Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([OH:14])=O)=[CH:7][CH:6]=1)(=[O:4])=[O:3].ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C.[CH2:32]([NH:34][C:35]1[C:36]([NH2:48])=[CH:37][C:38]([S:41]([C:44]([F:47])([F:46])[F:45])(=[O:43])=[O:42])=[CH:39][CH:40]=1)[CH3:33]>C(#N)C>[CH2:32]([NH:34][C:35]1[CH:40]=[CH:39][C:38]([S:41]([C:44]([F:45])([F:46])[F:47])(=[O:42])=[O:43])=[CH:37][C:36]=1[NH:48][C:12](=[O:14])[CH2:11][C:8]1[CH:7]=[CH:6][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:10][CH:9]=1)[CH3:33]
Reactant: CS(=O)(=O)c1ccc(CC(=O)O)cc1
Reactant: CCNc1ccc(S(=O)(=O)C(F)(F)F)cc1N
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCNc1ccc(S(=O)(=O)C(F)(F)F)cc1NC(=O)Cc1ccc(S(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-methylsulfonylphenylacetic acid (100 mg, 0.467 mmol) in acetonitrile was added 1-hydroxybenzotriazole (76 mg, 0.56 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carboiimide hydrochloride (108 mg, 0.56 mmol), triethylamine (0.143 mL, 1.03 mmol) and N1-ethyl-4-[(trifluoromethyl)sulfonyl]benzene-1,2-diamine (125 mg, 0.467 mmol). The mixture was stirred at room temperature for overnight. The reaction was extracted with ethyl acetate, washed with water and brine, dried, concentrated and recrystallized from ethyl acetate to give the title compound. 1H NMR (300 MHz, DMSO-d6) δ9.54 (br s, 1H, NH), 7.88 (d, J=8.3 Hz, 2H), 7.75 (d, J=2.1 Hz, 1H), 7.64 (dd, 1H), 7.61 (d, J=8.3 Hz, 2H), 6.90 (d, J=9.0 Hz, 1H), 6.70 (t, J=5.2 Hz, 1H, NH), 3.86 (s, 2H, CH2), 3.31 (s, 3H, CH3), 3.29 (m, 2H, NCH2CH3), 1.20 (t, J=7.1 Hz, 3H, NCH2CH3). MS 465 [M++1].
Reaction SMILES: Br[C:2]1[C:10]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[C:9]([O:17][CH3:18])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:19]([O:27][CH2:28][CH3:29])(=[O:26])[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22].[H-].[Na+]>[Cu]Br.C1(C)C=CC=CC=1>[C:4]([C:3]1[C:2]([CH:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:19]([O:27][CH2:28][CH3:29])=[O:26])=[C:10]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[C:9]([O:17][CH3:18])=[CH:8][CH:7]=1)([OH:6])=[O:5]
Reactant: CCCCCOc1c(OC)ccc(C(=O)O)c1Br
Reactant: CCOC(=O)CC(=O)OCC
Agent: [Cu]Br
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCCCCOc1c(OC)ccc(C(=O)O)c1C(C(=O)OCC)C(=O)OCC
Reaction time: 1 h

Procedure:
2-bromo4-methoxy-3-pentyloxybenzoic acid (80.1 g, 253 mmol), toluene (480 ml), copper (I) bromide (3.62 g, 25.3 mmol) and diethyl malonate (153.4 ml, 1.01 mol) were mixed, and sodium hydride (60% dispersion, 30.3 g, 758 mmol) was added to this suspension. The mixture was stirred at 78° C.-83° C. for 1 hour. Said reaction mixture was combined with a reaction mixture in which 2-bromo-4-methoxy-3-pentyloxybenzoic acid (49.43 g, 156 mmol) had been reacted in the same manner, and the resulting reaction mixture was extracted with water (1000 ml, 500 ml). The aqueous layer was washed with hexane (500 ml). Concentrated hydrochloric acid was added to make the aqueous layer acidic. The aqueous layer was extracted with ethyl acetate (1000 ml, 500 ml). The organic layers were combined, and dried over anhydrous sodium sulfate. The drying agent was filtered off, and the filtrate was concentrated under reduced pressure to give a crude product of diethyl 2-(6-carboxy-3-methoxy-2-pentyloxyphenyl)-malonate.
Reaction SMILES: [NH2:1][C:2]1[C:11]([C:12]([O:14]N2C3C=C(Cl)C=CC=3N=N2)=O)=[C:5]2[N:6]=[CH:7][C:8]([F:10])=[CH:9][N:4]2[N:3]=1.[NH2:25][C:26]1[CH:27]=[N:28][CH:29]=[C:30]([F:45])[C:31]=1[N:32]1[CH2:37][CH2:36][CH:35]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:34][CH2:33]1.C(O)C>N1C=CC=CC=1>[NH2:1][C:2]1[C:11]([C:12]([NH:25][C:26]2[CH:27]=[N:28][CH:29]=[C:30]([F:45])[C:31]=2[N:32]2[CH2:37][CH2:36][CH:35]([C:38]([O:40][C:41]([CH3:43])([CH3:42])[CH3:44])=[O:39])[CH2:34][CH2:33]2)=[O:14])=[C:5]2[N:6]=[CH:7][C:8]([F:10])=[CH:9][N:4]2[N:3]=1
Reactant: CC(C)(C)OC(=O)C1CCN(c2c(N)cncc2F)CC1
Reactant: Nc1nn2cc(F)cnc2c1C(=O)On1nnc2ccc(Cl)cc21
Solvent: c1ccncc1
Solvent: CCO
Product: CC(C)(C)OC(=O)C1CCN(c2c(F)cncc2NC(=O)c2c(N)nn3cc(F)cnc23)CC1
Temperature: 95 °C
Yield: 77.9 %

Procedure:
6-chloro-1H-benzo[d][1,2,3]triazol-1-yl 2-amino-6-fluoropyrazolo[1,5-a]pyrimidine-3-carboxylate 6a* (45 g, 129.4 mmol) and tert-butyl 1-(3-amino-5-fluoropyridin-4-yl)piperidine-4-carboxylate 27 (40.1 g, 135.9 mmol) were slurried in pyridine (675 ml). The mixture was heated at 95° C. under nitrogen until the reaction was complete (determined by HPLC analysis). The mixture was cooled and ethanol (450 ml) was added dropwise. The mixture was filtered and the filter cake washed with ethanol (2×70 ml). The damp cake was dried to give the product 28 as a yellow crystalline solid (47.7 g, 78%); 1H NMR (500 MHz, DMSO-d6) δ 10.45 (s, 1H), 9.58 (s, 1H), 9.51 (dd, 1H), 8.72 (dd, 1H), 8.25 (d, 1H), 6.81 (s, 2H), 3.15-2.93 (m, 4H), 2.55-2.47 (masked signal, 1H), 2.02-1.91 (m, 4H), 1.47 (s, 9H); 19F NMR (500 MHz, DMSO-d6) δ −153.5, −136.3; MS (ES+) 474.2.
Reaction SMILES: [O:1]=[C:2]1[CH:11]([NH:12][C:13](=[O:22])[O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[N:7][CH:8]=2)[NH:3]1.[CH2:23](O)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1.O1CCOCC1>[CH2:23]([N:3]1[C:4]2[C:9](=[CH:8][N:7]=[CH:6][CH:5]=2)[CH2:10][CH:11]([NH:12][C:13](=[O:22])[O:14][CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:2]1=[O:1])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: OCc1ccccc1
Reactant: O=C(NC1Cc2cnccc2NC1=O)OCc1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: O=C(NC1Cc2cnccc2N(Cc2ccccc2)C1=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 67.1 %

Procedure:
To a solution of 1E (297 mg, 1 mmol) in THF (8 mL) and 1,4-dioxane (6 mL) was added benzyl alcohol (103 μL, 1 mmol) and triphenylphosphine (393.5 mg, 1.5 mmol), followed by diethyl azodicarboxylate (0.24 mL, 1.5 mmol). The reaction mixture was stirred at RT for 10 min. After this time, no starting material was detected by LC-MS. The reaction was concentrated. The residue was purified by silica gel (40 g) column chromatography eluting with a gradient of methonal (0-5%) in EtOAc to give the title compound as a white solid (260 mg, 67%). LC/MS (method A): retention time=2.50 min, (M+H)+=388.
Reaction SMILES: Cl.[NH2:2][C@H:3]([CH2:16][F:17])[C@@H:4]([C:6]1[CH:11]=[CH:10][C:9]([S:12]([CH3:15])(=[O:14])=[O:13])=[CH:8][CH:7]=1)[OH:5].[C:18]([CH2:20][C:21](OCC)=[O:22])#[N:19].C(N(CC)CC)C>C(O)C>[C:18]([CH2:20][C:21]([NH:2][C@H:3]([CH2:16][F:17])[C@H:4]([OH:5])[C:6]1[CH:7]=[CH:8][C:9]([S:12]([CH3:15])(=[O:14])=[O:13])=[CH:10][CH:11]=1)=[O:22])#[N:19]
Reactant: CS(=O)(=O)c1ccc([C@@H](O)[C@H](N)CF)cc1
Reactant: CCOC(=O)CC#N
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CS(=O)(=O)c1ccc([C@@H](O)[C@@H](CF)NC(=O)CC#N)cc1

Procedure:
A mixture of (1R,2S)-2-amino-3-fluoro-1-(4-methylsulfonylphenyl)-1-propanol hydrochloride (5.66 g; 20 mmol), absolute ethanol (27 ml), ethyl cyanoacetate (22.62 g; 200 mmol) and triethylamine (3.03 g; 30 mmol) was refluxed for 21 hours.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([NH:16][C:17](=[O:31])[C:18]2[CH:23]=[C:22]([N:24]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]3)[CH:21]=[C:20]([F:30])[CH:19]=2)=[CH:8][CH:7]=1.[C:32]([N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1)(=[O:34])[CH3:33]>>[C:32]([N:35]1[CH2:40][CH2:39][N:38]([CH2:2][CH2:3][CH2:4][O:5][C:6]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([NH:16][C:17](=[O:31])[C:18]3[CH:23]=[C:22]([N:24]4[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]4)[CH:21]=[C:20]([F:30])[CH:19]=3)=[CH:8][CH:7]=2)[CH2:37][CH2:36]1)(=[O:34])[CH3:33]
Reactant: O=C(Nc1ccc(OCCCCl)c2ccccc12)c1cc(F)cc(N2CCCCC2)c1
Reactant: CC(=O)N1CCNCC1
Product: CC(=O)N1CCN(CCCOc2ccc(NC(=O)c3cc(F)cc(N4CCCCC4)c3)c3ccccc23)CC1

Procedure:
Compound is prepared from N-[4-(3-chloropropoxy)-naphthalen-1-yl]-3-fluoro-5-piperidin-1-yl-benzamide and N-acetylpiperizine according to conditions described in general procedure L. A white powder (0.13 g, 75.5%). Mp: 210-211° C. 1H NMR (300 MHz, DMSO-d6) δ 10.23 (s, 1H), 8.22 (br s, 1H), 7.84 (br s, 1H), 7.55 (m, 2H), 7.44 (m, 2H), 7.15 (br s, 1H), 6.98 (br s, 2H), 4.23 (br s, 2H), 3.42 (br s, 4H), 3.30 (br s, 4H), 2.57 (br s, 2H), 2.42 (m, 4H), 2.04 (m, 2H), 1.98 (s, 3H), 1.60 (br s, 6H). MS: 533.5 (M+1).
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[CH2:7][CH:6]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][N:9]=2)[C:5]2[CH:15]=[C:16]([C:19]#[N:20])[CH:17]=[CH:18][C:4]=2[O:3]1.C(OCC)(=[O:24])C>C1CCCCC1>[C:19]([C:16]1[CH:17]=[CH:18][C:4]2[O:3][C:2]([CH3:21])([CH3:1])[CH2:7][CH:6]([C:8]3[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][N+:9]=3[O-:24])[C:5]=2[CH:15]=1)#[N:20]
Reactant: CCOC(C)=O
Reactant: Cc1ccc(C2CC(C)(C)Oc3ccc(C#N)cc32)nc1
Solvent: C1CCCCC1
Product: Cc1ccc(C2CC(C)(C)Oc3ccc(C#N)cc32)[n+]([O-])c1

Procedure:
In an analogous manner to that described in the first paragraph of Example 7, from 3,4-dihydro-2,2-dimethyl-4-(5-methyl-2-pyridyl)-2H-1-benzopyran-6-carbonitrile there was obtained 2-(6-cyano-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-4-yl)-5-methylpyridine N-oxide of melting point 151°-153° C. (from ethyl acetate and cyclohexane).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[F:10][C:11]1[CH:28]=[CH:27][C:14]([CH2:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19](=[O:26])[NH:18][N:17]=2)=[CH:13][C:12]=1[C:29]([N:31]1[CH2:36][CH2:35][CH:34](O)[CH2:33][CH2:32]1)=[O:30].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>ClCCl>[F:10][C:11]1[CH:28]=[CH:27][C:14]([CH2:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19](=[O:26])[NH:18][N:17]=2)=[CH:13][C:12]=1[C:29]([N:31]1[CH2:32][CH2:33][CH:34]([O:1][C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=2)[CH2:35][CH2:36]1)=[O:30]
Reactant: O=C(c1cc(Cc2n[nH]c(=O)c3ccccc23)ccc1F)N1CCC(O)CC1
Reactant: N#Cc1ccc(O)cc1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: N#Cc1ccc(OC2CCN(C(=O)c3cc(Cc4n[nH]c(=O)c5ccccc45)ccc3F)CC2)cc1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 9 %

Procedure:
A solution of 4-hydroxybenzonitrile (48 mg, 0.40 mmol) and 4-(4-fluoro-3-(4-hydroxypiperidine-1-carbonyl)benzyl)phthalazin-1(2H)-one (2a) (150 mg, 0.39 mmol) in dichloromethane (5 mL) was treated with polymer supported triphenylphosphine (ex-Biotage, 742 mg, 1.37 mmol) and di-tert-butyl azodicarboxylate (300 mg, 1.30 mmol). The reaction mixture was agitated at ambient temperature for 4-5 hours. Mixture was then filtered to remove resin, and filter cake washed through with methanol. Filtrate was evaporated to afford a waxy yellow solid, which was purified by repeated preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 19 mm diameter, 100 mm length), firstly using decreasingly polar mixtures of water (containing 0.1% TFA) and MeCN as eluents, then using decreasingly polar mixtures of water (containing 1% ammonia) and MeCN as eluents (Waters Sunfire Prep C18 OBD column, 5μ silica, 19 mm diameter, 100 mm length). Fractions containing the desired compound were evaporated to dryness and lyophilised to afford the desired product (17 mg, 8% yield); 1H NMR (400.132 MHz, DMSO) δ 1.49-1.69 (2H, m), 1.83-1.91 (1H, m), 1.99-2.06 (1H, m), 3.14-3.22 (1H, m), 3.32-3.51 (2H, m), 3.94-4.04 (1H, m), 4.33 (2H, s), 4.78-4.84 (1H, m), 7.15-7.18 (2H, m), 7.23 (1H, t), 7.36-7.44 (2H, m), 7.75-7.78 (2H, m), 7.80-7.90 (2H, m), 7.97 (1H, d), 8.26 (1H, d), 12.56 (1H, s); m/z (LC-MS, ESI+), RT=2.20 (M+H 483.6).
Reaction SMILES: COC(=O)[C@H](CC1C=CC(OCC=C)=CC=1)[NH2:5].[CH3:18][O:19][C@@:20]([C:30]([F:33])([F:32])[F:31])([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:21](O)=[O:22].C1CCC(N=C=NC2CCCCC2)CC1>C(Cl)Cl>[CH3:18][O:19][C@@:20]([C:30]([F:33])([F:32])[F:31])([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:21]([NH2:5])=[O:22]
Reactant: C=CCOc1ccc(C[C@H](N)C(=O)OC)cc1
Reactant: CO[C@](C(=O)O)(c1ccccc1)C(F)(F)F
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CO[C@](C(N)=O)(c1ccccc1)C(F)(F)F

Procedure:
O-Allyltyrosine methyl ester (20 mg, 0.084 mmol) was added to a stirred solution of (S)-(-)-methoxy(trifluoromethyl)phenyl-acetic acid (28.0 mg, 0.120 mmol) and DCC (40 mg, 0.20 mmol) in CH2Cl2 (0.50 mL). After 3 h the reaction mixture was diluted with CH2Cl2 (10.0 mL), filtered, and washed with 0.5M aq NaOH. Drying and solvent removal afforded the crude (S)-(-)-methoxy-(trifluoromethyl)phenyl-acetamide as a waxy oil containing DCC and N,N-dicyclohexylurea: Rf 0.55 (50% ether/hexane); 1H NMR (CDCl3) δ3.05 (1H, dd, J=6.4, 14.4 Hz), 3.13 (1H, dd, J=5.4, 14.4 Hz), 3.24 (3H, s), 3.74 (3H, s), 4.52 (2H, d, J=5.2 Hz), 4.87 (1H, ddd, J=5.4, 6.0, 6.4 Hz), 5.29 (1H, d, J=10.4 Hz), 5.41 (1H, d, J=17.6 Hz), 6.06 (1H, m), 6.83 (2H, d, J=8.4 Hz), 7.05 (2H, d, J=8.4 Hz), 7.28 (1H, d, J=6.0 Hz), 7.39 (3H, m), 7.52 (2H, m); 13C NMR (CDCl3) δ28.9, 37.0, 52.5, 53.4, 53.7, 55.0, 69.0, 77.9, 115.2, 117.8, 127.8, 128.1, 128.7, 129.8, 130.4, 133.4, 158.0, 166.2, 171.9,; IR (film) 3411, 3140, 2953, 2851, 1745, 1696, 1511, 1244, 1233, 1224, 1178 cm-1 ; HRMS (M+1) calcd for C23H25F3NO5 452.1685, found 452.1685.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[CH2:6][C:5]2[C:7]([CH3:19])=[C:8]([N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[C:9]([CH3:12])=[C:10]([CH3:11])[C:4]=2[O:3]1.Br[C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[C:24]([F:30])[CH:23]=1>>[F:30][C:24]1[CH:23]=[C:22]([N:16]2[CH2:15][CH2:14][N:13]([C:8]3[C:9]([CH3:12])=[C:10]([CH3:11])[C:4]4[O:3][C:2]([CH3:20])([CH3:1])[CH2:6][C:5]=4[C:7]=3[CH3:19])[CH2:18][CH2:17]2)[CH:27]=[CH:26][C:25]=1[O:28][CH3:29]
Reactant: COc1ccc(Br)cc1F
Reactant: Cc1c(C)c(N2CCNCC2)c(C)c2c1OC(C)(C)C2
Product: COc1ccc(N2CCN(c3c(C)c(C)c4c(c3C)CC(C)(C)O4)CC2)cc1F
Yield: 36.4 %

Procedure:
By using 1-(2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl)piperazine (311 mg, 1.0 mmol) synthesized in Reference example 61 and 4-bromo-2-fluoroanisole (0.194 mL, 1.5 mmol), the reaction was carried out in the same manner as Example 23 to synthesize the title compound 145 mg (yield 36%). Melting point was 161 to 163° C. (hexane).
Reaction SMILES: O1[C:5]2[CH2:6][CH2:7][CH2:8][CH:9]([NH2:10])[C:4]=2[CH:3]=[CH:2]1.[CH3:11][O:12][C:13]1C=C2C(=C[CH:22]=1)C(=O)CCC2>>[CH3:11][O:12][C:13]1[CH:22]=[C:5]2[C:4](=[CH:3][CH:2]=1)[CH:9]([NH2:10])[CH2:8][CH2:7][CH2:6]2
Reactant: COc1ccc2c(c1)CCCC2=O
Reactant: NC1CCCc2occc21
Product: COc1ccc2c(c1)CCCC2N

Procedure:
Following the procedure for the preparation of 4,5,6,7-tetrahydro-1-benzofuran-4-amine but substituting 6-methoxy-3,4-dihydronaphthalen-1(2H)-one and making non-critical variations provided the title compound as a oil: 1H NMR (400 MHz, CDCl3) δ 7.34, 6.78, 6.63, 3.97, 3.79, 2.74, 1.77, 1.89; 13C NMR (100 MHz, CDCl3) δ 158.47, 138.45, 133.91, 129.64, 113.71, 112.67, 55.61, 49.23, 34.25, 30.31, 24.6, 23.23, 19.87.
Reaction SMILES: C([C:5]1[CH:6]=[C:7](C2OC=C(CCO)N=2)[CH:8]=[C:9](C(C)(C)C)[C:10]=1[OH:11])(C)(C)C.C(N(C(=O)CC)CC[C:29]1[CH:34]=[CH:33][C:32](O)=[CH:31][CH:30]=1)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>O1CCCC1>[C:29]1([O:11][C:10]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: CCC(=O)N(CC)CCc1ccc(O)cc1
Reactant: CC(C)(C)c1cc(-c2nc(CCO)co2)cc(C(C)(C)C)c1O
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: c1ccc(Oc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 22 h
Yield: 109.7 %

Procedure:
To a stirred solution of 2-(3,5-di-t-butyl-4-hydroxyphenyl)-4-(2-hydroxyethyl)oxazole (5.51 g, 17.38 mmole) in tetrahydrofuran (47 ml) was added N-ethyl,N-propionyl tyramine (3.5 g, 15.8 mmole) and triphenylphosphine (4.55 g, 17.38 mmole). After cooling to 0° C., a solution of diethylazodicarboxylate (2.73 ml, 17.38 mmole) in tetrahydrofuran (16 ml) was added dropwise over 10 minutes. The reaction was allowed to warm to room temperature and stir for 22 hours, evaporated, and triturated with methylene chloride (50 ml) and filtered The filtrate was chromatographed on silica gel twice using methylene chloride-ethyl acetate and hexane-acetone gradients to give the intermediate phenyl ether (2.95 g, 36%):
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])/[CH:4]=[CH:5]/[C:6]1[C:11]([C:12]#[C:13][CH2:14][CH2:15][CH2:16][CH2:17][O:18][CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][O:20]2)=[CH:10][CH:9]=[CH:8][C:7]=1[OH:25].Br[CH2:28][CH2:29][CH2:30][C:31]([CH3:37])([CH3:36])[C:32]([O:34][CH3:35])=[O:33]>>[CH3:35][O:34][C:32](=[O:33])[C:31]([CH3:37])([CH3:36])[CH2:30][CH2:29][CH2:28][O:25][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]([C:12]#[C:13][CH2:14][CH2:15][CH2:16][CH2:17][O:18][CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][O:20]2)[C:6]=1/[CH:5]=[CH:4]/[C:3]([O:2][CH3:1])=[O:26]
Reactant: COC(=O)/C=C/c1c(O)cccc1C#CCCCCOC1CCCCO1
Reactant: COC(=O)C(C)(C)CCCBr
Product: COC(=O)/C=C/c1c(C#CCCCCOC2CCCCO2)cccc1OCCCC(C)(C)C(=O)OC
Yield: 92 %

Procedure:
Using the procedure of example 122, rac-(E)-3-[2-hydroxy-6-[6-[(tetrahydro-2H-pyran-2-yl)oxy]-1-hexynyl]phenyl]-2-propenoic acid methyl ester (example 121) was alkylated with methyl 5-bromo-2,2-dimethylpentanoate giving the title compound, in 92% yield, as a colorless oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][C:8]1([C:11](=[O:14])[C:12]#[CH:13])[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[NH:16]([CH3:18])[CH3:17]>>[C:1]([O:5][C:6](=[O:15])[NH:7][C:8]1([C:11](=[O:14])/[CH:12]=[CH:13]/[N:16]([CH3:18])[CH3:17])[CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: C#CC(=O)C1(NC(=O)OC(C)(C)C)CC1
Reactant: CNC
Product: CN(C)/C=C/C(=O)C1(NC(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 67.4 %

Procedure:
(1-Propynoyl-cyclopropyl)-carbamic acid tert-butyl ester (2.2 g, 10.5 mmol) was dissolved in a solution of Me2NH (2 M in THF, 21 mL, 42 mmol) at 0° C. The reaction mixture was stirred at room temperature for 2 h and then the volatiles were removed in vacuo to give a crude solid. The solid was purified by washing with n-pentane and Et2O to give 1.8 g of the title compound as a yellow solid, m/z 255.36 [M+1]+.
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:15])[CH2:9][CH2:10][C:11]([O:13]C)=[O:12])=[CH:4][CH:3]=1.[Br:16][CH2:17][CH2:18][CH2:19]Br.C([O-])([O-])=O.[K+].[K+]>CC(CC)=O>[Br:16][CH2:17][CH2:18][CH2:19][S:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:15])[CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:4][CH:3]=1
Reactant: BrCCCBr
Reactant: COC(=O)CCC(=O)c1ccc(S)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: O=C(O)CCC(=O)c1ccc(SCCCBr)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of the product of Example 1, Step E (5 g), 1,3-dibromopropane (20 g) and K2CO3 (10 g) was refluxed in methylethylketone (100 ml) for 20 hours. The cooled reaction mixture was filtered, the solvent evaporated and the residue purified by chromatography over silica gel. The resulting ester of the title compound was hydrolyzed by dissolving in a mixture of 25 ml of methanol and 15 ml of 1N NaOH and stirring at 25° C. for 4 hours. The reaction mixture was diluted with 100 ml of water, acidified with citric acid and extracted with 2×100 ml of EtOAc. The combined organic layers were washed with brine, dried over Na2SO4 and evaporated to yield the title compound which was sufficiently pure for use in the next step, m.p. 91°-94°.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[C:25]2[CH2:30][C:29]([CH3:32])([CH3:31])[CH2:28][C:27]([CH3:34])([CH3:33])[CH2:26]2)[C:9]2[CH:14]=[CH:13][C:12]([C:15]3[C:16]([C:21]([O:23]C)=[O:22])=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[OH-].[Na+].Cl>CCO.C1COCC1>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[C:25]2[CH2:26][C:27]([CH3:34])([CH3:33])[CH2:28][C:29]([CH3:32])([CH3:31])[CH2:30]2)[C:9]2[CH:14]=[CH:13][C:12]([C:15]3[C:16]([C:21]([OH:23])=[O:22])=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccccc1-c1ccc(C(=C2CC(C)(C)CC(C)(C)C2)c2ccc(O)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CC1(C)CC(=C(c2ccc(O)cc2)c2ccc(-c3ccccc3C(=O)O)cc2)CC(C)(C)C1
Temperature: 60 °C
Reaction time: 8 h
Yield: 87.8 %

Procedure:
To a solution of methyl 4′-[(4-hydroxyphenyl)(3,3,5,5-tetramethylcyclohexylidene)methyl]-2-biphenylcarboxylate (248) (0.108 g, 0.24 mmol) in a mixture of EtOH (6 mL) and THF (4 mL) was added an aqueous solution of 1 N NaOH (10 mL). The mixture was stirred at 60° C. overnight. Upon cooling, the mixture was acidified to pH=2 with an aqueous solution of 1 N HCl. The mixture was extracted with EtOAc (2×50 mL). The combined organic extract was washed with brine and dried over Na2SO4. Concentration gave a white residue, which was triturated with hot hexanes containing 1% MeOH to yield the title compound (249) as white solid (92.8 mg, 89%). mp 230-231° C. 1H NMR (400 MHz, DMSO-d6): δ 0.88 (s, 6H), 0.89 (s, 6H), 1.25 (s, 2H), 1.91 (s, 4H), 6.67 (d, J=8.4 Hz, 2H), 6.95 (d, J=8.2 Hz, 2H), 7.14 (d, J=8.0 Hz, 2H), 7.23 (d, J=8.0 Hz, 2H), 7.34-7.44 (m, 2H), 7.50-7.55 (m, 1H), 7.65 (d, J=7.7 Hz, 1H), 9.27 (s, 1H), 12.72 (s, 1H). LCMS (ESI): m/z 441 (M+H)+, 439 (M−H)−.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[F:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]=[O:11])=[CH:8][CH:7]=1>S(=O)(=O)(O)O>[F:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]=[O:11])=[CH:8][C:7]=1[N+:1]([O-:4])=[O:2]
Reactant: O=Cc1ccc(F)cc1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=Cc1ccc(F)c([N+](=O)[O-])c1
Temperature: 5 °C
Reaction time: 1 h
Yield: 77 %

Procedure:
Nitration mixture (sulfuric acid 40 ml+nitric acid 5.5 ml) was added dropwise to 4-fluorobenzaldehyde (10 g, 80.57 mmol) at 0° C. and the mixture was stirred at 5° C. for 20 min and at RT for 1 h. The mixture was quenched by the addition of crushed ice. The precipitate formed was filtered and was washed repeatedly with water to give white solid. The solid was dried under vacuum to give the product in 77% yield (10.5 g). 1H NMR (300 MHz, CDCl3): δ 10.04 (s, 1H), 8.58 (dd, 1H), 8.22-8.18 (m, 1H), 7.5 (t, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:17]([O:19]C)=[O:18])=[N:4][C:5]([C:9]2[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:10]=2[F:16])=[C:6]([F:8])[CH:7]=1.O.[OH-].[Li+].C1COCC1.Cl>O>[NH2:1][C:2]1[C:3]([C:17]([OH:19])=[O:18])=[N:4][C:5]([C:9]2[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:10]=2[F:16])=[C:6]([F:8])[CH:7]=1
Reactant: COC(=O)c1nc(-c2c(F)cccc2F)c(F)cc1N
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Nc1cc(F)c(-c2c(F)cccc2F)nc1C(=O)O
Temperature: 50 °C
Yield: 85.7 %

Procedure:
To a mixture of methyl 3-amino-6-(2,6-difluorophenyl)-5-fluoropyridine-2-carboxylate (84.0 mg, 0.298 mmol) and lithium hydroxide, monohydrate (40.2 mg, 0.958 mmol), THF (2.0 mL) was added followed by water (1.0 mL). The mixture was heated at 50° C. for 3 h. The reaction was then cooled to 0° C. for, and 1 M HCl was added slowly until the pH reached 2. The reaction mixture was then diluted with water (20 mL), extracted with EtOAc (3×20 mL), and the combined organic extract was washed with brine (30 mL), dried over Na2SO4, and concentrated under reduced pressure to give the sub-title compound as a white solid (68.5 mg, 86%). LCMS calc. for C12H8F3N2O2 (M+H)+: m/z=269.0. found 269.0.
Reaction SMILES: [OH-].[K+].C([O:5][C:6]([C:8]1([C:14]([O:16]CC)=[O:15])[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)=[O:7])C>C(O)C>[O:11]1[CH2:10][CH2:9][C:8]([C:6]([OH:7])=[O:5])([C:14]([OH:16])=[O:15])[CH2:13][CH2:12]1
Reactant: CCOC(=O)C1(C(=O)OCC)CCOCC1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)C1(C(=O)O)CCOCC1
Temperature: 0 °C
Reaction time: 8 h
Yield: 60.9 %

Procedure:
6M potassium hydroxide solution (10 mL, 60 mmol) was added to an ice-cooled solution of tetrahydropyran-4,4-dicarboxylic acid diethyl ester (5 g, 21.7 mmol) in ethanol (40 mL) and heated at reflux overnight. The volatiles were evaporated, the residue diluted with water and acidified with conc. hydrochloric acid. The mixture was allowed to stand overnight then extracted with ether (3×25 mL). The combined ether layers were washed with brine, dried over sodium sulfate, and concentrated in vacuo to afford tetrahydro-pyran-4,4-dicarboxylic acid (2.3 g, 61%) as a white solid.