Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[C:5]([CH3:21])([O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)[CH3:2].[CH3:23][C:24]1[CH:52]=[CH:51][C:27]([CH2:28][N:29]2[CH2:33][CH:32]([CH2:34][CH2:35]OS(C3C=CC(C)=CC=3)(=O)=O)[N:31]([CH2:47][CH2:48][CH3:49])[C:30]2=[O:50])=[CH:26][CH:25]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:22])[C:5]([CH3:21])([O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:35][CH2:34][CH:32]2[CH2:33][N:29]([CH2:28][C:27]3[CH:51]=[CH:52][C:24]([CH3:23])=[CH:25][CH:26]=3)[C:30](=[O:50])[N:31]2[CH2:47][CH2:48][CH3:49])=[CH:9][CH:8]=1)[CH3:2]
Reactant: CCCN1C(=O)N(Cc2ccc(C)cc2)CC1CCOS(=O)(=O)c1ccc(C)cc1
Reactant: CCOC(=O)C(C)(Cc1ccc(O)cc1)Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCCN1C(=O)N(Cc2ccc(C)cc2)CC1CCOc1ccc(CC(C)(Oc2ccccc2)C(=O)OCC)cc1
Temperature: 55 °C
Yield: 68.6 %

Procedure:
A mixture of 3-(4-hydroxy-phenyl)-2-methyl-2-phenoxy-propionic acid ethyl ester (0.80 g, 2.66 mmol), toluene-4-sulfonic acid 2-[1-(4-methyl-benzyl)-2-oxo-3-propyl-imidazolidin-4-yl]-ethyl ester (1.26 g, 2.93 mmol) and Cs2CO3 (1.04 g, 3.19 mmol) in DMF (40 mL) is heated to 55° C. under N2 for 17 h. The reaction is cooled and quenched with 1 N HCl (20 mL) and worked up extractively with Et2O and water. The organic layer is dried and the solvent removed to afford crude product that is purified by flash chromatography using 7:1 hexanes:acetone to afford 1.02 g (68%) 2-methyl-3-(4-{2-[1-(4-methyl-benzyl)-2-oxo-3-propyl-imidazolidin-4-yl]-ethoxy}-phenyl)-2-phenoxy-propionic acid ethyl ester. The diasteriomeric products were separated by chiral HPLC (90:10 heptane:IPA, 280 mL/min, 220 nm,) to give products in >99% de. Rf=0.49 (1:1 acetone:hexanes). 1H NMR. MS (ES+) Calc'd for C34H43N2O5 (M+1) 559. Found m/z 559 (100%).
Reaction SMILES: CC1C=CC(S(O[C:12]2[C:13]3[CH2:23][CH2:22][CH2:21][C:20]4[N:24]([CH3:27])[N:25]=[CH:26][C:19]=4[C:14]=3[N:15]=[C:16]([NH2:18])[N:17]=2)(=O)=O)=CC=1.[NH:28]1[CH2:32][CH2:31][C@@H:30]([NH:33]C(=O)OC(C)(C)C)[CH2:29]1>>[NH2:33][C@@H:30]1[CH2:31][CH2:32][N:28]([C:12]2[C:13]3[CH2:23][CH2:22][CH2:21][C:20]4[N:24]([CH3:27])[N:25]=[CH:26][C:19]=4[C:14]=3[N:15]=[C:16]([NH2:18])[N:17]=2)[CH2:29]1
Reactant: Cc1ccc(S(=O)(=O)Oc2nc(N)nc3c2CCCc2c-3cnn2C)cc1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCNC1
Product: Cn1ncc2c1CCCc1c-2nc(N)nc1N1CC[C@@H](N)C1

Procedure:
The compound from Example 8C (65 mg, 0.168 mmol) was treated with (R)-tert-butyl pyrrolidin-3-ylcarbamate (36 mg, 0.2 mmol) as described in Example 2 to yield the title compound: 1H NMR (300 MHz, DMSO-d6) δ 7.80 (s, 1 H), 5.5 (br s, 2 H), 3.73 (m, 3 H), 3.55 (m, 2 H), 3.42 (m, 2 H), 3.11 (m, 1 H), 2.89 (m, 2 H), 2.59 (m, 2 H), 1.95 (m, 3 H), 1.57 (m, 1 H); MS (ESI+) m/z 300 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:26])[C:10]1[C:15]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([I:23])=[CH:19][C:18]=2[F:24])=[CH:14][N:13]=[CH:12][C:11]=1[F:25].C[Si](C)(C)N[Si](C)(C)C.[O:36]1CC[CH2:38][CH2:37]1>>[C:37]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:26])[C:10]1[C:15]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([I:23])=[CH:19][C:18]=2[F:24])=[CH:14][N:13]=[CH:12][C:11]=1[F:25])(=[O:36])[CH3:38]
Reactant: Nc1ccccc1NC(=O)c1c(F)cncc1Nc1ccc(I)cc1F
Reactant: C1CCOC1
Agent: C[Si](C)(C)N[Si](C)(C)C
Product: CC(=O)Nc1ccccc1NC(=O)c1c(F)cncc1Nc1ccc(I)cc1F
Reaction time: 18 h

Procedure:
69 mg of N-(2-aminophenyl)-3-fluoro-5-[(2-fluoro-4-iodophenyl)amino]isonicotinamide (0.148 mmol, 1 eq.) were dissolved in 1 mL of terahydrofurane under a nitrogen athmoshere, then 0.592 ml of a hexamethyl disilazane solution (1M in THF, 4 eq.) were added and stirring was continued at room temperature for 18 h. The reaction mixture was partitioned between 20 ml of ethyl acetate and 15 ml of aqueouse HCL solution (1M). The aqueouse layer was reextracted twice with 20 ml of ethyl acetate each. The combined organic layers were washed with 20 ml of brine, dried over a silicone filter and concentrated in vacuo. The residue was purified by flash chromatography to yield 14 mg (0.03 mmol, 19%) of the analytically pure target compound.
Reaction SMILES: [C:1]([N:9]([CH2:16][CH2:17][CH2:18][CH3:19])[CH2:10][CH2:11][CH2:12][C:13]([OH:15])=O)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:20]([NH:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][C:39]([O:41]CC)=[O:40])([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[OH-].[K+]>C(O)C>[C:1]([N:9]([CH2:16][CH2:17][CH2:18][CH3:19])[CH2:10][CH2:11][CH2:12][C:13]([N:33]([CH:20]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][C:39]([OH:41])=[O:40])=[O:15])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CCCCCNC(c1ccccc1)c1ccccc1
Reactant: CCCCN(CCCC(=O)O)C(=O)c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCCCN(CCCC(=O)N(CCCCCC(=O)O)C(c1ccccc1)c1ccccc1)C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Analogously to Example 1, by using equivalent quantities, reacting N-benzoyl-4-(n-butylamino)butyric acid and ethyl 6-benzhydrylaminocaproate and suitable processing, dissolving the evaporation residue in ethanol, adding an ethanolic solution of potassium hydroxide, stirring for 12 hours at room temperature and further processing yields N-[N-benzoyl-4-(n-butylamino)butyryl]-6-benzhydrylaminocaproic acid.
Reaction SMILES: O[C@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O.[C@@H]1(O[C@H]2[C@@H](O)[C@@H](CO)O[C@H](OC3C=CC(N)=CC=3)[C@@H]2O)O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O.[C@@H:43]1([O:54][C@H:55]2[C@@H:70]([OH:71])[C@@H:69]([CH2:72][OH:73])[O:68][C@H:57]([O:58][C:59]3[CH:64]=[CH:63][C:62]([N+:65]([O-:67])=[O:66])=[CH:61][CH:60]=3)[C@@H:56]2[OH:74])[O:51][C@H:50]([CH2:52][OH:53])[C@H:48]([OH:49])[C@H:46]([OH:47])[C@H:44]1[OH:45]>CO.[Pd]>[C@H:43]1([O:54][C@H:55]2[C@@H:70]([OH:71])[C@@H:69]([CH2:72][OH:73])[O:68][C@H:57]([O:58][C:59]3[CH:64]=[CH:63][C:62]([N+:65]([O-:67])=[O:66])=[CH:61][CH:60]=3)[C@@H:56]2[OH:74])[O:51][C@H:50]([CH2:52][OH:53])[C@H:48]([OH:49])[C@H:46]([OH:47])[C@H:44]1[OH:45]
Reactant: O=[N+]([O-])c1ccc(O[C@H]2O[C@H](CO)[C@H](O)[C@H](O[C@@H]3O[C@H](CO)[C@H](O)[C@H](O)[C@H]3O)[C@H]2O)cc1
Agent: [Pd]
Agent: Nc1ccc(O[C@H]2O[C@H](CO)[C@H](O)[C@H](O[C@@H]3O[C@H](CO)[C@H](O)[C@H](O)[C@H]3O)[C@H]2O)cc1
Agent: OC[C@H]1O[C@H](O)[C@H](O)[C@@H](O)[C@H]1O
Solvent: CO
Product: O=[N+]([O-])c1ccc(O[C@H]2O[C@H](CO)[C@H](O)[C@H](O[C@H]3O[C@H](CO)[C@H](O)[C@H](O)[C@H]3O)[C@H]2O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A reaction scheme illustrating the chemoenzymatic synthesis of the αGal epitope, p-aminophenyl 3-O-β-D-galactopyranosyl-α-D-galactopyranoside (22) is shown in FIG. 3. p-Nitrophenyl 3-O-α-D-galactopyranosyl-α-D-galactopyranoside (compound 21) was prepared enzymatically as described by Nilsson (Tetrahedron Lett. (1997) 38:133-136). A mixture of p-nitrophenyl 3-O-β-galactopyranosyl-α-D-galactopyranoside (70 mg, 0.15 mmol) and 10 mg Pd/C (10%) in methanol (4 mL) was stirred under hydrogen at room temperature overnight. The reaction mixture was then filtered through Celite and the filtrate was concentrated in vacuo to give (50 mg) as a yellowish solid: 1H NMR (CD3OD): δ 6.87 (t, 2 H), 6.57 (d, 2 H), 5.21 (d, 1 H), 4.98 (d, 1 H), 4.2-4.1 (m, 2 H), 4.1-3.8 (m, 3 H), 3.8-3.7 (m, 3 H), 3.7-3.5 (m,4 H); 13C NMR (CD3OD): δ 143.8, 120.1, 117.9, 115.4, 101.2, 97.6, 78.3, 77.0, 72.6, 71.5, 71.4, 70.3, 68.7, 67.4, 63.2, 62.6; MS (ESI): m/e (M+Na+) Calcd. for C18H27NO11Na: 456.2, obsd: 456.2.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:16]([CH2:17][CH2:18][C:19]([OH:21])=O)[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.C(N1C=CN=C1)([N:24]1C=CN=C1)=O.N>O1CCCC1.C(=O)=O.CC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:16]([CH2:17][CH2:18][C:19]([NH2:24])=[O:21])[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:4][CH:3]=1
Reactant: O=C(O)CCn1c(-c2ccc(Cl)cc2)nc2cccnc21
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: N
Agent: O=C=O
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: NC(=O)CCn1c(-c2ccc(Cl)cc2)nc2cccnc21
Temperature: 25 °C
Reaction time: 48 h
Yield: 52 %

Procedure:
A mixture of 2-(4-chlorophenyl)-3H-imidazo[4,5-b]pyridine-3-propanoic acid (5.52 g, 0.0183 mole) and 1,1'-carbonyldiimidazole (2.97 g, 0.0183 mole) was stirred at room temperature in dry tetrahydrofuran (100 ml) for 2.5 hours with a stream of nitrogen bubbling through it. Liquid ammonia (50 ml) was added to the reaction mixture (cooled in dry ice/acetone bath) and the mixture was allowed to warm to room temperature and was stirred for 2 days under nitrogen atmosphere. The solvents were removed under reduced pressure and the resulting solid was triturated in water (100 ml), collected by filtration, rinsed twice with water, twice with a 5% potassium hydroxide solution, and twice again with water. The solid was recrystallized from hot methanol and dried under high vacuum at 40° C. to give 2.86 g (52%) of title compound, mp. 248°-250° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH:14](O)[CH3:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.S(Cl)([Cl:19])=O>C1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH:14]([Cl:19])[CH3:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: CC(O)c1ccc(-c2ccc(Cl)cc2)cc1
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Product: CC(Cl)c1ccc(-c2ccc(Cl)cc2)cc1

Procedure:
To a stirred suspension of 238 g of 1-(4'-chloro[1,1']biphenyl-4-yl)ethanol in 2 liters of anhydrous benzene add 200 ml. of thionyl chloride over 40 minutes. With stirring, reflux the reaction mixture for 4 hours. Concentrate the reaction mixture and dissolve the resulting solid residue in 2 liters of methylene chloride. Wash the methylene chloride solution with three 500 ml portions of water, dry the resulting solution over sodium sulfate, concentrate, and triturate the solid residue with petroleum ether to yield 4'-chloro-4-(1-chloroethyl)[1,1']-biphenyl m.p. 100°-102° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:27]=[C:28]([F:30])[CH:29]=1)[CH2:5][O:6][CH2:7][C:8]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]1.[C:31]([C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1)#[N:32]>O1CCCC1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:30][C:28]1[CH:29]=[C:2]([C:36]2[CH:37]=[CH:38][C:33]([C:31]#[N:32])=[CH:34][CH:35]=2)[CH:3]=[C:4]([CH2:5][O:6][CH2:7][C:8]2([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]2)[CH:27]=1
Reactant: N#Cc1ccc(B(O)O)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(COCc2cc(F)cc(Br)c2)(c2ccccc2)CC1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: N#Cc1ccc(-c2cc(F)cc(COCC3(c4ccccc4)CCNCC3)c2)cc1
Temperature: 120 °C

Procedure:
tert-Butyl 4-((3-bromo-5-fluorobenzyloxy)methyl)-4-phenylpiperidine-1-carboxylate (100.0 mg, 0.21 mmol), 4-cyanophenylboronic acid (93 mg, 0.63 mmol), and tetrakis(triphenylphosphine) palladium(0) (33 mg, 0.02 mmol) were combined in dry tetrahydrofuran (3 mL) in a microwave tube and sealed. After flushing with nitrogen, 0.7 mL of a 1 N potassium hydroxide aqueous solution was introduced. The mixture was heated at 120° C. for 1 h via microwave. After cooling to room temperature, the reaction mixture was concentrated and treated with a trifluoroacetic acid/methylene chloride mixture (1:1, 2 mL) for 1 h. The solvent was removed in vacuo and the resulting crude mixture passed through a strong cation exchange column. After washing the column with several volumes of methanol, the product was eluted by washing the column with 2 M ammonia in methanol and concentrated to afford 48 mg (46%). 1H-NMR (CDCl3, 500 MHz) δ 7.72 (s, 1H), 7.70 (s, 1H), 7.57 (s, 1H), 7.56 (s, 1H), 7.31-7.38 (m, 4H), 7.19-7.22 (m, 1H), 7.11-7.13 (m, 1H), 7.08 (s, 1H), 6.84-6.86 (s, 1H), 4.40 (s, 2H), 3.45 (s, 2H), 2.89-2.93 (m, 2H), 2.73-2.78 (m, 2H), 2.17-2.20 (m, 2H), 1.88-1.94 (m, 2H). 13C-NMR (CDCl3, 126 MHz) δ 163.3 (d, J=247.6 Hz), 144.2, 142.5, 141.2, 132.7, 128.4, 127.8, 127.3, 126.2, 121.3, 118.7, 114.2, 114.0, 113.1, 111.7, 80.1, 72.3, 42.7, 41.9, 33.6. Mass spec.: 401.28 (MH)+. Accurate mass spec.: m/z 401.2026 [MH]+, Δ=0.8 ppm.
Reaction SMILES: [C:1]1([CH2:11][CH2:12][CH:13]2[C:17]3[NH:18][C:19]([C:21]([O:23]C)=[O:22])=[CH:20][C:16]=3[CH2:15][CH2:14]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[OH-].[Li+].CO>C1COCC1>[C:1]1([CH2:11][CH2:12][CH:13]2[C:17]3[NH:18][C:19]([C:21]([OH:23])=[O:22])=[CH:20][C:16]=3[CH2:15][CH2:14]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)c1cc2c([nH]1)C(CCc1cccc3ccccc13)CC2
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1cc2c([nH]1)C(CCc1cccc3ccccc13)CC2

Procedure:
The title compound was synthesized from methyl 6-(2-(naphthalen-1-yl)ethyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate (0.051 g, 0.16 mmol) and lithium hydroxide (0.067 g, 1.6 mmol in 3 mL water), according to General Procedure 7. A 1:1 mixture of methanol (MeOH) and THF (6 mL) was used. The resulting product was purified by column chromatography (Isco CombiFlash) eluting with a gradient of 0-60% EtOAc/heptane. 17 mg. 1H NMR (400 MHz, METHANOL-d4) δ ppm 1.85 (dq, J=13.45, 7.90 Hz, 1H) 2.08-2.27 (m, 2H) 2.46-2.62 (m, 1H) 2.62-2.80 (m, 2H) 3.04-3.22 (m, 3H) 6.61 (s, 1H) 7.29-7.41 (m, 2H) 7.41-7.54 (m, 2H) 7.64-7.73 (m, 1H) 7.80-7.87 (m, 1H) 8.03 (d, J=8.35 Hz, 1H); LCMS-MS (ESI−) 304.0 (M−H); HPLC (UV=95.2%), (ELSD=100%).
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][NH:6][CH2:5][CH2:4][NH:3]1.[CH2:8]([O:10][C:11](=[O:20])[C:12]1[CH:17]=[C:16]([Cl:18])[C:15](Cl)=[N:14][CH:13]=1)[CH3:9].C(=O)([O-])[O-].[K+].[K+]>CC(N(C)C)=O>[CH2:8]([O:10][C:11](=[O:20])[C:12]1[CH:17]=[C:16]([Cl:18])[C:15]([N:6]2[CH2:5][CH2:4][NH:3][C@H:2]([CH3:1])[CH2:7]2)=[N:14][CH:13]=1)[CH3:9]
Reactant: CCOC(=O)c1cnc(Cl)c(Cl)c1
Reactant: C[C@@H]1CNCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: CCOC(=O)c1cnc(N2CCN[C@H](C)C2)c(Cl)c1

Procedure:
Heat a solution of (R)-2-methyl-piperazine (0.07 mol), 5,6-dichloro-nicotinic acid ethyl ester (TCI America) (10.1 g, 0.046 mol) and potassium carbonate (31.7 g, 0.23 mol) in DMA at 110° C. for 48 h. Cool the solution, and partition between EtOAc and brine. Separate the layers and extract the aqueous portion with EtOAc (1×). Wash the combined organic layers with 10% NaOH (4×), dry (Na2SO4), and concentrate under reduced pressure to give an oil which crystallizes on standing.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[CH3:11][NH:12][C@H:13]1[CH2:32][N:17]2[C:18]3[C:23]([C:24]([CH2:25][C:26]([O:28]CCC)=[O:27])=[C:16]2[CH2:15][CH2:14]1)=[CH:22][CH:21]=[CH:20][CH:19]=3>>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:12]([CH3:11])[C@H:13]2[CH2:32][N:17]3[C:18]4[C:23]([C:24]([CH2:25][C:26]([OH:28])=[O:27])=[C:16]3[CH2:15][CH2:14]2)=[CH:22][CH:21]=[CH:20][CH:19]=4)=[O:7])=[CH:4][CH:3]=1
Reactant: CCCOC(=O)Cc1c2n(c3ccccc13)C[C@H](NC)CC2
Reactant: O=C(Cl)c1ccc(F)cc1
Product: CN(C(=O)c1ccc(F)cc1)[C@@H]1CCc2c(CC(=O)O)c3ccccc3n2C1

Procedure:
The title compound was prepared using analogous procedures described in Example 2 (Method B) from 4-fluorobenzoyl chloride and propyl [(7R)-7-(methylamino)-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl]acetate. MS (+ESI) m/z: 381.
Reaction SMILES: C([N:3](CC)CC)C.[C:8](Cl)(=[O:11])[CH:9]=[CH2:10].[C:13](Cl)(=[O:17])[C:14](C)=[CH2:15]>>[CH2:10]=[CH:9][C:8]([NH:3][C:13]([CH:14]=[CH2:15])=[O:17])=[O:11]
Reactant: CCN(CC)CC
Reactant: C=C(C)C(=O)Cl
Reactant: C=CC(=O)Cl
Product: C=CC(=O)NC(=O)C=C
Temperature: 25 °C
Yield: 75 %

Procedure:
PEG-diacrylate (PEGDA), PEG-dimethacrylate (PEGDM), PEG-diacrylamide (PEGDAA) and PEG-dimethacrylamide (PEGDMA) were synthesized from PEG (Mw 3400 KDa, Aldrich) or PEG-diamine (Mw 3400, Shearwater Polymers) as described with minor modifications. Briefly: PEG (or PEG-diamine) molecular weight 3400 (10 g, 5.88 mmol of functional group) was azeotropically distilled with 400 ml of toluene under argon, removing ca. 100 ml of toluene. The anhydrous solution was cooled at room temperature under argon and then cooled in an ice bath. Anhydrous dichloromethane (Aldrich) (ca. 50 ml) was added until the solution become clear. Triethylamine (1.23 ml, 8.82 mmol, Aldrich) was added dropwise with stirring, followed by the dropwise addition of 0.72 ml of acryloyl chloride (8.82 nm mot, Aldrich) or 0.85 ml of methacryloyl chloride (8.82 mmol, Aldrich). The reaction was stirred in the dark, overnight under argon. The solutions were then filtered under vacuum until clears and the product was precipitated in diethyl ether collected by filtration and dried under vacuum. Next, 10 g of the product were dissolved in 10 ml of distilled water, adding 5 g of NaCl (the pH was adjusted to 6). The derivatives were then extracted 3 times with dichloromethane and precipitated in diethyl ether, and collected by filtration and dried under vacuum. PEG diacrylate: yield 75%. 1H-NMR (DCCl3): 3.6 ppm (303.5H, PEG), 4.3 ppm (t, 4H, —CH2—CH2—O—CO—CH═CH2), 5.8 ppm (dd, 2H, CH2═CH—COO), 6.1 ppm, 6.4 ppm (dd, 4H, CH2═CH—COO—). Degree of substitution 95%. PEG dimethacrylate: yield 60%. 1H-NMR (DCCl3): 2.3 ppm (s, 6H, CH2═C(CH3)—COO—), 3.6 ppm (303.5H, PEG), 4.3 ppm (t, 4H, —CH2—CH2—O—CO—C(CH3)═CH2), 5.8 ppm, 6.1 ppm (d, 4H, CH2═C(CH3)—COO—). Degree of substitution 91%. PEG diacrylamide: yield 75%. 1H-NMR (DCCl3): 3.6 ppm (304.4H, PEG), 5.6 ppm (dd, 2H, CH2═CH—CON—), 6.1 ppm and 6.3 ppm (dd, 4H, CH2═CH—COC—). Degree of substitution 100%. PEG dimethacrylamide: yield 71%. 1H-NMR (DCCl3): 2 ppm (s, 6H, CH2═C(CH3)—CON—), 3.6 ppm (304.4H, PEG), 5.3 ppm, 5.8 ppm (d, 4H, CH2—C(CH3)—CON—). Degree of substitution 100%.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:38])[N:7]([NH:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:8]([C@H:12]([NH:16][CH2:17][CH2:18][CH2:19][N:20]3C(=O)C4C(=CC=CC=4)C3=O)[CH2:13][C:14]#[CH:15])=[N:9]2)=[CH:4][CH:3]=1.S(Cl)(Cl)(=O)=O.[CH3:44][C:45]1[CH:50]=[CH:49][C:48]([S:51](Cl)(=[O:53])=[O:52])=[CH:47][CH:46]=1>N1C=CC=CC=1.CC(N(C)C)=O.C(C#N)(C)=O>[NH2:20][CH2:19][CH2:18][CH2:17][N:16]([C@@H:12]([C:8]1[N:7]([NH:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:6](=[O:38])[C:5]2[C:10](=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:9]=1)[CH2:13][C:14]#[CH:15])[S:51]([C:48]1[CH:49]=[CH:50][C:45]([CH3:44])=[CH:46][CH:47]=1)(=[O:53])=[O:52]
Reactant: C#CC[C@@H](NCCCN1C(=O)c2ccccc2C1=O)c1nc2cc(Cl)ccc2c(=O)n1Nc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CC(=O)C#N
Solvent: O=S(=O)(Cl)Cl
Solvent: c1ccncc1
Solvent: CC(=O)N(C)C
Product: C#CC[C@H](c1nc2cc(Cl)ccc2c(=O)n1Nc1ccccc1)N(CCCN)S(=O)(=O)c1ccc(C)cc1
Temperature: 45 °C
Reaction time: 24 h

Procedure:
A solution of 2-{3-[(R)-1-(7-chloro-4-oxo-3-phenylamino-3,4-dihydro-quinazolin-2-yl)-but-3-ynylamino]-propyl}-isoindole-1,3-dione (52.6 mg, 0.10 μmol) in pyridine (0.5 mL) was treated with respective sulfonyl chloride (in this case 4-methyl benzenesulfonyl chloride, 0.25M solution in DMA/AcCN (1:1), 0.5 mL, 0.125 μmol). The mixture was stirred at 45° C. for 24 h. Solvent was removed under reduced pressure. Residue was taken in MeOH (1.0 mL) and treated with hydrazine (0.25 mL). Reaction mixture was stirred at room temperature for 16 h and solvent removed under reduced pressure. The product was purified with reverse phase chromatography to give final product. Yield (10.4 mg, 20%). LCMS: m/e 551 [M+H].
Reaction SMILES: Br[CH:2]([CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:3]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4].[C:21]([O:25][C:26](=[O:36])[C@H:27]([CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[NH2:28])([CH3:24])([CH3:23])[CH3:22].C(=O)([O-])[O-].[K+].[K+].CN(C)P(=O)(N(C)C)N(C)C>C(OCC)(=O)C>[C:21]([O:25][C:26](=[O:36])[C@H:27]([CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[NH:28][C@H:2]([C:3]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4])[CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([CH3:24])([CH3:22])[CH3:23].[C:21]([O:25][C:26](=[O:36])[C@H:27]([CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[NH:28][C@@H:2]([C:3]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4])[CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([CH3:24])([CH3:22])[CH3:23]
Reactant: O=C(OCc1ccccc1)C(Br)CCc1ccccc1
Reactant: CC(C)(C)OC(=O)[C@@H](N)Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)[C@H](Cc1ccccc1)N[C@@H](CCc1ccccc1)C(=O)OCc1ccccc1
Product: CC(C)(C)OC(=O)[C@H](Cc1ccccc1)N[C@H](CCc1ccccc1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 33 g of benzyl 2-bromo-4-phenylbutyrate, 22.1 g of (L)-phenylalanine tert-butyl ester, 13.8 g of potassium carbonate and 30 ml of hexamethylphosphoric triamide was stirred at room temperature overnight. Then, ethyl acetate was added to the mixture, and the insolubles were removed by filtration. The filtrate was washed and dried, and then the solvent was removed. The residue was purified by silica gel to obtain 16.6 g of N-((1S)-1-benzyloxycarbonyl-3-phenylpropyl)-(L)-phenylalanine tert-butyl ester and 9.9 g of N-((1R)-1-benzyloxycarbonyl-3-phenylpropyl)-(L)-phenylalanine tert-butyl ester as oily products, respectively.
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[CH2:4][N:3]1[P:5](Br)([N:7]1[CH2:9][C:8]1([CH3:11])[CH3:10])=[S:6].[CH3:14][N:15]([CH3:20])[CH2:16][CH2:17][CH2:18][NH2:19]>C1COCC1>[CH3:1][C:2]1([CH3:13])[CH2:4][N:3]1[P:5]([N:7]1[CH2:9][C:8]1([CH3:11])[CH3:10])(=[S:6])[NH:19][CH2:18][CH2:17][CH2:16][N:15]([CH3:20])[CH3:14]
Reactant: CC1(C)CN1P(=S)(Br)N1CC1(C)C
Reactant: CN(C)CCCN
Solvent: C1CCOC1
Product: CN(C)CCCNP(=S)(N1CC1(C)C)N1CC1(C)C
Temperature: 25 °C
Yield: 35 %

Procedure:
In a similar manner 0.025 moles of P,P-bis(2,2-dimethyl-1-aziridinyl)thiophosphinic bromide and about 170 ml of THF are treated by dropwise addition with 0.02 moles of 3-dimethylaminopropyl amine in 25 millimeters of THF stirred for several hours at ambient temperature, filtered, concentrated by rotary evaporation, and vacuum distilled to produce about 35% yield of P,P-bis(2,2-dimethyl-1-aziridinyl)-N-(3-dimethylaminopropyl)thiophosphinic amide.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][C:12]([OH:14])=[O:13].S(=O)(=O)(O)O.[C:20]([O-])(O)=O.[Na+]>CO>[CH3:20][O:13][C:12](=[O:14])[CH2:11][C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=2)[NH:7][CH:6]=1
Reactant: O=C([O-])O
Reactant: O=C(O)Cc1c[nH]c2ccc(F)cc12
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COC(=O)Cc1c[nH]c2ccc(F)cc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of (5-fluoro-1H-indol-3-yl)-acetic acid (1 g, 5.2 mmol) in MeOH (20 mL) is treated with sulfuric acid (20 μL) and stirred at rt for 1 h. This mixture is treated with 10% aqueous NaHCO3 (200 μL) and then concentrated in vacuo to afford (5-fluoro-1H-indol-3-yl)-acetic acid methyl ester, which is used in the next step without further purification. MS: 208 (M+H); 1H NMR (300 MHz, CD3OD): δ 3.68 (s, 3H), 3.72 (s, 2H), 6.86 (m, 1H), 7.16 (m, 1H), 7.21 (s, 1H), 7.28 (m, 1H).