Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[C@H:5]([CH2:9][C:10]1[C:15]([I:16])=[CH:14][C:13]([O:17]C)=[C:12]([O:19]C)[CH:11]=1)[NH:6][CH:7]=[O:8])[CH3:2].B(Br)(Br)Br>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:21])[C@H:5]([CH2:9][C:10]1[C:15]([I:16])=[CH:14][C:13]([OH:17])=[C:12]([OH:19])[CH:11]=1)[NH:6][CH:7]=[O:8])[CH3:2]
Reactant: CCOC(=O)[C@H](Cc1cc(OC)c(OC)cc1I)NC=O
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCOC(=O)[C@H](Cc1cc(O)c(O)cc1I)NC=O
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 64.6 %

Procedure:
To a solution of iodo derivative 3 (2 g, 4.9 mmol) in methylene chloride (35 mL) cooled in a -78° C. bath was added BBr3 (17.5 mL of 1M solution in methylene chloride) and the mixture was stirred at -78° C. for 15 min. The cooling bath was removed and the stirring continued until the mixture reached ambient temperature (~30 min). Finally, the reaction mixture was poured into ice water (100 mL), stirred at room temperature for 30 min. and the methylene chloride layer was separated. Evaporation of methylene chloride under reduced pressure resulted in a pale yellow solid 4 (1.2 g, 65%) m.p. 131°-132° C.
Reaction SMILES: [CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][C:7](=[O:16])[NH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH3:19][O:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25]Cl)=[CH:23][CH:22]=1.O>CN(C)C=O.C(OCC)(=O)C>[CH3:19][O:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25][N:6]2[C:7](=[O:16])[CH2:8][C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=3[C:11]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]2=3)=[CH:23][CH:22]=1
Reactant: O=C1Cc2ccccc2-c2ccccc2N1
Reactant: COc1ccc(CCl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc(CN2C(=O)Cc3ccccc3-c3ccccc32)cc1
Reaction time: 2 h
Yield: 89.2 %

Procedure:
To a solution of 0.82 g (4 mmol) of 5H,7H-dibenzo[b,d]azepin-6-one in 15 ml of dimethylformamide at room temperature 0.20 g (5 mmol) of sodium hydride 55% in oil was added. After stirring for 30 min at room temperature 0.75 g (5 mmol) of p-methoxybenzyl chloride were added and stirring was continued at room temperature for 2 hours. For workup the mixture was distributed between water and ethyl acetate. The organic layer was re-extracted with 1 N hydrochloric acid and the aqueous layers were washed with ethyl acetate. The combined organic layers were dried (MgSO4) and concentrated in vacuo. The residue was purified by column chromatography (hexane/ethyl acetate=1:1) to yield 1.175 g (91%) of 5-(4-methoxybenzyl)-5H,7H-dibenzo[b,d]azepin-6-one as a colourless oil; MS: m/e: 330.4 (M+H+).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[C:8]([OH:9])=[C:7]([N+:10]([O-])=O)[CH:6]=[CH:5][CH:4]=1.[Sn](Cl)Cl.[OH-].[Na+]>C(O)C>[NH2:10][C:7]1[CH:6]=[CH:5][CH:4]=[C:3]([C:2]([F:1])([F:13])[F:14])[C:8]=1[OH:9]
Reactant: O=[N+]([O-])c1cccc(C(F)(F)F)c1O
Agent: Cl[Sn]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Nc1cccc(C(F)(F)F)c1O
Temperature: 80 °C
Reaction time: 2 h
Yield: 87.9 %

Procedure:
A mixture of 6-trifluoromethyl-2-nitrophenol(1.84 g, 8.67 mmol) and tin (II) chloride (6.0 g, 26.2 mmol) in ethanol(150 mL) was heated at 80° C. under argon. After 2 hours, the starting material has disappeared and the solution was allowed to cool down and then poured into ice. The pH was made slightly basic (pH7-8), by addition of solid NaOH, before being extracted with ethyl acetate. The organic phase was washed with brine, dried over MgSO4 and filtered. The solvent was evaporated and chromatography of the resulting solid on silica gel (4% MeOH/CH2Cl2) gave the desired product(1.35 g, 88%). 1H NMR (CD3OD): d 6.93 (d, 1H), 6.82 (t, 1H), 6.78 (d, 1H).
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([N+:15]([O-])=O)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.C(=O)(O)[O-].[Na+]>C(O)C.[Fe]>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[NH2:15])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1ccc([N+](=O)[O-])cc1OC1CCCC1
Agent: [Fe]
Agent: Cl
Agent: O=C([O-])O
Solvent: CCO
Product: COc1ccc(N)cc1OC1CCCC1
Yield: 59.3 %

Procedure:
A mixture of 3-cyclopentyloxy-4-methoxy-1-nitrobenzene (5.02 g), iron powder (4.8 g) and hydrochloric acid (35%, 15 ml) in ethanol (40 ml) was stirred under reflux for 3 hours. Then the mixture was poured into aqueous sodium bicarbonate and extracted with ethyl acetate twice. The combined organic phase was washed with aqueous sodium bicarbonate and brine, dried over magnesium sulfate and concentrated to give 3-cyclopentyloxy-4-methoxyaniline (2.60 g) as an oil.
Reaction SMILES: [OH:1][N:2]=[C:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:4]#[N:5].[CH3:19]N(C)C=O.C(=O)([O-])[O-].[K+].[K+].CI>CCOCC>[CH3:19][O:1][N:2]=[C:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:4]#[N:5]
Reactant: N#CC(=NO)c1ccccc1Oc1ccccc1
Reactant: CN(C)C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CCOCC
Product: CON=C(C#N)c1ccccc1Oc1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 84 %

Procedure:
To α-hydroxyimino-2-phenoxyphenylacetonitrile (a mixture of E- and Z-isomers) (1.19 g, 0.005 mole) were added dried dimethylformamide (10 ml) and potassium carbonate (0.90 g, 0.006 mole), and methyl iodide (0.78 g, 0.0055 mole) was added dropwise to the mixture under ice cooling, followed by stirring at room temperature for 4 hours. After completion of the reaction, ether (150 ml) was added, followed by washing twice with water (100 ml). The ether layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (ethyl acetate/n-hexane) to obtain α-methoxyimino-2-phenoxyphenylacetonitrile (1.06 g, yield: 84.0%) as a colorless oil.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].C(#N)C.Br[CH2:21][CH2:22][CH2:23][Cl:24]>O>[Cl:24][CH2:23][CH2:22][CH2:21][O:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][CH:3]=1
Reactant: ClCCCBr
Reactant: NC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: NC(=O)c1ccc(OCCCCl)cc1
Temperature: 5 °C
Yield: 82 %

Procedure:
10.5 kg of 4-hydroxybenzamide, 10.58 kg of potassium carbonate and 83 kg of acetonitrile are introduced into a reactor. The mixture is stirred and then there are added 24.14 kg of a solution of 1-bromo-3-chloropropane. The reaction mixture is heated at reflux for 4 hours. Water (105 L) is added in the hot state, the mixture is then cooled to 5° C. and filtered. The filter cake is washed with water and then with acetonitrile. The title product is obtained in the form of a powder in a yield of 82%.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][CH2:8][C@@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][NH:10]1)([CH3:4])([CH3:3])[CH3:2].[CH3:16][C:17]1[N:21]=[C:20]([C:22]2[CH:30]=[CH:29][CH:28]=[CH:27][C:23]=2[C:24](O)=[O:25])[O:19][N:18]=1.C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>>[C:1]([O:5][C:6](=[O:15])[NH:7][CH2:8][C@@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][N:10]1[C:24]([C:23]1[CH:27]=[CH:28][CH:29]=[CH:30][C:22]=1[C:20]1[O:19][N:18]=[C:17]([CH3:16])[N:21]=1)=[O:25])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC[C@@H]1CCCCN1
Reactant: Cc1noc(-c2ccccc2C(=O)O)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: Cc1noc(-c2ccccc2C(=O)N2CCCC[C@H]2CNC(=O)OC(C)(C)C)n1
Temperature: 90 °C
Reaction time: 16 h

Procedure:
A mixture of (S)-1-piperidin-2-ylmethyl-carbamic acid tert butyl ester (2.0 g) and 2-(3-methyl-[1,2,4]oxadiazol-5-yl)-benzoic acid (1.9) in dimethylformaide (10 ml containing diisopropylethylamine (2.4 ml) was treated with [O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate] (3.55 g) and stirred at 90° C. for 16 hours. Solvent was removed at reduced pressure and the residue column chromatographed (silica gel, diethyl ether eluant) to give the title compound (3.4 g).
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([CH:14]([CH3:16])[CH3:15])[CH2:10][CH2:9]1)(C)(C)C>CO.Cl>[CH:14]([N:11]1[CH2:12][CH2:13][CH:8]([NH2:7])[CH2:9][CH2:10]1)([CH3:16])[CH3:15]
Reactant: CC(C)N1CCC(NC(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: CO
Product: CC(C)N1CCC(N)CC1
Reaction time: 16 h

Procedure:
To 4.8 g (1-Isopropyl-piperidin-4-yl)-carbamic acid tert-butyl ester in 15 mL methanol, 20 mL methanolic hydrochloric acid (8 M) were added and the mixture was stirred for 16 h. Removal of the solvent under reduced pressure, followed by removal of residual volatiles by twice coevaporating with toluene, gave the product. Yield: 5.42 g MS (ES+): m/e=143.
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([Cl:15])=[CH:8][C:9]([C:13]#[N:14])=[N:10]2)=[CH:5][CH:4]=1.[N-:16]=[N+:17]=[N-:18].[Na+]>CCO>[N:16]([CH2:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([Cl:15])=[CH:8][C:9]([C:13]#[N:14])=[N:10]2)=[CH:5][CH:4]=1)=[N+:17]=[N-:18]
Reactant: N#Cc1cc(Cl)c2ccc(CBr)cc2n1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CCO
Product: N#Cc1cc(Cl)c2ccc(CN=[N+]=[N-])cc2n1
Temperature: 25 °C

Procedure:
A mixture of 7-(bromomethyl)-4-chloroquinoline-2-carbonitrile (8.46 g, 30 mmol), sodium azide (2.15 g, 33 mmol) in EtOH (300 mL) was heated under reflux for 1 h. The mixture was then cooled to room temperature and evaporated to dryness. The crude material was purified by flash chromatography (eluting solvent: 100% CH2Cl2 to 5% acetone in CH2Cl2) to yield the title compound. 1H NMR (400 MHz, acetone-d6): δ 8.40 (d, 1H), 8.20 (m, 2H), 7.97 (d, 1H), 4.85 (s, 2H).
Reaction SMILES: [F:1][C:2]([F:29])([O:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH:18]=[N:17][C:16]([C:19]3[CH:28]=[CH:27][C:22]([C:23]([O:25]C)=[O:24])=[CH:21][CH:20]=3)=[N:15]2)=[CH:10][CH:9]=1)[C:3]([F:6])([F:5])[F:4].C1COCC1.[OH-].[Li+]>O>[F:29][C:2]([F:1])([O:7][C:8]1[CH:9]=[CH:10][C:11]([N:14]2[CH:18]=[N:17][C:16]([C:19]3[CH:20]=[CH:21][C:22]([C:23]([OH:25])=[O:24])=[CH:27][CH:28]=3)=[N:15]2)=[CH:12][CH:13]=1)[C:3]([F:6])([F:5])[F:4]
Reactant: COC(=O)c1ccc(-c2ncn(-c3ccc(OC(F)(F)C(F)(F)F)cc3)n2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccc(-c2ncn(-c3ccc(OC(F)(F)C(F)(F)F)cc3)n2)cc1
Temperature: 60 °C
Reaction time: 39 h
Yield: 95.9 %

Procedure:
In a 250 mL round bottomed flask equipped with an overhead stirrer, T-type thermocouple, and nitrogen inlet were added methyl 4-(1-(4-(perfluoroethoxy)phenyl)-1H-1,2,4-triazol-3-yl)benzoate (11.1 g, 26.9 mmol) and THF (100 mL). To this yellow suspension were added water (10 mL) and lithium hydroxide.monohydrate (LiOH.H2O; 3.4 g, 81 mmol). The reaction was stirred at 23° Cfor 39 h during which time it became a yellow solution. The solution was warmed to 60° C. and stirred at 60° C. until complete by LC-MS. The reaction was cooled to 4° C. in an icebath and water (100 mL) was added to give a light yellow solution. Concentrated HCI (8.0 g) was added (note: exothermic) resulting in a thick white precipitate. The white suspension was stirred at 5° C. for 30 min and then the solid was collected by vacuum filtration. The filter cake was washed with water (2×25 mL), air dried for 3 h, and dried under vacuum (700 mm Hg) at 50° C. for 16 h to give the title compound as a white solid (10.3 g, 96%): mp 227-229° C.; 1H NMR (400 MHz, CDCI3) δ 8.65 (s, 1H), 8.32 (d, J=8.4 Hz, 2H), 8.23 (d, J=8.4 Hz, 2H), 7.84 (d, J=8.9 Hz, 1H), 7.42 (d, J=8.9 Hz, 2H).
Reaction SMILES: CC[O:3][C:4]([CH2:6][C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8])=[O:5].[OH-].[Na+].Cl>CCO>[O:8]=[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:6][C:4]([OH:5])=[O:3]
Reactant: CCOC(=O)CC(=O)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)CC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of ethyl benzoyl acetate (2.88 g, 15 mmol) in EtOH (30 mL) was added 1N NaOH (30 mL). The reaction mixture was stirred at rt for 72 h. It was cooled to 0° C. and acidified with 1N HCl. EtOH was removed under reduced pressure. The aqueous layer was extracted twice with dichloromethane. The combined dichloromethane solution was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo to give a light yellow solid. (600 mg, 24%). MS 165.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([CH:8]=[O:9])=[C:5]([Cl:7])[N:6]=1.[CH2:10](O)[CH2:11][OH:12].C(=O)([O-])[O-].[Na+].[Na+]>O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>[Cl:1][C:2]1[S:3][C:4]([CH:8]2[O:12][CH2:11][CH2:10][O:9]2)=[C:5]([Cl:7])[N:6]=1
Reactant: O=Cc1sc(Cl)nc1Cl
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: Clc1nc(Cl)c(C2OCCO2)s1
Yield: 94.5 %

Procedure:
Add p-toluenesulfonic acid monohydrate (1.70 g, 8.94 mmol) to a stirred solution of 2,4-dichloro-thiazole-5-carbaldehyde (21.05 g, 116 mmol), ethylene glycol (20.0 mL, 359 mmol), and anhydrous toluene (300 mL). Add a Dean-Stark trap and heat the reaction to reflux under nitrogen for 7 h. Cool the reaction and pour it into 10% sodium carbonate (300 mL). Extract with ethyl acetate (3×150 mL) and wash with brine (150 mL). Dry the ethyl acetate over sodium sulfate and then filter off the sodium sulfate. Concentrate on a rotary evaporator and purify the crude product by flash chromatography on silica gel eluting with 10% ethyl acetate/hexanes to yield 24.77 g (95%) of 2,4-dichloro-5-[1,3]dioxolan-2-yl-thiazole: mass spectrum (ion spray): m/z=225.9 (M+1); 1H NMR (CDCl3): δ=6.08 (s, 1H), 4.19-4.03 (m, 4H).
Reaction SMILES: [CH3:1][NH:2][C:3](=[S:6])[NH:4][NH2:5].[Cl:7][CH2:8][C:9]([CH3:14])([CH3:13])[C:10](O)=O.P(Cl)(Cl)(Cl)=O.Cl>O1CCOCC1>[CH3:1][NH:2][C:3]1[S:6][C:10]([C:9]([CH3:14])([CH3:13])[CH2:8][Cl:7])=[N:5][N:4]=1
Reactant: CNC(=S)NN
Reactant: CC(C)(CCl)C(=O)O
Agent: Cl
Solvent: O=P(Cl)(Cl)Cl
Solvent: C1COCCO1
Product: CNc1nnc(C(C)(C)CCl)s1

Procedure:
To a well stirred suspension of 125 g of 4-methylthiosemicarbazide and 165 g of β-chloropivalic acid in 500 ml of dioxane was added 186 g of phosphorus oxychloride at a rate which maintained the temperature below 60°. The reaction mixture was then heated at reflux until HCl evolution ceased (about 4 hrs). After cooling, the supernatant liquid was decanted from the plastic mass and 500 ml of water was added. With cooling, sodium hydroxide pellets were added until a pH of 10 was maintained. The resulting precipitate was collected, washed with water and air dried giving 216 g m.p. 91°-93°, (87%). Recrystallization from methylene chloride-ether gave the analytical sample, m.p. 93°-95°.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:11][CH2:12][CH2:13][N:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][C:21]=2[C:23]([O:25][CH3:26])=[O:24])[CH:16]=[N:15]1>C(Cl)Cl>[O:11]=[CH:12][CH2:13][N:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][C:21]=2[C:23]([O:25][CH3:26])=[O:24])[CH:16]=[N:15]1
Reactant: COC(=O)c1cccc2cnn(CCO)c12
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Product: COC(=O)c1cccc2cnn(CC=O)c12
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
Oxalyl chloride (1.3 mL, 15.5 mmol) was added dropwise to a mixture of dimethyl sulfoxide (1.8 mL, 25.8 mmol) and methylene chloride (4 mL) at −78° C. After addition was complete, the mixture was stirred at −78° C. for 30 min. A solution of methyl 1-(2-hydroxyethyl)-1H-indazole-7-carboxylate (2.8 g, 12.9 mmol) from Step D above in methylene chloride (40 mL) and added dropwise while maintaining the temperature at −78° C. The reaction was then stirred at −78° C. for 1-2 h. The reaction was quenched with N,N-diisopropylethylamine, cooled to 0° C., and sat. NaHCO3 was added. The aqueous phase was extracted several times with methylene chloride and the combined organic layers were dried (Na2SO4), filtered and concentrated to give methyl 1-(2-oxoethyl)-1H-indazole-7-carboxylate as a yellow oil (3.8 g, crude): 1H NMR (300 MHz, CDCl3) δ 9.79 (s, 1H), 8.16 (s, 1H), 8.14-8.08 (m, 2H), 7.98 (d, J=7.5 Hz, 1H), 5.61 (s, 2H), 3.99 (s, 3H); MS (ESI+) m/z 219 (M+H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([CH3:8])[CH:7]=1.[CH3:10][CH:11]1[NH:13][CH2:12]1>C1(C)C=CC=CC=1.CCOCC>[CH3:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([CH3:8])[CH:7]=1)[O:9][CH2:10][CH:11]([NH2:13])[CH3:12]
Reactant: Cc1cc(C)cc(O)c1
Reactant: CC1CN1
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: Cc1cc(C)cc(OCC(C)N)c1
Yield: 69107.1 %

Procedure:
24.4 Grams (0.20 mol) of 3,5-dimethylphenol and 3.8 g (0.067 mmol) of propyleneimine in 20 ml of toluene were allowed to react in an autoclave at 10 kg/cm2G at 200° C. for 1 hour. The reaction product was dispersed in 50 ml of ether, and then subjected to extraction with 50 ml of 5% hydrochloric acid three times. The water layer of the product was neutralized with sodium hydroxide, and the product was subjected to extraction with 50 ml of ether three times. The ether layer was washed and dried. Then, ether was distilled off, and the residue was distilled under reduced pressure to give 8.3 g of 1-(3,5-dimethylphenoxy)-2-propylamine as a component having a boiling point of 87° to 89° C./0.3 mmHg. Its yield was as high as 70%.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[CH:4][C:3]=1[CH3:16].[Cl:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[N:24]=[C:25]=[O:26]>C1COCC1>[Cl:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[NH:24][C:25](=[O:26])[NH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][C:12]([CH3:13])([CH3:15])[CH3:14])=[O:10])=[CH:4][C:3]=1[CH3:16]
Reactant: Cc1cc(CC(=O)OC(C)(C)C)ccc1N
Reactant: O=C=Nc1ccccc1Cl
Solvent: C1CCOC1
Product: Cc1cc(CC(=O)OC(C)(C)C)ccc1NC(=O)Nc1ccccc1Cl
Reaction time: 6 h
Yield: 92.7 %

Procedure:
To a stirred mixture of tert-butyl 4-amino-3-methylphenylacetate (1.00 g, 4.52 mmol), 2-chlorophenyl isocyanate (0.55 ml, 4.52 mmol) in THF (10 ml) was added Et3 N (0.13 ml, 0.90 mmol) at room temperature. After 6 h stirring, the reaction mixture was concentrated in vacuo. The residue was triturated by the addition of n-hexane, to give tert-butyl 4-[N′-(2-chlorophenyl) ureido]-3-methylphenylacetate (1.57 g, 93%) as a pale yellow powder. mp 104–106° C. (dec.); 1H-NMR (CDCl3) δ 1.45 (s, 9H), 2.28 (s, 3H), 3.51 (s, 2H), 6.33 (br, 1H), 6.96 (t, J=7.6 Hz, 1H), 7.08 (br, 1H), 7.16–7.30 (m, 4H), 7.42 (m, 1H), 8.2 (d, J=8.1 Hz, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[C:5]=1[NH2:6])([O-:3])=[O:2].[Br:14]Br>C(O)(=O)C>[Br:14][C:9]1[CH:10]=[C:4]([N+:1]([O-:3])=[O:2])[C:5]([NH2:6])=[C:7]([N+:11]([O-:13])=[O:12])[CH:8]=1
Reactant: Nc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Reactant: BrBr
Solvent: CC(=O)O
Product: Nc1c([N+](=O)[O-])cc(Br)cc1[N+](=O)[O-]
Yield: 86 %

Procedure:
A mixture comprising 247.5 g (1.35 mol) 2,6-dinitroaniline, 2.5 L acetic acid and 250 mL bromine was heated to 100° C. for a few minutes. After cooling, the formed crystals were filtered and washed with n-hexane to give 304 g (86%) of the title compound.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[OH:6][C:7]12[CH2:16][CH:11]3[CH2:12][CH:13]([CH2:15][CH:9]([CH2:10]3)[CH2:8]1)[CH2:14]2>>[Cl:1][CH2:2][C:3]([O:6][C:7]12[CH2:8][CH:9]3[CH2:15][CH:13]([CH2:12][CH:11]([CH2:10]3)[CH2:16]1)[CH2:14]2)=[O:4]
Reactant: OC12CC3CC(CC(C3)C1)C2
Reactant: O=C(Cl)CCl
Product: O=C(CCl)OC12CC3CC(CC(C3)C1)C2

Procedure:
A mixture of 24.8 g (0.22 mol) of chloroacetyl chloride and 30.4 g (0.2 mol) of 1-hydroxyadamantane is heated in an oil bath at 50°-60° until a solution is obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2([CH:15]([F:17])[F:16])[NH:13][C:12](=O)[CH2:11][O:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:19].C(OCC)(=O)C>N1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2([CH:15]([F:17])[F:16])[NH:13][C:12](=[S:19])[CH2:11][O:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: O=C1COCC(c2cccc(Br)c2)(C(F)F)N1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: FC(F)C1(c2cccc(Br)c2)COCC(=S)N1

Procedure:
5-(3-Bromo-phenyl)-5-difluoromethyl-morpholin-3-one (6.10 g, 19.93 mmol) was dissolved in 63 ml dry pyridine, and P2S5 (5.32 g, 23.91 mmol) was added. The mixture was heated to 80° V for 2 hrs. After completion, the mixture was put between ethyl acetate and 1 H HCl solution. Phases were separated and the organic phase was washed with 1 N HCl, saturated NaHCO3 solution and brine. The organic phases were combined, dried over Na2SO4 and concentrated under reduced pressure to yield the title compound as off-white solid. 1H-NMR (360 MHz, DMSO-d6): 8.60 (s, 1H, NH), 7.80-7.35 (m, 4H), 6.54 (t, 1H, CHF2), 4.45 (m, 2H), 4.28 (d, 1H), 4.12 (d, 1H); MS: 322 [(M+H)+].
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].C(=O)([O-])[O-].[K+].[K+].[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CN(C=O)C>[CH2:17]([O:10][C:8]1[CH:7]=[CH:6][C:3]([C:4]#[N:5])=[C:2]([F:1])[CH:9]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: BrCc1ccccc1
Reactant: N#Cc1ccc(O)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(OCc2ccccc2)cc1F
Temperature: 5 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 2-fluoro-4-hydroxybenzonitrile, 29 (15.00 g, 0.1094 mol) in DMF (45.0 mL) cooled to 0° C. was added potassium carbonate (37.8 g, 0.274 mol) followed by stifling at 0-5° C. for 30 min. Benzyl bromide (13.7 mL, 0.115 mol) was added to the reaction mixture at <5° C., stirred at 5° C. for 1 h followed by warming to 20° C. and stirring for additional 2.5 h. The completed reaction was partitioned between water (180 ml) and MTBE (220 mL), the layers separated and the organic layer was washed with water (90 mL), concentrated and azeotroped to dry two times with EtOAc (150 mL each) to provide 4-(benzyloxy)-2-fluorobenzonitrile, 30 (24.64 g, 0.1084 mol, 99% yield) as white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@@H:12]1[CH:16]=[CH:17][C:18](OCC)=[O:19])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].C([Al+]CC(C)C)C(C)C>C(=O)([O-])O.[Na+]>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@@H:12]1[CH:16]=[CH:17][CH2:18][OH:19])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C=C[C@H]1CCCN1C(=O)OCc1ccccc1
Agent: CC(C)C[Al+]CC(C)C
Agent: O=C([O-])O
Agent: [H-]
Product: O=C(OCc1ccccc1)N1CCC[C@@H]1C=CCO
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 54 %

Procedure:
To a stirred solution of ethyl (R)-3-(N-benzyloxycarbonylpyrrolidin-2-yl)-2-propenoate (3.03 g, 10.00 mmol) in anhydrous tetreahydrofuran (75 mL) at −78° C. under nitrogen was added dropwise a solution of diisobutylaluminum hydride (1.0 M in hexanes, 22.0 mL, 22.0 mmol, 2.2 eq). The resulting solution was stirred at −78° C. under nitrogen for 30 minutes. The reaction solution was then allowed to warm to room temperature over the course of 2 hours. A saturated solution of sodium hydrogen carbonate (50 mL) was added, and the aqueous mixture was extracted with ethyl acetate (3×50 mL). The extracts were combined, dried (MgSO4), and evaporated under reduced pressure. Column chromatography of the residue with diethyl ether/hexanes [1:1] afforded the title compound as a clear colorless oil (1.41 g, 5.40 mmol, 54%): 1H NMR (CDCl3)δ7.40-7.25 (m, 5H), 5.75-5.53 (m, 2H), 5.20-5.00 (m, 2H), 4.38 (br m, 1H), 4.06 (br d, J=13.7 Hz, 2 H), 3.45 (br t, J=7.0 Hz, 1 H), 2.03-1.68 (m, 4 H); [α]25=+34° (MeOH, c=1.0); HRMS calculated for C15H19NO3 261.1365, found 261.1356.