Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([N:10]2[C:14]([CH3:15])=[N:13][CH:12]=[N:11]2)[CH:3]=1.[ClH:16].[H][H]>CCO.[Pd]>[ClH:16].[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[C:4]([N:10]2[C:14]([CH3:15])=[N:13][CH:12]=[N:11]2)[CH:3]=1
Reactant: Cc1ncnn1-c1cc(F)ccc1C#N
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: Cc1ncnn1-c1cc(F)ccc1CN
Yield: 91 %

Procedure:
A solution of 4-fluoro-2-(5-methyl-1H-1,2,4-triazol-1-yl)benzonitrile (2.9 g, 14 mmol) in EtOH (100 mL) was mixed with 1N—HCl (15 mL) and 10% Pd—C (0.7 g, Aldrich). This mixture was hydrogenated in a Parr shaker at 45-55 psi of hydrogen for 20 h. The catalyst was filtered over Celite®, and washed with EtOH. The filtrate was concentrated, and the residue triturated with EtOH-Et2O to obtain 3.17 g (13 mmol, 91% yield) of the title compound as an off-white powder: HPLC 0.47 min (AP 100% at 254 nm); LC/MS m/z 207 (M+H); 1H NMR (DMSO-d6, 300 MHz) δ ppm 2.40 (3H, s, CH3), 3.77 (2H, d, J=5.5 Hz, NCH2), 7.52-7.62 (1H, m), 7.66 (1H, dd, J=9.2, 2.6 Hz), 7.87 (1H, t, J=7 Hz), 8.14 (1H, s), 8.47 (3H, brs, NH3+).
Reaction SMILES: [CH3:1]C1C=CC(C2C=NN(C)C=2)=C(C=1)C(OC)=O.Cl[C:19]1[N:24]=[C:23]([C:25]2[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][C:26]=2[C:27]([O:29][CH3:30])=[O:28])[CH:22]=[CH:21][N:20]=1.CB1OB(C)OB(C)O1>>[CH3:35][C:32]1[CH:33]=[CH:34][C:25]([C:23]2[CH:22]=[CH:21][N:20]=[C:19]([CH3:1])[N:24]=2)=[C:26]([CH:31]=1)[C:27]([O:29][CH3:30])=[O:28]
Reactant: COC(=O)c1cc(C)ccc1-c1cnn(C)c1
Reactant: COC(=O)c1cc(C)ccc1-c1ccnc(Cl)n1
Agent: CB1OB(C)OB(C)O1
Product: COC(=O)c1cc(C)ccc1-c1ccnc(C)n1

Procedure:
The title compound was synthesized following the same general protocol as described for methyl 5-methyl-2-(1-methyl-1H-pyrazol-4-yl)benzoate in Example A1, using methyl 2-(2-chloropyrimidin-4-yl)-5-methylbenzoate and 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane. ESI-MS (m/z): 243 [M+1]+.
Reaction SMILES: C(O)(=O)C.[CH2:5]([O:7][CH:8]([O:18]CC)[C:9]1[N:10]=[CH:11][NH:12][C:13]=1[C:14](OC)=[O:15])C.C1(C)C=CC=CC=1>O>[CH:14]([C:13]1[N:12]=[CH:11][NH:10][C:9]=1[C:8]([O:7][CH3:5])=[O:18])=[O:15]
Reactant: CCOC(OCC)c1nc[nH]c1C(=O)OC
Solvent: O
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: COC(=O)c1[nH]cnc1C=O
Temperature: 25 °C
Reaction time: 6 h

Procedure:
Acetic acid (244 mmol, 34.7 equiv.) was added to a solution of methyl 4-(diethoxy-methyl)-1H-imidazole-5-carboxylate (7.04 mmol, 1 equiv.) in water (4.2 ml), and the resulting mixture was stirred for 6 h at 25° C. under nitrogen. Toluene was added to the reaction mixture, and the solvent was removed in vacuo in order thus to yield the desired product in the form of a yellow solid. This was used in the following stage without further purification. Yield: quantitative
Reaction SMILES: [CH:1]1([O:4][N:5]=[C:6]([C:10]2[N:11]=[C:12]([NH:15]C=O)[S:13][CH:14]=2)[C:7]([OH:9])=[O:8])[CH2:3][CH2:2]1.[ClH:18]>CO>[ClH:18].[NH2:15][C:12]1[S:13][CH:14]=[C:10]([C:6](=[N:5][O:4][CH:1]2[CH2:3][CH2:2]2)[C:7]([OH:9])=[O:8])[N:11]=1
Reactant: O=CNc1nc(C(=NOC2CC2)C(=O)O)cs1
Agent: Cl
Solvent: CO
Product: Nc1nc(C(=NOC2CC2)C(=O)O)cs1
Reaction time: 1.5 h

Procedure:
A mixture of 2-cyclopropyloxyimino-2-(2-formamidothiazol-4-yl) acetic acid (syn isomer) (255 mg) and conc. hydrochloric acid (0.21 ml) in methanol (1.3 ml) was stirred at 30° to 32° C. for 1.5 hours. The mixture was concentrated in vacuo, triturated with diisopropyl ether, diethyl ether and ethyl acetate in turn. The resultant solid was dried over phosphorus pentoxide to give 2-(2-aminothiazol-4-yl)-2-cyclopropyloxyiminoacetic acid hydrochloride (syn isomer) (265 mg).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:15][C:14]([NH:16][C:17]3[CH:18]=[CH:19][CH:20]=[C:21]4[C:26]=3[CH2:25][C:24](=[O:27])[CH2:23][CH2:22]4)=[N:13][CH:12]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C1C=CC(C2OC(NC3C=CC=C4C=3CC(=O)CC4)=NC=2)=CC=1>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:15][C:14]([NH:16][C:17]3[CH:18]=[CH:19][CH:20]=[C:21]4[C:26]=3[CH2:25][CH:24]([OH:27])[CH2:23][CH2:22]4)=[N:13][CH:12]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(-c2cnc(Nc3cccc4c3CC(=O)CC4)o2)cc1
Agent: O=C1CCc2cccc(Nc3ncc(-c4ccc(C(F)(F)F)cc4)o3)c2C1
Product: CC(C)(C)c1ccc(-c2cnc(Nc3cccc4c3CC(O)CC4)o2)cc1

Procedure:
The title compound was prepared using the procedure of Example 2, substituting the product of Example 3B for the product of Example 1I. 1H NMR (DMSO-d6) δ 9.07 (s, 1H), 7.58 (d, 1H, J=5.4 Hz), 7.46 (m, 3H), 7.30 (s, 1H), 7.08 (t, 1H, J=7.8 Hz), 6.83 (d, 1H, J=7.1 Hz), 4.80 (d, 1H, J=4.0 Hz), 3.91 (m, 1H), 2.72-2.96 (m, 4H), 1.86 (m, 1H), 1.62 (m, 1H), 1.29 (s, 9H); MS (ESI+) m/z 363 (M+H).
Reaction SMILES: [OH-].[K+].[I:3][C:4]1[N:5]=[C:6]([CH:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)[NH:7][C:8]=1[I:9].Cl.Cl[CH2:25][CH2:26][N:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1.P(=O)(O)(O)O>CN1CCCC1=O.O>[I:3][C:4]1[N:5]=[C:6]([CH:10]2[CH2:11][CH2:12][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:14][CH2:15]2)[N:7]([CH2:25][CH2:26][N:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[C:8]=1[I:9]
Reactant: ClCCN1CCCC1
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(I)c(I)[nH]2)CC1
Agent: Cl
Agent: O=P(O)(O)O
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(c2nc(I)c(I)n2CCN2CCCC2)CC1
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 99.4 %

Procedure:
Add potassium hydroxide (45.13 g, 4.0 eq) to a solution of tert-butyl 4-(4,5-diiodo-1H-imidazol-2-yl)piperidine-1-carboxylate (86 g, 170.9 mmol) in N-methylpyrrolidinone (258 mL) portionwise over 25 minutes, maintaining the temperature below 40° C. Stir the mixture for 25 minutes, then add 1-(2-chloroethyl)pyrrolidine hydrochloride (47.5 g, 1.6 eq) portionwise. Stir the resulting mixture for 16 hours at 40° C., then allow to cool to room temperature. Pour the reaction into water (3.1 L) and add aqueous 15% phosphoric acid to adjust the pH to 7.5-8. Stir the resulting suspension for one hour at 0-5° C. Filter, wash with water, and dry under vacuum at 50° C. to give tert-butyl 4-[4,5-diiodo-1-(2-pyrrolidin-1-ylethyl)imidazol-2-yl]piperidine-1-carboxylate (102 g, 99%). MS (ES) m/z=601 [M]+.
Reaction SMILES: CON(C)[C:4](=[O:12])[CH2:5][C:6]1[CH:11]=[CH:10][N:9]=[CH:8][CH:7]=1.[CH3:14][Mg+].[Br-]>C1COCC1>[N:9]1[CH:10]=[CH:11][C:6]([CH2:5][C:4](=[O:12])[CH3:14])=[CH:7][CH:8]=1
Reactant: CON(C)C(=O)Cc1ccncc1
Reactant: C[Mg+]
Agent: [Br-]
Solvent: C1CCOC1
Product: CC(=O)Cc1ccncc1
Temperature: 0 °C
Reaction time: 16 h
Yield: 51 %

Procedure:
To a 250-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of argon, was added THF (70 mL) and N-methoxy-N-methyl-2-(pyridin-4-yl)acetamide (7.0 g, 0.039 mol, 1.0 equiv). The mixture was cooled to 0° C. and CH3MgBr (3M in THF, 65 mL, 5.0 equiv) was added dropwise. The resulting solution was warmed to ambient temperature and stirred for 16 h. The reaction mixture was cooled to 0° C. and quenched by the addition of saturated NH4Cl (aq, 100 mL). The resulting solution was extracted with EtOAc (3×200 mL). The organic layers were combined, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude was purified by flash chromatography (silica gel, CH2Cl2/CH3OH (20:1)) to yield 2.7 g (51%) of the title compound as yellow oil. 1H-NMR (400 MHz, CDCl3): δ ppm 8.58 (m, 2H), 7.17 (d, J=0.4 Hz, 2H), 3.75 (s, 2H), 2.24 (s, 3H).
Reaction SMILES: [Cl-].[Cl:2][C:3]1[CH:28]=[C:27]([O:29][CH3:30])[C:26]([CH3:31])=[C:25]([Cl:32])[C:4]=1[CH2:5][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.ClC1C(C)=C(OC)C=C(Cl)C=1CCl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:65]([O:67][C:68](=[O:79])[CH:69]=[C:70]([CH3:78])[CH:71]=[CH:72][CH:73]=[C:74]([CH:76]=O)[CH3:75])[CH3:66].C1OC1CC>C1(C)C=CC=CC=1.CCCCCC>[CH2:65]([O:67][C:68](=[O:79])[CH:69]=[C:70]([CH3:78])[CH:71]=[CH:72][CH:73]=[C:74]([CH3:76])[CH:75]=[CH:5][C:4]1[C:25]([Cl:32])=[C:26]([CH3:31])[C:27]([O:29][CH3:30])=[CH:28][C:3]=1[Cl:2])[CH3:66]
Reactant: COc1cc(Cl)c(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c(Cl)c1C
Reactant: CCOC(=O)C=C(C)C=CC=C(C)C=O
Agent: CCC1CO1
Agent: COc1cc(Cl)c(CCl)c(Cl)c1C
Agent: [Cl-]
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: CCOC(=O)C=C(C)C=CC=C(C)C=Cc1c(Cl)cc(OC)c(C)c1Cl

Procedure:
100 g. of 2,6-dichloro-4-methoxy-5-methyl-benzyl-triphenylphosphonium chloride, prepared from 52 g. of 2,6-dichloro-4-methoxy-3-methyl-benzyl chloride and 57 g. of triphenylphosphine, are treated with 42 g. of 7-formyl-3-methyl-octa-2,4,6-trien-1-oic acid ethyl ester. After the addition of 120 ml. of 1,2-butylene oxide, the resulting mixture is heated to 80°-85° C. for 4 hours while stirring. The mixture is diluted with toluene/hexane (1:1 parts by volume) and exhaustively extracted with methanol/water (60:40 parts by volume). The resulting solution is evaporated under reduced pressure. The oily residue is purified by adsorption on silica gel using toluene for the elution. 9-(2,6-dichloro-4-methoxy-5-methyl-phenyl)-3,7-dimethyl-nona-2,4,6,8-tetraen-1-oic acid ethyl ester is obtained from the eluate and melts at 100°-101° C. after recrystallization from benzene/hexane (50:50 parts by volume).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH2:12][N:13]([C:15]4[N:20]=[CH:19][C:18]([C:21]([O:23][CH3:24])=[O:22])=[CH:17][N:16]=4)[CH2:14][C:5]=3[C:4]=2[CH:3]=1.C(O)(C(F)(F)F)=O.C([SiH](CC)CC)C>C(Cl)Cl>[CH3:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][CH:6]3[CH2:11][CH2:12][N:13]([C:15]4[N:16]=[CH:17][C:18]([C:21]([O:23][CH3:24])=[O:22])=[CH:19][N:20]=4)[CH2:14][CH:5]3[C:4]=2[CH:3]=1
Reactant: COC(=O)c1cnc(N2CCc3[nH]c4ccc(C)cc4c3C2)nc1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1cnc(N2CCC3Nc4ccc(C)cc4C3C2)nc1
Reaction time: 0.5 h
Yield: 27.4 %

Procedure:
Methyl 2-(8-methyl-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indol-2-yl)pyrimidine-5-carboxylate was obtained from Example 7 and 8-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole using the method described in Example 12. To a stirred solution of methyl 2-(8-methyl-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indol-2-yl)pyrimidine-5-carboxylate (0.250 g, 0.776 mmol) in dry DCM, TFA (2.5 ml, 129.81 mmol) was added and stirred for 30 min. Then triethylsilane (2.5 ml, 62.6 mmol) was added at room temperature and stirred for 2 h. The progress of the reaction was monitored by TLC and after completion, the reaction mixture was diluted with DCM and washed with saturated solution of sodium bicarbonate and the organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to furnish methyl 2-(8-methyl-1,3,4,4a,5,9b-hexahydro-2H-pyrido[4,3-b]indol-2-yl)pyrimidine-5-carboxylate (69 mg, 27.5%). 1H NMR (200 MHz, CDCl3): δ 1.69 (m, 2H), 2.35 (s, 3H), 2.7 (m; 2H), 3.01 (m, 4H), 3.90 (s, 3H), 6.23 (m, 1H), 6.80 (2H, m), 8.91 (s, 2H); m/e=325 (M+1).
Reaction SMILES: [C:1]([O-:24])(=[O:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].[Ag+:25].[Br:26]N1C(=O)CCC1=O>CC(C)=O>[Ag:25][Br:26].[C:1]([O-:24])(=[O:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].[Ag+:25]
Reactant: O=C1CCC(=O)N1Br
Agent: [Ag+]
Agent: CCCCCCCCCCCCCCCCCCCCCC(=O)[O-]
Solvent: CC(C)=O
Product: Br[Ag]

Procedure:
Next, to the polymer dispersion of silver behenate maintained at 50° C. while stirring at 500 rpm, was added an acetone solution containing N-bromosuccinimide (0.7 g of N-bromosuccinimide and 50 cc of acetone) at 25° C. over a period of 90 minutes and the reaction system was further stirred for 60 minutes resulting in the preparation of a polymer dispersion of both silver bromide and silver behenate. The average grain size (measured microscopically using transmitted light) of the silver bromide grains was about 0.06μ.
Reaction SMILES: IC.C[N:4]([CH:15]1[CH2:20][CH2:19][N:18]([C:21](=S)[NH:22][CH3:23])[CH2:17][CH2:16]1)[C:5](=O)OCC1C=CC=CC=1.C(O[CH:28](OCC)[CH2:29][NH2:30])C>CO>[CH3:5][NH:4][CH:15]1[CH2:16][CH2:17][N:18]([C:21]2[N:22]([CH3:23])[CH:28]=[CH:29][N:30]=2)[CH2:19][CH2:20]1
Reactant: CNC(=S)N1CCC(N(C)C(=O)OCc2ccccc2)CC1
Reactant: CCOC(CN)OCC
Solvent: CO
Solvent: CI
Product: CNC1CCN(c2nccn2C)CC1
Reaction time: 20 h

Procedure:
A solution of iodomethane (0.22 ml, 3.4267 mmol, 1.1 eq) in methanol (5 ml) was added dropwise over a period of 5 min to a solution of benzyl methyl(1-(methylcarbamothioyl)-piperidin-4-yl)carbamate (1 g, 3.115 mmol, 1 eq) in methanol (10 ml). Stirring was then carried out for 20 h at room temperature. When the reaction was complete according to TLC monitoring, the reaction mixture was concentrated under reduced pressure. The residue was taken up in pyridine (15 ml); aminoacetaldehyde-diethylacetal (455 mg, 3.4267 mmol, 1.1 eq) was added and refluxing was carried out for 10 h. The reaction mixture was concentrated under reduced pressure, 2 N HCl solution (20 ml) was added, and the mixture was refluxed for 5 h. The reaction mixture was concentrated under reduced pressure and dried by removal of toluene by distillation. The crude product was used in the next stage without being purified further. Yield: 1.1 g (5.67 mmol)
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[C:30]([O:31][CH3:32])=[CH:29][C:25]([C:26](O)=[O:27])=[C:24]([F:33])[CH:23]=4)=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:34][C@@H:35]1[CH2:40][CH2:39][CH2:38][N:37](C(OC(C)(C)C)=O)[CH2:36]1.C(O)(C(F)(F)F)=O>>[CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[C:30]([O:31][CH3:32])=[CH:29][C:25]([C:26]([NH:34][C@@H:35]5[CH2:40][CH2:39][CH2:38][NH:37][CH2:36]5)=[O:27])=[C:24]([F:33])[CH:23]=4)=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](N)C1
Reactant: COc1cc(C(=O)O)c(F)cc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(C(=O)N[C@@H]2CCCNC2)c(F)cc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C

Procedure:
The title compound was synthesized from 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-2-fluoro-5-methoxybenzoic acid and (R)-tert-butyl 3-aminopiperidine-1-carboxylate as described in the General procedure for amide bond synthesis. The Boc group was then deprotected using TFA. The final compound was purified by reverse phase HPLC and basified to give the free base. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.47 (m, 3H) 1.61 (m, 9H) 1.99 (s, 3H) 2.73 (m, 1H) 2.93 (m, 1H) 3.92 (s, 4H) 4.01-4.20 (t, J=14 Hz, 2H) 4.82 (m, 1H) 7.24 (d, J=6.8 Hz, 1H) 7.71-7.90 (m, 1H) 8.05 (s, 1H) 8.14-8.38 (m, 2H). [M+H] calc'd for C26H32F3N7O3, 548. found 548.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([C:24]2[CH:29]=[CH:28][C:27]([C:30](O)=[O:31])=[CH:26][CH:25]=2)=[CH:7][CH:8]=[C:9]([C:11]2[S:12][CH:13]=[C:14]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=3)[N:15]=2)[CH:10]=1)=[O:4].[CH3:33][C:34]1[CH:35]=[C:36]([CH:39]=[CH:40][CH:41]=1)[CH2:37][NH2:38]>>[Cl:23][C:18]1[CH:17]=[C:16]([C:14]2[N:15]=[C:11]([C:9]3[CH:10]=[C:5]([C:3]([OH:2])=[O:4])[C:6]([C:24]4[CH:29]=[CH:28][C:27]([C:30](=[O:31])[NH:38][CH2:37][C:36]5[CH:39]=[CH:40][CH:41]=[C:34]([CH3:33])[CH:35]=5)=[CH:26][CH:25]=4)=[CH:7][CH:8]=3)[S:12][CH:13]=2)[CH:21]=[CH:20][C:19]=1[Cl:22]
Reactant: Cc1cccc(CN)c1
Reactant: COC(=O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1-c1ccc(C(=O)O)cc1
Product: Cc1cccc(CNC(=O)c2ccc(-c3ccc(-c4nc(-c5ccc(Cl)c(Cl)c5)cs4)cc3C(=O)O)cc2)c1
Yield: 38.2 %

Procedure:
Using the conditions of General Procedure E for Amide Coupling in Parallel Mode, 4-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-biphenyl-2,4′-dicarboxylic acid 2-methyl ester (which may be prepared as described for Intermediate 8; 100 mg, 0.21 mmol) was reacted with 3-methylbenzylamine (available from Aldrich Chemical Company, Inc.; 75 mg, 0.62 mmol). The resulting ester was hydrolyzed and the acid was purified using HPLC Purification Conditions B to give 4-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-4′-(3-methyl-benzylcarbamoyl)-biphenyl-2-carboxylic acid (46 mg, 39%). 1H NMR (400 MHz, DMSO-d6) δ ppm 13.18 (br s, 1H), 9.07 (t, J=5.9 Hz, 1H), 8.46 (s, 1H), 8.38 (d, J=1.8 Hz, 1H), 8.33 (d, J=2.0 Hz, 1H), 8.24 (dd, J=8.0, 2.0 Hz, 1H), 8.09 (dd, J=8.5, 2.0 Hz, 1H), 7.97 (d, J=8.3 Hz, 2H), 7.76 (d, J=8.5 Hz, 1H), 7.59 (d, J=8.0 Hz, 1H), 7.50 (d, J=8.3 Hz, 2H), 7.19-7.26 (m, 1H), 7.11-7.18 (m, 2H), 7.07 (d, J=7.3 Hz, 1H), 4.48 (d, J=5.8 Hz, 2H), 2.30 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:32][CH2:31][C:11]3([CH2:15][N:14](C(OCC4C=CC=CC=4)=O)[C@H:13]([C:26]([O:28]CC)=[O:27])[CH2:12]3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([O:33][C@H:34]([C:39]2[CH:44]=[CH:43][C:42](Br)=[CH:41][C:40]=2[N:46]2[CH2:51][CH2:50][N:49](C(OCC3C=CC=CC=3)=O)[CH2:48][CH2:47]2)[C:35]([F:38])([F:37])[F:36])[N:3]=1.[CH:62]([O:65][C:66]1[CH:71]=[CH:70][C:69](B(O)O)=[CH:68][CH:67]=1)([CH3:64])[CH3:63]>>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:32][CH2:31][C:11]3([CH2:15][NH:14][C@H:13]([C:26]([OH:28])=[O:27])[CH2:12]3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([O:33][C@H:34]([C:39]2[CH:44]=[CH:43][C:42]([C:69]3[CH:70]=[CH:71][C:66]([O:65][CH:62]([CH3:64])[CH3:63])=[CH:67][CH:68]=3)=[CH:41][C:40]=2[N:46]2[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]2)[C:35]([F:38])([F:36])[F:37])[N:3]=1
Reactant: CC(C)Oc1ccc(B(O)O)cc1
Reactant: CCOC(=O)[C@@H]1CC2(CCN(c3cc(O[C@H](c4ccc(Br)cc4N4CCN(C(=O)OCc5ccccc5)CC4)C(F)(F)F)nc(N)n3)CC2)CN1C(=O)OCc1ccccc1
Product: CC(C)Oc1ccc(-c2ccc([C@@H](Oc3cc(N4CCC5(CC4)CN[C@H](C(=O)O)C5)nc(N)n3)C(F)(F)F)c(N3CCNCC3)c2)cc1

Procedure:
The title compound was prepared starting with (S)-2-benzyl 3-ethyl 8-(2-amino-6-((R)-1-(2-(4-((benzyloxy)carbonyl)piperazin-1-yl)-4-bromophenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate (intermediate from Step 8, Example 36d] via a Suzuki coupling with (4-isopropoxyphenyl)boronic acid as described for example 54b.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([CH3:20])([CH3:19])[C:16]([OH:18])=O)=[CH:11][CH:10]=2)[CH:6]=[N:7][CH:8]=1)#[N:2].[CH3:21][CH2:22][CH:23]([NH2:26])[CH2:24][CH3:25]>>[C:1]([C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[CH:11][C:12]([C:15]([CH3:20])([CH3:19])[C:16]([NH:26][CH:23]([CH2:24][CH3:25])[CH2:22][CH3:21])=[O:18])=[CH:13][CH:14]=2)[CH:6]=[N:7][CH:8]=1)#[N:2]
Reactant: CCC(N)CC
Reactant: CC(C)(C(=O)O)c1ccc(-c2cncc(C#N)c2)cc1
Product: CCC(CC)NC(=O)C(C)(C)c1ccc(-c2cncc(C#N)c2)cc1
Yield: 55 %

Procedure:
Prepared in a similar manner to Example 3 from 2-(4-(5-cyanopyridin-3-yl)phenyl)-2-methylpropanoic acid (example 21a) and 3-pentanamine. Yield 55%. 1H NMR (400 MHz, DMSO): δ 0.69-0.73 (t, 6H), 1.27 (m, 2H), 1.36 (m, 2H), 1.47 (s, 6H), 3.56 (m, 1H), 6.90-6.93 (d, 1H), 7.43-7.45 (d, 2H), 7.77-7.79 (d, 2H), 8.63-8.64 (t, 1H), 8.96-8.98 (d, 1H), 9.17-9.18 (d, 1H). MS (M+H, 336).
Reaction SMILES: [H-].[Na+].[CH2:3]1[C:9]2=[C:10]3[C:14](=[CH:15][CH:16]=[C:8]2[O:7][CH2:6][CH2:5][N:4]1C(OC(C)(C)C)=O)[NH:13][CH:12]=[CH:11]3.[CH3:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][C:27]=1[S:33](Cl)(=[O:35])=[O:34].Cl>CN(C=O)C.O.C(Cl)Cl.C(OCC)C>[CH3:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][C:27]=1[S:33]([N:13]1[C:14]2[C:10](=[C:9]3[CH2:3][NH:4][CH2:5][CH2:6][O:7][C:8]3=[CH:16][CH:15]=2)[CH:11]=[CH:12]1)(=[O:34])=[O:35]
Reactant: CC(C)(C)OC(=O)N1CCOc2ccc3[nH]ccc3c2C1
Reactant: COc1ccc(C)cc1S(=O)(=O)Cl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COc1ccc(C)cc1S(=O)(=O)n1ccc2c3c(ccc21)OCCNC3
Reaction time: 0.33 h
Yield: 83.1 %

Procedure:
Sodium hydride (60% in mineral oil, 16.6 mg, 0.312 mmol) was added to a solution of tert-butyl 1,3,4,8-tetrahydro-2H-[1,4]oxazepino[6,7-e]indole-2-carboxylate (Intermediate 18, 0.060 g, 0.21 mmol) in DMF (3 mL). The mixture was stirred for 20 minutes at room temperature before (2-methoxy-5-methylphenyl)sulfonyl chloride (69 mg, 0.31 mmol) was added. The mixture was stirred for 20 minutes and diluted with water and DCM. The aqueous phase was adjusted to pH 3 with 1 M HCl and extracted with DCM (2×). The combined organics were evaporated to approximately 5 mL. TFA (2 mL) was added and the mixture was stirred at room temperature for 3 hours and the reaction mixture was evaporated. The residue was dissolved in DCM and triethylamine (1 mL) was added and the mixture was evaporated. The crude product was purified by flash chromatography on silica gel using MeOH:DCM:NEt3 (3:96:1) as the eluent to give a white solid which was suspended in diethylether and filtered. The white powder was washed with cold diethylether (2×) and dried in vacuo to give the title compound (65 mg). MS m/z 373 [M+H]+.
Reaction SMILES: [C:1]1([CH:7]2[CH:12]([CH3:13])[CH:11]([OH:14])[CH:10]([CH3:15])[CH:9]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.[C:27](Cl)(=[O:39])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38]>>[C:27]([O:14][CH:11]1[CH:12]([CH3:13])[CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[NH:8][CH:9]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:10]1[CH3:15])(=[O:39])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38]
Reactant: CCCCCCCCCCCC(=O)Cl
Reactant: CC1C(c2ccccc2)NC(c2ccccc2)C(C)C1O
Agent: [Li]CCCC
Product: CCCCCCCCCCCC(=O)OC1C(C)C(c2ccccc2)NC(c2ccccc2)C1C
Yield: 74.4 %

Procedure:
The general procedure of Example 1 is repeated using 28.1 g (0.10 mol) of 2,6-diphenyl-3,5-dimethyl-4-hydroxypiperidine, 40 mL (0.10 mol) of n-butyllithium (2.5M in hexanes) and 21.8 g (0.10 mol) of lauroyl chloride. 34.5 g (74% yield) of the title compound is isolated after purification by LC (silica gel, ethyl acetate/hexane): mp 74°-76° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:18])=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][C:6]1([C:14](=[O:15])[NH:13][C:12](=[O:16])[N:11]1[CH3:17])[CH2:5]2.NC1C=C2[C:26](=[CH:27][C:28]=1Cl)[CH2:25][C:24]1([C:33](=O)[NH:32][C:31](=[O:35])[N:30]1[CH3:36])C2>>[Cl:18][C:3]1[C:2]([NH:1][C:14](=[O:15])[CH2:6][N:32]2[C:33]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[N:30]([C:36]3[CH:8]=[CH:9][CH:10]=[CH:2][N:1]=3)[C:31]2=[O:35])=[CH:10][CH:9]=[C:8]2[C:4]=1[CH2:5][C:6]1([C:14](=[O:15])[NH:13][C:12](=[O:16])[N:11]1[CH3:17])[CH2:7]2
Reactant: CN1C(=O)NC(=O)C12Cc1ccc(N)c(Cl)c1C2
Reactant: CN1C(=O)NC(=O)C12Cc1cc(N)c(Cl)cc1C2
Product: CN1C(=O)NC(=O)C12Cc1ccc(NC(=O)Cn3c(=O)n(-c4ccccn4)c4ccccc43)c(Cl)c1C2

Procedure:
Essentially following the procedures described for Example 93, but using 5′-amino-4′-chloro-3-methyl-spiro[imidazolidine-4,2′-indane]-2,5-dione, enantiomer B, (described in Intermediate 49) in place of 5′-amino-6′-chloro-3-methyl-spiro[imidazolidine-4,2′-indane]-2,5-dione, enantiomer B, the title compound was obtained. MS: m/z=517 (M+1). HRMS: m/z=517.1381; calculated m/z=517.1386 for C26H22ClN6O4.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[C:5](=[CH2:18])[CH2:6][CH2:7][O:8][CH2:9][CH2:10][CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)[CH3:2].ClC1C=CC=C(C(OO)=[O:28])C=1>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:5]1([CH2:6][CH2:7][O:8][CH2:9][CH2:10][CH2:11][CH:12]2[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]2)[CH2:18][O:28]1)=[O:19])[CH3:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=C(CCOCCCC1CCCCC1)C(=O)OCC
Solvent: ClCCl
Product: CCOC(=O)C1(CCOCCCC2CCCCC2)CO1

Procedure:
6.8 g of the title compound, in the form of a colourless oil, which is purified by chromatography on silica gel (migrating agent: 90:10 petroleum ether/ethyl acetate) are obtained by the procedure described in Example (1a) from 12.4 g of 4-(3-cyclohexylpropyloxy)-2-methylenebutyric acid ethyl ester and 18.7 g of m-chloroperbenzoic acid in 250 ml of methylene chloride. Thin layer chromatography on silica gel with petroleum ether/ethyl acetate/glacial acetic acid 80:20:3: Rf =0.65.