Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.C[NH:3][C@H:4]([C:15]([OH:17])=O)[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=1.C([N:20](CC)CC)C.CCOCC>CO>[N+:12]([C:9]1[CH:8]=[CH:7][C:6]([CH2:5][C@@H:4]([C:15]([NH2:20])=[O:17])[NH2:3])=[CH:11][CH:10]=1)([O-:14])=[O:13]
Reactant: CN[C@@H](Cc1ccc([N+](=O)[O-])cc1)C(=O)O
Reactant: CCN(CC)CC
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: NC(=O)[C@@H](N)Cc1ccc([N+](=O)[O-])cc1
Temperature: -10 °C
Reaction time: 42 h

Procedure:
A slurry of 1 (10.97 g, 42.1 mmol) in dry methanol (5 ml) was treated with triethylamine (6.45 ml). After clearing, anhydrous ether (200 ml) was added to the solution and cooled to -10° C. for one hour. Precipitated triethylamine hydrochloride was removed by filtration and the filtrate concentrated to a limpid yellow oil. The oil was added to dry methanol (250 ml) previously saturated with NH3 (g) at -10° C., tightly stoppered and left at -10° C. for 42 hours. The precipitated product was collected and dried under vacuum. The liquid filtrate was spotted on a TLC plate and developed with CHCl3 :MeOH (4:1) which revealed one spot at Rf =0.50, identical to that of the collected precipitate. The filtrate was therefore stripped to dryness and the remaining solid 2 combined with the precipitate (8.12 g, 92.3%): mp 160°-162° C.; 1H NMR (220 MHz, DMSO-d6), δ 8.07 (d, 2, J32 8.0), 7.5 (d, 2, J=8.0), 7.41 (s, 1), 7.00 (s, 1), 3.50 (t, 1, J=6.0), 3.09 (dd, 1, J=6.0, 16.0); 2.81 (dd, 1, J=6.0, 16.0) CI-MS 210 ((M+1)/z).
Reaction SMILES: [NH2:1][CH:2]1[C:19](=[O:20])[N:4]2[C:5]([C:16]([OH:18])=[O:17])=[C:6]([CH2:9][S:10][C:11]3[NH:15][CH:14]=[N:13][N:12]=3)[CH2:7][S:8][C@H:3]12.C[Si](C([Si](C)(C)C)C(N)=O)(C)C.[Cl:33][CH:34]([Cl:38])[C:35](Cl)=[O:36]>C(Cl)Cl>[Cl:33][CH:34]([Cl:38])[C:35]([NH:1][CH:2]1[C:19](=[O:20])[N:4]2[C:5]([C:16]([OH:18])=[O:17])=[C:6]([CH2:9][S:10][C:11]3[NH:15][CH:14]=[N:13][N:12]=3)[CH2:7][S:8][C@H:3]12)=[O:36]
Reactant: O=C(Cl)C(Cl)Cl
Reactant: NC1C(=O)N2C(C(=O)O)=C(CSc3nnc[nH]3)CS[C@H]12
Agent: C[Si](C)(C)C(C(N)=O)[Si](C)(C)C
Solvent: ClCCl
Product: O=C(O)C1=C(CSc2nnc[nH]2)CS[C@@H]2C(NC(=O)C(Cl)Cl)C(=O)N12
Reaction time: 0.5 h
Yield: 69.6 %

Procedure:
7-Amino-3-(4H-1,2,4-triazol-3-ylthiomethyl)-3-cephem-4-carboxylic acid (3.13 g) was suspended in dried methylene chloride (30 ml) and bis(trimethylsilyl)acetamide (6.10 g) was added to the suspension to give a solution. A solution of dichloroacetyl chloride (1.62 g) in dried methylene chloride (20 ml) was added slowly to the solution at -20° C. The mixture was stirred at the same temperature for 30 minutes and then allowed to stand at room temperature. Methylene chloride was distilled off from the reaction mixture under reduced pressure. To the residue was added ice water and the aqueous solution was adjusted to pH 8 with 5% aqueous sodium bicarbonate, washed with ethyl acetate and then filtered. The filtrate was adjusted to pH 2 with 10% hydrochloric acid and extracted with ethyl acetate (50 ml) three times. These extracts were put together, washed with water twice and with saturated aqueous sodium chloride and dried over magnesium sulfate. Ethyl acetate was distilled off from the solution under reduced pressure. To the residue was added ether and the mixture was stirred. Precipitates were collected by filtration and dried to give 7-dichloroacetamido-3-(4H-1,2,4-triazol-3-ylthiomethyl)-3-cephem-4-carboxylic acid (2.95 g).
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:25](=[O:26])[N:6]2[CH:7]([C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=3)=[O:13])[C:8](=O)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.C(N(C(C)C)CC)(C)C.[SH:51][C@@H:52]1[CH2:56][N:55]([C:57]([O:59][CH2:60][C:61]2[CH:66]=[CH:65][C:64]([N+:67]([O-:69])=[O:68])=[CH:63][CH:62]=2)=[O:58])[C@H:54]([C:70]([N:72]2[CH2:76][CH2:75][C@H:74]([N:77]3[CH:81]=[N:80][CH:79]=[N:78]3)[CH2:73]2)=[O:71])[CH2:53]1>C(#N)C>[OH:1][C@@H:2]([C@H:4]1[C:25](=[O:26])[N:6]2[C:7]([C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=3)=[O:13])=[C:8]([S:51][C@@H:52]3[CH2:56][N:55]([C:57]([O:59][CH2:60][C:61]4[CH:66]=[CH:65][C:64]([N+:67]([O-:69])=[O:68])=[CH:63][CH:62]=4)=[O:58])[C@H:54]([C:70]([N:72]4[CH2:76][CH2:75][C@H:74]([N:77]5[CH:81]=[N:80][CH:79]=[N:78]5)[CH2:73]4)=[O:71])[CH2:53]3)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3]
Reactant: O=C([C@@H]1C[C@H](S)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1)N1CC[C@H](n2cncn2)C1
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)C(=O)[C@H](C)[C@H]12
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@H]3C[C@@H](C(=O)N4CC[C@H](n5cncn5)C4)N(C(=O)OCc4ccc([N+](=O)[O-])cc4)C3)[C@H](C)[C@H]12
Reaction time: 1 h
Yield: 70.1 %

Procedure:
486 mg of 4-nitrobenzyl (1R,5R,6S)-6-[(1R)-1-hydroxyethyl]-1-methyl-2-oxo-1-carbapenam-3-carboxylate were dissolved in 5 ml of dry acetonitrile, and 379 mg of diphenylphosphoryl chloride and 182 mg of diisopropylethylamine were added dropwise, with ice-cooling, to the resulting solution. The mixture was then stirred at the same temperature for 1 hour. At the end of this time, a solution of 173 mg of diisoproylethylamine and 690 mg of (2S,4S)-4-mercapto-2-[(3S)-3-(1-1,2,4-triazolyl)-1-pyrrolidinylcarbonyl]-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (prepared as described in Preparation 119) in 4 ml of dry acetonitrile was added dropwise with ice-cooling, to the resulting mixture, and the mixture was stirred at the same temperature for 6 hours. The solvent was then removed by distillation under reduced pressure, and the resulting residue was dissolved in ethyl acetate. The resulting solution was then washed with water, with an aqueous solution of sodium hydrogencarbonate, again with water and finally with a saturated aqueous solution of sodium chloride. The aqueous layer was extracted with methylene chloride, and the aqueous layer was combined with the washings and dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, and the residue was purified by silica gel column chromatography, using a 5:1 by volume mixture of ethyl acetate and methanol as the eluent, to obtain 744 mg of the title compound, as a powder.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]3[CH:12]=[C:13]([CH:16]=[CH:17][C:18]=3[O:19][CH3:20])[CH:14]=O)=[CH:8][CH:9]=2)[CH:4]=[CH:3]1.[CH3:21][O:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=1)[C@H:26]([NH2:28])[CH3:27]>>[CH3:21][O:22][C:23]1[CH:24]=[C:25]([C@H:26]([NH:28][CH2:14][C:13]2[CH:16]=[CH:17][C:18]([O:19][CH3:20])=[C:11]([C:7]3[CH:6]=[C:5]4[C:10](=[CH:9][CH:8]=3)[N:2]([CH3:1])[CH:3]=[CH:4]4)[CH:12]=2)[CH3:27])[CH:29]=[CH:30][CH:31]=1
Reactant: COc1ccc(C=O)cc1-c1ccc2c(ccn2C)c1
Reactant: COc1cccc([C@@H](C)N)c1
Product: COc1cccc([C@@H](C)NCc2ccc(OC)c(-c3ccc4c(ccn4C)c3)c2)c1

Procedure:
The title compound was prepared from 3-(1-methylindol-5-yl)-4-methoxybenzaldehyde and (R)-3-methoxy-α-methylbenzylamine according to general procedure C.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9]([C:12]#[C:13][C:14]2[CH:19]=[CH:18][C:17]([S:20]([NH:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=3)(=[O:22])=[O:21])=[CH:16][CH:15]=2)=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].Cl>[OH-].[Na+]>[OH:1][C:2]1[CH:11]=[CH:10][C:9]([C:12]#[C:13][C:14]2[CH:15]=[CH:16][C:17]([S:20]([NH:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=3)(=[O:22])=[O:21])=[CH:18][CH:19]=2)=[CH:8][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COC(=O)c1cc(C#Cc2ccc(S(=O)(=O)Nc3ccccn3)cc2)ccc1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)c1cc(C#Cc2ccc(S(=O)(=O)Nc3ccccn3)cc2)ccc1O
Reaction time: 2 h

Procedure:
25 The ester from Example 1d (23.7 g, 58 mmol) was dissolved in 1M NaOH (190 ml) and refluxed for 6 h. The cooled solution was acidified with an excess of 6M HCl. The precipitated formed was allowed to stand for 2 h, filtered off and washed with water (3×200 ml). The white product was dried at 60° C. in vacuo. Yield 21.7 g (95
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([CH2:12][N:13]3[CH2:18][CH2:17][N:16]([C:19]4[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][N:20]=4)[CH2:15][CH2:14]3)[CH:10]=[N:11][C:5]=2[N:4]2[CH2:28][CH2:29][CH2:30][CH2:31][C@@H:3]12.[CH2:32]([N:34](C(C)C)C(C)C)C.Cl.CN>CN(C=O)C>[CH3:32][NH:34][C:23](=[O:24])[C:22]1[CH:26]=[CH:27][C:19]([N:16]2[CH2:15][CH2:14][N:13]([CH2:12][C:9]3[CH:10]=[N:11][C:5]4[N:4]5[CH2:28][CH2:29][CH2:30][CH2:31][C@H:3]5[C:2](=[O:1])[NH:7][C:6]=4[CH:8]=3)[CH2:18][CH2:17]2)=[N:20][CH:21]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: O=C(O)c1ccc(N2CCN(Cc3cnc4c(c3)NC(=O)[C@@H]3CCCCN43)CC2)nc1
Agent: CN
Agent: Cl
Solvent: CN(C)C=O
Product: CNC(=O)c1ccc(N2CCN(Cc3cnc4c(c3)NC(=O)[C@@H]3CCCCN43)CC2)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 30.7 %

Procedure:
(S)-6-(4-((6-oxo-6,6a,7,8,9,10-hexahydro-5H-dipyrido[1,2-a:3′,2′-e]pyrazin-3-yl)methyl)piperazin-1-yl)nicotinic acid (75 mg, 0.178 mmol) was taken up in DMF (0.9 mL). To the mixture was added N-ethyl-N-isopropylpropan-2-amine (93 μl, 0.53 mmol), 0-(7-Azabenzotriazole-1-yl)-N,N,N′N′-tetramethyluronium hexafluorophosphate (101 mg, 0.266 mmol), and methanamine hydrochloride (13.2 mg, 0.195 mmol). The reaction was stirred at room temperature overnight. The reaction was purified via HPLC (10-80 MeCN/H2O, TFA buffered). The fractions were collected and lyophilized to yield 23.8 mg (30%) of the product as a white solid. 1H NMR (DMSO-d6) δ (ppm): 10.48 (s, 1H), 8.56 (d, J=2.3 Hz, 1H), 8.20 (d, J=4.5 Hz, 1H), 7.92 (dd, J=9.0, 2.1 Hz, 1H), 7.65 (s, 1H), 6.98 (d, J=1.5 Hz, 1H), 6.82 (d, J=8.8 Hz, 1H), 4.50 (d, J=12.9 Hz, 1H), 3.77-3.94 (m, 1H), 3.56 (d, J=2.3 Hz, 4H), 3.34 (s, 2H), 2.74 (d, J=4.5 Hz, 3H), 2.53-2.69 (m, 1H), 2.41 (br. s., 4H), 1.99-2.08 (m, 1H), 1.84 (br. s., 1H), 1.59-1.69 (m, 1H), 1.31-1.57 (m, 3H). [M+H] calc'd for C25H33N7O2, 436; found, 436.
Reaction SMILES: NOS(O)(=O)=O.C[N:8](C)[C:9](=[N:11][C:12]([C:14]1[CH:15]=[N:16][C:17]([N:20]2[CH2:25][CH2:24][N:23]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=3)[CH2:22][CH2:21]2)=[CH:18][CH:19]=1)=[S:13])[CH3:10].N1C=CC=CC=1>CO.C(O)C>[CH3:10][C:9]1[N:11]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:25][CH2:24][N:23]([C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=4)[CH2:22][CH2:21]3)=[N:16][CH:15]=2)[S:13][N:8]=1
Reactant: CC(=NC(=S)c1ccc(N2CCN(c3cccc(C(F)(F)F)c3)CC2)nc1)N(C)C
Agent: NOS(=O)(=O)O
Solvent: CO
Solvent: c1ccncc1
Solvent: CCO
Product: Cc1nsc(-c2ccc(N3CCN(c4cccc(C(F)(F)F)c4)CC3)nc2)n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 34.5 %

Procedure:
A mixture of hydroxylamine-O-sulfonic acid (0.011 mol) in methanol (15 ml) was added at once to a mixture of intermediate 5 (0.01 mol) and pyridine (0.02 mol) in ethanol (40 ml). The mixture was stirred at room temperature for 90 minutes. The solvent was evaporated. The residue was dissolved in DCM, washed with water and an aqueous NaOH 0.1N solution, dried, filtered and the solvent was evaporated. The residue was taken up in methanol, filtered off and dried. The residue was taken up in acetonitrile (100 ml). The mixture was stirred and boiled until complete dissolution and then allowed to crystallize out. The precipitate was filtered off and dried, yielding 1.4 g (35%) of 1-[5-(3-methyl-1,2,4-thiadiazol-5-yl)-2-pyridinyl]-4-[3-(trifluoromethyl)-phenyl]piperazine (compound 8).
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[C:8]([CH:9]([CH3:11])[CH3:10])=[C:7]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][C:14]=2[CH3:20])[C:6]([O:21][C@@H:22]2[O:48][C@H:47]([CH2:49][O:50][C:51](=[O:56])[C:52]([CH3:55])([CH3:54])[CH3:53])[C@@H:39]([O:40][C:41](=[O:46])[C:42]([CH3:45])([CH3:44])[CH3:43])[C@H:31]([O:32][C:33](=[O:38])[C:34]([CH3:37])([CH3:36])[CH3:35])[C@H:23]2[O:24][C:25](=[O:30])[C:26]([CH3:29])([CH3:28])[CH3:27])=[N:5]1.Br[CH2:58][CH2:59][CH2:60][Cl:61].[OH-].[Na+].Cl>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1>[Cl:61][CH2:60][CH2:59][CH2:58][O:19][C:16]1[CH:17]=[CH:18][C:13]([CH2:12][C:7]2[C:6]([O:21][C@@H:22]3[O:48][C@H:47]([CH2:49][O:50][C:51](=[O:56])[C:52]([CH3:54])([CH3:53])[CH3:55])[C@@H:39]([O:40][C:41](=[O:46])[C:42]([CH3:45])([CH3:44])[CH3:43])[C@H:31]([O:32][C:33](=[O:38])[C:34]([CH3:35])([CH3:36])[CH3:37])[C@H:23]3[O:24][C:25](=[O:30])[C:26]([CH3:29])([CH3:28])[CH3:27])=[N:5][N:4]([CH2:3][CH2:2][OH:1])[C:8]=2[CH:9]([CH3:11])[CH3:10])=[C:14]([CH3:20])[CH:15]=1
Reactant: Cc1cc(O)ccc1Cc1c(O[C@@H]2O[C@H](COC(=O)C(C)(C)C)[C@@H](OC(=O)C(C)(C)C)[C@H](OC(=O)C(C)(C)C)[C@H]2OC(=O)C(C)(C)C)nn(CCO)c1C(C)C
Reactant: ClCCCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [Br-]
Solvent: C1CCOC1
Product: Cc1cc(OCCCCl)ccc1Cc1c(O[C@@H]2O[C@H](COC(=O)C(C)(C)C)[C@@H](OC(=O)C(C)(C)C)[C@H](OC(=O)C(C)(C)C)[C@H]2OC(=O)C(C)(C)C)nn(CCO)c1C(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1-(2-hydroxyethyl)-4-[(4-hydroxy-2-methylphenyl)methyl]-5-isopropyl-3-(2,3,4,6-tetra-O-pivaloyl-β-D-glucopyranosyloxy)-1H-pyrazole (0.69 g), 1-bromo-3-chloropropane (0.22 mL) and tetra(n-butyl)ammonium bromide (0.14 g) in tetrahydrofuran (8 mL) was added 5 mol/L aqueous sodium hydroxide solution (0.43 mL), and the mixture was stirred at room temperature overnight. The reaction mixture was poured into 0.5 mol/L hydrochloric acid, and the resulting mixture was extracted with diethylether. The extract was washed with water and brine successively, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=1/1) to give the title compound (0.56 g).
Reaction SMILES: [OH:1][CH2:2][CH:3]1[O:8][CH2:7][CH2:6][N:5](C(OC(C)(C)C)=O)[CH2:4]1.[C:16]([C:20](O)=[O:21])([F:19])([F:18])[F:17]>C(Cl)Cl>[F:17][C:16]([F:19])([F:18])[C:20]([O:1][CH2:2][CH:3]1[O:8][CH2:7][CH2:6][NH:5][CH2:4]1)=[O:21]
Reactant: CC(C)(C)OC(=O)N1CCOC(CO)C1
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(OCC1CNCCO1)C(F)(F)F

Procedure:
Tert-Butyl 2-(hydroxymethyl)-4-morpholinecarboxylate (5.13 g, 23.61 mmol) was treated with CF3CO2H (20 mL) in CH2Cl2 (50 mL) at room temperature for 3 h. The volatiles were removed in vacuo to give the subtitled compound (7.6 g).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:17])[CH2:10][CH2:11][C@@H:12]([C:14]([OH:16])=[O:15])N)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br-:18].[Na+].N([O-])=O.[Na+].S(=O)(=O)(O)O>Br.C(OCC)C>[CH2:1]([O:8][C:9](=[O:17])[CH2:10][CH2:11][CH:12]([Br:18])[C:14]([OH:16])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [Br-]
Reactant: N[C@@H](CCC(=O)OCc1ccccc1)C(=O)O
Agent: Br
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Solvent: CCOCC
Product: O=C(CCC(Br)C(=O)O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 46.2 %

Procedure:
To a solution of L-glutamic acid-5-benzylester (Fluka, 3.0 g, 0.013 mol) and sodium bromide (Fisher, 4.6 g, 0.044 mol) in aqueous hydrobromic acid (Fluka, 1 M, 22.5 mL) cooled to 0° C. was added portion wise sodium nitrite (Fluka, 1.6 g, 0.023 mol). After stirring for 2 h at 0° C., concentrated sulphuric acid (Merck, 1.2 mL) was added followed by diethyl ether (Eternell). The water phase was extracted three times with diethyl ether. The combined organic phases was washed four times with brine, dried over sodium sulphate and evaporated under reduced pressure. The crude product was purified using normal phase chromatography (Silica column (40 g), solvents: A=hexane, B=ethyl acetate, gradient: 10-35% B over 20 min, flow rate 40 mL/min, UV detection at 214 and 254 nm) affording 1.81 g of the pure product. Yield 46%. Structure verified by NMR.
Reaction SMILES: [C:1]([O:5][C:6](=[O:39])[C@@H:7]([NH:29][S:30]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)(=[O:32])=[O:31])[CH2:8][NH:9][C:10]([N:12]1[CH2:17][CH2:16][CH:15]([C:18]2[CH:27]=[CH:26][C:25]3[C:20](=[N:21][CH:22]=[C:23](Br)[CH:24]=3)[N:19]=2)[CH2:14][CH2:13]1)=[O:11])([CH3:4])([CH3:3])[CH3:2]>[Pd].CCO>[C:1]([O:5][C:6](=[O:39])[C@@H:7]([NH:29][S:30]([C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)(=[O:31])=[O:32])[CH2:8][NH:9][C:10]([N:12]1[CH2:13][CH2:14][CH:15]([C:18]2[CH:27]=[CH:26][C:25]3[CH2:24][CH2:23][CH2:22][NH:21][C:20]=3[N:19]=2)[CH2:16][CH2:17]1)=[O:11])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)[C@H](CNC(=O)N1CCC(c2ccc3cc(Br)cnc3n2)CC1)NS(=O)(=O)c1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)[C@H](CNC(=O)N1CCC(c2ccc3c(n2)NCCC3)CC1)NS(=O)(=O)c1ccccc1

Procedure:
A solution of bromide 3-6 (125 mg, 0.2021 mmol), 10% Pd/C (125 mg) and EtOH (5 ml) was stirred under 1 atm H2 for 1.0 h. The reaction mixture was then filtered through a celite pad and the filtrate concentrated to give urea 3-7 as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[C:8](Br)[C:7]([NH2:11])=[CH:6][C:5]=1[O:12][CH3:13].[CH3:15][Si:16]([CH3:21])([CH3:20])[C:17]#[C:18][CH3:19].C([O-])([O-])=O.[Na+].[Na+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN(C=O)C.[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:1][O:2][C:3]([C:4]1[CH:9]=[C:8]2[C:7](=[CH:6][C:5]=1[O:12][CH3:13])[NH:11][C:17]([Si:16]([CH3:21])([CH3:20])[CH3:15])=[C:18]2[CH3:19])=[O:14]
Reactant: CC#C[Si](C)(C)C
Reactant: COC(=O)c1cc(Br)c(N)cc1OC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CN(C)C=O
Product: COC(=O)c1cc2c(C)c([Si](C)(C)C)[nH]c2cc1OC

Procedure:
An indole hydrazide can also be prepared by treating a solution of 2-methoxy-4-amino-benzoic acid methyl ester (xvii) in ethanol with N-bromosuccinamide to form 2-methoxy-4-amino-5-bromo-benzoic acid methyl ester (xviii) (see Scheme VIII). A solution of 2-methoxy-4-amino-5-bromo-benzoic acid methyl ester (xviii) in DMF is then reacted with trimethyl-prop-1-ynyl silane (xix) in the presence of with palladium acetate, Na2CO3, triphenylphosphine and tetrabutylaminium iodide to form 6-methoxy-3-methyl-2-trimethylsilanyl-1H-indole-5-carboxylic acid methyl ester (xx). Compound (xx) is then treated with an aqueous HCl solution to remove the trimethylsilanyl group and form 6-methoxy-3-methyl-1H-indole-5-carboxylic acid methyl ester (xxi). Compound (xxi) is treated with NaOH in a THF/H2O solution to convert the ester to a carboxylic acid. The carboxylic acid is then activated by treating it with oxalyl chloride in dichloromethane and a catalytic amount of DMF, then the activated carboxylic acid is converted to a hydrazide by treating it with hydrazine hydrate in dichloromethane to form 6-methoxy-3-methyl-1H-indole-5-carboxylic acid hydrazide (xxii). Hydrazide (xxii) can be used in the method of Scheme Vor VI to form a compound of the invention
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8](=[O:16])[CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[C:4]([CH3:17])[N:3]=1.[Br:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23]Br)=[CH:21][CH:20]=1>>[Br:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][CH:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:8]([C:6]2[CH:5]=[C:4]([CH3:17])[N:3]=[C:2]([CH3:1])[CH:7]=2)=[O:16])=[CH:21][CH:20]=1
Reactant: Cc1cc(C(=O)Cc2ccccc2)cc(C)n1
Reactant: BrCc1ccc(Br)cc1
Product: Cc1cc(C(=O)C(Cc2ccc(Br)cc2)c2ccccc2)cc(C)n1

Procedure:
In analogy to example 43, step 1, from 1-(2,6-dimethyl-pyridin-4-yl)-2-phenyl-ethanone and 4-bromobenzylbromide was prepared the title compound as a yellow oil, MS (ESI+): m/z=394.0 ([M+H]+, 1Br).
Reaction SMILES: C[O:2][C:3]1[C:13]2[S:12][C:11]3[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=3[CH2:9][C:8](=[O:18])[C:7]=2[CH:6]=[CH:5][CH:4]=1.Cl.N1C=CC=CC=1.N#N>>[OH:2][C:3]1[C:13]2[S:12][C:11]3[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=3[CH2:9][C:8](=[O:18])[C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: COc1cccc2c1Sc1ccccc1CC2=O
Agent: Cl
Agent: N#N
Solvent: c1ccncc1
Product: O=C1Cc2ccccc2Sc2c(O)cccc21
Temperature: 25 °C

Procedure:
6-Methoxy-11H-dibenzo[b,f]thiepin-10-one (1.54 g, 6 mmol) and pyridine hydrochloride (10 g) were heated for 2 hours at 200° C. with stirring and N2 atmosphere. The reaction was cooled down to room temperature and then triturated in water (200 ml) The pale green precipitate was filtered and dried overnight in a vacuum oven (50° C.) (1.40 g, 96%). 1HNMR (300 MHz, DMSO-d6): δH=4.20 (2H, s), 7.05–7.69 (7H, m), 10.56 (1H, s).
Reaction SMILES: [NH2:1][C@@H:2]([CH:5]([CH2:8][CH3:9])[CH2:6][CH3:7])[CH2:3][OH:4].C(N(CC)CC)C.[Cl:17][C:18]1[S:22][C:21]([S:23](Cl)(=[O:25])=[O:24])=[CH:20][CH:19]=1>C(Cl)Cl>[Cl:17][C:18]1[S:22][C:21]([S:23]([NH:1][C@H:2]([CH2:3][OH:4])[CH:5]([CH2:8][CH3:9])[CH2:6][CH3:7])(=[O:25])=[O:24])=[CH:20][CH:19]=1
Reactant: CCC(CC)[C@H](N)CO
Reactant: O=S(=O)(Cl)c1ccc(Cl)s1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(CC)[C@@H](CO)NS(=O)(=O)c1ccc(Cl)s1
Temperature: 0 °C
Yield: 45.2 %

Procedure:
A mixture of (S)-2-amino 3ethyl pentan-1-ol (9) (200 mg) and methylene chloride (20 mL) was placed under argon, and cooled to 0° C. Triethyl amine (484 mg) was added followed by the drop wise addition of 5-chlorothiophene-2-sulfonyl chloride (347.2) in methylene chloride (5 mL) for 30 min to obtain (S)—N-(5-chlorothiophene-2-sulfonyl)-β,β-diethylalaninol (1A) (45.2% overall yield and 98% ee).
Reaction SMILES: [CH3:1][C:2]1([CH3:5])[CH2:4][S:3]1.[CH2:6]([NH:10][C:11]#[N:12])[CH2:7][CH2:8][CH3:9].C(=O)([O-])[O-].[K+].[K+].O>CC(=O)CC>[CH2:6]([N:10]1[CH2:4][C:2]([CH3:1])([CH3:5])[S:3][C:11]1=[NH:12])[CH2:7][CH2:8][CH3:9]
Reactant: CCCCNC#N
Reactant: CC1(C)CS1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: O
Product: CCCCN1CC(C)(C)SC1=N
Temperature: 80 °C
Yield: 66.6 %

Procedure:
A mixture of 2,2-dimethyl-thiirane (TCI, 1.5 g, 17 mmol), N-butyl-cyanamide (1.7 g, 17 mmol) (prepared as described in Ross J. Med. Chem. 1979, 22; 412) and potassium carbonate (2.4 g, 17 mmol) in 2-butanone (15 mL) was heated to 80° C. overnight. The mixture was poured into water, and extracted twice with ethyl acetate. The combined organic extracts were dried over Na2SO4, filtered, concentrated under reduced pressure to afford 2.11 g of the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][C:15]=1[C:16]([F:19])([F:18])[F:17])[O:12][CH2:11][C:10]1[N:5]2[CH:6]([CH3:29])[C:7](=[O:28])[N:8]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[N:9]=1.[C:30]([O:34][C:35]([N:37]1[CH2:40][C:39](=[CH2:41])[CH2:38]1)=[O:36])([CH3:33])([CH3:32])[CH3:31].CC1C(P(C2C(C)=CC=CC=2)C2C(C)=CC=CC=2)=CC=CC=1.C(N(CC)CC)C>CC#N.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:30]([O:34][C:35]([N:37]1[CH2:40][C:39](=[CH:41][C:2]2[CH:3]=[C:4]3[C:13](=[CH:14][C:15]=2[C:16]([F:18])([F:17])[F:19])[O:12][CH2:11][C:10]2[N:5]3[CH:6]([CH3:29])[C:7](=[O:28])[N:8]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:25])([CH3:26])[CH3:27])[N:9]=2)[CH2:38]1)=[O:36])([CH3:33])([CH3:32])[CH3:31]
Reactant: CC1C(=O)N(COCC[Si](C)(C)C)N=C2COc3cc(C(F)(F)F)c(Br)cc3N21
Reactant: C=C1CN(C(=O)OC(C)(C)C)C1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC1C(=O)N(COCC[Si](C)(C)C)N=C2COc3cc(C(F)(F)F)c(C=C4CN(C(=O)OC(C)(C)C)C4)cc3N21
Temperature: 25 °C
Yield: 20.3 %

Procedure:
A solution of 6-bromo-4-methyl-7-trifluoromethyl-2-(2-trimethylsilanyl-ethoxymethyl)-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one (Example #53, Step E, 0.30 g, 0.61 mmol), 3-methylene-azetidine-1-carboxylic acid tert-butyl ester (0.123 g, 0.73 mmol), Pd(OAc)2 (0.027 g, 0.12 mmol), tri-O-tolylphosphine (0.074 g, 0.24 mmol) and triethylamine (0.184 g, 1.82 mmol) in CH3CN (10 mL) was heated at 110° C. for 14 hr. The reaction mixture was cooled to ambient temperature and the solvent was removed in vacuo. The residue was purified by preparative TLC (eluting with 25% EtOAc in petroleum ether) to give 3-[4-methyl-3-oxo-7-trifluoromethyl-2-(2-trimethylsilanyl-ethoxymethyl)-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-ylmethylene]-azetidine-1-carboxylic acid tert-butyl ester (0.072 g, 20%) as a yellow solid. LC/MS (Table 1, Method 2) Rt=1.523 min.; MS m/z: 605 [M+23]+.