Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([S:18](OC4C(F)=C(F)C(F)=C(F)C=4F)(=[O:20])=[O:19])=[CH:15][CH:16]=3)[CH:11]=[CH:10][N:9]=2)[C:5]([O:33][CH3:34])=[CH:4][C:3]=1[C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([F:41])[CH:36]=1.[S:42]1[C:46]([NH2:47])=[N:45][CH:44]=[N:43]1.C(=O)([O-])[O-].[Cs+].[Cs+]>>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([S:18]([NH:47][C:46]4[S:42][N:43]=[CH:44][N:45]=4)(=[O:20])=[O:19])=[CH:15][CH:16]=3)[CH:11]=[CH:10][N:9]=2)[C:5]([O:33][CH3:34])=[CH:4][C:3]=1[C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([F:41])[CH:36]=1
Reactant: Nc1ncns1
Reactant: COc1cc(-c2cccc(F)c2)c(Cl)cc1-c1nccc2cc(S(=O)(=O)Oc3c(F)c(F)c(F)c(F)c3F)ccc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: COc1cc(-c2cccc(F)c2)c(Cl)cc1-c1nccc2cc(S(=O)(=O)Nc3ncns3)ccc12
Reaction time: 2 h
Yield: 64.4 %

Procedure:
A vial was charged with perfluorophenyl 1-(2-chloro-3′-fluoro-5-methoxy-[1,1′-biphenyl]-4-yl)isoquinoline-6-sulfonate (INTERMEDIATE TTTT; 71.85 mg, 0.118 mmol), 1,2,4-thiadiazol-5-amine (13.10 mg, 0.130 mmol), and cesium carbonate (115 mg, 0.353 mmol). The vial was flushed with Ar (g), and then acetonitrile (589 μl) was added. After 2 h, the mixture was diluted with EtOAc and 0.5 N aq. HCl. The layers were separated, and the aq. layer was extracted with EtOAc (2×). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated. The residue was concentrated from DCM/MeOH. The residue was then taken up in MeOH and filtered. The collected solid was washed with MeOH (1×), dried under a stream of N2 (g), then dried under vacuum to give 1-(2-chloro-3′-fluoro-5-methoxy-[1,1′-biphenyl]-4-yl)-N-(1,2,4-thiadiazol-5-yl)isoquinoline-6-sulfonamide (40 mg, 0.076 mmol, 64.4% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ=8.72 (d, J=5.7 Hz, 1H), 8.60 (d, J=1.7 Hz, 1H), 8.48 (s, 1H), 8.16 (d, J=5.7 Hz, 1H), 7.95-7.90 (m, 1H), 7.88-7.81 (m, 1H), 7.63-7.54 (m, 2H), 7.50-7.41 (m, 2H), 7.36-7.29 (m, 1H), 7.27 (s, 1H), 3.71 (s, 3H). m/z (ESI) 527.2 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6](Cl)=[O:7].[CH2:15]([NH:22][C:23]([C:25]1[S:29][C:28]([NH2:30])=[N:27][C:26]=1[CH3:31])=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH2:15]([NH:22][C:23]([C:25]1[S:29][C:28]([NH:30][C:6](=[O:7])[C:5]2[CH:9]=[CH:10][CH:11]=[CH:12][C:4]=2[O:3][C:2]([F:14])([F:13])[F:1])=[N:27][C:26]=1[CH3:31])=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Cc1nc(N)sc1C(=O)NCc1ccccc1
Reactant: O=C(Cl)c1ccccc1OC(F)(F)F
Product: Cc1nc(NC(=O)c2ccccc2OC(F)(F)F)sc1C(=O)NCc1ccccc1
Yield: 30 %

Procedure:
Following the procedure as described in Example 2, making variations only as required to use 2-trifluoromethoxybenzoyl chloride in place of benzoyl chloride to react with 2-amino-4-methylthiazole-5-carboxylic acid benzylamide, the title compound was obtained as a white solid in 30% yield; m.p. 140-141° C.; 1H NMR (CDCl3, 300 MHz) δ 7.98 (dd, J=1.8, 7.8 Hz, 1H), 7.60 (ddd, J=1.8, 7.6, 8.2 Hz, 1H), 7.43 (dt, J=1.0, 7.6 Hz, 1H), 7.46-7.25 (m, 6H), 5.98 (t, J=5.3 Hz, 1H), 4.57 (d, J=5.6 Hz, 2H), 3.1 (s, 3H); MS (ES+) m/z 436 (M+1).
Reaction SMILES: S(Cl)(Cl)=O.[CH:5]1([CH2:8][C:9]([OH:11])=[O:10])[CH2:7][CH2:6]1.[CH2:12](O)[CH2:13][CH2:14][CH3:15].C(N(CC)CC)C>CCOCC>[CH:5]1([CH2:8][C:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])=[O:10])[CH2:7][CH2:6]1
Reactant: O=C(O)CC1CC1
Reactant: CCCCO
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Solvent: CCOCC
Product: CCCCOC(=O)CC1CC1
Reaction time: 64 h
Yield: 49.8 %

Procedure:
Thionyl chloride (10.7 g, 90 mmol) was added to cyclopropaneacetic acid (9.0 g 90 mmol) [J. Med. Chem. 27, 1291 (1984); Chem. Lett., 1273 (1983); J. Org. Chem. 43. 3496 (1978)]. After stirring for 64 hours the liquid was dissolved in ether and added to a solution of butanol (6.7 g, 90 mmol) and triethylamine (9.1 g, 90 mmol) in 100 mL of diethyl ether at 0° C. The mixture was stirred for 16 hours and washed with water. The organic phase was dried over magnesium sulfate and concentrated in vacuo. The residue was distilled at 46° C. at 2 mm of Hg to give 7 g of the title compound. MS(CI): m/e =156 for M+ of C9H16O2.
Reaction SMILES: C([NH:3][CH:4]1[C:29](=[O:30])[N:6]2[C:7]([C:13]([O:15][CH:16]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[O:14])=[C:8]([C:11]#[CH:12])[CH2:9][S:10][C@H:5]12)=O.P(Cl)(Cl)(Cl)=O.C(OC(C)C)(C)C>CO.O1CCCC1>[NH2:3][CH:4]1[C:29](=[O:30])[N:6]2[C:7]([C:13]([O:15][CH:16]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[O:14])=[C:8]([C:11]#[CH:12])[CH2:9][S:10][C@H:5]12
Reactant: C#CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC=O)[C@H]2SC1
Solvent: CO
Solvent: O=P(Cl)(Cl)Cl
Solvent: CC(C)OC(C)C
Product: C#CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(N)[C@H]2SC1
Yield: 72.5 %

Procedure:
To a solution of benzhydryl 7-formamido-3-ethynyl-3-cephem-4-carboxylate (3 g) in a mixture of methanol (30 ml) and tetrahydrofuran (15 ml) was added phosphorus oxychloride (2.75 g) under ice-cooling. After the resultant mixture was stirred at room temperature for 30 minutes, the reaction mixture was added to diisopropyl ether (300 ml), and the precipitates were collected by filtration. The precipitates were added to a mixture of water (50 ml) and ethyl acetate (50 ml) under stirring, and the mixture was adjusted to pH 7.0 with saturated aqueous sodium bicarbonate. To the separated aqueous layer was added ethyl acetate (50 ml), and the mixture was acidified to pH 3.0 with 10% hydrochloric acid and the resultant precipitates were collected by filtration to give benzhydryl 7-amino-3-ethynyl-3-cephem-4-carboxylate (2.03 g).
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:14][CH3:15])[CH:12]=2)[NH:7][C:6]=1[C:16]([NH:18][CH3:19])=[O:17].O1CCCC1.[C:25](N1C=CN=C1)([N:27]1C=CN=[CH:28]1)=[O:26].CN>C(N(CC)CC)C>[CH3:15][O:14][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:16]([NH:18][CH3:19])=[O:17])=[C:5]2[CH2:4][CH2:3][NH:2][C:25](=[O:26])[NH:27][CH3:28]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CNC(=O)c1[nH]c2ccc(OC)cc2c1CCN
Agent: CN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CNC(=O)NCCc1c(C(=O)NC)[nH]c2ccc(OC)cc12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 80.4 %

Procedure:
To 3-(2-aminoethyl)-5-methoxy-N-methyl-1H-indole-2-carboxamide hydrochloride (167 mg) were added tetrahydrofuran (2.00 mL), triethylamine (0.246 mL), and 1,1′-carbonyldiimidazole (143 mg), followed by stirring at room temperature for 15 minutes. Then, methylamine (2 M tetrahydrofuran solution, 1.77 mL) was added thereto, followed by warming to 50° C. and stirring for 1 hour. The reaction mixture was cooled to room temperature, silica gel was added thereto, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform:methanol=100:0 to 20:1) to obtain 5-methoxy-N-methyl-3-{2-[(methylcarbamoyl)amino]ethyl}-1H-indole-2-carboxamide (144 mg) as a white solid.
Reaction SMILES: Cl[CH2:2]/[CH:3]=[CH:4]/[C:5]([N:7]1[CH2:28][CH2:27][C:10]2[C:11]3[C:16]([NH:17][C:18]4[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=4)=[N:15][CH:14]=[N:13][C:12]=3[S:26][C:9]=2[CH2:8]1)=[O:6].[CH3:29][N:30]1[CH2:34][CH2:33][CH:32]2[CH2:35][NH:36][CH2:37][CH:31]12>CN(C=O)C>[Cl:25][C:20]1[CH:19]=[C:18]([NH:17][C:16]2[C:11]3[C:10]4[CH2:27][CH2:28][N:7]([C:5](=[O:6])/[CH:4]=[CH:3]/[CH2:2][N:36]5[CH2:35][CH:32]6[CH:31]([N:30]([CH3:29])[CH2:34][CH2:33]6)[CH2:37]5)[CH2:8][C:9]=4[S:26][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:23]=[CH:22][C:21]=1[Cl:24]
Reactant: O=C(/C=C/CCl)N1CCc2c(sc3ncnc(Nc4ccc(Cl)c(Cl)c4)c23)C1
Reactant: CN1CCC2CNCC21
Solvent: CN(C)C=O
Product: CN1CCC2CN(C/C=C/C(=O)N3CCc4c(sc5ncnc(Nc6ccc(Cl)c(Cl)c6)c45)C3)CC21
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a suspension of Example 59A (80 mg, 0.16 mmol) in DMF (1 mL) was added 1-methyloctahydropyrrolo[3,4-b]pyrrole (41 mg, 0.32 mmol), and the mixture was stirred at rt for 20 h. After purification by preparative HPLC, the title compound was crystallized from dichloromethane/petroleum ether to yield 12 mg (14%).
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]([CH2:15][CH2:16][CH2:17]Cl)[S:5]([C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=1)(=[O:7])=[O:6].[CH3:19][C:20]1[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][C:21]=1[NH2:27].C(=O)([O-])[O-].[Na+].[Na+].[I-].[K+].C1(O)CCCCC1>O>[CH3:19][C:20]1[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][C:21]=1[N:27]1[CH2:17][CH2:16][CH2:15][N:4]([S:5]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)(=[O:7])=[O:6])[CH2:3][CH2:2]1
Reactant: Cc1ccc(S(=O)(=O)N(CCCl)CCCCl)cc1
Reactant: Cc1cccc(N)c1C
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: OC1CCCCC1
Product: Cc1ccc(S(=O)(=O)N2CCCN(c3cccc(C)c3C)CC2)cc1
Yield: 53.3 %

Procedure:
A mixture of 93 parts of N-(2-chloroethyl)-N-(3-chloropropyl)-4-methylbenzenesulfonamide, 30.3 parts of 2,3-dimethylbenzenamine, 63.6 parts of sodium carbonate, 1 part of potassium iodide and 240 parts of cyclohexanol was stirred and refluxed over weekend using a water separator. After cooling, the reaction mixture was poured into water. The product was extracted with methylbenzene. The extract was washed twice with water, dried, filtered and evaporated. The residue was crystallized from 2-propanol and a small amount of tetrahydrofuran. The product was filtered off and dried, yielding 47.8 parts (53.3%) of 1-(2,3-dimethylphenyl)hexahydro-4-[(4-methylphenyl)sulfonyl]-1H-1,4-diazepine; mp. 86.2° C. (intermediate 7).
Reaction SMILES: [O:1]=[C:2]1[C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:6][NH:5][C:4]([CH:16]=[O:17])=[CH:3]1.[Br:18]Br>CC(O)=O>[Br:18][C:3]1[C:2](=[O:1])[C:7]([O:8][CH2:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[CH:6][NH:5][C:4]=1[CH:16]=[O:17]
Reactant: O=Cc1cc(=O)c(OCc2ccccc2)c[nH]1
Reactant: BrBr
Solvent: CC(=O)O
Product: O=Cc1[nH]cc(OCc2ccccc2)c(=O)c1Br
Temperature: 25 °C
Yield: 74.1 %

Procedure:
2.62 g of 1,4-dihydro-4-oxo-5-(phenylmethoxy)-2-pyridine carboxaldehyde and 0.83 g NaAc were dissolved in 50 ml AcOH and 2 g Br2 were dropped in while stirring at room temperature. After 2 hours the solvent was distilled off and the residue stirred with 50 ml ice water. A precipitate of crude title compound was obtained. Isolation by filtration, washing with water and recrystallization from diozane yielded 2.61 g title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:5]=[CH:4][C:3]=1[OH:12].[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][CH:23]([N:26]2[C:30]3=[N:31][CH:32]=[N:33][C:34](Cl)=[C:29]3[CH:28]=[N:27]2)[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14].C(=O)([O-])[O-].[K+].[K+].C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C>[C:13]([O:17][C:18]([N:20]1[CH2:21][CH2:22][CH:23]([N:26]2[C:30]3=[N:31][CH:32]=[N:33][C:34]([O:12][C:3]4[CH:4]=[CH:5][C:6]([S:8]([CH3:11])(=[O:9])=[O:10])=[CH:7][C:2]=4[F:1])=[C:29]3[CH:28]=[N:27]2)[CH2:24][CH2:25]1)=[O:19])([CH3:16])([CH3:14])[CH3:15]
Reactant: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Cl)ncnc32)CC1
Reactant: CS(=O)(=O)c1ccc(O)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Oc4ccc(S(C)(=O)=O)cc4F)ncnc32)CC1
Temperature: 160 °C
Yield: 47.5 %

Procedure:
A mixture of 2-fluoro-4-methanesulfonyl-phenol (Intermediate 1; 112 mg, 0.6 mmol), 4-(4-chloro-pyrazolo[3,4-d]pyrimidin-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (200 mg, 0.6 mmol) and potassium carbonate (180 mg, 1.3 mmol) in DMF (2 mL) was heated in a microwave oven at 160° C. for 10 min. Saturated sodium carbonate solution was added to the reaction mixture to give a precipitate which was filtered off and dissolved in ethyl acetate. The organic solution was dried (sodium sulfate), filtered, evaporated, and purified by flash chromatography, eluting with 20% ethyl acetate/hexanes, to give 4-[4-(2-fluoro-4-methane-sulfonyl-phenoxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid tert-butyl ester (140 mg, 47%) as a white solid.
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][C:11](=[O:13])[CH2:10][C:9](=[O:14])[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C1(OC2C=CC=CC=2)C=CC=CC=1.C(Cl)Cl.[Pd]>[C:7]1([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:8]=[C:9]([OH:14])[CH:10]=[C:11]([OH:13])[CH:12]=1
Reactant: O=C1CC(=O)CC(c2ccccc2)C1
Agent: [Pd]
Solvent: ClCCl
Solvent: c1ccc(Oc2ccccc2)cc1
Product: Oc1cc(O)cc(-c2ccccc2)c1
Temperature: 230 °C
Reaction time: 2.5 h

Procedure:
A mixture of 5-phenyl-1,3-cyclohexanedione (2.5 g, 13 mM) and 10% Pd/C (0.5 g) in phenyl ether (30 mL) was heated to 230° C. over 30 minutes and held at 230° C. for 2.5 hours. The reaction was cooled, taken up in CH2Cl2 and filtered through Dicalite. The filtrate was concentrated and the residue purified by chromatography (CH2Cl2, then 5-10% EtOAc/CH2Cl2) to give the desired product.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[CH:9]=[CH:8][C:7]([N+:11]([O-:13])=[O:12])=[CH:6][C:5]=2[C:4]2[O:14][C:15]([C:19](O)=[O:20])=[CH:16][C:17](=[O:18])[C:3]1=2.C(N1C=CN=C1)(N1C=CN=C1)=O.O.[NH2:35][C:36]1[NH:40][N:39]=[N:38][N:37]=1.C(N(CC)CC)C.Cl[Si](C)(C)C>CN(C=O)C>[CH3:1][N:2]1[C:10]2[CH:9]=[CH:8][C:7]([N+:11]([O-:13])=[O:12])=[CH:6][C:5]=2[C:4]2[O:14][C:15]([C:19]([NH:35][C:36]3[NH:40][N:39]=[N:38][N:37]=3)=[O:20])=[CH:16][C:17](=[O:18])[C:3]1=2
Reactant: Cn1c2ccc([N+](=O)[O-])cc2c2oc(C(=O)O)cc(=O)c21
Reactant: Nc1nnn[nH]1
Agent: C[Si](C)(C)Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: Cn1c2ccc([N+](=O)[O-])cc2c2oc(C(=O)Nc3nnn[nH]3)cc(=O)c21
Temperature: 60 °C
Reaction time: 1 h

Procedure:
A mixture of 4.7 g (16.4 mmole) 4,5-dihydro-5-methyl-8-nitro-4-oxopyrano[3,2-b]indole-2-carboxylic acid and 3.8 g (23.4 mmole) 1,1'carbonyl-diimidazole in 100 ml DMF was heated at 60° C. for one hour and then cooled to room temperature. In a separate flask, a mixture of 1.8 g (17.5 mmole) 5-aminotetrazole monohydrate and 5.4 g (53.1 mmole) triethylamine were combined in 50 ml DMF. This mixture was cooled in an ice bath while 5.8 g (52.8 mmole) chlorotrimethylsilane was added in one portion. Stirring in ice was continued for one hour, followed by an additional two hours with the ice bath removed. The triethylamine mixture was then added to the original carboxylic acid mixture, and the new mixture was heated on a steam bath for one hour. The mixture was cooled, and the precipitated triethylamine hydrochloride was filtered and discarded. The filtrate was added to 500 g ice/water, the mixture was filtered by gravity, and the filtrate was acidified with 4 N hydrochloric acid. The precipitated crude product was filtered, washed with water and recrystallized twice from DMF-water to yield yellow solid of mp 295° C. dec.
Reaction SMILES: [C:1]1([N:7]2[C:11]([SH:12])=[N:10][N:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[C:16]([Cl:21])[C:15]=1[N:22]1[C:26](=[O:27])[C:25](Br)=[C:24]([NH:29][C:30](=[O:58])[C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([NH:37][C:38](=[O:57])[CH2:39][O:40][C:41]3[CH:46]=[CH:45][C:44]([C:47]([CH2:50][CH3:51])([CH3:49])[CH3:48])=[CH:43][C:42]=3[C:52]([CH2:55][CH3:56])([CH3:54])[CH3:53])[CH:32]=2)[NH:23]1.O>CN(C)C=O>[Cl:21][C:16]1[CH:17]=[C:18]([Cl:20])[CH:19]=[C:14]([Cl:13])[C:15]=1[N:22]1[C:26](=[O:27])[C:25]([N:10]2[C:11](=[S:12])[N:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[N:8]=[N:9]2)=[C:24]([NH:29][C:30](=[O:58])[C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([NH:37][C:38](=[O:57])[CH2:39][O:40][C:41]3[CH:46]=[CH:45][C:44]([C:47]([CH2:50][CH3:51])([CH3:49])[CH3:48])=[CH:43][C:42]=3[C:52]([CH2:55][CH3:56])([CH3:54])[CH3:53])[CH:32]=2)[NH:23]1
Reactant: Sc1nnnn1-c1ccccc1
Reactant: CCC(C)(C)c1ccc(OCC(=O)Nc2cccc(C(=O)Nc3[nH]n(-c4c(Cl)cc(Cl)cc4Cl)c(=O)c3Br)c2)c(C(C)(C)CC)c1
Solvent: CN(C)C=O
Solvent: O
Product: CCC(C)(C)c1ccc(OCC(=O)Nc2cccc(C(=O)Nc3[nH]n(-c4c(Cl)cc(Cl)cc4Cl)c(=O)c3-n3nnn(-c4ccccc4)c3=S)c2)c(C(C)(C)CC)c1

Procedure:
According to the method disclosed in Pharmazle, 29 (2) page 90, a mercuric salt of 1-phenyl-5-mercaptotetrazole and 1-(2,4,6-trichlorophenyl)-3-[3-(2,4-di-tert-amylphenoxyacetamido)benzamido]-4-bromo-5-pyrazolone were reacted in dimethylformamide. The reaction mixture was poured into water, was extracted with ethyl acetate and washed. After evaporating off the ethyl acetate under reduced pressure, the remaining substance was recrystallized from ethanol to provide 1-(2,4,6-trichlorophenyl)-3-[3-(2,4-di-tert-amylphenoxyacetamido)benzamido]-4-(4-phenyl-5-thioxotetrazolin-1-yl)-5-pyrazolone having a melting point of 169° to 171° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15](C(OCC)=O)[C:16]([O:18]CC)=[O:17])=[C:11]([N+:26]([O-:28])=[O:27])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]([OH:18])=[O:17])=[C:11]([N+:26]([O-:28])=[O:27])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(C(=O)OCC)c1ccc(OCc2ccccc2)cc1[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)Cc1ccc(OCc2ccccc2)cc1[N+](=O)[O-]
Temperature: 62.5 °C
Yield: 95 %

Procedure:
The synthetic approach for the proposed achiral seco-CI compounds starts from the reaction of the readily available diethyl 2-(4-benzyloxy-2-nitrophenyl)malonate (4c). Treatment of diethyl 2-(4-benzyloxy-2-nitrophenyl)malonate with NaOH in ethanol (25-80° C.), preferably refluxing, followed by acidification and mild heating (25-100° C.), preferably refluxing, the solution gave the desired 4-benzyloxy-2-nitrophenylacetic acid in 95% yield. Selective reduction of the carboxylic acid with borane at 0-50° C., preferably at room temperature, in THF produced 2-(4-benzyloxy-2-nitrophenyl)ethanol in 95% yield. The alcohol was then chlorinated at 0-50° C., preferably at room temperature, with triphenylphosphine and carbon tetrachloride in CH2Cl2 to give 2-(4-benzyloxy-2-nitrophenyl)ethyl chloride in 97% yield. The 2-(4-benzyloxy-2-nitrophenyl)ethyl bromide was obtained in 92% yield after reacting 2-(4-benzyloxy-2-nitrophenyl)ethanol with triphenylphosphine and carbon tetrabromide in acetonitrile. Catalytic reduction of 2-(4-benzyloxy-2-nitrophenyl)ethyl chloride and 2-(4-benzyloxy-2-nitrophenyl)ethyl bromide at atmospheric pressure, and at 0-50° C., preferably at room temperature, using 10% Pd/C in THF afforded 2-(2-amino-4-hydroxyphenyl)ethyl chloride and 2-(2-amino-4-hydroxyphenyl)ethyl bromide, respectively. 2-(2-Amino-4-hydroxyphenyl)ethyl bromide was directly coupled at 0-50° C., preferably at room temperature, with 5-(benzofuran-2-carboxamido)indole-2-carboxylic acid in the presence of EDCI [1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride] and DMF to give compound 4-(2-bromoethyl)-3-[5-(5-benzofuran-2-carboxamido)indole-2-carboxamido]phenol in a low 2% yield for the two steps after purification by silica gel column chromatography. Similarly, coupling of 2-(2-amino-4-hydroxyphenyl)ethyl chloride with 5-(benzofuran-2-carboxamido)indole-2-carboxylic acid in the presence of EDCI gave 4-(2-chloroethyl)-3-[5-(5-benzofuran-2-carboxamido)indole-2-carboxamido]phenol in 28% yield for the two steps following column chromatography.
Reaction SMILES: [H-].[Na+].[CH2:3](Br)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Cl:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][C:20]=1[Cl:21])[CH:15]=[N:16][OH:17]>CCCCCC.O1CCCC1.ClCCl>[CH2:3]([O:17][N:16]=[CH:15][C:14]1[CH:18]=[CH:19][C:20]([Cl:21])=[C:12]([Cl:11])[CH:13]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: ON=Cc1ccc(Cl)c(Cl)c1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Clc1ccc(C=NOCc2ccccc2)cc1Cl
Temperature: 22 °C
Reaction time: 18 h
Yield: 67 %

Procedure:
Sodium hydride (1.05 g of 60% suspension in mineral oil, 0.63 g, 26.3 mmol) was washed with hexane, suspended in tetrahydrofuran (10 ml) and then treated with benzyl bromide (2.7 ml, 22.8 mmol) A solution of the above oxime in tetrahydrofuran (10 ml) was then added dropwise and the resulting mixture was stirred at 22° C. for 18 h. The reaction mixture was then diluted with dichloromethane, washed with water, brine and dried. Evaporation of the solvent and chromatography of the residue on silica gel (elution hexane-toluene, 8:2 to 1:1) gave 4.30 g (67% yield) of the title oxime ether as a clear oil. 1HNMR 400 MHz (CDCl3) δ (ppm): 5.12 (2H, s, OCH2), 7.3-7.44 (7H, m, aromatics), 7.68 (1H, d, aromatic), 8.04 (1H, s, CH).
Reaction SMILES: C(O[C:4](=[O:18])[CH2:5][CH2:6][NH:7][C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9])C.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH:29]1([NH:34][C:35]2[C:40]([CH:41]=O)=[CH:39][N:38]=[C:37]([S:43][CH3:44])[N:36]=2)[CH2:33][CH2:32][CH2:31][CH2:30]1>O1CCCC1.C(OCC)(=O)C.O>[CH2:11]([O:10][C:8](=[O:9])[NH:7][CH2:6][C:5]1[C:4](=[O:18])[N:34]([CH:29]2[CH2:33][CH2:32][CH2:31][CH2:30]2)[C:35]2[N:36]=[C:37]([S:43][CH3:44])[N:38]=[CH:39][C:40]=2[CH:41]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CSc1ncc(C=O)c(NC2CCCC2)n1
Reactant: CCOC(=O)CCNC(=O)OCc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CSc1ncc2cc(CNC(=O)OCc3ccccc3)c(=O)n(C3CCCC3)c2n1

Procedure:
3-Benzyloxycarbonylamino-propionic acid ethyl ester (6.68 g, 26.58 mmol) was dissolved in tetrahydrofuran (40 mL) to which LiHMDS (28 mL, 28 mmol, 1.0 M in THF) was slowly added. 4-Cyclopentylamino-2-methylsulfanyl-pyrimidine-5-carbaldehyde (3.15 g, 13.29 mmol) was then added neat and the reaction mixture was brought to reflux for 7 hours. The reaction mixture was diluted with ethyl acetate and water, the layers separated, the organic layer dried over MgSO4 and the solvent evaporated to give a crude oil. The crude oil was purified by silica gel chromatography to give (8-cyclopentyl-2-methylsulfanyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-6-ylmethyl)-carbamic acid benzyl ester as pale yellow waxy solid (1.67 g, 29.6%). 1H NMR δ(400 MHz, CDCl3) 8.57 (s, 1H), 7.56 (s, 1H), 7.26-7.36 (m, 5H), 5.93 (m, 1H), 5.56 (t, J=6.1 Hz, 1H), 5.08 (s, 2H), 4.25 (d, J=6.2 Hz, 2H), 2.60 (s, 3H), 2.30 (m, 2H), 2.05 (m, 2H), 1.86 (m, 2H), 1.69 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH2:4][CH2:5][CH2:6][CH:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.C([O-])([O-])=O.[K+].[K+].I[CH2:21][CH2:22][CH2:23][CH2:24][N:25]1[C:33](=[O:34])[CH:32]2[CH:27]([CH:28]=[CH:29][CH:30]=[CH:31]2)[C:26]1=[O:35]>CC(C)=O>[CH3:1][O:2][C:3](=[O:13])[CH2:4][CH2:5][CH2:6][CH:7]1[CH2:12][CH2:11][N:10]([CH2:21][CH2:22][CH2:23][CH2:24][N:25]2[C:33](=[O:34])[CH:32]3[CH:27]([CH:28]=[CH:29][CH:30]=[CH:31]3)[C:26]2=[O:35])[CH2:9][CH2:8]1
Reactant: O=C1C2C=CC=CC2C(=O)N1CCCCI
Reactant: COC(=O)CCCC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)CCCC1CCN(CCCCN2C(=O)C3C=CC=CC3C2=O)CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 18.3 %

Procedure:
To a suspension of 2 (1.96 g, 8.86 mmol), K2CO3 (2.82 g, 17.72 mmol) and acetone (100 mL) was added 2-(4-iodobutyl)-3a,7a-dihydroisoindole-1,3-dione (2.93 g, 8.86 mmol). The newly formed suspension was stirred at ambient temperature for 48 hours. The solid was vacuum filtered and the filtrate was concentrated under vacuum. The resulting residue was subjected to column chromatography eluting with 0-100% ethyl acetate in hexanes to afford the desired product 3 (0.63 g, 40%) as a white solid: 1H NMR (500 MHz; CDCl3) δ 1.16-1.28 (m, 3H), 1.65 (m, 2H), 1.60-1.72 (m, 4H), 1.86 (m, 2H), 2.26 (t, 2H), 2.32 (t, 2H), 2.88 (d, 2H) 3.64 (s, 3H), 3.70 (t, 2H), 7.68 (d, 2H), 7.72 (d, 2H).