Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Na].[C:2]([O:9][CH2:10][CH3:11])(=[O:8])[C:3]([O:5]CC)=O.[C:12](#[N:21])[CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(O)C>[C:12]([CH:13]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:3](=[O:5])[C:2]([O:9][CH2:10][CH3:11])=[O:8])#[N:21]
Reactant: CCOC(=O)C(=O)OCC
Reactant: N#CCCc1ccccc1
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C(=O)C(C#N)Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 38 %

Procedure:
920 mg sodium (40 mmole) is dissolved in 45 ml ethanol and to the ice-bath cooled solution is added 4.66 g diethyl oxalate (31.9 mmole) and 4.17 g hydrocinnamonitrile (31.9 mmole). The mixture is stirred at room temperature for 1 hour, under reflux for 3 hours, and then allowed to stand at room temperature overnight. Evaporation, acidification of the residue, and extraction with methylene chloride affords ethyl 3-cyano-2-oxo-4-phenylbutanoate in 38% yield. The compound crystallizes from petroleum ether in colorless needles; m.p. 80°-83° C.
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][CH:3]=1.[C:10]1(=[O:16])[O:15][C:13](=[O:14])[CH2:12][CH2:11]1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1>[CH3:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][O:7][C:10](=[O:16])[CH2:11][CH2:12][C:13]([OH:15])=[O:14])=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)O1
Reactant: Cc1ccc(CO)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: Cc1ccc(COC(=O)CCC(=O)O)cc1
Temperature: 25 °C
Yield: 90.5 %

Procedure:
A mixture of 2.44 g (0.02 mol) of 4-methylbenzyl alcohol, 2.00 g (0.02 mol) of succinic acid anhydride, 6.50 g (0.02 mol) of cesium carbonate, and 150 mL of dioxane was stirred at reflux temperature for 4 hours. The mixture was cooled to room temperature and filtered to remove the solid portion. The solvent was removed under reduced pressure. The crude product was purified by column chromatography on silica gel (ethyl acetate-hexane) to provide 4.022 g of succinic acid mono-(4-methylbenzyl) ester (90.58%).
Reaction SMILES: [OH-].[K+].[CH3:3][O:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[O:10])=[CH:7][CH:6]=1.[N+:13]([CH2:15][C:16]([N:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1)=[O:17])#[C-:14]>CO>[CH3:3][O:4][C:5]1[CH:12]=[CH:11][C:8]([C@@H:9]2[O:10][CH:14]=[N:13][C@H:15]2[C:16]([N:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)=[O:17])=[CH:7][CH:6]=1
Reactant: COc1ccc(C=O)cc1
Reactant: [C-]#[N+]CC(=O)N1CCCC1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc([C@@H]2OC=N[C@H]2C(=O)N2CCCC2)cc1
Yield: 66.6 %

Procedure:
To a stirred and cooled (0° C.) solution of potassium hydroxide (0.37 g, 6.57 mmol) in methanol (30 mL) was added a mixture of 4-methoxy-benzaldehyde (0.88 mL, 7.23 mmol) and 2-isocyano-1-(pyrrolidin-1-yl)ethanone BLE 04098 (1.0 g, 6.57 mmol). The solution was stirred 4 h with continued cooling and then concentrated. The residue was partitioned between ethyl acetate and water. The organic layer was combined with additional ethyl acetate extracts, washed with aqueous sodium chloride and dried over MgSO4. Concentration afforded a crude product as a glassy solid. Flash chromatography over silica (ethyl acetate) yielded to trans-(4,5-dihydro-5-(4-methoxyphenyl)oxazol-4-yl)(pyrrolidin-1-yl)methanone SLA 07074 as a pale yellow solid (1.2 g, 90.5%).
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:5]2[N:6]([CH:10]([CH3:12])[CH3:11])[C:7](=O)[NH:8][C:4]=2[CH:3]=1.P(Cl)(Cl)([Cl:17])=O>>[Cl:17][C:7]1[N:6]([CH:10]([CH3:12])[CH3:11])[C:5]2[CH:13]=[CH:14][C:2]([Cl:1])=[CH:3][C:4]=2[N:8]=1
Reactant: CC(C)n1c(=O)[nH]c2cc(Cl)ccc21
Reactant: O=P(Cl)(Cl)Cl
Product: CC(C)n1c(Cl)nc2cc(Cl)ccc21
Temperature: 0 °C
Yield: 82.9 %

Procedure:
5-Chloro-1-isopropylbenzimidazol-2-one (81 g) in phosphorus oxychloride (207 g) was refluxed for 1 hour. The mixture was left to stand for cooling and then the reaction mixture was poured into ice-water and extracted with ethyl acetate. The ethyl acetate layer was washed with an aqueous sodium hydroxide solution, water and dried over anhydrous magnesium sulfate and then the solvent was distilled off under reduced pressure. To the residue was added acetonitrile (400 ml) and the insoluble material was removed by filtration and the solvent was distilled off under reduced pressure to give 2,5-dichloro-1-isopropylbenzimidazole (73 g). A part of the obtained product was subjected to silica gel column chromatography [eluted with chloroform] and recrystallized from hexane, which showed the following physical properties:
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:35]=[CH:34][C:18]([O:19][CH2:20][C:21]2[O:25][C:24]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[N:23][C:22]=2[CH:32]=O)=[CH:17][CH:16]=1.C(OP([CH2:44][C:45]([O:47][CH2:48][CH3:49])=[O:46])(OCC)=O)C.CN(C)C=O.[H-].[Na+]>O>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:35]=[CH:34][C:18]([O:19][CH2:20][C:21]2[O:25][C:24]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)=[N:23][C:22]=2/[CH:32]=[CH:44]/[C:45]([O:47][CH2:48][CH3:49])=[O:46])=[CH:17][CH:16]=1
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(OCc2oc(-c3ccccc3)nc2C=O)cc1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)/C=C/c1nc(-c2ccccc2)oc1COc1ccc(OCc2nc(-c3ccccc3)oc2C)cc1
Reaction time: 3 h
Yield: 47.8 %

Procedure:
To a mixture of 5-({4-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]phenoxy}methyl)-2-phenyl-1,3-oxazole-4-carbaldehyde (1.0 g), ethyl diethylphosphonoacetate (0.52 g) and N,N-dimethylformamide (20 mL) was added sodium hydride (60% in oil, 0.10 g) at room temperature, and the mixture was stirred at the same temperature for 3 hrs. The reaction mixture was poured into water 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 ethyl (2E)-3-[5-({4-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]phenoxy}methyl)-2-phenyl-1,3-oxazol-4-yl]-2-propenoate as colorless crystals (0.55 g, yield 49%) from a fraction eluted with ethyl acetate-hexane (1:4, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 107-108° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:9]2[O:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11][C@H:10]2[CH2:23][OH:24])[CH:5]=[CH:6][C:7]=1[Cl:8].[H-].[Na+].Br[CH2:28][C:29]1[CH:30]=[C:31]([CH:34]=[CH:35][CH:36]=1)[C:32]#[N:33].O>CN(C=O)C>[C:32]([C:31]1[CH:30]=[C:29]([CH:36]=[CH:35][CH:34]=1)[CH2:28][O:24][CH2:23][C@H:10]1[C@H:9]([C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)[O:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17])[CH2:11]1)#[N:33]
Reactant: N#Cc1cccc(CBr)c1
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(Cl)c2)[C@H](CO)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(Cl)c2)[C@H](COCc2cccc(C#N)c2)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85.8 %

Procedure:
To a solution of tert-butyl (6S,7R)-7-(3,4-dichlorophenyl)-6-(hydroxymethyl)-1,4-oxazepane-4-carboxylate (144.5 mg) in DMF (3 mL) was added 60% sodium hydride (36.9 mg) at 0° C., and the mixture was stirred for 30 min. 3-(Bromomethyl)benzonitrile (90 mg) was added, and the mixture was warmed to room temperature and stirred overnight. The reaction mixture was poured into water, and the mixture was extracted twice with ethyl acetate. The organic layers were combined, and the mixture was washed with brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (162 mg).
Reaction SMILES: [C:1]([C:4]1[S:8][C:7]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)=[C:6]([C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][CH:17]=2)[CH:5]=1)(=[O:3])[CH3:2].[BH4-].[Na+].C(O)(=O)C>CO>[F:15][C:12]1[CH:11]=[CH:10][C:9]([C:7]2[S:8][C:4]([CH:1]([OH:3])[CH3:2])=[CH:5][C:6]=2[C:16]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:23])=[O:24])=[CH:18][CH:17]=2)=[CH:14][CH:13]=1
Reactant: CC(=O)c1cc(-c2ccc(S(C)(=O)=O)cc2)c(-c2ccc(F)cc2)s1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC(O)c1cc(-c2ccc(S(C)(=O)=O)cc2)c(-c2ccc(F)cc2)s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 73.6 %

Procedure:
A mixture of 5-acetyl-2-(4-fluorophenyl)-3-[4-(methylsulfonyl)phenyl]thiophene (1 g) and sodium borohydride (0.12 g) in methanol (19 ml) was stirred at ambient temperature for 2 hours. Acetic acid (1 ml) was added and the mixture was concentrated. The residue was dissolved in ethyl acetate, washed with water and an aqueous solution of sodium bicarbonate, dried and concentrated. The residue was recrystallized from a mixture of hexane and ethyl acetate to give crystals of 2-(4-fluorophenyl)-5-(1-hydroxyethyl)-3-[4-(methylsulfonyl)phenyl]thiophene (0.74 g).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[C:10]([NH2:19])[C:9]=2[N:8]=[CH:7]1.[C:20]1([C:30](Cl)=[O:31])[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][CH:21]=1>>[NH2:19][C:10]1[C:9]2[N:8]=[CH:7][N:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:30]([C:20]3[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH:23]=[CH:22][CH:21]=3)=[O:31])[C:18]=2[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:11]=1
Reactant: O=C(Cl)c1cccc2ccccc12
Reactant: NCCCCn1cnc2c(N)nc3ccccc3c21
Product: Nc1nc2ccccc2c2c1ncn2CCCCNC(=O)c1cccc2ccccc12

Procedure:
According to the general method of Example 14, 1-(4-aminobutyl)-1H-imidazo[4,5-c]quinolin-4-amine and 1-naphthoyl chloride were combined to provide N1-[4-(4-amino-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-1-naphthamide as an off white powder, m.p. 174.5° C. (decomposition). 1H NMR (300 MHz, DMSO-d6) δ8.52 (t, J=5.6 Hz, 1H), 8.49 (s, 1H), 8.24 (m, 3H), 8.10 (d, J=8.1 Hz, 1H), 7.97 (m, 2H), 7.80 (d, J=8.2 Hz, 1H), 7.65 (t, J=7.3 Hz, 1H), 7.57-7.41 (m, 5H), 4.75 (t, J=6.9 Hz, 2H), 2.03-1.98 (m, 2H), 1.69-1.64 (m, 2H); MS (EI) m/e 409.1903 (409.1903 calcd for C25H23N5O).
Reaction SMILES: [CH:1]1([C:4]([NH:6][C:7]2[N:8]=[C:9]3[CH:14]=[CH:13][C:12]([S:15][C:16]4[CH:24]=[CH:23][CH:22]=[CH:21][C:17]=4[C:18](O)=[O:19])=[N:11][N:10]3[CH:25]=2)=[O:5])[CH2:3][CH2:2]1.[F:26][C:27]([F:36])([F:35])[C:28]1[CH:34]=[CH:33][C:31]([NH2:32])=[CH:30][CH:29]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH:1]1([C:4]([NH:6][C:7]2[N:8]=[C:9]3[CH:14]=[CH:13][C:12]([S:15][C:16]4[CH:24]=[CH:23][CH:22]=[CH:21][C:17]=4[C:18]([NH:32][C:31]4[CH:33]=[CH:34][C:28]([C:27]([F:26])([F:35])[F:36])=[CH:29][CH:30]=4)=[O:19])=[N:11][N:10]3[CH:25]=2)=[O:5])[CH2:2][CH2:3]1
Reactant: Nc1ccc(C(F)(F)F)cc1
Reactant: O=C(O)c1ccccc1Sc1ccc2nc(NC(=O)C3CC3)cn2n1
Agent: CN(C)C(On1nnc2cccnc21)=[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: O=C(Nc1ccc(C(F)(F)F)cc1)c1ccccc1Sc1ccc2nc(NC(=O)C3CC3)cn2n1
Yield: 74.2 %

Procedure:
In the same manner as in Example 278 and using 2-({2-[(cyclopropylcarbonyl)amino]imidazo[1,2-b]pyridazin-6-yl}thio)benzoic acid (150 mg, 0.42 mmol), 4-(trifluoromethyl)aniline (191 mg, 1.2 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (230 mg, 0.6 mmol), N,N-diisopropylethylamine (160 mg, 1.3 mmol) and N,N-dimethylformamide (5 mL) as starting materials, the title compound (155 mg, 74%) was obtained as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:34])[NH:4][CH:5]([C:9]([N:11]1[CH2:16][CH2:15][N:14]([CH2:17][C:18]([F:21])([F:20])[F:19])[CH2:13][CH:12]1[C:22]1[NH:23][CH:24]=[C:25]([C:27]2[CH:32]=[CH:31][C:30](Br)=[CH:29][CH:28]=2)[N:26]=1)=[O:10])[CH:6]([CH3:8])[CH3:7].[CH3:35][O:36][C:37](=[O:63])[NH:38][CH:39]([C:43]([N:45]1[CH2:49][CH2:48][CH2:47][CH:46]1[C:50]1[NH:51][C:52]([C:55]2[CH:60]=[CH:59][C:58]([C:61]#[CH:62])=[CH:57][CH:56]=2)=[CH:53][N:54]=1)=[O:44])[CH:40]([CH3:42])[CH3:41].C(N(CC)CC)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.[Cu]I.CN(C=O)C>[CH3:35][O:36][C:37](=[O:63])[NH:38][CH:39]([C:43]([N:45]1[CH2:49][CH2:48][CH2:47][CH:46]1[C:50]1[NH:51][C:52]([C:55]2[CH:60]=[CH:59][C:58]([C:61]#[C:62][C:30]3[CH:31]=[CH:32][C:27]([C:25]4[N:26]=[C:22]([CH:12]5[CH2:13][N:14]([CH2:17][C:18]([F:21])([F:19])[F:20])[CH2:15][CH2:16][N:11]5[C:9](=[O:10])[CH:5]([NH:4][C:3]([O:2][CH3:1])=[O:34])[CH:6]([CH3:8])[CH3:7])[NH:23][CH:24]=4)=[CH:28][CH:29]=3)=[CH:57][CH:56]=2)=[CH:53][N:54]=1)=[O:44])[CH:40]([CH3:42])[CH3:41]
Reactant: C#Cc1ccc(-c2cnc(C3CCCN3C(=O)C(NC(=O)OC)C(C)C)[nH]2)cc1
Reactant: COC(=O)NC(C(=O)N1CCN(CC(F)(F)F)CC1c1nc(-c2ccc(Br)cc2)c[nH]1)C(C)C
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)NC(C(=O)N1CCN(CC(F)(F)F)CC1c1nc(-c2ccc(C#Cc3ccc(-c4cnc(C5CCCN5C(=O)C(NC(=O)OC)C(C)C)[nH]4)cc3)cc2)c[nH]1)C(C)C
Temperature: 80 °C
Reaction time: 0.33 h
Yield: 8 %

Procedure:
{1-[2-[4-(4-Bromo-phenyl)-1H-imidazol-2-yl]-4-(2,2,2-trifluoro-ethyl)-piperazine-1-carbonyl]-2-methyl-propyl}-carbamic acid methyl ester (98.7 mg, 0.181 mmol) was combined with (1-{2-[5-(4-Ethynyl-phenyl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (71.2 mg, 0.181 mmol) and Pd(PPh3)4 (21.5 mg, 0.018 mmol) under an argon atmosphere. DMF (degassed with Argon) was added followed by triethylamine (181 mg, 1.8 mmol) and copper(I) iodide (3.5 mg, 0.018 mmol). The mixture was heated at 80° C. After 20 minutes, volatiles were removed in vacuo and the crude material was semi-purified via chromatography on silica gel (eluent EtOAc w MeOH 10%/hexanes) and further purified via RP-HPLC (eluent: water/MeCN w 0.1% TFA) to yield the product [1-(2-{5-[4-(4-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-4-(2,2,2-trifluoro-ethyl)-piperazin-2-yl]-1H-imidazol-4-yl}-phenylethynyl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester (12.4 mg): LCMS-ESI+: calc'd for C44H52F3N9O6: 859.9 (M+); Found: 860.5 (M+H+); 1H-NMR: 300 MHz, (MeOH-d4) δ: 7.91-7.68 (m, 10H), 6.06 (m, 2H), 5.24 (m, 1H), 4.43 (m, 1H), 4.23 (d, J=7.8 Hz, 1H), 4.11 (m, 1H), 3.85 (m, 1H), 3.68 (s, 3H), 3.66 (s, 3H), 3.49-3.45 (m, 2H), 3.15-3.02 (m, 3H), 2.77 (m, 1H), 2.58 (m, 1H), 2.29-2.01 (m, 5H), 1.07-0.83 (m, 12H).
Reaction SMILES: [CH2:1]([NH2:6])[CH2:2][CH:3]([CH3:5])[CH3:4].ClC1C=CC=CC=1C[N:11]1[C:15]([CH3:16])=[C:14]([CH3:17])[N:13]=[C:12]1[CH2:18]Cl.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:16][C:15]1[N:11]=[C:12]([CH2:18][NH:6][CH2:1][CH2:2][CH:3]([CH3:5])[CH3:4])[NH:13][C:14]=1[CH3:17]
Reactant: CC(C)CCN
Reactant: Cc1nc(CCl)n(Cc2ccccc2Cl)c1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1nc(CNCCC(C)C)[nH]c1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 46 %

Procedure:
To a solution of 7 ml (60 mmol) of isoamylamine in 3 ml of acetonitrile is added slowly a solution of 1-(2′-chlorobenzyl)-4,5-dimethyl-2-chloromethylimidazole in 10 ml of acetonitrile followed by added 1.5 g (10.8 mmol) of potassium carbonate powder. The reaction mixture is stirred overnight at room temperature under nitrogen and excess isoamylamine is evaporated in vacuo. The residue is dissolved in 50 ml of ethyl acetate and 25 ml of water. The ethyl acetate layer is separated, washed with brine, dried over anhydrous sodium sulfate and evaporated in vacuo. The crude product is purified by preparative TLC [silica gel, chloroform-methanol-ammonium hydroxide (90:10:1)] to give 1.39 g (46%) of N-[(4,5-dimethylimidazol-2-yl)methyl]-(3-methylbutyl)amine as a yellow oil. MS m/z (M++1) 320; 1H-NMR 400 MHz(δ, CDCl3): 0.81 (6H, d, J=6.4 Hz), 1.25 (2H, m), 1.51 (1H, m), 1.96 (3H, s), 2.17 (3H, s), 2.56 (2H, m), 3.68 (2H, s), 5.21 (2H, s), 6.39 (1H, d, J=7.6 Hz), 7.13 (1H, m), 7.19 (1H, m), 7.37 (1H, m) ppm.
Reaction SMILES: [CH2:1]([N:8]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[OH:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:17]1([N:23]2[C:27](=[O:28])[CH:26]=[CH:25][C:24]2=[O:29])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>O1CCCC1>[C:17]1([N:23]2[C:27](=[O:28])[CH2:26][CH:25]([O:9][N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:24]2=[O:29])[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: O=C1C=CC(=O)N1c1ccccc1
Reactant: ON(Cc1ccccc1)Cc1ccccc1
Solvent: C1CCOC1
Product: O=C1CC(ON(Cc2ccccc2)Cc2ccccc2)C(=O)N1c1ccccc1
Yield: 56.4 %

Procedure:
A suspension of 6.0 g (28 mmole) of N,N-dibenzylhydroxylamine and 4.87 g (28 mmole) of N-phenylmaleimide in 50 ml of dry tetrahydrofuran is heated at reflux for 40 hours. The solvent is removed in vacuo and the residue is recrystallized from toluene to give 6.1 g (56%) of a white solid, mp 91°-93° C.:
Reaction SMILES: Cl[C:2]1[NH:3][C:4](=[O:19])[C:5]2[CH:10]=[CH:9][N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[C:6]=2[N:7]=1.C(=O)([O-])[O-].[Na+].[Na+].[F:26][C:27]([F:38])([F:37])[C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1>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.C(O)C>[F:26][C:27]([F:38])([F:37])[C:28]1[CH:33]=[CH:32][C:31]([C:2]2[NH:3][C:4](=[O:19])[C:5]3[CH:10]=[CH:9][N:8]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[C:6]=3[N:7]=2)=[CH:30][CH:29]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: C[Si](C)(C)CCOCn1ccc2c(=O)[nH]c(Cl)nc21
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: CCO
Product: C[Si](C)(C)CCOCn1ccc2c(=O)[nH]c(-c3ccc(C(F)(F)F)cc3)nc21
Temperature: 150 °C
Yield: 65 %

Procedure:
A microwave reaction vial was charged with 2-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-3H-pyrrolo[2,3-d]pyrimidin-4(7H)-one (53.7 mg, 179 mop and ethanol (850 μL) (650 μL+200 μL rinse). The resulting mixture was treated with a 2M aqueous sodium carbonate solution (270 μL, 540 μmol), 4-(trifluoromethyl)phenylboronic acid (42.1 mg, 222 μmol), and tetrakis(triphenylphosphine)palladium(0) (13.2 mg, 11.4 μmol). The vial was tightly sealed and heated in a microwave at 150° C. for 8 min. At this time, the reaction was filtered through a pad of Celite®, rinsing copiously with methanol, and the filtrate was concentrated in vacuo onto Celite®. Flash chromatography (12 g silica gel column, 10-40% ethyl acetate/hexanes) afforded 2-(4-(trifluoromethyl)phenyl)-7-((2-(trimethylsilyl)ethoxy)methyl)-3H-pyrrolo[2,3-d]pyrimidin-4(7H)-one as a light yellow solid (47.7 mg, 65.0%). 1H NMR (300 MHz, DMSO-d6) δ ppm −0.13 (s, 9H) 0.85 (t, J=8.10 Hz, 2H) 3.56 (t, J=8.10 Hz, 2H) 5.58 (s, 2H) 6.59 (d, J=3.39 Hz, 1H) 7.34 (d, J=3.39 Hz, 1H) 7.90 (d, J=7.91 Hz, 2H) 8.36 (d, J=8.29 Hz, 2H) 12.45 (s, 1H). LC-MS calcd. for C19H23F3N3O2Si [(M+H)4] 410, obsd. 410.1.
Reaction SMILES: [C:1]([CH2:3][O:4][C:5]1[CH:6]=[C:7](I)[CH:8]=[CH:9][CH:10]=1)#[N:2].[F:12][C:13]1[CH:14]=[C:15]([O:28][CH2:29][C:30]#[CH:31])[CH:16]=[C:17]([C:19]2([O:26][CH3:27])[CH2:23][CH2:22][CH2:21][CH:20]2[O:24][CH3:25])[CH:18]=1.N1CCCCC1>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.C1(C)C=CC=CC=1>[C:1]([CH2:3][O:4][C:5]1[CH:6]=[C:7]([C:31]#[C:30][CH2:29][O:28][C:15]2[CH:16]=[C:17]([C:19]3([O:26][CH3:27])[CH2:23][CH2:22][CH2:21][CH:20]3[O:24][CH3:25])[CH:18]=[C:13]([F:12])[CH:14]=2)[CH:8]=[CH:9][CH:10]=1)#[N:2]
Reactant: C#CCOc1cc(F)cc(C2(OC)CCCC2OC)c1
Reactant: N#CCOc1cccc(I)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCNCC1
Solvent: Cc1ccccc1
Product: COC1CCCC1(OC)c1cc(F)cc(OCC#Cc2cccc(OCC#N)c2)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 52.3 %

Procedure:
A mixture of 3-cyanomethoxyphenyl iodide (0.355 g), tetrakis(triphenylphosphine)palladium (0.079 g) and toluene (7 ml) was stirred at ambient temperature for 15 minutes. To this mixture there were added in turn (1RS,2SR)-1-[5-fluoro-3-(2-propynyloxy)phenyl]-1,2-dimethoxycyclopentane (0.252 g), cuprous iodide (0.013 g) and piperidine (0.274 ml) and the mixture was stirred at ambient temperature for 2 hours. The mixture was partitioned between toluene and water. The organic layer was washed with a saturated aqueous sodium chloride solution, dried (MgSO4) and evaporated. The residue was purified by column chromatography using methylene chloride as eluent. There was thus obtained (1RS,2SR)-1-[3-(3-(3-cyanomethoxyphenyl)prop-2-ynyloxy)-5-fluorophenyl-1,2-dimethoxycyclopentane (0.194 g, 35%), as an oil.
Reaction SMILES: [CH3:1][C:2]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][C:3]=1[O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH:12]([O:17][CH3:18])[C:13](NC)=[O:14].CC1C=CC(C)=C[C:26]=1[O:27]CC1C=CC=CC=1C(O)C(OC)=O.CI>>[CH3:1][C:2]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][C:3]=1[O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH:12]([O:17][CH3:18])[C:13]([O:27][CH3:26])=[O:14]
Reactant: COC(=O)C(O)c1ccccc1COc1cc(C)ccc1C
Reactant: CNC(=O)C(OC)c1ccccc1COc1cc(C)ccc1C
Solvent: CI
Product: COC(=O)C(OC)c1ccccc1COc1cc(C)ccc1C

Procedure:
WO 95/27693 discloses that a 2-substituted phenyl-N-alkylacetamide compound having an alkoxy group at the 2-position typified by 2-[2-(2,5-dimethylphenoxymethyl)phenyl]-2-methoxy-N-methylacetamide is useful as an agricultural fungicide, and also discloses, as a method for producing the compound; a method in which methyl 2-[2-(2,5-dimethylphenoxymethyl)phenyl]-2-hydroxyacetate is reacted with methyl iodide to obtain methyl 2-[2-(2,5-dimethylphenoxymethyl)phenyl]-2-methoxyacetate, and then the methyl 2-[2-(2,5-dimethylphenoxymethyl)phenyl]-2-methoxyacetate is reacted with methylamine to obtain 2-[2-(2,5-dimethylphenoxymethyl)phenyl]-2-methoxy-N-methylacetamide.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:8](=[O:10])[CH3:9])[CH:5]=[N:6][CH:7]=1.[BrH:11].BrBr.C(OCC)C>C(O)(=O)C>[BrH:11].[Br:11][CH2:9][C:8]([C:4]1[CH:5]=[N:6][CH:7]=[C:2]([CH3:1])[CH:3]=1)=[O:10]
Reactant: CC(=O)c1cncc(C)c1
Agent: Br
Agent: BrBr
Solvent: CCOCC
Solvent: CC(=O)O
Product: Cc1cncc(C(=O)CBr)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 183.3 %

Procedure:
300 mg (2.22 mmol) of 1-(5-methylpyrid-3-yl)ethanone are dissolved in 15 mL of glacial acetic acid. 365 μl (2.22 mmol) of hydrobromic acid and 126 μl (2.44 mmol) of bromine are added to the medium. The reaction mixture is placed under magnetic stirring at room temperature for 2 hours. Ethyl ether is added to the solution until a precipitate appears. The precipitate corresponding to 2-bromo-1-(5-methylpyrid-3-yl)ethanone hydrobromide is filtered off, washed with ether and dried. The 600 mg of product obtained have the following characteristics:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=5[C:20](=[O:27])[O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.Br[CH2:29][C:30]1([F:34])[CH2:33][O:32][CH2:31]1>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=5[C:20](=[O:27])[O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][N:8]2[CH2:29][C:30]2([F:34])[CH2:33][O:32][CH2:31]2)=[CH:4][CH:3]=1
Reactant: FC1(CBr)COC1
Reactant: O=C1OC2(CCN(C(=O)c3c[nH]c4cc(Cl)ccc34)CC2)c2ccccc21
Product: O=C1OC2(CCN(C(=O)c3cn(CC4(F)COC4)c4cc(Cl)ccc34)CC2)c2ccccc21

Procedure:
Following the general procedure III as described above, the alkylation of 1′-[(6-chloro-1H-indol-3-yl)carbonyl]-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one (prepared according to example 16 above) with 3-bromomethyl-3-fluoro-oxetane (described in US2005215599) gave the title compound. ES-MS m/e (%): 469.2(M+H+).