Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:15]1([CH2:21][CH2:22][CH2:23][N:24]([CH3:26])[CH3:25])SCCCS1)[CH2:2][C:3]1([CH2:9][CH2:10][CH2:11][N:12]([CH3:14])[CH3:13])SCCCS1.[OH2:27].[OH2:28].O.[N+]([O-])([O-])=O.[Tl+3].[N+]([O-])([O-])=O.[N+]([O-])([O-])=O>CO.O1CCCC1>[CH3:13][N:12]([CH3:14])[CH2:11][CH2:10][CH2:9][C:3](=[O:28])[CH2:2][CH2:1][C:15](=[O:27])[CH2:21][CH2:22][CH2:23][N:24]([CH3:26])[CH3:25]
Reactant: O
Reactant: CN(C)CCCC1(CCC2(CCCN(C)C)SCCCS2)SCCCS1
Agent: O=[N+]([O-])[O-]
Agent: [Tl+3]
Solvent: C1CCOC1
Solvent: CO
Product: CN(C)CCCC(=O)CCC(=O)CCCN(C)C
Temperature: 25 °C
Yield: 43.6 %

Procedure:
First, 695 mg of 2,2'-ethylenebis[2-(3-dimethylaminopropyl)-m-dithian] was dissolved in 24 ml of absolute methanol and 6 ml of absolute tetrahydrofuran, and after adding dropwise a solution of 3.12 g of thallium (III) nitrate trihydrate in 18 ml of absolute methanol over 2 minutes while stirring at a room temperature, the mixture was stirred for 30 minutes, filtered to remove insoluble matter, and evaporated under a reduced pressure to remove the solvent. After adding 30 ml of water, the mixture was extracted with 100 ml and 50 ml of chloroform. The extracts were combined, washed with a saturated sodium chloride aqueous solution, dried over magnesium sulfate, filtered, and evaporated under a reduced pressure. The residue was applied to a silica gel column and eluted with chloroform/methanol/triethylamine (80:20:1) to obtain 178 mg of the title compound as a pale yellow liquid.
Reaction SMILES: NC(N)=O.[CH:5]([OH:7])=[O:6].[NH:8]1CC[CH2:13][C@H:9]1[C:10]([OH:12])=[O:11]>O.Cl.NC(N)=N>[NH2:8][C@H:9]([C:10]([OH:12])=[O:11])[CH2:13][C:5](=[O:7])[OH:6]
Reactant: O=CO
Reactant: O=C(O)[C@@H]1CCCN1
Agent: Cl
Agent: N=C(N)N
Agent: NC(N)=O
Solvent: O
Product: N[C@@H](CC(=O)O)C(=O)O

Procedure:
An aliquot (30 ul) of the urea soluble fraction was diluted with ten volumes of water, and the insoluble fusion protein was pelleted by centrifugation. The protein was then dissolved in 30 ul of 6M guanidine hydrochloride, and 70 μl 98% formic acid added (Digestion 1). In a parallel experiment, 70 μl 98% formic acid was added to an aliquot (30 μl) of the urea fraction directly (Digestion 2). Following two days incubation at 42° C., ten volumes of water were added, and the insoluble proteins were pelleted by centrifugation. The pellet was resuspended in 1×treatment buffer (100 μl), and 10 μl was used per well on 12.5% SDS-polyacrylamide gel. FIG. 10 shows a sample of the cleaved products (Digestion 1 and Digestion 2) both on a Commassie-stained gel and an immunoblot (using HIV-1 positive human serum as primary antibody). Only two major bands are visible on the Commassie-stained gel. These represent the products of cleavage at the unique Asp-Pro bond: the CKS portion, MW=26.5 kDa and the p41 portion, MW=23.5 kDa. Peptide sequencing confirmed that the lower molecular weight band was indeed the p41 peptide, and that the amino terminal residue was proline which results from expected cleavage between the Asp and Pro.
Reaction SMILES: Cl.[C:2]1([C:8]2[CH2:9][CH2:10][NH:11][CH2:12][CH:13]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:21][CH2:22][CH2:23][C:24]#[N:25]>C(#N)C>[C:2]1([C:8]2[CH2:13][CH2:12][N:11]([CH2:21][CH2:22][CH2:23][C:24]#[N:25])[CH2:10][CH:9]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1=C(c2ccccc2)CCNC1
Reactant: N#CCCCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: N#CCCCN1CC=C(c2ccccc2)CC1

Procedure:
5 g of 4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride (very toxic compound: New Engl. J. Med., 1983, 309, 310; Science, 1983, 219, 979; Psychiatry Res., 1979, 1, 249) and then 100 ml of acetonitrile are introduced into a 250 ml round-bottomed flask. 2.5 equivalents of anhydrous potassium carbonate are added and then 1.05 equivalents of 4-bromobutyronitrile, in solution in acetonitrile, are added dropwise. The mixture is heated at reflux for 16 hours and then filtered, the precipitate is washed with acetone and the filtrate is concentrated. The residue is taken up in ethyl acetate and washed 3 times with water. The organic phase is extracted with a 3M hydrochloric acid solution and the acid phase is washed with ethyl acetate. The acid phase is neutralized with 28% aqueous ammonia to pH>11. Extraction is carried out with ethyl acetate, the organic phase is washed with water and dried over anhydrous sodium sulphate and the mixture is concentrated. The nitrile is purified by chromatography on a silica column (eluent: ethyl acetate/hexane 80/20). White crystals are obtained. M.p.=57-59° C. Y=79%. 1H NMR (CDCl3, 330K): 1.81-1.95 (m, 2H, --CH2 --, 2.40-2.48 (t, 2H, --CH2 --), 2.54-2.60 (t, 4H, --H2C--CH2 --), 2.67-2.72 (t, 2H, --CH2 --), 3.12-3.17 (q, 2H, --CH2 --), 6.06-6.09 (m, 1H, --CH=), 7.24-7.44 (m, 5H, phe). 13C NMR (CDCl3): 14.7 (--CH2 --CH2 --C≡N), 22.8 (--CH2 --C≡N), 27.7 (>C--CH2 --CH2 --N<, pyrid), 50.0 (--CH2 --CH2 --N<, pyrid), 52.9 (=CH--CH2 --N<, pyrid), 55.9 (>N--CH2 --), 119.6 (--CN), 121.3 (>CH--), 124.6 (=CH--, pyri), 126.8 (>(CH)2 --), 128.1 (>CH)2 --), 134.7 (>C=C--, pyri), 140.4 (>C<).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:24])[N:9]3[CH2:23][CH2:22][CH2:21][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH:25]1(CCO)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>CCO.CCO.CCO.CCO.[Ti]>[Cl:1][C:2]1[C:7]2[C:8](=[O:24])[N:9]3[CH2:23][CH2:22][CH2:21][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([O:18][CH2:19][CH2:20][CH:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1ncn2c1[C@@H]1CCCN1C(=O)c1c(Cl)cccc1-2
Reactant: OCCC1CCCCC1
Agent: [Ti]
Solvent: CCO
Product: O=C(OCCC1CCCCC1)c1ncn2c1[C@@H]1CCCN1C(=O)c1c(Cl)cccc1-2
Reaction time: 0.25 h

Procedure:
A mixture of 6.93 g (0.02 mmol) of ethyl (S)-8-chloro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxylate 1.4 g of tetraethyl orthotitanate and 24 g of 2-cyclohexyl-ethanol is heated to 140° for 2.5 hours, evaporated in vacuo, the residue is taken up in chloroform and the solution is poured into about 20 percent hydrochloric acid. The mixture is stirred for 15 minutes, the chloroform phase is separated, washed successively with 2N hydrochloric acid and saturated sodium bicarbonate solution, dried over magnesium sulphate and evaporated. After chromatography on a silica gel column while eluting with ethyl acetate and subsequent crystallization from ethyl acetate/hexane, there is obtained 2-cyclohexylethyl (S)-8-chloro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxylate of melting point 131°-132°.
Reaction SMILES: [CH3:1][CH:2]([OH:7])[CH2:3][CH2:4][CH2:5][CH3:6].C[Al](C)C.[CH3:12][O:13][C:14]1[N:19]=[C:18]([CH3:20])[N:17]=[C:16]([NH:21][C:22]([NH:24][S:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[C:34](OC)=[O:35])(=[O:27])=[O:26])=[O:23])[N:15]=1>C1(C)C=CC=CC=1>[CH3:12][O:13][C:14]1[N:19]=[C:18]([CH3:20])[N:17]=[C:16]([NH:21][C:22]([NH:24][S:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[C:34]([O:7][CH:2]([CH3:1])[CH2:3][CH2:4][CH2:5][CH3:6])=[O:35])(=[O:27])=[O:26])=[O:23])[N:15]=1
Reactant: CCCCC(C)O
Reactant: COC(=O)c1ccccc1S(=O)(=O)NC(=O)Nc1nc(C)nc(OC)n1
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: CCCCC(C)OC(=O)c1ccccc1S(=O)(=O)NC(=O)Nc1nc(C)nc(OC)n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 57.8 %

Procedure:
2-Hexanol (0.61 g) in 2 ml dry toluene was slowly added at room temperature to a solution of 1.5 ml (2M) trimethylaluminum diluted with 5.0 ml dry toluene under nitrogen. The mixture was stirred at room temperature for 15 minutes and 0.95 g of N-[(4-methoxy-6-methyl-1,3,5-triazin-2-yl)aminocarbonyl]-2-methoxycarbonylbenzenesulfonamide was added. The mixture was warmed under N2 to reflux temperature for 2.5 hr. cooled to room temperature and carefully quenched with 20 ml 10% HCl. The organic phase was taken up in methylene chloride, separated, washed with water, dried over magnesium sulfate, filtered and the solvent evaporated under reduced pressure to give 0.65 g of the desired compound which melted at 125°-130° C. The infrared spectrum exhibited characteristic absorption for the product at 3300, 1725, 1730, 1585, 1555 cm-1.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([O:10][C:11]3[C:20]4[C:15](=[CH:16][C:17]([O:23][CH3:24])=[C:18]([O:21][CH3:22])[CH:19]=4)[N:14]=[CH:13][CH:12]=3)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[H-].[Na+].[F:27][CH2:28][CH2:29][NH:30][C:31](=O)[O:32]C1C=CC=CC=1>>[F:27][CH2:28][CH2:29][NH:30][C:31]([N:1]1[C:9]2[C:4](=[CH:5][C:6]([O:10][C:11]3[C:20]4[C:15](=[CH:16][C:17]([O:23][CH3:24])=[C:18]([O:21][CH3:22])[CH:19]=4)[N:14]=[CH:13][CH:12]=3)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1)=[O:32]
Reactant: O=C(NCCF)Oc1ccccc1
Reactant: COc1cc2nccc(Oc3ccc4[nH]ccc4c3)c2cc1OC
Agent: [H-]
Agent: [Na+]
Product: COc1cc2nccc(Oc3ccc4c(ccn4C(=O)NCCF)c3)c2cc1OC
Yield: 18.8 %

Procedure:
4-(1H-Indol-5-yloxy)-6,7-dimethoxyquinoline (75 mg, 0.3122 mmol), sodium hydride (13 mg, 0.3278 mmol) and phenyl N-(2-fluoroethyl)carbamate (45 mg, 0.3278 mmol) were used for reaction in the same manner as Example 310, followed by extraction with ethyl acetate/tetrahydrofuran, washing with saturated brine and drying over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was adsorbed onto silica gel and subjected to silica gel column chromatography (hexane/ethyl acetate system) to obtain the title compound (24 mg, 0.0586 mmol, 18.78%) as colorless crystals.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[C:5]([C:19]#[N:20])=[C:4]([C:21]#[N:22])[C:3]=1[S:23]([C:25]([F:28])([F:27])[F:26])=[O:24].[CH:29](OCC)(OCC)[O:30][CH2:31][CH3:32].C1(C)C=CC(S(O)(=O)=O)=CC=1>>[Cl:13][C:12]1[CH:11]=[C:10]([C:14]([F:15])([F:16])[F:17])[CH:9]=[C:8]([Cl:18])[C:7]=1[N:6]1[C:2]([N:1]=[CH:29][O:30][CH2:31][CH3:32])=[C:3]([S:23]([C:25]([F:27])([F:26])[F:28])=[O:24])[C:4]([C:21]#[N:22])=[C:5]1[C:19]#[N:20]
Reactant: CCOC(OCC)OCC
Reactant: N#Cc1c(S(=O)C(F)(F)F)c(N)n(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1C#N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CCOC=Nc1c(S(=O)C(F)(F)F)c(C#N)c(C#N)n1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Temperature: 100 °C
Reaction time: 1.17 h

Procedure:
A mixture of 5-amino-1-(2,6-dichloro-4-trifluoromethylphenyl)-2,3-dicyano-4-trifluoromethylsulfinylpyrrole (290 mg, 0.6 mmol), triethyl orthoformate (4.45 g, 29.7 mmol), and p-toluenesulfonic acid (10 mg, 0.1 mmol) was heated at 100° C. for 40 minutes, then at 120° C. for 70 minutes. Additional p-toluenesulfonic acid (a catalytic amount) was added and the resulting mixture was heated at 120° C. for 2.4 hour. It was then concentrated to dryness and diluted with dichloromethane (20 ml). The organic layer was washed with saturated sodium bicarbonate, brine, dried (sodium sulfate), and concentrated to afford the title compound as an orange oil which was used without purification for the next transformation. 19F-NMR: −64.23, −72.08.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH3:11])=[C:6]([CH:9]=1)[CH:7]=[O:8].Cl.Cl[CH2:14][C:15]1[C:16]([C:21]2[N:25]([CH:26]([CH3:28])[CH3:27])[N:24]=[CH:23][CH:22]=2)=[N:17][CH:18]=[CH:19][CH:20]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH:26]([N:25]1[C:21]([C:16]2[C:15]([CH2:14][O:1][C:2]3[CH:3]=[CH:4][C:5]([O:10][CH3:11])=[C:6]([CH:9]=3)[CH:7]=[O:8])=[CH:20][CH:19]=[CH:18][N:17]=2)=[CH:22][CH:23]=[N:24]1)([CH3:28])[CH3:27]
Reactant: CC(C)n1nccc1-c1ncccc1CCl
Reactant: COc1ccc(O)cc1C=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(OCc2cccnc2-c2ccnn2C(C)C)cc1C=O
Temperature: 70 °C
Yield: 65.1 %

Procedure:
A mixture of 5-hydroxy-2-methoxybenzaldehyde (395 mg, 2.58 mmol, 1 eq.), 3-(chloromethyl)-2-(1-isopropyl-1H-pyrazol-5-yl)pyridine hydrochloride (700 mg, 2.58 mmol, 1 eq.), and K2CO3 (1.4 g, 10.32 mmol, 4 eq.) in DMF (10.0 mL) was heated at 70° C. for 2 h. The mixture was cooled, filtered, concentrated, and purified on silica gel using a mixture of EtOAc and hexanes as eluent to give 5-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)-2-methoxybenzaldehyde (590 mg, 65%) as an off-white solid.
Reaction SMILES: [CH3:1][N:2]([CH2:14][C:15]([OH:17])=O)[NH:3][C:4](=[O:13])[NH:5][CH2:6][C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1.[NH2:18][C@@H:19]([CH2:42][C:43]1[CH:48]=[CH:47][C:46]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[CH:45][CH:44]=1)[C:20]([N:22]([CH2:32][C:33]1[C:34]2[CH:41]=[CH:40][CH:39]=[CH:38][C:35]=2[S:36][CH:37]=1)[C@@H:23]([CH3:31])[CH:24]([O:28][CH2:29][CH3:30])[O:25][CH2:26][CH3:27])=[O:21]>>[S:36]1[CH:37]=[C:33]([CH2:32][N:22]([C@@H:23]([CH3:31])[CH:24]([O:25][CH2:26][CH3:27])[O:28][CH2:29][CH3:30])[C:20](=[O:21])[C@@H:19]([NH:18][C:15](=[O:17])[CH2:14][N:2]([CH3:1])[NH:3][C:4]([NH:5][CH2:6][C:7]2[CH:8]=[CH:9][N:10]=[CH:11][CH:12]=2)=[O:13])[CH2:42][C:43]2[CH:44]=[CH:45][C:46]([O:49][C:50]([CH3:51])([CH3:53])[CH3:52])=[CH:47][CH:48]=2)[C:34]2[CH:41]=[CH:40][CH:39]=[CH:38][C:35]1=2
Reactant: CCOC(OCC)[C@H](C)N(Cc1csc2ccccc12)C(=O)[C@@H](N)Cc1ccc(OC(C)(C)C)cc1
Reactant: CN(CC(=O)O)NC(=O)NCc1ccncc1
Product: CCOC(OCC)[C@H](C)N(Cc1csc2ccccc12)C(=O)[C@H](Cc1ccc(OC(C)(C)C)cc1)NC(=O)CN(C)NC(=O)NCc1ccncc1

Procedure:
According to the procedure described in the synthesis method of Compound II-15, 2-(1-methyl-2-(pyridin-4-ylmethylcarbamoyl)hydrazinyl)acetic acid (Compound VI-6) 70 mg (0.29 mmol) was coupled with (S)-2-amino-N-(benzo[b]thiophen-3-ylmethyl)-3-(4-tert-butoxyphenyl)-N—((S)-1,1-diethoxypropan-2-yl)propanamide (Compound IV-6) 100 mg (0.20 mmol) to obtain the title compound.
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:24][CH3:25])[N:12]2[CH2:15][CH2:16][CH2:17][CH:18]2CC[CH2:21][CH2:20][NH:19]2)=[C:8]([NH2:26])[N:7]=1)[CH2:2][CH2:3][CH3:4].NC1N=C(OCCCC)N=C2C=1N=C(OC)N2CCC1CCN(C(OCC2C=CC=CC=2)=O)CC1>>[CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:24][CH3:25])[N:12]2[CH2:15][CH:16]2[CH2:17][CH2:18][NH:19][CH2:20][CH2:21]2)=[C:8]([NH2:26])[N:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCCC3CCCCN3)c2n1
Agent: CCCCOc1nc(N)c2nc(OC)n(CCC3CCN(C(=O)OCc4ccccc4)CC3)c2n1
Product: CCCCOc1nc(N)c2nc(OC)n(CC3CCNCC3)c2n1

Procedure:
Prepared similarly to Intermediate 32 from phenylmethyl 4-{[6-amino-2-(butyloxy)-8-(methyloxy)-9H-purin-9-yl]ethyl}-1-piperidinecarboxylate.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([CH2:10][CH3:11])[NH:9][CH2:8][CH2:7][S:6]1)=[O:4].[Cl:12][C:13]1[CH:14]=[C:15]([N:20]=[C:21]=[O:22])[CH:16]=[C:17]([Cl:19])[CH:18]=1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1([CH2:10][CH3:11])[N:9]([C:21](=[O:22])[NH:20][C:15]2[CH:16]=[C:17]([Cl:19])[CH:18]=[C:13]([Cl:12])[CH:14]=2)[CH2:8][CH2:7][S:6]1)=[O:4]
Reactant: O=C=Nc1cc(Cl)cc(Cl)c1
Reactant: CCC1(C(=O)OC)NCCS1
Solvent: Cc1ccccc1
Product: CCC1(C(=O)OC)SCCN1C(=O)Nc1cc(Cl)cc(Cl)c1
Yield: 78.4 %

Procedure:
A mixture of 0.62 g of the 2-ethyl thiazolidine-2-carboxylic acid methyl ester thus obtained, 0.66 g of 3,5-dichlorophenyl isocyanate and 10 ml of toluene was stirred at room temperature for 1 hour. Then, the precipitate was filtered to give 1.00 g (yield 77.8%) of 2-ethyl-3-(3,5-dichlorophenylcarbamoyl) thiazolidine-2-carboxylic acid methyl ester with a melting point of 187°-188° C. The results of the elementary analysis were as follows: Found (calculated in parentheses): C 46.48% (46.29%), H b 4.35% (4.44%), N 7.50% (7.71%), Cl 19.86% (19.52%).
Reaction SMILES: C[O-].[Na+].Cl.[NH2:5][C:6]([NH2:8])=[NH:7].O1CCCC1.Cl.[Cl:15][C:16]([C:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]([C:27]2[C:36]3[C:31](=[CH:32][CH:33]=[C:34]([C:37]([F:40])([F:39])[F:38])[CH:35]=3)[N:30]=[CH:29][CH:28]=2)[CH:19]=1)=[O:17]>CO.ClCCl>[ClH:15].[NH:7]([C:16]([C:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]([C:27]2[C:36]3[C:31](=[CH:32][CH:33]=[C:34]([C:37]([F:39])([F:38])[F:40])[CH:35]=3)[N:30]=[CH:29][CH:28]=2)[CH:19]=1)=[O:17])[C:6]([NH2:8])=[NH:5]
Reactant: O=C(Cl)c1cn(-c2ccnc3ccc(C(F)(F)F)cc23)c2ccccc12
Reactant: N=C(N)N
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Solvent: C1CCOC1
Product: N=C(N)NC(=O)c1cn(-c2ccnc3ccc(C(F)(F)F)cc23)c2ccccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
20 cm3 of methanol and 20 cm3 (10 mmol) of a 0.5M solution of sodium methoxide in methanol are added to 0.955 g (10 mmol) of guanidine hydrochloride under an argon atmosphere. After stirring at a temperature in the region of 25° C. for 1 hour, the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa) and the residue is three times successively dissolved in 20 cm3 of dichloromethane and evaporated to dryness under reduced pressure (2.7 kPa). 40 cm3 of tetrahydrofuran and 0.75 g (2 mmol) of 3-chlorocarbonyl-1-(6-(trifluoromethyl)quinol-4-yl)-1H-indole hydrochloride, suspended in 20 cm3 of dichloromethane, are subsequently added thereto under an argon atmosphere. After stirring at a temperature in the region of 20° C. for 16 hours, the reaction mixture is concentrated to give a solid which is purified by flash chromatography [eluent: ethyl acetate/methanol (9/1 and then 8/2 by volume)]. After concentrating the fractions to dryness under reduced pressure (2.7 kPa), the solid obtained is triturated in 20 cm3 of isopropyl ether and filtered off, resulting in 0.54 g of 3-guanidinocarbonyl-1-(6-(trifluoromethyl)quinol-4-yl)-1H-indole hydrochloride in the form of a white powder melting at 260° C. Mass spectrum (EI): m/e 397 (M+•), m/e 339 (base peak).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17](O)=[O:18])=[CH:14][CH:15]=2)[CH:10]=[C:9]1[C:20]1[CH:21]=[CH:22][C:23]([Cl:30])=[C:24]2[C:28]=1[C:27](=[O:29])[NH:26][CH2:25]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN=C=NCCCN(C)C.C1C=C2N=NN(O)C2=CC=1.O.[C:53]([O:57][C:58]([N:60]1[CH2:65][CH2:64][NH:63][CH2:62][CH2:61]1)=[O:59])([CH3:56])([CH3:55])[CH3:54]>CN(C=O)C.O>[Cl:30][C:23]1[CH:22]=[CH:21][C:20]([C:9]2[N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[C:16]3[C:11]([CH:10]=2)=[CH:12][C:13]([C:17]([N:63]2[CH2:62][CH2:61][N:60]([C:58]([O:57][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:59])[CH2:65][CH2:64]2)=[O:18])=[CH:14][CH:15]=3)=[C:28]2[C:24]=1[CH2:25][NH:26][C:27]2=[O:29]
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(Cl)c3c2C(=O)NC3)cc2cc(C(=O)O)ccc21
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccc3c(c2)cc(-c2ccc(Cl)c4c2C(=O)NC4)n3C(=O)OC(C)(C)C)CC1
Yield: 82.5 %

Procedure:
In a similar manner to Example 20, 7-[1-(tert-butoxycarbonyl)-5-carboxyindol-2-yl]-4-chloroisoindolinone (37.8 mg, 0.0886 mmol) was dissolved in DMF (1 mL), and the solution was treated with EDCI (34 mg, 0.18 mmol), HOBT monohydrate (12 mg, 0.089 mmol) and 1-(tert-butoxycarbonyl)piperazine (66 mg, 0.35 mmol). The mixture was added with water and the precipitated solid was collected by filtration, washed with water and then dried under reduced pressure to obtain 4-chloro-7-(1-(tert-butoxycarbonyl)-5-[-4-(tert-butoxycarbonyl)piperazin-1-ylcarbonyl]indol-2-yl)isoindolinone (43.5 mg, yield 83%).
Reaction SMILES: COC1C=C2C(=CC=1)C1OC(C3ON=C(C4C=CC=CC=4)C=3C(F)(F)F)=NC=1CC2.[CH3:31][O:32][C:33]1[CH:34]=[C:35]2[C:40](=[CH:41][CH:42]=1)[C:39](=[O:43])[CH:38]([NH:44][C:45]([C:47]1[C:51]([C:52]([F:55])([F:54])[F:53])=[C:50]([C:56]3[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=3)[O:49][N:48]=1)=O)[CH2:37][CH2:36]2>>[CH3:31][O:32][C:33]1[CH:34]=[C:35]2[C:40](=[CH:41][CH:42]=1)[C:39]1[O:43][C:45]([C:47]3[C:51]([C:52]([F:53])([F:55])[F:54])=[C:50]([C:56]4[CH:57]=[CH:58][CH:59]=[CH:60][CH:61]=4)[O:49][N:48]=3)=[N:44][C:38]=1[CH2:37][CH2:36]2
Reactant: COc1ccc2c(c1)CCC(NC(=O)c1noc(-c3ccccc3)c1C(F)(F)F)C2=O
Agent: COc1ccc2c(c1)CCc1nc(-c3onc(-c4ccccc4)c3C(F)(F)F)oc1-2
Product: COc1ccc2c(c1)CCc1nc(-c3noc(-c4ccccc4)c3C(F)(F)F)oc1-2

Procedure:
The titled compound was prepared using the experimental protocol described for Preparation 43B employing N-(6-methoxy-1-oxo-1,2,3,4-tetrahydronaphthalen-2-yl)-5-phenyl-4-(trifluoromethyl)isoxazole-3-carboxamide (Preparation 49A). 1H NMR (400 MHz, CDCl3) δ ppm 7.73 (2H, d, J=7.26 Hz), 7.51-7.60 (3H, m), 7.48 (1H, d, J=9.02 Hz), 6.78-6.84 (2H, m), 3.82 (3H, s), 3.08-3.17 (2H, m), 2.95-3.03 (2H, m).
Reaction SMILES: C(Cl)(=O)C([Cl:4])=O.[CH3:7][O:8][C:9]1[CH:10]=[C:11]([CH:34]=[CH:35][C:36]=1[O:37][CH2:38][C:39]1[N:40]=[C:41]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[O:42][C:43]=1[CH3:44])[CH2:12][N:13]1[C:25]2[CH:24]=[CH:23][CH:22]=[C:21]([O:26][CH2:27][CH2:28][CH:29]([CH3:33])[C:30](O)=[O:31])[C:20]=2[C:19]2[C:14]1=[CH:15][CH:16]=[CH:17][CH:18]=2>ClCCCl.CN(C)C=O>[CH3:44][C:43]1[O:42][C:41]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)=[N:40][C:39]=1[CH2:38][O:37][C:36]1[CH:35]=[CH:34][C:11]([CH2:12][N:13]2[C:25]3[CH:24]=[CH:23][CH:22]=[C:21]([O:26][CH2:27][CH2:28][CH:29]([CH3:33])[C:30]([Cl:4])=[O:31])[C:20]=3[C:19]3[C:14]2=[CH:15][CH:16]=[CH:17][CH:18]=3)=[CH:10][C:9]=1[O:8][CH3:7]
Reactant: COc1cc(Cn2c3ccccc3c3c(OCCC(C)C(=O)O)cccc32)ccc1OCc1nc(-c2ccccc2)oc1C
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: COc1cc(Cn2c3ccccc3c3c(OCCC(C)C(=O)Cl)cccc32)ccc1OCc1nc(-c2ccccc2)oc1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2.2 mL of oxalyl chloride was added to the solution of 10.0 g of (±)-4-{9-[3-methoxy-4-((5-methyl-2-phenyloxazole-4-yl)methoxy)-benzyl]-9H-carbazole-4-yloxy}-2-methyl-butyric acid prepared by the example 27 in 1,2-dichloroethane (100 mL), and then 5 drops of N,N-dimethylformamide was added thereto, and stirred at room temperature for 1 hour. The reaction mixture was vacuum concentrated, and (±)-4-(9-(4-((5-methyl-2-phenyloxazole-4-yl)methoxy)-3-methoxybenzyl)-9H-carbazole-4-yloxy)-2-methylbutanoyl chloride was prepared.
Reaction SMILES: CS(O[CH2:6][CH2:7][N:8]1[CH:12]=[C:11]([C:13]2[CH:18]=[C:17]([C:19]([O:21][CH3:22])=[O:20])[CH:16]=[CH:15][N:14]=2)[N:10]=[CH:9]1)(=O)=O.[CH3:23][NH:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C1(C)C=CC=CC=1>[CH2:25]([N:24]([CH3:23])[CH2:6][CH2:7][N:8]1[CH:12]=[C:11]([C:13]2[CH:18]=[C:17]([C:19]([O:21][CH3:22])=[O:20])[CH:16]=[CH:15][N:14]=2)[N:10]=[CH:9]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CNCc1ccccc1
Reactant: COC(=O)c1ccnc(-c2cn(CCOS(C)(=O)=O)cn2)c1
Solvent: Cc1ccccc1
Product: COC(=O)c1ccnc(-c2cn(CCN(C)Cc3ccccc3)cn2)c1
Yield: 73.2 %

Procedure:
A solution of methyl 2-(1-{2-[(methylsulfonyl)oxy]ethyl}-1H-imidazol-4-yl)pyridine-4-carboxylate (150 mg, 0.46 mmol) and N-methylbenzylamine (558 mg, 4.6 mmol) in toluene (8 mL) was heated at 110° C. in a sealed tube for 7 hrs. The solution was concentrated to an oily residue and chromatographed on silica gel (EtOAc/Hex, 1:1) to give the title compound (118 mg) as an amber oil: 1HNMR (400 MHz, CDCl3): δ 2.28 (3H, s), 2.78 (2H, t, J=4.2 Hz), 3.61 (2H, s), 3.94 (3H, s), 4.03 (2H, t, J=4.2 Hz), 7.19-7.27 (5H, m), 7.58 (1H, s), 7.61 (1H, s), 7.64 (1H, m), 8.47 (1H, s), 8.63 (1H, m). [M+H] Calc'd for C20H22N4O2, 351. Found, 351.