Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[C:3]([O:7][N:8]=[C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([OH:19])[CH:17]=2)[O:12][C:11]([C:20]2[N:25]=[CH:24][N:23]3[CH:26]=[CH:27][CH:28]=[C:22]3[CH:21]=2)=[CH:10]1)([CH3:6])([CH3:5])[CH3:4].Cl[CH2:30][CH2:31][O:32][C:33]1[CH:38]=[CH:37][N:36]=[CH:35][CH:34]=1.C1OCCOCCOCCOCCOC1>CN1C(=O)CCC1.[I-].C([N+](CCCC)(CCCC)CCCC)CCC.[Cl-].[NH4+]>[C:3]([O:7][N:8]=[C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([O:19][CH2:30][CH2:31][O:32][C:33]3[CH:38]=[CH:37][N:36]=[CH:35][CH:34]=3)[CH:17]=2)[O:12][C:11]([C:20]2[N:25]=[CH:24][N:23]3[CH:26]=[CH:27][CH:28]=[C:22]3[CH:21]=2)=[CH:10]1)([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)ON=c1cc(-c2cc3cccn3cn2)oc2ccc(O)cc12
Reactant: ClCCOc1ccncc1
Agent: C1COCCOCCOCCOCCO1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Solvent: CN1CCCC1=O
Product: CC(C)(C)ON=c1cc(-c2cc3cccn3cn2)oc2ccc(OCCOc3ccncc3)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 41 %

Procedure:
To a mixture of sodium hydride 60% in oil (11.5 mg, 0.28 mmol) in NMP (0.5 ml) was added at 0° C. a solution of 6-hydroxy-2-pyrrolo[1,2-c]pyrimidin-3-yl-chromen-4-one O-tert-butyl-oxime (example 81A) (100 mg, 0.28 mmol) in NMP (0.5 ml). After 1 hour at room temperature, a solution of 4-(2-Chloro-ethoxy)-pyridine (103 mg, 042 mmol), tetrabutyl ammonium iodide (53 mg, 0.14 mmol), 15-crown-5 (63 mg, 0.28 mmol) in NMP (0.5 ml) was added at 0° C. After stirring at room temperature for 24 hours, the reaction mixture was diluted with a saturated solution of ammonium chloride and extracted with ethyl acetate. The organic layers were washed with a saturated solution of ammonium chloride, water, brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography over silica gel (gradient cyclohexane/ethyl acetate: 0-70%) to yield the title compound (54 mg, 42%) as a yellow solid.
Reaction SMILES: [Br:1][C:2](Br)=[CH:3][C:4]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][CH:5]=1.CC(C)([O-])C.[K+].C1(C)C=CC=CC=1>O>[Br:1][C:2]#[C:3][C:4]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][CH:5]=1
Reactant: Fc1ccc(C=C(Br)Br)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: Fc1ccc(C#CBr)cc1
Temperature: 80 °C
Yield: 70.4 %

Procedure:
A mixture of 1-(2,2-dibromo-vinyl)-4-fluoro-benzene (0.6 g, 0.00214 mol), potassium tertbutoxide (0.48 g, 0.00428 mol) and toluene (6 mL) were heated at 80° C. for 4 h. After completion of reaction, the reaction mixture was cooled to RT, diluted with water (15 mL), and extracted with EtOAc (3×50 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduce pressure to obtain product as a yellow oil (0.3 g, 70%).
Reaction SMILES: C(N(C(C)C)CC)(C)C.[F:10][C:11]([F:23])([F:22])[C:12]1[CH:13]=[C:14]([S:18](Cl)(=[O:20])=[O:19])[CH:15]=[CH:16][CH:17]=1.Cl.[CH:25]1([NH:28][C:29](=[O:42])[C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([C:36]3[CH2:37][CH2:38][NH:39][CH2:40][CH:41]=3)[N:31]=2)[CH2:27][CH2:26]1>ClCCl>[CH:25]1([NH:28][C:29]([C:30]2[N:31]=[C:32]([C:36]3[CH2:37][CH2:38][N:39]([S:18]([C:14]4[CH:15]=[CH:16][CH:17]=[C:12]([C:11]([F:23])([F:22])[F:10])[CH:13]=4)(=[O:20])=[O:19])[CH2:40][CH:41]=3)[CH:33]=[CH:34][CH:35]=2)=[O:42])[CH2:26][CH2:27]1
Reactant: O=C(NC1CC1)c1cccc(C2=CCNCC2)n1
Reactant: O=S(=O)(Cl)c1cccc(C(F)(F)F)c1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(NC1CC1)c1cccc(C2=CCN(S(=O)(=O)c3cccc(C(F)(F)F)c3)CC2)n1
Reaction time: 0.5 h
Yield: 61.5 %

Procedure:
Diisopropyl ethyl amine (66 ml, 0.36 mmol) and 3-(trifluoromethyl)benzene sulfonyl chloride (6) (44 mg, 0.18 mmol, Aldrich) were sequentially added to a suspension of compound 5 (50 mg, 0.18 mmol) in dichloromethane at 0° C. while stirring. The reaction was completed within 0.5 hour and the crude product was purified without work-up on CombiFlash® with a gradient of 50-100% EtOAc in hexane to provide the title compound 7 as a white solid (50 mg, yield 64%). 1H NMR (400 MHz, CD3OD): δ 8.15 (m, 2H), 8.02-7.83 (m, 4H), 7.67 (dd, 1H, J=1.2, 7.6 Hz), 6.78 (m, 1H), 3.92 (m, 2H), 3.45 (m, 2H), 2.87 (m, 1H), 2.77 (m, 2H), 0.86 (m, 2H), 0.70 (m, 2H); MS: 452 (M+H+), 474 (M+Na).
Reaction SMILES: [C:1]1([C:7]#[C:8][C:9]2[S:10][C:11]([CH:14]=[O:15])=[CH:12][N:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:16]1([Mg]Br)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.CCOCC>C1COCC1>[C:16]1([CH:14]([C:11]2[S:10][C:9]([C:8]#[C:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[N:13][CH:12]=2)[OH:15])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Br[Mg]c1ccccc1
Reactant: O=Cc1cnc(C#Cc2ccccc2)s1
Solvent: CCOCC
Solvent: C1CCOC1
Product: OC(c1ccccc1)c1cnc(C#Cc2ccccc2)s1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 2-phenylethynyl-thiazole-5-carbaldehyde (Example 205, 197 mg, 0.924 mmol) in THF (5.0 mL) was cooled at 0° C. and treated with a 3.0 M solution of phenyl magnesium bromide in Ether (340 μL, 1.0 mmol). After stirring for about 30 minutes at 0° C., the reaction was quenched with saturated aqueous ammonium chloride (25 mL), diluted with EtOAc (25 mL), transferred to a 125-mL separatory funnel and extracted. The layers were separated and the aqueous layer was extracted again with EtOAc (25 mL). The combined organic layers were then washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by preparative TLC, eluting with 25% EtOAc in hexanes to afford the titled compound, pPhenyl-(2-phenylethynyl-thiazol-5-yl)-methanol (190 mg, 71%), as a pale yellow oil.
Reaction SMILES: [NH:1]([C:8]1[N:13]=[C:12]2[N:14]([C:27]3[CH:32]=[CH:31][C:30]([CH2:33][CH2:34][N:35]4C(=O)C5=CC=CC=C5C4=O)=[CH:29][CH:28]=3)[C:15](=[O:26])[N:16]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=3[Cl:25])[CH2:17][C:11]2=[CH:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.NN>CO.ClCCl>[NH2:35][CH2:34][CH2:33][C:30]1[CH:31]=[CH:32][C:27]([N:14]2[C:12]3=[N:13][C:8]([NH:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)=[N:9][CH:10]=[C:11]3[CH2:17][N:16]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=3[Cl:25])[C:15]2=[O:26])=[CH:28][CH:29]=1
Reactant: O=C1c2ccccc2C(=O)N1CCc1ccc(N2C(=O)N(c3ccc(Cl)cc3Cl)Cc3cnc(Nc4ccccc4)nc32)cc1
Agent: NN
Solvent: O
Solvent: ClCCl
Solvent: CO
Product: NCCc1ccc(N2C(=O)N(c3ccc(Cl)cc3Cl)Cc3cnc(Nc4ccccc4)nc32)cc1
Yield: 59.4 %

Procedure:
A solution of 195 mg (0.3 mmol) of 7-anilino-3-(2,4-dichlorophenyl)-3,4-dihydro-1-[4-(2-phthalimidoethyl)phenyl]-pyrimido[4,5-d]pyrimidin-2(1H)-one and 150 μl (3 mmol) of hydrazine hydrate in methanol/dichloromethane (3 ml:3 ml) was stirred at room temperature under an atmosphere of nitrogen overnight. The reaction mixture was evaporated and the residue purified by flash chromatography on silica gel eluting with dichloromethane/methanol/acetic acid/water (120:14:3:2). Product containing fractions were combined and evaporated and the residue re-evaporated with toluene. The residue was dissolved in 20 ml of dichloromethane, washed with saturated aqueous sodium bicarbonate (20 ml), dried over magnesium sulfate, filtered and evaporated to give 90 mg (67%) of 1-[4-(2-aminoethyl)phenyl]-7-anilino-3-(2,4-dichlorophenyl)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one as a white solid of melting point 117-121° C. [Mass spectrum (ESI) MH+ =505].
Reaction SMILES: [CH3:1][Si:2]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)([O:5][CH3:6])[O:3][CH3:4].[H][H]>[Cr].[Ni].[Cr].[Ni]>[CH3:1][Si:2]([CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)([O:3][CH3:4])[O:5][CH3:6]
Reactant: [H][H]
Reactant: CO[Si](C)(OC)c1ccccc1
Agent: [Cr]
Agent: [Ni]
Product: CO[Si](C)(OC)C1CCCCC1

Procedure:
An amount, as set forth in Table 1, of a Raney nickel-chromium catalyst, sold by Grace Company as "Raney 2400 chromium promoted nickel," containing 2-3% by weight of chromium, was loaded in the form of a suspension in a solvent at 30% by weight into an autoclave having a volume of 500 cm3. Then there was added methyl-phenyl-dimethoxysilane in the amount set forth in Table 1, together with an additional solvent until the total volume reached 200 cm3. The mixture was heated gradually over a period of one hour under strong stirring at the temperature and hydrogen pressure set forth in Table 1. After the reaction time indicated in Table 1, the hydrogenation was substantially complete. The final mass was cooled, the catalyst was separated by decantation and filtration, and the solvent was evaporated. Methyl-cyclohexyl-dimethoxy-silane was obtained, having a purity of 99.6%, in the amounts and yields set forth in Table 1.
Reaction SMILES: Br[C:2]1[S:18][C:5]2[N:6]=[C:7]([CH2:10][CH2:11][N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[N:8]=[CH:9][C:4]=2[CH:3]=1.[CH:19]1([NH:22][C:23](=[O:40])[C:24]2[CH:29]=[CH:28][C:27]([CH3:30])=[C:26](B3OC(C)(C)C(C)(C)O3)[CH:25]=2)[CH2:21][CH2:20]1.[F-].[Cs+].O1CCOCC1>CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[CH:19]1([NH:22][C:23](=[O:40])[C:24]2[CH:29]=[CH:28][C:27]([CH3:30])=[C:26]([C:2]3[S:18][C:5]4[N:6]=[C:7]([CH2:10][CH2:11][N:12]5[CH2:17][CH2:16][O:15][CH2:14][CH2:13]5)[N:8]=[CH:9][C:4]=4[CH:3]=3)[CH:25]=2)[CH2:20][CH2:21]1
Reactant: Brc1cc2cnc(CCN3CCOCC3)nc2s1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1B1OC(C)(C)C(C)(C)O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1cc2cnc(CCN3CCOCC3)nc2s1
Temperature: 150 °C

Procedure:
A 5 ml glass microwave reaction vessel was charged with 6-bromo-2-(2-morpholinoethyl)thieno[2,3-d]pyrimidine. (0.200 g, 0.582 mmol), N-cyclopropyl-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (0.135 g, 0.582 mmol), cesium fluoride (0.277 g, 1.75 mmol), tetrakis(triphenylphosphine)palladium(0) (0.046 g, 0.040 mmol), 1,4-dioxane (1 mL, 57 mmol) and water (1 ml). The reaction mixture was heated in a Smith Synthesizer microwave reactor (Personal Chemistry, Inc., Upssala, Sweden) at 150° C. for 20 min. The reaction mixture was diluted with EtOAc and filtered through Celite®. The organic solutions were evaporated under reduced pressure. The crude residue was suspended in DCM and washed with saturated sodium bicarbonate (1×25 mL) followed by brine (1×25 mL), water (1×25 mL) and dried over MgSO4. The organic solutions were evaporated under reduced pressure and the residue was adsorbed onto a plug of silica gel and chromatographed through a Redi-Sep pre-packed silica gel column (40 g), eluting with a gradient of 5% to 95% MeOH in DCM to provide the title compound (0.095 g) MS (ES+): 438 (M+H)+.
Reaction SMILES: [NH:1]([C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[C@H:2]([C:10]([OH:12])=O)[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[NH2:23][CH2:24][C:25]([NH:27][C@H:28]([C:33]([OH:35])=[O:34])[CH2:29][CH:30]([CH3:32])[CH3:31])=[O:26].C(N(CC)CC)C.O>O1CCOCC1>[NH:1]([C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[C@H:2]([C:10]([NH:23][CH2:24][C:25]([NH:27][C@H:28]([C:33]([OH:35])=[O:34])[CH2:29][CH:30]([CH3:32])[CH3:31])=[O:26])=[O:12])[CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CC(C)C[C@H](NC(=O)CN)C(=O)O
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)O)OCc1ccccc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CC(C)C[C@H](NC(=O)CNC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1)C(=O)O
Reaction time: 8 h
Yield: 73.6 %

Procedure:
The N-hydroxysuccinimide ester of Z-Phe-OH (19.15 g, 48.3 mmol) was dissolved in 50 mL of dioxane and the resulting solution was filtered into a solution consisting of H-Gly-Leu-OH (10.0 g, 53.1 mmol), triethylamine (10.1 mL, 72.4 mmol), and water (50 mL). This reaction mixture was stirred overnight at about 23°, and then concentrated approximately 60% by evaporation. The resulting concentrated solution was diluted with 1.0N hydrochloric acid until acidic. Product Z-Phe-Gly-Leu-OH was extracted into ethyl acetate, and the resulting extract was washed with 0.2N hydrochloric acid, followed by saturated aqueous sodium chloride adjusted to 0.10N hydrochloric acid. After washing, the ethyl acetate solution was dried over anhydrous sodium sulfate and filtered. The ethyl acetate was then evaporated to yield 22.5 g of a white, foamy product, which was subsequently crystallized from ethyl acetate to yield 16.7 g of Z-Phe-Gly-Leu-OH (m.p. 147°-148°).
Reaction SMILES: [CH3:1][Si](C=[N+]=[N-])(C)C.[CH2:8]([CH:11]1[CH2:16][CH2:15][CH:14]([C:17]([OH:19])=[O:18])[CH2:13][CH2:12]1)[C:9]#[CH:10]>CO.ClCCl>[CH2:8]([CH:11]1[CH2:16][CH2:15][CH:14]([C:17]([O:19][CH3:1])=[O:18])[CH2:13][CH2:12]1)[C:9]#[CH:10]
Reactant: C#CCC1CCC(C(=O)O)CC1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: ClCCl
Product: C#CCC1CCC(C(=O)OC)CC1

Procedure:
(Trimethylsilyl)diazomethane (2.0 M) solution in hexanes (1 mL, 2 mmol) was added to a solution of 5.4 (0.34 g, 2 mmol) in 15 mL of methanol:dichloromethane (3:7). The solvents were removed under reduced pressure resulting in 100% conversion of starting material to product. 1H NMR (300 MHz, CDCl3) δ2.24 (dt, J=3.66, 12.1 Hz, 1H), 2.10 (dd, J=2.7, 6.5 Hz, 2H), 2.06 (dd, J=1.54, 6.54 Hz, 1H), 2.00-1.89 (m, 3H), 1.76 (d, J=2.3 Hz, 1H), 1.43 (dq, J=3.28, 13.1 Hz, 2H), 1.03 (dq, J=3.28, 13.1 Hz, 2H). 13C NMR (300 MHz, CDCl3) δ176.8, 83.3, 69.8, 51.9, 43.4, 36.7, 31.9, 29.2, 26.3.
Reaction SMILES: N(OC(C)(C)C)=O.N[C:9]1[S:10][C:11]([CH2:14][CH2:15][CH:16]2[CH2:25][CH2:24][CH2:23][C:22]3[C:21]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:20][CH:19]=[CH:18][C:17]2=3)=[CH:12][N:13]=1.Cl>C(#N)C.C(O)(=O)C.[Zn]>[S:10]1[C:11]([CH2:14][CH2:15][CH:16]2[CH2:25][CH2:24][CH2:23][C:22]3[C:21]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:20][CH:19]=[CH:18][C:17]2=3)=[CH:12][N:13]=[CH:9]1
Reactant: CCOC(=O)c1cccc2c1CCCC2CCc1cnc(N)s1
Agent: CC(C)(C)ON=O
Agent: Cl
Agent: [Zn]
Solvent: CC#N
Solvent: CC(=O)O
Product: CCOC(=O)c1cccc2c1CCCC2CCc1cncs1
Yield: 75.7 %

Procedure:
0 87 g of cupric chloride was suspended in 20 ml of acetonitrile and 0.82 g of tertiary butyl nitrite was added thereto. A solution of 1.8 g of ethyl 5-(2-(2-aminothiazole-5-yl)ethyl)-5,6,7,8-tetrahydro-1-naphthalenecarboxylate in 5 ml of acetonitrile was added dropwise to the mixture. After evolution of gas ceased, 15% hydrochloric acid was added to the mixture. The resulting mixture was extracted with chloroform. The extract was washed with water, dried and then concentrated in vacuo. The residue was purifed by silica gel column chromatography with chloroform eluent to give an oily product. The product was dissolved in 30 ml of acetic acid, and a small amount of zinc powder was added thereto under refluxing. The above procedure was repeated four times at hourly intervals and the total amount of zinc was 0.4 g. The insoluble material was removed by filtration and the filtrate was concentrated in vacuo. The residue was dissolved in chloroform. The solution was washed with water and dried and then concentrated in vacuo. The residue was purified by silica gel column chromatography to give 1.3 g of ethyl 5-(2-(5-thiazolyl)ethyl)-5,6,7,8-tetrahydro-1-naphthalenecarboxylate as an oil.
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10]([CH3:12])[C:9]([NH:13][C:14](=[O:16])[CH3:15])=[C:8]([CH3:17])[C:3]=1[C:4]([NH:6][NH2:7])=[O:5].[C:18]1([S:24](Cl)(=[O:26])=[O:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>[OH-].[Na+]>[NH2:1][C:2]1[N:11]=[C:10]([CH3:12])[C:9]([NH:13][C:14](=[O:16])[CH3:15])=[C:8]([CH3:17])[C:3]=1[C:4]([NH:6][NH:7][S:24]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)(=[O:26])=[O:25])=[O:5]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CC(=O)Nc1c(C)nc(N)c(C(=O)NN)c1C
Agent: [Na+]
Agent: [OH-]
Product: CC(=O)Nc1c(C)nc(N)c(C(=O)NNS(=O)(=O)c2ccccc2)c1C

Procedure:
To a solution of 2-amino-5-acetamido-4,6-dimethylnicotinic acid hydrazide (34.4 g., 0.145 mole) in 1N sodium hydroxide solution (348 ml.) is added at ambient temperature and with vigorous stirring, benzenesulfonyl chloride (31.1 g., 0.16 mole) in one portion. After about three-quarters of an hour the acid chloride disappears; the maximum temperature attained by the reaction mixture, 36° C. The product is precipitated by pouring the reaction mixture into a stirred solution of acetic acid (8.3 ml.) in water (250 ml.). It is collected, slurried with water (150 ml.), refiltered and dried affording 49.52 g. (90%) of crude product, m.p. 216°-218° C. with gas evolution. Following purification by dissolving in hot (100° C.) dimethylformamide, filtering, and diluting with methanol (1 part) and water (3 parts) the product melts at 233°-234° C. (dec.).
Reaction SMILES: [CH2:1]([N:8]1[CH2:14][C:13]2[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=2[O:11][CH2:10][C:9]1=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl-].[Na+]>O1CCCC1>[CH2:1]([N:8]1[CH2:14][C:13]2[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=2[O:11][CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1COc2ccccc2CN1Cc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Product: c1ccc(CN2CCOc3ccccc3C2)cc1
Temperature: 25 °C
Yield: 93.1 %

Procedure:
A solution of 2.5 g of 4-benzyl-4,5-dihydro-benzo[f][1,4]oxazepin-3-one in 50 mL of tetrahydrofuran was added dropwise to a suspension of 1.14 g of lithium aluminum hydride in 50 mL of tetrahydrofuran. The mixture was refluxed for 5 hours and then allowed to cool down to room temperature. 2.2 mL of saturated aqueous sodium chloride solution was added in order to decompose excess lithium aluminum hydride. The precipitated solid was removed by filtration, and the filtrate was concentrated to give 2.2 g of pure 4-benzyl-2,3,4,5-tetrahydrobenzo[f][1,4]oxazepine as an oil. EI-MS: 239 (M+).
Reaction SMILES: [OH:1][NH:2][CH2:3][CH2:4][CH2:5][P:6](=[O:9])([OH:8])[OH:7].[N-:10]=[C:11]=[O:12].[K+].Cl.[OH-].[Na+]>O>[C:11]([N:2]([CH2:3][CH2:4][CH2:5][P:6](=[O:8])([OH:7])[OH:9])[OH:1])(=[O:12])[NH2:10]
Reactant: [N-]=C=O
Reactant: O=P(O)(O)CCCNO
Agent: Cl
Agent: [K+]
Agent: [Na+]
Solvent: O
Product: NC(=O)N(O)CCCP(=O)(O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 19.6 %

Procedure:
A mixture of 3-(N-hydroxyamino)propylphosphonic acid (1.64 g), potassium isocyanate (2.43 g) and water (17 ml) was stirred at ambient temperature for 3 hours, while maintaining the pH at around 5-7 with 3 N hydrochloric acid. The reaction mixture was adjusted to pH 9 with 1 N aqueous sodium hydroxide solution and then stirred at ambient temperature for 20 minutes. The resultant mixture was adjusted to the pH 1.8 with 3 N hydrochloric acid and concentrated under reduced pressure. The residue was extracted with methanol and the extract was concentrated under reduced pressure to give crude 3-(N-carbamoyl-N-hydroxyamino)propylphosphonic acid (2.50 g). A part (1 g) of the object compound was dissolved in water (5 ml), and the solution was passed through a column of nonionic adsorption resin Diaion HP 20 (trade name, made by Mitsubishi Chemical Industries). The object compound was eluted with water. The fractions containing the object compound was collected and evaporated to dryness to give powdery 3-(N-carbamoyl-N-hydroxyamino)propylphosphonic acid (410 mg).
Reaction SMILES: [N:1]1[C:2]2[C:14](=[O:15])[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[C:3]=2[NH:4][C:5](=[O:7])[CH:6]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.O.[CH2:28]([OH:30])[CH3:29]>C(O)CO.C1(C)C=CC=CC=1>[CH2:28]1[O:30][C:5]2([NH:4][C:3]3[C:8]4[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=4[C:14](=[O:15])[C:2]=3[N:1]=[CH:6]2)[O:7][CH2:29]1
Reactant: CCO
Reactant: O=C1c2ccccc2-c2[nH]c(=O)cnc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: OCCO
Solvent: O
Product: O=C1C2=C(NC3(C=N2)OCCO3)c2ccccc21
Temperature: 25 °C
Yield: 83 %

Procedure:
A suspension of 9H-indeno[1,2-b]pyrazine-3,9(4H)-dione (1.0 g, 5.05 mmol) in ethylene glycol (10 ml), toluene (20 ml) and p-toluenesulfonic acid (20 mg) was refluxed with water separation for 18 hours. The reaction mixture was cooled to room temperature, ethanol (5 ml) was added and the precipitate was filtered off and washed with ethanol and dried to give 1.014 g (83%) of the title compound. M.p. 296°-298° C. 1H-NMR (DMSO-d6, δ): 4.3-4.42 (m, 4H), 7.43-7.6 (m, 3H), 7.75 (d, 1H), 7.88 (s, 1H), 12.7 (s, 1H).
Reaction SMILES: [CH2:1]([Mg]Br)[CH:2]=[CH2:3].[CH3:6][C:7]1([CH3:14])[O:11][C@@H:10]([CH:12]=[O:13])[CH2:9][O:8]1>O1CCCC1>[CH3:6][C:7]1([CH3:14])[O:11][CH:10]([CH:12]([CH2:3][CH:2]=[CH2:1])[OH:13])[CH2:9][O:8]1
Reactant: C=CC[Mg]Br
Reactant: CC1(C)OC[C@H](C=O)O1
Solvent: C1CCOC1
Product: C=CCC(O)C1COC(C)(C)O1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
To a stirring -78° C. solution, under argon, of 556 ml of 1M allylmagnesium bromide is added, dropwise over 20 minutes, a solution of 36.4 g of product from Example 330 in 17 ml of tetrahydrofuran. The reaction mixture is stirred at -78° C. for 2 hours. Thin layer chromatography indicates the presence of starting material. An additional 280 ml of 1M allylmagnesium bromide is added and the reaction is stirred overnight at -78° C. The reaction is quenched with dropwise addition of saturated ammonium chloride, filtered through diatomaceous earth and washed with diethyl ether, ethyl acetate and 20% isopropyl alcohol/chloroform. The combined extracts are washed with saturated sodium chloride, dried and concentrated in vacuo to give, after Kugelrohr distillation at 85° C., 38.25 g of the desired product.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][NH:12][C:13](=[O:27])[C:14]1[CH:19]=[CH:18][C:17]([N:20]2[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]2)=[N:16][CH:15]=1.C(=O)([O-])O.[Na+].[N+:33]([O-])([OH:35])=[O:34]>>[O:1]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][NH:12][C:13](=[O:27])[C:14]1[CH:19]=[CH:18][C:17]([N:20]2[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]2)=[N:16][CH:15]=1)[N+:33]([O-:35])=[O:34]
Reactant: O=[N+]([O-])O
Reactant: CN1CCN(c2ccc(C(=O)NCCCCCCCCCCO)cn2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Product: CN1CCN(c2ccc(C(=O)NCCCCCCCCCCO[N+](=O)[O-])cn2)CC1
Reaction time: 4 h
Yield: 42 %

Procedure:
6.00 g of N-(10-hydroxy-1-decanyl)-6-(4-methyl-1-piperazinyl)nicotinamide were added under ice-cooling to 20 ml of fuming nitric acid and the mixture was stirred below -5° C. for 4 hrs. This mixture was poured into an aqueous sodium hydrogencarbonate solution, extracted with methylene chloride, washed with eater and a saturated sodium chloride solution, dried over anhydrous magnesium sulfate and concentrated. The concentrate was purified by silica gel column chromatography (chloroform:methanol=20:1) and recrystallized from acetone-hexane to give 2.80 g (42%) of the title compound. m.p.62°-64° C.