Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]([NH:13][CH3:14])[CH2:9][C:10]([OH:12])=[O:11])[CH:5]=[CH:6][CH:7]=1.S(=O)(=O)(O)O.C(=O)([O-])O.[Na+].[CH2:25](O)[CH3:26]>>[OH:1][C:2]1[CH:3]=[C:4]([CH:8]([NH:13][CH3:14])[CH2:9][C:10]([O:12][CH2:25][CH3:26])=[O:11])[CH:5]=[CH:6][CH:7]=1
Reactant: CCO
Reactant: CNC(CC(=O)O)c1cccc(O)c1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CCOC(=O)CC(NC)c1cccc(O)c1

Procedure:
3-(3-Hydroxyphenyl)-3-methylaminopropionic acid (24.1 g) obtained from Example 7a was dissolved in ethanol (200 ml), and concentrated sulfuric acid (10 ml) was added dropwise to the solution. The resulting mixture was heated under ref lux for 8 hours. The reaction mixture was neutralized with saturated aqueous sodium hydrogencarbonate solution and the solvent was removed under reduced pressure. The residual aqueous solution was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to afford the desired compound which was used in next step reaction without further purification.
Reaction SMILES: [CH3:1][C:2]([N:4](C)C)=O.[F:7][C:8]1[C:9](I)=[C:10](C)[CH:11]=[CH:12][CH:13]=1.C1C=C(Cl)C=C(C(OO)=O)C=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl.[C-]#N.[Zn+2].[C-]#N>[F:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH3:9])[C:1]=1[C:2]#[N:4]
Reactant: CC(=O)N(C)C
Reactant: Cc1cccc(F)c1I
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: ClCCl
Product: Cc1cccc(F)c1C#N
Temperature: 80 °C

Procedure:
A 10 L round bottom flask equipped with adapter, thermocouple and stir bar was charged with DMA (6 L) and degassed under vacuum and purged with N2 three times. To the mixture was added palladium tetrakis triphenylphosphine (87.5 g, 72.0 mmol) and the mixture was degassed under vacuum and purged with N2 three times. The reaction was heated to 80° C. for 30 min. 3-Fluoro-2-iodotoluene (575 g, 2.4 mol) and zinc cyanide (171.7 g, 1.46 mol) were added and the mixture was degassed under vacuum and purged with N2 three times. The reaction mixture was heated to 80° C. for 16 h and then allowed to cool to RT. The solution was added to a 2.0 L aqueous solution of 1N NH4OH, which was extracted three times with 1.5 L EtOAc, washed with 2 L brine, dried over Na2SO4, filtered and concentrated. The crude product was treated with mCPBA (˜0.2 equivalents) in cooled DCM to oxidize triphenylphosphine and facilitate purification, and was then purified by chromatography (PE/EA=10:1) to get the title compound.
Reaction SMILES: C(O)(=O)C1C=CC=CC=1.[C:10]([OH:21])(=O)[C:11]1[CH:19]=[CH:18][C:17]2[O:16][CH2:15][O:14][C:13]=2[CH:12]=1.C([O:26][C:27](=[O:54])[CH2:28][N:29]([C:39](=[O:53])[C@@H:40]([NH:44]C(=O)C1C=CC=CC=1)[CH:41]([CH3:43])[CH3:42])[CH:30]1[CH2:38][C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH2:31]1)(C)(C)C>>[O:16]1[C:17]2[CH:18]=[CH:19][C:11]([C:10]([NH:44][C@@H:40]([CH:41]([CH3:43])[CH3:42])[C:39]([N:29]([CH2:28][C:27]([OH:54])=[O:26])[CH:30]3[CH2:38][C:37]4[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=4)[CH2:31]3)=[O:53])=[O:21])=[CH:12][C:13]=2[O:14][CH2:15]1
Reactant: O=C(O)c1ccc2c(c1)OCO2
Reactant: CC(C)[C@H](NC(=O)c1ccccc1)C(=O)N(CC(=O)OC(C)(C)C)C1Cc2ccccc2C1
Agent: O=C(O)c1ccccc1
Product: CC(C)[C@H](NC(=O)c1ccc2c(c1)OCO2)C(=O)N(CC(=O)O)C1Cc2ccccc2C1

Procedure:
Compound 728 was prepared by a method similar to the method used to prepare compound 724, except benzoic acid is replaced with piperonylic acid in the preparation of compound 723. ##STR107##
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[CH:8][N:7]=[CH:6][C:5]=2[N:10]2[CH2:14][CH2:13][NH:12][C:11]2=[O:15])[CH2:3][CH2:2]1.[Cl:16][C:17]1[CH:22]=[C:21](Cl)[N:20]=[CH:19][N:18]=1.CN[C@@H]1CCCC[C@H]1NC.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu](I)I.O1CCOCC1>[Cl:16][C:17]1[N:18]=[CH:19][N:20]=[C:21]([N:12]2[CH2:13][CH2:14][N:10]([C:5]3[CH:6]=[N:7][CH:8]=[CH:9][C:4]=3[CH:1]3[CH2:3][CH2:2]3)[C:11]2=[O:15])[CH:22]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: O=C1NCCN1c1cnccc1C1CC1
Agent: I[Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: O=C1N(c2cc(Cl)ncn2)CCN1c1cnccc1C1CC1
Yield: 8.2 %

Procedure:
Using analogous reagents and reaction conditions as described in Example 1 above, 1-(4-cyclopropylpyridin-3-yl)imidazolidin-2-one (I-1d: 120 mg, 0.591 mmol) was reacted with 4,6-dichloropyrimidine (88.07 mg, 0.591 mmol), 1,4-dioxane (5 mL), copper iodide (11.21 mg, 0.059 mmol), trans-N,N′-dimethylcyclohexane-1,2-diamine (8.39 mg, 0.059 mmol) and potassium phosphate (375.96 mg, 1.77 mmol) to afford the crude product. Purification by column chromatography on silica gel (0.5% methanol in CHCl3) afforded 15.3 mg of the product (9% yield).
Reaction SMILES: Cl.[CH:2]([N:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH:15]3[CH2:20][CH2:19][N:18]([CH:21]([CH3:23])[CH3:22])[CH2:17][CH2:16]3)=[CH:11][CH:12]=2)[CH:7]=[C:6]1[C:24]([N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)=[O:25])([CH3:4])[CH3:3].[F:32][C:33]([F:39])([F:38])[S:34](Cl)(=[O:36])=[O:35]>>[CH:2]([N:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH:15]3[CH2:20][CH2:19][N:18]([CH:21]([CH3:23])[CH3:22])[CH2:17][CH2:16]3)=[CH:11][CH:12]=2)[CH:7]=[C:6]1[C:24]([N:26]1[CH2:27][CH2:28][N:29]([S:34]([C:33]([F:39])([F:38])[F:32])(=[O:36])=[O:35])[CH2:30][CH2:31]1)=[O:25])([CH3:3])[CH3:4]
Reactant: O=S(=O)(Cl)C(F)(F)F
Reactant: CC(C)N1CCC(Oc2ccc3c(c2)cc(C(=O)N2CCNCC2)n3C(C)C)CC1
Agent: Cl
Product: CC(C)N1CCC(Oc2ccc3c(c2)cc(C(=O)N2CCN(S(=O)(=O)C(F)(F)F)CC2)n3C(C)C)CC1

Procedure:
The title compound was prepared in analogy to example 51, from [1-isopropyl-5-(1-isopropyl-piperidin-4-yloxy)-1H-indol-2-yl]-piperazin-1-yl-methanone hydrochloride and trifluoromethanesulfonyl chloride. Light-yellow solid. MS (m/z): 545.3 (M+H)+.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH:5]([NH:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C:6]([OH:8])=[O:7].C1CCC(NC2CCCCC2)CC1.S(=O)(=O)(O)O.[F:35][C:36]1[C:41](O)=[C:40]([F:43])[C:39]([F:44])=[C:38]([F:45])[C:37]=1[F:46].C1(N=C=NC2CCCCC2)CCCCC1>C(OCC)(=O)C.O1CCOCC1.CCOCC>[F:35][C:36]1[C:41]([O:7][C:6](=[O:8])[C@H:5]([CH2:4][CH2:3][CH2:2][CH3:1])[NH:9][C:10]([O:12][C:13]([CH3:15])([CH3:14])[CH3:16])=[O:11])=[C:40]([F:43])[C:39]([F:44])=[C:38]([F:45])[C:37]=1[F:46]
Reactant: CCCCC(NC(=O)OC(C)(C)C)C(=O)O
Reactant: Oc1c(F)c(F)c(F)c(F)c1F
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: C1CCC(NC2CCCCC2)CC1
Agent: O=S(=O)(O)O
Solvent: CCOCC
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CCCC[C@H](NC(=O)OC(C)(C)C)C(=O)Oc1c(F)c(F)c(F)c(F)c1F
Temperature: 0 °C
Reaction time: 1 h

Procedure:
10.0g (24.3 mmoles) of BOC--Nle--OH.DCHA are added to a mixture of 75 ml of ether and 25 ml of 2 n aqueous sulfuric acid, and the mixture is shaken until the dissolution is complete. The phases are separated, and the etheral solution is washed again with 25 ml of 2 n aqueous sulfuric acid and water. The etheral solution is evaporated in vacuo. The resulting 5.44 g of oily residue and 4.42 g (24 mmoles) of pentafluorophenol are dissolved in 30 ml of ethyl acetate, the solution is cooled to 0° C., and 4.63 g (22.5 mmoles) of dicyclohexyl carbodiimide are added. The suspension is allowed to stand at a cold place for 1 hour, thereafter it is filtered, and the filtrate is evaporated in vacuo. The residue is dissolved in 50 ml of n-hexane and the solution is washed with 5×20 ml of 5% aqueous sodium bicarbonate solution and 2×20 ml of water. The organic solution is dried and evaporated in vacuo. The oily residue solidifies upon cooling. 8.12 g (91%) of BOC--Nle--OPFP are obtained; m.p.: 55°-57° C., [α]D : -26.8° (c=1.0, in dioxane), Rf2 =0.80Rf4 =0.85.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][NH:4][N:3]=1.[F:11][C:12]([F:24])([F:23])[O:13][C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1>>[CH3:1][C:2]1[C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][N:4]([C:17]2[CH:16]=[CH:15][C:14]([O:13][C:12]([F:11])([F:23])[F:24])=[CH:19][CH:18]=2)[N:3]=1
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Reactant: COC(=O)c1c[nH]nc1C
Product: COC(=O)c1cn(-c2ccc(OC(F)(F)F)cc2)nc1C
Yield: 26.8 %

Procedure:
Using methyl 3-methyl-1H-pyrazole-4-carboxylate (6.8 g) synthesized in Example 1(3) and 4-trifluoromethoxyphenylboronic acid (20.0 g) and in the same manner as in Example 17(1), the title object compound (3.9 g, 27%) was obtained as a white solid.
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([C:15]1[CH:20]=[CH:19][C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:17][CH:16]=1)=[CH:10][CH:9]=2)=[O:5])C.Br[C:26]1[CH:31]=[CH:30][C:29]([O:32][CH:33]2[CH2:37][CH2:36][CH2:35][CH2:34]2)=[C:28]([N+:38]([O-:40])=[O:39])[CH:27]=1>>[C:21]([C:18]1[CH:17]=[CH:16][C:15]([C:11]2[CH:12]=[C:13]3[C:8](=[CH:9][CH:10]=2)[N:7]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH:33]4[CH2:37][CH2:36][CH2:35][CH2:34]4)=[C:28]([N+:38]([O-:40])=[O:39])[CH:27]=2)[C:6]([C:4]([OH:5])=[O:3])=[CH:14]3)=[CH:20][CH:19]=1)([CH3:24])([CH3:22])[CH3:23]
Reactant: CCOC(=O)c1cc2cc(-c3ccc(C(C)(C)C)cc3)ccc2[nH]1
Reactant: O=[N+]([O-])c1cc(Br)ccc1OC1CCCC1
Product: CC(C)(C)c1ccc(-c2ccc3c(c2)cc(C(=O)O)n3-c2ccc(OC3CCCC3)c([N+](=O)[O-])c2)cc1

Procedure:
The title compound was prepared in accordance with Example 1(b) from 5-(4-tert-butylphenyl)indole-2-carboxylic acid ethyl ester (see Example 1(a)) and 4-bromo-1-cyclopentoxy-2-nitrobenzene (see step (a) above), followed by ester hydrolysis in accordance with the procedure described in Example 35, Method 3, step (b).
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:4][CH2:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].CCN(CC)CC.[F:27][C:28]1[CH:29]=[C:30]([CH:34]=[CH:35][C:36]=1[N+:37]([O-:39])=[O:38])[C:31](Cl)=[O:32]>C(Cl)Cl>[F:27][C:28]1[CH:29]=[C:30]([CH:34]=[CH:35][C:36]=1[N+:37]([O-:39])=[O:38])[C:31]([NH:2][C@H:3]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:4][CH2:5][C:6]([O:8][C:9]([CH3:12])([CH3:10])[CH3:11])=[O:7])=[O:32]
Reactant: CC(C)(C)OC(=O)CC[C@H](N)C(=O)OC(C)(C)C
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])c(F)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)CC[C@H](NC(=O)c1ccc([N+](=O)[O-])c(F)c1)C(=O)OC(C)(C)C

Procedure:
To a solution of di-tert butyl L-glutamate hydrochloride (20.0 g, 67.6 mol) in Et3N (19 ml, 136.0 mmol) was added dropwise a solution of 3-fluoro,4-nitro benzoyl chloride (13.8 g, 68.0 mmol) in CH2Cl2 (300 ml). Extractive workup gave an oil (13); yield (28.0 g, 97%); 1 H NMR (Me2SO-d6) δ1.40 (s, 9H, t-Bu), 1.42 (s, 9H, t-Bu), 1.99 (m, 2H, CH2CH2CO2 -t-Bu), 2.36 (t, 2H, J=7.45 Hz, CH2CH2CO2 -t-Bu), 4.35 (m, 1H, CH), 7.92 (dd, 1H, JH-6,H-5 =7.56 Hz, H-6), 8.01 (dd, 1H, JH-2,F =11.97 Hz, H-2), 8.29 (dd, 1H, JH-5,H-6 =7.83, JH-5,F =16.10 Hz, H-5), 8.97 (d, 1H, J=7.42 Hz, NH); 9F NMR (Me2SO-d6) δ-117.98 (dd, JF,H-2 =7.32, JF,H-5 =17.8 Hz); mass spectrum (CI) m/z 427 ([M+H+ ], 100); Anal: C20H27N2O7 F-0.25CH2Cl2 requires C-54.33, H-6.19, N-6.26, F-4.24, Cl-3.96, found C-54.22, H-6.38, N-6.05, F-4.34, Cl-4.15. (The presence of CH2 Cl2 noted in the elemental analysis was confirmed by NMR).
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][C:7]1[CH:36]=[CH:35][C:34]([F:37])=[CH:33][C:8]=1[O:9][CH2:10][CH2:11][O:12][CH:13]1[CH:18]([C:19]2[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=2)[CH2:17][CH2:16][N:15]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:14]1)(=[O:3])[CH3:2].Br[CH2:39][CH2:40][CH2:41][O:42][C:43]1[CH:48]=[CH:47][CH:46]=[C:45]([F:49])[CH:44]=1>>[C:1]([NH:4][CH2:5][CH2:6][C:7]1[CH:36]=[CH:35][C:34]([F:37])=[CH:33][C:8]=1[O:9][CH2:10][CH2:11][O:12][CH:13]1[CH:18]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:39][CH2:40][CH2:41][O:42][C:43]3[CH:48]=[CH:47][CH:46]=[C:45]([F:49])[CH:44]=3)=[CH:21][CH:20]=2)[CH2:17][CH2:16][N:15]([C:26]([O:28][C:29]([CH3:30])([CH3:31])[CH3:32])=[O:27])[CH2:14]1)(=[O:3])[CH3:2]
Reactant: Fc1cccc(OCCCBr)c1
Reactant: CC(=O)NCCc1ccc(F)cc1OCCOC1CN(C(=O)OC(C)(C)C)CCC1c1ccc(O)cc1
Product: CC(=O)NCCc1ccc(F)cc1OCCOC1CN(C(=O)OC(C)(C)C)CCC1c1ccc(OCCCOc2cccc(F)c2)cc1

Procedure:
Analogously to Method I, 0.26 g of tert-butyl 3-{2-[2-(2-acetylaminoethyl)-5-fluorophenoxy]ethoxy}-4-(4-hydroxyphenyl)piperidine-1-carboxylate and 0.153 g of 1-(3-bromopropoxy)-3-fluorobenzene are reacted. The title compound is obtained as a yellowish oil. Rf=0.41 (EtOAc); Rt=5.66.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH2:8][NH2:9])=[CH:6][CH:5]=[C:4]([CH3:10])[N:3]=1.Br[C:12]1[C:13](=[O:30])[N:14]([CH3:29])[N:15]=[C:16]([O:18][CH2:19][C@H:20]2[CH2:22][C@@H:21]2[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=2)[CH:17]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C(O[Na])(C)(C)C>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:1][C:2]1[C:7]([CH2:8][NH:9][C:12]2[C:13](=[O:30])[N:14]([CH3:29])[N:15]=[C:16]([O:18][CH2:19][C@H:20]3[CH2:22][C@@H:21]3[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)[CH:17]=2)=[CH:6][CH:5]=[C:4]([CH3:10])[N:3]=1
Reactant: Cc1ccc(CN)c(C)n1
Reactant: Cn1nc(OC[C@H]2C[C@@H]2c2ccccn2)cc(Br)c1=O
Agent: [Pd]
Agent: CC(C)(C)O[Na]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: Cc1ccc(CNc2cc(OC[C@H]3C[C@@H]3c3ccccn3)nn(C)c2=O)c(C)n1
Temperature: 80 °C

Procedure:
A mixture of (2,6-dimethylpyridin-3-yl)methanamine (30 mg, 0.2 mmol), 4-bromo-2-methyl-6-(((1S,2S)-2-(pyridin-2-yl)cyclopropyl)methoxy)pyridazin-3(2H)-one (68 mg, 0.2 mmol), Pd2(dba)3 (18 mg, 0.02 mmol), BINAP (18 mg, 0.03 mmol) and t-BuONa (38 mg, 0.4 mmol) in toluene (4 mL) under N2 was heated at 80° C. for 4 h. The mixture was filtered and concentrated to give crude product which was purified by Prep-HPLC to give the title compound as oil. 1H NMR (400 MHz, CD3OD) δ 8.34 (d, 1H), 7.67-7.62 (m, 1H), 7.47 (d, 1H), 7.21 (d, 1H), 7.16-7.13 (m, 1H), 7.05 (d, 1H), 5.67 (s, 1H), 4.35 (s, 2H), 4.20-4.16 (m, 1H), 4.03-3.98 (m, 1H), 3.63 (s, 3H), 2.50 (s, 3H), 2.46 (s, 3H), 2.11-2.07 (m, 1H), 1.84-1.79 (m, 1H), 1.26-1.21 (m, 1H), 1.09-1.04 (m, 1H), LCMS m/z (M+H) 392.2 found, 392.2 required.
Reaction SMILES: [CH:1]1([C:4](=[O:27])[CH2:5][O:6][C:7]2[C:22]([F:23])=[CH:21][C:20]([N+:24]([O-:26])=[O:25])=[CH:19][C:8]=2[CH2:9][N:10]([CH3:18])[C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH2:3][CH2:2]1.[BH4-].[Na+]>CO>[CH:1]1([CH:4]([OH:27])[CH2:5][O:6][C:7]2[C:22]([F:23])=[CH:21][C:20]([N+:24]([O-:26])=[O:25])=[CH:19][C:8]=2[CH2:9][N:10]([CH3:18])[C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH2:3][CH2:2]1
Reactant: CN(Cc1cc([N+](=O)[O-])cc(F)c1OCC(=O)C1CC1)C(=O)OC(C)(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CN(Cc1cc([N+](=O)[O-])cc(F)c1OCC(O)C1CC1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 56.2 %

Procedure:
21B (1.47 g, 3.84 mmol) was dissolved in MeOH (15 mL) at 0° C. NaBH4 (0.175 g, 4.61 mmol) was added. The reaction mixture was stirred rt for 1 h. quenched with water, extracted with EtOAc (2×). The extract was dried over sodium sulfate and concentrated. The crude was purified by prep HPLC. To give 21C (830 mg, 2.159 mmol, 56.2% yield). MS (ESI) m/z: 385.4 (M+H)+. 1H NMR (400 MHz, chloroform-d) δ ppm 7.95 (dd, J=11.86, 2.20 Hz, 1H) 7.88 (s, 1H) 4.70 (d, J=11.86 Hz, 1H) 4.51 (s, 3H) 4.35 (d, J=13.62 Hz, 1H) 4.20 (t, J=7.91 Hz, 1H) 3.21 (t, J=7.47 Hz, 1H) 2.75 (s, 3H) 1.45 (s, 9H) 0.90 (dd, J=8.13, 4.17 Hz, 1H) 0.49-0.61 (m, 2H) 0.41 (td, J=9.23, 4.83 Hz, 1H) 0.22-0.29 (m, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][O:16][CH2:17][C:18]([O:21][C:22]([F:39])([F:38])[C:23]([F:37])([F:36])[O:24][C:25]([F:35])([F:34])[C:26]([F:33])([F:32])[O:27][C:28]([F:31])([F:30])[F:29])([F:20])[F:19])=[CH:10][CH:9]=2)=[N:6][CH:7]=1.[CH2:40]([O:44][CH2:45][CH2:46][CH2:47][CH2:48]Cl)[CH2:41][CH2:42][CH3:43]>>[CH3:43][CH2:42][CH2:41][CH2:40][O:44][CH2:45][CH2:46][CH2:47][CH2:48][O:1][C:2]1[CH:7]=[N:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][O:16][CH2:17][C:18]([O:21][C:22]([F:39])([F:38])[C:23]([F:36])([F:37])[O:24][C:25]([F:34])([F:35])[C:26]([F:32])([F:33])[O:27][C:28]([F:29])([F:30])[F:31])([F:20])[F:19])=[CH:10][CH:9]=2)=[N:4][CH:3]=1
Reactant: CCCCOCCCCCl
Reactant: Oc1cnc(-c2ccc(CCOCC(F)(F)OC(F)(F)C(F)(F)OC(F)(F)C(F)(F)OC(F)(F)F)cc2)nc1
Product: CCCCOCCCCOc1cnc(-c2ccc(CCOCC(F)(F)OC(F)(F)C(F)(F)OC(F)(F)C(F)(F)OC(F)(F)F)cc2)nc1

Procedure:
The title compound was prepared essentially as in Example 12 by combining 5-hydroxy-2-[4-(2-(2-(2-(2-(trifluoromethoxy)tetrafluoroethoxy)tetrafluoroethoxy)-2,2-difluoroethoxy)ethyl)phenyl]pyrimidine (2.0 g, 3.5 mmol) with 4-butoxybutyl chloride (7.0 g, 4.2 mmol). The reaction mixture was quenched with water, and the resulting crude product was further purified by recrystallization from ethanol, followed by Kugelrohr distillation (210-15° C. at 0.15 torr), to provide a yield of 1.39 g.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[C:5]([O:9][C:10]([N:12]1[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH2:20]Br)[CH2:14][CH2:13]1)=[O:11])([CH3:8])([CH3:7])[CH3:6].C(OCC)(=O)C.[Cl-].[Na+]>CN(C=O)C>[C:5]([O:9][C:10]([N:12]1[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH2:20][N:1]=[N+:2]=[N-:3])[CH2:14][CH2:13]1)=[O:11])([CH3:8])([CH3:7])[CH3:6]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N1CCN(CCCBr)CC1
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(CCCN=[N+]=[N-])CC1
Yield: 92.3 %

Procedure:
Sodium azide (2.24 g, 34.2 mmol) is added to a stirred solution of 4-(3-bromo-propyl)-piperazine-1-carboxylic acid tert-butyl ester (4.80 g, 15.6 mmol) in anhydrous DMF (DMF) (40 mL). The resultant mixture is heated in an oil bath at 55° C. under nitrogen for 3 days. At ambient temperature, ethyl acetate (160 mL) and half-saturated aqueous sodium chloride (NaCl) (200 mL) are added to the mixture. The organic layer is separated, washed with half-saturated aqueous NaCl (200 mL), dried over magnesium sulfate, filtered, and concentrated to provide the title compound as a dark oil (3.88 g, 92% yield).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:9]2[NH:10][C:11]3[C:16]([C:17]=2[C:18](=O)[C:19]([N:21]2[CH2:26][CH2:25][N:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH2:23][CH2:22]2)=O)=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:5]=[C:6]([CH3:8])[CH:7]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[CH3:1][C:2]1[CH:3]=[C:4]([C:9]2[NH:10][C:11]3[C:16]([C:17]=2[CH2:18][CH2:19][N:21]2[CH2:22][CH2:23][N:24]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH2:25][CH2:26]2)=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: Cc1cc(C)cc(-c2[nH]c3ccccc3c2C(=O)C(=O)N2CCN(c3ccccc3)CC2)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: Cc1cc(C)cc(-c2[nH]c3ccccc3c2CCN2CCN(c3ccccc3)CC2)c1
Yield: 71.2 %

Procedure:
To a solution of 1-[2-(3,5-dimethylphenyl)-1H-indol-3-yl]-2-(4-phenylpiperazin-1-yl)ethane-1,2-dione (57 mg in 2 mL dry tetrahydrofuran) was added 30 mg of lithium aluminum hydride and the mixture heated to reflux on an oil bath. After 1 hour the mixture was cooled and quenched by the sequential addition of 1 mL water and 4 mL ammonium hydroxide and 5 mL ethyl acetate. The mixture was filtered to remove the solids. The organic portion was washed with brine, dried over magnesium sulfate and the concentrate purified by flash chromatography on silica gel (ethyl acetate:hexane, 1:5) to give the title compound (38 mg). m/e=410 (M+1)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:22][O:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH2:27]Br>>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:27][C:26]2[CH:29]=[CH:30][CH:31]=[C:24]([O:23][CH3:22])[CH:25]=2)=[CH:17][CH:16]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1cccc(CBr)c1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1ccc(O)cc1
Product: COc1cccc(COc2ccc(OC[C@H]3CCCN3C(=O)OC(C)(C)C)cc2)c1
Yield: 53.2 %

Procedure:
Followed the same procedure as that of step 2 in Example 91 with the use of (R)-2-(4-hydroxy-phenoxymethyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (150 mg, 0.5 mmol) and 3-methoxy-benzyl bromide (120 mg, 0.6 mmol) to afford the title product (110 mg, 53% yield); LCMS; 100% APCI+, Calcd: 413.56; Found m/z: 414.29 (M+1); 1H NMR (400 MHz, CDCl3); δ 1.47 (s, 9H), 1.80-2.09 (m, 4H), 3.28-3.46 (m, 2H), 3.69-3.91 (m, 1H), 3.82 (s, 3H), 4.02-4.18 (m 2H), 4.99 (s, 2H), 6.82-6.90 (m, 5H), 6.96-7.05 (m, 2H), 7.26-7.30 (m, 1H).
Reaction SMILES: [CH3:1][S-:2].[Na+].[CH:4]1([O:9][C:10]2[CH:11]=[C:12]([CH:21]=[CH:22][C:23]=2[N+]([O-])=O)[C:13]([O:15][CH:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)=[O:14])[CH2:8][CH2:7][CH2:6][CH2:5]1.[Cl-].[Na+]>CN1CCN(C)C1=O.O>[CH:4]1([O:9][C:10]2[CH:11]=[C:12]([CH:21]=[CH:22][C:23]=2[S:2][CH3:1])[C:13]([O:15][CH:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)=[O:14])[CH2:8][CH2:7][CH2:6][CH2:5]1
Reactant: O=C(OC1CCCC1)c1ccc([N+](=O)[O-])c(OC2CCCC2)c1
Reactant: C[S-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CN1CCN(C)C1=O
Product: CSc1ccc(C(=O)OC2CCCC2)cc1OC1CCCC1
Reaction time: 4 h
Yield: 81.1 %

Procedure:
Sodium thiomethoxide (0.177 g, 2.5 mmol) is added portionwise to a stirred solution of cyclopentyl 3-cyclopentyloxy-4-nitrobenzoate (0.64 g, 2 mmol) in N,N'-dimethylimidazolidinone (10 mL) at ambient temperature under an atmosphere of nitrogen and stirring continued for 4 hours. The mixture is then diluted with water (100 mL) containing sodium chloride (15 g) and extracted with ethyl acetate (2×50 mL). The combined extract is washed with saturated brine (1×100 mL) and then dried over magnesium sulfate and evaporated under reduced pressure to give cyclopentyl 3-cyclopentyloxy-4-(methylthio)benzoate (0.52 g, 81%) as a brown viscous oil which is used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:10][C:9](=[O:11])[CH2:8][CH:7]([C:12]([O:14][CH3:15])=[O:13])[CH2:6]1)=[O:4].[CH2:16](O)[CH2:17][OH:18].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[CH3:15][O:14][C:12]([CH:7]1[CH2:6][CH:5]([C:3]([O:2][CH3:1])=[O:4])[CH2:10][C:9]2([O:18][CH2:17][CH2:16][O:11]2)[CH2:8]1)=[O:13]
Reactant: COC(=O)C1CC(=O)CC(C(=O)OC)C1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)C1CC(C(=O)OC)CC2(C1)OCCO2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 5-oxocyclohexane-1,3-dicarboxylic acid dimethyl ester (22.8 g, 106.4 mmol), ethylene glycol (13.3 g, 215 mmol) and p-toluenesulfonic acid monohydrate (0.22 g, 1.3 mmol) in toluene (230 mL), in a flask fitted with Dean-Stark trap was heated under reflux for 5 h. The reaction was cooled to room temperature, water was added and the mixture was extracted with ethyl acetate. Organic layer was separated, washed with NaHCO3 solution and brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure to give an oil, which was triturated with hexane and left in the fridge overnight. The precipitated solid was filtered and dried under vacuum to provide 17.1 (63%) g of the title compound, 1,4-Dioxa-spiro[4.5]decane-7,9-dicarboxylic acid dimethyl ester as a white solid. 1HNMR (400 MHz, CDCl3), δ: 3.95 (m, 4H), 3.7 (s, 6H), 2.72-2.62 (m, 3H), 2.32-2.22 (m, 1H), 2.02-1.96 (m, 2H), 1.6-1.4 (m, 3H).
Reaction SMILES: [CH3:1][N:2]([CH3:15])[C:3]([C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11]C)=[O:10])=[CH:7][CH:6]=1)=[O:4].[Li+].[OH-]>CO>[CH3:1][N:2]([CH3:15])[C:3]([C:5]1[CH:14]=[CH:13][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1)=[O:4]
Reactant: COC(=O)c1ccc(C(=O)N(C)C)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: CN(C)C(=O)c1ccc(C(=O)O)cc1
Reaction time: 1.5 h
Yield: 65.2 %

Procedure:
To a soln. of methyl 4-(dimethylcarbamoyl)benzoate (100 mg, 0.483 mmol, crude from above preparation) in MeOH (4 ml) was added LiOH (1 ml, 3.00 mmol). The mixture was stirred at r.t for 1.5 hrs. Evaporated to remove the solvent. The residue was dissolved in water (3 ml), neutralized w/6M HCl to PH=3, extracted w/EtOAc (3×). The combined organic layer was dried (Na2SO4) and evaporated to afford 4-(dimethylcarbamoyl)benzoic acid (64 mg, 0.315 mmol, 65.2% yield) as solid, which was used for the next reaction directly.