Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][N:10]=[C:11]([C:14]#[N:15])[C:12]#[N:13])[CH:5]=[CH:6][C:7]=1[Cl:8].ClC1C=C(C=CC=1Cl)N.C(#N)CC#N.O.[NH2:31][NH2:32]>>[NH2:15][C:14]1[C:11](=[N:10][NH:9][C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)[C:12]([NH2:13])=[N:32][N:31]=1
Reactant: N#CC(C#N)=NNc1ccc(Cl)c(Cl)c1
Reactant: NN
Agent: Nc1ccc(Cl)c(Cl)c1
Solvent: N#CCC#N
Solvent: O
Product: NC1=NN=C(N)C1=NNc1ccc(Cl)c(Cl)c1
Yield: 39 %

Procedure:
This compound was prepared using 120 mg (0.5 mmol) of 2-[(3,4-dichlorophenyl)-hydrazono]malononitrile, which was derived from 3,4-dichloroaniline (162 mg, 1.0 mmol) and malononitrile (1.5 mmol) as described in Example 8, and hydrazine hydrate. Precipitate formed in the reaction tube immediately after the addition of hydrazine hydrate. The resulting solid was isolated by filtration, precipitated from an ethyl acetate solution by the addition of hexanes, and dried to yield 53 mg (39%) of the title compound as a yellow solid. 1H NMR (ppm, DMSO-d6): 6.30 (br, s, 4H), 7.55-7.79 (m, 2H), 7.95 (s, 1H), 10.80 (s, 1H).
Reaction SMILES: C([O:4][C:5]1[C:6](=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:7](Cl)=[O:8])(=O)C.C(OC1C(=CC=CC=1)C(O)=O)(=O)C.S(Cl)(Cl)=O.[NH2:31][C:32]1[CH:37]=[C:36]([Cl:38])[C:35]([OH:39])=[C:34]([Cl:40])[CH:33]=1>>[Cl:38][C:36]1[CH:37]=[C:32]([CH:33]=[C:34]([Cl:40])[C:35]=1[OH:39])[NH:31][C:7](=[O:8])[C:6]1[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=1[OH:4]
Reactant: Nc1cc(Cl)c(O)c(Cl)c1
Reactant: CC(=O)Oc1ccccc1C(=O)Cl
Agent: CC(=O)Oc1ccccc1C(=O)O
Solvent: O=S(Cl)Cl
Product: O=C(Nc1cc(Cl)c(O)c(Cl)c1)c1ccccc1O

Procedure:
Acetylsalicyloyl chloride prepared by reaction of acetylsalicylic acid with thionyl chloride was condensed with 4-amino-2,6-dichlorophenol, and then deacetylated to give 3',5'-dichloro-2,4'-dihydroxybenzanilide. That compound (4 g.) was dissolved in cold anhydrous acetic acid (50 ml.) and with stirring there was added with 3 drops of concentrated sulfuric acid. After reaction for 1-2 hours at 5°-6° C., the solution was poured into ice-cold water (500 ml.) and the white precipitate thus formed was collected by filtration, rinsed with water, dried and recrystallized from methanol to give white needle-like crystals (3.65 g.) of 2,4'-diacetoxy-3',5'-dichlorobenzanilide. Yield: 71.1%. Melting point: 154°-156° C.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[Cl-].[NH4+].[C:7]1([NH:13][C:14]2[C:23]3[C:18](=[CH:19][N:20]=[CH:21][CH:22]=3)[C:17]3[CH:24]=[CH:25][C:26]([C:28]#[N:29])=[CH:27][C:16]=3[N:15]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>CN(C)C=O.O>[C:7]1([NH:13][C:14]2[C:23]3[C:18](=[CH:19][N:20]=[CH:21][CH:22]=3)[C:17]3[CH:24]=[CH:25][C:26]([C:28]4[NH:29][N:3]=[N:2][N:1]=4)=[CH:27][C:16]=3[N:15]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1ccc2c(c1)nc(Nc1ccccc1)c1ccncc12
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: c1ccc(Nc2nc3cc(-c4nnn[nH]4)ccc3c3cnccc23)cc1
Temperature: 120 °C
Yield: 49.1 %

Procedure:
Sodium azide (65 mg, 1 mmol) and ammonium chloride (53 mg, 1 mmol) were added to a crude mixture of the 5-(phenylamino)benzo[c][2,6]naphthyridine-8-carbonitrile (25 mg, 0.084 mmol) in dimethylformamide (0.2 mL). The mixture was heated for 18 h at 120° C. at which time LCMS analysis indicated the absence of any starting material. The mixture was diluted with water and purified by preparative HPLC to give N-phenyl-8-(1H-tetrazol-5-yl)benzo[c][2,6]naphthyridin-5-amine (14 mg). LCMS (ESI) 340.3 (M+1)+. 1HNMR (400 MHz, CD3OD) 10.11 (1H, s), 8.96 (1H, d, 5.9 Hz), 8.85 (1H, d, 8.2 Hz), 8.53 (1H, d, 5.5 Hz), 8.47 (1H,$), 8.16 (1H, d, 8.6 Hz), 7.88 (1H, s), 7.86 (1H, d, 0.8 Hz), 7.57-7.51 (3H, m), 7.36-7.31 (2H, m).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:8]([O:10][C:11]1[CH:15]=[C:14]([N:16]2[C:24]3[CH:23]=[C:22]([CH2:25][OH:26])[N:21]=[CH:20][C:19]=3[N:18]=[CH:17]2)[S:13][C:12]=1[C:27]([NH2:29])=[O:28])[CH3:9].[CH3:30][S:31](Cl)(=[O:33])=[O:32].C(N(CC)CC)C>ClCCl>[CH3:30][S:31]([O:26][CH2:25][C:22]1[N:21]=[CH:20][C:19]2[N:18]=[CH:17][N:16]([C:14]3[S:13][C:12]([C:27](=[O:28])[NH2:29])=[C:11]([O:10][C@@H:8]([C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[F:1])[CH3:9])[CH:15]=3)[C:24]=2[CH:23]=1)(=[O:33])=[O:32]
Reactant: C[C@@H](Oc1cc(-n2cnc3cnc(CO)cc32)sc1C(N)=O)c1ccccc1F
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@@H](Oc1cc(-n2cnc3cnc(COS(C)(=O)=O)cc32)sc1C(N)=O)c1ccccc1F

Procedure:
In a similar manner as described for example 49 (step 1), 737 mg of 3-[(1R)-1-(2-fluorophenyl)ethoxy]-5-[6-(hydroxymethyl)-1H-imidazo[4,5-c]pyridin-1-yl]thiophene-2-carboxamide, 409 mg of methanesulfonyl chloride, and 362 mg of triethylamine in 18 ml dichloromethane give (1-{5-carbamoyl-4-[(1R)-1-(2-fluorophenyl)ethoxy]-2-thienyl}-1H-imidazo[4,5-c]pyridin-6-yl)methyl methanesulfonate as crude material that is used for step 2 without further purification.
Reaction SMILES: C(C1N=C(N2CCC(F)(F)C2)C2N=NN(CC)C=2N=1)(C)(C)C.[C:23]([C:27]1[N:28]=[C:29]([N:36]2[CH2:40][C:39]([F:42])([F:41])[C:38]([F:44])([F:43])[CH2:37]2)[C:30]2[N:35]=[N:34][NH:33][C:31]=2[N:32]=1)([CH3:26])([CH3:25])[CH3:24].Cl.Cl[CH2:47][C:48]1[N:52]([CH3:53])[N:51]=[N:50][CH:49]=1>>[C:23]([C:27]1[N:28]=[C:29]([N:36]2[CH2:40][C:39]([F:41])([F:42])[C:38]([F:43])([F:44])[CH2:37]2)[C:30]2[N:35]=[N:34][N:33]([CH2:47][C:48]3[N:52]([CH3:53])[N:51]=[N:50][CH:49]=3)[C:31]=2[N:32]=1)([CH3:26])([CH3:24])[CH3:25]
Reactant: Cn1nncc1CCl
Reactant: CC(C)(C)c1nc(N2CC(F)(F)C(F)(F)C2)c2nn[nH]c2n1
Agent: CCn1nnc2c(N3CCC(F)(F)C3)nc(C(C)(C)C)nc21
Agent: Cl
Product: Cn1nncc1Cn1nnc2c(N3CC(F)(F)C(F)(F)C3)nc(C(C)(C)C)nc21

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3-ethyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 61), the title compound was prepared from 5-tert-Butyl-7-(3,3,4,4-tetrafluoro-pyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 5-(chloromethyl)-1-methyl-1H-1,2,3-triazole hydrochloride and isolated as light-yellow gum. MS(m/e): 414.3 (MH+).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:15]=[C:14]2[C:9]([C:10]([O:16][C:17]3[CH:22]=[CH:21][C:20]([NH:23][C:24]([NH:26][CH2:27][CH2:28][CH3:29])=[O:25])=[C:19]([Cl:30])[CH:18]=3)=[CH:11][CH:12]=[N:13]2)=[CH:8][C:7]=1[O:31][CH3:32].C(=O)([O-])[O-].[K+].[K+].[CH3:39][NH:40][CH2:41][CH2:42][OH:43].O>CN(C)C=O>[Cl:30][C:19]1[CH:18]=[C:17]([O:16][C:10]2[C:9]3[C:14](=[CH:15][C:6]([O:5][CH2:4][CH2:3][CH2:2][N:40]([CH2:41][CH2:42][OH:43])[CH3:39])=[C:7]([O:31][CH3:32])[CH:8]=3)[N:13]=[CH:12][CH:11]=2)[CH:22]=[CH:21][C:20]=1[NH:23][C:24]([NH:26][CH2:27][CH2:28][CH3:29])=[O:25]
Reactant: CNCCO
Reactant: CCCNC(=O)Nc1ccc(Oc2ccnc3cc(OCCCBr)c(OC)cc23)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCNC(=O)Nc1ccc(Oc2ccnc3cc(OCCCN(C)CCO)c(OC)cc23)cc1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 98 %

Procedure:
A starting compound (N-(4-{[7-(3-bromopropoxy)-6-methoxy-4-quinolyl]oxy}-2-chlorophenyl)-N′-propylurea, 52 mg), potassium carbonate (138 mg), and 2-(methylamino)ethanol (0.040 ml) were dissolved in N,N-dimethylformamide (1 ml), and the solution was stirred at room temperature for 18 hr. Water was added to the reaction mixture, and the mixture was extracted with chloroform-propanol (3/1). The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed by distillation under the reduced pressure. The residue was washed with ether to give 51 mg (yield 98%) of the title compound.
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([CH3:9])=[C:4]([CH3:10])[C:3]=1[OH:11].[H-].[Na+].[CH3:14][O:15][CH2:16]Cl>CN(C)C=O.O>[Br:1][C:2]1[C:3]([O:11][CH2:14][O:15][CH3:16])=[C:4]([CH3:10])[C:5]([CH3:9])=[CH:6][C:7]=1[CH3:8]
Reactant: COCCl
Reactant: Cc1cc(C)c(Br)c(O)c1C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COCOc1c(C)c(C)cc(C)c1Br
Reaction time: 0.17 h
Yield: 99 %

Procedure:
Under nitrogen gas, a solution of 2-bromo-3,5,6-trimethylphenol (10 g) in N,N-dimethylformamide (50 mL) was added dropwise to a suspension of 60% sodium hydride (2.1 g) in N,N-dimethylformamide (20 mL) under ice-cooling and the mixture was stirred for 10 minutes. To this mixture was further added a solution of chloromethyl methyl ether (3.9 mL) in N,N-dimethylformamide (5mL) dropwise and the mixture was stirred for another 30 minutes. This reaction mixture was diluted with iced water and extracted with ethyl acetate. The extract was washed with saturated aqueous sodium chloride solution, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=97:3) to provide the title compound (12 g). Yield 99%.
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([NH:8][C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[NH:14][N:13]=[CH:12]3)=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O.O>[NH2:8][C:9]1[CH:10]=[CH:11][C:15]([N:14]2[C:15]3[C:11](=[CH:10][C:9]([NH:8][C:6](=[O:7])[C:5]4[CH:18]=[CH:19][C:2]([F:1])=[CH:3][CH:4]=4)=[CH:17][CH:16]=3)[CH:12]=[N:13]2)=[CH:16][CH:17]=1
Reactant: O=C(Nc1ccc2[nH]ncc2c1)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Product: Nc1ccc(-n2ncc3cc(NC(=O)c4ccc(F)cc4)ccc32)cc1
Temperature: 100 °C
Reaction time: 24 h
Yield: 135.1 %

Procedure:
4-Fluoro-N-(1H-indazol-5-yl)benzamide (10.3 g, 40 mmol), 4-fluoronitrobenze (4.3 mL, 40 mmol) and cesium carbonate (13 g, 40 mmol) were taken up in DMSO (400 mL). The solution was heated to 100° C. and stirred for 24 h. After the solution was cooled it was diluted with water until a precipitate formed and stirred well for 5 min. Filtration gave a yellow solid, which was then washed well with water, followed by hexanes. After the solid was dried under vacuum it was taken up in ethanol and stirred at RT under nitrogen. The solution was treated with Pd(OH)2 (100 mg) and placed under a balloon of H2 gas. After stirring at RT for 24 h, the catalyst was removed via filtration through celite. The filtrate was concentrated under reduced pressure to give 9.36 g (67%) of a crude product as a yellow solid
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[F:12][C:13]1[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[C:14]=1[CH2:15][S:16]([C:18]1[CH2:22][C:21]([CH2:24][CH3:25])([CH3:23])[O:20][N:19]=1)=[O:17].O>C(Cl)(Cl)Cl>[F:12][C:13]1[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[C:14]=1[CH2:15][S:16]([C:18]1[CH2:22][C:21]([CH2:24][CH3:25])([CH3:23])[O:20][N:19]=1)(=[O:9])=[O:17]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCC1(C)CC(S(=O)Cc2c(F)cccc2F)=NO1
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCC1(C)CC(S(=O)(=O)Cc2c(F)cccc2F)=NO1
Reaction time: 1 h
Yield: 70.6 %

Procedure:
1.0 g of m-chloroperbenzoic acid (purity: 70%, 4.1 mmoles) was added, with ice-cooling, to a solution of 0.8 g (2.8 mmoles) of 3-(2,6-difluorobenzylsulfinyl)-5-ethyl-5-methyl-2-isoxazoline dissolved in 50 ml of chloroform. The mixture was stirred for 1 hour and then at room temperature for 12 hours to give rise to a reaction. After the completion of the reaction. the reaction mixture was poured into water, followed by extraction with chloroform. The resulting organic layer was washed with an aqueous sodium hydrogensulfite solution, an aqueous sodium hydrogencarbonate solution, water and an aqueous sodium chloride solution in this order and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein. The residue was purified by silica gel column chromatography (developing solvent: hexane-ethyl acetate mixed solvent) to obtain 0.6 g (yield: 75.0%) of 3-(2,6-difluorobenzylsulfonyl)-5-ethyl-5-methyl-2-isoxazoline as a white powder (melting point: 64 to 65° C.).
Reaction SMILES: Br[C:2]1[CH:20]=[CH:19][C:5]([C:6]([NH:8][CH:9]2[C:14]([CH3:16])([CH3:15])[C@H:13]3[CH2:17][C@:10]2([CH3:18])[CH2:11][CH2:12]3)=[O:7])=[CH:4][C:3]=1[S:21]([N:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1)(=[O:23])=[O:22].[CH2:30]([OH:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C(OCC)(=O)C>CN(C)C=O>[CH2:30]([O:37][C:2]1[CH:20]=[CH:19][C:5]([C:6]([NH:8][CH:9]2[C:14]([CH3:16])([CH3:15])[C@H:13]3[CH2:17][C@:10]2([CH3:18])[CH2:11][CH2:12]3)=[O:7])=[CH:4][C:3]=1[S:21]([N:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1)(=[O:23])=[O:22])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: CC1(C)C(NC(=O)c2ccc(Br)c(S(=O)(=O)N3CCOCC3)c2)[C@@]2(C)CC[C@@H]1C2
Reactant: OCc1ccccc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC1(C)C(NC(=O)c2ccc(OCc3ccccc3)c(S(=O)(=O)N3CCOCC3)c2)[C@@]2(C)CC[C@@H]1C2
Temperature: 100 °C

Procedure:
4-Bromo-3-(morpholinosulfonyl)-N-((1S,4R)-1,3,3-trimethylbicyclo[2.2.1]heptan-2-yl)benzamide (2.4.AaBa, 1.00 g, 2.06 mmol) benzyl alcohol (3.1, 0.256 mL, 0.00247 mol) were dissolved in 10 mL dimethylformamide. The reaction was heated to 100° C. for 18 hours. Ethyl acetate (20 mL) was added and aqueous workup was performed. The organic layer was dried over magnesium sulfate evaporated and purified via SiO2 chromatography (16%-33% ethyl acetate/hexane) to yield 4-(benzyloxy)-3-(morpholinosulfonyl)-N-((1S,4R)-1,3,3-trimethylbicyclo[2.2.1]heptan-2-yl)benzamide (2I) as a white solid. MS analysis (m+1)=513.7.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]([C:11]1[N:12]=[CH:13][NH:14][CH:15]=1)[CH3:10].ClC1C(Cl)=CC=CC=1C(C1N=CNC=1)=C.C([O-])(O)=O.[Na+].C1C=CC(OC(Cl)=[S:44])=CC=1>O1CCCC1.O>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]([C:11]1[NH:12][C:13](=[S:44])[NH:14][CH:15]=1)[CH3:10]
Reactant: S=C(Cl)Oc1ccccc1
Reactant: CC(c1c[nH]cn1)c1cccc(Cl)c1Cl
Agent: C=C(c1c[nH]cn1)c1cccc(Cl)c1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(c1c[nH]c(=S)[nH]1)c1cccc(Cl)c1Cl
Reaction time: 5 h

Procedure:
A 1:1 mixture of 4-[1-(2,3-dichloro-phenyl)-ethyl]-1H-imidazole (Intermediate A4), and 4-[1-(2,3-dichloro-phenyl)-vinyl]-1H-imidazole (Intermediate A3) (0.77 g, 3.2 mmol) in tetrahydrofuran (THF) (10 mL) and water (10 mL) was treated with NaHCO3 (1.64 g, 19.5 mmol) at rt for 10 m. Phenyl chlorothionoformate (1.1 mL, 7.95 mmol) was added and stirring was continued for 5 h. The mixture was diluted with water and extracted with hexane:ethyl acetate (3×). The organic portions were combined, dried over MgSO4, filtered and the solvent was removed under vacuum. The residue was dissolved in MeOH (20 mL) and treated with triethylamine (NEt3) (1 mL) for 18 h at rt. The mixture was concentrated onto silica gel. The material was purified by elution from silica gel with 1 to 2% MeOH: CH2Cl2. The solids were titurated with CHCl3: hexanes and collected on a glass frit to give a white solid 4-[1-(2,3-dichloro-phenyl)-ethyl]-1,3-dihydro-imidazole-2-thione (Compound 1) 40 mg.
Reaction SMILES: CCCC[CH:5]1[C:10](=[O:11])[N:9]([C:12]2[CH:13]=[CH:14][C:15]([OH:18])=[CH:16][CH:17]=2)[N:8]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:6]1=[O:7].[C:25](Cl)(=[O:27])[CH3:26]>C(O)(=O)C>[C:19]1([N:8]2[C:6](=[O:7])[CH2:5][C:10](=[O:11])[N:9]2[C:12]2[CH:17]=[CH:16][C:15]([O:18][C:25](=[O:27])[CH3:26])=[CH:14][CH:13]=2)[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CCCCC1C(=O)N(c2ccccc2)N(c2ccc(O)cc2)C1=O
Reactant: CC(=O)Cl
Solvent: CC(=O)O
Product: CC(=O)Oc1ccc(N2C(=O)CC(=O)N2c2ccccc2)cc1

Procedure:
First, 1-Phenyl-2-(4'-acetyloxyphenyl)-3,5-pyrazolidinedione was prepared as follows. Oxyphenbutazone (1.00 g, 3.1 mmole) was suspended in 4 ml of glacial acetic acid and allowed to react with 2 ml of acetyl chloride at room temperature overnight. The solution was concentrated in vacuo at 86° C. to give a white residue (mp 126°-130° C.). The residue was crystallized from chloroformheptane (6:50) with cooling to give 0.81 g (mp 132°-134° C., 71% yield, lit., R. Pfester and F. Hafliger, Helvetica Chemica Acta, 40, 395 (1957) mp 135°-137° C. from methanol) of 1-phenyl-2-(4'acetyloxyphenyl)-3,5-pyrazolidinedione.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](S(C)(=O)=O)[N:3]=1.[C:19]1([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4]([N:28]2[CH2:29][CH2:30][N:25]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:26][CH2:27]2)[N:3]=1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: CS(=O)(=O)c1nc(N)nc(-c2ccco2)c1C#N
Solvent: COCCOC
Product: N#Cc1c(-c2ccco2)nc(N)nc1N1CCN(c2ccccc2)CC1

Procedure:
From 2-amino-4-furan-2-yl-6-methanesulfonyl-pyrimidine-5-carbonitrile and 1-phenylpiperazine in DME. ES-MS m/e (%): 347 (M+H+, 100).
Reaction SMILES: Cl.C[O:3][C:4](=[O:24])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:23])=[CH:10][CH:9]=1)[NH2:6].[CH3:25][C:26]1[NH:27][C:28]([CH3:37])=[C:29]([C:34](=[O:36])[CH3:35])[C:30]=1C(O)=O>>[Cl:23][C:17]1[CH:18]=[CH:19][CH:20]=[C:21]([Cl:22])[C:16]=1[CH2:15][O:14][C:11]1[CH:12]=[CH:13][C:8]([CH2:7][C@@H:5]([C:4]([OH:3])=[O:24])[NH:6][C:30]2[C:29]([C:34](=[O:36])[CH3:35])=[C:28]([CH3:37])[NH:27][C:26]=2[CH3:25])=[CH:9][CH:10]=1
Reactant: CC(=O)c1c(C)[nH]c(C)c1C(=O)O
Reactant: COC(=O)[C@@H](N)Cc1ccc(OCc2c(Cl)cccc2Cl)cc1
Agent: Cl
Product: CC(=O)c1c(C)[nH]c(C)c1N[C@@H](Cc1ccc(OCc2c(Cl)cccc2Cl)cc1)C(=O)O

Procedure:
from O-(2,6-dichlorobenzyl)-L-tyrosine methyl ester hydrochloride and 2,5-dimethyl-4-acetyl-pyrrole-3-carboxylic acid. Freeze drying afforded the title compound as a white amorphous solid (203 mg). δH (DMSO-d6) 11.2 (1H, s), 8.83 (1H, d, J 8.0 Hz), 7.56 (2H, app.d. J 8.0 Hz), 7.45 (1H, app.t, J 8.0 Hz), 7.21 (2H, d, J 8.5 Hz), 6.95 (2H, d, J 8.5 Hz), 5.17 (2H, s), 4.61-4.52 (1H, m), 3.11 (1H, dd, J 13.8, 4.3 Hz), 2.86 (1H, dd, J 13.8, 10.4 Hz), 2.31 (3H, s), 2.08 (3H, s), 2.07 (3H, s); m/z (ESI, 60V) 503 and 505 (MH+).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8]O)=[CH:6][CH:5]=[CH:4][C:3]=1[OH:10].P(Br)(Br)[Br:12].O>C(Cl)(Cl)Cl>[Br:12][CH2:8][C:7]1[C:2]([Cl:1])=[C:3]([OH:10])[CH:4]=[CH:5][CH:6]=1
Reactant: BrP(Br)Br
Reactant: OCc1cccc(O)c1Cl
Solvent: ClC(Cl)Cl
Solvent: O
Product: Oc1cccc(CBr)c1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 67 %

Procedure:
To a solution of 2-chloro-3-(hydroxymethyl)phenol (400 mg, 2.5 mmol) in anhydrous chloroform (8 mL) was added dropwise a solution of phosphorus tribromide (240 μL, 2.5 mmol) in anhydrous chloroform (2 mL) at 0° C. The mixture was stirred for 2 hours at room temperature. Water was added and extracted 3 times with dichloromethane. The combined organic phase was washed with brine and dried over magnesium sulfate. After evaporation of the solvent, 3-(bromomethyl)-2-chlorophenol was obtained (373 mg, 67% yield) and used for next step without further purification; 1H NMR (400 MHz, DMSO-d6): δ 4.70 (s, 2H), 6.94-6.97 (m, 1H), 7.02-7.04 (m, 1H), 7.13 (t, J=7.8 Hz, 1H), 10.32 (bs, 1H).
Reaction SMILES: CO[NH:3][C:4]1[N:5]=[CH:6][CH:7]=[C:8]2[CH:12]=[CH:11][O:10][C:9]=12.C(O)(=O)C>C(Cl)Cl.[Zn]>[O:10]1[C:9]2=[C:4]([NH2:3])[N:5]=[CH:6][CH:7]=[C:8]2[CH:12]=[CH:11]1
Reactant: CONc1nccc2ccoc12
Agent: [Zn]
Solvent: CC(=O)O
Solvent: ClCCl
Product: Nc1nccc2ccoc12
Yield: 97.5 %

Procedure:
N-methoxyfuro[2,3-c]pyridin-7-amine (43.0 g, 0.26 mol) in DCM (200 mL) was cooled in a water bath. Zinc dust (36.0 g, 0.64 mol) was added in one portion and stirred for a few min. Acetic acid (18.8 g, 0.31 mol) was added slowly over 5-10 min and stirred for 30 min. The water bath was removed and the mixture was stirred at RT for 16 h. At this point, TLC analysis (5% MeOH in DCM) indicated complete consumption of the starting material. The mixture was diluted with 400 mL of DCM and washed with saturated NaHCO3 until the pH of the wash was about 8.5. The DCM layer was then washed with water (2×100 mL) and then brine. The solution was dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The resulting crude product was purified by flash chromatography (2% MeOH:DCM) to provide 34 g (97%) of the title compound. 1H NMR (300 MHz, CDCl3): δ 4.89 (br s, 2H), 6.71 (d, J=1.8 Hz, 1H), 6.94 (d, J=5.4 Hz, 1H), 7.63 (d, J=1.8 Hz, 1H), 7.84 (d, J=5.4 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH3:21])[N:14]([CH2:15][CH2:16][CH2:17][C:18](=O)[CH3:19])[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.Cl.[NH2:23][OH:24].[OH-].[Na+]>C(O)C.O>[NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH3:21])[N:14]([CH2:15][CH2:16][CH2:17][C:18](=[N:23][OH:24])[CH3:19])[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1
Reactant: NO
Reactant: CC(=O)CCCn1c(C)nc2c(N)nc3ccccc3c21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(CCCn1c(C)nc2c(N)nc3ccccc3c21)=NO
Reaction time: 0.5 h

Procedure:
A solution of 5-(4-amino-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)pentan-2-one, 2.20 g, 7.80 mmol) in ethanol (50 mL) was heated at reflux, and a solution of hydroxylamine hydochloride (1.08 g, 15.6 mmol) in water (10 mL) was added, followed by a solution of sodium hydroxide (0.94 g, 23.5 mmol) in water (10 mL). After 30 minutes, the reaction mixture was cooled in an ice bath to cause crystallization of the product, which was isolated by filtration and recrystallized from aqueous DMSO to provide 5-(4-amino-2-methyl-1H-imidazo[4,5-c]quinolin-1-yl)pentan-2-one oxime in about a 16 to 1 mixture of E and Z isomers as yellow crystals, mp 264-266° C.
Reaction SMILES: [OH:1][CH:2]1[C:7](=[O:8])[CH:6]=[CH:5][N:4]=[C:3]1[CH3:9].[CH:10](N)([CH3:12])[CH3:11].C>O.CC(C)=O>[CH:10]([N:4]1[CH:5]=[CH:6][C:7](=[O:8])[C:2]([OH:1])=[C:3]1[CH3:9])([CH3:12])[CH3:11]
Reactant: CC1=NC=CC(=O)C1O
Reactant: CC(C)N
Solvent: O
Solvent: CC(C)=O
Product: Cc1c(O)c(=O)ccn1C(C)C
Reaction time: 0.5 h

Procedure:
1-Isopropyl-3-hydroxy-2-methylpyrid-4-one was prepared by refluxing 3-hydroxy-2-methylpyrid-4-one (Maltol) (10.0 g) with 3 equivalents of isopropylamine (99%) in 200 ml of water for 8 hours. Decolorizing charcoal was added after refluxing and the mixture was stirred for 0.5 hours. The mixture was then filtered through a medium frit filter containing 0.5 inches of Celite. The filtered solution was then concentrated in vacuo (rotary evaporator) to remove the water and excess amine, leaving a dark thick oil. The oil was then dissolved in minimal amounts of hot acetone and filtered (repeatedly) through a medium frit filter. Brownish crystals (product) remained on the frit and these were then washed (3X) with 1 ml portions of hot acetone to obtain white crystals. m.p. 239°-242 ° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[C:4]1[CH:9]=[C:8]([C:10]2[CH:15]=[C:14]([S:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([OH:23])[CH:18]=3)[N:13]=[C:12]([NH2:24])[N:11]=2)[C:7]([CH3:25])=[CH:6][C:5]=1[O:26][CH2:27][CH3:28].C(=O)([O-])[O-].[Cs+].[Cs+].CN(C)C=O.[C:41]([O:45][C:46](=[O:52])[NH:47][CH2:48][CH2:49][CH2:50]Br)([CH3:44])([CH3:43])[CH3:42]>C(OCC)(=O)C>[CH3:1][O:2][C:3](=[O:29])[C:4]1[CH:9]=[C:8]([C:10]2[CH:15]=[C:14]([S:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH2:50][CH2:49][CH2:48][NH:47][C:46]([O:45][C:41]([CH3:42])([CH3:44])[CH3:43])=[O:52])[CH:18]=3)[N:13]=[C:12]([NH2:24])[N:11]=2)[C:7]([CH3:25])=[CH:6][C:5]=1[O:26][CH2:27][CH3:28]
Reactant: CCOc1cc(C)c(-c2cc(Sc3cccc(O)c3)nc(N)n2)cc1C(=O)OC
Reactant: CC(C)(C)OC(=O)NCCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOc1cc(C)c(-c2cc(Sc3cccc(OCCCNC(=O)OC(C)(C)C)c3)nc(N)n2)cc1C(=O)OC
Temperature: 25 °C
Reaction time: 4 h
Yield: 94.4 %

Procedure:
5-[2-Amino-6-(3-hydroxyphenylsulfanyl)pyrimidin-4-yl]-2-ethoxy-4-methylbenzoic acid methyl ester (110 mg, 0.27 mmol) obtained in Step 1 above, cesium carbonate (133 mg, 0.41 mmol), and N,N-dimethylformamide (1.2 ml) were added to a reaction vessel, and then 3-bromopropylcarbamic acid tert-butyl ester (97 mg, 0.41 mmol) was added thereto. The resulting mixture was stirred at room temperature for 4 hours. The reaction solution was diluted with ethyl acetate (100 ml), and sequentially washed twice with a saturated aqueous ammonium chloride solution (50 ml), twice with water (50 ml), and with a saturated aqueous sodium chloride solution (50 ml). The washed ethyl acetate solution was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (developing solvent: n-hexane:ethyl acetate=2:3) to yield 5-{2-amino-6-[3-(3-tert-butoxycarbonylaminopropoxy)phenylsulfanyl]pyrimidin-4-yl}-2-ethoxy-4-methylbenzoic acid methyl ester (145 mg).