Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC1C=CC(NC(C)C(O)=O)=CC=1C(F)(F)F.COC(OC)CNCCCN1CCC2(CC2)[C@H](O)C1.[F:37][C:38]1[CH:43]=[CH:42][C:41]([NH:44][CH:45]([CH3:67])[C:46]([N:48]([CH2:61][CH:62](OC)OC)[CH2:49][CH2:50][CH2:51][N:52]2[CH2:59][CH2:58][C:55]3([CH2:57][CH2:56]3)[C@H:54]([OH:60])[CH2:53]2)=[O:47])=[CH:40][C:39]=1[C:68]([F:71])([F:70])[F:69]>>[F:37][C:38]1[CH:43]=[CH:42][C:41]([N:44]2[CH2:62][CH2:61][N:48]([CH2:49][CH2:50][CH2:51][N:52]3[CH2:59][CH2:58][C:55]4([CH2:57][CH2:56]4)[C@H:54]([OH:60])[CH2:53]3)[C:46](=[O:47])[C@@H:45]2[CH3:67])=[CH:40][C:39]=1[C:68]([F:70])([F:69])[F:71]
Reactant: COC(CN(CCCN1CCC2(CC2)[C@H](O)C1)C(=O)C(C)Nc1ccc(F)c(C(F)(F)F)c1)OC
Agent: CC(Nc1ccc(F)c(C(F)(F)F)c1)C(=O)O
Agent: COC(CNCCCN1CCC2(CC2)[C@H](O)C1)OC
Product: C[C@H]1C(=O)N(CCCN2CCC3(CC3)[C@H](O)C2)CCN1c1ccc(F)c(C(F)(F)F)c1

Procedure:
The title compound was produced in analogy with examples 74 and 75, steps D-F. Thus, coupling of 2-(4-fluoro-3-trifluoromethyl-phenylamino)-propionic acid (intermediate 13) with (S)-6-[3-(2,2-dimethoxy-ethylamino)-propyl]-6-aza-spiro[2.5]octan-4-ol (examples 74/75C) in step D led to 2-(4-fluoro-3-trifluoromethyl-phenylamino)-N-(2,2-dimethoxy-ethyl)-N-[3-((S)-4-hydroxy-6-aza-spiro[2.5]oct-6-yl)-propyl]-propionamide, which was cyclized in step E. Finally, HPLC purification of the epimeric mixture, 4-(4-fluoro-3-trifluoromethyl-phenyl)-1-[3-((S)-4-hydroxy-6-aza-spiro[2.5]oct-6-yl)-propyl]-3-methyl-piperazin-2-one, in step F afforded the title compound. Light yellow gum, MS: 444.3 (M+H)+.
Reaction SMILES: [CH:1]([O:14][C:15]1[C:16]2[C:35](=[O:36])[N:34]([CH2:37][C:38]3[CH:43]=[CH:42][C:41]([F:44])=[CH:40][CH:39]=3)[CH2:33][C:17]=2[C:18](OS(C(F)(F)F)(=O)=O)=[C:19]2[C:24]=1[N:23]=[CH:22][CH:21]=[CH:20]2)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[F:51][C:52]1[C:57](B(O)O)=[CH:56][CH:55]=[CH:54][N:53]=1.CCOC(C)=O.CCCCCC>C1(C)C=CC=CC=1.C(O)C.O.CCOC(C)=O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH:1]([O:14][C:15]1[C:16]2[C:35](=[O:36])[N:34]([CH2:37][C:38]3[CH:39]=[CH:40][C:41]([F:44])=[CH:42][CH:43]=3)[CH2:33][C:17]=2[C:18]([C:57]2[C:52]([F:51])=[N:53][CH:54]=[CH:55][CH:56]=2)=[C:19]2[C:24]=1[N:23]=[CH:22][CH:21]=[CH:20]2)([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OB(O)c1cccnc1F
Reactant: O=C1c2c(c(OS(=O)(=O)C(F)(F)F)c3cccnc3c2OC(c2ccccc2)c2ccccc2)CN1Cc1ccc(F)cc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCO
Product: O=C1c2c(c(-c3cccnc3F)c3cccnc3c2OC(c2ccccc2)c2ccccc2)CN1Cc1ccc(F)cc1
Temperature: 120 °C

Procedure:
To a solution of trifluoro-methanesulfonic acid 9-benzhydryloxy-7-(4-fluoro-benzyl)-8-oxo-7,8-dihydro-6H-pyrrolo[3,4-g]quinolin-5-yl ester 46 (40 mg, 0.064 mmol) dissolved in toluene (3 mL)/ethanol (0.6 mL)/water (0.4 mL) was added K2CO3 (29 mg, 0.16 mmol), 2-fluoropyridine-3-boronic acid (18 mg, 0.128 mmol) and tetrakis-(triphenylphosphine)-palladium(0)(15 mg, 0.01 mmol). The reaction mixture in the flask was flashed with argon three times. It was then heated to 120° C. under argon 3 hours. The reaction was monitored by TLC (EtOAc/hexane 3/7) (Rf 46=0.6, Rf 286=0.1) and LC/MS. After cooling to room temperature, the mixture was diluted with EtOAc (20 mL) and washed with 1N HCl, saturated NaHCO3 and brine. The organic phase was dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel with EtOAc/Hexane (1/1) to afford pure 9-benzhydryloxy-7-(4-fluoro-benzyl)-5-(2-fluoro-pyridin-3-yl)-6,7-dihydro-pyrrolo[3,4-g]quinolin-8-one (15), 10.6 mg, 29%.
Reaction SMILES: [CH2:1]([N:4]1[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1)[CH:2]=[CH2:3].[BH:10]1[CH:15]2[CH2:16][CH2:17][CH2:18][CH:11]1[CH2:12][CH2:13][CH2:14]2>C1COCC1>[CH:11]12[B:10]([CH2:3][CH2:2][CH2:1][N:4]3[CH2:9][CH2:8][O:7][CH2:6][CH2:5]3)[CH:15]([CH2:16][CH2:17][CH2:18]1)[CH2:14][CH2:13][CH2:12]2
Reactant: C=CCN1CCOCC1
Reactant: B1C2CCCC1CCC2
Solvent: C1CCOC1
Product: C1CC2CCCC(C1)B2CCCN1CCOCC1
Temperature: 25 °C

Procedure:
To a solution of 4-allylmorpholine (2.54 g, 20 mmol) in THF (40 mL) was added 9-BBN (2.44 g, 10 mmol). The reaction mixture was refluxed until the reaction was complete. After cooling to room temperature, the mixture was concentrated under reduced pressure to give the crude 4-(3-(9-borabicyclo[3.3.1]nonan-9-yl)propyl)morpholine that was used directly without further purification. LCMS ESI (+) m/z 250 (M+1) detected.
Reaction SMILES: [C:1]([O:5][C:6](=[O:32])[CH:7]([NH:23][C:24](=[O:31])[CH:25]([NH2:30])[CH2:26][CH:27]([CH3:29])[CH3:28])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[N:33]1([S:39](Cl)(=[O:41])=[O:40])[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1.C(N(CC)C(C)C)(C)C>CN(C1C=CN=CC=1)C.CN(C=O)C.C(OCC)(=O)C.C(Cl)(Cl)Cl.CCCCCC>[C:1]([O:5][C:6](=[O:32])[CH:7]([NH:23][C:24](=[O:31])[CH:25]([NH:30][S:39]([N:33]1[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1)(=[O:41])=[O:40])[CH2:26][CH:27]([CH3:28])[CH3:29])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:11][CH:10]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: O=S(=O)(Cl)N1CCCCC1
Reactant: CC(C)CC(N)C(=O)NC(Cc1ccc(OCc2ccccc2)cc1)C(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)CC(NS(=O)(=O)N1CCCCC1)C(=O)NC(Cc1ccc(OCc2ccccc2)cc1)C(=O)OC(C)(C)C
Reaction time: 72 h

Procedure:
A solution of the product from Example AI ([S-(R*,R*)]-2-(2-amino-4-methyl-pentanoylamino)-3-(4-benzyloxy-phenyl)-propionic acid tert-butyl ester) (220 mg, 0.50 mmol), piperidinesulfonyl chloride (102 mg, 0.55 mmol, prepared by the method of Von Geldern, et al., J. Med. Chem., 1996;39:968-981), N,N-diisopropylethylamine (129 mg, 1.00 mmol), and DMAP (20 mg) in DMF (1 mL) is stirred at room temperature for 48 hours, diluted with ethyl acetate, and washed with water, 1N HCl, saturated NaHCO3 solution and brine, dried over anhydrous sodium sulfate, and concentrated. The remaining oily residue was purified via preparative TLC (50% EtOAc/hexane) giving a clear oil which was dissolved in 0.5 mL CHCl3, and diluted with 5 mL hexane. After 3 days at 3° C., the crystals that had formed were collected, and weighed 34 mg (12%), mp=125-126° C.
Reaction SMILES: O[CH2:2][CH2:3][C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1.S(Cl)([Cl:12])=O>>[Cl:12][CH2:2][CH2:3][C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=S(Cl)Cl
Reactant: OCCc1cccnc1
Product: ClCCc1cccnc1

Procedure:
A mixture of 3-(2-hydroxyethyl)pyridine (1.2 g., 9.8 m.moles ) and thionyl chloride (10 ml.) was refluxed for 3 hours and then excess of the thionyl chloride was removed by evaporation. To the residue was added a 5% aqueous solution of Na2CO3 (20 ml.) and the mixture was extracted with chloroform (2×30 ml.). The extracts were combined, dried with anhydrous Na2SO4 and concentrated to dryness to yield 3-(2-chloroethyl)-pyridine, 1.3 g. (98%).
Reaction SMILES: Cl[C:2]1[C:7]([CH3:8])=[CH:6][C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[CH3:12].[CH:13]([C:16]1[CH:17]=[C:18]([OH:24])[CH:19]=[CH:20][C:21]=1[O:22][CH3:23])([CH3:15])[CH3:14].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CS(C)=O>[CH3:12][C:3]1[CH:4]=[C:5]([N+:9]([O-:11])=[O:10])[CH:6]=[C:7]([CH3:8])[C:2]=1[O:24][C:18]1[CH:19]=[CH:20][C:21]([O:22][CH3:23])=[C:16]([CH:13]([CH3:15])[CH3:14])[CH:17]=1
Reactant: COc1ccc(O)cc1C(C)C
Reactant: Cc1cc([N+](=O)[O-])cc(C)c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: COc1ccc(Oc2c(C)cc([N+](=O)[O-])cc2C)cc1C(C)C

Procedure:
4-Chloro-3,5-dimethylnitrobenzene (2.12 g), 1.9 g of 3-isopropyl-4-methoxyphenol, and 1.74 g of potassium carbonate are heated 18 hrs at 125° in 25 ml dimethylsulfoxide. The mixture is poured into ethyl acetate and extracted once with water and five times with brine. The ethyl acetate is dried, filtered, and stripped to yield an oil which is chromatographed on silica gel with 97:3 hexane:ethyl acetate to afford 3,5-dimethyl-4-(3'-isopropyl-4'-methoxyphenoxy)-nitro benzene NMR (CDCl3): δ1.1 (6H,d), 2.2 (6H,s), 3.3 (1H,m), 3.7 (3H, s) 6.3 (1H,d of d), 6.6 (1H,d), 6.7 (1H, d), 8.0 (2H, s).
Reaction SMILES: [OH:1][CH2:2][CH:3]=[C:4]([C:6]1[CH:11]=[C:10]([CH:12]([CH3:14])[CH3:13])[CH:9]=[C:8]([CH:15]([CH3:17])[CH3:16])[C:7]=1[OH:18])[CH3:5].I[CH2:20][CH2:21][CH3:22].[F-].[Cs+]>CN(C=O)C.CCOC(C)=O>[CH:15]([C:8]1[C:7]([O:18][CH2:20][CH2:21][CH3:22])=[C:6]([C:4]([CH3:5])=[CH:3][CH2:2][OH:1])[CH:11]=[C:10]([CH:12]([CH3:14])[CH3:13])[CH:9]=1)([CH3:17])[CH3:16]
Reactant: CCCI
Reactant: CC(=CCO)c1cc(C(C)C)cc(C(C)C)c1O
Agent: [Cs+]
Agent: [F-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCOc1c(C(C)=CCO)cc(C(C)C)cc1C(C)C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 97.2 %

Procedure:
To a solution of 2-(3-hydroxy-1-methyl-propenyl)-4,6-diisopropyl-phenol (Intermediate 12, 1.82 g, 7.3 mmol) and 1-iodopropane (0.79 mL, 8.1 mmol) in DMF (20 mL) at room temperature was added CsF (3.9 g, 25.6 mmol). The reaction was stirred at room temperature for 1.5 h, diluted with EtOAc, washed successively with H2O, brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (10% EtOAc-hexanes) to yield the title compound as an off-white solid (2.06 g, 97%).
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([NH:14][C:15](=[O:18])[CH2:16]Br)=[CH:11][CH:12]=2)[C:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([CH3:19])[CH2:6][C:5]1([CH3:27])[CH3:26])(=[O:3])[CH3:2].[F:28][C:29]1[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:30]=1[CH2:31][NH2:32].C(N(CC)C(C)C)(C)C>O1CCOCC1>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([NH:14][C:15]([CH2:16][NH:32][CH2:31][C:30]3[CH:33]=[CH:34][C:35]([F:37])=[CH:36][C:29]=3[F:28])=[O:18])=[CH:11][CH:12]=2)[C:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([CH3:19])[CH2:6][C:5]1([CH3:27])[CH3:26])(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2ccc(NC(=O)CBr)cc2C(C)(c2ccccc2)CC1(C)C
Reactant: NCc1ccc(F)cc1F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CC(=O)N1c2ccc(NC(=O)CNCc3ccc(F)cc3F)cc2C(C)(c2ccccc2)CC1(C)C
Temperature: 40 °C
Reaction time: 18 h

Procedure:
A mixture of 1-acetyl-6-(bromoacetyl)amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline (10 mg), 2,4-difluorobenzylamine (6.0 mg) and N,N-diisopropylethylamine (10 μl) in dioxane (2 ml) was stirred at 40° C. for 18 h. The reaction mixture was concentrated in vacuo. The residue was chromatographed on silicagel in dichloromethane/methanol=1/095/5 (v/v) as eluent.
Reaction SMILES: Cl[CH2:2][C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][CH:4]=1.[Cl:12][C:13]([Cl:18])([Cl:17])[C:14]([NH2:16])=[NH:15]>CCOCC>[NH:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:3]([CH2:2][NH:16][C:14](=[NH:15])[C:13]([Cl:18])([Cl:17])[Cl:12])=[CH:4]1
Reactant: N=C(N)C(Cl)(Cl)Cl
Reactant: ClCc1c[nH]c2ccccc12
Solvent: CCOCC
Product: N=C(NCc1c[nH]c2ccccc12)C(Cl)(Cl)Cl

Procedure:
A solution of 8.3 g. (0.05 mole) of 3-(chloromethyl) indole in 30 ml. of ether is mixed with a solution of 8.1 g. (0.05 mole) of trichloroacetamidine, also in ether. The mixture is heated at reflux for 3 hours, and concentrated in vacuo to an oil. This is taken up in warm chloroform, filtered, and the chloroform extracts washed first with water and then with dilute hydrochloric acid. The aqueous layers are combined, made basic with a saturated aqueous solution of sodium bicarbonate and the product extracted with chloroform. The combined chloroform extracts are washed with water, dried over magnesium sulfate, filtered and concentrated in vacuo affording N-(3-indolylmethyl) trichloroacetamidine m.p. 135.5 to 138.5 after recrystallization from benzene/hexane.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[CH3:11][N:12]1[CH2:17][CH2:16][CH:15]([CH2:18][OH:19])[CH2:14][CH2:13]1.CS(C)=O.[H-].[Na+]>O>[CH3:11][N:12]1[CH2:17][CH2:16][CH:15]([CH2:18][O:19][C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=2)[CH2:14][CH2:13]1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Reactant: CN1CCC(CO)CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CN1CCC(COc2ccc([N+](=O)[O-])cc2)CC1
Temperature: 70 °C
Reaction time: 3 h
Yield: 83.1 %

Procedure:
A mixture of 1-chloro-4-nitrobenzene (23) (2.37 g, 15.0 mmol), alcohol 22 (1.94 g, 15.0 mmol), and DMSO (25 mL) was treated portionwise with NaH (60% in mineral oil, 660 mg, 16.5 mmol) at 40° C. The mixture was stirred at 70° C. for 3 h, poured into water (150 mL), and extracted with Et2O (5×100 mL). The combined organic fractions were washed with water (250 mL) and brine (250 mL), dried (MgSO4), and the solvent was removed in vacuo. The resulting solid was recrystallized from Et2O to give 24 (3.12 g, 83%) as yellow needles. 1H NMR (300 MHz, CDCl3): δ=1.36-1.56 (m, 2 H, 3-Hax, 5-Hax), 1.75-1.91 (m, 3 H, 3-Heq, 4-H, 5-Heq), 1.98 (dt, J=11.9, 1.9 Hz, 2 H, 2-Hax, 6-Hax), 2.30 (s, 3 H, NMe), 2.85-2.98 (m, 2 H, 2-Heq, 6-Heq), 3.90 (d, J=5.8 Hz, 2 H, OCH2), 6.94 (mc, 2 H, 2′-H, 6′-H), 8.19 (mc, 2 H, 3′-H, 5′-H) ppm. —13C NMR (50.3 MHz, CDCl3): δ=28.9 (C-3, C-5), 35.1 (C-4), 46.4 (NMe), 55.3 (C-2, C-6), 73.3 (OCH2), 114.3 (C-2′, C-6′), 125.8 (C-3′, C-5′), 141.3 (C-4′), 164.1 (C-1′) ppm. −MS (70 eV, EI): m/z (%)=250 (79) [M]+, 249 (100) [M−H]+. —C13H18N2O3 (250.29): calcd. C, 62.38; H, 7.25; found C, 62.25; H, 7.40.
Reaction SMILES: C(OC([NH:8][CH:9]([C:21]([N:23]1[CH2:28][CH2:27][CH:26]([CH3:29])[CH2:25][CH2:24]1)=[O:22])[CH2:10][CH2:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=1)[C:15]([OH:17])=[O:16])=O)(C)(C)C.C(OC([N:37]1[C:45]2[CH:44]=[CH:43][CH:42]=[C:41]([S:46]([OH:48])=[O:47])[C:40]=2[CH:39]=[CH:38]1)=O)(C)(C)C.[Li]>>[NH:37]1[C:45]2[C:40](=[C:41]([S:46]([NH:8][CH:9]([C:21]([N:23]3[CH2:24][CH2:25][CH:26]([CH3:29])[CH2:27][CH2:28]3)=[O:22])[CH2:10][CH2:11][C:12]3[CH:13]=[C:14]([CH:18]=[CH:19][CH:20]=3)[C:15]([OH:17])=[O:16])(=[O:48])=[O:47])[CH:42]=[CH:43][CH:44]=2)[CH:39]=[CH:38]1
Reactant: CC(C)(C)OC(=O)n1ccc2c(S(=O)O)cccc21
Reactant: CC1CCN(C(=O)C(CCc2cccc(C(=O)O)c2)NC(=O)OC(C)(C)C)CC1
Agent: [Li]
Product: CC1CCN(C(=O)C(CCc2cccc(C(=O)O)c2)NS(=O)(=O)c2cccc3[nH]ccc23)CC1

Procedure:
Example 84 is prepared from 3-[3-tert-butoxycarbonylamino-4-(4-methyl-piperidin-1-yl)-4-oxo-butyl]-benzoic acid and lithum 1-(tert-butoxycarbonyl)-1H-indole-4-sulfinic acid in the same manner as Example 71. ESI MS Calc. 483.2; Found. 484.8 (M+H)+.
Reaction SMILES: [H-].[Na+].[O:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH:4]1[O:9][CH2:10][CH2:11][OH:12].[Cl:13][C:14]1[CH:15]=[C:16]([NH:21][C:22]2[C:31]3[C:26](=[CH:27][C:28](F)=[C:29]([N+:32]([O-:34])=[O:33])[CH:30]=3)[N:25]=[CH:24][N:23]=2)[CH:17]=[CH:18][C:19]=1[F:20]>O1CCCC1>[Cl:13][C:14]1[CH:15]=[C:16]([NH:21][C:22]2[C:31]3[C:26](=[CH:27][C:28]([O:12][CH2:11][CH2:10][O:9][CH:4]4[CH2:5][CH2:6][CH2:7][CH2:8][O:3]4)=[C:29]([N+:32]([O-:34])=[O:33])[CH:30]=3)[N:25]=[CH:24][N:23]=2)[CH:17]=[CH:18][C:19]=1[F:20]
Reactant: OCCOC1CCCCO1
Reactant: O=[N+]([O-])c1cc2c(Nc3ccc(F)c(Cl)c3)ncnc2cc1F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cc2c(Nc3ccc(F)c(Cl)c3)ncnc2cc1OCCOC1CCCCO1
Temperature: 35 °C
Reaction time: 0.25 h

Procedure:
3.64 g of sodium hydride (60%) are added batchwise to 13.00 g of 2-(tetrahydropyran-2-yloxy)-ethanol in 250 ml of tetrahydrofuran while cooling with an ice bath. Then the reaction mixture is heated to about 30-40° C. in a water bath and stirred for 15 minutes. It is then cooled again in the ice bath and combined with 15.60 g of 4-[(3-chloro-4-fluoro-phenyl)amino]-7-fluoro-6-nitro-quinazoline in 50 ml of tetrahydrofuran. The reaction mixture immediately turns dark red. After 10 minutes the ice bath is removed and the reaction mixture is stirred for one hour at ambient temperature. Then a total of 1.00 g of sodium hydride is added and stirring is continued for a further 1.5 hours at 50° C. until the reaction is complete. For working up about 200 ml of tetrahydrofuran are distilled off using a rotary evaporator. The residue is added to 1 litre of ice-water and neutralised with citric acid. The aqueous phase is extracted thoroughly with ethyl acetate. The combined organic phases are washed with 250 ml of semi-saturated sodium chloride solution, dried over magnesium sulphate and evaporated down. A yellow precipitate is formed, which is suction filtered and dried in the desiccator. The mother liquor is again evaporated down. The solid yellowish flask residue is triturated with tert.butyl methyl ether, suction filtered and also dried in the desiccator.
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[C:5]([C:7]2[N:8]([CH3:12])[N:9]=[CH:10][N:11]=2)[S:4][C:3]=1[C:13]1[N:17]2[N:18]=[C:19]([CH3:22])[CH:20]=[CH:21][C:16]2=[N:15][C:14]=1[CH3:23].[Li+].CC([N-]C(C)C)C.CCCCCCC.[CH2:39]1[CH2:43][O:42][CH2:41][CH2:40]1.C(C1C=CC=CC=1)C>C1COCC1.ClCCl>[Cl:1][C:2]1[CH:6]=[C:5]([C:7]2[N:8]([CH3:12])[N:9]=[CH:10][N:11]=2)[S:4][C:3]=1[C:13]1[N:17]2[N:18]=[C:19]([CH3:22])[CH:20]=[C:21]([C:41](=[O:42])[CH2:40][CH2:39][CH3:43])[C:16]2=[N:15][C:14]=1[CH3:23]
Reactant: C1CCOC1
Reactant: Cc1ccc2nc(C)c(-c3sc(-c4ncnn4C)cc3Cl)n2n1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCCCCCC
Solvent: ClCCl
Solvent: CCc1ccccc1
Product: CCCC(=O)c1cc(C)nn2c(-c3sc(-c4ncnn4C)cc3Cl)c(C)nc12
Temperature: 25 °C
Yield: 46.6 %

Procedure:
A solution of 3-[3-chloro-5-(2-methyl-2H-[1,2,4]triazol-3-yl)-thiophen-2-yl]-2,6-dimethyl-imidazo[1,2-b]pyridazine (0.20 g, 0.58 mmol), N-methoxy-N-methyl-butylamide (Wolberg, M. et. al. Chem. Europ. J. 2001, 7, 4562) (0.084 g, 0.64 mmol) in THF (3 mL) is cooled to a −78° C., and a 2.0 M solution of LDA in heptane/THF/ethyl benzene (0.58 mL, 1.16 mmol) is added. The solution is warmed to ambient temperature, diluted with dichloromethane (20 mL), and washed with a sat. NH4Cl solution (15 mL). The organic layer is dried over MgSO4, filtered and concentrated. The residue is purified by ISCO flash chromatography (20%-100% EtOAc gradient) to furnish the title compound (0.11 g, 0.27 mmol, 46%). 1H-NMR (CDCl3), δ 1.04 (t, J=7.0 Hz, 3H), 1.76-1.86 (m, 2H), 2.56 (s, 3H), 2.59 (s, 3H), 3.51 (t, J=7.1 Hz, 2H), 4.15 (s, 3H), 7.36 (s, 1H), 7.49 (s, 1H), 7.90 (s, 1H) ppm. LC/MS (m/z): calcd. for C19H19ClN6OS (M+H)+: 415.1; found: 415.3.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])[CH3:2].I[CH2:20][CH2:21][CH3:22]>O1CCOCC1>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([N:13]2[CH2:14][CH2:15][N:16]([CH2:20][CH2:21][CH3:22])[CH2:17][CH2:18]2)[CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])[CH3:2]
Reactant: CCOc1cc(N2CCNCC2)ccc1[N+](=O)[O-]
Reactant: CCCI
Solvent: C1COCCO1
Product: CCCN1CCN(c2ccc([N+](=O)[O-])c(OCC)c2)CC1
Temperature: 102 °C
Yield: 89.4 %

Procedure:
To 1-[3-(ethyloxy)-4-nitrophenyl]piperazine (Example 143, step A) (0.405 g, 1.61 mmol) in 10 mL of dioxane was added, 1-iodopropane (0.55 g, 3.22 mmol). The mixture was heated to 102° C. for 1 h. The solvent was rotovaped down and the crude product was purified by flash chromatography to give the title compound of step A (0.422 g, 1.44 mmol, 90%). 1H NMR (400 MHz, CD3OD) δ ppm 7.88 (d, J=9.34 Hz, 1H), 6.53 (dd, J=9.34, 2.56 Hz, 1H), 6.49 (d, J=2.56 Hz, 1H), 4.16 (q, J=7.02 Hz, 2H), 3.42-3.48 (m, 4H), 2.64-2.70 (m, 4H), 2.40-2.48 (m, 2H), 1.54-1.64 (m, 2H), 1.42 (t, J=6.96 Hz, 3H), 0.94 (t, J=7.42 Hz, 3H).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([O:19][CH3:20])[O:7][C@H:6]1[C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([CH2:28][C:29]2[CH:34]=[CH:33][C:32]([O:35][CH2:36][CH2:37][O:38][Si](C(C)(C)C)(C)C)=[CH:31][CH:30]=2)[CH:22]=1)(=[O:3])[CH3:2].C(O)(=O)C>C1COCC1.O>[C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([O:19][CH3:20])[O:7][C@H:6]1[C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([CH2:28][C:29]2[CH:34]=[CH:33][C:32]([O:35][CH2:36][CH2:37][OH:38])=[CH:31][CH:30]=2)[CH:22]=1)(=[O:3])[CH3:2]
Reactant: CO[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ccc(OCCO[Si](C)(C)C(C)(C)C)cc3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Solvent: CC(=O)O
Solvent: O
Solvent: C1CCOC1
Product: CO[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ccc(OCCO)cc3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 70.7 %

Procedure:
To a solution (2S,3S,4R,5S,6S)-2-(3-(4-(2-(tert-butyldimethylsilyloxy)ethoxy)benzyl)-4-chlorophenyl)-6-methoxytetrahydro-2H-pyran-3,4,5-triyl triacetate (300 mg, 0.452 mmol) in THF:Water (1:1, 3.2 mL) was added acetic acid (4.8 mL) at 0° C. The reaction mixture was stirred at r.t. for 24 h. After completion of reaction, as confirmed by TLC, the reaction mixture was evaporated in vacuo and the residue obtained was purified by column chromatography (silica gel, 1:1 Ethyl acetate:Pet. Ether) to afford title compound (176 mg, 80%).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([NH2:10])=[O:9].[C:14]1(=[O:24])[NH:18][C:17](=[O:19])[C:16]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:15]12.[K]>CN(C)C=O>[C:8]([C:7]1[CH:6]=[C:5]([CH2:4][CH2:3][CH2:2][N:18]2[C:17](=[O:19])[C:16]3=[CH:20][CH:21]=[CH:22][CH:23]=[C:15]3[C:14]2=[O:24])[CH:13]=[CH:12][CH:11]=1)(=[O:9])[NH2:10]
Reactant: NC(=O)c1cccc(CCCBr)c1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Product: NC(=O)c1cccc(CCCN2C(=O)c3ccccc3C2=O)c1
Temperature: 25 °C
Yield: 97 %

Procedure:
A mixture of 14.0 g (0.057 mole) 3-(3-bromopropyl)benzamide (the product of step (d)), 11.5 g potassium phthalimide and 26.3 ml dimethylformamide was heated to reflux under argon gas for four hours. The heat source was removed and the mixture was stirred to cool to room temperature. Water (about 85 ml) was added. The resulting slurry was stirred for 20 minutes, then filtered and washed three times with about 50 ml cold water (each wash made a slurry solution in the funnel). The solids were then washed with about 20 ml cold 1:1 isopropyl alcohol: water and dried under vacuum overnight to give 17.04 g of the above-identified product.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][N:9]=[C:10]2[NH:13][C:14](=[O:23])[O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:5][CH:4]=1.[H-].[Na+].Br[CH2:29][C:30]([O:32][CH3:33])=[O:31]>CN(C=O)C>[CH2:16]([O:15][C:14]([N:13]([C:10]1[C:11]2[C:6](=[CH:5][CH:4]=[C:3]([C:2]([F:24])([F:1])[F:25])[CH:12]=2)[CH:7]=[CH:8][N:9]=1)[CH2:29][C:30]([O:32][CH3:33])=[O:31])=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: COC(=O)CBr
Reactant: O=C(Nc1nccc2ccc(C(F)(F)F)cc12)OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)CN(C(=O)OCc1ccccc1)c1nccc2ccc(C(F)(F)F)cc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of benzyl (7-(trifluoromethyl)isoquinolin-1-yl)carbamate (212 mg, 0.61 mmol), from above step F in DMF (5 mL) was cooled in an ice bath and treated with NaH (27 mg, 0.67 mmol), and the mixture was stirred for 30 min and was treated with methyl bromoacetate (64 μL, 0.67 mmol). This solution was stirred and allowed to warm to room temperature over 18 h. The reaction was quenched with saturated NH4Cl and DMF was removed under vacuum. The residue was taken in EtOAc and washed with water, sat NaCl and dried over Na2SO4. EtOAc was removed under vacuum and the residue was purified by silica column chromatography to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)[N:5]=[CH:4][C:3]=1[C:14]([NH:16][CH2:17][C:18]([OH:26])([CH2:23][NH:24][CH3:25])[C:19]([F:22])([F:21])[F:20])=[O:15].[F:27][C:28]1[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[C:29]=1[C:30](O)=[O:31]>>[NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[CH:9][C:10]([F:13])=[CH:11][CH:12]=2)[N:5]=[CH:4][C:3]=1[C:14]([NH:16][CH2:17][C:18]([CH2:23][N:24]([C:30]([C:29]1[C:28]([F:27])=[CH:36][CH:35]=[CH:34][C:33]=1[F:37])=[O:31])[CH3:25])([OH:26])[C:19]([F:22])([F:21])[F:20])=[O:15]
Reactant: O=C(O)c1c(F)cccc1F
Reactant: CNCC(O)(CNC(=O)c1cnn(-c2ccc(F)cc2)c1N)C(F)(F)F
Product: CN(CC(O)(CNC(=O)c1cnn(-c2ccc(F)cc2)c1N)C(F)(F)F)C(=O)c1c(F)cccc1F

Procedure:
Similarly prepared to Example 6 from 5-amino-1-(4-fluorophenyl)-N-{3,3,3-trifluoro-2-hydroxy-2-[(methylamino)methyl]propyl}-1H-pyrazole-4-carboxamide and 2,6-difluorobenzoic acid.