Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][C:9]([C:29]1[CH:50]=[CH:49][C:32]([C:33]([NH:35][C@H:36]([C:44]([O:46][CH2:47][CH3:48])=[O:45])[CH2:37][CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40])=[O:34])=[CH:31][CH:30]=1)=[CH:10][C:11]1[CH:28]=[N:27][C:14]2[N:15]=[C:16]([NH:20][C:21](=[O:26])[C:22]([CH3:25])([CH3:24])[CH3:23])[N:17]=[C:18]([OH:19])[C:13]=2[CH:12]=1>C(O)(=O)C.CO.[Pt](=O)=O>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][CH:9]([C:29]1[CH:50]=[CH:49][C:32]([C:33]([NH:35][C@H:36]([C:44]([O:46][CH2:47][CH3:48])=[O:45])[CH2:37][CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40])=[O:34])=[CH:31][CH:30]=1)[CH2:10][CH:11]1[CH2:28][NH:27][C:14]2[N:15]=[C:16]([NH:20][C:21](=[O:26])[C:22]([CH3:23])([CH3:25])[CH3:24])[N:17]=[C:18]([OH:19])[C:13]=2[CH2:12]1
Reactant: CCOC(=O)CC[C@H](NC(=O)c1ccc(C(=Cc2cnc3nc(NC(=O)C(C)(C)C)nc(O)c3c2)COC2CCCCO2)cc1)C(=O)OCC
Agent: O=[Pt]=O
Solvent: CO
Solvent: CC(=O)O
Product: CCOC(=O)CC[C@H](NC(=O)c1ccc(C(COC2CCCCO2)CC2CNc3nc(NC(=O)C(C)(C)C)nc(O)c3C2)cc1)C(=O)OCC
Yield: 59.8 %

Procedure:
A solution of 1.16 g (1.68 mm) of diethyl N-[4-{1-(tetrahydropyr-2-yloxy)-3-(2-pivaloylamino-4-hydroxypyrido[2,3-d]pyrimidin-6-yl)prop-2-en-2-yl}benzoyl]glutamate and 174 mg (20%) of amorphous platinum (IV) oxide in 150 ml of glacial acetic acid was hydrogenated for 10 hours at 50 psi. The reaction mixture was diluted with 50 ml of methanol and filtered through Celite. The filtrate was concentrated and diluted with ethyl acetate. The solid which formed after cooling for 15 hour was collected by filtration, washed with cold ethyl acetate and dried to give 700 mg (68%) of diethyl N-[4-{1-(tetrahydropyr-2-yloxy)-3-(2-pivaloylamino-4-hydroxy-5,6,7,8-tetrahydropyrido[2,3-d]pyrimidin-6-yl)prop-2-yl}benzoyl]glutamate. mp 183°-186° C. Analysis calculated for C36H51O9N5 : C, 61.95; H, 7.37; N, 10.04. Found: C, 62.00; H, 7.17; N, 9.83. NMR (CDCL3), delta, 1.23 (t, 3H, J=7 Hz), 1.26 (s, 9H), 1.32 (t, 3H, J=7 Hz), 2.26-2.82 (m, 9H), 2.06-2.12 (m, 2H), 2.26-2.38 (m, 1H), 2.43-2.58 (m, 2H), 2.62-2.83 (m, 1H), 2.84-3.10 (m, 2H) 3.12-3.21 and 2.32-3.40 (m, m, 1H), 3.41-3.52 (m, 2H), 3.68-3.92 (m, 2H), 4.13 (q, 2H, J=7 Hz), 4.25 (q, 2H, J=7 Hz), 4.44-4.63 (m, 2H, CH, NH), 4.78-4.84 (m, 1H) 7.02 (brd, 1H, NH, J=7.1 Hz), 7.29 (brs, NH), 7.31-7.37 (m, 2H), 7.75-7.78 (m, 2H), 11.20 (brs, NH).
Reaction SMILES: [NH2:1][CH:2]([C:6]#[N:7])[C:3]([NH2:5])=[O:4].C[O-].[Na+].[C:11]([OH:14])(=O)C.[CH:15]([CH:17]=O)=O>CO>[CH3:11][O:14][C:6]1[C:2]([C:3]([NH2:5])=[O:4])=[N:1][CH:15]=[CH:17][N:7]=1
Reactant: O=CC=O
Reactant: N#CC(N)C(N)=O
Reactant: CC(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1nccnc1C(N)=O
Temperature: 20 °C
Reaction time: 2 h
Yield: 50 %

Procedure:
Under argon, 1 g (10.1 mmol) of 2-amino-2-cyanoacetamide was initially charged in 10 g of methanol. 0.25 g (1.4 mmol) of sodium methoxide solution (30%) was added and the mixture was stirred at 20° C. for 2 hours. After neutralization with 0.084 g (1.4 mmol) of acetic acid, 2.27 g (20 mmol) of glyoxal solution (40%) was added. The mixture was stirred at 20° C. for 2 hours and then at 50° C. for 2 hours. The solvent was distilled off. This gave 0.75 g of 3-methyoxypyrazine-2-carboxamide. The yield was 50 percent. Other data concerning the title product was:
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=O)C(C(O)=O)[CH:2]=1.[C:15](Cl)(=O)[C:16]([Cl:18])=[O:17].[Cl:21]CCl>CN(C=O)C>[Cl:21][C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[N:1]=[CH:2][C:15]=1[C:16]([Cl:18])=[O:17]
Reactant: O=C(Cl)C(=O)Cl
Reactant: ClCCl
Reactant: O=C(O)C1C=Nc2ccccc2C1=O
Solvent: CN(C)C=O
Product: O=C(Cl)c1cnc2ccccc2c1Cl
Reaction time: 1.5 h

Procedure:
A suspension of 4-quinolone-3-carboxylic acid (189 mg) in dichloromethane (5 ml) was treated with 1 drop DMF and oxalyl chloride (0.2 ml), stirred 1.5 hours and the solvent evaporated. The residue was briefly put under vacuum to provide 4-chloroquinoline-3-carbonyl chloride as a white solid.
Reaction SMILES: FC1C=C(C=CC=1F)[O:5][C:6]1[C:7](=[O:23])[O:8][C:9]([CH3:22])([CH3:21])[C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][CH:12]=1.C(OCC(Cl)=O)(=O)C.C1CCN2C(=NCCC2)CC1.Cl>CC#N.N1C=CC=CC=1>[CH3:21][C:9]1([CH3:22])[O:8][C:7](=[O:23])[C:6]([OH:5])=[C:10]1[C:11]1[CH:12]=[CH:13][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:15][CH:16]=1
Reactant: CC1(C)OC(=O)C(Oc2ccc(F)c(F)c2)=C1c1ccc(S(C)(=O)=O)cc1
Agent: CC(=O)OCC(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CC1(C)OC(=O)C(O)=C1c1ccc(S(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 7 h
Yield: 61.6 %

Procedure:
To a 0° C. solution of the alcohol of Example 1, Step 3 (29.5 g, 122 mmol) in CH3CN (350 mL) were added pyridine (25 mL) and acetoxyacetyl chloride (25 g, 183 mmol). After a period of 7 h at r.t., DBU (31 mL) was added to the reaction mixture. After a period of 1 h at 80° C., a second portion of DBU (35 mL) was added. The reaction mixture was kept at 80° C. for 18 h. The reaction mixture was allowed to cool to r.t. The mixture was poured onto ice-water (2.5 L) containing 100 mL of concentrated HCl. The brown solid was collected and dissolved in hot acetonitrile and was filtered through a plug of silica. The solvent was evaporated and the resultant solid was swished in EtOAc to give the title compound (21.2 g, 62%).
Reaction SMILES: Cl.Cl.Cl.[Cl:4][C:5]1[CH:6]=[C:7]([C:12]2[N:13]=[C:14]([CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)[N:15]([CH2:17][CH2:18][N:19]([CH3:21])[CH3:20])[CH:16]=2)[CH:8]=[CH:9][C:10]=1[F:11].Cl[C:29]1[C:30]2[C:37](=[CH:38][C:39]3[CH:44]=[CH:43][N:42]=[CH:41][CH:40]=3)[C:36](=[O:45])[NH:35][C:31]=2[N:32]=[CH:33][N:34]=1.CCN(C(C)C)C(C)C.CC(O)C>O>[Cl:4][C:5]1[CH:6]=[C:7]([C:12]2[N:13]=[C:14]([CH:22]3[CH2:23][CH2:24][N:25]([C:29]4[C:30]5[C:37](=[CH:38][C:39]6[CH:40]=[CH:41][N:42]=[CH:43][CH:44]=6)[C:36](=[O:45])[NH:35][C:31]=5[N:32]=[CH:33][N:34]=4)[CH2:26][CH2:27]3)[N:15]([CH2:17][CH2:18][N:19]([CH3:21])[CH3:20])[CH:16]=2)[CH:8]=[CH:9][C:10]=1[F:11]
Reactant: O=C1Nc2ncnc(Cl)c2C1=Cc1ccncc1
Reactant: CN(C)CCn1cc(-c2ccc(F)c(Cl)c2)nc1C1CCNCC1
Agent: Cl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: CN(C)CCn1cc(-c2ccc(F)c(Cl)c2)nc1C1CCN(c2ncnc3c2C(=Cc2ccncc2)C(=O)N3)CC1

Procedure:
Combine {2-[4-(3-chloro-4-fluoro-phenyl)-2-piperidin-4-yl-imidazol-1-yl]-ethyl}-dimethyl-amine tris hydrochloride (0.5 g; 0.0013 mol; 1.0 equiv); 4-chloro-5-[1-pyridin-4-yl-methylidene]-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one (0.34 g; 0.0013 mol; 1.0 equiv); DIPEA (1.7 mL; 0.0098 mol; 7.6 equiv); 2-propanol (15 mL) and microwave at 80° C. for 20 min. Cool and dilute with water. Extract with EA and wash with brine. Concentrate the crude and purify by reverse phase HPLC to give the title compound as a mixture of E and Z isomers (0.04 g; 5.4%). MS (ES+): m/z=573 (M+H). (Note: All olefin compounds are mixtures of E and Z isomers.)
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:4]=1[CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([CH:12]=O)[CH2:8][CH2:7]1.[OH:24][C@@H:25]1[CH2:30][CH2:29][CH2:28][CH2:27][C@H:26]1[NH:31][C:32]1[CH2:36][S:35][C:34](=[O:37])[N:33]=1.C([O-])(=O)C.[NH2+]1CCCCC1>CC(O)C>[F:1][C:2]([F:22])([F:23])[C:3]1[CH:17]=[C:16]([C:18]([F:20])([F:21])[F:19])[CH:15]=[CH:14][C:4]=1[CH2:5][N:6]1[CH2:7][CH2:8][CH:9](/[CH:12]=[C:36]2/[C:32]([NH:31][C@@H:26]3[CH2:27][CH2:28][CH2:29][CH2:30][C@H:25]3[OH:24])=[N:33][C:34](=[O:37])[S:35]/2)[CH2:10][CH2:11]1
Reactant: O=C1N=C(N[C@@H]2CCCC[C@H]2O)CS1
Reactant: O=CC1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Agent: C1CC[NH2+]CC1
Agent: CC(=O)[O-]
Solvent: CC(C)O
Product: O=C1N=C(N[C@@H]2CCCC[C@H]2O)/C(=C/C2CCN(Cc3ccc(C(F)(F)F)cc3C(F)(F)F)CC2)S1
Temperature: 80 °C
Reaction time: 8 h
Yield: 44.7 %

Procedure:
To a solution of 1-[2,4-bis(trifluoromethyl)benzyl]piperidine-4-carbaldehyde (1.01 g) in 2-propanol (15 mL) were added 4-{[(1R,2R)-2-hydroxycyclohexyl]amino}thiazol-2(5H)-one (960 mg) and piperidinium acetate (443 mg). The reaction mixture was stirred at 80° C. overnight, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) and silica gel column chromatography (NH, methanol/ethyl acetate), and recrystallized from ethyl acetate/heptane to give the title compound (712 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=O)([O-:3])=[O:2].[CH2:12]([O:14][C:15](=[O:24])[CH2:16][C:17]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=O)[CH3:13].[CH2:25]([O:27][C:28](=[O:37])[C:29](=[NH:36])[CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH3:26]>>[CH2:22]([O:21][C:19]([C:17]1[NH:36][C:29]([C:28]([O:27][CH2:25][CH3:26])=[O:37])=[C:30]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH:6]([C:5]2[CH:8]=[CH:9][CH:10]=[CH:11][C:4]=2[N+:1]([O-:3])=[O:2])[C:16]=1[C:15]([O:14][CH2:12][CH3:13])=[O:24])=[O:20])[CH3:23]
Reactant: CCOC(=O)CC(=N)C(=O)OCC
Reactant: O=Cc1ccccc1[N+](=O)[O-]
Reactant: CCOC(=O)CC(=O)C(=O)OCC
Product: CCOC(=O)C1=C(C(=O)OCC)C(c2ccccc2[N+](=O)[O-])C(C(=O)OCC)=C(C(=O)OCC)N1

Procedure:
A solution of 7.5 g of o-nitrobenzaldehyde, 9.5 g of oxalacetic acid diethyl ester and 9.4 g of iminosuccinic acid diethyl ester in 30 ccs of alcohol is heated under reflux overnight and subsequently cooled. After filtration, light yellow crystals of melting point 109° (ethanol) are obtained.
Reaction SMILES: [CH2:1]([CH:9]1[CH2:14][C:13](=[O:15])O[C:10]1=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].P(Cl)(Cl)(Cl)(Cl)[Cl:17].[Cl-:22]>>[CH2:1]([CH:9]([CH2:14][C:13]([Cl:17])=[O:15])[C:10]([Cl:22])=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: CCCCCCCCC1CC(=O)OC1=O
Reactant: [Cl-]
Product: CCCCCCCCC(CC(=O)Cl)C(=O)Cl
Yield: 79.2 %

Procedure:
n-Octylsuccinyl dichloride was prepared by reacting n-octylsuccinic anhydride with PCl5 at 105°-110° C. for about four hours. After working the product up 101.3 g of liquid was obtained which had a purity of 84.3% according to chloride content. The corrected yield was 79.2%.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4](=O)[C:5]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=3)[CH:9]=[CH:8][C:6]=2[N:7]=1.N1C(C)=CC=CC=1C.O=P(Cl)(Cl)[Cl:33]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH3:1][C:2]1[N:3]=[C:4]([Cl:33])[C:5]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([O:20][CH3:21])[CH:13]=3)[CH:9]=[CH:8][C:6]=2[N:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ccc(-c2ccc3nc(C)[nH]c(=O)c3n2)cc1OC
Solvent: Cc1cccc(C)n1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COc1ccc(-c2ccc3nc(C)nc(Cl)c3n2)cc1OC
Yield: 74.7 %

Procedure:
To a solution of 2-methyl-6-(3,4-dimethoxyphenyl)-pyrido[3,2-d]pyrimidin-4(3H)-one (416 mg, 1.4 mmol) in toluene (28 ml) was added 2,6-lutidine (490 μl, 4.2 mmol) and POCl3 (4.2 mmol, 385 μl). The mixture was refluxed under nitrogen atmosphere for 5 hours. The reaction mixture was cooled down, diluted with ethyl acetate (50 ml) and extracted with a saturated sodium bicarbonate solution. The combined organic layers were evaporated in vacuo and the residue was purified by silica gel column chromatography (the mobile phase being an ethyl acetate/hexane mixture in a ratio of 15:85), resulting in the pure title compound (330 mg, yield 75%) which was characterised by its mass spectrum as follows: MS (m/z): 316, 318 ([M+H]+, 100).
Reaction SMILES: C(N(CC)C(C)C)(C)C.[CH3:10][N:11]1[CH2:16][CH2:15][NH:14][CH2:13][C:12]1=[O:17].[F:18][C:19]1[CH:20]=[C:21]([N+:26]([O-:28])=[O:27])[CH:22]=[CH:23][C:24]=1F>C(#N)C>[F:18][C:19]1[CH:20]=[C:21]([N+:26]([O-:28])=[O:27])[CH:22]=[CH:23][C:24]=1[N:14]1[CH2:15][CH2:16][N:11]([CH3:10])[C:12](=[O:17])[CH2:13]1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Reactant: CN1CCNCC1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CN1CCN(c2ccc([N+](=O)[O-])cc2F)CC1=O

Procedure:
N,N-Diisopropylethylamine (11.5 ml) and 1-methyl-2-oxopiperazine (4.12 g) were added to a solution of 3,4-difluoronitrobenzene (1.82 ml) in acetonitrile (100 ml), and the mixture heated to reflux for 16 hours. Solvent was evaporated, and the residue chromatographed on silica, using as eluant a gradient increasing in polarity from 0 to 100% ethyl acetate in iso-hexane. Relevant fractions were combined and evaporated to give 3-fluoro-4-(4-methyl-3-oxopiperazin-1-yl)nitrobenzene (3.37 g).
Reaction SMILES: [C:1]([O:5][CH2:6][CH2:7][CH2:8][SiH2:9][O:10][Si:11]([CH3:14])([CH3:13])[CH3:12])(=[O:4])[CH:2]=[CH2:3].C([O:18][CH:19]=[CH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)(=O)C.CC(N=NC(C#N)(C)C)(C#N)C>C1COCC1>[OH:18][CH:19]=[CH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[C:1]([O:5][CH2:6][CH2:7][CH2:8][SiH2:9][O:10][Si:11]([CH3:14])([CH3:12])[CH3:13])(=[O:4])[CH:2]=[CH2:3]
Reactant: CC(=O)OC=Cc1ccccc1
Agent: C=CC(=O)OCCC[SiH2]O[Si](C)(C)C
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: C1CCOC1
Product: OC=Cc1ccccc1
Temperature: 65 °C
Reaction time: 8 h

Procedure:
10 g (3-acryloxypropyl)trimethylsiloxy silane, 36 g acetoxystyrene and 2.41 g AIBN were dissolved in 137 g THF and charged into a 3-neck flask. The system was then purged with N2 for 30 mins before the temperature was raised to 65° C. The reaction was carried out overnight under N2. On the second day, 100 g methanol and 30 mL 30% ammonia hydroxide were added to the system and the temperature was kept at 60° C. The reaction was carried out overnight under N2. On the third day, the solution was precipitated in 2000 mL water and 20 mL acetic acid. The polymer was collected and dried in vacuum oven overnight at 40° C. The molecular weight was determined by GPC to be 6.8K.
Reaction SMILES: [N+:1]([C:4]1[C:5]([S:10][NH:11][CH2:12][CH2:13][CH2:14][CH2:15][C@@H:16]([C:18]([NH:20][C@@H:21]([C:40]([O:42][CH2:43][CH3:44])=[O:41])[CH2:22][CH2:23][C:24]([N:26]2[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH2:28][C@H:27]2[C:35]([O:37][CH2:38][CH3:39])=[O:36])=[O:25])=[O:19])[NH2:17])=[N:6][CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].CN1CCOCC1.[CH2:52]1[O:72][C:71]2[CH:70]=[CH:69][C:56]([CH2:57][O:58][C:59](ON3C(=O)CCC3=O)=[O:60])=[CH:55][C:54]=2[O:53]1>C(Cl)Cl>[CH2:52]1[O:72][C:71]2[CH:70]=[CH:69][C:56]([CH2:57][O:58][C:59]([NH:17][C@H:16]([C:18]([NH:20][C@@H:21]([C:40]([O:42][CH2:43][CH3:44])=[O:41])[CH2:22][CH2:23][C:24]([N:26]3[C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[CH2:28][C@H:27]3[C:35]([O:37][CH2:38][CH3:39])=[O:36])=[O:25])=[O:19])[CH2:15][CH2:14][CH2:13][CH2:12][NH:11][S:10][C:5]3[C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=[CH:7][N:6]=3)=[O:60])=[CH:55][C:54]=2[O:53]1
Reactant: O=C(OCc1ccc2c(c1)OCO2)ON1C(=O)CCC1=O
Reactant: CCOC(=O)[C@@H](CCC(=O)N1c2ccccc2C[C@H]1C(=O)OCC)NC(=O)[C@@H](N)CCCCNSc1ncccc1[N+](=O)[O-]
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CCOC(=O)[C@@H](CCC(=O)N1c2ccccc2C[C@H]1C(=O)OCC)NC(=O)[C@H](CCCCNSc1ncccc1[N+](=O)[O-])NC(=O)OCc1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 3 h
Yield: 85.8 %

Procedure:
An aliquot (1.0 g) of the resulting ester was dissolved in 30 ml of methylene chloride, and 0.21 g of N-methylmorpholine and 1.07 g of N-(3,4-methylenedioxybenzyloxycarbonyloxy)succinimide were added, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was washed successively with saturated aqueous sodium bicarbonate solution, 5% aqueous potassium hydrogensulfate solution, and water, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure. The residue was recrystallized from ethanol/methanol to give 1.1 g of ethyl 1-[N2 -(3,4-methylenedioxybenzyloxycarbonyl)-N6 -(3-nitro-2-pyridinesulfenyl)-L-lysyl-O1 -ethyl-gamma-D-glutamyl]indoline-2(S)-carboxylate. mp. 130°-135° C. [α]D27 : -23.2° (dimethylformamide).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C@H:13]([NH:21][C:22]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:23])[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[CH:8][CH:7]=1.O[N:33]1[C:37](=[O:38])[C:36]2=[CH:39][CH:40]=[CH:41][CH:42]=[C:35]2[C:34]1=[O:43].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[O:43]=[C:34]1[C:35]2[C:36](=[CH:39][CH:40]=[CH:41][CH:42]=2)[C:37](=[O:38])[N:33]1[O:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]([CH2:12][C@H:13]([NH:21][C:22]([O:24][CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[O:23])[C:14]([O:16][C:17]([CH3:20])([CH3:18])[CH3:19])=[O:15])=[CH:10][CH:11]=1
Reactant: CC(C)(C)OC(=O)[C@H](Cc1ccc(OCCCO)cc1)NC(=O)OCc1ccccc1
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)[C@H](Cc1ccc(OCCCON2C(=O)c3ccccc3C2=O)cc1)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97 %

Procedure:
A mixture of tert-butyl (2S)-3-[4-(3-hydroxypropoxy)phenyl]-2-[(phenylmethoxy)carbonylamino]propanoate (0.215 g, 0.5 mmol), as prepared in the preceding step, N-hydroxyphthalimide ((0.098 g, 0.6 mmol), and triphenylphosphine (0.157 g, 0.6 mmol) in anhydrous tetrahydrofuran (10 mL) was treated with diethyl azodicarboxylate (0.095 g, 0.6 mmol). The reaction mixture was allowed to stir at room temperature overnight. The reaction mixture was evaporated to dryness and the residue was placed on a silica gel column (10 g Waters Sep-Pak) and eluted with 20% ethyl acetate and 80% hexane. The pure fractions were combined and evaporated to give the title compound (0.280 g, 97% yield). 1H NMR (300 MHz, CDCl3) δ7.84 (dd, J=5.6,3.0 Hz, 2H), 7.75 (dd, J=5.6, 3.0 Hz, 2H), 7.28-7.34 (m, 5H), 7.03 (d, J=8.7 Hz, 2H), 6.83 (d, J=8.7 Hz, 2H), 5.22 (br d, J=8.2 Hz, 1H), 5.09 (d, J=2.5 Hz, 2H), 4.48 (m, 1 H), 4.41 (t, J=6.3 Hz, 2H), 4.20 (t, J=6.2 Hz, 2H), 3.01 (br d, J=5.9 Hz, 2H), 2.23 (p, J=6.2 Hz, 2H), 1.41 (s, 9H).
Reaction SMILES: Cl.[CH3:2][O:3][C@:4]1([CH3:19])[C@:15]([O:17][CH3:18])([CH3:16])[O:14][C@@H:7]2[CH2:8][NH:9][CH2:10][C@H:11]([CH2:12][OH:13])[C@H:6]2[O:5]1.C([O-])([O-])=O.[K+].[K+].[CH2:26](Cl)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CN(C=O)C>[CH2:26]([N:9]1[CH2:10][C@H:11]([CH2:12][OH:13])[C@H:6]2[O:5][C@@:4]([O:3][CH3:2])([CH3:19])[C@:15]([O:17][CH3:18])([CH3:16])[O:14][C@@H:7]2[CH2:8]1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: ClCc1ccccc1
Reactant: CO[C@@]1(C)O[C@@H]2[C@@H](CO)CNC[C@H]2O[C@]1(C)OC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CO[C@@]1(C)O[C@@H]2[C@@H](CO)CN(Cc3ccccc3)C[C@H]2O[C@]1(C)OC
Temperature: 40 °C
Reaction time: 4 h
Yield: 97.9 %

Procedure:
To a solution of 2 (14.85 g, 50.0 mmol) in DMF (200 mL) was added K2CO3 (17.25 g, 125 mmol) and the mixture was stirred at 40° C. for about 4 hrs. At this point, BnCl (5.7 mL, 50.0 mmol) was added in one portion and the reaction was stirred at 40° C. overnight. The solvent was evaporated in vacuo and the residue was suspended in water (600 mL) and HCl was added to dissolve the residue. The solution was washed with Et2O and then basified with Na2CO3. The solution was extracted with EtOAc (2×) and the combined extracts were washed with water and then brine and then dried over MgSO4. The solution was filtered and the filtrate evaporated in vacuo to give the title compound (17.2 g, >95%) as a colorless to very pale yellow viscous oil which was used without further purification. 1H NMR (CDCl3) 7.3 (m, 5H), 3.6-3.8 (m, 2H), 3.5 (s, 3H), 3.4 (t, 1H), 3.26 (s, 3H), 3.268 (s, 3H), 2.9 (m, 2H), 2.2 (br s, 1H), 2.05 (m, 1H), 1.85 (t, 1H), 1.28 (s, 3H), 1.26 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[N:5]=[C:4]([CH3:9])[N:3]=1.[NH2:10][NH2:11].C(=O)([O-])[O-].[K+].[K+]>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]([NH:10][NH2:11])[N:5]=[C:4]([CH3:9])[N:3]=1
Reactant: NN
Reactant: Cc1nc(Cl)cc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1nc(Cl)cc(NN)n1
Temperature: 25 °C
Reaction time: 13 h
Yield: 96.1 %

Procedure:
To a solution of 4,6-dichloro-2-methylpyrimidine (10 g, 0.061 mol) in dry THF (500 ml) was added anhydrous hydrazine (1.96 g, 0.061 mol) followed by potassium carbonate (12.7 g, 0.092 mol). The reaction mixture was stirred at room temperature for 13 h and filtered. The filtrate was evaporated under reduced pressure to afford 9.3 g (45%) of the titled compound as a solid.
Reaction SMILES: [F:1][C:2]1[CH:28]=[CH:27][C:26]([C:29]([NH:31][C:32]2[CH:37]=[C:36]([CH3:38])[CH:35]=[CH:34][C:33]=2[F:39])=[O:30])=[CH:25][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([C:11]2[NH:15][CH:14]=[C:13]([C:16]([NH:18][CH2:19][CH2:20][C:21]([O:23]C)=[O:22])=[O:17])[CH:12]=2)[CH:6]=1.[OH-].[Na+].O.Cl>C1COCC1.CO>[F:1][C:2]1[CH:28]=[CH:27][C:26]([C:29]([NH:31][C:32]2[CH:37]=[C:36]([CH3:38])[CH:35]=[CH:34][C:33]=2[F:39])=[O:30])=[CH:25][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([C:11]2[NH:15][CH:14]=[C:13]([C:16]([NH:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22])=[O:17])[CH:12]=2)[CH:6]=1
Reactant: COC(=O)CCNC(=O)c1c[nH]c(-c2cc(Oc3cc(C(=O)Nc4cc(C)ccc4F)ccc3F)ccn2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(F)c(NC(=O)c2ccc(F)c(Oc3ccnc(-c4cc(C(=O)NCCC(=O)O)c[nH]4)c3)c2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of methyl 3-[({5-[4-(2-fluoro-5-{[(2-fluoro-5-methylphenyl)amino]carbonyl}phenoxy)pyridin-2-yl]-1H-pyrrol-3-yl}carbonyl)amino]propanoate (82 mg, 0.15 mmol) in a mixture of THF/MeOH (10 ml/10 ml) was added 1M NaOH solution (1 ml, 1 mmol). The mixture was stirred at room temperature for 2 hours and poured into 100 ml of water. 1M HCl was added dropwise until pH=4. The precipitates were filtered, washed with water and dried in vacuo to give 3-[({5-[4-(2-fluoro-5-{[(2-fluoro-5-methylphenyl)amino]carbonyl}phenoxy)pyridin-2-yl]-1H-pyrrol-3-yl}carbonyl)amino]propanoic acid as white solid. Yield: 70 mg, 88%.
Reaction SMILES: [C:1]1([CH:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:8]2[CH2:11][CH:10]([N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH:13]3[CH2:18][OH:19])[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:26]([O-:29])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[C:20]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]2[CH2:9][CH:10]([N:12]3[CH2:17][CH2:16][N:15]([C:26]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)=[O:29])[CH2:14][CH:13]3[CH2:18][OH:19])[CH2:11]2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C([O-])[O-]
Reactant: OCC1CNCCN1C1CN(C(c2ccccc2)c2ccccc2)C1
Agent: [Na+]
Solvent: ClCCl
Product: O=C(c1ccccc1)N1CCN(C2CN(C(c3ccccc3)c3ccccc3)C2)C(CO)C1
Temperature: 0 °C
Reaction time: 62 h

Procedure:
Compound 37c (1.03 mmol) was dissolved in CH2Cl2 (5 mL) and cooled in an ice water bath to 0° C. A 10% aqueous Na2CO3 solution (5 mL) was added and a solution of compound 37d (143 μL, 1.23 mmol) dissolved in CH2Cl2 (1 mL) was added dropwise. The resultant mixture was allowed to warm to 20° C. and then stirred rapidly for 62 h. CH2Cl2 (10 mL) was added to the reaction mixture and the aqueous phase was extracted with CH2Cl2 (2×20 mL). The combined organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated to give compound 37e (465 mg) as an off white foam. Compound 37e was used in the following step without further purification. 1H NMR (400 MHz, CDCl3): δ 7.39 (m, 9H), 7.22-7.32 (m, 4H), 7.14-7.23 (m, 2H), 4.35 (s, 1H), 4.07 (br. s, 1H), 3.30-3.71 (complex, 8H), 2.2-3.0 (complex, 6H); LCMS m/z (M+H+) 442.2.