Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[Li]CCCC.[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][N:21]([C:24]([C:27](OCC)=[O:28])([CH3:26])[CH3:25])[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12]>C1COCC1>[C:11]([O:15][C:16]([N:18]1[CH2:19][CH2:20][N:21]([C:24]([CH3:26])([CH3:25])[C:27](=[O:28])[N:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[CH2:22][CH2:23]1)=[O:17])([CH3:14])([CH3:13])[CH3:12]
Reactant: C1CCNC1
Reactant: CCOC(=O)C(C)(C)N1CCN(C(=O)OC(C)(C)C)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(C(C)(C)C(=O)N2CCCC2)CC1
Reaction time: 0.08 h

Procedure:
Amine preparation: to pyrrolidine (390 uL) in dry THF (4 mL) at 0° C. was added nBuLi (1.86 ml) The reaction mixture was stirred for 5 minutes and then 4-(1-ethoxycarbonyl-1-methyl-ethyl)-piperazine-1-carboxylic acid tert-butyl ester (700 mg) in THF (5 mL) was added. The reaction mixture was stirred at room temperature for 24 h and then quenched with aqueous ammonium chloride, extracted into DCM, washed with water, dried (MgSO4) and the solvent removed in vacuo to yield 4-(1,1-dimethyl-2-oxo-2-pyrrolidin-1-yl-ethyl)-piperazine-1-carboxylic acid tert-butyl ester (745 mg). Removal of the BOC group with HCl yielded the desired compound, which was isolated as the hydrochloride salt.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([C:15]2[CH:20]=[C:19]([O:21][C:22]([F:27])([F:26])[CH:23]([F:25])[F:24])[CH:18]=[C:17]([F:28])[CH:16]=2)[C:11]([O:13][CH3:14])=[O:12])=[CH:6][C:5]=1[C:29]([F:32])([F:31])[F:30].[Br:33][C:34]1[CH:41]=[CH:40][C:37]([CH2:38]Br)=[CH:36][CH:35]=1>CN(C=O)C>[Br:33][C:34]1[CH:41]=[CH:40][C:37]([CH2:38][C:10]([C:7]2[CH:8]=[CH:9][C:4]([F:3])=[C:5]([C:29]([F:32])([F:30])[F:31])[CH:6]=2)([C:15]2[CH:20]=[C:19]([O:21][C:22]([F:26])([F:27])[CH:23]([F:24])[F:25])[CH:18]=[C:17]([F:28])[CH:16]=2)[C:11]([O:13][CH3:14])=[O:12])=[CH:36][CH:35]=1
Reactant: BrCc1ccc(Br)cc1
Reactant: COC(=O)C(c1cc(F)cc(OC(F)(F)C(F)F)c1)c1ccc(F)c(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(Cc1ccc(Br)cc1)(c1cc(F)cc(OC(F)(F)C(F)F)c1)c1ccc(F)c(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 104.9 %

Procedure:
To a suspension of NaH (60% in oil, 66 mg, 1.65 mmol) in DMF (3 mL) at 0° C. was added a solution of methyl 2-(4-fluoro-3-(trifluoromethyl)phenyl)-2-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)acetate (600 mg, 1.34 mmol) in one portion. The reaction mixture was stirred at 0° C. for 10 min followed by addition of a solution of 4-bromobenzylbromide (343 mg, 1.37 mmol) in DMF (2 mL). The reaction was stirred at 0° C. for 5 min and quenched by the addition of saturated NH4Cl. The mixture was extracted with EtOAc (2×30 mL). The combined organic layers were dried over magnesium sulfate, filtered and concentrated to give methyl 3-(4-bromophenyl)-2-(4-fluoro-3-(trifluoromethyl)phenyl)-2-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)propanoate as a colorless oil (865 mg, 100% yield). LCMS: RT=2.26 min, no ionization (Phenomenex Luna C18 4.6×30 mm column, eluting with 10-90% MeOH/H2O containing 0.1% TFA, 2 min gradient, flow rate 5 mL/min, wavelength 220 nm); HPLC: RT=4.48 min (Phenomenex Luna C18 4.6×50 mm column, eluting with 10-90% MeOH/H2O containing 0.2% PPA, flow rate 4 mL/min, wavelength 220 nm); 1H NMR (400 MHz, CDCl3) δ ppm 7.29-7.33 (1H, m), 7.21-7.27 (4H, m), 7.11 (1H, t, J=9.23 Hz), 6.94 (1H, d, J=8.79 Hz), 6.82 (1H, d, J=9.67 Hz), 6.80 (1H, s), 6.52 (2H, d, J=8.35 Hz), 5.87 (1H, t, J=53.2 Hz), 3.75 (3H, s), 3.56-3.66 (2H, m).
Reaction SMILES: Cl[CH2:2][C:3]1[N:7]=[C:6]([CH:8]([CH3:22])[C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[C:11]([F:21])[CH:10]=2)[O:5][N:4]=1.[CH2:23]([N:25]([CH2:34][CH3:35])[C:26]([N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1)=[O:27])[CH3:24]>CN(C=O)C>[CH2:34]([N:25]([CH2:23][CH3:24])[C:26]([N:28]1[CH2:29][CH2:30][N:31]([CH2:2][C:3]2[N:7]=[C:6]([CH:8]([CH3:22])[C:9]3[CH:14]=[CH:13][C:12]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)=[C:11]([F:21])[CH:10]=3)[O:5][N:4]=2)[CH2:32][CH2:33]1)=[O:27])[CH3:35]
Reactant: CC(c1ccc(-c2ccccc2)c(F)c1)c1nc(CCl)no1
Reactant: CCN(CC)C(=O)N1CCNCC1
Solvent: CN(C)C=O
Product: CCN(CC)C(=O)N1CCN(Cc2noc(C(C)c3ccc(-c4ccccc4)c(F)c3)n2)CC1
Temperature: 100 °C
Yield: 77.3 %

Procedure:
A mixture of 2.14 g of 3-chloromethyl-5-(3-fluoro-4-phenyl-α-methylbenzyl)-1,2,4-oxadiazole, 2.54 g of N,N-diethyl-1-piperazine carboxamide and 15 ml of dry DMF was heated at 100° C. for 2 hours. After cooling, the reaction mixture was poured into ice-water and extracted with diethyl ether. The organic phase was washed with water, dried over magnesium sulfate and evaporated. The residue was chromatographed over silica gel using chloroform-methanol (50:1, v/v) to yield 2.43 g of 3-[4-(N,N-diethylcarbamoyl)piperazinomethyl]-5-(3-fluoro-4-phenyl-α-methylbenzyl)-1,2,4-oxadiazole as a light brown oil. To a solution of this product in ethanol was added equal mole of ethanolic hydrogen chloride and the mixture was concentrated to dryness under reduced pressure. Recrystallization of the residue from ethanol-diethyl ether gave colorless crystals, m.p. 181°-182° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:14])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[S:10][CH:11]=[CH:12][N:13]=1.[CH:15](O)([CH3:17])[CH3:16].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([O:14][CH:15]([CH3:17])[CH3:16])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[S:10][CH:11]=[CH:12][N:13]=1
Reactant: Oc1ccc(Oc2nccs2)c(Cl)c1
Reactant: CC(C)O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)Oc1ccc(Oc2nccs2)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89 %

Procedure:
To a mixture of Example 9B (2.3 g, 0.01 mol), isopropanol (1.2 mL, 0.015 mol) and triphenylphosphine (3.93 g, 0.015 mol) in dry tetrahydrofuran was added diethyl azodicarboxylate (2.61 g, 0.015 mol) drop wise and the reaction was stirred at room temperature overnight. The solvent was removed and the residue was purified on silica gel (ethyl acetate/hexane, 5˜35%) to give 2.4 g of product as a light yellow oil (89% yield), 1H NMR (300 MHz, CDCl3) δ ppm 1.35 (d, J=5.88 Hz, 6H) 4.42-4.57 (m, 1H) 6.76-6.86 (m, 2H) 6.99 (d, J=2.94 Hz, 1H) 7.19 (d, J=3.68 Hz, 1H) 7.23 (s, 1H), MS (ESI) m/z 269.9 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([CH2:23][CH2:24][CH2:25][O:26]C3CCCCO3)(=[O:22])=[O:21])=[CH:16][CH:15]=1)[C:6]([C:33](=[O:36])[CH2:34][CH3:35])=[C:5]2[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:13][C:14]1[CH:15]=[CH:16][C:17]([S:20]([CH2:23][CH2:24][CH2:25][OH:26])(=[O:21])=[O:22])=[CH:18][CH:19]=1)[C:6]([C:33](=[O:36])[CH2:34][CH3:35])=[C:5]2[C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1
Reactant: CCC(=O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccc(S(=O)(=O)CCCOC2CCCCO2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Product: CCC(=O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccc(S(=O)(=O)CCCO)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.1 %

Procedure:
To a solution of 6-bromo-4-phenyl-3-propionyl-2-[4-[3-(tetrahydropyran-2-yloxy)propan-1-sulfonyl]benzyl]-2H-isoquinolin-1-one (110 mg) in methanol (10 ml) was added p-toluenesulfonic acid monohydrate (49 mg), and the mixture was stirred at room temperature for 1 hr. The solvent was evaporated under reduced pressure and the residue was partitioned between ethyl acetate and 1N aqueous sodium hydroxide solution. The organic layer was washed with brine and dried by adding sodium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=3/2-+1/9) to give the title compound (95 mg, 98%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH:6]=[O:7].[Br:13]Br>CO>[Br:13][C:8]1[CH:9]=[C:10]([O:11][CH3:12])[C:3]([O:2][CH3:1])=[CH:4][C:5]=1[CH:6]=[O:7]
Reactant: BrBr
Reactant: COc1ccc(C=O)cc1OC
Solvent: CO
Product: COc1cc(Br)c(C=O)cc1OC

Procedure:
Bromination of 3,4-dimethoxybenzaldehyde using bromine in methanol to afford 2-bromo-4,5-dimethoxybenzaldehyde (B1).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[F:12])[N:8](C(OC1C=CC=CC=1)=O)[C:7](=[O:22])[C:6]2([C:33]1[C:34]([O:39][CH2:40][CH3:41])=[N:35][CH:36]=[CH:37][CH:38]=1)[O:23][C:24](OC1C=CC=CC=1)=[O:25])#[N:2].[CH3:42][N:43]1[CH2:48][CH2:47][CH:46]([N:49]2[CH2:54][CH2:53][NH:52][CH2:51][CH2:50]2)[CH2:45][CH2:44]1>O1CCCC1>[CH3:42][N:43]1[CH2:44][CH2:45][CH:46]([N:49]2[CH2:54][CH2:53][N:52]([C:24]([O:23][C:6]3([C:33]4[C:34]([O:39][CH2:40][CH3:41])=[N:35][CH:36]=[CH:37][CH:38]=4)[C:5]4[C:9](=[CH:10][C:11]([F:12])=[C:3]([C:1]#[N:2])[CH:4]=4)[NH:8][C:7]3=[O:22])=[O:25])[CH2:51][CH2:50]2)[CH2:47][CH2:48]1
Reactant: CCOc1ncccc1C1(OC(=O)Oc2ccccc2)C(=O)N(C(=O)Oc2ccccc2)c2cc(F)c(C#N)cc21
Reactant: CN1CCC(N2CCNCC2)CC1
Solvent: C1CCOC1
Product: CCOc1ncccc1C1(OC(=O)N2CCN(C3CCN(C)CC3)CC2)C(=O)Nc2cc(F)c(C#N)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 57 %

Procedure:
A mixture of 291 mg (0.53 mmol) of phenyl 5-cyano-3-(2-ethoxypyridin-3-yl)-6-fluoro-2-oxo-3-phenoxycarbonyloxy-2,3-dihydroindole-1-carboxylate, 289 mg (1.58 mmol) of 1-(1-methylpiperidin-4-yl)piperazine and 6 ml of dried tetrahydrofuran (THF) was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure and stirred with methanol. The precipitated solid was filtered off and dried in a vacuum drying oven. 158 mg of the title compound were obtained as a white solid.
Reaction SMILES: [N:1]([C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]([CH3:14])[C:6](=[O:15])[C:5]=1[N+:16]([O-])=O)=[N+]=[N-]>CCO.[Pd]>[NH2:16][C:5]1[C:6](=[O:15])[N:7]([CH3:14])[C:8]2[C:13]([C:4]=1[NH2:1])=[CH:12][CH:11]=[CH:10][CH:9]=2
Reactant: Cn1c(=O)c([N+](=O)[O-])c(N=[N+]=[N-])c2ccccc21
Agent: [Pd]
Solvent: CCO
Product: Cn1c(=O)c(N)c(N)c2ccccc21
Reaction time: 1 h
Yield: 92 %

Procedure:
A solution of 4-azido-1-methyl-3-nitro-1H-quinolin-2-one (1.0 g, 4.08 mmol) in EtOH (40 mL) was hydrogenated at 1 atm over 10% Pd/C (0.781 g, 0.734 mmol) at room temperature. After 1 h, the reaction vessel was purged with nitrogen, and the catalyst was removed by filtration, rinsing with MeOH. The filtrate was concentrated in vacuo, to give 0.71 g (92%) of 3,4-diamino-1-methyl-1H-quinolin-2-one. 1H-NMR (DMSO): δ 7.82 (d, 1H, J=7.2 Hz), 7.39 (m, 2H), 7.19 (t, 1H, J=2.4 Hz), 5.48 (s, 2H), 4.35 (s, 2H), 3.63 (s, 3H). MS: calculated for C10H11N3O+H 190.1; found: 190.2.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH3:5])[CH3:2].[N:6]1([C:11]2[CH:16]=[CH:15][C:14]([N:17]([CH2:29][CH2:30][CH3:31])[C:18]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH:21]3[C:26](Cl)=[O:27])=[O:19])=[CH:13][CH:12]=2)[CH:10]=[CH:9][N:8]=[CH:7]1>>[CH2:1]([N:3]([CH2:4][CH3:5])[C:26]([CH:21]1[CH2:22][CH2:23][CH2:24][CH2:25][CH:20]1[C:18]([N:17]([C:14]1[CH:15]=[CH:16][C:11]([N:6]2[CH:10]=[CH:9][N:8]=[CH:7]2)=[CH:12][CH:13]=1)[CH2:29][CH2:30][CH3:31])=[O:19])=[O:27])[CH3:2]
Reactant: CCCN(C(=O)C1CCCCC1C(=O)Cl)c1ccc(-n2ccnc2)cc1
Reactant: CCNCC
Product: CCCN(C(=O)C1CCCCC1C(=O)N(CC)CC)c1ccc(-n2ccnc2)cc1

Procedure:
In a manner similar to Preparation 16, react diethylamine with 2-[[[4-(1H-imidazol-1-yl)phenyl](propyl)amino]-carbonyl]cyclohexanecarbonyl chloride to obtain the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12](OB(O)O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:19]1(=[O:24])[CH2:23][CH2:22][CH:21]=[CH:20]1.C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C@H:21]2[CH2:22][CH2:23][C:19](=[O:24])[CH2:20]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OB(O)Oc1ccc(OCc2ccccc2)cc1
Reactant: O=C1C=CCC1
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Product: O=C1CC[C@H](c2ccc(OCc3ccccc3)cc2)C1
Yield: 91.3 %

Procedure:
4-Benzyloxyphenylboric acid (3.42 g, 15 mmol), cyclopentenone (1.1 mL, 13 mmol) and (S)-BINAP were used as ligands and treated in a similar manner to (Step 1) of (Example 3) to give the title compound (3.16 g, 95%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][C:12]([OH:18])=[CH:13][CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].CN(C)C=O.Cl[C:31]1[CH:39]=[CH:38][C:34]([C:35]([NH2:37])=[O:36])=[CH:33][N:32]=1>[Cl-].[Na+].O>[C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][C:12]([O:18][C:31]3[CH:39]=[CH:38][C:34]([C:35](=[O:36])[NH2:37])=[CH:33][N:32]=3)=[CH:13][CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: NC(=O)c1ccc(Cl)nc1
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(O)cc2C1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCc2ccc(Oc3ccc(C(N)=O)cn3)cc2C1
Temperature: 25 °C
Yield: 48.5 %

Procedure:
Combine 7-hydroxy-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (1.7 g, 6.8 mmol, Reference J. Med. Chem. 1998, 41 (25), 4983-4994), cesium carbonate (4.4 g, 13.6 mmol) and N,N-dimethylformamide (75 mL) and stir at room temperature for 30 minutes. Add 6-chloronicotinamide (1.1 g, 6.8 mmol) and heat at 100° C. for 2 days. Cool to room temperature, dilute with brine then extract with ethyl acetate (3× 125 mL). Dry the ethyl acetate extracts with sodium chloride/magnesium sulfate, filter, then concentrate on a rotary evaporator to yield 12 g of the crude product. The crude product is purified by flash column chromatography on silica gel eluting with (0.1% conc. ammonium hydroxide/1% ethanol) to (1% conc. ammonium hydroxide/10% ethanol) in chloroform to yield 7-(5-carbamoyl-pyridin-2-yloxy)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (1.2 g, 3.3 mmol): 1H NMR (CDCl3, 300.00 MHz): 8.59 (s, 1H); 8.17 (d, 1H); 7.20-7.17 (m, 2H); 6.98-6.89 (m, 2H); 5.97 (s, 2H); 4.57 (s, 2H); 3.68-3.66 (m, 2H); 2.83 (t, 2H); 1.48 (s, 9H).
Reaction SMILES: [F:1][C:2]1[C:3]2[O:28][N:27]=[C:26](S(C)(=O)=O)[C:4]=2[CH:5]=[C:6]2[C:19]=1[N:18]1[CH2:20][C@@H:21]([CH3:25])[O:22][C@@H:23]([CH3:24])[C@@H:17]1[C:8]1([C:13](=[O:14])[NH:12][C:11](=[O:15])[NH:10][C:9]1=[O:16])[CH2:7]2.[C-:33]#[N:34].[K+].C1OCCOCCOCCOCCOCCOC1>CN(C=O)C>[F:1][C:2]1[C:3]2[O:28][N:27]=[C:26]([C:33]#[N:34])[C:4]=2[CH:5]=[C:6]2[C:19]=1[N:18]1[CH2:20][C@@H:21]([CH3:25])[O:22][C@@H:23]([CH3:24])[C@@H:17]1[C:8]1([C:13](=[O:14])[NH:12][C:11](=[O:15])[NH:10][C:9]1=[O:16])[CH2:7]2
Reactant: C[C@@H]1CN2c3c(cc4c(S(C)(=O)=O)noc4c3F)CC3(C(=O)NC(=O)NC3=O)[C@H]2[C@H](C)O1
Reactant: [C-]#N
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: CN(C)C=O
Product: C[C@@H]1CN2c3c(cc4c(C#N)noc4c3F)CC3(C(=O)NC(=O)NC3=O)[C@H]2[C@H](C)O1
Temperature: 85 °C

Procedure:
To a stirred solution of (2R,4S,4aS)-rel-11-fluoro-2,4-dimethyl-8-(methylsulfonyl)-1,2,4,4a-tetrahydro-2′H,6H-spiro[1,4-oxazino[4,3-a][1,2]oxazolo[4,5-g]quinoline-5,5′-pyrimidine]-2′,4′,6′(1′H,3′H)-trione (Example 182, 1.0 g, 2.15 mmol) in DMF was added KCN (700 mg, 10.75 mmol) followed by 18-crown-6 (catalytic) and the mixture was heated at 85° C. for 12 hours. The reaction mixture was cooled to room temperature and precipitated with diethyl ether (repeated twice to remove complete DMF). The precipitate was dissolved in EtOAc (50 mL) and washed with water (2×10 mL), dried over anhydrous sodium sulfate and, filtered, concentrated. The residue was purified by ‘combiflash instrument’ to give product as a pale yellow solid.
Reaction SMILES: [OH-].[Li+].[CH2:3]([O:5]/[C:6](=[CH:12]\[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([N:25]([CH3:34])[C:26]([NH:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[O:27])[CH:20]=2)=[CH:15][CH:14]=1)/[C:7]([O:9]CC)=[O:8])[CH3:4].C(O)(=O)C.O>O1CCCC1.C(OCC)(=O)C>[CH2:3]([O:5]/[C:6](=[CH:12]\[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([N:25]([CH3:34])[C:26]([NH:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])=[O:27])[CH:20]=2)=[CH:15][CH:14]=1)/[C:7]([OH:9])=[O:8])[CH3:4]
Reactant: CCCCCNC(=O)N(C)c1cccc(-c2ccc(/C=C(\OCC)C(=O)OCC)cc2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CCCCCNC(=O)N(C)c1cccc(-c2ccc(/C=C(\OCC)C(=O)O)cc2)c1
Temperature: 68 °C
Reaction time: 18 h
Yield: 66.1 %

Procedure:
1.1 mL (1.1 mmol) of aqueous 1 M lithium hydroxide solution are added to a solution of 0.3 g (0.7 mmol) of ethyl (Z)-2-ethoxy-3-[3′-(1-methyl-3-pentylureido)biphenyl-4-yl]acrylate in 8 mL of tetrahydrofuran. The reaction mixture is stirred at 68° C. for 18 hours. After cooling, the reaction is worked up by addition of 1.1 mL (1.1 mmol) of aqueous 1 M acetic acid solution and 10 mL of water and extraction with ethyl acetate. The organic phases are combined, washed with saturated sodium chloride solution and then dried over magnesium sulfate. The solvents are evaporated off. The crude product obtained is purified by chromatography on a column of silica eluted with a 98/2 dichloromethane/methanol mixture to give 0.19 g (65%) of (Z)-2-ethoxy-3-[3′-(1-methyl-3-pentylureido)biphenyl-4-yl]acrylic acid in the form of a colorless oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[C:5]1[CH:10]=[C:9](Br)[C:8]([Cl:12])=[CH:7][C:6]=1[O:13][CH2:14][CH3:15])[CH3:2].[Cu][C:18]#[N:19]>CN(C)C=O.C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:16])[C:5]1[CH:10]=[C:9]([C:18]#[N:19])[C:8]([Cl:12])=[CH:7][C:6]=1[O:13][CH2:14][CH3:15])[CH3:2]
Reactant: CCOC(=O)c1cc(Br)c(Cl)cc1OCC
Reactant: N#C[Cu]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(C#N)c(Cl)cc1OCC
Yield: 47.2 %

Procedure:
To a solution of 5-bromo-4-chloro-2-ethoxy-benzoic acid ethyl ester (940 mg, 3.0 mmol) in 20 mL of dimethylformamide was added copper(I) cyanide (327 mg, 3.65 mmol). The reaction was stirred at reflux overnight. The reaction was diluted with methylene chloride. It was washed twice with brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. Purification of the crude residue by flash column chromatography (silica gel, eluting with a gradient of ethyl acetate in hexanes) gave 4-chloro-5-cyano-2-ethoxy-benzoic acid ethyl ester (359 mg, 47%). LC-MS: 254.1 [(M+H)+].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2[CH2:12][N:13]1[C:21]([C:22]2[N:26]([CH3:27])[CH:25]=[C:24]([C:28]([OH:30])=O)[CH:23]=2)=[C:20]2[C:15]([N:16]([CH2:34][CH:35]([CH3:37])[CH3:36])[C:17](=[O:33])[N:18]([CH3:32])[C:19]2=[O:31])=[N:14]1.[CH:38]1([NH2:41])[CH2:40][CH2:39]1.C(P(=O)(OCC)OCC)#N>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2[CH2:12][N:13]1[C:21]([C:22]2[N:26]([CH3:27])[CH:25]=[C:24]([C:28]([NH:41][CH:38]3[CH2:40][CH2:39]3)=[O:30])[CH:23]=2)=[C:20]2[C:15]([N:16]([CH2:34][CH:35]([CH3:36])[CH3:37])[C:17](=[O:33])[N:18]([CH3:32])[C:19]2=[O:31])=[N:14]1
Reactant: NC1CC1
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2c(-c3cc(C(=O)O)cn3C)n(Cc3ccnc4ccc(Cl)cc34)nc21
Agent: CCOP(=O)(C#N)OCC
Product: CC(C)Cn1c(=O)n(C)c(=O)c2c(-c3cc(C(=O)NC4CC4)cn3C)n(Cc3ccnc4ccc(Cl)cc34)nc21

Procedure:
This compound was synthesized by the reaction of 5-{2-[(6-chloroquinolin-4-yl)methyl]-7-isobutyl-5-methyl-4,6-dioxo-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-d]pyrimidin-3-yl}-1-methyl-1H-pyrrole-3-carboxylic acid and cyclopropylamine using diethyl cyanophosphonate as a coupling reagent. Mass: 560.22 (M+H).
Reaction SMILES: [C:1]1([C:7]2([CH2:13][CH2:14][CH2:15][C:16]([O:18]CC)=[O:17])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].Cl>CO>[C:1]1([C:7]2([CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)CCCC1(c2ccccc2)CCCCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)CCCC1(c2ccccc2)CCCCC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of ethyl 4-(1-phenylcyclohexyl)butanoate (0.211 g, 0.77 mmol) in MeOH (5 mL) was added 1M sodium hydroxide (1.155 mL, 1.155 mmol) and the mixture was stirred at room temperature for 5 hrs. Then an additional 0.39 ml of 1M NaOH was added and stirring was continued for 3 hrs. To the mixture was added 2 ml of 1N HCl and extracted with EtOAc (2×). The combined extracts were washed with brine, dried over Na2SO4 and evaporated to give an oily residue, which became white solid upon storing at room temperature.
Reaction SMILES: N[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[N:10]([O-])=O.[Na+].C1C(C(O)=O)=CC=C(N)C=1.C(O)(=O)C1C=CC=CC=1.C=CC1C=CC=CC=1>C(O)C.O>[NH2:10][C:7]1[CH:8]=[CH:9][C:4]([CH:3]=[CH2:2])=[CH:5][CH:6]=1
Reactant: O=N[O-]
Reactant: NC=Cc1ccccc1
Agent: Nc1ccc(C(=O)O)cc1
Agent: O=C(O)c1ccccc1
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: C=Cc1ccccc1
Product: C=Cc1ccc(N)cc1

Procedure:
The diazonium salt of 4-aminostyrene is prepared as above from 3.6 g aminostyrene, 2.1 g sodium nitrite, and 150 g water. Ethanol, 10 g, is added to completely dissolve the diazonium salt. A solution of PABA-treated MMC is added to the diazonium salt solution, and it is allowed to react for 18 hours under mixing. The solution is filtered to provide MMC solution at about 11 wt %. This MMC contains both benzoic acid and styrene functionalities covalently attached to the MMC particle.
Reaction SMILES: [OH:1][C:2]1[CH:6]=[C:5]([C:7]([O:9][CH3:10])=[O:8])[N:4]([CH3:11])[N:3]=1.IC.[C:14](=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:14][O:1][C:2]1[CH:6]=[C:5]([C:7]([O:9][CH3:10])=[O:8])[N:4]([CH3:11])[N:3]=1
Reactant: COC(=O)c1cc(O)nn1C
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(OC)nn1C
Temperature: 25 °C
Reaction time: 18 h
Yield: 78.7 %

Procedure:
A mixture of methyl 3-hydroxy-1-methyl-1H-pyrazole-5-carboxylate (2.34 g, 15.0 mmol), iodomethane (3.19 g, 22.5 mmol), potassium carbonate (4.15 g, 30.0 mmol) and N,N-dimethylformamide (15 mL) was stirred at room temperature for 18 hr. The mixture was diluted with water (50 mL), and extracted with ethyl acetate (50 mL×3). The organic layer was washed with water (10 mL×2), and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=100/0→50/50) to give the title compound (2.01 g, yield 79%) as a white solid.
Reaction SMILES: Cl.[NH2:2][C:3]([CH3:9])([CH3:8])[C:4]#[C:5][CH2:6][CH3:7].[Br:10][C:11]1[CH:12]=[C:13]([O:17][CH:18]([CH2:22][CH3:23])[C:19](O)=[O:20])[CH:14]=[N:15][CH:16]=1>>[Br:10][C:11]1[CH:12]=[C:13]([O:17][CH:18]([CH2:22][CH3:23])[C:19]([NH:2][C:3]([CH3:9])([C:4]#[C:5][CH2:6][CH3:7])[CH3:8])=[O:20])[CH:14]=[N:15][CH:16]=1
Reactant: CCC(Oc1cncc(Br)c1)C(=O)O
Reactant: CCC#CC(C)(C)N
Agent: Cl
Product: CCC#CC(C)(C)NC(=O)C(CC)Oc1cncc(Br)c1

Procedure:
This compound was prepared using a similar procedure to that described in Stage 3 of Example 1 except that 5-amino-5-methylhex-3-yne hydrochloride was used in place of 4-amino-4-methylpent-2-yne hydrochloride and 2-(5-bromo-3-pyridyloxy)butyric acid was used in place of 2-(5-chloro-3-pyridyloxy)butyric acid. The compound was characterised as follows: colourless solid, m.p. 90–92° C.; 1H NMR (CDCl3) δ: 1.02–1.06 (3H, t); 1.10–1.14 (3H, t); 1.62 (6H, s); 1.96–2.02 (2H, m); 2.16–2.22 (2H, m); 4.424.46 (1H, m); 6.30 (1H, br s); 7.40 (1H, m); 8.30 (1H, d); 8.36 (1H, d).