Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:9])(=[O:8])[C:2]([CH2:4][C:5]([OH:7])=[O:6])=[CH2:3].[C:10](Cl)(=O)C1C=CC=CC=1>CO>[CH3:10][O:6][C:5]([CH2:4][C:2]([C:1]([OH:9])=[O:8])=[CH2:3])=[O:7]
Reactant: O=C(Cl)c1ccccc1
Reactant: C=C(CC(=O)O)C(=O)O
Solvent: CO
Product: C=C(CC(=O)OC)C(=O)O

Procedure:
To a methanol (100 ml) solution of itaconic acid (100 g), benzoyl chloride (4 ml) was added dropwise under stirring. The reaction solution was stirred at 60-70° C. for 20 minutes and then concentrated under reduced pressure. The resulting solid was recrystallized from a mixed solution of benzene and petroleum ether to obtain 4-methyl itaconate (93 g, melting point: 65-67° C.).
Reaction SMILES: [CH2:1]([N:4]([CH2:23][CH2:24][CH3:25])[CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[N:10]([CH:20]([CH3:22])[CH3:21])[C:11]2[CH:17]=[C:16]([C:18]#[N:19])[CH:15]=[CH:14][C:12]=2[N:13]=1)[CH2:2][CH3:3].[OH-].[Na+]>C(O)C.[Ni]>[NH2:19][CH2:18][C:16]1[CH:15]=[CH:14][C:12]2[N:13]=[C:9]([CH2:8][CH2:7][CH2:6][CH2:5][N:4]([CH2:1][CH2:2][CH3:3])[CH2:23][CH2:24][CH3:25])[N:10]([CH:20]([CH3:21])[CH3:22])[C:11]=2[CH:17]=1
Reactant: CCCN(CCC)CCCCc1nc2ccc(C#N)cc2n1C(C)C
Agent: [Ni]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCN(CCC)CCCCc1nc2ccc(CN)cc2n1C(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 91 %

Procedure:
The compound (34.0 mg) obtained in Example 47-3 was dissolved in ethanol (2.0 ml) and added with a 1 mol/l sodium hydroxide aqueous solution (340 μl) and Raney nickel (4.0 mg). The whole was stirred overnight at room temperature under a hydrogen atmosphere. After completion of the reaction, the solution was filtrated through Celite and the solvent was distilled off. The resultant was subjected to extraction with chloroform and washed with a saturated saline solution. The organic layer was dried with anhydrous sodium sulfate. The solvent was distilled off, thereby obtaining the subject compound (31.3 mg) as a pale-yellow oily substance.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:12])[N:7]=[C:6]2[C:13]1[N:14]=[C:15]2[C:21]([CH:22]=[O:23])=[CH:20][N:19]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:16]2=[N:17][CH:18]=1.S(=O)(=O)([OH:34])N.Cl([O-])=O.[Na+].OP([O-])(O)=O.[K+]>O1CCOCC1.O.C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:12])[N:7]=[C:6]2[C:13]1[N:14]=[C:15]2[C:21]([C:22]([OH:34])=[O:23])=[CH:20][N:19]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:30])([CH3:29])[CH3:31])[C:16]2=[N:17][CH:18]=1
Reactant: NS(=O)(=O)O
Reactant: COc1ccc2c(c1)c(-c1cnc3c(n1)c(C=O)cn3COCC[Si](C)(C)C)nn2C
Agent: O=P([O-])(O)O
Agent: [K+]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc2c(c1)c(-c1cnc3c(n1)c(C(=O)O)cn3COCC[Si](C)(C)C)nn2C
Temperature: 25 °C
Reaction time: 18 h
Yield: 52 %

Procedure:
To a yellow suspension of 2-(5-methoxy-1-methyl-1H-indazol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carbaldehyde (443 mg, 1.01 mmol) in dioxane (14 mL) and water (4 mL) at 0° C. was added sulfamic acid (590 mg, 6.07 mmol, Eq: 6.00), followed by drop-wise addition of a solution of sodium chlorite (149 mg, 1.32 mmol) and KH2PO4 (1.65 g, 12.1 mmol2.00) in water (4.5 mL) via dropping funnel over 15 min. The ice bath was removed and the light yellow suspension was stirred at 25° C. for 18 h. LCMS indicated reaction about 50% complete, THF (10 mL) added to the yellow suspension then addition at 25° C. of more reagents: sulfamic acid (590 mg, 6.07 mmol, Eq: 6.00) solid, followed by a dropwise addition of a solution of sodium chlorite (149 mg, 1.32 mmol) and KH2PO4 (1.65 g, 12.1 mmo12.00) in 10 mL of water and stirring continued at 25° C. for 4 h. Mixture diluted with water (50 mL) and extracted with dichloromethane (3×40 mL). The combined organic layers were dried (MgSO4), added some charcoal heated to reflux, after cooling down to 25° C., filtered over a celite pad and evaporated. Light yellow solid residue was dissolved in dichloromethane/MeOH and dichloromethane evaporated to promote solid formation, solid separated by filtration, rinsed with MeOH and hexanes and dried to give 2-(5-methoxy-1-methyl-1H-indazol-3-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (238 mg, 525 μmol, 51.8%). MS (M+H)+=454 (>90% purity); 1H NMR (CDCl3) δ: 9.38 (s, 1H), 8.38 (s, 1H), 7.92 (d, J=2.6 Hz, 1H), 7.41 (d, J=9.1 Hz, 1H), 7.19 (dd, J=9.3, 2.5 Hz, 1H), 5.79 (s, 2H), 4.21 (s, 3H), 3.99 (s, 3H), 3.60-3.73 (m, 2H), 0.93-1.06 (m, 2H), 0.00 (s, 9H).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH2:5].C(N(CC)CC)C.Br[CH2:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[C:18]#[N:19]>C(Cl)Cl>[CH3:1][O:2][CH2:3][CH2:4][NH:5][CH2:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[C:18]#[N:19]
Reactant: COCCN
Reactant: N#Cc1cccc(CBr)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCCNCc1cccc(C#N)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 85.9 %

Procedure:
To a stirred solution of 2-methoxyethylamine (5.73 mL, 0.0612 mol) and triethylamine (4.05 mL, 0.0306 mol) in dry DCM (100 mL), was added 3-(bromomethyl)benzonitrile (6 g, 0.0306 mol) in portions over a period of 10 min at 0° C. After being stirred at RT for 5 h, the reaction mixture washed with water (2×100 mL), dried using sodium sulphate and concentrated under reduced pressure. The obtained crude was purified using column chromatography on silica gel (chloroform/methanol) to afford the title compound as a pale yellow liquid (5 g, 86%). 1H NMR (DMSO-d6, 400 MHz) δ 7.75 (s, 1H), 7.64-7.68 (m, 2H), 7.48-7.52 (m, 1H), 3.73 (s, 2H), 3.35-3.38 (m, 2H), 3.21 (s, 3H), 2.59-2.61 (m, 2H).
Reaction SMILES: C(O)(=O)C.[C:5]1([CH3:19])[CH:10]=[CH:9][C:8]([O:11][C:12]2[S:16][C:15]([CH:17]=O)=[CH:14][CH:13]=2)=[CH:7][CH:6]=1.[N+:20]([CH3:23])([O-:22])=[O:21].C([O-])(=O)C.[NH4+]>C(OCC)(=O)C.O>[N+:20](/[CH:23]=[CH:17]/[C:15]1[S:16][C:12]([O:11][C:8]2[CH:9]=[CH:10][C:5]([CH3:19])=[CH:6][CH:7]=2)=[CH:13][CH:14]=1)([O-:22])=[O:21]
Reactant: Cc1ccc(Oc2ccc(C=O)s2)cc1
Reactant: C[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: Cc1ccc(Oc2ccc(/C=C/[N+](=O)[O-])s2)cc1
Temperature: 100 °C
Reaction time: 2.5 h
Yield: 91.1 %

Procedure:
To an acetic acid (20.0 mL) solution of 5-p-tolyloxy-thiophene-2-carbaldehyde (2.30 g, 10.5 mmol) described in Manufacturing Example 48-1-2 were added nitromethane (3.20 g, 52.5 mmol) and ammonium acetate (1.62 g, 21.0 mmol) under nitrogen atmosphere at room temperature, which was stirred for 2.5 hours at 100° C. Water and ethyl acetate were added to the reaction mixture, and the organic layer was extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The solvent was evaporated from the filtrate under a reduced pressure to obtain the title compound (2.50 g) as a crude product.
Reaction SMILES: [NH2:1][C:2]([NH:4][C:5]1[S:6][C:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][CH:20]2[CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21]2)=[CH:8][C:9]=1[C:10]([NH2:12])=[O:11])=[O:3].FC(F)(F)C(O)=O>ClCCl>[NH2:1][C:2]([NH:4][C:5]1[S:6][C:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][CH:20]2[CH2:24][CH2:23][NH:22][CH2:21]2)=[CH:8][C:9]=1[C:10]([NH2:12])=[O:11])=[O:3]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccccc2-c2cc(C(N)=O)c(NC(N)=O)s2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC(=O)Nc1sc(-c2ccccc2OC2CCNC2)cc1C(N)=O
Reaction time: 1 h
Yield: 63.2 %

Procedure:
2-[(Aminocarbonyl)amino]-5-{2-[(1-tert-butyloxycarbonylpyrrolidin-3-yl)oxy]phenyl}-3-thiophenecarboxamide (200 mg) was suspended in dichloromethane (30 ml) and trifluoroacetic acid (5 ml) was added. The mixture was stirred for 1 h, followed by concentration in vacuo. The product was treated with 38% aqueous ammonia and then isolated by filtration as a brown powder (98 mg).
Reaction SMILES: [NH2:1][C@@H:2]([C:4]([C@@H:6]1[C@@H:11]([OH:12])[C@H:10]([OH:13])[C@@H:9]([CH2:14][OH:15])[O:8][C@@:7]1([NH2:42])[N:16]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[C:17](=[O:29])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[O:5])[CH3:3].[C:43]([NH:53][C@H:54]([C:66](O)=[O:67])[CH2:55][C:56]([O:58][CH2:59][C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1)=[O:57])([O:45][CH2:46][C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)=[O:44].N>ClCCl.CO>[C:43]([NH:53][C@H:54]([C:66]([NH:1][C@@H:2]([C:4]([C@@H:6]1[C@@H:11]([OH:12])[C@H:10]([OH:13])[C@@H:9]([CH2:14][OH:15])[O:8][C@@:7]1([NH2:42])[N:16]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[C:17](=[O:29])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[O:5])[CH3:3])=[O:67])[CH2:55][C:56](=[O:57])[O:58][CH2:59][C:60]1[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=1)([O:45][CH2:46][C:47]1[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=1)=[O:44]
Reactant: CCCCCCCCCCCCN(C(=O)CCCCCCCCCCC)[C@]1(N)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1C(=O)[C@@H](C)N
Reactant: O=C(C[C@H](NC(=O)OCc1ccccc1)C(=O)O)OCc1ccccc1
Agent: N
Solvent: CO
Solvent: ClCCl
Product: CCCCCCCCCCCCN(C(=O)CCCCCCCCCCC)[C@]1(N)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1C(=O)[C@@H](C)NC(=O)[C@H](CC(=O)OCc1ccccc1)NC(=O)OCc1ccccc1
Yield: 63 %

Procedure:
from N-(2D-alanyl-amino-2-deoxy-β-D-glucopyranosyl)-N-dodecyl-dodecanamide and N-carbobenzoxy-4-O-benzyl-L-aspartic acid. Yield 63%. Rf 0.57 (dichloromethane/methanol/conc. ammonia 15:1:0.1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][CH:26]=1)[CH2:5][O:6][C:7]1[CH:16]=[C:15]2[C:10]([CH2:11][CH:12]([CH2:18][C:19](OCC)=[O:20])[C:13](=[O:17])[NH:14]2)=[CH:9][CH:8]=1.[NH3:27]>CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][CH:26]=1)[CH2:5][O:6][C:7]1[CH:16]=[C:15]2[C:10]([CH2:11][CH:12]([CH2:18][C:19]([NH2:27])=[O:20])[C:13](=[O:17])[NH:14]2)=[CH:9][CH:8]=1
Reactant: N
Reactant: CCOC(=O)CC1Cc2ccc(OCc3cccc(Cl)c3)cc2NC1=O
Solvent: CO
Product: NC(=O)CC1Cc2ccc(OCc3cccc(Cl)c3)cc2NC1=O
Temperature: 25 °C
Yield: 60 %

Procedure:
Ethyl 2-(7-((3-chlorobenzyl)oxy)-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)acetate (Example 51, product from Step D, 200 mg, 0.54 mmol) was dissolved in a 7 N solution of ammonia in methanol (10 mL) and stirred at room temperature for 2 weeks. The resulting precipitate was collected by filtration, washed with methanol (3 mL) and was dried under vacuum to give the title compound as a white solid (111 mg, 60%). 1H NMR (400 MHz, DMSO-d6) δ 10.08 (s, 1H), 7.53-7.33 (m, 5H), 7.06 (d, J=8.3 Hz, 1H), 6.85 (br s, 1H), 6.57 (dd, J=2.4, 8.3 Hz, 1H), 6.51 (d, J=2.4 Hz, 1H), 5.05 (s, 2H), 2.93-2.70 (m, 2H), 2.71-2.54 (m, 2H), 2.11 (dd, J=8.5, 15.2 Hz, 1H). [M+H]=345.1.
Reaction SMILES: [C:1]([O:5][C:6](=[O:37])[NH:7][C:8]([C:10]1[S:11][C:12]([S:35][CH3:36])=[C:13]([S:15]([C:18]2[CH:19]=[C:20]([C:24]3[C:29]([NH2:30])=[CH:28][C:27]([N+:31]([O-])=O)=[CH:26][C:25]=3[CH3:34])[CH:21]=[CH:22][CH:23]=2)(=[O:17])=[O:16])[CH:14]=1)=[NH:9])([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.[CH3:45][O:46][C:47](=[O:55])[CH2:48][CH2:49][CH2:50][CH2:51][C:52](Cl)=[O:53]>C(Cl)Cl>[CH3:45][O:46][C:47](=[O:55])[CH2:48][CH2:49][CH2:50][CH2:51][C:52](=[O:53])[NH:30][C:29]1[CH:28]=[C:27]([NH2:31])[CH:26]=[C:25]([CH3:34])[C:24]=1[C:20]1[CH:21]=[CH:22][CH:23]=[C:18]([S:15]([C:13]2[CH:14]=[C:10]([C:8]([NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:37])=[NH:9])[S:11][C:12]=2[S:35][CH3:36])(=[O:17])=[O:16])[CH:19]=1
Reactant: COC(=O)CCCCC(=O)Cl
Reactant: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(-c2c(C)cc([N+](=O)[O-])cc2N)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)CCCCC(=O)Nc1cc(N)cc(C)c1-c1cccc(S(=O)(=O)c2cc(C(=N)NC(=O)OC(C)(C)C)sc2SC)c1
Reaction time: 1 h
Yield: 23.2 %

Procedure:
To a solution of {[4-(6′-amino-2′-methyl-4′-nitro-biphenyl-3-sulfonyl)-5-methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester ((Example 295: step h) 130 mg, 0.23 mmol), and Et3N (192 μL, 1.38 mmol) in DCM (5 mL) at 0° C. was added 5-chlorocarbonyl-pentanoic acid methyl ester (53 mg, 0.29). After stirring for 1 h, the solution was partitioned between EtOAc (70 mL) and aq NH4Cl (30 mL) and the layers were separated. The organic layer was washed with NaHCO3 (20 mL) and brine (30 mL) and was dried over sodium sulfate. The solution was concentrated and the residue was purified by SiO2 flash column chromatography to yield 36 mg of the amide product. The residue dissolved in EtOH (5 mL). Saturated aqueous NH4Cl (1.5 mL) was added followed by iron powder (110 mg, 2 mmol). The mixture was vigorously stirred at 80° C. for 30 min. The solution was filtered through a 0.22 μm filter and was then partitioned between EtOAc (70 mL) and water (20 mL). The layers were separated, the organic solution was dried over sodium sulfate, and the solution was concentrated to give the crude title compound which was used without further purification. 1H-NMR (CDCl3): δ 8.0 (m, 2H), 7.84 (s, 1H), 7.96 (m, 2H), 7.59 (t, 1H, J=7.7 Hz), 7.43 (m, 1H), 7.23 (br s, 1H), 6.86 (br s, 1H), 6.45 (br s, 1H), 3.85 (br s, 2H), 3.65 (s, 3H), 2.60 (m, 3H), 2.35 (m, 2H), 2.00 (m, 2H), 1.90 (s, 3H), 1.67 (m, 2H), 1.90 (s, 3H), 1.53 (s, 9H).
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:4]([CH:5]=O)[C:3]=1[OH:11].C(=O)([O-])[O-].[K+].[K+].[CH2:18]([O:20]C(OCC)CBr)[CH3:19].C(=O)(O)[O-].[Na+]>CN(C)C=O.C(O)(=O)C.CCOCC>[CH3:10][C:7]1[C:4]2[CH:5]=[C:19]([CH:18]=[O:20])[O:11][C:3]=2[C:2]([CH3:1])=[CH:9][CH:8]=1
Reactant: CCOC(CBr)OCC
Reactant: Cc1ccc(C)c(C=O)c1O
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: CCOCC
Solvent: CN(C)C=O
Product: Cc1ccc(C)c2oc(C=O)cc12
Temperature: 150 °C
Reaction time: 2.5 h

Procedure:
To 200 ml of a solution of 17.4 g of 3,6-dimethylsalicylaldehyde in N,N-dimethyformamide were added 32 g of anhydrous potassium carbonate and 17.8 ml of bromoacetaldehyde diethyl acetal. The resulting mixture was stirred at 150° C. for 2.5 hours, cooled to room temperature by allowing to stand, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The resulting residue was purified by silica gel column chromatography to give 23.4 g of an ether. This ether was dissolved in 120 ml of acetic acid. The resulting solution was refluxed under nitrogen stream for 8 hours, cooled to room temperature by allowing to stand, and poured into a saturated aqueous solution of sodium bicarbonate. The resulting mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The resulting crude product was washed with hexane to give 7.8 g of the title compound as a pale yellow solid.
Reaction SMILES: [C:1]1(C#N)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.C[Mg]Br.CC[O:18][CH2:19][CH3:20]>C1COCC1>[C:1]1([C:19](=[O:18])[CH3:20])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1
Reactant: N#Cc1nccc2ccccc12
Reactant: CCOCC
Agent: C[Mg]Br
Solvent: C1CCOC1
Product: CC(=O)c1nccc2ccccc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 75 %

Procedure:
A solution of isoquinoline-1-carbonitrile (Intemediate H1) (commercially available from Aldrich) (4.40 g, 28.5 mmol) in THF at 0° C. was treated with methylmagnesium bromide (20 mL, of a 3M soln in ether) for 3 h. (see procedure found in Vacher, B. et al J. Med. Chem. 1998 41, 5070; incorporated herein by reference). The mixture was quenched with a sat. solution of NH4Cl and stirred for 3 h at rt. The aqueous layer was basified with NaOH and extracted with ethyl acetate. The organic layers were dried over MgSO4, filtered and concentrated under reduced pressure. The material was purified by chromatography on silica gel with 10% ethyl acetate: hexane to give 1-isoquinolin-1-yl-ethanone (Intermediate H2) 3.65 g (75%).
Reaction SMILES: Br[C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([CH3:9])[N:3]=1.[F:10][C:11]1[C:16]([F:17])=[CH:15][C:14]([F:18])=[CH:13][C:12]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[F:8][C:7]1[C:2]([C:12]2[CH:13]=[C:14]([F:18])[CH:15]=[C:16]([F:17])[C:11]=2[F:10])=[N:3][C:4]([CH3:9])=[CH:5][CH:6]=1
Reactant: OB(O)c1cc(F)cc(F)c1F
Reactant: Cc1ccc(F)c(Br)n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: C1COCCO1
Product: Cc1ccc(F)c(-c2cc(F)cc(F)c2F)n1
Temperature: 120 °C
Yield: 87 %

Procedure:
To a solution of 2-bromo-3-fluoro-6-methylpyridine (1.0 equiv.) in dioxane (0.2 M) was added 2,3,5-trifluorophenylboronic acid and Pd(dppf)Cl2-DCM (0.1 equiv.). Aqueous sodium carbonate (2M solution, 2.0 equiv.) was added and the reaction was heated in the microwave at 120° C. for 15 min. The solution was partitioned between ethyl acetate and sat. NaHCO3, the organic phase was washed with brine, dried with magnesium sulfate, filtered, and concentrated. The crude material was purified via silica gel column chromatography eluting with ethyl acetate and hexanes (1:3) to give 3-fluoro-6-methyl-2-(2,3,5-trifluorophenyl)pyridine in 87% yield. LC/MS=242.1 (M+H), Rt=0.98 min.
Reaction SMILES: N[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4]([Br:12])=[CH:5][N:6]=[CH:7]2.CCO.N([O-])=O.[Na+].[F:20][B-](F)(F)F.[H+]>O.CCOCC>[Br:12][C:4]1[C:3]2[C:8](=[CH:9][CH:10]=[CH:11][C:2]=2[F:20])[CH:7]=[N:6][CH:5]=1
Reactant: F[B-](F)(F)F
Reactant: Nc1cccc2cncc(Br)c12
Agent: O=N[O-]
Agent: [H+]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: CCOCC
Product: Fc1cccc2cncc(Br)c12
Temperature: 0 °C
Yield: 42 %

Procedure:
5-Amino-4-bromo-isoquinoline (see Gordon et al., J. Heterocycl. Chem., 4, 1967, 410-411) (1.86 g, 8.34 mmol) was stirred in 48% fluoroboric acid (15 mL)/EtOH (15 mL) until completely dissolved. The solution was cooled to 0° C., and sodium nitrite (660 mg, 9.59 mmol) in H2O (1 mL) was added dropwise. The solution was diluted with Et2O (30 mL), and the tan diazonium fluoroborate salt was collected by filtration and dried under vacuum. The solid was placed in a flask and carefully heated over a flame to expel nitrogen. The dark brown residue was diluted with 10% NaOH and extracted with chloroform. Organics were washed with brine, dried over MgSO4, and concentrated in vacuo. Purification by silica gel chromatography (40% to 50% ethyl acetate/ hexanes) gave 798 mg (42%) of 4-bromo-5-fluoro-isoquinoline as a white solid. 1H NMR (300 MHz, CDCl3) δ 9.36 (d, 1H, J=2.4 Hz), 8.74 (s, 1H), 8.07-8.11 (m, 1H), 7.70-7.80 (m, 2H). Anal. (C9H5BrFN) C, H, N.
Reaction SMILES: [CH:1]1[CH:6]=[C:5]2[C:7]3[C:12]([S:13](=[O:15])(=[O:14])[C:4]2=[CH:3][CH:2]=1)=[CH:11][CH:10]=[CH:9][CH:8]=3.[N+:16]([O-])([OH:18])=[O:17]>S(=O)(=O)(O)O>[N+:16]([C:2]1[CH:1]=[CH:6][C:5]2[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=3[S:13](=[O:15])(=[O:14])[C:4]=2[CH:3]=1)([O-:18])=[O:17]
Reactant: O=[N+]([O-])O
Reactant: O=S1(=O)c2ccccc2-c2ccccc21
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1ccc2c(c1)S(=O)(=O)c1ccccc1-2
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 84.5 %

Procedure:
To a solution of 43.25 g of dibenzothiophene sulfone in 400 ml of concentrated sulfuric acid, cooled in an ice/salt bath, was added dropwise at 0° to 2° C., 17.0 g of 71% nitric acid over 16 minutes. This mixture was stirred at 0° to -10° C. for 30 minutes and then poured over 2 liters of crushed ice. The solid was collected, washed with water until neutral and dried. This solid was dissolved in 750 ml giving three successive crops of precipitate. These crops were combined, giving 44.14 g of the desired product as a solid, mp 260°-267° C.
Reaction SMILES: Cl.Cl.[CH3:3][C:4]1[CH:5]=[C:6]([O:19][S:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[S:29]([N:32]2[CH2:37][CH2:36][N:35]([CH2:38][C:39]([O:41]CC)=[O:40])[CH2:34][CH2:33]2)(=[O:31])=[O:30])(=[O:22])=[O:21])[CH:7]=[C:8]([CH:18]=1)[O:9][CH2:10][CH2:11][CH2:12][O:13][NH:14][C:15]([NH2:17])=[NH:16].C(C(=CC1C=CC(O)=CC=1)C(O)=O)#N>>[CH3:3][C:4]1[CH:5]=[C:6]([O:19][S:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[S:29]([N:32]2[CH2:37][CH2:36][N:35]([CH2:38][C:39]([OH:41])=[O:40])[CH2:34][CH2:33]2)(=[O:30])=[O:31])(=[O:21])=[O:22])[CH:7]=[C:8]([CH:18]=1)[O:9][CH2:10][CH2:11][CH2:12][O:13][NH:14][C:15]([NH2:17])=[NH:16]
Reactant: CCOC(=O)CN1CCN(S(=O)(=O)c2ccccc2S(=O)(=O)Oc2cc(C)cc(OCCCONC(=N)N)c2)CC1
Agent: Cl
Agent: N#CC(=Cc1ccc(O)cc1)C(=O)O
Product: Cc1cc(OCCCONC(=N)N)cc(OS(=O)(=O)c2ccccc2S(=O)(=O)N2CCN(CC(=O)O)CC2)c1
Yield: 85 %

Procedure:
The title compound was prepared in 85% yield from {3-[5-methyl-3-(2-(4-(ethoxycarbonylmethyl)piperazin-1-ylsulfonyl)phenylsulfonyloxy)phenoxy]propoxy}guanidine dihydrochloride, as prepared in step b of Example 58, in a manner analogous to Example 27. 1H-NMR (300 MHz, DMSO-d6) δ 11.12 (s, 1H), 8.27 (d, J=7.9 Hz, 1H), 8.18 (d, J=7.9 Hz, 1H), 8.08 (t, J=7.7 Hz, 1H), 7.94 (t, J=7.7 Hz, 1H), 7.69 (br s, 4H), 6.76 (s, 1H), 6.51 (s, 1H), 6.47 (s, 1H), 3.99 (t, J=6.2 Hz, 2H), 3.90 (t, J=6.3 Hz, 2H), 3.43 (br s, 6H), 3.25 (br s, 4H), 2.22 (s, 3H), 2.02 (pentet, J=6.2 Hz, 2H). Mass spectrum (MALDI-TOF, α-cyano-4-hydroxycinnamic acid matrix) calcd. for C23H31N5O9S2: 586.2 (M+H), 608.1 (M+Na). Found: 586.2, 608.0.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[C:11]([N+:13]([O-])=O)[CH:12]=1)[N:9]=[CH:8][CH:7]=[CH:6]2>[Pd].C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[C:11]([NH2:13])[CH:12]=1)[N:9]=[CH:8][CH:7]=[CH:6]2
Reactant: COc1cc([N+](=O)[O-])c2ncccc2c1
Agent: [Pd]
Solvent: C1CCOC1
Product: COc1cc(N)c2ncccc2c1
Temperature: 23 °C
Reaction time: 4 h
Yield: 95 %

Procedure:
A mixture of 9.20 g (45.1 mmol) 6-methoxy-8-nitroquinoline, 1.8 g of 10% Pd/C and 150 mL THF is placed under 40 psi of H2 and shaken in a Parr reactor at 23° C. for 4 h. The Pd/C is removed via filtration through celite, and the solvent evaporated. Flash chromatography on SiO2 gel, eluting with hexanes/EtOAc (1/1 to 1/3), gives 7.40 g (42.5 mmol, a 95% yield) of the title compound as an off-white solid. MS (ES) m/z 175 (MH)+.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([NH:15]OC)([CH2:12][CH2:13][CH3:14])[C:4](=[O:18])[C:3]=1[C:19]1[NH:24][C:23]2[CH:25]=[CH:26][C:27]([NH:29][S:30]([CH3:33])(=[O:32])=[O:31])=[CH:28][C:22]=2[S:21](=[O:35])(=[O:34])[N:20]=1.O>CC#N.[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[Mo]>[NH2:15][C:5]1([CH2:12][CH2:13][CH3:14])[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([OH:1])=[C:3]([C:19]2[NH:24][C:23]3[CH:25]=[CH:26][C:27]([NH:29][S:30]([CH3:33])(=[O:32])=[O:31])=[CH:28][C:22]=3[S:21](=[O:35])(=[O:34])[N:20]=2)[C:4]1=[O:18]
Reactant: CCCC1(NOC)C(=O)C(C2=NS(=O)(=O)c3cc(NS(C)(=O)=O)ccc3N2)=C(O)c2ccccc21
Agent: [Mo]
Agent: [C-]#[O+]
Solvent: CC#N
Solvent: O
Product: CCCC1(N)C(=O)C(C2=NS(=O)(=O)c3cc(NS(C)(=O)=O)ccc3N2)=C(O)c2ccccc21
Temperature: 25 °C
Yield: 69.7 %

Procedure:
To a solution of the product of Example 9 (20 mg, 0.038 mmol) in CH3CN (1.5 mL) was added H2O (100 uL) and molybdenum hexacarbonyl (7 mg, 0.027 mmol) and the solution was refluxed for 2 hours. After cooling to room temperature the solvent was removed in vacuo and the crude product was purified by column chromatography on C-1 8 silica gel (70:30:0.1 methanol:H2O:trifluoroacetic acid) to give the title compound as a colorless solid (13 mg, 69%): 1H NMR (d6-DMSO) δ 14.47 (s, 1H), 9.94 (s, 1H), 8.61 (s, 2H), 8.14, 8.11 (d, 1H), 7.70-7.42 (m, 5H), 7.37, 7.34 (d, 1H), 3.01 (s, 3H), 2.03-1.93 (m, 1H), 1.87-1.75 (m, 1H), 1.29-1.14 (m, 1H), 0.96-0.83 (m, 1H), 0.76-0.67 (t, 3H); MS (ESI) m/z 491 (M+H+).