Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[N:7]([CH2:9][C:10]1[CH:14]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:12]([S:21]([C:24]2[CH:25]=[N:26][CH:27]=[C:28](Br)[CH:29]=2)(=[O:23])=[O:22])[CH:11]=1)[CH3:8])(C)(C)C.[CH3:32]B(O)O.C(=O)([O-])[O-].[K+].[K+].C(=O)([O-])O.[Na+].C(OCC)(=O)C.[ClH:53]>C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O1CCOCC1>[ClH:53].[ClH:53].[CH3:8][NH:7][CH2:9][C:10]1[CH:14]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:12]([S:21]([C:24]2[CH:25]=[N:26][CH:27]=[C:28]([CH3:32])[CH:29]=2)(=[O:22])=[O:23])[CH:11]=1
Reactant: CB(O)O
Reactant: CN(Cc1cc(-c2ccccc2)n(S(=O)(=O)c2cncc(Br)c2)c1)C(=O)OC(C)(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])O
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CNCc1cc(-c2ccccc2)n(S(=O)(=O)c2cncc(C)c2)c1
Temperature: 80 °C
Reaction time: 24 h
Yield: 39 %

Procedure:
Under an argon atmosphere, a mixture of tert-butyl({1-[(5-bromopyridin-3-yl)sulfonyl]-5-phenyl-1H-pyrrol-3-yl}methyl)methylcarbamate (112 mg), methylboronic acid (18 mg), tetrakis(triphenylphosphine)palladium (23 mg), potassium carbonate (138 mg) and 1,4-dioxane (5 mL) was stirred at 80° C. for one day. The reaction mixture was poured into a saturated aqueous sodium hydrogencarbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=19:1→1:1) to give an oil. The oil was dissolved in ethanol (1 mL), and a 4 mol/L hydrogen chloride-ethyl acetate solution (1 mL) was added. After stirring at room temperature for 1 hr, the mixture was concentrated under reduced pressure. The residue was recrystallized from ethanol-ethyl acetate to give the title compound as a colorless solid (yield 32.6 mg, 39%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH:8]2[S:13][CH2:12][CH2:11][CH2:10][S:9]2)=[CH:6][C:5]([NH:14][N:15]=[CH:16][CH3:17])=[C:4]([F:18])[CH:3]=1.[O-:19][C:20]#[N:21].[K+].Cl[O-].[Na+]>C(O)(=O)C.O.C(OCC)(=O)C>[Cl:1][C:2]1[C:7]([CH:8]2[S:9][CH2:10][CH2:11][CH2:12][S:13]2)=[CH:6][C:5]([N:14]2[C:20](=[O:19])[NH:21][C:16]([CH3:17])=[N:15]2)=[C:4]([F:18])[CH:3]=1
Reactant: N#C[O-]
Reactant: CC=NNc1cc(C2SCCCS2)c(Cl)cc1F
Agent: [K+]
Agent: [Na+]
Agent: [O-]Cl
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: Cc1nn(-c2cc(C3SCCCS3)c(Cl)cc2F)c(=O)[nH]1
Temperature: 15 °C
Reaction time: 1.5 h

Procedure:
To a stirred mixture of 5.00 g (0.0145 mole) of acetaldehyde 4-chloro-2-fluoro-5-(1,3-dithian-2-yl)phenylhydrazone in 50 mL of acetic acid is added dropwise a solution of 1.38 g (0.017 mole) of potassium cyanate in 5 mL of water. This mixture is stirred at 15° C. for approximately 1.5 hour. Additional aqueous potassium cyanate solution may be added if analysis of the reaction mixture by thin layer chromatography indicates the presence of acetaldehyde 4-chloro-2-fluoro-5-(1,3-dithian-2-yl)phenylhydrazone. While maintaining a temperature of 15° C., 30 mL of an aqueous, 5% sodium hypochlorite solution is added. This mixture is stirred at 15° C. for approximately one hour. The solvents are removed by distillation under reduced pressure to leave a residue. This residue is dissolved in ethyl acetate and is washed in succession with an aqueous, saturated sodium bicarbonate solution, water, and an aqueous, saturated sodium chloride solution. The washed organic solution is dried over anhydrous magnesium sulfate and is filtered. The filtrate is evaporated under reduced pressure to yield 1-[4-chloro-2-fluoro-5-(1,3-dithian-2-yl)phenyl]-4,5-dihydro-3-methyl-1,2,4-triazol-5(1H)-one.
Reaction SMILES: Cl.O1CCOCC1.[Si]([O:15][C@H:16]1[CH2:20][CH2:19][N:18]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)[C:17]1=[O:29])(C(C)(C)C)(C)C>ClCCl>[Cl:28][C:25]1[CH:24]=[CH:23][C:22]([CH2:21][N:18]2[CH2:19][CH2:20][C@H:16]([OH:15])[C:17]2=[O:29])=[CH:27][CH:26]=1
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CCN(Cc2ccc(Cl)cc2)C1=O
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: O=C1[C@@H](O)CCN1Cc1ccc(Cl)cc1
Reaction time: 2 h
Yield: 102.3 %

Procedure:
A solution of 4 M HCl in dioxane (4.93 ml, 19.7 mmol) was added to a stirred solution of (S)-3-((tert-butyldimethylsilyl)oxy)-1-(4-chlorobenzyl)pyrrolidin-2-one (1.34 g, 3.94 mmol) in dichloromethane (4 mL) at RT. The reaction mixture was stirred for 2 h. The reaction mixture was concentrated in vacuo to afford (S)-1-(4-chlorobenzyl)-3-hydroxypyrrolidin-2-one (910 mg, 4.03 mmol, quantitative yield): LC-MS (M+H)+ 226.1; 1H NMR (500 MHz, methanol-d4) δ 7.37-7.33 (m, J=8.5 Hz, 2H), 7.27-7.23 (m, J=8.5 Hz, 2H), 4.52-4.37 (m, 2H), 4.34 (t, J=8.2 Hz, 1H), 3.30-3.18 (m, 2H), 1.84 (dq, J=12.8, 8.5 Hz, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([OH:13])=[O:12])[CH:10]=1)[NH:7][CH:6]=[CH:5]2.[C:14]1(B(O)O)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[Cl-].CC1C=C(C)C=C(C)C=1[N+]1C=CN(C2C(C)=CC(C)=CC=2C)C=1>O1CCOCC1.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:14]1([C:2]2[CH:3]=[C:4]3[C:8](=[C:9]([C:11]([OH:13])=[O:12])[CH:10]=2)[NH:7][CH:6]=[CH:5]3)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(O)c1cc(Br)cc2cc[nH]c12
Reactant: OB(O)c1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1cc(C)c(-n2cc[n+](-c3c(C)cc(C)cc3C)c2)c(C)c1
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)c1cc(-c2ccccc2)cc2cc[nH]c12
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 5-bromo-1H-indole-7-carboxylic acid (10 g, 41.8 mmol) in dioxane (150 mL) and water (50 mL) was added phenylboronic acid (19.5 g, 159.9 mmol), cesium carbonate (26.0 g, 79.8 mmol), 1,3-Bis(2,4,6-trimethylphenyl) imidazolium chloride (2.8 g, 8.2 mmol), and palladiumacetate (0.9 g, 4.01 mmol). The reaction mixture was stirred at ambient temperature for 15 min, and then was refluxed at 80° C. for 15 hr. The organic solvent was removed under reduced pressure and the water layer was adjusted to pH=1-2 with 6 M hydrochloric acid before ethyl acetate (350 mL) was added into it. The organic layer washed with water (100 mL×3), dried and concentrated at 45° C. to a thick oil (approximately 40 mL solvent left), cooled to −20° C., and filtered. The solid was washed with cold ethyl acetate (10 mL×3), and collected. The filtrate was concentrated to a thick oil at 45° C., then was cooled to −20° C., and off-white solid was obtained. The suspension was filtered and washed with cold ethyl acetate (5 mL×3). The filtrate was discard after 3 iterations of the above procedure.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N:7][CH:6]=[CH:5]2.O.[NH3:13].[OH-].[Na+]>ClCCl.O.O.O.O.O.S([O-])([O-])(=O)=O.[Cu+2]>[NH2:13][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N:7][CH:6]=[CH:5]2
Reactant: N
Reactant: Brc1ccc2cnccc2c1
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: Nc1ccc2cnccc2c1
Temperature: 190 °C
Reaction time: 6 h

Procedure:
6-bromoisoquinoline that weighed 17.2 g (see WO 2008/077553), 200 mL of 28% ammonia water and 10.8 g of copper (II) sulfate pentahydrate were put into the autoclave and tightly sealed, and the mixture was then stirred at 190° C. for 6 hours. After cooling to room temperature, the reaction solution was poured into 250 mL of a 10% aqueous sodium hydroxide solution, followed by extraction with ethyl acetate (100 mL×5). The extract was dried over anhydrous sodium sulfate, filtered, and then concentrated. The obtained crude product was suspended in dichloromethane and then filtered to obtain 10.2 g of the compound of interest as a light brown crystal (85%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:14]([F:15])=[CH:13][C:12]([CH2:16][OH:17])=[CH:11][C:10]=2[F:18])[CH:5]=[CH:4][N:3]=1.Cl[C:20]1[CH:21]=[C:22]2[N:29]([CH3:30])[C:28]([CH3:32])([CH3:31])[CH2:27][N:23]2[C:24](=[O:26])[N:25]=1>>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:14]([F:15])=[CH:13][C:12]([CH2:16][O:17][C:20]3[CH:21]=[C:22]4[N:29]([CH3:30])[C:28]([CH3:32])([CH3:31])[CH2:27][N:23]4[C:24](=[O:26])[N:25]=3)=[CH:11][C:10]=2[F:18])[CH:5]=[CH:4][N:3]=1
Reactant: CN1c2cc(Cl)nc(=O)n2CC1(C)C
Reactant: OCc1cc(F)c(Oc2ccnc(Cl)c2)c(F)c1
Product: CN1c2cc(OCc3cc(F)c(Oc4ccnc(Cl)c4)c(F)c3)nc(=O)n2CC1(C)C

Procedure:
The title compound was prepared by a procedure similar to that described for E9 starting from (4-((2-chloropyridin-4-yl)oxy)-3,5-difluorophenyl)methanol and 7-chloro-1,2,2-tri-methyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[C:14]([C:15]#[C:16][Si](C)(C)C)=[CH:13][N:12]=[CH:11][N:10]=2)[C:5](=[O:21])[N:4]2[C:22]3([CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)[NH:23][C:24](=[O:25])[C:3]=12.C(=O)([O-])[O-].[K+].[K+]>CO>[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[C:14]([C:15]#[CH:16])=[CH:13][N:12]=[CH:11][N:10]=2)[C:5](=[O:21])[N:4]2[C:22]3([CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)[NH:23][C:24](=[O:25])[C:3]=12
Reactant: C[Si](C)(C)C#Cc1cncnc1Nc1cc(Cl)c2n(c1=O)C1(CCCCC1)NC2=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#Cc1cncnc1Nc1cc(Cl)c2n(c1=O)C1(CCCCC1)NC2=O
Reaction time: 16 h

Procedure:
A flask was charged with 8′-chloro-6′-((5-((trimethylsilyl)ethynyl)pyrimidin-4-yl)amino)-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione (5, 300 mg, 0.67 mmol) and methanol (20 mL) followed by addition of potassium carbonate (469 mg, 3.39 mmol) at room temperature and reaction mixture was stirred for 16 h. After completion, solvent was concentrated under reduced pressure and the resulting residue was further washed with water followed by diethyl ether and pentane to afford 8′-chloro-6′-((5-ethynylpyrimidin-4-yl)amino)-2′H-spiro[cyclohexane-1,3′-imidazo[1,5-a]pyridine]-1′,5′-dione (Cpd. No. 144) as yellow solid. Yield: 100 mg, 40%; MS (ESI) m/z 370.09 [M+1]+; 1H NMR (400 MHz, DMSO-d6) δ 10.42 (s, 1H), 8.99 (s, 1H), 8.90 (s, 1H), 8.70 (s, 2H), 5.22 (s, 1H), 2.90 (brs, 2H), 1.73-1.64 (m, 2H), 1.61-1.56 (m, 3H), 1.56-1.53 (m, 2H), 1.27 (m, 1H).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][C:22]=2[O:31][CH3:32])[C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([S:12]([NH:15][C:16]1[S:17][CH:18]=[CH:19][N:20]=1)(=[O:14])=[O:13])=[CH:7][CH:6]=2.[CH3:33][O-:34].[Na+].CO>CS(C)=O.CCOC(C)=O>[CH3:33][O:34][C:2]1[N:3]=[C:4]([C:21]2[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][C:22]=2[O:31][CH3:32])[C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([S:12]([NH:15][C:16]1[S:17][CH:18]=[CH:19][N:20]=1)(=[O:14])=[O:13])=[CH:7][CH:6]=2
Reactant: C[O-]
Reactant: COc1cc(C(F)(F)F)ccc1-c1nc(Cl)cc2cc(S(=O)(=O)Nc3nccs3)ccc12
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: COc1cc2cc(S(=O)(=O)Nc3nccs3)ccc2c(-c2ccc(C(F)(F)F)cc2OC)n1
Temperature: 100 °C
Yield: 65.3 %

Procedure:
A vial was charged with 3-chloro-1-(2-methoxy-4-(trifluoromethyl)phenyl)-N-(thiazol-2-yl)isoquinoline-6-sulfonamide (Example 249) (35.79 mg, 0.072 mmol), sodium methoxide (25.1 mg, 0.465 mmol), and MeOH (477 μl). The vial was sealed and heated in a 100° C. heating bath for 1 h. The mixture was diluted with DMSO (0.5 mL) to solubilize the solids, and an additional portion of sodium methoxide (25.1 mg, 0.465 mmol) was added. The vial was sealed and heated to 120° C. for 1.5 h. The mixture was cooled to room temperature and diluted with EtOAc, then washed with 1N aq. HCl, washed with water, washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by chromatography on silica gel (0 to 5% MeOH/DCM) to give 3-methoxy-1-(2-methoxy-4-(trifluoromethyl)phenyl)-N-(thiazol-2-yl)isoquinoline-6-sulfonamide (23.2 mg, 0.047 mmol, 65.4% yield) as an off-white solid: 1H NMR (400 MHz, DMSO-d6) δ ppm=12.88 (s, 1H), 8.40 (s, 1H), 7.61-7.56 (m, 3H), 7.55-7.48 (m, 3H), 7.28 (d, J=4.6 Hz, 1H), 6.87 (d, J=4.6 Hz, 1H), 3.95 (s, 3H), 3.76 (s, 3H). m/z (ESI) 496.2 (M+H)+.
Reaction SMILES: [Br-].[C:2]([Mg]Br)#[CH:3].[Cl:6][C:7]1[CH:8]=[C:9](I)[CH:10]=[C:11]([Cl:13])[CH:12]=1>C1COCC1.[Cl-].[Na+].O.[Zn]>[Cl:6][C:7]1[CH:8]=[C:9]([C:2]#[CH:3])[CH:10]=[C:11]([Cl:13])[CH:12]=1
Reactant: Clc1cc(Cl)cc(I)c1
Reactant: C#C[Mg]Br
Agent: [Br-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: C#Cc1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of zinc, bromide (5.0 g, 22.2 mmol) in anhydrous THF (100 mL) at room temperature under a nitrogen atmosphere was added a solution of ethynyl magnesium bromide (0.5 M in THF, 44.4 mL, 44.4 mmol). After 5 minutes 3,5-dichloro-iodobenzene was added (4.03 g, 14.8 mmol) followed by tetrakis-triphenyl phosphine palladium (0) (855 mg, 0.74 mmol). The reaction was stirred at room temperature for 18 hours. The reaction mixture was poured into brine and extracted with ether (4×100 mL). The ether layer was washed with brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography with 100% hexanes to give the title compound as a yellow solid. 1H NMR (CDCl3, 500 MHz): 7.4 (d, J=1.6 Hz, 2H), 7.3 (d, J=1.6 Hz, 1H), 3.19 (s, 1H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[F:9][C:10]1[CH:18]=[C:17]2[C:13]([CH:14]=[N:15][NH:16]2)=[CH:12][CH:11]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].CNCCNC>[Cu]I.C1(C)C=CC=CC=1>[F:9][C:10]1[CH:11]=[CH:12][C:13]2[C:17]([CH:18]=1)=[N:16][N:15]([C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1)[CH:14]=2
Reactant: Fc1ccc2cn[nH]c2c1
Reactant: Oc1ccc(Br)cc1
Agent: [Cu]I
Agent: CNCCNC
Agent: O=P([O-])([O-])[O-]
Solvent: Cc1ccccc1
Product: Oc1ccc(-n2cc3ccc(F)cc3n2)cc1
Yield: 7.7 %

Procedure:
4-bromophenol (1.27 g, 7.3 mmol) was combined with 6-fluoro-1H-indazole (1.000 g, 7.35 mmol), CuI (69.9 mg, 0.367 mmol), K3PO4 (3.282 g, 15.4 mmol), toluene (15 mL), and dimethylethylenediamine (0.158 mL, 1.47 mmol). This was refluxed as a mixture for 3 d. The reaction was cooled and partitioned between ethyl acetate and sat. NH4Cl. The aqueous was extracted with ethyl acetate and the combined organics were dried over MgSO4. Purification by silica gel flash chromatography (ethyl acetate in heptane) gave 4-(6-fluoro-indazol-2-yl)-phenol (0.129 g, 8%) as a tan solid. The other regioisomer was also observed but was separated by chromatography. 1H NMR (400 MHz, DMSO-d6, δ): 9.86 (s, 1H) 8.96 (s, 1H) 7.75-7.91 (m, 3H) 7.41 (d, J=10.6 Hz, 1H) 6.99 (td, J=9.3, 2.2 Hz, 1H) 6.93 (d, J=8.8 Hz, 2H); MS (M+1): 229.2.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:10][C@H:9]2[N:11]([CH2:19][CH:20]2[CH2:22][CH2:21]2)[C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:30]1([CH3:39])[CH:35]=[CH:34][C:33]([C:36](Cl)=[O:37])=[CH:32][CH:31]=1.[Cl-].[NH4+]>C1COCC1>[C:14]([O:13][C:12](=[O:18])[N:11]([CH2:19][CH:20]1[CH2:22][CH2:21]1)[C@@H:9]1[CH2:10][C@H:8]1[C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:36](=[O:37])[C:33]2[CH:34]=[CH:35][C:30]([CH3:39])=[CH:31][CH:32]=2)=[CH:3][CH:4]=1)([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)OC(=O)N(CC1CC1)[C@@H]1C[C@H]1c1ccc(N)cc1
Reactant: Cc1ccc(C(=O)Cl)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)Nc2ccc([C@@H]3C[C@H]3N(CC3CC3)C(=O)OC(C)(C)C)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of tert-butyl [trans-2-(4-aminophenyl)cyclopropyl](cyclopropylmethyl)carbamate (75.0 mg) and triethylamine (41.5 μL) in THF (1.24 mL) was added 4-toluoyl chloride (39.4 μL). The mixture was stirred at room temperature overnight, and poured into saturated aqueous ammonium chloride solution. The mixture was extracted with ethyl acetate, and the extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the title compound (104.3 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11]2[CH:12]=[CH:13][C:14](/[CH:17]=[CH:18]/[C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)=[N:15][CH:16]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(OCC)(=O)C.[H][H]>C(O)C.[Pd]>[F:25][C:22]1[CH:21]=[CH:20][C:19]([CH2:18][CH2:17][C:14]2[CH:13]=[CH:12][C:11]([S:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)(=[O:10])=[O:9])=[CH:16][N:15]=2)=[CH:24][CH:23]=1
Reactant: O=S(=O)(c1ccc(F)cc1)c1ccc(/C=C/c2ccc(F)cc2)nc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: O=S(=O)(c1ccc(F)cc1)c1ccc(CCc2ccc(F)cc2)nc1
Reaction time: 20 h
Yield: 61.3 %

Procedure:
5-[(4-fluorophenyl)sulfonyl]-2-[(E)-2-(4-fluorophenyl)vinyl]-pyridine (Example 2, 0.42 g, 1.18 mmol) was taken up in ethanol (5 mL) and ethyl acetate (5 mL) and palladium (10% wt. on activated carbon, 60 mg) was added. The suspension was shaken in a Parr apparatus at 20 psi hydrogen for 6 hours, followed by 40 psi hydrogen for 3 days. The catalyst was removed by filtration and the solvent removed in vacuo. The residue was taken up in acetic acid (25 mL) and platinum(IV) oxide (20 mg) was added. The suspension was stirred under a balloon of hydrogen for 20 hours. Further platinum(IV) oxide (20 mg) was added and stirring under hydrogen continued for 24 hours. The catalyst was removed by filtration and most of the solvent removed in vacuo. The residue was partitioned between ethyl acetate and 4N sodium hydroxide solution. The organic phase was dried over MgSO4 and concentrated in vacuo while loading onto silica. Eluting through a plug of silica using 20% ethyl acetate/isohexane gave the title compound as a yellow solid (0.26 g, 61%). δH (500 MHz, d6 DMSO): 9.04 (1H, d, J=2.2 Hz), 8.23 (1H, dd, J=2.4, 8.3 Hz), 8.09-8.07 (2H, m), 7.49-7.45 (3H, m), 7.22-7.19 (2H, m), 7.04 (2H, t, J=8.8 Hz), 3.11-3.09 (2H, m), 2.98-2.95 (2H, m); m/z (ES+) 360 [MH+].
Reaction SMILES: Br[C:2]1[C:6]([Br:7])=[C:5]([NH:8][C:9]([CH:11]2[CH2:13][CH2:12]2)=[O:10])[S:4][N:3]=1.[CH3:14][N:15]1[CH:23]=[C:22]2[C:17]([CH:18]=[CH:19][C:20](B3OC(C)(C)C(C)(C)O3)=[CH:21]2)=[N:16]1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.[Cl-].[Na+].O.C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Br:7][C:6]1[C:2]([C:20]2[CH:19]=[CH:18][C:17]3[C:22](=[CH:23][N:15]([CH3:14])[N:16]=3)[CH:21]=2)=[N:3][S:4][C:5]=1[NH:8][C:9]([CH:11]1[CH2:13][CH2:12]1)=[O:10]
Reactant: O=C(Nc1snc(Br)c1Br)C1CC1
Reactant: Cn1cc2cc(B3OC(C)(C)C(C)(C)O3)ccc2n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Cn1cc2cc(-c3nsc(NC(=O)C4CC4)c3Br)ccc2n1
Yield: 50 %

Procedure:
Degas by bubbling nitrogen for 10; min through a mixture of cyclopropanecarboxylic acid (3,4-dibromo-isothiazol-5-yl)-amide (1.04; g, 3.19; mmol) and 2-methyl-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-2H-indazole (1.29; g, 3.51 mmol) in 1,4-dioxane (16; mL) and a 2M aqueous solution of sodium carbonate (7.98 mL). Add bis(triphenylphosphine)palladium(II) chloride (448; mg, 0.64; mmol) and heat at 80° C. for 12; h. Cool, dilute with brine and ethyl acetate and separate the layers. Extract the aqueous phase twice with ethyl acetate. Dry the combined organic phases over sodium sulfate, filter, concentrate and purify by silica gel chromatography, gradient eluting from 40:60; to 100:0; using ethyl acetate:hexanes, to give the title compound as a solid (0.6; g, 1.59; mmol, 50%). MS (m/z): 377, 379; (M+1).
Reaction SMILES: [C:1]([O:9][CH2:10][CH2:11][N:12]1[C:24]2[C:23]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[N:17]=[CH:16][C:15]=2[N:14]=[CH:13]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:25]O>C(O)(=O)C>[C:1]([O:9][CH2:10][CH2:11][N:12]1[C:24]2[C:23]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[N+:17]([O-:25])=[CH:16][C:15]=2[N:14]=[CH:13]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OO
Reactant: O=C(OCCn1cnc2cnc3ccccc3c21)c1ccccc1
Solvent: CC(=O)O
Product: O=C(OCCn1cnc2c[n+]([O-])c3ccccc3c21)c1ccccc1
Temperature: 65 °C

Procedure:
A mixture of 67.5 g (0.213 mole) of 1-(2-benzoyloxyethyl)-1H-imidazo[4,5-c]quinoline (from Example 118), 36.3 g (0.32 mole) of 30% hydrogen peroxide and 450 ml of glacial acetic acid was heated at 65° C. for two days with stirring. The solution was then evaporated in vacuo, and the residue was added to water. The mixture was neutralized with aqueous sodium hydroxide solution and sodium bicarbonate. The solid was separated by filtration, washed with water and recrystallized from methanol to provide tan solid 1-(2-benzoyloxyethyl)-1H-imidazo[4,5-c]-quinolin-5-oxide.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][C@H:13]1[CH2:18][CH2:17][C@H:16]([C:19]([OH:21])=[O:20])[CH2:15][CH2:14]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1CCC(N=C=NC2CCCCC2)CC1.CS(O)(=O)=O.[C:42]([C:45]1[CH:54]=[C:49]([C:50]([O:52][CH3:53])=[O:51])[C:48](O)=[CH:47][CH:46]=1)(=[NH:44])[NH2:43]>N1C=CC=CC=1>[CH2:1]([O:8][C:9]([NH:11][CH2:12][C@H:13]1[CH2:18][CH2:17][C@H:16]([C:19]([O:21][C:48]2[CH:47]=[CH:46][C:45]([C:42](=[NH:43])[NH2:44])=[CH:54][C:49]=2[C:50]([O:52][CH3:53])=[O:51])=[O:20])[CH2:15][CH2:14]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(NC[C@H]1CC[C@H](C(=O)O)CC1)OCc1ccccc1
Reactant: COC(=O)c1cc(C(=N)N)ccc1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CS(=O)(=O)O
Solvent: c1ccncc1
Product: COC(=O)c1cc(C(=N)N)ccc1OC(=O)[C@H]1CC[C@H](CNC(=O)OCc2ccccc2)CC1
Reaction time: 0.5 h

Procedure:
Into 40 ml of anhydrous pyridine, was dissolved 4.3 g of trans-4-benzyloxycarbonylaminomethylcyclohexanecarboxylic acid. To the solution, while being cooled in ice, was added 3.7 g of DCC. To the mixture which had been stirred for 30 minutes, was added 4.1 g of methyl 5-amidinosalicylate methanesulfonate. The mixture was stirred overnight at room temperature. The precipitate which was formed was separated by filtration and washed with pyridine. Ethyl ether was added to the filtrate and the precipitated white crystals were washed with ethyl ether and dissolved in DMF. The colorless crystals separated from the DMF solution by the addition of ethyl ether were recrystallized from ethanol to obtain 4.3 g of a colorless powder of 4-amidino-2-methoxycarbonylphenyl trans-4-benzyloxycarbonylamino-methylcyclohexanecarboxylate methanesulfonate.
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][C:14]2[N:17]=[C:18]([C:20]([NH:22][C@@H:23]3[CH2:28][CH2:27][CH2:26][CH2:25][C@@H:24]3[NH:29][C:30]([C:32]3[NH:33][C:34]4[C:39]([CH:40]=3)=[CH:38][C:37]([Cl:41])=[CH:36][CH:35]=4)=[O:31])=[O:21])[S:19][C:13]=2[CH2:12]1)=O)(C)(C)C.C(O)C.Cl>ClCCl>[ClH:41].[NH2:8][CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][C:14]2[N:17]=[C:18]([C:20]([NH:22][C@@H:23]3[CH2:28][CH2:27][CH2:26][CH2:25][C@@H:24]3[NH:29][C:30]([C:32]3[NH:33][C:34]4[C:39]([CH:40]=3)=[CH:38][C:37]([Cl:41])=[CH:36][CH:35]=4)=[O:31])=[O:21])[S:19][C:13]=2[CH2:12]1
Reactant: CC(C)(C)OC(=O)NCCN1CCc2nc(C(=O)N[C@@H]3CCCC[C@@H]3NC(=O)c3cc4cc(Cl)ccc4[nH]3)sc2C1
Agent: Cl
Solvent: CCO
Solvent: ClCCl
Product: NCCN1CCc2nc(C(=O)N[C@@H]3CCCC[C@@H]3NC(=O)c3cc4cc(Cl)ccc4[nH]3)sc2C1
Temperature: 25 °C
Reaction time: 0.02 h
Yield: 182.4 %

Procedure:
(±)-cis-N1-[[5-[2-(tert-Butoxycarbonylamino)-ethyl]-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl]carbonyl]-N2-[(5-chloroindol-2-yl)carbonyl]-1,2-cyclohexanediamine (450 mg) was dissolved in dichloromethane (5 ml), and a saturated ethanol solution (30 ml) of hydrochloric acid was added to stir the mixture at room temperature for 1 minute. The reaction mixture was concentrated under reduced pressure, ethyl acetate was added to the residue, and solids deposited were collected by filtration to obtain the title compound (367 mg) as a pale yellow amorphous solid.