Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:12]=[C:11]([O:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[N:10]([CH2:24][CH2:25][OH:26])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.N1C(C)=CC=CC=1C.O([Si:43]([C:46]([CH3:49])([CH3:48])[CH3:47])([CH3:45])[CH3:44])S(C(F)(F)F)(=O)=O>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:12]=[C:11]([O:13][C:14]3[CH:15]=[CH:16][C:17]([C:20]([F:22])([F:23])[F:21])=[CH:18][CH:19]=3)[N:10]([CH2:24][CH2:25][O:26][Si:43]([C:46]([CH3:49])([CH3:48])[CH3:47])([CH3:45])[CH3:44])[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: OCCn1nc(-c2cccc(Br)c2)cc1Oc1ccc(C(F)(F)F)cc1
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCCn1nc(-c2cccc(Br)c2)cc1Oc1ccc(C(F)(F)F)cc1
Reaction time: 0.5 h

Procedure:
A stirred solution of 2-{3-(3-bromophenyl)-5-[4-(trifluoromethyl)phenoxy]-1H-pyrazol-1-yl}ethanol (7.6 g, 18 mmol) and 2,6-lutidine (6.2 mL, 53 mmol) in 40 mL of CH2Cl2 under an argon atmosphere was cooled in an ice bath. TBDMS triflate (7.1 g, 27 mmol) was added dropwise and the mixture was stirred for 30 min. The mixture was diluted with CH2Cl2 and washed with saturated aqueous NaHCO3, water, brine, then dried over Na2SO4, filtered, and the solvents were removed under reduced pressure. The residue was chromatographed on a 120 g silica gel column using 0-70% CHCl3:hexanes over 40 min at 85 mL/min. The product-containing fractions were combined and the solvent was removed under reduced pressure to give 2-{3-(3-bromophenyl)-5-[4-(trifluoromethyl)phenoxy]-1H-pyrazol-1-yl}-1-(tert-butyldimethylsilyloxy)ethane as an oil. Calcd (M+1)+: 542.5. Found: 542.8
Reaction SMILES: C1[C@H]([N:6]2[C:10]3[N:11]=[C:12]([Cl:16])[N:13]=[C:14](N)[C:9]=3[N:8]=[CH:7]2)O[C@H](CO)[C@H]1O.C(Cl)(=O)C.N([O-])=O.C([N+](CC)(CC)CC)C1C=CC=CC=1>>[Cl:16][C:12]1[N:11]=[C:10]2[C:9]([NH:8][CH:7]=[N:6]2)=[CH:14][N:13]=1
Reactant: Nc1nc(Cl)nc2c1ncn2[C@H]1C[C@H](O)[C@@H](CO)O1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: O=N[O-]
Solvent: CC(=O)Cl
Product: Clc1ncc2[nH]cnc2n1

Procedure:
In preferred embodiments of the present invention, CldAdo is synthesized by employing acetyl chloride and benzyltriethylammonium nitrite (BTEA-NO2)-mediated diazotization/chloro-dediazoniation of 6-O-(2,4,6-triisopropylbenzenesulfonyl) (TIPBS) or 6-chloro derivatives that are readily obtained from dGuo. Non-aqueous diazotization/chloro-dediazoniation (acetyl chloride/benzyltriethylammonium nitrite) of 2, 2′b, or 5 gave the 2-chloropurine derivatives 3, 3′b, or 6, respectively. This new procedure for non-aqueous diazotization/chloro-dediazoniation27 (AcCl/BTEA-NO2/CH2Cl2/−5 to 0° C.) worked well for replacement of the 2-amino group of 2, 2′b, and 5 with chlorine to give 3a (89%), 3b (90%), 3′b (87%), 6a (95%), and 6b (91%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[C:11]([Cl:12])=[CH:10][C:9]([O:13][CH2:14][CH:15]=[C:16]([Cl:18])[Cl:17])=[CH:8][C:7]=1[Cl:19].[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][C:28](O)=[O:29])=[CH:23][CH:22]=1.C(N(CC)CC)C.CCN=C=NCCCN(C)C.Cl>C(OCC)(=O)C.ClCCl>[Cl:19][C:7]1[CH:8]=[C:9]([O:13][CH2:14][CH:15]=[C:16]([Cl:18])[Cl:17])[CH:10]=[C:11]([Cl:12])[C:6]=1[O:5][CH2:4][CH2:3][CH2:2][NH:1][C:28](=[O:29])[CH2:27][C:24]1[CH:25]=[CH:26][C:21]([Cl:20])=[CH:22][CH:23]=1
Reactant: O=C(O)Cc1ccc(Cl)cc1
Reactant: NCCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Cc1ccc(Cl)cc1)NCCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Temperature: 25 °C
Yield: 70.6 %

Procedure:
To a mixture of 0.35 g of 4-(3-aminopropyloxy)-3,5-dichloro-1-(3,3-dichloro-2-propenyloxy)benzene, 0.17 g of 4-chlorophenylacetic acid, 0.18 ml of triethylamine and 10 ml of dichloromethane was added 0.23 g of WSC hydrochloride, while stirring at room temperature. After stirring at room temperature for 6 hours, the reaction mixture was concentrated to give a residue. The residue was dissolved in 50 ml of ethyl acetate, and the ethyl acetate layer was successively washed with 10% hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated saline solution, dried over anhydrous magnesium sulfate, and then concentrated to give a residue. The residue was subjected to silica gel chromatography, which afforded 0.35 g of 3,5-dichloro-1-(3,3-dichloro-2-propenyloxy)-4-(3-(4-chlorophenylacetamido)propyloxy)benzene (70% yield), m.p., 108.4° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][O:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[CH:19][CH:18]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[N-:25]=[N+:26]=[N-:27].[Na+].[Cl-].[NH4+].CN(C)C=O>C(O)(=O)C.O>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][O:16][C:17]2[CH:18]=[CH:19][C:20]([C:23]3[NH:27][N:26]=[N:25][N:24]=3)=[CH:21][CH:22]=2)(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)NCCCCOc2ccc(C#N)cc2)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Solvent: O
Product: Cc1ccc(S(=O)(=O)NCCCCOc2ccc(-c3nnn[nH]3)cc2)cc1
Reaction time: 16 h

Procedure:
A mixture of 3.4 g of 4-methyl-N-[4-(4-cyanophenoxy)butyl]benzenesulfonamlde (Example 53), 1.3 g of sodium azide, 1.5 g of ammonium chloride, and 25 ml of dimethylformamide is stirred at 120°-130° C. (oil bath) for 16 hours. The reaction mixture is added to 200 ml of water and the resultant solution then acidified to pH 4-5 with acetic acid. The precipitate that forms is collected, washed with water, dried and recrystallized from boiling ethanol. Cooling gives the pure compound, m.p. 180°-182° C.; yield, 2.4 g.
Reaction SMILES: [OH-].[Na+].C1COCC1.[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:31][NH:32][C:33]2[CH:38]=[CH:37][C:36]([C:39]3[CH:44]=[CH:43][C:42]([F:45])=[C:41]([F:46])[CH:40]=3)=[CH:35][CH:34]=2)=[C:13]([C:15]2[CH:16]=[CH:17][C:18]([C:21]([NH:23][CH2:24][CH2:25][C:26]([O:28]CC)=[O:27])=[O:22])=[N:19][CH:20]=2)[CH:14]=1.Cl>CO>[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:31][NH:32][C:33]2[CH:38]=[CH:37][C:36]([C:39]3[CH:44]=[CH:43][C:42]([F:45])=[C:41]([F:46])[CH:40]=3)=[CH:35][CH:34]=2)=[C:13]([C:15]2[CH:16]=[CH:17][C:18]([C:21]([NH:23][CH2:24][CH2:25][C:26]([OH:28])=[O:27])=[O:22])=[N:19][CH:20]=2)[CH:14]=1
Reactant: CCOC(=O)CCNC(=O)c1ccc(-c2cc(Cl)ccc2CNc2ccc(-c3ccc(F)c(F)c3)cc2)cn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)CCNC(=O)c1ccc(-c2cc(Cl)ccc2CNc2ccc(-c3ccc(F)c(F)c3)cc2)cn1
Temperature: 55 °C

Procedure:
A 1M aqueous solution of NaOH (2.0 mL, 2.0 mmol) was added to a THF (1 mL) and MeOH (5 mL) solution of ethyl 3-(5-(5-chloro-2-(((3′,4′-difluoro-[1,1′-biphenyl]-4-yl)amino)methyl)phenyl)picolinamido)propanoate (50 mg, 0.09 mmol) and the resulting mixture was heated to 55° C. After 10 min the resulting mixture was neutralized with 2M aqueous HCl, concentrated and extracted with EtOAc. The combined extracts were concentrated and purified via column chromatography to yield the title compound.
Reaction SMILES: C([O:3][C:4](=[O:33])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]2[S:19][C:18]([C:20]3[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=3)=[N:17][C:16]=2[CH2:30][CH3:31])=[C:9]([CH3:32])[CH:8]=1)C.[Li+].[OH-].Cl>C1COCC1>[CH2:30]([C:16]1[N:17]=[C:18]([C:20]2[CH:21]=[CH:22][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:24][CH:25]=2)[S:19][C:15]=1[CH2:14][O:13][C:10]1[CH:11]=[CH:12][C:7]([O:6][CH2:5][C:4]([OH:33])=[O:3])=[CH:8][C:9]=1[CH3:32])[CH3:31]
Reactant: CCOC(=O)COc1ccc(OCc2sc(-c3ccc(C(F)(F)F)cc3)nc2CC)c(C)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCc1nc(-c2ccc(C(F)(F)F)cc2)sc1COc1ccc(OCC(=O)O)cc1C
Reaction time: 1 h
Yield: 106.2 %

Procedure:
To a solution of {4-[4-Ethyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-3-methyl-phenoxy}-acetic acid ethyl ester (80 mg) in THF (1 mL) is added LiOH (1.0 M, 1.0 mL), after 1 hr, acidified by 5 N HCl and extracted with ethyl, dried over sodium sulfate. Concentration gave the title acid compound (80 mg). MS (ES): 452.03 (M++1), the structure is also confirmed by proton NMR.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]1.Cl[C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18]>C1COCC1>[C:12]([O:11][C:9]([N:5]1[CH2:6][CH2:7][CH2:8][CH:3]([CH2:2][NH:1][C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])[CH2:4]1)=[O:10])([CH3:15])([CH3:14])[CH3:13]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCCC(CN)C1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCCC(CNC(=O)OCc2ccccc2)C1
Temperature: 0 °C

Procedure:
To a stirred solution of 3-(aminomethyl)-1-N-Boc-piperidine (1.64 g, 7.65 mmol) and TEA (1.6 mL, 11 mmol) in THF (5 mL) at 0° C., benzyl chloroformate (1.15 mL, 8.04 mmol) was added dropwise. The reaction was maintained at 0° C. for 1 h, then warmed to RT overnight. The solvent was evaporated in vacuo. The residue was taken up in a saturated solution of NH4Cl (aq) (15 mL) and extracted with EtOAc (10 mL). The organic layer was separated, dried over MgSO4, filtered and the solvent was evaporated in vacuo. The residue was purified by flash chromatography on silica gel (1:4, EtOAc:hexane) to yield the title compound as a colorless oil. MS m/z: 349.3 (M+H). Calc'd. for C19H28N2O4-348.44.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[NH:13][C:12]2[CH:14]=[CH:15][C:16](C(O)(C(F)(F)F)C(F)(F)F)=[CH:17][C:11]=2[S:10][CH2:9]1.NC1C=CC=CC=1S.BrC1C=CC=CC=1C(=O)CCl.[BH3-]C#N.[Na+]>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[NH:13][C:12]2[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=2[S:10][CH2:9]1
Reactant: OC(c1ccc2c(c1)SCC(c1ccccc1Cl)N2)(C(F)(F)F)C(F)(F)F
Agent: Nc1ccccc1S
Agent: O=C(CCl)c1ccccc1Br
Agent: [BH3-]C#N
Solvent: CN(C)C=O
Product: Clc1ccccc1C1CSc2ccccc2N1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
2-[3-(2-Chloro-phenyl)-3,4-dihydro-2H-1,4-benzothiazin-7-yl]-1,1,1,3,3,3-hexafluoro-propan-2-ol: To 2-amino-benzenethiol (1.07 mL, 10 mmol) in DMF (10 mL) under an argon atmosphere was added o-bromo-2-chloro-acetophenone (1.5 mL, 9.8 mmol) at 0° C. and the reaction was warmed to rt. After 10 min, NaBH3CN (1.5 g, 71 mmol) was added portion-wise over 5 min and the reaction was stirred for 16 h. The reaction was quenched with 1N HCl, then neutralized to pH 8 with conc. NaHCO3. The product was extracted with ether, washed with water, dried over MgSO4, and concentrated. The resulting residue was purified by flash chromatography to give 3-(2-chloro-phenyl)-3,4-dihydro-2H-1,4-benzothiazine (1.7 g). A mixture of this intermediate (420 mg, 1.6 mmol) and hexafluoroacetone: 1.5 H2O (620 mg, 3.2 mmol) in DCM (1 mL) was heated in a sealed tube in a microwave reactor at 160° C. for 80 min. The resulting mixture was purified by flash chromatography to give 200A (260 mg). LC/MS m/z 427.87 (M+H)+. 1H NMR (400 MHz, CDCl3) δ ppm 3.03-3.15 (m, 2H) 5.26 (m, 1H) 6.58 (d, J=8, 1H) 7.24-7.28 (m, 2H) 7.37-7.43 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[N:12]([S:13]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=3)(=[O:15])=[O:14])[CH:11]([CH2:23][CH2:24][C:25]3[NH:26][CH:27]=[CH:28][N:29]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH3:30]I.[H-].[Na+]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[N:12]([S:13]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=3)(=[O:15])=[O:14])[CH:11]([CH2:23][CH2:24][C:25]3[N:29]([CH3:30])[CH:28]=[CH:27][N:26]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)N2C(CCc3ncc[nH]3)CCC2c2ccc(F)cc2)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Product: Cc1ccc(S(=O)(=O)N2C(CCc3nccn3C)CCC2c2ccc(F)cc2)cc1

Procedure:
The title compound, light yellow oil, MS: m/e=428.5 (M+H+), was prepared by methylation of (2RS,5SR)-2-{2-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-ethyl}-1H-imidazole in accordance with the general method of example 8 (methyl iodide, sodium hydride).
Reaction SMILES: [C:1]([O:6][CH2:7][CH:8]1[O:10][CH2:9]1)(=[O:5])[CH2:2][CH2:3][CH3:4].O>CC(O)=O.C1COCC1>[C:1]([O:6][CH2:7][C@H:8]1[O:10][CH2:9]1)(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)OCC1CO1
Solvent: CC(=O)O
Solvent: O
Solvent: C1CCOC1
Product: CCCC(=O)OC[C@@H]1CO1
Yield: 44 %

Procedure:
Using the (R,R)-(salen)Co(II) precatalyst of 1 (91 mg, 0.15 mmol, 0.005equiv), (+/−)-glycidyl butyrate (4.32 g, 30.0 mmol), AcOH (32 mL, 0.6 mmol, 0.02 equiv), 0.3 mL THF, and H2O (297 ml,, 16.5 mmol, 0.55 equiv) and a procedure analogous to the one outlined for 5b, (S)-glycidyl butyrate 5d (1.90 g, 13.2 mmol, 44%) was obtained as a clear oil by vacuum distillation of the reaction mixture (30° C., 0.5 torr). The product was determined to be >99% ee by conversion to and analysis of the 2-napthylsulfide (obtained by ring opening with 2-napthalenethiol in methanol using 1 equiv TEA at 0° C.; Chiralcel OD, 97:3 hexanes:EtOH, 1 mL/min, 260 nm).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[C:24]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[N:18]=[C:17]3[O:25][C@H:26]4[CH2:49][N:29]([C:30](=[O:48])[C@H:31]([C:44]([CH3:47])([CH3:46])[CH3:45])[NH:32][C:33](=[O:43])[O:34][C@@H:35]5[CH2:42][C@H:36]5[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][C:16]=23)[C@H:28]([C:50]([O:52][CH3:53])=[O:51])[CH2:27]4)[CH2:10][CH2:9]1)=O)(C)(C)C.[F:54][C:55]([F:60])([F:59])[C:56]([OH:58])=[O:57]>ClCCl>[F:54][C:55]([F:60])([F:59])[C:56]([OH:58])=[O:57].[C:44]([C@H:31]1[C:30](=[O:48])[N:29]2[CH2:49][C@@H:26]([CH2:27][C@H:28]2[C:50]([O:52][CH3:53])=[O:51])[O:25][C:17]2=[N:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:24]=3[C:15]([O:14][CH:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)=[C:16]2[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37][C@@H:36]2[CH2:42][C@H:35]2[O:34][C:33](=[O:43])[NH:32]1)([CH3:47])([CH3:45])[CH3:46]
Reactant: COC(=O)[C@@H]1C[C@@H]2CN1C(=O)[C@H](C(C)(C)C)NC(=O)O[C@@H]1C[C@H]1CCCCCc1c(nc3ccccc3c1OC1CCN(C(=O)OC(C)(C)C)CC1)O2
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)[C@@H]1C[C@@H]2CN1C(=O)[C@H](C(C)(C)C)NC(=O)O[C@@H]1C[C@H]1CCCCCc1c(nc3ccccc3c1OC1CCNCC1)O2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of the product from step 1 in dichloromethane (2 mL) was added trifluoroacetic acid (2 mL). The resulting solution was stirred for 1 hour at room temperature until disappearance of the starting material. The solvent was removed in vacuo. Purification of the residue by flash chromatography (ISCO reverse phase, 5 to 95% acetonitrile in water (0.5% TFA buffer)) gave the desired product (170 mg). LRMS (ES+) m/z 637.5 (M+H)+.
Reaction SMILES: [OH:1][CH:2]([CH:6]([CH3:8])[CH3:7])[C:3]([OH:5])=[O:4].N1C=CN=C1.[CH3:14][C:15]([Si:18](Cl)([CH3:20])[CH3:19])([CH3:17])[CH3:16].Cl.[OH-].[K+]>CN(C=O)C.CN(C1C=CN=CC=1)C.C1COCC1.O>[Si:18]([O:1][CH:2]([CH:6]([CH3:8])[CH3:7])[C:3]([OH:5])=[O:4])([C:15]([CH3:17])([CH3:16])[CH3:14])([CH3:20])[CH3:19]
Reactant: CC(C)C(O)C(=O)O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: O
Product: CC(C)C(O[Si](C)(C)C(C)(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 45.2 %

Procedure:
To a solution of 2-hydroxy-3-methylbutanoic acid (5.0 g, 42.3 mmol) in DMF (21.2 mL) at 0° C. were added imidazole (6.34 g, 93.0 mmol) and DMAP (1.55 g, 12.7 mmol). The mixture was stirred for 5 min and TBDMS-Cl (14.0 g, 93.0 mmol) was added. The mixture was allowed to warm to ambient temperature. After 18 h, HCl (1.0 M in water) was added and the mixture was extracted with ethyl ether. The organic layer was washed with sat. NaHCO3, brine, dried over MgSO4, filtered and concentrated. The crude product was dissolved in THF (25 mL) and a solution of KOH (7.12 g, 127 mmol) in THF (130 mL) and water (40 mL) was added at 0° C. The mixture was stirred for 1 h. The solution was acidified and the mixture was extracted with ethyl acetate (5×). The combined organic extracts was dried over MgSO4, filtered and concentrated. Purification by silica gel chromatography (100% hexanes→60% hexanes/ethyl acetate) gave the title compound (4.44 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]([CH2:12][CH2:13][OH:14])[CH2:10][NH2:11])[CH:5]=[CH:6][C:7]=1[Cl:8].[OH-].[Na+].[C:17]([C:19]1[C:20]([O:32][CH3:33])=[C:21]([C:29](Cl)=[O:30])[C:22]2[C:27]([CH:28]=1)=[CH:26][CH:25]=[CH:24][CH:23]=2)#[N:18]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]([CH2:12][CH2:13][OH:14])[CH2:10][NH:11][C:29]([C:21]2[C:22]3[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:28]=[C:19]([C:17]#[N:18])[C:20]=2[O:32][CH3:33])=[O:30])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COc1c(C#N)cc2ccccc2c1C(=O)Cl
Reactant: NC[C@@H](CCO)c1ccc(Cl)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: COc1c(C#N)cc2ccccc2c1C(=O)NC[C@@H](CCO)c1ccc(Cl)c(Cl)c1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A solution of N-[2-(S)-(3,4-dichlorophenyl)-4-hydroxybutyl]amine in DCM was combined with 1N NaOH solution. The mixture was cooled to 0° C. and a solution of 3-cyano-2-methoxy-1-naphthoyl chloride in DCM was added dropwise over 30 min. After stirring overnight at room temperature, the organic phase was concentrated and purified by column chromatography to afford N-[2-(S)-(3,4-dichlorophenyl)4-hydroxybutyl]-3-cyano-2-methoxy-1-naphthamide. 1H NMR (300 MHz, CDCl3) d 8.19 (s, 1H), 7.83-7.80 (d, 1H)), 7.66-7.50 (m, 3H), 7.43-7.38 (m, 2H), 7.17-7.14 (dd, 1H), 6.10 (t, 1H), 4.01 (s, 3H), 3.92-3.68 (m, 3H), 3.60-3.52 (m, 1H), 3.23-3.17 (m, 1H), 2.13-2.02 (m, 1H), 1.93-1.82 (m, 1H); MS APCl, m/z=443 (M+). N-[2-(S)-(3,4-Dichlorophenyl)-3-carboxypropyl]-3-cyano-2-methoxy-1-naphthamide To a solution of Jones Reagent (prepare from 2.734 g of CrO3, 2.3 mL of concentrated H2SO4 and 10 mL of water) (13 mL) in acetone (100 mL) was added a solution of N-[2-(S)-(3,4-Di-chlorophenyl)-4-hydroxybutyl]-3-cyano-2-methoxy-1-napthamide (7.53 g, 17 mmol) in acetone (100 mL) dropwise at 0° C. The mixture was stirred at 0° C. for 2 h. Isopropyl alcohol was added until a blue color was persisted. The mixture was stirred 15 min at room temperature and EtOAC/water was added. Combined organic layer was washed with saturated NaCl, dried over MgSO4, filtered and concentrated, following chromatography purification to give product as a yellow solid (6.99 g, 90%yield). 1H NMR (CDCl3) δ 8.19 (s, 1H), 7.84-7.81 (d, 1H), 7.65-7.41 (m, 5H), 7.19-7.15 (dd, 1H), 6.15 (t, 1H), 4.00 (t, 3H), 3.93-2H), 3.54-3.45 (m, 1H), 2.94-2.70 (m, 2H). MS (APCI) m/z 479.2 (M+Na).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:14][CH2:13][CH2:12][C@H:11]2[CH2:15][N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)=[O:9])=[C:4]([F:21])[CH:3]=1.[F:22][C:23]([F:34])([F:33])[C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][CH:29]=1>>[F:21][C:4]1[CH:3]=[C:2]([C:28]2[CH:27]=[CH:26][CH:25]=[C:24]([C:23]([F:34])([F:33])[F:22])[CH:29]=2)[CH:7]=[CH:6][C:5]=1[C:8]([N:10]1[CH2:14][CH2:13][CH2:12][C@H:11]1[CH2:15][N:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1)=[O:9]
Reactant: O=C(c1ccc(Br)cc1F)N1CCC[C@H]1CN1CCCC1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Product: O=C(c1ccc(-c2cccc(C(F)(F)F)c2)cc1F)N1CCC[C@H]1CN1CCCC1

Procedure:
The title compound is prepared in a manner substantially analogous to Procedure SS starting from (4-bromo-2-fluoro-phenyl)-(2-(S)-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone and 3-Trifluoromethyl benzene boronic acid. MS (M+H) 421.2
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]([CH:12]=[O:13])[O:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C1COCC1>[C:1]1([C:7]2[CH:8]=[C:9]([CH:12]([OH:13])[CH2:12][CH2:9][CH2:8][CH2:7][CH2:1][CH:2]=[CH2:3])[O:10][CH:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=Cc1cc(-c2ccccc2)co1
Solvent: C1CCOC1
Product: C=CCCCCCC(O)c1cc(-c2ccccc2)co1
Reaction time: 0.5 h

Procedure:
The resulting Grignard solution was added to a solution of 4-phenyl-2-furaldehyde (1 eq.) in THF at 0° C. under Ar and the mixture was stirred for 30 min. The reaction was quenched by slow addition of sat. aq. NH4Cl solution and the desired product was extracted with EtOAc. The organic layer was washed with brine, dried (Na2SO4) and concentrated under reduced pressure. The crude was purified by column chromatography eluting with 5% EtOAc/Petroleum ether to afford the desired alcohol. 1H NMR (300 MHz, CD3Cl3) δ: 7.65 (2H, d, J=7.3 Hz), 7.42 (2H, t, J=7.2 Hz), 7.25-7.15 (1H, m), 6.60 (1H, d, J=5.3 Hz), 6.30 (1H, d, J=5.3 Hz), 5.87-5.75 (1H, m), 5.05-4.89 (2H, m), 4.75-4.65 (1H, m), 2.15-2.05 (2H, m), 1.87-1.75 (2H, m), 1.45-1.35 (6H, m). MS (ES) C18H22O2 requires: 270 found: 271 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH3:13])[N:11]=[CH:10][C:9]=2[CH2:14][O:15][C:16]2[CH:25]=[CH:24][C:19]([C:20](OC)=[O:21])=[CH:18][CH:17]=2)=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]([CH3:13])[N:11]=[CH:10][C:9]=2[CH2:14][O:15][C:16]2[CH:17]=[CH:18][C:19]([CH2:20][OH:21])=[CH:24][CH:25]=2)=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc(OCc2cnn(C)c2-c2ccc(F)cc2)cc1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: Cn1ncc(COc2ccc(CO)cc2)c1-c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 80.6 %

Procedure:
To a solution of methyl 4-{[5-(4-fluorophenyl)-1-methyl-1H-pyrazol-4-yl]methoxy}benzoate (920 mg, 2.70 mmol) in tetrahydrofuran (10 mL) was added lithium aluminum hydride (200 mg, 5.27 mmol) at 0° C., and the mixture was stirred at 0° C. for 1 hr. Sodium sulfate decahydrate (1.0 g) was added to the reaction mixture, and the mixture was allowed to warm to room temperature and stirred for 30 min. The insoluble material was filtered off, and the filtrate was concentrated to give the title compound (680 mg, yield 80%) as a yellow oil.
Reaction SMILES: C(=O)(O)[O-].[Na+].Br[CH2:7][CH2:8][CH2:9][CH2:10]Br.[NH2:12][C:13]1[CH:38]=[CH:37][C:16]([CH2:17][N:18]2[C:26]3[C:21](=[CH:22][C:23]([Cl:27])=[CH:24][CH:25]=3)[C:20]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[Cl:35])([CH3:28])[C:19]2=[O:36])=[C:15]([O:39][CH3:40])[CH:14]=1.Cl>CN(C)P(N(C)C)(N(C)C)=O.C(OCC)C>[Cl:27][C:23]1[CH:22]=[C:21]2[C:26](=[CH:25][CH:24]=1)[N:18]([CH2:17][C:16]1[CH:37]=[CH:38][C:13]([N:12]3[CH2:10][CH2:9][CH2:8][CH2:7]3)=[CH:14][C:15]=1[O:39][CH3:40])[C:19](=[O:36])[C:20]2([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[Cl:35])[CH3:28]
Reactant: BrCCCCBr
Reactant: COc1cc(N)ccc1CN1C(=O)C(C)(c2ccccc2Cl)c2cc(Cl)ccc21
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CCOCC
Product: COc1cc(N2CCCC2)ccc1CN1C(=O)C(C)(c2ccccc2Cl)c2cc(Cl)ccc21
Temperature: 115 °C

Procedure:
0.4 g of sodium bicarbonate powder and 0.14 ml of 1,4-dibromobutane are added to 0.5 g of the compound of Example 48 in 50 ml of hexamethyl-phosphoramide. The reaction mixture is heated at 115° C. for 10 hours. The reaction mixture is hydrolysed at room temperature and extracted with ethyl acetate. The organic phase is washed several times with water and dried over anhydrous sodium sulphate and then the solvents are evaporated under reduced pressure. The residue obtained is purified by chromatography on a column of silica gel, elution being carried out with a 95/5 (v/v) cyclohexane/ethyl acetate mixture. The oil obtained is treated with hydrochloric acid in diethyl ether; M.p.=198° C. (HCl.0.4H2O).
Reaction SMILES: [OH:1][C:2]1[C:9]([O:10][CH3:11])=[C:8]([O:12][CH3:13])[C:7]([N+:14]([O-:16])=[O:15])=[CH:6][C:3]=1[CH:4]=O.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][C:25](O)=[O:26])=[CH:20][CH:19]=1.C1(OP(Cl)(Cl)=O)C=CC=CC=1.C(N(CC)CC)C>ClCCCl>[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[C:25](=[O:26])[O:1][C:2]3[C:3]([CH:4]=2)=[CH:6][C:7]([N+:14]([O-:16])=[O:15])=[C:8]([O:12][CH3:13])[C:9]=3[O:10][CH3:11])=[CH:20][CH:19]=1
Reactant: COc1c([N+](=O)[O-])cc(C=O)c(O)c1OC
Reactant: O=C(O)Cc1ccc(Cl)cc1
Agent: O=P(Cl)(Cl)Oc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: COc1c([N+](=O)[O-])cc2cc(-c3ccc(Cl)cc3)c(=O)oc2c1OC

Procedure:
2-Hydroxy-3,4-dimethoxy-5-nitro-benzaldehyde (2.44 g), 4-chlorophenyl acetic acid (1.82 g), PhOPOCl2 (1.6 ml) and triethylamine (4.5 ml) in 1,2-dichloroethane (125 ml) were refluxed for 5 hours as described in example 1(a). Yield: 2.40 g.