Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]([CH:9]=[CH2:10])=[CH:3][O:4][Si](C)(C)C.[CH2:11]([O:13][CH:14](OCC)[CH3:15])[CH3:12].O>ClCCl.[Br-].[Zn+2].[Br-]>[Br:1][C:2](=[CH:3][CH2:4][CH:11]([O:13][CH2:14][CH3:15])[CH3:12])[CH:9]=[O:10]
Reactant: CCOC(C)OCC
Reactant: C=CC(Br)=CO[Si](C)(C)C
Agent: [Br-]
Agent: [Zn+2]
Solvent: ClCCl
Solvent: O
Product: CCOC(C)CC=C(Br)C=O
Yield: 77.8 %

Procedure:
A solution of 2.21 g (10 mmoles) of 2-bromo-1-trimethylsiloxybut-1,3-diene in 30 ml of anhydrous dichloromethane are introduced into a 100 ml reactor traversed by a stream of nitrogen. 1.18 g (about 11 mmoles) of 1,1-diethoxyethane are slowly added and then 100 mg of anhydrous zinc bromide. After reaction for 10 minutes, 20 ml of water are added, the organic phase is collected, and the aqueous phase is extracted with 20 ml of dichloromethane. The dichloromethane fractions are combined and dried with 5 g of anhydrous magnesium sulfate. The solvent is eliminated by vacuum evaporation and the residue distilled, the boiling point of the product being 66° C. under 0.15 mm Hg. 1.72 g of product are obtained, representing a yield of 78%. The structure of the product obtained is confirmed by NMR analysis and mass spectrometry.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18]2[CH2:17][CH2:16][CH2:15][CH2:14][C:13]=2[C:12](Br)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:20][N:21](C)P(N(C)C)(N(C)C)=O>C(Cl)Cl>[CH2:1]([O:8][C:9]1([C:20]#[N:21])[C:18]2[CH2:17][CH2:16][CH2:15][CH2:14][C:13]=2[CH:12]=[CH:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1ccc(OCc2ccccc2)c2c1CCCC2
Reactant: CN(C)P(=O)(N(C)C)N(C)C
Solvent: ClCCl
Product: N#CC1(OCc2ccccc2)CC=CC2=C1CCCC2

Procedure:
1-Benzyloxy-4-bromo-5,6,7,8-tetrahydronaphthalene (4.5 g, 14.2 mM), cuprous cyanide (1.71 g, 8.67 mM) pyridine (1 ml) and hexamethylphosphoramide (0.25 ml) was stirred at 170° C. for 16 hours. The resultant viscous mixture was dissolved in methylene chloride and washed with ammonium hydroxide solution, saturated brine solution, dried (sodium sulphate) and evaporated to give an oil (4.6 g). This oil was chromatographed on alumina (eluted with methylene chloride:petroleum ether, 1:1) to give the nitrile (5) as a solid (2.4 g) m pt 74°-75° C.
Reaction SMILES: Br[C:2]1[C:10]2[NH:9][C:8](=[O:11])[N:7]([CH3:12])[C:6]=2[C:5]([CH:13]([CH2:16][CH3:17])[CH2:14][CH3:15])=[CH:4][CH:3]=1.[CH3:18][Sn](C)(C)C>CN(C)P(=O)(N(C)C)N(C)C.O.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>[CH2:14]([CH:13]([C:5]1[C:6]2[N:7]([CH3:12])[C:8](=[O:11])[NH:9][C:10]=2[C:2]([CH3:18])=[CH:3][CH:4]=1)[CH2:16][CH3:17])[CH3:15]
Reactant: C[Sn](C)(C)C
Reactant: CCC(CC)c1ccc(Br)c2[nH]c(=O)n(C)c12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCC(CC)c1ccc(C)c2[nH]c(=O)n(C)c12
Yield: 57.1 %

Procedure:
A solution of 4-bromo-7-(1-ethylpropyl)-1-methyl-1,3-dihydro-2H-benzimidazol-2-one (250 mg, 0.84 mmol), tetrakis(triphenylphosphine)palladium (194 mg, 0.168 mmol), tetramethyltin (1.16 mL, 8.4 mmol) in hexamethylphosphoric triamide (5 mL) was refluxed for 18 h. After cooling, the mixture was diluted with water and extracted with dichloromethane. The organics were dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography on a silica gel (n-hexane/ethyl acetate=90:10-50:50) to give the title compound (111 mg, 0.48 mmol, 57%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH:12]([CH3:14])[CH:11]([OH:15])[CH:10]([CH3:16])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:17](OC(=O)C)(=[O:19])[CH3:18]>CN(C1C=CN=CC=1)C.N1C=CC=CC=1>[C:17]([O:15][CH:11]1[CH:12]([CH3:14])[CH2:13][N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:9][CH:10]1[CH3:16])(=[O:19])[CH3:18]
Reactant: CC1CN(Cc2ccccc2)CC(C)C1O
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CC(=O)OC1C(C)CN(Cc2ccccc2)CC1C
Temperature: 110 °C
Reaction time: 2 h

Procedure:
A mixture of N-benzyl-4-hydroxy-3,5-dimethylpiperidine (21.9 g, 0.1 mole), acetic anhydride (15.3 g), N,N-dimethyl-4-aminopyridine (0.01 g) and pyridine (100 ml) was stirred at 110° C. for 2 hr. The reaction mixture was concentrated to dryness, triturated with water (50 ml) and extracted with chloroform (2×50 ml). The extract was dried (Na2SO4) and concentrated to dryness to furnish a crude mixture of cis- and trans-4-acetoxy-1-benzyl-3,5-dimethylpiperidine. Yield 16 g (61.3%), C16H23NO2, m/z 262 (M+1).
Reaction SMILES: [Cl:1][CH2:2][C:3]([CH2:5]Cl)=O.[NH2:7][C:8]1[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][N:9]=1>C(O)C>[Cl:1][CH2:2][C:3]1[N:7]=[C:8]2[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][N:9]2[CH:5]=1
Reactant: Cc1cccnc1N
Reactant: O=C(CCl)CCl
Solvent: CCO
Product: Cc1cccn2cc(CCl)nc12
Temperature: 25 °C
Yield: 28.1 %

Procedure:
3.81 g of 1,3-dichloroacetone and 3.24 g of 2-amino-3-methylpyridine were dissolved in 30 ml of ethanol, and the solution was heated to reflux for 5 hours. The reaction mixture was cooled to room temperature and then concentrated under reduced pressure. To the residue, 50 ml of aqueous saturated sodium hydrogen carbonate was added and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography and then recrystallized from hexane-methyl-t-butyl ether to obtain 1.52 g of 2-(chloromethyl)-8-methylimidazo[1,2-a]pyridine.
Reaction SMILES: [O:1]=[C:2]1[C:11]([C:12]([O:14]CC)=[O:13])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:17][O:18][CH2:19][C:20]([F:23])([F:22])[F:21].O.[OH-].[Li+]>C(O)C.O>[O:1]=[C:2]1[C:11]([C:12]([OH:14])=[O:13])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:17][O:18][CH2:19][C:20]([F:23])([F:21])[F:22]
Reactant: CCOC(=O)c1nc2ccccc2n(COCC(F)(F)F)c1=O
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1nc2ccccc2n(COCC(F)(F)F)c1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 174.9 %

Procedure:
1.5 g (4.54 mmol) of ethyl 2-oxo-1-[(2,2,2-trifluoroethoxy)methyl]-1,2-dihydroquinoxaline-3-carboxylate and 0.28 g (6.81 mmol) of lithium hydroxide monohydrate were dissolved in a solvent mixture of ethanol (30 mL) and water (30 mL), and the solution was stirred for 2 hours at room temperature. The reaction solution was concentrated to a half the original volume, and then water was added to the residue. The mixture was acidified using 10% hydrochloric acid, and then extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate, and concentrated, to obtain 2.4 g (yield: 53%) of 2-oxo-1-[(2,2,2-trifluoroethoxy)methyl]-1,2-dihydroquinoxaline-3-carboxylic acid as a white powder.
Reaction SMILES: [CH:1]1([N:4]([CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[C:5](=[O:17])[C:6]2[CH:11]=[CH:10][C:9]([C:12]3[O:16][CH:15]=[N:14][CH:13]=3)=[CH:8][CH:7]=2)[CH2:3][CH2:2]1.[Br:24][C:25]1[CH:26]=[CH:27][C:28](F)=[N:29][CH:30]=1>>[Br:24][C:25]1[CH:26]=[CH:27][C:28]([N:21]2[CH2:22][CH2:23][CH:18]([N:4]([CH:1]3[CH2:3][CH2:2]3)[C:5](=[O:17])[C:6]3[CH:7]=[CH:8][C:9]([C:12]4[O:16][CH:15]=[N:14][CH:13]=4)=[CH:10][CH:11]=3)[CH2:19][CH2:20]2)=[N:29][CH:30]=1
Reactant: Fc1ccc(Br)cn1
Reactant: O=C(c1ccc(-c2cnco2)cc1)N(C1CCNCC1)C1CC1
Product: O=C(c1ccc(-c2cnco2)cc1)N(C1CC1)C1CCN(c2ccc(Br)cn2)CC1

Procedure:
The title compound is prepared from N-cyclopropyl-4-oxazol-5-yl-N-piperidin-4-yl-benzamide and 5-bromo-2-fluoro-pyridine following a procedure analogous to that described in Example 19. LC (method 10): tR=1.92 min; Mass spectrum (ESI+): m/z=467/469 (Br) [m+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:8]=[CH:9][CH:10]=1)[NH2:7])([O-:3])=[O:2].CO[CH:13]1[CH2:17][CH2:16][CH:15](OC)O1.CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[N+:1]([C:4]1[CH:5]=[C:6]([N:7]2[CH:13]=[CH:17][CH:16]=[CH:15]2)[CH:8]=[CH:9][CH:10]=1)([O-:3])=[O:2]
Reactant: Nc1cccc([N+](=O)[O-])c1
Reactant: COC1CCC(OC)O1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1cccc(-n2cccc2)c1

Procedure:
A mixture of 3-nitroaniline (15 g, 0.11 mmol), 2,5-dimethoxytetrahydrofuran (42 ml, 0.33 mol) and a catalytic amount of pTSA in dry toluene (150 ml) is heated to reflux for 2 hours. After cooling the mixture is concentrated under reduced pressure and the residue is purified by column-chromatography on silica gel using a mixture of ethyl acetate and petroleum ether (1:1) as the eluent. Yield: 16 g (78%). Mp 65-70° C.
Reaction SMILES: [C:1]([CH2:5][CH2:6][C:7]([NH:9][CH:10]([P:14](=[O:19])([O:17]C)[O:15]C)[CH:11]([CH3:13])[CH3:12])=[O:8])([O:3][CH3:4])=[O:2].C[Si](Br)(C)C>C(Cl)Cl>[C:1]([CH2:5][CH2:6][C:7]([NH:9][CH:10]([P:14](=[O:15])([OH:19])[OH:17])[CH:11]([CH3:13])[CH3:12])=[O:8])([O:3][CH3:4])=[O:2]
Reactant: COC(=O)CCC(=O)NC(C(C)C)P(=O)(OC)OC
Agent: C[Si](C)(C)Br
Solvent: ClCCl
Product: COC(=O)CCC(=O)NC(C(C)C)P(=O)(O)O

Procedure:
To a solution of a compound of formula 4, preferably dimethyl [1-[N-(3-carbomethoxypropionyl)amino]-2-methylpropyl]phosphonate, in an anhydrous polar aprotic solvent, such as methylene chloride, under an inert atmosphere, such as argon, is added trimethylsilyl bromide. The reaction is allowed to stir until complete. The product, a compound of formula 5, preferably [1-[N-(3-carbomethoxypropionyl)amino]-2-methylpropyl]phosphonic acid, may be isolated and purified by conventional means.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[C:11]([F:14])([F:13])[CH3:12].[Cl-].[NH4+].O>[Fe].CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[C:11]([F:13])([F:14])[CH3:12]
Reactant: CC(F)(F)c1cc([N+](=O)[O-])ccc1Cl
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: O
Product: CC(F)(F)c1cc(N)ccc1Cl
Temperature: 70 °C
Reaction time: 1 h
Yield: 87.8 %

Procedure:
480 mg (2.17 mmol) of 1-chloro-2-(1,1-difluoro-ethyl)-4-nitro-benzene, 464 mg (8.67 mmol) of ammonium chloride and 365 mg (6.51 mmol) of iron powder were added to a mixture of 1.5 mL of water and 3 mL of methanol. The slurry was stirred at 70° C. for 1 h, and then cooled down, filtered through a pad of celite washing with excess methanol and concentrated down under reduced pressure. The residue was dissolved in ethyl acetate, evaporated under reduced pressure on silica gel and purified on silica eluting with a 5-30% ethyl acetate in hexanes to give 365 mg of the pure product as a white solid. LC-MSD, m/z for C8H8ClF2N [M+H]+=192.0, 194.0;
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[C:16]1[S:17][CH:18]=[CH:19][N:20]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:16]2[S:17][CH:18]=[CH:19][N:20]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: Brc1nccs1
Product: CC(C)(C)OC(=O)N1CCC(Oc2nccs2)CC1

Procedure:
By a similar manner to Reference Example 44, 1-tert-butoxycarbonyl-4-hydroxypiperidine (1.01 g, 5.0 mmol) was reacted with 2-bromothiazole (0.59 mL, 6.5 mmol) to give the titled compound as pale yellow oily substance (189 mg, 13%).
Reaction SMILES: C[N:2]([CH3:16])[S:3]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:15])[CH2:9]2)(=[O:5])=[O:4].C[N:18]1[CH2:23][CH2:22][C:21]2=[C:24]([CH:27]=O)[NH:25][CH:26]=[C:20]2[C:19]1=[O:29].N1CCCCC1>C(O)C>[CH3:16][NH:2][S:3]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:15])[C:9]2=[CH:27][C:24]1[NH:25][CH:26]=[C:20]2[C:21]=1[CH2:22][CH2:23][NH:18][C:19]2=[O:29])(=[O:4])=[O:5]
Reactant: CN(C)S(=O)(=O)c1ccc2c(c1)CC(=O)N2
Reactant: CN1CCc2c(c[nH]c2C=O)C1=O
Solvent: CCO
Solvent: C1CCNCC1
Product: CNS(=O)(=O)c1ccc2c(c1)C(=Cc1[nH]cc3c1CCNC3=O)C(=O)N2
Temperature: 80 °C

Procedure:
A mixture of 2-oxo-2,3-dihydro-1H-indole-5-sulfonic acid dimethylamide (48 mg, 0.2 mmol), 5-methyl-4-oxo-4,5,6,7-tetrahydro-2H-pyrrolo[3,4-c]pyridine-1-carbaldehyde (35.6 mg, 0.2 mmol) and piperidine (0.1 mL) in ethanol (1 mL) was heated at 80° C. for 4 hours. The precipitate was collected by vacuum filtration, washed with ethanol and dried to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([CH:11]([OH:13])[CH3:12])[CH2:10][O:9][CH2:8][CH2:7][O:6]1)=[O:4].[C:14]1([CH3:24])[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1>N1C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1([CH:11]([O:13][S:20]([C:17]2[CH:18]=[CH:19][C:14]([CH3:24])=[CH:15][CH:16]=2)(=[O:22])=[O:21])[CH3:12])[CH2:10][O:9][CH2:8][CH2:7][O:6]1)=[O:4]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(=O)C1(C(C)O)COCCO1
Solvent: c1ccncc1
Product: COC(=O)C1(C(C)OS(=O)(=O)c2ccc(C)cc2)COCCO1
Temperature: 25 °C
Reaction time: 18 h
Yield: 63.3 %

Procedure:
A solution of 2-(1-hydroxy-ethyl)-[1,4]dioxane-2-carboxylic acid methyl ester (1.49 g, 7.8 mmol) in pyridine (8 mL) was stirred at room temperature. 4-Toluenesulfonyl chloride (1.50 g, 7.8 mmol) was added and the reaction mixture was stirred at room temperature for 18 h. The majority of the pyridine was evaporated, 1 M hydrochloric acid was added to acidify the mixture to pH 2 and the mixture was extracted with ethyl acetate. The organic extracts were combined and washed with brine. The organic solution was filtered through a hydrophobic frit and the filtrate was evaporated. The residue was purified by silica gel chromatography using a gradient of pentane/diethyl ether 3:1 to 0:1 to afford the title compound (1.70 g, 63%) as a yellow gum and as a 3:1 mixture of diastereoisomers. LCMS (m/z) 367.0 [M+Na], Tr=2.44 min.
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]=1[C:10]1[CH:17]=[CH:16][C:13]([CH:14]=O)=[CH:12][CH:11]=1.[C:18]([O:22][C:23]([N:25]1[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=2[N:27]=[C:26]1[CH2:34][NH:35][CH:36]1[C:45]2[N:44]=[CH:43][CH:42]=[CH:41][C:40]=2[CH2:39][CH2:38][CH2:37]1)=[O:24])([CH3:21])([CH3:20])[CH3:19].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:17]=[CH:16][C:13]([CH2:14][N:35]([CH2:34][C:26]2[N:25]([C:23]([O:22][C:18]([CH3:20])([CH3:21])[CH3:19])=[O:24])[C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=3[N:27]=2)[CH:36]2[C:45]3[N:44]=[CH:43][CH:42]=[CH:41][C:40]=3[CH2:39][CH2:38][CH2:37]2)=[CH:12][CH:11]=1
Reactant: O=Cc1ccc(-c2nc3ccccc3[nH]2)cc1
Reactant: CC(C)(C)OC(=O)n1c(CNC2CCCc3cccnc32)nc2ccccc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)n1c(CN(Cc2ccc(-c3nc4ccccc4[nH]3)cc2)C2CCCc3cccnc32)nc2ccccc21
Temperature: 60 °C
Reaction time: 3 h
Yield: 32.1 %

Procedure:
Using General Procedure B: To a solution 4-(benzimidazol-2-yl)-benzaldehyde (39 mg, 0.175 mmol) and (1-tert-butoxycarbonyl-1H-Benzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amine (60 mg, 0.16 mmol) in THF (2 mL) was added acetic acid (90 μL) and sodium triacetoxyborohydride (68 mg, 0.32 mmol) and the mixture stirred at 60° C. for 3 h. Purification of the crude product by radial chromatography on silica gel (0.7% MeOH/0.5% NH4OH/CH2Cl2) afforded the desired [4-(1H-benzimidazol-2-yl)-benzyl]-(N-tert-butoxycarbonylbenzimidazol-2-ylmethyl)-(5,6,7,8-tetrahydroquinolin-8-yl)-amine (30 mg, 39%) as a flaky white solid. 1H NMR (CDCl3) δ 1.72 (s, 10H), 1.97 (m, 2H), 2.26 (m, 1H), 2.73 (m, 2H), 3.80 (d, 1H, J=15.0 Hz), 4.00 (d, 1H, J=15.0 Hz), 4.35 (m, 1H), 4.71 (s, 2H), 7.00 (m, 1H), 7.14 (m, 2H), 7.24 (m, 3H), 7.33 (d, 2H, J=7.2 Hz), 7.47 (br, 1H), 7.53 (d, 1H, J=7.2 Hz), 7.63 (d, 1H, J=7.8 Hz), 7.67 (d, 2H, J=7.8 Hz), 7.79 (br, 1H), 8.39 (d, 1H, J=3.5 Hz), 9.92 (br, 1H (NH)).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([Si](C)(C)C)[CH:5]=[CH:4][C:3]=1[NH:12][C:13]1[C:14]([N+:24]([O-:26])=[O:25])=[C:15]2[O:23][CH2:22][CH2:21][N:16]2[C:17](=[O:20])[C:18]=1[CH3:19].[I:27]Cl>C(Cl)Cl.F[B-](F)(F)F.[Ag+]>[F:1][C:2]1[CH:7]=[C:6]([I:27])[CH:5]=[CH:4][C:3]=1[NH:12][C:13]1[C:14]([N+:24]([O-:26])=[O:25])=[C:15]2[O:23][CH2:22][CH2:21][N:16]2[C:17](=[O:20])[C:18]=1[CH3:19]
Reactant: ClI
Reactant: Cc1c(Nc2ccc([Si](C)(C)C)cc2F)c([N+](=O)[O-])c2n(c1=O)CCO2
Agent: [Ag+]
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: Cc1c(Nc2ccc(I)cc2F)c([N+](=O)[O-])c2n(c1=O)CCO2
Temperature: -50 °C
Reaction time: 1 h
Yield: 70 %

Procedure:
A stirred solution of 7-(2-fluoro-4-trimethylsilanyl-phenylamino)-6-methyl-8-nitro-2,3-dihydro-oxazolo[3,2-a]pyridin-5-one (0.25 g, 0.66 mmol) in dry DCM (10 mL) and iodine monochloride (0.8 mL) were added to silver tetrafluoroborate (0.4 g, 2.05 mmol) in DCM (10 mL) previously degassed with nitrogen for 30 minutes at −50° C. The resulting mixture was stirred at −50° C. for 1 hour. The reaction was monitored by TLC (50% ethylacetate in hexane). This was followed by the addition of 20 mL of sodium thiosulphate and filtered through celite. The filtrate was concentrated to afford 0.2 g of the product (70% yield).
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1.[C:12](Cl)(=[O:15])[CH:13]=[CH2:14].[Cl-].[Al+3].[Cl-].[Cl-]>>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12](=[O:15])[CH:13]=[CH2:14])=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: Brc1cccc2ccccc12
Reactant: C=CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Product: C=CC(=O)c1ccc2c(Br)cccc2c1
Yield: 4.2 %

Procedure:
1-bromonaphthalene (0.42 g), acryloyl chloride (0.31 g), and aluminium chloride (0.27 g) were treated in the same manner as described in Example 1 to obtain the title compound (22 mg).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][C:10](=O)[CH2:9][CH2:8]2)=[CH:3][CH:2]=1.O.[NH2:15][NH2:16]>C(O)C>[N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][C:10](=[N:15][NH2:16])[CH2:9][CH2:8]2)=[CH:3][CH:2]=1
Reactant: NN
Reactant: O=C1CCN(c2ccncc2)CC1
Solvent: O
Solvent: CCO
Product: NN=C1CCN(c2ccncc2)CC1

Procedure:
A solution of 1-(4-pyridyl)-4-piperidone (3.52 g) and hydrazine hydrate (1.25 q) in ethanol (50 ml) was stirred at room temperature for 15 hours. The reaction mixture was concentrated and the residue obtained was crystallized from ether to obtain [1-(4-pyridyl)-4-piperidinylidene]hydrazine (3.51 g) as colorless crystals.
Reaction SMILES: [CH:1]([NH:4][N:5]1[C:17]2[C:16]3[CH:15]=[CH:14][C:13]([CH:18]=[CH:19][C:20]4[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=4)=[CH:12][C:11]=3[N:10]=[C:9]([NH2:26])[C:8]=2[N:7]=[C:6]1[CH2:27][CH2:28][CH3:29])([CH3:3])[CH3:2]>CCO.CO.[Pd]>[CH:1]([NH:4][N:5]1[C:17]2[C:16]3[CH:15]=[CH:14][C:13]([CH2:18][CH2:19][C:20]4[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=4)=[CH:12][C:11]=3[N:10]=[C:9]([NH2:26])[C:8]=2[N:7]=[C:6]1[CH2:27][CH2:28][CH3:29])([CH3:3])[CH3:2]
Reactant: CCCc1nc2c(N)nc3cc(C=Cc4cccnc4)ccc3c2n1NC(C)C
Agent: [Pd]
Solvent: CO
Solvent: CCO
Product: CCCc1nc2c(N)nc3cc(CCc4cccnc4)ccc3c2n1NC(C)C
Temperature: 25 °C
Reaction time: 72 h
Yield: 23.1 %

Procedure:
A solution of N1-isopropyl-2-propyl-7-(2-pyridin-3-yl-vinyl)-1H-imidazo[4,5-c]quinoline-1,4-diamine (0.97 g, 2.5 mmol) in 15 mL of EtOH and 15 mL of MeOH was treated with palladium on carbon (0.10 g, 0.050 mmol, 5% w/w). The mixture was placed under an atmosphere of hydrogen (3.8×105 Pa) and shaken at ambient temperature. After 3 d, the reaction mixture was filtered through a pad of CELITE filter agent and rinsed with a 1:1 MeOH:EtOH until the filtrate ran clear. The filtrate was concentrated under reduced pressure to yield a light green solid. The solid was purified by chromatography (SiO2, 10–50% (80:18:2 CHCl3:MeOH:NH4OH) in CHCl3) to yield a clear oil. The oil was twice crystallized from MeCN to give N1-isopropyl-2-propyl-7-(2-pyridin-3-ylethyl)-1H-imidazo[4,5-c]quinoline-1,4-diamine (0.224 g) as white crystals. mp 100–103° C.; 1H NMR (300 MHz, DMSO-d6) δ 8.43 (d, J=1.6 Hz, 1H), 8.37 (dd, J=3.8, 1.6 Hz, 1H), 8.32 (d, J=8.4 Hz, 1H), 7.68–7.64 (m, 1H), 7.37 (d, J=1.5 Hz, 1H), 7.31–7.26 (m, 1H), 7.12 (dd, J=8.4, 1.7 Hz, 1H), 6.93 (d, J=1.4 Hz, 1H), 6.39 (s, 2H), 3.52–3.44 (m, 1H), 3.00 (s, 4H), 2.89 (bs, 2H), 1.91–1.79 (m, 2H), 1.04–1.00 (m, 9H); 13C NMR (125 MHz, DMSO-d6) δ 154.2, 152.0, 150.1, 147.5, 145.0, 139.6, 137.2, 136.3, 132.8, 125.4, 123.9, 123.7, 122.0, 121.1, 113.1, 51.2, 37.0, 34.1, 28.2, 21.1, 20.6, 14.3; MS (APCI) m/z 389 (M+H)+; Anal. Calcd for C23H28N6: C, 71.10; H, 7.26; N, 21.63; Found: C, 70.87; H, 7.54; N, 21.58.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]2[N:6]([CH2:10][CH2:11][CH2:12]Cl)[C:7](=[O:9])[S:8][C:4]=2[CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH:22]1[CH:23]=[CH:24][C:25]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[CH:26][CH:27]=1>CN(C=O)C>[Cl:1][C:2]1[CH:15]=[CH:14][C:5]2[N:6]([CH2:10][CH2:11][CH2:12][N:31]3[CH2:32][CH2:33][N:28]([C:25]4[CH:26]=[CH:27][CH:22]=[CH:23][CH:24]=4)[CH2:29][CH2:30]3)[C:7](=[O:9])[S:8][C:4]=2[CH:3]=1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: O=c1sc2cc(Cl)ccc2n1CCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=c1sc2cc(Cl)ccc2n1CCCN1CCN(c2ccccc2)CC1
Yield: 61.9 %

Procedure:
A solution of compound (X) (3.71 g, 20 mmol), K2CO3 (3.31 g, 24 tool), phenylpiperazine (XIb) (3.24 g, 20 mmol), and KI (3.98 g, 24 mmol) in DMF (20 ml) was stirred at 100° C. for 5 hours and concentrated in vacuo. The residue was extracted with dichloromethane, washed with a saturated saline solution and dried over MgSO4. The dichloromethane layer was subjected to column chromatography on silica gel. The eluate eluted with dichloromethane/ethyl acetate (4/1) was recrystallized from ethyl ether to obtain compound (XIIb) (4.8 g, yield=61.9%) as colorless prism-shaped crystals.
Reaction SMILES: [CH2:1]([S:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15](=[O:19])[NH:14][CH:13]=[C:12]2Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cu][C:22]#[N:23].CN1C(=O)CCC1>C(OCC)(=O)C>[CH2:1]([S:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15](=[O:19])[NH:14][CH:13]=[C:12]2[C:22]#[N:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#C[Cu]
Reactant: O=c1[nH]cc(Br)c2cc(SCc3ccccc3)ccc12
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: N#Cc1c[nH]c(=O)c2ccc(SCc3ccccc3)cc12
Temperature: 200 °C
Reaction time: 4 h

Procedure:
A vial was charged with 6-(benzylthio)-4-bromoisoquinolin-1(2H)-one (0.583 g, 1.684 mmol), copper (i) cyanide (0.052 ml, 1.684 mmol), and NMP (8.42 ml). The reaction was heated to 200° C. and stirred for four hours. The reaction was diluted with ethyl acetate and washed with water. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were dried with sodium sulfate, filtered, and concentrated. The material was purified via column chromatography (40 g silica gel column, gradient elution 0 to 10% MeOH:EtOAc) to afford 6-(benzylthio)-1-oxo-1,2-dihydroisoquinoline-4-carbonitrile as a brown solid. m/z (ESI) 293.1 (M+H)+.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[C:7]([C:10]#[N:11])[CH:8]=[CH:9][C:4]=2[CH:3]=[CH:2]1.[Br:12]N1C(=O)CCC1=O>CN(C=O)C.O>[Br:12][C:3]1[C:4]2[CH:9]=[CH:8][C:7]([C:10]#[N:11])=[CH:6][C:5]=2[S:1][CH:2]=1
Reactant: N#Cc1ccc2ccsc2c1
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccc2c(Br)csc2c1
Temperature: 25 °C

Procedure:
To a solution of 1-benzothiophene-6-carbonitrile (2.13 g, 13.4 mmol) in dry DMF (20 mL) at −10° C. was added freshly recrystallised N-bromosuccinimide (2.38 g, 13.4 mmol). The solution was allowed to warm to room temperature and stirred over the weekend. The mixture was diluted with water and extracted into diethyl ether, and the organic extract washed with water, then brine. The extracts were dried (MgSO4), filtered and evaporated in vacuo. The crude product was purified by flash chromatography on silica, eluting with ethyl acetate/hexane (1:9), to yield the title compound as a white solid.