Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C:16]([NH:18][C@@H:19]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH2:28][C:29]([F:32])([F:31])[F:30])=[CH:23][N:22]=3)[CH3:20])=[O:17])=[CH:11][CH:10]=2)O1.Cl[C:35]1[C:40]([CH3:41])=[N:39][CH:38]=[CH:37][N:36]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>[CH3:41][C:40]1[C:35]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C:16]([NH:18][C@@H:19]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH2:28][C:29]([F:31])([F:32])[F:30])=[CH:23][N:22]=3)[CH3:20])=[O:17])=[CH:11][CH:10]=2)=[N:36][CH:37]=[CH:38][N:39]=1
Reactant: C[C@@H](NC(=O)Cc1ccc(B2OC(C)(C)C(C)(C)O2)cc1)c1ccc(OCC(F)(F)F)cn1
Reactant: Cc1nccnc1Cl
Agent: [Pd]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: Cc1nccnc1-c1ccc(CC(=O)N[C@H](C)c2ccc(OCC(F)(F)F)cn2)cc1
Reaction time: 0.5 h
Yield: 73.5 %

Procedure:
To a solution of 1.00 g (2.15 mmol) 2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-N-{(1R)-1-[5-(2,2,2-trifluoroethoxy)pyridin-2-yl]ethyl}acetamide in 5.70 ml dioxane was added 0.31 g (2.58 mmol) 2-chloro-3-methylpyrazine, 0.014 mg (0.052 mmol) tricyclohexylphosphine, 0.020 g (0.022 mmol) Pd2dba3, and 2.88 mL (3.66 mmol) 1.7M potassium phosphate. The resulting suspension was degassed for 10mins. After 30 min in the microwave at 150° C., the reaction mixture was cooled, extracted with ethyl acetate, and washed with brine. The organic layer was dried over NaSO4, filtered and concentrated in vacuo. Purification by flash chromatography (silica gel, linear gradient 30-100% EtOAc:hexane) followed by purification by reverse phase chromatography afforded 0.68 g (73.3%) 2-[4-(3-methylpyrazin-2-yl)phenyl]-N-{(1R)-1-[5-(2,2,2-trifluoroethoxy)pyridin-2-yl]ethyl}acetamide. 1H NMR (CDCl3, 400 MHz) 8.49 (d, 1H, J=2.20 Hz); 8.45 (d, 1H, J=2.38 Hz); 8.21 (d, 1H, J=2.39 Hz); 7.57 (d, 2H, J=8.24 Hz); 7.41 (d, 2H, J=7.83 Hz); 7.24-7.17 (m, 2H); 6.73 (br d, 1H, J=7.33 Hz); 5.13 (m, 1H); 4.38 (q, 2H, J=8.05 Hz); 3.67 (s, 2H); 2.65 (s, 3H); 1.41 (d, 3H, J=6.77). FIRMS (ES) exact mass calcd for C22H21F3N4O2: 431.1689, Found: 431.1690. FLIPR alpha1I IP=24 nM.
Reaction SMILES: [N:1]1([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:14][C@H:15]3[CH2:19][CH2:18][N:17]([CH:20]4[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]4)[C@@H:16]3[CH2:26][NH:27][S:28]([CH2:31][CH2:32][N:33]3C(=O)C4C(=CC=CC=4)C3=O)(=[O:30])=[O:29])[N:9]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>CO.O.NN>[NH2:33][CH2:32][CH2:31][S:28]([NH:27][CH2:26][C@@H:16]1[C@@H:15]([NH:14][C:10]2[N:9]=[C:8]([N:1]3[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[CH:13]=[CH:12][N:11]=2)[CH2:19][CH2:18][N:17]1[CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)(=[O:29])=[O:30]
Reactant: O=C1c2ccccc2C(=O)N1CCS(=O)(=O)NC[C@@H]1[C@@H](Nc2nccc(N3CCCCCC3)n2)CCN1C1CCCCC1
Agent: NN
Solvent: CO
Solvent: O
Product: NCCS(=O)(=O)NC[C@@H]1[C@@H](Nc2nccc(N3CCCCCC3)n2)CCN1C1CCCCC1
Temperature: 40 °C
Reaction time: 8 h

Procedure:
To a solution of the compound 42 in methanol (2 mL), hydrazine monohydrate (98%, 19.5 μL) was added and stirred at 40° C. for overnight. The reaction solution was concentrated and purified by thin-layer chromatography to obtain the title compound (21.4 mg) having the following physical properties.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH:15]2[CH2:16][CH2:17][C:12]1([C:18]([OH:20])=O)[CH2:13][CH2:14]2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C)C=O.C(Cl)(=O)C([Cl:29])=O>O1CCCC1>[Cl:29][C:18]([C:12]12[N:11]([C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[O:10])[CH:15]([CH2:16][CH2:17]1)[CH2:14][CH2:13]2)=[O:20]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(OCc1ccccc1)N1C2CCC1(C(=O)O)CC2
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)N1C2CCC1(C(=O)Cl)CC2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 7-[(benzyloxy)carbonyl]-7-azabicyclo[2.2.1]heptane-1-carboxylic acid (550 mg) produced above, N,N-dimethylformamide (0.02 mL) and tetrahydrofuran (10 mL) was added dropwise ethanedioyl dichloride (0.80 mL) at room temperature. The mixture was stirred at room temperature for 30 min, and the reaction system was concentrated under reduced pressure. To the residue was added a small amount of tetrahydrofuran, and the mixture was concentrated again under reduced pressure to give a crude product (2.0 mmol) of the title compound. The obtained crude product of the title compound was used for the next reaction without further purification.
Reaction SMILES: [CH2:1]([C:3]1[C:24]([N:25]2[CH2:30][CH2:29][C:28](=O)[CH2:27][CH2:26]2)=[CH:23][C:6]2[C:7]([CH3:22])([CH3:21])[C:8]3[NH:9][C:10]4[C:15]([C:16]=3[C:17](=[O:18])[C:5]=2[CH:4]=1)=[CH:14][CH:13]=[C:12]([C:19]#[N:20])[CH:11]=4)[CH3:2].Cl.[NH2:33][OH:34]>C(O)C.C(OCC)(=O)C>[CH2:1]([C:3]1[C:24]([N:25]2[CH2:30][CH2:29][C:28](=[N:33][OH:34])[CH2:27][CH2:26]2)=[CH:23][C:6]2[C:7]([CH3:22])([CH3:21])[C:8]3[NH:9][C:10]4[C:15]([C:16]=3[C:17](=[O:18])[C:5]=2[CH:4]=1)=[CH:14][CH:13]=[C:12]([C:19]#[N:20])[CH:11]=4)[CH3:2]
Reactant: CCc1cc2c(cc1N1CCC(=O)CC1)C(C)(C)c1[nH]c3cc(C#N)ccc3c1C2=O
Reactant: NO
Agent: Cl
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCc1cc2c(cc1N1CCC(=NO)CC1)C(C)(C)c1[nH]c3cc(C#N)ccc3c1C2=O
Temperature: 60 °C
Reaction time: 6 h
Yield: 75.6 %

Procedure:
9-Ethyl-6,6-dimethyl-11-oxo-8-(4-oxopiperidin-1-yl)-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile (30 mg) and hydroxylamine hydrochloric acid salt (10 mg) were dissolved in ethanol (5 ml) and stirred at 60° C. for 6 hrs. The reaction mixture was diluted with ethyl acetate (20 ml). The organic layer was washed with 10% brine and concentrated under reduced pressure. The resulting residues were purified by silica gel column (dichloromethane/methanol=99/1 to 90/10) to obtain the title compound (23.5 mg, yield 74%).
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:8]=[C:9]([C:24]2[S:28][C:27]([CH:29]3[CH2:34][CH2:33][CH:32]([C:35](O)=[O:36])[CH2:31][CH2:30]3)=[N:26][CH:25]=2)[CH:10]=[C:11]([NH:13][C:14]2[N:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[CH:16][N:15]=2)[CH:12]=1)=[O:5])[CH3:2].C[N:39](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[Cl-].[NH4+]>C([O-])(O)=O.[Na+].CC1OCCC1>[CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:8]=[C:9]([C:24]2[S:28][C:27]([CH:29]3[CH2:34][CH2:33][CH:32]([C:35]([NH2:39])=[O:36])[CH2:31][CH2:30]3)=[N:26][CH:25]=2)[CH:10]=[C:11]([NH:13][C:14]2[N:19]=[C:18]([C:20]([F:21])([F:23])[F:22])[CH:17]=[CH:16][N:15]=2)[CH:12]=1)=[O:5])[CH3:2]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CCNC(=O)Nc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(C3CCC(C(=O)O)CC3)s2)c1
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC1CCCO1
Product: CCNC(=O)Nc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(C3CCC(C(N)=O)CC3)s2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The product of Step 1 (396 mg, 0.741 mmol) was dissolved in Mg (3.50 mL). To this solution was added HATU (563 mg, 1.482 mmol) and DIPEA (0.776 mL, 4.44 mmol), followed by ammonium chloride (119 mg, 2.222 mmol). Reaction was complete after stirring 1 hour at room temperature. The reaction mixture was diluted with saturated NaHCO3(aq) and 2-MeTHF. The phases were separated and the organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated to dryness. The mixture of syn and anti iomers was diluted in DMSO was purified by reversed phase HPLC (C18 column; MeCN/water with 0.1% TFA added) to yield:
Reaction SMILES: [Si:1]([O:8][CH2:9][C@H:10]1[O:14][C:13]([CH3:16])([CH3:15])[N:12]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C@H:11]1[CH2:24][C:25]1[N:26]=[CH:27][S:28][CH:29]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C([Li])CCC.[Si:35](Cl)([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:37])[CH3:36]>C1COCC1>[Si:35]([C:27]1[S:28][CH:29]=[C:25]([CH2:24][C@H:11]2[C@@H:10]([CH2:9][O:8][Si:1]([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3])[O:14][C:13]([CH3:15])([CH3:16])[N:12]2[C:17]([O:19][C:20]([CH3:21])([CH3:23])[CH3:22])=[O:18])[N:26]=1)([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:37])[CH3:36]
Reactant: CC(C)(C)OC(=O)N1[C@@H](Cc2cscn2)[C@@H](CO[Si](C)(C)C(C)(C)C)OC1(C)C
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1[C@@H](Cc2csc([Si](C)(C)C(C)(C)C)n2)[C@@H](CO[Si](C)(C)C(C)(C)C)OC1(C)C
Temperature: -50 °C

Procedure:
(4S,5S)-Tert-butyl 5-((tert-butyldimethylsilyloxy)methyl)-2,2-dimethyl-4-(thiazol-4-ylmethyl)oxazolidine-3-carboxylate (0.148 g, 0.334 mmol) in THF (3 mL) was cooled to −78° C. when n-butyllithium (2.5 M in hexanes) (0.160 ml, 0.401 mmol) was added dropwise. The solution was warmed to −50° C. for 40 minutes and then cooled to −78° C. TBS-Cl (0.0605 g, 0.401 mmol) in THF (2 mL) was added dropwise and the solution was allowed to slowly warm to 0° C. when it was quenched with saturated ammonium chloride. The layers were separated and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with water, brine and dried over sodium sulfate to afford the title compound, which was used without further purification.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[O:11][C:10](=[O:13])[C:9]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[C:8]2[OH:20].Br.C(OC(=O)C)(=O)C>C(O)(=O)C>[OH:20][C:8]1[C:7]2[C:12](=[C:3]([OH:2])[CH:4]=[CH:5][CH:6]=2)[O:11][C:10](=[O:13])[C:9]=1[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: COc1cccc2c(O)c(-c3ccccc3)c(=O)oc12
Agent: Br
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: O=c1oc2c(O)cccc2c(O)c1-c1ccccc1
Yield: 38.1 %

Procedure:
37.6 g. (0.14 mol) of 8-methoxy-4-hydroxy-3-phenylcoumarin are brought to reflux for 1 hour in a mixture of 750 ml. of 62% hydrobromic acid, 375 ml. of glacial acetic acid and 375 ml. of acetic anhydride. The mixture is poured on to 5.3 kg. of ice, filtered and dried. 25.3 g. of a solid are obtained, which is recrystallised from a mixture of dioxane and diisopropyl ether (50:50). Weight 13 g., yield 38.1% (theoretical yield 34.2 g.); M.P. 220° C.
Reaction SMILES: [SH:1][CH2:2][CH2:3][C:4]([OH:6])=[O:5].[NH2:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)[C:15]2[N:19]([CH3:20])[CH:18]=[N:17][CH:16]=2)=[CH:10][C:9]=1[CH:28]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([Cl:36])[CH:31]=1)O>O1CCOCC1>[NH2:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)[C:15]2[N:19]([CH3:20])[CH:18]=[N:17][CH:16]=2)=[CH:10][C:9]=1[CH:28]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([Cl:36])[CH:31]=1)[S:1][CH2:2][CH2:3][C:4]([OH:6])=[O:5]
Reactant: O=C(O)CCS
Reactant: Cn1cncc1C(c1ccc(Cl)cc1)c1ccc(N)c(C(O)c2cccc(Cl)c2)c1
Solvent: C1COCCO1
Product: Cn1cncc1C(c1ccc(Cl)cc1)c1ccc(N)c(C(SCCC(=O)O)c2cccc(Cl)c2)c1
Temperature: 80 °C
Reaction time: 5 h

Procedure:
3-mercapto-propanoic acid (0.00433 mol) was added slowly to a mixture of intermediate (17) (0.00456 mol) in dioxane (20 ml) and D (20 ml). The mixture was stirred at 80° C. for 5 hours. The solvent was evaporated till dryness. The product was used without further purification, yielding 3-[[[2-amino-5-[(4-chlorophenyl)(1-methyl-1H-imidazol-5-yl)methyl]phenyl](3-chlorophenyl)methyl]thio]-propanoic acid (intermediate 22).
Reaction SMILES: [C:1](Cl)(=[O:6])[CH2:2][CH2:3][CH2:4][CH3:5].[NH2:8][CH:9]1[C:15](=[O:16])[NH:14][C:13]2[CH:17]=[CH:18][CH:19]=[CH:20][C:12]=2[NH:11][C:10]1=[O:21].C(N(CC)CC)C>CN(C)C=O>[O:21]=[C:10]1[NH:11][C:12]2[CH:20]=[CH:19][CH:18]=[CH:17][C:13]=2[NH:14][C:15](=[O:16])[CH:9]1[NH:8][C:1](=[O:6])[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCC(=O)Cl
Reactant: NC1C(=O)Nc2ccccc2NC1=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCCC(=O)NC1C(=O)Nc2ccccc2NC1=O
Reaction time: 6 h

Procedure:
Add valeryl chloride (3.92 mL, 33.0 mmol) dropwise to a solution of 3-amino-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione (5.74 g, 30.0 mmol) and triethylamine (4.60 mL, 33.0 mmol) in anhydrous dimethylformamide (123 mL) and stir. After 6 hours, concentrate under reduced pressure to a residue and reconstitute the residue in a solution of isopropanol: chloroform (1:3, 500 mL). Stir overnight to give a solid and isolate the solid by suction filtration, washing the solid with dichloromethane. Vacuum dry the solid at ambient temperature 2 hours to afford the title compound. Wash the filtrate with a saturated aqueous solution of sodium bicarbonate (2×200 mL), and filter the extraction mixture to remove salt formed in the wash. Separate the organic phase and wash it with saturated aqueous sodium chloride (150 mL). Back extract the bicarbonate aqueous phase with dichloromethane. Combine all organics, and dry (sodium sulfate), filter, and concentrate under reduced pressure to a residue. Triturate the residue in diethyl ether, filter the resulting solid, and wash it with diethyl ether; repeat 2×. Dry the solid at ambient temperature under vacuum to give the title compound: mass spectrum (APCI, m/e): 276 (M+1); NMR (1H, 300 MHz, DMSO-d): δ 10.68 (s, 2H), 8.23 (d, 1H, J=7.5 Hz), 7.20 (m, 4H), 4.71 (d, 1H, J=7.5 Hz), 2.25 (t, 2H, J=7.5 Hz), 1.43 (m, 2H), 1.25 (m, 2H), 0.83 (t, 3H, J=7.5 Hz).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]2[N:19]([C:20]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:18]=[N:17][N:16]=2)=[CH:5][CH:4]=1.[CH3:39][CH2:40][CH2:41][CH2:42][CH2:43][NH2:44].C(=O)([O-])[O-].[K+].[K+]>C1COCC1>[CH2:43]([NH:44][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]2[N:19]([C:20]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:18]=[N:17][N:16]=2)=[CH:5][CH:4]=1)[CH2:42][CH2:41][CH2:40][CH3:39]
Reactant: BrCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: CCCCCN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCCCCNCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1

Procedure:
A solution of 5-(4′-bromomethylbiphenyl-2-yl)-1-trityl-1H-tetrazole (30 g, 50 mmol), n-amylamine (45 ml, 650 mmol) and potassium carbonate (7.5 g, 50 mmol) in THF (45 mL) were stirred overnight at room temperature. The mixture was concentrated in vacuo, and then extracted with 1M aq. KOH (50 mL) and chloroform (3×200 mL). The combined organic fractions were dried over Na2SO4, filtered and concentrated in vacuo to yield crude pentyl[2′-(1-trityl-1H-tetrazol-5-yl)biphenyl-4-ylmethyl]amine, which was used without further purification. A solution of the crude material (30 g) in 4M HCl in 1,4-dioxane (300 mL) was stirred at room temperature. After 1 hour, the precipitate was filtered and washed with hexane to afford the title compound as the HCl salt (18.0 g). MS m/z: [M+H]+ calcd for C19H23N5, 321.20. found 322.5.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8]CC2C=CC(OC)=CC=2)[CH:5]=[C:4]([C:18]2[C:26]3[C:21](=[N:22][CH:23]=[CH:24][CH:25]=3)[N:20]([S:27]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)(=[O:29])=[O:28])[CH:19]=2)[CH:3]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[C:4]([C:18]2[C:26]3[C:21](=[N:22][CH:23]=[CH:24][CH:25]=3)[N:20]([S:27]([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)(=[O:28])=[O:29])[CH:19]=2)[CH:3]=1
Reactant: COc1ccc(CNc2cc(-c3cn(S(=O)(=O)c4ccccc4)c4ncccc34)cc(Cl)n2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1cc(-c2cn(S(=O)(=O)c3ccccc3)c3ncccc23)cc(Cl)n1
Temperature: 35 °C
Yield: 58.3 %

Procedure:
To a solution of Example 150a (0.500 g, 0.990 mmol) in CH2Cl2 (9 mL) was added trifluoroacetic acid (4 mL, 51.9 mmol). The mixture was heated at 35° C. for 6 hours and concentrated. The residue was treated with saturated NaHCO3 and extracted with EtOAc. The organic layer was concentrated. The crude was triturated with EtOAc/diethyl ether to give 222 mg of the title compound. The filtrate was concentrated and purified on a 12 g column using the ISCO Companion flash system eluting with CH2Cl2/EtOAc (95:5 to 90:10) to give more title compound (84 mg).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:5][C:4]=1[O:15]C)[CH3:2]>C(Cl)Cl>[OH:15][C:4]1[CH:5]=[C:6]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:7]=[CH:8][C:3]=1[CH2:1][CH3:2]
Reactant: CCOC(=O)Cc1ccc(CC)c(OC)c1
Solvent: ClCCl
Product: CCOC(=O)Cc1ccc(CC)c(O)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.1 %

Procedure:
A solution of ethyl 4-ethyl-3-methoxyphenylacetate (4f; 3.0 g; 13.50 mmol) and CH2Cl2 (80 mL) was cooled to −78° C. and a solution of (5.10 mL; 53.94 mmol; 1.0 M in CH2Cl2) over 30 min. After 1 h at −78° C. the reaction was allowed to warm to rt and stirred for 12 h. The reaction was cooled in an ice-water bath and the reaction quenched with 20 mL of water. The aqueous phase was extracted with CH2Cl2:EtOAc (4:1 v/v), dried (Na2SO4), filtered and evaporated. The crude product was purified by silica gel chromatography and eluted with a CH2Cl2:EtOAc gradient (100:1→100:4) to yield 5b (2.0 g; 71%): m.s. 209.2 (M+H)+.
Reaction SMILES: [CH:1]1([NH:4][C:5]2[C:6]3[S:13][CH:12]=[C:11]([C:14]([NH:16][C:17]4[CH:18]=[C:19]([CH:23]=[CH:24][C:25]=4[CH3:26])[C:20]([OH:22])=O)=[O:15])[C:7]=3[N:8]=[CH:9][N:10]=2)[CH2:3][CH2:2]1.[CH2:27]([N:29]1[CH2:34][CH2:33][N:32]([C:35]2[N:40]=[CH:39][C:38]([NH2:41])=[CH:37][CH:36]=2)[CH2:31][CH2:30]1)[CH3:28]>>[CH:1]1([NH:4][C:5]2[C:6]3[S:13][CH:12]=[C:11]([C:14]([NH:16][C:17]4[CH:18]=[C:19]([C:20](=[O:22])[NH:41][C:38]5[CH:39]=[N:40][C:35]([N:32]6[CH2:33][CH2:34][N:29]([CH2:27][CH3:28])[CH2:30][CH2:31]6)=[CH:36][CH:37]=5)[CH:23]=[CH:24][C:25]=4[CH3:26])=[O:15])[C:7]=3[N:8]=[CH:9][N:10]=2)[CH2:2][CH2:3]1
Reactant: Cc1ccc(C(=O)O)cc1NC(=O)c1csc2c(NC3CC3)ncnc12
Reactant: CCN1CCN(c2ccc(N)cn2)CC1
Product: CCN1CCN(c2ccc(NC(=O)c3ccc(C)c(NC(=O)c4csc5c(NC6CC6)ncnc45)c3)cn2)CC1

Procedure:
The procedure of Step 5 of Example 1 was repeated except for using 3-(4-(cyclopropylamino)thieno[3,2-d]pyrimidine-7-carboxamido)-4-methylbenzoic acid obtained in Step 3 of Example 21 and 6-(4-ethylpiperazine-1-yl)pyridine-3-amine to obtain the title compound (see Table 1).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([O:11][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][C:13]2=O)[NH:8][N:7]=1)=[O:5])[CH3:2].CS(O)(=O)=O>C(O)(=O)C.C1(C)C=CC=CC=1>[N:7]1[N:8]2[C:9]([O:11][C:12]3[CH2:17][CH2:16][CH2:15][CH2:14][C:13]=32)=[CH:10][C:6]=1[C:4]([O:3][CH2:1][CH3:2])=[O:5]
Reactant: CCOC(=O)c1cc(OC2CCCCC2=O)[nH]n1
Agent: CS(=O)(=O)O
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: CCOC(=O)c1cc2oc3c(n2n1)CCCC3
Temperature: 25 °C
Yield: 59.5 %

Procedure:
A mixture of ethyl-5-[(2-oxocyclohexyl)oxy]-1H-pyrazole-3-carboxylate (127.6 mg, 0.5 mmol) and methane sulfonic acid (95 mg) in 5 ml of acetic acid and toluene (50 ml) was refluxed for 18 hours using a Dean-Stark trap to remove water. The reaction mixture was allowed to cool to room temperature. The reaction mixture was filtered. The filtrate was concentrated to an oil. The residue was dissolved in ethyl acetate and aqueous bicarbonate solution. The organic layer was washed with water and dried over MgSO4. After removal of the ethyl acetate, the residue was purified by silica gel chromatography eluting with 1:1 ethyl acetate/hexane to give 69.7 mg (59%) of the desired product as white solid. Mp; 55-57° C.; Electrospray-MS m/z 235.0 (M+H)+
Reaction SMILES: I[CH:2]([CH3:4])[CH3:3].[OH:5][C:6]1[CH:30]=[CH:29][C:9]([CH2:10][C:11]23[CH2:18][CH2:17][CH2:16][N:15]2[C:14](=[O:19])[N:13]([C:20]2[CH:25]=[C:24]([Cl:26])[N:23]=[C:22]([Cl:27])[CH:21]=2)[C:12]3=[O:28])=[CH:8][CH:7]=1>CN(C=O)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[CH:2]([O:5][C:6]1[CH:7]=[CH:8][C:9]([CH2:10][C:11]23[CH2:18][CH2:17][CH2:16][N:15]2[C:14](=[O:19])[N:13]([C:20]2[CH:21]=[C:22]([Cl:27])[N:23]=[C:24]([Cl:26])[CH:25]=2)[C:12]3=[O:28])=[CH:29][CH:30]=1)([CH3:4])[CH3:3]
Reactant: O=C1N(c2cc(Cl)nc(Cl)c2)C(=O)C2(Cc3ccc(O)cc3)CCCN12
Reactant: CC(C)I
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CN(C)C=O
Product: CC(C)Oc1ccc(CC23CCCN2C(=O)N(c2cc(Cl)nc(Cl)c2)C3=O)cc1
Reaction time: 4 h

Procedure:
2-Iodopropane (0.5 ml) was added to a suspension of Example 196 (0.17 g) and CS2CO3 (0.28 g) in DMF (3 mL) and the mixture was stirred for 4 hours. The mixture was diluted with citric acid and the solution was extracted with EtOAc. EtOAc layer was washed with water and brine, dried and evaporated. The residue was purified via HPLC to yield the titled compound (0.13 g). MS m/z 435(MH+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])/[CH:4]=[CH:5]\[C:6]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[C:7]=1[C:8]([O:10][CH:11]([CH3:13])[CH3:12])=[O:9].CO[CH2:25][N:26]([CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[CH2:27][Si](C)(C)C.FC(F)(F)C(O)=O>CCOC(C)=O.FC(F)(F)C(O)=O>[CH2:32]([N:26]1[CH2:27][C@H:5]([C:6]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[C:7]=2[C:8]([O:10][CH:11]([CH3:13])[CH3:12])=[O:9])[C@H:4]([C:3]([O:2][CH3:1])=[O:22])[CH2:25]1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: COC(=O)/C=C\c1cccc(C(F)(F)F)c1C(=O)OC(C)C
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)[C@@H]1CN(Cc2ccccc2)C[C@@H]1c1cccc(C(F)(F)F)c1C(=O)OC(C)C
Temperature: 65 °C
Reaction time: 4 h
Yield: 92.9 %

Procedure:
To a solution of (Z)-isopropyl 2-(3-methoxy-3-oxoprop-1-enyl)-6-(trifluoromethyl)benzoate (2.5 g, 7.9 mmol) in 30 mL of EtOAc was added N-(methoxymethyl)-N-(trimethylsilylmethyl)benzylamine (2.34 g, 9.9 mmol) and trifluoroacetic acid (0.12 mL, 1.6 mmol). The solution was allowed to stir at 65° C. for 4 h. Starting material still remained by TLC analysis and so additional N-(methoxymethyl)-N-(trimethylsilylmethyl)benzylamine (1.0 g, 4.2 mmol) and trifluoroacetic acid (0.05 mL, 0.65 mmol) were added and the reaction was stirred at 65° C. for an additional 3 h. The reaction was allowed to cool and was diluted with EtOAc, washed with sat'd aq NaHCO3 and brine, dried (MgSO4) and concentrated. The residue was purified by flash chromatography (5:1 hexane/EtOAc) to afford 3.3 g (93%) of the title compound as an oil. LRMS (ES)+: 450.35 (M+H)+.
Reaction SMILES: [CH2:1]([S:9]([OH:12])(=[O:11])=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH3:13][C:14]([N:16]([OH:51])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][NH:22][C:23]([CH2:25][CH2:26][C:27]([N:29]([OH:50])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][NH:35][C:36]([CH2:38][CH2:39][C:40]([N:42]([OH:49])[CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][NH2:48])=[O:41])=[O:37])=[O:28])=[O:24])=[O:15]>>[CH2:1]([S:9]([O-:12])(=[O:10])=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH3:13][C:14]([N:16]([OH:51])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][NH:22][C:23]([CH2:25][CH2:26][C:27]([N:29]([OH:50])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][NH:35][C:36]([CH2:38][CH2:39][C:40]([N:42]([OH:49])[CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][NH2:48])=[O:41])=[O:37])=[O:28])=[O:24])=[O:15]
Reactant: CCCCCCCCS(=O)(=O)O
Agent: CC(=O)N(O)CCCCCNC(=O)CCC(=O)N(O)CCCCCNC(=O)CCC(=O)N(O)CCCCCN
Product: CCCCCCCCS(=O)(=O)[O-]

Procedure:
Following a procedure analogous to that of Example 1, octane-1-sulphonic acid and desferrioxamine-B are reacted to give the octane-1-sulphonate salt of desferrioxamine-B. Mp 144° C. C33H66O11 N6S Calcd C: 52.50%, H:8.81%, N:11.13%, S:4.25%; Found C: 52.43%, H:8.75%, N:11.16%, S:4.18%.