Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O: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:11]=[CH:12][C:13]([NH:17][CH:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[C:14]([CH:16]=1)[NH2:15].Cl.[CH3:25][O:26][C:27]1[CH:28]=[C:29]([CH:35]=[CH:36][CH:37]=1)[C:30](=N)OCC.C(=O)([O-])O.[Na+]>CO>[O: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:11]=[CH:12][C:13]2[N:17]([CH:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[C:30]([C:29]3[CH:35]=[CH:36][CH:37]=[C:27]([O:26][CH3:25])[CH:28]=3)=[N:15][C:14]=2[CH:16]=1
Reactant: CCOC(=N)c1cccc(OC)c1
Reactant: Nc1cc(-c2nc3ccccc3o2)ccc1NC1CCOCC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: COc1cccc(-c2nc3cc(-c4nc5ccccc5o4)ccc3n2C2CCOCC2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.6 %

Procedure:
To a solution of 5-(benzoxazol-2-yl)-2-(tetrahydropyran-4-yl)aminoaniline (see Working Example 20-2) (200 mg, 0.646 mmol) in methanol (5 mL) was added ethyl 3-methoxybenzimidate hydrochloride (153 mg, 0.711 mmol), and this was stirred at room temperature for 8 hours. After the reaction was complete, saturated aqueous sodium hydrogen carbonate solution was added, and this was extracted with chloroform. After the organic layer obtained was dried over anhydrous sodium sulfate, it was filtered and concentrated. The crystals obtained were purified by silica gel column chromatography to yield the title compound (216 mg, 79% yield) as light brown crystals.
Reaction SMILES: [Cl:1][C:2]1[C:11](=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][CH:3]=1.P(Br)(Br)[Br:14]>CN(C=O)C>[Br:14][C:11]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[CH:3][C:2]=1[Cl:1]
Reactant: O=c1c(Cl)c[nH]c2ccccc12
Reactant: BrP(Br)Br
Solvent: CN(C)C=O
Product: Clc1cnc2ccccc2c1Br
Temperature: 0 °C
Reaction time: 0.07 h

Procedure:
To a cooled suspension of 3-chloroquinolin-4(1H)-one (A275-1) (5.15 g, 28.7 mmol) in DMF (43.4 mL) at 0° C. was added phosphorous tribromide (2.77 mL, 29.5 mmol) dropwise over 3 min and then the mixture became orange homogenous mixture. After 4 min, yellow precipitates were formed and the yellow heterogeneous mixture was further stirred at 0° C. for 15 min. After 15 min, the cooling bath was removed and the yellow heterogeneous mixture was stirred at room temperature. After 15 h, the mixture was poured into ice water (300 mL) and stirred at 0° C. for 20 min. The mixture was then neutralized by the addition of 2 M NaOH solution (50 mL) until pH was >9 (pH paper). The resulting precipitate was collected by filtration, washed the solid with water (400 mL), and dried under high vacuum to give 4-bromo-3-chloroquinoline (A275-2) as off-white solid. 1H NMR (400 MHz, DMSO-d6) δ 8.96 (1H, s), 8.20 (1H, dd, J=8.2, 1.6 Hz), 8.12 (1H, dd, J=8.3, 0.9 Hz), 7.81-7.93 (2H, m); LCMS (ESI) m/z 242.0 [M+H (79Br)]+ and 243.9 [M+H (81Br)]+.
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:14]([OH:16])=O)[CH:12]=2)[CH:7]=[CH:6]1)[CH2:2][CH2:3][CH3:4].C1C=CC2N(O)N=NC=2C=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:51][C@@H:52]([CH2:66][C:67]1[CH:72]=[C:71]([F:73])[CH:70]=[C:69]([F:74])[CH:68]=1)[C@H:53]([OH:65])[CH2:54][NH:55][CH2:56][C:57]1[CH:62]=[CH:61][CH:60]=[C:59]([CH2:63][CH3:64])[CH:58]=1>C(Cl)Cl.C(N(CC)CC)C>[CH2:1]([N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:14]([NH:51][C@@H:52]([CH2:66][C:67]3[CH:68]=[C:69]([F:74])[CH:70]=[C:71]([F:73])[CH:72]=3)[C@H:53]([OH:65])[CH2:54][NH:55][CH2:56][C:57]3[CH:62]=[CH:61][CH:60]=[C:59]([CH2:63][CH3:64])[CH:58]=3)=[O:16])[CH:12]=2)[CH:7]=[CH:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCc1cccc(CNC[C@@H](O)[C@@H](N)Cc2cc(F)cc(F)c2)c1
Reactant: CCCCn1ccc2ccc(C(=O)O)cc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCn1ccc2ccc(C(=O)N[C@@H](Cc3cc(F)cc(F)c3)[C@H](O)CNCc3cccc(CC)c3)cc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 39.3 %

Procedure:
To a mixture of 1-butyl-1H-indole-6-carboxylic acid (0.278 g) in methylene chloride (10 mL) was added triethylamine (0.129 g), HOBT (0.175 g) and, HATU (0.486 g). The mixture was stirred at room temperature for 30 minutes at which time (2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-[(3-ethylbenzyl)amino]butan-2-ol (0.408 g) was added. The resulting mixture was stirred at room temperature for 18 h then partitioned between water and methylene chloride. The layers were separated and the organic layer washed with water followed by brine and dried over anhydrous magnesium sulfate. Column chromatography on silica gel (100 mL) using 3% methanol in methylene chloride as eluent to give 0.256 g of the title compound: MS (ESI+) for C32H37F2N3O2 m/z 542.2 (M+H).
Reaction SMILES: O[C:2]1[C:11]2[C:6](=CC(S(O)(=O)=O)=CC=2O)[CH:5]=[C:4](S(O)(=O)=O)[CH:3]=1.[NH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[C:26]2[C:31]=1[C:30]([S:32]([OH:35])(=[O:34])=[O:33])=[CH:29][CH:28]=[CH:27]2>>[NH:21]([C:22]1[CH:23]=[CH:24][CH:25]=[C:26]2[C:31]=1[C:30]([S:32]([OH:35])(=[O:33])=[O:34])=[CH:29][CH:28]=[CH:27]2)[C:2]1[CH:11]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1cccc2cccc(S(=O)(=O)O)c12
Reactant: O=S(=O)(O)c1cc(O)c2c(O)cc(S(=O)(=O)O)cc2c1
Product: O=S(=O)(O)c1cccc2cccc(Nc3ccccc3)c12

Procedure:
4,5-dihydroxynaphthalene-2,7-disulfonic acid; 8-amino-1-naphthol-3,6-disulfonic acid; and 8-amino-1-naphthalene sulfonic acid.
Reaction SMILES: [F:1][C:2]1[C:12]([F:13])=[CH:11][CH:10]=[CH:9][C:3]=1[CH:4]=[CH:5][C:6]([OH:8])=[O:7]>C(O)C.[Pd]>[F:1][C:2]1[C:12]([F:13])=[CH:11][CH:10]=[CH:9][C:3]=1[CH2:4][CH2:5][C:6]([OH:8])=[O:7]
Reactant: O=C(O)C=Cc1cccc(F)c1F
Agent: [Pd]
Solvent: CCO
Product: O=C(O)CCc1cccc(F)c1F
Yield: 97.9 %

Procedure:
A solution of 2,3-difluorocinnamic acid (9.14 g) in ethanol (250 ml) with 10% palladium/carbon catalyst was hydrogenated for 5 h at room temperature and atmospheric pressure. The reaction mixture was filtered through celite and concentrated in vacuo to give the title compound as a colourless solid (9.05 g, quant.) 1H-NMR (CDCl3) δ 2.70 (2H, t), 3.02 (2H, t) and 7.01 (3H, m).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].Cl[CH2:13][O:14][CH3:15].CCN(C(C)C)C(C)C>ClCCl>[CH3:13][O:14][CH2:15][O:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1cccc(O)c1
Reactant: COCCl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCOc1cccc(C(=O)OC)c1
Temperature: 0 °C
Reaction time: 8 h
Yield: 78.8 %

Procedure:
In a 500 ml round-bottomed flask, under argon flush, methyl 3-hydroxybenzoate (5 g, 32.9 mmol) was dissolved in dichloromethane (100 ml) to give a white suspension. The reaction mixture was cooled at 0° C. At that temperature chloro(methyloxy)methane (2.75 ml, 36.1 mmol) and DIPEA (6.89 ml, 39.4 mmol) were added. The reaction mixture was stirred overnight. During that time, the reaction temperature was allowed to reach room temperature. The reaction mixture was then evaporated under vacuum to afford the crude product as a yellow oil which was purified by silica gel chromatography (Biotage SP1 system, 50 g SNAP column) with Cyclohexane/EtOAc as eluents (from 10/0 to 3/1 in 10 CV; then 3/1 for 5 CV). The collected fractions afforded the title compound (5.088 g).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:20]=[CH:19][C:12]2[CH:13]=[C:14]([C:16]([OH:18])=[O:17])[O:15][C:11]=2[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[OH-].[Na+]>[CH2:1]([O:8][C:9]1[CH:20]=[CH:19][C:12]2[CH2:13][CH:14]([C:16]([OH:18])=[O:17])[O:15][C:11]=2[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1cc2ccc(OCc3ccccc3)cc2o1
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)C1Cc2ccc(OCc3ccccc3)cc2O1
Reaction time: 16 h
Yield: 64 %

Procedure:
A solution of 6-(benzyloxy)benzofuran-2-carboxylic acid (3.4 g, 12.6 mmol) in aqueous NaOH (2.5N, 40 mL) is treated with 6% Na—Hg (20 g), stirred for 16 hr, allowed to stand without stirring and decanted. The supernatant is acidified with HCl and filtered. The filtercake is air-dried to afford the title product as a white solid, 2.2 g (64% yield) mp 118-119° C., identified by NMR and mass spectral analyses.
Reaction SMILES: [O:1]=[C:2]1[N:8]2[CH2:9][CH2:10][CH2:11][C@H:7]2[C:6]2=[C:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[N:13]=[CH:14][N:5]2[C:4]2[CH:20]=[CH:21][S:22][C:3]1=2.[C-]#N.[K+].C(O)C[OH:28]>>[O:1]=[C:2]1[N:8]2[CH2:9][CH2:10][CH2:11][C@H:7]2[C:6]2=[C:12]([C:15]([O:17][CH2:18][CH2:19][OH:28])=[O:16])[N:13]=[CH:14][N:5]2[C:4]2[CH:20]=[CH:21][S:22][C:3]1=2
Reactant: CCOC(=O)c1ncn2c1[C@@H]1CCCN1C(=O)c1sccc1-2
Reactant: OCCO
Agent: [C-]#N
Agent: [K+]
Product: O=C(OCCO)c1ncn2c1[C@@H]1CCCN1C(=O)c1sccc1-2
Temperature: 100 °C
Reaction time: 8 h

Procedure:
A mixture of 3.12 g (10 mmol) of ethyl (S)-10,11,12,12a-tetrahydro-8-oxo-8H-imidazo[5,1-c]pyrrolo[1,2-a]thieno[3,2-e][1,4]diazepine-1-carboxylate, 80 mg of powdered potassium cyanide and 30 ml of ethyleneglycol is stirred at 100° C. overnight. After removal of the ethyleneglycol, the residue is purified by column chromatography. There is obtained 2-hydroxyethyl (S)-10,11,12,12a-tetrahydro-8-oxo-8H-imidazo[5,1-c]pyrrolo[1,2-a]thieno[3,2-e][1,4]diazepine-1-carboxylate of melting point 182°-184° C.
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[C:14]([CH2:17]C(=O)C)(=[O:16])[CH3:15].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[C:8]1([CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:15][C:14](=[O:16])[CH3:17])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC(=O)CC(C)=O
Reactant: ICCCCCCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CC(=O)CCCCCCCc1ccccc1
Temperature: 25 °C
Yield: 53.5 %

Procedure:
6-Iodo-1-phenylhexane (17.43 g, 0.061 mol), acetyl acetone (6.66 g, 0.067) and potassium carbonate (8.41 g, 0.061 mol) were dissolved in dry absolute ethanol (75 ml) and the solution was refluxed for 18 hours. After cooling to room temperature the solution was filtered and evaporated under reduced pressure to an oil. This was partitioned between ethyl acetate (80 ml) and water (80 ml), and the organic layer was washed with brine, dried and evaporated to an orange oil (15.27 g). This was purified by flash chromatography on silica gel using petroleum ether/ethyl acetate to give 9-phenylnonan-2-one as a colourless oil (7.12 g, 54%).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:22])=[C:5]([CH2:18][C:19]([OH:21])=[O:20])[CH:6]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:7]=1[CH2:8][C:9]([OH:11])=[O:10].[N+]([O-])(O)=O.C(=O)([O-])[O-].[K+].[K+]>O>[CH3:22][C:4]1[C:5]([CH2:18][C:19]([OH:21])=[O:20])=[C:6]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:7]([CH2:8][C:9]([OH:11])=[O:10])=[C:2]([CH3:1])[N:3]=1
Reactant: CC1=C(CC(=O)O)C(c2ccccc2)C(CC(=O)O)=C(C)N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: O=[N+]([O-])O
Product: Cc1nc(C)c(CC(=O)O)c(-c2ccccc2)c1CC(=O)O
Reaction time: 0.5 h
Yield: 65.5 %

Procedure:
90.3 g (0.3 mol) of 1,4-dihydro-2,6-dimethyl-4-phenyl-3,5-bis(carboxymethyl)pyridine were added in portions at from 92° to 98° C. to a solution of 375 g of 98% strength nitric acid in 1580 ml of water in the course of 30 minutes. After a further 30 minutes at 95°-98° C., the mixture was cooled to +5° C. and brought to pH 9 with solid potassium carbonate. The mixture was extracted three times with methylene chloride, the combined extracts were concentrated under reduced pressure and the residue was crystallized at 0° C. using 1:1 diethyl ether/pentane (50 ml). 58.8 g (65.5% of theory) of 2,6-dimethyl-4-phenyl-3,5-bis(carboxymethyl)pyridine were obtained as white crystals of m.p. 137°-138° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:11][S:12]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([C:22]([F:25])([F:24])[F:23])[CH:16]=2)(=[O:14])=[O:13])[C:5]([C:8](O)=[O:9])=[N:6][CH:7]=1.[F:26][C:27]1[CH:28]=[CH:29][C:30]2[O:35][CH2:34][CH2:33][NH:32][C:31]=2[CH:36]=1.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>CCN(CC)CC>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([S:12]([NH:11][C:4]2[C:5]([C:8]([N:32]3[C:31]4[CH:36]=[C:27]([F:26])[CH:28]=[CH:29][C:30]=4[O:35][CH2:34][CH2:33]3)=[O:9])=[N:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)(=[O:14])=[O:13])=[CH:16][C:17]=1[C:22]([F:23])([F:25])[F:24]
Reactant: Fc1ccc2c(c1)NCCO2
Reactant: O=C(O)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCN(CC)CC
Product: O=C(c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1)N1CCOc2ccc(F)cc21

Procedure:
6-Fluoro-3,4-dihydro-2H-benzo[1,4]oxazine 5-chloro-3-(4-chloro-3-(trifluoromethyl)phenylsulfonamido)picolinic acid, T3P, and Et3N were reacted according to the procedure D to provide the title compound. HPLC purification provided 4-chloro-N-[5-chloro-2-(6-fluoro-2,3-dihydro-benzo[1,4]oxazine-4-carbonyl)-pyridin-3-yl]-3-trifluoromethyl-benzenesulfonamide: Reverse phase HPLC gradient acetonitrile 0.1% TFA 20-95% in 4 min: 3.041 min MS m/z: 550.1 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([CH:20]([CH3:22])[CH3:21])[NH:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.[CH:23](=[O:26])[C:24]#[CH:25]>C1COCC1>[F:19][C:16]1[CH:17]=[CH:18][C:13]([C:12]2[N:11]=[C:10]([CH:20]([CH3:22])[CH3:21])[N:9]([CH:25]=[CH:24][CH:23]=[O:26])[C:8]=2[C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)=[CH:14][CH:15]=1
Reactant: C#CC=O
Reactant: CC(C)c1nc(-c2ccc(F)cc2)c(-c2ccc(F)cc2)[nH]1
Solvent: C1CCOC1
Product: CC(C)c1nc(-c2ccc(F)cc2)c(-c2ccc(F)cc2)n1C=CC=O

Procedure:
To a solution of 4,5-bis(4-fluorophenyl)-2-(1-methylethyl)-1H-imidazole (492 mg) in dry THF under nitrogen was added propiolaldehyde (0.97 ml) and the reaction mixture heated to reflux. Further quantities of propiolaldehyde were added in portions (3×1.1 g) during successive 2 h periods. The reaction mixture was concentrated and the deep red residue was purified by FCC eluting with system A (1:4) to give the title product (398 mg) as an off-white solid and as a 1:1 mixture of geometric isomers. δ(CDCl3) 9.48 (d, 1H, J 7.5 Hz, cis CHO), 9.40 (d, 1H, J 7.5 Hz, trans CHO), 7.5 (d, 1H, J 15 Hz, trans CH=CHCHO), 7.45-6.85 (m, 17H, aromatic protons and cis CH=CHCHO), 5.98 (t, 1H, J 7.5 Hz, cis CH=CHCHO), 5.63 (dd, 1H, J 15 and 7.5 Hz, trans CH=CHCHO), 3.25 (septet, 1H, J 7 Hz, CH(CH3)2 of trans isomer), 3.05 (septet, 1H, J 7 Hz, CH(CH3)2 of cis isomer).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[N:6][C:5]([CH2:10]Cl)=[CH:4][N:3]=1.[NH2:12][C:13]1[CH:38]=[CH:37][C:16]([C:17]([NH:19][C@H:20]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:21][CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[O:18])=[CH:15][CH:14]=1.CCN(C(C)C)C(C)C.[K+].[Br-]>CN(C=O)C>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[N:6][C:5]([CH2:10][NH:12][C:13]2[CH:38]=[CH:37][C:16]([C:17]([NH:19][C@H:20]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:21][CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:27])[CH3:28])=[O:24])=[O:18])=[CH:15][CH:14]=2)=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)CC[C@H](NC(=O)c1ccc(N)cc1)C(=O)OC(C)(C)C
Reactant: N#Cc1nc(CCl)cnc1N
Agent: [Br-]
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CC[C@H](NC(=O)c1ccc(NCc2cnc(N)c(C#N)n2)cc1)C(=O)OC(C)(C)C
Reaction time: 20 h

Procedure:
2-Amino-5-chloromethylpyrazine-3-carbonitrile (1.68 g, 0.01 mol) was added in small portions over 10 min to a stirred solution of di-tert-butyl N-(4-aminobenzoyl)-L-glutamate (3.78 g, 0.01 mol) and i-Pr2NEt (1.74 mL, 1.29 g, 0.01 mol) in dry DMF (25 mL). After 20 hours at room temperature, the solvent was evaporated under reduced pressure and the residue was partitioned between CH2Cl2 and H2O. The organic layer was evaporated and the product purified by column chromatography on a column of neutral Al2O3 (120 g, 3×24 cm) with 50:1 CHCl3 --MeOH as the eluent. Fractions containing the above-specified glutamate (Rf 0.4, silica gel, 9:1 CHCl3 --MeOH) were allowed to evaporate passively in the hood until yellow crystals were formed; yield 3.60 g (59%); mp 71°-78° C; IR (KBr) 3400, 3210, 2990, 2940, 2230 (C≡N), 1730 (ester (C=O), 1635, 1615, 1575, 1515, 1495sh, 1460, 1420, 1395, 1375, 1335, 1315, 1285, 1260 cm-1 ; NMR (CDCl3) δ 1.41 (s, γ-t-OBu), 1.48 (s, α-t-OBu), 2.0-2.4 (m, CH2CH2), 4.37 (m, 2H, CH2NH), 5.35 (m, α-CH and NH), 6.61 (d, J=9 Hz, 3'- and 5'H), 7.67 (d, 9 Hz, 2'- and 4'-H), 8.22 (s, 6--H). Anal. (C26H34N6O5 -0.8 CHCl3) Calcd: C, 53.11; H, 5.79; N, 13.87. Found: C, 53.23; H, 5.94; N, 13.76.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:8][CH2:7][NH:6][C:5]1=[O:9].[H-].[Na+].[S:12]1[C:16]([C:17]2[C:22]([Br:23])=[CH:21][N:20]=[C:19](Cl)[N:18]=2)=[CH:15][C:14]2[CH:25]=[CH:26][CH:27]=[CH:28][C:13]1=2>C1COCC1.C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>[S:12]1[C:16]([C:17]2[C:22]([Br:23])=[CH:21][N:20]=[C:19]([O:1][CH2:2][CH2:3][N:4]3[CH2:8][CH2:7][NH:6][C:5]3=[O:9])[N:18]=2)=[CH:15][C:14]2[CH:25]=[CH:26][CH:27]=[CH:28][C:13]1=2
Reactant: O=C1NCCN1CCO
Reactant: Clc1ncc(Br)c(-c2cc3ccccc3s2)n1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C1NCCN1CCOc1ncc(Br)c(-c2cc3ccccc3s2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-(2-Hydroxyethyl)imidazolidin-2-one (0.6 g, 4.6 mmol) was taken up in anhydrous THF (5 mL) and added dropwise to a reaction flask containing a suspension of sodium hydride (0.147 g (60% in oil), 3.68 mmol) in anhydrous THF (10 mL) at 0° C. The ice bath was removed and the reaction allowed to warm up to room temperature over a 2 h period. 4-(benzo[b]thiophen-2-yl)-5-bromo-2-chloropyrimidine (0.3 g, 9.2 mmol), dissolved in THF was added dropwise. The reaction was stirred overnight. The reaction was then diluted with ethyl acetate and saturated sodium bicarbonate. The organic layer was then washed with water and brine. The organic portion was dried with sodium sulfate and then purified by flash chromatography on silica gel using a gradient of 0 to 10% methanol in dichloromethane to give a white solid. Yield=0.085 g. MS (M+H)+ 420.
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7]([CH2:11][NH:12][C:13]2[N:14]=[CH:15][NH:16][C:17]=2[C:18]([NH2:20])=[O:19])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4].[C:21]([N:29]=[C:30]=[S:31])(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(Cl)Cl.CO>[C:21]([NH:29][C:30]([CH:11]([NH:12][C:13]1[N:14]=[CH:15][NH:16][C:17]=1[C:18]([NH2:20])=[O:19])[C:7]1[NH:6][C:5]([CH2:1][CH2:2][CH2:3][CH3:4])=[N:9][C:8]=1[Cl:10])=[S:31])(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C(N=C=S)c1ccccc1
Reactant: CCCCc1nc(Cl)c(CNc2nc[nH]c2C(N)=O)[nH]1
Solvent: ClCCl
Solvent: CO
Product: CCCCc1nc(Cl)c(C(Nc2nc[nH]c2C(N)=O)C(=S)NC(=O)c2ccccc2)[nH]1
Temperature: 25 °C
Reaction time: 4 h
Yield: 37.7 %

Procedure:
4-{[(2-Butyl-4-chloro-1H-imidazol-5-yl)methyl]amino}-1H-imidazole-5-carboxamide (0.30 g, 1.01 mmol, obtained from Example 7(a)) was dissolved in CH2Cl2 (5 mL) and methanol (2 mL). Benzoylisothiocyanate (0.18 g, 1.11 mmol) was added and the mixture was stirred at r.t. for 4 h. The mixture was then concentrated in vacuo and dissolved in ethyl acetate and washed with water. The aqueous phase was extracted twice with ethyl acetate and the combined organic layers were dried (MgSO4) and concentrated. The crude product was purified by flash column chromatography (CH2Cl2/methanol gradient; 0 to 20% methanol), obtaining 0.175 g (38%) of the title compound. MS (ESI) m/z 460 (M+1).
Reaction SMILES: C(OC([NH:8][CH:9]1[CH2:15][S:14][CH2:13][CH2:12][N:11]([CH2:16][C:17]([O:19][CH3:20])=[O:18])[C:10]1=[O:21])=O)(C)(C)C.[F:22][C:23]([F:28])([F:27])[C:24]([OH:26])=[O:25]>>[F:22][C:23]([F:28])([F:27])[C:24]([OH:26])=[O:25].[NH2:8][CH:9]1[CH2:15][S:14][CH2:13][CH2:12][N:11]([CH2:16][C:17]([O:19][CH3:20])=[O:18])[C:10]1=[O:21]
Reactant: COC(=O)CN1CCSCC(NC(=O)OC(C)(C)C)C1=O
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)CN1CCSCC(N)C1=O

Procedure:
6-t-Butoxycarbonylamino-4-N-(carbomethoxymethyl)-perhydro-1,4-thiazepin-5-one (0.53 g) is dissolved in 2 ml of trifluoroacetic acid. At the end of one hour at room temperature the trifluoroacetic acid is removed under vacuum. The residue is partitioned between water and ether. The aqueous layer is washed three more times with ether, and then lyophilized to yield the product as a white solid (0.52 g).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8](Br)[C:9]2[C:14]([C:15]=1[OH:16])=[CH:13][CH:12]=[C:11]([O:17][C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=1[Cl:25])[CH:10]=2)=[O:5])[CH3:2].[C:27]([Cu])#[N:28].N#N.Cl>C(Cl)Cl.CN1C(=O)CCC1>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]([C:27]#[N:28])[C:9]2[C:14]([C:15]=1[OH:16])=[CH:13][CH:12]=[C:11]([O:17][C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=1[Cl:25])[CH:10]=2)=[O:5])[CH3:2]
Reactant: N#C[Cu]
Reactant: CCOC(=O)c1nc(Br)c2cc(Oc3ccc(F)cc3Cl)ccc2c1O
Agent: Cl
Agent: N#N
Solvent: ClCCl
Solvent: CN1CCCC1=O
Product: CCOC(=O)c1nc(C#N)c2cc(Oc3ccc(F)cc3Cl)ccc2c1O
Temperature: 130 °C
Reaction time: 3 h
Yield: 77.9 %

Procedure:
A 20-mL scintillation vial was charged with 1-bromo-4-hydroxy-7-(4-fluoro-2-chloro-phenoxy)-isoquinoline-3-carboxylic acid ethyl ester (340 mg, 0.77 mmol), CuCN (138 mg, 1.54 mmol) and NMP (1.8 mL). It was filled with N2 gas and close-capped. The mixture was stirred in a 130° C. oil bath for 3 h. Reaction mixture was diluted with CH2Cl2 (100 mL) and stirred at room temperature for 3 days. To the mixture was added 100 mL of 0.5 N HCl aq. solution. It was stirred vigorously for 3 min. Two phases were separated. Organic layer was washed with brine, dried over MgSO4, filtered and concentrated. Crude product was purified by silica gel chromatography, eluting with 5-50% EtOAc/hexanes to provide the title compound 231 mg (0.60 mmol) in 78% yield. 1H NMR (200 MHz) in CDCl3, δ ppm: 12.42 (s, 1H), 8.45 (d, J=8.8 Hz, 1H), 7.54 (dd, J=9.2, 2.6 Hz, 1H), 7.40-7.10 (m, 4H), 4.58 (q, J=7.0 Hz, 2H), 1.51 (t, J=7.0 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6](Cl)[C:5]([Cl:12])=[CH:4][N:3]=1.[CH2:13]([N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)[CH:14]([CH3:16])[CH3:15].C(N(C(C)C)CC)(C)C>C(O)(C)C>[Cl:12][C:5]1[C:6]([N:20]2[CH2:21][CH2:22][N:17]([CH2:13][CH:14]([CH3:16])[CH3:15])[CH2:18][CH2:19]2)=[C:7]([N+:8]([O-:10])=[O:9])[C:2]([NH2:1])=[N:3][CH:4]=1
Reactant: CC(C)CN1CCNCC1
Reactant: Nc1ncc(Cl)c(Cl)c1[N+](=O)[O-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: CC(C)CN1CCN(c2c(Cl)cnc(N)c2[N+](=O)[O-])CC1
Temperature: 45 °C

Procedure:
To a mixture of 2-amino-4,5-dichloro-3-nitropyridine (0.060 g, 0.29 mmol) and isopropanol (4.5 ml) was added 1-isobutyl-piperazine (0.045 g, 0.32 mmol) with the aid of isopropanol (0.5 ml) followed by diisopropylethylamine (0.06 ml, 0.32 mmol). The reaction mixture was heated at 45° C. for 18 h, then allowed to cool to room temperature, and concentrated in vacuo. The residue was absorbed on silica gel, the free running powder was placed on a 10 g isolute silica column which was eluted with ethyl acetate/dichloromethane (v/v; 1:1). The title compound was obtained as an orange solid (0.054 g, 60%); 1H-NMR (500 MHz, DMSO-d6) 0.87 (d, J=6.57 Hz, 6H, CH(CH3)2), 1.77 (m, 1H, CH(CH3)2), 2.08 (d, J=7.39 Hz, 2H, N—CH2), 2.45 (br s, 4H, piperazine N(CH2)2), 3.05 (br s, 4H, piperazine N(CH2)2), 6.94 (s, 2H, NH2), 8.06 (s, 1H, 6-H);