Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([C@@H:7]([NH2:10])[CH2:8][OH:9])=[CH:3][CH:2]=1.C(N(CC)CC)C.[O:18]1[CH:22]=[CH:21][CH:20]=[C:19]1[C:23](Cl)=[O:24]>O1CCCC1.CCOCC>[OH:9][CH2:8][C@H:7]([NH:10][C:23]([C:19]1[O:18][CH:22]=[CH:21][CH:20]=1)=[O:24])[C:4]1[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=1
Reactant: O=C(Cl)c1ccco1
Reactant: N[C@@H](CO)c1ccccc1
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: O=C(N[C@@H](CO)c1ccccc1)c1ccco1
Temperature: 0 °C
Reaction time: 1 h
Yield: 101.1 %

Procedure:
A solution of D-(-)-α-phenylglycinol (1.18 g, 8.43 mmole) and triethylamine (3.18 mL, 23 mmole) were dissolved in dry tetrahydrofuran (20 mL), cooled down to 0° C. (ice bath) and treated dropwise with furoyl chloride (0.76 mL or 1.0 g, 7.66 mmole). The reaction mixture was stirred at 0° C. for 1.0 hour, diluted with ether (100 mL) and washed with 5% HCl (20 mL). The aqueous phase was re-extracted with ether (100 mL) and the combined ether extracts were washed with brine (20 mL), dried (anhydrous MgSO4), filtered and evaporated to dryness to give the title compound (1.79 g, quantitative crude yield) as a solid, m.p. 130-131° C.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=[O:8])[C:5]([NH2:11])=[CH:4][CH:3]=1.[C:12](Cl)(Cl)=[O:13]>O1CCOCC1.C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:10]=[C:6]2[C:7]([O:9][C:12](=[O:13])[NH:11][C:5]2=[CH:4][CH:3]=1)=[O:8]
Reactant: O=C(Cl)Cl
Reactant: Cc1ccc(N)c(C(=O)O)c1
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Product: Cc1ccc2[nH]c(=O)oc(=O)c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.7 %

Procedure:
To a mixture of 10.0 g (66.0 mmol) of 5-methylanthranilic acid in 60 mL of 1,4-dioxane was slowly added 100 mL (193 mmol) of a 1.93 molar solution of phosgene in toluene, at room temperature. The mixture was stirred overnight at room temperature, followed by concentration in vacuo to a small volume. The concentrated reaction mixture was filtered through silica and the filter cake was washed with hexane to give 9.81 g (83.7%) of the 5-methylisatoic anhydride as a light yellow solid. MS (Cl mode) m/z 160 (M-18, 100%), 178 (M+H, 71%).
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH:7]1[CH2:15][C:14]2[NH:13][N:12]=[C:11]([CH3:16])[C:10]=2[C:9](=O)[CH2:8]1.[C:18]([NH:21][NH2:22])([NH2:20])=[NH:19].Cl.Cl.O>C(O)C>[ClH:1].[Cl:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH:7]1[CH2:15][C:14]2[NH:13][N:12]=[C:11]([CH3:16])[C:10]=2[C:9](=[N:22][NH:21][C:18]([NH2:20])=[NH:19])[CH2:8]1
Reactant: Cc1n[nH]c2c1C(=O)CC(c1sccc1Cl)C2
Reactant: N=C(N)NN
Agent: Cl
Solvent: O
Solvent: CCO
Product: Cc1n[nH]c2c1C(=NNC(=N)N)CC(c1sccc1Cl)C2
Yield: 148.5 %

Procedure:
A mixture of 6-(3-chloro-2-thienyl)-3-methyl-4,5,6,7-tetrahydroindazol-4-one (1.2 g), aminoguanidine hydrochloride (0.6 g), concentrated hydrochloric acid (1.1 ml), water (1.1 ml) and ethanol (50 ml) was refluxed for 3 hours. Under reduced pressure, the solvent was evaporated, and the residue was washed with ethanol to give 6-(3-chloro-2-thienyl)-4-guanidinoimino-3-methyl-4,5,6,7-tetrahydroindazole hydrochloride (Compound 119) (1.2 g) as colorless crystals.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][C:11]3[C:16]([C:17](=[O:20])[C:18]=2[OH:19])=[C:15]([OH:21])[CH:14]=[C:13]([OH:22])[C:12]=3[CH2:23][CH:24]=[C:25]([CH3:27])[CH3:26])=[CH:5][CH:4]=1.[C:30](=O)([O-])[O-].[Cs+].[Cs+].C(Br)C=C(C)C.Cl>O>[F:29][C:2]([F:1])([F:28])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][C:11]3[C:16]([C:17](=[O:20])[C:18]=2[O:19][CH3:30])=[C:15]([OH:21])[CH:14]=[C:13]([OH:22])[C:12]=3[CH2:23][CH:24]=[C:25]([CH3:26])[CH3:27])=[CH:5][CH:4]=1
Reactant: O=C([O-])[O-]
Reactant: CC(C)=CCc1c(O)cc(O)c2c(=O)c(O)c(-c3ccc(C(F)(F)F)cc3)oc12
Agent: CC(C)=CCBr
Agent: Cl
Agent: [Cs+]
Solvent: O
Product: COc1c(-c2ccc(C(F)(F)F)cc2)oc2c(CC=C(C)C)c(O)cc(O)c2c1=O
Reaction time: 8 h
Yield: 16.5 %

Procedure:
Intermediate 2-(4-trifluorophenyl)-3-methoxy-5,7-dihydroxy-4H-chrom-4-one (500 mg, 1.42 mmol) of compound 1 and cesium carbonate (4.95 g, 15 mmol) were dissolved into 25 mL water, and prenyl bromide (220 mg, 1.5 mmol) was dropped into the solution under icewater bath condition. After that, the solution was kept overnight under room temperature, and pH was adjusted about 6 with 2N hydrochloride. The solution was extracted with ethyl acetate for 2 times. Organic phases were combined, washed with saturated sodium chloride aqueous solution and dried with anhydrous sodium sulfate. After filtration, crude product was eluted with ethyl acetate/petroleum through silica gel column. Yellow target compound (95 mg, yield 16.5%) was obtained.
Reaction SMILES: CC(C)C([O:5][C@@H:6]1[C@@H:10]([CH2:11][O:12]C(=O)C(C)C)[O:9][C@@H:8]([N:18]2[C:22]3[N:23]=[C:24]([NH:29]C=O)[N:25]=[C:26]([O:27]C)[C:21]=3[C:20]([Cl:32])=[C:19]2[Cl:33])[CH2:7]1)=O.CC(O)=O>[OH-].[Na+]>[NH2:29][C:24]1[NH:25][C:26](=[O:27])[C:21]2[C:20]([Cl:32])=[C:19]([Cl:33])[N:18]([C@@H:8]3[O:9][C@H:10]([CH2:11][OH:12])[C@@H:6]([OH:5])[CH2:7]3)[C:22]=2[N:23]=1
Reactant: COc1nc(NC=O)nc2c1c(Cl)c(Cl)n2[C@H]1C[C@H](OC(=O)C(C)C)[C@@H](COC(=O)C(C)C)O1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: Nc1nc2c(c(Cl)c(Cl)n2[C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]1
Yield: 95.5 %

Procedure:
A suspension of compound (49) (200 mg, 0.4 mmol) in 2N aq. NaOH (8 ml) is boiled under reflux for 3 h. After the solution has been neutralized with conc. AcOH, the reaction product is filtered, washed with water and dried. Colorless crystals (128 mg, 96%) are obtained after crystallizing from CH3CN. 1H-NMR ([D6] DMSO): δ=2.22 (m, Ha—C(2′)), 2.92 (m, Hβ—C(2′)), 3.52 (m, H—C(5′)), 3.72 (m, H—C(4′)), 4.33 (m, H—C(3′)), 4.81 (t, 5′-OH), 5.22 (d, 3′-OH), 6.35 (dd, H—C(1′)), 6.46 (br., NH2), 10.75 (s, NH).
Reaction SMILES: [NH2:1][C:2]([CH3:6])([CH3:5])[CH2:3][OH:4].CC(C)([O-])C.[K+].F[C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=1.C(OC(C)C)(=O)C>O1CCCC1.O>[CH3:5][C:2]([NH2:1])([CH3:6])[CH2:3][O:4][C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: CC(C)(N)CO
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)OC(C)C
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(N)COc1ccc([N+](=O)[O-])cc1
Temperature: 20 °C
Reaction time: 2 h
Yield: 118.6 %

Procedure:
A solution of 2-amino-2-methyl-1-propanol (488 g, 5.47 mol) in tetrahydrofuran (1.46 L) was added over 35 mins to a solution of potassium tert-butoxide (634 g, 5.65 mol) in tetrahydrofuran (2.95 L) at 2±3° C. The mixture was maintained at this temperature for a further 55 minutes before 4-fluoronitrobenzene (551 mL, 3.90 mol) was added over 1 hour 25 mins keeping the temperature below 10° C. The mixture was warmed to 20±3° C. and stirred for 2 hours. Water (1.95 L) and Isopropyl acetate (1.95 L) were charged to the mixture which was stirred, settled and separated. The organic phase was washed again with water (1.95 L) before 5M hydrochloric acid (1.95 L) was charged, keeping the temperature below 25° C. Isooctane (1.95 L) was added and the layers separated. 5M hydrochloric acid (322 mL) was added to the aqueous phase which was then reduced to approximately 3.9 L by vacuum distillation, causing spontaneous crystallisation, and stirred at room temperature overnight. Filtration, washing with water (2×488 mL) and drying in vacuo at around 48° C. afforded the title intermediate as a white solid (972.1 g, 72% th).
Reaction SMILES: [Cl-].[Ce+3].[Cl-].[Cl-].[CH:5]1([Mg]Cl)[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.[O:13]=[C:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1.C(O)(=O)C>C1COCC1>[CH:5]1([C:14]2([OH:13])[CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:25])([CH3:24])[CH3:26])=[O:21])[CH2:18][CH2:19]2)[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: Cl[Mg]C1CCCCC1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: [Ce+3]
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC(O)(C2CCCCC2)CC1

Procedure:
Anhydrous cerium(III) chloride (10.0 g) was added to THF (100 ml) with stirring under ice-cooling and a mixture was stirred at ambient temperature overnight and then cooled in an ice bath. A solution of cyclohexyl magnesium chloride (2M solution in diethyl ether) (20.3 ml) was dropwise added to the mixture with stirring on ice bath (keeping the temperature below 6° C.). To the mixture was added dropwise a solution of tert-butyl 4-oxo-1-piperidinecarboxylate (5.38 g) in THF (25 ml) and the mixture was stirred at 0-6° C. for 1 hour. 10% aqueous acetic acid (100 ml) was added to the reaction mixture and extracted twice with ethyl acetate (100 ml). The extracts were collected, washed with saturated aqueous sodium chloride, dried over magnesium sulfate and evaporated in vacuo. The resulting residue was chromatographed on silica gel (400 ml) eluting with a mixture of n-hexane and ethyl acetate (2:1 v/v). The fractions containing the desired compound were collected and evaporated under reduced pressure to give tert-butyl 4-cyclohexyl-4-hydroxy-1-piperidinecarboxylate (7.27 g).
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][C:5]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:6]=1[O:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[N:13]([CH2:17][C:18]([O:20][CH3:21])=[O:19])[N:12]=[CH:11]2.ClC(Cl)(Cl)C[O:30][C:31](=O)[NH:32][C:33]1[N:37]([C:38]2[CH:43]=[CH:42][C:41]([CH3:44])=[CH:40][CH:39]=2)[N:36]=[C:35]([C:45]([CH3:48])([CH3:47])[CH3:46])[CH:34]=1.C(N(C(C)C)CC)(C)C>CC(N(C)C)=O>[C:45]([C:35]1[CH:34]=[C:33]([NH:32][C:31](=[O:30])[NH:3][CH2:4][C:5]2[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:6]=2[O:7][C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[N:13]([CH2:17][C:18]([O:20][CH3:21])=[O:19])[N:12]=[CH:11]3)[N:37]([C:38]2[CH:43]=[CH:42][C:41]([CH3:44])=[CH:40][CH:39]=2)[N:36]=1)([CH3:48])([CH3:47])[CH3:46]
Reactant: COC(=O)Cn1ncc2cc(Oc3ccc(F)cc3CN)ccc21
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)OCC(Cl)(Cl)Cl)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: COC(=O)Cn1ncc2cc(Oc3ccc(F)cc3CNC(=O)Nc3cc(C(C)(C)C)nn3-c3ccc(C)cc3)ccc21
Temperature: 80 °C
Yield: 88.6 %

Procedure:
A solution of methyl 2-(5-(2-(aminomethyl)-4-fluorophenoxy)-1H-indazol-1-yl)acetate dihydrochloride (17.5 g, 43.51 mmol) in dimethylacetamide (0.5M, 88 mL) was treated with 2,2,2-trichloroethyl-3-tert-butyl-1-p-tolyl-1H-pyrazol-5-ylcarbamate (17.96 g, 44.38 mmol), followed by diisopropylethylamine (30.3 mL, 174 mmol) at room temperature. The mixture was heated at 80° C. overnight. The mixture was concentrated in vacuo and the residue distributed between EtOAc and saturated aqueous NH4Cl. The organic layer was separated and washed with brine, filtered through 1PS paper, evaporated in vacuo to a brown foam. The foam was triturated in ether, and the precipitated solids were collected by filtration to provide 22.55 g (89%) of the desired compound. MS (APCI+) m/z 585 (M+1) detected. 1H NMR (400 MHz, DMSO-d6) δ 8.3 (s, 1H), 8.07 (s, 1H), 7.68 (d, 1H, J=8.9 Hz), 6.85-7.37 (m, 8H), 6.24 (s, 1H), 5.4 (s, 2H), 4.28 (d, 2H, J=5.8 Hz), 3.68 (s, 3H), 2.35 (s, 3H), 1.25 (s, 9H).
Reaction SMILES: [CH2:1]([S:4][C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]3[NH:27][N:26]=[N:25][N:24]=3)=[CH:13][CH:12]=2)[C:8]2[C:28]([C:32]([O:34]CC)=[O:33])=[CH:29][CH:30]=[CH:31][C:7]=2[N:6]=1)[CH2:2][CH3:3].[OH-].[Na+]>CO>[CH2:1]([S:4][C:5]1[N:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]3[NH:27][N:26]=[N:25][N:24]=3)=[CH:15][CH:16]=2)[C:8]2[C:28]([C:32]([OH:34])=[O:33])=[CH:29][CH:30]=[CH:31][C:7]=2[N:6]=1)[CH2:2][CH3:3]
Reactant: CCCSc1nc2cccc(C(=O)OCC)c2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCSc1nc2cccc(C(=O)O)c2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Yield: 89 %

Procedure:
A solution of ethyl 2-propylthio-1-[[2′-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylate (0.25 g) in methanol (5 ml) containing 1N-NaOH (1.5 ml) was heated under reflux for 2 hours. After removal of the solvent, the aqueous residue was adjusted to about pH 3-4 with 1N-HCl to give crystals. The crystals were collected by filtration. Recrystallization from ethyl acetate-hexane gave colorless crystals (0.21 g, 91%), m.p. 222-223° C. (decomp.).
Reaction SMILES: [CH2:1]([O:3][P:4]([CH3:6])[OH:5])[CH3:2].C(N(CC)CC)C.C[Si](Cl)(C)C.[F:19][C:20]([F:26])([F:25])/[CH:21]=[CH:22]/[C:23]#[N:24]>O1CCCC1>[C:23]([CH2:22][CH:21]([P:4]([CH3:6])(=[O:5])[O:3][CH2:1][CH3:2])[C:20]([F:26])([F:25])[F:19])#[N:24]
Reactant: CCOP(C)O
Reactant: N#C/C=C/C(F)(F)F
Agent: C[Si](C)(C)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOP(C)(=O)C(CC#N)C(F)(F)F
Temperature: 0 °C
Reaction time: 16 h

Procedure:
A solution of 2.16 g (20 mmol) of O-ethyl-P-methyl-phosphonous acid and 4.05 g (40 mmol) of triethylamine in 100 ml of dry tetrahydrofuran is stirred under an atmosphere of argon at 25°. To this solution are added at 25° 4.35 g (40 mmol) of trimethylsilyl chloride over a period of 10 minutes. A white precipitate is formed. The reaction mixture is stirred at 25° for additional 16 hours. Then, 2.42 g (20 mmol) of 4,4,4-trifluorocrotononitrile, dissolved in 20 ml of dry tetrahydrofuran, are added at 25° over a period of 10 minutes. The reaction mixture is refluxed for 40 hours, cooled to 25°, poured into ice-water and extracted with dichloromethane. The extracts are combined, washed with water, dried over anhydrous sodium sulphate and evaporated under reduced pressure to dryness. The crude product is chromatographed on 200 g of silica gel with trichloromethane as eluent. The product-containing fractions are combined and evaporated to give ethyl P-(3-cyano-1,1,1-trifluoro-prop-2-yl)-P-methyl-phosphinate as an oil.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5](Br)=[C:4]([CH3:9])[CH:3]=1.[CH3:10][O:11][C:12]1[CH:13]=[C:14]([OH:18])[CH:15]=[CH:16][CH:17]=1.CN(C)C(=O)N(C)C.CN1CCCC1=O>O>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([O:18][C:14]2[CH:15]=[CH:16][CH:17]=[C:12]([O:11][CH3:10])[CH:13]=2)=[C:4]([CH3:9])[CH:3]=1
Reactant: COc1cccc(O)c1
Reactant: Cc1ccc(Br)c(C)c1
Solvent: O
Solvent: CN1CCCC1=O
Solvent: CN(C)C(=O)N(C)C
Product: COc1cccc(Oc2ccc(C)cc2C)c1

Procedure:
A mixture of 1,3-dimethyl-4-bromobenzene, 10.5 g. of m-methoxyphenol, 4.65 g. of cuprous oxide, 40 ml. of tetramethylurea, and 75 ml. of N-methylpyrrolidone is stirred at 165° for 96 hours. The resultant mixture is diluted with water and extracted with methylene chloride. The methylene chloride extracts are chromatographed on 300 g. of alumina with gradient elution using hexane:ether to give 1,3-dimethyl-4-(m-methoxyphenyloxy)-benzene.
Reaction SMILES: [NH2:1]CCC1C2C(=CC=CC=2)NC=1.[C:13]1(=O)[O:18][C:16](=[O:17])[C:15]2=[CH:19][CH:20]=[CH:21][CH:22]=[C:14]12.O>C1(C)C=CC=CC=1>[C:13]1(=[O:18])[NH:1][C:16](=[O:17])[C:15]2=[CH:19][CH:20]=[CH:21][CH:22]=[C:14]12
Reactant: O=C1OC(=O)c2ccccc21
Reactant: NCCc1c[nH]c2ccccc12
Solvent: O
Solvent: Cc1ccccc1
Product: O=C1NC(=O)c2ccccc21
Reaction time: 12 h

Procedure:
A solution of 3.20 g (20.0 m mol) of tryptamine and 3.10 g (20.0 m mol) of phthalic anhydride in 40 ml of toluene was refluxed under a Dean-Stark water separator for 12 h. Cooling, filtration and concentration of the filtrate gave a crude phthalimide which was recrystallized from ethanol to produce 4.85 g (84%), of phthalimide, mp 164°-165° C.; reported 164°-165° C.3
Reaction SMILES: CC([O:4][C@@H:5]1[C:19](=[O:20])[C@H:18]2[C@@:8]([CH3:27])([CH2:9][CH2:10][C@@H:11]3[C@:17]2([CH3:21])[CH2:16][C@H:15]([C:22]2[CH:23]=[CH:24][O:25][CH:26]=2)[O:14][C:12]3=[O:13])[C@H:7]([C:28]([O:30][CH3:31])=[O:29])[CH2:6]1)=O.C([O-])(O)=O.[Na+]>C1COCC1.O.CCOC(C)=O>[CH3:27][C@:8]12[C@H:7]([C:28]([O:30][CH3:31])=[O:29])[CH2:6][C@H:5]([OH:4])[C:19](=[O:20])[C@@H:18]1[C@:17]1([CH3:21])[C@H:11]([C:12]([O:14][C@@H:15]([C:22]3[CH:23]=[CH:24][O:25][CH:26]=3)[CH2:16]1)=[O:13])[CH2:10][CH2:9]2
Reactant: COC(=O)[C@@H]1C[C@H](OC(C)=O)C(=O)[C@H]2[C@@]1(C)CC[C@H]1C(=O)O[C@@H](c3ccoc3)C[C@]21C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)[C@@H]1C[C@H](O)C(=O)[C@H]2[C@@]1(C)CC[C@H]1C(=O)O[C@@H](c3ccoc3)C[C@]21C
Temperature: 25 °C
Reaction time: 2 h
Yield: 58 %

Procedure:
12-epi-Salvinorin A (52 mg, 0.12 mmol) was dissolved in THF (3 mL) and H2O (3 mL). To this solution was added NaHCO3 (202 mg, 2.4 mmol), and the reaction was stirred at rt for two hours. The mixture was then diluted with EtOAc, washed with brine, and dried over MgSO4. After evaporation of the solvent, flash chromatography (0% to 5% MeOH in hexanes) gave alcohol 35 as an off-white solid. (27 mg, 58% yield); Rf 0.16 (98:2, CH2Cl2/MeOH); 1H NMR (300 MHz, CDCl3) δ 7.43 (m, 1H), 7.41 (t, J=1.6, 1H), 6.41 (m, 1H), 5.30 (dd, J=6.1, 11.5, 1H), 4.21-3.97 (m, 1H), 3.72 (s, 3H), 2.73 (dd, J=3.1, 13.5, 1H), 2.53-2.41 (m, 3H), 2.34 (dd, J=11.6, 14.6, 1H), 2.18-1.93 (2H), 1.92-1.69 (m, 4H), 1.63 (m, 1H), 1.39 (s, 3H), 1.04 (s, 3H).
Reaction SMILES: [CH3:1][C@H:2]([N:9]1[CH2:12][CH2:11][CH:10]1[C:13]([O:15][CH3:16])=[O:14])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>CCCCCC.C(OCC)(=O)C>[CH3:1][C@H:2]([N:9]1[CH2:12][CH2:11][C@H:10]1[C:13]([O:15][CH3:16])=[O:14])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:1][C@H:2]([N:9]1[CH2:12][CH2:11][C@@H:10]1[C:13]([O:15][CH3:16])=[O:14])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: COC(=O)C1CCN1[C@@H](C)c1ccccc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COC(=O)[C@@H]1CCN1[C@@H](C)c1ccccc1
Product: COC(=O)[C@H]1CCN1[C@@H](C)c1ccccc1

Procedure:
The obtained methyl N-[(S)-methylbenzyl]azetidine-2-(RS)-carboxylate (10 g) was subjected to silica gel column chromatography (eluate: hexane/ethyl acetate=10/1) to give methyl N-[(S)-methylbenzyl]azetidine-2-(S)-carboxylate (4.8 g) and methyl N-[(S)-methylbenzyl]azetidine-2-(R)-carboxylate (4.68 g).
Reaction SMILES: [CH2:1]([C:3]([CH2:8][OH:9])([CH2:6][OH:7])[CH2:4][CH3:5])[OH:2].CO[CH:12](OC)[CH3:13].[CH2:16](N(CC)CC)C>O1CCCC1.[NH4+].[NH4+].[O-][Mo]([O-])(=O)=O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:4]([C:3]1([CH2:8][OH:9])[CH2:6][O:7][C:12]([CH3:13])([CH3:16])[O:2][CH2:1]1)[CH3:5]
Reactant: CCC(CO)(CO)CO
Reactant: CCN(CC)CC
Reactant: COC(C)OC
Agent: O=[Mo](=O)([O-])[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: CCC1(CO)COC(C)(C)OC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 95 %

Procedure:
Trimethylolpropane (10.0 g; 74.6 mmol), 2,2-dimethoxyethane (9.01 g; 86.5 mmol) and p-toluenesulfonic acid monohydrate (0.369 g; 1.94 mmol) were dissolved in tetrahydrofuran (125 mL). The clear solution was stirred at ambient temperature for 24 h. TLC (stained with ammonium molybdate) confirmed near quantitative conversion of the starting triol. The reaction was neutralised with triethylamine (10 mL) and all volatiles were removed in vacuo. Colourless oily residue was passed through a silicagel column (eluent ethyl acetate/cyclohexane 1:1). The eluent was evaporated to provide (5-ethyl-2,2-dimethyl-1,3-dioxan-5-yl)methanol (12.34 g; 95% yield) as a colourless oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:11])([CH3:10])[CH3:9])=[CH:4][CH:3]=1.[N+:12]([O-])([OH:14])=[O:13].S(=O)(=O)(O)O>C(O)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:11])([CH3:10])[CH3:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13]
Reactant: O=[N+]([O-])O
Reactant: CC(C)(C)c1ccc(Br)cc1
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: CC(C)(C)c1ccc(Br)c([N+](=O)[O-])c1

Procedure:
The reaction was done as described in General Method 12 using 1-bromo-4-tert-butyl-benzene (15 g), acetic acid (10 mL), nitric acid (6.5 g), and sulfuric acid (13 g), MS(APCI): 291.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7](Cl)=[O:8])=[CH:4][CH:3]=1.[NH2:10][C:11]1[S:12][C:13]2[C:19]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)=[CH:18][CH:17]=[C:16]([O:26][CH3:27])[C:14]=2[N:15]=1>>[CH3:27][O:26][C:16]1[C:14]2[N:15]=[C:11]([NH:10][C:7]([C:5]3[S:6][C:2]([CH3:1])=[CH:3][CH:4]=3)=[O:8])[S:12][C:13]=2[C:19]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)=[CH:18][CH:17]=1
Reactant: Cc1ccc(C(=O)Cl)s1
Reactant: COc1ccc(N2CCOCC2)c2sc(N)nc12
Product: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccc(C)s3)nc12
Yield: 97 %

Procedure:
Using 5-methyl-thiophene-2-carbonyl chloride and 2-amino-4-methoxy-7-morpholin-4-yl-benzothiazol the title compound was obtained as a yellow solid in 97% yield.
Reaction SMILES: [CH:1]([Mg]Br)=[CH2:2].[C:5]([O:13][C@H:14]1[C@@H:20]2[C@@H:18]([O:19]2)[CH2:17][C@:16]([OH:25])([C:21]([O:23][CH3:24])=[O:22])[CH2:15]1)(=[O:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.B(F)(F)F.CCOCC>C1COCC1.[Cu]I>[C:5]([O:13][C@@H:14]1[CH2:15][C@@:16]([OH:25])([C:21]([O:23][CH3:24])=[O:22])[CH2:17][C@@H:18]([CH:1]=[CH2:2])[C@@H:20]1[OH:19])(=[O:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: C=C[Mg]Br
Reactant: COC(=O)[C@@]1(O)C[C@@H]2O[C@@H]2[C@H](OC(=O)c2ccccc2)C1
Agent: [Cu]I
Agent: FB(F)F
Solvent: C1CCOC1
Solvent: CCOCC
Product: C=C[C@@H]1C[C@](O)(C(=O)OC)C[C@@H](OC(=O)c2ccccc2)[C@H]1O
Reaction time: 1 h

Procedure:
Vinylmagnesium bromide can be added to a −78° C. suspension of CuI in THF. After stirring for 1 hour, a solution of Example 17D and BF3.Et2O in THF can be added. After stirring for 2 hours at −78° C., the reaction mixture can be quenched with saturated NH4Cl. The reaction mixture can be extracted several times with dichloromethane and the combined dichloromethane layers are washed with brine, dried (MgSO4), filtered and concentrated. The concentrate can be purified by flash column chromatography to afford the desired product.
Reaction SMILES: C(N(CC)CC)C.P(C#N)(OCC)(OCC)=O.[O:18]([CH2:25][C:26]([OH:28])=O)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[N+]([O-])(O)=O.[O:33]([CH2:37][CH2:38][NH2:39])[N+:34]([O-:36])=[O:35]>O1CCCC1>[O:33]([CH2:37][CH2:38][NH:39][C:26](=[O:28])[CH2:25][O:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[N+:34]([O-:36])=[O:35]
Reactant: O=C(O)COc1ccccc1
Reactant: NCCO[N+](=O)[O-]
Agent: CCOP(=O)(C#N)OCC
Solvent: CCN(CC)CC
Solvent: O=[N+]([O-])O
Solvent: C1CCOC1
Product: O=C(COc1ccccc1)NCCO[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h
Yield: 31.7 %

Procedure:
1.5 ml of triethylamine and 0.7 ml of diethyl cyanophosphate were added to a suspension of 0.65 g of phenoxyacetic acid and 0.6 g of 2-nitroxyethylamine nitrate in 20 ml of tetrahydrofuran with ice-cooling. The mixture was stirred at room temperature for 2 hours and the solvent was distilled off under reduced pressure. The residue was purified by column chromatography through silica gel (eluent; hexane: ethyl acetate=1:1) and then recrystallized from diisopropyl ether to give 0.27 g of the title compound as colorless needles.