Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:18]=[CH:17][CH:16]=[CH:15][C:7]=2[O:8][CH2:9][C:10]([O:12]CC)=O)=[N:2]1.[NH2:19][CH2:20][CH:21]([OH:33])[CH2:22][N:23]1[CH2:32][CH2:31][C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:24]1>CCO.C(OCC)(=O)C>[NH:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:18]=[CH:17][CH:16]=[CH:15][C:7]=2[O:8][CH2:9][C:10]([NH:19][CH2:20][CH:21]([OH:33])[CH2:22][N:23]2[CH2:32][CH2:31][C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH2:24]2)=[O:12])=[N:2]1
Reactant: NCC(O)CN1CCc2ccccc2C1
Reactant: CCOC(=O)COc1ccccc1-c1cc[nH]n1
Solvent: CCOC(C)=O
Solvent: CCO
Product: O=C(COc1ccccc1-c1cc[nH]n1)NCC(O)CN1CCc2ccccc2C1
Temperature: 120 °C
Yield: 51 %

Procedure:
To a solution of ethyl 2-(2-(1H-pyrazol-3-yl)phenoxy)acetate (100 mg, 0.41 mmol) in EtOH (10 mL) was added 1-amino-3-(3,4-dihydroisoquinolin-2(1H)-yl)propan-2-ol (84 mg, 0.41 mmol). The mixture was stirred at 120° C. under microwave heating for 2 h. The reaction mixture was diluted with ethyl acetate (30 mL) and washed with water (10 mL), dried over Na2SO4 and concentrated to give the crude product. The residue was purified by prep-HPLC to afford the desired title compound (85 mg, 44%). 1H NMR (400 MHz, MeOD): δ 7.71-7.69 (m, 2H), 7.34-7.33 (m, 1H), 7.10-7.01 (m, 6H), 6.74 (d, J=2 Hz, 1H), 4.67 (s, 1H), 4.04-4.02 (m, 1H), 3.67 (s, 2H), 3.50-3.49 (m, 1H), 3.37-3.33 (m, 1H), 2.89-2.87 (m, 2H), 2.81-2.78 (m, 2H), 2.58-2.57 (m, 2H) ppm; ESI-MS (m/z): 469.3 [M+1]+.
Reaction SMILES: [C:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=1)([OH:3])=O.C(Cl)(=O)C(Cl)=O.[C:18]([NH:22][CH2:23][CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])([CH3:21])([CH3:20])[CH3:19].C(N(CC)CC)C>ClCCl.CN(C)C=O>[C:18]([N:22]([CH2:23][CH2:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[C:1](=[O:3])[C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=1)([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)NCCC(=O)OC(C)(C)C
Reactant: O=Cc1ccc(C(=O)O)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CCN(C(=O)c1ccc(C=O)cc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 103.1 %

Procedure:
N,N-dimethylformamide (25 μL) was added to a room temperature suspension of 4-carboxybenzaldehyde (2.0 g, 13 mmol) and oxalyl chloride (1.14 mL, 13.3 mmol) in dichloromethane (50 mL). The reaction was stirred at room temperature 30 minutes, then heated to reflux for 5 hours. The reaction mixture was concentrated. A solution of tert-butyl 3-(tert-butylamino)propanoate (2.68 g, 13.3 mmol) and triethylamine (1.9 mL, 13 mmol) in dichloromethane (50 mL) was added to the crude acid chloride. The mixture was stirred at room temperature overnight. The reaction was washed with water, then brine. The organic layer was dried over magnesium sulfate, filtered and concentrated to give tert-butyl 3-(N-tert-butyl-4-formylbenzamido)propanoate (4.47 g, 100%). 1H NMR (400 MHz, CDCl3, δ): 10.01 (s, 1H), 7.86-7.91 (m, 2H), 7.45-7.49 (m, 2H), 3.46-3.54 (m, 2H), 2.34-2.41 (m, 2H), 1.52 (s, 9H), 1.31 (s, 9H).
Reaction SMILES: [OH:1][C@H:2]([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[CH2:3][NH:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][NH:13][CH2:14][C@H:15]([O:33][Si](C(C)(C)C)(C)C)[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[C:18]([NH:30][CH:31]=[O:32])[CH:17]=2)=[CH:7][CH:6]=1.F.F.F.C(N(CC)CC)C.[OH-].[Na+]>O1CCCC1.C(OC(C)C)(=O)C>[OH:1][C@H:2]([C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1)[CH2:3][NH:4][C:5]1[CH:6]=[CH:7][C:8]([CH2:11][CH2:12][NH:13][CH2:14][C@H:15]([OH:33])[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)=[C:18]([NH:30][CH:31]=[O:32])[CH:17]=2)=[CH:9][CH:10]=1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](CNCCc1ccc(NC[C@H](O)c2ccccc2)cc1)c1ccc(OCc2ccccc2)c(NC=O)c1
Agent: F
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CC(=O)OC(C)C
Product: O=CNc1cc([C@@H](O)CNCCc2ccc(NC[C@H](O)c3ccccc3)cc2)ccc1OCc1ccccc1
Reaction time: 20 h
Yield: 98.8 %

Procedure:
Intermediate 5 (5.2 g, 8.1 mmol) was dissolved in tetrahydrofuran (26 mL) and triethylamine trihydrofluoride (1.4 mL, 8.6 mmol) was added. The solution was stirred for 20 h. The reaction was quenched by addition of water (7.6 mL) followed by 10.0 N sodium hydroxide (3.8 mL, 38 mmol). After 3 min, the reaction was diluted with isopropyl acetate (20 mL) and transferred to a separatory funnel. The mixture was shaken and the biphasic mixture was filtered through celite to remove undissolved solids. The filtrate was returned to a separatory funnel and the phases were separated. The organic layer was washed with a mixture of 9 mL water and 9 mL saturated aqueous sodium chloride followed by 15 mL of saturated aqueous sodium chloride. The organic layer was dried over sodium sulfate and concentrated to afford the product 6 as a brown gelatinous solid (4.2 g, 8.0 mmol, 99%). m/z: [M+H+] calcd for C32H35N3O4 526.3; found 526.4.
Reaction SMILES: [O:1]=[S:2]1(=[O:25])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]1[N:21]2[C:16]([CH:17]=[N:18][C:19](S(C)=O)=[N:20]2)=[CH:15][CH:14]=1.[NH2:26][C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[NH:32][C:31](=[O:36])[C:30]2([CH3:38])[CH3:37]>>[O:1]=[S:2]1(=[O:25])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13]1[N:21]2[C:16]([CH:17]=[N:18][C:19]([NH:26][C:27]3[CH:28]=[C:29]4[C:33](=[CH:34][CH:35]=3)[NH:32][C:31](=[O:36])[C:30]4([CH3:38])[CH3:37])=[N:20]2)=[CH:15][CH:14]=1
Reactant: CC1(C)C(=O)Nc2ccc(N)cc21
Reactant: CS(=O)c1ncc2ccc(-c3ccccc3N3CCCS3(=O)=O)n2n1
Product: CC1(C)C(=O)Nc2ccc(Nc3ncc4ccc(-c5ccccc5N5CCCS5(=O)=O)n4n3)cc21
Yield: 23.9 %

Procedure:
Analogous to Example 1491c, 7-[2-(1,1-Dioxido-1,2-thiazolidin-2-yl)phenyl]-2-(methylsulfinyl)pyrrolo[2,1-f][1,2,4]triazine (68 mg, 0.18 mmol) and 5-Amino-3,3-dimethyl-1,3-dihydro-indol-2-one (0.0637 g, 0.361 mmol) were reacted to afford 5-({7-[2-(1,1-Dioxido-1,2-thiazolidin-2-yl)phenyl]pyrrolo[2,1-f][1,2,4]triazin-2-yl}amino)-3,3-dimethyl-1,3-dihydro-2H-indol-2-one as a yellow solid (21 mg, 24%). LCMS: 489 (M+H); 1H-NMR (DMSO-d6): 10.12 (s, 1H), 9.24 (s, 1H), 8.94 (s, 1H), 7.86 (m, 1H), 7.63 (m, 1H), 7.53 (m, 1H), 7.28 (dd, 1H, J=8.53 Hz), 6.98 (d, 1H, J=4.93 Hz), 6.91 (d, 1H, J=4.93 Hz), 6.69 (d, 1H, J=8.53 Hz), 3.29 (s, 2H), 3.24 (t, 2H, J=7.69 Hz), 2.14 (quin, 2H, J=7.69 Hz), 1.05 (s, 6H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1(C(N)=O)[CH2:18][CH2:17][CH2:16]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(OI(C1C=CC=CC=1)OC(=O)C(F)(F)F)=O.C(#[N:45])C>O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1([NH2:45])[CH2:18][CH2:17][CH2:16]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC#N
Reactant: NC(=O)C1(c2ccccc2OCc2ccccc2)CCC1
Agent: O=C(OI(OC(=O)C(F)(F)F)c1ccccc1)C(F)(F)F
Solvent: O
Product: NC1(c2ccccc2OCc2ccccc2)CCC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 1-(2-(benzyloxy)phenyl)cyclobutanecarboxamide (Example 268b 1.984 g) dissolved in acetonitrile (16 mL) and water (16 mL) under nitrogen was treated with [bis(trifluoroacetoxy)iodo]benzene (4.55 g). The resulting solution was stirred at room temperature for 16 h. The reaction mixture was diluted with water, extracted with diethyl ether. The aqueous layer was separated, basified to pH13 with aqueous 1N NaOH and extracted with ethyl acetate. The combined diethyl ether/ethyl acetate organic extracts were dried (MgSO4), filtered and the solvent was removed in vacuo. The residue was dissolved in dichloromethane and loaded on to an SCX cartridge. The impurities were washed through with ethyl acetate then methanol and discarded. Elution with 7N methanolic ammonia and evaporation in vacuo gave the subtitle product (1.164 g).
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]=1[NH:10]N1CCN=C1.[OH:16][S:17]([OH:20])(=O)=[O:18].O=S(=O)=O.C(=O)([O-])[O-].[Ca+2]>>[NH:3]1[CH2:4][CH2:5][N:1]=[C:2]1[NH:10][C:2]1[NH:1][C:5]2[CH:6]=[C:7]([S:17]([OH:20])(=[O:18])=[O:16])[CH:8]=[CH:9][C:4]=2[N:3]=1
Reactant: O=S(=O)(O)O
Reactant: C1=NCCN1Nc1nc2ccccc2[nH]1
Agent: O=C([O-])[O-]
Agent: O=S(=O)=O
Agent: [Ca+2]
Product: O=S(=O)(O)c1ccc2nc(NC3=NCCN3)[nH]c2c1
Temperature: 100 °C

Procedure:
2-(Benzimidazolylamino-2-imidazoline (5.00g) was treated cautiously with oleum (20 ml). The resulting solution was stirred and heated at 100°C for 11/2 hours. After cooling the solution was poured into ice/water (500 ml). Solid calcium carbonate was then added until the pH was 6.5. The white suspension was brought to the boil and the calcium sulphate filtered from the hot solution. The filtrate was concentrated under reduced pressure, brought to the boil again and filtered to remove a trace of insoluble material. The filtrate was acidified with glacial acetic acid and allowed to stand. A crystalline solid (3.98 g) separated on cooling. Recrystallisation from boiling water gave 2-(2-Imidazoline-2-ylamino)benzimidazole-5-sulphonic acid (1.16g) as colourless microcrystals. m.p. >360°C.
Reaction SMILES: FC(F)(F)C(O)=O.[Br:8][C:9]1[C:10]([F:38])=[C:11]([CH:15]2[CH:19]([C:20](O)=[O:21])[NH:18][CH:17]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C:16]32[C:35]2[C:30](=[CH:31][C:32]([Cl:36])=[CH:33][CH:34]=2)[NH:29][C:28]3=[O:37])[CH:12]=[CH:13][CH:14]=1.C(N(C(C)C)CC)(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[NH2:63][C:64]1[CH:71]=[CH:70][C:67]([C:68]#[N:69])=[CH:66][C:65]=1[O:72][CH3:73]>>[C:68]([C:67]1[CH:70]=[CH:71][C:64]([NH:63][C:20]([CH:19]2[NH:18][CH:17]([CH2:23][C:24]([CH3:26])([CH3:27])[CH3:25])[C:16]3([C:35]4[C:30](=[CH:31][C:32]([Cl:36])=[CH:33][CH:34]=4)[NH:29][C:28]3=[O:37])[CH:15]2[C:11]2[CH:12]=[CH:13][CH:14]=[C:9]([Br:8])[C:10]=2[F:38])=[O:21])=[C:65]([O:72][CH3:73])[CH:66]=1)#[N:69]
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Br)c2F)C12C(=O)Nc1cc(Cl)ccc12
Reactant: COc1cc(C#N)ccc1N
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(C#N)ccc1NC(=O)C1NC(CC(C)(C)C)C2(C(=O)Nc3cc(Cl)ccc32)C1c1cccc(Br)c1F
Yield: 40.2 %

Procedure:
In a manner similar to the method described in Example 5, rac-(2′S,3′R,4′S,5′R)-4′-(3-bromo-2-fluoro-phenyl)-6-chloro-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid trifluoroacetic acid prepared in Example 97 (0.4 g, 0.66 mmol), was reacted with diisopropylethylamine (0.43 g, 3.3 mmol), diphenylphosphinic chloride (0.31 g, 1.3 mmol), then reacted with 4-amino-3-methoxy-benzonitrile prepared in Example 57 (0.29 g, 2.0 mmol) to give rac-(2′S,3′R,4′S,5′R)-4′-(3-bromo-2-fluoro-phenyl)-6-chloro-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid (4-cyano-2-methoxy-phenyl)-amide as a white foam (Yield 0.17 g, 40%).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(Cl)(Cl)=O.[CH3:16]O>CCOCC>[Cl:1][C:2]1[N:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH3:16])=[O:5]
Reactant: CO
Reactant: O=C(O)c1ccc(Cl)nc1Cl
Solvent: O=S(Cl)Cl
Solvent: CCOCC
Product: COC(=O)c1ccc(Cl)nc1Cl
Temperature: 0 °C
Reaction time: 1 h
Yield: 97 %

Procedure:
A solution of 2,6-dichloronicotinic acid (20.2 g, 0.105 mol) in MeOH (500 mL) was cooled to 0 ° C. and neat thionyl chloride (38 mL, 63 g, 0.525 mol) was added over ˜0.5 hours. The reaction mixture was stirred at 0° C. for 1 hour. The cooling bath was removed, the reaction temperature was allowed to warm to 25° C., and the reaction was allowed to stir for an additional 2 days at 25° C. The solvent was removed under reduced pressure to give an off-white residue. The residue was dissolved in Et2O (˜500 mL) and the resulting solution was washed successively with saturated aqueous NaHCO3 solution (˜300 mL), water (˜300 mL), and brine solution (˜300 mL). The organic layer was separated, dried over anhydrous MgSO4, and filtered. Removal of the solvent under reduced pressure yielded methyl 2,6-dichloronicotinate (21.0 g, 97%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[Cl:25])=[N:10][N:11]3[C:16](O)=[CH:15][C:14]([CH3:18])=[N:13][C:12]=23)=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.O=P(Cl)(Cl)[Cl:37].C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[Cl:37][C:16]1[N:11]2[N:10]=[C:9]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[Cl:25])[C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)=[C:12]2[N:13]=[C:14]([CH3:18])[CH:15]=1
Reactant: Cc1cc(O)n2nc(-c3ccccc3Cl)c(-c3ccc(Cl)cc3)c2n1
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(Cl)n2nc(-c3ccccc3Cl)c(-c3ccc(Cl)cc3)c2n1
Temperature: 100 °C

Procedure:
To a slurry of 3-(4-chlorophenyl)-2-(2-chlorophenyl)-5-methylpyrazolo[1,5-a]pyrimidin-7-ol (I-3A-4a; 1.08 g, 2.92 mmol) and diisopropylethylamine (0.763 ml, 4.38 mmol) in toluene (30 ml) at room temperature was added POCl3 (1.36 ml, 14.6 mmol), dropwise. The mixture was heated at 100° C. for 16 hours, cooled to room temperature, then slowly added to a stirred mixture of ice, saturated aqueous sodium bicarbonate and ethyl acetate. The aqueous layer was separated and extracted with additional ethyl acetate. The combined organic layers were washed with brine, dried (MgSO4), and then concentrated, in vacuo, to afford the crude product. Purification on a Biotage™ Flash 40M column using 0–10% ethyl acetate in hexanes as eluant afforded I-3A-4b (1.05 g, 92%) as a yellow solid: +ESI MS (M+1) 388.1; 1H NMR (400 MHz, CD2Cl2) δ 7.55–7.35 (m, 6H), 7.26 (d, J=8.7 Hz, 2H), 6.98 (s, 1H), 2.64 (s, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:15]=[CH:14][C:7]2[NH:8][C:9](=[O:13])[CH2:10][CH2:11][CH2:12][C:6]=2[CH:5]=1)([O-:3])=[O:2].[H-].[Na+].[CH3:18]I>CN(C=O)C>[CH3:18][N:8]1[C:9](=[O:13])[CH2:10][CH2:11][CH2:12][C:6]2[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:15]=[CH:14][C:7]1=2
Reactant: O=C1CCCc2cc([N+](=O)[O-])ccc2N1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1C(=O)CCCc2cc([N+](=O)[O-])ccc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 87 %

Procedure:
7-Nitro-1,3,4,5-tetrahydro-benzo[b]azepin-2-one (200 mg, 0.97 mmol) was dissolved in anhydrous DMF (3 ml), and treated with sodium hydride (60% in mineral oil, 58 mg, 1.45 mmol) followed by methyl iodide (0.5 ml). The mixture was stirred 18 hours at room temperature, and then partitioned between ethyl acetate (30 ml) and water (30 ml). Washing once with water (30 ml), drying over anhydrous magnesium sulfate and concentration gave a yellow residue. Purification by preparative TLC (40% EtOAc/hexane) gave 1-Methyl-7-nitro-1,3,4,5-tetrahydrobenzo[b]azepin-2-one as a white solid, 185 mg. (87% yield) 1H NMR (400 MHz, DMSO-d6) δ 8.14-8.24 (m, 2H), 7.52-7.60 (m, 1H), 3.40 (s, 3H), 2.75-2.82 (m, 2H), 2.06-2.25 (m, 4H); MS (m/e) 221 (M+1).
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]3[C:25](=[O:26])[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[NH:18][CH:17]=3)=[O:15])=[C:9]([CH3:27])[CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1>[Pd]>[CH:1]1([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]3[C:25](=[O:26])[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[NH:18][CH:17]=3)=[O:15])=[C:9]([CH3:27])[CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Cc1cc(C2=CCCCC2)ccc1NC(=O)c1c[nH]c2ccccc2c1=O
Agent: [Pd]
Product: Cc1cc(C2CCCCC2)ccc1NC(=O)c1c[nH]c2ccccc2c1=O
Yield: 55.5 %

Procedure:
To N-(4-bromo-2-methyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide (50 mg, 0.14 mmol), cyclohexen-1-ylboronic acid (35 mg, 0.28), and Pd(dppf)Cl2-DCM (11 mg, 0.01 mmol) was added Na2CO3 (980 μL of 2 M, 1.96 mmol) and acetonitrile (2 mL). The reaction mixture was heated under microwave irradiation for 10 min at 150° C. under a N2 atmosphere. The reaction mixture was diluted with ethyl acetate, washed with 50% saturated sodium bicarbonate solution (2×20 mL), water, and brine. The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The crude product was purified via silcia gel column chromatography (30-100% ethyl acetate/hexane) to obtain N-(4-cyclohexen-1-yl-2-methyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide as a white solid (35 mg, 70%). N-(4-cyclohexen-1-yl-2-methyl-phenyl)-4-oxo-1H-quinoline-3-carboxamide (35 mg, 0.10 mmol) was stirred vigorously with 10% Pd/C (wet) (30 mg, 0.01 mmol) under an atmosphere of H2 for 30 min at 50° C. The reaction mixture was filtered, concentrated in vacuo, and purified by HPLC (30-95% CH3CN/5 mM HCl) to yield N-(4-cyclohexyl-2-methylphenyl)-4-oxo-1,4-dihydroquinoline-3-carboxamide (20 mg, 57% yield). LC/MS m/z 361.4 [M+H]+. 1H NMR (400.0 MHz, DMSO-d6) δ 12.94 (d, J=6.0 Hz, 1H), 12.24 (s, 1H), 8.89 (d, J=6.5 Hz, 1H), 8.35 (d, J=7.7 Hz, 1H), 8.22 (d, J=8.3 Hz, 1H), 7.82 (t, J=7.6 Hz, 1H), 7.76 (d, J=7.8 Hz, 1H), 7.55-7.51 (m, J=7.6 Hz, 1H), 7.11 (s, 1H), 7.05 (d, J=8.4 Hz, 1H), 2.45 (m, 1H), 2.38 (s, 3H), 1.80-1.69 (m, 5H), 1.42-1.21 (m, 5H).
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[CH:26]=[CH:25][C:18]2[NH:19][C:20]([CH:22](Cl)[CH3:23])=[N:21][C:17]=2[CH:16]=1)(=[O:8])=[O:7])(C)(C)C.[F:27][C:28]([F:37])([F:36])[C:29]1[CH:34]=[CH:33][C:32]([OH:35])=[CH:31][CH:30]=1.C([O-])([O-])=O.[Na+].[Na+].[Na+].[I-]>CN(C=O)C.ClCCCl.C(O)(C(F)(F)F)=O>[F:27][C:28]([F:36])([F:37])[C:29]1[CH:34]=[CH:33][C:32]([O:35][CH:22]([C:20]2[NH:19][C:18]3[CH:25]=[CH:26][C:15]([C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=4[S:6]([NH2:5])(=[O:7])=[O:8])=[CH:16][C:17]=3[N:21]=2)[CH3:23])=[CH:31][CH:30]=1
Reactant: Oc1ccc(C(F)(F)F)cc1
Reactant: CC(Cl)c1nc2cc(-c3ccccc3S(=O)(=O)NC(C)(C)C)ccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: CC(Oc1ccc(C(F)(F)F)cc1)c1nc2cc(-c3ccccc3S(N)(=O)=O)ccc2[nH]1
Reaction time: 24 h
Yield: 67 %

Procedure:
A mixture of N-tert-butyl-2-[2-(1-chloro-ethyl)-1H-benzoimidazol-5-yl]-benzenesulfonamide (0.042 g, 0.107 mmol), 4-trifluoromethyl-phenol (0.069 g, 0.428 mmol), Na2CO3 (0.045 g, 0.428 mmol), and NaI (0.064 g, 0.428 mmol) in DMF at rt (2 mL) was stirred for 24 hours. The reaction mixture was purified by chromatography (silica, hexanes: EtOAc, 1:1) to afford the protected product. This material dissolved in 1,2-dichloroethane (1 mL) and TFA (1 mL), was heated to 60° C. for 2 hours, and then cooled. The solvent was evaporated and the resulting crude material was purified by chromatography (silica, EtOAc: hexanes, 2:1) afforded the title compound as a pale yellow oil (0.033, 67%). 1H NMR (400 MHz, CD3OD) δ (ppm): 8.14 (dd, 1H, J=8.0 Hz, J=1.2 Hz), 7.70 (dd, 1H, J=1.6 Hz, J=0.8 Hz), 7.67-7.58 (m, 4H), 7.55 (td, 1H, J=8.6 Hz, J=1.6 Hz), 7.39 (td, 2H, J=9.0 Hz, J=1.6 Hz), 7.20 (d, 2H, J=8.8 Hz), 5.91 (q, 1H), 1.87 (d, 3H, J=6.8 Hz). Mass Spectrum (LCMS, ESI pos.) Calcd. For C24H22F3N4O3S: 503.5 (M+MeCN+H), Found 503.2.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:4][CH:3]=1.C([Li])CCC.[B:22](OC)([O:25]C)[O:23]C.Cl>C1COCC1>[O:9]1[C:10]2[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=2[N:12]=[C:8]1[C:5]1[CH:6]=[CH:7][C:2]([B:22]([OH:25])[OH:23])=[CH:3][CH:4]=1
Reactant: Brc1ccc(-c2nc3ccccc3o2)cc1
Reactant: COB(OC)OC
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OB(O)c1ccc(-c2nc3ccccc3o2)cc1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
In a 300 mL three-neck flask, 5.5 g (20 mmol) of 2-(4-bromophenyl)benzoxazole was placed, and the air in the flask was replaced with nitrogen. Then, 120 mL of THF was added in the flask, and the mixture was cooled to −78° C. under nitrogen stream. After cooling, 13 mL (22 mmol) of 1.6 M n-butyllithium was dripped into the solution, and the mixture was stirred at the same temperature for 2 hours. After a certain period, 4.4 mL (40 mmol) of trimethyl borate was added to the solution, and the temperature was raised to room temperature, and then, the solution was stirred for 16 hours. After a certain period, 100 mL of 1 M hydrochloric acid was added to the solution, and stirred for 1 hour. An aqueous layer of the obtained mixture was extracted with ethyl acetate. The resulting extracted solution and the organic layer were combined and washed with saturated saline, and then dried with magnesium sulfate. The mixture was gravity filtered, and the obtained filtrate was condensed to give a solid. The solid was recrystallized with ethyl acetate/hexane, so that 3.3 g of target white powder was obtained in a yield of 69%.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[NH:13]1[C:17](B(O)O)=[CH:16][CH:15]=[N:14]1.C([O-])(O)=O.[Na+]>COCCOC.O>[F:12][C:9]1[CH:10]=[CH:11][C:2]([C:15]2[NH:14][N:13]=[CH:17][CH:16]=2)=[C:3]([CH:8]=1)[C:4]([O:6][CH3:7])=[O:5]
Reactant: OB(O)c1ccn[nH]1
Reactant: COC(=O)c1cc(F)ccc1Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COC(=O)c1cc(F)ccc1-c1ccn[nH]1
Temperature: 23 °C
Yield: 44.9 %

Procedure:
Methyl 2-bromo-5-fluorobenzoate (1.0 g, 4.2 mmol) and (1H-pyrazol-5-yl)boronic acid (485 mg, 4.6 mmol) were combined and dissolved in degassed DME (15 ml) then treated with NaHCO3 (706 mg, 8.4 mmol) in water and the reaction purged with bubbling N2 for 5 minutes. The reaction was treated with Pd(PPh3)4 (243 mg (0.2 mmol) and then purged with bubbling for 5 minutes in a sealed vessel and then heated to reflux for 2 h. The reaction mixture was cooled to 23° C., filtered, and solid rinsed with EtOAc. The organic layers were separated, dried and concentrated. Purification via FCC (ethyl acetate/hexanes, 0-30%) afforded methyl 5-fluoro-2-(1H-pyrazol-5-yl)benzoate (415 mg, 44%).
Reaction SMILES: [CH:1]([N:4]1[C:9](=[O:10])[NH:8][CH:7](SC)[NH:6][C:5]1=[O:13])([CH3:3])[CH3:2].C(O)(=O)C.[CH:18]1([NH2:21])[CH2:20][CH2:19]1>O>[CH:1]([N:4]1[C:9](=[O:10])[NH:8][CH:7]([NH:21][CH:18]2[CH2:20][CH2:19]2)[NH:6][C:5]1=[O:13])([CH3:3])[CH3:2]
Reactant: CSC1NC(=O)N(C(C)C)C(=O)N1
Reactant: NC1CC1
Solvent: O
Solvent: CC(=O)O
Product: CC(C)N1C(=O)NC(NC2CC2)NC1=O
Temperature: 150 °C
Reaction time: 3 h

Procedure:
1-Isopropyl-4-methylthiotetrahydro-1,3,5-triazine-2,6-dione (6.0 g.) (obtained as described in U.K. patent specification No. 1,435,585) and cyclopropylamine acetate (17.85 g.) were heated together and stirred at 150° C. for 3 hours. The mixture was then cooled and water (150 ml.) was added. The white solid which formed was collected, washed with water and dried to give 1-isopropyl-4-cyclopropylaminotetrahydro-1,3,5-triazine-2,6-dione, m.p. 237°-239° C.
Reaction SMILES: [CH:1]1C=C[CH:4]=[CH:3][CH:2]=1.[Br:7][C:8]1[C:9](I)=[C:10]([CH3:23])[C:11]([C:21]#[N:22])=[C:12]2[C:16]=1[O:15][C:14]([C:17]([CH3:20])([CH3:19])[CH3:18])=[N:13]2.[OH2:25]>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>[Br:7][C:8]1[C:9]([C:1]2[O:25][CH:4]=[CH:3][CH:2]=2)=[C:10]([CH3:23])[C:11]([C:21]#[N:22])=[C:12]2[C:16]=1[O:15][C:14]([C:17]([CH3:20])([CH3:19])[CH3:18])=[N:13]2
Reactant: Cc1c(I)c(Br)c2oc(C(C)(C)C)nc2c1C#N
Reactant: c1ccccc1
Reactant: O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Product: Cc1c(-c2ccco2)c(Br)c2oc(C(C)(C)C)nc2c1C#N

Procedure:
Bis(triphenylphosphine)palladium(II) chloride (0.5 mg, 0.72 μmol) was added to a benzene (1.0 ml) solution of 7-bromo-2-tert-butyl-6-iodo-5-methyl-1,3-benzoxazole-4-carbonitrile (I-8) (30 mg, 71.6 μmol), (2-tri-n-butylstannyl)furan (23.7 μl, 75.2 μmol), followed by refluxing overnight. After cooling, water (30 ml) was added, the product was extracted with ethyl acetate (30 ml×2), the organic layer was washed with saturated brine (30 ml), then dried over anhydrous magnesium sulfate, concentrated under reduced pressure. The residue was purified by silica gel column chromatography (h-hexane:ethyl acetate=8:1) to obtain the entitled compound (19 mg) as a colorless solid.