Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:9]1[C:14](=[O:15])[C:13]([I:16])=[CH:12][NH:11][C:10]1=[O:17])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH:25]([Cl:28])[CH2:26][CH3:27].O>CN(C=O)C>[C:1]([N:9]1[C:14](=[O:15])[C:13]([I:16])=[CH:12][N:11]([CH2:27][CH2:26][CH2:25][Cl:28])[C:10]1=[O:17])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCC(Cl)Br
Reactant: O=C(c1ccccc1)n1c(=O)[nH]cc(I)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(c1ccccc1)n1c(=O)c(I)cn(CCCCl)c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.1 %

Procedure:
3-Benzoyl-5-iodo-1H-pyrimidine-2,4-dione (Prep36, 3 g, 8.77 mmol) and K2CO3 (1.2 g, 8.77 mmol) were suspended in dry DMF (45 mL) and stirred at room temperature for 1 h. Then, bromo-chloro-propane (2.7 mL, 17.5 mmol) was added dropwise and the mixture stirred at room temperature overnight. Water was added and the mixture was extracted with ethyl acetate. The organic phase was dried (Na2SO4), filtered and evaporated to give the title compound as a pale yellow oil (3.6 g, 98% yield).
Reaction SMILES: [CH3:1][C@:2]12[CH2:19][CH2:18][C@H:17]3[C@@H:7]([CH2:8][CH2:9][C:10]4[C@:15]3([CH3:16])[CH:14]=[CH:13][C:12](=[O:20])[CH:11]=4)[C@@H:6]1[CH2:5][CH2:4][C:3]2=[O:21].[OH2:22].[C:23]1([CH3:33])C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1.C(O)CO>[CH2:33]1[CH2:23][O:22][C:3]2([CH2:4][CH2:5][C@H:6]3[C@H:7]4[C@H:17]([CH2:18][CH2:19][C@:2]23[CH3:1])[C@:15]2([CH3:16])[C:10](=[CH:11][C:12](=[O:20])[CH:13]=[CH:14]2)[CH2:9][CH2:8]4)[O:21]1
Reactant: C[C@]12C=CC(=O)C=C1CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O
Solvent: c1ccccc1
Solvent: OCCO
Product: C[C@]12C=CC(=O)C=C1CC[C@@H]1[C@@H]2CC[C@@]2(C)[C@H]1CCC21OCCO1
Temperature: 25 °C
Yield: 95 %

Procedure:
To a solution of androsta-1,4-dien-3,17-dione (1, 10.0 g) in benzene (600 ml) and ethylene glycol (90 ml) was added toluene-p-sulfonic acid monohydrate (0.3 g), and the solution was refluxed for 8-10 hours with a Dean-Stark apparatus for collecting water. The reaction mixture was cooled to room temperature, diluted with ethyl acetate and washed thoroughly with water, dilute sodium bicarbonate solution, water and finally with brine. The organic phase was dried over anhydrous magnesium sulfate, filtered and the organic solvent removed by rotary evaporator. The resultant solid was crystallized from methanol to give 17,17-ethylenedioxyandrosta-1,4-dien-3-one (2) as a white crystalline solid in 95% yield (11.0 g).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]1[C:19]2[C:14](=[N:15][CH:16]=[N:17][C:18]=2[NH2:20])[NH:13][N:12]=1.C([O-])([O-])=O.[K+].[K+].[CH:27]1([CH2:30]Br)[CH2:29][CH2:28]1.O>CN(C=O)C>[CH:27]1([CH2:30][N:13]2[C:14]3=[N:15][CH:16]=[N:17][C:18]([NH2:20])=[C:19]3[C:11]([C:2]3[CH:3]=[CH:4][C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[CH:1]=3)=[N:12]2)[CH2:29][CH2:28]1
Reactant: Nc1ncnc2[nH]nc(-c3ccc4ccccc4c3)c12
Reactant: BrCC1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1ncnc2c1c(-c1ccc3ccccc3c1)nn2CC1CC1
Temperature: 60 °C

Procedure:
3-(naphthalen-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (50 mg, 0.21 mmol) was dissolved in DMF (1.5 mL) and K2CO3 (110 mg, 0.8 mmol) and cyclopropyl methyl bromide (22 μL, 0.25 mmol) were added. The reaction was heated to 60° C. overnight, then cooled to RT and poured into water (30 mL). The precipitate was collected by filtration. ESI-MS (M+H)+ m/z calcd 316.2, found 316.2.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[CH:7][C:6](Cl)=[CH:5][CH:4]=1.[CH3:12][O-:13].[Na+]>CO>[F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[CH:7][C:6]([O:13][CH3:12])=[CH:5][CH:4]=1
Reactant: C[O-]
Reactant: FC(F)(F)c1ccc(Cl)cc1
Agent: [Na+]
Solvent: CO
Product: COc1ccc(C(F)(F)F)cc1
Temperature: 150 °C
Reaction time: 6 h
Yield: 57.3 %

Procedure:
200 g (1.11mol) of 4-(trifluoromethyl)chlorobenzene, 179 g (3.31 mol) of sodium methoxide, and 600 ml of methanol were mixed together in a pressurized reaction vessel, followed by stirring for 6 hr at 150° C. under tight sealing. The resulting reaction mixture was filtered to remove precipitates. Water was added to the obtained filtrate, followed by extraction with n-hexane. The resulting organic layer was washed with water, followed by drying with magnesium sulfate anhydride and removal of the solvent by distillation. The obtained residue was purified by distillation, thereby obtaining 112 g (0.636 mol) of 4-(trifluoromethyl)anisole (yield: 57%).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[CH:15](O)=O>O>[F:14][C:11]([F:12])([F:13])[C:8]1[CH:7]=[C:3]2[C:2](=[CH:10][CH:9]=1)[N:1]=[CH:15][N:6]=[C:4]2[OH:5]
Reactant: NC(=O)c1cc(C(F)(F)F)ccc1N
Reactant: O=CO
Solvent: O
Product: Oc1ncnc2ccc(C(F)(F)F)cc12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 49.6 %

Procedure:
2-Amino-5-trifluoromethyl-benzamide (ButtPark) (1.00 g, 4.90 mmol, 1 eq.) and formic acid (3.30 mL, 87.2 mmol, 17.8 eq.) were refluxed for 2.5 hours. Cooled to rt then added water (10 mL). Stirred 15 minutes then filtered off solids which were present. The solids were dried at 110° C. for 3 hours to give 520 mg of white solids as product. LCMS detects (M+H)+=215.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH:5]=[O:6].N1C(C)=CC(C)=CC=1C.[Cl:21][CH2:22][C:23](Cl)=[O:24]>C(Cl)(Cl)Cl>[Cl:21][CH2:22][C:23]([O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH:5]=[O:6])=[O:24]
Reactant: O=C(Cl)CCl
Reactant: COc1ccc(C=O)cc1O
Solvent: ClC(Cl)Cl
Solvent: Cc1cc(C)nc(C)c1
Product: COc1ccc(C=O)cc1OC(=O)CCl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A stirred mixture containing 108 g. (710 mmol.) of 3-hydroxy-4-methoxybenzaldehyde, 500 ml. of chloroform, and 125 ml. of collidine was kept below 10° C., treated dropwise with 70 ml. (800 mmol.) of chloroacetyl chloride over a 1-hour period, and then stirred 2 hours at 25° C. The solution was serially extracted with 500-ml. portions of water, 0.3N HCl, and water (2×). Chloroform was evaporated and crude 3-chloroacetoxy-4-methoxybenzaldehyde was recrystallized from diethyl ether (147 g., 91%), m.p. 88°-89° C.
Reaction SMILES: CC(C[AlH]CC(C)C)C.[CH3:10][O:11][C@@H:12]1[O:17][C@@H:16]([CH2:18][CH2:19]/[CH:20]=[CH:21]\[C@@H:22]([C@@H:24]2[C@@H:29]([CH3:30])[CH2:28][O:27][CH:26]([C:31]3[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=3)[O:25]2)[CH3:23])[C@H:15]([CH3:39])[C@H:14]([O:40][CH2:41][O:42][CH3:43])[C@H:13]1[CH3:44].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[CH3:38][O:37][C:34]1[CH:33]=[CH:32][C:31]([CH2:26][O:25][C@@H:24]([C@@H:22]([CH3:23])/[CH:21]=[CH:20]\[CH2:19][CH2:18][C@H:16]2[C@H:15]([CH3:39])[C@H:14]([O:40][CH2:41][O:42][CH3:43])[C@@H:13]([CH3:44])[C@H:12]([O:11][CH3:10])[O:17]2)[C@@H:29]([CH3:30])[CH:28]=[O:27])=[CH:36][CH:35]=1
Reactant: COCO[C@H]1[C@@H](C)[C@H](CC/C=C\[C@H](C)[C@H]2OC(c3ccc(OC)cc3)OC[C@@H]2C)O[C@@H](OC)[C@@H]1C
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: CC(C)C[AlH]CC(C)C
Solvent: ClCCl
Product: COCO[C@H]1[C@@H](C)[C@H](CC/C=C\[C@H](C)[C@H](OCc2ccc(OC)cc2)[C@@H](C)C=O)O[C@@H](OC)[C@@H]1C
Reaction time: 2 h
Yield: 80.9 %

Procedure:
DIBAL (1.0 M in hexane, 2.1 mL, 2.1 mmol) was added dropwise to a solution of the acetal 36 (329 mg, 0.67 mmol) in dry CH2Cl2 (6.7 mL) at 0° C. After the mixture was stirred for 2 h, the reaction was quenched with saturated aqueous sodium tartrate (20 mL) followed by vigorous stirring for several hours. The aqueous phase was extracted with CH2Cl2 (3×10 mL) and the combined organic layers were washed with brine (10 mL). After drying over MgSO4 and evaporation under vacuum, the residue was used for the next reaction without further purification. The crude alcohol in CH2Cl2 (13 mL) was treated with Dess-Martin periodinane (340.8 mg, 0.80 mmol). After the reaction was complete, the mixture was quenched with saturated NaHCO3 (20 mL). The aqueous layer was extracted with CH2Cl2 (2×10 mL) and the combined extracts were dried over anhydrous MgSO4. Filtration and concentration followed by short flash column chromatography filtration (hexane/EtOAc 9:1) provided crude aldehyde 38 (267 mg, 81%) as a colorless oil which was used without further purification.
Reaction SMILES: [CH3:1][C:2]([CH3:31])([CH3:30])[C:3]([C:5]1[C:13]2[C:8](=[N:9][CH:10]=[C:11]([C:14]3[CH:15]=[C:16]([CH:19]=[CH:20][CH:21]=3)[CH:17]=O)[N:12]=2)[N:7]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[CH:6]=1)=[O:4].[N:32]1[N:33]=[CH:34][N:35]2[CH2:40][CH2:39][NH:38][CH2:37][C:36]=12.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[N:32]1[N:33]=[CH:34][N:35]2[CH2:40][CH2:39][N:38]([CH2:17][C:16]3[CH:15]=[C:14]([C:11]4[N:12]=[C:13]5[C:5]([C:3](=[O:4])[C:2]([CH3:1])([CH3:31])[CH3:30])=[CH:6][N:7]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:28])([CH3:29])[CH3:27])[C:8]5=[N:9][CH:10]=4)[CH:21]=[CH:20][CH:19]=3)[CH2:37][C:36]=12
Reactant: CC(C)(C)C(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3cccc(C=O)c3)nc12
Reactant: c1nnc2n1CCNC2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: CC(C)(C)C(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3cccc(CN4CCn5cnnc5C4)c3)nc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 39.8 %

Procedure:
To a solution of 3-[7-(2,2-Dimethyl-propionyl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-benzaldehyde (0.150 g, 0.3428 mmol) and 5,6,7,8-Tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine (0.064 g, 0.514 mmol) in 1.2 mL of dichloroethane was added 1.2 mL acetic acid and 0.109 g of sodium triacetoxyborohydride (0.514 mmol). The reaction was stirred overnight at room temperature before quenching with saturated aqueous Na2CO3. The reaction mixture was extracted 3 times with ethyl acetate, combined organics dried over MgSO4, filtered and concentrated in vacuo. Silica gel chromatography (0→100% EtOAc/hexanes over 30 minutes, followed by a flush with 100% methanol) afforded 0.0744 g (40% yield) of 1-[2-[3-(5,6-Dihydro-8H-[1,2,4]triazolo[4,3-a]pyrazin-7-ylmethyl)-phenyl]-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-2,2-dimethyl-propan-1-one as a white solid. MS (E/I): 546 (M+H)
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:6][CH2:7][CH3:8])[CH3:5])[CH3:2].[CH:9]([O:12][CH2:13][CH3:14])=[CH:10]C.[C:15](=O)([O-])[O-].[Na+].[Na+]>B(F)(F)F.CCOCC>[CH2:1]([O:3][CH:4]([O:6][CH2:7][CH3:8])[CH:5]([CH3:15])[CH:9]([O:12][CH2:13][CH3:14])[CH3:10])[CH3:2]
Reactant: CCOC(C)OCC
Reactant: O=C([O-])[O-]
Reactant: CC=COCC
Agent: FB(F)F
Agent: [Na+]
Solvent: CCOCC
Product: CCOC(C)C(C)C(OCC)OCC
Temperature: 35 °C
Reaction time: 0.5 h
Yield: 66.2 %

Procedure:
900 g (7.4 mol) of acetaldehyde diethyl acetal (purity according to GC: 97%) and 0.85 g (0.75 ml, 6 mmol, 0.25 mol %) of boron trifluoride etherate were placed in a 2 l two-necked round flask fitted with a magnetic stirrer, a thermometer and a dropping funnel. 220 g (2.5 mol) of ethyl (1-propenyl) ether were added dropwise within about 30 minutes while cooling occasionally with ice at a temperature of about 35° C., but a maximum of 40° C. After completion of the addition the mixture was stirred at room temperature for a further 30 minutes. Then, 4 g of solid, powdered sodium carbonate were added thereto and the mixture was stirred at room temperature for 2.5 hours. Then the mixture was suction filtered and the excess acetaldehyde diethyl acetal was distilled off on a Raschig column, (30×2.5 cm) at 100 mbar. About 1 l of acetaldehyde diethyl acetal (content according to GC: 91%) was recovered in this manner at a boiling point of 40°-43° C. The residue was then fractionated on the same column at a pressure of 12-13 mbar. This gave 344.5 g (66.2% yield) of 1,1,3-triethoxy-2-methyl-butane as a water-clear liquid with a boiling point of 81°-84° C. and a content of 98.2% according to GC.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([N:8]=[C:9]=[O:10])[CH:5]=[CH:6][CH:7]=1.[NH2:11][CH2:12][C:13]([N:15]([CH2:22][C:23]([N:25]1[CH2:34][CH2:33][C:28]2([CH2:32][CH2:31][CH2:30][CH2:29]2)[CH2:27][CH2:26]1)=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:14]>O1CCCC1>[CH2:29]1[C:28]2([CH2:33][CH2:34][N:25]([C:23](=[O:24])[CH2:22][N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:13](=[O:14])[CH2:12][NH:11][C:9]([NH:8][C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[CH:3]=3)=[O:10])[CH2:26][CH2:27]2)[CH2:32][CH2:31][CH2:30]1
Reactant: Cc1cccc(N=C=O)c1
Reactant: NCC(=O)N(CC(=O)N1CCC2(CCCC2)CC1)c1ccccc1
Solvent: C1CCOC1
Product: Cc1cccc(NC(=O)NCC(=O)N(CC(=O)N2CCC3(CCCC3)CC2)c2ccccc2)c1
Reaction time: 12 h
Yield: 41.5 %

Procedure:
0.49 g of 3-methylphenyl isocyanate is added at a temperature close to 25° C to a solution of 1.2 g of 2-amino-N-[2-(8-azaspiro[4,5]decan-8-yl)-2-oxoethyl]-N-phenylacetamide in 50 cm3 of anhydrous tetrahydrofuran. The mixture is stirred for 12 hours at a temperature close to 25° C and the insoluble product is separated off by filtration. After recrystallization from ethyl acetate, 0.7 g of N-[2-(8azaspiro[4,5]decan-8-yl)-2-oxoethyl]-2-[3-(3-methylphenyl)ureido]-N-phenylacetamide melting at 183° C. is obtained.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])C.[CH2:8]([O:10][C:11]([C:13]1[CH:17]=[CH:16][S:15][C:14]=1[NH2:18])=[O:12])[CH3:9]>C(O)=O>[CH2:8]([O:10][C:11]([C:13]1[CH:17]=[CH:16][S:15][C:14]=1[NH:18][CH:1]=[O:3])=[O:12])[CH3:9]
Reactant: CCOC(=O)c1ccsc1N
Reactant: CC(=O)OC(C)=O
Solvent: O=CO
Product: CCOC(=O)c1ccsc1NC=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To acetic anhydride (4.7 ml) under ice cooling, formic acid (4.7 ml) was added dropwise, to which 2-aminothiophene-3-carboxylic acid ethyl ester (2.8 g, 16.4 mmol) was added and stirred at room temperature for 2 hours. After the solvent was distilled off under reduced pressure, ether was added, and the precipitate that deposited was filtered off. Ether was distilled off under reduced pressure to obtain 2-formylaminothiophene-3-carboxylic acid ethyl ester (3.0 g, 15.3 mmol).
Reaction SMILES: [CH2:1]=[CH:2][CH2:3][CH:4]([C:8]1[CH:9]=[CH:10][C:11]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[C:12]2[C:16]=1[CH2:15][N:14]([CH3:17])[C:13]2=[O:18])[CH2:5]C=C>C(Cl)Cl>[CH:4]1([C:8]2[CH:9]=[CH:10][C:11]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:23])([CH3:25])[CH3:24])=[C:12]3[C:16]=2[CH2:15][N:14]([CH3:17])[C:13]3=[O:18])[CH2:5][CH:1]=[CH:2][CH2:3]1
Reactant: C=CCC(CC=C)c1ccc(NC(=O)OC(C)(C)C)c2c1CN(C)C2=O
Solvent: ClCCl
Product: CN1Cc2c(C3CC=CC3)ccc(NC(=O)OC(C)(C)C)c2C1=O
Temperature: 25 °C
Yield: 90 %

Procedure:
To a solution of tert-butyl [7-(hepta-1,6-dien-4-yl)-2-methyl-3-oxo-2,3-dihydro-1H-isoindol-4-yl]carbamate (Compound 243D, 180 mg, 0.50 mmol) in DCM (10 mL) was added (benzylidene)bis(tricyclohexylphosphine)ruthenium (IV) dichloride (21 mg, 0.025 mmol). The resulting mixture was stirred at rt under nitrogen. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (ISCO Combi-flash system, eluting with 10-30% EtOAc/Heptane) to give the title compound as a white solid, 150 mg, 90% yield. 1H NMR (CDCl3): 1.54 (s, 9H), 2.43-2.48 (m, 2H), 2.81-2.86 (m, 2H), 3.18 (s, 3H), 3.45 (m, 1H), 4.32 (s, 2H), 5.80-5.84 (m, 2H), 7.35 (d, J=8.6 Hz, 1H), 8.12 (d, J=8.6 Hz, 1H), 9.53 (br s, 1H). MS (ES+): m/z=329.13 [MH+]. HPLC: tR=4.65 min (ZQ3, polar—5 min).
Reaction SMILES: BrC1C=CC(OC)=C(C)C=1.[CH2:11]([O:18][C:19]1[CH:24]=[CH:23][C:22](Br)=[CH:21][C:20]=1[F:26])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[NH:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>>[CH2:11]([O:18][C:19]1[CH:24]=[CH:23][C:22]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[CH:21][C:20]=1[F:26])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: C1CNCCN1
Reactant: Fc1cc(Br)ccc1OCc1ccccc1
Agent: COc1ccc(Br)cc1C
Product: Fc1cc(N2CCNCC2)ccc1OCc1ccccc1
Yield: 54.1 %

Procedure:
Production Example 9 was repeated except that 5-bromo-2-methoxytoluene and 1-(2-phenethyl)piperazine were replaced with 1-benzyloxy-4-bromo-2-fluorobenzene (6.742 g) and piperazine (12.404 g), respectively. The resulting crude product was purified on silica gel column chromatography (eluent, chloroform: methanol=2:1) to provide 1-(4-benzyloxy-3-fluorophenyl)piperazine (3.716 g).
Reaction SMILES: [C:1]([CH:3]1[NH:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]1)#[N:2].[OH:16][CH2:17][CH2:18][O:19][CH2:20][CH:21]=O.C(O)=O.C([BH3-])#N.[Na+]>ClCCl.O>[C:1]([CH:3]1[N:8]([CH2:21][CH2:20][O:19][CH2:18][CH2:17][OH:16])[CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]1)#[N:2]
Reactant: O=CCOCCO
Reactant: CC(C)(C)OC(=O)N1CCNC(C#N)C1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: O=CO
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(CCOCCO)C(C#N)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of tert-butyl 3-cyanopiperazine-1-carboxylate, prepared as described in the previous step, (10 g, 0.047 mol) and 2-(2-hydroxyethoxy)acetaldehyde (14.8 g) (see: Bodin, A., Contact Dermatitis, 2001, 44:207) in dichloromethane was treated with formic acid (12.7 g), and the reaction mixture was stirred at room temperature overnight. Sodium cyanoborohydride (7.2 g, 0.118 mol) was added in portions. The reaction mixture was stirred at room temperature for 3 hours followed by the addition of water and extraction with dichloromethane. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography to provide the product.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][C:11]=3[CH:12]=2)[CH:5]=[CH:6][CH:7]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:26][CH2:27][CH2:28][O:29][C:30]1[CH:37]=[CH:36][C:33]([C:34]#[N:35])=[CH:32][CH:31]=1.O>CN(C=O)C>[C:34]([C:33]1[CH:36]=[CH:37][C:30]([O:29][CH2:28][CH2:27][CH2:26][O:1][C:2]2[CH:3]=[C:4]([C:8]3[O:9][C:10]4[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][C:11]=4[CH:12]=3)[CH:5]=[CH:6][CH:7]=2)=[CH:31][CH:32]=1)#[N:35]
Reactant: N#Cc1ccc(OCCCBr)cc1
Reactant: N#Cc1ccc2oc(-c3cccc(O)c3)cc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ccc(OCCCOc2cccc(-c3cc4cc(C#N)ccc4o3)c2)cc1
Temperature: 60 °C
Reaction time: 8 h
Yield: 84 %

Procedure:
A mixture of 2-(3-hydroxphenyl)-5-cyanobenzofuran (125) (1.176 g, 5 mmol) and K2CO3 (0.829 g, 6 mmol) in dry DMF (25 mL) was heated up to 60° C. 4-(3-Bromopropoxy)benzonitrile (129) was added in one portion and the reaction was kept at 80-100° C. overnight. The mixture was cooled down to room temperature and poured into iced water (100 mL) and stirred for 30 min. A precipitate formed was separated by filtration, washed with water (50 mL) and ethanol (50 mL). Drying under high vacuum and recrystallization from the mixture of DMF and ethanol afforded the desired product as white solid (1.65 g, 84%): mp 157-158° C. (DMF/EtOH). 1H NMR (DMSO-d6) δ8.24 (d, J=1.6 Hz, 1H), 7.86 (d, J=8.6 Hz, 1H), 7.78 (d, J=8.8 Hz, 2H), 7.77 (dd, J=8.6, 1.6 Hz, 1H), 7.61 (s, 1H), 7.55 (d, J=7.8 Hz, 1H), 7.52 (m, 1H), 7.45 (dd, J=7.8, 7.8 Hz, 1H), 7.16 (d, J=8.8 Hz, 2H), 7.07 (dd, J=7.8, 1.7 Hz, 1H), 4.35-4.15 (m, 4H), 2.30-2.15 (m, 2H). HPLC (method B) tR 9.63 min (100.0 area %). Anal. (C25H18N2O3) C, H, N.
Reaction SMILES: CC1(C)[O:7][C:6](=[O:8])[C:5](=[CH:9]/[CH:10]=[N:11]/[NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[C:4](=O)[O:3]1.C[O-].[Na+].Cl>CO>[O:3]=[C:4]1[C:5]([C:6]([OH:7])=[O:8])=[CH:9][CH:10]=[N:11][N:12]1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1
Reactant: CC1(C)OC(=O)C(=C/C=N/Nc2ccccn2)C(=O)O1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: O=C(O)c1ccnn(-c2ccccn2)c1=O
Yield: 44.5 %

Procedure:
A mixture of (E)-2,2-dimethyl-5-(2-(2-(pyridin-2-yl)hydrazono)ethylidene)-1,3-dioxane-4,6-dione (0.050 g, 0.182 mmol) and NaOMe (0.0118 g, 0.218 mmol) in MeOH (6 mL) was heated under reflux for 15 hours. The salt was treated with cold 1 N HCl solution, extracted with DCM, dried over MgSO4, and concentrated to afford 17.6 mg (45%) of the desired product. LRMS (apci pos): 218 (M+H).
Reaction SMILES: [NH:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=O)[C:2]1=[O:3]>NN>[NH:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:4][C:2]1=[O:3]
Reactant: O=C1Nc2ccccc2C1=O
Agent: NN
Product: O=C1Cc2ccccc2N1

Procedure:
Chem. Educ. 1993, 70 (4), p. 332 discloses that 2-oxindoles are prepared by a two-step reaction, the first step of which comprises reacting isatin with hydrazine hydrate in anhydrous methanol to give the intermediate isatin hydrazone and isolating and purifying the intermediate. In the second step, the purified and dried intermediate is subjected to a Wolf-Kishner reduction in an anhydrous ethanol solution in the presence of a strong base such as sodium ethoxide. The yields achieved by this preparation method are up to about 69%. However, the disadvantage of this variant is the necessity of isolating, purifying and drying the intermediate before the reduction step can take place. A further disadvantage is the use of expensive, anhydrous ethanol as solvent because of the readiness of sodium ethoxide to react with water. A further preparation variant is described by Synth. Commun. 1994, 24 (20), p. 2835-41. In this variant, isatin is first dissolved in pure hydrazine and then reacted with pure hydrazine under reflux to give 2-oxindole in yields of up to 76%. However, this method requires a large quantity of pure hydrazine which serves as solvent and as reagent. When pure hydrazine is used, there is known to be a risk of explosion on heating or on reaction with oxidizing agents, so that particular safety measures have to be taken. An improvement suggested by U.S. Pat. No. 5,973,165 comprises preparing 2-oxindoles by reacting isatin with hydrazine hydrate in the presence of a weak base as catalyst and in a polar solvent. In order to obtain the desired end product in pure form, after the end of the reaction, 2-oxindole (purity about 97%) is first extracted, the extract is dried and then dissolved in a suitable solvent, and activated carbon is then added to the solution to decolorize it. After filtering off the activated carbon, 2-oxindole is crystallized out of the solution and obtained in a purity of 99.5%. The yields which are obtained by this process according to Example 1 are around 85%, but otherwise from 52 to 72%.
Reaction SMILES: [H-].[Na+].O[C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1.[CH3:10][C:11]1[O:15][N:14]=[C:13]([C:16]2[CH:26]=[C:25]([CH3:27])[C:19]([O:20][CH2:21][CH2:22][CH2:23]I)=[C:18]([CH3:28])[CH:17]=2)[N:12]=1>CN(C=O)C>[CH3:10][C:11]1[O:15][N:14]=[C:13]([C:16]2[CH:26]=[C:25]([CH3:27])[C:19]([O:20][CH2:21][CH2:22][CH2:23][C:4]3[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=3)=[C:18]([CH3:28])[CH:17]=2)[N:12]=1
Reactant: Cc1nc(-c2cc(C)c(OCCCI)c(C)c2)no1
Reactant: Oc1cccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1nc(-c2cc(C)c(OCCCc3cccnc3)c(C)c2)no1
Temperature: 25 °C
Reaction time: 48 h
Yield: 55.1 %

Procedure:
To a suspension of sodium hydride (70 mg, 2.8 mmol) and 3-hydroxypyridine (0.24 g 2.56 mmol) in DMF was added dropwise 1 g (1g, 2.8 mmol) of 4-(5-methyl-1,2,4-oxadiazol-3-yl)-2,6-dimethyiphenoxypropyl iodide in DMF, and the mixture was stirred at room temperature for 2 days. The mixture was washed with water, extracted with ethyl acetate, and the organic layer was washed with water and dried over magnesium sulfate. The dry organic layer was concentrated in vacuo, passed through a pad of silica gel eluting with hexane/ethyl acetate (1:1) to afford 0.48 g (55.1% of 3-[3-[4-(5-methy-1,2,4-oxadiazol-3-yl) -2,6-dimethylphenoxy]propyl]-pyridine, as an oil, which crystallized on standing in ether, m.p. 46°-49° C.