Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]([C:21]([O:23]C)=[O:22])[CH:7]=[C:8]2[C:13]=1[O:12][C:11]([N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)=[CH:10][C:9]2=[O:20].Cl>CO.C(Cl)Cl>[Br:3][C:4]1[CH:5]=[C:6]([C:21]([OH:23])=[O:22])[CH:7]=[C:8]2[C:13]=1[O:12][C:11]([N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)=[CH:10][C:9]2=[O:20]
Reactant: COC(=O)c1cc(Br)c2oc(N3CCOCC3)cc(=O)c2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Product: O=C(O)c1cc(Br)c2oc(N3CCOCC3)cc(=O)c2c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 98.3 %

Procedure:
NaOH 2N (40.7 mL, 81.48 mmol) was added to methyl 8-bromo-2-morpholino-4-oxo-4H-chromene-6-carboxylate (10 g, 27.2 mmol) in a mixture of methanol (225 mL) and DCM (75 mL). The slurry was stirred at room temperature for 16 h. The solvents were evaporated, water (150 mL) was added to the slurry, the solution was cooled down to 0° C. and HCl 6N (15 mL, 89.6 mmol) solution was added dropwise to the reaction mixture until pH ˜3.4. The formed solid was collected by filtration, washed with water (3×50 mL), then toluene (3×50 mL) followed by Diethyl ether (3×50 mL), dried at 55° C. under vacuum over P2O5 to afford 8-bromo-2-morpholino-4-oxo-4H-chromene-6-carboxylic acid (9.47 g, 98%) as a beige solid. The crude product was used without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]2[N:11]([C:15](Br)=[CH:16][N:17]=2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:19]([Si:21]([CH3:24])([CH3:23])[CH3:22])#[CH:20].C(NC(C)C)(C)C>C(#N)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH2:1]([O:8][C:9]1[C:10]2[N:11]([C:15]([C:20]#[C:19][Si:21]([CH3:24])([CH3:23])[CH3:22])=[CH:16][N:17]=2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1cnc2c(OCc3ccccc3)cccn12
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CC(C)NC(C)C
Solvent: CC#N
Product: C[Si](C)(C)C#Cc1cnc2c(OCc3ccccc3)cccn12
Temperature: 25 °C
Yield: 63.7 %

Procedure:
A mixture of 8-(benzyloxy)-3-bromoimidazo[1,2-a]pyridine (10.0 g, 33.0 mmol), 9.39 mL (66.0 mmol) of ethynyltrimethylsilane, 0.580 g (0.825 mmol) of Pd(PPh3)2Cl2, 0.230 g (1.19 mmol) of CuI, and 5.09 mL (36.3 mmol) of diisopropylamine in 100 mL of acetonitrile was heated at reflux for 3 h under an atmosphere of N2. Upon cooling to ambient temperature, the reaction mixture was concentrated and the crude product was purified by silica gel flash chromatography (eluted with 20-50% EtOAc/hexanes) to provide 6.74 g of product: 321 m/z (M+H).
Reaction SMILES: [Cl-].[Cl-].[CH-:3]1[CH:7]=[CH:6][CH:5]=[CH:4]1.[CH-:8]1[CH:12]=[CH:11][CH:10]=[CH:9]1.[Ti+2:13].C[Li]>CCOCC.O>[CH3:8][C-:3]1[CH:7]=[CH:6][CH:5]=[CH:4]1.[C-:8]1([CH3:3])[CH:12]=[CH:11][CH:10]=[CH:9]1.[Ti+2:13]
Reactant: c1cc[cH-]c1
Agent: [Ti+2]
Agent: [Cl-]
Agent: [Li]C
Solvent: CCOCC
Solvent: O
Product: C[c-]1cccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 197 %

Procedure:
A solution of 2.49 g (10.0 mmol) of titanocene dichloride in 50 mL of ether in the dark at 0° C. was treated with 17.5 mL of 1.4 M methyllithium solution in ether maintaining the internal temperature below 5° C. The resulting yellow/orange mixture was stirred at room temperature for 30 minutes and the reaction was quenched by slowly adding 25 g of ice. The quenched reaction mixture was diluted with 50 mL of ether and 25 mL of water and the layers were separated. The organic layer was dried over magnesium sulfate and concentrated in vacuo to afford 2.03 g (98%) of the title compound as a light-sensitive solid. The dimethyl titanocene could be stored as a solution in toluene at 0° C. for at least 2 weeks without apparent chemical degradation. 1H NMR (CDCl3, 200 MHz, ppm): δ -0.15 (s, 6H), 6.06 (s, 10H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1F)[CH:5]=[O:6].CS(C)=O.[Na+].[CH3:16][S:17]([O-:19])=[O:18]>O>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[S:17]([CH3:16])(=[O:19])=[O:18])[CH:5]=[O:6]
Reactant: CS(=O)[O-]
Reactant: O=Cc1ccc(F)c(F)c1
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CS(=O)(=O)c1ccc(C=O)cc1F
Temperature: 90 °C

Procedure:
To a solution containing 0.5 g 3,4-difluorobenzaldehyde and 20 ml DMSO was added 0.71 g methanesulfinic acid sodium salt with stirring at 90° C. The solution was stirred 6 hours at 90° C. and then poured into water. Sodiumhydrogencarbonate was added and the product was extracted with ethyl acetate. The extract was evaporated to dryness in vacuo. The residue was triturated with 2-propanol, yield 0.93 g. 1H-NMR (DMSO-d6, 400 MHz): 3.52 (s, 3 H, CH3), 7.98-8.13 (m, 3 H, Ar), 10.22 (d, 1 H, CHO).
Reaction SMILES: [F:1][C:2]1[C:3]([OH:12])=[C:4]([C:7]([O:10][CH3:11])=[CH:8][CH:9]=1)[CH:5]=O.[C:13](#[N:16])[CH:14]=[CH2:15].CCCCCCCC>>[C:13]([C:14]1[CH2:15][O:12][C:3]2[C:4]([CH:5]=1)=[C:7]([O:10][CH3:11])[CH:8]=[CH:9][C:2]=2[F:1])#[N:16]
Reactant: C=CC#N
Reactant: COc1ccc(F)c(O)c1C=O
Solvent: CCCCCCCC
Product: COc1ccc(F)c2c1C=C(C#N)CO2
Yield: 13.6 %

Procedure:
Crude 3-fluoro-hydroxy-6-methoxybenzaldehyde (8.0 g) from above, acrylonitrile (13 mL; 193 mmol) and 1.4.diazadicyclo [2,2,2] octane (0.66 g; 5.9 mmol) were refluxed in a three-necked round-bottom flask (50 mL) under nitrogen for 4 h. Rotary-evaporation of the volatiles left a thick, red oil which was flash-chromatographed on a silica column eluted with methylene chloride/n-hexane (4:5). Concentration of relevant fractions gave an impure product (91% GC) which was crystallized form EtOAc to give 1.31 g of the title compound as colourless bars. Mp. 133°-135° C.
Reaction SMILES: [OH-].[Na+].[OH-].[K+].[C:5]([N:12]1[CH:16]=[CH:15]N=C1)([N:7]1[CH:11]=[CH:10]N=C1)=O.O1[CH2:21][CH2:20][CH2:19][CH2:18]1>C(Cl)Cl>[CH:16]1([N:12]=[C:5]=[N:7][CH:11]2[CH2:10][CH2:21][CH2:20][CH2:19][CH2:18]2)[CH2:15][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: C1CCOC1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: C(=NC1CCCCC1)=NC1CCCCC1

Procedure:
Ethyl cyanoacetate is alkylated (or dialkylated) by treatment with NaH in an appropriate solvent such as dimethylformamide or tetrahydrofuran at from 0° to 25° C. to give the alkylated nitrile (40). The nitrile is then treated with (n-Bu)3SnN3 in dioxane at reflux for 24 hours to give after acidic hydrolysis the tetrazole (41) which is then alkylated with an alkyl halide (R4Br) in CH3CN employing Et3N as base to give a mixture of regioisomers (42) and (43). The regioisomers are separated by flash chromatography and each ester is reduced by DIBAL-H in CH2Cl2 or toluene at -78° C. to give the corresponding alcohols (44) and (45). The alcohols are treated with methanesulfonyl chloride in CH2Cl2 using triethylamine as a base at 0° C. to give the corresponding mesylates which are then treated with KCN in dimethylformamide or dimethyl sulfoxide at 100° C. to give the corresponding nitriles (46) and (47). These are then hydrolyzed to the corresponding acids (48) and (49) by treatment with ethanolic NaOH (or KOH) at reflux. The acids are then coupled with an appropriate amine employing carbonyldiimidazole in tetrahydrofuran at room temperature or dicyclohexylcarbodiimide in CH2Cl2 at 0° C. to give the amides (50) and (51).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[Br:7][CH2:8][CH2:9]Br.[OH:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=[O:17])=[CH:14][CH:13]=1>CN(C=O)C>[Br:7][CH2:8][CH2:9][O:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=[O:17])=[CH:14][CH:13]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1ccc(OCCBr)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 64.4 %

Procedure:
To a suspention of K2CO3 (4.52 g, 32.7 mmol), 1,2-dibromoethane (10.6 ml, 122.8 mmol) in DMF (12 mL) was added a solution of 4-hydroxybenzaldehyde (1.0 g, 8.2 mmol) in DMF (3 mL) at 0° C. The mixture was stirred at room temperature for 18 h., filtered and evaporated. The residue was purified by silica gel column chromatography with gradient of EtOAc-hexane (increasing percentage of EtOAc from 20 to 25%) to afford the title compound (1.21 g, 64% yield). 1H NMR: (CDCl3) δ (ppm): 9.88 (s, 1H), 7.84 (d, J=8.0 Hz, 2H), 7.01 (d, J=8.0 Hz, 2H), 4.38 (t, J=6 Hz, 2H), 3.67 (t, J=6 Hz, 2H). LRMS (ESI): (calc.) 227.9, 229.9; (found) 229.1, 231.3 (MH)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:13][CH3:14])[C:10]=1[O:11][CH3:12])[CH2:6]O.CN(C)C1C=CC=CC=1.S(Cl)([Cl:26])=O>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:13][CH3:14])[C:10]=1[O:11][CH3:12])[CH2:6][Cl:26]
Reactant: COc1cc(CO)cc(OC)c1OC
Reactant: O=S(Cl)Cl
Solvent: CN(C)c1ccccc1
Solvent: ClCCl
Product: COc1cc(CCl)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Combine 3,4,5-trimethoxybenzyl alcohol (1.0 g, 5.04 mmol) and N,N-dimethylaniline (0.904 g, 7.46 mmol) in dichloromethane (10 mL). Cool in an ice bath. Add dropwise thionyl chloride (0.904 g, 7.6 mmol). Warm to ambient temperature. After 1 hour, partition the reaction mixture between a 1 M aqueous hydrochloric acid solution and dichloromethane. Separate the layers and extract the organic layer with a saturated solution of sodium bicarbonate. Dry the organic layer over Na2SO4, filter, and evaporate in vacuo to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[N+:11]([O-])([OH:13])=[O:12].S(=O)(=O)(O)O.O>C(Cl)Cl>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: O=[N+]([O-])O
Reactant: O=C(O)c1ccc(Cl)cc1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: ClCCl
Product: O=C(O)c1ccc(Cl)c([N+](=O)[O-])c1
Temperature: 42 °C

Procedure:
78.25 g (0.5mol) of 4-chlorobenzoic acid were suspended in 200 ml of methylene chloride, followed by the addition with stirring at room temperature of 33.5 g (0.55 mol) of 98% nitric acid. The mixture was heated with stirring to boiling temperature, followed by the dropwise addition over a period of 1 hour at that temperature of 63.5 g of 100% sulphuric acid. After cooling to 42° C., the mixture was stirred for 2 hours at that temperature. The reaction mixture was then poured onto 300 ml of water, and the methylene chloride subsequently distilled off. The residual suspension was filtered, the residue washed with water and dried at 90° C., giving 98.4 g (97.3% of the theoretical yield) of 4-chloro-3-nitrobenzoic acid melting at 182.9° to 184.0° C. with a purity of 99.5%. The content of unreacted 4-chlorobenzoic acid amounted to only about 0.1%.
Reaction SMILES: CO[CH:3](OC)[CH2:4][CH:5](OC)OC.Cl.[C:13]([NH:17][NH2:18])([CH3:16])([CH3:15])[CH3:14].Cl.O>CCO>[C:13]([N:17]1[CH:5]=[CH:4][CH:3]=[N:18]1)([CH3:16])([CH3:15])[CH3:14]
Reactant: COC(CC(OC)OC)OC
Reactant: CC(C)(C)NN
Agent: Cl
Solvent: CCO
Solvent: O
Product: CC(C)(C)n1cccn1
Yield: 89.1 %

Procedure:
A mixture of 1,1,3,3-tetramethoxypropane (37 g, 226 mmol), tert-butyl-hydrazine hydrochloride (28 g, 226 mmol) and conc HCl (60 mL, 720 mmol) in EtOH (300 mL) was heated at reflux overnight. The mixture was poured into water and the resulting mixture was extracted with ether. The combined organics were washed with brine, dried (MgSO4) and concentrated in vacuo to give 1-tert-butyl-1H-pyrazole (25 g, 89% yield). 1H NMR (400 MHz, DMSO-d6): δ7.73 (s, 1 H), 7.38 (s, 1 H), 6.17 (s, 1 H), 1.47 (s, 9 H); MS (ESI) m/z: 125.1 [M+H]+.
Reaction SMILES: [CH:1]([N:4]([CH:18]([CH3:20])[CH3:19])[CH2:5][CH2:6][N:7]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:10](=O)[C:8]1=[O:9])([CH3:3])[CH3:2].Cl.[NH2:22][NH:23][C:24]([NH2:26])=[O:25].C([O-])(=O)C.[Na+].C(O)C>O>[CH:1]([N:4]([CH:18]([CH3:20])[CH3:19])[CH2:5][CH2:6][N:7]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)/[C:10](=[N:22]\[NH:23][C:24]([NH2:26])=[O:25])/[C:8]1=[O:9])([CH3:3])[CH3:2]
Reactant: NNC(N)=O
Reactant: CC(C)N(CCN1C(=O)C(=O)c2ccccc21)C(C)C
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(C)N(CCN1C(=O)/C(=N/NC(N)=O)c2ccccc21)C(C)C
Yield: 74.7 %

Procedure:
A solution of 10.3 g of 1-(2-diisopropylaminoethyl)isatin, 5.1 g of semicarbazide hydrochloride and 3.7 g of sodium acetate in 150 ml of a mixture of ethanol and water (2:1) was stirred for 17 hours at room temperature. The yellow precipitates were collected by filtration and washed with aqueous ethanol. The filtrate and the washed the aqueous ethanol solution were combined and concentrated under reduced pressure. An aqueous sodium bicarbonate solution was added to the residue. The yellow precipitates were collected by filtration and washed with dichloromethane. The yellow precipitates were combined and recrystallized from aqueous methanol to obtain 9.3 g of (E)-1-(2-diisopropylaminoethyl)isatin 3-semicarbazone having a melting point of 193°-196° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.C(=O)([O-])[O-].[Cs+].[Cs+].Cl.Cl[CH2:23][CH2:24][N:25]([CH3:27])[CH3:26]>C(#N)C.CCOCC>[CH3:26][N:25]([CH3:27])[CH2:24][CH2:23][N:12]1[CH:13]=[C:9]([B:4]2[O:5][C:6]([CH3:7])([CH3:8])[C:2]([CH3:14])([CH3:1])[O:3]2)[CH:10]=[N:11]1.[CH3:26][N:25]([CH3:27])[CH2:24][CH2:23][N:12]1[CH:13]=[C:9]([B:4]2[O:5][C:6]([CH3:7])([CH3:8])[C:2]([CH3:14])([CH3:1])[O:3]2)[CH:10]=[N:11]1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: CN(C)CCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOCC
Solvent: CC#N
Product: CN(C)CCn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Temperature: 25 °C
Yield: 190.9 %

Procedure:
4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (2 g, 10.31 mmol), cesium carbonate (6.72 g, 20.61 mmol) and 2-chloro-N,N-dimethylethanamine hydrochloride (2.227 g, 15.46 mmol) were suspended in acetonitrile (30 mL) and the mixture was heated at reflux for 5 h, then cooled to room temperature, diluted with Et2O and filtered. The filtrate was concentrated in vacuo to give N,N-dimethyl-2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]ethanamine dimethyl{2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]ethyl}amine (2.61 g, 9.84 mmol, 95% yield) as an amber oil which was used in the next step without further purification.
Reaction SMILES: N1C=CN=C1[C@@H]1CCCN1C(OC(C)(C)C)=O.[I:18][C:19]1[N:20]=[C:21]([C@@H:25]2[CH2:29][CH2:28][CH2:27][N:26]2[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[NH:22][C:23]=1I.P(C(C)(C)C)(C(C)(C)C)C(C)(C)C.N1CCCCC1>CN(C=O)C.[Cu]I>[I:18][C:19]1[N:20]=[C:21]([C@@H:25]2[CH2:29][CH2:28][CH2:27][N:26]2[C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[NH:22][CH:23]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1c1nc(I)c(I)[nH]1
Agent: [Cu]I
Agent: CC(C)(C)OC(=O)N1CCC[C@H]1c1ncc[nH]1
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Solvent: CN(C)C=O
Solvent: C1CCNCC1
Product: CC(C)(C)OC(=O)N1CCC[C@H]1c1nc(I)c[nH]1
Temperature: 40 °C
Reaction time: 12 h
Yield: 99 %

Procedure:
A mixture of 5 (630 mg, 1.53 mmol), 6 (520 mg, 1.53 mmol), Pd (PPh3)2Cl2 (56 mg, 0.080 mmol) and CuI (8 mg, 0.04 mmol), P(t-Bu)3 (1.1 mL, 0.31 mmol), piperidine (1.05 mL, 4.60 mmol) in DMF (20 mL) was stirred at 40° C. for 12 h. The reaction mixture was partitioned between H2O and DCM. The organic layer was washed with H2O (4×50 mL) and brine (15 mL), dried over anhydrous Na2SO4, filtered and then concentrated in vacuo. The residue was purified by silica gel chromatography (DCM/MeOH=50/1 (v/v)) to afford 7 (550 mg, 50% yield) as a pale yellow solid. LC-MS (ESI) m/z 623.3 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=O)([O-:3])=[O:2].Cl.[NH2:13][OH:14]>CO.O>[N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=[N:13][OH:14])([O-:3])=[O:2]
Reactant: NO
Reactant: O=Cc1ccccc1[N+](=O)[O-]
Agent: Cl
Solvent: O
Solvent: CO
Product: O=[N+]([O-])c1ccccc1C=NO
Temperature: 30 °C
Reaction time: 2 h
Yield: 91.1 %

Procedure:
52.9 g (0.35 mol) of o-nitrobenzaldehyde was dissolved in 150 ml of methanol and an aqueous solution of 27.8 g (0.38 mol) of hydroxylamine hydrochloride in 35 ml of water was added dropwise over 30 minutes while maintaining the temperature at 30° C. The mixture was stirred at the same temperature for 2 hours and diluted with 300 ml of water. White crystals deposited were filtered, washed with water and dried. Thus, 53 g of o-nitrobenzaldoxime was obtained. Yield 91%; M.P. 95°-98° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1.Cl[C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH2:14][CH2:13][N:12]([C:16]3[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=3)[CH2:11][CH2:10]2)=[CH:7][CH:8]=1
Reactant: COc1ccc(N2CCNCC2)cc1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(N2CCN(c3ccc([N+](=O)[O-])cc3)CC2)cc1
Yield: 67 %

Procedure:
A mixture of 1-(4-methoxyphenyl)piperazine dihyclrochloride (0.050 mol), 1-chloro-4-nitrobenzene (0.050 mol) and potassium carbonate (10.0 g) in N,N-dimethylform-amide (100 ml) was stirred and refluxed overnight. The reaction mixture was diluted with water and extracted twice with trichloromethane. The organic layers were combined, dried (MgSO4), filtered and evaporated in vacuum. The residue was successively triturated in 4-methyl-2-pentanone and recrystallized from 1,4-dioxane. The product was filtered off and dried, yielding 10.5 g (67%) of 1-(4-methoxyphenyl)-4-(4-nitrophenyl)-piperazine; mp. 195.1° C. (interm. 1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([NH2:13])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:14][C:15]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:16]=1[CH:17]=O.[BH4-].[Na+]>CO>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([NH:13][CH2:17][C:16]2[CH:19]=[CH:20][C:21]([Cl:23])=[CH:22][C:15]=2[Cl:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](N)C1
Reactant: O=Cc1ccc(Cl)cc1Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC[C@H](NCc2ccc(Cl)cc2Cl)C1

Procedure:
Stir a mixture of (S)-3-amino-pyrrolidine-1-carboxylic acid tert-butyl ester (15.07 g, 81.0 mmol) and 2,4-dichlorobenzaldehyde (13.46 g, 76.9 mmol) in dry methanol (250 mL) at room temperature under nitrogen overnight. Add slowly sodium borohydride (4.74 g, 125.4 mmol) and stir for 10 min. Concentrate and add 2 N NaOH (150 mL) and extract with diethyl ether. Combine the organic layers, wash with saturated aqueous sodium chloride, dry (magnesium sulfate) and concentrate to give (S)-3-(2,4-dichlorobenzylamino)-pyrrolidine-1-carboxylic acid tert-butyl ester which may be used without further purification (26.9 g, 100%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[CH2:14][CH:13]([CH2:15][CH:16]3[CH2:21][CH2:20][N:19]([CH2:22][C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH2:18][CH2:17]3)[C:11](=[O:12])[C:6]2=[CH:7][C:8]=1[O:9][CH3:10].[C:29]([OH:37])(=[O:36])[CH:30]([CH2:32][C:33]([OH:35])=[O:34])[OH:31]>C(OCC)(=O)C.C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[CH2:14][CH:13]([CH2:15][CH:16]3[CH2:17][CH2:18][N:19]([CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH2:20][CH2:21]3)[C:11](=[O:12])[C:6]2=[CH:7][C:8]=1[O:9][CH3:10].[C:29]([O-:37])(=[O:36])[CH:30]([CH2:32][C:33]([O-:35])=[O:34])[OH:31]
Reactant: O=C(O)CC(O)C(=O)O
Agent: COc1cc2c(cc1OC)C(=O)C(CC1CCN(Cc3ccccc3)CC1)C2
Solvent: CCOC(C)=O
Solvent: CCO
Product: O=C([O-])CC(O)C(=O)[O-]

Procedure:
1.901 g of Donepezil is dissolved in 15 ml of ethyl acetate. A solution (4 ml) of malic acid (0.679 g) in absolute ethanol is added slowly and drop-wisely and the resulted solution is stirred. The solid precipitated is filtered with suction to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:8](I)=[CH:7][C:4]=1[CH:5]=[O:6].C(N(CC)CC)C.[C:19]([O:23]C)(=[O:22])[CH:20]=[CH2:21]>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>[CH:5]([C:4]1[CH:7]=[C:8]([CH:9]=[CH:10][C:3]=1[O:2][CH3:1])[CH:21]=[CH:20][C:19]([OH:23])=[O:22])=[O:6]
Reactant: COc1ccc(I)cc1C=O
Reactant: C=CC(=O)OC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COc1ccc(C=CC(=O)O)cc1C=O
Temperature: 67.5 °C

Procedure:
2-Methoxy-5-iodobenzaldehyde (1.0 g, 3.82 mmol) is dissolved in 25 ml of acetonitrile and oxygen is removed by bubbling nitrogen through the solution. Triethylamine (3.71 ml, 26.7 mmol) and methyl acrylate (0.686, ml, 7.63 mmol) are added dropwise with stirring to the solution, followed by four portions of 0.0214 g of tri-o-tolylphosphine (0.095 mmol) and 0.008 g of palladium (II) acetate (0.047 mmol) at 1 hour intervals. The mixture is then heated at 65-70° C. for 4 hours, volatiles are removed by distillation and the residue is dissolved in dichloromethane. The resulting solution is percolated through silica gel eluting with a mixture of hexane-ethyl acetate (6:4). The percolate is evaporated to dryness, re-dissolved in 20 ml of methanol and 10 ml of 20% aqueous potassium carbonate solution added. The mixture is stirred for 6 hours at room temperature and concentrated under reduced pressure to a third of its volume. The solution is taken to a pH value of 1 with concentrated hydrochloride acid and the precipitate is filtered and recrystallized from isopropanol, to give 0.472 g of 3-formyl-4-methoxycinnamic acid (2.29 mmol) as a crystalline white solid. A second harvest obtained by concentration of the mother liquor gave an additional 0.105 g.
Reaction SMILES: [Br:1][CH2:2][CH2:3]Br.[OH-].[Na+].[Br:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([Br:14])[C:9]=1[OH:15].C(OCC)(=O)C>O>[Br:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([Br:14])[C:9]=1[O:15][CH2:3][CH2:2][Br:1]
Reactant: BrCCBr
Reactant: Oc1c(Br)cccc1Br
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Product: BrCCOc1c(Br)cccc1Br
Yield: 55.9 %

Procedure:
1,2-Dibromoethane (5.0 ml, 58 mmol) was added to a solution of sodium hydroxide (2.5 g, 63 mmol) and 2,6-dibromophenol (14.5 g, 57.6 mmol) in 45 ml of water. The mixture was stirred under reflux for 20 hours and then extracted with ether. The combined organic layers was dried over Na2SO4, filtered and concentrated to give colorless oil. Silica gel chromatography, using a gradient of ethyl acetate, in hexanes to afforded 1,3-dibromo-2-(2-bromo-ethoxy)-benzene (11.55 g, 57% yield) as a colorless oil.
Reaction SMILES: NC(C1C=CC2C(=CC=C(O[C@H]3CC[C@H](C(C)(C)C)CC3)C=2)N=1)(C)CO.C(O)(C(F)(F)F)=O.C([O:36][C:37](=O)[C:38]([NH2:65])([C:40]1[CH:49]=[CH:48][C:47]2[C:42](=[CH:43][CH:44]=[C:45]([O:54][C@H:55]3[CH2:60][CH2:59][C@H:58]([C:61]([CH3:64])([CH3:63])[CH3:62])[CH2:57][CH2:56]3)[C:46]=2[C:50]([F:53])([F:52])[F:51])[N:41]=1)[CH3:39])C>>[NH2:65][C:38]([C:40]1[CH:49]=[CH:48][C:47]2[C:42](=[CH:43][CH:44]=[C:45]([O:54][C@H:55]3[CH2:56][CH2:57][C@H:58]([C:61]([CH3:64])([CH3:63])[CH3:62])[CH2:59][CH2:60]3)[C:46]=2[C:50]([F:51])([F:52])[F:53])[N:41]=1)([CH3:39])[CH2:37][OH:36]
Reactant: CCOC(=O)C(C)(N)c1ccc2c(C(F)(F)F)c(O[C@H]3CC[C@H](C(C)(C)C)CC3)ccc2n1
Agent: CC(N)(CO)c1ccc2cc(O[C@H]3CC[C@H](C(C)(C)C)CC3)ccc2n1
Solvent: O=C(O)C(F)(F)F
Product: CC(N)(CO)c1ccc2c(C(F)(F)F)c(O[C@H]3CC[C@H](C(C)(C)C)CC3)ccc2n1

Procedure:
2-Amino-2-[6-(trans-4-tert-butyl-cyclohexyloxy)-5-trifluoromethyl-quinolin-2-yl]-propan-1-ol Enantiomer 1 was synthesized as per 2-amino-2-[6-(trans-4-tert-butyl-cyclohexyloxy)-quinolin-2-yl]-propan-1-ol (Example 18) in 52% yield as bis-TFA salt using 2-amino-2-[6-(trans-4-tert-butyl-cyclohexyloxy)-5-trifluoromethyl-quinolin-2-yl]-propionic acid ethyl ester Enantiomer 1 as starting material. MS: m/z=425.30 [M+H]+. 1NMR (400 MHz, CHLOROFORM-d) δ ppm: 8.68 (d, J=8.8 Hz, 1H), 8.12 (d, J=9.0 Hz, 1H), 7.47-7.60 (m, 2H), 4.31-4.44 (m, 1H), 4.09-4.26 (m, 2H), 2.13-2.25 (m, 2H), 1.85-1.95 (m, 2H), 1.81 (s, 3H), 1.48-1.62 (m, 2H), 1.03-1.22 (m, 3H), 0.90 (s, 9H).