Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][NH:15][C:16]([C:18]3([NH:21][C:22](=[O:27])[C:23]([O:25]C)=O)[CH2:20][CH2:19]3)=[O:17])=[C:10]([F:28])[CH:9]=2)[C:3]=1[C:29]([O:31][CH3:32])=[O:30].[NH3:33]>C(Cl)Cl.CO>[NH2:33][C:23](=[O:25])[C:22]([NH:21][C:18]1([C:16]([NH:15][CH2:14][C:11]2[CH:12]=[CH:13][C:8]([C:4]3[C:3]([C:29]([O:31][CH3:32])=[O:30])=[C:2]([F:1])[CH:7]=[CH:6][CH:5]=3)=[CH:9][C:10]=2[F:28])=[O:17])[CH2:20][CH2:19]1)=[O:27]
Reactant: N
Reactant: COC(=O)C(=O)NC1(C(=O)NCc2ccc(-c3cccc(F)c3C(=O)OC)cc2F)CC1
Solvent: ClCCl
Solvent: CO
Product: COC(=O)c1c(F)cccc1-c1ccc(CNC(=O)C2(NC(=O)C(N)=O)CC2)c(F)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of methyl 3,3′-difluoro-4′-({[(1-{[methoxy(oxo)acetyl]-amino}cyclopropyl)carbonyl]amino}methyl)-1,1′-biphenyl-2-carboxylate (0.02 g, 0.045 mmol, Example 5) in methylene chloride (2 mL) at room temperature was added ammonia (0.224 mL of a 2M solution in methanol, 0.45 mmol). The reaction mixture was stirred at room temperature for 4 hrs and then concentrated to obtain the crude product. This crude product was purified by reverse phase HPLC (Vydac column #218TP1022, gradient elution 5–95% acetonitrile:water containing 0.1% TFA). The pure fractions were lyophilized to afford the title compound as a solid. Purity was determined by LCMS (ES MS, M++H found:432) and proton NMR (400 MHz, CDCl3: δ 7.86 (1H,s), 7.45(1H,dt, J=5.7 and 8.1 Hz), 7.35 (1H, t, J=7.8 Hz), 7.20–7.00 (4H,m), 6.59 (1H, m), 5.61(1H, s), 4.54 (2H, d,J=6.0 Hz), 3.74(3H,s), 1.68(2H,m), 1.12 (2H,m) ppm.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH:20]2[CH2:25][C:24]([CH3:27])([CH3:26])[CH2:23][C:22]([CH3:29])([CH3:28])[CH2:21]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])(=O)C.[Na+].[Br:35]Br.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(OCC)(=O)C.O.CO>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[CH:19]=[CH:18][C:17]([Br:35])=[CH:16][C:15]=2[CH:20]2[CH2:25][C:24]([CH3:27])([CH3:26])[CH2:23][C:22]([CH3:29])([CH3:28])[CH2:21]2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: BrBr
Reactant: CC1(C)CC(c2ccccc2N2CCN(C(=O)OC(C)(C)C)CC2)CC(C)(C)C1
Agent: CC(=O)[O-]
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CO
Product: CC1(C)CC(c2cc(Br)ccc2N2CCN(C(=O)OC(C)(C)C)CC2)CC(C)(C)C1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 77.1 %

Procedure:
To a mixture of 4-[2-(3,3,5,5-tetramethylcyclohexyl)phenyl]piperazine-1-carboxylic acid t-butyl ester (2.93 g, 7.31 mmol) produced in Example (8a), sodium acetate (6 g, 73.14 mmol) and methanol (50 mL) was added bromine (0.37 mL, 7.22 mmol), followed by stirring for 20 minutes at room temperature under a nitrogen atmosphere. Saturated aqueous solution of sodium thiosulfate, ethyl acetate and water were added to the reaction mixture and extraction was performed with ethyl acetate. The separated organic layer was washed with brine and then dried over anhydrous sodium sulfate. The desiccant was filtered off and the filtrate was concentrated under reduced pressure. The resultant residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give 2.67 g of the title compound as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([CH:14]=[O:15])=[CH:12][N:11]=[CH:10][CH:9]=2)=[C:4]([F:16])[CH:3]=1.[BH4-].[Na+]>CO.O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][N:11]=[CH:12][C:13]=2[CH2:14][OH:15])=[C:4]([F:16])[CH:3]=1
Reactant: O=Cc1cnccc1-c1ccc(Cl)cc1F
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: OCc1cnccc1-c1ccc(Cl)cc1F
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-(4-chloro-2-fluorophenyl)nicotinaldehyde (3 g, 12.73 mmol) in a mixture of methanol (5 mL) and tetrahydrofuran (5 mL) cooled to 0° C. was added NaBH4 (0.722 g, 19.10 mmol) and the solution stirred for 30 min. The reaction was quenched by addition of water (10 mL). The solution was extracted with ethyl acetate (3×15 mL). The combined organic extracts were washed with water (1×15 mL) and brine (1×15 mL), dried with sodium sulfate and concentrated under reduced pressure to yield (4-(4-chloro-2-fluorophenyl)pyridin-3-yl)methanol that was used without further purification in the next step. LCMS (ESI) m/e 238 [(M+H)+, calcd for C12H10ClFNO 238.0].
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([OH:9])[CH2:5][CH2:4]1.C(N1[C:19](=[O:20])[C:18]2=[CH:21][CH:22]=[CH:23][CH:24]=[C:17]2[C:16]1=[O:25])(OCC)=O.C(N(CC)CC)C>C(Cl)Cl.O>[OH:9][C@H:6]1[CH2:7][CH2:8][C@H:3]([N:2]2[C:19](=[O:20])[C:18]3[C:17](=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:16]2=[O:25])[CH2:4][CH2:5]1
Reactant: N[C@H]1CC[C@H](O)CC1
Reactant: CCOC(=O)N1C(=O)c2ccccc2C1=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: O=C1c2ccccc2C(=O)N1[C@H]1CC[C@H](O)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of trans-4-aminocyclohexanol hydrochloride (1.0 g, 6.6 mmol) (Aldrich, Cat. #263761), N-carbethoxyphthalimide (1.4 g, 6.6 mmol) (Aldrich, Cat. #C5459), and triethylamine (2.0 mL, 14 mmol) in methylene chloride (10 mL) was stirred at r.t. overnight. The mixture was diluted with water, and extracted with ethyl acetate (3×20 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column with ethyl acetate in hexanes to afford the desired product (1.2 g, 76%).
Reaction SMILES: [OH:1][C:2]1[CH:18]=[CH:17][C:5]2[NH:6][C:7]([NH:9][C:10]([NH:12][CH2:13][CH2:14][O:15][CH3:16])=[O:11])=[N:8][C:4]=2[CH:3]=1.[Cl:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[C:21]=1[S:27](Cl)(=[O:29])=[O:28].O>[OH-].[Na+]>[Cl:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[C:21]=1[S:27]([O:1][C:2]1[CH:18]=[CH:17][C:5]2[NH:6][C:7]([NH:9][C:10](=[O:11])[NH:12][CH2:13][CH2:14][O:15][CH3:16])=[N:8][C:4]=2[CH:3]=1)(=[O:29])=[O:28]
Reactant: O=S(=O)(Cl)c1c(Cl)cccc1Cl
Reactant: COCCNC(=O)Nc1nc2cc(O)ccc2[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COCCNC(=O)Nc1nc2cc(OS(=O)(=O)c3c(Cl)cccc3Cl)ccc2[nH]1
Temperature: 5 °C

Procedure:
To a solution of 175 mg of 1-(5-hydroxy-1H-benzimidazol-2-yl)-3-(2-methoxyethyl)urea in 15 cm3 of 0.1N aqueous sodium hydroxide solution are added 189 mg of finely ground 2,6-dichlorobenzenesulfonyl chloride. The suspension is stirred for about 20 hours at a temperature in the region of 20° C., 10 cm3 of water are then added and the mixture is cooled to about 5° C. for about 15 minutes. The precipitate is filtered off by suction, washed with three times 2 cm3 of water and dried under reduced pressure (13 kPa) over phosphorus pentoxide. After flash chromatography on a column of silica [eluent: dichloromethane/methanol/acetonitrile (95/3/2 by volume)], 65 mg of 2-{[(2-methoxyethyl)carbamoyl]amino}-1H-benzimidazol-5-yl 2,6-dichlorobenzenesulfonate are obtained in the form of a cream-coloured powder, the characteristics of which are as follows:
Reaction SMILES: O[C:2]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]([CH2:12][CH2:13][CH2:14][CH3:15])[C:4]2=[N:16][CH2:17][CH2:18][N:3]12.[BH4-].[Na+]>FC(F)(F)C(O)=O>[CH2:12]([N:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH:2]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:3]2[CH2:18][CH2:17][N:16]=[C:4]12)[CH2:13][CH2:14][CH3:15]
Reactant: CCCCN1C2=NCCN2C(O)(c2ccccc2)c2ccccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: CCCCN1C2=NCCN2C(c2ccccc2)c2ccccc21
Reaction time: 1 h
Yield: 65.8 %

Procedure:
To 20 ml of trifluoroacetic acid were added portionwise with stirring both of 0.48 g of 5-hydroxy-10-(n-butyl)-5-phenyl-2,3,5,10-tetrahydroimidazo[2,1-b]quinazoline and 0.57 g of sodium borohydride below 0° C. under nitrogen. The reaction mixture was stirred at 0°-5° C. for 1 hour and the trifluoroacetic acid was evaporated under reduced pressure. To the residue were added 20 ml of ice-water and then 15 ml of 40% sodium hydroxide solution. After stirring for a while, the mixture was extracted with chloroform and the chloroform layer was washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was chromatographed on silica gel using chloroform as an eluent to give 0.3 g of 10-(n-butyl)-5-phenyl-2,3,5,10-tetrahydroimidazo[2,1-b]quinazoline as a light yellow oil. An ethanol solution of the product was treated with ethanolic hydrogen chloride and evaporated under reduced pressure. The residue was recrystallized from ethanol to give colorless prisms (hydrochloride), m.p. 297° C. (decomp.).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:16][CH2:17][CH2:18][CH3:19])=[C:6]([C:8]2[CH:13]=[C:12]([Cl:14])[N:11]=[C:10]([NH2:15])[N:9]=2)[CH:7]=1.NC1N=[C:25]([C:27]2C=C(Br)C=CC=2O)[CH:24]=[C:23](Cl)N=1.C(O)C1C=CC=CC=1>>[CH2:17]([O:16][C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][C:6]=1[C:8]1[CH:13]=[C:12]([Cl:14])[N:11]=[C:10]([NH2:15])[N:9]=1)[C:18]1[CH:27]=[CH:25][CH:24]=[CH:23][CH:19]=1
Reactant: CCCOc1ccc(Br)cc1-c1cc(Cl)nc(N)n1
Reactant: Nc1nc(Cl)cc(-c2cc(Br)ccc2O)n1
Solvent: OCc1ccccc1
Product: Nc1nc(Cl)cc(-c2cc(Br)ccc2OCc2ccccc2)n1
Yield: 43 %

Procedure:
Following the method described in Example 135 for the synthesis of 4-(5-bromo-2-propoxy-phenyl)-6-chloro-pyrimidin-2-ylamine, 2-(2-amino-6-chloro-pyrimidin-4-yl)-4-bromo-phenol and benzyl alcohol provided 4-(2-benzyloxy-5-bromo-phenyl)-6-chloro-pyrimidin-2-ylamine (43% yield).
Reaction SMILES: [CH:1]([O:14][C:15]([C:17]1[N:18]2[CH:21]([S:22][CH2:23][C:24]=1[C:25]1[S:29][C:28]([C:30]3[CH:35]=[CH:34][N:33]=[CH:32][CH:31]=3)=[N:27][CH:26]=1)[CH:20]([NH:36][C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[C:19]2=[O:44])=[O:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:53])C=1>C(Cl)Cl>[CH:1]([O:14][C:15]([C:17]1[N:18]2[CH:21]([S:22](=[O:53])[CH2:23][C:24]=1[C:25]1[S:29][C:28]([C:30]3[CH:31]=[CH:32][N:33]=[CH:34][CH:35]=3)=[N:27][CH:26]=1)[CH:20]([NH:36][C:37]([O:39][C:40]([CH3:41])([CH3:43])[CH3:42])=[O:38])[C:19]2=[O:44])=[O:16])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(C)(C)OC(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(c3cnc(-c4ccncc4)s3)CSC12
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(c3cnc(-c4ccncc4)s3)CS(=O)C12
Yield: 93.4 %

Procedure:
A solution of 2-benzhydryloxycarbonyl-7-t-butoxycarbonylamino-8-oxo-3-[2-(pyridin-4-yl)-thiazol-5-yl]-5-thia-1-azabicyclo[4.2.0]oct-2-ene (24 g) in methylene chloride (370 cc) is oxidised with 85% pure meta-chloroperbenzoic acid (7.92 g) in accordance with the procedure described in Example 2 to give 2-benzhydryloxycarbonyl-7-t-butoxycarbonylamino-8-oxo-3-[2-(pyridin-4-yl)-thiazol-5-yl]-5-thia-1-azabicyclo[4.2.0]oct-2-ene 5-oxide (23 g) in the form of a brown-yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6]2.C(=O)([O-])[OH:14].[Na+].ClC1C=CC=C(C(OO)=O)C=1>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[O:14][C:8](=[O:12])[CH2:7][CH2:6]2
Reactant: O=C([O-])O
Reactant: COc1ccc2c(c1)CCC2=O
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc2c(c1)CCC(=O)O2
Temperature: 0 °C
Reaction time: 8 h
Yield: 79.7 %

Procedure:
To a solution of 5-methoxy-indan-1-one (4.2 g, 25.9 mmol) in 240 ml of dichloromethane cooled in an ice bath was added sodium hydrogencarbonate (4.35 g, 51.8 mmol). 3-Chloro-perbenzoic acid (11.61 g, 51.8 mmol) was added portionwise, and the reaction mixture was stirred at 0° C. for 2 h and at room temperature overnight. The precipitate was filtered off and washed with dichloromethane. The filtrate was washed with saturated solution of sodium hydrogencarbonate and dried with sodium sulfate. After evaporation of the solvent, 6-methoxy-chroman-2-one (3.68 g, 80%) was obtained as an orange oil which was used without further purification.
Reaction SMILES: [CH2:1]([OH:16])[CH2:2][O:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][OH:15].[C:17](Cl)([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O>C(#N)C.N1C=CC=CC=1>[C:18]1([C:17]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[O:15][CH2:14][CH2:13][O:12][CH2:11][CH2:10][O:9][CH2:8][CH2:7][O:6][CH2:5][CH2:4][O:3][CH2:2][CH2:1][OH:16])[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: OCCOCCOCCOCCOCCO
Solvent: c1ccncc1
Solvent: CC#N
Solvent: O
Product: OCCOCCOCCOCCOCCOC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 31.6 %

Procedure:
10 g of pentaethyleneglycol was dissolved in a mixture of 100 mL of acetonitrile and 30 mL of pyridine, to which 11 g of trityl chloride were added at 0° C., and then the solution was stirred overnight at room temperature. The reaction solution was mixed with iced water and subjected to extraction with ethyl acetate, and then the organic layer washed with water and concentrated under reduced pressure after drying. The residue was purified with silica gel column chromatography to obtain 6 g of the objective compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[CH2:7][CH2:8][C@H:9]([NH:13][C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])[C:10]([OH:12])=O)([CH3:4])([CH3:3])[CH3:2].[CH2:25]([O:29][C:30]([N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1)=[O:31])[CH2:26][CH2:27][CH3:28].C(N1CCOCC1)C.[B-](F)(F)(F)F.CCOC(C(C#N)=NOC(N(C)C)=[N+](C)C)=O>CN(C=O)C.C(OCC)(=O)C>[CH2:25]([O:29][C:30]([N:32]1[CH2:37][CH2:36][N:35]([C:10](=[O:12])[C@@H:9]([NH:13][C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])[CH2:8][CH2:7][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:24])[CH2:34][CH2:33]1)=[O:31])[CH2:26][CH2:27][CH3:28]
Reactant: CC(C)(C)OC(=O)CC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: CCCCOC(=O)N1CCNCC1
Agent: CCN1CCOCC1
Agent: CCOC(=O)C(C#N)=NOC(N(C)C)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)OCc2ccccc2)CC1
Reaction time: 12 h

Procedure:
To a solution of 9.06 g (S)-2-Benzyloxycarbonylamino-pentanedioic acid 5-tert-butyl ester in 100 ml DMF were added 5.00 g piperazine-1-carboxylic acid butyl ester hydrotrifluoroacetate, 13.7 ml N-ethylmorpholine and 8.8 g TOTU. After stirring for 12 h the solution was diluted with ethyl acetate and subsequently washed with aqueous LiCl (4%) and saturated NaHCO3. The crude product obtained after evaporation of the solvent was used without further purification. Yield: 15.8 g.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:14]3[C:15]([CH3:20])=[N:16][O:17][C:18]=3[CH3:19])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[N+:21]([O-:23])=[O:22].[CH3:24][C:25]1[S:26][C:27]([CH2:31][NH2:32])=[C:28]([CH3:30])[N:29]=1>C(#N)C.O>[CH3:20][C:15]1[C:14]([C:8]2[CH:7]=[C:6]3[C:11]([C:2]([NH:32][CH2:31][C:27]4[S:26][C:25]([CH3:24])=[N:29][C:28]=4[CH3:30])=[C:3]([N+:21]([O-:23])=[O:22])[CH:4]=[N:5]3)=[CH:10][C:9]=2[O:12][CH3:13])=[C:18]([CH3:19])[O:17][N:16]=1
Reactant: COc1cc2c(Cl)c([N+](=O)[O-])cnc2cc1-c1c(C)noc1C
Reactant: Cc1nc(C)c(CN)s1
Solvent: O
Solvent: CC#N
Product: COc1cc2c(NCc3sc(C)nc3C)c([N+](=O)[O-])cnc2cc1-c1c(C)noc1C
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To a solution of 4-chloro-7-(3,5-dimethyl-4-isoxazolyl)-6-(methyloxy)-3-nitroquinoline (for a preparation see Intermediate 18, 1.5 g) in acetonitrile was added [(2,4-dimethyl-1,3-thiazol-5-yl)methyl]amine (1.6 g) and the resulting mixture was stirred overnight at 80° C. Another portion of amine (0.64 g) was added and the mixture was stirred at 80° C. for 6 h. The reaction mixture was diluted with water, extracted with DCM and the organic phase were dried over Na2SO4, and concentrated to dryness to give a dark red oil. The residue was purified by flash chromatography on silica gel, eluting with DCM/methanol (99:1 then 95:5) to give 7-(3,5-dimethyl-4-isoxazolyl)-N-[(2,4-dimethyl-1,3-thiazol-5-yl)methyl]-6-(methyloxy)-3-nitro-4-quinolinamine (1.13 g) as an orange oil.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8](O)=[O:9])[C:5]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:4]([O:19][CH3:20])[CH:3]=1.C(Cl)(=O)C([Cl:24])=O>C1C=CC=CC=1.CN(C=O)C>[Br:1][C:2]1[N:7]=[C:6]([C:8]([Cl:24])=[O:9])[C:5]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:4]([O:19][CH3:20])[CH:3]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: COc1cc(Br)nc(C(=O)O)c1OCc1ccccc1
Solvent: c1ccccc1
Solvent: CN(C)C=O
Product: COc1cc(Br)nc(C(=O)Cl)c1OCc1ccccc1
Reaction time: 0.25 h

Procedure:
To a stirred mixture of 16 (2.54 g., 7.5 mmol) in benzene (30 mL) containing DMF (3 drops) was added oxalyl chloride (1.90 g, 15 mmol) in one portion. After gas evolution had ceased (about 45 min.), the now homogeneous solution was stirred an additional 15 min., then the solvent was evaporated. 1,2-Dichloroethane (30 mL) was added and again the solvent was evaporated to give a quantitative yield of 3 as a nearly colorless oil. This material was dissolved in CH2Cl2 (10 mL) or THF (10 mL) and used directly in subsequent coupling reactions.
Reaction SMILES: [N:1]1([CH2:6][C:7]2[N:11]([C:12]3[CH:13]=[C:14]4[C:18](=[CH:19][CH:20]=3)[N:17]([CH3:21])[CH:16]=[CH:15]4)[C:10]([C:22]3[CH:27]=[C:26]([CH:28]([CH3:30])[CH3:29])[C:25]([O:31]CC4C=CC=CC=4)=[CH:24][C:23]=3[O:39]CC3C=CC=CC=3)=[N:9][N:8]=2)[CH:5]=[CH:4][N:3]=[CH:2]1>CCO.[Pd]>[N:1]1([CH2:6][C:7]2[N:11]([C:12]3[CH:13]=[C:14]4[C:18](=[CH:19][CH:20]=3)[N:17]([CH3:21])[CH:16]=[CH:15]4)[C:10]([C:22]3[CH:27]=[C:26]([CH:28]([CH3:29])[CH3:30])[C:25]([OH:31])=[CH:24][C:23]=3[OH:39])=[N:9][N:8]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: CC(C)c1cc(-c2nnc(Cn3ccnc3)n2-c2ccc3c(ccn3C)c2)c(OCc2ccccc2)cc1OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CC(C)c1cc(-c2nnc(Cn3ccnc3)n2-c2ccc3c(ccn3C)c2)c(O)cc1O

Procedure:
Intermediate (D) obtained above was subjected to Pd (10%) catalyzed hydrogenation in 10 mL EtOH for 24 hours. Removal of Pd/C and solvent gave 5-[3-imidazol-1-ylmethyl-5-(2,4-dihydroxy-5-isopropyl-phenyl)-[1,2,4]triazol-4-yl]-1-methyl-1H-indole (E) as light brown solid (0.07 g, 0.16 mmol, 80%). 1H NMR (300 MHz, DMSO-d6), δ (ppm): 11.06 (s, 1H); 9.75 (s, 1H); 7.63 (d, J=8.1 Hz, 1H); 7.57 (d, J=2.1 Hz, 1H); 7.52 (d, J=3.0 Hz, 1H); 7.28 (s, 1H); 7.03 (dd, J=8.1 Hz, 2.1 Hz, 1H); 6.94 (d, J=1.2 Hz, 1H); 6.84 (d, J=1.2 Hz, 1H); 6.51 (d, J=3.0 Hz, 1H); 6.37 (s, 1H); 6.33 (s, 1H); 5.27 (s, 2H); 3.86 (s, 3H); 2.78 (hept, J=6.6 Hz, 1H); 0.55 (d, J=6.6 Hz, 6H). ESMS calcd. for C24H25N6O2 (M+H)+: 429.3. Found: 429.3.
Reaction SMILES: [CH2:1]([C:8]1[O:9][C:10]2[CH:30]=[CH:29][CH:28]=[CH:27][C:11]=2[C:12]=1[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][C:22]([CH:25]=[O:26])=[CH:21][CH:20]=2)=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].O>C(O)C.O1CCCC1>[CH2:1]([C:8]1[O:9][C:10]2[CH:30]=[CH:29][CH:28]=[CH:27][C:11]=2[C:12]=1[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][C:22]([CH2:25][OH:26])=[CH:21][CH:20]=2)=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(-c2ccc(-c3c(Cc4ccccc4)oc4ccccc34)cc2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: OCc1ccc(-c2ccc(-c3c(Cc4ccccc4)oc4ccccc34)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.7 %

Procedure:
To a solution of 4′-(2-benzylbenzofuran-3-yl)biphenyl-4-carbaldehyde (5.0 g, 12.9 mmol) in ethanol (100 mL) and tetrahydrofuran (25 mL) was added sodium borohydride (980 mg, 25.8 mmol) as a solid in 3 portions. The reaction was stirred at room temperature for 1 hour (TLC control) and then poured into water (100 mL) and extracted with diethyl ether (3×100 mL). The combined extract was washed with water, brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo to afford the title compound as a white solid (5.02 g, 99%).
Reaction SMILES: [C:1]([C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[NH:16][C:17]([N:19]([CH3:21])[NH2:20])=[S:18])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)CC>[Cl:15][C:13]1[CH:12]=[CH:11][C:10]2[NH:16][C:17](=[S:18])[N:19]([CH3:21])[N:20]=[C:1]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:9]=2[CH:14]=1
Reactant: CN(N)C(=S)Nc1ccc(Cl)cc1C(=O)c1ccccc1
Solvent: CCCO
Product: CN1N=C(c2ccccc2)c2cc(Cl)ccc2NC1=S

Procedure:
A mixture containing 20.0 grams of N-(2-benzoyl-4-chlorophenyl)-methyl-hydrazine-carbothioamide (Example 2) in 250 ml of n-propanol was refluxed for about 2 hours. The mixture was cooled in an ice bath, and the resulting yellow precipitate was collected, washed with isopropanol, and air dried to yield 7-chloro-1,3-dihydro-3-methyl-5-phenyl-2H-1,3,4-benzotriazepine-2-thione as a yellow solid. Additional product was obtained upon evaporation of the solvent under vacuum. The melting point was found to be 188°-190° C.
Reaction SMILES: [CH:1]([Si:4]([CH:14]([CH3:16])[CH3:15])([CH:11]([CH3:13])[CH3:12])[N:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1)([CH3:3])[CH3:2].[C:17](#[N:20])[CH:18]=[CH2:19]>>[CH:14]([Si:4]([CH:1]([CH3:3])[CH3:2])([CH:11]([CH3:13])[CH3:12])[N:5]1[CH2:10][CH2:9][N:8]([CH2:19][CH2:18][C:17]#[N:20])[CH2:7][CH2:6]1)([CH3:16])[CH3:15]
Reactant: C=CC#N
Reactant: CC(C)[Si](C(C)C)(C(C)C)N1CCNCC1
Product: CC(C)[Si](C(C)C)(C(C)C)N1CCN(CCC#N)CC1
Temperature: 70 °C
Reaction time: 4 h

Procedure:
A flask equipped with a stirrer, reflux condenser, dropping funnel and thermometer was charged with 194.0 g (0.8 mol) of 1-triisopropylsilylpiperazine (Synthesis Example 2) and heated at 70° C. Once the internal temperature became steady, 46.7 g (0.88 mol) of acrylonitrile was added dropwise over 2 hours. Stirring was continued for 4 hours at the temperature. On distillation of the reaction solution, 224.8 g of a fraction having a boiling point of 179-180° C./0.4 kPa was collected.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][C:7]([S:9][CH:10]1[N:13]([CH:14](O)[C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=2)=[O:16])[C:12](=[O:29])[CH2:11]1)=[O:8].S(Cl)([Cl:32])=O>>[CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][C:7]([S:9][CH:10]1[N:13]([CH:14]([Cl:32])[C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=2)=[O:16])[C:12](=[O:29])[CH2:11]1)=[O:8]
Reactant: COCCOCC(=O)SC1CC(=O)N1C(O)C(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: O=S(Cl)Cl
Product: COCCOCC(=O)SC1CC(=O)N1C(Cl)C(=O)OCc1ccc([N+](=O)[O-])cc1

Procedure:
To 800 mg. of p-nitrobenzyl 2-[4-(2-methoxyethoxyacetylthio)-2-oxo-1-azetidinyl]-2-hydroxyacetate was added (all at once) at 0° under N2 atmosphere, thionyl chloride (3 ml.) and the mixture was stirred at room temperature under N2 for 1 hour. The excess of thionyl chloride was removed in vacuo and the residue dissolved in dry benzene (10 ml.) and evaporated to dryness. There was obtained the title product (791 mg.) as a yellowish oil. nmr (CDCl3): δppm 2.9-3.9 (2H, m, H-3), 4.10 (3H, s, --OCH3), 3.5-3.9 (4H, m, --OCH2CH2O--), 4.24 (2H, s, O=C--CH2O--), 5.35-5.45 (2H, m, --CH2 --Ar), 5.70 (1H, m, H-4), 6.12 (1H, s, --CHCl), 7.52, 7.67, 8.21, 5.39 (4H, A2 ' B2 ', aromatic --H); ir (neat): 1780 cm-1 (broad, γc=o, β-lactam and ester), 1695 (γc=o, thioester), 1525 (γNO2).