Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:5]=1[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[Cl:19])=[O:12])([O-])=O.[Sn].Cl>C(O)C>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:5]=1[CH:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[Cl:19])[OH:12]
Reactant: O=C(c1ccccc1Cl)c1cc(F)ccc1[N+](=O)[O-]
Agent: Cl
Agent: [Sn]
Solvent: CCO
Product: Nc1ccc(F)cc1C(O)c1ccccc1Cl
Reaction time: 3 h
Yield: 100.7 %

Procedure:
To 0.5 g of (2-nitro-5-fluorophenyl)(2-chlorophenyl)methanone dissolved in 10 ml of ethanol are added 0.44 g of tin and 1.5 ml of 12M hydrochloric acid, and the mixture is left for 3 hours at room temperature. The reaction medium is concentrated and the residue is taken up in ethyl acetate and washed with 2M sodium hydroxide solution and then with saturated ammonium chloride solution. The organic phase is dried over anhydrous sodium sulfate and concentrated to give 0.453 g of the expected product.
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]2[NH:12][CH:11]=[C:10]([CH2:13][N:14]([CH3:22])[C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[C:9]=2[F:23])=[CH:6][CH:5]=[CH:4][N:3]=1.[H-].[Na+].C1OCCOCCOCCOCCOC1.[F:41][C:42]1[N:47]=[C:46]([S:48](Cl)(=[O:50])=[O:49])[CH:45]=[CH:44][CH:43]=1>O1CCCC1.O>[F:23][C:9]1[C:10]([CH2:13][N:14]([CH3:22])[C:15](=[O:21])[O:16][C:17]([CH3:19])([CH3:20])[CH3:18])=[CH:11][N:12]([S:48]([C:46]2[CH:45]=[CH:44][CH:43]=[C:42]([F:41])[N:47]=2)(=[O:50])=[O:49])[C:8]=1[C:7]1[C:2]([F:1])=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: CN(Cc1c[nH]c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Reactant: O=S(=O)(Cl)c1cccc(F)n1
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CN(Cc1cn(S(=O)(=O)c2cccc(F)n2)c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Reaction time: 0.25 h
Yield: 32.2 %

Procedure:
To a suspension of 2-(benzylthio)-6-fluoropyridine (310 mg) in acetic acid (3 mL) and water (1.5 mL) was added N-chlorosuccinimide (776 mg), and the mixture was stirred at room temperature for 5 hr. The reaction mixture was concentrated under reduced pressure, toluene was added to the residue, the mixture was filtrated, and the filtrate was concentrated under reduced pressure to give crude 6-fluoropyridine-2-sulfonyl chloride (240 mg). To a solution of tert-butyl {[5-(2-fluoropyridin-3-yl)-4-fluoro-1H-pyrrol-3-yl]methyl}methylcarbamate (102 mg) in tetrahydrofuran (3 mL) was added sodium hydride (60% in oil, 37 mg) at 0° C., and the mixture was stirred at the same temperature for 15 min. 15-Crown-5 (0.19 mL), then a solution of crude 6-fluoropyridine-2-sulfonyl chloride (240 mg) in tetrahydrofuran (2 mL) were added at the same temperature, and the mixture was stirred at room temperature for 30 min. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=2:1) to give the title compound as a brown oil (yield 49 mg, 7% from 2-(benzylthio)-6-fluoropyridine).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][C:5]=1[C:6](Cl)=[O:7])[CH3:2].[Cl:15][C:16]1[C:21]([Cl:22])=[CH:20][C:19]([NH2:23])=[C:18]([NH2:24])[CH:17]=1.C(N(CC)CC)C>ClCCl>[NH2:24][C:18]1[CH:17]=[C:16]([Cl:15])[C:21]([Cl:22])=[CH:20][C:19]=1[NH:23][C:6](=[O:7])[C:5]1[CH:9]=[CH:10][C:11]([C:13]#[N:14])=[CH:12][C:4]=1[O:3][CH2:1][CH3:2]
Reactant: Nc1cc(Cl)c(Cl)cc1N
Reactant: CCOc1cc(C#N)ccc1C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOc1cc(C#N)ccc1C(=O)Nc1cc(Cl)c(Cl)cc1N
Reaction time: 2 h
Yield: 104.3 %

Procedure:
A solution of 2-ethoxy-4-cyanobenzoyl chloride (10.9 g, 52 mmol), prepared as in Preparation 11, in dichloromethane (109 ml) was added dropwise in 5 h to a solution of 4,5-dichlorophenylendiamine (18.5 g, 104.5 mmol) and triethylamine (53 g=72.6 ml, 523 mmol) in dichloromethane (550 ml). Stirring was continued for additional 2 h. The solvent was removed under vacuum and the residue was triturated with water (100 ml), filtered and dried at 50° C. under vacuum. The solid was suspended in diethyl ether (200 ml), stirred for 1 h, filtered and dried under vacuum to give 19 g of N-(2-amino-4,5-dichlorophenyl)-2-ethoxy-4-cyanobenzamide (yield 51%), mp=195–198° C.
Reaction SMILES: Cl.[C@H:2]12[CH2:8][C@H:5]([NH:6][CH2:7]1)[CH2:4][N:3]2[C:9]([C@@:11]1([CH2:25][CH:26]([F:28])[F:27])[CH2:15][CH2:14][C@@H:13]([NH:16][C@@H:17]2[C@H:22]([O:23][CH3:24])[CH2:21][O:20][CH2:19][CH2:18]2)[CH2:12]1)=[O:10].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])([O-])=O.[Cs+].[Cs+].Cl[C:78]1[CH:83]=[C:82]([C:84]([F:87])([F:86])[F:85])[N:81]=[CH:80][N:79]=1>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CS(C)=O>[F:28][CH:26]([F:27])[CH2:25][C@:11]1([C:9]([N:3]2[CH2:4][C@@H:5]3[CH2:8][C@H:2]2[CH2:7][N:6]3[C:78]2[CH:83]=[C:82]([C:84]([F:87])([F:86])[F:85])[N:81]=[CH:80][N:79]=2)=[O:10])[CH2:15][CH2:14][C@@H:13]([NH:16][C@@H:17]2[C@H:22]([O:23][CH3:24])[CH2:21][O:20][CH2:19][CH2:18]2)[CH2:12]1
Reactant: FC(F)(F)c1cc(Cl)ncn1
Reactant: CO[C@@H]1COCC[C@@H]1N[C@@H]1CC[C@](CC(F)F)(C(=O)N2C[C@@H]3C[C@H]2CN3)C1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: Cl
Solvent: CS(C)=O
Solvent: C1COCCO1
Product: CO[C@@H]1COCC[C@@H]1N[C@@H]1CC[C@](CC(F)F)(C(=O)N2C[C@@H]3C[C@H]2CN3c2cc(C(F)(F)F)ncn2)C1
Temperature: 100 °C
Yield: 19.2 %

Procedure:
The HCl salt of 1,5-anhydro-2,3-dideoxy-3-{[(1R,3S)-3-{[(1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-yl]carbonyl}-3-(2,2-difluoroethyl)cyclopentyl]amino}-4-O-methyl-D-erythro-pentitol (177 mg, 0.42 mmol) was placed in a flask with 1,4-dioxane (3 ml). To the stirred solution was added Xantphos (36 mg, 0.062 mmol), Pd2(dba)3 (22 mg, 0.024 mmol), Cs2CO3 (350 mg, 1.07 mmol), and 4-chloro-6-(trifluoromethyl)pyrimidine (195 mg, 1.07 mmol) dissolved in 1,4-dioxane (1 ml). DMSO (0.5 ml) was added for solubility and the reaction was heated to 100° C. for 21.5 hours. The reaction was allowed to cool to room temperature and filtered through celite. The filtrate was concentrated under reduced pressure and purified with the Biotage (0-100% methanol/ethyl acetate 15 column volumes) to give 1,5-anhydro-2,3-dideoxy-3-{[(1R,3S)-3-(2,2-difluoroethyl)-3-({(1S,4S)-5-[6-(trifluoromethyl)pyrimidin-4-yl]-2,5-diazabicyclo[2.2.1]hept-2-yl}carbonyl)cyclopentyl]amino}-4-O-methyl-D-erythro-pentitol as a white foam (43 mg, 20%). LC/MS (M+H)=534.2504 exp, 534.2597 obs; 1H NMR (400 MHz, CDCl3) δ ppm 8.62 (1H), 6.74-6.46 (1H), 5.93-5.62 (1H), 5.29-4.50 (2H), 4.08-4.03 (1H), 3.93-3.88 (1H), 3.77-3.55 (2H), 3.52-3.32 (6H), 3.30-3.21 (3H), 2.76-2.65 (1H), 2.51-2.33 (1H), 2.21-1.84 (7H), 1.70-1.40 (5H)
Reaction SMILES: C([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[CH:11]([OH:15])[CH:10]([CH2:16][N:17]1[CH2:22][CH2:21][N:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:19][CH2:18]1)[CH2:9][CH2:8]2)(=O)C.[Cl-].[NH4+]>[OH-].[K+].O>[OH:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[CH:11]([OH:15])[CH:10]([CH2:16][N:17]1[CH2:22][CH2:21][N:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH2:19][CH2:18]1)[CH2:9][CH2:8]2
Reactant: CC(=O)Oc1ccc2c(c1)CCC(CN1CCN(c3ccccc3)CC1)C2O
Agent: [Cl-]
Agent: [K+]
Agent: [NH4+]
Solvent: O
Product: Oc1ccc2c(c1)CCC(CN1CCN(c3ccccc3)CC1)C2O
Temperature: 25 °C

Procedure:
1,2,3,4-Tetrahydro-6-acetoxy-2-[(4-phenyl-1-piperazinyl)methyl]-1-naphthalenol (3.96 g) in 32 ml of 8% methanolic potassium hydroxide is refluxed for 3 minutes under argon, cooled to room temperature and diluted with sufficient water to effect solution. Excess aqueous ammonium chloride solution is added dropwise, with stirring, and the reaction mixture is extracted several times with methylene chloride. The organic extracts are dried, filtered and evaporated to give the title compound.
Reaction SMILES: [CH3:1][N:2]([CH3:17])[CH2:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([CH3:13])=[C:9]([N+:14]([O-])=O)[CH:8]=1)=[O:5]>C(OCC)(=O)C.[Pd]>[NH2:14][C:9]1[CH:8]=[C:7]([NH:6][C:4](=[O:5])[CH2:3][N:2]([CH3:17])[CH3:1])[CH:12]=[CH:11][C:10]=1[CH3:13]
Reactant: Cc1ccc(NC(=O)CN(C)C)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: Cc1ccc(NC(=O)CN(C)C)cc1N
Yield: 148.7 %

Procedure:
N2,N2-dimethyl-N1-(4-methyl-3-nitrophenyl)glycinamide (7.0 g, 19.5 mmol) was dissolved in ethyl acetate and 10% Pd/C (500 mg) was added. The reaction was placed on a Fischer-Porter hydrogenation apparatus and treated with 50 psi of H2 gas overnight. Following purging with N2 the reaction solution was passed through a celite plug to afford analytically pure N1-(3-amino-4-methylphenyl)-N2,N2-dimethylglycinamide (6.0 g, 29.0 mmol, 98% yield) as a pale yellow oil. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.96 (s, 3 H), 2.24 (s, 6 H), 2.97 (s, 2 H), 4.79 (s, 2 H), 6.63 (dd, J=8.05, 2.01 Hz, 1 H), 6.78 (d, J=8.05 Hz, 1 H), 6.96 (d, J=2.01 Hz, 1 H), 9.24 (s, 1 H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([C:8]([OH:10])=O)=[CH:4][CH:3]=1.[C:11]([NH2:15])([CH3:14])([CH3:13])[CH3:12].C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:11]([NH:15][C:8]([C:5]1[N:6]=[N:7][C:2]([Cl:1])=[CH:3][CH:4]=1)=[O:10])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)N
Reactant: O=C(O)c1ccc(Cl)nn1
Agent: O=C([O-])O
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)NC(=O)c1ccc(Cl)nn1
Reaction time: 8 h
Yield: 49.3 %

Procedure:
To a solution of 6-chloro-3-pyridazinecarboxylic acid (0.12 g, 0.76 mmol) in methylene chloride (15 ml) were added t-butylamine (0.21 ml, 2.0 mmol) and N,N-bis(2-oxo-3-oxazolidinyl)phosphinic chloride (0.24 g, 0.93 mmol), and stirred overnight. The reaction mixture was added to saturated aqueous NaHCO3 and extracted three times with ethyl acetate. The combined organic layers were washed with brine and dried over Na2SO4. The solvent was evaporated and the residue was purified by silica gel chromatography (hexane/ethyl acetate=2/1) to give the title compound (0.080 g; 49%).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][C@@H:4]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:3]1.[Cl:13][C:14]1[N:19]=[C:18](Cl)[C:17]([F:21])=[CH:16][N:15]=1.C(N(C(C)C)CC)(C)C>C1COCC1>[Cl:13][C:14]1[N:19]=[C:18]([NH:1][C@H:2]2[CH2:7][CH2:6][CH2:5][C@@H:4]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:3]2)[C:17]([F:21])=[CH:16][N:15]=1
Reactant: Fc1cnc(Cl)nc1Cl
Reactant: CCOC(=O)[C@@H]1CCC[C@H](N)C1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)[C@@H]1CCC[C@H](Nc2nc(Cl)ncc2F)C1
Temperature: 25 °C

Procedure:
To a solution of (1R,3S)-ethyl 3-aminocyclohexanecarboxylate, 67b, (5.1 g, 24.1 mmol) and 2,4-dichloro-5-fluoropyrimidine (6.0 g, 36.0 mmol) in THF (60 mL) was added diisopropylethylamine (9.6 mL, 55.4 mmol). The mixture was heated to reflux overnight. The reaction was cooled to room temperature and concentrated in vacuo. The residue was diluted with water and extracted twice with ethyl acetate. The combined organic phases were dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (0-40% EtOAc/hexanes gradient) to provide 6.7 g of (1R,3S)-ethyl 3-(2-chloro-5-fluoropyrimidin-4-ylamino)cyclohexane-carboxylate as a white solid: LCMS RT=3.1 (M+H) 302.2.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:12]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:16][CH:15]=2)[CH2:11][C:10](=[CH2:26])[C:9]1=[O:27])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(=O)([O-])O.[Na+]>C1(C)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>[C:1]([O:5][C:6]([N:8]1[C@H:12]([CH2:13][C:14]2[CH:15]=[CH:16][C:17]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[CH:18][CH:19]=2)[CH:11]=[C:10]([CH3:26])[C:9]1=[O:27])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C=C1C[C@@H](Cc2ccc(-c3ccccc3)cc2)N(C(=O)OC(C)(C)C)C1=O
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: Cc1ccccc1C
Product: CC1=C[C@@H](Cc2ccc(-c3ccccc3)cc2)N(C(=O)OC(C)(C)C)C1=O
Reaction time: 8 h

Procedure:
The mixture of (R)-5-Biphenyl-4-ylmethyl-3-methylene-2-oxo-pyrrolidine-1-carboxylic acid tert-butylester (1a, R1=Boc) (0.36 g, 1 mmol), Pd(PPh3)4 (70 mg, 0.06 mmol), PPh3(31.5 mg, 0.12 mmol) and sodium hydrogencarbonate (0.27 g, 3.2 mmol) in 10 mL xylene is heated to reflux, and stirred overnight to give (R)-5-biphenyl-4-ylmethyl-3-methyl-2-oxo-2,5-dihydro-pyrrole-1-carboxylic acid tert-butyl ester (4a, R1=Boc) as determined by HPLC analysis. Spectroscopic data as for Example 2.
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[C:8]([CH:10]([CH3:15])[C:11]([O:13]C)=[O:12])[CH:7]=[CH:6][C:5]=2[C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=2)[CH2:3][CH2:2]1.Br[CH2:24][C:25]1[C:30]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])=[C:29]([O:38]C(OC(C)(C)C)=O)[C:28]([C:46]([F:49])([F:48])[F:47])=[CH:27][CH:26]=1>>[C:34]([O:33][C:31]([C:30]1[C:29]([OH:38])=[C:28]([C:46]([F:48])([F:47])[F:49])[CH:27]=[CH:26][C:25]=1[CH2:24][O:22][C:19]1[CH:18]=[CH:17][C:16]([C:5]2[CH:6]=[CH:7][C:8]([CH:10]([CH3:15])[C:11]([OH:13])=[O:12])=[CH:9][C:4]=2[CH:1]2[CH2:2][CH2:3]2)=[CH:21][CH:20]=1)=[O:32])([CH3:37])([CH3:36])[CH3:35]
Reactant: CC(C)(C)OC(=O)Oc1c(C(F)(F)F)ccc(CBr)c1C(=O)OC(C)(C)C
Reactant: COC(=O)C(C)c1ccc(-c2ccc(O)cc2)c(C2CC2)c1
Product: CC(C(=O)O)c1ccc(-c2ccc(OCc3ccc(C(F)(F)F)c(O)c3C(=O)OC(C)(C)C)cc2)c(C2CC2)c1
Yield: 45 %

Procedure:
According to a method similar to Example (2-3), Example (33-5) and Example (17-4), from methyl 2-(2-cyclopropyl-4′-hydroxy-1,1′-biphenyl-4-yl)propanoate (135 mg, 0.46 mmol) obtained in Example (112-1) and tert-butyl 6-(bromomethyl)-2-[(tert-butoxycarbonyl)oxy]-3-(trifluoromethyl)benzoate (249 mg, 0.55 mmol) obtained in Example (28-5), the title compound was obtained as a colorless powder (115 mg, three-step total yield: 45%).
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]2[C:9]([CH:10]=[C:11]3[C:16]=1[CH:15]=[CH:14][CH:13]=[CH:12]3)=[CH:8][CH:7]=[CH:6][CH:5]=2.[CH3:17][O:18][P:19]([O:22]C)[O:20][CH3:21]>>[CH3:17][O:18][P:19]([CH2:2][C:3]1[C:4]2[C:9]([CH:10]=[C:11]3[C:16]=1[CH:15]=[CH:14][CH:13]=[CH:12]3)=[CH:8][CH:7]=[CH:6][CH:5]=2)(=[O:22])[O:20][CH3:21]
Reactant: COP(OC)OC
Reactant: ClCc1c2ccccc2cc2ccccc12
Product: COP(=O)(Cc1c2ccccc2cc2ccccc12)OC
Yield: 40.5 %

Procedure:
A solution of 9-(chloromethyl)anthracene (2.5 g, 0.011M) in trimethylphosphite (5 mL, 5.26 g, 0.042 M) is heated at reflux temperature for 72 hours. Excess trimethylphosphite is removed under reduced pressure and the residue is chromatographed over silica gel (400 g, 40-63 μm, CH2Cl2, 50 mL fractions) using CH2Cl2 (60 fractions) and 2% CH3OH in CH2Cl2 for the remaining fractions. Fractions 86-93 (2.99 g) are found to contain desired material and an impurity and are rechromatographed (400 g silica gel, 40-63 lam, CH2Cl2, 50 mL fractions) using 2.5% acetone-CH2Cl2 to elute the column. Fractions 100-160 contains compound (1.495 g, 0.00498M, 45%) as a yellow solid. Crystallization from ethyl acetate gives the title compound (1.34 g) as yellow needles, mp 152°-153° C.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([OH:10])=[O:9].C(OC(=O)C)(=O)C.C(O)(=O)C.OS(O)(=O)=O.[N+:38]([O-])([OH:40])=[O:39]>>[Cl:1][C:2]1[CH:17]=[C:16]([C:18]([F:20])([F:19])[F:21])[CH:15]=[CH:14][C:3]=1[O:4][C:5]1[CH:13]=[CH:12][C:11]([N+:38]([O-:40])=[O:39])=[C:7]([CH:6]=1)[C:8]([OH:10])=[O:9]
Reactant: O=[N+]([O-])O
Reactant: O=C(O)c1cccc(Oc2ccc(C(F)(F)F)cc2Cl)c1
Agent: O=S(=O)(O)O
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: O=C(O)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Reaction time: 1.5 h
Yield: 80.3 %

Procedure:
3-(2-Chloro-4-trifluoromethylphenoxy)benzoic acid (275.9 g, 0.935 mole), acetic anhydride (276 g, 2.7 mole), glacial acetic acid (276 g, 4.6 mole) and conc. H2SO4 (44 g) were charged into a three-neck 5 liter flask equipped with a mechanical stirrer, thermometer and an addition funnel. Nitric acid (90%, 91.7 g, 1.3 mole) was added at 15°-25° C. over 0.5 hr. The cooling bath was substituted with a water bath and the reaction was stirred for 1.5 hrs. at 30° C. The reaction was quenched with 1250 ml of water (at 30° C.), stirred for 0.25 hr. The resultant yellow precipitate was filtered and washed with 2 liters of water. Recrystallization from toluene (750 ml) afforded 271.6 g of 5-(2-chloro-4-trifluoromethylphenoxy)-2-nitrobenzoic acid; m.p. 120°-121° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:18]=[C:17]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:16]([O:23][CH:24]([CH3:26])[CH3:25])=[C:15]([CH2:27]O)[C:14]=2[CH3:29])=[CH:7][CH:6]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:50]N1C(=O)CCC1=O>ClCCl>[CH3:1][O:2][C:3](=[O:30])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:18]=[C:17]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:16]([O:23][CH:24]([CH3:26])[CH3:25])=[C:15]([CH2:27][Br:50])[C:14]=2[CH3:29])=[CH:7][CH:6]=1
Reactant: COC(=O)Cc1ccc(C#Cc2cc(C(C)(C)C)c(OC(C)C)c(CO)c2C)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)Cc1ccc(C#Cc2cc(C(C)(C)C)c(OC(C)C)c(CBr)c2C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.8 %

Procedure:
A stirred, cooled (ice bath) solution of [4-(5-tert-butyl-3-hydroxymethyl-4-isopropoxy-2-methyl-phenylethynyl)-phenyl]-acetic acid methyl ester (Intermediate 147, 0.15 g, 0.37 mmol) and triphenylphosphine (0.125 g, 0.48 mmol) in anhydrous dichloromethane (5 mL) was treated with N-bromo succinimide (0.085 g, 0.48 mmol) under argon and the resulting reaction mixture was allowed to warm to ambient temperature and stirred overnight. The reaction mixture was quenched with dilute, aqueous sodium bicarbonate solution and extracted with diethyl ether. The organic phase was washed with water (×1) and brine (×1), dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo to a residue that on flash column chromatography over silica gel (230-400 mesh) using 4-5% ethyl acetate in hexane as the eluent afforded the title compound (0.12 g, 69%) as a colorless oil. It was used as such for the next step.
Reaction SMILES: [O:1]=[S:2]1(=[O:31])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][N:5]([C:13]2[CH:22]=[C:21]([NH:23][CH2:24][CH2:25][C:26]([O:28]C)=O)[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([CH3:30])[CH:19]=3)[N:14]=2)[CH2:4][CH2:3]1.[NH3:32]>CO>[O:31]=[S:2]1(=[O:1])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][N:5]([C:13]2[CH:22]=[C:21]([NH:23][CH2:24][CH2:25][C:26]([NH2:32])=[O:28])[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([CH3:30])[CH:19]=3)[N:14]=2)[CH2:4][CH2:3]1
Reactant: N
Reactant: COC(=O)CCNc1cc(N2CCS(=O)(=O)c3ccccc3C2)nc2ccc(C)cc12
Solvent: CO
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(NCCC(N)=O)c2c1
Temperature: 85 °C
Reaction time: 8 h

Procedure:
A mixture of methyl N-[2-(1,1-dioxido-2,3-dihydro-1,4-benzothiazepin-4(5H)-yl)-6-methylquinolin-4-yl]-beta-alaninate and a solution of ammonia in methanol (7 N, 10 mL) was heated with stirring at 85° C. in a sealed tube overnight. The resulting mixture was concentrated in vacuo. The residue was purified by preparative HPLC to afford 59.2 mg of the desired product as a solid. MS obsd. (ESI+) [(M+H)+] 425, 1H NMR (400 MHz, DMSO-d6) δ ppm 7.95 (d, J=6.82 Hz, 1 H), 7.88 (dd, J=7.83, 1.26 Hz, 1 H), 7.66-7.60 (m, 2 H), 7.50-7.42 (m, 2 H), 7.31 (d, J=8.59 Hz, 1 H), 7.22 (dd, J=8.46, 1.64 Hz, 1 H), 6.97 (brs, 1 H), 6.73 (t, J=5.68 Hz, 1 H), 6.06 (s, 1 H), 5.06 (brs, 2 H), 4.40 (brs, 2 H), 3.68-3.56 (m, 2 H), 3.51 (q, J=6.65 Hz, 2 H), 2.42 (t, J=7.07 Hz, 2 H), 2.34 (s, 3 H).
Reaction SMILES: [CH:1]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7](C(CC)C)[C:6]=1[OH:15])([CH2:3][CH3:4])[CH3:2].CCC=C.Cl>>[CH:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[OH:15])([CH2:3][CH3:4])[CH3:2]
Reactant: CCC(C)c1cccc(C(C)CC)c1O
Agent: C=CCC
Agent: Cl
Product: CCC(C)c1ccccc1O
Temperature: 275 °C
Reaction time: 2 h

Procedure:
In the reaction vessel of Example 1 place 190 parts of phenol and 2.4 parts of granular aluminum. Flush with nitrogen and heat to 180°C. to form aluminum phenoxide. Cool and vent. Add 206 parts of 2,6-di-sec-butylphenol and again seal the vessel. Heat to 275°C. and stir at this temperature for 2 hours. Then pressurized with butene-1 to 1000 psig and stir the reaction mixture under these conditions for an additional 4 hours. Cool and discharge the reaction mixture into a dilute aqueous hydrochloric acid solution to hydrolyze the catalyst. Wash with water until neutral and then distill the reaction mixture to recover o-sec-butylphenol. Residual 2,6-di-sec-butylphenol remaining is recycled to a subsequent reaction carried out in the same manner as the foregoing. The net result is that the 2,6-di-sec-butylphenol formed in each reaction is consumed in a subsequent reaction as the donor phenol forming o-sec-butylphenol, thus, avoiding accumulation of 2,6-di-sec-butylphenol and giving higher yields of o-sec-butylphenol.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]([CH3:13])[CH3:12])=[C:4](Cl)[N:3]=1.[NH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(O)CCC.CCOC(C)=O>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]([CH3:13])[CH3:12])=[C:4]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:3]=1
Reactant: CC(C)n1cnc2c(Cl)nc(Cl)nc21
Reactant: Nc1ccccc1
Solvent: CCCCO
Solvent: CCOC(C)=O
Product: CC(C)n1cnc2c(Nc3ccccc3)nc(Cl)nc21
Temperature: 120 °C

Procedure:
2,6-dichloro-9-isopropylpurine (0.019 g, 0.081 mmol) was dissolved in butanol (0.5 ml) and aniline (0.044 ml, 0.244 mmol) was added. The reaction mixture was heated to 120° C. for 10 hr, cooled, diluted with EtOAc and washed 3 times with water. The mixture was dried over MgSO4 and concentrated to an off white solid.
Reaction SMILES: [C:1](O)(=O)[CH:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[OH:3].[NH3:12].C1C=CC([C@@H](O)C(O)=O)=CC=1>>[C:1](#[N:12])[CH:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[OH:3]
Reactant: O=C(O)C(O)c1ccccc1
Reactant: N
Agent: O=C(O)[C@H](O)c1ccccc1
Product: N#CC(O)c1ccccc1

Procedure:
Microbial cells harvested from the plate culture were washed with a 50 mM phosphoric acid buffer solution (pH=7.5) and suspended in 10 ml of the same buffer solution to prepare a resting cell suspension at a cell concentration having an optical density at 630 nm (OD630 ) of from 1 to 50. To the cell suspension was added mandelonitrile to a concentration of 0.2 w/v %, and the system was allowed to react at 30° C. for 16 to 24 hours. Analysis of the reaction mixture by liquid chromatography (Shiseido ODS column); revealed the production of mandelic acid and ammonia. Further, analysis by means of a chiral cell for optical resolution("CHIRALPAK WH" column) revealed that the produced R(-)-mandelic acid had a high optical purity.