Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].Br[CH2:11][CH:12]([CH3:42])[C@@H:13]1[C@:30]2([CH3:31])[C@H:16]([C:17]3[C@H:27]([CH2:28][CH2:29]2)[C@:25]2([CH3:26])[C:20]([CH2:21][C@@H:22]([O:37][C:38]([O:40][CH3:41])=[O:39])[CH2:23][C@@H:24]2[O:32][C:33]([O:35][CH3:36])=[O:34])=[CH:19][CH:18]=3)[CH2:15][CH2:14]1.O>CS(C)=O>[CH3:42][CH:12]([C@@H:13]1[C@:30]2([CH3:31])[C@H:16]([C:17]3[C@H:27]([CH2:28][CH2:29]2)[C@:25]2([CH3:26])[C:20]([CH2:21][C@@H:22]([O:37][C:38]([O:40][CH3:41])=[O:39])[CH2:23][C@@H:24]2[O:32][C:33]([O:35][CH3:36])=[O:34])=[CH:19][CH:18]=3)[CH2:15][CH2:14]1)[CH2:11][S:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)O[C@@H]1CC2=CC=C3[C@@H]4CC[C@H](C(C)CBr)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@@H](OC(=O)OC)C1
Reactant: Sc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: COC(=O)O[C@@H]1CC2=CC=C3[C@@H]4CC[C@H](C(C)CSc5ccccc5)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@@H](OC(=O)OC)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 68.4 %

Procedure:
In 2 ml of dimethyl sulfoxide under ice-cooling, 55 mg of thiophenol and 20 mg of sodium hydroxide were stirred. Then, 54 mg of 21-bromo-20-methyl-1α,3β-bis(methoxycarbonyloxy)pregna-5,7-diene was added and the mixture was further stirred at ambient temperature for 3 hours. The reaction mixture was then poured into water and extracted with diethyl ether. The extract was washed with water and aqueous sodium chloride solution, dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography to give 39 mg of 20-methyl-1α,3β-bis(methoxycarbonyloxy)-21-phenylthiopregna-5, 7-diene.
Reaction SMILES: C[O:2][CH:3]=[C:4]1[CH2:9][CH2:8][CH:7]([C:10]([O:12][CH3:13])=[O:11])[CH2:6][CH2:5]1.Cl.CCCCCC>C1COCC1>[CH:3]([CH:4]1[CH2:5][CH2:6][CH:7]([C:10]([O:12][CH3:13])=[O:11])[CH2:8][CH2:9]1)=[O:2]
Reactant: COC=C1CCC(C(=O)OC)CC1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COC(=O)C1CCC(C=O)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 97.1 %

Procedure:
103 g of methyl 4-methoxymethylidenecyclohexanecarboxylate was dissolved in 350 mL of THF and 100 mL of 10% hydrochloric acid was added dropwise at 11 to 13° C. over 10 minutes. After stirring at room temperature for 3 hours, 80 mL of hexane was added. The aqueous layer was extracted with ethyl acetate and then combined with the organic layer, followed by washing in turn with water and saturated saline. The mixture was dried over anhydrous sodium sulfate and concentrated to obtain 92.4 g of methyl 4-formylcyclohexanecarboxylate as an oily substance. The gas chromatography analysis revealed that the resulting substance is a mixture of a cis isomer and a trans isomer in a mixing ratio of 64:36.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].[CH2:12](Br)[CH:13]=[CH2:14].C([O-])([O-])=O.[K+].[K+].O>CC(C)=O>[CH2:14]([O:11][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[C:1]([CH3:4])([CH3:2])[CH3:3])[CH:13]=[CH2:12]
Reactant: C=CCBr
Reactant: CC(C)(C)c1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: C=CCOc1ccccc1C(C)(C)C
Reaction time: 18 h
Yield: 81.3 %

Procedure:
To a stirred solution of o-(t-butyl)-phenol (11.3 g; 75 mmol) in acetone (150 ml) is added allyl bromide (10.9 g, 1.2 equiv.) and anhydrous K2CO3. After stirring 18 hr at reflux, the reaction is added to water (200 ml) and extracted with 3×150 ml portions of petroleum ether. The combined organic layers are dried (MgSO4), filtered, and concentrated in vacuo to give the crude product, which is purified by silica gel (sg) chromatography (hexane elution) to yield 1-prop-2-enyloxy-2-t-butylbenzene (11.6 g; 81% yield).
Reaction SMILES: [CH:1]([N:4]=[C:5](Cl)[C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][CH:7]=1)([CH3:3])[CH3:2].ClS(O)(=O)=O.[CH3:19][N:20]1[CH:24]=[C:23]([CH3:25])[CH:22]=[C:21]1[CH2:26][C:27]([O:29][CH3:30])=[O:28].[Cl:31]([OH:35])(=[O:34])(=[O:33])=[O:32]>>[Cl:31]([OH:35])(=[O:34])(=[O:33])=[O:32].[Cl:12][C:9]1[CH:10]=[CH:11][C:6]([C:5](=[N:4][CH:1]([CH3:3])[CH3:2])[C:24]2[N:20]([CH3:19])[C:21]([CH2:26][C:27]([O:29][CH3:30])=[O:28])=[CH:22][C:23]=2[CH3:25])=[CH:7][CH:8]=1
Reactant: CC(C)N=C(Cl)c1ccc(Cl)cc1
Reactant: COC(=O)Cc1cc(C)cn1C
Agent: O=S(=O)(O)Cl
Agent: [O-][Cl+3]([O-])([O-])O
Product: COC(=O)Cc1cc(C)c(C(=NC(C)C)c2ccc(Cl)cc2)n1C

Procedure:
The title compound was prepared as in Example X from N-isopropyl 4-chlorobenzimidoyl chloride (10.75 g, 49.8 mmole), chlorosulfonic acid (0.58 g, 5.0 mmole), methyl 1,4-dimethyl-1H-pyrrole-2-acetate (8.34 g, 50 mmole), and 70% perchloric acid (7.8 g, 55 mmole) to yield 14.2 g (64%) of a bright yellow solid, m.p. 94°-110° C. (dec).
Reaction SMILES: [OH:1][C:2]1[C:12]2[O:11][CH2:10][CH2:9][NH:8][C:7](=[O:13])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[C:15]1([CH2:14][O:1][C:2]2[C:12]3[O:11][CH2:10][CH2:9][NH:8][C:7](=[O:13])[C:6]=3[CH:5]=[CH:4][CH:3]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C1NCCOc2c(O)cccc21
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1NCCOc2c(OCc3ccccc3)cccc21
Yield: 67.4 %

Procedure:
A mixture of 9-hydroxy-3,4-dihydro-1,4-benzoxazepin-5(2H)-one (7.46 g, 41.6 mmol), benzyl bromide (Preparation 58) (5.45 ml, 45.8 mmol) and potassium carbonate (17.26 g, 125 mmol) was stirred and heated at 60° C. in DMF (75 ml) for 2 hours. Cooled, diluted with water (300 ml) and extracted with EtOAc (200 ml and 4×75 ml) and the combined organics washed with 3×100 ml of water. Dried (magnesium sulphate), evaporated, triturated with ether and filtered off to give 7.55 g of white solid. MS (ES): C16H15NO3 requires 269; found 270 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:6]([C:7](O)=[O:8])[C:5]([NH2:11])=[CH:4][CH:3]=1.C([O-])([O-])OC.C([O-])(=O)C.[NH4+:21].[CH3:22]O>O>[OH:1][C:2]1[CH:10]=[C:6]2[C:5](=[CH:4][CH:3]=1)[N:11]=[CH:22][NH:21][C:7]2=[O:8]
Reactant: Nc1ccc(O)cc1C(=O)O
Reactant: [NH4+]
Reactant: CO
Agent: CC(=O)[O-]
Agent: COC([O-])[O-]
Solvent: O
Product: O=c1[nH]cnc2ccc(O)cc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 74 %

Procedure:
In a 10-mL volume stainless steel pressure-resistant vessel were placed 1.00 g (6.6 mmol) of 5-hydroxyanthranilic acid, 2.80 g (26.4 mmol) of methyl orthoformate, 2.00 g (26.4 mmol) of ammonium acetate, and 4.0 mL of methanol. The reaction was carried out at 120° C. for 3 hours. After the reaction was complete, the reaction mixture was cooled to room temperature, and 40 mL of water was added to the reaction mixture. The resulting aqueous mixture was stirred for 15 minutes and filtered to give 0.78 g (isolated yield: 74%) of 6-hydroxyquinazolin-4-one as a pale gray crystalline product.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([C:12]2[CH:17]=[C:16]([OH:18])[CH:15]=[C:14]([C:19]#[N:20])[CH:13]=2)[O:9][N:8]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:27][O:28][CH2:29][CH2:30]Cl>CN(C)C=O.ClCCl>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([C:12]2[CH:17]=[C:16]([O:18][CH2:30][CH2:29][O:28][CH3:27])[CH:15]=[C:14]([C:19]#[N:20])[CH:13]=2)[O:9][N:8]=1
Reactant: COCCCl
Reactant: N#Cc1cc(O)cc(-c2nc(-c3ccccn3)no2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COCCOc1cc(C#N)cc(-c2nc(-c3ccccn3)no2)c1
Temperature: 150 °C
Yield: 50 %

Procedure:
A mixture of 3-(2-pyridyl)-5-(3-cyano-5-hydroxyphenyl)-1,2,4-oxadiazole (40 mg, 0.15 mmol), potassium carbonate (42 mg, 0.30 mmol) and 2-chloroethyl methyl ether (83 μL, 0.91 mmol) in N,N-dimethylformamide (1 mL) was heated in a sealed vial at 150° C. for 5 minutes. The reaction was cooled, diluted with dichloromethane, washed with water (3×) and saturated brine, filtered and concentrated. Silica gel chromatography using hexanes:ethyl acetate:dichloromethane 1:1:2 followed by trituration with diethyl ether afforded 24 mg, (50%) of 3-(2-pyridyl)-5-(3-cyano-5-(2-methoxyethoxy)phenyl)-1,2,4-oxadiazole: 1H NMR (CDCl3), δ (ppm): 8.87 (d, 1H), 8.23 (d, 1H), 8.17 (s, 1H), 8.04 (s, 1H), 7.91 (t, 1H), 7.49 (m, 1H), 7.45 (s, 1H), 4.27 (t, 2H), 3.81 (t, 2H), 3.48 (s, 3H).
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[CH3:24]C([O-])(C)C.[K+].[F:30][C:31]1[CH:32]=[C:33]2[C:38](=[C:39]([O:41][Si:42]([CH:49]([CH3:51])[CH3:50])([CH:46]([CH3:48])[CH3:47])[CH:43]([CH3:45])[CH3:44])[CH:40]=1)[N:37]=[C:36](C=O)[CH:35]=[CH:34]2>C1COCC1>[F:30][C:31]1[CH:32]=[C:33]2[C:38](=[C:39]([O:41][Si:42]([CH:43]([CH3:45])[CH3:44])([CH:46]([CH3:47])[CH3:48])[CH:49]([CH3:50])[CH3:51])[CH:40]=1)[N:37]=[C:36]([CH:24]=[CH:4][O:3][CH3:2])[CH:35]=[CH:34]2
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)[O-]
Reactant: CC(C)[Si](Oc1cc(F)cc2ccc(C=O)nc12)(C(C)C)C(C)C
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC=Cc1ccc2cc(F)cc(O[Si](C(C)C)(C(C)C)C(C)C)c2n1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
(Methoxymethyl)triphenylphosphonium chloride (8.355 g, 24.37 mmol) was dissolved in THF (130 mL), cooled to 0° C., and treated dropwise with a solution of 1M KOtBu in THF (26.5 ml, 26.5 mmol). The mixture was warmed and stirred at ambient temperature for 15 minutes. A solution of 6-fluoro-8-(triisopropylsilyloxy)quinoline-2-carbaldehyde (7.70 g, 22.1 mmol) dissolved in THF (15 mL) was added. The reaction was stirred at ambient temperature for 10 hours. The mixture was concentrated in vacuo and applied directly to a column of SiO2 eluting with a stepped gradient from 1-4% Et2O/hexanes, (4.75 g). 1H NMR (400 MHz, CDCl3) δ 7.86 (d, J=8.6 Hz, 1H), 7.74 (d, J=13 Hz, 1H), 7.23 (d, J=8.6 Hz, 1H), 6.93 (dd, J1=2.8 Hz, J2=8.7 Hz, 1H), 6.88 (dd, J1=2.7 Hz, J2=10.2 Hz, 1H), 6.02 (d, J=12.5 Hz, 1H), 3.77 (s, 3H), 1.47-1.38 (m, 3H), 1.15 (d, 18H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[CH2:5][CH:6]1[CH2:11][CH2:10][CH:9](O)[CH2:8][CH2:7]1)[CH3:2].[I:14]I.N1C=CN=C1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[CH2:1]([O:3][C:4](=[O:13])[CH2:5][CH:6]1[CH2:11][CH2:10][CH:9]([I:14])[CH2:8][CH2:7]1)[CH3:2]
Reactant: CCOC(=O)CC1CCC(O)CC1
Reactant: II
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCOC(=O)CC1CCC(I)CC1
Reaction time: 15 h
Yield: 71.1 %

Procedure:
To a mixture of 2-(4-hydroxycyclohexyl)acetic acid ethyl ester (3 g, 16.1 mmol), iodine (6.13 g, 24.2 mmol), imidazole (1.64 g, 24.2 mmol), and triphenylphosphine (6.34 g, 24.2 mmol) was added dichloromethane (100 mL) at room temperature under nitrogen atmosphere. The resulting brown suspension was stirred for 15 h at which time TLC analysis indicated the absence of starting material. Then, the solvent was removed under vacuum and most of the residue was dissolved in ethyl acetate (˜500 mL) and some of the residue was not dissolved which was found to be Ph3PO by 1H NMR. The ethyl acetate solution was washed two times with a solution of water and methanol (3:1) to remove the remaining triphenylphosphineoxide and then washed with brine solution. The organic layer was dried over anhydrous MgSO4, filtered, and concentrated to give the crude residue which was purified using an ISCO (120 g) column chromatography eluting with ethyl acetate in hexanes (0-50%). The desired fractions were combined and the solvent was removed under vacuum to obtain 2-(4-iodocyclohexyl)acetic acid ethyl ester (3.39 g, 71.1% yield) as a viscous light yellow oil. 1H NMR of this product indicated that it contained 30-40% of elimination product (olefin) which was not separable on TLC.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2=[N:15][N:16]([CH2:18][CH3:19])[CH2:17][N:13]2[C:12]2[S:20](=[O:23])[CH2:21][CH2:22][C:11]=2[CH2:10][N:9]=1.[CH3:24][N:25]=[C:26]=[O:27]>C(Cl)(Cl)Cl>[CH3:24][NH:25][C:26]([CH:21]1[S:20](=[O:23])[C:12]2[N:13]3[CH2:17][N:16]([CH2:18][CH3:19])[N:15]=[C:14]3[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])=[N:9][CH2:10][C:11]=2[CH2:22]1)=[O:27]
Reactant: CN=C=O
Reactant: CCN1CN2C(=N1)C(c1ccccc1Cl)=NCC1=C2S(=O)CC1
Solvent: ClC(Cl)Cl
Product: CCN1CN2C(=N1)C(c1ccccc1Cl)=NCC1=C2S(=O)C(C(=O)NC)C1

Procedure:
9 g of 6-o-chlorophenyl-8-ethyl-1,2-dihydro-4H-s-triazolo [3,4-c]-thieno[2,3-e][1,4]diazepin-1-one is dissolved in 50 ml of chloroform, and 5 ml of methyl isocyanate is added, and the resulting mixture is refluxed for 8 hours. Then the chloroform is removed under reduced pressure, and the remaining jelly-like substance is treated with ligroin to give the title compound as white crystals. The product, when recrystallized from a mixture of ethanol and chloroform, shows a melting point of 193°-194° C.
Reaction SMILES: [C:1]1([C:7]2[N:11]([S:12]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[CH:10]=[C:9]([CH:26]=O)[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl-:28].C[NH3+].[C:31]([BH3-])#[N:32].[Na+]>CO>[ClH:28].[CH3:31][NH:32][CH2:26][C:9]1[CH:8]=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:11]([S:12]([C:15]2[CH:16]=[CH:17][C:18]([O:21][C:22]([F:23])([F:25])[F:24])=[CH:19][CH:20]=2)(=[O:14])=[O:13])[CH:10]=1
Reactant: O=Cc1cc(-c2ccccc2)n(S(=O)(=O)c2ccc(OC(F)(F)F)cc2)c1
Reactant: [BH3-]C#N
Reactant: [Cl-]
Agent: C[NH3+]
Agent: [Na+]
Solvent: CO
Product: CNCc1cc(-c2ccccc2)n(S(=O)(=O)c2ccc(OC(F)(F)F)cc2)c1
Product: Cl
Temperature: 25 °C
Reaction time: 24 h
Yield: 69.1 %

Procedure:
To a solution (12 mL) of 5-phenyl-1-{[4-(trifluoromethoxy)phenyl]sulfonyl}-1H-pyrrole-3-carbaldehyde (0.41 g) in methanol were added methylammonium chloride (0.86 g) and sodium cyanoborohydride (0.27 g), and the mixture was stirred at room temperature for 24 hr. The reaction mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogencarbonate solution was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (eluent: hexane-ethyl acetate=2:1→1:1) to give free base of the title compound as an oil (0.32 g). The obtained oil (0.32 g) was dissolved in ethyl acetate (5 mL). A 4 mol/L hydrogen chloride-ethyl acetate solution (4 mL) was added, and the mixture was concentrated under reduced pressure. The residue was crystallized from ethyl acetate to give the title compound as white crystals (yield 0.29 g, 63%).
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li]CCCC.[B:20](OC(C)C)([O:25]C(C)C)[O:21]C(C)C.Cl>C1COCC1>[C:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[B:20]([OH:25])[OH:21])(=[O:8])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: CC(C)(C)NS(=O)(=O)c1ccccc1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)NS(=O)(=O)c1ccccc1B(O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 11.2 mmol of N-t-butylbenzenesulfonamide (from Step C) in anhydrous THF (20 mL) cooled to -40° C. under N2 was addeel 2.5M n-BuLi solution (11.2 mL, 2.5 equiv). The mixture was warmed to room temperature and stirred for 2 hours. To the mixture, containng the dianion at 0° C., was added triisopropyl borate (3.9 mL, 1.5 equiv). The next day, 2 N HCl (3 mL) was added and the mixture was stirred for 1 hour. The solvent was removed under reduced pressure and the residue was extracted with EtOAc. The organic solution was washed with 2N HCl, H2O and brine. The organic phase was dried over anhydrous MgSO4 and concentrated in vacuo to afford the titled compound. The material was used in the next step without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:16]([F:17])=[CH:15][C:12]([CH:13]=O)=[CH:11][C:10]=1[F:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:19]([O:26][C:27]1[C:28]([F:36])=[C:29]([CH:32]=[CH:33][C:34]=1[F:35])[CH:30]=O)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C1(P(C2C=CC=CC=2)(C2C=CC=CC=2)=[C:44]([CH3:50])[C:45]([O:47][CH2:48][CH3:49])=[O:46])C=CC=CC=1>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]1[C:16]([F:17])=[CH:15][C:12](/[CH:13]=[C:44](\[CH3:50])/[C:45]([O:47][CH2:48][CH3:49])=[O:46])=[CH:11][C:10]=1[F:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:19]([O:26][C:27]1[C:28]([F:36])=[C:29](/[CH:30]=[C:44](\[CH3:50])/[C:45]([O:47][CH2:48][CH3:49])=[O:46])[CH:32]=[CH:33][C:34]=1[F:35])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CCOC(=O)C(C)=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1cc(F)c(OCc2ccccc2)c(F)c1
Reactant: O=Cc1ccc(F)c(OCc2ccccc2)c1F
Solvent: Cc1ccccc1
Product: CCOC(=O)/C(C)=C/c1cc(F)c(OCc2ccccc2)c(F)c1
Product: CCOC(=O)/C(C)=C/c1ccc(F)c(OCc2ccccc2)c1F
Temperature: 110 °C
Reaction time: 12 h

Procedure:
Into a 100-mL round-bottom flask, was placed 4-(benzyloxy)-3,5-difluorobenzaldehyde and 3-(benzyloxy)-2,4-difluorobenzaldehyde (4 g, 16.11 mmol, 1.00 equiv, crude), ethyl 2-(triphenylphosphoranylidene)propanoate (8.75 g, 24.14 mmol, 1.50 equiv) and toluene (60 mL). The resulting solution was stirred for 12 h at 110° C. The resulting mixture was then concentrated under vacuum. The resulting residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:8) to yield ethyl (2E)-3-[4-(benzyloxy)-3,5-difluorophenyl]-2-methylprop-2-enoate and ethyl (2E)-3-[3-(benzyloxy)-2,4-difluorophenyl]-2-methylprop-2-enoate as yellow oil.
Reaction SMILES: [C:1]([O:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]=O)=[CH:8][CH:7]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:14][C:15]([CH3:17])=[O:16].[OH-].[Na+]>C(O)(=O)C>[C:1]([O:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]=[CH:14][C:15](=[O:16])[CH3:17])=[CH:8][CH:7]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)=O
Reactant: CC(C)(C)Oc1ccc(C=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: CC(=O)C=Cc1ccc(OC(C)(C)C)cc1
Reaction time: 5 h
Yield: 81 %

Procedure:
89 g (0.5 mole) of p-tert.-butoxy-benzaldehyde are added dropwise, in the course of 15 minutes, to a mixture of 290 g (5 moles) of acetone and 30 ml of 0.5% strength aqueous sodium hydroxide solution at 20°-25° C., whilst stirring. After all has been added, the pH must be not less than 10; if it is not, sodium hydroxide solution must then be added. The reaction is complete after about 5 hours, as is demonstrable by thin layer chromatography or gas chromatography. Acetic acid is then added to the solution until it is neutral, the excess acetone is distilled off under reduced pressure and the reaction product is taken up in ether. The ether solution is washed salt-free with water, the ether is distilled off and the reaction product is fractionated, giving 88 g of main fraction. This corresponds to a yield of 81% of theory.
Reaction SMILES: CS(O[CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:22]=[CH:21][C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)(=O)=O.[N-:23]=[N+:24]=[N-:25].[Na+]>CN(C=O)C.[Cl-].[Na+].O>[N:23]([CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:22]=[CH:21][C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)=[N+:24]=[N-:25]
Reactant: CCOC(=O)c1ccc(N2CCC(OS(C)(=O)=O)CC2)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1ccc(N2CCC(N=[N+]=[N-])CC2)cc1
Temperature: 80 °C
Yield: 86.5 %

Procedure:
To a solution of ethyl 4-(4-(methylsulfonyloxy)piperidin-1-yl)benzoate (10.5 g, 32.1 mmol) in DMF (50 mL) was added sodium azide (4.17 g, 64.2 mmol). The mixture was heated at 80° C. for 5 hours, cooled to room temperature, diluted with brine (300 mL), and extracted with ethyl acetate (400 mL). The organic phase was washed with brine (2×300 mL), dried over anhydrous MgSO4, filtered, and concentrated, to afford ethyl 4-(4-azidopiperidin-1-yl)benzoate as a yellow solid (7.62 g, 87%).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([N+:14]([O-:16])=[O:15])[C:8]([OH:13])=[C:9]([CH:12]=1)[CH:10]=O)([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:18]O.C([O-])=O.[Na+]>C(O)=O.O>[C:1]([C:5]1[CH:6]=[C:7]([N+:14]([O-:16])=[O:15])[C:8]([OH:13])=[C:9]([CH:12]=1)[C:10]#[N:18])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cc(C=O)c(O)c([N+](=O)[O-])c1
Reactant: NO
Agent: Cl
Agent: O=C[O-]
Agent: [Na+]
Solvent: O=CO
Solvent: O
Product: CC(C)(C)c1cc(C#N)c(O)c([N+](=O)[O-])c1
Temperature: 25 °C
Yield: 87.2 %

Procedure:
The above aldehyde (1.4 g, 6.3 mmol), hydroxylamine hydrochloride (0.438 g, 6.3 mmol), and sodium formate (0.771 g, 11.3 mmol) in formic acid (20 mL) were heated overnight, at reflux, then cooled to room temperature. The reaction was diluted with water, and the resulting precipitate was filtered. The solid was taken up in ether, dried over Na2SO4, filtered and concentrated in vacuo to yield 5-tert-butyl-2-hydroxyl-3-nitro-benzonitrile (1.21 g, 87%) as a yellow solid.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:8])=[N:4][CH:5]=[CH:6][CH:7]=1.[H-].[Na+].[Cl:11][CH2:12][CH2:13][CH2:14]I.[Na+].[Cl-]>CN(C)C=O.O>[Cl:11][CH2:12][CH2:13][CH2:14][O:1][C:2]1[C:3]([CH3:8])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ncccc1O
Reactant: ClCCCI
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ncccc1OCCCCl
Temperature: 25 °C
Yield: 95.7 %

Procedure:
Under a nitrogen atmosphere, a solution of 3-hydroxy-2-methylpyridine (2.00 g, 18.3 mmol) in N,N-dimethylformamide (DMF) (10 mL) was added drop-wise over 5 min to a cold (0-5° C.), stirring slurry of sodium hydride (0.576 g of an 80% dispersion in mineral oil, 19.2 mmol) in DMF (40 mL). The mixture was allowed to stir and warm to ambient temperature over 1 h. The slurry was cooled to 0-5° C., and 1-chloro-3-iodopropane (4.49 g, 22.0 mmol) was added drop-wise over 5 min. The resulting dark-brown mixture was stirred at ambient temperature for 2 h. Cold water (25 mL) was added, followed by saturated NaCl solution (25 mL), and the mixture was extracted with ether (4×100 mL). The combined ether extracts were dried (Na2SO4), filtered, and concentrated by rotary evaporation to a residue that was dried briefly under high vacuum to give 3.25 g (96.2%) of an oil.
Reaction SMILES: [C:1]([OH:8])(=O)[CH2:2][CH2:3][C:4]([CH3:6])=[O:5].C(N(CC)CC)C.ClC(OCC(C)C)=O.[CH3:24][NH:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CC(C)=O>[CH2:26]([N:25]([CH3:24])[C:1](=[O:8])[CH2:2][CH2:3][C:4](=[O:5])[CH3:6])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CNCc1ccccc1
Reactant: CC(=O)CCC(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: CC(=O)CCC(=O)N(C)Cc1ccccc1
Yield: 88.6 %

Procedure:
A! Starting from 10 g (0.086 mole) of levulinic acid, 11.8 ml (0.086 mole) of triethylamine, 11.2 ml (0.086 mole) of isobutyl chloroformate and 13.3 ml (0.103 mole) of N-methyl-benzylamine in 200 ml of acetone, and following the procedure of Example 6,B!, there were obtained 16.7 g (yield: 88%) of N-benzyl-N-methyl-4-oxo-pentanamide.
Reaction SMILES: [Cl-:1].Cl.[NH:3]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:4]1[C:5]([O:7][CH2:8][CH3:9])=[O:6].C([O-])([O-])=O.[K+].[K+].CCO[CH2:23][CH3:24]>CN(C=O)C>[Cl:1][C:4]1[CH:5]=[C:23]([CH2:24][N:3]2[CH2:13][CH2:12][CH2:11][CH2:10][CH:4]2[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH:12]=[CH:11][CH:10]=1
Reactant: CCOC(=O)C1CCCCN1
Reactant: [Cl-]
Reactant: CCOCC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1CCCCN1Cc1cccc(Cl)c1
Temperature: 60 °C
Reaction time: 72 h

Procedure:
A mixture of 3thlorobenzyl chloride (11 mmol, 1.4 mL), ethyl pipecolinate hydrochloride (10 mmol, 1.94 g) and K2CO3 (12 mmol, 1.69 g) in DMF (10 mL) was stirred at 60° C. for 3 days. It was then diluted with ether (50 mL) and filtered. The filtrate was concentrated in vacuo to give ethyl N-(3chlorophenylmethyl)pipecolinate as a yellow oil (2.79g): 1H NMR (300 MHz) δ 7.21-7.35 (m, 4 H), 4.20 (q, J=7.1 Hz, 2 H), 3.77 (d, J=13.6 Hz, 1 H), 3.37 (d, J=13.6 Hz, 1 H), 3.14 (dd, J=7.5 Hz, 4.6 Hz, 1 H), 2.92 (dt, J=11.9, 5.4 Hz, 1 H), 2.15 (m, 1 H), 1.34-1590 (m, 6 H), 1.29 (t, J=7.1 Hz, 3 H); 13C NMR δ 173.74 (s), 140.73 (s), 134.06 (s), 129.35 (d), 128.99 (d), 127.14 (d), 64.33 (d), 60.34 (t), 59.98 (t), 50.11 (t), 29.52 (t), 25.25 (t), 22.39 (t), 14.30 (q); MS (FAB) 282 (98, M+H), 208 (100); HRMS (FAB) m/e calcd for (C15H20ClNO2+H) 282.1261, found 282.1248.