Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[N:8][N:9]=[C:10]2O)=[CH:5][CH:4]=1.O=P(Cl)(Cl)[Cl:18]>>[Cl:18][C:10]1[C:11]2[C:6](=[CH:5][CH:4]=[C:3]([C:2]([F:15])([F:14])[F:1])[CH:12]=2)[CH:7]=[N:8][N:9]=1
Reactant: Oc1nncc2ccc(C(F)(F)F)cc12
Reactant: O=P(Cl)(Cl)Cl
Product: FC(F)(F)c1ccc2cnnc(Cl)c2c1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
Into a 50 mL round-bottom flask, was placed 7-(trifluoromethyl)phthalazin-1-ol (prepared as described in the previous step, 1.6 g, 7.48 mmol, 1.00 equiv) and POCl3 (12 mL). The reaction mixture was stirred for 2 h at 100° C. in an oil bath. The resulting mixture was concentrated under vacuum. The residue was dissolved in 50 mL of dichloromethane, washed with 3×5 mL of H2O, dried (Na2SO4), and concentrated under vacuum. The residue was purified by chromatography over a silica gel column with CH3CN/H2O (10:4). The title compound was obtained as a yellow solid.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([NH:10][C:11]([C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[N:19]=[C:18]([NH:23][C:24]([C:26]1[C:27]([C:32]3[CH:37]=[CH:36][C:35]([C:38]([F:41])([F:40])[F:39])=[CH:34][CH:33]=3)=[CH:28][CH:29]=[CH:30][CH:31]=1)=[O:25])[CH:17]=[CH:16]2)=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH:42](=O)[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH2:42]([NH:1][CH2:2][C@@H:3]([NH:10][C:11]([C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[N:19]=[C:18]([NH:23][C:24]([C:26]1[C:27]([C:32]3[CH:33]=[CH:34][C:35]([C:38]([F:41])([F:39])[F:40])=[CH:36][CH:37]=3)=[CH:28][CH:29]=[CH:30][CH:31]=1)=[O:25])[CH:17]=[CH:16]2)=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1
Reactant: NC[C@@H](NC(=O)c1ccc2nc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc2c1)c1ccccc1
Reactant: O=Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: O=C(N[C@H](CNCc1ccccc1)c1ccccc1)c1ccc2nc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc2c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
(S)-2-[(4′-Trifluoromethyl-biphenyl-2-carbonyl)-amino]-quinoline-6-carboxylic acid (2-amino-1-phenyl-ethyl)-amide (N, 30 mg, 0.05 mM) was dissolved in 1,2-dichloroethane. Benzaldehyde (0.15 mM) was added followed by sodium triacetoxy borohydride (110 mg, 0.51 mM). The mixture was stirred at room temperature for 16 h. The solution was concentrated, and the residue was purified by flash chromatography (silica gel) eluting with EtOAc/hexanes. HPLC retention time, 2.75 min; ESMS, 645; calc. Mw, 644
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([C:15]([CH:17]2[N:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:20](=[O:28])[NH:19][CH2:18]2)=[O:16])[CH2:11][CH2:10]1.[H-].[Na+].[Cl:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[S:38](Cl)(=[O:40])=[O:39]>>[Cl:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[S:38]([N:19]1[CH2:18][CH:17]([C:15]([N:12]2[CH2:13][CH2:14][N:9]([C:3]3[CH:4]=[C:5]([CH3:8])[CH:6]=[CH:7][C:2]=3[CH3:1])[CH2:10][CH2:11]2)=[O:16])[N:21]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:20]1=[O:28])(=[O:40])=[O:39]
Reactant: O=S(=O)(Cl)c1ccccc1Cl
Reactant: Cc1ccc(C)c(N2CCN(C(=O)C3CNC(=O)N3c3ccccc3)CC2)c1
Agent: [H-]
Agent: [Na+]
Product: Cc1ccc(C)c(N2CCN(C(=O)C3CN(S(=O)(=O)c4ccccc4Cl)C(=O)N3c3ccccc3)CC2)c1

Procedure:
In analogy to example 33, (RS)-5-[4-(2,5-dimethyl-phenyl)-piperazine-1-carbonyl]-1-phenyl-imidazolidin-2-one (example 33, step 1) was reacted with sodium hydride and 2-chlorobenzenesulfonyl chloride to give the title compound as a colorless solid. MS: 552.7 ([M+H]+)
Reaction SMILES: [CH3:1][S-:2].[Na+].C(=O)([O-])[O-].[K+].[K+].[Cl:10][C:11]1[CH:12]=[C:13]([C:18]2([C:32]([F:35])([F:34])[F:33])[O:22][N:21]=[C:20]([C:23]3[CH:24]=[CH:25][C:26](F)=[C:27]([CH:30]=3)[C:28]#[N:29])[CH2:19]2)[CH:14]=[C:15]([Cl:17])[CH:16]=1.O>CN(C)C=O>[Cl:10][C:11]1[CH:12]=[C:13]([C:18]2([C:32]([F:35])([F:34])[F:33])[O:22][N:21]=[C:20]([C:23]3[CH:24]=[CH:25][C:26]([S:2][CH3:1])=[C:27]([CH:30]=3)[C:28]#[N:29])[CH2:19]2)[CH:14]=[C:15]([Cl:17])[CH:16]=1
Reactant: C[S-]
Reactant: N#Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CSc1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1C#N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred suspension of sodium thiomethoxide (0.21 g, 3 mmol) and potassium carbonate (0.28 g, 2 mmol) in 4 mL of N,N-dimethylformamide was added a solution of 5-[5-(3,5-dichlorophenyl)-4,5-dihydro-5-(trifluoromethyl)-3-isoxazolyl]-2-fluorobenzonitrile (prepared by a method similar to Example 2, Step A and Step B; 1.00 g, 2.48 mmol) in N,N-dimethylformamide (6 mL). This mixture was stirred at ambient temperature for 1 h. Then an additional portion of sodium thiomethoxide (0.21 g, 3 mmol) was added. After an additional 15 minutes, water was added, and the mixture was successively extracted with diethyl ether and ethyl acetate. The organic extracts were combined and washed several times with water and saturated aqueous sodium chloride solution, and then dried over magnesium sulfate, and concentrated to leave an off-white solid. The solid was triturated with a mixture of diethyl ether and hexanes, collected on a glass frit, and dried in air to afford the title compound, a compound of the present invention, as a white solid (1.04 g).
Reaction SMILES: [Cl:1][C:2]1[C:3]([Cl:15])=[C:4]([Cl:14])[C:5]([Cl:13])=[C:6]2[C:11](=[O:12])[O:10][C:8](=[O:9])[C:7]=12.[NH2:16][C:17]1[CH:18]=[CH:19][C:20]([Cl:29])=[C:21]([CH:28]=1)[C:22]([O:24][CH:25]([CH3:27])[CH3:26])=[O:23]>C1(C)C=CC=CC=1>[Cl:13][C:5]1[C:4]([Cl:14])=[C:3]([Cl:15])[C:2]([Cl:1])=[C:7]([C:8]([NH:16][C:17]2[CH:18]=[CH:19][C:20]([Cl:29])=[C:21]([C:22]([O:24][CH:25]([CH3:27])[CH3:26])=[O:23])[CH:28]=2)=[O:9])[C:6]=1[C:11]([OH:10])=[O:12]
Reactant: CC(C)OC(=O)c1cc(N)ccc1Cl
Reactant: O=C1OC(=O)c2c(Cl)c(Cl)c(Cl)c(Cl)c21
Solvent: Cc1ccccc1
Product: CC(C)OC(=O)c1cc(NC(=O)c2c(Cl)c(Cl)c(Cl)c(Cl)c2C(=O)O)ccc1Cl
Reaction time: 8 h
Yield: 70 %

Procedure:
A mixture of tetrachlorophthalic anhydride (2.97 g, 0.010 mole), 1-methylethyl 5-amino-2-chlorobenzoate (2.22 g, 0.010 mole) and toluene (100 ml) was heated slowly to reflux with stirring, then left overnight at room temperature. Filtration of the reaction mixture gave the title compound, m.p. 178°-179° C. (3.45 g, 70% yield).
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)/[C:5](=[N:12]/[S:13]([C:16]2S[CH:18]=[CH:19][CH:20]=2)(=[O:15])=[O:14])/[CH:4]=[C:3]1[S:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24].[C:28]1(S(N)(=O)=O)C=CC=C[CH:29]=1>>[O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[N:12][S:13]([C:16]2[CH:20]=[CH:19][CH:18]=[CH:29][CH:28]=2)(=[O:14])=[O:15])[CH:4]=[C:3]1[S:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24]
Reactant: NS(=O)(=O)c1ccccc1
Reactant: CCOC(=O)CSC1=C/C(=N\S(=O)(=O)c2cccs2)c2ccccc2C1=O
Product: CCOC(=O)CSC1=CC(=NS(=O)(=O)c2ccccc2)c2ccccc2C1=O

Procedure:
5.2.18 Ethyl 2-(1-oxo-4-(phenylsulfonylimino)-1,4-dihydronaphthalen-2-ylthio)acetate (8c) was prepared according to the procedure for 8a except using benzenesulfonamide, which afforded 131.8 mg (31.7%) title compound as a yellow solid, m.p.: 93-95° C.
Reaction SMILES: [C:1]([C:4]1([C:7]2[CH:40]=[CH:39][CH:38]=[CH:37][C:8]=2[CH2:9][CH2:10][C:11]2[C:16]([CH3:17])=[CH:15][N:14]=[C:13]([NH:18][C:19]3[CH:20]=[N:21][N:22]([CH:24]4[CH2:29][CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26][CH2:25]4)[CH:23]=3)[N:12]=2)[CH2:6][CH2:5]1)(=[O:3])[NH2:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:17][C:16]1[C:11]([CH2:10][CH2:9][C:8]2[CH:37]=[CH:38][CH:39]=[CH:40][C:7]=2[C:4]2([C:1]([NH2:2])=[O:3])[CH2:5][CH2:6]2)=[N:12][C:13]([NH:18][C:19]2[CH:20]=[N:21][N:22]([CH:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)[CH:23]=2)=[N:14][CH:15]=1
Reactant: Cc1cnc(Nc2cnn(C3CCN(C(=O)OC(C)(C)C)CC3)c2)nc1CCc1ccccc1C1(C(N)=O)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cnc(Nc2cnn(C3CCNCC3)c2)nc1CCc1ccccc1C1(C(N)=O)CC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of tert-butyl 4-(4-((4-(2-(1-carbamoylcyclopropyl)phenethyl)-5-methylpyrimidin-2-yl)amino)-1H-pyrazol-1-yl)piperidine-1-carboxylate A43 (0.113 g, 0.207 mmol) in DCM (10 mL) was treated with TFA (0.32 mL, 4.1 mmol) and stirred for 20 hours at room temperature. The volatiles were evaporated in vacuo and aq. NaOH (2 M, 40 mL) was added to the residue. The aqueous phase was extracted with EtOAc (3×40 mL) and the combined organics were washed with brine and dried over MgSO4. The solvent was removed in vacuo and the solid was suspended in DCM. Cyclohexane was added and the suspension was sonicated for 10 minutes. The solid was isolated by vacuum filtration to give the title compound A44 as an off-white solid (0.066 g, 72%). LCMS-D: rt 2.88 min; m/z 446 [M+H]+.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:5]=[C:6]([OH:18])[CH:7]=[CH:8][C:9]=1[CH2:10][N:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1.CS(O[CH:24]1[CH2:27][N:26]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:25]1)(=O)=O.[OH-].[Na+]>CN(C=O)C.O>[F:3][C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][C:9]=1[CH2:10][N:11]1[CH2:12][CH2:13][N:14]([CH3:17])[CH2:15][CH2:16]1)[O:18][CH:24]1[CH2:25][N:26]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:27]1
Reactant: CC(C)(C)OC(=O)N1CC(OS(C)(=O)=O)C1
Reactant: CN1CCN(Cc2ccc(O)cc2F)CC1
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: CN1CCN(Cc2ccc(OC3CN(C(=O)OC(C)(C)C)C3)cc2F)CC1
Temperature: 80 °C
Reaction time: 0.33 h
Yield: 44.5 %

Procedure:
A mixture of NaH (55-65% disp. in oil, 0.50 g, 11.5 mmol) in dry DMF (10 mL) under nitrogen was cooled by an ice-bath. A solution of 29B (1.3 g, 5.8 mmol) in DMF (25 mL) was added drop-wise over 10 minutes. The mixture was stirred for 20 minutes and then tert-butyl 3-[(methylsulfonyl)oxy]azetidine-1-carboxylate (1.7 g, 6.9 mmol) in DMF (15 mL) was added. The mixture was heated to 80° C. for six days and then cooled to RT. Water and some aqueous NaOH was added and the mixture was extracted three times with EtOAc. The combined organic solutions were dried (MgSO4) and evaporated. The residue was purified by column chromatography on SiO2 using 5% triethylamine in EtOAc as eluent. There was obtained 0.98 g (45%) of 29C as a colorless oil. 1H NMR (500 MHz, CDCl3): δ 1.45 (s, 9H), 2.28 (s, 3H), 2.28-2.72 (bm, 8H), 3.52 (s, 2H), 3.91-4.03 (m, 2H), 4.22-4.33 (m, 2H), 4.76-4.89 (m, 1H), 6.39-6.52 (m, 2H), 7.19-7.28 (m, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([OH:12])[CH:6]=[CH:5]2.[C:13]1([CH2:19][C:20](Cl)=[O:21])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[OH:12][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[CH:3]=[C:2]([NH:1][C:20](=[O:21])[CH2:19][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH:11]=[CH:10]2
Reactant: Nc1ccc2cc(O)ccc2c1
Reactant: O=C(Cl)Cc1ccccc1
Product: O=C(Cc1ccccc1)Nc1ccc2cc(O)ccc2c1

Procedure:
The 6-aminonaphthalen-2-ol from Step (a) above (320 mg, 2.0 mmol) reacted with phenylacetyl chloride (683 mg, 4.4 mmol, Aldrich) under the conditions of Example 1d to give the title compound as a white solid. MS (ESI, pos. ion) m/z: 278.3 (M+1). Mass Calc'd for C18H15NO2: 277.11.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:12]=[C:13]([P:20]([O:24][CH3:25])([O:22][CH3:23])=[O:21])[C:14]([O:16][CH:17]([CH3:19])[CH3:18])=[O:15])[CH:6]=[C:7]([O:10][CH3:11])[C:8]=1[OH:9].C(=O)([O-])[O-].[K+].[K+].[CH3:32][O:33][C:34]1[CH:41]=[CH:40][C:37]([CH2:38]Cl)=[CH:36][CH:35]=1>C(#N)C>[CH3:11][O:10][C:7]1[CH:6]=[C:5]([CH:12]=[C:13]([P:20]([O:22][CH3:23])([O:24][CH3:25])=[O:21])[C:14]([O:16][CH:17]([CH3:19])[CH3:18])=[O:15])[CH:4]=[C:3]([O:2][CH3:1])[C:8]=1[O:9][CH2:38][C:37]1[CH:40]=[CH:41][C:34]([O:33][CH3:32])=[CH:35][CH:36]=1
Reactant: COc1ccc(CCl)cc1
Reactant: COc1cc(C=C(C(=O)OC(C)C)P(=O)(OC)OC)cc(OC)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccc(COc2c(OC)cc(C=C(C(=O)OC(C)C)P(=O)(OC)OC)cc2OC)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Isopropyl 3-(3,5-dimethoxy-4-hydroxyphenyl)-2-(dimethoxy-phosphinyl)propenoate (4 g; 0.01 mol; Table 1, No. 10) was dissolved in 60 ml of acetonitrile, and potassium carbonate (4.45 g; 0.032 mol) and 4-methoxybenzyl chloride (1.4 ml; 0.011 mol) were added and the mixture was initially stirred at room temperature for 8 hours. To complete the reaction, 0.7 ml of 4-methoxybenzyl chloride was added, followed by stirring for 4 hours, after which the result of a thin-layer chromatography showed that the reaction was complete. The filtrate after removal of potassium carbonate by filtration was evaporated to dryness under reduced pressure, and the residue is chromatographed (SiO2 ; CH2CI2 : AcOEt=8:2). This resulted in a slowly crystallizing oil which, on solidification, had a melting point of 68° to 69° C.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[CH:10]([NH:14][C:15](=[O:39])[CH2:16][CH:17]([C:32]1[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=1)[NH:18][S:19]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=1)(=[O:21])=[O:20])[CH2:9][CH2:8][CH2:7]2)(=O)[CH3:2].[CH2:40]([NH2:44])[CH:41]([CH3:43])[CH3:42].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].CC(O)=O>ClCCCl>[F:38][C:35]1[CH:36]=[CH:37][C:32]([CH:17]([NH:18][S:19]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:30])([F:29])[F:31])[CH:23]=2)(=[O:21])=[O:20])[CH2:16][C:15]([NH:14][CH:10]2[C:11]3[C:6](=[CH:5][C:4]([CH:1]([NH:44][CH2:40][CH:41]([CH3:43])[CH3:42])[CH3:2])=[CH:13][CH:12]=3)[CH2:7][CH2:8][CH2:9]2)=[O:39])=[CH:33][CH:34]=1
Reactant: CC(=O)c1ccc2c(c1)CCCC2NC(=O)CC(NS(=O)(=O)c1cccc(C(F)(F)F)c1)c1ccc(F)cc1
Reactant: CC(C)CN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CC(C)CNC(C)c1ccc2c(c1)CCCC2NC(=O)CC(NS(=O)(=O)c1cccc(C(F)(F)F)c1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 120 h

Procedure:
A mixture of N-(6-acetyl-1,2,3,4-tetrahydro-naphthalen-1-yl)-3-(4-fluoro-phenyl)-3-(3-trifluoromethyl-benzenesulfonylamino)-propionamide (161 mg, 0.286 mmol, 1.0 eq), isobutylamine (Aldrich, 126 mg, 1.72 mmol, 6.0 eq), NaBH(OAc)3 (Aldrich, 182 mg, 0.858 mmol, 3.0 eq) and glacial HOAc (J, T. Baker, 34 mg, 0.572 mmol, 2.0 eq) in ClCH2—CH2Cl (3 mL) was stirred at RT for 5 days. The reaction was quenched with saturated NaHCO3 (60 mL). The crude was extracted with CH2Cl2 (60 mL×3). The extract phase was washed with saturated NaCl, dried over Na2SO4, filtered and concentrated. Flash column chromatography (silica gel, 0-10% MeOH—CH2Cl2) afforded the title compound as a colorless thin film. MS (ESI, pos. ion) m/z: 620 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](=[S:8])[NH2:7])=[CH:4][C:3]=1[Br:11].Cl[CH2:13][C:14]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=O>C(O)C>[CH2:16]([C:14]1[N:7]=[C:6]([C:5]2[CH:9]=[CH:10][C:2]([NH2:1])=[C:3]([Br:11])[CH:4]=2)[S:8][CH:13]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: NC(=S)c1ccc(N)c(Br)c1
Reactant: O=C(CCl)Cc1ccccc1
Solvent: CCO
Product: Nc1ccc(-c2nc(Cc3ccccc3)cs2)cc1Br
Yield: 68 %

Procedure:
A mixture of 4-amino-3-bromobenzthioamide (1.66 g, 7.18 mmol) and 1-chloro-3-phenylacetone [Tarhouni, R. et al., Tetrahedron Letters, 835 (1964)] (1.36 g, 8.07 mmol, 1.1 eq) in absolute ethanol (18 mL) was heated at reflux under nitrogen for 2.5 hours. The resulting reaction mixture was evaporated under reduced pressure, and the residue was partitioned between ethyl acetate (20 mL) and a saturated solution of sodium hydrogen carbonate (20 mL). The ethyl acetate layer was removed, and the aqueous layer was extracted with ethyl acetate (2×20 mL). The organic extracts were combined, dried (MgSO4), and evaporated under reduced pressure. The residual solid was chromatographed using silica gel (approximately 175 g) and elution with an ethyl acetate gradient in hexanes [1:4 to 1:1] to afford the title compound (68%) as a pale yellow solid: top, 110°-115° C.; 13C NMR (CDCl3) δ 166.8, 157.1, 145.6, 139.1, 130.7, 129.1, 128.6, 126.9, 126.4, 125.4, 115.3, 113.2, 109.2, 38.0. Anal. calcd for C16H13BrN2S: C, 55.66; H, 3.79; N, 8.11. Found: C, 55.36; H, 3.71; N, 7.92.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:20])[NH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]([NH2:19])[C:17]#[N:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[S:30](Cl)(=[O:32])=[O:31])([O-])=O>>[CH2:1]([O:8][C:9](=[O:20])[NH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]([NH:19][S:30]([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:24]=1)(=[O:32])=[O:31])[C:17]#[N:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Reactant: N#CC(N)CCCCCNC(=O)OCc1ccccc1
Product: N#CC(CCCCCNC(=O)OCc1ccccc1)NS(=O)(=O)c1ccccc1
Yield: 40.9 %

Procedure:
Using the general procedure described in step A of scheme 1, (6-amino-6-cyano-hexyl -carbamic acid benzyl ester (2.8 g, 10 mmol) was sulfonylated with 2-nitrobenzenesulfonyl chloride (2.5 g, 11 mmol) at 0° C. to yield the titled compound (1.7 g, 36%); yellow oil.
Reaction SMILES: [CH2:1]([S:8][C:9]1[C:14]2[N:15]=[C:16](Cl)[N:17]=[C:18]([N:19]3[CH2:24][CH2:23][S:22](=[O:25])[CH2:21][CH2:20]3)[C:13]=2[N:12]=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:27]([NH:30][CH:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1)(=[O:29])[CH3:28]>>[C:27]([NH:30][CH:31]1[CH2:36][CH2:35][N:34]([C:16]2[N:17]=[C:18]([N:19]3[CH2:24][CH2:23][S:22](=[O:25])[CH2:21][CH2:20]3)[C:13]3[N:12]=[CH:11][N:10]=[C:9]([S:8][CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[C:14]=3[N:15]=2)[CH2:33][CH2:32]1)(=[O:29])[CH3:28]
Reactant: CC(=O)NC1CCNCC1
Reactant: O=S1CCN(c2nc(Cl)nc3c(SCc4ccccc4)ncnc23)CC1
Product: CC(=O)NC1CCN(c2nc(N3CCS(=O)CC3)c3ncnc(SCc4ccccc4)c3n2)CC1

Procedure:
This compound was prepared analogous to Example 1 from 8-benzylthio-2-chloro-4-(1-oxido-thiomorpholino)pyrimido[5,4-d]pyrimidine and 4-acetylamino-piperidine.
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2](Cl)=O.CN(C)C=O.[CH3:12][O:13][C:14]([C:16]1[S:17][C:18]([C:21]2[CH:22]=[C:23]3[C:27](=[CH:28][CH:29]=2)[N:26]([CH:30]([CH3:32])[CH3:31])[CH:25]=C3)=[CH:19][CH:20]=1)=[O:15]>ClCCl>[CH3:12][O:13][C:14]([C:16]1[S:17][C:18]([C:21]2[CH:29]=[C:28]3[C:27](=[CH:23][CH:22]=2)[N:26]([CH:30]([CH3:32])[CH3:31])[CH:25]=[C:2]3[CH:1]=[O:5])=[CH:19][CH:20]=1)=[O:15]
Reactant: O=C(Cl)C(=O)Cl
Reactant: COC(=O)c1ccc(-c2ccc3c(ccn3C(C)C)c2)s1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)c1ccc(-c2ccc3c(c2)c(C=O)cn3C(C)C)s1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 97.7 %

Procedure:
To anhydrous dichloromethane (30 mL) was added oxalyl chloride (0.1 mL, 1.2 mmol). N,N-dimethylformamide (0.1 mL, 1.2 mmol) was added at 0° C., and stirred for 30 min at 0° C. To this reaction solution was added 5-(1-isopropyl-indol-5-yl)thiophene-2-carboxylic acid methyl ester (0.3 g, 1.0 mmol) obtained in Preparation 32, which was then stirred for 1 h at room temperature. The solvent was removed, tetrahydrofuran (30 mL) and 20% aqueous ammonium acetate solution (30 mL) were added to the residue, and the mixture was heated for 30 min while being stirred under reflux. The reaction solution was cooled, ethyl acetate was added, and the mixture was washed with aqueous sodium bicarbonate solution. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting solid was filtered, washed with ethyl acetate and dried to give the title compound (0.32 g, 99% Yield).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[CH2:5][N:6]([CH3:14])[C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10].[CH:18]([C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1)=[O:19]>>[CH:18]([C:20]1[CH:25]=[CH:24][C:23]([C:2]2[CH:17]=[CH:16][CH:15]=[C:4]([CH2:5][N:6]([CH3:14])[C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH:3]=2)=[CH:22][CH:21]=1)=[O:19]
Reactant: O=Cc1ccc(B(O)O)cc1
Reactant: CN(Cc1cccc(Br)c1)C(=O)OC(C)(C)C
Product: CN(Cc1cccc(-c2ccc(C=O)cc2)c1)C(=O)OC(C)(C)C

Procedure:
In a manner similar to that of Example 1(e) by reacting 13.7 g (45 mmol) of tert-butyl (3-bromo benzyl)-N-methylcarbamate (prepared in Example 1(b)) with 10 g (67 mmol) of 4-formylbenzene-boronic acid, 11 g (76%) of the expected are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]2[N:6]3[C:10]([CH2:11][NH:12][CH2:13][C:4]=2[CH:3]=1)=[N:9][N:8]=[C:7]3[CH:14]1[CH2:19][CH2:18][N:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH2:16][CH2:15]1.C(=O)([O-])[O-].[K+].[K+].Cl[C:35]1[CH:40]=[CH:39][N:38]=[CH:37][N:36]=1>C(OCC)(=O)C>[Cl:1][C:2]1[CH:27]=[CH:26][C:5]2[N:6]3[C:10]([CH2:11][N:12]([C:35]4[CH:40]=[CH:39][N:38]=[CH:37][N:36]=4)[CH2:13][C:4]=2[CH:3]=1)=[N:9][N:8]=[C:7]3[CH:14]1[CH2:15][CH2:16][N:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH2:18][CH2:19]1
Reactant: Clc1ccncn1
Reactant: Clc1ccc2c(c1)CNCc1nnc(C3CCN(c4ccccn4)CC3)n1-2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: Clc1ccc2c(c1)CN(c1ccncn1)Cc1nnc(C3CCN(c4ccccn4)CC3)n1-2
Temperature: 95 °C
Reaction time: 18 h
Yield: 13.4 %

Procedure:
A mixture of the amine from example 4 (500 mg, 1.3 mmol), potassium carbonate (480 mg, 3.5 mmol) and 4-chloropyrimidine (300 mg, 2.6 mmol) was stirred at 95° C. for 18 hours. The cooled reaction mixture was diluted with ethyl acetate and the solution was washed with brine (5×), then dried over magnesium sulphate and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel using dichloromethane:methanol (100:0 to 95:5) as eluant, and the product was triturated with diethyl ether to afford the title compound (80 mg).
Reaction SMILES: CN(C)[CH:3]=[C:4]([C:13]1[CH:18]=[CH:17][N:16]=[C:15]([CH3:19])[CH:14]=1)[C:5]([C:7]1[CH:11]=[CH:10][O:9][C:8]=1[CH3:12])=O.[ClH:21].[N:22]1([C:28](=[NH:30])[NH2:29])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1.CC(C)([O-])C.[K+]>C(O)C>[ClH:21].[CH3:12][C:8]1[O:9][CH:10]=[CH:11][C:7]=1[C:5]1[C:4]([C:13]2[CH:18]=[CH:17][N:16]=[C:15]([CH3:19])[CH:14]=2)=[CH:3][N:29]=[C:28]([N:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)[N:30]=1
Reactant: Cc1cc(C(=CN(C)C)C(=O)c2ccoc2C)ccn1
Reactant: N=C(N)N1CCCCC1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CCO
Product: Cc1cc(-c2cnc(N3CCCCC3)nc2-c2ccoc2C)ccn1
Temperature: 25 °C
Yield: 30.7 %

Procedure:
A mixture of 3-(dimethylamino)-1-(2-methyl-3-f uranyl)-2-(2-methyl-4-pyridinyl)-2-propen-1-one (270 mg, 1 mmol) and 1-piperidinecarboximidamide hydrochloride (245 mg, 1.500 mmol) in ethanol (4 ml) was stirred at room temperature. Potassium tert-butoxide (224 mg, 2.000 mmol) was added and the mixture was heated at reflux for 90 minutes. After cooling to room temperature the solvent was evaporated and the residue was diluted with water and extracted with ethyl acetate. The organic extracts were combined, washed with water and brine, dried and evaporated. The residue was purified by silica gel chromatography eluting with 30-100% ethyl acetate in isohexane. The resulting oil was dissolved in dichloromethane (2 ml) and was treated with hydrogen chloride (1M in diethyl ether, 1 ml). The solvent was evaporated and the residue co-evaporated with diethyl ether (×2). The residue was triturated with diethyl ether and the resulting solid was collected, washed with diethyl ether and dried to give the title compound as a pale yellow solid (114 mg, 31%). LC/MS [M+H]+=335. 1H NMR (400 MHz, d6-DMSO): δ 8.60 (2H, d), 8.55 (1H, s), 7.83 (1H, b), 7.58-7.54 (1H, m), 7.51 (1H, d), 6.03 (1H, d), 3.90-3.85 (4H, m), 2.67 (3H, s), 2.38 (3H, s), 1.70-1.53 (6H, m).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([OH:21])=[C:7]([CH:20]=1)[CH:8]([C:13]1[N+:18]([O-:19])=[CH:17][CH:16]=[N:15][CH:14]=1)[CH:9]=[C:10]([CH3:12])[CH3:11])#[N:2]>C(OCC)C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:21][C:10]([CH3:12])([CH3:11])[CH2:9][CH:8]([C:13]3[CH:14]=[N:15][CH:16]=[CH:17][N+:18]=3[O-:19])[C:7]=2[CH:20]=1)#[N:2]
Reactant: CC(C)=CC(c1cc(C#N)ccc1O)c1cncc[n+]1[O-]
Solvent: CCOCC
Product: CC1(C)CC(c2cncc[n+]2[O-])c2cc(C#N)ccc2O1
Yield: 5.7 %

Procedure:
In an analogous manner to that described in the first paragraph of Example 8, from 0.35 g of 6-[5-cyano-2-hydroxy-α-(2-methylpropenyl)benzyl]pyrazine 1-oxide there was obtained 0.02 g of 2-(6-cyano-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-4-yl)pyrazine 1-oxide in the form of a white solid of melting point 166°-168° C. (from diethyl ether).