Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:14]=[C:13]2[C:9]([CH2:10][C:11]3([CH2:20][CH2:19][CH:18]([OH:21])[CH2:17][CH2:16]3)[C:12]2=[NH:15])=[CH:8][CH:7]=1.O=[C:23]([CH3:27])[C:24](=[S:26])[NH2:25]>CO>[F:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:14]=[C:13]2[C:9]([CH2:10][C:11]3([C:12]42[NH:25][C:24](=[S:26])[C:23]([CH3:27])=[N:15]4)[CH2:16][CH2:17][CH:18]([OH:21])[CH2:19][CH2:20]3)=[CH:8][CH:7]=1
Reactant: CC(=O)C(N)=S
Reactant: N=C1c2cc(OCCCF)ccc2CC12CCC(O)CC2
Solvent: CO
Product: CC1=NC2(NC1=S)c1cc(OCCCF)ccc1CC21CCC(O)CC1
Temperature: 60 °C
Yield: 36 %

Procedure:
To N-(5′-(3-fluoropropoxy)-4-hydroxyspiro[cyclohexane-1,2′-indene]-3′(1′H)-ylidene)-2-methylpropane-2-sulfinamide (Intermediate 32, 275 mg, 0.70 mmol) in dioxane (1 mL) under an atmosphere of nitrogen was added HCl (4 M in 1,4-dioxane, 1.74 mL, 6.95 mmol). The mixture was stirred at r.t. for 2 h and was then concentrated. DCM (1-2 mL) and Et2O was added and a solid was formed. The solid was filtered off and washed with diethylether. The solid was dissolved in DCM. Sat. aq. NaHCO3 was added and mixture was poured in to a phase separator. The organic phase was collected and concentrated to give 6′-(3-fluoropropoxy)-1′-imino-1′,3′-dihydrospiro[cyclohexane-1,2′-inden]-4-ol (227 mg). The obtained imine was mixed with 2-oxopropanethioamide (Intermediate 1, 239 mg, 2.32 mmol) in dry MeOH (4 mL) and the resulting orange solution was heated at 60° C. under an atmosphere of nitrogen overnight. The mixture was allowed to cool to r.t., and concentrated. The residue was purified by flash column chromatography using a gradient of 0-100% EtOAc in heptane, providing 104 mg (36% yield) of the title compound. 1H NMR (500 MHz, DMSO-d6) δ ppm 1.04-1.21 (m, 4 H) 1.41-1.48 (m, 2 H) 1.66-1.73 (m, 2 H) 2.02 (t, 1 H) 2.07 (quin, 1 H) 2.26 (s, 3 H) 2.93 (d, 1 H) 3.01 (d, 1 H) 3.22-3.29 (m, 1 H) 3.97 (tq, 2 H) 4.52 (t, 1 H) 4.55 (d, 1 H) 4.62 (t, 1 H) 6.32 (d, 1 H) 6.89 (dd, 1 H) 7.26 (d, 1 H) 12.28 (s, 1 H); MS (ES+) m/z 377.07 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]=[N:11][N:10]([CH3:13])[C:9]=2[C:14]#[C:15][C:16]2[CH:24]=[CH:23][C:19]([C:20]([OH:22])=O)=[CH:18][N:17]=2)=[CH:4][CH:3]=1.[NH2:25][CH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]=[N:11][N:10]([CH3:13])[C:9]=2[C:14]#[C:15][C:16]2[CH:24]=[CH:23][C:19]([C:20]([NH:25][CH:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)=[O:22])=[CH:18][N:17]=2)=[CH:6][CH:7]=1
Reactant: NC1CCOCC1
Reactant: Cn1nnc(-c2ccc(F)cc2)c1C#Cc1ccc(C(=O)O)cn1
Product: Cn1nnc(-c2ccc(F)cc2)c1C#Cc1ccc(C(=O)NC2CCOCC2)cn1
Yield: 74 %

Procedure:
As described for example 58d, 6-[5-(4-fluoro-phenyl)-3-methyl-3H-[1,2,3]triazol-4-ylethynyl]-nicotinic acid (69 mg, 0.21 mmol) was converted, using 4-aminotetrahydropyran instead of isopropylamine, to the title compound (64 mg, 74%) which was obtained as a light yellow solid. MS: m/e=406.2 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N+:17]([O-:19])=[O:18])[C:5]2[C:9]([CH:10]=1)=[N:8][N:7]([CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1)[CH:6]=2.[CH3:20][C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][CH:26]=1.O1CCOCC1.C(=O)([O-])[O-].[Na+].[Na+]>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].O>[CH3:20][C:21]1[CH:26]=[C:25]([C:2]2[CH:3]=[C:4]([N+:17]([O-:19])=[O:18])[C:5]3[C:9]([CH:10]=2)=[N:8][N:7]([CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)[CH:6]=3)[CH:24]=[CH:23][CH:22]=1
Reactant: Cc1cccc(B(O)O)c1
Reactant: O=[N+]([O-])c1cc(Br)cc2nn(C3CCCCO3)cc12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: Cc1cccc(-c2cc([N+](=O)[O-])c3cn(C4CCCCO4)nc3c2)c1
Temperature: 150 °C

Procedure:
6-Bromo-4-nitro-2-(tetrahydro-2H-pyran-2-yl)-2H-indazole (500 mg, 1.53 mmol), Pd(dppf)Cl2 (125 mg, 0.15 mmol), (3-methylphenyl)boronic acid (313 mg, 2.3 mmol), 1,4-dioxane (5 ml), 2 M sodium carbonate (aq) (2.3 ml) and water (5 ml) were combined and heated in a Biotage microwave at 150° C. for 30 mins. The crude reaction was combined with a separate reaction carried out at 1/10th scale. The combined reactions were partitioned between water (100 ml) and ethyl acetate (100 ml), filtered and the separated organic layer was washed several times with water, followed by brine, before being dried over magnesium sulphate and the solvent removed in vacuo. The residue was purified by silica gel chromatography, eluting with 0-25% ethyl acetate in cyclohexane, to give the title compound, 422 mg.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[N:11][CH:12]=[CH:13][C:14]=1[C@H:15]1[CH2:20][C@@H:19]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C@H:18]([OH:29])[C@@H:17]([CH3:30])[CH2:16]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:31][S:32](Cl)(=[O:34])=[O:33]>N1C=CC=CC=1>[CH3:31][S:32]([O:29][C@@H:18]1[C@@H:17]([CH3:30])[CH2:16][C@@H:15]([C:14]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:20][C@H:19]1[NH:21][C:22]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:28])(=[O:34])=[O:33]
Reactant: C[C@H]1C[C@@H](c2ccncc2NC(=O)OC(C)(C)C)C[C@@H](NC(=O)OC(C)(C)C)[C@@H]1O
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: C[C@H]1C[C@@H](c2ccncc2NC(=O)OC(C)(C)C)C[C@@H](NC(=O)OC(C)(C)C)[C@@H]1OS(C)(=O)=O
Reaction time: 0.08 h
Yield: 59 %

Procedure:
To a solution of (+/−)-tert-butyl ((1R,2R,3S,5R)-5-(3-((tert-butoxycarbonyl)amino)pyridin-4-yl)-2-hydroxy-3-methylcyclohexyl)carbamate (1.0 equiv.) in pyridine (0.17 M) was added MsCl (5.0 equiv.). The capped solution was stirred for 5 minutes and then the homogeneous solution was left standing at rt for 16 hrs. The volatiles were removed in vacuo and the residue was partitioned between EtOAc and H2O. The organic layer was washed with H2O, 10% CuSO4, H2O, Na2CO3(sat), NaCl(sat), dried over MgSO4, filtered, concentrated and purified by ISCO SiO2 chromatography to yield (+/−)-(1R,2R,4R,6 S)-2-(tert-butoxycarbonylamino)-4-(3-(tert-butoxycarbonylamino)pyridin-4-yl)-6-methylcyclohexyl methanesulfonate in 59% yield. LC/MS (m/z)=500.3 (MH+), Rt=0.74 min.
Reaction SMILES: [C:1]1([CH2:11][N:12]2[CH2:17][CH2:16][CH:15]([CH2:18][NH:19][C:20]3[NH:24][C:23]4[CH:25]=[CH:26][C:27]([CH:29]=O)=[CH:28][C:22]=4[N:21]=3)[CH2:14][CH2:13]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.Cl.[NH2:32]O.Cl.O1CCOCC1>CN(C)C=O.Cl.[OH-].[Na+]>[C:1]1([CH2:11][N:12]2[CH2:17][CH2:16][CH:15]([CH2:18][NH:19][C:20]3[NH:24][C:23]4[CH:25]=[CH:26][C:27]([C:29]#[N:32])=[CH:28][C:22]=4[N:21]=3)[CH2:14][CH2:13]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: NO
Reactant: O=Cc1ccc2[nH]c(NCC3CCN(Cc4cccc5ccccc45)CC3)nc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: N#Cc1ccc2[nH]c(NCC3CCN(Cc4cccc5ccccc45)CC3)nc2c1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 29 %

Procedure:
After dissolving 2-[(1-naphthalen-1-ylmethyl-piperidin-4-ylmethyl)-amino]-1H-benzimidazole-5-carboaldehyde (2.7 mg, 0.0570 mmol) in anhydrous dimethylformamide (1 ml) under a nitrogen stream, hydroxylamine hydrochloride (8 mg, 0.115 mmol) and one drop of 6N hydrochloric acid were added and the mixture was stirred at 80° C. for 2 hours and 30 minutes. Two drops of 5N aqueous sodium hydroxide were then added, and after extraction with ethyl acetate, extraction was repeated with dichloromethane. The organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain a residue. Anhydrous dimethylformamide (1 ml) and nine drops of a 4N hydrogen chloride/1,4-dioxane solution were added to the residue, and the mixture was stirred at 100° C. for 12 hours. After neutralization with 5N aqueous sodium hydroxide, the same extraction procedure was carried out and the obtained residue was purified by thin-layer silica gel chromatography (dichloromethane/methanol/triethylamine=85/10/5) to obtain 2-[(1-naphthalen-1-ylmethyl-piperidin-4-ylmethyl)-amino]-1H-benzimidazole-5-carbonitrile.
Reaction SMILES: [CH3:1][C:2]([CH3:37])([CH3:36])[C:3](=[O:35])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([C:17]2[CH:18]=[CH:19][C:20]3[O:24][C:23]([C:25]([NH:27][CH2:28][C:29]([OH:31])=[O:30])=[O:26])=[C:22]([CH3:32])[C:21]=3[CH:33]=2)([CH2:15][CH3:16])[CH2:13][CH3:14])=[CH:8][C:7]=1[CH3:34].[BH4-].[Na+]>>[CH2:13]([C:12]([C:17]1[CH:18]=[CH:19][C:20]2[O:24][C:23]([C:25]([NH:27][CH2:28][C:29]([OH:31])=[O:30])=[O:26])=[C:22]([CH3:32])[C:21]=2[CH:33]=1)([C:9]1[CH:10]=[CH:11][C:6]([O:5][CH2:4][CH:3]([OH:35])[C:2]([CH3:36])([CH3:37])[CH3:1])=[C:7]([CH3:34])[CH:8]=1)[CH2:15][CH3:16])[CH3:14]
Reactant: CCC(CC)(c1ccc(OCC(=O)C(C)(C)C)c(C)c1)c1ccc2oc(C(=O)NCC(=O)O)c(C)c2c1
Agent: [BH4-]
Agent: [Na+]
Product: CCC(CC)(c1ccc(OCC(O)C(C)(C)C)c(C)c1)c1ccc2oc(C(=O)NCC(=O)O)c(C)c2c1
Yield: 99.4 %

Procedure:
[(5-{1-[4-(3,3-Dimethyl-2-oxo-butoxy)-3-methyl-phenyl]-1-ethyl-propyl}-3-methyl-benzofuran-2-carbonyl)-amino]-acetic acid (190 mg, 0.375 mmol) is reduced with NaBH4 (28 mg, 0.750 mmol) analogous to Example 3 to give the title product (190 mg, 100%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([Cl:11])(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl.Cl.[CH2:14]([NH:16][CH2:17][CH2:18][CH2:19][N:20]1[CH2:30][CH2:29][C:28]2[C:31]3[CH:21]1[CH2:22][CH2:23][C:24]=3[CH:25]=[CH:26][CH:27]=2)[CH3:15].CCN(C(C)C)C(C)C>C(Cl)Cl>[ClH:11].[CH2:14]([N:16]([CH2:17][CH2:18][CH2:19][N:20]1[CH2:30][CH2:29][C:28]2[C:31]3[CH:21]1[CH2:22][CH2:23][C:24]=3[CH:25]=[CH:26][CH:27]=2)[S:8]([C:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=1)(=[O:10])=[O:9])[CH3:15]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCNCCCN1CCc2cccc3c2C1CC3
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCN(CCCN1CCc2cccc3c2C1CC3)S(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 41.4 %

Procedure:
4-Methylbenzenesulfonyl chloride (20.9 mg, 0.11 mmol) was added to a solution of Ethyl-[3-(2,2a,4,5-tetrahydro-1H-3-aza-acenaphthylen-3-yl)-propyl]-amine dihydrochloride (31.7 mg, 0.1 mmol) and N,N′-diisopropylethylamine (64.6 mg, 0.5 mmol) in CH2Cl2 (10 mL) and the mixture was stirred overnight at room temperature. The resulting solution was washed with water (3×10 mL), dried over Na2SO4 and evaporated to dryness. The free base was dissolved in ethyl acetate (1 ml). A 2.8 M solution of hydrogen chloride in ethanol (0.10 mL) was then added. The product was crystallized and collected by filtration, and vacuum dried to give a white solid (18.0 mg, 41%).
Reaction SMILES: Cl[C:2]1[C:7]([CH3:8])=[CH:6][N+:5]([O-:9])=[C:4]([CH3:10])[C:3]=1[CH3:11].[CH3:12][C:13]1([CH3:21])[O:18][CH2:17][CH:16]([CH2:19][OH:20])[CH2:15][O:14]1>C1(C)C=CC=CC=1>[CH3:12][C:13]1([CH3:21])[O:18][CH2:17][CH:16]([CH2:19][O:20][C:2]2[C:7]([CH3:8])=[CH:6][N+:5]([O-:9])=[C:4]([CH3:10])[C:3]=2[CH3:11])[CH2:15][O:14]1
Reactant: CC1(C)OCC(CO)CO1
Reactant: Cc1c[n+]([O-])c(C)c(C)c1Cl
Solvent: Cc1ccccc1
Product: Cc1c[n+]([O-])c(C)c(C)c1OCC1COC(C)(C)OC1
Reaction time: 2.5 h
Yield: 90.6 %

Procedure:
A mixture of 4-chloro-2,3,5-trimethylpyridine 1-oxide (840 g), (2,2-dimethyl-1,3-dioxan-5-yl)methanol (688 g) and toluene (2.52 L) was heated to reflux while removing moisture. While continuing the azeotropic dewatering, the mixture was charged with potassium hydroxide (0.58 kg) over 3 hours and 45 minutes, and the azeotropic dewatering was then continued for another 2.5 hours. The reaction system was cooled to 30° C. or less and then charged with ethyl acetate (2.5 L) and 17% saline solution (3.5 L). The resultant solution was left to stand overnight. The ethyl acetate layer was collected, and the aqueous layer was extracted with ethyl acetate (1.0 L×3). The combined ethyl acetate layers were filtered with Celite and then concentrated under reduced pressure to obtain 1.20 kg of the title compound.
Reaction SMILES: [C:1]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[C:17]([O:21][CH2:22][CH:23]1[C:35]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[C:29]2[C:24]1=[CH:25][CH:26]=[CH:27][CH:28]=2)(=[O:20])[NH:18][NH2:19].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O>[C:17]([NH:18][NH:19][C:14](=[O:16])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][NH:8][C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2])([O:21][CH2:22][CH:23]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:29]2[C:24]1=[CH:25][CH:26]=[CH:27][CH:28]=2)=[O:20]
Reactant: NNC(=O)OCC1c2ccccc2-c2ccccc21
Reactant: CC(C)(C)OC(=O)NCCCCCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCCCCC(=O)NNC(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 0 °C
Reaction time: 2 h
Yield: 60.8 %

Procedure:
A 250 ml round bottom flask was charged with 4,190 g (0.0181 mol) of N-BOC-6-aminocaproic acid, 4.60 g of 9-fluorenylmethyl carbazate (FMOC), (prepared by the method of Carpino et. al., 1972, J. Org. Chem., 37:3404) and 35 ml of N,N-dimethylformamide. The reaction solution was cooled to 0° C. and then 3.75 g (0.0182 mol) of 1,3-dicyclohexylcarbodiimide (Aldrich) was added. The reaction mixture was allowed to stir for 2 h at 0° C. The white precipitate which formed during this time was filtered off and the solvents evaporated under reduced pressure. The distillation residue was applied to a 225 cc pad of silica gel (Merck), which was then washed with 1L of chloroform. The product was then eluted from the column using 1L of 50% methanol in chloroform. The solvents were evaporated from the desired eluent fractions to give 4.98 g (0.011 mol, 59% yield) of N-BOC-6-aminocaproic acid (N'-FMOC-hydrazide) as a yellow oil. 1H NMR (DMSO-d6) showed the peaks observed in the starting material and new protons in the aromatic region between 7-8 ppm (FMOC group).
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:4]([NH:6][C@H:7]([C:25]([N:27]1[CH2:66][CH2:65][CH2:64][C@H:28]1[C:29]([NH:31][C@H:32]([C:34]([NH:36][C@H:37]([C:54]([O:56]CC1C=CC=CC=1)=[O:55])[CH2:38][CH2:39][CH2:40][CH2:41][NH:42]C(OCC1C=CC=CC=1Cl)=O)=[O:35])[CH3:33])=[O:30])=[O:26])[CH2:8][CH2:9][CH2:10][NH:11][C:12](=[NH:24])[NH:13]S(C1C=CC(C)=CC=1)(=O)=O)=[O:5])[CH3:3].C1(OC)C=CC=CC=1>>[NH2:1][C@H:2]([C:4]([NH:6][C@H:7]([C:25]([N:27]1[CH2:66][CH2:65][CH2:64][C@H:28]1[C:29]([NH:31][C@H:32]([C:34]([NH:36][C@H:37]([C:54]([OH:56])=[O:55])[CH2:38][CH2:39][CH2:40][CH2:41][NH2:42])=[O:35])[CH3:33])=[O:30])=[O:26])[CH2:8][CH2:9][CH2:10][NH:11][C:12](=[NH:13])[NH2:24])=[O:5])[CH3:3]
Reactant: Cc1ccc(S(=O)(=O)NC(=N)NCCC[C@H](NC(=O)[C@H](C)NC(=O)OC(C)(C)C)C(=O)N2CCC[C@H]2C(=O)N[C@@H](C)C(=O)N[C@@H](CCCCNC(=O)OCc2ccccc2Cl)C(=O)OCc2ccccc2)cc1
Solvent: COc1ccccc1
Product: C[C@H](N)C(=O)N[C@@H](CCCNC(=N)N)C(=O)N1CCC[C@H]1C(=O)N[C@@H](C)C(=O)N[C@@H](CCCCN)C(=O)O
Temperature: 0 °C
Reaction time: 1 h
Yield: 77.9 %

Procedure:
The solution of 250 mg (0.237 mmol) of Boc-Ala-Arg(Tos)-Pro-Ala-Lys(ClZ)OBzl (SEQ ID NO: 13), 1 ml of anisole and 2 ml of HF was stirred at 0° C. for 2 h. The reaction mixture was evaporated under reduced pressure to remove HF. To the residue 2 ml of HF were added and the solution was stirred at 0° C. for another 1 h. The reaction mixture was evaporated under reduced pressure to remove HF. The residue was triturated with ether and the resulted solid was purified on the Sephadex G-10 column. The collected fractions were lyophilized to provide 100 mg (77.8%) of the title compound. Mp. 224–6° C., FAB-MS (m/e) 542[M+H]+.
Reaction SMILES: [CH3:1][C:2]1[C:19]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=2[O:28][CH3:29])=[CH:18][CH:17]=[CH:16][C:3]=1[C:4]([NH:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([O:14]C)=[O:13])=[O:5].O.[OH-].[Li+]>C1COCC1.O>[CH3:1][C:2]1[C:19]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][C:21]=2[O:28][CH3:29])=[CH:18][CH:17]=[CH:16][C:3]=1[C:4]([NH:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[O:5]
Reactant: COC(=O)CCCCCNC(=O)c1cccc(-c2ccc(OC)cc2OC)c1C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(-c2cccc(C(=O)NCCCCCC(=O)O)c2C)c(OC)c1
Yield: 93.4 %

Procedure:
The procedure of the step 2 in Example 92 was repeated except that methyl 6-(2-methyl-3-(2,4-dimethoxyphenyl)-benzamido)hexanoate (30 mg, 0.075 mmol) and lithium hydroxide monohydrate (6 mg, 0.15 mmol) were dissolved in 3 mL of THF/H2O (2:1) to obtain the title compound (27 mg, 94%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:5]=[C:6]([O:11]CC2C=CC=CC=2)[C:7]=1[N+:8]([O-])=O>CCO.[C].[Pd]>[NH2:8][C:7]1[C:6]([OH:11])=[CH:5][C:4]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:3][C:2]=1[F:1]
Reactant: CCOC(=O)Cc1cc(F)c([N+](=O)[O-])c(OCc2ccccc2)c1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)Cc1cc(O)c(N)c(F)c1
Yield: 64.9 %

Procedure:
Ethyl 3-fluoro-4-nitro-5-benzyloxyphenylacetate (1.54 g, 4.62 mmol) and 10% palladium-carbon (122 mg) were subjected to catalytic hydrogenation for 20 hours under normal pressure while stirring at room temperature in EtOH (20 ml). From the reaction mixture, the catalyst was filtered off. The filtrate was distilled under reduced pressure to remove the solvent. The residue was purified by chromatography on a silica gel column, whereby from ethyl acetate/hexane (1/2) eluate fractions, ethyl 4-amino-3-fluoro-5-hydroxyphenylacetate (639 mg, 65%) was obtained as a brown oil.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:10][CH2:9][CH:8]([NH2:11])[CH2:7][CH2:6]1)=[O:4].C([N:29]=[C:30]=[S:31])(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O>>[CH3:1][O:2][C:3]([CH:5]1[CH2:10][CH2:9][CH:8]([NH:11][C:30]([NH2:29])=[S:31])[CH2:7][CH2:6]1)=[O:4]
Reactant: O=C(N=C=S)OCC1c2ccccc2-c2ccccc21
Reactant: COC(=O)C1CCC(N)CC1
Product: COC(=O)C1CCC(NC(N)=S)CC1
Yield: 26.7 %

Procedure:
4-Thioureido-cyclohexanecarboxylic acid methyl ester (150 mg) compound was prepared following general procedure D using 4-Amino-cyclohexanecarboxylic acid methyl ester (500 mg, 11.0 mmol), and Fmoc-isothiocyanate (730 mg). Purification: (Silica gel, ethyl acetate/hexane 1:1). LCMS m/z: 217.0 (M+1)+.
Reaction SMILES: [N:1]1([S:11]([C:14]2[CH:22]=[CH:21][C:17]([C:18](O)=[O:19])=[CH:16][CH:15]=2)(=[O:13])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[F:23][C:24]1[CH:33]=[CH:32][C:27]2[N:28]=[C:29]([NH2:31])[S:30][C:26]=2[CH:25]=1>>[N:1]1([S:11]([C:14]2[CH:15]=[CH:16][C:17]([C:18]([NH:31][C:29]3[S:30][C:26]4[CH:25]=[C:24]([F:23])[CH:33]=[CH:32][C:27]=4[N:28]=3)=[O:19])=[CH:21][CH:22]=2)(=[O:12])=[O:13])[C:2]2[C:7](=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:8][CH2:9][CH2:10]1
Reactant: O=C(O)c1ccc(S(=O)(=O)N2CCCc3ccccc32)cc1
Reactant: Nc1nc2ccc(F)cc2s1
Product: O=C(Nc1nc2ccc(F)cc2s1)c1ccc(S(=O)(=O)N2CCCc3ccccc32)cc1

Procedure:
4-(3,4-dihydroquinolin-1(2H)-ylsulfonyl)benzoic acid (1) (100 mg, 0.32 mmol) was treated with 6-fluorobenzo[d]thiazol-2-amine (41 mg, 0.24 mmol) using method B. The residue was purified using flash chromatography eluting with 0-40% EtOAc in hexanes to give 4-(3,4-dihydroquinolin-1(2H)-ylsulfonyl)-N-(6-fluorobenzo[d]thiazol-2-yl)benzamide as an off-white solid. Yield: 22 mg (19%). 1H-NMR: 8.22 (d, J=8.5 Hz, 2H), 7.94 (dd, J=8.5, 2.5 Hz, 1H), 7.84-7.75 (m, 3H), 7.61 (d, J=8.5 Hz, 2H), 7.33 (dt, J=9.0, 3.0 Hz, 1H), 7.24-7.19 (m, 1H), 7.14-7.08 (m, 2H), 3.84-3.80 (m, 2H), 2.45 (t, J=7.0 Hz, 2H), 1.66-1.58 (m, 2H).
Reaction SMILES: [C:1](Cl)(=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH2:9]([O:11][C@@H:12]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:28]=[C:27]([CH2:29][NH:30][CH3:31])[S:26][CH:25]=2)=[CH:20][CH:19]=1)[C:13]([O:15][CH3:16])=[O:14])[CH3:10].C(N(CC)CC)C>O1CCCC1>[CH2:9]([O:11][C@@H:12]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:28]=[C:27]([CH2:29][N:30]([C:1](=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[CH3:31])[S:26][CH:25]=2)=[CH:20][CH:19]=1)[C:13]([O:15][CH3:16])=[O:14])[CH3:10]
Reactant: CCCCCC(=O)Cl
Reactant: CCO[C@@H](Cc1ccc(-c2csc(CNC)c2)cc1)C(=O)OC
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCCCC(=O)N(C)Cc1cc(-c2ccc(C[C@H](OCC)C(=O)OC)cc2)cs1
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.2 %

Procedure:
0.18 ml (1.3 mmol) of hexanoyl chloride is added to a solution, cooled beforehand to 0° C., of 0.4 g (1.2 mmol) of methyl 2(S)-ethoxy-3-[4-(5-methylaminomethylthiophen-3-yl)phenyl]propanoate and 0.18 ml (1.3 mmol) of triethylamine in 20 ml of tetrahydrofuran. The reaction medium is stirred at room temperature for 2 hours, washed with water and extracted with ethyl acetate. The ethyl acetate phase is dried over magnesium sulfate, filtered and evaporated. The residue obtained is purified by thin-layer chromatography on silica eluted with a 70/30 heptane/ethyl acetate mixture. 0.4 g (83%) of methyl 2(S)-ethoxy-3-(4-{5-[(hexanoylmethylamino)methyl]thiophen-3-yl}phenyl)propanoate is obtained.
Reaction SMILES: [N:1]([CH:4]1[CH2:13][CH2:12][CH2:11][C:10]2[CH:9]=[C:8]([O:14][S:15]([C:18]([F:21])([F:20])[F:19])(=[O:17])=[O:16])[CH:7]=[CH:6][C:5]1=2)=[N+]=[N-].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O.Cl>C1COCC1>[NH2:1][CH:4]1[CH2:13][CH2:12][CH2:11][C:10]2[CH:9]=[C:8]([O:14][S:15]([C:18]([F:21])([F:19])[F:20])(=[O:17])=[O:16])[CH:7]=[CH:6][C:5]1=2
Reactant: [N-]=[N+]=NC1CCCc2cc(OS(=O)(=O)C(F)(F)F)ccc21
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: NC1CCCc2cc(OS(=O)(=O)C(F)(F)F)ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of trifluoro-methanesulfonic acid 5-azido-5,6,7,8-tetrahydro-naphthalen-2-yl ester (10.3 g, 32.1 mmol, 1.0 eq) in THF (70 mL) was added PPh3 (Aldrich, 8.4 g, 32.1 mmol, 1.0 eq), and H2O (30 mL) at 0° C. The mixture was warmed to RT and stirred overnight. 2N HCl was added until the mixture was acidic (pH ˜1–2). The mixture was extracted with toluene (3×100 mL). The aqueous phase was neutralized with 5N NaOH to pH around 12–13, and extracted with ether (3×150 mL). The ether solution was dried over Na2SO4, filtered and concentrated in vacuo. The crude was purified by flash chromatography (6% MeOH—CH2Cl2) to provide the title compound.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH:12]=[O:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[N:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[N:14]1[CH:19]=[CH:18][C:17]([C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH:12]=[O:13])[CH:10]=3)[N:5]=[CH:4][CH:3]=2)=[CH:16][CH:15]=1
Reactant: O=Cc1ccc2nccc(Cl)c2c1
Reactant: OB(O)c1ccncc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1ccc2nccc(-c3ccncc3)c2c1
Temperature: 100 °C
Yield: 51.2 %

Procedure:
A mixture of 4-chloro-6-quinolinecarbaldehyde (3.24 g, 16.92 mmol), 4-pyridylboronic acid (3.12 g, 25.38 mmol), tetrakistriphenylphosphine palladium (0) (0.978 g, 0.846 mmol), and 2M aqueous K2CO3 (7.02 g, 50.76 mmol, 25.4 mls of 2M solution) in DMF (100 mL) was heated at 100° C. for 3.0 h and cooled to room temperature. The mixture was filtered through Celite and the Celite was washed with EtOAc. The filtrate was transferred to a separatory funnel, washed with water and saturated NaCl, dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (5% MeOH:CH2Cl2) to give the title compound (2.03 g, 51%) as a tan solid. MS(ES)+ m/e 235 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][NH:5][CH:6]=1.[N+:7]([C:10]1[CH:17]=[CH:16][C:13]([CH2:14]Br)=[CH:12][CH:11]=1)([O-:9])=[O:8].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:1][C:2]1[N:3]([CH2:14][C:13]2[CH:16]=[CH:17][C:10]([N+:7]([O-:9])=[O:8])=[CH:11][CH:12]=2)[CH:4]=[N:5][CH:6]=1
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: Cc1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cncn1Cc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 2.8 %

Procedure:
A mixture of 4-methyl-1H-imidazole (25.5 g), 4-nitrobenzyl bromide (56 g), potassium carbonate (86 g) and N,N-dimethylformamide (500 ml) was stirred at room temperature for 14 hrs. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography to give 5-methyl-1-(4-nitrobenzyl)-1H-imidazole (1.6 g, 3%) as crystals from a fraction eluted with methanol-ethyl acetate (1:20, v/v). Recrystallization thereof from ethyl acetate-isopropyl ether gave colorless prism crystals. melting point: 120-121° C.