Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH2:4][C:5]12[CH2:11][CH:8]([CH:9]=[CH:10]1)[CH:7]1[C:12]([O:14][C:15](=[O:16])[CH:6]21)=[O:13])[CH:2]=[CH2:3].[CH2:17]([NH2:20])[CH:18]=[CH2:19]>>[CH2:17]([N:20]=[C:15]([CH:6]1[CH:7]([C:12]([OH:14])=[O:13])[CH:8]2[CH2:11][C:5]1([CH2:4][CH2:1][CH:2]=[CH2:3])[CH:10]=[CH:9]2)[OH:16])[CH:18]=[CH2:19]
Reactant: C=CCN
Reactant: C=CCCC12C=CC(C1)C1C(=O)OC(=O)C12
Product: C=CCCC12C=CC(C1)C(C(=O)O)C2C(O)=NCC=C

Procedure:
A mixture of 30 g of allylmethylbicyclo[2.2.1]hept-5-ene-2,3-dicarboxylic anhydride and 9.41 g of allylamine is heated at reflux temperature for 2 hours, water is distilled off and the product is rectified at 119°-127° C. and 2.66 Pa. This gives 30.24 g (85.5% of theory) of a pale yellow oil having the following characteristic data: n20 =1.5202, η25 =0.135 Pa.s.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:11]1([CH3:17])[CH:16]=CC=C[CH:12]=1>C(OCC)(=O)C>[C:11]([O:10][C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)([CH3:17])([CH3:16])[CH3:12]
Reactant: Cc1ccccc1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Solvent: CCOC(C)=O
Product: CC(C)(C)Oc1ccc([N+](=O)[O-])cc1

Procedure:
43.79 mmol of N-N-dimethylformamide di-tert-butyl acetal are added, at ambient temperature, to a solution of 10.78 mmol (1.5 g) of 4-nitrophenol in 10 ml of toluene. The reaction mixture is heated at reflux, with vigorous stirring, for 5 hours. The reaction mixture is diluted with ethyl acetate and then washed with water, with saturated aqueous sodium bicarbonate solution and then with 10% aqueous sodium chloride solution. The expected product is obtained by drying the organic phase and then concentrating.
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[C:12]2=[N:13][C:14]([C:17]3[C:25]4[C:20](=[CH:21][C:22]([F:26])=[CH:23][CH:24]=4)[NH:19][N:18]=3)=[CH:15][N:16]=[C:11]2[N:10]([C:27]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CS(O[CH2:51][CH2:52][CH:53]1[CH2:57][O:56][C:55]([CH3:59])([CH3:58])[O:54]1)(=O)=O.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[C:1]([NH:5][C:6]([C:8]1[C:12]2=[N:13][C:14]([C:17]3[C:25]4[C:20](=[CH:21][C:22]([F:26])=[CH:23][CH:24]=4)[N:19]([CH2:51][CH2:52][CH:53]4[CH2:57][O:56][C:55]([CH3:59])([CH3:58])[O:54]4)[N:18]=3)=[CH:15][N:16]=[C:11]2[N:10]([C:27]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:9]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC1(C)OCC(CCOS(C)(=O)=O)O1
Reactant: CC(C)(C)NC(=O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2ncc(-c3n[nH]c4cc(F)ccc34)nc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)NC(=O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2ncc(-c3nn(CCC4COC(C)(C)O4)c4cc(F)ccc34)nc12
Temperature: 65 °C
Yield: 92.2 %

Procedure:
To a solution of N-tert-butyl-2-(6-fluoro-1H-indazol-3-yl)-5-trityl-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide (80 mg, 0.135 mmol) in DMF (5 mL) was added 2-(2,2-dimethyl-1,3-dioxolan-4-yl)ethyl methanesulfonate (36 mg, 0.162 mmol) followed by K2CO3 (56 mg, 0.405 mmol). The mixture was heated at 65° C. for 4 hours. After cooling to room temperature, the mixture was poured into water, filtered and dried to give N-tert-butyl-2-(1-(2-(2,2-dimethyl-1,3-dioxolan-4-yl)ethyl)-6-fluoro-1H-indazol-3-yl)-5-trityl-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide (90 mg, 92%) The crude was used to the next step without purification. LCMS: (M+H)+=723.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[NH:6][C:7](=[O:22])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11]([Br:21])=[CH:10][CH:9]=2)=[O:4].[F:23][C:24]1[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=1[CH2:26]Br.C(N=P1(N(CC)CC)N(C)CCCN1C)(C)(C)C>CN(C)C=O>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:26][C:25]2[CH:28]=[CH:29][CH:30]=[CH:31][C:24]=2[F:23])[C:7](=[O:22])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11]([Br:21])=[CH:10][CH:9]=2)=[O:4]
Reactant: COC(=O)c1[nH]c(=O)c2ccc(Br)cc2c1-c1ccccc1
Reactant: Fc1ccccc1CBr
Agent: CCN(CC)P1(=NC(C)(C)C)N(C)CCCN1C
Solvent: CN(C)C=O
Product: COC(=O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccccc1F
Temperature: 25 °C
Reaction time: 15 h
Yield: 15.6 %

Procedure:
6-Bromo-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carboxylic acid methyl ester (54 mg), 2-fluorobenzylbromide (34 mg) and 2-tert-butylimino-2-diethylamino-1,3-dimethyl-perhydro-1,3,2-diazaphosphorine resin (2.2 mmol/g, 110 mg) were suspended in dimethylformamide (2 ml), and the suspension was shaken at room temperature for 15 hr. using a shaking machine. After filtration, the solvent was evaporated under reduced pressure, and the obtained residue was purified by preparative HPLC to give the title compound (11 mg, 15%).
Reaction SMILES: [CH2:1]([OH:5])[CH:2]([OH:4])[CH3:3].[C:6]([Si:10]([CH3:13])([CH3:12])Cl)([CH3:9])([CH3:8])[CH3:7].CCN(C(C)C)C(C)C>C(Cl)Cl.CCOCC>[Si:10]([O:5][CH2:1][CH:2]([OH:4])[CH3:3])([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:13])[CH3:12]
Reactant: CC(O)CO
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOCC
Solvent: ClCCl
Product: CC(O)CO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of propylene glycol (1.0 g, 13 mmol) in DCM (60.0 mL) was added tert-butyldimethylchlorosilane (2.0 g, 13 mmol) followed by DIPEA (3.2 mL, 18 mmol). The reaction mixture was stirred at ambient temperature for 18 hours. The solution was diluted with ether, washed with saturated aqueous NaHCO3, brine, dried over anhydrous MgSO4, filtered, and concentrated in vacuo to afford the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:43]=[CH:42][C:5]([CH2:6][NH:7][C:8]([CH:10]2[CH2:15][N:14]([C:16]3[CH:21]=[CH:20][N:19]=[C:18]([NH:22][C:23]4[CH:28]=[C:27]([O:29][CH3:30])[C:26]([O:31][CH3:32])=[C:25]([O:33][CH3:34])[CH:24]=4)[N:17]=3)[CH2:13][CH2:12][N:11]2C(OC(C)(C)C)=O)=[O:9])=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([CH:10]2[CH2:15][N:14]([C:16]3[CH:21]=[CH:20][N:19]=[C:18]([NH:22][C:23]4[CH:28]=[C:27]([O:29][CH3:30])[C:26]([O:31][CH3:32])=[C:25]([O:33][CH3:34])[CH:24]=4)[N:17]=3)[CH2:13][CH2:12][NH:11]2)=[O:9])=[CH:42][CH:43]=1
Reactant: COc1cc(Nc2nccc(N3CCN(C(=O)OC(C)(C)C)C(C(=O)NCc4ccc(C)cc4)C3)n2)cc(OC)c1OC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc(Nc2nccc(N3CCNC(C(=O)NCc4ccc(C)cc4)C3)n2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 18 h
Yield: 89 %

Procedure:
To a solution of 2.4 (43 mg, 0.073 mmol) in DCM was added TFA (10.8 μL, 0.145 mmol). The resulting solution was stirred at room temperature. After 18 hours, additional TFA (0.145 mmol) was introduced. After 30 hours, the reaction was concentrated. The material was brought up in MeOH (2 mL) and filtered through a Si-carbonate cartridge to give 2 in 89% yield. 1H NMR (300 MHz, CDCl3) δ ppm 1.86 (br. s., 1H) 2.31 (s, 3H) 2.79-3.07 (m, 2H) 3.25-3.37 (m, 1H) 3.40-3.54 (m, 2H) 3.75-3.97 (m, 10H) 4.09-4.22 (m, 1H) 4.39 (d, J=5.41 Hz, 2H) 6.10 (d, J=6.14 Hz, 1H) 6.87 (s, 2H) 7.11 (s, 4H) 7.26-7.34 (m, 1H) 8.00 (d, J=5.99 Hz, 1H); M+H 493.25580.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([C:9]2[NH:14][C:13]3[CH2:15][S:16][CH2:17][C:12]=3[C:11](=O)[N:10]=2)=[C:4]([F:19])[CH:3]=1.P(Cl)(Cl)([Cl:22])=O>>[Cl:22][C:11]1[C:12]2[CH2:17][S:16][CH2:15][C:13]=2[N:14]=[C:9]([C:5]2[CH:6]=[C:7]([F:8])[C:2]([Cl:1])=[CH:3][C:4]=2[F:19])[N:10]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1nc(-c2cc(F)c(Cl)cc2F)[nH]c2c1CSC2
Product: Fc1cc(-c2nc(Cl)c3c(n2)CSC3)c(F)cc1Cl
Temperature: 90 °C
Reaction time: 4 h

Procedure:
A mixture of 2-(4-chloro-2,5-difluorophenyl)-5,7-dihydrothieno[3,4-d]pyrimidin-4(1H)-one and phosphorous oxychloride was stirred at 90° C. for 4 hours to yield 4-chloro-2-(4-chloro-2,5-difluorophenyl)-5,7-dihydrothieno[3,4-d]pyrimidine.
Reaction SMILES: [N:1]1([C:6]2[C:7]([CH3:14])=[C:8]([CH:11]=[CH:12][CH:13]=2)[CH2:9][OH:10])[CH:5]=[CH:4][CH:3]=[CH:2]1>[O-2].[O-2].[Mn+4].C1C=CC=CC=1>[N:1]1([C:6]2[C:7]([CH3:14])=[C:8]([CH:11]=[CH:12][CH:13]=2)[CH:9]=[O:10])[CH:5]=[CH:4][CH:3]=[CH:2]1
Reactant: Cc1c(CO)cccc1-n1cccc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: c1ccccc1
Product: Cc1c(C=O)cccc1-n1cccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 82.4 %

Procedure:
A suspension of 6 g of (3-pyrrol-1-yl)2-methylbenzyl alcohol, 300 ml of benzene and 30 g of manganese dioxide was stirred at room temperature for 3 hours and 12 g of manganese dioxide were added thereto. After stirring for 2 hours, another 6 g of manganese dioxide were added to the mixture which was then stirred at room temperature for 19 hours and was vacuum filtered. The filter was rinsed with benzene and the filtrate was evaporated to dryness under reduced pressure to obtain 4.89 g of 3-(pyrrol-1-yl)-2-methylbenzaldehyde melting at 82° C.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:3]=1[C:4]#[N:5].[Cl:11]N1C(=O)CCC1=O>C(#N)C>[NH2:1][C:2]1[C:9]([Cl:11])=[CH:8][C:7]([F:10])=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: O=C1CCC(=O)N1Cl
Reactant: N#Cc1cc(F)ccc1N
Solvent: CC#N
Product: N#Cc1cc(F)cc(Cl)c1N
Temperature: 80 °C
Yield: 99.6 %

Procedure:
To a solution of 2-amino-5-fluorobenzonitrile (9.90 g, 72.8 mmol) in acetonitrile (200 mL) was added N-chlorosuccinimide (10.7 g, 80.1 mmol) in several portions. The reaction mixture was heated at 80° C. for 16 hours, then cooled and concentrated to approximately 100 mL under reduced pressure. The residue was poured into water (1 L), and the resultant precipitate was filtered, washed with water and dried (50° C. under vacuum) to give the title compound as a light brown solid (12.37 g, 100%). 1H NMR (300 MHz, CDCl3): δ 7.27 (dd, J=7.9, 2.9 Hz, 1H), 7.09 (dd, J=7.9, 2.9 Hz, 1H), 4.69 (br s, 2H).
Reaction SMILES: [BH4-].[Na+].C[O:4][C:5]([CH:7]1[CH2:11][S:10][CH:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:8]1[CH3:18])=O.Cl.C(O)C>C(O)C>[OH:4][CH2:5][CH:7]1[CH2:11][S:10][CH:9]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:8]1[CH3:18]
Reactant: COC(=O)C1CSC(c2ccccc2)N1C
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CN1C(CO)CSC1c1ccccc1
Temperature: -30 °C
Reaction time: 0.5 h
Yield: 47.8 %

Procedure:
A solution of 320 mg of sodium borohydride in 40 ml of ethanol was dropwise added to a solution of 680 mg of calcium chloride dihydrates in 20 ml of ethanol under chilling to -30° C. The resulting mixture was stirred at -30° C. for 30 minutes. To the mixture was added a solution of 2.37 g of 4-methoxycarbonyl-3-methyl-2-phenylthiazolidine in 10 ml of ethanol. The resulting mixture was stirred at 0° C. for 22 hours, and subsequently at room temperature for 1 hour. To the mixture was added 13 ml of 20% hydrochloric acid-ethanol solution. The resulting mixture was placed under reduced pressure to distill off the solvent. The residue was made alkaline by addition of 10 ml of conc. aqueous ammonia after addition of water. The aqueous mixture was extracted with methylene chloride. The extract was dried over anhydrous sodium sulfate and placed under reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography (eluent: chloroform) to give 1.00 g of 4-hydroxymethyl-3 -methyl-2-phenylthiazolidine.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:12][C:13]2[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[NH:15][N:14]=2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[CH3:22][N:23]=[C:24]=[O:25]>>[CH3:22][NH:23][C:24]([N:15]1[C:16]([C:18]([F:21])([F:19])[F:20])=[CH:17][C:13]([O:12][C:3]2[C:2]([Cl:1])=[CH:7][C:6]([C:8]([F:10])([F:9])[F:11])=[CH:5][N:4]=2)=[N:14]1)=[O:25]
Reactant: CN=C=O
Reactant: FC(F)(F)c1cnc(Oc2cc(C(F)(F)F)[nH]n2)c(Cl)c1
Product: CNC(=O)n1nc(Oc2ncc(C(F)(F)F)cc2Cl)cc1C(F)(F)F
Yield: 20.1 %

Procedure:
Reaction of 3-(3-chloro-5-trifluoromethylpyridin-2-yloxy)-5-trifluoromethylpyrazole with methyl isocyanate was carried out in the same manner as in Example 173, to give a white solid of N-methyl-3-(3-chloro-5-trifluoromethylpyridin-2-yloxy)-5-trifluoromethylpyrazole-1-carboxamide (0.39 g, yield: 20.1%). mp: 61-63° C.; 1H-NMR (CDCl3, TMS, ppm): δ 3.52 (s, 3H), 5.66 (s, 1H), 8.00 (d, J=11.8 Hz, 1H), 8.61 (d, J=1.8 Hz, 1H), 10.10-10.40 (m, 1H).
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:5]=[CH:6][C:7]2[N:13]3[CH:14]=[N:15][C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:12]3[CH2:11][N:10]([CH3:22])[C:9](=[O:23])[C:8]=2[CH:24]=1.[CH3:25]C(O)C>>[F:3][C:4]1[CH:5]=[CH:6][C:7]2[N:13]3[CH:14]=[N:15][C:16]([C:17]([O:19][CH:20]([CH3:25])[CH3:21])=[O:18])=[C:12]3[CH2:11][N:10]([CH3:22])[C:9](=[O:23])[C:8]=2[CH:24]=1
Reactant: CCOC(=O)c1ncn2c1CN(C)C(=O)c1cc(F)ccc1-2
Reactant: CC(C)O
Agent: [H-]
Agent: [Na+]
Product: CC(C)OC(=O)c1ncn2c1CN(C)C(=O)c1cc(F)ccc1-2
Temperature: 25 °C

Procedure:
100 ml of 2-propanol are treated with 100 mg of sodium hydride. 5 g of ethyl 8-fluoro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate are added thereto and the mixture is heated to boiling under reflux for 1 hour. Subsequently, the mixture is left to cool to room temperature, the separated crystals are filtered off and washed with 2-propanol and water, there being obtained isopropyl 8-fluoro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo [1,5-a][1,4]benzodiazepine-3-carboxylate of melting point 243°-244° C.
Reaction SMILES: C(C1C=C2C(C=C(C(O)=O)N2C)=CC=1)#[N:2].NC1C=CC(OCC(OC(C)(C)C)=O)=CC=1.[C:32]([C:34]1[CH:42]=[C:41]2[C:37]([CH:38]=[C:39]([C:44]([NH:46][C:47]3[CH:61]=[CH:60][C:50]([O:51][CH2:52][C:53]([O:55][C:56]([CH3:59])([CH3:58])[CH3:57])=[O:54])=[CH:49][CH:48]=3)=[O:45])[N:40]2[CH3:43])=[CH:36][CH:35]=1)#[N:33]>>[C:32]([C:34]1[CH:42]=[C:41]2[C:37]([CH:38]=[C:39]([C:44]([NH:46][C:47]3[CH:61]=[CH:60][C:50]([O:51][CH2:52][C:53]([O:55][C:56]([CH3:57])([CH3:58])[CH3:59])=[O:54])=[CH:49][CH:48]=3)=[O:45])[N:40]2[CH3:43])=[CH:36][CH:35]=1)(=[NH:2])[NH2:33]
Reactant: Cn1c(C(=O)O)cc2ccc(C#N)cc21
Reactant: Cn1c(C(=O)Nc2ccc(OCC(=O)OC(C)(C)C)cc2)cc2ccc(C#N)cc21
Agent: CC(C)(C)OC(=O)COc1ccc(N)cc1
Product: Cn1c(C(=O)Nc2ccc(OCC(=O)OC(C)(C)C)cc2)cc2ccc(C(=N)N)cc21

Procedure:
In the same manner as in Example 1 (2), 6-cyano-1-methyl-2-indolcarboxylic acid (52 mg, 0.26 mmol) and t-butyl 4-aminophenoxyacetate (63 mg, 0.29 mmol) were condensed to quantitatively give 109 mg of t-butyl 4-[(6-cyano-1-methyl-2-indolyl)carbonylamino]phenoxyacetate as a colorless solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:36]=[CH:35][C:12]([O:13][CH2:14][CH2:15][CH2:16][C:17]2[CH:34]=[CH:33][C:20]([O:21][CH2:22][C:23]3[CH:32]=[CH:31][CH:30]=[CH:29][C:24]=3[C:25]([O:27]C)=[O:26])=[CH:19][CH:18]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Li+].Cl>C1COCC1.O>[CH2:1]([O:8][C:9]1[CH:36]=[CH:35][C:12]([O:13][CH2:14][CH2:15][CH2:16][C:17]2[CH:18]=[CH:19][C:20]([O:21][CH2:22][C:23]3[CH:32]=[CH:31][CH:30]=[CH:29][C:24]=3[C:25]([OH:27])=[O:26])=[CH:33][CH:34]=2)=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccccc1COc1ccc(CCCOc2ccc(OCc3ccccc3)cc2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccccc1COc1ccc(CCCOc2ccc(OCc3ccccc3)cc2)cc1
Yield: 4.4 %

Procedure:
Methyl 2-[(4-{3-[4-(benzyloxy)phenoxy]propyl}phenoxy)methyl]benzoate (0.047 g, 0.097 mmol) was dissolved in a mixture of THF/water (7/1, 2 ml) and lithium hydroxide (9.3 mg, 0.39 mmol) was added. The reaction was performed in a single node microwave oven (7 min, 150° C.). The reaction mixture was acidified (HCl, 1 M, 1 ml) and the water phase was washed with two portions of EtOAc (2×5 ml). The organic phases were combined, dried (MgSO4) and the solvent was removed by evaporation. The crude product was purified by preparative HPLC (started with acetonitrile/buffer 60/40 and then the acetonitrile concentration was increased to 100%, the buffer was a mixture of acetonitrile/water 10/90 and ammonium acetate (0.1 M, column KR-100-7-C8, 50 mm×250 mm, flow 40 ml/min)). The product containing fractions were pooled and the acetonitrile was removed by evaporation. EtOAc (10 ml) was added and the organic phase was washed with two portions of brine and dried (MgSO4). Removing the solvent by evaporation gave 2 mg of 2-[(4{3-[4-(benzyloxy)phenoxy]propyl}phenoxy)methyl]-benzoic acid (yield 4.4%).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][N:10]=1)[C:6]#[N:7].[NH2:11][OH:12]>C(O)C>[OH:12][N:11]=[C:6]([NH2:7])[C:5]1[CH:8]=[CH:9][N:10]=[C:3]([CH2:2][OH:1])[CH:4]=1
Reactant: N#Cc1ccnc(CO)c1
Reactant: NO
Solvent: CCO
Product: NC(=NO)c1ccnc(CO)c1

Procedure:
A solution of 2-(hydroxymethyl)isonicotinonitrile (ChemPacific, 0.496 g; 3.7 mmol) and 50% aqueous hydroxylamine (1.2 mL) in ethanol (4.8 mL) was heated at 75° C. for 18 hours. The solvent was evaporated in vacuo. The residue was partitioned between DCM and water. The organic phase was poured through a hydrophobic frit and evaporated in vacuo to afford the title compound. 1H NMR (400 MHz, DMSO-d6) δ 10.02 (1 H, s), 8.50 (1 H, d, J=5.2 Hz), 7.80 (1 H, s), 7.52 (1 H, dd, J=5.2, 1.7 Hz), 5.99 (2 H, br s), 5.45 (1 H, t, J=5.8 Hz), 4.60 (2 H, d, J=5.8 Hz).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9](=[CH2:13])[CH2:10][CH2:11][OH:12])[CH:5]=[CH:6][C:7]=1[F:8].N1C=CN=C1.[C:19]([Si:23](Cl)([CH3:25])[CH3:24])([CH3:22])([CH3:21])[CH3:20].O>C(Cl)Cl.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([C:9](=[CH2:13])[CH2:10][CH2:11][O:12][Si:23]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:25])[CH3:24])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: C=C(CCO)c1ccc(F)c(Br)c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: C=C(CCO[Si](C)(C)C(C)(C)C)c1ccc(F)c(Br)c1
Yield: 95 %

Procedure:
The compound (2.17 g, 8.85 mmol) obtained in Example 91b was dissolved in methylene chloride (33 mL), imidazole (0.90 g, 13.3 mmol) and tert-butyl(chloro)dimethylsilane (1.60 g, 10.6 mmol) were added with stirring under ice cooling, and the mixture was stirred at room temperature under a nitrogen atmosphere for 20 hours. After the reaction was completed, water was added, and ethyl acetate was further added to separate the layers. The resulting organic layer was separated, washed with saturated sodium chloride solution, and then dried with anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=50:1, v/v) to give the title compound (3.02 g; yield, 95%) as a colorless oily substance.
Reaction SMILES: CS(C)=O.Cl[C:6]1[N:7]([CH2:28][CH:29]2[CH2:31][CH2:30]2)[C:8]2[C:13]([N:14]=1)=[C:12]([N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)[N:11]=[C:10]([C:21]1[CH:22]=[N:23][C:24]([NH2:27])=[N:25][CH:26]=1)[N:9]=2.[NH:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1>ClCCl.CO>[CH:29]1([CH2:28][N:7]2[C:6]([N:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)=[N:14][C:13]3[C:8]2=[N:9][C:10]([C:21]2[CH:22]=[N:23][C:24]([NH2:27])=[N:25][CH:26]=2)=[N:11][C:12]=3[N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[CH2:31][CH2:30]1
Reactant: Nc1ncc(-c2nc(N3CCOCC3)c3nc(Cl)n(CC4CC4)c3n2)cn1
Reactant: C1COCCN1
Solvent: ClCCl
Solvent: CO
Solvent: CS(C)=O
Product: Nc1ncc(-c2nc(N3CCOCC3)c3nc(N4CCOCC4)n(CC4CC4)c3n2)cn1
Reaction time: 4 h
Yield: 103.3 %

Procedure:
A dimethyl sulfoxide solution (1.0 ml) of 5-[8-chloro-9-(cyclopropylmethyl)-6-morpholin-4-yl-9H-purin-2-yl]pyrimidin-2-amine (75.3 mg, 0.19 mmol) and morpholine (65.8 μl, 0.75 mmol) was heated at 140° C. and stirred for 4 hours. Morpholine (32.9 μl, 0.38 mmol) was added at room temperature and the resulting mixture was further stirred at 140° C. for 2 hours. The resulting mixture was left standing to cool followed by the addition of dichloromethane-methanol (10:1) and the resulting mixture was washed with saturated aqueous sodium hydrogen carbonate solution. The organic layer was dried over anhydrous sodium sulfate, the mixture was filtrated, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by preparative thin layer silica gel chromatography (dichloromethane:methanol=15:1) to give the title compound (85.9 mg, 100%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[N:10]([CH2:11][C:12]([N:14]3[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][OH:22])[CH2:16][CH2:15]3)=[O:13])[C:9](=[O:23])[S:8][C:5]2=[N:6][CH:7]=1.[C:24](OC(=O)C)(=[O:26])[CH3:25]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]2[N:10]([CH2:11][C:12]([N:14]3[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][O:22][C:24](=[O:26])[CH3:25])[CH2:16][CH2:15]3)=[O:13])[C:9](=[O:23])[S:8][C:5]2=[N:6][CH:7]=1
Reactant: CC(=O)OC(C)=O
Reactant: O=C(Cn1c(=O)sc2ncc(Cl)cc21)N1CCN(CCO)CC1
Solvent: c1ccncc1
Product: CC(=O)OCCN1CCN(C(=O)Cn2c(=O)sc3ncc(Cl)cc32)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 79.5 %

Procedure:
To an ice-cooled solution of 6-chloro-2-oxo-1-{[4-(2-hydroxyethyl)-1-piperazinyl]carbonylmethyl]-1,2-dihydrothiazolo[5,4-b]pyridine (1.35 g) in dry pyridine (10 ml), acetic anhydride (0.73 g) was added dropwise and then the mixture was stirred at the temperature for 2 hours and at the room temperature for 4 hours. After removal of the solvent, the residual oil obtained was purified on an aluminum-oxide column chromatography using a mixture of chloroform and n-hexane (2:1). The fractions containing the objective compound were collected and evaporated to give crude crystals. The crude crystals were recrystallized from ethyl acetate to afford 6-chloro-2-oxo-1-{[4-(2-acetoxyethyl)-1-piperazinyl]carbonylmethyl}-1,2-dihydrothiazolo[5,4-b]pyridine (1,2 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[NH:11][C:10]=2[C:20](O)=[O:21])=[CH:5][CH:4]=1.Cl.[NH2:24][CH2:25][C:26]1[CH:40]=[CH:39][C:29]([C:30]([NH:32][C:33]2[N:38]=[CH:37][CH:36]=[CH:35][N:34]=2)=[O:31])=[CH:28][CH:27]=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:13]=[C:12]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[NH:11][C:10]=2[C:20]([NH:24][CH2:25][C:26]2[CH:40]=[CH:39][C:29]([C:30]([NH:32][C:33]3[N:34]=[CH:35][CH:36]=[CH:37][N:38]=3)=[O:31])=[CH:28][CH:27]=2)=[O:21])=[CH:5][CH:4]=1
Reactant: NCc1ccc(C(=O)Nc2ncccn2)cc1
Reactant: COc1ccc(-c2cc(-c3ccccc3)[nH]c2C(=O)O)cc1
Agent: Cl
Product: COc1ccc(-c2cc(-c3ccccc3)[nH]c2C(=O)NCc2ccc(C(=O)Nc3ncccn3)cc2)cc1
Yield: 58 %

Procedure:
This material was prepared using a method substantially similar to that of Example 5 from 3-(4-methoxyphenyl)-5-phenyl-1H-pyrrole-2-carboxylic acid and 4-(aminomethyl)-N-pyrimidin-2-ylbenzamide hydrochloride, yielding the title compound. 3-(4-Methoxyphenyl)-5-phenyl-N-{4-[(pyrimidin-2-ylamino)carbonyl]benzyl}-1H-pyrrole-2-carboxamide: Yield 58%; m.p. 190-191° C.; IR 3396, 3251, 1623, 1571, 1525, 1429, 1243 cm−1; 1H-NMR (300 MHz, δ ppm, CDCl3) 9.72 (s, 1H), 8.83 (s, 1H), 8.66 (d, J=4.9 Hz, 2H), 7.88 (d, J=8.3 Hz, 3H), 7.57 (d, J=7.1 Hz, 2H), 7.44-7.23 (m, 6H), 7.06 (t, J=4.9 Hz, 1H), 6.90 (d, J=8.7 Hz, 2H), 6.49 (d, J=3.1 Hz, 1H), 6.12 (t, J=5.8 Hz, 1H), 4.51 (d, J=5.9 Hz, 2H), 3.82 (s, 3H); 1C-NMR (75 MHz, δ ppm, CDCl3) 164.9, 161.6, 159.7, 158.7, 158.2, 143.1, 134.7, 133.6, 131.6, 130.9, 129.2, 128.4, 128.2, 127.9, 127.6, 125.0, 122.3, 117.1, 114.7, 109.9, 55.6, 43.1.
Reaction SMILES: [SH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][CH:3]=1.CCOC(C)=O.[CH3:17][N:18](C=O)[CH3:19]>>[CH3:17][N:18]([CH3:19])[C:6]([C:5]1[CH:9]=[CH:10][C:2]([SH:1])=[CH:3][CH:4]=1)=[O:7]
Reactant: CN(C)C=O
Reactant: O=C(O)c1ccc(S)cc1
Solvent: CCOC(C)=O
Product: CN(C)C(=O)c1ccc(S)cc1
Temperature: 150 °C

Procedure:
Di-Phosphorous pentoxide (923 mg) was added to a solution of 4-mercaptobenzoic acid (2000 mg) in DMF (10 ml). The mixture was stirred for sixteen hours at 150° C. under argon. The mixture was allowed to cool then EtOAc (150 ml) was added. The solution was washed with water (100 ml), brine (50 ml) and dried. The volatile material was removed by evaporation and the residue was purified by chromatography on silica gel, eluted with 2.5% MeOH in DCM to give two samples. One sample containing a mixture of thiol and disulphide was purified by chromatography on silica gel, eluted with 1-2.5% MeOH in DCM to give the title compound (760 mg) as a solid. NMR: 2.94 (s, 6H), 5.63 (s, 1H), 7.30 (m, 4H); m/z 180.