Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH3:55])([CH2:10][C:11]([O:13][C@H:14]1[CH2:31][CH2:30][C@@:29]2([CH3:32])[C@@H:16]([CH2:17][CH2:18][C@:19]3([CH3:52])[C@@H:28]2[CH2:27][CH2:26][C@H:25]2[C@@:20]3([CH3:51])[CH2:21][CH2:22][C@@:23]3(/[CH:40]=[CH:41]/[C:42]([NH:44][CH:45]4[CH2:50][CH2:49][CH2:48][CH2:47][CH2:46]4)=[O:43])[CH2:35][C:34](=[O:36])[C:33]([CH:37]([CH3:39])[CH3:38])=[C:24]32)[C:15]1([CH3:54])[CH3:53])=[O:12])[C:3]([O:5]C(C)(C)C)=[O:4].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:45]1([NH:44][C:42](=[O:43])/[CH:41]=[CH:40]/[C@:23]23[CH2:35][C:34](=[O:36])[C:33]([CH:37]([CH3:38])[CH3:39])=[C:24]2[C@@H:25]2[C@@:20]([CH3:51])([CH2:21][CH2:22]3)[C@@:19]3([CH3:52])[C@@H:28]([C@:29]4([CH3:32])[C@@H:16]([CH2:17][CH2:18]3)[C:15]([CH3:54])([CH3:53])[C@@H:14]([O:13][C:11](=[O:12])[CH2:10][C:2]([CH3:1])([CH3:55])[C:3]([OH:5])=[O:4])[CH2:31][CH2:30]4)[CH2:27][CH2:26]2)[CH2:50][CH2:49][CH2:48][CH2:47][CH2:46]1
Reactant: CC(C)C1=C2[C@H]3CC[C@@H]4[C@@]5(C)CC[C@H](OC(=O)CC(C)(C)C(=O)OC(C)(C)C)C(C)(C)[C@@H]5CC[C@@]4(C)[C@]3(C)CC[C@@]2(/C=C/C(=O)NC2CCCCC2)CC1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)C1=C2[C@H]3CC[C@@H]4[C@@]5(C)CC[C@H](OC(=O)CC(C)(C)C(=O)O)C(C)(C)[C@@H]5CC[C@@]4(C)[C@]3(C)CC[C@@]2(/C=C/C(=O)NC2CCCCC2)CC1=O
Temperature: 30 °C
Reaction time: 2 h
Yield: 32.4 %

Procedure:
To a solution of 1-tert-butyl 4-((3aS,5aR,5bR,7aR,9S,11aR,11bR,13aS)-3a-((E)-3-(cyclohexylamino)-3-oxoprop-1-en-1-yl)-1-isopropyl-5a,5b,8,8,11a-pentamethyl-2-oxo-3,3a,4,5,5a,5b,6,7,7a,8,9,10,11,11a,11b,12,13,13a-octadecahydro-2H-cyclopenta[a]chrysen-9-yl) 2,2-dimethylsuccinate (400 mg, 0.525 mmol) in DCM (10 mL) stirred at room temp was added TFA (5 mL, 64.9 mmol). The reaction mixture was stirred at 30° C. for 2 h. The mixture was evaporated to dryness, then diluted by 200 mL DCM. The organic phase was washed with saturated NaHCO3 solution, water and saturated brine, dried and concentrated under reduced pressure to afford crude product. This material was further purified by preparative-HPLC to afford the title compound (120 mg, 32%) as a white solid. 1H NMR (400 MHz, CHLOROFORM-d) δ=6.92 (d, J=15.8 Hz, 1H), 5.62 (d, J=15.8 Hz, 1H), 5.37 (d, J=8.3 Hz, 1H), 4.50 (dd, J=5.3, 11.0 Hz, 1H), 3.94-3.73 (m, 1H), 3.27-3.14 (m, 2H), 2.80-2.51 (m, 3H), 2.37-2.03 (m, 3H), 2.03-0.69 (m, 54H); LC/MS: m/z calculated 705.5. Found 706.3 (M+1)+.
Reaction SMILES: Cl[C:2]1[C:7]([NH2:8])=[C:6]([Cl:9])[N:5]=[C:4]([CH3:10])[N:3]=1.[CH3:11][S:12][CH2:13][CH2:14][NH2:15].C(N(CC)CC)C>C(O)(C)C>[Cl:9][C:6]1[N:5]=[C:4]([CH3:10])[N:3]=[C:2]([NH:15][CH2:14][CH2:13][S:12][CH3:11])[C:7]=1[NH2:8]
Reactant: Cc1nc(Cl)c(N)c(Cl)n1
Reactant: CSCCN
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: CSCCNc1nc(C)nc(Cl)c1N
Temperature: 25 °C
Yield: 93.3 %

Procedure:
Heat a solution of 4,6-dichloro-2-methyl-pyrimidin-5-amine (46.0 g, 0.258 mol), 2-(methylthio)ethyl amine (40.05 g, 0.439 mol) and triethylamine (53.3 g, 0.517 mol) in isopropanol (500 mL) at 90° C. for 30 h. Cool the reaction mixture to room temperature and concentrate. Dissolve the residue in dichloromethane (2 L) and wash with water (2×500 mL) and brine (500 mL). Dry the organic layer over solid sodium sulfate, filter, and evaporate to afford a brown solid. Purify the residue on a silica gel column eluting with ethyl acetate to give the title compound (56 g). ES/MS (m/z) 233 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:8][C:9]=1[NH2:10])=[O:4].[CH2:17]([O:19][C:20](=[O:32])[CH2:21][CH2:22][CH2:23][C:24]([CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)=O)[CH3:18].C1([SiH3])C=CC=CC=1.C([Sn](Cl)(Cl)CCCC)CCC>O1CCOCC1>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:8][C:9]=1[NH:10][CH:24]([CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)[CH2:23][CH2:22][CH2:21][C:20]([O:19][CH2:17][CH3:18])=[O:32])=[O:4]
Reactant: CCOC(=O)CCCC(=O)C1CCCCC1
Reactant: COC(=O)c1sc(-c2ccccc2)cc1N
Agent: CCCC[Sn](Cl)(Cl)CCCC
Agent: [SiH3]c1ccccc1
Solvent: C1COCCO1
Product: CCOC(=O)CCCC(Nc1cc(-c2ccccc2)sc1C(=O)OC)C1CCCCC1
Temperature: 120 °C
Yield: 15.4 %

Procedure:
A flask was charged with 3-amino-5-phenyl-thiophene-2-carboxylic acid methyl ester (515 mg, 2.2 mmol, 1.0 equiv), 5-cyclohexyl-5-oxo-pentanoic acid ethyl ester (500 mg, 2.2 mmol, 1.0 equiv), phenyl silane (240 mg, 2.2 mmol, 1.0 equiv), dibutyltin dichloride (67 mg, 0.22 mmol, 0.1 equiv) and dioxane (2.0 mL). The resulting solution was heated at 120° C. with microwave for 2 hours. The solution was then concentrated and the residue was purified by silica gel column chromatography, EtOAc/heptane 5% to 40%, to give oil that contained starting material. The material was further purified with silica gel column chromotography, EtOH/DCM 2% to 10% to give product 150 mg (yield 15%).
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([N:13]2[CH2:17][CH:16]([N:18]([CH3:23])[C:19]([O:21][CH3:22])=[O:20])[C:15]([C:24]3[CH:29]=[CH:28][C:27]([O:30]C(F)F)=[CH:26][CH:25]=3)=[N:14]2)=[O:12])=[CH:6][CH:5]=1.C(O)(C)(C)C.CC(C)([O-])C.[K+].C(O)(=O)C>O1CCCC1>[F:35][C:2]([F:1])([F:34])[O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([N:13]2[CH2:17][CH:16]([N:18]([CH3:23])[C:19]([O:21][CH3:22])=[O:20])[C:15]([C:24]3[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=3)=[N:14]2)=[O:12])=[CH:6][CH:5]=1
Reactant: COC(=O)N(C)C1CN(C(=O)Nc2ccc(OC(F)(F)F)cc2)N=C1c1ccc(OC(F)F)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COC(=O)N(C)C1CN(C(=O)Nc2ccc(OC(F)(F)F)cc2)N=C1c1ccc(O)cc1

Procedure:
To 25.5 g (50.8 mmole) of N-(4-trifluoromethoxyphenyl)-3-(4-difluoromethoxyphenyl)-4-(N-methyl-N-(methoxycarbonyl)amino)-4,5-dihydro-1H-pyrazole-1-carboxamide dissolved in 25 g of tetrahydrofuran and 25 g of t-butanol was added 10 g of potassium t-butoxide. The mixture was refluxed for 1 hour and an additional 3.5 g of potassium t-butoxide was added. After refluxing an additional hour the mixture was acidified with acetic acid, concentrated in vacuo, and partitioned between methylene chloride and water. The organic layer was dried over anhydrous magnesium sulfate, filtered, concentrated in vacuo, and chromatographed over silica gel using hexane and diethyl ether to yield the expected compound, a white solid, mp 228°-233° C.
Reaction SMILES: [CH3:1][C:2]([CH3:22])=[CH:3][CH2:4][CH2:5]/[C:6](/[CH3:21])=[CH:7]/[CH2:8][CH2:9]/[C:10](/[CH3:20])=[CH:11]/[CH2:12][S:13][CH2:14][C@H:15]([NH2:19])[C:16]([OH:18])=[O:17].C([O-])([O-])=O.[K+].[K+].[CH2:29]=[C:30]1[CH2:34][C:33](=[O:35])[O:32][C:31]1=[O:36].Cl>C1COCC1>[C:16]([C@@H:15]([NH:19][C:33](=[O:35])[CH2:34][C:30](=[CH2:29])[C:31]([OH:36])=[O:32])[CH2:14][S:13][CH2:12]/[CH:11]=[C:10](\[CH3:20])/[CH2:9][CH2:8]/[CH:7]=[C:6](\[CH3:21])/[CH2:5][CH2:4][CH:3]=[C:2]([CH3:22])[CH3:1])([OH:18])=[O:17]
Reactant: C=C1CC(=O)OC1=O
Reactant: CC(C)=CCC/C(C)=C/CC/C(C)=C/CSC[C@H](N)C(=O)O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=C(CC(=O)N[C@@H](CSC/C=C(\C)CC/C=C(\C)CCC=C(C)C)C(=O)O)C(=O)O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
S-trans, trans-Farnesyl-L-cysteine (500 mg, 1.54 mmol) was dissolved in mixture of THF and a first portion of K2CO3 (3 mmol) and the resulting solution was cooled to 5° C. with vigorous stirring. To this stirred solution was added 3-methylenedihydro-2,5-furandione (302 mg, 3.07 mmol) portionwise while maintaining the pH at 9.0-10.0 with another portion of K2CO3 (3 mmol). The mixture was stirred at room temperature for 3 h. HPLC analysis showed completion of the reaction. The pH of the reaction mixture then adjusted to 2.0 by the addition of 2 N HCl solution. The acidic solution was extracted three times with 15 mL of ethyl acetate. The combined organic extract was washed with water, brine and dried over Na2SO4, the solvent was removed under reduced pressure to afford crude Compound F, which was further purified by preparative HPLC (552 mg, 82%) to yield Compound F. 1H-NMR (500 MHz, CDCl3): δ 1.59 (s, 6H), 1.67 (s, 3H), 1.68 (s, 3H), 2.05 (m, 8H), 2.88 (dd, J=6.5, 14.0, 1H), 2.95 (dd, J=6.5, 14.0, 1H), 3.17-3.15 (m, 2H), 3.36 (d, J=14 Hz, 1H), 4.77 (dd, J=6, 12.5 Hz, 1H), 5.09 (bt, 2H), 5.22 (t, J=7.5 Hz, 1H), 5.93 (s, 1H), 6.46 (s, 1H). 13C-NMR (125 MHz, CDCl3): δ 16.0, 16.2, 17.7, 25.7, 26.7, 29.9, 32.8, 39.6, 39.7, 40.2, 52.0, 119.4, 123.7, 131.3, 132.0, 135.4, 140.3, 170.3, 171.5, 176.0; ES-MS: mass calcd for Chemical Formula: C23H35NO5S 437.6. Found (M+Na) m/z 446.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][CH:13]([OH:16])[CH2:12][CH2:11]2)=[CH:6][C:5]=1Br.[C:19]1(B(O)O)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][O:2][C:3]([C:4]1[C:5]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:6][C:7]([N:10]2[CH2:15][CH2:14][CH:13]([OH:16])[CH2:12][CH2:11]2)=[CH:8][CH:9]=1)=[O:18]
Reactant: OB(O)c1ccccc1
Reactant: COC(=O)c1ccc(N2CCC(O)CC2)cc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: COC(=O)c1ccc(N2CCC(O)CC2)cc1-c1ccccc1
Temperature: 90 °C
Yield: 91.6 %

Procedure:
A mixture of 2-bromo-4-(4-hydroxy-piperidin-1-yl)-benzoic acid methyl ester (1.2 g, 3.82 mmol), phenylboronic acid (800 mg; 6.56 mmol), potassium phosphate, tribasic, mono-hydrate (1.3 g, 10.7 mmol), and tetrakis(triphenylphosphine)palladium (500 mg, 0.433 mmol) in 1,2-dimethoxyethane (25 mL) and water (1 mL) is heated to 90° C. under a nitrogen atmosphere for 24 h. The mixture is concentrated and partitioned between ethyl acetate and water. The solvent layers are separated and the aqueous layer is extracted with ethyl acetate (3×). The combined ethyl acetate layers are dried (MgSO4), filtered, and concentrated under reduced pressure. The residue is purified on silica (120 g) eluting with a gradient of 0% to 100% ethyl acetate in heptane to provide the desired product (1.09 g, 92%) as a gummy residue. LC-ES/MS m/z 312.0 (M+1)
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C([O-])([O-])=O.[K+].[K+].[Br:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH2:17]Br>C(#N)C.O>[Br:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=1)[CH2:17][N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: C1COCCN1
Reactant: BrCc1cccc(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: Brc1cccc(CN2CCOCC2)c1
Temperature: 27.5 °C
Reaction time: 16 h
Yield: 47.1 %

Procedure:
To a stirred solution of morpholine (0.5 g, 5.8 mmol) in acetonitrile (5 ml) was added K2CO3 (2.4 g, 17.44 mmol), followed by 3-bromobenzyl bromide (1.45 g, 5.8 mmol) at 0° C. and the reaction mixture was stirred at 20-35° C. for 16 h. The progress of the reaction was monitored by TLC. After 16 h of stirring, the mixture was diluted with water (50 ml) and extracted with ethyl acetate (2×50 ml). The combined organic layers were washed with brine (50 ml), followed by drying over anhydrous Na2SO4 and filtering. The filtrate was rotary evaporated to get residue which was purified by column chromatography using a mixture of 5% ethyl acetate/hexane as an eluent to get the desired compound as a white solid (700 mg, 35%). 1H NMR (400 MHz, DMSO-d6) δ 7.26 (d, J=8.3 Hz, 2H), 7.19-7.15 (m, 2H), 5.18 (s, 2H), 3.56 (t, J=4.6 Hz, 4H), 2.58 (t, J=4.4 Hz, 4H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][NH:5][C:4](=[O:8])[CH:3]=1.[Cl:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=1)[C:13](Cl)=[O:14]>N1C=CC=CC=1>[Cl:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=1)[C:13]([O:8][C:4]1[CH:3]=[C:2]([O:1][C:13](=[O:14])[C:12]2[CH:16]=[CH:17][CH:18]=[C:10]([Cl:9])[CH:11]=2)[CH:7]=[CH:6][N:5]=1)=[O:14]
Reactant: O=C(Cl)c1cccc(Cl)c1
Reactant: O=c1cc(O)cc[nH]1
Solvent: c1ccncc1
Product: O=C(Oc1ccnc(OC(=O)c2cccc(Cl)c2)c1)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 50 %

Procedure:
A 1.00 g quantity of 4-hydroxy-2-pyridone was suspended in 30 ml of pyridine and 3.46 g of 3-chlorobenzoyl chloride was added to the suspension. The mixture was stirred at room temperature for 2 days. The reaction mixture was filtered and the filtrate was concentrated and the concentrate was extracted with ethyl acetate. The extract was concentrated and the concentrate was washed with water and with methanol, giving 1.74 g of the title compound in a yield of 50%.
Reaction SMILES: C([O:8][C:9](=[O:31])[CH2:10][NH:11][C:12]([C:14]1[C:15](=[O:30])[N:16]([CH3:29])[C:17]2[C:22]([C:23]=1[OH:24])=[CH:21][CH:20]=[C:19]([C:25]([O:27]C)=[O:26])[CH:18]=2)=[O:13])C1C=CC=CC=1.O.[OH-].[Li+]>O1CCOCC1.O>[C:9]([CH2:10][NH:11][C:12]([C:14]1[C:15](=[O:30])[N:16]([CH3:29])[C:17]2[C:22]([C:23]=1[OH:24])=[CH:21][CH:20]=[C:19]([C:25]([OH:27])=[O:26])[CH:18]=2)=[O:13])([OH:31])=[O:8]
Reactant: COC(=O)c1ccc2c(O)c(C(=O)NCC(=O)OCc3ccccc3)c(=O)n(C)c2c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: Cn1c(=O)c(C(=O)NCC(=O)O)c(O)c2ccc(C(=O)O)cc21

Procedure:
Methyl 3-((2-(benzyloxy)-2-oxoethyl)carbamoyl)-4-hydroxy-1-methyl-2-oxo-1,2-dihydroquinoline-7-carboxylate (26 mg, 61 μmol) (65689-17-3) was dissolved in 12 ml dioxane/H2O (5:1) and to this was added lithium hydroxide monohydrate (613 μl, 613 μmol) as a 1M aqueous solution. The resultant mixture was heated to 60 C for 4 hrs. The solvent was removed in vacuo and the aqueous layer was acidified with 2N HCl to pH2. Following dilution with EtOAc, the layers were separated and the aqueous layer was extracted with EtOAc (3×). The organic layer was washed with H2O and brine, then dried over Na2SO4. The solvent was removed by rotovap, azeotroping with benzene (3×) to give a light yellow solid which was rinsed with DCM followed by MeOH.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[C:5]([N+:10]([O-:12])=[O:11])[CH:4]=1.[C:13]([O:17][CH2:18][CH3:19])(=[O:16])[CH:14]=O.C1(C)C=CC=CC=1>C1(C)C=CC=CC=1>[C:13]([O:17][CH2:18][CH:19]=[N:7][C:6]1[CH:8]=[CH:9][C:3]([O:2][CH3:1])=[CH:4][C:5]=1[N+:10]([O-:12])=[O:11])(=[O:16])[CH3:14]
Reactant: CCOC(=O)C=O
Reactant: COc1ccc(N)c([N+](=O)[O-])c1
Solvent: Cc1ccccc1
Product: COc1ccc(N=CCOC(C)=O)c([N+](=O)[O-])c1

Procedure:
A mixture of 4-methoxy-2-nitroaniline (1.68 g, 10.0 mmol), ethyl glyoxylate/toluene solution (50 wt %, 1.98 ml, 10.0 mmol) and toluene (20 ml) was heated under reflux under a nitrogen gas atmosphere for 17 hours while removing water using a Dean-Stark apparatus. The solvent was removed under reduced pressure to yield [(4-methoxy-2-nitrophenyl)imino]ethyl acetate crude product.
Reaction SMILES: [C:1]1([C:7](=[C:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[C:8]#[N:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:16][CH2:17][N:18](CC)CC.ClCC#N>C1COCC1>[C:17]([CH2:16][N:13]1[CH2:14][CH2:15][C:10](=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:8]#[N:9])[CH2:11][CH2:12]1)#[N:18]
Reactant: N#CC(=C1CCNCC1)c1ccccc1
Reactant: CCN(CC)CC
Agent: N#CCCl
Solvent: C1CCOC1
Product: N#CCN1CCC(=C(C#N)c2ccccc2)CC1
Reaction time: 16 h
Yield: 21.2 %

Procedure:
To a solution of 2-phenyl-2-(piperidin-4-ylidene)acetonitrile (6.8 g, 34 mmol) in THF (150 mL) was added NEt3 (40 mL, 300 mmol) and chloroacetonitrile (20 mL, 315 mmol) and the reaction was stirred 16 h. The precipitates was filtered away and the filtrate concentrated to dryness. The residues was purified by silica gel chromatography (Biotage 40-short, 20% EtOAc/Hex to 50% EtOAc/Hex) to yield 42 (1.7 g, 7.2 mmol, 21%) as a yellow waxy solid. 1H NMR: (500 MHz, CDCl3) δ 7.44-7.34 (m, 3H), 7.30-7.27 (m, 2H), 3.65 (s, 2H), 2.96 (t, J=5.3 Hz, 2H), 2.90 (t, J=5.3 Hz, 2H), 2.70 (t, J=5.6 Hz, 2H), 2.62 (t, J=5.6 Hz, 2H); LC/MS: (ES+) m/z (M+H)+=238; HPLC Rt=1.33 min., column 0, conditions B.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:7])[C:4]#[C:5][CH3:6].Cl[C:9]1[CH:14]=[C:13]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=2[F:23])[N:12]=[CH:11][N:10]=1.[Cl-].[NH4+]>O1CCCC1>[CH2:3]([O:7][C:9]1[CH:14]=[C:13]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][C:17]=2[F:23])[N:12]=[CH:11][N:10]=1)[C:4]#[C:5][CH3:6]
Reactant: CC#CCO
Reactant: Fc1ccc(Cc2cc(Cl)ncn2)c(F)c1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC#CCOc1cc(Cc2ccc(F)cc2F)ncn1
Temperature: 25 °C
Yield: 92.1 %

Procedure:
In 2 ml of tetrahydrofuran was suspended 0.05 g of sodium hydride (60% in oil), to which 0.6 ml of a tetrahydrofuran solution containing 0.08 g of 2-butyn-1-ol was slowly added dropwise with stirring at room temperature. The mixture was stirred at room temperature for 20 minutes, to which 0.6 ml of a tetrahydrofuran solution containing 0.2 g of 4-chloro-6-(2,4-difluorobenzyl)pyrimidine was slowly added dropwise at room temperature, followed by stirring for 4 hours. The reaction mixture was then poured into a saturated aqueous ammonium chloride solution and extracted three times with chloroform. The chloroform layers were combined, washed with water, dried over anhydrous magnesium sulfate, and then concentrated. The residue was subjected to silica gel column chromatography to give 0.21 g of 4-(2-butynyloxy)-6-(2,4-difluorobenzyl)pyrimidine (the present compound (99)).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@@H:9]([NH:16][C:17](=[O:23])[CH2:18][CH2:19][C:20]([OH:22])=[O:21])[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:4][CH:3]=1.[F:24][C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:14]([O:13][C:11](=[O:12])[CH2:10][C@H:9]([NH:16][C:17](=[O:23])[CH2:18][CH2:19][C:20]([OH:22])=[O:21])[CH2:8][C:5]1[CH:6]=[CH:7][C:2]([C:28]2[CH:29]=[CH:30][C:25]([F:24])=[CH:26][CH:27]=2)=[CH:3][CH:4]=1)[CH3:15]
Reactant: CCOC(=O)C[C@@H](Cc1ccc(Br)cc1)NC(=O)CCC(=O)O
Reactant: OB(O)c1ccc(F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCOC(=O)C[C@@H](Cc1ccc(-c2ccc(F)cc2)cc1)NC(=O)CCC(=O)O
Temperature: 95 °C
Yield: 56.4 %

Procedure:
A mixture of (R)-4-(1-(4-bromophenyl)-4-ethoxy-4-oxobutan-2-ylamino)-4-oxobutanoic acid (50 mg, 0.129 mmol), 4-fluorophenylboronic acid (27.2 mg, 0.194 mmol), Pd(Ph3P)4 (14.96 mg, 0.013 mmol) and aqueous Na2CO3 (0.129 mL, 0.259 mmol) in toluene (1 mL) is allowed to stir at 95° C. under nitrogen. After stirring for 13 hours, the solution is cooled to ambient temperature and then quenched with aqueous 1 M HCl. The products are extracted with ethyl acetate, washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The obtained residue is purified by RP-HPLC (SunFire C18, H2O (0.1% TFA)/CH3CN), and then lyophilized to give (R)-3-(3-carboxy-propionylamino)-4-(4′-fluoro-biphenyl-4-yl)-butyric acid ethyl ester (29.2 mg). HPLC retention time=1.26 minutes (condition B); MS (m+1)=402.2; 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.29 (t, J=7 Hz, 3H) 2.47-2.67 (m, 6H) 2.87 (A of ABX, Jab=13.7 Hz, Jax=7.9 Hz, 1H) 2.99 (B of ABX, Jab=13.7 Hz, Jbx=6.6 Hz, 1H) 4.12-4.23 (m, 2H) 4.47-4.55 (m, 1H) 6.52 (br d, J=8.6 Hz, 1H) 7.08-7.14 (m, 2H) 7.24 (d, J=8.4 Hz, 2H) 7.46-7.55 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][CH2:10][C:11]1[C:15]([CH2:16][OH:17])=[C:14]([CH:18]([CH3:20])[CH3:19])[O:13][N:12]=1.O[C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:29]=[C:30]3[C:35](=[CH:36][CH:37]=2)[CH:34]=[C:33]([C:38]([O:40][CH3:41])=[O:39])[CH:32]=[CH:31]3)=[CH:24][CH:23]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][CH2:10][C:11]1[C:15]([CH2:16][O:17][C:22]2[CH:23]=[CH:24][C:25]([C:28]3[CH:29]=[C:30]4[C:35](=[CH:36][CH:37]=3)[CH:34]=[C:33]([C:38]([O:40][CH3:41])=[O:39])[CH:32]=[CH:31]4)=[CH:26][CH:27]=2)=[C:14]([CH:18]([CH3:20])[CH3:19])[O:13][N:12]=1
Reactant: COC(=O)c1ccc2cc(-c3ccc(O)cc3)ccc2c1
Reactant: CC(C)c1onc(CCc2c(Cl)cccc2Cl)c1CO
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc2cc(-c3ccc(OCc4c(CCc5c(Cl)cccc5Cl)noc4C(C)C)cc3)ccc2c1
Temperature: 80 °C
Yield: 24.5 %

Procedure:
A solution of [3-[2-(2,6-dichlorophenyl)ethyl]-5-(1-methylethyl)-4-isoxazolyl]methanol (0.085 g, 0.27 mmol), methyl 6-(4-hydroxyphenyl)-2-naphthalenecarboxylate (0.075 g, 0.27 mmol), triphenyl phosphine (0.071 g, 0.27 mmol) and diisopropyl azodicarboxylate (0.049 mL, 0.27 mmol) in toluene (2.7 mL) was placed in microwave reaction tube and heated to 80° C. for 1000 seconds. The solution was concentrated and the residue dissolved in a solution of ethyl acetate and methanol, filtered and concentrated. The filtrate was purified by chromatography (silica gel, hexane to 3:7 ethyl acetate:hexanes) to provide the title compound (0.038 g, 24.5%). 1H NMR (DMSO-d6): δ 8.62 (s, 1H), 8.25 (s, 1H), 8.18 (d, J=9 Hz, 1H), 8.06 (d, J=9 Hz, 1H), 7.97 (dd, J=1, 9 Hz, 1H), 7.92 (dd, J=2, 9 Hz, 1H), 7.81 (d, J=9 Hz, 2H), 7.42 (d, J=8 Hz, 2H), 7.25 (t, J=8 Hz, 1H), 7.14 (d, J=9 Hz, 2H), 4.99 (s, 2H), 3.90 (s, 3H), 3.35 (septet, J=7 Hz, overlapping H2O 1H), 3.24-3.20 (m, 2H), 2.89-2.85 (m, 2H), 1.25 (d, J=7 Hz, 6H). ESI-LCMS m/z 574 (M+H)+.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH2:9][O:8][C:7]2[CH:16]=[CH:17][CH:18]=[CH:19][C:6]1=2.S(O[CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([N:33]2[CH2:37][CH2:36][CH2:35][CH2:34]2)[CH:28]=1)(=O)(=O)C.C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+]>C(#N)C>[CH3:1][N:2]([CH2:3][CH2:4][N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH2:9][O:8][C:7]2[CH:16]=[CH:17][CH:18]=[CH:19][C:6]1=2)[CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([N:33]2[CH2:37][CH2:36][CH2:35][CH2:34]2)[CH:28]=1
Reactant: CNCCN1c2ccccc2COc2ccccc21
Reactant: CS(=O)(=O)OCCc1cccc(N2CCCC2)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Product: CN(CCc1cccc(N2CCCC2)c1)CCN1c2ccccc2COc2ccccc21
Temperature: 90 °C

Procedure:
5,11-Dihydro-5-[2-(N-methylamino)ethyl]dibenzo[b,e][1,4]oxazepine (254 mg, 1.00 mmol, prepared by a method disclosed in International Patent No. 0040570A1), 3-pyrrolidinophenethyl mesylate (296 mg, 1.10 mmol), sodium carbonate (138 mg, 1.30 mmol) and sodium iodide (20 mg, 0.13 mmol) were added to acetonitrile (20 ml), and they were heated at 90° C. under reflux for 6.5 hours. The solvent was evaporated under reduced pressure, and the residue was distributed into ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The organic layer was washed with water and then dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was subjected to the silica gel column chromatography. After the elution with hexane and ethyl acetate (10:1) and then with hexane and ethyl acetate (3:1) as the eluent, suitable fractions were collected and the solvent was evaporated under reduced pressure to obtain 5,11-dihydro-5-[2-[N-methyl-N-(3-pyrrolidinophenethyl)amino]-ethyl]dibenzo[b,e][1,4]oxazepine in the form of a light yellow oily substance (331 mg, 78%).