Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:20])[C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)=[CH:4][C:3]=1[C:21]1[C:30](=[O:31])[N:29]([CH3:32])[C:28]2[N:27]=[C:26](Cl)[N:25]=[CH:24][C:23]=2[N:22]=1.[CH3:34][NH2:35].C1COCC1>CS(C)=O>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:20])[C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[CH:11]=2)=[CH:4][C:3]=1[C:21]1[C:30](=[O:31])[N:29]([CH3:32])[C:28]2[N:27]=[C:26]([NH:35][CH3:34])[N:25]=[CH:24][C:23]=2[N:22]=1
Reactant: Cc1ccc(NC(=O)c2cccc(C(F)(F)F)c2)cc1-c1nc2cnc(Cl)nc2n(C)c1=O
Reactant: CN
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: CNc1ncc2nc(-c3cc(NC(=O)c4cccc(C(F)(F)F)c4)ccc3C)c(=O)n(C)c2n1

Procedure:
A Smith vial (2-5 mL) is charged with N-[4-methyl-3-(2-chloro-8-methyl-7-oxo-7,8-dihydropteridin-6-yl)-pheny]-3-trifluoromethyl-benzamide (15 mg, 0.032 mmol), 2M methylamine solution in THF (160 μL, 0.32 mmol), and DMSO (0.5 mL). After purging with Argon, the vial is sealed and irradiated at 100° C. for 45 minutes in a Smith Synthesizer. The resulting solution is subjected to purification by reverse-phase LC-MS to yield the title compound; 1H NMR 400 MHz (DMSO-d6) δ 10.51 (s, 1H), 8.68 (s, 1H), 8.31 (s, 1H), 8.26 (d, J=8.0 Hz, 1H), 8.02 (bs, 1H), 7.96 (d, J=7.2 Hz, 1H), 7.80-7.76 (m, 3H), 7.27 (d, J=8.2 Hz, 1H), 3.56 (s, 3H), 2.94 (s, 3H), 2.19 (s, 3H); MS m/z 469.3 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:22]=[CH:21][C:5]2[N:6]([CH2:9][C:10]3[CH:20]=[CH:19][C:13]4[N:14]=[C:15]([S:17][CH3:18])[S:16][C:12]=4[CH:11]=3)[CH:7]=[N:8][C:4]=2[CH:3]=1.ClC1C=CC=C(C(OO)=[O:31])C=1>C(Cl)Cl.CCOC(C)=O>[CH3:1][C:2]1[CH:22]=[CH:21][C:5]2[N:6]([CH2:9][C:10]3[CH:20]=[CH:19][C:13]4[N:14]=[C:15]([S:17]([CH3:18])=[O:31])[S:16][C:12]=4[CH:11]=3)[CH:7]=[N:8][C:4]=2[CH:3]=1
Reactant: CSc1nc2ccc(Cn3cnc4cc(C)ccc43)cc2s1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Cc1ccc2c(c1)ncn2Cc1ccc2nc(S(C)=O)sc2c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 106.3 %

Procedure:
To a stirred solution of 6-((5-methyl-1H-benzo[d]imidazol-1-yl)methyl)-2-(methylthio)benzo[d]thiazole (0.61 g, 1.8 mmol) from the previous step in DCM (20 mL) at 0° C. was added a solution of meta-chloroperbenzoic acid (0.40 g, 1.57 mmol) in DCM (3 mL). After stirring for 2 h at 0° C., the solution was diluted with EtOAc (100 mL) and washed sequentially with saturated aq Na2S2O3, saturated aq NaHCO3, and brine. The organic layer was separated, dried over Na2SO4, filtered, and concentrated under reduced pressure to afford 6-((5-methyl-1H-benzo[d]imidazol-1-yl)methyl)-2-(methylsulfinyl)benzo[d]thiazole (0.57 g, 89%) as a yellow solid which was not purified further.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([CH3:21])[C:5]2[C:11](=S)[NH:10][C@@H:9]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=3[Br:20])[CH2:8][C:6]=2[N:7]=1.[NH2:22][O:23][C@H:24]1[CH2:28][N:27]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[C@H:26]([C:36]([O:38][CH3:39])=[O:37])[CH2:25]1>[Hg](OC(C)=O)OC(C)=O.C1(C)C=CC=CC=1>[NH2:1][C:2]1[N:3]=[C:4]([CH3:21])[C:5]2=[C:6]([CH2:8][C@H:9]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=3[Br:20])[NH:10]/[C:11]/2=[N:22]\[O:23][C@H:24]2[CH2:28][N:27]([C:29]([O:31][C:32]([CH3:33])([CH3:34])[CH3:35])=[O:30])[C@H:26]([C:36]([O:38][CH3:39])=[O:37])[CH2:25]2)[N:7]=1
Reactant: COC(=O)[C@@H]1C[C@@H](ON)CN1C(=O)OC(C)(C)C
Reactant: Cc1nc(N)nc2c1C(=S)N[C@@H](c1ccc(F)cc1Br)C2
Agent: CC(=O)O[Hg]OC(C)=O
Solvent: Cc1ccccc1
Product: COC(=O)[C@@H]1C[C@@H](O/N=C2\N[C@@H](c3ccc(F)cc3Br)Cc3nc(N)nc(C)c32)CN1C(=O)OC(C)(C)C
Temperature: 100 °C
Yield: 72.5 %

Procedure:
A mixture of (R)-2-amino-7-(2-bromo-4-fluorophenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidine-5(6H)-thione (150 mg, 0.4 mmol), (2S,4R)-1-tert-butyl 2-methyl 4-(aminooxy)pyrrolidine-1,2-dicarboxylate (416 mg, 1.6 mmol), Hg(OAc)2 (256 mg, 0.8 mmol) and toluene (2 mL) was heated at 100° C. for 2 h. Cooled to rt, filtered through celite and purified to afford (2S,4R)-1-tert-butyl 2-methyl 4-((Z)—((R)-2-amino-7-(2-bromo-4-fluorophenyl)-4-methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-ylidene)aminooxy)pyrrolidine-1,2-dicarboxylate (172 mg, 570%) as off white solid. MS (ES) [M+H] calculated for C25H3iBrFN6O5, 593.14; found 593.10.
Reaction SMILES: [C:1]([C:3]1[CH:4]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([N+:34]([O-:36])=[O:35])[CH:29]=2)[C:5]2[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][C:16]([OH:27])=[C:17]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:18]=3)[C:6]=2[O:7][C:8]=1[N:9]1[CH:13]=[CH:12][CH:11]=[CH:10]1)#[N:2].[C:37](=O)([O-])[O-].[K+].[K+].CI.O>CN(C=O)C>[C:1]([C:3]1[CH:4]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([N+:34]([O-:36])=[O:35])[CH:29]=2)[C:5]2[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][C:16]([O:27][CH3:37])=[C:17]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:18]=3)[C:6]=2[O:7][C:8]=1[N:9]1[CH:10]=[CH:11][CH:12]=[CH:13]1)#[N:2]
Reactant: CCOC(=O)c1cc2ccc3c(c2cc1O)OC(n1cccc1)=C(C#N)C3c1cccc([N+](=O)[O-])c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CI
Product: CCOC(=O)c1cc2ccc3c(c2cc1OC)OC(n1cccc1)=C(C#N)C3c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Ethyl 3-cyano-9-hydroxy-4-(3-nitrophenyl)-2-(1-pyrrolyl)-4H-naphtho[1,2-b]pyran-8-carboxylate (4 g) was dissolved in dry DMF (50 ml). Solid potassium carbonate (2.3 g) and methyl iodide (1.05 ml) were added and the mixture stirred at room temperature for 16 hours. The solution was poured into water (400 ml) and extracted with ethyl acetate (4×200 ml). The combined organic extracts were washed with water (3×250 ml), dried over magnesium suphate, then solvent was removed under reduced pressure to yield a brown solid. This was triturated with ether (10 ml), the solid collected by filtration and dried to yield ethyl 3-cyano-9-methoxy-4-(3-nitrophenyl)-2-(1-pyrrolyl)-4H-naphtho[1,2-b]pyran-8-carboxylate as a dark yellow solid, m.p. 190°-191° C.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:27][C@@H:28](O)[CH2:29][C@H:30]([OH:32])[CH3:31].COCCOC(N=NC(OCCOC)=O)=O>C1COCC1.O>[O:7]([C@@H:28]([CH3:27])[CH2:29][C@H:30]([OH:32])[CH3:31])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C[C@@H](O)C[C@@H](C)O
Agent: COCCOC(=O)N=NC(=O)OCCOC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Oc1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: C[C@@H](O)C[C@H](C)Oc1ccccc1
Reaction time: 21 h

Procedure:
After phenol (300 mg, 3.19 mmol), triphenylphosphine (1008 mg, 3.83 mmol), (2R,4R)-2,4-pentanediol (399 mg, 3.83 mmol), and THF (12 ml) were added to a 50 ml flask, azodicarboxylic acid bis(2-methoxyethyl) ester (896 mg, 3.83 mmol) dissolved in THF (6 mL) was added dropwise thereto at 20° C., and the reaction was allowed to proceed for 21 hours. Water (0.5 ml) was added, and concentration was carried out. Then, water (10 ml) was added to the solution, and extraction was carried out using diethyl ether (10 ml,×2). Then, the organic layer was washed with water (10 ml) and saturated salt water (10 ml), and dehumidified with anhydrous magnesium sulfate. Subsequently, a crude product obtained by concentration was purified by column chromatography (silica gel, 40% ethyl acetate-hexane solution) to give (4S,2R)-4-phenoxypentane-2-ol as a colorless oily substance (481 mg, yield: 84%/phenol).
Reaction SMILES: C(OC([CH:8]1[NH:13][CH2:12][C:11]2[O:14][C:15]([C:17]([N:19]3[CH2:24][CH2:23][N:22]([S:25]([C:28]4[NH:29][C:30]5[C:35]([CH:36]=4)=[CH:34][C:33]([Cl:37])=[CH:32][CH:31]=5)(=[O:27])=[O:26])[CH2:21][CH:20]3[CH2:38][CH3:39])=[O:18])=[N:16][C:10]=2[CH2:9]1)=O)(C)(C)C.[F:40][C:41]([F:46])([F:45])[C:42]([OH:44])=[O:43]>C(Cl)Cl>[F:40][C:41]([F:46])([F:45])[C:42]([OH:44])=[O:43].[Cl:37][C:33]1[CH:34]=[C:35]2[C:30](=[CH:31][CH:32]=1)[NH:29][C:28]([S:25]([N:22]1[CH2:23][CH2:24][N:19]([C:17]([C:15]3[O:14][C:11]4[CH2:12][NH:13][CH2:8][CH2:9][C:10]=4[N:16]=3)=[O:18])[CH:20]([CH2:38][CH3:39])[CH2:21]1)(=[O:27])=[O:26])=[CH:36]2
Reactant: CCC1CN(S(=O)(=O)c2cc3cc(Cl)ccc3[nH]2)CCN1C(=O)c1nc2c(o1)CNC(C(=O)OC(C)(C)C)C2
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCC1CN(S(=O)(=O)c2cc3cc(Cl)ccc3[nH]2)CCN1C(=O)c1nc2c(o1)CNCC2
Reaction time: 0.17 h

Procedure:
To a solution of 1-[[6-(tert-butoxycarbonyl)-4,5,6,7-tetrahydrooxazolo[5,4-c]pyridin-2-yl]carbonyl]-4-[(5-chloroindol-2-yl)sulfonyl]-2-ethylpiperazine (320 mg) in methylene chloride (5.0 ml) was added trifluoroacetic acid (5.0 ml) at room temperature, followed by stirring for 10 minutes. The reaction mixture was concentrated under reduced pressure, whereby the title compound (423 mg) was obtained as a pale brown solid.
Reaction SMILES: C(N(CC)C(C)C)(C)C.[CH2:10]([O:17][C:18]([NH:20][C:21](=[N:24][C:25](=O)[C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=1)SC)=[O:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(O)(=O)C(O)=O.[CH2:41]([NH:43][NH2:44])[CH3:42].CCOCC>CN(C=O)C>[CH2:10]([O:17][C:18](=[O:19])[NH:20][C:21]1[N:24]=[C:25]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=2)[N:43]([CH2:41][CH3:42])[N:44]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CCNN
Reactant: COc1ccc(C(=O)N=C(NC(=O)OCc2ccccc2)SC)cc1
Agent: O=C(O)C(=O)O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCn1nc(NC(=O)OCc2ccccc2)nc1-c1ccc(OC)cc1
Temperature: 50 °C
Yield: 92.4 %

Procedure:
N,N-diisoproylethylamine (9.9 g, 76.8 mmol) is added to a solution of 1-benzyloxycarbonyl-3-(4-methoxy-benzoyl)-2-methyl-isothiourea (11.0 g, 30.7 mmol) and ethyl hydrazine oxalate (11.6 g, 76.8 mmol) in DMF (110.0 mL) and the reaction mixture is heated at 50° C. for 12 h. Ice and ether are added to the reaction mixture and the two phases are separated. The organic phase is dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford 10 g of [1-ethyl-5-(4-methoxy-phenyl)-1H-1,2,4-triazol-3-yl]-carbamic acid benzyl ester that is used in the next step without further purification. m/z 353 [M+H].
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[CH2:18][N:6]2[C:7](=[O:17])[CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=3)[N:10]=[C:5]2[NH:4][CH2:3]1.[H-].[Na+].[N:22]1[C:30]2[CH2:29][CH:28]([CH2:31]OS(C)(=O)=O)[CH2:27][C:26]=2[CH:25]=[CH:24][CH:23]=1.O>CN(C)C=O.C(Cl)Cl>[N:22]1[C:30]2[CH2:29][C@H:28]([CH2:31][N:4]3[C:5]4=[N:10][C:9]([C:11]5[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=5)=[CH:8][C:7](=[O:17])[N:6]4[CH2:18][C:2]([CH3:19])([CH3:1])[CH2:3]3)[CH2:27][C:26]=2[CH:25]=[CH:24][CH:23]=1
Reactant: CS(=O)(=O)OCC1Cc2cccnc2C1
Reactant: CC1(C)CNc2nc(-c3ccncc3)cc(=O)n2C1
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: O
Product: CC1(C)CN(C[C@@H]2Cc3cccnc3C2)c2nc(-c3ccncc3)cc(=O)n2C1
Reaction time: 0.67 h

Procedure:
A suspension of 0.51 g (2 mmol) of 7,7-dimethyl-2-(pyridin-4-yl)-6,7,8,9-tetrahydro-4H-pyrimido[1,2-a]pyrimidin-4-one in 10 ml of anhydrous dimethylformamide was treated with 96 mg (2 mmol) of sodium hydride (50% suspension in mineral oil) and the resulting mixture was stirred for 40 min. 0.455 g (2 mmol) of methanesulfonic acid 6,7-dihydro-5H-[1]pyrindin-6-ylmethyl ester in 2 ml of anhydrous dimethylformamide was added and the reaction mixture stirred at room temperature for 18 h. The solution was treated with water and extracted with ethyl acetate. The organic phase was dried and evaporated to give crude product, which was purified by silica gel chromatography, eluting with ethyl acetate/methanol/diethyl amine in the proportions 98/2/0.2 to give 0.3839 of pure product obtained in the form of free base. Mp: 182-184° C. [α]D20=+9.15° (c=0.5, CH2Cl2).
Reaction SMILES: [CH3:1][S:2][C:3]1[O:7][C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH2:14][S:15]([NH2:18])(=[O:17])=[O:16])=[N:5][N:4]=1.C1([O:25][C:26](=O)[NH:27][C:28]2[N:33]=[C:32]([O:34][CH3:35])[CH:31]=[C:30]([O:36][CH3:37])[N:29]=2)C=CC=CC=1.CCCCC=CCCCCC.Cl>O1CCOCC1.O>[CH3:35][O:34][C:32]1[CH:31]=[C:30]([O:36][CH3:37])[N:29]=[C:28]([NH:27][C:26]([NH:18][S:15]([CH2:14][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[C:6]2[O:7][C:3]([S:2][CH3:1])=[N:4][N:5]=2)(=[O:17])=[O:16])=[O:25])[N:33]=1
Reactant: COc1cc(OC)nc(NC(=O)Oc2ccccc2)n1
Reactant: CSc1nnc(-c2ccccc2CS(N)(=O)=O)o1
Agent: CCCCC=CCCCCC
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: COc1cc(OC)nc(NC(=O)NS(=O)(=O)Cc2ccccc2-c2nnc(SC)o2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 25.7 %

Procedure:
To a solution containing 0.62 g of the sulfonamide prepared in Example 3 contained in 10 ml of p-dioxane was added 0.6 g of phenyl(4.6-dimethoxy pyrimidin-2-yl)carbamate followed by dropwise addition of 0.33 g of 1,5-diazbicyclo[5.4.0]undec-5-ene (DBU). The solution was stirred at room temperature for two hours then diluted with about 100 ml of water. The clear solution was acidified with concentrated hydrochloric acid (red to litmus paper), to give a viscous oil. The oil was triturated by decanting off the aqueous solvent and stirring the oil residue in about 5 ml of acetonitrile. After filtering the suspension, the solid residue was washed with 1×5 ml of warm ethyl acetate to give 0.26 g of the subject compound; m.p. 174°-177° C.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH2:9][O:10][CH2:11][C@:12]([C:17]2[CH:22]=[C:21]([NH2:23])[CH:20]=[CH:19][C:18]=2[F:24])([CH:14]([F:16])[F:15])[N:13]=1)(C)(C)C.[Br:26][C:27]1[CH:28]=[N:29][C:30]2[C:35]([CH:36]=1)=[CH:34][CH:33]=[N:32][C:31]=2Cl.C([O-])(O)=O.[Na+]>C(O)(C)(C)C.Cl.O1CCOCC1>[NH2:7][C:8]1[CH2:9][O:10][CH2:11][C@:12]([C:17]2[CH:22]=[C:21]([NH:23][C:31]3[N:32]=[CH:33][CH:34]=[C:35]4[C:30]=3[N:29]=[CH:28][C:27]([Br:26])=[CH:36]4)[CH:20]=[CH:19][C:18]=2[F:24])([CH:14]([F:15])[F:16])[N:13]=1
Reactant: CC(C)(C)OC(=O)NC1=N[C@@](c2cc(N)ccc2F)(C(F)F)COC1
Reactant: Clc1nccc2cc(Br)cnc12
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: C1COCCO1
Product: NC1=N[C@@](c2cc(Nc3nccc4cc(Br)cnc34)ccc2F)(C(F)F)COC1
Temperature: 100 °C
Reaction time: 0.17 h

Procedure:
[(R)-5-(5-Amino-2-fluoro-phenyl)-5-difluoromethyl-5,6-dihydro-2H-[1,4]oxazin-3-yl]carbamic acid tert-butyl ester (CAS registry 1262859-09-5) (250 mg, 0.696 mmol) and 3-bromo-8-chloro-[1,7]naphthyridine [Heteroaryl 1] (186 mg, 0.765 mmol) were dissolved in tert-Butanol (4 ml) in a microwave vial and HCl (0.174 ml of a 4M solution in dioxane) was added. The vial was sealed and heated to 100° C. for 1 h. The reaction mixture was cooled to rt and added to a saturated NaHCO3 solution (20 ml) and stirred at rt for 10 min.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4](S(O)(=O)=O)=C[CH:2]=1.[O:12]1[CH2:17][CH2:16]OCC1.[OH2:18]>>[OH:12][CH:17]1[CH2:16][C:11](=[O:18])[C:1]([CH2:6][C:5]#[CH:4])=[CH:2]1
Reactant: O
Reactant: C1COCCO1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Product: C#CCC1=CC(O)CC1=O

Procedure:
To a solution of 40.2 g (0.295 mole) of the title compound of Example 1 in 800 ml of a 8:1 dioxane/water mixture was added 4 g (0.21 mole) of p-toluenesulfonic acid. The reaction mixture was heated at 83° for 36 hours under argon, cooled, and diluted with 500 ml of ethyl acetate. The organic phase was washed once with water and two times each with 5% sodium bicarbonate solution and brine solution. The aqueous washes were combined and extracted with ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered, and concentrated. Chromatography of the combined crude materials on silica gel (using 25% ethyl acetate in hexane as eluent) gave 12.45 g of the intermediate compound 4-hydroxy-5-(2-propynyl)-2-cyclopenten-1-one as a viscous oil. Structure assignment was confirmed by the proton nmr spectrum.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]1[CH:15]=[C:14]([C:16]2[C:20]3=[N:21][CH:22]=[CH:23][CH:24]=[C:19]3[N:18]([CH2:25][CH3:26])[N:17]=2)[CH:13]=[CH:12][C:11]1=[O:27].CI.[C:30]([O-])([O-])=O.[Cs+].[Cs+].O>CN(C=O)C>[CH2:25]([N:18]1[C:19]2[C:20](=[N:21][CH:22]=[CH:23][CH:24]=2)[C:16]([C:14]2[CH:13]=[CH:12][C:11](=[O:27])[N:10]([C:2]3[N:1]([CH3:30])[C:5]4[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=4[N:3]=3)[CH:15]=2)=[N:17]1)[CH3:26]
Reactant: O=C([O-])[O-]
Reactant: CCn1nc(-c2ccc(=O)n(-c3nc4ccccc4[nH]3)c2)c2ncccc21
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CI
Product: CCn1nc(-c2ccc(=O)n(-c3nc4ccccc4n3C)c2)c2ncccc21
Temperature: 25 °C
Reaction time: 12 h
Yield: 57.7 %

Procedure:
A mixture of 1-(1H-benzimidazol-2-yl)-5-(1-ethyl-1H-pyrazolo[4,3-b]pyridin-3-yl)pyridin-2(1H)-one (20 mg), MeI (11.95 mg) and Cs2CO3 (36.6 mg) in DMF (1 mL) was stirred at room temperature for 12 h, treated with water, and extracted with AcOEt. The organic layer was dried over MgSO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (AcOEt/hexane) and crystallized from hexane/AcOEt to give the title compound (12 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:33]=[CH:34][CH:35]=1)[C:5](=[O:32])[CH2:6][CH2:7][NH:8][C:9]1[C:17]2[C:12](=[CH:13][C:14]([Cl:19])=[CH:15][C:16]=2[Cl:18])[N:11](C(OC(C)(C)C)=O)[C:10]=1[C:27]([O:29][CH2:30][CH3:31])=[O:28].FC(F)(F)C(O)=O>C(Cl)Cl.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:33]=[CH:34][CH:35]=1)[C:5](=[O:32])[CH2:6][CH2:7][NH:8][C:9]1[C:17]2[C:12](=[CH:13][C:14]([Cl:19])=[CH:15][C:16]=2[Cl:18])[NH:11][C:10]=1[C:27]([O:29][CH2:30][CH3:31])=[O:28]
Reactant: CCOC(=O)c1c(NCCC(=O)c2cccc(F)c2)c2c(Cl)cc(Cl)cc2n1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCOC(=O)c1[nH]c2cc(Cl)cc(Cl)c2c1NCCC(=O)c1cccc(F)c1

Procedure:
Dissolve 3-[(m-fluorophenacyl)methylamino]-2-carbethoxy-4,6-dichloro-1-(tert-butyloxycarbonyl)-indole from above in methylene chloride (5 mL). Add trifluoracetic acid (3 mL) and stir for 5 hours. Concentrate the reaction in vacuo, dilute with ethyl acetate (100 mL), wash with saturated sodium carbonate, dry over magnesium sulfate, filter and concentrate in vacuo. Recrystallize the residue from ethyl acetate/hexane to yield the title compound (760 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:32]=[CH:33][CH:34]=1)[CH2:5][C@@H:6]([C:23]([NH:25][C:26](=[O:31])[C@H:27]([CH2:29][SH:30])[NH2:28])=[O:24])[NH:7][C:8](=[O:22])[CH:9]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.Br[CH2:36][C:37]1[CH:38]=[C:39]([CH:44]=[CH:45][CH:46]=1)[C:40]([O:42][CH3:43])=[O:41].C(N(C(C)C)CC)(C)C>>[CH3:1][C:2]1[CH:3]=[C:4]([CH:32]=[CH:33][CH:34]=1)[CH2:5][C@@H:6]([C:23]([NH:25][C:26](=[O:31])[C@H:27]([CH2:29][S:30][CH2:36][C:37]1[CH:46]=[CH:45][CH:44]=[C:39]([C:40]([O:42][CH3:43])=[O:41])[CH:38]=1)[NH2:28])=[O:24])[NH:7][C:8](=[O:22])[CH:9]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: COC(=O)c1cccc(CBr)c1
Reactant: Cc1cccc(C[C@H](NC(=O)C(c2ccccc2)c2ccccc2)C(=O)NC(=O)[C@@H](N)CS)c1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cccc(CSC[C@H](N)C(=O)NC(=O)[C@H](Cc2cccc(C)c2)NC(=O)C(c2ccccc2)c2ccccc2)c1

Procedure:
A solution of N-[3-methyl-N-(2,2-diphenylacetyl)-L-phenylalanyl]-L-cysteinamide (0.72 g, 1.51 mmol), methyl 3-(bromomethyl)-benzoate (0.35 g, 1.51 mmol), and diisopropylethylamine (0.27 mL, 1.53 mmol) is stirred at room temperature overnight. Solvent is evaporated, and the residue is treated with 1 N HCl (50 mL), and filtered to collect a white solid, which is washed with water and Et2O (100 mL each). Drying in vacuo yields N-[3-methyl-N-(2,2-diphenylacetyl)-L-phenylalanyl]-S-[[3-(methoxycarbonyl)phenyl]methyl]-L-cysteinamide, as a white solid.
Reaction SMILES: [NH:1]1[C:5]([NH2:6])=[N:4][C:3]([NH2:7])=[N:2]1.O=[C:9]([CH3:15])[CH2:10][C:11]([O:13][CH3:14])=[O:12].[Cl:16][C:17]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:18]=1[CH:19]=O.N1CCCCC1>C1COCC1.CCCCCCC>[NH2:6][C:5]1[N:4]=[C:3]2[NH:7][C:9]([CH3:15])=[C:10]([C:11]([O:13][CH3:14])=[O:12])[CH:19]([C:18]3[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:17]=3[Cl:16])[N:2]2[N:1]=1
Reactant: O=Cc1ccc(Cl)cc1Cl
Reactant: COC(=O)CC(C)=O
Reactant: Nc1n[nH]c(N)n1
Solvent: CCCCCCC
Solvent: C1CCNCC1
Solvent: C1CCOC1
Product: COC(=O)C1=C(C)Nc2nc(N)nn2C1c1ccc(Cl)cc1Cl
Temperature: 70 °C

Procedure:
To a stirred solution of 1H-1,2,4-triazole-3,5-diamine (1.0 g, 10.1 mmol), methyl 3-oxobutanoate (1.17 g, 10.1 mmol), and 2,4-dichlorobenzaldehyde (1.35 g, 10.1 mmol) in THF (30 mL) and heptane (8 mL) was added piperidine (30 mg, 0.3 mmol) and the reaction was heated to 70° C. for 2 days. The reaction was concentrated to afford crude methyl 2-amino-7-(2,4-dichlorophenyl)-5-methyl-4,7-dihydro-[1,2,4]-triazolo[1,5-a]pyrimidine-6-carboxylate as a light yellow solid.
Reaction SMILES: CC([O-])(C)C.[K+].[NH:7]1[C:15]2[C:10](=[N:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[N:8]1.[CH3:16][Si:17]([CH2:20][CH2:21][O:22][CH2:23]Cl)([CH3:19])[CH3:18]>C1COCC1.CCOC(C)=O.O>[CH3:16][Si:17]([CH3:19])([CH3:18])[CH2:20][CH2:21][O:22][CH2:23][N:7]1[C:15]2[C:10](=[N:11][CH:12]=[CH:13][CH:14]=2)[CH:9]=[N:8]1
Reactant: c1cnc2cn[nH]c2c1
Reactant: C[Si](C)(C)CCOCCl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: C[Si](C)(C)CCOCn1ncc2ncccc21
Temperature: 0 °C
Reaction time: 1 h

Procedure:
KOtBu (2.38 g, 21.24 mmol) was added to a solution of 1H-pyrazolo[4,3-b]pyridine (2.3 g, 19.3 mmol) in THF (60 mL) at 0° C. After stirring at 0° C. for 1 hr, trimethylsilylethoxymethyl chloride (3.54 g, 21.24 mmol) was added. The reaction mixture was kept at 0° C. for 1 hr with stirring, then 1.5 hr at rt. The mixture was diluted with EtOAc and water and extracted with EtOAc. The combined organic phases were washed with brine, dried with Na2SO4, and concentrated. The crude product was purified by flash chromatography to afford 1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-pyrazolo[4,3-b]pyridine in (2.32 g, 48%) and the regio-isomer.
Reaction SMILES: C[Si]([C:5]#[C:6][C:7]1[CH:12]=[C:11]([O:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH2:23]C)[C:10]([C:25]#[C:26][Si](C)(C)C)=[CH:9][C:8]=1[O:31][CH2:32][CH2:33][O:34][CH2:35][CH2:36][O:37][CH2:38][CH2:39][O:40][CH2:41]C)(C)C.[OH-].[Na+].O>C1COCC1.CO>[C:25]([C:10]1[CH:9]=[C:8]([O:31][CH2:32][CH2:33][O:34][CH2:35][CH2:36][O:37][CH2:38][CH2:39][O:40][CH3:41])[C:7]([C:6]#[CH:5])=[CH:12][C:11]=1[O:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH2:20][CH2:21][O:22][CH3:23])#[CH:26]
Reactant: CCOCCOCCOCCOc1cc(C#C[Si](C)(C)C)c(OCCOCCOCCOCC)cc1C#C[Si](C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: C#Cc1cc(OCCOCCOCCOC)c(C#C)cc1OCCOCCOCCOC

Procedure:
1,4-bis[(trimethylsilyl)ethynyl]-2,5-bis[2-[2-(2-ethoxyethoxy)ethoxy]ethoxy]benzene (0.595 g, 1 mmol) was dissolved in 20 mL of THF and 10 mL of methanol. To the solution, 8 mL of 1M NaOH(aq) was added and refluxed for 2 hours. Water was added to the mixture and extracted with ether. The organic layer was washed with water several times, and then dried with Na2SO4. Solvent was removed by rotary evaporation to give 1,4-diethynyl-2,5-bis[2-[2-(2-methoxyethoxy)ethoxy]ethoxy]benzene (3), shown in FIG. 2, as a reddish solid. 1H NMR (300 MHz, CDCl3): d 3.32 (s, 2H), 3.36 (s, 6H), 3.53 (m, 4H), 3.65 (m, 8H), 3.75 (m, 4H), 3.85 (m, 4H), 4.13 (m, 4H), 6.98 (s, 2H). 13C NMR (75 MHz, CDCl3): d 59.46, 69.96, 70.03, 71.00, 71.15, 71.50, 72.39, 80.00, 83.22, 114.02, 118.75, 154.49.