Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8](=[O:25])[NH:9][C@@H:10]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C@H:11]([C:13](=[O:17])[N:14]([CH3:16])[CH3:15])[OH:12])([CH3:6])([CH3:5])[CH3:4].[CH3:26]I.[Cl-].[NH4+]>O1CCCC1.C(OCC)(=O)C>[C:3]([O:7][C:8](=[O:25])[NH:9][C@@H:10]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C@H:11]([C:13](=[O:17])[N:14]([CH3:15])[CH3:16])[O:12][CH3:26])([CH3:6])([CH3:4])[CH3:5]
Reactant: CN(C)C(=O)[C@H](O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Reactant: CI
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CO[C@@H](C(=O)N(C)C)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C

Procedure:
Sodium hydride-oil dispersion (53 mg of 50%) was added to a solution of (1S,2R)-(1-benzyl-2-dimethylcarbamoyl-2-hydroxy-ethyl)-carbamic acid tert-butyl ester (322 mg, 1.0 mmol) in tetrahydrofuran (4 mL) at 0° C. After effervescence ceased (several minutes), methyl iodide (155 mg) was added, and after 15 minutes another 11 mg NaH dispersion and 23 mg methyl iodide were added. After 15 more minutes aqueous ammonium chloride solution and ethyl acetate were added, and the organic layer was separated, washed with water, 2N NaOH, dried and concentrated giving a viscous oil which was used without further purification: Yield 283 mg, 84%.
Reaction SMILES: [CH2:1]([C:4]1[C:19]([OH:20])=[CH:18][CH:17]=[CH:16][C:5]=1[O:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]1[NH:15][N:14]=[N:13][N:12]=1)[CH2:2][CH3:3].S(Cl)([Cl:24])(=O)=O>O1CCCC1>[CH2:1]([C:4]1[C:19]([OH:20])=[C:18]([Cl:24])[CH:17]=[CH:16][C:5]=1[O:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]1[NH:12][N:13]=[N:14][N:15]=1)[CH2:2][CH3:3]
Reactant: O=S(=O)(Cl)Cl
Reactant: CCCc1c(O)cccc1OCCCCc1nnn[nH]1
Solvent: C1CCOC1
Product: CCCc1c(OCCCCc2nnn[nH]2)ccc(Cl)c1O
Reaction time: 1 h

Procedure:
A solution of 1.38 g. of 5-[4-(2-propyl-3-hydroxyphenoxy)butyl]-tetrazole in 25 ml. of tetrahydrofuran was cooled to -10° C. by means of an external alcohol-ice bath. One millimole of sulfuryl chloride was slowly added and the reaction mixture was stirred for one hour. The mixture was evaporated under reduced pressure and the residue was triturated with diethyl ether. The ether was evaporated and the residue was purified by reverse phase high pressure liquid chromatography. The appropriate fractions provided 42 mg. of the desired title product plus 92 mg. of the 2-propyl-3-hydroxy-6-chlorophenoxy isomer and a small amount of the 2-propyl-3-hydroxy-4,6-dichlorophenoxy compound.
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[N:7][CH:8]=[C:9]([N+:11]([O-])=O)[CH:10]=[C:5]2[CH:4]=[N:3]1.C(O)(=O)C>C(Cl)Cl.[Zn]>[CH3:1][N:2]1[C:6]2=[N:7][CH:8]=[C:9]([NH2:11])[CH:10]=[C:5]2[CH:4]=[N:3]1
Reactant: Cn1ncc2cc([N+](=O)[O-])cnc21
Agent: [Zn]
Solvent: CC(=O)O
Solvent: ClCCl
Product: Cn1ncc2cc(N)cnc21
Temperature: 45 °C

Procedure:
To a solution of 1-methyl-5-nitro-1H-pyrazolo[3,4-b]pyridine (90 mg, 0.51 mmol) in CH2Cl2 (1 mL) is added zinc (200 mg, 3.06 mmol) and acetic acid (250 μL). The mixture is heated at 45° C. for 5 h. The zinc is removed by filtration and the filtrate was evaporated under reduced pressure. The residue is purified by flash column chromatography using a gradient of 0-10% methanol in CH2Cl2. 1N HCl in ether is added to the residue to afford the title compound as the hydrochloride salt (43 mg, 46%).
Reaction SMILES: [CH3:1][N:2]1[C:8](=[O:9])[C:7]2[CH:10]=[CH:11][C:12]([N+:14]([O-])=O)=[CH:13][C:6]=2[O:5][CH2:4][CH2:3]1>[Pd].C(O)C>[NH2:14][C:12]1[CH:11]=[CH:10][C:7]2[C:8](=[O:9])[N:2]([CH3:1])[CH2:3][CH2:4][O:5][C:6]=2[CH:13]=1
Reactant: CN1CCOc2cc([N+](=O)[O-])ccc2C1=O
Agent: [Pd]
Solvent: CCO
Product: CN1CCOc2cc(N)ccc2C1=O
Yield: 2 %

Procedure:
4-Methyl-8-nitro-3,4-dihydro-2H-benzo[f][1,4]oxazepin-5-one (0.16 g, 0.0072 mol) and 10% palladium on carbon in ethanol (70 mL) was hydrogenated. The reaction was filtered and evaporated. Purification by ISCO chromatography gave 8-amino-4-methyl-3,4-dihydro-2H-benzo[f][1,4]oxazepin-5-one (0.027 g, 84%) as a tan solid. MP: 169-170° C.; 1H-NMR (DMSO-d6) δ 7.36 (d, 1H), 6.27-9 (d, 1H), 6.08 (s, 1H), 5.60 (s, 1H), 4.22-5 (m, 2H), 3.46-9 (m, 2H), 3.00 (s, 3H); LC/MS (ESI+): 193 (M+H).
Reaction SMILES: [Cu][C:2]#[N:3].Cl[C:5]1[CH:6]=[C:7]2[C:23]([CH3:24])=[C:22]([CH3:25])[NH:21][C:8]2=[C:9]([N:11]2[CH2:20][CH2:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12]2)[N:10]=1.C(OCC)(=O)C>CN(C)C=O>[CH2:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:19][CH2:20][N:11]1[C:9]1[N:10]=[C:5]([C:2]#[N:3])[CH:6]=[C:7]2[C:23]([CH3:24])=[C:22]([CH3:25])[NH:21][C:8]=12
Reactant: Cc1[nH]c2c(N3CCc4ccccc4C3)nc(Cl)cc2c1C
Reactant: N#C[Cu]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1[nH]c2c(N3CCc4ccccc4C3)nc(C#N)cc2c1C
Temperature: 25 °C
Yield: 24.1 %

Procedure:
Copper(I) cyanide (9.3 g, 102.6 mmol) was added to a solution of 2-(5-chloro-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridin-7-yl)-1,2,3,4-tetrahydroisoquinoline (3.2 g, 10.3 mmol) prepared in Example 656 in anhydrous N,N-dimethylformamide (100 ml). The reaction mixture was refluxed for 24 hours and then cooled to room temperature. Ethyl acetate was added to the reaction mixture, which was then filtered to discard insoluble materials. The reaction mixture was washed with water. The organic layer was dried on anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting residue was purified with silica gel column chromatography (ethyl acetate/n-hexane=1/3, v/v) to give 750 mg of the titled compound as a white solid. (Yield: 26%)
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH:13]2[CH:9]1[CH2:10][N:11]([C:14](=[O:22])[C:15]1[CH:20]=[CH:19][C:18](I)=[CH:17][CH:16]=1)[CH2:12]2)(C)(C)C.[Cl:24][C:25]1[C:30]([F:31])=[CH:29][CH:28]=[C:27]([Cl:32])[C:26]=1[CH:33]([O:35][C:36]1[C:37]([NH2:51])=[N:38][CH:39]=[C:40](B2OC(C)(C)C(C)(C)O2)[CH:41]=1)[CH3:34].C(Cl)Cl.C([O-])([O-])=O.[Cs+].[Cs+].Cl.O1CCOCC1>COCCOC.C(OCC)(=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[NH2:7][CH:8]1[CH:9]2[CH:13]1[CH2:12][N:11]([C:14]([C:15]1[CH:16]=[CH:17][C:18]([C:40]3[CH:39]=[N:38][C:37]([NH2:51])=[C:36]([O:35][CH:33]([C:26]4[C:27]([Cl:32])=[CH:28][CH:29]=[C:30]([F:31])[C:25]=4[Cl:24])[CH3:34])[CH:41]=3)=[CH:19][CH:20]=1)=[O:22])[CH2:10]2
Reactant: CC(C)(C)OC(=O)NC1C2CN(C(=O)c3ccc(I)cc3)CC21
Reactant: CC(Oc1cc(B2OC(C)(C)C(C)(C)O2)cnc1N)c1c(Cl)ccc(F)c1Cl
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: Cl
Solvent: COCCOC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(Oc1cc(-c2ccc(C(=O)N3CC4C(N)C4C3)cc2)cnc1N)c1c(Cl)ccc(F)c1Cl
Yield: 25.6 %

Procedure:
To a mixture of [3-(4-iodo-benzoyl)-3-aza-bicyclo[3.1.0]hex-6-yl]-carbamic acid tert-butyl ester (100 mg, 0.234 mmol) and 3-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-2-ylamine (100 mg, 0.234 mmol) in DME (2 mL) was added Pd(dppf)2Cl2.CH2Cl2 (10 mg, 0.012 mmol) and Cs2CO3 (351 mg, 0.702 mmol). The mixture was bubbled with nitrogen for 10 min then microwaved at 150° C. for 30 min. LCMS checked that the reaction was completed. The crude reaction mixture was diluted with ethyl acetate followed by washings with water and brine. The solution was dried over MgSO4. Purification by prep-HPLC afforded a solid. The solid was stirred with 4 N HCl/dioxane (3 mL) for 3 hr at room temperature. Removal of the volatiles led to a residue that was purified by prep-HPLC to afford (6-amino-3-aza-bicyclo[3.1.0]hex-3-yl)-(4-{6-amino-5-[1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-phenyl)-methanone (30 mg, yield 26%).
Reaction SMILES: C([O:4][CH:5]1[C:9]2=[N:10][CH:11]=[C:12]([NH:31][C:32]([C:34]3[CH:39]=[CH:38][C:37]([F:40])=[C:36]([C:41]4[C:46]([F:47])=[CH:45][CH:44]=[CH:43][C:42]=4[F:48])[N:35]=3)=[O:33])[C:13]([N:14]3[CH2:19][C@H:18]([CH3:20])[C:17]([OH:22])([CH3:21])[C@H:16]([NH:23]C(OC(C)(C)C)=O)[CH2:15]3)=[C:8]2[CH2:7][CH2:6]1)(=O)C.[OH-].[Na+].Cl.O1CCOCC1>CO.C1COCC1>[NH2:23][C@H:16]1[C:17]([OH:22])([CH3:21])[C@@H:18]([CH3:20])[CH2:19][N:14]([C:13]2[C:12]([NH:31][C:32]([C:34]3[CH:39]=[CH:38][C:37]([F:40])=[C:36]([C:41]4[C:46]([F:47])=[CH:45][CH:44]=[CH:43][C:42]=4[F:48])[N:35]=3)=[O:33])=[CH:11][N:10]=[C:9]3[CH:5]([OH:4])[CH2:6][CH2:7][C:8]=23)[CH2:15]1
Reactant: CC(=O)OC1CCc2c1ncc(NC(=O)c1ccc(F)c(-c3c(F)cccc3F)n1)c2N1C[C@H](C)C(C)(O)[C@H](NC(=O)OC(C)(C)C)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: C[C@H]1CN(c2c(NC(=O)c3ccc(F)c(-c4c(F)cccc4F)n3)cnc3c2CCC3O)C[C@@H](N)C1(C)O
Reaction time: 1 h

Procedure:
4-{(3R,5S)-3-[(tert-Butoxycarbonyl)amino]-4-hydroxy-4,5-dimethylpiperidin-1-yl}-3-({[6-(2,6-difluorophenyl)-5-fluoropyridin-2-yl]carbonyl}amino)-6,7-dihydro-5H-cyclopenta[b]pyridin-7-yl acetate (118 mg, 0.176 mmol) was dissolved in a mixture of MeOH (1 mL) and THF (1 mL) and 0.5 M solution of aq. NaOH (1 mL, 0.5 mmol) was added. The reaction was stirred for 1 h, and then concentrated to dry under reduced pressure. To the residue was added 4.0 M solution of hydrogen chloride in dioxane (3 mL, 10 mmol). The reaction mixture was stirred for 1 h, and then evaporated to dryness. The resulting residue was dissolved in MeCN and purified by RP-HPLC (water SunFire™ C18 column, 19 mm×100 mm, 5 μm particle size, eluting with a gradient of MeCN/water containing 0.1% TFA, at flow rate of 30 mL/min.) to give four different diastereoisomers of the bis(trifluoroacetate) of the title compound as white solids.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]3[N:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=3)=[CH:8][CH:9]=2)[CH:4]=[N:3]1.C1C(=O)N([Br:25])C(=O)C1.C([O-])(O)=O.[Na+]>CN(C=O)C>[Br:25][C:15]1[C:14]([NH2:17])=[CH:13][CH:12]=[C:11]([C:7]2[CH:6]=[C:5]3[C:10](=[CH:9][CH:8]=2)[N:2]([CH3:1])[N:3]=[CH:4]3)[N:16]=1
Reactant: Cn1ncc2cc(-c3ccc(N)cn3)ccc21
Reactant: O=C1CCC(=O)N1Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1ncc2cc(-c3ccc(N)c(Br)n3)ccc21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
In a 50 mL round bottom flask, 6-(1-methyl-1H-indazol-5-yl)pyridin-3-amine (225 mg, 1.00 mmol) was dissolved in DMF (8 mL) at room temperature and the solution was cooled down to 0° C. for 5 min under argon atmosphere. A solution of NBS (179 mg, 1.00 mmol) in DMF (6 mL) was added dropwise. The resulting reaction mixture was stirred at 0° C. for 30 min and then was poured onto saturated aq NaHCO3 solution (30 mL). EtOAc (3×30 mL) was used for extraction. Organic phase was then washed with water (2×20 mL) and concentrated. Residue was purified on silica gel column with 0-30% to afford product. LCMS-ESI+: calc'd for: C13H11BrN4: 303.0, 305.0 (M+H+); found: 303.1, 305.1 (M+H+)
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:8]1[CH:13]=[C:12]([C:14]([CH3:20])([CH3:19])[C:15]([F:18])([F:17])[F:16])[CH:11]=[C:10]([Cl:21])[CH:9]=1)[CH2:4][C:5]([OH:7])=[O:6].[CH2:22](OCC)[CH3:23]>C(O)C>[ClH:21].[NH2:2][C@H:3]([C:8]1[CH:13]=[C:12]([C:14]([CH3:19])([CH3:20])[C:15]([F:16])([F:17])[F:18])[CH:11]=[C:10]([Cl:21])[CH:9]=1)[CH2:4][C:5]([O:7][CH2:22][CH3:23])=[O:6]
Reactant: CC(C)(c1cc(Cl)cc([C@@H](N)CC(=O)O)c1)C(F)(F)F
Reactant: CCOCC
Agent: Cl
Solvent: CCO
Product: CCOC(=O)C[C@H](N)c1cc(Cl)cc(C(C)(C)C(F)(F)F)c1

Procedure:
Absolute ethanol saturated with anhydrous HCl gas (10 mL) was added to a suspension of (S)-3-amino-3-(3-chloro-5-(1,1,1-trifluoro-2-methylpropan-2-yl)phenyl)propanoic acid (from step A above) (252.8 mg, 0.816 mmol) in absolute ethyl alcohol (5 mL) and the reaction mixture was heated at reflux for 4 h to give a colorless solution. The solvent was removed in vacuo to give a colorless gummy solid. The solid was slurried a couple of times with diethyl ether (2×5 mL). After the solvent was decanted off, the residue was dried in vacuo to give the desired (S)-ethyl 3-amino-3-(3-chloro-5-(1,1,1-trifluoro-2-methylpropan-2-yl)phenyl)propanoate hydrochloride salt as a cream foamy solid (293.76 mg). LC-MS analysis of the solid shows the desired product's mass: m/z 338 (35ClM+H), m/z 340 (37ClM+H), m/z 360 (35ClM+Na) and m/z 362 (37ClM+Na); Calcd for C15H19ClF3NO2: 337.77.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:9])[CH:5]=[CH:6][CH:7]=1.CC(C)([O-])C.[K+].Cl[CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28]>C1COCC1>[C:10]1([C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([O:1][CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[CH:3]=2)=[O:9])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C(c1ccccc1)c1cccc(O)c1
Reactant: C[Si](C)(C)CCOCCl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCOc1cccc(C(=O)c2ccccc2)c1
Reaction time: 2 h

Procedure:
To a solution of (3-hydroxyphenyl)(phenyl)methanone (30.0 g, 151 mmole) in anhydrous THF (300 mL) at 0° C. was slowly added a solution of potassium-t-butoxide (200 mL-1 M in THF, 0.200 mmole), followed by a slow addition of [2-(chloromethoxy)ethyl](trimethyl)silane (32.1 mL, 182 mmole). After stirring the mixture for 2 h, the solvent was removed in vacuo and the residue redissolved in a mixture of H2O (200 mL) and EtOAc (200 mL). The aqueous layer was further extracted with EtOAc (2×100 mL). The combined extracts were washed with H2O (200 mL), 0.1 N HCl (500 mL), brine (100 mL), dried over MgSO4, filtered and concentrated in vacuo to give an orange oil. The crude product was redissolved in hexanes and filtered through a silica-gel plug to give the product as an impure pale yellow oil which is carried on without further purification: ESHRMS m/z 329.1586 (M+H, C19H25O3Si, Calc'd 329.1567).
Reaction SMILES: Cl.O=C1C2(CCN([CH2:13][CH2:14][CH2:15][CH2:16][N:17]3[C:26](=[O:27])[C:25]4[CH:28]=[CH:29][CH:30]=[C:23]5[C:24]=4[C:19](=[CH:20][CH:21]=[CH:22]5)[C:18]3=[O:31])CC2)N(C2C=CC=CC=2)CN1.[Br:38][CH2:39][CH2:40]CCCCBr.BrCCCCBr>>[Br:38][CH2:39][CH2:40][CH2:13][CH2:14][CH2:15][CH2:16][N:17]1[C:26](=[O:27])[C:25]2[CH:28]=[CH:29][CH:30]=[C:23]3[C:24]=2[C:19](=[CH:20][CH:21]=[CH:22]3)[C:18]1=[O:31]
Reactant: O=C1c2cccc3cccc(c23)C(=O)N1CCCCN1CCC2(CC1)C(=O)NCN2c1ccccc1
Reactant: BrCCCCCCBr
Agent: Cl
Solvent: BrCCCCBr
Product: O=C1c2cccc3cccc(c23)C(=O)N1CCCCCCBr

Procedure:
Following the procedure of part (a) of example 26 but substituting 1,6-dibromohexane for the 1,4-dibromobutane, one obtains 2-(6-bromohexyl)-1H-benz[de]isoquinoline-1,3(2H)-dione; m.p. 95°-96°.
Reaction SMILES: C(NC1SC(Br)=C(C(=NOC)C(N[CH:13]2[C:30](=[O:31])[N:15]3[C:16]([C:27]([OH:29])=[O:28])=[C:17]([CH2:20][S:21][C:22]4[S:23][CH:24]=[N:25][N:26]=4)[CH2:18][S:19][C@H:14]23)=O)N=1)=O.[ClH:36]>>[ClH:36].[S:23]1[CH:24]=[N:25][N:26]=[C:22]1[S:21][CH2:20][C:17]1[CH2:18][S:19][C@@H:14]2[CH2:13][C:30](=[O:31])[N:15]2[C:16]=1[C:27]([OH:29])=[O:28]
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nncs3)CS[C@H]12)c1nc(NC=O)sc1Br
Agent: Cl
Product: O=C(O)C1=C(CSc2nncs2)CS[C@@H]2CC(=O)N12

Procedure:
7-[2-(2-Formamido-5-bromothiazol-4-yl)-2-methoxyiminoacetamido]-3-(1,3,4-thiadiazol-2-ylthiomethyl)-3-cephem-4-carboxylic acid (syn isomer, 1.2 g.) was treated with conc. hydrochloric acid (2 ml.) in a similar manner to that of Example 1-(2) to give 7-[2-2-amino-5-bromothiazol-4-yl)-2-methoxyiminoacetamido]-3-(1,3,4-thiadiazol-2-ylthiomethyl)-3-cephem-4-carboxylic acid hydrochloride (syn isomer, 1.2 g.).
Reaction SMILES: CN1CCOCC1.[CH3:8][C:9]1[O:13][N:12]=[C:11]([C:14]2[CH:15]=[C:16]([CH:28]=[CH:29][CH:30]=2)[O:17][CH:18]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:19]([OH:21])=O)[N:10]=1.[NH2:31][C:32]1[CH:37]=[CH:36][C:35]([N:38]2[CH2:43][CH2:42][CH2:41][CH2:40][C:39]2=[O:44])=[CH:34][CH:33]=1.Cl.CN(C)CCCN=C=NCC.O.OC1C2N=NNC=2C=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C>[CH3:8][C:9]1[O:13][N:12]=[C:11]([C:14]2[CH:15]=[C:16]([CH:28]=[CH:29][CH:30]=2)[O:17][CH:18]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:19]([NH:31][C:32]2[CH:37]=[CH:36][C:35]([N:38]3[CH2:43][CH2:42][CH2:41][CH2:40][C:39]3=[O:44])=[CH:34][CH:33]=2)=[O:21])[N:10]=1
Reactant: Cc1nc(-c2cccc(OC(C(=O)O)c3ccccc3)c2)no1
Reactant: Nc1ccc(N2CCCCC2=O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Solvent: O
Product: Cc1nc(-c2cccc(OC(C(=O)Nc3ccc(N4CCCCC4=O)cc3)c3ccccc3)c2)no1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
35 μl (0.322 mmol) of 4-methylmorpholine are added to a solution of 100 mg (0.322 mmol) of [3-(5-methyl-1,2,4-oxadiazol-3-yl)phenoxyl]-2-phenylacetic acid, 61.3 mg (0.322 mmol) of 1-(4-aminophenyl)piperidin-2-one (prepared from 1-(4-nitrophenyl)piperidin-2-one by hydrogenation using Raney nickel as catalyst), 61.7 mg (0.322 mmol) of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (DAPECI) and 49.3 mg (0.322 mmol) of hydroxybenzotriazole hydrate (HOBt) in 3 ml of DMF, and the mixture is stirred at room temperature for 48 hours. The reaction mixture is introduced into aqueous sodium carbonate solution, and the precipitate is filtered off, giving 2-[3-(5-methyl-1,2,4-oxadiazol-3-yl)phenoxy]-N-[4-(2-oxopiperidin-1-yl)phenyl]-2-phenylacetamide as a colourless solid; ESI 483.
Reaction SMILES: N[C@@H](CCC(N[C@H:11]([C:14]([NH:16][CH2:17][C:18]([OH:20])=[O:19])=O)[CH2:12]S)=O)C(O)=O.N1CCC[C@H]1C(O)=[O:24].CC1(C)S[C@@H]2[C@H](NC([C@H](N)C3C=CC=CC=3)=O)C(=O)N2[C@H]1C(O)=O>>[NH:16]1[CH2:14][C@H:11]([OH:24])[CH2:12][C@H:17]1[C:18]([OH:20])=[O:19]
Reactant: N[C@@H](CCC(=O)N[C@@H](CS)C(=O)NCC(=O)O)C(=O)O
Reactant: O=C(O)[C@@H]1CCCN1
Agent: CC1(C)S[C@@H]2[C@H](NC(=O)[C@H](N)c3ccccc3)C(=O)N2[C@H]1C(=O)O
Product: O=C(O)[C@@H]1C[C@@H](O)CN1
Temperature: 37 °C
Reaction time: 8 h

Procedure:
A plasmid (pGST-CM4, FIG. 60) containing the gene for collagen mimetic 4 (CM4, FIG. 61) (SEQ. ID. NO. 39) genetically linked to the 3′ end of the gene for S. japonicum glutathione S-transferase was used to transform by electroporation proline auxotrophic E. coli strain JM109 (F-). Transformation cultures were plated on LB agar containing 100 μg/ml ampicillin. After overnight incubation at 37° C., a single colony from a fresh transformation plate was used to inoculate 5 ml of LB media containing 100 μg/ml ampicillin. After overnight growth at 37° C., 500 μl of this culture was centrifuged, the supernatent discarded, and the cell pellet washed once with 500 μl of M9 medium (1× M9 salts, 0.5% glucose, 1 mM MgCl2, 0.01% thiamine, 200 μg/ml glycine, 200 μg/ml alanine, 100 μg/ml of the other amino acids except proline, and 400 μg/ml ampicillin). The cells were finally suspended in 5 ml of M9 medium containing 10 μm/ml proline and 2 ml of this was used to inoculate 30 ml of M9 medium containing 10 μg/ml proline. After incubation with shaking at 37° C. for 8 hours, the culture was centrifuged and the cell pellet washed once with M9 medium containing 5 μg/ml proline. The pellet was resuspended in 15 ml of M9 medium containing 5 μg/ml of proline and this culture was used to inoculate 1 L of M9 medium containing 5 μg/ml of proline. This culture was grown for 18 hours at 37° C. to proline starvation. At this time, the culture was centrifuged, the cells washed once with M9 medium (with no proline), and the cells resuspended in 1 L of M9 medium containing 80 mM hydroxyproline, 0.5M NaCl, and 1.5 mM isopropyl-β-D-thiogalactopyranoside. Incubation was continued at 37° C. with shaking for 22 hours. The cultures were centrifuged and the cell pellets stored at −20° C. until processed further.
Reaction SMILES: Br[CH2:2][CH2:3][CH:4]([Br:6])[CH3:5].[C:7]1(=[O:17])[NH:11][C:10](=[O:12])[C:9]2=[CH:13][CH:14]=[CH:15][CH:16]=[C:8]12.[K]>CN(C)C=O>[Br:6][CH:4]([CH3:5])[CH2:3][CH2:2][N:11]1[C:10](=[O:12])[C:9]2=[CH:13][CH:14]=[CH:15][CH:16]=[C:8]2[C:7]1=[O:17]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CC(Br)CCBr
Agent: [K]
Solvent: CN(C)C=O
Product: CC(Br)CCN1C(=O)c2ccccc2C1=O
Temperature: 20 °C
Reaction time: 8 h

Procedure:
1,3 dibromobutane (10.8 g, 0.05 mol) and potassium phthalimide (9.25 g, 0.05 mol) were added to dry N,N dimethylformamide (100 ml) and the resulting mixture stirred at ambient temperature (20° C.) overnight. The resulting mixture was filtered to remove any solid and the solvent removed from the filtrate to give a colourless oil. The product, N-(3-bromobutyl)phthalimide, was isolated from the oil by flash chromatography on a silica gel column using silica gel, 230 to 400 US mesh (0.062 mm to 0.037 mm) eluted with 2% methanol in dichloromethane as a brown solid in a yield of 7.9 g (55.7%).
Reaction SMILES: [F:1][C:2]1([F:29])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([O:19][CH:20]2[CH2:25][CH2:24][N:23]([CH:26]([CH3:28])[CH3:27])[CH2:22][CH2:21]2)=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1.[CH3:30][O:31][C:32]1[N:37]=[CH:36][C:35](B(O)O)=[CH:34][N:33]=1>>[F:29][C:2]1([F:1])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[N:11]([C:35]3[CH:34]=[N:33][C:32]([O:31][CH3:30])=[N:37][CH:36]=3)[C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([O:19][CH:20]2[CH2:25][CH2:24][N:23]([CH:26]([CH3:27])[CH3:28])[CH2:22][CH2:21]2)=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1
Reactant: CC(C)N1CCC(Oc2ccc3[nH]c(C(=O)N4CCC(F)(F)CC4)cc3c2)CC1
Reactant: COc1ncc(B(O)O)cn1
Product: COc1ncc(-n2c(C(=O)N3CCC(F)(F)CC3)cc3cc(OC4CCN(C(C)C)CC4)ccc32)cn1

Procedure:
In analogy to the procedure described for the synthesis of example 6, the title compound was synthesized from (4,4-difluoro-piperidin-1-yl)-[5-(1-isopropyl-piperidin-4-yloxy)-1H-indol-2-yl]-methanone (intermediate 1) and 2-methoxy-5-pyrimidineboronic acid. The title compound was obtained in 9% yield as yellow oil. MS (m/e): 514.3 (MH+, 100%).
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:12])=[N:4][CH:5]=[C:6]([CH:11]=1)[C:7]([NH:9][NH2:10])=[O:8].[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([OH:23])=[C:18]([C:20](=O)[CH3:21])[CH:19]=1>CO.C(O)(=O)C>[Br:1][C:2]1[C:3]([Cl:12])=[N:4][CH:5]=[C:6]([CH:11]=1)[C:7]([NH:9]/[N:10]=[C:20](/[C:18]1[CH:19]=[C:14]([Cl:13])[CH:15]=[CH:16][C:17]=1[OH:23])\[CH3:21])=[O:8]
Reactant: NNC(=O)c1cnc(Cl)c(Br)c1
Reactant: CC(=O)c1cc(Cl)ccc1O
Solvent: CO
Solvent: CC(=O)O
Product: C/C(=N\NC(=O)c1cnc(Cl)c(Br)c1)c1cc(Cl)ccc1O
Temperature: 120 °C
Yield: 33.1 %

Procedure:
5-Bromo-6-chloronicotinohydrazide (15 mg, 0.060 mmol) and 1-(5-chloro-2-hydroxyphenyl)ethanone (10.22 mg, 0.060 mmol) were dissolved in methanol (4 mL) in the presence of acetic acid as a catalyst and the reaction mixture was heated via microwave irradiation to 120° C. for 30 min. The reaction was monitored by TLC. Upon completion of the reaction and following cooling, the solvent was removed by vacuum, and the resulting crude material was purified by flash column chromatography (2% CH3OH/CH2Cl2) affording the title compound as a solid (8 mg). 1H NMR (400 MHz, DMSO-d6): δ 8.39 (d, 1H, J=2.4 Hz), 8.28 (s, 1H), 7.63 (d, 1H, J=2.4 Hz), 7.32 (dd, 1H, J=2.4 & 8.8 Hz), 7.06 (d, 1H, J=6.8 Hz), 6.92 (d, 1H, J=9.2 Hz), 6.81 (d, 1H, J=6.8 Hz), 2.47 (s, 3H). ESI-MS: 404.0 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]2[CH2:13][N:14]([C:16]3[CH:17]=[N:18][CH:19]=[C:20]([CH:24]=3)[C:21]([OH:23])=O)[CH2:15][C@H:10]2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:25][C:26]1[CH:27]=[C:28]([CH:30]=[C:31]([F:33])[CH:32]=1)[NH2:29]>>[F:25][C:26]1[CH:27]=[C:28]([NH:29][C:21]([C:20]2[CH:24]=[C:16]([N:14]3[CH2:13][C@@H:11]4[CH2:12][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:9][C@@H:10]4[CH2:15]3)[CH:17]=[N:18][CH:19]=2)=[O:23])[CH:30]=[C:31]([F:33])[CH:32]=1
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2CN(c3cncc(C(=O)O)c3)C[C@@H]2C1
Reactant: Nc1cc(F)cc(F)c1
Product: CC(C)(C)OC(=O)N1C[C@@H]2CN(c3cncc(C(=O)Nc4cc(F)cc(F)c4)c3)C[C@@H]2C1

Procedure:
The product from Example 33B and 3,5-difluoroaniline were processed as described in Example 33C to provide the title compound. MS (APCI) m/z 445 (M+H)+.