Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH3:9])[C:2]([CH:7]=O)=[CH:3][CH:4]=[CH:5][CH:6]=1.[C:10]1([NH:16][NH2:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[CH3:9][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]=[N:17][NH:16][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: NNc1ccccc1
Reactant: Cc1ccccc1C=O
Product: Cc1ccccc1C=NNc1ccccc1

Procedure:
In a procedure analogous to Example 1, o-tolualdehyde is combined with phenyl hydrazine to form N-(2-Methyl-benzylidene)-N′-phenyl-hydrazine.
Reaction SMILES: [C:1](=[O:8])([S:6][CH3:7])[O:2][CH:3](Cl)[CH3:4].[C:9]([OH:14])(=[O:13])[CH:10]([CH3:12])[CH3:11].C(N(C(C)C)CC)(C)C>CCOCC>[C:1](=[O:8])([S:6][CH3:7])[O:2][CH:3]([O:14][C:9](=[O:13])[CH:10]([CH3:12])[CH3:11])[CH3:4]
Reactant: CC(C)C(=O)O
Reactant: CSC(=O)OC(C)Cl
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Product: CSC(=O)OC(C)OC(=O)C(C)C
Temperature: 55 °C
Yield: 97 %

Procedure:
Compound (3) (308 g, 2 mol) was dissolved in isobutyric acid (264 g, 3 mol). This mixture was slowly added to a pre-mixed solution of isobutyric acid (264 g, 3 mol) and diisopropylethylamine (387 g, 3 mol), and the reaction mixture heated to 55° C. for 16 h, diluted with ether (10 L), washed with water (4×5 L), saturated bicarbonate solution (2×5 L) and brine (5 L), then dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give the title compound (2) as colorless liquid (400 g, 97% yield). The product was optionally further purified by vacuum distillation (135° C./20 Torr). 1H NMR (CDCl3, 400 MHz): δ 1.17 (d, J=6.8 Hz, 6H), 1.49 (d, J=5.6 Hz, 3H), 2.33 (s, 3H), 2.54 (m, 1H), 6.91 (q, J=5.2 Hz, 1H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Br[C:8]1[C:13]([O:14][CH3:15])=[CH:12][CH:11]=[CH:10][N:9]=1>>[CH3:15][O:14][C:13]1[C:8]([N:1]2[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]2)=[N:9][CH:10]=[CH:11][CH:12]=1
Reactant: COc1cccnc1Br
Reactant: C1CNCCN1
Product: COc1cccnc1N1CCNCC1
Yield: 82 %

Procedure:
Anhydrous piperazine (45.6 g) and 2-bromo-3-methoxypyridine (10.0 g) were heated neat in an autoclave at 100° C. for 20 h. Upon cooling, the mixture was treated with 5% NaCO3 (20 mL) and extracted with CH2Cl2 (3×50 mL). The extracts were dried using anhydrous K2CO3, filtered, and concentrated under reduced pressure to yield 1-(3-methoxy-2pyridinyl)piperazine (III; 8.43 g; 82%) after silica gel chromatography (CH2Cl2/MeOH/NH4OH; 93:7:0.7).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[CH3:10][NH:11][NH2:12]>C(O)C>[CH3:10][NH:11][N:12]=[CH:6][C:5]1[CH:8]=[CH:9][C:2]([Cl:1])=[CH:3][CH:4]=1
Reactant: CNN
Reactant: O=Cc1ccc(Cl)cc1
Solvent: CCO
Product: CNN=Cc1ccc(Cl)cc1
Yield: 97 %

Procedure:
56.2 g (0.4 mol) of 4-chlorobenzaldehyde were added dropwise to a solution of 18.4 g (0.4 mol) of methylhydrazine in 100 ml of ethanol. The mixture was then refluxed for 4 hours. After cooling, the reaction mixture was concentrated. The residue was taken up in methyl tert-butyl ether. The ether phase was finally washed with water, dried over magnesium sulfate and then concentrated. Yield: 97%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[I:12][C:13]1[C:21]2[C:16](=[CH:17][C:18]([CH:22]=O)=[CH:19][CH:20]=2)[N:15]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[N:14]=1>N1CCCCC1.CO>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])/[C:5]/2=[CH:22]/[C:18]1[CH:17]=[C:16]2[C:21]([C:13]([I:12])=[N:14][N:15]2[CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])=[CH:20][CH:19]=1
Reactant: C[Si](C)(C)CCOCn1nc(I)c2ccc(C=O)cc21
Reactant: O=C1Cc2cc(F)ccc2N1
Solvent: CO
Solvent: C1CCNCC1
Product: C[Si](C)(C)CCOCn1nc(I)c2ccc(/C=C3/C(=O)Nc4ccc(F)cc43)cc21
Temperature: 55 °C
Yield: 77.1 %

Procedure:
A round bottom flask was charged with 5-fluoroindolin-2-one (100 mg, 0.661 mmol), 3-iodo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-6-carbaldehyde (266.18 mg, 0.661 mmol), piperidine (13 uL, 0.013 mmol) and methanol (7.5 mL). The reaction was then heated to 55° C. for 4 h prior to cooling the reaction mass to room temperature. Filtration and washing with methanol (0.50 mL×2) gave the title compound as a yellow solid (273 mg, 77%). 1H NMR (400 MHz, CDCl3) δ 8.14 (s, 1H), 8.00 (s, 1H), 7.85 (s, 1H), 7.62 (d, J=8.4 Hz, 1H), 7.50 (d, J=8.4 Hz, 1H), 7.34 (dd, J=8.0, 2.4 Hz, 1H), 6.97 (td, J=6.4, 2.4 Hz, 1H), 6.85 (dd, J=8.4, 4.4 Hz, 1H), 5.80 (s, 2H), 3.58 (t, J=8.4 Hz, 2H), 0.92 (t, J=8.4 Hz, 2H), 0.03 (s, 9H).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[CH3:10][O:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[C:18]([OH:22])=[C:17]([C:23]1[CH:28]=[CH:27][C:26]([S:29][CH3:30])=[CH:25][CH:24]=1)[CH:16]=[CH:15]2.[H-].[Na+].C(OCC)(=O)C>CN1CCCC1=O>[CH3:10][O:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[C:18]([O:22][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1)=[C:17]([C:23]1[CH:28]=[CH:27][C:26]([S:29][CH3:30])=[CH:25][CH:24]=1)[CH:16]=[CH:15]2
Reactant: COc1ccc2c(O)c(-c3ccc(SC)cc3)ccc2c1
Reactant: O=Cc1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: COc1ccc2c(Oc3ccc(C=O)cc3)c(-c3ccc(SC)cc3)ccc2c1
Temperature: 25 °C
Yield: 31.9 %

Procedure:
Add 4-fluoro-benzaldehyde (2.20 mL, 20.3 mmol) to a solution of 6-methoxy-2-(4-methylsulfanyl-phenyl)-naphthalen-1-ol (3.0 g, 10.1 mmol) and 60% sodium hydride (400 mg, 10.1 mmol) in 1-methyl-2-pyrolidinone (30 mL). Heat the reaction to 170° C. for 70 minutes, then cool to ambient temperature. Dilute the reaction with ethyl acetate (200 mL) and wash twice with 5% aqueous lithium chloride (500 mL), brine, 1N aqueous hydrochloric acid, dry with solid magnesium sulfate and chromatograph on silica gel with dichloromethane/hexane mixtures to give 1.29 g of 4-[6-methoxy-2-(4-methylsulfanyl-phenyl)-naphthalen-1-yloxy]-benzaldehyde (32%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:13]=[CH:12][CH:11]=[C:5]2[C:6]([O:8][C:9](=[O:10])[C:4]=12)=[O:7].[Cl-].[Al+3].[Cl-].[Cl-].[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1.Cl>C(Cl)Cl.C(O)C>[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=1[C:6]([C:5]1[CH:11]=[CH:12][CH:13]=[C:3]([O:2][CH3:1])[C:4]=1[C:9]([OH:8])=[O:10])=[O:7]
Reactant: COc1ccc(OC)cc1
Reactant: COc1cccc2c1C(=O)OC2=O
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCO
Product: COc1ccc(OC)c(C(=O)c2cccc(OC)c2C(=O)O)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 41.1 %

Procedure:
3-Methoxyphthalic anhydride (17.8 g, 0.1 mole) was suspended in 100 ml. dry methylene chloride (previously distilled over anhydrous potassium carbonate). To the suspension was added anhydrous aluminum chloride (30.5 g, 0.23 mole) in one portion. The suspension quickly became bright yellow and was stirred at room temperature for 2 hours. A solution of p-dimethoxybenzene (27.6 g, 0.2 mole) in methylene chloride (100 ml) was added slowly to the vigorously stirred solution. The reaction mixture was stirred overnight at 25° and poured onto ice (300 g) and concentrated hydrochloric acid (50 ml). The slurry was stirred for 30 minutes and extracted with chloroform (4 × 150 ml). A white precipitate suspended in the aqueous layer is collected by filtration. The organic extract was washed once with water (200 ml) and washed with saturated sodium bicarbonate (4 × 150 ml). The aqueous bicarbonate extract was washed once with chloroform (150 ml) and acidified with concentrated hydrochloric acid, the mixture cooled on an ice bath and filtered. The residue was washed well with water and dried under reduced pressure and combined with the white precipitate to yield 2-(2',5'-dimethoxybenzoyl)-6-methoxybenzoic acid (I) as a pale yellow solid (13 g, 41% yield), m.p. 180°-182° C (from ethanol); IR (KBr) 2.95, 5.72μ; NMR (CDCl3) δ, 7.60-6.80 (m, 6H), 6.10 (s, 1H), 3.75 (s, 3H), 3.70 (s, 3H), 3.49 (s, 3H).
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([C:20]2[CH:25]=[CH:24][N:23]=[C:22]([NH:26][C:27](=[O:29])[CH3:28])[CH:21]=2)[S:5][C:6]=1[C:7]1[N:8]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[CH:9]=[CH:10][N:11]=1.[CH2:30](N(CC)CC)[CH3:31].C([Sn](CCCC)(CCCC)C=C)CCC>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.C1COCC1>[CH3:17][Si:16]([CH3:19])([CH3:18])[CH2:15][CH2:14][O:13][CH2:12][N:8]1[CH:9]=[CH:10][N:11]=[C:7]1[C:6]1[S:5][C:4]([C:20]2[CH:25]=[CH:24][N:23]=[C:22]([NH:26][C:27](=[O:29])[CH3:28])[CH:21]=2)=[N:3][C:2]=1[CH:30]=[CH2:31]
Reactant: CC(=O)Nc1cc(-c2nc(Br)c(-c3nccn3COCC[Si](C)(C)C)s2)ccn1
Reactant: CCN(CC)CC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: C=C[Sn](CCCC)(CCCC)CCCC
Solvent: C1CCOC1
Product: C=Cc1nc(-c2ccnc(NC(C)=O)c2)sc1-c1nccn1COCC[Si](C)(C)C
Yield: 72 %

Procedure:
N-(4-(4-bromo-5-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-2-yl)thiazol-2-yl)pyridin-2-yl)acetamide (0.80 g, 1.6 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.187 g, 0.162 mmol) were placed in a microwave vial and sealed under atmosphere of argon. Triethylamine (7.0 mL, 50 mM), THF (7 mL) and tributylethenyl stannane (0.708 mL, 2.43 mmol) were added and the mixture was irradiated at 95° C. for 3 hours. The solvent was evaporated and the residue was purified using column chromatography on silica gel (0 to 60% EA in hexane) to give the title compound (0.65 g, 72%). LCMS: (FA) ES+, 442. 1H NMR (400 MHz, CDCl3) δ: 8.80 (s, 1H), 8.41-8.31 (m, 1H), 8.09 (s, 1H), 7.70-7.40 (m, 3H), 6.81 (dd, J=17.2, 10.7 Hz, 1H), 6.38 (dd, J=17.2, 1.9 Hz, 1H), 5.54 (dd, J=10.7, 1.9 Hz, 1H), 5.27 (s, 2H), 3.48-3.34 (m, 2H), 2.25 (s, 3H), 0.90-0.84 (m, 2H), −0.04 (s, 9H).
Reaction SMILES: Cl[C:2]1[C:3]([C:12]#[N:13])=[N:4][C:5]([S:8][CH2:9][CH2:10][CH3:11])=[CH:6][CH:7]=1.[Cl:14][C:15]1[CH:16]=[C:17]([OH:22])[CH:18]=[CH:19][C:20]=1[Cl:21].CC([O-])(C)C.[K+]>CS(C)=O.C1COCC1>[Cl:14][C:15]1[CH:16]=[C:17]([CH:18]=[CH:19][C:20]=1[Cl:21])[O:22][C:2]1[C:3]([C:12]#[N:13])=[N:4][C:5]([S:8][CH2:9][CH2:10][CH3:11])=[CH:6][CH:7]=1
Reactant: Oc1ccc(Cl)c(Cl)c1
Reactant: CCCSc1ccc(Cl)c(C#N)n1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: CCCSc1ccc(Oc2ccc(Cl)c(Cl)c2)c(C#N)n1

Procedure:
3-Chloro-6-propylthio-2-pyridinecarbonitrile (6.2 g) was mixed with 5.7 g of 3,4-dichlorophenol and 3.9 g of t-BuOK in 30 ml of DMSO and 30 ml THF. The desired, 3-(3,4-dichlorophenoxy)-6-propylthio-2-pyridinecarbonitrile was recovered, b.p. 203° C. (at 0.2 mm Hg).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:21])=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([NH:16][CH2:17][CH:18]3[CH2:20][CH2:19]3)=[O:15])=[CH:10][CH:9]=2)[CH:7]=1.[S:22]1[CH:26]=[CH:25][C:24]([C:27](O)=[O:28])=[CH:23]1>>[CH:18]1([CH2:17][NH:16][C:14]([C:11]2[CH:12]=[CH:13][C:8]([C:6]3[C:5]([CH3:21])=[CH:4][CH:3]=[C:2]([NH:1][C:27]([C:24]4[CH:25]=[CH:26][S:22][CH:23]=4)=[O:28])[CH:7]=3)=[CH:9][CH:10]=2)=[O:15])[CH2:20][CH2:19]1
Reactant: O=C(O)c1ccsc1
Reactant: Cc1ccc(N)cc1-c1ccc(C(=O)NCC2CC2)cc1
Product: Cc1ccc(NC(=O)c2ccsc2)cc1-c1ccc(C(=O)NCC2CC2)cc1

Procedure:
N-(4′-{[(Cyclopropylmethyl)amino]carbonyl}-6-methyl-1,1′-biphenyl-3-yl)thiophene-3-carboxamide was prepared from 5′-amino-N-(cyclopropylmethyl)-2′-methyl-1,1′-biphenyl-4- carboxamide and 3-thiophene carboxylic acid using method D. NMR; δH [2H6]—DMSO 10.05,(1H, s), 8.62,(1H, t), 8.32,(1H, m), 7.93,(2H, d), 7.69,(1H, dd), 7.65-7.61,(3H, m), 7.44,(2H, d), 7.28,(1H, d), 3.16,(2H, t), 2.20,(3H, s), 1.04,(1H, m), 0.44,(2H, m), 0.24,(2H, m). LCMS: retention time 3.41 min, MH+391.
Reaction SMILES: [C:1]1([CH:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:8][CH:9]2[CH2:14][CH:13]3[CH2:15][CH2:16][N:10]2[CH2:11][CH2:12]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN(C)CCN(C)C.C([Li])CCC.[C:36]1(=[O:41])[CH2:40][CH2:39][CH2:38][CH2:37]1>CCCCCC.C1CCCCC1>[N:10]12[CH2:16][CH2:15][CH:13]([CH2:12][CH2:11]1)[CH2:14][CH:9]2[CH2:8][C:7]([C:36]1([OH:41])[CH2:40][CH2:39][CH2:38][CH2:37]1)([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=C1CCCC1
Reactant: c1ccc(C(CC2CC3CCN2CC3)c2ccccc2)cc1
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCCCC1
Solvent: CCCCCC
Product: OC1(C(CC2CC3CCN2CC3)(c2ccccc2)c2ccccc2)CCCC1
Reaction time: 1.2 h

Procedure:
A solution of 20.4 parts 2-(2,2-diphenylethyl)-1-azabicyclo[2.2.2]octane, 10.5 parts by volume of N,N,N',N'-tetramethylethylenediamine, 48 parts by volume of a 1.6 M solution of butyllithium in hexane in 500 parts by volume of cyclohexane is heated to reflux while being stirred for 1.2 hours under nitrogen. The reaction mixture is cooled to 10 and 6.8 parts by volume of cyclopentanone is added during 5 minutes. It is washed four times with water and one time with saturated sodium chloride solution, dried over anhydrous sodium sulfate and evaporated under reduced pressure. The residual solid is triturated with 40 parts diethyl ether and filtered. The filtrate is evaporated under reduced pressure to give residual solid and oil. This residue is put on a 25 mm volume of Woelm silica gel and eluted with a mixed solvent of ethanol, concentrated ammonia and toluene (ratio 2:0.25:98) under a pressure to maintain a flow rate of 8 ml per minute. The desired fraction is evaporated under reduced pressure giving residual oil which solidifies. The solid is washed with n-pentane and recrystallized from diethylether giving the product as a white solid: (XI) 1-[2-(1-azabicyclo [2.2.2]octan-2-yl)-1,1-diphenylethyl]cyclopentanol m.p. 178°-179.5°, MW 376. The hydrochloride of this compound is crystallized from a mixed solvent of isopropanol and diethyl ether: 1-[2-(1-azabicyclo[2.2.2]octan-2-yl)-1,1-diphenylethyl] cyclopentanol hydrochloride (XVII); m.p. 247°-249°; MW 412.
Reaction SMILES: Cl.Cl.[CH3:3][C:4]1([CH2:15][N:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[O:8][C:7]2=[N:9][C:10]([N+:12]([O-:14])=[O:13])=[CH:11][N:6]2[CH2:5]1.C(N(CC)CC)C.[Cl:29][C:30]1[CH:35]=[CH:34][C:33]([N:36]=[C:37]=[S:38])=[CH:32][CH:31]=1>C(Cl)Cl>[Cl:29][C:30]1[CH:35]=[CH:34][C:33]([NH:36][C:37]([N:19]2[CH2:18][CH2:17][N:16]([CH2:15][C:4]3([CH3:3])[O:8][C:7]4=[N:9][C:10]([N+:12]([O-:14])=[O:13])=[CH:11][N:6]4[CH2:5]3)[CH2:21][CH2:20]2)=[S:38])=[CH:32][CH:31]=1
Reactant: CC1(CN2CCNCC2)Cn2cc([N+](=O)[O-])nc2O1
Reactant: S=C=Nc1ccc(Cl)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(CN2CCN(C(=S)Nc3ccc(Cl)cc3)CC2)Cn2cc([N+](=O)[O-])nc2O1
Temperature: 25 °C
Reaction time: 1 h
Yield: 40.1 %

Procedure:
2-Methyl-6-nitro-2-(piperazin-1-ylmethyl)-2,3-dihydroimidazo[2,1-b]oxazole dihydrochloride prepared in Example 322 (196 mg, 0.73 mmol) was suspended in methylene chloride (10 ml), then neutralized with triethylamine (0.27 ml, 1.94 mmol). To the solution, 4-chlorophenyl isothiocyanate (140 mg, 0.83 mmol) was added followed by stirring at room temperature for 1 hour. The reaction mixture was washed with water, a saturated sodium hydrogencarbonate solution and a saturated saline solution in this order, dried over sodium sulfate and then filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methylene chloride/methanol=30/1) to afford 4-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethyl)piperazine-1-carbothioic acid (4-chlorophenyl)amide (128 mg, yield 40%) as a light brown powder.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl.[CH3:18][C:19]1[C:36]([CH3:37])=[CH:35][C:22]2[NH:23][C:24]([C:26]3[NH:27][N:28]=[C:29]4[C:34]=3[CH2:33][CH2:32][NH:31][CH2:30]4)=[N:25][C:21]=2[CH:20]=1.O>CN(C)C=O>[CH3:37][C:36]1[C:19]([CH3:18])=[CH:20][C:21]2[NH:25][C:24]([C:26]3[NH:27][N:28]=[C:29]4[C:34]=3[CH2:33][CH2:32][N:31]([C:2]3[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=3)[CH2:30]4)=[N:23][C:22]=2[CH:35]=1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: Cc1cc2nc(-c3[nH]nc4c3CCNC4)[nH]c2cc1C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc2nc(-c3[nH]nc4c3CCN(c3ccc([N+](=O)[O-])cn3)C4)[nH]c2cc1C
Temperature: 25 °C
Reaction time: 20 h
Yield: 85.5 %

Procedure:
287 mg of 2-chloro-5-nitropyridine and 500 mg of potassium carbonate are added to a solution of 500 mg of 3-(5,6-dimethyl-1H-benzimidazol-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-c]pyridine hydrochloride in 5 ml of dimethylformamide. After stirring for 20 hours at ambient temperature, the reaction medium is added to 50 ml of water. The precipitate formed is recovered by filtration through sintered glass, washed with 3 times 15 ml of water and then dried under reduced pressure. 548 mg of 3-(5,6-dimethyl-1H-benzimidazol-2-yl)-6-(5-nitropyridin-2-yl)-4,5,6,7-tetrahydro-2H-pyrazolo-[3,4-c]pyridine are thus obtained in the form of a yellow powder, the characteristics of which are as follows:
Reaction SMILES: Cl[C:2]1[C:7]([CH3:8])=[C:6]([CH3:9])[N:5]=[C:4]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[N:3]=1.Cl.[F:19][C:20]1([F:27])[CH2:25][CH2:24][CH:23]([NH2:26])[CH2:22][CH2:21]1>C(#N)C.O>[F:19][C:20]1([F:27])[CH2:25][CH2:24][CH:23]([NH:26][C:2]2[C:7]([CH3:8])=[C:6]([CH3:9])[N:5]=[C:4]([NH:10][CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=3)[N:3]=2)[CH2:22][CH2:21]1
Reactant: Cc1nc(NCc2ccccn2)nc(Cl)c1C
Reactant: NC1CCC(F)(F)CC1
Agent: Cl
Solvent: O
Solvent: CC#N
Product: Cc1nc(NCc2ccccn2)nc(NC2CCC(F)(F)CC2)c1C
Yield: 41 %

Procedure:
A solution of 4-chloro-5,6-dimethyl-N-(pyridin-2-ylmethyl)pyrimidin-2-amine (200 mg, 0.8 mmol, Example 29, Step C) and (4,4-difluorocyclohexyl)amine hydrochloride (172 mg, 1 mmol) in acetonitrile (5 mL) was refluxed overnight. The reaction mixture was diluted with water (50 mL) and a formed precipitate was collected by filtration. The crude material was purified by HPLC (column: YMC-PACK ODS-AQ C18, 250 mm×20 mm, 10 μm; gradient: 20-50% acetonitrile in 0.02% trifluoroacetic acid/water over fifteen minutes; 50-100% acetonitrile in 0.02% trifluoroacetic acid/water over five minutes; flow rate: 25 mL/min; temperature: 25° C.) to afford 114 mg, 25% of the titled compound as the trifluoroacetic acid salt as a white solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.45-1.55 (m, 4H), 1.70-1.82 (m, 2H), 1.88 (s, 3H), 1.90-2.00 (m, 2H), 2.25 (s, 3H), 3.90 (bs, 1H), 4.70 (d, J=5.37 Hz, 2H), 7.38 (t, J=6.25 Hz, 1H), 7.47 (d, J=7.52 Hz, 1H), 7.64 (d, J=7.52 Hz, 1H), 7.90 (t, J=7.52 Hz, 1H), 8.46-8.52 (m, 1H), 8.57 (d, J=4.57 Hz, 1H), 12.78 (bs, 1H); MS (ESI) m/z 348.8 (M+1)+. N4-(4,4-Difluorocyclohexyl)-5,6-dimethyl-N2-(pyridin-2-ylmethyl)pyrimidine-2,4-diamine trifluoroacetate was purified by column chromatography eluting with mixture of chloroform/ethanol/20% water solution of ammonia (200:10:1) to afford 58 mg (68%) of the titled compound as a white solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.40-1.51 (m, 2H), 1.60-1.71 (m, 3H), 1.81 (bs, 4H), 1.90-1.98 (m, 2H), 2.07 (s, 3H), 3.76-3.84 (m, 1H), 4.46 (d, J=5.91 Hz, 2H), 5.84 (d, J=7.25 Hz, 1H), 6.70-6.75 (m, 1H), 7.10-7.22 (m, 1H), 7.24 (d, J=7.79 Hz, 1H), 7.67 (t, J=7.52 Hz, 1H), 8.45 (d, J=4.30 Hz, 1H); MS (ESI) m/z 348.8 (M+1)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:18]3[C:17]([NH2:19])=[C:16]([O:20][CH3:21])[C:15]([O:22][CH3:23])=[CH:14][C:13]=3[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.[C:24](N1C=CN=C1)(N1C=CN=C1)=[S:25]>ClCCCl>[Br:1][C:2]1[CH:3]=[C:4]([N:8]2[C:9]3[C:18]4[C:13]([N:12]=[CH:11][N:10]=3)=[CH:14][C:15]([O:22][CH3:23])=[C:16]([O:20][CH3:21])[C:17]=4[NH:19][C:24]2=[S:25])[CH:5]=[CH:6][CH:7]=1
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: COc1cc2ncnc(Nc3cccc(Br)c3)c2c(N)c1OC
Solvent: ClCCCl
Product: COc1cc2ncnc3c2c(c1OC)NC(=S)N3c1cccc(Br)c1
Temperature: 90 °C
Reaction time: 4 h

Procedure:
To a solution of N4-(3-bromo-phenyl)-6,7-dimethoxy-quinazoline-4,5-diamine (80 mg, 0.21 mmol) (from Example 6, Step B, supra) in 1,2-dichloroethane (50 mL) was added 1,1′-thiocarbonyldiimidazole (0.38 g, 2.13 mmol) (Fluka). The reaction mixture was heated with stirring at 90° C. for 4 hours. The solvents were evaporated and the residue was purified by chromatography using EtOAc/CH2Cl2/Et3N (1:2:0.05) as eluent to give the desired 3-(3-bromo-phenyl)-8,9-dimethoxy-1H,3H-1,3,4,6-tetraaza-phenalene-2-thione as a yellow solid. (Yield 80 mg, 91%).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=O.[CH3:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[O:21][CH3:22]>>[CH3:22][O:21][C:16]1[CH:17]=[CH:18][C:19]([C:6]([C:5]2[CH:9]=[CH:10][CH:11]=[C:3]([C:2]([F:1])([F:13])[F:12])[CH:4]=2)=[O:8])=[CH:20][C:15]=1[CH3:14]
Reactant: COc1ccccc1C
Reactant: O=C(O)c1cccc(C(F)(F)F)c1
Product: COc1ccc(C(=O)c2cccc(C(F)(F)F)c2)cc1C
Temperature: 90 °C
Reaction time: 4.5 h

Procedure:
m-Trifluoromethylbenzoic acid (19.0g, 0.10 mole) and o-methylanisole(12.2g, 0.10 mole) are combined in 50 ml of polyphosphoric acid (PPA) and warmed with stirring to 90°C for 4.5 hours. The cooled reaction mixture is then poured into ice water and extracted into ethyl acetate (200 ml) to give, after extraction with 5% aqueous sodium hydroxide 15 g of product (53%), m.p. 56°-59°C, upon removal of the solvent in vacuo.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[CH:17][CH:18]=3)[NH:13][CH:12]=2)[CH:8]=[CH:7][C:4]=1[C:5]#[N:6].C(=O)([O-])[O-:21].[K+].[K+].OO>CS(C)=O.O>[CH3:1][O:2][C:3]1[CH:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[CH:17][CH:18]=3)[NH:13][CH:12]=2)[CH:8]=[CH:7][C:4]=1[C:5]([NH2:6])=[O:21]
Reactant: O=C([O-])[O-]
Reactant: COc1cc(-c2c[nH]c3ncccc23)ccc1C#N
Agent: OO
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: COc1cc(-c2c[nH]c3ncccc23)ccc1C(N)=O
Yield: 93.5 %

Procedure:
The nitrile 30 (10 mg, 40 μmol) was dissolved in dimethyl sulfoxide (0.5 ml). To this was added potassium carbonate (20 mg) and 30% hydrogen peroxide in water (100 μl). The reaction was warmed to approximately 60 C for 15 minutes. The reaction was concentrated to dryness and triturated in water. The resulting precipitate was filtered and dried in-vacuo overnight to give 31 (10 mg, 93%). 1H NMR DMSO-d6 11.99 (s, 1H), 8.32 (d, 1H), 8.24 (m, 1H), 8.01 (m, 1H), 7.88 (d, 1H), 7.59 (s, 1H), 7.40 (s, 1H), 7.37 (m, 2H), 7.15 (dd, 1H), 4.00 (s, 3H). LC/MS (M+1)=268.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH2:5][CH2:6][C@@H:7]2[OH:12].[C:13](=[O:16])([O-])O.[Na+]>C(Cl)Cl.O1C=CCCC1.O1CCOCC1>[Br:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH2:5][CH2:6][C@@H:7]2[O:12][CH:5]1[CH2:4][CH2:3][CH2:11][CH2:13][O:16]1
Reactant: O[C@H]1CCc2c(Br)cccc21
Reactant: O=C([O-])O
Agent: C1=COCCC1
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: C1COCCO1
Product: Brc1cccc2c1CC[C@@H]2OC1CCCCO1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
In methylene chloride (16.2 mL), 3,4-dihydro-2H-pyran (10.6 mL) was dissolved. To the solution, a solution of 4M hydrogen chloride in 1,4-dioxane (31.1 μL) was added and (1S)-4-bromo-2,3-dihydro-1H-inden-1-ol (10.0 g) that was commercially available or could be obtained by a known method was added. The resultant reaction mixture was stirred at room temperature for 3 hours. To the reaction mixture, a saturated aqueous sodium hydrogen carbonate solution (60 mL) was added and extracted with methylene chloride (60 mL). The organic phase was washed with brine (60 mL) and dried over anhydrous sodium sulfate. From the organic phase, the solvent was removed by evaporation under reduced pressure and the resultant residue was purified by silica gel column chromatography (eluent; n-hexane:ethyl acetate=95:5). From the eluted solution, the solvent was removed by evaporation under reduced pressure to give the title compound (15 g).