Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=C(C)C=C(C)[C:3]=1N1CCCC2=C(N)N(C)N=C12.[CH3:21][N:22]1[C:30]([NH2:31])=[C:29]2[C:24]([N:25]([C:32]3[C:37]([CH3:38])=[CH:36][C:35]([CH3:39])=[CH:34][C:33]=3[CH3:40])[CH2:26][CH2:27][CH2:28]2)=[N:23]1>>[CH2:3]([NH:31][C:30]1[N:22]([CH3:21])[N:23]=[C:24]2[C:29]=1[CH2:28][CH2:27][CH2:26][N:25]2[C:32]1[C:37]([CH3:38])=[CH:36][C:35]([CH3:39])=[CH:34][C:33]=1[CH3:40])[CH2:2][CH3:7]
Reactant: Cc1cc(C)c(N2CCCc3c2nn(C)c3N)c(Cl)c1
Reactant: Cc1cc(C)c(N2CCCc3c2nn(C)c3N)c(C)c1
Product: CCCNc1c2c(nn1C)N(c1c(C)cc(C)cc1C)CCC2

Procedure:
Compound 5-55 was prepared according to the procedure in Example 15, steps 1 and 2, except that in step 1, 7-(2-chloro-4,6-dimethylphenyl)-2-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridin-3-ylamine (5-45) was replaced with 2-methyl-7-(2,4,6-trimethyl-phenyl)-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-b]pyridin-3-ylamine (5-44).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:7]([O:9][CH3:10])=[O:8])[O:5][CH:6]=1.C([O-])([O-])=O.[Na+].[Na+].[CH2:17]([N:19]1[C:23](B2OC(C)(C)C(C)(C)O2)=[CH:22][CH:21]=[N:20]1)[CH3:18]>C1COCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:17]([N:19]1[C:23]([C:2]2[CH:3]=[C:4]([C:7]([O:9][CH3:10])=[O:8])[O:5][CH:6]=2)=[CH:22][CH:21]=[N:20]1)[CH3:18]
Reactant: CCn1nccc1B1OC(C)(C)C(C)(C)O1
Reactant: COC(=O)c1cc(Br)co1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Product: CCn1nccc1-c1coc(C(=O)OC)c1
Temperature: 70 °C
Reaction time: 2 h
Yield: 74.4 %

Procedure:
To a solution of methyl 4-bromo-2-furancarboxylate (1.0 g, 4.88 mmol) in THF (20 mL) was added aqueous Na2CO3(2N, 8 mL, 16 mmol.), PdCl2(dppf) (0.35 g, 0.49 mmol) and 1-ethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.3 g, 5.85 mmol). The reaction mixture was heated to 70° C. in a sealed tube. After 2 h, the reaction mixture was concentrated under vacuum and purified on silica (EtOAc/Hex, 20-40%) to afford the title compound (0.8 g, 74.5%) as a light yellow solid: LC-MS (ES) m/z=221 (M+H)+.
Reaction SMILES: I[CH2:2][CH2:3][S:4][CH:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH2:9][O:8][C:7]2[CH:16]=[CH:17][C:18]([C:20]([O:22][CH3:23])=[O:21])=[CH:19][C:6]1=2.[C:24]1([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C(O)C>[C:24]1([N:30]2[CH2:35][CH2:34][N:33]([CH2:2][CH2:3][S:4][CH:5]3[C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=4[CH2:9][O:8][C:7]4[CH:16]=[CH:17][C:18]([C:20]([O:22][CH3:23])=[O:21])=[CH:19][C:6]3=4)[CH2:32][CH2:31]2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: COC(=O)c1ccc2c(c1)C(SCCI)c1ccccc1CO2
Reactant: c1ccc(N2CCNCC2)cc1
Solvent: CCO
Product: COC(=O)c1ccc2c(c1)C(SCCN1CCN(c3ccccc3)CC1)c1ccccc1CO2

Procedure:
After 6.1 g of Compound j obtained in Reference Example 10 and 6.0 ml of 1-phenylpiperazine were heated under reflux in 300 ml of ethanol for 7.5 hours, the solvent was distilled off under reduced pressure. The residue was extracted with 500 ml of ethyl acetate. The extract was washed in succession with saturated sodium bicarbonate aqueous solution and saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate. Thereafter, the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography (eluent; hexane:ethyl acetate:triethylamine=30:10:3). The resulting crude product was solidified with diethyl ether to give 3.1 g of the objective compound.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1)#[N:2].Cl[S:11]([N:14]=C=O)(=[O:13])=[O:12]>C1(C)C=CC=CC=1>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([O:9][S:11](=[O:13])(=[O:12])[NH2:14])=[CH:5][CH:4]=1)#[N:2]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: N#Cc1ccc(O)cc1
Solvent: Cc1ccccc1
Product: N#Cc1ccc(OS(N)(=O)=O)cc1
Yield: 51 %

Procedure:
This compound was prepared by the procedure of Example 56 from a solution of 11.9 g (0.10 mole) of 4-cyanophenol (Aldrich Chemical Co.) and 9.1 ml (0.105 mole) of chlorosulfonyl isocyanate in 75 ml of toluene. The solid product was recrystallized from benzene-acetonitrile to give 10.1 g (51%) of white solid, mp 154°-156° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[CH2:11][C:10]2[C:9]([NH2:12])=[CH:8][CH:7]=[CH:6][C:5]=2[CH2:4][CH2:3]1.C(N(CC)CC)C.[F:21][CH:22]([F:32])[C:23]1[N:31]=[CH:30][CH:29]=[CH:28][C:24]=1[C:25](Cl)=[O:26]>C1COCC1>[F:32][CH:22]([F:21])[C:23]1[N:31]=[CH:30][CH:29]=[CH:28][C:24]=1[C:25]([NH:12][C:9]1[C:10]2[CH2:11][C:2]([CH3:13])([CH3:1])[CH2:3][CH2:4][C:5]=2[CH:6]=[CH:7][CH:8]=1)=[O:26]
Reactant: CC1(C)CCc2cccc(N)c2C1
Reactant: O=C(Cl)c1cccnc1C(F)F
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC1(C)CCc2cccc(NC(=O)c3cccnc3C(F)F)c2C1
Reaction time: 2 h

Procedure:
In a round bottom flask, 7,7-dimethyl-5,6,7,8-tetrahydronaphthalen-1-amine (150 mg, 0.86 mmol, 1.0 eq.) was dissolved in 5 ml of THF. Triethylamine (0.104 mg, 1.02 mmol, 1.2 eq) was added followed by a solution of 2-(difluoromethyl)nicotinoyl chloride (180 mg, 0.94 mmol, 1.1 eq) in 1 ml of THF. Stirring was allowed for 2 h at r.t. The reaction was quenched with water, the organic layer extracted with AcOEt, washed with brine and dried over chemelut cartridge. The solvent was removed under vacuum and purification of the crude material by
Reaction SMILES: [C:1]([OH:11])(=O)[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[Cl-].[Cl-].[Cl-].[Al+3]>>[C:12]1([CH:3]2[C:4]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[C:1](=[O:11])[CH2:2]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: c1ccccc1
Reactant: O=C(O)C=Cc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Product: O=C1CC(c2ccccc2)c2ccccc21
Yield: 600.2 %

Procedure:
To the solution of 90 g (0.0608 moles) of cinnamic acid in 400 ml of benzene 300 g (2.25 moles) of aluminium trichloride is added, beginning with a very slow addition rate. At the end, the mixture is kept refluxing for 22 hours. The resulting reaction mixture is hydrolysed with ice and is extracted with ethyl ether which is washed first with water until neutral, and then with a solution of 10% sodium hydroxide. The organic extract is then desiccated and evaporated. The residue is triturated with petroleum ether, is then filtered and is then washed with a small amount of diisopropyl ether, then once more with petroleum ether and is dried yielding 76 g (yield of 60%) of 3-phenyl-1-indanone.
Reaction SMILES: Br[C:2]1[C:14]([CH3:15])=[CH:13][C:5]([O:6][CH:7]2[CH2:12][CH2:11][S:10][CH2:9][CH2:8]2)=[CH:4][C:3]=1[CH3:16].CCCCCC.C([Li])CCC.[B:28](OC(C)C)([O:33]C(C)C)[O:29]C(C)C.Cl>O1CCCC1>[CH3:16][C:3]1[CH:4]=[C:5]([O:6][CH:7]2[CH2:12][CH2:11][S:10][CH2:9][CH2:8]2)[CH:13]=[C:14]([CH3:15])[C:2]=1[B:28]([OH:33])[OH:29]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: Cc1cc(OC2CCSCC2)cc(C)c1Br
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1cc(OC2CCSCC2)cc(C)c1B(O)O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 71 %

Procedure:
To a solution of 4-(4-bromo-3,5-dimethylphenoxy)tetrahydro-2H-thiopyran (3.01 g, 10.0 mmol) in tetrahydrofuran (50 mL) was added dropwise a hexane solution (1.6 M, 6.57 mL, 10.5 mmol) of n-butyllithium at −78° C. The reaction mixture was stirred at the same temperature for 1.5 hr, and triisopropyl borate (6.92 mL, 30.0 mmol) was added. After warming to room temperature, the mixture was stirred overnight. The reaction mixture was ice-cooled, 2 M hydrochloric acid (50 mL) was added, and the mixture was stirred for 2.5 hr. The mixture was separated into the aqueous layer and the organic layer. The organic layer was washed with saturated brine and saturated aqueous sodium hydrogencarbonate while adjusting to neutral, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was washed with cold hexane to give the title compound (1.89 g, yield 71%) as colorless crystals.
Reaction SMILES: [C:1]([O:4][C:5]1[C:10]([C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:9][C:8]([O:15]CC(C)=C)=[CH:7][C:6]=1[C:20]([CH3:23])([CH3:22])[CH3:21])(=[O:3])[CH3:2]>CN(C)C1C=CC=CC=1>[C:1]([O:4][C:5]1[C:10]([C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:9][C:8]2[O:15][C:6]([CH3:20])([CH3:7])[CH2:5][C:7]=2[C:6]=1[C:20]([CH3:23])([CH3:21])[CH3:22])(=[O:3])[CH3:2]
Reactant: C=C(C)COc1cc(C(C)(C)C)c(OC(C)=O)c(C(C)(C)C)c1
Solvent: CN(C)c1ccccc1
Product: CC(=O)Oc1c(C(C)(C)C)cc2c(c1C(C)(C)C)CC(C)(C)O2
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 107.2 %

Procedure:
4-Acetoxy-3,5-di-tert-butyl-l-(2-methyl-2-propenyloxy)benzene (2.22 g) was dissolved in N,N-dimethylaniline (8 ml) and the solution was refluxed under a nitrogen atmosphere for 36 h. After cooling to room temperature, the reaction solution was concentrated under reduced pressure and, after addition of 1N HCl (5 ml) and diethyl ether (10 ml), stirring was continued for 15 min. The organic layer was separated and the aqueous layer was subjected to extraction with diethyl ether. The combined extracts were washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The concentrate was purified by silica gel chromatography (5% ethyl acetate in n-hexane) to afford 5-acetoxy-4,6-di-tert-butyl-2,2-dimethyl-2,3-dihydrobenzofuran [1.19 g (yield, 54%)] as a white solid.
Reaction SMILES: C[O:2][C:3](=[O:40])[C:4]1[CH:9]=[C:8]([Cl:10])[C:7]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[NH:21][C:20]4[CH:22]=[C:23]([C:35]([F:38])([F:37])[F:36])[CH:24]=[C:25]([C:26]5[CH:31]=[C:30]([F:32])[C:29]([F:33])=[C:28]([F:34])[CH:27]=5)[C:19]=4[N:18]=3)[C@H:13]([CH3:39])[CH2:12]2)=[N:6][CH:5]=1.[OH-].[Na+].Cl>C1COCC1>[Cl:10][C:8]1[C:7]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[NH:18][C:19]4[C:25]([C:26]5[CH:31]=[C:30]([F:32])[C:29]([F:33])=[C:28]([F:34])[CH:27]=5)=[CH:24][C:23]([C:35]([F:38])([F:36])[F:37])=[CH:22][C:20]=4[N:21]=3)[C@H:13]([CH3:39])[CH2:12]2)=[N:6][CH:5]=[C:4]([CH:9]=1)[C:3]([OH:40])=[O:2]
Reactant: COC(=O)c1cnc(N2CCN(c3nc4c(-c5cc(F)c(F)c(F)c5)cc(C(F)(F)F)cc4[nH]3)[C@H](C)C2)c(Cl)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: C[C@@H]1CN(c2ncc(C(=O)O)cc2Cl)CCN1c1nc2cc(C(F)(F)F)cc(-c3cc(F)c(F)c(F)c3)c2[nH]1
Temperature: 50 °C
Reaction time: 16 h

Procedure:
A mixture of 5-chloro-6-{(3R)-3-methyl-4-[6-trifluoromethyl-4-(3,4,5-trifluoro-phenyl)-1H-benzoimidazol-2-yl]-piperazin-1-yl}-nicotinic acid methyl ester (58 mg, 0.1 mmol, Example 178c) and 1N NaOH (0.11 mL) in THF (1 mL) was stirred at 50° C. for 16 h. 1N HCl (0.11 mL) was added and the mixture was extracted with EtOAc (2×20 mL). The combined organic extracts were washed with brine (5 mL), dried over Na2SO4 and filtered. The filtrate was evaporated in vacuo and the residue was purified by silica gel column chromatography, eluting with 10% MeOH/EtOAc to give the title compound as a white amorphous solid. MS (ESI, pos. ion) m/e: 570 (M+1).
Reaction SMILES: [F:1][C:2]1[C:3]([NH:30][C@@H:31]([C:34]([CH3:37])([CH3:36])[CH3:35])[CH2:32][OH:33])=[N:4][C:5]([C:10]2[C:18]3[C:13](=[N:14][CH:15]=[C:16]([F:19])[CH:17]=3)[N:12]([S:20]([C:23]3[CH:29]=[CH:28][C:26]([CH3:27])=[CH:25][CH:24]=3)(=[O:22])=[O:21])[CH:11]=2)=[C:6]([CH:9]=1)[C:7]#[N:8].C(N(CC)CC)C.[CH3:45][S:46](Cl)(=[O:48])=[O:47]>ClCCl>[CH3:45][S:46]([O:33][CH2:32][C@@H:31]([NH:30][C:3]1[C:2]([F:1])=[CH:9][C:6]([C:7]#[N:8])=[C:5]([C:10]2[C:18]3[C:13](=[N:14][CH:15]=[C:16]([F:19])[CH:17]=3)[N:12]([S:20]([C:23]3[CH:29]=[CH:28][C:26]([CH3:27])=[CH:25][CH:24]=3)(=[O:21])=[O:22])[CH:11]=2)[N:4]=1)[C:34]([CH3:37])([CH3:36])[CH3:35])(=[O:48])=[O:47]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3nc(N[C@H](CO)C(C)(C)C)c(F)cc3C#N)c3cc(F)cnc32)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)n2cc(-c3nc(N[C@H](COS(C)(=O)=O)C(C)(C)C)c(F)cc3C#N)c3cc(F)cnc32)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a cold (0° C.) solution of (S)-5-fluoro-2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-6-((1-hydroxy-3,3-dimethylbutan-2-yl)amino)nicotinonitrile, 98a, (3.77 g, 7.17 mmol) and triethylamine (1.25 mL, 8.96 mmol) in dichloromethane (75 mL) was added methanesulfonyl chloride (0.69 mL, 8.96 mmol). The solution was stirred at room temperature for 1 hour. The solvent was removed under reduced pressure and water (100 mL) and EtOAc (200 mL) were added. The organic phase was separated, dried (MgSO4), filtered and concentrated under reduced pressure to afford 4.22 g of the desired product as a yellow foamy solid that was used without further purification: LC/MS (60-90% ACN/water 5 min with 0.9% FA, C4) m/z 604.45 (M+H) retention time=2.03 minutes.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][CH2:11][N:10]([CH3:14])[C:9]1=[O:15])(C)(C)C.[ClH:17].C(OCC)(=O)C>C(OCC)(=O)C>[ClH:17].[NH2:7][CH:8]1[CH2:13][CH2:12][CH2:11][N:10]([CH3:14])[C:9]1=[O:15]
Reactant: CN1CCCC(NC(=O)OC(C)(C)C)C1=O
Agent: Cl
Solvent: CCOC(C)=O
Product: CN1CCCC(N)C1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of tert-butyl(1-methyl-2-oxopiperidin-3-yl)carbamate (960 mg) in ethyl acetate (10 mL) was added 4N hydrogen chloride/ethyl acetate (5 mL) at room temperature. The reaction mixture was stirred at room temperature overnight, and the solvent was evaporated under reduced pressure to give the title compound as a crude product.
Reaction SMILES: C([N:5]1[C:12](=O)[N:11]2[C:7](=[N:8][C:9]3[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=32)[S:6]1)CCC.C([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1)#N>ClCCl>[N:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[C:12]1[N:11]2[C:7](=[N:8][C:9]3[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=32)[S:6][N:5]=1
Reactant: CCCCn1sc2nc3ccccc3n2c1=O
Reactant: N#Cc1ccccn1
Solvent: ClCCl
Product: c1ccc(-c2nsc3nc4ccccc4n23)nc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 67.9 %

Procedure:
A mixture of 2-butyl-1,2,4-thiadiazolo[4,5-a]benzimidazole-3(2H)-one (15.0 g, 60.7 mmole) and 2-cyanopyridine (13.3 g, 0.13 mole) in 150 mL of dichloromethane was stirred at room temperature for 72 h. The precipitate was filtered and washed with dichloromethane to give 10.4 g (68%) of 3-(2-pyridyl)-1,2,4-thiadiazolo[4,5-a]benzimidazole as a white solid: mp 173-174° C.; 1H NMR (CDCl3) δ 8.90 (d, 1H), 8.70 (d, 1H), 8.30 (d, 1H), 7.99 (t, 1H), 7.80 (d, 1H), 7.57 (t, 1H) 7.47 (t, 1H), 7.37 (t, 1H) ppm; 13C NMR (CDCl3) δ 166.10, 151.09, 150.11, 148.74, 147.73, 137.38, 130.50, 125.85, 125.24, 124.52, 121.41, 119.11, 116.33 ppm; IR (KBr) ν 3419, 3054, 1611, 1587, 1501, 1463, 1446, 727 cm-1. HRMS calcd for C13H8N4S 252.0470, found 252.0882. Anal. Calcd for C13H8N4S: C, 61.89; H, 3.20; N, 22.21. Found: C, 61.48; H, 3.30; N, 22.24.
Reaction SMILES: I[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.[CH2:13]([OH:16])[CH:14]=[CH2:15].C(=O)(O)[O-].[Na+].C1(C)C=CC=CC=1>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:9]([O:8][C:6](=[O:7])[C:5]1[CH:11]=[CH:12][C:2]([CH2:15][CH2:14][CH:13]=[O:16])=[CH:3][CH:4]=1)[CH3:10]
Reactant: CCOC(=O)c1ccc(I)cc1
Reactant: C=CCO
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ccc(CCC=O)cc1
Temperature: 77.5 °C
Reaction time: 0.25 h
Yield: 98.6 %

Procedure:
Ethyl 4-iodobenzoate (200 g, 0.725 mol) and allyl alcohol (63 g, 1.087 mol) are added to a stirred suspension of Sodium bicarbonate (152 g, 1.812 mol), tetrabutyl-ammounium bromide (117 g, 0.362 mol) and Palladium (II) acetate (3.2 g, 0.014 mol) in DMF (600 mL). The reaction mixture is warmed to 75-80° C. for 3-3.5 hours and cooled to 40° C. -50° C. Toluene (1 L) is added to the reaction mixture with vigorous agitation and the mixture is stirred for 15 min at room temperature. The resulting mixture is filtered through a celite pad. The pad is washed with toluene (2×200 mL). The filtrate and wash are combined, washed with water (3×1 L), evaporated to constant weight at 30° C.-40° C. and 10 mmHg. The crude product 147.5 g (98.8%, 84% by HPLC) of 4-(3-Oxo-propyl)-benzoic acid ethyl ester as dark brown oil is obtained. 1H NMR (DMSO-d6): δ1.38 (t, 3H), 2.81 (t, 2H), 3.03 (t, 2H), 4.39 (q, 2H), 7.27 (d, 2H), 7.98 (d, 2H), 9.81 (s, 1H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH:6](Cl)[C:7]2[CH:11]=[CH:10][S:9][CH:8]=2)=[CH:2]1.[OH:13][CH:14]1[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][CH2:22][O:23][C:24]2[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][C:25]=2[N+:31]([O-:33])=[O:32])[CH2:16][CH2:15]1.OC1CCN(CCCOC2C=CC=CC=2[N+]([O-])=O)CC1>>[S:1]1[CH:5]=[CH:4][C:3]([CH:6]([C:7]2[CH:11]=[CH:10][S:9][CH:8]=2)[O:13][CH:14]2[CH2:15][CH2:16][N:17]([CH2:20][CH2:21][CH2:22][O:23][C:24]3[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][C:25]=3[N+:31]([O-:33])=[O:32])[CH2:18][CH2:19]2)=[CH:2]1
Reactant: ClC(c1ccsc1)c1ccsc1
Reactant: Cc1ccc(OCCCN2CCC(O)CC2)c([N+](=O)[O-])c1
Agent: O=[N+]([O-])c1ccccc1OCCCN1CCC(O)CC1
Product: Cc1ccc(OCCCN2CCC(OC(c3ccsc3)c3ccsc3)CC2)c([N+](=O)[O-])c1

Procedure:
The procedure of Example 36 (a) was repeated except for using di(3-thienyl)methyl chloride and 4-hydroxy-1-[3-(4-methyl-2-nitrophenoxy)propyl]piperidine instead of phenyl-2-thienylmethyl chloride and 4-hydroxy-1-[3-(2-nitrophenoxy)propyl]piperidine to give oily 4-di(3-thienyl)methoxy-1-[3-(4-methyl-2-nitrophenoxy)propyl]piperidine.
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[C:4]([C:9]2[N:18]=[C:17]3[C:12]([C:13]([NH:20][C:21]4[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][N:22]=4)=[CH:14][C:15](O)=[N:16]3)=[CH:11][CH:10]=2)=[N:5][CH:6]=[CH:7][CH:8]=1.P(Cl)(Cl)([Cl:35])=O>>[Cl:35][C:15]1[CH:14]=[C:13]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][N:22]=2)[C:12]2[C:17](=[N:18][C:9]([C:4]3[C:3]([C:2]([F:32])([F:31])[F:1])=[CH:8][CH:7]=[CH:6][N:5]=3)=[CH:10][CH:11]=2)[N:16]=1
Reactant: Oc1cc(Nc2ccc(C(F)(F)F)cn2)c2ccc(-c3ncccc3C(F)(F)F)nc2n1
Reactant: O=P(Cl)(Cl)Cl
Product: FC(F)(F)c1ccc(Nc2cc(Cl)nc3nc(-c4ncccc4C(F)(F)F)ccc23)nc1

Procedure:
Heat 7-[3-(trifluoromethyl)pyridin-2-yl]-4-{[5-(trifluoromethyl)pyridin-2-yl]amino}-[1,8]naphthyridin-2-ol (112 mg) and phosphorus oxychloride (1 mL) at reflux for 1 hour. Evaporate to dryness, partition between ethyl acetate and saturated aqueous NaHCO3 and extract with EtOAc. Dry the combined organics over Na2SO4, concentrate under vacuum to obtain the title compound.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][OH:19])=[CH:12][CH:11]=2)[C:5]([C:20]#[N:21])=[C:4]([S:22][CH2:23][C:24]2[N:25]=[C:26]([C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=3)[S:27][CH:28]=2)[N:3]=1.[CH3:36][NH2:37].O>C1COCC1>[Cl:35][C:32]1[CH:31]=[CH:30][C:29]([C:26]2[S:27][CH:28]=[C:24]([CH2:23][S:22][C:4]3[C:5]([C:20]#[N:21])=[C:6]([C:10]4[CH:11]=[CH:12][C:13]([O:16][CH2:17][CH2:18][OH:19])=[CH:14][CH:15]=4)[C:7]([C:8]#[N:9])=[C:2]([NH:37][CH3:36])[N:3]=3)[N:25]=2)=[CH:34][CH:33]=1
Reactant: CN
Reactant: N#Cc1c(Cl)nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c1-c1ccc(OCCO)cc1
Solvent: O
Solvent: C1CCOC1
Product: CNc1nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c(-c2ccc(OCCO)cc2)c1C#N

Procedure:
At RT, 3.0 g (5.56 mmol) of 2-chloro-6-({(2-(4-chlorophenyl)-1,3-thiazol-4-yl)methyl}sulfanyl)-4-(4-(2-hydroxyethoxy)phenyl)pyridine-3,5-dicarbonitrile (Example 2A) and 11.12 ml (22.24 mmol) of methylamine were stirred in 75 ml of THF overnight. About 300 ml of water were added to the reaction mixture, and the precipitate formed was filtered off and washed with water and dried under high vacuum. This gave 2.69 g (91% of theory) of the desired target compound.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH:10]([OH:30])[CH:11]([NH:19]C(OCC1C=CC=CC=1)=O)[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CO.[C].[Pd]>[NH2:19][CH:11]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH:10]([C:2]1[O:1][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=1)[OH:30]
Reactant: O=C(NC(Cc1ccccc1)C(O)c1nc2ccccc2o1)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: NC(Cc1ccccc1)C(O)c1nc2ccccc2o1
Temperature: 25 °C
Reaction time: 18 h
Yield: 100.4 %

Procedure:
To a solution of the objective compound (3.63 g, 9.02 mmol) of Step (4) in methanol (50 mL) was added under nitrogen atmosphere 10% palladium carbon (480 mg) and the mixture was stirred at room temperature for 18 hours under hydrogen atmosphere. The catalyst was filtered off and washed with methanol. The filtrate was concentrated under reduced pressure to give the title compound as a brown solid (2.43 g, 100%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:10])[CH3:9])=[CH:4][CH:3]=1.[N+:11]([O-])([OH:13])=[O:12]>O>[CH:8]([C:5]1[CH:6]=[CH:7][C:2]([OH:1])=[C:3]([N+:11]([O-:13])=[O:12])[CH:4]=1)([CH3:10])[CH3:9]
Reactant: CC(C)c1ccc(O)cc1
Reactant: O=[N+]([O-])O
Solvent: O
Product: CC(C)c1ccc(O)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To a suspension of 5.0 g of 4-hydroxycumene in 14 ml of water was added dropwise 4.0 ml of 70% nitric acid while cooling with ice and the temperature of mixture was raised to room temperature and the reaction was carried out for 40 minutes. After 500 ml of water was added thereto, the reaction mixture was extracted with 500 ml of ethyl acetate, washed with water and a brine successively, and dried with anhydrous sodium sulfate. The drying agent was filtered off and the solvent was distilled away under reduced pressure. The residue was purified by subjecting silica-gel column-chromatography [eluent: ethyl acetate]to give 5.07 g of 4-isopropyl-2-nitrophenol.
Reaction SMILES: [NH2:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][C:7]2[NH:15][C:14]3[C:13](=[O:16])[N:12]([CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[F:24])[C:11](=[O:25])[N:10]([CH2:26][CH2:27][CH2:28][CH3:29])[C:9]=3[N:8]=2)=[CH:4][CH:3]=1.[Cl:32][C:33]1[CH:34]=[C:35]([S:40](Cl)(=[O:42])=[O:41])[CH:36]=[C:37]([Cl:39])[CH:38]=1>>[CH2:26]([N:10]1[C:9]2[N:8]=[C:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([NH:1][S:40]([C:35]4[CH:34]=[C:33]([Cl:32])[CH:38]=[C:37]([Cl:39])[CH:36]=4)(=[O:42])=[O:41])=[CH:31][CH:30]=3)[NH:15][C:14]=2[C:13](=[O:16])[N:12]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[F:24])[C:11]1=[O:25])[CH2:27][CH2:28][CH3:29]
Reactant: O=S(=O)(Cl)c1cc(Cl)cc(Cl)c1
Reactant: CCCCn1c(=O)n(Cc2ccccc2F)c(=O)c2[nH]c(Cc3ccc(N)cc3)nc21
Product: CCCCn1c(=O)n(Cc2ccccc2F)c(=O)c2[nH]c(Cc3ccc(NS(=O)(=O)c4cc(Cl)cc(Cl)c4)cc3)nc21

Procedure:
Prepared from 8-(4-amino-benzyl)-3-butyl-1-(2-fluoro-benzyl)-3,7-dihydro-purine-2,6-dione and 3,5-dichloro-benzenesulfonyl chloride. Purity (ELSD, based on MW=630.5)=97%.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([NH2:12])=[O:11])=[C:8]([F:15])[CH:7]=1.[Cl:16][CH2:17][C:18]([CH2:20]Cl)=O>C(#N)CC>[Cl:16][CH2:17][C:18]1[N:12]=[C:10]([C:9]2[CH:13]=[CH:14][C:6]([O:5][CH2:4][CH2:3][CH2:2][Cl:1])=[CH:7][C:8]=2[F:15])[O:11][CH:20]=1
Reactant: O=C(CCl)CCl
Reactant: NC(=O)c1ccc(OCCCCl)cc1F
Solvent: CCC#N
Product: Fc1cc(OCCCCl)ccc1-c1nc(CCl)co1
Temperature: 100 °C
Reaction time: 60 h
Yield: 44 %

Procedure:
A mixture of 4-(3-chloropropoxy)-2-fluorobenzamide i82 (0.41 g, 1.75 mmol, 1 eq) and 1,3-dichloroacetone (0.49 g, 3.85 mmol, 2.2 eq) in propionitrile (9 ml) is stirred at 100° C. for 60 h. The mixture is then concentrated under vacuum, taken up in dichloromethane, and washed with water. The organic phase is dried over magnesium sulfate and concentrated under reduced pressure. The residue is purified by chromatography over silicagel (eluent: dichloromethane) to afford 0.23 g of 4-(chloromethyl)-2-[4-(3-chloropropoxy)-2-fluorophenyl]-1,3-oxazole i84.