Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[C:3]=1[CH2:4][O:5][C:6]1[N:11]2[N:12]=[C:13]([CH3:18])[C:14]([C:15](O)=[O:16])=[C:10]2[CH:9]=[C:8]([CH2:19][CH3:20])[CH:7]=1.Cl.CN(C)CCCN=C=NCC.ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[NH2:57][CH2:58][C:59]([NH:64][C:65](=[O:71])[O:66][C:67]([CH3:70])([CH3:69])[CH3:68])([CH3:63])[CH2:60][CH2:61][CH3:62]>O1CCCC1>[C:67]([O:66][C:65](=[O:71])[NH:64][C:59]([CH3:63])([CH2:60][CH2:61][CH3:62])[CH2:58][NH:57][C:15]([C:14]1[C:13]([CH3:18])=[N:12][N:11]2[C:6]([O:5][CH2:4][C:3]3[C:21]([F:25])=[CH:22][CH:23]=[CH:24][C:2]=3[F:1])=[CH:7][C:8]([CH2:19][CH3:20])=[CH:9][C:10]=12)=[O:16])([CH3:70])([CH3:69])[CH3:68]
Reactant: CCc1cc(OCc2c(F)cccc2F)n2nc(C)c(C(=O)O)c2c1
Reactant: CCCC(C)(CN)NC(=O)OC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCCC(C)(CNC(=O)c1c(C)nn2c(OCc3c(F)cccc3F)cc(CC)cc12)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 19 %

Procedure:
A solution of 280 mg (0.19 mmol, 23% purity) of 7-[(2,6-difluorobenzyl)oxy]-5-ethyl-2-methylpyrazolo[1,5-a]pyridine-3-carboxylic acid (Example 168A) in 4 ml of tetrahydrofuran was admixed with 43 mg (0.22 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (CAS: 25952-53-8) and 30 mg (0.22 mmol) of 1-hydroxy-7-azabenzotriazole (CAS: 39968-33-7). The solution was stirred at room temperature for 20 minutes. The reaction mixture was admixed with 0.097 ml (0.56 mmol) of N,N-diisopropylethylamine and 48 mg (0.22 mmol) of rac-(1-amino-2-methylpentan-2-yl)carbamic acid tert-butyl ester (Example 152A). The mixture was stirred at room temperature for a further 24 hours, and the reaction mixture was then concentrated under reduced pressure. The residue was partitioned between dichloromethane and water. The organic phase was removed and concentrated under reduced pressure. The residue was purified by preparative HPLC chromatography (Method 21), which gave 19 mg (19% yield, 95% purity) of product.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[N:13]=[CH:12][N:11]=[C:10]([NH:14]C3C=C(OC)C(OC)=C(OC)C=3)[N:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.N.[NH2:28][C:29]1[CH:30]=[C:31]([CH:48]=[CH:49][CH:50]=1)[C:32]([NH:34][C:35]1[CH:40]=[CH:39][C:38]([O:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)=[CH:37][CH:36]=1)=[O:33]>CS(C)=O>[NH2:14][C:10]1[N:11]=[CH:12][N:13]=[C:8]([C:7]2[C:2]([NH:28][C:29]3[CH:30]=[C:31]([CH:48]=[CH:49][CH:50]=3)[C:32]([NH:34][C:35]3[CH:36]=[CH:37][C:38]([O:41][C:42]4[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=4)=[CH:39][CH:40]=3)=[O:33])=[N:3][CH:4]=[CH:5][CH:6]=2)[N:9]=1
Reactant: COc1cc(Nc2ncnc(-c3cccnc3Cl)n2)cc(OC)c1OC
Reactant: Nc1cccc(C(=O)Nc2ccc(Oc3ccccc3)cc2)c1
Agent: N
Solvent: CS(C)=O
Product: Nc1ncnc(-c2cccnc2Nc2cccc(C(=O)Nc3ccc(Oc4ccccc4)cc3)c2)n1
Reaction time: 8 h

Procedure:
[4-(2-Chloro-pyridin-3-yl)-[1,3,5]triazin-2-yl]-(3,4,5-trimethoxy-phenyl)amine (Example 2, Step 4) (247 mg, 1.08 mmol) was suspended in a 2 M solution of NH3 in IpOH (3 ml)(Aldrich), and the reaction mixture was stirred overnight in a sealed tube. Concentration, trituration in a small amount of MeOH, and filtration provided a white solid. A portion of this material (97 mg, 0.47 mmol) was mixed with 3-amino-N-(4-phenoxyphenyl)benzamide (320 mg, 0.96 mmol) and DMSO (250 ml), and stirred overnight at 90° C. The dark residue was diluted with IpOH, sonicated, triturated, and then concentrated. Upon dilution with IpOH, a light green solid was isolated by filtration. MS m/z=476.5. [M+H]+. Calc'd for C27H21N7O2: 475.18.
Reaction SMILES: [Cl:1][C:2]1([C:8]([O:10][CH3:11])=[O:9])[CH2:4][CH:3]1C(O)=O.[OH-].[Na+].[Na].[F-:15].[Na+]>O>[Cl:1][C:2]1([C:8]([O:10][CH3:11])=[O:9])[CH2:4][CH:3]1[F:15]
Reactant: COC(=O)C1(Cl)CC1C(=O)O
Reactant: [F-]
Agent: [Na+]
Agent: [Na]
Agent: [OH-]
Solvent: O
Product: COC(=O)C1(Cl)CC1F
Yield: 79.1 %

Procedure:
To 111 g of 2-chloro-2-methoxycarbonyl-1-cyclopropanecarboxylic acid was added 200 ml of water. Further, a solution of 24.87 g of sodium hydroxide dissolved in 300 ml of water was added thereto under ice-cooling and stirring to thereby give sodium salt. To this aqueous solution was added 52.25 g of sodium fluoride. Next, 1.3 equivalents, to carboxylic acid, of 10% (v/v) fluorine gas (diluted with nitrogen: 600 ml/min) was bubbled into this solution under ice-cooling and stirring. After the completion of the bubbling, the pH value of the reaction mixture was regulated to 8 to 9 by adding a 1N aqueous solution of sodium hydroxide. Then it was extracted with two 250 ml portions of dichloromethane. The organic layer was collected and dried over sodium sulfate. After evaporating the solvent under reduced pressure, 75 g of the title compound was obtained in the form of a crude product (cis:trans=3:2). After adjusting pH value of the separated aqueous layer to 2 to 3 with hydrochloric acid, it was extracted with two 100 ml portions of dichloromethane. Thus 23.1 g of the starting compound was recovered. After distilling the crude reaction product, the total yield of the cis- and trans-compounds was 76.4% (calculated by excluding the recovered starting compound). The analytical data of the title compound are as follows.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][CH:13]([CH2:16][OH:17])[CH2:12][CH2:11]2)=[CH:4][CH:3]=1.F[C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][CH:13]([CH2:16][O:17][C:19]3[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=3)[CH2:12][CH2:11]2)=[CH:4][CH:3]=1
Reactant: OCC1CCN(CCc2ccc(Cl)cc2)CC1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Product: O=[N+]([O-])c1ccc(OCC2CCN(CCc3ccc(Cl)cc3)CC2)cc1

Procedure:
In a manner similar to Preparation 2, react 1-[2-(4-chlorophenyl)ethyl]-4-piperidinemethanol with 1-fluoro4-nitrobenzene to obtain the title compound.
Reaction SMILES: [Br:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][C:5]([Br:11])=[CH:4][N:3]=1.C.[H][H]>[Pd].CO>[NH2:8][C:7]1[C:2]([Br:1])=[N:3][CH:4]=[C:5]([Br:11])[CH:6]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1cc(Br)cnc1Br
Agent: [Pd]
Solvent: CO
Product: Nc1cc(Br)cnc1Br
Yield: 0.1 %

Procedure:
43.00 g (152.52 mol) of 2,5-dibromo-3-nitropyridine are hydrogenated in 1.5 g of Pd (10%) on activated charcoal in 450 ml of methanol until the calculated mount of hydrogen has been consumed, the catalyst is filtered off, and the filtrate is freed from solvent, giving 37.56 g of 3-amino-2,5-dibromopyridine. ##STR12##
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][N:5]=[CH:4]1.FC(F)(F)S(O[CH2:14][C:15]([CH3:37])([O:17][C:18]1[CH:27]=[CH:26][C:25]2[C:24](=[O:28])[CH2:23][CH2:22][CH2:21][C:20]=2[C:19]=1[CH2:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH3:16])(=O)=O>C(#N)C>[N:3]1([CH2:14][C:15]([CH3:37])([CH3:16])[O:17][C:18]2[C:19]([CH2:29][CH2:30][C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)=[C:20]3[C:25](=[CH:26][CH:27]=2)[C:24](=[O:28])[CH2:23][CH2:22][CH2:21]3)[CH:7]=[CH:6][N:5]=[CH:4]1
Reactant: c1c[nH]cn1
Reactant: CC(C)(COS(=O)(=O)C(F)(F)F)Oc1ccc2c(c1CCc1ccccc1)CCCC2=O
Agent: [H-]
Agent: [Na+]
Solvent: CC#N
Product: CC(C)(Cn1ccnc1)Oc1ccc2c(c1CCc1ccccc1)CCCC2=O
Yield: 92 %

Procedure:
A mixture of sodium hydride (60% dispersion in oil, 32 mg, 0.81 mmol), acetonitrile (0.4 mL), and imidazole (275 mg, 4.0 mmol) was stirred at room temperature for 10 min, whereupon a solution of 2-methyl-2-{[5-oxo-1-(2-phenylethyl)-5,6,7,8-tetrahydro-2-naphthalenyl]oxy}propyl trifluoromethane-sulfonate (190 mg, 0.40 mmol) in acetonitrile (0.8 mL) was added. The resulting mixture was stirred at reflux for 20 min and was then concentrated. The residue was purified by dry-flash column chromatography (SiO2, 1-10% 2-propanol-dichloromethane) to give 6-[2-(1H-imidazol-1-yl)-1,1-dimethylethoxy]-5-(2-phenylethyl)-3,4-dihydro-1(2H)-naphthalenone as a colorless oil, 126 mg, 92% yield. NMR spectrum was consistent with structure. MS EI: M+• 388.2149 (M+• 388.2151).
Reaction SMILES: [CH2:1]([C:3]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)[N:4]=1)[CH3:2].[H-].[Na+].CN(C=O)C.[CH3:26][N:27]1[C:31]2=[N:32][CH:33]=[CH:34][CH:35]=[C:30]2[N:29]=[C:28]1S(C)(=O)=O>CO>[CH2:1]([C:3]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:17]=[CH:16][C:15]([O:18][C:28]3[N:27]([CH3:26])[C:31]4=[N:32][CH:33]=[CH:34][CH:35]=[C:30]4[N:29]=3)=[CH:14][CH:13]=2)[N:4]=1)[CH3:2]
Reactant: CCc1nn(-c2ccc(O)cc2)c2ncccc12
Reactant: Cn1c(S(C)(=O)=O)nc2cccnc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: CCc1nn(-c2ccc(Oc3nc4cccnc4n3C)cc2)c2ncccc12
Temperature: 180 °C
Reaction time: 1 h
Yield: 64.6 %

Procedure:
To a mixture of 4-(3-ethyl-1H-pyrazolo[3,4-b]pyridin-1-yl)phenol (120 mg) obtained in Example 8, step D), sodium hydride (60% in oil, 20.1 mg) and DMF (5.0 ml) was added 3-methyl-2-(methylsulfonyl)-3H-imidazo[4,5-b]pyridine (106 mg), and the mixture was stirred under microwave irradiation at 180° C. for 1 hr. The reaction mixture diluted with methanol, and the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (120 mg).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1.N1C=CC=CC=1.[O:19](S(C(F)(F)F)(=O)=O)[S:20]([C:23]([F:26])([F:25])[F:24])(=O)=[O:21]>C(Cl)(Cl)Cl>[F:24][C:23]([F:26])([F:25])[S:20]([O:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1)(=[O:21])=[O:19]
Reactant: O=C1CCc2ccc(O)cc2N1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: O=C1CCc2ccc(OS(=O)(=O)C(F)(F)F)cc2N1
Temperature: 15 °C
Yield: 96.1 %

Procedure:
Step R1-1: To a suspension of 7-hydroxy-3,4-dihydroquinolin-2(1H)-one (200 g) in CHCl3 (2.0 L) was added pyridine (212 g) at room temperature over 10 minutes. Tf2O (344 g) was added to the mixture over 35 minutes, keeping the temperature below 10° C. After the mixture was allowed to warm to 15° C. over 1 hour, the reaction mixture was cooled to 0° C. and quenched by addition of water (2.0 L). The organic layer was separated, washed with aqueous saturated KHSO4 and water twice, dried over Na2SO4 and concentrated to obtain 2-oxo-1,2,3,4-tetrahydroquinolin-7-yl trifluoromethanesulfonate as a pale yellow solid (346 g).
Reaction SMILES: [C:1]1([C:7]2([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:11]([CH2:12]O)[CH2:10][N:9]([CH:14]([CH3:16])[CH3:15])[C:8]2=[O:17])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)([Cl:26])=O.N1C=CC=CC=1.[OH-].[Na+]>C(Cl)(Cl)Cl>[Cl:26][CH2:12][CH:11]1[CH2:10][N:9]([CH:14]([CH3:16])[CH3:15])[C:8](=[O:17])[C:7]1([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)N1CC(CO)C(c2ccccc2)(c2ccccc2)C1=O
Reactant: O=S(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CC(C)N1CC(CCl)C(c2ccccc2)(c2ccccc2)C1=O

Procedure:
A solution of 43 g. (0.14 mole) of 3,3-diphenyl-4-hydroxymethyl-1-isopropyl-2-pyrrolidinone in 250 ml. of chloroform was treated with 33 g. (0.28 mole) of thionyl chloride over a one minute period followed by the dropwise addition of 22 g. (0.23 mole) of pyridine over a 30 minute period. The mixture was refluxed 18 hours and then poured onto ice. The cold mixture was made basic by the addition of sodium hydroxide. The chloroform layer was separated, dried over sodium sulfate and concentrated. The residue was crystallized using charcoal from a 25% ethyl acetate -- 75% isopropyl ether mixture. The crystalline solid was recrystallized from a 75% ethanol -- 25% water mixture and then from isopropyl ether. The dried 4-chloromethyl-3,3-diphenyl-1-isopropyl-2-pyrrolidinone weighed 23 g. and melted at 114°-116° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH2:12][CH3:13])=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5](OC)=[O:6].[H-].[Al+3].[Li+].[H-].[H-].[H-].O>C1COCC1>[NH2:1][C:2]1[C:3]([CH2:12][CH3:13])=[C:4]([CH2:5][OH:6])[CH:9]=[CH:10][CH:11]=1
Reactant: CCc1c(N)cccc1C(=O)OC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CCc1c(N)cccc1CO
Reaction time: 5 h
Yield: 90 %

Procedure:
To a solution of methyl 3-amino-2-ethylbenzoate (0.83 g, 4.63 mmol), in THF (40 ml) was added Lithium aluminium hydride (0.9 g, 23.7 mmol). The mixture was heated at 50 C. for 5 h, cooled to 0 C. and hydrolysed cautiously with water. The slurry was extracted with EtOAc (×5). The extracts were washed with brine, dried Na2SO4, and evaporated. The residue was purified by chromatography (CH2Cl2/MeOH) to give the title compound 0.63 g (89%) as a white powder.
Reaction SMILES: [CH3:1][C:2]1[CH2:11][N:10]([CH2:12][CH2:13][CH3:14])[C:9]2[N:8]3[CH2:15][N:16]([OH:18])[CH:17]=[C:7]3[CH:6]=[N:5][C:4]=2[C:3]=1[NH:19][S:20]([CH3:23])(=[O:22])=[O:21].[OH-].[Na+].Cl[C:27]([F:32])([F:31])C(O)=O>CN(C)C=O>[F:31][CH:27]([F:32])[O:18][N:16]1[CH:17]=[C:7]2[CH:6]=[N:5][C:4]3[C:3]([NH:19][S:20]([CH3:23])(=[O:22])=[O:21])=[C:2]([CH3:1])[CH2:11][N:10]([CH2:12][CH2:13][CH3:14])[C:9]=3[N:8]2[CH2:15]1
Reactant: O=C(O)C(F)(F)Cl
Reactant: CCCN1CC(C)=C(NS(C)(=O)=O)C2=C1N1CN(O)C=C1C=N2
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CCCN1CC(C)=C(NS(C)(=O)=O)C2=C1N1CN(OC(F)F)C=C1C=N2
Temperature: 150 °C

Procedure:
4.98 g 3-methyl-4-methylsulfonylamino-1-propyl-imidazo[1,5-a]pyrido[3,2-e]pyrazin-8-ol (Example 86) and 1.6 g sodium hydroxide were dissolved in 20 ml dimethylformamide. After 10 min stirring 1.85 ml chlorodifluoroacetic acid was added dropwise. The mixture was heated 5 h at 150° C. bath temperature with stirring. After cooling the product was extracted with ethyl acetate (200 ml, 300 ml), the combined organic phases were washed with water (2×100 ml), the organic phase was dried over sodium sulfate, filtered off, and evaporated to dryness.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=O)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[O:20]1[CH2:25][CH2:24][N:23]([CH2:26][CH2:27][NH:28][C:29](=[O:34])/[CH:30]=[C:31](\[NH2:33])/[CH3:32])[CH2:22][CH2:21]1>C1(C)C=CC=CC=1>[O:20]1[CH2:21][CH2:22][N:23]([CH2:26][CH2:27][NH:28][C:29]([C:30]2[C:31]([CH3:32])=[N:33][C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:11][C:10]=2[C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)=[O:34])[CH2:24][CH2:25]1
Reactant: C/C(N)=C/C(=O)NCCN1CCOCC1
Reactant: O=C(C=Cc1cccc([N+](=O)[O-])c1)c1ccccc1
Solvent: Cc1ccccc1
Product: Cc1nc(-c2ccccc2)cc(-c2cccc([N+](=O)[O-])c2)c1C(=O)NCCN1CCOCC1
Temperature: 25 °C
Yield: 31.2 %

Procedure:
A mixture of 3-(3-nitrophenyl)-1-phenyl-2-propen-1-one (20 g) and N-(2-morpholinoethyl)-3-aminocrotonamide (21.9 g) in toluene (200 ml) was refluxed for 5 hours. After allowing to cool at ambient temperature, the reaction mixture was concentrated in vacuo. The residue was subjected to a column chromatography on silica gel eluting with a mixture of ethyl acetate and tetrahydrofuran (100:1 V/V). The fractions containing the object compound were combined and concentrated in vacuo. The residue was recrystallized from ethyl alcohol to give 3-(2-morpholinoethylcarbamoyl)-2-methyl-4-(3-nitrophenyl)-6-phenylpyridine (11.0 g, yield 31.2 %).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:9][CH2:8][CH2:7][C:6]1=[O:10].[NH:11]1[C:19]2[C:14](=[CH:15][C:16]([NH:20][C:21]3[C:22]4[S:29][C:28]([C:30]5[CH:37]=[CH:36][C:33]([CH:34]=O)=[CH:32][CH:31]=5)=[CH:27][C:23]=4[N:24]=[CH:25][N:26]=3)=[CH:17][CH:18]=2)[CH:13]=[CH:12]1>>[NH:11]1[C:19]2[C:14](=[CH:15][C:16]([NH:20][C:21]3[C:22]4[S:29][C:28]([C:30]5[CH:37]=[CH:36][C:33]([CH2:34][NH:1][CH2:2][CH2:3][CH2:4][N:5]6[CH2:9][CH2:8][CH2:7][C:6]6=[O:10])=[CH:32][CH:31]=5)=[CH:27][C:23]=4[N:24]=[CH:25][N:26]=3)=[CH:17][CH:18]=2)[CH:13]=[CH:12]1
Reactant: NCCCN1CCCC1=O
Reactant: O=Cc1ccc(-c2cc3ncnc(Nc4ccc5[nH]ccc5c4)c3s2)cc1
Product: O=C1CCCN1CCCNCc1ccc(-c2cc3ncnc(Nc4ccc5[nH]ccc5c4)c3s2)cc1

Procedure:
The title compound was prepared from 1-(3-amino-propyl)-pyrrolidin-2-one and 4-[4-(1H-indol-5-ylamino)-thieno[3,2-d)pyrimidin-6-yl]-benzaldehyde by a procedure analogous to example 17. M.P. 139-146° C.; LC-MS: 497 (MH+); HPLC RT: 4.01 minutes.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[C:16]2[NH:15][C:14](=[O:17])[O:13][C:12]([CH3:19])([CH3:18])[C:11]=2[CH:10]=[CH:9][CH:8]=1.[C:20]([NH:23][C:24]1[CH:29]=[CH:28][C:27]([SH:30])=[CH:26][CH:25]=1)(=[O:22])[CH3:21]>>[C:20]([NH:23][C:24]1[CH:29]=[CH:28][C:27]([S:30][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]2[C:16]3[NH:15][C:14](=[O:17])[O:13][C:12]([CH3:19])([CH3:18])[C:11]=3[CH:10]=[CH:9][CH:8]=2)=[CH:26][CH:25]=1)(=[O:22])[CH3:21]
Reactant: CC1(C)OC(=O)Nc2c(OCCCCCl)cccc21
Reactant: CC(=O)Nc1ccc(S)cc1
Product: CC(=O)Nc1ccc(SCCCCOc2cccc3c2NC(=O)OC3(C)C)cc1

Procedure:
Prepared analogously to Example 1 from 8-(4-chlorobutoxy)-4,4-dimethyl-4H-3,1-benzoxazin-2-one and 4-acetamido-thiophenol.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]2[CH:14]=[CH:15][C:16](=[O:19])[NH:17][CH:18]=2)=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:26](I)[CH2:27][CH3:28]>CO>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]2[CH:14]=[CH:15][C:16](=[O:19])[N:17]([CH2:26][CH2:27][CH3:28])[CH:18]=2)=[CH:4][N:3]=1
Reactant: Nc1ncc(-c2ccc(=O)[nH]c2)c(-c2ccco2)n1
Reactant: CCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CCCn1cc(-c2cnc(N)nc2-c2ccco2)ccc1=O
Temperature: 50 °C
Reaction time: 17 h
Yield: 41.2 %

Procedure:
In a reaction vessel, 5-[2-amino-4-(2-furyl)-5-pyrimidinyl]-1,2-dihydro-2-pyridinone (100 mg, 0.393 mmol) and potassium carbonate (109 mg, 0.787 mmol) were suspended in methanol (2 ml). Then, propyl iodide (134 mg, 0.787 mmol) was added thereto, followed by stirring at 50° C. for 17 hours. After the reaction was terminated, the mixture was concentrated and suspended in dimethylsulfoxide. The insoluble matters were removed by filtration and the resulting filtrate was purified by HPLC, to give the title compound (48 mg, 41%) as a pale yellow solid.
Reaction SMILES: [F:1][C:2]1([F:20])[CH2:5][C:4]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][C:10]=2[O:18][CH3:19])([OH:6])[CH2:3]1>CO.[Pd]>[NH2:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:7][C:4]2([OH:6])[CH2:5][C:2]([F:20])([F:1])[CH2:3]2)=[C:10]([O:18][CH3:19])[CH:11]=1
Reactant: COc1cc([N+](=O)[O-])ccc1OCC1(O)CC(F)(F)C1
Agent: [Pd]
Solvent: CO
Product: COc1cc(N)ccc1OCC1(O)CC(F)(F)C1
Reaction time: 1.5 h
Yield: 100 %

Procedure:
A mixture of 3,3-difluoro-1-((2-methoxy-4-nitrophenoxy)methyl)cyclobutanol (32.0 g, 111 mmol) prepared in Part F and 10% Pd/C (2.0 g, 1.879 mmol) in 700 mL MeOH was stirred under H2 at 50 psi for 1.5 h. After filtration, the filtrate was concentrated to give 1-((4-amino-2-methoxyphenoxy)methyl)-3,3-difluorocyclobutanol (28.9 g, 111 mmol, quantitative yield) as a light purple solid. 1H NMR (400 MHz, CD3OD) δ ppm 6.68 (1H, d, J=8.56 Hz), 6.35 (1 H, d, J=2.52 Hz), 6.16 (1 H, dd, J=8.31, 2.52 Hz), 4.77 (3 H, br. s.), 3.78 (2 H, s), 3.68 (3 H, s), 2.68-2.82 (2 H, m), 2.38-2.56 (2 H, m).
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([C:10]#[N:11])[C:4]=2[CH:3]=[CH:2]1.[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[H-].[Na+]>CN(C=O)C>[CH2:12]([N:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([C:10]#[N:11])[C:4]=2[CH:3]=[CH:2]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: BrCc1ccccc1
Reactant: N#Cc1cccc2[nH]ccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1cccc2c1ccn2Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of indole-4-carbonitrile (2.0 g, 14.1 mmol, 1 eq) and benzyl bromide (2.17 mL, 18.3 mmol, 1.3 eq) in dry DMF (20 mL) was added, at rt, NaH (733 mg, 18.3 mmol, 1.3 eq) portionwise under Ar(g). The resulting reaction mixture was stirred at rt overnight, and was subsequently partitioned with H2O (30 mL), and then extracted with EtOAc (3×20 mL) and CH2Cl2 (20 mL). The combined organic extracts were dried over MgSO4 and the solvent was removed in vacuo. The residue was further purified by silica gel column chromatography with hexane/EtOAc (9:1-1:3) to furnish the product, 2, as a white solid (3.30 g, 99%).
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:6]([NH:8][C@H:9]([C:14]([NH2:16])=[O:15])[CH2:10][CH2:11][S:12][CH3:13])=[O:7])[CH2:3][CH2:4][CH3:5].[ClH:24]>C(OCC)(=O)C.CCOCC>[NH2:1][C@H:2]([C:6]([NH:8][C@H:9]([C:14]([NH2:16])=[O:15])[CH2:10][CH2:11][S:12][CH3:13])=[O:7])[CH2:3][CH2:4][CH3:5].[ClH:24]
Reactant: CCC[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](CCSC)C(N)=O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CCC[C@H](N)C(=O)N[C@@H](CCSC)C(N)=O
Reaction time: 1 h
Yield: 89 %

Procedure:
4.5 g (13 mmoles) of BOC-Nva-Met-NH2 are suspended in 20 ml of ethyl acetate, and 20 ml of a 6 n hydrochloric acid solution in ethyl acetate are added to the suspension. After one hour of standing the reaction mixture is diluted with ether, the separated precipitate is filtered off, and dried in vacuo over anhydrous sodium hydroxide. The resulting 4 g of crude product are recrystallized from a mixture of methanol and ether. 3.28 g (89%) of H-Nva-Met-NH2.HCl are obtained; m.p.: 198°-200° C., Rf5 =0.40, [α]D25 =+10.2° (c=1%, in methanol).
Reaction SMILES: [OH:1][C:2]([C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1)([C:6]1[N:7]=[CH:8][N:9]([C:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:10]=1)[CH:3]([CH3:5])[CH3:4].Br[C:40]1[N:45]=[C:44]([C:46]([NH:48][CH2:49][CH3:50])=[O:47])[CH:43]=[CH:42][CH:41]=1>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>[CH2:49]([NH:48][C:46]([C:44]1[CH:43]=[CH:42][CH:41]=[C:40]([C:33]2[CH:32]=[CH:31][C:30]([C:2]([OH:1])([C:6]3[N:7]=[CH:8][N:9]([C:11]([C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=4)([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)[C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH:10]=3)[CH:3]([CH3:5])[CH3:4])=[CH:35][CH:34]=2)[N:45]=1)=[O:47])[CH3:50]
Reactant: CC(C)C(O)(c1ccc(B(O)O)cc1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: CCNC(=O)c1cccc(Br)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: CCNC(=O)c1cccc(-c2ccc(C(O)(c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)C(C)C)cc2)n1
Yield: 59.5 %

Procedure:
By the reaction in the same manner as in Example 33-(ii) using 4-[1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl]phenylboronic acid (3.10 g), 6-bromo-N-ethyl-2-pyridinecarboxamide (1.20 g) and tetrakis(triphenylphosphine)palladium(0) (0.170 g), the title compound (1.89 g) was obtained as colorless powder crystals.
Reaction SMILES: [C:1]1([C:7]#[CH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:10]1[S:11][C:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:13][N:14]=1.C(N(CC)CC)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.[Cu]I.O1CCCC1>[CH2:18]([O:17][C:15]([C:12]1[S:11][C:10]([C:8]#[C:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[N:14][CH:13]=1)=[O:16])[CH3:19]
Reactant: CCOC(=O)c1cnc(Br)s1
Reactant: C#Cc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cnc(C#Cc2ccccc2)s1
Reaction time: 0.5 h
Yield: 72.7 %

Procedure:
A solution of phenylacetylene (6.15 ml, 55.9 mmol), ethyl 2-bromothiazole-5-carboxylate (7.59 ml, 50.8 mmol), bis(triphenylphosphine)palladium(II) chloride (1.07 g, 1.52 mmol), copper (I) iodide (581 mg, 3.05 mmol), triethylamine (100 ml, 717 mmol) and tetrahydrofuran (225 mL) was stirred at 25° C. for 16 h. The reaction was worked up by concentrating to remove the THF and taken up in 400 mL of CHCl3. The CHCl3 was washed with 2×75 mL of 3.7% aq. HCl, 75 mL of brine, and dried (Na2SO4). The material was purified by silica gel chromatography using a gradient elution going from 4.5% to 8.5% EtOAc in hexanes over 30 minutes to give the titled compound, 2-phenylethynyl-thiazole-5-carboxylic acid ethyl ester (9.5 g, 73% yield), as a solid, which was used without further purification in the next step.