Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([F:9])[C:3]=1[NH2:4].[Br:10]Br.N1C=CC=NC=1>C(Cl)(Cl)Cl>[Br:10][C:7]1[CH:8]=[C:2]([F:1])[C:3]([NH2:4])=[C:5]([F:9])[CH:6]=1
Reactant: Nc1c(F)cccc1F
Reactant: BrBr
Solvent: ClC(Cl)Cl
Solvent: c1cncnc1
Product: Nc1c(F)cc(Br)cc1F

Procedure:
In chloroform, commercially available compound [U], 2,6-difluoroaniline, is brominated with bromine in the presence of pyrimidine to yield compound [V], 4-bromo-2,6-difluoroaniline. In NMP, compound [V] is cyanated with copper (I) cyanide to form a copper complex. The copper complex is decomposed with EDA, to yield compound [W], 4-amino-3,5-difluorobenzonitrile. Compound [W] is converted into its corresponding diazonium salt with concentrated sulfuric acid in glacial acetic acid. In hydrobromic acid, the diazonium salt is brominated with copper (I) bromide to yield compound [X], 4-bromo-3,5-difluorobenzonitrile. Compound [X] is reacted with gaseous hydrogen chloride in anhydrous ethanol to yield compound [Y], 4-bromo-3,5-difluorobenzimidate hydrogen chloride. In ethanol, compound [Y] is reacted with gaseous ammonia to yield compound [Z], 4-bromo-3,5-difluorobenzamidine hydrogen chloride.
Reaction SMILES: [CH:1]([N:4]1[C:8]2[CH:9]=[CH:10][C:11]([N:13]3[CH2:17][C@H:16]([C:18]([O:20]C)=O)[O:15][C:14]3=[O:22])=[CH:12][C:7]=2[S:6][C:5]1=[O:23])([CH3:3])[CH3:2].[CH3:24][NH2:25]>CO>[CH3:24][NH:25][C:18]([C@@H:16]1[O:15][C:14](=[O:22])[N:13]([C:11]2[CH:10]=[CH:9][C:8]3[N:4]([CH:1]([CH3:2])[CH3:3])[C:5](=[O:23])[S:6][C:7]=3[CH:12]=2)[CH2:17]1)=[O:20]
Reactant: CN
Reactant: COC(=O)[C@H]1CN(c2ccc3c(c2)sc(=O)n3C(C)C)C(=O)O1
Solvent: CO
Product: CNC(=O)[C@H]1CN(c2ccc3c(c2)sc(=O)n3C(C)C)C(=O)O1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
The methyl (5R)-3-(2,3-dihydro-3-isopropyl-2-oxo-6-benzothiazolyl)-2-oxo-5-oxazolidinecarboxylate (EXAMPLE 31, Step 3, 2.89 g, 8.59 mmol) is treated with 2N methylamine in MeOH (8.2 mL), and the mixture is stirred at ambient temperature for 45 mins and then filtered to give the title compound, mp 172–173.5° C.; MS (ESI+) for C15H17N3O4S m/z 336 (M+H)+; [α]25D−43 (c 0.98, DMSO).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([O:23][CH3:24])[CH:17]=1.ClC(Cl)(O[C:29](=[O:35])OC(Cl)(Cl)Cl)Cl.[NH2:37][N:38]1[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:29]([NH:37][N:38]2[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]2)=[O:35])=[C:18]([O:23][CH3:24])[CH:17]=1
Reactant: COc1cc(Oc2ccnc3cc(OC)c(OC)cc23)ccc1N
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: NN1CCCCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(Oc2ccnc3cc(OC)c(OC)cc23)ccc1NC(=O)NN1CCCCC1
Yield: 62 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2-methoxyaniline (50 mg) was added to toluene (5 ml), and triethylamine (0.5 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (50 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, 1-aminopiperidine (50 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to the reaction solution to stop the reaction, and the reaction solution was then extracted with chloroform, followed by washing with water and saturated brine in that order. The organic layer was then dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by HPLC using chloroform/methanol for development to give the title compound (43 mg, yield 62%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:23]=[CH:24][C:25]=1[O:26][CH3:27])[CH2:6][CH:7]1[C:16]2[C:11](=[C:12]([O:21][CH3:22])[C:13]([O:19][CH3:20])=[C:14]([O:17][CH3:18])[CH:15]=2)[CH2:10][CH2:9][NH:8]1.Br[CH2:29][C:30](Br)=[O:31].[NH2:33][CH:34]1[CH2:42][C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH2:35]1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:23]=[CH:24][C:25]=1[O:26][CH3:27])[CH2:6][CH:7]1[C:16]2[C:11](=[C:12]([O:21][CH3:22])[C:13]([O:19][CH3:20])=[C:14]([O:17][CH3:18])[CH:15]=2)[CH2:10][CH2:9][N:8]1[CH2:29][C:30]([NH:33][CH:34]1[CH2:42][C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH2:35]1)=[O:31]
Reactant: COc1ccc(CC2NCCc3c2cc(OC)c(OC)c3OC)cc1OC
Reactant: NC1Cc2ccccc2C1
Reactant: O=C(Br)CBr
Product: COc1ccc(CC2c3cc(OC)c(OC)c(OC)c3CCN2CC(=O)NC2Cc3ccccc3C2)cc1OC

Procedure:
prepared by reaction of 1-(3,4-Dimethoxy-benzyl)-5,6,7-trimethoxy-1,2,3,4-tetrahydroisoquinoline and 2-bromoacetyl bromide with 2-amino-indane
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:37]=[CH:36][C:6]([C:7]([NH:9][C:10]2[C:11]([NH:16][C:17]([O:19][CH2:20][CH2:21][O:22][CH:23]3[CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25][CH2:24]3)=[O:18])=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:8])=[CH:5][CH:4]=1.FC(F)(F)C(O)=O.Cl>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([NH:9][C:10]2[C:11]([NH:16][C:17]([O:19][CH2:20][CH2:21][O:22][CH:23]3[CH2:24][CH2:25][NH:26][CH2:27][CH2:28]3)=[O:18])=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:8])=[CH:36][CH:37]=1
Reactant: COc1ccc(C(=O)Nc2ccccc2NC(=O)OCCOC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(C(=O)Nc2ccccc2NC(=O)OCCOC2CCNCC2)cc1
Reaction time: 0.5 h
Yield: 180.4 %

Procedure:
A solution of N1-(4-methoxybenzoyl)-N2-[2-[1-(tert-butoxycarbonyl)piperidin-4-yloxy]ethoxycarbonyl]-1,2-benzenediamine (180 mg, 0.362 mmol) in methylene chloride (2 mL) was treated with trifluoroacetic acid (0.30 mL). After 0.5 h, the mixture was concentrated in vacuo. The residue was treated with 1 N aqueous sodium hydroxide followed by ethyl acetate. The aqueous phase was extracted twice with ethyl acetate and the combined organic phases were dried (sodium sulfate), filtered, and concentrated in vacuo. The residue was taken up in methanol and treated with hydrochloric acid (gas,1-2 eq) and concentrated in vacuo yielding the hydrochloride salt of the title compound (270 mg).
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][CH:8]([N:11]3[C:16](=[O:17])[C:15]([CH2:18][C:19]4[CH:24]=[CH:23][C:22]([C:25]5[C:26]([C:31]#[N:32])=[CH:27][CH:28]=[CH:29][CH:30]=5)=[C:21]([CH3:33])[CH:20]=4)=[C:14]([CH2:34][CH2:35][CH3:36])[N:13]4[N:37]=[CH:38][CH:39]=[C:12]34)[CH2:7][CH2:6]2)[O:4]CC1.Cl.[OH-].[Na+]>O1CCCC1.C(OCC)(=O)C>[OH:4][C@H:5]1[CH2:6][CH2:7][C@H:8]([N:11]2[C:16](=[O:17])[C:15]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]4[C:26]([C:31]#[N:32])=[CH:27][CH:28]=[CH:29][CH:30]=4)=[C:21]([CH3:33])[CH:20]=3)=[C:14]([CH2:34][CH2:35][CH3:36])[N:13]3[N:37]=[CH:38][CH:39]=[C:12]23)[CH2:9][CH2:10]1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)c(C)c2)c(=O)n(C2CCC3(CC2)OCCO3)c2ccnn12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)c(C)c2)c(=O)n([C@H]2CC[C@H](O)CC2)c2ccnn12
Temperature: 60 °C
Reaction time: 12 h

Procedure:
To a solution of 4′-{[4-(1,4-dioxaspiro[4.5]dec-8-yl)-5-oxo-7-propyl-4,5-dihydropyrazolo[1,5-a]pyrimidin-6-yl]methyl}-2′-methylbiphenyl-2-carbonitrile (1.0 g) in tetrahydrofuran (10 mL) was added 3M hydrochloric acid (10 mL), and the mixture was stirred at 60° C. for 12 hr. The mixture was allowed to cool, and diluted with ethyl acetate, and the mixture was neutralized with 1 M aqueous sodium hydroxide solution. The mixture was extracted with ethyl acetate, and the organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was dissolved in ethanol (5 mL)-tetrahydrofuran (5 mL). Sodium borohydride (0.074 g) was added thereto at 0° C. After stirring for 2 hr, ethyl acetate and saturated aqueous ammonium chloride solution were added. The mixture was extracted with ethyl acetate, and the organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography to give the title compound as a pale-yellow amorphous solid (0.88 g, 94%).
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[O:3].S(=O)(=O)(O)O.[CH2:10]([OH:14])[CH2:11]CC>>[CH:11]1([NH:1][C:2]([NH2:4])=[O:3])[NH:4][C:2](=[O:3])[NH:1][C:10]1=[O:14]
Reactant: CCCCO
Reactant: NC(N)=O
Agent: O=S(=O)(O)O
Product: NC(=O)NC1NC(=O)NC1=O
Temperature: 85 °C

Procedure:
A mixture of 30.6 g of glyoxylic acid butyl ester butyl hemiacetal (0.15 mol), 30.0 g of urea (0.5 mol), 300 g of n-butanol and 7.5 g of 8% strength butanolic sulfuric acid was heated at 85° C. for a total of 4 hours. After the reaction had ended, the suspension formed was cooled to room temperature, whereupon a colorless precipitate separated out, which was filtered off, washed with methanol and dried in vacuo at 75° C. 23.1 g, that is to say 66% of theory, of crystalline allantoin acid butyl ester were obtained by this reaction.
Reaction SMILES: S(Cl)(Cl)=O.[CH2:5]([O:12][C:13]1[CH:14]=[C:15]([C@H:27]2[C@@H:36]([C:37]([OH:39])=O)[C:35]3[C:30](=[CH:31][C:32]([O:42][CH3:43])=[C:33]([O:40][CH3:41])[CH:34]=3)[C:29](=[O:44])[N:28]2[CH3:45])[CH:16]=[CH:17][C:18]=1[O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>C1C=CC=CC=1>[CH2:5]([O:12][C:13]1[C:18]([O:19][CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[CH:17][C:16]2[C:37](=[O:39])[C:36]3[C:35]4[C:30](=[CH:31][C:32]([O:42][CH3:43])=[C:33]([O:40][CH3:41])[CH:34]=4)[C:29](=[O:44])[N:28]([CH3:45])[C:27]=3[C:15]=2[CH:14]=1)[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: COc1cc2c(cc1OC)[C@H](C(=O)O)[C@H](c1ccc(OCc3ccccc3)c(OCc3ccccc3)c1)N(C)C2=O
Solvent: O=S(Cl)Cl
Solvent: c1ccccc1
Product: COc1cc2c3c(n(C)c(=O)c2cc1OC)-c1cc(OCc2ccccc2)c(OCc2ccccc2)cc1C3=O
Reaction time: 0.25 h
Yield: 63.9 %

Procedure:
Thionyl chloride (15 mL) was added with stirring to the cis acid 12h (1.2 g, 2.2 mmol). The result was an orange mixture that became dark red within 15 min. After 6 h, the reaction mixture was diluted with benzene (25 mL) and evaporated to dryness. Chloroform (7 mL) was added to the purple solid and the solid was collected and washed with ether to give a light purple solid (0.75 g, 64%): mp 238-240° C.; IR (thin film) 3027, 2963, 1685, 1649, 1493, 1458, 1252, 1203, 1088, 1014 cm−1; 1H NMR (CDCl3, 300 MHz) δ7.96 (s, 1H), 7.62 (s, 1H), 7.38 (m, 1H), 7.21 (s, 1H), 7.11 (s, 1H), 5.23 (d, 4H, J=5.2 Hz), 4.02 (s, 3H) 3.95 (s, 3H), 3.81 (s, 3H); CIMS m/z (relative intensity) 534 (MH+, 22). Anal. Calcd for C33H27NO6: C, H, N.
Reaction SMILES: O[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[S:10]1[CH2:14][C:13](=[O:15])[NH:12][C:11]1=[O:16].[C:17]([O-:20])(=[O:19])[CH3:18].[Na+].C(OC(=O)C)(=O)C>O.CC(N(C)C)=O>[C:17]([O:20][C:8]1[CH:7]=[CH:6][C:3]([CH:4]=[C:14]2[S:10][C:11](=[O:16])[NH:12][C:13]2=[O:15])=[CH:2][CH:9]=1)(=[O:19])[CH3:18]
Reactant: O=Cc1ccccc1O
Reactant: O=C1CSC(=O)N1
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)N(C)C
Product: CC(=O)Oc1ccc(C=C2SC(=O)NC2=O)cc1
Reaction time: 1 h

Procedure:
A mixture comprising 200 g of -hydroxybenzaldehyde, 22 g of thiazolidine-2,4-dione, 280 g of sodium acetate and 660 ml of dimethylacetamide was stirred at 150° for 1 hour. It was then cooled, and 540 ml of dimethylacetamide and 370 ml of acetic anhydride were added to the reaction mixture. The resulting mixture was then stirred at 50° C. for 1.5 hours, after which it was poured into water. The solid which precipitated was collected by filtration, washed with water, and dried over anhydrous sodium sulfate, to give the title compound.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[N:8]2[C:9]3[CH:34]=[CH:33][CH:32]=[CH:31][C:10]=3[O:11][C:12]3([CH2:17][CH2:16][N:15]([C:18]([C:20]4[CH:25]=[CH:24][C:23]([O:26][CH:27]([CH3:29])[CH3:28])=[C:22]([CH3:30])[CH:21]=4)=[O:19])[CH2:14][CH2:13]3)[C:7]2=[CH:6][CH:5]=1.[CH:35](OCC)=[O:36]>>[CH:27]([O:26][C:23]1[CH:24]=[CH:25][C:20]([C:18]([N:15]2[CH2:16][CH2:17][C:12]3([O:11][C:10]4[CH:31]=[CH:32][CH:33]=[CH:34][C:9]=4[N:8]4[C:4]([CH2:3][NH:2][CH:35]=[O:36])=[CH:5][CH:6]=[C:7]34)[CH2:13][CH2:14]2)=[O:19])=[CH:21][C:22]=1[CH3:30])([CH3:28])[CH3:29]
Reactant: Cc1cc(C(=O)N2CCC3(CC2)Oc2ccccc2-n2c(CN)ccc23)ccc1OC(C)C
Reactant: CCOC=O
Agent: Cl
Product: Cc1cc(C(=O)N2CCC3(CC2)Oc2ccccc2-n2c(CNC=O)ccc23)ccc1OC(C)C

Procedure:
A solution of (1-(aminomethyl)spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1′-yl)(4-isopropoxy-3-methylphenyl)methanone hydrochloride (60 mg, 0.13 mmol) in ethyl formate (109 μL, 1.35 mmol) was heated at 50° C. overnight. The solvent was removed under reduced pressure and the product was purified by reverse phase HPLC 10-99% acetonitrile in water (HCl modifier) to give N-((1′-(4-isopropoxy-3-methylbenzoyl)spiro[benzo[b]pyrrolo-[1,2-d][1,4]oxazine-4,4′-piperidine]-1-yl)methyl)formamide. 1H NMR (400 MHz, CDCl3) δ 8.23 (s, 1H), 7.40 (d, J=7.8 Hz, 1H), 7.30-7.22 (m, 1H), 7.20-7.01 (m, 3H), 6.83 (d, J=8.1 Hz, 1H), 6.28 (d, J=3.5 Hz, 1H), 5.99 (d, J=3.6 Hz, 1H), 5.89 (s, 1H), 4.77 (d, J=5.0 Hz, 2H), 4.62-4.52 (m, 1H), 3.50 (s, 2H), 2.21 (s, 3H), 2.17-1.78 (m, 4H), 1.70 (s, 2H), 1.36 (d, J=6.0 Hz, 6H). ESI-MS m/z calc. 473.6. found 474.5 (M+1)+; Retention time: 1.80 minutes (3 min run).
Reaction SMILES: [CH:1]1[CH:10]=[C:9]2[C:4]([CH:5]=[C:6]([SH:11])[CH:7]=[CH:8]2)=[CH:3][CH:2]=1.F[C:13]1[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=1[CH:15]=[O:16].C(=O)([O-])[O-].[K+].[K+]>C(O)(C)C.O>[CH:5]1[C:4]2[C:9](=[CH:10][CH:1]=[CH:2][CH:3]=2)[CH:8]=[CH:7][C:6]=1[S:11][C:13]1[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=1[CH:15]=[O:16]
Reactant: O=Cc1ccccc1F
Reactant: Sc1ccc2ccccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Solvent: O
Product: O=Cc1ccccc1Sc1ccc2ccccc2c1
Temperature: 25 °C

Procedure:
A mixture of 2-thionaphthol (5.29 g; 33 mmol), 2-fluorobenzaldehyde (3.73 g; 33 mmol) and potassium carbonate (4.57 g; 33 mmol) in 28 mL of iso-propanol was heated to reflux for 12 h. The mixture was cooled to r.t., diluted with water and filtered. The solution was diluted with EtOAc and washed with water, brine and dry over MgSO4. The crude product (7.9 g) was used as is for the next step.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=1.[N+:13]([O-])([OH:15])=[O:14]>C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]=1[N+:13]([O-:15])=[O:14]
Reactant: COc1ccc2ccccc2c1
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Product: COc1ccc2ccccc2c1[N+](=O)[O-]
Temperature: 10 °C
Reaction time: 2 h

Procedure:
100 g (0.63 mol) of 2-methoxynaphthalene were dissolved in 1.2 l of acetic acid and, at 10° C., 100 ml of 65% strength nitric acid were slowly added dropwise. The mixture was then stirred at 10° C. for 2 h. The resulting precipitate was then filtered off with suction to yield 72.5 g (57%). Melting point 129°-130° C.
Reaction SMILES: [F:1][C:2]1([F:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][C:3]1=[O:11].[H-].[Na+].Br[CH2:16][CH2:17][CH2:18][Cl:19]>CN(C)C=O>[Cl:19][CH2:18][CH2:17][CH2:16][N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:2]([F:1])([F:12])[C:3]1=[O:11]
Reactant: ClCCCBr
Reactant: O=C1Nc2ccccc2C1(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1N(CCCCl)c2ccccc2C1(F)F
Temperature: 25 °C
Yield: 100.3 %

Procedure:
A solution of 3,3-difluoroindolin-2-one (836.6 mg, 4.95 mmol, 1 equiv) in N,N-dimethylformamide was cooled to 0° C. Sodium hydride (60% dispersion) (217.6 mg, 5.44 mmol, 1.1 equiv) was slowly added and the reaction was stirred as such until all bubbling had stopped. 1-bromo-3-chloropropane (1.46 ml, 14.85 mmol, 3 equiv) was added to the reaction mixture in one portion. The reaction was allowed to warm to ambient temperature and stirred as such for 16 h. The crude mixture was partitioned between ethyl acetate and water. The organic layer was dried over MgSO4, filtered, concentrated, and the residue was purified using the Biotage flash chromatography system (SNAP 50 g cartridge, Rf=0.5, gradient—5%-30% ethyl acetate in hexanes) to afford the title compound as a yellow oil (1.22 g, quant); MS for C11H10ClF2NO m/z 247.01 (M+H)+.
Reaction SMILES: O=[C:2]1[CH2:17][NH:16][CH2:15][CH2:14][N:13]([CH2:18][CH2:19][OH:20])[CH2:12][C:11](=O)[NH:10][CH:9]2[CH:4]([CH2:5][CH2:6][CH2:7][CH2:8]2)[NH:3]1.B.C1COCC1.O>O1CCCC1>[OH:20][CH2:19][CH2:18][N:13]1[CH2:12][CH2:11][NH:10][CH:9]2[CH:4]([CH2:5][CH2:6][CH2:7][CH2:8]2)[NH:3][CH2:2][CH2:17][NH:16][CH2:15][CH2:14]1
Reactant: O=C1CNCCN(CCO)CC(=O)NC2CCCCC2N1
Agent: B
Solvent: C1CCOC1
Solvent: O
Product: OCCN1CCNCCNC2CCCCC2NCC1

Procedure:
Into a dry flask under nitrogen was placed 3.00 g. (10 mmol.) of compound (A) and 100 ml. of a 1M solution of BH3.THF in anhydrous tetrahydrofuran. The reaction mixture was refluxed for 12 hours. Water was added dropwise until no reaction was taking place with the excess of BH3.THF. The solvent was stripped off on a rotary evaporator after addition of a few ml. of methanol to avoid excessive foaming. The solid residue was treated with about 10 ml. of a concentrated solution of LiOF.H2O until the pH reached 12-13. This aqueous phase was extracted 6 times with 100 ml. of methylene chloride. The extracts were collected and dried over magnesium sulfate. The solvent was removed under vacuum to yield 2.62 g. of Compound (B) as a white powder that was used in the next step without further purification.
Reaction SMILES: [CH2:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[CH2:4]S(=O)O1.[C:12]([O:21][CH2:22][CH3:23])(=[O:20])/[CH:13]=[CH:14]/[C:15]([O:17][CH2:18][CH3:19])=[O:16]>C1(C)C=CC=CC=1>[C:12]([C@H:13]1[C@H:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:1][C:6]2[C:5](=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH2:4]1)([O:21][CH2:22][CH3:23])=[O:20]
Reactant: O=S1Cc2ccccc2CO1
Reactant: CCOC(=O)/C=C/C(=O)OCC
Solvent: Cc1ccccc1
Product: CCOC(=O)[C@@H]1Cc2ccccc2C[C@H]1C(=O)OCC
Temperature: 110 °C
Yield: 63.9 %

Procedure:
To a stirred solution of 1,4-dihydro-2,3-benzoxathiin 3-oxide (2.0 g, 11.9 mmol) in toluene (20 mL) was added diethyl fumarate (3.9 mL, 23.8 mmol). Upon completion of addition, the reaction mixture was heated to 110° C. for 16 h under nitrogen. The solvent was removed under vacuum to yield a residue. The residue was purified by silica gel chromatography eluting with 10% ethyl acetate in hexane to yield the title compound (2.1 g, 64%). 13C NMR (400 MHz, CDCl3) δ 174.1, 133.7, 128.3, 126.1, 60.5, 42.3, 42.0, 31.6, 14.3, 14.0. 1H NMR (400 MHz, CDCl3) δ 7.04-7.15 (m, 4H), 4.18 (m, 4H), 3.12 (dd, J=2.6, 12.4 Hz, 2H), 2.87-3.03 (m, 4H), 1.27 (t, J=7.5 Hz, 6H). MS [M+Na]+, 299.
Reaction SMILES: [CH:1]([S:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C@H:11]1[C@@H:15]([C:16]([O:18][CH3:19])=[O:17])[CH2:14][CH2:13][N:12]1[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])([CH3:3])[CH3:2].[OH:27]OS([O-])=O.[K+].[OH2:33]>CO>[CH:1]([S:4]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C@H:11]1[C@@H:15]([C:16]([O:18][CH3:19])=[O:17])[CH2:14][CH2:13][N:12]1[C:20]([O:22][C:23]([CH3:24])([CH3:26])[CH3:25])=[O:21])(=[O:27])=[O:33])([CH3:3])[CH3:2]
Reactant: O=S([O-])OO
Reactant: COC(=O)[C@H]1CCN(C(=O)OC(C)(C)C)[C@H]1c1ccccc1SC(C)C
Reactant: O
Agent: [K+]
Solvent: CO
Product: COC(=O)[C@H]1CCN(C(=O)OC(C)(C)C)[C@H]1c1ccccc1S(=O)(=O)C(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To 13A (0.24 g, 0.63 mmol) in methanol (3 mL) was added Oxone® (1.16 g, 1.90 mmol) in water (3 mL) at 0° C. The reaction was stirred for 3 h at rt. The reaction was quenched with 5% sodium bisulfite and then neutralized with 1 M sodium hydroxide. The solvent was evaporated and the aqueous layer was extracted with dichloromethane (3×). The organic extracts were combined, washed with saturated sodium chloride and dried over sodium sulfate. The solvent was evaporated and the crude residue was purified by flash column chromatography to give 0.17 g of 13B.
Reaction SMILES: [NH2:1][C:2]1[C:15]2[C:6](=[CH:7][C:8]3[C:9]4[C:14]=2[C:13](=[O:16])[N:12]([CH2:17][CH2:18][N:19]([CH3:21])[CH3:20])[C:11](=[O:22])[C:10]=4[CH:23]=[CH:24][CH:25]=3)[CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[C:34]([O:36][CH2:37][CH2:38][CH2:39][CH3:40])=[O:35]>ClCCl>[CH3:21][N:19]([CH3:20])[CH2:18][CH2:17][N:12]1[C:11](=[O:22])[C:10]2[CH:23]=[CH:24][CH:25]=[C:8]3[C:9]=2[C:14](=[C:15]2[C:2]([NH:1][C:34](=[O:35])[O:36][CH2:37][CH2:38][CH2:39][CH3:40])=[CH:3][CH:4]=[CH:5][C:6]2=[CH:7]3)[C:13]1=[O:16]
Reactant: CCCCOC(=O)Cl
Reactant: CN(C)CCN1C(=O)c2cccc3cc4cccc(N)c4c(c23)C1=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCOC(=O)Nc1cccc2cc3cccc4c3c(c12)C(=O)N(CCN(C)C)C4=O
Temperature: 25 °C

Procedure:
100 mg of 11-amino-2-[2-(dimethylamino)ethyl]-1H-dibenzo[de,h]isoquinoline-1,3(2H)-dione (obtained in example 3) (0.30 mmole) were dissolved in 6 ml of dichloromethane. 85 μl (2 molar equivalents) of triethylamine and 77 μl (2 molar equivalents) of butyl chloroformate were respectively added. The reaction mixture was maintained at room temperature for 3 hours. The solvent was then evaporated under reduced pressure and the residue was submitted to a flash chromatography (SiO2, CH2Cl2/MeOH 95/5). 119 mg of the desired product the desired product (formula shown hereinabove) were isolated as an orange powder (yield=83%) which was characterized as follows:
Reaction SMILES: C[Al](C)C.[CH:5]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([CH3:7])[CH3:6].[CH2:15]([N:22]1[CH2:26][C@@H:25]2[C@@H:27]([NH:30][C:31](=O)[O:32]C(C)(C)C)[CH2:28][CH2:29][C@@H:24]2[CH2:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1(C)C=CC=CC=1>[CH2:15]([N:22]1[CH2:26][C@@H:25]2[C@@H:27]([NH:30][C:31](=[O:32])[N:8]([CH:5]([CH3:7])[CH3:6])[C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH2:28][CH2:29][C@@H:24]2[CH2:23]1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CC(C)Nc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H]2CN(Cc3ccccc3)C[C@@H]21
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: CC(C)N(C(=O)N[C@H]1CC[C@@H]2CN(Cc3ccccc3)C[C@@H]21)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2 M Trimethylaluminum in toluene (0.198 mL, 0.395 mmol) was added dropwise to N-isopropylaniline (0.068 mL, 0.474 mmol) in toluene (2 mL) at 0° C. The reaction was warmed to room temperature and stirred for 1 hour. The aluminum amide solution was then added dropwise to a solution of tert-butyl(3aR,4S,6aS)-2-benzyloctahydrocyclopenta[c]pyrrol-4-ylcarbamate from Example 214 Step A (50 mg, 0.158 mmol) in 1 mL of toluene at 0° C. The reaction was heated at 90° C. overnight, and then the reaction was quenched with 1 mL of 5% aqueous sodium hydroxide. The separated toluene layer was applied directly to a silica gel cartridge (Analogix®, Burlington, Wis., RS-4) eluting with 1-10% methanol (2 N ammonia)/dichloromethane to give the title compound: 1H NMR (300 MHz, CDCl3) δ ppm 7.40 (ddd, J=1.8, 3.2, 5.7, 3H), 7.29 (d, J=4.4, 4H), 7.24-7.18 (m, 1H), 7.14 (t, J=2.0, 1H), 7.13-7.10 (m, 1H), 4.87 (dt, J=6.8, 13.6, 1H), 3.94-3.84 (m, 1H), 3.74 (d, J=7.1, 1H), 3.60 (d, J=13.0, 1H), 3.44 (d, J=13.0, 1H), 2.53 (t, J=5.5, 2H), 2.48-2.40 (m, 1H), 2.40-2.33 (m, 1H), 2.22 (dd, J=3.7, 8.8, 1H), 2.07 (ddd, J=5.1, 9.2, 11.7, 1H), 1.95 (td, J=6.0, 12.0, 1H), 1.63-1.52 (m, 1H), 1.40-1.30 (m, 1H), 1.29-1.17 (m, 1H), 1.05 (d, J=3.2, 3H), 1.02 (d, J=3.2, 3H); MS (ESI+) m/z 378 (M+H)+.