Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[N:3]([C:10]2[CH:20]=[CH:19][C:13]([C:14]([O:16]CC)=O)=[CH:12][CH:11]=2)[CH:2]=1.[F:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[C:24]([O:34][CH3:35])[CH:23]=1>>[F:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]2[CH2:29][CH2:30][N:31]([C:14]([C:13]3[CH:12]=[CH:11][C:10]([N:3]4[C:4]5=[N:5][CH:6]=[CH:7][CH:8]=[C:9]5[N:1]=[CH:2]4)=[CH:20][CH:19]=3)=[O:16])[CH2:32][CH2:33]2)=[C:24]([O:34][CH3:35])[CH:23]=1
Reactant: CCOC(=O)c1ccc(-n2cnc3cccnc32)cc1
Reactant: COc1cc(F)ccc1N1CCNCC1
Product: COc1cc(F)ccc1N1CCN(C(=O)c2ccc(-n3cnc4cccnc43)cc2)CC1
Yield: 16.1 %

Procedure:
Using ethyl 4-(imidazo[4,5-b]pyridin-3-yl)benzoate (300 mg) described in Preparation Example 77 and 1-(4-fluoro-2-methoxyphenyl)piperazine (236 mg) and by the reaction and treatment in the same manner as in Example 170, the title compound (78 mg) was obtained.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][N:5]=[C:4]2[N:9]([S:35]([C:38]3[CH:43]=[CH:42][C:41]([CH3:44])=[CH:40][CH:39]=3)(=[O:37])=[O:36])[C:10]([C:12]3[C:16]4=[N:17][C:18]([O:23][CH3:24])=[C:19]([O:21][CH3:22])[CH:20]=[C:15]4[N:14]([CH2:25][CH2:26][CH2:27][N:28]4[CH2:33][CH2:32]N(C)[CH2:30][CH2:29]4)[CH:13]=3)=[CH:11][C:3]=12.ClC1C(F)=CN=C2N(S(C3C=CC(C)=CC=3)(=O)=O)C(C3C4=NC(OC)=C([O:65]C)C=C4N(CC(I)C)C=3)=CC=12.C(=O)([O-])[O-].[K+].[K+].CN1CCNCC1>C(#N)C>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][N:5]=[C:4]2[N:9]([S:35]([C:38]3[CH:43]=[CH:42][C:41]([CH3:44])=[CH:40][CH:39]=3)(=[O:37])=[O:36])[C:10]([C:12]3[C:16]4=[N:17][C:18]([O:23][CH3:24])=[C:19]([O:21][CH3:22])[CH:20]=[C:15]4[N:14]([CH2:25][CH2:26][CH2:27][N:28]4[CH2:33][CH2:32][O:65][CH2:30][CH2:29]4)[CH:13]=3)=[CH:11][C:3]=12
Reactant: COc1cc2c(nc1OC)c(-c1cc3c(Cl)c(F)cnc3n1S(=O)(=O)c1ccc(C)cc1)cn2CC(C)I
Reactant: COc1cc2c(nc1OC)c(-c1cc3c(Cl)c(F)cnc3n1S(=O)(=O)c1ccc(C)cc1)cn2CCCN1CCN(C)CC1
Agent: CN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1cc2c(nc1OC)c(-c1cc3c(Cl)c(F)cnc3n1S(=O)(=O)c1ccc(C)cc1)cn2CCCN1CCOCC1

Procedure:
3-[4-Chloro-5-fluoro-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-2-yl]-5,6-dimethoxy-1-[3-(4-methylpiperazin-1-yl)propyl]-1H-pyrrolo[3,2-b]pyridine can be prepared as in example 2, stage 2(c), but starting with 0.300 g of 3-[4-chloro-5-fluoro-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-2-yl]-1-(2-iodopropyl)-5,6-dimethoxy-1H-pyrrolo[3,2-b]pyridine, 0.068 g of potassium carbonate and 0.090 g of 1-methylpiperazine in 50 cm3 of acetonitrile. 0.192 g of 3-[4-chloro-5-fluoro-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-2-yl]-5,6-dimethoxy-1-(3-morpholin-4-ylpropyl)-1H-pyrrolo[3,2-b]pyridine is obtained as a resin with the following characteristics:
Reaction SMILES: BrBr.[Cl:3][CH2:4][C@@H:5]([OH:12])[CH2:6][C@@H:7]([OH:11])[CH2:8][CH:9]=[O:10].C(=O)(O)[O-].[Na+].C(=O)=O.[O-]S([O-])(=S)=O.[Na+].[Na+]>C(Cl)Cl.O>[OH:11][C@@H:7]1[CH2:6][C@@H:5]([CH2:4][Cl:3])[O:12][C:9](=[O:10])[CH2:8]1
Reactant: O=CC[C@H](O)C[C@H](O)CCl
Agent: BrBr
Agent: O=C([O-])O
Agent: O=C=O
Solvent: O
Solvent: ClCCl
Product: O=C1C[C@H](O)C[C@@H](CCl)O1
Reaction time: 1 h
Yield: 82 %

Procedure:
At room temperature 2.1 ml bromine was added in 45 minutes to a mixture of 6.7 g (40 mmol) 6-chloro-2,4,6-trideoxy-D-erythro-hexose (compound I; prepared according to the method described in WO-A-96/31615) and 6.7 g sodium bicarbonate in 40 ml methylene chloride and 10 ml water. CO2 gas escaped, while the pH remained at 5. After stirring for one hour, according to gas-liquid chromatography (GLC) the starting material had been fully converted. The bromine excess was neutralized with solid Na2S2O3. After phase separation the water phase was extracted with 2 times 100 ml ethyl acetate. The combined organic phases were dried over Na2SO4 and filtered. After rotavap evaporation 5.5 g yellow oil was obtained (82% yield of the compound of formula (2) with X=Cl relative to compound I).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.N1C=CC=CC=1.[C:15]1([CH3:25])[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1>O>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][S:21]([C:18]2[CH:19]=[CH:20][C:15]([CH3:25])=[CH:16][CH:17]=2)(=[O:23])=[O:22])=[N:3][CH:4]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1ccc(Br)cn1
Solvent: c1ccncc1
Solvent: O
Product: Cc1ccc(S(=O)(=O)Nc2ccc(Br)cn2)cc1
Temperature: 90 °C
Reaction time: 24 h
Yield: 98 %

Procedure:
To a 500 mL round-bottomed flask was added 2-amino-5-bromopyridine (15.0 g, 86.7 mmol, Aldrich, St. Louis, Mo.), pyridine (150 mL, 1858 mmol) and finally para-toluenesulfonyl chloride (24.8 g, 130 mmol, Aldrich, St. Louis, Mo.) at rt. The mixture was stirred at 90° C. After 24 h, the mixture was allowed to cool to rt and then poured into water (600 mL). A precipitate formed and the mixture was stirred for 15 min and then filtered. The filtercake was washed with water and hexane and then dried under vacuum to afford the title compound as an off-white solid (27.8 g, 98%) that was carried on without further purification.
Reaction SMILES: [C:1]1([C:6]2[N:7]([Si:11]([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:17])[CH3:16])[CH:12]([CH3:14])[CH3:13])[CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][CH2:3][CH:2]=1.C1(C2C=CN([Si](C(C)C)(C(C)C)C(C)C)C=2)CCCC=1.[C:41]([O:50][CH2:51][CH3:52])(=[O:49])/[CH:42]=[CH:43]/[C:44]([O:46][CH2:47][CH3:48])=[O:45].C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N>C1C=CC=CC=1>[CH:12]([Si:11]([CH:15]([CH3:17])[CH3:16])([CH:18]([CH3:20])[CH3:19])[N:7]1[C:6]2[C:10](=[C:42]([C:41]([O:50][CH2:51][CH3:52])=[O:49])[C:43]([C:44]([O:46][CH2:47][CH3:48])=[O:45])=[C:2]3[CH2:3][CH2:4][CH2:5][C:1]3=2)[CH:9]=[CH:8]1)([CH3:13])[CH3:14]
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1cccc1C1=CCCC1
Reactant: CCOC(=O)/C=C/C(=O)OCC
Agent: CC(C)[Si](C(C)C)(C(C)C)n1ccc(C2=CCCC2)c1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: c1ccccc1
Product: CCOC(=O)c1c2c(c3c(ccn3[Si](C(C)C)(C(C)C)C(C)C)c1C(=O)OCC)CCC2
Temperature: 150 °C
Reaction time: 8 h
Yield: 21 %

Procedure:
A 2:1 mixture of 2-(cyclopenten-1-yl)-1-(triisopropylsilyl)pyrrole and 3-(cyclopenten-1-yl)-1-(triisopropylsilyl)pyrrole (1.16 g, 4.01 mmol) and diethyl fumarate (0.75 g, 4.36 mmol) were heated under nitrogen to 150° C. for 64 h, affording the crude Diels-Alder adduct as an amber oil. The pure Diels-Alder adduct could be isolated by chromatography on silica gel (hexanes-ether 90:10). NMR (CDCl3) δ 6.68 (d, 1H), 6.16 (d, 1H), 4.20 (m, 4H), 3.95 (d, 1H), 2.91 (t, 2H), 2.49 (m, 1H), 2.09 (m, 1H), 1.73 (m, 2H), 1.48 (septet, 3H), 1.30 (2t, 6H), 1.27 (d, 9H), 1.07 (d, 9H). MS m/e 462 (M+H)+. DDQ (2.2 g, 9.7 mmol) was added in three portions to a benzene solution (16 mL) of the crude Diels-Alder adduct at 50° C. until no starting material remained (TLC and NMR). After 8 h, the mixture was filtered through Celite®. The precipitate was rinsed with benzene, and the filtrate was evaporated to give 1.52 g of a black solid. This was chromatographed on silica gel (hexanes-ether 15:85 to 20:80) to give the product (380 mg, 21% yield, 35% yield from 2-isomer) as a colorless oil. NMR (CDCl3) δ 7.42 (d, 1H), 7.05 (d, 1H), 4.40 (2q, 4H), 3.20 (t, 2H), 3.12 (t, 2H), 2.17 (quintet, 2H), 1.67 (septet, 3H), 1.39 (t, 3H), 1.36 (t, 3H), 1.20 (d, 18H). MS m/e 458 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([NH:12][C:13]2[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][CH:14]=2)=[O:11])=[C:5]([C:22]([F:25])([F:24])[F:23])[CH:4]=1.[I:26][C:27]1[CH:42]=[CH:41][C:30]([CH2:31][NH:32][CH2:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])=[CH:29][CH:28]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.CC(=O)OCC>[I:26][C:27]1[CH:28]=[CH:29][C:30]([CH2:31][N:32]([CH2:33][C:34]([O:36][C:37]([CH3:38])([CH3:39])[CH3:40])=[O:35])[C:17](=[O:18])[C:16]2[CH:20]=[CH:21][C:13]([NH:12][C:10](=[O:11])[CH2:9][C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][C:5]=3[C:22]([F:25])([F:23])[F:24])=[CH:14][CH:15]=2)=[CH:41][CH:42]=1
Reactant: CC(C)(C)OC(=O)CNCc1ccc(I)cc1
Reactant: COc1ccc(CC(=O)Nc2ccc(C(=O)O)cc2)c(C(F)(F)F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc(CC(=O)Nc2ccc(C(=O)N(CC(=O)OC(C)(C)C)Cc3ccc(I)cc3)cc2)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 75 %

Procedure:
Prepared using General Procedure 8: To a stirring solution of 4-(2-(4-methoxy-2-(trifluoromethyl)phenyl)acetamido)benzoic acid INT-18 (1.38 g, 3.92 mmol), tert-butyl 2-((4-iodobenzyl)amino)acetate INT-35 (1.36 g, 3.92 mmol) and TEA (0.82 ml, 5.88 mmol) in DMF (8 mL) was added HATU (1.56 g, 4.11 mmol). After stirring at room temperature for 2 h, the reaction mixture was diluted with EA (150 mL) and washed successively with NaHCO3 (100 mL) and brine (100 mL). The organics were pre-absorbed onto silica gel and then purified by chromatography (EA/isohexanes) to afford 2.05 g (75%) of tert-butyl 2-(N-(4-iodobenzyl)-4-(2-(4-methoxy-2-(trifluoromethyl)phenyl)acetamido)benzamido)acetate INT-36. LCMS-ESI (m/z) calculated for C30H30F3IN2O5: 682; found 627 [M−tBu+H]+, tR=2.90 min (Method 10). 1H NMR (400 MHz, DMSO) δ 10.33 (s, 1H), 7.76-7.68 (m, 2H), 7.62 (dd, J=7.0, 1.8 Hz, 2H), 7.44 (d, J=8.3 Hz, 1H), 7.37-7.30 (m, 2H), 7.27-7.13 (m, 3H), 7.12-6.97 (s, 1H), 4.59 (s, 1H), 4.50 (s, 1H), 3.92 (m, 2H), 3.85 (s,2H), 3.83 (s, 3H), 1.41 (s, 4.5H), 1.31 (s, 4.5H).
Reaction SMILES: C([O:3][C:4](=[O:27])[CH2:5][CH:6]([C:21]1[CH:22]=[N:23][CH:24]=[N:25][CH:26]=1)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([NH:19][CH3:20])[N:14]=1)C.[OH-].[Na+].Cl>C1COCC1.CO.O>[CH3:20][NH:19][C:15]1[N:14]=[C:13]([CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH:6]([C:21]2[CH:22]=[N:23][CH:24]=[N:25][CH:26]=2)[CH2:5][C:4]([OH:27])=[O:3])[CH:18]=[CH:17][CH:16]=1
Reactant: CCOC(=O)CC(CCCCCCc1cccc(NC)n1)c1cncnc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CNc1cccc(CCCCCCC(CC(=O)O)c2cncnc2)n1
Reaction time: 0.5 h

Procedure:
To a solution of 6-13a (0.215 g, 0.580 mmol) in THF/MeOH/H2O 3:1:1(10 mL)) was added NaOH (1.16 mL of 1N solution in water, 1.16 mmol). After 30 minutes, the mixture was neutralized with HCl (1.16 mL of 1N solution in water, 1.16 mmol) and the solvents were evaporated. The residue chromatographed on silica gel (15% MeOH/CHCl3) to give 6-14a as a white solid.
Reaction SMILES: [CH:1]([C:4]1[C:5]([O:33]COC)=[CH:6][C:7]([O:29]COC)=[C:8]([C:10]2[N:11]([C:16]3[CH:21]=[CH:20][C:19]([CH2:22][N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)=[CH:18][CH:17]=3)[C:12](=[S:15])[NH:13][N:14]=2)[CH:9]=1)([CH3:3])[CH3:2].Cl.[OH-].[Na+]>C(O)C>[CH:1]([C:4]1[CH:9]=[C:8]([C:10]2[N:11]([C:16]3[CH:21]=[CH:20][C:19]([CH2:22][N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)=[CH:18][CH:17]=3)[C:12]([SH:15])=[N:13][N:14]=2)[C:7]([OH:29])=[CH:6][C:5]=1[OH:33])([CH3:3])[CH3:2]
Reactant: COCOc1cc(OCOC)c(C(C)C)cc1-c1n[nH]c(=S)n1-c1ccc(CN2CCOCC2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)c1cc(-c2nnc(S)n2-c2ccc(CN3CCOCC3)cc2)c(O)cc1O
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 54.8 %

Procedure:
Crystals of 5-(5-isopropyl-2,4-bis-methoxymethoxy-phenyl)-4-[4-(morpholin-4-ylmethyl)-phenyl]-2,4-dihydro-[1,2,4]triazol-3-thione (IM6-S-a02) (1.43 g, 2.77 mmol) and a mixed solvent of 5.0 N aqueous hydrochloric acid (15 mL) and ethanol (15 mL) were placed in a 100 mL eggplant shaped flask and stirred at room temperature for 3.5 hours. After completing the reaction, the reaction mixture was neutralized with 5 N aqueous sodium hydroxide and then extracted with ethyl acetate. After drying over anhydrous sodium sulfate the collected organic layer was concentrated under reduced pressure. The residue thus obtained was purified by silica gel column chromatography to obtain the title compound (SH-a02: 647 mg, 54.7%).
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH2:7]O)=[CH:5][C:4]([N+:9]([O-:11])=[O:10])=[N:3]1.P(Br)(Br)[Br:13].C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl.ClCCl>[Br:13][CH2:7][C:6]1[N:2]([CH3:1])[N:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=1
Reactant: BrP(Br)Br
Reactant: Cn1nc([N+](=O)[O-])cc1CO
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: Cn1nc([N+](=O)[O-])cc1CBr
Temperature: 25 °C
Reaction time: 1 h
Yield: 62.7 %

Procedure:
To a solution of (1-methyl-3-nitro-1H-pyrazol-5-yl)methanol (496 mg, 3.16 mmol) in chloroform (10 mL) at 0° C. was added phosphorus tribromide (854 mg, 0.30 mL, 3.16 mmol) drop wise via syringe. The resulting solution was warmed to room temperature and stirred for 1 h. The resulting solution was cooled to 0° C. and diluted with dichloromethane (50 ml). The resulting solution was made basic (pH 8.5) with saturated aqueous sodium bicarbonate (20 mL). The layers were separated, and the aqueous layer was extracted with dichloromethane (3×20 mL). The combined organic layers were dried over magnesium sulfate. The resulting mixture was filtered and concentrated in vacuo and the residue purified by flash chromatography (silica gel, 40 g, 20% to 40% ethyl acetate in hexanes) to give 5-(bromomethyl)-1-methyl-3-nitro-1H-pyrazole (436 mg, 63%) as a white solid. 1H NMR (300 MHz, DMSO-d6) 8 ppm 3.94 (s, 3 H) 4.85 (s, 2 H) 7.14 (s, 1 H).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([C:11]([OH:13])=O)[NH:6]2.Cl.Cl.Cl.[N:17]1([CH2:24][CH2:25][N:26]2[CH2:31][CH2:30][CH:29]([NH2:32])[CH2:28][CH2:27]2)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[N:17]1([CH2:24][CH2:25][N:26]2[CH2:27][CH2:28][CH:29]([NH:32][C:11]([C:5]3[NH:6][C:7]4[C:3]([CH:4]=3)=[C:2]([Br:1])[CH:10]=[CH:9][CH:8]=4)=[O:13])[CH2:30][CH2:31]2)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: O=C(O)c1cc2c(Br)cccc2[nH]1
Reactant: NC1CCN(CCN2CCCCCC2)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NC1CCN(CCN2CCCCCC2)CC1)c1cc2c(Br)cccc2[nH]1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.7 %

Procedure:
4-Bromo-1H-indole-2-carboxylic acid (1.5 g, 3.1 mmol), 1-(2-azepan-1-yl-ethyl)-piperidin-4-ylamine tri-hydrochloride (5) (2.1 g, 3.1 mmol) and DIEA (4.3 ml, 12.4 mmol) are dissolved under argon atmosphere in DMF (25 ml). TBTU (2.3 g, 3.4 mmol) is added at room temperature. The reaction mixture is stirred for 2 h at r.t., evaporated under high vacuum, dissolved in ethyl acetate and washed twice with 5% aqueous NaHCO3 solution. The organic layers are dried over sodium sulfate. Evaporation under reduced pressure gave 1.3 g (93%) of a beige solid.
Reaction SMILES: CN(C=O)C.[NH:6]1[C:39](=[O:40])[C@H:38]2[CH2:41][CH2:42][CH2:43][N:37]2[C:35](=[O:36])[C@H:27]([CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[NH:26][C:24](=[O:25])[C@H:16]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[NH:15][C:13](=[O:14])[C@@H:7]1[CH2:8][CH2:9][CH2:10][CH2:11][NH2:12].Cl.[C:45](OC(=O)C)(=[O:47])[CH3:46]>C(O)(=O)C>[NH:6]1[C:39](=[O:40])[C@H:38]2[CH2:41][CH2:42][CH2:43][N:37]2[C:35](=[O:36])[C@H:27]([CH2:28][C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[NH:26][C:24](=[O:25])[C@H:16]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[NH:15][C:13](=[O:14])[C@@H:7]1[CH2:8][CH2:9][CH2:10][CH2:11][NH:12][C:45]([CH3:46])=[O:47]
Reactant: CC(=O)OC(C)=O
Reactant: NCCCC[C@@H]1NC(=O)[C@H]2CCCN2C(=O)[C@H](Cc2ccccc2)NC(=O)[C@H](Cc2ccccc2)NC1=O
Agent: Cl
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CC(=O)NCCCC[C@@H]1NC(=O)[C@H]2CCCN2C(=O)[C@H](Cc2ccccc2)NC(=O)[C@H](Cc2ccccc2)NC1=O
Reaction time: 2 h

Procedure:
To a DMF (2 ml) solution of the cyclo(-L-Lys-L-Phe-L-Phe-D-Pro-).HCl (44 mg, 80 mmol) obtained in step 10-1, TEA(33 ml, 0.24 mmol) and acetic anhydride (12 ml, 0.12 mmol) were added under ice cooling and stirred for 2 hours. The reaction mixture was neutralized by addition of acetic acid and concentrated. The crude peptide was preparatively purified by reverse-phase HPLC (column: YMC-Pack ODS A-323, 10×250 mm, 30% CH3CH/0.1% TFA) and lyophilized to yield 57 mg (quant) of the titled compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=[C:11]([F:39])[C:12]=1[CH2:13][CH2:14][C:15]1[N:16]([C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=2)[C:17]([C:20]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([O:30][CH3:31])[CH:24]=2)([CH3:22])[CH3:21])=[CH:18][N:19]=1)[C:5]([O:7]CC)=[O:6].[OH-].[Na+]>CO.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=[C:11]([F:39])[C:12]=1[CH2:13][CH2:14][C:15]1[N:16]([C:32]2[CH:33]=[CH:34][C:35]([F:38])=[CH:36][CH:37]=2)[C:17]([C:20]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([O:30][CH3:31])[CH:24]=2)([CH3:22])[CH3:21])=[CH:18][N:19]=1)[C:5]([OH:7])=[O:6]
Reactant: CCOC(=O)c1cc(F)c(CCc2ncc(C(C)(C)c3ccc(Cl)c(OC)c3)n2-c2ccc(F)cc2)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1cc(C(C)(C)c2cnc(CCc3c(F)cc(C(=O)O)cc3Cl)n2-c2ccc(F)cc2)ccc1Cl
Reaction time: 1 h
Yield: 80.9 %

Procedure:
To a solution of ethyl 3-chloro-4-(2-(5-(2-(4-chloro-3-methoxyphenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazol-2-yl)ethyl)-5-fluorobenzoate (151 mg, 0.263 mmol) in MeOH (1.0 mL) was added dropwise a 2N solution of NaOH in H2O (0.5 mL). After stirring 1 h, the reaction mixture was concentrated under reduced pressure, diluted with H2O (1.5 mL), neutralized with 1N HCl and then extracted with DCM (10 mL×2). The combined extracts were dried (MgSO4), filtered and concentrated to give the title compound (116 mg, 81%) as gray solid. 1H NMR (400 MHz, DMSO) δ 7.69 (s, 1H), 7.57 (d, J=9.6 Hz, 1H), 7.27-7.17 (m, 2H), 7.05 (d, J=8.6 Hz, 1H), 7.03 (d, J=8.6 Hz, 1H), 6.69 (dd, J=8.6, 4.8 Hz, 2H), 6.54 (s, 1H), 6.53-6.48 (m, 1H), 3.69 (s, 3H), 2.94 (t, J=7.2 Hz, 2H), 2.57 (t, J=7.2 Hz, 2H), 1.48 (s, 6H).
Reaction SMILES: [CH:1]1([CH:6]([C:8]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[O:10][C:9]=2[CH3:19])O)[CH2:5][CH2:4][CH2:3][CH2:2]1.S(Cl)([Cl:22])=O>C1(C)C=CC=CC=1>[Cl:22][CH:6]([CH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)[C:8]1[CH:12]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[O:10][C:9]=1[CH3:19]
Reactant: Cc1oc(-c2ccccc2)cc1C(O)C1CCCC1
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: Cc1oc(-c2ccccc2)cc1C(Cl)C1CCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To a solution of cyclopentyl(2-methyl-5-phenylfuran-3-yl)methanol (0.9 g) in toluene (20 mL) was added thionyl chloride (0.5 mL), and the mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure to give the title compound (1.0 g, 100%) as an oil.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7](Cl)=[O:8].Cl.[CH2:11]([NH:14][CH:15]1[CH2:27][C:26]2[C:18](=[CH:19][C:20]3[CH2:24][CH2:23][O:22][C:21]=3[CH:25]=2)[CH2:17][CH2:16]1)[CH2:12][CH3:13]>C1C=CC=CC=1.C(N(CC)CC)C.O>[CH2:11]([N:14]([CH:15]1[CH2:27][C:26]2[C:18](=[CH:19][C:20]3[CH2:24][CH2:23][O:22][C:21]=3[CH:25]=2)[CH2:17][CH2:16]1)[C:7](=[O:8])[CH2:6][C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)[CH2:12][CH3:13]
Reactant: CCCNC1CCc2cc3c(cc2C1)OCC3
Reactant: O=C(Cl)Cc1cccs1
Agent: Cl
Solvent: c1ccccc1
Solvent: O
Solvent: CCN(CC)CC
Product: CCCN(C(=O)Cc1cccs1)C1CCc2cc3c(cc2C1)OCC3
Temperature: 25 °C
Reaction time: 3 h
Yield: 22 %

Procedure:
A solution of (2-thienyl)acetyl chloride in 15 ml of benzene is added dropwise to a solution of 13 g of the compound of Example 34 in 160 ml of benzene and 10.2 g of triethylamine. After being stirred at room temperature for 3 hours, the mixture is diluted with water, extracted with anhydrous sodium acetate and then evaporated under vacuum. After passage through a silica column using a mixture of methylene chloride and ethyl acetate (95:5) as eluant, 4 g of oil are obtained.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[C:19]([N:21]3[C:29]4[C:24](=[CH:25][C:26]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:27][CH:28]=4)[CH2:23][CH2:22]3)[N:18]=[CH:17][N:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:33][S:30]([C:26]1[CH:25]=[C:24]2[C:29](=[CH:28][CH:27]=1)[N:21]([C:19]1[N:18]=[CH:17][N:16]=[C:15]([NH:14][CH:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)[CH:20]=1)[CH2:22][CH2:23]2)(=[O:32])=[O:31]
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2cc(N3CCc4cc(S(C)(=O)=O)ccc43)ncn2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)c1ccc2c(c1)CCN2c1cc(NC2CCNCC2)ncn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 17 %

Procedure:
The solution of 6b obtained above was diluted with 5 mL of DCM and trifluoroacetic acid (5 mL, 60 eq) was added. The reaction mixture was stirred at room temperature for 2 h then concentrated under a stream of nitrogen overnight and purified on preparative HPLC to afford 104 mg (17%) of 6c.
Reaction SMILES: C[O:2][C:3](=[O:31])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:13][N:12]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([C@@H:21]4[O:26][C:25]5[CH:27]=[CH:28][CH:29]=[CH:30][C:24]=5[O:23][CH2:22]4)=[CH:17][CH:16]=3)[CH2:11]2)=[CH:6][CH:5]=1.O.[OH-].[Li+].Cl>O1CCOCC1.O>[O:26]1[C:25]2[CH:27]=[CH:28][CH:29]=[CH:30][C:24]=2[O:23][CH2:22][C@@H:21]1[C:18]1[CH:19]=[CH:20][C:15]([CH2:14][N:12]2[CH2:13][CH:10]([C:7]3[CH:6]=[CH:5][C:4]([C:3]([OH:31])=[O:2])=[CH:9][CH:8]=3)[CH2:11]2)=[CH:16][CH:17]=1
Reactant: COC(=O)c1ccc(C2CN(Cc3ccc([C@H]4COc5ccccc5O4)cc3)C2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)c1ccc(C2CN(Cc3ccc([C@H]4COc5ccccc5O4)cc3)C2)cc1

Procedure:
A solution of 4-{1-[(S)-4-(2,3-Dihydro-benzo[1,4]dioxin-2-yl)-benzyl]-azetidin-3-yl}-benzoic acid methyl ester (prepared from Intermediate A and 4-Azetidin-3-yl-benzoic acid methyl ester according to General Method G) (504 mg, 1.21 mmol) and lithium hydroxide monohydrate (210 mg, 5.0 mmol) in 1,4-dioxane (10 mL) and water (1.0 mL) is stirred at 50° C. for 16 h. The mixture is neutralized with 1M HCl and concentrated. The residue is triturated with water to give the title compound 254 as a solid. (LC/MS method 16: ES+ m/z 402.5 [M+H]+, Rt=2.70 min)
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][OH:8].[C:9](=O)([O:20]C1C=CC([N+]([O-])=O)=CC=1)[O:10][C@@H:11]1[CH2:15][O:14][C@@H:13]2[C@H:16]([OH:19])[CH2:17][O:18][C@H:12]12>CN(C)C1C=CN=CC=1.C(Cl)Cl>[C:9](=[O:20])([O:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][Cl:1])[O:10][C@@H:11]1[CH2:15][O:14][C@@H:13]2[C@H:16]([OH:19])[CH2:17][O:18][C@H:12]12
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)O[C@@H]1CO[C@H]2[C@@H]1OC[C@H]2O
Reactant: OCCCCCCCl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: O=C(OCCCCCCCl)O[C@@H]1CO[C@H]2[C@@H]1OC[C@H]2O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of (3R,3aR,6R,6aR)-6-hydroxyhexahydrofuro[3,2-b]furan-3-yl 4-nitrophenyl carbonate (1.13 g, 3.63 mmol) in DCM (15 ml), (prepared as described in EXAMPLE 7, Step C), 6-chlorohexanol (596 mg, 4.36 mmol) and 4-dimethylaminopyridine (89 mg, 0.73 mmol) were added and the mixture was stirred at room temperature for 18 hrs. Then the mixture was diluted with DCM and washed with a 5% solution of sodium dihydrogen phosphate (20 ml). The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography (Biotage SP1, EtOAc/n-hexane from 12 to 80%), affording the title compound as colorless oil.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:7]=1[S:13][C@H:14]1[CH2:23][CH2:22][C@@H:21]2[C@@H:16]([CH2:17][C@@H:18]([C:28]([O:30]CC)=[O:29])[N:19](C(OC)=O)[CH2:20]2)[CH2:15]1)=[O:5])C.Cl>>[ClH:12].[C:4]([C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:7]=1[S:13][C@H:14]1[CH2:23][CH2:22][C@@H:21]2[C@@H:16]([CH2:17][C@@H:18]([C:28]([OH:30])=[O:29])[NH:19][CH2:20]2)[CH2:15]1)([OH:5])=[O:3]
Reactant: CCOC(=O)c1ccc(Cl)cc1S[C@H]1CC[C@H]2CN(C(=O)OC)[C@H](C(=O)OCC)C[C@H]2C1
Agent: Cl
Product: O=C(O)c1ccc(Cl)cc1S[C@H]1CC[C@H]2CN[C@H](C(=O)O)C[C@H]2C1
Yield: 139.5 %

Procedure:
The intermediate from step B (30 mg, 0.06 mmol) was treated with 6M hydrochloric acid under reflux for 60 h. The solution was cooled down and concentrated in vacuo; followed by washing the resulting solid with acetone (3×5 mL), to give an off-white solid (17 mg, 68%)