Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[CH:20]=[CH:19][C:9]([O:10][C:11]2[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=2)=[CH:8][CH:7]=1.[CH3:21][N:22]([CH2:27][C:28]1[CH:37]=[CH:36][C:31]([C:32]([O:34][CH3:35])=[O:33])=[CH:30][CH:29]=1)[CH2:23][CH2:24][NH:25][CH3:26].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>ClCCl>[CH3:21][N:22]([CH2:27][C:28]1[CH:29]=[CH:30][C:31]([C:32]([O:34][CH3:35])=[O:33])=[CH:36][CH:37]=1)[CH2:23][CH2:24][N:25]([CH3:26])[CH2:15][C:14]1[CH:17]=[CH:18][C:11]([O:10][C:9]2[CH:19]=[CH:20][C:6]([C:2]3[O:1][CH:5]=[CH:4][N:3]=3)=[CH:7][CH:8]=2)=[CH:12][CH:13]=1
Reactant: O=Cc1ccc(Oc2ccc(-c3ncco3)cc2)cc1
Reactant: CNCCN(C)Cc1ccc(C(=O)OC)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)c1ccc(CN(C)CCN(C)Cc2ccc(Oc3ccc(-c4ncco4)cc3)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65 %

Procedure:
A solution of 4-[4-(2-oxazolyl)phenoxy]benzaldehyde (100 mg, 0.38 mmol) and methyl 4-[(methyl(2-(methylamino)ethyl)amino)methyl]benzoate (90 mg, 0.38 mmol) in dichloromethane (4 mL) was stirred for 15 minutes before the addition of sodium triacetoxyborohydride (160 mg, 76 mmol). The reaction mixture was stirred overnight at ambient temperature. Saturated sodium bicarbonate solution was then added. The mixture was stirred for 30 minutes and then extracted with dichloromethane. The combined organic layers were washed with water, dried over sodium sulfate, and concentrated under reduced pressure. Flash chromatography gave 120 mg of methyl 4-[[methyl[2-[methyl[[4-[4-(2-oxazolyl)phenoxy]phenyl]methyl]amino]ethyl]amino]methyl]benzoate; 1H NMR (300 MHz, CDCl3) δ 7.99 (d, 2H), 7.97 (d, 2H), 7.68 (d, 1H), 7.38 (d, 2H), 7.29 (d, 2H), 7.20 (d, 1H), 7.03 (d, 2H), 6.99 (d, 2H), 3.89 (s, 3H), 3.56 (s, 2H), 3.49 (s, 2H), 2.56 (m, 4H), 2.22 (s, 3H), 2.21 (s, 3H) ppm.
Reaction SMILES: [C@@H:1]12[N:8]([C:9]3[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[N:12]=[C:11]([N:19]([CH3:21])[CH3:20])[N:10]=3)[CH2:7][C@@H:6]1[CH2:5][CH2:4][NH:3][CH2:2]2.CC1C=C(C)N=C(N2[C@@H]3[C@@H](CCNC3)C2)N=1.[F:38][C:39]1[CH:40]=[CH:41][C:42]([N:48]2[N:52]=[CH:51][CH:50]=[N:49]2)=[C:43]([CH:47]=1)[C:44](O)=[O:45].S1C=CC=C1C1C=CC=CC=1C(O)=O>>[CH3:20][N:19]([CH3:21])[C:11]1[N:10]=[C:9]([N:8]2[C@@H:1]3[C@@H:6]([CH2:5][CH2:4][N:3]([C:44]([C:43]4[CH:47]=[C:39]([F:38])[CH:40]=[CH:41][C:42]=4[N:48]4[N:52]=[CH:51][CH:50]=[N:49]4)=[O:45])[CH2:2]3)[CH2:7]2)[CH:14]=[C:13]([C:15]([F:17])([F:18])[F:16])[N:12]=1
Reactant: CN(C)c1nc(N2C[C@@H]3CCNC[C@@H]32)cc(C(F)(F)F)n1
Reactant: O=C(O)c1cc(F)ccc1-n1nccn1
Agent: Cc1cc(C)nc(N2C[C@@H]3CCNC[C@@H]32)n1
Agent: O=C(O)c1ccccc1-c1cccs1
Product: CN(C)c1nc(N2C[C@@H]3CCN(C(=O)c4cc(F)ccc4-n4nccn4)C[C@@H]32)cc(C(F)(F)F)n1

Procedure:
The title compound was prepared in a manner analogous to Example 1, substituting (1R,6S)-[4-(3,8-diaza-bicyclo[4.2.0]oct-8-yl)-6-trifluoromethyl-pyrimidin-2-yl]-dimethyl-amine (Intermediate 11) for (1R,6S)8-(4,6-dimethyl-pyrimidin-2-yl)-3,8-diaza-bicyclo[4.2.0]octane and 5-fluoro-2-[1,2,3]triazol-2-yl-benzoic acid (Intermediate 13) for 2-thiophen-2-yl-benzoic acid. MS (ESI) mass calcd. for C22H22F4N8O, 490.46; m/z found 491.0 [M+H]+. 1H NMR (400 MHz, CDCl3): 8.17-7.73 (m, 2H), 7.44-7.09 (m, 2H), 7.07-6.58 (m, 1H), 5.87-5.54 (m, 1H), 4.51-3.30 (m, 7H), 3.20-2.75 (m, 7H), 2.28-1.87 (m, 2H).
Reaction SMILES: [CH3:1][CH:2]([C:8]([O:10]CC)=O)[C:3]([O:5][CH2:6][CH3:7])=[O:4].N1C=CC=CC=1.[Cl:19][C:20]1[CH:26]=[CH:25][C:23]([NH2:24])=[CH:22][C:21]=1[F:27]>>[Cl:19][C:20]1[CH:26]=[CH:25][C:23]([NH:24][C:8](=[O:10])[CH:2]([CH3:1])[C:3]([O:5][CH2:6][CH3:7])=[O:4])=[CH:22][C:21]=1[F:27]
Reactant: CCOC(=O)C(C)C(=O)OCC
Reactant: Nc1ccc(Cl)c(F)c1
Solvent: c1ccncc1
Product: CCOC(=O)C(C)C(=O)Nc1ccc(Cl)c(F)c1

Procedure:
The ester was prepared according to Procedure A using diethyl 2-methylmalonate (5.32 mL, 30.9 mmol), pyridine (3.33 mL, 41.2 mmol) and 4-chloro-3-fluoroaniline (3.00 g, 20.6 mmol). The residue was purified by column chromatography on silica gel (0-30% EtOAc/hexanes) to give ethyl 3-(4-chloro-3-fluorophenylamino)-2-methyl-3-oxopropanoate as a red oil. Mass Spectrum (ESI) m/e=274.1 (M+1).
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](Cl)=[O:9].CCN(CC)CC.[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH:24]=[CH:25][C:26]=1[O:27][C:28]1[N:33]=[CH:32][CH:31]=[CH:30][N:29]=1)[NH2:23]>C(Cl)Cl>[CH3:18][O:19][C:20]1[CH:21]=[C:22]([NH:23][C:8](=[O:9])[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][N:2]=2)[CH:24]=[CH:25][C:26]=1[O:27][C:28]1[N:29]=[CH:30][CH:31]=[CH:32][N:33]=1
Reactant: O=C(Cl)c1ccccn1
Reactant: COc1cc(N)ccc1Oc1ncccn1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(NC(=O)c2ccccn2)ccc1Oc1ncccn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 19.1 %

Procedure:
According to Scheme 3 Step 3: Picolinoyl chloride hydrochloride (1.33 mmol, 256 mg) and Et3N (2.67 mmol, 0.37 mL) were added sequentially to a solution of 3-methoxy-4-(pyrimidin-2-yloxy)aniline (0.89 mmol, 193 mg) in DCM (3 mL) at 0° C. The reaction mixture was stirred at room temperature for 2 hours. The organic phase was washed with a saturated solution of NaHCO3. The aqueous phase was extracted with AcOEt. The organic phase was washed with brine, was dried over MgSO4, was filtered and was concentrated under reduced pressure. The crude product was purified by flash chromatography over C18 column using water/ACN (70:30) as eluent to afford N-(3-methoxy-4-(pyrimidin-2-yloxy)phenyl)picolinamide (0.17 mmol, 55 mg, 19%) as a white solid.
Reaction SMILES: [Na].[OH:2][CH2:3][C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1.C[O:11][C:12](=O)[CH:13]([C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH:22]([CH3:24])[CH3:23])=[CH:17][CH:16]=1)[CH3:14]>O>[N:6]1[CH:7]=[CH:8][CH:9]=[C:4]([CH2:3][O:2][C:12](=[O:11])[CH:13]([C:15]2[CH:20]=[CH:19][C:18]([CH2:21][CH:22]([CH3:24])[CH3:23])=[CH:17][CH:16]=2)[CH3:14])[CH:5]=1
Reactant: COC(=O)C(C)c1ccc(CC(C)C)cc1
Reactant: OCc1cccnc1
Agent: [Na]
Solvent: O
Product: CC(C)Cc1ccc(C(C)C(=O)OCc2cccnc2)cc1
Temperature: 25 °C

Procedure:
A mixture of 0.05 g of sodium and 8 ml of 3-hydroxymethylpyridine was heated at 65°-70° C. for 10 hours. To this mixture was added 3.8 g of 2-(p-isobutylphenyl)propionic acid methyl ester, and the whole was heated at 95°-100° C. for 8 hours. After cooling to room temperature, 100 ml of water was added. The resulting mixture was extracted with ether, and the ether was distilled away from the extract to leave a residue. The residue was passed through a column of silica gel, and the adsorbate was eluted with chloroform. The eluates were freed of chloroform in vacuo to give 2.9 g of 2-(p-isobutylphenyl)propionic acid-3-pyridylmethyl ester as a colorless oil. The infrared spectrum showed strong C=O absorption at 1730 cm-1 characteristic for ester. Mass spectrum: parent ion 297 m/e.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[CH:5]([NH2:11])[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].C(=O)([O-])O.[K+].[CH2:18]([O:25][C:26](Cl)=[O:27])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>O1CCOCC1.O>[CH2:9]([O:8][C:6](=[O:7])[CH:5]([NH:11][C:26]([O:25][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:27])[C:4]([O:3][CH2:1][CH3:2])=[O:12])[CH3:10]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CCOC(=O)C(N)C(=O)OCC
Agent: O=C([O-])O
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)C(NC(=O)OCc1ccccc1)C(=O)OCC
Reaction time: 1.5 h

Procedure:
To a solution of 2-aminomalonic acid diethyl ester (10.0 g) in dioxane (60 ml) and water (36 ml), potassium hydrogen carbonate (10.4 g) was added. After completion of the effervescence benzylchloroformate (7.4 ml) was added. The mixture was stirred at 23° for 1.5 h then it was concentrated under reduced pressure, taken up with diethyl ether (400 ml) and washed with 5% HCl (50 ml) and brine (50 ml). The organic layer was dried over sodium sulphate and concentrated in vacuo to give the title compound as a colorless oil (13.6 g). T.l.c. EA/CH 1:4 Rf=0.25.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[CH2:10]([NH2:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.CC([O-])(C)C.[Na+].O(CCCC)CCCC>>[CH2:10]([NH:17][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: COc1ccc(Cl)cc1
Reactant: NCc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CCCCOCCCC
Product: COc1ccc(NCc2ccccc2)cc1
Temperature: 85 °C
Yield: 96.5 %

Procedure:
Following general procedure D, a mixture of 4-chloroanisole (1.23 mL, 10 mmol), benzylamine (1.52 mL, 14 mmol), NaOt-Bu (1.15 g, 12 mmol), 10 (4 mg, 0.05 mol %), 1 (2.5 mg, 0.05 mol %), and Bu2O (3 mL) was heated to 85° C. for 1 h. The crude product was purified via the Biotage SP4 (silica-packed 25+M; 0-50% EtOAc/hexanes) to provide the title compound as a yellow oil (2.059 g, 97%). 1H NMR (300 MHz, CDCl3) δ: 7.63-7.52 (m, 5H), 7.06 (d, J=9.0 Hz, 2H), 6.81 (d, J=9.0 Hz, 2H), 4.46 (s, 2H), 4.05 (s, 1H), 3.92 (s, 3H) ppm. 13C NMR (75 MHz, CDCl3) δ: 152.6, 143.1, 140.5, 129.2, 128.1, 127.7, 115.4, 114.6, 56.1, 49.5 ppm. IR (neat, cm−1): 3414, 3029, 2832, 1513, 1453, 1235, 1036, 820, 743, 698. Anal. Calcd. for C14H15NO: C, 78.84; H, 7.09. Found: C, 78.61; H, 7.10.
Reaction SMILES: [Cl:1][CH2:2][C:3]([N:5]([CH2:16][O:17][CH3:18])[C:6]1[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[CH:8][C:7]=1[O:14][CH3:15])=[O:4].[CH2:19](O)[CH2:20]C.CS(O)(=O)=O>CCOCC>[Cl:1][CH2:2][C:3]([N:5]([CH2:16][O:17][CH2:18][CH2:19][CH3:20])[C:6]1[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[CH:8][C:7]=1[O:14][CH3:15])=[O:4]
Reactant: COCN(C(=O)CCl)c1c(OC)cccc1OC
Reactant: CCCO
Agent: CS(=O)(=O)O
Solvent: CCOCC
Product: CCCOCN(C(=O)CCl)c1c(OC)cccc1OC
Reaction time: 16 h
Yield: 68 %

Procedure:
A mixture containing alpha-chloro-N-[methoxymethyl]-N-[2,6-dimethoxyphenyl]acetamide (4.4 g; 0.0161 mole), 150 ml. of n-propanol and 0.2 ml. of methanesulfonic acid was heated at reflux temperature for 9 hours in a soxhlet extractor containing 22 g. of activated 3A molecular sieves. The reaction mixture was allowed to stand at 26° C. for 16 hours and was then concentrated in vacuo yielding a crude product. The crude product was taken up in ether and the ether solution was washed with a 5% sodium carbonate solution. The layers were separated and the organic ether layer was dried over magnesium sulfate, filtered and concentrated in vacuo to yield a white solid. The white solid was recrystallized from hexane to yield alpha-chloro-N-[propoxymethyl]-N-[2,6-dimethoxyphenyl]acetamide (3.3 g; 68% yield) as a white solid having a melting point of 83°-85° C. and the following analysis:
Reaction SMILES: O1CCOCC1.O.Cl.[CH2:9]([O:11][C:12](=[O:15])[CH2:13][NH2:14])[CH3:10].[Cl:16][C:17]1[CH:18]=[CH:19][C:20]2[NH:25]C(=O)[O:23][C:22](=O)[C:21]=2[CH:28]=1>C(N(CC)CC)C>[NH2:25][C:20]1[CH:19]=[CH:18][C:17]([Cl:16])=[CH:28][C:21]=1[C:22]([NH:14][CH2:13][C:12]([O:11][CH2:9][CH3:10])=[O:15])=[O:23]
Reactant: O=c1[nH]c2ccc(Cl)cc2c(=O)o1
Reactant: CCOC(=O)CN
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Solvent: CCN(CC)CC
Product: CCOC(=O)CNC(=O)c1cc(Cl)ccc1N
Yield: 71.2 %

Procedure:
Into a mixed liquor of 160 ml of dioxane with 40 ml of water were dissolved 10.5 g of glycine ethyl ester hydrochloride, and 11.9 g of 6-chloro-2H-3,1-benzoxazine-2,4(1H)-dione were added. To this were added dropwise 8.1 g of triethylamine at room temperature under stirring, and the mixture was stirred for 30 minutes. After stirring further for 1 hour, dioxane was distilled off and 100 ml of water were added. The deposits were collected by filtration, washed with water and dried. Then, these were recrystallized from carbon tetrachloride to obtain 11.0 g of title compound, m.p. 108°-110° C.
Reaction SMILES: [OH-].[Li+].[C:3]([O:7][C:8]([NH:10][CH2:11][C@H:12]([N:17]1[CH2:22][CH2:21][N:20]([C:23](=[O:27])[CH:24]([CH3:26])[CH3:25])[CH2:19][CH2:18]1)[C:13]([O:15]C)=[O:14])=[O:9])([CH3:6])([CH3:5])[CH3:4].C(O)(=O)C>O1CCCC1.O>[C:3]([O:7][C:8]([NH:10][CH2:11][C@H:12]([N:17]1[CH2:22][CH2:21][N:20]([C:23](=[O:27])[CH:24]([CH3:25])[CH3:26])[CH2:19][CH2:18]1)[C:13]([OH:15])=[O:14])=[O:9])([CH3:6])([CH3:5])[CH3:4]
Reactant: COC(=O)[C@H](CNC(=O)OC(C)(C)C)N1CCN(C(=O)C(C)C)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Solvent: C1CCOC1
Product: CC(C)C(=O)N1CCN([C@@H](CNC(=O)OC(C)(C)C)C(=O)O)CC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
10 ml (10 mmol) of an aqueous solution of lithium hydroxide having a concentration of 1N are added to a solution of 2.0 g (5.6 mmol) of methyl (S)-3-tert-butoxycarbonylamino-2-(4-isobutyrylpiperazin-1-yl)propanoate in 40 ml of tetrahydrofuran and 8 ml of water, and then the reaction medium is stirred at ambient temperature for 20 h. After the addition of an aqueous solution of acetic acid having a concentration of 1N, the product is extracted with n-butanol. The organic phase is dried over magnesium sulfate, filtered and concentrated under vacuum, 1.5 g (78%) of (S)-3-tert-butoxycarbonylamino-2-(4-isobutyrylpiperazin-1-yl)propanoic acid are obtained in the form of a white solid.
Reaction SMILES: [CH3:1][N:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([N+:9]([O-])=O)[C:3]1=[O:12]>CO.[Ni]>[NH2:9][C:4]1[C:3](=[O:12])[N:2]([CH3:1])[CH:7]=[C:6]([CH3:8])[CH:5]=1
Reactant: Cc1cc([N+](=O)[O-])c(=O)n(C)c1
Agent: [Ni]
Solvent: CO
Product: Cc1cc(N)c(=O)n(C)c1
Yield: 98.8 %

Procedure:
A solution of 9.74 g (57.9 mmol) 1,5-dimethyl-3-nitropyridin-2(1H)-one (product from step 199.5), 2 g (57.9 mmol) Raney-Ni in 230 ml methanol was shaken in a duck glass under H2 atmosphere for 16 hours. After that, the mixture was filtered over celite, washed with MeOH, concentrated in vacuum and dried at high vacuum over night to obtain 7.9 g (57.2 mmol, 99% yield) of the title compound as a brownish solid. LCMS: (M+H)=139; tR=0.43 min (LC-MS 6). HPLC: tR=1.22 min (HPLC 8). 1H-NMR (DMSO-d6, 400 MHz) δ ppm 6.67 (m, 1H) 6.30 (m, 1H) 5.05 (bs, 2H) 3.38 (s, 3H) 1.93 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:14](=[CH:15][CH:16]=1)[CH:13]([CH2:17]OS(C1C=CC(C)=CC=1)(=O)=O)[CH:12]([C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=1)[CH:11]1[CH:6]2[CH2:7][CH2:8][CH2:9][CH2:10]1.[NH:37]1[CH2:41][CH2:40][CH2:39][CH2:38]1>C1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:14](=[CH:15][CH:16]=1)[CH:13]([CH2:17][N:37]1[CH2:41][CH2:40][CH2:39][CH2:38]1)[CH:12]([C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=1)[CH:11]1[CH:6]2[CH2:7][CH2:8][CH2:9][CH2:10]1
Reactant: C1CCNC1
Reactant: COc1ccc(C2C(COS(=O)(=O)c3ccc(C)cc3)c3ccc(OC)cc3C3CCCCC32)cc1
Solvent: c1ccccc1
Product: COc1ccc(C2C(CN3CCCC3)c3ccc(OC)cc3C3CCCCC32)cc1
Reaction time: 18 h
Yield: 84.5 %

Procedure:
Combine toluene-4-sulfonic acid 6-methoxy-10-(4-methoxy-phenyl)-1,2,3,4,4a,9,10,10a-octahydro-phenanthren-9-ylmethyl ester (0.087 g, 0.175 mmol), pyrrolidine (0.09 mL, 1.05 mmol), and benzene (5 mL), and reflux under nitrogen atmosphere. After 18 hours, concentrate reaction under vacuum then add ethyl acetate and wash with sodium bicarbonate solution (aq). Separate the organic phase and wash with brine. Dry the organic phase with anhydrous sodium sulfate and flash chromatograph using 2% to 4% (2M NH3 methanol)/methylene chloride to yield the titled compound (0.060 g, 86%) as a white solid. TLC Rf=0.25 in 4% 2M NH3 methanol:DCM. 1H NMR (CDCl3): 7.95 (d, 1H, J=8.4 Hz), 7.24 (d, 2H, J=8.4 Hz), 6.91 (m, 3H), 6.79 (dd, 1H, J=8.6, 2.4 Hz), 3.85 (s, 6H), 3.34 (t, 1H, J=9.2 Hz), 3.22 (s, 1H), 3.07 (dd, 1H, J=11.7, 3.3 Hz), 2.74 (dd, 1H, J=12.3, 7.5 Hz), 2.42 (m, 4H), 2.20 (m, 2H), 1.89 (m, 1H), 1.66 (m, 6H), 1.43 (m, 2H), 1.17 (m, 3H); MS m/z 406 (M+1).
Reaction SMILES: C1(COC([NH:11][CH:12]([CH3:63])[C:13]([O:15][CH2:16][CH2:17][CH2:18][NH:19][C:20]([CH:22]2[CH2:31][CH2:30][C:29]3[C:24](=[C:25]([CH2:60][CH2:61][CH3:62])[C:26]([O:32][CH2:33][CH2:34][CH2:35][O:36][C:37]4[CH:42]=[C:41]([O:43]CC5C=CC=CC=5)[C:40]([C:51]5[CH:56]=[CH:55][C:54]([F:57])=[CH:53][CH:52]=5)=[CH:39][C:38]=4[CH2:58][CH3:59])=[CH:27][CH:28]=3)[O:23]2)=[O:21])=[O:14])=O)C=CC=CC=1>CO.C(Cl)(Cl)Cl.[Pd]>[NH2:11][CH:12]([CH3:63])[C:13]([O:15][CH2:16][CH2:17][CH2:18][NH:19][C:20]([CH:22]1[CH2:31][CH2:30][C:29]2[C:24](=[C:25]([CH2:60][CH2:61][CH3:62])[C:26]([O:32][CH2:33][CH2:34][CH2:35][O:36][C:37]3[C:38]([CH2:58][CH3:59])=[CH:39][C:40]([C:51]4[CH:56]=[CH:55][C:54]([F:57])=[CH:53][CH:52]=4)=[C:41]([OH:43])[CH:42]=3)=[CH:27][CH:28]=2)[O:23]1)=[O:21])=[O:14]
Reactant: CCCc1c(OCCCOc2cc(OCc3ccccc3)c(-c3ccc(F)cc3)cc2CC)ccc2c1OC(C(=O)NCCCOC(=O)C(C)NC(=O)OCc1ccccc1)CC2
Agent: [Pd]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CCCc1c(OCCCOc2cc(O)c(-c3ccc(F)cc3)cc2CC)ccc2c1OC(C(=O)NCCCOC(=O)C(C)N)CC2
Yield: 95.2 %

Procedure:
3-((7-(3-(2-ethyl-4-(4-fluorophenyl)-5-(phenylmethyloxy)phenoxy)propoxy)-8-propylchroman-2-yl)carbonylamino)propyl 2-((phenylmethoxy)carbonylamino)propanoate (125 mg) is dissolved in methanol/chloroform (2:1, 7 mL) with 50 mg 10% Pd/C catalyst. Hydrogen gas is bubbled in for 3 hours, when the mixture is filtered through Celite® and concentrated to yield 88 mg of product as a white crunchy foam. Mass Spec (EI) m/z=637.5 (M+H)
Reaction SMILES: [CH3:1][CH:2]([CH2:5][CH2:6][C@H:7]1[CH2:11][CH:10]=[C:9]([CH3:12])[C:8]1([CH3:14])[CH3:13])[CH:3]=[O:4].C(O)(=O)C1C=CC=CC=1>>[CH3:1][CH:2]([CH2:5][CH2:6][C@H:7]1[CH2:11][CH:10]=[C:9]([CH3:12])[C:8]1([CH3:13])[CH3:14])[CH2:3][OH:4]
Reactant: CC1=CC[C@H](CCC(C)C=O)C1(C)C
Agent: O=C(O)c1ccccc1
Product: CC1=CC[C@H](CCC(C)CO)C1(C)C
Temperature: 100 °C

Procedure:
2-methyl-4-((S)-2,2,3-trimethylcyclopent-3-en-1-yl)butanal (as a 50/50 diastereoisomers mixture) (388 g, 2 mol.), benzoic acid (2.44 g, 0.02 mol., 1 mol.%) and (ethylenediamine) [1,2-bis(diphenylphosphino)ethane]ruthenium(bispivalate) (30.5 mg, 0.04 mmol, 0.002 mol.%) were loaded altogether in a 1 L autoclave equipped with a mechanical stirring device. Sealed autoclave was then purged under stirring with nitrogen (3 times 5 bars) and hydrogen (3 times 5 bars) before being pressurized to 50 bars hydrogen. It was then heated to 100° C. and hydrogen pressure was maintained to 50 bars during all the reaction to afford desired product with more than 99.0% selectivity as a 50/50 diastereoisomers mixture and no loss of optical purity. Upon complete reaction conversion (checked by both hydrogen consumption and GC), autoclave was cooled down to 25° C. It was then depressurized and purged with nitrogen (3 times 5 bars). After flash distillation, 2-methyl-4-((S)-2,2,3-trimethylcyclopent-3-en-1-yl)butan-1-ol was obtained in more than 98.0% yield.
Reaction SMILES: O[Li].O.C[O:5][C:6](=[O:25])[CH2:7][CH2:8][CH2:9][CH2:10][C:11]1[S:12][CH:13]=[C:14]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:17]=2[OH:24])[N:15]=1.Cl>O.O1CCOCC1>[OH:24][C:17]1[CH:18]=[C:19]([O:22][CH3:23])[CH:20]=[CH:21][C:16]=1[C:14]1[N:15]=[C:11]([CH2:10][CH2:9][CH2:8][CH2:7][C:6]([OH:25])=[O:5])[S:12][CH:13]=1
Reactant: COC(=O)CCCCc1nc(-c2ccc(OC)cc2O)cs1
Agent: Cl
Agent: [Li]O
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(-c2csc(CCCCC(=O)O)n2)c(O)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.8 %

Procedure:
Add a solution of LiOH.H2O (1.76 g, 41.9 mmol) in water (25 mL) to a rapidly stirred solution of 5-[4-(2-hydroxy-4-methoxy-phenyl)-thiazol-2-yl]-pentanoic acid methyl ester (2.69 g, 8.4 mmol) in dioxane (50 mL), stir at room temperature. After 1 hour, acidify to pH 1 with 5N HCl solution and cool under N2 in a refrigerator. Filter out solids and rinse with ice cold water. Dry solids in a vacuum oven overnight to afford the title compound (2.50 g, 96%). MS (IS) 308 (M+1)+.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][O:4][C:3]2[CH:7]=[CH:8][C:9]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:10][C:2]1=2.[H-].[Na+].I[CH3:20]>CN(C=O)C.O>[O:1]1[CH2:6][CH2:5][O:4][C:3]2[CH:7]=[CH:8][C:9]([CH:11]([CH3:20])[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:10][C:2]1=2
Reactant: CCOC(=O)Cc1ccc2c(c1)OCCO2
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)c1ccc2c(c1)OCCO2
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of Ethyl 2-(2,3-dihydrobenzo[b][1,4]dioxin-7-yl)acetate (257 mg, 1.16 mmol) in DMF (2 mL) was added NaH (50 mg, 1.25 mmol) and iodomethane (167 mg, 1.18 mmol) in DMF (0.5 mL) at 0° C. The reaction mixture was stirred for 1 hrs at 0° C. then diluted with H2O (20 mL) and extracted with EtOAc (20 mL). The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel using EtOAc:hexanes (1:6) as eluant.
Reaction SMILES: [OH:1][C:2]1[C:7]2[CH:8]=[C:9]([CH3:11])[O:10][C:6]=2[CH:5]=[C:4]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:3]=1.F[C:18]1[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:20][CH:19]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[CH3:11][C:9]1[O:10][C:6]2[CH:5]=[C:4]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:3]=[C:2]([O:1][C:18]3[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:20][CH:19]=3)[C:7]=2[CH:8]=1
Reactant: CCOC(=O)c1cc(O)c2cc(C)oc2c1
Reactant: CS(=O)(=O)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(Oc2ccc(S(C)(=O)=O)cc2)c2cc(C)oc2c1
Temperature: 120 °C
Yield: 66.4 %

Procedure:
The mixture of ethyl 4-hydroxy-2-methylbenzofuran-6-carboxylate (4.5 g, 20.4 mmol), 1-fluoro-4-(methylsulfonyl)benzene (5.34 g, 30.7 mmol) and Cs2CO3 (9.99 g, 30.7 mmol) in DMF(10 mL) was heated in a microwave at 120° C. for 60 min. The sample was filtered and the filtrate was concentrated to give an oil residue. The oil was purified by HPLC to give the title compound (5.074 g, 66%) as an off-white solid. 1H NMR (300 MHz, CHLOROFORM-D) d ppm 1.39 (t, J=7.16 Hz, 3 H) 2.46 (s, 3 H) 3.06 (s, 3H) 4.38 (q, J=7.16 Hz, 2 H) 6.21 (s, 1 H) 7.00-7.14 (m, 2 H) 7.62 (s, 1 H) 7.81-7.95 (m, 2 H) 8.01 (s, 1 H).
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][C:7]2[CH2:8][CH2:9][NH:10][CH2:11][CH2:12][C:6]=2[CH:5]=1)([O-:3])=[O:2].Cl[CH2:16][C:17]1[CH:26]=[CH:25][C:24]2[C:19](=[CH:20][CH:21]=[C:22]([N+:27]([O-:29])=[O:28])[CH:23]=2)[N:18]=1.[I-].[Na+].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[N+:1]([C:4]1[CH:14]=[CH:13][C:7]2[CH2:8][CH2:9][N:10]([CH2:16][C:17]3[CH:26]=[CH:25][C:24]4[C:19](=[CH:20][CH:21]=[C:22]([N+:27]([O-:29])=[O:28])[CH:23]=4)[N:18]=3)[CH2:11][CH2:12][C:6]=2[CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc2c(c1)CCNCC2
Reactant: O=[N+]([O-])c1ccc2nc(CCl)ccc2c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: O=[N+]([O-])c1ccc2c(c1)CCN(Cc1ccc3cc([N+](=O)[O-])ccc3n1)CC2

Procedure:
7-Nitro-1,2,4,5-tetrahydro-3H-3-benzazepine (0.35 g), 2-chloromethyl-6-nitroquinoline (0.4 g - see Chem. Pharm. Bull, 28, page 2441 [1980]), sodium iodide (0.27 g) and potassium carbonate (0.25 g) in acetonitrile were heated under reflux for 18 hours. The solvent was then removed in vacuo, the residue dissolved in methylene chloride and washed three times with aqueous sodium carbonate and twice with brine. The organic layer was dried (Na2SO4) and evaporated in vacuo to give an oil which was triturated with hexane to give the title compound, yield 0.61 g, m.p. 127°-130°.