Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[N:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[N:14]1[CH2:18][CH2:17][C@@H:16]([NH:19][C:20](=[O:63])[NH:21][CH2:22][CH2:23][NH:24][C:25]([C:27]2[N:35]=[C:34]3[C:30]([N:31]=[CH:32][N:33]3[C@@H:36]3[CH2:40][C@H:39]([NH:41][C:42](=[O:45])[CH2:43][CH3:44])[C@@H:38]([OH:46])[C@H:37]3[OH:47])=[C:29]([NH:48][CH2:49][CH:50]([C:57]3[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=3)[C:51]3[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=3)[N:28]=2)=[O:26])[CH2:15]1.NCCNC(N[C@H]1CCN(C2C=CC=CN=2)C1)=O>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[N:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[N:14]1[CH2:18][CH2:17][C@H:16]([NH:19][C:20](=[O:63])[NH:21][CH2:22][CH2:23][NH:24][C:25]([C:27]2[N:35]=[C:34]3[C:30]([N:31]=[CH:32][N:33]3[C@@H:36]3[CH2:40][C@H:39]([NH:41][C:42](=[O:45])[CH2:43][CH3:44])[C@@H:38]([OH:46])[C@H:37]3[OH:47])=[C:29]([NH:48][CH2:49][CH:50]([C:57]3[CH:58]=[CH:59][CH:60]=[CH:61][CH:62]=3)[C:51]3[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=3)[N:28]=2)=[O:26])[CH2:15]1
Reactant: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(C(=O)NCCNC(=O)N[C@@H]4CCN(c5ccccn5)C4)nc32)[C@H](O)[C@@H]1O
Agent: NCCNC(=O)N[C@H]1CCN(c2ccccn2)C1
Solvent: O=C(O)C(F)(F)F
Product: CCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(C(=O)NCCNC(=O)N[C@H]4CCN(c5ccccn5)C4)nc32)[C@H](O)[C@@H]1O

Procedure:
This compound is prepared analogously to 9-((1R,2S,3R,4S)-2,3-dihydroxy-4-propionylamino-cyclopentyl)-6-(2,2-diphenyl-ethylamino)-9H-purine-2-carboxylic acid {2-[3-((R)-1-pyridin-2-yl-pyrrolidin-3-yl)-ureido]-ethyl}-amide trifluoroacetate by replacing 1-(2-amino-ethyl)-3-((R)-1-pyridin-2-yl-pyrrolidin-3-yl)-urea with 1-(2-amino-ethyl)-3-((S)-1-pyridin-2-yl-pyrrolidin-3-yl)-urea.
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]1([C:11]([N:13]2[C:22]3[C:17](=[C:18]([O:41][C:42]4[CH:47]=[C:46]([CH3:48])[N:45]=[C:44]([CH3:49])[CH:43]=4)[C:19]([C:23]4[CH:24]=[N:25][N:26]([CH:28]5[CH2:33][CH2:32][N:31](C(OC(C)(C)C)=O)[CH2:30][CH2:29]5)[CH:27]=4)=[CH:20][CH:21]=3)[CH2:16][CH2:15][C@@H:14]2[CH3:50])=[O:12])[CH2:10][CH2:9]1>ClCCl>[CH:8]1([C:11]([N:13]2[C:22]3[C:17](=[C:18]([O:41][C:42]4[CH:43]=[C:44]([CH3:49])[N:45]=[C:46]([CH3:48])[CH:47]=4)[C:19]([C:23]4[CH:24]=[N:25][N:26]([CH:28]5[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]5)[CH:27]=4)=[CH:20][CH:21]=3)[CH2:16][CH2:15][C@@H:14]2[CH3:50])=[O:12])[CH2:9][CH2:10]1
Reactant: Cc1cc(Oc2c(-c3cnn(C4CCN(C(=O)OC(C)(C)C)CC4)c3)ccc3c2CC[C@H](C)N3C(=O)C2CC2)cc(C)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(Oc2c(-c3cnn(C4CCNCC4)c3)ccc3c2CC[C@H](C)N3C(=O)C2CC2)cc(C)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Trifluoroacetic acid (1 mL) was added to a solution of (S)-tert-butyl 4-(4-(1-(cyclopropanecarbonyl)-5-(2,6-dimethylpyridin-4-yloxy)-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (0.030 g, 0.05 mmol) in dichloromethane (3 mL), and the resulting solution stirred for 1 h at room temperature. The reaction mixture was concentrated under vacuum, and the residue was purified via column chromatography on silica gel (eluting with 1:2, ethyl acetate/petroleum ether). The crude product was further purified by preparative-HPLC with the following conditions (Waters I): Column, SunFire Prep C18, 5 um, 19×100 mm; mobile phase, water (0.05% ammonium bicarbonate) and acetonitrile (65% to 85% acetonitrile in 7 min, flow rate: 20 mL/min); Detector, UV 220254 nm. This afforded (S)-cyclopropyl(5-(2,6-dimethylpyridin-4-yloxy)-2-methyl-6-(1-(piperidin-4-yl)-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)methanone (0.003 g, 12%) as a white powder. 1H NMR (400 MHz, CD3OD) δ ppm 0.73-0.84 (m, 1H), 0.92-1.03 (m, 2H), 1.12-1.21 (m, 4H), 1.42-1.51 (m, 1H), 1.99-2.20 (m, 5H), 2.20-2.29 (m, 2H), 2.29-2.41 (m, 6H), 2.63-2.72 (m, 1H), 2.95-3.04 (m, 2H), 3.31-3.41 (m, 2H), 4.35-4.45 (m, 1H), 4.79-4.90 (m, 1H), 6.53 (s, 2H), 7.45 (d, J=8.40 Hz, 1H), 7.63 (d, J=8.80 Hz, 1H), 7.79 (s, 1H), 7.96 (s, 1H). MS (ESI, pos. ion) m/z 486 [M+H]+.
Reaction SMILES: [N:1]1([C:7]2[S:8][C:9](=[CH:13][C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH2:25][CH2:24][C:23](=O)[CH2:22][CH2:21]4)=[CH:16][CH:15]=3)[C:10](=[O:12])[N:11]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[NH2:27][CH2:28][C@H:29]([OH:39])[CH2:30][O:31][C:32]1[CH:37]=[CH:36][C:35]([OH:38])=[CH:34][CH:33]=1>>[OH:39][C@H:29]([CH2:30][O:31][C:32]1[CH:37]=[CH:36][C:35]([OH:38])=[CH:34][CH:33]=1)[CH2:28][NH:27][CH:23]1[CH2:24][CH2:25][N:20]([C:17]2[CH:18]=[CH:19][C:14]([CH:13]=[C:9]3[S:8][C:7]([N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)=[N:11][C:10]3=[O:12])=[CH:15][CH:16]=2)[CH2:21][CH2:22]1
Reactant: O=C1CCN(c2ccc(C=C3SC(N4CCOCC4)=NC3=O)cc2)CC1
Reactant: NC[C@H](O)COc1ccc(O)cc1
Product: O=C1N=C(N2CCOCC2)SC1=Cc1ccc(N2CCC(NC[C@H](O)COc3ccc(O)cc3)CC2)cc1

Procedure:
The title compound was prepared from 1-[4-(2-morpholin-4-yl-4-oxo-4H-thiazol-5-ylidenemethyl)-phenyl]-piperidin-4-one(which was obtained in Intermediate 28) and (2S)-1-amino-3-(4-hydroxy-phenoxy)-propan-2-ol (which was obtained in Intermediate 5) according to the procedure of Example 1 as a yellowish solid; mp>100° C. (dec.); 1H NMR (300 MHz, DMSO-d6) δ 1.20-1.40 (m, 2 H), 1.80-1.95 (m, 2 H), 2.50-3.00 (m, 7 H), 3.60-4.00 (m, 11H), 6.66(d, J=9.2 Hz, 2 H), 6.74 (d, J=8.9 Hz, 2 H), 7.02(d, J=9.2 Hz, 2 H), 7.45(d, J=8.9 Hz, 2 H), 7.54 (s, 1 H); MS (ES) m/z: 270.0 ((M+2H)2+, 100%); 539.1(MH+, 40%); HRMS Calcd. for C28H35N4O5S (MH+): 539.2328. Found: 539.2322.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:15]=[C:16]([F:23])[C:17]=1[NH:18][S:19]([CH3:22])(=[O:21])=[O:20])[CH2:5][NH:6][C:7]([C:9]1[S:10][C:11](Br)=[CH:12][CH:13]=1)=[O:8].[C:24]([C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1)([CH3:27])([CH3:26])[CH3:25]>>[F:1][C:2]1[CH:3]=[C:4]([CH:15]=[C:16]([F:23])[C:17]=1[NH:18][S:19]([CH3:22])(=[O:21])=[O:20])[CH2:5][NH:6][C:7]([C:9]1[S:10][C:11]([C:31]2[CH:32]=[CH:33][C:28]([C:24]([CH3:27])([CH3:26])[CH3:25])=[CH:29][CH:30]=2)=[CH:12][CH:13]=1)=[O:8]
Reactant: CC(C)(C)c1ccc(B(O)O)cc1
Reactant: CS(=O)(=O)Nc1c(F)cc(CNC(=O)c2ccc(Br)s2)cc1F
Product: CC(C)(C)c1ccc(-c2ccc(C(=O)NCc3cc(F)c(NS(C)(=O)=O)c(F)c3)s2)cc1
Yield: 70.4 %

Procedure:
5-Bromo-thiophene-2-carboxylic acid 3,5-difluoro-4-methanesulfonylamino-benzylamide (80 mg, 0.19 mmol) was reacted with 4-tert-butyl phenyl boronic acid (40.2 mg, 0.23 mmol) to give the title compound (64 mg, 71%) after purification by column chromatography (gradient 12% to 100% EtOAc in n-hexane).
Reaction SMILES: [F:1][C:2]1[CH:35]=[C:34]([CH:36]=[O:37])[CH:33]=[CH:32][C:3]=1[O:4][C:5]1[CH:6]=[C:7]([C:17]2[NH:21][C:20]([C:22]([O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:23])=[CH:19][CH:18]=2)[CH:8]=[C:9]([O:11][C@@H:12]([CH3:16])[CH2:13][O:14][CH3:15])[CH:10]=1.O.O.P([O-])(O)(O)=[O:41].[Na+].CC(=CC)C.Cl([O-])=O.[Na+]>[Cl-].[Na+].O.O.C(O)(C)(C)C>[CH2:25]([O:24][C:22]([C:20]1[NH:21][C:17]([C:7]2[CH:6]=[C:5]([CH:10]=[C:9]([O:11][C@@H:12]([CH3:16])[CH2:13][O:14][CH3:15])[CH:8]=2)[O:4][C:3]2[CH:32]=[CH:33][C:34]([C:36]([OH:41])=[O:37])=[CH:35][C:2]=2[F:1])=[CH:18][CH:19]=1)=[O:23])[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: COC[C@H](C)Oc1cc(Oc2ccc(C=O)cc2F)cc(-c2ccc(C(=O)OCc3ccccc3)[nH]2)c1
Reactant: O=P([O-])(O)O
Agent: CC=C(C)C
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)(C)O
Product: COC[C@H](C)Oc1cc(Oc2ccc(C(=O)O)cc2F)cc(-c2ccc(C(=O)OCc3ccccc3)[nH]2)c1
Reaction time: 2 h
Yield: 109.5 %

Procedure:
Benzyl 5-{3-(2-Fluoro-4-formylphenoxy)-5-[(1S)-2-methoxy-1-methylethoxy]phenyl}-1H-pyrrole-2-carboxylate (6.33 g, 12.6 mmol) synthesized in Example (66d) was suspended in a mixed solvent of t-butanol (120 mL) and water (40 mL), and sodium dihydrogen phosphate dihydrate (8.86 g, 56.8 mmol) and 2-methyl-2-butene (12.05 mL, 113 mmol) were added. Under ice cooling, sodium chlorite (80%, 2.93 g, 25.9 mmol) was added slowly, and stirring was carried out at room temperature for 2 hours. Saturated brine (200 mL) was added, followed by extraction with dichloromethane (200 mL), and drying was carried out over anhydrous magnesium sulfate to afford the desired compound (7.17 g, yield ˜100%) as a pale yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N:9]([CH:16]([CH3:18])[CH3:17])[C:10](=[O:15])[CH:11]=[C:12]([CH3:14])[CH3:13])[CH:5]=[CH:6][C:7]=1[CH3:8].[Al+3].[Cl-].[Cl-].[Cl-]>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]2[C:5]([C:12]([CH3:14])([CH3:13])[CH2:11][C:10](=[O:15])[N:9]2[CH:16]([CH3:18])[CH3:17])=[CH:6][C:7]=1[CH3:8]
Reactant: CC(C)=CC(=O)N(c1ccc(C)c(Br)c1)C(C)C
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: Cc1cc2c(cc1Br)N(C(C)C)C(=O)CC2(C)C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
3-Methyl-but-2-enoic acid (3-bromo-4-methyl-phenyl)-isopropyl-amide (Compound 42, 50 g, 161.2 mmol) was dissolved in dichloromethane (800 mL) and the solution was cooled to 0° C. and treated with AlCl3 (75.23 g, 564.2 mmol). The suspension was stirred at 0° C. for 1 hour and at room temperature for 1 hour and the reaction was quenched with ice. After 10% aqueous HCl was added, the layers were separated and the aqueous layer extracted twice with dichloromethane. The combined organic layers were washed with water and brine, dried with MgSO4, filtered, and concentrated under reduced pressure. The residue was filtered by silica gel chromatography (10% ethyl acetate in hexane, Rf=0.38) to give the title compound as an oil:
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=2)[C:6](=[C:16](OCC)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:5]1=[O:26])(=O)C.[CH3:27][N:28]1[CH2:33][CH2:32][N:31]([CH2:34][C:35]([N:37]([C:39]2[CH:45]=[CH:44][C:42]([NH2:43])=[CH:41][CH:40]=2)[CH3:38])=[O:36])[CH2:30][CH2:29]1.[OH-].[Na+]>CN(C=O)C.CO>[CH3:27][N:28]1[CH2:33][CH2:32][N:31]([CH2:34][C:35]([N:37]([C:39]2[CH:40]=[CH:41][C:42]([NH:43]/[C:16](=[C:6]3\[C:5](=[O:26])[NH:4][C:12]4[C:7]\3=[CH:8][C:9]([N+:13]([O-:15])=[O:14])=[CH:10][CH:11]=4)/[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:44][CH:45]=2)[CH3:38])=[O:36])[CH2:30][CH2:29]1
Reactant: CN1CCN(CC(=O)N(C)c2ccc(N)cc2)CC1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2ccc([N+](=O)[O-])cc21)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CO
Product: CN1CCN(CC(=O)N(C)c2ccc(N/C(=C3\C(=O)Nc4ccc([N+](=O)[O-])cc43)c3ccccc3)cc2)CC1

Procedure:
Prepared analogously to Example 82 from 1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-5-nitro-2-indolinone and 4-[N—(N-methylpiperazinomethylcarbonyl)-N-methyl-amino]-aniline in DMF and subsequent treatment with sodium hydroxide solution in methanol.
Reaction SMILES: [NH2:1][C:2]1[O:3][CH2:4][C@@:5]2([N:28]=1)[C:18]1[CH:17]=[C:16]([OH:19])[CH:15]=[C:14]([F:20])[C:13]=1[O:12][C:11]1[C:6]2=[CH:7][C:8]([C:21]2[C:22]([F:27])=[N:23][CH:24]=[CH:25][CH:26]=2)=[CH:9][CH:10]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C=O)C.FC(F)(F)S(O[CH2:46][C:47]([C:50]#[N:51])([CH3:49])[CH3:48])(=O)=O>O.CCOC(C)=O>[NH2:1][C:2]1[O:3][CH2:4][C@:5]2([N:28]=1)[C:6]1[CH:7]=[C:8]([C:21]3[C:22]([F:27])=[N:23][CH:24]=[CH:25][CH:26]=3)[CH:9]=[CH:10][C:11]=1[O:12][C:13]1[C:18]2=[CH:17][C:16]([O:19][CH2:46][C:47]([CH3:49])([CH3:48])[C:50]#[N:51])=[CH:15][C:14]=1[F:20]
Reactant: CC(C)(C#N)COS(=O)(=O)C(F)(F)F
Reactant: NC1=N[C@@]2(CO1)c1cc(-c3cccnc3F)ccc1Oc1c(F)cc(O)cc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C#N)COc1cc(F)c2c(c1)[C@]1(COC(N)=N1)c1cc(-c3cccnc3F)ccc1O2
Reaction time: 0.25 h

Procedure:
A vial was charged with (S)-2-amino-4′-fluoro-7′-(2-fluoropyridin-3-yl)-5H-spiro[oxazole-4,9′-xanthen]-2′-ol (45.0 mg, 0.118 mmol), cesium carbonate (57.7 mg, 0.177 mmol), and DMF (787 μL). The mixture was stirred vigorously for 15 min, then 2-cyano-2-methylpropyl trifluoromethanesulfonate (22.56 μL, 0.130 mmol) was added via syringe. The resulting mixture was stirred at room temperature for 19 hours before being diluted with water (10 mL) and EtOAc (10 mL). The layers were separated, and the aqueous layer was extracted with EtOAc (2×10 mL). The combined organic extracts were dried over sodium sulfate, filtered, and evaporated. The residue was purified by chromatography on a 12 g Redi-Sep column, eluting with 5-60% MeOH/DCM to give (S)-3-(2-amino-5′-fluoro-2′-(2-fluoropyridin-3-yl)-5H-spiro[oxazole-4,9′-xanthene]-7′-yloxy)-2,2-dimethylpropanenitrile as an off-white solid. (MS: MH+=463).
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([N+:9]([O-])=O)[C:3]=1[NH2:4].[H][H]>C(O)C.[Pd]>[CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([NH2:9])[C:3]=1[NH2:4]
Reactant: Cc1cccc([N+](=O)[O-])c1N
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Cc1cccc(N)c1N
Yield: 97.4 %

Procedure:
2-Methyl-6-nitroaniline (15.2 g, 0.1 mol) was dissolved by heating in ethanol (150 mL). The solution was cooled, 10% palladium on carbon (1.0 g) was added and the solution was hydrogenated (50 lb initial hydrogen pressure) until uptake of hydrogen ceased (1 hour). The catalyst was filtered off and the ethanol was removed under reduced pressure to give 11.9 g (98%) of 3-methyl-1,2-benzenediamine as a solid which was used without purification.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][NH:4][N:3]=1.[C:7]([CH:10]1[CH2:15][CH2:14][O:13][C:11]1=[O:12])(=O)[CH3:8]>C(O)C>[O:12]=[C:11]1[CH:10]([C:7](=[N:1][C:2]2[CH:6]=[CH:5][NH:4][N:3]=2)[CH3:8])[CH2:15][CH2:14][O:13]1
Reactant: Nc1cc[nH]n1
Reactant: CC(=O)C1CCOC1=O
Solvent: CCO
Product: CC(=Nc1cc[nH]n1)C1CCOC1=O
Temperature: 25 °C
Yield: 69.4 %

Procedure:
In 12 ml of anhydrous ethanol were added 0.83 g (10.00 mmol) of 3-aminopyrazole and 1.92 g (15.00 mmol) of 2-acetyl-γ-butyrolactone. While stirring at room temperature, 0.1 ml of a boron trifluoride methanol complex were added to the resultant solution, and the mixture was then stirred for 4 hours under the same conditions. Solids deposited were collected by filtration, washed with ethanol and air-dried to obtain 1.34 g (yield: 69.4%) of the intended product.
Reaction SMILES: [Li+].[OH-].C[O:4][C:5]([C:7]1[S:15][C:14]2[C:13](=[O:16])[N:12]([C:17]3[CH:22]=[CH:21][C:20]([N:23]4[CH2:29][CH2:28][CH2:27][N:26]([CH3:30])[CH2:25][CH2:24]4)=[CH:19][CH:18]=3)[CH:11]=[N:10][C:9]=2[CH:8]=1)=[O:6]>C1COCC1.O>[CH3:30][N:26]1[CH2:27][CH2:28][CH2:29][N:23]([C:20]2[CH:21]=[CH:22][C:17]([N:12]3[C:13](=[O:16])[C:14]4[S:15][C:7]([C:5]([OH:6])=[O:4])=[CH:8][C:9]=4[N:10]=[CH:11]3)=[CH:18][CH:19]=2)[CH2:24][CH2:25]1
Reactant: COC(=O)c1cc2ncn(-c3ccc(N4CCCN(C)CC4)cc3)c(=O)c2s1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CN1CCCN(c2ccc(-n3cnc4cc(C(=O)O)sc4c3=O)cc2)CC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A 2M LiOH solution (1.2 mL) was added to a solution of 3-[4-(4-methylperhydro-1,4-diazepin-1-yl)phenyl]-4-oxo-3,4-dihydrothieno[3,2-d]pyrimidine-6-carboxylic acid methyl ester (477.8 mg) in THF (5 mL) and water (5 mL), and the mixture was stirred at room temperature for 5 h. The solvent was then removed in vacuo and the crude product was purified by preparative HPLC. The product with the molecular weight of 384.45 (C19H20N4O3S) was obtained in this way; MS (ESI): 385 (M+H+).
Reaction SMILES: S(Cl)([Cl:3])=O.O[CH:6]([N:19]1[C@H:22]([CH2:23][CH2:24][C:25](=[O:31])[C@@H:26]2[CH2:30][CH2:29][CH2:28][O:27]2)[C@H:21]([N:32]2[C:36](=[O:37])[C:35]3=[CH:38][CH:39]=[CH:40][CH:41]=[C:34]3[C:33]2=[O:42])[C:20]1=[O:43])[C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)=[O:8].N1C(C)=CC=CC=1C>C1COCC1>[Cl:3][CH:6]([N:19]1[C@H:22]([CH2:23][CH2:24][C:25](=[O:31])[C@@H:26]2[CH2:30][CH2:29][CH2:28][O:27]2)[C@H:21]([N:32]2[C:36](=[O:37])[C:35]3=[CH:38][CH:39]=[CH:40][CH:41]=[C:34]3[C:33]2=[O:42])[C:20]1=[O:43])[C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)=[O:8]
Reactant: COc1ccc(COC(=O)C(O)N2C(=O)[C@@H](N3C(=O)c4ccccc4C3=O)[C@H]2CCC(=O)[C@@H]2CCCO2)cc1
Reactant: O=S(Cl)Cl
Solvent: C1CCOC1
Solvent: Cc1cccc(C)n1
Product: COc1ccc(COC(=O)C(Cl)N2C(=O)[C@@H](N3C(=O)c4ccccc4C3=O)[C@H]2CCC(=O)[C@@H]2CCCO2)cc1
Reaction time: 1 h

Procedure:
A solution of thionyl chloride (530 μl, 7.27mmol) in THF (3 ml) was added to 4-methoxybenzyl (RS)-2-hydroxy-2-[(3S, 4R)-4-[3-oxo-3-[(S)-tetrahydrofuran-2-yl]propyl]-3-phthalimidoazetidin-2-on-1-yl]acetate (2.59 g, 4.84 mmol) and 2,6-lutidine (850 μl, 7.30 mmol) in THF (50 ml) at -20° C. After stirring for 1 h, the reaction mixture was filtered through a pad of celite, and the filtrate evaporated in vacuo. Toluene was added and re-evaporated to yield 4-methoxybenzyl (RS)-2-chloro-2-[(3S,4R)-4-[3-oxo-3-[(S)-tetrahydrofuran-2-yl]propyl]-3-phthalimidoazetidin-2-on-1-yl]acetate.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][C:15]=2[C:17](O)=[O:18])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl-].[CH3:45][O:46][C:47]([C:49]1[CH:54]=[CH:53][C:52]([C@@H:55]([NH3+:57])[CH3:56])=[CH:51][CH:50]=1)=[O:48].CCN(C(C)C)C(C)C>C(#N)C>[CH3:45][O:46][C:47]([C:49]1[CH:54]=[CH:53][C:52]([C@@H:55]([NH:57][C:17]([C:15]2[CH:14]=[CH:13][CH:12]=[C:11]3[C:16]=2[N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][CH2:10]3)=[O:18])[CH3:56])=[CH:51][CH:50]=1)=[O:48]
Reactant: COC(=O)c1ccc([C@H](C)[NH3+])cc1
Reactant: CC(C)(C)OC(=O)N1CCc2cccc(C(=O)O)c21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COC(=O)c1ccc([C@H](C)NC(=O)c2cccc3c2N(C(=O)OC(C)(C)C)CC3)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1-(tert-butoxycarbonyl)indoline-7-carboxylic acid (0.5 g, 1.9 mmol), HATU (795 mg, 2.09 mmol) and (1S)-1-[4-(methoxycarbonyl)phenyl]ethanaminium chloride (511 mg, 2.85 mmol) were added to acetonitrile (12.7 ml). The solution was cooled in an ice bath and DIPEA (993 ul, 5.7 mmol) was added. The ice bath was removed and the mixture stirred for 2 hours at RT. The solvent was removed and the crude mixture purified by flash chromatography on silica gel. 1H NMR (500 MHz, DMSO-d6): δ 8.40 (d, 1H), 7.90 (d, 2H), 7.55 (d, 2H), 7.30 (d, 1H), 7.25 (d, 1H), 7.00 (t, 1H), 5.10 (m, 1H), 4.00 (m, 2H), 3.85 (s, 3H), 3.05 (m, 2H), 1.45 (d, 3H), 1.40 (s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:17]=[C:18]([CH2:22][CH2:23][CH3:24])[C:19]=1[O:20][CH3:21])[C:6]([N:8]1[CH2:11][C@@H:10]([CH2:12][CH3:13])[C@@H:9]1[C:14]([OH:16])=O)=[O:7].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.Cl.[CH2:69]([O:76][NH2:77])[C:70]1[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=1>CN(C=O)C.CCOC(C)=O>[CH2:69]([O:76][NH:77][C:14]([C@H:9]1[C@H:10]([CH2:12][CH3:13])[CH2:11][N:8]1[C:6](=[O:7])[C:5]1[CH:17]=[C:18]([CH2:22][CH2:23][CH3:24])[C:19]([O:20][CH3:21])=[C:3]([O:2][CH3:1])[CH:4]=1)=[O:16])[C:70]1[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=1
Reactant: NOCc1ccccc1
Reactant: CCCc1cc(C(=O)N2C[C@@H](CC)[C@@H]2C(=O)O)cc(OC)c1OC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCc1cc(C(=O)N2C[C@@H](CC)[C@@H]2C(=O)NOCc2ccccc2)cc(OC)c1OC
Temperature: 0 °C
Reaction time: 1 h
Yield: 68 %

Procedure:
To a solution of (+)-trans-1-(3,4-dimethoxy-5-propylbenzoyl)-3-ethylazetidine-2-carboxylic acid (110 mg, 0.33 mmol, 1 eq.) in dry DMF (2.5 mL) were added HATU (150 mg, 0.39 mmol, 1.2 eq.), DIEA (0.23 mL, 1.31 mmol, 4.0 eq.), HOBt (50 mg, 0.39 mmol, 1 eq.) and the mixture was cooled to 0° C. then the O-benzylhydroxylamine hydrochloride (63 mg, 0.39 mmol, 1.2 eq.) was added. The resulting mixture was stirred at 0° C. for 1 h, and then at room temperature overnight. The reaction was diluted with EtOAc, washed with 1M aqueous HCl solution, saturated NaHCO3 solution, and brine. The organic layer was dried over MgSO4, filtered and concentrated in vacuo to give (+)-trans-1-(3,4-dimethoxy-5-propylbenzoyl)-3-ethylazetidine-2-carboxylic acid benzyloxyamide in 68% yield, which was used without further purification. ESMS: m/z 441.3 [M+H].
Reaction SMILES: Br[C:2]1[N:6]([CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][F:15])[C:5]2[CH:16]=[CH:17][CH:18]=[CH:19][C:4]=2[N:3]=1.[CH3:20][N:21]([C:29]1[CH:34]=[CH:33][C:32]([C:35]#[CH:36])=[CH:31][CH:30]=1)[C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25]>>[F:15][CH2:14][CH2:13][O:12][CH2:11][CH2:10][O:9][CH2:8][CH2:7][N:6]1[C:5]2[CH:16]=[CH:17][CH:18]=[CH:19][C:4]=2[N:3]=[C:2]1[C:36]#[C:35][C:32]1[CH:31]=[CH:30][C:29]([N:21]([CH3:20])[C:22](=[O:28])[O:23][C:24]([CH3:25])([CH3:27])[CH3:26])=[CH:34][CH:33]=1
Reactant: FCCOCCOCCn1c(Br)nc2ccccc21
Reactant: C#Cc1ccc(N(C)C(=O)OC(C)(C)C)cc1
Product: CN(C(=O)OC(C)(C)C)c1ccc(C#Cc2nc3ccccc3n2CCOCCOCCF)cc1
Yield: 19.21 %

Procedure:
T541 was prepared using general procedure B from 2-bromo-1-(2-(2-(2-fluoroethoxy)ethoxy)ethyl)-1H-benzo[d]imidazole and tert-butyl methyl-4-(ethynyl)phenylcarbamate. Reaction was performed on a 72 mgs scale of 2-bromo-1-(2-(2-(2-fluoroethoxy)ethoxy)ethyl)-1H-benzo[d]imidazole. The crude product was purified by ISCO column to afford tert-butyl 4-((1-(2-(2-(2-fluoroethoxy)ethoxy)ethyl)-1H-benzo[d]imidazol-2-yl)ethynyl)phenyl(methyl)carbamate (0.02 g, 19.21%). It was then dissolved in acetonitrile (1.0 mL). To this solution was added 20% Sulfuric acid (1.0 mL, 3.75 mmol). The reaction mixture was stirred at room temperature for 30 mins. The crude product was purified by prep HPLC to afford T541 TFA salt (0.004 g, 19.44%). 1H NMR (400 MHz, CD3CN) δ 7.78-7.76 (m, 1H), 7.70-7.68 (m, 1H), 7.51-7.45 (m, 4H), 6.66-6.64 (m, 2H), 4.63-4.60 (m, 2H), 4.44-4.42 (m, 1H), 4.32-4.30 (m, 1H), 3.95-3.92 (m, 2H), 3.57-3.53 (m, 3H), 3.48-3.45 (m, 3H), 2.82 (m, 3H). MS (ESI): 382.1 (M+H+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([OH:13])[CH:10]([C:14]#[N:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:16]([O:20]C)(C)(C)[CH3:17]>C(OC=C)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][C@@H:10]([C:14]#[N:15])[C@H:11]([O:13][C:16](=[O:20])[CH3:17])[CH2:12]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(C)(C)C
Reactant: CC(C)(C)OC(=O)N1CC(O)C(C#N)C1
Solvent: C=COC(C)=O
Product: CC(=O)O[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]1C#N
Temperature: 22 °C

Procedure:
79.1 To a solution of 17.1 g (98.2% GC purity) of trans, rac-3-cyano-4-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester (prepared according to C. Y. Hong et al. (Bioorganic Medicinal Chemistry Letters, 2003, 13, 4399), by D. J. Kim et al. (Journal of Medicinal Chemistry, 1997, 40, 3584) or by S. U. Hansen & M. Bols (Acta Chemica Scandinavica, 1997, 52, 1214)) in 765 ml of t-butylmethyl ether and 85 ml of vinyl acetate was added 21.3 g of Lipase AK (Amano Enzyme Inc.) and the suspension was stirred at 22° C. until ca. 54% conversion (as calculated from the ee-values of substrate and product according to C. J. Sih et al. (J. Am. Chem. Soc., 1982, 104, 7294)) was reached. The enzyme was filtered off, the filtrate evaporated in vacuo and the residual oil chromatographed on 400 g silicagel (0.040-0.063 mm; dichloromethane/diethyl ether 9:1→3:1) to give the formed optically enriched (S,S)-3-acetoxy-4-cyano-pyrrolidine-1-carboxylic acid tert-butyl ester (10.7 g; 84% ee, optically further enriched in example 60.2) and the retained (R,R)-3-cyano-4-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester (6.9 g). Analytics: +EI-MS: 213.3 (M+H+); [α]D=+1.20° (c=1.00, CHCl3); 97.8% ee (GC on BGB-176; 30 m×0.25 mm; H2; 90 kPa; 130° C. to 200° C. with 2° C./min; inj. 200° C.).