Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[OH:8][C:9]1[C:14](=[O:15])[CH:13]=[CH:12][N:11]([CH3:16])[C:10]=1[CH3:17].[C:18](Cl)(=[O:26])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]>C(#N)C.C(Cl)Cl>[C:18]([O:8][C:9]1[C:14](=[O:15])[CH:13]=[CH:12][N:11]([CH3:16])[C:10]=1[CH3:17])(=[O:26])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCCCCCC(=O)Cl
Reactant: Cc1c(O)c(=O)ccn1C
Solvent: CC#N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCC(=O)Oc1c(C)n(C)ccc1=O
Reaction time: 0.05 h

Procedure:
With stirring, 0.56 ml of triethylamine is added at room temperature to a suspension of 0.556 g of 3-hydroxy-1,2-dimethyl-4(1H)-pyridinone in 40 ml of acetonitrile and 40 ml of methylene chloride, followed by the addition of 1.02 ml of caprylyl chloride. A solution forms within 3 minutes and after 30 minutes the reaction is complete, and the volatile constituents are removed by evaporation under reduced pressure. The residue is dried under a high vacuum and crystallised from a mixture of methylene chloride and ethyl acetate. The 3-(n-octanoyloxy)-1,2-dimethyl-4-(1H)-pyridinone so obtained begins to sinter at 140° C. and decomposes at 180° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:16]([O:18]C)=O)[C:5]2[C:6]3[C:14](=O)[CH2:13][NH:12][CH2:11][C:7]=3[NH:8][C:9]=2[CH:10]=1.[C:20](Cl)(=[O:25])[C:21]([CH3:24])([CH3:23])[CH3:22].C1(C(N2CC3NC4C=CC=C5C(=O)[NH:46][N:47]=C(C=3C=45)C2)=O)CC1>>[F:1][C:2]1[CH:3]=[C:4]2[C:16](=[O:18])[NH:46][N:47]=[C:14]3[C:6]4[C:5]2=[C:9]([NH:8][C:7]=4[CH2:11][N:12]([C:20](=[O:25])[C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:13]3)[CH:10]=1
Reactant: COC(=O)c1cc(F)cc2[nH]c3c(c12)C(=O)CNC3
Reactant: O=C1NN=C2CN(C(=O)C3CC3)Cc3[nH]c4cccc1c4c32
Reactant: CC(C)(C)C(=O)Cl
Product: CC(C)(C)C(=O)N1CC2=NNC(=O)c3cc(F)cc4[nH]c(c2c34)C1

Procedure:
Compound 52 was prepared from methyl 7-fluoro-4-oxo-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-5-carboxylate and pivaloyl chloride according to the procedures similar to those for Compound 47. 1H NMR (DMSO-d6) δ 11.9 (s, 1H), 10.2 (s, 1H), 7.45 (dd, 1H, J=2.4, 9.6 Hz), 7.22 (dd, 1H, J=2.4, 10.2 Hz), 4.92 (s, 2H), 4.42 (s, 2H), and 1.24 (s, 9H). MS (ESI) m/e [M+1]+ 329.
Reaction SMILES: C(OC([NH:11][C:12]1([C:15]2[C:16]([F:35])=[CH:17][C:18]3[C:28](=[O:29])[C:27]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:26][N:20]4[C@@H:21]([CH3:25])[CH2:22][O:23][C:24]=2[C:19]=34)[CH2:14][CH2:13]1)=O)C1C=CC=CC=1.[H][H].C(Cl)Cl.C(=O)([O-])O.[Na+]>C(O)(=O)C.[C].[Pd].O>[NH2:11][C:12]1([C:15]2[C:16]([F:35])=[CH:17][C:18]3[C:28](=[O:29])[C:27]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:26][N:20]4[C@@H:21]([CH3:25])[CH2:22][O:23][C:24]=2[C:19]=34)[CH2:13][CH2:14]1
Reactant: CCOC(=O)c1cn2c3c(c(C4(NC(=O)OCc5ccccc5)CC4)c(F)cc3c1=O)OC[C@@H]2C
Reactant: [H][H]
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)c1cn2c3c(c(C4(N)CC4)c(F)cc3c1=O)OC[C@@H]2C
Yield: 89.2 %

Procedure:
In 100 ml of acetic acid was dissolved 10 g of ethyl (S)-10-(1-benzyloxycarbonylaminocyclopropyl)-9-fluoro-3-methyl-7-oxo-2,3-dihydro-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylate. To the resulting solution was added 2 g of 5% palladium-carbon. The resulting mixture was stirred at room temperature for 2 hours at atmospheric pressure in a hydrogen stream. The reaction mixture was filtered. The filtrate was concentrated to dryness under reduced pressure. To the residue obtained were added 200 ml of methylene chloride and 200 ml of water in this order. The resulting mixture was adjusted to pH 7.7 with a saturated aqueous sodium hydrogen-carbonate solution. The organic layer was separated, washed with water and a saturated aqueous sodium chloride solution in this order, and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure. Diethyl ether was added to the residue obtained. The resulting crystals were collected by filtration to obtain 6.43 g (yield: 89.2%) of ethyl (S)-10-(1-aminocyclopropyl)-9-fluoro-3-methyl- 7-oxo-2,3-dihydro-7H-pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylate.
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[F:11][C:12]1[CH:34]=[CH:33][C:15]([CH2:16][NH:17][C:18]([C:20]2[S:24][C:23]([C:25]3[CH:30]=[N:29][CH:28]=[C:27](I)[N:26]=3)=[N:22][C:21]=2[CH3:32])=[O:19])=[CH:14][CH:13]=1.C(N(C(C)C)CC)(C)C>CC(N(C)C)=O>[F:11][C:12]1[CH:34]=[CH:33][C:15]([CH2:16][NH:17][C:18]([C:20]2[S:24][C:23]([C:25]3[CH:30]=[N:29][CH:28]=[C:27]([O:8][CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[N:26]=3)=[N:22][C:21]=2[CH3:32])=[O:19])=[CH:14][CH:13]=1
Reactant: Cc1nc(-c2cncc(I)n2)sc1C(=O)NCc1ccc(F)cc1
Reactant: OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: Cc1nc(-c2cncc(OCc3ccccc3)n2)sc1C(=O)NCc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 60 %

Procedure:
To a solution of benzyl alcohol (25 μL, 0.24 mmol) in dimethyl acetamide (0.5 mL) in the sealed tube was added NaH (10.4 mg, 0.26 mmol). The reaction mixture was stirred at room temperature. After 30 min, a solution of 2-(6-iodo-pyrazin-2-yl)-4-methyl-thiazole-5-carboxylic acid 4-fluoro-benzylamide (100 mg, 0.22 mmol) and diisopropyl ethylamine (96 μL, 0.55 mmol) was added to the reaction mixture. The reaction mixture was stirred at 100° C. After 12 hr, the reaction mixture was cooled to room temperature, quenched with methanol, diluted with CH2Cl2, washed with water and brine, then dried (Na2SO4), filtered, and concentrated in vacuo. The residue was purified by column chromatography to give the title compound in 60% yield. 1H NMR (400 MHz, CD2Cl2) δ 8.92 (s, 1H), 8.29 (s, 1H), 7.47-7.51 (m, 2H), 7.31-7.40 (m, 5H), 7.02-7.08 (m, 2H), 6.20 (bs, 1H), 5.44 (s, 2H), 4.57 (d, J=8.0 Hz, 2H), 2.72 (s; 3H); MS (ES+) m/z 435.2 (M+1), Rt=1.65 min.
Reaction SMILES: [CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]([O:24]C(C)(C)C)=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:7]2[CH:29]=[C:30]([C:34]3[N:35]=[C:36]([CH3:39])O[CH:38]=3)[CH:31]=[C:32]([CH3:33])[C:6]=2[N:5]=1)[CH2:2][CH3:3].CN.[CH3:42][NH:43]C=O.O>C(O)(=O)C>[OH2:23].[CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:11]=[CH:12][C:13]([C:16]3[C:17]([C:22]([OH:24])=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:14][CH:15]=2)[C:7]2[CH:29]=[C:30]([C:34]3[N:35]=[C:36]([CH3:39])[N:43]([CH3:42])[CH:38]=3)[CH:31]=[C:32]([CH3:33])[C:6]=2[N:5]=1)[CH2:2][CH3:3]
Reactant: CCCc1nc2c(C)cc(-c3coc(C)n3)cc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Reactant: CNC=O
Agent: CN
Solvent: CC(=O)O
Solvent: O
Product: CCCc1nc2c(C)cc(-c3cn(C)c(C)n3)cc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
A mixture of 1.5 g (3 mMol) of tert.butyl 4'-[(2-n-propyl-4-methyl-6-(2-methyl-oxazol-4-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylate, 10 ml of 40% N-methylamine solution and 15 ml of N-methylformamide is heated for 10 hours to 200° C. in an autoclave. After cooling, the contents of the autoclave are stirred with about 40 ml of water, this suspension is adjusted to pH 6.5 with glacial acetic acid, then the crude product precipitated is suction filtered and dissolved in 1N sodium hydroxide solution. This solution is washed successively with 25 ml of acetic acid and diethylether, then adjusted to pH 6 with 20% citric acid. The product precipitated is suction filtered, washed with about 30 ml of water and dried, then triturated with diethylether and dried in a high vacuum.
Reaction SMILES: [CH:1]1([NH:6][C:7]2[N:12]3[N:13]=[C:14]([C:28]4[CH:29]=[C:30]([CH:33]=[CH:34][CH:35]=4)[C:31]#N)[C:15]([C:16]4[CH:21]=[CH:20][N:19]=[C:18]([NH:22][CH:23]5[CH2:27][CH2:26][CH2:25][CH2:24]5)[N:17]=4)=[C:11]3[CH:10]=[CH:9][CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-:36].[K+].Cl.C[OH:40]>>[CH:1]1([NH:6][C:7]2[N:12]3[N:13]=[C:14]([C:28]4[CH:29]=[C:30]([CH:33]=[CH:34][CH:35]=4)[C:31]([OH:40])=[O:36])[C:15]([C:16]4[CH:21]=[CH:20][N:19]=[C:18]([NH:22][CH:23]5[CH2:27][CH2:26][CH2:25][CH2:24]5)[N:17]=4)=[C:11]3[CH:10]=[CH:9][CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: N#Cc1cccc(-c2nn3c(NC4CCCC4)cccc3c2-c2ccnc(NC3CCCC3)n2)c1
Reactant: [OH-]
Reactant: CO
Agent: Cl
Agent: [K+]
Product: O=C(O)c1cccc(-c2nn3c(NC4CCCC4)cccc3c2-c2ccnc(NC3CCCC3)n2)c1
Temperature: 85 °C
Yield: 19 %

Procedure:
To a solution of 3-{7-(cyclopentylamino)-3-[2-(cyclopentylamino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-2-yl}benzonitrile (50 mg, 0.1 mmol) in methanol was added 4N potassium hydroxide. After heating at 85° C. for 2 days, the reaction mixture was cooled to room temperature and acidified with 2N hydrochloric acid. The solution was extracted with ethyl acetate. The organic phases were combined and dried over magnesium sulfate. Filtration and concentration, followed by purification by flash chromatography (90:10 ethyl acetate:methanol) gave 3-{7-(cyclopentylamino)-3-[2-(cyclopentylamino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-2-yl}benzoic acid (10 mg, 19%) as a brown foam. 1H NMR (CDCl3): δ 8.11 (s, 1H), 8.00 (d, 1H), 7.96 (d, 1H), 7.80 (broad s, 1H), 7.64 (d, 1H), 7.46 (t, 1H), 7.37 (t, 1H), 6.98 (d, 1H), 6.57 (d, 1H), 6.21 (d, 1H), 6.11 (broad, 1H), 4.12 (m, 1H), 4.01 (m, 1H), 2.06 (m, 2H), 1.88 (m, 2H), 1.69–1.49 (m, 12H). MS m/z 483 (M+1); 481 (M−1).
Reaction SMILES: BrCCl.[CH3:4][O:5][C:6]([CH:8]1[CH:13]=[CH:12][C:11]2[CH:14]=[C:15]([F:18])[CH:16]=[CH:17][C:10]=2[O:9]1)=O.[Li]CCCC.CCCCCC>C1COCC1.O>[F:18][C:15]1[CH:16]=[CH:17][C:10]2[O:9][CH:8]([CH:6]3[CH2:4][O:5]3)[CH:13]=[CH:12][C:11]=2[CH:14]=1
Reactant: COC(=O)C1C=Cc2cc(F)ccc2O1
Agent: ClCBr
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: CCCCCC
Product: Fc1ccc2c(c1)C=CC(C1CO1)O2
Temperature: 22.5 °C
Yield: 91 %

Procedure:
2.5 g of bromochloromethane (19 mmol) were added at room temperature to a solution of 2.0 g of crude 6-Fluoro-1-benzopyran-2-carboxylic acid methyl ester (9.5 mmol) in 40 ml of THF. The solution was then cooled to −80/−85° C. and 7.8 ml of 2.5 M n-BuLi in hexane (19.5 mmol) were slowly added to maintain the internal temperature between −75° C. and −80° C. The reaction progress was monitored by TLC. A 1 M solution of BH3 in THF (10 ml, 10 mmol) was then slowly added to maintain the internal temperature between −70° C. and −80° C. The reaction progress was monitored by TLC. The mixture was hydrolyzed by the addition of water (15 ml) at 0° C. and the phases separated. A 30% aqueous solution of sodium hydroxide was then added to the organic layer and the mixture warmed up to reflux for 2 h until 2-Chloro-1-(6-fluoro-1-benzopyran-2-yl)-ethanol had disappeared. The biphasic mixture was cooled to 20-25° C., the phases separated. The organic layer was washed with water (5 ml) and concentrated until dryness to give 6-Fluoro-2-oxiranyl-1-benzopyran as a mixture of the 4 diastereoisomers [(R,S);(S,R):(R,R);(S,S)]=52:48 (1.7 g, 91% yield).
Reaction SMILES: F.[NH2:2][C:3]1[CH:4]=[C:5]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-])=[O:10].[H][H].[CH2:20]([OH:22])[CH3:21].O>[Pd]>[C:20]([OH:10])(=[O:22])[CH3:21].[N:12]1([C:5]2[CH:4]=[C:3]3[C:8](=[CH:7][CH:6]=2)[N:9]=[CH:21][CH:20]=[N:2]3)[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1
Reactant: [H][H]
Reactant: Nc1cc(N2CCNCC2)ccc1[N+](=O)[O-]
Reactant: CCO
Agent: [Pd]
Agent: F
Solvent: O
Product: CC(=O)O
Product: c1cnc2cc(N3CCNCC3)ccc2n1

Procedure:
1-(3-Amino-4-nitrophenyl)piperazine hydrofluoride (2.2 g., 0.0091 mol) is hydrogenated in 100 ml. of a 1:1 ethanol-water mixture in the presence of 1.1 g. of 10% Pd on carbon at an initial pressure of 35-40 psiq of hydrogen at ambient temperature. After three equivalents of hydrogen have been absorbed, the mixture is vented to nitrogen and filtered through diatomaceous earth into a flask containing 2 ml. of 40% (by weight) aqueous glyoxal. The total filtrate is concentrated under vacuum, the aqueous solution is basified with sodium hydroxide, and then extracted with chloroform. The chloroform extract is washed with water, dried over sodium sulfate and concentrated under vacuum to an oil which is treated with 50 ml. of ethanol and 2 ml. of 10N anhydrous ethanolic-hydrogen chloride. The precipitated hydrochloride is partitioned between aqueous sodium carbonate and methylenechloride and the methylene chloride extract is washed with water, dried over sodium sulfate and concentrated to an oil which is treated with 0.5 ml. of acetic acid in 40 ml. of isopropanol and 40 ml. of ether. The crystallized 6-(1-piperazinyl)quinoxaline acetate, m.p. 147°-148.5° C. is collected by filtration.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH:3]=[N:2]1.FC(F)(F)O[C:9]1[CH:14]=[CH:13][C:12]([N:15]=[C:16]=[O:17])=[CH:11][CH:10]=1.C(OCC)C>C(#N)C.C(N(CC)CC)C>[N:2]1([C:16]([NH:15][C:12]2[CH:13]=[CH:14][CH:9]=[CH:10][CH:11]=2)=[O:17])[CH2:3][CH2:4][CH:5]=[N:1]1
Reactant: C1=NNCC1
Reactant: O=C=Nc1ccc(OC(F)(F)F)cc1
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: O=C(Nc1ccccc1)N1CCC=N1
Reaction time: 2 h

Procedure:
2.76 g (0,008 mol) of 3-(4'-chlorophenyl)-4-(4"-methyl-3"-trifluoromethyl-Δ2" -1",2",4"-triazolin-5"-on-1"-yl)-4,5-dihydropyrazole are dissolved in 20 ml of acetonitrile (anhydrous) at 60° C. until a clear solution has formed, this solution is treated with 1.7 g of 4-trifluoromethoxy-phenyl isocyanate, and 2drops of triethylamine are added. The mixture is subsequently allowed to stand for 2 hours at room temperature. The solvent is subsequently stripped off in vacuo, the residue is treated with 20 ml of diethyl ether and, after 2 hours, the precipitate which has formed is filtered off with suction. 2.0 g (45.6% of theory) of N-(4-trifluormethoxy)-3-(4'-chlorophenyl)-4-(4"-methyl-3"-trifluoromethyl-Δ2" -1",2",4,"-triazolin-5"-on-1"-yl)-4,5-dihydro-1-pyrazole-carboxanilide having a melting point of 241° C. are obtained.
Reaction SMILES: [CH:1]([C:3]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:4]=1[CH:5]=O)=[CH2:2].[NH2:13]/[C:14](/[CH3:20])=[CH:15]\[C:16]([O:18][CH3:19])=[O:17].[C:21]([O:27][CH3:28])(=[O:26])[CH2:22][C:23]([CH3:25])=O.[OH-].[NH4+]>CO>[CH3:20][C:14]1[NH:13][C:23]([CH3:25])=[C:22]([C:21]([O:27][CH3:28])=[O:26])[CH:5]([C:4]2[CH:7]=[C:8]([O:11][CH3:12])[CH:9]=[CH:10][C:3]=2[CH:1]=[CH2:2])[C:15]=1[C:16]([O:18][CH3:19])=[O:17]
Reactant: COC(=O)CC(C)=O
Reactant: COC(=O)/C=C(/C)N
Reactant: C=Cc1ccc(OC)cc1C=O
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Product: C=Cc1ccc(OC)cc1C1C(C(=O)OC)=C(C)NC(C)=C1C(=O)OC

Procedure:
To compound (3d) (8.0 g, 49.3 mmol) in anhydrous methanol (50 ml) was added methyl 3-aminocrotonate (5.68 g, 49.3 mmol), methyl acetoacetate (5.72 g, 49.3 mmol), and concentrated ammonium hydroxide (1 ml) and the resulting solution heated at reflux under nitrogen for 4 days. The solvent was removed in vacuo and the residual material triturated with ether (20 ml) to give compound (3e) as a pale, yellowish solid, mp 141°-143°.
Reaction SMILES: [CH2:1]([C:3]1[C:8]([O:9][C:10]2[CH:15]=[CH:14][N:13]=[C:12]([C:16]3[CH:17]=[N:18][N:19]([CH3:21])[CH:20]=3)[CH:11]=2)=[CH:7][CH:6]=[C:5](F)[N:4]=1)[CH3:2].O.[NH2:24][NH2:25].C([O-])(O)=O.[Na+]>CC(O)C>[CH2:1]([C:3]1[C:8]([O:9][C:10]2[CH:15]=[CH:14][N:13]=[C:12]([C:16]3[CH:17]=[N:18][N:19]([CH3:21])[CH:20]=3)[CH:11]=2)=[CH:7][CH:6]=[C:5]([NH:24][NH2:25])[N:4]=1)[CH3:2]
Reactant: CCc1nc(F)ccc1Oc1ccnc(-c2cnn(C)c2)c1
Reactant: NN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)O
Product: CCc1nc(NN)ccc1Oc1ccnc(-c2cnn(C)c2)c1
Temperature: 90 °C
Reaction time: 18 h
Yield: 94.8 %

Procedure:
2-Ethyl-6-fluoro-3-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridine (0.15 g, 0.51 mmol) was suspended in 2-propanol (1.0 mL) in a screw-cap reaction vessel. Hydrazine hydrate (0.12 mL, 2.5 mmol) was added, the reaction vessel was sealed and the mixture was stirred at 90° C. for 18 h. Sat. NaHCO3 (aq) (20 mL) was added and the mixture was extracted wth EtOAc (4×35 mL). The combined organics were dried (Na2SO4) and concentrated in vacuo to afford 2-ethyl-6-hydrazinyl-3-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)pyridine (0.15 g, 96%) as a light yellow solid that was used in the next step without further purification. MS (ESI) m/z: 311.2 (M+H+).
Reaction SMILES: I[C:2]1[N:3]([CH2:18][C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:22]=[CH:21][CH:20]=2)[CH:4]=[C:5]2[C:10]=1[C:9](=[O:11])[N:8]([CH3:12])[C:7](=[O:13])[N:6]2[CH2:14][CH:15]([CH3:17])[CH3:16].[C:29]([OH:35])(=[O:34])[CH2:30][CH2:31][CH:32]=[CH2:33].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(#N)C>C(N(CC)CC)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:12][N:8]1[C:9](=[O:11])[C:10]2=[C:2]([CH2:33]/[CH:32]=[CH:31]/[CH2:30][C:29]([OH:35])=[O:34])[N:3]([CH2:18][C:19]3[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH:22]=[CH:21][CH:20]=3)[CH:4]=[C:5]2[N:6]([CH2:14][CH:15]([CH3:16])[CH3:17])[C:7]1=[O:13]
Reactant: C=CCCC(=O)O
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2c(I)n(Cc3cccc4ccccc34)cc21
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)Cn1c(=O)n(C)c(=O)c2c(C/C=C/CC(=O)O)n(Cc3cccc4ccccc34)cc21
Temperature: 25 °C

Procedure:
5-Iodo-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)-1H-pyrrolo[3,4-d]pyrimidine-2,4(3H,6H)-dione (100 mg), 4-pentenoic acid (0.042 ml), palladium acetate (5 mg) and tri(o-tolyl)phosphine (13 mg) were dissolved in triethylamine (1 ml) and acetonitrile (5 ml) and heated to 95° C. in a sealed pressure tube for 3 hours. The reaction mixture was allowed to cool to room temperature and was then evaporated to leave a residue which was chromatographed using ethyl acetate containing 1% acetic acid to give an oil (160 mg). Recrystallisation from diethyl ether/isohexane gave the title compound as a pale brown solid (48 mg).
Reaction SMILES: [Li+].[Cl-].[CH:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][N:4]=1.[I:13]I>C1COCC1>[I:13][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][N:4]=1
Reactant: c1ccc2cnccc2c1
Reactant: II
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Ic1nccc2ccccc12
Reaction time: 2 h
Yield: 96 %

Procedure:
A dry and argon flushed 10 mL flask, equipped with a magnetic stirrer and a septum, was charged with TMPMgCl LiCl (5 mL, 1.2 M in THF, 6.0 mmol). Isoquinoline (703 mg, 5.45 mmol) in THF (5 ml) was added dropwise at room temperature. During addition, the reaction mixture became red and the metalation was complete after 2 h (as checked by GC analysis of reaction aliquots quenched with a solution of I2 in THF, the conversion was more than 98%). A solution of I2 in THF (6 ml, 1 M in THF, 6.0 mmol) was slowly added at −20° C. The reaction mixture was quenched with sat. aqueous NH4Cl solution (10 mL). The aqueous phase was extracted with ether (4×10 mL), dried with Na2SO4 and concentrated in vacuo. The crude residue was purified by filter column chromatography (CH2Cl2/pentane) yielding 1-iodoisoquinoline (7a; 1.33 mg, 96%) as slightly yellow crystals (mp=74-76° C.).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH:11]=O)=[CH:8][C:6]=2[N:7]=1.[CH3:19][S:20]([CH:23]1[CH2:27][CH2:26][NH:25][CH2:24]1)(=[O:22])=[O:21].[N:28]1[CH:33]=[CH:32][CH:31]=[C:30](B(O)O)[CH:29]=1>>[CH3:19][S:20]([CH:23]1[CH2:27][CH2:26][N:25]([CH2:11][C:9]2[S:10][C:5]3[C:4]([N:13]4[CH2:18][CH2:17][O:16][CH2:15][CH2:14]4)=[N:3][C:2]([C:30]4[CH:29]=[N:28][CH:33]=[CH:32][CH:31]=4)=[N:7][C:6]=3[CH:8]=2)[CH2:24]1)(=[O:22])=[O:21]
Reactant: O=Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Reactant: CS(=O)(=O)C1CCNC1
Reactant: OB(O)c1cccnc1
Product: CS(=O)(=O)C1CCN(Cc2cc3nc(-c4cccnc4)nc(N4CCOCC4)c3s2)C1

Procedure:
2-Chloro-4-morpholinothieno[3,2-d]pyrimidine-6-carbaldehyde 10 from Example 3 (100 mg) was reacted with 3-(methanesulfonyl)pyrrolidine following the protocol in General Procedure C. One half of the crude material was then used with pyridine-3-boronic acid in General Procedure A to give 47 mg of 141 following reversed phase HPLC purification. MS (Q1) 460 (M)+.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[N:5][N:4]=[C:3]1[SH:7].Br[CH2:9][CH:10]1[CH2:12][CH2:11]1>C(O)C>[CH:10]1([CH2:9][S:7][C:3]2[N:2]([CH3:1])[CH:6]=[N:5][N:4]=2)[CH2:12][CH2:11]1
Reactant: Cn1cnnc1S
Reactant: BrCC1CC1
Solvent: CCO
Product: Cn1cnnc1SCC1CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 62.2 %

Procedure:
To 4-methyl-4H-1,2,4-triazole-3-thiol (5.2 g, 45 mmol) in absolute ethanol (30 mL) under nitrogen was added (bromomethyl)cyclopropane (4.50 mL, 46 mmol). The reaction was stirred at room temperature for 24 h and then concentrated in vacuo. The residue was partitioned between ethyl acetate and sat aq. Na2CO3 solution. The layers were separated and the aqueous phase further extracted with ethyl acetate (×3). The combined organic extracts were dried (MgSO4) and concentrated to give the title compound as a colourless oil (4.795 g, 28 mmol). 1H NMR (500 MHz, CDCl3) δ (ppm) 8.14 (1H, s), 3.62 (3H, s), 3.17 (2H, d, J=7.3 Hz), 1.27-1.15 (1H, m), 0.63-0.59 (2H, m), 0.30-0.27 (2H, m); m/z (ES+) 170 (M+H).
Reaction SMILES: C1(C)C=CC=CC=1.[C:8]([O:12][C:13]([NH:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[O:22][CH:21](O)[CH2:20][CH2:19]2)=[O:14])([CH3:11])([CH3:10])[CH3:9].[C:27]([CH:32]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:29][CH2:30][CH3:31])=[O:28].[O-]CC.[Na+]>C1(C)C=CC=CC=1>[C:8]([O:12][C:13]([NH:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[O:22][CH:21]([CH2:32][C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:20][CH2:19]2)=[O:14])([CH3:11])([CH3:10])[CH3:9]
Reactant: CC(C)(C)OC(=O)Nc1ccc2c(c1)CCC(O)O2
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCOC(=O)CC1CCc2cc(NC(=O)OC(C)(C)C)ccc2O1
Temperature: 80 °C
Reaction time: 18 h

Procedure:
Into the 6-(tert-butyloxycarbonylamino)chroman-2-ol toluene solution of Example 2 (8 L) was added 1225 g of (carbethoxymethylene)triphenylphosphorane (95%) and 1.1 g of sodium ethoxide. The stirred reaction was heated to 80° C. for 2 h. An additional 3.2 g of sodium ethoxide was added, and the mixture stirred at 80° C. for 18 h. Because the reaction was not complete by TLC, an additional 122 g of (carbethoxymethylene)triphenylphosphorane and 1.0 g of sodium ethoxide was added. The reaction mixture was stirred at 80° C. for 3 h after the addition. The reaction was cooled to room temperature, and 3750 g of silica gel and 7 L of toluene were added. The mixture was stirred for 2 h, filtered, and the filter cake was washed with 2×12 L of toluene. The filtrate and washings were combined, and the volume reduced to about 7 L by distillation under reduced pressure (T≦60° C.) to provide a toluene solution of ethyl 2-(6-(tert-butyloxycarbonylamino)chroman-2-yl)acetate.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:3]=1[CH:4]=[O:5].[CH:14]1([CH2:17][NH:18][CH2:19][CH2:20][CH3:21])[CH2:16][CH2:15]1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>C1(C)C=CC=CC=1.O>[CH:14]1([CH2:17][N:18]([CH2:19][CH2:20][CH3:21])[C:2]2[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:3]=2[CH:4]=[O:5])[CH2:16][CH2:15]1
Reactant: O=Cc1cc(C(F)(F)F)ccc1F
Reactant: CCCNCC1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCCN(CC1CC1)c1ccc(C(F)(F)F)cc1C=O
Temperature: 120 °C
Reaction time: 8 h

Procedure:
2-Fluoro-5-trifluoromethyl-benzaldehyde (5 g) and cyclopropylmethyl-propyl-amine (5.57 ml) is dissolved in toluene (50 ml), and thereto is added potassium carbonate (10.7 g) and the mixture is stirred at 120° C. overnight. The reaction solution is cooled to room temperature, and thereto are added ethyl acetate and water, and the mixture is separated, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane:ethyl acetate=20:1) to give 2-(cyclopropylmethyl-propyl-amino)-5-trifluoromethyl-benzaldehyde (6.8 g). MS (m/z): 286 [M+H]+