Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[C:7]([OH:9])=O.C(Cl)(=O)C([Cl:13])=O>C(Cl)Cl.CN(C=O)C>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[C:7]([Cl:13])=[O:9]
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)C1CCCCO1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)C1CCCCO1
Temperature: 25 °C
Reaction time: 18 h
Yield: 99.6 %

Procedure:
To a solution of tetrahydro-pyran-2-carboxylic acid (6.94 g, 47.96 mmol) in DCM (200 mL) are added oxalyl chloride (4.81 mL, 56.83 mmol) as a solution in DCM (50 mL) and DMF (3 drops). The reaction is stirred at room temperature for 18 h, then concentrated under reduced pressure to afford 7.1 g of tetrahydro-pyran-2-carbonyl chloride, which is used in the next step. Yield: 99%; by 58° C., 1 mm Hg; 1H NMR (250 MHz, CHLOROFORM-d) δ ppm 1.49-1.98 (5H, m), 2.02-2.19 (1H, m), 3.46-3.66 (1H, m), 3.96-4.12 (1H, m), 4.24 (1H, dd, J=9.14, 3.20 Hz)
Reaction SMILES: [Br:1][C:2]1[C:7]2[CH2:8][C:9]([CH3:12])([CH3:11])[O:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.S(OOS([O-])(=O)=O)([O-])(=O)=[O:14].[K+].[K+]>O.C(#N)C.O.O.O.O.O.S([O-])([O-])(=O)=O.[Cu+2]>[Br:1][C:2]1[C:7]2[C:8](=[O:14])[C:9]([CH3:12])([CH3:11])[O:10][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CC1(C)Cc2c(Br)cccc2O1
Reactant: O=S(=O)([O-])OOS(=O)(=O)[O-]
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CC1(C)Oc2cccc(Br)c2C1=O
Yield: 67 %

Procedure:
Under a nitrogen atmosphere, a stirred solution of 3.0 grams (0.013 mole) 4-bromo-2,3-dihydro-2,2-dimethylbenzofuran, 10.7 grams (0.039 mole) of potassium persulfate, and 3.3 grams (0.013 mole) of copper(II) sulfate pentahydrate in 30 mL of water and 30 mL of acetonitrile was heated at reflux for one hour. After this time the reaction mixture was poured into 200 mL of water. The mixture was then extracted with one 200 mL portion of diethyl ether. The extract was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residual oil. The oil was subjected to column chromatography on silica gel. Elution was accomplished using 1:1 petroleum ether and methylene chloride. The product-containing fractions were combined and concentrated under reduced pressure, yielding 2.1 grams of 4-bromo-2,3-dihydro-2,2-dimethyl-3-benzofuranone. The NMR spectrum was consistent with the proposed structure. Steps A through C were repeated.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1.Cl[C:13]1[N:18]=[C:17]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([N:26]3[CH:30]=[C:29]([CH3:31])[N:28]=[CH:27]3)=[C:22]([O:32][CH3:33])[CH:21]=2)[CH:16]=[CH:15][CH:14]=1>>[CH3:33][O:32][C:22]1[CH:21]=[C:20]([NH:19][C:17]2[CH:16]=[CH:15][CH:14]=[C:13]([NH:7][C:6]3[CH:8]=[CH:9][C:3]([C:2]([F:10])([F:11])[F:1])=[CH:4][CH:5]=3)[N:18]=2)[CH:25]=[CH:24][C:23]=1[N:26]1[CH:30]=[C:29]([CH3:31])[N:28]=[CH:27]1
Reactant: COc1cc(Nc2cccc(Cl)n2)ccc1-n1cnc(C)c1
Reactant: Nc1ccc(C(F)(F)F)cc1
Product: COc1cc(Nc2cccc(Nc3ccc(C(F)(F)F)cc3)n2)ccc1-n1cnc(C)c1

Procedure:
Prepared in analogy to example 62 from 4-trifluoromethylaniline and (6-chloro-pyridin-2-yl)-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine. The title compound was obtained as a brownish solid (Yield=18%). MS ISN (m/e): 438.4 (100) [(M−H)−]. 1H NMR (CDCl3, 300 MHz): δ (ppm)=7.64 (s, 1H), 7.60-7.45 (m, 4H), 7.44 (d, 1H), 7.20-7.10 (m, 2H), 6.95 (dxd, 1H), 6.88 (s, 1H), 6.52 (s, 1H), 6.46 (s, 1H), 6.39 (t, 2H), 3.73 (s, 3H), 2.31 (s, 3H).
Reaction SMILES: [N+](C1C=CC(C([O:10][C@H:11]([CH3:41])[C@H:12]([C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:39])([F:38])[F:37])[C:31]=2[F:40])[NH:13][C:14]([N:16]2[CH2:25][CH2:24][C:23]3[CH:22]=[N:21][C:20]([NH:26][CH:27]([CH3:29])[CH3:28])=[N:19][C:18]=3[CH2:17]2)=[O:15])=O)=CC=1)([O-])=O.C([O-])([O-])=O.[K+].[K+].O>CO>[F:40][C:31]1[C:32]([C:36]([F:37])([F:38])[F:39])=[CH:33][CH:34]=[CH:35][C:30]=1[C@H:12]([NH:13][C:14]([N:16]1[CH2:25][CH2:24][C:23]2[CH:22]=[N:21][C:20]([NH:26][CH:27]([CH3:29])[CH3:28])=[N:19][C:18]=2[CH2:17]1)=[O:15])[C@H:11]([OH:10])[CH3:41]
Reactant: CC(C)Nc1ncc2c(n1)CN(C(=O)N[C@@H](c1cccc(C(F)(F)F)c1F)[C@@H](C)OC(=O)c1ccc([N+](=O)[O-])cc1)CC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CC(C)Nc1ncc2c(n1)CN(C(=O)N[C@@H](c1cccc(C(F)(F)F)c1F)[C@@H](C)O)CC2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of (1S,2R)-1-(2-fluoro-3-(trifluoromethyl)phenyl)-1-(2-(isopropylamino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine-7-carboxamido)propan-2-yl 4-nitrobenzoate (40 mg, 0.040 mmol) in MeOH (1 mL) was added 2M K2CO3 (40 μL, 0.079 mmol) at RT. The solution was stirred at RT for 30 min. Water was added and reaction was extracted with DCM. The organic layer was concentrated and the resulting residue was purified by reverse phase column chromatography (SP4) eluting with a MeCH/H2O gradient (5 to 95% MeCN). The recovered product was further purified by SiO2 chromatography eluting with a MeOH/EtOAc (1 to 3% MeOH) to afford 0.6 mg (3.3%) of I-19: LCMS (ACPI-pos) m/z 420.3 (M+H)+.
Reaction SMILES: [Li+].[OH-].[O:3]=[C:4]1[N:10]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C@H:20]([CH2:42][C:43]3[CH:48]=[C:47]([C:49]([F:52])([F:51])[F:50])[C:46]([NH2:53])=[C:45]([Cl:54])[CH:44]=3)[C:21]([N:23]3[CH2:28][CH2:27][CH:26]([N:29]4[CH2:34][CH2:33][CH:32]([CH2:35][CH2:36][C:37]([O:39]CC)=[O:38])[CH2:31][CH2:30]4)[CH2:25][CH2:24]3)=[O:22])=[O:18])[CH2:13][CH2:12]2)[CH2:9][CH2:8][C:7]2[CH:55]=[CH:56][CH:57]=[CH:58][C:6]=2[NH:5]1>O.C1COCC1>[O:3]=[C:4]1[N:10]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C@H:20]([CH2:42][C:43]3[CH:48]=[C:47]([C:49]([F:51])([F:50])[F:52])[C:46]([NH2:53])=[C:45]([Cl:54])[CH:44]=3)[C:21]([N:23]3[CH2:24][CH2:25][CH:26]([N:29]4[CH2:30][CH2:31][CH:32]([CH2:35][CH2:36][C:37]([OH:39])=[O:38])[CH2:33][CH2:34]4)[CH2:27][CH2:28]3)=[O:22])=[O:18])[CH2:13][CH2:12]2)[CH2:9][CH2:8][C:7]2[CH:55]=[CH:56][CH:57]=[CH:58][C:6]=2[NH:5]1
Reactant: CCOC(=O)CCC1CCN(C2CCN(C(=O)[C@@H](Cc3cc(Cl)c(N)c(C(F)(F)F)c3)OC(=O)N3CCC(N4CCc5ccccc5NC4=O)CC3)CC2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Nc1c(Cl)cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCC(N3CCC(CCC(=O)O)CC3)CC2)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A solution of 2.40 mg (0.10 mmol) LiOH in 1 mL water was added to 50 mg (0.06 mmol) (R)-1-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-2-[4-(2-ethoxycarbonyl-ethyl)-1,4′-bipiperidinyl-1′-yl]-2-oxo-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate in 3 mL THF and the reaction mixture was stirred for 4 h at RT. THF was eliminated in a nitrogen stream, the residue was taken up in a little water and purified by HPLC; the fractions containing the product were combined and lyophilised.
Reaction SMILES: C(O[CH:4](OCC)[CH2:5][N:6]([C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20])[C:7]1[CH:12]=[C:11]([O:13][CH3:14])[C:10]([O:15][CH3:16])=[C:9]([O:17][CH3:18])[CH:8]=1)C.[ClH:32].[OH:33][C:34]1[CH:35]=[C:36]([CH:40]=[CH:41][C:42]=1[OH:43])[CH2:37][CH2:38][NH2:39].C(O)CCC>O>[ClH:32].[CH2:22]([O:21][C:19]([N:6]([CH2:5][CH:4]1[C:40]2[C:36](=[CH:35][C:34]([OH:33])=[C:42]([OH:43])[CH:41]=2)[CH2:37][CH2:38][NH:39]1)[C:7]1[CH:8]=[C:9]([O:17][CH3:18])[C:10]([O:15][CH3:16])=[C:11]([O:13][CH3:14])[CH:12]=1)=[O:20])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CCOC(CN(C(=O)OCc1ccccc1)c1cc(OC)c(OC)c(OC)c1)OCC
Reactant: NCCc1ccc(O)c(O)c1
Agent: Cl
Solvent: CCCCO
Solvent: O
Product: COc1cc(N(CC2NCCc3cc(O)c(O)cc32)C(=O)OCc2ccccc2)cc(OC)c1OC
Yield: 70.1 %

Procedure:
N-benzyloxycarbonyl-3,4,5-trimethoxyanilinoacetaldehyde diethyl acetal (21 g) and 3,4-dihydroxyphenethylamine hydrochloride (8.3 g) were added to a mixture of n-butyl alcohol (210 ml) and water (30 ml) and then the mixture was refluxed for 11 hours in a stream of nitrogen. In the course of the reaction, amounts of the above-mentioned acetal (2.1 g, 2.1 g and 4.2 g) were added to the mixture after 5 hours, 6 hours and 7 hours, respectively, from the beginning of the reaction, respectively. The reaction mixture was concentrated to dryness under reduced pressure and the residue was washed with ether and acetone to give 1-(N-benzyloxycarbonyl-3,4,5-trimethoxyanilinomethyl)-6,7-dihydroxy,1,2,3,4-tetrahydroisoquinoline hydrochloride (16.3 g). The product was recrystallized from a mixed solvent of ethanol and ether to give a pure product, mp 197° to 199° C. (dec).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[F:5][C:6]1[CH:7]=[C:8]([NH2:13])[CH:9]=[CH:10][C:11]=1[F:12]>N1C=CC=CC=1>[F:5][C:6]1[CH:7]=[C:8]([NH:13][C:1](=[O:3])[CH3:2])[CH:9]=[CH:10][C:11]=1[F:12]
Reactant: CC(=O)Cl
Reactant: Nc1ccc(F)c(F)c1
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc(F)c(F)c1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
1 Acetyl chloride (82.61 mL, 774.50 mmol) was added slowly to a solution of 3,4-Difluoro-phenylamine (100 g, 774.50 mmol) in pyridine (250 mL) in ice bath. The mixture was stirred at 0° C. for 45 min then was kept at room temperature for 3 hrs. Solvent was removed under reduced pressure. The residue was crystallized in acetone/water to give a solid. 1H NMR (300 MHz, CDCl3): δ 7.86 (br, 1H), 7.62-7.55 (m, 1H), 7.07 (m, 2H), 2.16 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6](B(O)O)[CH:7]=1.I[C:13]1[CH:18]=[CH:17][N:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([C:13]2[CH:18]=[CH:17][N:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=2)[CH:7]=1
Reactant: OB(O)c1cc(F)ccc1O
Reactant: FC(F)(F)c1cc(I)ccn1
Product: Oc1ccc(F)cc1-c1ccnc(C(F)(F)F)c1

Procedure:
(5-Fluoro-2-hydroxyphenyl)boronic acid and 4-iodo-2-(trifluoromethyl)pyridine were reacted under Suzuki conditions to produce 4-fluoro-2-[2-(trifluoromethyl)pyridin-4-yl]phenol.
Reaction SMILES: [OH-].[K+].[CH2:3]([O:5][C:6](=[O:28])[CH:7]([CH2:13][C:14]1[CH:15]=[N:16][C:17]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[CH:18][CH:19]=1)[C:8]([O:10]CC)=[O:9])[CH3:4]>C(O)C.C(Cl)Cl>[CH2:3]([O:5][C:6](=[O:28])[CH:7]([CH2:13][C:14]1[CH:15]=[N:16][C:17]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[CH:18][CH:19]=1)[C:8]([OH:10])=[O:9])[CH3:4]
Reactant: CCOC(=O)C(Cc1ccc(NC(=O)OC(C)(C)C)nc1)C(=O)OCC
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: ClCCl
Product: CCOC(=O)C(Cc1ccc(NC(=O)OC(C)(C)C)nc1)C(=O)O
Temperature: 25 °C
Reaction time: 18 h
Yield: 49.7 %

Procedure:
A solution of KOH (0.37 g, 6.54 mmol) in ethanol (5 mL) was added to a solution of 2-(6-tert-butoxycarbonylamino-pyridin-3-ylmethyl)-malonic acid diethyl ester (2.18 g, 5.95 mmol) in ethanol (25 mL) and methylene chloride (10 mL) at 0° C. The mixture was stirred for 18 h at room temperature. The mixture was concentrated under reduced pressure and the residue dissolved in water. The aqueous layer was washed with ether, acidified to pH 4 by 1M HCl and extracted with methylene chloride. The organic layer was washed with water, brine and dried. After filtration and concentration under reduced pressure, the crude product was purified by flash chromatography (methanol/CH2Cl2, 1:20) to yield 2-(6-tert-butoxycarbonylamino-pyridin-3-ylmethyl)-malonic acid monoethyl ester (1.00 g, 50%).
Reaction SMILES: ClC(Cl)(Cl)C(C1[C:13]2[C:8](=[N:9][CH:10]=[CH:11][C:12]=2[O:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][C:16]=2[F:24])[NH:7][CH:6]=1)=O.CO.C1COCC1.[OH-].[Na+].C[CH2:37][O:38][C:39]([CH3:41])=[O:40]>>[F:24][C:16]1[CH:17]=[C:18]([N+:21]([O-:23])=[O:22])[CH:19]=[CH:20][C:15]=1[O:14][C:12]1[CH:11]=[CH:10][N:9]=[C:8]2[NH:7][CH:6]=[C:41]([C:39]([O:38][CH3:37])=[O:40])[C:13]=12
Reactant: O=C(c1c[nH]c2nccc(Oc3ccc([N+](=O)[O-])cc3F)c12)C(Cl)(Cl)Cl
Reactant: CCOC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1c[nH]c2nccc(Oc3ccc([N+](=O)[O-])cc3F)c12
Temperature: 25 °C
Reaction time: 3 h
Yield: 61 %

Procedure:
To a solution of 2,2,2-trichloro-1-(4-(2-fluoro-4-nitrophenoxy)-1H-pyrrolo[2,3-b]pyridin-3-yl)ethanone (490 mg, 1.17 mmol, See: Step A of Example 270) in a mixed solvent (10 mL of MeOH and 10 mL of THF) was added 1 N NaOH (10 mL, 10 mmol). The reaction mixture was stirred at room temperature for 3 h, and diluted with EtOAc (30 mL). The organic layer was washed with sat. aq. NaHCO3, solution, dried and concentrated in vacuo to give the desired product (235 mg, 61%) as a light brown solid. MS(ESI+) m/z 332.2 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][CH:17]=3)[NH:13][CH:14]=2)=[CH:6][CH:5]=1.F[C:25]1[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=1>>[CH3:1][O:2][C:3](=[O:23])[C:4]1[CH:5]=[CH:6][C:7]([C:10]2[N:11]=[C:12]([CH2:15][C:16]3[CH:17]=[CH:18][C:19]([Br:22])=[CH:20][CH:21]=3)[N:13]([C:25]3[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=3)[CH:14]=2)=[CH:8][CH:9]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: COC(=O)c1ccc(-c2c[nH]c(Cc3ccc(Br)cc3)n2)cc1
Product: COC(=O)c1ccc(-c2cn(-c3ccc([N+](=O)[O-])cc3)c(Cc3ccc(Br)cc3)n2)cc1

Procedure:
4-[2-(4-Bromo-benzyl)-1H-imidazol-4-yl]-benzoic acid methyl ester (12.3 g, 33 mmol) was treated as described in general procedure B using 1-fluoro-4-nitrobenzene to give 4-[2-(4-bromo-benzyl)-1-(4-Nitro-phenyl)-1H-imidazol-4-yl]-benzoicacid methyl ester.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([CH:8]=[O:9])[N:5]([CH3:7])[CH:6]=1.C([Sn](CCCC)(CCCC)[C:15]1[S:16][CH:17]=[CH:18][CH:19]=1)CCC>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.CN(C=O)C>[CH3:7][N:5]1[CH:6]=[C:2]([C:15]2[S:16][CH:17]=[CH:18][CH:19]=2)[N:3]=[C:4]1[CH:8]=[O:9]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccs1
Reactant: Cn1cc(Br)nc1C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: Cn1cc(-c2cccs2)nc1C=O
Temperature: 160 °C
Yield: 50.6 %

Procedure:
A glass vial was charged with 4-bromo-1-methyl-1H-imidazole-2-carbaldehyde (1420 mg, 7.5 mmol), tributyl-(2-thienyl)-stannane (3.50 g, 9.38 mmol), DMF (15 mL) and the slurry was deoxygenated by bubbling argon through then tetrakis(triphenylphosphine)palladium(0) (216 mg, 0.1875 mmol) was added and the vessel sealed and heated in a microwave reactor at 160° C. for 30 minutes. The volatiles were removed in vacuo then EtOAc (50 mL) was added followed by saturated sodium bicarbonate solution (25 mL). The organic layer was separated and the aqueous extracted with EtOAc (50 mL). The combined extracts were dried over Na2SO4, filtered and the volatiles removed in vacuo. The residue was purified by column chromatography on silica gel (Gradient: n-heptane/EtOAc=4/1 to EtOAc 100%) to yield the title compound (730 mg, 51%) as a yellow solid. 1H NMR (500 MHz, CDCl3): δ 9.72 (s, 1H), 7.99 (s, 1H), 7.49-7.47 (m, 1H), 7.40-7.38 (m, 1H), 7.12-7.08 (m, 1H), 3.95 (s, 3H).
Reaction SMILES: Br[C:2]1([CH3:29])[CH:7]([C:8]([O:10][CH2:11][C:12]([Cl:15])([Cl:14])[Cl:13])=[O:9])[N:6]2[C:16](=[O:28])[CH:17]([NH:18][C:19](=[O:27])[CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C@H:5]2[S:4][CH2:3]1.[NH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>C(Cl)Cl.F[B-](F)(F)F.[Ag+]>[NH:30]([CH2:3][C:2]1([CH3:29])[CH:7]([C:8]([O:10][CH2:11][C:12]([Cl:15])([Cl:13])[Cl:14])=[O:9])[N:6]2[C:16](=[O:28])[CH:17]([NH:18][C:19](=[O:27])[CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C@H:5]2[S:4]1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: Nc1ccccc1
Reactant: CC1(Br)CS[C@@H]2C(NC(=O)Cc3ccccc3)C(=O)N2C1C(=O)OCC(Cl)(Cl)Cl
Agent: [Ag+]
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: CC1(CNc2ccccc2)S[C@@H]2C(NC(=O)Cc3ccccc3)C(=O)N2C1C(=O)OCC(Cl)(Cl)Cl
Yield: 48 %

Procedure:
2,2,2-Trichloroethyl 3-bromo-3-methyl-7-(2-phenylacetamido)cepham-4-carboxylate (1.10 g) was dissolved in methylene chloride (15 ml) and to this solution was added aniline (0.28 g). And to the solution was added silver fluoroborate (0.5 g) under stirring under ice-cooling and the mixture was stirred for 4 hours at the same temperature. After the reaction was completed, the reaction mixture was filtered. The filtrate was washed with a dilute aqueour solution of phosphoric acid and then with water, dried over magnesium sulfate and concentrated. The residue was subjected to column chromatography on silica gel (25 g) and eluted with chloroform. The eluate was separated into fractions of each about 20 ml and the second to eighth fractions were collected and then the solvent was distilled off to give 2,2,2-trichloroethyl 2-anilinomethyl-2-methyl-6-(2-phenylacetamido)penam-3-carboxylate (0.54 g), mp 148° to 149° C.
Reaction SMILES: [C:1]1([NH:7][C:8]2[C:13]([NH2:14])=[CH:12][CH:11]=[CH:10][N:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:15][C:16]([CH3:18])=O.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[CH:16]([NH:14][C:13]1[C:8]([NH:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[N:9][CH:10]=[CH:11][CH:12]=1)([CH3:18])[CH3:15]
Reactant: Nc1cccnc1Nc1ccccc1
Reactant: CC(C)=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(C)Nc1cccnc1Nc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.4 %

Procedure:
N2-phenylpyridine-2,3-diamine (14.1 g, 76 mmol) and acetone (8.39 mL, 114 mmol) was added to a solution of acetic acid and dichloromethane. Sodium triacetoxyborohydride (22.59 g, 107 mmol) was added to the reaction mixture and stirred overnight at room temperature. Reaction mixture was quenched with 1N HCl. Organic layer was extracted with ethyl acetate. Ethyl acetate solution was washed with 1N sodium hydroxide solution followed by brine and dried over anhd. MgSO4. N3-isopropyl-N2-phenylpyridine-2,3-diamine (16.3 g, 94% yield) was isolated from crude by column chromatography using hexanes and ethyl acetate as eluent.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][C:5]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:9]([C:10](=[O:14])[CH:11]([CH3:13])[CH3:12])[N:8]=[C:7]([C:15]2[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=2[F:22])[S:6]1.[N:29]#[C:30]Br.C(N(CC)CC)C>C(Cl)Cl>[F:22][C:16]1[CH:17]=[CH:18][C:19]([F:21])=[CH:20][C:15]=1[C:7]1[S:6][C:5]([CH2:4][CH2:3][CH2:2][NH:1][C:30]#[N:29])([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:9]([C:10](=[O:14])[CH:11]([CH3:13])[CH3:12])[N:8]=1
Reactant: CC(C)C(=O)N1N=C(c2cc(F)ccc2F)SC1(CCCN)c1ccccc1
Reactant: N#CBr
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)C(=O)N1N=C(c2cc(F)ccc2F)SC1(CCCNC#N)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1-(2-(3-aminopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-2-methylpropan-1-one (33 mg, 0.0817867 mmol) was weighed into a 10 ml flask and dissolved in 1.0 mL of CH2Cl2, followed by addition of cyanogen bromide (11.2618 mg, 0.106323 mmol) and dropwise addition of triethylamine (0.0398980 mL, 0.286253 mmol). The reaction was then stirred at ambient temperature for 1 hour. The reaction was then concentrated in vacuo and the resulting tan foam was used in the next step without purification.
Reaction SMILES: [CH3:1][C@@H:2]1[C@H:19]([OH:20])[C@@H:18]([CH3:21])[C:16](=[O:17])[C:15]([CH3:23])([CH3:22])[C@@H:14]([OH:24])[CH2:13][C:11](=[O:12])[O:10][C@H:9](/[C:25](/[CH3:33])=[CH:26]/[C:27]2[N:31]=[C:30]([CH3:32])[S:29][CH:28]=2)[CH2:8][CH:7]=[C:6]([CH3:34])[CH2:5][CH2:4][CH2:3]1.CC1(C)O[O:37]1>C(Cl)Cl>[CH3:1][C@@H:2]1[C@H:19]([OH:20])[C@@H:18]([CH3:21])[C:16](=[O:17])[C:15]([CH3:22])([CH3:23])[C@@H:14]([OH:24])[CH2:13][C:11](=[O:12])[O:10][C@H:9](/[C:25](/[CH3:33])=[CH:26]/[C:27]2[N:31]=[C:30]([CH3:32])[S:29][CH:28]=2)[CH2:8][C@@H:7]2[O:37][C@:6]2([CH3:34])[CH2:5][CH2:4][CH2:3]1
Reactant: CC1(C)OO1
Reactant: CC1=CC[C@@H](/C(C)=C/c2csc(C)n2)OC(=O)C[C@H](O)C(C)(C)C(=O)[C@H](C)[C@@H](O)[C@@H](C)CCC1
Agent: C/C1=C/C[C@@H](/C(C)=C/c2csc(C)n2)OC(=O)C[C@H](O)C(C)(C)C(=O)[C@H](C)[C@@H](O)[C@@H](C)CCC1
Solvent: ClCCl
Product: C/C(=C\c1csc(C)n1)[C@@H]1C[C@@H]2O[C@]2(C)CCC[C@H](C)[C@H](O)[C@@H](C)C(=O)C(C)(C)[C@@H](O)CC(=O)O1
Temperature: -50 °C
Reaction time: 1 h

Procedure:
To a solution of desoxyepothilone B (0.0022 g, 0.0041 mmol) in CH2Cl2 (0.25 mL) at −50° C. was added dimethyldioxirane (0.1 mL, 0.0095 mmol) dropwise. The resulting solution was stirred at −50° C. for 1 h. The dimethyldioxirane and solvent were removed by a stream of N2. The residue was purified by flash column chromatography (hexanes/ethyl acetate, 1:1) gave 0.0015 g (70%) of epothiolone B (2) as a pale yellow oil which was identical with an authentic sample in 1H NMR, IR, mass spectrum, and [α]D.
Reaction SMILES: Br[C:2]1[C:3]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[N:4][N:5]([CH3:13])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH2:20]([SH:24])[CH2:21][CH2:22][CH3:23].N1C2C(=CC=CC=2)C=CC=1.Cl>N1C=CC=CC=1>[CH2:20]([S:24][C:2]1[C:3]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[N:4][N:5]([CH3:13])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH2:21][CH2:22][CH3:23]
Reactant: CCCCS
Reactant: Cn1nc(-c2ccccc2)c(Br)c1-c1ccccc1
Agent: Cl
Solvent: c1ccncc1
Solvent: c1ccc2ncccc2c1
Product: CCCCSc1c(-c2ccccc2)nn(C)c1-c1ccccc1
Yield: 97.1 %

Procedure:
A mixture of 4-bromo-1-methyl-3,5-diphenylpyrazole (21 g, 0.0671 mole), copper(1)salt of butanethiol (12.58 g, 0.08 mole), pyridine (10 ml) and quinoline (100 ml) is stirred and heated at 175° C to 180° C for 8 hours. The reaction mixture is cooled, poured into dilute hydrochloric acid (500 ml) and extracted with benzene. The benzene layer is separated and stripped in vacuo to give a brown oil. The oil is slurried with petroleum ether (b.p. 40° C to 60° C), filtered and the filtrate stripped in vacuo to give a brown syrup 21 g (97%), >95% pure by glc.
Reaction SMILES: [F:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([CH2:11][C:12]([O:14]CC)=[O:13])=[C:4]([C:17]#[C:18][Si](C)(C)C)[CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:29]1COC[CH2:30]1.CO>CCOCC>[CH2:29]([CH:11]([C:5]1[CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]([F:1])=[CH:3][C:4]=1[C:17]#[CH:18])[C:12]([OH:14])=[O:13])[CH3:30]
Reactant: C1CCOC1
Reactant: CCOC(=O)Cc1cc([N+](=O)[O-])c(F)cc1C#C[Si](C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CCOCC
Product: C#Cc1cc(F)c([N+](=O)[O-])cc1C(CC)C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Ethyl 2-(4-fluoro-5-nitro-2-(2-(trimethylsilyl)ethynyl)phenyl)acetate (0.85 g, 2.6 mmol) and K2CO3 (3.6 g) were dissolved in THF/MeOH (5:1, 30 mL) and the mixture was stirred overnight at RT. The reaction mixture was diluted with Et2O and washed with sat'd NH4Cl solution. The organic layer was dried (MgSO4), filtered, and concentrated. The residue was purified by silica gel column chromatography to obtain ethyl 2-(2-ethynyl-4-fluoro-5-nitrophenyl)acetic acid.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH2:14][CH2:15][CH2:16][C:17]([C:20]2[CH:25]=[CH:24][C:23]([O:26]C)=[CH:22][CH:21]=2)([CH3:19])[CH3:18])[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br.C(O)(=O)C>O>[O:1]([C:8]1[CH:9]=[C:10]([CH2:14][CH2:15][CH2:16][C:17]([C:20]2[CH:21]=[CH:22][C:23]([OH:26])=[CH:24][CH:25]=2)([CH3:19])[CH3:18])[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(C(C)(C)CCCc2cccc(Oc3ccccc3)c2)cc1
Agent: Br
Solvent: CC(=O)O
Solvent: O
Product: CC(C)(CCCc1cccc(Oc2ccccc2)c1)c1ccc(O)cc1
Temperature: 25 °C
Yield: 87.4 %

Procedure:
A mixture of 5.0 g of 1-(3-phenoxyphenyl)-4-(4-methoxyphenyl)-4-methylpentane, 30 ml of 47% hydrobromic acid and 30 ml of acetic acid was heated under reflux for 8 h. After cooling to room temperature, the reaction mixture was poured into water. After extraction with benzene, the benzene solution was washed with water and dried. Benzene was distilled off under reduced pressure and the obtained oily product was purified according to column chromatography (silica gel, developer: benzene) to obtain 4.2 g of 1-(3-phenoxyphenyl)-4-(4-hydroxyphenyl)-4-methylpentane.