Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(OC)(O[CH3:5])(=O)=O.[C:8]1([C:14]2([CH2:27][O:28][CH2:29][C:30]3[CH:31]=[C:32]([C:39]([F:42])([F:41])[F:40])[CH:33]=[C:34]4[C:38]=3[NH:37][CH:36]=[CH:35]4)[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.CC(C)([O-])C.[K+]>O1CCCC1>[CH3:5][N:37]1[C:38]2[C:34](=[CH:33][C:32]([C:39]([F:41])([F:42])[F:40])=[CH:31][C:30]=2[CH2:29][O:28][CH2:27][C:14]2([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:25])([CH3:26])[CH3:24])=[O:21])[CH2:18][CH2:19]2)[CH:35]=[CH:36]1
Reactant: CC(C)(C)OC(=O)N1CCC(COCc2cc(C(F)(F)F)cc3cc[nH]c23)(c2ccccc2)CC1
Reactant: COS(=O)(=O)OC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Cn1ccc2cc(C(F)(F)F)cc(COCC3(c4ccccc4)CCN(C(=O)OC(C)(C)C)CC3)c21
Temperature: 25 °C
Reaction time: 1 h
Yield: 65.8 %

Procedure:
Dimethyl sulfate (0.020 ml, 0.209 mmol) was added to a solution of tert-butyl 4-phenyl-4-(((5-(trifluoromethyl)-1H-indol-7-yl)methoxy)methyl)piperidine-1-carboxylate (93 mg, 0.190 mmol) and potassium tert-butoxide (23.5 mg, 0.209 mmol) in tetrahydrofuran (5 ml). The reaction was stirred 1 h at ambient temperature. The reaction was quenched with water (10 mL) and extracted with ethyl acetate (3×10 mL). The combined organic layers were dried with magnesium sulfate and evaporated. The residue was purified by chromatography on silica gel with a gradient of 8% to 66% ethyl acetate/hexanes. The product tert-butyl 4-(((1-methyl-5-(trifluoromethyl)-1H-indol-7-yl)methoxy)methyl)-4-phenylpiperidine-1-carboxylate (63 mg, 0.125 mmol, 65.9% yield) was obtained as a white solid. 1H-NMR (CDCl3, 400 MHz) δ 7.83 (s, 1H), 7.22-7.36 (m, 6H), 6.95 (s, 1H), 6.50 (s, 1H), 4.66 (s, 2H), 3.66 (s, 3H), 3.62 (m, 2H), 3.41 (m, 2H), 2.99 (m, 2H), 2.09 (m, 2H), 1.77 (m, 2H), 1.40 (s, 9H); Mass spec.(MH)+: 503.19.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:6]([CH:7]=O)[C:5]([OH:10])=[CH:4][CH:3]=1.[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[O:21])[CH3:20])=[CH:15][CH:14]=1.[OH-].[K+].Cl>C(O)C.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:10])=[C:6]([CH:7]=[CH:20][C:19]([C:16]2[CH:17]=[CH:18][C:13]([O:12][CH3:11])=[CH:14][CH:15]=2)=[O:21])[CH:9]=1
Reactant: COc1ccc(C(C)=O)cc1
Reactant: O=Cc1cc(Br)ccc1O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1ccc(C(=O)C=Cc2cc(Br)ccc2O)cc1
Reaction time: 8 h

Procedure:
5-Bromosalicylaldehyde (20.1 g) and p-methoxyacetophenone (15.0 g) were dissolved in ethanol (80 ml) and a solution of potassium hydroxide (26.5 g) in water (40 ml) was added, with cooling. The reaction mixture was allowed to stand overnight, and then was acidified by addition to excess hydrochloric acid. The precipitated 5-bromo-2-hydroxy.4'-methoxychalcone was filtered off, washed with water, and recrystallised from ethanol, 27.5 g, m.p. 177°-179°.
Reaction SMILES: [CH3:1][P:2]([CH2:5][N:6]1[CH2:11][CH2:10][C:9]2([C:19]3[C:14](=[CH:15][C:16]([O:20]C)=[CH:17][CH:18]=3)[CH:13]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[O:12]2)[CH2:8][CH2:7]1)([CH3:4])=[O:3].CP(CN1CCC2(C3C(=CC=CC=3)C(C3C=CC(OC)=CC=3)O2)CC1)(C)=O>>[CH3:4][P:2]([CH2:5][N:6]1[CH2:7][CH2:8][C:9]2([C:19]3[C:14](=[CH:15][C:16]([OH:20])=[CH:17][CH:18]=3)[CH:13]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[O:12]2)[CH2:10][CH2:11]1)([CH3:1])=[O:3]
Reactant: COc1ccc2c(c1)C(c1ccccc1)OC21CCN(CP(C)(C)=O)CC1
Agent: COc1ccc(C2OC3(CCN(CP(C)(C)=O)CC3)c3ccccc32)cc1
Product: CP(C)(=O)CN1CCC2(CC1)OC(c1ccccc1)c1cc(O)ccc12

Procedure:
A solution of 1,3-dihydro-1'-dimethylphosphinylmethyl-6-methoxy-3-phenylspiro[isobenzofuran-1,4'-piperidine] and 48% hydrobromic acid is heated under reflux, cooled, diluted with water, neutralized with sodium bicarbonate and extracted with chloroform. The chloroform solution is dried and the chloroform evaporated off, affording 1,3-dihydro-1'-dimethylphosphinylmethyl-6-hydroxy-3-phenylspiro[isobenzofuran-1,4'-piperidine]. In an analogous manner, 1,3-dihydro-1'-dimethylphosphinylmethyl-5-methoxy-3-phenylspiro[isobenzofuran-1,4'-piperidine] and 1,3-dihydro-1'-dimethylphosphinylmethyl-3-(4-methoxyphenyl)spiro[isobenzofuran-1,4'-piperidine] are treated to provide 1,3-dihydro-1'-dimethylphosphinylmethyl-5-hydroxy-3-phenylspiro[isobenzofuran-1,4'-piperidine] and 1,3-dimethylphosphinylmethyl-3-(4-hydroxyphenyl)spiro[isobenzofuran-1,4'-piperidine], respectively.
Reaction SMILES: [OH:1][C@H:2]1[C@H:6]2[CH2:7][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:9][CH2:10][N:5]2[CH2:4][CH2:3]1.Cl[C:19]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][N:20]=1.CC(C)([O-])C.[K+]>O1CCCC1>[Cl:25][C:22]1[CH:23]=[CH:24][C:19]([O:1][C@H:2]2[C@H:6]3[CH2:7][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:9][CH2:10][N:5]3[CH2:4][CH2:3]2)=[N:20][CH:21]=1
Reactant: Clc1ccc(Cl)nc1
Reactant: CC(C)(C)OC(=O)N1CCN2CC[C@@H](O)[C@H]2C1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN2CC[C@@H](Oc3ccc(Cl)cn3)[C@H]2C1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
(8R*,8aR*)-tert-Butyl 8-hydroxyhexahydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylate (Example 36A, 0.969 g, 4.0 mmol) and 2,5-dichloropyridine (0.651 g, 4.40 mmol) were treated with potassium tert-butoxide (0.987 g, 8.80 mmol) in dry tetrahydrofuran (5 mL). The mixture was heated to 80° C. and stirred for 16 hours. After the mixture cooled to room temperature, the mixture was purified via HPLC (Gilson®, Xbridge™ 30×100 mm column, eluted with pH=10 aqueous ammonium bicarbonate-ammonium hydroxide/methanol, UV=222 nm) to give the tert-butoxycarbonyl protected product, (8R*,8aR*)-tert-butyl 8-(5-chloropyridin-2-yloxy)hexahydropyrrolo[1,2-a]pyrazine-2(1H)-carboxylate. This tert-butoxycarbonyl compound was dissolved in dichloromethane (5 mL) and trifluoroacetic acid (2 mL) was added. The reaction mixture was stirred at room temperature for 3 hours. The mixture was concentrated and then purified via HPLC (Gilson®, Xbridge™ 30×100 mm column, eluted with pH=10 aqueous ammonium bicarbonate-ammonium hydroxide/methanol, UV=220 nm) to give the title compound. 1H NMR (300 MHz, methanol-d4) δ ppm 1.72-1.86 (m, 1H), 2.08-2.22 (m, 3H), 2.31-2.45 (m, 1H), 2.69-2.80 (m, 2H), 2.87-2.98 (m, 1H), 2.99-3.21 (m, 3H), 5.51 (ddd, 1H, J=7, 4, 2 Hz), 6.77 (d, 1H, J=9 Hz), 7.65 (dd, 1H, J=8, 2 Hz), 8.07 (d, 1H, J=2 Hz); MS (DCI) m/z 254 (M+H)+.
Reaction SMILES: COC(=O)N[C@@H](C(C)C)C(N1[C@H](C2NC(C3C=CC(C4C=CC5C(=CC=C(C6NC([C@@H]7CCCN7[C:48](=[O:61])[C@H:49]([NH:56][C:57]([O:59][CH3:60])=[O:58])[C:50]7[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=7)=NC=6)C=5)C=4)=CC=3)=CN=2)CC2(OCCO2)C1)=O.Cl.Cl.Cl.[F:69][C:70]1([F:121])[C:82]2[CH:81]=[C:80]([C:83]3[CH:84]=[CH:85][C:86]4[N:90]=[C:89]([C@@H:91]5[C@H:96]6[CH2:97][C@@H:93]([CH2:94][CH2:95]6)[N:92]5[C:98](=[O:109])[C@@H:99]([NH:104][C:105](=[O:108])[O:106][CH3:107])[C@H:100]([O:102][CH3:103])[CH3:101])[NH:88][C:87]=4[CH:110]=3)[CH:79]=[CH:78][C:77]=2[C:76]2[C:71]1=[CH:72][C:73]([C:111]1[NH:115][C:114]([C@@H:116]3[CH2:120][CH2:119][CH2:118][NH:117]3)=[N:113][CH:112]=1)=[CH:74][CH:75]=2>>[CH3:107][O:106][C:105](=[O:108])[NH:104][C@@H:99]([C@H:100]([O:102][CH3:103])[CH3:101])[C:98]([N:92]1[C@H:91]([C:89]2[NH:88][C:87]3[CH:110]=[C:83]([C:80]4[CH:79]=[CH:78][C:77]5[C:76]6[C:71](=[CH:72][C:73]([C:111]7[NH:115][C:114]([C@@H:116]8[CH2:120][CH2:119][CH2:118][N:117]8[C:48](=[O:61])[C@H:49]([NH:56][C:57]([O:59][CH3:60])=[O:58])[C:50]8[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=8)=[N:113][CH:112]=7)=[CH:74][CH:75]=6)[C:70]([F:69])([F:121])[C:82]=5[CH:81]=4)[CH:84]=[CH:85][C:86]=3[N:90]=2)[C@H:96]2[CH2:97][C@H:93]1[CH2:94][CH2:95]2)=[O:109]
Reactant: COC(=O)N[C@H](C(=O)N1[C@@H]2CC[C@H](C2)[C@H]1c1nc2ccc(-c3ccc4c(c3)C(F)(F)c3cc(-c5cnc([C@@H]6CCCN6)[nH]5)ccc3-4)cc2[nH]1)[C@@H](C)OC
Reactant: COC(=O)N[C@H](C(=O)N1CC2(C[C@H]1c1ncc(-c3ccc(-c4ccc5cc(-c6cnc([C@@H]7CCCN7C(=O)[C@H](NC(=O)OC)c7ccccc7)[nH]6)ccc5c4)cc3)[nH]1)OCCO2)C(C)C
Agent: Cl
Product: COC(=O)N[C@H](C(=O)N1[C@@H]2CC[C@H](C2)[C@H]1c1nc2ccc(-c3ccc4c(c3)C(F)(F)c3cc(-c5cnc([C@@H]6CCCN6C(=O)[C@H](NC(=O)OC)c6ccccc6)[nH]5)ccc3-4)cc2[nH]1)[C@@H](C)OC

Procedure:
The title compound was prepared according to the method employed to prepare (S)-1-((S)-8-(5-(4-(6-(2-((S)-1-((R)-2-(methoxycarbonylamino)-2-phenylacetyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)-1,4-dioxa-7-azaspiro[4.4]nonan-7-yl)-3-methyl-1-oxobutan-2-ylcarbamic acid methyl ester, except that methyl (2S,3R)-1-((1R,3S,4R)-3-(6-(9,9-difluoro-7-(2-((S)-pyrrolidin-2-yl)-1H-imidazol-5-yl)-9H-fluoren-2-yl)-1H-benzo[d]imidazol-2-yl)-2-azabicyclo[2.2.1]heptan-2-yl)-3-methoxy-1-oxobutan-2-ylcarbamate 3HCl salt was used instead of methyl (S)-3-methyl-1-oxo-1-((S)-8-(5-(4-(6-(2-((S)-pyrrolidin-2-yl)-1H-imidazol-5-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)-1,4-dioxa-7-azaspiro[4.4]nonan-7-yl)butan-2-ylcarbamate 3HCl salt. MS (ESI) m/z 913.74 [M+H]+. (91.4 mg, 56%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([NH:8][S:9]([CH3:12])(=[O:11])=[O:10])[C:5]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:4][C:3]=1[C:20]([CH3:22])=[O:21].Cl(O)(=O)(=O)=O.[CH2:28](OCC)C>C([O-])([O-])OCC>[CH3:12][S:9]([NH:8][C:6]1[C:5]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:4][C:3]2[C:20](=[O:21])[CH:22]=[CH:28][O:1][C:2]=2[CH:7]=1)(=[O:11])=[O:10]
Reactant: CC(=O)c1cc(Oc2ccccc2)c(NS(C)(=O)=O)cc1O
Reactant: CCOCC
Agent: CCOC([O-])[O-]
Agent: [O-][Cl+3]([O-])([O-])O
Product: CS(=O)(=O)Nc1cc2occc(=O)c2cc1Oc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87.6 %

Procedure:
In 16 ml of ethyl orthoformate was suspended 3.21 g of methyl 2-hydroxy-4-methylsulfonylamino-5-phenoxyphenyl ketone. To the mixture being ice-cooled was dropwise added 2.15 g of a 70% aqueous perchloric acid solution in 10 minutes. Stirring was conducted for 30 minutes at 20°-25° C. 50 ml of diethyl ether was added thereto. The resulting crystal was collected by filtration. The crystal was mixed with 50 ml of water, and the mixture was refluxed for 2 minutes and then cooled to room temperature. The resulting crystal was collected by filtration and recrystallized from acetonitrile to obtain 2.90 g (yield: 87.6%) of 7-methylsulfonylamino-6-phenoxy-4H-1-benzopyran-4-one.
Reaction SMILES: BrC1C(N2CCN(C(NC3C=CC=CC=3)=O)CC2)=C2N=C(C3C=CC(N(C)C)=CC=3)NC2=NC=1.[Br:35][C:36]1[C:37]([N:46]2[CH2:51][CH2:50][N:49]([CH2:52][C:53]3[CH:54]=[N:55][CH:56]=[CH:57][CH:58]=3)[CH2:48][CH2:47]2)=[C:38]([N+:43]([O-])=O)[C:39]([NH2:42])=[N:40][CH:41]=1.[O-]S(S([O-])=O)=O.[Na+].[Na+].[CH3:67][N:68]1[CH:72]=[C:71]([CH:73]=O)[CH:70]=[N:69]1>C(O)C.CN(C=O)C>[Br:35][C:36]1[C:37]([N:46]2[CH2:51][CH2:50][N:49]([CH2:52][C:53]3[CH:54]=[N:55][CH:56]=[CH:57][CH:58]=3)[CH2:48][CH2:47]2)=[C:38]2[N:43]=[C:73]([C:71]3[CH:70]=[N:69][N:68]([CH3:67])[CH:72]=3)[NH:42][C:39]2=[N:40][CH:41]=1
Reactant: Nc1ncc(Br)c(N2CCN(Cc3cccnc3)CC2)c1[N+](=O)[O-]
Reactant: Cn1cc(C=O)cn1
Agent: CN(C)c1ccc(-c2nc3c(N4CCN(C(=O)Nc5ccccc5)CC4)c(Br)cnc3[nH]2)cc1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CN(C)C=O
Product: Cn1cc(-c2nc3c(N4CCN(Cc5cccnc5)CC4)c(Br)cnc3[nH]2)cn1
Reaction time: 6 h
Yield: 26.7 %

Procedure:
This was prepared using the same procedure as for 4-(6-bromo-2-(4-(dimethylamino)phenyl)-3H-imidazo[4,5-b]pyridin-7-yl)-N-phenylpiperazine-1-carboxamide, but here using 5-bromo-3-nitro-4-(4-(pyridin-3-ylmethyl)piperazin-1-yl)pyridin-2-amine (75 mg, 0.19 mmol), DMF (0.85 mL), ethanol (0.15 mL), 1M Na2S2O4 (3 eq, 0.57 mmol, 0.57 mL) and 1-methyl-1H-pyrazole-4-carboxaldehyde (1.1 eq, 0.21 mmol, 23 mg). After 6 h, concentration in vacuo and preparation by preparative tlc (CH2Cl2-MeOH, 9:1) gave the product (23 mg, 24%) as a colourless solid; 1H-NMR (500 MHz, DMSO-d6) 2.60 (br s, 4H, piperazine N(CH2)2), 3.60 (t, J=4.5 Hz, 4H, piperazine N(CH2)2), 3.61 (s, 2H, CH2), 3.93 (s, 3H, NCH3), 7.40 (dd, J=7.6, 4.8 Hz, 1H, pyridine H-5), 7.78 (d, br, J=7.7 Hz, 1H, pyridine H-4), 8.06 (s, 1H, pyrazole H-2 or H-4), 8.19 (s, 1H, imidazo[4,5-b]pyridine H-5), 8.35 (s, 1H, pyrazole H-2 or H-4), 8.50 (d, br, J=4.7 Hz, 1H, pyridine H-6), 8.57 (s, br, 1H, pyridine H-2), 13.21 (br s, 1H, imidazo[4,5-b]pyridine NH);
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1.S(=O)(=O)(O)O.[CH3:19]O>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:19])=[O:7])=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1
Reactant: CO
Reactant: O=C(O)c1ccc(Br)cc1[N+](=O)[O-]
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(Br)cc1[N+](=O)[O-]

Procedure:
To a methanol solution (50 ml) of 4-bromo-2-nitrobenzoic acid (2.54 g) was added concentrated sulfuric acid (1.0 ml), followed by heating at reflux for 4 hours. The reaction solution was concentrated under reduced pressure, and water (20 ml) was added to the residue. Under ice cooling, 5 N aqueous sodium hydroxide solution (2.0 ml) and a saturated aqueous sodium hydrogen carbonate solution were added, and extracted with dichloromethane. The organic layer was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to afford methyl 4-bromo-2-nitrobenzoate (619 mg).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[C:4]1[CH:9]=[C:8](Br)[CH:7]=[C:6]([CH3:11])[C:5]=1[N:12]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[S:13]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)(=[O:15])=[O:14].[CH:32]#[C:33][CH2:34][CH2:35][CH2:36][CH3:37]>CN(C=O)C.C(N(CC)CC)C.CCOCC.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu]I>[CH3:1][O:2][C:3](=[O:31])[C:4]1[CH:9]=[C:8]([C:32]#[C:33][CH2:34][CH2:35][CH2:36][CH3:37])[CH:7]=[C:6]([CH3:11])[C:5]=1[N:12]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[S:13]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)(=[O:15])=[O:14]
Reactant: COC(=O)c1cc(Br)cc(C)c1N(Cc1ccccc1)S(=O)(=O)c1ccc(OC)cc1
Reactant: C#CCCCC
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCCCC#Cc1cc(C)c(N(Cc2ccccc2)S(=O)(=O)c2ccc(OC)cc2)c(C(=O)OC)c1
Yield: 60.9 %

Procedure:
To a solution of 0.324 g (0.643 mmol) of the product of Example 11 in 2.0 mL of DMF and 2.0 mL of triethylamine was added 0.088 mL (0.771 mmol) of 1-hexyne, 9 mg (0.013 mmol) of bis(triphenylphosphine)palladium(II)dichloride and 1.2 mg of copper(I)iodide. The reaction mixture was then heated to 65 degrees for 5 h and an additional 0.22 mL of 1-hexyne was added to the reaction. The motion was then heated to zeflux for 6 h and then cooled to room tempemaure and diluted with ether. The organics were washed with water and brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was chromatographed on silica eluting with EtOAc-Hex (1:10) to provide 0.198 g (61%) of the desired product as a yellow oil. Electrospray Mass Spec: 506.3 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[N:17][CH:16]=[CH:15][C:3]=1[C:4]([NH:6][NH:7][C:8]1[CH:13]=[C:12]([I:14])[CH:11]=[CH:10][N:9]=1)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C[Si](N=[N+]=[N-])(C)C.N(C(OCC)=O)=NC(OCC)=O.C1(C)C=CC=CC=1>O1CCCC1>[Cl:1][C:2]1[CH:18]=[N:17][CH:16]=[CH:15][C:3]=1[C:4]1[N:9]2[CH:10]=[CH:11][C:12]([I:14])=[CH:13][C:8]2=[N:7][N:6]=1
Reactant: O=C(NNc1cc(I)ccn1)c1ccncc1Cl
Agent: CCOC(=O)N=NC(=O)OCC
Agent: C[Si](C)(C)N=[N+]=[N-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: Clc1cnccc1-c1nnc2cc(I)ccn12
Yield: 55 %

Procedure:
To a mixture of 3-chloro-N′-(4-iodopyridin-2-yl)isonicotinohydrazide (1.53 g, 4.08 mmol) and polymer supported triphenyl phosphine (2.83 g, 6.19 mmol) in tetrahydrofuran (35 mL) was added trimethylsilylazide (0.82 mL, 6.20 mmol) and a 40% solution of diethyl azodicarboxylate in toluene (3.40 mL, 7.42 mmol) and it was stirred in an orbital stirrer at room temperature for 2.5 hours. The mixture was filtered and rinsed with ethyl acetate, concentrated under reduced pressure and the resulting crude was purified by flash chromatography eluting with hexanes:isopropyl alcohol (3:2) to give the title compound (0.80 g, 55%) as a yellowish solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C@H:20]3[C@H:15]([CH2:16][CH:17]=[CH:18][CH2:19]3)[C:14](=[O:21])[NH:13][N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH:22]1(NN)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C@H:20]3[C@H:15]([CH2:16][CH:17]=[CH:18][CH2:19]3)[C:14](=[O:21])[N:13]([CH:22]3[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)[N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: NNC1CCCCCCC1
Reactant: COc1ccc(C2=NNC(=O)[C@H]3CC=CC[C@@H]23)cc1OC
Product: COc1ccc(C2=NN(C3CCCCCCC3)C(=O)[C@H]3CC=CC[C@@H]23)cc1OC

Procedure:
Prepared from compound 3 and cyclooctylhydrazine as described for compound 35. Purified by chromatography (dichloromethane) and crystallized from petroleum ether (40-60° C.). M.p. 75-77° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[CH:5]2.[OH-].[K+].I[CH3:21]>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:21])[C:6]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[CH:5]2
Reactant: CCCCCCCc1cc2cc(Cl)ccc2[nH]1
Reactant: CI
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CCCCCCCc1cc2cc(Cl)ccc2n1C
Reaction time: 0.5 h

Procedure:
To the solution of 5-chloro-2-heptyl-1H-indole in DMSO was added KOH at RT and was stirred for 30 minutes. Then to this mixture, iodomethane was added and stirred for 3 hours. The reaction was quenched with saturated ammonium chloride solution and extracted with ethyl acetate. The product, 5-chloro-2-heptyl-1-methyl-1H-indole was purified by column chromatography.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[CH:5]([Si:8]([CH:22]([CH3:24])[CH3:23])([CH:19]([CH3:21])[CH3:20])[N:9]1[C:13]2=[N:14][CH:15]=[C:16]([NH2:18])[CH:17]=[C:12]2[CH:11]=[CH:10]1)([CH3:7])[CH3:6].[Cl-].[NH4+].C(OCC)(=O)C>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[CH:22]([Si:8]([CH:5]([CH3:7])[CH3:6])([CH:19]([CH3:21])[CH3:20])[N:9]1[C:13]2=[N:14][CH:15]=[C:16]([NH:18][C:1](=[O:3])[CH3:2])[CH:17]=[C:12]2[CH:11]=[CH:10]1)([CH3:24])[CH3:23]
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2cc(N)cnc21
Reactant: CC(=O)Cl
Agent: CN(C)c1ccncc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(=O)Nc1cnc2c(ccn2[Si](C(C)C)(C(C)C)C(C)C)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 52.8 %

Procedure:
Acetyl chloride (75 μL, 1.0 mmol) was added to a solution of 1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridin-5-ylamine (230 mg, 0.8 mmol) and 4-dimethylaminopyridine (5 mg) in pyridine (1.6 mL). The mixture was stirred at RT for 24 h and a saturated solution of ammonium chloride (30 mL) and ethyl acetate (30 mL) were added. The separated aqueous layer was extracted with ethyl acetate (3×25 mL) and the combined organic layers were dried, filtered and concentrated to provide an oil which was purified by preparative HPLC to afford N-(1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-acetamide (140 mg, 53%) as an oil: LCMS; m/z 332 (M+H+). B. At RT under argon, a solution of borane-dimethylsulfide complex (665 μL, 6.6 mmol, 10 M) was added to N-methyl-N-(1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-acetamide (110 mg, 0.33 mmol) in THF (3.0 mL). The mixture was heated to 65° C. for 2 h., cooled down and a 6N hydrochloric acid solution was slowly added. The mixture was heated to 100° C. and vigorously stirred for 12 h., cooled down and a 6 N sodium hydroxide solution was added until pH 7 was reached. The mixture was extracted with ethyl acetate (3×15 mL) and the combined organic layers were dried, filtered and evaporated to provide an oil which was purified through silica gel-SCX column (arylsulfonic acid with washes with methanol and 2N NH3 in methanol) to afford ethyl-(1H-pyrrolo[2,3-b]pyridin-5-yl)-amine. LCMS; m/z 203 (M+AcCN), 162 (M+H)+.
Reaction SMILES: [NH:1]([C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])[C@H:2]([C:10]([NH:12][CH2:13][C:14]([NH:16][C@H:17]([C:22]([NH:24][C@@H:25]([C:33]([NH:35][C@H:36]([C:40]([NH:42][C@H:43]([C:45]([O:47]C)=[O:46])[CH3:44])=[O:41])[CH:37]([CH3:39])[CH3:38])=[O:34])[CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:23])[CH2:18][C:19](=[O:21])[OH:20])=[O:15])=[O:11])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:9])[NH2:8].[OH-].[Na+]>CO>[NH:1]([C:49]([O:51][C:52]([CH3:55])([CH3:53])[CH3:54])=[O:50])[C@H:2]([C:10]([NH:12][CH2:13][C:14]([NH:16][C@H:17]([C:22]([NH:24][C@@H:25]([C:33]([NH:35][C@H:36]([C:40]([NH:42][C@H:43]([C:45]([OH:47])=[O:46])[CH3:44])=[O:41])[CH:37]([CH3:39])[CH3:38])=[O:34])[CH2:26][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)=[O:23])[CH2:18][C:19](=[O:20])[OH:21])=[O:15])=[O:11])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:8])[NH2:9]
Reactant: COC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)[C@@H](Cc1ccccc1)NC(=O)[C@H](CC(=O)O)NC(=O)CNC(=O)[C@H](CCCNC(=N)N)NC(=O)OC(C)(C)C)C(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)[C@H](NC(=O)[C@@H](Cc1ccccc1)NC(=O)[C@H](CC(=O)O)NC(=O)CNC(=O)[C@H](CCCNC(=N)N)NC(=O)OC(C)(C)C)C(=O)N[C@@H](C)C(=O)O
Reaction time: 3 h

Procedure:
2.0 g of BOC-Arg-Gly-Asp-D-Phe-Val-Ala-OMe are dissolved in 60 ml of methanol, 1.5 ml of 2N sodium hydoxide solution are added and the mixture is stirred for 3 hours at 20°. After evaporation the residue is taken up in water, acidified to pH 3 with dilute HCl and extracted with ethyl acetate. The extract is dried over Na2SO4, evaporated again and the BOC-Arg-Gly-Asp-D-Phe-Val-Ala-OH obtained is stirred at 20° for 2 hours with 20 ml of 2N HCl in dioxane. The mixture is evaporated, the H-Arg-Gly-Asp-D-Phe-Val-Ala-OH obtained is dissolved in a mixture of 1800 ml of dichloromethane and 200 ml of DMF and cooled to 0°, 0.5 g of DCCI, 0.3 g of HOBt and 0.23 ml of N-methylmorpholine are added successively with stirring, and the mixture is stirred for a further 24 hours at 0° and 48 hours at 20°. The solution is concentrated and tested with a mixed bed ion exchange to free it from salts. This is then filtered off, the solution is evaporated and the residue is purified by chromatography. Cyclo(-Arg-Gly-Asp-D-Phe-Val-Ala) M+ : 646 FAB is obtained;
Reaction SMILES: [CH3:1][C:2]1[CH:41]=[C:40]([CH3:42])[CH:39]=[CH:38][C:3]=1[C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]([CH2:28][N:29](C(OC(C)(C)C)=O)[CH3:30])[C:15]([NH:17][C:18]2[CH:19]=[C:20]3[C:25](=[CH:26][CH:27]=2)[CH:24]=[N:23][CH:22]=[CH:21]3)=[O:16])=[CH:10][CH:9]=1)=[O:5].Cl>C(Cl)Cl>[CH3:1][C:2]1[CH:41]=[C:40]([CH3:42])[CH:39]=[CH:38][C:3]=1[C:4]([O:6][CH2:7][C:8]1[CH:9]=[CH:10][C:11]([CH:14]([CH2:28][NH:29][CH3:30])[C:15]([NH:17][C:18]2[CH:19]=[C:20]3[C:25](=[CH:26][CH:27]=2)[CH:24]=[N:23][CH:22]=[CH:21]3)=[O:16])=[CH:12][CH:13]=1)=[O:5]
Reactant: Cc1ccc(C(=O)OCc2ccc(C(CN(C)C(=O)OC(C)(C)C)C(=O)Nc3ccc4cnccc4c3)cc2)c(C)c1
Agent: Cl
Solvent: ClCCl
Product: CNCC(C(=O)Nc1ccc2cnccc2c1)c1ccc(COC(=O)c2ccc(C)cc2C)cc1
Reaction time: 9 h

Procedure:
To 4-(3-(tert-butoxycarbonyl(methyl)amino)-1-(isoquinolin-6-ylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethylbenzoate (E205-2) in CH2Cl2 was added HCl (4 N in dioxane) and the solution was stirred for 8-10 h. The solvents were evaporated to give pure 4-(1-(isoquinolin-6-ylamino)-3-(methylamino)-1-oxopropan-2-yl)benzyl 2,4-dimethylbenzoate (E206).