Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C@H:11]([C:12]3[CH:17]=[CH:16][C:15]([C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([OH:24])[CH:19]=4)=[CH:14][CH:13]=3)[C@@H:10]([CH2:25][CH2:26][C@@H:27]([C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=3)[OH:28])[C:9]2=[O:36])=[CH:4][CH:3]=1.[Br-:37].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.S([O-])([O-])(=O)=S.[Na+].[Na+].C(#N)C>C(Cl)(Cl)Cl.O>[Br:37][C:23]1[CH:22]=[CH:21][C:20]([OH:24])=[CH:19][C:18]=1[C:15]1[CH:14]=[CH:13][C:12]([C@H:11]2[N:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[C:9](=[O:36])[C@@H:10]2[CH2:25][CH2:26][C@@H:27]([C:29]2[CH:30]=[CH:31][C:32]([F:35])=[CH:33][CH:34]=2)[OH:28])=[CH:17][CH:16]=1
Reactant: [Br-]
Reactant: O=C1[C@H](CC[C@H](O)c2ccc(F)cc2)[C@@H](c2ccc(-c3cccc(O)c3)cc2)N1c1ccc(F)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: O
Solvent: CC#N
Solvent: ClC(Cl)Cl
Product: O=C1[C@H](CC[C@H](O)c2ccc(F)cc2)[C@@H](c2ccc(-c3cc(O)ccc3Br)cc2)N1c1ccc(F)cc1
Reaction time: 0.17 h
Yield: 35.4 %

Procedure:
(3R,4S)-1-(4-Fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-(3′-hydroxybiphenyl-4-yl)azetidin-2-one (19.2 mg, 0.04 mmol) was dissolved in chloroform (0.4 mL) and tetrabutylammonium tribromide (18.8 mg, 0.04 mmol) was added at room temperature. After 10 minutes, saturated aqueous sodium thiosulfate (2 mL) was added to quench the reaction. The mixture was poured into a seperatory funnel, extracted with dichloromethane (4×10 mL), dried over sodium sulfate, filtered and concentrated. (3R,4S)-4-(2′-bromo-5′-hydroxybiphenyl-4-yl)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]azetidin-2-one was purified by chromatography (12 g silica gel, 5% to 95% ethyl acetate-hexane) and then by reverse-phase HPLC (21 mm column, 50% to 100% acetonitrile-0.1% trifluoroacetic acid in water) to afford (3R,4S)-4-(2′-bromo-5′-hydroxybiphenyl-4-yl)-1-(4-fluorophenyl)-3-[(3S)-3-(4-fluorophenyl)-3-hydroxypropyl]azetidin-2-one (8.0 mg, 34% yield) as a clear foam; Rf 0.51 (50% ethyl acetate-hexane); 1H NMR (300 MHz, CDCl3) δ 7.49 (d, J=8.7 Hz, 1H), 7.40 (m, 4H), 7.29 (m, 4H), 7.02 (t, J=8.7 Hz, 2H), 6.95 (t, J=8.7 Hz, 2H), 6.80 (d, J=3.3, 1H), 6.73 (dd, J=3.0, 3.0 Hz, 1H), 4.74 (t, J=6.2 Hz, 2H), 4.67 (d, J=2.1 Hz, 1H), 3.14 (m, 1H) 1.99 (m, 4H) ppm; MS [M−OH] 547.4.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][CH:9]=1)[NH2:6].[CH3:10][C:11]([CH3:18])([CH3:17])[C:12](=O)[C:13]([OH:15])=[O:14].C(O)(=O)C.[B-]C#N.[Na+]>CO.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:6][CH:12]([C:11]([CH3:18])([CH3:17])[CH3:10])[C:13]([OH:15])=[O:14])[CH:7]=[CH:8][CH:9]=1
Reactant: CC(C)(C)C(=O)C(=O)O
Reactant: COc1cccc(N)c1
Agent: [B-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Solvent: O
Product: COc1cccc(NC(C(=O)O)C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 15.8 %

Procedure:
To a mixture of 3-methoxyaniline (100 mg, 0.812 mmol) and trimethylpyruvic acid (211 mg, 1.624 mmol) in methanol (3 mL) at rt was added acetic acid (0.930 mL, 16.24 mmol). The mixture was stirred for 30 min at rt then heated at 70° C. for 2 hrs. The mixture was cooled down to rt before adding sodium cyanotrihydroborate (1.624 mL, 1.624 mmol). The mixture was stirred overnight at rt. Water (10 mL) was added, and the mixture was extracted with ethyl acetate (3×10 mL). The organic layer was washed with sat. NaHCO3 and brine solution, and then dried over Na2SO4, filtered, and evaporated to dryness. The residue was purified by preparative HPLC to get a white solid (30.5 mg, 16%) as product.
Reaction SMILES: [C:1]1([O:7][P:8]([CH2:17][NH:18][C@@H:19]([CH2:28][C:29]2[CH:34]=[CH:33][C:32]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[CH:31][CH:30]=2)[C:20]([NH:22][CH2:23][CH2:24][C:25]([OH:27])=[O:26])=[O:21])([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.Cl[CH2:49][C:50]([N:52]([CH2:55][CH3:56])[CH2:53][CH3:54])=[O:51].[I-].[Na+]>C(OCC)(=O)C>[C:1]1([O:7][P:8]([CH2:17][NH:18][C@@H:19]([CH2:28][C:29]2[CH:30]=[CH:31][C:32]([C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)=[CH:33][CH:34]=2)[C:20]([NH:22][CH2:23][CH2:24][C:25]([O:27][CH2:49][C:50](=[O:51])[N:52]([CH2:55][CH3:56])[CH2:53][CH3:54])=[O:26])=[O:21])([O:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)CCNC(=O)[C@H](Cc1ccc(-c2ccccc2)cc1)NCP(=O)(Oc1ccccc1)Oc1ccccc1
Reactant: CCN(CC)C(=O)CCl
Agent: [I-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCN(CC)C(=O)COC(=O)CCNC(=O)[C@H](Cc1ccc(-c2ccccc2)cc1)NCP(=O)(Oc1ccccc1)Oc1ccccc1

Procedure:
To a stirred solution of (S)-N-[2-(diphenylphosphonomethylamino)-3-(4-biphenylyl)-propionyl]-3-aminopropionic acid (0.6 g, 1.07 mmol) in ethyl acetate (9 mL) is added triethylamine (0.19 mL, 1.34 mmol) followed by 2-chloro-N,N-diethylacetamide (0.18 mL, 1.34 mmol) and sodium iodide (20 mg, 0.13 mmol). The solution is heated under nitrogen at 80° for 12 hours. The precipitate is filtered off and the filtrate is treated with water (10 mL) and 2N HCl (0.5 mL). The organic layer is separated, dried over sodium sulfate and filtered. After evaporation of the solvent under reduced pressure, the semi-solid residue is purified by flash chromatography on silica gel, eluting with ethyl acetate. The title compound is finally crystallized from ethyl acetate-hexane to yield N,N-diethylcarbamoylmethyl (S)-N-[2-(diphenylphosphonomethylamino)-3-(4-biphenylyl)-propionyl]-3-aminopropionate, m.p. 68°-74°, [α]D =-20.55 (c=0.84, CHCl3).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH:12]3[C:21]4[C:16](=[CH:17][CH:18]=[C:19]([O:22][CH2:23][CH2:24][NH:25][S:26]([CH2:29][CH2:30][CH3:31])(=[O:28])=[O:27])[CH:20]=4)[CH2:15][CH2:14][N:13]3/[C:32](/[NH:44]C(=O)OCC3C=CC=CC=3)=[N:33]/C(=O)OCC3C=CC=CC=3)[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C[O-].[Na+].Br[CH2:59][CH:60]([O:63][CH3:64])[O:61][CH3:62]>C(O)C>[CH3:62][O:61][CH:60]([O:63][CH3:64])[CH2:59][NH:44][C:32]([N:13]1[CH2:14][CH2:15][C:16]2[C:21](=[CH:20][C:19]([O:22][CH2:23][CH2:24][NH:25][S:26]([CH2:29][CH2:30][CH3:31])(=[O:28])=[O:27])=[CH:18][CH:17]=2)[CH:12]1[C:8]1([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[CH2:11][CH2:10][CH2:9]1)=[NH:33]
Reactant: COC(CBr)OC
Reactant: CCCS(=O)(=O)NCCOc1ccc2c(c1)C(C1(c3ccc(F)cc3)CCC1)N(/C(=N/C(=O)OCc1ccccc1)NC(=O)OCc1ccccc1)CC2
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Product: CCCS(=O)(=O)NCCOc1ccc2c(c1)C(C1(c3ccc(F)cc3)CCC1)N(C(=N)NCC(OC)OC)CC2
Temperature: 120 °C
Reaction time: 1.33 h

Procedure:
1-[1-(4-Fluorophenyl)cyclobutyl]-7-{2-[(propylsulfonyl)amino]ethoxy}-3,4-dihydroisoquinoline-2(1H)-carboximidamide acetate (140 mg, 0.255 mmol, cf. example 72) was suspended in ethanol (2 mL). Sodium methylate (138 mg, 0.142 mmol) and 2-bromo-1,1-dimethoxyethane (65 mg, 0.383 mmol) were added. The reaction mixture was stirred at 120° C. in the microwave (80 W) for 80 min. The solvent was evaporated in vacuo and the crude product was used without further purification for the next step.
Reaction SMILES: [CH3:1][C@@H:2]1[N:7]2[C:8]3[C:17]4[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=4)[N:11]=[C:10]([NH2:18])[C:9]=3[N:19]=[C:6]2[CH2:5][O:4][CH2:3]1.C(Cl)(Cl)Cl>FC(F)(F)C(O)=O.[Pt]=O>[CH3:1][C@@H:2]1[N:7]2[C:8]3[C:17]4[CH2:16][CH2:15][CH2:14][CH2:13][C:12]=4[N:11]=[C:10]([NH2:18])[C:9]=3[N:19]=[C:6]2[CH2:5][O:4][CH2:3]1
Reactant: C[C@H]1COCc2nc3c(N)nc4ccccc4c3n21
Agent: O=[Pt]
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: C[C@H]1COCc2nc3c(N)nc4c(c3n21)CCCC4
Reaction time: 48 h
Yield: 49.6 %

Procedure:
(11S)-11-Methyl-10,11-dihydro-8H-[1,4]oxazino[4′,3′:1,2]imidazo[4,5-c]quinolin-6-amine (1.13 g, 4.45 mmol) was dissolved in 20 mL of trifluoroacetic acid and the solution was placed in a pressure bottle. Platinum oxide (1.34 g) was then added and the reaction mixture was shaken under H2 at 50 PSI (3.4×105 Pa). After 2 days, the reaction mixture was filtered through a pad of CELITE filter agent. The pad was rinsed with 1,2-dichloroethane and the combined filtrates were concentrated under reduced pressure to give a peach colored oil. The oil was partitioned between dilute NH4OH solution and CH2Cl2. The layers were separated and the organic portion was washed successively with dilute NH4OH solution and brine. The organic portion was then dried over Na2SO4, filtered and concentrated under reduced pressure to give a white foam. Chromatography (SiO2, 10-30% CMA/CHCl3) gave (11S)-11-methyl-2,3,4,8,10,11-hexahydro-1H-[1,4]oxazino[4′,3′:1,2]imidazo[4,5-c]quinolin-6-amine (0.57 g) as a white solid, mp 209-211° C.
Reaction SMILES: [H-].[Na+].[NH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1.[H][H].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CS(C)=O.O>[NH2:3][CH2:4][CH2:5][CH2:6][N:7]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1)[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: NCCCNc1ccccn1
Reactant: [H][H]
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: NCCCN(Cc1ccccc1)c1ccccn1
Temperature: 75 °C

Procedure:
A mixture of sodium hydride (0.7 g) and 2-(3-aminopropylamino)pyridine (4.02 g) in DMSO (25 ml) was heated slowly to 75° C. under nitrogen. After the evolution of hydrogen had ceased the solution was cooled to room temperature and benzyl bromide (3.17 ml) added dropwise below 35° C. After a further 30 minutes water was added and the mixture extracted with chloroform. The chloroform extracts were washed with 2N hydrochloric acid, the pH of the aqueous layers ajusted to 4.5 and re-extracted with chloroform. The pH was further raised to 14 and again extracted with chloroform. After drying (K2CO3), the final chloroform extract, on stripping, afforded 2-[N-(3-aminopropyl)-N-benzylamino]pyridine as an oil (3.91 g) which was used without further purification. (ii) 2-[N-(3-aminopropyl)-N-benzylamino]pyridine (1.64 g) and 2-nitroamino-5-(6-methylpyrid-3-ylmethyl)pyrimid-4-one (1.48 g) were heated together under reflux in pyridine (15 ml) for 20 hr. After stripping the residue was treated with wet ether and the resulting solid recrystallised from ethanol/water to give 2-[3-(N-benzyl-N-pyrid-2-ylamino)propylamino]-5-(6-methylpyrid-3-ylmethyl)-pyrimid-4-one 0.75H2O, 1.46 g (56%) mp 90°-96° C.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][NH:10][C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=[CH:13][C:12]=2[C:21](O)=[O:22])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.C(N(CC)C(C)C)(C)C.Cl.[CH3:56][O:57][C:58](=[O:63])[C:59]([NH2:62])([CH3:61])[CH3:60]>CN(C=O)C>[CH3:56][O:57][C:58](=[O:63])[C:59]([CH3:61])([NH:62][C:21]([C:12]1[CH:13]=[CH:14][C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:11]=1[NH:10][CH2:9][CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:22])[CH3:60]
Reactant: COC(=O)C(C)(C)N
Reactant: O=C(O)c1ccc2ccccc2c1NCCCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C(C)(C)NC(=O)c1ccc2ccccc2c1NCCCc1ccccc1
Reaction time: 0.5 h
Yield: 33.2 %

Procedure:
Under argon atmosphere 16 mg 1-(3-phenyl-propylamino)-naphthalene-2-carboxylic acid, 10 mg 1-hydroxybenzotriazole, 12 mg 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride and 18 μl of N,N-diisopropylethylamine in 1 ml of dry DMF were stirred at 0° C. After 30 minutes at 0° C. 8 mg of 2-aminoisobutyric acid methyl ester hydrochloride, followed by 18 μl of N,N-diisopropylethylamine were added. After 16 h at room temperature the reaction mixture was concentrated, and the residue was purified by RP-HPLC to yield 7 mg of 2-methyl-2-{[1-(3-phenyl-propylamino)-naphthalene-2-carbonyl]-amino}-propionic acid methyl ester.
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]([CH3:10])=[C:5]([CH2:7][CH2:8][OH:9])[N:6]=1.[CH2:11]([O:13][C:14](=[O:26])[CH2:15][C@H:16]1[C:24]2[C:19](=[CH:20][C:21](O)=[CH:22][CH:23]=2)[CH2:18][CH2:17]1)[CH3:12].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1CCN(C(N=NC(N2CCCCC2)=O)=O)CC1>C1COCC1>[CH2:11]([O:13][C:14](=[O:26])[CH2:15][C@H:16]1[C:24]2[C:19](=[CH:20][C:21]([O:9][CH2:8][CH2:7][C:5]3[N:6]=[C:2]([Br:1])[S:3][C:4]=3[CH3:10])=[CH:22][CH:23]=2)[CH2:18][CH2:17]1)[CH3:12]
Reactant: Cc1sc(Br)nc1CCO
Reactant: CCOC(=O)C[C@@H]1CCc2cc(O)ccc21
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)C[C@@H]1CCc2cc(OCCc3nc(Br)sc3C)ccc21
Temperature: 25 °C
Reaction time: 72 h
Yield: 75.2 %

Procedure:
To a solution of Example 173 (975 mg, 4.39 mmol) and ethyl[(1S)-5-hydroxy-2,3-dihydro-1H-inden-1-yl]acetate (1.06 g, 4.83 mmol) in THF (20 mL) were added Ph3P (1.88 g, 7.46 mmol) and ADDP (1.96 g, 7.46 mmol). The mixture was vigorously stirred at rt for 72 hours, the solvent removed under reduced pressure, and the residue purified by silica gel flash chromatography (6:1 hexanes/EtOAc) to yield the product (1.4 g, 76%) as a colorless oil that solidifies upon standing. (C19H22BrNO3S) LC-MS, RT 3.92 min., M+H 424.5; 1H NMR (CDCl3): δ 1.26 (t, 3H), 1.65-1.81 (m, 1H), 2.28-2.45 (m, 2H), 2.37 (s, 3H), 2.69 (dd, 1H), 2.75-2.93 (m, 2H), 3.07 (t, 2H), 3.44-3.56 (m, 1H), 4.15 (t, 2H), 4.18 (q, 2H), 6.67 (dd, 1H), 6.73 (d, 1H), 7.03 (d, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:16][N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[S:5][C:6]=1[S:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[CH:9]=1.[F:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[C:2]1[CH:3]=[C:4]([CH2:16][N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[S:5][C:6]=1[S:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[CH:9]=1
Reactant: COc1cccc(Sc2sc(CN(C)C(=O)OC(C)(C)C)cc2Br)c1
Reactant: OB(O)c1ccccc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COc1cccc(Sc2sc(CN(C)C(=O)OC(C)(C)C)cc2-c2ccccc2F)c1
Temperature: 105 °C
Reaction time: 4 h
Yield: 74.5 %

Procedure:
tert-Butyl ({4-bromo-5-[(3-methoxyphenyl)thio]-2-thienyl}methyl)methylcarbamate (596 mg), (2-fluorophenyl)boronic acid (225 mg), sodium carbonate (341 mg) and tetrakis(triphenylphosphine)palladium (0) (155 mg) were suspended in a mixture of 1,2-dimethoxyethane (10 mL) and water (4 mL), and the suspension was stirred at 105° C. for 4 hr under a nitrogen atmosphere. The reaction mixture was allowed to cool to room temperature, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (eluent: hexane-ethyl acetate=19:1→9:1) to give the title compound as a colorless oil (yield 459 mg, yield 75%).
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:11])[C:9]#[N:10])=[CH:4][CH:3]=1.N([O-])=[O:13].[Na+].S(=O)(=O)(O)O>Cl.O>[OH:13][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:11])[C:9]#[N:10])=[CH:4][CH:3]=1
Reactant: CC(C#N)c1ccc(N)cc1
Reactant: O=N[O-]
Agent: Cl
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: CC(C#N)c1ccc(O)cc1
Reaction time: 0.33 h
Yield: 81 %

Procedure:
Finely ground 2-(4-aminophenyl) propionitrile (73 g., 0.5 mole) was suspended in concentrated hydrochloric acid (125 ml.). The stirred suspension was diazotised at 0° - 5°C by the dropwise addition of a solution of sodium nitrite (36.23 g., 0.525 mole) in water (60 ml.) during 1 - 2 hours. The almost clear solution was stirred for a further 20 minutes at 5° - 10°C, then poured into a stirred, boiling solution of concentrated sulphuric acid (250 ml.) in water (2.5 l.). After 6 minutes it was cooled in an ice-bath, then extracted with ether (×4). The combined ether extracts were extracted with 2N-sodium hydroxide solution (×6). The combined alkaline extracts were cooled in ice-bath, acidified with concentrated hydrochloric acid and extracted with ether (×3). The combined ether extracts were washed with saturated sodium chloride solution (×3), dried (Na2SO4) and evaporated to leave a dark brown oil (66.7 g.) which on distillation gave 2-(4-hydroxyphenyl) propionitrile (59.58 g.), b.p. 112° - 122°C/0.125 m.m., m.p. 41° - 46°C.
Reaction SMILES: [Cl:1][C:2]1[CH:43]=[CH:42][C:5]2[NH:6][C:7]([C@@H:9]([NH:16][C:17](=[O:41])[C:18]3[CH:23]=[CH:22][C:21]([C:24]([N:26]4[CH2:30][CH2:29][CH2:28][C@H:27]4[CH2:31][NH:32]C(OC(C)(C)C)=O)=[O:25])=[C:20]([Cl:40])[CH:19]=3)[CH2:10][CH2:11][S:12]([CH3:15])(=[O:14])=[O:13])=[N:8][C:4]=2[CH:3]=1.FC(F)(F)C(O)=O.ClCCl.CO.N.ClCl>>[Cl:1][C:2]1[CH:43]=[CH:42][C:5]2[NH:6][C:7]([C@@H:9]([NH:16][C:17](=[O:41])[C:18]3[CH:23]=[CH:22][C:21]([C:24]([N:26]4[CH2:30][CH2:29][CH2:28][C@H:27]4[CH2:31][NH2:32])=[O:25])=[C:20]([Cl:40])[CH:19]=3)[CH2:10][CH2:11][S:12]([CH3:15])(=[O:13])=[O:14])=[N:8][C:4]=2[CH:3]=1
Reactant: CC(C)(C)OC(=O)NC[C@@H]1CCCN1C(=O)c1ccc(C(=O)N[C@@H](CCS(C)(=O)=O)c2nc3cc(Cl)ccc3[nH]2)cc1Cl
Agent: ClCl
Agent: N
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Solvent: ClCCl
Product: CS(=O)(=O)CC[C@H](NC(=O)c1ccc(C(=O)N2CCC[C@H]2CN)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 17 from N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)-3-methylsulfonylpropyl]-3-chloro-4-[(2S)-2-(N-tert-butoxycarbonylaminomethyl)pyrrolidin 1-ylcarbonyl]benzamide and trifluoroacetic acid. Yield: quantitative; Rf value: 0.10 (silica gel; dichloromethane/methanol/ammonia=9:1:0.1); C24H27Cl2N5O4S (552.48); mass spectrum: (M+H)+=552/554/556 (chlorine isotope).
Reaction SMILES: C([O:5][C:6]([NH:8][C@@H:9]1[CH2:14][C@@H:13]([C:15](=[O:19])[N:16]([CH3:18])[CH3:17])[CH2:12][CH2:11][C@@H:10]1[NH:20][C:21]([C:23]1[N:24]=[CH:25][C:26]2[C:31]([CH:32]=1)=[CH:30][CH:29]=[C:28]([Cl:33])[CH:27]=2)=[O:22])=O)(C)(C)C.Cl.[CH3:35][N:36]1[CH2:41][CH2:40][C:39]2[N:42]=[C:43](C([O-])=O)[S:44][C:38]=2[CH2:37]1.[Li+]>C(O)C>[ClH:33].[Cl:33][C:28]1[CH:27]=[C:26]2[C:31]([CH:32]=[C:23]([C:21]([NH:20][C@H:10]3[CH2:11][CH2:12][C@H:13]([C:15](=[O:19])[N:16]([CH3:17])[CH3:18])[CH2:14][C@H:9]3[NH:8][C:6]([C:43]3[S:44][C:38]4[CH2:37][N:36]([CH3:35])[CH2:41][CH2:40][C:39]=4[N:42]=3)=[O:5])=[O:22])[N:24]=[CH:25]2)=[CH:30][CH:29]=1
Reactant: CN(C)C(=O)[C@H]1CC[C@H](NC(=O)c2cc3ccc(Cl)cc3cn2)[C@H](NC(=O)OC(C)(C)C)C1
Reactant: CN1CCc2nc(C(=O)[O-])sc2C1
Agent: Cl
Agent: [Li+]
Solvent: CCO
Product: CN1CCc2nc(C(=O)N[C@@H]3C[C@@H](C(=O)N(C)C)CC[C@@H]3NC(=O)c3cc4ccc(Cl)cc4cn3)sc2C1

Procedure:
(1S,2R,4S)-N2-(tert-Butoxycarbonyl)-N1-[(7-chloroisoquinolin-3-yl)carbonyl]-4-(N,N-dimethyl-carbamoyl)-1,2-cyclohexanediamine was treated with a saturated ethanol solution of hydrochloric acid and then condensed with lithium 5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxylate in a similar manner to Example 118 to obtain the title compound.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[C:5]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([S:15](Cl)(=[O:17])=[O:16])=[CH:11][CH:10]=1)(=[O:7])[CH3:6]>CC(C)=O.O>[C:5]([NH:8][C:9]1[CH:10]=[CH:11][C:12]([S:15]([N:1]=[N+:2]=[N-:3])(=[O:17])=[O:16])=[CH:13][CH:14]=1)(=[O:7])[CH3:6]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Cl)cc1
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: CC(=O)Nc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 87.4 %

Procedure:
Sodium azide (7.8 g, 120 mmol) was charged in a 1 L round bottom flask with water. 4-Acetamidobenzene-1-sulfonyl chloride (23.4 g, 100 mmol) was dissolved in acetone, and this solution was slowly added to the solution of sodium azide. The reaction was then stirred for 16 hours at room temperature and diluted with water. The acetone was then removed. The solid was filtered to give 4-acetamidobenzenesulfonyl azide (21 g, 87%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9]([N:12]([CH2:22][P:23](=[O:30])([O:27][CH2:28][CH3:29])[O:24][CH2:25][CH3:26])[C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[NH:18][CH2:17][CH2:16]3)(=[O:11])=[O:10])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[C:31](OC(=O)C)(=[O:33])[CH3:32].[OH-].[Na+]>ClCCl>[C:31]([N:18]1[C:19]2[C:15](=[CH:14][C:13]([N:12]([CH2:22][P:23](=[O:30])([O:24][CH2:25][CH3:26])[O:27][CH2:28][CH3:29])[S:9]([C:4]3[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[CH:3]=3)(=[O:10])=[O:11])=[CH:21][CH:20]=2)[CH2:16][CH2:17]1)(=[O:33])[CH3:32]
Reactant: CC(=O)OC(C)=O
Reactant: CCOP(=O)(CN(c1ccc2c(c1)CCN2)S(=O)(=O)c1cc(Cl)cc(Cl)c1)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CCOP(=O)(CN(c1ccc2c(c1)CCN2C(C)=O)S(=O)(=O)c1cc(Cl)cc(Cl)c1)OCC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1.45 g diethyl {[(3,5-dichloro-phenylsulphonyl)-(2,3-dihydro-1H-indol-5-yl)-amino]-methyl}-phosphonate are dissolved in 20 ml dichloromethane, combined with 2 ml acetic anhydride and stirred for 2 hours at ambient temperature. The mixture is diluted with dichloromethane, cooled to 0° C. and 20 ml of 4 N sodium hydroxide solution are added thereto. After stirring for 30 minutes the phases are separated and the organic phase is washed with saturated sodium chloride solution. Then it is dried on magnesium sulphate, the solvents are eliminated in vacuo and the residue is chromatographed on silica gel (dichloromethane/methanol 95:5 to 75:25).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([Cl:9])[CH:6]=[CH:5][C:3]=1[NH2:4].I[CH2:11][C:12](=[O:14])[CH3:13].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[Cl:1][C:2]1[CH:8]=[C:7]([Cl:9])[CH:6]=[CH:5][C:3]=1[NH:4][CH2:11][C:12](=[O:14])[CH3:13]
Reactant: CC(=O)CI
Reactant: Nc1ccc(Cl)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)CNc1ccc(Cl)cc1Cl
Temperature: 100 °C
Yield: 49.9 %

Procedure:
A mixture of 2,4-dichloroaniline (20.2 g, 0.125 mol), iodoacetone (26.6 g, 0.145 mol) and potassium carbonate (18.1 g, 0.13 mol) in DMF (200 ml) was heated under nitrogen at 100° C. overnight. After cooling to rt, water was added and the mixture extracted with ether (×3). The combined organic extracts were washed with water, dried (Na2SO4), filtered and concentrated. Flash chromatography (Heptane:EtOAc 90: 10-80:20) afforded 13.6 g (50%) of the title compound as a brown solid.
Reaction SMILES: [N:1]1([C:8]([NH:10][C@@H:11]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:12]([OH:14])=O)=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)C(C)C)(C)C.[C:28]1([CH:34]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH2:35][NH2:36])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(OCC)C>CN(C=O)C>[C:37]1([CH:34]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:35][NH:36][C:12]([C@@H:11]([NH:10][C:8]([N:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]2)=[O:9])[CH2:15][CH:16]([CH3:18])[CH3:17])=[O:14])[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1
Reactant: NCC(c1ccccc1)c1ccccc1
Reactant: CC(C)C[C@H](NC(=O)N1CCCCCC1)C(=O)O
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)C[C@H](NC(=O)N1CCCCCC1)C(=O)NCC(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 85.8 %

Procedure:
(S)-2-[(Azepane-1-carbonyl)-amino]-4-methyl-pentanoic acid (0.51 g, 2.0 mmol, Example 1, Step B) was dissolved in dry DMF (5 mL) under nitrogen atmosphere and cooled to 0° C. in an ice-water bath. To this solution were added, in succession, N,N-diisopropylethylamine (0.68 mL, 3.9 mmol) and solid O-benzotriazol-1-yl-N,N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.74 g, 2.0 mmol). The resulting reaction mixture was stirred at that temperature for 30 minutes; 2,2-diphenylethylamine (0.38 g, 1.9 mmol, Aldrich, Milwaukee, Wis.) was then added. After additional 30 minutes stirring at 0° C., reaction mixture was mixed with 60 mL of diethyl ether; the resulting mixture was successively washed with 5% aqueous HCl solution, brine, saturated aqueous NaHCO3 solution, brine, and was dried over Na2SO4. The solution was concentrated in vacuo, a white solid was obtained. Recrystallization from EtOAc-hexanes afforded 0.71 g (84%) of the pure titled compound as a white solid; mp 194-195° C. APCI-MS m/z 436.3 (MH+).