Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:8])([F:7])[CH2:3][CH2:4][CH:5]=[O:6].[Br:9]Br>O1CCOCC1>[Br:9][CH:4]([CH2:3][C:2]([F:8])([F:7])[F:1])[CH:5]=[O:6]
Reactant: O=CCCC(F)(F)F
Reactant: BrBr
Solvent: C1COCCO1
Product: O=CC(Br)CC(F)(F)F
Temperature: 0 °C
Reaction time: 2 h
Yield: 76.2 %

Procedure:
To a mixture of 4,4,4-trifluorobutyraldehyde (5 g, 39.68 mmol) in 1,4-dioxane (5 ml) cooled to 0° C., was added bromine (2.24 ml, 43.65 mmol), dropwise. The reaction mixture was stirred at 0° C. for 2 h. The resulting reaction mixture was filtered through a pad of diatomaceous earth and the filtrate was washed with NaHCO3 (aqueous sat. solution). The organic layer was separated, dried (MgSO4) and evaporated in vacuo to yield compound D8 (6.2 g, 76%) that was used in the next reaction step without further purification.
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([N:14]([CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[CH:24][CH:23]=2)[C:15](=[O:20])[C:16]([F:19])([F:18])[F:17])[CH2:11][CH2:10][NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:32]1([N:38]=[C:39]=[O:40])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>C1(C)C=CC=CC=1>[CH2:1]([C@@H:8]1[CH2:13][C@@H:12]([N:14]([CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]=[CH:24][CH:23]=2)[C:15](=[O:20])[C:16]([F:18])([F:19])[F:17])[CH2:11][CH2:10][N:9]1[C:39](=[O:40])[NH:38][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(N(Cc1ccnc2ccccc12)[C@H]1CCN[C@H](Cc2ccccc2)C1)C(F)(F)F
Reactant: O=C=Nc1ccccc1
Solvent: Cc1ccccc1
Product: O=C(Nc1ccccc1)N1CC[C@H](N(Cc2ccnc3ccccc23)C(=O)C(F)(F)F)C[C@H]1Cc1ccccc1
Reaction time: 2 h

Procedure:
A solution of 200 mg (0.468 mmol) of (2R*,4S*)-2-benzyl-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamine is added to a solution of 72 mg (0.608 mmol) of phenyl isocyanate in 5 ml of toluene, and the reaction mixture is stirred at 100° for 2 hours. The white suspension is cooled and filtered. The title compound is obtained as white crystals of melting point 245° (decomposition). TLC: methylene chloride/methanol/conc. ammonia (700:50:1) Rf =0.76, FD-MS: M+ =546.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].[Cl:9][CH2:10][C:11](=O)[CH2:12][C:13](OCC)=[O:14].S(=O)(=O)(O)O.O>C(O)(=O)C>[Cl:9][CH2:10][C:11]1[C:8]2[C:1](=[CH:3][C:4]([OH:5])=[CH:6][CH:7]=2)[O:2][C:13](=[O:14])[CH:12]=1
Reactant: Oc1cccc(O)c1
Reactant: CCOC(=O)CC(=O)CCl
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)O
Product: O=c1cc(CCl)c2ccc(O)cc2o1
Temperature: 60 °C
Reaction time: 3 h
Yield: 97.2 %

Procedure:
Resorcinol (275 g) was dissolved in acetic acid (560 mL) at 50° C. to prepare a solution. Separately, ethyl 4-chloroacetoacetate (205 g) was dissolved in acetic acid (187 ml), and concentrated sulfuric acid (100 mL) was added at 8° C. The solution was added at 8° C. to the resorcinol solution prepared in advance, and the mixture was stirred at 25° C. for 1 hr and at 60° C. for 3 hr. Warm water (3.24 L) was added at 40° C., and the mixture was stirred at 25° C. for 2 hr. The precipitated solid was collected by filtration. The solid was washed with water and air-dried to give the title compound (255 g) as a yellow solid.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:8][C:9]=1[N:10]([CH:20]([CH3:22])[CH3:21])[C:11]([CH:13]1[CH2:18][CH2:17][C:16](=[CH2:19])[CH2:15][CH2:14]1)=[O:12])=[O:4].[Li+].[OH-]>C1COCC1.CO.O>[CH:20]([N:10]([C:11]([CH:13]1[CH2:14][CH2:15][C:16](=[CH2:19])[CH2:17][CH2:18]1)=[O:12])[C:9]1[CH:8]=[C:7]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[S:6][C:5]=1[C:3]([OH:4])=[O:2])([CH3:22])[CH3:21]
Reactant: C=C1CCC(C(=O)N(c2cc(-c3ccccc3)sc2C(=O)OC)C(C)C)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: C=C1CCC(C(=O)N(c2cc(-c3ccccc3)sc2C(=O)O)C(C)C)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 51.7 %

Procedure:
3-[Isopropyl-(4-methylene-cyclohexanecarbonyl)-amino]-5-phenyl-thiophene-2-carboxylic acid methyl ester (50 mg, 0.126 mmol) was taken in a mixture of THF:MeOH:H2O (3:2:1, 3 mL) and then 1N aqueous solution of LiOH.H20 (0.8 mL, 0.800 mmol) was added. The reaction mixture was stirred at room temperature for 12 h. Solvents were removed and the residue was partitioned between water and ethyl acetate. The aqueous layer was acidified using 10% KHSO4 solution. The organic layer was separated, dried (Na2SO4) and concentrated. The residue was purified by silica gel column chromatography using chloroform and methanol (8:2) to obtain 3-[Isopropyl-(4-methylene-cyclohexanecarbonyl)-amino]-5-phenyl-thiophene-2-carboxylic acid (compound 28) (25 mg, 52%) as a white solid. 1H NMR (CDCl3, 400 MHz): δ7.61 (d, J=7 Hz, 2H), 7.40-7.38 (m, 3H), 7.04 (s, 1H), 4.92 (m, 1H), 4.50 (d, J=7.6 Hz, 2H), 2.21-1.43 (m, 9H), 1.15 (bd, 3H), 0.93 (bd, 3H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][CH3:9])[CH:3]=1.[Mg].[C:11](=[O:13])=[O:12].Cl>O1CCCC1>[CH2:8]([C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=1)[C:11]([OH:13])=[O:12])[CH3:9]
Reactant: CCc1cccc(Br)c1
Reactant: O=C=O
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Product: CCc1cccc(C(=O)O)c1
Reaction time: 0.5 h
Yield: 93 %

Procedure:
Under an argon atmosphere, a solution of 1-bromo-3-ethylbenzene (5.1 g, 28 mmol) in tetrahydrofuran (45 mL) was added dropwise to a mixture of magnesium turnings (0.74 g, 31 mmol) in tetrahydrofuran (5.0 mL), and the mixture was stirred for 30 minutes under the same condition. The reaction mixture was added to crashed dry ice, and the mixture was stirred for 1 hour. To the reaction mixture was added 1N-hydrochloric acid, and extracted with ethyl acetate. The extracts were dried, filtrated and concentrated. The residue was purified by silica gel column chromatography (hexane-ethyl acetate=5:1) to obtain a title compound (3.87 g, yield 93%).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]2[CH2:6][C:7](=[O:18])[NH:8][C:9]3[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:10]=3[C:11]=2[N:12]=1.Br[C:20]1[CH:21]=[C:22]([CH2:28][CH2:29][CH2:30][N:31]([CH3:33])[CH3:32])[C:23]([O:26][CH3:27])=[N:24][CH:25]=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:17][C:15]1[CH:14]=[CH:13][C:10]2[C:11]3[N:12]=[C:2]([NH:1][C:20]4[CH:25]=[N:24][C:23]([O:26][CH3:27])=[C:22]([CH2:28][CH2:29][CH2:30][N:31]([CH3:32])[CH3:33])[CH:21]=4)[N:3]=[CH:4][C:5]=3[CH2:6][C:7](=[O:18])[NH:8][C:9]=2[CH:16]=1
Reactant: Nc1ncc2c(n1)-c1ccc(Cl)cc1NC(=O)C2
Reactant: COc1ncc(Br)cc1CCCN(C)C
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: COc1ncc(Nc2ncc3c(n2)-c2ccc(Cl)cc2NC(=O)C3)cc1CCCN(C)C
Temperature: 150 °C
Yield: 20 %

Procedure:
A mixture of 2-amino-9-chloro-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one (0.36 g, 1.38 mmol), 3-(5-bromo-2-methoxypyridin-3-yl)-N,N-dimethylpropan-1-amine (0.38 g, 1.38 mmol), xphos (0.047 g, 0.099 mmol), and tris(dibenzylideneacetone)dipalladium(0) (0.023 g, 0.026 mmol) in a sealed microwave tube was evacuated and purged with nitrogen three times. To the solids were added tert-butyl alcohol (3.6 mL) and t-BuOK (1M in t-BuOH, 2.63 mL) via syringe. The mixture was stirred well and then subjected to microwave irradiation (150 watts) while heating at 150° C. for 45 min. The reaction mixture was then poured into water (25 mL) with vigorous stirring. The precipitate that formed was filtered, washed with water, and air dried. The residue was purified by column chromatography to give 9-chloro-2-({5-[3-(dimethylamino)propyl]-6-methoxypyridin-3-yl}amino)-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one (0.125 g, 18%).
Reaction SMILES: [CH:1]([NH:4][C:5]1[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=1[CH2:7][OH:8])([CH3:3])[CH3:2]>C1(C)C=CC=CC=1.[O-2].[O-2].[Mn+4]>[CH:1]([NH:4][C:5]1[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=1[CH:7]=[O:8])([CH3:3])[CH3:2]
Reactant: CC(C)Nc1ccccc1CO
Agent: [Mn+4]
Agent: [O-2]
Solvent: Cc1ccccc1
Product: CC(C)Nc1ccccc1C=O
Reaction time: 0.5 h

Procedure:
While heating a solution of 40 g of 2-isopropylaminobenzyl alcohol in 200 ml toluene at 100° C., 58 g in total of activated manganese dioxide was added several times to the solution. After stirring at the same temperature for 30 minutes, insoluble matters were filtered off. The solvent was distilled off to give 2-isopropylaminobenzaldehyde.
Reaction SMILES: [O:1]=[C:2]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C@@H:6]([C:15]([OH:17])=O)[CH2:5][O:4][CH2:3]1.ON1C2C=CC=CC=2N=N1.CN1CCOCC1.[CH2:35]([NH2:42])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.C(Cl)CCl>C(Cl)Cl>[O:1]=[C:2]1[N:7]([CH2:8][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[C@@H:6]([C:15]([NH:42][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[O:17])[CH2:5][O:4][CH2:3]1
Reactant: NCc1ccccc1
Reactant: O=C(O)[C@H]1COCC(=O)N1Cc1ccccc1
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Solvent: ClCCCl
Product: O=C(NCc1ccccc1)[C@H]1COCC(=O)N1Cc1ccccc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 101 %

Procedure:
A mixture of (3R)-5-oxo-4-(phenylmethyl)-3-morpholinecarboxylic acid (69.67 g, 296.2 mmol) and 1-hydroxybenzotriazole (48.01 g, 355.4 mmol) in DCM (990 mL) was cooled to 0° C. To the mixture was added 4-methylmorpholine (163 mL, 1483 mmol), benzyl amine (35.6 mL, 325.9 mmol), and EDC (62.46 g, 325.8 mmol). The yellow solution was stirred overnight at room temperature, and was then washed with water (500 mL), 6 N aqueous HCl (300 mL), and water (200 mL). The organic phase was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give crude (3R)-5-oxo-N,4-bis(phenylmethyl)-3-morpholinecarboxamide (97.05 g, >100% crude yield) as a yellow foam. LCMS: (M+H)+: 325.2.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7](F)=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl.[NH:12]1[CH2:17][CH2:16][C:15](=[O:18])[CH2:14][CH2:13]1.C(N(CC)CC)C.O>C(#N)C>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:12]2[CH2:17][CH2:16][C:15](=[O:18])[CH2:14][CH2:13]2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: O=C1CCNCC1
Agent: Cl
Solvent: O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Yield: 79.4 %

Procedure:
In 20 ml of acetonitrile were dissolved 2.8 g of 4-nitrofluorobenzene, 3 g of 4-piperidone hydrochloride and 6.9 ml of triethylamine, and the solution was then heated under reflux for 6 hours. After cooling, the reaction mixture was poured into 100 ml of water, and the deposited crystals were collected by filtration. The crystals were washed with water and then with ether, and they were recrystallized from isopropanol/hexane (1/1 in terms of volume ratio), collected by filtration, washed, and dried in order to obtain 3.47 g of 1-(4-nitrophenyl)-4-oxopiperidine (compound 62).
Reaction SMILES: ClCC[O:4]C1C=CC([NH2:11])=CC=1.[Cl:12][CH2:13][CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[CH:18][CH:17]=1>C(O)C>[NH4+:11].[OH-:4].[Cl:12][CH2:13][CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1
Reactant: O=[N+]([O-])c1ccc(OCCCl)cc1
Agent: Nc1ccc(OCCCl)cc1
Solvent: CCO
Product: [NH4+]
Product: [OH-]
Temperature: 70 °C

Procedure:
4-(2-Chloro-ethoxy)-phenylamine can be synthesized by the following procedure. A suspension of 1-(2-chloro-ethoxy)-4-nitro-benzene (1.5 mmol) (from Example 1c) and SnCl2-2H2O (5.9 mmol) in absolute ethanol (120 mL) is heated at 70° C. for 2 h. The solvent is removed under vacuum and the residue is dissolved in 5% NaOH and extracted with EtOAc (3×50 mL). The organic layer is washed with 5% NaOH (1×50 mL), water (1×50 mL), brine, and dried over Na2SO4 and reduced to dryness. The dark crude residue is purified by silica chromatography using a mixture of DCM:MeOH:NH4OH=9:1:0.1 to isolate 4-(2-chloro-ethoxy)-phenylamine (90%) which is converted in the hydrochloride salt by treatment with HCl (1 eq of a 4N solution in dioxane). 1HNMR (400 MHz, CD3OD) δ 7.35-7.33 (m, 2H), 7.16-7.05 (m, 2H), 4.38 (m, 2H), 3.87 (m, 2H). MS (m/z) (M+1)+ 173.1.
Reaction SMILES: O(S(C(F)(F)F)(=O)=O)S(C(F)(F)F)(=O)=O.[CH2:16]([O:23][N:24]1[C:30](=[O:31])[N:29]2[CH2:32][C@H:25]1[CH2:26][CH2:27][C@H:28]2[C:33]([NH:35][NH:36][C:37](=[O:49])[CH2:38][CH2:39][N:40]([CH3:48])[C:41](=[O:47])[O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=O)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.N1C=CC=CC=1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH2:16]([O:23][N:24]1[C:30](=[O:31])[N:29]2[CH2:32][C@H:25]1[CH2:26][CH2:27][C@H:28]2[C:33]1[O:49][C:37]([CH2:38][CH2:39][N:40]([CH3:48])[C:41](=[O:47])[O:42][C:43]([CH3:44])([CH3:45])[CH3:46])=[N:36][N:35]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CN(CCC(=O)NNC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1)C(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CN(CCc1nnc([C@@H]2CC[C@@H]3CN2C(=O)N3OCc2ccccc2)o1)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 3 h
Yield: 51.2 %

Procedure:
Tf2O (7.2 mL, 0.0423 mol) was added slowly, drop-wise to a −78° C. solution of tert-butyl 3-(2-((2S,5R)-6-(benzyloxy)-7-oxo-1,6-diaza-bicyclo[3.2.1]octane-2-carbonyl)hydrazinyl)-3-oxopropyl(methyl)carbamate (6.7 g, 14.1 mmol) and pyridine (9.1 mL, 0.113 mol) in dry DCM (110 mL). The reaction mixture was allowed to warm to 0° C. then was stirred at 0° C. for 3 hrs. Aqueous NaHCO3 was added at 0° C. very slowly. The organic layer was separated and the water layer was washed with DCM (3×). The combined organic layer was dried over Na2SO4, and concentrated. The crude product was purified by reverse-phase biotage (water/acetonitrile gradient) to afford tert-butyl 2-(5-((2S,5R)-6-(benzyloxy)-7-oxo-1,6-diaza-bicyclo[3.2.1]octan-2-yl)-1,3,4-oxadiazol-2-yl)ethyl(methyl)carbamate (3.3 g, 51%) as a light yellow solid. ESI-MS (EI+, m/z): 458.0 [M+H]+; 1H NMR (500 MHz, CDCl3): δ 7.45-7.36 (m, 5H), 5.09 (d, J=11.5 Hz, 1H), 4.94 (d, J=11.5 Hz, 1H), 4.71 (t, J=4.5 Hz, 1H), 3.67-3.59 (m, 2H), 3.37 (s, 1H), 3.31 (t, J=6.5 Hz, 2H), 2.94-2.86 (m, 2H), 2.82 (s, 3H), 2.32-2.28 (m, 2H), 2.15-2.12 (m, 1H), 2.00-1.95 (m, 1H), 1.45 (s, 9H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[N+:4]([O-:8])[CH:5]=[CH:6][CH:7]=1.[N+:9]([O-])([OH:11])=[O:10]>S(=O)(=O)(O)O>[F:1][C:2]1[CH:3]=[N+:4]([O-:8])[CH:5]=[CH:6][C:7]=1[N+:9]([O-:11])=[O:10]
Reactant: O=[N+]([O-])O
Reactant: [O-][n+]1cccc(F)c1
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1cc[n+]([O-])cc1F
Temperature: 25 °C

Procedure:
Concentrated H2SO4 (75 ml) was carefully added to 3-fluoropyridine N-oxide (Preparation 5) (50 g, 0.44 mol), cooled at room temperature by using a water bath. Fuming nitric acid (55 ml) was dissolved in concentrated sulfuric acid (75 ml) and the colourless solution was added drop-wise to the substrate over 15 minutes at room temperature. The yellow mixture was heated for 1.5 hours at 90° C. The mixture was allowed to reach room temperature and slowly poured onto ice (900 g). The aqueous layer was extracted with dichloromethane (3×500 ml) and the solvent evaporated under reduced pressure to yield a yellow solid. This was washed with pentane (200 ml). The residue was dissolved in dichloromethane (50 ml). A yellow precipitate formed which was filtered off to yield the title compound (10 g).
Reaction SMILES: [Cl:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:14](Cl)(=O)C(Cl)=O.CO>O1CCCC1>[Cl:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH3:14])=[O:5]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1Cl
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1cccc([N+](=O)[O-])c1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 96.4 %

Procedure:
To a solution of 2-chloro-3-nitrobenzoic acid (100 g, 0.496 mol) in tetrahydrofuran (1000 mL) was added dropwise oxalyl chloride (46.8 mL, 0.546 mol) at 0° C., and the mixture was stirred at room temperature for 3 hr. To the mixture was added dropwise methanol (300 mL) at 0° C., and the mixture was stirred at room temperature for 14 hr. The mixture was concentrated and the residue was neutralized with saturated aqueous sodium hydrogen carbonate, and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to give the solid, which was washed with n-hexane to give the title compound (103 g, 0.478 mol, 96%).
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:14]=[CH:15][C:16]=2[S:17][CH3:18])[C:10]([O:12]C)=[O:11])[CH2:5][CH2:4][CH2:3][CH2:2]1.O.C(=O)([O-])[O-].[K+].[K+]>CO>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:14]=[CH:15][C:16]=2[S:17][CH3:18])[C:10]([OH:12])=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COC(=O)c1ccc(SC)c(OC2CCCC2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CSc1ccc(C(=O)O)cc1OC1CCCC1

Procedure:
A suspension of methyl 3-cyclopentyloxy-4-(methylthio)benzoate (0.8 g; that is prepared as described in Reference Example 54) in methanol (10 mL) and water (5 mL) is treated with potassium carbonate (0.48 g) and the mixture is heated at reflux for 7 hours. The mixture is concentrated, and the resulting residue is partitioned between diethyl ether (20 mL) and water (20 mL). The aqueous layer is separated, acidified to pH 1 by treatment with dilute hydrochloric acid (2 N), and extracted with dichloromethane (2×25 mL). The combined organic extracts are dried and concentrated, to give 3-cyclopentyloxy-4-(methylthio)benzoic acid (0.7 g) in the form of a white solid m.p. 150°-152° C.
Reaction SMILES: Cl.[NH:2]1[CH2:5][CH:4]([OH:6])[CH2:3]1.C([O-])([O-])=O.[K+].[K+].Cl[C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15]>O.C1COCC1>[CH2:17]([O:16][C:14]([N:2]1[CH2:5][CH:4]([OH:6])[CH2:3]1)=[O:15])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: OC1CNC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: O=C(OCc1ccccc1)N1CC(O)C1
Temperature: 22.5 °C
Reaction time: 0.5 h
Yield: 99.2 %

Procedure:
To a solution of azetidin-3-ol hydrochloride 7 (25 g, 0.23 mol) in water (150 mL) and THF (300 mL) was added K2CO3 (63.1 g, 0.46 mol). The mixture was stirred for 30 min. at 20-25° C. Then benzyl chloroformate (40.9 g, 0.24 mol) was added within 30 min. at 0-5° C. followed by stirring the mixture overnight at 20-25° C. THF was removed on a rotavap at 30° C./vacuum and the mixture was extracted with ethyl acetate (2×150 mL). The combined organic layer was washed with water (1×50 mL), dried over Na2SO4 and concentrated. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate-heptanes 1:1 and 4:1 to yield 8 as a clear oil (47.3 g, 100%). 1H NMR (300 MHz, CDCl3): δ 3.72 (1H, d, J=6.2 Hz), 3.85 (2H, dd, J=9.5, 4.4 Hz), 4.17 (2H, dd, J=9.5, 6.7 Hz), 4.49-4.57 (1H, m), 5.06 (2H, s), 7.31-7.38 (5H, m); 13C NMR (75 MHz, CDCl3): δ 59.2, 61.6, 66.9, 127.9, 128.1, 128.5, 136.5, 156.6; IR: (film) 3406, 1686, 1438 cm−1; ES-HRMS m/z: (M++1H) calcd. for C11H14NO3 208.0968. found 208.0967.
Reaction SMILES: [Br:1][CH2:2][CH2:3][C:4]([OH:6])=[O:5].[C:7]1([P:13]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C(#N)C>[Br-:1].[C:4]([CH2:3][CH2:2][P+:13]([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)([OH:6])=[O:5]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: O=C(O)CCBr
Solvent: CC#N
Product: O=C(O)CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Product: [Br-]
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 3-bromopropionic acid (50 g.), triphenylphosphine (85.8 g.) and acetonitrile (250 ml.) is heated under reflux for 23 hrs. and then 166 ml. of acetonitrile is removed by distillation. After cooling the remaining solution to room temperature, benzene (250 ml.) is added and the mixture is allowed to stand for 16 hrs. The solid which separates is removed by filtration to give 120.5 g. of the title compound, m.p. 197°-200°; infrared absorptions at 2900, 2610, 2540, 1745, 1620, 1585, 1485, 1435, 1385, 1325, 1230, 1110, 750, 725 and 690 cm-1 ; NMR peaks at 2.7-3.3 (broad), 3.5-4.2 (broad) and 7.6-7.9 (multiplet) δ.
Reaction SMILES: [CH:1]([C:3]1[C:24]([CH3:25])=[CH:23][C:6]([O:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2/[C:15](=[CH:20]\[O:21][CH3:22])/[C:16]([O:18][CH3:19])=[O:17])=[C:5]([CH3:26])[CH:4]=1)=[O:2].[CH2:27]([Mg]Br)[CH3:28].Cl>O1CCCC1.O>[OH:2][CH:1]([C:3]1[C:24]([CH3:25])=[CH:23][C:6]([O:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2/[C:15](=[CH:20]\[O:21][CH3:22])/[C:16]([O:18][CH3:19])=[O:17])=[C:5]([CH3:26])[CH:4]=1)[CH2:27][CH3:28]
Reactant: CC[Mg]Br
Reactant: CO/C=C(/C(=O)OC)c1ccccc1COc1cc(C)c(C=O)cc1C
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: CCC(O)c1cc(C)c(OCc2ccccc2/C(=C\OC)C(=O)OC)cc1C
Yield: 79 %

Procedure:
A solution of 0.2 g (0.56 mmol) of (E)-methyl 2-(2-((4-formyl-2,5-dimethylphenoxy)methyl)phenyl)-3-methoxyacrylate obtained in Step 1 in 15 mL of tetrahydrofuran (THF) was refrigerated at −78° C. and reacted at that temperature for 2 hours with ethyl magnesium bromide (0.22 mL, 1.2 eq) while stirring. After completion of the reaction, the reaction mixture was adjusted to pH 7 at 0° C. with 1N-HCl and concentrated in a vacuum. The residue thus obtained was stirred in water (10 mL) and extracted twice with 10 mL of dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, filtrated and concentrated in a vacuum to remove the solvent. The concentrate was purified by silica gel chromatography to yield (E)-methyl 2-(2-((4-(1-hydroxypropyl)-2,5-dimethylphenoxy)methyl)phenyl)-3-methoxyacrylate as a white oil (0.17 g, yield 79%).
Reaction SMILES: Br[C:2]1[CH:13]=[CH:12][CH:11]=[CH:10][C:3]=1[CH2:4][C@@H:5]([C:7]([OH:9])=[O:8])[NH2:6].C([O-])([O-])=O.[K+].[K+]>Cl[Cu].CN1C(=O)CCC1>[NH:6]1[C:10]2[C:3](=[CH:2][CH:13]=[CH:12][CH:11]=2)[CH2:4][C@H:5]1[C:7]([OH:9])=[O:8]
Reactant: N[C@@H](Cc1ccccc1Br)C(=O)O
Agent: Cl[Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: O=C(O)[C@@H]1Cc2ccccc2N1
Temperature: 80 °C
Reaction time: 3.5 h
Yield: 49.5 %

Procedure:
A flask was charged successively with 9.76 g (40.0 mmol) (S)-2-bromophenylalanine, 5.80 g (42.0 mmol) K2CO3, 40 mg (0.4 mmol) CuCl and 40 g NMP. The reactor was flushed with argon and then kept under a slow stream of argon. The reaction mixture was stirred and heated until 80° C. and kept at this temperature. Samples were taken regularly and analyzed by HPLC. After 3.5 h full conversion of (S)-2-bromophenylalanine was found. The reaction mixture was cooled to 25° C. and then 40 mL H2O and 50 mL aqueous EtOAc were added. The pH of this mixture was adjusted to 3.3 with 3.5 g 37% aqueous HCl. The phases were separated. The H2O phase was extracted with 2×50 mL aqueous EtOAc. The combined organic layers were washed with 25 mL sat aqueous NaCl. Then the organic phase was concentrated. The residue was dissolved in 16 mL 5N HCl, followed by pH adjustment to 2.1 with 9.4 g 32% aqueous NaOH. The precipitated (S)-2,3-dihydro-1H-indole-2-carboxylic acid was isolated by filtration and washed with 2×10 mL H2O. 3.24 g (19.8 mmol) (S)-2,3-dihydro-1H-indole-2-carboxylic acid was found after drying. Yield 49.5%, ee>99%.