Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][N:11]([CH2:17][C:18]1[CH:19]=[C:20]([CH:54]=[CH:55][CH:56]=1)[C:21]([NH:23][C:24]1[S:25][C:26]2[CH2:53][CH2:52][CH2:51][CH2:50][C:27]=2[C:28]=1[C:29]([NH:31][C:32]1[CH:37]=[CH:36][C:35]([CH2:38][CH2:39][C:40]2[CH:49]=[CH:48][C:43]([C:44]([O:46][CH3:47])=[O:45])=[CH:42][CH:41]=2)=[CH:34][CH:33]=1)=[O:30])=[O:22])[CH:12]([CH2:15][CH3:16])[CH2:13][CH3:14])=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:8][CH2:9][CH2:10][N:11]([CH2:17][C:18]1[CH:19]=[C:20]([CH:54]=[CH:55][CH:56]=1)[C:21]([NH:23][C:24]1[S:25][C:26]2[CH2:53][CH2:52][CH2:51][CH2:50][C:27]=2[C:28]=1[C:29]([NH:31][C:32]1[CH:37]=[CH:36][C:35]([CH2:38][CH2:39][C:40]2[CH:49]=[CH:48][C:43]([C:44]([O:46][CH3:47])=[O:45])=[CH:42][CH:41]=2)=[CH:34][CH:33]=1)=[O:30])=[O:22])[CH:12]([CH2:13][CH3:14])[CH2:15][CH3:16]
Reactant: CCC(CC)N(CCNC(=O)OC(C)(C)C)Cc1cccc(C(=O)Nc2sc3c(c2C(=O)Nc2ccc(CCc4ccc(C(=O)OC)cc4)cc2)CCCC3)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCC(CC)N(CCN)Cc1cccc(C(=O)Nc2sc3c(c2C(=O)Nc2ccc(CCc4ccc(C(=O)OC)cc4)cc2)CCCC3)c1
Reaction time: 1 h
Yield: 100.4 %

Procedure:
To a mixture of 240 mg of methyl 4-(2-{4-[({2-[(3-{[{2-[(tert-butoxycarbonyl)amino]ethyl}(pentan-3-yl)amino]methyl}benzoyl)amino]-4,5,6,7-tetrahydro-1-benzothiophen-3-yl}carbonyl)amino]phenyl}ethyl)benzoate and 5.0 mL of methylene chloride was added 3.0 mL of TFA under ice cooling, followed by stirring for 1 hour at the same temperature and then stirring for 5 hours at room temperature. The reaction mixture was concentrated under reduced pressure, chloroform and a saturated aqueous sodium hydrogen carbonate solution were added thereto, followed by extraction with chloroform. The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure, thereby obtaining 210 mg of methyl 4-(2-{4-[({2-[(3-{[(2-aminoethyl)(pentan-3-yl)amino]methyl}benzoyl)amino]-4,5,6,7-tetrahydro-1-benzothiophen-3-yl}carbonyl)amino]phenyl}ethyl)benzoate.
Reaction SMILES: Cl.[C:2]([O:6][C:7](=[O:13])[C@H:8]([CH:10]([CH3:12])[CH3:11])[NH2:9])([CH3:5])([CH3:4])[CH3:3].CN1CCOCC1.[Br:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:33]=[CH:32][C:31]([S:34](Cl)(=[O:36])=[O:35])=[CH:30][CH:29]=2)=[CH:24][CH:23]=1>ClCCl>[C:2]([O:6][C:7](=[O:13])[C@@H:8]([NH:9][S:34]([C:31]1[CH:30]=[CH:29][C:28]([C:25]2[CH:26]=[CH:27][C:22]([Br:21])=[CH:23][CH:24]=2)=[CH:33][CH:32]=1)(=[O:35])=[O:36])[CH:10]([CH3:11])[CH3:12])([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(C)[C@H](N)C(=O)OC(C)(C)C
Reactant: O=S(=O)(Cl)c1ccc(-c2ccc(Br)cc2)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CC(C)[C@H](NS(=O)(=O)c1ccc(-c2ccc(Br)cc2)cc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 60.3 %

Procedure:
To a solution of L-valine-tert-butyl ester hydrochloride (15.7 g, 0.075 mol) and N-methylmorpholine (15.2 g, 0.15 mol) in dichloromethane (250 mL) was added in one portion 4'-bromobiphenyl-4-sulfonyl chloride (25 g, 0.075 mol). The solution was stirred at room temperature for 16 hours, filtered, and the filtrate was concentrated in vacuo. The residue was diluted with ethyl acetate (250 mL) and washed with HCl (1N), saturated sodium chloride, and dried over magnesium sulfate. The drying agent was filtered, and the filtrate was concentrated in vacuo leaving a cream-colored solid. The crude product was purified using silica gel chromatography (elution with chloroform) to give the title compound (21.2 g, 60%) as a white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:9][CH2:10][C@H:11]2[CH2:15][CH2:14][CH2:13][N:12]2[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH:5]=[N:6][C:7]=1[Cl:8].[CH3:23][C:24]([CH3:30])([CH3:29])[CH:25]=[CH:26][CH:27]=[CH2:28].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>C(#N)C.CCOC(C)=O>[CH3:23][C:24]([CH3:30])([CH3:29])[CH:25]=[CH:26][CH:27]=[CH:28][C:2]1[CH:3]=[C:4]([O:9][CH2:10][C@H:11]2[CH2:15][CH2:14][CH2:13][N:12]2[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH:5]=[N:6][C:7]=1[Cl:8]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1cnc(Cl)c(Br)c1
Reactant: C=CC=CC(C)(C)C
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC(C)(C)C=CC=Cc1cc(OC[C@H]2CCCN2C(=O)OC(C)(C)C)cnc1Cl
Reaction time: 96 h
Yield: 26.7 %

Procedure:
A solution of 5-bromo-6-chloro-3-(1-BOC-2-(R)-pyrrolidinylmethoxy)pyridine from Example 69a (480 mg, 1.2 mmol), 5-(5,5-dimethyl-1,3-hexadiene (200 mg, 1.8 mmol), Pd(OAc)4 (25 mg), tris(o-tolyl)phosphine (125 mg), and triethylamine (2.5 mL) in acetonitrile (5 mL) was sealed in a tube and headed at 100° C. for 4 days. The solution was then diluted with EtOAc, and the mixture was extracted with water and aqueous NaHCO3 solution. The organic layer was dried and concentrated. The residue was chromatographed on a silica gel column, eluting with hexane:Et2O 100:5-100:15 to afford the title compound (135 mg, 43% yield). MS (CI/NH3) m/z 421 (M+H)+. 1H NMR (CDCl3, 300 MHz) δ 1.08 (s, 9H), 1.48 (s, 9H), 1.89 (m, 2H), 2.00 (m, 2H), 3.38 (m, 2H), 3.95 (m, 1H), 4.13 (m, 1H), 4.23 (m, 1H), 5.99 (m, 1H), 6.22 (m, 1H), 6.71 (m, 1H), 6.95 (m, 1H), 7.74 (br s, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:19]2[S:23][C:22]([C:24]3(O)[CH2:29][CH2:28][S:27][CH2:26][CH2:25]3)=[N:21][CH:20]=2)[CH:5]=[C:6]([NH:8][C:9]2[N:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][N:10]=2)[CH:7]=1.CS(O)(=O)=O.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>C([O-])(O)=O.[Na+]>[S:27]1[CH2:26][CH:25]=[C:24]([C:22]2[S:23][C:19]([C:4]3[CH:5]=[C:6]([NH:8][C:9]4[N:14]=[C:13]([C:15]([F:16])([F:17])[F:18])[CH:12]=[CH:11][N:10]=4)[CH:7]=[C:2]([CH3:1])[CH:3]=3)=[CH:20][N:21]=2)[CH2:29][CH2:28]1
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(C3(O)CCSCC3)s2)c1
Agent: CS(=O)(=O)O
Agent: O=C([O-])O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(C3=CCSCC3)s2)c1
Temperature: 70 °C
Reaction time: 3 h
Yield: 41.7 %

Procedure:
4-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]tetrahydro-2H-thiopyran-4-ol (Step 1, Example 132, 250 mg, 0.552 mmol) was combined with Eaton's reagent (1.0 mL, 6.3 mmol) and stirred at 70° C. for 3 hrs. The dark brown reaction mixture was cooled to room temperature, carefully neutralized/diluted with aqueous saturated NaHCO3 (4 mL) and extracted with EtOAc (2×5 mL). The combined organic layers were washed with brine, dried (MgSO4), filtered and evaporated. Column chromatography on silica (gradient elution, 0 to 40% EtOAc in hexanes) afforded the title compound (0.100 g, 0.23 mmol, 41.7% yield) as a yellow foam. MS ESI: [M+H]+ m/z 435.0. 1H NMR (500 MHz, DMSO-d6) δ 10.27 (s, 1H), 8.83 (d, J=4.9, 1H), 8.06 (s, 1H), 8.01 (bs, 1H), 7.45 (bs, 1H), 7.28 (d, J=4.9, 1H), 7.18 (bs, 1H), 6.81 (m, 1H), 3.39-3.35 (m, 2H), 2.85-2.83 (m, 2H), 2.77-2.75 (m, 2H), 2.31 (s, 3H). rhSYK activity=+++.
Reaction SMILES: [C:1]1([CH:7]([OH:9])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ON1C(=O)C2=CC=CC=C2C1=O.O=O.OO>C(#N)C>[C:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)(=[O:9])[CH3:8]
Reactant: CC(O)c1ccccc1
Agent: O=C1c2ccccc2C(=O)N1O
Agent: O=O
Agent: OO
Solvent: CC#N
Product: CC(=O)c1ccccc1
Yield: 36 %

Procedure:
A mixture of 5 mmol of 1-phenylethanol, 0.5 mmol of N-hydroxyphthalimide, and 5 ml of acetonitrile was stirred at 75° C. in an oxygen atmosphere (1 atm) for 24 hours. An iodometric analysis of a reaction mixture revealed that hydrogen peroxide was formed in yield of 32% (selectivity: 84%). Separately, a gas chromatographic analysis of the reaction mixture revealed that the conversion rate from 1-phenylethanol was 38%, and acetophenone was formed in yield of 36%.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])/[CH:4]=[CH:5]/[C:6]1[C:7]([C:16]([O:18][CH3:19])=[O:17])=[CH:8][C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[CH:11][CH:10]=2.FC(F)(F)C(O)=O.CO[CH2:30][N:31]([CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[CH2:32][Si](C)(C)C>C(Cl)Cl>[CH2:37]([N:31]1[CH2:32][C@@H:5]([C:6]2[C:7]([C:16]([O:18][CH3:19])=[O:17])=[CH:8][C:9]3[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH:15]=2)[C@H:4]([C:3]([O:2][CH3:1])=[O:20])[CH2:30]1)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Reactant: COC(=O)/C=C/c1cc2ccccc2cc1C(=O)OC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1cc2ccccc2cc1[C@@H]1CN(Cc2ccccc2)C[C@H]1C(=O)OC
Temperature: 25 °C
Reaction time: 18 h
Yield: 85.5 %

Procedure:
To a solution of (E)-methyl 3-(3-methoxy-3-oxoprop-1-enyl)-2-naphthoate (1.65 g, 6.09 mmol) in 15 mL of methylene chloride was added trifluoroacetic acid (0.07 mL, 0.91 mmol) and N-(methoxymethyl)-N-(trimethylsilylmethyl)benzylamine (2.34 mL, 9.13 mmol). The reaction mixture was allowed to stir at ambient temperature for 18 h. The solution was concentrated in vacuo and purified (ISCO, elution with 0-25% EtOAc/hexane) to afford 2.1 g (86%) of the title compound as an oil. 1H NMR (CDCl3): δ 8.34 (s, 1H), 8.15 (s, 1H), 7.87-7.80 (m, 2H), 7.58-7.53 (m, 1H), 7.50-7.41 (m, 3H), 7.39-7.33 (m, 2H), 7.30-7.25 (m, 1H), 4.57-4.51 (m, 1H), 3.94 (s, 3H), 3.74 (ABq, 2H), 3.68 (s, 3H), 3.36-3.31 (m, 1H), 3.27-3.20 (m, 1H), 3.07-3.02 (m, 2H), 2.80-2.75 (m, 1H). LRMS (ESI): 404.0 (M+H)+.
Reaction SMILES: [OH:1][CH2:2][C:3]1[NH:4][CH:5]=[C:6]([C:8](=[O:10])[CH3:9])[N:7]=1.[Br:11]Br>Br>[BrH:11].[OH:1][CH2:2][C:3]1[NH:4][CH:5]=[C:6]([C:8](=[O:10])[CH2:9][Br:11])[N:7]=1
Reactant: BrBr
Reactant: CC(=O)c1c[nH]c(CO)n1
Agent: Br
Product: O=C(CBr)c1c[nH]c(CO)n1
Temperature: 80 °C
Yield: 112.8 %

Procedure:
1.826 g (0.013 mole) of 2-hydroxymethyl-4-acetylimidazole was dissolved in 40 ml of 48% hydrobromic acid and 2.1 g (0.013 mole) of bromine was added. The reaction was warmed at 80° C. for 2 hours and then concentrated in vacuo to a solid. This material was triturated with isopropyl ether and the resultant solid was collected by filtration and was washed with ether and dried to give 2.2 g (56%) of 2-hydroxymethyl-4-bromoacetylimidazole hydrobromide, m.p. 183° C. with decomposition. 1H-NMR(DMSO-d6)ppm(delta): 8.8 (s, 1H), 4.8 (s, 2×2H).
Reaction SMILES: [NH2:1][C:2]1[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[C:3]=1[CH2:4][NH:5][C:6]1[C:7]2[N:8]([C:12]([CH:16]=[O:17])=[C:13]([CH3:15])[N:14]=2)[CH:9]=[CH:10][CH:11]=1.Cl[C:24]([O:26][CH2:27][CH2:28][Cl:29])=[O:25]>ClCCl>[Cl:29][CH2:28][CH2:27][O:26][C:24]([NH:1][C:2]1[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[C:3]=1[CH2:4][NH:5][C:6]1[C:7]2[N:8]([C:12]([CH:16]=[O:17])=[C:13]([CH3:15])[N:14]=2)[CH:9]=[CH:10][CH:11]=1)=[O:25]
Reactant: O=C(Cl)OCCCl
Reactant: Cc1cccc(N)c1CNc1cccn2c(C=O)c(C)nc12
Solvent: ClCCl
Product: Cc1cccc(NC(=O)OCCCl)c1CNc1cccn2c(C=O)c(C)nc12

Procedure:
According to the procedure indicated in Example 1a, 8-(2-amino-6-methylbenzylamino)-3-formyl-2-methylimidazo[1,2-a]pyridine (2.03 g) and 2-chloroethyl chloroformate (1.01 g) in dichloromethane (120 ml) give the title compound as a brown oil, which is used directly for further reaction in Example 3b.
Reaction SMILES: Cl.[CH3:2][NH:3][CH3:4].[CH3:5][C:6]([O:9][C:10]([NH:12][CH:13]([C:20]([OH:22])=O)[CH2:14][C:15]1[N:19]=[CH:18][S:17][CH:16]=1)=[O:11])([CH3:8])[CH3:7]>>[C:6]([O:9][C:10](=[O:11])[NH:12][C@H:13]([C:20](=[O:22])[N:3]([CH3:4])[CH3:2])[CH2:14][C:15]1[N:19]=[CH:18][S:17][CH:16]=1)([CH3:5])([CH3:7])[CH3:8]
Reactant: CNC
Reactant: CC(C)(C)OC(=O)NC(Cc1cscn1)C(=O)O
Agent: Cl
Product: CN(C)C(=O)[C@H](Cc1cscn1)NC(=O)OC(C)(C)C

Procedure:
Dimethylamine hydrochloride (1.2 mmol) and Boc-L-3-(4-thiazolyl)alanine (1.0 mmol) were coupled according to Procedure A (0-25° C. reaction temperature) and the product purified by chromatography on silica gel eluted with 1-16% ethanol In dichloromethane containing 0.5% ammonium hydroxide. Yield 124 mg, 41%.
Reaction SMILES: Cl[C:2](Cl)([O:4]C(=O)OC(Cl)(Cl)Cl)Cl.[NH2:13][C:14]1[CH:19]=[C:18]([O:20][C:21]2[CH:30]=[C:29]3[C:24]([CH2:25][CH2:26][CH:27]([C:31]([NH:33][C:34]4[CH:39]=[CH:38][CH:37]=[C:36]([C:40]([CH3:43])([CH3:42])[CH3:41])[CH:35]=4)=[O:32])[CH2:28]3)=[CH:23][CH:22]=2)[CH:17]=[CH:16][N:15]=1>C1COCC1>[C:40]([C:36]1[CH:35]=[C:34]([NH:33][C:31]([CH:27]2[CH2:26][CH2:25][C:24]3[C:29](=[CH:30][C:21]([O:20][C:18]4[CH:17]=[CH:16][N:15]=[C:14]([N:13]=[C:2]=[O:4])[CH:19]=4)=[CH:22][CH:23]=3)[CH2:28]2)=[O:32])[CH:39]=[CH:38][CH:37]=1)([CH3:43])([CH3:42])[CH3:41]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC(C)(C)c1cccc(NC(=O)C2CCc3ccc(Oc4ccnc(N)c4)cc3C2)c1
Solvent: C1CCOC1
Product: CC(C)(C)c1cccc(NC(=O)C2CCc3ccc(Oc4ccnc(N=C=O)c4)cc3C2)c1
Temperature: 0 °C
Yield: 113.2 %

Procedure:
A solution of triphosgene (304 mg, 1.02 mmol) in THF (15 mL) was cooled to 0° C. To this solution was added TEA (0.74 mL, 5.32 mmol). A solution of 7-[(2-aminopyridin-4-yl)oxy]-N-(3-tert-butylphenyl)-1,2,3,4-tetrahydronaphthalene-2-carboxamide (850 mg, 2.04 mmol) in THF (6 mL) was added dropwise to the reaction mixture over the 20 min. The reaction mixture was allowed to stir at 0° C. and then to warm to rt and stir for 1 h. The reaction mixture was filtered and the filtrate was evaporated. The residue was purified by column chromatography to give N-(3-tert-butylphenyl)-7-[(2-isocyanatopyridin-4-yl)oxy]-1,2,3,4-tetrahydronaphthalene-2-carboxamide (510 mg, 56%) as yellow solid. LCMS: (FA) ES+442.5.
Reaction SMILES: [NH2:1][C@@H:2]([CH3:18])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([Cl:17])[CH:10]=2)=[N:5]1.[N:19]1[C:27]2[C:22](=[N:23][C:24]([C:28](O)=[O:29])=[CH:25][CH:26]=2)[NH:21][CH:20]=1.CCN(C(C)C)C(C)C.C1C=C2N=NN(O)C2=CC=1.O.CCN=C=NCCCN(C)C>>[Cl:17][C:11]1[CH:10]=[C:9]([C:6]2[CH:7]=[CH:8][N:4]([CH2:3][C@@H:2]([NH:1][C:28]([C:24]3[N:23]=[C:22]4[NH:21][CH:20]=[N:19][C:27]4=[CH:26][CH:25]=3)=[O:29])[CH3:18])[N:5]=2)[CH:16]=[CH:15][C:12]=1[C:13]#[N:14]
Reactant: C[C@H](N)Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1
Reactant: O=C(O)c1ccc2nc[nH]c2n1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1ccc2nc[nH]c2n1
Yield: 83.4 %

Procedure:
The title compound was prepared from (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chlorobenzonitrile (0.063 g, 0.384 mmol), 3H-imidazo[4,5-b]pyridine-5-carboxylic acid (0.100 g, 0.384 mmol), DIPEA (0.200 ml, 1.151 mmol), HOBt hydrate (0.088 g, 0.575 mmol) and EDCI (0.110 g, 0.575 mmol) using the method of Example 274 affording 0.130 g of the title compound. 1H-NMR (400 MHz; d6-DMSO): δ 1.17 (d, 3H), 4.45 (m, 3H), 6.93 (d, 1H), 7.99 (m, 6H), 8.64 (s, 1H), 8.99 (d, 1H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](S(C)=O)[C:5]([C:11]#[N:12])=[C:4]([S:13][CH3:14])[N:3]=1.O.[NH2:16][NH2:17]>C(#N)C>[NH2:1][C:2]1[N:7]=[C:6]([NH:16][NH2:17])[C:5]([C:11]#[N:12])=[C:4]([S:13][CH3:14])[N:3]=1
Reactant: CSc1nc(N)nc(S(C)=O)c1C#N
Reactant: NN
Solvent: CC#N
Solvent: O
Product: CSc1nc(N)nc(NN)c1C#N
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a 50 mL round-bottomed flask were added 2-Amino-4-methanesulfinyl-6-methylsulfanyl-pyrimidine-5-carbonitrile (8:100 mg, 0.4 mmol.), hydrazine hydrate (0.8 mmol), and acetonitrile (2 mL). The reaction mixture was stirred at room temperature for 4 hr. The precipitate was filtered and gave to white solid. No further purification was necessary (76 mg). LC-MS: (ES+) m/z 197 (M+1).
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[N:11](COCC[Si](C)(C)C)[CH:12]=[C:13]([C:15]([NH:17][C@@H:18]([CH3:34])[CH2:19][N:20]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][C:28]([C:31]#[N:32])=[C:27]([Cl:33])[CH:26]=3)=[N:21]2)=[O:16])[N:14]=1)(C(C)(C)C)(C)C>Cl>[ClH:33].[Cl:33][C:27]1[CH:26]=[C:25]([C:22]2[CH:23]=[CH:24][N:20]([CH2:19][C@@H:18]([NH:17][C:15]([C:13]3[N:14]=[C:10]([CH2:9][OH:8])[NH:11][CH:12]=3)=[O:16])[CH3:34])[N:21]=2)[CH:30]=[CH:29][C:28]=1[C:31]#[N:32]
Reactant: C[C@@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1cn(COCC[Si](C)(C)C)c(CO[Si](C)(C)C(C)(C)C)n1
Agent: Cl
Product: C[C@@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1c[nH]c(CO)n1

Procedure:
(S)-2-((tert-Butyldimethylsilyloxy)methyl)-N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-carboxamide (0.4 g, 15.9 mmol) in 6 N HCl (25 ml) was stirred at 45° C. for 24 h. The resulting mixture was evaporated completely and triturated twice from diethyl ether. In the end all precipitates were combined. Yield 200 mg. 1H-NMR (400 MHz; DMSO-d6): δ 1.19 (d, 3H), 4.31-4.34 (m, 3H), 4.68 (s, 2H), 6.93 (s, 1H), 7.89-7.95 (m, 3H), 8.05 (s, 1H), 8.30 (s, 1H), 9.15 (d, 1H), 14.8 (bs, 1H).
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.C([Si](C(C)C)(C(C)C)[N:23]1[C:31]2[C:26](=[CH:27][C:28]([CH2:32][CH2:33][CH2:34][C:35]3[CH:44]=[CH:43][C:42]4[C:37](=[N:38][CH:39]=[CH:40][CH:41]=4)[N:36]=3)=[CH:29][CH:30]=2)[CH:25]=[CH:24]1)(C)C>C1COCC1>[NH:23]1[C:31]2[C:26](=[CH:27][C:28]([CH2:32][CH2:33][CH2:34][C:35]3[CH:44]=[CH:43][C:42]4[C:37](=[N:38][CH:39]=[CH:40][CH:41]=4)[N:36]=3)=[CH:29][CH:30]=2)[CH:25]=[CH:24]1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2cc(CCCc3ccc4cccnc4n3)ccc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: c1cnc2nc(CCCc3ccc4[nH]ccc4c3)ccc2c1
Reaction time: 1 h
Yield: 100 %

Procedure:
Tetrabutylammonium fluoride [1.0 M in THF] (5.10 mL, 5.10 mmol) was added to a solution of 2-[3-(1-triisopropylsilanyl-1H-indol-5-yl)-propyl]-[1,8]naphthyridine (1.14 g, 2.57 mmol) in THF (20 mL) at room temperature and stirred for 1 h. The solvent was removed and the resulting crude product was purified via column chromatography on silica gel, eluting with ethyl acetate/hexane (2/1) to give the title product (100% yield). 1H NMR (CDCl3) δ 9.08 (dd, J=2.0, 4.3 Hz, 1H), 8.28 (br, 1H), 8.14 (dd, J=2.0, 8.1, 1H), 8.07 (d, J=8.4 Hz, 1H), 7.45 (m, 2H), 7.36 (d, J=8.3, 1H), 731 (d, J=8.3 Hz, 1H), 7.18 (t, J=2.8 Hz, 1H), 7.05 (dd, J=1.6, 8.3 Hz, 1H), 6.47 (m, 1H), 3.10 (t, J=7.8 Hz, 2H), 2.84 (t, J=7.7 Hz, 2H), 2.28 (m, 2H). Mass Spectrum (LCMS, ESI) calculated for C19H18N3 288.2 (M+H); found 288.2.
Reaction SMILES: [C:1]1([C:7]2([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:12][CH2:11][CH2:10][NH:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:19]=[C:20]1[C:25]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:24][CH2:23][CH2:22][N:21]1[CH2:38][C:39](O)=[O:40].Cl.C(N=C=NCCCN(C)C)C>ClCCl.CN(C)C1C=CN=CC=1>[C:1]1([C:7]2([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:12][CH2:11][CH2:10][N:9]([C:39](=[O:40])[CH2:38][N:21]3[CH2:22][CH2:23][CH2:24][C:25]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[C:20]3=[O:19])[CH2:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(C2(c3ccccc3)CCCNC2)cc1
Reactant: O=C(O)CN1CCCC(c2ccccc2)(c2ccccc2)C1=O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: O=C(CN1CCCC(c2ccccc2)(c2ccccc2)C1=O)N1CCCC(c2ccccc2)(c2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3,3-diphenylpiperidine (Example 24A, 0.24 g, 1.00 mmol) in dichloromethane (20 mL) was added 2-(2-oxo-3,3-diphenylpiperidin-1-yl)acetic acid (Example 68E, 0.308 g, 1.00 mmol), under nitrogen. To the reaction was added N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (0.38 g, 2.00 mmol) and N,N-dimethylpyridin-4-amine (0.012 g, 0.10 mmol), and the reaction mixture was stirred overnight at room temperature. The reaction was concentrated, and the residue was partitioned in ethyl acetate:water (8:2). The organic layer was separated, washed with water and then brine, dried over MgSO4, filtered and concentrated. Silica gel chromatography eluting with 3% methanol/dichloromethane gave the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 7.12-7.33 (m, 20H), 4.23 (s, 2H), 4.13 (s, 2H), 3.35-3.46 (m, 4H), 2.57-2.64 (m, 2H), 2.45-2.51 (m, 2H), 1.72-1.85 (m, 2H), 1.46-1.56 (m, 2H); MS (DCI+) m/z 529 (M+H)+.
Reaction SMILES: [Si]([O:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[CH:12][N:13]2[CH2:18][CH2:19][N:20]([CH2:28][C@H:29]([OH:36])[C:30]1[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=1)[C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[OH:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[CH:12][N:13]2[CH2:18][CH2:19][N:20]([CH2:28][C@H:29]([OH:36])[C:30]1[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=1)[C:21](=[O:27])[O:22][C:23]([CH3:24])([CH3:26])[CH3:25]
Reactant: CC(C)(C)OC(=O)N(CCn1ccc2c(O[Si](C)(C)C(C)(C)C)cccc21)C[C@H](O)c1cccnc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N(CCn1ccc2c(O)cccc21)C[C@H](O)c1cccnc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 97.3 %

Procedure:
To a solution of tert-butyl [2-(4-{[tert-butyl(dimethyl)silyl]oxy}-1H-indol-1-yl)ethyl][(2R)-2-hydroxy-2-pyridin-3-ylethyl]carbamate (316 mg, 0.618 mmol) in tetrahydrofuran (5 mL) is added a 1.0M solution of tetrabutylammonium fluoride in tetrahydrofuran (927 μL, 1.5 equivalent), and the mixture is stirred at room temperature for 3 hours. Further, to the mixture is added a 1.0 M solution of tetrabutyl-ammonium fluoride in tetrahydrofuran (927 μL, 1.5 equivalent), and the mixture is stirred for 15 hours. The reaction mixture is concentrated under reduced pressure, and the obtained brown residue is purified by silica gel column (ammonia-chloroform:methanol=100:1→50:1→20:1) to give the title compound as oil (239 mg, yield: 97%).
Reaction SMILES: [CH3:1][CH2:2][C@@H:3]([C@H:5]([N:36]([C:38]([C@@H:40]([NH:44][C:45]([C@@H:47]([N:51]([CH3:53])[CH3:52])[CH:48]([CH3:50])[CH3:49])=[O:46])[CH:41]([CH3:43])[CH3:42])=[O:39])[CH3:37])[C@H:6]([O:34][CH3:35])[CH2:7][C:8]([N:10]1[C@H:14]([C@H:15]([O:32][CH3:33])[C@H:16]([C:18]([NH:20][C@H:21]([C:29]([OH:31])=[O:30])[CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:19])[CH3:17])[CH2:13][CH2:12][CH2:11]1)=[O:9])[CH3:4].C([NH:61][C@H:62]([C:64]([OH:66])=[O:65])[CH3:63])(OC(C)(C)C)=O.[OH:67][CH2:68][CH2:69][CH2:70][NH-:71].FC(F)(F)C(O)=O>ClCCl>[CH3:1][CH2:2][C@@H:3]([C@H:5]([N:36]([C:38]([C@@H:40]([NH:44][C:45]([C@@H:47]([N:51]([CH3:53])[CH3:52])[CH:48]([CH3:50])[CH3:49])=[O:46])[CH:41]([CH3:43])[CH3:42])=[O:39])[CH3:37])[C@H:6]([O:34][CH3:35])[CH2:7][C:8]([N:10]1[C@H:14]([C@H:15]([O:32][CH3:33])[C@H:16]([C:18]([NH:20][C@H:21]([C:29]([OH:31])=[O:30])[CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:19])[CH3:17])[CH2:13][CH2:12][CH2:11]1)=[O:9])[CH3:4].[OH:67][CH2:68][CH2:69][CH2:70][NH-:71].[NH2:61][C@H:62]([C:64]([OH:66])=[O:65])[CH3:63]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1ccccc1)C(=O)O)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)C)C(C)C
Agent: [NH-]CCCO
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@H](N)C(=O)O
Temperature: 23 °C
Reaction time: 1 h

Procedure:
Auristatin F-hydroxypropylamide Boc-L-Alanine (112 mg, 0.115 mmol, prepared as described in Example 49) was taken up in dichloromethane (3 mL) and excess trifluoroacetic acid was added. The mixture was stirred at 23° C. for 1 hour and the solvent removed under high vacuum. The resulting oil was taken up in dichloromethane (1.5 mL) and precipitation from diethyl ether (30 mL to give the title compound as white solid (96.2 mg, 85%).