Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@H:2]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C@@H:3]([OH:32])[CH2:4][C@H:5]([NH:19][C:20]([C@@H:22]([NH:27][C:28](=[O:31])[O:29][CH3:30])[C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1.[CH2:40]([N:47]([CH3:59])[C:48]([NH:50][C@@H:51]([C:55]([CH3:58])([CH3:57])[CH3:56])[C:52](O)=[O:53])=[O:49])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1.CCOP(ON1N=NC2C=CC=CC=2C1=O)(OCC)=O.C(N(CC)C(C)C)(C)C>C1COCC1>[CH3:30][O:29][C:28](=[O:31])[NH:27][C@@H:22]([C:23]([CH3:26])([CH3:25])[CH3:24])[C:20](=[O:21])[NH:19][C@H:5]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1)[CH2:4][C@H:3]([OH:32])[C@H:2]([CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[NH:1][C:52](=[O:53])[C@H:51]([C:55]([CH3:57])([CH3:56])[CH3:58])[NH:50][C:48](=[O:49])[N:47]([CH3:59])[CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: COC(=O)N[C@H](C(=O)N[C@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](O)[C@@H](N)Cc1ccccc1)C(C)(C)C
Reactant: CN(Cc1ccccc1)C(=O)N[C@H](C(=O)O)C(C)(C)C
Agent: CCOP(=O)(OCC)On1nnc2ccccc2c1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COC(=O)N[C@H](C(=O)N[C@H](Cc1ccc(-c2ccccn2)cc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](NC(=O)N(C)Cc1ccccc1)C(C)(C)C)C(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 73 %

Procedure:
A solution containing the product from Example 1H (0.020 g, 0.038 mmol) in THF (0.4 mL) was treated with the product from Example 63C (0.013 g, 0.047 mmol), DEPBT (0.017 g, 0.057 mmol), and N,N-diisopropylethylamine (0.035 mL, 0.201 mmol) and the mixture was stirred at 25° C. for 16 hours. The mixture was partitioned between ethyl acetate and 10% Na2CO3 solution. The organic phase was washed with additional 10% Na2CO3 solution and brine, dried over MgSO4, filtered and concentrated. The residue was chromatographed on silica gel eluting with 0-100% ethyl acetate/dichloromethane to give the title compound (0.022 g, 74% yield). 1H NMR (300 MHz, DMSO-d6) δ ppm 0.75(m, 9H), 0.78(m, 9H), 1.35-1.22(m, 1H), 1.65-1.54(m, 1H), 2.77-2.60(m, 4H), 2.79(s, 3H), 3.57(s, 3H), 3.83-3.77(m, 1H), 3.94-3.83(m, 1H), 4.09-4.06(d, J=8.82 Hz, 1H), 4.21-4.10(m, 1H), 4.51-4.38(m, 2H), 4.77-4.75(d, J=5.52 Hz, 1H), 5.43-5.40(d, J=8.82 Hz, 1H), 6.85-6.82(d, J=9.52 Hz, 1H), 7.26-7.10(m, 10H), 7.35-7.30(m, 1H). 3H), 7.60-7.57(d, J=9.19, 1H), 7.79-7.77(d, J=7.72 Hz, 1H), 7.93-7.82(m, 4H), 8.65-8.62(m, 1H).
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)[C:10]([C:11](=[O:13])[CH3:12])=[C:6]2[CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+]>C(N)CCC>[CH2:6]([NH:7][C:2]1[N:7]2[N:8]=[C:9]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)[C:10]([C:11](=[O:13])[CH3:12])=[C:6]2[CH:5]=[CH:4][CH:3]=1)[CH2:5][CH2:4][CH3:3]
Reactant: CC(=O)c1c(-c2ccc(F)cc2)nn2c(Cl)cccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCN
Product: CCCCNc1cccc2c(C(C)=O)c(-c3ccc(F)cc3)nn12
Temperature: 25 °C
Yield: 166.5 %

Procedure:
A mixture of 1-[7-chloro-2-(4-fluorophenyl)pyrazolo[1,5-α]pyridin-3-yl]ethanone (969 mg, 3.4 mmol) and potassium carbonate (9.6 g, 69.4 mmol) in n-butylamine (20 mL) was heated to reflux for 5 hours. The mixture was cooled to room temperature and concentrated in vacuo. The residue was taken up in ethyl acetate and water. The organic layer was washed with brine. The aqueous layer was extracted with ethyl acetate and the combined organics were dried over sodium sulfate. Filtration and concentration followed by flash chromatography (2:1 hexanes-ethyl acetate) provided 1-[7-(butylamino)-2-(4-fluorophenyl)pyrazolo[1 ,5-α]pyridin-3-yl]ethanone (921 mg, 84%) as a tinted oil. 1H NMR (CDCl3): δ 7.71 (d, 1H), 7.63 (dd, 2H), 7.49 (t, 1H), 7.23 (t, 2H), 6.16 (d, 1H), 6.10 (m, 1H), 3.40 (m, 2H), 2.18 (s, 3H), 1.78 (m, 2H), 1.52 (m, 2H), 1.02 (t, 3H); MS m/z 326 (M+1); Rf 0.6 (1:1 hexanes:ethyl acetate).
Reaction SMILES: [NH3:1].[N:2]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH:15]=[N:14][C:13]([CH3:16])=[N:12]2)=[C:7]([O:17][CH3:18])[CH:6]=1)=[C:3]=[S:4]>>[CH3:18][O:17][C:7]1[CH:6]=[C:5]([NH:2][C:3]([NH2:1])=[S:4])[CH:10]=[CH:9][C:8]=1[N:11]1[CH:15]=[N:14][C:13]([CH3:16])=[N:12]1
Reactant: N
Reactant: COc1cc(N=C=S)ccc1-n1cnc(C)n1
Product: COc1cc(NC(N)=S)ccc1-n1cnc(C)n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 87 %

Procedure:
Step F (4): Methanolic ammonia (1.0 M, 100 mL, 100 mmol) was added to a flask charged with 1-(4-isothiocyanato-2-methoxyphenyl)-3-methyl-1H-1,2,4-triazole (3.91 g, 15.88 mmol) in a ice-water bath. After the addition was complete, the resulting slurry was stirred for 10 min and then allowed to warm to rt. After 24 h, the reaction mixture was concentrated to dryness in vacuo to afford 1-(3-methoxy-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl)thiourea (4.18 g, 13.81 mmol, 87% yield) as a white solid. LC-MS (M+H)+ 264.0.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:8][C@@H:9]2[CH:16]3[CH2:17][N:12]4[CH2:13][CH:14]([CH2:18][CH:10]2[CH2:11]4)[CH2:15]3)[CH:5]=[N:6][CH:7]=1.[NH:19]1[C:27]2[C:22](=[CH:23][C:24](B(O)O)=[CH:25][CH:26]=2)[CH:21]=[CH:20]1.N>>[NH:19]1[C:27]2[C:22](=[CH:23][C:24]([C:2]3[CH:3]=[C:4]([NH:8][C@@H:9]4[CH:16]5[CH2:17][N:12]6[CH2:13][CH:14]([CH2:18][CH:10]4[CH2:11]6)[CH2:15]5)[CH:5]=[N:6][CH:7]=3)=[CH:25][CH:26]=2)[CH:21]=[CH:20]1
Reactant: OB(O)c1ccc2[nH]ccc2c1
Reactant: Brc1cncc(NC2C3CC4CC2CN(C4)C3)c1
Agent: N
Product: c1cc2cc(-c3cncc(NC4C5CC6CC4CN(C6)C5)c3)ccc2[nH]1

Procedure:
Prepared from the product of Example 69A (150 mg, 0.50 mmol) and 5-indolylboronic acid (160 mg, 1.0 mmol; Aldrich) according to Method E: 1H NMR (300 MHz, methanol-D4) δ ppm 1.59-1.77 (m, 1H), 1.79-1.93 (m, 2H), 1.93-2.07 (m, 2H), 2.28-2.32 (m, 2H), 3.10-3.32 (m, 6H), 3.88 (s, 1H), 6.51 (dd, J=3.0, 0.7 Hz, 1H), 7.27 (d, J=3.4 Hz, 1H), 7.30-7.34 (m, 1H), 7.36 (d, J=1.7 Hz, 1H), 7.47 (d, J=8.3 Hz, 1H), 7.78 (d, J=1.0 Hz, 1H), 7.93 (d, J=2.4 Hz, 1H), 8.03 (d, J=1.7 Hz, 1H). MS (DCI/NH3) m/z=345 (M+H)+.
Reaction SMILES: C(=O)(O)[O-:2].[Na+].Cl.NO.[F:9][C:10]([F:21])([F:20])[CH2:11][C:12]1[CH:17]=[CH:16][N:15]=[C:14]([C:18]#[N:19])[CH:13]=1>C(O)C>[F:21][C:10]([F:9])([F:20])[CH2:11][C:12]1[CH:17]=[CH:16][N:15]=[C:14]([C:18]([NH2:19])=[O:2])[CH:13]=1
Reactant: N#Cc1cc(CC(F)(F)F)ccn1
Reactant: O=C([O-])O
Agent: Cl
Agent: NO
Agent: [Na+]
Solvent: CCO
Product: NC(=O)c1cc(CC(F)(F)F)ccn1
Reaction time: 4 h
Yield: 91.2 %

Procedure:
To 3 ml of ethanol were added 0.2 g of sodium bicarbonate and 0.17 g of hydroxylamine hydrochloride, and the mixture was heated to reflux for 1 hour. After allowing to cool, 0.3 g of 4-(2,2,2-trifluoroethyl)pyridine-2-carbonitrile was added at 0° C., and the mixture was stirred for 4 hours, and concentrated. To the residue was added water, the resultant solution was extracted with ethyl acetate three times, and the organic layers were combined, washed with an aqueous saturated sodium chloride solution, dried with anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography to obtain 0.3 g of 4-(2,2,2-trifluoroethyl)pyridine-2-carboxamide=oxime.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:10]2[C:19]3[C:14](=[CH:15][C:16]([F:21])=[C:17]([Cl:20])[N:18]=3)[C:13](=[O:22])[C:12]([C:23]([O:25]CC)=[O:24])=[CH:11]2)[C:5]([F:9])=[CH:6][C:7]=1[Cl:8].CO.ClC(Cl)C>C(O)(=O)C.[Pd]>[NH2:1][C:2]1[CH:3]=[C:4]([N:10]2[C:19]3[C:14](=[CH:15][C:16]([F:21])=[C:17]([Cl:20])[N:18]=3)[C:13](=[O:22])[C:12]([C:23]([OH:25])=[O:24])=[CH:11]2)[C:5]([F:9])=[CH:6][C:7]=1[Cl:8]
Reactant: CCOC(=O)c1cn(-c2cc(N)c(Cl)cc2F)c2nc(Cl)c(F)cc2c1=O
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: Nc1cc(-n2cc(C(=O)O)c(=O)c3cc(F)c(Cl)nc32)c(F)cc1Cl
Reaction time: 8 h
Yield: 40.8 %

Procedure:
Ethyl 1-(3-amino-4-chloro-6-fluorophenyl)-7-chloro-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate (1.00 g) was dissolved in 10 ml of acetic acid, 10 ml of methanol and 20 ml of dichloroethane, to which was added a suspension of 132 mg of 10% palladium on carbon in 20 ml of acetic acid. Under a hydrogen atmosphere, the solution was stirred overnight. The palladium on carbon was removed by a membrane filter and 10% sodium hydroxide was added to the filtrate, which was extracted with chloroform. The organic layer was dried, and the solvent was distilled off. The solid was collected by filtration, to give 0.380 g of the title compound.
Reaction SMILES: O1CCCCC1[O:7][NH:8][C:9]([C@H:11]([C@@H:21]([CH2:30][CH:31]([CH3:33])[CH3:32])[C:22]([NH:24][NH:25][S:26]([CH3:29])(=[O:28])=[O:27])=[O:23])[CH2:12]/[CH:13]=[CH:14]/[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:10].CS(O)(=O)=O>CO.ClCCl>[OH:7][NH:8][C:9]([C@H:11]([C@@H:21]([CH2:30][CH:31]([CH3:32])[CH3:33])[C:22]([NH:24][N:25]([CH2:9][CH:11]([CH3:21])[CH3:12])[S:26]([CH3:29])(=[O:28])=[O:27])=[O:23])[CH2:12]/[CH:13]=[CH:14]/[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:10]
Reactant: CC(C)C[C@@H](C(=O)NNS(C)(=O)=O)[C@H](C/C=C/c1ccccc1)C(=O)NOC1CCCCO1
Agent: CS(=O)(=O)O
Solvent: ClCCl
Solvent: CO
Product: CC(C)C[C@@H](C(=O)NN(CC(C)C)S(C)(=O)=O)[C@H](C/C=C/c1ccccc1)C(=O)NO
Temperature: 25 °C
Reaction time: 3 h
Yield: 102.7 %

Procedure:
A solution of 0.246 g of (E)-2(R)-[1(S)-[(tetrahydro-2(RS)-pyranyloxy)carbamoyl]-4-phenyl-3-butenyl]-2′-(methanesulphonyl)-4-methylvalerohydrazide in a mixture of 10 ml of methanol and 2 ml of dichloromethane was treated with 0.006 ml of methanesulphonic acid. The mixture was stirred for 3 hours at room temperature and then the solvent was evaporated. The residue was partitioned between ethyl acetate and water. The ethyl acetate layer was dried over anhydrous magnesium sulphate and the solvent evaporated. The residue was triturated with hexane to give 0.119 g of (E)-2(R)-[1(S)-(hydroxycarbamoyl)-4-phenyl-3-butenyl]-2′-isobutyl-2′-(methanesulphonyl)-4-methylvalerohydrazide in the form of a white solid.
Reaction SMILES: [C:1]1([CH:7]([O:14][C:15]([C:17]2[N:22]3[C:23](=[O:63])[C@@H:24]([NH:25][C:26](=[O:62])/[C:27](/[C:49]4[N:50]=[C:51]([NH:54][C:55]([O:57][C:58]([CH3:61])([CH3:60])[CH3:59])=[O:56])[S:52][CH:53]=4)=[N:28]\[O:29][C:30]([C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=4)([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)[C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[C@H:21]3[S:20][CH2:19][C:18]=2[CH2:64][S:65][C:66]2[N:67]=[N:68][NH:69][CH:70]=2)=[S:16])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClC1C=CC=C(C(OO)=[O:79])C=1>ClCCl.CO.S([O-])([O-])(=O)=S.[Na+].[Na+]>[C:1]1([CH:7]([O:14][C:15]([C:17]2[N:22]3[C:23](=[O:63])[C@@H:24]([NH:25][C:26](=[O:62])/[C:27](/[C:49]4[N:50]=[C:51]([NH:54][C:55]([O:57][C:58]([CH3:60])([CH3:61])[CH3:59])=[O:56])[S:52][CH:53]=4)=[N:28]\[O:29][C:30]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)[C:43]4[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=4)[C@H:21]3[S:20](=[O:79])[CH2:19][C:18]=2[CH2:64][S:65][C:66]2[N:67]=[N:68][NH:69][CH:70]=2)=[S:16])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC(c2ccccc2)(c2ccccc2)c2ccccc2)C(=O)N[C@@H]2C(=O)N3C(C(=S)OC(c4ccccc4)c4ccccc4)=C(CSc4c[nH]nn4)CS[C@H]23)cs1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC(c2ccccc2)(c2ccccc2)c2ccccc2)C(=O)N[C@@H]2C(=O)N3C(C(=S)OC(c4ccccc4)c4ccccc4)=C(CSc4c[nH]nn4)CS(=O)[C@H]23)cs1
Reaction time: 1 h
Yield: 90.7 %

Procedure:
To a solution of 7β-[(Z)-2-(2-t-butoxycarbonylaminothiazol-4-yl)-2-trityloxyiminoacetamido]-3-(1,2,3-triazol-4-yl)thiomethylthio-3-cephem-4-carboxylic acid diphenylmethyl ester (511 mg: 0.5 mMol.) in a mixture of dichloromethane (10 ml) and methanol (10 ml) is added m-chloroperbenzoic acid (purity: 80%: 54 mg: 0.25 mMol.) at -30° C., and the mixture is stirred for 1 hour. The reaction mixture is diluted with aqueous 5% sodium thiosulfate and extracted with ethyl acetate. The extract solution was washed with aqueous sodium hydrogencarbonate, diluted hydrochloric acid, and brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (toluene-ethyl acetate=2:1 to 1:1) to give 7β-[(Z)-2-(2-t-butoxycarbonylaminothiazol-4-yl)-2-trityloxyiminoacetamido]-3-(1,2,3-triazol-4-yl)thiomethylthio-3-cephem-4-carboxylic acid diphenylmethyl ester 1-oxide (232 mg). Yield: 45%. A part of the starting material (236 mg: 48%) was recovered.
Reaction SMILES: [OH:1][C@H:2]1[CH2:27][CH2:26][C@@:25]2([CH3:28])[C@@:4]([OH:30])([CH2:5][CH2:6][C@@H:7]3[C@@H:24]2[CH2:23][CH2:22][C@@:21]2([CH3:29])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C@H:12]([CH3:20])[CH2:13][CH2:14][CH2:15][C:16]([OH:19])([CH3:18])[CH3:17])[CH2:3]1.CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O.CO>CC(C)=O>[O:1]=[C:2]1[CH2:27][CH2:26][C@@:25]2([CH3:28])[C@@:4]([OH:30])([CH2:5][CH2:6][C@@H:7]3[C@@H:24]2[CH2:23][CH2:22][C@@:21]2([CH3:29])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C@H:12]([CH3:20])[CH2:13][CH2:14][CH2:15][C:16]([OH:19])([CH3:18])[CH3:17])[CH2:3]1
Reactant: C[C@H](CCCC(C)(C)O)[C@H]1CC[C@H]2[C@@H]3CC[C@@]4(O)C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Solvent: CO
Product: C[C@H](CCCC(C)(C)O)[C@H]1CC[C@H]2[C@@H]3CC[C@@]4(O)CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Reaction time: 0.25 h
Yield: 76.4 %

Procedure:
A solution of 750 mg of the 3β ,5α -25-trihydroxy-cholestane (VI) in 300 ml of acetone was treated dropwise with 10cc of Jones reagent. The reaction mixture was treated with 10 ml of methanol, left for 15 minutes at room temperature and concentrated in vacuum. The residue was extracted with ether and washed with water. The ether extract was evaporated in vacuo and the residue was crystallized from benzene to give 570 mg of 3-keto-5α,25-dihydroxy-cholestane (VII) m.p. 215°-217°. Nmr δ 0.70 (s, 3H), 1.15 (s, 3H), 0.95 (d, J=5Hz, 1H), 1.22 (s, 3H) Anal. Calcd for C27H46O2 : C, 77.5; H, 11.1%. Found: C, 77.0; H, 10.5%.
Reaction SMILES: [CH2:1]([Si:3](Cl)([CH2:6]C)[CH2:4]C)C.[OH:9][CH2:10][C@@H:11]1[CH:26]=[C:25]2[C@@H:15]([CH2:16][CH:17]3[C:27]4[C:20](=[CH:21][CH:22]=[CH:23][C:24]2=4)[NH:19][CH2:18]3)[N:13]([CH3:14])[CH2:12]1.C(N(CC)CC)C.O>CN(C1C=CN=CC=1)C.CN(C)C=O>[CH3:6][Si:3]([CH3:1])([CH3:4])[O:9][CH2:10][C@@H:11]1[CH:26]=[C:25]2[C@@H:15]([CH2:16][C:17]3[C:27]4[C:20](=[CH:21][CH:22]=[CH:23][C:24]2=4)[NH:19][CH:18]=3)[N:13]([CH3:14])[CH2:12]1
Reactant: CC[Si](Cl)(CC)CC
Reactant: CN1C[C@H](CO)C=C2c3cccc4c3C(CN4)C[C@H]21
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CN1C[C@H](CO[Si](C)(C)C)C=C2c3cccc4[nH]cc(c34)C[C@H]21
Temperature: 25 °C
Yield: 78.5 %

Procedure:
Triethylsilyl chloride (TES-Cl, 1.30 g) is added into a mixture of dihydrolysergol (1.47 g), triethylamine (1.74 g) and DMAP (0.14 g) in N,N-dimethylformamide (10 mL) and the mixture is stirred at room temperature. After complete reaction, the mixture is cooled and water (15 mL) is added. The resulted suspension is stirred for an additional 2 h and then filtered and washed with water. The product is dried and recrystallized from dichloromethane/heptanes to give 1.47 g of 8β-(trimethylsiloxymethyl)-9,10-didehydro-6-methyl-ergoline in 70% yield.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]#[C:9]C(C)(O)C)=[CH:4][CH:3]=1.[OH-].[Na+]>C1(C)C=CC=CC=1>[C:8]([C:5]1[CH:4]=[CH:3][C:2]([NH2:1])=[N:7][CH:6]=1)#[CH:9]
Reactant: CC(C)(O)C#Cc1ccc(N)nc1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: C#Cc1ccc(N)nc1
Yield: 36.4 %

Procedure:
A solution of 4-(6-amino-pyridin-3-yl)-2-methyl-but-3-yn-2-ol (example D.1 method 2 step 1) (22.5 g, 128 mmol) in toluene (500 mL) was refluxed in the presence of powdered NaOH (3.83 g, 96 mmol) for 16 h. The solvent was removed under reduced pressure to leave a brown residue which was purified by silica gel column chromatography with dichloromethane and ether, followed by trituration with heptane to give the title compound (5.5 g, 36%) (31.1 g, 100%) as light red solid. MS (EI) 118.1 [(M)+]; mp 143° C.
Reaction SMILES: [C:1]1([C:7]2[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:15][C:14]3[C:9](=[N:10][CH:11]=[CH:12][CH:13]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N#N>CCO.[Pd]>[C:17]1([C:16]2[CH:15]=[C:14]3[C:9](=[N:8][C:7]=2[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[NH:10][CH2:11][CH2:12][CH2:13]3)[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: c1ccc(-c2cc3cccnc3nc2-c2ccccc2)cc1
Agent: [Pd]
Agent: N#N
Solvent: CCO
Product: c1ccc(-c2cc3c(nc2-c2ccccc2)NCCC3)cc1
Reaction time: 8 h

Procedure:
A solution of 2,3-diphenyl-[1,8]naphthyridine (Intermediate A) (2 g, 7.08 mmol) in EtOH (50 ml) was purged with N2 and 10% palladium on carbon (0.754 g, 0.708 mmol) was added. The reaction mixture was placed under an atmosphere of hydrogen overnight. The mixture was filtered through Celite® (filter material) and the catalyst was washed with EtOAc (400 ml). The filtrate was concentrated in vacuo to yield the title compound as an off white solid;
Reaction SMILES: [CH:1]([C:4]1[CH:19]=[CH:18][CH:17]=[C:16]([CH:20]([CH3:22])[CH3:21])[C:5]=1[NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N+:13]([O-])=O)([CH3:3])[CH3:2].[H][H]>[Pd].C(O)C>[CH:20]([C:16]1[CH:17]=[CH:18][CH:19]=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5]=1[NH:6][C:7]1[C:8]([NH2:13])=[CH:9][CH:10]=[CH:11][CH:12]=1)([CH3:21])[CH3:22]
Reactant: CC(C)c1cccc(C(C)C)c1Nc1ccccc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CC(C)c1cccc(C(C)C)c1Nc1ccccc1N
Yield: 99 %

Procedure:
2,6-diisopropyl-N-(2-nitrophenyl)aniline (9.5 g, 32 mmol) and 10% palladium on carbon (0.4 g) were mixed with 150 ml of ethanol under nitrogen in a plastic coated hydrogenation vessel. The mixture was put on a par hydrogenator and reacted under 40 psi of hydrogen until there is no pressure drop. The catalyst was filtered off through a Celite bed. The solvent was evaporated. The product was used for the next step without further purification. 8.5 g of desired product was obtained.
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@H:9]([O:15]C(=O)C)[C@@H:8]([CH2:19][O:20]C(=O)C)[O:7][C@H:6]1[N:24]1C(=O)C(=CC2C=CC=CC=2)S[C:25]1=[S:37])(=O)C.[NH3:38]>CO>[C@@H:6]1([NH:24][C:25]([NH2:38])=[S:37])[O:7][C@H:8]([CH2:19][OH:20])[C@@H:9]([OH:15])[C@H:10]([OH:11])[C@H:5]1[OH:4]
Reactant: N
Reactant: CC(=O)OC[C@H]1O[C@@H](N2C(=O)C(=Cc3ccccc3)SC2=S)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Solvent: CO
Product: NC(=S)N[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
N-(2,3,4,6-Tetra-O-acetyl-β-D glucopyranosyl)-5-benzylidenerhodanine(5.52 g., 0.01 mole) was added to a solution of 50 ml. of methanol saturated with ammonia at 0° in a pressure bottle. The mixture was stirred at room temperature for 18 hours with the stopper well closed. The mixture was evaporated to a syrupy material below 30° in vacuo. The residue was dissolved in the minimum amount of methanol and passed through a silica gel column(2.54×15 cm) with aid of additional methanol. One hundred ml. of effluent was collected and concentrated. During the concentration, a precipitate was formed. The white precipitate was filtered and dried at room temperature in vacuo, yielding 2.04 g. (86.8%); m.p. 207°-209°(dec.). (Lit. m.p. 207°-210°(83), m.p. 211°-212°(32), m.p. 205°-207°(86).
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:9][O:10][C:11]1[CH:12]=[C:13]([CH:19]2[CH:27]3[C:22]([CH2:23][CH2:24][CH2:25][CH2:26]3)=[N+:21]([O-:28])[CH2:20]2)[CH:14]=[CH:15][C:16]=1[O:17][CH3:18]>CCOCC.O1CCCC1>[CH3:9][O:10][C:11]1[CH:12]=[C:13]([CH:19]2[CH:27]3[C:22]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)([CH2:23][CH2:24][CH2:25][CH2:26]3)[N:21]([OH:28])[CH2:20]2)[CH:14]=[CH:15][C:16]=1[O:17][CH3:18]
Reactant: COc1ccc(C2C[N+]([O-])=C3CCCCC32)cc1OC
Reactant: Br[Mg]c1ccccc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1ccc(C2CN(O)C3(c4ccccc4)CCCCC23)cc1OC
Temperature: 35 °C
Yield: 23.6 %

Procedure:
A volume of 75 ml of 3 M phenylmagnesium bromide in ether was added over a period of five minutes to a warm (35° C) stirred solution of 41.25 g (0.015 mole) of 3,3a,4,5,6,7-hexahydro-3-(3,4-dimethoxyphenyl)-2H-indole-1-oxide in 500 ml of tetrahydrofuran. After stirring for 2 hours at room temperature, most of the THF was distilled off at atmospheric pressure. Ice water (1 liter) was added and the paste-like solid was filtered. The damp filter cake was added to 500 ml of 1N HCl. The taffy-like material which remained out of solution was added to 10 MKOH (300 ml). The mixture was extracted into 1.5 l methylenechloride and the extract was dried (K2CO3), charcoaled, filtered and concentrated. The residue was dissolved in 200 ml of petroleum ether. There was obtained 12.5 g (23.6%) of a white solid melting at 166°-168° C. Recrystallization from 2-propanol gave pure material melting at 168°-170° C.
Reaction SMILES: [N:1]1[N:2]=[C:3]([C:19]2[CH:24]=[CH:23][C:22]([CH2:25][OH:26])=[CH:21][CH:20]=2)[N:4]2[C:10]=1[C:9]1[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=1[NH:7][C:6]1[N:15]=[CH:16][CH:17]=[CH:18][C:5]2=1.C(N(C(C)C)CC)(C)C.[CH3:36][S:37](Cl)(=[O:39])=[O:38]>ClCCl>[CH3:36][S:37]([O:26][CH2:25][C:22]1[CH:23]=[CH:24][C:19]([C:3]2[N:4]3[C:5]4[CH:18]=[CH:17][CH:16]=[N:15][C:6]=4[NH:7][C:8]4[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=4[C:10]3=[N:1][N:2]=2)=[CH:20][CH:21]=1)(=[O:39])=[O:38]
Reactant: OCc1ccc(-c2nnc3n2-c2cccnc2Nc2ccccc2-3)cc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CS(=O)(=O)OCc1ccc(-c2nnc3n2-c2cccnc2Nc2ccccc2-3)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of (4-(9H-benzo[f]pyrido[2,3-b][1,2,4]triazolo[4,3-d][1,4]diazepin-3-yl)phenyl)methanol (1.35 g, 3.95 mmol) in dichloromethane (70 mL) was added diisopropylethylamine (1.72 mL, 9.89 mmol) and methanesulfonyl chloride (0.767 mL, 9.89 mmol). The reaction mixture was stirred at room temperature for 30 minutes. The mixture was washed with water (50 mL), saturated aqueous sodium bicarbonate solution (50 mL) and water (3×50 mL). The organic phase was dried over sodium sulfate, filtered and concentrated in vacuo, yielding the 4-(9H-benzo[f]pyrido[2,3-b][1,2,4]triazolo[4,3-d][1,4]diazepin-3-yl)benzyl methanesulfonate as a light yellow solid (1.7 g, quantitative). M.p.=252-253° C.; 400 MHz 1H NMR (DMSO-d6) δ: 8.82 (br.s, 1H), 8.22 (dd, J=4.8, 1.6 Hz, 1H), 7.97 (dd, J=7.6, 1.6 Hz, 1H), 7.6-7.4 (m, 5H), 7.36 (dd, J=8.0, 1.2 Hz, 1H), 7.2-7.1 (m, 2H), 6.92 (dd, J=7.6, 4.4 Hz, 1H), 5.33 (s, 2H), 3.28 (s, 3H); LCMS [M+H]: 420.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([Cl:11])[CH:10]=1)[NH:7][C:6]1[C:12]([C:22]([F:25])([F:24])[F:23])([O:17][Si](C)(C)C)[CH2:13][CH2:14][CH2:15][CH2:16][C:5]2=1.[OH-].[K+]>C1COCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([Cl:11])[CH:10]=1)[NH:7][C:6]1[C:12]([C:22]([F:24])([F:25])[F:23])([OH:17])[CH2:13][CH2:14][CH2:15][CH2:16][C:5]2=1
Reactant: C[Si](C)(C)OC1(C(F)(F)F)CCCCc2c1[nH]c1c(Cl)cc(Cl)cc21
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: OC1(C(F)(F)F)CCCCc2c1[nH]c1c(Cl)cc(Cl)cc21
Temperature: 25 °C
Yield: 2.1 %

Procedure:
2,4-Dichloro-6-(trifluoromethyl)-6-(trimethylsilyloxy)-5,6,7,8,9,10-hexahydrocyclohepta[b]indole (0.3 g, 7.0 mmol) was dissolved in THF (5 mL) and KOH (0.2 g, 3.6 mmol) in water (5 mL) was added to the mixture. The reaction mixture was refluxed for 1 h and then cooled to room temperature, diluted with water and extracted with EtOAc (3×20 mL). The combined organic extracts were dried over Na2SO4 and concentrated under reduced pressure. The crude residue was purified by silica gel chromatography [EtOAc-hexane (1:17) as eluant] to furnish the title compound as a pale yellow solid (0.05 g, 21%). 1H NMR (500 MHz, CDCl3, δ in ppm) 8.67 (br s, 1H), 7.43 (d, J=1.5 Hz, 1H), 7.41 (d, J=1.5 Hz, 1H), 2.9 (m, 1H), 2.73 (m, 1H), 2.49 (s, 1H) 2.43-2.4 (m, 1H), 2.08-2.03 (m, 4H), 1.16-1.54 (m, 1H)