Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH:19]([F:21])[F:20])[CH:13]=2)(=[O:11])=[O:10])=[CH:6][C:5](B2OC(C)(C)C(C)(C)O2)=[CH:4][N:3]=1.Cl[C:32]1[CH:33]=[CH:34][C:35]2[N:36]([CH:38]=[C:39]([NH:41][C:42](=[O:44])[CH3:43])[N:40]=2)[N:37]=1.C(=O)([O-])[O-].[Na+].[Na+].O1CCOCC1>[Pd+2].ClC1C=C[C-](P(C2C=CC=CC=2)C2C=CC=CC=2)C=1Cl.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].O>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([C:32]2[CH:33]=[CH:34][C:35]3[N:36]([CH:38]=[C:39]([NH:41][C:42](=[O:44])[CH3:43])[N:40]=3)[N:37]=2)=[CH:6][C:7]=1[NH:8][S:9]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH:19]([F:20])[F:21])[CH:13]=1)(=[O:10])=[O:11]
Reactant: CC(=O)Nc1cn2nc(Cl)ccc2n1
Reactant: CC1(C)OB(c2cnc(Cl)c(NS(=O)(=O)c3cccc(OC(F)F)c3)c2)OC1(C)C
Agent: [Fe+2]
Agent: [Pd+2]
Agent: Clc1cc[c-](P(c2ccccc2)c2ccccc2)c1Cl
Solvent: C1COCCO1
Solvent: O
Product: CC(=O)Nc1cn2nc(-c3cnc(Cl)c(NS(=O)(=O)c4cccc(OC(F)F)c4)c3)ccc2n1
Temperature: 90 °C
Yield: 82.9 %

Procedure:
A sealable vial was charged with N-(2-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-yl)-3-(difluoromethoxy)benzenesulfonamide (765.9 mg, 1663 μmol), N-(6-chloroimidazo[1,2-b]pyridazin-2-yl)acetamide (291.8 mg, 1385 μmol, Example 1, Step 4), dichloro 1,1′-bis(diphenylphosphino)ferrocene palladium(II) (53.76 mg, 96.98 μmol, Strem Chemical, Inc., Newburyport, Mass.) and sodium carbonate (293.7 mg, 2771 μmol). The vial was sealed with a septum cap and dioxane (2 mL, 1 M) and water (1 mL, 2 M) were added via syringe. The mixture was sparged 10 min with N2, then heated at 90° C. for 18 h. The solution was cooled to rt, and concentrated for purification by MPLC (CombiFlash® Companion®, Teledyne Isco, Lincoln, Nebr.). The crude residue was taken up in minimal CH2Cl2/MeOH and absorbed onto a 25 g silica loading cartridge and passed through a Redi-Sep® pre-packed silica gel column (80 g) (Teledyne Isco, Lincoln, Nebr.) using a gradient of 1% MeOH in CH2Cl2 to 10% MeOH in CH2Cl2 to afford N-(6-(6-chloro-5-(3-(difluoromethoxy)phenylsulfonamido)pyridin-3-yl)imidazo[1,2-b]pyridazin-2-yl)acetamide (584.0 mg, 82.83% yield) as a brown solid. LCMS (ESI) m/z: 509.1 (M+1).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([NH:7][C:8]([C:10]2[N:11]([CH3:18])[CH:12]=[C:13]([N+:15]([O-])=O)[CH:14]=2)=[O:9])[CH:4]=[C:3]1[C:19]([NH:21][CH2:22][CH2:23][CH2:24][N:25]([CH3:27])[CH3:26])=[O:20]>CO.[Pd]>[CH3:1][N:2]1[CH:6]=[C:5]([NH:7][C:8]([C:10]2[N:11]([CH3:18])[CH:12]=[C:13]([NH2:15])[CH:14]=2)=[O:9])[CH:4]=[C:3]1[C:19]([NH:21][CH2:22][CH2:23][CH2:24][N:25]([CH3:26])[CH3:27])=[O:20]
Reactant: CN(C)CCCNC(=O)c1cc(NC(=O)c2cc([N+](=O)[O-])cn2C)cn1C
Agent: [Pd]
Solvent: CO
Product: CN(C)CCCNC(=O)c1cc(NC(=O)c2cc(N)cn2C)cn1C
Reaction time: 3 h

Procedure:
1-Methyl-4-{[(1-methyl-4-nitro-1H-pyrrol-2-yl)carbonyl]amino}-N-[3-(dimethylamino)propyl]-1H-pyrrole-2-carboxamide (59 mg, 0.156 mmol; see Preparation 2(ii) above) was suspended in methanol (25 mL) to which Pd/C-10% (59 mg) was added at 0° C. under a nitrogen with stirring. The reaction mixture was hydrogenated for 3 h at room temperature and atmospheric pressure. The catalyst was removed over kieselguhr and methanol was removed under reduced pressure to give the amine, which was dissolved in DMF (1.5 mL, dry) and used without further purification.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[O:19]1[CH:23]=[CH:22][C:21]([C:24]2[CH:31]=[CH:30][C:27]([CH:28]=[O:29])=[CH:26][CH:25]=2)=[CH:20]1.[F:32][C:33]([Si](C)(C)C)([F:35])[F:34].Cl>C1COCC1>[F:32][C:33]([F:35])([F:34])[CH:28]([C:27]1[CH:30]=[CH:31][C:24]([C:21]2[CH:22]=[CH:23][O:19][CH:20]=2)=[CH:25][CH:26]=1)[OH:29]
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: O=Cc1ccc(-c2ccoc2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: C1CCOC1
Product: OC(c1ccc(-c2ccoc2)cc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 4 h
Yield: 83.3 %

Procedure:
Tetrabutylammonium fluoride (0.024 ml; 1.0 M solution in tetrahydrofuran) was added to a solution of 4-furan-3-yl-benzaldehyde (410 mg, 2.38 mmol) and trifluoromethyltrimethylsilane (TMSCF3) (423 μl, 2.86 mmol) in 5 ml THF at 0° C. The formed mixture was warmed up to room temperature and stirred at room temperature for 4 hours. The reaction mixture was then treated with 5 ml of 1N HCl and stirred at room temperature overnight. The product was extracted with ethyl acetate (3×50 ml). The organic layer was separated and dried over sodium sulfate. The organic solvent was evaporated to give 480 mg of 2,2,2-trifluoro-1-(4-furan-3-yl-phenyl)-ethanol, yield: 83%.
Reaction SMILES: [N:1]([C:3]1[C:4]([NH2:12])=[N:5][C:6]([NH2:11])=[N:7][C:8]=1[O:9][CH3:10])=O.[ClH:13]>C(O)C.[Pd]>[ClH:13].[ClH:13].[CH3:10][O:9][C:8]1[N:7]=[C:6]([NH2:11])[N:5]=[C:4]([NH2:12])[C:3]=1[NH2:1]
Reactant: COc1nc(N)nc(N)c1N=O
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: COc1nc(N)nc(N)c1N
Temperature: 25 °C
Reaction time: 16 h
Yield: 78.9 %

Procedure:
To a solution of 7.60 g (0.045 mol) 5-nitroso-2,4-diamino-6-methoxypyrimidine from step 1.2 in 400 ml ethanol was added 1.5 g (0.04 mol %) palladium on charcoal (5%). The mixture was shaken at room temperature for 16 h under an atmosphere of hydrogen at 1 bar. The reaction mixture was then poured into 80 ml dilute hydrochloric acid (0.23 mol), the catalyst was filtered off and the filtrate was concentrated almost to dryness. The precipitated crystals were filtered off with suction and washed with tert-butyl methyl ether. 6-Methoxy-2,4,5-pyrimidinetriamine dihydrochloride (8.10 g, 79%) was obtained as light yellow crystals.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH2:9]([O:11][C:12]1[C:13]([OH:20])=[C:14]([CH:17]=[CH:18][CH:19]=1)[CH:15]=[O:16])[CH3:10]>C(#N)C>[Br:1][C:18]1[CH:19]=[C:12]([O:11][CH2:9][CH3:10])[C:13]([OH:20])=[C:14]([CH:17]=1)[CH:15]=[O:16]
Reactant: CCOc1cccc(C=O)c1O
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: CCOc1cc(Br)cc(C=O)c1O
Temperature: 25 °C
Reaction time: 3 h
Yield: 33.6 %

Procedure:
After adding 5.59 g of N-bromosuccinimide to a solution of 5.11 g of 3-ethoxy-2-hydroxybenzaldehyde in 100 ml of acetonitrile, the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated, water was added to the residue, and extraction was performed with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. The desiccating agent was filtered off and the filtrate was concentrated under reduced pressure. The residue was recrystallized using t-butyl methyl ether-heptane to give 5-bromo-3-ethoxy-2-hydroxybenzaldehyde (2.53 g).
Reaction SMILES: [C:1]1([N:7]2[C:11]([CH2:12][CH2:13][CH3:14])=[CH:10][C:9]([CH2:15][CH2:16][CH:17]=O)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:19][C:20]1[CH:21]=[C:22]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[CH:23]=[CH:24][C:25]=1[Cl:26].CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[Cl:19][C:20]1[CH:21]=[C:22]([N:27]2[CH2:32][CH2:31][N:30]([CH2:17][CH2:16][CH2:15][C:9]3[CH:10]=[C:11]([CH2:12][CH2:13][CH3:14])[N:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[N:8]=3)[CH2:29][CH2:28]2)[CH:23]=[CH:24][C:25]=1[Cl:26]
Reactant: CCCc1cc(CCC=O)nn1-c1ccccc1
Reactant: Clc1ccc(N2CCNCC2)cc1Cl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: CCCc1cc(CCCN2CCN(c3ccc(Cl)c(Cl)c3)CC2)nn1-c1ccccc1

Procedure:
77 mg (47%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-phenyl-5-propyl-1H-pyrazol-3-yl)propanal (80 mg, 0.330 mmol), 1-(3,4-dichlorophenyl)piperazine (76 mg, 0.330 mmol), DIPEA (0.090 mL, 0.495 mmol) and NaBH(OAc)3 (210 mg, 0.990 mmol).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)[N:5]=[CH:4][N:3]=1.[N:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][C:26]=2[OH:28])[CH:21]=[CH:20][C:19]=1[OH:29].N12CCCN=C1CCCCC2>C(#N)C.CCOC(C)=O>[F:15][C:14]([F:17])([F:16])[C:11]1[CH:12]=[CH:13][C:8]([C:6]2[N:5]=[CH:4][N:3]=[C:2]([O:28][C:26]3[CH:25]=[CH:24][CH:23]=[C:22]4[C:27]=3[NH:18][C:19](=[O:29])[CH:20]=[CH:21]4)[CH:7]=2)=[CH:9][CH:10]=1
Reactant: FC(F)(F)c1ccc(-c2cc(Cl)ncn2)cc1
Reactant: Oc1ccc2cccc(O)c2n1
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: O=c1ccc2cccc(Oc3cc(-c4ccc(C(F)(F)F)cc4)ncn3)c2[nH]1
Temperature: 25 °C

Procedure:
To a mixture of 4-chloro-6-(4-trifluoromethyl-phenyl)-pyrimidine, (Example 2(a), Method A), (0.10 g, 0.39 mmol) and 2,8-quinolinediol (0.075 g, 0.46 mmol, Fluka) in acetonitrile (5 mL) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (0.069 mL, 0.46 mmol, Aldrich). The mixture was heated to reflux for 6 h, allowed to cool to room temperature, and diluted with EtOAc. The solids were filtered, washed with EtOAc and dried in vacuum for 16 h to yield the title compound as long white needles. Mp: 312° C., MS (ESI, pos. ion) m/z: 384 (M+1).
Reaction SMILES: [H-].[Na+].[C:3]1([C:9]2[C:18]3[C:13](=[N:14][CH:15]=[CH:16][CH:17]=3)[NH:12][C:11](=[O:19])[CH:10]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:20](Br)[C:21]#[CH:22].[Br-].[Li+]>[Cl-].[Na+].O.O1CCOCC1>[C:3]1([C:9]2[C:18]3[C:13](=[N:14][CH:15]=[CH:16][CH:17]=3)[N:12]([CH2:22][C:21]#[CH:20])[C:11](=[O:19])[CH:10]=2)[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: C#CCBr
Reactant: O=c1cc(-c2ccccc2)c2cccnc2[nH]1
Agent: [Br-]
Agent: [Cl-]
Agent: [H-]
Solvent: C1COCCO1
Solvent: O
Product: C#CCn1c(=O)cc(-c2ccccc2)c2cccnc21
Temperature: 110 °C
Reaction time: 0.5 h
Yield: 9 %

Procedure:
Sodium hydride (210 mg, 60% dispersion) was added to a dioxane solution (100 ml) of 4-phenyl-1,8-naphthyridin-2(1H)-one (1.01 g, 4.55 mmol), and the mixture was stirred at 110° C. for 30 minutes. After cooling to room temperature, propargyl bromide (650 mg, 5.46 mmol) and lithium bromide (830 mg, 9.55 mmol) were added, and the mixture was heated under reflux for 2 days. After cooling to room temperature, brine was added, and the mixture was extracted with chloroform. The organic layer was washed with brine and dried over anhydrous sodium sulfate. After removing sodium sulfate by filtration, the solvent was evaporated under reduced pressure and the resulting residue was purified by silica gel column chromatography (hexane-ethyl acetate) and further recrystallized from diisopropyl ether to give 4-phenyl-1-propargyl-1,8-naphthyridin-2(1H)-one (107 mg, 9%).
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]2[N:6]([CH:11]3[CH2:15][N:14]([CH2:16][C:17]4[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=4)[C:13](=[O:25])[CH2:12]3)[C:7]([CH2:9]Cl)=[N:8][C:4]=2[CH:3]=1.[CH3:28][S:29]([C:32]1[C:40]2[C:35](=[CH:36][N:37]=[CH:38][CH:39]=2)[NH:34][N:33]=1)(=[O:31])=[O:30].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.O.CCOC(C)=O>[Cl:1][C:2]1[CH:27]=[CH:26][C:5]2[N:6]([CH:11]3[CH2:15][N:14]([CH2:16][C:17]4[CH:18]=[CH:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=4)[C:13](=[O:25])[CH2:12]3)[C:7]([CH2:9][N:34]3[C:35]4=[CH:36][N:37]=[CH:38][CH:39]=[C:40]4[C:32]([S:29]([CH3:28])(=[O:30])=[O:31])=[N:33]3)=[N:8][C:4]=2[CH:3]=1
Reactant: CS(=O)(=O)c1n[nH]c2cnccc12
Reactant: COc1ccc(CN2CC(n3c(CCl)nc4cc(Cl)ccc43)CC2=O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccc(CN2CC(n3c(Cn4nc(S(C)(=O)=O)c5ccncc54)nc4cc(Cl)ccc43)CC2=O)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 4-[5-chloro-2-(chloromethyl)-1H-benzimidazol-1-yl]-1-(4-methoxybenzyl)pyrrolidin-2-one (294 mg, 1.492 mmol) in 50 mL of DMF was added 3-(methylsulfonyl)-1H-pyrazolo[3,4-c]pyridine (722 mg, 1.791 mmol) and Cs2CO3 (584 mg, 2.985 mmol). The resulting mixture was stirred at RT for 4 hours, then diluted with 40 mL of H2O and EtOAc. The separated aqueous phase was extracted with EtOAc (15 mL×3). The combined organic phases were washed with 30 mL of brine, and then dried over Na2SO4, then filtered and concentrated in vacuo. The residue was purified by column chromatography (DCM: MeOH=20:1) to give 4-(5-chloro-2-{[3-(methylsulfonyl)-1H-pyrazolo[3,4-c]pyridin-1-yl]methyl}-1H-benzimidazol-1-yl)-1-(4-methoxybenzyl)pyrrolidin-2-one as a solid.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][N:8]([CH:12]=[O:13])[CH2:9]2)=[CH:4][CH:3]=1.[CH3:14][O:15][C:16]1[CH:24]=[CH:23][C:19]([C:20](Cl)=[O:21])=[CH:18][C:17]=1[C:25]([F:28])([F:27])[F:26]>>[CH:12]([N:8]1[CH2:7][CH2:6][C:5]2[C:10](=[CH:11][C:2]([NH:1][C:20](=[O:21])[C:19]3[CH:23]=[CH:24][C:16]([O:15][CH3:14])=[C:17]([C:25]([F:28])([F:26])[F:27])[CH:18]=3)=[CH:3][CH:4]=2)[CH2:9]1)=[O:13]
Reactant: Nc1ccc2c(c1)CN(C=O)CC2
Reactant: COc1ccc(C(=O)Cl)cc1C(F)(F)F
Product: COc1ccc(C(=O)Nc2ccc3c(c2)CN(C=O)CC3)cc1C(F)(F)F

Procedure:
7-Amino-2-formyl-1,2,3,4-tetrahydroisoquinoline (0.176 g) was converted into the title compound by reaction with 4-methoxy-3-trifluoromethylbenzoyl chloride, following the procedure of Example 3. The product was isolated as a white solid (0.035 g).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[OH-].[K+].[C:18]1([SH:24])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CCO.O>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][CH:3]=[C:2]2[S:24][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: COc1cc2nccc(Cl)c2cc1OC
Reactant: Sc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1cc2nccc(Sc3ccccc3)c2cc1OC
Temperature: 100 °C

Procedure:
To a solution of 4-chloro-6,7-dimethoxy-quinoline (214 mg, 0.96 mmol) in EtOH (10 mL) and H2O (10 mL), was added KOH (107 mg, 1.44 mmol). The solution was stirred in a 100° C. bath. Then thiophenol (148 μL, 1.44 mmol) was added. The reaction was stirred at 100° C. for 1 h. The solvent was removed by rotary evaporation. The resulting residue was worked up with water and extracted with EtOAc 3×. The combined organic layer was washed with water and brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude material was purified by silica gel prep-TLC with 100% EtOAc to give the titled compound. MS (ESI, pos. ion) m/z: 298.1 (M+1).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([F:24])=[C:8]([NH:10][CH:11]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[C:17]([O:22][CH3:23])[CH:16]=2)[C:12]([OH:14])=O)[CH:9]=1)(=[O:3])[NH2:2].Cl.[CH:26]1([S:29]([C:32]2[CH:37]=[CH:36][C:35]([NH:38][C:39]([N:41]([CH3:43])[CH3:42])=[O:40])=[CH:34][C:33]=2[C@H:44]2[C@@H:48]([C:49]([O:51][CH2:52][CH3:53])=[O:50])[CH2:47][CH2:46][NH:45]2)(=[O:31])=[O:30])[CH2:28][CH2:27]1>>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([F:24])=[C:8]([NH:10][C@H:11]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[C:17]([O:22][CH3:23])[CH:16]=2)[C:12]([N:45]2[CH2:46][CH2:47][C@H:48]([C:49]([O:51][CH2:52][CH3:53])=[O:50])[C@@H:44]2[C:33]2[CH:34]=[C:35]([NH:38][C:39]([N:41]([CH3:43])[CH3:42])=[O:40])[CH:36]=[CH:37][C:32]=2[S:29]([CH:26]2[CH2:28][CH2:27]2)(=[O:31])=[O:30])=[O:14])[CH:9]=1)(=[O:3])[NH2:2]
Reactant: COc1cc(C(Nc2cc(C(N)=O)ccc2F)C(=O)O)ccc1F
Reactant: CCOC(=O)[C@H]1CCN[C@H]1c1cc(NC(=O)N(C)C)ccc1S(=O)(=O)C1CC1
Agent: Cl
Product: CCOC(=O)[C@H]1CCN(C(=O)[C@H](Nc2cc(C(N)=O)ccc2F)c2ccc(F)c(OC)c2)[C@H]1c1cc(NC(=O)N(C)C)ccc1S(=O)(=O)C1CC1

Procedure:
Example 80 was prepared according to the general coupling condition using 27A and 76O. 1H NMR (400 MHz, Methanol-d4) δ ppm 0.84 (t, J=7.20 Hz, 3H) 0.95-1.17 (m, 3H) 1.33-1.47 (m, 1H) 2.20-2.35 (m, 1H) 2.41 (d, J=6.82 Hz, 1H) 2.91-3.06 (m, 6H) 3.16-3.27 (m, 1H) 3.50-3.64 (m, 2H) 3.69 (s, 3H) 3.71-3.79 (m, 1H) 3.81-3.97 (m, 1H) 4.13-4.28 (m, 1H) 5.46 (s, 1H) 6.26 (d, J=8.34 Hz, 1H) 6.66 (d, J=2.27 Hz, 1H) 6.90-7.09 (m, 4H) 7.10-7.17 (m, 1H) 7.30 (dd, J=8.34, 2.02 Hz, 1H) 7.38-7.45 (m, 1H) 7.66 (d, J=8.84 Hz, 1H), LC-MS 728 (M+H).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])C.[Br:8][C:9]1[N:14]=[C:13]([O:15][CH3:16])[C:12]([NH2:17])=[CH:11][CH:10]=1>C(O)=O>[Br:8][C:9]1[N:14]=[C:13]([O:15][CH3:16])[C:12]([NH:17][CH:1]=[O:3])=[CH:11][CH:10]=1
Reactant: CC(=O)OC(C)=O
Reactant: COc1nc(Br)ccc1N
Solvent: O=CO
Product: COc1nc(Br)ccc1NC=O
Reaction time: 0.42 h

Procedure:
Acetic anhydride (203 mL) was added dropwise to formic acid (204 mL) under ice-cooling, and the mixture was stirred at the same temperature for 25 min. 6-bromo-2-methoxypyridine-3-amine power (CAS#89466-18-2, 146 g) was put into the reaction mixture over 10 minutes, and the reaction solution was stirred at the same temperature for 30 minutes. The water bath was removed. tert-Butyl methyl ether (300 mL) and n-heptane (500 mL) were sequentially added dropwise to the reaction solution, and then the reaction solution was stirred for 30 minutes.
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@H:10]([N:12]1[C:16]2[N:17]=[CH:18][N:19]=[C:20](Cl)[C:15]=2[CH:14]=[CH:13]1)[CH3:11])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]>C(O)C.N.[Pd]>[Si:1]([O:8][CH2:9][C@@H:10]([N:12]1[C:16]2[N:17]=[CH:18][N:19]=[CH:20][C:15]=2[CH:14]=[CH:13]1)[CH3:11])([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3]
Reactant: C[C@@H](CO[Si](C)(C)C(C)(C)C)n1ccc2c(Cl)ncnc21
Agent: [Pd]
Agent: N
Solvent: CCO
Product: C[C@@H](CO[Si](C)(C)C(C)(C)C)n1ccc2cncnc21
Yield: 94 %

Procedure:
Palladium (10% on carbon, 18 g) was added to 7-[(1S)-2-{[tert-butyl(dimethyl)silyl]oxy}-1-methylethyl]-4-chloro-7H-pyrrolo[2,3-d]pyrimidine (182 g, 558 mmol) (see Preparation 1) in ethanol (900 mL) and concentrated ammonia solution (100 mL) and hydrogenated (60 psi, 20° C.) for 18 hours. The reaction mixture was filtered through Arbocel™ and the filtrate was evaporated in vacuo. Diethyl ether (300 mL) was added to the residue and the mixture was filtered. The filtrate was evaporated in vacuo to afford the title compound as an orange oil in 94% yield, 162.7 g.
Reaction SMILES: N(C(OC(C)C)=O)=NC(OC(C)C)=O.O[CH2:16][CH2:17][CH:18]1[CH2:22][C:21]2[C:23]([CH3:37])=[C:24]([O:29][CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:25]([CH3:28])=[C:26]([CH3:27])[C:20]=2[O:19]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:57]1(=[O:67])[NH:61][C:60](=[O:62])[C:59]2=[CH:63][CH:64]=[CH:65][CH:66]=[C:58]12>O1CCCC1>[CH2:30]([O:29][C:24]1[C:25]([CH3:28])=[C:26]([CH3:27])[C:20]2[O:19][CH:18]([CH2:17][CH2:16][N:61]3[C:57](=[O:67])[C:58]4=[CH:66][CH:65]=[CH:64][CH:63]=[C:59]4[C:60]3=[O:62])[CH2:22][C:21]=2[C:23]=1[CH3:37])[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: Cc1c(C)c2c(c(C)c1OCc1ccccc1)CC(CCO)O2
Reactant: O=C1NC(=O)c2ccccc21
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1c(C)c2c(c(C)c1OCc1ccccc1)CC(CCN1C(=O)c3ccccc3C1=O)O2
Reaction time: 2 h
Yield: 94.3 %

Procedure:
5.7 ml of diisopropyl azodicarboxylate is added, dropwise, to a mixture of 6.0 g of 2-(RS)-(2-hydroxyethyl)-2,3-dihydro-5-benzyloxy-4,6,7-trimethylbenzofurane cold to 0° C., 7.6 g of triphenylphosphine and 3.1 g of phthalimide in 35 ml of anhydrous tetrahydrofurane. After these additions, the mixture is brought to room temperature and stirred for 2 hours. After the solvent has been evaporated, the residue is purified with chromatography column (SiO2), which produces 8.0 g of N-[2-(2,3-dihydro-5-benzyloxy-4,6,7-trimethyl-2-benzofuranyl)ethyl]phthalimide m.p. 108°-110° C.: IR(KBr): 1772, 1716 cm-1 (νO=CNC=O). The phthalimide thus obtained is solubilized in a mixture of 50 ml of tetrahydrofurane and 20 ml of absolute ethanol. 3.2 ml of hydrated hydrazine are added dropwise and the mixture is kept under reflux with stirring for 2 hours. After the mixture has been brought to room temperature the formed phthalhydrazine is filtered out, and the filtrate is concentrated to a volume of about 20 ml. The additional phthalhydrazine which forms is filtered out. After the solvent is evaporated from the filtrate, the residue is treated with ethylic ether saturated with HCL to obtain the precipitate of the hydrochloride of the product. The precipitate is filtered under a vacuum, which gives 4.0 g of a white solid. m.p. 192°-193° C.; IR (KBr): 3032 cm-1 (νNH3 +); 1H-NMR (CD3OD): δ7.5-7.2 (5H,m), 4.7 (2H,s), 3.4-2.7 (4H,m), 2.4-2.2 (2H,m), 2.2 (6H,s), 2.1 (3H,s).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH:3]([CH2:6][OH:7])[CH2:2]1.C(N(CC)CC)C.[C:15]1([CH3:25])[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1>ClCCl>[CH3:25][C:15]1[CH:20]=[CH:19][C:18]([S:21]([O:7][CH2:6][CH:3]2[CH2:4][CH2:5][O:1][CH2:2]2)(=[O:23])=[O:22])=[CH:17][CH:16]=1
Reactant: OCC1CCOC1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OCC2CCOC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.8 %

Procedure:
To a solution of (tetrahydrofuran-3-yl)methanol (5.15 g, 50.4 mmol) in dichloromethane (200 mL) were added triethylamine (21.08 mL, 151 mmol) and p-toluenesulfonyl chloride (9.61 g, 50.4 mmol) and the mixture was stirred at room temperature overnight. The reaction mixture was washed with water (100 mL) and brine (100 mL). The organic layer was dried with sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography using an Analogix® Intelliflash280™ (SiO2, 0-40% ethyl acetate in hexane) to provide the title compound (12.5 g, 97%) as colorless viscous liquid. 1H NMR (300 MHz, DMSO-D6) δ ppm 1.40-1.51 (m, 1H) 1.83-1.95 (m, 1H) 2.43 (s, 3H) 3.28-3.31 (m, 1H) 3.31-3.37 (m, 1H) 3.51-3.67 (m, 3H) 3.90-4.00 (m, 2H) 7.48-7.51 (m, 2H) 7.78-7.82 (m, 2H); MS (DCI/NH3) m/z 274 (M+NH4)+.
Reaction SMILES: N1CCCN=[C:2]1[S:7][CH2:8][C:9]1[NH:10][C:11]([CH3:33])=[C:12]([C:29]([O:31][CH3:32])=[O:30])[CH:13]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([N+:26]([O-:28])=[O:27])[CH:21]=2)[C:14]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16].Br.BrC[CH2:37][NH2:38].[OH-].[Na+].[C:41]([OH:48])(=[O:47])/[CH:42]=[CH:43]/[C:44]([OH:46])=[O:45]>[Br-].C([P+](CCCC)(CCCC)CCCC)CCCCCCCCCCCCCCC.C(OCC)(=O)C.CO.C1C=CC=CC=1>[C:41]([OH:48])(=[O:47])/[CH:42]=[CH:43]/[C:44]([OH:46])=[O:45].[NH2:38][CH2:37][CH2:2][S:7][CH2:8][C:9]1[NH:10][C:11]([CH3:33])=[C:12]([C:29]([O:31][CH3:32])=[O:30])[CH:13]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([N+:26]([O-:28])=[O:27])[CH:21]=2)[C:14]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: NCCBr
Reactant: CCOC(=O)C1=C(CSC2=NCCCN2)NC(C)=C(C(=O)OC)C1c1cccc([N+](=O)[O-])c1
Agent: Br
Agent: CCCCCCCCCCCCCCCC[P+](CCCC)(CCCC)CCCC
Agent: O=C(O)/C=C/C(=O)O
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Solvent: CO
Product: CCOC(=O)C1=C(CSCCN)NC(C)=C(C(=O)OC)C1c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
A mixture of (-)-2-[(1,4,5,6-tetrahydropyrimidin-2-yl)thio]methyl-3-carboethoxy-5-carbomethoxy-4-(m-nitrophenyl)-6-methyl-1,4-dihydropyridine (g 2), hexadecyltributyl phosphonium bromide (mg 180), 2-bromoethylaminehydrobromide (mg 900), NaOH (35%, ml 8) and benzene is stirred for 40 minutes at room temperature. After the usual work-up, an oily residue is obtained that is dissolved in ethyl acetate and treated with fumaric acid to give 1.9 g of (-)-2-(aminoethylthio)methyl-3-carboethoxy-5-carbomethoxy-4-(3-nitrophenyl)-6-methyl-1,4-dihydropyridine fumarate, m.p. 104°-110° C. [α]D =-11 (C=4 in MeOH).