Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH3:9])#[CH:2].[CH3:10][O:11][C:12]([C:14]1[C:19](Br)=[CH:18][N:17]=[C:16]([S:21][CH3:22])[N:15]=1)=[O:13].C(N(CC)CC)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl.[Cu]I.CN(C)C=O>[CH3:10][O:11][C:12]([C:14]1[C:19]([C:2]#[C:1][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[CH3:9])=[CH:18][N:17]=[C:16]([S:21][CH3:22])[N:15]=1)=[O:13]
Reactant: COC(=O)c1nc(SC)ncc1Br
Reactant: C#Cc1ccccc1C
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1nc(SC)ncc1C#Cc1ccccc1C
Temperature: 100 °C
Yield: 79.4 %

Procedure:
A mixture of 1-ethynyl-2-methylbenzene (0.53 g, 4.6 mmol), 5-bromo-2-methylsulfanylpyrimidine-4-carboxylic acid methyl ester (11.0 g, 3.8 mmol), triethylamine (2.5 ml), triphenylphosphine (0.125 g, 0.48 mmol), copper (I) iodide (0.025 g, 0.13 mmol), bistriphenyphosphinepalladium (II) dichloride (0.10 g, 0.14 mmol) and dimethylformamide (1 ml) was stirred in a heavy-walled Smith process vial and irradiated with microwaves to maintain 100° C. for 20 min. The cooled mixture was diluted with dichloromethane (20 ml) and washed with 5% hydrochloric acid (20 ml), water (20 ml), saturated aqueous sodium hydrogencarbonate solution (20 ml) and water (20 ml) then dried (MgSO4) and evaporated in vacuo. The residual oil was purified by flash column chromatography over silica using a 1:4 mixture of hexane and dichloromethane as eluant. Appropriate fractions were combined and the solvents removed in vacuo to give 2-methylsulfanyl-5-(2-methylphenyl)ethynylpyrimidine-4-carboxylic acid methyl ester (0.9 g) as an orange oil. 250 MHz 1H-NMR (CDCl3) δ (ppm): 2.45 (s, 3H) (ArCH3), 2.55 (s, 3H) (—SCH3), 3.95 (s, 3H)(CO2CH3), 7.05-7.25 (m, 3H) (3×ArH), 7.45 (m, 1H) (ArH), 8.7 (s, 1H) (ArH); m/z (M+H)+. 299, HPLC purity 96%, HPLC retention time 4.15 min.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:21]([CH3:22])=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[C:17]([C:23]3[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=3)[CH:18]=2)[C:13]=1[C:29]1[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=1)[C:7]([O:9]CC)=[O:8])([CH3:4])([CH3:3])[CH3:2].O[Li].O>C1COCC1.CO.O.CN(C=O)C>[C:1]([O:5][C@@H:6]([C:12]1[C:21]([CH3:22])=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[C:17]([C:23]3[CH:24]=[CH:25][N:26]=[CH:27][CH:28]=3)[CH:18]=2)[C:13]=1[C:29]1[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2cc(-c3ccncc3)ccc2c1-c1ccc(Cl)cc1
Agent: [Li]O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc2cc(-c3ccncc3)ccc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O
Temperature: 50 °C
Yield: 51.9 %

Procedure:
A solution (S)-ethyl 2-tert-butoxy-2-(1-(4-chlorophenyl)-3-methyl-6-(pyridin-4-yl)naphthalen-2-yl)acetate (0.043 g, 0.088 mmol) in THF/MeOH/H2O (1 mL each) was treated with LiOH.H2O (0.025 g, 0.59 mmol) and heated to 50° C. overnight. The resulting solution was diluted with DMF and purified by preparatory reverse phase HPLC (Gemini column, 15 to 100% MeCN/H2O, 0.1% TFA). Lyophilization of appropriate fractions afforded 0.021 g of 53 as an off-white amorphous powder. 1H-NMR: 400 MHz, (CD3CN) δ: 8.77 (br s, 2H); 8.37 (br s, 1H); 8.17 (br s, 2H); 7.91 (s, 1H); 7.76 (dd, J=8.8, 2.4 Hz, 1H); 7.62-7.54 (m, 3H); 7.46 (d, J=8.8 Hz, 1H); 7.38 (br d, J=8.8 Hz, 1H); 5.25 (s, 1H); 2.61 (s, 3H); 0.99 (s, 9H). LCMS-ESI− (m/z): [2M−H]− calcd for C56H51Cl2N2O6: 917.31; found: 917.51.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:3]=1[C:4]([NH:6][C:7]1[C:12]2[O:13][C:14]([CH3:18])=[C:15]([CH2:16][OH:17])[C:11]=2[CH:10]=[CH:9][CH:8]=1)=[O:5].[C:24](OC(=O)C)(=[O:26])[CH3:25].N1C=CC=CC=1>ClCCl>[C:24]([O:17][CH2:16][C:15]1[C:11]2[CH:10]=[CH:9][CH:8]=[C:7]([NH:6][C:4](=[O:5])[C:3]3[C:19]([Cl:23])=[CH:20][CH:21]=[CH:22][C:2]=3[Cl:1])[C:12]=2[O:13][C:14]=1[CH3:18])(=[O:26])[CH3:25]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1oc2c(NC(=O)c3c(Cl)cccc3Cl)cccc2c1CO
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)OCc1c(C)oc2c(NC(=O)c3c(Cl)cccc3Cl)cccc12
Yield: 83.5 %

Procedure:
A mixture of 7-(2,6-dichlorobenzoylamino)-3-hydroxymethyl-2-methylbenzo[b]furan (123 mg), acetic anhydride (43 mg) and pyridine (48 mg) in dichloromethane (5 ml) was refluxed for 2 hours. The reaction mixture was washed with 1N-hydrochloric acid, brine and aqueous saturated sodium bicarbonate, dried over sodium sulfate and evaporated in vacuo. The residue was crystallized from diethyl ether to give 3-acetoxymethyl-7-(2,6-dichlorobenzoylamino)-2-methylbenzo[b]furan (115 mg).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]2[CH:11]=[CH:12][C:13](N)=[CH:14][C:8]=2[CH:7]=1)=[O:5])[CH3:2].Cl.N([O-])=O.[Na+].[Na+].[I-:22]>C(Cl)Cl.O>[CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]2[CH:11]=[CH:12][C:13]([I:22])=[CH:14][C:8]=2[CH:7]=1)=[O:5])[CH3:2]
Reactant: [I-]
Reactant: CCOC(=O)c1cc2cc(N)ccc2s1
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)c1cc2cc(I)ccc2s1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To 5-amino-benzo[b]thiophene-2-carboxylic acid ethyl ester (18.37 g, 83.02 mmol) was added an aqueous HCl solution (21 mL conc. HCl in 200 mL H2O, 252 mmol)) and the resulting mixture was cooled to 0° C. A solution of NaNO2 (6.02 g in 60 mL H2O, 87.25 mmol) was added and the mixture was allowed to stir at 0° C. for 10 min. A solution of NaI (13.07 g in 60 μL H2O, 87.20 mmol) was added slowly. The reaction mixture became difficult to stir during the addition of NaI. A total of 300 mL of water was added in several portions. After the addition was complete, the reaction was warmed to rt and allowed to stir at rt for 2 h. The mixture was then diluted with CH2Cl2 (800 mL) and water (100 mL). The organic layer was separated, washed with 200 mL of saturated NaHCO3 and dried over Na2SO4. After filtration, the filtrate was concentrated and the residue was filtered through a pad of silica gel, washing with EtOAc/hexanes (0% to 10%). The filtrate was then concentrated and the residue was recrystallized from MeOH to give 5-iodo-benzo[b]thiophene-2-carboxylic acid ethyl ester as light orange solid. MS (EI): cal'd 332.9 (MH+), exp 333.1 (M+).
Reaction SMILES: CO[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]1[N:13]([CH3:18])[N:14]=[C:15]([C:16]#[N:17])[C:7]1=[CH:6]2.[H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:25]([OH:27])C>O1CCCC1.C1(C)C=CC=CC=1.[Pd]>[CH3:25][O:27][C:12]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]3[C:15]([CH2:16][NH2:17])=[N:14][N:13]([CH3:18])[C:8]3=[N:9]2)=[CH:4][CH:3]=1
Reactant: CCO
Reactant: COc1ccc2nc3c(cc2c1)c(C#N)nn3C
Agent: [Pd]
Agent: [Al+3]
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: COc1ccc2cc3c(CN)nn(C)c3nc2c1
Temperature: 25 °C

Procedure:
A mixture of 8.6 g 6-methoxy-1-methyl-1H-pyrazolo[3,4-b]quinoline-3-carbonitrile (Example 33) and 3.8 g lithium aluminum hydride in 500 ml tetrahydrofuran was stirred at room temperature for about sixteen hours. The crude product was isolated and dissolved in 200 ml toluene. Ethanol (10 ml) and 2 g palladium-on-carbon catalyst (10%) was added, and the mixture was heated to reflux and stirred for about sixteen hours. The reaction mixture was filtered and concentrated, and the residue was chromatographed and crystallized from ethanol to give 2.9 g 7-methoxy-1-methyl-1H-pyrazolo[3,4-b]quinoline-3-methanamine, brownish-yellow solid, m.p. 119°-120° C.
Reaction SMILES: [N+:1]([C:4]1[N:5]=[CH:6][NH:7][CH:8]=1)([O-:3])=[O:2].Br[CH:10]([CH3:12])[CH3:11].C(=O)([O-])[O-].[K+].[K+]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C(#N)C>[CH:10]([N:7]1[CH:8]=[C:4]([N+:1]([O-:3])=[O:2])[N:5]=[CH:6]1)([CH3:12])[CH3:11]
Reactant: CC(C)Br
Reactant: O=[N+]([O-])c1c[nH]cn1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CC#N
Product: CC(C)n1cnc([N+](=O)[O-])c1
Temperature: 25 °C
Yield: 38.1 %

Procedure:
A mixture of 4-nitro-1H-imidazole (1.0 gm, 8.8 mmole), 2-bromopropane (1.1 gm, 8.8 mmole), potassium carbonate (1.8 gm, 13 mmole) and tetrabutylammonium iodide (0.10 gm, 0.27 mmole) in dry acetonitrile (10 mL) was heated at reflux for 7 hr. After cooling to room temperature, the reaction was filtered and the solvents removed from the filtrate. The residue was chromatographed (silica gel column, gradient elution with mixtures of dichloromethane containing 0 to 50% ethyl acetate) to afford the product as a solid (0.52 gm, 39% yield). HPLC retention time=1.12 min; MS (M+H)+=155, 1H NMR (500 MHz, CD3OD) δ 1.56 (d, J=6.71 Hz, 6H) 4.53-4.61 (m, 1H) 7.85 (s, 1H) 8.27 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[N:10]1[C:14](=[O:15])[CH:13]=[C:12]([NH:16][C:17]2[CH:22]=[C:21]([NH2:23])[CH:20]=[CH:19][C:18]=2[O:24][CH3:25])[NH:11]1.[C:26](Cl)(=[O:40])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39]>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[N:10]1[C:14](=[O:15])[CH:13]=[C:12]([NH:16][C:17]2[CH:22]=[C:21]([NH:23][C:26](=[O:40])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[CH:20]=[CH:19][C:18]=2[O:24][CH3:25])[NH:11]1
Reactant: COc1ccc(N)cc1Nc1cc(=O)n(-c2c(Cl)cc(Cl)cc2Cl)[nH]1
Reactant: CCCCCCCCCCCCCC(=O)Cl
Product: CCCCCCCCCCCCCC(=O)Nc1ccc(OC)c(Nc2cc(=O)n(-c3c(Cl)cc(Cl)cc3Cl)[nH]2)c1

Procedure:
The 1-(2,4,6-trichlorophenyl)-3-(2-methoxy-5-aminoanilino)-5-pyrazolone prepared in the above procedure was reacted with myristic acid chloride prepared using Method (3) of Synthesis Example 1 to give the desired product having a melting point of 89°-93°C.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25](Br)=[CH:24][N:23]=[C:22]([N:27]4[CH2:30][CH:29]([F:31])[CH2:28]4)[N:21]=3)[C@H:14]2[CH3:32])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[Cl:35][C:36]1[CH:37]=[C:38](B(O)O)[C:39]([O:42][CH3:43])=[N:40][CH:41]=1.C([O-])([O-])=O.[K+].[K+]>[Pd](Cl)Cl.C(P(C(C)(C)C)[C-]1C=CC=C1)(C)(C)C.[C-]1(P(C(C)(C)C)C(C)(C)C)C=CC=C1.[Fe+2]>[F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25]([C:38]4[C:39]([O:42][CH3:43])=[N:40][CH:41]=[C:36]([Cl:35])[CH:37]=4)=[CH:24][N:23]=[C:22]([N:27]4[CH2:30][CH:29]([F:31])[CH2:28]4)[N:21]=3)[C@H:14]2[CH3:32])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: C[C@H]1[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1nc(N2CC(F)C2)ncc1Br
Reactant: COc1ncc(Cl)cc1B(O)O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(C)(C)P([c-]1cccc1)C(C)(C)C
Product: COc1ncc(Cl)cc1-c1cnc(N2CC(F)C2)nc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Temperature: 125 °C

Procedure:
(4S,5R)-5-[3,5-Bis(trifluoromethyl)phenyl]-3-{[5-bromo-2-(3-fluoroazetidin-1-yl)pyrimidin-4-yl]methyl}-4-methyl-1,3-oxazolidin-2-one (INTERMEDIATE 14, 425 mg, 0.763 mmol), 5-chloro-2-methoxypyridin-3-ylboronic acid (214 mg, 1.144 mmol), 1,1′-bis(di-tert-butylphosphino)ferrocene palladium dichloride (49.7 mg, 0.076 mmol) and K2CO3 (316 mg, 2.288 mmol) were added to a reaction vial that was evacuated and charged with nitrogen three times. The solid reactants were then mixed with THF (4 mL) and water (400 μl), degassed and refilled with nitrogen, capped and heated for 30 minutes at 125° C. in a BIOTAGE microwave reactor, after which LCMS showed complete conversion to product. The reaction was diluted with 5 mL acetonitrile and filtered through a 1 g RP C18 silica cartridge, eluting with 15 mL acetonitrile until filtrate was colorless. The filtrate was concentrated prior to RP Prep purification on a X-Bridge 30×300 mm RP column. The sample was loaded in 7:3:1 CH3CN/water/DMSO (5 mL) and eluted with a 10-100% acetonitrile/water (0.1% NH4OH) linear gradient over 20 minutes. The product of interest eluted in 80% portion of above gradient. Pure fractions (rich cut; impure discarded) were concentrated and lyophilized to give a white solid. LCMS (M+H)+: 619.1. 1H NMR (CDCl3, 500 MHz): δ 8.24 (s, 1H) 8.16 (s, 1H) 7.93 (s, 1H) 7.77 (s, 2H) 7.53 (s, 1H) 5.73 (m, 1H) 5.57 (m, 0.5H) 5.46 (m, 0.5H), 4.70 (d, J=17.4 Hz, 1H), 4.48 (m, 4H), 4.06 (d, J=17.5 Hz, 1H), 3.97 (s, 3H), 0.78 (bs, 3H). Rotomers gave broad signals. SPA IC50: 38 nM.
Reaction SMILES: C[C:2]12[CH2:11][CH2:10][CH2:9][CH2:8][CH:7]1[C:6](=[O:12])[O:5][C:3]2=[O:4].C(C1CC(=O)OC1=O)=CCCCCCCCCCC.CC#C>>[C:6]1(=[O:12])[O:5][C:3](=[O:4])[C:2]2=[CH:11][CH:10]=[CH:9][CH:8]=[C:7]12
Reactant: CC12CCCCC1C(=O)OC2=O
Agent: C#CC
Agent: CCCCCCCCCCC=CC1CC(=O)OC1=O
Product: O=C1OC(=O)c2ccccc21

Procedure:
The procedures of Example 1 were repeated except that 38.2 g. of methylhexahydrophthalic anhydride (Example 2) and 61.2 g. of dodecenylsuccinic anhydride (Example 3) which was a maleinization product of propylene tetramer or butylene trimer, were employed, respectively, instead of 34 g. of phthalic anhydride, to give light yellow resins. The properties thereof are shown in Table 1.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N:7][C:6]([NH:12][C:13](=[O:41])[O:14][CH2:15][CH:16]([N:27]([CH3:40])[C:28]([NH:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[C:33]=1[Cl:39])=[O:29])[CH2:17][C:18]([CH3:26])([CH3:25])[CH2:19][O:20][P:21]([OH:24])([OH:23])=[O:22])=[CH:5]2.[OH-].[Na+:43]>CO>[P:21]([O-:24])([O-:23])([O:20][CH2:19][C:18]([CH3:25])([CH3:26])[CH2:17][C@H:16]([N:27]([CH3:40])[C:28]([NH:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[C:33]=1[Cl:39])=[O:29])[CH2:15][O:14][C:13](=[O:41])[NH:12][C:6]1[N:7]=[CH:8][C:9]2[C:4]([CH:5]=1)=[CH:3][C:2]([F:1])=[CH:11][CH:10]=2)=[O:22].[Na+:43].[Na+:43]
Reactant: CN(C(=O)NCc1cccc(F)c1Cl)C(COC(=O)Nc1cc2cc(F)ccc2cn1)CC(C)(C)COP(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CN(C(=O)NCc1cccc(F)c1Cl)[C@H](COC(=O)Nc1cc2cc(F)ccc2cn1)CC(C)(C)COP(=O)([O-])[O-]
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 96.4 %

Procedure:
To a solution of S)-2-(3-(2-chloro-3-fluorobenzyl)-1-methylureido)-4,4-dimethyl-5-(phosphonooxy)pentyl 6-fluoroisoquinolin-3-ylcarbamate (340 mg, 0.55 mmol) in MeOH (30 mL) was added NaOH (0.1 N, 10.8 mL, 1.08 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 10 min and concentrated. The residue was dissolved in small amount of water and lyophilized to give sodium (S)-4-(3-(2-chloro-3-fluorobenzyl)-1-methylureido)-5-(6-fluoroisoquinolin-3-ylcarbamoyloxy)-2,2-dimethylpentyl phosphate (343 mg, 94.1%) as white solid. LRMS (M−2Na++3H+) m/z 615.5.
Reaction SMILES: [CH2:1]1[CH:6]([CH2:7][N:8]2[C:13](=[O:14])[CH:12]=[CH:11][C:9]2=[O:10])[CH2:5][CH2:4][CH:3]([C:15]([O:17][N:18]2[C:23](=[O:24])[CH:22](S(O)(=O)=O)[CH2:21][C:19]2=[O:20])=[O:16])[CH2:2]1.C1C(CN2C(=O)C=CC2=O)CCC(C(ON2C(=O)C(S([O-])(=O)=O)CC2=O)=O)C1.[Na+].C([O-])(=O)CCC([O-])=O.C(N(CC(O)=O)CC(O)=O)CN(CC(O)=O)CC(O)=O>CC(N(C)C)=O.C1N(CCCS(O)(=O)=O)CCN(CCO)C1>[CH2:1]1[CH:6]([CH2:7][N:8]2[C:13](=[O:14])[CH:12]=[CH:11][C:9]2=[O:10])[CH2:5][CH2:4][CH:3]([C:15]([O:17][N:18]2[C:19](=[O:20])[CH2:21][CH2:22][C:23]2=[O:24])=[O:16])[CH2:2]1
Reactant: O=C(ON1C(=O)CC(S(=O)(=O)O)C1=O)C1CCC(CN2C(=O)C=CC2=O)CC1
Agent: O=C(O)CN(CCN(CC(=O)O)CC(=O)O)CC(=O)O
Agent: O=C(ON1C(=O)CC(S(=O)(=O)[O-])C1=O)C1CCC(CN2C(=O)C=CC2=O)CC1
Agent: O=C([O-])CCC(=O)[O-]
Solvent: CC(=O)N(C)C
Product: O=C(ON1C(=O)CCC1=O)C1CCC(CN2C(=O)C=CC2=O)CC1

Procedure:
The conjugates of the present invention can also be prepared by in situ process according to the following procedures. Antibodies (21 clones) were conjugated to DM1 using the sulfosuccinimidyl 4-(N-maleimidomethyl)cyclohexane-1-carboxylate (sulfo-SMCC) linker Stock solutions of DM1 and sulfo-SMCC heterobifunctional linker were prepared in DMA. Sulfo-SMCC and DM1 thiol were mixed together to react for 10 minutes at 25° C. in DMA containing 40% v/v of aqueous 50 mM succinate buffer, 2 mM EDTA, pH 5.0, at the ratio of DM1 to linker of 1.3:1 mole equivalent and a final concentration of DM1 of 1.95 mM. The antibody was then reacted with an aliquot of the reaction to give a mole equivalent ratio of SMCC to Ab of around 6.5:1 under final conjugation conditions of 2.5 mg/mL of Ab in 50 mM EPPS, pH 8.0 and 10% DMA (v/v). After approximately 18 hours at 25° C., the conjugation reaction mixture was purified using a SEPHADEX™ G25 column equilibrated with 10 mM succinate, 250 mM glycine, 0.5% sucrose, 0.01% Tween 20, pH 5.5.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[C:15]1([CH3:28])[CH:20]=[CH:19][C:18]([NH:21][CH:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[CH:17][CH:16]=1.[CH:29]([CH2:31][C:32]1([CH2:38][CH2:39][N:40]2[C:44](=[O:45])[C:43]3=[CH:46][CH:47]=[CH:48][CH:49]=[C:42]3[C:41]2=[O:50])[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1)=O.C(O)(=O)C.C(=O)([O-])O.[Na+]>ClCCCl>[C:15]1([CH3:28])[CH:16]=[CH:17][C:18]([NH:21][CH:22]2[CH2:27][CH2:26][N:25]([CH2:29][CH2:31][C:32]3([CH2:38][CH2:39][N:40]4[C:44](=[O:45])[C:43]5=[CH:46][CH:47]=[CH:48][CH:49]=[C:42]5[C:41]4=[O:50])[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37]3)[CH2:24][CH2:23]2)=[CH:19][CH:20]=1
Reactant: Cc1ccc(NC2CCNCC2)cc1
Reactant: O=CCC1(CCN2C(=O)c3ccccc3C2=O)CCCCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: Cc1ccc(NC2CCN(CCC3(CCN4C(=O)c5ccccc5C4=O)CCCCC3)CC2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 108.4 %

Procedure:
After adding sodium triacetoxyborohydride (0.82 g, 3.85 mmol) to a solution of 4-(p-toluidino)piperidine (0.73 g, 3.85 mmol), N-[2-[1-(formylmethyl)cyclohexyl]ethyl]phthalimide (0.77 g, 2.57 mmol) and acetic acid (0.30 mL, 5.14 mmol) in 1,2-dichloroethane (10 mL), the mixture was stirred at room temperature for 1.5 hours. Saturated aqueous sodium hydrogencarbonate was then added, and extraction was performed with chloroform-ethanol (10:1). After drying (anhydrous sodium sulfate), the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (25 g Merck Art 9385, chloroform:methanol=20:1) to obtain the title compound as a colorless oil (1.32 g).
Reaction SMILES: C(N(CC)CC)C.C([C:11]1[CH:16]=[C:15](C(C)C)[CH:14]=[C:13]([CH:20]([CH3:22])C)[C:12]=1S(Cl)(=O)=O)(C)C.C[CH2:28][O:29]CC>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH:13]1([CH2:20][C@H:22]2[CH2:28][O:29]2)[CH2:12][CH2:11][CH2:16][CH2:15][CH2:14]1
Reactant: CC(C)c1cc(C(C)C)c(S(=O)(=O)Cl)c(C(C)C)c1
Reactant: CCOCC
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C1CCC(C[C@H]2CO2)CC1
Temperature: 0 °C
Reaction time: 14 h
Yield: 75 %

Procedure:
To a solution of the product from Example 15B in CH2Cl2 was added triethylamine (6.6 mL), 2,4,6-triisopropylbenzenesulfonyl chloride (11.5 g), and DMAP (0.386 g). After 14 hours, the reaction was diluted with ether, chilled to 0° C., filtered through celite, and concentrated. The residue was dissolved in ethanol (100 mL) and 1M NaOH (32 mL) was added. After 30 minutes, the reaction was carefully concentrated, diluted with water (100 mL), and extracted into ether (3×50 mL). The organic extracts were washed with brine (20 mL), dried (MgSO4), filtered, and concentrated to provide a colorless aromatic oil which was purified first by passage through a plug of silica gel eluting with 5% EtOAc/hexanes, then by bulb-to-bulb distillation under reduced pressure to provide 3.3 g (75%) of the title compound as a colorless aromatic oil.
Reaction SMILES: [F:1][CH:2]([F:23])[O:3][C:4]1[C:5]([OH:22])=[C:6]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[C:17](=[O:21])[O:16][CH2:15]3)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].C(=O)([O-])[O-].[K+].[K+].Br[CH2:31][C:32]1[CH:37]=[CH:36][C:35]([S:38]([CH3:41])(=[O:40])=[O:39])=[CH:34][CH:33]=1>C(#N)C>[F:23][CH:2]([F:1])[O:3][C:4]1[C:5]([O:22][CH2:31][C:32]2[CH:33]=[CH:34][C:35]([S:38]([CH3:41])(=[O:40])=[O:39])=[CH:36][CH:37]=2)=[C:6]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[C:17](=[O:21])[O:16][CH2:15]3)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: CS(=O)(=O)c1ccc(CBr)cc1
Reactant: COc1ccc(-c2ccc3c(c2)COC3=O)c(O)c1OC(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccc(-c2ccc3c(c2)COC3=O)c(OCc2ccc(S(C)(=O)=O)cc2)c1OC(F)F
Temperature: 70 °C
Yield: 33.2 %

Procedure:
To a stirring solution of 5-(3-(difluoromethoxy)-2-hydroxy-4-methoxyphenyl)isobenzofuran-1(3H)-one (80 mg, 0.246 mmol) in acetonitrile (10 mL) was added potassium carbonate (102 mg, 0.738 mmol) and 1-(bromomethyl)-4-(methylsulfonyl)benzene (123 mg, 0.496 mmol) and the resultant reaction mixture was heated to 70° C. for 16 h. The reaction mixture was cooled to RT, filtered through celite and the filtrate was concentrated under reduced pressure. The obtained residue was purified by column chromatography (silica gel, 0-70% ethyl acetate in pet ether) to afford the title compound as a solid (40 mg, 33%).
Reaction SMILES: C(OC(CCC(N[C@H](C(N[C@H](C([NH:37][C@H:38]([C:47]([NH:49][C@H](C(N[C@H](C(O)=O)CC(C)C)=O)C(C)(C)C)=[O:48])[CH2:39][C:40]1[CH:45]=CC=C[C:41]=1C)=O)CCC(=O)OC(C)(C)C)=O)CC(=O)OC(C)(C)C)=O)=O)(C)(C)C.CN1CCOCC1.ClC(OCC(C)C)=O.FC(F)(F)C(O)=O.C(C(B1OC(C)(C)C(C)(C)O1)N)CC>CN(C)C=O.ClCCl>[NH2:37][C@H:38]([C:47]([NH2:49])=[O:48])[CH2:39][CH:40]([CH3:45])[CH3:41]
Reactant: Cc1ccccc1C[C@H](NC(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)[C@H](CC(=O)OC(C)(C)C)NC(=O)CCC(=O)OC(C)(C)C)C(=O)N[C@H](C(=O)N[C@@H](CC(C)C)C(=O)O)C(C)(C)C
Agent: CC(C)COC(=O)Cl
Agent: CCCC(N)B1OC(C)(C)C(C)(C)O1
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)C[C@H](N)C(N)=O
Temperature: -15 °C
Reaction time: 0.17 h

Procedure:
0.2 g (0.218 mmol) of N-[N-[N-[N-[N-[3-(tert-butoxycarbonyl)propionyl]-O-tert-butyl-L-α-aspartyl]-O-tert-butyl-L-α-glutamyl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-L-leucine was dissolved in 2 ml of dimethylformamide and 6 ml of dichloromethane. 0.12 ml (1.1 mmol) of N-methylmorpholine was added and the solution was cooled to -15° C. under a nitrogen atmosphere. 40 mg (0.31 mmol) of isobutyl chloroformate were added and the solution was stirred for 10 minutes at -15° C. 0.14 g (0.44 mmol) of α-(RS)-propyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-methylamine trifluoroacetate was added and the mixture was stirred at room temperature for 66 hours. After evaporation the residue was partitioned between ethyl acetate and 2M hydrochloric acid. The organic layer was washed with 2M hydrochloric acid, water and saturated sodium chloride solution and then dried over anhydrous sodium sulphate. After evaporation there was obtained 0.17 g of N2-[N-[N-[N-[N-[3-(tert-butoxycarbonyl)propionyl]-O-tert-butyl-L-α-aspartyl]-O-tert-butyl-L-α-glutamyl]-2-methyl-L-phenylalanyl]-3-methyl-L-valyl]-N1-N1(RS)-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)butyl]-L-leucinamide in the form of a solid; NMR (DMSO, 400 MHz) δ: 0.75-0.9 (m,17H), 1.01-1.08 (m,6H), 1.15-1.25 (m,1H), 1.35 9s,36H), 1.4-1.7 (m,4H), 1.75-1.8 (m,1H), 2.05-2.15 (m,2H), 2.23 (s,3H), 2.29-2.41 (m,6H), 2.55-2.6 (m,1H), 2.7-2.74 (m,1H), 2.95-3.05 (m,1H), 4.15-4.25 (m,3H), 4.48-4.55 (m,1H), 4.6-4.7 (m,1H), 7.05-7.11 (m,4H), 7.7-7.81 (m,2H), 8.05-8.12 (m,2H), 8.15-8.25 (m,2H).
Reaction SMILES: [Br:1][C:2]1[CH:15]=[C:14]([Br:16])[CH:13]=[C:12]([Br:17])[C:3]=1[O:4][CH2:5][C:6]1([CH2:10]Cl)[CH2:9][O:8][CH2:7]1.[Br:18][C:19]1[C:24]([OH:25])=[C:23]([Br:26])[C:22]([Br:27])=[C:21]([Br:28])[C:20]=1[Br:29].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>O.CN(C)C=O>[Br:1][C:2]1[CH:15]=[C:14]([Br:16])[CH:13]=[C:12]([Br:17])[C:3]=1[O:4][CH2:5][C:6]1([CH2:10][O:25][C:24]2[C:23]([Br:26])=[C:22]([Br:27])[C:21]([Br:28])=[C:20]([Br:29])[C:19]=2[Br:18])[CH2:9][O:8][CH2:7]1
Reactant: ClCC1(COc2c(Br)cc(Br)cc2Br)COC1
Reactant: Oc1c(Br)c(Br)c(Br)c(Br)c1Br
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Brc1cc(Br)c(OCC2(COc3c(Br)c(Br)c(Br)c(Br)c3Br)COC2)c(Br)c1

Procedure:
To 31.5 g. (0.07 moles) of 3-[2,4,6-tribromophenoxymethyl]-3-[chloromethyl]oxetane was added pentabromophenol (36 g., 0.074 moles), potassium carbonate (10 g., 0.077 moles), potassium iodide (0.5 g.) and dimethyl formamide (75 ml.). The reactants were stirred in a nitrogen atmosphere and heated to 140°-148° C. for 21/2 hours. The cooled reaction mixture was diluted with 500 ml. of water. The resulting solid 3-[2,4,6-tribromophenoxymethyl]-3-[pentabromophenoxymethyl]oxetane was collected by filtration and washed on the funnel with water and with ethanol. The yield was 48 g. (76%). A small sample recrystallized from dioxane (6 ml./g.) melted at 202°-204° C.