Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([C:12]3[N:16]4[CH:17]=[C:18]([CH:21]([N:26]5[CH2:30][CH2:29][C@H:28]([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[CH2:27]5)[C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:20][C:15]4=[N:14][N:13]=3)=[N:9]2)=[CH:4][CH:3]=1.P([CH:52]1[CH2:57][CH2:56]CCC1)(C1CCCCC1)C1CCCCC1.C1(B(O)O)CC1.C(OCC)(=O)C>C1(C)C=CC=CC=1.O.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH:56]1([C:2]2[CH:11]=[C:10]3[C:5]([CH:6]=[CH:7][C:8]([C:12]4[N:16]5[CH:17]=[C:18]([CH:21]([N:26]6[CH2:30][CH2:29][C@H:28]([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:35])([CH3:37])[CH3:36])[CH2:27]6)[C:22]([F:25])([F:23])[F:24])[CH:19]=[CH:20][C:15]5=[N:14][N:13]=4)=[N:9]3)=[CH:4][CH:3]=2)[CH2:57][CH2:52]1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN(C(c2ccc3nnc(-c4ccc5ccc(Br)cc5n4)n3c2)C(F)(F)F)C1
Reactant: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: OB(O)C1CC1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H]1CCN(C(c2ccc3nnc(-c4ccc5ccc(C6CC6)cc5n4)n3c2)C(F)(F)F)C1
Temperature: 25 °C
Yield: 862.5 %

Procedure:
A solution of tert-butyl (3S)-1-(1-(3-(7-bromo quinolin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)-2,2,2-trifluoroethyl)pyrrolidin-3-ylcarbamate (Example 2, Step A; 0.25 g, 0.42 mmol), Pd(OAc)2 (0.0048 g, 0.021 mmol), P(Cy)3 (0.013 g, 0.047 mmol), and cyclopropylboronic acid (0.073 g, 0.85 mmol) in toluene (4 mL) and water (0.4 mL) was stirred at 100° C. for 6 hours. After cooling to ambient temperature, ethyl acetate (20 mL) and water (5 mL) were added. The organic layer was separated, washed with brine, dried (sodium sulfate), filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (ethyl acetate) to give tert-butyl (3S)-1-(1-(3-(7-cyclopropylquinolin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)-2,2,2-trifluoroethyl)pyrrolidin-3-ylcarbamate (0.224 g, 95.9%) as a solid.
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5]1[CH:6]=[C:7]([CH:13]([N:18]2[C:22](=[O:23])[C:21]3=[CH:24][CH:25]=[CH:26][CH:27]=[C:20]3[C:19]2=[O:28])[CH2:14][C:15](O)=[O:16])[CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH3:3].C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[NH2:42][OH:43]>O1CCCC1>[OH:43][NH:42][C:15](=[O:16])[CH2:14][CH:13]([C:7]1[CH:8]=[CH:9][C:10]([O:11][CH3:12])=[C:5]([O:4][CH:2]([CH3:3])[CH3:1])[CH:6]=1)[N:18]1[C:22](=[O:23])[C:21]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:20]2[C:19]1=[O:28]
Reactant: NO
Reactant: COc1ccc(C(CC(=O)O)N2C(=O)c3ccccc3C2=O)cc1OC(C)C
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: COc1ccc(C(CC(=O)NO)N2C(=O)c3ccccc3C2=O)cc1OC(C)C
Yield: 68.5 %

Procedure:
N-Hydroxy-3-{3-(2-propoxy)-4-methoxyphenyl}-3-phthalimidopropionamide was prepared by the procedure of Example 1 from 3-{3-(2-propoxy)-4-methoxyphenyl}-3-phthalimidopropanoic acid (2.0 g, 5.2 mmol), carbonyldiimidazole (1.02 g, 6.29 mmol), and hydroxylamine hydrochloride (481 mg, 6.92 mmol) in tetrahydrofuran (10 mL) to afford N-hydroxy-3-{3-(2-propoxy)-4-methoxyphenyl}-3-phthalimidopropionamide as a white solid (1.42 g, 68% yield): mp, 119.0-121.0° C.; 1H NMR (DMSO-d6) δ1.24 (d, J=6.0 Hz, 3H, CH3), 1.243 (d, J=6.0 Hz, 3H, CH3), 3.12 (d, J=7.9 Hz, 2H, CH2), 3.71 (s, 3H, CH3), 4.45-4.51 (m, 1H, CH), 5.68 (t, J=7.9 Hz, 1H, NCH), 6.91 (br s, 2H, Ar), 7.05 (br s, 1H, Ar), 7.84-7.86 (m, 4H, Ar), 8.79 (br s, 1H, OH), 10.60 (1H, NH); 13C NMR (DMSO-d6) δ21.80, 21.88, 34.19, 50.13, 55.49, 70.44, 112.18, 114.97, 120.12, 123.11, 131.13, 131.21, 134.59, 146.37, 149.51, 165.99, 167.62; Anal Calcd for C21H22N2O60.9H2O: C, 60.83; H, 5.79; N, 6.76. Found: C, 60.83; H, 5.73; N, 6.56; H2O, 4.02.
Reaction SMILES: C(#N)C.O.CN(C)C1C=CC(C=CC=O)=CC=1.OC(CCCC[C@H]1[C@@H]2[C@@H](NC(N2)=O)CS1)=O.[CH3:34][N:35]([CH2:52][CH2:53][CH2:54][NH:55][C:56]([CH2:58][CH2:59][CH2:60][CH2:61][CH:62]1[S:66][CH2:65][C@@H:64]2[NH:67][C:68]([NH:70][C@H:63]12)=[O:69])=[O:57])[CH2:36][CH2:37][CH2:38][NH:39][C:40]1[CH:45]=[CH:44][C:43]([N:46]=[N+:47]=[N-:48])=[CH:42][C:41]=1[N+:49]([O-:51])=[O:50]>O>[N:46]([C:43]1[CH:44]=[CH:45][C:40]([NH:39][CH2:38][CH2:37][CH2:36][N:35]([CH2:52][CH2:53][CH2:54][NH:55][C:56](=[O:57])[CH2:58][CH2:59][CH2:60][CH2:61][C@H:62]2[C@@H:63]3[C@@H:64]([NH:67][C:68]([NH:70]3)=[O:69])[CH2:65][S:66]2)[CH3:34])=[C:41]([N+:49]([O-:51])=[O:50])[CH:42]=1)=[N+:47]=[N-:48]
Reactant: CN(CCCNC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)CCCNc1ccc(N=[N+]=[N-])cc1[N+](=O)[O-]
Agent: CN(C)c1ccc(C=CC=O)cc1
Agent: O=C(O)CCCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21
Solvent: O
Solvent: CC#N
Product: CN(CCCNC(=O)CCCC[C@@H]1SC[C@@H]2NC(=O)N[C@@H]21)CCCNc1ccc(N=[N+]=[N-])cc1[N+](=O)[O-]

Procedure:
d-Biotinyl-N-hydroxysuccinimide ester (III) was synthesized from d-biotin (I) by the DCC method of Bayer and Wilchek (1980) "Methods of Biochemical Analysis" 26, 1-45 except that the ester was isolated by precipitation from ether and used without further purification. N-(3-Aminopropyl)-N'-(4-azido-2-nitrophenyl)-N-methyl-1,3-propanediamine (VI; approx. 5 mmol) was dissolved in a solution containing d-biotinyl-N-hydroxysuccinimide ester (1.7 g, 5.0 mmol) in pyridine-water (7:3 v/v, 50 ml), and the solution was incubated at 37° C. for 2 h. TLC on alumina with tetrahydrofuran-water (19:1; v/v) showed the reaction to be complete. The solvent was removed and the residue was dissolved in a mixture of 0.5M NaHCO3 (100 ml) and 2-butanol (100 ml). The large volume was necessary to visualize the interface between the phases. The 2-butanol layer was removed, washed successively with water (100 ml) and saturated NaCl (100 ml), and then slowly added to ether (900 ml). The suspension was stirred, the red precipitate was allowed to settle, and the supernatant was decanted. The precipitate was washed with ether (100 ml) and dried in vacuo to give the product (1.33 g, 50% yield from 4-fluoro-3-nitrophenyl azide), m.p. 114.5°-115° C. (corrected). % Elemental analysis calculated for C23H35N9O4S: C 51.8, H 6.6, N 23.6. % Found: C 50,6 H 6.8, N 23.4 (Australian Mineral Development Laboratories). TLC on alumina with methanol showed the product to be a single spot with RF 0.75 (the symmetrical disubstitution product formed from compounds IV and V has RF 0.6). TLC on silica with acetonitrile-water (19:1, v/v), using p-dimethylaminocinnamaldehyde spray to detect biotin derivatives (21), showed the product to be free of compounds I, II and III. Photobiotin is poorly soluble in water.
Reaction SMILES: CS([O:5][C@@H:6]1[CH2:10][CH2:9][N:8]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)[C:7]1=[O:24])(=O)=O.[F:25][C:26]1[CH:27]=[C:28]([CH:33]=[CH:34][C:35]=1O)[C:29]([O:31][CH3:32])=[O:30].C([O-])([O-])=O.[K+].[K+]>CS(C)=O>[F:25][C:26]1[CH:27]=[C:28]([C:29]([O:31][CH3:32])=[O:30])[CH:33]=[CH:34][C:35]=1[O:5][C@H:6]1[CH2:10][CH2:9][N:8]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)[C:7]1=[O:24]
Reactant: CC(C)(C)OC(=O)N1CCC(N2CC[C@@H](OS(C)(=O)=O)C2=O)CC1
Reactant: COC(=O)c1ccc(O)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COC(=O)c1ccc(O[C@H]2CCN(C3CCN(C(=O)OC(C)(C)C)CC3)C2=O)c(F)c1
Temperature: 70 °C
Reaction time: 8 h
Yield: 96.4 %

Procedure:
(R)-tert-butyl 4-(3-(methylsulfonyloxy)-2-oxopyrrolidin-1-yl)piperidine-1-carboxylate (Preparation D; 1.0 g, 2.8 mmol) was dissolved in dry DMSO (15 mL) and methyl 3-fluoro-4-hydroxybenzoate (0.56 g, 3.3 mmol) and K2CO3 (0.46 g, 3.3 mmol) were added and the reaction heated to 70° C. under nitrogen. The reaction became purple and then black. The reaction was cooled to ambient temperature after 3 hours, stirred at ambient temperature overnight, partitioned between water and EtOAc, extracted with EtOAc, washed with brine, dried over Na2SO4, filtered and concentrated. The residue was purified over silica gel (60% EtOAc in hexanes) to afford (S)-tert-butyl 4-(3-(2-fluoro-4-(methoxycarbonyl)phenoxy)-2-oxopyrrolidin-1-yl)piperidine-1-carboxylate (1.2 g, 2.7 mmol, 100% yield) as a white solid.
Reaction SMILES: C(N(CC)CC)C.O.[NH2:9][C@@H:10]1[C:28](=[O:29])[N:12]2[C:13]([C:25]([OH:27])=[O:26])=[C:14]([CH2:17][S:18][C:19]3[N:23]([NH2:24])[N:22]=[N:21][N:20]=3)[CH2:15][S:16][C@H:11]12.[C:30]([NH:49][C:50]1[S:51][CH:52]=[C:53](/[C:55](=[N:68]/[O:69][CH3:70])/[C:56](ON2C3C=CC=CC=3N=N2)=[O:57])[N:54]=1)([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>CC(N(C)C)=O>[C:30]([NH:49][C:50]1[S:51][CH:52]=[C:53](/[C:55](=[N:68]/[O:69][CH3:70])/[C:56]([NH:9][C@@H:10]2[C:28](=[O:29])[N:12]3[C:13]([C:25]([OH:27])=[O:26])=[C:14]([CH2:17][S:18][C:19]4[N:23]([NH2:24])[N:22]=[N:21][N:20]=4)[CH2:15][S:16][C@H:11]23)=[O:57])[N:54]=1)([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)([C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: CO/N=C(\C(=O)On1nnc2ccccc21)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: N[C@@H]1C(=O)N2C(C(=O)O)=C(CSc3nnnn3N)CS[C@H]12
Solvent: CC(=O)N(C)C
Solvent: CCN(CC)CC
Solvent: O
Product: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(CSc3nnnn3N)CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 0 °C
Yield: 57.6 %

Procedure:
To a solution of triethylamine (7.02 g, 69.4 mmol) and water (2.2 ml) in dimethylacetamide (72 ml) was added 7β-amino-3-[(1-amino-1H-tetrazol-5-yl)thiomethyl]-3-cephem-4-carboxylic acid (11.5 g, 34.7 mmol) at room temperature and the mixture was stirred to dissolve it. The mixture was cooled to -6° to -3° C. and a solution of 1-benzotriazolyl 2-(2-tritylaminothiazol-4-yl)-(Z)-2-methoxyiminoacetate (29.2 g, 52.1 mmol) in dimethylacetamide (120 ml) was added dropwise to the mixture and allowed to react at 5° C. for 17 hours. The reaction mixture was poured into ice-water (500 ml). The aqueous layer was washed with ethyl acetate (100 ml)--tetrahydrofuran (50 ml) and adjusted to pH 3 with 20% aqueous sulfuric acid. Precipitated material was extracted with ethyl acetate (200 ml)--tetrahydrofuran (100 ml). The organic layer was filtered to remove insoluble material, washed with water, dried over magnesium sulfate and evaporated under reduced pressure. The residue was treated with ether to give pale yellow substance of 7β-[2-(2-tritylaminothiazol-4-yl)-(Z)-2-methoxyiminoacetamido]-3-[(1-amino-1H-tetrazol-5-yl)thiomethyl]-3-cephem-4-carboxylic acid (15.1 g, 57.7%), mp~175° C. (decomposition).
Reaction SMILES: S(O)(O)(=O)=O.[CH3:6][O:7][C:8](=[NH:10])[NH2:9].[OH-].[Ca+2].[OH-].[C:14]([CH:17]1[CH2:22][CH2:21][O:20][C:18]1=[O:19])(=O)[CH3:15]>O.C(O)C>[CH3:6][O:7][C:8]1[NH:9][C:18](=[O:19])[C:17]([CH2:22][CH2:21][OH:20])=[C:14]([CH3:15])[N:10]=1
Reactant: COC(=N)N
Reactant: CC(=O)C1CCOC1=O
Agent: O=S(=O)(O)O
Agent: [Ca+2]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1nc(C)c(CCO)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of O-methylisourea hydrogen sulfate (17.2 g, 0.1 mol) in water (90 ml) was added calcium hydroxide (8.14 g, 0.11 mol) followed by a solution of 2-acetylbutyrolactone (10.7 ml, 0.1 mol) in ethanol (70 ml). The mixture was stirred at room temperature for two days, filtered and washed with ethanol. The filtrate was concentrated in vaccuum and purified by flash chromatografy (dichloromethane/methanol=95/5). Yield 2.6 g (14%) of a white solid.
Reaction SMILES: [ClH:1].C(OC([NH:12][C@@H:13]([C:21]([NH:23][C@H:24]([C:29]([NH:31][C@H:32]([C:40]([N:42]1[CH2:53][CH2:52][CH2:51][C@H:43]1[C:44]([NH:46][CH2:47][C:48]([NH2:50])=[O:49])=[O:45])=[O:41])[CH2:33][CH2:34][CH2:35][NH:36][C:37](=[NH:39])[NH2:38])=[O:30])[CH2:25][CH:26]([CH3:28])[CH3:27])=[O:22])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=O)C1C=CC=CC=1>[Pd].CO>[ClH:1].[NH2:12][C@@H:13]([C:21]([NH:23][C@H:24]([C:29]([NH:31][C@H:32]([C:40]([N:42]1[CH2:53][CH2:52][CH2:51][C@H:43]1[C:44]([NH:46][CH2:47][C:48]([NH2:50])=[O:49])=[O:45])=[O:41])[CH2:33][CH2:34][CH2:35][NH:36][C:37](=[NH:38])[NH2:39])=[O:30])[CH2:25][CH:26]([CH3:27])[CH3:28])=[O:22])[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CC(C)C[C@H](NC(=O)[C@@H](Cc1ccccc1)NC(=O)OCc1ccccc1)C(=O)N[C@@H](CCCNC(=N)N)C(=O)N1CCC[C@H]1C(=O)NCC(N)=O
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CC(C)C[C@H](NC(=O)[C@H](N)Cc1ccccc1)C(=O)N[C@@H](CCCNC(=N)N)C(=O)N1CCC[C@H]1C(=O)NCC(N)=O

Procedure:
A solution of 3.9 g. of Nα -benzyloxycarbonyl-D-phenylalanyl-L-leucyl-L-arginyl-L-prolyl-glycinamide hydrochloride in 100 ml. of methanol with 500 mg. of 20% palladium-on-carbon is stirred under hydrogen gas at slightly above atmospheric pressure for four hours. The solution is filtered and the filtrate is evaporated to dryness at 40° C. under reduced pressure to give a white foam suitable for use without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][NH:9][OH:10].N1C=CN=C1.[Si:16](Cl)([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17].CCCCCC>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][NH:9][O:10][Si:16]([CH3:18])([CH3:17])[C:19]([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: ONCc1ccccc1Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: CC(C)(C)[Si](C)(C)ONCc1ccccc1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 59.6 %

Procedure:
A stirred solution of 10.0 grams (0.063 mole) of N-(2-chlorophenyl)methylhydroxylamine (Example 1, Step A-2) and 12.9 grams (0.19 mole) of imidazole in 50 ml of dry dimethylformamide was cooled in an ice-water bath. To this stirred solution was added dropwise during a 20 minute period 10.6 grams (0.07 mole) of tert-butyldimethylsilyl chloride in 25 ml of dry dimethylformamide. During the addition the reaction mixture temperature was maintained at 5°. Upon completion of addition the reaction mixture was allowed to warm to ambient temperature at which it was stirred for 18 hours. Most of the dimethylformamide was removed from the reaction mixture under water aspirator pressure. The residue was taken up in 300 ml of methylene chloride and washed with three 100-ml portions of water. The organic layer was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to give on cooling a semi-solid residue. A sample of the semi-solid was slurried with hexane and the insolubles collected by filtration. The filtrate was concentrated to give an oil residue. The above procedure was repeated on the remainder of the semi-solid using 75 ml of hexane. The hexane filtrate was concentrated under reduced pressure to give an oil residue. The oil was distilled under reduced pressure to give 10.2 grams of [(2-chlorophenyl)methyl]-[dimethyl(1,1-dimethylethyl)silyloxy]amine; bp 88°-89°/0.7 Pa.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:24][C:23]2[C:25](=[O:26])[C:18](=[CH:19][C:20]([C:22]=2[O:27][CH3:28])=[O:21])[NH:17][C:15](=[O:16])[C:14]([CH3:29])=[CH:13][CH:12]=[CH:11][C@H:10]([O:30][CH3:31])[C@@H:9]([O:32][C:33]([NH2:35])=[O:34])[C:8]([CH3:36])=[CH:7][C@H:6]([CH3:37])[C@@H:5]([OH:38])[C@@H:4]([O:39][CH3:40])[CH2:3]1.F[B-](F)(F)F.[CH3:46][O+](C)C.CN(C)C1C2C(=CC=CC=2N(C)C)C=CC=1>ClCCl.C(OCC)(=O)C>[CH3:1][C@@H:2]1[CH2:24][C:23]2[C:25](=[O:26])[C:18](=[CH:19][C:20]([C:22]=2[O:27][CH3:28])=[O:21])[NH:17][C:15](=[O:16])[C:14]([CH3:29])=[CH:13][CH:12]=[CH:11][C@H:10]([O:30][CH3:31])[C@@H:9]([O:32][C:33]([NH2:35])=[O:34])[C:8]([CH3:36])=[CH:7][C@H:6]([CH3:37])[C@@H:5]([O:38][CH3:46])[C@@H:4]([O:39][CH3:40])[CH2:3]1
Reactant: C[O+](C)C
Reactant: COC1=C2C[C@@H](C)C[C@H](OC)[C@H](O)[C@@H](C)C=C(C)[C@H](OC(N)=O)[C@@H](OC)C=CC=C(C)C(=O)NC(=CC1=O)C2=O
Agent: CN(C)c1cccc2cccc(N(C)C)c12
Agent: COC1=C2C[C@@H](C)C[C@H](OC)[C@H](O)[C@@H](C)/C=C(\C)[C@H](OC(N)=O)[C@@H](OC)/C=C\C=C(/C)C(=O)NC(=CC1=O)C2=O
Agent: COC1=C2C[C@@H](C)C[C@H](OC)[C@H](OC)[C@@H](C)/C=C(\C)[C@H](OC(N)=O)[C@@H](OC)/C=C\C=C(/C)C(=O)NC(=CC1=O)C2=O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COC1=C2C[C@@H](C)C[C@H](OC)[C@H](OC)[C@@H](C)C=C(C)[C@H](OC(N)=O)[C@@H](OC)C=CC=C(C)C(=O)NC(=CC1=O)C2=O
Temperature: 40 °C
Reaction time: 2 h

Procedure:
To a suspension of geldanamycin (1 equiv.) in dichloromethane (20 mL per mmol of geldanamycin) is added trimethyloxonium tetrafluoroborate (3 equiv.) and N, N, N′, N′-tetra-methylnaphthalene-1,8-diamine (3.5 equiv). After stirring at 40° C. for 2 h, the suspension was diluted with ethyl acetate and washed sequentially with 0.1 M aqueous hydrochloric acid, saturated aqueous sodium bicarbonate solution, and saturated aqueous sodium chloride. The organic solution was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness, giving a brown solid. Purification by flash chromatography on silica gel (eluted using mixed dichloromethane/ethyl acetate/methanol solvents) gave 11-O-methyl-geldanamycin (compound I-e) as a yellow solid. Electrospray ionization time-of-flight mass spectrometry (“ESI TOF MS”) m/z 597.2770, calc'd for C30H42N2O9Na [M+Na]+, 597.2783. 13C NMR (CDCl3, 100 MHz) δ (relative to CDCl3 at 77.0 ppm) 12.2, 13.9, 16.0, 21.5, 29.5, 32.5, 33.7, 36.5, 56.2, 57.4, 59.4, 61.5, 78.9, 79.4, 81.7, 83.3, 111.0, 125.7, 128.1, 130.5, 131.9, 134.5, 136.6, 137.8, 155.9, 156.9, 168.6, 183.9, 184.1.
Reaction SMILES: [CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:30]=[CH:29][C:13]3[C:14](=[CH:23]/[C:24](/[NH:27][OH:28])=[N:25]\[H])[C:15]4[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=4[CH2:17][CH2:18][C:12]=3[CH:11]=2)[C:7]2[CH:31]=[CH:32][CH:33]=[CH:34][C:6]=2[N:5]=1)[CH2:2][CH3:3].[CH:35](OCC)(OCC)OCC>>[CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:30]=[CH:29][C:13]3/[C:14](=[CH:23]/[C:24]4[N:25]=[CH:35][O:28][N:27]=4)/[C:15]4[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=4[CH2:17][CH2:18][C:12]=3[CH:11]=2)[C:7]2[CH:31]=[CH:32][CH:33]=[CH:34][C:6]=2[N:5]=1)[CH2:2][CH3:3]
Reactant: [H]/N=C(\C=C1c2ccccc2CCc2cc(Cn3c(CCC)nc4ccccc43)ccc21)NO
Reactant: CCOC(OCC)OCC
Product: CCCc1nc2ccccc2n1Cc1ccc2c(c1)CCc1ccccc1/C2=C\c1ncon1
Temperature: 80 °C
Reaction time: 2 h
Yield: 42 %

Procedure:
[step 2] To (E)-[2-(2-propylbenzimidazol-1-yl)methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene]-N-hydroxyacetamidine (65 mg, 0.149 mmol) obtained in step 1 was added triethyl orthoformate (1 mL), and the mixture was stirred at 80° C. for 2 hr. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=80/20 to 0/100) to give the title compound (compound 9) (28 mg, 42%).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:4]=1N.Cl.[N+:12]([O-:15])([O-])=[O:13].[Na+].S([O-])([O-])(=O)=O>O>[Cl:2][C:3]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:4]=1[N+:12]([O-:15])=[O:13]
Reactant: Nc1c(F)cccc1Cl
Reactant: O=[N+]([O-])[O-]
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=[N+]([O-])c1c(F)cccc1Cl
Reaction time: 1 h

Procedure:
To a solution of 17.2 g. of 2-chloro-6-fluoroaniline hydrochloride and 12.5 ml. of concentrated hydrochloric acid in 150 ml. of water is added slowly a solution of 9 g. of sodium nitrate in 25 ml. of water. The temperature of the solution of kept below 5° at all times. This solution is then added to a stirred suspension of 18 g. of cuprocupric sulfate and 60 g. of sodium nitrate in 300 ml. of water at room temperature. The mixture is stirred for 1 hour then steam distilled until no trace of product is noted condensing in the distillate. The distillate is extracted with ether, dried (magnesium sulfate) concentrated and distilled to give 7.8 g. of product, b.p. 148°-152° at 30 mm. Gas chromatography analysis shows this to be greater than 95% pure.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([C:13]3([C:19]#[N:20])[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[CH:9][CH:8]=2)[CH2:2]1.[C:21]1(=O)[CH2:24][CH2:23][CH2:22]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1.C(=O)([O-])[O-].[Na+].[Na+]>[CH:21]1([N:1]2[CH2:4][CH:3]([CH2:5][O:6][C:7]3[CH:8]=[CH:9][C:10]([C:13]4([C:19]#[N:20])[CH2:18][CH2:17][O:16][CH2:15][CH2:14]4)=[CH:11][CH:12]=3)[CH2:2]2)[CH2:24][CH2:23][CH2:22]1
Reactant: N#CC1(c2ccc(OCC3CNC3)cc2)CCOCC1
Reactant: O=C1CCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: N#CC1(c2ccc(OCC3CN(C4CCC4)C3)cc2)CCOCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81.4 %

Procedure:
4-[4-(azetidin-3-ylmethoxy)phenyl]tetrahydro-2H-pyran-4-carbonitrile (0.29, 0.73 mmol) was dissolved in THF (2 mL). Cyclobutanone (0.06 mL, 0.80 mmol) and acetic acid (0.042 mL, 0.73 mmol) were added. The mixture was stirred at room temperature for 30 minutes. Sodium triacetoxyborohydride (0.311 g, 1.47 mmol) was added. The mixture was stirred at room temperature for 18 hours. The reaction mixture was diluted with 10% aqueous sodium carbonate (5 mL) then extracted with DCM (2×50 mL). The organics were combined, dried over sodium sulphate, filtered and concentrated in vacuo to provide a clear oil. This was purified by flash chromatography on silica gel eluting with dichloromethane:methanol:ammonia (96:4:0.4 to 95:5:0.5) to provide the title compound (0.194 g, 81%) as a clear oil. 1H NMR (400 MHz, CDCl3) δ 1.60-1.70 (m, 2H), 1.70-1.80 (m, 2H), 1.80-1.90 (m, 2H), 1.95-2.00 (m, 2H), 2.0-2.15 (m, 2H), 2.9 (m, 1H), 3.1 (t, 2H), 3.16 (m, 1H), 3.4 (t, 2H), 3.9 (m, 2H), 4.10 (m, 4H), 6.90 (d, 2H), 7.40 (d, 2H). HRMS ESI+ m/z 327.2059 [MH]+.
Reaction SMILES: N[C:2]1SC(C2C=CC=C(Br)C=2F)=N[C:3]=1C(NC1C=NN(C)C=1N1CCC[C@@H](N)CC1)=O.[CH2:32]([O:39][C:40]([NH:42][C@@H:43]1[CH2:49][CH2:48][CH2:47][N:46]([C:50]2[N:54]([CH3:55])[N:53]=[CH:52][C:51]=2[NH:56][C:57]([C:59]2[N:60]=[C:61]([C:72]3[CH:77]=[CH:76][CH:75]=[C:74](Br)[C:73]=3[F:79])[S:62][C:63]=2[NH:64][C:65](=[O:71])[O:66][C:67]([CH3:70])([CH3:69])[CH3:68])=[O:58])[CH2:45][CH2:44]1)=[O:41])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.CC1(C)C(C)(C)OB(C=C)O1.C([O-])([O-])=O.[Na+].[Na+].C([O-])(=O)C.[K+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(#N)C>[CH2:32]([O:39][C:40]([NH:42][C@@H:43]1[CH2:49][CH2:48][CH2:47][N:46]([C:50]2[N:54]([CH3:55])[N:53]=[CH:52][C:51]=2[NH:56][C:57]([C:59]2[N:60]=[C:61]([C:72]3[CH:77]=[CH:76][CH:75]=[C:74]([CH:2]=[CH2:3])[C:73]=3[F:79])[S:62][C:63]=2[NH:64][C:65](=[O:71])[O:66][C:67]([CH3:70])([CH3:69])[CH3:68])=[O:58])[CH2:45][CH2:44]1)=[O:41])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: Cn1ncc(NC(=O)c2nc(-c3cccc(Br)c3F)sc2N)c1N1CCC[C@@H](N)CC1
Reactant: Cn1ncc(NC(=O)c2nc(-c3cccc(Br)c3F)sc2NC(=O)OC(C)(C)C)c1N1CCC[C@@H](NC(=O)OCc2ccccc2)CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: C=CB1OC(C)(C)C(C)(C)O1
Solvent: CC#N
Product: C=Cc1cccc(-c2nc(C(=O)Nc3cnn(C)c3N3CCC[C@@H](NC(=O)OCc4ccccc4)CC3)c(NC(=O)OC(C)(C)C)s2)c1F
Temperature: 25 °C

Procedure:
The Boc and Cbz protected intermediate of compound 373 from Example 373, tert-butyl N-[4-[[5-[(4R)-4-(benzyloxycarbonylamino)azepan-1-yl]-1-methyl-pyrazol-4-yl]carbamoyl]-2-(3-bromo-2-fluoro-phenyl)thiazol-5-yl]carbamate, (158 mg; 0.213 mmol), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (98 mg, 0.11 mmol), dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) (16 mg, 0.021 mmol), a 1M solution of Na2CO3 (0.32 mL), a 1M solution of potassium acetate (0.32 mL) and acetonitrile (3.5 mL) were charged in a microwave reaction vial. The mixture was irradiated to 130° C. with a microwave for 30 min and cooled to room temperature. It was filtered through Celite and thoroughly washed with methanol. The filtrate was concentrated and the residue was purified via flash chromatography, 0 to 100% ethyl acetate in heptane to give tert-butyl N-[4-[[5-[(4R)-4-(benzyloxycarbonylamino)azepan-1-yl]-1-methyl-pyrazol-4-yl]carbamoyl]-2-(2-fluoro-3-vinyl-phenyl)thiazol-5-yl]carbamate.