Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:12])=[C:6]([C:8](=O)[CH2:9][F:10])[CH:7]=1.[CH3:13][C:14]([S@:17]([NH2:19])=[O:18])([CH3:16])[CH3:15].O.CCOC(C)=O>O1CCCC1.[O-]CC.[Ti+4].[O-]CC.[O-]CC.[O-]CC>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:12])=[C:6](/[C:8](=[N:19]/[S@@:17]([C:14]([CH3:16])([CH3:15])[CH3:13])=[O:18])/[CH2:9][F:10])[CH:7]=1
Reactant: CC(C)(C)[S@](N)=O
Reactant: O=C(CF)c1cc(Br)ccc1F
Agent: [Ti+4]
Agent: CC[O-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)[S@@](=O)/N=C(\CF)c1cc(Br)ccc1F
Reaction time: 18 h
Yield: 84.9 %

Procedure:
Titanium (IV) ethoxide (4.05 mL, 19.6 mmol) was added via syringe to a solution of 1-(5-bromo-2-fluorophenyl)-2-fluoroethanone (2.3 g, 9.79 mmol) and (R)-(+)-2-methyl-2-propanesulfinamide (2.37 g, 19.57 mmol) in tetrahydrofuran (20 ml) at RT. The reaction was stirred for 18 hours and then the reaction was slowly poured into a vigorously stirred water/EtOAc mixture. After stirring 15 minutes, the mixture was filtered through a Celite pad, which was rinsed with ethyl acetate, and the phases were separated. The aqueous layer was extracted with ethyl acetate; the combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by silica-gel chromatography, eluting with 10% EtOAc in hexanes, to provide the title compound (2.81 g, 8.31 mmol, 85% yield) as a yellow oil. LC/MS (ESI+) m/z=338, 340 (M+H; 2 bromine isotopes).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:13][CH2:12][CH2:11][CH:10]1[C:14]([OH:16])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)CCl.[CH3:21][C:22]1(C)OC(=O)CC(=O)[O:23]1.OS([O-])(=O)=O.[Na+]>C(Cl)Cl.CN(C1C=CN=CC=1)C.CCOC(C)=O>[O:23]=[C:22]1[N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH:9]2[CH2:13][CH2:12][CH2:11][CH:10]2[C:14](=[O:16])[CH2:21]1
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: CC(C)(C)OC(=O)NC1CCCC1C(=O)O
Agent: CN(C)c1ccncc1
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1C(=O)CC(=O)C2CCCC21
Temperature: 25 °C
Reaction time: 18 h
Yield: 93.1 %

Procedure:
To a stirred solution of 2-[(tert-butoxycarbonyl)amino]cyclopentanecarboxylic acid (0.24 g, 1.06 mmol) in DCM (4.5 mL) was added EDC (0.31 g, 1.59 mmol), DMAP (0.19 g, 1.59 mmol) and Meldrum's acid (0.15 g, 1.06 mmol). After stirring for 18 h at r.t., the reaction mixture was poured into aqueous 1M NaHSO4 solution (5 mL) and extracted with DCM (3×20 mL). The combined organics were dried over MgSO4, filtered and concentrated in vacuo to give a clear yellow oil which was dissolved in EtOAc (5 mL) and heated to 80° C. for 18 h. The reaction mixture was then cooled and concentrated in vacuo to give the title compound (0.25 g, 42%) as a yellow solid that was used without further purification. δH (CDCl3) 4.64-4.55 (1H, m), 2.98-2.92 (1H, m), 2.37-2.20 (2H, m), 1.99-1.60 (6H, m), 1.58 (9H, s). LCMS (ES+) 198.0 ((M−tBu)+H)+.
Reaction SMILES: [CH:1]1([Mg]Br)[CH2:3][CH2:2]1.[Cl:6][C:7]1[CH:8]=[CH:9][C:10]([C:31]([O:33]C)=O)=[C:11]2[C:15]=1[N:14]=[C:13]1[N:16]([C:20]3[C:21]([O:29][CH3:30])=[N:22][C:23]([CH3:28])=[N:24][C:25]=3[O:26][CH3:27])[CH2:17][CH2:18][CH2:19][N:12]21.O1[CH2:39][CH2:38][CH2:37]C1>>[Cl:6][C:7]1[C:15]2[N:14]=[C:13]3[N:16]([C:20]4[C:25]([O:26][CH3:27])=[N:24][C:23]([CH3:28])=[N:22][C:21]=4[O:29][CH3:30])[CH2:17][CH2:18][CH2:19][N:12]3[C:11]=2[C:10]([C:31]([CH:37]2[CH2:38][CH2:39]2)([CH:1]2[CH2:3][CH2:2]2)[OH:33])=[CH:9][CH:8]=1
Reactant: C1CCOC1
Reactant: Br[Mg]C1CC1
Reactant: COC(=O)c1ccc(Cl)c2nc3n(c12)CCCN3c1c(OC)nc(C)nc1OC
Product: COc1nc(C)nc(OC)c1N1CCCn2c1nc1c(Cl)ccc(C(O)(C3CC3)C3CC3)c12
Temperature: 50 °C
Reaction time: 11 h
Yield: 55 %

Procedure:
Cyclopropylmagnesium bromide (1.0 M solution in tetrahydrofuran, 1.9 mL, 1.9 mmol) was added to a stirred solution of methyl 9-chloro-1-(4,6-dimethoxy-2-methylpyrimidin-5-yl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole-6-carboxylate (159 mg, 0.381 mmol) in tetrahydrofuran (3.8 mL), and the mixture was stirred at 50° C. for 11 hr. The reaction was quenched by aqueous saturated ammonium chloride, and the mixture was extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 15-50% ethyl acetate/n-hexane gradient mixture. The filtrate was concentrated in vacuo to give the solid, which was recrystallized from ethanol/ethyl acetate to give the title compound as a colorless crystal (98.6 mg, 0.210 mmol, 55%).
Reaction SMILES: C(C1C(I)=C[C:6]([C:7]([O:9][CH3:10])=O)=C(C)C=1)#N.[C:15]([C:17]1[C:26]([OH:27])=[CH:25][C:20]([C:21]([O:23]C)=[O:22])=[C:19]([CH3:28])[CH:18]=1)#[N:16].C1([OH:35])C=CC=CC=1.COCCBr>>[NH2:16][C:15]([C:17]1[C:26]([O:27][CH2:6][CH2:7][O:9][CH3:10])=[CH:25][C:20]([C:21]([OH:23])=[O:22])=[C:19]([CH3:28])[CH:18]=1)=[O:35]
Reactant: COC(=O)c1cc(O)c(C#N)cc1C
Reactant: COC(=O)c1cc(I)c(C#N)cc1C
Reactant: Oc1ccccc1
Agent: COCCBr
Product: COCCOc1cc(C(=O)O)c(C)cc1C(N)=O

Procedure:
Synthesized according to the method of reagent preparation 41 by replacement of step 6 with the conversion of methyl 4-cyano-5-iodo-2-methylbenzoate to methyl 4-cyano-5-hydroxy-2-methylbenzoate according to the method described in Chemical & Pharmaceutical Bulletin (2007), 55(9), 1361-1364 followed by phenol alkylation with 2-bromoethyl methyl ether then proceeding with steps 7 and 8. MS (EI) for C12H15NO5: 254 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:17]3[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[CH:19][CH:18]=3)=[N:10][NH:11][C:12]=2[C:13]([F:16])([F:15])[F:14])=[CH:4][CH:3]=1.[CH2:27](Br)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C(OCC)(=O)C.CCCCCC>[CH2:27]([N:11]1[C:12]([C:13]([F:16])([F:14])[F:15])=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[C:9]([C:17]2[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:24])=[O:25])=[CH:19][CH:18]=2)=[N:10]1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CS(=O)(=O)c1ccc(-c2n[nH]c(C(F)(F)F)c2-c2ccc(F)cc2)cc1
Reactant: BrCc1ccccc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CS(=O)(=O)c1ccc(-c2nn(Cc3ccccc3)c(C(F)(F)F)c2-c2ccc(F)cc2)cc1
Temperature: 140 °C
Reaction time: 1 h
Yield: 48.6 %

Procedure:
A mixture of 0.10 g of 4-(4-fluorophenyl)-3-[4-(methylsulfonyl)phenyl]-5-(trifluoromethyl)-1H-pyrazole (Example 1, Step 3) and 3.0 g of benzyl bromide was heated at 140° C. for 4 days then at 210° C. for 1 hour. The reaction mixture was dissolved in 10% ethyl acetate-hexane and filtered. The filtrate was concentrated in vacuo and the residue was purified by HPLC (10% ethyl acetate-hexane). The first fraction was benzyl bromide. The second fraction eluted with 30% ethyl acetate-hexane yielded 1-benzyl-4- (4-fluorophenyl)-3-[4-(methylsulfonyl)phenyl]-5-(trifluoromethyl)pyrazole (60 mg, 49%): mp 125.5°-126.5° C.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CI.[I-].[CH3:20][N+]1C=CC=CC=1.[BH4-].[Na+]>>[C:1]1([CH2:7][CH2:8][C:9]([C:11]2[CH2:12][N:13]([CH3:20])[CH2:14][CH2:15][CH:16]=2)=[O:10])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(CCc1ccccc1)c1cccnc1
Reactant: C[n+]1ccccc1
Agent: [BH4-]
Agent: [I-]
Agent: [Na+]
Solvent: CI
Product: CN1CCC=C(C(=O)CCc2ccccc2)C1

Procedure:
Employing the general methods of Examples 4 and 6 above, 10 g (47.3 mmol) of 3-phenyl-1-(3-pyridinyl)-1-propanone were first converted by the action of methyl iodide to the N-methylpyridinium iodide and then reduced by the action of sodium borohydride to produce 3-phenyl-1-(1,2,5,6-tetrahydro-1-methyl-3-pyridinyl)-1-propanone which was isolated as the hydrochloride salt (5.2 g, 58%), mp 195°-197° C. cl EXAMPLE 8
Reaction SMILES: [B-](F)(F)(F)F.[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+]([F:21])(CC2)C1.C1C=CN=CC=1.[FH:28].[C:29]1([C:35]2([C:40]3[CH:49]=[CH:48][C:43]([C:44]([O:46][CH3:47])=[O:45])=[CH:42][CH:41]=3)SCCS2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C(Cl)Cl>[F:28][C:35]([F:21])([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:40]1[CH:49]=[CH:48][C:43]([C:44]([O:46][CH3:47])=[O:45])=[CH:42][CH:41]=1
Reactant: F[N+]12CC[N+](CCl)(CC1)CC2
Reactant: COC(=O)c1ccc(C2(c3ccccc3)SCCS2)cc1
Reactant: F
Agent: *CC*
Agent: F[B-](F)(F)F
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1ccc(C(F)(F)c2ccccc2)cc1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
Selectfluor (1.07 mmol, 381 mg) and HF-pyridine reagent (1.5 mL, HF: Pyridine=70:30 wt %) were dissolved in CH2Cl2 (4 mL) in a polyethylene bottle and cooled to 0° C. A solution of 64b (0.512 mmol, 162 mg) in CH2Cl2 (2 mL) was slowly added and the mixture was stirred for 45 min at room temperature. When TLC indicated the consumption of all 64b, the reaction was diluted with CH2Cl2. The combined organics were dried over anhydrous Na2SO4 and concentrated. The crude product was purified by flash column chromatography (silica gel, 5% EtOAc/hexanes) to afford compound 64c as a clear oil.
Reaction SMILES: Br[C:2]1[C:6]2[N:7]=[CH:8][N:9]=[C:10]([Cl:11])[C:5]=2[NH:4][CH:3]=1.[Li]C(C)(C)C.[F:17][C:18]([F:38])([F:37])[C:19]([C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[N:26]([C:30]1[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=1)[N:25]=[CH:24]2)=[O:20]>C1COCC1>[Cl:11][C:10]1[C:5]2[NH:4][CH:3]=[C:2]([C:19]([C:21]3[CH:22]=[C:23]4[C:27](=[CH:28][CH:29]=3)[N:26]([C:30]3[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=3)[N:25]=[CH:24]4)([OH:20])[C:18]([F:37])([F:17])[F:38])[C:6]=2[N:7]=[CH:8][N:9]=1
Reactant: O=C(c1ccc2c(cnn2-c2ccc(F)cc2)c1)C(F)(F)F
Reactant: Clc1ncnc2c(Br)c[nH]c12
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: OC(c1ccc2c(cnn2-c2ccc(F)cc2)c1)(c1c[nH]c2c(Cl)ncnc12)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 33.1 %

Procedure:
To a chilled (−78° C.) solution of 7-bromo-4-chloro-5H-pyrrolo[3,2-d]pyrimidine (80 mg, 0.34 mmol, 1 equiv.) in 5 mL of THF was added tert-BuLi (1.7 M in pentane, 0.43 mL, 0.73 mmol, 2.1 equiv.) dropwise. After 5 minutes, a chilled (−78° C.) solution of 2,2,2-trifluoro-1-[1-(4-fluorophenyl)-1H-indazol-5-yl]ethanone (106 mg, 0.34 mmol, 1 equiv.) in 1 mL of THF was added in one portion. After 15 minutes, the reaction was quenched with 15 mL of water, warmed to room temperature, diluted with 100 mL of saturated aqueous ammonium chloride, and then extracted with EtOAc. The combined organic layers were dried, filtered, and concentrated in vacuo. The residue was dissolved in DMF and purified by reverse phase HPLC (5-95% CH3CN/water+0.1% TFA). The major fractions collected were made basic with saturated NaHCO3 and the CH3CN was concentrated in vacuo. The aqueous was extracted with EtOAc and washed with brine. The organic layers were dried, filtered, and concentrated in vacuo to provide 52 mg (32%) of the title compound as a white solid. MS m/z 462.56 (MH+).
Reaction SMILES: [C:1]1([C:7]2[N:12]=[CH:11][C:10]([C:13]3[N:14]=[C:15]([CH:18]4[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]4)[NH:16][CH:17]=3)=[CH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:25]1[N+:30]([O-])=[N:29][CH:28]=[CH:27][CH:26]=1>CS(C)=O.O>[C:1]1([C:7]2[N:12]=[CH:11][C:10]([C:13]3[N:14]=[C:15]([CH:18]4[CH2:23][CH2:22][N:21]([C:28]5[N:29]=[N:30][CH:25]=[CH:26][CH:27]=5)[CH2:20][CH2:19]4)[NH:16][CH:17]=3)=[CH:9][N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: [O-][n+]1ncccc1Cl
Reactant: c1ccc(-c2ncc(-c3c[nH]c(C4CCNCC4)n3)cn2)cc1
Solvent: CS(C)=O
Solvent: O
Product: c1ccc(-c2ncc(-c3c[nH]c(C4CCN(c5cccnn5)CC4)n3)cn2)cc1

Procedure:
The title compound is prepared in a similar manner described above using Buchwald-Hartwig amination conditions or as described in PCT International Application 2006/058338, 1 Jun. 2006. In this case, a solution consisting of 2-phenyl-5-(2-(piperidin-4-yl)-1H-imidazol-4-yl)pyrimidine and 6-chloropyridazine 1-oxide (preparation of this reagent can be found in PCT International Application 2007/106670, 20 Sep. 2007 and Chemical and Pharmaceutical Bulletin, 1963, 11, 261-263) in dimethylsulfoxide is heated at 80° C. for 18 hours. The reaction mixture is cooled, diluted with water and the organic material is extracted with ethyl acetate. The organic phase is washed with brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue is chromatographed on silica to afford the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[H-].[Na+].[H][H].[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CN(C=O)C.O>[CH2:21]([O:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:6][C:5]3[CH:15]=[CH:16][CH:2]=[CH:3][CH:4]=3)=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: [H][H]
Reactant: O=C(c1ccc(O)cc1)c1ccc(O)cc1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(c1ccc(OCc2ccccc2)cc1)c1ccc(OCc2ccccc2)cc1
Temperature: 100 °C
Reaction time: 1 h
Yield: 193.7 %

Procedure:
To a solution of 4,4′-dihydroxybenzophenone (5.0 g, 23.34 mmol) in anhydrous DMF (150 mL) at 0° C. was added sodium hydride (60% in mineral oil, 2.1 g, 51.35 mmol), in two portions. After stirring for 20 min at which no more evolution of hydrogen was observed, benzyl bromide (8.96 g, 51.35 mmol) was added. The resulting yellow suspension was then stirred under an atmosphere of nitrogen at 100° C. for 1 h. Upon cooling to room temperature, water (500 mL) was added to the suspension and the precipitate that formed was filtered and washed exhaustively with water. After air-drying overnight at room temperature, the white solid (10.1 g) that collected was recrystallised from hot toluene to give LWO02007A as white flaky plate crystals (8.92 g, 22.61 mmol, 96.9%); m.p. 188-190° C.
Reaction SMILES: [NH2:1][C:2]1[C:11]([OH:12])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[C:13](OC(=O)C)(=[O:15])[CH3:14].[CH:20]([O:23]C(C)C)(C)[CH3:21]>N1C=CC=CC=1>[C:13]([NH:1][C:2]1[C:11]([O:12][C:20](=[O:23])[CH3:21])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5])(=[O:15])[CH3:14]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)OC(C)C
Reactant: COC(=O)c1cccc(O)c1N
Solvent: c1ccncc1
Product: COC(=O)c1cccc(OC(C)=O)c1NC(C)=O
Temperature: 20 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 2-amino-3-hydroxybenzoate (882 mg) in pyridine (2 ml) was added acetic anhydride (1.2 ml) and the mixture was stirred at 20° C. for 8 hours. The reaction mixture was diluted with diisopropyl ether, and the resulting solid was collected and washed with diisopropyl ether. The solid was triturated with diisopropyl ether to give methyl 2-acetamido-3-acetoxybenzoate (1.25 g) as solid.
Reaction SMILES: [CH2:1]([N:3]1[C:7]([C:8]2[S:18][C:11]3[N:12]=[CH:13][N:14]=[C:15]([S:16][CH3:17])[C:10]=3[CH:9]=2)=[C:6]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:5]=[CH:4]1)[CH3:2].[CH:25]1(N)CC1>>[CH:1]1([N:3]2[C:7]([C:8]3[S:18][C:11]4[N:12]=[CH:13][N:14]=[C:15]([S:16][CH3:17])[C:10]=4[CH:9]=3)=[C:6]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:5]=[CH:4]2)[CH2:25][CH2:2]1
Reactant: CCn1cnc(-c2ccccc2)c1-c1cc2c(SC)ncnc2s1
Reactant: NC1CC1
Product: CSc1ncnc2sc(-c3c(-c4ccccc4)ncn3C3CC3)cc12

Procedure:
The title compound was prepared by a similar process to that described for Intermediate 70 but using cyclopropylamine in place of ethylamine. Solid (25 mg, 14%) (contains 30% of 1-cyclopropyl-4,5-phenyl-1H-imidazole);
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[CH:12]=[CH:11][C:7]2[O:8][CH2:9][O:10][C:6]=2[CH:5]=1.NC(N)=[S:15].[OH-].[Na+]>C(O)C.O>[O:8]1[C:7]2[CH:11]=[CH:12][C:4]([CH2:3][CH2:2][SH:15])=[CH:5][C:6]=2[O:10][CH2:9]1
Reactant: BrCCc1ccc2c(c1)OCO2
Reactant: NC(N)=S
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: SCCc1ccc2c(c1)OCO2
Yield: 95.5 %

Procedure:
750 g of 5-(2-bromoethyl)-1,3-benzodioxole was dissolved in 1 l of ethanol. 312 g of thiourea was added to the solution and the mixture was heated under reflux on a boiling water bath for 2 h. The reaction mixture was cooled and a solution of 300 g of sodium hydroxide in 1 l of water was added thereto. The resulting mixture was heated under reflux on a boiling water bath for 45 min. After cooling, 3 l of water was added thereto. After extraction with 5 l of ethyl acetate, the extract was washed with dilute hydrochloric acid and then with water until the washing became almost neutral. After drying over anhydrous sodium sulfate followed by distillation of the solvent at 40° C., about 570 g of a faint yellow oil was obtained. This product was purified according to column chromatography (hexane/benzene=2:1) with about 3 kg of silica gel to obtain 310 g of the intended compound in the form of a colorless oil.
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[C:5]([O:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[NH2:18])[CH:6]=[CH:7][CH:8]=2)[NH:3]1.[OH-].[Na+:20].[O:21]1CCOCC1>O>[NH2:3][C:4]1[C:5]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[NH2:18])=[CH:6][CH:7]=[CH:8][C:9]=1[CH2:10][C:2]([O-:21])=[O:1].[Na+:20]
Reactant: Nc1ccccc1Oc1cccc2c1NC(=O)C2
Reactant: C1COCCO1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Nc1ccccc1Oc1cccc(CC(=O)[O-])c1N

Procedure:
A mixture of 2-oxo-7-(2-aminophenoxy)indoline (3.5 g.), sodium hydroxide (1.2 g.), dioxane (10 ml.) and water (50 ml.) was refluxed under heating for 48 hours with stirring. After cooling, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was dissolved in ethanol under warming and filtered. The filtrate was concentrated under reduced pressure, and the residue was crystallized with a mixture of ethanol and ethyl acetate to give the captioned compound (3 g.). mp 103° to 110° C.
Reaction SMILES: [C:1]([O:9][CH2:10][C@H:11]1[O:16][CH:15]=[CH:14][C@@H:13]([OH:17])[C@@H:12]1[OH:18])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:19](OC=C)(=[O:21])[CH3:20]>>[C:19]([O:17][C@H:13]1[C@H:12]([OH:18])[C@@H:11]([CH2:10][O:9][C:1](=[O:8])[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[O:16][CH:15]=[CH:14]1)(=[O:21])[CH3:20]
Reactant: O=C(OC[C@H]1OC=C[C@@H](O)[C@@H]1O)c1ccccc1
Reactant: C=COC(C)=O
Product: CC(=O)O[C@@H]1C=CO[C@H](COC(=O)c2ccccc2)[C@H]1O
Temperature: 25 °C
Reaction time: 5 h
Yield: 88 %

Procedure:
1.0 g (4 mmol) of 6-O-benzoylglucal is taken up in 10-20 ml of vinyl acetate and stirred with 1 g of lipase (Pseudomonas spec.) at room temperature for 5 h. Filtering off the enzyme and crystallization or chromatography on silica gel (ethyl acetate/hexane 1:1) yields 3-O-acetyl-6-O-benzoylglucal in 88-94% yield (1.03-1.10 g).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2[S:10][C:9]([CH2:11]N3CC4(CCN(C)CC4)C3)=[CH:8][C:6]=2[N:7]=1.[NH:28]1[CH2:33][CH2:32][CH:31]([N:34]2[CH2:37][CH2:36][C:35]2=[O:38])[CH2:30][CH2:29]1>>[Cl:1][C:2]1[N:3]=[C:4]([N:22]2[CH2:23][CH2:24][O:25][CH2:26][CH2:27]2)[C:5]2[S:10][C:9]([CH2:11][N:28]3[CH2:33][CH2:32][CH:31]([N:34]4[CH2:37][CH2:36][C:35]4=[O:38])[CH2:30][CH2:29]3)=[CH:8][C:6]=2[N:7]=1
Reactant: O=C1CCN1C1CCNCC1
Reactant: CN1CCC2(CC1)CN(Cc1cc3nc(Cl)nc(N4CCOCC4)c3s1)C2
Product: O=C1CCN1C1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1

Procedure:
Prepared according to the method used in the preparation of 2-chloro-6-(7-methyl-2,7-diaza-spiro[3.5]non-2-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine using 1-piperidin-4-yl-azetidin-2-one in place of 7-methyl-2,7-diaza-spiro[3.5]nonane. The title compound was obtained as a pale yellow solid (205 mg, 81%).
Reaction SMILES: CS(OS(C)(=O)=O)(=O)=O.[CH3:10][O:11][C:12]1[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=1[CH2:14]O.C(N(C(C)C)CC)(C)C.[CH3:29][O:30][C:31](=[O:54])[C@H:32]([CH2:41][C:42]1[N:46]=[CH:45][N:44](C(OC(C)(C)C)=O)[CH:43]=1)[NH:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>ClCCl>[CH3:29][O:30][C:31](=[O:54])[C@H:32]([CH2:41][C:42]1[N:46]([CH2:14][C:13]2[CH:16]=[CH:17][CH:18]=[CH:19][C:12]=2[O:11][CH3:10])[CH:45]=[N:44][CH:43]=1)[NH:33][C:34]([O:36][C:37]([CH3:40])([CH3:38])[CH3:39])=[O:35]
Reactant: COC(=O)[C@H](Cc1cn(C(=O)OC(C)(C)C)cn1)NC(=O)OC(C)(C)C
Reactant: COc1ccccc1CO
Agent: CS(=O)(=O)OS(C)(=O)=O
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@H](Cc1cncn1Cc1ccccc1OC)NC(=O)OC(C)(C)C
Temperature: 0 °C

Procedure:
A solution of 8 g methanesulfonic anhydride in 45 mL dichloromethane is chilled to -50° C. and treated dropwise with a solution of 6.2 mL 2-methoxybenzyl alcohol, 8.0 mL diisopropylethylamine and 45 mL dichloromethane. The resulting solution is warmed to 0° C. over 30 min and treated dropwise with 15.0 g N,1-bis-BOC-histidine methyl ester dissolved in 45 mL dichloromethane. The mixture is then heated at reflux 24 hr, poured into 400 mL 0.25M, pH=7 potassium phosphate buffer and the organic layer is separated, dried and evaporated. Chromatography on silica gel, eluting with chloroform-methanol (99:1) gives 3-(2-methoxyphenyl)methyl-N-BOC-histidine methyl ester as a gum. NMR (CDCl3) 4.96 (s, 2H, NCH2Ar).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[CH:10]([OH:12])=O.O.[C:14]1(C)C=CC=CC=1>>[CH3:14][CH:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[N:1]([CH:10]=[O:12])[CH2:2]1
Reactant: Cc1ccccc1
Reactant: O=CO
Reactant: c1ccc2c(c1)CCN2
Solvent: O
Product: CC1CN(C=O)c2ccccc21
Temperature: 25 °C

Procedure:
Indoline (23.3 g, 175 mmol) with formic acid (11.5 ml, 305 mmol) was refluxed in toluene (250 mL) with a Dean-Stark trap to collect the formed water. After 1 h of reflux, 6 mL of water was tapped off and the reaction mixture was cooled to RT, some greenish solid was formed in the mixture. Water (250 mL) was added and the organic layer was washed with another portion of water (250 mL) and with brine (250 mL), dried over Na2SO4, filtered and evaporated to dryness. Yield: 22.5 g (80% of a yellow oil, identified as 3 by 1H-NMR. This crude material was crystallized from 2-propanol, the formed crystals were collected by filtration and washed with 2-propanol. Yield: 3.0 g (11%). The mother liquor was evaporated to dryness and the residue was purified by column chromatography (Silica, EtOAc: heptanes=1:3→1:1). Yield: 15.5 g (55%) of a yellowish oil that crystallized upon standing. The two portions were combined and used as such in the next step.
Reaction SMILES: Cl[C:2]1[C:3](=[O:15])[N:4](C2CCCCO2)[N:5]=[CH:6][C:7]=1Cl.[F:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:18]=1[OH:24].C[O:26][C:27](=[O:37])[CH:28](Br)[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[F:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:18]=1[O:24][C:7]1[CH:6]=[N:5][N:4]([CH:28]([CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:27]([OH:26])=[O:37])[C:3](=[O:15])[CH:2]=1
Reactant: COC(=O)C(Br)Cc1ccccc1
Reactant: O=c1c(Cl)c(Cl)cnn1C1CCCCO1
Reactant: Oc1c(F)cccc1F
Product: O=C(O)C(Cc1ccccc1)n1ncc(Oc2c(F)cccc2F)cc1=O

Procedure:
In an analogous manner to the stepwise sequence outlined in intermediate 19, starting from 4,5-dichloro-2-(tetrahydropyran-2-yl)-2H-pyridazin-3-one (Intermediate 20) and 2,6-difluoro-phenol and alkylating with 2-bromo-3-phenyl-propionic acid methyl ester (Intermediate 13) afforded 2-[4-(2,6-difluoro-phenoxy)-6-oxo-6H-pyridazin-1-yl]-3-phenyl-propionic acid as a white solid (555.8 mg, 96% for the final step); ES+-HRMS m/e calcd for C19H14N2O4F2 [M+H+] 373.0995, found 373.0994. 1H NMR (400 MHz, DMSO-d6) δ ppm 3.28-3.37 (m, 1H), 3.44 (dd, J=14.3, 4.7 Hz, 1H), 5.64 (dd, J=11.1, 4.7 Hz, 1H), 5.96 (d, J=2.7 Hz, 1H), 7.09-7.25 (m, 5H), 7.30-7.41 (m, 2H), 7.41-7.52 (m, 1H), 8.19 (d, J=2.7 Hz, 1H), 13.24 (br s, 1H).