Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH3:8][C:9]1[CH:48]=[C:47]([CH3:49])[CH:46]=[CH:45][C:10]=1[O:11][CH2:12][CH:13]([OH:44])[CH2:14][NH:15][C:16]1[CH:21]=[CH:20][N:19]=[C:18]([O:22]C)[C:17]=1[C:24]1[NH:35][C:34]2[C:26](=[CH:27][C:28]3[CH2:29][N:30]([CH:37]4[CH2:42][CH2:41][N:40]([CH3:43])[CH2:39][CH2:38]4)[C:31](=O)[C:32]=3[CH:33]=2)[N:25]=1.CC1C=C(C)C=CC=1OCC(O)CNC1C=CNC(=O)C=1C1NC2C(=CC3CN(C4CCN(C)CC4)C(=O)C=3C=2)N=1.C[Si](C=[N+]=[N-])(C)C>CO.C1COCC1.CC#N>[CH3:8][C:9]1[CH:48]=[C:47]([CH3:49])[CH:46]=[CH:45][C:10]=1[O:11][CH2:12][CH:13]([OH:44])[CH2:14][NH:15][C:16]1[CH:21]=[CH:20][NH:19][C:18](=[O:22])[C:17]=1[C:24]1[NH:35][C:34]2[C:26]([N:25]=1)=[CH:27][C:28]1[CH2:29][N:30]([CH:37]3[CH2:38][CH2:39][N:40]([CH3:43])[CH2:41][CH2:42]3)[CH2:31][C:32]=1[CH:33]=2
Reactant: COc1nccc(NCC(O)COc2ccc(C)cc2C)c1-c1nc2cc3c(cc2[nH]1)C(=O)N(C1CCN(C)CC1)C3
Agent: C[Si](C)(C)C=[N+]=[N-]
Agent: Cc1ccc(OCC(O)CNc2cc[nH]c(=O)c2-c2nc3cc4c(cc3[nH]2)C(=O)N(C2CCN(C)CC2)C4)c(C)c1
Solvent: CC#N
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(OCC(O)CNc2cc[nH]c(=O)c2-c2nc3cc4c(cc3[nH]2)CN(C2CCN(C)CC2)C4)c(C)c1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
TFA salt of 2-{4-[3-(2,4-dimethyl-phenoxy)-2-hydroxy-propylamino]-2-methoxy-pyridin-3-yl}-6-(1-methyl-piperidin-4-yl)-6,7-dihydro-3H-1,3,6-triaza-s-indacen-5-one: To a suspension of 2-{4-[3-(2,4-dimethyl-phenoxy)-2-hydroxy-propylamino]-2-oxo-1,2-dihydro-pyridin-3-yl}-6-(1-methyl-piperidin-4-yl)-6,7-dihydro-3H-1,3,6-triaza-s-indacen-5-one (19 mg, 0.034 mmol) in a mixed solvent of THF/CH3CN (1 mL/1 mL) was added a solution of TMSCH2N2 (2.0 M, 2 mL, 4 mmol) at 0° C. After it was stirred at 0° C. for 2 h, the reaction mixture was mixed with MeOH (1 mL), stirred at the room temperature for 22 h, and purified with a preparative TLC plate to furnish a crude which was subjected to HPLC re-purification to afford the title compound in TFA salt form (4.98 mg, 21%). 1H NMR (DMSO-d6) δ 1.92-2.10 (4H), 2.19 (s, 3H, CH3), 2.22 (s, 3H, CH3), 2.81 (s, 3H, CH3), 3.20 (m, 2H), 3.40 (s, 3H, OCH3), 3.45-3.55 (3H), 3.68 (m, 1H), 4.00 (s, 2H), 4.12 (m, 1H), 4.30 (m, 1H), 4.43 (s, 1H), 4.48 (s, 1H), 5.47 (br s, 1H, NH), 6.27 (d, J=6 Hz, 1H), 6.82 (d, J=8 Hz, 1H), 6.89-6.97 (2H), 6.98 (s, 1H), 7.15 (s, 0.5H), 7.30 (s, 0.5H), 7.65-7.72 (1.5H), 7.80 (s, 0.5H), 7.95 (s, 0.5H), 9.65 (br s, 1H, NH), 11.11 (br s, 1H, NH); ESI-MS m/z 571.5 (MH+).
Reaction SMILES: [Li].[C:2]([O:8][CH2:9][CH3:10])(=[O:7])[CH2:3][C:4]([O-:6])=O.[Br:11][C:12]1[CH:20]=[CH:19][C:15](C(Cl)=O)=[C:14]([Cl:21])[CH:13]=1>>[Br:11][C:12]1[CH:20]=[CH:19][C:15]([C:4]([CH2:3][C:2]([O:8][CH2:9][CH3:10])=[O:7])=[O:6])=[C:14]([Cl:21])[CH:13]=1
Reactant: O=C(Cl)c1ccc(Br)cc1Cl
Reactant: CCOC(=O)CC(=O)[O-]
Agent: [Li]
Product: CCOC(=O)CC(=O)c1ccc(Br)cc1Cl

Procedure:
The starting material was prepared by conventional procedures starting from the lithium salt of monoethyl malonate and 4-bromo-2-chlorobenzoyl chloride which reacted to form ethyl 4-bromo-2-chlorobenzoylacetate. The latter was caused to react with dimethylformamide dimethylacetal to give ethyl 3-dimethylamino-2-(4-bromo2-chlorobenzoyl)propenoate, which by reaction with 4-fluoroaniline afforded said starting material.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][C:5]([Cl:9])=[C:4]([Cl:10])[C:3]=1[CH3:11].[C:12](O)(=[O:16])[C:13](O)=[O:14]>Cl>[Cl:10][C:4]1[C:3]([CH3:11])=[C:2]2[C:7](=[CH:6][C:5]=1[Cl:9])[NH:8][C:13](=[O:14])[C:12](=[O:16])[NH:1]2
Reactant: O=C(O)C(=O)O
Reactant: Cc1c(N)c(N)cc(Cl)c1Cl
Agent: Cl
Product: Cc1c(Cl)c(Cl)cc2[nH]c(=O)c(=O)[nH]c12
Yield: 65.7 %

Procedure:
A mixture of 2,3-diamino-5,6-dichlorotoluene (21.6 g, 0.137 mol) and oxalic acid (18.45 g, 0.206 mol) in hydrochloric acid (4M, 900 mL) was heated at reflux for 6 hours, cooled and filtered. The dark brown solid was suspended in diethyl ether, filtered and washed with more ether to give 1,4-dihydro-6,7-dichloro-5-methyl-quinoxaline-2,3-dione (22.06 g, 66%). 1H NMR (300 MHz, DMSO) 2.40 (3H, s), 7.14 (1H, s), 11.37 (1H, s), 11.94 (1H, s).
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[CH:4][C:3]=1[C:7]([C:9]1[S:10][CH:11]=[CH:12][CH:13]=1)=[O:8].CN(C)[CH:16]=[CH:17][C:18]([C:20]1[C:21]([F:32])=[CH:22][C:23]([F:31])=[C:24]([N:26]([CH3:30])[C:27](=[O:29])[CH3:28])[CH:25]=1)=O.C(OCC)(=O)C>C(O)(=O)C>[F:31][C:23]1[CH:22]=[C:21]([F:32])[C:20]([C:18]2[N:6]3[N:5]=[CH:4][C:3]([C:7]([C:9]4[S:10][CH:11]=[CH:12][CH:13]=4)=[O:8])=[C:2]3[N:1]=[CH:16][CH:17]=2)=[CH:25][C:24]=1[N:26]([CH3:30])[C:27](=[O:29])[CH3:28]
Reactant: Nc1[nH]ncc1C(=O)c1cccs1
Reactant: CC(=O)N(C)c1cc(C(=O)C=CN(C)C)c(F)cc1F
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CC(=O)N(C)c1cc(-c2ccnc3c(C(=O)c4cccs4)cnn23)c(F)cc1F
Yield: 69.3 %

Procedure:
A mixture of 0.217 g (1.12 mmol) of (5-amino-1H-pyrazol-4-yl)-thiophene-2-yl-methanone and 0.3 g (1.12 mmol) of N-[5-(3-dimethylamino-acryloyl)-2,4-difluoro-phenyl]-N-methyl-acetamide in 10 mL of glacial acetic acid was refluxed for 2.5 hours and then the solvent was removed by reduced pressure distillation. To the resulting residue were added 15 mL of dichloromethane and 10 mL of saturated sodium bicarbonate solution. The two layers were separated, and the aqueous layer was washed with 10 mL of dichloromethane. The organic layers were washed with 10 mL of water and dried over magnesium sulfate. The dichloromethane layer was evaporated to dryness to yield an oil which, in the presence of ethyl acetate, gave 320 mg of N-{2,4-difluoro-5-[3-(thiophene-2-carbonyl)-pyrazolo[1,5-a]pyrimidin-7-yl]-phenyl}-N-methyl-acetamide as a solid (yield 69%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:30])[N:7]([CH2:28][CH3:29])[CH2:8][C:9]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][C:10]=1B1OC(C)(C)C(C)(C)O1)([CH3:4])([CH3:3])[CH3:2].[CH3:31][O:32][C:33](=[O:42])[CH2:34][C:35]1[CH:36]=[N:37][CH:38]=[C:39](Br)[CH:40]=1.C(=O)([O-])[O-].[K+].[K+]>COCCOC.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>[CH3:31][O:32][C:33](=[O:42])[CH2:34][C:35]1[CH:36]=[N:37][CH:38]=[C:39]([C:10]2[CH:11]=[CH:12][C:13]([C:15]([F:18])([F:16])[F:17])=[CH:14][C:9]=2[CH2:8][N:7]([C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:30])[CH2:28][CH3:29])[CH:40]=1
Reactant: COC(=O)Cc1cncc(Br)c1
Reactant: CCN(Cc1cc(C(F)(F)F)ccc1B1OC(C)(C)C(C)(C)O1)C(=O)OC(C)(C)C
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: [K+]
Solvent: O
Solvent: COCCOC
Product: CCN(Cc1cc(C(F)(F)F)ccc1-c1cncc(CC(=O)OC)c1)C(=O)OC(C)(C)C
Temperature: 80 °C
Reaction time: 12 h

Procedure:
Ethyl-[2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-5-trifluoromethyl-benzyl]-carbamic acid tert-butyl ester (1.0 g, 2.33 mmol), (5-bromo-pyridin-3-yl)-acetic acid methyl ester (0.535 g, 2.33 mmol), potassium carbonate (0.807 g, 5.8 mmol), and tetrakis(triphenylphosphine)palladium(0) (0.100 g, 0.09 mmol) were combined in DME (8 mL) and H2O (4 mL). The solution was purged with N2, and then the reaction was stirred at 80° C. for 12 hours. The mixture was partitioned between EtOAc and H2O, and the aqueous layer was extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered, and concentrated, and the residue was purified by silica gel chromatography to give (5-{2-[(N-tert-butoxycarbonyl-N-ethyl-amino)-methyl]-4-trifluoromethyl-phenyl}-pyridin-3-yl)-acetic acid methyl ester.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH:9]([CH2:13][C:14]([F:17])([F:16])[F:15])[C:10]([NH2:12])=[O:11])[C:5]([F:18])=[CH:4][C:3]=1[C:19]#[N:20].[NH2:21][C:22]1[CH:23]=[N:24][C:25]2[C:30]([CH:31]=1)=[CH:29][CH:28]=[CH:27][CH:26]=2.O.O.O.[O-]C1C=CC=CC=1.[Na+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:19]([C:3]1[CH:4]=[C:5]([F:18])[C:6]([NH:8][CH:9]([CH2:13][C:14]([F:17])([F:16])[F:15])[C:10]([NH2:12])=[O:11])=[N:7][C:2]=1[NH:21][C:22]1[CH:23]=[N:24][C:25]2[C:30]([CH:31]=1)=[CH:29][CH:28]=[CH:27][CH:26]=2)#[N:20]
Reactant: Nc1cnc2ccccc2c1
Reactant: N#Cc1cc(F)c(NC(CC(F)(F)F)C(N)=O)nc1Cl
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: C1COCCO1
Product: N#Cc1cc(F)c(NC(CC(F)(F)F)C(N)=O)nc1Nc1cnc2ccccc2c1
Reaction time: 3 h
Yield: 122.9 %

Procedure:
A mixture of the crude 2-(6-chloro-5-cyano-3-fluoropyridin-2-ylamino)-4,4,4-trifluorobutanamide (109 mg, 0.350 mmol), 3-aminoquinoline (52 mg, 0.361 mmol), sodium phenoxide trihydrate (85 mg, 0.500 mmol), xantphos (30 mg, 0.051 mmol) and Pd2 dba3 (20 mg, 0.021 mmol) in dioxane (2 mL) was degassed with Ar, then was stirred at 105 C for 3 h. Water and EtOAc were added. The organic phase was washed with aq. 1N NaOH, dried over Na2SO4, concentrated in vacuo to give crude 2-(5-cyano-3-fluoro-6-(quinolin-3-ylamino)pyridin-2-ylamino)-4,4,4-trifluorobutanamide (180 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[C:9](=[O:12])[O:10][CH2:11][C:7]=2[CH:6]=[C:5]([CH:13]=[CH2:14])[CH:4]=1.ClC1C=CC=C(C(OO)=[O:23])C=1>C(Cl)Cl.C(=O)(O)[O-].[Na+]>[CH3:1][O:2][C:3]1[C:8]2[C:9](=[O:12])[O:10][CH2:11][C:7]=2[CH:6]=[C:5]([CH:13]2[CH2:14][O:23]2)[CH:4]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=Cc1cc2c(c(OC)c1)C(=O)OC2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COc1cc(C2CO2)cc2c1C(=O)OC2
Reaction time: 12 h

Procedure:
To a solution of 7-methoxy-5-vinyl-2-benzofuran-1(3H)-one in DCM (5 mL) was added meta-chloro perbenzoic acid (0.18 g, 1.05 mmol) at 0° C. and stirred for 12 h. TLC indicated completion of the reaction; the mixture was diluted with saturated sodium bicarbonate solution and extracted with DCM (2×). The combined organic extracts were washed with brine, dried (Na2SO4), filtered and concentrated in vacuo. The resulting epoxide was purified by silica gel column chromatography (hexanes/EtOAc=1/1) to give 7-methoxy-5-oxiran-2-yl-2-benzofuran-1(3H)-one. LC/MS: [(M+1)]+=207.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:23][CH3:24])=[C:6]([CH:22]=1)[C:7]([NH:9][CH2:10][CH2:11][C:12]1[S:13][C:14]([S:18](=[O:21])(=[O:20])[NH2:19])=[CH:15][C:16]=1[CH3:17])=[O:8].[O:25]([C:27]#[N:28])[K]>C(N(CC)CC)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:23][CH3:24])=[C:6]([CH:22]=1)[C:7]([NH:9][CH2:10][CH2:11][C:12]1[S:13][C:14]([S:18]([NH:19][C:27]([NH2:28])=[O:25])(=[O:20])=[O:21])=[CH:15][C:16]=1[CH3:17])=[O:8]
Reactant: N#CO[K]
Reactant: COc1ccc(Cl)cc1C(=O)NCCc1sc(S(N)(=O)=O)cc1C
Solvent: CCN(CC)CC
Product: COc1ccc(Cl)cc1C(=O)NCCc1sc(S(=O)(=O)NC(N)=O)cc1C

Procedure:
311 mg (0.8 mmol) of 2-[2-(5-chloro-2-methoxybenzoyl-amino)ethyl]-3-methyl-5-sulfamoylthiophene were treated with 448 mg of KOCN and 0.6 ml of triethylamine, and the mixture was then heated to reflux for 4 h. The cooled solution was filtered and evaporated to dryness. The residue was stirred with 40 ml of H2O, 25 ml of triethylamine and 25 ml of ethyl acetate. The organic phase was extracted 3 times with water/1% triethylamine. The combined aqueous phases were acidified with 2N hydrochloric acid. The precipitate formed was stirred for 3 hours in an ice bath and filtered off with suction.
Reaction SMILES: Br[CH2:2][C:3]1[C:13]([Cl:14])=[N:12][CH:11]=[CH:10][C:4]=1[C:5]([O:7]CC)=O.Cl.[CH3:16][C:17]1[N:22]=[C:21]([CH:23]([NH2:25])[CH3:24])[CH:20]=[N:19][C:18]=1[O:26][CH2:27][C:28]([F:31])([F:30])[F:29]>>[Cl:14][C:13]1[C:3]2[CH2:2][N:25]([CH:23]([C:21]3[CH:20]=[N:19][C:18]([O:26][CH2:27][C:28]([F:30])([F:31])[F:29])=[C:17]([CH3:16])[N:22]=3)[CH3:24])[C:5](=[O:7])[C:4]=2[CH:10]=[CH:11][N:12]=1
Reactant: Cc1nc(C(C)N)cnc1OCC(F)(F)F
Reactant: CCOC(=O)c1ccnc(Cl)c1CBr
Agent: Cl
Product: Cc1nc(C(C)N2Cc3c(ccnc3Cl)C2=O)cnc1OCC(F)(F)F
Yield: 80 %

Procedure:
The title compound is prepared in 80% yield (300 mg, brown solid) from ethyl 3-(bromomethyl)-2-chloroisonicotinate (270 mg, 0.96 mmol, Step-1 of Intermediate-1) and 1-(6-methyl-5-(2,2,2-trifluoroethoxy)pyrazin-2-yl)ethanamine hydrochloride (260 mg, 0.96 mmol, Amine-55, single enantiomer) in a similar manner to Intermediate-2.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[Br:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]=[CH:10]2.[OH-].[Na+].CN(C)[CH:20]=[O:21]>>[Br:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]=[C:10]2[CH:20]=[O:21]
Reactant: Brc1ccc2[nH]ccc2c1
Reactant: CN(C)C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: O=Cc1c[nH]c2ccc(Br)cc12
Temperature: 10 °C
Reaction time: 1 h
Yield: 97.7 %

Procedure:
To a solution of phosphorous oxychloride (26.1 g) and dry dimethylformamide (50.9 ml), cooled to -10° C., was added 5-bromoindole (30 g) in portions. The reaction mixture was stirred at 10° C. for 1 hr. and at 35° C. for 1 hr. Ice (100 g) was added to the reaction mixture, followed by sodium hydroxide solution (50 ml). The mixture was heated on a steam bath for one-half hour. The precipitate was collected and recrystallized from ethanol to give 35.5 g (97.7%) of product.
Reaction SMILES: Cl[C:2]1[C:9]([Cl:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[SH:11][CH2:12][CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16]>>[Cl:10][C:9]1[CH:8]=[CH:7][CH:6]=[C:3]([CH:4]=[O:5])[C:2]=1[S:11][CH2:12][CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CCOC(=O)CCCS
Reactant: O=Cc1cccc(Cl)c1Cl
Product: CCOC(=O)CCCSc1c(Cl)cccc1C=O

Procedure:
Ethyl 4-(2-chloro-6-formylphenylthio)butyrate was synthesized from 2,3-dichlorobenzaldehyde and ethyl 4-mercaptobutyrate in the same manner as Example 2. After column chromatography, vacuum concentration yielded ethyl 4-(2-chloro-6-formylpehylthio)butyrate (Yield 70%) as a yellow oily matter.
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH2:11][O:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+:13]([O-])([OH:15])=[O:14].O>C(O)(=O)C>[N+:13]([C:4]1[CH:5]=[CH:6][C:1]([CH:7]2[CH2:8][CH2:9][O:10][CH2:11][CH2:12]2)=[CH:2][CH:3]=1)([O-:15])=[O:14]
Reactant: O=[N+]([O-])O
Reactant: c1ccc(C2CCOCC2)cc1
Solvent: CC(=O)O
Solvent: O
Product: O=[N+]([O-])c1ccc(C2CCOCC2)cc1
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
A solution of 32.4 g of 4-(phenyl)-tetrahydropyran [Ber., Vol. 56 (1923), p. 2013] in 60 ml of acetic acid was added at -10 to -12° C over an hour to a solution of 120 ml of concentrated nitric acid and 50 ml of acetic acid and the mixture was stirred for 30 minutes at -10° C. 100 ml of ice and 100 ml of water were added to the mixture and the mixture was filtered. The recovered precipitate was washed with water and dried to obtain 35 g of 4-(p-nitrophenyl)-tetrahydropyran melting at 124° C.
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]([O:9][CH3:10])=[O:8])=[CH:4][CH:3]=1.[Cl:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.C(OCC)(=O)C.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>[Cl:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:2]1[S:6][C:5]([C:7]([O:9][CH3:10])=[O:8])=[CH:4][CH:3]=1
Reactant: OB(O)c1ccccc1Cl
Reactant: COC(=O)c1ccc(Br)s1
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: CCOC(C)=O
Solvent: O
Product: COC(=O)c1ccc(-c2ccccc2Cl)s1
Temperature: 110 °C
Reaction time: 20 h

Procedure:
Under argon, 310 mg (1.40 mmol) of methyl 5-bromothiophene-2-carboxylate together with 328 mg (2.10 mmol) of 2-chlorophenylboronic acid were dissolved in 10 ml of dioxane, and 81 mg (0.07 mmol) of tetrakis(triphenylphosphine)palladium(0) were added. The mixture was heated to 110° C., 1.4 ml (2.80 mmol) of 2 M aqueous sodium carbonate solution were added and the mixture was stirred at this temperature for 20 h. For work-up, the reaction mixture was allowed to cool to RT and diluted with 20 ml of ethyl acetate and 20 ml of water. After phase separation, the aqueous phase was extracted two more times with in each case 20 ml of ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified chromatographically on silica gel (mobile phase: cyclohexane/ethyl acetate 15:1, then 10:1). This gave 289 mg (61% of theory) of the target compound in a purity of 75%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]([CH:14]=[C:15]([O:17][CH3:18])[CH:16]=2)[C:11]([OH:13])=O)[CH:5]=[CH:6][CH:7]=1.C(Cl)(=O)C(Cl)=O.[NH2:25][C:26]1[C:27]([F:34])=[C:28]([OH:33])[CH:29]=[CH:30][C:31]=1[F:32].O>C(Cl)Cl.CN(C=O)C.C1COCC1>[F:34][C:27]1[C:28]([OH:33])=[CH:29][CH:30]=[C:31]([F:32])[C:26]=1[NH:25][C:11](=[O:13])[C:10]1[CH:14]=[C:15]([O:17][CH3:18])[CH:16]=[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)[CH:9]=1
Reactant: Nc1c(F)ccc(O)c1F
Reactant: COc1cc(C(=O)O)cc(-c2cccc(F)c2)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COc1cc(C(=O)Nc2c(F)ccc(O)c2F)cc(-c2cccc(F)c2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 67.9 %

Procedure:
To a solution of 3-(3-fluorophenyl)-5-methoxy-benzoic acid (747 mg, 3.0 mmol, 1.1 eq) in DCM (20 mL) was added oxalyl chloride (1.05 g, 8.3 mmol, 3.0 eq) and DMF (3 drops). The reaction mixture was stirred at room temperature for 2 h, then concentrated. The oil obtained was dissolved in THF (5 mL) and added dropwise to a cooled solution of 3-Amino-2,4-difluoro-phenol (intermediate X(a)) (400 mg, 2.76 mmol, 1.0 eq) in THF (25 mL) at 0° C. After addition, the reaction mixture was stirred at room temperature for 2 h. The resulting mixture was poured into water and extracted with EtOAc. The organic extract was washed with water and brine, dried (Na2SO4), filtered, evaporated in vacuo and purified by column chromatography (EtOAc:petroleum ether, 0:1 to 1:3) to give the title compound as a yellow solid (700 mg, 68%).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[CH2:7])=[CH:4][CH:3]=1.[C:10]([O:14][C:15]([O:17][C:18]1[CH:25]=[CH:24][C:21]([CH:22]=[CH2:23])=[CH:20][CH:19]=1)=[O:16])([CH3:13])([CH3:12])[CH3:11].[CH2:26]([O:28][CH:29]=[CH2:30])[CH3:27]>>[CH2:26]([O:28][CH2:29][CH2:30][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[CH2:7])=[CH:4][CH:3]=1)[CH3:27].[OH:17][C:18]1[CH:25]=[CH:24][C:21]([CH:22]=[CH2:23])=[CH:20][CH:19]=1.[C:10]([O:14][C:15]([O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[CH2:7])=[CH:4][CH:3]=1)=[O:16])([CH3:13])([CH3:12])[CH3:11]
Reactant: C=COCC
Agent: C=Cc1ccc(O)cc1
Agent: C=Cc1ccc(OC(=O)OC(C)(C)C)cc1
Product: C=Cc1ccc(OCCOCC)cc1

Procedure:
Using 11.4 g of poly(p-hydroxystyrene/p-tert-butoxycarbonyloxystyrene) obtained according to (2) above and 2.5 g of ethylvinyl ether, the procedure of (3) of Preparation Example 1 was carried out for reaction and after-treatments to obtain 6.7 g of poly(p-1-ethoxyethoxystyrene/p-hydroxystyrene/p-tert-butoxycarbonyloxystyrene) as white powdery crystal. P-1-ethoxyethoxystyrene unit/p-hydroxystyrene unit/p-tert-butoxycarbonyloxystyrene unit molar ratio in the polymer≈30:64:6 (1H NMR). Mw≈20,000; Mw/Mn=1.90 (GPC with polystyrene calibration).
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@@H:9]([CH2:15][O:16][C:17](=[O:19])[CH3:18])[O:8][C@H:7](Br)[C@@H:6]1[NH:21][C:22](=[C:24]1[C:29](=[O:30])[CH2:28][C:27]([CH3:32])([CH3:31])[CH2:26][C:25]1=[O:33])[CH3:23])(=[O:3])[CH3:2].C(=O)([O-])O.[Na+].[N-:39]=[N+:40]=[N-:41].[Na+]>C(OCC)(=O)C.S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC>[N:39]([C@H:7]1[O:8][C@H:9]([CH2:15][O:16][C:17](=[O:19])[CH3:18])[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:5]([O:4][C:1](=[O:3])[CH3:2])[C@H:6]1[NH:21][C:22](=[C:24]1[C:29](=[O:30])[CH2:28][C:27]([CH3:32])([CH3:31])[CH2:26][C:25]1=[O:33])[CH3:23])=[N+:40]=[N-:41]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(=O)OC[C@H]1O[C@H](Br)[C@H](NC(C)=C2C(=O)CC(C)(C)CC2=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: O=S(=O)([O-])O
Solvent: CCOC(C)=O
Product: CC(=O)OC[C@H]1O[C@H](N=[N+]=[N-])[C@H](NC(C)=C2C(=O)CC(C)(C)CC2=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reaction time: 16 h
Yield: 75.3 %

Procedure:
3,4,6-tri-O-Acetyl-2-deoxy-2-[1-(4,4-dimethyl-2,6-dioxocyclohex-1-ylidene)-ethylamino]-α-D-glucopyranosyl bromide (3) (150 g, 0.282 mol) is suspended in ethyl acetate (3 L)and a solution of 10% aqueous sodium hydrogen carbonate (1500 mnL) containing sodium azide (22 g, 0.338 mol) is added. Tetrabutylammonium hydrogen sulfate (28.7 g, 30 mol %) was added and the biphasic mnixture stirred vigorously for 16 h. The organic layer was then separated, extracted and dried, then the solvent removed at reduced pressure. The residue was chromatographed as above to yield the desired product (105 g, 75%). 1H NMR (500 MHz, CDCl3) δ 13.90 (d, J=9.6, 1H), 5.22 (t, J=9.6, 1H), 5.11 (t, J=9.7, 1H), 4.90 (d, J=8.9, 1H), 4.36 (dd, J=4.5, 12.5, 1H), 4.17 (dd, J=12.4, 1.7, 1H), 3.81-3.91 (m, 2H), 2.60 (s, 3H, 2.42 (s, 2H), 2.36 (s, 2H), 2.11, (s, 3H), 2.04 (s, 3H), 1.03 (s, 3H). m/z 495 (M+H).
Reaction SMILES: [Si]([N:8]1[CH:12]=[CH:11][N:10]=[CH:9]1)(C(C)(C)C)(C)C.C([Li])CCC.[CH2:18]([N:21]([CH2:35][CH2:36][CH3:37])[C:22]([C:24]1[CH:25]=[C:26]([CH:31]=[C:32](I)[CH:33]=1)[C:27]([O:29][CH3:30])=[O:28])=[O:23])[CH2:19][CH3:20]>O1CCCC1.C(OCC)(=O)C.[Cl-].[Zn+2].[Cl-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd]>[CH2:35]([N:21]([CH2:18][CH2:19][CH3:20])[C:22]([C:24]1[CH:25]=[C:26]([CH:31]=[C:32]([C:9]2[NH:8][CH:12]=[CH:11][N:10]=2)[CH:33]=1)[C:27]([O:29][CH3:30])=[O:28])=[O:23])[CH2:36][CH3:37]
Reactant: CC(C)(C)[Si](C)(C)n1ccnc1
Reactant: CCCN(CCC)C(=O)c1cc(I)cc(C(=O)OC)c1
Agent: [Pd]
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCN(CCC)C(=O)c1cc(C(=O)OC)cc(-c2ncc[nH]2)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a −70° C. stirred solution of 1-tert-butyldimethylsilylimidazole (602 mg, 3.3 mmol) in tetrahydrofuran (10 mL) is added n-butyllithium (1.6 M in hexanes, 2.3 mL, 3.63 mmol). After 30 min, zinc chloride (1 M in diethyl ether, 9.9 mL, 9.9 mmol) is added and the reaction mixture is warmed to 0° C. for 1 h. To this mixture is then added methyl 3-[(dipropylamino)carbonyl]-5-iodobenzoate prepared by the method in EXAMPLE SP-281, step2 (1.17 g, 3 mmol) followed by palladium(0) tetrakis(triphenylphosphine) (173 mg, 0.15 mmol). The reaction mixture is heated at reflux for 15 h. The reaction mixture is diluted with ethyl acetate (50 mL), washed with water, and brine, dried (sodium sulfate), filtered, and concentrated under reduced pressure. Purification by flash column chromatography (silica gel, 1–5% methanol/methylene chloride) provides the title compound in pure form. 1H NMR (300 MHz, CDCl3) δ 8.64 (s, 1H), 8.14 (s, 1H), 7.97 (s, 1H), 7.19 (s, 2H), 3.96 (s, 3H), 3.51 (m, 2H), 3.32 (m, 2H), 1.73 (m, 2H), 1.57 (m, 2H), 1.01 (m, 3H), 0.73 (m, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][NH:7][CH2:8][C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])=[CH:4][CH:3]=1.[C:21](OC(=O)C)(=[O:23])[CH3:22]>C(Cl)Cl>[Br:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][N:7]([CH2:8][C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[C:21](=[O:23])[CH3:22])=[CH:4][CH:3]=1
Reactant: CC(=O)OC(C)=O
Reactant: O=C(CNCc1ccc(Br)cc1)OCc1ccccc1
Solvent: ClCCl
Product: CC(=O)N(CC(=O)OCc1ccccc1)Cc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.2 %

Procedure:
To a solution of 80A (500 mg, 1.50 mmol) in 5 mL CH2Cl2, were added TEA (0.229 mL, 1.65 mmol) and acetic anhydride (0.156 mL, 1.65 mmol). The mixture was stirred at rt for 2 h, then concentrated. The crude product was purified via flash chromatography (0 to 100% EtOAc in hexanes) to afford 80B (560 mg, 99%). MS (ESI) m/z 376.0 (M+H)+.