Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:21]3[C:20]4[CH:19]=[C:18]([O:22][CH:23]([C:35]5[S:36][CH:37]=[CH:38][CH:39]=5)[CH2:24][NH:25]C(=O)OCC[Si](C)(C)C)[C:17]([O:40][CH3:41])=[CH:16][C:15]=4[N:14]=[CH:13][C:12]=3[N:11]([CH3:42])[C:10]2=[O:43])=[C:5]([F:44])[CH:4]=1)#[N:2].[F-].[Cs+]>CS(C)=O>[NH2:25][CH2:24][CH:23]([C:35]1[S:36][CH:37]=[CH:38][CH:39]=1)[O:22][C:18]1[C:17]([O:40][CH3:41])=[CH:16][C:15]2[N:14]=[CH:13][C:12]3[N:11]([CH3:42])[C:10](=[O:43])[N:9]([C:6]4[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][C:5]=4[F:44])[C:21]=3[C:20]=2[CH:19]=1
Reactant: COc1cc2ncc3c(c2cc1OC(CNC(=O)OCC[Si](C)(C)C)c1cccs1)n(-c1ccc(C#N)cc1F)c(=O)n3C
Agent: [Cs+]
Agent: [F-]
Solvent: CS(C)=O
Product: COc1cc2ncc3c(c2cc1OC(CN)c1cccs1)n(-c1ccc(C#N)cc1F)c(=O)n3C
Temperature: 25 °C
Reaction time: 8 h
Yield: 45.1 %

Procedure:
2-Trimethylsilanylethyl {2-[1-(4-cyano-2-fluorophenyl)-7-methoxy-3-methyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-8-yloxy]-2-thiophen-2-ylethyl}carbamate (239 mg, 377 μmol) was dissolved in dimethyl sulfoxide (40 ml) under a dry nitrogen atmosphere. CsF (1.15 g, 7.60 mmol) was subsequently added, and the reaction mixture was stirred at room temperature for 18 h overnight. For work-up, the mixture was decanted off into water (300 ml), and saturated NaHCO3 solution (25 ml) was added. The aqueous phase was extracted three times with ethyl acetate (100 ml each time). The combined organic phases were washed with saturated sodium chloride solution (50 ml), dried over Na2SO4 and filtered. After evaporation of the filtrate, the residue was purified by preparative HPLC (water/1-50% by vol. of acetonitrile in 15 min, flow rate 50 ml/min), giving 4-[8-(2-amino-1-thiophen-2-ylethoxy)-7-methoxy-3-methyl-2-oxo-2,3-dihydroimidazo[4,5-c]quinolin-1-yl]-3-fluorobenzonitrile (83 mg, 170 μmol) as lyophilisate after freeze-drying of the product fractions. MS: 490.1 (M+H+), TLC (HPTLC): Rf=0.50 (methanol/iPr2EtN 99:1, parts by volume).
Reaction SMILES: [Na+:1].Br[CH2:3][C:4]([NH:6][C@@H:7]1[C:14](=[O:15])[N:13]2[C@@H:8]1[S:9][CH2:10][C:11](/[CH:19]=[C:20]1/[C:21](=[O:28])[N:22]([CH:25]3[CH2:27][CH2:26]3)[CH2:23][CH2:24]/1)=[C:12]2[C:16]([O-:18])=[O:17])=[O:5].[Na].[SH:30][C:31]1[NH:32][C:33]2[CH:39]=[CH:38][CH:37]=[CH:36][C:34]=2[N:35]=1>CN(C)C=O>[Na+:1].[NH:32]1[C:33]2[CH:39]=[CH:38][CH:37]=[CH:36][C:34]=2[N:35]=[C:31]1[S:30][CH2:3][C:4]([NH:6][C@@H:7]1[C:14](=[O:15])[N:13]2[C@@H:8]1[S:9][CH2:10][C:11](/[CH:19]=[C:20]1/[C:21](=[O:28])[N:22]([CH:25]3[CH2:27][CH2:26]3)[CH2:23][CH2:24]/1)=[C:12]2[C:16]([O-:18])=[O:17])=[O:5]
Reactant: Sc1nc2ccccc2[nH]1
Reactant: O=C(CBr)N[C@@H]1C(=O)N2C(C(=O)[O-])=C(/C=C3\CCN(C4CC4)C3=O)CS[C@H]12
Agent: [Na+]
Agent: [Na]
Solvent: CN(C)C=O
Product: O=C(CSc1nc2ccccc2[nH]1)N[C@@H]1C(=O)N2C(C(=O)[O-])=C(/C=C3\CCN(C4CC4)C3=O)CS[C@H]12

Procedure:
(E)-(6R,7R)-7-(2-bromo-acetylamino)-3-(1-cyclopropyl-2-oxo-pyrrolidin-3-ylidenemethyl)-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid sodium salt (1:1) (see ex. C4a) (200 mg, 0.42 mmol) was dissolved in 4 ml N,N-dimethylformamide and 2-mercaptobenzimidazole sodium salt (79.2 mg, 0.46 mmol) was added in a single portion. After completion of the reaction, the solvent was stripped off at a rotary evaporator. The residue was dissolved in water and chromatographed on MCI gel (75-150μ, Mitsubishi Kasei Corporation) with a gradient of water:acetonitril (10:1, 9:1). The organic solvent was evaporated and the aqueous phase was freeze-dried.
Reaction SMILES: [CH3:1][N:2]([CH3:17])[C:3]1[CH:4]=[C:5]([C:9]2([OH:16])[CH2:14][CH2:13][C:12](=O)[CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1.[NH:18]1[CH2:21][CH:20]([NH:22][C:23]([CH2:25][NH:26][C:27](=[O:38])[C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:36])[F:35])[CH:29]=2)=[O:24])[CH2:19]1>>[CH3:1][N:2]([CH3:17])[C:3]1[CH:4]=[C:5]([C:9]2([OH:16])[CH2:14][CH2:13][CH:12]([N:18]3[CH2:21][CH:20]([NH:22][C:23]([CH2:25][NH:26][C:27](=[O:38])[C:28]4[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:35])[F:36])[CH:29]=4)=[O:24])[CH2:19]3)[CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Reactant: CN(C)c1cccc(C2(O)CCC(=O)CC2)c1
Product: CN(C)c1cccc(C2(O)CCC(N3CC(NC(=O)CNC(=O)c4cccc(C(F)(F)F)c4)C3)CC2)c1

Procedure:
The title compound was prepared as a white solid by reductive amination of 4-(3-dimethylamino-phenyl)-4-hydroxy-cyclohexanone (as prepared in the previous step) and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide (as prepared in step B of Example 4) using the procedure described in Step C of Example 4.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:14])[CH2:9][CH2:10][C:11](O)=[O:12])=[CH:4][C:3]=1[S:15](=[O:18])(=[O:17])[NH2:16].O1CCCC1.ClC(OCC)=O.[CH3:30][NH2:31]>C(N(CC)CC)C>[OH:14][C:8]1([C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[C:3]([S:15](=[O:18])(=[O:17])[NH2:16])[CH:4]=2)[N:31]([CH3:30])[C:11](=[O:12])[CH2:10][CH2:9]1
Reactant: Cc1ccc(C(=O)CCC(=O)O)cc1S(N)(=O)=O
Reactant: CN
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1ccc(C2(O)CCC(=O)N2C)cc1S(N)(=O)=O

Procedure:
9.4 g of 4-(4-methyl-3-sulfamoylphenyl)-4-oxobutanoic acid are reacted analogously to the instructions indicated in Example 1 using 64 ml of absolute tetrahydrofurane, 6.7 ml of triethylamine, 4.7 ml of ethyl chloroformate and 90 ml of 40% strength aqueous methylamine solution to yield 5-hydroxyl-1-methyl-5-(4-methyl-3-sulfamoylphenyl)-2-oxopyrrolidine.
Reaction SMILES: C(O[C:4](=[O:6])C)=O.C(O)=O.[CH3:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[C:12]=1[N:18]1[CH2:22][CH2:21][N:20]([C:23]2[C:28]([CH3:29])=[CH:27][CH:26]=[CH:25][C:24]=2[CH3:30])[C:19]1=[NH:31].C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl.C(O)(=O)C>[CH3:30][C:24]1[CH:25]=[CH:26][CH:27]=[C:28]([CH3:29])[C:23]=1[N:20]1[CH2:21][CH2:22][N:18]([C:12]2[C:11]([CH3:10])=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:17])[C:19]1=[N:31][CH:4]=[O:6]
Reactant: CC(=O)OC=O
Reactant: Cc1cccc(C)c1N1CCN(c2c(C)cccc2C)C1=N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=CO
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: Cc1cccc(C)c1N1CCN(c2c(C)cccc2C)C1=NC=O
Reaction time: 4 h

Procedure:
A solution of 7.5 g (85 mmoles) of acetyl formate (a mixed anhydride of formic acid and acetic acid) in 30 ml of dry chloroform is added dropwise, at room temperature, to a solution of 5.0 g (17.0 mmoles) of 1,3-bis(2',6'-dimethylphenyl)-2-imino-imidazolidine, prepared as described in Method (a) of Example 1, in 50 ml of dry chloroform. The resulting mixture is stirred at 45° to 50° C. for 4 hours, thereafter it is cooled with ice, and 10 ml of a 10% aqueous sodium hydrogencarbonate solution are added dropwise to the stirred mixture at a temperature not exceeding +10° C. The aqueous phase is separated, the chloroform phase is washed thrice with 50 ml of water each, dried over anhydrous sodium sulfate, filtered, and the solvent is evaporated under reduced pressure, 4.6 g (84.2%) of 1,3-bis(2',6'-dimethylphenyl)-2-formylimino-imidazolidine are obtained; the product melts at 306°-308° C. after recrystallization from methanol.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:17]=1[CH:24]([C:26]1[S:27][CH:28]=[CH:29][N:30]=1)[OH:25]>CO.C(Cl)Cl.[O-2].[O-2].[Mn+4]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:17]=1[C:24]([C:26]1[S:27][CH:28]=[CH:29][N:30]=1)=[O:25]
Reactant: COc1ccc(Oc2ccnc3cc(OC)c(OC)cc23)c(C(O)c2nccs2)c1
Agent: [Mn+4]
Agent: [O-2]
Solvent: CO
Solvent: ClCCl
Product: COc1ccc(Oc2ccnc3cc(OC)c(OC)cc23)c(C(=O)c2nccs2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.6 %

Procedure:
[2-(6,7-Dimethoxy-quinolin-4-yloxy)-5-methoxy-phenyl]-thiazol-2-yl-methanol (90 mg) was dissolved in methanol/methylene chloride (3 ml/9 ml) to prepare a solution, manganese dioxide (90 mg) was added to the solution, and the mixture was stirred at room temperature overnight. The reaction solution was filtered through Celite, water was added to the filtrate, and the mixture was extracted with ethyl acetate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by column chromatography using acetone-hexane to give the title compound (65 mg, yield 74%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.Cl[C:24](Cl)([O:26][C:27](=[O:33])OC(Cl)(Cl)Cl)Cl.[CH:35]1([CH2:41]CO)[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:27](=[O:33])[O:26][CH2:24][CH2:41][CH:35]2[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]2)=[CH:18][CH:17]=1
Reactant: OCCC1CCCCC1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2ncnc(Oc3ccc(N)cc3)c2cc1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COc1cc2ncnc(Oc3ccc(NC(=O)OCCC4CCCCC4)cc3)c2cc1OC
Yield: 63.2 %

Procedure:
4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]aniline (50 mg) was added to toluene (5 ml), and triethylamine (0.5 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (77 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, 2-cyclohexyl-1-ethanol (33 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution, water, and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (48 mg, yield 54%).
Reaction SMILES: C(OC([NH:8][C:9]1[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=1)=O)(C)(C)C.O1CC(=O)N=N1.C(OC(=O)CCNC(=O)C1C=CC(C2[NH:38][O:39][C:40](=[O:42])N=2)=CC=1)C>C(Cl)Cl.C(O)(C(F)(F)F)=O>[O:39]1[C:40](=[O:42])[N:14]=[C:13]([C:12]2[CH:11]=[CH:10][C:9]([NH2:8])=[CH:16][CH:15]=2)[NH:38]1
Reactant: CCOC(=O)CCNC(=O)c1ccc(-c2nc(=O)o[nH]2)cc1
Reactant: CC(C)(C)OC(=O)Nc1ccc(C#N)cc1
Agent: O=C1CON=N1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1ccc(-c2nc(=O)o[nH]2)cc1

Procedure:
Compound 14 (3.25 g, 14.9 mmol) was converted into oxadiazolone 15 as described earlier for the preparation of compound 3. The resulting crude light orange solid was stirred for 5 h in a mixture of DCM (15 mL) and TFA (8 mL). Concentration under reduced pressure and evaporation with toluene (2×10 mL) gave a brown solid which was purified by silica gel (40 g) column chromatography (eluent: EtOAc) to yield compound 16 (1.81 g, 69% over the three steps). Rf 0.5 (EtOAc).
Reaction SMILES: [C:1]1([CH:7]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:8][NH:9][C:10]2[N:18]=[C:17]([C:19]([O:21]CC)=[O:20])[N:16]=[C:15]3[C:11]=2[N:12]=[CH:13][NH:14]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN1CCO[CH2:33][CH2:32]1.FC(F)(F)S(O[Si](C)(C)C)(=O)=O.C(O[C@@H:53]1[O:65][C@H:64]([CH2:66][O:67][C:68](=[O:70])[CH3:69])[C@@H:59]([O:60][C:61](=[O:63])[CH3:62])[C@H:54]1[O:55][C:56](=[O:58])[CH3:57])(=O)C.C(=O)(O)[O-].[Na+]>COCCOC.C(OCC)(=O)C>[CH2:32]([C:17]1[N:16]=[C:15]2[C:11]([N:12]=[CH:13][N:14]2[C@H:53]2[C@H:54]([O:55][C:56](=[O:58])[CH3:57])[C@H:59]([O:60][C:61](=[O:63])[CH3:62])[C@@H:64]([CH2:66][O:67][C:68](=[O:70])[CH3:69])[O:65]2)=[C:10]([NH:9][CH2:8][CH:7]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:18]=1)[CH3:33].[N:18]1[CH:10]=[C:11]2[C:15]([NH:14][CH:13]=[N:12]2)=[N:16][C:17]=1[C:19]([O-:21])=[O:20]
Reactant: CC(=O)OC[C@H]1O[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: CCOC(=O)c1nc(NCC(c2ccccc2)c2ccccc2)c2nc[nH]c2n1
Reactant: CN1CCOCC1
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: CCc1nc(NCC(c2ccccc2)c2ccccc2)c2ncn([C@@H]3O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H]3OC(C)=O)c2n1
Product: O=C([O-])c1ncc2nc[nH]c2n1
Temperature: 55 °C

Procedure:
To a suspension of ethyl 6-[(2,2-diphenylethyl)amino]-9H-purine-2-carboxylate (Preparation 63) (40.0 g, 0.103 moles) in anhydrous 1,2-dimethoxyethane (240 ml) under an atmosphere of nitrogen was added 4-methylmorpholine (11.5 g, 12.5 ml, 0.114 moles) and the resultant mixture was heated to 45° C. with stirring. To this mixture was then added trimethylsilyl trifluoromethanesulphonate (27.5 g, 22.4 ml, 0.124 moles) over a period of 10 minutes. The resultant orange solution was then heated to 55° C., and a solution of 1,2,3,5-tetra-O-acetyl-β-D-ribofuranose (36.1 g, 0.113 moles) in 1,2-dimethoxyethane (100 ml plus 20 ml to rinse through) was added over a period of 10 minutes. The reaction was then stirred at 57-60° C. for 2 hours after which time the mixture was cooled to ambient temperature. The reaction mixture was then cautiously added to a mixture of saturated aqueous sodium bicarbonate solution (400 ml) and ethyl acetate (400 ml) with vigorous stirring. The layers were separated and the aqueous phase was extracted with ethyl acetate (400 ml). The combined organic phases were dried over anhydrous magnesium sulphate and were then concentrated in vacuo to give the crude product as an orange foam (74.9 g) that could be used as such for the next step. This crude product can be purified using flash chromatography on silica gel eluting with a gradient system of 10% v/v diethyl ether in dichloromethane changing to 25% v/v diethyl ether in dichloromethane to give the title compound as a colourless foam.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH:11]=O.[CH3:14][NH:15][CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[BH4-].[Na+]>CO.S(=O)(=O)(O)O>[CH3:1][O:2][C:3](=[O:13])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][N:15]([CH3:14])[CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CNCCc1ccccc1
Reactant: COC(=O)CCCCCCCC=O
Agent: O=S(=O)(O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)CCCCCCCCN(C)CCc1ccccc1

Procedure:
To a solution of 9-oxononanoic acid methyl ester (J. Org. Chem. 2007, 72, 9471; 303 mg, 1.63 mmol) and N-methyl-2-phenylethylamine (220 mg, 1.63 mmol) in methanol (10 mL) was added concentrated sulfuric acid (5 drops) at room temperature, then after 40 h the solution was heated at reflux for 2 h. After cooling sodium borohydride (123 mg, 3.25 mmol) was added, then after 1 h the reaction mixture was partitioned between water and dichloromethane. The organic layer was dried over sodium sulfate, filtered, and evaporated to afford 9-(methyl-phenethyl-amino)-nonanoic acid methyl ester as a light yellow liquid.
Reaction SMILES: [NH2:1][CH2:2][C:3]1([NH2:8])[CH2:7][CH2:6][CH2:5][CH2:4]1.[NH2:9][C:10]1[C:11]([C:18]([NH:20][C:21](=N)SC)=[O:19])=[N:12][C:13]([Cl:17])=[C:14]([NH2:16])[N:15]=1>CC(O)C>[NH:8]1[C:3]2([CH2:7][CH2:6][CH2:5][CH2:4]2)[CH2:2][NH:1]/[C:21]/1=[N:20]/[C:18]([C:11]1[C:10]([NH2:9])=[N:15][C:14]([NH2:16])=[C:13]([Cl:17])[N:12]=1)=[O:19]
Reactant: CSC(=N)NC(=O)c1nc(Cl)c(N)nc1N
Reactant: NCC1(N)CCCC1
Solvent: CC(C)O
Product: Nc1nc(N)c(C(=O)/N=C2/NCC3(CCCC3)N2)nc1Cl
Temperature: 70 °C

Procedure:
A solution of crude 1-aminomethyl-cyclopentylamine (Intermediate J) (80 mg, 0.70 mmol) in propan-2-ol (1.0 ml) is added to a suspension of 1-(3,5-diamino-6-chloro-pyrazine-2-carbonyl)-2-methyl-isothiourea (Intermediate A) (208 mg, 0.54 mmol) in propan-2-ol (1.08 ml) and heated at 70° C. for 2 days. After cooling to room temperature, the reaction mixture is filtered under vacuum, and the solid is rinsed with MeOH. The filtrate is concentrated in vacuo to afford a bright yellow residue which is loaded onto a SCX-2 cartridge and eluted with 33% NH3 (4 drops) in MeOH (5 ml×2). The methanolic ammonia fractions are combined and concentrated in vacuo. Purification using mass directed preparative LCMS eluting with 95% Water+0.1% NH3: 5% Acetonitrile to affords the title compound; [M+H]+ 310.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[C:6]([O:19][CH2:20][C:21]3[C:26]([F:27])=[CH:25][CH:24]=[CH:23][C:22]=3[F:28])[C:7]3[N:8]([C:10]([C:14]([O:16]CC)=[O:15])=[C:11]([CH3:13])[N:12]=3)[CH:9]=2)[CH2:3][CH2:2]1.[OH-].[Li+].Cl>O1CCCC1.CO>[CH:1]1([C:4]2[CH:5]=[C:6]([O:19][CH2:20][C:21]3[C:26]([F:27])=[CH:25][CH:24]=[CH:23][C:22]=3[F:28])[C:7]3[N:8]([C:10]([C:14]([OH:16])=[O:15])=[C:11]([CH3:13])[N:12]=3)[CH:9]=2)[CH2:2][CH2:3]1
Reactant: CCOC(=O)c1c(C)nc2c(OCc3c(F)cccc3F)cc(C3CC3)cn12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1nc2c(OCc3c(F)cccc3F)cc(C3CC3)cn2c1C(=O)O
Temperature: 40 °C
Reaction time: 4 h

Procedure:
470 mg of ethyl 6-cyclopropyl-8-[(2,6-difluorobenzyl)oxy]-2-methylimidazo[1,2-a]pyridine-3-carboxylate (Example 41A) were initially charged in 36 ml of tetrahydrofuran/methanol 5:1, and 6.1 ml of 1N aqueous lithium hydroxide solution were added. The mixture was stirred at 40° C. for 4 h and then acidified with 6 N hydrochloric acid and concentrated. The residue was taken up in water and repeatedly extracted with dichloromethane. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried with magnesium sulphate and filtered, and the filtrate was concentrated. This gave 470 mg of the desired product (90% pure; 97% of theory) which was reacted without further purification.
Reaction SMILES: C([O:4][C:5](=[O:17])[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH:13]([CH3:15])[CH3:14])=[C:8]([Br:16])[CH:7]=1)(C)C>CCO.[OH-].[Na+]>[Br:16][C:8]1[CH:7]=[C:6]([CH:11]=[CH:10][C:9]=1[O:12][CH:13]([CH3:15])[CH3:14])[C:5]([OH:17])=[O:4]
Reactant: CC(C)OC(=O)c1ccc(OC(C)C)c(Br)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)Oc1ccc(C(=O)O)cc1Br
Temperature: 80 °C

Procedure:
To a solution of 3-bromo-4-isopropoxy-benzoic acid isopropyl ester (5.32 g, 17.7 mmol, 1 eq.) in EtOH (100 mL), 1M aq. NaOH soln. (80 mL) was added. The resulting solution was heated at 80° C. for 18 hours, then concentrated in vacuo. The resulting aq. layer was carefully acidified with 2N aq. HCl soln. The mixture was extracted with DCM (3×100 mL). The comb. org. phases were dried over MgSO4 and concentrated in vacuo to give 3-bromo-4-isopropoxy-benzoic acid. The product was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[N:11]=[C:10](I)[CH:9]=2)=[CH:4][CH:3]=1.[Br:19][C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][CH:25]=1>>[Br:19][C:20]1[CH:25]=[C:24]([C:10]2[CH:9]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[N:11]=2)[CH:23]=[CH:22][CH:21]=1
Reactant: OB(O)c1cccc(Br)c1
Reactant: FC(F)(F)c1cc(-c2ccc(Cl)cc2)cc(I)n1
Product: FC(F)(F)c1cc(-c2ccc(Cl)cc2)cc(-c2cccc(Br)c2)n1

Procedure:
The title compound was prepared from 4-(4-chloro-phenyl)-2-iodo-6-trifluoromethyl-pyridine (example A.50) (9 g, ca. 35% pure, ca. 8.2 mmol) and commercially available 3-bromo-benzene-boronic acid (1.80 g, 9 mmol) according to the general procedure IVb. Obtained as a white solid (1.7 g, 50%). MS (ISP) 412.0 [(M+H)+], 414.1 [(M+2+H)+] and 416.1 [(M+4+H)+].
Reaction SMILES: [C:1]([O-:4])(=[O:3])[CH3:2].[Na+].[CH2:6]([O:8][C:9]([C:11](=[CH:16][C:17]1[O:18][C:19]([CH3:22])=[CH:20][CH:21]=1)[CH2:12][C:13](O)=O)=[O:10])[CH3:7]>C(OC(=O)C)(=O)C.ClCCl>[C:1]([O:4][C:13]1[C:21]2[CH:20]=[C:19]([CH3:22])[O:18][C:17]=2[CH:16]=[C:11]([C:9]([O:8][CH2:6][CH3:7])=[O:10])[CH:12]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)[O-]
Reactant: CCOC(=O)C(=Cc1ccc(C)o1)CC(=O)O
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: ClCCl
Product: CCOC(=O)c1cc(OC(C)=O)c2cc(C)oc2c1
Yield: 50 %

Procedure:
Sodium acetate (30 g, 0.36 mol) was added under vigorous stirring to a solution of 3-(ethoxycarbonyl)-4-(5-methyl-2-furyl)but-3-enoic acid (45 g, 0.19 mol) in 250 mL of acetic anhydride. The reaction mixture was refluxed for 2 h and evaporated in vacuum (˜20 mmHg) at 70° C. until the solvent distillation ceased. The obtained crude product was suspended in 500 mL of dichloromethane. The suspension was filtered. The solid was washed with 200 mL of dichloromethane. The combined solutions were washed with 200 mL of a saturated aqueous solution of NaHCO3 and evaporated in vacuum to dryness. The obtained crude product was chromatographed on a layer of silica gel (200×150 mm) with hexane/ethyl acetate mixture, 3:1 as eluent to give 25 g (95 mmol, 51%) of desired compound as a yellow solid.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11](=[O:13])[CH3:12])=[CH:5][CH:4]=1)#[N:2].C(=O)(O)[O-:15].[K+].OO>CO.C(=O)([O-])[O-].[K+].[K+]>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11](=[O:13])[CH3:12])=[CH:5][CH:4]=1)(=[O:15])[NH2:2]
Reactant: CC(=O)CCc1ccc(C#N)cc1
Reactant: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: CO
Product: CC(=O)CCc1ccc(C(N)=O)cc1
Reaction time: 24 h

Procedure:
To a stirred solution of 9.70 g (0.056) mole of 4-(4-cyanophenyl)-2-butanone (the product of step (a)) in 15 ml of methanol, 1.80 g of potassium bicarbonate and 0.20 g of potassium carbonate were added. To the resulting mixture, 10.0 ml (0.088 mole) of 30% hydrogen peroxide was added dropwise over an hour. The reaction mixture was stirred for 24 hours and then chilled. The solid was collected by filtration, was rinsed twice with water and was dried to give 9.67 g of the above-identified product, melting point 152°-154° C. The 1H NMR was consistent with the assigned structure.
Reaction SMILES: [CH:1]1([CH:7]([C:9]2[C:10]([CH2:20][O:21][CH3:22])=[N:11][N:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:13]=2)O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]([N:32]([CH3:40])[CH2:33][CH2:34][C:35]([O:37]CC)=[O:36])=[O:31])=[CH:26][CH:25]=1>>[CH:1]1([CH:7]([NH:23][C:24]2[CH:25]=[CH:26][C:27]([C:30]([N:32]([CH3:40])[CH2:33][CH2:34][C:35]([OH:37])=[O:36])=[O:31])=[CH:28][CH:29]=2)[C:9]2[C:10]([CH2:20][O:21][CH3:22])=[N:11][N:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:13]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COCc1nn(-c2ccccc2)cc1C(O)C1CCCCC1
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(N)cc1
Product: COCc1nn(-c2ccccc2)cc1C(Nc1ccc(C(=O)N(C)CCC(=O)O)cc1)C1CCCCC1
Yield: 39.3 %

Procedure:
Using cyclohexyl[3-(methoxymethyl)-1-phenyl-1H-pyrazol-4-yl]methanol (0.50 g) synthesized in Example 37(3) and ethyl 3-{[(4-aminophenyl)carbonyl](methyl)amino}propanoate (0.42 g) synthesized in Example 2(2) and in the same manner as in Example 1(7), the title object compound (0.33 g, 39%) was obtained as a white solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([O:11][CH3:12])[CH:3]=1.[N:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:12][O:11][C:4]1[CH:3]=[C:2]([C:16]2[CH:17]=[CH:18][N:13]=[CH:14][CH:15]=2)[CH:7]=[CH:6][C:5]=1[N+:8]([O-:10])=[O:9]
Reactant: COc1cc(Cl)ccc1[N+](=O)[O-]
Reactant: OB(O)c1ccncc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: COc1cc(-c2ccncc2)ccc1[N+](=O)[O-]
Temperature: 102 °C
Yield: 79.9 %

Procedure:
A solution of 4-chloro-2-(methyloxy)-1-nitrobenzene (34.7 g, 184.8 mmol), PdCl2(PPh3)2 (6.5 g, 9.24 mmol) and 4-pyridylboronic acid (25.0 g, 203.2 mmol) in dioxane was deoxygenated by bubbling with N2 (g) for ca 15 min. To this solution was added degassed 3.0 N Na2CO3 (aq) (203 mL, 3.0 equiv.) and the resulting slurry was warmed to 102° C. for 4 h. The dioxane was removed under reduced pressure and the solids were dissolved in EtOAc and washed twice with brine. The organic layer was dried over Na2SO4, taken to a residue under reduced pressure, and the residue purified by trituration with diethyl ether to afford 4-[3-(methyloxy)-4-nitrophenyl]pyridine as a brown solid (34.0 g, 147.68 mmol, 80%) of sufficient purity for use in subsequent transformations. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.64-8.73 (m, 2H), 8.00 (d, J=8.43 Hz, 1H), 7.78-7.85 (m, 2H), 7.67 (d, J=1.83 Hz, 1H), 7.51 (dd, J=8.43, 1.83 Hz, 1H), 4.03 (s, 3H).