Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9]([NH:11][C:12]2[CH:17]=[C:16]([CH3:18])[CH:15]=[CH:14][C:13]=2[CH3:19])=[O:10])[CH2:5][CH2:4]1)#[N:2].O.[SH-:21].[Na+].Cl.C(NCC)C>CN(C)C=O>[CH3:19][C:13]1[CH:14]=[CH:15][C:16]([CH3:18])=[CH:17][C:12]=1[NH:11][C:9]([N:6]1[CH2:7][CH2:8][CH:3]([C:1](=[S:21])[NH2:2])[CH2:4][CH2:5]1)=[O:10]
Reactant: [SH-]
Reactant: Cc1ccc(C)c(NC(=O)N2CCC(C#N)CC2)c1
Agent: Cl
Agent: [Na+]
Solvent: CCNCC
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(C)c(NC(=O)N2CCC(C(N)=S)CC2)c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of 4-cyano-N-(2,5-dimethylphenyl)piperidinecarboxamide (i.e. the product of Example 14, Step A) (12.75 g, 49.6 mmol), sodium hydrosulfide hydrate (11.1 g, 150 mmol) and diethylamine hydrochloride (10.9 g, 100 mmol) in N,N-dimethylformamide (50 mL) was stirred at room temperature for 3 days. The resulting thick, green suspension was added dropwise into ice water (600 mL). The resulting solid was filtered, washed with water and air-dried to give 12.5 g of the title compound as a tan solid decomposing at 155-156° C.
Reaction SMILES: [C:1]1(/[CH:7]=[CH:8]/[C:9]([C:11]2[CH:24]=[CH:23][C:14]([CH2:15][CH:16]3[S:20][C:19](=[O:21])[NH:18][C:17]3=[O:22])=[CH:13][CH:12]=2)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([SiH](CC)CC)C.CCCCCC.C(OCC)(=O)C>FC(F)(F)C(O)=O.O>[C:1]1([CH2:7][CH2:8][CH2:9][C:11]2[CH:24]=[CH:23][C:14]([CH2:15][CH:16]3[S:20][C:19](=[O:21])[NH:18][C:17]3=[O:22])=[CH:13][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1NC(=O)C(Cc2ccc(C(=O)/C=C/c3ccccc3)cc2)S1
Agent: CC[SiH](CC)CC
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: O=C(O)C(F)(F)F
Product: O=C1NC(=O)C(Cc2ccc(CCCc3ccccc3)cc2)S1
Reaction time: 0.42 h

Procedure:
A solution of the title product of Example 39 (2.0 g, 5.9 mmol) in trifluoroacetic acid (20 ml), cooled to 0° C., was treated with triethylsilane (2.8 ml, 18 mmol). After 25 minutes at 0° C., the solution was diluted with water (60 ml) and extracted with ether (2×50 ml). The combined extracts were washed with water (2×50 ml) and brine (50 ml), dried over sodium sulfate and concentrated in vacuo, leaving a brown oil. Present title product was isolated by flash-chromatography (hexane:ethyl acetate, 5:1) as an oil (1.11 g, 58%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH2:9][C:10]2[CH:15]=[C:14]([O:16][CH:17]([CH3:21])[C:18](=O)[CH3:19])[C:13]([O:22][CH3:23])=[C:12]([O:24][CH3:25])[CH:11]=2)=[CH:4][N:3]=1.[OH-].[NH4+]>>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH2:9][C:10]2[C:15]3[C:18]([CH3:19])=[C:17]([CH3:21])[O:16][C:14]=3[C:13]([O:22][CH3:23])=[C:12]([O:24][CH3:25])[CH:11]=2)=[CH:4][N:3]=1
Reactant: COc1cc(Cc2cnc(N)nc2N)cc(OC(C)C(C)=O)c1OC
Agent: [NH4+]
Agent: [OH-]
Product: COc1cc(Cc2cnc(N)nc2N)c2c(C)c(C)oc2c1OC
Temperature: 0 °C
Yield: 79.2 %

Procedure:
A mixture of 0.70 g (0.002 mole) of 2,4-diamino-5-(3,4-dimethoxy-5-(1-methyl-2oxopropoxy)benzyl)pyrimidine in 11 g of polyphosphoric acid was stirred and heated on a steam bath for 20 minutes then poured onto 100 g of ice. The resulting mixture was basified with concentrated ammonium hydroxide, then extracted with methylene chloride (100 mL). The extract was washed with water (150 mL), dried over anhydrous magnesium sulfate and concentrated in vacuo to give the title compound (0.52 g, 78%). Recrystallization from absolute ethanol gave an analytical sample; mp>249° dec. Anal. Calcd for C17H20N4O3 : C, 62.18, H, 6.14; N, 17.06. Found: C, 62.01; H, 6.17, N, 17.01.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([O:12]CC)=[O:11])=[CH:5][CH:4]=1.[OH-].[Na+]>O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][C:10]([OH:12])=[O:11])=[CH:7][CH:8]=1
Reactant: CCOC(=O)Cc1ccc(OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1ccc(CC(=O)O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.3 %

Procedure:
To a solution of ethyl 2-(4-methoxyphenyl)acetate (12 g, 0.06 mol) MeOH (150 mL) was added dropwise a solution of NaOH (9.8 g, 0.24 mol) in water (50 mL). The mixture was then stirred at RT for 1 h and concentrated in vacuo, the residue was acidified with HCl (1N) and extracted with EtOAc (2×400 mL). The combined organic layers were washed with water, dried over Na2SO4 and concentrated in vacuo to afford 2-(4-methoxyphenyl)acetic acid (10 g, 67%) as a yellow oil.
Reaction SMILES: C([O:8][C:9](=[O:40])[C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([C:19]2[CH:28]=[CH:27][C:26]3[C:21](=[CH:22][CH:23]=[C:24]([O:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[CH:25]=3)[CH:20]=2)=[O:18])=[CH:12][CH:11]=1)C1C=CC=CC=1.[H][H]>[Pd].C1COCC1>[CH2:30]([O:29][C:24]1[CH:25]=[C:26]2[C:21](=[CH:22][CH:23]=1)[CH:20]=[C:19]([C:17]([O:16][C:13]1[CH:14]=[CH:15][C:10]([C:9]([OH:40])=[O:8])=[CH:11][CH:12]=1)=[O:18])[CH:28]=[CH:27]2)[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39]
Reactant: [H][H]
Reactant: CCCCCCCCCCOc1ccc2cc(C(=O)Oc3ccc(C(=O)OCc4ccccc4)cc3)ccc2c1
Agent: [Pd]
Solvent: C1CCOC1
Product: CCCCCCCCCCOc1ccc2cc(C(=O)Oc3ccc(C(=O)O)cc3)ccc2c1
Yield: 97.5 %

Procedure:
To 37.6 g (0.07 mol) of the 4-(6-decyloxy-2-naphthoyloxy)benzoic acid benzyl ester obtained in the first stage was added 3.76 g of 5% palladium/carbon, and further added 188 g of THF. Then, hydrogen gas was blown into the mixture. The resultant mixture was stirred overnight and filtered to obtain 30.6 g of 4-(6-decyloxy-2-naphthoyloxy)benzoic acid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[N:10]=[C:11](O)[C:12]2[S:17][CH:16]=[CH:15][C:13]=2[N:14]=1.N.P(Cl)(Cl)([Cl:22])=O>>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]1[N:10]=[C:11]([Cl:22])[C:12]2[S:17][CH:16]=[CH:15][C:13]=2[N:14]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1ccccc1Nc1nc(O)c2sccc2n1
Agent: N
Product: Cc1ccccc1Nc1nc(Cl)c2sccc2n1

Procedure:
2-(2-Methylphenylamino)-4-hydroxythieno[3,2-d]-pyrimidine (2 g, 0.0078 mol) and phosphorus oxychloride (20 ml) were heated under reflux for 1 hour. The solution was poured onto ice, basified with concentrated NH3 solution, and extracted with dichloromethane (3×100 ml). The dichloromethane extracts were combined, dried over magnesium sulphate and evaporated to give a yellow solid, 2.08 g. Recrystallization from methanol gave an analytically pure sample, m.p. 87°-89°.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][C:11]([OH:13])=O)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[NH:14]1[C:18]2=[N:19][CH:20]=[CH:21][CH:22]=[C:17]2[C:16]([C:23]2[N:24]=[C:25]([NH2:28])[S:26][CH:27]=2)=[CH:15]1.C(N(CC)CC)C>C1COCC1>[N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][C:11]([NH:28][C:25]2[S:26][CH:27]=[C:23]([C:16]3[C:17]4[C:18](=[N:19][CH:20]=[CH:21][CH:22]=4)[NH:14][CH:15]=3)[N:24]=2)=[O:13])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: Nc1nc(-c2c[nH]c3ncccc23)cs1
Reactant: O=C(O)Cc1cccc([N+](=O)[O-])c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Cc1cccc([N+](=O)[O-])c1)Nc1nc(-c2c[nH]c3ncccc23)cs1
Yield: 66 %

Procedure:
Prepared from 3-nitrophenyl acetic acid (1 g, 5.52 mmol), N-(1-methanesulfonyl)-benzotriazole (1.5 eq, 1.6 g), 4-(1H-pyrrolo[2,3-b]pyridin-3-yl)-thiazol-2-ylamine and triethylamine (3eq, 2.3 ml) in THF (20 mL) by microwave irradiation at 170° C. for 10 mins as described above. The reaction mixture was concentrated to dryness and CH3CN added. The desired final product was filtered and washed with ether to give clean 2-(3-nitrophenyl)-N-[4-(1H-pyrrolo[2,3-b]pyridin-3-yl)-thiazol-2-yl]-acetamide (1.4 g, 66% yield.)
Reaction SMILES: C([NH+]([CH2:6][CH3:7])CC)C.[C:8]12(C(Cl)=O)C[CH:12]3[CH2:13][CH:14](C[CH:10]([CH2:11]3)[CH2:9]1)[CH2:15]2>C(#N)C.N1C=CC=CC=1>[CH3:14][CH2:15][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:6][CH3:7]
Reactant: CC[NH+](CC)CC
Reactant: O=C(Cl)C12CC3CC(CC(C3)C1)C2
Solvent: CC#N
Solvent: c1ccncc1
Product: CCCCCCCCCC

Procedure:
The dimethoxytrityl group of the derivatized CPG from Example 9 is removed by a treatment with 2% dichloroacetic acid followed by washing with dry acetonitrile. The CPG is washed with acetonitrile-pyridine (1:1) followed by a simultaneous treatment of the CPG with 10 to 30 equivalents of the 10-O-(dimethoxytrityl)decyl-phosphonic acid as the triethylammonium salt, 20-30 equivalents of adamantane carbonyl chloride in acetonitrile-pyridine. The CPG is then washed with acetonitrile-pyridine and then treated with diisopropyl phosphite adamantane carbonyl chloride (0.2M) to cap all unreacted hydroxyl groups. Finally, the CPG is washed with acetonitrile/pyridine 1:1 and then acetonitrile. An estimate of coupling efficiency is derived from the treatment of the CPG with dichloracetic acid in acetonitrile followed by a measurement of the absorbance of an aliquot at 498 nm. Repeating the above procedure n times will yield an oligomer with n+1 decane units and n H-phosphonate linkages. The oligomer is tethered to a LCAA CPG by a succinate group as described above.
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.[F:7][C:8]1[CH:17]=[CH:16][C:11]([C:12](=[O:15])[CH2:13]Br)=[CH:10][CH:9]=1>C(OCC)(=O)C.O>[F:7][C:8]1[CH:17]=[CH:16][C:11]([C:12](=[O:15])[CH2:13][N:3]2[CH:4]=[CH:5][N:6]=[C:2]2[CH3:1])=[CH:10][CH:9]=1
Reactant: O=C(CBr)c1ccc(F)cc1
Reactant: Cc1ncc[nH]1
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1nccn1CC(=O)c1ccc(F)cc1
Temperature: 25 °C
Yield: 42.3 %

Procedure:
A mixture of 2-methylimidazole (8.0 g, 97.5 mmol) and 4-fluorophenacyl bromide (21.16 g, 97.5 mmol) dissolved in ethyl acetate (40 ml) at ambient temperature was treated with tiethylamine (16.4 ml, 117 mmol) and the cloudy mixture heated at reflux for 16 hours. The mixture was cooled to ambient temperature and diluted with ethyl acetate and water, washed with water and brine, dried and evaporated to dryness. The residue was recrystallised (3×) from dichloromethane/methanol/isohexane to give 1-(4-fluorophenyl)-2-(2-methylimidazol-1-yl)ethanone (1, 9.0 g, 42%).
Reaction SMILES: [Na].[Cl:2][C:3]1[N:4]=[C:5]2[C:9](=[CH:10][C:11]=1[Cl:12])[NH:8][C:7](=[O:13])[CH2:6]2.[S:14]1[CH:18]=[CH:17][CH:16]=[C:15]1[C:19](OCC)=[O:20].Cl>C(O)C>[Cl:2][C:3]1[N:4]=[C:5]2[C:9](=[CH:10][C:11]=1[Cl:12])[NH:8][C:7](=[O:13])[CH:6]2[C:19](=[O:20])[C:15]1[S:14][CH:18]=[CH:17][CH:16]=1
Reactant: O=C1Cc2nc(Cl)c(Cl)cc2N1
Reactant: CCOC(=O)c1cccs1
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: O=C1Nc2cc(Cl)c(Cl)nc2C1C(=O)c1cccs1
Temperature: 0 °C

Procedure:
Pellets of sodium metal (0.29 g, 12.6 mmol) were added to dry ethanol (10 mL) in a dry round-bottomed flask. When dissolution of the sodium was complete, solid 5,6-dichloro-4-azaoxindole (500 mg, 2.46 mmol) was added followed by ethyl 2-thiophenecarboxylate (0.67 mL. 5.0 mmol). The mixture was heated at reflux for one day under nitrogen. The mixture was cooled, poured into ice/water and acidified to pH 3 with 6N HCl solution. The title compound was collected by filtration and dried in vacuo to afford 607 mg (79%).
Reaction SMILES: [Si:1]([O:18][CH2:19][C@H:20]1[O:27][CH:26]2[C@:22]([CH3:30])([O:23][C:24]([CH3:29])([CH3:28])[O:25]2)[C@@H:21]1O)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1.[I:56]I>C1(C)C=CC=CC=1>[C:14]([Si:1]([O:18][CH2:19][C@H:20]1[O:27][CH:26]2[C@:22]([CH3:30])([O:23][C:24]([CH3:28])([CH3:29])[O:25]2)[C@H:21]1[I:56])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)([CH3:15])([CH3:16])[CH3:17]
Reactant: II
Reactant: CC1(C)OC2O[C@H](CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)[C@@H](O)[C@@]2(C)O1
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CC1(C)OC2O[C@H](CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)[C@H](I)[C@@]2(C)O1
Yield: 78.9 %

Procedure:
To a mixture of (5R,6R,6aR)-5-((tert-butyldiphenylsilyloxy)methyl)-2,2,6a-trimethyl-tetrahydrofuro[3,2-d][1,3]dioxol-6-ol (from step 5) (32.4 g, 0.0736 mol), triphenylphosphine (57.9 g, 0.2209 mol), Imidazole (15.03 g, 0.2209 mol) in 400 mL anhydrous toluene was added iodine (42.96 g, 0.169 mol) in portions over a period of 30 min and refluxed for 12 h. The mixture was diluted with 300 mL toluene and washed with saturated NaHCO3 solution and saturated sodium thiosulfate solution. The organic layers were dried over anhydrous Na2SO4, filtered and concentrated. Purification was done by column chromatography using a gradient mixture of hexane and ethyl ether to give 32.08 g (80% yield) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([C:9]([O:11][CH3:12])=[O:10])[C:3]=1I.[CH:14]([Sn](CCCC)(CCCC)CCCC)=[CH2:15]>ClCCCl.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>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([C:9]([O:11][CH3:12])=[O:10])[C:3]=1[CH:14]=[CH2:15]
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: COC(=O)c1nc(Cl)cc(Cl)c1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCCl
Product: C=Cc1c(Cl)cc(Cl)nc1C(=O)OC
Temperature: 25 °C
Yield: 76 %

Procedure:
Methyl 4,6-dichloro-3-iodopicolinate (0.56 g, 1.7 mmol), vinyltributylstannane (580 μl, 0.63 g, 2.0 mmol) and bis(triphenylphosphine)palladium(II) chloride (0.12 g, 0.17 mmol) were combined in 1,2-dichloroethane (8 mL) and the mixture was sparged with a stream of nitrogen for 15 min. The reaction mixture was stirred at reflux for 21 h, cooled to room temperature, and diluted with ethyl acetate (15 mL). A solution of 20% KHF2 (10 ml) was added and the mixture was stirred for 45 minutes. The mixture was filtered through Celite. The organic phase was washed with water, washed with saturated sodium chloride, dried over sodium sulfate, and concentrated under vacuum. The crude product was purified by flash chromatography (SiO2, ethyl acetate/hexanes) to afford the title compound as a solid (0.30 g, 70%): 1H NMR (400 MHz, CDCl3) δ 7.50 (s, 1H), 6.82 (ddd, J=17.8, 11.5, 1.7 Hz, 1H), 5.66 (dd, J=11.4, 8.1 Hz, 1H), 5.55 (dt, J=17.7, 5.0 Hz, 1H), 3.92 (s, 3H); EIMS m/z 231.
Reaction SMILES: C1(O[C:8](=[O:16])[NH:9][C:10]2[CH:15]=[CH:14][N:13]=[CH:12][N:11]=2)C=CC=CC=1.[F:17][C:18]1([F:34])[O:22][C:21]2[CH:23]=[CH:24][C:25]([CH2:27][N:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)=[CH:26][C:20]=2[O:19]1>>[N:13]1[CH:14]=[CH:15][C:10]([NH:9][C:8]([N:31]2[CH2:32][CH2:33][N:28]([CH2:27][C:25]3[CH:24]=[CH:23][C:21]4[O:22][C:18]([F:34])([F:17])[O:19][C:20]=4[CH:26]=3)[CH2:29][CH2:30]2)=[O:16])=[N:11][CH:12]=1
Reactant: FC1(F)Oc2ccc(CN3CCNCC3)cc2O1
Reactant: O=C(Nc1ccncn1)Oc1ccccc1
Product: O=C(Nc1ccncn1)N1CCN(Cc2ccc3c(c2)OC(F)(F)O3)CC1

Procedure:
The title compound was prepared from pyrimidin-4-yl-carbamic acid phenyl ester and 1-(2,2-difluoro-benzo[1,3]dioxol-5-ylmethyl)-piperazine in analogy with Example 142. 1H NMR (400 MHz, CDCl3): 8.76 (s, 1H), 8.54 (d, J=6.1 Hz, 1H), 7.97 (d, J=5.3 Hz, 1H), 7.65-7.39 (m, 2H), 7.19-7.01 (m, 2H), 4.03-3.55 (m, 6H), 2.91-2.49 (m, 4H).
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1.[NH2:16][C@H:17]([C:20]([OH:22])=[O:21])[CH2:18][OH:19]>CS(C)=O>[C:20]([C@@H:17]([NH:16][C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1)[CH2:18][OH:19])([OH:22])=[O:21]
Reactant: O=C(O)c1cc2cc(Cl)ccc2nc1Cl
Reactant: N[C@@H](CO)C(=O)O
Solvent: CS(C)=O
Product: O=C(O)c1cc2cc(Cl)ccc2nc1N[C@@H](CO)C(=O)O

Procedure:
In close analogy to the procedure described in Example 1, 2,6-dichloroquinoline-3-carboxylic acid is reacted with L-serine in DMSO to provide the title compound in good yield.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[N:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH2:17][OH:18]>>[N:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH2:17][O:18][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9]
Reactant: OCc1ccccn1
Reactant: O=[N+]([O-])c1cnccc1Cl
Product: O=[N+]([O-])c1cnccc1OCc1ccccn1
Yield: 68.3 %

Procedure:
In accordance with the same procedures as in Preparation 2, except for using 4-chloro-3-nitropyridine prepared in Step 1 of Preparation 1 and 2-pyridyl carbinol, the titled compound was obtained as a yellow solid. (Yield: 68.3%)
Reaction SMILES: [F:1][C:2]1[CH:30]=[CH:29][CH:28]=[CH:27][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([C:14]2[N:15]=[C:16](I)[C:17]3[C:22]([CH3:24])([CH3:23])[C:21](=[O:25])[NH:20][C:18]=3[N:19]=2)=[N:6]1.[CH2:31]([N:33]1[CH2:37][CH2:36][NH:35][C:34]1=[O:38])[CH3:32].C(=O)([O-])[O-].[Cs+].[Cs+].OC1C=CC=CC=1C=NO>C(#N)C.[Cu-]=O>[CH2:31]([N:33]1[CH2:37][CH2:36][N:35]([C:16]2[C:17]3[C:22]([CH3:24])([CH3:23])[C:21](=[O:25])[NH:20][C:18]=3[N:19]=[C:14]([C:7]3[C:8]4[C:9](=[N:10][CH:11]=[CH:12][CH:13]=4)[N:5]([CH2:4][C:3]4[CH:27]=[CH:28][CH:29]=[CH:30][C:2]=4[F:1])[N:6]=3)[N:15]=2)[C:34]1=[O:38])[CH3:32]
Reactant: CC1(C)C(=O)Nc2nc(-c3nn(Cc4ccccc4F)c4ncccc34)nc(I)c21
Reactant: CCN1CCNC1=O
Agent: O=[Cu-]
Agent: O=C([O-])[O-]
Agent: ON=Cc1ccccc1O
Solvent: CC#N
Product: CCN1CCN(c2nc(-c3nn(Cc4ccccc4F)c4ncccc34)nc3c2C(C)(C)C(=O)N3)C1=O
Temperature: 200 °C

Procedure:
Under argon atmosphere, 150 mg (purity 62%, 0.18 mmol) of 2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-4-iodo-5,5-dimethyl-5,7-dihydro-6H-pyrrolo[2,3-d]pyrimidin-6-one (example 15A) was suspended in 2 ml of absolute acetonitrile and 413 mg (3.62 mmol) of 1-ethylimidazolidin-2-one, 118 mg (0.36 mmol) of caesium carbonate, 5 mg (0.04 mmol) of copper(I) oxide and 20 mg (0.15 mmol) of 2-hydroxybenzaldehyde-oxime were added. The mixture was heated in the microwave for 1 h at 200° C. The reaction solution was filtered and purified by preparative HPLC (eluent: acetonitrile/water, gradient 20:80→100:0). 35 mg (purity 91%, 35% of theor.) of the target compound was obtained.
Reaction SMILES: Cl.[C:2]([C:5]1[CH:6]=[C:7]2[CH:13]=[C:12]([C:14]([O:16]CC)=[O:15])[O:11][C:8]2=[N:9][CH:10]=1)(=[NH:4])[NH2:3].Cl[C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21].[OH-].[Na+].Cl>O1CCCC1>[CH2:23]([O:22][C:20]([NH:3][C:2]([C:5]1[CH:6]=[C:7]2[CH:13]=[C:12]([C:14]([OH:16])=[O:15])[O:11][C:8]2=[N:9][CH:10]=1)=[NH:4])=[O:21])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CCOC(=O)c1cc2cc(C(=N)N)cnc2o1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: N=C(NC(=O)OCc1ccccc1)c1cnc2oc(C(=O)O)cc2c1
Temperature: 25 °C
Yield: 40.2 %

Procedure:
Tetrahydrofuran (32 ml) was added to ethyl 5-amidinofuro[2,3-b]pyridine-2-carboxylate hydrochloride (2.05 g, 5.10 mmol), and benzyl chloroformate (1.09 ml, 7.65 mmol) was dropwise added under ice-cooling while maintaining the mixture at pH 10-12 with a 1N aqueous sodium hydroxide solution. Thereafter, the mixture was stirred under ice-cooling for 30 minutes and at room temperature for 1.5 hours. Tetrahydrofuran (20 ml) and a 1N aqueous sodium hydroxide solution (20 ml) were added to this reaction mixture and the mixture was stirred at room temperature for 1.5 hours. The mixture was adjusted to pH 4-5 with 1N hydrochloric acid and low boiling matters were distilled away under reduced pressure. The residue was purified by reversed-phase column (Chromatorex-ODS DM1020T, Fuji Silysia Chemical) chromatography. (water-acetonitrile) to give 695 mg of 5-(benzyloxycarbonylamidino)furo[2,3-b]pyridine-2-carboxylic acid as a yellow solid (35%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]([N:14]3[CH:18]=[N:17][CH:16]=[N:15]3)([CH3:13])[CH3:12])[CH2:10][O:9]2)=[CH:4][CH:3]=1.[NH:19]1[CH:23]=[N:22][CH:21]=[N:20]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[N:19]1([CH2:10][C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)([OH:9])[C:11]([N:14]2[CH:18]=[N:17][CH:16]=[N:15]2)([CH3:13])[CH3:12])[CH:23]=[N:22][CH:21]=[N:20]1
Reactant: CC(C)(n1cncn1)C1(c2ccc(Cl)cc2)CO1
Reactant: c1nc[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(n1cncn1)C(O)(Cn1cncn1)c1ccc(Cl)cc1
Yield: 71 %

Procedure:
A mixture of 2-(4-chlorophenyl)-2-[2-(1H-1,2,4-triazol-1-yl)prop-2-yl]oxirane (1.1 g.), 1,2,4-triazole (2 g.), potassium carbonate (5 g.) and dry dimethylformamide (25 ml.) was heated at 80° under a nitrogen atmosphere for 16 hours. The reaction mixture was then cooled, filtered, washed with xylene and the filtrate was evaporated in vacuo. The residue was azeotroped with xylene (2×30 ml.) and then partitioned between methylene chloride (50 ml.) and water (50 ml.). The aqueous phase was extracted with methylene chloride (3×50 ml), and the combined organic phases were washed with water (50 ml.), and dried (MgSO4). The residue obtained after removal of the solvent was flash chromatographed on silica (150 g) using methylene chloride/methanol/saturated aqueous ammonia (93:7:1 v/v/v), for elution. The product-containing fractions on evaporation followed by crystallisation from ethyl acetate/hexane yielded 983 mg. (71% yield) of the title compound, m.p. 128°-9°.
Reaction SMILES: C1C2C(=CC=CC=2)C=C[NH2+]1.[Cl-].[CH3:12][O:13][C:14]1[CH:15]=[C:16]([C:22]([CH:43]([CH3:45])[CH3:44])([C:41]#[N:42])[CH2:23][CH2:24][CH2:25][C:26]2[CH2:35][C:34]3[C:29](=[CH:30][C:31]([O:38][CH3:39])=[C:32]([O:36][CH3:37])[CH:33]=3)[CH2:28][N+:27]=2[CH3:40])[CH:17]=[CH:18][C:19]=1[O:20][CH3:21]>>[CH3:12][O:13][C:14]1[CH:15]=[C:16]([C:22]([CH:43]([CH3:45])[CH3:44])([C:41]#[N:42])[CH2:23][CH2:24][CH2:25][CH:26]2[CH2:35][C:34]3[C:29](=[CH:30][C:31]([O:38][CH3:39])=[C:32]([O:36][CH3:37])[CH:33]=3)[CH2:28][N:27]2[CH3:40])[CH:17]=[CH:18][C:19]=1[O:20][CH3:21]
Reactant: COc1ccc(C(C#N)(CCCC2=[N+](C)Cc3cc(OC)c(OC)cc3C2)C(C)C)cc1OC
Agent: C1=Cc2ccccc2C[NH2+]1
Agent: [Cl-]
Product: COc1ccc(C(C#N)(CCCC2Cc3cc(OC)c(OC)cc3CN2C)C(C)C)cc1OC

Procedure:
The dihydroisoquinolinium salt of formula 34 is then hydrogenated to produce a compound of formula 1 (step 6). This reaction is performed using a suitable hydrogenating agent, preferably a boron hydride derivative, particularly NaBH4. The solvent used is preferably a lower alkanol, particularly MeOH. The reaction is carried out at a temperature of about -10° C. to about 50° C., preferably about 0° C., over about 10 minutes to about 3 hours, preferably 1 hour. For example, 3-[4-(3,4-dimethoxyphenyl)-4-isopropyl-4-cyanobutyl]-6,7-dimethoxy-N-methyl-1,4-dihydroisoquinolinium chloride (34) is suspended in MeOH at 0° C., then treated with NaBH4 for about 1 hour to produce 3-[4-(3,4-dimethoxyphenyl)-4-isopropyl-4-cyanobutyl]-6,7-dimethoxy-N-methyl-1,2,3,4-tetrahydroisoquinoline (1).
Reaction SMILES: Br[C:2]1[C:3]([NH2:9])=[N:4][CH:5]=[C:6]([Br:8])[N:7]=1.C(N(CC)CC)C.[CH3:17][Si:18]([C:21]#[CH:22])([CH3:20])[CH3:19].C(OCC)(=O)C>C(#N)C.[Cu]I.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>[Br:8][C:6]1[N:7]=[C:2]([C:22]#[C:21][Si:18]([CH3:20])([CH3:19])[CH3:17])[C:3]([NH2:9])=[N:4][CH:5]=1
Reactant: Nc1ncc(Br)nc1Br
Reactant: C#C[Si](C)(C)C
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1nc(Br)cnc1N
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 74.9 %

Procedure:
To a 500 ml three necked round bottom flask, 3,5-dibromopyrazine-2-amine (25.0 g, 0.0988 mole) was taken in acetonitrile (250 ml). The reaction mixture was cooled to 0° C. and triethylamine (50.0 g, 0.4941 mole), copper (1) iodide (2.26 g, 0.0119 mole), and Pd(PPh3)4 (5.7 g, 0.0049 mole) were added under nitrogen atmosphere. The reaction mixture was stirred for 10 min at 0° C. followed by slow addition of trimethylsilylacetylene (10.7 g, 0.1089 mole) over 15 min at the same temperature. After completion of the addition, the reaction mixture was warmed up to RT and stirred for 90 min. The completion of the reaction was monitored on TLC using hexanes:ethyl acetate (5:5) as a mobile phase. After completion of the reaction, the reaction mixture was diluted by ethyl acetate and filtered through high flow. Filtrate was collected and washed with water. Layers were separated and aq. layer was re-extracted by ethyl acetate. Combined organic layer was dried over Na2SO4, filtered and concentrated to afford crude product which was subjected for the column purification. The crude compound was purified using column purification by eluting the compound with 7-10% ethyl acetate in hexanes to yield 20.0 g of 5-bromo-3-((trimethylsilyl)ethynyl)pyrazine-2-amine.