Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][P:4]([C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[N:21]=[C:20]([NH:22][CH2:23][C:24]3[C:25]([N:30]([CH3:35])[S:31]([CH3:34])(=[O:33])=[O:32])=[N:26][CH:27]=[CH:28][CH:29]=3)[C:19]([C:36]([F:39])([F:38])[F:37])=[CH:18][N:17]=2)=[CH:11][CH:10]=1)(=[O:8])[O:5]CC)C.Cl>>[CH3:35][N:30]([S:31]([CH3:34])(=[O:33])=[O:32])[C:25]1[C:24]([CH2:23][NH:22][C:20]2[C:19]([C:36]([F:39])([F:37])[F:38])=[CH:18][N:17]=[C:16]([NH:15][C:12]3[CH:11]=[CH:10][C:9]([P:4](=[O:3])([OH:5])[OH:8])=[CH:14][CH:13]=3)[N:21]=2)=[CH:29][CH:28]=[CH:27][N:26]=1
Reactant: CCOP(=O)(OCC)c1ccc(Nc2ncc(C(F)(F)F)c(NCc3cccnc3N(C)S(C)(=O)=O)n2)cc1
Agent: Cl
Product: CN(c1ncccc1CNc1nc(Nc2ccc(P(=O)(O)O)cc2)ncc1C(F)(F)F)S(C)(=O)=O

Procedure:
Also prepared by heating diethyl[4-({4-[({2-[methyl(methylsulfonyl)amino]pyridin-3-yl}methyl)amino]-5-(trifluoromethyl)pyrimidin-2-yl}amino)phenyl]phosphonate (Example 2) at 100° C. with an excess of concentrated hydrochloric acid for 6 h. The reaction mixture was concentrated in vacuo and the residue purified by preparative HPLC (MDP) afford the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[C:10]([F:13])([F:12])[F:11])[CH:5]=O.[CH3:14][C:15]([S@@:18]([NH2:20])=[O:19])([CH3:17])[CH3:16]>C(Cl)Cl.S([O-])([O-])(=O)=O.[Cu+2]>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[C:10]([F:13])([F:12])[F:11])/[CH:5]=[N:20]/[S@:18]([C:15]([CH3:17])([CH3:16])[CH3:14])=[O:19]
Reactant: CC(C)(C)[S@@](N)=O
Reactant: O=Cc1ccc(C(F)(F)F)c(F)c1
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: ClCCl
Product: CC(C)(C)[S@](=O)/N=C/c1ccc(C(F)(F)F)c(F)c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of 3-fluoro-4-(trifluoromethyl)benzaldehyde (5.7 g, 29.7 mmol) in DCM (60 mL) was added (S)-2-methylpropane-2-sulfinamide (7.19 g, 59.3 mmol) and copper (II) sulfate (18.94 g, 119 mmol). The suspension was stirred at rt under N2 for 20 h. The suspension was then filtered through Celite® brand filter agent, and the solids were washed with DCM (2×20 mL). The filtrates were concentrated and purified by ISCO (120 g, SiO2, 10-50% EtOAc/hexanes) to give (S,E)-N-(3-fluoro-4-(trifluoromethyl)benzylidene)-2-methylpropane-2-sulfinamide as a white solid.
Reaction SMILES: Br[C:2]1[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][C:3]=1[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]([CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)[C:15]3[CH:23]=[CH:24][C:25]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:26][C:14]=3[N:13]=2)=[CH:8][CH:7]=1.[Cl:37][C:38]1[CH:43]=[CH:42][C:41](B(O)O)=[CH:40][CH:39]=1.C(=O)([O-])O.[Na+].C(Cl)(Cl)Cl>COCCOC.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>[Cl:37][C:38]1[CH:43]=[CH:42][C:41]([C:2]2[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][C:3]=2[CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([C:12]3[N:16]([CH:17]4[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]4)[C:15]4[CH:23]=[CH:24][C:25]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:26][C:14]=4[N:13]=3)=[CH:8][CH:7]=2)=[CH:40][CH:39]=1
Reactant: CCOC(=O)c1ccc2c(c1)nc(-c1ccc(OCc3cc(Cl)ccc3Br)cc1)n2C1CCCCC1
Reactant: OB(O)c1ccc(Cl)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: ClC(Cl)Cl
Solvent: COCCOC
Product: CCOC(=O)c1ccc2c(c1)nc(-c1ccc(OCc3cc(Cl)ccc3-c3ccc(Cl)cc3)cc1)n2C1CCCCC1
Yield: 85.1 %

Procedure:
Ethyl 2-[4-(2-bromo-5-chlorobenzyloxy)phenyl]-1-cyclohexylbenzimidazole-5-carboxylate (49 g) obtained in Example 4, 4-chlorophenylboronic acid (18 g) and tetrakis(triphenylphosphine)palladium (10 g) were suspended in 1,2-dimethoxyethane (600 ml). Saturated aqueous sodium hydrogencarbonate solution (300 ml) was added and the mixture was refluxed under heating for 2 hr. Chloroform was added to the reaction mixture. The organic layer was washed successively with saturated aqueous sodium hydrogencarbonate solution, water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (developing solvent, chloroform:ethyl acetate=97:3). Ethyl acetate and diisopropyl ether were added to the resulting oil for crystallization and the resulting crystals were collected by filtration to give the title compound (44 g, yield 85%).
Reaction SMILES: [C:1]1([CH:7]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][NH:18][C:19]3[CH:20]=[CH:21][C:22]4[N:23]([C:25](=[O:28])[NH:26][N:27]=4)[N:24]=3)[CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].[C:41]([O:47][CH2:48]Cl)(=[O:46])[C:42]([CH3:45])([CH3:44])[CH3:43]>CN(C)C=O>[C:29]1([CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[O:8][CH:9]2[CH2:10][CH2:11][N:12]([CH2:15][CH2:16][CH2:17][NH:18][C:19]3[CH:20]=[CH:21][C:22]4[N:23]([C:25](=[O:28])[N:26]([CH2:48][O:47][C:41](=[O:46])[C:42]([CH3:45])([CH3:44])[CH3:43])[N:27]=4)[N:24]=3)[CH2:13][CH2:14]2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: O=c1[nH]nc2ccc(NCCCN3CCC(OC(c4ccccc4)c4ccccc4)CC3)nn12
Reactant: CC(C)(C)C(=O)OCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)C(=O)OCn1nc2ccc(NCCCN3CCC(OC(c4ccccc4)c4ccccc4)CC3)nn2c1=O
Temperature: 25 °C
Reaction time: 15 h

Procedure:
0.560 g of 6-[3-[4-(diphenylmethoxy)piperidino]propylamino][1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one was suspended in 3 ml of N,N-dimethylformamide; 0.210 g of potassium carbonate and 0.220 ml of chloromethyl pivalate were added, followed by stirring at room temperature for 15 hours. After ice water was added, the reaction mixture was extracted with ethyl acetate; the extract was washed with saline and dried over magnesium sulfate. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography and eluted with ethyl acetate-methanol-triethylamine (185:15:2). The desired fraction was collected and concentrated; the crystal obtained was filtered, washed with diethyl ether, and dried, to yield 0.39 g of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[C:19]([N+:21]([O-])=O)[CH:18]=[CH:17][C:4]=1[O:5][CH2:6][CH2:7][N:8]1[CH2:13][CH2:12][CH:11]([C:14]([NH2:16])=[O:15])[CH2:10][CH2:9]1.ClCCl.CO.N>>[NH2:21][C:19]1[CH:18]=[CH:17][C:4]([O:5][CH2:6][CH2:7][N:8]2[CH2:13][CH2:12][CH:11]([C:14]([NH2:16])=[O:15])[CH2:10][CH2:9]2)=[C:3]([O:2][CH3:1])[CH:20]=1
Reactant: COc1cc([N+](=O)[O-])ccc1OCCN1CCC(C(N)=O)CC1
Agent: N
Solvent: CO
Solvent: ClCCl
Product: COc1cc(N)ccc1OCCN1CCC(C(N)=O)CC1

Procedure:
Prepared analogously to Example 3.1.b. from 1 g (3.1 mmol) of 1-[2-(2-methoxy-4-nitrophenoxy)ethyl]piperidine-4-carboxylic acid amide. Yield: 0.8 g (88% of theory); C15H23N3O3 (M=298.38); calc.: molecular ion peak (M+H)+: 294; found: molecular ion peak (M+H)+: 294; Rf value: 0.3 (silica gel, dichloromethane/methanol/ammonia (9:1:0.1)).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[S:10])=[CH:4][CH:3]=1.[NH2:11][C:12]1[CH:17]=[C:16]([NH2:18])[CH:15]=[CH:14][C:13]=1[CH3:19]>O1CCOCC1>[CH3:19][C:13]1[CH:14]=[CH:15][C:16]([NH:18][C:9]([NH:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)=[S:10])=[CH:17][C:12]=1[NH:11][C:9]([NH:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)=[S:10]
Reactant: S=C=Nc1ccc(Cl)cc1
Reactant: Cc1ccc(N)cc1N
Solvent: C1COCCO1
Product: Cc1ccc(NC(=S)Nc2ccc(Cl)cc2)cc1NC(=S)Nc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A solution of 4-chlorophenylisothiocyanate (1.39 g, 8.20 mmol) in dry dioxane (20 mL) is added dropwise, under nitrogen atmosphere, to a solution of 2,4-diaminotoluene (0.5 g, 4.10 mmol) in dry dioxane (20 mL). After 72 hours of stirring at room temperature the mixture is heated to 80° C. for 6 hours, and the solvent is eliminated under reduced pressure. The oily residue obtained is stirred with IsprOH (25 mL) for 4 hours. The white solid that precipitates is filtered and washed with n-hexane (3×25 mL) and ethyl ether (3×25 mL). The title compound is obtained as white powder. mp: 93-95° C.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[C:16]2[C:7](=[CH:8][C:9]3[CH2:10][CH2:11][CH2:12][N:13]([CH2:17][CH2:18]C)[C:14]=3[CH:15]=2)[NH:6][C:5](=[O:20])[CH:4]=1.C(=O)C>>[F:22][C:2]([F:1])([F:21])[C:3]1[C:16]2[C:7](=[CH:8][C:9]3[CH2:10][CH2:11][CH2:12][N:13]([CH2:17][CH3:18])[C:14]=3[CH:15]=2)[NH:6][C:5](=[O:20])[CH:4]=1
Reactant: CCCN1CCCc2cc3[nH]c(=O)cc(C(F)(F)F)c3cc21
Agent: CC=O
Product: CCN1CCCc2cc3[nH]c(=O)cc(C(F)(F)F)c3cc21

Procedure:
This compound was prepared in a similar fashion as that described in Example 84 from Compound 192 (Structure 33 of Scheme VI, where R1═H, n=1) and acetaldehyde. 1H NMR (400 MHz, CDCl3) 11.23 (br. s, 1H), 7.07 (s, 1H), 7.00 (s, 1H), 6.82 (s, 1H), 3.39 (q, 2H, J=7.1), 3.31 (t, 2H, J=5.6), 2.88 (t, 2H, J=6.4), 1.98 (m, 2H), 1.18 (t, 3H, J=7.1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:28]2[CH:29]=[C:30]3[C:35](=[CH:36][CH:37]=2)[N:34]([CH3:38])[C:33](=[O:39])[CH:32]=[C:31]3[C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)([OH:27])[C:9]2[N:10]=[C:11]([Si](CC)(CC)CC)[N:12]([S:14]([N:17]([CH3:19])[CH3:18])(=[O:16])=[O:15])[CH:13]=2)=[CH:4][CH:3]=1.[NH4+].[OH-]>S(=O)(=O)(O)O.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:28]2[CH:29]=[C:30]3[C:35](=[CH:36][CH:37]=2)[N:34]([CH3:38])[C:33](=[O:39])[CH:32]=[C:31]3[C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)([OH:27])[C:9]2[N:10]=[CH:11][N:12]([S:14]([N:17]([CH3:18])[CH3:19])(=[O:15])=[O:16])[CH:13]=2)=[CH:4][CH:3]=1
Reactant: CC[Si](CC)(CC)c1nc(C(O)(c2ccc(Cl)cc2)c2ccc3c(c2)c(-c2ccccc2)cc(=O)n3C)cn1S(=O)(=O)N(C)C
Agent: O=S(=O)(O)O
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: CN(C)S(=O)(=O)n1cnc(C(O)(c2ccc(Cl)cc2)c2ccc3c(c2)c(-c2ccccc2)cc(=O)n3C)c1
Temperature: 110 °C
Yield: 11.2 %

Procedure:
A mixture of intermediate (3-a) (26 g) in sulfuric acid (2.5 ml) and water (250 ml) was stirred and heated at 110° C. for 2 hours. The mixture was poured into ice, basified with NH4OH and extracted with DCM. The organic layer was dried (MgSO4), filtered off and evaporated till dryness. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2 /CH3OH/NH4OH 99/1/0.2). The pure fractions were collected and evaporated, yielding 2.4 g (11%) of (±)-4-[(4-chlorophenyl)(1,2-dihydro-1-methyl-2-oxo-4-phenyl-6-quinolinyl)hydroxymethyl]-N,N-dimethyl-1H-imidazole-1-sulfonamide (interm. 3-b).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:30]=[CH:31][CH:32]=1)[CH2:5][NH:6][C:7]([C:9]1O[CH:11]=[C:12]([CH:24]([OH:29])[C:25]([CH3:28])([CH3:27])[CH3:26])[C:13](=[O:23])[C:14]=1[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:8].C(O)C.[CH3:36][O:37][CH:38]([O:41][CH3:42])[CH2:39][NH2:40]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:30]=[CH:31][CH:32]=1)[CH2:5][NH:6][C:7]([C:9]1[N:40]([CH2:39][CH:38]([O:41][CH3:42])[O:37][CH3:36])[CH:11]=[C:12]([CH:24]([OH:29])[C:25]([CH3:28])([CH3:27])[CH3:26])[C:13](=[O:23])[C:14]=1[O:15][CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)=[O:8]
Reactant: CC(C)(C)C(O)c1coc(C(=O)NCc2cccc(Cl)c2)c(OCc2ccccc2)c1=O
Reactant: COC(CN)OC
Solvent: CCO
Solvent: C1CCOC1
Product: COC(Cn1cc(C(O)C(C)(C)C)c(=O)c(OCc2ccccc2)c1C(=O)NCc1cccc(Cl)c1)OC
Temperature: 60 °C
Reaction time: 24 h

Procedure:
To a solution of 3-benzyloxy-5-(1-hydroxy-2,2-dimethylpropyl)-4-oxo-4H-pyran-2-carboxylic acid 3-chlorobenzylamide (0.22 g) in tetrahydrofuran (1.5 ml)-ethanol (1.5 ml) was added aminoacetaldehyde dimethyl acetal (0.16 ml) and the mixture was stirred at 60° C. for 24 hr. The solvent was evaporated and purified by silica gel column chromatography (ethyl acetate:hexane=1:1-ethyl acetate) to give 3-benzyloxy-1-(2,2-dimethoxyethyl)-5-(1-hydroxy-2,2-dimethylpropyl)-4-oxo-1,4-dihydropyridine-2-carboxylic acid 3-chlorobenzylamide (198 mg).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[C:4]1[CH:9]=[CH:8][C:7]([Cl:10])=[C:6]([N:11]2[C:16]([CH3:17])=[CH:15][C:14]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=3[F:27])=[CH:13][C:12]2=[O:28])[CH:5]=1.[Br:30]NC(=O)CCC(N)=O>C(#N)C>[Br:30][C:13]1[C:12](=[O:28])[N:11]([C:6]2[CH:5]=[C:4]([CH:9]=[CH:8][C:7]=2[Cl:10])[C:3]([O:2][CH3:1])=[O:29])[C:16]([CH3:17])=[CH:15][C:14]=1[O:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=1[F:27]
Reactant: NC(=O)CCC(=O)NBr
Reactant: COC(=O)c1ccc(Cl)c(-n2c(C)cc(OCc3ccc(F)cc3F)cc2=O)c1
Solvent: CC#N
Product: COC(=O)c1ccc(Cl)c(-n2c(C)cc(OCc3ccc(F)cc3F)c(Br)c2=O)c1
Yield: 66 %

Procedure:
methyl 3-[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-4-chlorobenzoate was prepared by reacting methyl-4-chloro-3-[4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]benzoate (2.3 g, 5.47 mmol) with N-bromosuccinamide (0.97 g, 5.47 mmol) in acetonitrile (10 mL) at 0° C., using a similar procedure as described in step 3 of Example 465, to give 1.80 g (66.2%) of the desired product. 1H NMR (400 MHz, DMSO-d6) δ 8.06-8.03 (m, 2H), 7.86 (d, J=9.70 Hz, 1H), 7.68 (q, J=7.62, 1H), 7.34 (dt, J=10.07, 2.46 Hz, 1H), 7.17 (dt,J=8.72, 2.90 Hz, 1H), 6.73 (s, 1H), 5.33 (s, 2H), 3.85 (s, 3H), 1.91 (s, 3H). ES-MS m/z 495.9757 (M−H calcd for C21H14BrClF2NO4, requires 495.9795).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][C@H:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:13][C@H:9]1[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:24]1([CH2:34][NH2:35])[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26][CH:25]=1>>[C:24]1([CH2:34][NH:35][C:10](=[O:12])[C@@H:9]2[CH2:13][C@@H:14]([O:16][CH2:17][C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH2:15][N:8]2[C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:7])[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26][CH:25]=1
Reactant: NCc1cccc2ccccc12
Reactant: CC(C)(C)OC(=O)N1C[C@H](OCc2ccccc2)C[C@H]1C(=O)O
Product: CC(C)(C)OC(=O)N1C[C@H](OCc2ccccc2)C[C@H]1C(=O)NCc1cccc2ccccc12

Procedure:
The title compound was prepared using the procedure in Example 1 step H using N-t-butoxycarbonyl-4(R)-benzyloxyproline and naphth-1-ylmethylamine.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([N:10]2[CH2:14][CH2:13][N:12]=[C:11]2SC)=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[NH2:17][N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1>>[N:18]1([N:17]2[C:2]3[N:3]=[CH:4][CH:5]=[CH:6][C:7]=3[C:8](=[O:9])[N:10]3[CH2:14][CH2:13][N:12]=[C:11]23)[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1
Reactant: NN1CCOCC1
Reactant: CSC1=NCCN1C(=O)c1cccnc1Cl
Product: O=C1c2cccnc2N(N2CCOCC2)C2=NCCN12
Temperature: 160 °C
Yield: 51.6 %

Procedure:
A mixture of 5.00 g (19.5 mmoles) of the product of Example 12 and 6.40 g (62.6 mmoles) of N-aminomorpholine was heated in an oil bath at 160° C. for 1 hour. The resulting mixture was cooled and partitioned between methylene chloride and water. The organic layer was dried (sodium sulfate) and concentrated. The crystalline residue was triturated with hexane. The resulting solid was collected to give 2.75 g of 2,10-dihydro-10-(4-morpholinyl)imidazo[1,2-a]pyrido[2,3-d]pyrimidin-5(3H)-one. Melting point 225°-226° C. Total yield 52%. This compound exhibits the following formula: ##STR9##
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([OH:11])=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[Br:12][C:13]1[CH:14]=[C:15]([N:19]=[C:20]=[O:21])[CH:16]=[CH:17][CH:18]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CN(C)C=O.O>[N:1]1[C:10]2[C:5](=[CH:6][C:7]([O:11][C:20](=[O:21])[NH:19][C:15]3[CH:16]=[CH:17][CH:18]=[C:13]([Br:12])[CH:14]=3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: Oc1ccc2ncccc2c1
Reactant: O=C=Nc1cccc(Br)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Nc1cccc(Br)c1)Oc1ccc2ncccc2c1

Procedure:
A mixture of quinolin-6-ol (0.29 g, 2 mmol), 3-bromo-phenyl isocyanate (0.47 g., 2.4 mmol), potassium carbonate 0.28 g. (0.28 g. 2 mmol) and potassium iodide (0.32 g.) in dry dimethylformamide (2 ml) was heated at 80° C. for 20 hours. The reaction mixture was diluted with water (5 ml), extracted with ethyl acetate (2×5 ml) and dried over sodium sulphate. The combined ethyl acetate fractions were concentrated under vaccum. The residue was washed with methanol (2×3 ml) to give 1d, yield: 0.34 g. (49.5%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([Cl:9])[N:3]=1.[OH-].[NH4+:11]>CC(C)=O>[NH2:11][C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([Cl:9])[N:3]=1
Reactant: [NH4+]
Reactant: Clc1nc(Cl)nc(Cl)n1
Agent: [OH-]
Solvent: CC(C)=O
Product: Nc1nc(Cl)nc(Cl)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2,4,6-Trichloro-1,3,5-triazine (XVIII) (10.0 g, 55 mmol) was dissolved in acetone (80 mL) and poured into ice-water (80 mL) to form a very fine suspension. To this mixture, 1 N ammonium hydroxide solution (108 mL, 109.4 mmol) was added at 0° C. The reaction was stirred for 30 min at ambient temperature and for additional 60 min at 25° C. The precipitate was filtered off, washed with water (3×25 mL). After drying over calcium chloride under high vacuum, 6-amino-2,4-dichloro-[1,3,5]triazine (XXXVII) was isolated as white powder (7.4 g, 82% yield). LCMS (ESI) m/z=165 (M+H)+.
Reaction SMILES: [H-].[Na+].[C:3]1([C:9]2[N:14]=[C:13]3[N:15]=[C:16]([NH2:19])[CH:17]=[CH:18][C:12]3=[N:11][CH:10]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:20]([N:23]=[C:24]=[S:25])[CH:21]=[CH2:22]>CN(C)C=O>[CH2:20]([NH:23][C:24]([NH:19][C:16]1[CH:17]=[CH:18][C:12]2[C:13]([N:15]=1)=[N:14][C:9]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1)=[CH:10][N:11]=2)=[S:25])[CH:21]=[CH2:22]
Reactant: C=CCN=C=S
Reactant: Nc1ccc2ncc(-c3ccccc3)nc2n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCNC(=S)Nc1ccc2ncc(-c3ccccc3)nc2n1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
0.246 g of sodium hydride (6.14 mmol) is introduced into 5 ml of anhydrous dimethylformamide under nitrogen as protective gas. The mixture is cooled to 0° C. in an ice bath. 1.05 g of 3-phenylpyrido[2,3-b]pyrazin-6-ylamine (4.72 mmol) are dissolved in 5 ml of anhydrous dimethylformamide and added dropwise. The cooling bath is removed, and the mixture is left to stir at RT for 30 minutes. The mixture is then cooled to 0° C. again in the ice bath, and 0.469 g of allyl isothiocyanate (4.72 mmol), dissolved in 4 ml of anhydrous dimethylformamide, is added dropwise. After the addition is complete, the cooling bath is removed, and the mixture is then left to stir at room temperature for 1.5 hours. For working up, the mixture is poured into about 250 ml of distilled water, and the precipitated orange solid is filtered off with suction. Purification by column chromatography several times (mobile phases dichloromethane/methanol mixtures) and subsequent purification by preparative HPLC afford a yellow solid.
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[CH2:13][CH2:12][CH2:11][C:10](=O)[C:9]2[CH:15]=[CH:16][C:17]([Cl:19])=[CH:18][C:8]1=2)=[O:6])([CH3:3])[CH3:2].Cl.[NH2:21][OH:22].C([O-])(=O)C.[Na+]>CCO.O>[CH:1]([O:4][C:5]([N:7]1[CH2:13][CH2:12][CH2:11][C:10](=[N:21][OH:22])[C:9]2[CH:15]=[CH:16][C:17]([Cl:19])=[CH:18][C:8]1=2)=[O:6])([CH3:3])[CH3:2]
Reactant: CC(C)OC(=O)N1CCCC(=O)c2ccc(Cl)cc21
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC(C)OC(=O)N1CCCC(=NO)c2ccc(Cl)cc21
Temperature: 60 °C
Yield: 96.1 %

Procedure:
To a solution of 8-Chloro-5-oxo-2,3,4,5-tetrahydro-benzo[b]azepine-1-carboxylic acid isopropyl ester (3.40 g, 12.1 mmole) in EtOH/H2O (96.0 ml/24.0 ml) was added hydroxylamine hydrochloride (8.39 g, 121 mmole) followed by sodium acetate (9.93 g, 121 mmole). The reaction was heated under 60° C. for 3 hours. The mixture was partitioned between ethyl acetate (100 ml) and 1.00N HCl (100 ml). After separated the two layers, the aqueous layer was extracted with more acetate (2×100 ml). The combined organics washed with NaHCO3 (aq) and followed by brine (2×200 ml). Dried over Na2SO4, filtered and concentrated to provide the crude product (3.45 g, 96%), which was used directly for the next step without further purification. MS (ES+): 297 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[CH2:7][CH2:6][CH2:5][C:4]=2[C:3]=1[OH:11].[Na].[C:13]1([CH:19]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[N:20]2[CH2:23][CH:22](OS(C)(=O)=O)[CH2:21]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.S([O-])(=O)(=O)C>CC(C)CC(=O)C>[Cl:1][C:2]1[C:3]([O:11][CH:22]2[CH2:23][N:20]([CH:19]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:21]2)=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][CH2:6][CH2:5]2
Reactant: Oc1c(Cl)ccc2c1CCC2
Reactant: CS(=O)(=O)OC1CN(C(c2ccccc2)c2ccccc2)C1
Agent: CS(=O)(=O)[O-]
Agent: [Na]
Solvent: CC(=O)CC(C)C
Product: Clc1ccc2c(c1OC1CN(C(c3ccccc3)c3ccccc3)C1)CCC2
Temperature: 120 °C
Reaction time: 64 h
Yield: 91.4 %

Procedure:
2 g of 5-chloro-2,3-dihydro-1H-inden-4-ol were stirred in 75 ml of a 2N sodium hydroxyde solution for 1 hour. To the clear solution were added 75 ml of 4-methyl-2-pentanone and 3.76 g of 1-(diphenylmethyl)-3-methanesulfonyloxy-azetidine and the mixture was heated in an oil bath at 120° C. for 3.5 hours. Then another 2 g of mesylate were added and heating was continued for 64 hours. The upper layer was separated and washed with water. Evaporation in vacuo and chromatography with toluene/ethyl acetate (95:5) gave 4.22 g of 3-[(5-chloro-2,3-dihydro-1H-inden-4-yl)oxy]-1-(diphenylmethyl )-azetidine as a clear oil that solidified spontaneous. M.S. (C.I.) (M/Z): 391 [M+H]+.
Reaction SMILES: S(Cl)(Cl)=O.[CH2:5]([S:8][C:9]1[C:10]([S:17]([NH:20][C:21]([CH3:24])([CH3:23])[CH3:22])(=[O:19])=[O:18])=[C:11]([C:14]([OH:16])=[O:15])[S:12][CH:13]=1)[CH2:6][CH3:7].[CH3:25]O>>[CH2:5]([S:8][C:9]1[C:10]([S:17]([NH:20][C:21]([CH3:23])([CH3:22])[CH3:24])(=[O:19])=[O:18])=[C:11]([C:14]([O:16][CH3:25])=[O:15])[S:12][CH:13]=1)[CH2:6][CH3:7]
Reactant: CCCSc1csc(C(=O)O)c1S(=O)(=O)NC(C)(C)C
Reactant: CO
Solvent: O=S(Cl)Cl
Product: CCCSc1csc(C(=O)OC)c1S(=O)(=O)NC(C)(C)C
Temperature: -10 °C

Procedure:
Thionyl chloride (2.3 mL) was added dropwise to 110 mL methanol cooled to -10° C. Next 10.4 g 4-propylthio-3-(N-(1,1-dimethylethyl)aminosulfonyl)-2-thiophenecarboxylic acid was added in one portion. The solution was warmed to reflux for 6 hours, then cooled to -45° C., and the product precipitated in sufficiently pure form for the purposes of this invention; yield 8.45 g; m.p. 93°-98° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[O:11][C:10]([CH:12]=O)=[CH:9][CH:8]=2)[CH:2]=1.[CH3:14][NH:15][CH3:16].Cl.C([BH3-])#N.[Na+]>CO.O1CCOCC1>[CH3:14][N:15]([CH3:16])[CH2:12][C:10]1[O:11][C:7]([C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)=[CH:8][CH:9]=1
Reactant: O=Cc1ccc(-c2cccnc2)o1
Reactant: CNC
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CO
Product: CN(C)Cc1ccc(-c2cccnc2)o1
Temperature: 25 °C
Reaction time: 48 h
Yield: 36.7 %

Procedure:
To a solution of 23 (54 mg, 0.31 mmol) was added a solution of dimethylamine (2.9 M, 0.65 mL, 1.89 mmol) in anhydrous CH3OH, a solution of HCl (4.0 M, 0.16 mL, 0.63 mmol) in anhydrous 1,4-dioxane and sodium cyanoborohydride (20 mg, 0.31 mmol). The flask was purged with argon and stirred under an atmosphere of argon at room temperature for 48 h. The solution was adjusted to pH 2 with conc. HCl and the solvent was removed in vacuo. The residue was dissolved in water, washed with Et2O (3×10 mL), adjusted to pH 10 with NaOH(aq) (10 N), extracted with Et2O (3×20 mL), dried (Na2SO4), filtered and the solvent was removed in vacuo. The crude material was chromatographed on silica gel (CH3OH/CHCl3, 5/95, Rf=0.2) to afford the title compound 43 (23 mg, 37% yield) as a yellow oil: 1H NMR (CDCl3) δ 8.91 (m, 1H), 8.46 (m, 1H), 7.94 (m, 1H), 7.28 (m, 1H), 6.68 (d, J=3.3 Hz, 1H), 6.32 (d, J=3.4 Hz, 1H), 2.31 (s, 6H); LRMS (ESI) m/z calcd for C12H15N2O [M+H]+ 203. found 203; m/z calcd for C10H8NO [M−N(CH3)2]+ 158. found 158; HRMS (ESI) m/z calcd for C12H15N2O [M+H]+ 203.1184. found 203.1205; HPLC>99% (tR=6.00 min, 60 (A):40 (B): 0.07 (C); tR=5.10 min, 60 (A):40 (B): 0.1 (C)).