[C:21]([C@:23]23[CH2:31][O:30][C@H:29]([CH2:32][F:33])[C@H:28]2[CH2:27][S:26][C:25]([NH2:34])=[N:24]3)[CH:22]=1.[OH-].[Na+]>CN1CCN(C)C1=O.C(O)CC.CCOC(C)=O.O>[NH2:34][C:25]1[S:26][CH2:27][C@@H:28]2[C@@H:29]([CH2:32][F:33])[O:30][CH2:31][C@:23]2([C:21]2[CH:22]=[C:17]([NH:16][C:9]([C:6]3[CH:5]=[N:4][C:3]([O:2][CH3:1])=[CH:8][N:7]=3)=[O:11])[CH:18]=[C:19]([F:36])[C:20]=2[F:35])[N:24]=1
Reactant: COc1cnc(C(=O)O)cn1
Reactant: NC1=N[C@@]2(c3cc(N)cc(F)c3F)CO[C@H](CF)[C@H]2CS1
Agent: [Na+]
Agent: [OH-]
Solvent: CCCO
Solvent: CCOC(C)=O
Solvent: CN1CCN(C)C1=O
Product: COc1cnc(C(=O)Nc2cc(F)c(F)c([C@]34CO[C@H](CF)[C@H]3CSC(N)=N4)c2)cn1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 75.2 %

Procedure:
A suspension of 5-methoxypyrazine-2-carboxylic acid (4.01 g, 0.026 mol, 1.10 equiv.) in N,N′-dimethylimidazoline-2-one (22.5 mL) was stirred at ambient temperature for 15 min, then cooled to 0° C. Thionyl chloride (2.24 mL, 0.031 mol, 1.3 equiv.) was added while maintaining temperature under 10° C. The resulting suspension was stirred at 0-10° C. for 2 h while it transitioned to a clear solution. In another vessel, (4aS,5S,7aS)-7a-(5-amino-2,3-difluorophenyl)-5-(fluoromethyl)-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-amine (7.60 g, 0.024 mol, 1.0 equiv.) was dissolved into N,N′-dimethylimidazoline-2-one (22.5 mL). The resolution solution was added to the solution of acyl chloride while maintaining temperature below 10° C. The reaction mixture was stirred for 30 min. Water (112 mL) was charged while maintaining temperature below 30° C. The resolution mixture was stirred for 30 min., and then EtOAc (112 mL) was added. To this mixture was added, 50% aq. NaOH (10.0 g) until the pH of the aqueous layer reached 11. The aq. layer was extracted with EtOAc (75 mL). The organics were combined, washed with sat. aq. NaCl (38 mL) and water (38 mL). The organics were filtered over a pad of silica gel (15 g) and rinsed with EtOAc (37.5 mL). The organics were concentrated under vacuum to afford a solid. To the solid was added 1-propanol (112 mL), and the suspension was heated to 100° C. The mixture was cooled to −10° C. and held for 1 h. The solid was filtered, rinsed with cold 1-propanol (15 mL) and dried under vacuum (35° C.) until constant weight to afford the title compound (8.18 g). 1H NMR (500 MHz, DMSO) δ ppm 10.73 (s, 1H), 8.88 (d, =0.8 Hz, 1H), 8.39 (d, J=0.9 Hz, 1H), 8.11-7.87 (m, 1H), 7.73 (d, J=5.0 Hz, 1H), 6.07 (s, 2H), 4.68-4.44 (m, 2H), 4.41-4.28 (m, 1H), 4.23 (d, J=8.3 Hz, 1H), 4.01 (s, 3H), 3.82 (dd, J=8.1, 2.4 Hz, 1H), 3.18 (dd, J=13.5, 3.5 Hz, 1H), 3.01 (dd, J=13.5, 3.8 Hz, 1H), 2.77-2.69 (m, 1H); 13C NMR (125 MHz, DMSO) δ ppm 162.24, 162.20, 150.05 (dd, JCF=242.1, 14.4 Hz), 149.37, 144.42 (dd, JCF=245.5, 13.7 Hz), 142.18, 138.09, 134.73 (dd, JCF=10.3, 2.7 Hz), 134.03, 133.22 (d, JCF=9.1 Hz), 116.6, 108.42 (d, JCF=22.4 Hz), 83.98 (d, JCF=169.9 Hz), 79.21 (d, JCF=18.2 Hz), 77.96 (d, JCF=5.2 Hz), 66.26, 54.78, 36.23, 23.64.
Reaction SMILES: [CH2:1]([N:3]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[C:14]3[C:15]4[CH:28]=[CH:27][S:26][C:16]=4[C:17](=[O:25])[NH:18][C:19]=3[CH:20]=[CH:21][C:22]=2[O:23]C)=[CH:9][CH:8]=1)[CH2:4][CH3:5])[CH3:2].BrB(Br)Br>>[CH2:1]([N:3]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[C:14]3[C:15]4[CH:28]=[CH:27][S:26][C:16]=4[C:17](=[O:25])[NH:18][C:19]=3[CH:20]=[CH:21][C:22]=2[OH:23])=[CH:11][CH:12]=1)[CH2:4][CH3:5])[CH3:2]
Reactant: CCN(CC)Cc1ccc(-c2c(OC)ccc3[nH]c(=O)c4sccc4c23)cc1
Agent: BrB(Br)Br
Product: CCN(CC)Cc1ccc(-c2c(O)ccc3[nH]c(=O)c4sccc4c23)cc1
Yield: 41.7 %

Procedure:
Following General Procedure F, 9-{4-[(diethylamino)methyl]phenyl}-8-methoxythieno[2,3-c]quinolin-4(5H)-one (30 mg, 0.076 mmol) was reacted with tribromoborane (1.0 M in methylene chloride, 0.46 mL, 0.46 mmol) to afford the desired product (12 mg, 42%) as a white solid: 1H NMR (500 MHz, CD3OD) δ 7.69 (d, J=8.1 Hz, 2H), 7.56 (d, J=5.4 Hz, 1H), 7.48-7.42 (m, 3H), 7.18 (d, J=8.9 Hz, 1H), 6.03 (d, J=5.4 Hz, 1H), 4.50 (s, 2H), 3.36-3.31 (m, 4H), 1.43 (t, J=7.3 Hz, 6H); ESI MS m/z 379 [C22H22N2O2S+H]+; HPLC 97.2% (AUC), tR=8.27 min.
Reaction SMILES: [Cl:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[F:12][C:13]1([F:32])[CH2:18][CH2:17][CH:16]([CH:19]([C:22]2[CH:23]=[N:24][C:25]([C:28]([F:31])([F:30])[F:29])=[N:26][CH:27]=2)[CH2:20][NH2:21])[CH2:15][CH2:14]1>>[Cl:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:21][CH2:20][CH:19]([CH:16]1[CH2:15][CH2:14][C:13]([F:32])([F:12])[CH2:18][CH2:17]1)[C:22]1[CH:27]=[N:26][C:25]([C:28]([F:29])([F:30])[F:31])=[N:24][CH:23]=1)=[O:6]
Reactant: NCC(c1cnc(C(F)(F)F)nc1)C1CCC(F)(F)CC1
Reactant: O=C(O)c1cccc(F)c1Cl
Product: O=C(NCC(c1cnc(C(F)(F)F)nc1)C1CCC(F)(F)CC1)c1cccc(F)c1Cl

Procedure:
From 2-chloro-3-fluorobenzoic acid and 2-(4,4-difluorocyclohexyl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)ethanamine. LCMS (MH+): m/z=466.1, tR (minutes, Method F)=2.67