Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(O)C=CC=CC=1.[CH3:8][O:9][C:10]1[CH:11]=[C:12]([OH:16])[CH:13]=[CH:14][CH:15]=1.[N+](=[C:19]1[C:28](=[O:29])[C:27]2[C:22](=[CH:23][CH:24]=[C:25]([O:30][CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[CH:26]=2)[O:21][CH2:20]1)=[N-]>>[CH2:31]([O:30][C:25]1[CH:26]=[C:27]2[C:22](=[CH:23][CH:24]=1)[O:21][CH2:20][CH:19]([O:16][C:12]1[CH:13]=[CH:14][CH:15]=[C:10]([O:9][CH3:8])[CH:11]=1)[C:28]2=[O:29])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: COc1cccc(O)c1
Reactant: [N-]=[N+]=C1COc2ccc(OCc3ccccc3)cc2C1=O
Solvent: Oc1ccccc1
Product: COc1cccc(OC2COc3ccc(OCc4ccccc4)cc3C2=O)c1

Procedure:
Replacing the phenol with a molar equivalent of 3-methoxyphenol, the method of Example 9 was employed to convert 3-diazo-6-benzyloxy-4-chromanone (76 g) to present title product, 5.5 g, m.p. 98-100° C.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([C:10]1[CH:15]=[CH:14][C:13]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])=[C:12]([C:21]#[C:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:11]=1)[CH3:9])(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:20][S:17]([NH:16][C:13]1[CH:14]=[CH:15][C:10]([CH:8]([NH2:7])[CH3:9])=[CH:11][C:12]=1[C:21]#[C:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)(=[O:19])=[O:18]
Reactant: CC(NC(=O)OC(C)(C)C)c1ccc(NS(C)(=O)=O)c(C#Cc2ccccc2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(N)c1ccc(NS(C)(=O)=O)c(C#Cc2ccccc2)c1
Reaction time: 24 h
Yield: 193.3 %

Procedure:
[1-(4-Methanesulfonylamino-3-phenylethynylphenyl)ethyl]carbamic acid tert-butyl ester (300 mg, 0.724 mmol) and trifluoroacetic acid (279 μl, 3.619 mmol, 3 eq) were added in methylene chloride. The reaction mixture was stirred for 24 hrs. A reaction solvent was removed in vacuo to yield 1-(4-methanesulfonylamino-3-phenylethynylphenyl)ethylamine (440.1 mg, 100%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH:15]CC2C=CC(OC)=CC=2OC)=[N:5][C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([O:13][CH3:14])=[CH:8][CH:7]=2.FC(F)(F)C(O)=O>ClCCl>[NH2:15][C:4]1[C:3]([O:2][CH3:1])=[N:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:13][CH3:14])[CH:10]=2)[N:5]=1
Reactant: COc1ccc(CNc2nc3ccc(OC)cc3nc2OC)c(OC)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc2nc(N)c(OC)nc2c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 95.2 %

Procedure:
To 3,6-dimethoxy-2-(2,4-dimethoxybenzylamino)quinoxaline (4.45 g, 12.8 mmol), 70 ml of 50% trifluoroacetic acid in dichloromethane was added at room temperature. The resulting mixture was stirred at room temperature for 18 hours and concentrated under the reduced pressure to remove the solvent. The residue was neutralized with saturated sodium bicarbonate solution and then NaCl solution was added thereto. The product was extracted with dichloromethane and the organic layer was dried over MgSO4. After concentration under the reduced pressure, the crude product was purified by SiO2 column chromatography. Extraction of the residue with a n-hexane:ethyl acetate mixture and concentration gave 2.50 g of the titled compound (yield, 95%).
Reaction SMILES: C([O:8][C@H:9]1[CH2:14][C@H:13]2[CH2:15][C@@H:10]1[CH2:11][C@@H:12]2[O:16][Si:17]([C:30]([CH3:33])([CH3:32])[CH3:31])([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)C1C=CC=CC=1.[H][H]>CO.[Pd]>[Si:17]([O:16][C@H:12]1[CH2:11][C@H:10]2[CH2:15][C@@H:13]1[CH2:14][C@@H:9]2[OH:8])([C:30]([CH3:33])([CH3:31])[CH3:32])([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC(C)(C)[Si](O[C@H]1C[C@H]2C[C@@H]1C[C@@H]2OCc1ccccc1)(c1ccccc1)c1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)[Si](O[C@H]1C[C@H]2C[C@@H]1C[C@@H]2O)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Palladium (10 wt. % on activated carbon, 1.50 g) was added to a solution of ((1R,2S,4R,5S)-5-(benzyloxy)bicyclo[2.2.1]heptan-2-yloxy)(tert-butyl)diphenylsilane (8.47 g, 18.5 mmol) in methanol (50 mL). The mixture was placed under a balloon of hydrogen. After stirring at ambient temperature for 24 h, the mixture was filtered through a pad of Celite. Solvents were removed in vacuo to give the title compound as a colorless viscous oil.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[C:5]([CH3:15])=[C:4]([CH3:16])[N:3]=1.[N:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH2:23][NH2:24].Cl>C(#N)C.O1CCOCC1>[ClH:1].[CH:9]1([NH:8][C:6]2[C:5]([CH3:15])=[C:4]([CH3:16])[N:3]=[C:2]([NH:24][CH2:23][C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][N:17]=3)[N:7]=2)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: Cc1nc(Cl)nc(NC2CCCCC2)c1C
Reactant: NCc1ccccn1
Agent: Cl
Solvent: C1COCCO1
Solvent: CC#N
Product: Cc1nc(NCc2ccccn2)nc(NC2CCCCC2)c1C
Temperature: 25 °C
Yield: 50.3 %

Procedure:
To a stirred solution of 2-chloro-N-cyclohexyl-5,6-dimethylpyrimidin-4-amine (0.1 g, 0.40 mmol) and (pyridin-2-ylmethyl)amine (0.04 g, 0.400 mmol) in acetonitrile (5 mL) was added a 3.5 M solution of hydrogen chloride in dioxane (0.2 mL). The resulting mixture was irradiated in CEM Focused Microwave™ Synthesis System at 160° C. for 120 minutes. The resulting mixture was cooled to ambient temperature. The formed precipitate was collected by filtration and dried to yield 0.07 g (48.2%) of the titled compound as the hydrochloride salt. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.99-1.03 (m, 2H), 1.13 (d, J=12.63 Hz, 1H), 1.20-1.26 (m, 2H), 1.51-1.59 (m, 2H), 1.60-1.63 (m, 3H), 1.89 (s, 3H), 2.24 (s, 3H), 3.70 (s, 1H), 4.62 (d, J=5.10 Hz, 2H), 7.24 (dd, J=7.25, 4.84 Hz, 1H), 7.31 (d, J=7.79 Hz, 1H), 7.58 (d, J=7.72 Hz, 1H, 7.74 (t, J=7.66 Hz, 1H), 8.1 (s, 1H), 8.50 (d, J=4.84 Hz, 1H); MS (ESI) m/z 312.3 (M+1)+.
Reaction SMILES: S(Cl)([Cl:3])=O.[Cl:5][C:6]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[C:8]([Cl:16])[C:7]=1[N:17]1[CH:21]=[C:20]2[CH:22](O)[CH2:23][CH2:24][C:19]2=[N:18]1.CCOC(C)=O.C([O-])(O)=O.[Na+]>C1COCC1>[Cl:5][C:6]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[C:8]([Cl:16])[C:7]=1[N:17]1[CH:21]=[C:20]2[CH:22]([Cl:3])[CH2:23][CH2:24][C:19]2=[N:18]1
Reactant: OC1CCc2nn(-c3c(Cl)cc(C(F)(F)F)cc3Cl)cc21
Reactant: O=S(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: FC(F)(F)c1cc(Cl)c(-n2cc3c(n2)CCC3Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Thionyl chloride (0.1 mL, 1.37 mmol) was added to a solution of (62) (100.0 mg, 0.29 mmol) in THF (2 mL). After stirring for 2 hours at ambient temperature, EtOAc (10 mL) was added and the resulting mixture was poured into 5% aq. NaHCO3 (20 mL) at 4° C. The resulting mixture was extracted with EtOAc (10 mL). The organic layer was washed with 5% NaHCO3 (20 mL) at 4° C., dried (Na2SO4) and concentrated in vacuo to give the title compound as a pale solid in quantitative yield. 1H NMR (CDCl3); δ 7.72 (s, 2H), 7.42 (s, 1H), 5.43 (d, 1H, J=5.6), 3.22-2.94 (m, 2H), 2.85-2.70 (m, 2H); MS (M++1) 355.4.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[N:12]([C:14](I)=[C:15]([NH:17][C:18](=[O:20])[CH3:19])[N:16]=3)[N:13]=2)=[CH:4][C:3]=1[NH:22][S:23]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([O:32][CH:33]([F:35])[F:34])[CH:27]=1)(=[O:25])=[O:24].CC1(C)C(C)(C)OB([C:44]2[CH2:49][CH2:48][N:47]([C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])[CH2:46][CH:45]=2)O1>>[C:18]([NH:17][C:15]1[N:16]=[C:11]2[CH:10]=[CH:9][C:8]([C:5]3[CH:6]=[N:7][C:2]([Cl:1])=[C:3]([NH:22][S:23]([C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([O:32][CH:33]([F:35])[F:34])[CH:27]=4)(=[O:25])=[O:24])[CH:4]=3)=[N:13][N:12]2[C:14]=1[C:44]1[CH2:49][CH2:48][N:47]([C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])[CH2:46][CH:45]=1)(=[O:20])[CH3:19]
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: CC(=O)Nc1nc2ccc(-c3cnc(Cl)c(NS(=O)(=O)c4cccc(OC(F)F)c4)c3)nn2c1I
Product: CC(=O)Nc1nc2ccc(-c3cnc(Cl)c(NS(=O)(=O)c4cccc(OC(F)F)c4)c3)nn2c1C1=CCN(C(=O)OC(C)(C)C)CC1
Yield: 25.9 %

Procedure:
Following the procedure described in Example 49, N-(6-(6-chloro-5-(3-(difluoromethoxy)phenylsulfonamido)pyridin-3-yl)-3-iodoimidazo[1,2-b]pyridazin-2-yl)acetamide (370.0 mg, 583 μmol)was combined with tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (216 mg, 699 μmol, (Carbocore, The Woodlands, Tex.) to afford tert-butyl 4-(2-acetamido-6-(6-chloro-5-(3-(difluoromethoxy)phenylsulfonamido)pyridin-3-yl)imidazo[1,2-b]pyridazin-3-yl)-5,6-dihydropyridine-1(2H)-carboxylate (104 mg, 25.9% yield) as a yellow solid. LCMS (ESI positive ionization) m/z: 691 (M+1).
Reaction SMILES: Cl.C(N=C=NCCCN(C)C)C.Cl.C[O:15][C:16]([C:18]1([NH2:24])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)=[O:17].ON1C2C=CC=CC=2N=N1.[CH2:35]([O:37][C:38]1[CH:42]=[CH:41][S:40][C:39]=1[C:43](O)=[O:44])[CH3:36].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[CH2:35]([O:37][C:38]1[CH:42]=[CH:41][S:40][C:39]=1[C:43]([NH:24][C:18]1([C:16]([OH:15])=[O:17])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)=[O:44])[CH3:36]
Reactant: CCOc1ccsc1C(=O)O
Reactant: COC(=O)C1(N)CCCCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOc1ccsc1C(=O)NC1(C(=O)O)CCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.5 %

Procedure:
633 mg (3.3 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride was added to a solution of 581 mg (3 mmol) of 1-aminocyclohexanecarboxylic acid methyl ester hydrochloride, 482 mg (3.1 mmol) of 1-hydroxybenzotriazole, 517 mg (3 mmol) of 3-ethoxy-2-thiophenecarboxylic acid and 1.16 g (9 mmol) of diisopropylethylamine in 10 ml of methylene chloride under ice-cooling. After the solution was stirred at room temperature overnight, the reaction solution was concentrated under reduced pressure, ethyl acetate was added thereto, and the mixture was washed with water, a 10% aqueous potassium hydrogensulfate solution, a saturated aqueous sodium hydrogencarbonate solution and then saturated brine, followed by drying with anhydrous sodium sulfate. After the solvent was distilled off under reduced pressure, diisopropyl ether was added to the residue, followed by stirring overnight and the crystal was collected by filtration. Subsequently, the obtained crystal was dissolved in 3 ml of tetrahydrofuran solution, 2.8 ml of 2N—NaOH aqueous solution was added thereto, and the mixture was refluxed under heating for 3 hours. Ether was added to the reaction solution and the aqueous layer was separated. After the separated aqueous layer was neutralized by concentrated hydrochloric acid, the layer was extracted with ethyl acetate. After the obtained organic layer was washed with saturated brine, it was dried with anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain 656 mg (73%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=O)=[C:4]([OH:17])[CH:3]=1.[C:18]([CH2:23][CH:24]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)(OCC)=[O:19].[Cl-].[NH4+]>C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:5]([C:8]([C:10]3[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=3)=[C:23]([CH3:24])[C:18](=[O:19])[O:17]2)=[CH:6][CH:7]=1
Reactant: O=C(c1ccc(F)cc1)c1ccc(Cl)cc1O
Reactant: CCOC(=O)CC=P(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Product: Cc1c(-c2ccc(F)cc2)c2ccc(Cl)cc2oc1=O
Temperature: 200 °C
Reaction time: 15 h
Yield: 51.7 %

Procedure:
A mixture of (4-chloro-2-hydroxyphenyl)(4-fluorophenyl)methanone (200 mg) and (carboethoxyethylidene)triphenylphosphorane (435 mg) was heated with stirring at 200° C. for 15 hours. After cooling, the reaction mixture was diluted with ethyl acetate and the solution was poured into an aqueous saturated ammonium chloride solution. The mixture was extracted with ethyl acetate, and the organic layer was washed with water and brine, and filtered through a column of porous diatomite (Chem Elut). The filtrate was concentrated and the resulted residue was purified by column chromatography on silica gel (Solvent: n-hexane/ethyl acetate=97/3 to 90/10) to give the titled compound (119 mg) as a yellow powder.
Reaction SMILES: [C:1]1([CH3:22])[CH:6]=[CH:5][C:4]([P:7]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)[C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)=[CH:3][CH:2]=1.O.[Ru:24](Cl)([Cl:26])[Cl:25]>CO>[Ru:24]([Cl:26])[Cl:25].[C:18]1([CH3:21])[CH:19]=[CH:20][C:15]([P:7]([C:8]2[CH:9]=[CH:10][C:11]([CH3:14])=[CH:12][CH:13]=2)[C:4]2[CH:5]=[CH:6][C:1]([CH3:22])=[CH:2][CH:3]=2)=[CH:16][CH:17]=1.[C:18]1([CH3:21])[CH:19]=[CH:20][C:15]([P:7]([C:8]2[CH:9]=[CH:10][C:11]([CH3:14])=[CH:12][CH:13]=2)[C:4]2[CH:5]=[CH:6][C:1]([CH3:22])=[CH:2][CH:3]=2)=[CH:16][CH:17]=1.[C:18]1([CH3:21])[CH:19]=[CH:20][C:15]([P:7]([C:8]2[CH:9]=[CH:10][C:11]([CH3:14])=[CH:12][CH:13]=2)[C:4]2[CH:5]=[CH:6][C:1]([CH3:22])=[CH:2][CH:3]=2)=[CH:16][CH:17]=1
Reactant: Cl[Ru](Cl)Cl
Agent: Cc1ccc(P(c2ccc(C)cc2)c2ccc(C)cc2)cc1
Solvent: O
Solvent: CO
Product: Cl[Ru]Cl

Procedure:
Using the procedure of Example 1, 50 mls. of methanol, 6.0 grams of tri-paratolylphosphine and 1.0 gram of ruthenium trichloride hydrate are stirred and heated at reflux under nitrogen for 24 hours to form tris(tri-paratolylphosphine) ruthenium dichloride as an insoluble powder which is recovered by filtration (4.2 grams).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:18][CH2:17][C:16]2[C:11](=[CH:12][C:13]([O:19][CH2:20][C:21](O)=[O:22])=[CH:14][CH:15]=2)[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:24]([NH2:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C=O)C>[C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:18][CH2:17][C:16]2[C:11](=[CH:12][C:13]([O:19][CH2:20][C:21]([NH:31][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[O:22])=[CH:14][CH:15]=2)[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCc2ccc(OCC(=O)O)cc2C1
Reactant: NCc1ccccc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@H]1CCc2ccc(OCC(=O)NCc3ccccc3)cc2C1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
2.26 g (7 mmole) of (2S)-2-tert-butoxycarbonylamino-7-hydroxycarbonylmethoxy-tetralin were mixed with 80 ml of DMF and 0.749 g (7 mmole) of benzylamine, 3.1 g of BOP and 1.47 ml (10.5 mmole) of triethylamine were added. The mixture was stirred at ambient temperature for 6 hours then left to stand overnight without stirring. The solvent was evaporated off; the residue was taken up in ethyl acetate and washed with a 5% sodium bicarbonate solution. The organic phase was dried and the solvent was evaporated off under reduced pressure. The compound of the heading was obtained.
Reaction SMILES: [CH3:1]CN(C(C)C)C(C)C.[CH3:10][CH2:11][C@H:12]([C@H:14]([NH:59][C:60]([C@@H:62]1[N:67]([CH3:68])[CH2:66][CH2:65][CH2:64][CH2:63]1)=[O:61])[C:15]([N:17]([C@@H:26]([CH:56]([CH3:58])[CH3:57])[CH2:27][C@@H:28]([O:52][C:53]([CH3:55])=[O:54])[C:29]1[S:33][CH:32]=[C:31]([C:34]([NH:36][C@H:37]([CH2:46][C@@H:47]([C:49]([OH:51])=[O:50])[CH3:48])[CH2:38][C:39]2[CH:40]=[CH:41][C:42](O)=[CH:43][CH:44]=2)=[O:35])[N:30]=1)[CH2:18][O:19][C:20]([CH2:22][CH:23]([CH3:25])[CH3:24])=[O:21])=[O:16])[CH3:13]>CN(C=O)C>[CH3:10][CH2:11][C@@H:12]([C@H:14]([NH:59][C:60]([C@@H:62]1[N:67]([CH3:68])[CH2:66][CH2:65][CH2:64][CH2:63]1)=[O:61])[C:15]([N:17]([C@@H:26]([CH:56]([CH3:58])[CH3:57])[CH2:27][C@@H:28]([O:52][C:53]([CH3:55])=[O:54])[C:29]1[S:33][CH:32]=[C:31]([C:34]([NH:36][C@H:37]([CH2:46][C@@H:47]([C:49]([OH:51])=[O:50])[CH3:48])[CH2:38][C:39]2[CH:44]=[CH:43][C:42]([CH3:1])=[CH:41][CH:40]=2)=[O:35])[N:30]=1)[CH2:18][O:19][C:20]([CH2:22][CH:23]([CH3:25])[CH3:24])=[O:21])=[O:16])[CH3:13]
Reactant: CC[C@@H](C)[C@H](NC(=O)[C@H]1CCCCN1C)C(=O)N(COC(=O)CC(C)C)[C@H](C[C@@H](OC(C)=O)c1nc(C(=O)N[C@@H](Cc2ccc(O)cc2)C[C@H](C)C(=O)O)cs1)C(C)C
Reactant: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC[C@H](C)[C@H](NC(=O)[C@H]1CCCCN1C)C(=O)N(COC(=O)CC(C)C)[C@H](C[C@@H](OC(C)=O)c1nc(C(=O)N[C@@H](Cc2ccc(C)cc2)C[C@H](C)C(=O)O)cs1)C(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 136.4 %

Procedure:
To a solution of pyridine dithioethylamine hydrochloric salt (15.8 mg, 0.071 mmole) in anhydrous DMF (1.5 mL) was added DIEA (25 μL, 0.142 mmole) followed by a solution of tubulysin A (40 mg, 0.047 mmole) in anhydrous DMF (0.5 mL). The reaction mixture was stirred under argon at room temperature for 2 h. The mixture was then evaporated under vacuum. The crude product was purified by silica gel column chromatography (CH2Cl2/MeOH, 15/1) to afford white solid (54 mg) in quantitative yield.
Reaction SMILES: [F:1][C:2]1[C:27]([F:28])=[CH:26][C:5]2[N:6]([C:19]3[CH:20]=[N:21][CH:22]=[C:23]([F:25])[CH:24]=3)[C:7]([C@@H:9]([NH:11]C(=O)OC(C)(C)C)[CH3:10])=[N:8][C:4]=2[CH:3]=1.O1CCOCC1>Cl>[F:1][C:2]1[C:27]([F:28])=[CH:26][C:5]2[N:6]([C:19]3[CH:20]=[N:21][CH:22]=[C:23]([F:25])[CH:24]=3)[C:7]([C@@H:9]([NH2:11])[CH3:10])=[N:8][C:4]=2[CH:3]=1
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1nc2cc(F)c(F)cc2n1-c1cncc(F)c1
Agent: Cl
Solvent: C1COCCO1
Product: C[C@H](N)c1nc2cc(F)c(F)cc2n1-c1cncc(F)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of (S)-tert-butyl 1-(5,6-difluoro-1-(5-fluoropyridin-3-yl)-1H-benzo[d]-imidazol-2-yl)ethylcarbamate (0.460 g, 1.17 mmol) in hydrochloric acid, 4 M solution in 1,4-dioxane (5.86 mL, 23.45 mmol) was stirred at rt. After 4 h, the mixture was partitioned between DCM (50 mL) and water (50 mL). The aqueous layer was washed with DCM (1×50 mL) to remove an organic impurity. The aqueous layer was treated with satd. aq. sodium bicarbonate solution (50 mL) and extracted with DCM (1×50 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. The crude material was absorbed onto a plug of silica gel and purified by chromatography through a Redi-Sep™ pre-packed silica gel column (40 g), eluting with a gradient of 0% to 50% DCM:MeOH:NH4OH (89:9:1) in DCM, to provide (S)-1-(5,6-difluoro-1-(5-fluoropyridin-3-yl)-1H-benzo[d]imidazol-2-yl)ethanamine as a colorless syrup: 1H NMR (400 MHz, DMSO-d6) δ ppm 8.84 (1H, d, J=2.7 Hz), 8.75 (1H, s), 8.24 (1H, dt, J=9.4, 2.3 Hz), 7.79 (1H, dd, J=11.0, 7.4 Hz), 7.40 (1H, dd, J=10.4, 7.2 Hz), 3.96 (1H, q, J=6.6 Hz), 2.00 (2H, d, J=4.5 Hz), 1.37 (3H, d, J=6.7 Hz); LC-MS (ESI) m/z 293.0 [M+H]+.
Reaction SMILES: Br[C:2]1[C:6]([Cl:7])=[C:5]([CH3:8])[N:4]([CH2:9][O:10][CH2:11][CH2:12][Si:13]([CH3:16])([CH3:15])[CH3:14])[C:3]=1[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18].[Li]CCCC.C1C=CC(S(N(S(C2C=CC=CC=2)(=O)=O)[F:39])(=O)=O)=CC=1>C1COCC1>[Cl:7][C:6]1[C:2]([F:39])=[C:3]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[N:4]([CH2:9][O:10][CH2:11][CH2:12][Si:13]([CH3:16])([CH3:15])[CH3:14])[C:5]=1[CH3:8]
Reactant: Cc1c(Cl)c(Br)c(C(=O)OC(C)(C)C)n1COCC[Si](C)(C)C
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1c(Cl)c(F)c(C(=O)OC(C)(C)C)n1COCC[Si](C)(C)C
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
tert-butyl 3-bromo-4-chloro-5-methyl-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrole-2-carboxylate (Intermediate 265, 480 mg, 1.13 mmol) was dissolved in dry THF (8 ml), cooled down to −78° C., n-BuLi (2.5M in Hexane, 3.39 mmol) was added dropwise into the mixture via syringe and the mixture was stirred at −78° C. for 30 min followed by a quick addition of N-Fluorobenzensulfonimide (1.25 g, 3.96 mmol in 5 ml of THF/Toluene 1:1), the resulting mixture was then stirred at −78° C. for 30 min and slowly warmed up to room temperature during a period of 12 hrs. The reaction was quenched at 0° C. with drops of saturated NH4Cl solution and further diluted with EtOAc (50 ml). The organic phase was washed with brine and dried over anhydrous MgSO4, concentrated to an oil and purified by flash column chromatography eluted with 10% EtOAc in Hexanses. The desired product was obtained as an oil (125 mg).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][C:5]=1[NH2:11].NC1C=C(F)C=CC=1C(O)=[O:17].CCN(C(C)C)C(C)C.ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl.O>[F:10][C:7]1[CH:8]=[CH:9][C:4]2[C:3](=[O:12])[O:2][C:1](=[O:17])[NH:11][C:5]=2[CH:6]=1
Reactant: COC(=O)c1ccc(F)cc1N
Reactant: Nc1cc(F)ccc1C(=O)O
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: O
Product: O=c1[nH]c2cc(F)ccc2c(=O)o1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 68 %

Procedure:
2-Amino-4-fluorobenzoic acid methyl ester. 2-Amino-4fluorobenzoic acid (5.0 g, 32 mmol) was dissolved in DCM (50 mL) and cooled to 0° C. Hünig's base (11 ml, 64 mmol) was added followed by triphosgene (3.8 g, 13 mmol). The reaction mixture was stirred for 5 min then allowed to warm to ambient temperature over 45 min. Water was added to the mixture, which was then extracted with DCM (3×), and the combined organic layers were dried (MgSO4). Filtration and concentration provided 7-fluoro-1H-benzo[d][1,3]oxazine-2,4-dione as a tan solid (3.94 g, 21.8 mmol, 68%), which was taken on directly to the next step. To a solution of 7-fluoro-1H-benzo[d][1,3]oxazine-2,4-dione (3.94 g, 21.8 mmol) in DMF (20 mL) was added dry methanol (8.8 mL, 220 mmol) and DMAP (0.27 g, 2.2 mmol). The mixture was allowed to stand overnight, and was then partitioned between EtOAc and water. The organic layer was washed with water (3×) and dried (MgSO4). Filtration and purification on silica gel (MLPC, hexanes/EtOAc) provided the title methyl ester as a white solid (1.89 g, 11.1 mmol, 51%). HPLC (reversed-phase): RT=8.66 min). 1H NMR (400 MHz, CDCl3): 7.87 (m, 1H), 6.37 (m, 2H), 3.86 (s, 3H).
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:10]([NH:12][C@H:13]([C:25]([NH2:27])=[O:26])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([CH3:24])([CH3:23])[CH3:22])[CH:16]=1)=[O:11])[CH2:3][CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1.[C:35]([OH:41])([C:37]([F:40])([F:39])[F:38])=[O:36]>C(Cl)Cl>[C:35]([OH:41])([C:37]([F:40])([F:39])[F:38])=[O:36].[NH2:1][C@H:2]([C:10]([NH:12][C@H:13]([C:25]([NH2:27])=[O:26])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([CH3:24])([CH3:22])[CH3:23])[CH:16]=1)=[O:11])[CH2:3][CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1
Reactant: CC(C)(C)OC(=O)N[C@@H](CC1CCCCC1)C(=O)N[C@@H](Cc1cccc(C(C)(C)C)c1)C(N)=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)c1cccc(C[C@H](NC(=O)[C@@H](N)CC2CCCCC2)C(N)=O)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 322 mg (0.681 mmol) of Boc-Cha-Phe(3-tBu)-NH2 in 2 ml of methylene chloride, 1 ml of TFA was added and the mixture was stirred at room temperature for 2 hours. The solvent was distilled off under reduced pressure to give a TFA salt of Cha-Phe(3-tBu)-NH2; to a solution of the TFA salt in 2 ml of DMF, 0.1 ml of TEA, 343 mg (0.817 mmol) of Z-Phe-ONp and 125 mg (1.02 mmol) of DMAP were added and the mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with ethyl acetate and washed first with saturated aqueous NaHCO3, then with water and finally with saturated brine. The organic layer was dried with anhydrous magnesium sulfate and concentrated under reduced pressure; the resulting residue was subjected to silica gel column chromatography (eluting solvent; chloroform:methanol=10:1) to give Z-Phe-Cha-Phe(3-tBu)-NH2 in the amount of 192 mg (43%).
Reaction SMILES: C(OC(=O)[CH:5]([C:11](=[O:22])[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=1)C(OCC)=O)C>CS(C)=O.O>[N+:19]([C:16]1[CH:15]=[CH:14][C:13]([CH2:12][C:11](=[O:22])[CH3:5])=[CH:18][CH:17]=1)([O-:21])=[O:20]
Reactant: CCOC(=O)C(C(=O)Cc1ccc([N+](=O)[O-])cc1)C(=O)OCC
Solvent: O
Solvent: CS(C)=O
Product: CC(=O)Cc1ccc([N+](=O)[O-])cc1
Temperature: 150 °C
Reaction time: 10 h
Yield: 20.6 %

Procedure:
2-[2-(4-Nitro-phenyl)-acetyl]-malonic acid diethyl ester (1.4 g) was taken up in a mixture of DMSO (8 ml) and water (4 ml) and heated at 150° C. with stirring for 10 hr. The product was extracted with ethyl acetate (50 ml). The organic layer was washed with water, aqueous sodium bicarbonate solution and brine. The organic layer was then dried over sodium sulphate, filtered and evaporated. Purification by column chromatography over silica gel using ethyl acetate and hexane (6:94) as eluent yielded 1-(4-nitro-phenyl)-propan-2-one (160 mg, 24%).