Azzindani/Open_Reaction_Data huggingface dataset:
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.[I-].[K+]>CC(C)=O.O>[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: [I-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: N#Cc1ccc(OCc2ccccc2)cc1F
Reaction time: 18 h
Yield: 89.7 %

Procedure:
A solution of 2-fluoro-4-hydroxy-benzonitrile (80 g, 0.58 mol), potassium carbonate (162 g, 1.17 mol) and benzyl bromide (76.4 mL, 0.64 mol) and potassium iodide (9.6 g, 0.058 mol) in acetone (600 mL) was stirred at RT and a significant exothermic reaction was observed. Stirring continued for 18 h without cooling. Reaction progress was monitored by TLC analysis. The reaction mixture was diluted with H2O (600 mL) and extracted with EtOAc (500 mL×2). The combined organic extracts were washed with saturated aqueous NaCl solution (500 mL), dried over Na2SO4, filtered and concentrated in vacuo. The resultant residue was triturated in cyclohexane (300 mL) and the crystalline solid was filtered off and washed to afford 4-Benzyloxy-2-fluoro-benzonitrile (118.2 g, 90%). 1H NMR (400 MHz, CDCl3): 7.51 (1 H, dd, J=8.70, 7.48 Hz), 7.40 (5 H, m), 6.86-6.76 (2 H, m), 5.11 (2 H, s).
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][CH2:6][C:7]#[C:8][CH2:9][CH2:10][C:11]([OH:13])=O)=[O:4].[O:14]1[CH:18]=[CH:17][CH:16]=[CH:15]1.ClC(Cl)C(OC(=O)C(Cl)Cl)=O>C1(C)C=CC=CC=1>[O:13]=[C:11]([C:15]1[O:14][CH:18]=[CH:17][CH:16]=1)[CH2:10][CH2:9][C:8]#[C:7][CH2:6][CH2:5][C:3]([O:2][CH3:1])=[O:4]
Reactant: COC(=O)CCC#CCCC(=O)O
Reactant: c1ccoc1
Agent: O=C(OC(=O)C(Cl)Cl)C(Cl)Cl
Solvent: Cc1ccccc1
Product: COC(=O)CCC#CCCC(=O)c1ccco1
Yield: 64.9 %

Procedure:
A mixture of 6-methoxycarbonyl-1-carboxy-3-hexyne [VI-1] (18.4 g, 0.1 mole), furan (13.6 g, 0.2 mole), dichloroacetic anhydride (28.8 g, 0.12 mole), boron trifluoride ether complex (3.2 g) and toluene (100 ml) is reacted at 20°-30° C. for 10 hours. After completion of the reaction, the reaction mixture is cooled and washed successively with water, 5% aqueous sodium carbonate solution and water. The organic layer is dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography to give 1-oxo-1-furyl-7-methoxycarbonyl-4-heptyne [VII-1] (15.2 g), b.p. 120°-125° C./0.3 mmHg.
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]#N)=[CH:5][C:4]=1[Cl:11].[H-].C([Al+]CC(C)C)C(C)C.Cl.[OH2:23]>C1(C)C=CC=CC=1>[Br:1][CH2:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[O:23])=[CH:5][C:4]=1[Cl:11]
Reactant: O
Reactant: N#Cc1ccc(CBr)c(Cl)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: Cc1ccccc1
Product: O=Cc1ccc(CBr)c(Cl)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
To a stirred solution of 4-(bromomethyl)-3-chlorobenzonitrile (4.8 g, 17 mmol) in toluene (50 mL) at 0° C. was added dropwise diisobutylaluminum hydride (DIBAL-H, 1.0 M solution in toluene; 23.9 mL), and the reaction mixture was stirred at 0° C. for 1 h. 10 M HCl in H2O (5 mL) was added until the reaction mixture turned to a white slurry and then additional 1 N HCl (20 mL) was added. The organic layer was collected and the aqueous layer was extracted with CHCl3. The combined organic layer was dried over Na2SO4 and concentrated under reduced pressure. The crude compound was purified by flash column chromatography (SiO2, 100-200 mesh; 5% EtOAc in n-Hexane) to afford the title compound as a white solid (3.8 g, 80%): mp 64-66° C.; 1H NMR (400 MHz, CDCl3) δ 10.00 (s, 1H), 7.92 (s, 1H), 7.78 (d, J=8.0 Hz, 1H), 7.64 (d, J=8.0 Hz, 1H), 4.60 (s, 2H); ESIMS m/z 232.78 ([M+H]+).
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]2[S:9][N:8]=[C:7]([N:10]3[CH2:15][CH2:14][N:13]([CH2:16][C@H:17]4[C@H:22]([CH2:23][N:24]5[C:34](=[O:35])[C@H:33]6[C@H:27]([C@H:28]7[CH2:32][C@@H:31]6[CH2:30][CH2:29]7)[C:25]5=[O:26])[CH2:21][CH2:20][CH2:19][CH2:18]4)[CH2:12][CH2:11]3)[C:5]=2[CH:6]=1.O.O.[C:38]([OH:43])(=[O:42])[C:39]([OH:41])=[O:40]>CC(C)=O>[CH:1]1[CH:2]=[CH:3][C:4]2[S:9][N:8]=[C:7]([N:10]3[CH2:15][CH2:14][N:13]([CH2:16][C@H:17]4[C@H:22]([CH2:23][N:24]5[C:34](=[O:35])[C@H:33]6[C@H:27]([C@H:28]7[CH2:32][C@@H:31]6[CH2:30][CH2:29]7)[C:25]5=[O:26])[CH2:21][CH2:20][CH2:19][CH2:18]4)[CH2:12][CH2:11]3)[C:5]=2[CH:6]=1.[C:38]([O-:43])(=[O:42])[C:39]([O-:41])=[O:40]
Reactant: O=C(O)C(=O)O
Agent: O=C1[C@@H]2[C@H]3CC[C@H](C3)[C@@H]2C(=O)N1C[C@@H]1CCCC[C@H]1CN1CCN(c2nsc3ccccc23)CC1
Solvent: CC(C)=O
Solvent: O
Product: O=C([O-])C(=O)[O-]
Temperature: 25 °C

Procedure:
A mixture consisting of acetone (4750 mL) and lurasidone base (431 g) is refluxed until dissolved. Oxalic acid dihydrate (110 g) is added, and the mixture is cooled to ambient temperature, and then cooled for two hours at 10° C. The solid is filtered, and 435 g of substantially pure lurasidone oxalate is obtained after drying.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([OH:16])[CH2:10][N:11]1[CH:15]=[CH:14][N:13]=[CH:12]1.[OH-].[Na+:18].C(O)(C)C.[Cl:23][C:24]1[S:25][CH:26]=[CH:27][C:28]=1[CH2:29][Br:30]>C1CCCCC1>[CH:5]1[C:6]([Cl:8])=[CH:7][C:2]([Cl:1])=[C:3]([CH:9]([O:16][CH2:29][C:28]2[CH:27]=[CH:26][S:25][C:24]=2[Cl:23])[CH2:10][N:11]2[CH:12]=[N:13][CH:14]=[CH:15]2)[CH:4]=1.[Br-:30].[Na+:18]
Reactant: Clc1sccc1CBr
Reactant: OC(Cn1ccnc1)c1ccc(Cl)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCCCC1
Solvent: CC(C)O
Product: Clc1ccc(C(Cn2ccnc2)OCc2ccsc2Cl)c(Cl)c1
Product: [Br-]
Temperature: 25 °C

Procedure:
(Step B) A second reactor was charged with about 1-(2,4-dichlorophenyl)-2-(1-imidazolyl)ethanol (about 102.9 g), sodium hydroxide pellets (about 15.7 g) and isopropanol (about 384.1 g). The contents were stirred and refluxed for about three hours. After cooling to room temperature, the cyclohexane solution of 2-chloro-3-bromomethylthiophene of step A was added to the reactor and the contents stirred overnight yielding a solution of crude tioconazole and solid sodium bromide. Water (about 75.7 g) was added to the reaction mixture to dissolve the solids. The crude reaction yield was ca. 49% based on 2-chloro-3-methylthiophene.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][O:10][CH3:11])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:19][Si:20]([C:23]#[CH:24])([CH3:22])[CH3:21]>[Cu](I)I.O.C(OCC)(=O)C>[CH3:19][Si:20]([CH3:22])([CH3:21])[C:23]#[C:24][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][O:10][CH3:11])=[CH:4][CH:3]=1
Reactant: COCOc1ccc(I)cc1
Reactant: C#C[Si](C)(C)C
Agent: I[Cu]I
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COCOc1ccc(C#C[Si](C)(C)C)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
5.74 g (21.7 mmol) of 1-iodo-4-methoxymethoxybenzene, 100 ml of triethylamine and a mixture of 1.53 g (2.18 mmol) of dichloro-bis(triphenylphosphine)palladium and 831 mg (4.37 mmol) of copper iodide are introduced into a three-necked flask. 6.14 ml (43.5 mmol) of trimethylsilylacetylene are then added and the medium is stirred for 48 h at room temperature. It is then poured into a water/ethyl acetate mixture. The organic phase is washed twice with water and, after separation of the phases by settling, it is washed with magnesium sulphate and concentrated.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[C:11](Cl)(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[C:11]([N:7]1[C:8]2[C:4](=[CH:3][C:2]([CH3:1])=[CH:10][CH:9]=2)[CH:5]=[CH:6]1)(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Cc1ccc2[nH]ccc2c1
Product: Cc1ccc2c(ccn2C(=O)c2ccccc2)c1

Procedure:
The 5-methylindole 1a is benzoylated with benzoyl chloride of a substituted benzoic acid to give N-benzoyl-5-methylindole, 1b. The bromination of 1b with N-bromosuccinimide and a catalytic amount of azobisisobutyronitrile in refluxing carbon tetrachloride affords N-benzoyl-5-bromomethylindole, 1c. ##STR43##
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[CH3:11].S(=O)(=O)(O)O.[CH3:17]O>>[CH3:17][O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([Br:1])=[C:3]([CH3:11])[CH:4]=1
Reactant: Cc1cc(C(=O)O)ccc1Br
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(Br)c(C)c1

Procedure:
To a suspension of 4-bromo-3-methylbenzoic acid (10.0 g, 46.5 mmol) in methanol (125 mL) was added concentrated sulfuric acid (1 mL). The reaction was heated at reflux overnight with a homogeneous solution obtained after several minutes of heating. After cooling, the methanol was removed in vacuo and the residue was dissolved in dichloromethane and washed with saturated aqueous sodium bicarbonate. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give 10.2 g of title compound as a brown solid, m.p. 41-43° C.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=1)(C(C)(C)C)(C)C.C([N-]C(C)C)(C)C.[Cl:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][C:31]=1[Cl:32])[CH:27]=[O:28].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[Cl:23][C:24]1[CH:25]=[C:26]([CH:27]([OH:28])[CH:9]([C:10]2[CH:11]=[CH:12][N:13]=[CH:14][CH:15]=2)[OH:8])[CH:29]=[CH:30][C:31]=1[Cl:32]
Reactant: CC(C)(C)[Si](C)(C)OCc1ccncc1
Reactant: O=Cc1ccc(Cl)c(Cl)c1
Agent: CC(C)[N-]C(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: OC(c1ccncc1)C(O)c1ccc(Cl)c(Cl)c1
Temperature: -40 °C
Reaction time: 0.75 h
Yield: 79.3 %

Procedure:
4-(tert-Butyldimethylsilyloxymethyl)-pyridine (T. F. Gallagher et al, Bioorganic and Medicinal Chemistry; 1997, 5, 49) (67 g, 0.3 mol) was dissolved in THF (250 ml) and cooled to −40° C. The solution was treated with a 2M solution of lithuim diisopropylamide in THF (200 ml, 0.4 mol) and stirred for 45 min maintaining a temperature of −40 to −20° C., before the dropwise addition of 3,4-dichlorobenzaldehyde (55.13 g, 0.32 mol) in THF (250 ml). The mixture was allowed to warm to room temperature then stirred for a further 18 hours. After re-cooling to 0° C. the reaction was quenched with saturated ammonium chloride solution (500 ml), and the resulting two phase mixture separated. The aqueous phase was extracted with ethyl acetate and the combined organics concentrated under reduced pressure. The residue was dissolved in ethyl acetate, washed with saturated sodium bicarbonate solution, water and brine, dried (MgSO4) and concentrated under reduced pressure to an oil (129 g). The oil was dissolved in THF (300 ml) and a 1M solution of tetrabutylammonium fluoride (360 ml, 0.36 mol) added dropwise. The solution was stirred at room temperature for 45 min, then concentrated to an oil under reduced pressure. The oil was dissolved in ethyl acetate and washed with saturated sodium bicarbonate solution, water and brine, dried (MgSO4) and evaporated under reduced pressure. The oil was triturated with hexane and the resulting solid filtered and washed with hexane to afford the title compound (67.58 g 79%) as a tan solid; MS(AP+) m/e 284/286/288 [M+H]+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([O:10][C:11]3[CH:39]=[C:38]([N:40]4[CH2:45][CH2:44][N:43]([CH2:46][C:47]5[CH2:48][C:49]6([CH2:54][CH2:55][C:56]=5[C:57]5[CH:62]=[CH:61][C:60]([Cl:63])=[CH:59][CH:58]=5)OCC[O:50]6)[CH2:42][CH2:41]4)[CH:37]=[CH:36][C:12]=3[C:13]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][CH2:26][CH:27]4[CH2:32][CH2:31][O:30][CH2:29][CH2:28]4)=[C:21]([N+:33]([O-:35])=[O:34])[CH:20]=3)(=[O:18])=[O:17])=[O:14])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>CC(C)=O.O>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([O:10][C:11]3[CH:39]=[C:38]([N:40]4[CH2:41][CH2:42][N:43]([CH2:46][C:47]5[CH2:48][C:49](=[O:50])[CH2:54][CH2:55][C:56]=5[C:57]5[CH:62]=[CH:61][C:60]([Cl:63])=[CH:59][CH:58]=5)[CH2:44][CH2:45]4)[CH:37]=[CH:36][C:12]=3[C:13]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][CH2:26][CH:27]4[CH2:32][CH2:31][O:30][CH2:29][CH2:28]4)=[C:21]([N+:33]([O-:35])=[O:34])[CH:20]=3)(=[O:18])=[O:17])=[O:14])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: O=C(NS(=O)(=O)c1ccc(NCC2CCOCC2)c([N+](=O)[O-])c1)c1ccc(N2CCN(CC3=C(c4ccc(Cl)cc4)CCC4(C3)OCCO4)CC2)cc1Oc1ccc2[nH]ccc2c1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: CC(C)=O
Product: O=C1CCC(c2ccc(Cl)cc2)=C(CN2CCN(c3ccc(C(=O)NS(=O)(=O)c4ccc(NCC5CCOCC5)c([N+](=O)[O-])c4)c(Oc4ccc5[nH]ccc5c4)c3)CC2)C1

Procedure:
A mixture of EXAMPLE 249E (20 mg) and pyridinium p-toluenesulfonate (16.8 mg) in acetone/H2O (1:1, 3 mL) was heated in a microwave to 135° C. for 8 minutes.
Reaction SMILES: S(=O)(=O)(O)O.[NH2:6][C:7]1[CH:8]=[C:9]([CH:14]=[CH:15][CH:16]=1)[C:10]([O:12][CH3:13])=[O:11].[S-:17][C:18]#[N:19].[K+].C1OCCOCCOCCOCCOCCOC1>ClC1C=CC=CC=1>[CH3:13][O:12][C:10](=[O:11])[C:9]1[CH:14]=[CH:15][CH:16]=[C:7]([NH:6][C:18]([NH2:19])=[S:17])[CH:8]=1
Reactant: N#C[S-]
Reactant: COC(=O)c1cccc(N)c1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: Clc1ccccc1
Product: COC(=O)c1cccc(NC(N)=S)c1
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
At −10° C. sulfuric acid (0.46 mL) is added dropwise to a solution of methyl 3-aminobenzoate (17.2 mmol) in chlorobenzene (19 mL). After 15 min potassium thiocyanate (18.2 mmol) is added portionwise over 30 min. The mixture is treated with 18-crown-6, heated to 100° C. for 16 h and allowed to cool to RT. After 4 h the obtained precipitate is filtered off and washed successively with chlorobenzene (33 mL) and hexane (three times 130 mL). The residue is diluted with water (390 mL) and the suspension is stirred for 30 min. After filtration the residue is washed twice with water (130 mL each), concentrated in vacuo and dried additionally by azeotropic removal of water with toluene. The obtained product is used without further purification. LC-MS: tR=0.66 min; [M+H]+=211.0.
Reaction SMILES: [CH2:1]([OH:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[N:10]1[CH:15]=[CH:14][N:13]=[CH:12][C:11]=1[C:16](O)=[O:17].Cl>C(Cl)Cl>[N:10]1[CH:15]=[CH:14][N:13]=[CH:12][C:11]=1[C:16]([O:9][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])=[O:17]
Reactant: CCCCCCCCO
Reactant: O=C(O)c1cnccn1
Agent: Cl
Solvent: ClCCl
Product: CCCCCCCCOC(=O)c1cnccn1
Yield: 60.1 %

Procedure:
A four-necked flask was charged with 100 g (0.768 mole) of 1-octanol and 10 g (0.081 mole) of pyrazinecarboxylic acid and while the internal temperature was maintained under stirring at 70°-80° C., 15 g (0.411 mole) of hydrogen chloride was introduced through a gas inlet tube over a period of 3 hours. Upon completion of the introduction of hydrogen chloride, the reaction mixture was cooled and 100 ml of methylene chloride was added. The mixture was transferred to a separatory funnel, in which it was washed with a small quantity of aqueous sodium carbonate solution. From the oil layer which separated, the methylene chloride was first distilled off and the residue was subjected to distillation under reduced pressure to give 11.5 g of octyl pyrazinecarboxylate. Yield: 60% (based on pyrazinecarboxylic acid)
Reaction SMILES: [C:1]([O-:5])(=[O:4])[CH:2]=O.[K+].C([O-])(=O)C.[NH4+:11].[C:12]1([OH:18])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>O>[CH:14]1[C:15]([CH:2]([NH2:11])[C:1]([OH:5])=[O:4])=[CH:16][CH:17]=[C:12]([OH:18])[CH:13]=1
Reactant: [NH4+]
Reactant: O=CC(=O)[O-]
Reactant: Oc1ccccc1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: O
Product: NC(C(=O)O)c1ccc(O)cc1
Reaction time: 24 h
Yield: 28.8 %

Procedure:
42.1 g of potassium glyoxylate, 75 g of ammonium acetate, 60 g of phenol and 130 ml of water are treated in the same manner as described in Example 1. The reaction was conducted for a period of 24 hours. 18.1 g of DL-p-hydroxyphenylglycine are thereby obtained as crystals. Yield 33.6%.
Reaction SMILES: [C:1]([O-:5])(=[O:4])[CH:2]=O.[Na+].C([O-])=O.[NH4+:10].[C:11]1([OH:17])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>O>[CH:13]1[C:14]([CH:2]([NH2:10])[C:1]([OH:5])=[O:4])=[CH:15][CH:16]=[C:11]([OH:17])[CH:12]=1
Reactant: Oc1ccccc1
Reactant: O=CC(=O)[O-]
Reactant: [NH4+]
Agent: O=C[O-]
Agent: [Na+]
Solvent: O
Product: NC(C(=O)O)c1ccc(O)cc1
Yield: 28.8 %

Procedure:
36.9 g of sodium glyoxylate, 61.3 g of ammonium formate, 60 g of phenol and 130 g of water are treated in the same manner as described in Example 1. 18.5 g of DL-p-hydroxyphenylglycine are thereby obtained as crystals. Yield: 34.2% M.p. 225°-228° C. (decomp.).
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:22]=[CH:21][C:7]([CH2:8][O:9][C:10]2[CH:11]=[CH:12][C:13]([NH:16]C(=O)OC)=[N:14][CH:15]=2)=[CH:6][CH:5]=1.CO>O>[NH2:16][C:13]1[CH:12]=[CH:11][C:10]([O:9][CH2:8][C:7]2[CH:21]=[CH:22][C:4]([Cl:3])=[CH:5][CH:6]=2)=[CH:15][N:14]=1
Reactant: COC(=O)Nc1ccc(OCc2ccc(Cl)cc2)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Nc1ccc(OCc2ccc(Cl)cc2)cn1
Reaction time: 8 h

Procedure:
10% Sodium hydroxide (8 ml) is added to methyl N-[5-(4-chlorobenzyloxy)-2-pyridyl]carbamate (59 mg, 0.20 mmol), and the mixture is heated rapidly to 85°. About 4 ml of methanol is added to the mixture after it has been heated for 2 hours. Heating is continued, and after another hour about 4 ml more of methanol is added to the mixture. Heating at 85° is continued overnight. The reaction is then cooled, and the methanol is rotoevaporated off. The reaction is poured into water and extracted with chloroform. The organic phase is washed with water and with brine to yield 2-amino-5-(4-chlorobenzyloxy)pyridine.
Reaction SMILES: Cl.C(OC([NH:9][C@H:10]([CH2:15][CH2:16][CH2:17][C:18]([C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=1)=O)[C:11]([O:13][CH3:14])=[O:12])=O)(C)(C)C>C(OCC)(=O)C>[Cl:26][C:23]1[CH:24]=[CH:25][C:20]([C@H:18]2[NH:9][C@@H:10]([C:11]([O:13][CH3:14])=[O:12])[CH2:15][CH2:16][CH2:17]2)=[CH:21][CH:22]=1
Reactant: COC(=O)[C@@H](CCCC(=O)c1ccc(Cl)cc1)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Product: COC(=O)[C@H]1CCC[C@@H](c2ccc(Cl)cc2)N1
Temperature: 25 °C
Reaction time: 12 h
Yield: 37.8 %

Procedure:
To a solution of (R)-6-oxopiperidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (9.00 g) in THF (120 mL), 4-chlorophenylmagnesium bromide (1.0 M solution in diethyl ether, 42 mL) was added in a nitrogen atmosphere at −78° C. over 20 minutes. The reaction solution was heated from −78° C. to −40° C. over 1.5 hours while stirring, and then quenched with a saturated ammonium chloride solution at −40° C. Water was added to the reaction solution, followed by extraction with ethyl acetate. The resulting extract was dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate system) to obtain methyl (R)-2-tert-butoxycarbonylamino-6-(4-chlorophenyl)-6-oxohexanoate (9.53 g). A solution of 4 N hydrochloric acid in ethyl acetate (90 mL) was added to a solution of methyl (R)-2-tert-butoxycarbonylamino-6-(4-chlorophenyl)-6-oxohexanoate (9.53 g) in ethyl acetate (90 mL) at room temperature, and the reaction solution was stirred at room temperature for 12 hours. The reaction solution was concentrated under reduced pressure, and the residue was made basic with a saturated sodium bicarbonate solution. Then, chloroform was added to the residue, and the mixture was stirred at room temperature for two hours. The organic layer was separated, dried over magnesium sulfate, and then concentrated under reduced pressure. Sodium cyanoborohydride (3.29 g) and then acetic acid (4.27 mL) were added to a solution of the residue in methanol (150 mL) at 0° C., and the reaction solution was stirred at 0° C. for one hour and at room temperature for one hour. A saturated sodium bicarbonate solution was added to the reaction solution, followed by extraction with chloroform. The resulting extract was dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate system) and solidified with a heptane-diisopropyl ether system to obtain 2.47 g of the title compound. The property values of the compound are as follows.
Reaction SMILES: [CH2:1](Br)[CH:2]=[CH2:3].[CH3:5][C:6]1[CH2:11][CH2:10][CH2:9][C:8]([CH3:13])([CH3:12])[C:7]=1[CH:14]=[O:15].[NH4+].[Cl-]>CCOCC>[CH3:5][C:6]1[CH2:11][CH2:10][CH2:9][C:8]([CH3:12])([CH3:13])[C:7]=1[CH:14]([OH:15])[CH2:3][CH:2]=[CH2:1]
Reactant: C=CCBr
Reactant: CC1=C(C=O)C(C)(C)CCC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: C=CCC(O)C1=C(C)CCCC1(C)C
Temperature: 0 °C
Yield: 57 %

Procedure:
In a typical experiment 10.7 g. of Mg turnings and 5 g. of allyl bromide were allowed to react in 70 ml. of dry ether. The reaction was exothermic and the temperature of the reaction mixture increased up to the boiling point of the solvent. To this solution allyl bromide (46 g.) and β-cyclocitral (61 g.) in 160 ml. of ether were added with vigorous stirring at such a rate as to maintain the ether at the boiling temperature. The reaction mixture was then kept at reflux during 6 hours and after cooling it was poured into a ice-cold concentrated aqueous solution of NH4Cl. The ethereal layer after the usual treatments gave 2,6,6-trimethyl-1-[1-hydroxy-3-butenyl]-1-cyclohexene (44.5 g.; 57 % yield): B.p. 60°-2°/0.001 Torr; nD20 = 1.4964; d420 = 0.9398; NMR spectrum (CCl4): 0.98 (3 H, s); 1.10 (3 H, s); 1.82 (3 H, s); 1.20-2.80 (9 H, m); 4.22 (1 H, m); 5.04 (2 H, d, J = 15 cps); 5.88 (1 H, m) δ ppm.
Reaction SMILES: [C:1](O)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.ClC(OCC(C)C)=O.[N:25]1([C:31]([C:33]2[CH:34]=[C:35]3[C:39](=[CH:40][CH:41]=2)[NH:38][C:37](=[O:42])[CH2:36]3)=[O:32])[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>CN(C=O)C>[C:1]([N:28]1[CH2:29][CH2:30][N:25]([C:31]([C:33]2[CH:34]=[C:35]3[C:39](=[CH:40][CH:41]=2)[NH:38][C:37](=[O:42])[CH2:36]3)=[O:32])[CH2:26][CH2:27]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccccc1
Reactant: O=C1Cc2cc(C(=O)N3CCNCC3)ccc2N1
Agent: CC(C)COC(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C1Cc2cc(C(=O)N3CCN(C(=O)c4ccccc4)CC3)ccc2N1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 20.8 %

Procedure:
To a solution of 3.2 g of benzoic acid and 4 ml of triethylamine in 50 ml of DMF was added dropwise a solution of 3.87 g of isobutyl chloroformate in 2 ml of DMF. After stirring the mixture for 30 minutes at room temperature, a solution of 8.8 g of 5-(1-piperazinylcarbonyl)oxindol in 3 ml of DMF was added dropwise thereto, and the mixture was stirred for 30 minutes at room temperature and then for 1 hour at 50° to 60° C. The reaction mixture was poured into a large amount of a saturated saline solution, extracted with chloroform, washed with water and dried. The solvent was distilled off, and the residue was recrystallized from methanol to give 1.9 g of 5-(4-benzoyl-1-piperazinylcarbonyl)oxindol.
Reaction SMILES: [F:1][C:2]([C:5]1([C:8]([OH:10])=O)[CH2:7][CH2:6]1)([F:4])[F:3].Cl.[CH3:12][O:13][NH:14][CH3:15].C1CCC(N=C=NC2CCCCC2)CC1>C(Cl)Cl>[CH3:12][O:13][N:14]([CH3:15])[C:8]([C:5]1([C:2]([F:4])([F:3])[F:1])[CH2:7][CH2:6]1)=[O:10]
Reactant: O=C(O)C1(C(F)(F)F)CC1
Reactant: CNOC
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: ClCCl
Product: CON(C)C(=O)C1(C(F)(F)F)CC1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 71 %

Procedure:
Trifluoromethyl cyclopropane carboxylic acid (500 mg, 3.24 mmol) was added to a freshly prepared solution of Weinreb amine (3.90 mmol) prepared by treating N-methoxymethanamine HCl salt with EtN-iPr2 (3.90 mmol) in CH2Cl2 at −40° C. and stirring for 5 min. DCC (801 mg, 3.90 mmol) in 5.0 mL of DCM was then added slowly over 3 min while cooling the solution at 0° C. The reaction mixture was stirred at RT for 48 h. It was then filtered through a plug of silica gel washing with Et2O. The volatiles were removed and the residue was purified on an ISCO 12 g column (20-70% EtOAc:Hexanes) to yield N-methoxy-N-methyl-1-(trifluoromethyl)cyclopropanecarboxamide (456 mg, 71% yield) as a clear colorless oil. A reference for this procedure could be found in: J. Org. Chem. 2005, 70, pages 5721-5724.