Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:5][C@H:6]([C:8]([N:10]1[CH2:17][CH2:16][CH2:15][C@H:11]1[C:12]([OH:14])=[O:13])=[O:9])[CH3:7])([CH3:4])([CH3:3])[CH3:2].C(OC(N[C@H](C(O)=O)C)=O)C1C=CC=CC=1.C(N1CCC[C@H]1C(O)=O)(C)(C)C.C1(N=C=NC2CCCCC2)CCCCC1.[C:61]([NH:69][CH:70]([S:74][C:75](=[O:82])[C:76]1[CH:81]=[CH:80][CH:79]=[CH:78][CH:77]=1)[C:71](O)=[O:72])(=[O:68])[C:62]1[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=1>C(#N)C.O1CCCC1>[C:1]([N:5]([C:71](=[O:72])[CH:70]([S:74][C:75](=[O:82])[C:76]1[CH:77]=[CH:78][CH:79]=[CH:80][CH:81]=1)[NH:69][C:61](=[O:68])[C:62]1[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=1)[C@H:6]([C:8]([N:10]1[CH2:17][CH2:16][CH2:15][C@H:11]1[C:12]([OH:14])=[O:13])=[O:9])[CH3:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[C@H](NC(C)(C)C)C(=O)N1CCC[C@H]1C(=O)O
Reactant: O=C(NC(SC(=O)c1ccccc1)C(=O)O)c1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CC(C)(C)N1CCC[C@H]1C(=O)O
Agent: C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Solvent: C1CCOC1
Solvent: CC#N
Product: C[C@@H](C(=O)N1CCC[C@H]1C(=O)O)N(C(=O)C(NC(=O)c1ccccc1)SC(=O)c1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.9 %

Procedure:
12.1 g (50 millimoles) of tert.-butyl alanylproline (prepared by coupling benzyloxycarbonylalanine with tert.-butyl proline using dicyclohexylcarbodiimide, followed by hydrogenolytic elimination of the protective group) were dissolved in 150 ml of dry acetonitrile, a solution of 15.8 g (50 millimoles) of N-benzoyl-α-(benzoylthio)-glycine in 150 ml of dry tetrahydrofuran and 10.3 g (50 millimoles) of dicyclohexylcarbodiimide were added and the mixture was stirred overnight at room temperature. The precipitated dicyclohexylurea was filtered off under suction, and the filtrate was evaporated down under reduced pressure. The residue was chromatographed with 1:1 cyclohexane/ethyl acetate over a column containing deactivated silica gel. 20.2 g (75%) of tert.-butyl N-[N-benzoyl-α-(benzoylthio)glycyl]-alanylproline were obtained as a diastereomer mixture. Crystallization from cyclohexane/ethyl acetate gave 7.5 g of a low-melting isomer of melting point 97°-100° C.; 7.8 g of a high-melting isomer of melting point 147°-150° C. were obtained from the mother liquor after crystallizing the product twice from cyclohexane/ethyl acetate. Cleavage of the two isomers separately, using 6 N HCl/dioxane in a procedure similar to that described in Example 1b, gave N-[N-benzoyl-α-(benzoylthio)-glycyl]-alanylproline as diastereomer I (obtained in crystalline form from ethyl acetate, melting point 185°-188° C., Rf=0.18 in system I, [α]D20 =+29° (c=1 in chloroform)) and diastereomer II (obtained in crystalline form from ethyl acetate, melting point 203°-206° C., Rf=0.18 in system I, [α]D20 =-167° (c=1 in chloroform)).
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[CH2:23][CH2:22][C@:12]34[C:13]5[C:14]6[O:21][C@H:11]3[CH:10]([CH:24]3[O:28][CH2:27][CH2:26][O:25]3)[CH2:9][CH2:8][C@@:7]4([OH:29])[C@H:6]2[CH2:19][C:18]=5[CH:17]=[CH:16][C:15]=6[OH:20])[CH2:3][CH2:2]1.N1C=CN=C1.[CH:35]([Si:38]([CH:43]([CH3:45])[CH3:44])([CH:40]([CH3:42])[CH3:41])Cl)([CH3:37])[CH3:36].O>C(Cl)Cl>[CH:35]([Si:38]([CH:43]([CH3:45])[CH3:44])([CH:40]([CH3:42])[CH3:41])[O:20][C:15]1[CH:16]=[CH:17][C:18]2[CH2:19][C@H:6]3[N:5]([CH2:4][CH:1]4[CH2:2][CH2:3]4)[CH2:23][CH2:22][C@:12]45[C:13]=2[C:14]=1[O:21][C@H:11]4[CH:10]([CH:24]1[O:25][CH2:26][CH2:27][O:28]1)[CH2:9][CH2:8][C@@:7]35[OH:29])([CH3:37])[CH3:36]
Reactant: Oc1ccc2c3c1O[C@H]1C(C4OCCO4)CC[C@@]4(O)[C@@H](C2)N(CC2CC2)CC[C@]314
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Agent: c1c[nH]cn1
Solvent: O
Solvent: ClCCl
Product: CC(C)[Si](Oc1ccc2c3c1O[C@H]1C(C4OCCO4)CC[C@@]4(O)[C@@H](C2)N(CC2CC2)CC[C@]314)(C(C)C)C(C)C

Procedure:
17-(cyclopropylmethyl)-4,5a-epoxy-3,14-dihydroxy-6-(1,3-dioxolan-2-yl)morphinan (3.85 g, 10 mmol) was dissolved in 20 ml of methylene chloride, then imidazole (0.68 g, 10 mmol) and triisopropylchlorosilane (1.92 g, 10 mmol) were added with stirring. The whole system was refluxed to react for 4 hours. After the reaction was complete, water was added for extraction and then extracted with methylene chloride for 3 times. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated for crystallization to afford a white solid.
Reaction SMILES: [CH3:1][C:2]1[N:7]2[C:8](=[O:15])[C:9]([C:12]([OH:14])=O)=[CH:10][N:11]=[C:6]2[CH:5]=[CH:4][CH:3]=1.[CH2:16]([N:18](CC)[CH2:19][CH3:20])[CH3:17].ClC(OC)=O.N1CCCC1>C(Cl)(Cl)Cl>[CH3:1][C:2]1[N:7]2[C:8](=[O:15])[C:9]([C:12]([N:18]3[CH2:19][CH2:20][CH2:17][CH2:16]3)=[O:14])=[CH:10][N:11]=[C:6]2[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cccc2ncc(C(=O)O)c(=O)n12
Reactant: CCN(CC)CC
Agent: COC(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: C1CCNC1
Product: Cc1cccc2ncc(C(=O)N3CCCC3)c(=O)n12
Reaction time: 0.33 h
Yield: 32.3 %

Procedure:
A mixture containing 20.4 g (0.1 mol) of 6-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxylic acid and 15.5 ml (0.11 mol) of triethylamine in 600 ml of chloroform is cooled below -10° C. by ice-salt. A solution of 10 ml (0.1 mol) of methyl chloroformate dissolved in 50 ml of chloroform is dropped to the above mixture at -10° C. during 30 to 35 minutes. After stirring for 20 minutes, 9 g (0.11 mol) of pyrrolidine dissolved in 100 ml of chloroform are dropped to the above solution at a temperature between -5° C. and -8° C. during 1 hour. The reaction mixture is stirred at the same temperature for 1 hour, then allowed to stand overnight under cooling by ice. For working up, the reaction mixture is washed 3 times with 400 ml of 5% sodium hydrogen carbonate solution each, then 3 times with 400 ml of water each. The organic phase is dried over anhydrous sodium sulfate, filtered and evaporated. After suspending the oily residue in petroleum ether, 8.3 g (32.3%) of the named compound are obtained, which forms yellow crystals after recrystallization from ethanol, m.p.: 132°-134° C.
Reaction SMILES: [NH:1]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17][O:16][CH2:15][CH2:14][O:13][CH2:12][CH2:11][O:10][CH2:9][CH2:8][O:7][CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[C:22](Cl)(=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24]>>[C:23]([C:22]([N:1]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17][O:16][CH2:15][CH2:14][O:13][CH2:12][CH2:11][O:10][CH2:9][CH2:8][O:7][CH2:6][CH2:5][O:4][CH2:3][CH2:2]1)=[O:27])([CH3:26])([CH3:25])[CH3:24]
Reactant: C1COCCOCCOCCOCCOCCOCCN1
Reactant: CC(C)(C)C(=O)Cl
Product: CC(C)(C)C(=O)N1CCOCCOCCOCCOCCOCCOCC1

Procedure:
Analogously to Example 14 from 1 -aza-4,7,10,13,16,19-hexaoxacycloheneicosane and pivalyl chloride.
Reaction SMILES: [Li]CCCC.[Cl:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14](C(C3N(C)C(C)=NC=3)O)[CH:15]=2)[N:10]=[C:9]([O:26][CH3:27])[C:8]=1[CH2:28][C:29]1[CH:30]=[N:31][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:33][CH:34]=1.[CH3:39][C:40]1[N:47]=[C:46]([CH3:48])[CH:45]=[CH:44][C:41]=1[CH:42]=[O:43]>C1COCC1>[Cl:6][C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([CH:42]([C:41]3[C:40]([CH3:39])=[N:47][C:46]([CH3:48])=[CH:45][CH:44]=3)[OH:43])[CH:15]=2)[N:10]=[C:9]([O:26][CH3:27])[C:8]=1[CH2:28][C:29]1[CH:30]=[N:31][C:32]([C:35]([F:36])([F:38])[F:37])=[CH:33][CH:34]=1
Reactant: Cc1ccc(C=O)c(C)n1
Reactant: COc1nc2ccc(C(O)c3cnc(C)n3C)cc2c(Cl)c1Cc1ccc(C(F)(F)F)nc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1nc2ccc(C(O)c3ccc(C)nc3C)cc2c(Cl)c1Cc1ccc(C(F)(F)F)nc1
Temperature: 25 °C
Reaction time: 0.03 h

Procedure:
A solution of n-BuLi (2.5 M in hexanes, 1.6 mL, 4.0 mmol) was added dropwise by syringe to a solution of 6-bromo-4-chloro-2-methoxy-3-((6-(trifluoromethyl)pyridin-3-yl)methyl)quinoline (1.711 g, 3.964 mmol, Intermediate 45: step d) in dry THF (20 mL) in a dry ice-acetone bath. After 1-2 minutes, a solution of 2,6-dimethylnicotinaldehyde (0.8 mL, 6.3 mmol) in dry THF (6 mL) was added dropwise. The reaction was stirred for 5 minutes, then was removed from the cold bath and allowed to warm to room temperature. The reaction was quenched with saturated aqueous ammonium chloride. The mixture was partitioned between water and dichloromethane. The separated aqueous phase was further extracted with dichloromethane. The organic phase was dried (Na2SO4), filtered, and concentrated. The crude product was purified by flash column chromatography (silica gel, 0-3% MeOH-DCM) to provide the title compound.
Reaction SMILES: [N:1]1([C:6]2[CH2:10][O:9][C:8](=[O:11])[CH:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C([Li])(C)(C)C.[Cl:17][CH2:18][C:19]([CH2:21]Cl)=[CH2:20].CO>O1CCCC1.CCCCC>[Cl:17][CH2:18][C:19](=[CH2:20])[CH2:21][CH:10]1[O:9][C:8](=[O:11])[CH:7]=[C:6]1[N:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C1C=C(N2CCCC2)CO1
Reactant: C=C(CCl)CCl
Agent: [Li]C(C)(C)C
Solvent: CCCCC
Solvent: CO
Solvent: C1CCOC1
Product: C=C(CCl)CC1OC(=O)C=C1N1CCCC1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
800 mg (5.22 mmol) of 4-pyrrolidin-1-ylfuran-2(5H)-one (Shandala, M. Y. et al. J. Heterocycl. Chem. 1984, 21, 1753-1754) are dissolved in 80 ml of tetrahydrofuran and cooled to −78° C., and 3.07 ml (5.22 mmol) of a 1.7M solution of tert-butyllithium in pentane are added. After 30 min of stirring at −78° C., 1.21 ml (10.45 mmol) of 3-chloro-2-(chloromethyl)prop-1-ene are added and the mixture is stirred at −78° C. for a further 30 minutes, warmed to room temperature over a period of about 16 hours and stirred at room temperature for a further 3 hours. After addition of methanol and concentration under reduced pressure, the residue is purified by column chromatography on silica gel (silica gel 60, Merck, particle size: 0.04 to 0.063 mm) using the mobile phase ethyl acetate. This gives 735 mg (57% of theory) of 5-[2-(chloromethyl)prop-2-en-1-yl]-4-pyrrolidin-1-ylfuran-2(5H)-one.
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].BrCC1OC(C(F)(F)F)=CC=1.[NH:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]2([C:39]3[C:30](=[CH:31][C:32]4[O:37][CH2:36][CH2:35][O:34][C:33]=4[CH:38]=3)[O:29][CH2:28]2)[C:20]1=[O:40].CC1C2C=C3C4(C5C(=CC=CC=5)NC4=O)COC3=CC=2ON=1>>[O:40]=[C:20]1[C:21]2([C:39]3[C:30](=[CH:31][C:32]4[O:37][CH2:36][CH2:35][O:34][C:33]=4[CH:38]=3)[O:29][CH2:28]2)[C:22]2[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:19]1[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCCO3
Reactant: CCOC(=O)CBr
Agent: Cc1noc2cc3c(cc12)C1(CO3)C(=O)Nc2ccccc21
Agent: FC(F)(F)c1ccc(CBr)o1
Product: CCOC(=O)CN1C(=O)C2(COc3cc4c(cc32)OCCO4)c2ccccc21

Procedure:
Following the procedure as described in EXAMPLE 9 and making non-critical variations using ethyl bromoacetate to replace 2-(bromomethyl)-5-(trifluoromethyl)furan, and 2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one to replace 3-methylspiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-2′(1′H)-one, ethyl (2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)acetate was obtained (90%): mp 58-59° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, CDCl3) δ 7.29-7.23 (m, 1H), 7.18-7.15 (m, 1H), 7.08-7.02 (m, 1H), 6.77-6.74 (m, 1H), 6.47 (s, 1H), 6.34 (s, 1H), 4.89-4.39 (m, 4H), 4.25-4.15 (m, 4H), 4.11-4.08 (m, 2H), 1.26 (t, J=9.0 Hz, 3H); MS (ES+) m/z 381.8 (M+1).
Reaction SMILES: [N:1]1(C(OC(C)(C)C)=O)[CH2:6][CH2:5][CH:4]([C:7]([O:9][CH2:10][N:11]2[CH:16]=[C:15]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)[C:14](=[O:24])[C:13]([C:25](=[O:56])[NH:26][C:27]3[CH:32]=[CH:31][C:30]([O:33][C:34]4[CH:39]=[CH:38][N:37]=[C:36]([NH:40][CH:41]([C:48]5[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=5)[C:42]5[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=5)[C:35]=4[Cl:54])=[C:29]([F:55])[CH:28]=3)=[CH:12]2)=[O:8])[CH2:3][CH2:2]1.Cl>C(Cl)Cl>[NH:1]1[CH2:6][CH2:5][CH:4]([C:7]([O:9][CH2:10][N:11]2[CH:16]=[C:15]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)[C:14](=[O:24])[C:13]([C:25](=[O:56])[NH:26][C:27]3[CH:32]=[CH:31][C:30]([O:33][C:34]4[CH:39]=[CH:38][N:37]=[C:36]([NH:40][CH:41]([C:48]5[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=5)[C:42]5[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=5)[C:35]=4[Cl:54])=[C:29]([F:55])[CH:28]=3)=[CH:12]2)=[O:8])[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)OCn2cc(C(=O)Nc3ccc(Oc4ccnc(NC(c5ccccc5)c5ccccc5)c4Cl)c(F)c3)c(=O)c(-c3ccc(F)cc3)c2)CC1
Agent: Cl
Solvent: ClCCl
Product: O=C(Nc1ccc(Oc2ccnc(NC(c3ccccc3)c3ccccc3)c2Cl)c(F)c1)c1cn(COC(=O)C2CCNCC2)cc(-c2ccc(F)cc2)c1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 107.1 %

Procedure:
To a solution of 4-(3-(4-(2-(benzhydrylamino)-3-chloropyridin-4-yloxy)-3-fluorophenylcarbamoyl)-5-(4-fluorophenyl)-4-oxopyridin-1(4H)-yl)methyl 1-tert-butyl piperidine-1,4-dicarboxylate (135 mg, 0.154 mmol) in DCM (5 mL) at rt, was added HCl (4 N in dioxane, 1 mL). The reaction mixture was stirred at rt for 3 h. The solvents were removed in vacuo and the resulting residue was purified by preparative -HPLC to give the desired product (128 mg) as a white solid. MS (ESI+) m/z 776 (M+H)+.
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]=[O:11])[C:5]=12.[N+:12]([O-:15])(O)=[O:13].[C:16]([O-])([O-])=O.[Na+].[Na+]>S(=O)(=O)(O)O>[CH3:16][C:2]1[N:1]=[C:5]2[C:6]([CH:10]=[O:11])=[CH:7][CH:8]=[CH:9][N:4]2[C:3]=1[N+:12]([O-:15])=[O:13]
Reactant: O=Cc1cccn2ccnc12
Reactant: O=C([O-])[O-]
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: Cc1nc2c(C=O)cccn2c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3 h
Yield: 90 %

Procedure:
To a cooled solution of 4a (149 mg, 0.93 mmol) in concentrated sulfuric acid (4 mL), was added nitric acid (155 μl, d=1.38). After being stirred for 3 h at room temperature, the solution is crushed on ice (10g), made basic by the addition of aqueous saturated Na2CO3 solution (45 mL) and extracted with CH2Cl2. The organic layers were dried (MgSO4), filtered and evaporated to dryness to give 4m (171 mg, 90%); mp 182-184° C.; IR (KBr) 1698, 1380, 1134 cm−1; 1H NMR (400 MHz, CDCl3) δ 2.95 (s, 3H), 7.40 (t, 1H, J=7 Hz), 8.21 (d, 1H, J=7 Hz), 9.66 (d, 1H, J=7 Hz), 10.83 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 17.4, 115.7, 123.4, 130.3, 130.4, 131.9, 144.3, 152.0, 187.3; MS m/z 205 (M+, 31), 177 (100), 104 (40), 78 (37), 51 (33).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C@H:13]([O:19][CH3:20])[C@@H:14]([CH3:18])[C:15]([OH:17])=[O:16])=[O:7])([CH3:4])(C)C.Cl.[CH:22]1[C:34]2C(COC(ON3C(=O)CCC3=O)=O)[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:26]=2[CH:25]=[CH:24][CH:23]=1.CO>O1CCOCC1.COCCOC>[CH:31]1[C:32]2[CH:4]([CH2:1][O:5][C:6]([N:8]3[CH2:12][CH2:11][CH2:10][C@H:9]3[C@H:13]([O:19][CH3:20])[C@@H:14]([CH3:18])[C:15]([OH:17])=[O:16])=[O:7])[C:34]3[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:27]=2[CH:28]=[CH:29][CH:30]=1
Reactant: O=C(OCC1c2ccccc2-c2ccccc21)ON1C(=O)CCC1=O
Reactant: CO[C@H]([C@@H](C)C(=O)O)[C@@H]1CCCN1C(=O)OC(C)(C)C
Agent: Cl
Solvent: COCCOC
Solvent: C1COCCO1
Solvent: CO
Product: CO[C@H]([C@@H](C)C(=O)O)[C@@H]1CCCN1C(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirring solution of #11 (2.4 g, 8.4 mmol, 1.0 eq.) in 10 mL of dioxane under nitrogen, 4M HCl in dioxane (20 mL, 80 mM, 10 eq.) was added. The reaction was allowed to stir at room temperature for 3 hours before being concentrated in vacuo and placed underneath high vacuum. Crude material was then dissolved with 30 mL of 10% Na2CO3. This solution was then added to a stirring solution of 1-{[(9H-fluoren-9-ylmethoxy)carbonyl]oxy}pyrrolidine-2,5-dione (2.96 g, 8.77 mmol, 1.05 eq.) in 30 mL of DME. Reaction was allowed to stir at room temperature until TLC (20% methanol/40% ethyl acetate/40% heptanes) indicated the consumption of Boc de-protected starting material. The reaction was concentrated in vacuo to a smaller volume, washed twice with ether, acidified to pH 2 using concentrated HCl and then extracted three times with a solution of 90% dichloromethane 10% methanol. The organics where washed with saturated sodium bicarbonate and brine before being dried over sodium sulfate, filtered, and concentrated in vacuo to a brown solid #119 (3.4 g, quant.). LC-MS (Protocol Q): m/z 410.0 [M+H+], retention time=1.81 minutes.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@H:4]([C:14]([O:16][CH3:17])=[O:15])[CH2:3]1.N1C=CN=C1.[Si:23](Cl)([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24]>CN(C=O)C.CCOC(C)=O>[Si:23]([O:1][C@@H:2]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:11])([CH3:12])[CH3:13])=[O:8])[C@H:4]([C:14]([O:16][CH3:17])=[O:15])[CH2:3]1)([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24]
Reactant: COC(=O)[C@@H]1C[C@H](O)CN1C(=O)OC(C)(C)C
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)[C@@H]1C[C@H](O[Si](C)(C)C(C)(C)C)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 96 h
Yield: 95.7 %

Procedure:
A mixture of (2S,4S)-1-tert-butyl 2-methyl 4-hydroxypyrrolidine-1,2-dicarboxylate (10 g, 40.7 mmol), imidazole (5.54 g, 81.4 mmol) and t-butyldimethylsilyl chloride (6.6 g, 45 mmol) in DMF (50 ml) was stirred and r.t. for 4 days. The mixture was diluted with EtOAc and washed with H2O and sat. NH4Cl. The organic layer was dried over MgSO4 and concentrated. 14 g of an oil product was obtained and used without further purification.
Reaction SMILES: [C:1]1([C:7]2[C:11](=[O:12])[N:10]([C:13]3[CH:14]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:16]=[CH:17][CH:18]=3)[NH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:29](I)[CH3:30]>C(O)C>[CH2:29]([N:9]1[CH:8]=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:11](=[O:12])[N:10]1[C:13]1[CH:14]=[C:15]([C:19]([F:21])([F:22])[F:20])[CH:16]=[CH:17][CH:18]=1)[CH3:30]
Reactant: O=c1c(-c2ccccc2)c[nH]n1-c1cccc(C(F)(F)F)c1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCn1cc(-c2ccccc2)c(=O)n1-c1cccc(C(F)(F)F)c1

Procedure:
A mixture of 2.2 grams of the pyrazolinone prepared above, 2 grams potassium carbonate, 25 ml. ethyl iodide and 25 ml. ethanol was refluxed for about 3 hours. The reaction mixture was worked up in the usual manner to yield an oil which was identified by NMR analysis as the desired product.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:23])[C:5]([CH3:22])=[C:6]([CH2:12][C:13]2[CH:21]=[CH:20][C:16]([C:17]([OH:19])=[O:18])=[CH:15][CH:14]=2)[C:7](=O)[C:8]=1[O:9][CH3:10].[C:24](=O)([O-])[O-].[K+].[K+].Cl.[CH3:31][OH:32]>O>[CH3:31][O:32][C:7]1[C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[C:4]([O:23][CH3:24])=[C:5]([CH3:22])[C:6]=1[CH2:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([OH:19])=[O:18])=[CH:15][CH:14]=1
Reactant: O=C([O-])[O-]
Reactant: CO
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(C(=O)O)cc2)=C(C)C1=O
Agent: Cl
Agent: [K+]
Solvent: O
Product: COc1c(C)c(Cc2ccc(C(=O)O)cc2)c(OC)c(OC)c1OC
Temperature: 70 °C
Reaction time: 3 h
Yield: 76 %

Procedure:
The compound (160 mg, 0.45 mmol) obtained in Step 3 was dissolved in a mixture of an aqueous solution of potassium carbonate (91 mg, 0.66 mmol) in water (1 ml) and methanol (2 ml) and the mixture was stirred at 70° C. for 3 hours. The reaction mixture was acidified by adding concentrated hydrochloric acid and then was extracted with diethylether. The extract was washed with water, dried, and then the solvent was distilled off to yield the title compound (116 mg, 0.34 mmol, yield 76%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH:9]([S:20]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH2:30][CH3:31])=[CH:25][CH:24]=1)(=[O:22])=[O:21])[C:10]1[C:11]([CH3:19])=[CH:12][C:13]([C:16]([OH:18])=O)=[N:14][CH:15]=1.[NH2:32][CH2:33][CH2:34][OH:35].ON1C2C=CC=CC=2N=N1.CN1CCOCC1.Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH:9]([S:20]([C:23]1[CH:24]=[CH:25][C:26]([O:29][CH2:30][CH3:31])=[CH:27][CH:28]=1)(=[O:21])=[O:22])[C:10]1[C:11]([CH3:19])=[CH:12][C:13]([C:16]([NH:32][CH2:33][CH2:34][OH:35])=[O:18])=[N:14][CH:15]=1
Reactant: CCOc1ccc(S(=O)(=O)C(c2cnc(C(=O)O)cc2C)c2cc(F)ccc2F)cc1
Reactant: NCCO
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CCOc1ccc(S(=O)(=O)C(c2cnc(C(=O)NCCO)cc2C)c2cc(F)ccc2F)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 5-[(2,5-difluorophenyl)[(4-ethoxyphenyl)sulfonyl]methyl]-4-methylpyridine-2-carboxylic acid (112 mg, 0.25 mmol) in methylene chloride (3 ml), 2-aminoethanol (0.017 ml, 0.28 mmol), 1-hydroxybenzotriazole (37 mg, 0.28 mmol), 4-methylmorpholine (0.030 ml, 0.28 mmol), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (53 mg, 0.28 mmol) were added at room temperature. After stirring for 3 hours at room temperature, the reaction mixture was washed with water and then saturated brine. The organic layer was dried over anhydrous sodium sulfate and filtered, then the filtrate was concentrated under reduced pressure, and the obtained residue was subjected to flash silica gel chromatography. The fraction obtained from an elution with hexane:ethyl acetate=1:2 was concentrated under reduced pressure, and the resulting residue was washed with a mixed solvent of ethanol and diethyl ether, and was collected by filtration to obtain the title compound mg, 0.20 mmol, 79%) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[CH:16][CH:17]=[C:18]3[C:23]=2[NH:22][C:21](=[O:24])[CH2:20][CH2:19]3)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:25]C(C)([O-])C.[K+].CI>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[CH:15]=[CH:16][CH:17]=[C:18]3[C:23]=2[N:22]([CH3:25])[C:21](=[O:24])[CH2:20][CH2:19]3)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc3c2NC(=O)CC3)CC1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CI
Product: CN1C(=O)CCc2cccc(N3CCN(C(=O)OC(C)(C)C)CC3)c21
Reaction time: 0.25 h

Procedure:
A second intermediate compound, 1-Methyl-8-piperazin-1-yl-3,4-dihydro-1H-quinolin-2-one hydrochloride, was produced as follows: To a solution of 4-(2-oxo-1,2,3,4-tetrahydro-quinolin-8-yl)-piperazine-1-carboxylic acid tert-butyl ester (2.5 g, 7.54 mmol) in THF (45 mL) cooled to −50° C. was added a solution of potassium t-butoxide, 1M in THF (8.3 mL, 8.30 mmol). After stirring for 15 minutes, methyl iodide (0.47 mL, 7.54 mmol) was added followed by stirring for 16 hours at 25° C. The mixture was evaporated and the residue was taken up into dichloromethane. The solution was washed consecutively with 1N citric acid, saturated sodium bicarbonate and brine. The organic phase was dried over sodium sulfate, filtered and evaporated to give a white foam, which was purified by chromatography on silica gel eluting with a gradient of dichloromethane and ethyl acetate. Evaporation of the appropriate fractions gave 4-(1-methyl-2-oxo-1,2,3,4-tetrahydro-quinolin-8-yl)-piperazine-1-carboxylic acid tert-butyl ester (2.1 g).
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[CH2:3][NH:4][C:5]([NH:7][C:8]1[CH:9]=[C:10]([C:14]2[N:18]3[N:19]=[CH:20][C:21]([C:23]4[CH:24]=[N:25][N:26]([CH:28]([CH3:32])[C:29]([OH:31])=O)[CH:27]=4)=[CH:22][C:17]3=[N:16][CH:15]=2)[CH:11]=[CH:12][CH:13]=1)=[O:6].[CH3:35][NH2:36]>>[CH3:35][NH:36][C:29](=[O:31])[CH:28]([N:26]1[CH:27]=[C:23]([C:21]2[CH:20]=[N:19][N:18]3[C:14]([C:10]4[CH:11]=[CH:12][CH:13]=[C:8]([NH:7][C:5]([NH:4][CH2:3][C:2]([F:1])([F:34])[F:33])=[O:6])[CH:9]=4)=[CH:15][N:16]=[C:17]3[CH:22]=2)[CH:24]=[N:25]1)[CH3:32]
Reactant: CC(C(=O)O)n1cc(-c2cnn3c(-c4cccc(NC(=O)NCC(F)(F)F)c4)cnc3c2)cn1
Reactant: CN
Product: CNC(=O)C(C)n1cc(-c2cnn3c(-c4cccc(NC(=O)NCC(F)(F)F)c4)cnc3c2)cn1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 54, Step 3 starting from 2-(4-{3-[3-({[(2,2,2-trifluoro ethyl)amino]carbonyl}amino)phenyl]imidazo[1,2-b]pyridazin-7-yl}-1H-pyrazol-1-yl)propanoic acid (prepared from the procedure for Example 54, step 2) and methylamine (2.0 N in THF). LCMS (M+H)+: m/z=487.2.