Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:3]=1[C:4]#[N:5].C1C(=O)N([Br:18])C(=O)C1>OS(C(F)(F)F)(=O)=O>[Br:18][C:7]1[C:6]([CH3:10])=[C:3]([C:2]([F:1])=[CH:9][CH:8]=1)[C:4]#[N:5]
Reactant: Cc1cccc(F)c1C#N
Reactant: O=C1CCC(=O)N1Br
Agent: O=S(=O)(O)C(F)(F)F
Product: Cc1c(Br)ccc(F)c1C#N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Commercially available 2-fluoro-6-methylbenzonitrile (Apollo Scientific, 15.0 g, 111 mmol) was dissolved in triflic acid (75 mL) at 0° C. then NBS (20.7 g, 117 mmol) was added. The reaction mixture was stirred at RT for 1 h then poured into ice water and extracted twice with DCM. The organic layer was washed with brine, dried over Na2SO4, then filtered and evaporated to dryness to yield 3-bromo-6-fluoro-2-methylbenzonitrile: LC-MS: M+1=216.
Reaction SMILES: C[C:2]1[C:3](Cl)=[N:4][C:5]([Cl:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[Cl:13][C:14]1[CH:22]=[CH:21][C:17]([CH2:18][CH2:19][NH2:20])=[CH:16][CH:15]=1.[C:23]([N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24]>>[C:26]([O:25][C:23]([N:30]1[CH2:35][CH2:34][N:33]([C:3]2[CH:2]=[CH:10][C:6]([C:7](=[O:9])[NH:20][CH2:19][CH2:18][C:17]3[CH:21]=[CH:22][C:14]([Cl:13])=[CH:15][CH:16]=3)=[C:5]([Cl:11])[N:4]=2)[CH2:32][CH2:31]1)=[O:24])([CH3:29])([CH3:27])[CH3:28]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Cc1cc(C(=O)O)c(Cl)nc1Cl
Reactant: NCCc1ccc(Cl)cc1
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(C(=O)NCCc3ccc(Cl)cc3)c(Cl)n2)CC1

Procedure:
In analogy to example 38 methyl 2,6-dichloronicotinic acid was coupled with 4-chlorophenethylamine and then reacted with N-Boc-piperazine. Light yellow solid.
Reaction SMILES: [NH2:1][C:2]1[C:11]([O:12][C@@H:13](C2C=CC=CC=2)[CH2:14][N:15]2[CH:19]=[CH:18][N:17]=[CH:16]2)=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][C:7]2=[O:26].[C:27]1([C:37]([OH:39])=O)[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=[CH:29][N:28]=1.CN(C(ON1N=N[C:50]2[CH:51]=[CH:52][CH:53]=[N:54][C:49]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC>C(Cl)Cl>[N:15]1([CH2:14][C@H:13]([C:52]2[CH:53]=[N:54][CH:49]=[CH:50][CH:51]=2)[O:12][C:11]2[CH:10]=[CH:9][C:8]3[C:7](=[O:26])[CH2:6][CH2:5][CH2:4][C:3]=3[C:2]=2[NH:1][C:37]([C:27]2[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH:30]=[CH:29][N:28]=2)=[O:39])[CH:19]=[CH:18][N:17]=[CH:16]1
Reactant: O=C(O)c1nccc2ccccc12
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: Nc1c(O[C@H](Cn2ccnc2)c2ccccc2)ccc2c1CCCC2=O
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1CCCc2c1ccc(O[C@H](Cn1ccnc1)c1cccnc1)c2NC(=O)c1nccc2ccccc12
Temperature: 25 °C
Reaction time: 5 h
Yield: 78.7 %

Procedure:
To a mixture of 5-amino-6-((S)-2-imidazol-1-yl-1-phenyl-ethoxy)-3,4-dihydro-2H-naphthalen-1-one (100 mg, 0.287 mmol), 1-isoquinoline carboxylic acid (60 mg, 0.344 mmol), and HATU (131 mg, 0.344 mmol) was added CH2Cl2 (3 mL) and Et3N (48 μL, 0.344 mmol). The reaction was stirred at RT for 5 h. The mixture was diluted with CH2Cl2 and washed with H2O, saturated aqueous NaHCO3 and brine, dried over Na2SO4, and concentrated to give a foam/oil. Purification by chromatography (SiO2, 5-8% MeOH/CH2Cl2) afforded the title compound as a foam (114 mg, 0.226 mmol, 79%). The structure was confirmed by NMR and mass spectrometry. MS m/z 504 (M++H).
Reaction SMILES: [C:1]([O-])(=[O:3])C.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[Pb+4].[OH:18][C:19]1[C:39]([CH2:40][CH2:41][CH3:42])=[CH:38][C:22]2[CH:23]([C:26]3[CH:31]=[C:30]([O:32][CH3:33])[C:29]([O:34][CH3:35])=[C:28]([O:36][CH3:37])[CH:27]=3)[CH2:24][O:25][C:21]=2[CH:20]=1>CO>[CH3:1][O:3][C:22]12[CH:38]=[C:39]([CH2:40][CH2:41][CH3:42])[C:19](=[O:18])[CH:20]=[C:21]1[O:25][CH2:24][CH:23]2[C:26]1[CH:31]=[C:30]([O:32][CH3:33])[C:29]([O:34][CH3:35])=[C:28]([O:36][CH3:37])[CH:27]=1
Reactant: CC(=O)[O-]
Reactant: CCCc1cc2c(cc1O)OCC2c1cc(OC)c(OC)c(OC)c1
Agent: [Pb+4]
Solvent: CO
Product: CCCC1=CC2(OC)C(=CC1=O)OCC2c1cc(OC)c(OC)c(OC)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Lead tetraacetate (200 mg) was added to a solution of 6-hydroxy-3-(3,4,5-trimethoxyphenyl)-5-propyl-2,3-dihydrobenzofuran (100 mg) in dry methanol (10 ml), and the mixture was stirred at room temperature for 1 hour. The solution was evaporated to a residue, which was put on a flash column of silica gel and eluted with hexane-ethyl acetate (4:1, v/v). The title compound was isolated as a mixture of epimers.
Reaction SMILES: [F:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[NH:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[N:15]=[C:14]1[C:22]1[C:26]([NH2:27])=[CH:25][NH:24][N:23]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.O>[NH:15]1[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[N:13]=[C:14]1[C:22]1[C:26]([NH:27][C:4](=[O:6])[C:3]2[CH:7]=[CH:8][CH:9]=[C:10]([O:11][CH3:12])[C:2]=2[F:1])=[CH:25][NH:24][N:23]=1
Reactant: Nc1c[nH]nc1-c1nc2ccccc2[nH]1
Reactant: COc1cccc(C(=O)O)c1F
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: COc1cccc(C(=O)Nc2c[nH]nc2-c2nc3ccccc3[nH]2)c1F
Temperature: 25 °C
Reaction time: 20 h
Yield: 8 %

Procedure:
A mixture of 2-fluoro-3-methoxybenzoic acid (47 mg, 0.28 mmol), 3-(1H-benzimidazol-2-yl)-1H-pyrazol-4-ylamine (50 mg, 0.25 mmol), EDC (58 mg, 0.30 mmol) and HOBt (41 mg, 0.30 mmol) in DMF (1.5 ml) was stirred at ambient temperature for 20 h. The reaction mixture was poured into water (30 ml) and the resultant solid collected by filtration and purified by re-crystallisation from MeOH/petrol to yield N-[3-(1H-benzimidazol-2-yl)-1H-pyrazol-4-yl]-2-fluoro-3-methoxy-benzamide (7 mg, 8%) as a gray solid. (LC/MS: Rt 3.63, [M+H]+ 352.00).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([O:20][CH:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[C:5]2[C:10](I)=[CH:9][N:8]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:6]=2[N:7]=1.[CH3:27][N:28]1[CH:32]=[C:31](B2OC(C)(C)C(C)(C)O2)[CH:30]=[N:29]1.O1CCOCC1>O>[Cl:1][C:2]1[N:3]=[C:4]([O:20][CH:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[C:5]2[C:10]([C:31]3[CH:30]=[N:29][N:28]([CH3:27])[CH:32]=3)=[CH:9][N:8]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:6]=2[N:7]=1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: C[Si](C)(C)CCOCn1cc(I)c2c(OC3CCOCC3)nc(Cl)nc21
Solvent: O
Solvent: C1COCCO1
Product: Cn1cc(-c2cn(COCC[Si](C)(C)C)c3nc(Cl)nc(OC4CCOCC4)c23)cn1
Temperature: 110 °C
Reaction time: 2 h
Yield: 88 %

Procedure:
To a degassed mixture of 2-chloro-5-iodo-4-((tetrahydro-2H-pyran-4-yl)oxy)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (1 equiv), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.1 equiv) and potassium phosphate tribasic trihydrate (3 equiv) in a 10:1 mixture of 1,4-dioxane and water (0.09 M)) was added palladium 1,1-bis(diphenylphosphion)ferrocene dichloride (0.2 equiv). The mixture was stirred at 110° C. for 2 h. The suspension was cooled to room temperature and filtered. The filtrate was concentrated and the residue obtained was purified by silica gel chromatography (20% ethyl acetate in petroleum ether) to afford the title compound (88% yield). MS (ESI) m/z=464.1 [M+1]+.
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[H-].[Na+].Br[CH2:19][C:20]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[O:24][CH2:23][CH2:22][O:21]1.O>CN(C=O)C>[CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[N:6]([CH2:19][C:20]3([C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)[O:21][CH2:22][CH2:23][O:24]3)[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3
Reactant: BrCC1(c2ccccc2)OCCO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc2c(c1)c1c(n2CC2(c3ccccc3)OCCO2)CCN(C)C1
Temperature: 100 °C

Procedure:
2,8-Dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (2 g, 10 mmol) was dissolved in 20 mL of DMF. The resulting solution was cooled in an ice-water bath and sodium hydride (840 mg, 4.2 mmol) was added under nitrogen atmosphere. 2-Bromomethyl-2-phenyl[1,3]dioxolane (2.43 g, 10 mmol) was added and the reaction mixture was heated at 100° C. overnight. Water was added and the product was extracted with EtOAc. The organic layer was washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 0-5% MeOH:DCM.
Reaction SMILES: [CH:1]1([CH:4]([C:7](=O)[CH3:8])[C:5]#[N:6])[CH2:3][CH2:2]1.CC(O)=O.O.[NH2:15][NH2:16].C([O-])(O)=O.[Na+]>C(O)C.O>[CH:1]1([C:4]2[C:7]([CH3:8])=[N:15][NH:16][C:5]=2[NH2:6])[CH2:3][CH2:2]1
Reactant: CC(=O)C(C#N)C1CC1
Reactant: NN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: CC(=O)O
Product: Cc1n[nH]c(N)c1C1CC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 93.5 %

Procedure:
Into a 250-mL round-bottom flask, was placed a solution of 2-cyclopropyl-3-oxobutanenitrile (compound 266.1, 4.0 g, 32.5 mmol) in ethanol (18 mL). AcOH (3 mL) and hydrazine hydrate (3.15 mL, 65 mmol) were added and the reaction was stirred overnight at 80° C. The reaction was cooled, then the pH was carefully adjusted to 9 with NaHCO3 (aq. sat.). The mixture was diluted with water, then extracted with ethyl acetate (6×60 mL) and the combined organic extracts were washed with brine (80 mL), dried (Na2SO4), filtered and concentrated under reduced pressure to obtain the title compound as a brown oil (4.17 g, crude), which was used in the next step without purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[C:6]([NH2:11])[CH:5]=1.O.[N:14]#[C:15][Br:16]>C(#N)C>[BrH:16].[NH2:14][C:15]1[NH:10][C:7]2[CH:8]=[CH:9][C:4]([C:3]([O:2][CH3:1])=[O:12])=[CH:5][C:6]=2[N:11]=1
Reactant: N#CBr
Reactant: COC(=O)c1ccc(N)c(N)c1
Solvent: O
Solvent: CC#N
Product: Br
Product: COC(=O)c1ccc2[nH]c(N)nc2c1
Temperature: 0 °C
Reaction time: 16 h
Yield: 98 %

Procedure:
3,4-Diaminobenzoic acid methyl ester (58.72 mmoles, 9.35 g, 1 equivalent, commercially available from Oakwood Products) was dissolved in acetonitrile (20 ml) and water (200 ml) and cooled to 0-5° C. (ice-water). Cyanogen bromide (8.64 g, 81.55 mmoles, 1.4 equivalent) was added over a period of 5 minutes, and the reaction mixture was allowed to go to room temperature and stirred for 16 hours. The reaction mixture was then evaporated under reduced pressure to 15.60 g of methyl 2-amino-1H-benzo[d]imidazole-5-carboxylate hydrobromide (yield: 98%) which was used directly in the next reaction without any further reaction. 1H-NMR (400 MHz DMSO-d6) δ 12.64 (br s, 2H), 8.80 (bs, 3H), 7.91 (s, 1H), 7.82 (d, 1H), 7.51 (d, 1H), 3.82 (s, 3H). MS (EI): 192 (MH+).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)[C:3]=1[CH2:21][C:22]([O:24][CH3:25])=[O:23].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH2:36]1[CH2:40]OC[CH2:37]1.ICCC>CN(C=O)C>[CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)[C:3]=1[CH:21]([CH2:37][CH2:36][CH3:40])[C:22]([O:24][CH3:25])=[O:23]
Reactant: COC(=O)Cc1c(C)nc2sc3c(c2c1-c1ccc(Cl)cc1)CCC3
Reactant: C1CCOC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCCI
Solvent: CN(C)C=O
Product: CCCC(C(=O)OC)c1c(C)nc2sc3c(c2c1-c1ccc(Cl)cc1)CCC3
Yield: 44 %

Procedure:
This compound was prepared according to the procedure C from methyl [2-methyl-4-(4-chlorophenyl)-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl]acetate (0.100 g; 0.269 mmol), LHMDS 1N in THF (0.305 mL; 0.305 mmol), 1-iodopropane (0.044 mL; 0.451 mmol) in DMF (3.8 mL) for 4 h. Purification by flash chromatography on silica gel using a gradient of ethyl acetate (5-15%) in heptane furnished 0.049 g (44%) of the title compound as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:27]=[CH:26][C:11]([CH2:12][O:13][C:14]([C:22]([F:25])([F:24])[F:23])([C:18]([F:21])([F:20])[F:19])[C:15](O)=[O:16])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.S(Cl)([Cl:30])=O.CN(C)C=O>C1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[CH:10][C:11]([CH2:12][O:13][C:14]([C:18]([F:19])([F:20])[F:21])([C:22]([F:24])([F:25])[F:23])[C:15]([Cl:30])=[O:16])=[CH:26][CH:27]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)C(OCc1ccc(-c2ccc(Cl)cc2)cc1)(C(F)(F)F)C(F)(F)F
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: c1ccccc1
Product: O=C(Cl)C(OCc1ccc(-c2ccc(Cl)cc2)cc1)(C(F)(F)F)C(F)(F)F

Procedure:
A mixture of 2-[4-(4-chlorophenyl)benzyloxy]-3,3,3-trifluoro-2-trifluoromethylpropionic acid (3.0 g.), thionyl chloride (3.0 ml.), dimethylformamide (0.16 g.) and benzene (10 ml.) is heated under reflux until the solution becomes turbid (ca. 10 minutes). The mixture is evaporated in vacuo, benzene (10 ml.) is added and the evaporation is repeated. Light petroleum (10 ml., b.p. 40°-60° C.) is added to the residue, and the solution is separated from insoluble oils and evaporated to give 2-[4-(4-chlorophenyl)benzyloxy]-3,3,3-trifluoro-2-trifluoromethylpropionyl chloride (3.07 g.), m.p. 30°-35° C.
Reaction SMILES: [C:1]([C:3]([C:16](=[O:29])[N:17]([CH3:28])[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=1)=[CH:4][NH:5][C:6](=[NH:15])[N:7]1[CH2:11][C:10]([CH3:13])([CH3:12])[NH:9][C:8]1=[O:14])#[N:2].O.[OH-].[Na+]>C(O)=O.ClCCl>[CH3:28][N:17]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:25])([F:26])[F:27])[CH:19]=1)[C:16]([C:3]1[C:1]([NH2:2])=[N:15][C:6]([N:7]2[CH2:11][C:10]([CH3:13])([CH3:12])[NH:9][C:8]2=[O:14])=[N:5][CH:4]=1)=[O:29]
Reactant: CN(C(=O)C(C#N)=CNC(=N)N1CC(C)(C)NC1=O)c1cccc(C(F)(F)F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=CO
Solvent: O
Product: CN(C(=O)c1cnc(N2CC(C)(C)NC2=O)nc1N)c1cccc(C(F)(F)F)c1
Yield: 56.9 %

Procedure:
A solution of 1.634 g (4 mmol) of 1-cyano-1-[N-methyl-N-(3-trifluoromethylphenyl)carbamoyl]-2-[imino(4,4-dimethyl-2-oxo-1-imidazolidinyl)methylamino]ethene (compound IV) in 3 ml of formic acid (98-100% strength) was heated at 50° C. for 2 hours. The formic acid was then stripped off in vacuo, the residue was taken up in dichloromethane, 20 ml of water were added, and the pH was adjusted to between 9 and 10 with dilute sodium hydroxide solution. The organic phase was separated off. The aqueous phase was extracted twice more with dichloromethane. The combined dichloromethane extracts were washed successively with 2 ml of 0.5N NaOH and twice with water, dried with MgSO4 and evaporated in vacuo. The remaining solid residue was mixed with ether/heptane 1:1 and filtered off with suction. After drying (compare Example 13), 0.93 g (=56.9% yield) of pure 4-amino-2-(4,4-dimethyl-2-oxo-1-imidazolidinyl)pyrimidine-5-carboxylic acid N-methyl-N-(3-trifluoromethylphenyl) amide was obtained, melting point 210°-211° C.; TLC in CH2Cl2 /C2 H5OH=10:1.
Reaction SMILES: C(O)=O.[CH3:4][N:5]([CH2:7][C:8]1[CH:25]=[CH:24][C:11]([O:12][CH:13]2[CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14]2)=[C:10]([CH3:26])[CH:9]=1)[CH3:6]>Cl.CO>[NH:15]1[CH2:14][CH:13]([O:12][C:11]2[CH:24]=[CH:25][C:8]([CH2:7][N:5]([CH3:6])[CH3:4])=[CH:9][C:10]=2[CH3:26])[CH2:16]1
Reactant: Cc1cc(CN(C)C)ccc1OC1CN(C(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: CO
Solvent: O=CO
Product: Cc1cc(CN(C)C)ccc1OC1CNC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.1 %

Procedure:
Intermediate 16A (1.9 g, 5.93 mmol) was dissolved in a 4.0 M solution of HCl in MeOH (30 mL) and the reaction mixture was stirred at RT overnight. The mixture was concentrated and the residue was dissolved in water. The aqueous solution was basified to pH=10 with aqueous NaOH (1.0 M) and then extracted with DCM (4×30 mL). The combined organic phases were filtered through a phase separator and the solvent was removed by evaporation. There was obtained 1.02 g (78%) of 16B as a colorless oil. 1H NMR (500 MHz, CDCl3): δ 2.21 (s, 6H), 2.33 (s, 3H), 3.30 (s, 2H), 3.73-3.84 (m, 2H), 3.85-3.96 (m, 2H), 4.91-5.03 (m, 1H), 6.52 (d, 1H), 6.58 (s, 1H), 7.11 (d, 1H).
Reaction SMILES: C(N[CH:5]([CH3:7])[CH3:6])(C)C.[Li]CCCC.CCCCCC.[Li+].CC([N-]C(C)C)C.[CH2:27]([C:33]1[CH:37]=[CH:36][S:35][CH:34]=1)[CH2:28][CH2:29][CH2:30][CH2:31][CH3:32].C[O:39][B:40](OC)[O:41]C.C(O)CCO>C(OCC)C>[CH2:27]([C:33]1[CH:37]=[C:36]([B:40]2[O:41][CH2:6][CH2:5][CH2:7][O:39]2)[S:35][CH:34]=1)[CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]
Reactant: CC(C)NC(C)C
Reactant: CCCCCCc1ccsc1
Reactant: COB(OC)OC
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: OCCCO
Solvent: CCOCC
Solvent: CCCCCC
Product: CCCCCCc1csc(B2OCCCO2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of diisopropylamine (9.0 ml, 64.21 mmol) in 100 ml of anhydrous diethyl ether was added 2.5 M n-BuLi in hexane (20.5 ml, 51.2 mmol) at room temperature. After stirring at room temperature for 30 min, the resulting LDA solution was cooled to −76° C. A solution of 3-hexylthiophene (8.617 g, 51.2 mmol) in 100 ml of diethyl ether was cooled to −76° C. and added to the above LDA solution. The temperature was allowed to rise slowly to −40° C., whereupon it was stirred for 1 h. The solution was then recooled to −76° C. and trimethylborate (8.6 ml, 76.8 mmol) was added slowly. The mixture was allowed to warm to room temperature and stirred for 2 h. After quenching with 10% HCl (100 ml) the organic layer was separated and the aqueous layer was extracted with ether (2×). The combined organic layer was dried over MgSO4, filtered and concentrated. The residue was added 1,3-propanediol (3.7 ml, 51.2 mmol) and refluxed for 2 h. The mixture was then placed directly on a silica column and eluted first with hexane, then chloroform to give the product, 2.82 g, 22%. 1H NMR (CDCl3-d3, 500 MHz): δ 7.36 ppm (s, 1 H), 7.13 ppm (s, 1 H), 4.14-4.12 ppm (t, 4 H, J=8.6 Hz), 2.60-2.63 ppm (t, 2 H, J=8.6 Hz), 2.04 ppm (m, 2 H), 1.60 ppm (m, 2H), 1.28 ppm (m, 4 H), 0.87 ppm (t, 3 H, J=7.5 Hz); 13C-NMR (CDCl3, 500 MHz): δ 144.9, 137.2, 126.8, 126.7, 62.50, 32.09, 31.04, 30.48, 29.38, 27.87, 22.99, 14.46 ppm. EI, MS m/z (%): 252 (100, M+).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[C:4]([N:13]2[CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[S:16](=[O:25])(=[O:24])[CH2:15][CH2:14]2)[CH:3]=1.[NH2:26][CH2:27][C@H:28]([OH:31])[CH2:29][OH:30]>>[O:24]=[S:16]1(=[O:25])[C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[CH2:19][N:13]([C:4]2[CH:3]=[C:2]([NH:26][CH2:27][C@H:28]([OH:31])[CH2:29][OH:30])[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=3)[N:5]=2)[CH2:14][CH2:15]1
Reactant: NC[C@H](O)CO
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(Cl)c2c1
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(NC[C@H](O)CO)c2c1

Procedure:
The title compound was prepared in analogy to Example 3-1 in Scheme 5 by using 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and (2S)-3-aminopropane-1,2-diol. MS obsd. (ESI+) [(M+H)+] 428, 1H NMR (400 MHz, CD3OD) δ ppm 7.98 (dd, J=7.83, 1.26 Hz, 1 H), 7.89 (d, J=7.33 Hz, 1 H), 7.63 (td, J=7.45, 1.26 Hz, 1 H), 7.57 (s, 1 H), 7.50-7.35 (m, 2 H), 7.29 (dd, J=8.59, 1.77 Hz, 1 H), 6.13 (s, 1 H), 5.14 (s, 2 H), 4.55 (brs, 2 H), 4.04-3.89 (m, 1 H), 3.69 (d, J=5.56 Hz, 2 H), 3.64-3.49 (m, 4 H), 2.41 (s, 3 H).
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@H:10](OS(C)(=O)=O)[CH2:9][C@H:8]1[CH2:17][CH2:18][N:19]1[CH:23]=[CH:22][N:21]=[C:20]1[CH2:24][OH:25])=[O:6])[CH:2]=[CH2:3].[C:26]([SH:29])(=[O:28])[CH3:27]>>[C:26]([S:29][C@@H:10]1[CH2:11][N:7]([C:5]([O:4][CH2:1][CH:2]=[CH2:3])=[O:6])[C@H:8]([CH2:17][CH2:18][N:19]2[CH:23]=[CH:22][N:21]=[C:20]2[CH2:24][OH:25])[CH2:9]1)(=[O:28])[CH3:27]
Reactant: C=CCOC(=O)N1C[C@H](OS(C)(=O)=O)C[C@H]1CCn1ccnc1CO
Reactant: CC(=O)S
Product: C=CCOC(=O)N1C[C@@H](SC(C)=O)C[C@H]1CCn1ccnc1CO

Procedure:
(2R,4R)-1-Allyloxycarbonyl-2-[2-(2-hydroxymethyl-imidazol-1-yl) ethyl]-4-methanesulfonyloxypyrrolidine (15.7 g) was reacted with thioacetic S-acid (6.30 ml) in substantially the same manner as that of Preparation 4-12) to give (2R,4S)-4-acetylthio-1-allyloxycarbonyl-2-[2-(2-hydroxymethylimidazol-1-yl) ethyl]pyrrolidine (5.93 g) as an orange paste.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[C:13]3[CH:14]=[CH:15][CH:16]=[C:7]([C:8]=23)[S:6]1(=[O:18])=[O:17].[H-].[Na+].BrCCC[CH2:25][Cl:26].C1C=C2NS(C3=CC=CC(=C23)C=1)(=O)=O>CN(C)C=O>[Cl:26][CH2:25][CH2:2][CH2:3][CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[C:13]3[CH:14]=[CH:15][CH:16]=[C:7]([C:8]=23)[S:6]1(=[O:18])=[O:17]
Reactant: ClCCCCBr
Reactant: O=S1(=O)c2cccc3cccc(c23)N1CCCCl
Agent: O=S1(=O)Nc2cccc3cccc1c23
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=S1(=O)c2cccc3cccc(c23)N1CCCCCl

Procedure:
2-(4-Chlorobutyl)naphtho[1,8-cd]isothiazole 1,1-dioxide may be obtained in the following manner: operating as in Example 1 for the preparation of 2-(3-chloropropyl)naphtho[1,8-cd]isothiazole 1,1-dioxide, starting with sodium hydride (4.8 g) in a 50% dispersion in vaseline oil, 1-bromo-4-chlorobutane (11.9 cc) and 1,8-naphthosultam (20.5 in dimethylformamide (250 cc). After purification by flash-chromatography on a silica under a current of argon at medium pressure (0.5-1.5 bar) with a mixture of dichloromethane and cyclohexanone (30-70 vol) as eluant, 2-(4-chlorobutyl)naphtho[1,8-cd]isothiazole 1,1-dioxide (24.6 g) is obtained in the form of a yellow oil which is used in the crude state in the subsequent syntheses.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[C:9]([F:10])=[CH:8][C:7]([N+:11]([O-:13])=[O:12])=[CH:6][C:5]=1[OH:14].I[CH3:16]>CN(C=O)C.C1COCC1>[F:10][C:9]1[CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[CH:6]=[C:5]([O:14][CH3:16])[C:4]=1[F:3]
Reactant: CI
Reactant: O=[N+]([O-])c1cc(O)c(F)c(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COc1cc([N+](=O)[O-])cc(F)c1F
Temperature: 80 °C
Reaction time: 0.17 h
Yield: 49.1 %

Procedure:
Step M (4): Sodium hydride (120 mg, 5 mmol) was added to a solution of 2,3-difluoro-5-nitrophenol (250 mg, 1.4 mmol) in DMF/THF (4 mL/4 mL). After 10 min, iodomethane (0.2 mL, 5 mmol) was added. The mixture was heated at 80° C. for 2 h. The reaction mixture was quenched with 1 N HCl. The mixture was diluted with water and extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo to afford 1,2-difluoro-3-methoxy-5-nitrobenzene (130 mg, 48% yield).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:11](O)[CH2:10][C:9]3[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=3[S:7][C:6]=2[CH:17]=1.C1C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:11]=[CH:10][C:9]3[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=3[S:7][C:6]=2[CH:17]=1
Reactant: OC1Cc2ccccc2Sc2cc(Br)ccc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: Brc1ccc2c(c1)Sc1ccccc1C=C2

Procedure:
17 G. 3-bromo-11-hydroxy-10,11-dihydrodibenzo[b,f]thiepin are dissolved in 600 cc. benzene; 1 gram p-toluene sulfonic acid is added and the mixture is refluxed with elimination of water for two hours. The solution is cooled and washed with aqueous sodium bicarbonate solution and water, dried and stripped to a solid residue. 16 G. of 3-bromodibenzo[b,f]thiepin are obtained.