Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](N1C=CC=CC1=O)(N1C=CC=CC1=O)=[S:2].[CH3:17][O:18][C:19]1[N:24]=[CH:23][C:22]([C:25]2[CH:30]=[C:29]([NH2:31])[N:28]=[CH:27][N:26]=2)=[CH:21][N:20]=1>ClCCl.CN(C)C=O>[N:31]([C:29]1[N:28]=[CH:27][N:26]=[C:25]([C:22]2[CH:21]=[N:20][C:19]([O:18][CH3:17])=[N:24][CH:23]=2)[CH:30]=1)=[C:1]=[S:2]
Reactant: O=c1ccccn1C(=S)n1ccccc1=O
Reactant: COc1ncc(-c2cc(N)ncn2)cn1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1ncc(-c2cc(N=C=S)ncn2)cn1
Temperature: 60 °C

Procedure:
To a solution of 1,1′-thiocarbonyldipyridin-2(1H)-one (0.832 g, 3.58 mmol) in dichloromethane/N,N-dimethylformamide at room temperature was added 2′-methoxy-4,5′-bipyrimidin-6-amine (0.56 g, 2.76 mmol). The orange mixture was heated at 60° C. for 18 hours. The LC/MS showed the desired product peak as the major peak. The deep orange mixture was purified by silica gel chromatography (0-40% ethyl acetate-hexanes) to afford 4-isothiocyanato-6-methoxypyrimidine (0.1 g, 0.408 mmol, 15% yield) as an orange solid. LCMS R.T.=2.29; [M+H]+=246.03.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:33]=[CH:32][C:12]([O:13][C:14]2[CH:15]=[CH:16][C:17]([N+:29]([O-])=O)=[C:18]([N:20]([CH3:28])[C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH:19]=2)=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>[Pd].O1CCCC1.C(OCC)(=O)C>[NH2:29][C:17]1[CH:16]=[CH:15][C:14]([O:13][C:12]2[CH:11]=[CH:10][C:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[CH:33][CH:32]=2)=[CH:19][C:18]=1[N:20]([CH3:28])[C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24]
Reactant: CN(C(=O)OC(C)(C)C)c1cc(Oc2ccc(NC(=O)OC(C)(C)C)cc2)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CN(C(=O)OC(C)(C)C)c1cc(Oc2ccc(NC(=O)OC(C)(C)C)cc2)ccc1N
Yield: 101.2 %

Procedure:
In a similar manner to that described in Reference Example 7, a reaction was carried out using t-butyl N-[5-(4-t-butoxycarbonylaminophenoxy)-2-nitrophenyl]-N-methylcarbamate (27.7 g), palladium on carbon (10%, 1.07 g) and tetrahydrofuran/ethyl acetate=9/8 (170 ml) and the reaction mixture was purified to give the title compound (26.2 g).
Reaction SMILES: [NH2:1][C:2]1[N:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][N:17]3[CH2:22][CH2:21][CH:20]([N:23]4[C:27]5[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=5[NH:25][C:24]4=[O:32])[CH2:19][CH2:18]3)=[CH:12][CH:11]=2)[C:7]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[CH:6][C:3]=1[C:4]#[N:5].[CH2:39]([N:41]=[C:42]=[O:43])[CH3:40]>C1COCC1>[C:4]([C:3]1[C:2]([NH:1][C:42]([NH:41][CH2:39][CH3:40])=[O:43])=[N:9][C:8]([C:10]2[CH:11]=[CH:12][C:13]([CH2:16][N:17]3[CH2:18][CH2:19][CH:20]([N:23]4[C:27]5[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=5[NH:25][C:24]4=[O:32])[CH2:21][CH2:22]3)=[CH:14][CH:15]=2)=[C:7]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:6]=1)#[N:5]
Reactant: CCN=C=O
Reactant: N#Cc1cc(-c2ccccc2)c(-c2ccc(CN3CCC(n4c(=O)[nH]c5ccccc54)CC3)cc2)nc1N
Solvent: C1CCOC1
Product: CCNC(=O)Nc1nc(-c2ccc(CN3CCC(n4c(=O)[nH]c5ccccc54)CC3)cc2)c(-c2ccccc2)cc1C#N

Procedure:
The mixture of 2-amino-6-(4-{[4-(2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)piperidin-1-yl]methyl}phenyl)-5-phenylnicotinonitrile (6-3; 0.025 g, 0.05 mmol) and ethylisocyanate (0.007 mg, 0.100mmol) in THF (1 mL) was heated to 100 C for 0.5 h and concentrated. The residue was purified by silica gel chromatography (3-6% MeOH in CH2Cl2) to give the title compound (7-1). LRMS m/z (M+H) Calcd: 572.7, found: 572.2.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([N:15]=[C:16]=[O:17])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5].[NH2:18]/[C:19](/[CH3:27])=[C:20](/[CH3:26])\[C:21]([O:23][CH2:24][CH3:25])=[O:22]>>[Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([NH:15][C:16]([NH:18][C:19]([CH3:27])=[C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH3:26])=[O:17])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:8])[CH3:9])=[O:5]
Reactant: CC(C)OC(=O)c1cc(N=C=O)c(F)cc1Cl
Reactant: CCOC(=O)/C(C)=C(/C)N
Product: CCOC(=O)C(C)=C(C)NC(=O)Nc1cc(C(=O)OC(C)C)c(Cl)cc1F

Procedure:
using isopropyl 2-chloro-4-fluoro-5-isocyanatobenzoate and ethyl 3-amino-2-methylcrotonate there is obtained isopropyl 2-chloro-4-fluoro-5-{3-[2-(ethoxycarbonyl)-1-methylpropenyl]ureido}-benzoate, m.p. 145°-147° C.,
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N+:8]([O-:10])=[O:9])=[N:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:17][N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1.Cl>CS(C)=O.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH3:17][N:18]1[CH2:23][CH2:22][N:21]([C:2]2[CH:7]=[N:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=2)[CH2:20][CH2:19]1
Reactant: O=[N+]([O-])c1ccc(Br)cn1
Reactant: CN1CCNCC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CS(C)=O
Product: CN1CCN(c2ccc([N+](=O)[O-])nc2)CC1
Temperature: 120 °C
Yield: 83.1 %

Procedure:
To 5-Bromo-2-nitro-pyridine (2.00 g, 9.85 mmol) in 10 mL dimethylsulfoxide was added potassium carbonate (2.72 g, 19.7 mmol), 1-methylpiperazine (1.64 mL, 14.8 mmol), and tetrabutylammonium iodide (36 mg, 0.097 mmol) and was heated at 120° C. for 18 hours. The mixture was made acidic with 1M aq. HCl and was partitioned between dichloromethane and water. The aqueous layer was made basic with 2M aq. sodium carbonate and was extracted with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, concentrated in vacuo, and was triturated with water to yield 1-Methyl-4-(6-nitro-pyridin-3-yl)-piperazine (1.82 g, 8.19 mmol). MS (ESI) 223.1 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:9][C:10](=[O:18])[C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[N:13][CH:12]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[Cl:19][C:20]1[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=1[C:22](O)=[O:23]>>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([C:10]([NH:9][C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([NH:1][C:22](=[O:23])[C:21]3[CH:25]=[CH:26][CH:27]=[CH:28][C:20]=3[Cl:19])[CH:3]=2)=[O:18])=[CH:12][N:13]=1
Reactant: O=C(O)c1ccccc1Cl
Reactant: Nc1cc(NC(=O)c2ccc(Cl)nc2)ccc1Cl
Product: O=C(Nc1ccc(Cl)c(NC(=O)c2ccccc2Cl)c1)c1ccc(Cl)nc1

Procedure:
N-(3-amino-4-chlorophenyl)-6-chloronicotinamide (0.2 mmol) was used in general procedure 2 with 2-chlorobenzoic acid (0.8 mmol). The product was purified by RP-HPLC to give 6-chloro-N-(4-chloro-3-(2-chlorobenzamido)phenyl)nicotinamide. MS (Q1) 419.8 (M)+
Reaction SMILES: [F:1][C:2]1([F:30])[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[O:18][N:17]=[C:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[O:25][CH3:26])[N:15]=3)=[CH:10][C:9]=2[N+:27]([O-])=O)[CH2:3]1>CCO.C([O-])(O)=O.[Na+]>[F:30][C:2]1([F:1])[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[O:18][N:17]=[C:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[O:25][CH3:26])[N:15]=3)=[CH:10][C:9]=2[NH2:27])[CH2:3]1
Reactant: COc1ccccc1-c1noc(-c2ccc(N3CCCC(F)(F)C3)c([N+](=O)[O-])c2)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: COc1ccccc1-c1noc(-c2ccc(N3CCCC(F)(F)C3)c(N)c2)n1
Temperature: 70 °C
Reaction time: 3 h
Yield: 100.4 %

Procedure:
Stannous chloride dihydrate (285 mg; 1.26 mmol; 5 eq.) was added to a solution of Example 12 (105 mg; 0.25 mmol; 1 eq.) in EtOH (20 mL) and the resulting mixture was stirred at 70° C. for 3 hours, then at room temperature for 16 hours. The solution was diluted with sat. aq. NaHCO3 and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over magnesium sulfate and concentrated in vacuo to afford the title compound (97 mg, 100%) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:35]C(=O)OC(C)(C)C)[CH:5]=[C:6]([F:34])[C:7]=1[CH2:8][S:9][C:10]1[N:11]([C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)[C:12]([C:15]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([O:25][CH3:26])[CH:19]=2)([CH3:17])[CH3:16])=[CH:13][N:14]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([F:34])[C:7]=1[CH2:8][S:9][C:10]1[N:11]([C:27]2[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=2)[C:12]([C:15]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([O:25][CH3:26])[CH:19]=2)([CH3:16])[CH3:17])=[CH:13][N:14]=1)[NH2:35]
Reactant: COc1cc(C(C)(C)c2cnc(SCc3c(F)cc(NC(=O)OC(C)(C)C)cc3Cl)n2-c2ccc(F)cc2)ccc1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc(C(C)(C)c2cnc(SCc3c(F)cc(N)cc3Cl)n2-c2ccc(F)cc2)ccc1Cl
Reaction time: 1 h
Yield: 90.2 %

Procedure:
A solution of tert-butyl 3-chloro-4-((5-(2-(4-chloro-3-methoxyphenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazol-2-ylthio)methyl)-5-fluorophenylcarbamate (200 mg) in DCM (1 mL) was treated with TFA (1 mL) with stirring. After 1 h, the solution was concentrated under reduced pressure, diluted with DCE (5 mL). The organic layer was washed with water, satd NaHCO3 and brine, then dried (MgSO4) and concentrated to afford the title compound (152 mg, 90%). 1H NMR (400 MHz, MeOD) δ 7.40 (s, 1H), 7.36 (d, J=9.1 Hz, 1H), 6.93 (d, J=8.4, 1H), 6.87 (d, J=8.4 Hz, 1H), 6.68-6.61 (m, 2H), 6.53 (s, 1H), 6.40-6.27 (m, 3H), 4.01 (s, 2H), 3.76 (s, 3H), 1.58 (s, 6H); MS (EI) m/z 534 (MH+).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([S:8][CH3:9])[N:3]=1.[O:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[CH:12]=[C:11]1B(O)O.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[O:10]1[C:11]2=[CH:12][CH:13]=[CH:18][C:17]2=[CH:16][CH:15]=[C:14]1[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([S:8][CH3:9])[N:3]=1
Reactant: OB(O)c1cc2ccccc2o1
Reactant: CSc1nccc(Cl)n1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CSc1nccc(-c2ccc3cccc-3o2)n1
Yield: 41.3 %

Procedure:
4-Chloro-2-methylthiopyrimidine (1.6 g, 10.0 mmol), 2-benzofuranboronic acid (1.9 g, 12.0 mmol), tetrakis-(triphenylphosphine)-palladium (0.3 g, 0.3 mmol) were dissolved in dioxane (10 ml) and aqueous Na2CO3 (11 ml, 2M solution in water, 22 mmol) was added. The reaction was heated to 80° C. under argon for 16 h after which time the dioxane was evaporated and the reaction mixture diluted with water and extracted with CH2Cl2. The organic was dried (Na2SO4), concentrated and the residue purified by flash column chromatography (CH2Cl2:n-heptane 8:2) to afford the title compound (1.0 g, 43%) as a white solid. MS: 243.0 (MH+).
Reaction SMILES: [F:1][C:2]1[C:9]([O:10][CH3:11])=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[CH:12]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=1)[OH:13]>C1(C)C=CC=CC=1.[O-2].[O-2].[Mn+4]>[F:1][C:2]1[C:9]([O:10][CH3:11])=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[C:12](=[O:13])[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[CH:15]=1
Reactant: COc1cc(C#N)cc(C(O)c2cccc(F)c2)c1F
Agent: [Mn+4]
Agent: [O-2]
Solvent: Cc1ccccc1
Product: COc1cc(C#N)cc(C(=O)c2cccc(F)c2)c1F
Temperature: 60 °C
Reaction time: 24 h
Yield: 9.2 %

Procedure:
To a solution of 7.0 g of 4-fluoro-3-[(3-fluorophenyl)-hydroxymethyl]-5-methoxybenzonitrile in 70 ml toluene was added 11.1 g of activated manganese dioxide at room temperature. After stirring at 60° C. for one day, the manganese dioxide was filtered off through Celite. The solvent was removed and the crude product was purified and separated by silica gel column chromatography (ethyl acetate:n-hexane=1:3), to give 640 mg of the title compound as colorless crystals.
Reaction SMILES: [Br:1][C@H:2]1[C@H:8]2[C@H:5]([C:6](=[O:9])[O:7]2)[CH2:4][C@H:3]1[NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14].[BH4-].[Li+]>C1COCC1>[Br:1][C@H:2]1[C@H:8]([OH:7])[C@H:5]([CH2:6][OH:9])[CH2:4][C@H:3]1[NH:10][C:11](=[O:17])[O:12][C:13]([CH3:15])([CH3:14])[CH3:16]
Reactant: CC(C)(C)OC(=O)N[C@@H]1C[C@H]2C(=O)O[C@H]2[C@@H]1Br
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H]1C[C@@H](CO)[C@@H](O)[C@@H]1Br
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 99.1 %

Procedure:
Tert-butyl [(1R,3R,4R,5R)-4-bromo-7-oxo-6-oxabicyclo[3.2.0]hept-3-yl]carbamate (450.0 g, 1.470 mol) was dissolved in THF (6 L) and the mixture was cooled to 0° C. 2.0M lithium tetrahydroborate in THF (730 ml) was added slowly, maintaining an internal temperature lower than 10° C. The mixture was then stirred at 0° C. for 30 minutes, after which HPLC indicated that the starting material had been consumed. At 0° C., a mixture of saturated ammonium chloride in water (2.5 L) and water (2.5 L) was added slowly, maintaining an internal temperature lower than 10° C. The mixture was then allowed to warm to ambient temperature, at which point the THF layer was separated. The THF layer was concentrated to about 2 L, and the aqueous layer was extracted twice with ethyl acetate (4 L). The organic layers were combined and washed twice with water (4 L). The organic layer was then washed with saturated sodium chloride in water (4 L) and concentrated to yield the title compound (452 g, 99%) as a yellow residue. 1H NMR (300 MHz, CDCl3): δ 4.83 (m, 1H), 4.54 (m, 1H), 4.43 (m, 1H), 4.31 (m, 1H), 3.87 (m, 1H), 3.74 (m, 1H), 2.71 (m, 1H), 2.02 (m, 1H), 1.70 (m, 1H) and 1.41 (bs, 9H).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C@@H:7]2[O:15][C@H:14]([CH2:16][O:17][C:18](=[O:20])[CH3:19])[C@@H:9]([O:10][C:11](=[O:13])[CH3:12])[C@@H:8]2[F:21])[CH:5]=[N:4][C:3]=1[C:22]([OH:24])=O.F[C@@H]1[C@H](O)[C@@H](CO)OC1O.[Cl-].[N+:36](=[CH2:38])=[N-:37]>O1CCCC1.C(OCC)C>[C:11]([O:10][C@@H:9]1[C@@H:14]([CH2:16][O:17][C:18](=[O:20])[CH3:19])[O:15][C@@H:7]([N:6]2[C:2]([N:1]=[CH:5][N:6]([CH3:7])[CH3:2])=[C:3]([C:22](=[O:24])[CH:38]=[N+:36]=[N-:37])[N:4]=[CH:5]2)[C@H:8]1[F:21])(=[O:13])[CH3:12]
Reactant: C=[N+]=[N-]
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc(C(=O)O)c2N)[C@@H](F)[C@@H]1OC(C)=O
Agent: OC[C@H]1OC(O)[C@H](F)[C@@H]1O
Agent: [Cl-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(=O)OC[C@H]1O[C@@H](n2cnc(C(=O)C=[N+]=[N-])c2N=CN(C)C)[C@@H](F)[C@@H]1OC(C)=O
Temperature: 25 °C
Yield: 75 %

Procedure:
Compound (35) (93 mg) obtained in item (3) above was dissolved in tetrahydrofuran (4.5 ml), to which was then added N,N-dimethylchloroforminium chloride (135 mg) under ice-cooling. The resulting mixture was allowed to undergo the reaction for 30 minutes. The reaction solution containing compound (36) thus produced was then added to a 0.2M diazomethane solution (30 ml) in diethylether and the reaction was maintained at room temperature for 1 hour. The reaction solution so obtained was filtered and the filtrate was concentrated to give the titled compound (37) (83 mg) as a syrup. Yield: 75%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[C:9](\[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH:20]([CH3:22])[CH3:21])=[CH:15][CH:14]=2)/[C:10](O)=[O:11])=[CH:4][C:3]=1[O:23][CH3:24].P([N:41]=[N+:42]=[N-:43])(OC1C=CC=CC=1)(OC1C=CC=CC=1)=O.CCN(CC)CC>C1C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[C:9](\[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH:20]([CH3:22])[CH3:21])=[CH:15][CH:14]=2)/[C:10]([N:41]=[N+:42]=[N-:43])=[O:11])=[CH:4][C:3]=1[O:23][CH3:24]
Reactant: COc1cc(/C=C(/C(=O)O)c2ccc(OC(C)C)cc2)ccc1F
Reactant: [N-]=[N+]=NP(=O)(Oc1ccccc1)Oc1ccccc1
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: COc1cc(/C=C(/C(=O)N=[N+]=[N-])c2ccc(OC(C)C)cc2)ccc1F
Reaction time: 16 h
Yield: 51.4 %

Procedure:
(E)-3-(4-fluoro-3-methoxyphenyl)-2-(4-isopropoxyphenyl)acrylic acid (4.38 g, 13.26 mmol), (PhO)2PON3 (2.71 mL, 12.60 mmol), and Et3N (3.70 mL, 26.5 mmol) were dissolved in benzene and stirred for 16 h. The solution was concentrated under vacuum and the residue was purified by silica gel chromatography using 20% EtOAc/Hexanes to give (E)-3-(4-fluoro-3-methoxyphenyl)-2-(4-isopropoxyphenyl)acryloyl azide (2.3 g, 49% yield). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.80 (s, 1H), 7.16-7.11 (m, 2H), 6.97-6.92 (m, 2H), 6.84-6.78 (m, 1H), 6.63-6.53 (m, 2H), 4.63-4.54 (m, 1H), 3.49 (s, 3H), 1.38-1.35 (m, 6H).
Reaction SMILES: [CH2:1]([NH:5][C:6]1[S:7][CH:8]=[CH:9][C:10]=1[C:11]([O:13][CH3:14])=[O:12])[CH:2]([CH3:4])[CH3:3].[OH-].[Na+].O.ClC(Cl)([O:21]C(=O)OC(Cl)(Cl)Cl)Cl>ClCCl.CO>[CH2:1]([N:5]1[C:6]2[S:7][CH:8]=[CH:9][C:10]=2[C:11](=[O:12])[O:13][C:14]1=[O:21])[CH:2]([CH3:4])[CH3:3]
Reactant: COC(=O)c1ccsc1NCC(C)C
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: ClCCl
Product: CC(C)Cn1c(=O)oc(=O)c2ccsc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 89.7 %

Procedure:
A mixture of methyl 2-(isobutylamino)thiophene-3-carboxylate (2.1 g, 9.9 mmol), sodium hydroxide (0.39 g, 9.8 mmol), water (20 mL) and methanol (10 mL) was heated at reflux for 2 h and cooled to room temperature. Methanol was removed under reduced pressure; the residue was diluted with dichloromethane (10 mL) and cooled to 0° C. Triphosgene (5.85 g, 19.7 mmol) was added portionwise; the reaction mixture was stirred for 18 h and diluted with dichloromethane. The organic layer was separated, dried over anhydrous sodium sulfate and concentrated to provide the crude product as a light brown solid (2.0 g). This material was used in the next step (Step D) without any purification. 1H NMR (400 MHz, CDCl3): δ 7.25 (d, 1H), 6.95 (d, 1H), 3.79 (d, 2H), 2.40-2.36 (m, 1H), 1.02 (d, 6H).
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[Cl:12][C:13]1[CH:33]=[CH:32][C:16]([C:17]([C:19]2[N:23]=[C:22]([CH2:24][S:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[O:21][N:20]=2)=[O:18])=[CH:15][CH:14]=1.[O-]S([O-])(=S)=O.[Na+].[Na+].CCOCC>C(Cl)Cl>[Cl:12][C:13]1[CH:33]=[CH:32][C:16]([C:17]([C:19]2[N:23]=[C:22]([CH2:24][S:25]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:6])[O:21][N:20]=2)=[O:18])=[CH:15][CH:14]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=C(c1ccc(Cl)cc1)c1noc(CSc2ccccc2)n1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOCC
Product: O=C(c1ccc(Cl)cc1)c1noc(CS(=O)c2ccccc2)n1
Reaction time: 0.5 h
Yield: 71 %

Procedure:
A solution of 5.8 g of m-chloroperoxybenzoic acid (85%) in 150 ml of CH2Cl2 was added dropwise at -70° under N2 to a solution of 9.0 g of 3-(4-chlorobenzoyl)-5-phenylthiomethyl-1,2,4-oxadiazole in 200 ml of CH2Cl2. The reaction temperature was maintained below -65° by controlling the rate of addition. After stirring further for 30 minutes, the reaction mixture was poured directly into a separatory funnel containing 300 ml of 10% Na2S2O3 and 600 ml of Et2O. The organics were washed with saturated NaHCO3 and dried over MgSO4. Concentration gave an oil which solidified on standing. Recrystallization from acetone/hexane gave 6.7 g (67%) of needles, m.p. 93°-95°.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15]([C:17]1[O:18][C:19]2[C:25]([O:26][CH2:27][CH2:28][N:29]([CH:33]([CH3:35])[CH3:34])[CH:30]([CH3:32])[CH3:31])=[CH:24][CH:23]=[CH:22][C:20]=2[CH:21]=1)=[O:16])(C)(C)C.NC1C=CC=CC=1NC(C1SC2C=CC(OCCN(C)C)=CC=2C=1)=O>>[NH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15]([C:17]1[O:18][C:19]2[C:25]([O:26][CH2:27][CH2:28][N:29]([CH:33]([CH3:35])[CH3:34])[CH:30]([CH3:31])[CH3:32])=[CH:24][CH:23]=[CH:22][C:20]=2[CH:21]=1)=[O:16]
Reactant: CC(C)N(CCOc1cccc2cc(C(=O)Nc3ccccc3NC(=O)OC(C)(C)C)oc12)C(C)C
Agent: CN(C)CCOc1ccc2sc(C(=O)Nc3ccccc3N)cc2c1
Product: CC(C)N(CCOc1cccc2cc(C(=O)Nc3ccccc3N)oc12)C(C)C

Procedure:
was prepared from (2-{[7-(2-Diisopropylamino-ethoxy)-benzofuran-2-carbonyl]-amino}-phenyl)-carbamic acid tert-butyl ester (20) in an analogous manner to that described for the preparation of (1) example 1, step 5; exact MW [M+H] calc'd: 396.23; MW found [M+H]: 396.2.
Reaction SMILES: [CH:1]([O:4][C:5](=[O:34])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[C:13]([NH2:33])=[CH:14][C:15]2[N:19]=[C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[N:17]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:16]=2[CH:32]=1)([CH3:3])[CH3:2].[Cl:35][C:36]1[CH:41]=[CH:40][C:39]([S:42](Cl)(=[O:44])=[O:43])=[CH:38][CH:37]=1>>[CH:1]([O:4][C:5](=[O:34])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[C:13]([NH:33][S:42]([C:39]2[CH:40]=[CH:41][C:36]([Cl:35])=[CH:37][CH:38]=2)(=[O:44])=[O:43])=[CH:14][C:15]2[N:19]=[C:18]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[N:17]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:16]=2[CH:32]=1)([CH3:3])[CH3:2]
Reactant: CC(C)OC(=O)CCCCCOc1cc2c(cc1N)nc(-c1ccccc1)n2-c1ccccc1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Product: CC(C)OC(=O)CCCCCOc1cc2c(cc1NS(=O)(=O)c1ccc(Cl)cc1)nc(-c1ccccc1)n2-c1ccccc1

Procedure:
6-[(5-Amino-1,2-diphenyl-1H-benzimidazol-6-yl)oxy]hexanoic acid isopropyl ester was reacted according to general operating instructions 13 with 4-chlorobenzenesulfonic acid chloride.
Reaction SMILES: [CH2:1]([CH2:4][CH:5]([OH:14])[C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:7])[CH:2]=[CH2:3].[OH-].[K+].CO.Cl>C(O)CCC>[OH:14][CH:5]([CH2:4][CH:1]=[CH:2][CH3:3])[C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:7]
Reactant: C=CCCC(O)C(=O)c1ccccc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: CCCCO
Product: CC=CCC(O)C(=O)c1ccccc1
Temperature: 0 °C
Yield: 45.1 %

Procedure:
Then to 233 grams of 3-allyl-2-hydroxypropiophenone are added 212 grams of potassium hydroxide, 200 ml of methanol and 1100 ml of n-butanol and the mixture is heated to reflux for twenty four hours. It is then poured into ice water, acidified with concentrated hydrochloric acid, crystals separated out therefrom are collected by filtration, washed with water and recrystallized from methanol to give 105 grams of 2-hydroxy-3-propenylpropiophenone, yellow needles, melting point 83° to 85° C.
Reaction SMILES: [F:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([S:12]([Cl:15])(=[O:14])=[O:13])=[CH:4][CH:3]=1.ClS(O)(=O)=O.FC1C=CC=C2C=1CCCC2>ClCCl>[F:1][C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[C:5]([S:12]([Cl:15])(=[O:13])=[O:14])=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(F)c2ccccc12
Agent: Fc1cccc2c1CCCC2
Agent: O=S(=O)(O)Cl
Solvent: ClCCl
Product: O=S(=O)(Cl)c1ccc(F)c2c1CCCC2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The compound was prepared according to Scheme 10 in a similar manner to the method for preparing 4-fluoro-naphthalene-1-sulfonyl chloride. Chlorosulfonic acid (2.65 g, 1.5 mL, 22.7 mmol) was stirred in a round-bottom flask cooled by a water bath at room temperature. 5-Fluoro-1,2,3,4-tetrahydro-naphthalene (0.62 g, 4.13 mmol) was added dropwise and the dark mixture was stirred for 30 minutes until gas evolution ceased. The reaction mixture was poured carefully over a mixture of ice (75 g) and dichloromethane (100 mL) and charged to a separatory funnel. The organic layer was separated, washed with brine and dried over MgSO4. Filtration and concentration in vacuo afforded a tan solid. Wt.: 860 mg (86%). 1H NMR (300 MHz, CDCl3) δ 7.97 (dd, 1H), 7.02 (t, 1H), 3.27 (m, 2H), 2.80 (m, 2H), 1.86 (m, 4H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16](Cl)=[O:17])=[CH:11][C:10]=1[O:19][CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)(O)[O-].[Na+].[NH2:26][CH2:27][C:28]1([OH:37])[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH2:30][CH2:29]1>C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([NH:26][CH2:27][C:28]2([OH:37])[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH2:30][CH2:29]2)=[O:17])=[CH:11][C:10]=1[O:19][CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCC1(O)CCc2ccccc21
Reactant: COc1cc(CC(=O)Cl)ccc1OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COc1cc(CC(=O)NCC2(O)CCc3ccccc32)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.1 %

Procedure:
To a solution of 4-benzyloxy-3-methoxyphenylacetyl chloride (18 mmol), the product of Example 4, in 50 mL of methylene chloride was added 50 mL of saturated aqueous sodium bicarbonate solution, followed by a solution of 1-aminomethyl-1-hydroxyindan (3.15 g, 19 mmol), the product of Example 1, in 20 mL of methylene chloride. The resulting two-phase mixture was stirred vigorously at ambient temperature for 2 hours. The aqueous and organic phases were separated and the aqueous phase was extracted with methylene chloride (75 mL). The combined organic layers were washed with 100 mL of 1M aqueous hydrochloric acid solution, dried over anhydrous magnesium sulfate, filtered and concentrated to give a yellow oil. The oil was purified by flash chromatography on silica gel eluting with 1:1 ethyl acetate/methylene chloride to give 6.17 g (82% yield) of the title compound as a white solid; 1H NMR (CDCl3).δ.1.96-2.08 (m, 1H), 2.18-2.28 (m, 1 H), 2.67-2.80 (m, 1H), 2.87-2.98 (m, 1H), 3.29-3.37 (m, 2H), 3.53-3.65 (m, 3H), 3.88 (s, 3H), 5.16 (s, 2H), 5.80-5.88 (m, 1H), 6.71 (dd, 1H, J=8.7, 3.0 Hz), 6.79 (d, 1H, J=3.0 Hz), 6.85 (d, 1H, J=8.7 Hz), 7.10-7.47 (m, 9H).