Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2]C(C1N(CC2N3C=C(C)C=CC3=NC=2C2C=CC(C)=CC=2)N=CN=1)=O.[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2[N:36]=[C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][N:38]3[C:43]=2[CH2:44][N:45]2[C:49]([CH3:50])=[CH:48][C:47]([C:51](OC)=[O:52])=[N:46]2)=[CH:31][CH:30]=1.CN>>[Cl:28][C:29]1[CH:30]=[CH:31][C:32]([C:35]2[N:36]=[C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][N:38]3[C:43]=2[CH2:44][N:45]2[C:49]([CH3:50])=[CH:48][C:47]([C:51]([NH:2][CH3:1])=[O:52])=[N:46]2)=[CH:33][CH:34]=1
Reactant: COC(=O)c1cc(C)n(Cc2c(-c3ccc(Cl)cc3)nc3ccccn23)n1
Reactant: CNC(=O)c1ncnn1Cc1c(-c2ccc(C)cc2)nc2ccc(C)cn12
Agent: CN
Product: CNC(=O)c1cc(C)n(Cc2c(-c3ccc(Cl)cc3)nc3ccccn23)n1

Procedure:
The title compound was prepared according to the procedure described for compound 68 from methyl 1-((2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl)methyl)-5-methyl-1H-pyrazole-3-carboxylate and methylamine. M/e+ 381 for C20H19ClN5O (M+H)+; 1H-NMR (400 MHz, CDCl3) δ 8.20 (d, J=6.9 Hz, 1H), 7.68 m, 1H), 7.65 (d, J=8.4 Hz, 2H), 7.47 (d, J=8.4 Hz, 2H), 7.28 (m, 1H), 6.86 (td, J=6.9, 1.1 Hz, 1H), 6.62 (m, 1H), 6.52 (s, 1H), 5.64 (s, 2H), 2.93 (d, J=5.1 Hz, 3H), 1.99 (s, 3H) ppm.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:25]=[CH:24][C:9]([CH2:10][O:11][C:12]2[O:13][C:14]3[C:19]([C:20](=[O:23])[C:21]=2[CH3:22])=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:8][CH:7]=1.[S:26](Cl)([C:29]1[CH:35]=[CH:34][C:32]([CH3:33])=[CH:31][CH:30]=1)(=[O:28])=[O:27]>ClCCl.CN(C1C=CN=CC=1)C.O>[CH3:22][C:21]1[C:20](=[O:23])[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[O:13][C:12]=1[O:11][CH2:10][C:9]1[CH:8]=[CH:7][C:6]([CH2:5][CH2:4][CH2:3][CH2:2][O:1][S:26]([C:29]2[CH:35]=[CH:34][C:32]([CH3:33])=[CH:31][CH:30]=2)(=[O:28])=[O:27])=[CH:25][CH:24]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1c(OCc2ccc(CCCCO)cc2)oc2ccccc2c1=O
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCCCCc2ccc(COc3oc4ccccc4c(=O)c3C)cc2)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 50 %

Procedure:
To a solution 2-[4-(4-hydroxy-butyl)-benzyloxy]-3-methyl-chromen-4-one (101 mg, 0.30 mmol) dissolved in anhydrous dichloromethane (3.0 mL) was added TsCl (68 mg, 0.36 mmol), DMAP (55 mg, 0.45 mmol) and TEA (0.050 mL, 0.36 mmol). The reaction mixture continued stirring at room temperature. After 20 h, the reaction mixture was diluted with water. The aqueous layer was separated and extracted with ethyl acetate (3×). All combined organic layers were dried over Na2SO4, filtered, and concentrated to yield an oil. The crude material was purified using silica gel chromatography (4:1 pentane:ethyl acetate) to yield toluene-4-sulfonic acid 4-[4-(3-methyl-4-oxo-4H-chromen-2-yloxymethyl)-phenyl]-butyl ester (75.2 mg, 0.15 mmol) in moderate yield (51%). 1H (CDCl3, 600 MHz): δ 8.21 (1H, dd, J=8.2,1.5 Hz), 7.77 (2H, d, J=8.3 Hz). 7.60 (1H, m), 7.33 (2H, d, J=8.0 Hz), 7.36 (2H, d, J=8.0 Hz), 7.39 (2H, d, J=8.2 Hz), 7.33 (2H, d, J=8.0 Hz), 7.99 (2H, d, J=7.9 Hz), 5.43 (2H, s), 4.04 (2H, t, J=5.9 Hz), 2.59 (2H, t, J=7.3 Hz), 2.44 (3H, s), 1.99 (3H, s), 1.68 (4H, m);); 13C (CDCl3, 150 MHz): δ 178.2, 161.8, 152.2, 144.2, 141.9, 132.7, 132.2, 131.9, 129.3, 128.3, 127.7, 127.4, 125.6, 127.7, 122.1, 116.1, 70.1, 69.8, 34.3, 27.9, 26.5, 21.1, 6.7. HRMS calcd for C28H28O6S: 545.1498. found. 515.1493.
Reaction SMILES: [N:1]1[C:8]([Cl:9])=[N:7][C:5](Cl)=[N:4][C:2]=1[Cl:3].[OH:10][CH2:11][C:12]([NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=1)=[O:13].CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:9][C:8]1[N:1]=[C:2]([Cl:3])[N:4]=[C:5]([O:10][CH2:11][C:12]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:22])([F:23])[F:24])[CH:16]=2)=[O:13])[N:7]=1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: O=C(CO)Nc1cccc(C(F)(F)F)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(COc1nc(Cl)nc(Cl)n1)Nc1cccc(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 59.9 %

Procedure:
To a 200 mL recovery flask was added cyanuric chloride (504 mg, 2.73 mmol, 1.0 eq.) and CH2Cl2 (50 mL). The solution was cooled to 0° C. In a separate flask, a solution of 2-hydroxy-N-(3-trifluoromethyl-phenyl)-acetamide (599 mg, 2.73 mmol, 1.0 eq.) and i-Pr2NEt (524 μL, 2.00 mmol, 1.1 eq.) in 10 mL was prepared and then slowly added to the reaction flask. The reaction was stirred for 2 h while warming to room temperature. The reaction was quenched with H2O (50 mL). The organic phase washed with brine (1×50 mL). The combined aqueous phases were extracted with CH2Cl2 (2×25 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to give an off-white solid. The crude material was purified via flash chromatography (1:4 EtOAc/Hexanes) to give 2-(4,6-dichloro-[1,3,5]triazin-2-yloxy)-N-(3-trifluoromethyl-phenyl)-acetamide as a white solid (600 mg, 60%). LC/MSD (HP Series 1100 MSD) Expected MW: 365.99, Observed M+H: 367.0, Retention time: 1.59. 1H-NMR, DMSO-d6, Varian 400 MHz δ 11.19 (s, 1H), 10.63 (s, 1H), 8.08 (s, 1H), 7.75 (d, 1H), 7.59 (t, 1H), 7.44 (d, 1H), 4.99 (s, 2H) ppm.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[C@H:29]([NH:30][C:31](=[O:41])[C:32](=[N:39][OH:40])[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:28](=[O:42])[N:10]2[C:11]=1[C:12]([O:14][CH:15]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])(=[O:3])[CH3:2].N1C=CC=CC=1.[C:49](Cl)(=[O:56])[C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1>C(OCC)(=O)C>[C:1]([O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[C@H:29]([NH:30][C:31](=[O:41])[C:32](=[N:39][O:40][C:49](=[O:56])[C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)[C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)[C:28](=[O:42])[N:10]2[C:11]=1[C:12]([O:14][CH:15]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:13])(=[O:3])[CH3:2]
Reactant: CC(=O)OCC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](NC(=O)C(=NO)c3ccccc3)[C@H]2SC1
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(=O)OCC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)[C@@H](NC(=O)C(=NOC(=O)c3ccccc3)c3ccccc3)[C@H]2SC1
Reaction time: 1 h

Procedure:
To a solution of diphenylmethyl 3-acetoxymethyl-7β-(2-hydroxyimino-2-phenylacetamido)ceph-3-em-4-carboxylate (1.0 g) and pyridine (1.5 ml.) in ethyl acetate (30 ml.) was added benzoyl chloride (1.5 ml.) and the mixture allowed to stand for one hour at room temperature. The solution was then washed with 2 N-hydrochloric acid (50 ml.) and saturated brine, dried (sodium sulphate) and concentrated to ca. 5 ml. The concentrate was added dropwise to petroleum (b.p. 40°-60°; 350 ml.) and the precipitated solid filtered, washed with petroleum and dried, yielding the title ester as a yellow solid (1.0 g; 85%), [α]D +6.4° (c 0.94, DMSO), λmax. (EtOH) 259 nm (ε 26,700), νmax. (CHBr3) 1780 (β-lactam), 1640 and 1522 cm.-1 (CONH), τ (DMSO-d6) values include -0.27 (doublet J 8 Hz; NH), 1.8-2.8 (multiplet; aromatic protens), 8.01 (singlet; OCOCH3) .
Reaction SMILES: [F:1][CH:2]([F:20])[O:3][C:4]1[CH:19]=[CH:18][C:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15](=O)[CH3:16])=[CH:11][CH:10]=2)=[CH:6][CH:5]=1.[NH2:21][OH:22]>C(O)C>[F:1][CH:2]([F:20])[O:3][C:4]1[CH:19]=[CH:18][C:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15](=[N:21][OH:22])[CH3:16])=[CH:11][CH:10]=2)=[CH:6][CH:5]=1
Reactant: NO
Reactant: CC(=O)c1ccc(Oc2ccc(OC(F)F)cc2)cc1
Solvent: CCO
Product: CC(=NO)c1ccc(Oc2ccc(OC(F)F)cc2)cc1

Procedure:
A mixture of 1.37 g (4.92 mmol) of 1-[4-(4-difluoromethoxy-phenoxy)-phenyl]-ethanone and 1.16 mL hydroxylamine solution (50% in water) in 5 mL ethanol was refluxed for 3 hours. Then the mixture was concentrated and evaporated down several times with ethanol, and the residue was purified by chromatography (silica gel column, petroleum ether/ethyl acetate).
Reaction SMILES: [Cl:1][CH2:2][C@@H:3]([OH:27])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([C:15]2[CH:26]=[CH:25][C:18]([O:19][CH2:20][C@H:21]([OH:24])[CH2:22][OH:23])=[CH:17][CH:16]=2)([CH3:14])[CH3:13])=[CH:8][CH:7]=1.C(O[C:32](=[O:34])[CH3:33])(=O)C>N1C=CC=CC=1.CN(C1C=CN=CC=1)C>[C:4]([O:23][CH2:22][C@@H:21]([O:24][C:32](=[O:34])[CH3:33])[CH2:20][O:19][C:18]1[CH:17]=[CH:16][C:15]([C:12]([C:9]2[CH:8]=[CH:7][C:6]([O:5][CH2:4][C@H:3]([O:27][C:18](=[O:19])[CH3:17])[CH2:2][Cl:1])=[CH:11][CH:10]=2)([CH3:14])[CH3:13])=[CH:26][CH:25]=1)(=[O:5])[CH3:3]
Reactant: CC(C)(c1ccc(OC[C@H](O)CO)cc1)c1ccc(OC[C@H](O)CCl)cc1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CC(=O)OC[C@H](COc1ccc(C(C)(C)c2ccc(OC[C@@H](CCl)OC(C)=O)cc2)cc1)OC(C)=O
Reaction time: 14 h
Yield: 187.7 %

Procedure:
To a solution of (R)-3-(4-(2-(4-((S)-3-chloro-2-hydroxypropoxy)phenyl)propan-2-yl)phenoxy)propane-1,2-diol (500 mg, 1.27 mmol) in anhydrous pyridine (6.0 mL) were successively added acetic anhydride (605 μL, 6.35 mmol) and a catalytic amount of DMAP. After 14 h, the reaction mixture was quenched with an aqueous solution of sodium chloride and stirred for 15 min, and the resulting mixture was extracted twice with dichloromethane. The organic phases were combined, dried over anhydrous magnesium sulfate, and filtered. Solvents were evaporated, and the resulting crude material was purified by silica gel flash chromatography (eluent: 2% methanol in dichloromethane) to provide the title compound (621 mg, 94%) as a sticky solid.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]([OH:14])[CH2:4][N:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6]1.N1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][C:23]=2[O:25][CH2:26][C:27](OCC)=[O:28])C=CC=1>CCO>[OH:14][C@H:3]([CH2:4][N:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6]1)[CH2:2][NH:1][C:27](=[O:28])[CH2:26][O:25][C:23]1[CH:24]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: NC[C@H](O)CN1Cc2ccccc2C1
Reactant: CCOC(=O)COc1cccc2cccnc12
Solvent: CCO
Product: O=C(COc1ccccc1)NC[C@H](O)CN1Cc2ccccc2C1
Yield: 31 %

Procedure:
A solution of (S)-1-amino-3-(isoindolin-2-yl)propan-2-ol (100 mg, 0.52 mmol), ethyl 2-(quinolin-8-yloxy)acetate (120 mg, 0.52 mmol) in EtOH (1 mL) was heated under microwave conditions at 120° C. for 0.5 h. The reaction mixture was concentrated and purified by preparative HPLC purification. (60 mg, yield 31%) MS (ESI+) e/z: 378.1 [M+1]+. 1H NMR (MeOD, 400 MHz), δ ppm: 8.93-8.88 (m, 1H), 8.44-8.38 (m, 1H), 7.66-7.57 (m, 3H), 7.34-7.29 (m, 1H), 7.24-7.14 (m, 4H), 4.82-4.79 (m, 2H), 4.08-4.03 (m, 1H), 3.99 (s, 4H), 3.60-3.55 (m, 1H), 3.46-3.40 (m, 1H), 2.91-2.85 (m, 1H), 2.8-2.78 (m, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[C:13](Br)=[CH:12][O:11][C:10]=1[C:17]([O:19][CH3:20])=[O:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:21]1[CH:25]=[CH:24][N:23]=[C:22]1[Sn](CCCC)(CCCC)CCCC>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([O:8][C:9]1[C:14](=[O:15])[C:13]([C:22]2[S:21][CH:25]=[CH:24][N:23]=2)=[CH:12][O:11][C:10]=1[C:17]([O:19][CH3:20])=[O:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1occ(Br)c(=O)c1OCc1ccccc1
Reactant: CCCC[Sn](CCCC)(CCCC)c1nccs1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: COC(=O)c1occ(-c2nccs2)c(=O)c1OCc1ccccc1
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 63.1 %

Procedure:
To a solution of methyl 3-benzyloxy-5-bromo-4-oxo-4H-pyran-2-carboxylate (2.3 g) in dioxane (25 ml) were added tetrakis(triphenylphosphine)palladium(0) (1.57 g) and (2-thiazolyl)tributyltin (5.08 g) under an argon stream, and the mixture was stirred at 100° C. for 1.5 hr. The obtained reaction mixture was concentrated, and subsequently purified by silica gel column chromatography (ethyl acetate:hexane=1:4–1:2) to give methyl 3-benzyloxy-4-oxo-5-(thiazol-2-yl)-4H-pyran-2-carboxylate (1.47 g).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:23]=[C:22]3[C:18]([CH2:19][CH2:20][N:21]3[C:24](=[O:26])[CH3:25])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:27](Cl)(=[O:36])[CH:28]=[CH:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C(N(CC)CC)C>C(Cl)Cl>[C:24]([N:21]1[C:22]2[C:18](=[CH:17][CH:16]=[C:15]([N:14]([CH:11]3[CH2:12][CH2:13][N:8]([CH2:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[CH2:9][CH2:10]3)[C:27](=[O:36])/[CH:28]=[CH:29]/[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH:23]=2)[CH2:19][CH2:20]1)(=[O:26])[CH3:25]
Reactant: O=C(Cl)C=Cc1ccccc1
Reactant: CC(=O)N1CCc2ccc(NC3CCN(Cc4ccccc4)CC3)cc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N1CCc2ccc(N(C(=O)/C=C/c3ccccc3)C3CCN(Cc4ccccc4)CC3)cc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 84 %

Procedure:
To a solution of 1-[6-(1-benzyl-piperidin-4-ylamino)-2,3-dihydro-indol-1-yl]-ethanone (250 mg, 0.72 mmol) in CH2Cl2 (10 mL) was added cinnamoyl chloride (160 mg, 0.93 mmol) and triethylamine (TEA, 0.30 mL, 2.2 mmol). The mixture was stirred at 25° C. for 16 h. After concentration, the residue was purified by preparative TLC (PTLC, 20% EtOAc/CH2Cl2) to provide 290 mg (85%) of the desired product. 1H NMR (500 MHz, CDCl3): 8.05 (s, 1H), 7.62 (d, J=15.5 Hz, 1H), 7.32-7.20 (m, 10H), 7.17 (d, J=7.9 Hz, 1H), 6.74 (dd, J=6.8, 1.5 Hz, 1H), 6.15 (d, J=15.5 Hz, 1H), 4.80-4.69 (m, 1H), 4.20-4.09 (m, 3H), 3.51-3.45 (m, 1H), 3.31-3.20 (m, 2H), 2.95-2.82 (m, 2H), 2.23 (s, 3H), 2.19-2.08 (m, 2H), 1.91-1.71 (m, 2H). MS: exact mass calculated for C31H33N3O2, 479.26; m/z found, 480.3 [M+H]+.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:9]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[C:11](=[O:20])[CH:10]2[CH2:21][CH2:22][CH:23]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[OH:24])[CH:6]=[CH:7][CH:8]=1.[OH:32][CH:33]([CH:47]([OH:54])[CH:48]([OH:53])[CH:49]([OH:52])[CH2:50][OH:51])[C:34]([NH:36][CH2:37][CH2:38][O:39][CH2:40][CH2:41][O:42][CH2:43][C:44](O)=[O:45])=[O:35].C(N=C=NC(C)C)(C)C.OC1C2N=NNC=2C=CC=1>CN(C)C=O>[F:19][C:16]1[CH:15]=[CH:14][C:13]([N:12]2[C:11](=[O:20])[CH:10]([CH2:21][CH2:22][CH:23]([C:25]3[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=3)[OH:24])[CH:9]2[C:5]2[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=2)[CH2:2][NH:1][C:44]([CH2:43][O:42][CH2:41][CH2:40][O:39][CH2:38][CH2:37][NH:36][C:34](=[O:35])[CH:33]([OH:32])[CH:47]([OH:54])[CH:48]([OH:53])[CH:49]([OH:52])[CH2:50][OH:51])=[O:45])=[CH:18][CH:17]=1
Reactant: NCc1cccc(C2C(CCC(O)c3ccc(F)cc3)C(=O)N2c2ccc(F)cc2)c1
Reactant: O=C(O)COCCOCCNC(=O)C(O)C(O)C(O)C(O)CO
Agent: CC(C)N=C=NC(C)C
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Product: O=C(COCCOCCNC(=O)C(O)C(O)C(O)C(O)CO)NCc1cccc(C2C(CCC(O)c3ccc(F)cc3)C(=O)N2c2ccc(F)cc2)c1

Procedure:
21 is prepared similarly to 18 starting from 100 mg of 4-(3-aminomethylphenyl)-1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]azetidin-2-one (15), 122 mg of {2-[2-(2,3,4,5,6-pentahydroxyhexanoylamino)ethoxy]ethoxy}acetic acid (20), 93 μl of diisopropylcarbodiimide and 65 mg of hydroxybenzotriazole in 2 ml of dimethylformamide. This gives 21: C37H45F2N3O11 (745.78) MS (ESI) 746 (M+H)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[C@H:9]1[CH:21]=[O:22])=[O:7])([CH3:4])([CH3:3])[CH3:2].C[Si](C)(C)[C:25]([F:28])([F:27])[F:26]>[F-].[Cs+].Cl>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[C@H:9]1[C@@H:21]([OH:22])[C:25]([F:28])([F:27])[F:26])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C=O
Reactant: C[Si](C)(C)C(F)(F)F
Agent: Cl
Agent: [Cs+]
Agent: [F-]
Product: CC(C)(C)OC(=O)N1CC[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1[C@@H](O)C(F)(F)F
Temperature: 25 °C
Reaction time: 24 h
Yield: 46.7 %

Procedure:
To (2S,3R)-3-(tert-butyldimethylsilanyloxy)-2-formylpyrrolidine-1-carboxylic acid tert-butyl ester (7C) (2.10 g, 6.38 mmol) was added trimethyl(trifluoromethyl)silane (800 μL, 6.57 mmol) and cesium fluoride (dried under high vacuum at 130° C. for 12 h) (10.0 mg, 0.066 mmol). The reaction was stirred at rt for 24 h then heated to 50° C. for 5 h. After cooling to rt, 4N HCl (ca. 10 mL) was added and the reaction was stirred overnight. The brown aqueous solution was decanted and the remaining waxy yellow solid was dried under high vacuum overnight then recrystallized from hexane to provide (2R,3R)-3-(tert-butyldimethylsilanyloxy)-2-[(1R)-(2,2,2-trifluoro-1-hydroxyethyl)]-pyrrolidine-1-carboxylic acid tert-butyl ester (7D) (1.19 g) as a white solid. The mother liquor was concentrated and purified via flash chromatography eluting with 5-20% EtOAc/hexane to provide (2R,3R)-3-(tert-butyldimethylsilanyloxy)-2-[(1S)-(2,2,2-trifluoro-1-hydroxy-ethyl)]-pyrrolidine-1-carboxylic acid tert-butyl ester (7E) (192 mg) as an oil and a mixture of (2R,3R)-3-(tert-butyldimethylsilanyloxy)-2-[(1R)-(2,2,2-trifluoro-1-hydroxy-ethyl)]-pyrrolidine-1-carboxylic acid tert-butyl ester (7D) and starting material (306 mg). The latter was recrystallized from hexane to provide additional (2R,3R)-3-(tert-butyldimethylsilanyloxy)-2-[(1R)-(2,2,2-trifluoro-1-hydroxy-ethyl)]-pyrrolidine-1-carboxylic acid tert-butyl ester (7D) (100 mg).
Reaction SMILES: C(O[C:9]([N:11]([CH:13]([CH:37]([CH3:39])[CH3:38])[C:14]([NH:16][CH:17]([CH:30]1[NH:34][C:33](=[O:35])[NH:32][C:31]1=[O:36])[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[C:21]([C:26]([CH3:29])([CH3:28])[CH3:27])[CH:20]=1)=[O:15])C)=O)C1C=CC=CC=1.[H][H]>CO.[C].[Pd]>[CH3:38][CH:37]([CH3:39])[CH:13]([NH:11][CH3:9])[C:14]([NH:16][CH:17]([CH:30]1[NH:34][C:33](=[O:35])[NH:32][C:31]1=[O:36])[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[C:21]([C:26]([CH3:29])([CH3:28])[CH3:27])[CH:20]=1)=[O:15]
Reactant: [H][H]
Reactant: CC(C)C(C(=O)NC(Cc1ccc(O)c(C(C)(C)C)c1)C1NC(=O)NC1=O)N(C)C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CNC(C(=O)NC(Cc1ccc(O)c(C(C)(C)C)c1)C1NC(=O)NC1=O)C(C)C
Yield: 95.6 %

Procedure:
To a solution of 5-(1-(2-(benzyloxycarbonyl-N-methylamino)-3-methylbutyrylamino)-2-(3-tert-butyl-4-hydroxylphenyl)ethyl)imidazolidine-2,4-dione (363 mg, 0.675 mmol) in methanol (10 ml), 10% palladium carbon (50 mg) was added and stirred at room temperature in a hydrogen atmosphere overnight. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give the titled compound (261 mg, 96%).
Reaction SMILES: [CH3:1][N:2]([CH3:17])[CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([NH2:16])[CH:9]=[CH:10][C:11]=1[C:12]([F:15])([F:14])[F:13].[Cl:18][C:19]1[C:20]([C:36]#[N:37])=[C:21]([CH:33]=[CH:34][CH:35]=1)[O:22][C:23]1[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[CH:25][CH:24]=1>C(Cl)(Cl)Cl>[Cl:18][C:19]1[C:20]([C:36]#[N:37])=[C:21]([CH:33]=[CH:34][CH:35]=1)[O:22][C:23]1[CH:24]=[CH:25][C:26]([S:29]([NH:16][C:8]2[CH:9]=[CH:10][C:11]([C:12]([F:13])([F:14])[F:15])=[C:6]([O:5][CH2:4][CH2:3][N:2]([CH3:17])[CH3:1])[CH:7]=2)(=[O:30])=[O:31])=[CH:27][CH:28]=1
Reactant: N#Cc1c(Cl)cccc1Oc1ccc(S(=O)(=O)Cl)cc1
Reactant: CN(C)CCOc1cc(N)ccc1C(F)(F)F
Solvent: ClC(Cl)Cl
Product: CN(C)CCOc1cc(NS(=O)(=O)c2ccc(Oc3cccc(Cl)c3C#N)cc2)ccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a mixture of 3-(2-dimethylamino-ethoxy)-4-trifluoromethyl-phenylamine (0.10 g, 0.4 mmol) in CHCl3 (2.5 mL) was added 4-(3-chloro-2-cyano-phenoxy) benzenesulfonyl chloride (0.13 g, 0.4 mmol) at rt. After stirring at rt for 72 h, the solvent was evaporated and the residue was purified by vacuum filtration through silica gel eluting successively with 4% MeOH in CH2Cl2 and 10% MeOH in CH2Cl2 followed by a mixture of CH2Cl2, MeOH and conc. NH4OH (90:10:1). The solvent was removed from the desired fractions and the residue was recrystallized from a mixture of MeOH and EtOAc to afford the title compound as a white solid; yield 0.01 g (5%): LCMS 540 (M++H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:32])[NH:11][C:12]2[CH:17]=[CH:16][C:15]([S:18]([NH:21][C:22]3[CH:27]=[CH:26][C:25]([S:28](=[O:31])(=[O:30])[NH2:29])=[CH:24][CH:23]=3)(=[O:20])=[O:19])=[CH:14][CH:13]=2)[CH:6]=[CH:7][CH:8]=1)#[N:2].[CH2:33]([N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1)[CH2:34][CH2:35][CH3:36]>>[CH2:33]([N:37]1[CH2:42][CH2:41][N:40]([C:1](=[NH:2])[C:3]2[CH:4]=[C:5]([NH:9][C:10](=[O:32])[NH:11][C:12]3[CH:17]=[CH:16][C:15]([S:18]([NH:21][C:22]4[CH:27]=[CH:26][C:25]([S:28](=[O:31])(=[O:30])[NH2:29])=[CH:24][CH:23]=4)(=[O:20])=[O:19])=[CH:14][CH:13]=3)[CH:6]=[CH:7][CH:8]=2)[CH2:39][CH2:38]1)[CH2:34][CH2:35][CH3:36]
Reactant: N#Cc1cccc(NC(=O)Nc2ccc(S(=O)(=O)Nc3ccc(S(N)(=O)=O)cc3)cc2)c1
Reactant: CCCCN1CCNCC1
Product: CCCCN1CCN(C(=N)c2cccc(NC(=O)Nc3ccc(S(=O)(=O)Nc4ccc(S(N)(=O)=O)cc4)cc3)c2)CC1
Yield: 16.5 %

Procedure:
The title compound was prepared from 4-(3-(3-cyanophenyl)ureido)-N-(4-sulfamoylphenyl)benzenesulfonamide following procedure C and using 1.2 equivalents of n-butylpiperazine as secondary amine. The product was purified by preparative HPLC.
Reaction SMILES: [C:1]12([CH2:11][OH:12])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.F[C:14]1[CH:19]=[C:18]([I:20])[CH:17]=[CH:16][N:15]=1.[H-].[Na+]>O1CCCC1>[C:1]12([CH2:11][O:12][C:14]3[CH:19]=[C:18]([I:20])[CH:17]=[CH:16][N:15]=3)[CH2:8][CH:7]3[CH2:6][CH:5]([CH2:4][CH:3]([CH2:9]3)[CH2:2]1)[CH2:10]2
Reactant: OCC12CC3CC(CC(C3)C1)C2
Reactant: Fc1cc(I)ccn1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Ic1ccnc(OCC23CC4CC(CC(C4)C2)C3)c1

Procedure:
1-Adamantanemethanol (0.820 g) and 2-fluoro-4-iodopyridine (0.22 g) in tetrahydrofuran (5 mL) was treated with sodium hydride (60% in mineral oil) (0.057) at room temperature for 6 hours. The reaction was quenched with ice-water and extracted with ethyl acetate (3×10 mL). The organic layer was dried over MgSO4, filtered, and concentrated. The residue was purified by preparative TLC, eluting with petroleum ether/ethyl acetate (20/1) to provide the title compound.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Br:12])[CH:8]=2)[CH:3]=1.[C:13]1(B(O)O)[C:26]2[C:27]3=[C:28]4[C:23](=[CH:24][CH:25]=2)[CH:22]=[CH:21][CH:20]=[C:19]4[CH:18]=[CH:17][C:16]3=[CH:15][CH:14]=1.C([O-])([O-])=O.[Na+].[Na+].CCO>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1>[Br:12][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[CH:3]=[C:2]([C:20]1[C:19]3[C:28]4=[C:27]5[C:16](=[CH:17][CH:18]=3)[CH:15]=[CH:14][CH:13]=[C:26]5[CH:25]=[CH:24][C:23]4=[CH:22][CH:21]=1)[CH:11]=[CH:10]2
Reactant: OB(O)c1ccc2ccc3cccc4ccc1c2c34
Reactant: Brc1ccc2cc(Br)ccc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: Brc1ccc2cc(-c3ccc4ccc5cccc6ccc3c4c56)ccc2c1
Temperature: 90 °C
Yield: 48.1 %

Procedure:
A mixture of 12.1 g (42.4 mmol) of 2,6-dibromonaphthalene, 10.43 g (42.4 mmol) of Pyren-1-ylboronic acid, 0.5 g (0.424 mmol) of Tetrakis(triphenylphosphine)palladium, 32 ml of 2M Na2CO3, 80 ml of EtOH and 160 ml toluene was degassed and placed under nitrogen, and then heated at 90° C. for 24 h. After the reaction finish, the mixture was allowed to cool to room temperature. The organic layer was extracted with ethyl acetate and water, dried with anhydrous magnesium sulfate, the solvent was removed and the residue was purified, by column chromatography on silica (hexane-dichloromethane) to give product 8.3 g (48%) as a white solid.