Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]2[N:8]([CH:11]([C@H:13]3[CH2:18][CH2:17][C@H:16]([CH3:19])[CH2:15][CH2:14]3)[CH3:12])[CH:9]=[N:10][C:6]=2[CH:5]=[C:4]([Cl:20])[N:3]=1.[Cl:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[N:26][CH:27]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[Cl:20][C:4]1[N:3]=[C:2]([C:24]2[CH:25]=[N:26][CH:27]=[C:22]([Cl:21])[CH:23]=2)[C:7]2[N:8]([CH:11]([C@H:13]3[CH2:18][CH2:17][C@H:16]([CH3:19])[CH2:15][CH2:14]3)[CH3:12])[CH:9]=[N:10][C:6]=2[CH:5]=1
Reactant: OB(O)c1cncc(Cl)c1
Reactant: CC([C@H]1CC[C@H](C)CC1)n1cnc2cc(Cl)nc(Cl)c21
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Product: CC([C@H]1CC[C@H](C)CC1)n1cnc2cc(Cl)nc(-c3cncc(Cl)c3)c21
Temperature: 90 °C

Procedure:
Racemic 4,6-dichloro-3-[1-(trans-4-methylcyclohexyl)ethyl]-3H-imidazo[4,5-c]pyridine (Preparative Example 4.3) (5 g, 16 mmol), 5-chloropyridine-3-boronic acid (2.77 g, 17.61 mmol), cesium carbonate (15.65 g, 48 mmol), and 1,1′-Bis(diphenylphosphino)ferrocene-palladium(II)dichloride (1.17 g, 1.6 mmol) were combined in a flask that had been oven-dried and flushed with nitrogen. Dioxane (43 mL) and water (10.6 mL) were added, and the vial was capped and heated to 90° C. for 3 hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate, and washed with water. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-100% ethyl acetate/hexanes, linear gradient) to afford racemic 6-chloro-4-(5-chloropyridin-3-yl)-3-[1-(trans-4-methylcyclohexyl)ethyl]-3H-imidazo[4,5-c]pyridine. MS ESI calc'd. for C20H22Cl2N4 [M+H]+ 389. found 389.
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]1[CH:8]=[C:7]([C:9](=[O:19])[N:10]([CH2:15][CH2:16][CH2:17][CH3:18])[CH2:11][CH2:12][CH2:13][CH3:14])[N:6]=[C:5]1[C:20]1[CH:29]=[CH:28][C:23]([C:24]([O:26][CH3:27])=[O:25])=[CH:22][C:21]=1[C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31].C(N(C(C)C)CC)(C)C.[CH3:49][N:50]1[CH2:55][CH2:54][NH:53][CH2:52][CH2:51]1>CN(C=O)C.O>[CH2:15]([N:10]([CH2:11][CH2:12][CH2:13][CH3:14])[C:9]([C:7]1[N:6]=[C:5]([C:20]2[CH:29]=[CH:28][C:23]([C:24]([O:26][CH3:27])=[O:25])=[CH:22][C:21]=2[C:30]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[O:31])[N:4]([CH2:3][CH2:2][N:53]2[CH2:54][CH2:55][N:50]([CH3:49])[CH2:51][CH2:52]2)[CH:8]=1)=[O:19])[CH2:16][CH2:17][CH3:18]
Reactant: CN1CCNCC1
Reactant: CCCCN(CCCC)C(=O)c1cn(CCCl)c(-c2ccc(C(=O)OC)cc2C(=O)OCc2ccccc2)n1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CCCCN(CCCC)C(=O)c1cn(CCN2CCN(C)CC2)c(-c2ccc(C(=O)OC)cc2C(=O)OCc2ccccc2)n1
Temperature: 90 °C
Yield: 45 %

Procedure:
To a solution of 3-benzyl 1-methyl 4-(1-(2-chloroethyl)-4-(dibutylcarbamoyl)-1H-imidazol-2-yl)isophthalate (120 mg, 0.21 mmol) in dry DMF (2 mL) was added diisopropylethyl amine (26.5 mg, 0.21 mmol) and 1-methylpiperazine (21 mg, 0.21 mmol at room temperature. The reaction mixture was heated at 90° C. for 16 h, diluted with water and extracted with MTBE (3×). The combined organic layer was dried over Na2SO4 and concentrated in vacuo to give the crude product. The crude material was purified by flash chromatography (gradient from 0 to 5% MeOH/CH2Cl2) to provide the title compound (60 mg, 45%). MS(ESI+) m/z 619.2 (M+H)+
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH2:5][CH:6]1[CH2:9][N:8]([C:10]([O:12]C(C)(C)C)=O)[CH2:7]1)[CH3:2].O1CCOCC1.C(N(CC)[CH:28]([CH3:30])[CH3:29])(C)C.C1(C(Cl)=O)CC1>Cl.ClCCl.O>[CH:28]1([C:10]([N:8]2[CH2:7][CH:6]([CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:17])[CH2:9]2)=[O:12])[CH2:30][CH2:29]1
Reactant: CCOC(=O)CC1CN(C(=O)OC(C)(C)C)C1
Reactant: CCN(C(C)C)C(C)C
Agent: Cl
Agent: O=C(Cl)C1CC1
Solvent: O
Solvent: C1COCCO1
Solvent: ClCCl
Product: CCOC(=O)CC1CN(C(=O)C2CC2)C1
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 115.2 %

Procedure:
In a round bottom flask, a solution of 1,1-dimethylethyl 3-[2-(ethyloxy)-2-oxoethyl]-1-azetidinecarboxylate (10.55 g, 43.3 mmol) in 4M HCl in dioxane (50 mL, 200 mmol) was stirred at room temperature for 1 h. Analysis by LCMS showed that the reaction was complete; conversion was observed to the des-BOC intermediate [M+H]+=144.0 (by ELS, no UV214 detection) and an unknown [M+H]+=179.9. The reaction was concentrated in vacuo. A solution of this intermediate (as the HCl salt) in dichloromethane (50 mL) was treated with N,N-diisopropylethylamine (15.14 mL, 87 mmol) and stirred for 2 min at room temperature. The pale yellow solution was treated with cyclopropanecarbonyl chloride (4.33 mL, 47.7 mmol) by syringe at room temperature and then stirred for 1 h. The reaction was diluted with water (200 mL), the layers were separated and the aqueous layer was extracted with dichloromethane (100 mL). The organic layers were combined, dried over MgSO4, and concentrated in vacuo to give the title compound as an orange liquid (10.54 g, 65% pure, 75% yield). This product could also be prepared by using 10% TFA in dichloromethane. 1H NMR in DMSO-d6 showed ˜2:1 desired product: by-product. MS(ES)+ m/e 211.9 [M+H]+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5]([C:7]1[N:15]=[C:14]2[C:10]([N:11]=[CH:12][N:13]2[C@H:16]2[C@H:20]([OH:21])[C@H:19]([OH:22])[C@@H:18]([C:23]([NH:25][CH2:26][CH3:27])=[O:24])[O:17]2)=[C:9]([NH:28][CH2:29][CH:30]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[N:8]=1)=[O:6].N1([C:48]([NH:50][CH2:51][C:52]2[CH:67]=[CH:66][C:55]([C:56]([O:58][CH2:59][C:60]3[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=3)=[O:57])=[CH:54][CH:53]=2)=[O:49])C=CN=C1>>[C:31]1([CH:30]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH2:29][NH:28][C:9]2[N:8]=[C:7]([C:5]([NH:4][CH2:3][CH2:2][NH:1][C:48]([NH:50][CH2:51][C:52]3[CH:67]=[CH:66][C:55]([C:56]([O:58][CH2:59][C:60]4[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=4)=[O:57])=[CH:54][CH:53]=3)=[O:49])=[O:6])[N:15]=[C:14]3[C:10]=2[N:11]=[CH:12][N:13]3[C@H:16]2[C@H:20]([OH:21])[C@H:19]([OH:22])[C@@H:18]([C:23]([NH:25][CH2:26][CH3:27])=[O:24])[O:17]2)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: O=C(OCc1ccccc1)c1ccc(CNC(=O)n2ccnc2)cc1
Reactant: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(C(=O)NCCN)nc32)[C@H](O)[C@@H]1O
Product: CCNC(=O)[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(C(=O)NCCNC(=O)NCc4ccc(C(=O)OCc5ccccc5)cc4)nc32)[C@H](O)[C@@H]1O

Procedure:
Prepared from N-(2-aminoethyl)-6-[(2,2-diphenylethyl)amino]-9-{(2R,3R,4S,5S)-5-[(ethylamino)carbonyl]-3,4-dihydroxytetrahydro-2-furanyl}-9H-purin-2-carboxamide (Preparation 10) and benzyl 4-{[(1H-imidazol-1 ylcarbonyl)amino]methyl}benzoate (Preparation 54) by a similar method to Example 1. The target compound was obtained as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:13]([C:14](OCC)=[O:15])=[CH:12][N:11]([CH3:19])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Li+].[Al+3].[H-].[H-].[H-].O.O.O.O.O.O.O.O.O.O.[O-]S([O-])(=O)=O.[Na+].[Na+]>O1CCCC1>[CH2:1]([O:8][C:9]1[C:13]([CH2:14][OH:15])=[CH:12][N:11]([CH3:19])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cn(C)nc1OCc1ccccc1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: Cn1cc(CO)c(OCc2ccccc2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 158.4 %

Procedure:
To a solution of ethyl 3-benzyloxy-1-methyl-1H-pyrazole-4-carboxylate (18.00 g) in tetrahydrofuran (200 ml) was added aluminum lithium hydride (2.62 g) at 0° C. and the mixture was stirred at room temperature for 1 hr. To the reaction mixture was added sodium sulfate 10 hydrate (22.20 g) and the mixture was stirred at room temperature for 1 hr. The precipitate was removed by filtration and the filtrate was concentrated. The residue was subjected to silica gel column chromatography, and (3-benzyloxy-1-methyl-1H-pyrazol-4-yl)methanol (23.90 g, yield 91%) was obtained as a colorless oil from a fraction eluted with ethyl acetate.
Reaction SMILES: Cl[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][N:12]3[CH2:17][CH2:16][N:15](S(C)(=O)=O)[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.F[C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][N:30]=1.NO>CN(C=O)C>[O:25]1[CH2:26][CH2:27][N:22]([C:4]2[C:5]3[S:10][C:9]([CH2:11][N:12]4[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]4)=[CH:8][C:6]=3[N:7]=[C:2]([C:32]3[CH:33]=[CH:34][C:29]([NH:22][CH2:23][CH2:24][OH:25])=[N:30][CH:31]=3)[N:3]=2)[CH2:23][CH2:24]1
Reactant: OB(O)c1ccc(F)nc1
Reactant: CS(=O)(=O)N1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Agent: NO
Solvent: CN(C)C=O
Product: OCCNc1ccc(-c2nc(N3CCOCC3)c3sc(CN4CCNCC4)cc3n2)cn1

Procedure:
2-Chloro-6-((4-methanesulfonylpiperazin-1-yl)methyl)-4-morpholinothieno[3,2-d]pyrimidine (100 mg) was reacted with 2-fluoropyridine-5-boronic acid following General Procedure A. One half of the crude material was heated in the microwave with excess hydroxylamine in DMF to give 188 after reversed phase HPLC purification. MS (Q1) 534 (M)+.
Reaction SMILES: [Cl:1][C:2]1[C:3]2([O:25][CH2:24][CH2:23][O:22]2)[CH2:4][C@H:5]2[C@:18]([CH3:20])([CH:19]=1)[C@@H:17]1[C@H:8]([C@H:9]3[C@@:13]([CH2:15][CH2:16]1)([CH3:14])[C@@H:12]([OH:21])[CH2:11][CH2:10]3)[CH2:7][CH2:6]2.[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O>CN(C)C=O>[Cl:1][C:2]1[C:3]2([O:22][CH2:23][CH2:24][O:25]2)[CH2:4][C@H:5]2[C@:18]([CH3:20])([CH:19]=1)[C@@H:17]1[C@H:8]([C@H:9]3[C@@:13]([CH2:15][CH2:16]1)([CH3:14])[C:12](=[O:21])[CH2:11][CH2:10]3)[CH2:7][CH2:6]2
Reactant: C[C@]12C=C(Cl)C3(C[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](O)CC[C@@H]12)OCCO3
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Solvent: CN(C)C=O
Product: C[C@]12C=C(Cl)C3(C[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12)OCCO3
Yield: 100.6 %

Procedure:
5.0 g of 2-chloro-3,3-ethylenedioxy-5α-androst-1-en-17β-ol is stirred in 50 ml of dimethylformamide with 10 g of pyidinium dichromate for 17 hours at room temperature and then worked up as described in Example 10B. After evaporation, 5 g of 2-chloro-3,3-ethylenedioxy-5α-androst-1-en-17-one is obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:14](=O)[N:13]([C@@H:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH3:17])[CH2:12][CH2:11][CH2:10][O:9]2)[CH:5]=[CH:6][CH:7]=1.CO.[OH-].[Na+]>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]2[CH2:14][N:13]([C@@H:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH3:17])[CH2:12][CH2:11][CH2:10][O:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: C[C@H](c1ccccc1)N1CCCOC(c2cccc(Br)c2)C1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: C[C@H](c1ccccc1)N1CCCOC(c2cccc(Br)c2)C1
Temperature: 0 °C
Yield: 98.6 %

Procedure:
To a solution of 2-(3-bromo-phenyl)-4-((R)-1-phenyl-ethyl) -[1,4]oxazepan-3-one (diastereomer 1) (9.39 g, 25.1 mmol) in tetrahydrofuran (75 ml) was added 1.0M-borane-tetrahydrofuran complex in tetrahydrofuran (75.0 ml, 75.0 mmol) at 0° C. The mixture was refluxed for 4 hours. The mixture was cooled to 0° C. and methanol (100 ml) and 6.0 N aqueous sodium hydroxide (100 ml) was added carefully. The mixture was refluxed for 2 hours and cooled to room temperature. The solvent was removed under reduced pressure. The residue was partitioned between water and chloroform. The organic layer was washed with brine, dried over sodium sulfate, concentrated in vacuo. The residue was purified by silica gel column chromatography (eluant; hexane/ethyl acetate=4/1) to afford diastereomerically pure 2-(3-bromophenyl)-4-((R)-1-phenyl-ethyl)-[1,4]oxazepane as colorless oil (8.92 g, 99%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:12])=[C:6]([S:8](Cl)(=[O:10])=[O:9])[CH:7]=1.[CH3:13][NH:14][CH3:15]>C1COCC1.CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:12])=[C:6]([S:8]([N:14]([CH3:15])[CH3:13])(=[O:10])=[O:9])[CH:7]=1
Reactant: Cc1ccc(F)cc1S(=O)(=O)Cl
Reactant: CNC
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ccc(F)cc1S(=O)(=O)N(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99 %

Procedure:
A mixture of 5-fluoro-2-methylbenzene sulfonylchloride (2.1 mL, 14.3 mmol) in THF (18 mL) and 2 M dimethylamine in methanol (18 mL), was stirred at room temperature for 0.5 h. The resulting mixture was concentrated under reduced pressure to give a crude product as a mixture of white solid and colourless oil. The crude product was purified by column (30% EtOAc in Hexane) to give the titled compound as a colourless oil (3.09 g, 99% yield).
Reaction SMILES: [F:1][C:2]([F:39])([F:38])[C:3]([F:37])([C:33]([F:36])([F:35])[F:34])[CH2:4][C:5]([F:32])([F:31])[CH2:6][C:7]([F:30])([F:29])[CH2:8][CH:9]([C:25]([F:28])([F:27])[F:26])[CH2:10][CH:11]([C:21]([F:24])([F:23])[F:22])[CH2:12][CH:13]([C:17]([F:20])([F:19])[F:18])[CH2:14][CH2:15]I.C(O)C.[S-:43][C:44]#[N:45].[K+]>C(O)(=O)C>[F:1][C:2]([F:39])([F:38])[C:3]([F:37])([C:33]([F:36])([F:35])[F:34])[CH2:4][C:5]([F:32])([F:31])[CH2:6][C:7]([F:30])([F:29])[CH2:8][CH:9]([C:25]([F:28])([F:27])[F:26])[CH2:10][CH:11]([C:21]([F:24])([F:23])[F:22])[CH2:12][CH:13]([C:17]([F:20])([F:19])[F:18])[CH2:14][CH2:15][S:43][C:44]#[N:45]
Reactant: FC(F)(CC(CC(CC(CCI)C(F)(F)F)C(F)(F)F)C(F)(F)F)CC(F)(F)CC(F)(C(F)(F)F)C(F)(F)F
Reactant: N#C[S-]
Agent: [K+]
Solvent: CCO
Solvent: CC(=O)O
Product: N#CSCCC(CC(CC(CC(F)(F)CC(F)(F)CC(F)(C(F)(F)F)C(F)(F)F)C(F)(F)F)C(F)(F)F)C(F)(F)F
Reaction time: 8 h
Yield: 94.4 %

Procedure:
According to scheme (27) above, in a flask that can be equipped with an agitator, thermocouple and a reflux condenser, 20 grams (27 mmol) of 1,1,1,2,4,4,6,6-octafluoro-2,8,10,12-tetrakis(trifluoromethyl)-14-iodotetradecane (see, e.g. Published Patent Applications), 20 ml of absolute ethanol, 3.9 grams (40.5 mmol) of potassium thiocyanate (KSCN) and 0.5 ml of glacial acetic acid (HOAc) can be placed to form a mixture. The mixture can be heated to reflux (84.7 C) and maintained stirring for overnight. The mixture can be concentrated in vacuo to afford what can be observed as a thick yellow slurry. The slurry can be extracted with 300 ml of diethyl ether and decanted twice and filtered to afford a wet cake and a filtrate. The wet cake can be washed with three 100 ml portions of diethyl ether and the filtrates combined. The combined filtrates can be concentrated in vacuo to afford 17.12 grams (94.6% yield) of the 1,1,1,2,4,4,6,6-octafluoro-2,8,10,12-tetrakis(trifluoromethyl)-14-thiocyanatotetradecane product that can be observed as a light yellow oil. The product structure can be confirmed by NMR and/or chromatographic analysis.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][CH3:15])=[C:8]2[C:3]=1[C:4](=[O:17])[C:5](I)=[CH:6][NH:7]2.[N:18]1[CH:23]=[CH:22][CH:21]=[C:20](B(O)O)[CH:19]=1.C(=O)([O-])[O-].[Na+].[Na+].O>COCCOC.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].ClCCl>[F:1][C:2]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][CH3:15])=[C:8]2[C:3]=1[C:4](=[O:17])[C:5]([C:20]1[CH:19]=[N:18][CH:23]=[CH:22][CH:21]=1)=[CH:6][NH:7]2
Reactant: OB(O)c1cccnc1
Reactant: CCCOc1ccc(F)c2c(=O)c(I)c[nH]c12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: COCCOC
Solvent: O
Product: CCCOc1ccc(F)c2c(=O)c(-c3cccnc3)c[nH]c12
Temperature: 90 °C
Reaction time: 2 h
Yield: 35.8 %

Procedure:
5-Fluoro-3-iodo-8-propoxy-1H-quinolin-4-one (600 mg, 1.73 mmol) was suspended in 1,2-dimethoxyethane (12 ml). 3-pyridine boronic acid (752 mg), 1,1′-bis(diphenylphosphino)ferrocene dichloro palladium(II)-dichloromethane complex (PdCl2(DPPF)) (76 mg, 0.093 mmol), and 2N sodium carbonate aqueous solution (2.54 ml) were added to the resulting suspension in that order. The mixture was stirred at 90° C. for 2 hours under a nitrogen atmosphere. After the reaction mixture was cooled to room temperature, water was added, and the resulting mixture was extracted with ethyl acetate. The organic layer was concentrated under reduced pressure, and the residue was then purified by silica gel column chromatography (dichloromethane:methanol=15:1). The purified product was concentrated under reduced pressure, and then recrystallized from ethanol to thereby obtain 185 mg of powdery pale brown 5-fluoro -8-propoxy-3-pyridin-3-yl-1H-quinolin-4-one (yield: 36%).
Reaction SMILES: C([O:5][C:6](=[O:43])[C@@H:7]([NH:29][S:30]([C:33]1[CH:38]=[CH:37][C:36]([NH:39][C:40](=[O:42])[CH3:41])=[CH:35][CH:34]=1)(=[O:32])=[O:31])[CH2:8][NH:9][C:10](=[O:28])[C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][C:19](=[O:27])[NH:20][C:21]2[NH:22][CH2:23][CH2:24][CH2:25][N:26]=2)=[CH:13][CH:12]=1)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[C:40]([NH:39][C:36]1[CH:35]=[CH:34][C:33]([S:30]([NH:29][C@@H:7]([CH2:8][NH:9][C:10](=[O:28])[C:11]2[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][C:19](=[O:27])[NH:20][C:21]3[NH:26][CH2:25][CH2:24][CH2:23][N:22]=3)=[CH:13][CH:12]=2)[C:6]([OH:43])=[O:5])(=[O:31])=[O:32])=[CH:38][CH:37]=1)(=[O:42])[CH3:41]
Reactant: CC(=O)Nc1ccc(S(=O)(=O)N[C@@H](CNC(=O)c2ccc(CCC(=O)NC3=NCCCN3)cc2)C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)Nc1ccc(S(=O)(=O)N[C@@H](CNC(=O)c2ccc(CCC(=O)NC3=NCCCN3)cc2)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
57 mg (0.09 mmol) of (2S)-2-(4-acetylamino-benzenesulfonylamino)-3-(4-(2-(1,4,5,6-tetrahydropyrimidin-2-ylcarbamoyl)-ethyl)-benzoylamino)-propionic acid tert-butyl ester was dissolved in 2 ml of dichloromethane and 2 ml of trifluoroacetic acid was added. The solution was stirred at room temperature for 3 hours. The solvent was removed in vacuo and toluene was added to the residue and then removed in vacuo. The residue was dissolved in acetonitrile/water (1/1) and lyophilized. Yield 42 mg. MS (ES+): m/e=559.2 (M+H+).
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=[C:11]2[C:19](OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:20][CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:37][O:38][CH2:39][CH2:40][S:41]([C:44]1[CH:49]=[CH:48][C:47](B(O)O)=[CH:46][CH:45]=1)(=[O:43])=[O:42].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.C(OCC)(=O)C.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>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=[C:11]2[C:19]([C:47]2[CH:48]=[CH:49][C:44]([S:41]([CH2:40][CH2:39][O:38][CH3:37])(=[O:42])=[O:43])=[CH:45][CH:46]=2)=[CH:20][CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COCCS(=O)(=O)c1ccc(B(O)O)cc1
Reactant: Cc1ccc(S(=O)(=O)OC(=CC2CCCC2)c2cc3cccnc3n2S(=O)(=O)c2ccccc2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COCCS(=O)(=O)c1ccc(C(=CC2CCCC2)c2cc3cccnc3n2S(=O)(=O)c2ccccc2)cc1
Yield: 59 %

Procedure:
To a mixture of toluene-4-sulfonic acid 1-(1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-cyclopentyl-vinyl ester (prepared as in Example 43, 2.14 g, 4 mmol), 4-(2-methoxy-ethanesulfonyl)-phenylboronic acid (prepared as in Example 88, 2.5 g, 10 mmol) and dichlorobis(triphenylphosphine)palladium (II) (280 mg, 0.4 mmol) in dioxane (20 mL) was added an aqueous sodium carbonate solution (2 M, 10 mL). The resulting mixture was subjected to microwave irradiation for 2 h at 100° C. The mixture was diluted with ethyl acetate (100 mL), washed with a saturated aqueous sodium bicarbonate solution (2×50 mL), brine, dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by flash silica gel chromatography (silica gel from QingDao, 200-300 mesh, glass column from Shanghai SD company, 25% ethyl acetate/hexanes) afforded 1-benzenesulfonyl-2-{2-cyclopentyl-1-[4-(2-methoxy-ethanesulfonyl)-phenyl]-vinyl}-1H-pyrrolo[2,3-b]pyridine (1.3 g, 57%) as a white solid: LC/MS m/e calcd for C29H30N2O5S2 [M+H]+ 551.70, observed 551.4.
Reaction SMILES: [CH3:1][C:2]1([CH3:32])[CH2:11][CH:10]=[C:9](/[CH:12]=[CH:13]/[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:7]=[C:6](/[CH:20]=[CH:21]/[C:22]3[CH:31]=[CH:30][C:25]([C:26]([O:28]C)=[O:27])=[CH:24][CH:23]=3)[CH:5]=[CH:4][C:3]1=2.[OH-].[Na+].Cl>O1CCCC1.C(O)C>[CH3:1][C:2]1([CH3:32])[CH2:11][CH:10]=[C:9](/[CH:12]=[CH:13]/[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:7]=[C:6](/[CH:20]=[CH:21]/[C:22]3[CH:23]=[CH:24][C:25]([C:26]([OH:28])=[O:27])=[CH:30][CH:31]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: COC(=O)c1ccc(/C=C/c2ccc3c(c2)C(/C=C/c2ccccc2)=CCC3(C)C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CC1(C)CC=C(/C=C/c2ccccc2)c2cc(/C=C/c3ccc(C(=O)O)cc3)ccc21
Reaction time: 8 h

Procedure:
To a stirred solution of methyl 4-[(E)-[5,6-dihydro-5,5-dimethyl-8-[(E)-phenylethenyl]-2-naphthalenyl]ethenyl]benzoate (0.206 g, 0.49 mmol) in a mixture of tetrahydrofuran/ethanol (1:1, 2 mL) was added aqueous sodium hydroxide (5N, 0.98 mL, 4.90 mmol). The mixture was stirred overnight. Hydrochloric acid 1N was then added to precipitate the acid and ≈half of the volume of the solvents was evaporated. The white solid was filtered and washed with water. The solid was then dissolved in dichloromethane/ethanol, filtered and recrystallized from this mixture by evaporating the solvents. The title compound was obtained (0.149 g, 75%) as a white solid.
Reaction SMILES: [C:1]([N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[NH:6][C:5]1=[O:13])([CH3:3])=C.[H-].[Na+].Cl.ClCC[N:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.Cl>CN(C=O)C.O>[N:20]1([CH2:3][CH2:1][N:4]2[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=3[NH:6][C:5]2=[O:13])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: ClCCN1CCCCC1
Reactant: C=C(C)n1c(=O)[nH]c2ccccc21
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1[nH]c2ccccc2n1CCN1CCCCC1
Temperature: 45 °C
Yield: 46.7 %

Procedure:
A solution of 1-isopropenyl-1,3-dihydro-2H-benzimidazol-2-one (35 g, 0.2 moles) in DMF (250 ml) was added dropwise to a suspension of 80% sodium hydride (6 g, 0.2 moles) in DMF (50 ml). The reaction mixture was first heated at 45° C. for 30 minutes, allowed to cool at room temperature, and an additional amount of 80% sodium hydride (7.2 g, 0.24 moles) was added. Then 1-(2-chloroethyl)piperidine hydrochloride (44.16 g, 0.24 moles) was added portionwise and the reaction mixture was heated at 80° C.-90° C. for 3 hours. The mixture was then cooled at room temperature, adjusted to pH 3 with 37% aqueous HCl, and heated to 80° C. for additional 2 hours. The reaction mixture was poured into water and washed with ethyl acetate. The aqueous phase was adjusted to pH 8-9 with a saturated sodium carbonate solution and extracted into ethyl acetate. The organic layer was taken to dryness to give an ivory solid which after crystallization from isopropyl ether afforded 22.9 g of the title compound. M.p. 123° C.-125° C.
Reaction SMILES: [O:1]=[C:2]([NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:3][C:4]([O:6]CC)=[O:5].CO[CH:18]=[CH:19][C:20](=O)[CH3:21].[O-]CC.[Na+].O.[OH-].[Li+]>CO.O>[CH3:18][C:19]1[N:9]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:2](=[O:1])[C:3]([C:4]([OH:6])=[O:5])=[CH:21][CH:20]=1
Reactant: CCOC(=O)CC(=O)Nc1ccccc1
Reactant: COC=CC(C)=O
Agent: CC[O-]
Agent: [Li+]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Cc1ccc(C(=O)O)c(=O)n1-c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.1 %

Procedure:
Ethyl 3-oxo-3-(phenylamino)propionate (56.8 g, 0.27 mol) and 4-methoxy-3-buten-2-one (30.2 g, 0.30 mol) were dissolved in methanol (300 mL), and 20% sodium ethoxide. (112 g, 0.33 mol) was added dropwise thereto at room temperature. After the dropwise addition, the mixture was refluxed for 8 hours under heating. The reaction mixture was cooled and then concentrated under reduced pressure, and thus obtained residue was dissolved in a mixed solution of 1,4-dioxane (200 mL) and water (200 mL). To the resultant solution, lithium hydroxide monohydrate (23.0 g, 0.55 mol) was added, and the mixture was stirred overnight at room temperature. The reaction mixture was poured into water, and washed with ethyl acetate. The aqueous layer was acidified by adding citric acid, and then extracted with chloroform. The organic layer was washed with water, dried, and concentrated, and thus obtained crystal was washed with ethyl acetate, to obtain 43.4 g of a desired product (yield: 69%).