Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:17])=[C:11](F)[C:12]=3[O:14][CH3:15])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:3][CH2:2]1.[NH2:22][CH2:23][CH:24]1[CH2:29][CH2:28][CH2:27][NH:26][CH2:25]1.C(N(CC)CC)C>C(#N)C.CN(C)C=O>[NH2:22][CH2:23][CH:24]1[CH2:29][CH2:28][CH2:27][N:26]([C:11]2[C:12]([O:14][CH3:15])=[C:13]3[C:8]([C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5][N:4]3[CH:1]3[CH2:3][CH2:2]3)=[CH:9][C:10]=2[F:17])[CH2:25]1
Reactant: COc1c(F)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Reactant: NCC1CCCNC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COc1c(N2CCCC(CN)C2)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12

Procedure:
A suspension of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid (1.48 g), 3-aminomethylpiperidine (1.14 g) and triethylamine (1.5 g) in acetonitrile (20 ml) and N,N-dimethylformamide (10 ml) was refluxed overnight. Concentration of the reaction mixture followed by purification by silica gel column chromatography (chloroform:methanol:ammonium hydroxide=15:5:1) gave 7-(3-aminomethylpiperidin-1-yl)-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid, which was recrystallized from isopropanol-water to afford yellow prisms. m.p. 192°-193° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6](B(O)O)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[F:13][C:14]1[CH:15]=[C:16]([CH:28]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:30]=1)[C:17]([NH:19][C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[C:22](I)[CH:21]=1)=[O:18].C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C(O)C.O.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>[F:13][C:14]1[CH:15]=[C:16]([CH:28]=[C:29]([C:31]([F:32])([F:33])[F:34])[CH:30]=1)[C:17]([NH:19][C:20]1[CH:25]=[C:24]([C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[C:23]([CH3:26])=[CH:22][CH:21]=1)=[O:18]
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
Reactant: Cc1ccc(NC(=O)c2cc(F)cc(C(F)(F)F)c2)cc1I
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: [K+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: Cc1ccc(NC(=O)c2cc(F)cc(C(F)(F)F)c2)cc1-c1cccc([N+](=O)[O-])c1
Yield: 97.8 %

Procedure:
(3-Nitrophenyl)boronic acid (1.7 g, 10.0 mmol) was mixed with 3-fluoro-N-(3-iodo-4-methylphenyl)-5-(trifluoromethyl)benzamide (4.30 g, 10.2 mmol) and potassium carbonate (2.5 g, 18 mmol) in toluene (75.00 mL), ethanol (11.00 mL) and water (10.00 mL) and was degassed. To the mixture was added tetrakis(triphenylphosphine)palladium(0) (0.50 g, 0.43 mmol) and the resulting mixture was heated to reflux for 18 hours. The reaction was extracted with ethyl acetate and the organic extracts were washed with water, saturated NaCl, dried (MgSO4) and then concentrated in vacuo. The residue was purified by column chromatography using 20% EtOAc/hexanes to give the product (4.09 g, 96% yield). MS (EI) m/z=419 (M+H).
Reaction SMILES: O.S(=O)(=O)(O)O.[Cl:7][C:8]1[CH:14]=[CH:13][C:12]([SH:15])=[CH:11][C:9]=1[NH2:10].[C:16]1([C:22](O)([CH3:24])[CH3:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>O1CCCC1>[Cl:7][C:8]1[CH:14]=[CH:13][C:12]([S:15][C:22]([CH3:24])([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH3:23])=[CH:11][C:9]=1[NH2:10]
Reactant: CC(C)(O)c1ccccc1
Reactant: Nc1cc(S)ccc1Cl
Agent: O=S(=O)(O)O
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(Sc1ccc(Cl)c(N)c1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 58.4 %

Procedure:
To a mixture of water (10 mL) and concentrated sulfuric acid (10 mL) was added 2-chloro-5-mercaptoaniline (1.6 g) at room temperature, and the mixture was stirred for 15 minutes. To the mixture was added a solution of 2-phenyl-2-propanol (1.36 g) in tetrahydrofuran (10 mL) in a dropwise manner, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was poured into ice water, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water, a saturated aqueous sodium hydrogen carbonate solution and brine successively, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane−n-hexane/ethyl acetate=4/1) to give the title compound (1.62 g).
Reaction SMILES: Br[CH2:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([C:13]([OH:41])([C:17]3[N:18]=[CH:19][N:20]([C:22]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH:21]=3)[CH:14]([CH3:16])[CH3:15])=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[C:42]([O:44]C)=O.CO.[CH3:48][NH2:49]>C1COCC1>[OH:41][C:13]([C:9]1[CH:10]=[CH:11][C:12]2[C:3]3[CH2:2][N:49]([CH3:48])[C:42](=[O:44])[C:4]=3[CH:5]=[CH:6][C:7]=2[CH:8]=1)([C:17]1[N:18]=[CH:19][N:20]([C:22]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:21]=1)[CH:14]([CH3:15])[CH3:16]
Reactant: COC(=O)c1ccc2cc(C(O)(c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)C(C)C)ccc2c1CBr
Reactant: CN
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)C(O)(c1ccc2c3c(ccc2c1)C(=O)N(C)C3)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
Methyl 1-bromomethyl-6-[1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl]-2-naphthoate (0.80 g) was dissolved in THF (8 ml) and 40% methylamine methanol solution (8 ml) was added. The reaction mixture was stirred at room temperature for 20 hrs. and the solvent was evaporated. The residue was suspended in ethyl acetate and filtrated to give 7-[1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl]-2-methyl-1,2-dihydro-3H-benzo[e]isoindol-3-one as a colorless solid (0.77 g). This solid was suspended in a mixed solution of THF and methanol (1:3, 20 ml) and pyridine hydrochloride (0.23 g) was added. The reaction mixture was stirred with heating at 60° C. for 6 hrs., and the solvent was evaporated. The residue was diluted with saturated aqueous sodium hydrogen carbonate and extracted twice with ethyl acetate-THF (1:1). The organic layers were combined, dried over anhydrous magnesium sulfate and concentrated. The residue was recrystallized from THF-methanol to give the title compound as colorless crystals (0.28 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[C:9](O)([CH3:12])([CH3:11])[CH3:10].S(=O)(=O)(O)O>C(Cl)Cl>[C:9]([C:6]1[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=1[OH:8])([CH3:12])([CH3:11])[CH3:10]
Reactant: CC(C)(C)O
Reactant: Oc1ccc(F)cc1
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: CC(C)(C)c1cc(F)ccc1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 41.2 %

Procedure:
4-Fluorophenol (5 g, 45 mmol) and tert-butanol (5.9 mL, 63 mmol) were dissolved in CH2Cl2 (80 mL) and treated with concentrated sulfuric acid (98%, 3 mL). The mixture was stirred at room temperature overnight. The organic layer was washed with water, neutralized with NaHCO3, dried over MgSO4 and concentrated. The residue was purified by column chromatography (5-15% EtOAc-Hexane) to give 2-tert-butyl-4-fluorophenol (3.12 g, 42%). 1H NMR (400 MHz, DMSO-d6) δ 9.32 (s, 1H), 6.89 (dd, J=11.1, 3.1 Hz, 1H), 6.84-6.79 (m, 1H), 6.74 (dd, J=8.7, 5.3 Hz, 1H), 1.33 (s, 9H).
Reaction SMILES: [CH3:1][C:2]12[CH2:15][C:6]1([C:7]([O:9]CC(Cl)(Cl)Cl)=[O:8])[N:5]1[C:16](=[O:36])[CH:17]([NH:18][C:19](=[O:35])[CH:20]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[Cl:28])[C@H:4]1[S:3]2.C(O)(=O)C.C(O)(=O)C.[CH2:45]([NH:52][CH2:53][CH2:54][NH:55][CH2:56][C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1)[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1>CN(C)C=O.C(O)(=O)C.CO.O.[Zn]>[CH2:45]([NH:52][CH2:53][CH2:54][NH:55][CH2:56][C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1)[C:46]1[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=1.[CH3:1][C:2]12[CH2:15][C:6]1([C:7]([OH:9])=[O:8])[N:5]1[C:16](=[O:36])[CH:17]([NH:18][C:19](=[O:35])[CH:20]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[Cl:28])[C@H:4]1[S:3]2
Reactant: CC12CC1(C(=O)OCC(Cl)(Cl)Cl)N1C(=O)C(NC(=O)C(Oc3ccccc3Cl)c3ccccc3)[C@H]1S2
Agent: [Zn]
Agent: c1ccc(CNCCNCc2ccccc2)cc1
Solvent: O
Solvent: CN(C)C=O
Solvent: CO
Product: CC12CC1(C(=O)O)N1C(=O)C(NC(=O)C(Oc3ccccc3Cl)c3ccccc3)[C@H]1S2
Reaction time: 1.5 h
Yield: 216 %

Procedure:
To a solution of 2,2,2-trichloroethyl 2-methyl-2,3-methylene-6-[2-phenyl-2-(2-chlorophenoxy)acetamido]penam-3-carboxylate (1.18 g.) in a mixture of dimethylformamide (5 ml.) and acetic acid (1.5 ml.) was added zinc powder (1.2 g.) under ice-cooling, and the mixture was stirred for 1.5 hours. After the reaction, the residue (0.65 g.) obtained by post-treating the reaction mixture in the similar manner as described in Example 1 was dissolved in methanol (2 ml.) and a solution of N,N'-dibenzylethylenediamine diacetate (0.20 g.) in water (10 ml.) was added to the solution. Crystals obtained in this manner were dissolved in methanol and subjected to reprecipitation with water to give N,N'-dibenzylethylenediamine salt of 2-methyl-2,3-methylene-6-[2-phenyl-2-(2-chlorophenoxy)acetamido]penam-3-carboxylic acid (0.55 g.), mp 107° to 110°C (dec.)
Reaction SMILES: [N+:1]([C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][C:7]([NH2:13])=[C:6]([NH2:14])[CH:5]=1)([O-:3])=[O:2]>C(O)C>[CH2:9]([C:4]1[C:5]([CH2:6][CH3:7])=[N:14][C:6]2[C:7](=[CH:8][C:9]([N+:10]([O-:12])=[O:11])=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[N:13]=1)[CH3:8]
Reactant: Nc1cc([N+](=O)[O-])c([N+](=O)[O-])cc1N
Solvent: CCO
Product: CCc1nc2cc([N+](=O)[O-])c([N+](=O)[O-])cc2nc1CC
Temperature: 25 °C
Yield: 144.8 %

Procedure:
4,5-Dinitro-1,2-phenylenediamine (1000 mg, 5.0 mmol), 3,4-hexadione (685 mg, 6.0 mmol) and ethanol (50 mL) were mixed in a round bottom flask equipped with a condenser. The reaction mixture was refluxed overnight. The mixture was cooled down to room temperature and ethanol was removed under reduced pressure. It was then extracted with methylene chloride and the organic phase was washed with water and dried over Na2SO4. The product obtained as off-white solid (1000 mg, 72%) was purified by column chromatography.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH:10]=[C:9]([O:12][C:13]1[CH:14]=[CH:15][C:16]3[N:20]=[C:19]([CH2:21][O:22][C:23]4[CH:36]=[CH:35][C:26]([CH2:27][CH:28]5[S:32][C:31](=[O:33])[NH:30][C:29]5=[O:34])=[CH:25][CH:24]=4)[N:18]([CH3:37])[C:17]=3[CH:38]=1)[CH:8]=[CH:7]2.[C:39]12([N:49]=[C:50]=[O:51])[CH2:48][CH:43]3[CH2:44][CH:45]([CH2:47][CH:41]([CH2:42]3)[CH2:40]1)[CH2:46]2>CN(C)C=O>[C:39]12([NH:49][C:50]([NH:1][C:2]3[C:11]4[C:6](=[CH:7][CH:8]=[C:9]([O:12][C:13]5[CH:14]=[CH:15][C:16]6[N:20]=[C:19]([CH2:21][O:22][C:23]7[CH:24]=[CH:25][C:26]([CH2:27][CH:28]8[S:32][C:31](=[O:33])[NH:30][C:29]8=[O:34])=[CH:35][CH:36]=7)[N:18]([CH3:37])[C:17]=6[CH:38]=5)[CH:10]=4)[CH:5]=[CH:4][CH:3]=3)=[O:51])[CH2:48][CH:43]3[CH2:44][CH:45]([CH2:47][CH:41]([CH2:42]3)[CH2:40]1)[CH2:46]2
Reactant: Cn1c(COc2ccc(CC3SC(=O)NC3=O)cc2)nc2ccc(Oc3ccc4cccc(N)c4c3)cc21
Reactant: O=C=NC12CC3CC(CC(C3)C1)C2
Solvent: CN(C)C=O
Product: Cn1c(COc2ccc(CC3SC(=O)NC3=O)cc2)nc2ccc(Oc3ccc4cccc(NC(=O)NC56CC7CC(CC(C7)C5)C6)c4c3)cc21
Temperature: 25 °C
Reaction time: 120 h
Yield: 67.3 %

Procedure:
To a solution of 5-[4-[6-(8-aminonaphthalen-2-yloxy)-1-methyl-1H-benzimidazol-2-ylmethoxy]benzyl]thiazolidine-2,4-dione (0.5 g) in anhydrous N,N-dimethylformamide (10 ml) was added 1-adamantyl isocyanate (0.18 g) and the mixture was stirred at room temperature for 5 days. The reaction mixture was concentrated. The residue was purified by preparative reverse phase high performance liquid chromatography using acetonitrile:water=50:50→60:40→70:30 as the eluant to afford the title compound (0.45 g, mp 250° C. (dec)).
Reaction SMILES: [H-].[Na+].[I:3][C:4]1[CH:5]=[C:6]([CH:9]=[O:10])[NH:7][CH:8]=1.Br[CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14]>O1CCCC1>[CH:9]([C:6]1[N:7]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:8]=[C:4]([I:3])[CH:5]=1)=[O:10]
Reactant: CCOC(=O)CBr
Reactant: O=Cc1cc(I)c[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)Cn1cc(I)cc1C=O
Reaction time: 0.25 h
Yield: 49 %

Procedure:
Sodium hydride (1.62 g, 60% w/w dispersion in mineral oil, 67.9 mmol) was added to a solution of 4-iodo-1H-pyrrole-2-carbaldehyde (5.0 g, 22.6 mmol) in tetrahydrofuran (30 mL) over 10 min. The reaction mixture was stirred for 15 min, then ethyl bromoacetate (7.56 g, 45.2 mmol) was added and the mixture stirred for 2 h at ambient temperature. The reaction was quenched with methanol and concentrated in vacuo. The crude compound was then extracted into ethyl acetate. The organic layer washed with water, brine, dried over anhydrous sodium sulfate, filtered and concentrated under in vacuo to afford the crude compound. Purification by column chromatography over silica gel (100-200 mesh) using 2% ethyl acetate in petroleum ether afforded ethyl 2-(2-formyl-4-iodo-pyrrol-1-yl)acetate (3.4 g, 49%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:24]=[O:25])=[C:6]2[C:10]=1[N:9]=[C:8]1[N:11]([C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=3[Cl:23])[CH2:12][CH2:13][CH2:14][N:7]21.[CH:26]1([Mg]Br)[CH2:28][CH2:27]1.[Cl-].[NH4+]>O1CCCC1>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=4[Cl:23])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:24]([CH:26]2[CH2:28][CH2:27]2)[OH:25])=[CH:4][CH:3]=1
Reactant: COc1ccc(N2CCCn3c2nc2c(Cl)ccc(C=O)c23)c(Cl)c1
Reactant: Br[Mg]C1CC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1ccc(N2CCCn3c2nc2c(Cl)ccc(C(O)C4CC4)c23)c(Cl)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 77 %

Procedure:
To a solution of 9-chloro-1-(2-chloro-4-methoxyphenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole-6-carbaldehyde (274 mg, 0.728 mmol) in tetrahydrofuran (10 mL) was added cyclopropylmagnesium bromide in tetrahydrofuran (1.0 M, 2.2 mL, 2.2 mmol) at 0° C. The mixture was stirred at 0° C. for 0.5 hr. Aqueous ammonium chloride was added to the reaction mixture at 0° C. and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with a 50-80% ethyl acetate/n-hexane gradient mixture to give the title compound (261.7 mg, 0.57 mmol, 77%) as colorless crystals.
Reaction SMILES: [F:1][CH2:2][CH2:3][C:4]1([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:13][CH3:14])[CH:10]=2)[C:5]1=[O:15].[Cl:21]N1C(=O)CCC1=O>CN(C=O)C>[Cl:21][C:10]1[C:9]([O:13][CH3:14])=[CH:8][CH:7]=[C:6]2[C:11]=1[CH2:12][C:4]([CH2:3][CH2:2][F:1])([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:5]2=[O:15]
Reactant: CCOC(=O)C1(CCF)Cc2cc(OC)ccc2C1=O
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Product: CCOC(=O)C1(CCF)Cc2c(ccc(OC)c2Cl)C1=O
Temperature: 50 °C
Reaction time: 6 h

Procedure:
To a solution of ethyl 2-(2-fluoroethyl)-5-methoxy-1-oxoindane-2-carboxylate (44.6 g, 159 mmol) in DMF (159 mL) was added N-chlorosuccinimide (23.4 g, 175 mmol) in portions. The solution was heated at 50° C. and the reaction was monitored periodically by NMR analysis of aliquots. After 6 hours, the reaction was approximately 80% complete by NMR analysis. The reaction mixture was allowed to cool to room temperature and stand overnight. After reheating to 50° C., additional N-chlorosuccinimide (2.12 g, 15.9 mmol) was added. Monitoring by NMR was continued, and after 4.5 hours another portion of N-chlorosuccinimide (2.12 g, 15.9 mmol) was added. After another 3 hours, the reaction was allowed to cool to room temperature and stand overnight. Most of the DMF was removed by evaporation at reduced pressure and the residue was partitioned between EtOAc and water. The organic phase was washed with water (4 times) and brine and dried over Na2SO4. Filtration and removal of the solvent under reduced pressure gave crude ethyl 4-chloro-2-(2-fluoroethyl)-5-methoxy-1-oxoindane-2-carboxylate. This material was used in the next step without purification.
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[I:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20](=[O:22])[CH3:21].[CH2:23]1[CH2:28][CH2:27][CH:26]([CH:29]=[O:30])[CH2:25][CH2:24]1>C1COCC1>[CH:26]1([CH:29]([OH:30])[CH2:21][C:20]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[I:13])=[O:22])[CH2:27][CH2:28][CH2:23][CH2:24][CH2:25]1
Reactant: O=CC1CCCCC1
Reactant: CC(=O)c1ccccc1I
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: O=C(CC(O)C1CCCCC1)c1ccccc1I
Temperature: -30 °C
Reaction time: 0.75 h
Yield: 77.4 %

Procedure:
To a solution of diisopropylamine (1.6 mL, 11.1 mmol) in THF (38 mL) at 0° C. was added n-BuLi (4.1 mL, 10.2 mmol) under an atmosphere of N2. After 30 min the solution was cooled to −30° C. and a solution of 1-(2-iodophenyl)ethanone (2.27 g, 9.23 mmol) in THF (6 mL) was added dropwise to the mixture and was stirred for 45 min at −30° C. The mixture was cooled to −78° C. and cyclohexylcarboxaldehyde (1.2 mL, 9.69 mmol) was added dropwise and the mixture was allowed to warm to −40° C. over 2 h. The reaction was quenched by the addition of saturated aqueous NH4Cl. The aqueous layer was extracted with EtOAc (2×50 mL). The combined organic layers were washed with brine, dried (Na2SO4), filtered and concentrated. The residue was purified by flash column chromatography to afford the title compound as yellow oil (2.56 g, 78%). 1H NMR: 1.02-1.27 (m, 4H), 1.41-1.49 (m, 1H), 1.66-1.76 (m, 4H), 1.89 (d, 1H, J=12.4 Hz), 2.88 (d, 1H, J=3.2 Hz), 2.98 (dd, 1H, J=9.2 Hz, 17.2 Hz), 3.13 (dd, 1H, J=2.0 Hz, 17.2 Hz), 3.99-4.01 (m, 1H), 7.11-7.15 (m, 1H), 7.42 (d, 2H, J=4.4 Hz), 7.93 (d, 1H, J=8.0 Hz).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([S:10]([N:13]([CH2:41][CH:42]([CH3:44])[CH3:43])[CH2:14][C@@H:15]([OH:40])[C@@H:16]([NH:28][C:29](=[O:39])[O:30][C@@H:31]3[C@H:38]4[C@H:34]([O:35][CH2:36][CH2:37]4)[O:33][CH2:32]3)[CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][NH2:27])=[CH:20][CH:19]=3)(=[O:12])=[O:11])=[CH:9][C:4]=2[O:3][CH2:2]1.C(N(CC)C(C)C)(C)C.[C:54](Cl)(=[O:56])[CH3:55]>C1COCC1.C(Cl)Cl>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([S:10]([N:13]([CH2:41][CH:42]([CH3:44])[CH3:43])[CH2:14][C@@H:15]([OH:40])[C@@H:16]([NH:28][C:29](=[O:39])[O:30][C@@H:31]3[C@H:38]4[C@H:34]([O:35][CH2:36][CH2:37]4)[O:33][CH2:32]3)[CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][NH:27][C:54](=[O:56])[CH3:55])=[CH:20][CH:19]=3)(=[O:12])=[O:11])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CC(=O)Cl
Reactant: CC(C)CN(C[C@@H](O)[C@H](Cc1ccc(OCCN)cc1)NC(=O)O[C@H]1CO[C@H]2OCC[C@H]21)S(=O)(=O)c1ccc2c(c1)OCO2
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)NCCOc1ccc(C[C@H](NC(=O)O[C@H]2CO[C@H]3OCC[C@H]32)[C@H](O)CN(CC(C)C)S(=O)(=O)c2ccc3c(c2)OCO3)cc1
Temperature: 25 °C
Yield: 86 %

Procedure:
A solution of 21 mg (0.033 mmol) of (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl (1S,2R)-3-[(1,3-benzodioxol-5-ylsulfonyl)(isobutyl)amino]-2-hydroxy-1-[4-(2-aminoethoxy)benzyl]propylcarbamate in 2 mL of 1:1 THF/CH2Cl2 was treated with 9 μL (0.050 mmol) of N,N-diisopropylethylamine followed by 2.6 μL (0.036 mmol) of acetyl chloride. The resulting solution was stirred at RT. After 1.5 hours the solution was concentrated in vacuo and the residue subjected to flash chromatography (SiO2, 95:5 CH2Cl2/MeOH) to afford the desired compound in 86% yield as a white foam. 1H NMR (CDCl3): 7.29 (dd, 1H), 7.16-7.04 (m, 3H), 7.05 (d, 1H), 6.76 (d, 2H), 6.05 (s, 2H), 5.91 (br s, 1H), 5.01 (d, 1H), 5.05-4.89 (m, 2H), 3.94 (m, 3H), 3.80 (m, 3H), 3.72-3.51 (m, 5H), 3.08 (dd, 1H), 3.01-2.83 (m, 44), 2.74 (m, 2H), 1.97 (s, 3H), 1.86-1.45 (m, 3H), 0.90 (d, 3H), 0.84 (d, 3H). MS(ESI): 678(M+H).
Reaction SMILES: [Cl:1][C:2]([Cl:7])([Cl:6])[C:3](Cl)=[O:4].[CH3:8][O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]1[CH:21]=[CH:20][C:19]([C:22]([N:24]2[C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=3[CH2:28][N:27]3[CH:35]=[CH:36][CH:37]=[C:26]3[CH2:25]2)=[O:23])=[CH:18][CH:17]=1.C(N(CC)C(C)C)(C)C>ClCCl>[Cl:1][C:2]([Cl:7])([Cl:6])[C:3]([C:35]1[N:27]2[C:26]([CH2:25][N:24]([C:22]([C:19]3[CH:20]=[CH:21][C:16]([C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=4[O:9][CH3:8])=[CH:17][CH:18]=3)=[O:23])[C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=3[CH2:28]2)=[CH:37][CH:36]=1)=[O:4]
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Reactant: COc1ccccc1-c1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccccc1-c1ccc(C(=O)N2Cc3ccc(C(=O)C(Cl)(Cl)Cl)n3Cc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57 %

Procedure:
Trichloroacetyl chloride (2.63 mL, 23.6 mmol) was added dropwise over five minutes to a solution of (2′-methoxy-biphenyl-4-yl)-(5H,11H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl)-methanone (3.0 g, 7.60 mmol) and N,N-diisopropylethyl amine (2.65 mL, 15.2 mmol) in dichloromethane (60 mL). The reaction was stirred under nitrogen at room temperature overnight and then quenched with water. The organic layer was washed with 0.1N hydrochloric acid and water, dried over anhydrous magnesium sulfate, filtered and concentrated to an oil. The oil was purified by flash chromatography over silica gel Merck-60 using a 0-5% gradient of ethyl acetate in dichloromethane to give the title compound (2.34 g) as a yellow foam.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([Br:12])[CH:11]=1)[C:6](O)=[O:7].C[N:16](C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.N>CN(C)C=O.O>[Br:12][C:10]1[CH:9]=[C:5]([CH:4]=[C:3]([C:2]([F:14])([F:13])[F:1])[CH:11]=1)[C:6]([NH2:16])=[O:7]
Reactant: CCN=C=NCCCN(C)C
Reactant: O=C(O)c1cc(Br)cc(C(F)(F)F)c1
Agent: N
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: NC(=O)c1cc(Br)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.7 %

Procedure:
To a solution (18 mL) of 3-trifluoromethyl-5-bromobenzoic acid (5.0 g, 19 mmol) in N,N-dimethylformamide were added N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide (4.3 g, 22 mmol), 1-hydroxybenzotriazole (3.4 g, 22 mmol) and 28% aqueous ammonia (1.7 mL, 28 mmol), and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The resulting crude title compound was to recrystallized (hexane-ethyl acetate) to give the title compound (3.7 g, 74%) as colorless crystals.