Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4](S(C)(=O)=O)[C:5]2[N:10]=[C:9]([CH2:11][CH2:12][C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[S:8][C:6]=2[N:7]=1.C(N(C(C)C)CC)(C)C.[NH2:33][C@H:34]1[CH2:38][CH2:37][N:36]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:35]1>ClCCl>[NH2:1][C:2]1[N:3]=[C:4]([NH:33][C@H:34]2[CH2:38][CH2:37][N:36]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:35]2)[C:5]2[N:10]=[C:9]([CH2:11][CH2:12][C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[S:8][C:6]=2[N:7]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](N)C1
Reactant: CS(=O)(=O)c1nc(N)nc2sc(CCc3ccc(F)cc3)nc12
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CC[C@H](Nc2nc(N)nc3sc(CCc4ccc(F)cc4)nc23)C1
Yield: 42.1 %

Procedure:
To a solution of 5-amino-2-[2-(4-fluorophenyl)ethyl]-7-methanesulfonyl-thiazolo[5,4-d]pyrimidine (150 mg, 0.42 mmol) in dichloromethane (10 ml) was added diisopropylethylamine (3.0 mmol, 492 μL) and tert-butyl 3-(S)-aminopyrrolidine-1-carboxylate (2.1 mmol). The reaction mixture was refluxed for 40 hours whereupon the mixture was extracted with a saturated sodium bicarbonate solution. The organic phase was dried over magnesium sulfate and the solvent was removed in vacuo. The resulting residue was purified by flash chromatography on silica, the mobile phase being a mixture of methanol and dichloromethane (in a ratio gradually ranging from 100% CH2Cl2 to 1% CH3OH in CH2Cl2), yielding the pure title compound (81 mg) which was characterized by its mass spectrum: MS m/z (%): 459 ([M+H]+, 100).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH:5]=[CH2:6].[CH2:7]([O:9][P:10]([O:14]CC)[O:11][CH2:12][CH3:13])[CH3:8]>>[CH2:2]([P:10](=[O:14])([O:11][CH2:12][CH3:13])[O:9][CH2:7][CH3:8])[CH2:3][CH2:4][CH:5]=[CH2:6]
Reactant: C=CCCCBr
Reactant: CCOP(OCC)OCC
Product: C=CCCCP(=O)(OCC)OCC

Procedure:
5-bromo-1-pentene was combined with triethylphosphite in the absence of solvent using microwave conditions at 150° C. to give diethyl 4-pentenylphosphonate. Diethyl 4-pentenylphosphonate was combined with bromotrimethyl silane and subsequently quenched with methanol to afford diethyl 4-pentenylphosphonic acid according to Scheme 8.
Reaction SMILES: [NH2:1][CH:2]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=1)[CH2:3][CH2:4][C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].[CH2:21]([OH:23])[CH3:22].[OH-].[Na+]>O1CCOCC1.C(OC(=O)C)(=O)C>[C:21]([NH:1][CH:2]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=1)[CH2:3][CH2:4][C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6])(=[O:23])[CH3:22]
Reactant: COc1cccc(CC(N)CCC(=O)OC(C)(C)C)c1
Reactant: CCO
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CC(=O)OC(C)=O
Product: COc1cccc(CC(CCC(=O)OC(C)(C)C)NC(C)=O)c1
Reaction time: 1.33 h

Procedure:
To a solution of tert-butyl 4-amino-5-(3-methoxyphenyl)valerate (0.22 g) in 1,4-dioxane (0.2 ml), acetic anhydride (0.08 ml) was added and the solution was stirred for 80 minutes. To the solution, ethanol was added and the solution was stirred for 15 minutes. The pH of the solution was adjusted to 12 with sodium hydroxide solution and the solution was extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous sodium sulfate, and evaporated in vacuo to give tert-butyl 4-acetylamino-5-(3-methoxyphenyl)valerate (246 mg).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[CH:8][C:7]=2/[CH:14]=[CH:15]/[C:16]2[N:17]=[C:18]3[N:22]([C:23]=2[C:24]([OH:26])=O)[CH:21]=[CH:20][S:19]3)[CH2:3][CH2:2]1.[NH:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH2:30][CH2:29][CH2:28]1.C(N(CC)CC)C>ClCCl>[CH:1]1([CH2:4][O:5][C:6]2[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[CH:8][C:7]=2/[CH:14]=[CH:15]/[C:16]2[N:17]=[C:18]3[N:22]([C:23]=2[C:24]([N:27]2[C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[CH2:30][CH2:29][CH2:28]2)=[O:26])[CH:21]=[CH:20][S:19]3)[CH2:2][CH2:3]1
Reactant: c1ccc2c(c1)CCCN2
Reactant: COc1cccc(/C=C/c2nc3sccn3c2C(=O)O)c1OCC1CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cccc(/C=C/c2nc3sccn3c2C(=O)N2CCCc3ccccc32)c1OCC1CC1

Procedure:
The title compound was prepared according to the general procedure (Method A) by coupling Intermediate 1 (100 mg, 0.269 mmol) with 1,2,3,4-tetrahydroquinoline (39 μL, 0.296 mmol) in the presence of triethylamine (68 mg, 0.674 mmol) in dichloromethane (5 mL) gave 79 mg of the product as an off-white solid; 1H NMR (300 MHz, DMSO-d6) δ 0.21-0.22 (m, 2H), 0.45-0.47 (m, 2H), 1.09-1.11 (m, 1H), 1.97-2.00 (m, 2H), 2.85-2.87 (m, 2H), 3.66 (d, J=6.6 Hz, 2H), 3.76 (s, 3H), 3.83-3.85 (m, 2H), 6.75 (d, J=16.2 Hz, 1H), 6.85-6.93 (m, 4H), 6.98-7.03 (m, 2H), 7.13-7.15 (m, 1H), 7.26 (d, J=4.2 Hz, 1H), 7.56 (s, 1H), 7.61-7.64 (m, 1H); ESI-MS (m/z) 486.45 (MH)+.
Reaction SMILES: [CH:1]1([C:4]2[O:5][CH:6]=[C:7]([C:9]([O:11][CH3:12])=[O:10])[N:8]=2)[CH2:3][CH2:2]1.C1C(=O)N([Br:20])C(=O)C1.C(Cl)(Cl)(Cl)Cl>CCOC(C)=O>[Br:20][C:6]1[O:5][C:4]([CH:1]2[CH2:2][CH2:3]2)=[N:8][C:7]=1[C:9]([O:11][CH3:12])=[O:10]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1coc(C2CC2)n1
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Product: COC(=O)c1nc(C2CC2)oc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.2 %

Procedure:
Into a 5000-mL 3-necked round-bottom flask were placed methyl 2-cyclopropyloxazole-4-carboxylate (140 g, 838.32 mmol, 1.00 equiv.), NBS (224 g, 1.26 mol, 1.50 equiv.), CCl4 (1400 mL) and BPO (20 g, 82.64 mmol, 0.10 equiv). The resulting solution was stirred overnight at room temperature, then it was diluted with 2000 mL of EtOAc. The solid was filtrated out. The filtrate was dried over anhydrous calcium chloride and concentrated under vacuum. The residue was applied onto a silica gel column and eluted with ethyl acetate/petroleum ether (1:50˜1:20). This resulted in 120 g (58% yield) of methyl 5-bromo-2-cyclopropyloxazole-4-carboxylate as a white solid.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[OH:6][CH2:7][CH2:8][N:9]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[S:11][C:10]1=[O:18].C(N(CC)CC)C>ClCCl>[S:2]([O:6][CH2:7][CH2:8][N:9]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[S:11][C:10]1=[O:18])([CH3:1])(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: O=c1sc2ccccc2n1CCO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCn1c(=O)sc2ccccc21

Procedure:
Methanesulfonyl chloride (1.625 ml, 2.4 g, 21 mmol) in dichloromethane (10 ml) was added dropwise with stirring to 3-(2-hydroxyethyl)benzothiazolin-2-one (3.9 g, 20 mmol) (J. J. D'Amico and F. G. Bollinger; J. Heterocyclic Chemistry 1988, 25, 1601).and triethylamine (3.478 ml, 2.525 g, 25 mmol) in dichloromethane (80 ml) and stirred for one hour at room temperature. The reaction mixture was then washed with water and dried (MgSO4), filtered and the solvent evaporated in-vacuo to give the title product.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:11])[CH2:5][C:6]1[N:7]=[CH:8][NH:9][CH:10]=1)[CH3:2].[H-].[Na+].[CH3:14][Si:15]([CH3:22])([CH3:21])[CH2:16][CH2:17][O:18][CH2:19]Cl>O1CCCC1.C(OCC)(=O)C>[CH3:14][Si:15]([CH3:22])([CH3:21])[CH2:16][CH2:17][O:18][CH2:19][N:9]1[CH:10]=[C:6]([CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:11])[N:7]=[CH:8]1
Reactant: CCOC(=O)Cc1c[nH]cn1
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)Cc1cn(COCC[Si](C)(C)C)cn1
Reaction time: 0.5 h
Yield: 48.5 %

Procedure:
To a solution of 383 gm (2.48 mmol) of 1H-imidazole-4-acetic acid ethyl ester (prepared according to the procedure of Bashkin et al; J. Org. Chem., 1990, 55, 5125-5132.) in 5 mL of dry tetrahydrofuran under a nitrogen atmosphere was added 109 mg (2.73 mmol) of 60% sodium hydride/oil dispersion. The resulting mixture was stirred for 30 minutes at which time was added dropwise by syringe 0.53 mL (3.0 mmol) of 2-trimethylsilylethoxymethyl chloride. The reaction mixture was stirred for 4 hours at room temperature then diluted with 150 mL of ethyl acetate. The solution was washed with saturated aqueous sodium bicarbonate, dried over magnesium sulfate, filtered and the solvent removed under vacuum. The resulting material was purified by column chromatography on silica gel, eluting with chloroform/10% concentrated ammonium hydroxide in methanol (96:4), to afford 342 mg (48%) of the products in a 1.5:1 ratio of N-1:N-3 imidazole regioisomers as a colorless oil. FAB-MS: calculated for C13H24N2O3Si 284; found 285 (M+H, 100%). 1H NMR (200 MHz, CDCl3): 0.00 (s, 18H), 0.90 (m, 4H), 1.25 (t, 7 Hz, 6H), 3.45 (m, 4H), 3.65 (s, 2H), 3.70 (s, 2H), 4.15 (m, 4H), 5.20 (s, 2H), 5.35 (s, 2H), 7.00 (s, 1H), 7.02 (s, 1H), 7.65 (s, 1H), 7.97 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[CH2:11][CH:10]([NH2:13])[CH2:9][CH2:8]2.[C:14](OC(=O)C)(=[O:16])[CH3:15]>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[CH2:11][CH:10]([NH:13][C:14](=[O:16])[CH3:15])[CH2:9][CH2:8]2
Reactant: CC(=O)OC(C)=O
Reactant: COc1cccc2c1CC(N)CC2
Product: COc1cccc2c1CC(NC(C)=O)CC2
Yield: 69 %

Procedure:
Using a procedure similar to that described in Example 1, 0.30 g of 8-methoxy-2-amino-tetralin yielded 0.23 g (69%) of 8-methoxy-2-acetamido-tetralin following treatment with acetic anhydride.
Reaction SMILES: [CH:1]1([NH:4][C:5]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=3)[CH:8]=[C:7]([C:17]3[CH:18]=[N:19][CH:20]=[C:21]([C:23]#[C:24][Si](C)(C)C)[CH:22]=3)[CH:6]=2)[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+]>CO.CCOC(C)=O>[CH:1]1([NH:4][C:5]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=3)[CH:8]=[C:7]([C:17]3[CH:18]=[N:19][CH:20]=[C:21]([C:23]#[CH:24])[CH:22]=3)[CH:6]=2)[CH2:2][CH2:3]1
Reactant: C[Si](C)(C)C#Cc1cncc(-c2cc(NC3CC3)nc(-c3ccccn3)c2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CCOC(C)=O
Product: C#Cc1cncc(-c2cc(NC3CC3)nc(-c3ccccn3)c2)c1

Procedure:
Cyclopropyl-(5″-trimethylsilanylethynyl-[2,2′;4′,3″]terpyridin-6′-yl)-amine (Example 2.128, step1) (1 eq, 0.127 mmol, 49 mg) is dissolved in MeOH (2 ml) and potassium carbonate is added (2 eq, 0.255 mmol, 35 mg). The reaction mixture is dissolved in EtOAc and washed with water. The organic layer is washed with brine, dried over drying agent MgSO4, filtered and the organic solvent is reduced in vacuo. The crude residue is purified by reverse phase column chromatography (Isolute™ C18, 0-20% acetonitrile in water—0.1% TFA). The appropriate fractions by HPLC are combined and concentrated in vacuo. The resulting residue is dissolved in MeOH and loaded onto a SCX-2 cartridge eluting with MeOH followed by 2M NH3 in MeOH. The methanolic ammonia fractions are combined, concentrated in vacuo and dried under vacuum to afford the title compound; [M+H]+ 313.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N:12]1[CH:16]=[CH:15][CH:14]=[CH:13]1)[N:8]=[CH:7][C:6]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:5]2[OH:22].C(=O)([O-])[O-].[K+].[K+].Br[CH:30]([F:32])[CH3:31]>CN(C)C=O>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N:12]1[CH:16]=[CH:15][CH:14]=[CH:13]1)[N:8]([CH:30]([F:32])[CH3:31])[CH:7]=[C:6]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:5]2=[O:22]
Reactant: CCOC(=O)c1cnc2cc(-n3cccc3)c(F)cc2c1O
Reactant: CC(F)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(C(C)F)c2cc(-n3cccc3)c(F)cc2c1=O
Temperature: 60 °C
Reaction time: 7 h
Yield: 61.7 %

Procedure:
A mixture of 3.2 g (0.011 mol) of ethyl 6-fluoro-7-(pyrrol-1-yl)-4-hydroxyquinoline-3-carboxylate and 4 g (2.5×0.011 mol) of potassium carbonate in 20 ml of dimethylformamide is heated for 30 minutes at 60° C. and left to cool, 7 g (5×0.011 mol) of bromofluoroethane are added, the mixture is kept for 7 hours at 80° C., left to cool and poured into a water/ice mixture, and the precipitate formed is filtered off, washed with water and recrystallized from a dimethylformamide/water mixture (1:1) to give 2.35 g of a solid melting at 231°-234° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13](I)[CH:12]=[CH:11][C:10]=1[N:16]1[S:20](=[O:22])(=[O:21])[N:19]([CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[C:18](=[O:29])[CH2:17]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:30]([O:34][C:35](=[O:42])[NH:36][C:37]([CH3:41])([CH3:40])[CH:38]=[CH2:39])([CH3:33])([CH3:32])[CH3:31].C(N(CC)CC)C>CN(C=O)C>[C:30]([O:34][C:35](=[O:42])[NH:36][C:37]([CH3:41])([CH3:40])/[CH:38]=[CH:39]/[C:13]1[CH:12]=[CH:11][C:10]([N:16]2[CH2:17][C:18](=[O:29])[N:19]([CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[S:20]2(=[O:22])=[O:21])=[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:14]=1)([CH3:33])([CH3:32])[CH3:31]
Reactant: C=CC(C)(C)NC(=O)OC(C)(C)C
Reactant: C[Si](C)(C)CCN1C(=O)CN(c2ccc(I)cc2OCc2ccccc2)S1(=O)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(/C=C/c1ccc(N2CC(=O)N(CC[Si](C)(C)C)S2(=O)=O)c(OCc2ccccc2)c1)NC(=O)OC(C)(C)C
Temperature: 80 °C
Reaction time: 18 h

Procedure:
To a solution of 5-(2-benzyloxy-4-iodophenyl)-1,1-dioxo-2-(2-trimethylsilanylethyl)-1,2,5-thiadiazolidin-3-one (1.4 g, 3 mmol) in DMF (20 mL) is added (1,1-dimethylallyl)-carbamic acid tert-butyl ester (560 mg, 3 mmol), triethylamine (0.7 mL, 5 mmol) and tert-di(mu-acetato) bis[o-(di-o-tolylphosphino)benzyl]dipalladium (II) (25 mg). The mixture is stirred at 80° C. for 18 h. The solvent is removed under reduced pressure and the residue is purified by flash chromatography to give the title compound
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([CH:17]=[CH:18][C:19]=1[O:20][CH3:21])[CH2:7][CH:8]([C:13]([O:15][CH3:16])=[O:14])[C:9]([O:11][CH3:12])=[O:10].[Cl:22][C:23]1[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:24]=1[N:30]=[C:31]=[O:32]>>[Cl:22][C:23]1[CH:28]=[C:27]([Cl:29])[CH:26]=[CH:25][C:24]=1[NH:30][C:31]([O:1][CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([CH:17]=[CH:18][C:19]=1[O:20][CH3:21])[CH2:7][CH:8]([C:9]([O:11][CH3:12])=[O:10])[C:13]([O:15][CH3:16])=[O:14])=[O:32]
Reactant: COC(=O)C(Cc1ccc(OC)c(CCO)c1)C(=O)OC
Reactant: O=C=Nc1ccc(Cl)cc1Cl
Product: COC(=O)C(Cc1ccc(OC)c(CCOC(=O)Nc2ccc(Cl)cc2Cl)c1)C(=O)OC

Procedure:
Using dimethyl 2-[3-(2-hydroxyethyl)-4-methoxybenzyl]malonate and 2,4-dichlorophenylisocyanate, the title compound was obtained in the same manner as described in Example 192b).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13](B2OC(C)(C)C(C)(C)O2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:25])[CH:11]=2)[CH:6]=1.Br[C:28]1[CH:33]=[CH:32][C:31]([S:34][C:35]2[CH:40]=[C:39]([Cl:41])[CH:38]=[CH:37][C:36]=2[Cl:42])=[CH:30][CH:29]=1.C(=O)(O)[O-].[Na+].O>C(COC)OC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][O:2][C:3](=[O:26])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([C:28]2[CH:29]=[CH:30][C:31]([S:34][C:35]3[CH:40]=[C:39]([Cl:41])[CH:38]=[CH:37][C:36]=3[Cl:42])=[CH:32][CH:33]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:25])[CH:11]=2)[CH:6]=1
Reactant: COC(=O)Cc1cc2ccc(F)cc2c(B2OC(C)(C)C(C)(C)O2)c1C
Reactant: Clc1ccc(Cl)c(Sc2ccc(Br)cc2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COC(=O)Cc1cc2ccc(F)cc2c(-c2ccc(Sc3cc(Cl)ccc3Cl)cc2)c1C
Yield: 33.3 %

Procedure:
A stirred solution of [6-fluoro-3-methyl-4-(4,4,5,5-tetra methyl-[1,3,2]-dioxaborolan-2-yl)-naphthalen-2-yl]-acetic acid methyl ester (0.2 g, 0.55 mmol) in dimethoxyethane (5 mL) was purged with argon for 5 minutes at room temperature. Tetrakis(triphenylphosphine)palladium(0) (0.032 g, 0.028 mmol), impure 1-(4-bromo-phenylsulfanyl)-2,5-dichlorobenzene (0.2 g) and 1.0 M aqueous sodium bicarbonate (5 mL, 5 mmol) were added simultaneously to the reaction mixture under argon. The reaction mixture was refluxed for 2 hours and then brought to room temperature. Water was added and the resulting mixture was extracted twice with ethyl acetate. The combined organic extracts were washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude product, which was finally purified using flash chromatography (0-3% ethyl acetate in hexanes) to give {4-[4-(2,5-dichloro-phenylsulfanyl)-phenyl]-6-fluoro-3-methyl-naphthalen-2-yl}-acetic acid methyl ester (0.089 g, 33%) as a solid.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8](C)=[CH:9][CH:10]=2)[N:5]=[C:4]([C:13]([F:22])([F:21])[C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[N:3]=1.FC(F)(C1C=CC(F)=CC=1)C1N=[C:33]([OH:35])C2C(=CC(C)=CC=2)N=1.FC(F)(C1C=CC(F)=CC=1)C1N=C(O)C2C(=CC(OC)=CC=2)N=1>>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:35][CH3:33])=[CH:9][CH:10]=2)[N:5]=[C:4]([C:13]([F:22])([F:21])[C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[N:3]=1
Reactant: Cc1ccc2c(Cl)nc(C(F)(F)c3ccc(F)cc3)nc2c1
Reactant: Cc1ccc2c(O)nc(C(F)(F)c3ccc(F)cc3)nc2c1
Agent: COc1ccc2c(O)nc(C(F)(F)c3ccc(F)cc3)nc2c1
Product: COc1ccc2c(Cl)nc(C(F)(F)c3ccc(F)cc3)nc2c1

Procedure:
4-Chloro-2-(difluoro(4-fluorophenyl)methyl)-7-methoxyquinazoline was obtained according to the procedure described in Example 26 for synthesis of 4-chloro-2-(difluoro(4-fluorophenyl)methyl)-7-methylquinazoline, substituting 2-(difluoro(4-fluorophenyl)methyl)-7-methylquinazolin-4-ol in Example 26 with 2-(difluoro(4-fluorophenyl)methyl)-7-methoxyquinazolin-4-ol. 4-Chloro-2-(difluoro(4-fluorophenyl)methyl)-7-methoxyquinazoline was isolated as a light yellow solid (0.290 g, 89%). LC-MS (ESI) m/z 339 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][NH2:9].[CH:10]1[N:15]=[C:14](Cl)[C:13]2[N:17]=[CH:18][N:19]([C@@H:20]3[O:24][C@H:23]([CH2:25][OH:26])[C@@H:22]([OH:27])[C@H:21]3[OH:28])[C:12]=2[N:11]=1.C(N(C(C)C)CC)(C)C>O1CCOCC1>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][NH:9][C:14]1[C:13]2[N:17]=[CH:18][N:19]([C:12]=2[N:11]=[CH:10][N:15]=1)[C@@H:20]1[O:24][C@H:23]([CH2:25][OH:26])[C@@H:22]([OH:27])[C@H:21]1[OH:28]
Reactant: OC[C@H]1O[C@@H](n2cnc3c(Cl)ncnc32)[C@H](O)[C@@H]1O
Reactant: Cc1ccccc1CN
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: Cc1ccccc1CNc1ncnc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Temperature: 60 °C

Procedure:
The title compound was prepared by reacting (2-methylphenyl)methylamine (1.51 g, 12.5 mmol) with 6-chloropurine riboside (2.87 g, 10.0 mmol) in dioxan (100 ml) in the presence of diisopropylethylamine (1.94 g, 15.0 mmol). The reaction mixture was heated at 60° C. for 6 h, cooled, filtered and evaporated. The residue was purified by flash chromatography, eluting initially with dichloromethane, and later increasing polarity to dichloromethanethanol (9:1), to provide the product (2.6 g, 70%) as a solid which was recrystallised from methanol to give N-[(2-methylphenyl)methyl]adenosine as white crystals (1.75 g, 47%), mp 161.5°-163.5° C., 1H NMR (DMSO-d6)δ 2.35 (3H, s, --CH3), 3.53-3.60 (1H, m, H-5'a), 3.65-3.72 (1H, m, H-5'b), 3.98 (1H, q, H-4'), 4.16 (1H, m, H-3'), 4.64 (1H, q, H-2'), 5.41 (1H, t, 5'-0H), 5.21, 5.48 (2H, 2d, 2'- and 3'-OH), 5.92 (1H, d, H-1'), 7.06-7.24 (4H, m, Ar--H), 8.20 and 8.40 (3H, s and br s, H-2, H-8 and N--H).
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[CH3:19])[CH:11]=2)[C:6](=[C:20](OCC)[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:5]1=[O:30])(=O)C.[NH2:31][C:32]1[CH:42]=[CH:41][C:35]([C:36]([O:38][CH2:39][CH3:40])=[O:37])=[CH:34][CH:33]=1>>[CH2:39]([O:38][C:36]([C:35]1[CH:34]=[CH:33][C:32]([NH:31]/[C:20](=[C:6]2\[C:5](=[O:30])[NH:4][C:12]3[C:7]\2=[CH:8][CH:9]=[C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH3:19])[CH:11]=3)/[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[CH:42][CH:41]=1)=[O:37])[CH3:40]
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2cc(-c3ccccc3C)ccc21)c1ccccc1
Reactant: CCOC(=O)c1ccc(N)cc1
Product: CCOC(=O)c1ccc(N/C(=C2\C(=O)Nc3cc(-c4ccccc4C)ccc32)c2ccccc2)cc1

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-6-(2-tolyl)-2-indolinone and ethyl 4-aminobenzoate
Reaction SMILES: [CH:1]1([CH2:4][C:5]([OH:7])=O)[CH2:3][CH2:2]1.[F:8][C:9]1[C:37]([N:38]2[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]2)=[CH:36][C:12]2[N:13]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([O:31][C:32]([F:35])([F:34])[F:33])=[CH:27][CH:26]=3)[C:14]([CH2:16][O:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:15][C:11]=2[CH:10]=1>ClCCl>[CH:1]1([CH2:4][C:5]([N:41]2[CH2:42][CH2:43][N:38]([C:37]3[C:9]([F:8])=[CH:10][C:11]4[N:15]=[C:14]([CH2:16][O:17][C:18]5[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=5)[N:13]([CH2:24][C:25]5[CH:26]=[CH:27][C:28]([O:31][C:32]([F:35])([F:34])[F:33])=[CH:29][CH:30]=5)[C:12]=4[CH:36]=3)[CH2:39][CH2:40]2)=[O:7])[CH2:2][CH2:3]1
Reactant: O=C(O)CC1CC1
Reactant: Fc1cc2nc(COc3ccccc3)n(Cc3ccc(OC(F)(F)F)cc3)c2cc1N1CCNCC1
Solvent: ClCCl
Product: O=C(CC1CC1)N1CCN(c2cc3c(cc2F)nc(COc2ccccc2)n3Cc2ccc(OC(F)(F)F)cc2)CC1

Procedure:
0.020 ml of cyclopropyl-acetic acid (0.2 mmol) and 40 mg of 1′1-carbonyldiimidazole (0.24 mmol) were refluxed in 4 ml dichloromethane under nitrogen for 40 minutes. 100 mg 5-Fluoro-2-phenoxymethyl-6-piperazin-1-yl-1-(4-trifluoromethoxy-benzyl)-1H-benzoimidazole (0.2 mmol) were added and the resulting mixture refluxed for additional 26 h. The reaction mixture was then diluted with dichloromethane, washed with water, saturated sodium bicarbonate and brine, dried with magnesium sulfate, filtered and concentrated in vacuo, leading to 129 mg yellow solid. This residue was purified by column chromatography (24 g silicagel, dichloromethane/methanol 24:1) leading to 77 mg light yellow solid (63%). MS (ISP) 583.3 (M+H)+.
Reaction SMILES: C[O-].[Na+].[CH:4](OCC)=[O:5].[C:9]1([CH2:15][C:16]#[N:17])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C1C=CC=CC=1>[CH:4]([CH:15]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:16]#[N:17])=[O:5]
Reactant: CCOC=O
Reactant: N#CCc1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: c1ccccc1
Product: N#CC(C=O)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a suspension of sodium methoxide (5.56 g) in benzene (200 ml) is added dropwise with stirring a mixture of ethyl formate (8.14 g) and phenylacetonitrile (11.7 g) under ice cooling. After 30 minutes, the ice bath is taken off. After reacting for 3 hours, ice water is added to the reaction mixture, and the aqueous layer is separated. The organic layer is washed with 0.5 N sodium hydroxide solution (50 ml×3), and the aqueous layer and the washings are combined and adjusted to pH 3-4 with conc. hydrochloric acid. The mixture is stirred under ice cooling for 20 minutes, and the resulting precipitate is separated by filtration and washed with water to give α-formylphenylacetonitrile. The product is used in the subsequent procedure without further purification.
Reaction SMILES: C(OC([N:8]1[CH2:12][C@H:11]([S:13][C:14]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][C@H:9]1[CH2:33][O:34][CH2:35][C:36]1[CH:41]=[C:40]([F:42])[C:39]([F:43])=[CH:38][C:37]=1[F:44])=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:44][C:37]1[CH:38]=[C:39]([F:43])[C:40]([F:42])=[CH:41][C:36]=1[CH2:35][O:34][CH2:33][C@@H:9]1[CH2:10][C@@H:11]([S:13][C:14]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:12][NH:8]1
Reactant: CC(C)(C)OC(=O)N1C[C@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)C[C@H]1COCc1cc(F)c(F)cc1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Fc1cc(F)c(COC[C@@H]2C[C@@H](SC(c3ccccc3)(c3ccccc3)c3ccccc3)CN2)cc1F
Temperature: 25 °C
Yield: 99 %

Procedure:
A solution of 9.37 g (15.11 mmol) (2S,4R)-2-(2,4,5-Trifluoro-benzyloxymethyl)-4-tritylsulfanyl-pyrrolidine-1-carboxylic acid tert-butyl ester in 30 ml CH2Cl2 was treated at −20° C. with 34 ml TFA and warmed up to RT during 5.5 h. The reaction was evaporated and treated with aqueous sat NaHCO3 solution/EtOAc (3×) to give 7.77 g (quantitative) (2S,4R)-2-(2,4,5-Trifluoro-benzyloxymethyl)-4-tritylsulfanyl-pyrrolidine, MS: 520 (M).