Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5][C:6](=[O:40])[CH2:7][CH2:8][CH2:9][N:10]([CH2:12][C@@H:13]([O:15][C:16]1[C:17]2[C:24]([C:25]3[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=3)=[C:23]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=3[F:39])[O:22][C:18]=2[N:19]=[CH:20][N:21]=1)[CH3:14])[CH3:11])(C)(C)C>Cl.O1CCOCC1>[F:39][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=1[C:23]1[O:22][C:18]2[N:19]=[CH:20][N:21]=[C:16]([O:15][C@@H:13]([CH3:14])[CH2:12][N:10]([CH3:11])[CH2:9][CH2:8][CH2:7][C:6]([OH:40])=[O:5])[C:17]=2[C:24]=1[C:25]1[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=1
Reactant: COc1ccc(-c2c(-c3ccccc3F)oc3ncnc(O[C@@H](C)CN(C)CCCC(=O)OC(C)(C)C)c23)cc1
Agent: Cl
Solvent: C1COCCO1
Product: COc1ccc(-c2c(-c3ccccc3F)oc3ncnc(O[C@@H](C)CN(C)CCCC(=O)O)c23)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Dissolve 102 mg (93% purity, 0.19 mmol) 4-{[(2S)-2-{[6-(2-fluorophenyl)-5-(4-methoxyphenyl)furo[2,3-d]pyrimidin-4-yl]oxy}propyl](methyl)amino}butyric acid tert.-butyl ester in 2 ml 4 N hydrogen chloride in dioxan and stir for 16 h at RT. After concentrating the reaction solution by evaporation under vacuum, purify the residue by preparative RP-HPLC (gradient: water/acetonitrile). 48 mg (52% of theor.) of the desired product is obtained.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][O:4][C:3]2[CH:7]=[C:8]([OH:11])[CH:9]=[CH:10][C:2]1=2.CC1SC2C=CC(O)=CC=2N=1.[C:23]1([CH:29]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[N:30]2[C:38]3[C:33](=[C:34]([F:39])[CH:35]=[CH:36][CH:37]=3)[C:32](=[O:40])[C:31]2=[O:41])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.N1C2C(=CC=CC=2)C(=O)C1=O>>[C:42]1([CH:29]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:30]2[C:38]3[C:33](=[C:34]([F:39])[CH:35]=[CH:36][CH:37]=3)[C:32]([OH:40])([C:9]3[C:8]([OH:11])=[CH:7][C:3]4[O:4][CH2:5][CH2:6][O:1][C:2]=4[CH:10]=3)[C:31]2=[O:41])[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1
Reactant: O=C1C(=O)N(C(c2ccccc2)c2ccccc2)c2cccc(F)c21
Reactant: Oc1ccc2c(c1)OCCO2
Agent: Cc1nc2cc(O)ccc2s1
Agent: O=C1Nc2ccccc2C1=O
Product: O=C1N(C(c2ccccc2)c2ccccc2)c2cccc(F)c2C1(O)c1cc2c(cc1O)OCCO2

Procedure:
Following the procedure as described in PREPARATION 1A and making non-critical variations using 2,3-dihydrobenzo[b][1,4]dioxin-6-ol to replace 2-methylbenzo[d]thiazol-5-ol, and 1-(diphenylmethyl)-4-fluoro-1H-indole-2,3-dione to replace isatin, 1-(diphenylmethyl)-4-fluoro-3-hydroxy-3-(7-hydroxy-2,3-dihydro-1,4-benzodioxin-6-yl)-1,3-dihydro-2H-indol-2-one was obtained (83%) as a colourless solid: mp 209-211° C. (dec.); 1H NMR (300 MHz, DMSO-d6) δ 9.15 (s, 1H), 7.43-7.27 (m, 11H), 7.01 (ddd, J=8.2, 8.2, 5.9 Hz, 1H), 6.87 (s, 1H), 6.79 (s, 1H), 6.61 (dd, J=8.8, 8.8 Hz, 1H), 6.21 (s, 1H), 6.16 (d, J=7.9 Hz, 1H), 4.25-4.14 (m, 4H); 13C NMR (75 MHz, DMSO-d6) δ 176.2, 157.9 (d, 1JC-F=248 Hz), 147.1, 145.0 (d, 3JC-F=8.7 Hz), 142.7, 137.7 (d, 2JC-F=30.9 Hz), 135.4, 130.1 (d, 3JC-F=8.7 Hz), 128.4 (d, 3JC-F=13.9 Hz), 128.3 (d, 3JC-F=8.4 Hz), 127.5 (d, 3JC-F=11.9 Hz), 119.4, 117.9 (d, 2JC-F=18.9 Hz), 116.1, 109.3 (d, 2JC-F=20.3 Hz), 107.2 (d, 4JC-F=2.1 Hz), 103.1, 73.0, 64.2, 63.7, 57.5; MS (ES+) m/z 506.0 (M+23).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([CH2:7][C:8]2[CH:15]=[CH:14][C:11]([CH:12]=O)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[N+:16]([CH3:19])([O-:18])=[O:17].C([O-])(=O)C.[NH4+]>C(O)(=O)C>[CH3:1][C:2]1[O:6][C:5]([CH2:7][C:8]2[CH:15]=[CH:14][C:11](/[CH:12]=[CH:19]/[N+:16]([O-:18])=[O:17])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(Cc2ccc(C=O)cc2)o1
Reactant: C[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Product: Cc1ccc(Cc2ccc(/C=C/[N+](=O)[O-])cc2)o1
Temperature: 100 °C
Reaction time: 3 h
Yield: 102.8 %

Procedure:
To a mixture of 4-(5-methyl-furan-2-ylmethyl)-benzaldehyde (96 mg, 0.48 mmol) described in Manufacturing Example 46-1-3 and acetic acid (1 mL) were added nitromethane (190 μL, 3.6 mmol) and ammonium acetate (110 mg, 1.4 mmol) at room temperature, which was stirred for 3 hours at 100° C. The reaction mixture was cooled to room temperature, and extracted by addition of water and ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and dried over magnesium sulfate. The filtrate was concentrated under a reduced pressure to obtain the title compound (120 mg) as a crude product. This compound was used in the following reaction without further purification.
Reaction SMILES: [F:1][C@@:2]1([CH2:15]OS(C(F)(F)F)(=O)=O)[CH2:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1.[N-:24]=[N+:25]=[N-:26].[Na+].CC(OC)(C)C.O>CN(C=O)C>[N:24]([CH2:15][C@:2]1([F:1])[CH2:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1)=[N+:25]=[N-:26]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@](F)(COS(=O)(=O)C(F)(F)F)C1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: COC(C)(C)C
Product: CC(C)(C)OC(=O)N1CCC[C@@](F)(CN=[N+]=[N-])C1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
1,1-Dimethylethyl (3S)-3-fluoro-3-({[(trifluoromethyl)sulfonyl]oxy}methyl)-1-piperidinecarboxylate (1 wt) is dissolved in N,N,-dimethylformamide (3 vol) at 20° C. and sodium azide (1.1 eq, 0.20 wt) is added. The resulting suspension is stirred at 20-30° C. for 6 h. TBME (5 vol) and water (9 vol) are added. The mixture is stirred for 5 min and the layers are separated. The aqueous phase is extracted with TBME (5 vol) and the TBME phases are combined. The combined organics are washed with water (2×5 vol), filtered and concentrated under reduced pressure to give the title compound as an orange oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:37])/[CH:7]=[CH:8]/[C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:19][C:18](=[O:20])[N:17]([CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[S:16]2(=[O:28])=[O:27])=[C:11]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2]>[Pt]>[C:1]([O:5][C:6](=[O:37])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:19][C:18](=[O:20])[N:17]([CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[S:16]2(=[O:28])=[O:27])=[C:11]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)/C=C/c1ccc(N2CC(=O)N(CC[Si](C)(C)C)S2(=O)=O)c(OCc2ccccc2)c1
Agent: [Pt]
Product: CC(C)(C)OC(=O)CCc1ccc(N2CC(=O)N(CC[Si](C)(C)C)S2(=O)=O)c(OCc2ccccc2)c1
Reaction time: 5 h

Procedure:
A mixture of (E)-3-{3-benzyloxy-4-[1,1,4-trioxo-5-(2-trimethylsilanylethyl)-1,2,5-thiadiazolidin-2-yl]-phenyl}-acrylic acid tert-butyl ester (485 mg, 0.89 mmol) and 5% platinum-on-carbon (50 mg) is stirred under an atmosphere of hydrogen for 5 h. The catalyst is filtered through Celite and solvent removed under reduced pressure to give the title compound.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11](O)=[O:12])=[CH:10][C:5]=2[N:4]=[C:3]1[NH:14][C:15]1[S:16][C:17]2[CH:23]=[C:22]([O:24][C:25]([F:28])([F:27])[F:26])[CH:21]=[CH:20][C:18]=2[N:19]=1.[NH2:29][CH2:30][C:31]1[S:32][CH:33]=[CH:34][N:35]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[S:32]1[CH:33]=[CH:34][N:35]=[C:31]1[CH2:30][NH:29][C:11]([C:9]1[CH:8]=[CH:7][C:6]2[N:2]([CH3:1])[C:3]([NH:14][C:15]3[S:16][C:17]4[CH:23]=[C:22]([O:24][C:25]([F:28])([F:26])[F:27])[CH:21]=[CH:20][C:18]=4[N:19]=3)=[N:4][C:5]=2[CH:10]=1)=[O:12]
Reactant: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)O)ccc21
Reactant: NCc1nccs1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)NCc3nccs3)ccc21
Yield: 86.9 %

Procedure:
1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (thiazol-2-ylmethyl)-amide (44 mg) was prepared by following General Procedure F using 1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzimidazole-5-carboxylic acid (41 mg), 2-aminomethyl-thiazole (38 mg), HBTU (38 mg), and DIEA (0.1 ml). LC/MS: m/z 506. 1H NMR (DMSO-d6, 400 MHz): δ 9.36 (br, 1H), 8.13 (s, 1H), 7.93 (s, 1H), 7.82 (br, 1H), 7.75 (d, 1H), 7.63 (d, 1H), 7.54 (d, 1H), 7.36 (d, 1H), 4.77 (d, 2H), and 3.67 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:26][CH2:27][NH2:28])[CH:5]=[CH:6][C:7]=1[C:8]1[S:9][C:10]2[C:15]([N:16]=1)=[CH:14][CH:13]=[C:12]([C:17]1([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:19][CH2:18]1)[N:11]=2.[C:29](Cl)(=[O:31])[CH3:30]>C1COCC1.C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH2:26][CH2:27][NH:28][C:29](=[O:31])[CH3:30])[CH:5]=[CH:6][C:7]=1[C:8]1[S:9][C:10]2[C:15]([N:16]=1)=[CH:14][CH:13]=[C:12]([C:17]1([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:18][CH2:19]1)[N:11]=2
Reactant: CC(=O)Cl
Reactant: NCCc1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(=O)NCCc1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-(3-Fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)phenyl)-ethanamine (90 mg, 0.23 mmol) was dissolved in THF (2.3 mL) before acetyl chloride (33 μl, 0.462 mmol) was added and stirred at ambient temperature for 2 h. The reaction mixture was diluted with 100 mL of DCM, added to a separatory funnel, partitioned with sodium bicarbonate (saturated, aqueous), washed 2 times with 75 mL of sodium bicarbonate (saturated, aqueous), separated, dried over sodium sulfate, and concentrated via rotovap to give the title compound after purification via preparatory LC. MS (ESI) m/z: Calculated: 431.1; Observed: 432.1 (M++H).
Reaction SMILES: [Si]([O:8][C:9]1[CH:10]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[CH:11]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:13][CH:14]=1)(C(C)(C)C)(C)C.[F:32][C:33]([F:54])([F:53])[C:34]1[CH:35]=[C:36]([C@@H:44](OC(=N)C(Cl)(Cl)Cl)[CH3:45])[CH:37]=[C:38]([C:40]([F:43])([F:42])[F:41])[CH:39]=1.[H+].[B-](F)(F)(F)F>CCOCC>[F:32][C:33]([F:53])([F:54])[C:34]1[CH:35]=[C:36]([C@H:44]([O:8][C@H:9]2[CH2:14][CH2:13][C@H:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C@@H:11]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C@@H:10]2[C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[CH3:45])[CH:37]=[C:38]([C:40]([F:41])([F:42])[F:43])[CH:39]=1
Reactant: CCOC(=O)C1CC=C(O[Si](C)(C)C(C)(C)C)C(c2ccc(F)cc2)C1C(=O)OCC
Reactant: C[C@H](OC(=N)C(Cl)(Cl)Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: F[B-](F)(F)F
Agent: [H+]
Solvent: CCOCC
Product: CCOC(=O)[C@H]1[C@H](c2ccc(F)cc2)[C@@H](O[C@H](C)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)CC[C@@H]1C(=O)OCC
Temperature: 0 °C
Reaction time: 2 h
Yield: 59.1 %

Procedure:
To a solution of 9.09 g (26.9 mmol) of the first eluting isomer diethyl (1S,2S,3R,4S)-3-(4-fluorophenyl)-4-hydroxycyclohexane-1,2-dicarboxylate (step D) and 21.5 g (53.5 mmol) of (1S)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl-2,2,2-trichloroethanimidoate (step E) in 250 mL of cyclohexane/1,2-chloroethane (3/1) under nitrogen atmosphere at −5° C. was added 0.51 mL (3.58 mmol) of 54% HBF4 in ether. The reaction mixture was stirred at −5° C. to at 0° C. for 2 hr then diluted with ether. The mixture was washed with sat. aq. NaHCO3. The organic layer was dried over drying agent, filtered and the solvent evaporated under vacuum. The residue was purified by flash column chromatography on silica gel eluting with EtOAc/hexanes (1/4) to give 9.2 g of the title compound as an oil. 1H-NMR (CDCl3): δ: δ: 7.70 (1H, s), 7.20 (2H, s), 7.00 (2H, m), 6.85 (2H, t, J=8.5 Hz), 4.43 (1H, q, J=6.0 Hz), 4.20-4.10 (2H, m), 3.80-3.73 (2H, m), 3.36 (1H, m), 2.90-2.76 (2H, m), 2.40 (1H, m), 2.28 (1H, m), 1.63-1.55 (2H, m), 1.33 (3H, d, J=6.0 Hz), 1.25 (3H, t, J=7.2 Hz), 0.82 (3H, t, J=7.2 Hz). Unreacted starting alcohol could be recovered by flushing the column with EtOAc and reused in the above reaction.
Reaction SMILES: N(C(OC(C)C)=O)=NC(OC(C)C)=O.[CH2:15]([O:22][C:23]([N:25]1[CH2:30][CH2:29][N:28]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[OH:37])[CH2:27][CH2:26]1)=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[C:38]([O:42][C:43]([N:45]1[CH2:50][CH2:49][CH:48](O)[CH2:47][CH2:46]1)=[O:44])([CH3:41])([CH3:40])[CH3:39].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[CH2:15]([O:22][C:23]([N:25]1[CH2:30][CH2:29][N:28]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=2[O:37][CH:48]2[CH2:49][CH2:50][N:45]([C:43]([O:42][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:44])[CH2:46][CH2:47]2)[CH2:27][CH2:26]1)=[O:24])[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: O=C(OCc1ccccc1)N1CCN(c2ccccc2O)CC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccccc2N2CCN(C(=O)OCc3ccccc3)CC2)CC1
Temperature: 0 °C
Reaction time: 16 h
Yield: 42 %

Procedure:
Diisopropyl azodicarboxylate (0.70 mL, 3.55 mmol) was added dropwise to a stirred solution of 4-(2-hydroxy-phenyl)-piperazine-1-carboxylic acid benzyl ester (0.74 g, 2.4 mmol), 4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (0.48 g, 2.4 mmol) and triphenylphosphine (0.93 g, 3.6 mmol) in THF (25 mL) cooled to 0° C. The resulting solution was warmed to r.t. and stirred for about 16 hours. The solvent was removed in vacuo and the residue purified by silica gel chromatography (20% ethyl acetate in hexanes) to afford the final compound (0.50 g, 43%) as a clear oil.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][C:5]1[N:6]([CH2:19][CH2:20][CH3:21])[C:7]2[C:16]3[CH:15]=[CH:14][C:13]([OH:17])=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:18]=1.C(OC1C=C(C=CC=1)N)C1C=CC=CC=1.[Cl-].COCCCO.C(OC1C=CC(N)=CC=1)C1C=CC=CC=1.[Cl-].N(C(OC(C)C)=O)=NC(OC(C)C)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[CH:94]1[CH2:99][CH2:98][N:97]([C:100]([O:102][C:103]([CH3:106])([CH3:105])[CH3:104])=[O:101])[CH2:96][CH2:95]1>O1CCCC1>[CH3:1][O:2][CH2:3][CH2:4][C:5]1[N:6]([CH2:19][CH2:20][CH3:21])[C:7]2[C:16]3[CH:15]=[CH:14][C:13]([O:17][CH:94]4[CH2:99][CH2:98][N:97]([C:100]([O:102][C:103]([CH3:106])([CH3:105])[CH3:104])=[O:101])[CH2:96][CH2:95]4)=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:18]=1
Reactant: CCCn1c(CCOC)nc2cnc3cc(O)ccc3c21
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: COCCCO
Agent: Nc1ccc(OCc2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCn1c(CCOC)nc2cnc3cc(OC4CCN(C(=O)OC(C)(C)C)CC4)ccc3c21
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A modification on the methods described in Parts A-H of Example 2 were used to prepare 2-(2-methoxyethyl)-1-propyl-1H-imidazo[4,5-c]quinolin-7-ol, with 3-benzyloxyaniline and 3-methoxypropanol chloride used in lieu of 4-benzyloxyaniline and ethoxyacetyl, chloride, respectively. A solution of diisopropyl azodicarboxylate (6.28 mL, 31.9 mmol) in tetrahydrofuran (25.5 mL) was added dropwise to a mixture of 2-(2-methoxyethyl)-1-propyl-1H-imidazo[4,5-c]quinolin-7-ol (7.28 g, 25.5 mmol), triphenylphosphine (8.36 g, 31.9 mmol), and t-butyl 4-hydroxypiperidine-1-carboxylate (6.42 g, 31.9 mmol) in tetrahydrofuran (191 mL) at 5° C. The mixture was allowed to warm to room temperature. After 2 days, the solvent was removed under reduced pressure and the residue was purified by flash chromatography (silica gel, gradient elution with 1.5-4% methanol in dichloromethane) to yield 9.77 g of tert-butyl 4-{[2-(2-methoxyethyl)-1-propyl-1H-imidazo[4,5-c]quinolin-7-yl]oxy}piperidine-1-carboxylate as a gray amorphous solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][NH2:9])=[CH:4][CH:3]=1.[CH2:10]([CH2:12][CH2:13][CH2:14][C:15](CC([O-])=O)=[O:16])[CH3:11]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:15](=[O:16])[CH2:14][C:13]([CH2:12][CH2:10][CH3:11])=[N:9]2)=[CH:4][CH:3]=1
Reactant: NNc1ccc(Br)cc1
Reactant: CCCCCC(=O)CC(=O)[O-]
Product: CCCC1=NN(c2ccc(Br)cc2)C(=O)C1

Procedure:
From the reaction of 4-bromophenylhydrazine and ethylbutyrylacetate, 2-(4-bromphenyl)-2,4-dihydro-5-propyl-3H-pyrazol-3-one is obtained. Subsequent reaction with 2-ethylaniline yields 2-(4-bromophenyl)-4-(2-ethylanilinomethylene)-2,4-dihydro-5-propyl-3H-pyrazol-3-one, Mp.: 126.9° C.
Reaction SMILES: CC1(C)[O:6][C@H:5]([CH2:7][N:8]2[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:35])[C@@H:15]([N:21]3[CH2:25][C:24]([O:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=4[Cl:33])=[CH:23][C:22]3=[O:34])[CH2:16][CH:17]([CH3:20])[CH2:18][CH3:19])=[N:9]2)[CH2:4][O:3]1.Cl>O1CCCC1>[OH:6][C@@H:5]([CH2:4][OH:3])[CH2:7][N:8]1[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:35])[C@@H:15]([N:21]2[CH2:25][C:24]([O:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[Cl:33])=[CH:23][C:22]2=[O:34])[CH2:16][CH:17]([CH3:20])[CH2:18][CH3:19])=[N:9]1
Reactant: CCC(C)C[C@@H](C(=O)Nc1ccn(C[C@@H]2COC(C)(C)O2)n1)N1CC(Oc2ccccc2Cl)=CC1=O
Agent: Cl
Solvent: C1CCOC1
Product: CCC(C)C[C@@H](C(=O)Nc1ccn(C[C@@H](O)CO)n1)N1CC(Oc2ccccc2Cl)=CC1=O
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 85.4 %

Procedure:
A solution of (S)-2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-hexanoic acid [1-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethyl)-1H-pyrazol-3-yl]-amide (360 mg, 0.7 mmol) in tetrahydrofuran (15 mL) was treated with 2N aqueous hydrochloric acid (7.5 mL) and stirred at room temperature for 2.5 h. At this time the mixture was partitioned between ethyl acetate and water. The layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine and dried over sodium sulfate. The mixture was filtered and concentrated in vacuo and the residue was purified by ISCO flash chromatography (RediSep silica column 12 g, 30% to 80% (10% methanol/dichloromethane)hexanes) which afforded (S)-2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-hexanoic acid [1-((R)-2,3-dihydroxy-propyl)-1H-pyrazol-3-yl]-amide (285 mg, 86%) as a white fluffy solid: HR-ES-MS (m/z) calculated for C23H29ClN4O5 [M+H]+ 477.1899, observed 477.1897. 1H NMR showed mixture of diastereomers (400 MHz, DMSO-d6) δ ppm 0.77-0.96 (m, 6H), 1.04-1.93 (m, 5H), 3.23-3.33 (m, 2H), 3.77 (br. s., 1H), 3.82-3.91 (m, 1H), 4.04-4.14 (m, 1H), 4.11-4.29 (m, 1H), 4.58, 4.63 (2×d, J=18.7 Hz, 1H), 4.71 (br. s., 1H), 4.79, 4.81 (2×s, 1H), 4.86-4.97 (m, 2H), 6.42 (br. s., 1H), 7.37 (t, J=7.7 Hz, 1H), 7.46 (t, J=7.5 Hz, 1H), 7.49-7.56 (m, 2H), 7.65 (d, J=7.9 Hz, 1H), 10.77, 10.79 (2×s, 1H)
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([N:14]1[CH2:19][C:18](=O)[NH:17][C@H:16]([CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:15]1=O)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.S([O-])([O-])(=O)=O.[Na+].[Na+].O>O1CCCC1>[CH2:7]([N:14]1[CH2:19][CH2:18][NH:17][C@H:16]([CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:15]1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=C1CN(Cc2ccccc2)C(=O)[C@@H](CCc2ccccc2)N1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: c1ccc(CC[C@@H]2CN(Cc3ccccc3)CCN2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 103.4 %

Procedure:
Lithium aluminum hydride (1.04 g) was added to a solution of (3R)-1-benzyl-3-phenethylpiperazine-2,5-dione (B, 1.68 g) in tetrahydrofuran (60 mL) at 0° C. After stirring at room temperature for 18 hr, anhydrous sodium sulfate and then water were added at 0° C. The insoluble materials were removed by filtration. The resulting mixture was concentrated in vacuo and then partitioned between chloroform and saturated sodium hydrogen carbonate. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo to give the titled compound (1.58 g) as an orange oil, which was used in the next reaction without further purification.
Reaction SMILES: [OH-].[Na+].[OH:3][CH2:4][C:5]1[O:6][C:7]([CH3:13])=[CH:8][C:9](=[O:12])[C:10]=1[OH:11].[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[OH:3][CH2:4][C:5]1[O:6][C:7]([CH3:13])=[CH:8][C:9](=[O:12])[C:10]=1[O:11][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Cc1cc(=O)c(O)c(CO)o1
Reactant: BrCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Product: Cc1cc(=O)c(OCc2ccccc2)c(CO)o1
Yield: 80 %

Procedure:
Sodium hydroxide (4.84 g, 121 mmol, 1.1 eq.) dissolved in 10 ml distilled water was added to 100 ml methanol containing 2-hydroxymethyl-3-hydroxy-6-methyl-pyran-4(1H)-one (17.2 g, 110 mmol, 1 eq.) and heated to reflux. Benzyl bromide (20.7 g, 121 mmol, 1 eq.) was added dropwise over 30 minutes and then refluxed overnight. The reaction mixture was concentrated in vacuo, the residue taken up into 300 ml dichloromethane and the inorganic salts filtered off. The dichloromethane layer was washed with 2×100 ml 5% w/v sodium hydroxide solution, 100 ml water, dried (Na2SO4), and concentrated in vacuo to yield the crude product as a yellow crystalline solid. Recrystallisation from CH2Cl2/Pet. ether 40/60 afforded the title product in 80% yield (21.6 g) as a white crystalline solid. m.p. 115-116° C. [lit. 114-116° C. Tilbrook (1995)].
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C@@H:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[OH:5].[C:12]([O:16][C:17]([O:19][C:20]1[CH:25]=[CH:24][C:23](O)=[C:22]([CH3:27])[CH:21]=1)=[O:18])([CH3:15])([CH3:14])[CH3:13].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[Cl:1][CH2:2][CH2:3][C@H:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[O:5][C:23]1[CH:24]=[CH:25][C:20]([O:19][C:17]([O:16][C:12]([CH3:14])([CH3:13])[CH3:15])=[O:18])=[CH:21][C:22]=1[CH3:27]
Reactant: O[C@@H](CCCl)c1ccccc1
Reactant: Cc1cc(OC(=O)OC(C)(C)C)ccc1O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1cc(OC(=O)OC(C)(C)C)ccc1O[C@H](CCCl)c1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 87.3 %

Procedure:
An oven dried, three-necked, 2-L, round-bottomed flask was charged with (S)-3-chloro-1-phenyl-propanol (52 g, 304 mmol), 4-((tert-butoxycarbonyl)oxy)-2-methylphenol (73.86 g, 329 mmol), triphenylphosphine (87.36 g, 333 mmol) and anhydrous tetrahydrofuran (600 ml). The reaction mixture was cooled at 0° C., and a solution of diisopropylazadicarbox-ylate (76 ml, 365 mmol,) in dry tetrahydrofuran (100 mL) was added over 6 hours. The reaction mixture was stirred for an additional two hours at 0° C. and was then allowed to warm gradually to room temperature. The reaction mixture was further stirred at room temperature for 24 hours and the reaction mixture was concentrated under reduced pressure. The residue was treated with 2 L of 9:1 pentane:ethyl acetate. The resulting suspension was stored at −20° C. for 24 hours and the insoluble materials were removed by filtration. The precipitate was washed with 9:1 pentane:ethyl acetate (200 mL). The combined filtrates were concentrated under reduced pressure. The crude residue (150 grams) was purified by 150 flash Biotage pre-packed column eluting with 3% ethyl acetate in hexane to provide (R)-3-chloro-1-phenyl-1-(2-methyl-4-((tert-butoxycarbonyl)oxy)-phenoxy)propane (100 g) in 85% yield.