Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:7][CH2:6][C@@H:5]([NH:8][C:9]2[N:10]=[CH:11][C:12](/[CH:15]=[CH:16]/[C:17]([O:19][CH3:20])=[O:18])=[N:13][CH:14]=2)[CH2:4]1.CCN(C(C)C)C(C)C.[CH3:30][N:31]([CH3:40])[C:32]1[CH:39]=[CH:38][CH:37]=[CH:36][C:33]=1[CH:34]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:30][N:31]([CH3:40])[C:32]1[CH:39]=[CH:38][CH:37]=[CH:36][C:33]=1[CH2:34][N:3]1[CH2:7][CH2:6][C@@H:5]([NH:8][C:9]2[N:10]=[CH:11][C:12](/[CH:15]=[CH:16]/[C:17]([O:19][CH3:20])=[O:18])=[N:13][CH:14]=2)[CH2:4]1
Reactant: CN(C)c1ccccc1C=O
Reactant: COC(=O)/C=C/c1cnc(N[C@@H]2CCNC2)cn1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)/C=C/c1cnc(N[C@@H]2CCN(Cc3ccccc3N(C)C)C2)cn1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a suspension of methyl (2E)-3-{5-[(3R)-3-pyrrolidinylamino]-2-pyrazinyl}acrylate dihydrochloride (240 mg) in CH2Cl2 (2.4 mL) was added DIEA (260 uL), 2-(dimethylamino) benzaldehyde (122.6 mg), and sodium triacetoxyborohydride (317 mg), which was stirred at room temperature for 15 hours. To the resultant was added saturated NaHCO3 aq., which was stirred for 20 min. The mixture was extracted with CH2Cl2. The organic phase was washed with brine and dried over Na2SO4, filtered, and evaporated in vacuo. The residue was washed with hexane to give methyl (2E)-3-[5-({(3R)-1-[2-(dimethylamino)benzyl]-3-pyrrolidinyl}amino)-2-pyrazinyl]acrylate as a beige powder.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]([OH:29])[CH:17]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C1C=CC=CN=1)C.[C:39]1([CH3:49])[CH:44]=[CH:43][C:42]([S:45](Cl)(=[O:47])=[O:46])=[CH:41][CH:40]=1>N1C=CC=CC=1>[CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]([O:29][S:45]([C:42]1[CH:43]=[CH:44][C:39]([CH3:49])=[CH:40][CH:41]=1)(=[O:47])=[O:46])[CH:17]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(c1ccccc1)C(O)CCCCNC(=O)OCc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccccn1
Solvent: c1ccncc1
Product: CCOC(=O)C(c1ccccc1)C(CCCCNC(=O)OCc1ccccc1)OS(=O)(=O)c1ccc(C)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 47.6 %

Procedure:
3.5 g (8.6 mmol) of ethyl 7-(N-benzyloxycarbonylamino)-3-hydroxy-2-phenylheptanoate obtained in Example 9 was dissolved in 28 ml of pyridine. 240 mg (1.96 mmol) of dimethylaminopyridine was added to the mixture. The mixture was cooled at 0° C. in an ice bath. 2.5 g (13 mmol) of p-toluenesulfonyl chloride was added for 5 minutes, which was stirred for one hour at a same temperature and further stirred at room temperature for 48 hours. After the consumption of the raw material was confirmed by means of HPLC, 100 ml of ethylacetate was added and 2N hydrochloric acid were further added to the reaction mixture to adjust the pH to 4 to extract. A saturated sodium bicarbonate solution was added to the organic layer prepared to neutralize. The neutralized organic layer was washed with saturated brine and then deied with magnesium sulfate anhydride. After the organic layer was concentrated under reduced pressure, the residue was purified by means of SGIC (eluent: hexane/ethylacetate=3/1) to obtain the target compound as a pale yellow oil in an amount 2.3 g at a yield of 47.6%. The analytical results on the target compound are given below.
Reaction SMILES: [CH:1](=O)[C:2]([CH3:5])([CH3:4])[CH3:3].[CH3:7][NH:8][C:9](=[O:15])[C@H:10]([CH:12]([CH3:14])[CH3:13])[NH2:11].O>CCCCC>[CH3:7][NH:8][C:9](=[O:15])[C@H:10]([CH:12]([CH3:14])[CH3:13])[N:11]=[CH:1][C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(C)(C)C=O
Reactant: CNC(=O)[C@@H](N)C(C)C
Solvent: CCCCC
Solvent: O
Product: CNC(=O)[C@@H](N=CC(C)(C)C)C(C)C

Procedure:
There were added 95.7 ml (870 mmols) of pivalaldehyde to 112.0 grams (864 mmoles) of (S)-valine monomethylamide dissolved in 300 ml of n-pentane. The reaction mixture was boiled at a water separator until the formation of water was ended (4 hours). The solvent was removed under reduced pressure and there remained behind 130 grams (76% of theory) of (S)-N-(2',2'-dimethyl-propylidene)-valine monomethylamide, which could be further worked without purification. To ascertain the exact material data, a test of sample was purified by distillation.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][C:14]([CH2:22][CH2:23][C:24](=O)[NH:25][C:26]2[CH:31]=[C:30]([C:32]#[N:33])[CH:29]=[CH:28][C:27]=2[NH:34][CH2:35][C:36](=[O:44])[NH:37][CH:38]2[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]2)([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:13][CH2:12]1)=[O:10])C1C=CC=CC=1>C(O)(=O)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][C:14]([CH2:22][CH2:23][C:24]2[N:34]([CH2:35][C:36](=[O:44])[NH:37][CH:38]3[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43]3)[C:27]3[CH:28]=[CH:29][C:30]([C:32]#[N:33])=[CH:31][C:26]=3[N:25]=2)([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:13][CH2:12]1)=[O:10])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CCOC(=O)C1(CCC(=O)Nc2cc(C#N)ccc2NCC(=O)NC2CCCCC2)CCN(C(=O)OCc2ccccc2)CC1
Solvent: CC(=O)O
Product: CCOC(=O)C1(CCc2nc3cc(C#N)ccc3n2CC(=O)NC2CCCCC2)CCN(C(=O)OCc2ccccc2)CC1
Yield: 137.3 %

Procedure:
A solution of 4-[2-[5-cyano-2-(cyclohexylcarbamoylmethylamino)-phenylcarbamoyl]ethyl]-4-ethoxycarbonylpiperidine-1-carboxylic acid benzyl ester (300 mg) in acetic acid (10 ml) was stirred at 100° C. for 24 hours. After completion of the reaction, the reaction mixture was extracted with ethyl acetate and washed with aqueous sodium hydrogencarbonate solution. The organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:3) and dried under reduced pressure to give the title compound (200 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:31]=[CH:32][C:33]=1[O:34][CH3:35])[CH2:6][CH:7]1[C:16]2[C:11](=[C:12]([O:18][CH3:19])[CH:13]=[CH:14][C:15]=2[OH:17])[CH2:10][CH2:9][N:8]1[CH2:20][C:21]([NH:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1)=[O:22].[CH2:36](Br)[CH2:37][CH3:38]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:31]=[CH:32][C:33]=1[O:34][CH3:35])[CH2:6][CH:7]1[C:16]2[C:11](=[C:12]([O:18][CH3:19])[CH:13]=[CH:14][C:15]=2[O:17][CH2:36][CH2:37][CH3:38])[CH2:10][CH2:9][N:8]1[CH2:20][C:21]([NH:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1)=[O:22]
Reactant: CCCBr
Reactant: COc1ccc(CC2c3c(O)ccc(OC)c3CCN2CC(=O)NCc2ccccn2)cc1OC
Product: CCCOc1ccc(OC)c2c1C(Cc1ccc(OC)c(OC)c1)N(CC(=O)NCc1ccccn1)CC2

Procedure:
prepared by reaction of 2-[1-(3,4-dimethoxy-benzyl)-8-hydroxy-5-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(pyridin-2-yl-methyl)-acetamide with propyl bromide
Reaction SMILES: [C:1]([O:4][CH:5]([CH3:18])[C:6](=[O:17])[C:7]1[CH2:11][CH2:10][CH2:9][C:8]=1N1CCCC1)(=[O:3])[CH3:2].C(O)(=[O:21])C>O1CCCC1.O.ClCCl>[C:1]([O:4][CH:5]([CH3:18])[C:6](=[O:17])[CH:7]1[CH2:11][CH2:10][CH2:9][C:8]1=[O:21])(=[O:3])[CH3:2]
Reactant: CC(=O)O
Reactant: CC(=O)OC(C)C(=O)C1=C(N2CCCC2)CCC1
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: O
Product: CC(=O)OC(C)C(=O)C1CCCC1=O

Procedure:
Stir a mixture of 1-oxo-1-(2-(pyrrolidin-1-yl)cyclopent-1-enyl)propan-2-yl acetate (952.0 g), acetic acid (1500 mL) and water (1500 mL) in tetrahydrofuran (3000 mL) at room temperature for 2 days. Dilute the mixture with water (1200 mL) and dichloromethane (1200 mL). The organic layer is washed with brine, dried over anhydrous Na2SO4 and concentrated under vacuum. Purify the residue by silica gel chromatograph (eluting with 3% to 10% ethyl acetate in petroleum ether) to give 1-oxo-1-(2-oxocyclopentyl)propan-2-yl acetate as oil (573.4 g, 2.89 mol, 72.6% for 2 steps).
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[CH:6][N:5]=[C:4]([OH:9])[N:3]=1.Cl[CH2:11][O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CC#N>[NH2:1][C:2]1[C:7]([F:8])=[CH:6][N:5]([CH2:11][O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:4](=[O:9])[N:3]=1
Reactant: Nc1nc(O)ncc1F
Reactant: ClCOCc1ccccc1
Solvent: CC#N
Product: Nc1nc(=O)n(COCc2ccccc2)cc1F
Temperature: 65 °C
Reaction time: 1.5 h
Yield: 44.9 %

Procedure:
A 25 mL Schlenk-type flask was charged with 4-amino-5-fluoropyrimidin-2-ol (500 mg, 3.87 mmol), CH3CN (10 mL), and BSA (1.42 mL, 5.81 mmol). The resulting white suspension was then heated at 65° C. After 90 min, the clear, colorless solution was cooled to room temperature and benzyl chloromethyl ether (1.07 mL, 7.72 mmol) was added, giving a cloudy white suspension. After stirring for 2 h at room temperature, the reaction mixture was concentrated in vacuo to give a white residue which was purified by reverse phase column chromatography yielding 4-amino-1-(benzyloxymethyl)-5-fluoropyrimidin-2(1H)-one (14; 433 mg, 45%) as a white solid: mp 213-217° C.; 1H NMR (400 MHz, CDCl3) δ 7.98 (d, J=6.5 Hz, 1H), 7.81 (br s, 1H), 7.56 (br s, 1H), 7.24-7.36 (m, 5H), 5.11 (s, 2H), 4.54 (s, 2H); IR 3302 (s), 3082 (s), 2939 (w), 2869 (w), 1688 (s), 1619 (s), 1522 (s), 1468 (m), 1333 (m), 1131 (w), 1054 (m) cm−1; ESIMS m/z 250 ([M+H]+).
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:6]=1[N:15]([S:19]([CH2:22][CH:23](O)[CH2:24][CH2:25][CH2:26][CH3:27])(=[O:21])=[O:20])[CH:16]([CH3:18])[CH3:17].N12CCCCC1CNCC=C2.Cl>C(Cl)Cl.C(N(CC)CC)C.S(Cl)(C)(=O)=O>[CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:6]=1[N:15]([S:19]([CH:22]=[CH:23][CH2:24][CH2:25][CH2:26][CH3:27])(=[O:20])=[O:21])[CH:16]([CH3:18])[CH3:17]
Reactant: CCCCC(O)CS(=O)(=O)N(c1ccc(C(F)(F)F)cc1OCOC)C(C)C
Agent: C1=CN2CCCCC2CNC1
Agent: CS(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCC=CS(=O)(=O)N(c1ccc(C(F)(F)F)cc1OCOC)C(C)C
Reaction time: 0.17 h
Yield: 91.3 %

Procedure:
To a solution of 2-(N-isopropyl-2-hydroxyhexylsulfonylamino)-5-trifluoromethylphenyl methoxymethyl ether (160 mg; prepared in Reference Example 31) in methylene chloride (2.0 ml), triethylamine (104 μl) and mesylchloride (35 μl) were added in a stream of argon at 0° C. The mixture was stirred for 10 minutes. To the mixture, 1,5-diazabicyclo[5,4,0]undecene (134 μl) was added. The mixture was stirred for 2 hours at room temperature. To the reaction mixture, diluted HCl was added. The mixture was extracted with ethyl acetate, washed, dried over and concentrated with the reduced pressure. The residue was purified on silica gel column chromatography (hexane:AcOEt=8:1) to give the title compound (140 mg) having the following physical data.
Reaction SMILES: [N:1]1([C:5]2[N:10]=[C:9]([CH2:11][CH3:12])[N:8]=[C:7]([NH:13][NH:14][C:15](=[O:35])[C@H:16]([CH2:29][CH:30]3[CH2:34][CH2:33][CH2:32][CH2:31]3)[CH2:17][N:18]([O:21]CC3C=CC=CC=3)[CH:19]=[O:20])[C:6]=2[F:36])[CH2:4][CH2:3][CH2:2]1>CO>[N:1]1([C:5]2[N:10]=[C:9]([CH2:11][CH3:12])[N:8]=[C:7]([NH:13][NH:14][C:15](=[O:35])[C@H:16]([CH2:29][CH:30]3[CH2:31][CH2:32][CH2:33][CH2:34]3)[CH2:17][N:18]([OH:21])[CH:19]=[O:20])[C:6]=2[F:36])[CH2:2][CH2:3][CH2:4]1
Reactant: CCc1nc(NNC(=O)[C@H](CC2CCCC2)CN(C=O)OCc2ccccc2)c(F)c(N2CCC2)n1
Solvent: CO
Product: CCc1nc(NNC(=O)[C@H](CC2CCCC2)CN(O)C=O)c(F)c(N2CCC2)n1
Yield: 76.5 %

Procedure:
[(2R)-3-{2-[6-(1-Azetidinyl)-2-ethyl-5-fluoro-4-pyrimidinyl]hydrazino}-2-(cyclopentylmethyl)-3-oxopropyl][(phenylmethyl)oxy]formamide (160 mg, 0.32 mmol) was dissolved in 10 mL of MeOH, degassed and placed under argon. 5% Pd/C (40 mg) was added, and the contents were thoroughly degassed and stirred under a hydrogen balloon until the reaction was deemed complete by LCMS. The contents were then degassed and filtered through Celite, and the Celite pad was washed with DCM and MeOH. The resulting filtrate was concentrated in vacuo to provide [(2R)-3-{2-[6-(1-azetidinyl)-2-ethyl-5-fluoro-4-pyrimidinyl]hydrazino}-2-(cyclopentylmethyl)-3-oxopropyl]hydroxyformamide (100 mg, 76%). LCMS: (M+H)+: 409.2.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5]([OH:7])=[O:6]>N1CCCCC1>[N:10]1([C:2]2[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=2)[C:5]([OH:7])=[O:6])[CH2:9][CH2:8][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)c1ccnc(Br)c1
Solvent: C1CCNCC1
Product: O=C(O)c1ccnc(N2CCCCC2)c1
Temperature: 105 °C
Yield: 171.4 %

Procedure:
A mixture of 2-bromoisonicotinic acid (40 g, 0.198 mol) and piperidine (200 mL) was refluxed at 105° C. for 24 h under N2 atmosphere. The excess piperidine was distilled under vacuum and crude residue was diluted with water (500 mL) and extracted with chloroform (3×250 mL), washed with brine and dried. The solvent was removed under vacuum to give 2-Piperidin-1-yl-isonicotinic acid (35 g, 85%) as a solid.
Reaction SMILES: C(OCC)(=O)CC(O[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13](=O)[C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)[CH:8]=1)=O.S(=O)(=O)(O)O.O.[C:32]([OH:35])(=[O:34])[CH3:33]>>[Cl:20][C:17]1[CH:16]=[CH:15][C:14]([CH2:13][C:9]2[CH:8]=[C:7]([CH2:6][CH2:33][C:32]([OH:35])=[O:34])[CH:12]=[CH:11][CH:10]=2)=[CH:19][CH:18]=1
Reactant: CC(=O)O
Reactant: CCOC(=O)CC(=O)OCc1cccc(C(=O)c2ccc(Cl)cc2)c1
Agent: O=S(=O)(O)O
Solvent: O
Product: O=C(O)CCc1cccc(Cc2ccc(Cl)cc2)c1
Temperature: 25 °C

Procedure:
A solution of 15.2 g of ethyl 3-(p-chlorobenzoyl)-benzyl malonate in 50 ml of acetic acid was added to a solution of 50 ml of sulfuric acid and 50 ml of water and the mixture was refluxed under a nitrogen atmosphere for 20 hours and then cooled to room temperature. The mixture was poured into water and then extracted with methylene chloride. The organic phase was extracted with N sodium hydroxide and the alkaline phase was treated with activated carbon, filtered and acidified by addition at 10° C with stirring of 270 ml of N hydrochloric acid. The mixture was vacuulm filtered and the precipitate was washed with water and dried under reduced pressure to obtain 3.11 g of 3-(3'-p-chlorobenzyl-phenyl)-propionic acid which was used as is for the next step.
Reaction SMILES: [CH3:1][C:2]([NH:4][CH:5]1[C:15]2[CH:16]=[C:17]([OH:20])[CH:18]=[CH:19][C:14]=2[C:13]2[C:8](=[CH:9][C:10]([O:25][CH3:26])=[C:11]([O:23][CH3:24])[C:12]=2[O:21][CH3:22])[CH2:7][CH2:6]1)=[O:3].[C:27](O)(=[O:35])[CH2:28][CH2:29][CH2:30][CH2:31][C:32]([OH:34])=[O:33].C(N(C(C)C)CC)(C)C>C(#N)C>[C:2]([NH:4][C@@H:5]1[C:15]2[CH:16]=[C:17]([O:20][C:27]([CH2:28][CH2:29][CH2:30][CH2:31][C:32]([OH:34])=[O:33])=[O:35])[CH:18]=[CH:19][C:14]=2[C:13]2[C:12]([O:21][CH3:22])=[C:11]([O:23][CH3:24])[C:10]([O:25][CH3:26])=[CH:9][C:8]=2[CH2:7][CH2:6]1)(=[O:3])[CH3:1]
Reactant: COc1cc2c(c(OC)c1OC)-c1ccc(O)cc1C(NC(C)=O)CC2
Reactant: O=C(O)CCCCC(=O)O
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2c(c(OC)c1OC)-c1ccc(OC(=O)CCCCC(=O)O)cc1[C@@H](NC(C)=O)CC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 31 %

Procedure:
N-Acetyl-colchicinol (0.3 g; 0.84 mmol) was added under argon atmosphere to a solution of adipic acid (0.147 g; 1 mmol, O-(7-(azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.383 g; 1 mmol) and diisopropylethylamine (0.352 ml; 2 mmol) in acetonitrile (20 ml). The reaction mixture was stirred at ambient temperature overnight and evaporated to dryness. The residue was taken up in water (4 ml), the pH was adjusted to 6.5 with 0.1M hydrochloric acid. The solution was purified by preparative HPLC eluting with a 0–40% gradient of methanol/ammonium carbonate buffer (2 g/l pH7) to give 5-[{(5S)-5-(acetylamino)-9,10,11-trimethoxy-6,7-dihydro-5H-dibenzo[a,c]cyclohepten-3-yl}oxycarbonyl]pentanoic acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9](O)[CH:10]([CH3:12])[CH3:11])=[CH:5][CH:4]=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>O>[CH2:9]([C:6]1[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=1)[CH:10]([CH3:12])[CH3:11]
Reactant: COc1ccc(C(O)C(C)C)cc1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: COc1ccc(CC(C)C)cc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
1.9 g 1-(4-methoxy-phenyl)-2-methyl-propan-1-ol are dissolved in 30 ml dissolved, cooled to 0° C. and mixed with 3.37 ml triethylsilane. The mixture is stirred for 10 minutes and then 1.62 ml trifluoroacetic acid are added. Within 1 hour the mixture is heated to 10° C., then the reaction is stopped by the addition of water and the phases are separated. The organic phase is washed with saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride solution and then dried on magnesium sulphate. The solvents are eliminated in vacuo and the residue is chromatographed on silica gel (cyclohexane/ethyl acetate 95:5 to 80:20).
Reaction SMILES: [N:1]([CH2:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH3:14])[CH:8]=1)=[O:6])=[N+]=[N-].[ClH:15]>[Pd].CO>[ClH:15].[NH2:1][CH2:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH3:14])[CH:8]=1)=[O:6]
Reactant: COc1cccc(C(=O)CN=[N+]=[N-])c1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: COc1cccc(C(=O)CN)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 123.8 %

Procedure:
Palladium on carbon (10 wt %, 10.41 g, 9.78 mmol) was added to a solution of 2-azido-1-[3-(methyloxy)phenyl]ethanone (1.87 g, 9.78 mmol) and hydrochloric acid (8.14 mL, 98 mmol) in CH3OH (50 mL) under nitrogen, and the reaction mixture was stirred under hydrogen overnight at 25° C. The mixture was filtered, washing with CH2Cl2 (50 mL) and CH3OH (100 mL), and then concentrated. Water (150 mL) was added, and the mixture was lyophilized to afford an HCl salt of the title compound (2.0 g) as a brown solid. LC-MS (ES) m/z=166 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([O:12][Si:13]([CH:20]([CH3:22])[CH3:21])([CH:17]([CH3:19])[CH3:18])[CH:14]([CH3:16])[CH3:15])[CH:6]=[CH:5]2.[CH3:23][Si:24]([C:27]#[CH:28])([CH3:26])[CH3:25].CCOCC>C1COCC1.C(NC(C)C)(C)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>[CH:20]([Si:13]([CH:14]([CH3:16])[CH3:15])([CH:17]([CH3:18])[CH3:19])[O:12][C:7]1[CH:6]=[CH:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([C:28]#[C:27][Si:24]([CH3:26])([CH3:25])[CH3:23])[CH:3]=2)[CH:8]=1)([CH3:22])[CH3:21]
Reactant: CC(C)[Si](Oc1ccc2cc(Br)ccc2c1)(C(C)C)C(C)C
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CC(C)NC(C)C
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)[Si](Oc1ccc2cc(C#C[Si](C)(C)C)ccc2c1)(C(C)C)C(C)C
Temperature: 70 °C
Reaction time: 8 h

Procedure:
35.0 g (90.4 mmol) of (6-bromonaphthalen-2-yloxy)triisopropylsilane are initially introduced in 120 ml of THF and 70 ml of diisopropylamine, and, after addition of 3.50 g (5.0 mmol) of bis(triphenylphosphine)palladium(II) chloride and 1.0 g (5.3 mmol) of copper(I) iodide, 25.0 g (0.255 mol) of trimethylsilylacetylene in 30 ml of THF are added dropwise at 70° C. The batch is left to stir for 4 h at 70° C. and overnight at room temp., 150 ml of MTB ether are added, and the mixture is washed three times with water, dried over sodium sulfate and evaporated in vacuo. Filtration of the crude product through silica gel with heptane gives 2-triisopropylsilanyloxy-6-trimethylsilanylethynylnaphthalene, which is employed in the next step without further purification.
Reaction SMILES: [NH2:1][C@H:2]([C:4]1[N:5]=[C:6]2[S:20][CH:19]=[C:18]([CH3:21])[N:7]2[C:8](=[O:17])[C:9]=1[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1)[CH3:3].[NH2:22][C:23]1[N:31]=[C:30]2[C:26]([NH:27][CH:28]=[N:29]2)=[C:25](Br)[N:24]=1.C(N(CC)C(C)C)(C)C>C(O)CCC>[NH2:22][C:23]1[N:31]=[C:30]2[C:26]([N:27]=[CH:28][NH:29]2)=[C:25]([NH:1][C@H:2]([C:4]2[N:5]=[C:6]3[S:20][CH:19]=[C:18]([CH3:21])[N:7]3[C:8](=[O:17])[C:9]=2[C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=2)[CH3:3])[N:24]=1
Reactant: Cc1csc2nc([C@H](C)N)c(-c3cccc(F)c3)c(=O)n12
Reactant: Nc1nc(Br)c2[nH]cnc2n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: Cc1csc2nc([C@H](C)Nc3nc(N)nc4[nH]cnc34)c(-c3cccc(F)c3)c(=O)n12
Temperature: 100 °C
Yield: 18.7 %

Procedure:
A solution of 7-[(1S)-1-aminoethyl]-6-(3-fluorophenyl)-3-methyl-5H-[1,3]thiazolo[3,2-a]pyrimidin-5-one (0.10 g, 0.33 mmol) and 2-amino-6-bromopurine (0.11 g, 0.49 mmol) in 1-butanol (0.66 mL) was treated with N,N-diisopropylethylamine (86 μL, 0.49 mmol), degassed with nitrogen for 5 min and heated at 100° C. for 18 hours. The reaction was not complete and was, therefore, heated at 115° C. for an additional 5 hours. The reaction mixture was diluted with methanol (10 mL), stirred, and filtered. The filtrate was purified by RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 60 mL/min) to give the desired product (27 mg, 19%) as a white solid. LCMS for C20H18FN8OS (M+H)+: m/z=437.0.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([F:13])[C:5]([O:9][CH2:10][O:11][CH3:12])=[C:6]([F:8])[CH:7]=1.[CH2:14]([O:16][CH:17]([O:20]CC)[CH:18]=[CH2:19])[CH3:15].C(N(C(C)C)CC)(C)C.O>[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:8][C:6]1[CH:7]=[C:2]([CH2:19][CH2:18][C:17]([O:16][CH2:14][CH3:15])=[O:20])[CH:3]=[C:4]([F:13])[C:5]=1[O:9][CH2:10][O:11][CH3:12]
Reactant: COCOc1c(F)cc(Br)cc1F
Reactant: C=CC(OCC)OCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CCc1cc(F)c(OCOC)c(F)c1
Temperature: 90 °C
Reaction time: 18 h
Yield: 41.7 %

Procedure:
To a solution of 5-bromo-1,3-difluoro-2-(methoxymethoxy)benzene (4.4 g, 21 mmol), acrolein diethyl acetal (9.4 mL, 62 mmol), tetrabutylammonium chloride (5.7 g, 21 mmol) and diisopropylethylamine (18 mL, 0.10 mol) in N,N-dimethylformamide (40 mL) was added palladium acetate (0.14 g, 0.62 mmol), and the mixture was stirred under argon atmosphere at 90° C. for 18 hours. After the reaction solution was returned to room temperature, water was added thereto, and the reaction mixture was extracted with ethyl acetate. The extract was washed with water, and then concentrated under reduced pressure. The residue was purified with silica gel column chromatography (hexane/ethyl acetate=49:1 to 4:1) to give the title compound (2.4 g, yield 42%).
Reaction SMILES: [CH3:1][N:2]([CH3:16])[CH:3]=[C:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N+:13]([O-:15])=[O:14])[CH:5]=O.[N+:17]([CH2:20][C:21]([O:23][CH3:24])=[O:22])([O-:19])=[O:18].C(OC(=O)C)(=O)C>>[CH3:24][O:23][C:21](=[O:22])[C:20]([N+:17]([O-:19])=[O:18])=[CH:5][C:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N+:13]([O-:15])=[O:14])=[CH:3][N:2]([CH3:16])[CH3:1]
Reactant: CN(C)C=C(C=O)c1ccccc1[N+](=O)[O-]
Reactant: COC(=O)C[N+](=O)[O-]
Solvent: CC(=O)OC(C)=O
Product: COC(=O)C(=CC(=CN(C)C)c1ccccc1[N+](=O)[O-])[N+](=O)[O-]
Yield: 80.4 %

Procedure:
A mixture of 63.0 g (0.29 mol) of the compound of Example 14 and 35.7 g (0.30 mol) of methyl nitroacetate in 600 ml. of acetic anhydride was heated at 85° for 2 hours. The resulting product was worked up and recrystallized from benzene-DMF (2:1) affording 74.9 g (81%) of product as red orange crystals, m.p. 211-214°.