Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[N:2]([CH3:19])[CH:3]=[CH:4][C:5]([C:7]1[CH:8]=[C:9]([N:13]([CH2:17][CH3:18])[C:14](=[O:16])[CH3:15])[CH:10]=[CH:11][CH:12]=1)=O.Cl.N[C:22]1[C:26]([C:27]#[N:28])=C[NH:24][N:23]=1.Cl>O.CO>[CH3:18][CH2:17][N:13]([C:14]([CH3:15])=[O:16])[C:9]1[CH:10]=[CH:11][CH:12]=[C:7]([C:5]2[N:24]3[N:23]=[CH:22][C:26]([C:27]#[N:28])=[C:19]3[N:2]=[CH:3][CH:4]=2)[CH:8]=1
Reactant: N#Cc1c[nH]nc1N
Reactant: CCN(C(C)=O)c1cccc(C(=O)C=CN(C)C)c1
Agent: Cl
Solvent: CO
Solvent: O
Product: CCN(C(C)=O)c1cccc(-c2ccnc3c(C#N)cnn23)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96 %

Procedure:
N-[3-[3-(dimethylamino)-1-oxo-2-propenyl]phenyl]-N-ethylacetamide (2.6 g, 0.01 mol) and 3-amino-4-cyanopyrazole-hydrochloride (1.44 g, 0.01 mol) were dissolved in the mixture of water (35 cm3) and methanol (20 cm3). Concentrated (37%) hydrochloric acid (0.83 cm3, 0.01 mol) was then added and the mixture was stirred at room temperature for about 2 hours. The reaction mixture was then cooled to about 5° C. and the crystalline product formed was collected, washed with water and dried at about 60° C. to yield zaleplon (2.93 g, 96.1%) in 99.16% purity as determined by HPLC.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH3:15].[F:16][C:17]([F:32])([F:31])[C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][C:26]=1[C:27]([F:30])([F:29])[F:28])[C:21](O)=[O:22]>CCCCCCC.CCOC(C)=O>[CH3:1][N:2]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH3:15])[C:21](=[O:22])[C:20]1[CH:24]=[CH:25][C:26]([C:27]([F:28])([F:29])[F:30])=[C:18]([C:17]([F:16])([F:31])[F:32])[CH:19]=1
Reactant: O=C(O)c1ccc(C(F)(F)F)c(C(F)(F)F)c1
Reactant: CNc1cnccc1-c1ccccc1C
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: Cc1ccccc1-c1ccncc1N(C)C(=O)c1ccc(C(F)(F)F)c(C(F)(F)F)c1

Procedure:
The title compound was prepared in analogy to example 90, from N-methyl-4-o-tolylpyridin-3-amine (example 1, intermediate a) and 3,4-bis(trifluoromethyl)benzoic acid (CAS RN 133804-66-7) and using a gradient of n-heptane:EtOAc (100:0 to 0:100) for the chromatographic purification. Yellow solid (43%). MS (ESI): m/z=439.12 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](S(C)(=O)=O)[C:5]([C:12]#[N:13])=[C:4]([C:14]2[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=2)[N:3]=1.[C:26]1([OH:32])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([O:32][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:5]([C:12]#[N:13])=[C:4]([C:14]2[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=2)[N:3]=1
Reactant: COc1cc(-c2nc(N)nc(S(C)(=O)=O)c2C#N)cc(OC)c1OC
Reactant: Oc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: COCCOC
Product: COc1cc(-c2nc(N)nc(Oc3ccccc3)c2C#N)cc(OC)c1OC

Procedure:
From 2-amino-4-methanesulfonyl-6-(3,4,5-trimethoxy-phenyl)-pyrimidine-5-carbonitrile, phenol and DBU in DME. ES-MS m/e (%): 379 (M+H+, 100).
Reaction SMILES: [Br:1][C:2]1[CH:19]=[CH:18][C:5]2[C:6]([CH:15]([CH3:17])[CH3:16])=[N:7][C:8]3[CH:9]=[CH:10][NH:11][C:12](=[O:14])[C:13]=3[C:4]=2[CH:3]=1.C1C(=O)N([I:27])C(=O)C1>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[CH:19]=[CH:18][C:5]2[C:6]([CH:15]([CH3:16])[CH3:17])=[N:7][C:8]3[C:9]([I:27])=[CH:10][NH:11][C:12](=[O:14])[C:13]=3[C:4]=2[CH:3]=1
Reactant: O=C1CCC(=O)N1I
Reactant: CC(C)c1nc2cc[nH]c(=O)c2c2cc(Br)ccc12
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)c1nc2c(I)c[nH]c(=O)c2c2cc(Br)ccc12
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a stirred suspension of 9-bromo-6-isopropylbenzo[c]-1,6-naphthyridin-1(2H)-one (81 mg, 0.26 mmol) in DMF (1.5 ml) was added NIS (86 mg, 0.38 mmol), and stirred for 24 hours at room temperature. The reaction mixture was diluted with EtOAc until a solution was formed, and washed with a mixture of 10% aqueous sodium thiosulfate and 1N NaOH. The organic layer was dried over sodium sulfate, filtered and concentrated. The crude material was adsorbed on to silica gel and purified by silica gel chromatography using an EtOAc/Hexanes gradient to afford 9-bromo-4-iodo-6-isopropylbenzo[c]-1,6-naphthyridin-1(2H)-one. LRMS (ESI) calc'd for (C15H12BrIN2O) [M+H]+, 442.9; found 442.8.
Reaction SMILES: [CH2:1]=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH:6]=[CH:5][N:4]2[C:13](S(C)=O)=[N:14][N:15]=[C:3]12.[CH3:19][O-:20].[Na+]>>[CH3:19][O:20][C:13]1[N:4]2[C:3]([C:2](=[CH2:1])[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=3[CH:6]=[CH:5]2)=[N:15][N:14]=1
Reactant: C[O-]
Reactant: C=C1c2ccccc2C=Cn2c1nnc2S(C)=O
Agent: [Na+]
Product: C=C1c2ccccc2C=Cn2c(OC)nnc21

Procedure:
The reaction of 11-methylene-3-methylsulfinyl-11H-s-triazolo[3,4-b][3]benzazepine with sodium methoxide yielded 3-methoxy-11-methylene-11H-s-triazolo[3,4-b][3]benzazepine. Colorless needles (as recrystallized from ethyl acetate), melting point: 160°-161° C.
Reaction SMILES: [I:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[CH3:9].CCCCCC.C(O[CH:19]=[C:20]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[C:21]([O:23][CH2:24][CH3:25])=[O:22])C>>[I:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][CH:19]=[C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:4][C:3]=1[CH3:9]
Reactant: Cc1cc(N)ccc1I
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Solvent: CCCCCC
Product: CCOC(=O)C(=CNc1ccc(I)c(C)c1)C(=O)OCC
Temperature: 130 °C

Procedure:
4-iodo-3-methylaniline (5.75 g) was suspended in diethyl ethoxymethylenemalonate (5.5 mL). The mixture was heated at 130° C. for 2.5 h. After cooling to ˜90° C., hexane was added and the mixture stirred while cooling to room temperature. The product crystallized out, and was filtered off, washing well with more hexane. The solid was dried in vacuo to yield the title compound as a pale grey powder (7.947 g); 1H NMR δ (CDCl3) 1.33 (3H, t), 1.38 (3H, t), 2.43 (3H, s), 4.25 (2H, q), 4.3 (2H, q), 6.69 (1H, dd), 7.01 (1H, d), 7.75 (1H, d), 8.46 (1H, d), and 10.95 (1H, br d).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([NH:17][NH2:18])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:19][C:20]([CH3:27])([CH3:26])[C:21](=O)[CH2:22][C:23]#[N:24].Cl>CCO>[CH2:1]([O:8][C:9]([N:11]1[CH2:12][CH2:13][CH:14]([N:17]2[C:23]([NH2:24])=[CH:22][C:21]([C:20]([CH3:27])([CH3:26])[CH3:19])=[N:18]2)[CH2:15][CH2:16]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NNC1CCN(C(=O)OCc2ccccc2)CC1
Reactant: CC(C)(C)C(=O)CC#N
Agent: Cl
Solvent: CCO
Product: CC(C)(C)c1cc(N)n(C2CCN(C(=O)OCc3ccccc3)CC2)n1
Yield: 21.4 %

Procedure:
A yellow solution of Intermediate 16a (1.80 g, 7.22 mmol), 4,4-dimethyl-3-oxopentanenitrile (1.08 g, 8.66 mmol), and HCl (4M in dioxane, 2.70 mL, 10.8 mmol) in EtOH (25 mL) was stirred at reflux for 4 h. The cooled solution was applied to an SCX-2 cartridge (50 g), washed with MeOH (100 mL). The product was eluted with 2M NH3 in MeOH (100 mL); concentration in vacuo left a yellow oil (772 mg). FCC, using 0-5% MeOH in DCM, gave the title compound as a yellow gum (550 mg, 21%). LCMS (Method 3): Rt 2.88 min, m/z 357 [MH+].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([Mg]Br)=[CH:6]2.Cl[CH2:15][C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:15][C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1
Reactant: COc1ccc2[nH]c([Mg]Br)cc2c1
Reactant: ClCc1cccnc1
Product: COc1ccc2[nH]cc(Cc3cccnc3)c2c1

Procedure:
The above mentioned compound was prepared analogously to the procedure described in J. Het. Chem. 3, 67 (1966) from 5-methoxy-indolyl-magnesium bromide and 3-chloromethylpyridine. After purification by Flash Chromatography on silica gel using as eluent methylene chloride/methanol/ammonia (98:2:0,1), the desired compound was obtained.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:9]([N:10]=1)=[CH:8][CH:7]=[C:6]([O:11][C:12]1[CH:13]=[CH:14][C:15]([CH3:32])=[C:16]([NH:18][C:19](=[O:31])[C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]4([C:29]#[N:30])[CH2:28][CH2:27]4)[CH:21]=3)[CH:17]=1)[N:5]=2.C([O:36][CH2:37][C:38](Cl)=[O:39])(=O)C>N1C=CC=CC=1>[C:29]([C:26]1([C:22]2[CH:21]=[C:20]([CH:25]=[CH:24][CH:23]=2)[C:19]([NH:18][C:16]2[CH:17]=[C:12]([O:11][C:6]3[N:5]=[C:4]4[S:3][C:2]([NH:1][C:37](=[O:36])[CH2:38][OH:39])=[N:10][C:9]4=[CH:8][CH:7]=3)[CH:13]=[CH:14][C:15]=2[CH3:32])=[O:31])[CH2:27][CH2:28]1)#[N:30]
Reactant: Cc1ccc(Oc2ccc3nc(N)sc3n2)cc1NC(=O)c1cccc(C2(C#N)CC2)c1
Reactant: CC(=O)OCC(=O)Cl
Solvent: c1ccncc1
Product: Cc1ccc(Oc2ccc3nc(NC(=O)CO)sc3n2)cc1NC(=O)c1cccc(C2(C#N)CC2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 46 %

Procedure:
To a solution of N-{5-[(2-amino[1,3]thiazolo[5,4-b]pyridin-5-yl)oxy]-2-methylphenyl}-3-(1-cyanocyclopropyl)benzamide (200 mg, 0.453 mmol) produced in Example C29(iv) in pyridine (4.0 mL) was added 2-chloro-2-oxoethyl acetate (73 μL, 0.68 mmol), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with methanol (2.0 mL). 1N Aqueous sodium hydroxide solution (2.0 mL) was added, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, 1N hydrochloric acid was added to neutralize the residue, and the mixture was extracted with ethyl acetate (100 mL). The organic layer was washed with water (100 mL) and saturated brine (100 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (ethyl acetate/methanol=100/0→80/20), and the obtained solution was concentrated under reduced pressure. The residue was crystallized from ethyl acetate/tetrahydrofuran/hexane to give the title compound (104 mg, 46%) as a colorless powder.
Reaction SMILES: [I:1][C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.C([O-])([O-])=O.[Cs+].[Cs+].CN(C=O)C.[CH3:18][O:19][C:20](=[O:23])[CH2:21]Cl>CCOC(C)=O>[CH3:18][O:19][C:20](=[O:23])[CH2:21][N:4]1[CH:3]=[C:2]([I:1])[CH:6]=[N:5]1
Reactant: Ic1cn[nH]c1
Reactant: COC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)Cn1cc(I)cn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 4-iodopyrazole (1.000 g, 5.155 mmol), Cs2CO3 (2.016 g, 6.186 mmol) and DMF (20 mL, 0.2 mol) was added chloroacetic acid methyl ester (0.5440 mL, 6.186 mol) at 0° C. The reaction was allowed to stir for 1 h at rt. The material was transferred to a separatory funnel, diluted with EtOAc, and washed with water several times to remove DMF. The organic layer was dry-loaded onto silica gel, and column chromatography was used to purify, eluting with 3:1 Hexanes/EtOAc, affording the title compound as a clear liquid. 1H NMR (400 MHz, CDCl3): δ=3.79 (s, 3H), 4.93 (s, 2H), 7.54 (s, 1H), 7.57 (s, 1H). MS (ES+): m/z=266.95 (100) [MH+]. HPLC: tR=2.73 min (ZQ3, polar—5 min).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:33])([CH2:27][N:28]1[CH:32]=[N:31][N:30]=[N:29]1)[C:10]([F:26])([F:25])[C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:18]=[N:19][C:20](OC)=[N:21][CH:22]=2)=[CH:13][N:12]=1.P(Cl)(Cl)([Cl:36])=O>CN(C=O)C>[Cl:36][C:20]1[N:19]=[CH:18][C:17]([C:14]2[CH:15]=[CH:16][C:11]([C:10]([F:26])([F:25])[C:9]([C:3]3[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=3[F:1])([OH:33])[CH2:27][N:28]3[CH:32]=[N:31][N:30]=[N:29]3)=[N:12][CH:13]=2)=[CH:22][N:21]=1
Reactant: COc1ncc(-c2ccc(C(F)(F)C(O)(Cn3cnnn3)c3ccc(F)cc3F)nc2)cn1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: OC(Cn1cnnn1)(c1ccc(F)cc1F)C(F)(F)c1ccc(-c2cnc(Cl)nc2)cn1
Temperature: 80 °C
Reaction time: 2 h
Yield: 31 %

Procedure:
To 2-(2,4-difluorophenyl)-1,1-difluoro-1-(5-(2-methoxypyrimidin-5-yl)pyridin-2-yl)-3-(1H-tetrazol-1-yl)propan-2-ol (37; 80 mg, 0.17 mmol) was added phosphorus oxychloride (POCl3; 1.0 mL) followed by DMF (cat) at RT under inert atmosphere. The reaction mixture was gradually heated to 80° C. and stirred for 2 h. After complete consumption of the starting material (by TLC), the reaction mixture was cooled to RT, diluted with ice-cold water (30 mL), made basic (pH ˜8) using satd NaHCO3 solution and extracted with EtOAc (2×50 mL). The combined organic extracts were washed with water (50 mL) and brine (50 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to obtain the crude material. Purification by silica gel column chromatography (eluting with 38% EtOAc/hexane) afford 57 (25 mg, 0.05 mmol, 31%) as a semi-solid. 1H NMR (500 MHz, CDCl3): δ 8.84 (s, 2H), 8.74 (s, 1H), 8.71 (s, 1H), 8.01 (dd, J=8.0, 2.5 Hz, 1H), 7.77 (d, J=8.0 Hz, 1H), 7.42-7.39 (m, 1H), 7.05 (br s, OH), 6.82-6.77 (m, 1H), 6.73-6.69 (m, 1H), 5.52 (d, J=14.5 Hz, 1H), 5.23 (d, J=14.5 Hz, 1H). MS (ESI): m/z 466 (M+H)+. HPLC: 93%.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[NH:15][C@H:14]2[CH3:19])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[H-].[Na+].[Br:24][C:25]1[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][C:26]=1[CH2:34]Br>C1COCC1>[F:21][C:2]([F:1])([F:20])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:34][C:26]3[CH:27]=[C:28]([N+:31]([O-:33])=[O:32])[CH:29]=[CH:30][C:25]=3[Br:24])[C@H:14]2[CH3:19])[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1
Reactant: O=[N+]([O-])c1ccc(Br)c(CBr)c1
Reactant: C[C@@H]1NC(=O)O[C@@H]1c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C[C@H]1[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1cc([N+](=O)[O-])ccc1Br
Reaction time: 1.5 h

Procedure:
To a solution of (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one (5.3 g, 16.95 mmol) in THF (100 mL) at 0° C., NaH (746 mg, 60 w/w % in mineral oil, 18.65 mmol, 1.1 eq.) was added in one portion. The resulting foaming mixture was stirred in an ice bath. Additional THF (100 mL) was added into the reaction. The mixture was stirred at 0° C. for 30 min. A solution of 1-bromo-2-(bromomethyl)-4-nitrobenzene (5.0 g, 16.95 mmol) in THF (25 mL) was added. The resulting mixture was stirred cold for 30 min and then allowed to warm to ambient. The reaction was completed in 1.5 h. The reaction was quenched with sat. aqueous NH4Cl (100 mL). Crude mixture was extracted with EtOAc, and dried over Na2SO4. The resulting clear gel was purified by SiO2 (Biotage 40M cartridge, EtOAc/hexane, gradient, 25% to 45%). The titled compound was obtained as a crystalline solid. LC-MS: 529.11 (M+1)+. 1H NMR (CDCl3, 500 MHz) δ 8.24 (d, J=2.5 Hz, 1H), 8.07 (dd, J=8.7, 2.8 Hz, 1H), 7.91 (s, 1H), 7.79-7.83 (m, 3H), 5.82 (d, J=7.8 Hz, 1H), 4.82 (d, J=16.2 Hz, 1H), 4.44 (d, J=16.3, 1H), 4.11-4.20 (m, 1H), 0.84 (d, J=6.6 Hz, 3H).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[C:7]([CH:10]([S:12][CH:13]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]2[O:25][CH2:26][O:27][C:21]=2[CH:20]=1)[C:14]([O:16][CH3:17])=[O:15])[CH3:11])([OH:9])=O>CN(C=O)C.O1CCCC1>[CH2:26]1[O:27][C:21]2[C:22](=[CH:23][C:24]3[C:7](=[O:9])[C@H:10]([CH3:11])[S:12][C@@H:13]([C:14]([O:16][CH3:17])=[O:15])[CH2:18][C:19]=3[CH:20]=2)[O:25]1
Reactant: COC(=O)C(Cc1ccc2c(c1)OCO2)SC(C)C(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COC(=O)[C@H]1Cc2cc3c(cc2C(=O)[C@H](C)S1)OCO3
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 72.5 %

Procedure:
Oxalyl chloride (13.6 g) and DMF (3 drops) were successively added dropwise to a solution of methyl 2-(1-carboxyethyl)thio-3-(3,4-methylenedioxyphenyl)propionate (27.8 g) in tetrahydrofuran (THF) (200 ml), followed by stirring for 1.5 hours at room temperature and concentrated under reduced pressure. The residual oil was dissolved in dichloromethane (250 ml). To the solution was added dropwise tin(IV) tetrachloride (SnCl4)(51.0 g) under ice-cooling. The mixture was stirred for an hour under ice-cooing, to which 2NHCl (100 ml) was added dropwise. The dichloromethane layer was separated, washed with water, dried (MgSO4) and distilled off the solvent. The residual oil was dissolved in methanol (250 ml), to which a solution of sodium methoxide in methanol (28%, 10 ml) was added. The resultant solution was stirred for 1.5 hours at room temperature to which 2N--HCl (250 ml) was added. The precipitated crystals were collected by filtration to give methyl trans-7,8-methylenedioxy-4-methyl-5-oxo-1,2,4,5-tetrahydro-3-benzothiepine-2-carboxylate (19.0 g, 73%). Recrystallization from ethyl acetate gave colorless prisms.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]1([C:10]([OH:12])=O)[CH2:9][CH2:8]1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.Cl.Cl.[NH2:48][C:49]1[CH:50]=[CH:51][C:52]([N:56]2[CH2:61][CH2:60][CH2:59][C@@H:58]([C:62]([N:64]3[CH2:68][CH2:67][CH2:66][CH2:65]3)=[O:63])[CH2:57]2)=[N:53][C:54]=1[NH2:55]>ClCCl>[NH2:55][C:54]1[C:49]([NH:48][C:10]([C:7]2([C:2]3[CH:3]=[N:4][CH:5]=[CH:6][N:1]=3)[CH2:8][CH2:9]2)=[O:12])=[CH:50][CH:51]=[C:52]([N:56]2[CH2:61][CH2:60][CH2:59][C@@H:58]([C:62]([N:64]3[CH2:68][CH2:67][CH2:66][CH2:65]3)=[O:63])[CH2:57]2)[N:53]=1
Reactant: Nc1ccc(N2CCC[C@@H](C(=O)N3CCCC3)C2)nc1N
Reactant: O=C(O)C1(c2cnccn2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Nc1nc(N2CCC[C@@H](C(=O)N3CCCC3)C2)ccc1NC(=O)C1(c2cnccn2)CC1
Reaction time: 0.17 h
Yield: 34.3 %

Procedure:
To a solution of 1-(pyrazin-2-yl)cyclopropanecarboxylic acid (0.11 g, 0.669 mmol) in anhydrous dichloromethane (15 mL) was added O-(7-azabenzotriazol-1-yl)-N,N,N′,N′,-tetramethyluronium hexafluorophosphate (HATU) (0.3 g, 0.803 mmol) and diisopropylethylamine (0.35 mL, 2 mmol) at room temperature. The mixture was stirred for 10 min and then (R)-(1-(5,6-diaminopyridin-2-yl)piperidin-3-yl)(pyrrolidin-1-yl)methanone dihydrochloride (0.29 g, 0.803 mmol) was added. The reaction mixture was stirred for 30 min. The solvent was removed under reduced pressure and the residue was partitioned between ethyl acetate and water. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified via column chromatography (100-200 mesh silica gel, 0-5% methanol in dichloromethane) to afford (R)—N-(2-amino-6-(3-(pyrrolidine-1-carbonyl)piperidin-1-yl)pyridin-3-yl)-1-(pyrazin-2-yl)cyclopropanecarboxamide (100 mg). MS (ES+APCI) (M+H) 436.1.
Reaction SMILES: [Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.[CH3:12][CH2:13][C@@H:14]([C@H:16]([N:46]([C:48]([C@@H:50]([NH:54][C:55]([C@@H:57]([N:61]([CH3:63])[CH3:62])[CH:58]([CH3:60])[CH3:59])=[O:56])[CH:51]([CH3:53])[CH3:52])=[O:49])[CH3:47])[C@H:17]([O:44][CH3:45])[CH2:18][C:19]([N:21]1[C@H:25]([C@H:26]([O:42][CH3:43])[C@H:27]([C:29]([NH:31][C@@H:32]([C@@H:34]([OH:41])[C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH3:33])=[O:30])[CH3:28])[CH2:24][CH2:23][CH2:22]1)=[O:20])[CH3:15]>C(Cl)Cl.N1C=CC=CC=1>[CH3:63][N:61]([CH3:62])[C@H:57]([C:55]([NH:54][C@H:50]([C:48]([N:46]([C@@H:16]([C@@H:14]([CH3:15])[CH2:13][CH3:12])[C@H:17]([O:44][CH3:45])[CH2:18][C:19]([N:21]1[CH2:22][CH2:23][CH2:24][C@H:25]1[C@H:26]([O:42][CH3:43])[C@@H:27]([CH3:28])[C:29]([NH:31][C@H:32]([CH3:33])[C:34](=[O:41])[C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)=[O:30])=[O:20])[CH3:47])=[O:49])[CH:51]([CH3:53])[CH3:52])=[O:56])[CH:58]([CH3:60])[CH3:59]
Reactant: 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](C)[C@@H](O)c1ccccc1)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)C)C(C)C
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: 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](C)C(=O)c1ccccc1)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)C)C(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Pyridinium chlorochromate (PCC) (13.6 mg, 0.06 mmol, 4.5 eq.) was added to a solution of Auristatin E (29a) (10 mg, 0.014 mmol, 1 eq.) in CH2Cl2 (2 mL) and pyridine (50 μL). The reaction mixture was stirred at room temperature for 3 h. HPLC analysis of the reaction mixture showed complete conversion of the 10.2 min peak into a new 11.3 min peak with different UV spectrum (max 245 nm, shoulder 280 nm). The product was purified by flash chromatography on a silica gel column (120×12 mm) in a step gradient of MeOH in CH2Cl2 from 0 to 10%. After concentration in vacuum, the residue was triturated with hexane to give white solid. Yield 35: 6.4 mg (64%); Rf 0.3 (CH2Cl2/MeOH, 10/1); UV λmax 215, 245 nm. HRMS m/z: found 730.5119 [M+H]+. C40H68N5O7 requires 730.5108.
Reaction SMILES: [ClH:1].C(OC([N:9]1[CH2:14][CH2:13][C@@H:12]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][C:17]=2[N+:23]([O-:25])=[O:24])[C@H:11]([OH:26])[CH2:10]1)=O)(C)(C)C>O1CCOCC1.ClCCl>[ClH:1].[Br:22][C:19]1[CH:20]=[CH:21][C:16]([NH:15][C@@H:12]2[CH2:13][CH2:14][NH:9][CH2:10][C@H:11]2[OH:26])=[C:17]([N+:23]([O-:25])=[O:24])[CH:18]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](Nc2ccc(Br)cc2[N+](=O)[O-])[C@H](O)C1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: O=[N+]([O-])c1cc(Br)ccc1N[C@@H]1CCNC[C@H]1O
Reaction time: 16 h
Yield: 89 %

Procedure:
Add 4.0 M hydrogen chloride in dioxane (70 mL) slowly to a solution of (3R,4R)-4-(4-bromo-2-nitro-phenylamino)-3-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (0.027 mol, 11.5 g) in dry dichloromethane (40 mL) at room temperature and stir for 16 h. Filter the precipitate and dry under vacuum to obtain the title compound (8.68 g, 89%) as a yellow solid. 1H NMR (400 MHz, CD3OD) δ 1.81-1.86 (m, 1H), 2.39-2.44 (m, 1H), 3.02-3.07 (m, 1H), 3.18-3.26 (m, 1H), 3.34-3.40 (m, 1H), 3.45 (dd, 1H), 3.87-3.91 (m, 2H), 7.17 (d, 1H), 7.61 (dd, 1H), 8.28 (d, 1H).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([C:11]([CH3:15])([CH3:14])[CH2:12]Cl)[CH:5]=1>O1CCCC1>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]2[O:10][CH2:12][C:11]([CH3:15])([CH3:14])[C:6]=2[CH:5]=1
Reactant: CC(C)(CCl)c1cc(Cl)ccc1O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC1(C)COc2ccc(Cl)cc21
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a suspension of NaH (1.44 g, 36 mmol) in anhydrous tetrahydrofuran was added 4-chloro-2-(1-chloro-2-methylpropan-2-yl)phenol (721) (6.6 g, 30.0 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 1 hour. The reaction was quenched with methanol, diluted with water, and extracted with ether. The ethereal extract was washed with brine, dried over anhydrous sodium sulfate, filtered and evaporated in vacuo. The residue was purified by flash chromatography on silica gel to give 5-chloro-3,3-dimethyl-2,3-dihydrobenzofuran (722).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[OH:20][C:21]1[CH:30]=[C:29]2[C:24]([C:25](=[O:39])[N:26]([CH2:31][O:32][C:33](=[O:38])[C:34]([CH3:37])([CH3:36])[CH3:35])[CH:27]=[N:28]2)=[CH:23][C:22]=1[O:40][CH3:41].[CH3:42][S:43]([CH2:46][CH2:47][CH2:48]O)(=[O:45])=[O:44].CCOC(/N=N/C(OCC)=O)=O>C(Cl)Cl>[CH3:41][O:40][C:22]1[CH:23]=[C:24]2[C:29](=[CH:30][C:21]=1[O:20][CH2:48][CH2:47][CH2:46][S:43]([CH3:42])(=[O:45])=[O:44])[N:28]=[CH:27][N:26]([CH2:31][O:32][C:33](=[O:38])[C:34]([CH3:35])([CH3:36])[CH3:37])[C:25]2=[O:39]
Reactant: COc1cc2c(=O)n(COC(=O)C(C)(C)C)cnc2cc1O
Reactant: CS(=O)(=O)CCCO
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1cc2c(=O)n(COC(=O)C(C)(C)C)cnc2cc1OCCCS(C)(=O)=O
Yield: 90.7 %

Procedure:
Triphenylphosphine (8.9 g, 35.2 mmol) was added to a suspension of 7-hydroxy-6-methoxy-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one (6 g, 19.6 mmol), (prepared as described for the starting material in Example 7), in methylene chloride (150 ml). This was followed by the addition of 3-methylsulphonylpropanol (3.5 g, 25.4 mmol) and diethylazodicarboxylate (5.55 ml, 35.2 mmol) in portions. The reaction was complete once the reaction became homogeneous. Silica was added and the volatiles were removed by evaporation. The free flowing powder was placed on the top of a flash chromatography column pre-equilibrated with ethyl acetate (100%). Elution was done using ethyl acetate (100%) followed by methylene chloride/ethyl acetate/methanol (60/35/3). The volatiles were removed by evaporation to give 6-methoxy-7-(3-methylsulphonylpropoxy)-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one (7.58 g, 91%) as a white solid.