Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:11])[C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.[CH2:12]([C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1)[CH2:13][CH2:14][CH3:15]>>[CH2:12]([C:16]1[CH:17]=[CH:18][C:19]([NH:20][CH2:7][C:6]2[CH:9]=[CH:10][C:3]([N:2]([CH3:11])[CH3:1])=[CH:4][CH:5]=2)=[CH:21][CH:22]=1)[CH2:13][CH2:14][CH3:15]
Reactant: CN(C)c1ccc(C=O)cc1
Reactant: CCCCc1ccc(N)cc1
Product: CCCCc1ccc(NCc2ccc(N(C)C)cc2)cc1
Yield: 36.1 %

Procedure:
By the reaction and treatment in the same manner as in Preparation Example 1 using 4-dimethylaminobenzaldehyde (10.0 g) and 4-butylaniline (10.0 g) as starting materials, (4-butylphenyl)[(4-dimethylaminophenyl)methyl]amine (6.83 g) was obtained. melting point: 60–61° C.
Reaction SMILES: [ClH:1].[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[C@@H:4]([NH:10][C:11]([C:13]1[S:14][C:15]3[C:21]([C:22]4[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=4)[C:25](O)=[O:26])=[CH:20][CH:19]=[CH:18][C:16]=3[CH:17]=1)=[O:12])[CH2:3]2.[CH3:31][N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>>[ClH:1].[ClH:1].[N:2]12[CH2:7][CH2:6][CH:5]([CH2:8][CH2:9]1)[C@@H:4]([NH:10][C:11]([C:13]1[S:14][C:15]3[C:21]([C:22]4[CH:30]=[CH:29][CH:28]=[C:24]([C:25]([N:35]5[CH2:36][CH2:37][N:32]([CH3:31])[CH2:33][CH2:34]5)=[O:26])[CH:23]=4)=[CH:20][CH:19]=[CH:18][C:16]=3[CH:17]=1)=[O:12])[CH2:3]2
Reactant: O=C(O)c1cccc(-c2cccc3cc(C(=O)N[C@H]4CN5CCC4CC5)sc23)c1
Reactant: CN1CCNCC1
Agent: Cl
Product: CN1CCN(C(=O)c2cccc(-c3cccc4cc(C(=O)N[C@H]5CN6CCC5CC6)sc34)c2)CC1

Procedure:
50 mg (0.11 mmol) of 3-(2-{[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]carbonyl}-1-benzothien-7-yl)benzoic acid hydrochloride (Example 75) and 22.6 mg (0.23 mmol) of N-methylpiperazine are reacted together by general method E. 4.2 mg (6.6% of theory) of the title compound are obtained.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)=[N:10][NH:11][CH:12]=2)[CH:5]=[CH:4][N:3]=1.[F:20][C:21]1[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=1[NH2:23]>CO>[F:20][C:21]1[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=1[NH:23][C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)=[N:10][NH:11][CH:12]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Nc1ccccc1F
Reactant: Fc1ccc(-c2n[nH]cc2-c2ccnc(Cl)n2)cc1
Solvent: CO
Product: Fc1ccc(-c2n[nH]cc2-c2ccnc(Nc3ccccc3F)n2)cc1
Temperature: 180 °C
Yield: 77 %

Procedure:
A mixture of 2-chloro-4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]pyrimidine (0.37 g; 0.0013 mol; prepared as set forth in Example A-299), 7 mL of 2-fluoroaniline and 2 drops of methanol was heated at 180° C. in a sealed tube for 16 hours. Excess amine was removed by vacuum distillation and the residue was treated with ethyl acetate to give 0.35 g of N-(2-fluorophenyl)-4-[3-(4-fluorophenyl)-1H-pyrazol-4-yl]-2-pyrimidinamine as a yellow solid (77%), mp: 239-240° C. Anal. Calc'd. for C19H13F2N5: C, 65.33; H, 3.75; N, 20.05. Found: C, 64.95; H, 3.80; N, 19.77.
Reaction SMILES: S(Cl)([Cl:3])=O.[N:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH:11](O)[CH:12]2[CH2:17][CH:16]3[N:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:13]2[CH2:14][CH2:15]3)[CH:6]=1>>[N:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH:11]([Cl:3])[CH:12]2[CH2:17][CH:16]3[N:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH:13]2[CH2:14][CH2:15]3)[CH:6]=1
Reactant: O=S(Cl)Cl
Reactant: CCOC(=O)N1C2CCC1C(C(O)c1cccnc1)C2
Product: CCOC(=O)N1C2CCC1C(C(Cl)c1cccnc1)C2

Procedure:
Thionyl chloride (1 mL) was added to ethyl 2-((3-pyridyl)hydroxymethyl)-7-azabicyclo[2.2.1]heptane-7-carboxylate (100 mg, 0.362 mmol) and the mixture was refluxed for 2 h and cooled. The excess thionyl chloride was removed under vacuum to give ethyl 2-((3-pyridyl)chloromethyl)-7-azabicyclo[2.2.1]heptane-7-carboxylate, which was dissolved in 30 ml of water:ethanol (1:1 v/v volume) and treated with wet Raney nickel (0.5 g) under a nitrogen atmosphere. The suspension was shaken under 50 psi of hydrogen in a Parr hydrogenation apparatus for 24 h and filtered through a pad of celite. The celite was washed with ethanol (50 mL) and the combined ethanol solutions were concentrated by rotary evaporation. The remaining aqueous solution was extracted with chloroform (3×50 mL). The combined chloroform extracts were dried over anhydrous potassium carbonate, filtered, and rotary evaporated. The residue was chromatographed on a Merck silica gel 60 (70-230 mesh) column, with chloroform:methanol (95:5) as eluant. This afforded ethyl 2-((3-pyridyl)methyl)-7-azabicyclo[2.2.1]heptane-7-carboxylate (90 mg, 96%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]=1[CH:13]([NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH3:24])[C:14](N)=[O:15].[OH-:25].[K+]>C(O)C>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]=1[CH:13]([NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH3:24])[C:14]([OH:25])=[O:15]
Reactant: COc1ccc2ccccc2c1C(Nc1ccccc1C)C(N)=O
Reactant: [OH-]
Agent: [K+]
Solvent: CCO
Product: COc1ccc2ccccc2c1C(Nc1ccccc1C)C(=O)O
Yield: 35.5 %

Procedure:
A mixture of 13.6 parts of 2-methoxy-α-[(2-methylphenyl)amino]-1-naphthaleneacetamide and 120 parts of a solution of potassium hydroxide in ethanol 1 N is stirred and refluxed for 64 hours. The reaction mixture is evaporated and the residue is taken up in 250 parts of water. The unreacted starting material "A" is filtered off and the filtrate is neutralized with glacial acetic acid. The precipitated product is filtered off and dissolved in 140 parts of 1,1'-oxybisethane. The solution is washed with 100 parts of water, dried, filtered and evaporated. The solid residue is crystallized from 40 parts of 2-propanol at 0° C. The product is filtered off and dried, yielding 4.8 parts (35.5%) of 2-methoxy-α-[(2-methylphenyl)amino]-1-naphthaleneacetic acid; mp. 187.5° C.
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][C:10]2=[C:13]3[C:3]=1[O:4][CH2:5][C@H:6]([CH3:17])[N:7]3[C:8]([C@@H:14]([NH2:16])[CH3:15])=[N:9]2.[NH2:18][C:19]1[C:24]([C:25]#[N:26])=[C:23](Cl)[N:22]=[CH:21][N:20]=1.CCN(C(C)C)C(C)C>CC(O)C>[NH2:18][C:19]1[C:24]([C:25]#[N:26])=[C:23]([NH:16][C@H:14]([C:8]2[N:7]3[C:13]4[C:3]([O:4][CH2:5][C@@H:6]3[CH3:17])=[C:2]([F:1])[CH:12]=[CH:11][C:10]=4[N:9]=2)[CH3:15])[N:22]=[CH:21][N:20]=1
Reactant: N#Cc1c(N)ncnc1Cl
Reactant: C[C@H](N)c1nc2ccc(F)c3c2n1[C@@H](C)CO3
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: C[C@H](Nc1ncnc(N)c1C#N)c1nc2ccc(F)c3c2n1[C@@H](C)CO3
Temperature: 100 °C
Yield: 78.6 %

Procedure:
A mixture of (S)-1-((S)-6-fluoro-3-methyl-3,4-dihydro-5-oxa-1,2a-diazaacenaphthylen-2-yl)ethylamine (86 mg, 0.36 mmol), 4-amino-6-chloro-5-cyanopyrimidine (56 mg, 0.36 mmol) and DIPEA (125 μL, 0.92 mmol) in IPA (1 mL) was heated for 18 h at 100° C. After cooling to RT, the volatiles were removed in vacuo and the resulting brown residue was purified by column chromatography (Si—PPC, gradient 0-5% 2M NH3/MeOH in DCM) to afford 440 as a white solid (100 mg, 79%). LCMS (Method K): RT 2.86 min [M+H]+ 354.1. 1H NMR (DMSO, 400 MHz): δ 8.01 (1H, s), 7.08 (1H, dd, J=8.8, 3.1 Hz), 6.94 (1H, dd, J=12.3, 8.8 Hz), 5.67 (1H, q, J=7.0 Hz), 5.04 (1H, qdd, J=6.6, 2.6, 1.7 Hz), 4.47 (1H, dd, J=11.9, 1.7 Hz), 4.20 (1H, dd, J=11.9, 2.6 Hz), 1.71 (3H, d, J=7.0 Hz), 1.45 (3H, d, J=6.6 Hz)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1([CH3:17])[O:13][CH:12]([CH2:14][O:15][CH3:16])[CH2:11][O:10]1.[Br:18]Br>BrBr.ClC(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1([CH2:17][Br:18])[O:13][CH:12]([CH2:14][O:15][CH3:16])[CH2:11][O:10]1
Reactant: COCC1COC(C)(c2ccc(Cl)cc2Cl)O1
Reactant: BrBr
Solvent: ClC(Cl)(Cl)Cl
Product: COCC1COC(CBr)(c2ccc(Cl)cc2Cl)O1
Temperature: 20 °C
Reaction time: 2 h

Procedure:
To 100 parts of 2-(2,4-dichlorophenyl)-2-methyl-4-(methoxymethyl)-1,3-dioxolane in 480 parts of tetrachloromethane are added at 45° C. a few drops of bromine till the reaction starts. Subsequently 19.6 parts of bromine are added dropwise and the whole is stirred for 2 hours at 20° C. The pale yellow solution is washed with a sodium hydrogen carbonate solution, dried and evaporated. A high vacuum distillation yields 65 parts of pure 2-(2,4-dichlorophenyl)-2-(bromomethyl)-4-(methoxymethyl)-1,3-dioxolane; bp. 129°-132° C. at 0.01 mm. pressure.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[OH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][N:18]1[C:27](=[O:28])[C:26]2[N:25]([CH3:29])[CH:24]=[N:23][C:22]=2[N:21]([CH3:30])[C:19]1=[O:20].C(N(CC)CC)C>ClCCl.O>[O:11]=[CH:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][N:18]1[C:27](=[O:28])[C:26]2[N:25]([CH3:29])[CH:24]=[N:23][C:22]=2[N:21]([CH3:30])[C:19]1=[O:20]
Reactant: Cn1cnc2c1c(=O)n(CCCCCCO)c(=O)n2C
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cn1cnc2c1c(=O)n(CCCCCC=O)c(=O)n2C
Reaction time: 0.25 h
Yield: 87.2 %

Procedure:
Dimethyl sulfoxide (156 μl, 172 mg, 2.2 mmol) was slowly added to a solution of oxalyl chloride (103 μl, 150 mg, 1.2 mmol) in dichloromethane at -78° C. A solution of 1-(6-hydroxyhexyl)-3,7-dimethylxanthine (300 mg, 1.1 mmol), prepared in the previous step, in dichloromethane (5 ml) was added to this solution and the resulting reaction mixture stirred for 15 minutes. The cold bath was removed after addition of triethylamine (765 μl, 555 mg, 5.5 mmol). The reaction was added at ambient temperature to 20 ml water and extracted with three 50 ml aliquots of methylene chloride. The combined organic layers were washed with 1% aqueous hydrogen chloride (20 ml), saturated aqueous sodium bicarbonate (20 ml), and saturated aqueous salt solution (20 ml), and then dried over sodium sulfate. Evaporating the solvents and recrystallizing a residue in chloroform/petroleum ether produced 267 mg of 1-(6-oxohexyl)-3,7-dimethylxanthine (87% yield).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([S:14]([CH3:17])(=[O:16])=[O:15])[CH2:10][CH2:9]1)C1C=CC=CC=1.C1CCCCC1>C(O)C.[OH-].[OH-].[Pd+2]>[CH3:17][S:14]([N:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1)(=[O:16])=[O:15]
Reactant: CS(=O)(=O)N1CCN(Cc2ccccc2)CC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1CCCCC1
Solvent: CCO
Product: CS(=O)(=O)N1CCNCC1
Temperature: 80 °C
Reaction time: 4 h
Yield: 98.2 %

Procedure:
A suspension of 1-benzyl-4-methylsulfonylpiperazine (2.5 g, 9.8 mmol) and cyclohexane (30 ml) in ethanol (70 ml) containing 20% palladium hydroxide on carbon (500 mg) was stirred at 80° C. for 4 hours. The mixture was cooled, filtered and the filtrate was evaporated to give 1-methylsulfonylpiperazine (1.58 g, 98%).
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:26])[C:15]([NH:17][C:18]2[CH:23]=[CH:22][C:21](O)=[CH:20][C:19]=2[CH3:25])=[O:16])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:29])=O>C(OCC)C>[CH2:1]([CH:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:26])[C:15]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([Cl:29])=[CH:20][C:19]=2[CH3:25])=[O:16])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cc(O)ccc1NC(=O)C(=O)N1CCC(Cc2ccccc2)CC1
Reactant: O=S(Cl)Cl
Solvent: CCOCC
Product: Cc1cc(Cl)ccc1NC(=O)C(=O)N1CCC(Cc2ccccc2)CC1

Procedure:
The title compound is prepared from 2-(4-benzyl-piperidin-1-yl)-N-(4-hydroxy-methyl-phenyl)-2-oxo-acetamide (Example 117) and thionyl chloride according to the method described in Example 115. Melting Point: 105-108° C. (diethylether)
Reaction SMILES: [O:1]=[C:2]([N:16]1[CH2:21][CH2:20][N:19]2[C:22]([C:25]([F:28])([F:27])[F:26])=[N:23][N:24]=[C:18]2[CH2:17]1)[CH2:3][CH:4]([NH2:15])[CH2:5][C:6]1[CH:11]=[C:10]([F:12])[C:9]([F:13])=[CH:8][C:7]=1[F:14].[P:29](=[O:33])([OH:32])([OH:31])[OH:30]>C(O)(C)C>[P:29]([OH:33])([OH:32])([OH:31])=[O:30].[O:1]=[C:2]([N:16]1[CH2:21][CH2:20][N:19]2[C:22]([C:25]([F:28])([F:27])[F:26])=[N:23][N:24]=[C:18]2[CH2:17]1)[CH2:3][C@@H:4]([NH2:15])[CH2:5][C:6]1[CH:11]=[C:10]([F:12])[C:9]([F:13])=[CH:8][C:7]=1[F:14]
Reactant: NC(CC(=O)N1CCn2c(nnc2C(F)(F)F)C1)Cc1cc(F)c(F)cc1F
Agent: O=P(O)(O)O
Solvent: CC(C)O
Product: N[C@H](CC(=O)N1CCn2c(nnc2C(F)(F)F)C1)Cc1cc(F)c(F)cc1F
Temperature: 72.5 °C
Reaction time: 2.5 h

Procedure:
In a 25 mL round bottom flask isopropanol (4.0 mL) was taken. Then (2R:2S, 70:30)-4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-1-(2,4,5-trifluorophenyl)butan-2-amine (2.0 g) was added. The reaction mixture was heated at 70-75° C. Subsequently 85% Phosphoric acid (481 mg, 0.33 mL) was added over a period of 15-20 mins. Solid mass was precipitated out during addition. After a solvent mixture of water (1.8 mL) and IPA (14.0 mL) was added into the reaction mixture, keeping the temperature between 68-70° C. The slurry was aged for 2-3 h at 68-70° C. Then the slurry was cooled to room temperature. Solid mass was filtered off and washed with cold IPA. Solid mass was dried and collected. Wt. of titled compound-1.8 g. % Purity by HPLC-99.7%, % chiral purity by HPLC of R-isomer 72.8%.
Reaction SMILES: [C:1]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:6]=[CH:5][C:4]([CH2:7][NH:8][C:9]2[CH:14]=[CH:13][C:12]([CH:15]([CH3:17])[CH3:16])=[CH:11][CH:10]=2)=[CH:3][CH:2]=1.[CH:24]([C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([CH:33]([CH3:35])[CH3:34])[C:28]=1[N:36]=[C:37]=[O:38])([CH3:26])[CH3:25]>>[C:1]1([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:2]=[CH:3][C:4]([CH2:7][N:8]([C:9]2[CH:14]=[CH:13][C:12]([CH:15]([CH3:17])[CH3:16])=[CH:11][CH:10]=2)[C:37]([NH:36][C:28]2[C:27]([CH:24]([CH3:25])[CH3:26])=[CH:32][CH:31]=[CH:30][C:29]=2[CH:33]([CH3:35])[CH3:34])=[O:38])=[CH:5][CH:6]=1
Reactant: CC(C)c1ccc(NCc2ccc(-c3ccccc3)cc2)cc1
Reactant: CC(C)c1cccc(C(C)C)c1N=C=O
Product: CC(C)c1ccc(N(Cc2ccc(-c3ccccc3)cc2)C(=O)Nc2c(C(C)C)cccc2C(C)C)cc1
Yield: 52.6 %

Procedure:
By the reaction and treatment in the same manner as in Example 2 using (4-biphenylylmethyl)(4-isopropylphenyl)amine (1.0 g) and 2,6-diisopropylphenyl isocyanate (0.88 g) as starting materials, N-(4-biphenylylmethyl)-N′-(2,6-diisopropylphenyl)-N-(4-isopropylphenyl)urea (0.88 g) was obtained.
Reaction SMILES: [CH2:1]([CH:3]1[CH2:8][CH2:7][CH:6]([CH2:9][CH2:10][CH:11]=[O:12])[CH2:5][CH2:4]1)[CH3:2].C(C1C=CC(C=O)=CC=1)C>>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][CH:11]=[O:12])=[CH:5][CH:4]=1)[CH3:2]
Reactant: CCC1CCC(CCC=O)CC1
Agent: CCc1ccc(C=O)cc1
Product: CCc1ccc(CCC=O)cc1

Procedure:
4-Ethyl cyclohexanepropanal was similarly prepared as described in Examples I and II. First, 4-ethyl benzaldehyde (925 g, commercially available from Mitsubishi Gas Chemical America, Inc.) was used to obtain 3-(4-ethyl-phenyl)-propionaldehyde (878 g) with a boiling point of 129° C. at a pressure of 12 mmHg 3-(4-Ethyl-phenyl)-propionaldehyde (350 g) was consequently used to provide 4-ethyl cyclohexanepropanal (201 g) with a boiling point of 85° C. at a pressure of 3 mmHg
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][C@@H:9]1[CH:21]=[CH2:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C12BC(CCC1)CCC2.I[C:33]1[CH:38]=[CH:37][C:36]([C:39]([F:42])([F:41])[F:40])=[CH:35][CH:34]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[OH-].[Na+]>>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][C@@H:9]1[CH2:21][CH2:22][C:33]1[CH:38]=[CH:37][C:36]([C:39]([F:42])([F:41])[F:40])=[CH:35][CH:34]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=C[C@H]1CN(Cc2ccccc2)CCN1Cc1ccccc1
Reactant: FC(F)(F)c1ccc(I)cc1
Agent: B1C2CCCC1CCC2
Agent: [Na+]
Agent: [OH-]
Product: FC(F)(F)c1ccc(CC[C@H]2CN(Cc3ccccc3)CCN2Cc2ccccc2)cc1
Reaction time: 24 h
Yield: 37.1 %

Procedure:
Combine (S)-1,4-dibenzyl-2-vinyl-piperazine (6.0 g, 20.52 mmol) and 9-borabicyclo[3.3.1]nonane (164.1 ml, 82.07 mmol, 0.5 M in THF) and stir at ambient temperature. After 24 hrs, add 1-iodo-4-trifluoromethyl-benzene (8.37 g, 30.78 mmol), triphenylphosphine (861.0 mg, 3.28 mmol), tetrakis(triphenylphosphine)palladium(0 )(474.1 mg, 0.41 mmol), and 3N NaOH (16.8 ml) and stir at 60°. After 22 hrs, remove the THF under vacuum, stir the residue in 2N NaOH, and extract with diethyl ether. Wash the organic with 1N H2SO4 then adjust the aqueous to pH 14. Extract the aqueous with diethyl ether and combine, wash (brine), dry (sodium sulfate), and reduce the extracts to residue. Recrystallize the residue in warm ethanol to give 3.34 g (37%) of the title compound: mass spectrum (ion spray): mp 71°–75°; m/z=439.2 (M+1); Analysis for C27H29F3N2: calcd: C, 73.95; H, 6.67; N, 6.39; found: C, 74.15; H, 6.72; N, 6.52.
Reaction SMILES: [CH2:1]1[O:19][C:4]([CH2:17][CH3:18])([CH2:5][C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([C:12]([O:14][CH3:15])=[O:13])[C:7]=2[NH2:16])[O:3][CH2:2]1.[C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[C:28]1[CH:33]=[CH:32][C:31]([CH2:34]Br)=[CH:30][CH:29]=1)#[N:21].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[CH2:2]1[O:3][C:4]([CH2:17][CH3:18])([CH2:5][C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([C:12]([O:14][CH3:15])=[O:13])[C:7]=2[NH:16][CH2:34][C:31]2[CH:30]=[CH:29][C:28]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[C:20]#[N:21])=[CH:33][CH:32]=2)[O:19][CH2:1]1
Reactant: N#Cc1ccccc1-c1ccc(CBr)cc1
Reactant: CCC1(Cc2cccc(C(=O)OC)c2N)OCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCC1(Cc2cccc(C(=O)OC)c2NCc2ccc(-c3ccccc3C#N)cc2)OCCO1
Yield: 43.2 %

Procedure:
A mixture of 1-(2-amino-3-methoxycarbonylphenyl)butan-2-one ethylene ketal (37) (0.7 g) (prepared, e.g., as described in Preparation 25), 2'-(cyano)biphenyl-4-yl-methylbromide (0.826 g) and potassium carbonate (0.41 g) in dimethylformamide (20 ml) was heated at 80°-90° C. for 16 hours under an inert atmosphere. The reaction mixture was concentrated under reduced pressure, and the residue obtained was diluted with ethyl acetate (100 ml), washed twice with cold water, and then brine. The solvent was removed under reduced pressure and the residue was chromatographed on silica gel, eluting with 20% ethyl acetate/hexane, to give 1-[2-(2"-cyanobiphenyl-4'-ylmethylamino)-3-methoxycarbonylphenyl]butan-2-one ethylene ketal (0.52 g), a compound of Formula (38), as an oil.
Reaction SMILES: [C:1]1([C:7]2([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:11][CH2:10][O:9][C:8]2=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:19][CH2:20][CH2:21][OH:22]>C(OCC)(=O)C.[Cl-].[Zn+2].[Cl-]>[OH:22][CH2:21][CH2:20][N:19]1[CH2:10][CH2:11][C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:8]1=[O:9]
Reactant: O=C1OCCC1(c1ccccc1)c1ccccc1
Reactant: NCCO
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CCOC(C)=O
Product: O=C1N(CCO)CCC1(c1ccccc1)c1ccccc1

Procedure:
3,3-Diphenyldihydrofuran-2(3H)-one (1.0 g, 4.20 mmol), 2-aminoethanol (2.56 g, 42.0 mmol) and zinc chloride (0.020 g, 0.147 mmol) were heated together at 100° C. for 18 hours. The reaction was cooled, diluted with ethyl acetate, washed with water and brine, dried with MgSO4, filtered and concentrated. Silica gel chromatography eluting with 5% methanol/dichloromethane gave the title compound. MS (DCI+) m/z 282.2 (M+H)+.
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: ClCCl
Solvent: c1ccncc1
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: [C:1]([C:4]1[C:9](=[O:10])[CH:8]=[CH:7][N:6]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)[N:5]=1)(=[O:3])[CH3:2].CO[C:23](OC)([N:25]([CH3:27])[CH3:26])[CH3:24]>>[CH3:26][N:25]([CH3:27])[C:23]([CH3:24])=[CH:2][C:1]([C:4]1[C:9](=[O:10])[CH:8]=[CH:7][N:6]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:19])([F:20])[F:18])[CH:12]=2)[N:5]=1)=[O:3]
Reactant: COC(C)(OC)N(C)C
Reactant: CC(=O)c1nn(-c2cccc(C(F)(F)F)c2)ccc1=O
Product: CC(=CC(=O)c1nn(-c2cccc(C(F)(F)F)c2)ccc1=O)N(C)C
Temperature: 25 °C
Yield: 68.8 %

Procedure:
A slurry of 3-acetyl-1-[3-(trifluoromethyl)phenyl]pyridazin-4(1H)-one (0.369 g, 1.30 mmol) in N,N-dimethylacetamide dimethylacetal (3.5 mL, 18.3 mmol) was heated under microwave conditions at 120° C. for 5 min. After this time, the reaction was cooled to room temperature and concentrated onto silica gel. The crude product was purified by column chromatography (silica gel, dichloromethane to 90:10 dichloromethane/methanol) to give 3-[3-(dimethylamino)but-2-enoyl]-1-[3-(trifluoromethyl)phenyl]pyridazin-4(1H)-one (0.314 g, 68%) as a yellow foam.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([CH2:10][CH2:11][CH2:12][NH2:13])[CH:6]=[CH:7][C:8]=1[Cl:9].[Cl:14]C1C=C(Cl)C=CC=1CCC(O)=O>>[ClH:2].[Cl:14][C:6]1[CH:7]=[C:8]([Cl:9])[CH:3]=[CH:4][C:5]=1[CH2:10][CH2:11][CH2:12][NH2:13]
Reactant: O=C(O)CCc1ccc(Cl)cc1Cl
Reactant: NCCCc1ccc(Cl)c(Cl)c1
Agent: Cl
Product: NCCCc1ccc(Cl)cc1Cl

Procedure:
Intermediate 2 was prepared according to the procedures described in Intermediate 1 using 3-(2,4-dichlorophenyl)propanoic acid as the starting material. LC-MS (ESI) m/z 204.0 (M+H)+, RT=1.56 min (Method B).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[CH3:9][NH2:10]>C(O)C>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([NH:10][CH3:9])=[N:3][CH:4]=1
Reactant: Brc1ccc(Br)nc1
Reactant: CN
Solvent: CCO
Product: CNc1ccc(Br)cn1
Temperature: 80 °C

Procedure:
A 20 ml microwave reaction vessel is charged with 2,5-Dibromo-pyridine (2.00 g, 8.44 mmol) and treated with methylamine (10.45 ml of a 33% solution in ethanol, 84.43 mmol) and warmed to 80° C. for 3 days. After this time the reaction is concentrated and the remaining solid is treated with 1M HCl (50 ml) and DCM. The layers are separated and the aqueous phase is basified using 1N NaOH (to pH˜11). The product was extracted into DCM (2×) and the combined organics were dried (MgSO4), filtered and concentrated to give the desired product I-96bis (1.20 g). 1H-NMR (400 MHz, DMSO-d6): 2.75 ppm (d, 3H), 6.44 ppm (d, 1H), 6.72 ppm (bs, 1H), 7.51 ppm (dd, 1H), 8.05 ppm (s, 1H)