Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:21]=[CH:22][C:23]=1[N+:24]([O-])=O)[CH2:12][CH:13]1[NH:19][C:18](=[O:20])[CH2:17][CH2:16][CH2:15][CH2:14]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.O.[Sn](Cl)Cl.O>CCOC(C)=O>[NH2:24][C:23]1[CH:22]=[CH:21][C:11]([CH2:12][CH:13]2[NH:19][C:18](=[O:20])[CH2:17][CH2:16][CH2:15][CH2:14]2)=[CH:10][C:9]=1[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCCCC(Cc2ccc([N+](=O)[O-])c(OCc3ccccc3)c2)N1
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCOC(C)=O
Product: Nc1ccc(CC2CCCCC(=O)N2)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 7-(3-benzyloxy-4-nitrobenzyl)-azepan-2-one (600 mg, 1.7 mmol) in EtOAc (20 mL) is added tin (II) chloride dihydrate. The mixture is stirred at RT for 18 h then water is added. The mixture is extracted with EtOAc and the organic phase is washed with water and brine. The solution is dried over sodium sulfate and the solvent removed under reduced pressure to give the title compound: (M+1)+=325.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[O:6][C@@H:5]([C@H:7]2[O:11][CH:10]([OH:12])[C@H:9]3[O:13][C:14]([CH3:17])([CH3:16])[O:15][C@@H:8]23)[CH2:4][O:3]1.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>ClCCl>[CH3:1][C:2]1([CH3:18])[O:6][C@@H:5]([C@H:7]2[O:11][C:10](=[O:12])[C@H:9]3[O:13][C:14]([CH3:17])([CH3:16])[O:15][C@@H:8]23)[CH2:4][O:3]1
Reactant: CC1(C)O[C@H]2[C@@H]([C@H]3COC(C)(C)O3)OC(O)[C@H]2O1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CC1(C)O[C@H]2[C@@H]([C@H]3COC(C)(C)O3)OC(=O)[C@H]2O1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 2,3:5,6-di-O-isopropylidene-D-mannofuranose (diacetone mannose) (20 g, 76.9 mmol) in dichloromethane (100 ml) was added to a solution of pyridinium chlorochromate (33.2 g, 2.0 equiv) and dry powdered molecular sieve (40 g) in dichloromethane (300 ml) at 0° C. under nitrogen. The reaction mixture was stirred at room temperature for 30 min [when TLC (ether:hexane, 2:1) showed no starting material (Rf 0.36) and one major product (Rf 0.24)], diluted with ether (400 ml) and filtered through a silica plug. The silica plug was washed with ether and the filtrates were combined and the solvents removed to give, after recrystallization from ether, 2,3:5,6-di-O-isopropylidene-D-mannono-1,4-lactone (11), (18.0 g, 90%), m.p. 125°-126° C. [lit. m.p. 125°-125° C.; Ohle et al., Chem. Ber. 58, 2590 (1925); Goodyear and Haworth, J. Chem. Soc. 1927, 3136⟧
Reaction SMILES: [NH2:1][C:2]1[CH:35]=[CH:34][C:5]2[NH:6][C:7]([C:12]3[C:13](=[O:33])[C:14]([NH:29][C:30](=[O:32])[CH3:31])([CH2:23][CH2:24][C:25]([CH3:28])([CH3:27])[CH3:26])[C:15]4[C:20]([C:21]=3[OH:22])=[CH:19][CH:18]=[CH:17][CH:16]=4)=[N:8][S:9](=[O:11])(=[O:10])[C:4]=2[CH:3]=1.C(N(CC)CC)C.[CH3:43][S:44](Cl)(=[O:46])=[O:45]>ClCCl.C(OCC)(=O)C>[CH3:27][C:25]([CH3:28])([CH3:26])[CH2:24][CH2:23][C:14]1([NH:29][C:30](=[O:32])[CH3:31])[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:21]([OH:22])=[C:12]([C:7]2[NH:6][C:5]3[CH:34]=[CH:35][C:2]([NH:1][S:44]([CH3:43])(=[O:46])=[O:45])=[CH:3][C:4]=3[S:9](=[O:10])(=[O:11])[N:8]=2)[C:13]1=[O:33]
Reactant: CS(=O)(=O)Cl
Reactant: CC(=O)NC1(CCC(C)(C)C)C(=O)C(C2=NS(=O)(=O)c3cc(N)ccc3N2)=C(O)c2ccccc21
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(=O)NC1(CCC(C)(C)C)C(=O)C(C2=NS(=O)(=O)c3cc(NS(C)(=O)=O)ccc3N2)=C(O)c2ccccc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 82.2 %

Procedure:
To a solution of product of Example 74D (1.16 g, 2.33 mmol) in dichloromethane (20 mL) was added triethylamine (1.6 mL, 11.7 mmol) followed by dropwise addition of methanesulfonyl chloride (0.45 mL, 5.84 mmol). The reaction mixture was stirred at room temperature for 18 h. The solution was diluted with ethyl acetate (30 mL), washed with aqueous 1 N HCl (2×15 mL), dried (Na2SO4), and concentrated in vacuo. The resulting residue was taken up in methanol (20 mL) and treated with excess K2CO3 for 2 h. The mixture was filtered. The filtrate was concentrated in vacuo and the resulting residue was taken up in 3:1 dichloromethane:isopropanol (15 mL) and washed with aqueous 1 N HCl (2×10 mL), dried (Na2SO4), and concentrated in vacuo to afford the title compound as a light yellow solid (1.1 g, 82%). 1H NMR (500 MHz, DMSO-d6), δ ppm 0.44-0.54 (m, 1H), 0.66 (s, 9H), 0.87-0.98 (m, 1H), 1.80-1.89 (m, 4H), 1.95-2.05 (m, 1H), 3.08 (s, 3H), 7.53 (t, J=7.25 Hz, 2H), 7.58 (dd, J=8.69, 2.32 Hz, 1H), 7.64 (d, J=2.32 Hz, 1H), 7.70-7.78 (m, 2H), 8.12 (d, J=7.54 Hz, 1H), 9.14 (s, 1H), 10.24 (s, 1H), 13.61 (s, 1H); MS m/z 575.2 (M+H)+.
Reaction SMILES: CC(C[AlH]CC(C)C)C.C[O:11][C:12](=O)[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH:20]([C:24]2[CH:25]=[N:26][C:27]([C:33]3[C:38]([CH2:39][CH3:40])=[CH:37][CH:36]=[CH:35][C:34]=3[CH2:41][CH3:42])=[CH:28][C:29]=2[O:30][CH2:31][CH3:32])[CH2:21][CH2:22][CH3:23])[CH:14]=1>C1COCC1.CCOCC>[CH2:41]([C:34]1[CH:35]=[CH:36][CH:37]=[C:38]([CH2:39][CH3:40])[C:33]=1[C:27]1[N:26]=[CH:25][C:24]([CH:20]([O:19][C:15]2[CH:14]=[C:13]([CH2:12][OH:11])[CH:18]=[CH:17][CH:16]=2)[CH2:21][CH2:22][CH3:23])=[C:29]([O:30][CH2:31][CH3:32])[CH:28]=1)[CH3:42]
Reactant: CCCC(Oc1cccc(C(=O)OC)c1)c1cnc(-c2c(CC)cccc2CC)cc1OCC
Agent: CC(C)C[AlH]CC(C)C
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCCC(Oc1cccc(CO)c1)c1cnc(-c2c(CC)cccc2CC)cc1OCC
Reaction time: 2 h

Procedure:
DIBAL-H (1.5 M in Toluene, 0.3 mL) is added dropwise to a solution of 3-{1-[6-(2,6-diethyl-phenyl)-4-ethoxy-pyridin-3-yl]-butoxy}-benzoic acid methyl ester (80 mg, 0.17 mmol) in THF (3 mL) at room temperature. The reaction mixture is stirred for 2 hours, then diluted with ether (5 mL) and treated with Na2SO4.10H2O. The resulting mixture is stirred for one hour and filtered through Celite. Concentration of the filtrate at reduced pressure gives (3-{1-[6-(2,6-diethyl-phenyl)-4-ethoxy-pyridin-3-yl]-butoxy}-phenyl)-methanol. 1H NMR (CDCl3) 8.53 (s, 1H), 7.10-7.30 (m, 4H), 6.74-6.90 (m, 4H), 5.60 (m, 1H), 4.51 (s, 2H), 4.13 (, 21), 2.47 (s, 1H), 2.24-2.37 (m, 4H), 1.80-2.10 (m, 2H), 1.4-1.6 (m, 1H), 0.90-1.05 (m, 9H).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[CH3:6][N:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([C:16](=[O:19])[CH:17]=[CH2:18])=[CH:8]1>C(OCC)(=O)C>[N:1]1([CH2:18][CH2:17][C:16]([C:9]2[C:10]3[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=3)[N:7]([CH3:6])[CH:8]=2)=[O:19])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: C=CC(=O)c1cn(C)c2ccccc12
Reactant: c1c[nH]cn1
Solvent: CCOC(C)=O
Product: Cn1cc(C(=O)CCn2ccnc2)c2ccccc21
Reaction time: 18 h
Yield: 59 %

Procedure:
Imidazole (0.433 g) was added to a solution of 1-(1-methyl-1H-indol-3-yl)-1-prop-2-enone (0.393 g) in ethyl acetate (12 ml) and the mixture was stirred and heated at reflux for 2.25 h. The mixture was cooled and allowed to stand for 18 h at room temperature. The resulting precipitate was filtered off, washed with ethyl acetate (2 ml) and ether (10 ml) and dried to give the title compound (0.317 g), m.p. 121°-123°; λmax (EtOH) 245.5 nm (ε14,080), λinf 248 nm (ε13,750), λinf 258 nm (ε9,400), λmax 304 nm (ε14,000).
Reaction SMILES: COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:10])=CC=1.[C:23]1(/[CH:29]=[CH:30]/[CH2:31][C:32]([NH2:34])=O)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C1(C)C=CC=CC=1>[C:23]1(/[CH:29]=[CH:30]/[CH2:31][C:32](=[S:10])[NH2:34])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: NC(=O)C/C=C/c1ccccc1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: NC(=S)C/C=C/c1ccccc1
Temperature: 25 °C
Yield: 58.2 %

Procedure:
Lawesson's reagent (1.88 g, 4.65 mmol) was added to (E)-4-phenylbut-3-enamide (500 mg, 3.10 mmol) in toluene (25 mL). The reaction mixture was refluxed for 24 h then cooled to room temperature. The solvent was then removed under reduced pressure. The crude residue was purified twice by column chromatography to give >90% pure (E)-4-phenylbut-3-enethioamide (320 mg).
Reaction SMILES: [CH:1]1([C:4]2[O:8][C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([C:16]4[CH:21]=[CH:20][C:19]([C:22]56[CH2:29][CH2:28][C:25]([CH2:30][C:31]([O:33]C)=[O:32])([CH2:26][CH2:27]5)[O:24][CH2:23]6)=[CH:18][CH:17]=4)=[CH:12][CH:11]=3)=[N:6][N:5]=2)[CH2:3][CH2:2]1.[OH-].[Na+:36]>>[Na+:36].[CH:1]1([C:4]2[O:8][C:7]([NH:9][C:10]3[CH:11]=[CH:12][C:13]([C:16]4[CH:21]=[CH:20][C:19]([C:22]56[CH2:29][CH2:28][C:25]([CH2:30][C:31]([O-:33])=[O:32])([CH2:26][CH2:27]5)[O:24][CH2:23]6)=[CH:18][CH:17]=4)=[CH:14][CH:15]=3)=[N:6][N:5]=2)[CH2:2][CH2:3]1
Reactant: COC(=O)CC12CCC(c3ccc(-c4ccc(Nc5nnc(C6CC6)o5)cc4)cc3)(CC1)CO2
Agent: [Na+]
Agent: [OH-]
Product: O=C([O-])CC12CCC(c3ccc(-c4ccc(Nc5nnc(C6CC6)o5)cc4)cc3)(CC1)CO2

Procedure:
The title compound was prepared analogous to Example 4, Step 5 starting from methyl 2-(4-(4′-((5-cyclopropyl-1,3,4-oxadiazol-2-yl)amino)-[1,1′-biphenyl]-4-yl)-2-oxabicyclo[2.2.2]octan-1-yl)acetate (413 mg, 0.90 mmol) and NaOH (2.70 ml, 2.70 mmol). After completion of the reaction, the mixture was concentrated to dryness and taken up in water. The resulting slurry was filtered and washed with water to afford the title compound as white solid after drying (392 mg, 93% yield). HR/MS (M+H)+ found 446.2077. calc. 446.2080. RT: 1.54 (Condition L). 1H NMR (400 MHz, DMSO-d6) δ ppm 10.54 (br. s., 1H) 7.58-7.64 (m, 4H) 7.55 (d, J=8.34 Hz, 2H) 7.36 (d, J=8.34 Hz, 2H) 3.84 (s, 2H) 2.16-2.27 (m, 2H) 2.13 (tt, J=8.37, 5.02 Hz, 1H) 2.00 (s, 2H) 1.88-1.99 (m, 2H) 1.69-1.88 (m, 4H) 1.03-1.10 (m, 2H) 0.91-0.98 (m, 2H)
Reaction SMILES: C(NC(C)C)(C)C.CCCCCC.C([Li])CCC.[C:19]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])(=[O:21])[CH3:20].Br[CH2:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]#[N:36])=[CH:31][CH:30]=1.[NH4+].[Cl-]>C1COCC1.O.CCCCCC.C(OCC)(=O)C>[C:23]([O:22][C:19]([CH2:20][CH2:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]#[N:36])=[CH:31][CH:30]=1)=[O:21])([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(=O)OC(C)(C)C
Reactant: N#Cc1ccc(CBr)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)CCc1ccc(C#N)cc1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 84.7 %

Procedure:
To a mixture of 10.2 ml (73 mmols) of diisopropylamine and 35 ml of THF was added 27.5 ml (66 mmols) of hexane solution (2.4 mol dm-3 solution) of butyl lithium at 0° C. in argon atmosphere, and the mixture was stirred for 15 minutes and then cooled to -78° C. With addition of 20 ml of a solution of 8.07 ml (60 mmols) of t-butyl acetate in THF, the mixture was stirred for 30 minutes. Subsequently 30 ml of THF solution of 9.8 g (50 mmols) of α-bromo-p-tolunitrile was added. After stirring the mixture at -78° C. for 1 hour, 20 ml of saturated aqueous solution of NH4Cl was added to the mixture. The resulting mixture was heated to room temperature and diluted with 100 ml of water, followed by extraction with ether. The extract was dried over MgSO4 and concentrated to obtain an oil, which was subjected to silica gel column chromatography (90:10 hexane-ethyl acetate to 60:40 hexane-ethyl acetate), giving 9.8 g (yield 85%) of 4-(2-t-butoxycarbonylethyl)-benzonitrile in the form of an oil.
Reaction SMILES: [CH3:1][C:2]([CH3:15])([CH2:6][O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3](O)=[O:4].C(Cl)(=O)C([Cl:19])=O>CN(C)C=O.ClCCl>[CH3:1][C:2]([CH3:15])([CH2:6][O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]([Cl:19])=[O:4]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(C)(COCc1ccccc1)C(=O)O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(COCc1ccccc1)C(=O)Cl
Temperature: 0 °C
Reaction time: 5 h

Procedure:
Adapting procedures or variations thereof according to Lopez et al., Bioorg. & Med. Lett. 2003, 13(11), 1873-1878, a 500 mL round-bottomed flask equipped with a magnetic stirring bar was charged with 5.7 g (27.6 mmol) of 2,2-dimethyl-3-(phenylmethoxy)propanoic acid (26b), 20 mL of anhydrous dichloromethane (DCM), and 3 drops of N,N-dimethylformamide (DMF). Four-point-eight (4.8) mL (7.1 g, 55.2 mmol) of neat oxalyl chloride was slowly added to the solution. The reaction mixture was stirred at ca. 0° C. (ice-bath) for 5 hours. The solvents were removed under reduced pressure to provide the crude title compound (26c), which was used in the next step without further purification. 1H NMR (400 MHz, CDCl3): δ=1.34 (s, 6H), 3.54 (s, 2H), 4.56 (s, 2H), 7.29-7.37 (m, 5H) ppm. The analytical data was consistent with the proposed structure.
Reaction SMILES: [Na+].[NH2:2][C@H:3]([C:9]([O-:11])=[O:10])[CH2:4][CH2:5][C:6]([OH:8])=[O:7].[OH-].[Na+].[C:14](Cl)(=[O:18])[C:15]([CH3:17])=[CH2:16]>>[C:14]([NH:2][C@H:3]([C:9]([OH:11])=[O:10])[CH2:4][CH2:5][C:6]([OH:8])=[O:7])(=[O:18])[C:15]([CH3:17])=[CH2:16]
Reactant: C=C(C)C(=O)Cl
Reactant: N[C@@H](CCC(=O)O)C(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Product: C=C(C)C(=O)N[C@@H](CCC(=O)O)C(=O)O
Yield: 48 %

Procedure:
The same procedure as described in Example A is utilized with 100 g (0.6 mol) of L-glutamic acid monosodium salt, 50 g (0.125 mol) of sodium hydroxide, and 63 g of methacryloyl chloride to yield 62 g (48.7%) of a crystalline material, melting point 128°-130° C. NMR (D2O), 5.7 gamma (s, 1H, =CH2), 5.4 gamma (s, 1H, =CH2), 4.4 gamma (2 d, 1H, CH), 2.0-2.7 gamma (m, 4H, CH2CH2), and 1.9 gamma (s, 3H, CH3).
Reaction SMILES: [CH:1]([C@:4]1([C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[N:21]=[CH:20][N:19]=3)[CH2:14][CH2:13]2)=[O:11])[CH2:8][CH2:7][C@@H:6]([NH2:9])[CH2:5]1)([CH3:3])[CH3:2].[CH3:28][O:29][CH:30]1[C:35](=O)[CH2:34][CH2:33][O:32][CH2:31]1.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH:1]([C@:4]1([C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[CH:23]=[C:22]([C:24]([F:27])([F:25])[F:26])[N:21]=[CH:20][N:19]=3)[CH2:14][CH2:13]2)=[O:11])[CH2:8][CH2:7][C@@H:6]([NH:9][CH:35]2[CH2:34][CH2:33][O:32][CH2:31][CH:30]2[O:29][CH3:28])[CH2:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)[C@]1(C(=O)N2CCN(c3cc(C(F)(F)F)ncn3)CC2)CC[C@@H](N)C1
Reactant: COC1COCCC1=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC1COCCC1N[C@@H]1CC[C@@](C(=O)N2CCN(c3cc(C(F)(F)F)ncn3)CC2)(C(C)C)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (1R,3S)-3-isopropyl-3-(4-[6-(trifluoromethyl)pyrimidin-4-yl]piperazin-1-ylcarbonyl)cyclopentanamine (120 mg, 0.30 mmol), 3-methoxytetrahydro-4H-pyran-4-one (120 mg, 0. 90 mmol), and triethylamine (0.12 mL, 0.90 mmol) in methylene chloride (20 mL) was added sodium triacetoxyborohydride (0.19 g, 0.90 mmol). After being stirred at room temperature overnight, the reaction mixture was diluted with methylene chloride, washed with brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography to provide the desired product as a mixture of four isomers. LCMS calculated for C24H37F3N5O3:(M+H) 500.3; found 500.3 for four isomers.
Reaction SMILES: [CH2:1]([NH:13][C:14]([C:16]1[CH:30]=[CH:29][C:19]([CH2:20][NH:21]C(=O)OC(C)(C)C)=[CH:18][CH:17]=1)=[O:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[ClH:31]>C(Cl)Cl>[ClH:31].[NH2:21][CH2:20][C:19]1[CH:18]=[CH:17][C:16]([C:14]([NH:13][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[O:15])=[CH:30][CH:29]=1
Reactant: CCCCCCCCCCCCNC(=O)c1ccc(CNC(=O)OC(C)(C)C)cc1
Agent: Cl
Solvent: ClCCl
Product: CCCCCCCCCCCCNC(=O)c1ccc(CN)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98 %

Procedure:
To a solution of tert-butyl 4-[(dodecylamino)carbonyl]benzylcarbamate (2.35 g) in DCM (30 mL) was added a HCl solution (4N in dioxane, 30 mL). The resulting mixture was stirred at rt for 1 h. Evaporation of the solvents gave 4-(aminomethyl)-N-dodecylbenzamide hydrochloride compound as a white powder (1.97 g, 98%). M+(LC/MS(ESI)): 319.4; M−(LC/MS(ESI)): 317.4. HPLC (Condition A), Rt: 4.20 min (HPLC purity: 100%). 1H NMR (DMSO-d6, 300 MHz) δ 8.52 (br s, 3H), 7.87 (d, J=7.5 Hz, 2H), 7.56 (d, J=7.5 Hz, 2H), 4.06 (br s, 2H), 3.25-3.30 (m, 2H), 1.45-1.55 (m, 2H), 1.30-1.56 (m, 18H), 0.84 (t, J=8.3 Hz, 3H).
Reaction SMILES: Cl[C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[F:11][C:12]1[CH:13]=[C:14]([CH:16]=[CH:17][C:18]=1[F:19])[NH2:15]>>[N:6]1[C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[NH:3][C:2]=1[NH:15][C:14]1[CH:16]=[CH:17][C:18]([F:19])=[C:12]([F:11])[CH:13]=1
Reactant: Clc1nc2ccccc2[nH]1
Reactant: Nc1ccc(F)c(F)c1
Product: Fc1ccc(Nc2nc3ccccc3[nH]2)cc1F

Procedure:
The title compound was prepared from 2-chlorobenzimidazole and 3,4-difluoroaniline by Procedure A. The product was isolated by filtration to give the title compound as a hydrochloride salt (white solid, mp 283-284° C.). MS(ES+) m/z 246 ([M+1]+, 100).
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[N:8]([C:18]3[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=3)[C:9]3[C:14]([C:15]=2[C:16]#[N:17])=[CH:13][CH:12]=[CH:11][CH:10]=3)=[C:5]([CH3:25])[O:4][N:3]=1.Cl.[NH2:27][OH:28].C(N(CC)CC)C>CCO.CO>[CH3:1][C:2]1[C:6]([C:7]2[N:8]([C:18]3[CH:19]=[CH:20][C:21]([OH:24])=[CH:22][CH:23]=3)[C:9]3[C:14]([C:15]=2/[C:16](=[N:27]/[OH:28])/[NH2:17])=[CH:13][CH:12]=[CH:11][CH:10]=3)=[C:5]([CH3:25])[O:4][N:3]=1
Reactant: Cc1noc(C)c1-c1c(C#N)c2ccccc2n1-c1ccc(O)cc1
Reactant: NO
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Solvent: CCO
Product: Cc1noc(C)c1-c1c(/C(N)=N/O)c2ccccc2n1-c1ccc(O)cc1
Temperature: 25 °C

Procedure:
Under nitrogen atmosphere, a solution of 2-(3,5-dimethyl-isoxazol-4-yl)-1-(4-hydroxy-phenyl)-1H-indole-3-carbonitrile (Example 51), 12 eq hydroxylamine hydrochloride and 12 eq triethylamine in EtOH was heated at 100° C. for 24 hours. The reaction mixture was cooled to rt, diluted with methanol, precipitation filtered off and subjected to reversed phase preparative HPLC. Appropriate fractions were combined and evaporated, and identified by 1H-NMR and LC/MS. Purity was determined by analytical HPLC. ES/MS m/z: 363.5 (M+H), 361.6 (M−H); 1H NMR (acetone-d6, 500 MHz): 8.14-8.13 (s, OH), 8.08-8.04 (m, 1H), 7.23-7.14 (m, 3H), 7.15-7.06 (m, 2H), 6.96-6.91 (m, 2H), 5.18-5.07 (m, 2H), 2.16 (s, 3H), 2.00 (s, 3H).
Reaction SMILES: N[C:2]1[S:3][C:4]([N+:7]([O-:9])=[O:8])=[CH:5][N:6]=1.N([O-])=O.[Na+].[BrH:14]>O.CCCCCO>[Br:14][C:2]1[S:3][C:4]([N+:7]([O-:9])=[O:8])=[CH:5][N:6]=1
Reactant: Br
Reactant: Nc1ncc([N+](=O)[O-])s1
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CCCCCO
Product: O=[N+]([O-])c1cnc(Br)s1
Temperature: -10 °C
Reaction time: 2 h
Yield: 60 %

Procedure:
To 72.5 g of 2-amino-5-nitrothiazole in 300 mL of 48% hydrobromic acid and 200 mL of water stirred and cooled to about -10° C. was slowly added, in portions, 51.8 g of sodium nitrite dissolved in 80 mL of water from one addition funnel and 250 mL of n-amyl alcohol from a second addition funnel. The addition of both solutions required about 3 hours. The cooling bath was removed and the mixture allowed to warm to about 15° C. overnight and then stirred at room temperature for 2 hours. The solid was collected by vacuum filtration and steam distilled to give 67 g of crude product. The crude product was recrystallized from hot ethanol to give 61 g (60% yield) of the 2-bromo-5-nitrothiazole as a yellow solid.
Reaction SMILES: [CH3:1][O:2][CH2:3]/[CH:4]=[CH:5]/[C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:16][CH2:15][C:14]3([CH2:21][CH2:20][N:19]([S:22]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[O:31][C:32]([F:35])([F:34])[F:33])(=[O:24])=[O:23])[CH2:18][CH2:17]3)[C:13]2=[O:36])=[CH:8][CH:7]=1>CO.[Pd]>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:7]=[CH:8][C:9]([N:12]2[CH2:16][CH2:15][C:14]3([CH2:21][CH2:20][N:19]([S:22]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[O:31][C:32]([F:33])([F:34])[F:35])(=[O:23])=[O:24])[CH2:18][CH2:17]3)[C:13]2=[O:36])=[CH:10][CH:11]=1
Reactant: COC/C=C/c1ccc(N2CCC3(CCN(S(=O)(=O)c4ccccc4OC(F)(F)F)CC3)C2=O)cc1
Agent: [Pd]
Solvent: CO
Product: COCCCc1ccc(N2CCC3(CCN(S(=O)(=O)c4ccccc4OC(F)(F)F)CC3)C2=O)cc1

Procedure:
2-[4-((E)-3-Methoxy-propenyl)-phenyl]-8-(2-trifluoromethoxy-benzenesulfonyl)-2,8-diaza-spiro[4.5]decan-1-one (0.07 g), product of example 144), in methanol (10 ml) was hydrogenated over Pd on charcoal (10%) at atmospheric pressure for 12 h. The catalyst was removed by filtration, the solvent evaporated off to give the desired material as white solid. MS (ESI): 527.18 (MH+).
Reaction SMILES: C([O:3][C:4]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]1[C:17]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)=[C:16]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=2)[N:15]=[CH:14]1)=[O:5])C.[OH-].[Na+]>>[C:4]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]1[C:17]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)=[C:16]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=2)[N:15]=[CH:14]1)([OH:5])=[O:3]
Reactant: CCOC(=O)CCCCCCCn1cnc(-c2ccc(OC)cc2)c1-c1ccc(OC)cc1
Agent: [Na+]
Agent: [OH-]
Product: COc1ccc(-c2ncn(CCCCCCCC(=O)O)c2-c2ccc(OC)cc2)cc1
Yield: 46 %

Procedure:
1-(7-Ethoxycarbonylheptyl)-4,5-bis(4-methoxyphenyl)-imidazole (0.58 g) was reacted with 2N sodium hydroxide in a method similar to Example 10. Recrystallisations from ethanol and water gave 1-(7-carboxyheptyl)-4,5-bis(4-methoxyphenyl)-imidazole (0.25 g, 46%) as a white solid, m.p. 142°-143°.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:22])=[C:4]([CH:19]=[CH:20][CH:21]=1)[O:5][CH2:6][C@@H:7]1[CH2:11][CH2:10][CH2:9][N:8]1[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13].C([O-])(=O)C.[K+].C(OC(=O)C)(=O)C.C(O[N:41]=O)CC(C)C>C1C=CC=CC=1>[NH:1]1[C:2]2[C:3](=[C:4]([O:5][CH2:6][C@@H:7]3[CH2:11][CH2:10][CH2:9][N:8]3[C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH:19]=[CH:20][CH:21]=2)[CH:22]=[N:41]1
Reactant: CC(C)CCON=O
Reactant: Cc1c(N)cccc1OC[C@@H]1CCCN1C(=O)OC(C)(C)C
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CC(=O)OC(C)=O
Solvent: c1ccccc1
Product: CC(C)(C)OC(=O)N1CCC[C@H]1COc1cccc2[nH]ncc12
Temperature: 25 °C

Procedure:
A solution of t-butyl (2S)-2-[(3-amino-2-methylphenoxy) methyl]pyrrolidine-1-carboxylate (5.00 g, 16.33 mmol), potassium acetate (1.92 g, 19.6 mmol) and acetic anhydride (4.9 mL, 52.3 mmol) in benzene is treated dropwise with isoamylnitrite (4.3 mL, 32.7 mmol), heated at reflux temperature overnight, cooled to room temperature and filtered. The filtercake is washed with benzene. The filtrates are combined and concentrated in vacuo to give a yellow oil residue. The residue is purified by chromatography (silica gel, EtOAc:hexanes, 15:85). The purified oil (5.05 g) is dissolved in ethanol, treated with 40% aqueous NaOH, heated at reflux temperature for 45 min, cooled in an ice-water bath, neutralized to pH 8 with concentrated HCl and concentrated in vacuo to remove the ethanol. The resultant aqueous residue is extracted with EtOAc. The combined extracts are washed sequentially with water and brine, dried over MgSO4 and concentrated in vacuo to give a yellow oil. This oil is purified by chromatography (silica gel, EtOAc:hexanes, 30:70) to give the title product as an off-white solid, 3.52 g, mp 125° C., identified by NMR and mass spectral analyses.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([S:10](Cl)(=[O:12])=[O:11])=[CH:7][C:6]=2[CH:14]=1.N1C=CC=CC=1.[NH2:21][C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=1)[C:25]([OH:27])=[O:26]>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([S:10]([NH:21][C:22]3[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=3)[C:25]([OH:27])=[O:26])(=[O:12])=[O:11])=[CH:7][C:6]=2[CH:14]=1
Reactant: Nc1cccc(C(=O)O)c1
Reactant: Cc1ccc2sc(S(=O)(=O)Cl)cc2c1
Solvent: c1ccncc1
Product: Cc1ccc2sc(S(=O)(=O)Nc3cccc(C(=O)O)c3)cc2c1
Yield: 66 %

Procedure:
The product was prepared according to General Procedure 6, described in Example 65, with 5-methylbenzothiophene-2-sulfonyl chloride (30.0 mg, 0.12 mmol), pyridine (49 μL, 0.61 mmol) and 3-aminobenzoic acid (16.7 mg, 0.10 mmol). The title compound was obtained in 66% yield (23 mg). MS (ESI+) calcd mass for C16H13NO4S2 347.028599, found 347.029559.