Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCN=C=NCCCN(C)C.[F:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[N:18]([CH3:22])[C:17]([C:23]([OH:25])=O)=[CH:16]2.[NH2:26][C@H:27]([C:31]([NH:33][CH:34]([CH:43]([OH:46])[CH2:44][F:45])[CH2:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])=[O:32])[CH:28]([CH3:30])[CH3:29]>CN(C1C=CN=CC=1)C.CN(C=O)C>[F:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[N:18]([CH3:22])[C:17]([C:23]([NH:26][C@H:27]([C:31]([NH:33][CH:34]([CH:43]([OH:46])[CH2:44][F:45])[CH2:35][C:36]([O:38][C:39]([CH3:40])([CH3:41])[CH3:42])=[O:37])=[O:32])[CH:28]([CH3:29])[CH3:30])=[O:25])=[CH:16]2
Reactant: CC(C)[C@H](N)C(=O)NC(CC(=O)OC(C)(C)C)C(O)CF
Reactant: Cn1c(C(=O)O)cc2cc(F)ccc21
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Product: CC(C)[C@H](NC(=O)c1cc2cc(F)ccc2n1C)C(=O)NC(CC(=O)OC(C)(C)C)C(O)CF
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
DMAP (257 mg, 2.08 mmol) and EDAC (427 mg, 2.23 mmol) were added as solids to a solution of 5-fluoro-1-methylindole-2-carboxylic acid (359 mg, 86 mmol in 3 mL of DMF), and the resultant reaction mixture was stirred for 10 minutes under a nitrogen atmosphere at 0° C. N-(Valinyl)-3-amino-4-hydroxy-5-fluoropentanoic acid, t-butyl ester (579 mg, 1.86 mmol) in DMF (3 mL) was added and the resulting solution was stirred for 1 hour under a nitrogen atmosphere at 0° C. and 4 hours at room temperature. The reaction mixture was partitioned between ethyl acetate and 5% KHSO4 solution and the aqueous solution was back-extracted with ethyl acetate. The combined ethyl acetate solutions were washed with 5% KHSO4 solution, saturated sodium bicarbonate solution (2×) and brine, dried over sodium sulfate, and concentrated to give the title product as a slightly yellow solid (0.827 mg). TLC: (methanol/methylene chloride, 1:9): Rf =0.52.
Reaction SMILES: [C:1]1([CH:7]2[NH:12][CH2:11][CH2:10][N:9]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[Cl:26])=[CH:16][CH:15]=3)[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O[BH-](O[C:37](=O)[CH3:38])OC(=O)C)(=O)C.[Na+].[C:41](O)(=O)C>ClC(Cl)C.CC(C)=O.ClCCl>[CH:37]([N:12]1[CH2:11][CH2:10][N:9]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[Cl:26])=[CH:16][CH:15]=2)[CH2:8][CH:7]1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)([CH3:38])[CH3:41]
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: Clc1ccccc1-c1ccc(CN2CCNC(c3ccccc3)C2)cc1
Reactant: CC(=O)O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CC(Cl)Cl
Solvent: ClCCl
Product: CC(C)N1CCN(Cc2ccc(-c3ccccc3Cl)cc2)CC1c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
This compound could be made the following manner: 100 mg of 3-phenyl-1-(2′-chloro-biphenyl-4-ylmethyl)-piperazine would be dissolved in a 2:1 mixture of dichloroethane and acetone, 2 equiv. of sodium triacetoxyborohydride would be added followed by 30 μL of acetic acid. The reaction would be stirred at room temperature under nitrogen overnight. The reaction would be diluted with 5 mL of dichloromethane. The reaction mixture would be washed with 1M aqueous sodium hydroxide solution and brine, then dried over sodium sulfate, filtered and concentrated in vacuo. The crude residue would be purified by column chromatography to afford the title compound.
Reaction SMILES: [N:1]1[C:10]2[CH:9]=[C:8]3[CH:11]=[N:12][CH:13]=[C:7]3[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.N[CH2:15][C:16]([O-])=[O:17].[K+].C(OC(=O)C)(=O)C>>[C:16]([C:2]1[CH:3]=[CH:4][C:5]2[CH2:6][C:7]3=[CH:13][N:12]=[CH:11][C:8]3=[CH:9][C:10]=2[N:1]=1)(=[O:17])[CH3:15]
Reactant: C1=NC=C2Cc3cccnc3C=C12
Reactant: NCC(=O)[O-]
Agent: [K+]
Solvent: CC(=O)OC(C)=O
Product: CC(=O)c1ccc2c(n1)C=C1C=NC=C1C2

Procedure:
The pyrrolo[3,4-g]quinoline derivatives of formula (1) and (2) are prepared by reacting a 7-dimethylaminomethylene-6-oxo-trans-quinoline derivative of formula (7a) or (7b) with potassium glycinate, followed by treatment of the thus formed intermediate product with acetic anhydride. This yields a 2-acetylpyrrolo[3,4-g]quinoline compound. The acetyl group is removed by basic hydrolysis, for example using sodium ethoxide in ethanol. Preparation of the pyrrolo3,4-g]-quinolines of formula (1) is illustrated in Reaction Scheme III: ##STR17## The pyrrolo[3,4-g]quinolines of formula (2) are prepared using the same procedure and starting materials of formula (7b).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:4][N:3]=1.Cl[O:17]OC1C=C(C=CC=1)C(O)=O.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[O:9]([CH2:8][C:5]1[CH:6]=[CH:7][C:2]([CH2:1][OH:17])=[N:3][CH:4]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C(O)c1cccc(OOCl)c1
Reactant: Cc1ccc(COc2ccccc2)cn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: OCc1ccc(COc2ccccc2)cn1
Temperature: 25 °C
Reaction time: 7 h
Yield: 48 %

Procedure:
To a solution of 2-methyl-5-phenoxymethyl-pyridine described in Preparation Example 186 (323 mg, 1.62 mmol) in methylene chloride was added 3-chloroperoxylbenzoic acid (473 mg, 1.78 mmol, 65%) at 0° C., and the solution was stirred at room temperature for 7 hours. An aqueous solution of saturated sodium bicarbonate was added to the reaction solution at 0° C., which was then partitioned with ethyl acetate. The organic layer was separated, washed with an aqueous solution of saturated sodium bicarbonate and brine, and then, dried over anhydrous magnesium sulfate. The organic layer was filtered, then, the solvent was evaporated in vacuo. Acetic anhydride (4 mL) was added to this residue, which was then stirred for 30 minutes at 120° C. This reaction solution was cooled to room temperature, then, the solvent was evaporated in vacuo. Ethanol (5 mL), and an aqueous solution of 5N sodium hydroxide (2 mL) were added to this residue, and the solution was stirred at room temperature for 45 minutes. This reaction solution was concentrated in vacuo, the residue was partitioned in water and ethyl acetate. The organic layer was separated, washed with brine, and then, dried over anhydrous magnesium sulfate. The organic layer was filtered, then, the solvent was evaporated in vacuo, the residue was purified by NH silica gel column chromatography (heptane/ethyl acetate=1/1), and the title compound (167 mg, 48%) was obtained as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:47]=[C:46]([O:48][CH3:49])[CH:45]=[C:44]([O:50][CH3:51])[C:4]=1[CH:5]=[CH:6][CH:7]([S:17]([CH:20]([CH:30]=[CH:31][C:32]1[C:37]([O:38][CH3:39])=[CH:36][C:35]([O:40][CH3:41])=[CH:34][C:33]=1[O:42][CH3:43])[C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([NH2:29])[CH:22]=1)(=[O:19])=[O:18])[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([NH2:16])[CH:9]=1.[N+:52]([C:55]1[CH:62]=[CH:61][C:58](C=O)=[CH:57][CH:56]=1)([O-:54])=[O:53]>CO.O>[CH3:51][O:50][C:44]1[CH:45]=[C:46]([O:48][CH3:49])[CH:47]=[C:3]([O:2][CH3:1])[C:4]=1[CH:5]=[CH:6][CH:7]([S:17]([CH:20]([CH:30]=[CH:31][C:32]1[C:33]([O:42][CH3:43])=[CH:34][C:35]([O:40][CH3:41])=[CH:36][C:37]=1[O:38][CH3:39])[C:21]1[CH2:22]/[C:23](=[N:29]\[C:58]2[CH:57]=[CH:56][C:55]([N+:52]([O-:54])=[O:53])=[CH:62][CH:61]=2)/[C:24]([O:27][CH3:28])=[CH:25][CH:26]=1)(=[O:19])=[O:18])[C:8]1[CH2:9]/[C:10](=[N:16]\[C:58]2[CH:61]=[CH:62][C:55]([N+:52]([O-:54])=[O:53])=[CH:56][CH:57]=2)/[C:11]([O:14][CH3:15])=[CH:12][CH:13]=1
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Reactant: COc1cc(OC)c(C=CC(c2ccc(OC)c(N)c2)S(=O)(=O)C(C=Cc2c(OC)cc(OC)cc2OC)c2ccc(OC)c(N)c2)c(OC)c1
Solvent: CO
Solvent: O
Product: COC1=CC=C(C(C=Cc2c(OC)cc(OC)cc2OC)S(=O)(=O)C(C=Cc2c(OC)cc(OC)cc2OC)C2=CC=C(OC)/C(=N/c3ccc([N+](=O)[O-])cc3)C2)C/C1=N\c1ccc([N+](=O)[O-])cc1
Reaction time: 5 h

Procedure:
To a solution of 2,4,6-trimethoxystyryl-3-amino-4-methoxybenzylsulfone (10 mmol) in methanol (40 mL) is added 4-nitrobenzaldehyde (10 mmol). The solution is refluxed with vigorous stirring for 5 h. The reaction mixture is cooled, diluted with water and the aqueous mixture is then extracted twice with dichloromethane and organic layer is dried over anhydrous magnesium sulfate. The dried organic solution is evaporated and the residue is recrystallized to give (E)-2,4,6-trimethoxystyryl-3-(4-nitrophenylimino)-4-methoxybenzylsulfone.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:13])C(OC)=O)=[CH:4][CH:3]=1.[OH:14][CH:15]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[C:16]([OH:18])=[O:17].[CH2:35]([Sn](=O)CCCC)CCC>>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:13][CH2:35][O:14][CH:15]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[C:16]([OH:18])=[O:17])=[CH:6][CH:7]=1
Reactant: COC(=O)C(C)c1ccc(O)cc1
Reactant: CCCCCCCCCCCCCCCCC(O)C(=O)O
Reactant: CCCC[Sn](=O)CCCC
Product: CCCCCCCCCCCCCCCCC(OCCCc1ccc(O)cc1)C(=O)O

Procedure:
360 parts of methyl p-hydroxyphenylpropionate was reacted with 300 parts of hydroxystearic acid in the presence of 3 parts of dibutyl tin oxide at 150°C. in a nitrogen current for 10 hours. After completion of the reaction, the unreacted excessive methyl p-hydroxyphenylphropionate was distilled at 150°C. under reduced pressure to obtain crude p-hydroxyphenylpropyloxystearic acid. Recrystallization of this crude product from a mixed solvent of methylethylketone and n-hexane gave 350 parts of p-hydroxyphenylpropyloxystearic acid.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:15]([OH:17])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH2:3][CH2:2]1.[F:18][C:19]([F:29])([F:28])[C@H:20]([NH2:27])[C:21]1[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=1>>[CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:15]([NH:27][C@H:20]([C:21]3[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=3)[C:19]([F:18])([F:28])[F:29])=[O:17])=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:13][CH2:14]2)[CH2:2][CH2:3]1
Reactant: O=C(O)c1ccc(C2CC2)c(OCC2CC2)n1
Reactant: N[C@H](c1cccnc1)C(F)(F)F
Product: O=C(N[C@H](c1cccnc1)C(F)(F)F)c1ccc(C2CC2)c(OCC2CC2)n1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-cyclopropyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (Example 42 a) and (R)-2,2,2-trifluoro-1-pyridin-3-yl-ethylamine (CAN 1212813-98-3) as starting materials, MS (EI): m/e=392.2 [M+H]+.
Reaction SMILES: [CH2:1]1[CH:5]2[C@@H:6]3C=C[C@H]([CH:4]2C=[CH:2]1)C3.[CH3:11][O:12][C:13](=[O:16])[CH:14]=[CH2:15].C1(C=CC(O)=CC=1)O>>[CH3:11][O:12][C:13]([CH:14]1[CH2:4][CH:5]2[CH2:6][CH:15]1[CH:2]=[CH:1]2)=[O:16]
Reactant: C=CC(=O)OC
Reactant: C1=CC2C(C1)[C@@H]1C=C[C@H]2C1
Agent: Oc1ccc(O)cc1
Product: COC(=O)C1CC2C=CC1C2
Temperature: 180 °C
Yield: 85 %

Procedure:
DCPD (dicyclopentadiene, Aldrich, 256.5 ml, 1.9 mol), methylacrylate (Aldrich, 405 ml, 4.5 mol) and hydroquinone (3.2 g, 0.03 mol) were charged into a 2 L high-pressure autoclave, and the temperature was raised to 180° C. The resulting mixture was reacted for 5 hours with stirring at 300 rpm. After the reaction was completed, the reaction mixture was cooled and transferred to a distilling apparatus. The reaction mixture was distilled under a reduced pressure (1 torr) using a vacuum pump to yield the title compound at 50° C. (yield: 85%, exo/endo=41/59).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:8]([N:9]=[C:10]3[C:15]=1[CH:14]=[CH:13][CH:12]=[CH:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2.C1(O)C=CC=CC=1.[CH2:23]([NH2:26])[CH2:24][NH2:25]>[OH-].[Na+]>[ClH:1].[CH:4]1[C:3]2[C:8](=[N:9][C:10]3[C:15]([C:2]=2[NH:25][CH2:24][CH2:23][NH2:26])=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH:7]=[CH:6][CH:5]=1
Reactant: Clc1c2ccccc2nc2ccccc12
Reactant: NCCN
Agent: [Na+]
Agent: [OH-]
Solvent: Oc1ccccc1
Product: Cl
Product: NCCNc1c2ccccc2nc2ccccc12
Temperature: 110 °C
Yield: 52.5 %

Procedure:
A mixture of 9-chloroacridine (1.21 g, 5.7 mmol) and phenol (10.8 g, 57 mmol) was mixed and heated at 110° C. for 45 min under argon. Distilled ethylene diamine (3.4 g, 57 mmol) was added via syringe. After the reaction mixture was heated at 110° C. for additional 2 hrs, it was poured into 2N NaOH solution (60 mL). The product was extracted with ethyl ether (3×100 mL). The combined organic layer was washed with 2N NaOH solution (40 mL) and water (2×100 mL) and dried with anhydrous potassium carbonate. The solution was concentrated to 15 mL. Ethanol (15 mL) was added, followed by the addition of concentrated hydrochloric acid (10 mL). The mixture was cooled in freezer (−20° C.) for 4 hrs. The yellow solid formed was collected by centrifugation, washed with ethyl ether (10 mL) and dried under vacuum to provide Compound 7 as yellow powder 0.82 g (53%) which was used without any further purification. The structure of Compound 7 is given below:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([CH2:17][O:18][Si](C(C)(C)C)(C)C)[CH:15]=2)[CH:10]=[C:9]1[C:26]1[CH:31]=[C:30]([C:32]2[CH:37]=[C:36]([CH3:38])[C:35]([OH:39])=[C:34]([CH3:40])[CH:33]=2)[N:29]=[N:28][C:27]=1[O:41][CH3:42])=[O:7])([CH3:4])([CH3:3])[CH3:2].O.O.O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([CH2:17][OH:18])[CH:15]=2)[CH:10]=[C:9]1[C:26]1[CH:31]=[C:30]([C:32]2[CH:33]=[C:34]([CH3:40])[C:35]([OH:39])=[C:36]([CH3:38])[CH:37]=2)[N:29]=[N:28][C:27]=1[O:41][CH3:42])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1nnc(-c2cc(C)c(O)c(C)c2)cc1-c1cc2ccc(CO[Si](C)(C)C(C)(C)C)cc2n1C(=O)OC(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: COc1nnc(-c2cc(C)c(O)c(C)c2)cc1-c1cc2ccc(CO)cc2n1C(=O)OC(C)(C)C
Reaction time: 2 h
Yield: 82.7 %

Procedure:
3.06 g 6-(tert-Butyldimethylsiloxymethyl)-2-[6-(4-hydroxy-3,5-dimethyl-phenyl)-3-methoxy-pyridazin-4-yl]-indole-1-carboxylic acid tert-butyl ester is dissolved in 50 mL THF. After addition of 4.1 g tetrabutylammonium fluoride trihydrate, the red solution is stirred for 2 hours. The reaction mixture is diluted with EtOAc, washed with saturated aqueous ammonium chloride, water, and brine, dried with MgSO4 and concentrated in vacuo. Purification on silica affords 2.04 g (82%) 6-hydroxymethyl-2-[6-(4-hydroxy-3,5-dimethyl-phenyl)-3-methoxy-pyridazin-4-yl]-indole-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [CH:1]([C:3]1[S:7][C:6]([C:8]2[S:9][CH:10]=[CH:11][CH:12]=2)=[CH:5][CH:4]=1)=O.[CH3:13][C:14]([CH:16]([O:19][CH3:20])[O:17][CH3:18])=[O:15].[OH-].[K+].O>C(O)C>[CH3:18][O:17][CH:16]([O:19][CH3:20])[C:14](=[O:15])[CH:13]=[CH:1][C:3]1[S:7][C:6]([C:8]2[S:9][CH:10]=[CH:11][CH:12]=2)=[CH:5][CH:4]=1
Reactant: O=Cc1ccc(-c2cccs2)s1
Reactant: COC(OC)C(C)=O
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COC(OC)C(=O)C=Cc1ccc(-c2cccs2)s1

Procedure:
To a solution of 5-formyl-2,2'-bithiophene (4.0 g) in ethanol (120 ml) was added dimethoxymethyl methyl ketone (3 ml). Potassium hydroxide aqueous solution (50%) was added dropwisely into the solution mixture at 16° C. Color changed from yellowish brown into dark green, then dark brown. Yellow solid was formed during the reaction. Water was added. Solid residue was filtered and washed with water, redissolved in acetone and separated by silica gel chromatography eluted with ethyl acetate/n-hexane.(1:9). Yellowish crystals 1.88 g were obtained, melting point 74° C.
Reaction SMILES: [BH4-].[Na+].[O:3]=[CH:4][CH2:5][C:6]1[N:11]=[CH:10][C:9]([C:12]#[N:13])=[CH:8][CH:7]=1.O>CO>[OH:3][CH2:4][CH2:5][C:6]1[N:11]=[CH:10][C:9]([C:12]#[N:13])=[CH:8][CH:7]=1
Reactant: N#Cc1ccc(CC=O)nc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: N#Cc1ccc(CCO)nc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
NaBH4 (2.5 g, 67 mmol) was added in small portions to a solution of 6-(2-oxoethyl)pyridine-3-carbonitrile (5.0 g, crude) in 80 mL of MeOH at 0° C. The mixture was stirred at room temperature for 30 minutes and poured to 50 mL of water. The mixture was extracted with EtOAc (100 mL×5) and the combined organic layer was condensed. The residue was purified by flash chromatography to afford 6-(2-hydroxyethyl)pyridine-3-carbonitrile. TEA (2.1 g, 21 mmol) was added drop wise to a solution of 6-(2-hydroxyethyl)pyridine-3-carbonitrile (3.0 g, 20 mmol) and MsCl (2.3 g, 20 mmol) in 200 mL of DCM at 0° C. The mixture was stirred at RT for 30 minutes and washed with water and brine, dried over anhydrous Na2SO4 and condensed under vacuum below 30° C. to afford the title compound which was used immediately without further purification.
Reaction SMILES: [CH3:1][NH:2][C@H:3]([CH3:12])[C@@H:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[OH:5].BrC1SC(C([C@H:22]2[CH2:27][CH2:26][C@H:25]([C:28]([OH:30])=[O:29])[CH2:24][CH2:23]2)(O)C)=NC=1>>[OH:5][C@@H:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C@@H:3]([NH2+:2][CH3:1])[CH3:12].[CH:25]1([C:28]([O-:30])=[O:29])[CH2:26][CH2:27][CH2:22][CH2:23][CH2:24]1
Reactant: CN[C@H](C)[C@H](O)c1ccccc1
Reactant: CC(O)(c1ncc(Br)s1)[C@H]1CC[C@H](C(=O)O)CC1
Product: C[NH2+][C@@H](C)[C@@H](O)c1ccccc1
Product: O=C([O-])C1CCCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(1R,2R)-2-(methylamino)-1-phenylpropan-1-ol (0.25 g, 1.50 mmol) was added to a solution of racemic trans-4-[1-(5-bromo-1,3-thiazol-2-yl)-1-hydroxyethyl]cyclohexanecarboxylic acid (500 mg, 1.50 mmol) and the resulting solution was stirred at room temperature overnight, at which point crystallization occurred. The resulting solid was collected by filtration and washed with 1:1 EtOAc:hexane. The resulting mother liquor was concentrated in vacuo and then isopropanol (3.5 mL) and (1S,2S)-2-(methylamino)-1-phenylpropan-1-ol were added. The reaction was stirred overnight, at which point crystallization occurred. Then EtOAc (3 mL) was added and after 20 minutes, the solid was collected via filtration and the filter cake was washed with EtOAc and then dried under a nitrogen bag to afford (1S,2S)-1-hydroxy-N-methyl-1-phenylpropan-2-aminium trans-4-[(1R or 1S)-1-(5-bromo-1,3-thiazol-2-yl)-1-hydroxyethyl]cyclohexanecarboxylate as a white solid. MS ESI calc'd. for C12H17BrNO3S [M+H]+ 334, 336. found 334, 336. 1H NMR (500 MHz, DMSO-d6) δ 7.73 (s, 1H), 7.30-7.27 (m, 4H), 7.25-7.19 (m, 1H), 5.95 (s, 1H), 4.20 (d, J=7.7, 1H), 2.60-2.52 (m, 1H), 2.29 (s, 3H), 2.03-1.92 (m, 1H), 1.92-1.86 (m, 1H), 1.86-1.78 (m, 2H), 1.63-1.52 (m, 1H), 1.48-1.37 (m, 4H), 1.27-1.08 (m, 4H), 1.06-0.89 (m, 1H), 0.68 (d, J=6.4, 3H).
Reaction SMILES: [C:1]([CH:4]1[C:9](=[O:10])[CH2:8][CH:7]([CH:11]([CH3:24])[CH2:12][S:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH2:6][C:5]1=[O:25])(=O)[CH3:2].Cl.[CH2:27]([O:29][NH2:30])[CH3:28].C(=O)([O-])[O-].[K+].[K+].O>CO>[CH2:27]([O:29][NH:30][C:1](=[C:4]1[C:9](=[O:10])[CH2:8][CH:7]([CH:11]([CH3:24])[CH2:12][S:13][C:14]2[CH:15]=[CH:16][C:17]([C:20]([F:21])([F:23])[F:22])=[CH:18][CH:19]=2)[CH2:6][C:5]1=[O:25])[CH3:2])[CH3:28]
Reactant: CCON
Reactant: CC(=O)C1C(=O)CC(C(C)CSc2ccc(C(F)(F)F)cc2)CC1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CCONC(C)=C1C(=O)CC(C(C)CSc2ccc(C(F)(F)F)cc2)CC1=O

Procedure:
0.4 Gram of 2-acetyl-5-[1-methyl-2-(4-trifluoromethylphenylthio)ethyl]cyclohexane-1,3-dione and 0.1 g of ethoxyamine hydrochloride were dissolved in 10 ml of methanol and 0.15 g of potassium carbonate was added to the resulting solution which was then refluxed for 3 hours. The reaction solution was poured into water and extracted with chloroform. After removing chloroform, the residue was purified by thin layer chromatography (eluent, hexane:ethyl acetate=5:1) to obtain 0.3 g of 2-(1-ethoxyaminoethylidene)-5-[1-methyl-2-(4-trifluoromethylphenylthio)ethyl]cyclohexane-1,3-dione.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]2[C:14](=[O:15])[O:13][C:12]([CH3:17])([CH3:16])[O:11][C:10]2=[O:18])[CH:5]=[CH:6][CH:7]=1.[CH2:19]([Mg]Cl)[CH:20]=[CH2:21]>C1COCC1>[OH:1][C:2]1[CH:3]=[C:4]([CH:8]([CH:9]2[C:10](=[O:18])[O:11][C:12]([CH3:16])([CH3:17])[O:13][C:14]2=[O:15])[CH2:21][CH:20]=[CH2:19])[CH:5]=[CH:6][CH:7]=1
Reactant: C=CC[Mg]Cl
Reactant: CC1(C)OC(=O)C(=Cc2cccc(O)c2)C(=O)O1
Solvent: C1CCOC1
Product: C=CCC(c1cccc(O)c1)C1C(=O)OC(C)(C)OC1=O
Yield: 36.6 %

Procedure:
To a solution of 8.1 (8.00 g, 32 mmol) in THF (100 mL) was added allylmagnesium chloride (available from Aldrich) (2.0 M in THF) (97 mL, 193 mmol) dropwise at 0° C. over 1 hour. When the addition was complete, the reaction was quenched with 1 N HCl and extracted with EtOAc. The combined organic layers were washed with brine, dried (MgSO4), and concentrated. The crude product was chromatographed on silica gel (20-30% EtOAc/hexane) to afford 43.1 (3.4 g, 36%) as a pale yellow oil.
Reaction SMILES: C([O:4][CH2:5][CH2:6][N:7]([CH2:15][C:16](OCC)=[O:17])[C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=1)(=O)C.[BH4-].[Li+].O>O1CCCC1>[OH:4][CH2:5][CH2:6][N:7]([C:8]1[CH:9]=[CH:10][C:11]([F:14])=[CH:12][CH:13]=1)[CH2:15][CH2:16][OH:17]
Reactant: CCOC(=O)CN(CCOC(C)=O)c1ccc(F)cc1
Agent: [BH4-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: OCCN(CCO)c1ccc(F)cc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 96.8 %

Procedure:
To a solution of N-ethoxycarbonylmethyl-N-(4-fluorophenyl)-aminoethyl acetate (13.51 g) in tetrahydrofuran (135 ml) was added lithium borohydride (4.15 g) and the mixture was stirred at 60° C. for 1 hr. The reaction mixture was poured into water (300 ml) and extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated to give the title compound (9.2 g) as a yellow oil.
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:16][C:17]1[CH:26]=[CH:25][CH:24]=[CH:23][C:18]=1[C:19]([O:21][CH3:22])=[O:20].O>C1COCC1>[CH3:22][O:21][C:19]([C:18]1[CH:23]=[CH:24][CH:25]=[CH:26][C:17]=1[CH2:16][S:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[CH:6][CH:7]=1)=[O:20]
Reactant: O=C(O)CCc1ccc(S)cc1
Reactant: COC(=O)c1ccccc1CBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1ccccc1CSc1ccc(CCC(=O)O)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 62.4 %

Procedure:
3-(4-Mercaptophenyl)propanoic acid (2.0 g, 10.97 mmol) was dissolved in dry THF (60 ml) and cooled to 0° C. Sodium hydride (0.64 g, 24.1 mmol) was added. The mixture was stirred for 30 minutes, methyl 2-(bromomethyl)benzoate (2.77 g, 12.07 mmol) dissolved in dry THF (10 ml) was added dropwise. The solution was allowed to warm up to room temperature and was stirred overnight. Dropwise addition of water (10 ml) deactivated the remaining sodium hydride. The solvent was removed by evaporation, and the residue was acidified to pH 3 (HCl 1%). The water phase was washed with EtOAc (3×10 ml). The organic phases was combined, dried (MgSO4) and evaporated. The crude was purified by preparative HPLC (started with acetonitrile/buffer 60/40 and then the acetonitrile concentration was increased to 100%, the buffer was a mixture of acetonitrile/water 10/90 and ammonium acetate (0.1 M, column KR-100-7-C8, 50 mm×250 mm, flow 40 ml/min). The product containing fractions was pooled and the acetonitrile was removed by evaporation. EtOAc (10 ml) was added and the organic phase was washed with two potions of brine and dried (MgSO4). Removing the solvent by evaporation gave 2.26 gram of 3-(4-{[2-(methoxycarbonyl)benzyl]thio}phenyl)propanoic acid (yield 62.3%).