Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([NH:14][C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16])[CH2:4][N:5]1[CH2:13][CH2:12][CH2:11][C@H:6]1[C:7]([O:9][CH3:10])=[O:8].C(N(CC)CC)C.[CH3:32][S:33](Cl)(=[O:35])=[O:34]>ClCCl.CN(C)C1C=CN=CC=1>[CH3:32][S:33]([O:1][CH2:2][C@@H:3]([NH:14][C:15]([O:17][CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)=[O:16])[CH2:4][N:5]1[CH2:13][CH2:12][CH2:11][C@H:6]1[C:7]([O:9][CH3:10])=[O:8])(=[O:35])=[O:34]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)[C@@H]1CCCN1C[C@@H](CO)NC(=O)OCc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H]1CCCN1C[C@@H](COS(C)(=O)=O)NC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 99.9 %

Procedure:
Methyl 1-[(2S)-3-hydroxy-2-({[(phenylmethyl)oxy]carbonyl}amino) propyl]-L-prolinate (200 mg, 0.594 mmol) was dissolved in dichloromethane (5 mL) followed by the addition of 4-(dimethylamino)pyridine (3.6 mg, 0.039 mmol) and triethylamine (0.125 mL, 0.891 mmol) and the resulting mixture was cooled to 0° C. Methanesulfonyl chloride (0.060 mL, 0.773 mmol) was added dropwise and the reaction mixture was stirred for 1 h at 0° C. The mixture was partitioned between dichloromethane and saturated aqueous sodium bicarbonate. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to afford methyl 1-[(2S)-3-[(methylsulfonyl)oxy]-2-({[(phenylmethyl)oxy]carbonyl}amino)propyl]-L-prolinate (246 mg, 100%) as a clear and colorless oil. MS (EI) for C18H27N2O7S: 415 (MH+).
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[CH3:9][O:10][C:11](=[O:22])[CH2:12][N:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH3:14].Br[CH2:24][CH:25]=[C:26]([CH3:28])[CH3:27]>C1COCC1>[CH3:9][O:10][C:11](=[O:22])[CH:12]([CH2:24][CH:25]=[C:26]([CH3:28])[CH3:27])[N:13]([C:15]([O:17][C:18]([CH3:19])([CH3:21])[CH3:20])=[O:16])[CH3:14]
Reactant: COC(=O)CN(C)C(=O)OC(C)(C)C
Reactant: CC(C)=CCBr
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)C(CC=C(C)C)N(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 63.7 %

Procedure:
A 2 M solution of LDA (70.32 ml, 0.14 mol) was added (via syringe) to a solution of N-t-butoxycarbonyl-sarcosine methyl ester (26 g, 0.1279 mol) in 40 ml of dry THF at -78° C. under nitrogen and the mixture was stirred at this temperature for 30 minutes. To the above mixture was added 4-bromo-2-methyl-2-butene (20 g, 0.134 mol) with stirring continuing at -78° C., and the resulting mixture was allowed to warm to room temperature. The reaction mixture was quenched with 6 ml of saturated ammonium chloride solution at -78° C., 20 ml of water added, and the resulting reaction mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulfate, and concentrated in vacuo to yield a yellow oil, which was purified by silica gel column chromatography (20% ethyl acetate in hexane) to afford 22.1 g (63.7 %) of N-t-butoxycarbonyl-2-(3-methyl-2-butenyl)-sarcosine methyl ester as an oil.
Reaction SMILES: F[C:2](F)(F)[C:3]([OH:5])=O.F[C:9]1[N:16]=[CH:15][CH:14]=[CH:13][C:10]=1[C:11]#[N:12].[CH:17]([N:20](C(C)C)[CH2:21]C)(C)[CH3:18]>ClCCl.O1CCCC1>[CH:3]12[CH2:2][CH:17]([N:20]([C:9]3[N:16]=[CH:15][CH:14]=[CH:13][C:10]=3[C:11]#[N:12])[CH2:21]1)[CH2:18][O:5]2
Reactant: N#Cc1cccnc1F
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Solvent: ClCCl
Product: N#Cc1cccnc1N1CC2CC1CO2
Temperature: 115 °C
Yield: 51 %

Procedure:
The product from Example 88B (1.57 g, 7.9 mmol) in dichloromethane (25 mL) was treated with trifluoroacetic acid (5 mL) for 30 min at rt. The reaction mixture was concentrated to dryness. To the residue was added 2-fluoro-nicotinonitrile (1.0 g, 8.19 mmol) and diisopropyl ethylamine (3.2 mL) in tetrahydrofuran (8 mL). The reaction mixture was heated at 115° C. for 10 min under microwave condition. The mixture was concentrated to dryness, and the residue was chromatographed using hexane/ethyl acetate (9:1-6:1) to give the title compound (806 mg, 51%). MS (DCI/NH3) m/z 202 (M+1)+. 1HNMR (400 MHz, CDCl3) δ ppm 1.98 (s, 2H) 3.67 (d, J=10.13 Hz, 1H) 3.91 (dd, J=7.98, 1.53 Hz, 1H) 3.96 (m, 2H) 4.69 (s, 1H) 5.16 (s, 1H) 6.64 (dd, J=7.67, 4.91 Hz, 1H) 7.71 (dd, J=7.36, 1.84 Hz, 1H) 8.26 (dd, J=4.60, 1.84 Hz, 1H).
Reaction SMILES: [CH3:1][C:2]1([CH3:37])[C:32]2=[CH:33][CH:34]=[N:35][CH:36]=[C:31]2[C:5]2[C:6]([OH:30])=[CH:7][C:8]([CH:10]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH3:11])=[CH:9][C:4]=2[O:3]1.[C:38](OC(=O)C)(=[O:40])[CH3:39]>N1C=CC=CC=1>[C:38]([O:30][C:6]1[C:5]2[C:31]3[C:32]([C:2]([CH3:1])([CH3:37])[O:3][C:4]=2[CH:9]=[C:8]([CH:10]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH3:11])[CH:7]=1)=[CH:33][CH:34]=[N:35][CH:36]=3)(=[O:40])[CH3:39]
Reactant: CC(=O)OC(C)=O
Reactant: CCCCCCCCCCCCCCCCCCC(C)c1cc(O)c2c(c1)OC(C)(C)c1ccncc1-2
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCCCCCC(C)c1cc(OC(C)=O)c2c(c1)OC(C)(C)c1ccncc1-2

Procedure:
10-Acetoxy-5,5-dimethyl-8-(2-eicosyl)-5H-[1]benzopyrano[3,4-d]pyridine is prepared by reacting 5,5-dimethyl-10-hydroxy-8-(2-eicosyl)-5H-[1]benzopyrano[3,4-d]pyridine and acetic anhydride in the presence of pyridine according to the method of Example 12.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][OH:10])[CH:5]=[C:4]([Br:11])[C:3]=1[OH:12].CC(C)([O-])C.[K+].[Cl:19][C:20]1[N:21]=[N:22][C:23](Cl)=[CH:24][C:25]=1[CH:26]([CH3:28])[CH3:27]>CN(C)C(=O)C.O>[Br:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][OH:10])[CH:5]=[C:4]([Br:11])[C:3]=1[O:12][C:23]1[N:22]=[N:21][C:20]([Cl:19])=[C:25]([CH:26]([CH3:28])[CH3:27])[CH:24]=1
Reactant: CC(C)c1cc(Cl)nnc1Cl
Reactant: OCCc1cc(Br)c(O)c(Br)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CC(C)c1cc(Oc2c(Br)cc(CCO)cc2Br)nnc1Cl
Temperature: 10 °C
Yield: 49.7 %

Procedure:
A mixture of 2,6-dibromo-4-(2-hydroxy-ethyl)-phenol (11) (183.3 g, 0.619 mol) in N,N-dimethyl acetamide (300 mL) was treated with potassium tert-butoxide (70.5 g, 0.59 mol) under nitrogen at room temperature. The suspension was heated to 10° C. and stirred until a solution formed. At this time, 3,6-dichloro-4-isopropyl pyridazine (7) (100 g, 0.50 mol) was added to the solution and the reaction mixture was stirred at 135° C. for 24 h. The reaction was cooled to room temperature, diluted with water (350 mL) and extracted with tert-butyl methyl ether (1×600 mL) followed by isopropyl acetate (1×600 mL). The organic layers were combined and washed with a 1N aqueous sodium hydroxide solution (1×256 mL) and water (2×200 mL). The organic layer was distilled to about 300 mL. The residue was treated with heptane (300 mL). The mixture was stirred under reflux for 30 min and then was cooled to room temperature. The resulting solid was filtered, washed with a 2:1 mixture of tert-butyl methyl ether: heptane (240 mL) and dried overnight to afford 2-[3,5-dibromo-4-(6-chloro-5-isopropyl-pyridazin-3-yloxy)-phenyl]-ethanol (12) (112 g, 49%) as an off-white solid; LRMS for C15H15Br2ClN2O2 (M+) at m/z=450. Molecular Weight=450.5600; Exact Mass=447.9189
Reaction SMILES: Br.Br[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1.CCN(C(C)C)C(C)C.[C:19]1([S:25]([O-:27])=[O:26])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[Na+]>CC#N>[C:19]1([S:25]([CH2:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=2)(=[O:27])=[O:26])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=S([O-])c1ccccc1
Reactant: BrCc1ccccn1
Agent: Br
Agent: [Na+]
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=S(=O)(Cc1ccccn1)c1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 79.7 %

Procedure:
To a stirred suspension of 2.5 g (0.010 mol) of 2-bromomethyl-pyridine hydrobromide in 10 mL of CH3CN at RT, was added 1.78 mL (0.0105 mol, 1.05 eq.) of Hunig's base. After complete dissolution of the salt, 1.62 g (0.010 mol, 1 eq.) of sodium benzene sulfinat and 0.52 g (0.002 mol, 0.2 eq.) were added. The mixture was stirred at RT for 48 hours, and then the reaction was quenched by addition of water, and the product extracted with EtOAc. The combined organic phases were dried over Na2SO4, filtered and dried under vacuum to afford 1.86 g (80%) of 2-benzenesulfonylmethyl-pyridine.
Reaction SMILES: [CH3:1][CH:2]([CH3:13])[CH2:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=O)=[CH:6][CH:5]=1.Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.O[NH:38][C:39](=[NH:48])[C:40]1[CH:45]=[CH:44][C:43]([CH2:46][OH:47])=[CH:42][CH:41]=1>CN(C=O)C>[CH3:13][CH:2]([CH3:1])[CH2:3][C:4]1[CH:5]=[CH:6][C:7]([C:8]2[O:10][N:48]=[C:39]([C:40]3[CH:45]=[CH:44][C:43]([CH2:46][OH:47])=[CH:42][CH:41]=3)[N:38]=2)=[CH:11][CH:12]=1
Reactant: N=C(NO)c1ccc(CO)cc1
Reactant: CC(C)Cc1ccc(C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)Cc1ccc(-c2nc(-c3ccc(CO)cc3)no2)cc1
Temperature: 140 °C
Reaction time: 2 h
Yield: 95.2 %

Procedure:
A solution of 10.0 g (56.2 mmol) of 4-(2-methylpropyl)benzoic acid, 10.8 g (56.2 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and 7.6 g (56.2 mmol) of 1-hydroxybenzotriazole hydrate in 70 mL of DMF was stirred at rt for 30 min. N-Hydroxy-4-(hydroxymethyl)benzamidine (9.3 g, 56.2 mmol, from Step A) was added to the reaction mixture at rt and the resulting slurry was stirred at 140° C. for additional 2 h. The reaction was cooled to rt and quenched with 50 mL of water. The aqueous layer was extracted with 200 mL of ethyl acetate. The organic layer was washed with 0.5 N HCl solution, saturated NaHCO3 solution and water and then was concentrated to dryness to afford 16.5 g of the title compound: 1H NMR (400 Mhz, CD3OD) δ 0.95 (d, J=6.7, 6H), 1.96 (m, 1H), 2.61 (d, J=7.3, 2H), 7.42 (d, J=8.0, 2H), 7.54 (d, J=8.2, 2H), 8.13 (m, 4H).
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[N:15]=1.[I:21]I.S([O-])([O-])=O.[Na+].[Na+]>O1CCCC1.C(OCC)C>[F:13][C:14]1[C:19]([I:21])=[CH:18][CH:17]=[C:16]([F:20])[N:15]=1
Reactant: Fc1cccc(F)n1
Reactant: II
Agent: O=S([O-])[O-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: CCOCC
Product: Fc1ccc(I)c(F)n1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of butyllithium (38.8 ml, 97 mmol) in tetrahydrofuran (194 ml) at −78° C. was added diisopropylamine (13.8 ml, 97 mmol) dropwise. After 15 minutes at −78° C., 2,6-difluoropyridine (8.8 ml, 97 mmol) was added slowly. After 1 hour slowly, a solution of iodine (24.6 g, 97 mmol) in tetrahydrofuran (50 ml) was carefully added, keeping the internal temperature at −78° C. Sodium sulfite (3.0 g, 24 mmol) was added and the temperature was allowed to gradually increase to ambient temperature. The reaction mixture was diluted with ethyl ether, washed with water, then dried over magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography on silica gel, eluting (ethyl acetate/isohexane gradient) to give 2,6-difluoro-3-iodopyridine.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:10]=[C:11]([CH:16]=[CH:17][CH:18]=2)[O:12][CH2:13][C:14]#[N:15])[C:5]([Cl:19])=[CH:4][N:3]=1.[CH2:20]([N:22]1[CH2:28][CH2:27][C:26]2[CH:29]=[C:30]([NH2:33])[CH:31]=[CH:32][C:25]=2[CH2:24][CH2:23]1)[CH3:21]>>[Cl:19][C:5]1[C:6]([NH:8][C:9]2[CH:10]=[C:11]([CH:16]=[CH:17][CH:18]=2)[O:12][CH2:13][C:14]#[N:15])=[N:7][C:2]([NH:33][C:30]2[CH:31]=[CH:32][C:25]3[CH2:24][CH2:23][N:22]([CH2:20][CH3:21])[CH2:28][CH2:27][C:26]=3[CH:29]=2)=[N:3][CH:4]=1
Reactant: CCN1CCc2ccc(N)cc2CC1
Reactant: N#CCOc1cccc(Nc2nc(Cl)ncc2Cl)c1
Product: CCN1CCc2ccc(Nc3ncc(Cl)c(Nc4cccc(OCC#N)c4)n3)cc2CC1

Procedure:
The title compound was prepared from [3-(2,5-dichloropyrimidin-4-ylamino)-phenoxy]acetonitrile and 3-ethyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine in an analogous manner to Example 195 (microwave: 130° C., 2 hours) to afford a white foam (30 mg, 40%). Mp: 104-6° C. LCMS (m/e) 449 (M+1); 1H-NMR (CDCl3, 400 MHz) δ 8.10 (s, 1H), 7.81 (s, 1H), 7.30 (m, 4H), 7.12 (s, 1H), 7.06 (m, 2H), 6.76 (d, J=6 Hz, 1H), 4.68 (s, 2H), 2.90 (m, 4H), 2.70-2.55 (m, 6H), 1.12 (t. J=7 Hz, 3H).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:17]=[CH:16][C:13]([CH2:14]O)=[CH:12][CH:11]=1.S(Br)([Br:20])=O.N1C(C)=CC=CC=1C>C(Cl)Cl>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:17]=[CH:16][C:13]([CH2:14][Br:20])=[CH:12][CH:11]=1
Reactant: OCc1ccc(-c2nc3ccccc3o2)cc1
Reactant: O=S(Br)Br
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: BrCc1ccc(-c2nc3ccccc3o2)cc1
Temperature: 25 °C

Procedure:
To 4-(benzoxazol-2-yl)benzyl alcohol (20.9 g; 100 mmol) dissolved in CH2Cl2 (330 ml) and cooled to 0°-5° C. is added thionyl bromide (9.2 ml; 120 mmol) and allowed to warm to room temperature after removing the bath. After 11/2 hours, 2,6-lutidine (11.6 ml; 100 mmol) is added to the mixture and warmed to 30° C. The reaction mixture is then diluted with CH2Cl2, washed with H2O 1×, 0.2M HCl 1×, NaHCO3 2×, brine, dried (MgSO4) and concentrated to dryness. The residue is recrystallized from EtOAc to obtain 4-(benzoxazol-2-yl)benzyl bromide as white-orange needles which is used directly in Step E.
Reaction SMILES: Cl[C:2]1[N:6]([C:7]2[N:12]=[CH:11][N:10]=[C:9]([NH2:13])[CH:8]=2)[C:5]2[CH:14]=[CH:15][CH:16]=[CH:17][C:4]=2[N:3]=1.[NH2:18][C:19]1[CH:20]=[C:21]([CH:41]=[CH:42][C:43]=1[CH3:44])[C:22]([NH:24][C:25]1[CH:30]=[CH:29][C:28]([N:31]2[CH:35]=[CH:34][N:33]=[C:32]2[CH3:36])=[C:27]([C:37]([F:40])([F:39])[F:38])[CH:26]=1)=[O:23].CS(O)(=O)=O>CN1CCN(C)C1=O>[NH2:13][C:9]1[N:10]=[CH:11][N:12]=[C:7]([N:6]2[C:5]3[CH:14]=[CH:15][CH:16]=[CH:17][C:4]=3[N:3]=[C:2]2[NH:18][C:19]2[CH:20]=[C:21]([CH:41]=[CH:42][C:43]=2[CH3:44])[C:22]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([N:31]3[CH:35]=[CH:34][N:33]=[C:32]3[CH3:36])=[C:27]([C:37]([F:40])([F:39])[F:38])[CH:26]=2)=[O:23])[CH:8]=1
Reactant: Nc1cc(-n2c(Cl)nc3ccccc32)ncn1
Reactant: Cc1ccc(C(=O)Nc2ccc(-n3ccnc3C)c(C(F)(F)F)c2)cc1N
Agent: CS(=O)(=O)O
Solvent: CN1CCN(C)C1=O
Product: Cc1ccc(C(=O)Nc2ccc(-n3ccnc3C)c(C(F)(F)F)c2)cc1Nc1nc2ccccc2n1-c1cc(N)ncn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 6-(2-Chloro-benzoimidazol-1-yl)-pyrimidin-4-ylamine (15 mg, 0.056 mmol), 3-amino-4-methyl-N-[4-(2-methyl-imidazol-1-yl)-3-trifluoromethyl-phenyl]-benzamide (22 mg, 0.059 mmol), and MeSO3H (11.0 μL, 0.17 mmol) in 1,3-dimethyl-2-imidazolidinone (0.2 ml) is heated at 80° C. After stirring for overnight, the reaction mixture is cooled to room temperature. Purification by reverse-phase LC-MS afforded the title compound: 1H NMR 600 MHz (DMSO-d6) δ 11.50-11.00 (bs, 1H), 10.90 (s, 1H), 9.02 (s, 1H), 8.57 (s, 1H), 8.55 (d, J=2.0 Hz, 1H), 8.37 (dd, J=8.2, 2.0 Hz 1H), 7.92 (s, 1H), 7.87 (d, J=8.2 Hz, 1H), 7.81 (d, J=2.0 Hz, 1H), 7.70 (s, 1H), 7.69 (s, 1H), 7.55-7.46 (m, 4H), 7.87 (d, J=8.2 Hz, 1H), 7.27 (t, J=8.2 Hz, 1H), 7.22 (t, J=8.2 Hz, 1H), 2.46 (s, 3H), 2.41 (s, 3H); MS m/z 584.2 (M+1).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH:4]1[CH2:8][O:7][C:6]([CH3:10])([CH3:9])[O:5]1.C(N(CC)CC)C.[CH3:18][S:19](Cl)(=[O:21])=[O:20]>C1COCC1>[CH3:18][S:19]([O:1][CH2:2][CH2:3][CH:4]1[CH2:8][O:7][C:6]([CH3:10])([CH3:9])[O:5]1)(=[O:21])=[O:20]
Reactant: CC1(C)OCC(CCO)O1
Reactant: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC1(C)OCC(CCOS(C)(=O)=O)O1

Procedure:
The 4-(2-hydroxyethyl)-2,2-dimethyl-1,3-dioxolane (Aldrich, 0.19 g, 1.2 mmol), triethylamine (0.56 mL, 4.1 mmol), and methanesulfonyl chloride (0.15 mL, 1.9 mmol) in 10 mL THF were processed as described in Example 1C to give the title compound that was used directly in the next reaction.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][NH:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([NH2:17])[C:12]=1[NH2:18].[CH:19](O)=O>>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][NH:7][CH2:8][CH2:9][O:10][C:11]1[C:12]2[N:18]=[CH:19][NH:17][C:13]=2[CH:14]=[CH:15][CH:16]=1
Reactant: Nc1cccc(OCCNCc2cccs2)c1N
Reactant: O=CO
Product: c1csc(CNCCOc2cccc3[nH]cnc23)c1

Procedure:
The general procedures used in example 2 utilizing 3-{2-[(thiophen-2-ylmethyl)-amino]-ethoxy}-benzene-1,2-diamine (4c) and formic acid afforded:
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH3:31])=[C:4]2[O:13][C:12]([CH2:15][O:16][C:17]3[CH:18]=[CH:19][C:20]([CH2:23][CH:24]4[S:30][C:28](=[O:29])[NH:27][C:25]4=[O:26])=[CH:21][CH:22]=3)([CH3:14])[CH2:11][CH2:10][C:5]2=[C:6]([CH3:9])[C:7]=1[OH:8].C1(=O)OC(=O)CC1.C(Cl)CCl.O[N:44]1[C:48](=[O:49])[CH2:47][CH2:46][C:45]1=[O:50]>N1C=CC=CC=1>[CH3:1][C:2]1[C:3]([CH3:31])=[C:4]2[O:13][C:12]([CH2:15][O:16][C:17]3[CH:18]=[CH:19][C:20]([CH2:23][CH:24]4[S:30][C:28](=[O:29])[NH:27][C:25]4=[O:26])=[CH:21][CH:22]=3)([CH3:14])[CH2:11][CH2:10][C:5]2=[C:6]([CH3:9])[C:7]=1[OH:8].[C:45]1(=[O:50])[NH:44][C:48](=[O:49])[CH2:47][CH2:46]1
Reactant: O=C1CCC(=O)N1O
Agent: Cc1c(C)c2c(c(C)c1O)CCC(C)(COc1ccc(CC3SC(=O)NC3=O)cc1)O2
Agent: O=C1CCC(=O)O1
Solvent: c1ccncc1
Solvent: ClCCCl
Product: O=C1CCC(=O)N1

Procedure:
To make the succinyl CS-045 conjugate of β-phycoerythrin, first 44 mg of CS-045 was reacted for 5 hours at room temperature with 20 mg succinic anhydride in pyridine. Then 4 mg of the resulting succinyl CS-045 was reacted overnight at 4° C. with 2 mg EDC and 1.2 mg N-hydroxysuccinimide to produce CS-045 succinimide. Forty micrograms of this CS-045 succinimide was reacted for 4 hours at room temperature with 500 μg β-phycoerythrin. The final succinyl CS-045 conjugate of β-phycoerythrin was precipitated with 60% final (w/v) saturated ammonium sulfate and resuspended in phosphate buffered saline.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:15])[CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:4][CH:3]=1.[H-].[Na+].[CH3:18][N:19]([CH3:23])[C:20](Cl)=[S:21]>CN(C)C=O.O>[CH3:18][N:19]([CH3:23])[C:20]([O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8](=[O:15])[CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:6][CH:7]=1)=[S:21]
Reactant: COC(=O)CCC(=O)c1ccc(O)cc1
Reactant: CN(C)C(=S)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)CCC(=O)c1ccc(OC(=S)N(C)C)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of the product from Step B, 25 g, in anhydrous dimethylformamide (DMF) (300 ml) was cooled to 0° and 99% NaH, 3.46 g, was added in two portions. The mixture was stirred for 1 hour at 0° then dimethylthiocarbamoyl chloride, 19.3 g, was added and the mixture heated at 90° under a N2 atmosphere for 1.5 hours. The mixture was cooled to room temperature and diluted with water to 1,200 mL. The resulting solution was then extracted with ethyl acetate (3×50 ml). The combined organic layers were washed with brine and then dried over Na2SO4 and evaporated to dryness in vacuo to yield a residue which was purified by chromatography on silica gel to Yield the title compound, mp 62°-64°.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[C@H:4]([CH2:13][CH2:14][CH2:15][CH2:16][NH:17][C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19])[NH:5][C:6]([O:8]C(C)(C)C)=O.[CH2:29]([O:36][C:37]1[CH:55]=[CH:54][C:40]([CH2:41][C@@H:42](C(O)=O)[NH:43][C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])=[CH:39][CH:38]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C(N(CC)CC)C.C1(N=C=NC2CCCCC2)CCCCC1>FC(F)(F)C(O)=O.C(Cl)(Cl)Cl>[CH3:1][O:2][C:3](=[O:28])[C@H:4]([CH2:13][CH2:14][CH2:15][CH2:16][NH:17][C:18]([O:20][CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)=[O:19])[NH:5][C:6](=[O:8])[C@H:42]([CH2:41][C:40]1[CH:39]=[CH:38][C:37]([O:36][CH2:29][C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)=[CH:55][CH:54]=1)[NH:43][C:44]([O:46][C:47]([CH3:50])([CH3:48])[CH3:49])=[O:45]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(=O)O
Reactant: COC(=O)[C@H](CCCCNC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](CCCCNC(=O)OCc1ccccc1)NC(=O)[C@H](Cc1ccc(OCc2ccccc2)cc1)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 29.1 %

Procedure:
A solution of 1.04 g (2.64 mmol) of Nε -benzyloxycarbonyl-Nα -(tert-butoxycarbonyl)-L-lysine methyl ester in 5.3 mL of trifluoroacetic acid was stirred for 2 hours at room temperature. The reaction mixture was evaporated in vacuo to give a colorless oil, which was mixed with 0.966 g (2.6 mmol) of O-benzyl-N-(tert-butoxycarbonyl)-L-tyrosine, 0.37 mL (2.6 mmol) of triethylamine and 20.8 mL of chloroform. To that mixture was added, in one portion, 0.54 g (2.6 mL) of dicyclohexylcarbodiimide at 0° C. The reaction mixture was stirred for one hour at 0° C. and then overnight at room temperature. The solvent was removed by evaporation and the residue was chromatographed on silica gel, using first methylene chloride and then 1:1 methylene chloride/ethyl acetate as eluents, to give 0.49 g (29.1%) of a colorless solid. NMR (CDCl3) δ 7.3 (10 H, m), 7.1 (2H, d), 6.85 (2H, d), 6.5 (1H, m), 5.1 (2H, s), 5.0 (1H, m), 4.7-4.1 (2H, m), 3.65 (3H, s), 3.3-2.9 (4H, m), 1.4 (9H, s). A portion of the product was recrystallized from a mixture of ethyl acetate and isopropyl ether to give crystals melting at 167°-168° C. The product has the formula ##STR118## as confirmed by elemental analysis.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[C:6](=[O:23])[N:7]([CH:15]1[CH2:20][CH2:19][C:18](=[O:21])[NH:17][C:16]1=[O:22])[C:8]([CH3:14])=[N:9]2.[C:24](Cl)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(N(CC)C(C)C)(C)C>C(#N)C>[O:22]=[C:16]1[CH:15]([N:7]2[C:6](=[O:23])[C:5]3[C:10](=[CH:11][CH:12]=[CH:13][C:4]=3[CH2:3][NH:2][C:24](=[O:31])[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[N:9]=[C:8]2[CH3:14])[CH2:20][CH2:19][C:18](=[O:21])[NH:17]1
Reactant: Cc1nc2cccc(CN)c2c(=O)n1C1CCC(=O)NC1=O
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc2cccc(CNC(=O)c3ccccc3)c2c(=O)n1C1CCC(=O)NC1=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 35.7 %

Procedure:
To a stirred mixture of 3-(5-aminomethyl-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione hydrogen chloride (0.59 g, 1.8 mmol) in acetonitrile (10 mL), was added benzoyl chloride (0.31 mL, 2.7 mmol) and N,N-diisopropyl ethylamine (0.77 mL, 4.4 mmol). The mixture was stirred at room temp for 15 minutes. The solvent was evaporated, and the residue was purified by flash column chromatography (Silica gel, methanol/methylene chloride 4%/96%) to give N-[3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-5-ylmethyl]-benzamide as a white solid (260 mg, 36% yield); HPLC, Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 10/90 CH3CN/0.1% H3PO4, gradient to 95/5 in 5 min, kept for 5 min, 5.70 min (99.6%); mp, 247-249° C.; 1HNMR (DMSO-d6) 2.17-2.23 (m, 1H, CHH), 2.59-2.90 (m, 6H, CHCH2, CH3), 4.92-5.09 (m, 2H, CH2NH), 5.26 (dd, J=6, 12 Hz, 1H, CH), 7.47-7.94 (m, 8H, Ar), 8.93 (t, J=5 Hz, 1H, CH2NH), 11.05 (s, 1H, NH); 13C NMR (DMSO-d6) δ 20.82, 23.29, 30.60, 42.12, 56.53, 117.65, 124.01, 125.43, 127.20, 128.37, 131.30, 133.95, 134.21, 140.99, 148.50, 154.81, 161.11, 166.26, 169.54, 172.62. LCMS MH=405; Anal Calcd For C22H20N4O4+0.5H2O: C, 63.91; H, 5.12; N, 13.55. Found: C, 63.78; H, 4.82; N, 13.45.
Reaction SMILES: [CH:1]1([CH2:11][C:12]([OH:14])=[O:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][NH:2]1.OS(O)(=O)=O.[CH3:20]O>>[CH3:20][O:13][C:12](=[O:14])[CH2:11][CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][NH:2]1
Reactant: CO
Reactant: O=C(O)CC1NCCc2ccccc21
Agent: O=S(=O)(O)O
Product: COC(=O)CC1NCCc2ccccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-(1,2,3,4-Tetrahydroisoquinolin-1-yl)acetic acid (7.90 g, 41.3 mmol) was dissolved in methanol (200 ml), and H2SO4 (4.4 ml, 82.6 mmol) was added under a nitrogen atmosphere. The reaction solution was heated under reflux and, when the reaction was complete, was stirred overnight at room temperature. The methanol was removed in vacuo and the resulting residue was taken up in ethyl acetate (200 ml). The solution was washed with saturated NaHCO3 solution (150 ml), dried (sodium sulfate) and concentrated.