Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:4]=1[C@H:10]1[CH2:14][C:13]([F:16])([F:15])[CH2:12][NH:11]1.Br[C:18]1[CH:23]=[CH:22][N:21]2[N:24]=[CH:25][C:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[C:20]2[CH:19]=1>>[F:2][C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:4]=1[CH:10]1[CH2:14][C:13]([F:15])([F:16])[CH2:12][N:11]1[C:18]1[CH:23]=[CH:22][N:21]2[N:24]=[CH:25][C:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[C:20]2[CH:19]=1
Reactant: Fc1ccc(F)c([C@H]2CC(F)(F)CN2)c1
Reactant: CCOC(=O)c1cnn2ccc(Br)cc12
Agent: Cl
Product: CCOC(=O)c1cnn2ccc(N3CC(F)(F)CC3c3cc(F)ccc3F)cc12

Procedure:
The title compound (Int-72) was prepared by the method similar to that for Int-84 using (R)-2-(2,5-difluorophenyl)-4,4-difluoropyrrolidine hydrochloride and Ethyl 5-bromopyrazolo[1,5-a]pyridine-3-carboxylate to afford as yellow solid. LCMS (ESI): m/z 408.1 (M+H).
Reaction SMILES: [CH2:1]([N:5]1[C:10](=[O:11])[C:9]([C:12]2[NH:13][S:14](=[O:24])(=[O:23])[C:15]3[CH:21]=[C:20]([OH:22])[CH:19]=[CH:18][C:16]=3[N:17]=2)=[C:8]([OH:25])[C:7]([CH:26]([CH3:28])[CH3:27])=[N:6]1)[CH2:2][CH2:3][CH3:4].Br[CH2:30][C:31]([NH2:33])=[O:32].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH2:1]([N:5]1[C:10](=[O:11])[C:9]([C:12]2[NH:13][S:14](=[O:24])(=[O:23])[C:15]3[CH:21]=[C:20]([O:22][CH2:30][C:31]([NH2:33])=[O:32])[CH:19]=[CH:18][C:16]=3[N:17]=2)=[C:8]([OH:25])[C:7]([CH:26]([CH3:27])[CH3:28])=[N:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: NC(=O)CBr
Reactant: CCCCn1nc(C(C)C)c(O)c(C2=Nc3ccc(O)cc3S(=O)(=O)N2)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCn1nc(C(C)C)c(O)c(C2=Nc3ccc(OCC(N)=O)cc3S(=O)(=O)N2)c1=O
Temperature: 80 °C
Yield: 49.2 %

Procedure:
To a solution of 2-Butyl-5-hydroxy-4-(7-hydroxy-1,1-dioxo-1,2-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-6-isopropyl-2H-pyridazin-3-one (5f) (38.7 mg, 95.2 μmol) in anhydrous DMF (4 mL), 2-Bromo-acetamide (14.5 mg, 104.7 μmol) was added followed by K2CO3 (39.5 mg, 285.6 μmol). The resulted mixture was heated at 80° C. overnight with stirring. The reaction mixture was concentrated under reduced vacuum and the residue was purified by flash chromatography on silica gel to give the desired product (5g) (21.7 mg) in 49.2% yield. 1H NMR (400 MHz, DMSO-d6): δ7.63-7.66 (m, 1H), 7.62 (br, 1 H), 7.40 (br, 1H), 7.34-7.39 (m, 2 H), 4.58 (s, 2H), 4.10 (m, 2H), 3.23 (m, 1H, J=6.8 Hz), 1.72 (m, 2H, J=7.2 Hz), 1.32 (m, 2H. J=7.2 Hz), 1.21 (d, 6H, J=6.4 Hz), 0.91 (t, 3H, J=7.2 Hz); LC-MS (ESI+): m/e=464.1-[M+1]+ (exact MS: 463.15).
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[Br:5][C:6]1[CH:7]=[C:8]2[CH:14]=[CH:13][NH:12][C:9]2=[N:10][CH:11]=1.[C:15](Cl)(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>ClCCl>[Br:5][C:6]1[CH:7]=[C:8]2[C:14]([C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:22])=[CH:13][NH:12][C:9]2=[N:10][CH:11]=1
Reactant: Brc1cnc2[nH]ccc2c1
Reactant: O=C(Cl)c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C(c1ccccc1)c1c[nH]c2ncc(Br)cc12
Reaction time: 0.75 h
Yield: 40 %

Procedure:
To a suspension of AlCl3 (338 mg, 2.54 mmol) in dichloromethane (10 mL) was added 5-bromo-1H-pyrrolo[2,3-b]pyridine (100 mg, 0.507 mmol). After stirring for 45 min, benzoyl chloride (0.3 mL, 2.54 mmol) was added and the reaction mixture was stirred for 3 h, before quenching with MeOH at 0° C. The mixture was concentrated in vacuum, the pH was changed to 4 by addition of 1N aqueous NaOH, and the aqueous layer was extracted twice with EtOAc. The organic layer was dried over MgSO4, filtered and adsorbed on silica gel. Purification on silica gel with a gradient of EtOAc/hexanes afforded (5-bromo-1H-pyrrolo[2,3-b]pyridine-3-yl)-phenyl-methanone as a white solid (61 mg, 40% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:14]=1[NH:13][C:12]1[C:11](=[O:15])[CH2:10][CH2:9][CH2:8][C:7]2=1.[CH3:16][CH:17]([S:19](Cl)(=[O:21])=[O:20])[CH3:18]>N1C=CC=CC=1>[O:15]=[C:11]1[C:12]2[NH:13][C:14]3[C:6](=[CH:5][CH:4]=[CH:3][C:2]=3[NH:1][S:19]([CH:17]([CH3:18])[CH3:16])(=[O:21])=[O:20])[C:7]=2[CH2:8][CH2:9][CH2:10]1
Reactant: Nc1cccc2c3c([nH]c12)C(=O)CCC3
Reactant: CC(C)S(=O)(=O)Cl
Solvent: c1ccncc1
Product: CC(C)S(=O)(=O)Nc1cccc2c3c([nH]c12)C(=O)CCC3
Temperature: 25 °C
Reaction time: 2 h
Yield: 19 %

Procedure:
To a mixture of 8-amino-2,3,4,9-tetrahydro-1H-carbazol-1-one (0.35 g) and pyridine (8 mL) was added propane-2-sulfonyl chloride (0.24 mL) at 0° C., and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated, 10% aqueous citric acid solution was added, and the resulting crystals were filtrated, washed with water and dried. The obtained crystals were subjected to silica gel column chromatography and the title compound (1.94 g, yield 19%) was obtained as colorless crystals from a fraction eluted with tetrahydrofuran-hexane (1:1, volume ratio). The crystals were recrystallized from ethyl acetate. melting point 267-268° C.
Reaction SMILES: S(Cl)(Cl)=O.C[N:6](C)[CH:7]=[O:8].[CH3:10][C:11]1[N:15]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][N:17]=2)[N:14]=[CH:13][C:12]=1C(O)=O>C1(C)C=CC=CC=1>[CH3:10][C:11]1[N:15]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:23])[F:24])=[CH:18][N:17]=2)[N:14]=[CH:13][C:12]=1[C:7]([NH2:6])=[O:8]
Reactant: CN(C)C=O
Reactant: Cc1c(C(=O)O)cnn1-c1ccc(C(F)(F)F)cn1
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: Cc1c(C(N)=O)cnn1-c1ccc(C(F)(F)F)cn1
Temperature: 80 °C

Procedure:
Thionyl chloride (3.95 g) and N,N-dimethylformamide (catalytic amounts) were added at room temperature to 5-methyl-1-[5-(trifluoromethyl)pyridin-2-yl]-1H-pyrazole-4-carboxylic acid (3.0 g) described in Reference Example 8 in toluene (55 ml), and stirred at 80° C. for an hour. The solvent and an excess amount of thionyl chloride were evaporated, tetrahydrofuran (55 ml) was added to the residue, 25% aqueous ammonia (44 ml) was added under ice-cooling and stirred at room temperature for two hours. After the reaction, 1N aqueous solution of sodium hydroxide was added, and the precipitated solid was filtered to give 5-methyl-1-[5-(trifluoromethyl)pyridin-2-yl]-1H-pyrazole-4-carboxamide (2.9 g) as a white solid.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][C:12](=O)[NH:11][C@H:10]([CH2:15][O:16][CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][O:18]2)[C:9]1=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH2:1]([N:8]1[CH2:13][CH2:12][NH:11][C@H:10]([CH2:15][O:16][CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][O:18]2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CN(Cc2ccccc2)C(=O)[C@@H](COC2CCCCO2)N1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: c1ccc(CN2CCN[C@H](COC3CCCCO3)C2)cc1
Reaction time: 1 h
Yield: 102.4 %

Procedure:
To a 0° C. suspension of compound 32 (1.153 g, 3.62 mmol) in dry THF (60 mL) on ice was added LiAlH4 (0.566 g, 14.89 mmol). The mixture was then heated at reflux for 2 h. The solution was cooled, stirred 1 h then the excess LiAlH4 was quenched by the sequential addition of 0.6 mL water, 1.2 mL 4 M NaOH solution and 0.6 mL water. The solids that formed will filtered (Celite) and the filtrate concentrated to give 33 as a pale colored oil (1.076 g, 99% yield). 1H NMR (400 MHz, CDCl3): δ 1.44-1.62 (m, 4H), 1.64-1.74 (m, 1H), 1.74-1.94 (m, 2H), 2.08-2.17 (m, 1H), 2.35 (bs, 1H, NH), 2.71-2.79 (m, 2H), 2.87-2.95 (m, 1H), 2.95-3.08 (m, 2H), 3.26 (m, 0.5H), 3.36 (dd, J=4.0, 9.9 Hz, 0.5H), 3.45-3.52 (m, 3H), 3.61-3.73 (m, 1H), 3.78-3.86 (m, 1H), 4.56 (m, 1H); 3C NMR (100 MHz, CDCl3): δ 19.4, 19.5, 25.3, 30.5, 45.1, 53.4, 53.5, 54.5, 54.7, 55.7, 62.2, 62.4, 63.3, 69.5, 69.9, 98.8, 99.5, 127.0, 128.2, 129.1, 137.9.
Reaction SMILES: [CH:1]1[C:6]2[C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[CH2:9][CH2:10][CH2:11][C:5]=2[C:4]([C:16]#[N:17])=[CH:3][CH:2]=1.Cl.C([OH:21])C>[OH-].[Na+]>[CH:1]1[C:6]2[C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[CH2:9][CH2:10][CH2:11][C:5]=2[C:4]([C:16]([NH2:17])=[O:21])=[CH:3][CH:2]=1
Reactant: CCO
Reactant: N#Cc1cccc2c1CCCc1ccccc1-2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: NC(=O)c1cccc2c1CCCc1ccccc1-2

Procedure:
Under a dry nitrogen atmosphere a stirred mixture of 6,7-dihydro-5H-dibenzo[a,c]cyclohepten-4-carbonitrile (1.0 gram, 0.0045 mole) in ethanol (20 ml) and 10% aqueous sodium hydroxide (20 ml) was heated at reflux for two days. The mixture was cooled and poured into dilute hydrochloric acid (150 ml). The resulting mixture was extracted with five 100 ml portions of methylene chloride and the extracts combined. The combined extracts were washed with two 100 ml portions of water, dried over anhydrous magnesium sulfate and filtered. The solvent was removed from the filtrate by distillation under reduced pressure to leave 6,7-dihydro-5H-dibenzo[a,c]cyclohepten-4-carboxamide as a white solid (1.1 grams, mp>250°).
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:5][CH:4]=1)=O.[H][H]>C1C=CC=CC=1>[CH3:1][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:5][CH:4]=1
Reactant: [H][H]
Reactant: O=Cc1ccc(-c2ccccc2)cc1
Solvent: c1ccccc1
Product: Cc1ccc(-c2ccccc2)cc1

Procedure:
5 g/hr of the solution dissolved 10% by weight of 4-formylbiphenyl in a benzene was continuously fed in the hydrogenation reactor, while keep the hydrogen pressure under 10 atm and the reaction temperature at 130° C. Product water was removed from the reaction product solution by phase separation and then benzene was distilled off to obtain 4-methylbiphenyl. The conversion of 4-formylbiphenyl was 99.3% and the selectivity to 4-methylbiphenyl was 99.0% by mole. A small amount of 4-biphenylmethanol and high boiling point products was further contained in 4-methylbiphenyl. Product water was separated from the reaction product solution and then the 4-biphenylmethanol and high boiling point by-products were removed by distillation, whereby 4-methylbiphenyl with a purity of 98% by weight or above was obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([NH2:13])=[O:12])=[C:5]2[S:14]([N:17]1[C:21](O)=[CH:20][CH:19]=[C:18]1O)(=[O:16])=[O:15].ClC1C=C(C=CC=1)C(OO)=[O:29].O1CCCC1>CC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([NH2:13])=[O:12])=[C:5]2[S:14]([N:17]1[CH2:18][C@@H:19]2[C@@H:20]([O:29]2)[CH2:21]1)(=[O:16])=[O:15]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: NC(=O)c1[nH]c2ccc(Br)cc2c1S(=O)(=O)n1c(O)ccc1O
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: NC(=O)c1[nH]c2ccc(Br)cc2c1S(=O)(=O)N1C[C@@H]2O[C@@H]2C1
Reaction time: 3 h

Procedure:
To a stirring suspension of 5-bromo-3-(2,5-dihydroxy-1H-pyrrol-1-ylsulfonyl)-1H-indole-2-carboxamide (10 mg, 0.027 mmol, 1.0 equiv.) in 2 mL of acetone was added m-chloroperoxybenzoic acid (6.5 mg, 0.038 mmol, 1.4 equiv.). After stirring for 3 hours, 3 mL of tetrahydrofuran and m-chloroperoxybenzoic acid (6.5 mg, 0.038 mmol, 1.4 equiv.) were added. After stirring an additional 72 hours, more m-chloroperoxybenzoic acid (13 mg, 0.076 mmol, 2.8 equiv.) was added and, after 3 hours, the solvent was removed in vacuo. The title compound was obtained after purification by preparative reversed phase HPLC. Proton NMR for the product was consistent with the titled compound. ESI+MS: 385.96 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:16]([CH2:17][C:18]([OH:20])=O)[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.[C:21](N1C=CN=C1)([N:23]1C=CN=C1)=O.CN>O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:16]([CH2:17][C:18]([NH:23][CH3:21])=[O:20])[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)Cn1c(-c2ccc(F)cc2)nc2cccnc21
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CN
Solvent: C1CCOC1
Product: CNC(=O)Cn1c(-c2ccc(F)cc2)nc2cccnc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 43.9 %

Procedure:
A mixture of 2-(4-fluorophenyl)-3H-imidazo[4,5-b]pyridine-3-acetic acid (5.0 g, 0.01845 mole) and 1,1'-carbonyldiimidazole (2.99 g, 0.01845 mole) was stirred at room temperature in dry tetrahydrofuran (100 ml) for three hours with a stream of nitrogen bubbling through it. A solution of methylamine in tetrahydrofuran (37 ml of a 3.03M solution, 0.111 mole) was added and the reaction mixture was stirred at room temperature under nitrogen overnight. The solvents were removed under reduced pressure and the residue was triturated in water (100 ml). The solid was collected by filtration, rinsed twice with water, twice with a 5% potassium hydroxide solution and twice again with water. The solid was dissolved in hot isopropyl alcohol, filtered hot, cooled to room temperature and isopropyl ether was added to the cloud point. The resulting solid was collected by filtration, rinsed with isopropyl ether, and dried under high vacuum at 42° C. overnight to give 2.30 g (44%) of title compound, mp. 215°- 217° C.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:10][C@H:9]([CH3:11])[N:8]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[CH2:7][C@H:6]1[CH3:20])=[O:4].[CH2:21]([O:23][C:24](=[O:34])[CH2:25][C:26]1[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:27]=1[OH:33])[CH3:22].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(=O)CC.C(OCC)(=O)C>[CH2:21]([O:23][C:24](=[O:34])[CH2:25][C:26]1[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:27]=1[O:33][CH2:2][C:3]([N:5]1[CH2:10][C@H:9]([CH3:11])[N:8]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[CH2:7][C@H:6]1[CH3:20])=[O:4])[CH3:22]
Reactant: C[C@@H]1CN(Cc2ccc(F)cc2)[C@@H](C)CN1C(=O)CCl
Reactant: CCOC(=O)Cc1cc(Cl)ccc1O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCC(C)=O
Product: CCOC(=O)Cc1cc(Cl)ccc1OCC(=O)N1C[C@H](C)N(Cc2ccc(F)cc2)C[C@H]1C
Yield: 97.8 %

Procedure:
To a solution of 2-chloro-1-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1-yl]-ethanone (3.3 g, 11.0 mmol) in 2-butanone (100 mL) was added (5-chloro-2-hydroxy-phenyl)-acetic acid ethyl ester (2.3 g, 11.0 mmol), potassium carbonate (3.05 g, 22.1 mmol), and potassium iodide (1.83 g, 11.0 mmol). The reaction was heated at reflux for 48 hrs. The solution was cooled, diluted with ethyl acetate and washed with brine. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The crude product was purified by dissolving in dichloromethane and passing through a pad of silica gel. Concentration in vacuo gave the title compound (5.13 g).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:43]=[CH:42][C:12]([O:13][CH2:14][C@@H:15]([OH:41])[CH2:16][N:17]([CH2:25][CH2:26][C:27]2[CH:32]=[CH:31][C:30]([NH:33][CH:34]3[S:38][C:37](=[O:39])[NH:36][C:35]3=[O:40])=[CH:29][CH:28]=2)C(=O)OC(C)(C)C)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([O:13][CH2:14][C@@H:15]([OH:41])[CH2:16][NH:17][CH2:25][CH2:26][C:27]2[CH:28]=[CH:29][C:30]([NH:33][CH:34]3[S:38][C:37](=[O:39])[NH:36][C:35]3=[O:40])=[CH:31][CH:32]=2)=[CH:42][CH:43]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N(CCc1ccc(NC2SC(=O)NC2=O)cc1)C[C@H](O)COc1ccc(OCc2ccccc2)cc1
Solvent: O=C(O)C(F)(F)F
Product: O=C1NC(=O)C(Nc2ccc(CCNC[C@H](O)COc3ccc(OCc4ccccc4)cc3)cc2)S1
Yield: 58 %

Procedure:
This compound was prepared from tert-butyl (2 S)-3-[4-(benzyloxy)phenoxy]-2-hydroxypropyl{4-[(2,4-dioxo-1,3-thiazolidin-5-yl)amino]phenethyl}carbamate and trifluoroacetic acid in substantially the same manner as described in example 1, step e, with one modification, the product was isolated as the free base and recrystallized from methanol, tetrahydrofuran, hexanes to give a yellow foam solid (58% yield): mp 152° C.; MS m/e 508 (M+H)+; 1H NMR (DMSO-d6 300 MHz) δ2.68 (m, 2 H), 2.81 (m, 1 H), 2.88 (m, 4 H), 3.85 (m, 2 H), 4.00 (m, 1 H), 5.02 (s, 2 H), 5.45 (br, 1 H), 5.99 (d, 1 H), 6.59 (d, 2 H), 6.66 (d, 1 H), 6.84 (d, 2 H), 6.86 ( m, 2 H) 6.92 (m, 2 H), 7.28 (m, 5 H), 8.80 (br, 1 H);
Reaction SMILES: [NH2:1][C:2]1[C:16]([CH2:17][NH:18][CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)=[CH:15][C:5]([C:6]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]Cl)=[O:7])=[CH:4][C:3]=1[Br:25].[Cl:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([Cl:33])[C:28]=1[NH:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[CH2:41][C:42]([O-:44])=[O:43].[Na+]>>[NH2:1][C:2]1[C:16]([CH2:17][NH:18][CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)=[CH:15][C:5]([C:6]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][O:44][C:42](=[O:43])[CH2:41][C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=2[NH:34][C:28]2[C:27]([Cl:26])=[CH:32][CH:31]=[CH:30][C:29]=2[Cl:33])=[O:7])=[CH:4][C:3]=1[Br:25]
Reactant: O=C([O-])Cc1ccccc1Nc1c(Cl)cccc1Cl
Reactant: Nc1c(Br)cc(C(=O)OCCCCCCl)cc1CNC1CCCCC1
Agent: [Na+]
Product: Nc1c(Br)cc(C(=O)OCCCCCOC(=O)Cc2ccccc2Nc2c(Cl)cccc2Cl)cc1CNC1CCCCC1

Procedure:
This compound was prepared from 5-(4-amino-3-bromo-5-cyclohexylaminomethyl-benzoyloxy)-n-pentyl chloride and sodium 2-[(2,6-dichlorophenyl)-amino]-phenylacetate analogous to Example 8.
Reaction SMILES: [C:1]1(=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:7][C@H:8]1[CH2:19][O:18][C:17](=[O:20])[C:16]2[CH:21]=[C:22]([O:33][Si](C(C)(C)C)(C)C)[CH:23]=[C:24]([O:25][Si](C(C)(C)C)(C)C)[C:15]=2[CH2:14][S:13][CH2:12][C@@H:11]([C:41]([O:43][CH3:44])=[O:42])[NH:10][C:9]1=[O:45]>>[CH:1]1([NH:7][C@H:8]2[CH2:19][O:18][C:17](=[O:20])[C:16]3[CH:21]=[C:22]([OH:33])[CH:23]=[C:24]([OH:25])[C:15]=3[CH2:14][S:13][CH2:12][C@@H:11]([C:41]([O:43][CH3:44])=[O:42])[NH:10][C:9]2=[O:45])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C1CCCC1
Reactant: COC(=O)[C@@H]1CSCc2c(O[Si](C)(C)C(C)(C)C)cc(O[Si](C)(C)C(C)(C)C)cc2C(=O)OC[C@H](N)C(=O)N1
Product: COC(=O)[C@@H]1CSCc2c(O)cc(O)cc2C(=O)OC[C@H](NC2CCCC2)C(=O)N1

Procedure:
Operating in an analogues manner as described in Example 150, but replacing acetone by cyclopentanone, and using the product of Example 112 (a) as starting material, there was obtained methyl (4R, 7S)-7-(cyclopentylamino)-1,3,4,5,6,7,8,10-octahydro-12,14-dihydroxy-6,10-dioxo-9,2,5-benzoxathiaazacyclododecine-4-carboxylate.
Reaction SMILES: [CH3:1][NH:2][CH3:3].Cl[C:5]([CH:7]([CH3:29])[CH2:8][CH2:9][N:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[C:18]([CH3:19])[C:13]=2[N:12]=[C:11]1[CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=1)=[O:6]>CO>[CH3:1][N:2]([CH3:3])[C:5]([CH:7]([CH3:29])[CH2:8][CH2:9][N:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[C:18]([CH3:19])[C:13]=2[N:12]=[C:11]1[CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=1)=[O:6]
Reactant: Cc1cccc2c1nc(COc1ccc(Cl)cc1)n2CCC(C)C(=O)Cl
Reactant: CNC
Solvent: CO
Product: Cc1cccc2c1nc(COc1ccc(Cl)cc1)n2CCC(C)C(=O)N(C)C
Temperature: 25 °C
Reaction time: 64 h
Yield: 63 %

Procedure:
In an dimethylamine (40% in water, 10 ml) was placed 1-[3-(chlorocarbonyl)butyl]-2-[(4-chlorophenoxy)methyl]-4-methylbenzimidazole (600 mg, 1.5 mmol). To this mixture 10 ml of methanol were added, to enhance solubility and the mixture was stirred for about 64 hours at room temperature. The reaction mixture was then concentrated under reduced pressure to produce 600 mg as a tan foam. The crude material was further purified by flash silica gel chromatography, eluting with a gradient solvent of 19:1 ethyl acetate:methanol to 9:1 ethyl acetate:methanol. The fractions containing the desired material were combined and concentrated in vacuo to yield 375 mg (63%) of the desired title compound as a white foam.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]=[C:12]([N:32]2[CH2:36][CH:35]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[C:34]([C:43]3[CH:48]=[CH:47][C:46]([Cl:49])=[CH:45][CH:44]=3)=[N:33]2)[NH:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)(OC)[O:21]C)(=[O:10])=[O:9])=[CH:4][CH:3]=1>C1COCC1.CO.Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]=[C:12]([N:32]2[CH2:36][CH:35]([C:37]3[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=3)[C:34]([C:43]3[CH:44]=[CH:45][C:46]([Cl:49])=[CH:47][CH:48]=3)=[N:33]2)[NH:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)=[O:21])(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: COC(CCCCCCNC(=NS(=O)(=O)c1ccc(Cl)cc1)N1CC(c2ccccc2)C(c2ccc(Cl)cc2)=N1)(OC)c1ccc(F)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: O=C(CCCCCCNC(=NS(=O)(=O)c1ccc(Cl)cc1)N1CC(c2ccccc2)C(c2ccc(Cl)cc2)=N1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 115.8 %

Procedure:
Part B: 4-Chloro-N-{[3-(4-chlorophenyl)-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl]-[7-(4-fluoro-phenyl)-7,7-dimethoxyheptylamino] methylene}-benzenesulfonamide (0.200 g, 0.258 mmol) was dissolved in a 1:1 mixture of THF/methanol (30 ml) and 1 N hydrochloric acid (5 ml) was added and the resulting mixture was stirred at room temperature for 20 hours. The mixture was quenched with 5% aqueous NaHCO3. Most of the THF and methanol were removed by evaporation in vacuo. The remaining water layer was twice extracted with ethylacetate. The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The obtained crude 4-chloro-N-{[3-(4-chlorophenyl)-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl]-[7-(4-fluorophenyl)-7-oxo-heptylamino] methylene}benzenesulfonamide (203 mg) was not further purified. Some characteristic aromatic 1H-NMR signals are: (400 MHz, CDCl3) δ 7.12 (d, J˜8, 2H), 7.22-7.33 (m, 5H) 7.39 (d, J˜8, 2H), 7.50 (d, J˜8, 2H), 7.72 (d, J˜8, 2H), 7.84 (d, J˜8, 2H), 8.05 (d, J˜8, 2H).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][C:11]1[N:12]([CH2:22][C:23](O)=[O:24])[C:13]2[C:18]([C:19](=[O:21])[N:20]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2.[CH3:26][C:27]([N:34]1[CH2:39][CH2:38][CH:37]([NH:40][CH2:41][C:42]2[CH:47]=[CH:46][C:45]([C:48]3[CH:53]=[CH:52][C:51]([O:54][C:55]([F:58])([F:57])[F:56])=[CH:50][CH:49]=3)=[CH:44][CH:43]=2)[CH2:36][CH2:35]1)([CH3:33])[C:28]([O:30][CH2:31][CH3:32])=[O:29].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][C:11]1[N:12]([CH2:22][C:23]([N:40]([CH2:41][C:42]2[CH:47]=[CH:46][C:45]([C:48]3[CH:49]=[CH:50][C:51]([O:54][C:55]([F:57])([F:56])[F:58])=[CH:52][CH:53]=3)=[CH:44][CH:43]=2)[CH:37]2[CH2:36][CH2:35][N:34]([C:27]([CH3:26])([CH3:33])[C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:39][CH2:38]2)=[O:24])[C:13]2[C:18]([C:19](=[O:21])[N:20]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2
Reactant: CCOC(=O)C(C)(C)N1CCC(NCc2ccc(-c3ccc(OC(F)(F)F)cc3)cc2)CC1
Reactant: O=C(O)Cn1c(CCc2cccc(F)c2F)nc(=O)c2ccccc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)N1CCC(N(Cc2ccc(-c3ccc(OC(F)(F)F)cc3)cc2)C(=O)Cn2c(CCc3cccc(F)c3F)nc(=O)c3ccccc32)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 73.5 %

Procedure:
A mixture of [2-[2-(2,3-difluorophenyl)ethyl]-4-oxo-1(4H)-quinazolinyl]acetic acid (Int. C1) (124 mg, 1.2 equiv), ethyl 2-methyl-2-{4-[({4′-[(trifluoromethyl)oxy]-4-biphenylyl}methyl)amino]-1-piperidinyl}propanoate (Int. B3) (139 mg, 1 equiv), DMF (1.2 ml) and DIPEA (0.16 ml, 3 equiv) was shaken at room temperature for 30 min, then HATU (176 mg, 1.5 equiv) was added and shaking continued for 4 h. Reverse phase HPLC (Preparative Method B) gave ethyl 2-{4-[{[2-[2-(2,3-difluorophenyl)ethyl]-4-oxo-1(4H)-quinazolinyl]acetyl}({4′-[(trifluoromethyl)oxy]-4-biphenylyl}methyl)amino]-1-piperidinyl}-2-methylpropanoate as a white solid (174 mg).