Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:11])[C:6]([C:12]([O:14]CC)=O)=[C:5]2[C:17](=O)[C:18]([O:20][CH3:21])=[O:19].[C:23]1([NH:29][NH2:30])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.O.CC(C)=O>C(O)(=O)C>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH3:11])[C:6]3[C:12](=[O:14])[N:29]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[N:30]=[C:17]([C:18]([O:20][CH3:21])=[O:19])[C:5]=3[C:4]=2[CH:3]=1
Reactant: CCOC(=O)c1c(C(=O)C(=O)OC)c2cc(Cl)ccc2n1C
Reactant: NNc1ccccc1
Solvent: CC(=O)O
Solvent: CC(C)=O
Solvent: O
Product: COC(=O)c1nn(-c2ccccc2)c(=O)c2c1c1cc(Cl)ccc1n2C
Reaction time: 15 h
Yield: 79.7 %

Procedure:
A solution of 19 g (59 mmol) of methyl 5-chloro-2-(ethoxycarbonyl)-1-methyl-α-oxo-1H-indole-3-acetate and 26 g (240 mmol) of phenylhydrazine in 250 ml of acetic acid is heated at reflux for 2 h. The mixture is cooled, 250 ml of a 1/1 mixture of water and of acetone are added and the mixture is left standing at 4° C. for 15 h. The precipitate is collected by filtration, washed with water and with acetone and dried under reduced pressure. 17.4 g (47 mmol) of solid are obtained.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[C:11](=O)([O-])[O-].[K+].[K+].IC.O>CN(C=O)C>[F:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1ccc(O)cc1F
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(C#N)c(F)c1
Yield: 96.6 %

Procedure:
2-Fluoro-4-hydroxybenzonitrile (0.50 g, 3.7 mmol), potassium carbonate (0.53 g, 3.8 mmol) and iodomethane (0.34 mL, 0.78 g, 5.5 mmol) in dry DMF (5 mL) were stirred at ambient temperature for 21 h. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with 1N sodium hydroxide solution (2×), water (3×), brine (1×), and dried over MgSO4. After filtration, the solvent was removed in vacuo to yield 2-fluoro-4-methoxy-benzonitrile (0.54 g, 98%) as a white crystalline solid.
Reaction SMILES: [CH2:1]([N:4]1[C:14]2[C:9](=[CH:10][C:11]([O:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])=O)=[CH:12][CH:13]=2)[CH:8]=[CH:7][C:5]1=[O:6])[CH:2]=[CH2:3].C1CCN2C(=NCCC2)CC1.ClC(OCC(C)C)=O.[CH:41]1([N:47]2[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]2)[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]1>CO.C(Cl)(Cl)Cl>[CH2:1]([N:4]1[C:14]2[C:9](=[CH:10][C:11]([O:15][CH2:16][CH2:17][CH2:18][C:19]([N:50]3[CH2:51][CH2:52][N:47]([CH:41]4[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]4)[CH2:48][CH2:49]3)=[O:21])=[CH:12][CH:13]=2)[CH:8]=[CH:7][C:5]1=[O:6])[CH:2]=[CH2:3]
Reactant: C1CCC(N2CCNCC2)CC1
Reactant: C=CCn1c(=O)ccc2cc(OCCCC(=O)O)ccc21
Agent: CC(C)COC(=O)Cl
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: C1CCC2=NCCCN2CC1
Product: C=CCn1c(=O)ccc2cc(OCCCC(=O)N3CCN(C4CCCCC4)CC3)ccc21
Reaction time: 5 h

Procedure:
Into 200 ml of chloroform were added 5.9 g of 1-allyl-6-(3-carboxypropoxy)carbostyril and 3.2 g of DBU. The outside of the reaction vessel containing the above mentioned mixture was ice-cooled and 2.8 g of isobutyl chloroformate was added dropwise to the mixture under stirring condition. After the addition operation the reaction mixture was stirred for 1 hour, then 3.7 g of N-cyclohexylpiperazine was added dropwise to the reaction mixture and the reaction was continued for 5 hours. After the reaction was compleated, the reaction mixture was washed with a 1% NaOH aqueous solution and water, then the organic layer was dried with anhydrous Na2SO4. The drying agent was removed by filtration and the mother liquor was concentrated. The residue thus obtained was treated by a silica-gel column chromatography (solvent used was a mixture of chloroform:methanol=30:1) to obtain elute. 4.2 Grams of 1-allyl-6-[3-(4-cyclohexyl-1-piperazinylcarbonyl)propoxy]carbostyril was obtained from the elute, in the form of a colorless oily substance.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([OH:9])=[CH:4][C:3]=1[N:10]1[C:14](=[O:15])[N:13]([CH2:16][F:17])[C:12]([CH3:18])=[N:11]1.C(=O)([O-])[O-].[K+].[K+].Br[CH:26]([CH3:32])[C:27]([O:29][CH2:30][CH3:31])=[O:28]>CC(C)=O.CCCCC.[I-].[Na+]>[Cl:8][C:6]1[CH:7]=[C:2]([Cl:1])[C:3]([N:10]2[C:14](=[O:15])[N:13]([CH2:16][F:17])[C:12]([CH3:18])=[N:11]2)=[CH:4][C:5]=1[O:9][CH:26]([CH3:32])[C:27]([O:29][CH2:30][CH3:31])=[O:28]
Reactant: CCOC(=O)C(C)Br
Reactant: Cc1nn(-c2cc(O)c(Cl)cc2Cl)c(=O)n1CF
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCCCC
Solvent: CC(C)=O
Product: CCOC(=O)C(C)Oc1cc(-n2nc(C)n(CF)c2=O)c(Cl)cc1Cl
Reaction time: 0.25 h
Yield: 93.9 %

Procedure:
A mixture of 0.56 g (0.0019 mole) of 1-(2,4-dichloro-5-hydroxyphenyl)-4-fluoromethyl-4,5-dihydro-3-methyl-1,2,4-triazol-5(1H)-one and 1.1 g (0.0076 mole) of anhydrous potassium carbonate in 15 mL of acetone was stirred for 15 minutes. Sodium iodide (approximately 0.01 g) and 0.37 g (0.002 mole) of ethyl 2-bromopropionate were added, and the resultant mixture was heated at reflux for 1.5 hours. The mixture was cooled and filtered. The filtrate was evaporated under reduced pressure, leaving a residue. This residue was partitioned between diethyl ether and water. The organic phase was washed with water, dried over anhydrous magnesium sulfate, and filtered. The filtrate was evaporated under reduced pressure, leaving an oil. This oil was stirred in n-pentane, and the supernant was decanted, leaving an oily residue. The oil was dried at 70° C. under a stream of nitrogen to yield 0.70 g of ethyl 2-[2,4-dichloro-5-(4-fluoromethyl-4,5-dihydro-3-methyl-5-oxo-1H-1,2,4-triazol-1-yl)phenoxy]propionate, Compound 13.
Reaction SMILES: Br[C:2]1[S:3][C:4]([O:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][CH:15]([CH3:17])[CH3:16])=[CH:10][CH:9]=2)=[N:5][N:6]=1.C([Sn](CCCC)(CCCC)[C:23]1[S:24][CH:25]=[CH:26][CH:27]=1)CCC>COCCOC>[CH:15]([O:14][C:11]1[CH:12]=[CH:13][C:8]([O:7][C:4]2[S:3][C:2]([C:23]3[S:24][CH:25]=[CH:26][CH:27]=3)=[N:6][N:5]=2)=[CH:9][CH:10]=1)([CH3:17])[CH3:16]
Reactant: CC(C)Oc1ccc(Oc2nnc(Br)s2)cc1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccs1
Solvent: COCCOC
Product: CC(C)Oc1ccc(Oc2nnc(-c3cccs3)s2)cc1
Temperature: 25 °C
Yield: 195.5 %

Procedure:
A solution of Example 24C (0.58 g, 1835 mmol) and 2-tributylstannylthiophene (0.816 ml, 2.57 mmol) in DME (15 mL) was degassed by bubbling nitrogen into the reaction mixture via a 20-gauge needle for 10 minutes. PdCl2(PPh3)2 was added and the reaction was heated at reflux under a nitrogen atmosphere for 20 hours. The reaction was cooled to 25° C. and concentrated under reduced pressure on a rotary evaporator to provide 1.6 g of a golden oil. The concentrate was purified by flash chromatography on silica gel eluting with a solvent gradient from 1% to 15% ethyl acetate in hexanes to provide 0.51 g (88%) of the title compound as a pale purple oil which crystallized on standing, 1H NMR (300 MHz, DMSO-d6) δ ppm 7.79 (d, J=5.15 Hz, 1H) 7.66 (d, J=3.68 Hz, 1H) 7.40 (d, J=9.19 Hz, 2H) 7.18 (dd, J=5.15, 3.68 Hz, 1H) 7.03 (d, J=9.19 Hz, 2H) 4.64 (heptet, J=5.88 Hz, 1H) 1.28 (d, J=5.88 Hz, 6H); MS (DCI) m/z 319 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][N:8]=1)=[O:5].[C:19]([O:23][C:24]([NH:26][CH2:27][CH2:28][O:29][C:30]1[CH:38]=[C:37]([N:39]2[CH2:44][CH2:43][O:42][CH2:41][CH2:40]2)[CH:36]=[CH:35][C:31]=1[C:32](O)=[O:33])=[O:25])([CH3:22])([CH3:21])[CH3:20]>>[C:19]([O:23][C:24]([NH:26][CH2:27][CH2:28][O:29][C:30]1[CH:38]=[C:37]([N:39]2[CH2:44][CH2:43][O:42][CH2:41][CH2:40]2)[CH:36]=[CH:35][C:31]=1[C:32]([NH:1][C:2]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][N:8]=1)=[O:5])=[O:33])=[O:25])([CH3:22])([CH3:20])[CH3:21]
Reactant: Nc1cc(Cl)ccc1C(=O)Nc1ccc(Cl)cn1
Reactant: CC(C)(C)OC(=O)NCCOc1cc(N2CCOCC2)ccc1C(=O)O
Product: CC(C)(C)OC(=O)NCCOc1cc(N2CCOCC2)ccc1C(=O)Nc1cc(Cl)ccc1C(=O)Nc1ccc(Cl)cn1
Yield: 74 %

Procedure:
Using methods substantially equivalent to those described in Example 29-G, 2-[2-(2-tert-butoxycarbonylaminoethoxy)-4-(morpholin-4-yl)benzoylamin]-4-chloro-N-(5-chloropyridin-2-yl)benzamide was prepared in a 74% yield from 2-amino-4-chloro-N-(5-chloropyridin-2-yl)benzamide and 2-(2-tert-butoxycarbonylaminoethoxy)-4-(morpholin-4-yl)benzoic acid.
Reaction SMILES: C([O:3][C:4]([C:6]1([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:18]=2[O:24][CH:25]([CH3:27])[CH3:26])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])C.O1CCOCC1.CO>O>[CH:25]([O:24][C:18]1[C:19]([CH3:23])=[CH:20][CH:21]=[CH:22][C:17]=1[CH2:16][NH:15][C:6]1([C:4]([OH:5])=[O:3])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)([CH3:27])[CH3:26]
Reactant: CCOC(=O)C1(NCc2cccc(C)c2OC(C)C)Cc2ccccc2C1
Solvent: O
Solvent: CO
Solvent: C1COCCO1
Product: Cc1cccc(CNC2(C(=O)O)Cc3ccccc3C2)c1OC(C)C
Reaction time: 39 h
Yield: 72.2 %

Procedure:
A 100 mL round bottom flask containing 2-(2-isopropoxy-3-methyl-benzylamino)-indan-2-carboxylic acid ethyl ester (365, 360 mg, 0.98 mmol) is charged with 1,4-dioxane (3 mL) and MeOH (3 mL). A stirring bar is added and stirring is initiated. After dissolution, water (1.5 mL) is added followed by the LiOH monohydrate (104 mg, 2.47 mmol). After 39 h, tlc analysis (silica, 50% EtOAc/Heptanes) indicates that the starting material is completely consumed. Amberlyst highly acidic exchange resin (0.5 g) is added to the reaction vial. The reaction is capped and allowed to stir at ambient temperature. After 15 days, the contents of the flask are filtered through a pad of Celite. The solvent is removed from the filtrate. The residue is reconstituted with iPrOH/toluene (20+20 mL) and the solvent is removed. This process is repeated 1 time. Pumping to constant weight provided white solid (0.24 g, 72%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[C:9]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)[C:10]([C:11]3[NH:15][C:14](=[O:16])[O:13][N:12]=3)=[C:4]2[CH:3]=1.Br[CH2:26][CH2:27][Cl:28].N12CCCN=C1CCCCC2>CN(C)C(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][N:5]2[N:8]=[C:9]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)[C:10]([C:11]3[N:15]([CH2:26][CH2:27][Cl:28])[C:14](=[O:16])[O:13][N:12]=3)=[C:4]2[CH:3]=1
Reactant: COc1ccc(-c2nn3ccc(Br)cc3c2-c2noc(=O)[nH]2)cc1
Reactant: ClCCBr
Solvent: CC(=O)N(C)C
Solvent: C1CCC2=NCCCN2CC1
Product: COc1ccc(-c2nn3ccc(Br)cc3c2-c2noc(=O)n2CCCl)cc1
Yield: 18.7 %

Procedure:
A mixture of Example 19H (0.64 g, 1.653 mmol), 1-bromo-2-chloroethane (0.206 mL, 2.479 mmol), and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.374 mL, 2.479 mmol) in N,N-dimethylacetamide (8 mL) was heated at 100° C. for 20 hours, cooled and partitioned with ethyl acetate and 1 M aqueous HCl. The organic layer was washed with brine twice, dried with sodium sulfate, filtered and concentrated. Purification on a 40 g silica cartridge eluting with 1-2% methanol in dichloromethane provided the title compound as a solid (0.139 g, 19%). MS (ESI+) m/z 449/451 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([OH:29])[CH2:9][NH:10][CH:11]([CH3:28])[CH2:12][C:13]2[CH:27]=[CH:26][C:16]3[O:17][C:18]([C:23]([OH:25])=[O:24])([C:20]([OH:22])=[O:21])[O:19][C:15]=3[CH:14]=2)[CH:5]=[CH:6][CH:7]=1.[CH:30]1([CH2:33]O)[CH2:32][CH2:31]1.Cl.[K+].[Br-]>C(Cl)(Cl)Cl>[CH:30]1([CH2:33][O:24][C:23]([C:18]2([C:20]([O:22][CH2:33][CH:30]3[CH2:32][CH2:31]3)=[O:21])[O:17][C:16]3[CH:26]=[CH:27][C:13]([CH2:12][CH:11]([NH:10][CH2:9][CH:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=4)[OH:29])[CH3:28])=[CH:14][C:15]=3[O:19]2)=[O:25])[CH2:32][CH2:31]1
Reactant: CC(Cc1ccc2c(c1)OC(C(=O)O)(C(=O)O)O2)NCC(O)c1cccc(Cl)c1
Reactant: OCC1CC1
Agent: Cl
Agent: [Br-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: CC(Cc1ccc2c(c1)OC(C(=O)OCC1CC1)(C(=O)OCC1CC1)O2)NCC(O)c1cccc(Cl)c1

Procedure:
The title compound was prepared from 5-{2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-benzo[1,3]dioxole-2,2-dicarboxylic acid and cyclopropylmethanol according to the procedure of Example 30 as a white solid (HCl salt); 1H NMR (CDCl3) δ 0.33 (m, 4H), 0.61 (m, 4H), 1.21, (m, 2H), 1.32 (bs, 3H), 2.80 (m, 1H), 3.19 (m, 2H), 3.48 (m, 2H), 4.15 (d, J=7.3 Hz, 4H), 5.50 (bd, 1H), 5.70 (bs, 1H), 6.80 (m, 3H), 7.25 (m, 2H), 7.45 (s, 1H), 8.70 (bs, 1H), 10.10 (bs, 1 H); IR (KBr): 1757, 1778 cm-1 (C=O); MS (ES) m/z 530 (MH+); [α]D25 -26° (c, 1.0, CHCl3). Anal. Calcd. for C28H32ClNO7 ·HCl: C, 59.37; H, 5.69; N, 2.47; Cl, 12.53. Found: C, 59.19; H, 5.88; N, 2.29; Cl, 12.87.
Reaction SMILES: IC1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.[F:9][C:10]([F:18])([C:14]([F:17])([F:16])[F:15])[C:11]([O-])=O.[K+].O.CCOCC>CN(C=O)C.[Cu](I)I>[CH3:8][C:5]1[CH:6]=[CH:7][C:11]([C:10]([F:18])([F:9])[C:14]([F:17])([F:16])[F:15])=[CH:3][CH:4]=1
Reactant: Cc1ccc(I)cc1
Reactant: O=C([O-])C(F)(F)C(F)(F)F
Agent: I[Cu]I
Agent: [K+]
Solvent: CCOCC
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(C(F)(F)C(F)(F)F)cc1
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 92.6 %

Procedure:
Procedure adapted from Syn. Comm., (1988) 18(9):965-972. A mixture of copper iodide (129 g, 679 mmol), 1-iodo-4-methylbenzene (1) (74 g, 339 mmol) and potassium 2,2,3,3,3-pentafluoropropanoate (120 g, 594 mmol) were dissolved in DMF (500 mL) and heated to 120° C. for 30 minutes and then heated at 160° C. for 4 hours, after which the mixture was allowed to cool to room temperature. Water (200 mL) and ether (200 mL) were added and after stirring for 30 minutes the solids were filtered and washed with ether. The phases were separated and the organic layer was washed with brine/water (3×250 mL). The organic layer was dried and concentrated to yield 1-methyl-4-(perfluoroethyl)benzene (66 g, 92%) as a dark oil.
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[CH3:19])[CH2:10][CH2:9][C:8]2=[N:20]O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(C)C=CC(S(Cl)(=O)=[O:29])=CC=1.Cl>N1C=CC=CC=1>[CH3:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[CH:11]1[CH2:12][CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[NH:20][C:8](=[O:29])[CH2:9][CH2:10]1
Reactant: Cc1ccccc1C1CCC(=NO)C(c2ccccc2)C1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: c1ccncc1
Product: Cc1ccccc1C1CCC(=O)NC(c2ccccc2)C1
Temperature: 0 °C
Yield: 64.2 %

Procedure:
To a 250mL round-bottomed flask equipped with nitrogen inlet were added 8.20 grams (29.4 mmol) 2-phenyl-4-(2-methylphenyl)cyclohexanone oxime and 80 mL pyridine. Once the solid had dissolved, the solution was cooled to 0° C., and 27.9 grams (147 mmol) p-toluenesulfonyl chloride was added. The reaction was allowed to stir for 16 hours while the ice bath melted and the reaction warmed to room temperature. It was then poured into 300 mL 3N HCl, extracted into ethyl acetate, and the organic layer washed with additional hydrochloric acid and brine, dried over sodium sulfate, and evaporated. The residue was chromatographed on silica gel using methanol/methylene chloride as eluant to afford 5.27 grams (64%) of an amorphous solid.
Reaction SMILES: FC(F)(F)C(O)(C)C(O)=O.CC(O)C.[C:15]1([C:21]2[CH:38]=[CH:37][C:24]([CH2:25][NH:26][CH:27]([CH3:36])[C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=3[Cl:35])=[CH:23][CH:22]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>O>[C:15]1([C:21]2[CH:22]=[CH:23][C:24]([CH2:25][NH:26][C@H:27]([CH3:36])[C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=3[Cl:35])=[CH:37][CH:38]=2)[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CC(NCc1ccc(-c2ccccc2)cc1)c1ccc(Cl)cc1Cl
Agent: CC(O)(C(=O)O)C(F)(F)F
Solvent: O
Solvent: CC(C)O
Product: C[C@@H](NCc1ccc(-c2ccccc2)cc1)c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 2,46 g (15.56 mmol) of racemic 3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid dissolved in a mixed solvent of 20.82 g of water and 16.65 g of 2-propanol at 55° C. was added at 55° C. to a solution of 2.80 g (7.85 mmol) of ()-N-(4-phenylbenzyl)-2,4-dichloro-α-methylbenzylamine in a mixed solvent of 20.78 g of water and 16.62 g of 2-propanol and the resulting solution was mixed under stirring. The solution was inoculated at 55° C. and then cooled to 25° C. under stirring over 1.5 hours and kept at the temperature for 2 hours. The precipitated crystals were collected by filtration and the collected crystals were washed with a mixed solvent of 2.50 g of water and 2.00 g of 2-propanol and dried to yield 2.75 g of (R)-N-(4-phenylbenzyl)-2,4-dichloro-α-methylbenzylamine salt of (S)-3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid with an optical purity of 97% ee.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:9][CH2:10][CH2:11][CH2:12][CH3:13])=[CH:4][CH:3]=1.C([Li])CCC.CN(C)[CH:21]=[O:22]>O1CCCC1>[CH2:10]([O:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([CH:21]=[O:22])=[CH:3][CH:4]=1)[CH2:11][CH2:12][CH3:13]
Reactant: CCCCOCc1ccc(Br)cc1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCCOCc1ccc(C=O)cc1
Temperature: -78 °C
Reaction time: 0.92 h
Yield: 81.3 %

Procedure:
To a solution of 1-bromo-4-butoxymethyl-benzene (11.5 g, 47.3 mmol) described in Manufacturing Example 4-1-1 in tetrahydrofuran (200 mL) was added n-butyl lithium (32.5 mL, 1.6 M hexane solution, 52.0 mmol) at −78° C. This mixture was stirred for 55 minutes at −78° C., and N,N-dimethylformamide (4.4 mL, 56.8 mmol) was added thereto at −78° C. This mixture was warmed to room temperature, and stirred for 20 minutes. The reaction solution was partitioned into water and ethyl acetate at 0° C. The organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous magnesium sulfate, and the solvent was evaporated under a reduced pressure. The residue was purified by silica gel column chromatography (heptane:ethyl acetate=10:1) to obtain the title compound (7.39 g, 81%).
Reaction SMILES: C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[CH3:11][O:12][C:13](=[O:21])[CH2:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.[CH3:22]I>O1CCCC1.O>[CH:15]1([CH:14]([CH3:22])[C:13]([O:12][CH3:11])=[O:21])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]1
Reactant: CI
Reactant: COC(=O)CC1CCCCC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)C(C)C1CCCCC1
Temperature: -78 °C
Reaction time: 1 h
Yield: 92.7 %

Procedure:
1.0 M of Lithium hexamethyldisilazide in tetrahydrofuran (2.2 mL, 2.2 mmol) was added to a solution of methylcyclohexylacetate (0.30 g, 1.9 mmol) (Aldrich, Cat. #209600) in tetrahydrofuran (7.0 mL) at −78° C. The mixture was stirred at −78° C. for 1 h., then methyl iodide (0.14 mL, 2.3 mmol) was added. The mixture was allowed to warm slowly to r.t., and stirred at r.t. overnight. The mixture was diluted with water, and extracted with ethyl acetate (3×10 mL). The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column with ethyl acetate in hexanes (0-10%) to afford the desired product (0.30 g, 92%).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([C:10]([CH3:21])([CH3:20])[CH2:11][C:12]([OH:19])([C:15]([F:18])([F:17])[F:16])[CH:13]=O)[C:4]=2[O:3][CH2:2]1.[NH2:22][C:23]1[CH:31]=[CH:30][CH:29]=[C:28]2[C:24]=1[CH2:25][NH:26][C:27]2=[O:32]>C(O)(=O)C>[OH:19][C:12]1([C:15]([F:16])([F:17])[F:18])[CH2:11][C:10]([CH3:20])([CH3:21])[C:9]2[C:4]3[O:3][CH2:2][O:1][C:5]=3[CH:6]=[CH:7][C:8]=2[CH:13]1[NH:22][C:23]1[CH:31]=[CH:30][CH:29]=[C:28]2[C:24]=1[CH2:25][NH:26][C:27]2=[O:32]
Reactant: Nc1cccc2c1CNC2=O
Reactant: CC(C)(CC(O)(C=O)C(F)(F)F)c1cccc2c1OCO2
Solvent: CC(=O)O
Product: CC1(C)CC(O)(C(F)(F)F)C(Nc2cccc3c2CNC3=O)c2ccc3c(c21)OCO3
Yield: 63.5 %

Procedure:
800 mg (2.63 mmol) of 4-(1,3-benzodioxol-4-yl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanal is stirred in 5.2 ml of glacial acetic acid with 389 mg (2.63 mmol) of 4-amino-2,3-dihydroisoindol-1-one overnight at room temperature. The reaction mixture is spun in until a dry state is reached, and the residue is chromatographed on a Flashmaster. 725 mg (62.8%) of the desired compound is isolated as a racemate. Racemate cleavage (Chiralpak AD 20μ; mobile solvent: hexane/ethanol/diethylamine) yields 279.2 mg of the (+)-enantiomer {[α]D=+20.7 (c=1.03, methanol)}and 297.5 mg of the (−)-enantiomer {[α]D=−23.4 (c=1.02, methanol)}
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:11]1[C:40]([CH3:41])=[C:39]([CH3:42])[C:38]2=[N:43][C:35]3=[CH:36][N:37]2[C:12]=1[N:13]1[CH2:49][CH2:48][C:16]([CH3:50])([O:17][CH2:18][CH2:19][CH2:20][CH2:21][C@H:22]([CH3:47])[O:23][C:24]2[CH:25]=[CH:26][C:27]([F:46])=[C:28]([F:45])[C:29]=2[C:30]2[CH:44]=[C:34]3[CH:33]=[CH:32][CH:31]=2)[CH2:15][CH2:14]1)[C:7]([O:9]C)=[O:8])([CH3:4])([CH3:3])[CH3:2].C(O[C@@H](C1C(C)=CC2=NC3=C(Cl)N2C=1N1CCC(C)(OCCCC[C@H](C)OC2C=CC(C)=CC=2C2C=C3C=CC=2)CC1)C(O)=O)(C)(C)C>>[C:1]([O:5][C@@H:6]([C:11]1[C:40]([CH3:41])=[C:39]([CH3:42])[C:38]2=[N:43][C:35]3=[CH:36][N:37]2[C:12]=1[N:13]1[CH2:14][CH2:15][C:16]([CH3:50])([O:17][CH2:18][CH2:19][CH2:20][CH2:21][C@H:22]([CH3:47])[O:23][C:24]2[CH:25]=[CH:26][C:27]([F:46])=[C:28]([F:45])[C:29]=2[C:30]2[CH:44]=[C:34]3[CH:33]=[CH:32][CH:31]=2)[CH2:48][CH2:49]1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)c(C)c2nc3cn2c1N1CCC(C)(CC1)OCCCC[C@H](C)Oc1ccc(F)c(F)c1-c1cccc-3c1
Agent: Cc1ccc2c(c1)-c1cccc(c1)-c1nc3cc(C)c([C@H](OC(C)(C)C)C(=O)O)c(n3c1Cl)N1CCC(C)(CC1)OCCCC[C@H](C)O2
Product: Cc1c([C@H](OC(C)(C)C)C(=O)O)c2n3cc(nc3c1C)-c1cccc(c1)-c1c(ccc(F)c1F)O[C@@H](C)CCCCOC1(C)CCN2CC1
Yield: 25.8 %

Procedure:
Prepared in 25.8% yield from methyl(2S)-2-(tert-butoxy)-2-[(22S)-16,17-difluoro-4,5,22,28-tetramethyl-21,27-dioxa-1,7,34-triazahexacyclo[26.2.2.16,9.110,14.02,7.015,20]tetratriaconta-2,4,6(34),8,10(33),11,13,15(20),16,18-decaen-3-yl]acetate following the procedure for (2S)-2-(tert-butoxy)-2-[(22S)-8-chloro-4,17,22,28-tetramethyl-21,27-dioxa-1,7,34-triazahexacyclo[26.2.2.16,9.110,14.02,7.015,20]tetratriaconta-2,4,6(34),8,10(33),11,13,15(20),16,18-decaen-3-yl]acetic acid. 1H NMR (500 MHz, DMSO-d6) δ 8.14 (d, J=8.1 Hz, 1H), 7.97 (s, 1H), 7.87 (s, 1H), 7.53 (t, J=7.7 Hz, 1H), 7.38 (q, J=9.4 Hz, 1H), 7.31 (d, J=7.7 Hz, 1H), 6.99 (d, J=6.6 Hz, 1H), 5.92 (br. s., 1H), 4.62 (br. s., 1H), 3.86 (t, J=11.2 Hz, 1H), 3.58 (t, J=10.6 Hz, 1H), 3.44 (br. s., 4H), 2.48 (s, 3H), 2.30 (s, 3H), 1.92-1.79 (m, 3H), 1.77-1.58 (m, 7H), 1.18 (s, 3H), 1.15 (s, 9H), 1.07 (d, J=5.9 Hz, 3H); LCMS (ESI, M): 675.3.
Reaction SMILES: C1C2C(COC(=O)[NH:17][C:18]3[CH:23]=[CH:22][C:21]([S:24][C:25]4[CH:30]=[CH:29][C:28]([C:31](=[O:42])[NH:32][C:33]5[S:34][C:35]([C:38]([CH3:41])([CH3:40])[CH3:39])=[CH:36][N:37]=5)=[CH:27][C:26]=4[NH:43][C:44]4[C:45]5[CH:53]=[CH:52][C:51]([CH:54]([CH3:56])[CH3:55])=[N:50][C:46]=5[N:47]=[CH:48][N:49]=4)=[CH:20][CH:19]=3)C3C(=CC=CC=3)C=2C=CC=1.O.[OH-].[Li+].Cl>O1CCOCC1.O.C(OCC)(=O)C>[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([S:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]([NH:32][C:33]3[S:34][C:35]([C:38]([CH3:39])([CH3:40])[CH3:41])=[CH:36][N:37]=3)=[O:42])=[CH:27][C:26]=2[NH:43][C:44]2[C:45]3[CH:53]=[CH:52][C:51]([CH:54]([CH3:56])[CH3:55])=[N:50][C:46]=3[N:47]=[CH:48][N:49]=2)=[CH:20][CH:19]=1
Reactant: CC(C)c1ccc2c(Nc3cc(C(=O)Nc4ncc(C(C)(C)C)s4)ccc3Sc3ccc(NC(=O)OCC4c5ccccc5-c5ccccc54)cc3)ncnc2n1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: CC(C)c1ccc2c(Nc3cc(C(=O)Nc4ncc(C(C)(C)C)s4)ccc3Sc3ccc(N)cc3)ncnc2n1
Temperature: 65 °C
Yield: 65.3 %

Procedure:
A solution of the product of Example 161E (123.4 mg, 0.1558 mmol) in 1,4-dioxane (4 mL) was treated with a solution of lithium hydroxide monohydrate (13 mg, 0.3 116 mmol) in water (2 mL) at ambient temperature, then heated at 65° C. for 1 hour. The reaction was cooled to room temperature, diluted with ethyl acetate (100 mL) and water (30 mL), adjusted the aqueous pH to 6 with 1N aqueous hydrochloric acid, and separated the layers. The organic phase was washed with water (2×25 mL) and brine (25 mL), dried over anhydrous sodium sulfate, filtered, and concentrated by rotary evaporation in vacuo. Purification of the residue by silica gel flash chromatography with 4% methanol/methylene chloride afforded the title compound (58 mg, 65%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 1.28 (s, 9 H) 1.34 (d, J=6.99 Hz, 6 H) 3.17-3.34 (m, 1 H) 5.64 (s, 2 H) 6.65 (d, J=8.46 Hz, 2 H) 6.80 (s, 1 H) 6.82 (d, J=8.46 Hz, 1 H) 7.16 (d, J=8.46 Hz, 2 H) 7.65 (d, J=8.46 Hz, 1 H) 7.88-7.98 (dd, 1 H) 8.11 (s, 1 H) 8.58 (s, 1 H) 8.89 (d, J=8.46 Hz, 1 H) 10.13 (s, 1 H) 12.47 (s, 1 H); MS (ESI+) m/z 570 (M+H)+, (ESI−) m/z 568 (M−H)−.