Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10](=[O:21])[C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)[CH2:5][CH2:4]1)=O.ClC1C=CC(C(F)(F)F)=CC=1C(N[C@H]1CC[C@H](C=O)CC1)=O.[NH2:44][C:45]1[CH:54]=[CH:53][CH:52]=[C:51]2[C:46]=1[CH:47]=[CH:48][CH:49]=[N:50]2.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[N:50]1[C:51]2[C:46](=[C:45]([NH:44][CH2:1][C@H:3]3[CH2:8][CH2:7][C@H:6]([NH:9][C:10](=[O:21])[C:11]4[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=4)[CH2:5][CH2:4]3)[CH:54]=[CH:53][CH:52]=2)[CH:47]=[CH:48][CH:49]=1
Reactant: O=C[C@H]1CC[C@H](NC(=O)c2cccc(C(F)(F)F)c2)CC1
Reactant: Nc1cccc2ncccc12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C[C@H]1CC[C@H](NC(=O)c2cc(C(F)(F)F)ccc2Cl)CC1
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: O=C(N[C@H]1CC[C@H](CNc2cccc3ncccc23)CC1)c1cccc(C(F)(F)F)c1
Temperature: 140 °C

Procedure:
To a solution of trans-N-(4-formyl-cyclohexyl)-3-trifluoromethyl-benzamide (prepared analogously to trans-2-chloro-N-(4-formyl-cyclohexyl)-5-trifluoromethyl-benzamide (Ex. 1 step 3) from the appropriate starting compounds) (100 mg, 0.33 mmol) and 5-aminoquinoline (48 mg, 0.33 mmol) in dry 1,2-dichloroethane (2 mL) in a 2-5 mL capacity microwave tube, is added acetic acid (0.06 mL, 1.0 mmol) and sodium triacetoxyborohydride (178 mg, 0.84 mmol). The tube is sealed with a septum and the mixture is heated at 140° C. for 10 minutes in a Biotage Initiator microwave. After cooling to room temperature, the solvents are removed under reduced pressure and the residue is purified by chromatography on a pre-packed reverse phase column. [MH+428.45].
Reaction SMILES: C(O)C(N)(CO)CO.Cl.SCCO.P([O:26][CH2:27][C@H:28]1O[C@@H](N2C3N=CN=C(N)C=3N=C2)[C@H:30](O)[C@@H:29]1O)(OP(OP(O)(O)=O)(O)=O)(=O)O.[C:45]([O-:50])(=[O:49])[C:46]([O-:48])=[O:47].[Mg+2:51]>>[C:45]([O-:50])(=[O:49])[C:46]([O-:48])=[O:47].[Mg+2:51].[CH3:30][CH2:29][CH2:28][CH:27]=[O:26]
Reactant: Nc1ncnc2c1ncn2[C@@H]1O[C@H](COP(=O)(O)OP(=O)(O)OP(=O)(O)O)[C@@H](O)[C@H]1O
Agent: Cl
Agent: NC(CO)(CO)CO
Agent: O=C([O-])C(=O)[O-]
Product: CCCC=O

Procedure:
100 μl of a DNA ligase reaction mixture (50 mM Tris-HCl (pH 8.0 at 25° C.); 10 mM 2-mercaptoethanol; 1 mM ATP; 2 μg lambda DNA digested with Hind III; 2 Weiss units of T4 DNA ligase) was added to the prepared reaction tubes. Following incubation of the magnesium oxalate-containing tube with the DNA ligase reaction mixture at 30° C. for t=1, 2, 3, 5 and 10 min., 15 μl samples were removed to clean tubes (without magnesium oxalate) and incubation proceeded for an additional hour at 30° C. Electrophoretic analysis indicated that an incubation time of 10 min at 30° C. was needed to allow enough magnesium to diffuse from the resin in order to activate T4 DNA ligase (FIG. 3, lane 5).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH3:5][O:6][C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=1.[C:17]([O:22][CH2:23][CH3:24])(=[O:21])[C:18]([CH3:20])=[O:19]>O1CCCC1>[OH:19][C:18]([C:7]1([O:6][CH3:5])[CH:16]=[CH:15][C:14]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH2:8]1)([CH3:20])[C:17]([O:22][CH2:23][CH3:24])=[O:21]
Reactant: CCOC(=O)C(C)=O
Reactant: COc1ccc2ccccc2c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: C1CCOC1
Product: CCOC(=O)C(C)(O)C1(OC)C=Cc2ccccc2C1
Temperature: 20 °C
Reaction time: 1 h
Yield: 2 %

Procedure:
Aluminium chloride (1,62 g, 12,2 mmol) was added in 3 portions to a solution of 2-methoxynaphthalene (1,28 g, 8,09 mmol) in tetrahydrohydrofuran (20 mL) at 5° C. Ethyl pyruvate (1,41 g, 12,2 mmol) in tetrahydrofuran (10 mL) was added oveer 1 hour at this temperature. The reaction was allowed to proceed for 1 hour and warmed to 20° C. for 1 hour. Ethyl 2-hydroxy-2-(6-methoxynaphth-6-yl)propionate was formed in 2% yield with 98% recovery of the starting material.
Reaction SMILES: Cl.[C:2]([O:6][C:7](=[O:18])[C@H:8]([CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[NH2:9])([CH3:5])([CH3:4])[CH3:3].C(=O)([O-])[O-].[K+].[K+].[CH2:25](Br)[CH:26]=[CH2:27]>C(#N)C>[C:2]([O:6][C:7](=[O:18])[C@H:8]([CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[NH:9][CH2:27][CH:26]=[CH2:25])([CH3:4])([CH3:5])[CH3:3]
Reactant: CC(C)(C)OC(=O)C[C@H](N)C(=O)OC(C)(C)C
Reactant: C=CCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C=CCN[C@@H](CC(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.9 %

Procedure:
L-aspartic acid di-tert-butyl ester hydrochloride (1.0 g, 3.5 mmol) was dissolved in acetonitrile (7 ml), potassium carbonate (0.98 g, 7.1 mmol) and allyl bromide (0.29 mL, 3.4 mmol) were added, and the mixture was stirred at room temperature overnight. The insoluble material was removed by filtration, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=95/5) to give N-allyl-L-aspartic acid di-tert-butyl ester (0.50 g, 1.8 mmol).
Reaction SMILES: C([O:5][C:6](=[O:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]#[CH:17])(C)(C)C.[CH2:19]([NH:21][S:22]([C:25]1[CH:30]=[CH:29][C:28]([CH3:31])=[C:27](Br)[CH:26]=1)(=[O:24])=[O:23])[CH3:20]>>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:7][C:6]([OH:5])=[O:18])=[C:10]([C:16]#[C:17][C:27]2[CH:26]=[C:25]([S:22]([NH:21][CH2:19][CH3:20])(=[O:23])=[O:24])[CH:30]=[CH:29][C:28]=2[CH3:31])[CH:11]=1
Reactant: CCNS(=O)(=O)c1ccc(C)c(Br)c1
Reactant: C#Cc1cc(Cl)ccc1OCC(=O)OC(C)(C)C
Product: CCNS(=O)(=O)c1ccc(C)c(C#Cc2cc(Cl)ccc2OCC(=O)O)c1

Procedure:
Following the general method as outlined in Example 10, starting from tert-butyl(4-chloro-2-ethynylphenoxy)acetate (Intermediate 3) and N-ethyl 3-bromo-4-methylbenzenesulfonamide (Combi-Blocks), the title compound was obtained as a beige solid after purification by preparative HPLC.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([OH:13])=O.O=S(Cl)[Cl:16]>>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([Cl:16])=[O:13]
Reactant: O=C(O)c1ccc2ccccc2c1
Reactant: O=S(Cl)Cl
Product: O=C(Cl)c1ccc2ccccc2c1
Yield: 100 %

Procedure:
A 100 mL round bottom flask was charged with 2-naphthoic acid (2 g, 11.6 mmol) and SOCl2 (15 mL). The solution was refluxed for 4 hours and then concentrated to yield a yellow solid which was used without further purification (2.21 g, 100% yield); 1H NMR (CDCl3) δ 8.76 (s, 1H, ArH), 8.04 (2H, ArH), 7.93 (d, 2H, ArH, J=8.9 Hz), 7.66 (m, 2H, ArH).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][NH:4][C:5]([N:7]([CH2:17][CH2:18][CH2:19][O:20][CH3:21])[CH:8]1[O:16][CH2:15][C@@H:13]([OH:14])[C@@H:11]([OH:12])[C@@H:9]1[OH:10])=[O:6].[N+:22]([O-])([N+]([O-])=O)=[O:23]>>[Cl:1][CH2:2][CH2:3][N:4]([N:22]=[O:23])[C:5]([N:7]([CH2:17][CH2:18][CH2:19][O:20][CH3:21])[CH:8]1[O:16][CH2:15][C@@H:13]([OH:14])[C@@H:11]([OH:12])[C@@H:9]1[OH:10])=[O:6]
Reactant: COCCCN(C(=O)NCCCl)C1OC[C@@H](O)[C@@H](O)[C@@H]1O
Reactant: O=[N+]([O-])[N+](=O)[O-]
Product: COCCCN(C(=O)N(CCCl)N=O)C1OC[C@@H](O)[C@@H](O)[C@@H]1O
Yield: 55.7 %

Procedure:
3.3 g of 1-(2-chloroethyl)-3-(3-methoxy-n-propyl)-3-(D-arabinopyranosyl)urea and 5 g of nitrogen tetroxide gas are treated in the same manner as described in Example 10-(2). 2.0 g of 1-(2-chloroethyl)-1-nitroso-3-(3-methoxy-n-propyl)-3-(D-arabinopyranosyl)urea are thereby obtained as pale yellow powder.
Reaction SMILES: BrCCBr.Cl[Si](C)(C)C.[CH3:10][C:11]([O:14][C:15]([NH:17][C@@H:18]([CH2:28]I)[CH2:19][CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[O:16])([CH3:13])[CH3:12].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.I[C:53]1[CH:58]=[CH:57][C:56]([C:59]2[N:60]=[C:61]3[C:66]([CH3:67])=[CH:65][CH:64]=[CH:63][N:62]3[CH:68]=2)=[CH:55][CH:54]=1>CN(C=O)C.CCOC(C)=O.[Zn].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:10][C:11]([O:14][C:15]([NH:17][C@@H:18]([CH2:28][C:53]1[CH:58]=[CH:57][C:56]([C:59]2[N:60]=[C:61]3[C:66]([CH3:67])=[CH:65][CH:64]=[CH:63][N:62]3[CH:68]=2)=[CH:55][CH:54]=1)[CH2:19][CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[O:16])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)CC[C@H](CI)NC(=O)OC(C)(C)C
Reactant: Cc1cccn2cc(-c3ccc(I)cc3)nc12
Agent: [Pd]
Agent: C[Si](C)(C)Cl
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: BrCCBr
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cccn2cc(-c3ccc(C[C@@H](CCC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)cc3)nc12
Temperature: 100 °C
Reaction time: 0.25 h
Yield: 90 %

Procedure:
A flask containing zinc dust (6.0 equiv, 325 mesh, Strem) was heated with a heat gun while evacuating and filling with nitrogen (3 times). Under nitrogen, degassed DMF (14 mL) was added via syringe followed by 1,2-dibromoethane (0.35 equiv). The grey reaction mixture was stirred in an oil bath at 100° C. for 15 minutes and then cooled to room temperature. Chlorotrimethylsilane (0.25 equiv) was added to the mixture via syringe and the reaction was stirred at room temperature for 30 minutes. A solution of 1,1-dimethylethyl (4R)-4-({[(1,1-dimethylethyl)oxy]carbonyl}amino)-5-iodopentanoate (2.0 g, 1.2 equiv) in degassed DMF (14 mL) was added to the reaction mixture via cannula. The flask containing the solution was rinsed with degassed DMF (4 mL) and cannulated into the reaction mixture. The reaction was stirred at room temperature for 1 hour. Then, tris(dibenzylideneacetone)dipalladium (0) (2.5 mol %), tri-o-tolylphosphine (10 mol %) and 2-(4-iodophenyl)-8-methylimidazo[1,2-a]pyridine (1.4 g, 1.0 equiv) were added through the top all at once. The reaction mixture was stirred at room temperature for 17 hours. The reaction was diluted with EtOAc (40 mL) and filtered through Celite®. The filtrate was washed with H2O (20 mL) and brine (20 mL), and the organic layer was dried over MgSO4 and concentrated in vacuo. Purification by silica gel chromatography (Analogix IF280, 5-90% EtOAc/hexanes) afforded the title compound as a white solid (90%). ESMS [M+H]+=480.4.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([OH:35])[C:12]2[C:13](=[O:34])[C:14]3[C:19]([O:20][C:21]=2[C:22]=1[CH2:23][CH:24]=[CH2:25])=[C:18]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH:17]=[CH:16][CH:15]=3)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:38]I.CO>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([O:35][CH3:38])[C:12]2[C:13](=[O:34])[C:14]3[C:19]([O:20][C:21]=2[C:22]=1[CH2:23][CH:24]=[CH2:25])=[C:18]([O:26][CH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[CH:17]=[CH:16][CH:15]=3)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CI
Reactant: C=CCc1c(OCc2ccccc2)cc(O)c2c(=O)c3cccc(OCc4ccccc4)c3oc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: C=CCc1c(OCc2ccccc2)cc(OC)c2c(=O)c3cccc(OCc4ccccc4)c3oc12
Temperature: 50 °C
Yield: 85.2 %

Procedure:
To a solution of xanthone 6 (63 g, 135 mmol) in dry DMF (300 mL) was added sodium hydride (9 g 60% in oil, 225 mmol) portionwise at room temperature. Methyl Iodide (180 g, 1.28 mol) was added and the mixture was heated to 50° C. for 90 minutes. The reaction was then chilled with an ice bath and methanol was added dropwise (20 mL) until the remaining sodium hydride was consumed. The reaction mixture was diluted with ethyl acetate (1.2L) and washed with brine (3×500 mL), dried over magnesium sulfate, filtered over a pad of silica gel (60×100 mm) and the solvent was removed in vacuo to afford the xanthone 7 as a solid (55 g, 115 mmol, 85%).
Reaction SMILES: C(O)(CC)(C)C.[NH:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][C:8]1=[O:16].[NH2:17][C:18]1[CH:32]=[CH:31][C:21]([C:22]([C:24]2[CH:29]=[CH:28][C:27]([NH2:30])=[CH:26][CH:25]=2)=O)=[CH:20][CH:19]=1.CC(C)([O-])C.[K+].Cl>O>[NH2:17][C:18]1[CH:19]=[CH:20][C:21]([C:22]([C:24]2[CH:29]=[CH:28][C:27]([NH2:30])=[CH:26][CH:25]=2)=[C:9]2[C:10]3[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=3)[NH:7][C:8]2=[O:16])=[CH:31][CH:32]=1
Reactant: O=C1Cc2ccccc2N1
Reactant: Nc1ccc(C(=O)c2ccc(N)cc2)cc1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CCC(C)(C)O
Solvent: O
Product: Nc1ccc(C(=C2C(=O)Nc3ccccc32)c2ccc(N)cc2)cc1
Yield: 14.9 %

Procedure:
To 200 ml of t-amyl alcohol were poured 12.9 g of 97% oxindole, 20.0 g of 4,4'-diaminobenzophenone, and 26.43 g of potassium-t-butoxide. By use of a Molecular Sieves 4A tower which served as a dehydrator, the resultant mixture was refluxed with heat for 12 hours. Thereafter, the reaction mixture was cooled. An aqueous solution prepared by diluting 25 g of 35% HCl with 200 g water was added. The resultant mixture was stirred for 1.5 hours while being cooled with ice, and yellow crystals that precipitated were collected by filtration. The resultant crude product was washed with acetone, to thereby obtain 4.6 g (yield 15%) of the title compound in the form of yellow crystals. The melting point and elementary analysis data are shown in Table 15, and NMR and MS spectrum data are shown in Table 16.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:22]=[CH:21][C:6]([C:7]([CH:9]2[CH2:14][CH2:13][N:12]([CH:15]3[CH2:19][CH2:18][NH:17][C:16]3=[O:20])[CH2:11][CH2:10]2)=[O:8])=[CH:5][CH:4]=1.Cl[CH2:24][C:25]1[NH:26][C:27](=[O:35])[C:28]2[CH:33]=[C:32]([CH3:34])[S:31][C:29]=2[N:30]=1.[H-].[Na+]>C1COCC1.CCOCC>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([CH:9]2[CH2:14][CH2:13][N:12]([CH:15]3[CH2:19][CH2:18][N:17]([CH2:24][C:25]4[NH:26][C:27](=[O:35])[CH:28]5[CH:33]=[C:32]([CH3:34])[S:31][CH:29]5[N:30]=4)[C:16]3=[O:20])[CH2:11][CH2:10]2)=[O:8])=[CH:21][CH:22]=1
Reactant: COc1ccc(C(=O)C2CCN(C3CCNC3=O)CC2)cc1
Reactant: Cc1cc2c(=O)[nH]c(CCl)nc2s1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1ccc(C(=O)C2CCN(C3CCN(CC4=NC5SC(C)=CC5C(=O)N4)C3=O)CC2)cc1
Temperature: 70 °C
Yield: 88.5 %

Procedure:
To a solution of 3-[4-(4-methoxy-benzoyl)-piperidin-1-yl]-pyrrolidin-2-one (0.165 mmol, 50 mg) and 2-chloromethyl-6-methyl-3H-thieno[2,3-d]pyrimidin-4-one (0.165 mmol, 33 mg) in THF (2 mL) was added sodium hydride (60%, 0.331 mmol, 23 mg) and heated to 70° C. for 1 hour. The reaction was allowed to cool to ambient temperature, diluted with 10 mL of ether, and the resulting solid in suspension was filtered and dried under vacuum provided the title compound as an off-white solid (70.5 mg, 95.4% yield). HRMS calculated for C25H28N4O4S 480.5903. found (ESI, [M+H]+) 481.1907. 1H NMR (400 MHz, MeOD) δ ppm 1.66-1.93 (m, 4H) 2.05-2.30 (m, 2H) 2.51-2.63 (m, 1H) 2.79-2.90 (m, 1H) 2.90-2.98 (m, 1H) 3.03-3.18 (m, 1H) 3.33-3.54 (m, 4H) 3.65-3.75 (m, 1H) 3.87 (s, 3H) 4.20-4.31 (m, 1H) 4.51-4.62 (m, 1H) 6.94-7.06 (m, 3H) 7.98 (d, J=9.03 Hz, 2H), analytical RP-HPLC retention time=3.22 min
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[C:8]([C:11](Cl)=[O:12])[CH:9]=[CH:10][C:5]=2[O:4][C:3]1=[O:14].Br[CH2:16][C:17]1[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][C:18]=1[Cl:25].C([O-])(O)=O.[Na+]>COCCOC.[Zn].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>[Cl:25][C:18]1[CH:19]=[CH:20][C:21]([O:23][CH3:24])=[CH:22][C:17]=1[CH2:16][C:11]([C:8]1[CH:9]=[CH:10][C:5]2[O:4][C:3](=[O:14])[N:2]([CH3:1])[C:6]=2[CH:7]=1)=[O:12]
Reactant: COc1ccc(Cl)c(CBr)c1
Reactant: Cn1c(=O)oc2ccc(C(=O)Cl)cc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Product: COc1ccc(Cl)c(CC(=O)c2ccc3oc(=O)n(C)c3c2)c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 36 %

Procedure:
To a suspension of 3-methyl-2-oxo-2,3-dihydro-benzooxazole-5-carboxylic acid (820 mg, obtained in Example 116, step 5) in CH2Cl2 (10 mL) were added two drops of DMF and oxalylchloride (0.58 mL). The mixture was stirred at room temperature for 1 hour and was then concentrated to dryness. 1,2-Dimethoxyethane (20 mL) was added and the solvent was evaporated again to give the crude acid chloride (3-methyl-2-oxo-2,3-dihydro-benzooxazole-5-carbonyl chloride). To a suspension of zinc powder (555 mg) in 1,2-dimethoxyethane (10 mL) was added tetrakis(triphenylphosphine)palladium(0) (49 mg). A suspension of the acid chloride in 1,2-dimethoxyethane (5 mL) was added. The mixture was cooled in an ice bath and a solution of 2-bromomethyl-1-chloro-4-methoxy-benzene (1.0 g, [CAS Reg. No. 3771-13-9]) in 1,2-dimethoxyethane (5 mL) was slowly added over a period of 15 minutes. The mixture was stirred for 10 minutes at 0° C. and then for 2 hours at r.t. The reaction mixture was poured into ice and basified with sat. NaHCO3. The aqueous phase was then extracted two times with ethyl acetate and the organic layers were washed with brine, dried over Na2SO4, filtered and the solvent was evaporated. The residue was purified by flash chromatography (silica gel, heptane:ethyl acetate=6:4) to give the title compound as a colorless solid (510 mg, 36%). MS (neg. ion, m/e)=330.3 [(M−H)−].
Reaction SMILES: [N+](C1C=CC(C2SC=CC=2)=CC=1NC(=O)C1C=CC(C2NN=NN=2)=CC=1)([O-])=O.[C:29]([O:32][CH2:33][CH2:34][N:35]1[C:39]2[CH:40]=[CH:41][C:42]([C:44](=[O:60])[NH:45][C:46]3[CH:51]=[C:50]([C:52]4[S:53][CH:54]=[CH:55][CH:56]=4)[CH:49]=[CH:48][C:47]=3[N+:57]([O-])=O)=[CH:43][C:38]=2[N:37]=[C:36]1[CH3:61])(=[O:31])[CH3:30].CO>C(OCC)(=O)C>[C:29]([O:32][CH2:33][CH2:34][N:35]1[C:39]2[CH:40]=[CH:41][C:42]([C:44](=[O:60])[NH:45][C:46]3[CH:51]=[C:50]([C:52]4[S:53][CH:54]=[CH:55][CH:56]=4)[CH:49]=[CH:48][C:47]=3[NH2:57])=[CH:43][C:38]=2[N:37]=[C:36]1[CH3:61])(=[O:31])[CH3:30]
Reactant: CC(=O)OCCn1c(C)nc2cc(C(=O)Nc3cc(-c4cccs4)ccc3[N+](=O)[O-])ccc21
Agent: O=C(Nc1cc(-c2cccs2)ccc1[N+](=O)[O-])c1ccc(-c2nnn[nH]2)cc1
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(=O)OCCn1c(C)nc2cc(C(=O)Nc3cc(-c4cccs4)ccc3N)ccc21
Yield: 96 %

Procedure:
Following the same procedure as described in Example 48, step 3 (scheme 36) but substituting compound 171 for the compound 307 and using ethyl acetate as a solvent instead of methanol, the title compound 308 was obtained in 96% yield. 1H NMR: (DMSO) δ (ppm): 9.70 (s, 1H), 8.23 (s, 1H), 7.87 (dd; J=1.0, 8.4 Hz; 1H); 7.62 (d, J=8.4 Hz; 1H), 7.48 (d; J=2.0 Hz; 1H); 7.34 (dd; J=0.8, 4.8 Hz; 1H); 7.28 (dd; J=2.0, 8.0 Hz; 1H); 7.23 (dd; J=0.8, 3.6 Hz; 1H); 7.03 (dd; J=1.2, 4.8 Hz; 1H); 6.81 (d; J=8.0 Hz; 1H); 5.15 (bs, 2H); 4.52 (t; J=4.8 Hz; 2H); 4.35 (t; J=4.8 Hz; 2H); 2.60 (s, 3H); 1.91 (s, 3H). MS: calc: 434.5; found: 435.2 (M+H)
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][S:7][C:8]2[C:9](=[O:17])[CH2:10][C:11]([CH3:16])([CH3:15])[CH2:12][C:13]=2[OH:14])=[CH:4][CH:3]=1.[OH:20]O>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][S:7]([C:8]2[C:13](=[O:14])[CH2:12][C:11]([CH3:16])([CH3:15])[CH2:10][C:9]=2[OH:17])=[O:20])=[CH:18][CH:19]=1
Reactant: CC1(C)CC(=O)C(SCc2ccc(Cl)cc2)=C(O)C1
Reactant: OO
Solvent: CC(=O)O
Product: CC1(C)CC(=O)C(S(=O)Cc2ccc(Cl)cc2)=C(O)C1
Temperature: 0 °C
Reaction time: 23 h

Procedure:
A mixture of 2-(p-chlorobenzylthio)-3-hydroxy-5,5-dimethyl-2-cyclohexen-1-one (10.0 g., 0.0338 mole), 30 percent hydrogen peroxide (3.83 g., 0.0338 mole), and 350 ml. of glacial acetic acid was allowed to stand at room temperature for 23 hours. The solution was poured into ice water, and the precipitated pink solid was filtered and dried (10 g., m.p. 143.5°-145°C.).
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8]([Br:11])=[CH:9][S:10][C:6]=2[C:5]([CH2:12][OH:13])=[CH:4][N:3]=1>C1COCC1.O=[Mn]=O>[NH2:1][C:2]1[C:7]2[C:8]([Br:11])=[CH:9][S:10][C:6]=2[C:5]([CH:12]=[O:13])=[CH:4][N:3]=1
Reactant: Nc1ncc(CO)c2scc(Br)c12
Agent: O=[Mn]=O
Solvent: C1CCOC1
Product: Nc1ncc(C=O)c2scc(Br)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.7 %

Procedure:
A solution of Example 277E (1 g, 3.86 mmol) in THF (100 mL) was treated with MnO2 (2.66 g, 42.1 mmol), stirred overnight at room temperature, and filtered through diatomaceous earth (Celite®). The pad was washed with THF and dichloromethane and the combined filtrates were concentrated to provide 0.88 g (89% yield ) of the desired product. MS (ESI(+)) m/e 256.8, 258.8 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:13])[CH:10]=NO)=[CH:4][CH:3]=1.[OH:14]S(O)(=O)=O>>[Cl:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[NH:8][C:9](=[O:13])[C:10]2=[O:14]
Reactant: O=S(=O)(O)O
Reactant: O=C(C=NO)Nc1ccc(Cl)cc1
Product: O=C1Nc2ccc(Cl)cc2C1=O
Temperature: 80 °C

Procedure:
To a hot solution of conc. H2SO4 (20 mL) at 60° C. was added portion wise N-(4-chloro-phenyl)-2-hydroxyimino-acetamide (5.5 g, 27.0 mmol). After the addition, the temperature was increased to 80° C. and maintained for one hour. After completion of the reaction, the reaction mixture was poured on to crushed ice and the resulting precipitated solid was separated, filtered, washed with water (2-3 times) and dried to obtain the title compound as brick red solid.
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[CH:12]1[CH2:33][C:15]2[N:16]([CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[N:27]=3)[C:17]3[CH:18]=[CH:19][C:20]([C:23]#[N:24])=[CH:21][C:22]=3[C:14]=2[CH2:13]1.O.NN>C(O)C.O1CCCC1.C(OCC)(=O)C>[NH2:3][CH:12]1[CH2:33][C:15]2[N:16]([CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[N:27]=3)[C:17]3[CH:18]=[CH:19][C:20]([C:23]#[N:24])=[CH:21][C:22]=3[C:14]=2[CH2:13]1
Reactant: N#Cc1ccc2c(c1)c1c(n2Cc2cccc(F)n2)CC(N2C(=O)c3ccccc3C2=O)C1
Agent: NN
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1ccc2c(c1)c1c(n2Cc2cccc(F)n2)CC(N)C1
Yield: 91.5 %

Procedure:
Dissolve (±)-2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-4-(6-fluoro-pyridin-2-ylmethyl)-1,2,3,4-tetrahydro-cyclopenta[b]indole-7-carbonitrile (5.31 g, 12.2 mmol) in ethanol (15 mL)/tetrahydrofuran (85 mL). Add hydrazine monohydrate (4.43 ml, 91.2 mmol, 7.50 equivalents) and stir at room temperature under nitrogen overnight. Dilute with ethyl acetate (150 ml), filter off white solids, wash the organic layer with 10% potassium carbonate twice, dry over anhydrous sodium sulfate, filter, and concentrate to obtain the title compound as an orange oil (3.42 g, 91%). LCMS 307.0 (M+1), 305.0 (M−1).
Reaction SMILES: C([O:8][C:9](=[O:62])[C@H:10]([CH2:55][C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1)[NH:11][C:12](=[O:54])[C@H:13]([CH2:43][C:44]([O:46]CC1C=CC=CC=1)=[O:45])[NH:14][C:15](=[O:42])[CH2:16][CH2:17][CH2:18][CH2:19][NH:20][C:21](=[O:41])[C:22]1[CH:27]=[CH:26][C:25]([C:28](=[NH:40])[NH:29]C(OCC2C=CC=CC=2)=O)=[CH:24][CH:23]=1)C1C=CC=CC=1>C(O)(=O)C.[Pd]>[C:28]([C:25]1[CH:26]=[CH:27][C:22]([C:21]([NH:20][CH2:19][CH2:18][CH2:17][CH2:16][C:15]([NH:14][C@H:13]([C:12]([NH:11][C@H:10]([C:9]([OH:62])=[O:8])[CH2:55][C:56]2[CH:57]=[CH:58][CH:59]=[CH:60][CH:61]=2)=[O:54])[CH2:43][C:44](=[O:45])[OH:46])=[O:42])=[O:41])=[CH:23][CH:24]=1)(=[NH:29])[NH2:40]
Reactant: N=C(NC(=O)OCc1ccccc1)c1ccc(C(=O)NCCCCC(=O)N[C@@H](CC(=O)OCc2ccccc2)C(=O)N[C@@H](Cc2ccccc2)C(=O)OCc2ccccc2)cc1
Agent: [Pd]
Solvent: CC(=O)O
Product: N=C(N)c1ccc(C(=O)NCCCCC(=O)N[C@@H](CC(=O)O)C(=O)N[C@@H](Cc2ccccc2)C(=O)O)cc1
Yield: 88.7 %

Procedure:
443 mg of N-[3-[(benzyloxy)carbonyl]-N-[5-[p-[N-[(benzyloxy)-carbonyl]amidino]benzamido]valeryl]-L-alanyl]-3-phenyl-L-alanine benzyl ester and 111 mg of Pd/C in 9 ml of acetic acid were stirred under hydrogen gas for 31/2hours. The solution was filtered and evaporated, the residue was dissolved in water and the solution was again evaporated. The residue was stirred in water, filtered off with suction and dried. 246 mg of N-[N-[5-(p-amidinobenzamido)valeryl]-L-α-aspartyl]-3-phenyl-L-alanine, m.p. 241° C., was obtained as the hydrate (1:2).