Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([Cl:13])[C:8]=2[Cl:14])[N:6]=1.[N:15]1([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Cl:14][C:8]1[C:9]([Cl:13])=[CH:10][CH:11]=[CH:12][C:7]=1[C:5]1[N:6]=[C:2]([N:18]2[CH2:17][CH2:16][N:15]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:20][CH2:19]2)[S:3][CH:4]=1
Reactant: Clc1cccc(-c2csc(Br)n2)c1Cl
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(c2nc(-c3cccc(Cl)c3Cl)cs2)CC1
Yield: 7.4 %

Procedure:
A solution of 2-bromo-4-(2,3-dichlorophenyl)-1,3-thiazole (3.68 mg, 12.3 mmol), tert-butyl piperazine-1-carboxylate (4.44 g, 24.6 mmol) and potassium carbonate (1.65 g, 12.3 mmol) in dimethylformamide (40 ml) was stirred at 120° C. for 13 hours. Water was poured to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water, and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1) to give 376 mg (7.6%) of the desired product as a solid.
Reaction SMILES: Br[C:2]1[S:6][CH:5]=[C:4]([C:7]([N:9]2[CH2:14][CH2:13][N:12]([C:15]3[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][N:16]=3)[CH2:11][CH2:10]2)=[O:8])[CH:3]=1.[S:23]1(=[O:29])(=[O:28])[CH2:27][CH2:26][CH2:25][NH:24]1>>[CH3:21][C:20]1[C:15]([N:12]2[CH2:13][CH2:14][N:9]([C:7]([C:4]3[CH:3]=[C:2]([N:24]4[CH2:25][CH2:26][CH2:27][S:23]4(=[O:29])=[O:28])[S:6][CH:5]=3)=[O:8])[CH2:10][CH2:11]2)=[N:16][CH:17]=[C:18]([CH3:22])[CH:19]=1
Reactant: Cc1cnc(N2CCN(C(=O)c3csc(Br)c3)CC2)c(C)c1
Reactant: O=S1(=O)CCCN1
Product: Cc1cnc(N2CCN(C(=O)c3csc(N4CCCS4(=O)=O)c3)CC2)c(C)c1
Yield: 50.7 %

Procedure:
Using (5-bromothiophen-3-yl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (107 mg) described in Preparation Example 244 and isothiazolidine 1,1-dioxide (41 mg) and by the reaction and treatment in the same manner as in Example 1, the title compound (60 mg) was obtained.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1.Cl[C:14](OC(Cl)(Cl)Cl)=[O:15]>C1COCC1>[N:8]([C:7]1[CH:9]=[CH:10][C:4]([O:3][C:2]([F:11])([F:12])[F:1])=[CH:5][CH:6]=1)=[C:14]=[O:15]
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: Nc1ccc(OC(F)(F)F)cc1
Solvent: C1CCOC1
Product: O=C=Nc1ccc(OC(F)(F)F)cc1
Yield: 164.1 %

Procedure:
To a solution of 0.41 ml (3.00 mmol) of 4-(trifluoromethoxy)aniline in 5.4 ml of THF was added 0.22 ml (1.80 mmol) of trichloromethyl chloroformate an heated to reflux for 45 min. The solution was evaporated under reduced pressure, dissolved in toluene and evaporated (2×) to give 0.60 g (99%) of the titled compound as pink solid. MS: 203 M+.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C@@H:9](OS(C(F)(F)F)(=O)=O)[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:23][C@H:24]1[CH2:30][S:29][CH:28]([C:31]2[S:32][CH:33]=[CH:34][CH:35]=2)[CH2:27][N:26]([CH2:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[C:25]1=[O:44].C(N(CC)CC)C>C(Cl)Cl>[CH2:13]([O:12][C:10]([C@@H:9]([NH:23][C@H:24]1[CH2:30][S:29][CH:28]([C:31]2[S:32][CH:33]=[CH:34][CH:35]=2)[CH2:27][N:26]([CH2:36][C:37]([O:39][C:40]([CH3:42])([CH3:41])[CH3:43])=[O:38])[C:25]1=[O:44])[CH2:8][CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)=[O:11])[CH3:14]
Reactant: CC(C)(C)OC(=O)CN1CC(c2cccs2)SC[C@H](N)C1=O
Reactant: CCOC(=O)[C@@H](CCc1ccccc1)OS(=O)(=O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)[C@H](CCc1ccccc1)N[C@H]1CSC(c2cccs2)CN(CC(=O)OC(C)(C)C)C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.4 %

Procedure:
A solution of 4.0 g of ethyl 4-phenyl-2-(R)-trifluoromethanesulfonyloxybutyrate in 15 ml of methylene chloride was added dropwise to a solution of 4.0 g of t-butyl α-[6(R)-amino-5-oxo-2-(2-thienyl)perhydro-1,4-thiazepin-4-yl]acetate [prepared as described in step (g) above] and 1.62 ml of triethylamine in 50 ml of methylene chloride. The reaction mixture was stirred for 2 hours at room temperature, after which it was washed with water and dried over anhydrous magnesium sulfate; the solvent was then evaporated off under reduced pressure. The residue was purified by silica gel column chromatography, using a 20:1 by volume mixture of methylene chloride and ethyl acetate as the eluent, to give 5.5 g of the title compound in the form of a syrup.
Reaction SMILES: Br[C:2]1[C:3]2[CH2:10][CH2:9][CH:8]([NH:11][S:12]([CH2:15][CH3:16])(=[O:14])=[O:13])[C:4]=2[CH:5]=[N:6][CH:7]=1.[F:17][C:18]1[CH:19]=[C:20](B(O)O)[CH:21]=[CH:22][C:23]=1[C:24]([F:27])([F:26])[F:25]>>[F:17][C:18]1[CH:19]=[C:20]([C:2]2[C:3]3[CH2:10][CH2:9][CH:8]([NH:11][S:12]([CH2:15][CH3:16])(=[O:14])=[O:13])[C:4]=3[CH:5]=[N:6][CH:7]=2)[CH:21]=[CH:22][C:23]=1[C:24]([F:25])([F:26])[F:27]
Reactant: OB(O)c1ccc(C(F)(F)F)c(F)c1
Reactant: CCS(=O)(=O)NC1CCc2c(Br)cncc21
Product: CCS(=O)(=O)NC1CCc2c(-c3ccc(C(F)(F)F)c(F)c3)cncc21
Yield: 72 %

Procedure:
In analogy to the procedure described for the preparation of example 1, (rac)-N-(4-bromo-6,7-dihydro-5H-cyclopenta[c]pyridin-7-yl)ethanesulfonamide (intermediate A-7) was reacted with 3-fluoro-4-(trifluoromethyl)phenylboronic acid to give the title compound as off-white solid in 72% yield. MS: 389.1 (M+H+).
Reaction SMILES: [F:1][CH:2]([F:38])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]=[C:10]([N:20]3[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:33]=[CH:34][CH:35]=[C:36]([OH:37])[C:5]=2[N:4]=1.Br[CH2:40][CH2:41][CH2:42][OH:43].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[F:38][CH:2]([F:1])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:15][CH2:16][O:17][CH2:18][CH2:19]3)[N:11]=[C:10]([N:20]3[CH2:25][CH2:24][N:23]([C:26]([O:28][C:29]([CH3:32])([CH3:30])[CH3:31])=[O:27])[CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:33]=[CH:34][CH:35]=[C:36]([O:37][CH2:40][CH2:41][CH2:42][OH:43])[C:5]=2[N:4]=1
Reactant: OCCCBr
Reactant: CC(C)(C)OC(=O)N1CCN(c2nc(N3CCOCC3)nc(-n3c(C(F)F)nc4c(O)cccc43)n2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(c2nc(N3CCOCC3)nc(-n3c(C(F)F)nc4c(OCCCO)cccc43)n2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99 %

Procedure:
A mixture of 0.60 g (1.1 mmol) of tert-butyl 4-[4-[2-(difluoromethyl)-4-hydroxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]piperazine-1-carboxylate, 0.47 g (3.3 mmol) of 3-bromo-1-propanol, and 0.80 g (5.5 mmol) of powdered K2CO3 in 20 mL dry DMF was stirred at room temperature for 8 hrs. Dilution with water gave 0.66 g, (99% yield) of tert-butyl 4-[4-[2-(difluoromethyl)-4-(3-hydroxypropoxy)-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-1-piperazinecarboxylate: 1H NMR (CDCl3) δ 7.94 (dd, J=8.4. 0.7 Hz, 1H), 7.49 (t, JHF=53.4 Hz, 1H), 7.34 (t, J=8.1 Hz, 1H), 6.92 (dd, J=8.0, 0.6 Hz, 1H), 4.47 (t, J=5.9 Hz, 2H), 3.98 (t, J=5.4 Hz, 2H), 3.87 (m, 8H), 3.79 (m, 4H), 3.54 (m, 4H), 3.30 (m, exchangeable with D2O, 1H), 2.14 (pentet, J=5.8 Hz, 2H), 1.50 (s, 9H).
Reaction SMILES: C[O:2][C:3](=[O:41])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([C@H:13]2[C@H:17]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[C:20]([Cl:25])[CH:19]=3)[C@:16]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=3[F:35])([C:26]#[N:27])[C@H:15]([CH2:36][C:37]([CH3:40])([CH3:39])[CH3:38])[NH:14]2)=[O:12])=[CH:6][CH:5]=1.[OH-].[Na+].CO.Cl>O1CCCC1>[Cl:25][C:20]1[CH:19]=[C:18]([C@@H:17]2[C@:16]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=3[F:35])([C:26]#[N:27])[C@H:15]([CH2:36][C:37]([CH3:40])([CH3:39])[CH3:38])[NH:14][C@H:13]2[C:11]([NH:10][C:7]2[CH:6]=[CH:5][C:4]([C:3]([OH:41])=[O:2])=[CH:9][CH:8]=2)=[O:12])[CH:23]=[CH:22][C:21]=1[F:24]
Reactant: COC(=O)c1ccc(NC(=O)[C@@H]2N[C@@H](CC(C)(C)C)[C@](C#N)(c3ccc(Cl)cc3F)[C@H]2c2ccc(F)c(Cl)c2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)C[C@@H]1N[C@@H](C(=O)Nc2ccc(C(=O)O)cc2)[C@H](c2ccc(F)c(Cl)c2)[C@@]1(C#N)c1ccc(Cl)cc1F
Temperature: 80 °C
Yield: 94.7 %

Procedure:
To a solution of rac-4-{[(2R,3R,4R,5S)-3-(3-chloro-4-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-benzoic acid methyl ester prepared in Example 338 (0.11 g, 0.18 mmol) in tetrahydrofuran (9 mL) was added an aqueous solution (1 N) of NaOH (9 mL, 9 mmol) and methanol (3 mL). The reaction mixture was heated at 80° C. for 2 h, and the “pH” of the solution was adjusted to 5 by aqueous HCl solution. The mixture was extracted ethyl acetate twice. The combined organic extracts were washed with water, brine, dried over MgSO4, and concentrated to give rac-4-{[(2R,3R,4R,5S)-3-(3-chloro-4-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-benzoic acid as a white solid (0.1 g, 94%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH3:10])[C:5]([C:8]#[N:9])=[N:6][CH:7]=1.[F:11][CH2:12]OS(C1C=CC(C)=CC=1)(=O)=O.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.CCOC(C)=O>[F:11][CH2:12][O:1][C:2]1[CH:3]=[C:4]([CH3:10])[C:5]([C:8]#[N:9])=[N:6][CH:7]=1
Reactant: Cc1cc(O)cnc1C#N
Reactant: Cc1ccc(S(=O)(=O)OCF)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cc(OCF)cnc1C#N
Temperature: 100 °C
Reaction time: 1 h

Procedure:
To a solution of 5-hydroxy-3-methyl-pyridine-2-carbonitrile (CAS registry 228867-86-5) (228 mg, 1.70 mmol) in DMF (10 ml) was added a solution of toluene-4-sulfonic acid fluoromethyl ester (CAS registry 114435-86-8) (521 mg, 2.55 mmol) and Cs2CO3 (1.386 g, 4.26 mmol) in DMF (4 ml). The reaction mixture was stirred for 1 h at 100° C., then for 1 h at 70° C., diluted with EtOAc and washed with saturated aqueous NH4Cl soln. and brine. The aqueous layers were reextracted with EtOAc, the combined organic layers dried over Na2SO4, filtrated and the filtrate was concentrated. The title compound was obtained as a white solid after flash chromatography on silica gel (cyclohexane/EtOAc gradient 0-3 min 95:5, 3-30 min 95:5 to 65:35).
Reaction SMILES: [OH-].[K+].[SH:3][C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[CH:6][CH:5]=1.Cl[CH2:13][C:14]#[C:15][CH2:16][O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(O)C.O>[O:17]([CH2:16][C:15]#[C:14][CH2:13][S:3][C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[CH:6][CH:5]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: ClCC#CCOc1ccccc1
Reactant: N#Cc1ccc(S)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: N#Cc1ccc(SCC#CCOc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 4.5 h

Procedure:
A solution of potassium hydroxide (7.5 g) in a mixture of ethanol (220 ml) and water (55 ml) was added at ambient temperature under nitrogen to a stirred solution of 4-mercaptobenzonitrile (18.0 g; prepared according to the method of S. Krishnamurthy and D. Aimino, J. Org. Chem., 1989, 54, 4458) in a mixture of ethanol (195 ml) and water (12 ml), then the mixture was stirred at ambient temperature for 4.5 hours. A solution of 1-chloro-4-phenoxybut-2-yne (24.1 g; prepared in a similar manner to that described in Example 5) in a mixture of ethanol (195 ml) and water (12 ml) was added dropwise over 1.5 hours, then the mixture was stirred at ambient temperature for 17 hours. The mixture was concentrated in vacuo to remove the ethanol, then the product was diluted with water (150 ml) and extracted into ethyl acetate (2×250 ml). The combined extracts were washed with water (100 ml) and saturated brine (100 ml), dried (MgSO4), and the solvent removed in vacuo to leave 4-(4-phenoxybut-2-ynylthio)benzonitrile as an off-white solid (37.7 g).
Reaction SMILES: [CH3:1][N:2]([CH3:50])[CH2:3][C:4]([N:6]1[C:15]2[C:10](=[CH:11][C:12]([O:48][CH3:49])=[C:13]([NH:16][C:17]3[N:18]=[C:19]([NH:37][C:38]4[CH:46]=[CH:45][CH:44]=[C:43]([F:47])[C:39]=4[C:40]([NH2:42])=[O:41])[C:20]4[C:25]([CH3:26])=[CH:24][N:23](S(C5C=CC(C)=CC=5)(=O)=O)[C:21]=4[N:22]=3)[CH:14]=2)[CH2:9][CH2:8][CH2:7]1)=[O:5].[OH-].[Na+]>O1CCOCC1.CCOC(C)=O>[CH3:50][N:2]([CH3:1])[CH2:3][C:4]([N:6]1[C:15]2[C:10](=[CH:11][C:12]([O:48][CH3:49])=[C:13]([NH:16][C:17]3[NH:22][C:21]4=[N:23][CH:24]=[C:25]([CH3:26])[C:20]4=[C:19]([NH:37][C:38]4[CH:46]=[CH:45][CH:44]=[C:43]([F:47])[C:39]=4[C:40]([NH2:42])=[O:41])[N:18]=3)[CH:14]=2)[CH2:9][CH2:8][CH2:7]1)=[O:5]
Reactant: COc1cc2c(cc1Nc1nc(Nc3cccc(F)c3C(N)=O)c3c(C)cn(S(=O)(=O)c4ccc(C)cc4)c3n1)N(C(=O)CN(C)C)CCC2
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COc1cc2c(cc1Nc1nc(Nc3cccc(F)c3C(N)=O)c3c(C)cnc-3[nH]1)N(C(=O)CN(C)C)CCC2
Temperature: 120 °C
Yield: 78.4 %

Procedure:
2-({2-{[1-(N,N-dimethylglycyl)-6-(methyloxy)-1,2,3,4-tetrahydro-7-quinolinyl]amino}-5-methyl-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)-6-fluorobenzamide (146 mg, 0.208 mmol) was dissolved in dioxane (3 mL) and 2N NaOH (2 mL) was added in a microwave safe vessel. The reaction was then heated in a microwave at 120° C. for 10 min. Reaction was diluted with EtOAc and the organic layer was washed with water and a saturated brine solution and dried over sodium sulfate. Solvents were removed under reduced pressure and the residue purified by chromatography on SiO2 to afford 2-[(2-{[1-(N,N-dimethylglycyl)-6-(methyloxy)-1,2,3,4-tetrahydro-7-quinolinyl]amino}-5-methyl-1H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-6-fluorobenzamide (89 mg, 0.163 mmol) as a pink solid. 1 H NMR (400 MHz, DMSO-d6) δ ppm 1.81-1.92 (m, 2 H) 2.10 (br. s., 6 H) 2.42 (s, 3 H) 2.67 (br. s., 2 H) 3.20 (s, 2 H) 3.66-3.74 (m, 2 H) 3.84 (s, 3 H) 6.74 (s, 1 H) 6.79-6.86 (m, 1 H) 6.86-6.96 (m, 1 H) 7.31-7.40 (m, 1 H) 7.42 (s, 1 H) 8.12 (d, J=14.92 Hz, 2 H) 8.40 (d, J=8.61 Hz, 2 H) 9.88 (s, 1 H) 10.99-11.11 (m, 1 H). ESIMS (M+H)+=547
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C@:9]1([OH:21])[CH2:19][CH2:18][C@@H:17]([OH:20])[C:12]2=[N:13][CH:14]=[CH:15][CH:16]=[C:11]2[CH2:10]1.[O:22]=[C:23]1[NH:31][C:26]2=[N:27][CH:28]=[CH:29][CH:30]=[C:25]2[N:24]1[CH:32]1[CH2:37][CH2:36][N:35]([C:38](OC2C=CC([N+]([O-])=O)=CC=2)=[O:39])[CH2:34][CH2:33]1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>CN(C)C=O>[O:22]=[C:23]1[NH:31][C:26]2=[N:27][CH:28]=[CH:29][CH:30]=[C:25]2[N:24]1[CH:32]1[CH2:33][CH2:34][N:35]([C:38]([O:20][C@H:17]2[C:12]3=[N:13][CH:14]=[CH:15][CH:16]=[C:11]3[CH2:10][C@@:9]([C:3]3[CH:4]=[CH:5][CH:6]=[C:7]([F:8])[C:2]=3[F:1])([OH:21])[CH2:19][CH2:18]2)=[O:39])[CH2:36][CH2:37]1
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)N1CCC(n2c(=O)[nH]c3ncccc32)CC1
Reactant: O[C@@H]1CC[C@@](O)(c2cccc(F)c2F)Cc2cccnc21
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(O[C@@H]1CC[C@@](O)(c2cccc(F)c2F)Cc2cccnc21)N1CCC(n2c(=O)[nH]c3ncccc32)CC1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 100.3 %

Procedure:
In an oven-dried 100 mL round-bottom flask was dissolved (6S,9R)-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridine-6,9-diol (71 mg, 0.244 mmol) (azeotroped with dry benzene) and 4-nitrophenyl 4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxylate (121 mg, 0.317 mmol) in dimethylformamide (2 mL) to give a light yellow suspension under nitrogen. NaHMDS (0.926 mL, 0.926 mmol) was added dropwise. The resulting yellow suspension was stirred under nitrogen at room temperature for 3.5 h. LCMS showed complete conversion. The reaction was quenched with saturated sodium bicarbonate and diluted with ethyl acetate. The layers were separated and the aqueous layer was extracted with ethyl acetate (LCMS showed no product left in the aqueous phase). The combined organic layers were washed with water, brine, dried with sodium sulfate, and concentrated to give a yellow oil. Purification by FCC up to 10% methanol/methylene chloride afforded the desired product (131 mg, 100%) as a white powder. LCMS and HPLC showed >99% purity. MS(ESI)[M+H+]=536.26; 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 11.31 (br. s., 1H) 8.35-8.50 (m, 1H) 7.97-8.11 (m, 1H) 7.31-7.60 (m, 3H) 7.02-7.18 (m, 3H) 6.98 (dd, J=7.48, 5.34 Hz, 1H) 6.03 (d, J=10.68 Hz, 1H) 4.60 (br. s., 2H) 4.40 (br. s., 1H) 3.97 (d, J=14.34 Hz, 1H) 2.80-3.20 (m, 4H) 2.67 (t, J=11.75 Hz, 2H) 2.17-2.40 (m, 2H) 2.08 (t, J=12.67 Hz, 2H) 1.89 (d, J=11.29 Hz, 2H); 19F NMR (470 MHz, CHLOROFORM-d) δ ppm −138.72 (d, J=15.15 Hz, 2F).
Reaction SMILES: [C:1]([C:5]1[CH:33]=[CH:32][C:8]([O:9][CH2:10][C:11]([NH:13][C:14]2[NH:15][C:16](=[O:31])[C:17]3[N:18]=[CH:19][N:20]([C:29]=3[N:30]=2)[C@@H:21]2[O:28][C@H:25]([CH2:26][OH:27])[C@@H:23]([OH:24])[CH2:22]2)=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[Cl-].[N+:35]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=1[CH:44]([CH3:55])[CH2:45][O:46][C:47](N1C=C[N+](C)=C1)=[O:48])([O-:37])=[O:36]>ClCCl>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([O:9][CH2:10][C:11]([NH:13][C:14]2[NH:15][C:16](=[O:31])[C:17]3[N:18]=[CH:19][N:20]([C:29]=3[N:30]=2)[C@@H:21]2[O:28][C@H:25]([CH2:26][OH:27])[C@@H:23]([O:24][C:47]([O:46][CH2:45][CH:44]([C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=3[N+:35]([O-:37])=[O:36])[CH3:55])=[O:48])[CH2:22]2)=[O:12])=[CH:32][CH:33]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(COC(=O)n1cc[n+](C)c1)c1ccccc1[N+](=O)[O-]
Reactant: CC(C)(C)c1ccc(OCC(=O)Nc2nc3c(ncn3[C@H]3C[C@H](O)[C@@H](CO)O3)c(=O)[nH]2)cc1
Agent: [Cl-]
Solvent: ClCCl
Product: CC(COC(=O)O[C@H]1C[C@H](n2cnc3c(=O)[nH]c(NC(=O)COc4ccc(C(C)(C)C)cc4)nc32)O[C@@H]1CO)c1ccccc1[N+](=O)[O-]
Yield: 80.7 %

Procedure:
As described for 11 with N2-((4-tertbutylphenoxy)acetyl)-2′-deoxyguanosine (6) (5 g, 6.58 mmol) in 50 ml dichloromethane and 2 (2.57 g, 7.9 mmol) in 50 ml dichloromethane. Purification via flash chromatography (0-10% methanol in toluene/ethyl acetate (1:1) yielded 3.53 g (81%) of the title compound.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([F:20])=[C:5]([O:10][C:11]2[CH:16]=[C:15]([C:17]#[N:18])[CH:14]=[C:13]([Cl:19])[N:12]=2)[C:6]([Cl:9])=[CH:7][CH:8]=1.[Cl:21][C:22]1[N:23]=[C:24]([CH3:30])[NH:25][C:26]=1[C:27](O)=[O:28]>>[Cl:21][C:22]1[N:23]=[C:24]([CH3:30])[NH:25][C:26]=1[C:27]([NH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([Cl:9])=[C:5]([O:10][C:11]2[CH:16]=[C:15]([C:17]#[N:18])[CH:14]=[C:13]([Cl:19])[N:12]=2)[C:4]=1[F:20])=[O:28]
Reactant: N#Cc1cc(Cl)nc(Oc2c(Cl)ccc(CN)c2F)c1
Reactant: Cc1nc(Cl)c(C(=O)O)[nH]1
Product: Cc1nc(Cl)c(C(=O)NCc2ccc(Cl)c(Oc3cc(C#N)cc(Cl)n3)c2F)[nH]1
Yield: 62.6 %

Procedure:
The previously described 2-{[3-(aminomethyl)-6-chloro-2-fluorophenyl]oxy}-6-chloro-4-pyridinecarbonitrile (0.040 g, 0.13 mmol) and 4-chloro-2-methyl-1H-imidazole-5-carboxylic acid (0.023 g, 0.14 mmol) were employed in a similar process described herein to prepare the title compound (0.037 g, 64%) as a white solid after purification by Reverse-Phase HPLC (water:acetonitrile with 0.1% TFA) followed by neutralization. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 11.92 (br. s., 1H) 7.13-7.34 (m, 5H) 4.72 (d, J=5.91 Hz, 2H) 2.36 (s, 3H). ES-LCMS: m/z 453.9, 456.0 (M+1).
Reaction SMILES: S(Cl)(Cl)=O.[CH2:5]([C:9]1[NH:10][C:11]2[CH:17]=[C:16]([C:18]([OH:20])=O)[CH:15]=[CH:14][C:12]=2[N:13]=1)[CH2:6][CH2:7][CH3:8].[NH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1O.[OH-].[Na+]>CN1CCCC1=O>[CH2:5]([C:9]1[NH:10][C:11]2[CH:17]=[C:16]([C:18]3[O:20][C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=4[N:21]=3)[CH:15]=[CH:14][C:12]=2[N:13]=1)[CH2:6][CH2:7][CH3:8]
Reactant: CCCCc1nc2ccc(C(=O)O)cc2[nH]1
Reactant: Nc1ccccc1O
Agent: [Na+]
Agent: [OH-]
Solvent: O=S(Cl)Cl
Solvent: CN1CCCC1=O
Product: CCCCc1nc2ccc(-c3nc4ccccc4o3)cc2[nH]1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
1.43 g (12 mMol) of thionyl chloride are added dropwise at 10° C. with stirring to a suspension of 2.52 g (10 mMol) of 2-n-butyl-benzimidazole-5-carboxylic acid in 15 ml of N-methylpyrrolidinone. The mixture is stirred for a further 15 minutes at ambient temperature, then 1.31 g (11 mMol) of 2-aminophenol are added and the mixture is heated to 140° C. for 2 hours. The mixture is then poured onto about 50 g of ice and 5 ml of 30% sodium hydroxide solution are added with stirring. The crude product precipitated is suction filtered and purified by column chromatography (300 g of silica gel; eluant:methylene chloride+3% ethanol).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:12]=[C:11]([F:13])[CH:10]=[C:9]2[C:5]=1[CH:6]=[CH:7][NH:8]2.[N+:14]([C:17]1[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1)([O-:16])=[O:15].O>CN(C=O)C>[Br:3][C:4]1[CH:12]=[C:11]([F:13])[CH:10]=[C:9]2[C:5]=1[CH:6]=[CH:7][N:8]2[S:23]([C:20]1[CH:19]=[CH:18][C:17]([N+:14]([O-:16])=[O:15])=[CH:22][CH:21]=1)(=[O:24])=[O:25]
Reactant: Fc1cc(Br)c2cc[nH]c2c1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccc(S(=O)(=O)n2ccc3c(Br)cc(F)cc32)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Sodium hydride (299 mg, 7.48 mmol) was added to a stirred solution of 4-bromo-6-fluoro-1H-indole (800 mg, 3.74 mmol) in DMF (20 ml) that had been cooled in an ice bath to 0° C. and placed under nitrogen. The mixture was stirred for 5 mins before 4-nitrobenzenesulfonyl chloride (911 mg, 4.11 mmol) was added. The mixture was stirred at 0° C. for 1 hour. The resultant orange/brown solution was poured into stirring water (40 ml). The mixture was rapidly stirred for 30 mins. The resulting brown suspension was collected by filtration, washed with water and dried in a vacuum oven at 50° C. overnight to give a pale brown solid, which was purified by Flashmaster II, on a silica cartridge (100 g) using a gradient of ethylacetate and cyclohexane to afford the title compound as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH2:18][N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][C:8]([C:12]([O:14]CC)=O)=[C:7]2[OH:17].[Cl:25][C:26]1[CH:33]=[CH:32][C:29]([CH2:30][NH2:31])=[CH:28][CH:27]=1.CCOCC>O>[NH2:1][C:2]1[CH:3]=[C:4]([CH2:18][N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][C:8]([C:12]([NH:31][CH2:30][C:29]1[CH:32]=[CH:33][C:26]([Cl:25])=[CH:27][CH:28]=1)=[O:14])=[C:7]2[OH:17]
Reactant: CCOC(=O)c1cnc2c(N)cc(CN3CCOCC3)cc2c1O
Reactant: NCc1ccc(Cl)cc1
Solvent: CCOCC
Solvent: O
Product: Nc1cc(CN2CCOCC2)cc2c(O)c(C(=O)NCc3ccc(Cl)cc3)cnc12
Temperature: 180 °C

Procedure:
A mixture of ethyl 8-amino-4-hydroxy-6-(4-morpholinylmethyl)-3-quinolinecarboxylate (Preparation 2, 1.0 g) and 4-chlorobenzylamine (4 mL) is heated at 180° C. The solution is cooled and stirred with ether (6 mL) and water (6 mL). The resulting precipitate is removed by filtration, washed with water followed by ether and dried to afford 1.05 g of the title compound. Physical characteristics: 1H NMR (DMSO-d6) δ2.35, 3.45, 3.57, 4.54, 5.65, 7.02, 7.39, 8.62, 10.6, 11.1.
Reaction SMILES: N[C:2]1[S:3][C:4]([CH3:10])=[C:5]([CH3:9])[C:6]=1C#N.[C:11]([NH:13][C:14]([NH2:16])=[NH:15])#[N:12].Cl.[OH-].[Na+]>O>[CH3:9][C:5]1[C:6]2[C:11]([NH2:12])=[N:13][C:14]([NH2:16])=[N:15][C:2]=2[S:3][C:4]=1[CH3:10]
Reactant: Cc1sc(N)c(C#N)c1C
Reactant: N#CNC(=N)N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1sc2nc(N)nc(N)c2c1C
Temperature: 25 °C
Yield: 5.2 %

Procedure:
A mixture of 2-amino-4,5-dimethylthiophene-3-carbonitrile (500 mg, 3.29 mmol), cyanoguanidine (276.6 mg, 3.29 mmol) and HCl (2 N, 1.5 mL) in water (10 mL) was refluxed under nitrogen for 2 h. The reaction mixture was cooled to room temperature, and basified with diluted NaOH aqueous solution to PH 7-8. After evaporation of water, the residue was purified by preparative HPLC eluting with acetonitrile and water to give the title compound (33 mg, 5%). 1H NMR (400 MHz, DMSO-d6) δ 2.22 (s, 3H), 2.27 (s, 3H), 5.85 (bs, 2H), 6.29 (bs, 2H). MS 195 (MH+).