Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCN(C(C)C)C(C)C.[Cl:10][C:11]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:12]=1[C:13]([OH:15])=O.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[O:42]=[C:43]([N:60]1[CH2:65][CH2:64][NH:63][CH2:62][CH2:61]1)[CH2:44][NH:45][C:46]([C:48]1[CH:53]=[CH:52][C:51]([C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=2)=[CH:50][CH:49]=1)=[O:47]>CN(C=O)C.O>[Cl:10][C:11]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:12]=1[C:13]([N:63]1[CH2:62][CH2:61][N:60]([C:43](=[O:42])[CH2:44][NH:45][C:46]([C:48]2[CH:53]=[CH:52][C:51]([C:54]3[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=3)=[CH:50][CH:49]=2)=[O:47])[CH2:65][CH2:64]1)=[O:15]
Reactant: O=C(O)c1cc(F)ccc1Cl
Reactant: O=C(NCC(=O)N1CCNCC1)c1ccc(-c2ccccc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC(=O)N1CCN(C(=O)c2cc(F)ccc2Cl)CC1)c1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 29.2 %

Procedure:
DIPEA (149.8 mg, 0.2 mL, 1.15 mmol) was added to a stirred solution of 2-chloro-5-fluoro-benzoic acid (44.9 mg, 0.25 mmol) in DMF (3 mL). HOBT (38.2 mg, 0.28 mmol) and EDCI (123 mg, 0.34 mmol) were then added at room temperature. After 2 minutes, Biphenyl-4-carboxylic acid (2-oxo-2-piperazin-1-yl-ethyl)-amide (100 mg, 0.30 mmol) was added and the resulting mixture was stirred at room temperature overnight. Cold water was then added and the product was extracted with EtOAc and the organic layer was washed with brine. The organic phase was dried over Na2SO4 and concentrated under reduced pressure to get the residue. The obtained residue was purified by column chromatography (using silica gel of 60-120 mesh and 60% EtOAc in Hexane as eluent) to afford 35 mg (28.3% yield) of biphenyl-4-carboxylic acid {2-[4-(2-chloro-5-fluoro-benzoyl)-piperazin-1-yl]-2-oxo-ethyl}-amide. LCMS Purity: 98.32%. 1H NMR (DMSO-d6): δ 8.7-8.6 (t, 1H), 8.02-7.92 (d, 2H), 7.84-7.7 (q, 4H), 7.68-7.58 (m, 1H), 7.54-7.28 (m, 5H), 4.3-4.1 (dd, 2H), 3.8-3.44 (m, 6H), 3.26-3.12 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[O:6][C:5]([C:7]([CH:9]2[C:18](=[O:19])[CH2:17][CH2:16][C:11]3([O:15][CH2:14][CH2:13][O:12]3)[CH2:10]2)=[O:8])=[CH:4][CH:3]=1.NC1C=CC(C(N)=[O:26])=CC=1C.CC1C=CC(S(O)(=O)=O)=CC=1>CCO>[Br:1][C:2]1[O:6][C:5]([C:7](=[O:8])[CH2:9][CH2:10][C:11]2([CH2:16][CH2:17][C:18]([OH:19])=[O:26])[O:12][CH2:13][CH2:14][O:15]2)=[CH:4][CH:3]=1
Reactant: O=C1CCC2(CC1C(=O)c1ccc(Br)o1)OCCO2
Reactant: Cc1cc(C(N)=O)ccc1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: O=C(O)CCC1(CCC(=O)c2ccc(Br)o2)OCCO1
Yield: 30 %

Procedure:
7-(5-bromofuran-2-carbonyl)-1,4-dioxaspiro[4.5]decan-8-one. (2.00 g, 5.78 mmol), 4-amino-3-methylbenzamide (1.04 mg, 6.90 mmol) and TsOH (100 mg, 0.578 mmol) were taken up into EtOH (20 mL). The resulted mixture was heated to reflux for 61 h. After evaporation under reduced pressure, the crude product was purified by a silica gel column chromatography (EA:PE=1:1) to afford 3-(2-(3-(5-bromofuran-2-yl)-3-oxopropyl)-1,3-dioxolan-2-yl)propanoic acid as a yellow solid (760 mg, yield: 30%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([OH:9])=O.[NH2:10][CH2:11][CH2:12][N:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([CH2:22][C:23]2[NH:24][CH:25]=[CH:26][N:27]=2)=[CH:14]1>O1CCOCC1>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([NH:10][CH2:11][CH2:12][N:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([CH2:22][C:23]2[NH:27][CH:26]=[CH:25][N:24]=2)=[CH:14]1)=[O:9]
Reactant: O=C(O)c1ccccn1
Reactant: NCCn1cc(Cc2ncc[nH]2)c2ccccc21
Solvent: C1COCCO1
Product: O=C(NCCn1cc(Cc2ncc[nH]2)c2ccccc21)c1ccccn1
Yield: 29 %

Procedure:
A mixture of 2-picolinic acid (0.25 g) and N,N'-carbonyldiimidazole (0.33 g) was heated on a steam bath for 30 minutes in dioxan (10 ml) to give a clear solution. 1-(2-Aminoethyl)-3-(1-imidazolylmethyl) indole (0.48 g) in dioxan (2 ml) was added and the solution was heated on a steam bath for 1 hour and then evaporated. The residue was dissolved in ethyl acetate and the solution was washed with water and dried (NaSO4). Evaporation of the solvent gave a solid which was chromatographed on silica gel. Elution with chloroform gave some impurity and pure product was eluted with a mixture of chloroform and methanol (20:1). Evaporation of the product containing fractions gave a solid which was crystallised from isopropanol/petrol to give 1-[2-(2-picolinoylamino) ethyl]-3-(1-imidazolylmethyl)indole (0.2 g), m.p. 183°-184° C. Found: C, 69.67; H, 5.6; N, 19.42. C20H19N5O requires: C, 69.54; H, 5.55; N, 20.28%.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH2:10][CH:11]=[CH2:12])[C:5]([CH3:13])=[CH:4][C:3]=1[CH3:14].[Li]CCCC.C[O:21][B:22](OC)[O:23]C>C1COCC1>[CH2:9]([O:8][C:6]1[C:5]([CH3:13])=[CH:4][C:3]([CH3:14])=[C:2]([B:22]([OH:23])[OH:21])[CH:7]=1)[CH2:10][CH:11]=[CH2:12]
Reactant: COB(OC)OC
Reactant: C=CCCOc1cc(Br)c(C)cc1C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C=CCCOc1cc(B(O)O)c(C)cc1C
Temperature: -70 °C
Reaction time: 1 h

Procedure:
In the glovebox, a 100-mL round bottomed flask is charged with 1-bromo-5-(but-3-enyloxy)-2,4-dimethylbenzene (3.142 g, 13.6 mmol) and THF (100 mL). The flask is sealed with a septum and removed from the glovebox. The flask is cooled to −70° C. under nitrogen purge. BuLi (1.6M in hexanes, 8.2 mL, 13 mmol) is added slowly, keeping the temperature below −68° C., and the reaction mixture is stirred for one hr at −70° C. Trimethylborate (1.3 mL, 12 mmol) is added, and the mixture is stirred as it slowly warms to room temperature. Solvents are removed on a rotovap, and ice (60 g) containing hydrochloric acid (HCl) (conc, 5 mL) is added, and then ether (60 mL). A white precipitate forms, and this is collected on a fine frit. Yield=1.283 g of a white solid. 1H NMR is taken by suspending the solid in d6-dimethylsulfoxide (d6-DMSO) and adding a trace of HCl.
Reaction SMILES: Cl.Cl.[N:3]12[CH2:10][CH2:9][CH:6]([CH2:7][CH2:8]1)[C@@H:5]([O:11][C:12](=[O:21])[CH:13]([NH2:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:4]2.[CH:22]([C:24]1[S:28][C:27]([C:29]([O:31][CH:32]([C:43]2[CH:48]=[CH:47][C:46]([O:49][CH3:50])=[C:45]([O:51][CH2:52][CH3:53])[CH:44]=2)[CH2:33][C:34]2[C:39]([Cl:40])=[CH:38][N+:37]([O-:41])=[CH:36][C:35]=2[Cl:42])=[O:30])=[CH:26][CH:25]=1)=O.C(O)(=O)C.C([BH3-])#N.[Na+]>C(O)C>[Cl:40][C:39]1[CH:38]=[N+:37]([O-:41])[CH:36]=[C:35]([Cl:42])[C:34]=1[CH2:33][CH:32]([O:31][C:29]([C:27]1[S:28][C:24]([CH2:22][NH:20][CH:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:12](=[O:21])[O:11][C@@H:5]2[CH:6]3[CH2:7][CH2:8][N:3]([CH2:10][CH2:9]3)[CH2:4]2)=[CH:25][CH:26]=1)=[O:30])[C:43]1[CH:48]=[CH:47][C:46]([O:49][CH3:50])=[C:45]([O:51][CH2:52][CH3:53])[CH:44]=1
Reactant: CCOc1cc(C(Cc2c(Cl)c[n+]([O-])cc2Cl)OC(=O)c2ccc(C=O)s2)ccc1OC
Reactant: NC(C(=O)O[C@H]1CN2CCC1CC2)c1ccccc1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: CCOc1cc(C(Cc2c(Cl)c[n+]([O-])cc2Cl)OC(=O)c2ccc(CNC(C(=O)O[C@H]3CN4CCC3CC4)c3ccccc3)s2)ccc1OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 25 %

Procedure:
To a solution of [(3R)-quinuclidin-3-yl]2-amino-2-phenylacetate bis hydrochloride salt (273 mg, 0.82 mmol) in ethanol (10 mL) was added the single enantiomer 2 of [2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3-ethoxy-4-methoxy-phenyl)ethyl] 5-formylthiophene-2-carboxylate (Intermediate 75, 135 mg, 0.27 mmol) and acetic acid (40 μL, 0.68 mmol). The resulting mixture was stirred at room temperature for 16 h. Sodium cyanoborohydride (45 mg, 0.68 mmol) was added and the reaction mixture was stirred at room temperature for a further 24 h. The solvent was removed by evaporation under reduced pressure and the residue was partitioned between 1 M aqueous hydrochloric acid (3 mL) and ethyl acetate (3 mL). The layers were separated and the aqueous phase was extracted with ethyl acetate (2×3 mL). The aqueous phase was basified with saturated aqueous sodium bicarbonate solution and then extracted with ethyl acetate (2×3 mL). The combined organic fractions were extracted with 1 M aqueous hydrochloric acid (2 mL). Brine (2 mL) was added and the aqueous layer was extracted with chloroform (5 mL and 2 mL). The combined organic fractions were washed with saturated aqueous sodium bicarbonate solution (2 mL), passed through a hydrophobic frit and the solvent was removed by evaporation under reduced pressure. Purification by preparative HPLC gave the title compound as an off-white solid (50 mg, 25%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[N:10][C:9]=2[C:17]2[C:18]([F:30])=[C:19]([NH:23][C:24](=[O:29])[O:25][CH2:26][CH:27]=[CH2:28])[CH:20]=[CH:21][CH:22]=2)[CH:5]=[CH:4][N:3]=1.[NH3:31].CO>>[NH2:31][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[N:10][C:9]=2[C:17]2[C:18]([F:30])=[C:19]([NH:23][C:24](=[O:29])[O:25][CH2:26][CH:27]=[CH2:28])[CH:20]=[CH:21][CH:22]=2)[CH:5]=[CH:4][N:3]=1
Reactant: N
Reactant: C=CCOC(=O)Nc1cccc(-c2nc(C(C)(C)C)sc2-c2ccnc(Cl)n2)c1F
Solvent: CO
Product: C=CCOC(=O)Nc1cccc(-c2nc(C(C)(C)C)sc2-c2ccnc(N)n2)c1F

Procedure:
A solution of 2-propen-1-yl {3-[5-(2-chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}carbamate (535 mg, 1.197 mmol) and ammonia in MeOH 7N (6 ml, 42.0 mmol) was heated to 80° C. for 24 h. The crude reaction mixture was evaporated onto silica gel and chromatographed, (0-15% MeOH in DCM). The title compound was obtained as a yellow foam (233 mg, 41% yield). MS (ESI): 428.1 [M+H]+.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[CH2:11]([O:13][C:14]([CH:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1)=[O:15])[CH3:12].C(=O)([O-])[O-].[K+].[K+]>CC#N>[CH2:11]([O:13][C:14]([CH:16]1[CH2:21][CH2:20][N:19]([C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=2)[CH2:18][CH2:17]1)=[O:15])[CH3:12]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: CCOC(=O)C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)C1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Yield: 51.3 %

Procedure:
A solution of 1-fluoro-4-nitrobenzene (2.0 g, 1.50 mL, 14 mmol), piperidine-4-carboxylic acid ethyl ester (2.2 g, 2.15 mL, 14 mmol), and potassium carbonate (9.7 g, 70 mmol) in CH3CN (20 mL) was stirred at room temperature overnight. The resulting mixture was filtered and concentrated. The residue was purified by chromatography on silica gel (gradient elution with 5-50% ethyl acetate in hexanes) to produce 2.0 g of 1-(4-nitro-phenyl)-piperidine-4-carboxylic acid ethyl ester as a yellow solid. 1.0 g of the above 1-(4-nitro-phenyl)-piperidine-4-carboxylic acid ethyl ester was hydrogenated using 10% Pd/C (200 mg) in MeOH, under 50 psi pressure of hydrogen for 2 hours. The catalyst was filtered, and the residue was concentrated to produce 1-(4-amino-phenyl)-piperidine-4-carboxylic acid ethyl ester. This material was directly used in the next step without further purification.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([CH3:14])[N:12]=2)[C:7](=[O:15])[C:6]([C:16]([OH:18])=[O:17])=[CH:5]1.S(OC)(O[CH3:23])(=O)=O>C(O)C.[OH-].[Na+]>[CH3:23][O:1][CH2:2][CH2:3][N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([CH3:14])[N:12]=2)[C:7](=[O:15])[C:6]([C:16]([OH:18])=[O:17])=[CH:5]1
Reactant: COS(=O)(=O)OC
Reactant: Cc1ccc2c(=O)c(C(=O)O)cn(CCO)c2n1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COCCn1cc(C(=O)O)c(=O)c2ccc(C)nc21

Procedure:
1,4-Dihydro-1-(2-hydroxyethyl)-7-methyl-4-oxo-1,8-naphthyridine-3-carboxylic acid (1 g) in ethanol (30 ml) and aqueous sodium hydroxide (10 ml, 40%) was treated alternatively with dimethyl sulphate (5 ml) and aqueous sodium hydroxide (10 ml, 40 %) until dimethylsulphate (25 ml) had been added. The mixture was refluxed for 1.5 hours and concentrated to a volume of 20 ml. Concentrated hydrochloric acid was added and the solid was collected and washed with water and dried. The product had m.p. 244°-245° (d).
Reaction SMILES: [SH:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([C:11]#[N:12])[CH:8]=[CH:7][C:5]=2[N:6]=1.[Cl:13][C:14]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[CH:16][C:15]=1F.[H-].[Na+]>CN(C=O)C>[Cl:13][C:14]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[CH:16][C:15]=1[S:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([C:11]#[N:12])[CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: O=[N+]([O-])c1ccc(F)c(Cl)c1
Reactant: N#Cc1ccc2nc(S)sc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1ccc2nc(Sc3ccc([N+](=O)[O-])cc3Cl)sc2c1
Yield: 93.2 %

Procedure:
The title compound was prepared using the method of example 258, starting with 2-mercapto-benzothiazole-6-carbonitrile (241) (960 mg, 5.0 mmol), 2-chloro-1-fluoro-4-nitrobenzene (Aldrich, 878 mg, 5.0 mmol) and NaH (Aldrich, 60% suspension, 200 mg, 5.0 mmol) in DMF (25 mL). Compound 261 (1.62 g, 93%) was obtained as a yellow solid.
Reaction SMILES: C1(C[O:5][C:6]2[C:7]([O:26][CH3:27])=[CH:8][CH:9]=[C:10]3[C:15]=2[NH:14][C:13](=[O:16])[CH:12]=[C:11]3[NH:17][C:18]2[C:23]([Cl:24])=[CH:22][N:21]=[CH:20][C:19]=2[Cl:25])CC1.Cl>O>[Cl:25][C:19]1[CH:20]=[N:21][CH:22]=[C:23]([Cl:24])[C:18]=1[NH:17][C:11]1[C:10]2[C:15](=[C:6]([OH:5])[C:7]([O:26][CH3:27])=[CH:8][CH:9]=2)[NH:14][C:13](=[O:16])[CH:12]=1
Reactant: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)[nH]c2c1OCC1CC1
Agent: Cl
Solvent: O
Product: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)[nH]c2c1O
Temperature: 0 °C
Reaction time: 1 h
Yield: 97.6 %

Procedure:
A solution of 8-(cyclopropylmethoxy)-4-(3,5-dichloropyridin-4-ylamino)-7-methoxyquinolin-2(1H)-one (99%. 23.8 g, 57.9 mmol) and conc. HCl (150 mL) was warmed at 40° C. for 30 min and then water (0° C., 150 mL) was added. The resulting mixture was stirred vigorously at 0° C. for 1 h, filtered, and then washed with water (0° C., 100 mL). A mixture of the resulting solid and 0.5 M pH 7 phosphate buffer (300 mL) was stirred vigorously at 0° C. for 30 min, filtered, washed with water (0° C., 300 mL), and then dried in an oven to give 19.9 g of 4-(3,5-dichloropyridin-4-ylamino)-8-hydroxy-7-methoxyquinolin-2(1H)-one as a yellow solid. 1H NMR (400 MHz, DMSO-d6): δ 9.69 (s, 1H), 9.51 (s, 1H), 8.78 (s, 3H), 7.65 (d, 1H), 7.01 (d, 1H), 3.90 (s, 3H); MS (ESI): 352.2.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:21])[C:5]([NH:8][CH2:9][C:10]2[CH:20]=[CH:19][C:13]3[N:14]=[C:15]([S:17][CH3:18])[S:16][C:12]=3[CH:11]=2)=[CH:6][CH:7]=1.Br[C:23]1C=C(NCC2C=CC3N=C(SC)SC=3C=2)C(N)=CC=1OC>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[N:8]([CH2:9][C:10]3[CH:20]=[CH:19][C:13]4[N:14]=[C:15]([S:17][CH3:18])[S:16][C:12]=4[CH:11]=3)[CH:23]=[N:21][C:4]=2[CH:3]=1
Reactant: CSc1nc2ccc(CNc3ccc(Br)cc3N)cc2s1
Reactant: COc1cc(N)c(NCc2ccc3nc(SC)sc3c2)cc1Br
Product: CSc1nc2ccc(Cn3cnc4cc(Br)ccc43)cc2s1

Procedure:
6-((5-Bromo-1H-benzo[d]imidazol-1-yl)methyl)-2-(methylthio)benzo[d]thiazole was synthesized as a white solid (630 mg, 57%) using a procedure analogous to that described in Step 3 of Example 41, substituting 4-bromo-N1-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)benzene-1,2-diamine from Step 3 of this Example for 4-bromo-5-methoxy-N2-((2-(methylthio)benzo[d]thiazol-6-yl)methyl)benzene-1,2-diamine used in Example 41. 1H NMR (300 MHz, DMSO-d6) δ 8.51 (s, 1H), 8.00 (s, 1H), 7.75-7.91 (m, 2H), 7.54 (d, J=8.5 Hz, 1H), 7.33-7.45 (m, 2H), 5.62 (s, 2H), 2.77 (s, 3H). LCMS (ESI) m/z 389 and 391 (M+H)+.
Reaction SMILES: C[O:2][C:3](=[O:22])[CH:4]([NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:5][S:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1.[OH-].[Na+]>CO>[C:18]([O:17][C:15]([NH:14][CH:4]([CH2:5][S:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1)[C:3]([OH:22])=[O:2])=[O:16])([CH3:21])([CH3:19])[CH3:20]
Reactant: COC(=O)C(CSc1ccc(F)cc1)NC(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)NC(CSc1ccc(F)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A suspension of 2-tert-butoxycarbonylamino-3-(4-fluoro-phenylsulfanyl)-propionic acid methyl ester (2.28 g, 6.93 mmol) in methanol (10 ml) was vigorously stirred at room temperature during the addition of 2N aqueous sodium hydroxide solution (7 ml, 14 mmol). The resulting mixture was stirred at room temperature for 2 hours and then concentrated in vacuo. The residue was diluted with water (65 ml) and the aqueous layer was extracted with diethyl ether (2*50 ml). The aqueous layer was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The organic phase was dried (anhydrous magnesium sulfate) and concentrated in vacuo to give, after purification by flash chromatography on silica gel, (dichloromethane/methanol: 98/2 to 96/4) 2-tert-butoxycarbonylamino-3-(4-fluoro-phenylsulfanyl)-propionic acid (2.06 g, 95%) as a pale yellow oil. Mass spectrum, 315 [M+H]+.
Reaction SMILES: [C:1]1([C:7]2[CH:19]=[CH:18][C:10]([C:11]([O:13]C(C)(C)C)=[O:12])=[C:9]([NH:20][S:21](/[CH:24]=[CH:25]/[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)(=[O:23])=[O:22])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>FC(F)(F)C(O)=O>[C:1]1([C:7]2[CH:19]=[CH:18][C:10]([C:11]([OH:13])=[O:12])=[C:9]([NH:20][S:21](/[CH:24]=[CH:25]/[C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)(=[O:23])=[O:22])[CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1NS(=O)(=O)/C=C/c1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1ccc(-c2ccccc2)cc1NS(=O)(=O)/C=C/c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
10 mL of trifluoroacetic acid was added to the obtained tert-butyl 4-phenyl-2-(((E)-2-phenylvinyl) sulfonamido)benzoate and stirred at room temperature for 2 hours. The solvent: was evaporated under reduced pressure and diisopropyl ether was added to the obtained residue and a solid substance was separated by filtration to obtain 26 mg of 4-phenyl-2-(((E)-2-phenylvinyl)sulfonamido)benzoic acid as white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([Si](C)(C)C)=[C:10]([F:18])[CH:9]=2)[N:5]=[C:4]([C:19]([O:21][CH3:22])=[O:20])[C:3]=1[Cl:23].[I:24]Cl.[O-]S([O-])=O.[Na+].[Na+]>ClCCl>[NH2:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([I:24])=[C:10]([F:18])[CH:9]=2)[N:5]=[C:4]([C:19]([O:21][CH3:22])=[O:20])[C:3]=1[Cl:23]
Reactant: COC(=O)c1nc(-c2ccc([Si](C)(C)C)c(F)c2)cc(N)c1Cl
Reactant: ClI
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)c1nc(-c2ccc(I)c(F)c2)cc(N)c1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 99.2 %

Procedure:
To a 250-mL round bottom flask, equipped with a stir bar, was added methyl 4-amino-3-chloro-6-(3-fluoro-4-(trimethylsilyl)phenyl)picolinate (0.328 g, 0.930 mmol), and dichloromethane (5.0 mL). To this solution iodine monochloride (0.141 mL, 2.79 mmol) was added. The reaction mixture was allowed to stir at room temperature for 18 hrs. Another portion of iodine monochloride (0.141 mL, 2.79 mmol) was added, and the reaction was allowed to stir at room temperature for an additional 4.5 hrs. The reaction mixture was poured into 1 M Na2SO3, and the layers were partitioned. The aqueous phase was extracted with additional ethyl acetate (2×100 mL). The combined organic layers were dried over anhydrous magnesium sulfate, filtered and concentrated to afford the title compound as a white solid (0.375 g, 99%):
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[CH:12]([CH2:25][O:26][CH:27]([CH3:29])[CH3:28])[CH2:13][NH:14][C:15](=[O:24])[O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.CN>C(O)C>[NH2:3][CH:12]([CH2:25][O:26][CH:27]([CH3:29])[CH3:28])[CH2:13][NH:14][C:15](=[O:24])[O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC(C)OCC(CNC(=O)OCc1ccccc1)N1C(=O)c2ccccc2C1=O
Agent: CN
Solvent: CCO
Product: CC(C)OCC(N)CNC(=O)OCc1ccccc1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
2.3 g of rac-benzyl [2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-3-isopropoxypropyl]carbamate (5.6 mmol, 1 equivalent) were dissolved in 30 ml of ethanol, 7.3 ml of 40% strength aqueous methylamine solution (84.4 mmol, 15 equivalent) were added and the mixture was stirred at 60° C. overnight. The reaction mixture was concentrated and the residue was then chromatographed on silica gel (Biotage Isolera; mobile phase: dichloromethane/methanol gradient). This gave 730 mg (49% of theory) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[CH:13]=[C:12]([C:14]2[CH:15]=[C:16]([NH:20][CH2:21][CH2:22][NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH:17]=[CH:18][CH:19]=2)[O:11][N:10]=1.C(N(CC)CC)C.[Cl:38][CH:39]([Cl:43])[C:40](Cl)=[O:41]>ClCCl>[Cl:38][CH:39]([Cl:43])[C:40]([N:20]([CH2:21][CH2:22][NH:23][C:24](=[O:30])[O:25][C:26]([CH3:27])([CH3:29])[CH3:28])[C:16]1[CH:17]=[CH:18][CH:19]=[C:14]([C:12]2[O:11][N:10]=[C:9]([C:3]3[C:4]([Cl:8])=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[CH:13]=2)[CH:15]=1)=[O:41]
Reactant: CC(C)(C)OC(=O)NCCNc1cccc(-c2cc(-c3c(Cl)cccc3Cl)no2)c1
Reactant: O=C(Cl)C(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCN(C(=O)C(Cl)Cl)c1cccc(-c2cc(-c3c(Cl)cccc3Cl)no2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
tert-Butyl 2-(3-(3-(2,6-dichlorophenyl)isoxazol-5-yl)phenylamino)ethylcarbamate (230 mg, 0.51 mmol) was dissolved in anhydrous dichloromethane with triethylamine (120 μL, 0.82 mmol). The mixture was cooled in an ice-bath under nitrogen, then a solution of dichloroacetyl chloride (120 mg, 0.82 mmol) was added dropwise. After the addition was completed the ice-bath was removed and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with dichloromethane and then washed successively with water, 10% hydrochloric acid and saturated sodium bicarbonate solution. The organic solution was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography, on silica gel, eluting with 95:5 hexanes:ethyl acetate to yield tert-butyl 2-(2,2-dichloro-N-(3-(3-(2,6-dichlorophenyl)isoxazol-5-yl)phenyl)acetamido)ethylcarbamate. 1H NMR (CDCl3): 7.99 (d, 1H), 7.82 (br s, 1H), 7.62 (m, 1H), 7.48-7.30 (m, 4H), 6.78 (s, 1H), 5.82 (s, 1H), 4.95 (m, 1H), 3.95 (m, 2H), 3.43 (m, 2H), 1.42 ppm (s, 9H).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[B]1OC2C(=CC=CC=2)O1.[OH-].[Na+]>CO>[C:4]1([C@@H:1]([OH:3])[CH3:2])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(=O)c1ccccc1
Agent: [B]1Oc2ccccc2O1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: C[C@H](O)c1ccccc1
Temperature: -78 °C
Reaction time: 24 h
Yield: 88.4 %

Procedure:
(S)-1-phenylethanol was synthesized as shown in FIG. 7. Thiourea (12 mg, 0.025 mmol), which was obtained as shown in Example 1, and 4 Å molecular sieve, which was freshly dried by flame under vacuum for 30 min and cooled under argon, 250 mg, were added to an oven-dried vial and flushed with argon three times. Toluene (0.7 mL) was added to the mixture, followed by acetophenone (30 mg, 0.25 mmol). The mixture was cooled to −78° C. and a solution of catecholborane (1.0 M in Toluene, 0.4 mL, 0.4 mmol) was added slowly along the side of the vial. The resulting reaction mixture was put into a−46° C.˜−48° C. bath. After stirring for 24 hours at −46° C.˜-48° C., MeOH (1 mL) was added followed by 3 N NaOH (1 mL). The mixture was gradually warmed to room temperature and stirred for another 1 hour at room temperature, and then extracted with ether (10 mL×3), dried over Na2SO4 and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel using Hexanes/EtOAc (6:1) as eluent to give (S)-1-phenylethanol as colorless oil (27 mg, 88% yield); 98% ee, HPLC analysis (Chiralcel OD, 250 mm×4.6 mm, 2% iPrOH/Hexane, 1.0 mL/min, 254 nm; tr(major)=19.2 min, tr(minor)=15.0 min); [α]20D=−51.7 (c 1.09, CHCl3, lit. (Sokeirik 2007) (R)-1-phenylethanol, 96% ee, [α]D=+42.92 (c 1.04, CHCl3)); 1H NMR (CDCl3, 300 MHz) δ=7.38-7.23 (m, 5H), 4.87 (q, J=6.3 Hz, 1H), 2.03 (br s, 1H), 1.90 (d, J=6.3 Hz, 3H); 13C NMR (CDCl3, 75 MHz) δ=145.9, 128.6 (2C), 127.6, 125.5 (2C), 70.5, 25.3.