Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][C:5]([NH2:9])=[N:6][C:7]=1Cl.[F:10][C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>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.O1CCOCC1>[F:10][C:11]1[CH:16]=[CH:15][C:14]([C:2]2[N:3]=[CH:4][C:5]([NH2:9])=[N:6][C:7]=2[C:14]2[CH:15]=[CH:16][C:11]([F:10])=[CH:12][CH:13]=2)=[CH:13][CH:12]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: Nc1cnc(Br)c(Cl)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Nc1cnc(-c2ccc(F)cc2)c(-c2ccc(F)cc2)n1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
A mixture of 5-bromo-6-chloropyrazin-2-amine (2 g, 9.66 mmol, 1.00 equiv), 4-fluorophenylboronic acid (3.38 g, 24.14 mmol, 2.50 equiv), Pd(PPh3)4 (1.11 g, 0.96 mmol, 0.10 equiv), K3PO4 (8.19 g, 38.66 mmol, 4.00 equiv), and 1,4-dioxane (10 mL) was stirred overnight at 100° C. in an oil bath. The resulting mixture was concentrated in vacuo, and the residue was purified via silica gel column chromatography (ethyl acetate: petroleum ether (1:20)), resulting in 1.7 g (62%) of 5,6-bis(4-fluorophenyl)pyrazin-2-amine as a brown solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]=[C:10]=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].Cl.[NH2:13][CH2:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[CH2:17][N:18]([CH:25]1[CH2:30][CH2:29][C:28](=[O:31])[NH:27][C:26]1=[O:32])[C:19]2=[O:24].C(N(CC)CC)C>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([NH:13][CH2:14][C:15]2[CH:23]=[CH:22][CH:21]=[C:20]3[C:16]=2[CH2:17][N:18]([CH:25]2[CH2:30][CH2:29][C:28](=[O:31])[NH:27][C:26]2=[O:32])[C:19]3=[O:24])=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C=Nc1ccc(Cl)c(Cl)c1
Reactant: NCc1cccc2c1CN(C1CCC(=O)NC1=O)C2=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C1CCC(N2Cc3c(CNC(=O)Nc4ccc(Cl)c(Cl)c4)cccc3C2=O)C(=O)N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.9 %

Procedure:
3,4-Dichlorophenyl isocyanate (0.5 g, 2.7 mmol) was added to a stirred suspension of 3-(4-aminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione hydrochloride (0.7 g, 2.1 mmol) and triethylamine (0.3 g, 2.9 mmol) in THF (30 mL). The mixture was stirred at room temperature overnight. The mixture was concentrated, and the residue was stirred with 1N HCl (30 mL). The mixture was filtered, and the solid was slurried with hot methanol (20 mL) to give 1-(3,4-dichloro-phenyl)-3-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-4-ylmethyl]-urea (0.6 g, 67%) as a white solid: mp 253-255° C.; 1H NMR (DMSO-d6) δ 2.00-2.05 (m, 1H), 2.37-2.65 (m, 2H), 2.86-3.00 (m, 1H), 4.36-4.58 (m, 4H, 2CH2), 5.11-5.18 (dd, J=4.9 and 13.1 Hz, 1H, CH), 6.89 (t, J=5.6 Hz, 1H, NH), 7.24-7.84 (m, 6H, Ar), 8.96 (s, 1H, NH), 11.01 (s, 1H, NH); 13C NMR (DMSO-d6) δ 22.56, 31.17, 39.69, 46.19, 51.58, 117.86, 118.83, 121.58, 122.37, 128.29, 130.38, 130.86, 131.64, 135.27, 139.91, 140.56, 154.87, 168.05, 170.98, 172.81; Anal. calcd. for C21H18N4O4Cl2: C, 54.68; H, 3.93; N, 12.15; Cl, 15.37. Found: C, 54.52; H, 3.78; N, 11.89; Cl, 15.28.
Reaction SMILES: [N:1]([CH:4]([C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]=1Br)[CH3:5])=[N+:2]=[N-:3].[F:17][C:18]1[CH:19]=[C:20](B(O)O)[CH:21]=[N:22][CH:23]=1.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>[N:1]([CH:4]([C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]=1[C:20]1[CH:21]=[N:22][CH:23]=[C:18]([F:17])[CH:19]=1)[CH3:5])=[N+:2]=[N-:3]
Reactant: OB(O)c1cncc(F)c1
Reactant: CC(N=[N+]=[N-])c1ccc2ccccc2c1Br
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: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: CC(N=[N+]=[N-])c1ccc2ccccc2c1-c1cncc(F)c1
Temperature: 100 °C

Procedure:
To a mixture of 2(1-azidoethyl)-1-bromonaphthalene (0.080 g, 0.29 mmol) and (5-fluoropyridin-3-yl)boronic acid (49.0 mg, 0.348 mmol) in 1,4-dioxane (2 mL) was added a 1 M solution of sodium carbonate in water (0.34 mL) and tetrakis(triphenylphosphine)palladium(0) (16.7 mg, 0.0145 mmol). The reaction mixture was heated at 100° C. overnight. After cooling to room temperature, the mixture was diluted with ethyl acetate, washed with water and brine, dried over MgSO4, and then concentrated. The residue was purified on silica gel, eluting with 0 to 50% EtOAc in hexane, to give the desired product. LCMS calculated for C17H14FN4(M+H)+: m/z=293.1; found: 293.0.
Reaction SMILES: Br[C:2]1[C:3]([F:17])=[C:4]2[O:8][C:7]([CH:9]3[CH2:11][CH2:10]3)=[N:6][C:5]2=[C:12]([C:15]#[N:16])[C:13]=1[CH3:14].C([Sn](CCCC)(CCCC)[C:23]([O:25][CH2:26][CH3:27])=[CH2:24])CCC>C1(C)C=CC=CC=1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(C1(C)C(O)=C(C(C)(C)C)C=CC1)(C)(C)C>[CH:9]1([C:7]2[O:8][C:4]3[C:5](=[C:12]([C:15]#[N:16])[C:13]([CH3:14])=[C:2]([C:23]([O:25][CH2:26][CH3:27])=[CH2:24])[C:3]=3[F:17])[N:6]=2)[CH2:11][CH2:10]1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: Cc1c(Br)c(F)c2oc(C3CC3)nc2c1C#N
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)C1=C(O)C(C)(C(C)(C)C)CC=C1
Solvent: Cc1ccccc1
Product: C=C(OCC)c1c(C)c(C#N)c2nc(C3CC3)oc2c1F
Yield: 108.5 %

Procedure:
6-Bromo-2-cyclopropyl-7-fluoro-5-methyl-1,3-benzoxazole-4-carbonitrile (I-77) (8.88 g, 30.08 mmol) was dissolved in toluene (130 ml), then tributyl(1-ethoxyvinyl)tin (11.2 ml, 33.09 mmol) and 2,6-di-tert-butylcresol (66 mg, 0.30 mmol) and bis(triphenylphosphine)palladium(II) dichloride (1.06 g, 1.50 mmol) were added, followed by heating under reflux for 17 hours under nitrogen atmosphere. The reaction liquid was cooled, the insoluble matter was separated by filtration through Celite, the solvent was concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography, followed by removing tin-derived side products with n-hexane and by elution with a mixed solvent of n-hexane/ethyl acetate (7:1, v/v) to obtain the a crude product (9.34 g, quant.) as a yellow white solid.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:21]=[CH:20][C:11]([CH2:12][CH:13]3[S:17][C:16](=[O:18])[NH:15][C:14]3=[O:19])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[NH2:22][CH2:23][C@H:24]([OH:33])[CH2:25][O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>CN(C)C=O>[OH:33][C@H:24]([CH2:25][O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:23][NH:22][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:21]=[CH:20][C:11]([CH2:12][CH:13]3[S:17][C:16](=[O:18])[NH:15][C:14]3=[O:19])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1
Reactant: NC[C@H](O)COc1ccccc1
Reactant: O=C1CCN(c2ccc(CC3SC(=O)NC3=O)cc2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: O=C1NC(=O)C(Cc2ccc(N3CCC(NC[C@H](O)COc4ccccc4)CC3)cc2)S1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
5-{4-(4-Oxo-piperidin-1-yl)-benzyl]-thiazolidine-2,4-dione (which was obtained in Example 38) (0.15 g, 0.5 mmol) and (2S)-1-amino-3-phenoxy-propan-2-ol (which was obtained in Example 3) (0.12 g, 0.75 mmol) were mixed in N,N-dimethylformamide (15 mL) and then treated with sodium triacetoxyborohydride (0.16 g, 0.75 mmol) and acetic acid (0.045 g, 0.75 mmol). After stirring at room temperature under a nitrogen atmosphere for one day the mixture was quenched with 1N NaOH and then poured into a saturated aqueous NaHCO3. The aqueous solution was extracted with 1-butanol and the combined organic layers were concentrated. The residue was purified by preparative thin layer chromatography (10% MeOH/CH2CH2) to give the title compound as a pale yellowish solid; mp 218–220° C.; 1H NMR (300 MHz, DMSO-d6) δ 1.30–1.60 (m, 2 H), 1.80–2.00 (m, 2 H), 2.50–3.00 (m, 5 H), 3.00–3.50 (m, 3 H), 3.50–3.70 (m, 2 H), 3.85–4.00 (m, 3 H), 4.48 (dd, J=9.8, 3.8 Hz, 1 H), 6.85 (d, J=8.6 Hz, 2 H), 6.90–6.97 (m, 3 H), 7.04 (d, J=8.6 Hz, 2 H), 7.25–7.38 (m, 3 H); MS (ES) m/z: 456.0 (MH+); HRMS Calcd. for C24H29N3O4S (M+): 455.1878. Found: 455.1880.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10])[NH2:5].[C:12]([C:16]1[O:20][N:19]=[C:18]([NH:21][C:22](=O)[O:23]C2C=CC=CC=2)[CH:17]=1)([CH3:15])([CH3:14])[CH3:13].CCN(C(C)C)C(C)C>C1COCC1.CN(C1C=CN=CC=1)C>[C:12]([C:16]1[O:20][N:19]=[C:18]([NH:21][C:22]([NH:5][C:4]2[CH:6]=[CH:7][C:8]([N+:9]([O-:11])=[O:10])=[C:2]([CH3:1])[CH:3]=2)=[O:23])[CH:17]=1)([CH3:15])([CH3:13])[CH3:14]
Reactant: Cc1cc(N)ccc1[N+](=O)[O-]
Reactant: CC(C)(C)c1cc(NC(=O)Oc2ccccc2)no1
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cc1cc(NC(=O)Nc2cc(C(C)(C)C)on2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 164.9 %

Procedure:
To a stirred solution of 3-methyl-4-nitroaniline (566 mg, 3.7 mmol) in THF (10 mL) was added phenyl 5-tert-butylisoxazol-3-ylcarbamate (1.0 g, 3.7 mmol), DIEA (972 mL, 5.6 mmol), and DMAP (50 mg, 0.41 mmol). The resulting mixture was refluxed for 60 h. The reaction mixture was then cooled to rt, partitioned between EtOAc (50 mL) and 3N HCl (15 mL). The organic layer was washed with sat. NaHCO3 (15 mL), brine (20 mL), dried over MgSO4, filtered, and concentrated under reduced pressure to afford crude 1-(5-tert-butylisoxazol-3-yl)-3-(3-methyl-4-nitrophenyl)urea (2.0 g, 6.1 mmol). LC-MS (ESI) m/z 319 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]2[N:6]=[C:7]([NH:9][C:10]3[N:14]([CH3:15])[C:13]4[CH:16]=[CH:17][C:18]([C:20]([OH:22])=O)=[CH:19][C:12]=4[N:11]=3)[S:8][C:4]=2[CH:3]=1.[NH2:25][CH2:26][CH2:27][CH2:28][CH2:29][OH:30].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[OH:30][CH2:29][CH2:28][CH2:27][CH2:26][NH:25][C:20]([C:18]1[CH:17]=[CH:16][C:13]2[N:14]([CH3:15])[C:10]([NH:9][C:7]3[S:8][C:4]4[CH:3]=[C:2]([Cl:1])[CH:24]=[CH:23][C:5]=4[N:6]=3)=[N:11][C:12]=2[CH:19]=1)=[O:22]
Reactant: Cn1c(Nc2nc3ccc(Cl)cc3s2)nc2cc(C(=O)O)ccc21
Reactant: NCCCCO
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1c(Nc2nc3ccc(Cl)cc3s2)nc2cc(C(=O)NCCCCO)ccc21
Yield: 44.1 %

Procedure:
2-(6-Chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylic acid (4-hydroxy-butyl)-amide (37 mg) was prepared by following General Procedure F starting from 2-(6-chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylic acid (70 mg), 4-amino-butan-1-ol (20 mg), HBTU (80 mg), and DIEA (70 uL) in DMF (1 mL). LC/MS: m/z 429.6.
Reaction SMILES: [C:1]([N:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]2[N:13](C3CCCCO3)[C:14]3[C:19]([N:20]=2)=[C:18]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[N:17]=[C:16]([NH:27][C:28]2[C:29]([NH2:34])=[CH:30][CH:31]=[CH:32][CH:33]=2)[N:15]=3)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[F:41][C:42]([F:47])([CH3:46])[C:43](O)=O.CN(C)C=O.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(O)(=O)C>>[C:1]([N:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]2[NH:13][C:14]3[C:19]([N:20]=2)=[C:18]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[N:17]=[C:16]([N:27]2[C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[N:34]=[C:43]2[C:42]([F:47])([F:41])[CH3:46])[N:15]=3)[CH2:7][CH2:6]1)([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(F)(F)C(=O)O
Reactant: CC(C)(C)N1CCN(Cc2nc3c(N4CCOCC4)nc(Nc4ccccc4N)nc3n2C2CCCCO2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CC(=O)O
Solvent: CCN(C(C)C)C(C)C
Product: CC(F)(F)c1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCN(C(C)(C)C)CC3)[nH]c2n1
Temperature: 0 °C
Reaction time: 8 h
Yield: 18.9 %

Procedure:
N1-(8-((4-tert-butylpiperazin-1-yl)methyl)-6-morpholino-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-2-yl)benzene-1,2-diamine (0.085 g, 0.15 mmol) and 2,2-difluoropropanoic acid (0.019 g, 0.17 mmol) were dissolved in N,N-dimethylformamide (2 mL, 0.02 mol). N,N-Diisopropylethylamine (0.054 mL, 0.31 mmol) was added. The resulting solution was cooled at 0° C. for 20 minutes. N,N,N′,N′-Tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (0.070 g, 0.00018 mol) was added and the reaction stirred overnight at room temperature. The reaction mixture was concentrated to dryness. Acetic acid (3.0 mL, 0.053 mol) was added to the crude residue and the reaction mixture was heated at 90° C. for 18 hours. The reaction mixture was cooled, filtered and concentrated to dryness. The crude was purified by reverse phase HPLC to give 457 (15.3 mg, 18%). [M+H]+=540.3
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][N:3]=1.[CH3:11][C:12]([C:14]1[C:19]([NH2:20])=[CH:18][C:17]2[O:21][CH2:22][O:23][C:16]=2[CH:15]=1)=[O:13]>>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([C:6]([NH:20][C:19]2[CH:18]=[C:17]3[O:21][CH2:22][O:23][C:16]3=[CH:15][C:14]=2[C:12]([CH3:11])=[O:13])=[O:7])=[CH:9][CH:10]=1
Reactant: O=C(Cl)c1ccc(Cl)nc1
Reactant: CC(=O)c1cc2c(cc1N)OCO2
Product: CC(=O)c1cc2c(cc1NC(=O)c1ccc(Cl)nc1)OCO2

Procedure:
The title compound was prepared from 6-chloronicotinoyl chloride and 2-amino-4,5-methylenedioxyacetophenone as a light grey-yellow solid as described in Example 1. 1H NMR (CDCl3): 9.09-9.08 (m, 1H), 8.55 (s, 1H), 8.30-8.27 (m, 1H), 7.50-7.47 (m, 1H), 7.35 (s, 1H), 6.10 (s, 2H), 2.64 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]([CH3:10])=[CH:5][C:6]=1[C:7]([OH:9])=O.S(Cl)(Cl)=O.[NH:15]([C:22]1[CH:27]=[C:26]([N+:28]([O-:30])=[O:29])[CH:25]=[CH:24][C:23]=1[OH:31])C1C=CC=CC=1>>[OH:31][C:23]1[CH:24]=[CH:25][C:26]([N+:28]([O-:30])=[O:29])=[CH:27][C:22]=1[NH:15][C:7]([C:6]1[CH:5]=[C:4]([CH3:10])[S:3][C:2]=1[Br:1])=[O:9]
Reactant: O=[N+]([O-])c1ccc(O)c(Nc2ccccc2)c1
Reactant: Cc1cc(C(=O)O)c(Br)s1
Solvent: O=S(Cl)Cl
Product: Cc1cc(C(=O)Nc2cc([N+](=O)[O-])ccc2O)c(Br)s1

Procedure:
In the same manner as in Starting Material Synthesis Example 67 and using 2-bromo-5-methyl-3-thiophenecarboxylic acid, thionyl chloride and 2-amiino-4-nitrophenol, N-(2-hydroxy-5-nitrophenyl)-2-bromo-5-methyl-3-thiophenecarboxamide is obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:11]([OH:13])=O)[S:5][C:6]=1[CH:7]=[C:8]([CH3:10])[CH3:9].C([O:21][C:22]1[C:31]([CH3:32])=[CH:30][C:25]([C:26]([NH:28][NH2:29])=O)=[CH:24][C:23]=1[CH2:33][CH3:34])C1C=CC=CC=1>>[CH2:33]([C:23]1[CH:24]=[C:25]([C:26]2[O:13][C:11]([C:4]3[S:5][C:6]([CH2:7][CH:8]([CH3:9])[CH3:10])=[C:2]([CH3:1])[CH:3]=3)=[N:29][N:28]=2)[CH:30]=[C:31]([CH3:32])[C:22]=1[OH:21])[CH3:34]
Reactant: CC(C)=Cc1sc(C(=O)O)cc1C
Reactant: CCc1cc(C(=O)NN)cc(C)c1OCc1ccccc1
Product: CCc1cc(-c2nnc(-c3cc(C)c(CC(C)C)s3)o2)cc(C)c1O

Procedure:
2-Ethyl-4-[5-(5-isobutyl-4-methyl-thiophen-2-yl)-[1,3,4]oxadiazol-2-yl]-6-methyl-phenol is prepared from 4-methyl-5-(2-methyl-propenyl)-thiophene-2-carboxylic acid and 4-benzyloxy-3-ethyl-5-methyl-benzoic acid hydrazide in analogy to Example 29; LC-MS: tR=1.13 min, [M+1]+=357.49.
Reaction SMILES: [CH3:1][N:2]=[C:3]=[S:4].[SH:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9]>N1C=CC=CC=1.[OH-].[Na+]>[CH3:1][NH:2][C:3]([S:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9])=[S:4]
Reactant: CN=C=S
Reactant: O=C(O)CCS
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Product: CNC(=S)SCCC(=O)O
Reaction time: 2 h

Procedure:
Methylisothiocyanate (4 g) is added to a solution of 3-mercaptopropanoic acid (5.3 g) in a mixture of pyridine (250 ml) and 0.5 N sodium hydroxide (100 ml). The solution is kept at 40° for two hours and concentrated to dryness in vacuo. The residue is dissolved in water (100 ml.), acidified with concentrated hydrochloric acid and extracted with ether. The organic phase is concentrated to dryness to yield 3-[[(methylamino)thiocarbonyl]thio]propanoic acid, m.p. 86°-87°.
Reaction SMILES: [CH2:1]([NH:16][C:17]([O:19][CH2:20][C:21](=[CH2:24])[CH2:22][OH:23])=[O:18])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].[Br:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][C:33](O)=[O:34]>>[CH2:1]([NH:16][C:17]([O:19][CH2:20][C:21](=[CH2:24])[CH2:22][O:23][C:33](=[O:34])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][Br:25])=[O:18])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: C=C(CO)COC(=O)NCCCCCCCCCCCCCCC
Reactant: O=C(O)CCCCCCCBr
Product: C=C(COC(=O)CCCCCCCBr)COC(=O)NCCCCCCCCCCCCCCC

Procedure:
Following the procedure described in Preparation 9, but replacing 3-octadecylaminocarbonyloxy-2-methylenepropan-1-ol with 3-pentadecylaminocarbonyloxy-2-methylenepropan-1-ol (from Preparation 4), and replacing 6-bromohexanoic acid with 8-bromooctanoic acid, the desired product was obtained.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[NH:13][N:12]=[C:11]([CH:14]2[CH2:19][CH2:18][N:17](C(OCC3C=CC=CC=3)=O)[CH2:16][CH2:15]2)[CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[C].[Pd]>[NH:17]1[CH2:18][CH2:19][CH:14]([C:11]2[CH:10]=[C:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:3])([CH3:2])[CH3:4])[NH:13][N:12]=2)[CH2:15][CH2:16]1
Reactant: CC(C)(C)OC(=O)Nc1cc(C2CCN(C(=O)OCc3ccccc3)CC2)n[nH]1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)Nc1cc(C2CCNCC2)n[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 104.3 %

Procedure:
10% palladium-carbon (M type, wet product, 2.50 g) was added to a solution of benzyl 4-{5-[(tert-butoxycarbonyl)amino]-1H-pyrazol-3-yl}piperidine-1-carboxylate (12.25 g, 30.59 mmol) produced in Reference Example 28 in methanol (130 mL), and the mixture was stirred at room temperature for 8 hours under a hydrogen atmosphere. The catalyst in the reaction solution was filtered off, and the solvent in the obtained filtrate was distilled off under reduced pressure to obtain the title compound (8.50 g).
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[CH:4]([CH:5]=[CH:6][C:7]([O:9][CH2:10][CH2:11][CH3:12])=[O:8])[CH:3]1[C:13]([OH:15])=[O:14].[CH3:17][C:18]1([CH3:30])[CH:20]([CH:21]=[CH:22][C:23]([O:25][CH3:26])=[O:24])[CH:19]1[C:27]([OH:29])=[O:28].C(C(C1C(F)=C(F)C(F)=C(F)C=1F)O)#N>>[CH3:16][C:2]1([CH3:1])[CH:4]([CH:5]=[CH:6][C:7]([O:9][CH2:10][CH2:11][CH3:12])=[O:8])[CH:3]1[C:13]([OH:15])=[O:14].[CH3:17][C:18]1([CH3:30])[CH:20]([CH:21]=[CH:22][C:23]([O:25][CH3:26])=[O:24])[CH:19]1[C:27]([O-:29])=[O:28]
Reactant: COC(=O)C=CC1C(C(=O)O)C1(C)C
Agent: CCCOC(=O)C=CC1C(C(=O)O)C1(C)C
Agent: N#CC(O)c1c(F)c(F)c(F)c(F)c1F
Product: COC(=O)C=CC1C(C(=O)[O-])C1(C)C

Procedure:
Using the procedure of Example 9, (1R, cis, ΔZ)-2,2-dimethyl-3-(3-methoxy-3-oxo-1-propenyl)-cyclopropane-carboxylic acid and (RS) cyano (2,3,4,5,6-pentafluoro-phenyl)methanol were reacted to obtain (RS) cyano (2,3,4,5,6-pentafluoro-phenyl)-methyl (1R, cis, ΔZ) 2,2-dimethyl-3-(3-methoxy-3-oxo-1-propeny)-cyclopropane-carboxylate.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][OH:6].C(=O)([O-])[O-].[K+].[K+].Br[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH2:23][C:24]([OH:26])=[O:25].Cl>O.CN(C=O)C>[OH:6][CH2:5][C:4]1[CH:3]=[C:2]([CH:9]=[CH:8][CH:7]=1)[O:1][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH2:23][C:24]([OH:26])=[O:25]
Reactant: OCc1cccc(O)c1
Reactant: O=C(O)Cc1ccccc1Br
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(O)Cc1ccccc1Oc1cccc(CO)c1
Temperature: 140 °C
Reaction time: 2 h
Yield: 130.1 %

Procedure:
3-Hydroxybenzyl alcohol (31.0 g) was ground finely and stirred with potassium carbonate (34.6 g), 2-bromophenylacetic acid (26.9 g) and cuprous chloride (large spatula full) under nitrogen. The mixture was warmed to 140° C., and stirred vigorously for 31/2 hours. DMF (60 ml) was then added to the stirred melt and the solution was allowed to cool, poured into water and acidified with dilute hydrochloric acid. The aqueous layer was extracted with ether, and the ether extracts were washed with water, dried and evaporated to give 2-(3-hydroxymethylphenoxy)phenylacetic acid as a brown oil (42.03 g) which was used without further purification.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([F:8])[C:4]([CH3:7])([OH:6])[CH3:5].Cl[C:10]([O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:11].N1C=CC=CC=1>C(Cl)Cl>[C:13]1([O:12][C:10](=[O:11])[NH:1][CH2:2][C@@H:3]([F:8])[C:4]([OH:6])([CH3:7])[CH3:5])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CC(C)(O)[C@H](F)CN
Reactant: O=C(Cl)Oc1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(O)[C@H](F)CNC(=O)Oc1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 65.3 %

Procedure:
To a solution of (R)-4-amino-3-fluoro-2-methylbutan-2-ol (100 mg, 0.825 mmol) in DCM (3 mL) was added phenyl chloroformate (0.124 mL, 0.990 mmol) at 0° C. followed by pyridine (0.100 mL, 1.238 mmol); the reaction mixture was stirred at RT for 12 h. The reaction mixture was quenched with water and extracted with ethyl acetate (3×10 mL). The combined organic layer was washed with a 1.5 N aq. solution of HCl, dried over Na2SO4, filtered and the filtrate evaporated under vacuum to afford Intermediate 336A as a colorless liquid (130 mg, 65%). The crude product was used in the subsequent transformation without further purification. 1H NMR (300 MHz, chloroform-d) δ ppm 7.33-7.44 (m, 2H), 7.06-7.31 (m, 3H), 5.48 (bs, 1H), 4.30-4.56 (m, 1H), 3.73 (m, 1H), 3.33-3.51 (m, 1H), 1.91 (m, 1H), 1.32 (dd, J=11.95, 1.23 Hz, 6H).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:15]=1[O:16][CH2:17][CH2:18][O:19][CH3:20])[N:12]=[CH:11][N:10]=[C:9]2[NH:21][C:22]1[CH:23]=[C:24]([C:28]#[C:29]C(C)(O)C)[CH:25]=[CH:26][CH:27]=1.[OH-].[Na+].[ClH:36]>CC(O)C>[ClH:36].[C:28]([C:24]1[CH:23]=[C:22]([NH:21][C:9]2[C:8]3[C:13](=[CH:14][C:15]([O:16][CH2:17][CH2:18][O:19][CH3:20])=[C:6]([O:5][CH2:4][CH2:3][O:2][CH3:1])[CH:7]=3)[N:12]=[CH:11][N:10]=2)[CH:27]=[CH:26][CH:25]=1)#[CH:29]
Reactant: COCCOc1cc2ncnc(Nc3cccc(C#CC(C)(C)O)c3)c2cc1OCCOC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Product: C#Cc1cccc(Nc2ncnc3cc(OCCOC)c(OCCOC)cc23)c1
Temperature: 137.5 °C
Reaction time: 2 h

Procedure:
4-[3-[[6,7-Bis(2-methoxyethoxy]-4-quinazolinyl]amino]phenyl]-2-methyl-3-butyn-2-ol, prepared above (20.0 g, 44.3 mmol), anhydrous solid sodium hydroxide (260 mg, 6.5 mmol) and propan-2-ol (200 mL) were stirred together and heated in a pressure vessel at 135-140° C. for 23 hours. The reaction mixture was cooled to 60-65° C. and concentrated hydrochloric acid (4.8 mL) was added. The resultant mixture was granulated overnight at 20-25° C. to establish crystallization. The mixture was treated with water (10 mL) and stirred at 58-60° C. for 21 hours, cooled to 15-20° C. and granulated for 2 hours. The title product crystals were isolated by filtration, washed with propan-2-ol (2×30 mL) and dried under vacuum at 45-50° C. to remove propan-2-ol. Yield (17.6 g, 92%).
Reaction SMILES: [N+:1]([N:4]1[C:9](=[O:10])[CH:8]=[CH:7][NH:6][C:5]1=[O:11])([O-:3])=[O:2].N1CCC[CH2:14][CH2:13]1>C(O)C>[CH:13]([C:8]1[C:9](=[O:10])[N:4]([N+:1]([O-:3])=[O:2])[C:5](=[O:11])[NH:6][CH:7]=1)=[CH2:14]
Reactant: O=c1cc[nH]c(=O)n1[N+](=O)[O-]
Reactant: C1CCNCC1
Solvent: CCO
Product: C=Cc1c[nH]c(=O)n([N+](=O)[O-])c1=O

Procedure:
As shown in Scheme 1, a suitable nitro-uracil precursor, (1), is mixed with an appropriate aldehyde, (2), and piperidine, in a suitable solvent such as ethanol. The solution is heated to reflux for approximately 10-20 hours. After reflux, the mixture is concentrated and purified using conventional methods, such as thin layer chromatography, to produce the vinyl-nitro-uracil (3).