Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [SH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[CH3:16]O>>[SH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:16])=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(S)cc1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(S)cc1

Procedure:
To a solution of 4-mercaptobenzoic acid (Apin, 1.72 g, 11.17 mmol) in anhydrous methyl alcohol (20.0 mL) was added concentrated sulfuric acid (0.43 mL). The reaction mixture is then warmed to reflux for 16 h, concentrated in vacuo, diluted with ethyl acetate (100 mL) and washed with saturated sodium bicarbonate (2×100 mL). The organic phase is then separated, dried over anhydrous magnesium sulfate and concentrated in vacuo to give 712 mg (Y: 38%) of the title product; 1H-NMR (CDCl3): δ7.89 (d, J=8.7 Hz, 2H), 7.29 (d, J=8.7 Hz, 2H), 3.90 (s, 3H), 3.60 (s, 1H).
Reaction SMILES: [CH2:1]([C:3]1([CH3:14])N=[C:7]([CH2:9][CH3:10])[CH2:6][C:5]([CH2:12][CH3:13])([CH3:11])[NH:4]1)[CH3:2].Cl.C(=O)([O-])[O-:17].[K+].[K+]>[Br-].[NH4+].CO>[CH2:1]([C:3]1([CH3:14])[CH:9]([CH3:10])[C:7](=[O:17])[CH2:6][C:5]([CH2:12][CH3:13])([CH3:11])[NH:4]1)[CH3:2]
Reactant: CCC1=NC(C)(CC)NC(C)(CC)C1
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [Br-]
Agent: [K+]
Solvent: CO
Product: CCC1(C)CC(=O)C(C)C(C)(CC)N1
Reaction time: 8 h

Procedure:
19.6 g of 2,4,6-triethyl-2,6-dimethyl-1,2,5,6-tetrahydropyrimidine and 0.4 g of ammonium bromide were added to 200 ml of methanol. To the mixture was added dropwise 10 g of 37% hydrochloric acid at 10° C., with stirring. After completion of the addition the whole was stirred at room temperature for 4 hours and there was then added a further 20 ml of 18% hydrochloric acid, The mixture was then heated at 30°-40° C for 7 hours and allowed to stand overnight at room temperature. The mixture was made alkaline with 40% aqueous potassium carbonate solution and, after methanol had been distilled off under reduced pressure, the mixture was extracted with ether. The ether solution was dried over potassium carbonate and the ether was removed. The residue was subjected to distillation under reduced pressure to give 15.1 g of 2,6-diethyl-2,3,6-trimethyl-4-oxopiperidine as an oil boiling at 91°-93° C/2.0 mm Hg.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([CH:35]([CH3:37])[CH3:36])[N:11](/[CH:20]=[CH:21]/[C@@H:22]([OH:34])[CH2:23][C@@H:24]([OH:33])[CH2:25][C:26]([O:28]C(C)(C)C)=[O:27])[C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.[OH-].[Na+]>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([CH:35]([CH3:37])[CH3:36])[N:11](/[CH:20]=[CH:21]/[C@@H:22]([OH:34])[CH2:23][C@@H:24]([OH:33])[CH2:25][C:26]([OH:28])=[O:27])[C:12]=2[C:13]2[CH:14]=[CH:15][C:16]([F:19])=[CH:17][CH:18]=2)=[CH:4][CH:3]=1
Reactant: CC(C)c1nc(-c2ccc(F)cc2)c(-c2ccc(F)cc2)n1/C=C/[C@@H](O)C[C@@H](O)CC(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)c1nc(-c2ccc(F)cc2)c(-c2ccc(F)cc2)n1/C=C/[C@@H](O)C[C@@H](O)CC(=O)O
Yield: 77.3 %

Procedure:
A solution of 1,1-dimethyleth-1-yl (3R,5S,E)-7-[4,5-bis(4-fluorophenyl)-2-(1-methylethyl)-1H-imidazol-1-yl]-3,5-dihydroxy-6-heptenoate (726 mg) in redistilled THF (40 ml) was treated with 0.1M aqueous sodium hydroxide solution (14.5 ml). After 1/2 h the mixture was concentrated to ca. 10 ml and then diluted with water (50 ml). The mixture was acidified to pH 2 with 2N-hydrochloric acid, brought back to pH 4 with aqueous sodium hydrogen carbonate solution, ammonium sulphate added and then the mixture was extracted with ethyl acetate (3×50 ml). The combined extracts were dried and concentrated to ca. 4 ml when a solid crystallised. The crystals were collected and dried to give the title compound (500 mg), m.p. 172°-3° C., [α]D +15.7° (c 1.02, DMSO), (RS:SR=99.5:0.5).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]1([CH3:14])[C:12]([OH:13])=[CH:11][CH:10]=[CH:9][CH:8]=1.Br[C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][C:24]=1[O:25][CH3:26])[C:19]([OH:21])=[O:20]>CN(C=O)C.[Cu]>[CH3:26][O:25][C:24]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=[O:20])=[CH:17][C:16]=1[O:13][C:12]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH3:14]
Reactant: Cc1ccccc1O
Reactant: COc1ccc(C(=O)O)cc1Br
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)O)cc1Oc1ccccc1C
Temperature: 165 °C
Reaction time: 2 h
Yield: 53.7 %

Procedure:
Potassium carbonate (1.20 g, 8.66 mmol), o-cresol (468 mg, 4.33 mmol), copper powder (28 mg, 0.43 mmol) and 3-bromo-4-methoxybenzoic acid (1.00 g, 4.33 mmol) were suspended in DMF (5 ml) and heated to 165° C. overnight. Potassium carbonate (1.20 g, 8.66 mmol) and o-cresol (468 mg, 4.33 mmol) were added once again and heating was continued for another 2 h. The crude mixture was partitioned between EA and 2 N hydrochloric acid, the aqueous phase extracted with EA, and the combined organic phases were dried over magnesium sulfate, filtered and evaporated to dryness. The residue was purified by silica gel chromatography (HEP/EA gradient) to yield 600 mg of the title compound.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[Al+3].[Cl-].[Cl-].[Cl-]>>[C:1]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccccc1
Reactant: O=C(Cl)c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Product: O=C(c1ccccc1)c1ccccc1

Procedure:
Methoxyaryl 1g can be coupled with benzoyl chloride 2g, either commercially available or prepared in situ from the corresponding benzoic acid, using a Lewis acid, typically AlCl3 or the like, to give benzophenone product 3g. Reduction of 3g can be accomplished by triethylsilane and an appropriate protic or Lewis acid, typically trifluoroacetic acid or borontrifluoroetherate, to give arylbenzyl 4g.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([Cl:10])[N:5]=[C:4]([N:11]([CH2:14][CH3:15])[CH2:12][CH3:13])[N:3]=1.[CH:16]1([NH2:19])[CH2:18][CH2:17]1>CC(C)=O>[Cl:10][C:6]1[C:7]([C:8]#[N:9])=[C:2]([NH:19][CH:16]2[CH2:18][CH2:17]2)[N:3]=[C:4]([N:11]([CH2:14][CH3:15])[CH2:12][CH3:13])[N:5]=1
Reactant: CCN(CC)c1nc(Cl)c(C#N)c(Cl)n1
Reactant: NC1CC1
Solvent: CC(C)=O
Product: CCN(CC)c1nc(Cl)c(C#N)c(NC2CC2)n1
Reaction time: 16 h
Yield: 33.4 %

Procedure:
To a stirred solution of 6.9 grams of 4,6-dichloro-2-diethylamino-5-pyrimidinecarbonitrile in 80 ml of acetone was added dropwise 3.2 grams of cyclopropylamine in 20 ml of acetone. The reaction mixture stood for 16 hours; then the acetone was removed by evaporation under reduced pressure. The residue was washed with water, and the resultant solid was collected. The solid was washed several times with water, then dried, to give 6.5 grams of crude product; mp, 100°-105°. The crude product was recrystallized from petroleum ether to give 2.5 grams of 4-chloro-6-cyclopropylamino-2-diethylamino-5-pyrimidinecarbonitrile; mp, 120°-122°.
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]([N:5]1[CH:10]2[CH2:11][CH2:12][CH:6]1[CH2:7][C:8](=[C:13]1[C:26]3[CH:25]=[CH:24][CH:23]=[C:22](OS(C(F)(F)F)(=O)=O)[C:21]=3[O:20][C:19]3[C:14]1=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:9]2)=[O:4].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.[C:83](=[NH:96])([C:90]1[CH:95]=[CH:94][CH:93]=[CH:92][CH:91]=1)[C:84]1[CH:89]=[CH:88][CH:87]=[CH:86][CH:85]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1COCC1.[Pd].C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:83](=[N:96][C:22]1[C:21]2[O:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13](=[C:8]3[CH2:9][CH:10]4[N:5]([C:3](=[O:4])[C:2]([F:1])([F:35])[F:36])[CH:6]([CH2:12][CH2:11]4)[CH2:7]3)[C:26]=2[CH:25]=[CH:24][CH:23]=1)([C:90]1[CH:91]=[CH:92][CH:93]=[CH:94][CH:95]=1)[C:84]1[CH:89]=[CH:88][CH:87]=[CH:86][CH:85]=1
Reactant: N=C(c1ccccc1)c1ccccc1
Reactant: O=C(N1C2CCC1CC(=C1c3ccccc3Oc3c(OS(=O)(=O)C(F)(F)F)cccc31)C2)C(F)(F)F
Agent: [Pd+2]
Agent: [Pd]
Agent: CC(=O)[O-]
Solvent: C1CCOC1
Product: O=C(N1C2CCC1CC(=C1c3ccccc3Oc3c(N=C(c4ccccc4)c4ccccc4)cccc31)C2)C(F)(F)F

Procedure:
A solution of trifluoromethanesulfonic acid 9-[8-(2,2,2-trifluoroacetyl)-8-aza-bicyclo[3.2.1]oct-3ylidene]-9H-xanthen-4-yl ester in THF (0.1 to 1 M solution) may be treated with a catalytic amount of a palladium catalyst such as palladium acetate (0.01 to 0.05 equiv), BINAP (0.01 to 0.05 equiv), benzophenone imine (1.05 to 1.5 equiv), and cesium carbonate (1.2 to 2 equiv) under an argon atmosphere. The mixture may be heated to reflux for a period of 10 to 24 hr. After removal of the solvent via evaporation, the residue may be taken up in a halogenated solvent such as methylene chloride, and the solution may be washed with water, dried over a suitable drying agent such as magnesium sulfate, filtered, and concentrated. The residue may be purified via column chromatography to yield Compound 1c.
Reaction SMILES: [NH2:1][C:2]1[CH:22]=[CH:21][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)[N:8]=2)=[C:4]([F:23])[CH:3]=1.[F:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31][C:32]([N:34]=[C:35]=[O:36])=[O:33])=[CH:27][CH:26]=1.COC1C=CC(CNC2N=CN=C(OC3C=CC(NC(NC(=O)CC4C=CC(F)=CC=4)=O)=CC=3F)C=2)=CC=1>C1COCC1>[F:23][C:4]1[CH:3]=[C:2]([NH:1][C:35]([NH:34][C:32](=[O:33])[CH2:31][C:28]2[CH:29]=[CH:30][C:25]([F:24])=[CH:26][CH:27]=2)=[O:36])[CH:22]=[CH:21][C:5]=1[O:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]2[CH:15]=[CH:16][C:17]([F:20])=[CH:18][CH:19]=2)[N:8]=1
Reactant: O=C=NC(=O)Cc1ccc(F)cc1
Reactant: Nc1ccc(Oc2ccnc(Nc3ccc(F)cc3)n2)c(F)c1
Agent: COc1ccc(CNc2cc(Oc3ccc(NC(=O)NC(=O)Cc4ccc(F)cc4)cc3F)ncn2)cc1
Solvent: C1CCOC1
Product: O=C(Cc1ccc(F)cc1)NC(=O)Nc1ccc(Oc2ccnc(Nc3ccc(F)cc3)n2)c(F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93 %

Procedure:
A solution of 4-(4-amino-2-fluorophenoxy)-N-(4-fluorophenyl)pyrimidin-2-amine (10 mg, 0.032 mmol) in THF (1 mL) was cooled in an ice bath and treated with a solution of 2-(4-fluorophenyl)acetyl isocyanate in toluene (Compound D of Example of 11, 228 μL, 0.064 mmol) and stirred at RT for 2 h. The reaction mixture was concentrated in vacuo and the residue triturated with isopropyl ether to give the title compound (15 mg, 93%) as a white solid. 1H NMR (DMSO-d6) δ 11.06 (s, 1H), 10.56 (s, 1H), 9.68 (s, 1H), 8.39 (d, 1H, J=5.7 Hz), 7.76 (dd, 1H, J=13.5, 2.1 Hz), 7.43 (br s, 2H), 7.46-7.35 (m, 6H), 7.18 (dd, 2H, J=8.8, 8.8 Hz), 6.57 (d, 1H, J=5.4 Hz), 3.76 (s, 2H); MS (ESI+) m/z 492.0 (M+H)+.
Reaction SMILES: F[C:2]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[F:15][C:16]([F:22])([F:21])[C:17]([CH3:20])([OH:19])[CH3:18].C(=O)([O-])[O-].[Cs+].[Cs+].C(O)=O>CN(C)C(=O)C>[CH3:14][S:11]([C:8]1[CH:9]=[CH:10][C:2]([O:19][C:17]([CH3:20])([CH3:18])[C:16]([F:22])([F:21])[F:15])=[C:3]([CH:7]=1)[C:4]([OH:6])=[O:5])(=[O:13])=[O:12]
Reactant: CC(C)(O)C(F)(F)F
Reactant: CS(=O)(=O)c1ccc(F)c(C(=O)O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O=CO
Solvent: CC(=O)N(C)C
Product: CC(C)(Oc1ccc(S(C)(=O)=O)cc1C(=O)O)C(F)(F)F
Temperature: 170 °C
Reaction time: 72 h
Yield: 99 %

Procedure:
To a solution of 2.75 mmol 2-fluoro-5-methanesulfonyl-benzoic acid in 10 ml N,N-dimethylacetamide were added 14.7 mmol 1,1,1-trifluoro-2-methyl-propan-2-ol and 8.29 mmol cesium carbonate and the mixture was stirred at 170° C. for 72 hours. The reaction mixture was then cooled to room temperature, acidified by addition of formic acid, and then concentrated in vacuo. The residue was purified by preparative HPLC to afford the title compound as a light brown solid (yield 99%). MS (m/e): 325.3. ([M−H]−, 100%)
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH2:10]N)=O)=[CH:4][CH:3]=1.[C:12]1([NH2:23])[C:17](F)=[C:16](F)[C:15](F)=[C:14]([NH2:21])[C:13]=1F.Cl.Cl>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[C:8]([CH3:10])=[C:17]3[CH2:16][CH2:15][NH:21][CH2:14][CH2:13][C:12]3=[N:23][C:6]=2[CH:7]=1
Reactant: Nc1c(F)c(N)c(F)c(F)c1F
Reactant: Cc1ccc(C(=O)CN)cc1
Agent: Cl
Product: Cc1ccc2c(C)c3c(nc2c1)CCNCC3

Procedure:
1,2,4,5-Tetrahydro-8,11-dimethyl-3H-azepino[4,5-b]quinoline, 2,3,4,5-tetrahydro-8,11-dimethyl-1H-azepino[4,5-b]quinoline and their dihydrochlorides were prepared from hexahydro-azepinone-(4) hydrochloride and 2-amino-4-methyl-acetophenone analogous to Example 127. Yield of the dihydrochloride of the [4,5-b]-isomer: 17% of theory; m.p. 290°-292° C. (decomp.).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:24])=[C:8]2[C:15]([Br:16])=[C:14]([Br:17])[N:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:9]2=[C:10](Br)[N:11]=1)=[O:5])[CH3:2].[C:25]([Cu])#[N:26]>>[CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:24])=[C:8]2[C:15]([Br:16])=[C:14]([Br:17])[N:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:9]2=[C:10]([C:25]#[N:26])[N:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nc(Br)c2c(c1O)c(Br)c(Br)n2-c1ccccc1
Reactant: N#C[Cu]
Product: CCOC(=O)c1nc(C#N)c2c(c1O)c(Br)c(Br)n2-c1ccccc1

Procedure:
Prepared in analogy to that of Example 105(a) from 2,3,7-tribromo-4-hydroxy-1-phenyl-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester and CuCN. The title compound, ESI MS (m/z): 464 (M+H)+.
Reaction SMILES: [OH:1]/[N:2]=[C:3](/[C:9](=[O:11])[CH3:10])\[C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH:12]1(Br)[CH2:16][CH2:15][CH2:14][CH2:13]1>>[CH:12]1([O:1]/[N:2]=[C:3](/[C:9](=[O:11])[CH3:10])\[C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: CCOC(=O)/C(=N\O)C(C)=O
Reactant: BrC1CCCC1
Product: CCOC(=O)/C(=N\OC1CCCC1)C(C)=O
Reaction time: 8 h
Yield: 80 %

Procedure:
Ethyl (Z)-2-(hydroxyimino)-3-oxobutyrate (7.9 g) was treated with cyclopentyl bromide as described in Example 4a, Method 2, except that the reaction was stirred overnight to give the title compound as a colourless liquid (9.Og, 80%), (Found: M+ +H, 228.1241. C11H17NO4 requires M+H, 228.1236); νmax (film) 2960 1745, 1700 cm-1 ; δH (CDCl3) 1.30 (3H, t), 1.6-2.0 (8H, m), 2.37 (3H, s), 4.31 (2H, q),and 4.87 (1H, m).
Reaction SMILES: [CH3:1][C:2]1[C:7]([O:8][CH3:9])=[C:6]([CH3:10])[C:5]([CH2:11][S:12]([C:14]2[N:18]([CH2:19][CH3:20])[C:17]3[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:16]=3[N:15]=2)=[O:13])=[C:4]([N:26]2[C:30](=[O:31])[C:29]3=[CH:32][CH:33]=[CH:34][CH:35]=[C:28]3[C:27]2=[O:36])[CH:3]=1.[NH2:37][NH2:38]>>[Cl:25][C:23]1[CH:22]=[CH:21][C:17]2[N:18]([CH2:19][CH3:20])[C:14]([S:12]([CH2:11][C:5]3[C:6]([CH3:10])=[C:7]([O:8][CH3:9])[C:2]([CH3:1])=[CH:3][C:4]=3[NH:26][C:27]([C:28]3[CH:35]=[CH:34][CH:33]=[CH:32][C:29]=3[C:30]([NH:37][NH2:38])=[O:31])=[O:36])=[O:13])=[N:15][C:16]=2[CH:24]=1
Reactant: CCn1c(S(=O)Cc2c(N3C(=O)c4ccccc4C3=O)cc(C)c(OC)c2C)nc2cc(Cl)ccc21
Reactant: NN
Product: CCn1c(S(=O)Cc2c(NC(=O)c3ccccc3C(=O)NN)cc(C)c(OC)c2C)nc2cc(Cl)ccc21
Yield: 57 %

Procedure:
2-[(4,6-Dimethyl-5-methoxy-2-phthalimidylphenyl)methylsulfinyl]-5-chloro-1-ethyl-1H-benzimidazole (Example 121) (66 mg, 0.13 mmol) was treated with hydrazine according to the procedure of Example 39 to give the crude acyl hydrazide as an oil which was triturated with ether to give the partially deprotected amine as the title compound (28 mg, 57%). 1H NMR δ1.29, (t, 3H), 2.26 (s, 3H), 2.34 (s, 3H), 3.66 (s, 3H), 4.16 (s, 2H), 4.29 (m, 2H), 4.95 (q, 2H), 7.24 (s, 2H), 7.37 (s, 1H), 7.48 (s, 1H), 7.55 (m, 2H), 7.69 (m, 1H), 7.82 (m, 1H), 7.87 (s, 1H).
Reaction SMILES: N(C(OC(C)C)=O)=NC(OC(C)C)=O.[CH:15]1([N:18]2[C:24]3[N:25]=[CH:26][C:27]([CH2:29][CH2:30][OH:31])=[CH:28][C:23]=3[C:22](=[O:32])[NH:21][C:20]3[C:33]([CH3:38])=[CH:34][C:35]([F:37])=[N:36][C:19]2=3)[CH2:17][CH2:16]1.O[C:40]1[C:49]2[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=2)[N:43]=[CH:42][CH:41]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C1COCC1>[CH:15]1([N:18]2[C:24]3[N:25]=[CH:26][C:27]([CH2:29][CH2:30][O:31][C:40]4[C:49]5[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=5)[N:43]=[CH:42][CH:41]=4)=[CH:28][C:23]=3[C:22](=[O:32])[NH:21][C:20]3[C:33]([CH3:38])=[CH:34][C:35]([F:37])=[N:36][C:19]2=3)[CH2:17][CH2:16]1
Reactant: Cc1cc(F)nc2c1NC(=O)c1cc(CCO)cnc1N2C1CC1
Reactant: Oc1ccnc2ccccc12
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1cc(F)nc2c1NC(=O)c1cc(CCOc3ccnc4ccccc34)cnc1N2C1CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 51.9 %

Procedure:
Diisopropyl azodicarboxylate (DIAD) (131 μL, 0.66 mmol) was added drop-wise to a solution of 11-(cyclopropyl)-5,11-dihydro-2-fluoro-8-(2-hydroxyethyl)-4methyl-6H-dipyrido[3,2-b:2′,3′-e] [1,4]diazepin-6-one (140 mg, 0.44 mmol), 4-hydroxyquinoline (96.4 mg, 0.66 mmol) and Ph3P (124 mg, 0.66 mmol) in THF (2.2 mL) at room temperature. The mixture was stirred at room temperature for 3 h then was concentrated under reduced pressure. The residue was dissolved in EtOAc (60 mL) and the solution was successively washed with 3 N aqueous NaOH (3×20 mL), aqueous saturated NH4Cl (20 mL) and brine (20 mL) then was dried (MgSO4), filtered and concentrated under reduced pressure. The residue was partially purified by flash chromatography (EtOAc:MeOH; 95:5). The solid was further purified by reverse phase HPLC (CombiPrep ADS-AQ 50×20 mm, 5 μ120 A, 5-100% MeCN+0.10% TFA/water+0.10% TFA in 25 min) to give the bifluoroacetic acid salt of the title compound (104 mg, 43% yield) as a white solid: MS (ESI) m/z 456 (MH)+.
Reaction SMILES: C1(C(=[N:14][C:15]2[CH:16]=[C:17]([O:21][C:22]3[N:23]=[C:24]([NH:33][C:34]4[CH:39]=[CH:38][C:37]([N:40]5[CH2:45][CH2:44][N:43]([CH3:46])[CH2:42][CH2:41]5)=[CH:36][CH:35]=4)[C:25]([C:30]([NH2:32])=[O:31])=[N:26][C:27]=3[CH2:28][CH3:29])[CH:18]=[N:19][CH:20]=2)C2C=CC=CC=2)C=CC=CC=1.Cl>O1CCCC1>[NH2:14][C:15]1[CH:16]=[C:17]([O:21][C:22]2[N:23]=[C:24]([NH:33][C:34]3[CH:35]=[CH:36][C:37]([N:40]4[CH2:45][CH2:44][N:43]([CH3:46])[CH2:42][CH2:41]4)=[CH:38][CH:39]=3)[C:25]([C:30]([NH2:32])=[O:31])=[N:26][C:27]=2[CH2:28][CH3:29])[CH:18]=[N:19][CH:20]=1
Reactant: CCc1nc(C(N)=O)c(Nc2ccc(N3CCN(C)CC3)cc2)nc1Oc1cncc(N=C(c2ccccc2)c2ccccc2)c1
Agent: Cl
Solvent: C1CCOC1
Product: CCc1nc(C(N)=O)c(Nc2ccc(N3CCN(C)CC3)cc2)nc1Oc1cncc(N)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 54.6 %

Procedure:
To a mixture of 5-({5-[(diphenylmethylene)amino]pyridin-3-yl}oxy)-6-ethyl-3-{[4-(4-methylpiperazin-1-yl)phenyl]amino}pyrazine-2-carboxamide (130 mg) and tetrahydrofuran (2.17 mL) was added 1 M hydrochloric acid (0.26 mL), followed by stirring at room temperature for 3 hours. To the residue obtained by evaporating the solvent was added ethyl acetate, followed by extraction with water. The aqueous phase was neutralized with a 1 M aqueous sodium hydroxide solution and extracted by the addition of a mixed solvent of chloroform:methanol (10:1). The organic phase was washed with saturated brine and dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (NH2 type: eluent; chloroform:methanol=1:0-9:1) to obtain 5-[(5-aminopyridin-3-yl)oxy]-6-ethyl-3-{[4-(4-methylpiperazin-1-yl)phenyl]amino}pyrazine-2-carboxamide (52 mg) as a yellow solid.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:15]1([P:20](Cl)(Cl)=[O:21])[CH2:19][CH2:18][CH2:17][CH2:16]1>CC1CCCCC1>[CH:15]1([P:20]2(=[O:21])[C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[CH2:1][N:8]2[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: O=P(Cl)(Cl)C1CCCC1
Reactant: c1ccc(CNc2ccccc2)cc1
Solvent: CC1CCCCC1
Product: O=P1(C2CCCC2)c2ccccc2CN1c1ccccc1

Procedure:
The procedure of Example 1 was employed utilizing N-benzylaniline and cyclopentyl phosphonic dichloride. The crude product produced as a result of the chromatographic separation was slurried in methylcyclohexane and further purified on a chromatographic system employing an alumina column using chloroform (containing 0.75% ethyl alcohol) as the eluant. Fractions containing the benzazaphosphole were crystallized using benzene and methylcyclohexane to yield 1-cyclopentyl-2-phenyl-2,3-dihydro-1H-2,1-benzazaphosphole-1-oxide as a yellow solid. A second crop was obtained to give a total yield of 0.85 g (5% yield) of 1-cyclopentyl-2-phenyl-2,3-dihydro-1H-2,1-benzazaphosphole-1-oxide having a melting point of 123°-125° C. and the following analysis:
Reaction SMILES: [ClH:1].[OH:2][CH:3]([CH2:18][O:19][C:20]1[CH:25]=[CH:24][C:23](OC)=[CH:22][CH:21]=1)[CH2:4][NH:5][C:6]([CH3:17])([CH3:16])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1.Cl.OC(COC1C=CC(C(C)(C)C)=CC=1)[CH2:31][NH:32]C(C)(C)CC1C=CC(OC)=CC=1>>[ClH:1].[OH:2][CH:3]([CH2:18][O:19][C:20]1[CH:21]=[CH:22][CH:23]=[C:24]([C:31]#[N:32])[CH:25]=1)[CH2:4][NH:5][C:6]([CH3:17])([CH3:16])[CH2:7][C:8]1[CH:9]=[CH:10][C:11]([O:14][CH3:15])=[CH:12][CH:13]=1
Reactant: COc1ccc(CC(C)(C)NCC(O)COc2ccc(OC)cc2)cc1
Reactant: COc1ccc(CC(C)(C)NCC(O)COc2ccc(C(C)(C)C)cc2)cc1
Agent: Cl
Product: COc1ccc(CC(C)(C)NCC(O)COc2cccc(C#N)c2)cc1

Procedure:
GC/EI-MS, m/z (rel. int.) 339 (M−15,0.1), 234 (15), 233 (100), 121 (21), 102 (7), 90 (6).
Reaction SMILES: [CH2:1]([S:3](Cl)(=[O:5])=[O:4])[CH3:2].[Br:7][C:8]1[CH:9]=[C:10]([CH:12]=[CH:13][C:14]=1[O:15][CH2:16][CH:17]1[CH2:19][CH2:18]1)[NH2:11].N1C=CC=CC=1.Cl>C(Cl)Cl>[Br:7][C:8]1[CH:9]=[C:10]([NH:11][S:3]([CH2:1][CH3:2])(=[O:5])=[O:4])[CH:12]=[CH:13][C:14]=1[O:15][CH2:16][CH:17]1[CH2:19][CH2:18]1
Reactant: Nc1ccc(OCC2CC2)c(Br)c1
Reactant: CCS(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCS(=O)(=O)Nc1ccc(OCC2CC2)c(Br)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 96.7 %

Procedure:
Ethylsulfonyl chloride (233 uL, 2.4 mmol) was added to a stirred solution of 3-bromo-4-(cyclopropylmethoxy)aniline (520 mg, 2.2 mmol) and pyridine (520 uL, 6.5 mmol) in DCM (4 mL) at 0° C. under nitrogen. After the mixture was allowed to warm to rt and stir for 12 h, it was treated with 1N HCl (15 mL) and extracted with DCM (3×15 mL); the combined organic extracts were washed with saturated bicarbonate solution (aq), dried over sodium sulfate, filtered and concentrated in vacuo. The resulting residue was purified by silica gel column chromatography using a gradient of EtOAc (10 to 100%) in hexanes to afford the title compound (711 mg, 98%) as a yellow solid. LCMS (M+H)+=335.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][N:10]([CH2:13][C:14]([C:16]3[CH:27]=[C:26]([C:28]([CH3:31])([CH3:30])[CH3:29])[C:19]([O:20][CH2:21][C:22]([O:24]C)=[O:23])=[C:18]([C:32]([CH3:35])([CH3:34])[CH3:33])[CH:17]=3)=[O:15])[CH2:9][CH2:8]2)=[CH:3][CH:2]=1.Cl>O1CCOCC1.O>[N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:8][CH2:9][N:10]([CH2:13][C:14]([C:16]3[CH:27]=[C:26]([C:28]([CH3:30])([CH3:29])[CH3:31])[C:19]([O:20][CH2:21][C:22]([OH:24])=[O:23])=[C:18]([C:32]([CH3:35])([CH3:34])[CH3:33])[CH:17]=3)=[O:15])[CH2:11][CH2:12]2)=[CH:3][CH:2]=1
Reactant: COC(=O)COc1c(C(C)(C)C)cc(C(=O)CN2CCN(c3ccncc3)CC2)cc1C(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)c1cc(C(=O)CN2CCN(c3ccncc3)CC2)cc(C(C)(C)C)c1OCC(=O)O
Temperature: 100 °C

Procedure:
A solution of methyl 4-(2-[4-(4-pyridyl)piperazin-1-yl]acetyl)-2,6-di-tert-butylphenoxyacetate (241 mg) in dioxane (2.0 ml) was treated with 1N hydrochloric acid and the mixture heated at 100° C. for 20 hours. The mixture was cooled, diluted with water, filtered and the filtrate freeze-dried. The solid residue was purified by flash chromatography on silica eluting with toluene/ethyl acetate/0.880 ammonia/ethanol (60:20:10:35 v/v/v/v). The fractions containing the desired product were evaporated, the residue treated with dioxane, filtered and the filtrate diluted with water and freeze dried to give a white foam, which on drying at 55° C. gave the title compound, 90 mg: NMR (d6DMSO) δ8.16 (2H, d), 7.97 (2H, s), 6.84 (2H, d), 4.22 (2H, s), 3.86 (2H, s), 3.37 (4H, t), 2.64 (4H, t), 1.39 (18H, s); m/e 468 (M+H)+ ; calculated for C27H37N3O4.2H2O: C, 64.4; H, 8.2; N, 8.3. found C, 64.6; H, 7.9; N, 7.9%.