Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N[C:2]1[C:12]([O:13][CH3:14])=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3]=1[Cl:15].C(#N)C.[I:19]CI.N(OCCC(C)C)=O>CCCCCCC.C(OCC)(=O)C>[Cl:15][C:3]1[CH:4]=[C:5]([CH:11]=[C:12]([O:13][CH3:14])[C:2]=1[I:19])[C:6]([O:8][CH2:9][CH3:10])=[O:7]
Reactant: ICI
Reactant: CCOC(=O)c1cc(Cl)c(N)c(OC)c1
Agent: CC(C)CCON=O
Solvent: CCCCCCC
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc(Cl)c(I)c(OC)c1
Temperature: 70 °C
Reaction time: 0.17 h
Yield: 66.6 %

Procedure:
To ethyl 4-amino-3-chloro-5-methoxybenzoate (15.8 g, 68.8 mmol), were added acetonitrile (40 mL) and diiodomethane (22.2 mL, 275 mmol) in this order, and the mixture was stirred at 70° C., and then isoamyl nitrite (13.9 mL, 103 mmol) was added dropwise thereto over 10 minutes. The mixture was stirred at 70° C. for 40 minutes. The mixture was returned to room temperature, the solvent was then distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (a mixed solvent of n-heptane and ethyl acetate: n-heptane/ethyl acetate=8/1 then 5/1) to obtain the title compound (15.6 g, 45.8 mmol)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH2:4][N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[NH:9][CH2:8][C@H:7]([NH:16]C(OC(C)(C)C)=O)[C:6]1=[O:24].C(Cl)[Cl:27]>>[ClH:27].[CH3:1][O:2][C:3](=[O:25])[CH2:4][N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[NH:9][CH2:8][C@H:7]([NH2:16])[C:6]1=[O:24]
Reactant: COC(=O)CN1C(=O)[C@@H](NC(=O)OC(C)(C)C)CNc2ccccc21
Reactant: ClCCl
Product: COC(=O)CN1C(=O)[C@@H](N)CNc2ccccc21
Product: Cl

Procedure:
(600a/103, 4.0 g, 11.4 mmol) in 20 ml of CH2Cl2 for 20 min then stirred for 1 h at RT. The reaction was evaporated to give (3S)-2-oxo-3-amino-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine-1-acetic acid methyl ester hydrochloride as a white solid.
Reaction SMILES: C(C1CN([O:14][CH2:15][C:16]2[CH:39]=[CH:38][C:19]([O:20][CH2:21][C:22]3[N:23]=[C:24]([C:28]4[CH:37]=[CH:36][C:31]([C:32]([O:34][CH3:35])=[O:33])=[CH:30][CH:29]=4)[O:25][C:26]=3[CH3:27])=[C:18]([O:40][CH3:41])[CH:17]=2)N(C2C=CC=CC=2)C=1)=O.[CH2:42]([P:51](=[O:58])([O:55][CH2:56][CH3:57])[O:52][CH2:53][CH3:54])P(=O)(OCC)OCC.[CH3:59][N:60]([CH3:63])C=O.[H-].[Na+]>O>[CH2:56]([O:55][P:51](/[CH:42]=[CH:27]/[C:26]1[C:22]([O:14][CH2:15][C:16]2[CH:39]=[CH:38][C:19]([O:20][CH2:21][C:22]3[N:23]=[C:24]([C:28]4[CH:29]=[CH:30][C:31]([C:32]([O:34][CH3:35])=[O:33])=[CH:36][CH:37]=4)[O:25][C:26]=3[CH3:27])=[C:18]([O:40][CH3:41])[CH:17]=2)=[N:23][N:60]([C:63]2[CH:38]=[CH:39][CH:16]=[CH:17][CH:18]=2)[CH:59]=1)([O:52][CH2:53][CH3:54])=[O:58])[CH3:57]
Reactant: CCOP(=O)(CP(=O)(OCC)OCC)OCC
Reactant: CN(C)C=O
Reactant: COC(=O)c1ccc(-c2nc(COc3ccc(CON4CC(C=O)=CN4c4ccccc4)cc3OC)c(C)o2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: CCOP(=O)(/C=C/c1cn(-c2ccccc2)nc1OCc1ccc(OCc2nc(-c3ccc(C(=O)OC)cc3)oc2C)c(OC)c1)OCC
Reaction time: 15 h
Yield: 65 %

Procedure:
To a mixture of methyl 4-{4-[(4-{[(4-formyl-1-phenyl-1H-pyrazol-2-yl)oxy]methyl}-2-methoxyphenoxy)methyl]-5-methyl-1,3-oxazol-2-yl}benzoate (0.57 g), tetraethyl methylenediphosphonate (0.32 g) and N,N-dimethylformamide (20 mL) was added sodium hydride (60% in oil, 0.05 g) at room temperature, and the mixture was stirred at the same temperature for 15 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give methyl 4-[4-({4-[({4-[(E)-2-(diethoxyphosphoryl)ethenyl]-1-phenyl-1H-pyrazol-3-yl}oxy)methyl]-2-methoxyphenoxy}methyl)-5-methyl-1,3-oxazol-2-yl]benzoate as colorless crystals (0.45 g, yield 65%) from a fraction eluted with ethyl acetate-hexane (5:1, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 129-130° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[O:12][CH2:13][CH3:14])[CH:7]=O)[CH3:2].[C:15]([NH:19][OH:20])([CH3:18])([CH3:17])[CH3:16]>>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:7]=[N+:19]([C:15]([CH3:18])([CH3:17])[CH3:16])[O-:20])[CH:9]=[CH:10][C:11]=1[O:12][CH2:13][CH3:14])[CH3:2]
Reactant: CCOc1ccc(C=O)cc1OCC
Reactant: CC(C)(C)NO
Product: CCOc1ccc(C=[N+]([O-])C(C)(C)C)cc1OCC

Procedure:
The title compound was prepared according to the procedure described in Example 11 using 3,4-diethoxybenzaldehyde and N-tert-butylhydroxylamine. The title compound was isolated in 93.7% yield as a solid, m.p. 57.9° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH:14]([CH3:16])[CH3:15])[C:9]=2[O:17][CH2:18][CH2:19][OH:20])=[CH:4][CH:3]=1.[CH3:21][O:22][C:23](=[O:33])[C:24]([C:26]1[CH:31]=[CH:30][C:29](O)=[CH:28][CH:27]=1)=[O:25].N(C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[CH3:21][O:22][C:23](=[O:33])[C:24](=[O:25])[C:26]1[CH:27]=[CH:28][C:29]([O:20][CH2:19][CH2:18][O:17][C:9]2[C:10]([CH:14]([CH3:15])[CH3:16])=[CH:11][CH:12]=[CH:13][C:8]=2[C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)=[CH:30][CH:31]=1
Reactant: CC(C)c1cccc(-c2ccc(F)cc2)c1OCCO
Reactant: COC(=O)C(=O)c1ccc(O)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)C(=O)c1ccc(OCCOc2c(-c3ccc(F)cc3)cccc2C(C)C)cc1
Yield: 48 %

Procedure:
As in Example 15, (2-[4'-fluoro-3-(1-methylethyl)[1,1'-biphenyl]-2-yloxy]ethanol (0.393 g) was treated with 4-hydroxyphenylglyoxylic acid methyl ester (0.258 g) in the presence of diethyl azodicarboxylate (0.298 g) and triphenylphosphine (0.449 g) in tetrahydrofuran (25 mL). The usual work up afforded 0.6 g of crude product which was purified by flash chromatography over silica gel (60 g; ethyl acetate-hexane; 3:7) to furnish 0.3 g of 4-[2-[4'-fluoro-3-(1-methylethyl)[1,1'-biphenyl]-2-yloxy]ethoxy]-alpha-oxobenzeneacetic acid methyl ester. Crystallization of the ester from ethyl acetatehexane yielded the analytical specimen, mp 77°-79° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15](B3OC(C)(C)C(C)(C)O3)[CH:16]=2)[N:11]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[N:10]=1.Br[C:36]1[CH:37]=[CH:38][C:39]([OH:50])=[C:40]([C:42]([N:44]2[CH2:49][CH2:48][O:47][CH2:46][CH2:45]2)=[O:43])[CH:41]=1.C(=O)([O-])[O-].[Na+].[Na+].C(=O)(O)[O-].[Na+]>C(#N)C.ClCCl>[OH:50][C:39]1[CH:38]=[CH:37][C:36]([C:15]2[CH:16]=[C:17]3[C:9]([C:4]4[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=4[O:2][CH3:1])=[N:10][N:11]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:33])([CH3:34])[CH3:32])[C:12]3=[N:13][CH:14]=2)=[CH:41][C:40]=1[C:42]([N:44]1[CH2:45][CH2:46][O:47][CH2:48][CH2:49]1)=[O:43]
Reactant: COc1ccccc1-c1nn(COCC[Si](C)(C)C)c2ncc(B3OC(C)(C)C(C)(C)O3)cc12
Reactant: O=C(c1cc(Br)ccc1O)N1CCOCC1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CC#N
Product: COc1ccccc1-c1nn(COCC[Si](C)(C)C)c2ncc(-c3ccc(O)c(C(=O)N4CCOCC4)c3)cc12
Yield: 30 %

Procedure:
A mixture of 3-(2-methoxy-phenyl)-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-b]pyridine (100 mg, 0.21 mmol), (5-bromo-2-hydroxy-phenyl)-morpholin-4-yl-methanone (66 mg (0.23 mmol) and 1,1′-bis(diphenylphosphino)ferrocenepalladium(II)-dichloride dichlormethane adduct (9 mg, 11 μmol) in acetonitrile (2 mL) and aqueous solution of sodium carbonate (2M, 2 mL) was irradiated in a Personal Chemistry Optimizer at 135° C. for 20 min. The crude reaction mixture was distributed between dichloromethane and a saturated aqueous solution of sodium bicarbonate. The aqueous phase was then extracted with dichloromethane and the combined organic phases were dried over sodium sulfate, filtered and concentrated. The crude product was then purified by flash silica gel chromatography using a gradient of ethyl acetate in hexanes to afford {2-hydroxy-5-[3-(2-methoxy-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-phenyl}-morpholin-4-yl-methanone (35 mg, 30% yield) as a colorless solid. 1H-NMR (500 MHz, d6-DMSO) δ 8.86 (d, 1H), 8.27 (d, 1H), 7.64 (dd, 1H), 7.62 (dd, 1H), 7.54 (d, 1H), 7.49 (ddd, 1H), 7.24 (d, br, 1H), 7.11 (ddd, 1H), 7.00 (d, 1H), 5.84 (s, 2H), 3.84 (s, 3H), 3.69 (t, 2H), 3.7-3.2 (m, 8H), 0.86 (t, 2H), −0.08 (s, 9H). MS: m/z 583 [MNa+], 561 [MH+], 443 [MH+-(Me3Si(CH2)2O)]
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[N:11]=[CH:10][CH:9]=[CH:8][N:7]=1.[C:12]([N:20]=[C:21]=[S:22])(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[C:12]([NH:20][C:21]([NH:1][CH2:2][CH2:3][S:4][CH2:5][C:6]1[N:7]=[CH:8][CH:9]=[CH:10][N:11]=1)=[S:22])(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: NCCSCc1ncccn1
Reactant: O=C(N=C=S)c1ccccc1
Product: O=C(NC(=S)NCCSCc1ncccn1)c1ccccc1

Procedure:
By the procedure of Example 18, 2-[(2-aminoethyl)thiomethyl]pyrimidine is reacted with benzoyl isothiocyanate to give N-benzoyl-N'-[2-(2-pyrimidylmethylthio)ethyl]thiourea. Removing the benzoyl group by the procedure of Example 18 gives N-[2-(2-pyrimidylmethylthio)ethyl]thiourea.
Reaction SMILES: [CH:1]1([C:4]([N:6]2[CH2:11][CH2:10][N:9]([C:12]([C:14]3[CH:19]=[CH:18][C:17]([CH:20]4[C:25]5=[N:26][NH:27][C:28](=[O:33])[C:29]6[CH:30]=[CH:31][CH:32]=[C:23]([C:24]=65)[NH:22][CH:21]4[C:34]4[CH:41]=[CH:40][C:37]([CH:38]=O)=[CH:36][CH:35]=4)=[CH:16][CH:15]=3)=[O:13])[CH2:8][CH2:7]2)=[O:5])[CH2:3][CH2:2]1.[CH3:42][NH:43][CH3:44].[BH4-].[Na+]>CO>[CH:1]1([C:4]([N:6]2[CH2:7][CH2:8][N:9]([C:12]([C:14]3[CH:19]=[CH:18][C:17]([CH:20]4[C:25]5=[N:26][NH:27][C:28](=[O:33])[C:29]6[CH:30]=[CH:31][CH:32]=[C:23]([C:24]=65)[NH:22][CH:21]4[C:34]4[CH:41]=[CH:40][C:37]([CH2:38][N:43]([CH3:44])[CH3:42])=[CH:36][CH:35]=4)=[CH:16][CH:15]=3)=[O:13])[CH2:10][CH2:11]2)=[O:5])[CH2:3][CH2:2]1
Reactant: O=Cc1ccc(C2Nc3cccc4c(=O)[nH]nc(c34)C2c2ccc(C(=O)N3CCN(C(=O)C4CC4)CC3)cc2)cc1
Reactant: CNC
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CN(C)Cc1ccc(C2Nc3cccc4c(=O)[nH]nc(c34)C2c2ccc(C(=O)N3CCN(C(=O)C4CC4)CC3)cc2)cc1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 4.9 %

Procedure:
A mixture of 4-(9-(4-(4-(cyclopropanecarbonyl)piperazine-1-carbonyl)phenyl)-3-oxo-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazin-8-yl)benzaldehyde (80 mg, 0.15 mmol) and 27% dimethylamine solution (62 mg, 0.44 mmol) in methanol (10 mL) was stirred at room temperature for 40 min. Then the mixture was cooled to 0° C. Sodium borohydride (8.3 mg, 0.22 mmol) was added. After the addition, the mixture was stirred at this temperature for 2 hr. Methanol was removed under reduced pressure. The residue was washed with ethyl acetate/methanol (10/1) and filtered. The filtrate was concentrated to give the crude product. The crude product was purified by prep-HPLC to give 9-(4-(4-(cyclopropanecarbonyl)piperazine-1-carbonyl)phenyl)-8-(4((dimethylamino)methyl)phenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one (4.2 mg, yield 5%) as a light yellow solid. 1H-NMR (400 MHz, CD3OD) δ (ppm): 0.73-0.79 (m, 4H), 1.84 (m, 1H), 2.69 (s, 6H), 3.47-3.72 (m, 8H), 4.14 (s, 2H), 4.31-4.33 (d, J=8.0 Hz, 1H), 7.12-7.35 (m, 9H), 7.47-7.58 (m, 2H); LC-MS (ESI) m/z: 577 (M+1)+.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([C:8]2[N:12]([CH3:13])[N:11]=[C:10]([C:14]3[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:15]=3[Cl:21])[N:9]=2)=[O:7])=[CH:4][CH:3]=1.[CH3:24][Mg]Br.S(=O)(=O)(O)O.O>C(OCC)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([C:8]2[N:12]([CH3:13])[N:11]=[C:10]([C:14]3[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:15]=3[Cl:21])[N:9]=2)([OH:7])[CH3:24])=[CH:22][CH:23]=1
Reactant: Cn1nc(-c2c(F)cccc2Cl)nc1C(=O)c1ccc(Cl)cc1
Reactant: C[Mg]Br
Agent: O=S(=O)(O)O
Solvent: CCOCC
Solvent: O
Product: Cn1nc(-c2c(F)cccc2Cl)nc1C(C)(O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Under an atmosphere of nitrogen, to a solution of 1.5 of 5-(4-chlorobenzoyl)-3-(2-chloro-6-fluorophenyl)-1-methyl-1H 1,2,4-triazole in diethl ether at -70° C. was added dropwise 12 ml of methylmagnesium bromide. After 1 hour, the reaction mixture was warmed to room temperature stirred overnight, Then 36 ml of a 2N aqueous solution of sulfuric acid was added to the solution under iced-cooling, the mixture was poured into iced water and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gelchromatography to afford 1.3 g of 5-(4-chloro-α-hydroxy-α-methylbenzyl)-3-(2-chloro-6-fluorophenyl)-1-methyl 1H-1,2,4-triazole. mp.198°-200° C.
Reaction SMILES: [F:1][CH:2]([C@H:7]1[C@H:11]([OH:12])[CH2:10][CH:9]=[CH:8]1)[C:3]([O:5][CH3:6])=[O:4].CC([O:17]O)(C)C>C1(C)C=CC=CC=1.C/C(/O)=C\C(C)=O.C/C(/O)=C\C(C)=O.O=[V]>[F:1][CH:2]([C@H:7]1[C@H:8]([OH:17])[CH2:9][C@H:10]2[C@@H:11]1[O:12]2)[C:3]([O:5][CH3:6])=[O:4]
Reactant: COC(=O)C(F)[C@@H]1C=CC[C@H]1O
Reactant: CC(C)(C)OO
Agent: O=[V]
Agent: CC(=O)/C=C(\C)O
Solvent: Cc1ccccc1
Product: COC(=O)C(F)[C@@H]1[C@H]2O[C@H]2C[C@H]1O
Temperature: 14 °C
Reaction time: 2 h

Procedure:
To a solution of olefin 2 (1.92 kg, 11.0 mol) in toluene (4.83 L) was added vanadyl acetylacetonate (VO(acac)2, 58.3 g, 0.22 mol) at 0° C. After a solution of TBHP (5.7 M in decane, 38.6 mL) was added to the solution at 0° C., the resulting suspension was allowed to warm to 14° C. Additional solution of TBHP (5.7 M in decane, 4.36 L) was slowly added to the reaction mixture over 50 min while maintaining the batch temperature between 14-28° C. The resulting suspension was stirred for another 2 h, and then heated at 40° C. for 8 h. Excess TBHP was quenched with aqueous Na2S2O3 solution (2.95 kg Na2S2O3 and 4.71 kg H2O), which was slowly added at 0° C. The resulting mixture was stirred at 20° C. for 1.5 h. The disappearance of peroxides was confirmed by test paper. The aqueous layer was separated and extracted with EtOAc (9.42 L×2). The combined organic solutions were washed with brine (6.33 L). The brine layer was back-extracted with EtOAc (3.42 L×4). GC assay of the combined organic solutions indicated product 3. The combined organic solutions were concentrated, and the resulting residue was purified by silica gel chromatography in a filter pot (first eluted with hexanes/EtOAc (4/1) then pure EtOAc). Analytically pure sample was prepared by flash silica gel column chromatography (hexanes/MTBE) followed by recrystallization (EtOAc) as pale yellow crystals: mp 31-33° C.; 1H NMR (400 MHz, CDCl3) δ 5.01 (dd, J=48.3, 3.9 Hz, 1H), 4.13 (br s, 1H), 3.86 (s, 3H), 3.71 (m, 1H), 3.59 (m, 1H), 2.77 (dd, J=32.8, 3.9 Hz, 1H), 2.30 (br s, 1H), 2.11 (m, 2H); 13C NMR (101 MHz, CDCl3) δ 168.4 (d, J=24.1 Hz), 88.1 (d, J=186.1 Hz), 73.2 (d, J=1.6 Hz), 58.4, 57.1 (d, J=5.6 Hz), 52.8, 51.6 (d, J=19.3 Hz), 37.7 (d, J=1.6 Hz); 19F NMR (376 MHz, CDCl3) δ −200.8 (dd, J=48.3, 32.8 Hz); LRMS m/z 191 (M+1), 189 (M−1), 172 ([M−H2O]+), 59 ([COOCH3]+, base peak); [α]D25=−56 (c 1.0, CHCl3).
Reaction SMILES: [C:1]([C:3]1[C:8]2[N:9]=[C:10]([N:12]3[CH2:17][CH2:16][CH:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:14][CH2:13]3)[O:11][C:7]=2[C:6](F)=[C:5]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:4]=1[CH3:30])#[N:2].C(N(CC)CC)C.[CH3:38][N:39]([CH3:45])[C@H:40]1[CH2:44][CH2:43][NH:42][CH2:41]1>CS(C)=O>[C:1]([C:3]1[C:8]2[N:9]=[C:10]([N:12]3[CH2:17][CH2:16][CH:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:14][CH2:13]3)[O:11][C:7]=2[C:6]([N:42]2[CH2:43][CH2:44][C@H:40]([N:39]([CH3:45])[CH3:38])[CH2:41]2)=[C:5]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:4]=1[CH3:30])#[N:2]
Reactant: CN(C)[C@H]1CCNC1
Reactant: CCOC(=O)C1CCN(c2nc3c(C#N)c(C)c(-c4ccccc4)c(F)c3o2)CC1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CCOC(=O)C1CCN(c2nc3c(C#N)c(C)c(-c4ccccc4)c(N4CC[C@H](N(C)C)C4)c3o2)CC1
Temperature: 150 °C
Reaction time: 4 h

Procedure:
Ethyl 1-(4-cyano-7-fluoro-5-methyl-6-phenyl-1,3-benzoxazol-2-yl)piperidine-4-carboxylate (I-161) (0.27 g, 0.66 mmol) was dissolved in dimethyl sulfoxide (5 ml), then triethylamine (0.19 ml, 1.37 mmol) and (3S)-3-(dimethylamino)pyrrolidine (0.17 ml, 1.34 mmol) were added, followed by stirring in a sealed tube at an external temperature of about 150° C. for 4 hours.
Reaction SMILES: Cl.Cl.[CH3:3][CH:4]1[CH2:9][N:8]([C:10]2[N:15]=[N:14][C:13]([NH:16][NH2:17])=[CH:12][CH:11]=2)[CH2:7][CH:6]([CH3:18])[O:5]1.C([O-])(=O)C.[Na+].[CH3:24][C:25](=O)[CH2:26][CH2:27][C:28](=O)[CH3:29]>C(O)(=O)C>[CH3:3][CH:4]1[CH2:9][N:8]([C:10]2[N:15]=[N:14][C:13]([NH:16][N:17]3[C:28]([CH3:29])=[CH:27][CH:26]=[C:25]3[CH3:24])=[CH:12][CH:11]=2)[CH2:7][CH:6]([CH3:18])[O:5]1
Reactant: CC1CN(c2ccc(NN)nn2)CC(C)O1
Reactant: CC(=O)CCC(C)=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1ccc(C)n1Nc1ccc(N2CC(C)OC(C)C2)nn1

Procedure:
The compound is prepared according to the procedure of example 2 by contacting 3.8 g (12.8 m moles) of 6-(2,6-dimethyl-morpholino)-3-hydrazino-pyridazine dihydrochloride (prepared according to the procedure described in U.K. Pat. No. 1.157.642; m.p. 217°-220° C.), 2.2 g (25.6 m moles) of sodium acetate and 1.61 g (14.1 m moles) of 2,5-hexanedione in 20 ml of acetic acid. The yield is 1.8 g (47%) of the product of the title which melts at 147°-148° C. when crystallized from ethyl ether.
Reaction SMILES: [Br:1][C:2]1[CH:6]=[C:5]([C:7](=[O:9])[CH3:8])[O:4][N:3]=1.[Br-:10].[Br-].[Br-].C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.O1CCCC1>O>[Br:1][C:2]1[CH:6]=[C:5]([C:7](=[O:9])[CH2:8][Br:10])[O:4][N:3]=1
Reactant: CC(=O)c1cc(Br)no1
Reactant: [Br-]
Agent: C[N+](C)(C)c1ccccc1
Solvent: O
Solvent: C1CCOC1
Product: O=C(CBr)c1cc(Br)no1
Temperature: 25 °C
Reaction time: 18 h
Yield: 37.7 %

Procedure:
A mixture of 3-bromo-5-acetylisoxazole (which was obtained in Example 117) (16.7 g, 87.9 mmol), phenyltrimethylammonium tribromide (33.4 g, 88.8 mmol) and tetrahydrofuran (150 mL) was stirred at ambient temperature for 18 hours, poured into water and extracted with ether. The organic extracts were washed with brine and dried over MgSO4. Evaporation and purification by distillation gave a light yellow oil (8.9 g, 40% yield); 1H NMR (300 MHz, CDCl3) δ 4.40. (s, 3H), 7.10 (s, 1H).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]3[O:15][CH2:16][CH2:17][O:18][C:11]=3[CH:10]=2)[C:5]([F:19])=[CH:4][N:3]=1.[CH2:20]([O:22][C:23]1[CH:29]=[CH:28][C:26]([NH2:27])=[CH:25][CH:24]=1)[CH3:21]>>[CH2:20]([O:22][C:23]1[CH:29]=[CH:28][C:26]([NH:27][C:2]2[N:7]=[C:6]([NH:8][C:9]3[CH:14]=[CH:13][C:12]4[O:15][CH2:16][CH2:17][O:18][C:11]=4[CH:10]=3)[C:5]([F:19])=[CH:4][N:3]=2)=[CH:25][CH:24]=1)[CH3:21]
Reactant: Fc1cnc(Cl)nc1Nc1ccc2c(c1)OCCO2
Reactant: CCOc1ccc(N)cc1
Product: CCOc1ccc(Nc2ncc(F)c(Nc3ccc4c(c3)OCCO4)n2)cc1

Procedure:
In like manner to the preparation of N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidinediamine, 2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine and 4-ethoxyaniline were reacted to yield N2-(4-ethoxyphenyl)-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-2,4-pyrimidinediamine. 1H NMR (CDCl3): δ 7.88 (bs, 1H), 7.40 (bd, 2H, J=8.7 Hz), 7.27 (bd, 2H, J=6.3 Hz), 6.95 (dd, 1H, J=3 and 9 Hz), 6.86-6.77 (m, 3H), 6.58 (s, 1H), 4.28 (bs, 4H), 4.01 (q, 2H, J=6.9 Hz), 1.40 (t, 3H, J=6.9 Hz); LCMS: ret. time: 24.46 min.; purity: 90%; MS (m/e): 383 (MH+)
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Br:8])[CH:7]=1.[CH:9]([C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1)=[CH2:10].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Br:8][C:6]1[CH:5]=[N:4][CH:3]=[C:2](/[CH:10]=[CH:9]/[C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)[CH:7]=1
Reactant: Brc1cncc(Br)c1
Reactant: C=Cc1ccncc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Brc1cncc(/C=C/c2ccncc2)c1
Yield: 36 %

Procedure:
A solution of 3,5-dibromopyridine (5.56 g, 23.4 mmol), 4-vinylpyridine (5.1 mL), palladium acetate (1.05 g), tri-o-tolylphosphine (5.00 g) and triethylamine (33 mL) in acetonitrile (100 mL) was heated overnight at 80° C. and concentrated. The residue was partitioned between 5% NaHCO3 and dichloromethane and filtered. The filtrate was separated and the organic layer was washed with water, dried (MgSO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 4% methanol/dichloromethane to provide the desired product (2.18 g, 36%). (DCI/NH3) m/e 261, 263 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[CH2:6][CH2:5][C:4]([CH3:8])([CH3:7])[CH:3]1[CH2:9]Br.[Mg].[C:13]([NH:20][C:21]1(C=O)[CH2:23][CH2:22]1)([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14].[CH3:26]COCC>>[C:13]([NH:20][C:21]1([C:9]([CH:3]2[C:2]([CH3:11])([CH3:1])[CH2:6][CH2:5][C:4]2([CH3:8])[CH3:7])=[CH2:26])[CH2:23][CH2:22]1)([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14]
Reactant: CC1(C)CCC(C)(C)C1CBr
Reactant: CCOCC
Reactant: CC(C)(C)OC(=O)NC1(C=O)CC1
Agent: [Mg]
Product: C=C(C1C(C)(C)CCC1(C)C)C1(NC(=O)OC(C)(C)C)CC1
Reaction time: 8 h

Procedure:
A solution of 2,2,5,5-Tetramethyl-1-cyclopentylmethyl bromide in ether is added slowly to magnesium turnings until the Grignard reagent begins to form. The remainder of the alkyl bromide is then added and the mixture is stirred until all the magnesium dissolves. At 0° C. a solution of N-Boc-1-amino-1-cyclopropanecarboxaldehyde is then added and the mixture is stirred overnight. The reaction is quenched with 1M HCl, extracted with ether and the extracts are evaporated. The residue is dissolved in dioxane and 2M H2SO4 is added. The mixture is heated until the alcohol is dehydrated, as shown by thin layer chromatography. Water is added and the mixture is extracted with ether. The organic layer is dried over MgSO4 and evaporated to give N-Boc-1-amino-1-(2,2,5,5-tetramethyl-1-cyclopentyl)ethenylcyclopropane.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH:7]([CH3:13])[CH2:6]2.N12CCCN=C1CCCC[CH2:15]2.[CH:25]([C:27]([CH3:29])=[O:28])=C>O1CCCC1.CCOC(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[C:7]([CH3:15])([CH2:13][CH2:25][C:27](=[O:28])[CH3:29])[CH2:6]2
Reactant: COc1ccc2c(c1)CC(C)C2=O
Reactant: C=CC(C)=O
Reactant: C1CCC2=NCCCN2CC1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1ccc2c(c1)CC(C)(CCC(C)=O)C2=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 332.6 %

Procedure:
A solution of 5-methoxy-2-methyl-1-indanone (0.5 g, 2.84 mmol) in anhydrous tetrahydrofuran (3 mL) was treated with 1,8-diazabicyclo[5.4.0]undec-7-ene (0.085 mL, 0.57 mmol) and methyl vinyl ketone (0.473 mL, 5.68 mmol). The resulting solution was placed under a nitrogen atmosphere and stirred at room temperature overnight. The mixture was diluted with EtOAc (25 mL), washed with 0.2N HCl (25 mL) and brine (10 mL), dried over MgSO4, filtered, and evaporated under vacuum to a yellow oil (800 mg). The oil was dissolved in CH2Cl2 (10 mL) and the solution added to a small column of EM silica gel 60 (8 mL). The column was eluted with CH2Cl2 (30 ml) and the eluant evaporated under vacuum to afford 5-methoxy-2-methyl-2-(3-oxo-butyl)-1-indanone (467 mg) as an oil.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]([CH3:14])[CH2:12][CH3:13])=[C:4](Cl)[N:3]=1.C(O)CCC.[NH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(O)(C)C>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]([CH3:14])[CH2:12][CH3:13])=[C:4]([NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:3]=1
Reactant: CCC(C)n1cnc2c(Cl)nc(Cl)nc21
Reactant: Nc1ccccc1
Solvent: CCCCO
Solvent: CC(C)O
Product: CCC(C)n1cnc2c(Nc3ccccc3)nc(Cl)nc21
Reaction time: 22 h

Procedure:
The operation is carried out as in Stage 2 of Example 9 starting from 200 mg of the product obtained in Stage 1 of Example 9 and 4 ml of butanol and using 0.091 ml of aniline in place of the benzylamine. Agitation is carried out at ambient temperature then the reaction medium is taken to a temperature of 80 to 85° C. for approximately 22 hours, left to return to ambient temperature, diluted with 4 ml of isopropanol and placed for two days at a temperature of approximately 0° C., followed by separating, washing with 5 ml of isopropanol and drying at a temperature of approximately 80° C. After purification on silica eluting with methylene chloride/ethyl acetate in a proportion of 90/10, 176 mg of expected product is obtained in the form of white crystals.