Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([CH3:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=[N:48][C:43]2[CH:44]=C[CH:46]=[N:47][C:42]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.CN1CC(N)C1>>[CH:1]1([N:6]2[CH2:12][C:11]([F:14])([CH3:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:48][CH:43]5[CH2:42][N:47]([CH3:46])[CH2:44]5)=[O:27])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(C)(F)C(=O)N2C
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN1CC(N)C1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Product: COc1cc(C(=O)NC2CN(C)C2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(C)(F)C(=O)N2C

Procedure:
The title compound was synthesized from 4-(9-cyclopentyl-7-fluoro-5,7-dimethyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acid as described in the General procedure for amide bond synthesis using HATU and 1-methylazetidin-3-amine hydrochloride. The final compound was purified by reverse phase HPLC and basified to give the free base. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.44-1.65 (m, 5H) 1.65-1.88 (m, 4H) 1.88-2.01 (m, 1H) 2.92 (dd, J=4.7, 2.4 Hz, 3H) 3.28 (s, 3H) 3.95 (s, 3H) 4.01-4.25 (m, 2H) 4.31-4.55 (m, 2H) 4.64-4.89 (m, 2H) 7.44-7.63 (m, 2H) 8.21 (d, J=8.3 Hz, 1H) 8.18 (s, 1H) 8.97-9.09 (m, 1H) 9.78 (br. s., 1H). [M+H] calc'd for C26H34FN7O3, 512. found 512.
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[NH2:8][C:9]1[CH:10]=[C:11]([CH:14]=[C:15]([N:18]2[CH2:23][CH2:22][C@@H:21]([NH2:24])[C@H:20]([O:25][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27])[CH2:19]2)[C:16]=1[Cl:17])[C:12]#[N:13]>ClCCl>[NH2:8][C:9]1[C:16]([Cl:17])=[C:15]([N:18]2[CH2:23][CH2:22][C@@H:21]([NH:24][C:5](=[O:7])[CH3:6])[C@H:20]([O:25][Si:26]([C:29]([CH3:31])([CH3:30])[CH3:32])([CH3:27])[CH3:28])[CH2:19]2)[CH:14]=[C:11]([C:12]#[N:13])[CH:10]=1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1CN(c2cc(C#N)cc(N)c2Cl)CC[C@H]1N
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Product: CC(=O)N[C@@H]1CCN(c2cc(C#N)cc(N)c2Cl)C[C@H]1O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.3 %

Procedure:
Acetic anhydride (0.011 mL, 0.119 mmol) was added to a solution of (+/−)-3-amino-5-((3R,4R)-4-amino-3-((tert-butyldimethylsilyl)oxy)piperidin-1-yl)-4-chlorobenzonitrile (Example 7, 41 mg, 0.108 mmol) in dichloromethane (5 mL) at 0° C. The reaction mixture was stirred at room temperature for 1 h. Solvent was evaporated and the crude product was purified by flash chromatography on silica gel using an automated ISCO system (24 g column, eluting with 0.5-5% methanol/dichloromethane). (+/−)-N-((3R,4R)-1-(3-amino-2-chloro-5-cyanophenyl)-3-((tert-butyldimethylsilyl)oxy)piperidin-4-yl)acetamide (44 mg) was obtained as a colorless oil which solidified upon standing.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)[CH:5]=[CH:4][N:3]=[N:2]1.[H-].[Na+].Cl[CH2:20][C:21]1[N:22]=[C:23](/[CH:26]=[CH:27]/[C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)[O:24][CH:25]=1.O>CN(C=O)C>[F:34][C:31]1[CH:32]=[CH:33][C:28](/[CH:27]=[CH:26]/[C:23]2[O:24][CH:25]=[C:21]([CH2:20][O:16][C:13]3[CH:12]=[CH:11][C:10]([CH2:9][CH2:8][CH2:7][CH2:6][N:1]4[CH:5]=[CH:4][N:3]=[N:2]4)=[CH:15][CH:14]=3)[N:22]=2)=[CH:29][CH:30]=1
Reactant: Oc1ccc(CCCCn2ccnn2)cc1
Reactant: Fc1ccc(/C=C/c2nc(CCl)co2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Fc1ccc(/C=C/c2nc(COc3ccc(CCCCn4ccnn4)cc3)co2)cc1
Yield: 87.6 %

Procedure:
In an argon atmosphere, 4-[4-(1H-1,2,3-triazol-1-yl)butyl]phenol (218 mg) and 65% oily sodium hydride (39 mg) were dissolved in DMF (5 ml) added thereto. With stirring under ice cooling, 4-(chloromethyl)-2-[(E)-2-(4-fluorophenyl)ethenyl]-1,3-oxazole (250 mg) was added, followed by stirring at room temperature for 3 hours. After water was added, the reaction mixture was extracted with ethyl acetate. The extract was washed with water and saturated saline and dried over sodium sulfate, after which it was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform-ethanol=24:1), after which it was recrystallized from ethyl acetate to yield the titled compound (368 mg) as colorless crystals.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:18]3[C:13](=[CH:14][C:15]([O:19][CH2:20][CH2:21][N:22]([CH3:24])[CH3:23])=[CH:16][CH:17]=3)[C:12](=[CH2:25])[C:11]([CH3:27])([CH3:26])[CH2:10]2)=[CH:5][CH:4]=1.[H][H]>C(O)C.[Pd]>[ClH:2].[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[C:18]3[C:13](=[CH:14][C:15]([O:19][CH2:20][CH2:21][N:22]([CH3:24])[CH3:23])=[CH:16][CH:17]=3)[CH:12]([CH3:25])[C:11]([CH3:26])([CH3:27])[CH2:10]2)=[CH:7][CH:8]=1
Reactant: [H][H]
Reactant: C=C1c2cc(OCCN(C)C)ccc2C(c2ccc(Cl)cc2)CC1(C)C
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CC1c2cc(OCCN(C)C)ccc2C(c2ccc(Cl)cc2)CC1(C)C

Procedure:
A solution of 4-(4-chlorophenyl)-2,2-dimethyl-7-(2-dimethylaminoethoxy)-1-methylidene tetralin hydrochloride (4 g) in ethanol (150 ml) was hydrogenated in the presence of 10% palladium on charcoal (0.4 g) until hydrogen uptake was complete. After filtration the solvent was removed in vacuo to give 4-(4-chlorophenyl)-1,2,2-trimethyl-7-(2-dimethylaminoethoxy)tetralin hydrochloride. Recrystallisation from ethanol-ether gave white prisms, m.p. 173°-6° (3.6 g, 90%).
Reaction SMILES: [CH3:1][Si](C=[N+]=[N-])(C)C.[NH2:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=1[N+:18]([O-:20])=[O:19])[C:12]([OH:14])=[O:13]>C(Cl)Cl.CO>[NH2:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=1[N+:18]([O-:20])=[O:19])[C:12]([O:14][CH3:1])=[O:13]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: Nc1cc(C(=O)O)ccc1[N+](=O)[O-]
Solvent: ClCCl
Solvent: CO
Product: COC(=O)c1ccc([N+](=O)[O-])c(N)c1
Temperature: 25 °C

Procedure:
(Trimethylsilyl)diazomethane (6 mL, 2M solution in hexanes) was added to a solution of 3-amino-4-nitro-benzoic acid in CH2Cl2 (25 mL) and methanol (25 mL). Stirred at room temperature until bubbling ceased. Concentrated under vacuum to provide 1.2 g of desired product. MS (DCI) m/e 197 (M+H)+.
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[F:7][S:8]([F:21])([F:20])([F:19])([F:18])[C:9]1[CH:17]=[CH:16]C(C(O)=O)=[CH:11][CH:10]=1.CN(C)C=O>ClC(Cl)C.ClCCl.CN(C)C=O>[F:7][S:8]([F:18])([F:19])([F:20])([F:21])[C:9]1[CH:10]=[CH:11][C:1]([C:2]([Cl:4])=[O:3])=[CH:16][CH:17]=1
Reactant: O=C(O)c1ccc(S(F)(F)(F)(F)F)cc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CC(Cl)Cl
Product: O=C(Cl)c1ccc(S(F)(F)(F)(F)F)cc1
Temperature: 45 °C
Yield: 100.6 %

Procedure:
Oxalyl chloride (1.53 g) was added to a stirred solution of 4-pentafluorosulphanylbenzoic acid (0.99 g) in dichloroethane. A solution of N,N-dimethylformamide in dichloromethane (3 ml of a solution prepared by the addition of 2 drops of N,N-dimethylformamide to 10 ml of dichloromethane) was added. After 15 minutes the solution was heated for a further 15 minutes at 45° C., and evaporated to dryness to give 4-pentafluorosulphanylbenzoyl chloride as an orange oil (1.07 g). This was used directly in the subsequent reaction stage.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[CH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.[N:21]([C:24]1[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=1)=[C:22]=[O:23]>CN(C=O)C>[C:27]1([CH3:30])[CH:28]=[CH:29][C:24]([NH:21][C:22]([N:18]2[CH2:19][CH2:20][CH:15]([C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][N:7]=3)[CH2:16][CH2:17]2)=[O:23])=[CH:25][CH:26]=1
Reactant: COc1cc2ncnc(C3CCNCC3)c2cc1OC
Reactant: Cc1ccc(N=C=O)cc1
Solvent: CN(C)C=O
Product: COc1cc2ncnc(C3CCN(C(=O)Nc4ccc(C)cc4)CC3)c2cc1OC
Yield: 84.2 %

Procedure:
A solution of 6,7-dimethoxy-4-piperidin-4-yl-quinazoline (20 mg, 0.0733 mmol), as prepared in Example 1d, in DMF (1 mL) was treated with 1-isocyanato-4-methyl-benzene (15 mg, 0.113 mmol) at RT overnight. The reaction was then partitioned between EtOAc (10 mL) and H2O (10 mL). The organic phase was dried over Na2SO4 and concentrated in vacuo. Purification by prep tlc (1:9 MeOH/DCM) afforded the title compound as a brown solid (25.1 mg, 84%). 1H NMR (300 MHz, CDCl3) δ 9.09 (s, 1H), 7.26-7.21 (m, 3H), 7.12 (m, 3H), 6.37 (br s, NH), 4.30-4.26 (m, 2H), 4.07 (s, 6H), 3.60 (m, 1H), 3.18 (m, 2H), 2.30 (s, 3H), 2.17 (m, 2H), 2.01-1.98 (m, 2H); LC/MS (ESI) calcd mass 406.2, found 407.3 [M+1]+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([OH:15])[CH:11]=2)[CH:6]=1)=[O:4].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:23][C:24]([O:26][CH3:27])=[O:25]>CC(C)=O.CCOC(C)=O>[CH3:1][O:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:15][CH2:23][C:24]([O:26][CH3:27])=[O:25])[CH:11]=2)[CH:6]=1)=[O:4]
Reactant: COC(=O)CBr
Reactant: COC(=O)c1ccc2cc(O)ccc2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: COC(=O)COc1ccc2cc(C(=O)OC)ccc2c1
Yield: 84.6 %

Procedure:
To a stirred solution of 6-hydroxy-2-naphthoic acid methyl ester (0.500 g, 2.47 mmol) in acetone (25 mL) at rt was added Cs2CO3 (0.886 g, 2.72 mmol) followed by methyl bromoacetate (0.257 mL, 2.72 mmol) dropwise. After 18 h at this temperature, it was diluted with EtOAc (200 mL). This layer was washed with 1 N HCl (20 mL), sat. aq. NaHCO3 (20 mL), and brine (20 mL) and then dried (MgSO4). After concentration, the residue was recrystallized from MeOH:H2O to afford the product (0.573 g, 85%) as a solid; 1H NMR (DMSO-d6) δ3.71 (s, 3H), 3.87 (s, 3H), 4.95 (s, 2H), 7.30 (dd, J=2.6, 8.9 Hz, 1H), 7.38 (d, J=2.4 Hz, 1H), 7.87 (d, J=8.7 Hz, 1H), 7.92 (dd, J=1.6, 8.6 Hz, 1H), 8.06 (d, J=9.1 Hz, 1H), 8.55 (s, 1H); mass spectrum [(+) ESI], m/z 275 (M+H)+.
Reaction SMILES: C(=O)(O)[O-:2].[Na+].[O-2:6].[Ce+3].[O-2:8].[O-2:9].[Ce+3].[NH2:11][C:12]1[CH:17]=[C:16]([NH2:18])[CH:15]=[CH:14][C:13]=1[CH3:19]>>[N+:11]([C:12]1[CH:17]=[C:16]([N+:18]([O-:2])=[O:9])[CH:15]=[CH:14][C:13]=1[CH3:19])([O-:8])=[O:6]
Reactant: Cc1ccc(N)cc1N
Reactant: O=C([O-])O
Reactant: [O-2]
Agent: [Ce+3]
Agent: [Na+]
Product: Cc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]

Procedure:
The catalyst of the present example is an Au/CeO2 (263.6 mg) which is subjected to further treatment consisting of impregnation with sodium bicarbonate (3.2 mg) in order to neutralize by doping the possible acid centers of the surface of the nanocrystalline cerium oxide. The carbamoylation reaction of the 2,4-diaminotoluene is carried out as described in Example 1 but using as a catalyst Au/(Na+)CEO2 (208.2 mg) whereby after 23 hrs of reaction was obtained a mixture wherein the conversion of 2,4-dinitrotoluene was 96%, being present the 2,4-diaminotoluene and the corresponding dicarbamate with a selectivity of 37 and 63%, respectively.
Reaction SMILES: [CH:1]1[C:13]2[C:12](=[O:14])[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([C:15]([Cl:17])=[O:16])[CH:10]=3)[C:5]=2[CH:4]=[CH:3][C:2]=1[C:18](Cl)=[O:19].[CH2:21]([OH:23])[CH3:22].[N:24]1([CH2:30][CH2:31][CH2:32][OH:33])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>C(Cl)(Cl)Cl>[ClH:17].[ClH:17].[N:24]1([CH2:30][CH2:22][CH2:21][O:23][C:18]([C:2]2[CH:3]=[CH:4][C:5]3[C:6]4[C:11](=[CH:10][C:9]([C:15]([O:33][CH2:32][CH2:31][CH2:30][N:24]5[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]5)=[O:16])=[CH:8][CH:7]=4)[C:12](=[O:14])[C:13]=3[CH:1]=2)=[O:19])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: CCO
Reactant: O=C(Cl)c1ccc2c(c1)C(=O)c1cc(C(=O)Cl)ccc1-2
Reactant: OCCCN1CCCCC1
Solvent: ClC(Cl)Cl
Product: Cl
Product: O=C(OCCCN1CCCCC1)c1ccc2c(c1)C(=O)c1cc(C(=O)OCCCN3CCCCC3)ccc1-2
Temperature: 25 °C

Procedure:
A suspension of 30.5 g (0.12 mole) of fluoren-9-one-2,7-dicarbonyl chloride in 1 liter of dry chloroform free from ethanol is stirred and treated with 37.5 g (0.26 mole) of 3-piperidino-1-propanol resulting in a mildly exothermic reaction. The resulting mixture is stirred and refluxed for two hours, cooled to room temperature, filtered, and the filtrate washed three times with 250 ml portions of saturated sodium bicarbonate solution. The chloroform solution is then washed with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate, and filtered. Most of the solvent is removed from the filtrate on a steam bath under vacuum, and the residue is dissolved in butanone. The solution is made acidic to Congo Red with ethereal HCl causing the product to precipitate as a yellow crystalline solid. The solid is filtered, recrystallized from butanone-methanol and dried to give bis(3-piperidinopropyl)-9-oxofluorene-2,7-dicarboxylate dihydrochloride, M.P. 293°-295° C. (dec.).
Reaction SMILES: [N:1]1[C:2]([C:10]2[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=2)[C:13]#[N:14])=[CH:3][N:4]2[C:9]=1[CH:8]=[CH:7][CH:6]=[N:5]2.[NH2:18][OH:19].Cl.CCN([CH2:26][CH3:27])CC.C(OC(=O)C)(=O)C>CCO.CN(C1C=CN=CC=1)C.C1COCC1>[CH3:27][C:26]1[O:19][N:18]=[C:13]([C:12]2[CH:11]=[C:10]([C:2]3[N:1]=[C:9]4[CH:8]=[CH:7][CH:6]=[N:5][N:4]4[CH:3]=3)[CH:17]=[CH:16][CH:15]=2)[N:14]=1
Reactant: CCN(CC)CC
Reactant: NO
Reactant: N#Cc1cccc(-c2cn3ncccc3n2)c1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCO
Solvent: CC(=O)OC(C)=O
Solvent: C1CCOC1
Product: Cc1nc(-c2cccc(-c3cn4ncccc4n3)c2)no1

Procedure:
A mixture of 0.5 mmol 3-(imidazo[1,2-b]pyridazin-2-yl)benzonitrile, 1 mmol NH2OH.HCl and 1 mmol Et3N in EtOH were stirred at reflux for 4 h then cooled. Excess of solvent was removed in vacuo to afford the crude product. Acetic anhydride (2 mmol) was added to the mixture solution of the crude product, THF (15 ml), and DMAP (cat.) at room temperature and then the mixture was heated to reflux for 12 h. The mixture was concentrated in vacuo and the crude product was purified by column chromatography on silica gel to give the 2-(3-(5-methyl-1,2,4-oxadiazol-3-yl)phenyl)imidazo[1,2-b]pyridazine.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]([O-:6])=[O:5].[Ca+2:7].[NH2:8][CH2:9][CH2:10][C:11]([O-:13])=[O:12].[CH3:14][C:15]1([CH3:22])[CH:20]([OH:21])[C:18](=[O:19])[O:17][CH2:16]1>CO>[CH3:14][C:15]([CH:20]([OH:21])[C:18]([NH:1][CH2:2][CH2:3][C:4]([O-:6])=[O:5])=[O:19])([CH2:16][OH:17])[CH3:22].[CH3:14][C:15]([CH:20]([OH:21])[C:18]([NH:8][CH2:9][CH2:10][C:11]([O-:13])=[O:12])=[O:19])([CH2:16][OH:17])[CH3:22].[Ca+2:7]
Reactant: CC1(C)COC(=O)C1O
Reactant: NCCC(=O)[O-]
Agent: [Ca+2]
Solvent: CO
Product: CC(C)(CO)C(O)C(=O)NCCC(=O)[O-]

Procedure:
reacting the anhydrous calcium beta-alaninate with dl-pantolactone in methanol at a temperature of from about 55° to about 65° C. for from about 6 to about 9 hours and therafter cooling and filtering the reaction product and removing methanol to obtain dl-calcium pantothenate.
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([N+:13]([O-:15])=[O:14])=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6]([O:8][CH3:9])=[O:7].[CH3:16][NH:17][CH3:18]>CO>[CH3:16][N:17]([CH2:2][C:3]1[C:4]([N+:13]([O-:15])=[O:14])=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6]([O:8][CH3:9])=[O:7])[CH3:18]
Reactant: COC(=O)c1cccc(CBr)c1[N+](=O)[O-]
Reactant: CNC
Solvent: CO
Product: COC(=O)c1cccc(CN(C)C)c1[N+](=O)[O-]
Reaction time: 8 h

Procedure:
Methyl 3-bromomethyl-2-nitrobenzoate (1.6 g) was dissolved in methanol (5 mL). Methanol solution (6 mL) of 2M dimethylamine was added thereto and stirred overnight. After removing the solvent, the residue was diluted with 1M hydrochloric acid and washed with ethyl acetate. The water layer was alkalized with sodium hydrate aqueous solution and extracted with ethyl acetate. The usual workup procedure was conducted to obtain methyl 3-dimethylaminomethyl-2-nitrobenzoate.
Reaction SMILES: CS[C:3](SC)=[CH:4][N+:5]([O-:7])=[O:6].[NH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.[NH3:16]>ClCC(Cl)(Cl)Cl>[NH2:16][C:3]([N:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)=[CH:4][N+:5]([O-:7])=[O:6]
Reactant: CSC(=C[N+](=O)[O-])SC
Reactant: C1CCNCC1
Reactant: N
Agent: ClCC(Cl)(Cl)Cl
Product: NC(=C[N+](=O)[O-])N1CCCCC1

Procedure:
16.5 grams of 1,1-bis-(methylthio)-2-nitroethene are dissol ved under hot conditions in 100 ml of tetrachloroethane, 8.5 grams of piperidine are added, the mixture is heated under reflux for 2 hours, is then cooled and anhydrous gaseous ammonia is added until saturated.
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[C:16](=[O:17])[C:15]3[C:10](=[N:11][CH:12]=[CH:13][CH:14]=3)[N:9]([C:18]3[CH:19]=[C:20]([C:24]4[CH:29]=[CH:28][C:27]([C:30]([OH:32])=[O:31])=[CH:26][CH:25]=4)[CH:21]=[CH:22][CH:23]=3)[CH:8]=2)=[O:6])[CH2:3][CH2:2]1.Br[C:34]1C=CC(C(OCC)=O)=C[CH:35]=1.C([O-])([O-])=O.[Na+].[Na+]>C(O)CC.CN(C=O)C.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>[CH:1]1([NH:4][C:5]([C:7]2[C:16](=[O:17])[C:15]3[C:10](=[N:11][CH:12]=[CH:13][CH:14]=3)[N:9]([C:18]3[CH:19]=[C:20]([C:24]4[CH:25]=[CH:26][C:27]([C:30]([O:32][CH2:34][CH3:35])=[O:31])=[CH:28][CH:29]=4)[CH:21]=[CH:22][CH:23]=3)[CH:8]=2)=[O:6])[CH2:2][CH2:3]1
Reactant: CCOC(=O)c1ccc(Br)cc1
Reactant: O=C(O)c1ccc(-c2cccc(-n3cc(C(=O)NC4CC4)c(=O)c4cccnc43)c2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCCO
Product: CCOC(=O)c1ccc(-c2cccc(-n3cc(C(=O)NC4CC4)c(=O)c4cccnc43)c2)cc1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
A mixture of NAPHTHYRIDINONE 3 (1 eq), ethyl 4-bromobenzoate (3 eq), Na2CO3 (3.5eq.; 2M in H2O), Pd(PPh3)4 (0.15eq.) in n-propanol-DMF (1:1, 0.1M) was stirred at 80° C. for 2 h. The mixture was cooled to rt, quenched with brine and diluted with EtOAc. The organic extracts were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was triturated in ether/EtOAc and then isolated by filtration to afford the title compound as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH2:14][P:15]([OH:18])(=[O:17])[OH:16])[C:9](=[O:19])[C:8](=[O:20])[NH:7]2)([O-])=O.C([O-])=O.[NH4+].O>CO.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH2:14][P:15]([OH:18])(=[O:16])[OH:17])[C:9](=[O:19])[C:8](=[O:20])[NH:7]2
Reactant: O=c1[nH]c2cc([N+](=O)[O-])ccc2n(CP(=O)(O)O)c1=O
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: O
Solvent: CO
Product: Nc1ccc2c(c1)[nH]c(=O)c(=O)n2CP(=O)(O)O
Yield: 74 %

Procedure:
300 mg of 1-(6-nitro-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-yl)methanephosphonic acid is dissolved in 60 mg of methanol and combined under nitrogen in succession with 50 mg of Pd/C (10%), 300 mg of ammonium formate, and 18 ml of water, and heated for one hour to 80° C. After cooling, the mixture is filtered off from the catalyst, the filtrate is concentrated by evaporation, and the residue is freeze-dried, thus obtaining 200 mg of 1-(6-amino-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-1-yl)methanephosphonic acid in the form of a white solid.
Reaction SMILES: CO[N:3]=[CH:4][CH:5]1[CH:11]([CH:12]=NOC)[CH:10]2[CH2:16][CH:6]1[CH2:7][N:8]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:9]2.F[C:25](F)(F)C(O)=O.C(OCC)(=O)C.C(=O)([O-])[O-].[Na+].[Na+]>ClC(Cl)C>[C:18]1([CH2:17][N:8]2[CH2:7][CH:6]3[CH2:16][CH:10]([C:11]4[C:5]3=[CH:4][N:3]=[CH:25][CH:12]=4)[CH2:9]2)[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: O=C(O)C(F)(F)F
Reactant: CON=CC1C2CC(CN(Cc3ccccc3)C2)C1C=NOC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CCOC(C)=O
Product: c1ccc(CN2CC3CC(C2)c2cnccc23)cc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 3-(phenylmethyl)-3-azabicyclo[3.2.1]octane-6,7-dicarbaldehye bis (O-methyloxime) (Preparation 33, 5.0 g, 15.2 mmol) in dichloroethane (150 ml) was added trifluoroacetic acid (17 ml) and the reaction mixture was stirred under nitrogen at room temperature for 20 min. The reaction mixture was heated under reflux for 2 h and then concentrated to give a brown oil. Ethyl acetate (100 ml) was added and the solution was treated with saturated sodium carbonate solution (70 ml) the layers were separated and the organic layer washed with brine and dried (Na2SO4) and concentrated to give an oil (4.0 g). The crude oil was purified by flash chromatography using silica gel eluting with ethyl acetate to give the title compound as an orange oil (1.93 g, 51%).
Reaction SMILES: [C:1]([C:4]1[C:13]([NH:14][C:15]([C:17](N)=[O:18])=O)=[CH:12][C:11]([O:20][CH3:21])=[C:10]2[C:5]=1[CH:6]=[CH:7][CH:8]=[N:9]2)(=[O:3])[CH3:2].[OH2:22].[CH3:23]N(C)C=O>>[CH3:23][O:22][C:17]([C:15]1[NH:14][C:13]2[C:4](=[C:5]3[C:10](=[C:11]([O:20][CH3:21])[CH:12]=2)[N:9]=[CH:8][CH:7]=[CH:6]3)[C:1](=[O:3])[CH:2]=1)=[O:18]
Reactant: CN(C)C=O
Reactant: O
Reactant: COc1cc(NC(=O)C(N)=O)c(C(C)=O)c2cccnc12
Product: COC(=O)c1cc(=O)c2c(cc(OC)c3ncccc32)[nH]1

Procedure:
2 g of anhydrous potassium tert.-butylate are added to a solution of 2.5 g of N-(5-acetyl-8-methoxyquinolin-6-yl)oxamide acid methyl ester in 50 ml of anhydrous N,N-dimethylformamide and the whole is heated, with the exclusion of water, for 10 hours at 130°. The solution is then allowed to cool and is evaporated to dryness in vacuo. The residue is treated in succession with 2 N acetic acid and water. By chromatographic purification on silica gel and fractionated crystallisation from N,N-dimethylformamide, the 6-methyoxy-1-oxo-1,4-dihydro-4,7-phenanthroline-3-carboxylic acid methyl ester having a melting point of 280° (with decomposition) is obtained.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][N:12]3[C:16]4=[N:17][C:18](/[C:21](=[N:23]/[O:24][CH2:25][CH2:26][N:27]5C(=O)C6C(=CC=CC=6)C5=O)/[CH3:22])=[CH:19][N:20]=[C:15]4[N:14]=[N:13]3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.O.NN>CO>[NH2:27][CH2:26][CH2:25][O:24]/[N:23]=[C:21](/[C:18]1[N:17]=[C:16]2[N:12]([CH2:11][C:7]3[CH:6]=[C:5]4[C:10](=[CH:9][CH:8]=3)[N:1]=[CH:2][CH:3]=[CH:4]4)[N:13]=[N:14][C:15]2=[N:20][CH:19]=1)\[CH3:22]
Reactant: C/C(=N\OCCN1C(=O)c2ccccc2C1=O)c1cnc2nnn(Cc3ccc4ncccc4c3)c2n1
Agent: NN
Solvent: O
Solvent: CO
Product: C/C(=N\OCCN)c1cnc2nnn(Cc3ccc4ncccc4c3)c2n1
Yield: 36.9 %

Procedure:
To a solution of (E)-2-(2-(1-(1-(quinolin-6-ylmethyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-6-yl)ethylideneaminooxy)ethyl)isoindoline-1,3-dione (70 mg, 0.142 mmol) in MeOH (10 mL) was added hydrazine monohydrate (35.6 mg, 0.711 mmol). The solution was heated at reflux for 30 h and concentrated in vacuo. The crude was purified by column chromatography to afford 19 mg (37%) of the title compound. 1H-NMR (400 MHz, DMSO-d6+D2O) δ ppm 9.35 (s, 1H), 8.98 (s, 1H), 8.35 (d, 1H), 8.02 (s, 1H), 8.01 (d, 1H), 7.81 (d, 1H), 7.53 (m, 1H), 6.20 (s, 2H), 4.47 (s, 2H), 3.22 (s, 2H), 2.34 (s, 3H). LCMS (method B): [MH]+=363, tR=1.57 min.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:9][C:10]1[C:11]([Cl:27])=[N:12][C:13]([N:17]2[CH2:22][CH2:21][C:20]3[CH:23]=[CH:24][S:25][C:19]=3[CH:18]2[CH3:26])=[N:14][C:15]=1[CH3:16]>CN(C)C=O>[ClH:27].[CH3:9][C:10]1[C:11]([N:2]([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[CH3:1])=[N:12][C:13]([N:17]2[CH2:22][CH2:21][C:20]3[CH:23]=[CH:24][S:25][C:19]=3[CH:18]2[CH3:26])=[N:14][C:15]=1[CH3:16]
Reactant: Cc1nc(N2CCc3ccsc3C2C)nc(Cl)c1C
Reactant: CNc1ccccc1
Solvent: CN(C)C=O
Product: Cc1nc(N2CCc3ccsc3C2C)nc(N(C)c2ccccc2)c1C
Product: Cl
Yield: 20 %

Procedure:
After N-methylaniline(0.5 ml, 4 mmol) was added to a mixture solution of 5,6-dimethyl-2-(7-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-6-yl)-4-chloropyrimidine(0.64 g, 2 mmol) and dimethylformamide(10 ml), 0.16 g of the titled compound was obtained in accordance with the same procedure as in Step 4 of Example 57.