Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@@H:2]([CH3:41])[CH2:3][CH2:4][CH:5]1[O:40][CH2:39][CH2:38][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].[CH:42]1C=CC=CC=1.[N+](=C)=[N-].CN(N=O)C(N)=O>C(O)(=O)C.C(OCC)C>[OH:1][C@@H:2]([CH3:41])[CH2:3][CH2:4][CH:5]1[O:40][CH2:39][CH2:38][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:24]=[CH:25][CH:26]=[CH:27][CH:28]=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]([O:16][CH3:42])=[O:15]
Reactant: c1ccccc1
Reactant: C[C@H](O)CCC1OCCOC1CCC/C=C/c1cc(OCc2ccccc2)cc(OCc2ccccc2)c1C(=O)O
Agent: C=[N+]=[N-]
Agent: CN(N=O)C(N)=O
Solvent: CCOCC
Solvent: CC(=O)O
Product: COC(=O)c1c(/C=C/CCCC2OCCOC2CC[C@H](C)O)cc(OCc2ccccc2)cc1OCc1ccccc1
Reaction time: 0.25 h

Procedure:
To a suspension of 48 g. of 2-(10(S)-hydroxy-6-ethylenedioxy-trans-undecenyl)-4,6-dibenzyloxybenzoic acid in 300 ml. of benzene is added a stoichiometric excess of diazomethane in 250 ml. of diethyl ether. The diazomethane is freshly prepared from N-methylnitrosourea. The solution becomes light yellow and is stirred for 15 minutes after the addition of the diazomethane. Acetic acid is then added to the mixture to decompose the excess diazomethane, and the solvents are removed to provide 48.8 g. of light yellow oil. The oil is purified by chromatography on 1250 g. of SilicAR, CC-7, an absorbent silica gel obtainable from Mallinckrodt Chemical Works, using a chloroform solvent. About 41 g. of a colorless oil of methyl 2-(10(S)-hydroxy-6-ethylenedioxy-trans-undecenyl)-4,6-dibenzyloxybenzoate are obtained. This oil analyzes as containing 72.92 wt. % carbon and 7.24 wt. % hydrogen, as compared to theoretical values of 73.17 wt. % carbon and 7.32 wt. % hydrogen.
Reaction SMILES: Cl[C:2]1[CH:13]=[C:12]([CH2:14][CH3:15])[C:5]([C:6]([N:8]=[C:9]([NH2:11])[NH2:10])=[O:7])=[CH:4][C:3]=1[S:16]([CH3:19])(=[O:18])=[O:17].[C:20]([O-:23])([O-])=O.[K+].[K+]>C[Si](C)(C)OC1C=NC=CC=1>[NH2:10][C:9]([NH2:11])=[N:8][C:6](=[O:7])[C:5]1[C:12]([CH2:14][CH3:15])=[CH:13][C:2]([O:23][C:20]2[CH:9]=[N:8][CH:6]=[CH:5][CH:4]=2)=[C:3]([S:16]([CH3:19])(=[O:18])=[O:17])[CH:4]=1
Reactant: CCc1cc(Cl)c(S(C)(=O)=O)cc1C(=O)N=C(N)N
Reactant: O=C([O-])[O-]
Agent: C[Si](C)(C)Oc1cccnc1
Agent: [K+]
Product: CCc1cc(Oc2cccnc2)c(S(C)(=O)=O)cc1C(=O)N=C(N)N

Procedure:
1.5 g of 4-chloro-N-diaminomethylene-3-methylsulfonyl-6-ethyibenzamide [obtainable by reacting guanidine with 3-methylsulfonyl-4-chloro-6-ethyl-benzoic acid], 10 ml of 3-trimethylsilyloxypyridine and 2.9 g of K2CO3 are stirred, at 140° for three hours, in small sealed flasks. After cooling, the solid residue is separated off, washed with a little diethyl ether and dissolved in 50 ml of water. After the customary working-up, N-diaminomethylene-3-methylsulfonyl-6-ethyl-4-(3-pyridyloxy)benzamide is obtained, m.p. 219-223°.
Reaction SMILES: [N:1]([CH2:4][CH2:5][O:6][CH2:7][CH2:8][OH:9])=[N+:2]=[N-:3].N1C=CC=CC=1.[C:16]1([CH3:26])[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[N:1]([CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][S:22]([C:19]1[CH:20]=[CH:21][C:16]([CH3:26])=[CH:17][CH:18]=1)(=[O:24])=[O:23])=[N+:2]=[N-:3]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: [N-]=[N+]=NCCOCCO
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCCOCCN=[N+]=[N-])cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 77.2 %

Procedure:
A solution of 2-(2-azido-ethoxy)-ethanol 2 (14.1 g, 0.108 mol) and pyridine (13 ml, 1.5 equiv.) in CH2Cl2 (150 ml) was cooled in an ice bath. p-Toluenesulfonyl chloride (30.7 g, 1.5 equiv.) then DMAP (173 mg, 0.01 equiv.) were added. The reaction mixture was stirred at RT for 72 h, then washed with a 1 M HCl aqueous solution (3×50 ml), dried over MgSO4, filtrated then concentrated under reduced pressure. Purification by flash column chromatography (eluent: pet. ether/AcOEt 9:1 then 7:3) afforded tosylate 3 as a colorless oil (23.8 g, 78%). 1H and 13C NMR spectra matched the literature data (Gill, H. et al. J. Med. Chem. 2009, 52, 5816-5825).
Reaction SMILES: [C:1]([CH2:3][P:4](=[O:11])([O:8][CH2:9][CH3:10])[O:5][CH2:6][CH3:7])#[N:2].Br[C:13]1[CH:25]=[CH:24][C:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[CH:15][CH:14]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C.C1(C)C=CC=CC=1>[C:1]([CH:3]([P:4]([O:8][CH2:9][CH3:10])([O:5][CH2:6][CH3:7])=[O:11])[C:13]1[CH:25]=[CH:24][C:16]([C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])=[CH:15][CH:14]=1)#[N:2]
Reactant: CCOP(=O)(CC#N)OCC
Reactant: CC(C)(C)OC(=O)c1ccc(Br)cc1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CCOP(=O)(OCC)C(C#N)c1ccc(C(=O)OC(C)(C)C)cc1
Temperature: 100 °C

Procedure:
Diethyl cyanomethylphosphonate (0.35 ml, 2.164 mmol), tert-butyl 4-bromobenzoate (0.5096 g, 1.982 mmol), bis(tri-t-butylphosphine)palladium (0.051 g, 0.099 mmol), potassium phosphate, tribasic (1.2381 g, 5.83 mmol) and toluene (6 ml) were combined in a flask. Nitrogen was bubbled through the reaction for approximately two minutes to deoxygenate the reaction. The reaction was allowed to heat at 100° C. until complete (3-24 h). The reaction was filtered over celite. The resulting material was partially purified by column chromatography on silica gel. The partially purified material was further purified by HPLC. 1H NMR (CDCl3, 600 MHz) δ 8.01 (d, J=6 Hz, 2H), 7.52 (d, J=6.9 Hz, 2H), 4.30 (d, JP-H=26.4 Hz, 1H), 4.19-4.01 (m, 4H), 1.59 (s, 9H), 1.32 (m, 3H), 1.26 (m, 3H). MS: cal'd 354 (MH+), exp 354 (MH+).
Reaction SMILES: [Li+].CC([N-]C(C)C)C.[C:9]([O:13][CH2:14][CH3:15])(=[O:12])[CH2:10][CH3:11].[Br:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21]Br)=[CH:19][CH:18]=1.O>C1COCC1>[Br:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21][CH:10]([CH3:11])[C:9]([O:13][CH2:14][CH3:15])=[O:12])=[CH:19][CH:18]=1
Reactant: CCOC(=O)CC
Reactant: BrCc1ccc(Br)cc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)C(C)Cc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To the LDA solution at -78° C., was added dropwise a solution of 5 mL (44 mmoles) of ethyl propionate in 20 mL of THF. Stirring was continued at —78° C. for 1 hour, after which a solution of 10 g (40 mmoles) of p-bromo benzylbromide in 25 mL of THF was added dropwise. Stirring was continued at −78° C. for 2 hours. Water was then added dropwise and the reaction was allowed to warm to room temperature.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]2[CH:9]=[N:10][NH:11][C:3]=12.[CH2:12]([NH2:16])[CH:13]([CH3:15])[CH3:14]>O.C(O)C>[CH3:8][C:6]1[N:5]=[C:4]2[CH:9]=[N:10][NH:11][C:3]2=[C:2]([NH:16][CH2:12][CH:13]([CH3:15])[CH3:14])[CH:7]=1
Reactant: CC(C)CN
Reactant: Cc1cc(Cl)c2[nH]ncc2n1
Solvent: O
Solvent: CCO
Product: Cc1cc(NCC(C)C)c2[nH]ncc2n1
Yield: 40.8 %

Procedure:
A mixture of 7-chloro-5-methyl-1H-pyrazolo[4,3-b]pyridine (1.0 g, 0.006 mole) and isobutylamine (58 g) in water (100 ml) and ethanol (50 ml) was heated under reflux for 10 days. The reaction mixture was cooled and evaporated to dryness. The oily residue was basified to pH8-9 with 10% sodium carbonate solution. The residue was extracted with ethyl acetate (3×100 ml), dried (Na2SO4) and evaporated to dryness to give a yellow oil. This was purified by column chromatography on alumina, and eluted with chloroform/methanol to give the desired compound as a white solid (500 mg). m.p. 162°-164° C.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[O:8][C:7]2[C:9]3[C:14]([C:15](=[O:18])[C:16](=[O:17])[C:6]=2[S:5][CH2:4]1)=[CH:13][CH:12]=[CH:11][CH:10]=3.C(N(CC)CC)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>ClCCl>[CH3:26][S:27]([O:1][CH2:2][CH:3]1[O:8][C:7]2[C:9]3[C:14]([C:15](=[O:18])[C:16](=[O:17])[C:6]=2[S:5][CH2:4]1)=[CH:13][CH:12]=[CH:11][CH:10]=3)(=[O:29])=[O:28]
Reactant: O=C1C(=O)c2ccccc2C2=C1SCC(CO)O2
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCC1CSC2=C(O1)c1ccccc1C(=O)C2=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 84.8 %

Procedure:
To a solution of 2-(hydroxymethyl)-2,3-dihydronaphtho[1,2-b][1,4]oxathiine-5,6-dione (1.0 g, 3.81 mmol) in dichloromethane (10 mL) was added triethylamine (1.0 mL, 7.63 mmol) and methanesulfonyl chloride (0.60 mL, 7.63 mmol). The resulting mixture was stirred for 1.5 hours at room temperature. Product was collected by filtration, washed with dichloromethane (10 mL) and dried under reduced pressure to provide the product as a purple solid (1.1 g, 85%). M.p.=230-232° C.; 400 MHz 1H NMR (DMSO-d6) δ: 7.89 (d, J=6.8 Hz, 1H), 7.75 (m, 2H), 7.56 (m, 1H), 4.81 (m, 1H), 4.65 (m, 1H), 4.54 (m, 1H), 3.05 (m, 2H), 1.16 (m, 3H); LCMS: 341 [M+H].
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.Cl[CH2:18][CH2:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[NH:25][C:24](=[O:29])[CH2:23]2.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C>[F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:18][CH2:19][C:20]4[CH:21]=[C:22]5[C:26](=[CH:27][CH:28]=4)[NH:25][C:24](=[O:29])[CH2:23]5)[CH2:13][CH2:14]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Reactant: O=C1Cc2cc(CCCl)ccc2N1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1Cc2cc(CCN3CCC(c4noc5cc(F)ccc45)CC3)ccc2N1
Temperature: 90 °C

Procedure:
Under N2 a mixture of 4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine V (2.0 g, 9.08 mmol), 5-(2-chloroethyl)oxindole (0.95 g, 10 mmol), Na2CO3 (1.06 g, 10 mmol) and KI (1.0 g, 6.0 mmol) in 45 ml dry DMF was heated at 90° C. for 72 hours. The reaction mixture was then poured over 150 ml ice/water, stirred, and filtered to give 3.04 g of brown solids. Chromatography on silica gel (230-400 mesh), eluting with 95% EtOAc: 5% triethylamine provided clean product, 0.645 g (19%), light brown solid, m.p. 199°-204° C. Analysis for C22H22FN3O2.0.5H2O: C 68.03, H 5.97, N 10.82. Found: C 67.94, H 5.57, N 10.81; MS(%): 379 (1, p+), 253 (4), 234 (32), 233 (100). NMR (300 MHz, CDCl3, delta), 2.0-2.4 (m, 6H), 2.65 (m, 2H), 2.8 (m, 2H), 3.1-3.2 (m,3H), 3.5 (s, 2H), 6.75 (d, 1H), 7.1 (m, 3H), 7.2 (s, 1H), 7.7 (m, H), 8.25 (br s, 1H).
Reaction SMILES: [C:1]1([C:7]23[CH2:12][CH:11]2[CH2:10][NH:9][CH2:8]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:13]1(=[O:23])[O:18][C:16](=[O:17])[C:15]2=[CH:19][CH:20]=[CH:21][CH:22]=[C:14]12>C1(C)C=CC=CC=1>[C:1]1([C:7]23[CH2:12][CH:11]2[CH2:10][N:9]([C:13]([C:14]2[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=2[C:16]([OH:18])=[O:17])=[O:23])[CH2:8]3)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(C23CNCC2C3)cc1
Reactant: O=C1OC(=O)c2ccccc21
Solvent: Cc1ccccc1
Product: O=C(O)c1ccccc1C(=O)N1CC2CC2(c2ccccc2)C1
Reaction time: 8 h

Procedure:
A mixture of 7.95 g. of 1-phenyl-3-azabicyclo-[3.1.0]hexane and 7.4 g. of phthalic anhydride in 300 ml. of toluene is refluxed for 1/2 hour and then allowed to stand overnight. The solution is extracted three times with 1N sodium hydroxide and made extremely acid with 1N hydrochloric acid. The solid which separates is extracted with chloroform, dried over magnesium sulfate, filtered and filtrate evaporated to a glass residue. This glass is triturated in hexane and filtered giving the product as a light pink solid, IR 5.85, 6.10μ.
Reaction SMILES: [CH2:1]([N:5]([CH2:27][CH3:28])[C:6]1[C:7]2[C:15]([CH3:16])=[CH:14][N:13]([C:17]3[C:22]([CH3:23])=[CH:21][C:20]([CH2:24]O)=[CH:19][C:18]=3[CH3:26])[C:8]=2[N:9]=[C:10]([CH3:12])[N:11]=1)[CH2:2][CH2:3][CH3:4].CN(S(F)(F)[F:33])C>C(Cl)Cl>[CH2:1]([N:5]([CH2:27][CH3:28])[C:6]1[C:7]2[C:15]([CH3:16])=[CH:14][N:13]([C:17]3[C:22]([CH3:23])=[CH:21][C:20]([CH2:24][F:33])=[CH:19][C:18]=3[CH3:26])[C:8]=2[N:9]=[C:10]([CH3:12])[N:11]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CN(C)S(F)(F)F
Reactant: CCCCN(CC)c1nc(C)nc2c1c(C)cn2-c1c(C)cc(CO)cc1C
Solvent: ClCCl
Product: CCCCN(CC)c1nc(C)nc2c1c(C)cn2-c1c(C)cc(CF)cc1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of {4-[4-(butyl-ethyl-amino)-2,5-dimethyl-pyrrolo[2,3-d]pyrimidin-7-yl]-3,5-dimethylphenyl}-methanol (0.071 g, 0.186 mmol) in 2 ml anhydrous methylene chloride was cooled to −78° C. and treated with dimethylaminosulfur trifluoride (0.063g, 0.390 mmol) and stirred at room temperature for 1 hour. The mixture was quenched with water and extracted with chloroform. The organic layer was washed with brine, dried, and concentrated to give an oil which was purified through silica gel using 2% methanol/chloroform as eluent to give the title compound as an off-white solid, mp 163-165° C.
Reaction SMILES: [OH:1][C:2]1([C:13]2[CH:18]=[CH:17][C:16]([CH:19]([CH3:21])[CH3:20])=[CH:15][C:14]=2[OH:22])[C:10](=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:12].[C:23](Cl)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(N(CC)CC)C>C(Cl)Cl.CC(NP(OC1C=CC(Cl)=CC=1Cl)(OC)=S)C>[C:23]([O:1][C:2]1([C:13]2[CH:18]=[CH:17][C:16]([CH:19]([CH3:20])[CH3:21])=[CH:15][C:14]=2[OH:22])[C:10](=[O:11])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:12])(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(C)c1ccc(C2(O)C(=O)c3ccccc3C2=O)c(O)c1
Agent: COP(=S)(NC(C)C)Oc1ccc(Cl)cc1Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)c1ccc(C2(OC(=O)c3ccccc3)C(=O)c3ccccc3C2=O)c(O)c1
Yield: 60 %

Procedure:
2-hydroxy-2-(2-hydroxy-4-isopropyl-phenyl)-indan-1,3-dione (1.00 g, 3.37 mmol) was completely dissolved in anhydrous methylene chloride (20 ml). This solution was added with benzoyl chloride (0.94 g, 6.74 mmol), triethylamine (0.41 g, 4.04 mmol), and DMPA (0.01 g), followed by heating 24 hrs under reflux. After the reaction mixture was concentrated, extracted with dichloromethane, and the organic layer was concentrated and purified using column chromatography (ethylacetate:hexane=1:4) to afford the title compound (0.81 g, 14%).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH2:10][O:11][CH3:12])[N:5]=[C:4]([NH:13][C:14]([NH:16][C@@H:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH3:18])=[O:15])[CH:3]=1.O.[NH2:26][NH2:27]>CCO>[NH2:9][C:8]1[C:7]2[C:6]([CH2:10][O:11][CH3:12])=[N:5][C:4]([NH:13][C:14]([NH:16][C@@H:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH3:18])=[O:15])=[CH:3][C:2]=2[NH:27][N:26]=1
Reactant: NN
Reactant: COCc1nc(NC(=O)N[C@H](C)c2ccccc2)cc(Cl)c1C#N
Solvent: CCO
Solvent: O
Product: COCc1nc(NC(=O)N[C@H](C)c2ccccc2)cc2[nH]nc(N)c12

Procedure:
A solution of (R)-1-(4-chloro-5-cyano-6-(methoxymethyl)pyridin-2-yl)-3-(1-phenylethyl)urea (151.4 mg, 0.439 mmol) and hydrazine hydrate (75 μl, 1.546 mmol) in EtOH (4 ml) was heated to 100° C. in a sealed vial for 18 hr. The mixture was concentrated in vacuo and purified via flash chromatography (0-20% MeOH/EtOAc) to provide (R)-1-(3-amino-4-(methoxymethyl)-1H-pyrazolo[4,3-c]pyridin-6-yl)-3-(1-phenylethyl)urea. MS ESI calc'd for C17H21N6O2 [M+H]+ 341. found 341. 1H NMR (ppm, 500 MHz, DMSO-d6) δ 11.60 (s, 1H), 8.97 (s, 1H), 7.33 (m, 4H), 7.22 (m, 1H), 7.14 (s, 1H), 5.35 (s, 2H), 4.85 (t, J=7.1, 1H), 4.65 (m, 2H), 3.31 (s, 3H, overlaps with H2O peak), 3.15 (d, J=5.1 Hz, 1H), 1.39 (d, J=7.1 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C@@:7]([C:16]([F:19])([F:18])[F:17])([OH:15])[C:6]=2[CH:5]=[C:4]([OH:20])[CH:3]=1.C1(C)C=CC(S(O[CH2:31][CH2:32][C:33]([OH:36])([CH3:35])[CH3:34])(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Cl:1][C:2]1[C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C@@:7]([C:16]([F:18])([F:19])[F:17])([OH:15])[C:6]=2[CH:5]=[C:4]([O:20][CH2:31][CH2:32][C:33]([OH:36])([CH3:35])[CH3:34])[CH:3]=1
Reactant: Oc1cc(Cl)c2c(c1)[C@@](O)(C(F)(F)F)c1ccccc1-2
Reactant: Cc1ccc(S(=O)(=O)OCCC(C)(C)O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(O)CCOc1cc(Cl)c2c(c1)[C@@](O)(C(F)(F)F)c1ccccc1-2
Temperature: 70 °C
Reaction time: 8 h
Yield: 69.3 %

Procedure:
Under a nitrogen atmosphere, (9R)-4-chloro-9-(trifluoromethyl)-9H-fluorene-2,9-diol (55.5 g) was dissolved in N,N-dimethylformamide (550 ml), 3-hydroxy-3-methylbutyl toluene-4-sulfonate (49.6 g) and potassium carbonate (39.5 g) were added, and the mixture was stirred at an oil bath temperature of 70° C. overnight. To the reaction mixture was added a solution of 3-hydroxy-3-methylbutyl toluene-4-sulfonate (4.0 g) in N,N-dimethylformamide (5 ml), and the mixture was further stirred at the same temperature for 9.5 hr. The reaction mixture was ice-cooled, water (800 ml) was added, and the mixture was extracted with ethyl acetate (900 ml). The obtained organic layer was washed with water (500 ml, 3 times) and saturated brine (500 ml). The obtained organic layer was dried over anhydrous sodium sulfate, the insoluble material was filtered off, and the solvent in the filtrate was evaporated. The obtained residue was purified by silica gel column chromatography (a mixture of hexane and ethyl acetate was used as an elution solvent, first eluted with a mixture of (hexane:ethyl acetate) at a mixing ratio 3:1, and then with the mixture at a mixing ratio 2:1, and further with the mixture at a mixing ratio 3:2) to give the title compound (49.5 g).
Reaction SMILES: [Si]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][NH:17][CH2:18][C@@H:19]([C:21]2[CH:32]=[CH:31][C:24]3[O:25][C:26]([CH3:30])([CH3:29])[O:27][CH2:28][C:23]=3[CH:22]=2)[OH:20])=[CH:11][CH:10]=1)(C(C)(C)C)(C)C.[C:33](N1C=CN=C1)(N1C=CN=C1)=[O:34].O>C1COCC1>[CH3:30][C:26]1([CH3:29])[O:25][C:24]2[CH:31]=[CH:32][C:21]([C@H:19]3[O:20][C:33](=[O:34])[N:17]([CH2:16][CH2:15][C:12]4[CH:11]=[CH:10][C:9]([OH:8])=[CH:14][CH:13]=4)[CH2:18]3)=[CH:22][C:23]=2[CH2:28][O:27]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC1(C)OCc2cc([C@@H](O)CNCCc3ccc(O[Si](C)(C)C(C)(C)C)cc3)ccc2O1
Solvent: O
Solvent: C1CCOC1
Product: CC1(C)OCc2cc([C@@H]3CN(CCc4ccc(O)cc4)C(=O)O3)ccc2O1
Reaction time: 21.5 h
Yield: 72.7 %

Procedure:
A solution of (1R)-2-{[2-(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)ethyl]amino}-1-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)ethanol (4.803 g) in THF (100 ml) under nitrogen was treated with 1,1′carbonyldimidazole (1.702 g) and the mixture was stirred at 20° for 21.5 h. Water (125 ml) was added, the mixture was stirred for 10 min and then extracted with Et2O. The extract was dried (Na2SO4) and the solvent evaporated in vacuo. The residue was dissolved in THF (60 ml) and was treated with a solution of tetrabutyl ammonium fluoride in THF (1.0 M, 15.95 ml). The mixture was stirred at 20° for 100 min, water (30 ml) was added and the mixture was extracted with Et2O. The extract was washed with water, dried (Na2SO4) and the solvent evaporated in vacuo to give a residue which was purified by chromatography on a Biotage cartridge (90 g). Elution with EtOAc-petroleum ether (2:3) gave the title compound (2.82 g). LCMS RT=3.01 min ES+ve 370 (MH)+.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[C:7]([OH:10])(=[S:9])[CH3:8].[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([CH2:20]Cl)[CH:13]=1>CN(C)C=O.C(OCC)(=O)C>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([CH:13]=1)[CH2:20][S:9][C:7](=[O:10])[CH3:8]
Reactant: CC(O)=S
Reactant: COc1ccc(Cl)cc1CCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc(Cl)cc1CSC(C)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 96 %

Procedure:
To a solution of cesium carbonate (0.55 g, 1.70 mmol) in dimethylformamide (13 mL) was added thioacetic acid (0.24 g, 3.14 mmol) followed by addition of 4-chloro-2-chloromethyl-1-methoxybenzene (0.50 g, 2.62 mmol) in one portion. The reaction was stirred in the dark at ambient temperature overnight. The reaction was diluted with ethyl acetate, washed with water, 5% aqueous sodium hydrogen carbonate, and brine. The organic layer was separated, dried over sodium sulfate, filtered and concentrated in vacuo. Chromatography on silica gel gave the title compound (0.58 g).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH2:9][C:10](=[O:16])[NH:11]3)=[CH:3][CH:2]=1.[CH2:17]([C:19]1[NH:23][C:22]([CH:24]=O)=[C:21]([CH2:26][CH2:27][C:28]([OH:30])=[O:29])[CH:20]=1)[CH3:18]>>[CH2:17]([C:19]1[NH:23][C:22]([CH:24]=[C:9]2[C:8]3[C:12](=[CH:13][CH:14]=[CH:15][C:7]=3[C:4]3[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=3)[NH:11][C:10]2=[O:16])=[C:21]([CH2:26][CH2:27][C:28]([OH:30])=[O:29])[CH:20]=1)[CH3:18]
Reactant: O=C1Cc2c(cccc2-c2ccncc2)N1
Reactant: CCc1cc(CCC(=O)O)c(C=O)[nH]1
Product: CCc1cc(CCC(=O)O)c(C=C2C(=O)Nc3cccc(-c4ccncc4)c32)[nH]1

Procedure:
4-Pyridin-4-yl-1,3-dihydroindol-2-one was condensed with 3-(5-ethyl-2-formyl-1H-pyrrol-3-yl)-propionic acid to give the title compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[CH:5]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[NH:4][C:3]1=[O:12].Cl[Si](C)(C)C.[CH3:19][OH:20]>>[C:6]1([CH:5]([NH2:4])[C:2]([CH3:13])([CH3:1])[C:3]([O:20][CH3:19])=[O:12])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CC1(C)C(=O)NC1c1ccccc1
Reactant: CO
Agent: C[Si](C)(C)Cl
Product: COC(=O)C(C)(C)C(N)c1ccccc1
Yield: 98 %

Procedure:
A solution of 15.4 g of 3,3-dimethyl-4-phenylazetidin-2-one and 14.3 g of chlorotrimethylsilane in 150 cm3 of anhydrous methanol are refluxed for 6 hours. The solution is then evaporated and ethyl acetate and aqueous sodium bicarbonate at 5% are added. The organic phase is washed with water, is dried on sodium sulphate, and is then evaporated, obtaining 17.8 g of methyl 3-phenyl-3-amino-2,2-dimethylpropanoate (yield 98%).
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][CH2:15][C:16]([OH:18])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:19]([NH:22][NH:23][C:24](=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([CH3:21])[CH3:20].C(N(C(C)C)CC)(C)C.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH:19]([N:22]([C:16](=[O:18])[CH2:15][CH2:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[O:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[NH:23][C:24](=[O:31])[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)([CH3:21])[CH3:20]
Reactant: O=C(O)CCc1ccccc1Oc1ccccc1
Reactant: CC(C)NNC(=O)c1ccccc1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)N(NC(=O)c1ccccc1)C(=O)CCc1ccccc1Oc1ccccc1
Yield: 22.1 %

Procedure:
A solution of 3-(2-phenoxy-phenyl)-propionic acid (110 mg, 0.45 mmoles) and benzoic acid N′-isopropyl-hydrazide (97 mg, 0.54 mmoles) in DMF (5 mL) was treated with diisopropylethylamine (0.20 mL, 1.13 mmol), and PyBroP (315 mg, 0.68 mmol) at room temperature for 18 h. The reaction mixture was partitioned between 1N HCl and ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulfate, filtered and concentrated. The crude was absorbed on silica and purified on a silica gel column with a 30-50% ethyl acetate/hexanes gradient to afford the product as a solid (40 mg, 22%). LC-MS m/e 425.44 (M+H+)
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[C:7]2[OH:12].[Cl-].[CH3:14][O:15][C:16]1[C:28]([O:29][CH3:30])=[CH:27][CH:26]=[CH:25][C:17]=1[CH:18]=[N+:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1>>[NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH:18]([C:17]1[CH:25]=[CH:26][CH:27]=[C:28]([O:29][CH3:30])[C:16]=1[O:15][CH3:14])[N:19]1[CH2:20][CH2:21][O:22][CH2:23][CH2:24]1)=[C:7]2[OH:12]
Reactant: COc1cccc(C=[N+]2CCOCC2)c1OC
Reactant: Nc1cccc2c(O)cccc12
Agent: [Cl-]
Product: COc1cccc(C(c2ccc3c(N)cccc3c2O)N2CCOCC2)c1OC

Procedure:
The preparation was carried out in accordance with general synthesis instructions 4 from 5-amino-1-naphthol and 4-(2,3-dimethoxy-benzylidene)-morpholin-4-ium chloride, which had been prepared in accordance with example 21.