Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7](=[N:17][O:18][CH2:19][CH2:20][CH2:21][NH:22]C(=O)OC(C)(C)C)[C:8]2[NH:16][C:11]3=[CH:12][N:13]=[CH:14][CH:15]=[C:10]3[CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.FC(F)(F)C(O)=O.C(Cl)[Cl:38]>>[ClH:38].[NH2:22][CH2:21][CH2:20][CH2:19][O:18][N:17]=[C:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:8]1[NH:16][C:11]2=[CH:12][N:13]=[CH:14][CH:15]=[C:10]2[CH:9]=1
Reactant: CC(C)(C)OC(=O)NCCCON=C(c1ccccc1)c1cc2ccncc2[nH]1
Reactant: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cl
Product: NCCCON=C(c1ccccc1)c1cc2ccncc2[nH]1
Reaction time: 1 h

Procedure:
tert-Butyl 3-[[[phenyl(1H-pyrrolo[2,3-c]pyridin-2-yl)methylene]amino]oxy]propylcarbamate (Example 76) (60 mg, 0.15 mmol) was dissolved in methylene chloride (4 mL) and trifluoroacetic acid (1 mL) was added. The reaction mixture was stirred for 1 h. The solvents were removed under vacuum and the residue was dissolved in ethyl acetate. Saturated sodium bicarbonate solution was added and the mixture was stirred for 10 min. The layers were separated and the aqueous layer extracted with ethyl acetate (2×). The combined organic extracts were washed with water and brine, dried over sodium sulfate, and concentrated to an oil. The oil was dissolved in ethyl acetate (4 mL), 2 M ethereal hydrogen chloride (0.2 mL) was added and the precipitate formed. Removal of the solvents and drying under vacuum produced phenyl(1H-pyrrolo[2,3-c]pyridin-2-yl)methanone O-(3-aminopropyl)oxime hydrochloride, a mixture of isomers (39 mg, 71%) as an off-white solid: mp 168-174° C. dec.; 1H NMR (500 MHz, CD3OD) δ2.02-2.31 (2H, m), 2.98-3.27 (2H, m), 4.47-4.59 (2H, m), 6.75 (0.24H, s) 7.12 (0.76H, s), 7.47-7.59 (5H, m), 8.05-8.27 (2H, m), 8.96 (0.24H, s), 9.13 (0.76H, br s); ESI MS m/z 295 [C17H18N4O+H]+; HPLC (Method A) 91.5% (AUC), tR=14.0 min.
Reaction SMILES: C([O:4][CH2:5][C@H:6]([N:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][C:17]=2[NH2:21])[C:12]1=[O:22])[CH2:7][CH:8]([CH3:10])[CH3:9])(=O)C.[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([C@@H:30]([CH3:34])[C:31](O)=[O:32])=[CH:26][CH:25]=1.CN(C)C=O.C(=O)(O)[O-].[Na+].[OH-].[Na+]>CO>[Cl:23][C:24]1[CH:25]=[CH:26][C:27]([C@@H:30]([CH3:34])[C:31]([NH:21][C:17]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:18]=2[CH:19]=[CH:20][N:11]([C@@H:6]([CH2:5][OH:4])[CH2:7][CH:8]([CH3:9])[CH3:10])[C:12]3=[O:22])=[O:32])=[CH:28][CH:29]=1
Reactant: C[C@@H](C(=O)O)c1ccc(Cl)cc1
Reactant: CC(=O)OC[C@@H](CC(C)C)n1ccc2c(N)cccc2c1=O
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CO
Product: CC(C)C[C@H](CO)n1ccc2c(NC(=O)[C@H](C)c3ccc(Cl)cc3)cccc2c1=O
Temperature: 50 °C
Reaction time: 8 h

Procedure:
Into a 20 ml reaction vial reaction vial was combined (R)-2-(5-amino-1-oxoisoquinolin-2(1H)-yl)-4-methylpentyl acetate (0.23 g, 0.00076 mol), (R)-2-(4-chlorophenyl)propanoic acid (0.175 g, 0.000949 mol) N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (0.58 g, 0.0015 mol) N,N-diisopropylethylamine (0.26 mL, 0.0015 mol), and N,N-dimethylformamide (4 mL, 0.06 mol). The mixture was heated at 50° C. for 3 hours and allowed to cool to room temperature. The mixture was poured on to saturated sodium bicarbonate (200 ml) and extracted with ethyl acetate (3×100 ml). The combined extracts were dried over sodium sulfate and reduced in vacuo to yield a light brown oil. The oil was taken up in methanol (10 ml) and 2N NaOH (10 ml) was added. The mixture was allowed to stir overnight. The volatiles were removed and the mixture was extracted with methylene chloride (2×20 ml). The combined extracts were reduced in vacuo and the mixture was purified by reversed phase prep HPLC using an acetonitrile: water gradient at pH 10. The combined pure fractions were reduced in vacuo to yield the title compound as yellow solid.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]2[N:13]([CH2:16][CH3:17])[N:14]=[CH:15][C:3]=12.[CH:18]1([NH2:23])[CH2:22][CH2:21][CH2:20][CH2:19]1.C(N(CC)CC)C>C(O)C>[CH:18]1([NH:23][C:2]2[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]3[N:13]([CH2:16][CH3:17])[N:14]=[CH:15][C:3]=23)[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: NC1CCCC1
Reactant: CCOC(=O)c1cnc2c(cnn2CC)c1Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC(=O)c1cnc2c(cnn2CC)c1NC1CCCC1
Temperature: 80 °C
Yield: 121.7 %

Procedure:
Intermediate 1 (0.051 g) and cyclopentyl amine (0.019 g) were suspended in ethanol (2 ml) and triethylamine (0.14 ml) was added. The mixture was stirred under nitrogen and heated at 80° C. for 16 h. After cooling to room temperature, ethanol was removed by evaporation under a stream of nitrogen and the residue partitioned between DCM and water. The organic layer was loaded directly onto an SPE cartridge (silica, 5 g) and eluted sequentially with; (i) DCM, (ii) DCM:Et2O (2:1), (iii) DCM:Et2O (1:1), (iv) Et2O, (v) EtOAc and (vi) MeOH. Fractions containing desired material were combined and concentrated in vacuo to afford Intermediate 2 (0.074 g). LCMS showed MH+303; TRET=3.45 min
Reaction SMILES: [CH3:1][C:2]12[CH2:8][CH:7]([OH:9])[CH:6]1[C:5]([CH3:11])([CH3:10])[C:4](=[O:12])[CH2:3]2.ClC1C=CC=C(C(OO)=[O:21])C=1.C(=O)([O-])O.[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl>[CH3:1][C:2]12[CH2:8][CH:7]([OH:9])[CH:6]1[C:5]([CH3:10])([CH3:11])[O:21][C:4](=[O:12])[CH2:3]2
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC12CC(=O)C(C)(C)C1C(O)C2
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CC12CC(=O)OC(C)(C)C1C(O)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.7 %

Procedure:
To a solution of 400 mg of the hydroxyketone (IV) in 8 ml of methylene chloride, while being cooled in ice, were added 770 mg of m-chloroperbenzoic acid and 480 mg of sodium hydrogencarbonate. The mixture was stirred overnight at room temperature and then treated with 10 ml of 10% sodium thiosulfate solution. The aqueous layer was separated and extracted three time with methylene chloride. The combined methylene chloride layer was washed with saturated aqueous sodium bicarbonate solution, then with an aqueous sodium chloride solution, dried over magnesium sulfate, and concentrated in vacuo to give 415 mg of a colorless oil (III); nD20 1.4845; MS: m/e 169 (M+ --CH3), 166 (M+ --H2O).
Reaction SMILES: C([O:3][C:4](=[O:23])[C:5]([CH3:22])([O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH3:21])[CH2:6][C:7]1[CH:12]=[CH:11][C:10](O)=[CH:9][CH:8]=1)C.[CH3:24][C:25]1[O:29][C:28]([C:30]2([CH3:36])[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)=[N:27][C:26]=1[CH2:37][CH2:38][O:39]S(C1C=CC(C)=CC=1)(=O)=O>>[CH3:22][C:5]([O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH3:21])([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:39][CH2:38][CH2:37][C:26]2[N:27]=[C:28]([C:30]3([CH3:36])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]3)[O:29][C:25]=2[CH3:24])=[CH:9][CH:8]=1)[C:4]([OH:23])=[O:3]
Reactant: CCOC(=O)C(C)(Cc1ccc(O)cc1)Oc1ccccc1C
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(C3(C)CCCCC3)oc2C)cc1
Product: Cc1ccccc1OC(C)(Cc1ccc(OCCc2nc(C3(C)CCCCC3)oc2C)cc1)C(=O)O

Procedure:
The title compound was prepared using the representative Standard Procedure (E) from 3-(4-Hydroxy-phenyl)-2-methyl-2-o-tolyloxy-propionic acid ethyl ester and Toluene-4-sulfonic acid 2-[5-methyl-2-(1-methyl-cyclohexyl)-oxazol-4-yl]-ethyl ester. 1H NMR (400 MHz, CDCl3): δ 7.14-7.11 (m, 3H), 7.08-7.04 (m, 1H), 6.91 (t, 1H, J=7.82 Hz), 6.81 (d, 1H, J=8.60 Hz), 6.76 (d, 2H, J=8.60 Hz), 4.10 (t, 2H, J=6.26 Hz), 3.24 (d, 1H, J=14.08 Hz), 3.18 (d, 1H, J=14.08 Hz), 2.93 (t, 2H, J=6.26 Hz), 2.27 (s, 3H), 2.17 (s, 3H), 2.13-2.06 (m, 2H), 1.54-1.48 (m, 8H), 1.40-1.34 (m, 3H), 1.27 (s, 3H). MS [EI+] 492 (M+H)+, [EI−] 490 (M−H)+.
Reaction SMILES: [C:1]1([CH3:9])[CH:6]=[CH:5][C:4]([NH:7][NH2:8])=[CH:3][CH:2]=1.[C:10]([O:15][CH2:16][CH3:17])(=[O:14])[C:11]([CH3:13])=O>C(Cl)Cl>[CH3:9][C:1]1[CH:6]=[CH:5][C:4]([NH:7][N:8]=[C:11]([CH3:13])[C:10]([O:15][CH2:16][CH3:17])=[O:14])=[CH:3][CH:2]=1
Reactant: CCOC(=O)C(C)=O
Reactant: Cc1ccc(NN)cc1
Solvent: ClCCl
Product: CCOC(=O)C(C)=NNc1ccc(C)cc1
Reaction time: 0.5 h
Yield: 96.7 %

Procedure:
para-Tolylhydrazine (1.2024 g, 9.84 mmol, 1.0 eq.) was combined with ethyl pyruvate (1.08 ml, 9.84 mmol, 1.0 eq.) and 3A sieves (3.6 g, 300% by weight) in methylene chloride (9.8 ml, 1M) at room temperature. After 30 minutes, the reaction was filtered through anhydrous magnesium sulfate and concentrated to give the title A compound (2.095 g) which was used in the next step without purification or characterization.
Reaction SMILES: [C:1]1([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[CH:6]=[CH:5][C:4]([C:7]2[C:39]([F:40])=[CH:38][C:10]3[N:11](CC4C=CC(C5C=CC=CC=5)=CC=4)[C:12]([O:14][CH:15]4[CH2:19][CH2:18][CH:17]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:16]4)=[N:13][C:9]=3[C:8]=2[F:41])=[CH:3][CH:2]=1.C1CC=CCC=1>CCOC(C)=O.CCO.[OH-].[OH-].[Pd+2]>[C:1]1([C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=2)[CH:2]=[CH:3][C:4]([C:7]2[C:39]([F:40])=[CH:38][C:10]3[NH:11][C:12]([O:14][CH:15]4[CH2:19][CH2:18][CH:17]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:16]4)=[N:13][C:9]=3[C:8]=2[F:41])=[CH:5][CH:6]=1
Reactant: CCOC(=O)C1CCC(Oc2nc3c(F)c(-c4ccc(-c5ccccc5)cc4)c(F)cc3n2Cc2ccc(-c3ccccc3)cc2)C1
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1=CCC=CC1
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOC(=O)C1CCC(Oc2nc3c(F)c(-c4ccc(-c5ccccc5)cc4)c(F)cc3[nH]2)C1

Procedure:
To a solution of ethyl 3-{[5-(biphenyl-4-yl)-1-(biphenyl-4-ylmethyl)-4,6-difluoro-1H-benzimidazol-2-yl]oxy}cyclopentanecarboxylate (0.088 g, 0.140 mmol) and Pd(OH)2 (0.026 g, 0.036 mmol) in 1.5 mL of EtOAc and 0.75 mL of EtOH was added 1,4-cyclohexadiene (0.337 mL, 3.60 mmol). The resulting black suspension was microwaved at 130° C. for 2 h, and then filtered through a Celite™ pad eluting with 100% EtOAc. The resulting filtrate was then concentrated in vacuo. Purification of the resulting residue by reverse phase Gilson™ HPLC (30-100% MeCN/H2O) gave the title compound. LCMS: calculated for C27H24F2N2O3 462.49, observed m/e 462.9 (M+H)+484.9 (M+Na) (Rt 2.45/4 min).
Reaction SMILES: O[CH2:2][C:3]1[S:7][C:6]([C:8]([O:10][CH3:11])=[O:9])=[CH:5][CH:4]=1.S(Cl)([Cl:14])=O>C(Cl)(Cl)Cl>[Cl:14][CH2:2][C:3]1[S:7][C:6]([C:8]([O:10][CH3:11])=[O:9])=[CH:5][CH:4]=1
Reactant: O=S(Cl)Cl
Reactant: COC(=O)c1ccc(CO)s1
Solvent: ClC(Cl)Cl
Product: COC(=O)c1ccc(CCl)s1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 111.8 %

Procedure:
To a solution of methyl 5-(hydroxymethyl)thiophene-2-carboxylate (1.440 g, 8.362 mmol) in anhydrous chloroform (7.5 ml) was added dropwise thionyl chloride (3.62 ml, 50.17 mmol) at 0° C. After stirring at room temperature for 1.5 hrs, the mixture was concentrated under reduced pressure. The residue was dissolved in anhydrous chloroform (10 ml), and the mixture was concentrated again under reduced pressure. This operation was repeated 3 times to remove thionyl chloride azeotropically. The residue was dried under reduced pressure to give crude methyl 5-(chloromethyl)thiophene-2-carboxylate (1.782 g) as a brown oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:29]=[CH:30][CH:31]=1)[CH2:6][C:7]1[O:11][C:10]([NH:12][C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[N:18](C(OC(C)(C)C)=O)[N:17]=[CH:16]3)=[N:9][N:8]=1.[ClH:32]>O1CCOCC1>[ClH:32].[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:29]=[CH:30][CH:31]=1)[CH2:6][C:7]1[O:11][C:10]([NH:12][C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[NH:18][N:17]=[CH:16]3)=[N:9][N:8]=1
Reactant: COc1cccc(Cc2nnc(Nc3ccc4c(cnn4C(=O)OC(C)(C)C)c3)o2)c1
Agent: Cl
Solvent: C1COCCO1
Product: COc1cccc(Cc2nnc(Nc3ccc4[nH]ncc4c3)o2)c1
Yield: 94 %

Procedure:
250 mg of tert-butyl 5-[5-(3-methoxybenzyl)-1,3,4-oxadiazol-2-ylamino]-indazole-1-carboxylate are stirred in 10 ml of 4N HCl in dioxane in a screw-lid vial until the starting material has completely reacted. The reaction solution is evaporated, and the residue is stirred with ethyl acetate and filtered off with suction, giving 200 mg of 5-[5-(3-methoxybenzyl)-1,3,4-oxadiazol-2-ylamino]-1H-indazole hydrochloride (94%); MS-FAB (M+H+)=322.34; Rf (polar method): 1.687 min.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1.[Br:11]Br>C(O)(=O)C>[Br:11][CH2:9][C:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=1)=[O:10]
Reactant: CC(=O)c1cccc(Br)c1
Reactant: BrBr
Solvent: CC(=O)O
Product: O=C(CBr)c1cccc(Br)c1
Temperature: 60 °C

Procedure:
Into a 500-mL 3-necked round-bottom flask, was placed a solution of 1-(3-bromophenyl)ethanone (40 g, 202.02 mmol, 1.00 equiv) in acetic acid (200 mL). This was followed by the addition of a solution of Br2 (32 g, 200.00 mmol) in acetic acid (50 mL) dropwise with stirring at 60° C. The resulting solution was stirred for 3 h at 60° C. in an oil bath. The resulting mixture was concentrated under vacuum. The crude product was re-crystallized from petroleum ether:ethyl acetate in the ratio of 8:1. This resulted in 24 g (43%) of 2-bromo-1-(3-bromophenyl)ethanone as a yellow solid.
Reaction SMILES: Cl[C:2]1[S:6][N:5]=[C:4]([S:7][CH2:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)[N:3]=1.[CH2:16]([OH:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[H-].[Na+].[Cl-].[Na+]>CN(C)C=O>[CH2:16]([O:23][C:2]1[S:6][N:5]=[C:4]([S:7][CH2:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)[N:3]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: OCc1ccccc1
Reactant: Clc1ccc(CSc2nsc(Cl)n2)cc1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Clc1ccc(CSc2nsc(OCc3ccccc3)n2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 76.5 %

Procedure:
Into 3 ml of N,N-dimethylformamide were dissolved 416 mg of 5-chloro-3-(4-chlorobenzylthio)-1,2,4-thiadiazole and 162 mg of benzyl alcohol, 48 mg of sodium hydride (60% in oil) was added thereto under ice-cooling, and the reaction mixture was stirred for 15 minutes under ice-cooling and for 1 hour at room temperature. The reaction mixture was added to saturated sodium chloride aqueous solution, and extracted with t-butyl methyl ether. The organic layer was concentrated, and the residue obtained was subjected to silica gel column chromatography to give 400 mg of 5-benzyloxy-3-(4-chlorobenzyl)thio-1,2,4-thiadiazole (hereinafter, referred to as the present compound (32)).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]=[C:12]1[NH:16][C:15]([CH3:18])([CH3:17])[CH2:14][S:13]1.[CH3:19][C:20](=[CH2:23])[CH2:21][Br:22]>>[BrH:22].[CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]=[C:12]1[N:16]([CH2:21][C:20]([CH3:23])=[CH2:19])[C:15]([CH3:18])([CH3:17])[CH2:14][S:13]1
Reactant: C=C(C)CBr
Reactant: Cc1cc([N+](=O)[O-])ccc1N=C1NC(C)(C)CS1
Product: Br
Product: C=C(C)CN1C(=Nc2ccc([N+](=O)[O-])cc2C)SCC1(C)C

Procedure:
1,1-Dimethyl-2-hydroxyamine was converted to 1,1-dimethyl-2-chloroethylammonium chloride according to Method B7a. 2-Methyl-4-nitrophenyl isothiocyanate was reacted with 1,1-dimethyl-2-chloroethylammonium chloride according to Method C1a to give 2-(2-methyl-4-nitrophenylimino)-4,4-dimethyl-1,3-thiazolidine. The thiazolidine was reacted with 2-methylprop-2-en-1-yl bromide according to Method D2g to afford 2-(2-methyl-4-nitrophenylimino)-4,4-dimethyl-3-(2-methylprop-2-en-1-yl)-1,3-thiazolidine HBr salt.
Reaction SMILES: [CH3:1]OC.[CH3:4][C@@H:5]1[NH:40][C:38](=[O:39])[C@@H:37]2[N:41]([CH3:44])[C:42](=[O:43])[C@@H:21]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([O:29][C:30]4[CH:35]=[C:34]([CH2:36]2)[CH:33]=[CH:32][C:31]=4[OH:45])=[CH:25][CH:24]=3)[N:20]([CH3:46])[C:18](=[O:19])[C@@H:17]([CH3:47])[NH:16][C:14](=[O:15])[C@H:13]([CH2:48][C:49]2[CH:54]=[CH:53][C:52]([O:55][CH3:56])=[CH:51][CH:50]=2)[N:12]([CH3:57])[C:10](=[O:11])[C@H:9]([CH3:58])[NH:8][C:6]1=[O:7].C[C@@H]1NC(=O)[C@@H]2N(C)C(=O)[C@@H](CC3C=CC(OC4C=C(C2)C=CC=4O)=CC=3)N(C)C(=O)[C@@H](C)NC(=O)[C@H](CC2C=CC(OC)=CC=2)N(C)C(=O)[C@H](C)NC1=O.C[C@@H]1NC(=O)[C@@H]2N(C)C(=O)[C@@H](CC3C=CC(OC4C=C(C2)C=CC=4O)=CC=3)N(C)C(=O)[C@@H](C)NC(=O)[C@H](CC2C=CC(OC)=CC=2)N(C)C(=O)[C@H](C)NC1=O.C[C@@H]1NC(=O)[C@@H]2N(C)C(=O)[C@@H](CC3C=CC(OC4C=C(C2)C=CC=4O)=CC=3)N(C)C(=O)[C@@H](C)NC(=O)[C@H](CC2C=CC(OC)=CC=2)N(C)C(=O)[C@H](C)NC1=O.O.O.O.O.O.CI>COCCOC>[CH3:4][C@H:5]1[NH:40][C:38](=[O:39])[C@H:37]2[N:41]([CH3:44])[C:42](=[O:43])[C@H:21]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([O:29][C:30]4[CH:35]=[C:34]([CH2:36]2)[CH:33]=[CH:32][C:31]=4[O:45][CH3:1])=[CH:25][CH:24]=3)[N:20]([CH3:46])[C:18](=[O:19])[C@H:17]([CH3:47])[NH:16][C:14](=[O:15])[C@H:13]([CH2:48][C:49]2[CH:54]=[CH:53][C:52]([O:55][CH3:56])=[CH:51][CH:50]=2)[N:12]([CH3:57])[C:10](=[O:11])[C@H:9]([CH3:58])[NH:8][C:6]1=[O:7]
Reactant: COC
Reactant: COc1ccc(C[C@H]2C(=O)N[C@H](C)C(=O)N(C)[C@@H]3Cc4ccc(cc4)Oc4cc(ccc4O)C[C@H](C(=O)N[C@@H](C)C(=O)N[C@@H](C)C(=O)N2C)N(C)C3=O)cc1
Solvent: COCCOC
Solvent: CI
Solvent: O
Product: COc1ccc(C[C@H]2C(=O)N[C@@H](C)C(=O)N(C)[C@H]3Cc4ccc(cc4)Oc4cc(ccc4OC)C[C@@H](C(=O)N[C@H](C)C(=O)N[C@@H](C)C(=O)N2C)N(C)C3=O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In 10 ml of anhydrous 1,2-dimethoxy ethane, 100 mg of the methylether derivative of TPC-A was dissolved and 240 mg of potassium fluoride-alumina and excess amount of methyl iodide were added and the mixture was shielded from the light while stirring at room temperature overnight. After completion of the reaction, the solution was filtered, the filtrate was subjected to distillation in vacuo to remove solvent and the residue obtained was purified by P-TLC followed by the recrystallization from methanol to obtain N-methyl derivative of the methylether of TPC-A (98 mg) as colorless crystal having m.p. of 285° to 292° C. (decomp) and [α]D27 of -166° (CHCl3).
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].[F:4][CH:5]([F:35])[C:6]([N:8]1[C@H:12]([CH2:13][F:14])[C@@H:11]([C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:22]=[CH:23][C:24]([CH2:27]OS(C)(=O)=O)=[N:25][CH:26]=3)=[CH:17][CH:16]=2)[O:10][C:9]1([CH3:34])[CH3:33])=[O:7]>O1CCCC1>[CH2:1]([NH:3][CH2:27][C:24]1[N:25]=[CH:26][C:21]([C:18]2[CH:19]=[CH:20][C:15]([C@H:11]3[O:10][C:9]([CH3:34])([CH3:33])[N:8]([C:6](=[O:7])[CH:5]([F:35])[F:4])[C@@H:12]3[CH2:13][F:14])=[CH:16][CH:17]=2)=[CH:22][CH:23]=1)[CH3:2]
Reactant: CC1(C)O[C@H](c2ccc(-c3ccc(COS(C)(=O)=O)nc3)cc2)[C@@H](CF)N1C(=O)C(F)F
Reactant: CCN
Solvent: C1CCOC1
Product: CCNCc1ccc(-c2ccc([C@H]3OC(C)(C)N(C(=O)C(F)F)[C@@H]3CF)cc2)cn1
Reaction time: 8 h
Yield: 544.8 %

Procedure:
To a stirred solution of ethylamine (2.0M solution in tetrahydrofuran; 0.31 mL, 0.027 mmol) in tetrahydrofuran (5 mL) is added methanesulfonic acid 5-{4-[(4S,5R)-3-(2,2-difluoro-acetyl)-4-fluoromethyl-2,2-dimethyl-oxazolidin-5-yl]-phenyl}-pyridin-2-ylmethyl ester (0.1 g, 0.212 mmol) at room temperature then stirred overnight. Solvent is evaporated in vacuo. The crude material is purified by combi-flash chromatography using 10% methanol in CH2Cl2 as an eluent to afford the title compound (0.062 g). 1H-NMR (400 MHz, DMSO-d6) δ: 1.09 (t, J=7.12 Hz, 3H), 1.52 (s, 3H), 1.60 (S, 3H), 2.66-2.71 (q, 2H), 3.96 (s, 2H), 4.51-4.56 (m, 0.5H), 4.57-4.58 (m, 1H), 4.59-4.69 (m, 0.5H), 4.70-4.82 (m, 1H), 5.27 (d, J=3.56 Hz, 1H), 6.64 (t, J=52.4 Hz, 1H), 7.53 (d, J=8.2 Hz, 1H), 7.60 (d, J=8.12 Hz, 2H), 7.79 (d, J=8.2 Hz, 2H), 8.09-8.11 (dd, J1=2.28 Hz, J2=8.08 Hz, 1H), 8.86 (d, J=2.08 Hz, 1H). LC-MS (m/z): [M+H]=422.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:12](O)[CH3:13].P(Br)(Br)[Br:16].C([O-])(O)=O.[Na+]>C(Cl)Cl>[Br:16][CH:12]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([C:8]([F:11])([F:10])[F:9])[C:2]=1[Cl:1])[CH3:13]
Reactant: BrP(Br)Br
Reactant: CC(O)c1cccc(C(F)(F)F)c1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(Br)c1cccc(C(F)(F)F)c1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 194.8 %

Procedure:
To an ice cooled solution of (±)-1-(2-chloro-3-(trifluoromethyl)phenyl)ethanol (1.1 g, 4.9 mmol) in DCM (16 mL) was added phosphorus tribromide (0.23 mL, 2.5 mmol) dropwise. The reaction was allowed to warm to rt and stirred for 3 h. Saturated aqueous NaHCO3 was added, and the mixture was extracted with DCM (×3). The combined organic extracts were dried (Na2SO4), filtered, and concentrated to give the desired product as a yellow oil (1.4 g, 97%). 1H NMR (400 MHz, CDCl3) δ 7.93-7.81 (m, 1H), 7.69-7.64 (m, 1H), 7.42 (t, J=7.9 Hz, 1H), 5.73 (q, J=7.0 Hz, 1H), 2.05 (d, J=7.0 Hz, 3H).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH2:5]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[N:23]=[C:22]2[C:18](=[N:19][CH:20]=[N:21]2)[C:17](=[O:24])[N:16]=1)[CH2:6][CH3:7].[OH-].[NH4+]>S(=O)(=O)(O)O>[CH2:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N+:1]([O-:4])=[O:2])=[CH:11][C:10]=1[C:15]1[N:23]=[C:22]2[C:18](=[N:19][CH:20]=[N:21]2)[C:17](=[O:24])[N:16]=1)[CH2:6][CH3:7]
Reactant: CCCOc1ccccc1C1=NC(=O)C2=NC=NC2=N1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Agent: [NH4+]
Agent: [OH-]
Product: CCCOc1ccc([N+](=O)[O-])cc1C1=NC(=O)C2=NC=NC2=N1
Temperature: 0 °C

Procedure:
A mixture of fuming nitric acid (0.23 ml) and sulphuric acid (4 ml) was added dropwise to a stirred solution of 2-(2-propoxyphenyl)purin-6-one (1.0 g) in sulphuric acid (4 ml) at 0 to -5° C. The temperature was maintained between −5° C. and +4° C. for 20 hours and then the mixture was poured into ice-water. The filtered solution was treated with concentrated ammonium hydroxide to pH 9 to give a crude product, 0.55 g. Recrystallisation twice from aqueous ethanol then once from acetonitrile gave the title compound, 0.2 g, m.p. 254-256° C.
Reaction SMILES: N1C=CC=CC=1.[CH3:7][C:8]([CH3:15])([C:12](Cl)=[O:13])[C:9](Cl)=[S:10].[Cl:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH2:23][NH:24][OH:25]>C(Cl)Cl>[Cl:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH2:23][N:24]1[C:9](=[S:10])[C:8]([CH3:15])([CH3:7])[C:12](=[O:13])[O:25]1
Reactant: CC(C)(C(=O)Cl)C(=S)Cl
Reactant: ONCc1ccccc1Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC1(C)C(=O)ON(Cc2ccccc2Cl)C1=S
Temperature: -40 °C
Reaction time: 1 h
Yield: 32.7 %

Procedure:
A stirred solution of 9.5 grams (0.12 mole) of pyridine in 170 ml of methylene chloride under an argon atmosphere was cooled to -10° C. and a solution of 11.1 grams (0.06 mole) of dimethylthiomalonyl chloride in 30 ml of methylene chloride was added slowly. The reaction mixture was cooled to -40° C. and 9.5 grams (0.06 mole) of N-(2-chlorophenylmethyl)hydroxylamine was added in one portion. The addition caused the reaction mixture temperature to quickly rise to -20° C. The reaction mixture was stirred at -20° C. for one hour, then was diluted with 150 ml of methylene chloride. The solution was washed with 100 ml of water, two portions of 75 ml each of aqueous 2 N hydrochloric acid, and finally, 50 ml of water. The organic layer was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residual oil. The oil was purified by column chromatography using 450 grams of silica gel. Elution was accomplished with chloroform. Early fractions from the chromatography yielded 5.3 grams of 2-[(2-chlorophenyl)methyl]-4,4-dimethylisoxazolidine-5-one-3-thione; mp 51°-53° C. Later fractions were combined to give 2.2 grams of 2-[(2-chlorophenyl)methyl]-4,4-dimethylisoxazolidine-3-one-5-thione as an oil. The nmr and the ir spectra were consistent with the proposed structure.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][S:15](/[CH:18]=[CH:19]/[C:20]2[S:30][C:29]3[N:31]4[C:22](=[CH:23][N:24]=[C:25]4[CH:26]=[CH:27][CH:28]=3)[CH:21]=2)(=[O:17])=[O:16])[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:32]>C(O)C>[ClH:32].[ClH:32].[NH:8]1[CH2:13][CH2:12][CH:11]([CH2:14][S:15](/[CH:18]=[CH:19]/[C:20]2[S:30][C:29]3[N:31]4[C:22](=[CH:23][N:24]=[C:25]4[CH:26]=[CH:27][CH:28]=3)[CH:21]=2)(=[O:17])=[O:16])[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC(CS(=O)(=O)/C=C/C2=Cc3cnc4cccc(n34)S2)CC1
Agent: Cl
Solvent: CCO
Product: O=S(=O)(/C=C/C1=Cc2cnc3cccc(n23)S1)CC1CCNCC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To the above crude (E)-4-[2-[1-(tert-butoxycarbon-yl)piperidin-4-ylmethanesulfonyl]vinyl]-5-thia-1,8b-diazaacenaphthylene was added 3 ml of concentrated hydrochloric acid, and the mixture was stirred at room temperature for 10 minutes. To this reaction mixture was added ethanol, and the resulting precipitate was recovered by filtration and rinsed serially with ethanol and diethyl ether to provide the title compound.