Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[C:4]([CH3:11])[CH:3]=1.[C:12](=O)([O-])[O-].[Cs+].[Cs+].IC.CN([CH:23]=[O:24])C>>[CH3:12][O:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:24][CH3:23])=[O:7])=[C:4]([CH3:11])[CH:3]=1
Reactant: CN(C)C=O
Reactant: O=C([O-])[O-]
Reactant: Cc1cc(O)ccc1C(=O)O
Agent: [Cs+]
Solvent: CI
Product: COC(=O)c1ccc(OC)cc1C

Procedure:
To a suspension of 4-hydroxy-2-methyl benzoic acid (10.0 g, 65.7 mmol) and cesium carbonate (53.5 g, 164.3 mmol) in DMF (70 mL) at 0° C., iodomethane (10.3 mL, 164.3 mmol) in DMF (10 mL) was added over 20 min. The reaction warmed from 0° C. to room temperature overnight. The mixture filtered and washed with ether. The filtrate was washed with water and the layers separated. The aqueous was washed with ether (3×100 mL). The organics were combined and washed with H2O then brine, dried over Na2SO4, and concentrated under reduced pressure to give methyl 4-methoxy-2-methylbenzoate (11.4 g) as a yellow oil. 1H NMR (300 MHz, CDCl3): δ 7.95 (m, 1H), 6.76 (m, 2H), 3.87 (s, 3H), 3.85 (s, 3H), 2.62 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][C@H:13]2[CH:22]=[CH:21][C:20]3[C:15](=[C:16]([C:24]4[C:29]([Cl:30])=[CH:28][CH:27]=[CH:26][C:25]=4[Cl:31])[CH:17]=[C:18]([F:23])[CH:19]=3)[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[H][H]>C(OCC)(=O)C.C(O)C.[Pt](=O)=O>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][C@H:13]2[CH2:22][CH2:21][C:20]3[C:15](=[C:16]([C:24]4[C:25]([Cl:31])=[CH:26][CH:27]=[CH:28][C:29]=4[Cl:30])[CH:17]=[C:18]([F:23])[CH:19]=3)[O:14]2)(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2C=Cc3cc(F)cc(-c4c(Cl)cccc4Cl)c3O2)cc1
Reactant: [H][H]
Agent: O=[Pt]=O
Solvent: CCOC(C)=O
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)OC[C@H]2CCc3cc(F)cc(-c4c(Cl)cccc4Cl)c3O2)cc1
Yield: 79.8 %

Procedure:
A solution of [(R)-(8-(2,6-dichlorophenyl)-6-fluoro-2H-chromen-2-yl]methyl 4-methylbenzenesulfonate (0.6 g, 1.25 mmol) in ethyl acetate/ethanol (10/10 mL) was added platinum(IV) oxide (45 mg, 0.198 mmol) and the mixture hydrogenated at 45 psi of hydrogen for 2 hours. The reaction mixture was then filtered through celite and the filtrate concentrated under reduced pressure. Chromatography with 0–15% ethyl acetate in hexanes afforded 0.48 g (80%) of [(R)-8-(2,6-dichlorophenyl)-6-fluorochroman-2-yl]methyl 4-methylbenzenesulfonate as a colorless oil. [α]D25=+9.51° (c 5.3 mg/0.7 mL MeOH); MS (ES) m/z 498.0 ([M+NH4]+).
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[OH2:11].Cl.Cl.CO[CH2:16][C:17]1[N:18]=[C:19](N2CCNCC2)[C:20]2[S:26][CH2:25][CH2:24][CH2:23][C:21]=2[N:22]=1>C1COCC1.CN(C=O)C>[CH2:3]([O:10][CH2:16][C:17]1[N:18]=[C:19]([OH:11])[C:20]2[S:26][CH2:25][CH2:24][CH2:23][C:21]=2[N:22]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: OCc1ccccc1
Reactant: COCc1nc2c(c(N3CCNCC3)n1)SCCC2
Reactant: O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Oc1nc(COCc2ccccc2)nc2c1SCCC2

Procedure:
Sodium hydride (0.68 g 53% mineral oil) was suspended in THF (80 ml) and 1.5 ml of benzyl alcohol was added dropwise with stirring. To this clear solution was added product from Example 3, Step A (2.6 g) dissolved in 25 ml of DMF. After stirring for 2 hours at 25° C. the reaction mixture was heated at reflux for 10 minutes. The solvent was removed in vacuo , water was added to the residue followed by enough diluted HCl to render the solution slightly acidic and it was extracted with ethyl acetate. The ethyl acetate layer was dried and evaporated to give title compound as an oil that was used directly in Step B.
Reaction SMILES: [CH3:1][O:2][N:3]([CH3:15])[C:4]([C:6]1[NH:14][C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[CH:7]=1)=[O:5].[F:16][C:17]1[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][CH:22]=1.N1C=CC=CC=1>C(Cl)Cl>[F:16][C:17]1[CH:22]=[C:21]([N:14]2[C:9]3=[N:10][CH:11]=[CH:12][CH:13]=[C:8]3[CH:7]=[C:6]2[C:4]([N:3]([O:2][CH3:1])[CH3:15])=[O:5])[CH:20]=[CH:19][CH:18]=1
Reactant: OB(O)c1cccc(F)c1
Reactant: CON(C)C(=O)c1cc2cccnc2[nH]1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CON(C)C(=O)c1cc2cccnc2n1-c1cccc(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.5 %

Procedure:
Activated molecular sieves (3.8 g) 4 Å were placed in an oven dried flask and cooled to room temperature under nitrogen. To the flask was charged with N-methoxy-N-methyl-1H-pyrrolo[2,3-b]pyridine-2-carboxamide (0.29 g, 1.4 mmol), (3-fluorophenyl)boronic acid (0.59 g, 4.2 mmol), cupric acetate (0.38 g, 2.1 mmol), methylene chloride (35 mL) and then pyridine (0.46 mL, 5.6 mmol). The reaction mixture was stirred at room temperature overnight. The mixture was filtered through a pad of Celite. The filtrate was concentrated and purified on silica gel (eluting with 0-50% EtOAc/hexane followed by 0-5% MeOH/dichloromethane) to give the desired product (0.35 g, 83%). LCMS calculated for C16H15FN3O2(M+H)+: m/z=300.1. Found: 300.0.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C@H:3]([OH:6])[CH2:2]1.Cl[C:8]1[N:13]=[CH:12][C:11](/[C:14](/[C:24]2[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=2)=[C:15](\[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)/[CH2:16][CH3:17])=[CH:10][CH:9]=1>>[C:18]1(/[C:15](/[CH2:16][CH3:17])=[C:14](/[C:24]2[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=2)\[C:11]2[CH:12]=[N:13][C:8]([O:6][C@H:3]3[CH2:4][CH2:5][NH:1][CH2:2]3)=[CH:9][CH:10]=2)[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CC/C(=C(\c1ccc(O)cc1)c1ccc(Cl)nc1)c1ccccc1
Reactant: O[C@H]1CCNC1
Product: CC/C(=C(\c1ccc(O)cc1)c1ccc(O[C@H]2CCNC2)nc1)c1ccccc1
Yield: 75.6 %

Procedure:
Following the same procedure as described in example 3, (S)-pyrrolidin-3-ol (558 mg, 10 eq) was reacted with (Z)-4-(1-(6-chloropyridin-3-yl)-2-phenylbut-1-enyl)phenol (100 mg, 1 eq, prepared from example 1) to give the desired product (87 mg, 76% yield). 1H NMR (400 MHz, DMSO-d6) δ 9.50 (s, 1H), δ 7.54 (s, 1H), 7.20-7.23 (m, 2H), 7.10-7.16 (m, 4H), 7.00(d, J=8.4 Hz, 2H), 6.77 (d, J=8.4 Hz, 2H), 6.49 (d, J=8.4 Hz, 1H), 5.28 (bs, 1H), 3.15-3.32 (m, 2H), 2.94-3.05 (m, 2H), 2.43 (q, J=7.6 Hz, 1H) 1.90-2.10 (m, 1H), 1.79-1.89 (m, 1H), 0.86 (t, J=7.6 Hz, 3H); m/z=387 [M+1]+.
Reaction SMILES: C([O-])(O)=O.[Na+].N[C:7]1[C:8]([Cl:14])=[N:9][C:10]([CH3:13])=[CH:11][CH:12]=1.[Br:15][C:16]1[CH:17]=[C:18]([C:23](Cl)=[O:24])[C:19]([Cl:22])=[N:20][CH:21]=1.BrC1C=C(C(O)=O)C(O)=[N:31]C=1.O=S(Cl)Cl>CC#N.O>[Br:15][C:16]1[CH:17]=[C:18]([C:23]([NH:31][C:11]2[C:10]([CH3:13])=[N:9][C:8]([Cl:14])=[CH:7][CH:12]=2)=[O:24])[C:19]([Cl:22])=[N:20][CH:21]=1
Reactant: Cc1ccc(N)c(Cl)n1
Reactant: O=C(O)c1cc(Br)cnc1O
Reactant: O=C(Cl)c1cc(Br)cnc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: O=S(Cl)Cl
Solvent: CC#N
Product: Cc1nc(Cl)ccc1NC(=O)c1cc(Br)cnc1Cl
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 31 %

Procedure:
NaHCO3 (3.9 g, 46.4 mmol) was added to a solution of 3-amino-2-chloro-6- methylpyridine (2.2 g, 15.4 mmol; prepared as described by K. G. Grozinger et al. J. Heterocyclic Chem. 1995,32,259-263) in MeCN (50 mL). The resulting suspension was stirred for 15 min. and a solution of crude 5-bromo-2-chloro-3-pyridinecarbonyl chloride (prepared from 5-bromo-2-hydroxy-3-pyridinecarboxylic acid and SOCl2 [as described by T. W. Gero et al. in Synth. Commun. 1989, 19, 553-559 (incorporated herein by reference) but with omission of the aqueous work-up] (4 g,) in MeCN (10 mL) was introduced over 30 min. The resulting suspension was stirred at room temperature. After 24 h, the mixture was poured into a mixture of water (100 mL) and ice (10 g) and stirred for 20 min. The suspension was filtered and the resulting solid was washed with water (50 mL) and hexane (25 mL), then dried over P2O5 under reduced pressure to give the title compound (1.8 g, 31% yield) as a white powder.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:41])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26]([C:28]3[CH:32]=[CH:31][S:30][CH:29]=3)[CH:25]=[C:24](I)[CH:23]=2)[C:10]=1[CH2:34][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH3:2].[C:42]1(B(O)O)[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>>[CH2:1]([O:3][C:4](=[O:41])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:23]=[C:24]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[CH:25]=[C:26]([C:28]3[CH:32]=[CH:31][S:30][CH:29]=3)[CH:27]=2)[C:10]=1[CH2:34][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH3:2]
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(I)cc(-c3ccsc3)c2)c1CCC(=O)OCC
Reactant: OB(O)c1ccccc1
Product: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(-c3ccccc3)cc(-c3ccsc3)c2)c1CCC(=O)OCC
Yield: 55.2 %

Procedure:
A similar procedure as described in Example 12, step 8 was used, starting from 4-{3-[6-(3-iodo-5-thiophen-3-yl-phenoxy)-hexyl]-2-(2-ethoxycarbonyl-ethyl)-phenoxy}-butyric acid ethyl ester (216 mg, 0.31 mmol) and phenylboronic acid (152 mg, 1.25 mmol) to give 4-{2-(2-ethoxycarbonyl-ethyl)-3-[6-(5-thiophen-3-yl-biphenyl-3-yloxy)-hexyl]-phenoxy}-butyric acid ethyl ester (110 mg, 55%) as a colorless oil: ES(+)-HRMS m/e calculated for C39H46O6S (M+Na)+ 665.2907, found 665.2907.
Reaction SMILES: [C:1]([C:4]1[C:5]([OH:25])=[C:6]([NH:18][C:19](=[O:24])[C:20](Br)([CH3:22])[CH3:21])[CH:7]=[C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:9]=1)(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:1]([C:4]1[C:5]2[O:25][C:20]([CH3:22])([CH3:21])[C:19](=[O:24])[NH:18][C:6]=2[CH:7]=[C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1cc(OCc2ccccc2)cc(NC(=O)C(C)(C)Br)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(=O)c1cc(OCc2ccccc2)cc2c1OC(C)(C)C(=O)N2

Procedure:
6.60 g (16.2 mmol) of N-(3-acetyl-5-benzyloxy-2-hydroxyphenyl)-2-bromo-2-methylpropionamide and 2.76 g (20 mmol) of potassium carbonate are stirred for 1 hour in 70 mL acetonitrile at reflux temperature. The solid is suction filtered, the filtrate is evaporated down, and the residue is combined with 30 mL of ethyl acetate. After fresh filtration and distilling off the solvent, the crude product is crystallized from a little methanol. Yield: 1.00 g (19%); mass spectroscopy [M+H]+=326; melting range=148° C. -150° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:13]([CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:23]=[C:24]4[C:29](=[CH:30][CH:31]=3)[C:28]([C:32]([OH:34])=O)=[CH:27][CH:26]=[CH:25]4)=[CH:18][CH:17]=2)=[C:12]([CH:35]([CH3:37])[CH3:36])[O:11][N:10]=1.C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O.[N:53]1C=CC=CC=1.C(=O)([O-])O.[NH4+]>C(#N)C>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[C:9]1[C:13]([CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:23]=[C:24]4[C:29](=[CH:30][CH:31]=3)[C:28]([C:32]([NH2:53])=[O:34])=[CH:27][CH:26]=[CH:25]4)=[CH:18][CH:17]=2)=[C:12]([CH:35]([CH3:36])[CH3:37])[O:11][N:10]=1
Reactant: c1ccncc1
Reactant: CC(C)c1onc(-c2c(Cl)cccc2Cl)c1COc1ccc(-c2ccc3c(C(=O)O)cccc3c2)cc1
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [NH4+]
Solvent: CC#N
Product: CC(C)c1onc(-c2c(Cl)cccc2Cl)c1COc1ccc(-c2ccc3c(C(N)=O)cccc3c2)cc1
Temperature: 25 °C
Yield: 98.3 %

Procedure:
6-[4-({[3-(2,6-dichlorophenyl)-5-(1-methylethyl)-4-isoxazolyl]methyl}oxy)phenyl]-1-naphthalenecarboxylic acid (97 mg, 0.180 mmol), di-tert-butyl dicarbonate (60 mg, 0.273 mmol), and pyridine (0.021 mL, 0.273 mmol) were combined into anhydrous acetonitrile (5 mL). The mixture was stirred at ambient temperature for half an hour. Ammonium hydrogen carbonate (25 mg, 0.273 mmol) was then added to the mixture and the reaction was stirred at ambient temperature for 48 hours. The solvent was then removed on a rotary evaporator and the crude residue was dissolved in ethyl acetate. The organic solution was then washed with water three times, followed by saturated sodium bicarbonate, and then brine. The crude organic extract was then dried over magnesium sulfate, filtered, and then evaporated to dryness. The residue was washed with hexanes several times to remove the residual di-tert-butyl dicarbonate, and the solids were removed via filtration to give the title compound as a white solid (94 mg, 98%) 1H NMR (CDCl3): δ 8.48 (d, J=9 Hz, 1H), 7.88-8.00 (m, 2H), 7.75 (d, J=9 Hz, 1H), 7.68 (d, J=9 Hz, 1H), 7.58 (d, J=9 Hz, 2H), 7.36-7.51 (m, 3H) 7.25 (d, J=9 Hz, 1 H), 6.88 (d, J=9 Hz, 2H), 6.42 (broad s, 1H), 6.13 (broad s, 1H), 4.81 (s, 2H), 3.26-3.44 (m, 1H), 1.37-1.47 (m, 6H). ESI-LCMS m/z 531 (M+H)+.
Reaction SMILES: [NH2:1][CH:2]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)[CH2:3][CH:4]1[CH2:8][CH2:7][O:6][CH2:5]1.CS(OC1CCOCC1)(=O)=O.[Li+].CC([N-]C(C)C)C>>[NH2:1][CH:2]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)[CH:3]1[CH2:4][CH2:5][O:6][CH2:7][CH2:8]1
Reactant: NC(CC1CCOC1)c1cccnc1
Agent: CC(C)[N-]C(C)C
Agent: CS(=O)(=O)OC1CCOCC1
Agent: [Li+]
Product: NC(c1cccnc1)C1CCOCC1

Procedure:
The methaneamine derivative was synthesized essentially according to the procedure described for the synthesis of 1-amino-1-(3-pyridyl)-2-(3-tetrahydrofuranyl)-ethane. Thus, tetrahydropyran-4-ol methane sulfonate (0.99 g, 5.5 mmol), prepared according to the procedure of Suto et al., J. Med. Chem., 34:2484 (1991), was treated with the imine anion generated by reacting N-(diphenylmethylidene)-3-(aminomethyl)pyridine (1.36 g, 5.0 mmol) with LDA (5.5 mmol in 5.0 mL tetrahydrofuran). A work up similar to the one described for the synthesis of 1-amino-1-(3-pyridyl)-2-(3-tetrahydrofuranyl)-ethane, followed by purification by column chromatography (15% methanol in chloroform) yielded 1-amino-1-(3-pyridyl)-1-(4-tetrahydropyranyl)-methane (499 mg) in 52% yield.
Reaction SMILES: [CH2:1]([C:4]1([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH3:12])[CH2:6][CH2:5]1)[CH:2]=C.[O:24]=[O+][O-].[BH4-].[Na+]>C(Cl)Cl>[CH3:14][C:13]([CH3:15])([CH3:16])[C@@H:11]([N:7]1[CH2:6][CH2:5][C:4]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)([CH2:1][CH2:2][OH:24])[O:9][C:8]1=[O:10])[CH3:12]
Reactant: O=[O+][O-]
Reactant: C=CCC1(c2ccc(F)cc2)CCN([C@@H](C)C(C)(C)C)C(=O)O1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Product: C[C@H](N1CCC(CCO)(c2ccc(F)cc2)OC1=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 4 %

Procedure:
A solution of 6-allyl-3-((S)-3,3-dimethylbutan-2-yl)-6-(4-fluorophenyl)-1,3-oxazinan-2-one (80 mg, crude) in dry CH2Cl2 (5 mL) was treated with ozone at −78° C. until the mixture turned blue. The system was then flushed with oxygen to move excess ozone. NaBH4 (47 mg, 1.25 mmol) was added to the mixture in portions at rt. The mixture was stirred overnight at rt. The mixture was quenched with water and the layers were separated. The aqueous layer was extracted with CH2Cl2 (2×6 mL). The organic layer was combined, washed with brine, dried over anhydrous Na2SO4 and concentrated to give the crude product, which was purified by preparative TLC to give 3-((2S)-3,3-dimethylbutan-2-yl)-6-(4-fluorophenyl)-6-(2-hydroxyethyl)-1,3-oxazinan-2-one (5 mg, yield: 4%).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]3[CH:19]=[N:20][CH:21]=[C:22]([CH:27]=3)[C:23]([O:25]C)=[O:24])=[O:16])[CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].Cl>C1COCC1.CO>[C:1]1([CH2:7][CH2:8][CH:9]2[CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]3[CH:19]=[N:20][CH:21]=[C:22]([CH:27]=3)[C:23]([OH:25])=[O:24])=[O:16])[CH2:13][CH2:14]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)c1cncc(OC(=O)N2CCC(CCc3ccccc3)CC2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1cncc(OC(=O)N2CCC(CCc3ccccc3)CC2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.4 %

Procedure:
Methyl 5-({[4-(2-phenylethyl)piperidin-1-yl]carbonyl}oxy)nicotinate (3.95 g) was dissolved in THF (32 ml) and methanol (16 ml), and under ice cooling, aqueous 1 M sodium hydroxide solution (16 ml) was dropwise added thereto. This was stirred at room temperature for 30 minutes, and under ice cooling, this was neutralized with 1 M hydrochloric acid (16 ml). The colorless solid precipitated was collected by filtration, and recrystallized from methanol/water to obtain 5-({[4-(2-phenylethyl)piperidin-1-yl]carbonyl}oxy)nicotinic acid (3.70 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([CH2:9][C@@H:10]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[NH2:11])[CH:6]=[CH:5][CH:4]=1.[C:17]([NH:24][CH2:25][C:26](O)=[O:27])([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C.O>[C:20]([O:19][C:17]([NH:24][CH2:25][C:26]([NH:11][C@H:10]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:9][C:7]1[CH:6]=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[N:8]=1)=[O:27])=[O:18])([CH3:23])([CH3:22])[CH3:21]
Reactant: CCOC(=O)[C@@H](N)Cc1cccc(OC)n1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)[C@H](Cc1cccc(OC)n1)NC(=O)CNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 72.6 %

Procedure:
To a 100-mL round-bottomed flask was added ethyl 3-(6-methoxy-2-pyridinyl)alaninate (1.045 g, 4.66 mmol), N-boc-glycine (0.898 g, 5.13 mmol, Aldrich, St. Louis, Mo.), HATU (2.126 g, 5.59 mmol, Aldrich, St. Louis, Mo.), and N,N-diisopropylethylamine (2.43 mL, 13.98 mmol, Aldrich, St. Louis, Mo.) in DMF (5 mL). The reaction mixture was stirred at room temperature for 3 h. The reaction mixture was diluted with water (40 mL) and extracted with EtOAc (2×50 mL). The organic extract was washed with saturated NaCl (30 mL) and dried over Na2SO4. The solution was filtered and concentrated in vacuo to give the crude material as light-yellow oil. The crude product was purified by silica gel chromatography, eluting with 70% EtOAc/hexanes to give ethyl N-(tert-butoxycarbonyl)glycyl-3-(6-methoxy-2-pyridinyl)alaninate (1.29 g) as a colorless oil.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]#[N:5].[C:6]([O:15][CH2:16][CH3:17])(=[O:14])/[CH:7]=[CH:8]/[C:9]([O:11][CH2:12][CH3:13])=[O:10].[N:18]([O-])=O.[Na+].N([O-])=O>C(OCC)(=O)C.O>[CH2:16]([O:15][C:6]([CH:7]1[CH:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:4]([C:3]#[N:2])[N:5]=[N:18]1)=[O:14])[CH3:17]
Reactant: N#CCN
Reactant: O=N[O-]
Reactant: CCOC(=O)/C=C/C(=O)OCC
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)C1N=NC(C#N)C1C(=O)OCC
Temperature: 24 °C
Reaction time: 3 h

Procedure:
To a one liter round bottom flask containing a cold (0° C.) slurry of 67.6 g (0.6756 mol) of aminoacetonitrile hydrochloride and 44.2 ml (0.2702 mol) of diethyl fumarate in 300 ml of ethyl acetate, were added dropwise, over one hour, an aqueous solution of 46.6 g (0.6756 mol) of sodium nitrite dissolved in 90 ml of water. The temperature of the reaction mixture was maintained at about 0° C. during the nitrite addition, then warmed to room temperature (24° C.) where the mixture was stirred for about 3 hours. The organic layer was separated from the aqueous layer and then stirred at room temperature overnight to provide a solution of 5-cyano-4,5-dihydro-3H-pyrazole-3,4-dicarboxylic acid diethyl ester dissolved in ethyl acetate.
Reaction SMILES: [SiH](CC)(CC)CC.[Br:8][C:9]1[CH:10]=[CH:11][C:12]([Cl:26])=[C:13]([CH:25]=1)[C:14]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH3:24])=[CH:18][CH:17]=1)=O.B(F)(F)F.CCOCC>ClCCCl.CC#N>[CH3:24][CH2:23][O:22][C:19]1[CH:18]=[CH:17][C:16]([CH2:14][C:13]2[CH:25]=[C:9]([Br:8])[CH:10]=[CH:11][C:12]=2[Cl:26])=[CH:21][CH:20]=1
Reactant: CCOc1ccc(C(=O)c2cc(Br)ccc2Cl)cc1
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Solvent: CCOCC
Solvent: CC#N
Solvent: ClCCCl
Product: CCOc1ccc(Cc2cc(Br)ccc2Cl)cc1
Temperature: 20 °C
Reaction time: 8 h
Yield: 61.4 %

Procedure:
To a stirred solution of Et3SiH (400 mL, 2.51 mol and 5-bromo-2-chloro-4′-ethoxybenzophenone (390 g, 1.15 mol) in 900 mL of a 1:2 mixture 1,2-dichloroethane/MeCN at 10° C. was added BF3.Et2O (150 mL, 1.58 mol) at such a rate that the temperature did not exceed 20°. Caution a moderate exotherm insues during the addition. After stirring overnight at 20° C., HPLC revealed the reaction to be 90% complete. After adding an additional 40 mL Et3SiH and 15 mL of BF3.Et2O, the reaction was heated to 50° for 3 hr. (Note elevated temperatures increase formation of the Ritter reaction product N-acetyl 5-bromo-2-chloro-4′-ethoxydiphenylmethylamine). Upon cooling, the reaction was quenched with 120 g of KOH in 300 mL of H2O. After stirring 2 hr, the layers were separated. The aqueous layer was extracted 2× with CH2Cl2; the combined organic layers were washed 1× with 300 mL portions of 2M KOH, 2× with H2O containing 10% brine to aid phase separation and with brine 2× prior to drying over Na2SO4. After removal of the volatiles, the residue was recrystallized from absolute EtOH to yield 230 g of 5-bromo-2-chloro-4′-ethoxydiphenylmethane as a white solid.
Reaction SMILES: C([O:5][C:6](=[O:33])[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH2:17][C:16]([C:22]3[CH:27]=[C:26]([Cl:28])[C:25]([C:29]#[N:30])=[C:24]([Cl:31])[CH:23]=3)([C:18]([F:21])([F:20])[F:19])[O:15][N:14]=2)=[CH:9][C:8]=1[CH3:32])(C)(C)C.FC(CC(O)=O)(F)F.C(OCC)(=O)C>ClCCl>[Cl:31][C:24]1[CH:23]=[C:22]([C:16]2([C:18]([F:21])([F:19])[F:20])[O:15][N:14]=[C:13]([C:10]3[CH:11]=[CH:12][C:7]([C:6]([OH:33])=[O:5])=[C:8]([CH3:32])[CH:9]=3)[CH2:17]2)[CH:27]=[C:26]([Cl:28])[C:25]=1[C:29]#[N:30]
Reactant: Cc1cc(C2=NOC(c3cc(Cl)c(C#N)c(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)OC(C)(C)C
Agent: O=C(O)CC(F)(F)F
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cc1cc(C2=NOC(c3cc(Cl)c(C#N)c(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)O
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of 4-[5-(3,5-Dichloro-4-cyano-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-benzoic acid tert-butyl ester (763 mg) in dichloromethane (9 ml) was added trifluoromethyl acetic acid (“TFA”) (0.9 ml). The reaction mixture was stirred at ambient temperature for 20 hours. Ethyl acetate was added and the mixture was washed with water, dried over sodium sulfate and concentrated to give 4-[5-(3,5-Dichloro-4-cyano-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-benzoic acid. 19F-NMR (CDCl3, 75 MHz): −78.91 ppm.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[O:10])[O:8][C:6](=[O:7])[C:5]2=[CH:11][CH:12]=1.[Br:13]([O-])(=O)=O.[K+].[OH2:18]>>[Br:13][C:12]1[CH:11]=[C:5]([C:6]([OH:7])=[O:18])[C:4]([C:9]([OH:8])=[O:10])=[CH:3][C:2]=1[CH3:1]
Reactant: [O-][Br+2]([O-])[O-]
Reactant: O
Reactant: Cc1ccc2c(c1)C(=O)OC2=O
Agent: [K+]
Product: Cc1cc(C(=O)O)c(C(=O)O)cc1Br
Temperature: 90 °C

Procedure:
A suspension of 4-methylphthalic anhydride (1) (58.8 g, 0.363 mol) and potassium bromate (66.7 g, 0.400 mol) in 250 ml of water was heated to 90° C., and after the removal of the heating bath used, 250 ml of concentrated sulfuric acid was slowly added dropwise with vigorous stirring. After the completion of the dropping, the heating bath was attached again to heat the mixture at 90 to 100° C. for 3 hours with stirring. The mixture was then allowed to cool down to ambient temperature, and the precipitated solid was separated on a filter, and rinsed with cold water. The filtrate was extracted with three portions of ether. The combined organic phase was washed with successive water and saturated saline solution, and dried over anhydrous sodium sulfate. The ether solution was then concentrated to obtain a solid. The solid was combined with the solid separated previously on the filter were combined, and water was separated therefrom as a toluene azeotrope, to obtain a crude 5-bromo-4-methylphthalic acid (2).