Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[CH:6]=[C:5]([Cl:7])[C:4]([Cl:8])=[C:3]([C:9]2[N:14]=[N:13][C:12]([NH2:15])=[N:11][C:10]=2[NH2:16])[CH:2]=1.ClC1C(Cl)=CC=CC=1C(C#N)=O.ClC1C(Cl)=CC=CC=1C(OC(=O)C1C=CC=C(Cl)C=1Cl)=O.C(=O)(O)O.NNC(N)=N>S(=O)(=O)(O)O>[Cl:8][C:4]1[C:5]([Cl:7])=[CH:6][CH:1]=[CH:2][C:3]=1/[C:9](=[N:14]/[NH:13][C:12]([NH2:15])=[NH:11])/[C:10]#[N:16]
Reactant: Nc1nnc(-c2cccc(Cl)c2Cl)c(N)n1
Agent: N#CC(=O)c1cccc(Cl)c1Cl
Agent: N=C(N)NN
Agent: O=C(O)O
Product: N#C/C(=N\NC(=N)N)c1cccc(Cl)c1Cl

Procedure:
The synthesis of lamotrigine is illustrated in Reference Example 1. 2,3-Dichlorobenzoyl cyanide, which is intermediate 1.4 in that synthesis, may contain up to 10% of 2,3-dichlorobenzoic anhydride as a contaminant. When the 2,3-dichlorobenzoyl cyanide is treated with a solution of aminoguanidine bicarbonate in sulphuric acid, which is step (d) in Reference Example 1, the adduct (Z)-2-(2,3-dichlorophenyl)-2-(guanidinoimino)acetonitrile (intermediate 1.5) is produced. The anhydride contaminant can then react with the latter adduct to form (Z)-2-(2,3-dichlorophenyl)-2-[N′-(2,3-dichlorobenzoyl)guanidinoimino]acetonitrile, which is the direct precursor to compound B. Cyclisation of the precursor in propan-1-ol under reflux yields compound B.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][C:16]([N:18]2[CH2:23][CH2:22][CH2:21][C@@H:20]([C:24]([NH:26][C@H:27]([C:32]#[CH:33])[CH2:28][C:29]([OH:31])=[O:30])=[O:25])[CH2:19]2)=[O:17])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:34][C:35]([F:45])([F:44])[C:36]1[CH:43]=[CH:42][C:39]([CH2:40]O)=[CH:38][CH:37]=1.Cl.C(N=C=NCCCN(C)C)C>ClCCl>[F:34][C:35]([F:44])([F:45])[C:36]1[CH:43]=[CH:42][C:39]([CH2:40][O:30][C:29](=[O:31])[CH2:28][C@@H:27]([C:32]#[CH:33])[NH:26][C:24]([C@@H:20]2[CH2:21][CH2:22][CH2:23][N:18]([C:16](=[O:17])[CH2:15][CH2:14][CH:11]3[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:13][CH2:12]3)[CH2:19]2)=[O:25])=[CH:38][CH:37]=1
Reactant: OCc1ccc(C(F)(F)F)cc1
Reactant: C#C[C@H](CC(=O)O)NC(=O)[C@@H]1CCCN(C(=O)CCC2CCN(C(=O)OC(C)(C)C)CC2)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: C#C[C@H](CC(=O)OCc1ccc(C(F)(F)F)cc1)NC(=O)[C@@H]1CCCN(C(=O)CCC2CCN(C(=O)OC(C)(C)C)CC2)C1
Temperature: 0 °C

Procedure:
To a mixture of N-[(R)-1-{3-(1-tert-butoxycarbonyl-4-piperidyl)propionyl}-3-piperidylcarbonyl]-3(S)ethynyl-β-alanine (0.63 g), 4-(trifluoromethyl)benzyl alcohol (0.23 ml) and N,N-dimethylaminopyridine (18 mg) in dichloromethane (7 ml) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.32 g) under stirring at 0° C. After stirring at ambient temperature for overnight, the solution was evaporated in vacuo. The residue was poured into water and extracted with ethyl acetate. The extract was washed with saturated aqueous NaHCO3 solution, water and brine, and dried over MgSO4, and evaporated in vacuo. The residue was purified by column chromatography on silica gel eluting with (CHCl3:MeOH=100:1) to give N-[(R)-1-{3-(1-tert-butoxycarbonyl-4-piperidyl)propionyl}-3-piperidylcarbonyl]-3(S)-ethynyl-β-alanine 4-trifluoromethylbenzyl ester (0.71 g) as an oil.
Reaction SMILES: [CH2:1]([N:3]1[CH2:9][CH2:8][C:7]2[CH:10]=[C:11]([NH2:14])[CH:12]=[CH:13][C:6]=2[CH2:5][CH2:4]1)[CH3:2].Cl[C:16]1[N:21]=[C:20]([NH:22][CH2:23][C:24]([NH:27][S:28]([CH3:31])(=[O:30])=[O:29])([CH3:26])[CH3:25])[C:19]([Cl:32])=[CH:18][N:17]=1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>CC(O)C>[Cl:32][C:19]1[C:20]([NH:22][CH2:23][C:24]([NH:27][S:28]([CH3:31])(=[O:30])=[O:29])([CH3:26])[CH3:25])=[N:21][C:16]([NH:14][C:11]2[CH:12]=[CH:13][C:6]3[CH2:5][CH2:4][N:3]([CH2:1][CH3:2])[CH2:9][CH2:8][C:7]=3[CH:10]=2)=[N:17][CH:18]=1
Reactant: CCN1CCc2ccc(N)cc2CC1
Reactant: CC(C)(CNc1nc(Cl)ncc1Cl)NS(C)(=O)=O
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: CC(C)O
Product: CCN1CCc2ccc(Nc3ncc(Cl)c(NCC(C)(C)NS(C)(=O)=O)n3)cc2CC1
Temperature: 120 °C
Yield: 34.3 %

Procedure:
3-Ethyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine (86.7 mg, 0.456 mmol, 1.0 eq), N-[2-(2,5-dichloro-pyrimidin-4-ylamino)-1,1-dimethyl-ethyl]-methanesulfonamide (157 mg, 0.502 mmol, 1.1 eq), and 10-camphorsulfonic acid (116 mg, 0.502 mmol, 1.1 eq) were dissolved in IPA (3 mL) and heated at 120° C. in a microwave for 60 minutes. The reaction was then concentrated under reduced pressure and the residue was taken up in CH2Cl2 (20 mL) and washed with sat. NaHCO3 (20 mL). The organic layer was dried (sodium sulfate), filtered, and concentrated under reduced pressure. Purification by basic alumina chromatography using a gradient of 0-100% EtOAc/hex as the eluting solvent to obtain N-{2-[5-chloro-2-(3-ethyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino)-pyrimidin-4-ylamino]-1,1-dimethyl-ethyl}-methanesulfonamide as a pink solid (73 mg, 34%). m.p.=118-121° C.; LCMS (m/e) 467 (M+1); 1H-NMR (CDCl3, 400 MHz) δ 7.95 (s, 1H), 7.34-7.26 (m, 2H), 7.05 (d, 1H, J=7.7 Hz), 6.98 (s 1H), 5.82-5.72 (m, 2H), 3.65 (d, 1H, J=6.4 Hz), 2.94 (s, 3H), 3.00-2.85 (m, 4H), 2.73-2.55 (m, 4H), 2.58 (q, 2H, J=6.6 Hz), 1.44 (s, 6H), 1.11 (t, 3H, J=7.1 Hz).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][OH:14]>ClCCl.[O-2].[Mn+4].[O-2]>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH:13]=[O:14]
Reactant: Cc1onc(-c2ccccc2)c1CO
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: Cc1onc(-c2ccccc2)c1C=O
Reaction time: 168 h
Yield: 90.3 %

Procedure:
To a solution of (5-methyl-3-phenyl-4-isoxazolyl)methanol (8.0 g, 42 mmol) in dichloromethane (1 L) was added manganese(IV) oxide (81.7 g, 0.85 mol) and the resulting mixture stirred vigorously for 7 days. The mixture was then filtered and the filtrate evaporated to afford the title compound (7.1 g, 89%) as a light yellow solid. MS: m/e=188.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5]([CH2:6][CH:7]([C:10]#[N:11])[C:8]#[N:9])=[CH:4][CH:3]=1.[H-].[Na+].I[CH2:17][CH2:18][C:19]([F:25])([F:24])[C:20]([F:23])([F:22])[F:21]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]([CH2:17][CH2:18][C:19]([F:25])([F:24])[C:20]([F:23])([F:22])[F:21])([C:8]#[N:9])[C:10]#[N:11])=[CH:12][CH:13]=1
Reactant: N#CC(C#N)Cc1ccc(Cl)cc1
Reactant: FC(F)(F)C(F)(F)CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CC(C#N)(CCC(F)(F)C(F)(F)F)Cc1ccc(Cl)cc1
Yield: 26.6 %

Procedure:
Using 1.00 g of (4-chlorobenzyl)malononitrile, 10 ml of N,N-di-methylformamide, 0.21 g of sodium hydride (60% in oil), and 1.44 g of 4-iodo-1,1,1,2,2-pentafluorobutane, and according to the process described in the Production Example 1, there was obtained 0.47 g of 2-(4-chlorobenzyl)-2-(3,3,4,4,4-pentafluorobutyl)malononitrile (the present compound (23)).
Reaction SMILES: ClC1N=C2C(C3C=CC=CC=3OC)=CC=CN2N=1.[C:19]([O:23][C:24]([N:26]1[CH2:32][CH2:31][C:30]2[CH:33]=[CH:34][C:35](N)=[CH:36][C:29]=2[CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20].C1(P(C2CCCCC2)C2(P(C3CCCCC3)C3CCCCC3)CC=CC=C2C2C=CC=CC=2)CCCCC1.C(=O)([O-])[O-].[Cs+].[Cs+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O1CCOCC1>[C:19]([O:23][C:24]([N:26]1[CH2:32][CH2:31][C:30]2[CH:33]=[CH:34][CH:35]=[CH:36][C:29]=2[CH2:28][CH2:27]1)=[O:25])([CH3:22])([CH3:20])[CH3:21]
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(N)cc2CC1
Agent: [Pd+2]
Agent: C1=CCC(P(C2CCCCC2)C2CCCCC2)(P(C2CCCCC2)C2CCCCC2)C(c2ccccc2)=C1
Agent: CC(=O)[O-]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCc2ccccc2CC1
Temperature: 100 °C
Yield: 141.9 %

Procedure:
To an oven-dried Schlenck flask under an atmosphere of argon was added 2-chloro-8-(2-methoxy-phenyl)-[1,2,4]triazolo[1,5-a]pyridine (0.460 g, 1.77 mmol), 7-amino-1,2,4,5-tetrahydro-3-benzazepine-3-carboxylic acid tert-butyl ester (0.558 g, 2.12 mmol), palladium acetate (0.0875 g, 0.390 mmol), 2,2-bis-dicyclohexylphosphanyl-biphenyl (0.242 g, 0.443 mmol), cesium carbonate (1.44 g, 4.43 mmol), followed by 1,4-dioxane (12.00 mL) and was degassed under an atmosphere of argon for 5 min and heated at 100° C. overnight, cooled at room temperature, diluted with dichloromethane, filtered through diatomaceous earth and concentrated. The reaction was purified via chromatography (silica gel 20%-30% ethyl acetate/hexanes) and concentrated to give 748-(2-methoxy-phenyl)[1,2,4]triazolo[1,5-a]pyridin-2-ylamino]-1,2,4,5-tetrahydro-3-benzazepine-3-carboxylic acid tert-butyl ester (0.744 g, 87%). 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.54 (s, 1H), 8.78 (d, 1H), 7.55 (m, 2H), 7.45 (m, 2H), 7.35 (s, 1H) 7.15 (m, 1H), 7.05 (m, 3H), 3.74 (s, 3H), 3.48 (m, 4H), 2.78 (m, 4H), 1.41 (s, 9H): MS=486 (MH)+.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[S:14][C:13](/[CH:15]=[CH:16]/[C:17]([O:19]C)=[O:18])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[OH-].[Na+]>C1COCC1.C(O)C>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[S:14][C:13](/[CH:15]=[CH:16]/[C:17]([OH:19])=[O:18])=[CH:12][CH:11]=2)=[CH:8][CH:9]=1)([CH3:3])[CH3:2]
Reactant: COC(=O)/C=C/c1ccc(-c2ccc(C(C)C)cc2)s1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)c1ccc(-c2ccc(/C=C/C(=O)O)s2)cc1
Reaction time: 20 h
Yield: 89685.9 %

Procedure:
To a solution of methyl (E)-3-[5-(4-isopropylphenyl)thiophen-2-yl]acrylate (0.75 mg) in THF/ethanol (10/10 ml) was added at room temperature 2N sodium hydroxide solution (2.0 ml), and the mixture was stirred for 20 hours. Under reduced pressure, the mixture was concentrated, and to the residue was added 1N hydrochloric acid (10 ml). The mixture was extracted with ethyl acetate, and the organic layer was washed with saturated brine, dried with magnesium sulfate and concentrated. The resulting crystals were collected by filtration to give pale yellow crystals of (E)-3-[5-(4-isopropylphenyl)thiophen-2-yl]acrylic acid (639.7 mg).
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.[CH:13]1([CH3:25])[CH2:18][CH2:17][CH:16]([CH:19]([CH3:21])[CH3:20])[CH:15]([C:22](Cl)=[O:23])[CH2:14]1.C(Cl)Cl.Cl>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:6]([NH:7][C:22]([CH:15]2[CH2:14][CH:13]([CH3:25])[CH2:18][CH2:17][CH:16]2[CH:19]([CH3:21])[CH3:20])=[O:23])=[C:5]([N+:10]([O-:12])=[O:11])[CH:4]=1
Reactant: CC1CCC(C(C)C)C(C(=O)Cl)C1
Reactant: COc1ccc(N)c([N+](=O)[O-])c1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ccc(NC(=O)C2CC(C)CCC2C(C)C)c([N+](=O)[O-])c1
Temperature: 50 °C
Reaction time: 6 h
Yield: 81.4 %

Procedure:
4-Methoxy-2-nitroaniline (5 g, 0.018 mol) was dissolved in pyridine (50) and treated with menthoyl chloride (3.57 g, 0.018 mol). The reaction mixture was heated to 50° C. and stirred vigorously for 6 h. The reaction mixture was cooled to room temperature and poured into a mixture of CH2Cl2 (100 mL) and 1N HCl (100 mL)). The heterogeneous mixture was transferred to a reparatory funnel where the aqueous phase was separated and re-extracted with CH2Cl2 (2×100 mL). The organic phases were combined and washed with 1N HCl (8×100 mL), H2O (1×100 mL), 1N NaOH (2×100 mL), brine (100 mL), dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (20 to 50% ethyl acetate/hexane for elution) provided the title compounds as colorless solid (4.9 g, 83%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:8]([O:22][CH2:23][CH2:24]OS(C)(=O)=O)[C@@H:9]2[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10]2)[CH:5]=[CH:6][CH:7]=1.CN(C=O)C.[N-:35]=[N+:36]=[N-:37].[Na+]>CCOC(C)=O>[N:35]([CH2:24][CH2:23][O:22][C@@H:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=1)[C@@H:9]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10]1)=[N+:36]=[N-:37]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]([C@@H](OCCOS(C)(=O)=O)c2cccc(Cl)c2)C1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC[C@@H]([C@@H](OCCN=[N+]=[N-])c2cccc(Cl)c2)C1
Temperature: 80 °C
Yield: 99.1 %

Procedure:
(R)-tert-butyl 3-((R)-(3-chlorophenyl)(2-(methylsulfonyloxy)ethoxy)methyl)piperidine-1-carboxylate (15 g, 34 mmol) was dissolved into anhydrous DMF (150 mL), solid NaN3 (6.7 g, 102 mmol, 3 eq) was added and the reaction mixture was heated to 80° C. for overnight. The reaction mixture was cooled to rt and then was added with EtOAc (500 mL), the organic phase was washed with water (3×100 mL) and brine (2×80 mL), dried over Na2SO4 and concentrated in vacuo to provide crude (R)-tert-butyl 3-((R)-(2-azidoethoxy)(3-chlorophenyl)methyl)piperidine-1-carboxylate (13.3 g), which was used for next step without purification.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:26])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][C:18]2[C:23]([NH2:24])=[CH:22][N:21]=[C:20](Cl)[N:19]=2)=[CH:13][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:27]1[CH:32]=[CH:31][CH:30]=[C:29](B(O)O)[CH:28]=1.C([O-])([O-])=O.[Cs+].[Cs+].O>O1CCOCC1.CCO.CCOC(C)=O>[CH2:1]([O:8][C:9](=[O:26])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][C:18]2[C:23]([NH2:24])=[CH:22][N:21]=[C:20]([C:29]3[CH:28]=[N:27][CH:32]=[CH:31][CH:30]=3)[N:19]=2)=[CH:13][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OB(O)c1cccnc1
Reactant: Nc1cnc(Cl)nc1Oc1ccc(NC(=O)OCc2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Nc1cnc(-c2cccnc2)nc1Oc1ccc(NC(=O)OCc2ccccc2)cc1
Yield: 64.5 %

Procedure:
To a teflon-lined septum sealed Schlenk tube, a mixture of Compound 11a (1.0 g; 2.7 mmol), pyridin-3-yl boronic acid (0.83 g; 6.75 mmol), Cs2CO3 (2.60 g; 8.1 mmol) and [1,1′-Bis(diphenylphosphino)-ferrocene]dichloro-palladium(II) (0.49 g; 0.6 mmol) in a mixture of dioxane (15 mL) and EtOH (1 mL) was irradiated in a microwave reactor at 150° C. for 55 min. The reaction mixture was poured into water, diluted with EtOAc and the solid was collected by filtration. The organic phase was isolated and dried over MgSO4. and the reaction mixture was concentrated under reduced pressure. The resultant residue was purified by reverse phase HPLC, eluting with a CH3CN—H2O (0.5% TFA) gradient to afford Compound 11b (0.72 g; 42% yield based on di-TFA). 1H-NMR (300 MHz, MeOH-d4): δ 9.2 (s, 1H), 8.9 (d, 1H), 8.7 (d, 1H), 8.2 (s, 1H), 8.0 (m, 1H), 7.5 (d, 2H), 7.5-7.3 (m, 6H), 7.2 (m, 2H), 5.2 (s, 2H); MS: m/z 414.2 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C@:10]([OH:18])([CH:15]([CH3:17])[CH3:16])[CH2:11][C:12]([OH:14])=[O:13])=[CH:4][CH:3]=1.Cl.C[C@@H](N)C1C=CC=CC=1.C(O)(C)C>CCOC(C)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C@@:10]([OH:18])([CH:15]([CH3:16])[CH3:17])[CH2:11][C:12]([OH:14])=[O:13])=[CH:6][CH:7]=1
Reactant: CC(C)[C@@](O)(CCc1ccc(F)cc1)CC(=O)O
Agent: C[C@@H](N)c1ccccc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: CC(C)[C@](O)(CCc1ccc(F)cc1)CC(=O)O
Temperature: 25 °C

Procedure:
The mother liquors from the isolation of the G-11 (R) enantiomer were combined, treated with 1N HCl and extracted with EtOAc. The organic phase was washed with brine, dried (MgSO4), filtered and concentrated to liberate the free β-hydroxy acid. HPLC analysis indicated the isolated material was 79% (S):21% (R). β-Hydroxy acid G-11 (22.6 g, 89.0 mmol) was dissolved in 250 mL EtOAc and treated with (R)-α-methylbenzylamine (9.17 g, 75.64 mmol). The resulting mixture was placed on a steam bath, heated to reflux, diluted with additional ˜100 mL EtOAc, and treated with hot isopropanol until solids completely dissolved. The solution was allowed to cool to room temperature slowly overnight and then cooled to −10 to −15° C. Cold EtOAc was added; the solids were filtered off and washed with cold EtOAc and Et2O to yield the title compound. The free acid was obtained by treating the salt with 1N HCl followed by extraction with EtOAc. The organic phased was washed with brine, dried (MgSO4), filtered and concentrated to afford the resolved β-hydroxy acid. HPLC analysis of isolated solid (as the free acid): (AS chiralpak column, 1 mL/min., 98% Hexanes:2% IPA:+0.1% Formic acid)
Reaction SMILES: [CH2:1]([OH:10])/[CH:2]=[CH:3]\[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]>CCOCC.[O-2].[O-2].[Mn+4]>[CH:1](=[O:10])/[CH:2]=[CH:3]\[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCCCC/C=C\CO
Agent: [Mn+4]
Agent: [O-2]
Solvent: CCOCC
Product: CCCCCC/C=C\C=O

Procedure:
Cis-2-nonenol (5 g, mole) is stirred with manganese dioxide (50 g, mole) in ether (250 ml) at room temperature for 1 hour. The mixture is filtered, ether removed, and the residue distilled to give cis-2-nonenal.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][NH:9][CH2:10][C:11]1[CH:12]=[C:13]([C:17]2[CH:22]=[CH:21][C:20]([CH2:23][CH:24]3[S:28][C:27](=[O:29])[NH:26][C:25]3=[O:30])=[CH:19][CH:18]=2)[CH:14]=[CH:15][CH:16]=1.[S:31]1[CH:35]=[CH:34][CH:33]=[C:32]1[C:36](Cl)=[O:37]>>[O:29]=[C:27]1[NH:26][C:25](=[O:30])[CH:24]([CH2:23][C:20]2[CH:19]=[CH:18][C:17]([C:13]3[CH:14]=[CH:15][CH:16]=[C:11]([CH2:10][N:9]([CH3:8])[C:36]([C:32]4[S:31][CH:35]=[CH:34][CH:33]=4)=[O:37])[CH:12]=3)=[CH:22][CH:21]=2)[S:28]1
Reactant: CNCc1cccc(-c2ccc(CC3SC(=O)NC3=O)cc2)c1
Reactant: O=C(Cl)c1cccs1
Solvent: O=C(O)C(F)(F)F
Product: CN(Cc1cccc(-c2ccc(CC3SC(=O)NC3=O)cc2)c1)C(=O)c1cccs1

Procedure:
In a manner similar to that of Example 37(e), by reacting 1 g (2.2 mmol) of 5-(3′-methylaminomethyl-biphenyl-4-ylmethyl)thiazolidine-2,4-dione trifluoro-acetate with 200 μl (2.5 mmol) of 2-thiophenecarboxylic acid chloride, and after purification, 500 mg (50%) of N-[4′-(2,4-dioxothiazolidin-5-ylmethyl)biphenyl-3-ylmethyl]-N-methylthiophene-2-carboxamide are obtained in the form of a white solid with a melting point of 160° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[S:9](Cl)(=[O:11])=[O:10].[OH:13][CH2:14][P:15](=[O:24])([O:20][CH:21]([CH3:23])[CH3:22])[O:16][CH:17]([CH3:19])[CH3:18].C(N(CC)CC)C>CCOCC.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[S:9]([O:13][CH2:14][P:15](=[O:24])([O:16][CH:17]([CH3:19])[CH3:18])[O:20][CH:21]([CH3:23])[CH3:22])(=[O:10])=[O:11]
Reactant: CC(C)OP(=O)(CO)OC(C)C
Reactant: Cc1cccc(Cl)c1S(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: Cc1cccc(Cl)c1S(=O)(=O)OCP(=O)(OC(C)C)OC(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.6 %

Procedure:
A solution of 21.7 g of 2-chloro-6-methylbenzenesulfonyl chloride dissolved in 40 ml of ether was added dropwise over 90 minutes to a mixture of 20.6 g of diisopropyl P-(hydroxymethyl)-phosphonate, (Example 17), 80 ml of ether, and 15.4 ml of triethylamine. The addition was mildly exothermic and the reaction was cooled using a cool water bath (no ice). The reaction was allowed to stir overnight at room temperature and then was diluted with 300 ml of ethyl acetate, washed with three 100 ml portions of water, the organic phase dried with magnesium sulfate, filtered and concentrated under reduced pressure to yield 34.0 g of the desired product as a yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12](Cl)=[O:13])[CH:6]=[CH:5]2.[NH2:15][C:16]1[CH:25]=[C:24]2[C:19]([CH2:20][CH:21]([CH2:26][OH:27])[CH2:22][NH:23]2)=[CH:18][CH:17]=1>>[OH:27][CH2:26][CH:21]1[CH2:20][C:19]2[C:24](=[CH:25][C:16]([NH:15][C:12]([C:7]3[CH:6]=[CH:5][C:4]4[C:9](=[CH:10][CH:11]=[C:2]([Br:1])[CH:3]=4)[CH:8]=3)=[O:13])=[CH:17][CH:18]=2)[NH:23][CH2:22]1
Reactant: Nc1ccc2c(c1)NCC(CO)C2
Reactant: O=C(Cl)c1ccc2cc(Br)ccc2c1
Product: O=C(Nc1ccc2c(c1)NCC(CO)C2)c1ccc2cc(Br)ccc2c1

Procedure:
This material was prepared analogous to the procedure described for Example 1(c). 6-Bromo-naphthalene-2-carbonyl chloride, Example 2(a), (258 mg, 0.96 mmol) reacted with (7-amino-1,2,3,4-tetrahydro-quinolin-3-yl)-methanol (171 mg, 0.96 mmol, prepared according to the procedure described in WO03049702) to give the title compound as an light-brown amorphous solid. MS (ESI, pos. ion) m/z: 413 (M+1).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[F:12].CC1(C)C(C)(C)OB([C:21]2[CH:22]=[N:23][CH:24]=[C:25]([CH:30]=2)[C:26]([O:28][CH3:29])=[O:27])O1>>[F:12][C:3]1[CH:4]=[C:5]([C:8]([F:11])([F:10])[F:9])[CH:6]=[CH:7][C:2]=1[C:21]1[CH:22]=[N:23][CH:24]=[C:25]([CH:30]=1)[C:26]([O:28][CH3:29])=[O:27]
Reactant: COC(=O)c1cncc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: Fc1cc(C(F)(F)F)ccc1Br
Product: COC(=O)c1cncc(-c2ccc(C(F)(F)F)cc2F)c1

Procedure:
According to General Method 1A, 5.0 g (20.6 mmol) of 1-bromo-2-fluoro-4-(trifluoromethyl)benzene and 13.53 g (51.44 mmol) of methyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinate were reacted. Yield: 3.6 g (58% of theory)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([CH2:11][CH:12]([C:19]2[C:23]([CH:24]3[CH2:26][CH2:25]3)=[C:22]([CH:27]3[CH2:30][CH:29]([CH2:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:28]3)[O:21][N:20]=2)[CH2:13][CH2:14][C:15]([O:17]C)=[O:16])=[O:10])=[C:4]([CH3:36])[CH:3]=1.Br.C([O-])(=O)C.[Na+]>C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([CH2:11][CH:12]([C:19]2[C:23]([CH:24]3[CH2:25][CH2:26]3)=[C:22]([CH:27]3[CH2:28][CH:29]([CH2:31][C:32]([CH3:34])([CH3:33])[CH3:35])[CH2:30]3)[O:21][N:20]=2)[CH2:13][CH2:14][C:15]([OH:17])=[O:16])=[O:10])=[C:4]([CH3:36])[CH:3]=1
Reactant: COC(=O)CCC(CC(=O)Nc1ccc(Cl)cc1C)c1noc(C2CC(CC(C)(C)C)C2)c1C1CC1
Agent: Br
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1cc(Cl)ccc1NC(=O)CC(CCC(=O)O)c1noc(C2CC(CC(C)(C)C)C2)c1C1CC1
Temperature: 60 °C
Yield: 69.6 %

Procedure:
Methyl 5-(4-chloro-2-methylphenylcarbamoyl)-4-{4-cyclopropyl-5-[3-(2,2-dimethylpropyl)cyclobutyl]isoxazol-3-yl}valerate (72.5 mg) and acetic acid (0.725 mL) were mixed. To the mixture was added 48 w/v % hydrobromic acid (0.363 mL) at RT. The mixture was stirred at 60° C., and then to the reaction mixture was added sodium acetate (287 mg) at ice temperature. The mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, then dried over magnesium sulfate. The magnesium sulfate was filtered off and the filtrate was concentrated in vacuo. The resultant residue was purified by preparative chromatography (Eluent: methanol/chloroform/acetic acid=1/20/0.05) to give the title compound (49.1 mg). The specific optical rotation value of the title compound was [α]D25=+32.0° (c=1.00, methanol). The title compound was analyzed using a chiral column. The retention time of the title compound was 26.8 min., and the optical purity thereof was 94.8% ee.