Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([Cl:9])=[CH:4][C:3]=1[F:10].C([Mg]Cl)(C)C.C(O[B:20]1[O:24][C:23]([CH3:26])([CH3:25])[C:22]([CH3:28])([CH3:27])[O:21]1)(C)C.C(OCC)C>O1CCCC1>[Cl:9][C:5]1[C:6]([Cl:8])=[CH:7][C:2]([B:20]2[O:24][C:23]([CH3:26])([CH3:25])[C:22]([CH3:28])([CH3:27])[O:21]2)=[C:3]([F:10])[CH:4]=1
Reactant: Fc1cc(Cl)c(Cl)cc1Br
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Agent: CC(C)[Mg]Cl
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC1(C)OB(c2cc(Cl)c(Cl)cc2F)OC1(C)C
Temperature: -10 °C
Reaction time: 1 h
Yield: 71.1 %

Procedure:
1-Bromo-4,5-dichloro-2-fluorobenzene (1.0 g, 4.11 mmol) was dissolved in tetrahydrofuran (THF; 20 mL) and cooled to −10° C. A 2.0M solution of isopropylmagnesium chloride (2.3 mL, 4.6 mmol) in THF was added dropwise via a syringe. The reaction mixture was stirred at −10° C. for 1 hour, allowed to warm toward 0° C. for 1 hour, then cooled to −10° C. again. A solution of 2-isopropoxy-4,4,5,5-tetramethyl[1,3,2]dioxaborolane (0.85 g, 4.56 mmol) in THF (1.0 mL) was then added dropwise and the reaction was allowed to warm to ambient temperature. The reaction mixture was then added to diethyl ether and extracted with 1N sodium hydroxide. The aqueous phases were combined, acidified to pH 3 with concentrated HCl, and extracted with dichloromethane twice. The organic phases were combined, dried, filtered and concentrated to give the title compound (0.85 g, 71% yield) that was used without further purification: 1H NMR (CDCl3): δ 7.73 (d, 1H), 7.12 (d, 1H), 1.3 (s, 12H).
Reaction SMILES: O1CCO[CH:2]1[CH2:6][CH:7]([CH3:16])[C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=O.[C:17]([NH:20][CH2:21][CH2:22][NH2:23])(=[O:19])[CH3:18]>C(O)(=O)C>[CH3:16][C:7]1[CH:6]=[CH:2][N:23]([CH2:22][CH2:21][NH:20][C:17](=[O:19])[CH3:18])[C:8]=1[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: CC(CC1OCCO1)C(=O)c1ccccc1
Reactant: CC(=O)NCCN
Solvent: CC(=O)O
Product: CC(=O)NCCn1ccc(C)c1-c1ccccc1
Reaction time: 18 h
Yield: 58.9 %

Procedure:
3-(1,3-Dioxolan-2-yl)-2-methylpropiophenone (7.1 g) was added to a solution of 6.6 g of N-acetylethylenediamine in 100 ml of acetic acid under argon and while stirring. The reaction solution was boiled for 18 hours and the acetic acid was subsequently removed in a vacuum. The residue was taken up in 200 ml of methylene chloride and washed with a mixture of 100 ml of saturated sodium hydrogen carbonate solution and 160 ml of 2N sodium hydroxide solution. The aqueous phase was back-extracted twice with 100 ml of methylene chloride each time. The organic phases were combined, dried with MgSO4 and freed from solvent. The residue, 7.6 g of brown oil was chromatographed on 350 g of silica gel with ethyl acetate/hexane mixtures (1:3 to 2:1) as the eluent. 4.6 g (59%) of N-[2-[3-methyl-2-phenylpyrrol-1-yl]ethyl]acetamide were isolated as a brown, amorphous solid. MS: m/e=242 (M+ ).
Reaction SMILES: [OH:1][CH:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]CCCC)[C:3]([OH:5])=O.[Cl-].[CH2:21]([O:28][C:29](=[O:38])/[CH:30]=[CH:31]/[C@@H:32]([NH3+:37])[CH2:33][CH2:34][CH2:35][CH3:36])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C1C=CC2N(O)N=NC=2C=1>C(Cl)Cl.CCN(CC)CC>[OH:1][CH:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[C:3]([NH:37][C@@H:32]([CH2:33][CH2:34][CH2:35][CH3:36])/[CH:31]=[CH:30]/[C:29]([O:28][CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)=[O:38])=[O:5]
Reactant: CCCCCCCCCCCCCCC(O)C(=O)O
Reactant: CCCC[C@H]([NH3+])/C=C/C(=O)OCc1ccccc1
Agent: On1nnc2ccccc21
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCC(O)C(=O)N[C@H](/C=C/C(=O)OCc1ccccc1)CCCC
Temperature: 0 °C
Reaction time: 24 h

Procedure:
To a stirred solution of 2-hydroxyhexadecanoic acid (0.54 g, 2.0 mmol) and (E,4S)-1-(benzyloxy)-1-oxooct-2-en-4-aminium chloride (0.28 g, 1.0 mmol) in CH2Cl2 (5 mL), Et3N (0.3 mL) and subsequently WSCI (0.57 g, 3.0 mmol) and HOBt (0.32 g, 2.0 mmol) were added at 0° C. The reaction mixture was stirred for 1 h at 0° C. and at room temperature for 1 day. The organic layer was washed with brine, dried over Na2SO4 and evaporated under reduced pressure. The residue was purified by column chromatography (CHCl3/MeOH 98/2). Yield 0.33 g (75%); [α]D−10.3 (c 0.5 CHCl3);
Reaction SMILES: C(OC([N:8]([CH2:25][C:26]1([C:30]2[C:35]([F:36])=[CH:34][CH:33]=[CH:32][N:31]=2)[CH2:29][CH2:28][CH2:27]1)[C:9]1[N:14]=[N:13][C:12]([C:15]2[NH:19][N:18]=[C:17]([C:20]([O:22]CC)=O)[CH:16]=2)=[CH:11][CH:10]=1)=O)(C)(C)C.[NH3:37]>CO>[F:36][C:35]1[C:30]([C:26]2([CH2:25][NH:8][C:9]3[N:14]=[N:13][C:12]([C:15]4[NH:19][N:18]=[C:17]([C:20]([NH2:37])=[O:22])[CH:16]=4)=[CH:11][CH:10]=3)[CH2:29][CH2:28][CH2:27]2)=[N:31][CH:32]=[CH:33][CH:34]=1
Reactant: N
Reactant: CCOC(=O)c1cc(-c2ccc(N(CC3(c4ncccc4F)CCC3)C(=O)OC(C)(C)C)nn2)[nH]n1
Solvent: CO
Product: NC(=O)c1cc(-c2ccc(NCC3(c4ncccc4F)CCC3)nn2)[nH]n1
Temperature: 110 °C
Yield: 12 %

Procedure:
Ethyl 5-(6-(t-butoxycarbonyl((1-(3-fluoropyridin-2-yl)cyclobutyl)methyl)amino)pyridazin-3-yl)-1H-pyrazole-3-carboxylate (0.28 g, 0.56 mmol) and 7N ammonia in MeOH were combined in a microwave reactor and heated to 110° C. for 1 h. The reaction mixture was then concentrated, diluted with EtOAc, and washed with satd. aq. NaHCO3 and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated. The resultant oil was diluted in 10 mL of DCM and TFA (15 mL) was added. The reaction mixture was then concentrated and purified by reverse phase chromatography to give the title compound as a white solid (18 mg, 12%), (m/z [M+H]=368.1).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6](=[CH:11][C:12]1[C:13]([CH3:17])=[N:14][NH:15][CH:16]=1)[CH2:7][C:8]([OH:10])=O)=[O:5])[CH3:2].C([O-])(=O)C.[Na+].C([O-])(O)=O.[Na+]>C(OC(=O)C)(=O)C>[CH3:17][C:13]1[C:12]2[C:16](=[C:8]([OH:10])[CH:7]=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH:11]=2)[NH:15][N:14]=1
Reactant: CCOC(=O)C(=Cc1c[nH]nc1C)CC(=O)O
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: CCOC(=O)c1cc(O)c2[nH]nc(C)c2c1
Temperature: 25 °C
Yield: 54.1 %

Procedure:
A solution of 3-(ethoxycarbonyl)-4-(3-methyl-1H-pyrazol-4-yl)but-3-enoic acid (20 g, 84 mmol) in acetic anhydride (80 mL), sodium acetate (13.8 g, 168 mmol) was added at room temperature and the mixture was heated at reflux for 4 hours. The reaction mixture was cooled to room temperature, basified (pH˜9) using aqueous NaHCO3 solution and extracted with ethyl acetate (2×100 mL). The combined organic layers were washed with water (50 mL), saturated aqueous NaCl (50 mL), dried over anhydrous Na2SO4 and concentrated to obtain crude product; which was purified by column chromatography (100-200 mesh silica gel) using 6-8% ethyl acetate in pet-ether as eluents to afford ethyl 3-methyl-7-hydroxy-1H-indazole-5-carboxylate (10 g, 40%) as orange solid. 1H NMR (CDCl3) δ 8.25 (s, 1H), 7.9 (s, 1H), 4.4 (q, 2H), 2.75 (s, 3H), 2.6 (s, 3H), 2.4 (s, 3H), 1.4 (t, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:25]=[CH:24][CH:23]=[CH:22][C:5]=1[O:6][C@@H:7]1[CH2:12][CH2:11][CH2:10][N:9]([C:13]2[N:18]=[CH:17][C:16]([C:19]([OH:21])=O)=[CH:15][N:14]=2)[CH2:8]1)[CH3:2].Cl.[NH2:27][CH2:28][C:29]1[CH:30]=[C:31]([CH:36]=[CH:37][C:38]=1[CH3:39])[C:32]([O:34]C)=[O:33].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Li+].[OH-]>>[CH2:1]([O:3][C:4]1[CH:25]=[CH:24][CH:23]=[CH:22][C:5]=1[O:6][C@@H:7]1[CH2:12][CH2:11][CH2:10][N:9]([C:13]2[N:14]=[CH:15][C:16]([C:19]([NH:27][CH2:28][C:29]3[CH:30]=[C:31]([CH:36]=[CH:37][C:38]=3[CH3:39])[C:32]([OH:34])=[O:33])=[O:21])=[CH:17][N:18]=2)[CH2:8]1)[CH3:2]
Reactant: COC(=O)c1ccc(C)c(CN)c1
Reactant: CCOc1ccccc1O[C@@H]1CCCN(c2ncc(C(=O)O)cn2)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Product: CCOc1ccccc1O[C@@H]1CCCN(c2ncc(C(=O)NCc3cc(C(=O)O)ccc3C)cn2)C1

Procedure:
(R)-3-((2-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrimidine-5-carboxamido)methyl)-4-methylbenzoic acid was prepared from (R)-2-(3-(2-ethoxyphenoxy)piperidin-1-yl)pyrimidine-5-carboxylic acid and methyl 3-(aminomethyl)-4-methylbenzoate hydrochloride using Amidation Method 1 (HATU) and Ester Hydrolysis Method 1 (LiOH). 1H NMR (400 MHz, DMSO-d6) δ 8.82 (m, 1H), 8.78 (s, 2H), 7.85 (s, 1H), 7.72 (d, 1H), 7.15 (d, 1H), 7.05 (d, 1H), 6.90 (m, 3H), 4.43 (d, 2H), 4.30 (m, 1H), 4.22 (d, 1H), 3.90 (m, 4H), 3.72 (m, 1H), 2.32 (s, 3H), 2.05 (m, 1H), 1.83 (m, 2H), 1.52 (m, 1H), 1.21 (t, 3H). MS (ES+) 491.2 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7](O)=[O:8].S(=O)(=O)(O)O.[BH4-].[Na+]>C(O)C>[Br:1][C:2]1[CH:10]=[C:6]([CH2:7][OH:8])[CH:5]=[N:4][CH:3]=1
Reactant: O=C(O)c1cncc(Br)c1
Agent: O=S(=O)(O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: OCc1cncc(Br)c1

Procedure:
The required aldehyde, 5-bromopyridine-3-carboxaldehyde, can be prepared from 5-bromonicotinic acid (commercially available from Aldrich Chemical Company and Lancaster Synthesis, Inc.). The 5-bromonicotinic acid can be treated with ethyl chloroformate producing the mixed anhydride, which can be reduced with lithium aluminum hydride in tetrahydrofuran (THF) at −78° C., to afford 5-bromo-3-hydroxymethylpyridine, as reported by A. Ashimori et al., Chem. Pharm. Bull. 38(9): 2446-2458 (1990). Alternatively, the 5-bromonicotinic acid can be esterified in the presence of sulfuric acid and ethanol, and the intermediate ethyl ester can be reduced with an excess of sodium borohydride to yield 5-bromo-3-hydroxymethylpyridine, according to the techniques reported in C. F. Nutaitis et al., Org. Prep. and Proc. Int. 24:143-146 (1992). The resulting 5-bromo-3-hydroxymethylpyridine can then be converted to 5-bromo-3-pyridinecarboxaldehyde by Swern oxidation using oxalyl chloride and dimethylsulfoxide according to the methods of M. J. Stocks et al., Tetrahedron Lett. 36(36): 6555-6558 (1995) and A. J. Mancuso et al., J. Org Chem. 44(23): 4148-4150 (1979). The aldehyde, 4-bromopyridine-3-carboxaldehyde can be synthesized according to methodology described by Chin et al. PCT WO 94/29893 or by methodology described by Ojea et al., Synlett. 6: 622-624 (1995). 6-Bromopyridine-3-carboxaldehyde can be prepared according to procedures described in Windschief and Voegtle, Synthesis 1: 87-92 (1994) or Fey et al German Patent No. 93/4320432.
Reaction SMILES: [Cl-].[F:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:5][CH:4]=1.CC(C)([O-])C.[K+].[CH2:35]1[O:45][C:38]2([CH2:43][CH2:42][C:41](=O)[CH2:40][CH2:39]2)[O:37][CH2:36]1>C1COCC1>[F:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]=[C:41]2[CH2:42][CH2:43][C:38]3([O:45][CH2:35][CH2:36][O:37]3)[CH2:39][CH2:40]2)=[CH:7][CH:8]=1
Reactant: Fc1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: O=C1CCC2(CC1)OCCO2
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Product: Fc1ccc(C=C2CCC3(CC2)OCCO3)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 79.3 %

Procedure:
To a stirring solution of 4-fluorophenylmethyl triphenylphosphonium chloride (39 g, 96 mmol, Lancaster) in 500 mL of dry THF at −78° C. was added 1 M potassium t-butoxide in THF (106 mL, 106 mmol, Aldrich). The reaction was stirred for 30 min and then warmed to 0° C. The reaction was stirred for 30 min and then 1,4-cyclohexanedione mono-ethylene ketal (15.0 g, 96 mmol, Aldrich) was added. After 30 min, the reaction was warmed to room temperature and allowed to stir overnight. The reaction was heated to reflux for 4 h and then cooled to room temperature. The reaction was quenched with saturated ammonium chloride (500 mL) and ethyl acetate (500 mL). The organic layer was separated, washed with brine, dried over sodium sulfate, and conc in vacuo to a white solid. The solid was purified by flash chromatography (SiO2, 19:1 hexanes:ethyl acetate) to yield 18.9 g of a colorless oil. MS (ESI) 251 (M+H).
Reaction SMILES: [OH:1][CH:2]1[CH2:5][N:4]([CH:6]2[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]2)[CH2:3]1.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>ClCCl>[CH3:19][S:20]([O:1][CH:2]1[CH2:3][N:4]([CH:6]2[CH2:7][CH2:8][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:10][CH2:11]2)[CH2:5]1)(=[O:22])=[O:21]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC(N2CC(O)C2)CC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(N2CC(OS(C)(=O)=O)C2)CC1

Procedure:
Into a 100-mL 3-necked round-bottom flask, was placed a solution of tert-butyl 4-(3-hydroxyazetidin-1-yl)piperidine-1-carboxylate (300 mg, 1.15 mmol, 1.00 equiv, 98%) in dichloromethane (20 mL), TEA (240 mg, 2.33 mmol, 2.00 equiv, 98%). To the resulting mixture was added MsCl (0.6 mg, 0.01 mmol, 4.50 equiv, 98%) dropwise with stirring. The resulting solution was stirred for 2 h at room temperature in an ice/salt bath. The reaction was then quenched by the addition of water. The resulting solution was extracted with dichloromethane (2×50 mL) and the organic layers combined. The resulting mixture was washed with sodium chloride/H2O (1×100 mL). The resulting mixture was dried over anhydrous sodium sulfate and concentrated under vacuum to yield tert-butyl 4-(3-(methylsulfonyloxy)azetidin-1-yl)piperidine-1-carboxylate as a white solid. MS: 335 (MH+).
Reaction SMILES: [CH3:1][C:2]([CH2:6][CH2:7][CH:8]=[C:9]([CH3:21])[CH2:10][CH2:11][CH:12]=[C:13]([CH3:20])[CH2:14][CH2:15][CH:16]=[C:17]([CH3:19])[CH3:18])=[CH:3][CH2:4][NH2:5].[CH3:22][O:23]C(OC)N(C)C.C(=O)([O-])[O-].[Na+].[Na+]>O1CCCC1>[CH3:1][C:2]([CH2:6][CH2:7][CH:8]=[C:9]([CH3:21])[CH2:10][CH2:11][CH:12]=[C:13]([CH3:20])[CH2:14][CH2:15][CH:16]=[C:17]([CH3:19])[CH3:18])=[CH:3][CH2:4][NH:5][CH:22]=[O:23]
Reactant: CC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCN
Reactant: COC(OC)N(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCNC=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 64.6 %

Procedure:
To a stirred solution of 580 mg (2 mmol) of 3,7,11, 15-tetramethyl-2,6,10,14-hexadecatetraenylamine (hereinafter abbreviated as tetraprenylamine) II-1 in 20 ml of anhydrous tetrahydrofuran is added 953 mg (8 mmol) of N,N-dimethylformamide dimethylacetal. The mixture is heated under reflux for 3 hours, mixed with 15 ml of 10% aqueous sodium carbonate, and stirred at room temperature for 4 hours. The reaction mixture is concentrated, and the resulting residue is dissolved in 50 ml of CH2Cl2 and washed twice with 50 ml of water. The resulting mixture is dried over anhydrous sodium sulfate and evaporated under reduced pressure. The residue is purified by silica-gel column chromatography and eluted with AcOEt to give 410 mg of the titled compound I-1 as colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][C:14]([OH:16])=[O:15].[S:17]1[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18]1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([S:22]([C:19]1[CH:20]=[CH:21][S:17][CH:18]=1)(=[O:24])=[O:23])[CH:7]=[C:6]2[CH2:12][CH2:13][C:14]([OH:16])=[O:15]
Reactant: COc1ccc2[nH]cc(CCC(=O)O)c2c1
Reactant: O=S(=O)(Cl)c1ccsc1
Product: COc1ccc2c(c1)c(CCC(=O)O)cn2S(=O)(=O)c1ccsc1

Procedure:
3-[5-Methoxy-1-(thiophene-3-sulfonyl)-1H-indol-3-yl]-propionic acid 99 was prepared from 3-(5-methoxy-1H-indol-3-yl)-propionic acid 96 and 3-thienyl-sulfonyl chloride using the same protocol as described in step 8, Example 4. (M−1=364.4)
Reaction SMILES: C([N:8]([CH2:13][CH:14]([C:16]1[CH:24]=[CH:23][C:22]([O:25]CC2C=CC=CC=2)=[C:21]2[C:17]=1[CH:18]=[C:19]([CH2:33][OH:34])[NH:20]2)[OH:15])[C:9]([CH3:12])([CH3:11])[CH3:10])C1C=CC=CC=1>CO.[C].[Pd]>[C:9]([NH:8][CH2:13][CH:14]([C:16]1[CH:24]=[CH:23][C:22]([OH:25])=[C:21]2[C:17]=1[CH:18]=[C:19]([CH2:33][OH:34])[NH:20]2)[OH:15])([CH3:12])([CH3:10])[CH3:11]
Reactant: CC(C)(C)N(Cc1ccccc1)CC(O)c1ccc(OCc2ccccc2)c2[nH]c(CO)cc12
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)NCC(O)c1ccc(O)c2[nH]c(CO)cc12
Yield: 68.3 %

Procedure:
229 mg of 2-(N-benzyl-N-tert-butylamino)-1-(7-benzyloxy-2-hydroxymethylindol-4-yl)ethanol is hydrogenated in 10 ml of methanol for 10 minutes in the presence of 40 mg of 10% palladium-carbon, filtered, the filtrate concentrated and recrystallized from ethanol/diisopropyl ether, yielding 95 mg of 2-(N-tert-butylamino)-1-(7-hydroxy-2-hydroxymethylindol-4-yl) ethanol, mp 150° C. (decomposition).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH3:24])[C:10]([C:16]1[CH:17]=[CH:18][C:19](=[O:23])[N:20]([CH3:22])[CH:21]=1)([OH:15])[C:11]([F:14])([F:13])[F:12].[CH3:25][O:26][C:27](=[O:39])[C:28]1[C:33]([C:34]([F:37])([F:36])[F:35])=[CH:32][C:31](Cl)=[N:30][CH:29]=1.C(N(CC)CC)C.N12CCN(CC1)CC2>CN(C)C(=O)C.CCOC(C)=O.O>[CH3:25][O:26][C:27](=[O:39])[C:28]1[C:33]([C:34]([F:35])([F:36])[F:37])=[CH:32][C:31]([O:8][C:6]2[CH:5]=[CH:4][C:3]([CH:9]([CH3:24])[C:10]([OH:15])([C:16]3[CH:17]=[CH:18][C:19](=[O:23])[N:20]([CH3:22])[CH:21]=3)[C:11]([F:13])([F:14])[F:12])=[C:2]([Cl:1])[CH:7]=2)=[N:30][CH:29]=1
Reactant: COC(=O)c1cnc(Cl)cc1C(F)(F)F
Reactant: CC(c1ccc(O)cc1Cl)C(O)(c1ccc(=O)n(C)c1)C(F)(F)F
Agent: C1CN2CCN1CC2
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CC(=O)N(C)C
Product: COC(=O)c1cnc(Oc2ccc(C(C)C(O)(c3ccc(=O)n(C)c3)C(F)(F)F)c(Cl)c2)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 4 h
Yield: 97.3 %

Procedure:
To a solution of 5-[2-(2-chloro-4-hydroxy-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-1-methyl-1H-pyridin-2-one (Example 151, step 7, 180 mg) in N,N-dimethylacetamide (2 ml) were added methyl-6-chloro-4-(trifluoromethyl)-nicotinate (119 mg), triethylamine (65 mg) and 1,4-diazabicyclo[2.2.2]octane (8 mg). The mixture was stirred at room temperature for 4 h and then diluted with EtOAc. Water was added. The mixture was extracted with EtOAc. The organic phase was washed with water, dried (MgSO4), filtered and concentrated. The product was purified by chromatography (SiO2, cyclohexane/EtOAc 7:3=>EtOAc) to give the title compound (273 mg) as a colorless foam. MS (m/e)=565.3 [M+H+].
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])/[CH:5]=[C:6](/[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][CH2:16][CH3:17])\[CH3:7])[CH3:2].[Br:19]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[CH2:1]([O:3][C:4](=[O:18])/[CH:5]=[C:6](/[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][CH2:16][CH3:17])\[CH2:7][Br:19])[CH3:2]
Reactant: CCCc1ccccc1O/C(C)=C/C(=O)OCC
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCCc1ccccc1O/C(=C/C(=O)OCC)CBr
Yield: 49.7 %

Procedure:
To a stirred mixture of (E)-3-(2-propyl-phenoxy)-but-2-enoic acid ethyl ester (3.10 g, 0.012 mol) in carbon tetrachloride (20 mL) under a nitrogen atmosphere was added N-bromosuccinimide (3.30 g, 0.019 mol) and benzoyl peroxide (300 mg, 0.001 mol). Nitrogen gas was bubbled through the mixture for 5 min, and the resulting mixture was heated to reflux for 4 h. The reaction mixture was then placed in the refrigerator overnight. The solids formed were removed by filtration and the filtrate concentrated in vacuo. The crude product obtained was purified using flash column chromatography (silica gel (100-200 mesh), ethyl acetate/hexanes) to afford (E)-4-bromo-3-(2-propyl-phenoxy)-but-2-enoic acid ethyl ester (1.95 g, 48%) as a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:8]([NH:10][CH:11]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-])=O)[CH:13]=2)[CH3:9])[CH:5]=[CH:6][CH:7]=1.[BH4-].[Na+]>O.O.O.O.O.O.[Ni](Cl)Cl.CO>[F:27][C:24]1[CH:25]=[CH:26][C:21]([CH:11]([NH:10][C@@H:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)[CH3:9])[C:12]2[CH:13]=[C:14]([NH2:18])[CH:15]=[CH:16][CH:17]=2)=[CH:22][CH:23]=1
Reactant: C[C@@H](NC(c1ccc(F)cc1)c1cccc([N+](=O)[O-])c1)c1cccc(F)c1
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: C[C@@H](NC(c1ccc(F)cc1)c1cccc(N)c1)c1cccc(F)c1

Procedure:
Following a similar procedure to that described in Example (1b), 1.63 g of isomer B of N-[(R)-1-(3-fluorophenyl)ethyl]-N-[(4-fluorophenyl)-(3-nitrophenyl)methyl]amine [prepared as described in step (a) above], 2.11 g of nickel chloride hexahydrate, 6.74 g of sodium borohydride and 20 ml of methanol were reacted, to obtain 1.45 g of isomer B of the title compound as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]3([CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]3)[CH2:9][N:8]([C:23]3[C:24]4[C@H:31]([CH3:32])[CH2:30][C@@H:29]([O:33]C(=O)C5C=CC([N+]([O-])=O)=CC=5)[C:25]=4[N:26]=[CH:27][N:28]=3)[C:5]2=[CH:6][CH:7]=1.ClC1C=C2C3(CCN(C(OC(C)(C)C)=O)CC3)CN(C3C4[C@H](C)C[C@H](OC(=O)C5C=CC([N+]([O-])=O)=CC=5)C=4N=CN=3)C2=CC=1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]3([CH2:11][CH2:12][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:14][CH2:15]3)[CH2:9][N:8]([C:23]3[C:24]4[C@H:31]([CH3:32])[CH2:30][C@H:29]([OH:33])[C:25]=4[N:26]=[CH:27][N:28]=3)[C:5]2=[CH:6][CH:7]=1
Reactant: C[C@@H]1C[C@@H](OC(=O)c2ccc([N+](=O)[O-])cc2)c2ncnc(N3CC4(CCN(C(=O)OC(C)(C)C)CC4)c4cc(Cl)ccc43)c21
Agent: C[C@@H]1C[C@H](OC(=O)c2ccc([N+](=O)[O-])cc2)c2ncnc(N3CC4(CCN(C(=O)OC(C)(C)C)CC4)c4cc(Cl)ccc43)c21
Product: C[C@@H]1C[C@H](O)c2ncnc(N3CC4(CCN(C(=O)OC(C)(C)C)CC4)c4cc(Cl)ccc43)c21

Procedure:
tert-butyl 5-chloro-1-((5R,7S)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)spiro[indoline-3,4′-piperidine]-1′-carboxylate was prepared by the procedures described in Example 3, Step 12, substituting (tert-butyl 5-chloro-1-((5R,7R)-5-methyl-7-(4-nitrobenzoyloxy)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)spiro[indoline-3,4′-piperidine]-1′-carboxylate with tert-butyl 5-chloro-1-((5R,7S)-5-methyl-7-(4-nitrobenzoyloxy)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)spiro[indoline-3,4′-piperidine]-1′-carboxylate. LCMS (APCI+) m/z 471, 473 [M+H]+; Rt=4.05 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:16][C:17](=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19]>C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:16][C:17](=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:4][CH:3]=1
Reactant: CC(C)(C)C(=O)CCl
Reactant: Sc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)C(=O)CSc1ccc(Cl)cc1

Procedure:
A 14.45 g quantity of p-chlorothiophenol and 13.8 g of anhydrous potassium carbonate were added to 200 ml of acetonitrile, and 13.45 of 1-chloro-3,3-dimethyl-2-butanone was added in small portions to the mixture while stirring the mixture. After stirring the mixture at 70° to 75° C. for 6 hours, the solid separating out was filtered off. The filtrate was concentrated to obtain a residue, which was subjected to extraction with benzene. To the extract was added 200 ml of 10% sodium hydroxide solution, followed by stirring at room temperature for 1 hour. The benzene layer was separated off, washed with water, then dried over anhydrous magnesium sulfate and distilled in a vacuum to remove the solvent, giving 20.2 g of the above-identified desired compound in the form of a pale yellow oil.