Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2-].[Na+].[CH3:3][C:4](=[O:9])[C:5]([CH3:8])([CH3:7])[CH3:6].[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[N:21]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=3[Cl:29])[N:20]=[C:19]([C:30](OCC)=[O:31])[C:18]=2[CH3:35])=[CH:13][CH:12]=1.Cl>C1COCC1>[Cl:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]2[N:21]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=3[Cl:29])[N:20]=[C:19]([C:30](=[O:31])/[CH:3]=[C:4](\[OH:9])/[C:5]([CH3:8])([CH3:7])[CH3:6])[C:18]=2[CH3:35])=[CH:15][CH:16]=1
Reactant: CCOC(=O)c1nn(-c2ccc(Cl)cc2Cl)c(-c2ccc(Cl)cc2)c1C
Reactant: CC(=O)C(C)(C)C
Agent: Cl
Agent: [NH2-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1c(C(=O)/C=C(\O)C(C)(C)C)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Temperature: 80 °C
Yield: 37.2 %

Procedure:
To a solution of sodium amide (215 mg, 5.5 mmol) in THF (5 mL) was added pinacolone (1.0 M THF solution, 5 mL, 5.0 mmol). The reaction mixture was refluxed at 80° C. for 30 min and then ethyl 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxylate (4) (2.05 g, 5.0 mmol) in THF (15 mL) was added. The resulting solution was stirred and refluxed at 80° C. overnight. HCl aquous solution (11.0M, 50 mL) was added and extracted organic layer with ethyl acetate (50 mL twice). The combined organic phase was evaporated under vacuum. The crude residue was further purified by prep HPLC to provide 0.862 g (1.86 mmol, 37%) of the title compound.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH:25]1[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=2[N:27]=[C:26]1[C:34]([C:36]1[CH:51]=[CH:50][C:39]([O:40][C:41]2[C:42]([C:47](O)=[O:48])=[N:43][CH:44]=[CH:45][N:46]=2)=[CH:38][CH:37]=1)=[O:35].C(N(C(C)C)CC)(C)C.[C:61]1([CH2:67][CH2:68][NH2:69])[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1>CN(C=O)C>[NH:27]1[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[N:25]=[C:26]1[C:34]([C:36]1[CH:37]=[CH:38][C:39]([O:40][C:41]2[C:42]([C:47]([NH:69][CH2:68][CH2:67][C:61]3[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=3)=[O:48])=[N:43][CH:44]=[CH:45][N:46]=2)=[CH:50][CH:51]=1)=[O:35]
Reactant: O=C(c1ccc(Oc2nccnc2C(=O)O)cc1)c1nc2ccccc2[nH]1
Reactant: NCCc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(c1ccc(Oc2nccnc2C(=O)NCCc2ccccc2)cc1)c1nc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
HATU (123 mg, 0.324 mmol) was added to a mixture of 3-(4-(1H-benzo[d]imidazole-2-carbonyl)phenoxy)pyrazine-2-carboxylic acid (106 mg, 0.294 mmol) and diisopropylethylamine (102 μL, 0.588 mmol) in DMF (1 mL) and the mixture was stirred at RT for 10 min. 2-Phenylethylamine (55.8 μL, 0.441 mmol) was added and the mixture was stirred at RT for 1 h. The mixture was purified by chromatography on silica gel to deliver 3-(4-(1H-benzo[d]imidazole-2-carbonyl)phenoxy)-N-phenethylpyrazine-2-carboxamide as a white solid. MS (ESI, pos. ion) m/z: 464.0 (M+1). IC50 (uM) +++++.
Reaction SMILES: [C:1]([C:3]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:15])[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1)#[N:2].[C:16]([O:20][C:21]([NH:23][CH2:24][CH2:25][CH2:26]Br)=[O:22])([CH3:19])([CH3:18])[CH3:17].C(N(C(C)C)CC)(C)C>CN(C=O)C>[C:16]([O:20][C:21]([NH:23][CH2:24][CH2:25][CH2:26][N:6]1[CH2:7][CH2:8][C:3]([C:1]#[N:2])([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:15])[CH2:4][CH2:5]1)=[O:22])([CH3:19])([CH3:18])[CH3:17]
Reactant: Cc1ccccc1C1(C#N)CCNCC1
Reactant: CC(C)(C)OC(=O)NCCCBr
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccccc1C1(C#N)CCN(CCCNC(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A solution of 4-cyano-4-(o-tolyl)piperidine (5.00 g, 24.9 mmol) and 1-(tert-butoxycarbonylamino)-3-bromopropane (16, 6.55 g, 27.5 mmol) in DMF (100 mL) was treated with diisopropylethylamine (4.50 mL, 25.8 mmol) at room temperature. The resulting mixture was stirred at room temperature (3 d). The solvent was removed in vacuo and the residue dissolved in dichloromethane and sodium bicarbonate solution. The aqueous layer was extracted with two additional portions of dichloromethane and the combined organic extracts were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. Flash chromatography on silica gel (5% methanol/dichloromethane) afforded the title compound (25).
Reaction SMILES: CC(C)([O-])C.[K+].[CH2:7]([NH:9][C:10]([C:12]1[S:30][C:15]2[N:16]=[C:17]([NH2:29])[N:18]=[C:19]([C:20]3[CH:25]=[C:24]([OH:26])[C:23]([Cl:27])=[CH:22][C:21]=3[Cl:28])[C:14]=2[CH:13]=1)=[O:11])[CH3:8].O.[CH2:32]([O:34][CH:35]([O:38][CH2:39][CH3:40])[CH2:36]Br)[CH3:33]>C(#N)C>[CH2:7]([NH:9][C:10]([C:12]1[S:30][C:15]2[N:16]=[C:17]([NH2:29])[N:18]=[C:19]([C:20]3[CH:25]=[C:24]([O:26][CH2:36][CH:35]([O:38][CH2:39][CH3:40])[O:34][CH2:32][CH3:33])[C:23]([Cl:27])=[CH:22][C:21]=3[Cl:28])[C:14]=2[CH:13]=1)=[O:11])[CH3:8]
Reactant: CCOC(CBr)OCC
Reactant: CCNC(=O)c1cc2c(-c3cc(O)c(Cl)cc3Cl)nc(N)nc2s1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CCNC(=O)c1cc2c(-c3cc(OCC(OCC)OCC)c(Cl)cc3Cl)nc(N)nc2s1

Procedure:
Potassium tert-butoxide was added to a suspension of 2-Amino-4-(2,4-dichloro-5-hydroxyphenyl)-thieno[2,3-d]pyrimidine-6-carboxylic acid ethyl amide in acetonitrile, bromoacetaldehyde diethyl acetal was added and the suspension heated under reflux for ˜8 hrs. The resulting suspension was allowed to cool and water added, the mixture was extracted with ethyl acetate and the extracts washed with water and saturated aqueous sodium chloride solution. The solution was dried over anhydrous sodium sulphate and concentrated to a red/brown gum. The crude product was purified by chromatography on silica eluting with mixtures of ethyl acetate and hexane.
Reaction SMILES: [OH:1][CH:2]([CH:5]1[CH2:7][CH:6]1[N:8]1[CH:15]=[CH:14][C:12](=O)[NH:11][C:9]1=[O:10])[CH2:3][OH:4].C[Si](C)(C)[NH:18][Si](C)(C)C.C(N)=O>CO>[OH:1][CH:2]([CH:5]1[CH2:7][CH:6]1[N:8]1[CH:15]=[CH:14][C:12]([NH2:18])=[N:11][C:9]1=[O:10])[CH2:3][OH:4]
Reactant: O=c1ccn(C2CC2C(O)CO)c(=O)[nH]1
Reactant: C[Si](C)(C)N[Si](C)(C)C
Solvent: CO
Solvent: NC=O
Product: Nc1ccn(C2CC2C(O)CO)c(=O)n1
Temperature: 140 °C
Reaction time: 85 h

Procedure:
To 85.8 mg (0.42 mmol) of 1-(2'-(1",2"-dihydroxyethyl) cyclopropyl)uracil, the product of Step B of Example 9, is added 0.44 mL (2.1 mmol) of hexamethyldisilazane and 0.034 mL (0.82 mmol) of formamide and the resultant mixture is heated with stirring in a sealed tube at 140° C. After 85 h, 10 mL of methanol is added to the cooled reaction mixture, the tube resealed and heated to 65° C. After 3 h at 65° C., the cooled reaction mixture is concentrated under reduced pressure. The residue is dissolved in 10 mL of water and the resultant aqueous solution treated with 50 mg of Darco G-60 charcoal, filtered and concentrated under reduced pressure. Purification of the residue by column chromatography on silica gel eluted with a gradient of methanol in methylene chloride from 100% methylene chloride to 30% methanol affords the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].C[Al](C)C.C([O:15][C:16]([C:18]1[CH:23]=[C:22]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)[CH:21]=[C:20]([CH3:31])[N:19]=1)=O)C>O1CCOCC1.CCCCCC>[Cl:1][C:2]1[CH:3]=[C:4]([NH:5][C:16]([C:18]2[CH:23]=[C:22]([C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)[CH:21]=[C:20]([CH3:31])[N:19]=2)=[O:15])[CH:6]=[CH:7][CH:8]=1
Reactant: Nc1cccc(Cl)c1
Reactant: CCOC(=O)c1cc(-c2ccc(F)cc2)cc(C)n1
Agent: C[Al](C)C
Solvent: CCCCCC
Solvent: C1COCCO1
Product: Cc1cc(-c2ccc(F)cc2)cc(C(=O)Nc2cccc(Cl)c2)n1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 73.9 %

Procedure:
To a solution of 113 μl (138 mg, 1.08 mmol, 4.0 equiv.) of 3-Chloroaniline in 7 ml of dry dioxane were added 540 μl (1.08 mmol, 4.0 equiv.) of a 2M solution of trimethylaluminium in hexane. The solution was stirred for 45 min at room temperature. Then a solution of 70.0 mg (0.27 mmol) of 4-(4-Fluoro-phenyl)-6-methyl-pyridine-2-carboxylic acid ethyl ester in 1 ml of dry dioxane was added and the reaction was heated to 100° C. for 1 h. The reaction was quenched by cautious addition of 0.7 ml of water. Then approximately 1 g of anhydrous sodium sulfate were added to bind the water and the mixture was stirred vigorously for 5 min. The mixture was diluted by addition of 10 ml of methylenene chloride and filtered over Speedex filter aid which was washed with methylene chloride. The filtrate was concentrated in vaccuo and the residue (248 mg orange solid) was purified by flash chromatography (heptane/ethyl acetate 4:1) to yield the title compound (68.0 mg, 74%) as a crystalline white solid, MS (ISP): m/e=341.0, 343.0 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[N:13][C:12]([NH2:15])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[H-].[Na+].CS(O[CH:25]([C:29]1[CH:39]=[CH:38][C:32]([C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:31][CH:30]=1)[CH2:26][CH2:27][CH3:28])(=O)=O>CN(C)C=O.C(OCC)(=O)C>[F:17][C:2]([F:1])([F:16])[C:3]1[CH:4]=[CH:5][C:6]([C:9]2[N:14]=[N:13][C:12]([NH:15][CH:25]([C:29]3[CH:39]=[CH:38][C:32]([C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:31][CH:30]=3)[CH2:26][CH2:27][CH3:28])=[CH:11][CH:10]=2)=[CH:7][CH:8]=1
Reactant: CCCC(OS(C)(=O)=O)c1ccc(C(=O)OCC)cc1
Reactant: Nc1ccc(-c2ccc(C(F)(F)F)cc2)nn1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCC(Nc1ccc(-c2ccc(C(F)(F)F)cc2)nn1)c1ccc(C(=O)OCC)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 10 %

Procedure:
A solution of 6-(4-(trifluoromethyl)phenyl)pyridazin-3-amine (140 mg, 0.585 mmol) in N,N-dimethylformamide (2 mL) was added to a suspension of 60% sodium hydride (27.2 mg, 0.679 mmol) in N,N-dimethylformamide (2 mL) at 0° C. The mixture was stirred at room temperature for 30 minutes. A mixture of ethyl 4-(1-(methylsulfonyloxy)butyl)benzoate (0.170 g, 0.566 mmol) in N,N-dimethylformamide (3 mL) was then added at room temperature. The reaction was stirred for 2 hours. The reaction was diluted with ethyl acetate and washed with water and brine. The organics were dried over sodium sulfate, filtered and concentrated. Purification by column chromatography (0-15% ethyl acetate in heptanes) gave ethyl 4-(1-(6-(4-(trifluoromethyl)phenyl)pyridazin-3-ylamino)butyl)benzoate (25.0 mg, 10%) as an oil. 1H NMR (400 MHz, CDCl3, δ): 7.98-8.05 (m, 4 H), 7.67 (d, J=8.19 Hz, 2 H), 7.53 (d, J=9.36 Hz, 1 H), 7.44 (d, J=8.19 Hz, 2 H), 6.57 (d, J=9.36 Hz, 1 H), 5.56-5.67 (m, 1 H), 4.82-4.93 (m, 1 H), 4.34 (q, J=7.22 Hz, 2 H), 1.79-2.01 (m, 2 H), 1.36 (t, J=7.22 Hz, 3 H), 1.28-1.54 (m, 2 H), 0.96 (t, J=7.32 Hz, 3 H). MS (M+1): 444.1.
Reaction SMILES: Br[C:2]1[CH:25]=[CH:24][C:5]([O:6][CH2:7][C:8]2[N:12]([C:13]3[C:18]([Cl:19])=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:20])[N:11]=[N:10][C:9]=2[CH:21]([CH3:23])[CH3:22])=[CH:4][C:3]=1[CH3:26].[CH3:27][O:28][C:29](=[O:38])[C:30]1[CH:35]=[CH:34][C:33]([C:36]#[CH:37])=[CH:32][CH:31]=1.C(N(CC)CC)C>CN(C=O)C.[O-]S(C(F)(F)F)(=O)=O.[Zn+2].[O-]S(C(F)(F)F)(=O)=O>[CH3:27][O:28][C:29](=[O:38])[C:30]1[CH:35]=[CH:34][C:33]([C:36]#[C:37][C:2]2[CH:25]=[CH:24][C:5]([O:6][CH2:7][C:8]3[N:12]([C:13]4[C:18]([Cl:19])=[CH:17][CH:16]=[CH:15][C:14]=4[Cl:20])[N:11]=[N:10][C:9]=3[CH:21]([CH3:22])[CH3:23])=[CH:4][C:3]=2[CH3:26])=[CH:32][CH:31]=1
Reactant: Cc1cc(OCc2c(C(C)C)nnn2-c2c(Cl)cccc2Cl)ccc1Br
Reactant: C#Cc1ccc(C(=O)OC)cc1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Zn+2]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(C#Cc2ccc(OCc3c(C(C)C)nnn3-c3c(Cl)cccc3Cl)cc2C)cc1
Temperature: 80 °C
Reaction time: 3 h
Yield: 64.6 %

Procedure:
To a room temperature solution of 5-(4-bromo-3-methyl-phenoxymethyl)-1-(2,6-dichloro-phenyl)-4-isopropyl-1H-[1,2,3]triazole (50 mg, 0.110 mmol) in DMF (1 mL) are added 4-ethynyl-benzoic acid methyl ester (18 mg, 0.110 mmol) and triethylamine (107 μL, 0.770 mmol). The reaction mixture is degassed for 20 minutes with nitrogen. To the reaction mixture are added dichloro(bistriphenylphosphine) palladium (II) (8 mg, 0.011 mmol, 10 mol %) and zinc (II) triflate (40 mg, 0.110 mmol). The reaction mixture is heated to 80° C. After 3 h, the reaction is concentrated and the residue is chromatographed (40 g SiO2, 0% to 5% EtOAc/Hexanes) to yield 4-{4-[3-(2,6-Dichloro-phenyl)-5-isopropyl-3H-[1,2,3]triazol-4-ylmethoxy]-2-methyl-phenylethynyl}-benzoic acid methyl ester (38 mg, 64%). LC/MS m/e 534.2 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[CH:4][N:3]=1.O.N1C2C(=CC=C3C=2N=CC=C3)C=CC=1.[C:24](#[N:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>[Cu]Br>[Br:8][C:6]1[CH:5]=[CH:4][N:3]2[N:31]=[C:24]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[N:1]=[C:2]2[CH:7]=1
Reactant: N#Cc1ccccc1
Reactant: Nc1cc(Br)ccn1
Agent: [Cu]Br
Agent: c1cnc2c(c1)ccc1cccnc12
Solvent: O
Product: Brc1ccn2nc(-c3ccccc3)nc2c1
Temperature: 110 °C
Yield: 79 %

Procedure:
A mixture of 2-amino-4-bromopyridine (1.00 g, 5.66 mmol), copper (I) bromide (41.5 mg, 0.28 mmol), 1,10-phenanthroline monohydrate (56.7 mg, 0.28 mmol) and benzonitrile (13 mL) was heated in a 100-mL 4-necked flask to 110° C. During 23 h a gentle flow of O2/N2 (5:95) was bubbled through the reaction mixture (>99% conversion, HPLC method cf. example 1.1). The dark brown suspension was then cooled to 0-5° C. and filtered. The filter cake was washed with TBME (50 mL) and dried to yield crude 7-bromo-2-phenyl-[1,2,4]triazolo[1,5-a]pyridine (1.21 g, 79%) as a green solid with 99.0% purity (HPLC area-%, HPLC method cf. example 1.1).
Reaction SMILES: NC[C:3]1[CH:17]=[CH:16][C:6]([C:7]([NH:9]C2C=NC=CC=2)=[O:8])=[CH:5][CH:4]=1.CN1C(S(Cl)(=O)=O)=CN=C1C>N1C=CC=CC=1>[C:7]([NH2:9])(=[O:8])[C:6]1[CH:16]=[CH:17][CH:3]=[CH:4][CH:5]=1
Reactant: NCc1ccc(C(=O)Nc2cccnc2)cc1
Agent: Cc1ncc(S(=O)(=O)Cl)n1C
Solvent: c1ccncc1
Product: NC(=O)c1ccccc1
Temperature: 20 °C
Reaction time: 16 h

Procedure:
A mixture of 4-(aminomethyl)-N-(3-pyridinyl)benzamide (33) (341 mg, 1.5 mmol) and 1,2-dimethyl-1H-imidazole-5-sulfonyl chloride (292 mg, 1.5 mmol) in dry pyridine (10 mL) was stirred at 20° C. for 16 h. The solvent was evaporated and the residue stirred in ice/water (20 mL) for 1 h. The precipitate was filtered, washed with water (5 mL) and dried. The crude solid was purified by column chromatography, eluting with a gradient (0-20%) of MeOH/EtOAc, to give benzamide I-6 (201 mg, 35%) as a white powder: mp (MeOH/EtOAc) 238-240° C.; 1H NMR δ 10.37 (s, 1 H, CONH), 8.92 (br s, 1 H, H-2′), 8.31 (dd, J=4.7, 1.5 Hz, 1 H, H-6′), 8.18 (ddd, J=8.3, 2.5, 1.5Hz, 1 H, H-4′), 7.97 (br s, 1 H, NHSO2), 7.91 (br dd, J=8.3, 1.7Hz, 2 H, H-2, H-6), 7.61 (s, 1 H, H-5″), 7.44 (br d, J=8.3Hz, 2 H, H-3, H-5), 7.39 (ddd, J=8.3, 4.6, 0.6Hz, 1 H, H-5′), 4.10 (br d, J=6.0Hz, 2 H, CH2N), 3.58 (s, 3 H, NCH3), 2.30 (s, 3 H, CH3); 13C NMR δ 165.7, 146.4, 144.5, 142.5, 142.0, 137.1, 135.8, 132.9, 127.5 (2), 127.4 (2), 127.3, 124.7, 123.5, 45.7, 32.8, 12.4; MS m/z 386.6 (MH+, 100%). Anal. calcd for C18H19N5O3S: C, 56.09; H, 4.97; N, 18.17. Found: C, 56.15; H, 5.08; N, 18.00%.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:2]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Cl[Si](C)(C)C.[Br:28]N1C(=O)CCC1=O>C1COCC1.O>[Br:28][CH:7]([C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)Cc1cccnc1
Agent: C[Si](C)(C)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)C(Br)c1cccnc1
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
Ethyl 3-pyridylacetate (1.0 g, 1.0 eq) was dissolved in THF (50 mL) and cooled to −78° C. Lithium bis (trimethylsilyl) amide (6.66 mL, 1.1 eq) was added to the reaction and stirred for 20 minutes. Chlorotrimethylsilane (1.44 mL, 1.875 eq) was added at −78° C. and stirred for 20 minutes. N-bromosuccinimide (1.09 g, 1.01 eq) was added to the reaction mixture. The reaction mixture was allowed to stir and warm to room temperature overnight. The reaction mixture was diluted with H2O. The organic layer was extracted with ethyl acetate. The organic phase was dried over sodium sulfate and the solvent was evaporated to give a yellow oil. The resulting oil was chromatographed on silica gel using hexanes and ethyl acetate (1:1) to give ethyl 2-bromo-2(3-pyridyl)acetate.
Reaction SMILES: [C:1]([C:3]1[C:8]([C:9]#[N:10])=[N:7][C:6](Cl)=[C:5]([Cl:12])[N:4]=1)#[N:2].[C:13]1([OH:19])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[OH-].[Na+]>O1CCCC1.O>[C:9]([C:8]1[C:3]([C:1]#[N:2])=[N:4][C:5]([Cl:12])=[C:6]([O:19][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:7]=1)#[N:10]
Reactant: Oc1ccccc1
Reactant: N#Cc1nc(Cl)c(Cl)nc1C#N
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1nc(Cl)c(Oc2ccccc2)nc1C#N
Temperature: 0 °C
Reaction time: 1 h
Yield: 50.7 %

Procedure:
2,3-Dicyano-5,6-dichloropyrazine (1.00 g; 0.005 mole) was dissolved in 50 ml of tetrahydrofuran, and the solution was cooled to -15° to -10° C. A solution of 0.47 g (0.005 mole) of phenol and 0.21 g (0.005 mole) of sodium hydroxide in 25 ml of water was added dropwise over the period of 30 minutes. The mixture was stirred at -15° to -10° C. for 1 hour. The reaction mixture was poured into 100 ml of ice water, and the precipitate was collected by filtration. The precipitate was dissolved in 50 ml of chloroform, washed with 20 ml of a dilute aqueous solution of sodium hydroxide and 30 ml of water, dried over anhydrous calcium chloride, and concentrated under reduced pressure. The crude product was chromatographed on a column containing 60 g of silica gel using benzene as an eluent to afford 0.65 g (yield 50%) of 2,3-dicyano-5-chloro-6-phenoxypyrazine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]([C:12]1[CH:16]=[C:15](Br)[S:14][C:13]=1[Br:18])[N:7]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:6][CH2:5]2.[N:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O1CCOCC1.O>>[Br:18][C:13]1[S:14][C:15]([C:29]2[CH:30]=[CH:31][N:26]=[CH:27][CH:28]=2)=[CH:16][C:12]=1[CH:8]1[C:9]2[C:4](=[CH:3][C:2]([Cl:1])=[CH:11][CH:10]=2)[CH2:5][CH2:6][N:7]1[C:19]([O:21][C:22]([CH3:24])([CH3:23])[CH3:25])=[O:20]
Reactant: CC(C)(C)OC(=O)N1CCc2cc(Cl)ccc2C1c1cc(Br)sc1Br
Reactant: OB(O)c1ccncc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCc2cc(Cl)ccc2C1c1cc(-c2ccncc2)sc1Br
Temperature: 100 °C
Yield: 40.8 %

Procedure:
A mixture of tert-butyl 6-chloro-1-(2,5-dibromo-3-thienyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (177.0 mg, 0.3486 mmol), pyridine-4-boronic acid (51.43 mg, 0.4184 mmol) tetrakis(triphenylphosphine)palladium(0) (20.1 mg, 0.0174 mmol) and cesium carbonate (0.341 g, 1.04 mmol) in 1,4-dioxane (6.0 mL, 77 mmol) and water (2.0 mL, 110 mmol) was degassed and heated at 100° C. for 1 h. The mixture was extracted with EtOAc. The organic layer was separated and washed with water. The organic layer was dried and evaporated to leave a residue which was purified by chromatography to afford tert-butyl 1-(2-bromo-5-pyridin-4-yl-3-thienyl)-6-chloro-3,4-dihydroisoquinoline-2(1H)-carboxylate as a white solid (72 mg, 41%). LCMS AA ES+ 505.1, 507.1
Reaction SMILES: ClC1C=CC2SC=C(C[N:10]3[CH2:14][CH2:13][N:12]([C:15]4SC(C(O)=O)=[C:18]([CH3:20])[N:19]=4)C3=O)C=2C=1.[F:27][C:28]1[CH:49]=[CH:48][C:31]([CH2:32][N:33]2[CH2:37][CH2:36][N:35]([C:38]3[S:39][C:40]([C:44]([OH:46])=O)=[C:41]([CH3:43])[N:42]=3)[C:34]2=[O:47])=[CH:30][CH:29]=1.N1C=CC(CN)=NC=1>>[F:27][C:28]1[CH:29]=[CH:30][C:31]([CH2:32][N:33]2[CH2:37][CH2:36][N:35]([C:38]3[S:39][C:40]([C:44]([NH:10][CH2:14][C:13]4[CH:20]=[CH:18][N:19]=[CH:15][N:12]=4)=[O:46])=[C:41]([CH3:43])[N:42]=3)[C:34]2=[O:47])=[CH:48][CH:49]=1
Reactant: Cc1nc(N2CCN(Cc3csc4ccc(Cl)cc34)C2=O)sc1C(=O)O
Reactant: Cc1nc(N2CCN(Cc3ccc(F)cc3)C2=O)sc1C(=O)O
Agent: NCc1ccncn1
Product: Cc1nc(N2CCN(Cc3ccc(F)cc3)C2=O)sc1C(=O)NCc1ccncn1
Yield: 71 %

Procedure:
Following the procedure as described in Example 32, making variations as required to replace 2-(3-((5-chlorobenzo[b]thiophen-3-yl)methyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid with 2-(3-(4-fluorobenzyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid to react with pyrimidin-4-ylmethanamine, the title compound was obtained as a colorless solid in 71% yield: mp 175-176° C.; 1H NMR (300 MHz, CDCl3) δ 9.18 (s, 1H), 8.69 (d, J=6.0 Hz, 1H), 7.35-7.25 (m, 3H), 7.07-7.02 (m, 2H), 6.94 (br s, 1H), 4.70 (d, J=6.0 Hz, 2H), 4.47 (s, 2H), 4.10 (t, J=9.0 Hz, 2H), 3.47 (t, J=9.0 Hz, 2H), 2.64 (s, 3H); MS (ES+) m/z 427.2 (M+1).
Reaction SMILES: [OH-].[Na+].[N:3]1([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([O:23]CC)=[O:22])[C:15]2[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[N:8]=[CH:7][C:6]=2[N:5]=[CH:4]1>O.C(O)C>[N:3]1([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22])[C:15]2[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[N:8]=[CH:7][C:6]=2[N:5]=[CH:4]1
Reactant: CCOC(=O)CCCCCn1cnc2cnc3ccccc3c21
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)CCCCCn1cnc2cnc3ccccc3c21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of sodium hydroxide (1.66 g, 41.7 mmol) in water (15 mL) was added to a solution of ethyl 6-(1H-imidazo[4,5-c]quinolin-1-yl)hexanoate (10.0 g, 32.1 mmol, prepared in Part A of Example 10) in ethanol (75 mL), and the reaction was stirred at ambient temperature for two hours and then concentrated under reduced pressure. The residue was diluted with water and adjusted to pH 5 with the addition of 10% hydrochloric acid. The mixture was extracted with dichloromethane, and the combined extracts were dried over magnesium sulfate, filtered, and concentrated under reduced pressure to provide 2.5 g of 6-(1H-imidazo[4,5-c]quinolin-1-yl)hexanoic acid.
Reaction SMILES: N(OCC(C)C)=O.[Cl:8][C:9]1[CH:39]=[CH:38][C:12]([CH2:13][CH2:14][NH:15][C:16]([C:18]2[CH:36]=[CH:35][C:21]([O:22][C:23]3[CH:28]=[CH:27][C:26]([CH2:29][C:30]([O:32][CH3:33])=[O:31])=[CH:25][C:24]=3[Cl:34])=[C:20](N)[CH:19]=2)=[O:17])=[CH:11][CH:10]=1>CN(C=O)C.C(OCC)(=O)C>[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:13][CH2:14][NH:15][C:16]([C:18]2[CH:36]=[CH:35][C:21]([O:22][C:23]3[CH:28]=[CH:27][C:26]([CH2:29][C:30]([O:32][CH3:33])=[O:31])=[CH:25][C:24]=3[Cl:34])=[CH:20][CH:19]=2)=[O:17])=[CH:38][CH:39]=1
Reactant: COC(=O)Cc1ccc(Oc2ccc(C(=O)NCCc3ccc(Cl)cc3)cc2N)c(Cl)c1
Agent: CC(C)CON=O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)Cc1ccc(Oc2ccc(C(=O)NCCc3ccc(Cl)cc3)cc2)c(Cl)c1
Temperature: 60 °C
Reaction time: 1 h
Yield: 72.4 %

Procedure:
Isobutyl nitrite (0.0751 ml, 0.634 mmol) was diluted with DMF (1 mL), placed under nitrogen and heated to 60° C. Methyl 2-(4-(4-((4-chlorophenethyl)carbamoyl)-2-aminophenoxy)-3-chlorophenyl)acetate (100 mg, 0.211 mmol) in DMF (1 mL) was added dropwise and the reaction was stirred for 1 hour. The reaction was cooled, diluted with ethyl acetate and washed with 2N HCl, saturated sodium bicarbonate and brine. The organic layer was dried over MgSO4, filtered and concentrated. The material was purified using a biotage 12i column, eluting with DCM:MeOH (99:1) to yield methyl 2-(4-(4-((4-chlorophenethyl)carbamoyl)phenoxy)-3-chlorophenyl)acetate (70 mg, 72.3% yield).
Reaction SMILES: [I:1][C:2]1[N:3]=[CH:4][NH:5][CH:6]=1.[Cl:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][CH2:15]OS(C)(=O)=O>>[Cl:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][CH2:15][N:5]1[CH:6]=[C:2]([I:1])[N:3]=[CH:4]1
Reactant: Ic1c[nH]cn1
Reactant: CS(=O)(=O)OCCc1ccccc1Cl
Product: Clc1ccccc1CCn1cnc(I)c1

Procedure:
The compound is synthesized using the method described in example 4C starting from 4-iodo-1H-imidazole and methanesulfonic acid 2-(2-chlorophenyl)-ethyl ester (example 78D).