Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH:5]1[OH:10])([CH3:3])[CH3:2].[CH2:11]1[O:15][CH:12]1[CH2:13][CH3:14].[C:16]([CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH:21]1[OH:26])([CH3:19])([CH3:18])C.C1OC1C>>[CH:1]([CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH:5]1[OH:10])([CH3:3])[CH3:2].[CH:16]([CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH:21]1[O:26][CH2:11][CH:12]([OH:15])[CH2:13][CH3:14])([CH3:18])[CH3:19]
Reactant: CC(C)(C)C1CCCCC1O
Reactant: CCC1CO1
Agent: CC(C)C1CCCCC1O
Agent: CC1CO1
Product: CCC(O)COC1CCCCC1C(C)C

Procedure:
The synthesis was carried out in the same manner as described in Example 1, except that 20.0 g (0.141 mol) of 2-isopropylcyclohexanol (cis:trans=6:4) and 10.1 g (0.141 mol) of 1,2-butyleneoxide were used instead of 30.0 g (0.192 mol) of 2-tert-butylcyclohexanol (cis:trans=8:2) and 11.1 g (0.192 mol) of propyleneoxide. 6.5 g of 2-isopropylcyclohexanol and 16.6 g of 1-(2-isopropylcyclohexyloxy)-2-butanol (cis:trans=6:4) were obtained in a 55% yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:23]=[CH:24][C:25]=1[O:26][CH3:27])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:21][CH3:22])=[C:14]([O:19][CH3:20])[C:15]=2[O:17][CH3:18])[CH2:10][CH2:9][NH:8]1.Br[CH2:29][C:30](Br)=[O:31].[CH3:33][O:34][C:35]1[CH:42]=[CH:41][CH:40]=[CH:39][C:36]=1[CH2:37][NH2:38]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:23]=[CH:24][C:25]=1[O:26][CH3:27])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:21][CH3:22])=[C:14]([O:19][CH3:20])[C:15]=2[O:17][CH3:18])[CH2:10][CH2:9][N:8]1[CH2:29][C:30]([NH:38][CH2:37][C:36]1[CH:39]=[CH:40][CH:41]=[CH:42][C:35]=1[O:34][CH3:33])=[O:31]
Reactant: O=C(Br)CBr
Reactant: COc1ccc(CC2NCCc3cc(OC)c(OC)c(OC)c32)cc1OC
Reactant: COc1ccccc1CN
Product: COc1ccccc1CNC(=O)CN1CCc2cc(OC)c(OC)c(OC)c2C1Cc1ccc(OC)c(OC)c1

Procedure:
prepared by reaction of 1-(3,4-Dimethoxy-benzyl)-6,7,8-trimethoxy-1,2,3,4-tetrahydroisoquinoline and 2-bromoacetyl bromide with 2-methoxy-benzyl-amine
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH2:7]O)=[N:5][CH:4]=[N:3]1.S(Cl)([Cl:11])=O>>[ClH:11].[Cl:11][CH2:7][C:6]1[N:2]([CH3:1])[N:3]=[CH:4][N:5]=1
Reactant: Cn1ncnc1CO
Reactant: O=S(Cl)Cl
Product: Cl
Product: Cn1ncnc1CCl
Temperature: 80 °C
Reaction time: 2 h

Procedure:
Thionyl chloride (20 mL) was added to (1-methyl-1H-1,2,4-triazol-5-yl)methanol (2.0 g) at 0° C. The reaction mixture was stirred for 2 h at 80° C. The mixture was cooled to room temperature and then was concentrated under reduced pressure. Ethyl acetate was added to the resulting precipitate and the mixture was filtered under a nitrogen atmosphere to afford 5-(chloromethyl)-1-methyl-1H-1,2,4-triazole hydrochloride (1.5 g). The material was used for the next step without further purification. MS (EI+) (M+) 131.0
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.N1C=CC=CC=1.Cl[Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23]>C(Cl)Cl.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Oc1ccc(-c2ccc(Br)cc2)cc1
Solvent: O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)[Si](C)(C)Oc1ccc(-c2ccc(Br)cc2)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 61.2 %

Procedure:
To a 0° C. solution of 4-(4-bromophenyl)phenol (1.0 g, 4.0 mmol) and pyridine (0.65 mL, 8 mmol) in CH2Cl2 (20 mL) was added chloro-tert-butyldimethylsilane (0.72 g, 4.8 mmol). The resulting mixture was allowed to warm to room temperature and stirred for 3 days, then diluted with water and extracted with CH2Cl2. The organic layer was washed with a 2N HCl solution, a 1N KOH solution, dried (MgSO4) and concentrated under reduced pressure to yield 1-(4-bromophenyl)-4-tert-butyldimethylsilyloxybenzene (0.89 g, 61%) as a white solid: TLC (33% EtOAc/hex) Rf 0.57.
Reaction SMILES: [C:1](#[N:5])[CH2:2][C:3]#[N:4].[CH2:6]1[CH2:16][CH2:15]N2C(=NCCC2)[CH2:8][CH2:7]1.BrCCCCCBr>CN(C=O)C>[C:2]1([C:1]#[N:5])([C:3]#[N:4])[CH2:15][CH2:16][CH2:6][CH2:7][CH2:8]1
Reactant: N#CCC#N
Reactant: C1CCC2=NCCCN2CC1
Agent: BrCCCCCBr
Solvent: CN(C)C=O
Product: N#CC1(C#N)CCCCC1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
Malononitril (15.0 g) was dissolved in dry DMF (200 mL). Subsequently, DBU (75 mL) and 1,5-dibromopentane (34 mL) were added at 0° C. (ice bath). The ice bath was removed and the reaction was stirred for 2 h at 80° C. After cooling down, the reaction was poured into DCM. The organic layer was washed several times with 5% NaHCO3, the organic layer dried over Na2SO4 and the solvent evaporated under reduced pressure. The crude product was purified by flash chromatography eluting with PA:EtOAc (9:1) yielding 25.7 g white crystals. 1H NMR (400 MHz, CDCl3) δ 1.48-1.61 (m, 2H), 1.68-1.84 (m, 4H), 2.13 (t, J=6 Hz, 4H).
Reaction SMILES: C([O:3][C:4](=[O:35])[CH2:5][CH:6]1[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([O:17][C:18]3[CH:23]=[CH:22][N:21]=[C:20]([NH:24][CH2:25][CH2:26][NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[N:19]=3)[CH:14]=[C:15]([CH3:16])[C:7]1=2)C.[OH-].[Li+]>C1COCC1.O>[C:31]([O:30][C:28]([NH:27][CH2:26][CH2:25][NH:24][C:20]1[N:19]=[C:18]([O:17][C:13]2[CH:14]=[C:15]([CH3:16])[C:7]3[CH:6]([CH2:5][C:4]([OH:35])=[O:3])[O:10][B:9]([OH:11])[C:8]=3[CH:12]=2)[CH:23]=[CH:22][N:21]=1)=[O:29])([CH3:34])([CH3:33])[CH3:32]
Reactant: CCOC(=O)CC1OB(O)c2cc(Oc3ccnc(NCCNC(=O)OC(C)(C)C)n3)cc(C)c21
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(Oc2ccnc(NCCNC(=O)OC(C)(C)C)n2)cc2c1C(CC(=O)O)OB2O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of {6-[2-(2-tert-butoxycarbonylamino-ethylamino)-pyrimidin-4-yloxy]-1-hydroxy-4-methyl-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl}-acetic acid ethyl ester (0.35 g, 0.72 mmol) in THF (5 mL) was treated with lithium hydroxide (0.084 g, 3.60 mmol) in water (5 mL) at 0° C. The mixture was stirred at 0° C. for 1 hour then at room temperature for 1 hour. The mixture was quenched with 2N HCl to pH 2 then concentrated to approximately half of the entire volume. The mixture was diluted with brine and extracted with ethyl acetate. The organic extracts were dried (Na2SO4), filtered and concentrated to give {6-[2-(2-tert-butoxycarbonylamino-ethylamino)-pyrimidin-4-yloxy]-1-hydroxy-4-methyl-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl}-acetic acid, as a light yellow solid (0.18 g) after lyophilization. The aqueous layer was lyophilized, diluted with water (3 mL) and extracted with ethyl acetate. The organic extracts were dried (Na2SO4), filtered and concentrated to a light yellow solid after lyophilization, to give a total of 0.21 g (64%) of product. 1H NMR (400 MHz, CD3OD) δ8.13 (d, J=6.64 Hz, 1H), 7.25 (s, 1H), 7.12 (s, 1H), 6.46 (m, 1H), 5.67 (dd, J=8.21, 2.40 Hz, 1H), 3.17 (dd, J=15.63, 3.13 Hz, 1H), 3.20-3.00 (m, 3H), 2.38 (br s, 4H), 1.40 (br s, 10H).
Reaction SMILES: FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.[CH3:16][NH:17][C:18](=O)[C:19](=[N:26][O:27][CH2:28][C:29]1[N:34]=[C:33]([NH:35][C:36](=[O:42])[O:37][C:38]([CH3:41])(C)C)[CH:32]=[CH:31][CH:30]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.N1[CH:49]=[CH:48]C=CC=1.[N-:50]=[N+:51]=[N-:52].[Na+]>C(#N)C>[CH2:38]([O:37][C:36](=[O:42])[NH:35][C:33]1[CH:32]=[CH:31][CH:30]=[C:29]([CH2:28][O:27][N:26]=[C:19]([C:18]2[N:17]([CH3:16])[N:52]=[N:51][N:50]=2)[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:34]=1)[CH2:41][C:48]#[CH:49]
Reactant: [N-]=[N+]=[N-]
Reactant: c1ccncc1
Reactant: CNC(=O)C(=NOCc1cccc(NC(=O)OC(C)(C)C)n1)c1ccccc1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: [Na+]
Solvent: CC#N
Product: C#CCCOC(=O)Nc1cccc(CON=C(c2ccccc2)c2nnnn2C)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
At −10° C., trifluoromethanesulphonic anhydride (42 μl, 1.5 eq.) was added to a solution of 63 mg (0.16 mmol) of tert-butyl{6-[({[2-(methylamino)-2-oxo-1-phenylethylidene]amino}oxy)methyl]pyridin-2-yl}carbamate (36:64 mixture of Z and E diastereoisomers) and pyridine (53 μl, 4 eq.) in acetonitrile (1.6 ml). After warming to room temperature, the mixture was stirred for a further 1 h at 50° C. and then cooled again to room temperature. Then, 32 mg of sodium azide were added and the mixture was stirred again at 50° C. for one hour. The mixture was cooled to room temperature and a sample was analyzed using LCMS. The sample comprises 87% of the expected tert-butyl {6-[({[(1-methyl-1H-tetrazol-5-yl)(phenyl)methylene]amino}oxy)methyl]pyridin-2-yl}carbamate (36:64 mixture of Z and E diastereoisomers).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([C:9]2[CH:13]=[C:12]([CH2:14]O)[O:11][N:10]=2)[CH:6]=[CH:7][CH:8]=1.C(O)C#C.S(Cl)([Cl:24])=O>>[Cl:24][CH2:14][C:12]1[O:11][N:10]=[C:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:17])([F:16])[F:1])[CH:4]=2)[CH:13]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1cc(-c2cccc(C(F)(F)F)c2)no1
Agent: C#CCO
Product: FC(F)(F)c1cccc(-c2cc(CCl)on2)c1

Procedure:
To 17.6 g (0.0724 ml) of 3-(m-trifluoromethylphenyl-5-isoxazole methanol (prepared as described in Example 1 except that propargyl alcohol was used instead of propargyl bromide) was added 50 ml of thionyl chloride dropwise under nitrogen. After complete addition of thionyl chloride, the reaction mixture was heated on a steam bath for 30 minutes, thereafter excess thionyl chloride was removed under reduced pressure. The residue was triturated with hexane and an oil precipitate resulted. After partial removal of hexane in a rotary evaporator under reduced pressure, the oil precipitate crystallized and was filtered to give a tan solid, mp 33°-36° C. The tan solid (6 g) was recrystallized from hexane to give 3.0 g of brown solid, mp 33°-37° C. which was Kugelrohr distilled (1 mm, 140° C.) to give 2.9 g of solid, mp, 36°-38° C. Combined filtrates were concentrated and the residue (14.8 g) was Kugelrohr distilled (1 mm, 140° C.) to give 13.6 g of yellow oil which crystallized upon standing, mp 29°-36.5° C.; total yield 16.5 g (87%).
Reaction SMILES: [CH:1]([C:4]1[CH:22]=[CH:21][CH:20]=[C:19]([CH:23]([CH3:25])[CH3:24])[C:5]=1[O:6][C:7]([O:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12](O)=[O:13])=[O:8])([CH3:3])[CH3:2].Cl.C([O:31][C:32](=[O:36])[CH2:33][CH2:34][NH2:35])(C)(C)C.C(N(C(C)C)CC)(C)C>CN(C=O)C.C(OCC)(=O)C>[CH:1]([C:4]1[CH:22]=[CH:21][CH:20]=[C:19]([CH:23]([CH3:25])[CH3:24])[C:5]=1[O:6][C:7]([O:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12]([NH:35][CH2:34][CH2:33][C:32]([OH:31])=[O:36])=[O:13])=[O:8])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)CCN
Reactant: CC(C)c1cccc(C(C)C)c1OC(=O)Oc1ccccc1C(=O)O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)c1cccc(C(C)C)c1OC(=O)Oc1ccccc1C(=O)NCCC(=O)O
Temperature: 25 °C
Reaction time: 14 h
Yield: 8 %

Procedure:
To a solution of crude compound (106) (0.4 g, 1.1 mmol) from above and beta-alanine tert-butyl ester hydrochloride (0.2 g, 1.1 mmol) in DMF (5 mL) was added diisopropylethylamine (0.41 mL, 2.3 mmol) followed by O-(benotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.44 g, 1.1 mmol). The resulting reaction mixture was stirred at room temperature for 14 h, diluted with ethyl acetate (50 mL), washed with 10% aqueous citric acid solution (30 mL), followed by saturated aqueous NaHCO3 solution (30 mL) and brine (2×20 mL). The organic phase was dried over MgSO4 and concentrated in vacuo. The crude residue was then dissolved in anhydrous dichloromethane (5 mL) and cooled to 0° C. before a solution of hydrochloric acid (1 mL, 4 N in dioxane) was added. The reaction was stirred for 2 h at 0° C. and the solvent was removed in vacuo. The crude residue was purified by preparative LC/MS to afford 50 mg (8% yield over three steps) of the title compound (103). 1H NMR (400 MHz, CDCl3): δ 7.85 (dd, J=7.6, 1.6 Hz, 1H), 7.51–7.48 (m, 1H), 7.34–7.13 (m, 5H), 3.72 (q, J=6.0 Hz, 2H), 3.13–3.10 (m, 2H), 2.67 (t, J=6.4 Hz, 2H), 1.25 (d, J=6.8 Hz, 121). MS (ESI) m/z 414.3 (M+H+).
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][NH2:10])=[CH:5][CH:4]=1.C(O[CH:14]=[C:15]([C:21]#[N:22])[C:16]([O:18][CH2:19][CH3:20])=[O:17])C.C(=O)([O-])[O-].[K+].[K+].O>C(O)C>[CH2:19]([O:18][C:16]([C:15]1[CH:14]=[N:10][N:9]([C:6]2[CH:7]=[CH:8][C:3]([F:2])=[CH:4][CH:5]=2)[C:21]=1[NH2:22])=[O:17])[CH3:20]
Reactant: NNc1ccc(F)cc1
Reactant: CCOC=C(C#N)C(=O)OCC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1cnn(-c2ccc(F)cc2)c1N
Yield: 74 %

Procedure:
A stirred mixture of 11.38 g (70.0 mmole) of a commercially available sample of 4-fluorophenylhydrazine hydrochloride, 11.84 g (70.0 mmole) of ethyl (ethoxymethylene)cyanoacetate and 9.67 g (70.0 mmole) of potassium carbonate in 100 ml of ethanol was refluxed overnight and then treated with 300 ml of water. The precipitate was filtered and dried in vacuo to furnish 12.87 g (74% yield) of pale yellow crystalline solid. The sample was recrystallized from ethanol m.p. 151-2° C.
Reaction SMILES: [C:1]([CH:6]1[NH:9][C:8](=[O:10])[CH:7]1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([O:3][CH2:4][CH3:5])=[O:2].C(N(CC)CC)C.[F:24][C:25]([F:29])([F:28])[S:26]Cl>C(Cl)Cl.CCOCC>[C:1]([CH:6]1[N:9]([S:26][C:25]([F:29])([F:28])[F:24])[C:8](=[O:10])[CH:7]1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([O:3][CH2:4][CH3:5])=[O:2]
Reactant: CCOC(=O)C1NC(=O)C1c1ccccc1
Reactant: FC(F)(F)SCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CCOC(=O)C1C(c2ccccc2)C(=O)N1SC(F)(F)F

Procedure:
To a mixture of 1.2 g of 4-carboethoxy-3-phenylazetidin-2-one and 1.2 ml of triethylamine in 25 ml of methylene chloride at 0° was added dropwise over 10 minutes 11.25 ml of a 10% solution of trifluoromethanesulfenyl chloride in ether. After stirring for several hours the solution was washed with water, dried over sodium sulfate, filtered and evaporated. The crude residue was chromatographed to yield pure 4-carboethoxy-3-phenyl-1-trifluoromethanesulfenylazetidin-2-one as an oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[NH2:10])[C:5]#[N:6].[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][CH:21]([O:24][C:25]2[CH:35]=[CH:34][C:28]([O:29][CH2:30][C:31](O)=[O:32])=[CH:27][CH:26]=2)[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12]>O1CCCC1>[C:11]([O:15][C:16]([N:18]1[CH2:19][CH2:20][CH:21]([O:24][C:25]2[CH:35]=[CH:34][C:28]([O:29][CH2:30][C:31](=[O:32])[NH:1][C:2]3[CH:3]=[C:4]([C:5]#[N:6])[CH:7]=[CH:8][C:9]=3[NH2:10])=[CH:27][CH:26]=2)[CH2:22][CH2:23]1)=[O:17])([CH3:14])([CH3:13])[CH3:12]
Reactant: N#Cc1ccc(N)c(N)c1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(OCC(=O)O)cc2)CC1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(OCC(=O)Nc3cc(C#N)ccc3N)cc2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 93.4 %

Procedure:
To a solution of 3,4-diaminobenzonitrile (474 mg), 4-(1-tert-butoxycarbonylpiperidin-4-yloxy)phenoxyacetic acid (1.25 g) in tetrahydrofuran (50 ml) was added 1-ethoxycarbonyl-2-ethoxy-1,2-dihydroxyquinoline (1.06 g) with ice-cooling, and the mixture was stirred at room temperature for 16 hours. After completion of the reaction, the solvent was evaporated and to the obtained residue were added chloroform and hexane. The resultant solid was collected by filtration and dried under reduced pressure to give the title compound (1.55 g).
Reaction SMILES: [C:1]1([C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)(O)[CH2:8][CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)(C)C.S(=O)(=O)(O)O.C(CC(C)(C)C)(C)C>O>[C:1]1([C:7]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[CH:8][CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCC(O)(c1ccccc1)c1ccccc1
Agent: O=S(=O)(O)O
Solvent: CC(C)CC(C)(C)C
Solvent: O
Solvent: CC(C)O
Product: CC=C(c1ccccc1)c1ccccc1
Yield: 49.4 %

Procedure:
A mixture of 1,1-diphenyl-1-propanol (64 g, 0.30 mol), isopropanol (300 ml) and a 5 N solution of sulphuric acid (150 ml) was heated at reflux temperature for 18 h. The reaction mixture was cooled, diluted with water (600 ml) and extracted with toluene (3×150 ml). The combined organic phases was dried over sodium sulphate and the solvent was evaporated in vacuo to give a solid residue which was trituated with iso-octane. The solid was collected by filtration to give 28.8 g (49%) of 1,1-diphenyl-1-propene.
Reaction SMILES: [C:1]1([OH:13])[CH:12]=[C:6]([CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH:5]=[C:3]([OH:4])[CH:2]=1.C(N)(C)(C)C.[CH3:19][C:20](=[CH:22][CH2:23][CH2:24][C:25](=[CH:27][CH:28]=O)[CH3:26])[CH3:21]>C1(C)C=CC=CC=1>[CH3:11][CH2:10][CH2:9][CH2:8][CH2:7][C:6]1[CH:5]=[C:3]([OH:4])[C:2]2[CH:28]=[CH:27][C:25]([CH2:24][CH2:23][CH:22]=[C:20]([CH3:21])[CH3:19])([CH3:26])[O:13][C:1]=2[CH:12]=1
Reactant: CC(C)=CCCC(C)=CC=O
Reactant: CCCCCc1cc(O)cc(O)c1
Solvent: CC(C)(C)N
Solvent: Cc1ccccc1
Product: CCCCCc1cc(O)c2c(c1)OC(C)(CCC=C(C)C)C=C2
Temperature: 25 °C

Procedure:
To a three-necked round bottomed flask (100 ml capacity), fitted with a dropping funnel and a condenser was added 5 g. olivetol (27.8 mmole) and 2.03 g. (2.96 ml., 27.8 mmole) t-butyl amine in 55 ml toluene and the mixture was heated to 50°-60° C., 4.23 g. (4.76 ml., 27.8 mmole) of citral was then added dropwise. The mixture was refluxed for 9 hours, after which time it was cooled to room temperature and the solvent evaporated to give 9.3 g. of crude reaction mixture. Gas chromatographic analysis of the reaction mixture showed 59.46% CBC (molar conversion), 5.04% cannabicitran and trace amount of iso-CBC.
Reaction SMILES: [F:1][C:2]([C:5]([C:7](F)(F)F)=[O:6])([F:4])[F:3].FC(F)(F)[C:13]([O:15][C:16](=[O:21])[C:17](F)(F)F)=O.N1C=[CH:28][CH:27]=[CH:26][CH:25]=1.O>C(Cl)Cl>[CH3:13][O:15][C:16](=[O:21])[CH2:17][CH2:25][CH2:26][CH2:27][CH2:28][CH2:7][C:5](=[O:6])[C:2]([F:4])([F:3])[F:1]
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reactant: O=C(C(F)(F)F)C(F)(F)F
Reactant: c1ccncc1
Solvent: O
Solvent: ClCCl
Product: COC(=O)CCCCCCC(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 49 %

Procedure:
To a solution of suberic acid monomethyl ester (1.00 g, 5.31 mmol) in THF (15 mL) was added oxalyl chloride (2 mL) followed by DMF (1 drop). The solution was stirred for 2 h, then concentrated under reduced pressure. Volatiles were removed under high vacuum overnight, leaving a yellow oil (1.08 g, 5.22 mmol, 98%). This crude acid chloride was then transformed into the trifluoromethyl ketone by a literature method as follows. (65) To a solution of the acid chloride (1.08 g, 5.22 mmol) in CH2Cl2 (45 mL) at 0° C. were added trifluoroacetic anhydride (4.64 mL, 32.81 mmol) and pyridine (3.54 mL, 43.74 mmol). The mixture was allowed to warm to ambient temperature and stirred for 2 h. After returning to 0° C., ice-cold H2O (20 mL) was added carefully. Additional H2O (100 mL) was added and the layers separated. The aqueous phase was extracted with CH2Cl2 (2×30 mL) and the organic layers combined, washed with brine, dried over MgSO4, and filtered. Evaporation under reduced pressure left a brown oil, which was purified by flash chromatography (2–4% MeOH/CH2Cl2) to give 71 as a clear oil (641 mg, 2.67 mmol, 49%). TLC Rf 0.24 (2% MeOH/CH2Cl2); 1H-NMR (400 MHz, CDCl3) δ 3.67 (s, 3H), 2.71 (t, 2H), 2.31 (t, 2H), 1.65 (m, 4H), 1.35 (m, 4H).
Reaction SMILES: [CH3:1][Si:2]([CH3:6])([CH2:4][Cl:5])Cl.[CH3:7][Si:8]([CH3:11])([CH3:10])Cl.[OH2:12]>>[CH3:7][Si:8]([CH3:11])([CH3:10])[O:12][Si:2]([CH3:6])([CH3:1])[CH2:4][Cl:5]
Reactant: O
Reactant: C[Si](C)(Cl)CCl
Reactant: C[Si](C)(C)Cl
Product: C[Si](C)(C)O[Si](C)(C)CCl

Procedure:
134 ml. dimethylchloromethylchlorosilane (1 mole) and 127 ml. (1 mole) of trimethylchlorosilane are mixed and shaken thoroughly. When 600 ml. of distilled water is added, exothermic hydrolytic reactions occur immediately. The mixture is shaken on a mechanical shaker overnight to complete hydrolysis. The upper oily layer is separated and is dried over anhydrous sodium carbonate. After drying, the product is distilled through a column of 13 theoretical plates and the fraction which distills at 151°-152° C. is collected. The yield of pentamethylchloromethyldisiloxane (B.P. 151.8° C., d25 =0.910, nD20 =1.4106) is 30%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:4]=1[NH2:5].[H-].[Na+].Cl[C:17]1[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][C:18]=1[N+:27]([O-:29])=[O:28].O>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:9]=[CH:8][C:7]([C:10]([F:11])([F:12])[F:13])=[CH:6][C:4]=1[NH:5][C:17]1[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:24])[F:25])=[CH:19][C:18]=1[N+:27]([O-:29])=[O:28]
Reactant: COc1ccc(C(F)(F)F)cc1N
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(C(F)(F)F)cc1Nc1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 60 h

Procedure:
To an ice cooled solution of 2-Methoxy-5-trifluoromethylaniline (311 mmol, 59.4 g) in 500 ml dry dimethylformamide is added sodiumhydride (438 mmol, 17.5 g 60%) followed by slow addition of 2-chloro-5-trifluoromethyl-nitrobenzene (311 mmol, 47.4 ml) and the mixture is stirred for 60 hours. More sodiumhydride (10 g 60%) is added and after stirring for additional two hours is another portion of 2-chloro-5-trifluoromethyl-nitrobenzene (5 ml) and sodiumhydride (2 g 60%) added. Upon completion is the reaction mixture poured into water and a black precipitate is formed. The crude product is filtered of and is washed with 1M HCl and petroleum ether yielding the title compound as grey crystals, M.p. 86°-88° C.
Reaction SMILES: [CH:1]1([CH2:7][C:8]2([OH:25])[CH2:13][CH2:12][N:11]([C:14]3[CH:24]=[CH:23][C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:16][CH:15]=3)[CH2:10][CH2:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[CH3:28]N(C)P(N(C)C)(N(C)C)=O.CI>C1COCC1.OS([O-])(=O)=O.[Na+]>[CH:1]1([CH2:7][C:8]2([O:25][CH3:28])[CH2:13][CH2:12][N:11]([C:14]3[CH:24]=[CH:23][C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:16][CH:15]=3)[CH2:10][CH2:9]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CN(C)P(=O)(N(C)C)N(C)C
Reactant: CCOC(=O)c1ccc(N2CCC(O)(CC3CCCCC3)CC2)cc1
Agent: O=S(=O)([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(N2CCC(CC3CCCCC3)(OC)CC2)cc1
Temperature: 50 °C

Procedure:
A solution of EXAMPLE 1F (380 mg) in THF (5 mL) was treated with NaH (96 mg, 60% dispersion in mineral oil), heated to 50° C. for 2 hours, and treated with hexamethylphosphoramide (1 mL) followed by MeI (1 mL). The reaction mixture was refluxed overnight, cooled to 0° C., and diluted with saturated aqueous NaHSO4 solution (10 mL). The resulting two-phase mixture was separated, the aqueous phase was extracted twice with ether, and the combined organic layers washed with water and brine. After drying over MgSO4, the mixture was concentrated in vacuo and purified by silica gel chromatography eluting with 15% ethyl acetate in hexanes.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]=[O:9])=[N:6][CH:7]=1.[CH2:10]([Mg]Br)[CH3:11].C(OCC)C>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([OH:9])[CH2:10][CH3:11])=[N:6][CH:7]=1
Reactant: O=Cc1ccc(Br)cn1
Reactant: CC[Mg]Br
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCC(O)c1ccc(Br)cn1
Temperature: 25 °C
Reaction time: 6 h
Yield: 45 %

Procedure:
To a solution of 5-bromopicolinaldehyde (2.0 g, 10.8 mmol) in THF (20 mL) was added 3.0 M solution of ethyl magnesium bromide in diethyl ether (7.1 ml, 21.5 mmol) at 0° C. The reaction mixture was allowed to warm to room temperature and was stirred for 6 h. The reaction mixture was quenched with saturated ammonium chloride solution (20 mL) and water (15 mL), extracted with ethyl acetate (200 mL), dried over sodium sulphate and concentrated under reduced pressure to obtain crude product. The crude product was purified by a Biotage Isolera® One column (using 10% ethyl acetate and hexane (0.72 g, (45% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.57 (d, 1H), 8.01-7.98 (dd, 1H), 7.445 (d, 1H), 5.36 (d, 1H), 4.49-4.45 (dd, 1H), 1.65-1.61 (m, 2H), 0.815 (t, 3H).