Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.[NH2:11][C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[N:15][C:16]([Cl:22])=[CH:17][CH:18]=2)[N:13]=1.CC(O)C>O>[Cl:22][C:16]1[N:15]=[C:14]2[C:19]([CH:20]=[CH:21][C:12]([NH:11][C:6](=[O:8])[C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:10][CH:9]=3)=[N:13]2)=[CH:18][CH:17]=1
Reactant: O=C(O)c1ccc(F)cc1
Reactant: Nc1ccc2ccc(Cl)nc2n1
Solvent: O
Solvent: CC(C)O
Product: O=C(Nc1ccc2ccc(Cl)nc2n1)c1ccc(F)cc1
Temperature: 4 °C
Yield: 68.9 %

Procedure:
The procedure is similar to that described in Example 1, but starting with 4-fluorobenzoic acid (11.2 g), N,N'-carbonyldiimidazole (12.9 g) and 2-amino-7-chloro-1,8-naphthyridine (8.9 g). The product produced by precipitation in water (14.3 g; m.p. 230° C.) is dissolved in boiling 2-propanol (800 cc). After 4 hours' cooling at 4° C., the crystallised solid is separated by filtration, washed with 2-propanol (3×10 cc) and dried at 40° C. under reduced pressure (0.067 kPa). N-(7-chloro-1,8-naphthyridin-2-yl)-4-fluorobenzamide (10.3 g) is produced, m.p. 236° C. EXAMPLE 16
Reaction SMILES: [OH:1][C@@H:2]([CH2:17][N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)[CH2:3][N:4]1[CH2:9][CH2:8][C:7]2[NH:10][C:11]([CH:14]=O)=[C:12]([CH3:13])[C:6]=2[C:5]1=[O:16].[F:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[C:26]=1[C:32]1[CH:40]=[CH:39][CH:38]=[C:37]2[C:33]=1[CH2:34][C:35](=[O:41])[NH:36]2>>[F:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([F:31])[C:26]=1[C:32]1[CH:40]=[CH:39][CH:38]=[C:37]2[C:33]=1/[C:34](=[CH:14]/[C:11]1[NH:10][C:7]3[CH2:8][CH2:9][N:4]([CH2:3][C@@H:2]([OH:1])[CH2:17][N:18]4[CH2:19][CH2:20][O:21][CH2:22][CH2:23]4)[C:5](=[O:16])[C:6]=3[C:12]=1[CH3:13])/[C:35](=[O:41])[NH:36]2
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(C[C@@H](O)CN1CCOCC1)CC2
Reactant: O=C1Cc2c(cccc2-c2c(F)cccc2F)N1
Product: Cc1c(/C=C2\C(=O)Nc3cccc(-c4c(F)cccc4F)c32)[nH]c2c1C(=O)N(C[C@@H](O)CN1CCOCC1)CC2
Yield: 84.7 %

Procedure:
The title compound was prepared under the same conditions as described in step 6 of Example 5 with (S)-5-(2-hydroxy-3-morpholin-4-yl-propyl)-3-methyl-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde 5f obtained from step 5 of Example 5 and 4-(2,6-difluoro-phenyl)-1,3-dihydro-indol-2-one as starting materials to give (S,Z)-2-[4-(2,6-difluoro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-5-(2-hydroxy-3-morpholin-4-yl-propyl)-3-methyl-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one 20 (52 mg, yield 84.7%) as a yellow solid.
Reaction SMILES: Cl[CH2:2][CH2:3][NH:4][C:5]([NH:7][CH:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][CH2:10][CH2:9]1)=[O:6].CC(C)([O-])C.[K+]>O1CCCC1>[CH:8]1([N:7]2[CH2:2][CH2:3][NH:4][C:5]2=[O:6])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][CH2:10][CH2:9]1
Reactant: O=C(NCCCl)NC1CCCc2ccccc21
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=C1NCCN1C1CCCc2ccccc21
Reaction time: 8 h
Yield: 21.6 %

Procedure:
To a stirred solution of 3.8 grams (0.015 mole) of 1-(2-chloroethyl)-3-(1,2,3,4-tetrahydro-1-naphthyl)urea in 75 ml. dry tetrahydrofuran is added dropwise a solution of 2.25 grams (0.02 mole) of potassium tert-butoxide in 50 ml. of dry tetrahydrofuran under a nitrogen atmosphere. The reaction is then allowed to proceed at ambient temperature overnight. The mixture is then evaporated at reduced pressure. The residue is partitioned between water and ether. The ether layer is washed with water, dried, sodium sulfate, and evaporated at reduced pressure. Crystallization of the residue from acetone-ether-hexane gives 0.70 gram of product, melting point 134° C. to 139.5° C. Recrystallization from acetone-hexane gives the analytical sample, melting point 138° C. to 141.5° C. Analysis calculated for C13H16N2O: C, 72.19; H, 7.46; N, 12.95. Found: C, 72.04; H, 7.43; N, 12.89.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C@@H:10]([C:35](O)=[O:36])[N:11]([C:16]([C:18]1[C:19]([NH:28][CH2:29][C:30]2[O:31][CH:32]=[CH:33][CH:34]=2)=[N:20][C:21]([C:24]([CH3:27])([CH3:26])[CH3:25])=[N:22][CH:23]=1)=[O:17])[CH2:12][CH:13]([CH3:15])[CH3:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].[N:38]1(O)C2C=CC=CC=2N=N1.C(N(CC)CC)C.CCN=C=NCCCN(C)C.Cl>ClCCCl.CN(C=O)C>[NH2:38][C:35](=[O:36])[C@@H:10]([N:11]([C:16]([C:18]1[C:19]([NH:28][CH2:29][C:30]2[O:31][CH:32]=[CH:33][CH:34]=2)=[N:20][C:21]([C:24]([CH3:26])([CH3:27])[CH3:25])=[N:22][CH:23]=1)=[O:17])[CH2:12][CH:13]([CH3:14])[CH3:15])[CH2:9][NH:8][C:6](=[O:7])[O:5][C:1]([CH3:3])([CH3:2])[CH3:4]
Reactant: On1nnc2ccccc21
Reactant: CC(C)CN(C(=O)c1cnc(C(C)(C)C)nc1NCc1ccco1)[C@@H](CNC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)CN(C(=O)c1cnc(C(C)(C)C)nc1NCc1ccco1)[C@@H](CNC(=O)OC(C)(C)C)C(N)=O
Temperature: 25 °C
Reaction time: 21 h
Yield: 61.3 %

Procedure:
3-[(tert-Butoxycarbonyl)amino]-N-({2-tert-butyl-4-[(furan-2-ylmethyl)amino]pyrimidin-5-yl}carbonyl)-N-(2-methylpropyl)-L-alanine (147 mg), 1H-1,2,3-benzotriazol-1-ol ammoniate (130 mg) and triethylamine (160 μl) were dissolved in 1,2-dichloroethane-DMF (3:1, 15 ml), WSC.HCl (163 mg) was added and the mixture was stirred at room temperature for 21 hr. The reaction mixture was concentrated under reduced pressure, and diluted with saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and the fraction eluted with ethyl acetate-hexane (1:9) to ethyl acetate was concentrated under reduced pressure to give the object compound (90 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8](B(O)O)=[CH:7][CH:6]=[CH:5][N:4]=1.Br[C:13]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][C:14]=1[C:15]([O:17][CH3:18])=[O:16].C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:1][O:2][C:3]1[C:8]([C:13]2[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][C:14]=2[C:15]([O:17][CH3:18])=[O:16])=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: COC(=O)c1cc([N+](=O)[O-])ccc1Br
Reactant: COc1ncccc1B(O)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc([N+](=O)[O-])ccc1-c1cccnc1OC
Temperature: 80 °C
Reaction time: 8 h
Yield: 81.7 %

Procedure:
A mixture of 2-methoxypyridin-3-ylboronic acid (1.00 g, 6.54 mmol), methyl 2-bromo-5-nitrobenzoate (2.21 g, 8.50 mmol), cesium carbonate (6.39 g, 17.6 mmol) and bis(triphenylphosphine)palladium(II) dichloride (230 mg, 0.33 mmol) was suspended in anhydrous N,N-dimethylformamide (15 mL), and then the mixture was stirred under nitrogen atmosphere at 80° C. overnight. After cooling down, water (100 mL) was added thereto, and then the whole was extracted with ethyl acetate (80 mL, twice). The combined organic layer was washed with saturated brine (100 mL), dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled reference compound (1.54 g) as a yellow solid. (Yield 81%)
Reaction SMILES: [S-2:1].[Na+:2].[Na+].[SH-].[Na+].[C:6]([Cl:15])(=[O:14])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]>O>[S-2:1].[Na+:2].[Na+:2].[C:6]([O-:14])(=[S:1])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].[Na+:2].[Cl-:15].[Na+:2]
Reactant: CCCCCCCC(=O)Cl
Agent: [Na+]
Agent: [S-2]
Agent: [SH-]
Solvent: O
Product: CCCCCCCC([O-])=S
Product: [Cl-]

Procedure:
A nominal 20 weight percent aqueous solution of sodium sulfide was prepared by dissolving sodium sulfide (ca. 166 grams, 2.12 moles) in the form of hydrated flakes (276 grams, ca. 60%) into 552 grams of water in a 5-liter round-bottomed flask. This solution was then cooled by means of an ice-water bath and converted to an aqueous solution of sodium hydrosulfide (NaSH) by saturating it with an excess of hydrogen sulfide by adding hydrogen sulfide with stirring until no more was absorbed. A dropping funnel was charged with octanoyl chloride (345 grams, 2.12 moles). With the temperature of the sodium hydrosulfide solution in the 5-liter flask at 9.5° C. the addition of the octanoyl chloride to the 5-liter flask was begun with stirring of the contents of the 5-liter flask with a mechanical stirrer. No phase transfer catalyst was added. The addition of the octanoyl chloride was completed over the course of 2 hours with a final temperature of 14° C. The content of the 5-liter flask was kept between 8 and 12° C. during the course of the addition. A pH measurement, using pH paper, revealed that the solution was alkaline. Additional octanoyl chloride was added dropwise (totaling 15 additional grams) to the stirred solution until a neutral pH reading was obtained. The content of the 5-liter flask was then allowed to reach ambient temperature and stirring was stopped, yielding a clear, slightly viscous, one-phase aqueous solution of sodium thiooctanoate and sodium chloride.
Reaction SMILES: [CH2:1]([S:3]([CH2:6][CH2:7][C:8]([NH:10][NH:11][C:12]([N:14]1[CH2:20][C:19]2[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=2[O:17][C:16]2[CH:25]=[CH:26][C:27]([NH2:29])=[CH:28][C:15]1=2)=[O:13])=[O:9])(=[O:5])=[O:4])[CH3:2].[CH:30](=O)[CH3:31].C([BH3-])#N.[Na+].O.[C:38](#N)[CH3:39]>C(O)(=O)C>[CH2:1]([S:3]([CH2:6][CH2:7][C:8]([NH:10][NH:11][C:12]([N:14]1[CH2:20][C:19]2[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=2[O:17][C:16]2[CH:25]=[CH:26][C:27]([N:29]([CH2:30][CH3:31])[CH2:38][CH3:39])=[CH:28][C:15]1=2)=[O:13])=[O:9])(=[O:5])=[O:4])[CH3:2]
Reactant: CCS(=O)(=O)CCC(=O)NNC(=O)N1Cc2ccccc2Oc2ccc(N)cc21
Reactant: CC#N
Reactant: CC=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CCN(CC)c1ccc2c(c1)N(C(=O)NNC(=O)CCS(=O)(=O)CC)Cc1ccccc1O2
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a stirred solution of the title compound of Example 13 (2.0 g), acetaldehyde (3.0 mL), sodium cyanoborohydride (0.904 g), and water (2.6 mL) in acetonitrile (20 mL) was added glacial acetic acid (0.5 mL) over a period of 6 minutes. The reaction was stirred for 2.5 hours at ambient temperature, and then glacial acetic acid was added (0.5 mL), and the reaction was stirred for an additional 30 minutes. The resulting mixture was evaporated under vacuum, and the residue was partitioned between ethyl acetate and saturated sodium bicarbonate. The layers were separated, and the aqueous layer was extracted once more with ethyl acetate. The combined ethyl acetate extracts were washed with brine, dried over magnesium sulfate, and evaporated under vacuum to a clear, greenish oil. The oil was chromatographed four times: twice through silica gel 60 using 97:3 ethyl acetate:ethanol; next through silica gel 60 using 3:1 chloroform:tetrahydrofuran; and finally through reverse phase silica gel (C18) using 80:20:1 acetonitrile:water:ammonium hydroxide. The product from the last column was co-evaporated three times with ethanol to azeotrope water from the product and dried under vacuum at room temperature to yield the title compound as a white solid containing 1.86% water. HPLC: 99.53% pure.
Reaction SMILES: [C:1]1([P:7](Cl)(Cl)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:11]1([C:13](=[CH:15][CH:16]=[CH:17][CH:18]=1)[OH:14])[OH:12].C(N(CC)CC)C>CCOCC>[C:1]1([P:7]2(=[O:8])[O:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:11]=3[O:12]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=P(Cl)(Cl)c1ccccc1
Reactant: Oc1ccccc1O
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: O=P1(c2ccccc2)Oc2ccccc2O1
Reaction time: 0.13 h
Yield: 93.4 %

Procedure:
To a solution of 3.11 g of phenylphosphonic acid dichloride in 10 ml of ether were added 1.76 g of pyrocatechol and 20 ml of ether. The resulting solution was cooled to -25° C. to -28° C. and a solution of 3.23 g of triethylamine in 10 ml of ether was added dropwise thereto with stirring over 8 minutes. Thereafter, the reaction mixture was allowed to return to room temperature (20°-25° C.), and the precipitate was filtered off under nitrogen atmosphere and washed with 30 ml of ether. The filtrate and washings were combined and the ether was distilled off under reduced pressure to give 3.46 g (94.4% yield) of 2-phenyl-2-oxo-1, 3,2-benzodioxaphosphole as a colorless oil. Upon standing in a refrigerator overnight, it crystallized.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][C@H:10]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[C@@H:9]1[C@H:21]([NH:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[C:26]([Cl:32])[C:25]=1[CH3:33])[CH3:22])=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl.CCOC(C)=O>[Si:14]([O:13][C@H:10]1[CH2:11][CH2:12][NH:8][C@@H:9]1[C@H:21]([NH:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[C:26]([Cl:32])[C:25]=1[CH3:33])[CH3:22])([C:17]([CH3:19])([CH3:20])[CH3:18])([CH3:16])[CH3:15]
Reactant: Cc1c(N[C@H](C)[C@H]2[C@@H](O[Si](C)(C)C(C)(C)C)CCN2C(=O)OC(C)(C)C)ccc(C#N)c1Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: Cc1c(N[C@H](C)[C@H]2NCC[C@@H]2O[Si](C)(C)C(C)(C)C)ccc(C#N)c1Cl
Temperature: 25 °C
Reaction time: 10 h
Yield: 93.9 %

Procedure:
Intermediate 80E (36 mg, 0.073 mmol) was dissolved in DCM (900 μL) and TFA (100 μL) was added. The mixture was stirred at rt for 10 h. The reaction was diluted with EtOAc, washed with saturated sodium bicarbonate solution (3×5 mL), brine (5 mL), dried (MgSO4), filtered and concentrated to give the title compound 80F (27 mg): MS (ES) m/z 394.5 [M+H]+.
Reaction SMILES: C1(C)C=CC(S([O:10][CH2:11][CH2:12][CH:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)(=O)=O)=CC=1.[OH:20][C:21]1[CH:26]=[C:25]([OH:27])[CH:24]=[CH:23][N:22]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[O:16]1[CH2:15][CH2:14][CH:13]([CH2:12][CH2:11][O:10][C:25]2[CH:24]=[CH:23][N:22]=[C:21]([OH:20])[CH:26]=2)[CH2:18][CH2:17]1.[O:16]1[CH2:15][CH2:14][CH:13]([CH2:12][CH2:11][O:10][C:21]2[CH:26]=[C:25]([OH:27])[CH:24]=[CH:23][N:22]=2)[CH2:18][CH2:17]1
Reactant: Cc1ccc(S(=O)(=O)OCCC2CCOCC2)cc1
Reactant: Oc1ccnc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Oc1cc(OCCC2CCOCC2)ccn1
Product: Oc1ccnc(OCCC2CCOCC2)c1
Temperature: 80 °C
Reaction time: 6 h

Procedure:
To a solution of 2-(tetrahydro-2H-pyran-4-yl)ethyl p-toluenesulfonate (465 mg) in DMF (5 mL) were added 2,4-dihydroxypyridine (363 mg) and potassium carbonate (339 mg), and the mixture was stirred at 80° C. for 6 hours. The reaction mixture was allowed to cool to room temperature, and water (50 mL) was added thereto, followed by extraction with ethyl acetate (20 mL×3). The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: methanol/chloroform=0/100˜10/90) to obtain 4-[2-(tetrahydro-2H-pyran-4-yl)ethoxy]pyridin-2-ol (160 mg) as a major product, and 2-[2-(tetrahydro-2H-pyran-4-yl)ethoxy]pyridin-4-ol (Production Example 347) (43 mg) as a minor product.
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[NH:7][C:8]1[C:9]([C:13]2[CH:18]=[CH:17][C:16]([O:19]CC3C=CC(OC)=CC=3)=[CH:15][CH:14]=2)=[N:10][O:11][CH:12]=1)([CH3:4])([CH3:3])[CH3:2].ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl.O.C(Cl)Cl.C(OCC)(=O)C>C(Cl)Cl.O>[C:1]([O:5][C:6](=[O:29])[NH:7][C:8]1[C:9]([C:13]2[CH:14]=[CH:15][C:16]([OH:19])=[CH:17][CH:18]=2)=[N:10][O:11][CH:12]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc(COc2ccc(-c3nocc3NC(=O)OC(C)(C)C)cc2)cc1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: ClCCl
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)Nc1conc1-c1ccc(O)cc1
Reaction time: 60 h
Yield: 101.9 %

Procedure:
To a solution of {3-[4-(4-methoxy-benzyloxy)-phenyl]-isoxazol-4-yl}-carbamic acid tert-butyl ester (3.01 g, 7.6 mmol) in CH2Cl2 (80 mL) and water (8 mL) was added 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (5.17 g, 23 mmol). After stirring for 60 h, the reaction mixture was suspended between a water/CH2Cl2 bilayer. The organic phase was removed and the aqueous phase was extracted twice with CH2Cl2. The combined organic phases were dried over Na2SO4, filtered and concentrated in vacuo to give a deep red oil. [3-(4-Hydroxy-phenyl)-isoxazol-4-yl]-carbamic acid tert-butyl ester (2.14 g, 92%) was isolated by chromatography (1-100% ethyl acetate in hexanes).
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])([CH3:14])[CH2:12][O:11][C:10]([NH2:16])=[N:9]2)[CH:7]=1.[F:19][C:20]1[CH:21]=[CH:22][C:23]([C:26](O)=[O:27])=[N:24][CH:25]=1>>[NH2:16][C:10]1[O:11][CH2:12][C@@:13]([F:15])([CH3:14])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:26]([C:23]3[CH:22]=[CH:21][C:20]([F:19])=[CH:25][N:24]=3)=[O:27])[CH:3]=[CH:4][C:5]=2[F:18])([CH3:17])[N:9]=1
Reactant: O=C(O)c1ccc(F)cn1
Reactant: C[C@]1(F)COC(N)=N[C@]1(C)c1cc(N)ccc1F
Product: C[C@]1(F)COC(N)=N[C@]1(C)c1cc(NC(=O)c2ccc(F)cn2)ccc1F

Procedure:
The condensation of (4R,5R)-4-(5-amino-2-fluoro-phenyl)-5-fluoro-4,5-dimethyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (A8.3) and 5-fluoro-pyridine-2-carboxylic acid following procedure I yielded the title compound as a colorless solid. MS (ISP): m/z=379.3 [M+H]+.
Reaction SMILES: F[C:2]1[CH:19]=[CH:18][C:5]([O:6][CH2:7][C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)=[CH:4][C:3]=1[N+:20]([O-:22])=[O:21].Cl.[Br:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29][NH2:30])=[CH:27][CH:26]=1.CCN(C(C)C)C(C)C>CC(N(C)C)=O>[Br:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29][NH:30][C:2]2[CH:19]=[CH:18][C:5]([O:6][CH2:7][C:8]3[CH:17]=[CH:16][C:15]4[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=4)[N:9]=3)=[CH:4][C:3]=2[N+:20]([O-:22])=[O:21])=[CH:27][CH:26]=1
Reactant: O=[N+]([O-])c1cc(OCc2ccc3ccccc3n2)ccc1F
Reactant: NCc1ccc(Br)cc1
Agent: Cl
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1cc(OCc2ccc3ccccc3n2)ccc1NCc1ccc(Br)cc1
Temperature: 100 °C
Reaction time: 24 h
Yield: 113.1 %

Procedure:
To a 250 mL round-bottomed flask were added a stir bar, 2-((4-fluoro-3-nitrophenoxy)methyl)quinoline (15.0 g, 40 mmol) and 4-bromobenzyl amine hydrochloride (11 g, 50 mmol), DMA (130 mL), and DIPEA (22 mL, 125 mmol). The resulting mixture was heated to 100° C. After 24 h, the mixture was cooled and concentrated to dryness. The residue was triturated with IPA (200 mL) and the orange solid was collected by vacuum filtration. The collected solid was washed with IPA (2×50 mL) and hexanes (2×50 mL) to afford the title compound (21 g, 84%). MS (ESI): mass calcd. for C23H18BrN3O3, 463.05; m/z found 464.1 [M+H]+. 1H NMR (600 MHz, CDCl3) δ 8.34-8.27 (m, 1H), 8.21 (d, J=8.4, 1H), 8.12-8.06 (m, 1H), 7.87-7.81 (m, 2H), 7.75 (ddd, J=8.4, 6.9, 1.4, 1H), 7.63 (d, J=8.5, 1H), 7.58-7.53 (m, 1H), 7.49-7.46 (m, 2H), 7.25-7.18 (m, 3H), 6.71 (d, J=9.4, 1H), 5.34 (s, 2H), 4.49 (d, J=5.8, 2H).
Reaction SMILES: [CH2:1]([P:5]([O:10][CH2:11][CH3:12])(=[O:9])[O:6][CH2:7][CH3:8])[CH:2]=[CH:3][CH3:4].O1CCCC1.C([Li])CCC.[CH2:23](Cl)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>Cl.CCCCCC>[CH2:23]([CH:1]([P:5]([O:6][CH2:7][CH3:8])(=[O:9])[O:10][CH2:11][CH3:12])[CH:2]=[CH:3][CH3:4])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: ClCc1ccccc1
Reactant: CC=CCP(=O)(OCC)OCC
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC=CC(Cc1ccccc1)P(=O)(OCC)OCC
Temperature: -70 °C
Reaction time: 1 h
Yield: 82.6 %

Procedure:
1.92 g of diethyl 2-butenephosphonate was placed in 10 ml. of dry tetrahydrofuran, and the solution was cooled to -70° C. in an atmosphere of argon. 7 ml. of n-butyl lithium (as a 15% by weight n-hexane solution) was gradually added, and the mixture was stirred at -70° C. for 1 hour. The reaction mixture was turbid assuming a pale yellow color. When 1.7 g of benzyl chloride was added to this mixture, it became clear. The temperature of the reaction mixture was gradually elevated to room temperature, and it was stirred for an additional 2 hours. The reaction mixture was then diluted with dilute hydrochloric acid, and extracted with ether. The extract was washed with a solution of sodium hydrogen carbonate, washed with water, and dried. The solution was concentrated, and then the residue was distilled at reduced pressure to afford 2.33 g of diethyl 1-benzyl-2-butenephosphonate having a boiling point of 144° C. (0.3 mmHg) in a yield of 93%. The analysis values of the product were as follows:
Reaction SMILES: [O:1]=[C:2]1[N:10]([CH2:11][CH2:12][CH3:13])[C:9]2[N:8]=[C:7]([C:14]34[CH2:21][CH2:20][C:17]([C:22]([OH:24])=O)([CH2:18][CH2:19]3)[CH2:16][CH2:15]4)[NH:6][C:5]=2[C:4](=[O:25])[N:3]1[CH2:26][CH2:27][CH3:28].C[N:30](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.N>CN(C=O)C.O1CCOCC1>[O:1]=[C:2]1[N:10]([CH2:11][CH2:12][CH3:13])[C:9]2[N:8]=[C:7]([C:14]34[CH2:15][CH2:16][C:17]([C:22]([NH2:30])=[O:24])([CH2:20][CH2:21]3)[CH2:18][CH2:19]4)[NH:6][C:5]=2[C:4](=[O:25])[N:3]1[CH2:26][CH2:27][CH3:28]
Reactant: CCCn1c(=O)c2[nH]c(C34CCC(C(=O)O)(CC3)CC4)nc2n(CCC)c1=O
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: N
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: CCCn1c(=O)c2[nH]c(C34CCC(C(N)=O)(CC3)CC4)nc2n(CCC)c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 40.5 %

Procedure:
To a solution of 200 mg of 4-(2,6-Dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[2.2.2]octane-1-carboxylic acid (Example 13) (0.515 mmol) in 5 ml of DMF was added 235 mg of HATU (0.618 mmol) and 0.4 ml of N,N-diisopropylethyl amine. Let stir at rt for 30 min. Added 2.1 ml of 0.5 M NH3 in dioxane (1.03 mmol) dropwise over 5 min. Let stir overnight added 0.5 eq. of 0.5M NH3 in dioxane (0.5 ml). Added EtOAc and 1N NaOH until pH=9 and washed with 10% citric acid, sat'd NaHCO3 and brine. Dried over NaSO4 and conc'd in vacuo to afford 80.9 mg (40%) of pure product (MH+=388.34).
Reaction SMILES: Cl[C:2]1[C:7]2[O:8][CH2:9][CH2:10][N:11]([CH:12]3[CH2:17][CH2:16][N:15]([C:18]([O:20][CH:21]([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]3)[C:6]=2[N:5]=[CH:4][N:3]=1.[F:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][C:32]=1[OH:33])[C:28]#[N:29].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CO>[C:28]([C:27]1[CH:30]=[CH:31][C:32]([O:33][C:2]2[C:7]3[O:8][CH2:9][CH2:10][N:11]([CH:12]4[CH2:17][CH2:16][N:15]([C:18]([O:20][CH:21]([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]4)[C:6]=3[N:5]=[CH:4][N:3]=2)=[C:25]([F:24])[CH:26]=1)#[N:29]
Reactant: CC(C)OC(=O)N1CCC(N2CCOc3c(Cl)ncnc32)CC1
Reactant: N#Cc1ccc(O)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CN(C)C=O
Product: CC(C)OC(=O)N1CCC(N2CCOc3c(Oc4ccc(C#N)cc4F)ncnc32)CC1
Temperature: 120 °C
Reaction time: 72 h
Yield: 7.8 %

Procedure:
To a solution of isopropyl 4-(4-chloro-6H-pyrimido[5,4-b][1,4]oxazin-8(7H)-yl)piperidine-1-carboxylate from Example 20A (10.0 mg, 0.029 mmol) and 3-fluoro-4-hydroxybenzonitrile (12.07 mg, 0.088 mmol) in DMF (0.4 mL) was added K2CO3 (12.17 mg, 0.088 mmol). The reaction mixture was stirred in a sealed vial for 3 days at 120° C. The reaction mixture was cooled to RT. The reaction mixture was diluted with MeOH, filtered and purified by reverse phase HPLC (H2O/CH3CN) to give isopropyl 4-(4-(4-cyano-2-fluorophenoxy)-6H-pyrimido[5,4-b][1,4]oxazin-8(7H)-yl)piperidine-1-carboxylate (1.0 mg, 2.265 μmol, 7.72% yield) as Example 148 as an off-white solid. 1H NMR (400 MHz, CDCl3) δ ppm 1.27 (d, J=6.05 Hz, 6H) 1.55-1.79 (m, 4H) 2.85-2.95 (m, 2H) 3.44-3.54 (m, 2H) 4.05-4.15 (m, 2H) 4.24-4.35 (m, 2H) 4.84-4.95 (m, 2H) 7.29-7.40 (m, 1H) 7.45-7.52 (m, 2H) 7.88 (s, 1H). LRMS (ESI): 442.5 [M+H]+.
Reaction SMILES: C([NH:3][C:4](CC(C)=C)(C(OCC)=O)[C:5]([O:7][CH2:8][CH3:9])=[O:6])=O.[CH:19]([NH:21][CH2:22][C:23]([NH:25][CH:26]([CH2:31][CH:32]=[CH2:33])[C:27]([O:29][CH3:30])=[O:28])=[O:24])=[O:20]>C(Cl)Cl.CO>[NH2:3][CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:33][CH:32]=[CH:31][CH:26]([NH:25][C:23](=[O:24])[CH2:22][NH:21][CH:19]=[O:20])[C:27]([O:29][CH3:30])=[O:28]
Reactant: C=CCC(NC(=O)CNC=O)C(=O)OC
Reactant: C=C(C)CC(NC=O)(C(=O)OCC)C(=O)OCC
Solvent: ClCCl
Solvent: CO
Product: CCOC(=O)C(N)CC=CC(NC(=O)CNC=O)C(=O)OC

Procedure:
Using the procedure of preparation B of Example 1, diethyl (formylamino)-(2-methyl-2-propenyl)-propanedioate in Step 2 was replaced by methyl 2-[(N-formylglycyl)-amino]-2-(2-propenyl)ethanoate to obtain the expected product with an Rf=0.2 in a methylene chloride/methanol (9:1) mixture.