Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[C:13](=[O:17])[NH:14][CH2:15][CH2:16][C:11]=3[NH:10][C:9]=2[CH:18]=O)=[CH:4][CH:3]=1.[F:20][C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][C:29]=1[NH:30][CH2:31][C:32]1[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=1)[NH:26][C:25](=[O:39])[CH2:24]2>>[F:20][C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][C:29]=1[NH:30][CH2:31][C:32]1[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=1)[NH:26][C:25](=[O:39])[C:24]2=[CH:18][C:9]1[NH:10][C:11]2[CH2:16][CH2:15][NH:14][C:13](=[O:17])[C:12]=2[C:8]=1[C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1
Reactant: O=Cc1[nH]c2c(c1-c1ccc(F)cc1)C(=O)NCC2
Reactant: O=C1Cc2cc(F)c(NCc3ccc(F)cc3)cc2N1
Product: O=C1Nc2cc(NCc3ccc(F)cc3)c(F)cc2C1=Cc1[nH]c2c(c1-c1ccc(F)cc1)C(=O)NCC2
Yield: 43.5 %

Procedure:
The title compound was prepared under the same conditions as described in Example 46 with 3-(4-fluoro-phenyl)-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde and 5-fluoro-6-(4-fluoro-benzylamino)-1,3-dihydro-indol-2-one as starting materials to give 2-[5-fluoro-6-(4-fluoro-benzylamino)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-3-(4-fluoro-phenyl)-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one (34 mg, 43.5%) as a red solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](/[C:9](/[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:10]\[CH:11]=[CH:12]\[C:13]([OH:15])=[O:14])[CH:6]=[CH:7][CH:8]=1.[N+:22]([C:25]1[CH:30]=[CH:29][C:28](O)=[CH:27][CH:26]=1)([O-:24])=[O:23].C1(N=C=NC2CCCCC2)CCCCC1>ClCCl>[N+:22]([C:25]1[CH:30]=[CH:29][C:28]([O:14][C:13](=[O:15])/[CH:12]=[CH:11]/[CH:10]=[C:9](\[C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)/[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[CH:27][CH:26]=1)([O-:24])=[O:23]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: COc1cccc(/C(=C\C=C\C(=O)O)c2ccccc2)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: COc1cccc(/C(=C\C=C\C(=O)Oc2ccc([N+](=O)[O-])cc2)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 1.25 h
Yield: 73.5 %

Procedure:
As in Example 115, (2E,4Z)-5-(3-methoxyphenyl)-5-phenyl-2,4-pentadienoic acid (2.85 g) and 4-nitrophenol (1.56 g) in dichloromethane (35 mL) was treated with 1,3-dicyclohexylcarbodiimide (2.1 g) and the mixture was stirred at room temperature for 75 minutes. The usual work up furnished 3.5 g of crude product which was crystallized from 2-propanol to give 3.0 g of (2E,4Z)-5-(3-methoxyphenyl)-5-phenyl-2,4-pentadienoic acid 4-nitrophenyl ester mp 155°-157° C. Anal. Calculated for C24H19NO5 : C, 71.81; H, 4.77; N, 3.49 Found: C, 72.09; H, 5.03; N, 3.55.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Si:8]([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9])=[CH:4][N:3]=1.[Br-].[N:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[Zn+].N>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O1CCCC1>[Si:8]([C:5]1[CH:6]=[CH:7][C:2]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][N:16]=2)=[N:3][CH:4]=1)([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9]
Reactant: [Zn+]c1ccccn1
Reactant: CC(C)(C)[Si](C)(C)c1ccc(Br)nc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N
Agent: [Br-]
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)c1ccc(-c2ccccn2)nc1
Temperature: 25 °C

Procedure:
To a reaction container equipped with a cooling apparatus, 0.64 g of tetrakis(triphenylphosphine)palladium, 1 g of 2-bromo-5-tert-butyldimethylsilylpyridine obtained in the above-mentioned Example 3-1 and 25 mL of tetrahydrofuran were added. To the obtained mixture, 7.35 mL of 2-pyridyl zinc bromide (0.5 M/tetrahydrofuran solution) was added with stirring at room temperature. The obtained mixture was stirred at 50° C. for 7 hours and 40 minutes to effect reaction. The reaction mixture was cooled until room temperature and then, 33 mL of 28% aqueous ammonia solution was added thereto. The obtained mixture was extracted three times with 50 mL of chloroform. The obtained organic layers were mixed and dried with magnesium sulfate. After removing magnesium sulfate by filtration, the filtrate was concentrated to obtain a crude product. The crude product was purified with silica gel column chromatography followed by further recrystallization with hexane to obtain 0.35 g of 5-tert-butyldimethylsilyl-2,2′-bipyridine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[C:13]([CH3:15])[CH:12]=[CH:11][CH:10]=1.[Se](=O)=[O:17]>O1CCOCC1>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[C:13]([CH:15]=[O:17])[CH:12]=[CH:11][CH:10]=1
Reactant: O=[Se]=O
Reactant: Cc1cccc(-c2ccc(Cl)cc2Cl)n1
Solvent: C1COCCO1
Product: O=Cc1cccc(-c2ccc(Cl)cc2Cl)n1

Procedure:
1.5 g of 6-(2,4-dichlorophenyl)-2-methylpyridine was dissolved in 200 ml of 1,4-dioxane and treated with 1.05 g of selenium dioxide (Aldrich, Gold Label). The mixture was refluxed for 72 hours. An additional 1.2 g of selenium dioxide was added and the mixture was heated a further 48 hours. The solids were removed by filtration and the dioxane was evaporated to afford crude 6-(2,4-dichlorophenyl)-2-pyridinecarboxaldehyde which was chromatographed on silica-gel to afford 1.5 g of 6-(2,4-dichlorophenyl)-2-pyridinecarboxaldehyde as a white solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH3:7])=[CH:3][CH:2]=1.[F:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][CH:10]=1>C(OC(=O)C)(=O)C>[F:8][C:9]1[CH:16]=[CH:15][C:12](/[CH:13]=[CH:7]/[C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)=[CH:11][CH:10]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: Cc1ccncc1
Solvent: CC(=O)OC(C)=O
Product: Fc1ccc(/C=C/c2ccncc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 59.2 %

Procedure:
A mixture of 4-picoline (15.6 ml, 161 mmol) and 4-fluorobenzaldehyde (20 g, 161 mmol) in acetic anhydride (125 ml) was heated at reflux overnight. The reaction was cooled and the solvent evaporated. Water (100 ml) was added to the residue, and the mixture stirred at room temperature for 30 minutes. Saturated sodium carbonate solution (100 ml) and ethyl acetate (150 ml) were then added, and stirring continued for a further 30 minutes. The two phases were separated, and the aqueous phase extracted with ethyl acetate (3×200 ml). The combined organic phases were dried (MgSO4) and evaporated. The residue was purified by flash chromatography, eluting with 50% ethyl acetate/petrol (60°-80°). The appropriate fractions were combined and concentrated to yield (E)-4-[2-(4-fluorophenyl)ethenyl]pyridine (19 g, 60%) as a beige solid. δH (CDCl3) 6.93 (1H, d, J 16.3 Hz, ArCHCH), 7.05-7.13 (2H, m, ArH), 7.26 (1H, d, J 16.3 Hz, ArCHCH), 7.34-7.36 (2H, m, ArH), 7.48-7.54 (2H, m, ArH) and 8.56-8.60 (2H, m, ArH).
Reaction SMILES: [CH3:1][N:2]([CH:4]=[C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][C:6]1=[O:14])[CH3:3].Br[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([F:24])[CH:17]=1.[H-].[Na+]>CCOCC.CCCCC>[F:24][C:18]1[CH:17]=[C:16]([N:7]2[C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:5](=[CH:4][N:2]([CH3:1])[CH3:3])[C:6]2=[O:14])[CH:21]=[CH:20][C:19]=1[O:22][CH3:23]
Reactant: COc1ccc(Br)cc1F
Reactant: CN(C)C=C1C(=O)Nc2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CCCCC
Product: COc1ccc(N2C(=O)C(=CN(C)C)c3ccccc32)cc1F

Procedure:
By the procedure of Example C1, without chromatography, but directly crystallizing the crude product from ether/pentane, 3-(dimethylaminomethylene)-2(1H,3H)-indolone (3.77 g, 20 mmoles) and 4-bromo-2-fluoroanisole (4.10 g, 20 mmoles) with NaH (0.96 g of 50% dispersion in oil, 20 mmoles) and Cu2Br2 (5.74 g, 20 mmoles), were converted to title product, 0.79 g, m.p. 113°-114°.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][C:5]1[C:9]([Cl:10])=[CH:8][S:7][CH:6]=1.[CH2:11]1[O:19][CH:12]1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[OH:19][CH:12]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:11][N:2]([CH3:1])[CH2:3][CH2:4][C:5]1[C:9]([Cl:10])=[CH:8][S:7][CH:6]=1
Reactant: CNCCc1cscc1Cl
Reactant: c1ccc(C2CO2)cc1
Product: CN(CCc1cscc1Cl)CC(O)c1ccccc1

Procedure:
N-methyl 4-chloro-thiophene-3-ethylamine was reacted with styrene oxide as described in Example 20(b) to give the title product as an oil.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[NH2:10][C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:41]([C:44]1[CH:45]=[CH:46][C:47]([O:53][CH2:54][C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)=[C:48]([CH:52]=1)[C:49](O)=[O:50])(=[O:43])[CH3:42]>CN(C)C=O.CCCCCC.C(OCC)(=O)C.O.C(OCC)(=O)C>[C:41]([C:44]1[CH:45]=[CH:46][C:47]([O:53][CH2:54][C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)=[C:48]([CH:52]=1)[C:49]([NH:10][C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1)=[O:50])(=[O:43])[CH3:42]
Reactant: Nc1cccnc1
Reactant: CC(=O)c1ccc(OCc2ccccc2)c(C(=O)O)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(=O)c1ccc(OCc2ccccc2)c(C(=O)Nc2cccnc2)c1
Reaction time: 2 h

Procedure:
Diisopropylethylamine (0.97 ml, 5.55 mmol), 3-aminopyridine (418 mg, 4.44 mmol) and HATU (1.27 g, 3.33 mmol) were added to a solution of 5-acetyl-2-[(phenylmethyl)oxy]benzoic acid (commercially available from Acros; 600 mg, 2.22 mmol) in dimethylformamide (10 ml). The solution was stirred for 2 hours. Ethyl acetate (40 ml) and H2O (40 ml) were added and the organic layer washed with H2O (3×20 ml), dried and the solvent removed in vacuo to give a solid. Trituration with 3:1 hexane/ethyl acetate yielded the title compound as a yellow solid. 541 mg.
Reaction SMILES: C(OC([NH:8][C@H:9]([C:32]([O:34]C(C)(C)C)=[O:33])[CH2:10][CH:11]([CH2:19][CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][CH2:30][F:31])=[CH:24][CH:23]=1)[C:12]([O:14]C(C)(C)C)=[O:13])=O)(C)(C)C.C1(C)C=CC=CC=1>FC(F)(F)C(O)=O>[F:31][CH2:30][CH2:29][CH2:28][C:25]1[CH:24]=[CH:23][C:22]([CH2:21][CH2:20][CH2:19][CH:11]([C:12]([OH:14])=[O:13])[CH2:10][C@@H:9]([C:32]([OH:34])=[O:33])[NH2:8])=[CH:27][CH:26]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(CCCc1ccc(CCCF)cc1)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: N[C@@H](CC(CCCc1ccc(CCCF)cc1)C(=O)O)C(=O)O

Procedure:
Di-tert-butyl N-(tert-butoxycarbonyl)-4-{3-[4-(3-fluoropropyl)phenyl]propyl}-L-glutamate (40 mg, 0.07 mmol) was dissolved in 3 ml trifluoroacetic acid and stirred at room temperature for 1d. Then, 5 ml toluene were added and the solution was concentrated in vacuo. The product was purified by preparative HPLC. The appropriate fractions were collected, the acetonitrile evaporated under reduced pressure and the remaining aqueous solution was lyophilized.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]2[CH:16]=[CH:17][C:18]3[NH:23][C:22](=[O:24])[O:21][CH:20]([CH3:25])[C:19]=3[CH:26]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[OH:27]O>>[Cl:1][C:2]1[CH:3]=[C:4]([S:9]([CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]2[CH:16]=[CH:17][C:18]3[NH:23][C:22](=[O:24])[O:21][CH:20]([CH3:25])[C:19]=3[CH:26]=2)=[O:27])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: OO
Reactant: CC1OC(=O)Nc2ccc(OCCCCSc3ccc(Cl)c(Cl)c3)cc21
Product: CC1OC(=O)Nc2ccc(OCCCCS(=O)c3ccc(Cl)c(Cl)c3)cc21

Procedure:
Prepared analogously to Example 2 from 6-[4-(3,4-dichloro-phenylmercapto)-butoxy]-4-methyl-4H-3,1-benzoxazin-2-one and hydrogen peroxide.
Reaction SMILES: Cl[C:2]1[C:3]2[N:10]([CH2:11][CH2:12][O:13][CH2:14][CH3:15])[CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH3:16][C:17]1[CH:18]=[C:19]([CH:21]=[CH:22][C:23]=1[O:24][C:25]1[CH:26]=[N:27][C:28]([CH3:31])=[CH:29][CH:30]=1)[NH2:20]>CN1CCCC1=O.C(=O)([O-])O.[Na+]>[CH2:14]([O:13][CH2:12][CH2:11][N:10]1[C:3]2[C:2]([NH:20][C:19]3[CH:21]=[CH:22][C:23]([O:24][C:25]4[CH:26]=[N:27][C:28]([CH3:31])=[CH:29][CH:30]=4)=[C:17]([CH3:16])[CH:18]=3)=[N:7][CH:6]=[N:5][C:4]=2[CH:8]=[CH:9]1)[CH3:15]
Reactant: Cc1ccc(Oc2ccc(N)cc2C)cn1
Reactant: CCOCCn1ccc2ncnc(Cl)c21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: CCOCCn1ccc2ncnc(Nc3ccc(Oc4ccc(C)nc4)c(C)c3)c21
Temperature: 120 °C
Reaction time: 2 h
Yield: 66.8 %

Procedure:
To a solution of 4-chloro-5-(2-ethoxyethyl)-5H-pyrrolo[3,2-d]pyrimidine (160 mg) in 1-methyl-2-pyrrolidone (1.4 mL) was added 3-methyl-4-[(6-methylpyridin-3-yl)oxy]aniline (228 mg), and the reaction mixture was stirred at 120° C. for 2 hrs. The reaction mixture was allowed to cool to room temperature, diluted with 5% aqueous sodium hydrogen carbonate solution (25 mL), and extracted with ethyl acetate (40 mL×3). The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (eluent:hexane/ethyl acetate=90/10→0/100). The object fraction was concentrated under reduced pressure and dried to give the title compound (191 mg) as a colorless transparent oil.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([C:18](=[O:22])[C@@H:19]([OH:21])[CH3:20])[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:37]2[CH:38]=[N:39][C:40]([NH2:43])=[N:41][CH:42]=2)O1>>[NH2:43][C:40]1[N:41]=[CH:42][C:37]([C:2]2[N:3]=[C:4]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[C:5]3[S:10][C:9]([CH2:11][N:12]4[CH2:17][CH2:16][N:15]([C:18](=[O:22])[C@@H:19]([OH:21])[CH3:20])[CH2:14][CH2:13]4)=[CH:8][C:6]=3[N:7]=2)=[CH:38][N:39]=1
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Reactant: C[C@H](O)C(=O)N1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Product: C[C@H](O)C(=O)N1CCN(Cc2cc3nc(-c4cnc(N)nc4)nc(N4CCOCC4)c3s2)CC1
Yield: 49.3 %

Procedure:
(S)-1-(4-((2-Chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)-2-hydroxypropan-1-one (61 mg) was reacted with 51 mg of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine via General Procedure A to give 34.2 mg of 207. MS (Q1) 485.3 (M)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:29]=[CH:28][CH:27]=[CH:26][C:4]=1[C:5]([NH:7][CH:8]1[C:14]2=[N:15][C:16]([C:20]3[CH:25]=[CH:24][N:23]=[CH:22][N:21]=3)=[CH:17][C:18](=[O:19])[N:13]2[CH2:12][CH2:11][NH:10][CH2:9]1)=[O:6].C=O.[C:32](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[CH3:1][O:2][C:3]1[N:29]=[CH:28][CH:27]=[CH:26][C:4]=1[C:5]([NH:7][CH:8]1[C:14]2=[N:15][C:16]([C:20]3[CH:25]=[CH:24][N:23]=[CH:22][N:21]=3)=[CH:17][C:18](=[O:19])[N:13]2[CH2:12][CH2:11][N:10]([CH3:32])[CH2:9]1)=[O:6]
Reactant: COc1ncccc1C(=O)NC1CNCCn2c1nc(-c1ccncn1)cc2=O
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: COc1ncccc1C(=O)NC1CN(C)CCn2c1nc(-c1ccncn1)cc2=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 24.5 %

Procedure:
To a solution of 0.055 g (0.14 mmol) of (+/−)-2-methoxy-N-(4-oxo-2-pyrimidin-4-yl-4,5,6,7,8,9-hexahydro-1,4a,7-triaza-benzocyclohepten-9-yl)-nicotinamide (example 3) in 3.00 mL of dichloroethane was added 0.050 mL (0.70 mmol) of formaldehyde (37% in water solution), 0.089 g (0.42 mmol) of sodium triacetoxyborohydride. The reaction mixture was stirred at room temperature for 12 hours. A solution of sodium hydroxyl (35%) was added and the mixture was extracted with dichloromethane, washed with a saturated aqueous solution of sodium chloride, dried over sodium sulfate and evaporated. The residue was chromatographed on silica gel eluting with a mixture of dichloromethane/methanol/aqueous ammonia solution (29%) in the proportions 90/10/1 to afford 0.014 g (24%) of pure product.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[C:13]([N:15]2[C:19]3[CH:20]=[CH:21][C:22]([C:24]4[N:25]=[N:26][N:27]([CH2:29][CH2:30][C:31]([OH:34])([CH3:33])[CH3:32])[CH:28]=4)=[CH:23][C:18]=3[N:17]=[CH:16]2)[CH:12]=[C:11]([NH:35]C(=O)C)[CH:10]=1.[OH-].[Na+]>C(O)C>[NH2:35][C:11]1[CH:12]=[C:13]([N:15]2[C:19]3[CH:20]=[CH:21][C:22]([C:24]4[N:25]=[N:26][N:27]([CH2:29][CH2:30][C:31]([CH3:33])([OH:34])[CH3:32])[CH:28]=4)=[CH:23][C:18]=3[N:17]=[CH:16]2)[CH:14]=[C:9]([C:3]2[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[F:1])[CH:10]=1
Reactant: CC(=O)Nc1cc(-c2ccc(F)cc2F)cc(-n2cnc3cc(-c4cn(CCC(C)(C)O)nn4)ccc32)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(O)CCn1cc(-c2ccc3c(c2)ncn3-c2cc(N)cc(-c3ccc(F)cc3F)c2)nn1
Temperature: 90 °C
Yield: 38 %

Procedure:
To a solution of the compound of Example 44 (400 mg, 0.77 mmol) in ethanol (20 ml) was added aqueous solution of NaOH (385 mg, 9.63 mmol, 12.5 eq.) and the mixture was heated at 90° C. for 3 h. The mixture was quenched and extracted as in Example 1(d). The solvent was distilled off to give the product in 38% yield (140 mg).
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.C(N(CC)CC)C.Cl[CH2:13][C:14]1[N:15]=[C:16]([CH:19]2[CH2:24][CH:23]([C:25]3[CH:30]=[CH:29][C:28]([CH2:31][CH3:32])=[CH:27][CH:26]=3)[CH2:22][N:21]([C:33]([N:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)=[O:34])[CH2:20]2)[S:17][CH:18]=1>CN1CCCC1=O>[CH:1]1([NH:4][CH2:13][C:14]2[N:15]=[C:16]([CH:19]3[CH2:24][CH:23]([C:25]4[CH:26]=[CH:27][C:28]([CH2:31][CH3:32])=[CH:29][CH:30]=4)[CH2:22][N:21]([C:33]([N:35]4[CH2:36][CH2:37][O:38][CH2:39][CH2:40]4)=[O:34])[CH2:20]3)[S:17][CH:18]=2)[CH2:3][CH2:2]1
Reactant: CCc1ccc(C2CC(c3nc(CCl)cs3)CN(C(=O)N3CCOCC3)C2)cc1
Reactant: NC1CC1
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: CCc1ccc(C2CC(c3nc(CNC4CC4)cs3)CN(C(=O)N3CCOCC3)C2)cc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 4 %

Procedure:
24 mg (0.411 mmol) of cyclopropylamine and 70 mg (0.685 mmol) of triethylamine were added to a solution of 119 mg (0.274 mmol) of the compound from Example 141A in 2 ml of N-methylpyrrolidone. The reaction mixture was stirred at 80° C. overnight. Diastereomer separation of 13 mg of the cis/trans isomer mixture according to Method 15C gave 5 mg of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH2:3][CH:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12]([C:14](OCC)=[O:15])=[O:13])[CH:7]([CH:19]([C:21]([O:23][CH3:24])=[O:22])[CH3:20])[CH2:6][CH2:5]2.F[B-](F)(F)F.O=[N+:31]=O.[N+]([O-])([O-])=O.[NH4+].FC(F)(F)C(OC(=O)C(F)(F)F)=O>ClCCl.C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[CH2:5][CH2:6][CH:7]([CH:19]([C:21]([O:23][CH3:24])=[O:22])[CH3:20])[N:8]3[C:12](=[O:13])[C:14](=[O:15])[NH:31][C:10]([CH:11]=1)=[C:9]23
Reactant: CCOC(=O)C(=O)N1C2=CC=C(Br)CC2CCC1C(C)C(=O)OC
Reactant: O=[N+]=O
Agent: F[B-](F)(F)F
Agent: O=[N+]([O-])[O-]
Agent: [NH4+]
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: COC(=O)C(C)C1CCc2cc(Br)cc3[nH]c(=O)c(=O)n1c23

Procedure:
The title compound was prepared by the route outlined in Example 22-6 to 7 starting with 6-bromo-N-ethoxalyl-2-(1-methoxycarbonylethyl)tetrahydroquinoline (more polar). In nitration step of Example 22-6, conditions of nitronium tetrafluoroborate in dichloromethane at room temperature were employed instead of those of refluxing ammonium nitrate-trifluoroacetic anhydride in chloroform: mp 256°~257° C.; 1H NMR (270 MHz, DMSO-d6) δ12.12 (s, 1H), 7.19 (s, 1H), 7.16 (s, 1H), 5.11 (bd, 1H, J=9 Hz), 3.58 (s, 3H), 2.89 (ddd, 1H, J=17.1, 13.5, 4.5 Hz), 2.72~2.87 (m, 2H), 2.03 (dm, 1H, J=13.5 Hz), 1.76~1.94 (m, 1H), 0.97 (d, 3H, J=7 Hz).
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([C:15]([O:17]C)=[O:16])=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]#[N:14])[CH:8]=2)[N:6]=1.O.O.[OH-].[Li+]>O1CCCC1>[CH3:1][C:2]1[S:3][C:4]([C:15]([OH:17])=[O:16])=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]#[N:14])[CH:8]=2)[N:6]=1
Reactant: COC(=O)c1sc(C)nc1-c1cccc(C#N)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1nc(-c2cccc(C#N)c2)c(C(=O)O)s1
Temperature: 25 °C
Reaction time: 16 h
Yield: 99 %

Procedure:
To a solution of of 2-methyl-4-(3-cyanophenyl)-5-carbomethoxythiazole from Example 9, Part A (0.96 g, 3.7 mmol) in 20 mL of tetrahydrofuran and 10 mL of water was added lithium hydroxide monohydrate (0.31 g, 7.4 mmol). The resulting mixture was stirred at room temperature for 16 h. The mixture was-concentrated in vacuo, diluted with H2O and saturated aqueous NaHCO3 and extracted with hexane. The organic layer was discarded and the aqueous layer was acidified and extracted twice with ethyl acetate. The combined ethyl acetate extracts were washed with brine, dried over MgSO4 and concentrated in vacuo to afford 0.90 g (99%) of the title compound, which was sufficiently pure to be used without purification. MS(NH3—CI) 245 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.[F:12][C:13]1[CH:14]=[C:15]([C:19]2[CH:20]=[CH:21][C:22]([NH2:25])=[N:23][CH:24]=2)[CH:16]=[CH:17][CH:18]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]([NH:25][C:22]2[CH:21]=[CH:20][C:19]([C:15]3[CH:16]=[CH:17][CH:18]=[C:13]([F:12])[CH:14]=3)=[CH:24][N:23]=2)=[O:11])=[CH:4][CH:3]=1
Reactant: Nc1ccc(-c2cccc(F)c2)cn1
Reactant: O=C(O)Cc1ccc(Cl)nc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Cc1ccc(Cl)nc1)Nc1ccc(-c2cccc(F)c2)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 2-(6-chloropyridin-3-yl)acetic acid (521 mg, 3.03 mmol), 5-(3-fluorophenyl)pyridin-2-amine (570 mg, 3.03 mmol), HATU (1250 mg, 3.29 mmol) and DIEA (784 μl, 4.50 mmol) in DMF (10 ml) was stirred at room temperature overnight. DMF was mostly removed by evaporation under reduced pressure. The residue was dissolved in EtOAc (50 ml), washed with 3% Na2CO3 solution (30 ml) and water (50 mL), and dried over Na2SO4. After concentration by evaporation, the residue was subjected to silica gel column chromatography to give 2-(6-chloropyridin-3-yl)-N-(5-(3-fluorophenyl)pyridin-2-yl)acetamide 140-1.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:23])=[C:8]2[C:15]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)=[N:14][S:13][C:9]2=[C:10](Br)[N:11]=1)=[O:5])[CH3:2].[CH3:24][Si:25]([C:28]#[CH:29])([CH3:27])[CH3:26].C(N)(C)C>C1COCC1.CCOC(C)=O.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.[Cu]I>[CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:23])=[C:8]2[C:15]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)=[N:14][S:13][C:9]2=[C:10]([C:29]#[C:28][Si:25]([CH3:27])([CH3:26])[CH3:24])[N:11]=1)=[O:5])[CH3:2]
Reactant: C#C[Si](C)(C)C
Reactant: CCOC(=O)c1nc(Br)c2snc(-c3ccc(F)cc3)c2c1O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCOC(C)=O
Solvent: CC(C)N
Solvent: C1CCOC1
Product: CCOC(=O)c1nc(C#C[Si](C)(C)C)c2snc(-c3ccc(F)cc3)c2c1O
Yield: 35.3 %

Procedure:
To a solution of 7-Bromo-3-(4-fluoro-phenyl)-4-hydroxy-isothiazolo[5,4-c]pyridine-5-carboxylic acid ethyl ester (124.9 mg, 0.39 mmol) in THF (5.6 mL) was added trimethylsilylacetylene (0.11 mL, 0.78 mmol), PdCl2(PPh3)2 (55.1 mg, 0.078 mmol), CuI (29.9 mg, 0.156 mmol) and isopropylamine (0.34 mL, 2.42 mmol). The reaction mixture refluxed for 16 h with stirring. After cooling to r. t. the mixture was diluted with EtOAc (20 mL), filtered and the filter cake washed with EtOAc (10 mL). The filtrate was concentrated in vacuo. The residue was purified by flash column chromatography on silica gel. Elution with 0-20% EtOAc/CH2Cl2 gave the title compound as white solid (57 mg): MS (m/z) 415.1 (M+1).
Reaction SMILES: C([O:3][C:4](=[O:37])[C:5]([NH:7][C:8]1[CH:34]=[C:33]([CH3:35])[C:11]([O:12][C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[N:18](C(=O)C(OCC)=O)[N:17]=[C:16]3[CH2:29][CH:30]([CH3:32])[CH3:31])=[C:10]([CH3:36])[CH:9]=1)=[O:6])C.[O-]CC.[Na+]>C(O)C>[CH3:36][C:10]1[CH:9]=[C:8]([NH:7][C:5](=[O:6])[C:4]([OH:37])=[O:3])[CH:34]=[C:33]([CH3:35])[C:11]=1[O:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][N:17]=[C:16]2[CH2:29][CH:30]([CH3:32])[CH3:31]
Reactant: CCOC(=O)C(=O)Nc1cc(C)c(Oc2ccc3c(c2)c(CC(C)C)nn3C(=O)C(=O)OCC)c(C)c1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: Cc1cc(NC(=O)C(=O)O)cc(C)c1Oc1ccc2[nH]nc(CC(C)C)c2c1
Yield: 31.3 %

Procedure:
In an analogous manner to the procedure of Example 9, 47 mg (0.092 mmol) of ethyl [5-(4-{[ethoxy(oxo)acetyl]amino}-2,6-dimethylphenoxy)-3-isobutyl-1H-indazol-1-yl](oxo)acetate in 10 ml of ethanol are reacted with a spatula-tipful of sodium ethoxide to give 11 mg (31%) of ({3,5-dimethyl-4-[(3-isobutyl-1H-indazol-5-yl)oxy]phenyl}amino) (oxo)acetic acid.