Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2([OH:14])[CH2:13][CH2:12][NH:11][CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1.[C:15](#N)[CH3:16].C(=O)([O-])[O-].[K+].[K+].ICC>O>[F:1][C:2]1[CH:3]=[C:4]([C:9]2([OH:14])[CH2:13][CH2:12][N:11]([CH2:15][CH3:16])[CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: CC#N
Reactant: OC1(c2cc(F)cc(F)c2)CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCI
Product: CCN1CCC(O)(c2cc(F)cc(F)c2)C1
Temperature: 100 °C

Procedure:
In a sealed tube a mixture of enantiomer E1 of 3-(3,5-difluorophenyl)pyrrolidin-3-ol (0.14 g, 0.70 mmol), acetonitrile (4 mL), potassium carbonate (0.09 g, 1.75 mmol) and iodoethane (0.12 g, 0.77 mmol) was heated under microwave irradiation at 100° C. for 5 minutes. Water (30 mL) was added and the aqueous phase extracted with ethyl acetate (2×50 mL), the combined organic phase was dried (MgSO4) and evaporated. Purification by flash chromatography on silica gel (ethyl acetate/methanol, 2:1 to 1:1) gave the title compound (0.11 g). [α]D=+18.7° (methanol). The amine was converted to the oxalic acid salt and recrystallized from ethanol/diisopropyl ether: M.p. 137-139° C.; MS m/z (relative intensity, 70 eV) 227 (M+, 19), 212 (15), 141 (15), 127 (15), 71 (bp).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH2:9][CH:10]2[C:13]([OH:15])=O)=[CH:5][CH:4]=1.[CH:16]([C:19]1[CH:24]=[CH:23][C:22]([NH:25][CH2:26][C:27]2[CH:28]=[N:29][C:30]([O:33][CH3:34])=[CH:31][CH:32]=2)=[CH:21][CH:20]=1)([CH3:18])[CH3:17]>>[CH:16]([C:19]1[CH:20]=[CH:21][C:22]([N:25]([CH2:26][C:27]2[CH:28]=[N:29][C:30]([O:33][CH3:34])=[CH:31][CH:32]=2)[C:13]([CH:10]2[C:11]3[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:12]=3)[CH2:7][CH2:8][CH2:9]2)=[O:15])=[CH:23][CH:24]=1)([CH3:18])[CH3:17]
Reactant: COc1ccc2c(c1)C(C(=O)O)CCC2
Reactant: COc1ccc(CNc2ccc(C(C)C)cc2)cn1
Product: COc1ccc2c(c1)C(C(=O)N(Cc1ccc(OC)nc1)c1ccc(C(C)C)cc1)CCC2

Procedure:
By the reaction and treatment in the same manner as in Example 12 using 7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (0.50 g) and (4-isopropylphenyl)[(6-methoxypyridin-3-yl)methyl]amine (0.62 g) as starting materials, N-(4-isopropylphenyl)-N-[(6-methoxypyridin-3-yl)methyl]-7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide was obtained. This was dissolved in ether, and 4N-hydrochloric acid/dioxane was added. The precipitated solid was collected by filtration to give N-(4-isopropylphenyl)-N-[(6-methoxypyridin-3-yl)methyl]-7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide monohydrochloride (0.47 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][N:9]1[C:13]([CH2:14][C:15]([CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)(C(OCC)=O)[C:16]([O:18]CC)=[O:17])=[CH:12][N:11]=[C:10]1[S:33][CH2:34][CH2:35][CH3:36].[OH-].[K+].O>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][N:9]1[C:13]([CH2:14][CH:15]([CH2:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:16]([OH:18])=[O:17])=[CH:12][N:11]=[C:10]1[S:33][CH2:34][CH2:35][CH3:36]
Reactant: CCCSc1ncc(CC(Cc2ccccc2)(C(=O)OCC)C(=O)OCC)n1Cc1ccccc1Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCSc1ncc(CC(Cc2ccccc2)C(=O)O)n1Cc1ccccc1Cl
Yield: 87.4 %

Procedure:
A mixture of diethyl [1-{(2-chlorophenyl)methyl}-2-propylthio-1H-imidazol-5-yl]methyl-2-benzyl-malonate (0.72 g, 1.36 mmol), potassium hydroxide (0.83 g, 14.7 mmol), water (15 mL) and ethanol (25 mL) was refluxed for 4 hours. The ethanol was evaporated, the residual aqueous layer was extracted with diethyl ether, and the basic solution was adjusted to pH 3.75 with concentrated hydrochloric acid. The precipitated product was extracted into methylene chloride, dried, and concentrated. This crude product was flash chromatographed on silica gel with 10% methanol in methylene chloride to give 0.51 g (86%) of 3-[1-{(2-chlorophenyl)methyl}-2-propylthio-1H-imidazol-5-yl]-2-benzylpropanoic acid; mp 123°-127° C.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:32])[C@H:10](NC(OC(C)(C)C)=O)[CH2:11][C:12]([NH:14][C@H:15]([C:20](=[O:23])[NH:21][CH3:22])[C:16]([CH3:19])([CH3:18])[CH3:17])=[O:13])[C:2]1[CH:7]=CC=CC=1.C(OC(=O)[C@@H](CC([O-])=O)[NH:39][C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])(=C)C.CNC(=O)[C@H](C(C)(C)C)N.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>>[CH2:1]([O:8][C:9](=[O:32])[CH2:10][C@@H:11]([NH:39][C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[C:12]([NH:14][C@H:15]([C:20](=[O:23])[NH:21][CH3:22])[C:16]([CH3:17])([CH3:18])[CH3:19])=[O:13])[CH:2]=[CH2:7]
Reactant: C=C(C)OC(=O)[C@@H](CC(=O)[O-])NC(=O)OC(C)(C)C
Reactant: CNC(=O)[C@@H](NC(=O)C[C@@H](NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1)C(C)(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CNC(=O)[C@@H](N)C(C)(C)C
Agent: F[B-](F)(F)F
Product: C=CCOC(=O)C[C@@H](NC(=O)OC(C)(C)C)C(=O)N[C@H](C(=O)NC)C(C)(C)C
Yield: 84 %

Procedure:
According to Example 1(b) for 3 (R)-t-butyloxycarbonylamino-N-(2,2-dimethyl-1(S)-(methylcarbamoyl)propyl)succinamic acid benzyl ester, β-allyl-N-t-butoxycarbonyl-D-aspartate (Belshaw, P.; Mzengeza, S.; Lajoie, G. Syn Commun 1990, 20, 3157-3160; 2.00 g, 7.32 mmol) and L-t-leucine N-methylarnide (Malon, P.; Pancoska, P.; Budesinsky, M.; Hlavacek, J.; Pospisek, J.; Blaha, K. Coll. Czech. Chem Commun. 1983, 48, 2844-2861; 1.05 g, 7.32 mmol) were coupled with TBTU. The resultant yellow oil was routinely used without further purification. Flash column chromatography with 2% MeOH/CH2Cl2 provided 2.44 g (84%) of 3(R)-(t-butoxycarbonylamino)-N-(2,2-dimethyl-1(S)-(methylcarbamoyl)propyl)succinamic acid allyl ester as a pale yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C@H:4]([CH2:6][NH:7][C:8](=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[NH2:5].[Cl:17][C:18]1[CH:26]=[C:25]([C:27]([NH:29][CH2:30][C:31]2[CH:39]=[CH:38][CH:37]=[C:36]3[C:32]=2[CH:33]=[CH:34][NH:35]3)=[O:28])[CH:24]=[CH:23][C:19]=1[C:20](O)=[O:21].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>CN(C=O)C.O>[CH3:1][O:2][C:3](=[O:16])[C@H:4]([CH2:6][NH:7][C:8](=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[NH:5][C:20](=[O:21])[C:19]1[CH:23]=[CH:24][C:25]([C:27]([NH:29][CH2:30][C:31]2[CH:39]=[CH:38][CH:37]=[C:36]3[C:32]=2[CH:33]=[CH:34][NH:35]3)=[O:28])=[CH:26][C:18]=1[Cl:17]
Reactant: O=C(NCc1cccc2[nH]ccc12)c1ccc(C(=O)O)c(Cl)c1
Reactant: COC(=O)[C@@H](N)CNC(=O)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)[C@H](CNC(=O)c1ccccc1)NC(=O)c1ccc(C(=O)NCc2cccc3[nH]ccc23)cc1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 47.2 %

Procedure:
3-(Benzoylamino)-L-alanine methyl ester (Example 299; 77 mg, 0.35 mmol) was mixed with 2-chloro-4-[[(1H-indol-4-yl-methyl)amino]carbonyl]benzoic acid (Example 36; 115 mg, 0.35 mmol), HOBT (57 mg, 0.42 mmol) and EDCl (80.5 mg, 0.42 mmol) in DMF (4 mL). The reaction mixture was stirred at room temperature for 16 h and then diluted with water (about 20 ml). The solution was extracted with ethyl acetate (3×10 ml) and the ethyl acetate layer was washed with dilute aqueous NaCl solution and then brine, dried (Na2SO4), concentrated, and chromatographed (40-80% ethyl acetate/hexanes) to give 3-(benzoylamino)-N-[2-chloro-4-[[(1H-indol-4-ylmethyl)amino]carbonyl]benzoyl]-L-alanine methyl ester (88 mg, 47%). A solution of the ester (51 mg, 0.096 mmol) and lithium hydroxide monohydrate (8 mg, 0.19 mmol) in tetrahydrofuran/methanol/water (3:1:1; 2 mL) was stirred at room temperature for 3 h. The solvent was removed and the product was purified by HPLC to give 3-(benzoylamino)-N-[2-chloro-4-[[(1H-indol-4-ylmethyl)amino]carbonyl]benzoyl]-L-alanine (37 mg, 75%) as a white fluffy powder.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][CH:3]=1.[F:11][C:12]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[C:13]=1[CH2:14]Br>CN(C=O)C>[F:11][C:12]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[C:13]=1[CH2:14][O:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][CH:3]=1
Reactant: N#CCc1ccc(O)cc1
Reactant: Fc1cccc(F)c1CBr
Solvent: CN(C)C=O
Product: N#CCc1ccc(OCc2c(F)cccc2F)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 2-(4-Hydroxyphenyl)acetonitrile (5 g, 37.5 mmol) and K7CO3 (6.74 g, 48.8 mmol) in dry DMF (20 ml) was added 2,6-Difluorobenzyl bromide (7.77 g, 37.5 mmol). The reaction mixture was stirred for 4 hours at room temperature and concentrated in vacuo. The crude residue was taken in EtOAc and washed with water and brine. The aqueous layer was washed one more time with EtOAc. The combined organic layer was dried over Na2SO4, filtered, and concentrated to provide the title compound as a white solid.
Reaction SMILES: N1C(C)=CC=CC=1C.S(Cl)([Cl:11])=O.O[CH:14]([N:28]1[CH:31]([S:32][CH3:33])[CH2:30][C:29]1=[O:34])[C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=1)=[O:16]>O1CCCC1.C(OCC)(=O)C>[Cl:11][CH:14]([N:28]1[CH:31]([S:32][CH3:33])[CH2:30][C:29]1=[O:34])[C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=1)=[O:16]
Reactant: CSC1CC(=O)N1C(O)C(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: O=S(Cl)Cl
Solvent: Cc1cccc(C)n1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CSC1CC(=O)N1C(Cl)C(=O)OCc1ccc([N+](=O)[O-])cc1
Temperature: -20 °C

Procedure:
2,6-Lutidine (626 mg) and thionyl chloride (695 mg) were successively added dropwise to a solution of p-nitrobenzyl 2-hydroxy-2-(4-methylthio-2-azetidinon-1-yl)acetate (1.59 g) in tetrahydrofuran (30 ml), whilst stirring at -20° C. The reaction mixture was stirred at -20° to -15° C. for 30 minutes, diluted with ethyl acetate, washed with water (once), neutralized with a dilute aqueous solution of sodium bicarbonate solution and further washed with water.
Reaction SMILES: Cl[Si:2]([CH3:22])([CH3:21])[CH:3]1[C:14]2[C:6](=[CH:7][C:8]3[CH2:9][CH2:10][CH2:11][C:12]=3[CH:13]=2)[C:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:4]1.CCN(CC)CC.[CH:30]1([NH2:36])[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1>CCCCCC>[CH:30]1([NH:36][Si:2]([CH3:22])([CH3:21])[CH:3]2[C:14]3[C:6](=[CH:7][C:8]4[CH2:9][CH2:10][CH2:11][C:12]=4[CH:13]=3)[C:5]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:4]2)[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1
Reactant: NC1CCCCC1
Reactant: C[Si](C)(Cl)C1C=C(c2ccccc2)c2cc3c(cc21)CCC3
Solvent: CCCCCC
Solvent: CCN(CC)CC
Product: C[Si](C)(NC1CCCCC1)C1C=C(c2ccccc2)c2cc3c(cc21)CCC3
Reaction time: 24 h
Yield: 94.5 %

Procedure:
Chlorodimethyl(1,5,6,7-tetrahydro-3-phenyl-s-indacen-1-yl) silane (3.8523 g, 0.01182 moles) was stirred in hexane (100 mL) as NEt3 (1.5136 g, 0.01496 moles) and cyclohexylamine (1.2107 g, 0.01221 moles) were added. This mixture was allowed to stir for 24 hours. After the reaction period the mixture was filtered and the volatiles removed resulting in the isolation of the desired product as a yellow oil (4.3313 g, 94.5 percent).
Reaction SMILES: N12CCN(CC1)CC2.[CH2:9]([N:11]([CH2:19][CH3:20])[C:12]1[S:16][C:15]([CH:17]=O)=[CH:14][CH:13]=1)[CH3:10].[CH2:21]([O:23][C:24]([C:26]1[C:30]([C:31]([O:33][CH2:34][CH3:35])=[O:32])=[C:29]([NH2:36])[S:28][C:27]=1[NH2:37])=[O:25])[CH3:22]>C1(C)C=CC=CC=1.[Ti](Cl)(Cl)(Cl)Cl>[CH2:21]([O:23][C:24]([C:26]1[C:30]([C:31]([O:33][CH2:34][CH3:35])=[O:32])=[C:29]([N:36]=[CH:17][C:15]2[S:16][C:12]([N:11]([CH2:19][CH3:20])[CH2:9][CH3:10])=[CH:13][CH:14]=2)[S:28][C:27]=1[NH2:37])=[O:25])[CH3:22]
Reactant: CCOC(=O)c1c(N)sc(N)c1C(=O)OCC
Reactant: CCN(CC)c1ccc(C=O)s1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: C1CN2CCN1CC2
Solvent: Cc1ccccc1
Product: CCOC(=O)c1c(N)sc(N=Cc2ccc(N(CC)CC)s2)c1C(=O)OCC
Yield: 67 %

Procedure:
In a 50 mL round bottom flask, 67 mg of 2,5-diamino-thiophene-3,4-dicarboxylic acid diethyl ester was dissolved in 20 mL of anhydrous toluene to which was subsequently added 1,4-diazabicyclo[2.2.2]octane (DABCO, 32 mg), 286 μL of titanium(IV) chloride, 1.0M solution in toluene at 0° C. and 5-diethylamino-thiophene-2-carbaldehyde (52 mg). The mixture was refluxed for two hours and the solvent removed. Purification by flash chromatography (SiO2) yielded the title product as a yellow-orange solid (67%). 1H-NMR (300 MHz, [D] acetone): δ=7.96 (s, 1H), 7.23 (s, 2H), 7.21 (d, 1H, 3J=4.4 Hz), 5.93 (d, 1H, 3J=4.2 Hz), 4.27 (q, 2H, 3J=7.2 Hz), 4.17 (q, 2H, 3J=7.1 Hz), 3.43 (q, 4H, 3J=7.1 Hz), 1.35 (t, 3H, 3J=7.1 Hz), 1.24 (t, 3H, 3J=7.1 Hz), 1.21 (t, 3H, 3J=7.1 Hz). 13C-NMR (300 MHz, [D] acetone): δ=164.5, 162.3, 159.3, 146.9, 135.7, 125.5, 124.5, 102.2, 101.7, 60.7, 59.7, 47.3, 14.2, 14.1, 12.0.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[CH:3][C:2]=1[NH:11][C:12]1[O:13][C@:14]2([CH2:22][N:23]=1)[CH:19]1[CH2:20][CH2:21][N:16]([CH2:17][CH2:18]1)[CH2:15]2.ClC1C=C(C=CC=1)C(OO)=[O:29]>C1COCC1>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[CH:3][C:2]=1[NH:11][C:12]1[O:13][C@:14]2([CH2:22][N:23]=1)[CH:19]1[CH2:18][CH2:17][N+:16]([O-:29])([CH2:21][CH2:20]1)[CH2:15]2
Reactant: c1ccc2nc(NC3=NC[C@@]4(CN5CCC4CC5)O3)cnc2c1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: C1CCOC1
Product: [O-][N+]12CCC(CC1)[C@]1(CN=C(Nc3cnc4ccccc4n3)O1)C2
Yield: 96.1 %

Procedure:
A solution of (R)—N-(quinoxalin-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine (190 mg, 0.614 mmol) and 3-chlorobenzoperoxoic acid (165 mg, 0.737 mmol) in 4 mL THF was stirred at room temperature for 2 h. The reaction was concentrated and the crude product was purified by flash chromatography on a 40 g silica gel cartridge with 1 to 30% [9:1 MeOH/NH4OH] in EtOAc. Pure fractions were pooled, concentrated, redissolved in CHCl3, and filtered through a 0.45 u filter to yield (S)-2-(quinoxalin-2-ylamino)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octane]1′-oxide (192 mg, 96% yield). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 9.89 (1H, br. s.), 8.58 (1H, s), 7.93 (1H, dd, J=8.31, 1.26 Hz), 7.70 (1H, dd, J=8.31, 1.01 Hz), 7.60 (1H, ddd, J=8.25, 6.99, 1.38 Hz), 7.50 (1H, ddd, J=8.25, 6.99, 1.38 Hz), 4.01 (1H, d, J=10.07 Hz), 3.84 (1H, d, J=9.82 Hz), 3.78-3.83 (1H, m), 3.64 (1H, dd, J=14.35, 2.27 Hz), 3.26-3.58 (4H, m), 2.50-2.65 (1H, m), 2.27 (1H, br. s.), 2.06-2.19 (1H, m, J=14.26, 10.42, 4.15, 4.15 Hz), 1.88-2.03 (2H, m). LCMS: RT=0.72 min, MH+=326.1 [ Waters Acquity SDS: 2 to 98% B, 1 min gradient; hold 98% B, 0.5 min; flow rate 0.8 mL/min; Solvent A: 100% H2O/0.05% TFA; Solvent B: 100% ACN/0.05% TFA]. LCMS: RT=1.15 min, MH-=324.2, MH+=326.2 [ Phenomenex LUNA C18 3 m (2.0×30 mm); 0 to 100% B, 2 min gradient; flow rate 1 mL/min; Solvent A: 5% MeOH: 95% water: 10 mM NH4OAc; Solvent B: 95% MeOH: 5% water: 10 mM NH4OAc; 220 nM].
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[CH:11]=[C:10]([C:15]([O:17]C)=[O:16])[CH:9]=[CH:8]2)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>CO>[C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[CH:11]=[C:10]([C:15]([OH:17])=[O:16])[CH:9]=[CH:8]2)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1ccc2cc(C(C)(C)C)ccc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)c1ccc2cc(C(=O)O)ccc2c1
Temperature: 60 °C
Yield: 77.3 %

Procedure:
A mixture of methyl 6-tert-butyl-2-naphthoate (843 mg, 3.48 mmol) and 2M sodium hydroxide solution (6.96 mmol, 3.48 mmol) in MeOH (30 ml) was heated at 60° C. for 3 hours. After cooling to ambient temperature, the solvent was evaporated in vacuo and the residue was acidified to pH 2 with 2M hydrochloric aqueous solution. The aqueous layer was extracted with EtOAc and the combined solution was washed with brine, dried over sodium sulfate and evaporated in vacuo to give the crude product which was recrystallized from EtOAc and hexane to furnish the title compound as a white solid (614 mg, 77%). 1H NMR (DMSO-d6): δ ppm 1.39 (9H, s), 7.70-7.76 (1H, m), 7.90-8.08 (4H, m), 8.55 (1H, br.s), 13.00 (1H, br.s).
Reaction SMILES: [Br:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.C([O-])([O-])=O.[Na+].[Na+].[I:15]I>O>[Br:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[C:4]([I:15])[N:3]=1
Reactant: Oc1cccnc1Br
Reactant: II
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: Oc1ccc(I)nc1Br
Reaction time: 1 h

Procedure:
To a solution of 2-bromopyridin-3-ol (1.00 g, 5.80 mmol) in water (30 mL) was added Na2CO3 (1.23 g, 11.60 mmol) and I2 (1.53 g, 5.80 mmol). After 1 hour, the reaction was quenched with 1 N HCl (20 mL), extracted with EtOAc (2×100 mL), and washed with aq. NaHSO3 and brine (50 mL each). The organic layer was dried over Na2SO4, filtered and concentrated. Purification of the residue by flash chromatography on silica gel (20 to 40% EtOAc/hexanes) afforded 2-bromo-6-iodopyridin-3-ol. Rf=0.44 (25% EtOAc/hexanes). LCMS=301.9 (M+1)+. 1H NMR (CDCl3, 500 MHz) δ 7.56 (d, J=8.3 Hz, 1H), 6.99 (d, J=8.3 Hz, 1H), 5.65 (s, 1H).
Reaction SMILES: [CH2:1]([NH:9][C:10](=[O:31])[CH:11]([NH:23][C:24](=[O:30])[C@H:25](Br)[CH:26]([CH3:28])[CH3:27])[C:12]([NH:14][CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:13])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:32](O)(=[S:34])[CH3:33].CN(C)C=O.C(=O)([O-])[O-].[Cs+].[Cs+]>O.C(OC(=O)C)C.CCCCCC>[CH2:1]([NH:9][C:10](=[O:31])[CH:11]([NH:23][C:24](=[O:30])[C@@H:25]([C:32](=[S:34])[CH3:33])[CH:26]([CH3:28])[CH3:27])[C:12]([NH:14][CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:13])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CC(C)[C@@H](Br)C(=O)NC(C(=O)NCCc1ccccc1)C(=O)NCCc1ccccc1
Reactant: CC(O)=S
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: CC(=S)[C@H](C(=O)NC(C(=O)NCCc1ccccc1)C(=O)NCCc1ccccc1)C(C)C
Reaction time: 18 h

Procedure:
Combine N,N′-diphenethyl-2-((R)-2-bromo-3-methylbutyrylamino)malonamide (0.20 g, 0.41 mmol), thioacetic acid (0.08 mL, 1.1 mmol), and dimethylformamide (8 mL). Degas by repeated cycles of vacuum and filling with nitrogen gas. Add cesium carbonate (0.215 g, 0.664 mmol). After 18 hours, dilute with water and extract with ethyl acetate. Extract the organic layer with brine, dry over Na2SO4, filter, and evaporate in vacuo to give a residue. Chromatograph the residue on silica gel eluting with 1/1 hexane ethyl acetate to give the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=O)[CH2:5][N:6]([CH3:8])[CH3:7])[CH3:2].Br[C:11]1[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=1>>[CH3:7][N:6]([CH2:5][CH:4]1[CH2:14][CH:15]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)[C:16]2[C:1](=[CH:2][CH:13]=[CH:12][CH:11]=2)[O:3]1)[CH3:8]
Reactant: FC(F)(F)c1ccc(Br)cc1
Reactant: CCOC(=O)CN(C)C
Product: CN(C)CC1CC(c2ccc(C(F)(F)F)cc2)c2ccccc2O1

Procedure:
The process of example 4 was repeated using N,N-dimethylglycine ethyl ester in place of N,N-dimethylalanine ethyl ester in part (a), and using 4-bromobenzotrifluoride in place of 4-bromochlorobenzene in part (c) to yield the title compound.
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:8]([NH2:9])=[CH:7][C:6]([S:10][C:11]([F:14])([F:13])[F:12])=[CH:5][N:4]=1.[CH:15](O)=O>O>[CH3:1][N:2]1[C:3]2=[N:4][CH:5]=[C:6]([S:10][C:11]([F:12])([F:14])[F:13])[CH:7]=[C:8]2[N:9]=[CH:15]1
Reactant: CNc1ncc(SC(F)(F)F)cc1N
Reactant: O=CO
Solvent: O
Product: Cn1cnc2cc(SC(F)(F)F)cnc21

Procedure:
A mixture of 10.0 g of N2-methyl-5-trifluoromethylsulfanylpyridine-2,3-diamine, 41 ml of formic acid and 5 ml of water was stirred under heating and refluxing for 2 hours. The reaction mixture was concentrated under reduced pressure, a saturated aqueous sodium bicarbonate solution was added to the resulting residue, and the mixture was extracted with methyl-tert-butyl ether. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was applied to a silica gel column chromatography to obtain 7.80 g of 3-methyl-6-trifluoromethylsulfanyl-3H-imidazo[4,5-b]pyridine.
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C:7](=[CH:8][C:9](=[N:28][OH:29])[C@@H:10]3[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[O:24][C:25](=[O:27])[CH3:26])[CH2:6]1)(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:37][CH2:38][CH2:39][Cl:40].O>CC(CC)=O>[C:1]([O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C:7](=[CH:8][C:9](=[N:28][O:29][CH2:37][CH2:38][CH2:39][Cl:40])[C@@H:10]3[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[O:24][C:25](=[O:27])[CH3:26])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@H]1CC[C@@]2(C)C(=CC(=NO)[C@H]3[C@@H]4CC[C@H](OC(C)=O)[C@@]4(C)CC[C@@H]32)C1
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCC(C)=O
Product: CC(=O)O[C@H]1CC[C@@]2(C)C(=CC(=NOCCCCl)[C@H]3[C@@H]4CC[C@H](OC(C)=O)[C@@]4(C)CC[C@@H]32)C1
Reaction time: 8 h
Yield: 58.8 %

Procedure:
A mixture of 7-oximino-5-androstene-3β,17β-diol diacetate (1 g, 2.48 mmol) and anhydrous potassium carbonate (2 g) was stirred and refluxed in ethyl methyl ketone (100 Ml) at 110° C. for 3 h. 1-Bromo-3-chloropropane (0.25 Ml, 2.48 mmol) was added to the reaction mixture and further refluxed for 20 h with continuous stirring. The completion of the reaction was monitored by TLC. The slurry was cooled, filtered and excess of solvent was removed under reduced pressure to obtain an oily residue. Iced water was added to the oily residue and it was allowed to stand overnight. The precipitate obtained was filtered, washed with water, dried and crystallized from pet-ether (60-80° C.) to afford 7-[O-(3-chloropropyl)oximino]-5-androstene-3β,17β-diol diacetate (23) (0.7 g, 58.82%), mp 155° C. (Decomp).
Reaction SMILES: C(N([C@H:10]([CH3:19])[C@H:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[OH:12])CCCC)CCC.C(=O)CCCCCCCC.C([Zn]CC)C.C[Si](C)(C)Cl.N1CCNCC1.Cl>CCCCCC>[CH3:19][CH2:10][C@H:11]([OH:12])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCN(CCCC)[C@H](C)[C@@H](O)c1ccccc1
Agent: C1CNCCN1
Agent: CCCCCCCCC=O
Agent: CC[Zn]CC
Solvent: CCCCCC
Product: CCCCCC[C@@H](O)CC
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
At room temperature, a three-neck flask equipped with a reflux condenser, internal thermometer, dropping funnel and stirrer under protective nitrogen gas was initially charged with 0.16 g of (1S,2R)-(−)-2-(N,N-di-n-butylamino)-1-phenylpropan-1-ol (0.6 mmol) in 18 ml of hexane and 1.4 g of nonanal (10 mmol) were added. The mixture was stirred for 15 min and cooled to 0° C. 12 ml of a 1 M solution of diethylzinc in hexane (12 mmol) were added to this mixture, and the mixture was stirred at 0° C. for 14 h. 1.6 g of trimethylchlorosilane (15 mmol) were then added, and the mixture was heated to 40° C. for 30 min. 1.3 g of piperazine (15 mmol) were then added and the mixture was stirred for 60 min. At −10° C., 2.3 ml of 6 N hydrochloric acid were subsequently added and the mixture was stirred at 15° C. for 30 min. After water together with hexane had been distilled off, 40 ml of pentane were added, the suspension was cooled to −20° C. and solid formed was filtered off. The solid was washed three times with 10 ml of cold pentane. Pentane was distilled off under reduced pressure (recovery of pentane) and the desired product (S)-(+)-3-nonanol was obtained in a yield of 1.6 g (89% of theory) and a purity of >95% and 87% ee (HPLC). The zinc content of the product was 30 ppm (ICP).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]([CH3:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[CH2:11](O)[CH2:12][OH:13].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2([CH3:10])[O:13][CH2:12][CH2:11][O:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: OCCO
Reactant: CC(=O)c1cccc(Br)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: CC1(c2cccc(Br)c2)OCCO1

Procedure:
30.1 g (151 mmol) of (3-bromophenyl)methyl ketone and 13.8 g (222 mmol) of ethylene glycol are dissolved in 120 mL of benzene, mixed with 60 mg of 4-toluenesulphonic acid and boiled under reflux at a water separator (Dean-Stark apparatus) until no more water is separated off. The reaction solution is washed with 50 mL of a 0.5 M NaHCO3 solution, the organic phase is separated off and dried over anhydrous MgSO4. After removal of the benzene in a rotary evaporator, the residue becomes the product with a purity (GC) of 97% in nearly quantitative yield as colorless oily liquid. C10H11O2Br.