Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH:4]([CH2:17][CH2:18][CH2:19][CH:20]([OH:26])[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:5][CH2:6][CH2:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[CH:10][CH:9]=1)(=[O:3])[CH3:2].[C:27](OC(=O)C)(=[O:29])[CH3:28]>C(OCC)C>[C:1]([CH:4]([CH2:17][CH2:18][CH2:19][CH:20]([O:26][C:27](=[O:29])[CH3:28])[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:5][CH2:6][CH2:7][C:8]1[CH:9]=[CH:10][C:11]([C:12]([OH:14])=[O:13])=[CH:15][CH:16]=1)(=[O:3])[CH3:2]
Reactant: CCCCCC(O)CCCC(CCCc1ccc(C(=O)O)cc1)C(C)=O
Reactant: CC(=O)OC(C)=O
Solvent: CCOCC
Product: CCCCCC(CCCC(CCCc1ccc(C(=O)O)cc1)C(C)=O)OC(C)=O
Temperature: 60 °C

Procedure:
A mixture of 4-(4-acetyl-8-hydroxytridecyl)benzoic acid (9.0 g., 0.025 mole) and acetic anhydride (6.1 g., 0.06 mole) is heated at 60° C. for 18 hours. The mixture is then cooled and dissolved in 80 ml. ethyl ether. The solution is extracted with an ice-cold solution of 8 g. sodium hydroxide in 150 ml. water. The basic solution is separated and acidified with concentrated hydrochloric acid. The oily acid which separates is taken up in ether, washed with water, and dried over sodium sulfate. The ether is evaporated to leave the oily crude product.
Reaction SMILES: I[C:2]1[S:6][C:5]([O:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][CH:15]([CH3:17])[CH3:16])=[CH:10][CH:9]=2)=[N:4][CH:3]=1.C(N(CC)CC)C.[CH3:25][C:26]([CH:28]=[CH2:29])=[O:27]>CN(C)C=O.[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.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>[CH:15]([O:14][C:11]1[CH:12]=[CH:13][C:8]([O:7][C:5]2[S:6][C:2](/[CH:29]=[CH:28]/[C:26](=[O:27])[CH3:25])=[CH:3][N:4]=2)=[CH:9][CH:10]=1)([CH3:17])[CH3:16]
Reactant: C=CC(C)=O
Reactant: CC(C)Oc1ccc(Oc2ncc(I)s2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(=O)/C=C/c1cnc(Oc2ccc(OC(C)C)cc2)s1
Temperature: 75 °C
Yield: 85.6 %

Procedure:
To a solution of the product from Example 7B (1.6 g, 4.43 mmole) in N,N-dimethylformamide (25 mL) was consecutively added triethylamine (8 mL), tetrabutyl ammonium chloride (1.2 g, 4.3 mmole), methylvinylketone (2 g, 28.5 mmole) and dichlorobis(triphenylphosphine)palladium(II) (155 mg, 0.22 mmole). The reaction mixture was heated at 75° C. overnight. The reaction mixture was diluted with ethyl acetate and washed with 0.5N aqueous HCl, followed by brine. The reaction mixture was dried over magnesium sulfate filtered and evaporated. The product was purified via silica column, using a gradient of 5-25% ethyl acetate in hexane, to yield 1.15 g (85%) of orange solid. 1H NMR (300 MHz, CDCl3) δ ppm 7.50 (d, J=15.44 Hz, 1H) 7.42 (s, 1H) 7.13-7.24 (m, 2 H) 6.84-7.00 (m, 2H) 6.23 (d, J=15.81 Hz, 1H) 4.38-4.63 (m, 1H) 2.30 (s, 3H) 1.35 (t, J=5.52 Hz, 6H). Mass spectrum DCI 304 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([C:14]([O:16]C)=[O:15])=[CH:10][C:9]=1[CH2:18][O:19][CH3:20].CO.O.O.[OH-].[Li+]>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([C:14]([OH:16])=[O:15])=[CH:10][C:9]=1[CH2:18][O:19][CH3:20]
Reactant: COCc1cc(C(=O)OC)ccc1-c1ccccc1F
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: COCc1cc(C(=O)O)ccc1-c1ccccc1F
Reaction time: 12 h
Yield: 92.3 %

Procedure:
To a solution of methyl 2′-fluoro-2-(methoxymethyl)biphenyl-4-carboxylate (12.0 g, 43.7 mmol) in a mixture of THF (50 ml), MeOH (50 ml) and water (25 ml) was added lithium hydroxide monohydrate (5.50 g, 131.2 mmol) in portions. After 12 hours at RT, the reaction mixture was concentrated and the aqueous residual layer was acidified with a concentrated aqueous solution of HCl, and then extracted with EtOAc. The organic layers were washed with water and brine, combined, dried (Na2SO4) and concentrated under reduced pressure to afford of the title compound as a white solid (10.5 g, 92%). LC/MS (Method B): 259.0 (M−H)−. 1H NMR (DMSO-d6, 400 MHz) δ 13.07 (1H, brs), 8.10 (1H, s), 7.92 (1H, d), 7.48 (1H, m), 7.27-7.37 (4H, m), 4.26 (2H, s), 3.18 (3H, s).
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[C:3]=1[C:11]#[N:12].CN(C)C=O.F[C:19]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=1[N+:26]([O-:28])=[O:27].C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C.O>[F:25][C:23]1[CH:22]=[CH:21][C:20]([N+:26]([O-:28])=[O:27])=[C:19]([CH:24]=1)[NH:1][C:2]1[S:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[C:3]=1[C:11]#[N:12]
Reactant: N#Cc1c(N)sc2ccccc12
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1c(Nc2cc(F)ccc2[N+](=O)[O-])sc2ccccc12
Temperature: 55 °C
Reaction time: 5.5 h

Procedure:
To a solution of 2-aminobenzo[b]thiophene-3-carbonitrile (116 g), dimethylformamide (370 ml) and 2,4-difluoronitrobenzene (73 ml) was added pulverized potassium carbonate (276 g), and the mixture was stirred at 55° C. for 5.5 hours. The reaction mixture was stirred under ice-cooling for 30 minutes and water (1.9 L) was added. The mixture was further stirred for 30 minutes. The precipitated crystals were filtered by suction and washed with water (1.9 L) and dried in a drying box overnight to give crude crystals (198 g). The obtained crude crystals were suspended in ethyl acetate (700 ml) and the mixture was stirred under reflux with heating while removing water for 2 hours. The reaction mixture was cooled and stirred at 20° C. for 1 hour. The precipitated crystals were filtered by suction, washed with ethyl acetate (150 ml) and dried to give 2-(5-fluoro-2-nitroanilino)benzo[b]thiophene-3-carbonitrile (123 g) as red crystalline powder.
Reaction SMILES: [NH2:1][C@H:2]([C:9]([OH:11])=[O:10])[CH2:3][C:4]1[N:8]=[CH:7][NH:6][CH:5]=1.[C:12]([OH:21])(=[O:20])[CH:13]([CH:15]([C:17]([OH:19])=[O:18])[OH:16])[OH:14].C(=O)C1C(=CC=CC=1)O>C(O)(=O)C>[OH:19][C:17]([CH:15]([CH:13]([C:12]([OH:21])=[O:20])[OH:14])[OH:16])=[O:18].[NH2:1][C@@H:2]([C:9]([OH:11])=[O:10])[CH2:3][C:4]1[N:8]=[CH:7][NH:6][CH:5]=1
Reactant: N[C@@H](Cc1c[nH]cn1)C(=O)O
Agent: O=C(O)C(O)C(O)C(=O)O
Solvent: CC(=O)O
Solvent: O=Cc1ccccc1O
Product: N[C@H](Cc1c[nH]cn1)C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 97 %

Procedure:
A mixture of 0.1 mole (15.5 g) of L-histidine, 0.1 mole (15.1 g) of (+) tartaric acid and 0.05 mole (5.2 ml) of salicylaldehyde in 95 ml of acetic acid was stirred mechanically for two hours at 80°-100° C. The mixture was cooled to 25° C. and the formed salt was filtered. The crude D-histidine bitartrate (a very light yellow solid) was obtained in 97% yield. The volume of recovered acetic acid containing salicylaldehyde was 85 ml (89.5% recovery). The crude D-His-(+)TA was stirred and heated in 45 ml water at 80°-90° C. for 35 minutes, cooled to 30° C. and filtered. Drying in air gave 26.7 g (87.5%) of pure D-His-(+)TA. [α]18D =+13.04[C=1.35, H2O].
Reaction SMILES: [Cl:1][C:2]1[C:10]([O:11][CH2:12][C:13]([CH3:15])=[O:14])=[C:9]([S:16]([CH2:19][CH3:20])(=[O:18])=[O:17])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:21]1(=O)[CH2:26][CH2:25][CH2:24][C:23](=[O:27])[CH2:22]1.Cl.CN(C)CCCN=C=NCC.CC1C=CN=C(N)C=1C>C(Cl)Cl>[Cl:1][C:2]1[C:10]([O:11][CH2:12][C:13]([CH3:15])=[O:14])=[C:9]([S:16]([CH2:19][CH3:20])(=[O:18])=[O:17])[CH:8]=[CH:7][C:3]=1[C:4]([O:6][C:21]1[CH2:26][CH2:25][CH2:24][C:23](=[O:27])[CH:22]=1)=[O:5]
Reactant: O=C1CCCC(=O)C1
Reactant: CCS(=O)(=O)c1ccc(C(=O)O)c(Cl)c1OCC(C)=O
Agent: CCN=C=NCCCN(C)C
Agent: Cc1ccnc(N)c1C
Agent: Cl
Solvent: ClCCl
Product: CCS(=O)(=O)c1ccc(C(=O)OC2=CC(=O)CCC2)c(Cl)c1OCC(C)=O

Procedure:
0.295 g (0.9 mmol) of 2-chloro-3-(methylcarbonylmethoxy)-4-ethylsulfonylbenzoic acid, 0.113 g (1.0 mmol) of cyclohexane-1,3-dione, 0.180 g (0.9 mmol) of N′-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride and 0.001 g of dimethyl-aminopyridine were stirred in 25 ml of CH2Cl2 at RT for 2 h. The mixture was then diluted with CH2Cl2 and washed with 0.5 N HCl, with water, with saturated NaHCO3 solution and again with water. The combined organic phases were dried over Na2SO4 and then evaporated to dryness, giving 3-oxo-1-cyclohexenyl 2-chloro-3-(methylcarbonylmethoxy)-4-ethylsulfonylbenzoate in the form of a brown resin which was sufficiently pure for the subsequent reaction.
Reaction SMILES: [CH2:1]1[C:7]2[CH:8]=[CH:9][C:10]([O:12][C:13]3[CH:21]=[CH:20][C:16]([C:17]([NH2:19])=[O:18])=[CH:15][N:14]=3)=[CH:11][C:6]=2[CH2:5][CH2:4][CH2:3][NH:2]1.C([O-])([O-])=O.[K+].[K+].Br[CH2:29][CH2:30][CH2:31][C:32]([F:35])([F:34])[F:33].C(OCC)(=O)C>CN(C=O)C>[F:33][C:32]([F:35])([F:34])[CH2:31][CH2:30][CH2:29][N:2]1[CH2:3][CH2:4][CH2:5][C:6]2[CH:11]=[C:10]([O:12][C:13]3[CH:21]=[CH:20][C:16]([C:17]([NH2:19])=[O:18])=[CH:15][N:14]=3)[CH:9]=[CH:8][C:7]=2[CH2:1]1
Reactant: FC(F)(F)CCCBr
Reactant: NC(=O)c1ccc(Oc2ccc3c(c2)CCCNC3)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: NC(=O)c1ccc(Oc2ccc3c(c2)CCCN(CCCC(F)(F)F)C3)nc1
Temperature: 95 °C

Procedure:
Mix 6-(2,3,4,5-tetrahydro-1H-benzo[c]azepin-7-yloxy)nicotinamide (Example 447, Part E, 0.350 g, 1.24 mmol), K2CO3 (0.427 g, 3.09 mmol), and 4-bromo-1,1,1-trifluorobutane (0.248 g, 1.30 mol) in DMF (6.2 mL). Heat at 95° C. for 5.5 hours, then at 50° C. overnight. Cool the reaction mixture to room temperature and add ethyl acetate (100 mL). Wash with water (1× 30 mL) and brine (1× 30 mL). Dry the organic layer over Na2SO4, filter and concentrate. Purify by flash chromatography eluting with 6% to 20% (2.0 M NH3 in methanol) in ethyl acetate to give the title compound: MS ES+ 394.2 (M+H)+, HRMS calcd for C20H23N3O2F3 394.1742 (M+H)+, found 394.1733, time 0.53 min; HPLC [YMC-Pro pack C-18 (150×4.6 mm, S-5 microm), 0.05% TEA/acetonitrile in 0.05% TFA/water at 1.0 mL/min, 10-20% over 5 min, 20-95% over 18 min], tR 10.1 min, 100% purity.
Reaction SMILES: [CH3:1][C:2]1([CH:8]([OH:23])[CH:9]([N:18]2[CH:22]=[N:21][CH:20]=[N:19]2)[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)[CH2:7][O:6][CH2:5][O:4][CH2:3]1.[H-].[Na+].[CH2:26](Br)[CH:27]=[CH2:28].O>O1CCCC1>[CH3:1][C:2]1([CH:8]([O:23][CH2:28][CH:27]=[CH2:26])[CH:9]([N:18]2[CH:22]=[N:21][CH:20]=[N:19]2)[CH2:10][C:11]2[CH:12]=[CH:13][C:14]([Cl:17])=[CH:15][CH:16]=2)[CH2:3][O:4][CH2:5][O:6][CH2:7]1
Reactant: C=CCBr
Reactant: CC1(C(O)C(Cc2ccc(Cl)cc2)n2cncn2)COCOC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: C=CCOC(C(Cc1ccc(Cl)cc1)n1cncn1)C1(C)COCOC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 85.4 %

Procedure:
A solution of 23.6 g (0.07 mole) of 1-(5-methyl-1,3-dioxan-5-yl)-2-(1,2,4-triazol-1-yl)-3-(4-chlorophenyl)-propan-1-ol in 100 ml of tetrahydrofuran is added dropwise to a suspension of 2.4 g of sodium hydride in 120 ml of dry tetrahydrofuran. After stirring the mixture for 12 hours at 25° C, a solution of 9.7 g (0.08 mole) of allyl bromide in 20 ml of tetrahydrofuran is added dropwise. The reaction mixture is stirred for 36 hours, 20 ml of water are then added cautiously, and the batch is evaporated down. The residue is taken up in 350 ml of methylene chloride, the solution is washed with three times 100 ml of water, and the organic phase is dried and evaporated down. The residue is mixed with 30 ml of petroleum ether and 10 ml of ether and left to stand overnight at +3° C. The crystalline, colorless precipitate is filtered off, washed with petroleum ether and dried. 22.6 g (87.5%) of 1-(5-methyl-1,3-dioxan-5-yl)-1-allyloxy-2-(1,2,4-triazol-1-yl)-3-(4-chlorophenyl)-propane, of melting point 113°-115° C., are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:11])[C:5](=[CH:9][CH:10]=1)[C:6](O)=[O:7].C([O-])([O-])OC.C([O-])(=O)C.[NH4+:21].[CH3:22]O>O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:5]([C:6](=[O:7])[NH:21][CH:22]=[N:11]2)=[CH:9][CH:10]=1
Reactant: [NH4+]
Reactant: CO
Reactant: Nc1cc(Cl)ccc1C(=O)O
Agent: CC(=O)[O-]
Agent: COC([O-])[O-]
Solvent: O
Product: O=c1[nH]cnc2cc(Cl)ccc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 92 %

Procedure:
In a 10-mL volume stainless steel pressure-resistant vessel were placed 1.00 g (5.8 mmol) of 4-chloroanthranilic acid, 2.47 g (23.3 mmol) of methyl orthoformate, 1.80 g (23.3 mmol) of ammonium acetate, and 4.0 mL of methanol. The reaction was carried out at 120° C. for 3 hours. After the reaction was complete, the reaction mixture was cooled to room temperature, and 40 mL of water was added to the reaction mixture. The resulting aqueous mixture was stirred for 15 minutes and filtered to give 0.96 g (isolated yield: 92%) of 7-chloroquinazolin-4-one as a white crystalline product.
Reaction SMILES: [S:1]1[CH:5]=[C:4]([C:6]2[CH:31]=[CH:30][C:9]([CH2:10][O:11][C:12]3[CH:20]=[CH:19][C:18]4[NH:17][C:16]5[CH:21]([CH2:24][C:25]([O:27]CC)=[O:26])[CH2:22][CH2:23][C:15]=5[C:14]=4[CH:13]=3)=[CH:8][CH:7]=2)[N:3]=[N:2]1.[Li+].[OH-]>O1CCOCC1.CCOC(C)=O>[S:1]1[CH:5]=[C:4]([C:6]2[CH:31]=[CH:30][C:9]([CH2:10][O:11][C:12]3[CH:20]=[CH:19][C:18]4[NH:17][C:16]5[CH:21]([CH2:24][C:25]([OH:27])=[O:26])[CH2:22][CH2:23][C:15]=5[C:14]=4[CH:13]=3)=[CH:8][CH:7]=2)[N:3]=[N:2]1
Reactant: CCOC(=O)CC1CCc2c1[nH]c1ccc(OCc3ccc(-c4csnn4)cc3)cc21
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: O=C(O)CC1CCc2c1[nH]c1ccc(OCc3ccc(-c4csnn4)cc3)cc21
Reaction time: 8 h

Procedure:
To a solution of ethyl 2-(7-(4-(1,2,3-thiadiazol-4-yl)benzyloxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetate (42.7 mg, 0.030 mmol) in dioxane was added 1M LiOH (0.394 mL, 0.394 mmol). The reaction was stirred overnight. The reaction mixture was taken up in EtOAc and washed with 1 M HCl. The EtOAc extract was dried over MgSO4 and concentrated. The residue was purified by silica gel column chromatography to give the title compound as a solid. LCMS m/z=406.4 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.03-2.12 (m, 1H), 2.36 (dd, J=16.04, 8.97 Hz, 1H), 2.58-2.79 (m, 4H), 3.41-3.51 (m, 1H), 5.16 (s, 2H), 6.74 (dd, J=8.78, 2.46 Hz, 1H), 6.95 (d, J=2.40 Hz, 1H), 7.21 (d, J=8.72 Hz, 1H), 7.63 (d, J=8.21 Hz, 2H), 8.15 (d, J=8.21 Hz, 2H), 9.61 (s, 1H), 10.46 (s, 1H), 12.19 (bs, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:6]2=[C:7]([OH:11])[CH:8]=[CH:9][CH:10]=[C:5]2[O:4][N:3]=1.[F:12][C:13]1[CH:14]=[C:15]([N+:20]([O-:22])=[O:21])[CH:16]=[CH:17][C:18]=1F.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[F:12][C:13]1[CH:14]=[C:15]([N+:20]([O-:22])=[O:21])[CH:16]=[CH:17][C:18]=1[O:11][C:7]1[C:6]2[C:2]([NH2:1])=[N:3][O:4][C:5]=2[CH:10]=[CH:9][CH:8]=1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Reactant: Nc1noc2cccc(O)c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Nc1noc2cccc(Oc3ccc([N+](=O)[O-])cc3F)c12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
94.37 mg (0.63 mmol) of 3-amino-1,2-benzisoxazol-4-ol (from example V), 100 mg (0.63 mmol) of 3,4-difluoronitrobenzene and 95.56 mg (0.69 mmol) of potassium carbonate are suspended in 3 ml of anhydrous dimethylformamide and stirred at room temperature for 16 hours. The reaction solution is then diluted with water, and the precipitate is filtered off. The product is dried under high vacuum.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:7]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[NH:5][N:4]=1.Cl[C:13]([O:15][CH3:16])=[O:14]>O1CCOCC1>[C:8]([C:6]1[NH:5][N:4]=[C:3]([N:2]([CH3:1])[C:13](=[O:14])[O:15][CH3:16])[CH:7]=1)([CH3:11])([CH3:9])[CH3:10]
Reactant: COC(=O)Cl
Reactant: CNc1cc(C(C)(C)C)[nH]n1
Solvent: C1COCCO1
Product: COC(=O)N(C)c1cc(C(C)(C)C)[nH]n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 18.7 %

Procedure:
15.5 g of 3-(N-methylamino)-5-t-butylpyrazole as prepared in Reference Example was dissolved in 50 ml of dioxane, and 11.3 g of methyl chloroformate was added to the solution. The mixture was then allowed to react at 100° C. for 5 hours. After the reaction was completed, the solvent was distilled off and the residue was dissolved in an alcohol. The solution was added in 200 ml of a 5% aqueous solution of sodium hydroxide and the mixture was stirred at room temperature for 30 minutes. After neutralization, the mixture was extracted with methylene chloride, and the methylene chloride layer was dried over anhydrous sodium sulfate, followed by distilling off the methylene chloride. The residue was recrystallized from a mixture of toluene and hexane, whereby 4 g of methyl N-(5-t-butyl-3-pyrazolyl)-N-methylcarbamate was obtained.
Reaction SMILES: [CH2:1]([N:4]([CH:22]([C:28]([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[O:29][SiH2:30][C:31]([CH3:34])([CH3:33])[CH3:32])[C:23]([OH:27])(C)[CH:24]=C)[S:5]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:10][CH:9]=1)(=[O:7])=[O:6])[CH:2]=[CH2:3].C(OCC=C)C=C>C=CC1C=CC=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Ru]Cl.C(Cl)Cl>[CH2:15]([O:14][C:11]1[CH:10]=[CH:9][C:8]([S:5]([N:4]2[CH2:1][CH:2]=[CH:3][C:23]([CH3:24])([OH:27])[CH:22]2[C:28]([C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)([C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=2)[O:29][SiH2:30][C:31]([CH3:32])([CH3:33])[CH3:34])(=[O:6])=[O:7])=[CH:13][CH:12]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: C=CCN(C(C(C)(O)C=C)C(O[SiH2]C(C)(C)C)(c1ccccc1)c1ccccc1)S(=O)(=O)c1ccc(OCc2ccccc2)cc1
Agent: Cl[Ru]Cl
Agent: C=CCOCC=C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: C=Cc1ccccc1
Product: CC(C)(C)[SiH2]OC(c1ccccc1)(c1ccccc1)C1N(S(=O)(=O)c2ccc(OCc3ccccc3)cc2)CC=CC1(C)O
Yield: 73.1 %

Procedure:
A mixture of N-allyl-4-benzyloxy-N-[1-(tert-butyl-diphenyl-silanyloxymethyl)-2-hydroxy-2-methyl-but-3-enyl]-benzenesulfonamide (compound of formula VII, 4.0 g, 6.1 mmol), diallyl ether (0.82 ml, 0.66 g, 6.7 mmol), bis(tricyclohexylphosphine)benzylidine ruthenium (IV) dichloride (0.34 g, 0.4 mmol) and methylene chloride (116 ml) was stirred at reflux for about 3 hours. The mixture was concentrated in vacuo then purified using a Flash 40 system (silica gel cartridge, eluting with 10% ethyl acetate in hexane) to afford 2.8 g of 1-(4-benzyloxy-benzenesulfonyl)-2-(tert-butyldiphenyl-silanyloxymethyl)-3-methyl-1,2,3,6-tetrahydro-pyridin-3-ol (compound of formula VIII) as a colorless solid.
Reaction SMILES: [CH2:1]([N:7]1[CH:11]=[CH:10][N:9]=[CH:8]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].CS(O[CH2:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH2:23][CH:24]([O:45][C:46]1[CH:51]=[CH:50][N:49]=[CH:48][N:47]=1)[CH2:25][O:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])(=O)=O.[Cl:52]CCl>C(O)C>[Cl-:52].[CH2:1]([N+:7]1[CH:11]=[CH:10][N:9]([CH2:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH2:23][CH:24]([O:45][C:46]2[CH:51]=[CH:50][N:49]=[CH:48][N:47]=2)[CH2:25][O:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])[CH:8]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCCCCCCCCCCCCCOCC(COCCOCCOS(C)(=O)=O)Oc1ccncn1
Reactant: ClCCl
Reactant: CCCCCCn1ccnc1
Solvent: CCO
Product: CCCCCCCCCCCCCCCCCCOCC(COCCOCCn1cc[n+](CCCCCC)c1)Oc1ccncn1
Product: [Cl-]
Temperature: 80 °C

Procedure:
1-Hexylimidazole [304 mg (2 millimoles)] was dissolved in 2-[2-[3-octadecyloxy-2-(pyrimidin-4-yloxy)propoxy]ethoxy]ethyl methanesulfonate [800 mg (1.36 millimole)], and the mixture was heated at 80° C. for 2.5 hours. The mixture was dissolved in a mixture of dichloromethane and ethanol (95:5; 60 ml) and shaken with 30% saline for separation into layers. The lower layer collected was concentrated and purified by silica gel column chromatography [Merck, Art. 7734, 30 g (eluent: chloroform-methanol=9:1-65:25)] to give the above-identified compound [760 mg (82%)].
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:14][CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]2)=[CH:4][C:3]=1[NH:22][S:23]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)(=[O:25])=[O:24].[C:32]1([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[CH:37]=[CH:36][C:35]([S:38]([Cl:41])(=[O:40])=[O:39])=[CH:34][CH:33]=1>>[ClH:41].[N:8]1([C:5]2[CH:6]=[CH:7][C:2]([NH:1][S:38]([C:35]3[CH:36]=[CH:37][C:32]([C:42]4[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=4)=[CH:33][CH:34]=3)(=[O:40])=[O:39])=[C:3]([NH:22][S:23]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)(=[O:25])=[O:24])[CH:4]=2)[CH2:14][CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCCN(c2ccc(N)c(NS(=O)(=O)c3ccccc3)c2)CC1
Reactant: O=S(=O)(Cl)c1ccc(-c2ccccc2)cc1
Product: Cl
Product: O=S(=O)(Nc1ccc(N2CCCNCC2)cc1NS(=O)(=O)c1ccccc1)c1ccc(-c2ccccc2)cc1

Procedure:
N-{4-(1,4-diazepan-1-yl)-2-[(phenylsulfonyl)amino]phenyl}[1,1′-biphenyl]-4-sulfonamide hydrochloride was synthesized from N-{2-amino-5-(4-t-butyloxycarbonyl-1,4-diazepan-1-yl)-phenyl}benzenesulfonamide (0.081 g, 0.18 mmol) and, 1,1′-biphenyl-4-sulfonyl chloride (0.059 g, 0.24 mmol) to give 42.9 mg of a light purple solid; Anal. (C24H27ClN4O3S) C, H, N, S.; M+563.5 Calcd 563.17.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][OH:9])=[N:6][CH:7]=1.[H-].[Na+].[CH3:12]I>CN(C=O)C.[Cl-].[Na+].O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][O:9][CH3:12])=[N:6][CH:7]=1
Reactant: CI
Reactant: OCc1ccc(Br)cn1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COCc1ccc(Br)cn1
Reaction time: 8 h
Yield: 102.6 %

Procedure:
A solution of this (5-bromo-pyridin-2-yl)-methanol (4.80 g, 23.0 mmol) in DMF (25 mL) was added drop wise over 5 minutes to a slurry of sodium hydride (1.10 g, 27.6 mmol) in DMF (50 mL) at 0° C. under N2. The mixture was stirred for 15 minutes before the drop wise addition of a solution of methyl iodide (1.57 mL, 25.3 mmol) in DMF (25 mL). The mixture was allowed to reach room temperature and was then stirred overnight. The mixture was poured into brine and extracted with EtOAc. The combined organic layers were thoroughly washed with brine, dried over MgSO4 and evaporated to dryness to give the title compound as a yellow oil (4.77 g, 98%) sufficiently pure for the next step.
Reaction SMILES: OC(C(F)(F)F)=O.[NH2:8][N:9]=[CH:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][CH2:19][CH2:20][NH:21][C:22]([NH:24][CH:25]([C:32]2[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=2)[CH2:26][C:27]([O:29]CC)=[O:28])=[O:23])=[CH:13][CH:12]=1.[Li+].[OH-].Cl>CO>[NH2:8][N:9]=[CH:10][C:11]1[CH:12]=[CH:13][C:14]([CH2:17][CH2:18][CH2:19][CH2:20][NH:21][C:22]([NH:24][CH:25]([C:32]2[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=2)[CH2:26][C:27]([OH:29])=[O:28])=[O:23])=[CH:15][CH:16]=1
Reactant: CCOC(=O)CC(NC(=O)NCCCCc1ccc(C=NN)cc1)c1cccnc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: NN=Cc1ccc(CCCCNC(=O)NC(CC(=O)O)c2cccnc2)cc1
Reaction time: 0.5 h
Yield: 9.1 %

Procedure:
ethyl β-[[[[4-[4-(aminoiminomethyl)phenyl]butyl]amino]carbonyl]amino]-3-pyridinepropanoate TFA (100 mg; 2 mmol), methanol (5ml), and 2N LiOH (5ml) were stirred for 30 min. The solution was acidified to pH=3 with 3N HCl and reduced to dryness on a rotary evaporator. The residue was dissolved in acetonitrile/water and purified by HPLC on a C-18 HPLC column (30cm×5cm). A gradient of 10 to 40% acetonitrile/water/ 0.05% TFA in 30 min. was used and the acid eluted at an acetonitrile concentration of 15%. Fractions containing the desired peak were lyophilized to give 70 mg of white solid. FAB-MS: MH+ =384.