Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@H:2]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][C:16]2[N:17]=[C:18]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH:29]([CH3:31])[CH3:30])=[CH:24][CH:23]=3)[O:19][C:20]=2[CH3:21])=[CH:9][CH:8]=1)[C:3]([OH:5])=[O:4].[F:32][C:33]1[CH:38]=[CH:37][C:36]([C:39](=[O:45])[CH2:40][C:41](=O)[CH2:42][CH3:43])=[CH:35][CH:34]=1>>[CH2:42](/[C:41](/[NH:1][C@@H:2]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:14][CH2:15][C:16]2[N:17]=[C:18]([C:22]3[CH:23]=[CH:24][C:25]([O:28][CH:29]([CH3:31])[CH3:30])=[CH:26][CH:27]=3)[O:19][C:20]=2[CH3:21])=[CH:11][CH:12]=1)[C:3]([OH:5])=[O:4])=[CH:40]/[C:39]([C:36]1[CH:35]=[CH:34][C:33]([F:32])=[CH:38][CH:37]=1)=[O:45])[CH3:43]
Reactant: CCC(=O)CC(=O)c1ccc(F)cc1
Reactant: Cc1oc(-c2ccc(OC(C)C)cc2)nc1CCOc1ccc(C[C@H](N)C(=O)O)cc1
Product: CC/C(=C/C(=O)c1ccc(F)cc1)N[C@@H](Cc1ccc(OCCc2nc(-c3ccc(OC(C)C)cc3)oc2C)cc1)C(=O)O

Procedure:
The title compound was prepared (as described above for the preparation of Example 2) from 75 mg (0.177 mmol) of Intermediate 51 and 39 mg (0.194 mmol) of Intermediate 32 to yield 70 mg of Example 15: TLC (DCM/MeOH (4:1): Rf=0.55; 1H NMR (DMSO-d6, 300 MHz) δ11.53 (d, 1H, J=9.6), 7.89 (dd, 2H, J=8.8, 5.7), 7.85 (d, 2H, J=8.8), 7.26 (t, 2H, J=8.8), 7.18 (d, 2H, J=8.5), 7.05 (d, 2H, J=8.8), 6.86 (d, 2H, J=8.5), 5.60 (s, 1H), 4.73 (hept, 1H, J=6.0), 4.19 (t, 2H, J=6.7), 4.13 (br s, 1H), 3.19 (m, 1H), 2.92 (t, 2H, J=6.6), 2.80 (dd, 1H, J=14.0, 9.2), 2.36 (s, 3H), 2.07 (m, 2H), 1.34 (d, 6H, J=6.0), 0.99 (t, 3H, J=7.5); low resolution MS (ES+)m/e 601.1 (MH+).
Reaction SMILES: I[C:2]1[C:3]([CH3:19])=[N:4][C:5]([NH2:18])=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][CH:9]=1.[CH3:20][Si:21]([C:24]#[CH:25])([CH3:23])[CH3:22].C(N(CC)CC)C>CN(C=O)C.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>[CH3:17][S:14]([C:11]1[CH:12]=[CH:13][C:8]([C:7]2[C:2]([C:25]#[C:24][Si:21]([CH3:23])([CH3:22])[CH3:20])=[C:3]([CH3:19])[N:4]=[C:5]([NH2:18])[N:6]=2)=[CH:9][CH:10]=1)(=[O:16])=[O:15]
Reactant: C#C[Si](C)(C)C
Reactant: Cc1nc(N)nc(-c2ccc(S(C)(=O)=O)cc2)c1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1nc(N)nc(-c2ccc(S(C)(=O)=O)cc2)c1C#C[Si](C)(C)C

Procedure:
The title compound is synthesized according to general procedure GP2 starting from 3.0 g (7.7 mmol) 5-iodo-4-methyl-6-(4-methanesulfonyl-phenyl)-pyrimidin-2-ylamine (A-33) and 1.6 mL (12 mmol) trimethylsilylethyne using 147 mg (0.77 mmol) CuI, 541 mg (0.77 mmol) PdCl2(PPh3)2 and 11 mL (7.7 mmol) triethylamine in 18 mL dry DMF. For the work-up the solvent is removed in vacuo and the product is purified by chromatography on silica (DCM/MeOH gradient). Yield: 2.45 g (71%, approximately 80% pure).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH2:9][CH2:8][CH:7]([N:15]([CH3:17])[CH3:16])[CH2:6][C:5]2=1.[F:18][C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=1[F:28])[C:22](Cl)=[O:23]>>[F:18][C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=1[F:28])[C:22]([NH:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH2:9][CH2:8][CH:7]([N:15]([CH3:17])[CH3:16])[CH2:6][C:5]2=1)=[O:23]
Reactant: O=C(Cl)c1ccc(F)c(F)c1
Reactant: CN(C)C1CCc2[nH]c3ccc(N)cc3c2C1
Product: CN(C)C1CCc2[nH]c3ccc(NC(=O)c4ccc(F)c(F)c4)cc3c2C1
Yield: 42.4 %

Procedure:
Beginning with 10.4 mg (0.046 mMol) 6-amino-3-(dimethyl)amino-1,2,3,4-tetrahydro-9H-carbazole and 8.6 μL (0.051 mMol) 3,4-difluorobenzoyl chloride, 7.2 mg (42%) of the title compound were recovered as a beige solid.
Reaction SMILES: I[CH2:2][C@@H:3]([CH3:17])[CH2:4][N:5]1[C:10]2[CH:11]=[C:12]([CH3:15])[CH:13]=[CH:14][C:9]=2[O:8][CH2:7][C:6]1=[O:16].[CH2:18]([CH:23]1[CH2:29][CH:28]2[NH:30][CH:25]([CH2:26][CH2:27]2)[CH2:24]1)[CH2:19][CH2:20][CH2:21][CH3:22]>CCN(CC)CC>[CH2:18]([CH:23]1[CH2:24][CH:25]2[N:30]([CH2:2][C@@H:3]([CH3:17])[CH2:4][N:5]3[C:10]4[CH:11]=[C:12]([CH3:15])[CH:13]=[CH:14][C:9]=4[O:8][CH2:7][C:6]3=[O:16])[CH:28]([CH2:27][CH2:26]2)[CH2:29]1)[CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: Cc1ccc2c(c1)N(C[C@H](C)CI)C(=O)CO2
Reactant: CCCCCC1CC2CCC(C1)N2
Solvent: CCN(CC)CC
Product: CCCCCC1CC2CCC(C1)N2C[C@@H](C)CN1C(=O)COc2ccc(C)cc21
Yield: 69.3 %

Procedure:
Crude (S)-4-(3-Iodo-2-methylpropyl)-6-methyl-4H-benzo[1,4]oxazin-3-one (0.15 g), Et3N (0.5 mL) and 3-pentyl-8-azabicyclo[3.2.1]octane (95 mg, 5.2 mmol) were reacted according to GP17. Flash CC (SiO2; CH2Cl2/I—PrOH 92:8) gave the title compound (0.12 g, 68%). 1H NMR (CD3OD) δ 7.06 (s, 1H), 6.86 (d, J=8.0 Hz, 1H), 6.81 (brd, J=8.0 Hz, 1H), 4.52 (ABq, J=14.8, 27.2 Hz, 2H), 4.06 (dd, J=5.6, 14.2 Hz, 1H), 4.96 (dd, J=8.8, 14.2 Hz, 1H), 3.16-3.02 (m, 2H), 2.34-2.07 (m, 7H), 2.31 (s, 3H), 2.04-181 (m, 3H), 1.70-1.55 (m, 3H), 1.46-1.21 (m, 10H), 0.92-0.85 (m, 6H); 13C NMR (CD3OD) δ167.2, 145.1, 133.6, 129.4, 125.5 117.7, 117.5, 68.7, 61.6, 60.2, 58.6, 46.1, 49.6, 36.9, 33.1, 32.4, 29.6, 29.5, 28.5, 27.8, 23.7, 21.18, 17.0, 14.4.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:36][CH2:35][C:11]2([C:15](=[O:16])[N:14]([C:17]3[CH:22]=[CH:21][C:20]([CH:23]4[CH2:28][CH2:27][CH:26](OS(C)(=O)=O)[CH2:25][CH2:24]4)=[CH:19][C:18]=3[F:34])[CH2:13][CH2:12]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:37][C@H:38]1[CH2:42][CH2:41][CH2:40][NH:39]1>>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11]2([C:15](=[O:16])[N:14]([C:17]3[CH:22]=[CH:21][C:20]([CH:23]4[CH2:28][CH2:27][CH:26]([N:39]5[CH2:40][CH2:41][CH2:42][C@@H:38]5[CH3:37])[CH2:25][CH2:24]4)=[CH:19][C:18]=3[F:34])[CH2:13][CH2:12]2)[CH2:35][CH2:36]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CCN(c1ccc(C3CCC(OS(C)(=O)=O)CC3)cc1F)C2=O
Reactant: C[C@H]1CCCN1
Product: C[C@H]1CCCN1C1CCC(c2ccc(N3CCC4(CCN(C(=O)OC(C)(C)C)CC4)C3=O)c(F)c2)CC1

Procedure:
The title compound was synthesized in the same manner as Example 13 by condensing 2-[2-fluoro-4-(4-methanesulfonyloxy-cyclohexyl)-phenyl]-1-oxo-2,8-diaza-spiro[4.5]decane-8-carboxylic acid tert-butyl ester (Intermediate 28) (150 mg, 0.3 mmol, 1 equiv.) with (S)-2-methyl-pyrrolidine (101.2 mg, 1.19 mmol) to obtain 67 mg (88% yield) of the compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][CH:14]([CH2:17][C:18]([OH:20])=O)[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23.[NH2:21][C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1>>[Br:1][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][CH:14]([CH2:17][C:18](=[O:20])[NH:21][C:22]3[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=3)[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23
Reactant: O=C(O)CC1CCc2cc(Br)cc3[nH]c(=O)c(=O)n1c23
Reactant: Nc1ccncc1
Product: O=C(CC1CCc2cc(Br)cc3[nH]c(=O)c(=O)n1c23)Nc1ccncc1
Yield: 69.4 %

Procedure:
A procedure similar to that described in Example 51 was carried out with 9-bromo-5-carboxymethyl-6,7-dihydro-1H, 5H-pyrido[1,2,3-de]quinoxaline-2,3-dione (170 mg, 0.5 mmol) and 4-aminopyridine (60 mg, 0.64 mmol) to give 144 mg of the title compound (69%): mp>270° C.; 1H NMR (270 MHz, DMSO-d6) δ12.10 (bs, 1H), 10.90 (s, 1H), 9.04 (d, 1H, J=2 Hz), 8.50 (d, 2H, J=5.4 Hz), 8.31 (d, 1H, J=9 Hz), 7.78 (dd, 1H, J=5.4, 9 Hz), 7.24 (d, 1H, J=2 Hz), 7.19 (d, 1H, J=2 Hz), 5.17~5.28 (m, 1H), 3.05 (ddd, 1H, J=17.1, 13.5, 4.5 Hz), 2.83 (dm, 1H, J=17.1 Hz), 2.69 (d, 2H, J=7.2 Hz), 2.13 (dm, 1H, J=13.5 Hz), 1.80~1.96 (m, 1H).
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[C:3]=1[C:4]([N:6]=[C:7]=[O:8])=[O:5].[Cl:14][C:15]1[CH:38]=[C:37]([C:39]([F:42])([F:41])[F:40])[CH:36]=[CH:35][C:16]=1[O:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][S:25][N:26]([CH3:33])[C:27](=[O:32])[O:28][CH2:29][CH2:30][CH3:31])=[C:20]([F:34])[CH:19]=1>C(Cl)Cl>[Cl:14][C:15]1[CH:38]=[C:37]([C:39]([F:40])([F:41])[F:42])[CH:36]=[CH:35][C:16]=1[O:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]([C:7](=[O:8])[NH:6][C:4]([C:3]2[C:2]([F:1])=[CH:12][CH:11]=[CH:10][C:9]=2[F:13])=[O:5])[S:25][N:26]([CH3:33])[C:27]([O:28][CH2:29][CH2:30][CH3:31])=[O:32])=[C:20]([F:34])[CH:19]=1
Reactant: O=C=NC(=O)c1c(F)cccc1F
Reactant: CCCOC(=O)N(C)SNc1ccc(Oc2ccc(C(F)(F)F)cc2Cl)cc1F
Solvent: ClCCl
Product: CCCOC(=O)N(C)SN(C(=O)NC(=O)c1c(F)cccc1F)c1ccc(Oc2ccc(C(F)(F)F)cc2Cl)cc1F
Reaction time: 4 h

Procedure:
A solution of 2,6-difluorobenzoyl isocyanate (2.0 g) in dry methylene chloride (10 ml) was added rapidly to a stirred solution of the compound of Example 2 (4.5 g) in the same solvent (20 ml) at room temperature. After stirring for 4 hours the solvent was removed under reduced pressure, and the residue was purified by chromatography (2x) on silica, using first methylene chloride and then diethyl ether as eluant. The product thus obtained was finally purified by crystallisation from diethyl ether/light petroleum affording colourless crystals (4.5 g) melting at 98°-99° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[S:7]1[C:11]2[CH:12]=[C:13]([N:16]3[CH2:20][CH2:19][N:18]([C:21]4[CH:22]=[N:23][CH:24]=[CH:25][C:26]=4[CH:27]=O)[C:17]3=[O:29])[CH:14]=[CH:15][C:10]=2[N:9]=[CH:8]1.CO>C(O)(=O)C.C(Cl)(Cl)Cl>[S:7]1[C:11]2[CH:12]=[C:13]([N:16]3[CH2:20][CH2:19][N:18]([C:21]4[CH:22]=[N:23][CH:24]=[CH:25][C:26]=4[CH2:27][N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)[C:17]3=[O:29])[CH:14]=[CH:15][C:10]=2[N:9]=[CH:8]1
Reactant: O=Cc1ccncc1N1CCN(c2ccc3ncsc3c2)C1=O
Reactant: C1COCCN1
Solvent: CC(=O)O
Solvent: CO
Solvent: ClC(Cl)Cl
Product: O=C1N(c2ccc3ncsc3c2)CCN1c1cnccc1CN1CCOCC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 20.5 %

Procedure:
Morpholine (0.032 mL, 0.3699 mmol) was added to a stirred solution of 3-(3-Benzothiazol-6-yl-2-oxo-imidazolidin-1-yl)-pyridine-4-carbaldehyde (I-177b: 100 mg, 0.3082 mmol) in acetic acid (2 mL) and stirred at room temperature for 4 hours. This was followed by the addition of NaBH (OAc)3 (98 mg, 0.4624 mmol). The resulting reaction mass was stirred at room temperature for 24 hours. The reaction was monitored by TLC (10% methanol in chloroform). The reaction mixture was concentrated under reduced pressure, added ice, basified using saturated NaHCO3 solution and extracted using ethyl acetate. The organic layer was washed with water, brine solution, dried over Na2SO4 and concentrated. Purification by column chromatography on silica gel (2% methanol in chloroform) followed by preparative HPLC afforded 25 mg of the product (20.6% yield).
Reaction SMILES: Cl.[CH2:2](Cl)[C:3]1[CH:8]=[CH:7][CH:6]=[N:5][CH:4]=1.[CH2:10]([C:12]1([CH2:16][OH:17])[CH2:15][O:14][CH2:13]1)[CH3:11].N1C=CC=CC=1.C(=O)([O-])[O-:25].[Na+].[Na+]>ClCCl>[N:5]1[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([O:17][CH2:16][C:12]2([CH2:10][CH3:11])[CH2:15][O:14][CH2:13]2)=[O:25])[CH:4]=1
Reactant: ClCc1cccnc1
Reactant: O=C([O-])[O-]
Reactant: CCC1(CO)COC1
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCC1(COC(=O)c2cccnc2)COC1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
Nicotinyl chloride hydrochloride (8.9 gm.) was added to a stirred solution of 3-ethyl-3-hydroxymethyloxetane (5.8 gm.) and dry pyridine (20 ml.) in dry dichloromethane (150 ml.) at 0°. The mixture was stirred at room temperature for 4 days and poured into aqueous sodium carbonate solution. The aqueous mixture was extracted with dichloromethane. The extracts were washed with water and dried over anhydrous magnesium sulphate. The solvent was removed in vacuo. The residue was purified by chromatography on silica eluting with 5% triethylamine in dichloromethane. (3-Ethyloxetan-3-yl)methyl 3-pyridinecarboxylate was obtained as a pale yellow oil (7.0 gm.).
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[C:18]([C:20]3[C:31](=[O:32])[N:30]([CH3:33])[C:23]4[N:24]=[C:25](SC)[N:26]=[CH:27][C:22]=4[CH:21]=3)[C:17]([CH3:34])=[CH:16][C:15]=2[F:35])=[O:12])[O:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:36][NH2:37]>>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[C:18]([C:20]3[C:31](=[O:32])[N:30]([CH3:33])[C:23]4[N:24]=[C:25]([NH:37][CH3:36])[N:26]=[CH:27][C:22]=4[CH:21]=3)[C:17]([CH3:34])=[CH:16][C:15]=2[F:35])=[O:12])[O:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CSc1ncc2cc(-c3cc(NC(=O)Nc4cc(C(C)(C)C)no4)c(F)cc3C)c(=O)n(C)c2n1
Reactant: CN
Product: CNc1ncc2cc(-c3cc(NC(=O)Nc4cc(C(C)(C)C)no4)c(F)cc3C)c(=O)n(C)c2n1
Yield: 5.6 %

Procedure:
Using a procedure analogous to Example A1, 1-(3-tert-butylisoxazol-5-yl)-3-(2-fluoro-4-methyl-5-(8-methyl-2-(methylthio)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)urea (1.70 g, 3.426 mmol) and methylamine (2 ml, 4 mmol, 2.0M in THF) were combined to provide 1-(3-tert-butylisoxazol-5-yl)-3-(2-fluoro-4-methyl-5-(8-methyl-2-(methylamino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)urea (92 mg, 42% yield). 1H NMR (400 MHz, DMSO-d6): δ 10.28 (brs, 1H), 8.67 (brs, 1H), 8.61 (s, 1H), 7.89 (d, J=9 Hz, 1H), 7.82 (brs, 1H), 7.68 (s, 1H), 7.17 (d, J=12 Hz, 1H), 6.00 (s, 1H), 3.58 (s, 3H), 2.90 (d, J=5 Hz, 3H), 2.08 (s, 3H), 1.21 (s, 9H); MS (ESI) m/z: 480.2(M+H+).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]([NH:13][C:14]3[CH:24]=[CH:23][C:17]([C:18]([O:20]CC)=[O:19])=[CH:16][CH:15]=3)=[O:12])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.[OH-].[K+].O.C(O)C>>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]([NH:13][C:14]3[CH:24]=[CH:23][C:17]([C:18]([OH:20])=[O:19])=[CH:16][CH:15]=3)=[O:12])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)c1ccc(NC(=O)c2ccc3c(c2)OCCO3)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1ccc(NC(=O)c2ccc3c(c2)OCCO3)cc1

Procedure:
Hydrolysis of this ester with potassium hydroxide/water/ethanol at 50° C. during 2 hours yielded p-(1,4-benzodioxane-6-carboxamido)benzoic acid, melting point 278°-280° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH2:8])[N:5]=[C:4]([NH2:9])[N:3]=1.C([O-])(=O)C.[Na+].[Cl-].[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([N+:23]#[N:24])=[CH:19][CH:18]=1>O.C(O)(=O)C>[Cl:1][C:2]1[N:3]=[C:4]([NH2:9])[N:5]=[C:6]([NH2:8])[C:7]=1[N:24]=[N:23][C:20]1[CH:21]=[CH:22][C:17]([Cl:16])=[CH:18][CH:19]=1
Reactant: N#[N+]c1ccc(Cl)cc1
Reactant: Nc1cc(Cl)nc(N)n1
Agent: CC(=O)[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Nc1nc(N)c(N=Nc2ccc(Cl)cc2)c(Cl)n1
Reaction time: 0.33 h
Yield: 41.4 %

Procedure:
To a suspension of 4-chloro-2,6-diaminopyrimidine (21.68 g, 0.150 mol) in water (750 ml) and acetic acid (750 ml) was added sodium acetate (300 g). Solution occurred after stirring for 20 minutes, and then the solution of 4-chlorobenzenediazonium chloride (0.166 mol) was added with cooling over 30 minutes at a rate that kept the reaction at 18°. The reaction was stirred overnight at room temperature, and the orange crystals were filtered, washed with water (4×400 ml), and dried in vacuo to give 17.6 g of 6-chloro-5-[(4-chlorophenyl)azo]-2,4-pyrimidinediamine. The mother liquors were cooled to 5° for 20 hours, and the crystals were collected and dried in vacuo to give 6.94 g of additional 6-chloro-5-[(4-chlorophenyl)-azo]-2,4-pyrimidineadiamine.
Reaction SMILES: [CH:1]1([NH:5][S:6]([C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[NH:15][CH:14]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21](Br)[CH:20]=2)[CH2:13][C:12]3([CH3:27])[CH3:26])(=[O:8])=[O:7])[CH2:4][CH2:3][CH2:2]1.[OH:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.C(OCC)(=O)C.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>[CH:1]1([NH:5][S:6]([C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[NH:15][CH:14]([C:19]2[CH:20]=[C:21]([C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=4[OH:28])[CH:22]=[CH:23][CH:24]=2)[CH2:13][C:12]3([CH3:27])[CH3:26])(=[O:8])=[O:7])[CH2:4][CH2:3][CH2:2]1
Reactant: OB(O)c1ccccc1O
Reactant: CC1(C)CC(c2cccc(Br)c2)Nc2ccc(S(=O)(=O)NC3CCC3)cc21
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: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: CC1(C)CC(c2cccc(-c3ccccc3O)c2)Nc2ccc(S(=O)(=O)NC3CCC3)cc21
Yield: 53.3 %

Procedure:
To a mixture of 2-(3-bromo-phenyl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-sulfonic acid cyclobutylamide (748.1 mg, 1.67 mmol), 2-hydroxy-phenylboronic acid (276.0 mg, 2.0 mmol) and tetrakis(triphenylphosphine)palladium(0) (193.0 mg, 0.17 mmol) in dioxane (5.0 mL) was added 2 M sodium carbonate solution in water (1.7 mL). The resulting mixture was subjected to microwave irradiation for 2 h at 110° C. The mixture was diluted with ethyl acetate (200 mL), washed with saturated aqueous sodium bicarbonate solution (50 mL×2), brine, dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by flash silica gel chromatography (silica gel from QingDao, 200-300 mesh, glass column from Shanghai SD company) (10% ethyl acetate/hexanes) afforded 2-(2′-hydroxy-biphenyl-3-yl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-sulfonic acid cyclobutylamide (412.1 mg, 53.4%) as a white solid: MS (ESI) M+1=463.1.
Reaction SMILES: [C:1]([C:4]1[C:9]2[CH2:10][C:11](=[CH:19][CH2:20][CH2:21][N:22]3[CH2:27][CH2:26][C:25]([C:29]4[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=4)([OH:28])[CH2:24][CH2:23]3)[C:12]3[C:13]([O:18][C:8]=2[CH:7]=[CH:6][CH:5]=1)=[N:14][CH:15]=[CH:16][CH:17]=3)([OH:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].[CH2:42](I)[CH2:43][CH3:44]>CN(C=O)C.C(OCC)(=O)C>[Cl:35][C:32]1[CH:31]=[CH:30][C:29]([C:25]2([OH:28])[CH2:26][CH2:27][N:22]([CH2:21][CH2:20][CH:19]=[C:11]3[C:12]4[C:13](=[N:14][CH:15]=[CH:16][CH:17]=4)[O:18][C:8]4[CH:7]=[CH:6][CH:5]=[C:4]([C:1]([O:3][CH2:42][CH2:43][CH3:44])=[O:2])[C:9]=4[CH2:10]3)[CH2:23][CH2:24]2)=[CH:34][CH:33]=1
Reactant: CCCI
Reactant: O=C(O)c1cccc2c1CC(=CCCN1CCC(O)(c3ccc(Cl)cc3)CC1)c1cccnc1O2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCOC(=O)c1cccc2c1CC(=CCCN1CCC(O)(c3ccc(Cl)cc3)CC1)c1cccnc1O2
Temperature: 55 °C
Yield: 87.8 %

Procedure:
To a solution of the compound of Example 118 (109 mg, 0.22 mmol) in dry DMF (5 mL) was added potassium carbonate (91 mg) followed by propyl iodide (24 μL, 0.66 mmol). The mixture was heated to 55° C. for 14 hours. The mixture was diluted with ethyl acetate (200 mL), washed twice with water (200 mL) and then with brine (100 mL), and dried with sodium sulfate. The organic solvent was removed under reduced pressure and the residue subjected to silica gel chromatography using a dichloromethane: methanol gradient (0 to 5% MeOH over 1 hour) to give the title compound (103 mg).
Reaction SMILES: C(OC([NH:11][CH:12]([CH:25]1[NH:29][C:28](=[O:30])[NH:27][C:26]1=[O:31])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[C:16]([C:21]([CH3:24])([CH3:23])[CH3:22])[CH:15]=1)=O)C1C=CC=CC=1.[H][H].[C:34]([N:44]([CH3:52])[C@H:45]([C:49]([OH:51])=O)[CH:46]([CH3:48])[CH3:47])([O:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:35].O>CO.C1COCC1.[C].[Pd]>[CH2:37]([O:36][C:34]([N:44]([CH:45]([CH:46]([CH3:47])[CH3:48])[C:49]([NH:11][CH:12]([CH:25]1[NH:29][C:28](=[O:30])[NH:27][C:26]1=[O:31])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[C:16]([C:21]([CH3:24])([CH3:22])[CH3:23])[CH:15]=1)=[O:51])[CH3:52])=[O:35])[C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1
Reactant: CC(C)[C@@H](C(=O)O)N(C)C(=O)OCc1ccccc1
Reactant: [H][H]
Reactant: CC(C)(C)c1cc(CC(NC(=O)OCc2ccccc2)C2NC(=O)NC2=O)ccc1O
Agent: [Pd]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)C(C(=O)NC(Cc1ccc(O)c(C(C)(C)C)c1)C1NC(=O)NC1=O)N(C)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 52.9 %

Procedure:
To a solution of 5-(1-(benzyloxycarbonylamino)-2-(3-tert-butyl-4-hydroxylphenyl)ethyl)imidazolidine-2,4-dione (543 mg, 1.28 mmol) in methanol (10 ml), 10% palladium carbon (55 mg) was added and stirred at room temperature in a hydrogen atmosphere for 3 hours. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure; to a solution of the thus obtained residue in THF (13 ml), Z-N-Me-Val-OH (509 mg, 1.92 mmol), CMPI (491 mg, 1.92 mmol) and TEA (0.535 ml, 3.84 mmol) were added under cooling with ice and stirred at room temperature for 3 hours. The reaction mixture was mixed with water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated to remove the solvent under reduced pressure; the thus obtained residue was subjected to silica gel column chromatography (developing solvent: ethyl acetate:n-hexane=2:1), giving the titled compound (365 mg, 53%).
Reaction SMILES: [OH:1][C:2]1[C:10]([OH:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH2:12](I)[CH2:13][CH3:14].[OH-].[K+].C>C(O)C.O>[CH2:12]([O:11][C:10]1[CH:9]=[CH:8][CH:7]=[C:3]([C:4]([OH:6])=[O:5])[C:2]=1[OH:1])[CH2:13][CH3:14]
Reactant: O=C(O)c1cccc(O)c1O
Reactant: CCCI
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCCOc1cccc(C(=O)O)c1O
Yield: 65 %

Procedure:
2,3-Dihydroxybenzoic acid (6.16 g) and propyl iodide (6.8 g) were added to a mixture of aqueous potassium hydroxide solution (20 ml, 25% w/v), water (50 ml) and ethanol (50 ml) and the mixture was stirred and heated at reflux for 5 hours. A further quantity of propyl iodide (17 g) was then added and the mixture was again heated at reflux for 4 hours, small quantities of solid potassium hydroxide being added meanwhile in order to keep the pH at about 10. Decolourizing charcoal was then carefully added, the mixture was filtered hot and the filtrate was acidified to pH 1 by treatment with concentrated hydrochloric acid. The resulting solid was filtered off and dissolved in aqueous ammonia solution (2N), and the solution was treated with decolourizing charcoal, filtered, and the filtrate was acidified to pH 1 by treatment with hydrochloric acid to give 3-propoxysalicylic acid (5.1 g), m.p. 114°-118° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][C:2]1=[O:7].ClCCl.O1CCOCC1.[C:17]1([S:23](Cl)(=[O:25])=[O:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>N1C=CC=CC=1>[C:17]1([S:23]([N:4]2[CH2:5][CH2:6][NH:1][C:2](=[O:7])[CH2:3]2)(=[O:25])=[O:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: O=C1CNCCN1
Solvent: C1COCCO1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C1CN(S(=O)(=O)c2ccccc2)CCN1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2-piperazinone was suspended in a mixed solvent of dichloromethane and dioxane and then pyridine and benzenesulfonyl chloride were added thereto. After stirring at room temperature for 16 hours, the solvent was removed by evaporation and the resulting solid was suspended in 1N hydrochloric acid, filtered, and washed with diisopropyl ether to obtain 4-(phenylsulfonyl)-2-piperazinone.
Reaction SMILES: Br[C:2]1[CH2:6][CH2:5][CH2:4][C:3]=1[Br:7].[C:8]1(B(O)O)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>>[Br:7][C:3]1[CH2:4][CH2:5][CH2:6][C:2]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: BrC1=C(Br)CCC1
Reactant: OB(O)c1ccccc1
Product: BrC1=C(c2ccccc2)CCC1
Yield: 40.8 %

Procedure:
Following a synthetic procedure which was similar to the one outlined in Step 2 of Example 1, 4.40 g (19.4 mmol) of 1,2-dibromocyclopentene was reacted with 2.0 g (17.7 mmol) of phenylboronic acid (Aldrich). Purification by silica gel chromatography (Waters Prep-500) with hexane gave 1.61 g (42%) of 1-bromo-2-phenylcyclopentene as an oil: NMR (CDCl3) d 2.01-2.10 (m, 2H) , 2.74-2.82 (m, 2H) , 2.82-2.90 (m, 2H) , 7.27-7.33 (m, 1H) , 7.33-7.41 (m, 2H) , 7.57-7.63 (m, 2H) .