Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH2:3](Br)[CH:4]=[CH2:5].[Cl:7][C:8]1[CH:9]=[C:10]([CH:21]=[C:22]([Cl:24])[CH:23]=1)[O:11][C:12]1[C:13]([CH2:19][CH3:20])=[N:14][NH:15][C:16]=1[CH2:17][CH3:18]>CN(C)C=O>[CH2:3]([N:14]1[C:13]([CH2:19][CH3:20])=[C:12]([O:11][C:10]2[CH:21]=[C:22]([Cl:24])[CH:23]=[C:8]([Cl:7])[CH:9]=2)[C:16]([CH2:17][CH3:18])=[N:15]1)[CH:4]=[CH2:5]
Reactant: C=CCBr
Reactant: CCc1n[nH]c(CC)c1Oc1cc(Cl)cc(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCn1nc(CC)c(Oc2cc(Cl)cc(Cl)c2)c1CC
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.8 %

Procedure:
Sodium hydride (60% dispersion in oil, 770 mg, 19.2 mmol) was added to a stirred solution of allyl bromide (1.70 ml, 19.2 mmol) and the pyrazole of Example 3 (5.00 g, 17.5 mmol) in N,N-dimethylformamide (20 ml) at 0° C. under nitrogen. The reaction was warmed to room temperature and stirred for 1 hour. The reaction mixture was quenched by the addition of water (100 ml) and the aqueous phase was extracted with ether (2×50 ml). The combined organic phases were washed with water (30 ml) and brine (30 ml), dried over magnesium sulphate, filtered and concentrated under reduced pressure to leave a brown oil. The crude product was purified by flash column chromatography on silica gel eluting with pentane:ethyl acetate (80:20, by volume) to provide the title compound (5.00 g) as a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[CH:13]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[CH3:31])[CH2:14][C:15]([C:17]1[CH:22]=[CH:21][C:20](=[O:23])[N:19]([CH3:24])[CH:18]=1)=O)[O:5][CH2:6][C:7]([OH:9])=[O:8].Cl.[NH2:33][OH:34].C([O-])(O)=O.[Na+]>>[F:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[CH:13]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[CH3:31])[CH2:14]/[C:15](=[N:33]\[OH:34])/[C:17]1[CH:22]=[CH:21][C:20](=[O:23])[N:19]([CH3:24])[CH:18]=1)[O:5][CH2:6][C:7]([OH:9])=[O:8]
Reactant: NO
Reactant: Cc1ccccc1C(CC(=O)c1ccc(=O)n(C)c1)c1ccc(OCC(=O)O)cc1F
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1ccccc1C(C/C(=N\O)c1ccc(=O)n(C)c1)c1ccc(OCC(=O)O)cc1F

Procedure:
In analogy to example 151, step 3, {3-fluoro-4-[3-(1-methyl-6-oxo-1,6-dihydro-pyridin-3-yl)-3-oxo-1-o-tolyl-propyl]-phenoxy}-acetic acid was reacted with hydroxylamine hydrochloride in the presence of NaHCO3 to give the title compound containing less than 10% of the corresponding Z isomer as a light brown solid, MS (ESI+): m/z=439.2 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:18]([O:19][CH3:20])=[CH:17][C:6]2[CH2:7][C:8](=[O:16])[N:9]([CH:12]([Cl:15])[CH2:13][CH3:14])[CH2:10][CH2:11][C:5]=2[CH:4]=1.[CH3:21][NH:22][CH2:23][CH2:24][C:25]1[CH:30]=[C:29]([O:31][CH3:32])[C:28]([O:33][CH3:34])=[C:27]([O:35][CH3:36])[CH:26]=1>>[ClH:15].[CH3:1][O:2][C:3]1[C:18]([O:19][CH3:20])=[CH:17][C:6]2[CH2:7][C:8](=[O:16])[N:9]([CH2:12][CH2:13][CH2:14][N:22]([CH3:21])[CH2:23][CH2:24][C:25]3[CH:26]=[C:27]([O:35][CH3:36])[C:28]([O:33][CH3:34])=[C:29]([O:31][CH3:32])[CH:30]=3)[CH2:10][CH2:11][C:5]=2[CH:4]=1
Reactant: CCC(Cl)N1CCc2cc(OC)c(OC)cc2CC1=O
Reactant: CNCCc1cc(OC)c(OC)c(OC)c1
Product: COc1cc2c(cc1OC)CC(=O)N(CCCN(C)CCc1cc(OC)c(OC)c(OC)c1)CC2
Product: Cl

Procedure:
This compound was prepared analogous to Example 5(b) by reacting 1-(7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-on-3-yl)-chloro-propane with N-methyl-N-[2-(3,4,5-trimethoxy-phenyl)-ethyl]-amine.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)=O.[C:12]([NH:15][C:16]([NH2:18])=[NH:17])(=[O:14])[CH3:13]>C(#N)C>[F:11][C:8]1[CH:9]=[CH:10][C:5]([C:3]2[N:17]=[C:16]([NH:15][C:12](=[O:14])[CH3:13])[NH:18][CH:2]=2)=[CH:6][CH:7]=1
Reactant: O=C(CBr)c1ccc(F)cc1
Reactant: CC(=O)NC(=N)N
Solvent: CC#N
Product: CC(=O)Nc1nc(-c2ccc(F)cc2)c[nH]1
Yield: 33.7 %

Procedure:
3.00 g (13.82 mmol) 2-bromo-4′-fluoroacetophenone, 2.80 g (27.64 mmol) acetylguanidine and 15 ml acetonitrile were combined and were together brought to reaction in the microwave (at 100 Watt) for 60 minutes at 40° C. by “heating by cooling”. After cooling, the solid formed was filtered off of the solvent. In addition, a total amount of 1.02 g N-[4-(4-fluorphenyl)-1H-imidazole-2-yl]acetamide were isolated by fractional crystallization with ethanol of the remainder of the mother liquor.
Reaction SMILES: [C:1]([O:5][C:6](=[O:40])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:23]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:22][N:21]4[N:30]=[C:31]([C:34]5[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=5)[C:32](Br)=[C:20]4[N:19]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[C:41]1(B(O)O)[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>O1CCOCC1.C(Cl)Cl.C1C=CC(P([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C1C=CC(P([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Fe]>[C:1]([O:5][C:6](=[O:40])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:23]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:22][N:21]4[N:30]=[C:31]([C:34]5[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=5)[C:32]([C:41]5[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=5)=[C:20]4[N:19]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(Br)c(-c5ccccc5)nn4cc3-c3ccccc3)cc2)CCC1
Reactant: OB(O)c1ccccc1
Agent: Cl[Pd]Cl
Agent: [Fe]
Agent: [CH]1[CH][CH][C](P(c2ccccc2)c2ccccc2)[CH]1
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(-c5ccccc5)c(-c5ccccc5)nn4cc3-c3ccccc3)cc2)CCC1
Temperature: 100 °C
Yield: 72.5 %

Procedure:
A mixture of compound 9-3 (60 mg 0.1 mmol), phenyl boronic acid (19 mg, 0.15 mmol), aq.Na2 CO3 (2M, 0.25 mmol, 0.12 mL) and Pd(DPPF)Cl2 (10 mg) in dioxane (2 mL) was heated at 100° C. in microwave system under N2 atmosphere for 30 min. After cooling, the mixture was diluted with 15 mL of DCM, the combined organic phase was washed with 0.1N HClaq and brine, dried over anhydrous Na2SO4 and concentrated. The residue was purified by prep.TLC to give 43 mg of 9-5.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([NH:6][C:7](=O)[C:8]3[N:9]2[CH:12]=[CH:13][N:14]=3)=[CH:4][C:3]=1[C:16]([F:19])([F:18])[F:17].CN(C)C1C=CC=CC=1.P(Cl)(Cl)([Cl:31])=O>O.[OH-].[Na+]>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([N:6]=[C:7]([Cl:31])[C:8]3[N:9]2[CH:12]=[CH:13][N:14]=3)=[CH:4][C:3]=1[C:16]([F:19])([F:18])[F:17]
Reactant: O=c1[nH]c2cc(C(F)(F)F)c(Br)cc2n2ccnc12
Reactant: O=P(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)c1ccccc1
Solvent: O
Product: FC(F)(F)c1cc2nc(Cl)c3nccn3c2cc1Br
Temperature: 120 °C
Yield: 80.4 %

Procedure:
8-Bromo-7-(trifluoromethyl)imidazo[1,2-a]quinoxalin-4(5H)-one (9.4 g, 0.0283 mol) is stirred under nitrogen with N,N-dimethylaniline (14.5 mL, 0.1123 mol) and phosphoryl chloride (190 mL, 2.0119 mol) at reflux (120° C.) for 1.5 hour. After cooling down to room temperature, the mixture is slowly poured in a mixture of water (2 L) and sodium hydroxide 5N (1 L) below 10° C. The mixture is extracted four times with ethyl acetate (200 mL) and the combined organic phases are washed with water (200 mL), dried over sodium sulfate and concentrated to about 100 mL. Cyclohexane (500 mL) is added at room temperature. The mixture is cooled to 0-5° C. and filtered. The cake is washed with cyclohexane and dried under vacuum to afford the title compound as a yellow solid (7.98 g, 80.4%)
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([CH2:30][C:31]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[NH:33][CH:32]=1)[C:9]([N:11]1[CH2:16][CH2:15][C:14]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:17]([NH:19][N:20]([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]1)=[O:10])(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:22][N:20]([CH3:21])[NH:19][C:17]([C:14]1([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:13][CH2:12][N:11]([C:9](=[O:10])[CH:8]([NH2:7])[CH2:30][C:31]2[C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[NH:33][CH:32]=2)[CH2:16][CH2:15]1)=[O:18]
Reactant: CN(C)NC(=O)C1(Cc2ccccc2)CCN(C(=O)C(Cc2c[nH]c3ccccc23)NC(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(C)NC(=O)C1(Cc2ccccc2)CCN(C(=O)C(N)Cc2c[nH]c3ccccc23)CC1
Reaction time: 0.5 h
Yield: 192.8 %

Procedure:
To a solution of (2-(4-benzyl-4-(N′,N′-dimethylhydrazinocarbonyl)piperidine-1-yl)-1-(1H-indole-3-ylmethyl)-2-oxoethyl)carbamic acid tert-butyl ester (0.40 g, 0.73 mmol) in methylene chloride (3 ml) at 0° C. was added trifluoroacetic acid (3 ml) and the mixture was stirred for 30 min. The mixture was quenched with ethanol (20 ml), concentrated in vacuo and stripped three times with methylene chloride to give 0.63 g of 1-(2-amino-3-(1H-indol-3-yl)propionyl)-4-benzylpiperidine-4-carboxylic acid N′,N′-dimethylhydrazide as a colorless oil.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([CH:7]=[CH:8][C:9](Cl)=[O:10])[C:4]([N+:12]([O-:14])=[O:13])=[N:3]1.[CH3:15][OH:16]>>[CH3:1][N:2]1[CH:6]=[C:5]([CH:7]=[CH:8][C:9]([O:16][CH3:15])=[O:10])[C:4]([N+:12]([O-:14])=[O:13])=[N:3]1
Reactant: Cn1cc(C=CC(=O)Cl)c([N+](=O)[O-])n1
Reactant: CO
Product: COC(=O)C=Cc1cn(C)nc1[N+](=O)[O-]

Procedure:
The same product is obtained when 0.22 g. of the 3-(1-methyl-3-nitro-4-pyrazolyl)-acrylic acid chloride described in Example 2 is allowed to react in 1.8 ml. methanol for 30 minutes at ambient temperature and the resultant crystals filtered off with suction.
Reaction SMILES: [O:1]=[C:2]1[C:10]2([C:14]3=[CH:15][C:16]4[O:20][CH2:19][O:18][C:17]=4[CH:21]=[C:13]3[O:12][CH2:11]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:22][C:23]1[CH:24]=[C:25]([CH:30]=[CH:31][CH:32]=1)[C:26]([O:28]C)=[O:27].O=C1C2(C3=CC4OCOC=4C=C3OC2)C2C(=CC=CC=2)N1CC1C=CC=CC=1C(OC)=O>>[O:1]=[C:2]1[C:10]2([C:14]3=[CH:15][C:16]4[O:20][CH2:19][O:18][C:17]=4[CH:21]=[C:13]3[O:12][CH2:11]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:22][C:23]1[CH:24]=[C:25]([CH:30]=[CH:31][CH:32]=1)[C:26]([OH:28])=[O:27]
Reactant: COC(=O)c1cccc(CN2C(=O)C3(COc4cc5c(cc43)OCO5)c3ccccc32)c1
Agent: COC(=O)c1ccccc1CN1C(=O)C2(COc3cc4c(cc32)OCO4)c2ccccc21
Product: O=C(O)c1cccc(CN2C(=O)C3(COc4cc5c(cc43)OCO5)c3ccccc32)c1

Procedure:
Following the procedure described in EXAMPLE 6, and making non-critical variations using methyl 3-[(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)methyl]benzoate to replace methyl 2-[(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)methyl]benzoate, the title compound was obtained (100%): 1H NMR (300 MHz, CDCl3) δ 13.03 (s, 1H), 7.86-7.80 (m, 2H), 7.59-7.57 (m, 1H), 7.48-7.44 (m, 1H), 7.25-7.16 (m, 2H), 7.03-6.95 (m, 2H), 6.68 (s, 1H), 6.18 (s, 1H), 5.90 (s, 2H), 5.05 (ABq, 2H), 4.75 (ABq, 2H); 13C NMR (75 MHz, CDCl3) δ 177.4, 167.5, 155.9, 148.9, 142.5, 142.3, 137.3, 132.2, 131.7, 129.6, 129.4, 128.8, 128.1, 124.3, 123.7, 120.1, 109.9, 103.3, 101.9, 93.9, 80.3, 58.0, 43.2; MS (ES+) m/z 416.2 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:12][C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[NH:18][CH:17]=[C:16]4[CH3:22])=[N:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:23][CH3:24].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:32][CH2:33][CH2:34][N:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1>CN(C=O)C>[CH3:24][O:23][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:2]=1[O:1][CH2:32][CH2:33][CH2:34][N:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1)[N:9]=[CH:8][N:7]=[C:6]2[O:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][CH:17]=[C:16]2[CH3:22]
Reactant: COc1cc2c(Oc3ccc4[nH]cc(C)c4c3)ncnc2cc1O
Reactant: ClCCCN1CCOCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc4[nH]cc(C)c4c3)ncnc2cc1OCCCN1CCOCC1
Temperature: 80 °C
Reaction time: 2 h
Yield: 51 %

Procedure:
A mixture of 7-hydroxy-6-methoxy-4-(3-methylindol-5-yloxy)quinazoline (800 mg, 2.49 mmol), (prepared as described in Example 271), potassium carbonate (687 mg, 4.98 mmol) and 1-chloro-3-morpholinopropane (448 mg, 2.74 mmol), (prepared as described for the starting material in Example 1), in DMF (20 ml) was stirred at 80° C. for 2 hours and allowed to cool to ambient temperature. The reaction mixture was filtered and the filtrate evaporated in vacuo. The residue was purified by silica column chromatography, gradient elution (dichloromethane, 5% methanol/95% dichloromethane, methanol/dichloromethane/0.880 saturated aqueous ammonia (100/8/1)) and the product was recrystallised from ethanol to give 6-methoxy-4-(3-methylindol-5-yloxy)-7-(3-morpholinopropoxy)quinazoline (570 mg, 51%).
Reaction SMILES: [CH2:1]=O.[O:3]1[C:8]2[CH:9]=[CH:10][C:11]([CH2:13][NH:14][CH:15]3[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][S:23][C:24]4[CH:33]=[N:32][C:31]5[C:26](=[CH:27][C:28]([O:34][CH3:35])=[CH:29][CH:30]=5)[N:25]=4)[CH2:17][CH2:16]3)=[CH:12][C:7]=2[O:6][CH2:5][CH2:4]1>>[O:3]1[C:8]2[CH:9]=[CH:10][C:11]([CH2:13][N:14]([CH:15]3[CH2:16][CH2:17][N:18]([CH2:21][CH2:22][S:23][C:24]4[CH:33]=[N:32][C:31]5[C:26](=[CH:27][C:28]([O:34][CH3:35])=[CH:29][CH:30]=5)[N:25]=4)[CH2:19][CH2:20]3)[CH3:1])=[CH:12][C:7]=2[O:6][CH2:5][CH2:4]1
Reactant: COc1ccc2ncc(SCCN3CCC(NCc4ccc5c(c4)OCCO5)CC3)nc2c1
Reactant: C=O
Product: COc1ccc2ncc(SCCN3CCC(N(C)Cc4ccc5c(c4)OCCO5)CC3)nc2c1

Procedure:
The title compound is prepared as a yellow foam (30 mg, 29% yield) following Scheme 3 and in analogy to Example 40 using paraformaldehyde (37 mg, 0.64 mmol 3.0 eq) and (2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-{1-[2-(7-methoxy-quinoxalin-2-ylsulfanyl)-ethyl]-piperidin-4-yl}-amine (100 mg, 0.22 mmol, 1.0 eq) as starting materials.
Reaction SMILES: [CH2:1]([N:8]([C@H:16]([C:24](=[O:35])[CH:25]=[C:26]([NH2:34])[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:42](Cl)(=[O:44])[CH3:43]>C1(C)C=CC=CC=1>[CH2:1]([N:8]([C@H:16]([C:24](=[O:35])[CH:25]=[C:26]([NH:34][C:42](=[O:44])[CH3:43])[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC(=CC(=O)[C@H](Cc1ccccc1)N(Cc1ccccc1)Cc1ccccc1)Cc1ccccc1
Reactant: CC(=O)Cl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CC(=O)NC(=CC(=O)[C@H](Cc1ccccc1)N(Cc1ccccc1)Cc1ccccc1)Cc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 90.6 %

Procedure:
(2S)-2-(N,N-dibenzylamino)-5-amino-1,6-diphenyl-4-hexene-3-one (100.0 g, 214.1 mmol) was dissolved in toluene (500 ml), to which pyridine (10 ml, 124.3 mmol) was added under a nitrogen stream. Acetyl chloride (25.7 g, 321.1 mmol) was slowly added to the resultant mixture while chilling with ice water so as not to raise the temperature above 10° C. The reaction mixture was further stirred at 50° C. for 5 hours and 25° C. for 16 hours. The mixture was then washed twice with a small amount of a 10% aqueous solution of sodium carbonate and with an aqueous sodium chloride, and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting crude product was recrystallized from methanol (1000 ml), thereby obtaining the title compound (97.5 g, 89.4%) as pale yellow crystals.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:7]=[C:8]([CH2:12][OH:13])[CH:9]=[CH:10][CH:11]=1.N1C=CC=CC=1.[Cl:20][C:21]([Cl:31])=[CH:22][C@@H:23]1[C@H:25]([C:26](Cl)=[O:27])[C:24]1([CH3:30])[CH3:29]>C1(C)C=CC=CC=1>[Cl:20][C:21]([Cl:31])=[CH:22][C@@H:23]1[C@H:25]([C:26]([O:13][CH2:12][C:8]2[CH:9]=[CH:10][CH:11]=[C:6]([C:2]3[O:1][CH:5]=[CH:4][CH:3]=3)[CH:7]=2)=[O:27])[C:24]1([CH3:29])[CH3:30]
Reactant: OCc1cccc(-c2ccco2)c1
Reactant: CC1(C)[C@H](C=C(Cl)Cl)[C@@H]1C(=O)Cl
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CC1(C)[C@H](C=C(Cl)Cl)[C@@H]1C(=O)OCc1cccc(-c2ccco2)c1
Yield: 94.3 %

Procedure:
This reaction was conducted in the manner of Example 3, Step 2 using 1.5 g (0.009 mol) of 3-(2-furanyl)phenylmethanol, 0.7 g (0.009 mol) of pyridine, 50 mL of toluene, and 2.0 g (0.009 mol) of cis-3-(2,2-dichloroethenyl)-2,2-dimethylcyclopropanecarbonyl chloride. The crude oily product was subjected to distillation under reduced pressure to give 3.1 g of [3-(2-furanyl)phenyl]methyl cis-3-(2,2-dichloroethenyl)-2,2-dimethylcyclopropanecarboxylate, b.p. 160° C./0.1 mm.
Reaction SMILES: [OH-].[K+].[Cl:3][CH2:4][C:5]1[O:9][N:8]=[C:7]([C:10]([O:12]CC)=[O:11])[CH:6]=1>C(O)C>[Cl:3][CH2:4][C:5]1[O:9][N:8]=[C:7]([C:10]([OH:12])=[O:11])[CH:6]=1
Reactant: CCOC(=O)c1cc(CCl)on1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1cc(CCl)on1
Temperature: 65 °C
Reaction time: 6 h
Yield: 76.8 %

Procedure:
14 g (250 mmol) of potassium hydroxide were added to 47.3 g (250 mmol) of ethyl 5-chloromethylisoxazole-3-carboxylate in 150 ml of ethanol, and the reaction mixture was stirred for 6 hours at 60-70° C. After cooling, the mixture was concentrated in vacuo, the residue was taken up in water and extracted with ether, the aqueous phase was acidified with hydrochloric acid and subsequently extracted repeatedly with ether, and the ether phase was dried over sodium sulfate and concentrated in vacuo (oil pump, 50° C.). 31 g of the required product resulted (77% of theory)
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][N:5]2[C:10]([C:11]3[CH:12]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:14]=[CH:15][CH:16]=3)=[CH:9][CH:8]=[N:7][C:6]=12.[CH3:21][N:22](C)C=O>>[F:18][C:17]([F:20])([F:19])[C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([C:10]2[N:5]3[N:4]=[CH:3][C:2]([C:21]#[N:22])=[C:6]3[N:7]=[CH:8][CH:9]=2)[CH:12]=1
Reactant: FC(F)(F)c1cccc(-c2ccnc3c(Br)cnn23)c1
Reactant: CN(C)C=O
Product: N#Cc1cnn2c(-c3cccc(C(F)(F)F)c3)ccnc12

Procedure:
A mixture of 0.95 g. of 3-bromo-7-(α,α,α-trifluoro-m-tolyl)pyrazolo[1,5-a]pyrimidine, 0.45 g. cuprous cyanide and 25 ml. of dimethylformamide is refluxed for 16 hours. Evaporation of the reaction mixture gave a residue which was triturated with methylene chloride. The methylene chloride solution is passed through a short column of hydrous magnesium silicate. The effluent is collected and refluxed on a steam bath with gradual addition of n-hexane and the desired nitrile crystallized from solution, m.p. 141°-143° C.
Reaction SMILES: [CH:1](=[O:5])[CH2:2][CH2:3][CH3:4].[H][H]>[Pd]>[CH:1](=[O:5])[CH2:2][CH2:3][CH3:4].[CH2:3]([CH:2]([CH2:1][CH2:2][CH2:3][CH3:4])[CH:1]=[O:5])[CH3:4]
Reactant: [H][H]
Agent: [Pd]
Solvent: CCCC=O
Product: CCCCC(C=O)CC

Procedure:
Using the apparatus described above, n-butyraldehyde was fed at a WHSV of 1.2, using hydrogen as the carrier gas, at atmospheric pressure and at 200° C. over an ALPO4 -31 catalyst loaded with 0.5% of palladium. The reaction resulted in an n-butyraldehyde conversion of 50% with about 10% selectivity to 2-ethylhexaldehyde.
Reaction SMILES: [C:1]1([S:7]([O:10][C:11]2[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][O:19][C:20]3[CH:33]=[CH:32][C:23]([CH:24]=[C:25]4[S:29][C:28](=[O:30])[NH:27][C:26]4=[O:31])=[CH:22][CH:21]=3)=[CH:13][CH:12]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C(OCC)(=O)C.C(O)(=O)C.[Pd]>[C:1]1([S:7]([O:10][C:11]2[CH:12]=[CH:13][C:14]([CH2:17][CH2:18][O:19][C:20]3[CH:33]=[CH:32][C:23]([CH2:24][CH:25]4[S:29][C:28](=[O:30])[NH:27][C:26]4=[O:31])=[CH:22][CH:21]=3)=[CH:15][CH:16]=2)(=[O:8])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C1NC(=O)C(=Cc2ccc(OCCc3ccc(OS(=O)(=O)c4ccccc4)cc3)cc2)S1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: O=C1NC(=O)C(Cc2ccc(OCCc3ccc(OS(=O)(=O)c4ccccc4)cc3)cc2)S1
Yield: 48.6 %

Procedure:
1.5 g (3.1 mmole) 5-(4-[2-(4-(benzenesulfonyloxy)phenyl)ethoxy]benzylidene)thiazolidine-2,4-dione was hydrogenated on 1 g Pd/C (5%) in ethyl acetate and acetic acid (2.5%) at atmospheric pressure for 24 hours. The reaction mixture was filtered through celite and the solvent was evaporated in vacuo. The starting material was not completely consumed, therefore the hydrogenation was restarted twice with Pd/C (10%), followed by purification by chromatography on silica gel using dichloromethane:methanol (95:5) as eluent to give 0.728 g (yield 48.6%) of the desired product.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([C:9]2[CH:14]=[C:13](Cl)[CH:12]=[C:11]([Cl:16])[C:10]=2[Cl:17])=[C:4]([CH3:18])[N:3]=1.ClC1C(Cl)=CC=CC=1CC#N>>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([Cl:16])[C:10]=2[Cl:17])=[C:4]([CH3:18])[N:3]=1
Reactant: Cc1nc(N)nc(N)c1-c1cc(Cl)cc(Cl)c1Cl
Agent: N#CCc1cccc(Cl)c1Cl
Product: Cc1nc(N)nc(N)c1-c1cccc(Cl)c1Cl

Procedure:
This compound was made in an analogous manner to the compound of Example 6 from 2,3-dichlorophenylacetonitrile, m.pt. 245°-247° C.
Reaction SMILES: [Mg].[CH3:2][C:3]1[N:8]=[C:7]([CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14](Br)=[CH:13][CH:12]=2)[CH:6]=[CH:5][CH:4]=1.[CH3:18][CH2:19][C:20]([C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=1)=[O:21].[Cl-].[NH4+]>O1CCCC1>[CH3:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([C:20]([C:22]3[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=3)([OH:21])[CH2:19][CH3:18])=[CH:13][CH:12]=2)[N:8]=1
Reactant: Cc1cccc(COc2ccc(Br)cc2)n1
Reactant: CCC(=O)c1ccc(F)cc1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCC(O)(c1ccc(F)cc1)c1ccc(OCc2cccc(C)n2)cc1
Temperature: 25 °C

Procedure:
To a Gringard reactant prepared from 2.2 g. of magnesium turnings and 25 g. of 4-[(6-methylpyrid-2-yl)-methoxy]-bromobenzene in 120 ml. of dry tetrahydrofurane a solution of 9.1 g. of 4-fluoropropiophenone in 45 ml. of tetrahydrofurane is added dropwise at 0° C. The reaction mixture is stirred at room temperature for two additional hours, and is then decomposed with a saturated aqueous ammonium chloride solution, under cooling. The aqueous phase is extracted with tetrahydrofurane. The tetrahydrofurane phase is washed with a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and evaporated in vacuo. Crystallization of the crude product from a mixture of ethyl acetate and n-hexane yields 15.2 g. of the title compound, melting at 103° to 104° C.
Reaction SMILES: O.Cl.[NH:3]1[CH2:8][CH2:7][C:6](=O)[CH2:5][CH2:4]1.[CH3:10][O:11][NH3+:12].[Cl-]>N1C=CC=CC=1>[CH3:10][O:11][N:12]=[C:6]1[CH2:7][CH2:8][NH:3][CH2:4][CH2:5]1
Reactant: CO[NH3+]
Reactant: O=C1CCNCC1
Agent: Cl
Agent: [Cl-]
Solvent: c1ccncc1
Solvent: O
Product: CON=C1CCNCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.7 %

Procedure:
53 ml of anhydrous pyridine were added to a mixture of 3.34 g of 4-piperidone hydrochloride monohydrate and 2.0 g of o-methylhydroxylamine hydrochloride, and the mixture was kept stirred overnight at room temperature. After completion of the reaction, the solvent was distilled off, and the crystalline residue was washed with ethyl acetate and collected by filtration. The crystals were washed with saturated aqueous sodium bicarbonate solution until basic and then extracted with chloroform. The chloroform layer was dried over anhydrous magnesium sulfate and the solvent was stripped off, giving 2.5 g of the title compound.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]=[C:8]([N:11]3[CH2:16][CH2:15][N:14]([C:17]4[C:22]([C:23]([F:26])([F:25])[F:24])=[CH:21][CH:20]=[CH:19][N:18]=4)[CH2:13][CH2:12]3)[N:7]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[C:6]=2[CH:5]=[C:4]([C:35]([F:38])([F:37])[F:36])[CH:3]=1.[NH:39]1[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]1>>[N:39]1([C:2]2[C:10]3[N:9]=[C:8]([N:11]4[CH2:16][CH2:15][N:14]([C:17]5[C:22]([C:23]([F:26])([F:25])[F:24])=[CH:21][CH:20]=[CH:19][N:18]=5)[CH2:13][CH2:12]4)[N:7]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[C:6]=3[CH:5]=[C:4]([C:35]([F:38])([F:37])[F:36])[CH:3]=2)[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]1
Reactant: C[Si](C)(C)CCOCn1c(N2CCN(c3ncccc3C(F)(F)F)CC2)nc2c(Br)cc(C(F)(F)F)cc21
Reactant: C1CCNCC1
Product: C[Si](C)(C)CCOCn1c(N2CCN(c3ncccc3C(F)(F)F)CC2)nc2c(N3CCCCC3)cc(C(F)(F)F)cc21

Procedure:
4-Bromo-6-trifluoromethyl-2-[4-(3-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazole from step (a) above (160 mg, 0.26 mmol) and piperidine (84 mg, 1 mmol) reacted under the conditions of Example 127b to give the title compound as an oil. MS (ESI, pos. ion) m/z: 629 (M+1).