Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[C:6]([N:10]3[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][O:20][C:21]4[CH:30]=[C:29]5[C:24]([CH:25]=[CH:26][C:27](=[O:31])[NH:28]5)=[CH:23][CH:22]=4)[CH2:12][CH2:11]3)=[CH:7][CH:8]=[CH:9][C:2]1=2.C(N(CC)CC)C.[C:39](Cl)(=[O:51])[CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50].O>ClCCl>[C:39]([O:31][C:27]1[CH:26]=[CH:25][C:24]2[C:29](=[CH:30][C:21]([O:20][CH2:19][CH2:18][CH2:17][CH2:16][N:13]3[CH2:12][CH2:11][N:10]([C:6]4[C:3]5[CH:4]=[CH:5][S:1][C:2]=5[CH:9]=[CH:8][CH:7]=4)[CH2:15][CH2:14]3)=[CH:22][CH:23]=2)[N:28]=1)(=[O:51])[CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50]
Reactant: CCCCCCCCCCCC(=O)Cl
Reactant: O=c1ccc2ccc(OCCCCN3CCN(c4cccc5sccc45)CC3)cc2[nH]1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CCCCCCCCCCCC(=O)Oc1ccc2ccc(OCCCCN3CCN(c4cccc5sccc45)CC3)cc2n1

Procedure:
To a solution of 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy]-1H-quinolin-2-one (800 mg) in dichloromethane (20 ml) synthesized in the same manner as in WO2006/112464 (Example 1) was added triethylamine (0.77 ml), with stirring under ice-cooling, dodecanoylchloride (1.1 ml) was added and the mixture was stirred at room temperature for 4 hr. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate) to give 7-[4-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)-butoxy]-quinolin-2-yl dodecanoate (1.34 g).
Reaction SMILES: C1C(=O)N([I:8])C(=O)C1.[NH2:9][C:10]1[C:15]2[C:16]([C:19]3[CH:20]=[C:21]4[C:25](=[CH:26][CH:27]=3)[N:24]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:23][CH2:22]4)=[CH:17][O:18][C:14]=2[CH:13]=[CH:12][N:11]=1.O>CN(C=O)C>[NH2:9][C:10]1[C:15]2[C:16]([C:19]3[CH:20]=[C:21]4[C:25](=[CH:26][CH:27]=3)[N:24]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:23][CH2:22]4)=[CH:17][O:18][C:14]=2[C:13]([I:8])=[CH:12][N:11]=1
Reactant: O=C1CCC(=O)N1I
Reactant: CC(C)(C)OC(=O)N1CCc2cc(-c3coc4ccnc(N)c34)ccc21
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCc2cc(-c3coc4c(I)cnc(N)c34)ccc21
Temperature: 25 °C
Yield: 93.5 %

Procedure:
A solution of NIS (0.985 g, 4.38 mmol) in DMF (20 mL) was added dropwise to a solution of 1,1-dimethylethyl 5-(4-aminofuro[3,2-c]pyridin-3-yl)-2,3-dihydro-1H-indole-1-carboxylate (1.505 g, 4.28 mmol) in DMF (20 mL) at −40° C. under Nitrogen. The mixture was stirred and allowed to slowly warm to room temperature for 17 hours. LCMS indicated about 85% conversion, so the mixture was cooled to about −30° C. and another portion of NIS (0.193 g, 0.858 mmol) in DMF (3 mL) was added dropwise. It was then allowed to slowly warm to room temperature and stirred for another 24 hours. The reaction mixture was then poured into water (ca. 200 mL) and the precipitate was collected by vacuum filtration and rinsed with Et2O (50 mL) to give 1,1-dimethylethyl 5-(4-amino-7-iodofuro[3,2-c]pyridin-3-yl)-2,3-dihydro-1H-indole-1-carboxylate (2.384 g, 4.00 mmol, 93% yield) as a tan solid. LC/MS (ES) m/z=478 [M+H]+.
Reaction SMILES: ClC(Cl)(Cl)[C:3]([C:5]1[NH:9][CH:8]=[C:7]([CH:10]=[O:11])[CH:6]=1)=[O:4].[CH2:14]([O-])[CH3:15].[Na+].C([OH:20])C>>[CH:10]([C:7]1[CH:6]=[C:5]([C:3]([O:4][CH2:14][CH3:15])=[O:20])[NH:9][CH:8]=1)=[O:11]
Reactant: O=Cc1c[nH]c(C(=O)C(Cl)(Cl)Cl)c1
Reactant: CCO
Reactant: CC[O-]
Agent: [Na+]
Product: CCOC(=O)c1cc(C=O)c[nH]1
Reaction time: 0.33 h

Procedure:
To a solution of the compound obtained in Step B (83.7 mmoles) in ethanol (200 ml) there is added, dropwise and over 20 minutes, a solution of sodium ethanolate (13.4 mmoles) in ethanol (45 ml) at ambient temperature. After stirring for 3 hours, the mixture is evaporated to dryness and then taken up in ethyl ether (200 ml). To that organic phase there is added aqueous 2N HCl solution (150 ml) and the resulting mixture is stirred; the phases are then separated and the aqueous phase is extracted with ethyl ether. The organic phase is washed with saturated aqueous NaHCO3 solution and with saturated aqueous NaCl solution, dried over sodium sulphate, filtered and evaporated to dryness to yield the title product (brown crystals), which is used directly in the next Step.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([CH2:25][C:26](O)=[O:27])[C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[N:21]=[CH:20][CH:19]=[CH:18]3)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:29]([NH:31][CH2:32][CH2:33][OH:34])[CH3:30]>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[N:21]=[CH:20][CH:19]=[CH:18]3)[CH2:25][C:26]([N:31]([CH2:29][CH3:30])[CH2:32][CH2:33][OH:34])=[O:27])(=[O:12])=[O:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(S(=O)(=O)N(CC(=O)O)c2ccc3ncccc3c2)cc1
Reactant: CCNCCO
Product: CCN(CCO)C(=O)CN(c1ccc2ncccc2c1)S(=O)(=O)c1ccc(C(C)(C)C)cc1

Procedure:
prepared by reaction of [(4-tert-butyl-benzenesulfonyl)-quinolin-6-yl-amino]-acetic acid with 2-ethylamino-ethanol
Reaction SMILES: Cl.[CH2:2]([O:9][NH2:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.N1C=CC=CC=1.Cl[C:18]([O:20][CH2:21][C:22]([Cl:25])([Cl:24])[Cl:23])=[O:19]>C(#N)C>[Cl:23][C:22]([Cl:25])([Cl:24])[CH2:21][O:20][C:18](=[O:19])[NH:10][O:9][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: NOCc1ccccc1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: CC#N
Product: O=C(NOCc1ccccc1)OCC(Cl)(Cl)Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Under anhydrous conditions, 50 g of O-benzylhydroxylamine hydrochloride is suspended in 783 ml of acetonitrile. To the suspension is added 50.6 ml of pyridine followed by dropwise addition of 43.15 ml trichloroethyl chloroformate in 235 ml of acetonitrile. The reaction is allowed to stir overnight at room temperature. The mixture is concentrated in vacuo and diluted with ethyl acetate. The organic layer is washed with 0.5M citric acid,water, saturated sodium bicarbonate, saturated sodium chloride, dried and concentrated in vacuo. The residue is purified by Kugelrohr distillation (bp 150° C. at 0.5 mm g.) to give 70 g of the desired product.
Reaction SMILES: [CH:1]1([NH:7][C:8]2[CH:17]=[C:16]3[C:11]([C:12](=[O:25])[C:13]([CH:23]=O)=[CH:14][N:15]3[CH:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)=[CH:10][C:9]=2[F:26])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[ClH:27].[NH2:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31].[H][H]>[C].[Pd].C(O)C>[ClH:27].[CH2:33]([O:32][C:30](=[O:31])[CH2:29][NH:28][CH2:23][C:13]1[C:12](=[O:25])[C:11]2[C:16](=[CH:17][C:8]([NH:7][CH:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)=[C:9]([F:26])[CH:10]=2)[N:15]([CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)[CH:14]=1)[CH3:34]
Reactant: CCOC(=O)CN
Reactant: O=Cc1cn(C2CCCC2)c2cc(NC3CCCCC3)c(F)cc2c1=O
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CCOC(=O)CNCc1cn(C2CCCC2)c2cc(NC3CCCCC3)c(F)cc2c1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 47.5 %

Procedure:
To a 5.0 ml ethanol solution of 500 mg of 7-(cyclohexylamino)-1-cyclopentyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carbaldehyde was added 215 mg of ethyl aminoacetate hydrochloride, followed by stirring at room temperature for 2 hours. Next, 50 mg of palladium-carbon was added thereto, followed by stirring at room temperature for 4 hours in an atmosphere of hydrogen. The reaction mixture was filtered through celite and then evaporated under a reduced pressure. The resulting residue was purified by silica gel column chromatography. To a 3.6 ml dioxane solution of the resulting compound was added 4.0 ml of a 4 M hydrogen chloride dioxane solution, followed by overnight stirring at room temperature. The insoluble materials were collected by filtration to obtain 320 mg of ethyl({[7-(cyclohexylamino)-1-cyclopentyl-6-fluoro-4-oxo-1,4-dihydroquinolin-3-yl]methyl}amino)acetate hydrochloride.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][C:8]([Cl:14])=[CH:9][CH:10]=2)[N:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:4]=1.[C:21]1([N:27]2[CH:31]=[C:30]([C:32](O)=[O:33])[CH:29]=[N:28]2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[Cl:14][C:8]1[CH:7]=[C:6]2[C:11]([C:12](=[O:13])[C:3]([CH2:2][NH:1][C:32]([C:30]3[CH:29]=[N:28][N:27]([C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH:31]=3)=[O:33])=[CH:4][N:5]2[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[CH:10][CH:9]=1
Reactant: O=C(O)c1cnn(-c2ccccc2)c1
Reactant: NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O
Product: O=C(NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O)c1cnn(-c2ccccc2)c1

Procedure:
Phenyl-1H-pyrazole-4-carboxylic acid (7-chloro-4-oxo-1-phenyl-1,4-dihydro-quinolin-3-ylmethyl)-amide was prepared starting from intermediate D and 1-phenyl-1H-pyrazole-4-carboxylic acid. MS calcd. for C26H20ClN4O2 [(M+H)+] 455.1, obsd. 455.0.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]([OH:18])[CH2:4][N:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1.[CH:19]1([N:24]2[C:33]3[N:32]=[C:31]([NH:34][C:35]4[CH:36]=[CH:37][C:38]([C:44](O)=[O:45])=[C:39]5[C:43]=4[O:42][CH2:41][CH2:40]5)[N:30]=[CH:29][C:28]=3[N:27]([CH3:47])[C:26](=[O:48])[C@H:25]2[CH2:49][CH3:50])[CH2:23][CH2:22][CH2:21][CH2:20]1.C(N(C(C)C)CC)(C)C.N>ClCCl.O>[CH:19]1([N:24]2[C:33]3[N:32]=[C:31]([NH:34][C:35]4[CH:36]=[CH:37][C:38]([C:44]([NH:1][CH2:2][C@H:3]([OH:18])[CH2:4][N:5]5[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:15])([CH3:17])[CH3:16])=[O:12])[CH2:7][CH2:6]5)=[O:45])=[C:39]5[C:43]=4[O:42][CH2:41][CH2:40]5)[N:30]=[CH:29][C:28]=3[N:27]([CH3:47])[C:26](=[O:48])[C@H:25]2[CH2:49][CH3:50])[CH2:20][CH2:21][CH2:22][CH2:23]1
Reactant: CC[C@@H]1C(=O)N(C)c2cnc(Nc3ccc(C(=O)O)c4c3OCC4)nc2N1C1CCCC1
Reactant: CC(C)(C)OC(=O)N1CCN(C[C@@H](O)CN)CC1
Agent: N
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CC[C@@H]1C(=O)N(C)c2cnc(Nc3ccc(C(=O)NC[C@H](O)CN4CCN(C(=O)OC(C)(C)C)CC4)c4c3OCC4)nc2N1C1CCCC1
Reaction time: 2 h
Yield: 32.3 %

Procedure:
Tert-butyl 4-[(2S)-3-amino-2-hydroxy-propyl]piperazine-1-carboxylate 7c (355 mg, 1.37 mmol), 7-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2-yl]amino]-2,3-dihydrobenzofuran-4-carboxylic acid 1q (600 mg, 1.37 mmol), O-(benzotriazol-1-yl)-N,N,N′-tetra methyluronium tetrafluoroborate (440 mg, 1.37 mmol) and diisopropylethylamine (390 mg, 3.01 mmol) were dissolved in 40 mL of dichloromethane. The reaction solution was stirred for 2 hours. The resulting solution was added with 50 mL of water and 10 mL of aqueous ammonia successively, stirred for 0.5 hours, extracted with dichloromethane (50 mL×3). The combined organic phase was washed with saturated sodium chloride solution (50 mL), dried over anhydrous magnesium sulfate. The filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound tert-butyl 4-[(2S)-3-[[7-[[(7R)-8-cyclopentyl-7-ethyl-5-methyl-6-oxo-7H-pteridin-2-yl]amino]-2,3-dihydrobenzofuran-4-carbonyl]amino]-2-hydroxy-propyl]piperazine-1-carboxylate 7d (300 mg, yield: 32.3%) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][C:8]1[C:13]([NH2:14])=[CH:12][C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[C:16]=2[F:22])=[C:10]([N:23]([CH3:25])[CH3:24])[CH:9]=1)([CH3:4])([CH3:3])[CH3:2].C([O:31][C:32](=O)[CH2:33][C:34](=[O:54])[C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([N:41]2[C:45]([CH2:46][O:47][CH:48]3[CH2:53][CH2:52][CH2:51][CH2:50][O:49]3)=[CH:44][N:43]=[N:42]2)[CH:36]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:26])[NH:7][C:8]1[C:13]([NH:14][C:32](=[O:31])[CH2:33][C:34](=[O:54])[C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([N:41]3[C:45]([CH2:46][O:47][CH:48]4[CH2:53][CH2:52][CH2:51][CH2:50][O:49]4)=[CH:44][N:43]=[N:42]3)[CH:36]=2)=[CH:12][C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[C:16]=2[F:22])=[C:10]([N:23]([CH3:24])[CH3:25])[CH:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-n2nncc2COC2CCCCO2)c1
Reactant: CN(C)c1cc(NC(=O)OC(C)(C)C)c(N)cc1-c1cccc(F)c1F
Product: CN(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-n3nncc3COC3CCCCO3)c2)cc1-c1cccc(F)c1F

Procedure:
The title compound was prepared from (5-amino-2-dimethylamino-2′,3′-difluoro-biphenyl-4-yl)-carbamic acid tert.-butyl ester (Example J3) and (RS)-3-oxo-3-{3-[5-(tetrahydro-pyran-2-yloxymethyl)-[1,2,3]triazol-1-yl ]-phenyl}-propionic acid tert-butyl ester (Example K5) according to the general procedure M. Obtained as a yellow solid (253 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:21]=[CH:20][C:6]2[NH:7][C:8](=[O:19])[N:9]([CH:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH:13]3[CH3:18])[CH2:10][CH2:11][C:5]=2[CH:4]=1.Cl[C:23]1[N:28]=[CH:27][N:26]=[C:25]([C:29]([C:31]2[CH:41]=[C:40]([CH3:42])[C:34]3[N:35]([CH3:39])[C:36](=[O:38])[O:37][C:33]=3[CH:32]=2)=[O:30])[CH:24]=1.CO>CN(C=O)C>[CH3:39][N:35]1[C:34]2[C:40]([CH3:42])=[CH:41][C:31]([C:29]([C:25]3[N:26]=[CH:27][N:28]=[C:23]([N:15]4[CH2:16][CH2:17][CH:12]([N:9]5[CH2:10][CH2:11][C:5]6[CH:4]=[C:3]([O:2][CH3:1])[CH:21]=[CH:20][C:6]=6[NH:7][C:8]5=[O:19])[CH:13]([CH3:18])[CH2:14]4)[CH:24]=3)=[O:30])=[CH:32][C:33]=2[O:37][C:36]1=[O:38]
Reactant: Cc1cc(C(=O)c2cc(Cl)ncn2)cc2oc(=O)n(C)c12
Reactant: COc1ccc2c(c1)CCN(C1CCNCC1C)C(=O)N2
Solvent: CO
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(C(=O)c4cc(C)c5c(c4)oc(=O)n5C)ncn3)CC1C)C(=O)N2

Procedure:
60 mg (0.21 mmol) 7-methoxy-3-(3-methyl-piperidin-4-yl)-1,3,4,5-tetrahydro-benzo[d]-[1,3]diazepin-2-one, 60 mg (0.20 mmol) 6-(6-chloro-pyrimidine-4-carbonyl)-3,4-dimethyl-3H-benzoxazol-2-one and 0.040 mL (0.29 mmol) TEA were stirred overnight in 1 mL DMF at RT. Then the reaction mixture was combined with 2 mL MeOH, the precipitate formed was suction filtered, washed with MeOH and diethyl ether and dried.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]Br)[O:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[CH:5][CH:4]=1.[C-:28]#[N:29].[K+]>C(O)C.O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:28]#[N:29])[O:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[CH:5][CH:4]=1
Reactant: [C-]#N
Reactant: COc1ccc(-c2nc(CCCCCBr)oc2-c2ccc(OC)cc2)cc1
Agent: [K+]
Solvent: O
Solvent: CCO
Product: COc1ccc(-c2nc(CCCCCC#N)oc2-c2ccc(OC)cc2)cc1
Yield: 80 %

Procedure:
A solution of 5 g of 4,5-Bis(4-methoxyphenyl)-2-(5-bromopentyl)oxazole in 23 cm3 of ethanol and 1.1 g of potassium cyanide dissolved in 9 cm3 of water are brought to reflux for 15 hours. After evaporation of the solvent, the organic/inorganic residue is dissolved in 40 cm3 of diethyl ether and 10 cm3 of water, and the ether phase is separated and washed with 10 cm3 of saturated sodium chloride solution, dried over magnesium sulphate, filtered and concentrated to dryness. The viscous residue (4.4 g) is chromatographed on a column of useful diameter 2 cm containing 80 g of silica gel (50 to 200μ). The column is eluted with 1.2 liters of diazopropyl ether, collecting 50 cm3 fractions. The fractions emerging at between 0.2 and 1.2 liters are concentrated to dryness. 3.5 g (80%) of 6-[4,5-bis(4-methoxyphenyl)-2-oxazolyl]hexanenitrile are obtained in the form of a pale yellow oil.
Reaction SMILES: Cl[C:2]1[C:3]2[N:4]([C:17]([CH2:20][CH:21]3[CH2:26][CH2:25][S:24][CH2:23][CH2:22]3)=[N:18][N:19]=2)[C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14]C)=[O:13])=[C:7]([CH3:16])[CH:6]=2.[O:27]1CCCC1.[OH-].[Na+].Cl>CO>[CH3:16][C:7]1[CH:6]=[C:5]2[C:10]([NH:11][C:2](=[O:27])[C:3]3[N:4]2[C:17]([CH2:20][CH:21]2[CH2:26][CH2:25][S:24][CH2:23][CH2:22]2)=[N:18][N:19]=3)=[CH:9][C:8]=1[C:12]([OH:14])=[O:13]
Reactant: C1CCOC1
Reactant: COC(=O)c1cc2nc(Cl)c3nnc(CC4CCSCC4)n3c2cc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1cc2c(cc1C(=O)O)[nH]c(=O)c1nnc(CC3CCSCC3)n12
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To a mixed liquid of 1.70 g of methyl 4-chloro-8-methyl-1-(tetrahydro-2H-thiopyran-4-ylmethyl)[1,2,4]triazolo[4,3-a]quinoxaline-7-carboxylate, 18.0 mL of tetrahydrofuran, and 18.0 mL of methanol was added 9.20 mL of a 3 M aqueous sodium hydroxide solution, followed by stirring at 60° C. overnight. 3 M hydrochloric acid was added thereto to adjust the pH to about 3, and the precipitated solid was collected by filtration and dried under reduced pressure to obtain 1.20 g of 8-methyl-4-oxo-1-(tetrahydro-2H-thiopyran-4-ylmethyl)-4,5-dihydro[1,2,4]triazolo[4,3-a]quinoxaline-7-carboxylic acid as a yellow solid.
Reaction SMILES: [C:1]([C@@H:3]1[C@@H:10]2[C@@H:6]([O:7][C:8]([CH3:12])([CH3:11])[O:9]2)[C@H:5]([N:13]2[CH:21]=[N:20][C:19]3[C:14]2=[N:15][CH:16]=[N:17][C:18]=3[NH:22][CH:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)[O:4]1)#[CH:2].I[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[C:35]([F:38])([F:37])[F:36].C(N(CC)CC)C>O1CCCC1.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)I>[CH3:11][C:8]1([CH3:12])[O:7][C@@H:6]2[C@@H:10]([C@@H:3]([C:1]#[C:2][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[C:35]([F:38])([F:37])[F:36])[O:4][C@H:5]2[N:13]2[CH:21]=[N:20][C:19]3[C:14]2=[N:15][CH:16]=[N:17][C:18]=3[NH:22][CH:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)[O:9]1
Reactant: C#C[C@H]1O[C@@H](n2cnc3c(NC4CCCC4)ncnc32)[C@@H]2OC(C)(C)O[C@@H]21
Reactant: FC(F)(F)c1ccccc1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC1(C)O[C@@H]2[C@H](O1)[C@@H](C#Cc1ccccc1C(F)(F)F)O[C@H]2n1cnc2c(NC3CCCC3)ncnc21
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of [9-((1R,2R,4R,5R)-4-ethynyl-7,7-dimethyl-3,6,8-trioxabicyclo[3.3.0]oct-2-yl)purin-6-yl]cyclopentylamine (40 mg, 0.12 mmol), a compound of formula (5), in tetrahydrofuran (4 ml) under nitrogen was added catalytic amounts (3 mg) of dichlorobis(triphenylphosphine)palladium(II) and copper(II)iodide, followed by 1-iodo-2-trifluoromethylbenzene (0.25 ml, 0.3 mmol). Triethylamine (0.4 ml) was then added, and the mixture stirred for 15 minutes at room temperature. The solvent was removed under reduced pressure, and the residue was purified by preparative TLC, eluting with methanol:methylene chloride (6.5:1), to yield [9-((1R,2R,4R,5R)-7,7-dimethyl-4-{2-[2-(trifluoromethyl)-phenyl]ethynyl}-3,6,8-trioxabicyclo[3.3.0]oct-2-yl)purin-6-yl]cyclopentylamine, a compound of formula (6).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[N:5][C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[N:33]1[C:37](=[O:38])[C:36]2=[CH:39][CH:40]=[CH:41][CH:42]=[C:35]2[C:34]1=[O:43].CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[N:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH:12]=[C:3]([CH2:2][O:1][N:33]2[C:34](=[O:43])[C:35]3=[CH:42][CH:41]=[CH:40][CH:39]=[C:36]3[C:37]2=[O:38])[CH:4]=1
Reactant: OCc1cnc2ccccc2c1
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1c2ccccc2C(=O)N1OCc1cnc2ccccc2c1
Reaction time: 8 h
Yield: 90 %

Procedure:
3-(hydroxymethyl)quinoline (400 mg, 2.52 mmol), triphenyl phosphine (692 mg, 2.64 mmol, 1.05 equiv) and N-hydroxyphthalimide (430 mg, 2.64 mmol, 1.05 equiv) were dissolved in 10 mL of dry THF. Diethylazodicarboxylate (0.44 mL, 2.80 mmol, 1.11 equiv) was then added dropwise and the reaction was stirred overnight. The reaction mixture placed in a freezer for 2 hours, and then filtered to give the desired product (0.69 g) as a fluffy white solid. MS(CI) m/e 305 (M+H)+.
Reaction SMILES: [CH:1]1([NH:4][C:5]2[CH:10]=[CH:9][C:8](I)=[CH:7][N:6]=2)[CH2:3][CH2:2]1.Cl[C:13]1[CH:18]=CC(C#C)=CN=1.ClC1C=CC(I)=CN=1.C1(N)CC1.[CH:33]1([CH2:36][NH:37][C:38]2[CH:43]=[CH:42][C:41]([I:44])=[CH:40][N:39]=2)[CH2:35]C1>>[CH:1]1([NH:4][C:5]2[CH:10]=[CH:9][C:8]([C:13]#[CH:18])=[CH:7][N:6]=2)[CH2:3][CH2:2]1.[CH:36]1([NH:37][C:38]2[CH:43]=[CH:42][C:41]([I:44])=[CH:40][N:39]=2)[CH2:33][CH2:35]1
Reactant: Ic1ccc(NCC2CC2)nc1
Reactant: C#Cc1ccc(Cl)nc1
Agent: Clc1ccc(I)cn1
Agent: Ic1ccc(NC2CC2)nc1
Agent: NC1CC1
Product: C#Cc1ccc(NC2CC2)nc1

Procedure:
Cyclopropyl-(5-ethynyl-pyridin-2-yl)-amine was prepared from cyclopropyl-(5-iodo-pyridin-2-yl)-amine in the same manner as 2-chloro-5-ethynyl-pyridine (Example 1). Cyclopropyl-(5-iodo-pyridin-2-yl)-amine was prepared from 2-chloro-5-iodo-pyridine and cyclopropyl amine in the same manner as cyclopropylmethyl-(5-iodo-pyridin-2-yl)-amine (Example 2).
Reaction SMILES: [CH2:1]([OH:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]=[CH2:11].[C:13]1([CH3:23])[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1.Cl>N1C=CC=CC=1>[C:13]1([CH3:23])[CH:18]=[CH:17][C:16]([S:19]([O:12][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]=[CH2:11])(=[O:21])=[O:20])=[CH:15][CH:14]=1
Reactant: C=CCCCCCCCCCO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: c1ccncc1
Product: C=CCCCCCCCCCOS(=O)(=O)c1ccc(C)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 95.9 %

Procedure:
4.32 g (54.0 mM) of dry pyridine was added to 3.40 g (20.0 mM) of 10-undecene-1-ol, followed by stirring for 10 minutes at 0° C. To the mixture, 3.80 g (20.0 mM) of p-toluenesulfonyl chloride was added, followed by stirring for 4 hours at room temperature. After the reaction, the reaction mixture was acidified with 2M-hydrochloric acid (HCl) and extracted with ether to obtain an extract. The extract was dried with anhydrous sodium sulfate, followed by distilling-off of ether to obtain 6.20 g (19.1 mM) of 10-undecenyl p-toluenesulfonate (Yield: 95.5%).
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1.[CH2:17]([N:24](C)[CH2:25][CH2:26][CH3:27])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[CH2:29](O)CCC>>[CH2:17]([N:24]([C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1)[CH2:25][CH:26]([CH3:27])[CH3:29])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CCCCO
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Reactant: CCCN(C)Cc1ccccc1
Product: CC(C)CN(Cc1ccccc1)c1ncnc2c1ncn2C1CCCCO1
Yield: 97 %

Procedure:
A mixture of 10.7 g. (40 mmole) 6-chloro-9-tetrahydropyran-2-yl purine, 19.5 g. (120 mmole) N-benzyl--methylpropylamine and 60 ml. butanol is heated under reflux for 16 hours. The reaction mixture is evaporated and the residue is taken up in dichloromethane, washed with dilute acetic acid and subsequently with water, dried over anhydrous sodium sulphate, evaporated and the residue triturated with ligroin. There are obtained 14.2 g. of the title compound (97% of theory); m.p. 93°-95° C.