Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[CH:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][C:10]=1[OH:19]>C(Cl)Cl.[Cl-].[Cl-].[Cl-].[Cl-].[Zr+4]>[Cl:1][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][C:10]=1[OH:19]
Reactant: Oc1ccc2ccccc2c1
Reactant: O=C1CCC(=O)N1Cl
Agent: [Zr+4]
Agent: [Cl-]
Solvent: ClCCl
Product: Oc1ccc2ccccc2c1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 75.4 %

Procedure:
To a cooled (0-5° C.) solution of N-chlorosuccinimide (1.4 g, 10.4 mmol) in 100 mL of CH2Cl2, ZrCl4 (0.122 g, 5% mol) was added followed by 1.5 g (10.4 mmol) of naphthalen-2-ol. The mixture was stirred for 18 h at room temperature until the complete disappearance of the starting material as judged by TLC and GC analysis. The mixture was quenched with saturated NH4Cl aqueous solution (30 mL) and transferred to a separatory funnel. The two phases were separated and the organic one was washed with water (3×10 mL), dried over Na2SO4 and evaporated under vacuum to give yellow oil. The crude was purified by flash cromatography (petroleum ether/ethyl acetate 85:15) to afford 1-chloronaphtalen-2-ol (1.4 gr, 78% yield), as white solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[C@H:5]([CH2:7][C:8]1[N:12]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[Cl:20])[C:11]([CH2:21][CH2:22][CH2:23][CH3:24])=[N:10][CH:9]=1)[NH2:6])[CH3:2].[CH:26](=O)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C([BH3-])#N.[Na+]>>[CH2:1]([O:3][C:4](=[O:25])[C@H:5]([CH2:7][C:8]1[N:12]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[Cl:20])[C:11]([CH2:21][CH2:22][CH2:23][CH3:24])=[N:10][CH:9]=1)[NH:6][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH3:2]
Reactant: CCCCc1ncc(C[C@H](N)C(=O)OCC)n1Cc1ccccc1Cl
Reactant: O=Cc1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Product: CCCCc1ncc(C[C@H](NCc2ccccc2)C(=O)OCC)n1Cc1ccccc1Cl

Procedure:
The title compound is prepared by reductive alkylation of 2-n-butyl-3-(2-chlorophenyl)methylhistidine ethyl ester with benzaldehyde in the presence of sodium cyanoborohydride to give 3-[(2-chlorophenyl)methyl]-2-n-butyl-N-benzylhistidine ethyl ester. Hydrolysis of the ester group is accomplished according to Example 2 (iii) to provide the title compound.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[F:13][C:14]1[CH:15]=[C:16]([CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:28]=1)[C:17]([N:19]([CH:23]([CH3:25])[CH3:24])[CH:20]([CH3:22])[CH3:21])=[O:18].CN([CH:36]=[O:37])C>CCCCCC.C(OCC)C>[F:13][C:14]1[C:15]([CH:36]=[O:37])=[C:16]([CH:26]=[C:27]([C:29]([F:30])([F:31])[F:32])[CH:28]=1)[C:17]([N:19]([CH:23]([CH3:25])[CH3:24])[CH:20]([CH3:21])[CH3:22])=[O:18]
Reactant: CC(C)N(C(=O)c1cc(F)cc(C(F)(F)F)c1)C(C)C
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: CCCCCC
Solvent: CCOCC
Product: CC(C)N(C(=O)c1cc(C(F)(F)F)cc(F)c1C=O)C(C)C
Temperature: -75 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
A dried 200 ml round-bottomed flask containing 20 ml diethylether was cooled to −75° C. then 22.15 mmol diisopropylamine, 22.15 mmol 1.6M n-butyllithium in hexane, and a solution of 14.77 mmol 3-fluoro-N,N-diisopropyl-5-trifluoromethyl-benzamide in 20 ml diethylether were added sequentially. The mixture was stirred at −75° C. for 2 hours. 2.9 ml DMF was added dropwise. After the reaction was stirred for another hour, the mixture was warmed and stirred at room temperature for 30 minutes. The mixture was quenched with 100 ml 10% citric acid and extracted 3 times with ether. The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by chromatography (SiO2, heptane/ethyl acetate) to yield the title compound as a light yellow solid (90% yield). MS (m/e): 320.1 (M+H+, 100%)
Reaction SMILES: [C:1]([OH:6])(=[O:5])[C:2]([CH3:4])=[CH2:3].C(Cl)Cl.N1C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:27]([O:29][CH2:30][CH3:31])[CH3:28]>>[CH2:27]([O:29][CH:30]([O:5][C:1](=[O:6])[C:2]([CH3:4])=[CH2:3])[CH3:31])[CH3:28]
Reactant: CCOCC
Reactant: C=C(C)C(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: C=C(C)C(=O)OC(C)OCC
Yield: 96 %

Procedure:
In a flask having four inlets, 15.1 grams (0.21 mols) of ethylvinylehter and 20 grams (0.23 mols) of methacrylic acid were dissolved into 200 ml of methylene chloride. Then, 0.53 grams (0.0021 mols) of p-toluenesulfonic acid pyridine salt was added to the mixture, and stirred for complete dissolution of p-toluenesulfonic acid pyridine salt into the mixture. The resultant solution was stood at room temperature for six hours. Then, 200 ml of diethylether was added into the solution. The resultant solution was washed three times with 2.5% aqueous sodium hydroxide, and further six times with water. Then, an ether layer was dehydrated with magnesium sulfate. After filtering magnesium sulfate out, a methylene chloride layer was evaporated. As a result, there was obtained 31.8 grams of 1-ethoxyethylmethacrylate. The yield was 96%. With respect to a structure of the target material, IR was measured with an analyzer, IR-470 model available from Shimazu Seisakusho, and 1H-NMR was measured with an analyzer, AMX-400 model available from Bruker Instruments.
Reaction SMILES: [Br:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([CH3:9])=[C:4]([Cl:10])[CH:3]=1.[Br:11]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl.CCCCCCC>[Br:1][C:2]1[CH:3]=[C:4]([Cl:10])[C:5]([CH2:9][Br:11])=[CH:6][C:7]=1[F:8]
Reactant: Cc1cc(F)c(Br)cc1Cl
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: CCCCCCC
Solvent: ClC(Cl)(Cl)Cl
Product: Fc1cc(CBr)c(Cl)cc1Br
Temperature: 85 °C

Procedure:
A solution of 4-bromo-2-chloro-5-fluorotoluene (997 mg, 4.46 mmol), N-bromosuccinimide (837 mg, 4.70 mmol) and benzoyl peroxide (35 mg, 0.14 mmol) in carbon tetrachloride (20 mL) was heated to reflux at 85° C. for 18.5 hours under nitrogen. The reaction mixture was concentrated in vacuo to afford a cream solid residue. The residue was suspended in heptane (40 mL), filtered and the filtrate then concentrated in vacuo to afford the title compound a clear oil (1.35 g, 100%). The compound was used without further purification in the next step.
Reaction SMILES: C([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([NH2:20])[C:15]=1[C:21]#[N:22])(=O)C.[S:23](Cl)(=[O:26])(=[O:25])N.[N:28]1C=CC=CC=1.[OH-].[Na+]>CC(N(C)C)=O>[NH2:28][C:21]1[C:15]2[C:14]([O:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][OH:4])=[CH:19][CH:18]=[CH:17][C:16]=2[NH:20][S:23](=[O:26])(=[O:25])[N:22]=1
Reactant: CC(=O)OCCCCCCCCOc1cccc(N)c1C#N
Reactant: NS(=O)(=O)Cl
Reactant: c1ccncc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)N(C)C
Product: NC1=NS(=O)(=O)Nc2cccc(OCCCCCCCCO)c21
Temperature: 25 °C
Yield: 57.3 %

Procedure:
To a solution of 8-(3-amino-2-cyanophenoxy)octyl acetate (746 μmol, 227 mg) in DMA (3 mL) was added sulfamoyl chloride (1.492 mmol, 172 mg) and pyridine (4.476 mmol, 362 L). The reaction mixture was stirred at room temperature until completion, then quenched with sat. NaHCO3 (15 mL) and solid NaCl added. The precipate was collected and washed with water. The wet precipitate was suspended in EtOH (15 mL) and treated with NaOH (8.952 mmol, 1N, 8.95 mL). The reaction mixture was refluxed until completion then cooled to room temperature. Most of the EtOH and water were removed in vacuo, then the reaction mixture was dissolved in water (15 mL), extracted with ether (3×5 mL), filtered through a 0.45 μm PTFE frit, then acidified with 10% citric acid/water solution to pH 4-5. The precipitate was filtered off, washed with water and dried to give the desired product 146 mg (57.3%) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) 1.265 (m, 6H), 1.380 (m, 4H), 1.785 (pentet, J=7 Hz, 2H), 3.348 (q, J=6 Hz, 2H), 4.303 (t, J=5 Hz, 2H), 6.580 (d, J=8 Hz, 1H), 6.724 (d, J=8 Hz, 1H), 7.428 (t, J=8 Hz, 1H), 7.796 (br. s, 1H), 8.329 (br. s, 1H), 10.922 (s, 1H). MS 342 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:12][NH:13][CH3:14].O.C(OCC)(=O)C>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:13]([CH3:14])[CH3:12])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CNC
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CN(C)S(=O)(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of 50 g of 4-fluorobenzenesulfonyl chloride in 250 ml of THF was cooled to 0° C., and then, 100 ml of an aqueous 50% dimethylamine solution was added dropwise thereto, and the mixture was stirred at room temperature for 1 day. To the reaction mixture were added water and ethyl acetate, the mixture was stirred and then the liquids were separated. The organic layer was washed with a saturated aqueous sodium bicarbonate solution and dried, the solvent was evaporated, and disopropyl ether and hexane were added to the residue. Then, the precipitates were collected by filtration and washed with hexane to obtain 49.9 g of 4-fluoro-N,N-dimethyl-benzenesulfonamide. (2) In 600 ml of DMSO were suspended 25 g of (S)-(+3-(tert-butoxycarbonylamino)pyrrolidine, 47.9 g of 4-fluoro-N,N-dimethyl-benzenesulfonamide and 139 g of potassium carbonate, and the mixture was stirred at 130° C. for 1 day. To the reaction mixture were added water and ethyl acetate, the resulting mixture was stirred and the liquids were separated. The organic layer was washed with water, and then dried, and the solvent was evaporated. The residue was dissolved in chloroform, NH silica gel was added thereto and the mixture was allowed to stand for a while, and silica gel was filtered off. The silica gel was further washed with ethyl acetate. The filtrate and the washed solution were combined, and the residue obtained by concentration under reduced pressure was purified by silica gel column chromatography (hexane:ethyl acetate=80:20→67:33) to obtain 8.39 g of tert-butyl [(S)-1-(4-dimethylsulfamoylphenyl)-pyrrolidin-3-yl]carbamate.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:16])=[C:6]([NH:8][C:9](=[S:15])[NH:10][CH2:11][C:12](N)=[O:13])[CH:7]=1.[CH2:17](I)[CH3:18]>C(O)C>[CH2:17]([S:15][C:9]1[N:8]([C:6]2[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=2[CH3:16])[C:12](=[O:13])[CH2:11][N:10]=1)[CH3:18]
Reactant: Cc1ccc(F)cc1NC(=S)NCC(N)=O
Reactant: CCI
Solvent: CCO
Product: CCSC1=NCC(=O)N1c1cc(F)ccc1C
Yield: 66.9 %

Procedure:
A mixture of 2-[3-(5-fluoro-2-methylphenyl)-thioureido]-acetamide (6.0 g), ethyl iodide (15.6 g), and ethanol (120 mL) was heated at reflux for 4 hours. The solvent was evaporated. The residue was treated with ethyl acetate (400 mL) and filtered. The filtrate was washed with water (300 mL). The organic phase was evaporated to dryness. The residue was dissolved in ethanol. The solution was saturated with hydrogen chloride. The solvent was evaporated and the residue was crystallized from ethyl acetate and dried under vacuum to give the mono-hydrochloride of the title compound as a white solid (4.2 g), m.p. 181°-183° C. Anal. Calcd. for. C12H13F N2O S . HCl: C, 49.91; H, 4.89; N, 9.70. Found: C, 49.83; H, 4.82; N, 9.71. Mass spectrum (+FAB,[M+H]+) m/z 253. 1H-NMR (DMSO-d6 ; 400 MHz) δ7.50-8.45 (broad s, 2 H), 7.45 (m, 1 H), 7.27-7.34 (m, 2 H), 4.48 (q, 2 H), 3.21 (m, 2 H), 2.10 (s, 3 H), and 1.29 ppm (t, 3 H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:28]=[CH:29][CH:30]=1)[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([C:15]([NH:17][S:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[CH3:27])(=[O:20])=[O:19])=[O:16])=[CH:12][CH:13]=2)[CH:8]=[CH:7]1.C[CH:32]([CH2:37][CH3:38])[CH2:33][C:34]([OH:36])=O.Cl.[CH3:40]N(C)CCCN=C=NCC>CN(C)C1C=CN=CC=1.ClCCl>[CH3:40][CH:37]([CH3:38])[CH2:32][CH2:33][C:34]([NH:1][C:2]1[CH:3]=[C:4]([CH:28]=[CH:29][CH:30]=1)[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([C:15]([NH:17][S:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[CH3:27])(=[O:20])=[O:19])=[O:16])=[CH:12][CH:13]=2)[CH:8]=[CH:7]1)=[O:36]
Reactant: CCC(C)CC(=O)O
Reactant: CCN=C=NCCCN(C)C
Reactant: Cc1ccccc1S(=O)(=O)NC(=O)c1ccc2c(ccn2Cc2cccc(N)c2)c1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: Cc1ccccc1S(=O)(=O)NC(=O)c1ccc2c(ccn2Cc2cccc(NC(=O)CCC(C)C)c2)c1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
A mixture of the amine (Example 4) (0.25 g), 3-methylvaleric acid (0.07 g), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.126 g) and 4-dimethylaminopyridine (0.02 g) in dichloromethane (5 ml) was stirred at room temperature for 96 hours. The reaction mixture was washed with water then saturated brine, dried over anhydrous magnesium sulphate, filtered and evaporated in vacuo. Purification by flash chromatography on silica, eluting with 0-30% ethyl acetate in hexane, afforded N-{1-[3-(3-methylbutylcarbonylamino)benzyl]indol-5-ylcarbonyl}-2-methylbenzene sulphonamide.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl.[CH2:14]([O:16][C:17](=[O:21])[CH2:18][CH2:19][NH2:20])[CH3:15].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>O.CN(C)C=O.C(N(CC)CC)C>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:8]([NH:20][CH2:19][CH2:18][C:17]([O:16][CH2:14][CH3:15])=[O:21])=[O:10])=[CH:11][CH:12]=1)([O-:3])=[O:2]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Reactant: CCOC(=O)CCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CCOC(=O)CCNC(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To a mixture of 4-nitrobenzoic acid (16.7 g), β-alanine ethyl ester hydrochloride (18.4 g), 1-hydroxybenzotriazol.monohydrate (18.4 g), triethylamine (16.7 mL) and N,N-dimethylformamide (200 mL) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (23.0 g), and the mixture was stirred at room temperature for 8 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with 1N hydrochloric acid and saturated aqueous sodium hydrogen carbonate, dried over magnesium sulfate, and concentrated under reduced pressure to give a white solid. Recrystallization from ethyl acetate-hexane gave the title object compound (26.6 g, 100%) as white crystals.
Reaction SMILES: [Br:1][C:2]1[C:7](=[O:8])[NH:6][CH:5]=[C:4]([C:9]([O:11][CH3:12])=[O:10])[CH:3]=1.[C:13](=O)([O-])[O-].[K+].[K+].CI>CN(C=O)C>[Br:1][C:2]1[C:7](=[O:8])[N:6]([CH3:13])[CH:5]=[C:4]([C:9]([O:11][CH3:12])=[O:10])[CH:3]=1
Reactant: COC(=O)c1c[nH]c(=O)c(Br)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)c1cc(Br)c(=O)n(C)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A mixture of methyl 5-bromo-6-oxo-1,6-dihydropyridine-3-carboxylate (1.5 g, 6.5 mmol) and potassium carbonate (0.99 g, 7.15 mmol) in DMF (25 mL) was stirred at room temperature for 15 min followed by the addition of methyl iodide (0.42 mL, 6.83 mmol). The resulting suspension was stirred at room temperature for 17 h. The mixture was partitioned between ethylacetate and water. The organic phase was separated and the aqueous phase was extracted with ethylacetate. The organic extracts were combined, washed with brine, dried over MgSO4 and concentrated to afford the title compound as a light yellow solid. MS m/z: 246 (M+1).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[N:5][C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2>CO.O.[Pt](=O)=O>[OH:1][CH2:2][CH:3]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][CH2:4]1
Reactant: OCc1cnc2ccccc2c1
Agent: O=[Pt]=O
Solvent: O
Solvent: CO
Product: OCC1CNc2ccccc2C1
Reaction time: 6 h
Yield: 83.2 %

Procedure:
3-Hydroxymethylquinoline (0.45 g, 2.83 mmoles) (prepared as described in: B. R. Brown, D. Ll. Hammick and B. H. Thewlis, J. Chem. Soc., 1951,1145-1149.) was dissolved in methanol (100 mL) and placed in a Parr bomb. Platinum (IV) oxide monohydrate (0.225 g, 0.918 mmoles) was added and the mixture was hydrogenated at 50 psi at 25° C. for 6 h. The catalyst was removed by decantation and washed with methanol. The methanol was evaporated to dryness and the product was chromatographed on silica gel using 3% (10% conc. NH4OH in methanol)-dichloromethane as the eluant to give the title compound (0.3843 g, 83%): CIMS: m/z 164.35 (MH+); δH (CDCl3) 6.50 (1H, d, Ar—H8), 6.64 (1H, t, Ar—H6), 6.98 (1H, d, Ar—H5) and 6.99 ppm(1H, m, Ar—H7); δC (CDCl3) CH2: 29.5, 44.0, 65.2; CH: 34.9, 114.2, 117.4, 126.9, 129.8; C: 120.2, 144.5.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:12]([C:13]([OH:15])=O)=[C:11]([CH3:16])[O:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.Cl.C(N=C=NCCCN(C)C)C.[CH3:29][O:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1>ClCCl>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:12]([C:13]([N:40]3[CH2:39][CH2:38][N:37]([C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=4[O:30][CH3:29])[CH2:42][CH2:41]3)=[O:15])=[C:11]([CH3:16])[O:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccccc1N1CCNCC1
Reactant: Cc1onc(-c2cccc(F)c2)c1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: COc1ccccc1N1CCN(C(=O)c2c(-c3cccc(F)c3)noc2C)CC1
Yield: 80.4 %

Procedure:
In a similar manner as described in Example 1, by using dichloromethane (30 mL), 3-(3-fluorophenyl)-5-methylisoxazol-4-carboxylic acid (407 mg, 1.84 mmol), 1-ethyl-3-(dimethylaminopropyl)carbodiimide hydrochloride (388 mg, 2.02 mmol) and 1-(2-methoxyphenyl)piperazine (354 mg, 1.84 mmol), a white solid required compound (586 mg, 1.48 mmol, 81%) was obtained.
Reaction SMILES: [Cl:1][C:2]1[C:37]([C:38]([F:41])([F:40])[F:39])=[CH:36][CH:35]=[CH:34][C:3]=1[CH2:4][N:5]([CH2:20][CH:21]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-])=O)[C:11]=1[CH3:19].C(Cl)(Cl)Cl>CO.[Pd]>[Cl:1][C:2]1[C:37]([C:38]([F:39])([F:40])[F:41])=[CH:36][CH:35]=[CH:34][C:3]=1[CH2:4][N:5]([CH2:20][CH:21]([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:6][CH2:7][CH2:8][O:9][C:10]1[C:11]([CH3:19])=[C:12]([NH2:16])[CH:13]=[CH:14][CH:15]=1
Reactant: Cc1c(OCCCN(Cc2cccc(C(F)(F)F)c2Cl)CC(c2ccccc2)c2ccccc2)cccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: Cc1c(N)cccc1OCCCN(Cc1cccc(C(F)(F)F)c1Cl)CC(c1ccccc1)c1ccccc1
Reaction time: 2.5 h
Yield: 75 %

Procedure:
(2-Chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl)-[3-(2-methyl-3-nitro-phenoxy)-propyl]-amine (300 mg, 0.51 mmol) was dissolved in methanol (100 ml), and hydrogenated with 10% Pd/C (40 mg) at 60 psi at room temperature. After 2.5 h, the reaction mixture was filtered and concentrated in vacuo to give an amber oil, 0.25 g (89%). Flash silica gel chromatography (Supelco Discovery DSC-Si) (CHCl3) afforded the title compound as a pure oil (75%). MS (ESI) 552.5 (M−H+).
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[N:11]([CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([CH:23]5[CH2:28][CH2:27][N:26]([C:29]([CH3:33])([CH3:32])[C:30]#[N:31])[CH2:25][CH2:24]5)[CH:20]=[CH:19][C:16]=43)[CH:10]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].S(=O)(=O)(O)[OH:35].C(=O)([O-])[O-].[Na+].[Na+]>>[CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[C:16]4[CH:19]=[CH:20][C:21]([CH:23]5[CH2:28][CH2:27][N:26]([C:29]([CH3:33])([CH3:32])[C:30]([NH2:31])=[O:35])[CH2:25][CH2:24]5)=[CH:22][C:15]=4[O:14][CH2:13][CH2:12][N:11]3[CH:10]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2]
Reactant: O=S(=O)(O)O
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(C3CCN(C(C)(C)C#N)CC3)cc1OCC2
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(C3CCN(C(C)(C)C(N)=O)CC3)cc1OCC2
Yield: 60 %

Procedure:
2-{4-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yl]-piperidin-1-yl}-2-methyl-propionitrile (312 mg, 0.70 mmol) was added concentrated sulfuric acid (3.5 mL). The resultant mixture was stirred for 3.5 hours at RT before being poured onto ice and basified with sodium carbonate. The aqueous mixture was extracted with 10% MeOH in DCM (×5). The combined organic layers were dried (Na2SO4) and concentrated in vacuo. The resultant residue was purified by flash column chromatography (SiO2, gradient 0-10% MeOH in DCM), then triturated with diethyl ether (x 3), to afford 287 (196 mg, 0.42 mmol, 60%). LCMS: RT=2.67 min, [M+H]+=464. 1H NMR δ (ppm)(DMSO-d): 8.27 (1 H, d, J=8.27 Hz), 7.86 (1 H, d, J=0.63 Hz), 7.85 (1 H, s), 7.17 (1 H, d, J=3.55 Hz), 7.03 (1 H, dd, J=8.34, 1.74 Hz), 6.91-6.89 (2 H, m), 5.89-5.79 (1 H, m), 4.48-4.41 (4 H, m), 2.80 (2 H, d, J=10.82 Hz), 2.17-2.09 (2 H, m), 1.77-1.60 (4 H, m), 1.44 (6 H, d, J=6.60 Hz), 1.05 (6 H, s). 1H obscured by solvent.
Reaction SMILES: C(N)(C)(C)C.[CH3:6][O:7][C:8](=[O:17])[C:9](=[C:14]([CH3:16])[CH3:15])[CH2:10][C:11]([OH:13])=[O:12]>CO>[CH3:6][O:7][C:8](=[O:17])[C@H:9]([CH:14]([CH3:15])[CH3:16])[CH2:10][C:11]([OH:13])=[O:12]
Reactant: COC(=O)C(CC(=O)O)=C(C)C
Solvent: CC(C)(C)N
Solvent: CO
Product: COC(=O)[C@@H](CC(=O)O)C(C)C
Temperature: 0 °C
Reaction time: 22 h

Procedure:
A solution of the tert-butylamine salt of 2-isopropylidenesuccinic acid 1-methyl ester (162 g, 0.66 mol) in methanol (800 mL) was transferred to a 2 L high pressure hydrogenation vessel and degassed by pressurizing and venting four times with 10 bar of hydrogen. The vessel was then cooled to 0° C. and a solution of [Rh(COD)(S,S)-Me-BPE]OTf (0.80 g, 0.0013 mmol) in methanol (10 mL) was added through the solvent port. The reaction was purged again with hydrogen and stirred at 0° C. under a pressure of hydrogen of 10−7 bar. After 22 hours, the temperature was allowed to raise to room temperature, the vessel was vented in a fume hood, the reaction mixture was transferred to a round-bottomed flask and the solvent was evaporated under reduced pressure. A sample (1 g) of the resulting solid residue was partitioned between HCl 2N (5 mL) and ethyl acetate (5 mL). The organic layer was dried over MgSO4 and evaporated to give 2-(S)-isopropylsuccinic acid 1-methyl ester, ee 96% by GC. The bulk residue was suspended in ethyl acetate (600 mL) and stirred at room temperature for 48 hours, then collected and dried under vacuum to give 154 g of the tert-butylamine salt of 2-(S)-isopropylsuccinic acid monomethyl ester (yield: 94%). A sample (1 g) of the salt was worked up and analyzed as above, indicating an enantiomeric excess of 99% for the free acid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)=[CH:9][CH2:10][NH:11][C:12]2[CH:22]=[CH:21][C:15]([C:16]([O:18]CC)=[O:17])=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.C(O)C.[OH-].[Na+].C(O)(=O)C>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:23]2[CH:24]=[CH:25][C:26]([Cl:29])=[CH:27][CH:28]=2)=[CH:9][CH2:10][NH:11][C:12]2[CH:22]=[CH:21][C:15]([C:16]([OH:18])=[O:17])=[CH:14][CH:13]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1ccc(NCC=C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)c1ccc(NCC=C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)cc1

Procedure:
A suspension of 1.3 g. of p-[[3,3-bis(p-chlorophenyl)allyl]amino]benzoic acid, ethyl ester, 40 ml. of ethanol, and 4.6 ml. of 1N sodium hydroxide is heated at reflux for 28 hours, cooled, and then diluted with an equal volume of water. A 0.26 ml. portion of glacial acetic acid is added, and the mixture is cooled in ice. The solid is collected, washed with water, and recrystallized from absolute ethanol, giving 600 mg. of the desired product, m.p. 231°-235° C.
Reaction SMILES: [NH2:1]/[C:2](/[CH2:9][CH2:10][CH3:11])=[CH:3]/[C:4]([O:6][CH2:7][CH3:8])=[O:5].[O:12]1[CH2:17][C:16](=O)[CH2:15][C:14](=[O:19])[CH2:13]1.[Br:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][C:28]=1[F:29])[CH:24]=O>C(O)C>[Br:20][C:21]1[CH:22]=[C:23]([CH:24]2[C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])=[C:2]([CH2:9][CH2:10][CH3:11])[NH:1][C:16]3[CH2:17][O:12][CH2:13][C:14](=[O:19])[C:15]2=3)[CH:26]=[CH:27][C:28]=1[F:29]
Reactant: O=Cc1ccc(F)c(Br)c1
Reactant: O=C1COCC(=O)C1
Reactant: CCC/C(N)=C\C(=O)OCC
Solvent: CCO
Product: CCCC1=C(C(=O)OCC)C(c2ccc(F)c(Br)c2)C2=C(COCC2=O)N1
Temperature: 25 °C
Reaction time: 16 h
Yield: 88.2 %

Procedure:
The product from Example 95A (0.083 g, 0.52 mmol), the product from Example 11B (0.050 g, 0.44 mmol) and 3-bromo-4-fluorobenzaldehyde (0.116 g, 0.57 mmol) in ethanol (1 mL) were heated to 80 C. for 16 hours in a sealed tube, cooled to ambient temperature and concentrated to dryness. The residue was purified on silica gel eluting with 2% methanol in dichloromethane to provide the title compound (0.17 g).