Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([N:12]([CH2:15][CH3:16])[CH2:13][CH3:14])[C:6]([O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[C:5]2[Cl:24].C([Li])CCC.[Cl:30][C:31]1[CH:36]=[CH:35][C:34]([C:37]([C:39]2[N:43]([CH3:44])[CH:42]=[N:41][CH:40]=2)=[O:38])=[CH:33][CH:32]=1>O1CCCC1>[Cl:24][C:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([C:37]([C:34]3[CH:35]=[CH:36][C:31]([Cl:30])=[CH:32][CH:33]=3)([C:39]3[N:43]([CH3:44])[CH:42]=[N:41][CH:40]=3)[OH:38])[CH:3]=2)[N:8]=[C:7]([N:12]([CH2:15][CH3:16])[CH2:13][CH3:14])[C:6]=1[O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CCN(CC)c1nc2ccc(Br)cc2c(Cl)c1Oc1ccccc1
Reactant: Cn1cncc1C(=O)c1ccc(Cl)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCN(CC)c1nc2ccc(C(O)(c3ccc(Cl)cc3)c3cncn3C)cc2c(Cl)c1Oc1ccccc1
Reaction time: 0.08 h

Procedure:
To a solution of 6-bromo-4-chloro-N,N-diethyl-3-phenoxyquinolin-2-amine (525 mg, 1.29 mmol, Intermediate 5, step d) in tetrahydrofuran (12 mL) at −78° C. was added n-butyllithium (1.6 M solution in hexanes, 1.2 mL, 1.94 mmol) dropwise over 1 minute and stirred at this temperature for 5 minutes. To the resulting dark red solution was added (4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methanone (428 mg, 1.94 mmol, Intermediate 1, step b) and stirred in an ice bath (0° C.) for 0.5 hours. The yellow-orange solution was quenched with water and diluted with EtOAc. The organic phase was separated, dried (MgSO4), filtered and concentrated. The residue was purified by flash column chromatography (silica gel, 5% MeOH-DCM), affording the title compound. 1H NMR (400 MHz, DMSO-d6) δ 7.88 (d, J=2.02 Hz, 1H), 7.64-7.70 (m, 2H), 7.46 (dd, J=2.02, 9.09 Hz, 1H), 7.42 (d, J=9.09 Hz, 2H), 7.29-7.35 (m, 4H), 7.06 (t, J=7.33 Hz, 1H), 6.98 (s, 1H), 6.80 (d, J=7.58 Hz, 2H), 6.16 (d, J=1.01 Hz, 1H), 3.51 (q, J=7.07 Hz, 4H), 3.34 (br. s., 3H), 1.05 (t, J=7.07 Hz, 6H)); MS m/e 548.8 [M+H]+.
Reaction SMILES: Cl.[CH3:2][O:3][N:4]1[C:9](=[O:10])[C:8]2[CH2:11][NH:12][CH2:13][CH2:14][C:7]=2[NH:6][C:5]1=[O:15].C(N(CC)CC)C.[Cl:23][C:24]1[CH:32]=[CH:31][C:27]([C:28](Cl)=[O:29])=[CH:26][CH:25]=1.O>C(Cl)Cl>[Cl:23][C:24]1[CH:32]=[CH:31][C:27]([C:28]([N:12]2[CH2:13][CH2:14][C:7]3[NH:6][C:5](=[O:15])[N:4]([O:3][CH3:2])[C:9](=[O:10])[C:8]=3[CH2:11]2)=[O:29])=[CH:26][CH:25]=1
Reactant: COn1c(=O)[nH]c2c(c1=O)CNCC2
Reactant: O=C(Cl)c1ccc(Cl)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: COn1c(=O)[nH]c2c(c1=O)CN(C(=O)c1ccc(Cl)cc1)CC2

Procedure:
3-Methoxy-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine-2,4-dione hydrochloride (790 mg) was suspended in methylene chloride, and triethylamine (1.17 ml) and 4-chlorobenzoyl chloride (0.43 ml) were added under ice cooling and the resultant mixture was stirred at the same temperature for 1.5 hours. To the reaction solution, water was added and the resultant mixture was concentrated. To the residue, diethyl ether was added and insoluble matter was obtained by filtration. The titled compound (684 mg) was obtained as a white powder. The resultant compound was used in a next reaction without further purifying.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:10][CH2:9][C@@H:8]([O:11][Si:12]([C:25]([CH3:28])([CH3:27])[CH3:26])([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:7][C@H:6]1[C:29]([O:31]CC1C=CC=CC=1)=[O:30])=[O:4]>CCO.[Pd]>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:10][CH2:9][C@@H:8]([O:11][Si:12]([C:25]([CH3:28])([CH3:26])[CH3:27])([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:7][C@H:6]1[C:29]([OH:31])=[O:30])=[O:4]
Reactant: COC(=O)[C@@H]1CC[C@@H](O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)C[C@H]1C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: COC(=O)[C@@H]1CC[C@@H](O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)C[C@H]1C(=O)O
Reaction time: 16 h

Procedure:
To a solution of compound 5 (12.2 mmol) in anhydrous EtOH (50 mL) was added Pd/C 10% (20% w/w). The vessel was flushed with nitrogen and H2 was added. The reaction mixture was stirred under hydrogen atmosphere for 16 hrs. The catalyst was filtered off and washed several times with EtOH. The filtrate was concentrated in vacuo to yield compound 6 as a colourless oil in a quantitative yield.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[N:6]1[N:10]2[CH2:11][CH2:12][CH2:13][N:14](C=O)[C:9]2=[CH:8][CH:7]=1.O.[C:18](=O)([O-])[O-:19].[Na+].[Na+]>CN(C)C=O>[N:6]1[N:10]2[CH2:11][CH2:12][CH2:13][NH:14][C:9]2=[C:8]([CH:18]=[O:19])[CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: O=CN1CCCn2nccc21
Agent: [Na+]
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: O=Cc1cnn2c1NCCC2
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To N,N-dimethylformamide (307 ml) was added dropwise phosphorus oxychloride (123 ml) under ice-cooling. To the mixture was added a solution of 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-4-carbaldehyde (100 g) in N,N-dimethylformamide (200 ml) under ice-cooling. The reaction mixture was stirred at 80° C. for 2 hours. After cooling, water was added to the reaction mixture, and the mixture was neutralized with sodium carbonate. The mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The residue was triturated with hexane and dried in vacuo to give 4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carbaldehyde (65 g) as a solid.
Reaction SMILES: [NH:1]([C:8]1[S:9][C:10]2[N:18]=[CH:17][CH:16]=[CH:15][C:11]=2[C:12](=[O:14])[N:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Li+].[CH2:21](I)[CH2:22][CH2:23][CH3:24]>>[CH2:21]([N:13]1[C:12](=[O:14])[C:11]2[CH:15]=[CH:16][CH:17]=[N:18][C:10]=2[S:9][C:8]1=[N:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH2:22][CH2:23][CH3:24]
Reactant: O=c1nc(Nc2ccccc2)sc2ncccc12
Reactant: CCCCI
Agent: [H-]
Agent: [Li+]
Product: CCCCn1c(=Nc2ccccc2)sc2ncccc2c1=O

Procedure:
The reaction procedure of Example 11 was followed except that 383 mg of 2-anilino-4H-pyrido[3,2-e]-1,3-thiazin-4-one, 14 mg of lithium hydride and 0.17 ml of butyl iodide were used. As a result, 280 mg of 3-butyl-2-phenylimino-2,3-dihydro-4H-pyrido[3,2-e]-1,3-thiazin-4-one was obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([O:9][CH3:10])=[CH:4][C:3]=1[CH:11]([OH:14])[C:12]#[N:13].CO.[ClH:17].[O:18]1CCOC[CH2:19]1>C(OCC)C>[ClH:17].[F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([O:9][CH3:10])=[CH:4][C:3]=1[CH:11]([OH:14])[C:12](=[NH:13])[O:18][CH3:19]
Reactant: COc1cc(C(O)C#N)c(F)cc1F
Reactant: C1COCCO1
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: COC(=N)C(O)c1cc(OC)c(F)cc1F
Temperature: 4 °C
Reaction time: 24 h

Procedure:
To 98B (427 mg, 2.1 mmol) in anhydrous diethyl ether (10 mL) at 0° C. was added MeOH (0.87 mL, 10 eq.) and 4.0 N HCl in dioxane (4.2 mL, 16.8 mmol). The mixture was stirred at 4° C. for 24 h. Solvent was removed to give methyl 2-(2,4-difluoro-5-methoxyphenyl)-2-hydroxyacetimidate HCl salt. To this salt in CH2Cl2 (8.0 mL) was added H2O (8.0 mL). The mixture was stirred at rt for 30 min, then extracted with CH2Cl2 (2×50 mL). The combined organic extracts were dried and concentrated to give product 98C (493 mg, 99% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm 3.41 (d, J=4.83 Hz, 1H) 3.72 (s, 3H) 3.80 (s, 3H) 5.32 (d, J=4.83 Hz, 1H) 6.78-6.84 (m, 1H) 6.90 (dd, J=9.01, 6.81 Hz, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]=C(C2C=CC=CC=2)C2C=CC=CC=2)[CH:10]([N:28]=[N+:29]=[N-:30])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC1C=CC(S([O-])(=O)=O)=CC=1.C1C=C[NH+]=CC=1>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([NH2:14])[C@H:10]([N:28]=[N+:29]=[N-:30])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(N=C(c2ccccc2)c2ccccc2)C(N=[N+]=[N-])C1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC[C@H](N)[C@H](N=[N+]=[N-])C1

Procedure:
tert-butyl-3-azido-4-[(diphenylmethylene)amino]piperidine-1-carboxylate (Intermediate 269, 1.36 g; 3.3 mmol) was dissolved in 10 ml's of aqueous THF (5% H2O). PPTS (850 mg; 3.4 mmol; 1.03 eq.) was added in a single portion. The initial cloudy solution became clear within minutes. Upon completion (as determined by LC/MS analysis) the reaction was concentrated and azeotropically dried with acetonitrile. No further purification. (LC/MS: see disappearance of starting material and formation of Ph2C═O. Product is not observable due to lack of chromophore).
Reaction SMILES: [C:1](Cl)(=[O:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:26])[CH2:20][CH2:21][C:22]([O:24]C)=[O:23])=[CH:15][CH:14]=1>>[C:1]([NH:12][C:13]1[CH:14]=[CH:15][C:16]([C:19](=[O:26])[CH2:20][CH2:21][C:22]([OH:24])=[O:23])=[CH:17][CH:18]=1)(=[O:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=C(Cl)C=Cc1ccccc1
Reactant: COC(=O)CCC(=O)c1ccc(N)cc1
Product: O=C(O)CCC(=O)c1ccc(NC(=O)C=Cc2ccccc2)cc1
Yield: 60.6 %

Procedure:
In a manner similar to that described in Example 3, cinnamoyl chloride (0.057 g, 0.00034 mol) was allowed to react with 4-(4-amino-phenyl)-4-oxo-butyric acid, methyl ester (0.052 g, 0.00025 mol), and the resulting intermediate was hydrolyzed to give 0.049 g of 4-[4-(cinnamoylamino)-phenyl]-4-oxo-butyric acid as a yellow solid; MS-(AP+) MH+324.
Reaction SMILES: Cl.[OH:2][C@H:3]1[CH2:8][CH2:7][CH2:6][CH2:5][C@@H:4]1[N:9]1[C:18](=[O:19])[C:17]2[C:12](=[C:13]3[CH:31]=[CH:30][CH:29]=[CH:28][C:14]3=[C:15]([CH2:20][C:21]3[CH:22]=[N:23][C:24]([CH3:27])=[CH:25][CH:26]=3)[CH:16]=2)[N:11]=[CH:10]1.C(N(CC)CC)C.ClC1C=C(C=CC=1)C(OO)=[O:44]>ClCCl>[OH:2][C@H:3]1[CH2:8][CH2:7][CH2:6][CH2:5][C@@H:4]1[N:9]1[C:18](=[O:19])[C:17]2[C:12](=[C:13]3[CH:31]=[CH:30][CH:29]=[CH:28][C:14]3=[C:15]([CH2:20][C:21]3[CH:22]=[N+:23]([O-:44])[C:24]([CH3:27])=[CH:25][CH:26]=3)[CH:16]=2)[N:11]=[CH:10]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1ccc(Cc2cc3c(=O)n([C@H]4CCCC[C@@H]4O)cnc3c3ccccc23)cn1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(Cc2cc3c(=O)n([C@H]4CCCC[C@@H]4O)cnc3c3ccccc23)c[n+]1[O-]
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a suspension of 3-[(1S,2S)-2-hydroxycyclohexyl]-6-[(6-methylpyridin-3-yl)methyl]benzo[h]quinazolin-4(3H)-one hydrochloride (0.050 g, 0.12 mmol) in 0.6 mL of dichloromethane was added triethylamine (0.012 g, 0.12 mmol). Upon dissolution of the suspension, 3-chloroperoxybenzoic acid (0.031 g, 0.13 mmol) was added and the mixture was stirred at rt for 15 h. The mixture was diluted with dichloromethane, washed with saturated aqueous sodium carbonate, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified via silica gel chromatography, eluting with 0-10% methanol in dichloromethane, to provide the title compound that gave proton NMR spectra consistent with theory and a mass ion (ES+) of 416.1967 for [M+H]+: 1H NMR (400 MHz, CDCl3) δ 8.99-8.96 (m, 1H), 8.29 (s, 1H), 8.12 (s, 1H), 7.98 (s, 1H), 7.79-7.76 (m, 1H), 7.65-7.59 (m, 2H), 6.91 (d, J=8.1 Hz, 1H), 4.61 (br s, 1H), 4.31 (s, 2H), 4.00 (br s, 1H), 2.50-2.40 (m, 1H), 2.41 (s, 3H), 2.26-2.21 (m, 1H), 2.06-1.98 (m, 1H), 1.98-1.82 (m, 3H), 1.58-1.40 (m, 3H).
Reaction SMILES: O[CH2:2][C:3]1[CH:7]=[CH:6][N:5]([C:8]2[N:18]=[CH:17][CH:16]=[CH:15][C:9]=2[C:10]([O:12][CH2:13][CH3:14])=[O:11])[N:4]=1.[Cl:19]CCl>>[Cl:19][CH2:2][C:3]1[CH:7]=[CH:6][N:5]([C:8]2[N:18]=[CH:17][CH:16]=[CH:15][C:9]=2[C:10]([O:12][CH2:13][CH3:14])=[O:11])[N:4]=1
Reactant: ClCCl
Reactant: CCOC(=O)c1cccnc1-n1ccc(CO)n1
Product: CCOC(=O)c1cccnc1-n1ccc(CCl)n1
Yield: 101.7 %

Procedure:
To a solution of ethyl 2-(3-(hydroxymethyl)-1H-pyrazol-1-yl)nicotinate (3.76 g, 13.69 mmol) in dichloromethane (100 mL) thionyl chloride (1.1 mL, 15.07 mmol) was added dropwise under stirring. After the reaction was completed, the mixture was concentrated and purified by chromatography over silica gel (eluent CH2Cl2+0-5% methanol) to give 3.7 g of the title compound as clear oil; ESI-MS [M+H]+: 266.1. 1H-NMR (400 MHz, DMSO), δ[ppm]: 8.64 (dd, 1H), 8.49 (d, 1H), 8.13 (dd, 1H), 7.53 (dd, 1H), 6.65 (d, 2H), 4.23 (q, 2H), 1.17 (t, 3H).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[C:13]([NH2:14])=[N:12][NH:11][C:10]=3[C:5]2=[C:4]([CH3:15])[CH:3]=1.[CH3:16][C:17]([CH3:19])=O.C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl.C(Cl)Cl>[CH:17]([NH:14][C:13]1[C:9]2[S:8][C:6]3[C:5]([C:10]=2[NH:11][N:12]=1)=[C:4]([CH3:15])[CH:3]=[C:2]([CH3:1])[N:7]=3)([CH3:19])[CH3:16]
Reactant: Cc1cc(C)c2c(n1)sc1c(N)n[nH]c12
Reactant: CC(C)=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: ClCCCl
Product: Cc1cc(C)c2c(n1)sc1c(NC(C)C)n[nH]c12
Reaction time: 0.25 h

Procedure:
The 6,8-dimethyl-1H-pyrazolo[3′,4′:4,5]thieno[2,3-b]pyridin-3-amine (75 mg, 0.34 mmol) was stirred in DCE (3.4 mL). To this solution was added acetone (0.08 mL, 1.03 mmol) and acetic acid (0.060 mL, 1.03 mmol). The mixture was stirred 15 minutes, then NaBH(AcO)3 (150 mg, 0.70 mmol) was added. The resulting slurry was stirred about 2 hrs. LC/MS indicates the reaction is complete. The reaction was diluted with DCM (15 mL) and quenched with aqueous 2N NaOH. The aqueous layer was separated and extracted with DCM. The combined organic layers were dried over Na2SO4, and concentrated under vacuum to give a crude residue. The residue was purified by trituration with MeOH to give the pure product, 30 mg, (33%), as a light tan solid. 1H NMR (400 MHz, DMSO-d6): δ ppm 7.09 (s, 1H), 5.65 (bs, 1H), 3.61 (bs, 1H), 2.63 (s, 3H), 2.50 (s, 3H), 1.17 (d, J=6.32, 6H). LC/MS: RT=0.55 min., m/z=261.0 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH3:13])[C:3]=1[C:4]([O:6]C)=O.[C:14]([C:20]([O:22][CH3:23])=[O:21])#[C:15][C:16]([O:18][CH3:19])=[O:17].CC(C)([O-])C.[K+]>C(O)(C)(C)C>[OH:6][C:4]1[C:3]2[C:2](=[CH:11][CH:10]=[CH:9][C:8]=2[O:12][CH3:13])[N:1]=[C:15]([C:16]([O:18][CH3:19])=[O:17])[C:14]=1[C:20]([O:22][CH3:23])=[O:21]
Reactant: COC(=O)C#CC(=O)OC
Reactant: COC(=O)c1c(N)cccc1OC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: COC(=O)c1nc2cccc(OC)c2c(O)c1C(=O)OC
Temperature: 25 °C
Yield: 65 %

Procedure:
A solution of methyl 2-amino-6-methoxybenzoate ((1.30 g, 7.17 mM) and dimethyl acetylenedicarboxylate (1.17 g, 8.23 mM) in t-butanol (11 mL) was refluxed under a nitrogen atmosphere for 4 hr. The reaction mixture was cooled to room temperature, potassium t-butoxide (0.92 g, 8.23 mM) was added, and the resulting mixture was heated to 90° C. for 1.5 hr during which solids precipitated out of solution. The mixture was cooled to room temperature, filtered and the collected solids were dissolved in water. The resulting solution was acidified with 1N H2SO4 to form a light tan precipitate. The solids were collected, filtered, washed with water and air dried to provide the desired compound (1.35 g, 65%) as a tan solid. A 0.28 g portion of this material was recrystallized from ethyl acetate to provide an analytical sample (0.24 g) of the title compound as a white solid, mp 184°-186° C.; MS(CI): 292 (M+H).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:4]=[C:5]2[C:14](=[CH:15][CH:16]=1)[C:8]1=[N:9][NH:10][C:11](=[O:13])[CH:12]=[C:7]1[CH2:6]2.O1[CH:22]=[CH:21][C:20](=[O:23])[CH:19]=[CH:18]1.N>O>[O:23]=[C:20]1[CH:21]=[CH:22][N:2]([C:3]2[CH:4]=[C:5]3[C:14](=[CH:15][CH:16]=2)[C:8]2=[N:9][NH:10][C:11](=[O:13])[CH:12]=[C:7]2[CH2:6]3)[CH:18]=[CH:19]1
Reactant: Nc1ccc2c(c1)Cc1cc(=O)[nH]nc1-2
Reactant: O=c1ccocc1
Agent: Cl
Agent: N
Solvent: O
Product: O=c1ccn(-c2ccc3c(c2)Cc2cc(=O)[nH]nc2-3)cc1

Procedure:
A stirred mixture of 7-amino-[5H]indeno[1,2-c]-pyridazin-3(2H)-one hydrochloride (1.0 g) and 4H-pyran-4-one (0.48 g) in water (10 ml) was heated under reflux for 1 hour in a nitrogen atmosphere. The warm mixture was neutralised with aqueous ammonia to give a solid, 0.9 g, m.p. >300° C. This solid was triturated with warm dilute hydrochloric acid and washed with water to give the title compound, 0.42 g m.p. >300° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N:8]=[CH:9][N:10]([CH3:12])[CH3:11])=[C:6]([Cl:13])[N:5]=[C:4]([N:14]=CN(C)C)[N:3]=1.Cl.CO.C(Cl)(Cl)Cl.[OH-].[NH4+]>C(O)C>[NH2:14][C:4]1[N:3]=[C:2]([Cl:1])[C:7]([N:8]=[CH:9][N:10]([CH3:11])[CH3:12])=[C:6]([Cl:13])[N:5]=1
Reactant: CN(C)C=Nc1nc(Cl)c(N=CN(C)C)c(Cl)n1
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: CN(C)C=Nc1c(Cl)nc(N)nc1Cl
Yield: 94.7 %

Procedure:
4,6-Dichloro-2,5-bis-{[(dimethylamino)methylene]amino}pyrimidine (Example 1, 5.87 g, 20.3 mmol) was dissolved in 95% ethanol (200 mL) and 6 N aqueous hydrochloric acid (13.5 mL) added. The solution was heated in an oil bath at 55° C. under nitrogen for 30 minutes, at which point TLC (silica gel, 5% methanol-chloroform) showed that starting material had been cleanly converted to a lower-Rf product. The cooled (ice bath) solution was adjusted to pH ˜8 with concentrated ammonium hydroxide and the resulting mixture (white precipitate formed) concentrated on a rotary evaporator to ˜5 mL to remove ethanol. Additional water (20 mL) was added and the cooled mixture was filtered. The white precipitate was washed with additional water (2×20 mL) and dried to give the title compound as a white powder (4.50 g, 95%), m.p. >dec 250° C.; mass spectrum (CI/CH4): 236, 234 (M+1); 1H-NMR (DMSO-d6)δ: 7.59 (s, 1, CH), 6.90 (s, 2, NH2), 3.00 and 2.94 (both s, 3 each, 2CH3); UV (pH 7 phosphate buffer) λmax: 328 nM (ε4500), 255 (15,800).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][NH:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].CS(O[CH2:28][C:29]([CH3:37])([CH3:36])[CH2:30]OS(C)(=O)=O)(=O)=O.[I-].[K+]>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:30][C:29]([CH3:37])([CH3:36])[CH2:28][N:9]1[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NNC(=O)OC(C)(C)C
Reactant: CC(C)(COS(C)(=O)=O)COS(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC1(C)CN(C(=O)OC(C)(C)C)N(C(=O)OC(C)(C)C)C1
Yield: 2 %

Procedure:
41.8 g of hydrazine-N,N'-dicarboxylic acid di-tert-butyl ester, 74.5 g of potassium carbonate, 52.0 g of 2,2-dimethyl-1,3-propanediol dimethanesulfonate and 2.0 g of potassium iodide are stirred for 48 hours at 120°-130° C. in 360 ml of N,N-dimethylformamide. The reaction mixture is then concentrated; diethyl ether is added and the organic phase is washed with water. Mter drying over sodium sulfate, the reaction mixture is concentrated and purified by means of column chromatography to yield 1.1 g of the desired product, 4,4-dimethyl-pyrazolidine-N,N'-dicarboxylic acid di-tert-butyl ester, in the form of white crystals.
Reaction SMILES: CC(C)([O-])C.[K+].C(NC(C)C)(C)C.C([Li])CCC.Cl.Cl.[CH3:21][C:22]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=1)([CH3:31])[CH:23]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[NH2:24].C(=N/[S@@:46]([C:48]([CH3:51])([CH3:50])[CH3:49])=[O:47])\C1C=CC=CC=1>O1CCCC1>[CH3:49][C:48]([S@:46]([NH:24][C@@H:23]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:22]([CH3:21])([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=1)[CH3:31])=[O:47])([CH3:51])[CH3:50]
Reactant: CC(C)(c1ccccn1)C(N)c1ccccc1
Reactant: CC(C)(C)[S@@](=O)/N=C/c1ccccc1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CC(C)(c1ccccn1)[C@@H](N[S@](=O)C(C)(C)C)c1ccccc1
Temperature: -25 °C
Reaction time: 0.33 h
Yield: 65.4 %

Procedure:
To a 1.0 Molar solution of potassium t-butoxide in tetrahydrofuran (3000 mL, 3.000 moles) was added diisopropylamine (425 mL, 306.8 g, 3.032 moles). The resulting solution was cooled by a dry ice/acetone bath to −50° C. n-Butyllithium solution (980 mL of 2.5 Molar, 2.450 moles) was added drop wise over a period of 40 minutes, giving a bright orange solution. The mixture was allowed to stir for an additional 20 minutes at −25° C., then was cooled back down to −55° C. 2-isopropylpyridine (1) (240.0 g, 1.981 moles) was then added drop wise over a period of 20 minutes while maintaining the internal temperature between −50° C. to −55° C., giving a deep, reddish-purple solution. The mixture was allowed to stir for an additional 2 hours at −50° C., then was used directly in the next step. To the cooled (−50° C.) mixture containing the 2-Isopropylpyridyl anion was added a solution of (R,E)-N-benzylidene-2-methylpropane-2-sulfinamide (2) (360.0 g, 1.720 moles) in anhydrous tetrahydrofuran (3000 mL), drop wise over a period of 3 hours while maintaining the internal temperature between −50° C. and −55° C. The reaction mixture was allowed to warm gradually over 3 hours to 0° C., then checked for completion by working up an aliquot and checking by HPLC. The reaction was quenched by treatment with saturated sodium bicarbonate solution (3000 mL), added drop wise over 20 minutes. After stirring for an additional 30 minutes, the mixture was further diluted with water (3000 mL), and divided into three portions (˜4500 mL each). Each portion was partitioned with ethyl acetate (1000 mL), and the layers separated. The combined aqueous layer was further extracted with ethyl acetate (3×1000 mL). The combined organic extracts were washed with saturated brine (1500 mL), then dried (anhydrous magnesium sulfate). Filtration, followed by removal of the solvent under reduced pressure, left the crude product as a cream-colored solid (575.8 g, 101.3% crude yield), which was a 9:1 mixture of diastereomers. The crude material was recrystallized from a mixture of Hexane/EtOAc (2:1) to give pure desired single diastereomer (371.9 g, 65.4% yield). 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 8.62 (dd, J=4.85, 1.05 Hz, 1 H) 7.52 (td, J=7.80, 2.11 Hz, 1H) 7.09-7.19 (m, 4 H) 6.99 (d, J=8.01 Hz, 1 H) 6.85-6.94 (m, 2 H) 5.80 (d, J=8.01 Hz, 1 H) 4.49 (d, J=8.43 Hz, 1 H) 1.46 (s, 3 H) 1.33 (s, 3 H) 1.10 (s, 9 H). MS: m/z 331.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([CH2:6][C:7]#[N:8])=[O:5].[C:13]1([N:19](C2C=CC=CC=2)[CH:20]=N)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([C:6](=[CH:20][NH:19][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]#[N:8])=[O:5]
Reactant: N#CCC(=O)c1ccccc1Cl
Reactant: N=CN(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: N#CC(=CNc1ccccc1)C(=O)c1ccccc1Cl
Yield: 52.2 %

Procedure:
A solution of 2-chlorobenzoylacetonitrile (1.0 g, 5.6 mmol, 1.0 eq) and diphenylformamidine (1.10 g, 5.6 mmol, 1.0 eq) in 50 mL of toluene was heated to 85° C. overnight. The heat source was removed and desired product slowly began to precipitate from solution. The resulting solid was filtered and dried to provide the desired product (826 mg, 52%). HPLC (4 minute 10-90 gradient) tR 3.13 min; MS m/z 283.2 [M+H]+.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][C:13](=[O:23])[CH2:14][CH2:15][CH:16]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)=[CH:7][C:6]=1[N+:24]([O-])=O)([CH3:4])([CH3:3])[CH3:2]>[Zn].C(O)(=O)C>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][C:13](=[O:23])[CH2:14][CH2:15][CH:16]2[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]2)=[CH:7][C:6]=1[NH2:24])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(CCC(=O)CCC2CCCCCC2)cc1[N+](=O)[O-]
Agent: [Zn]
Solvent: CC(=O)O
Product: CC(C)(C)c1ccc(CCC(=O)CCC2CCCCCC2)cc1N
Reaction time: 1 h

Procedure:
3.08 g (47.1 mmol) of zinc powder and then 0.32 ml of acetic acid were added to 16 ml of a methanolic solution containing 847 mg (2.36 mmol) of 2-t-butyl-5-(5-cycloheptyl-3-oxopentyl)-1-nitrobenzene (prepared as described in Preparation 6), in an ice bath. The mixture was then stirred for 1 hour. At the end of this time, a further 0.32 ml of acetic acid was added, and the mixture was stirred for a further 1 hour. The reaction mixture was then filtered using a Celite filter aid. The insoluble material was washed with ethyl acetate. The filtrate and the washings were combined, condensed to about 10 ml by evaporation under reduced pressure, and diluted with ethyl acetate to distribute the desired compound between the organic solvent and water. In order to remove the insoluble material, the solution was filtered again using a Celite filter aid and the insoluble material was washed again with ethyl acetate. The organic layer was combined with the washings and washed with a saturated aqueous solution of sodium hydrogen carbonate and then with water. The solvent was then removed by distillation under reduced pressure, to obtain 789 mg (a quantitative yield) of the title compound as an oily substance.