Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH:6]([C:26]2[CH:31]=[CH:30][C:29]([CH2:32]O)=[CH:28][CH:27]=2)[C:7]([NH:9][C:10]2[C:11]([CH3:25])=[C:12]([CH2:16][CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH:13]=[CH:14][CH:15]=2)=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(Br)(Br)(Br)[Br:35].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[Br:35][CH2:32][C:29]1[CH:30]=[CH:31][C:26]([CH:6]([CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[C:7]([NH:9][C:10]2[C:11]([CH3:25])=[C:12]([CH2:16][CH2:17][C:18]([O:20][C:21]([CH3:22])([CH3:24])[CH3:23])=[O:19])[CH:13]=[CH:14][CH:15]=2)=[O:8])=[CH:27][CH:28]=1
Reactant: BrC(Br)(Br)Br
Reactant: Cc1c(CCC(=O)OC(C)(C)C)cccc1NC(=O)C(c1ccc(CO)cc1)C1CCCC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1c(CCC(=O)OC(C)(C)C)cccc1NC(=O)C(c1ccc(CBr)cc1)C1CCCC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
6.0 g (13.29 mmol) of tert-butyl(+/−)-3-[3-({cyclopentyl[4-(hydroxymethyl)phenyl]acetyl}amino)-2-methylphenyl]propanoate were dissolved in 375 ml of dry THF, and 9.25 g (27.9 mmol) of carbon tetrabromide were added. Over a period of 1.5 h, 9.06 g (34.54 mmol) of triphenylphosphine were then added in small portions. The reaction mixture was stirred at RT for 5 h, and the solid was then filtered off and the filtrate was concentrated. The residue was purified by chromatography on silica gel (mobile phase cyclohexane/ethyl acetate 5:1→1:1). This gave 7.22 g (about 100% of theory, purity about 95%) of the title compound.
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][N:16]=2)[CH:11]=[C:10]([C:18]([O:20]CC)=[O:19])[C:9]1=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].O>O1CCOCC1>[CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][N:16]=2)[CH:11]=[C:10]([C:18]([OH:20])=[O:19])[C:9]1=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cc2cccnc2n(Cc2ccccc2)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)c1cc2cccnc2n(Cc2ccccc2)c1=O
Temperature: 50 °C
Reaction time: 3 h
Yield: 96.8 %

Procedure:
1.95 g (6.3 mmol) of ethyl 1-benzyl-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxylate was dissolved in 1,4-dioxane (30 mL), and 1.31 g (9.5 mmol) of potassium carbonate and 60 mL of water were added to this solution at room temperature. The resulting mixture was stirred for 3 hours at 50° C. The solvent of the reaction mixture was distilled off under reduced pressure, and the residue was dissolved in water. Concentrated hydrochloric acid was added to make the solution acidic, and the mixture was extracted with chloroform. The organic phase was dried, filtered, and concentrated, and thus 1.71 g (yield: 97%) of the title compound was obtained as colorless crystals.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[N:7]1[CH:12]=[CH:11][C:10]([NH:13][NH2:14])=[CH:9][CH:8]=1.Cl[CH:16]([CH2:19]Cl)[C:17]#[N:18]>O>[N:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH:19]=[CH:16][C:17]([NH2:18])=[N:14]2)=[CH:9][CH:8]=1
Reactant: NNc1ccncc1
Reactant: N#CC(Cl)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: Nc1ccn(-c2ccncc2)n1
Temperature: 10 °C
Reaction time: 8 h
Yield: 6 %

Procedure:
To a solution of potassium carbonate (4.46 g, 32 mmol) in water (20 ml) was added pyridine-4-yl-hydrazine×2HCl (1.47 g, 8 mmol) and the mixture was cooled to 10° C. 2,3-Dichloropropionitrile (1.0 g, 8 mmol) was added dropwise at that temperature. Subsequently, the mixture was stirred at 45° C. for 3 h and at ambient temperature overnight. The reaction mixture was extracted with dichloromethane, the organic phases were combined, washed with brine, dried and the solvent was evaporated. Silica gel chromatography using a heptane/ethyl acetate gradient yielded the amine as yellow solid (80 mg, 6%).
Reaction SMILES: [CH2:1]([NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=1[F:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].C(N(CC)CC)C.[CH3:24][C:25]([CH3:32])([CH2:29][CH2:30][CH3:31])[C:26](Cl)=[O:27].Cl>C(OCC)C>[F:16][C:10]1[CH:11]=[C:12]([F:15])[CH:13]=[CH:14][C:9]=1[CH2:8][N:7]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[C:26](=[O:27])[C:25]([CH3:32])([CH3:24])[CH2:29][CH2:30][CH3:31]
Reactant: CCCCCCNCc1ccc(F)cc1F
Reactant: CCCC(C)(C)C(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CCCCCCN(Cc1ccc(F)cc1F)C(=O)C(C)(C)CCC
Temperature: 25 °C
Reaction time: 18 h

Procedure:
22.7 g (0.10 mol) of N-hexyl-2,4-difluorobenzylamine and 24.3 g (0.24 mol) of triethylamine are dissolved in 150 ml of diethyl ether. A solution of 17.8 g (0.12 mol) of 2,2-dimethylpentanoyl chloride in 50 ml of diethyl ether is added dropwise at room temperature over the course of 30 minutes. The mixture is stirred for a further 18 hours at room temperature until the reaction is complete (GC check). For work-up, the resultant suspension is adjusted to pH 7 using 70 ml of 2N hydrochloric acid. Everything dissolves, and two phases form, which are separated. The organic phase is washed with 50 ml of water, dried using magnesium sulfate, filtered and evaporated on a vacuum rotary evaporator. 37.8 g of a pale yellow liquid, which is subjected to fractional distillation, are obtained. 21.4 g (63% of theory) of a colourless oil which boils at 126°-127° C. and 0.4 mbar are obtained.
Reaction SMILES: CON(C)[C:4]([C:6]1([CH3:9])[CH2:8][CH2:7]1)=[O:5].[CH2:11]([Mg]Br)[CH:12]=[CH2:13]>O1CCCC1>[CH3:9][C:6]1([C:4](=[O:5])[CH2:13][CH:12]=[CH2:11])[CH2:8][CH2:7]1
Reactant: C=CC[Mg]Br
Reactant: CON(C)C(=O)C1(C)CC1
Solvent: C1CCOC1
Product: C=CCC(=O)C1(C)CC1
Temperature: -60 °C
Reaction time: 1 h

Procedure:
To a solution of N-methoxy-N,1-dimethylcyclopropanecarboxamide (C50) (18 g, 0.126 mol) in tetrahydrofuran (360 mL) was added a solution of allylmagnesium bromide (1.0 M in diethyl ether, 500 mL, 0.5 mol) drop-wise at −60° C. The mixture was stirred at −60° C. for 1 hour, then was quenched with saturated aqueous ammonium chloride solution (50 mL). The reaction was extracted with dichloromethane (2×500 mL), the organic layers were washed with saturated aqueous sodium chloride solution (200 mL), dried, and concentrated in vacuo to give the product as a yellow oil, which was used directly in the next step.
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[O:14][CH2:15][CH:16]([CH3:18])[CH3:17])=[N:5][CH:4]=[C:3]1[C:19]([O:21]CC)=O.[OH-].[NH4+:25]>>[O:1]=[C:2]1[NH:7][C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[O:14][CH2:15][CH:16]([CH3:18])[CH3:17])=[N:5][CH:4]=[C:3]1[C:19]([NH2:25])=[O:21]
Reactant: CCOC(=O)c1cnc(-c2ccccc2OCC(C)C)[nH]c1=O
Reactant: [NH4+]
Agent: [OH-]
Product: CC(C)COc1ccccc1-c1ncc(C(N)=O)c(=O)[nH]1
Yield: 83 %

Procedure:
A mixture of ethyl 1,6-dihydro-6-oxo-2-(2-isobutoxyphenyl)-pyrimidine-5-carboxylate (10.0 g., 0.0316 mole) and ammonium hydroxide (110 ml., d=0.9) was heated in a sealed steel bomb for 4.5 hours. The solution was partially evaporated and the residue acidified with 6N hydrochloric acid. The mixture was filtered and the collected solid recrystallized from N,N-dimethylformamide to give the title compound (7.5 g., 83% yield), m.p. 230°-231°.
Reaction SMILES: [Mg].Br[C:3]1[C:8]2[S:9][CH:10]=[C:11]([CH2:12][CH3:13])[C:7]=2[CH:6]=[CH:5][CH:4]=1.CI.[C:16](=[O:18])=[O:17].Cl>CCOCC>[C:16]([C:3]1[C:8]2[S:9][CH:10]=[C:11]([CH2:12][CH3:13])[C:7]=2[CH:6]=[CH:5][CH:4]=1)([OH:18])=[O:17]
Reactant: O=C=O
Reactant: CCc1csc2c(Br)cccc12
Agent: Cl
Agent: [Mg]
Solvent: CI
Solvent: CCOCC
Product: CCc1csc2c(C(=O)O)cccc12
Temperature: 0 °C
Reaction time: 0.83 h

Procedure:
Magnesium (2.67 g) was stirred in ether (15 ml) at room temperature. A solution of 7-bromo-3-ethylbenzo[b]thiophene (4.40 g) and methyl iodide (7.76 g) in ether (50 ml) were added dropwise over 30 min. Then, refluxing was conducted for 50 min and the reaction mixture was cooled in ice water bath. Using a separate reaction vessel, pulverized dry ice was stirred in ether, and the Grignard reagent prepared above was transferred to the vessel for about 5 min. To the reaction mixture was added 2N hydrochloric acid to acidify the solution, and the ether layer was separated. The solution was made alkaline with a 5% aqueous sodium hydroxide solution. The separated aqueous layer was acidified with 2N hydrochloric acid. After extraction with ether, the extract was dried over sodium sulfate and concentrated to give the objective compound (3.22 g) as crystals.
Reaction SMILES: [C:1]1([N:7]2[C:15]3[N:14]=[CH:13][NH:12][C:11]=3[C:10](=[O:16])[N:9]([CH2:17][P:18](=[O:21])([CH3:20])[CH3:19])[C:8]2=[O:22])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[CH2:24][CH:25]1[CH2:27][CH2:26]1.C(=O)([O-])[O-].[K+].[K+]>>[CH:25]1([CH2:24][N:12]2[C:11]3[C:10](=[O:16])[N:9]([CH2:17][P:18](=[O:21])([CH3:20])[CH3:19])[C:8](=[O:22])[N:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[C:15]=3[N:14]=[CH:13]2)[CH2:27][CH2:26]1
Reactant: ClCC1CC1
Reactant: CP(C)(=O)Cn1c(=O)c2[nH]cnc2n(-c2ccccc2)c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CP(C)(=O)Cn1c(=O)c2c(ncn2CC2CC2)n(-c2ccccc2)c1=O

Procedure:
3.9 g (0.0123 mol) of [1-(3-phenylxanthin-1-yl)methyl]dimethylphosphine oxide (Example 70) were stirred at 70° C. for 6 hours with 1.33 g (0.0147 mol) of chloromethylcyclopropane and 2 g of potassium carbonate. The solution was filtered and concentrated, and the residue which remained was chromatographed on silica gel (eluent: ethyl acetate/methanol 10:1).
Reaction SMILES: [C:1]1([N:7]2[C:19]3[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][C:14]=3[C:13]3[C:8]2=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C:30]1[C:31]([C:36]2[CH:41]=[CH:40][C:39]([C:42]3[N:46]([C:47]4[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=4)[C:45]4[CH:53]=[CH:54][CH:55]=[CH:56][C:44]=4[N:43]=3)=[CH:38][CH:37]=2)=[CH:32][CH:33]=[CH:34][CH:35]=1.C([O-])([O-])=O.[Na+].[Na+].O>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O1CCOCC1>[C:1]1([N:7]2[C:19]3[CH:18]=[CH:17][C:16]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[C:30]4[C:31]([C:36]5[CH:41]=[CH:40][C:39]([C:42]6[N:46]([C:47]7[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=7)[C:45]7[CH:53]=[CH:54][CH:55]=[CH:56][C:44]=7[N:43]=6)=[CH:38][CH:37]=5)=[CH:32][CH:33]=[CH:34][CH:35]=4)=[CH:15][C:14]=3[C:13]3[C:8]2=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OB(O)c1ccc2c(c1)c1ccccc1n2-c1ccccc1
Reactant: Brc1ccccc1-c1ccccc1-c1ccc(-c2nc3ccccc3n2-c2ccccc2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: c1ccc(-n2c(-c3ccc(-c4ccccc4-c4ccccc4-c4ccc5c(c4)c4ccccc4n5-c4ccccc4)cc3)nc3ccccc32)cc1

Procedure:
Following the procedure for Host-1, (9-phenyl-9H-carbazol-3-yl)boronic acid (0.458 g, 1.60 mmol), Compound 3 (0.800 g, 1.60 mmol), tetrakis(triphenylphosphine)palladium(0) (73.7 mg, 63.8 μmol), Na2CO3 (0.530 g, 5.00 mmol), H2O (5 mL) and 1,4-dioxane (25 mL) provided Host-2 (0.78 g, 74%) as an off-white solid after flash chromatography (SiO2, 17:3-hexanes: acetone) and recrystallization from methanol (CH3OH): confirmed by LCMS (APCI): calculated for C49H33N3 (M+): 664; Found: 664.
Reaction SMILES: [C:1]([C@H:5]1[CH2:10][CH2:9][C@H:8]([C:11]([OH:13])=O)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[CH3:14][Li]>C(OCC)C>[C:1]([C@H:5]1[CH2:6][CH2:7][C@H:8]([C:11](=[O:13])[CH3:14])[CH2:9][CH2:10]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: [Li]C
Reactant: CC(C)(C)[C@H]1CC[C@H](C(=O)O)CC1
Solvent: CCOCC
Product: CC(=O)[C@H]1CC[C@H](C(C)(C)C)CC1

Procedure:
To trans-4-tert-butyl-cyclohexanecarboxylic acid (921 mg, 5.0 mmol) in ethyl ether (35 mL) was added methyl lithium (1.6 M in ethyl ether, 7.1 mL, 11.4 mmol) to produce 1-(trans-4-tert-butyl-cyclohexyl)-ethanone (769 mg, 4.22 mmol, 84%) following a method analogous to General Procedure A1. Workup involved treatment of the reaction mixture with water (50 mL), and the organic portion was washed with aq NaHCO3 and then brine, and dried over sodium sulfate. Solvent evaporation under reduced pressure gave the crude methyl ketone (769 mg). This crude ketone product was converted into the corresponding 2-bromoketone (525 mg, 2.01 mmol) following a method analogous to General Procedure B2 using bromine (0.228 mL, 4.43 mmol) and MeOH (about 10 mL).
Reaction SMILES: O=C1CCC(=O)N1O[C:9]([NH:11][C:12]1[CH:28]=[CH:27][C:15]([O:16][CH2:17][CH2:18][NH:19]C(=O)OC(C)(C)C)=[C:14]([C:29]2[N:33]([CH3:34])[N:32]=[CH:31][CH:30]=2)[CH:13]=1)=[O:10].CN(C)C=O.[CH2:40]1[C:49]2[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=2)[CH2:43][CH2:42][NH:41]1.Cl.CCOCC>Cl>[NH2:19][CH2:18][CH2:17][O:16][C:15]1[CH:27]=[CH:28][C:12]([NH:11][C:9]([N:41]2[CH2:42][CH2:43][C:44]3[C:49](=[CH:48][CH:47]=[CH:46][CH:45]=3)[CH2:40]2)=[O:10])=[CH:13][C:14]=1[C:29]1[N:33]([CH3:34])[N:32]=[CH:31][CH:30]=1
Reactant: Cn1nccc1-c1cc(NC(=O)ON2C(=O)CCC2=O)ccc1OCCNC(=O)OC(C)(C)C
Reactant: c1ccc2c(c1)CCNC2
Agent: Cl
Solvent: CCOCC
Solvent: CN(C)C=O
Product: Cn1nccc1-c1cc(NC(=O)N2CCc3ccccc3C2)ccc1OCCN
Temperature: 25 °C
Reaction time: 18 h
Yield: 42.9 %

Procedure:
A 2 mL aliquot of tert-butyl {2-[4-({[(2,5-dioxopyrrolidin-1-yl)oxy]carbonyl}amino)-2-(1-methyl-1H-pyrazol-5-yl)phenoxy]ethyl}carbamate in dimethylformamide (60.0 μmol) was added to 1,2,3,4-tetrahydroisoquinoline (9.59 mg, 1.2 eq) and stirred at room temperature for 18 hr. To this was added 2.0M hydrochloric acid in ether (150 μL, 5 eq) and the reaction was stirred at room temperature for 60 hr. Some of the deprotections were incomplete so 2-3 drops of concentrated hydrochloric acid was added to these and they were stirred for another 24 hr. The ether and hydrochloric acid were evaporated under a stream of nitrogen and it was purified by HPLC. The proper fractions were collected and lyophilized to afford the title compound as a white solid in 42.9% yield. LCMS m/z (%)=392 (M+H, 100). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.85 (t, J=5-81 Hz, 2 H), 3.09-3.17 (m, 2 H), 3.69 (t, J=5.6 Hz, 2 H), 3.69 (s, 3 H), 4.12 (t, J=5.56 Hz, 2 H), 4.63 (s, 2 H), 6.32 (d, J=2.02 Hz, 1 H), 7.13 (d, J=9.09 Hz, 1 H), 7.19 (s, 3H), 7.43 (d, J=2.53 Hz, 1 H), 7.47 (d, J=1.52 Hz, 1 H), 7.57 (dd, J=9.09, 3.03 Hz, 1 H), 7.87 (s, 2 H), 8.60 (s, 1 H).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:13][CH3:14])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1.[CH2:15]([N:18]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:19](Cl)=[O:20])[CH:16]=[CH2:17].C(N(CC)CC)C>C1(C)C(C)=CC=CC=1>[CH2:15]([N:18]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:19](=[O:20])[O:12][C:9]1[CH:10]=[CH:11][C:6]([O:5][CH2:4][CH:3]([O:2][CH3:1])[O:13][CH3:14])=[CH:7][CH:8]=1)[CH:16]=[CH2:17]
Reactant: COC(COc1ccc(O)cc1)OC
Reactant: C=CCN(Cc1ccccc1)C(=O)Cl
Solvent: Cc1ccccc1C
Solvent: CCN(CC)CC
Product: C=CCN(Cc1ccccc1)C(=O)Oc1ccc(OCC(OC)OC)cc1
Temperature: 25 °C

Procedure:
4-(2,2-Dimethoxyethoxy)phenol (0.05 mole), N-allyl-N-benzylcarbamoyl chloride (0.08 mole), triethylamine (0.05 mole) and xylene (50 ml) are charged into a glass reaction flask equipped with a mechanical stirrer, thermometer and reflux condenser. The mixture is stirred and heated at reflux for a period of about 12 hours. After this time the reaction mixture is cooled to room temperature and is filtered. The filtrate is then washed with water and dried over anhydrous magnesium sulfate. The dried solution is then filtered and stripped of solvent and unreacted starting materials to yield the desired product O-[4-(2,2-dimethoxyethoxy)phenyl] N-allyl-N-benzylcarbamate as the residue.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:25])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[O:16][N:15]=[C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[O:23][CH3:24])[CH:13]=1>CO>[CH3:24][O:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[C:14]1[CH:13]=[C:12]([CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][C:5]([OH:25])=[O:4])[O:16][N:15]=1
Reactant: COC(=O)CCCCCCc1cc(-c2ccccc2OC)no1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccccc1-c1cc(CCCCCCC(=O)O)on1
Reaction time: 3 h
Yield: 99.3 %

Procedure:
Add 2 N sodium hydroxide (15 mL) to a solution of 7-[3-(2-methoxyphenyl)isoxazol-5-yl]heptanoic acid methyl ester (2.89 g, 8 mmol) in methanol (50 mL) at room temperature under nitrogen and stir for 3 hours. Remove the solvent under reduced pressure, dilute the residue with water (100 mL), and wash with methyl tert-butyl ether (100 mL). Acidify the mixture to pH 1 with 1 N HCl and extract with ethyl acetate (3×100 mL). Wash the combined organic extracts with water (100 mL) and brine (100), dry over sodium sulfate, and remove the solvent under reduced pressure to provide 7-[3-(2-methoxyphenyl)isoxazol-5-yl]heptanoic acid (2.41 g, 98%): APCI mass spectrum m/z 302 [C17H211NO4−H]−.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:35]=[CH:34][C:20]4[CH2:21][CH2:22][N:23]([CH2:26][CH2:27][CH2:28][C:29]([O:31]CC)=[O:30])[CH2:24][CH2:25][C:19]=4[CH:18]=3)[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].[OH-].[Na+].C(O)(=O)C>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:35]=[CH:34][C:20]4[CH2:21][CH2:22][N:23]([CH2:26][CH2:27][CH2:28][C:29]([OH:31])=[O:30])[CH2:24][CH2:25][C:19]=4[CH:18]=3)[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:10])[CH3:11]
Reactant: CCOC(=O)CCCN1CCc2ccc(-c3noc(-c4ccc(OC(C)C)c(Cl)c4)n3)cc2CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CC(=O)O
Product: CC(C)Oc1ccc(-c2nc(-c3ccc4c(c3)CCN(CCCC(=O)O)CC4)no2)cc1Cl
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 30.3 %

Procedure:
A solution of ethyl 4-[7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1,2,4,5-tetrahydro-3H-3-benzazepin-3-yl]butanoate (Preparation 50) (100 mg, 0.201 mmol) in ethanol (6 ml) was stirred at room temp and sodium hydroxide (1.5 ml, 3.00 mmol) added. The reaction mixture was stirred at room temperature for 90 mins and was then acidified with acetic acid to pH 5, and the mixture concentrated in vacuo. The resultant residue was dissolved in EtOAc (˜30 ml) and water (˜30 ml) and the layers partitioned, the aqueous was re-extracted with EtOAc (˜20 ml) and the combined organics were passed through a phase separation cartridge and the solvent reduced in vacuo. The residue was purified by trituration with methanol, the solid filtered and dried on the sinter to yield the title compound (30 mg, 0.061 mmol, 30% yield). δH (d6DMSO, 400 MHz): 8.19 (1H, s), 8.11 (1H, d), 7.79-7.90 (2H, m), 7.44 (1H, d), 7.34 (1H, d), 4.89 (1H, sept), 3.46-3.24 (2H, hidden under H2O peak), 3.01-2.93 (4H, m), 2.68-2.59 (4H, m), 2.28 (2H, t), 1.70 (2H, quintet) 1.37 (6H, d). MS (ES): C25H2835ClN3O4 requires 469; found 470 [M+H]+.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9](Cl)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:12]1[CH2:17][CH2:16][CH2:15][CH:14]([CH2:18][OH:19])[CH2:13]1.C(N(CC)CC)C>ClCCl>[OH:19][CH2:18][CH:14]1[CH2:15][CH2:16][CH2:17][N:12]([C:9](=[O:10])[CH2:8][CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:13]1
Reactant: OCC1CCCNC1
Reactant: O=C(Cl)CCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CCc1ccccc1)N1CCCC(CO)C1
Temperature: 0 °C
Reaction time: 22 h

Procedure:
A solution of 3-phenylpropionyl chloride (29.7 ml) in dichloromethane (100 ml) was added dropwise to a stirred solution of 3-piperidinemethanol (23 g) and triethylamine (22.2 g) in dichloromethane (200 ml) at 0° C. over 1.25 hours, maintaining the temperature at 0° C. The mixture was stirred at 0°-5° C. for 22 hours. After washing (saturated sodium bicarbonate solution), the organic layer was separated off, dried and evaporated to give 3-hydroxymethyl-1-(3-phenylpropionyl)piperidine as an oil.
Reaction SMILES: [CH3:1][C:2]1[C@@H](O)C[C@]2(O)C(C)(C)C=1[C@@H](O)C([C@@]1(C)[C@H]([C@@H]2OC(C2C=CC=CC=2)=O)[C@]2(OC(C)=O)CO[C@@H]2C[C@@H]1O)=O.[CH3:40]/[CH:41]=[C:42](/[C:44]([NH:46][C@H:47]([C@@H:54]([OH:99])[C:55]([O:57][C@@H:58]1[C:79]([CH3:80])=[C:78]2[C:81]([CH3:83])([CH3:82])[C@:60]([OH:98])([C@@H:61]([O:89][C:90]([C:92]3[CH:93]=[CH:94][CH:95]=[CH:96][CH:97]=3)=[O:91])[C@@H:62]3[C@:67]4([O:70][C:71]([CH3:73])=[O:72])[CH2:68][O:69][C@@H:66]4[CH2:65][C@H:64]([OH:74])[C@@:63]3([CH3:88])[C:75]([C@@H:77]2[O:84][C:85]([CH3:87])=[O:86])=[O:76])[CH2:59]1)=[O:56])[C:48]1[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=1)=[O:45])\[CH3:43]>>[CH3:80][C:79]1[C@@H:58]([O:57][C:55]([C@H:54]([OH:99])[C@@H:47]([NH:46][C:44]([C:42]2[CH:43]=[CH:1][CH:2]=[CH:40][CH:41]=2)=[O:45])[C:48]2[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=2)=[O:56])[CH2:59][C@:60]2([OH:98])[C:81]([CH3:82])([CH3:83])[C:78]=1[C@@H:77]([O:84][C:85]([CH3:87])=[O:86])[C:75]([C@@:63]1([CH3:88])[C@H:62]([C@@H:61]2[O:89][C:90]([C:92]2[CH:93]=[CH:94][CH:95]=[CH:96][CH:97]=2)=[O:91])[C@:67]2([O:70][C:71]([CH3:73])=[O:72])[CH2:68][O:69][C@@H:66]2[CH2:65][C@@H:64]1[OH:74])=[O:76]
Reactant: C/C=C(\C)C(=O)N[C@@H](c1ccccc1)[C@@H](O)C(=O)O[C@H]1C[C@@]2(O)[C@@H](OC(=O)c3ccccc3)[C@@H]3[C@]4(OC(C)=O)CO[C@@H]4C[C@H](O)[C@@]3(C)C(=O)[C@H](OC(C)=O)C(=C1C)C2(C)C
Reactant: CC(=O)O[C@@]12CO[C@@H]1C[C@H](O)[C@@]1(C)C(=O)[C@H](O)C3=C(C)[C@@H](O)C[C@@](O)([C@@H](OC(=O)c4ccccc4)[C@H]21)C3(C)C
Product: CC(=O)O[C@H]1C(=O)[C@@]2(C)[C@H]([C@H](OC(=O)c3ccccc3)[C@]3(O)C[C@H](OC(=O)[C@H](O)[C@@H](NC(=O)c4ccccc4)c4ccccc4)C(C)=C1C3(C)C)[C@]1(OC(C)=O)CO[C@@H]1C[C@@H]2O
Yield: 0.01 %

Procedure:
The solid was chromatographed as described under Example 1 except that RPLC C8 silica (100 g) was used in methanol/water 20%. A pressure of 50 psi was used to obtain an adequate rate. One hundred fifty fractions of 10 ml were collected, while a gradient of 25, 35, 45, 55 and 65% methanol in water was being used. The fractions were monitored as before and fractions containing 10-deacetylbaccatin III (fractions 25-35), brevitaxane A (fractions 60-90), cephalomannine (fractions 120-125) and taxol (fractions 135-150) were combined separately, concentrated to dryness and recrystallized from chloroform/hexane (1:1) to give the pure compounds. 10-deacetylbaccatin III, brevitaxane A, 2.0 g (0.2% yield, based on plant material), cephalomannine, 0.03 g (0.003% yield, based on plant material) and taxol 0.1 g (0.01% yield, based on plant material).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([NH2:28])[C:5]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]3[CH:19]=[N:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=3)=[C:12]([O:26][CH3:27])[CH:11]=2)=[N:6][CH:7]=1.[CH:29](OCC)(OCC)OCC>C(O)C.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[I:1][C:2]1[CH:3]=[C:4]2[N:28]=[CH:29][N:8]([CH2:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]4[CH:19]=[N:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=4)=[C:12]([O:26][CH3:27])[CH:11]=3)[C:5]2=[N:6][CH:7]=1
Reactant: CCOC(OCC)OCC
Reactant: COc1ccc(COc2ccc(CNc3ncc(I)cc3N)cc2OC)cn1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCO
Product: COc1ccc(COc2ccc(Cn3cnc4cc(I)cnc43)cc2OC)cn1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 86.9 %

Procedure:
To a stirred suspension of 5-iodo-N2-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)pyridine-2,3-diamine (11.67 g, 23.70 mmol) in ethanol (175 mL) was added triethyl orthoformate (8.90 g, 60.05 mmol) and p-toluenesulfonic acid monohydrate (0.23 g, 1.19 mmol). As the mixture was warmed to reflux, the solids dissolved to provide a brown solution. After 30 min, the reaction mixture was cooled to 0° C., resulting in the formation of a precipitate. The solids were isolated by filtration, washed with a small amount of cold ethanol, and dried to provide 10.34 g (87%) of 6-iodo-3-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-3H-imidazo[4,5-b]pyridine as an off-white solid.