Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C@@:3]1([CH:32]2[CH2:34][CH2:33]2)[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:14][C:15]3[CH:16]=[N:17][N:18]([CH:20]4[CH2:23][N:22]([C:24](OC(C)(C)C)=[O:25])[CH2:21]4)[CH:19]=3)[N:9]=2)[C:4]1=[O:31])#[N:2].Cl.O.C(#N)C.[C:40]([O:43][CH2:44]C)(=O)C>>[CH:32]1([C@:3]2([C:1]#[N:2])[CH2:7][CH2:6][N:5]([C:8]3[CH:13]=[CH:12][N:11]=[C:10]([NH:14][C:15]4[CH:16]=[N:17][N:18]([CH:20]5[CH2:23][N:22]([C:24](=[O:25])[CH2:40][O:43][CH3:44])[CH2:21]5)[CH:19]=4)[N:9]=3)[C:4]2=[O:31])[CH2:34][CH2:33]1
Reactant: CC(C)(C)OC(=O)N1CC(n2cc(Nc3nccc(N4CC[C@@](C#N)(C5CC5)C4=O)n3)cn2)C1
Reactant: CCOC(C)=O
Agent: Cl
Solvent: CC#N
Solvent: O
Product: COCC(=O)N1CC(n2cc(Nc3nccc(N4CC[C@@](C#N)(C5CC5)C4=O)n3)cn2)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of tert-butyl 3-(4-((4-((3S)-3-cyano-3-cyclopropyl-2-oxopyrrolidin-1-yl)pyrimidin-2-yl)amino)-1H-pyrazol-1-yl)azetidine-1-carboxylate (300 mg) obtained in Step C of Example 131 in ethyl acetate (5 mL) was added a solution of 4 M hydrogen chloride in ethyl acetate (10 mL), and the mixture was stirred at room temperature for 30 min. The solvent was evaporated under reduced pressure, to a suspension of the reaction mixture in tetrahydrofuran (10 mL) were added triethylamine (1.3 g) and methoxyacetyl chloride (77 mg) at room temperature, and the mixture was stirred at room temperature for 3 hr. The solvent was evaporated under reduced pressure, and the reaction mixture was poured into water, and extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/methanol). The obtained crude product was subjected to HPLC (C18, mobile phase: water/acetonitrile (containing 10 mM NH4HCO3)), and the obtained fraction was concentrated under reduced pressure. The residue was recrystallized (ethyl acetate/diisopropyl ether) to give the title compound (60 mg).
Reaction SMILES: [Br:1]Br.[F:3][C:4]([F:20])([F:19])[C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]2[CH:18]=[CH:17][CH:16]=[CH:15]2)(=[O:13])=[O:12])=[CH:7][CH:6]=1.[OH-].[Na+]>C(O)(=O)C.C(Cl)Cl>[Br:1][C:16]1[CH:17]=[CH:18][N:14]([S:11]([C:8]2[CH:7]=[CH:6][C:5]([C:4]([F:3])([F:19])[F:20])=[CH:10][CH:9]=2)(=[O:13])=[O:12])[CH:15]=1
Reactant: O=S(=O)(c1ccc(C(F)(F)F)cc1)n1cccc1
Reactant: BrBr
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CC(=O)O
Product: O=S(=O)(c1ccc(C(F)(F)F)cc1)n1ccc(Br)c1
Temperature: 100 °C
Yield: 75.6 %

Procedure:
Bromine (4.12 mL, 80.1 mmol) was added to a solution of 1-(4-(trifluoromethyl)phenylsulfonyl)-1H-pyrrole (111) (21 g, 76.2 mmol) in acetic acid (254 mL) and the resulting solution was heated to 100° C. for 1 h. The mixture was diluted with CH2Cl2 and poured slowly into ice cold aqueous sodium hydroxide (3 N). The solution was adjusted to pH 7 with aqueous sodium hydroxide (3 N), extracted with CH2Cl2. The organic phase was separated, dried (Na2SO4), filtered and concentrated under vacuum and purified on a silica gel column (eluant hexane/EtOAc, 4/1, v/v) to give compound 112 (20.4 g, 57.6 mmol, 75%). MS (ESI) 354.0 (M+H).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1)(=O)[CH3:2].[NH2:10][C@H:11]([C:14]([OH:16])=[O:15])[CH2:12][SH:13].O>C(O)C>[CH3:2][C:1]1([C:4]2[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=2)[NH:10][CH:11]([C:14]([OH:16])=[O:15])[CH2:12][S:13]1
Reactant: CC(=O)c1cccnc1
Reactant: N[C@@H](CS)C(=O)O
Solvent: CCO
Solvent: O
Product: CC1(c2cccnc2)NC(C(=O)O)CS1
Yield: 37.8 %

Procedure:
A mixture of 3.63 g of 3-acetylpyridine, 3.63 g of L-cysteine, 25 ml of water and 25 ml of ethanol was refluxed for 24 hours. The reaction mixture was concentrated under reduced pressure, isopropanol was added to the residue, and the resultant powder was collected by filtration. Ethanol was added to the powder, the insoluble matter was filtered off, and the filtrate was concentrated to dryness. The residue was dissolved in water and adjusted to pH 6 by addition of diluted hydrochloric acid under ice cooling and stirring, and the resultant powder was collected by filtration, washed with ethanol and dried to give 2.54 g of 2-methyl-2-(3-pyridyl)thiazolidine-4- carboxylic acid.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[C:11]3[CH2:19][CH2:18][NH:17][CH2:16][C:12]=3[N:13]=[CH:14][N:15]=2)=[CH:5][CH:4]=1.[C:22]1([CH3:31])[CH:27]=[CH:26][CH:25]=[C:24](B(O)O)[CH:23]=1.C(N(CC)CC)C>C1COCC1.CC([O-])=O.CC([O-])=O.[Cu+2]>[F:21][C:2]([F:1])([F:20])[C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10]2[C:11]3[CH2:19][CH2:18][N:17]([C:24]4[CH:23]=[C:22]([CH3:31])[CH:27]=[CH:26][CH:25]=4)[CH2:16][C:12]=3[N:13]=[CH:14][N:15]=2)=[CH:7][CH:8]=1
Reactant: Cc1cccc(B(O)O)c1
Reactant: FC(F)(F)c1ccc(Nc2ncnc3c2CCNC3)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1cccc(N2CCc3c(ncnc3Nc3ccc(C(F)(F)F)cc3)C2)c1
Reaction time: 6 h
Yield: 4.7 %

Procedure:
N-(4-(Trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-amine (100 mg, 0.34 mmol) was dissolved in anhydrous THF (2 mL). To the mixture was added m-tolylboronic acid (92 mg, 0.68 mmol), Cu(OAc)2 (124 mg, 0.68 mmol) and triethylamine (0.68 g, 0.095 mL). The mixture was agitated for 6 h and the solvent was removed under a vacuum. The residue was purified using a gradient of ethyl acetate:hexane (0-100%) to give the desired compound as reddish powder (6.2 mg, 5%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10](Cl)=[C:9]([NH:12][C:13](=[O:15])[CH3:14])[CH:8]=[C:7]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([O:23][CH3:24])[C:17]=2[F:25])[N:6]=1)=[O:4].[CH2:26]([Sn](CCCC)(CCCC)C=C)[CH2:27]CC>C(#N)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>[CH3:1][O:2][C:3]([C:5]1[C:10]([CH:26]=[CH2:27])=[C:9]([NH:12][C:13](=[O:15])[CH3:14])[CH:8]=[C:7]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([O:23][CH3:24])[C:17]=2[F:25])[N:6]=1)=[O:4]
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: COC(=O)c1nc(-c2ccc(Cl)c(OC)c2F)cc(NC(C)=O)c1Cl
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CC#N
Product: C=Cc1c(NC(C)=O)cc(-c2ccc(Cl)c(OC)c2F)nc1C(=O)OC
Temperature: 110 °C
Yield: 60 %

Procedure:
4-Acetylamino-3-chloro-6-(4-chloro-2-fluoro-3-methoxyphenyl)pyridine-2-carboxylic acid methyl ester (0.5 g, 1.29 mmol), tributyl(vinyl)tin (0.821 g, 2.58 mmol), bis(triphenylphosphine)palladium(II) dichloride (0.091 g, 0.129 mmol), and tetrabutylammonium triphenyldifluorosilicate (1.4 g, 2.58 mmol) were combined in acetonitrile (3 ml) and heated to 110° C. for 15 min in a CEM microwave reactor. The cooled reaction mixture was concentrated onto silica gel and purified by flash chromatography on silica gel (ethyl acetate/hexane gradient) to yield the title compound (0.293 g, 60% yield) as a white solid, mp 143-145° C. 1H NMR (CDCl3) δ 7.66 (m, 1H), 7.22 (d, 1H), 7.12 (m, 1H), 6.85 (dd, 1H), 5.66 (dd, 1H), 5.57 (dd, 1H), 4.61 (br s, 2H), 3.97 (s, 3H), 3.94 (d, 3H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][CH:9]=[CH:8]2)#[N:2].[H-].[Na+].[CH3:14][Si:15]([CH2:18][CH2:19][O:20][CH2:21]Cl)([CH3:17])[CH3:16]>CN(C=O)C>[CH3:14][Si:15]([CH3:17])([CH3:16])[CH2:18][CH2:19][O:20][CH2:21][N:10]1[C:11]2[C:7](=[CH:6][CH:5]=[CH:4][C:3]=2[C:1]#[N:2])[CH:8]=[CH:9]1
Reactant: C[Si](C)(C)CCOCCl
Reactant: N#Cc1cccc2cc[nH]c12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1ccc2cccc(C#N)c21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78 %

Procedure:
7-Cyanoindole (1.0 g, 7.0 mmol) was stirred in DMF (10 mL) at 0° C. Sodium hydride (60%, 310 mg, 7.7 mmol) was added, and the reaction stirred 30 min at rt. SEM-chloride was added, and the reaction stirred 16 h. The solution was concentrated in vacuo and purified by silica gel chromatography (10-40% EtOAc/hexanes) to give 1.5 g (78%) of the title compound as a clear oil. 1H NMR (400 MHz, CDCl3): δ 7.85 (dd, 1H, J=7.9, 0.9 Hz), 7.56 (d, 1H, J=7.5 Hz), 7.26 (d, 1H, J=6.3 Hz), 7.17 (t, 1H, J=7.7 Hz), 6.62 (d, 1H, J=3.3 Hz), 5.79 (s, 2H), 3.58 (t, 2H, J=8.1 Hz), 0.92 (t, 2H, J=8.2 Hz), −0.05 (s, 9H). [M+H] calc'd for C15H20N2OSi, 273; found 273.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[N:22]=[C:21]([NH:23][CH2:24][CH:25]4[CH2:30][CH2:29][CH2:28][NH:27][CH2:26]4)[C:20]4[C:15](=[N:16][CH:17]=[CH:18][N:19]=4)[CH:14]=3)=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.C=O.[BH-](OC(C)=O)(OC(C)=O)O[C:35](C)=O.[Na+]>C1COCC1>[CH3:35][N:27]1[CH2:28][CH2:29][CH2:30][CH:25]([CH2:24][NH:23][C:21]2[C:20]3[C:15](=[N:16][CH:17]=[CH:18][N:19]=3)[CH:14]=[C:13]([C:10]3[CH:11]=[CH:12][C:7]([N:4]4[CH2:5][CH2:6][O:1][CH2:2][CH2:3]4)=[CH:8][CH:9]=3)[N:22]=2)[CH2:26]1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: c1cnc2c(NCC3CCCNC3)nc(-c3ccc(N4CCOCC4)cc3)cc2n1
Agent: C=O
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1CCCC(CNc2nc(-c3ccc(N4CCOCC4)cc3)cc3nccnc23)C1

Procedure:
A solution of 7-(4-morpholinophenyl)-N-(piperidin-3-ylmethyl)pyrido[4,3-b]pyrazin-5-amine (Compound 3, 40 mg, 0.1 mmol) and formaldehyde (60 mg, 2.0 mmol), NaBH(OAc)3 (25 mg, 0.15 mmol) in THF (20 mL) was stirred at ambient temperature overnight, then concentrated under reduced pressure. The residue was purified by chromatography to afford the title compound. MS (m/z): 419 (M+H)+.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:22][C:23]2[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:24]=2)[C:7](/[CH:10]=[C:11]2\[NH:12][C:13](=[O:21])[N:14]([CH2:17][CH2:18][CH2:19][CH3:20])[C:15]\2=[O:16])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4].C([O-])([O-])=O.[K+].[K+].[ClH:39].[NH2:40][C:41]1[S:42][CH:43]=[C:44]([CH2:46][Cl:47])[N:45]=1.Cl>CN(C=O)C.CCOCC>[ClH:47].[ClH:39].[CH2:1]([C:5]1[N:6]([CH2:22][C:23]2[CH:32]=[CH:31][C:26]([C:27]([O:29][CH3:30])=[O:28])=[CH:25][CH:24]=2)[C:7](/[CH:10]=[C:11]2\[N:12]([CH2:46][C:44]3[N:45]=[C:41]([NH2:40])[S:42][CH:43]=3)[C:13](=[O:21])[N:14]([CH2:17][CH2:18][CH2:19][CH3:20])[C:15]\2=[O:16])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: Nc1nc(CCl)cs1
Reactant: CCCCc1ncc(/C=C2\NC(=O)N(CCCC)C2=O)n1Cc1ccc(C(=O)OC)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCCCc1ncc(/C=C2/C(=O)N(CCCC)C(=O)N2Cc2csc(N)n2)n1Cc1ccc(C(=O)OC)cc1
Reaction time: 48 h

Procedure:
To a solution of methyl Z-4-[[2-butyl-5-[(1-butyl-2,5-dioxo-4-imidazolidinylidene) methyl]-1H-imidazol-1-yl]methyl]benzoate (0.569 g, 1.2 mmol) in DMF (5 mL) is added K2CO3 (2.0 g, 15 mmol). After stirring for 5 minutes 2-amino-4-chloromethylthiazole hydrochloride (0.222 g, 1.2 mmol) is added. The mixture is stirred for 48 hours and the filtered. The filtrate is concentrated in vacuo and dissolved in methylene chloride (30 mL). This solution is washed with water and drived over K2CO3 and charcoal. A viscous oil is obtained by evaporation of the solvents in vacuo. This oil is dissolved in ether and treated with ethereal HCl to precipitate a gum which is collected by decantation. This gum is recrystallized from 2-propanol/ether.
Reaction SMILES: [Na].[OH:2][C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1.O=C1[N:14]2[CH2:15][CH2:16][N:17]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:18][CH:13]2[CH2:12]O1>CN(C=O)C>[N:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH2:12][C@@H:13]2[NH:14][CH2:15][CH2:16][N:17]([C:19]([O:21][C:22]([CH3:23])([CH3:25])[CH3:24])=[O:20])[CH2:18]2)[CH:4]=1
Reactant: CC(C)(C)OC(=O)N1CCN2C(=O)OCC2C1
Reactant: Oc1cccnc1
Agent: [Na]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN[C@@H](COc2cccnc2)C1
Temperature: 120 °C
Yield: 50.8 %

Procedure:
3-Hydroxypyridine sodium salt (Acros, 7.23 g, 61.7 mmol) was added to a solution of tert-butyl tetrahydro-3-oxo-1H-oxazolo[3,4-a]pyrazine-7(3H)-carboxylate (5.00 g, 20.6 mmol) in DMF (50 mL). The reaction mixture was heated to 120° C. for 60 h. Upon cooling to rt, the reaction mixture was concentrated under reduced pressure. The material was dissolved in H2O (100 mL) and was extracted with EtOAc (3×150 mL). The combined organics were washed with 1 N NaOH (3×200 mL) and brine (200 mL), dried over dried over Na2SO4, filtered, and concentrated under reduced pressure. Recrystallization from EtOAc/Hexanes (1:4) gave 3.068 g (51%) of the desired product as an off-white solid.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9](=[O:16])[CH2:8]2)[CH2:4][CH2:3]1.CCN(CC)CC.[CH:24]1[CH:29]=[CH:28][C:27]([CH2:30][O:31][C:32](Cl)=[O:33])=[CH:26][CH:25]=1>C(Cl)Cl>[O:16]=[C:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:5]2([CH2:6][CH2:7][N:2]([C:32]([O:31][CH2:30][C:27]3[CH:28]=[CH:29][CH:24]=[CH:25][CH:26]=3)=[O:33])[CH2:3][CH2:4]2)[CH2:8]1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: O=C1CC2(CCNCC2)c2ccccc21
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1CC2(CCN(C(=O)OCc3ccccc3)CC2)c2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.2 %

Procedure:
To a solution spiro[indene-1,4′-piperidin]-3(2H)-one hydrochloride (5.0 g, 24.84 mmol) and Et3N (7.54 g, 74.53 mol) in CH2Cl2 (50 mL) was added drop-wise Cbz-Cl (4.66 g, 27.33 mmol) at 0° C. The reaction was allowed to warm to room temperature and stirred overnight. The precipitate was filtered, washed with Et2O and dried to furnish benzyl 3-oxo-2,3-dihydrospiro[indene-1,4′-piperidine]-1′-carboxylate (6.1 g, yield 99%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][NH:11][C:12]2[N:17]=[C:16]([NH2:18])[C:15]([N+:19]([O-:21])=[O:20])=[CH:14][CH:13]=2)[N:5]2[CH:22]=[C:23]([CH3:25])[N:24]=[C:4]2[CH:3]=1.[Cl:26][C:27]1[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:28]=1B(O)O>>[Cl:26][C:27]1[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:28]=1[C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][NH:11][C:12]2[N:17]=[C:16]([NH2:18])[C:15]([N+:19]([O-:21])=[O:20])=[CH:14][CH:13]=2)[N:5]2[CH:22]=[C:23]([CH3:25])[N:24]=[C:4]2[CH:3]=1
Reactant: OB(O)c1ccc(Cl)cc1Cl
Reactant: Cc1cn2c(NCCNc3ccc([N+](=O)[O-])c(N)n3)nc(Cl)cc2n1
Product: Cc1cn2c(NCCNc3ccc([N+](=O)[O-])c(N)n3)nc(-c3ccc(Cl)cc3Cl)cc2n1

Procedure:
In analogy to the procedure described for Example 7, 9.3 mg (13% of theory) of the product are obtained starting from 60 mg (0.15 mmol) of N6-{2-[(7-chloro-2-methylimidazo[1,2-c]pyrimidin-5-yl)amino]ethyl}-3-nitropyridine-2,6-diamine (Example 23A) by coupling with 29.3 mg (0.15 mmol) of (2,4-dichlorophenyl)boronic acid and subsequent purification by preparative HPLC.
Reaction SMILES: C(OC([N:8]1[C:13](=[O:14])[CH:12]2[CH:10]([CH:11]2[C:15]([O-:17])=[O:16])[CH:9]1[C:18]([O-:20])=[O:19])=O)(C)(C)C.[CH2:21]([NH2:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C1COCC1.[C-]#N.[K+]>[C:15]([CH:11]1[CH:12]([C:13]([NH:28][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:14])[CH:10]1[CH:9]([C:18]([OH:20])=[O:19])[NH2:8])([OH:17])=[O:16]
Reactant: CC(C)(C)OC(=O)N1C(=O)C2C(C(=O)[O-])C2C1C(=O)[O-]
Reactant: NCc1ccccc1
Agent: [C-]#N
Agent: [K+]
Solvent: C1CCOC1
Product: NC(C(=O)O)C1C(C(=O)O)C1C(=O)NCc1ccccc1
Reaction time: 8 h
Yield: 117.8 %

Procedure:
To a solution of ethyl (1SR, 2 SR, 5RS, 6RS) 3-tert-butoxycarbonyl-4-oxo-3-azabicyclo[3.1.0]hexane-2,6-dicarboxylate (307 mg, 0.9 mmol) in dry THF (7 mL) under argon was added benzylamine (590 μL, 5.4 mmol) and potassium cyanide (3 mg, 0.05 mmol). After stirring overnight in an ultrasonic bath, the solvent was removed under reduced pressure. The residue was directly purified by flash chromatography (hexane/ethyl acetate 3/1) to give 310 mg of the desired compound (80% yield).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:11]([O:20][CH3:21])=[CH:12][C:13]([O:18][CH3:19])=[C:14]([CH:17]=1)[CH:15]=O.[C:22]([C:25]1[CH:33]=[CH:32][C:28]([C:29]([OH:31])=[O:30])=[CH:27][CH:26]=1)(=[O:24])[CH3:23]>>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:11]([O:20][CH3:21])=[CH:12][C:13]([O:18][CH3:19])=[C:14](/[CH:15]=[CH:23]/[C:22]([C:25]2[CH:33]=[CH:32][C:28]([C:29]([OH:31])=[O:30])=[CH:27][CH:26]=2)=[O:24])[CH:17]=1
Reactant: CC(=O)c1ccc(C(=O)O)cc1
Reactant: COc1cc(OC)c(-c2nc3ccccc3[nH]2)cc1C=O
Product: COc1cc(OC)c(-c2nc3ccccc3[nH]2)cc1/C=C/C(=O)c1ccc(C(=O)O)cc1

Procedure:
The title compound was prepared by condensing 5-(1H-benzoimidazol-2-yl)-2,4-dimethoxy-benzaldehyde (Ex-70A) and 4-acetylbenzoic acid in a similar manner as described in Ex-3. Yellow solid, mp>240° C. (dec.). 1H-NMR (DMSO-d6) δ 8.72 (s, 1H), 12.10 (s, 1H), 8.18 (d, J=8.4 Hz, 2H), 8.08–8.02 (m, 3H), 7.80 (d, J=15.4 Hz, 1H), 7.59 (s, 2H), 7.17–7.13 (m, 2H), 6.89 (s, 1H), 4.10 (s, 3H), 4.03 (s, 3H). MS m/z=429 ([M+H]+, 100%).
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([CH2:7][O:8][CH2:9][CH:10]([OH:13])[CH2:11][OH:12])=[CH:3][CH:2]=1.[CH3:14][CH2:15][C:16](=O)[CH2:17][CH3:18].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])O.[Na+]>O1CCCC1>[CH2:7]([O:8][CH2:9][CH:10]1[CH2:11][O:12][C:16]([CH2:17][CH3:18])([CH2:15][CH3:14])[O:13]1)[C:4]1[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=1
Reactant: CCC(=O)CC
Reactant: OCC(O)COCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCC1(CC)OCC(COCc2ccccc2)O1
Reaction time: 22 h
Yield: 67.1 %

Procedure:
To a tetrahydrofuran (30 ml) solution of DL-α-O-benzyl glycerol (3 g, 16.5 mmol), 3-pentanone (17.5 ml, 165 mmol) and p-toluenesulfonic acid monohydrate (300 mg, 1.58 mmol) were added at room temperature and the mixture was stirred at the same temperature for 22 hours. To the reaction mixture, a saturated aqueous sodium hydrogen carbonate solution (5 ml) was added to adjust pH to about 8. The generated precipitate was removed by filtration and the filtrate was concentrated. The obtained residue was purified by silica gel column chromatography (NH silica gel, elution solvent: heptane/ethyl acetate=1/0 to 3/1 gradient). A desired fraction was concentrated to obtain the title compound (2.77 g, 67.1% yield) as a colorless oil.
Reaction SMILES: C1OCCOCCOCCOCCOCCOC1.C1C=CC=CC=1.Cl[CH2:26][N:27]1[C:37](=[O:38])[C:36]2[C:31](=[CH:32][C:33]([O:42][CH3:43])=[CH:34][C:35]=2[CH:39]([CH3:41])[CH3:40])[S:28]1(=[O:30])=[O:29].[N-:44]=[N+:45]=[N-:46].[Na+]>O>[N:44]([CH2:26][N:27]1[C:37](=[O:38])[C:36]2[C:31](=[CH:32][C:33]([O:42][CH3:43])=[CH:34][C:35]=2[CH:39]([CH3:41])[CH3:40])[S:28]1(=[O:30])=[O:29])=[N+:45]=[N-:46]
Reactant: COc1cc(C(C)C)c2c(c1)S(=O)(=O)N(CCl)C2=O
Reactant: [N-]=[N+]=[N-]
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [Na+]
Solvent: O
Solvent: c1ccccc1
Product: COc1cc(C(C)C)c2c(c1)S(=O)(=O)N(CN=[N+]=[N-])C2=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 26 %

Procedure:
A solution of 18-crown-6 ether (0.60 g) and benzene (60 mL) was heated under reflux with a water separator for 1 hour, then cooled to room temperature. 2-Chloromethyl-4-isopropyl-6-methoxysaccharin (3.03 g) and sodium azide (0.65 g) were added, and the mixture was stirred for a week at room temperature, then chromatographed on a column of silica gel (silica gel 60, 83 g) using benzene as eluant. The fractions containing the product, which were identified by thin layer chromatography, were combined and concentrated affording 2-azidomethyl-4-isopropyl-6-methoxysaccharin as a solution in benzene (250 mL).
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[S:15][C:14]([CH2:16]O)=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].C(N(CC)CC)C.S(Cl)([Cl:27])=O>C(Cl)Cl>[Cl:27][CH2:16][C:14]1[S:15][C:11]([C:8]2[CH:9]=[CH:10][C:5]([CH2:1][CH2:2][CH2:3][CH3:4])=[CH:6][CH:7]=2)=[CH:12][CH:13]=1
Reactant: CCCCc1ccc(-c2ccc(CO)s2)cc1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCc1ccc(-c2ccc(CCl)s2)cc1
Reaction time: 8 h

Procedure:
To a solution of 60.4 (40 mg, 0.16 mmol) in DCM (0.8 mL) were added triethylamine (23 μL, 0.16 mmol) and thionyl chloride (18 μL, 0.24 mmol) at room temperature. The mixture was stirred overnight and concentrated to afford 60.5. The crude product was used without further purification.
Reaction SMILES: [C:1]([O:11][CH3:12])(=[O:10])[CH2:2][C:3]#[C:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[H][H]>S([O-])([O-])(=O)=O.[Ba+2].[Pd+2].S([O-])([O-])(=O)=O.N1C=CC=CC=1>[C:1]([O:11][CH3:12])(=[O:10])[CH2:2][CH:3]=[CH:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: [H][H]
Reactant: CCCCCC#CCC(=O)OC
Agent: [Pd+2]
Agent: O=S(=O)([O-])[O-]
Agent: [Ba+2]
Solvent: c1ccncc1
Product: CCCCCC=CCC(=O)OC

Procedure:
A mixture of 5 g. of 1-bromo-2-octyne, 7 g. of potassium cyanide and 35 ml. of dimethylsulfoxide is stirred and heated under nitrogen for about 2.5 hrs. at reflux temperature. The mixture is then poured into water and extracted with ether. The ether extract is washed with water, than with saturated aqueous sodium chloride, dried over sodium sulfate, and evaporated under reduced pressure leaving a residue comprising 3-nonynenitrile. The thus obtained residue is mixed with 45 ml. of 25% hydrogen chloride in methanol containing 0.5 ml. of water while cooling in an ice bath. The ice is allowed to melt and the mixture is stirred for about 18 hrs., then is poured into water and extracted with ether. The ether extract is washed with water, aqueous sodium bicarbonate, and saturated aqueous sodium chloride, dried over sulfate, and evaporated under reduced pressure leaving a residue comprising methyl 3-nonynoate. A mixture of the thus obtained methyl 3-nonynoate, 500 mg. of 5% palladium-barium sulfate catalyst and 40 ml. of pyridine is shaken under hydrogen for about 2 hrs., until the uptake of hydrogen practically ceases. The mixture is then filtered, diluted with water, and extracted with ether. The ether extract is washed with water, dilute hydrochloric acid, and aqueous sodium bicarbonate, then is dried over sodium sulfate and evaporated to leave a residue comprising methyl 3-nonenoate.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:6]([N:13]1[C:21]2[C:16](=[CH:17][C:18]([NH:22][C:23]3[C:24]4[CH:32]=[C:31](Cl)[N:30]=[CH:29][C:25]=4[N:26]=[CH:27][N:28]=3)=[CH:19][CH:20]=2)[CH:15]=[N:14]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>>[CH2:6]([N:13]1[C:21]2[C:16](=[CH:17][C:18]([NH:22][C:23]3[C:24]4[CH:32]=[C:31]([N:1]5[CH2:5][CH2:4][CH2:3][CH2:2]5)[N:30]=[CH:29][C:25]=4[N:26]=[CH:27][N:28]=3)=[CH:19][CH:20]=2)[CH:15]=[N:14]1)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: Clc1cc2c(Nc3ccc4c(cnn4Cc4ccccc4)c3)ncnc2cn1
Reactant: C1CCNC1
Product: c1ccc(Cn2ncc3cc(Nc4ncnc5cnc(N6CCCC6)cc45)ccc32)cc1
Reaction time: 18 h

Procedure:
Pyrrolidine (2 ml) was reacted with (1-Benzyl-1H-indazol-5-yl)-(6-chloro-pyrido[3,4-d]pyrimidin-4-yl)-amine (0.4 g) in a reacti-vial at 100° C. (Procedure C). After 18 hours, the cooled mixture was poured onto water and the precipitate washed with hot ether and crystallised from acetone to give the title compound; δH [2H6]DMSO 10.53(1H,s), 9.75(1H,s), 8.79(1H,s), 8.30(1H,s), 8.23(1H,s), 8.14(1H,s), 7.70(2H,m), 7.28(5H,m), 7.14(1H,s), 5.68(2H,s) 3.50(4H,m), 2.02(4H,m); m/z (M+) 422.