Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH3:19])[CH2:9][C:10](O)=[O:11])[CH:5]=[CH:6][CH:7]=1.Cl.[CH3:21][NH:22][O:23][CH3:24]>>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH3:19])[CH2:9][C:10]([N:22]([O:23][CH3:24])[CH3:21])=[O:11])[CH:5]=[CH:6][CH:7]=1
Reactant: CNOC
Reactant: Cc1ccccc1C(CC(=O)O)c1cccc(Br)c1
Agent: Cl
Product: CON(C)C(=O)CC(c1cccc(Br)c1)c1ccccc1C

Procedure:
In analogy to example 74, step 4, from 3-(3-bromo-phenyl)-3-o-tolyl-propionic acid and N,O-dimethylhydroxylamine hydrochloride was prepared the title compound as a white solid, mp 89° C., MS (ESI+): m/z=362.07 ([M+H]+, 1 Br).
Reaction SMILES: [I:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[OH:11].[CH2:12](I)[CH3:13].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C)C=O>[CH2:12]([O:11][C:3]1[CH:4]=[CH:5][C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]=1[I:1])[CH3:13]
Reactant: CCI
Reactant: O=[N+]([O-])c1ccc(O)c(I)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOc1ccc([N+](=O)[O-])cc1I
Temperature: 25 °C
Yield: 22.4 %

Procedure:
A suspension of 2-iodo-4-nitrophenol (21 g, 79.2 mmol) [ref: Kometani, T.; Watt, D. S.; Ji, T., Tetrahedron Lett. (1985), 26(17), 2043], ethyl iodide (9 mL, 0.48 mol) and potassium carbonate (40.7 g, 0.3 mol) in 100 mL of N,N-dimethylformamide was heated at 70° C. for 3 hours. The reaction was cooled to room temperature and ethyl acetate was added. The inorganic salts were filtered and washed with ethyl acetate. The organic material was washed with water (3×) and brine, dried over magnesium sulfate and filtered. Upon concentration of the filtrate a solid appeared. This solid was filtered and washed with hexanes to give 5.2 g of 1-ethoxy-2-iodo-4-nitrobenzene as white crystals. Concentration of the filtrate provided an additional 11.3 g of the desired product, mp 81-83° C.; 1H NMR (400 MHz, DMSO-d6) δ 1.42 (t, 3H), 4.26 (q, 2H), 7.18 (d, 1H), 8.26 (dd, 1H), 8.55 (d, 1H)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:20]2[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:5]=[CH:6][C:7]=1[CH2:8][C:9]1[C:14](=[O:15])[NH:13][C:12]([CH3:16])=[N:11][C:10]=1[CH2:17][CH2:18][CH3:19].[CH3:28][C:29]1([CH3:41])[CH2:33][C:32]2[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][C:31]=2[O:30]1.N1C=CC=CC=1.C(N(CC)CC)C>C(OCC)(=O)C.C([O-])(=O)C.[Cu+2].C([O-])(=O)C.ClCCl>[CH3:28][C:29]1([CH3:41])[CH2:33][C:32]2[CH:34]=[C:35]([N:13]3[C:14](=[O:15])[C:9]([CH2:8][C:7]4[CH:6]=[CH:5][C:4]([C:20]5[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=5)=[CH:3][C:2]=4[F:1])=[C:10]([CH2:17][CH2:18][CH3:19])[N:11]=[C:12]3[CH3:16])[CH:36]=[CH:37][C:31]=2[O:30]1
Reactant: CCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1F
Reactant: CC1(C)Cc2cc(B(O)O)ccc2O1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CCCc1nc(C)n(-c2ccc3c(c2)CC(C)(C)O3)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1F
Reaction time: 16 h
Yield: 70.2 %

Procedure:
A mixture of 3′-fluoro-4′-[(2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (0.72 g), (2,2-dimethyl-2,3-dihydro-1-benzofuran-5-yl)boronic acid (0.77 g), copper(II) acetate (0.73 g), pyridine (0.81 mL), triethylamine (1.4 mL), molecular sieves 4 A (1.5 g) and dichloromethane (10 mL) was stirred for 16 hr. The reaction mixture was diluted with ethyl acetate, and the insoluble material was filtered off. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound (0.71 g, 70%) as a pale-yellow liquid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:12])[C:9](=[O:11])[CH3:10].[Br:13]Br.C(O)(=O)C.C(Cl)(Cl)Cl>>[Br:13][CH2:10][C:9](=[O:11])[C:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Cl:1])=[O:12]
Reactant: CC(=O)C(=O)c1ccccc1Cl
Reactant: BrBr
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: O=C(CBr)C(=O)c1ccccc1Cl
Temperature: 60 °C
Reaction time: 17 h

Procedure:
A mixture of 1-(2-chlorophenyl)propane-1,2-dione (4.2379 g, 23.208 mmol), bromine (1.1891 mL, 23.208 mmol), and glacial acetic acid (0.67005 mL, 11.604 mmol) in chloroform (58.020 mL, 23.208 mmol) was heated at 60° C. After 17 h of stirring at 60° C., the mixture was removed from heat and concentrated under reduced pressure to give 3-bromo-1-(2-chlorophenyl)propane-1,2-dione as an orange liquid: LC-MS: a peak of m/z 261.0 [M+H(79Br)]+ and 262.9 [M+H (81Br)]+. The orange liquid was carried on crude without purification for the next step.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([NH2:10])=[O:9])=[C:6]([N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[N:18]([CH3:33])[CH:19]=[C:20]([C:22]4[CH:27]=[CH:26][C:25]([F:28])=[C:24]([C:29]([F:32])([F:31])[F:30])[CH:23]=4)[N:21]=3)[CH2:13][CH2:12]2)[N:5]=[CH:4][N:3]=1.NC1C(C#N)=C(N2CCC(C3N(C[CH2:66][N:67]([CH:69]([CH3:71])[CH3:70])[CH3:68])C=C(C4C=CC(F)=C(C(F)(F)F)C=4)N=3)CC2)N=CN=1>>[NH2:1][C:2]1[C:7]([C:8]([NH2:10])=[O:9])=[C:6]([N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[N:18]([CH2:33][CH2:66][N:67]([CH:69]([CH3:71])[CH3:70])[CH3:68])[CH:19]=[C:20]([C:22]4[CH:27]=[CH:26][C:25]([F:28])=[C:24]([C:29]([F:32])([F:31])[F:30])[CH:23]=4)[N:21]=3)[CH2:13][CH2:12]2)[N:5]=[CH:4][N:3]=1
Reactant: CC(C)N(C)CCn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc(N)c2C#N)CC1
Reactant: Cn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc(N)c2C(N)=O)CC1
Product: CC(C)N(C)CCn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCN(c2ncnc(N)c2C(N)=O)CC1

Procedure:
The title compound was prepared in an analogous manner as 4-Amino-6-{4-[4-(4-fluoro-3-trifluoromethyl-phenyl)-1-methyl-1H-imidazol-2-yl]-piperidin-1-yl}-pyrimidine-5-carboxamide using 4-Amino-6-(4-{4-(4-fluoro-3-trifluoromethyl-phenyl)-1-[2-(isopropyl-methyl-amino)-ethyl]-1H-imidazol-2-yl}-piperidin-1-yl)-pyrimidine-5-carbonitrile instead of 4-amino-6-(4-{4-[4-fluoro-3-(trifluoromethyl)phenyl]-1-methyl-1H-imidazol-2-yl}piperidin-1-yl)pyrimidine-5-carbonitrile. LC-MS: (M+1=549, obsd.=549).
Reaction SMILES: [C:1]([C:4]1[O:5][C:6]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([Br:16])[C:7]=2[C:8]=1[NH2:9])(=[O:3])[CH3:2].[CH:17]([C:19]1[N:20]=[C:21]([NH:24][C:25](=[O:29])[CH:26]([CH3:28])[CH3:27])[S:22][CH:23]=1)=O.[OH-].[Na+].O>C1COCC1>[NH2:9][C:8]1[C:7]2[C:10]([Br:16])=[C:11]([O:14][CH3:15])[CH:12]=[CH:13][C:6]=2[O:5][C:4]=1[C:1](=[O:3])[CH:2]=[CH:17][C:19]1[N:20]=[C:21]([NH:24][C:25](=[O:29])[CH:26]([CH3:27])[CH3:28])[S:22][CH:23]=1
Reactant: COc1ccc2oc(C(C)=O)c(N)c2c1Br
Reactant: CC(C)C(=O)Nc1nc(C=O)cs1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc2oc(C(=O)C=Cc3csc(NC(=O)C(C)C)n3)c(N)c2c1Br
Temperature: 0 °C
Yield: 61.5 %

Procedure:
A mixture of 12G (2 g, 7 mmol), 11D (2.8 g, 14.5 mmol) in THF (20 mL) was cooled to 0° C. To the mixture was added NaOH (2 g). The reaction mixture was reacted at room temperature overnight. TLC monitored the reaction. After reaction completed, the reaction mixture was added dropwise into water. The precipitated solids were collected by filtration to give 16A (2 g, 61% yield).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4](=[C:8]([NH2:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:5](=O)[CH3:6].P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:18].C1(Cl)C(=O)C(Cl)=C(Cl)C(=O)C=1Cl>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]([C:4]1[C:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:15][S:18][C:5]=1[CH3:6])=[O:16]
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: COC(=O)C(C(C)=O)=C(N)c1ccccc1
Agent: O=C1C(Cl)=C(Cl)C(=O)C(Cl)=C1Cl
Solvent: Cc1ccccc1
Product: COC(=O)c1c(-c2ccccc2)nsc1C
Temperature: 25 °C
Yield: 42.6 %

Procedure:
A mixture of 2-(amino-phenyl-methylene)-3-oxo-butyric acid methyl ester (4.48 mmol), phosphorus pentasulfide (13.43 mmol), chloranil (4.48 mmol), and toluene was refluxed for 15 minutes before it was cooled to room temperature and filtered. The filtrate was concentrated and the residue was purified by flash column chromatography with a gradient of ethyl acetate and hexanes on silica gel (40 g) to give the title compound as a red oil (445 mg); 1H NMR (CDCl3, 200 MHz): δ=7.51 (m, 2H), 7.42 (m, 3H), 3.75 (s, 3H), 2.74 (s, 3H); MS: (+) m/z 224.32 (M+H+).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH:8]=1)(=O)=O.C(N(CC)CC)C.[CH3:26][Si:27]([C:30]#[CH:31])([CH3:29])[CH3:28].C(OCC)(=O)C>CCCCCC.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:13]([C:9]1[CH:8]=[C:7]([C:31]#[C:30][Si:27]([CH3:29])([CH3:28])[CH3:26])[CH:12]=[CH:11][CH:10]=1)([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)c1cccc(OS(=O)(=O)C(F)(F)F)c1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CC(C)(C)c1cccc(C#C[Si](C)(C)C)c1

Procedure:
Following General Procedure D and using trifluoromethanesulfonic acid, 3-tertbutyl-phenyl ester (Intermediate 101, 2.54 g, 9.0 mmol), triethyl amine (2 mL), copper(I)iodide (0.63 g, 3.33 mmol), trimethylsilyl acetylene (5 mL, 36 mmol) and dichlorobis(triphenylphosphine)palladium(II) (1.6 g, 2.25 mmol) followed by flash column chromatography over silica gel (230-400 mesh) using 10% ethyl acetate in hexane as the eluent, the title compound was obtained as a brown oil that was used as such for the next step.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH2:10][C:11](O)=O)=[CH:5][CH:4]=1)#[N:2].[C:14]1([N:20]([CH2:32][CH2:33][CH2:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[C:21](=[O:31])[C:22]2[CH:27]=[CH:26][C:25]([NH:28][CH3:29])=[C:24]([NH2:30])[CH:23]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>ClCCl.CO>[C:14]1([N:20]([CH2:32][CH2:33][CH2:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[C:21]([C:22]2[CH:27]=[CH:26][C:25]3[N:28]([CH3:29])[C:11]([CH2:10][NH:9][C:6]4[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=4)=[N:30][C:24]=3[CH:23]=2)=[O:31])[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: N#Cc1ccc(NCC(=O)O)cc1
Reactant: CNc1ccc(C(=O)N(CCCC(=O)OC(C)(C)C)c2ccccc2)cc1N
Solvent: ClCCl
Solvent: CO
Product: Cn1c(CNc2ccc(C#N)cc2)nc2cc(C(=O)N(CCCC(=O)OC(C)(C)C)c3ccccc3)ccc21
Yield: 65 %

Procedure:
Prepared analogously to Example 25c from N-(4-cyanophenyl)glycine and 3-amino-4-methylaminobenzoic acid-N-phenyl-N-(3-tert-butyloxycarbonylpropyl)amide. Yield: 65% of theory; Rf value: 0.17 (silica gel; dichloromethane/methanol=19:1).
Reaction SMILES: C[O:2][C:3]1[CH:20]=[CH:19][C:6]([CH2:7][C:8]2[S:9][C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:11][CH:12]=2)=[CH:5][CH:4]=1.B(Br)(Br)Br>>[C:13]1([C:10]2[S:9][C:8]([CH2:7][C:6]3[CH:5]=[CH:4][C:3]([OH:2])=[CH:20][CH:19]=3)=[CH:12][CH:11]=2)[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: COc1ccc(Cc2ccc(-c3ccccc3)s2)cc1
Agent: BrB(Br)Br
Product: Oc1ccc(Cc2ccc(-c3ccccc3)s2)cc1
Yield: 100.1 %

Procedure:
The title compound (480 mg, 99%) was prepared from the product of step 3 (0.50 g, 1.8 mmol) and BBr3 (1.3 g, 5.3 mmol) using the procedure of Example 146, step 2.
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[CH:5]=[C:6](/[CH:16]=[CH:17]/[C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:7]=[N:8][C:9]=1[NH:10][C@@H:11]1[CH2:15][CH2:14][NH:13][CH2:12]1.[Cl:23][C:24]1[CH:32]=[CH:31][C:27]([C:28](Cl)=[O:29])=[CH:26][CH:25]=1.CCN(CC)CC.CCOC(C)=O>CN(C=O)C.O>[Cl:3][C:4]1[CH:5]=[C:6](/[CH:16]=[CH:17]/[C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:7]=[N:8][C:9]=1[NH:10][C@@H:11]1[CH2:15][CH2:14][N:13]([C:28](=[O:29])[C:27]2[CH:31]=[CH:32][C:24]([Cl:23])=[CH:25][CH:26]=2)[CH2:12]1
Reactant: CCOC(=O)/C=C/c1cnc(N[C@@H]2CCNC2)c(Cl)c1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: CCOC(=O)/C=C/c1cnc(N[C@@H]2CCN(C(=O)c3ccc(Cl)cc3)C2)c(Cl)c1
Yield: 96.8 %

Procedure:
A solution of ethyl (2E)-3-{5-chloro-6-[(3R)-3-pyrrolidinylamino]-3-pyridinyl}acrylate dihydrochloride (500 mg), 4-chlorobenzoyl chloride (249 mg) and Et3N (0.624 ml) in DMF (20 ml) was stirred at ambient temperature for 10 hours. The reaction mixture was poured into a mixture of AcOEt and H2O and the organic layer was washed with brine and dried over MgSO4. The solvent was evaporated in vacuo and the residue was washed with IPE and n-hexane to give ethyl (2E)-3-(5-chloro-6-{[(3R)-1-(4-chlorobenzoyl)-3-pyrrolidinyl]amino}-3-pyridinyl)acrylate (570 mg).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:46])=[C:4]([C@:8]([C@@H:16]2[CH2:21][CH2:20][CH2:19][N:18]([C:22]([NH:24][C@@H:25]([CH2:39][CH:40]3[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]3)[C@@H:26]([OH:38])[CH2:27][NH:28]C(=O)OCC[Si](C)(C)C)=[O:23])[CH2:17]2)([OH:15])[CH2:9][CH2:10][CH2:11][CH2:12][O:13][CH3:14])[CH:5]=[CH:6][CH:7]=1>C(#N)C.[F-].C([N+](CC)(CC)CC)C>[NH2:28][CH2:27][C@H:26]([OH:38])[C@@H:25]([NH:24][C:22]([N:18]1[CH2:19][CH2:20][CH2:21][C@@H:16]([C@@:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=2[F:46])([OH:15])[CH2:9][CH2:10][CH2:11][CH2:12][O:13][CH3:14])[CH2:17]1)=[O:23])[CH2:39][CH:40]1[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]1
Reactant: COCCCC[C@@](O)(c1cccc(Cl)c1F)[C@@H]1CCCN(C(=O)N[C@@H](CC2CCCCC2)[C@@H](O)CNC(=O)OCC[Si](C)(C)C)C1
Agent: CC[N+](CC)(CC)CC
Agent: [F-]
Solvent: CC#N
Product: COCCCC[C@@](O)(c1cccc(Cl)c1F)[C@@H]1CCCN(C(=O)N[C@@H](CC2CCCCC2)[C@@H](O)CN)C1
Temperature: 50 °C
Reaction time: 2 h
Yield: 117 %

Procedure:
To a solution of 2-(trimethylsilyl)ethyl (2S,3S)-3-((R)-3-((S)-1-(3-chloro-2-fluorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamido)-4-cyclohexyl-2-hydroxybutylcarbamate (25.8 mg, 0.038 mmol) in acetonitrile (2 mL), tetraethylammonium fluoride (excess) was added. The resulting solution was stirred at 50° C. for 2 h, and purified directly with preparative HPLC to give (R)-N-((2S,3S)-4-amino-1-cyclohexyl-3-hydroxybutan-2-yl)-3-((S)-1-(3-chloro-2-fluorophenyl)-1-hydroxy-5-methoxy-pentyl)piperidine-1-carboxamide (24.1 mg, 96%) as its TFA salt; 1H NMR (400 MHz, CD3OD) δ 7.54 (dd, 1H), 7.38 (dd, 1H), 7.14 (dd, 1H), 4.36 (d, 1H); 3.94 (m, 2H), 3.78 (m, 1H), 3.28 (m, 2H), 3.24 (s, 3H), 2.94 (dd, 1H), 2.84 (m, 2H), 2.64 (dd, 1H), 2.16 (m, 1H), 1.98 (m, 3H), 0.78-1.86 (m, 20H); MS m/z 542 (M+H+).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20]Cl)[CH:15]=2)=[C:10]([CH3:22])[CH:9]=1.[OH:23][C:24]1[CH:31]=[CH:30][C:27]([CH:28]=[O:29])=[CH:26][CH:25]=1>CN(C=O)C>[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][O:23][C:24]3[CH:31]=[CH:30][C:27]([CH:28]=[O:29])=[CH:26][CH:25]=3)[CH:15]=2)=[C:10]([CH3:22])[CH:9]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: Cc1cc(Cl)ccc1-c1cccc(CCl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(Cl)ccc1-c1cccc(COc2ccc(C=O)cc2)c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
Potassium carbonate was added to a DMF solution of 4-chloro-3′-(chloromethyl)-2-methylbiphenyl and 4-hydroxybenzaldehyde, followed by stirring at room temperature for 20 hours to obtain 4-[(4′-chloro-2′-methylbiphenyl-3-yl)methoxy]benzaldehyde.
Reaction SMILES: [CH:1]1([C:6]2[CH:7]=[C:8]3[C:13](=[CH:14][CH:15]=2)[C:12](=[O:16])[NH:11][C:10](=[O:17])[CH2:9]3)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:18][O:19][CH:20](OC)OC>C(O)(=O)C>[CH:1]1([C:6]2[CH:7]=[C:8]3[C:13](=[CH:14][CH:15]=2)[C:12](=[O:16])[NH:11][C:10](=[O:17])[C:9]3=[CH:18][O:19][CH3:20])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COC(OC)OC
Reactant: O=C1Cc2cc(C3CCCC3)ccc2C(=O)N1
Solvent: CC(=O)O
Product: COC=C1C(=O)NC(=O)c2ccc(C3CCCC3)cc21
Temperature: 90 °C

Procedure:
A mixture of 6-cyclopentyl-4H-isoquinoline-1,3-dione (222 mg, 0.97 mmole), 10 mL of acetic acid and trimethylorthoformate (212 mg, 2.0 mmole) is stirred and heated to 90° C. After 2 hours at that temperature the reaction mixture is cooled and the solvents were removed in-vacuo and the residue taken up in 4% methanol in dichloromethane, passed through a short pad of Florisil and eluted with 4% methanol in dichloromethane. The eluate is evaporated and the product is treated with 4:1 hexanes-ethyl acetate and collected by filtration to give a yellow solid, 165 mg, (62%), MS (ES+): m/z 272.2 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]1[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=1)[N:6]=[CH:5]2.[O:18]1[CH2:23][CH2:22][N:21]([C:24]2[CH:32]=[CH:31][C:27]([C:28]([O-:30])=O)=[CH:26][CH:25]=2)[CH2:20][CH2:19]1>>[O:18]1[CH2:19][CH2:20][N:21]([C:24]2[CH:25]=[CH:26][C:27]([C:28]([NH:1][C:2]3[CH:3]=[C:4]4[C:8](=[CH:9][CH:10]=3)[N:7]([C:11]3[CH:16]=[CH:15][C:14]([N:17]5[CH2:22][CH2:23][O:18][CH2:19][CH2:20]5)=[CH:13][CH:12]=3)[N:6]=[CH:5]4)=[O:30])=[CH:31][CH:32]=2)[CH2:22][CH2:23]1
Reactant: Nc1ccc(-n2ncc3cc(N)ccc32)cc1
Reactant: O=C([O-])c1ccc(N2CCOCC2)cc1
Product: O=C(Nc1ccc2c(cnn2-c2ccc(N3CCOCC3)cc2)c1)c1ccc(N2CCOCC2)cc1

Procedure:
Compound 537 was prepared according to the procedure described in Scheme IV from 5-amino-1-(4-aminophenyl)indazole and 4-morpholinobenzoate. [M+H]+ calcd for C28H29N5O3: 484.23; found: 484.11.
Reaction SMILES: C([O:8][C:9]([NH:11][C:12]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:13]=1[C:14]([OH:16])=[O:15])=O)C1C=CC=CC=1.P(Br)(Br)Br>C(OCC)C>[Cl:21][C:19]1[CH:18]=[CH:17][C:13]2[C:14](=[O:16])[O:15][C:9](=[O:8])[NH:11][C:12]=2[CH:20]=1
Reactant: O=C(Nc1cc(Cl)ccc1C(=O)O)OCc1ccccc1
Agent: BrP(Br)Br
Solvent: CCOCC
Product: O=c1[nH]c2cc(Cl)ccc2c(=O)o1
Reaction time: 120 h
Yield: 91.9 %

Procedure:
A mixture of 2-benzyloxycarbonylamino-4-chlorobenzoic acid (564 g) and phosphorus tribromide (1.5 kg) in diethyl ether (9 l) was refluxed for 40 hours and allowed to stand at room temperature for 5 days. The resulting precipitates were collected by filtration and washed in turn with diethyl ether (5 l) and ethanol (3 l) to give 7-chloro-2H-3,1-benzoxazine-2,4(1H)-dione (335 g).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[CH:10][CH:9]=2)[CH2:4][CH2:3]1>CO.[Ni]>[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)[CH2:6][CH2:7]1
Reactant: CN1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Agent: [Ni]
Solvent: CO
Product: CN1CCN(c2ccc(N)cc2)CC1

Procedure:
44.3 g (0.2 Mol) of 1-Methyl-4-(4-nitro-phenyl)-piperazine is dissolved in 1200 mL of CH3OH and subjected to catalytic hydration at rt using Raney-Ni (10 g) as catalyst. After filtration over Celite, the crude product is purified via solid-distillation (0.16 mbar, 180° C.; heat temp 125° C.) to obtain 4-(4-methyl-piperazin-1-yl)-phenylamine. Title compound: ES-MS: 192.1 [M+H]+; single peak at tR=1.08 min (System 1); Rf=0.33 (CH2Cl2/MeOH 4:1).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9](=O)[C:10]([OH:12])=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:14][C@H:15]([C:17]([N:19]1[CH2:26][CH2:25][CH2:24][C@H:20]1[C:21]([OH:23])=[O:22])=[O:18])[CH3:16].C([BH3-])#N.[Na+]>O>[C:10]([CH:9]([NH:14][C@H:15]([C:17]([N:19]1[CH2:26][CH2:25][CH2:24][C@H:20]1[C:21]([OH:23])=[O:22])=[O:18])[CH3:16])[CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)([OH:12])=[O:11]
Reactant: O=C(O)C(=O)CCc1ccccc1
Reactant: C[C@H](N)C(=O)N1CCC[C@H]1C(=O)O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Product: C[C@H](NC(CCc1ccccc1)C(=O)O)C(=O)N1CCC[C@H]1C(=O)O

Procedure:
A mixture of 4-phenyl-2-oxobutyric acid (1.49 g) and L-alanyl-L-proline (0.31 g) in water are adjusted to pH 7.5 with caustic and treated with sodium cyanoborohydride (0.32 g) overnight. The product is absorbed on strong acid ion exchange resin and eluted with 2% pyridine in water to give 0.36 g of crude diastereomeric product, N-(1-carboxy-3-phenylpropyl)-L-alanyl-L-proline. A portion is purified by gel filtration (LH-20) for spectrographic analysis. The nmr spectrum in DMSO shows aromatic hydrogen at 7.20, a broad singlet at 4.30, broad multiplets at 3.0 to 3.9, 2.67 and 1.94, and a doublet at 1.23 and 1.15. The mass spectrum shows a molecular ion at 492 m/e for the ditrimethylsilylated species.
Reaction SMILES: [CH3:1][CH:2]1[O:7][CH:6]([CH3:8])[CH2:5][NH:4][CH2:3]1.Cl[CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:8][CH:6]1[O:7][CH:2]([CH3:1])[CH2:3][N:4]([CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:5]1
Reactant: CC1CNCC(C)O1
Reactant: CCOC(=O)CCCl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCOC(=O)CCN1CC(C)OC(C)C1

Procedure:
This intermediate (26.0 g.) was prepared using the procedure described in Example 4a except using 24.5 ml. (0.2 mole) of 2,6-dimethylmorpholine, 19.2 ml. (0.20 mole) of ethyl 3-chloropropionate, and 30.3 ml. (0.22 mole) of triethylamine in 60 ml. of toluene and was isolated as a colorless liquid boiling 88°-88.5° C. at 5 mm of Hg.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][O:15][C:16]3[CH:17]=[C:18]4[C:22](=[CH:23][CH:24]=3)[C:21](=[O:25])[N:20]([CH:26]3[CH2:30][CH2:29][CH2:28][CH2:27]3)[CH2:19]4)[CH:9]=2)=[CH:4][C:3]=1[C:31]([O:33]C)=[O:32].[Li+].[OH-]>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][O:15][C:16]3[CH:17]=[C:18]4[C:22](=[CH:23][CH:24]=3)[C:21](=[O:25])[N:20]([CH:26]3[CH2:30][CH2:29][CH2:28][CH2:27]3)[CH2:19]4)[CH:9]=2)=[CH:4][C:3]=1[C:31]([OH:33])=[O:32]
Reactant: COC(=O)c1cc(-c2cccc(COc3ccc4c(c3)CN(C3CCCC3)C4=O)c2)ccc1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)c1cc(-c2cccc(COc3ccc4c(c3)CN(C3CCCC3)C4=O)c2)ccc1Cl
Yield: 45.2 %

Procedure:
Crude methyl 4-chloro-3′-((2-cyclopentyl-1-oxoisoindolin-5-yloxy)methyl)biphenyl-3-carboxylate (109 mg, 0.23 mmol) was dissolved in tetrahydrofuran (17 mL) and 2M LiOH (0.57 mL, 1.15 mmol) was added and the mixture was heated at reflux for 3 h. The solvent was evaporated and the residue was dissolved in water and neutralized using 2M HCl. The aqueous layer was extracted with ethyl acetate and the organic layer was dried over anhydrous Na2SO4. The solvent was evaporated in vacuo to obtain the crude acid as a yellow solid. The crude residue was purified using automated prep-HPLC to yield the desired compound (48 mg, 46%) as a white solid. 1H NMR (400 MHz, CDCl3): δ 8.18 (s, 1H), 7.78 (d, J=8.5 Hz, 1H), 7.65-7.41 (m, 6H), 7.05 (d, J=8.5 Hz, 1H), 6.99 (s, 1H), 5.16 (s, 2H), 4.74 (m, 1H), 4.30 (s, 2H), 1.97 (m, 2H), 1.76-1.59 (m, 6H). HRMS: calcd. for C27H24CINO4 [M+H]+ 462.1467; found 462.1468.
Reaction SMILES: [CH3:1][N:2]([CH3:28])[C:3]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:8][CH2:7][C:6]([C:9]2[NH:10][C:11]3[C:16]([C:17]=2[CH2:18][CH2:19][CH2:20][OH:21])=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:5][CH2:4]1>Br.CCO>[CH3:28][N:2]([CH3:1])[C:3]1([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:8][CH2:7][CH:6]([C:9]2[NH:10][C:11]3[C:16]([C:17]=2[CH2:18][CH2:19][CH2:20][OH:21])=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH2:5][CH2:4]1
Reactant: CN(C)C1(c2ccccc2)CC=C(c2[nH]c3ccccc3c2CCCO)CC1
Agent: Br
Solvent: CCO
Product: CN(C)C1(c2ccccc2)CCC(c2[nH]c3ccccc3c2CCCO)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
(±)-3-[2-(4-Dimethylamino-4-phenylcyclohex-1-enyl)-1H-indol-3-yl]propan-1-ol (500 mg, 1.335 mmol) was dissolved in HBr/glacial acetic acid (33% HBr, 10 ml). Sn powder (1.57 g, 13.35 mmol) was then added to the mixture in portions at RT in the course of 2 h. When the addition had ended, the reaction mixture was stirred at RT for a further 16 h. For working up, the mixture was diluted with EtOH (10 ml) and concentrated to dryness on a rotary evaporator. The residue which remained was rendered basic by addition of 5 N NaOH (40 ml). The aqueous mixture obtained was extracted with methylene chloride (4×20 ml). The combined organic phases were dried over Na2SO4 and then concentrated. It was possible for the crude product obtained to be purified by column chromatography [silica gel 60 (50 g); MeOH (600 ml)]. 3-(2-(4-(Dimethylamino)-4-phenylcyclohexyl)-1H-indol-3-yl]propan-1-ol (non-polar diastereomer) was obtained in a yield of 160 mg (32%) as a white solid. The more polar diastereomer was obtained in a yield of 130 mg (26%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[S:6][CH:5]=[N:4][CH:3]=1.[F:7][B-:8]([F:11])([F:10])[F:9].[CH3:12][O+](C)C>C(Cl)Cl>[F:7][B-:8]([F:11])([F:10])[F:9].[Cl:1][C:2]1[S:6][CH:5]=[N+:4]([CH3:12])[CH:3]=1
Reactant: C[O+](C)C
Reactant: Clc1cncs1
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: C[n+]1csc(Cl)c1

Procedure:
Starting material prepared by reaction of 5-chlorothiazole with trimethyloxonium tetrafluoroborate in CH2Cl2 at ambient temperature for 3 hours to give 5-chloro-3-methylthiazolium tetrafluoroborate.