Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH2:8][O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:6]([C:16](=O)[CH3:17])[CH:5]=[CH:4][C:3]=1[C:19](=[CH:24][CH3:25])[C:20]([O:22][CH3:23])=[O:21].Cl.[CH3:27][O:28][NH2:29]>CO>[CH3:1][C:2]1[C:7]([CH2:8][O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:6]([CH2:16][CH:17]=[N:29][O:28][CH3:27])[CH:5]=[CH:4][C:3]=1[C:19](=[CH:24][CH3:25])[C:20]([O:22][CH3:23])=[O:21]
Reactant: CC=C(C(=O)OC)c1ccc(C(C)=O)c(COc2ccccc2)c1C
Reactant: CON
Agent: Cl
Solvent: CO
Product: CC=C(C(=O)OC)c1ccc(CC=NOC)c(COc2ccccc2)c1C
Temperature: 25 °C
Yield: 72.7 %

Procedure:
22 g (67.4 mmol) of methyl α-[2-methyl-4-acetylphenyloxymethylphenyl]-β-methylacrylate and 11.3 g (0.135 mol) of O-methylhydroxylamine hydrochloride were refluxed in 600 ml of methanol for 6 hours. The mixture was allowed to cool to about 25° C., was hydrolyzed and extracted with ice water. The organic phases were washed with water, dried and evaporated down. There was obtained 18 g of the title compound in the form of pale yellow crystals (m.p.: 55°-60° C.).
Reaction SMILES: [OH-].[Li+].CO.[S:5]1[CH:9]=[CH:8][C:7]2[C:10]([N:14]3[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][CH2:22][O:23][C:24]4[C:33]5[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=5)[N:27]=[C:26]([C:34]([O:36]CC)=[O:35])[CH:25]=4)[CH2:16][CH2:15]3)=[CH:11][CH:12]=[CH:13][C:6]1=2.[ClH:39]>O>[ClH:39].[S:5]1[CH:9]=[CH:8][C:7]2[C:10]([N:14]3[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][CH2:22][O:23][C:24]4[C:33]5[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=5)[N:27]=[C:26]([C:34]([OH:36])=[O:35])[CH:25]=4)[CH2:16][CH2:15]3)=[CH:11][CH:12]=[CH:13][C:6]1=2
Reactant: CCOC(=O)c1cc(OCCCN2CCN(c3cccc4sccc34)CC2)c2ccccc2n1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1cc(OCCCN2CCN(c3cccc4sccc34)CC2)c2ccccc2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98 %

Procedure:
An aqueous solution of 4N lithium hydroxide (3 ml) was added to a methanol solution (7 ml) of ethyl 4-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]-quinolin-2-carboxylate (1.5 g), followed by stirring at room temperature overnight. Then, water (10 ml) and aqueous solution (3 ml) of 4N lithium hydroxide were further added, followed by stirring at 50° C. for 11 hours. The reaction mixture was cooled in an ice-bath, and an aqueous solution (4 ml) of 6N—HCl was added thereto. Then, crystals precipitated were filtered out, washed with water and dried to obtain 4-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]quinolin-2-carboxylic acid hydrochloride (1.43 g, yield: 98%) as white powder.
Reaction SMILES: [CH2:1]([C@@H:8]1[NH:13][CH2:12][CH2:11][N:10]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:15]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.C([O:42][CH2:43][C:44](Cl)=[O:45])C1C=CC=CC=1>C1COCC1.CCOC(C)=O.O.CO>[CH2:1]([C@H:8]1[CH2:9][N:10]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:15]=2)[CH2:11][CH2:12][N:13]1[C:43](=[O:42])[CH2:44][OH:45])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(N2CCN[C@@H](Cc3ccccc3)C2)cc1OC1CCCC1
Reactant: O=C(Cl)COCc1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COc1ccc(N2CCN(C(=O)CO)[C@@H](Cc3ccccc3)C2)cc1OC1CCCC1
Reaction time: 2 h
Yield: 10.6 %

Procedure:
A solution of (S)-3-Benzyl-1-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazine (Example 2) (73 mg, 0.2 mmol) in THF (1.5 mL) at room temperature was treated with triethylamine (42 μL, 0.3 mmol) followed by benzyloxyacetyl chloride (19 μL, 0.2 mmol). The reaction mixture was stirred for 2 h then diluted with EtOAc (2 mL) and water (2 mL). The organic phase was isolated and further washed with an additional portion of a water (2 mL) followed by a brine solution (2 mL). The organic component was dried over MgSO4, filtered, and evaporated to an oil which was purified by silica gel flash chromatography with 20% then 40% EtOAc/hexane as eluant to afford coupled product as an oil (69 mg, 67%). LC/MS 7.64 min, [M+1]+ 515. The intermediate benzyloxy ether (60 mg,0.117 mmol) was dissolved in MeOH (20 mL), purged with a stream of nitrogen, treated with 20% Pd/C (140 mg, 50% water content), and hydrogenated under 40 psi pressure of hydrogen for 4 h. The crude reaction mixture was then purged with nitrogen, filtered, evaporated, and purified by silica gel flash chromatography with 40% then 75% EtOAc/hexane as eluant to afford product as an oil (9 mg, 18%). LC/MS 6.55 min, [M+1]+ 425.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:10]=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[Br:11]N1C(=O)CCC1=O>C(Cl)Cl.CO>[Br:11][C:10]1[C:3]2[C:2]([Cl:1])=[N:7][CH:6]=[N:5][C:4]=2[NH:8][CH:9]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Clc1ncnc2[nH]ccc12
Solvent: ClCCl
Solvent: CO
Product: Clc1ncnc2[nH]cc(Br)c12
Temperature: 25 °C
Reaction time: 3 h

Procedure:
[To a suspension of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (F-1) (3.99 g, 26.0 mmol, 1.0 eq) in anhydrous DCM (150 mL) under argon, N-bromosuccinimide (6.02 g, 33.8 mmol, 1.3 eq) is added and the resulting mixture is stirred at RT for 3 h. The reaction mixture is diluted with MeOH (30 mL) and then concentrated in vacuo. The residue is triturated with H2O (150 mL). This is collected by filtration and then re-crystallized in MeOH to afford the product, 5-bromo-4-chloro-7H-pyrrolo[2,3-d]pyrimidine (G-1).
Reaction SMILES: Cl[C:2]1[N:3]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=2)[N:4]=[C:5]2[C:10]=1[CH:9]=[CH:8][C:7]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[O:17][CH3:18])=[CH:6]2.[OH-:29].[K+]>CO>[CH3:18][O:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[C:7]1[CH:6]=[C:5]2[C:10]([C:2](=[O:29])[N:3]([C:19]3[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=3)[NH:4]2)=[CH:9][CH:8]=1
Reactant: COc1ccccc1-c1ccc2c(Cl)n(-c3ccc(C(F)(F)F)cc3)nc2c1
Reactant: [OH-]
Agent: [K+]
Solvent: CO
Product: COc1ccccc1-c1ccc2c(=O)n(-c3ccc(C(F)(F)F)cc3)[nH]c2c1
Temperature: 160 °C

Procedure:
The product of Step 1 (100 mg) was dissolved in 1N KOH in MeOH (2 mL) and heated at 160° C. for 2 min via microwave irradiation. The resulting yellow solution was concentrated, diluted with water and acidified with 2N HCl. The precipitate was collected and recrystallised from EtOH/H2O to give 21 mg of product as colourless needles. 1H NMR (500 MHz, DMSO): 3.81 (3H, s), 7.08 (1H, t, J 7.4 Hz), 7.18 (1H, d J 7.4 Hz), 7.31 (1H, dd, J 1.2 and 8.0 Hz), 7.38 (1H, dd, J 1.2 and 8.0 Hz), 7.39-7.42 (1H, m), 7.44 (1H, s), 7.79 (1H, d, J 8.0 Hz). 7.89 (2H, d, J 8.5 Hz), 8.18 (2H, d, J 8.5 Hz), 10.76 (1H, s).
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[NH:2][NH2:3].[Cl:7][C:8]1[CH:16]=[CH:15][C:11]([C:12](Cl)=[O:13])=[CH:10][CH:9]=1>>[Cl:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]([NH:3][NH:2][C:1]([O:5][CH3:6])=[O:4])=[O:13])=[CH:10][CH:9]=1
Reactant: COC(=O)NN
Reactant: O=C(Cl)c1ccc(Cl)cc1
Product: COC(=O)NNC(=O)c1ccc(Cl)cc1
Yield: 81.5 %

Procedure:
36.0 g. (0.4 moles) of methyl carbazate and 70.0 g. (0.4 moles) of p-chloro-benzoyl chloride are reacted in an analogous manner to Example 2. Thus 74.5 g. of the desired compound are obtained, yield 81.5%, M.p.: 160° C.
Reaction SMILES: [H-].[Na+].[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4]1.[CH2:12]([N:14]([CH2:18][CH3:19])[C:15](Cl)=[O:16])[CH3:13].O>C1COCC1>[CH2:12]([N:14]([CH2:18][CH3:19])[C:15]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4]1)=[O:16])[CH3:13]
Reactant: CCN(CC)C(=O)Cl
Reactant: c1ccc2[nH]ccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCN(CC)C(=O)n1ccc2ccccc21
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 99.4 %

Procedure:
To a suspension of NaH (60% dispersion in mineral oil, 1.2 g, 30 mmol, 1.5 eq., Aldrich) in THF (20 mL) at 0° C. was slowly added a solution of indole (2.4 g, 20 mmol, Aldrich) in THF (20 mL). The resulting mixture was stirred at 0° C. for 20 min, after which N,N-diethylcarbamoyl chloride (2.9 mL, 22 mmol, 1.1 eq., Aldrich) was added. Then, the reaction mixture was stirred at 0° C. for 30 min. H2O (10 mL) was added to quench the reaction and the mixture was transferred to a separatory funnel. The organic and aqueous layers were separated and the aqueous layer was extracted with EtOAc (3×20 mL). The combined organic layers were washed with brine, dried with MgSO4 and concentrated under reduced pressure. After purification of the residue by a short silica gel column (silica gel 60, 230-400 mesh) with EtOAc/hexanes as eluent, the product N,N-diethyl-1H-indole-1-carboxamide (4.3 g, 99% yield) was obtained as a light yellow oil. Further purification using flash column chromatography was deemed unnecessary. 1H NMR (400 MHz, CDCl3) δ ppm: 7.67 (d, J=8.17 Hz, 1H), 7.63 (d, J=7.65 Hz, 1H), 7.36-7.26 (m, 2H), 7.21 (t, J=7.24 Hz, 1H), 6.62 (d, J=2.77 Hz, 1H), 3.51 (q, J=7.10 Hz, 4H), 1.27 (t, J=7.11 Hz, 6H); 13C NMR (101 MHz, CDCl3) δ ppm: 154.39, 135.51, 129.27, 125.89, 123.36, 121.55, 120.90, 112.98, 105.35, 42.41, 13.46.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([OH:12])[C:9]2[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=2[N:3]=1.[CH3:13][CH:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:17][CH2:16][NH:15]1>>[CH3:13][CH:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH2:17][CH2:16][N:15]1[C:2]1[N:11]=[C:10]([OH:12])[C:9]2[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=2[N:3]=1
Reactant: Oc1nc(Cl)nc2c1CCCC2
Reactant: CC1NCCc2ccccc21
Product: CC1c2ccccc2CCN1c1nc(O)c2c(n1)CCCC2
Yield: 34.5 %

Procedure:
In accordance with the same procedure as in Step 2 of Example 57, except that 2-chloro-4-hydroxy-5,6,7,8-tetrahydroquinazoline (2.0 g, 10.8 mmol) prepared in the above Step 1 and 1-methyl-1,2,3,4-tetrahydroisoquinoline(3.3 g, 22.4 mmol) were used as starting materials, 1.1 g of the titled compound was prepared. (Yield: 34.5%)
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[CH:4]([CH:5]=O)[CH:3]1[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8].[O:15]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(O)C.[Na]>O.C1(C)C=CC=CC=1>[CH3:1][C:2]1([CH3:14])[C@H:4]([CH:5]=[C:22]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:23]([O:25][CH2:26][CH3:27])=[O:24])[C@H:3]1[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8]
Reactant: CC(C)(C)OC(=O)C1C(C=O)C1(C)C
Reactant: CCOC(=O)COc1ccccc1
Agent: [Na]
Solvent: CCO
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)C(=C[C@@H]1[C@@H](C(=O)OC(C)(C)C)C1(C)C)Oc1ccccc1
Temperature: 20 °C
Reaction time: 16 h

Procedure:
9.9 g of tert.-butyl 2,2-dimethyl-3-formyl-cyclopropane-carboxylate and 28 g of ethyl phenoxyacetate were added dropwise at 0° C. to a mixture of 0.05 ml of ethanol, 1.25 g of sodium in small pieces and 25 ml of toluene and the solution was stirred at 20° C. for 16 hours. 20 ml of toluene were added thereto and the mixture was stirred for 4 hours and was poured into iced water. The mixture was extracted with methylene chloride and the organic phase was evaporated to dryness under reduced pressure. The residue was chromatographed over silica gel and was eluted with a 7-3 hexane-ethyl acetate mixture to obtain 12.47 g of E or Z isomer of tert.-butyl (1R,trans) 2,2-dimethyl-3-[2-phenoxy-2-ethoxycarbonyl-ethenyl]-cyclopropane-carboxylate.
Reaction SMILES: [S:1]1[C:9]2[C:4](=[N:5][C:6]([C:10]([OH:12])=[O:11])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[CH3:13]O>>[S:1]1[C:9]2[C:4](=[N:5][C:6]([C:10]([O:12][CH3:13])=[O:11])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: O=C(O)c1ccc2sccc2n1
Reactant: CO
Product: COC(=O)c1ccc2sccc2n1
Temperature: 25 °C
Yield: 70 %

Procedure:
To a cold solution of HCI (10%) in MeOH (10 mL) was added thieno[3,2-b]pyridine-5-carboxylic acid (1.0 g, 5.6 mmol, and the mixture heated to reflux for 2 hr. After cooling to r.t., half the solvent was removed by evaporation and the remainder was partitioned between EtOAc and H2O. Solid NaHCO3 was added until the system remained basic. Separation, drying and evaporation of the organic layer afforded 0.75 g (70%) of the title compound.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][C:7]([C:13]#[N:14])=[C:6]2[CH2:15][CH:16]([CH3:18])[CH3:17])=O.COC1C=CC(/C=[C:34]2/[C:35]([NH:37][C:38]([S:40]/2)=[NH:39])=[O:36])=CC=1OC1CCCC1.C([O-])(=O)C.[Na+]>C(O)(=O)C>[NH2:39][C:38]1[S:40]/[C:34](=[CH:1]\[C:3]2[CH:4]=[C:5]3[C:10](=[CH:11][CH:12]=2)[N:9]=[CH:8][C:7]([C:13]#[N:14])=[C:6]3[CH2:15][CH:16]([CH3:18])[CH3:17])/[C:35](=[O:36])[N:37]=1
Reactant: COc1ccc(/C=C2\SC(=N)NC2=O)cc1OC1CCCC1
Reactant: CC(C)Cc1c(C#N)cnc2ccc(C=O)cc12
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(C)Cc1c(C#N)cnc2ccc(/C=C3\SC(N)=NC3=O)cc12

Procedure:
Similar procedure as described in example 38 was used, starting from 6-formyl-4-isobutyl-quinoline-3-carbonitrile (example 46f), pseudothiohydantoin, sodium acetate and acetic acid to give 6-[2-amino-4-oxo-4H-thiazol-(5Z)-ylidenemethyl]-4-isobutyl-quinoline-3-carbonitrile. LC-MS m/e 337 (MH+).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.CN(C)C=O.[CH:11]([NH:13][C:14]1[S:15][CH:16]=[C:17]([C:19](=[N:23][O:24][CH2:25][S:26][CH3:27])[C:20]([OH:22])=O)[N:18]=1)=[O:12].[NH2:28][CH:29]1[C:39](=[O:40])[N:31]2[C:32]([C:36]([OH:38])=[O:37])=[CH:33][CH2:34][S:35][C@H:30]12>C(OCC)(=O)C.O>[CH:11]([NH:13][C:14]1[S:15][CH:16]=[C:17]([C:19](=[N:23][O:24][CH2:25][S:26][CH3:27])[C:20]([NH:28][CH:29]2[C:39](=[O:40])[N:31]3[C:32]([C:36]([OH:38])=[O:37])=[CH:33][CH2:34][S:35][C@H:30]23)=[O:22])[N:18]=1)=[O:12]
Reactant: NC1C(=O)N2C(C(=O)O)=CCS[C@H]12
Reactant: CSCON=C(C(=O)O)c1csc(NC=O)n1
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CSCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=CCS[C@H]12)c1csc(NC=O)n1
Reaction time: 0.5 h
Yield: 13.9 %

Procedure:
Phosphoryl chloride (0.754 g.) was added dropwise to a solution of N,N-dimethylformamide (0.36 g.) in ethyl acetate (2 ml.) at -10° to -5° C. and stirred at the same temperature for 30 minutes. Ethyl acetate (13 ml.) and 2-(2-formamidothiazol-4-yl)-2-methylthiomethoxyiminoacetic acid (syn isomer, 1.13 g.) were added to the mixture at -10° to 5° C. and stirred at the same temperature for 30 minutes to give an activated acid solution. The solution was added to a solution of 7-amino-3-cephem-4-carboxylic acid (0.82 g.) and bis-(trimethylsilyl)acetamido (4.17 g.) in ethyl acetate (8.2 ml.) at -20° C. and the resulting reaction mixture was stirred at -10° to -5° C. for 30 minutes. After adding water to the resultant solution, the mixture was extracted twice with ethyl acetate. The extracts were washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and concentrated in vacuo. The residue was pulverized with diisopropyl ether, and the precipitates were collected by filtration and dried to give 7-[2-(2-formamidothiazol-4-yl)-2-methylthiomethoxyiminoacetamido]-3-cephem-4-carboxylic acid (syn isomer, 0.26 g.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]=[N:7][C:6]=2[CH:10]=1.C([Li])CCC.Br[C:17]1[CH:25]=[CH:24][C:20]([CH2:21][C:22]#[N:23])=[C:19]([F:26])[CH:18]=1>C1COCC1.[Cl-].[Cl-].[Zn+2].Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:17]3[CH:25]=[CH:24][C:20]([CH2:21][C:22]#[N:23])=[C:19]([F:26])[CH:18]=3)=[N:7][C:6]=2[CH:10]=1
Reactant: N#CCc1ccc(Br)cc1F
Reactant: Clc1ccc2ocnc2c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: N#CCc1ccc(-c2nc3cc(Cl)ccc3o2)cc1F
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
To a stirred solution of 5-chlorobenzoxazole (200 mg, 1.3 mmol) in 5 mL THF at −78° C., was added n-Butyllithium (640 μL, 2.5M in hexane, 1.6 mmol). The reaction was stirred for 15 min at −78° C. followed by the addition of ZnCl2 (3.9 mL, 1M in Et2O, 3.9 mmol) via a syringe. The reaction was then warmed at 0° C. for 1 h. A solution of 4-bromo-2-fluoro benzyl cyanide (214 mg, 1.0 mmol) in THF (2 mL) was added, along with Pd0 (a fresh suspension prepared as follows: 200 μL, n-Butyllithium, 2.5M in hexanes added to 144 mg of PdCl2(PPh3)2 in 5 mL of THF). The reaction was then stirred at reflux overnight and quenched with sat. NaHCO3 (50 mL). After diluting the mixture with EtOAc (300 mL), the organic extract was washed with H2O (50 mL), dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, hexanes:EtOAc 5:1) to afford the desired [4-(5-chloro-1,3-benzoxazol-2-yl)-2-fluorophenyl]acetonitrile as yellow solid. 1H NMR (CD3OD, 300 Hz), δ8.10(d, 1H), 7.99 (d, 1H), 7.79 (d, 1H), 7.68 (t, 1H), 7.52 (d, 1H), 7.39 (q, 1H), 3.90 (s, 1H). MS (ESI) 287 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:9])=[CH:4][C:3]=1I.[C:17]([C:19]1[CH:33]=[CH:32][C:22]([CH2:23][N:24]2[CH2:27][CH:26]([C:28]([O:30][CH3:31])=[O:29])[CH2:25]2)=[CH:21][C:20]=1[F:34])#[CH:18]>>[C:8]([C:5]1[CH:6]=[CH:7][C:2]2[O:1][C:17]([C:19]3[CH:33]=[CH:32][C:22]([CH2:23][N:24]4[CH2:27][CH:26]([C:28]([O:30][CH3:31])=[O:29])[CH2:25]4)=[CH:21][C:20]=3[F:34])=[CH:18][C:3]=2[CH:4]=1)(=[O:9])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C(c1ccccc1)c1ccc(O)c(I)c1
Reactant: C#Cc1ccc(CN2CC(C(=O)OC)C2)cc1F
Product: COC(=O)C1CN(Cc2ccc(-c3cc4cc(C(=O)c5ccccc5)ccc4o3)c(F)c2)C1

Procedure:
Synthesized according to Scheme B3, Step 3 and general procedure G from (4-hydroxy-3-iodophenyl)(phenyl)methanone and methyl 1-(4-ethynyl-3-fluorobenzyl)azetidine-3-carboxylate: yellow-orange solid. MS (ESI) m/z: Calculated: 443.2; Observed: 444 (M++1).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([OH:23])([C:17]([CH:20]2[CH2:22][CH2:21]2)([CH3:19])[CH3:18])[CH2:11][N:12]2[CH:16]=[N:15][CH:14]=[N:13]2)=[CH:6][CH:5]=1.[CH3:24]I.O>CN(C=O)C>[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([O:23][CH3:24])([C:17]([CH:20]2[CH2:21][CH2:22]2)([CH3:19])[CH3:18])[CH2:11][N:12]2[CH:16]=[N:15][CH:14]=[N:13]2)=[CH:6][CH:5]=1
Reactant: CC(C)(C1CC1)C(O)(Cn1cncn1)c1ccc(Cl)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(Cn1cncn1)(c1ccc(Cl)cc1)C(C)(C)C1CC1
Reaction time: 0.5 h

Procedure:
To a suspension of 0.8 g NaH 80% in 25 ml DMF are added dropwise, at room temperature, a solution of 7.64 g 2-(4-chlorophenyl)-3-cyclopropyl-3-methyl-1-(1H-1,2,4-triazol-1-yl)-butan-2-ol in 50 ml DMF. The reaction is stirred at 40° for 30 minutes. Then are added dropwise, at 50°, 3.76 g CH3I. The mixture is stirred for 18 hours at 20°, then poured into one liter of water and extracted with CH2Cl2. The organic phases are washed with water, dried over MgSO4 and concentrated by continuous flask evaporation. The title compound is then obtained by chromatography of the residue on silica gel (mobile phase diethylether/triethylamine 10:2) in the form of white crystals, m.p. 87°-89°.
Reaction SMILES: [CH3:1][CH2:2][C@@:3]1([OH:60])[CH2:19][N:18]2[CH2:20][CH2:21][C@@:16]34[C@@H:17]2[C@@H:5]([CH2:6][C@:7]([C:56]([O:58][CH3:59])=[O:57])([C:22]2[CH:27]=[C:26]5[C@@:28]67[C@@H:39]([N:40]([CH:41]=[O:42])[C:25]5=[CH:24][C:23]=2[O:54][CH3:55])[C@@:38]([OH:47])([C:43]([O:45][CH3:46])=[O:44])[C@H:37]([O:48][C:49]([CH3:51])=[O:50])[C@:33]2([CH2:52][CH3:53])[CH:34]=[CH:35][CH2:36][N:31]([C@H:32]62)[CH2:30][CH2:29]7)[C:8]3=[N:9][C:10]2[C:15]4=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:4]1.[BH4-].[Na+].[OH-].[NH4+]>C(O)(=O)C>[CH3:1][CH2:2][C@@:3]1([OH:60])[CH2:19][N:18]2[CH2:17][C@@H:5]([CH2:6][C@:7]([C:56]([O:58][CH3:59])=[O:57])([C:22]3[CH:27]=[C:26]4[C@:28]56[C@@H:32]7[C@:33]([CH2:52][CH3:53])([C@@H:37]([O:48][C:49]([CH3:51])=[O:50])[C@:38]([OH:47])([C:43]([O:45][CH3:46])=[O:44])[C@@H:39]5[N:40]([CH:41]=[O:42])[C:25]4=[CH:24][C:23]=3[O:54][CH3:55])[CH:34]=[CH:35][CH2:36][N:31]7[CH2:30][CH2:29]6)[C:8]3[NH:9][C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=4[C:16]=3[CH2:21][CH2:20]2)[CH2:4]1
Reactant: CC[C@]1(O)C[C@@H]2C[C@](C(=O)OC)(c3cc4c(cc3OC)N(C=O)[C@H]3[C@@](O)(C(=O)OC)[C@H](OC(C)=O)[C@]5(CC)C=CCN6CC[C@]43[C@@H]65)C3=Nc4ccccc4[C@@]34CCN(C1)[C@@H]24
Agent: [BH4-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CC(=O)O
Product: CC[C@]1(O)C[C@H]2CN(CCc3c([nH]c4ccccc34)[C@@](C(=O)OC)(c3cc4c(cc3OC)N(C=O)[C@H]3[C@@](O)(C(=O)OC)[C@H](OC(C)=O)[C@]5(CC)C=CCN6CC[C@]43[C@@H]65)C2)C1

Procedure:
To the solution of 53 mg (0.06 mmole) cyclovincristine in 5 ml abs. glacial acetic acid an excess of sodium borohydride (ca. 40 mg) is added in portions at ambient temperature. The reaction is controlled by TLC (Merck Kieselgel 60F254, Rf of starting material>Rf of product). When the reaction has been completed (ca. 2-3 hours at 25° C.), the solution is poured onto ice-water, rendered alkaline with concentrated aqueous ammonium hydroxide solution to pH 9, then extracted with 2×20 ml of dichloromethane. The combined organic phase is washed with 2×15 ml of water, dried (MgSO4) and evaporated in vacuo. The crude product obtained is purified by preparative chromatography (Kieselgel PF254+366).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:23]=[CH:22][CH:21]=[CH:20][C:4]=1[C:5]([NH:7][S:8]([C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][CH:12]=1)(=[O:10])=[O:9])=[O:6]>C(O)C.Cl.[Zn]>[CH3:1][O:2][C:3]1[CH:23]=[CH:22][CH:21]=[CH:20][C:4]=1[C:5]([NH:7][S:8]([C:11]1[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=1)(=[O:10])=[O:9])=[O:6]
Reactant: COc1ccccc1C(=O)NS(=O)(=O)c1ccc([N+](=O)[O-])cc1
Agent: Cl
Agent: [Zn]
Solvent: CCO
Product: COc1ccccc1C(=O)NS(=O)(=O)c1ccc(N)cc1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
50.0 g (0.15 mol) of 2-methoxy-N-(4-nitrophenylsulfonyl)benzamide are suspended in a mixture of 450 ml of ethanol and 750 ml of 2N HCl, and the mixture is heated to 50° C. 97.2 g (1.5 mol) of zinc powder are added in portions at this temperature and the mixture is stirred for a further 2 hours. After cooling, the mixture is filtered, the filtrate is concentrated to half its volume and cooled, and the precipitate is filtered off with suction and dried; Yield: 43.6 g (96%); M.p.: 180-182° C.
Reaction SMILES: [C:1]1([C:7]([O:9][Si](C)(C)C)=[CH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][C:15]=1[CH2:24][S:25][CH:26]([C:30](O)=[O:31])[C:27](O)=[O:28]>>[OH:31][C:30]1[CH:8]=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[O:9][C:27](=[O:28])[C:26]=1[S:25][CH2:24][C:15]1[CH:16]=[CH:17][C:18]2[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:14]=1
Reactant: O=C(O)C(SCc1ccc2ccccc2c1)C(=O)O
Reactant: C=C(O[Si](C)(C)C)c1ccccc1
Product: O=c1oc(-c2ccccc2)cc(O)c1SCc1ccc2ccccc2c1

Procedure:
The title compound was prepared by Method A using 1-phenyl-1-(trimethylsilyloxy)ethylene (0.475 g, 2.46 mmol) and dimethyl ester of [(2-naphthalenylmethyl)thio]propanedioic acid (0.500 g, 1.64 mmol). m.p. dec>250° C.; 1H NMR (250 MHz, DMSO-d6) δ 4.06 (s, 2 H), 6.47 (s, 1 H), 7.46 (m, 6 H), 7.78 (m, 6 H).
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[CH:5]([OH:6])[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[C:3]1[C:13]1[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=1.N1C=CC=CC=1.[CH3:30][C:31](OC(C)=O)=[O:32]>C(Cl)Cl.CN(C1C=CN=CC=1)C.CCOC(C)=O.O>[CH3:1][C:2]1([CH3:23])[CH:5]([O:6][C:31](=[O:32])[CH3:30])[C:4]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[C:3]1[C:13]1[CH:14]=[CH:15][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:17][CH:18]=1
Reactant: CC(=O)OC(C)=O
Reactant: CC1(C)C(c2ccc(S(C)(=O)=O)cc2)=C(c2ccccc2)C1O
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)OC1C(c2ccccc2)=C(c2ccc(S(C)(=O)=O)cc2)C1(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of Example 62 (150 mg) in CH2Cl2 (3 mL) at r.t., was added pyridine (370 mL), Ac2O (215 μL) and DMAP (5 mg). The mixture was stirred at r.t. for 2 hr and diluted with EtOAc and H2O. The organic phase was washed with HCl 1N, brine, dried (MgSO4) and the solvents evaporated. The residue was purified by flash chromatography (silica gel; hexane/EtOAc (70:30)) to give the title compound as a white solid, m.p. 60°-61° C.