Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:4]([C:8]1[CH:13]=[C:12]([C:14]2[C:15]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[N:16][N:17]3[CH:22]=[CH:21][CH:20]=[N:19][C:18]=23)[CH:11]=[CH:10][N:9]=1)[C:5](=[O:7])[CH3:6])(=[O:3])[CH3:2].[BH4-].[Na+].O.[CH2:32]([OH:34])[CH3:33]>>[C:1]([N:4]([C:8]1[CH:13]=[C:12]([C:14]2[C:15]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[N:16][N:17]3[CH2:22][CH2:21][CH2:20][N:19]([C:32](=[O:34])[CH3:33])[C:18]=23)[CH:11]=[CH:10][N:9]=1)[C:5](=[O:7])[CH3:6])(=[O:3])[CH3:2]
Reactant: CC(=O)N(C(C)=O)c1cc(-c2c(-c3ccccc3)nn3cccnc23)ccn1
Reactant: CCO
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Product: CC(=O)N1CCCn2nc(-c3ccccc3)c(-c3ccnc(N(C(C)=O)C(C)=O)c3)c21
Yield: 46 %

Procedure:
To a mixture of N-acetyl-N-[4-(2-phenylpyrazolo[1,5-a]pyrimidin-3-yl)pyridin-2-yl]acetamide (158 mg, 0.43 mmol, 1 eq) in 3 mL of ethanol is added sodium borohydride (35 mg, 0.94 mmol, 2.2 eq). The mixture is refluxed for 1 h. The mixture is then poured into water, extracted with dichloromethane (3×50 mL), dried over anhydrous magnesium sulphate, filtered and concentrated under reduced pressure. The crude material is purified by column chromatography using silica gel in heptane and ethyl acetate (1:0 to 0:1) as eluent and 66 mg (46%) of N-acetyl-N-[4-(4-acetyl-2-phenyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-3-yl)pyridin-2-yl]acetamide are obtained as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][CH:12]=[C:6]2[C:7]([O:9][C:10](=[O:11])[C:5]=12)=O)([O-:3])=[O:2].[CH3:15][C@@H:16]([NH2:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(Cl)(Cl)Cl>[C:17]1([C@H:16]([N:23]2[C:10](=[O:11])[C:5]3[C:6](=[CH:12][CH:13]=[CH:14][C:4]=3[N+:1]([O-:3])=[O:2])[C:7]2=[O:9])[CH3:15])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: C[C@@H](N)c1ccccc1
Reactant: O=C1OC(=O)c2c1cccc2[N+](=O)[O-]
Solvent: ClC(Cl)Cl
Product: C[C@H](c1ccccc1)N1C(=O)c2cccc([N+](=O)[O-])c2C1=O
Temperature: 180 °C
Yield: 72.7 %

Procedure:
386 mg of 3-nitrophthalic anhydride and 242 mg of (R)-α-methylbenzylamine were charged in an egg-plant type flask of 50 ml, followed by stirring under heating at a temperature of 180° C. for 1.5 hours. After cooled, the reaction product was dissolved in chloroform, purified by silica gel column chromatography (eluent; methylene chloride:methanol=30:1 v/v), recrystallized from a mixed solvent of n-hexane-ethyl acetate, to obtain 430 mg of the desired product as a light yellow powder. Yield: 73%. m.p. 115-117° C.; MS(EI+) 296(M)+
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5](B(O)O)=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12].Br[C:16]1[CH:25]=[CH:24][C:23]2[N:22]=[CH:21][C:20]3[N:26]([CH3:40])[C:27](=[N:37][C:38]#[N:39])[N:28]([C:29]4[CH:30]=[N:31][C:32]([O:35][CH3:36])=[CH:33][CH:34]=4)[C:19]=3[C:18]=2[CH:17]=1.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C>[NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:16]2[CH:25]=[CH:24][C:23]3[N:22]=[CH:21][C:20]4[N:26]([CH3:40])[C:27](=[N:37][C:38]#[N:39])[N:28]([C:29]5[CH:30]=[N:31][C:32]([O:35][CH3:36])=[CH:33][CH:34]=5)[C:19]=4[C:18]=3[CH:17]=2)=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12]
Reactant: COc1ccc(-n2c(=NC#N)n(C)c3cnc4ccc(Br)cc4c32)cn1
Reactant: Nc1ncc(B(O)O)cc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(-n2c(=NC#N)n(C)c3cnc4ccc(-c5cnc(N)c(C(F)(F)F)c5)cc4c32)cn1
Temperature: 110 °C

Procedure:
6-amino-5-(trifluoromethyl)pyridin-3-ylboronic acid (1.677 mmol) and palladium dichlorobis triphenylphosphine (10 mol %) were added to a solution of N-(8-bromo-1-(6-methoxypyridin-3-yl)-3-methyl-1H-imidazo[4,5-c]quinolin-2(3H)-ylidene)cyanamide (compound of step 5, 1.118 mmol) in dry DMF in an inert atmosphere. Saturated Na2CO3 (0.3 ml) was added to the reaction mixture and the resulting solution was heated at 110° C. for 3 h. The solvent was removed; the crude material was extracted in EtOAc, washed with brine and dried over anhydrous Na2SO4. The solvent was evaporated and the crude solid was purified (silica gel column, EtOAc/MeOH as eluent) to obtain the title compound. 1H NMR (300 MHz, DMSO-d6): δ 9.20 (s, 1H), 8.66 (d, J=3 Hz, 1H), 8.38 (d, J=3 Hz, 1H), 8.22 (m, 2H), 8.06 (dd, J=9 Hz, 3 Hz, 1H), 7.55 (s, 1H), 7.19 (d, J=9 Hz, 1H), 7.03 (d, J=3 Hz, 1H), 6.79 (s, 2H), 3.99 (s, 3H), 3.84 (s, 3H); MS (m/z): 491.2 (M+1)+.
Reaction SMILES: ClCC1C=CC(C(Cl)=O)=CC=1.[CH3:12][O:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][C:23]=1[O:24][CH3:25])[N:20]=[CH:19][CH:18]=[C:17]2[O:26][C:27]1[CH:33]=[CH:32][C:30]([NH2:31])=[C:29]([F:34])[CH:28]=1.[Cl:35][CH2:36][C:37]1[CH:42]=[CH:41][C:40]([C:43]([N:45]=[C:46]=[S:47])=[O:44])=[CH:39][CH:38]=1>C1(C)C=CC=CC=1.C(O)C>[Cl:35][CH2:36][C:37]1[CH:38]=[CH:39][C:40]([C:43]([N:45]=[C:46]=[S:47])=[O:44])=[CH:41][CH:42]=1.[Cl:35][CH2:36][C:37]1[CH:38]=[CH:39][C:40]([C:43]([NH:45][C:46]([NH:31][C:30]2[CH:32]=[CH:33][C:27]([O:26][C:17]3[C:16]4[C:21](=[CH:22][C:23]([O:24][CH3:25])=[C:14]([O:13][CH3:12])[CH:15]=4)[N:20]=[CH:19][CH:18]=3)=[CH:28][C:29]=2[F:34])=[S:47])=[O:44])=[CH:41][CH:42]=1
Reactant: COc1cc2nccc(Oc3ccc(N)c(F)c3)c2cc1OC
Agent: O=C(Cl)c1ccc(CCl)cc1
Agent: O=C(N=C=S)c1ccc(CCl)cc1
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4ccc(CCl)cc4)c(F)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
4-(Chloromethyl)-1-benzenecarbonyl isothiocyanate was prepared using commercially available 4-(chloromethyl)-1-benzenecarbonyl chloride (80 mg) as a starting compound according to the description of the literature. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2-fluoroaniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. A solution of 4-(chloromethyl)-1-benzenecarbonyl isothiocyanate in ethanol (1 ml) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (68 mg, yield 80%).
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5]P(OC)(OC)=O)=[O:4].[H-].[Na+].[Cl:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][C:16]=1[N+:23]([O-:25])=[O:24].O>C1COCC1>[CH3:1][O:2][C:3](=[O:4])[CH:5]=[CH:19][C:18]1[CH:21]=[CH:22][C:15]([Cl:14])=[C:16]([N+:23]([O-:25])=[O:24])[CH:17]=1
Reactant: O=Cc1ccc(Cl)c([N+](=O)[O-])c1
Reactant: COC(=O)CP(=O)(OC)OC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)C=Cc1ccc(Cl)c([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Trimethyl phosphonoacetate (245 mg, 1.35 mmol) in THF (2.5 mL) was added dropwise (caution—vigorous reaction!) to sodium hydride (60% in oil) (83 mg, 2.02 mmol) under an atmosphere of nitrogen at 0° C. The reaction mixture was stirred for 15 minutes at 0° C. and then 4-chloro-3-nitrobenzaldehyde (46) (250 mg, 1.35 mmol) in THF was added dropwise. After 2 hours, water was added and the solvent concentrated in vacuo. The solid was filtered and dried to provide the crude title compound. Yield: 190 mg
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:9]1([CH3:14])[O:13][CH2:12][CH2:11][O:10]1)[C:4]([O:6][CH2:7][CH3:8])=[O:5].[F:15][C:16]1[CH:26]=[CH:25][CH:24]=[C:18]2[C:19]([O:21][C:22](=O)[C:17]=12)=[O:20]>>[F:15][C:16]1[CH:26]=[CH:25][CH:24]=[C:18]2[C:17]=1[C:22](=[O:21])[N:1]([CH2:2][CH:3]([C:9]1([CH3:14])[O:10][CH2:11][CH2:12][O:13]1)[C:4]([O:6][CH2:7][CH3:8])=[O:5])[C:19]2=[O:20]
Reactant: O=C1OC(=O)c2c(F)cccc21
Reactant: CCOC(=O)C(CN)C1(C)OCCO1
Product: CCOC(=O)C(CN1C(=O)c2cccc(F)c2C1=O)C1(C)OCCO1

Procedure:
Ethyl 3-(4-fluoro-1,3-dioxo-1,3-dihydro-isoindol-2-yl)-2-(2-methyl-[1,3]dioxolan-2-yl)propionate was prepared (0.25 g, 28%) in the same manner as described in the above example 5 (20) from ethyl 3-amino-2-(2-methyl-[1,3]dioxolan-2-yl)propionate (0.50 g, 2.64 mmol) and 3-fluorophthalic anhydride (0.57 g, 3.43 mmol), and the obtained product was identified with the following NMR data.
Reaction SMILES: [Cl-].[Mg+2].[Cl-].Cl[C:5]1[N:10]=[CH:9][NH:8][C:7]2=[N:11][CH:12]=[CH:13][C:6]=12.[Cl-].[NH4+].[CH2:16]1COCC1>>[CH3:16][C:5]1[C:6]2[CH:13]=[CH:12][NH:11][C:7]=2[N:8]=[CH:9][N:10]=1
Reactant: Clc1nc[nH]c2nccc1-2
Reactant: C1CCOC1
Agent: [Cl-]
Agent: [Mg+2]
Agent: [NH4+]
Product: Cc1ncnc2[nH]ccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 69 %

Procedure:
A 3.00 M solution of magnesium chloride in THF (13.0 mL, 39.0 mmol) was added dropwise to a stirred solution of 4-chloro-1H-pyrrolo[2,3-d]pyrimidine (2.50 g, 16.3 mmol) and ferric acetylacetonate (700. mg 1.98 mmol) in THF (30.0 mL) under an atmosphere of argon. The resulting reaction mixture was stirred at rt for 8 h. The mixture was poured onto a mixture of ice (100 mL) and ammonium chloride (1.00 g) and the mixture was extracted with chloroform. Volatiles were removed in vacuo, and C-18 column chromatography eluting with a gradient of 0 to 60% AcCN in water with 0.1% AA afforded the title compound (1.50 g, 69%). LC/MS: Rt=0.94 min, ES+ 134 (AA standard).
Reaction SMILES: Cl[C:2]1[C:3]2[CH:30]=[C:29]([Cl:31])[CH:28]=[CH:27][C:4]=2[N:5]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)[C:6](=[O:17])[CH:7]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[Cl:16])[N:8]=1.[CH3:32][N:33]1[C:37]2[CH:38]=[C:39](B3OC(C)(C)C(C)(C)O3)[CH:40]=[CH:41][C:36]=2[NH:35][C:34]1=[O:51].[Li+].[Cl-].O>O1CCOCC1.C(OCC)(=O)C>[Cl:31][C:29]1[CH:28]=[CH:27][C:4]2[N:5]([CH2:18][C:19]3[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=3)[C:6](=[O:17])[CH:7]([CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[Cl:16])[N:8]=[C:2]([C:39]3[CH:40]=[CH:41][C:36]4[NH:35][C:34](=[O:51])[N:33]([CH3:32])[C:37]=4[CH:38]=3)[C:3]=2[CH:30]=1
Reactant: Cn1c(=O)[nH]c2ccc(B3OC(C)(C)C(C)(C)O3)cc21
Reactant: COc1ccc(CN2C(=O)C(Cc3ccccc3Cl)N=C(Cl)c3cc(Cl)ccc32)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccc(CN2C(=O)C(Cc3ccccc3Cl)N=C(c3ccc4[nH]c(=O)n(C)c4c3)c3cc(Cl)ccc32)cc1
Temperature: 100 °C
Yield: 77.4 %

Procedure:
5,7-Dichloro-3-(2-chlorobenzyl)-1-(4-methoxybenzyl)-1H-benzo[e][1,4]diazepin-2(3H)-one (0.416 g, 0.878 mmol) and 1-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazol-2(3H)-one (0.241 g, 0.878 mmol) were dissolved in 1,4-dioxane (5 mL) and LiCl (0.112 g, 2.63 mmol), and then CsOH (0.442 g, 2.63 mmol) was added followed by water (0.5 mL). The mixture was purged with nitrogen, then [tetrakis(triphenylphosphine)]palladium(0) (0.1 g, 0.088 mmol) was added and the flask was lowered into an 80° C. oil bath and heated at 100° C. for 5.5 h. After cooling to room temperature, the mixture was diluted with ethyl acetate and washed twice with water then once with brine. The organic layer was dried over MgSO4, then filtered and concentrated onto silica gel. Chromatography eluting with 50-100% ethyl acetate in hexanes gave 7-chloro-3-(2-chlorobenzyl)-1-(4-methoxybenzyl)-5-(3-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)-1H-benzo[e][1,4]diazepin-2(3H)-one (0.4 g, 0.68 mmol) as a yellow oil.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([NH:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[C:18]([O:22][CH3:23])[NH:19]2)=[C:15]([NH2:24])[N:14]=1)[CH2:9][CH2:10][CH3:11].C(=O)([O-])[O-].[K+].[K+].Br[CH2:32][CH2:33][CH2:34][Cl:35]>CN(C=O)C>[CH2:8]([NH:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[C:18]([O:22][CH3:23])[N:19]2[CH2:32][CH2:33][CH2:34][Cl:35])=[C:15]([NH2:24])[N:14]=1)[CH2:9][CH2:10][CH3:11]
Reactant: ClCCCBr
Reactant: CCCCNc1nc(N)c2nc(OC)[nH]c2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: CCCCNc1nc(N)c2nc(OC)n(CCCCl)c2n1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
N2-Butyl-8-(methyloxy)-9H-purine-2,6-diamine trifluoroacetic acid salt (for example, as prepared for Intermediate 8) (701 mg, 2.001 mmol) and potassium carbonate (690 mg, 4.99 mmol) were suspended in DMF (10 mL) and the mixture heated at 50° C. under nitrogen for 2 hours. The mixture was allowed to cool and then 1-bromo-3-chloropropane (198 μL, 2.002 mmol) was added and the reaction mixture stirred at ambient temperature overnight. After 16 hours the reaction mixture was partitioned between water and DCM (25 mL of each). The aqueous phase was extracted with further DCM (2×20 mL). The combined DCM extracts were dried over magnesium sulphate and concentrated in vacuo to give the impure title compound as a pale yellow oil with some solid present (0.76 g) which was used without further purification.
Reaction SMILES: [C:1]([OH:10])(=[O:9])/[CH:2]=[CH:3]\[CH:4]=[CH:5]\[C:6]([OH:8])=[O:7].II>C(O)CC>[C:1]([OH:10])(=[O:9])/[CH:2]=[CH:3]/[CH:4]=[CH:5]/[C:6]([OH:8])=[O:7]
Reactant: O=C(O)/C=C\C=C\C(=O)O
Agent: II
Solvent: CCCO
Product: O=C(O)/C=C/C=C/C(=O)O
Temperature: 25 °C
Reaction time: 24 h
Yield: 72.8 %

Procedure:
cis,trans-Muconic acid (103 mg, 0.725 mmol) is dissolved in n-propanol (10 mL) at room temperature and a crystal of iodine (10 mg, 0.04 mmol) is added. The reaction mixture is allowed to stir at room temperature for 24 hours. The precipitate is filtered, washed with acetonitrile and dried under reduced pressure to yield 75 mg of trans,trans-muconic acid, a 73 percent yield.
Reaction SMILES: [Na].[N:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][NH2:11])=[CH:4][CH:3]=1.[CH2:12]1[O:14][CH2:13]1.[Cl-].[NH4+]>N>[N:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:12][CH2:13][OH:14])[CH2:9][CH2:10][NH2:11])=[CH:4][CH:3]=1
Reactant: C1CO1
Reactant: NCCCc1ccncc1
Agent: N
Agent: [Cl-]
Agent: [NH4+]
Product: NCCC(CCO)c1ccncc1
Reaction time: 0.5 h
Yield: 19 %

Procedure:
To stirred liquid ammonia (300 mls) was added ferric nitrate (50 mgs) followed by sodium metal (4.5 gms). The mixture was allowed to stand for 30 minutes and then 3-(4-pyridyl)-1-amino propane (13.5 gms) was added. A deep yellow colour was allowed to develop over 1 hour and ethylene oxide (5.0 gms) was then added. The mixture was stirred for a further 2 hours after which time solid ammonium chloride (12 gms) was added. The solvent was allowed to evaporate overnight and the residual solid was extracted into pyridine. Evaporation of the pyridine and crystallisation of the residue from benzene yielded 3-(4-pyridyl)-1-amino-5-hydroxy pentane (3.4 gms; 17%). Characterised by the following spectral data:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]([CH:9]1[CH:13]([O:14][Si](C(C)(C)C)(C)C)[CH2:12][N:11]([C:22](=[O:30])[C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)[CH2:10]1)[C:5](=[O:8])[CH2:6]Cl.NCCN(C1C(C(=O)C2C=CC(Cl)=CC=2)(O)CNC1)C(=O)CCl.C([O-])([O-])=O.[K+].[K+].CCOC(C)=O>CN(C=O)C>[Cl:29][C:26]1[CH:27]=[CH:28][C:23]([C:22]([N:11]2[CH2:12][CH:13]([OH:14])[CH:9]([N:4]3[CH2:3][CH2:2][NH:1][CH2:6][C:5]3=[O:8])[CH2:10]2)=[O:30])=[CH:24][CH:25]=1
Reactant: CC(C)(C)[Si](C)(C)OC1CN(C(=O)c2ccc(Cl)cc2)CC1N(CCN)C(=O)CCl
Agent: NCCN(C(=O)CCl)C1CNCC1(O)C(=O)c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(c1ccc(Cl)cc1)N1CC(O)C(N2CCNCC2=O)C1
Temperature: 90 °C
Reaction time: 8 h
Yield: 37 %

Procedure:
A mixture of N-(2-amino-ethyl)-N-[4-(tert-butyl-dimethyl-silanyloxy)-1-(4-chloro-benzoyl)-pyrrolidin-3-yl]-2-chloro-acetamide and N-(2-amino-ethyl)-2-chloro-N-[4-(4-chloro-benzoyl)-4-hydroxy-pyrrolidin-3-yl]-acetamide (200 mg) was dissolved in 2 mL of DMF, Then K2CO3 (117 mg, 0.84 mmol) and Cat. KI were added. The mixture was stirred at 90° C. for overnight. EtOAc (5 mL) was added. The organic phase was washed with Sat. NaHCO3, dried over Na2SO4, and concentrated. The residue was purified by column chromatography (Ethyl acetate:Methanol:Et3N:3:1:0.04) to give the desired product (50 mg, 37% yield) as a colorless oil. MS (ESI), M/Z, 324 (M+1). Retention time: 1.13 min (FA-polar).
Reaction SMILES: [CH2:1]([N:8]1[C@@H:13]2[C@H:14]([S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)(=[O:18])=[O:17])[CH2:15][C@@:9]1([C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)[C@@:10](/[CH:26]=[C:27](/[C:29]1[CH:34]=[C:33]([O:35][C:36]([F:39])([F:38])[F:37])[CH:32]=[CH:31][C:30]=1[O:40][CH:41]1[CH2:43][CH2:42]1)\I)([OH:25])[CH2:11][CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)CCCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(C(C)C)C(C)C)C.[O:89]1CCC[CH2:90]1>C(OCC)(=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:1]([N:8]1[C@H:13]2[CH2:12][CH2:11][C@@:10]3([CH:26]=[C:27]([C:29]4[CH:34]=[C:33]([O:35][C:36]([F:38])([F:39])[F:37])[CH:32]=[CH:31][C:30]=4[O:40][CH:41]4[CH2:42][CH2:43]4)[C:90](=[O:89])[O:25]3)[C@:9]1([C:44]1[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=1)[CH2:15][C@H:14]2[S:16]([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)(=[O:17])=[O:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(=O)(c1ccccc1)[C@@H]1C[C@]2(c3ccccc3)N(Cc3ccccc3)[C@H]1CC[C@@]2(O)/C=C(\I)c1cc(OC(F)(F)F)ccc1OC1CC1
Reactant: C1CCOC1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: c1ccc(P(CCCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: O=C1O[C@@]2(C=C1c1cc(OC(F)(F)F)ccc1OC1CC1)CC[C@H]1[C@H](S(=O)(=O)c3ccccc3)C[C@]2(c2ccccc2)N1Cc1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 58 %

Procedure:
A mixture of (1R*,2R*,5S*,6R*)-8-benzyl-2-[(Z)-2-(2-cyclopropyloxy-5-trifluoromethoxyphenyl)-2-iodoethenyl]-1-phenyl-6-phenylsulphonyl-8-azabicyclo[3.2.1]octan-2-ol (Description 9; 690 mg, 0.86 mmol), 1,4-bis(diphenylphosphino)butane (45 mg, 0.1 mmol), Pd2(dba)3 (140 mg, 1.5 mmol), ethyl di-iso-propyl amine (0.75 ml) and tetrahydrofuran (20 ml) was stirred under an atmosphere of carbon monoxide (1 atm) at +50° C. for 24 hours. Additional portion of 1,4-bis(diphenylphosphino)butane (45 mg, 0.1 mmol) and Pd2(dba)3 (140 mg, 1.5 mmol) were added and the mixture was stirred for an additional 24 hours. After cooling to room temperature the mixture was diluted with ethyl acetate and filtered through a pad of Celite™. The filtrate was concentrated and the residue was purified by chromatography on silica gel (iso-hexane:ethyl acetate 0-35%) to give the title compound (350 mg, 58%).
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[C:31]([O:32][CH3:33])=[CH:30][C:8]2[NH:9][C:10](=[O:29])[C:11]3[CH:17]=[CH:16][C:15]([C:18]4[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[C:20]([O:27][CH3:28])[CH:19]=4)=[CH:14][C:12]=3[NH:13][C:7]=2[CH:6]=1.[NH:34]1[CH2:38][CH2:37][CH2:36][CH2:35]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:33][O:32][C:31]1[C:5]([O:4][CH2:3][CH2:2][N:34]2[CH2:38][CH2:37][CH2:36][CH2:35]2)=[CH:6][C:7]2[NH:13][C:12]3[CH:14]=[C:15]([C:18]4[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[C:20]([O:27][CH3:28])[CH:19]=4)[CH:16]=[CH:17][C:11]=3[C:10](=[O:29])[NH:9][C:8]=2[CH:30]=1
Reactant: COc1cc2c(cc1OCCCl)Nc1cc(-c3ccc([N+](=O)[O-])c(OC)c3)ccc1C(=O)N2
Reactant: C1CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(cc1OCCN1CCCC1)Nc1cc(-c3ccc([N+](=O)[O-])c(OC)c3)ccc1C(=O)N2
Temperature: 25 °C
Yield: 51.7 %

Procedure:
A mixture of Example 497 (11 mg, 0.023 mmol), pyrrolidine (3.9 μL, 0.046 mmol), K2CO3 (6.5 mg, 0.046 mmol) and DMF (0.5 mL) was heated overnight at 50° C., cooled to room temperature, and filtered. The filtrate was purified by preparative HPLC to provide 6 mg (51%) of the desired product. MS (ESI) m/e 505 (M+H)+; 1H NMR (500 MHz, DMSO-d6) 9.72 (s, 1H), 8.02 (d, J=8.4 Hz, 1H), 7.78-7.80 (m, 2H), 7.53 (d, J=1.6 Hz, 1H), 7.29-7.35 (m, 3H), 6.78 (s, 1H), 6.73 (s, 1H), 4.18 (t, J=5.0 Hz, 2H), 4.03 (s, 3H), 3.71 (s, 3H), 3.44-3.68 (m, 4H), 3.11-3.17 (m, 2H), 2.00-2.07 (m, 2H), 1.95-1.93 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[N:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17]C)=[CH:13][CH:12]=3)[S:10][C:6]=2[CH:5]=[C:4]([O:19]C)[CH:3]=1.Cl>B(Br)(Br)Br>[Cl:1][C:2]1[C:7]2[N:8]=[C:9]([C:11]3[CH:12]=[CH:13][C:14]([OH:17])=[CH:15][CH:16]=3)[S:10][C:6]=2[CH:5]=[C:4]([OH:19])[CH:3]=1
Reactant: COc1ccc(-c2nc3c(Cl)cc(OC)cc3s2)cc1
Agent: BrB(Br)Br
Agent: Cl
Product: Oc1ccc(-c2nc3c(Cl)cc(O)cc3s2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 98.2 %

Procedure:
4-Chloro-6-methoxy-2-(4-Methoxy-phenyl)-benzothiazole (0.27 g, 0.88 mmol) was suspended in boron tribromide (1M in methylene chloride, 7.0 mL) and stirred at room temp under nitrogen for 18.0 hr. Reaction was poured cautiously into aqueous 1M hydrochloric acid and extracted with ethyl acetate. Ethyl acetate extracts were washed with: 1) hydrochloric acid (1.0M), 2) saturated brine and concentrated in vacuo. Solid was washed with methylene chloride/methanol (97:3, 10 mL), and dried under vacuum yielding the title compound (0.240 g, 98%) as a tan solid. Mass spec: MH+=278 The starting 4-Chloro-6-methoxy-2-(4-Methoxy-phenyl)-benzothiazole was prepared as follows:
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[N:8]=[CH:7][C:6]([C:9]([OH:11])=O)=[CH:5][N:4]=1.C(Cl)(=O)C(Cl)=O.[CH3:20][N:21]1[C:29]2[C:24](=[CH:25][C:26]([CH2:30][NH2:31])=[CH:27][CH:28]=2)[CH:23]=[C:22]1[C:32]([F:35])([F:34])[F:33].C(N(CC)CC)C>C(Cl)Cl.CN(C=O)C>[CH3:20][N:21]1[C:29]2[C:24](=[CH:25][C:26]([CH2:30][NH:31][C:9]([C:6]3[CH:7]=[N:8][C:3]([C:2]([F:1])([F:13])[F:12])=[N:4][CH:5]=3)=[O:11])=[CH:27][CH:28]=2)[CH:23]=[C:22]1[C:32]([F:33])([F:34])[F:35]
Reactant: O=C(O)c1cnc(C(F)(F)F)nc1
Reactant: Cn1c(C(F)(F)F)cc2cc(CN)ccc21
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cn1c(C(F)(F)F)cc2cc(CNC(=O)c3cnc(C(F)(F)F)nc3)ccc21
Reaction time: 2 h
Yield: 34.1 %

Procedure:
2-(Trifluoromethyl)-5-pyrimidinecarboxilic acid (Bio-Farma; 152 mg, 0.789 mmol) was stirred in DCM (10 ml). Oxalyl chloride (0.115 ml, 1.315 mmol) then DMF (0.509 μl, 6.57 μmol) were added. The reaction mixture was then left to stir for 2 hrs under agon. The reaction mixture was then evaporated to dryness and the resulting residues were dissolved in DCM (10 ml). A solution of [(1-methyl-2-trifluoromethylindol-5-yl)methyl]amine (Intermediate 11, 150 mg, 0.657 mmol) in DCM (10 ml) was added followed by triethylamine (0.183 ml, 1.315 mmol). The reaction mixture was then left to stir at room temperature for 1 h. The reaction mixture was quenched with methanol (10 ml) and evaporated to dryness. The resulting residues were then partitioned between ethyl acetate and a 1M solution of citric acid. The organic layer was collected, dried (MgSO4), filtered and the solvent removed. The resulting residues were purified by MDAP and evaporated to dryness to give the title compound (90 mg);
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([C:11]([OH:13])=O)[N:2]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:38][O:39][C:40]([C:42]1[C:50]2[N:49]=[C:48]([NH2:51])[NH:47][C:46]=2[CH:45]=[C:44]([C:52]2[CH:57]=[CH:56][N:55]=[CH:54][CH:53]=2)[CH:43]=1)=[O:41]>>[CH3:38][O:39][C:40]([C:42]1[C:50]2[NH:49][C:48]([NH:51][C:11]([C:3]3[N:2]=[CH:1][C:10]4[C:5]([CH:4]=3)=[CH:6][CH:7]=[CH:8][CH:9]=4)=[O:13])=[N:47][C:46]=2[CH:45]=[C:44]([C:52]2[CH:57]=[CH:56][N:55]=[CH:54][CH:53]=2)[CH:43]=1)=[O:41]
Reactant: COC(=O)c1cc(-c2ccncc2)cc2[nH]c(N)nc12
Reactant: O=C(O)c1cc2ccccc2cn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: COC(=O)c1cc(-c2ccncc2)cc2nc(NC(=O)c3cc4ccccc4cn3)[nH]c12
Yield: 75 %

Procedure:
0.3 g (75%) of 2-[(isoquinoline-3-carbonyl)-amino]-6-pyridin-4-yl-3H-benzoimidazole-4-carboxylic acid methyl ester was synthesized from 0.16 g (0.09 mmol) of isoquinoline-3-carboxylic acid, 0.4 g (1 mmol) of HBTU, and 0.25 g (0.09 mmol) of the above synthesized 2-amino-6-pyridin-4-yl-1H-benzoimidazole-4-carboxylic acid methyl ester as described in general procedure A. LCMS: 424 (M+1)+.