Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1](=[C:3]1[N:7]=[C:6]([CH3:8])[C:5]([CH3:13])([CH2:9][CH2:10][CH2:11][CH3:12])[S:4]1)[OH:2].[CH3:14][N:15]=[C:16]=[O:17]>>[CH3:14][NH:15][C:16]([O:2][N:1]=[C:3]1[N:7]=[C:6]([CH3:8])[C:5]([CH3:13])([CH2:9][CH2:10][CH2:11][CH3:12])[S:4]1)=[O:17]
Reactant: CCCCC1(C)SC(=NO)N=C1C
Reactant: CN=C=O
Product: CCCCC1(C)SC(=NOC(=O)NC)N=C1C

Procedure:
2-oxo-4,5-dimethyl-5-butyl-3-thiazoline-oxime was reacted with methyl isocyanate as described in Example 4 to yield 2-oxo-4,5-dimethyl-5-butyl-3-thiazoline-O-(methylcarbamoyl)-oxime as a viscous oil; nD44.5 =1.5324. The 2-oxo-4,5-dimethyl-5-butyl-3-thiazoline-oxime starting material melts at 100°-102° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[C:14]1[CH:19]=[CH:18][N:17]2[N:20]=[CH:21][C:22]([C:23]([NH:25][O:26][CH2:27][C@@H:28]3[CH2:32][O:31]C(C)(C)[O:29]3)=[O:24])=[C:16]2[N:15]=1.Cl>C1COCC1.C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[C:14]1[CH:19]=[CH:18][N:17]2[N:20]=[CH:21][C:22]([C:23]([NH:25][O:26][CH2:27][C@@H:28]([OH:29])[CH2:32][OH:31])=[O:24])=[C:16]2[N:15]=1
Reactant: CC1(C)OC[C@@H](CONC(=O)c2cnn3ccc(N4CCC[C@@H]4c4cc(F)ccc4F)nc23)O1
Agent: Cl
Solvent: C1CCOC1
Solvent: ClCCl
Product: O=C(NOC[C@@H](O)CO)c1cnn2ccc(N3CCC[C@@H]3c3cc(F)ccc3F)nc12
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)-N-(((S)-2,2-dimethyl-1,3-dioxolan-4-yl)methoxy)pyrazolo[1,5-a]pyrimidine-3-carboxamide (135 mg, 0.285 mmol) in THF (4.0 mL) was added 6M HCl (1.0 mL) dropwise and the mixture was stirred at ambient temperature for 1.5 hours. The reaction mixture was concentrated to approximately 1 mL and was diluted with H2O (5 mL). The resulting milky white mixture was extracted with EtOAc and the combined extracts were washed with 1M Na2CO3 and saturated NaCl. The EtOAc solution was dried over MgSO4 and filtered through a packed Celite pad capped with a layer of MgSO4. The solution was concentrated to give a colorless foam that was dissolved in minimal CH2Cl2 and treated with hexanes to give a white suspension. The suspension was concentrated to give the title compound as a white solid that was dried in vacuum (102 mg, 82%). MS (apci) m/z=434.0 (M+H).
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH2:12][CH2:13][CH2:14][CH2:15][N:16]([CH2:27][C:28]1[N:32](S(O)(=O)=O)[C:31]2[CH2:37][CH2:38][CH2:39][CH2:40][C:30]=2[N:29]=1)[CH:17]1[C:26]2[N:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH2:20][CH2:19][CH2:18]1.Cl.[OH-].[Na+]>>[NH:29]1[C:30]2[CH2:40][CH2:39][CH2:38][CH2:37][C:31]=2[N:32]=[C:28]1[CH2:27][N:16]([CH:17]1[C:26]2[N:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH2:20][CH2:19][CH2:18]1)[CH2:15][CH2:14][CH2:13][CH2:12][N:3]1[C:2](=[O:1])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]1=[O:11]
Reactant: O=C1c2ccccc2C(=O)N1CCCCN(Cc1nc2c(n1S(=O)(=O)O)CCCC2)C1CCCc2cccnc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C1c2ccccc2C(=O)N1CCCCN(Cc1nc2c([nH]1)CCCC2)C1CCCc2cccnc21
Temperature: 25 °C
Yield: 66.2 %

Procedure:
2-{[[4-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-butyl]-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-methyl}-4,5,6,7-tetrahydro-benzoimidazole-1-sulfonic acid (0.4564 g, 0.77 mmol) and 2 N HCl (7.5 mL) were stirred at reflux for 23 hours. The reaction mixture was cooled to room temperature and 15% (w/v) aqueous NaOH (5 mL) was added. The aqueous layer was extracted with CH2Cl2 (3×150 mL), and the combined organic extracts were washed with brine (1×100 mL), dried (Na2SO4), and concentrated. 0.2466 g (64%) of the crude 2-{4-[(4,5,6,7-tetrahydro-1H-benzoimidazol-2-ylmethyl)-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-butyl}-isoindole-1,3-dione was isolated as a pale yellow foam. 1H NMR (CDCl3) δ 1.37-1.39 (m, 2H), 1.79-1.88 (m, 10H), 1.98-2.11 (m, 2H), 2.51-2.63 (m, 8H), 3.50-3.52 (m, 1H), 3.66-3.86 (m, 2H), 3.97-3.99 (m, 1H), 7.02-7.11 (m, 2H), 7.37-7.40 (m, 2H), 7.68-7.71 (m, 1H), 7.80-7.82 (m, 1H), 8.44-8.46 (m, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:19])=[C:6]([C:8]2[CH:17]=[C:16]3[C:11]([CH:12]=[C:13]([NH2:18])[N:14]=[CH:15]3)=[CH:10][CH:9]=2)[CH:7]=1.[F:20][B-](F)(F)F.F[B-](F)(F)F.ClC[N+]12CC[N+](F)(CC1)CC2>C(#N)C.O>[F:20][C:12]1[C:11]2[C:16](=[CH:17][C:8]([C:6]3[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=3[CH3:19])=[CH:9][CH:10]=2)[CH:15]=[N:14][C:13]=1[NH2:18]
Reactant: Cc1ccc(F)cc1-c1ccc2cc(N)ncc2c1
Reactant: F[B-](F)(F)F
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: O
Solvent: CC#N
Product: Cc1ccc(F)cc1-c1ccc2c(F)c(N)ncc2c1
Reaction time: 16 h

Procedure:
7-(5-Fluoro-2-methylphenyl)isoquinolin-3-amine (203 mg, 806 mop and 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (313 mg, 883 mop were dissolved together in acetonitrile (2.0 mL) at ambient temperature and the mixture stirred for 16 h, at which time LCMS indicated approx 40% conversion. The mixture was diluted with water, extracted three times into dichloromethane and the combined organic phases washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash chromatography (silica, ISCO, 0-6% methanol in dichloromethane) to yield the impure title compound as a pale solid (107 mg), used without further purification.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([NH:15][C:16]([NH:18][CH:19]2[CH:26]3[CH:22]([CH2:23][NH:24][CH2:25]3)[CH2:21][CH2:20]2)=[O:17])[CH:6]=[C:7]([C:9]2[N:13]([CH3:14])[N:12]=[N:11][N:10]=2)[CH:8]=1)[CH3:2].[F:27][C:28]1[CH:33]=[CH:32][C:31]([CH2:34][CH2:35]OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:30][CH:29]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:1]([C:3]1[CH:4]=[C:5]([NH:15][C:16]([NH:18][CH:19]2[CH:26]3[CH:22]([CH2:23][N:24]([CH2:35][CH2:34][C:31]4[CH:32]=[CH:33][C:28]([F:27])=[CH:29][CH:30]=4)[CH2:25]3)[CH2:21][CH2:20]2)=[O:17])[CH:6]=[C:7]([C:9]2[N:13]([CH3:14])[N:12]=[N:11][N:10]=2)[CH:8]=1)[CH3:2]
Reactant: CCc1cc(NC(=O)NC2CCC3CNCC32)cc(-c2nnnn2C)c1
Reactant: Cc1ccc(S(=O)(=O)OCCc2ccc(F)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCc1cc(NC(=O)NC2CCC3CN(CCc4ccc(F)cc4)CC32)cc(-c2nnnn2C)c1
Temperature: 25 °C
Reaction time: 15.5 h
Yield: 75.6 %

Procedure:
A mixture of N-[3-ethyl-5-(1-methyl-1H-tetrazol-5-yl)-phenyl]-N′-[(3aRS,4RS,6aSR)-octahydrocyclopenta[c]-pyrrol-4-yl]urea (60 mg, 169 μmol), toluene-4-sulfonic acid 2-(4-fluorophenyl)ethyl ester (55 mg, 169 μmol), potassium carbonate (24 mg, 169 μmol) and acetonitrile (1 mL) was heated to reflux. After 15.5 hours, the mixture was cooled to room temperature and concentrated. The residue was purified by flash column chromatography, eluting with 2% methanol/dichloromethane containing 0.2% aqueous ammonia, to provide a white glass (61 mg, 76%). 1H NMR (300 MHz, CDCl3) δ7.75 (s, 1H), 7.27 (s, 2H), 7.23 (m, 2H), 7.08 (s, 1H), 7.04 (m, 2H), 6.24 (broad s, 1H), 4.23 (broad s, 1H), 4.19 (s, 3H), 3.0-2.6 (m, 10H), 2.3-2.1 (m, 2H), 2.05 (m, 1H), 1.8-1.5 (m, 4H), 1.35 (m, 1H), 1.27 (t, J=7 Hz, 3H). Mass spec (ES+) m/z 478.3 (M+H+, 100%)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]3([CH2:14][C:13](=[O:15])[N:12]([CH2:16][C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=4)[C:11]3=[O:24])[C:9](=[O:25])[N:8]([CH2:26][C:27]([O:29]C)=[O:28])[C:5]2=[CH:6][CH:7]=1.I[Si](C)(C)C.Cl.C(OCC)(=O)C>C(Cl)(Cl)Cl.C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]3([CH2:14][C:13](=[O:15])[N:12]([CH2:16][C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=4)[C:11]3=[O:24])[C:9](=[O:25])[N:8]([CH2:26][C:27]([OH:29])=[O:28])[C:5]2=[CH:6][CH:7]=1
Reactant: COC(=O)CN1C(=O)C2(CC(=O)N(Cc3cccc(Cl)c3)C2=O)c2cc(Cl)ccc21
Agent: C[Si](C)(C)I
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Solvent: CC#N
Product: O=C(O)CN1C(=O)C2(CC(=O)N(Cc3cccc(Cl)c3)C2=O)c2cc(Cl)ccc21

Procedure:
Alternatively, a solution of methyl [5-chloro-1′-(3-chlorobenzyl)-2,2′,5′-trioxospiro[indole-3,3′-pyrrolidin]-1(2H)-yl)acetate, intermediate 48, (250 mg, 0.56 mmol) in chloroforme or acetonitrile (10 ml) was treated with iodotrimethylsilane (0.31 ml, 2.24 mmol) and heated up to reflux until completion. Addition of 1.0 N HCl (10 ml), product extraction with ethyl acetate or chloroforme (3×5 ml), washing of the combined extracts with sat. sodium thiosulfate (10 ml) and drying (MgSO4) gave the title compound as in quant.yield as slightly yellow solid (75% purity by HPLC using chloroform; 68% purity by HPLC using acetonitrile). MS (ESI+): 434.3; MS (ESI−): 431.4.
Reaction SMILES: [OH:1][CH:2]([CH2:10][OH:11])[CH2:3][N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.Cl[C:13]1[N:21]=[CH:20][CH:19]=[CH:18][C:14]=1[C:15]([OH:17])=[O:16]>O1CCOCC1>[OH:1][CH:2]([CH2:10][OH:11])[CH2:3][N:4]1[CH2:9][CH2:8][N:7]([C:13]2[N:21]=[CH:20][CH:19]=[CH:18][C:14]=2[C:15]([OH:17])=[O:16])[CH2:6][CH2:5]1
Reactant: OCC(O)CN1CCNCC1
Reactant: O=C(O)c1cccnc1Cl
Solvent: C1COCCO1
Product: O=C(O)c1cccnc1N1CCN(CC(O)CO)CC1

Procedure:
Grams 32 of 1-(2,3-dihydroxypropyl)piperazine and 15.7 g of 2-chloronicotinic acid in 500 ml dioxane were refluxed for 8 hours. The reaction mixture was cooled, settled, the solvent separated and removed. The residue was triturated under heating with absolute ethanol and gave 16.2 g of 2-[4-(2,3-dihydroxypropyl)piperazin-1-yl]nicotinic acid melting at 210°-212° C. (with decomposition)
Reaction SMILES: [CH2:1]([N:5]([CH2:31][CH2:32][SH:33])[CH2:6][CH2:7][CH2:8][N:9]([CH2:20][CH2:21][CH2:22][N:23]([CH2:27][CH2:28][CH2:29][CH3:30])[CH2:24][CH2:25][SH:26])S(C1C=CC(C)=CC=1)(=O)=O)[CH2:2][CH2:3][CH3:4].N.[Na].C(OCC)C>O1CCCC1.O.C(O)C>[CH2:1]([N:5]([CH2:6][CH2:7][CH2:8][NH:9][CH2:20][CH2:21][CH2:22][N:23]([CH2:27][CH2:28][CH2:29][CH3:30])[CH2:24][CH2:25][SH:26])[CH2:31][CH2:32][SH:33])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN(CCS)CCCN(CCCN(CCS)CCCC)S(=O)(=O)c1ccc(C)cc1
Agent: N
Agent: [Na]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CCO
Product: CCCCN(CCS)CCCNCCCN(CCS)CCCC
Temperature: -78 °C

Procedure:
Dissolve N,N-bis-{3-[butyl-(2-mercapto-ethyl)-amino]-propyl}-4-methyl-benzenesulfonamide (10 mmol) prepared in Scheme IX, step B in dry tetrahydrofuran (50 mL) and cool the solution to -78° C. Add excess dry ammonia followed by excess sodium. Stir the reaction for 4 hours and then warm to room temperature overnight. Add diethyl ether (100 mL) followed by cautious addition of ethanol (30 mL). After stirring for 30 minutes cautiously add water dropwise (5 mL) and then concentrate the reaction under vacuum. Extract the residue with diethyl ether (100 mL) and chloroform (100 mL). Combine the organic extracts, dry over anhydrous sodium sulfate, filter and concentrate under vacuum. Purify the residue by flash chromatography (silica gel, methanol/methylene chloride) to provide the title compound.
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[C:11](=O)([O-])[O-].[K+].[K+].IC>CN(C=O)C.C(OCC)(=O)C>[CH3:11][O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([I:1])=[CH:3][CH:4]=1
Reactant: O=C([O-])[O-]
Reactant: O=C(O)c1ccc(I)cc1
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(I)cc1
Reaction time: 17 h
Yield: 83.4 %

Procedure:
To a solution of 4-iodobenzoic acid (9.92 g, 40 mmol) in DMF (80 mL) is added potassium carbonate (5.8 g, 42 mmol) and iodomethane (2.6 mL, 42 mmol). The resulting mixture is stirred for 17 hours, diluted with ethyl acetate, washed with water and brine, dried over MgSO4 and concentrated. The crude solid is recrystallized in ethyl acetate/hexane to give 8.74 g of title compound. 1H NMR (CDCl3) δ 3.91 (s, 3H), 7.74 (d, J=8 Hz, 2H), 7.80 (d, J=8 Hz, 2H). MS (EI) m/z 262 (M+).
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:7]2[O:8][C:9]([CH2:22][CH2:23][CH2:24][OH:25])=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=3)[N:11]=2)[CH:4]=[CH:5][N:6]=1.[CH3:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1O.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1>[CH3:1][C:2]1[N:3]([C:7]2[O:8][C:9]([CH2:22][CH2:23][CH2:24][O:25][C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=3[CH3:26])=[C:10]([C:12]3[CH:13]=[CH:14][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:17]=3)[N:11]=2)[CH:4]=[CH:5][N:6]=1
Reactant: Cc1ccccc1O
Reactant: Cc1nccn1-c1nc(-c2ccc(C(F)(F)F)cc2)c(CCCO)o1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: Cc1ccccc1OCCCc1oc(-n2ccnc2C)nc1-c1ccc(C(F)(F)F)cc1
Reaction time: 1 h

Procedure:
To a mixture of 2-(2-methyl-1-imidazolyl)-4-(4-trifluoromethylphenyl)-5-oxazolepropanol (700 mg), 2-methylphenol (432 mg), tributylphosphine (607 mg) and tetrahydrofuran (10 mL) was added 1,1′-(azodicarbonyl)dipiperidine (750 mg) at room temperature and the mixture was stirred for 1 h. The reaction mixture was concentrated and the residue was subjected to silica gel column chromatography. The title compound was obtained as crystals from an eluate from ethyl acetate-hexane (2:3, v/v). Recrystallization from acetone-isopropyl ether gave colorless prism crystals (591 mg, 67%). melting point: 101-102° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:12]([O-:14])=[O:13])[C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[C:15]([O-])([O-])=O.[Na+].[Na+].IC>CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([N+:12]([O-:14])=[O:13])[C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([O:9][CH3:15])=[O:8]
Reactant: O=C([O-])[O-]
Reactant: Cc1c(C(=O)O)cc(Cl)cc1[N+](=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: O
Product: COC(=O)c1cc(Cl)cc([N+](=O)[O-])c1C
Temperature: 25 °C
Reaction time: 19 h

Procedure:
To a solution of 5-chloro-2-methyl-3-nitrobenzoic acid (1.17 g, 5.43 mmol) in DMF (11 ml) at room temperature and nitrogen was added Na2CO3 (862 mg, 8.14 mmol) followed by iodomethane (0.51 ml, 8.14 mmol). The reaction mixture was stirred at room temperature for 19 hours before being diluted with deionized water (30 ml) and extracted with EtOAc (3×30 ml). The combined organic phases were washed with saturated NaHCO3(aq) (30 ml), dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by FCC (10 g silica, Isolute cartridge, gradient of eluents; 99:1 Heptane:EtOAc to 95:5 Heptane:EtOAc) to give 900 of the title compound as a pale yellow oil. LC-MS 89%, m/z=no ionisation, 1H NMR (500 MHz, Chloroform-d) δ 8.00 (1H, d, J=2.21 Hz), 7.86 (1H, d, J=2.21 Hz), 3.96 (3H, s), 2.60 (3H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:26][CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[C:13]([NH:15][C:16]2[CH:20]=[CH:19][N:18]([CH2:21][CH2:22][C:23](O)=[O:24])[N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C(Cl)(=O)C(Cl)=O.[N:38]1C(C)=C[CH:41]=[CH:40][C:39]=1C.C(N)C=C>C(Cl)Cl>[CH2:39]([NH:38][C:23]([CH2:22][CH2:21][N:18]1[CH:19]=[CH:20][C:16]([NH:15][C:13](=[O:14])[C@@H:12]([C:4]2[CH:5]=[CH:6][C:7]([S:8]([CH3:11])(=[O:9])=[O:10])=[C:2]([Cl:1])[CH:3]=2)[CH2:26][CH:27]2[CH2:28][CH2:29][CH2:30][CH2:31]2)=[N:17]1)=[O:24])[CH:40]=[CH2:41]
Reactant: Cc1cccc(C)n1
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2ccn(CCC(=O)O)n2)cc1Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: C=CCN
Product: C=CCNC(=O)CCn1ccc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 16.1 %

Procedure:
To a solution containing 3-{3-[2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionylamino]-pyrazol-1-yl}-propionic acid (prepared in example 9, 50 mg, 0.11 mmol) in methylene chloride (2 mL), was then added a 2.0 M solution of oxalylchloride in methylene chloride (59 μL, 0.12 mmol) at 0° C. and allowed to stir at 25° C. for 1 h, after which time 2,6-lutidine (17 μL, 0.14 mmol) was added to the solution at 0° C. After 1 h, allylamine (9 μL, 0.11 mmol) was added and the reaction was allowed to proceed for 16 h. The reaction solution was washed with 1.0 M aqueous hydrochloric acid solution, dried over sodium sulfate, concentrated in vacuo and purified by ISCO flash column chromatography (Teledyne Isco RediSep Flash Column 10 g; 0% methanol/methylene chloride to 10% methanol/methylene chloride) to afford N-[1-(2-allylcarbamoyl-ethyl)-1H-pyrazol-3-yl]-2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionamide (9 mg, 16%) as a white solid: ESI-LRMS m/e calcd for C23H29ClN4O4S [M+] 506.19, found 507.34 [M+H+]; 1H NMR (400 MHz, CDCl3) δ ppm 1.06-1.20 (m, 2H, CH2), 1.42-1.94 (m, 8H, 4×CH2), 2.12-2.30 (m, 1H, CH), 2.65 (t, J=6.3 Hz, 2H, COCH2), 3.26 (s, 3H, SO2CH3), 3.54 (t, J=7.5 Hz, 1H, CH), 3.79-3.84 (m, 2H, CONCH2), 4.31 (t, J=6.3 Hz, 2H, NCH2), 5.02-5.07 (m, 1H, vinylic), 5.06-5.09 (m, 1H, vinylic), 6.55 (brm, 1H, NH), 5.67-5.78 (m, 1H, vinylic), 6.60 (d, J=2.3 Hz, 1H, Ar), 7.30 (d, J=2.3 Hz, 1H, Ar), 7.46 (dd, Jo=8.2, Jm=1.7 Hz. 1H, Ar), 7.59 (d, Jm=1.7 Hz, 1H, Ar), 8.02 (s, 1H, NH), 8.09 (d, Jo=8.2 Hz, 1H, Ar).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([F:18])[C:5]([O:9][C:10]2[CH:15]=[CH:14][C:13]([CH:16]=[CH2:17])=[CH:12][CH:11]=2)=[C:6]([F:8])[CH:7]=1.B1C2CCCC1CCC2.[OH-:28].[Na+].OO>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([F:18])[C:5]([O:9][C:10]2[CH:11]=[CH:12][C:13]([CH2:16][CH2:17][OH:28])=[CH:14][CH:15]=2)=[C:6]([F:8])[CH:7]=1
Reactant: C=Cc1ccc(Oc2c(F)cc(Cl)cc2F)cc1
Reactant: [OH-]
Agent: B1C2CCCC1CCC2
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Product: OCCc1ccc(Oc2c(F)cc(Cl)cc2F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.6 %

Procedure:
To the solution of 5-chloro-1,3-difluoro-2-(4-vinylphenoxy)benzene (2.6 g, 9.75 mmol) in dry THF (10 mL), was added 9-BBN (39.0 mL, 19.50 mmol) at 0° C. The mixture was stirred at room temperature overnight. aq. NaOH (7.0 mL, 21.00 mmol), and 30% H2O2 (2.0 mL, 19.58 mmol) were added then. The reaction mixture was heated at 50° C. for 4 h. Then THF was removed under reduced pressure, and the residue was diluted with EA. The organic layer was washed with water and brine, dried over anhydrous Na2SO4 and concentrated and purified by flash chromatography to afford the title compound (1.6 g, 5.62 mmol, 57.6% yield) as a white oil.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:14][C:13]2[CH:12]=[C:11]3[O:15][CH2:16][C@H:17]([C:19]4[CH:24]=[CH:23][C:22]([O:25]C(=O)C)=[CH:21][CH:20]=4)[O:18][C:10]3=[CH:9][C:8]=2[CH2:7][N:6]1[C@H:29]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH2:30][CH3:31])=[O:4].C([O-])(O)=O.[Na+].O.CCOC(C)=O>CO>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:14][C:13]2[CH:12]=[C:11]3[O:15][CH2:16][C@H:17]([C:19]4[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=4)[O:18][C:10]3=[CH:9][C:8]=2[CH2:7][N:6]1[C@H:29]([C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)[CH2:30][CH3:31])=[O:4]
Reactant: CC[C@@H](c1ccccc1)N1Cc2cc3c(cc2C[C@H]1C(=O)OC)OC[C@H](c1ccc(OC(C)=O)cc1)O3
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: O
Product: CC[C@@H](c1ccccc1)N1Cc2cc3c(cc2C[C@H]1C(=O)OC)OC[C@H](c1ccc(O)cc1)O3
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 100.1 %

Procedure:
(3S,8S)-3-(4-Acetoxy-phenyl)-7-((S)-1-phenyl-propyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carboxylic acid methyl ester (120 mg) was dissolved in methanol (5 mL). To this solution was added NaHCO3 (400 mg). The mixture was stirred at rt for 2-3 h. After completion of the reaction, the mixture was poured into water (10 mL) and was extraxcted with EtOAc (30 mL). The organic layer was washed with water, brine, dried and concentracted to get the desired product as a white solid (110 mg) LCMS (m/z): 461.
Reaction SMILES: Cl[CH:2]([F:4])[F:3].[CH3:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]2[CH2:18][NH:17][C:16](=[O:19])[NH:15][CH2:14]2)=[CH:9][C:8]=1[OH:20].[OH-].[Na+]>O.O1CCOCC1>[CH3:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]2[CH2:14][NH:15][C:16](=[O:19])[NH:17][CH2:18]2)=[CH:9][C:8]=1[O:20][CH:2]([F:4])[F:3]
Reactant: FC(F)Cl
Reactant: COc1ccc(C2CNC(=O)NC2)cc1O
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(C2CNC(=O)NC2)cc1OC(F)F
Temperature: 60 °C
Reaction time: 1 h

Procedure:
Chlorodifluoromethane was bubbled into a solution of (102 mg, 0.459 mmol, 1.0 eq) of tetrahydro-5-(4-methoxy-3-hydroxyphenyl)-2(1H)-pyrimidinone and 64 mg (1.61 mmol, 3.5 eq) of NaOH in 3 ml of H2O and 3 ml of 1,4-dioxane. After 1 hour at room temperature, the reaction mixture was heated to 60° C. for 1.5 hours. Chlorodifluoromethane was bubbled in continuously. The reaction mixture was cooled to room temperature, poured into 150 ml of H2O and 75 ml of ethyl acetate, extracted twice with ethyl acetate. The ethyl acetate extracts were washed twice with 2N NaOH, once with brine, dried over Na2SO4, and concentrated to yield 13.5 mg of a white solid, which was recrystallized from ethyl acetate-hexane to afford 8.4 mg, 7%, of off-white crystals. M.P.: 215°-216° C. Elemental Analysis: Calc'd for C12 H14N2O3F2 : Calc'd: C, 52.95; H, 5.18; N, 10.29. Found: C, 52.88; H, 4.91; N, 10.13.
Reaction SMILES: [NH:1]([C:5]1[C:18]2[C:17](=[O:19])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=[O:20])[C:9]=2[CH:8]=[CH:7][CH:6]=1)C(C)=O.[OH-].[Na+]>CO>[NH2:1][C:5]1[C:18]2[C:17](=[O:19])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=[O:20])[C:9]=2[CH:8]=[CH:7][CH:6]=1
Reactant: CC(=O)Nc1cccc2c1C(=O)c1ccccc1C2=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Nc1cccc2c1C(=O)c1ccccc1C2=O
Temperature: 25 °C
Yield: 94.8 %

Procedure:
363 g (1.37 moles) of 1-acetamino-anthraquinone are warmed with 3.5 kg of methanol and 150 ml of concentrated sodium hydroxide solution (d = 1.48) in a stainless steel autoclave for 3 hours at 85° C. After cooling to room temperature, the red suspension is suction filtered. The residue on the suction filter is washed with hot water until the filtrate has a neutral reaction. After drying, 290 g of 1-amino-anthraquinone are obtained (yield: 95%). Degree of purity: 98 to 99%.
Reaction SMILES: [Cl:1][C:2]1[N:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:3]=1[C:4]#N.CC(C[AlH]CC(C)C)C.C(O)(=[O:25])C.O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[N:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:25]
Reactant: N#Cc1ccc(C(F)(F)F)nc1Cl
Reactant: CC(=O)O
Agent: CC(C)C[AlH]CC(C)C
Solvent: O
Solvent: Cc1ccccc1
Product: O=Cc1ccc(C(F)(F)F)nc1Cl
Temperature: -78 °C
Reaction time: 1 h
Yield: 33.3 %

Procedure:
2-Chloro-6-(trifluoromethyl)nicotinonitrile (340 mg, 1.65 mmol) was diluted with toluene (2.0 mL), placed under nitrogen and cooled to −78° C. DIBAL-H (3292 μl, 3.29 mmol) was added dropwise and the reaction was stirred for 1 hour. The reaction was warmed to 0° C. and acetic acid (1 mL) was added followed by 5 mL of water. After stirring for 2 hours, the reaction was extracted twice with ethyl acetate, washed with Rochelle's salt, dried over MgSO4, filtered and concentrated. The material was loaded onto silica gel and eluted with 5% ethyl acetate/hexanes to 30% ethyl acetate/hexanes to yield the desired compound (115 mg, 0.549 mmol, 33.3% yield) as a clear oil.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1>CO.C(O)(=O)C(O)=O>[OH:1][CH:5]=[CH:4][C:3]1[CH:5]=[CH:4][CH:3]=[CH:2][CH:2]=1
Reactant: C1CCOC1
Agent: O=C(O)C(=O)O
Solvent: CO
Product: OC=Cc1ccccc1

Procedure:
Each Polymers 27 to 34 obtained by the above-mentioned prescription was dissolved in a mixed solvent of methanol and tetrahydrofuran, and oxalic acid was added thereto to perform a deprotection reaction at 40° C. Usual reprecipitation purification was performed after a neutralization treatment with pyridine to obtain Polymers 35 to 41 and 51 having a hydroxystyrene unit.
Reaction SMILES: C1(C2[C:13]([C:14]3[NH:18][C:17](C)=[N:16][N:15]=3)=[CH:12]C(C(O)=O)=C(C)C=2)CCC1.[F:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([OH:28])=[O:27])=[C:24]([CH3:31])[CH:23]=1.C(NN)(=O)CC>>[CH2:13]([C:14]1[NH:18][C:17]([C:30]2[C:22]([F:21])=[CH:23][C:24]([CH3:31])=[C:25]([CH:29]=2)[C:26]([OH:28])=[O:27])=[N:16][N:15]=1)[CH3:12]
Reactant: Cc1nnc(-c2cc(C(=O)O)c(C)cc2C2CCC2)[nH]1
Reactant: Cc1cc(F)ccc1C(=O)O
Agent: CCC(=O)NN
Product: CCc1nnc(-c2cc(C(=O)O)c(C)cc2F)[nH]1

Procedure:
The title compound was synthesized using standard chemical manipulations and procedures similar to those used for the preparation of compound 152.8 using 4-fluoro-2-methylbenzoic acid instead of 4-bromo-2-methylbenzoic acid and propionohydrazide instead of acetohydrazide.