Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:8]1[C:13](I)=[CH:12][CH:11]=[C:10]([N:15]2[CH2:19][C@@H:18]([F:20])[C@H:17]([F:21])[CH2:16]2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:22]([C@:24]1([OH:32])[CH:29]2[CH2:30][CH2:31][N:26]([CH2:27][CH2:28]2)[CH2:25]1)#[CH:23].C(N(CC)CC)C.N>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.CO>[CH2:1]([C:8]1[C:13]([C:23]#[C:22][C@:24]2([OH:32])[CH:29]3[CH2:30][CH2:31][N:26]([CH2:27][CH2:28]3)[CH2:25]2)=[CH:12][CH:11]=[C:10]([N:15]2[CH2:19][C@@H:18]([F:20])[C@H:17]([F:21])[CH2:16]2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: F[C@@H]1CN(c2ccc(I)c(Cc3ccccc3)n2)C[C@H]1F
Reactant: C#C[C@@]1(O)CN2CCC1CC2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N
Solvent: CCN(CC)CC
Solvent: CO
Product: O[C@]1(C#Cc2ccc(N3C[C@@H](F)[C@H](F)C3)nc2Cc2ccccc2)CN2CCC1CC2
Temperature: 75 °C
Reaction time: 3 h
Yield: 40.4 %

Procedure:
A mixture of 152 mg of 2-benzyl-6-[(3R,4R)-3,4-difluoropyrrolidine-1-yl]-3-iodopyridine, 60 mg of (3R)-3-ethynyl-3-quinuclidinol, 22 mg of tetrakis(triphenylphosphine)palladium(0), 7 mg of cuprous iodide, 106 μl of triethylamine and 1.5 ml of methanol was heated under stirring for 3 hours at 75° C. in a nitrogen atmosphere. The reaction solution was poured into an aqueous dilute ammonia and then extracted with ethyl acetate. The extract was washed with brine and the solvent was removed. The residue was subjected to NH-silica gel (Fuji Silicia) column chromatography, eluted with hexane/ethyl acetate (1:1) and then with ethyl acetate/methanol (15:1) and crystallized from hexane/ethyl acetate, to give 65 mg of the target compound.
Reaction SMILES: N[C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:7][C:6]=2[CH:17]=1.[CH3:18][S:19]SC.C(OCC)(=O)C.O>C(#N)C>[CH3:18][S:19][C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:7][C:6]=2[CH:17]=1
Reactant: CSSC
Reactant: CCOC(=O)C1=Cc2cc(N)ccc2OCC1
Solvent: CC#N
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)C1=Cc2cc(SC)ccc2OCC1
Temperature: 50 °C
Reaction time: 2.5 h

Procedure:
The mixture of ethyl 2,3-dihydro-7-amino-1-benzoxepin-4-carboxylate (2.0 g), dimethyl disulfide (2.3 ml) and t-butylnitrile (1.2 ml) in acetonitrile (4 ml) was stirred at 50° C. for 2.5 hours. The mixture was poured into a mixture of ethyl acetate and water. The separated organic layer was washed with water, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel using a mixture of hexane and toluene (1:1) as an eluent. The eluted fractions containing the desired product were collected and evaporated in vacuo to give ethyl 2,3-dihydro-7-methylthio-1-benzoxepin-4-carboxylate (1.24 g).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH:8]([CH3:10])[CH3:9])=[C:6]([Cl:11])[CH:5]=[C:4]([N+:12]([O-])=O)[C:3]=1[OH:15].[H][H].CC(C)=O>CO.[Ni]>[ClH:1].[Cl:1][C:2]1[C:7]([CH:8]([CH3:10])[CH3:9])=[C:6]([Cl:11])[CH:5]=[C:4]([NH2:12])[C:3]=1[OH:15]
Reactant: [H][H]
Reactant: CC(C)c1c(Cl)cc([N+](=O)[O-])c(O)c1Cl
Agent: [Ni]
Solvent: CO
Solvent: CC(C)=O
Product: CC(C)c1c(Cl)cc(N)c(O)c1Cl
Product: Cl
Yield: 85 %

Procedure:
80 g (0.31 mole) of 2,4-dichloro-3-isopropyl-6-nitrophenol were hydrogenated in 425 ml of methanol with 5 g of Raney Ni in an autoclave at 25° to 30° C. and under 10 bar of H2. The mixture was stirred for an additional 30 minutes after hydrogen was no longer being absorbed, then the pressure was released and, after addition of 0.5 ml of hydrazine hydrate to the hydrogenation solution, the catalyst was filtered off under protective gas, washed with 50 ml of methanol, and the filtrate was acidified with 200 ml of concentrated HCl, while cooling to 15° to 20° C. The precipitated crystals were filtered off with suction, washed with 200 ml of cold acetone and dried. Crystals I obtained comprised 53.5 g of 98% pure material; this is 70% of theory. A further 11-12 g of 85 to 90% pure material was obtained by evaporation of the wash acetone, this corresponding to 15% of theory. The hydrogenation mother liquor was discarded.
Reaction SMILES: [CH:1](=O)[CH:2]=O.[NH2:5][N:6]1[C:10]([NH2:11])=[N:9][N:8]=[C:7]1[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1>>[N:9]1[N:8]=[C:7]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)[N:6]2[C:10]=1[N:11]=[CH:2][CH:1]=[N:5]2
Reactant: Nc1nnc(Cc2ccc(O)cc2)n1N
Reactant: O=CC=O
Product: Oc1ccc(Cc2nnc3nccnn23)cc1

Procedure:
General procedure A was followed with the reaction of ethanedial and 4-(4,5-diamino-4H-[1,2,4]triazol-3-ylmethyl)-phenol to provide 4-[1,2,4]triazolo[4,3-b][1,2,4]triazin-3-ylmethyl-phenol (example 7).
Reaction SMILES: [ClH:1].[NH2:2][C:3]([C:5]1[CH:6]=[N:7][C:8]2[C:13]([C:14]=1[NH:15][C:16]1[CH:21]=[CH:20][C:19]([F:22])=[C:18]([O:23][CH3:24])[CH:17]=1)=[CH:12][C:11]([S:25]([CH2:28][CH2:29][C:30]([OH:32])=O)(=[O:27])=[O:26])=[CH:10][C:9]=2[CH3:33])=[O:4].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[NH:58]1[CH2:63][CH2:62][O:61][CH2:60][CH2:59]1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[ClH:1].[F:22][C:19]1[CH:20]=[CH:21][C:16]([NH:15][C:14]2[C:13]3[C:8](=[C:9]([CH3:33])[CH:10]=[C:11]([S:25]([CH2:28][CH2:29][C:30]([N:58]4[CH2:63][CH2:62][O:61][CH2:60][CH2:59]4)=[O:32])(=[O:26])=[O:27])[CH:12]=3)[N:7]=[CH:6][C:5]=2[C:3]([NH2:2])=[O:4])=[CH:17][C:18]=1[O:23][CH3:24]
Reactant: COc1cc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)CCC(=O)O)cc23)ccc1F
Reactant: C1COCCN1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)CCC(=O)N4CCOCC4)cc23)ccc1F
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of Example 481 (0.035 g) in N,N-dimethylformamide (2 ml) was added O-(7-azabenzotriazole-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.029 g). After 5 min, morpholine (0.007 ml, available from Aldrich) and N,N-diisopropylethylamine (0.026 ml ) were added. The resulting solution was stirred at room temperature overnight, and applied directly to an SCX cartridge (IST Isolute™, 5 g). Elution with methanol and 2M ammonia/methanol gave an orange residue, which was further purified by mass directed preparative HPLC (Method C) to give the title compound as a yellow solid (0.006 g).
Reaction SMILES: [C:1]1([C:7]2[CH2:13][CH2:12][CH2:11][C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=3[C:8]=2[C:18]2[CH:23]=[CH:22][C:21]([CH:24]=[CH:25][C:26]([OH:28])=O)=[CH:20][CH:19]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:29][S:30]([NH2:33])(=[O:32])=[O:31]>>[C:1]1([C:7]2[CH2:13][CH2:12][CH2:11][C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=3[C:8]=2[C:18]2[CH:23]=[CH:22][C:21]([CH:24]=[CH:25][C:26]([NH:33][S:30]([CH3:29])(=[O:32])=[O:31])=[O:28])=[CH:20][CH:19]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)C=Cc1ccc(C2=C(c3ccccc3)CCCc3ccccc32)cc1
Reactant: CS(N)(=O)=O
Product: CS(=O)(=O)NC(=O)C=Cc1ccc(C2=C(c3ccccc3)CCCc3ccccc32)cc1

Procedure:
Prepared by coupling 2e and methylsulfonamide in accordance with Procedure 1, Method A described hereinabove. Yield (68%); 1H NMR (CDCl3) δ 7.66 (d, J=15.7 Hz, 1H), 7.18 (m, 10H), 6.95 (d, J=8.1 Hz, 2H), 6.84 (d, J=7.3 Hz, 1H), 6.28 (d, J=15.7 Hz, 1H), 3.36 (s, 3H), 2.82 (t, J=7.0 Hz, 2H), 2.41 (t, J=7.0 Hz, 2H), 2.19 (m, 2H); ESI m/z: 442 (M−H−, 100%).
Reaction SMILES: [CH3:1][N:2]1[C:14]2[CH2:13][CH2:12][CH2:11][C:10](=[O:15])[C:9]=2[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2.[CH3:16][C:17]1[NH:18][CH:19]=[CH:20][N:21]=1.[CH3:22]N(CN(C)C)C.Cl[Si](C)(C)C>C(#N)C>[CH3:1][N:2]1[C:14]2[CH2:13][CH2:12][CH:11]([CH2:22][N:18]3[CH:19]=[CH:20][N:21]=[C:17]3[CH3:16])[C:10](=[O:15])[C:9]=2[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2
Reactant: CN(C)CN(C)C
Reactant: Cc1ncc[nH]1
Reactant: Cn1c2c(c3ccccc31)C(=O)CCC2
Agent: C[Si](C)(C)Cl
Solvent: CC#N
Product: Cc1nccn1CC1CCc2c(c3ccccc3n2C)C1=O
Yield: 60 %

Procedure:
2.0 g of 1,2,3,9-tetrahydro-9-methyl-4H-carbazol-4-one, 1.65 g of 2-methyl imidazole and 2 ml of N,N,N′,N′-tetramethyldiaminomethane were suspended in 30 ml of acetonitrile, and then 4 ml of chlorotrimethylsilane was slowly added thereto. The reaction mixture was stirred under reflux for 10 hours. The reaction mixture was concentrated to remove the solvent, and then 40 ml of water was added to the resulting residue. The resulting solid was filtered and dried, which was then suspended in acetone and stirred for 3 hours, and then filtered and dried under a reduced pressure to give 1.76 g of title compound (yield 60%).
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([F:9])[CH:6]=[C:5]([CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:14][CH:13]=2)[C:3]=1[NH2:4].[CH2:23]([N:30]=[C:31]=[O:32])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29].C1C=CC=CC=1>C1COCC1>[CH2:23]([NH:30][C:31]([NH:4][C:3]1[C:5]([CH2:10][CH2:11][C:12]2[CH:13]=[CH:14][C:15]([CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:16][CH:17]=2)=[CH:6][C:7]([F:9])=[CH:8][C:2]=1[F:1])=[O:32])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: CC(C)(C)Cc1ccc(CCc2cc(F)cc(F)c2N)cc1
Reactant: CCCCCCCN=C=O
Solvent: c1ccccc1
Solvent: C1CCOC1
Product: CCCCCCCNC(=O)Nc1c(F)cc(F)cc1CCc1ccc(CC(C)(C)C)cc1
Temperature: 25 °C

Procedure:
A solution of the product from step (d) (4.5 g) in THF (50 ml) was stirred at room temperature and heptyl isocyanate (5.5 g containing 36 mole % benzene, prepared by the method described in Organic Syntheses, Collective Volume 3, p. 846) and N,N-dimethylaminopyridine (750 mg) were added. The mixture was stirred at room temperature for ca 60 hours, then evaporated under reduced pressure to give an oil which was flash chromatographed through a silica column using ether/hexane (2:1 v/v). The eluate was evaporated under reduced pressure and the residue crystallised from hexane and triturated with methanol to give 4.5 g of material. The latter was flash chromatographed through a silica column using ether/hexane (2:1 v/v) and then freeze-dried from dioxan to give 5.3 g of the desired product, mp 105°-107° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC[N:19]([CH:23]([CH3:25])C)[CH:20]([CH3:22])C.C1C=[CH:28][C:29]2N(O)N=[N:32][C:30]=2C=1.N1C=CC=CC=1CCN.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl.C(Cl)CCl>[N:19]1[CH:20]=[CH:22][C:28]([CH2:29][CH2:30][NH:32][C:14]([CH:11]2[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:13][CH2:12]2)=[O:16])=[CH:25][CH:23]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: On1nnc2ccccc21
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Agent: NCCc1ccccn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCCl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(C(=O)NCCc2ccncc2)CC1

Procedure:
The following was added to DCM: 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (600 mg, 2.62 mmol), DIPEA (1.37 mL, 7.85 mmol), EDC (552 mg, 2.88 mL), HOBT (441 mg, 2.88 mmol), and pyridylethylamine (0.34 mL, 2.88 mL). The solution was stirred at rt for 17 h, at which time the DCM was stripped off and 10% aq. sodium carbonate was added. Material was extracted out with EtOAc (3×). The organic extractions were pooled, dried over magnesium sulfate, and concentrated in vacuo. The residue was taken up in a small amount of EtOAc and diethyl ether was added. The precipitate was collected over a filter and washed with diethyl ether to give the title compound as an off-white solid. (Yield: 634 mg, 1.9 mmol, 73%) 1H NMR (400 MHz, CDCl3) 8.49, 7.09, 5.67-5.54, 4.10, 3.52, 2.81, 2.68, 2.14, 1.81-1.66, 1.56, 1.43
Reaction SMILES: CS(O)(=O)=O.[NH2:6][CH2:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[C:13](=[O:17])[N:12]([CH:18]1[CH2:23][CH2:22][C:21](=[O:24])[NH:20][C:19]1=[O:25])[CH2:11]2.C1N=CN([C:31](N2C=NC=C2)=[O:32])C=1.[NH:38]1[C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][C:41]=2[N:40]=[C:39]1[C:47]1[CH:48]=[C:49]([NH2:54])[CH:50]=[CH:51][C:52]=1[Cl:53].O>CN(C=O)C.CCOCC>[NH:38]1[C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][C:41]=2[N:40]=[C:39]1[C:47]1[CH:48]=[C:49]([NH:54][C:31]([NH:6][CH2:7][C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[C:13](=[O:17])[N:12]([CH:18]2[CH2:23][CH2:22][C:21](=[O:24])[NH:20][C:19]2=[O:25])[CH2:11]3)=[O:32])[CH:50]=[CH:51][C:52]=1[Cl:53]
Reactant: Nc1ccc(Cl)c(-c2nc3ccccc3[nH]2)c1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: NCc1ccc2c(c1)CN(C1CCC(=O)NC1=O)C2=O
Agent: CS(=O)(=O)O
Solvent: O
Solvent: CCOCC
Solvent: CN(C)C=O
Product: O=C1CCC(N2Cc3cc(CNC(=O)Nc4ccc(Cl)c(-c5nc6ccccc6[nH]5)c4)ccc3C2=O)C(=O)N1
Temperature: 25 °C
Reaction time: 18 h
Yield: 21.8 %

Procedure:
A mixture of 3-(5-aminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione methanesulfonic acid salt (0.40 g, 1.1 mmol) and CDI (0.21 g, 1.3 mmol) in DMF (5 mL) was stirred at room temperature for 18 h. To the mixture was added 3-(1H-benzoimidazol-2-yl)-4-chloro-phenylamine (0.32 g, 1.3 mmol) at room temperature, and the mixture was stirred at 100° C. for 18 hours. To the mixture was added water (25 mL) and ether (20 mL). The mixture was stirred at room temperature for 2 h. The solvent was decanted. The solid was purified with Prep HPLC to give 1-[3-(1H-benzoimidazol-2-yl)-4-chloro-phenyl]-3-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-urea as a white solid (130 mg, 22% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 20/80 CH3CN/0.1% H3PO4, 4.44 min (99.2%); mp: 275-277° C.; 1H NMR (DMSO-d6) δ 1.90-2.10 (m, 1H, CHH), 2.23-2.46 (m, 1H, CHH), 2.54-2.68 (m, 1H, CHH), 2.80-3.02 (m, 1H, CHH), 4.31 (d, J=17.4 Hz, 1H, CHH), 4.37-4.51 (m, 3H, CHH, CH2), 5.11 (dd, J=5.0, 13.3 Hz, 1H, NCH), 6.89 (t, J=5.9 Hz, 1H, NH), 7.23 (d, J=4.5 Hz, 2H, Ar), 7.40-7.76 (m, 7H, Ar), 8.07 (d, J=2.5 Hz, 1H, Ar), 9.02 (s, 1H, NH), 10.98 (s, 1H, NH), 12.64 (br. s., 1H, NH); 13C NMR (DMSO-d6) δ 22.39, 31.10, 42.75, 47.02, 51.48, 111.62, 118.88, 120.11, 120.62, 121.55, 121.83, 122.56, 122.85, 126.85, 129.79, 130.23, 130.35, 134.56, 139.56, 142.29, 143.00, 144.58, 149.12, 154.96, 162.96, 167.86, 170.91, 172.76; LCMS MH=543, 545; Anal. Calcd for C28H23N6O4Cl+3H2O: C, 56.33; H, 4.90; N, 14.08. Found: C, 56.73; H, 4.67; N, 14.09.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:14]=[C:13]2[C:8]([CH2:9][N:10](CC3C=CC(OC)=CC=3)[C:11](=[O:23])[N:12]2[C:15]2[C:20]([Cl:21])=[CH:19][CH:18]=[CH:17][C:16]=2[Cl:22])=[C:7]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[Cl:39])[CH:6]=1)=[O:4].[NH:40]1[CH2:45][CH2:44]O[CH2:42][CH2:41]1>>[Cl:39][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=1[C:7]1[CH:6]=[C:5]([C:3](=[O:4])[CH2:2][N:40]2[CH2:45][CH2:44][N:12]([CH:13]([CH3:14])[CH3:8])[CH2:42][CH2:41]2)[CH:14]=[C:13]2[C:8]=1[CH2:9][NH:10][C:11](=[O:23])[N:12]2[C:15]1[C:16]([Cl:22])=[CH:17][CH:18]=[CH:19][C:20]=1[Cl:21]
Reactant: COc1ccc(CN2Cc3c(-c4ccccc4Cl)cc(C(=O)CBr)cc3N(c3c(Cl)cccc3Cl)C2=O)cc1
Reactant: C1COCCN1
Product: CC(C)N1CCN(CC(=O)c2cc(-c3ccccc3Cl)c3c(c2)N(c2c(Cl)cccc2Cl)C(=O)NC3)CC1

Procedure:
The title compound was prepared from 7-(bromoacetyl)-5-(2-chlorophenyl)-1-(2,6-dichlorophenyl)-3-(4-methoxybenzyl)-3,4-dihydroquinazolin-2(1H)-one and using morpholine as an amine as described in EXAMPLE ABA1. 1H NMR (CDCl3, 500MHz): δ 7.53-7.27 (m, 8H); 6.92 (s, 1H); 5.91 (brs, 1H); 4.45 (d, J=15.5 Hz, 1H); 4.28 (d, J=15.5 Hz, 1H); 3.64 (m, 4H); 3.55 (Abq, J=3.7, 15.8 Hz, 2H); 2.44 (m, 4H). Mass spectrum (ESI): 530 (M+1).
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][NH:14][C:13]3=[O:20])=[CH:6][CH:5]=1.Cl[CH2:24][C:25]1[O:26][CH:27]=[C:28]([C:30]([O:32][CH3:33])=[O:31])[N:29]=1.C(=O)([O-])[O-].[K+].[K+]>CC(N(C)C)=O.O.ClCCl>[O:20]=[C:13]1[C:12]2[C:17](=[CH:18][CH:19]=[C:10]([C:7]3[CH:8]=[CH:9][C:4]([O:3][C:2]([F:1])([F:21])[F:22])=[CH:5][CH:6]=3)[CH:11]=2)[N:16]=[CH:15][N:14]1[CH2:24][C:25]1[O:26][CH:27]=[C:28]([C:30]([O:32][CH3:33])=[O:31])[N:29]=1
Reactant: COC(=O)c1coc(CCl)n1
Reactant: O=c1[nH]cnc2ccc(-c3ccc(OC(F)(F)F)cc3)cc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Solvent: ClCCl
Product: COC(=O)c1coc(Cn2cnc3ccc(-c4ccc(OC(F)(F)F)cc4)cc3c2=O)n1

Procedure:
A solution of 500 mg 6-(4-(trifluoromethoxy)phenyl)quinazolin-4(3H)-one, 340 mg of methyl 2-(chloromethyl)oxazole-4-carboxylate, and 220 mg potassium carbonate in 5 mL of DMA was heated at 80° C. for 16 h. The reaction was diluted with water and dichloromethane, aqueous layer washed with dichloromethane, combined organic layers dried over sodium sulphate and concentrated. The residue was recrystallized from acetonitrile to produce methyl 2-((4-oxo-6-(4-(trifluoromethoxy)phenyl)quinazolin-3(4H)-yl)methyl)oxazole-4-carboxylate Compound 177-A as a white solid (420 mg). MS m/z (ESI)=446.0 (base peak, M+H+); 891.1 (2M+H+); 913.1 (2M+Na+).
Reaction SMILES: OC[C@@H](NC(C1C=NC(N2CCCC2)=C(OCCC)N=1)=O)CC(C)C.[CH:26]1([NH:32][C:33]2[N:34]=[CH:35][C:36]([C:45](O)=[O:46])=[N:37][C:38]=2[O:39][CH2:40][C:41]([F:44])([F:43])[F:42])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1.[CH3:48][O:49][C:50](=[O:57])[C:51]([NH2:56])([CH2:54][CH3:55])[CH2:52][CH3:53]>>[CH3:48][O:49][C:50](=[O:57])[C:51]([NH:56][C:45]([C:36]1[CH:35]=[N:34][C:33]([NH:32][CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)=[C:38]([O:39][CH2:40][C:41]([F:43])([F:44])[F:42])[N:37]=1)=[O:46])([CH2:54][CH3:55])[CH2:52][CH3:53]
Reactant: CCC(N)(CC)C(=O)OC
Reactant: O=C(O)c1cnc(NC2CCCCC2)c(OCC(F)(F)F)n1
Agent: CCCOc1nc(C(=O)N[C@H](CO)CC(C)C)cnc1N1CCCC1
Product: CCC(CC)(NC(=O)c1cnc(NC2CCCCC2)c(OCC(F)(F)F)n1)C(=O)OC

Procedure:
In analogy to the procedure described for the synthesis of 6-propoxy-5-pyrrolidin-1-yl-pyrazine-2-carboxylic acid ((S)-1-hydroxymethyl-3-methyl-butyl)-amide (example 10, step d) the title compounds was prepared from 5-cyclohexylamino-6-(2,2,2-trifluoro-ethoxy)-pyrazine-2-carboxylic acid and 2-amino-2-ethyl-butyric acid methyl ester (European Journal of Medicinal Chemistry 1984, 19, 261). m/z (ES+): 447.5 (M+H).
Reaction SMILES: [C:1]([C:6]1[C:14]2[C:9](=[CH:10][C:11]([C:15]([O:17][CH3:18])=[O:16])=[CH:12][CH:13]=2)[NH:8][C:7]=1[CH2:19][CH2:20][CH3:21])(=[O:5])[CH:2]([CH3:4])[CH3:3].[Br:22]N1C(=O)CCC1=O.N(C(C)(CC(OC)(C)C)C#N)=NC(C)(CC(C)(OC)C)C#N>C(Cl)(Cl)(Cl)Cl>[Br:22][CH:19]([C:7]1[NH:8][C:9]2[C:14]([C:6]=1[C:1](=[O:5])[CH:2]([CH3:4])[CH3:3])=[CH:13][CH:12]=[C:11]([C:15]([O:17][CH3:18])=[O:16])[CH:10]=2)[CH2:20][CH3:21]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCCc1[nH]c2cc(C(=O)OC)ccc2c1C(=O)C(C)C
Agent: COC(C)(C)CC(C)(C#N)N=NC(C)(C#N)CC(C)(C)OC
Solvent: ClC(Cl)(Cl)Cl
Product: CCC(Br)c1[nH]c2cc(C(=O)OC)ccc2c1C(=O)C(C)C
Yield: 69.9 %

Procedure:
To a solution of methyl 3-isobutyryl-2-propylindole-6-carboxylate (201 mg) in carbon tetrachloride (7 ml) was added N-bromosuccinimide (187 mg) and 2,2'-azobis(4-methoxy-2,4-dimethylvaleronitrile) (20 mg) and refluxed for 30 minutes. The resulting mixture was filtered and the filtrate was evaporated in vacuo. The residue was purified by preparative thin layer chromatography on silica gel eluting with a mixture of hexane and ethyl acetate (2:1) to give methyl 2-(1-bromopropyl)-3-isobutyrylindole-6-carboxylate (179 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[N:9]([O-])=O.[Na+].C([O-])(=O)C.[Na+].[C:18]([CH2:21][C:22](=[O:24])[CH3:23])(=[O:20])[CH3:19]>C(O)(=O)C.Cl.O.C(O)C>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][N:9]=[C:21]([C:22](=[O:24])[CH3:23])[C:18](=[O:20])[CH3:19])=[CH:4][CH:3]=1
Reactant: CC(=O)CC(C)=O
Reactant: Nc1ccc(Cl)cc1
Reactant: O=N[O-]
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)C(=NNc1ccc(Cl)cc1)C(C)=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 89.4 %

Procedure:
To a solution of 4-chloroaniline (1000 mg, 7.87 mmol) in 10 mL of acetic acid and 2 mL of concentrated hydrochloride solution, sodium nitrite (652 mg, 9.45 mmol) in 4 mL of water was added dropwise at 0° C., and the mixture was stirred at 0° C. for 1 h. Then to the reaction mixture was added dropwise a solution of sodium acetate (1936 mg, 23.61 mmol) and acetylacetone (1023 mg, 10.23 mmol) in 10 mL of ethanol and 6 mL of water. The mixture was stirred at room temperature overnight, filtered, washed with water, EtOH/H2O (1:1) and hexane, and dried to give 3-[(4-chlorophenyl)hydrazono]pentane-2,4-dione (1680 mg, 90%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([Mg]Br)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:17]([O:24][C:25]1[CH:26]=[C:27](Br)[CH:28]=C[CH:30]=1)[C:18]1C=CC=CC=1.[Mg].Cl.[O:34]1CCCC1>>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:27]2([OH:34])[CH2:26][CH:25]([CH3:30])[O:24][CH:17]([CH3:18])[CH2:28]2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Br[Mg]c1cccc(OCc2ccccc2)c1
Reactant: Brc1cccc(OCc2ccccc2)c1
Reactant: C1CCOC1
Agent: Cl
Agent: [Mg]
Product: CC1CC(O)(c2cccc(OCc3ccccc3)c2)CC(C)O1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 2,60dimethyltetrahydropyran-4-one (2.2 g) in tetrahydrofuran (5 ml) was added to a solution of 3-benzyloxyphenylmagnesium bromide [prepared by heating a mixture of 3-benzyloxybromobenzene (5 g), magnesium (0.5 g) and tetrahydrofuran (20 ml)] in tetrahydrofuran and the mixture was stirred at ambient temperature for 3 hours. The mixture was cooled to 5° C., ice (5 ml) and 2N hydrochloric acid solution (25 ml) were added, and the mixture was extracted with ethyl acetate. The organic phase was washed with a saturated sodium chloride solution, dried (MgSO4) and evaporated. The residue was purified by column chromatography using increasingly polar mixtures of toluene and ethyl acetate as eluent. There were thus obtained two isomers of 4-(3-benzyloxyphenyl)-4-hydroxy-2,6-dimethyltetrahydropyran: a less polar isomer (2.41 g, 45%),
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[C:12]1([C:18]2[O:22][N:21]=[CH:20][C:19]=2[CH2:23][CH2:24][C:25](O)=[O:26])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>O.CN(C)C=O>[N:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:10]=[CH:11][C:2]=1[NH:1][C:25](=[O:26])[CH2:24][CH2:23][C:19]1[CH:20]=[N:21][O:22][C:18]=1[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: Nc1ccc2ccccc2n1
Reactant: O=C(O)CCc1cnoc1-c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: O=C(CCc1cnoc1-c1ccccc1)Nc1ccc2ccccc2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.1 %

Procedure:
A mixture of 2-aminoquinoline (0.55 g), 3-(5-phenyl-4-isoxazolyl)propionic acid (0.82 g), 1-hydroxy-1H-1,2,3-benzotriazole hydrate (0.68 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.91 g) and N,N-dimethylformamide (15 ml) was stirred at room temperature overnight. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with dilute hydrochloric acid, saturated aqueous sodium hydrogencarbonate and then saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and N-(2-quinolyl)-3-(5-phenyl-4-isoxazolyl)propionamide (1.09 g, yield 84%) was obtained as colorless crystals from a fraction eluted with ethyl acetate-hexane (1:1, volume ratio). The crystals were recrystallized from ethyl acetate-hexane. melting point: 112–113° C.