Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:7][C:8]([CH3:17])([CH3:16])[CH2:9][CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:18]([C@@H:20]1[C@@H:24]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:23][N:22]([C@H:31]([CH:44]2[CH2:49][CH2:48][CH2:47][CH2:46][CH2:45]2)[C:32]([O:34]CC2C=CC(OC)=CC=2)=[O:33])[CH2:21]1)=O>>[CH3:16][C:8]([CH3:17])([CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH2:9][CH:10]1[CH2:11][CH2:12][N:13]([CH2:18][C@@H:20]2[C@@H:24]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH2:23][N:22]([C@H:31]([CH:44]3[CH2:49][CH2:48][CH2:47][CH2:46][CH2:45]3)[C:32]([OH:34])=[O:33])[CH2:21]2)[CH2:14][CH2:15]1
Reactant: CC(C)(Cc1ccccc1)CC1CCNCC1
Reactant: COc1ccc(COC(=O)[C@@H](C2CCCCC2)N2C[C@H](c3ccccc3)[C@@H](C=O)C2)cc1
Product: CC(C)(Cc1ccccc1)CC1CCN(C[C@H]2CN([C@@H](C(=O)O)C3CCCCC3)C[C@@H]2c2ccccc2)CC1

Procedure:
The title compound was prepared from 9 mg (0.05 mmol) of 4-(3-phenyl-2,2-dimethylpropyl)piperidine (from EXAMPLE 98, Step I) and 20 mg (0.05 mmol) of 2-(R)-(3-(R)-formyl-4-(S)-phenylpyrrolidin-1-yl)-2-(cyclohexyl)acetic acid, 4-methoxybenzyl ester (from EXAMPLE 33, Step E) using procedures analogous to those described in EXAMPLE 1, Step J and EXAMPLE 10, Step F. For the title compound: ESI-MS 531 (M+H).
Reaction SMILES: [C:1]1([CH3:15])[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[O:11][CH:10]=[N:9][C:8]=2[C:12]([OH:14])=O)[CH:2]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:47][C:48]1[CH:49]=[N:50][N:51]([CH2:53][CH2:54][OH:55])[CH:52]=1>C(Cl)Cl.O.CN(C=O)C>[OH:55][CH2:54][CH2:53][N:51]1[CH:52]=[C:48]([NH:47][C:12]([C:8]2[N:9]=[CH:10][O:11][C:7]=2[C:3]2[CH:2]=[C:1]([CH3:15])[CH:6]=[CH:5][CH:4]=2)=[O:14])[CH:49]=[N:50]1
Reactant: Nc1cnn(CCO)c1
Reactant: Cc1cccc(-c2ocnc2C(=O)O)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Cc1cccc(-c2ocnc2C(=O)Nc2cnn(CCO)c2)c1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To a solution of 5-(m-tolyl)oxazole-4-carboxylic acid (5.50 g, 27.07 mmol) in DCM (80 mL), TBTU (13.04 g, 40.60 mmol) and DIPEA (13.90 mL, 81.20 mmol) was added. After stirring for 40 min at rt, 2-(4-amino-1H-pyrazol-1-yl)ethanol (3.47 g, 27.07 mmol) dissolved in DCM (10 mL) and DMF (4 mL) was added to the reaction mixture and stirred at rt for 1 h, then the reaction mixture was diluted with DCM and water, the org. layer was separated and the aq. layer extracted with DCM (1×). The combined org. layers were washed with brine, dried (MgSO4), filtered and the solvent was removed under reduced pressure. Purification by FC (DCM/MeOH, 95:5 to DCM/MeOH 9:1) yielded the tiltle compound as a white solid. LC-MS conditions A: tR=0.71 min, [M+H]+=313.44.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([N+:11]([O-:13])=[O:12])[CH:5]=1)[CH3:2].[Br:14]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(OCC)(=O)C>[Br:14][CH2:10][C:7]1[CH:8]=[CH:9][C:4]([O:3][CH2:1][CH3:2])=[CH:5][C:6]=1[N+:11]([O-:13])=[O:12]
Reactant: CCOc1ccc(C)c([N+](=O)[O-])c1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: CCOC(C)=O
Product: CCOc1ccc(CBr)c([N+](=O)[O-])c1
Temperature: 90 °C
Reaction time: 8 h
Yield: 66.7 %

Procedure:
A mixture of 4-ethoxy-1-methyl-2-nitrobenzene (11.8 g), N-bromosuccinimide (17.4 g), 2,2′-azobisisobutyronitrile (1.07 g) and ethyl acetate (300 mL) was stirred under an argon atmosphere at 90° C. overnight. The solvent was evaporated under reduced pressure, and the residue was diluted with diethyl ether, and the mixture was washed three times with water. The separated organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound as a yellow oil (11.3 g).
Reaction SMILES: C([O:3][C:4](=[O:33])[CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH3:16])[CH:13]=2)[N:8]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH:19]=2)[C:7]=1[CH3:32])C.C(OC(=O)CC1C2C(=CC=C(OC)C=2)NC=1C)C.[H-].[Na+].C(OC1C=C(C=CC=1)CCl)C1C=CC=CC=1>>[CH2:25]([O:24][C:20]1[CH:19]=[C:18]([CH2:17][N:8]2[C:9]3[C:14](=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=3)[C:6]([CH2:5][C:4]([OH:33])=[O:3])=[C:7]2[CH3:32])[CH:23]=[CH:22][CH:21]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CCOC(=O)Cc1c(C)n(Cc2cccc(OCc3ccccc3)c2)c2ccc(OC)cc12
Agent: CCOC(=O)Cc1c(C)[nH]c2ccc(OC)cc12
Agent: ClCc1cccc(OCc2ccccc2)c1
Agent: [H-]
Product: COc1ccc2c(c1)c(CC(=O)O)c(C)n2Cc1cccc(OCc2ccccc2)c1
Yield: 42 %

Procedure:
1-[(3-Benzyloxyphenyl)methyl]-5-methoxy-2-methyl-1H-indole-3-acetic acid ethyl ester. Using the procedure described in Example 1 Part F, 494 mg (2 mmol) of 5-methoxy-2-methyl-1H-indole-3-acetic acid ethyl ester was reacted with 80 mg (2 mmol) of 60% NaH/mineral oil and 465 mg (2 mmol) of meta-benzyloxybenzyl chloride and after chromatography on silica (eluting with 20% EtOAc/hexane) and crystallizing from MeOH there was obtained 376 mg (42%) of 1-[(3-benzyloxyphenyl)methyl]-5-methoxy-2-methyl-1H-indole-3-acetic acid, mp, 60°-70° C.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:18][CH2:19][O:20][CH2:21][CH2:22][NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1)[CH2:2][CH2:3][CH3:4].ClC1C=C(C=CC=1)C(OO)=[O:36].C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH2:1]([C:5]1[N:6]([CH2:18][CH2:19][O:20][CH2:21][CH2:22][NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N+:10]([O-:36])=[CH:9][C:8]=2[N:17]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2cnc3ccccc3c2n1CCOCCNC(=O)OC(C)(C)C
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCCCc1nc2c[n+]([O-])c3ccccc3c2n1CCOCCNC(=O)OC(C)(C)C
Reaction time: 5 h
Yield: 85.9 %

Procedure:
A solution of tert-butyl 2-[2-(2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)ethoxy]ethylcarbamate (4.12 g, 10.0 mmol) in 50 mL of CH2Cl2 was treated with 3-chloroperoxybenzoic acid (MCPBA, 77%, 2.5 g, 11.2 mmol). After stirring for 5 h, the reaction mixture was treated with saturated NaHCO3 solution and the layers were separated. The organic portion was washed with H2O and brine then dried over Na2SO4 and concentrated to give 3.68 g of tert-butyl 2-[2-(2-butyl-5-oxido-1H-imidazo[4,5-c]quinolin-1-yl)ethoxy]ethylcarbamate as a light brown foam.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]([N:5]1[CH2:11][CH:10]([CH3:12])[C:9]2[CH:13]=[C:14]([Cl:18])[C:15]([OH:17])=[CH:16][C:8]=2[CH2:7][CH2:6]1)=[O:4].[CH2:21](Br)[CH:22]=[CH2:23].C1CCN2C(=NCCC2)CC1>ClCCl.CCOC(C)=O>[F:20][C:2]([F:19])([F:1])[C:3]([N:5]1[CH2:11][CH:10]([CH3:12])[C:9]2[CH:13]=[C:14]([Cl:18])[C:15]([O:17][CH2:23][CH:22]=[CH2:21])=[CH:16][C:8]=2[CH2:7][CH2:6]1)=[O:4]
Reactant: CC1CN(C(=O)C(F)(F)F)CCc2cc(O)c(Cl)cc21
Reactant: C=CCBr
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCOC(C)=O
Product: C=CCOc1cc2c(cc1Cl)C(C)CN(C(=O)C(F)(F)F)CC2
Reaction time: 2 h
Yield: 84.8 %

Procedure:
A solution of N-trifluoroacetyl-8-chloro-7-hydroxy-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine (24 mg, 0.078 mmol) in dichloromethane (2 mL) was treated with allyl bromide (18 mg, 0.15 mmol), DBU (23 mg, 0.15 mmol) and stirred 2 hours at 20 C. The product mixture was diluted with EtOAc (10 mL), washed with 5% aqueous HCl (5 mL), brine (5 mL), dried with Na2SO4 and concentrated. Flash chromatography (15% EtOAc in hexane, silica) resulted in 23 mg of a white solid. MS calculated for C16H17ClF3NO2+H: 348, observed: 348.
Reaction SMILES: [CH:1]([C:3]1[S:4][CH:5]=[C:6]([C@@H:8]2[CH2:12][C@@H:11]([O:13][S:14]([CH3:17])(=[O:16])=[O:15])[CH2:10][N:9]2[C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=2)=[O:19])[N:7]=1)=[O:2].[BH4-].[Na+].C(O)(=O)C>CO.O1CCCC1>[OH:2][CH2:1][C:3]1[S:4][CH:5]=[C:6]([C@@H:8]2[CH2:12][C@@H:11]([O:13][S:14]([CH3:17])(=[O:16])=[O:15])[CH2:10][N:9]2[C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=2)=[O:19])[N:7]=1
Reactant: CS(=O)(=O)O[C@@H]1C[C@@H](c2csc(C=O)n2)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: CO
Product: CS(=O)(=O)O[C@@H]1C[C@@H](c2csc(CO)n2)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 92.1 %

Procedure:
To a solution of (2S,4R)-2-(2-formylthiazol-4-yl)-4-methanesulfonyloxy-1- (4-nitrobenzyloxycarbonyl)pyrrolidine (2.26 g) in a mixture of methanol (30 ml) and tetrahydrofuran (30 ml) was added sodium borohydride (94 mg) at 0° C. After stirring at 0° C. for 30 minutes, acetic acid (0.6 ml) was added to the solution. After the mixture was evaporated, the residue was dissolved in ethyl acetate, washed with water, saturated sodium bicarbonate and brine successively. The dried organic layer was evaporated to give (2S, 4R)-2-[2-(hydroxymethyl) thiazol-4-yl]-4-(methanesulfonyloxy)-1-(4-nitrobenzyloxycarbonyl) pyrrolidine (2.09 g)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[O:5][CH2:6][CH:7]1[CH2:11][CH2:10][N:9]([C:12](OC(C)(C)C)=O)[CH2:8]1.ClC1[N:44]=[CH:43][C:42]([Cl:45])=[CH:41][C:24]=1[C:25]([NH:27][C:28]1([C:31]2[CH:40]=[CH:39][C:34]([C:35]([O:37][CH3:38])=[O:36])=[CH:33][CH:32]=2)[CH2:30][CH2:29]1)=[O:26]>>[Cl:45][C:42]1[CH:43]=[N:44][C:12]([N:9]2[CH2:10][CH2:11][CH:7]([CH2:6][O:5][C:4]3[CH:19]=[CH:20][CH:21]=[C:2]([F:1])[CH:3]=3)[CH2:8]2)=[C:24]([CH:41]=1)[C:25]([NH:27][C:28]1([C:31]2[CH:32]=[CH:33][C:34]([C:35]([O:37][CH3:38])=[O:36])=[CH:39][CH:40]=2)[CH2:30][CH2:29]1)=[O:26]
Reactant: COC(=O)c1ccc(C2(NC(=O)c3cc(Cl)cnc3Cl)CC2)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(COc2cccc(F)c2)C1
Product: COC(=O)c1ccc(C2(NC(=O)c3cc(Cl)cnc3N3CCC(COc4cccc(F)c4)C3)CC2)cc1
Yield: 42.9 %

Procedure:
The title compound (D200) (38 mg) was prepared according to the experimental procedure described in Description 160 starting from tert-butyl 3-((3-fluorophenoxy)methyl)pyrrolidine-1-carboxylate (D40) (100 mg, 0.338 mmol) and reacting in the second step with methyl 4-(1-(2,5-dichloronicotinamido)cyclopropyl)benzoate (D97) (61.8 mg, 0.169 mmol).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[C:5]([NH2:11])=[C:4]([CH3:12])[CH:3]=1.[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1B1OC(C)(C)C(C)(C)O1>>[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:2]1[CH:3]=[C:4]([CH3:12])[C:5]([NH2:11])=[C:6]([NH2:8])[CH:7]=1
Reactant: CC1(C)OB(c2ccccc2F)OC1(C)C
Reactant: Cc1cc(Br)cc([N+](=O)[O-])c1N
Product: Cc1cc(-c2ccccc2F)cc(N)c1N

Procedure:
The title compound was prepared from 4-bromo-2-methyl-6-nitro-phenylamine and 2-(2-fluoro-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane using the procedures described in Example 1, steps D and E. 1H-NMR (400 MHz, CDCl3) δ: 7.36 (td, J=7.8, 1.9 Hz, 1H), 7.16-7.23 (m, 1H), 7.03-7.15 (m, 2H), 6.84 (s, 1H), 6.79-6.82 (m, 1H), 3.47 (br. s., 4H), 2.20 (s, 3H).
Reaction SMILES: C(N=C=NC(C)C)(C)C.[C:10](O)([CH3:13])([CH3:12])[CH3:11].ClCCl.[Br:18][CH2:19][C:20]([CH3:25])([CH3:24])[C:21]([OH:23])=[O:22]>[Cu]Cl.C(O)(=O)C>[C:10]([CH:19]([Br:18])[C:20]([CH3:25])([CH3:24])[C:21]([OH:23])=[O:22])([CH3:13])([CH3:12])[CH3:11]
Reactant: CC(C)(CBr)C(=O)O
Reactant: CC(C)(C)O
Agent: Cl[Cu]
Agent: CC(C)N=C=NC(C)C
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(C)(C)C(Br)C(C)(C)C(=O)O
Reaction time: 96 h

Procedure:
At room temperature under shielded light, to N,N′-diisopropylcarbodiimide (99.75 g) was added copper(I) chloride (1.57 g), and then tert-butanol (83 ml) was added dropwise over 20 minutes, followed by stirring for 4 days. The supernatant (78 ml) was added dropwise to a dichloromethane suspension (270 ml) of 3-bromo-2,2-dimethylpropanoic acid (49.4 g) at room temperature over 30 minutes, followed by stirring for 18 hours. Acetic acid (18.8 ml) was added, and stirred for 1 hour. The reaction suspension was filtered, and ice water and sodium hydrogen carbonate were added to the filtrate for neutralization. After the precipitate was filtered off, the organic layer separated from the filtrate was washed with saturated sodium hydrogen carbonate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. After pentane was added to the residue, insolubles were filtered off, and the filtrate was concentrated under reduced pressure to afford tert-butyl 3-bromo-2,2-dimethylpropanoic acid (18.81 g).
Reaction SMILES: N[C@H](C(O)=O)CC[C:5]([OH:7])=[O:6].[CH3:11][N:12]([C:26]1[CH:27]=[CH:28][C:29](C(N[C@H](C(O)=O)CCC(O)=O)=O)=[CH:30][CH:31]=1)[CH2:13][C:14]1[CH:15]=[N:16][C:17]2[N:23]=[C:22]([NH2:24])[N:21]=[C:20]([NH2:25])[C:18]=2[N:19]=1>>[NH2:24][C:22]1[N:21]=[C:20]([NH2:25])[C:18]2[C:17](=[N:16][CH:15]=[C:14]([CH2:13][N:12]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[C:5]([OH:7])=[O:6])[CH3:11])[N:19]=2)[N:23]=1
Reactant: N[C@@H](CCC(=O)O)C(=O)O
Reactant: CN(Cc1cnc2nc(N)nc(N)c2n1)c1ccc(C(=O)N[C@@H](CCC(=O)O)C(=O)O)cc1
Product: CN(Cc1cnc2nc(N)nc(N)c2n1)c1ccccc1C(=O)O

Procedure:
The title compound was prepared by carboxypeptidase G cleavage of glutamic acid from methotrexate as described in the literature (J. Med. Chem. 24, 1450-1455 (1981)). The yield of I obtained was virtually quantitative.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:10][CH:9]2[NH:11]C(=O)OC(C)(C)C)=[CH:4][CH:3]=1.Cl.O1CCOCC1>ClCCl>[ClH:1].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:10][CH:9]2[NH2:11])=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)NC1CC1c1ccc(Cl)cc1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: NC1CC1c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 198.2 %

Procedure:
tert-Butyl 2-(4-chlorophenyl)cyclopropylcarbamate (51.9 mg, 0.1938 mmol) was dissolved in Dichloromethane (1 ml) and 4M HCl solution in dioxane (0.4846 ml, 1.938 mmol) was added. The mixture was stirred for 3 hours at ambient temperature, during which time a white solid precipitated out of solution. The crude mixture was concentrated and chased with EtOAc (2×10 ml). The residual fine solid was dried under high vacuum to provide 39.2 mg of the title compound as a solid (99%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][N:9]1[C:13]([CH2:14][C@@H:15]([C:24]([OH:26])=[O:25])[NH:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:12][N:11]=[C:10]1[CH2:27][CH2:28][CH2:29][CH3:30].[CH3:31]I>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][N:9]1[C:13]([CH2:14][C@@H:15]([C:24]([OH:26])=[O:25])[N:16]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH3:31])=[CH:12][N:11]=[C:10]1[CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: CI
Reactant: CCCCc1ncc(C[C@H](NCc2ccccc2)C(=O)O)n1Cc1ccccc1Cl
Product: CCCCc1ncc(C[C@@H](C(=O)O)N(C)Cc2ccccc2)n1Cc1ccccc1Cl

Procedure:
3-[(2-chlorophenyl)methyl]-2-n-butyl-N-benzylhistidine (prepared in Example 13) is reacted with methyl iodide to give the title compound.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:10][CH2:11][CH3:12])[C:5]([O:7]CC)=O)[CH3:2].[Na].CO.Cl.[C:17]([O:20][CH2:21][CH3:22])(=[O:19])[CH3:18]>O>[CH2:11]([O:10][CH:4]([O:3][CH2:1][CH3:2])[C:5](=[O:7])[CH2:18][C:17]([O:20][CH2:21][CH3:22])=[O:19])[CH3:12]
Reactant: CCOC(C)=O
Reactant: CCOC(=O)C(OCC)OCC
Agent: Cl
Agent: [Na]
Solvent: CO
Solvent: O
Product: CCOC(=O)CC(=O)C(OCC)OCC
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 40 g of ethyl diethoxyacetate (227 mmol) in 67 mL of ethyl acetate there are added under argon, in portions, 6 g of sodium (261 mmol). The reaction mixture is then stirred at ambient temperature for 48 hours. There are added 10 mL of methanol, and then the mixture is hydrolysed with 65 mL of water. The pH of the reaction mixture is adjusted to pH 6 by adding 1N aqueous HCl solution. The mixture is separated and then extracted with ethyl acetate. The organic phases are combined, washed with brine, dried over MgSO4, filtered and concentrated to dryness. The title product is obtained in the form of an oil which is used in the next Step without being otherwise purified.
Reaction SMILES: [C:1]([O:5][C:6](=[O:42])[CH:7]([NH:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:8][C:9]1[CH:14]=[C:13]([C:15](=[O:30])[C:16]2[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[C:18]([C:26]([F:29])([F:28])[F:27])[CH:17]=2)[CH:12]=[CH:11][C:10]=1[N+:31]([O-])=O)([CH3:4])([CH3:3])[CH3:2]>[Pd].C(O)(C)C>[C:1]([O:5][C:6](=[O:42])[CH:7]([NH:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:8][C:9]1[CH:14]=[C:13]([C:15](=[O:30])[C:16]2[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[C:18]([C:26]([F:27])([F:28])[F:29])[CH:17]=2)[CH:12]=[CH:11][C:10]=1[NH2:31])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(C)OC(=O)NC(Cc1cc(C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)ccc1[N+](=O)[O-])C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)NC(Cc1cc(C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)ccc1N)C(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 89 %

Procedure:
The nitrobenzophenone derivative 52 (0.7475 g, 1.23 mmol), isopropanol (40 mL), and 10% palladium on activated carbon (131 mg, 0.131 mmol) were added to a single-necked 200 mL pear-shaped round-bottom flask. The flask was sealed with a rubber septum and charge-purged three times using a hydrogen-filled balloon followed by house vacuum. The reaction vessel was equipped with two hydrogen-filled balloons and allowed to stir at room temperature for exactly 15 minutes. During this time a filter funnel was prepared with celite and packed with isopropanol. The reaction mixture was immediately vacuum filtered through the funnel into a 100 mL round-bottom flask. The solvent was removed in vacuo and the crude mixture was purified by flash chromatography (20% EtOAc:hexanes) to afford 58 as a yellow solid (0.631 g, 89%): m.p. 134–135° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]([CH:17]([CH3:19])[CH3:18])[CH:9]=2)=[CH:4][CH:3]=1.C1COCC1.C1C=C[NH+]=CC=1.[Br:31][Br-]Br.C(=O)([O-])O.[Na+]>ClC1C=CC=CC=1>[Br:31][C:9]1[N:10]([CH:17]([CH3:19])[CH3:18])[C:11]2[C:16]([C:8]=1[C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)=[CH:15][CH:14]=[CH:13][CH:12]=2
Reactant: CC(C)n1cc(-c2ccc(F)cc2)c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Agent: c1cc[nH+]cc1
Solvent: Clc1ccccc1
Solvent: C1CCOC1
Product: CC(C)n1c(Br)c(-c2ccc(F)cc2)c2ccccc21
Temperature: 3 °C
Reaction time: 1.25 h

Procedure:
20 g (78.95 mmol) of 3-(4-fluorophenyl)-1-isopropyl-1H-indole, 200 ml of THF and 200 ml of chlorobenzene are introduced into a 1.5 liter sulfonating flask, equipped with an anchor stirrer, thermometer and nitrogen delivery line, and cooled to 3° C. with stirring. 26.58 g (78.95 mmol) of pyridinium bromide perbromide are then added and stirring is carried out for 1.25 hours at 3° C. 680 g of a 5% sodium hydrogen carbonate solution are then added dropwise in the course of 10 min. The phases are separated and the aqueous phase is extracted three times with 150 ml of chlorobenzene. The combined organic phases are washed twice with 340 ml of 5% sodium hydrogen carbonate solution and twice with 220 ml of water, dried over magnesium sulfate, filtered and concentrated by evaporation. The brown residue is dissolved in 125 ml of methylene chloride, 125 ml of 94% ethanol are added and the methylene chloride is distilled off at normal pressure. The solution is cooled slowly to room temperature and then to 3° C., and the precipitate is filtered off, washed three times with 10 ml of ice-cold 94% ethanol and dried overnight at RT/125 T. Beige crystals having a melting point of from 110 to 111.5° C. are obtained. Elemental analysis: Found 4.95% H; 61.23% C; 4.04% N; 22.9% Br; 5.67% F. Theory 4.55% H; 61.46% C; 4.22% N; 24.05% Br; 5.72% F.
Reaction SMILES: [CH2:1]=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[H][H].C([Al](CC)CC)C>C1CCCCC1.[Ni]>[CH2:1]=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:1]=[CH:2][C:3](=[CH2:4])[CH3:8]
Reactant: [H][H]
Agent: [Ni]
Agent: CC[Al](CC)CC
Solvent: C=Cc1ccccc1
Solvent: C1CCCCC1
Product: C=CC(=C)C
Reaction time: 3 h

Procedure:
A copolymer of styrene and isoprene was prepared by polymerization of a mixture of the two monomers in cyclohexane solution, resulting in a tapered copolymer having 37.5 wt.% styrene. The polymer, in cyclohexane solvent, was then subjected to hydrogenation utilizng a catalyst comprising the reaction product of 2.5 moles of aluminum triethyl per mole of nickel-2-ethylhexoate. The hydrogenation reacton conditions comprised 700 psig hydrogen pressure, 80°C, 18% polymer solids in the solution and 4.0 mmoles nickel per pound of polymer. After 180 minutes hydrogenation time, 93.5% of the olefinic unsaturation had been reduced. At this point, triethyl aluminum (TEA) was added, causing substantially complete interruption of hydrogenation. This was indicated by the fact that after holding for 30 additional minutes, the percent of hydrogenation of olefinic bonds had only increased about 1%. In a parallel run with no supplemental TEA being added, the percentage of olefin reduction is about 97.3% after a total of 210 minutes hydrogenation under the same conditions. In the process according to the invention as described above, one mole of supplemental TEA was added per mole of nickel.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)([OH:16])[CH2:9][C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)=[CH:4][CH:3]=1>[Pt].C(O)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:17]2[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=2)([OH:16])[CH2:9][CH:10]2[CH2:11][CH2:12][NH:13][CH2:14][CH2:15]2)=[CH:6][CH:7]=1
Reactant: OC(Cc1ccncc1)(c1ccc(F)cc1)c1ccc(F)cc1
Agent: [Pt]
Solvent: CC(=O)O
Product: OC(CC1CCNCC1)(c1ccc(F)cc1)c1ccc(F)cc1
Reaction time: 9 h
Yield: 84.9 %

Procedure:
A mixture of 12.25 g (0.0394 mole) of α,α-bis(4-fluorophenyl)-4-pyridineethanol and 1.3 g of 5% platinum on carbon catalyst in 250 ml of acetic acid was shaken under an atmosphere of hydrogen (53 psi) for 9 hr. The solution was filtered through Celite®, and the solvent was removed in vacuo. The residue was partitioned between methylene chloride and dilute sodium hydroxide. The solvent was removed in vacuo to give a solid. Recrystallization from acetonitrile gave 10.62 g (85% yield) of title compound as a white, crystalline solid, mp 169°-171° C.
Reaction SMILES: [Si]([O:8][C@@H:9]([C:23]1[CH:28]=[CH:27][C:26]([C:29]2[N:33]=[C:32]([C:34]3[O:38][N:37]=[C:36]([C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)[C:35]=3[C:45]([F:48])([F:47])[F:46])[O:31][N:30]=2)=[CH:25][CH:24]=1)[CH2:10][N:11]1[CH2:16][CH2:15][CH2:14][C@H:13]([CH2:17][C:18]([O:20]CC)=[O:19])[CH2:12]1)(C(C)(C)C)(C)C.Cl.O1CCOCC1>>[OH:8][CH:9]([C:23]1[CH:24]=[CH:25][C:26]([C:29]2[N:33]=[C:32]([C:34]3[O:38][N:37]=[C:36]([C:39]4[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=4)[C:35]=3[C:45]([F:48])([F:47])[F:46])[O:31][N:30]=2)=[CH:27][CH:28]=1)[CH2:10][N:11]1[CH2:16][CH2:15][CH2:14][C@H:13]([CH2:17][C:18]([OH:20])=[O:19])[CH2:12]1
Reactant: CCOC(=O)C[C@H]1CCCN(C[C@@H](O[Si](C)(C)C(C)(C)C)c2ccc(-c3noc(-c4onc(-c5ccccc5)c4C(F)(F)F)n3)cc2)C1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(O)C[C@H]1CCCN(CC(O)c2ccc(-c3noc(-c4onc(-c5ccccc5)c4C(F)(F)F)n3)cc2)C1
Yield: 99.2 %

Procedure:
Ethyl 2-((R)-1-((S)-2-(tert-butyldimethylsilyloxy)-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)ethyl)piperidin-3-yl)acetate (840 mg, 1.227 mmol) was heated in 1:1 6N HCl/dioxane at 50° C. overnight. The product was concentrated in vacuo and freeze dried from MeCN/water to yield 660 mg of 2-((3R)-1-(2-hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)ethyl)piperidin-3-yl)acetic acid. Characterization of product by 1H NMR and chiral HPLC matched Example 18 prepared in previous synthesis.