Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.C1(C)C=CC=CC=1.[C:18]([C:20]1[CH:25]=[C:24]([CH3:26])[CH:23]=[CH:22][N:21]=1)#N.Cl.[OH2:28]>ClCCl>[CH3:26][C:24]1[CH:23]=[CH:22][N:21]=[C:20]([CH:18]=[O:28])[CH:25]=1
Reactant: O
Reactant: Cc1ccnc(C#N)c1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: Cc1ccnc(C=O)c1
Reaction time: 2 h
Yield: 37 %

Procedure:
Diisobutyl aluminium hydride in toluene (1.5 M, 43.5 ml, 65 mmol) was added dropwise to a solution of 2-cyano-4-methylpyridine (7.0 g, 59 mmol) in dichloromethane (180 ml) at −78° C., and the mixture was stirred at the same temperature for 2 hrs. The reaction mixture was combined with concentrated hydrochloric acid (28 ml) and water (112 ml), and the water layer and the organic layer were separated. The organic layer was extracted with 2 N hydrochloric acid. The water layer was combined, neutralized with sodium hydrogen carbonate and extracted with diethyl ether. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated to give the titled compound (2.7 g, 37%).
Reaction SMILES: [Na+].[C:2]([C:5]1[N:6]=[C:7]([N:10]2[CH2:13][CH:12]([S:14][C:15]3[C@H:16]([CH3:29])[C@@H:17]4[C@@H:24]([C@H:25]([OH:27])[CH3:26])[C:23](=[O:28])[N:18]4[C:19]=3[C:20]([O-:22])=[O:21])[CH2:11]2)[S:8][CH:9]=1)(=[O:4])[NH2:3].[CH2:30](I)[CH3:31].C(OCC)(=O)C.C(OCC)C>CN(C)C=O.C(Cl)Cl.CCCCCC>[C:2]([C:5]1[N:6]=[C:7]([N:10]2[CH2:13][CH:12]([S:14][C:15]3[C@H:16]([CH3:29])[C@@H:17]4[C@@H:24]([C@H:25]([OH:27])[CH3:26])[C:23](=[O:28])[N:18]4[C:19]=3[C:20]([O:22][CH2:30][CH3:31])=[O:21])[CH2:11]2)[S:8][CH:9]=1)(=[O:4])[NH2:3]
Reactant: CCI
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(SC3CN(c4nc(C(N)=O)cs4)C3)[C@H](C)[C@H]12
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: CCOC(=O)C1=C(SC2CN(c3nc(C(N)=O)cs3)C2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Temperature: 25 °C
Reaction time: 1 h
Yield: 106.9 %

Procedure:
To a solution of (1R,5S,6S)-2-[1-(4-carbamoyl-1,3-thiazol-2-yl)azetidin-3-yl]thio-6-[(R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylic acid sodium salt (357 mg, 0.80 mmol) (obtained as described in Example 3) in dimethylformamide (5 ml) was added ethyl iodide (357 mg, 2.40 mmol) at 0° C. under an atmosphere of nitrogen and the mixture was stirred for 1 hour. The mixture was further stirred for 2 hours while gradually raising the temperature to room temperature. At the end of this time, to the reaction mixture was added ethyl acetate and the organic layer was washed sequentially with 10% aqueous sodium chloride solution, 10% aqueous sodium thiosulfate solution saturated aqueous sodium hydrogencarbonate solution, and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using ethyl acetate—20% acetonitrile; ethyl acetate—40% acetonitrile; ethyl acetate—60% acetonitrile and ethyl acetate to give a purified product, which was dissolved in methylene chloride and diethyl ether and hexane were sequentially added to the solution to afford ethyl (1R,5S,6S)-2-[1-(4-carbamoyl-1,3-thiazol-2-yl)azetidin-3-yl]thio-6-[(R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylate (387 mg, yield 95%) as a colorless powder.
Reaction SMILES: [C:1]([C:3]1[C:12](B2OC(C)(C)C(C)(C)O2)=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5]([OH:22])[C:4]=1[CH3:23])#[N:2].Cl[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]2[CH:36]=[CH:35][CH:34]=[N:33]2)=[CH:28][CH:27]=1.O.O.O.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].ClCCl>[C:1]([C:3]1[C:12]([CH2:25][C:26]2[CH:27]=[CH:28][C:29]([N:32]3[CH:36]=[CH:35][CH:34]=[N:33]3)=[CH:30][CH:31]=2)=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5]([OH:22])[C:4]=1[CH3:23])#[N:2]
Reactant: COC(=O)c1cc(B2OC(C)(C)C(C)(C)O2)c(C#N)c(C)c1O
Reactant: ClCc1ccc(-n2cccn2)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Solvent: ClCCl
Product: COC(=O)c1cc(Cc2ccc(-n3cccn3)cc2)c(C#N)c(C)c1O
Temperature: 90 °C
Reaction time: 16 h
Yield: 22.5 %

Procedure:
To a solution of methyl 4-cyano-2-hydroxy-3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (3.50 g) in 1,4-dioxane (30.0 mL) were added 1-(4-(chloromethyl)phenyl)-1H-pyrazole (2.12 g), tripotassium phosphate trihydrate (5.90 g) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane adduct (0.34 g), and the mixture was stirred at 90° C. for 16 hr under nitrogen atmosphere. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by flash silica gel column chromatography (ethyl acetate/petroleum ether) to give the title compound (0.86 g).
Reaction SMILES: [OH:1][CH:2]([CH:4]([CH:10]([NH:23]CC1C=CC=CC=1)[CH:11]([CH3:22])[C:12]([O:14][CH2:15][C:16]1C=CC=CC=1)=[O:13])[C:5]([O:7]CC)=[O:6])[CH3:3]>CO.[OH-].[Pd+2].[OH-].[C]>[OH:1][CH:2]([CH:4]([CH:10]([NH2:23])[CH:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH3:22])[C:5]([OH:7])=[O:6])[CH3:3]
Reactant: CCOC(=O)C(C(C)O)C(NCc1ccccc1)C(C)C(=O)OCc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CCOC(=O)C(C)C(N)C(C(=O)O)C(C)O
Temperature: 25 °C

Procedure:
Ethyl benzyl (2SR,3RS,4RS)-2-[1(SR)-hydroxyethyl]-3-benzylamino-4-methylpentanedioate (509 mg) was dissolved in methanol (5 ml), and palladium hydroxide-carbon (102 mg) was added thereto, followed by shaking at room temperature under hydrogen atmosphere (3 to 4 kg/cm2). After consumption of the designed amount of hydrogen, the catalyst was removed by filtration. The filtrate was concentrated under reduced pressure to give (2SR,3RS,4RS)-2-[1(SR)-hydroxyethyl]-3-amino-4-ethoxycarbonylpentanoic acid.
Reaction SMILES: [O:1]=[C:2]1[C:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:11][CH:10]=2)=[C:6]([CH2:23][CH2:24][CH3:25])[N:5]2[N:26]=[CH:27][N:28]=[C:4]2[N:3]1[CH:29]1[CH2:34][CH2:33][C:32](=O)[CH2:31][CH2:30]1.[NH:36]1[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1.C([BH3-])#N.[Na+].O>C(O)(=O)C>[N:36]1([CH:32]2[CH2:31][CH2:30][CH:29]([N:3]3[C:2](=[O:1])[C:7]([CH2:8][C:9]4[CH:10]=[CH:11][C:12]([C:15]5[C:16]([C:21]#[N:22])=[CH:17][CH:18]=[CH:19][CH:20]=5)=[CH:13][CH:14]=4)=[C:6]([CH2:23][CH2:24][CH3:25])[N:5]4[N:26]=[CH:27][N:28]=[C:4]34)[CH2:34][CH2:33]2)[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCC(=O)CC2)c2ncnn12
Reactant: C1COCCN1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCC(N3CCOCC3)CC2)c2ncnn12
Temperature: 25 °C
Reaction time: 16 h
Yield: 35 %

Procedure:
To a solution (5 mL) of 4′-{[5-oxo-4-(4-oxocyclohexyl)-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (0.5 g) and morpholine (0.14 mL) in acetic acid was added sodium cyanoborohydride (0.34 g), and the mixture was stirred at room temperature for 16 hr. Water was added to the reaction mixture, and the solvent was evaporated under reduced pressure. The obtained residue was poured into saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The obtained extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.2 g, 35%).
Reaction SMILES: C(OC([NH:8][CH:9]([CH2:15][C:16]1[C:17]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[N:18][O:19][C:20]=1[C:21]([O:23]CC)=[O:22])[C:10]([O:12]CC)=[O:11])=O)(C)(C)C.Cl>[OH-].[Na+]>[NH2:8][CH:9]([CH2:15][C:16]1[C:17]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[N:18][O:19][C:20]=1[C:21]([OH:23])=[O:22])[C:10]([OH:12])=[O:11]
Reactant: CCOC(=O)c1onc(OCc2ccccc2)c1CC(NC(=O)OC(C)(C)C)C(=O)OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: NC(Cc1c(OCc2ccccc2)noc1C(=O)O)C(=O)O
Temperature: 5 °C
Yield: 23.3 %

Procedure:
A mixture of ethyl (RS)-2-[(tert-butoxycarbonyl)amino]-3-[3-benzyloxy-5-(ethoxycarbonyl)isoxazol-4-yl]propionate (0.65 mg, 1.4 mmol) and 1 M NaOH (50 mL) was boiled under reflux for 16 h. The mixture was cooled (5° C.), acidified with dilute aqueous HCl, and concentrated in vacuo. The residue was recrystallized from water to give (RS)-2-amino-3-(3-benzyloxy-5-carboxyisoxazol-4-yl)propionic acid (0.1 g, 23%): mp 209-211° C. (dec); 1H NMR (DMSO-d6) δ2.95 (dd, 1 H), 3.05 (dd, 1 H), 3.99 (t, 1 H), 5.26 (s, 2 H), 7.31-7.52 (m, 5 H); MS ((M+H)+) m/z 307. Anal. calcd, C, 54.89; H, 4.62; N, 9.15; found, C, 54.31; H, 4.56; N, 8.97.
Reaction SMILES: C[O:2][CH:3]=[C:4]1[CH2:13][CH2:12][CH2:11][C:10]2[C:9]([C:14]#[N:15])=[CH:8][CH:7]=[CH:6][C:5]1=2.B(Br)(Br)Br>C(Cl)Cl>[CH:3]([CH:4]1[CH2:13][CH2:12][CH2:11][C:10]2[C:9]([C:14]#[N:15])=[CH:8][CH:7]=[CH:6][C:5]1=2)=[O:2]
Reactant: COC=C1CCCc2c(C#N)cccc21
Agent: BrB(Br)Br
Solvent: ClCCl
Product: N#Cc1cccc2c1CCCC2C=O
Reaction time: 3 h

Procedure:
A solution of 5-(methoxymethylene)-5,6,7,8-tetrahydronaphthalene-1-carbonitrile (320 mg, 1.61 mmol) in DCM (7 mL) was added BBr3 (1.2 g, 4.8 mmol) dropwise at −78° C. under N2, then the mixture was stirred at this temperature for 3 h. It was poured into ice-saturated NaHCO3 solution, and extracted with DCM. The organic layer was washed with brine and dried over Na2SO4. The solvent was removed in vacuo to give crude title compound, which was used for next step.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:7](OC)(=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C(Cl)Cl>[C:7]([N:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1)(=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: COC(=O)c1ccccc1
Reactant: C1CNCCN1
Solvent: ClCCl
Product: O=C(c1ccccc1)N1CCNCC1

Procedure:
Mono-benzoylation of unsymmetric substituted piperazines could be achieved by using one of the following procedures (Scheme 57), in which all the methods were exemplified by mono-alkyl substituted piperazines. (a) Unsymmetric piperazines were treated with 2 equivalents of n-butyllithium, followed by the addition of benzoyl chloride at room temperature to afford a mixture of two regioisomers, which could be separated by chromatography (Wang et al, Ref. 89 and 90(b), Scheme 58 eq. 06); (b) Benzoic acid was converted to its pentafluorophenyl ester, and then further reaction with 2-alkylpiperazine to provide the mono-benzoylpiperazines with the benzoyl group at the less hindered nitrogen (Adamczyk et al, Ref. 90(a), Scheme 58, eq. 07); (c) A mixture of piperazine and methyl benzoate was treated with dialkylaluminum chloride in methylene chloride for 2-4 days to yield the mono-benzoylpiperazine with the benzoyl group at the less hindered nitrogen (Scheme 58 eq. 08); (d) Unsymmetric piperazines were treated with 2 equivalents of n-butyllithium, followed by subsequent addition of triethylsilyl chloride and benzoyl chloride in THF at room temperature to afford mono-benzoylpiperazines with the benzoyl group at the more hindered nitrogen (Wang et al, Ref. 90(b), Scheme 58, eq. 09). When the substituent at position 2 was a ester or amide, the mono-benzoylation with benzoyl chloride occurred at the less hindered nitrogen of the piperazine with triethylamine as base in THF (Scheme 58, eq. 10).
Reaction SMILES: [OH:1][C@H:2]([CH3:41])[CH2:3][CH2:4][CH:5]1OCC[O:37][CH:6]1[CH2:7][CH2:8][CH2:9]/[CH:10]=[CH:11]/[C:12]1[CH:20]=[C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:18]=[C:17]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:13]=1[C:14]([OH:16])=[O:15].O1CCCC1.Cl(O)(=O)(=O)=O>O>[OH:1][C@H:2]([CH3:41])[CH2:3][CH2:4][CH2:5][C:6](=[O:37])[CH2:7][CH2:8][CH2:9]/[CH:10]=[CH:11]/[C:12]1[CH:20]=[C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:18]=[C:17]([O:29][CH2:30][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:13]=1[C:14]([OH:16])=[O:15]
Reactant: C[C@@H](O)CCC1OCCOC1CCC/C=C/c1cc(OCc2ccccc2)cc(OCc2ccccc2)c1C(=O)O
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: O
Solvent: C1CCOC1
Product: C[C@@H](O)CCCC(=O)CCC/C=C/c1cc(OCc2ccccc2)cc(OCc2ccccc2)c1C(=O)O
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of 20 g. of 2-(10(R)-hydroxy-6-ethylenedioxy-trans-undecenyl)-4,6-dibenzyloxybenzoic acid in 150 ml. of tetrahydrofuran is added, while cooling, 100 ml. of an aqueous solution containing 220 g. perchloric acid per liter. The mixture is stirred for 6 hours at room temperature, then poured into water and extracted with chloroform. The extract is washed with water and an aqueous solution saturated with sodium chloride and is dried over sodium sulfate. Upon removal of the solvents, 17.8 g. of oil containing 2-(10(R)-hydroxy-6-oxo-trans-undecenyl)-4,6-dibenzyloxybenzoic acid are obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[C:13]([CH3:35])=[C:14]([C:18]2[C:30]3[C:29]4[C:24](=[CH:25][C:26]([Br:31])=[CH:27][CH:28]=4)[NH:23][C:22]=3[C:21]([C:32]([OH:34])=O)=[N:20][CH:19]=2)[CH:15]=[CH:16][CH:17]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[NH4+].C([N:41](CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CN1CCOCC1>CN(C=O)C.O>[Br:31][C:26]1[CH:25]=[C:24]2[C:29]([C:30]3[C:18]([C:14]4[C:13]([CH3:35])=[C:12]([NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]5[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=5)[CH:17]=[CH:16][CH:15]=4)=[CH:19][N:20]=[C:21]([C:32](=[O:34])[NH2:41])[C:22]=3[NH:23]2)=[CH:28][CH:27]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: Cc1c(NC(=O)OCc2ccccc2)cccc1-c1cnc(C(=O)O)c2[nH]c3cc(Br)ccc3c12
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(NC(=O)OCc2ccccc2)cccc1-c1cnc(C(N)=O)c2[nH]c3cc(Br)ccc3c12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 4-(3-(benzyloxycarbonylamino)-2-methylphenyl)-7-bromo-9H-pyrido[3,4-b]indole-1-carboxylic acid (1.174 g, 2.214 mmol), ammonium chloride (0.474 g, 8.85 mmol), N,N-diisopropylethylamine (1.856 mL, 10.63 mmol), BOP (1.273 g, 2.88 mmol), and N-methylmorpholine (0.949 mL, 8.63 mmol) in DMF (Volume: 10 mL) was stirred at room temperature for 2 hr. To the mixture was added water (120 mL), and the resulting mixture was stirred at room temperature for 20 min. The precipitating product (1.23 g) was collected as a beige solid by suction filtration and dried over Drierite at 50° C. This product was 80% pure, but was used in the next step without further purification.
Reaction SMILES: [H-].[Na+].[CH:3]1([OH:9])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.[Cl:10][C:11]1[N:15]2[N:16]=[C:17](Cl)[CH:18]=[CH:19][C:14]2=[N:13][N:12]=1.O>O1CCCC1>[Cl:10][C:11]1[N:15]2[N:16]=[C:17]([O:9][CH:3]3[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]3)[CH:18]=[CH:19][C:14]2=[N:13][N:12]=1
Reactant: Clc1ccc2nnc(Cl)n2n1
Reactant: OC1CCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Clc1nnc2ccc(OC3CCCCC3)nn12
Reaction time: 0.25 h
Yield: 27.5 %

Procedure:
106 mg of sodium hydride at 60% in oil are added to a solution of 530 mg of cyclohexanol in 5 cm3 of tetrahydrofuran at 0° C. under argon. After stirring for 15 min, 500 mg of 3,6-dichloro[1,2,4]triazolo[4,3-b]pyridazine (commercial) are added. The brown suspension is stirred, allowing the temperature to return gradually to 20° C. for 24 h. The reaction medium is poured into water and the mixture is extracted with ethyl acetate. After concentration to dryness under vacuum, a brown powder is obtained, which is washed with ether. The filtrate is concentrated to dryness and the oily yellow residue is chromatographed on Biotage Quad 12/25 (KP-SIL, 60 A; 32-63 μm), elution being carried out with a gradient of 100% dichloromethane to 95:5 dichloromethane/methanol. 184 mg of 3-chloro-6-(cyclohexyloxy)[1,2,4]-triazolo[4,3-b]pyridazine are thus obtained in the form of a white powder, the characteristics of which are as follows:
Reaction SMILES: C(OC(=O)[NH:7][C:8]1([CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH2:27][C:28]3[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=3)=[C:20]([C:38]([F:41])([F:40])[F:39])[CH:19]=2)[CH2:13][O:12]C(C)(C)[O:10][CH2:9]1)(C)(C)C.[ClH:43]>C(O)C>[ClH:43].[NH2:7][C:8]([CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH2:27][C:28]2[CH:29]=[CH:30][C:31]([C:34]([F:35])([F:36])[F:37])=[CH:32][CH:33]=2)=[C:20]([C:38]([F:39])([F:40])[F:41])[CH:19]=1)([CH2:13][OH:12])[CH2:9][OH:10]
Reactant: CC(C)(C)OC(=O)NC1(CCc2ccc(OCCCc3ccc(C(F)(F)F)cc3)c(C(F)(F)F)c2)COC(C)(C)OC1
Agent: Cl
Solvent: CCO
Product: NC(CO)(CO)CCc1ccc(OCCCc2ccc(C(F)(F)F)cc2)c(C(F)(F)F)c1
Temperature: 80 °C
Reaction time: 2.5 h

Procedure:
Compound 11-3 (800 mg) was dissolved in ethanol (20 ml), concentrated hydrochloric acid (2 ml) was added, and the mixture was stirred at 80° C. for 2.5 hr. The reaction mixture was concentrated, and the residue was washed with diethyl ether to give the object product (592 mg) as a white powder.
Reaction SMILES: [C:1]([NH:9][CH:10]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH:11]([C:13]([OH:15])=[O:14])[OH:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH:23]([O:25][CH:26](Cl)[CH3:27])[CH3:24]>C(Cl)Cl>[C:1]([NH:9][CH:10]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH:11]([C:13]([O:15][CH:23]([O:25][CH2:26][CH3:27])[CH3:24])=[O:14])[OH:12])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(Cl)OC(C)Cl
Reactant: O=C(NC(c1ccccc1)C(O)C(=O)O)c1ccccc1
Solvent: ClCCl
Product: CCOC(C)OC(=O)C(O)C(NC(=O)c1ccccc1)c1ccccc1

Procedure:
The epoxide of the cis-cinnamate is then regioselectively opened to produce 3-phenyl isoserinamide. This 3-phenyl isoserinamide is hydrolyzed to produce 3-phenyl-isoserine, which in turn is reacted with benzoyl chloride to form N-benzoyl-3-phenyl-isoserine. Next, the N-benzoyl-3-phenyl-isoserine is reacted with 1-chloroethyl ether and a tertiary amine in methylene chloride to form N-benzoyl-O-(1-ethoxyethyl)-3-phenyl-isoserine. Then, N-benzoyl-O-(1-ethoxyethyl)-3-phenyl-isoserine is reacted with the alcohol shown below: ##STR8## This resulting intermediate is converted to taxol by hydrolytically removing the 1-ethoxyethyl and triethylsilyl protecting groups.
Reaction SMILES: [Br:1][C:2]1[C:10]2[O:9][CH2:8][C:7]([CH3:12])([CH3:11])[C:6]=2[CH:5]=[C:4]([C:13]([OH:15])=O)[CH:3]=1.[CH3:16][N:17](C=O)C.Cl.CN.N1C=CC=CC=1>C1COCC1.C(OCC)(=O)C.O>[CH3:16][NH:17][C:13]([C:4]1[CH:3]=[C:2]([Br:1])[C:10]2[O:9][CH2:8][C:7]([CH3:12])([CH3:11])[C:6]=2[CH:5]=1)=[O:15]
Reactant: CN(C)C=O
Reactant: CC1(C)COc2c(Br)cc(C(=O)O)cc21
Agent: CN
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: CNC(=O)c1cc(Br)c2c(c1)C(C)(C)CO2
Reaction time: 1 h
Yield: 223.8 %

Procedure:
To a solution of 7-bromo-3,3-dimethyl-2,3-dihydro-benzofuran-5-carboxylic acid (4.99 g, 18.41 mmol) in dry THF (40 mL) was added at room temperature thionychloride (2 mL, 27.61 mmol) and DMF (0.14 mL, 1.84 mmol). The reaction mixture was stirred 1 hr then methylamine hydrochloride (2.48 g, 36.82 mmol) was added followed by slow addition of pyridine (4.5 mL, 55.23 mmol). The reaction mixture was stirred overnight then water and ethyl acetate were added. The layers were separated. The aqueous layer was extracted twice with ethyl acetate. The combined extracts were washed successively with water and brine, dried over anhydrous magnesium sulfate, filtered and evaporated. The residue was chromatographed on silica gel (50% to 100% ethyl acetate in hexane, then 40% MeOH in Ethyl acetate) to give 1.17 g of 7-bromo-3,3-dimethyl-2,3-dihydro-benzofuran-5-carboxylic acid methylamide (22%). 1H NMR (300 MHz; CDCl3): 1.36 (s, 6H), 2.99 (d, J=4.5 Hz, 3H), 4.39 (s, 2H), 6.25 (br s, 1H), 7.54 (d, J=1.5 Hz, 1H), 7.70 (d, J=1.5 Hz, 1H).
Reaction SMILES: Cl[C:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH3:14])[CH:8]=2)=[N:5][S:4][N:3]=1.[F-:15].[K+]>S1(CCCC1)(=O)=O>[F:15][C:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH3:14])[CH:8]=2)=[N:5][S:4][N:3]=1
Reactant: COc1cccc(-c2nsnc2Cl)c1
Reactant: [F-]
Agent: [K+]
Solvent: O=S1(=O)CCCC1
Product: COc1cccc(-c2nsnc2F)c1
Yield: 25.9 %

Procedure:
By the method of M. Geisel and R. Mews (Chem. Ber. 115, 2135 (1982), incorporated herein by reference, 2.0 g (0.0088 mole) of 3-chloro-4-(3-methoxyphenyl)-1,2,5-thiadiazole (from Example 2) was heated with 2.04 g (0.035 mole) of potassium fluoride in 20 ml of sulfolane at 180° C. to produce 0.48 g of 3-fluoro-4-(3-methoxyphenyl)-1,2,5-thiadiazole, Compound 21 of Table I. Compounds 18-20 of Table I were also prepared by this method.
Reaction SMILES: [CH3:1][C:2]1([CH3:37])[CH2:7][CH2:6][C:5]([C:8]2[C:13]([NH:14][C:15]([C:17]3[N:18](COCC[Si](C)(C)C)[C:19]([C:22]#[N:23])=[CH:20][N:21]=3)=[O:16])=[CH:12][CH:11]=[C:10]([C:32]([O:34]CC)=[CH2:33])[N:9]=2)=[CH:4][CH2:3]1.CCO.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:32]([C:10]1[N:9]=[C:8]([C:5]2[CH2:6][CH2:7][C:2]([CH3:37])([CH3:1])[CH2:3][CH:4]=2)[C:13]([NH:14][C:15]([C:17]2[NH:18][C:19]([C:22]#[N:23])=[CH:20][N:21]=2)=[O:16])=[CH:12][CH:11]=1)(=[O:34])[CH3:33]
Reactant: C=C(OCC)c1ccc(NC(=O)c2ncc(C#N)n2COCC[Si](C)(C)C)c(C2=CCC(C)(C)CC2)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCO
Product: CC(=O)c1ccc(NC(=O)c2ncc(C#N)[nH]2)c(C2=CCC(C)(C)CC2)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The title compound was prepared from 5-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylic acid [2-(4,4-dimethyl-cyclohex-1-enyl)-6-(1-ethoxy-vinyl)-pyridin-3-yl]-amide (as prepared in the previous step, 12 mg, 0.023 mmol)) as a solution in 10 mL of DCM with 0.4 mL of EtOH and 10 mL of TFA; the mixture was stirred for 1 h at RT. The mixture was concentrated and triturated with Et2O to give (4.4 mg, 52%). Mass spectrum (ESI, m/z): Calcd. for C20H21N5O2, 364.1 (M+H). found 364.1.
Reaction SMILES: C1CO[C:3]2([CH:8]=[CH:7][C@H:6]3[C@H:9]4[C@H:19]([CH2:20][CH2:21][C@:4]23[CH3:5])[C@:17]2([CH3:18])[C:12]([CH2:13][C@@H:14]([OH:22])[CH2:15][CH2:16]2)=[CH:11][CH2:10]4)[O:2]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(C)=O.O>[OH:22][CH:14]1[CH2:15][CH2:16][C@@:17]2([CH3:18])[C:12](=[CH:11][CH2:10][C@@H:9]3[C@@H:19]2[CH2:20][CH2:21][C@@:4]2([CH3:5])[C@H:6]3[CH:7]=[CH:8][C:3]2=[O:2])[CH2:13]1
Reactant: C[C@]12CC[C@H](O)CC1=CC[C@@H]1[C@@H]2CC[C@@]2(C)[C@H]1C=CC21OCCO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC(C)=O
Product: C[C@]12CCC(O)CC1=CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)C=C[C@@H]12
Reaction time: 5 h

Procedure:
17,17-Ethylenedioxy-androst-5,15(16)-dien-3β-ol from Example 28B or otherwise obtained is dissolved in acetone (500 mL) and water (60 mL) and the solution is cooled to 0° C. To the 0° C. solution is added p-toluenesulfonic acid monohydrate (1.000 g, 5.257 mmol). The 0° reaction mixture is stirred for 5 hours and then stored at 40° for 16 hours. The chilled reaction solution is diluted with water (300 mL) and acetone is evaporated under reduced pressure. The aqueous slurry remaining is extracted with EtOAc (2×300 mL) and the combined organic phases are washed with saturated aqueous NaHCO3 (200 mL) and brine (200 mL), dried over MgSO4, filtered and concentrated. The residue is purified by flash chromatography (1:1 EtOAc/CH2Cl2) to afford 3-hydroxy-androst-5,15(16)-dien-17-one (C3-alcohol).
Reaction SMILES: [C:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13]C)[CH:11]=2)[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([O:21]C)=[CH:17][CH:16]=2)[CH:4]=1)#[N:2].N1C(=O)CC[C@H]1C(O)=O.Br>>[C:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([OH:13])[CH:11]=2)[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)[CH:4]=1)#[N:2]
Reactant: COc1ccc(-c2cc(C#N)c3cc(OC)ccc3n2)cc1
Agent: Br
Agent: O=C1CC[C@@H](C(=O)O)N1
Product: N#Cc1cc(-c2ccc(O)cc2)nc2ccc(O)cc12
Yield: 89 %

Procedure:
This compound was prepared from 9a using Pyr./HBr according to method I. Yellow solid; Yield: 89%; mp>240° C. (dec.); 1H-NMR (300 MHz, DMSO-d6) δ 6.92 (d, J=8.7 Hz, 2H), 7.30 (d, J=2.6 Hz, 1H), 7.45 (dd, J=9.1, 2.6 Hz, 1H), 8.02 (d, J=9.1 Hz, 1H), 8.13 (d, J=8.7 Hz, 2H), 8.58 (s, 1H), 9.93 (s, 1H), 10.64 (s, 1H); MS (ESI) m/z 261 ([M−H]−), 263 ([M+H]+); Anal. Calcd for C16H10N2O2: C: 73.27, H: 3.84, N: 10.68. Found: C: 71.75, H: 3.86, N: 10.14.