Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][CH:8]([C@H:11]3[CH2:27][C@H:15]4[O:16][C:17]5[C:22]([F:23])=[C:21]([O:24][CH2:25][CH3:26])[CH:20]=[CH:19][C:18]=5[C@@H:14]4[CH2:13][CH2:12]3)[CH2:7][CH2:6]2)[O:4]CC1.C(O)=O.O>C1(C)C=CC=CC=1>[CH2:25]([O:24][C:21]1[CH:20]=[CH:19][C:18]2[C@@H:14]3[CH2:13][CH2:12][C@@H:11]([CH:8]4[CH2:9][CH2:10][C:5](=[O:4])[CH2:6][CH2:7]4)[CH2:27][C@H:15]3[O:16][C:17]=2[C:22]=1[F:23])[CH3:26]
Reactant: CCOc1ccc2c(c1F)O[C@@H]1C[C@H](C3CCC4(CC3)OCCO4)CC[C@@H]21
Solvent: O
Solvent: Cc1ccccc1
Solvent: O=CO
Product: CCOc1ccc2c(c1F)O[C@@H]1C[C@H](C3CCC(=O)CC3)CC[C@@H]21
Reaction time: 18 h

Procedure:
13.3 g (35.3 mmol) of (±)-(3R*,4aR*,9bS*)-3-(1,4-dioxaspiro[4.5]dec-8-yl)-7-ethoxy-6-fluoro-1,2,3,4,4a,9b-hexahydrodibenzofuran are dissolved in 200 ml of toluene and stirred vigorously together with 40 ml (1.06 mol) of formic acid with addition of 1.0 ml (55.6 mmol) of water. After 18 h, the organic phase is separated off, and the formic acid is extracted with toluene. The combined organic phases are washed successively with water, sat. sodium hydrogencarbonate solution and sat. sodium chloride solution and dried using sodium sulfate. The crude product remaining after removal of the solvent is purified by column chromatography (SiO2, toluene:ethyl acetate=4:1), giving (±)-4-((3R*,4aR*,9bS*)-7-ethoxy-6-fluoro-1,2,3,4,4a,9b-hexahydrodibenzofuran-3-yl)cyclohexanone as colourless solid.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([CH:18]=[C:19]([N:21]([CH3:26])[S:22]([CH3:25])(=[O:24])=[O:23])[CH:20]=1)[C:6]([NH:8][C@@H:9]([C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)[CH3:10])=[O:7].[OH:27][CH2:28][C:29]([NH:38]C(=O)OC(C)(C)C)([CH2:36][OH:37])[CH2:30][C:31]1[CH:35]=[CH:34][S:33][CH:32]=1.C(C1C=CC=C(C(C)(C)C)N=1)(C)(C)C.[C:60]([OH:66])([C:62]([F:65])([F:64])[F:63])=[O:61]>C(Cl)Cl.[O-]S(C(F)(F)F)(=O)=O.[Ag+]>[NH2:38][C:29]([CH2:30][C:31]1[CH:35]=[CH:34][S:33][CH:32]=1)([CH2:28][OH:27])[CH2:36][O:37][CH2:2][C:3]1[CH:4]=[C:5]([CH:18]=[C:19]([N:21]([CH3:26])[S:22]([CH3:25])(=[O:24])=[O:23])[CH:20]=1)[C:6]([NH:8][C@@H:9]([C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)[CH3:10])=[O:7].[C:60]([OH:66])([C:62]([F:65])([F:64])[F:63])=[O:61]
Reactant: CC(C)(C)OC(=O)NC(CO)(CO)Cc1ccsc1
Reactant: C[C@@H](NC(=O)c1cc(CBr)cc(N(C)S(C)(=O)=O)c1)c1ccc(F)cc1
Agent: [Ag+]
Agent: CC(C)(C)c1cccc(C(C)(C)C)n1
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@@H](NC(=O)c1cc(COCC(N)(CO)Cc2ccsc2)cc(N(C)S(C)(=O)=O)c1)c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 0.67 h

Procedure:
To a solution of intermediate A 3-(bromomethyl)-N-[(1R)-1-(4-fluorophenyl)ethyl]-5-[methyl(methylsulfonyl)amino]benzamide (50 mg, 0.11 mmol) in 1 mL CH2Cl2 cooled to 0° C. was added intermediate III tert-butyl 2-hydroxy-1-(hydroxymethyl)-1-(thien-3-ylmethyl)ethylcarbamate (81 mg, 0.28 mmol), silver triflate (72 mg, 0.28 mmol) and 2,6-ditert-butylpyridine (76 μL, 0.34 mmol). The reaction mixture was stirred at 0° C. for 40 min and purified by flash chromatography (20 g silica, 30->80% EtOAc/hexanes) and by preparative HPLC (5% to 95% CH3CN in water containing 0.1% TFA, C18 PRO YMC 20×150 mm) to afford tert-butyl 2-({3-({[(1R)-1-(4-fluorophenyl)ethyl]amino}carbonyl)-5-[methyl(methylsulfonyl)amino]benzyl}oxy)-1-(hydroxymethyl)-1-(thien-3-ylmethyl) contaminated with 2,6-ditert-butylpyridine. Treatment with 10% TFA in CH2Cl2 for 30 min, followed by concentration under a stream of nitrogen, and purification by preparative HPLC (5% to 95% CH3CN in water containing 0.1% TFA, C18 PRO YMC 20×150 mm) afforded 3-{[2-amino-3-hydroxy-2-(thien-3-ylmethyl)propoxy]methyl}-N-[(1R)-1-(4-fluorophenyl)ethyl]-5-[methyl(methylsulfonyl)amino]benzamide as a TFA salt. 1H NMR (400 MHz, d4-MeOH) δ 8.86 (d, J=7.9 Hz, 1H), 7.83 (s, 1H), 7.80 (s, 1H), 7.65 (s, 1H), 7.48-7.36 (m, 3H), 7.17 (s, 1H), 7.10-7.00 (m, 2H), 6.95 (d, J=5.0 Hz, 1H), 5.30-5.20 (m, 1H), 4.68 (A of AB, d, J=12.0 Hz, 1H), 4.63 (B of AB, d, J=12.0 Hz, 1H), 3.57 (s, 2H), 3.51 (A of AB, d, J=11.0 Hz, 1H), 3.45 (B of AB, d, J=11.0 Hz, 1H), 3.09 (s, 3H), 3.04 (A of AB, d, J=13.6 Hz, 1H), 3.45 (B of AB, d, J=13.6 Hz, 1H), 2.94 (s, 3H), 1.58 (d, J=7.1 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:20])[C:10]([C:15]1[CH:19]=CN[N:16]=1)=[CH:11][N:12]([CH3:14])[CH3:13].ClC1C=C(Cl)C=CC=1C(=O)[CH2:30][C:31]1[N:32]=C(C)NC=1>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:20])[C:10]([C:15]1[N:16]=[C:31]([CH3:30])[NH:32][CH:19]=1)=[CH:11][N:12]([CH3:13])[CH3:14]
Reactant: CN(C)C=C(C(=O)c1ccc(Cl)cc1Cl)c1cc[nH]n1
Reactant: Cc1nc(CC(=O)c2ccc(Cl)cc2Cl)c[nH]1
Product: Cc1nc(C(=CN(C)C)C(=O)c2ccc(Cl)cc2Cl)c[nH]1

Procedure:
Made using the same procedure as for 1-(2,4-dichlorophenyl)-3-(dimethylamino)-2-pyrazolylprop-2-en-1-one except that 1-(2,4-dichlorophenyl)-2-(2-methylimidazolyl)ethan-1-one (VI, 1.0 g, 3.7 mmol) was used. The crude residue was used without purification.
Reaction SMILES: C1C(=O)N([Cl:8])C(=O)C1.C(O)(=O)C.C(=O)(OCC)N.[CH3:19][O:20][C:21]1[CH:22]=[CH:23][C:24]2[C:25](=[O:33])[CH:26]3[CH2:32][NH:31][CH2:30][CH:27]3[C:28]=2[CH:29]=1>ClCCCl>[Cl:8][C:29]1[C:28]2[CH:27]3[CH2:30][NH:31][CH2:32][CH:26]3[C:25](=[O:33])[C:24]=2[CH:23]=[CH:22][C:21]=1[O:20][CH3:19]
Reactant: O=C1CCC(=O)N1Cl
Reactant: COc1ccc2c(c1)C1CNCC1C2=O
Agent: CCOC(N)=O
Solvent: ClCCCl
Solvent: CC(=O)O
Product: COc1ccc2c(c1Cl)C1CNCC1C2=O
Temperature: 60 °C
Reaction time: 8 h

Procedure:
NCS (0.25 g, 1.9 mmol) and acetic acid (10 mL) were added to a solution of ethyl carbamate-5-methoxy-2,3,3a,8a-tetrahydro-1H-2-aza-cyclopenta[a]inden-8-one (0.52 g, 1.9 mmol) in DCE (10 mL), and stirred overnight at 60° C. The reaction was quenched with aqueous HCl (1 M) and washed with brine. The organic extracts were dried over MgSO4, and concentrated. The crude product was purified by column chromatography (SiO2) using a 0-60% EtOAc-hexanes gradient to afford the subtitle compound as a mixture of regioisomers. MS calculated for C15H16ClNO4+H: 310, observed: 310.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[C:12]3[C:13]([O:17][CH:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)=[N:14][CH:15]=[CH:16][C:11]=3[N:10](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[N:9]=2)[CH:5]=[CH:4][N:3]=1.Cl.[NH:44]1[CH2:47][CH2:46][CH2:45]1>>[N:44]1([C:2]2[CH:7]=[C:6]([C:8]3[C:12]4[C:13]([O:17][CH:18]5[CH2:19][CH2:20][O:21][CH2:22][CH2:23]5)=[N:14][CH:15]=[CH:16][C:11]=4[NH:10][N:9]=3)[CH:5]=[CH:4][N:3]=2)[CH2:47][CH2:46][CH2:45]1
Reactant: C1CNC1
Reactant: Clc1cc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c3ccnc(OC4CCOCC4)c23)ccn1
Agent: Cl
Product: c1cc(-c2n[nH]c3ccnc(OC4CCOCC4)c23)cc(N2CCC2)n1
Yield: 22 %

Procedure:
Prepared according to the procedure described in Example 111, by reacting 3-(2-chloropyridin-4-yl)-4-(tetrahydro-2H-pyran-4-yloxy)-1-trityl-1H-pyrazolo[4,3-c]pyridine with azetidine hydrochloride to give the title compound (11.3 mg, 22% over two steps). LC-MS (Method G): m/z=352.1 [M+H]+; 3.24 min. 1H-NMR (400 MHz, DMSO): δ 13.72 (s, 1H), 8.17-8.11 (m, 1H), 7.91 (d, J=5.6, 1H), 7.29-7.22 (m, 1H), 7.17 (d, J=5.6, 1H), 6.93 (s, 1H), 5.56-5.46 (m, 1H), 4.09-3.95 (m, 4H), 3.85-3.75 (m, 2H), 3.58-3.48 (m, 2H), 2.41-2.31 (m, 2H), 2.11-2.01 (m, 2H), 1.77-1.63 (m, 2H).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH2:8]2)(=[O:3])[CH3:2].[H-].[Na+].C1COCC1.[Cl:22][C:23]1[C:32]2[C:27](=[CH:28][C:29]([O:35][CH2:36][CH2:37][O:38][CH3:39])=[C:30]([O:33][CH3:34])[CH:31]=2)[N:26]=[CH:25][N:24]=1>CN(C=O)C>[ClH:22].[C:1]([NH:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH:8]2[C:23]1[C:32]2[C:27](=[CH:28][C:29]([O:35][CH2:36][CH2:37][O:38][CH3:39])=[C:30]([O:33][CH3:34])[CH:31]=2)[N:26]=[CH:25][N:24]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc2c(c1)CC(=O)N2
Reactant: COCCOc1cc2ncnc(Cl)c2cc1OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COCCOc1cc2ncnc(C3C(=O)Nc4ccc(NC(C)=O)cc43)c2cc1OC
Product: Cl
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 56 %

Procedure:
A solution of 5-acetamidooxindole (212 mg, 1.1 mmol), (Zh. Obshch. Khim 1956, 26, 2019-2022), in DMF (2 ml) was added dropwise to sodium hydride.(89 mg, 2.23 mmol, prewashed with THF) in DMF (2 ml). The mixture was stirred for 5 minutes at ambient temperature and a solution of 4-chloro-6-methoxy-7-(2-methoxyethoxy)quinazoline (100 mg, 0.37 mmol), (prepared as described for the starting material in Example 2), in DMF (2 ml) was added. The mixture was stirred for 1.5 hours at ambient temperature, the solvent was removed by evaporation and the mixture was partitioned between methylene chloride and water. The aqueous layer was adjusted to pH7 with 2M hydrochloric acid. The organic layer was separated, dried (MgSO4) and the solvent was removed by evaporation. The residue was purified by chromatography eluting with methanol/methylene chloride (gradient from 5/95 to 15/85). The purified solid was dissolved in methylene chloride and 4M methanolic hydrogen chloride (4ml) was added. The volatiles were removed by evaporation, the solid residue was triturated with ether, collected by filtration, washed with ether and dried under vacuum at 60° C. to give 4-(5-acetamidooxindol-3-yl)-6-methoxy-7-(2-methoxyethoxy)quinazoline hydrochloride (95 mg, 56%).
Reaction SMILES: [CH3:1][N:2]([CH:4]([CH:7]1[CH2:16][CH2:15][C:10]2([O:14][CH2:13][CH2:12][O:11]2)[CH2:9][CH2:8]1)[C:5]#N)[CH3:3].C1COCC1.[F:22][C:23]1[CH:28]=[CH:27]C([Mg]Br)=[CH:25][CH:24]=1.[Cl-].[NH4+]>O>[O:14]1[C:10]2([CH2:15][CH2:16][CH:7]([CH:4]([N:2]([CH3:3])[CH3:1])[C:5]3[CH:27]=[CH:28][C:23]([F:22])=[CH:24][CH:25]=3)[CH2:8][CH2:9]2)[O:11][CH2:12][CH2:13]1
Reactant: Fc1ccc([Mg]Br)cc1
Reactant: CN(C)C(C#N)C1CCC2(CC1)OCCO2
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: CN(C)C(c1ccc(F)cc1)C1CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of the aminonitrile 4 (19.89 g, 88 mmol) in absol. THF (160 ml) was added dropwise to a 1 M solution of 4-fluorophenylmagnesium bromide in THF (220 ml, 220 mmol) under argon and while cooling with ice and the mixture was stirred at RT for 20 h. The reaction mixture was worked up by adding saturated ammonium chloride solution (100 ml) and water (100 ml) while cooling with ice, and extracting the mixture with diethyl ether (3×100 ml). The organic phase was washed with water and saturated sodium chloride solution, dried (Na2SO4) and concentrated.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:20][C:21]([O:23]CC)=[O:22])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]=1.CO.O[Li].O.Cl>O.C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:20][C:21]([OH:23])=[O:22])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]=1
Reactant: CCOC(=O)Cc1ccc(OCc2ccc3ccccc3n2)c(Cl)c1
Agent: Cl
Agent: [Li]O
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=C(O)Cc1ccc(OCc2ccc3ccccc3n2)c(Cl)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 12.2 %

Procedure:
To a solution of ethyl 2-(3-chloro-4-(quinolin-2-ylmethoxy)phenyl)acetate (1.0 g, 0.02 mol) in 1:1 MeOH:THF (20 mL) was added LiOH.H2O (1.76 g, 0.008 mol). The reaction mixture was then stirred at RT for 16 h and then concentrated in vacuo to obtain the crude product. The crude material was diluted with water and adjusted to pH 4 using 1N HCl. The mixture was then filtered and the residue was dried in vacuo to afford 2-(3-chloro-4-(quinolin-2-ylmethoxy)phenyl)acetic acid (800 mg, 86%) as a solid.
Reaction SMILES: [O:1]=O.[CH:3]1([OH:14])[CH:8]([OH:9])[CH:7]([OH:10])[CH:6]([OH:11])[CH:5]([OH:12])[CH:4]1[OH:13]>C1N(CCCS(O)(=O)=O)CCOC1>[O:14]=[CH:3][C@@H:8]([C@H:7]([C@@H:6]([C@@H:5]([C:4]([OH:13])=[O:1])[OH:12])[OH:11])[OH:10])[OH:9]
Reactant: OC1C(O)C(O)C(O)C(O)C1O
Reactant: O=O
Agent: O=S(=O)(O)CCCN1CCOCC1
Product: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)C(=O)O

Procedure:
The enzyme reaction was carried out in 0.7 L reactors with temperature, pH, agitation and dissolved oxygen control. A solution of 50 g/L myo-inositol in 50 mM MOPS at pH 6.5 (200 mL) was used in the standard protocol. Temperature was controlled at 15° C. Pure air, air enriched with oxygen or pure oxygen were used to supply enough oxygen for the reaction to proceed. The air was supplied either in the headspace of the reactor or was sparged into the liquid. The formation of glucuronic acid results in a decrease in the pH of the broth. To keep the pH at the desired value, pH 6.5, the acid was neutralized with 4 N NaOH. The enzyme solution was added to reach an initial concentration of 2 g soluble protein/L. The reaction proceeded very fast immediately after the enzyme addition and the rate decayed over time. Different experiments varied the number and/or amount of enzyme additions. The progress of the reaction was followed by HPLC analysis.
Reaction SMILES: [Br:1][C:2]1[C:24]([CH3:25])=[CH:23][C:5]([O:6][CH:7]([C:14]2[CH:22]=[CH:21][C:17]([C:18](O)=[O:19])=[CH:16][CH:15]=2)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])=[CH:4][C:3]=1[CH3:26].C(N(CC)CC)C.[CH3:34][O:35][C:36](=[O:40])[CH2:37][CH2:38][NH2:39].CCN=C=NCCCN(C)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:34][O:35][C:36](=[O:40])[CH2:37][CH2:38][NH:39][C:18](=[O:19])[C:17]1[CH:16]=[CH:15][C:14]([CH:7]([O:6][C:5]2[CH:23]=[C:24]([CH3:25])[C:2]([Br:1])=[C:3]([CH3:26])[CH:4]=2)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])=[CH:22][CH:21]=1
Reactant: COC(=O)CCN
Reactant: CCCCCCC(Oc1cc(C)c(Br)c(C)c1)c1ccc(C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCC(Oc1cc(C)c(Br)c(C)c1)c1ccc(C(=O)NCCC(=O)OC)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 43.9 %

Procedure:
To a mixture of 4-[1-(4-bromo-3,5-dimethyl-phenoxyl)-heptyl]-benzoic acid (1790 mg, 4.27 mmol) in methylene chloride (43 mL) are added triethyl amine (1.79 mL, 12.82 mmol), DMAP (5.0 mg), 3-amino-propionic acid methyl ester (895 mg, 6.4 mmol) and EDCI (2463 mg, 12.8 mmol) at room temperature. The reaction mixture is stirred at room temperature overnight, loaded on silica gel, eluted with eluted with hexanes with a gradient from 0% of ethyl acetate to 100% of ethyl acetate giving racemic 3-{4-[1-(4-bromo-3,5-dimethyl-phenoxyl)-heptyl]-benzoylamino}-propionic acid methyl ester (945 mg).
Reaction SMILES: [Li][CH2:2]CCC.C(NC(C)C)(C)C.[CH3:13][CH2:14][O:15][C:16]([CH3:18])=[O:17].O=[C:20]1[O:25][C:24]([C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=2)=[N:23][C:22]2[C:36]([C:40]([O-:42])=[O:41])=[CH:37][CH:38]=[CH:39][C:21]1=2.C[O-].[Na+]>C1COCC1.CO>[O:25]=[C:20]1[C:21]2[C:22](=[C:36]([C:40]([O:42][CH3:2])=[O:41])[CH:37]=[CH:38][CH:39]=2)[NH:23][C:24]([C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:34])([F:33])[F:35])[CH:27]=2)=[C:18]1[C:16]([O:15][CH2:14][CH3:13])=[O:17]
Reactant: CCOC(C)=O
Reactant: O=C([O-])c1cccc2c(=O)oc(-c3cccc(C(F)(F)F)c3)nc12
Reactant: [Li]CCCC
Agent: C[O-]
Agent: [Na+]
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Solvent: CO
Product: CCOC(=O)c1c(-c2cccc(C(F)(F)F)c2)[nH]c2c(C(=O)OC)cccc2c1=O
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 39.6 %

Procedure:
n-BuLi (4.4 mL, 2.5 M in hexanes, 11.0 mmol) was added to a solution of diisopropylamine (1.57 mL, 11.2 mmol) in THF (30 mL) at −78° C. After stirring for 20 min, EtOAc (1.09 mL, 11.2 mmol) was added. The solution was stirred at −78° C. for 10 min, warmed to 0° C., stirred for 10 min, then cooled back to −78° C. A solution of 4-oxo-2-(3-(trifluoromethyl)phenyl)-4H-benzo[d][1,3]oxazine-8-carboxylate 42 (2.00 g, 5.72 mmol) in THF (50 mL) was added over 5 min to the reaction mixture and stirring at −78° C. continued for 1 h. The reaction mixture was then allowed to warm to room temperature over 2 h. MeOH (50 mL) was added followed by solid NaOMe (1.62 g, 30 mmol), and the reaction stirred vigorously for 12 h at room temperature. The solution was concentrated to 20 mL total volume in vacuo, H2O (100 mL) was added, and the mixture was extracted with ethyl acetate (2×100 mL). The combined organic layers were dried (MgSO4) and concentrated in vacuo. The crude residue was purified by MPLC eluting with pentane/EtOAc (10-50%) to give 43 (950 mg, 39% yield).
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH2:12][CH2:13][CH2:14][CH:15]2[C:20]([N:22]([C:29]1[CH:30]=[N:31][C:32]([CH:35]([CH3:37])[CH3:36])=[CH:33][CH:34]=1)[CH2:23][C:24]1[CH:25]=[N:26][NH:27][CH:28]=1)=[O:21])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45]>>[CH2:2]([O:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH2:12][CH2:13][CH2:14][CH:15]2[C:20]([N:22]([CH2:23][C:24]1[CH:25]=[N:26][N:27]([CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])[CH:28]=1)[C:29]1[CH:30]=[N:31][C:32]([CH:35]([CH3:37])[CH3:36])=[CH:33][CH:34]=1)=[O:21])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CC(C)c1ccc(N(Cc2cn[nH]c2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cn1
Reactant: CCCCCCCBr
Agent: Cl
Product: CCCCCCCn1cc(CN(C(=O)C2CCCc3c(OCc4ccccc4)cccc32)c2ccc(C(C)C)nc2)cn1

Procedure:
By the reaction and treatment in the same manner as in Example 83 using 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide hydrochloride (0.72 g) and 1-bromoheptane (0.283 mL) as starting materials, 5-benzyloxy-N-[(1-heptylpyrazol-4-yl)methyl]-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.86 g) was obtained. By the reaction and treatment of this compound in the same manner as in Example 139, N-[(1-heptylpyrazol-4-yl)methyl]-5-hydroxy-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide hydrochloride (0.62 g) was obtained.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][NH:6][C@H:5]([CH3:8])[CH2:4][NH:3]1.Cl[S:10]([C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=1)[C:16]([OH:18])=[O:17])(=[O:12])=[O:11].[OH-:22].[Na+]>O>[C:16]([C:15]1[CH:14]=[C:13]([S:10]([N:3]2[CH2:4][CH:5]([CH3:8])[N:6]([S:10]([C:13]3[CH:21]=[CH:20][CH:19]=[C:15]([C:16]([OH:18])=[O:17])[CH:14]=3)(=[O:11])=[O:22])[CH2:7][CH:2]2[CH3:1])(=[O:12])=[O:11])[CH:21]=[CH:20][CH:19]=1)([OH:18])=[O:17]
Reactant: O=C(O)c1cccc(S(=O)(=O)Cl)c1
Reactant: C[C@@H]1CN[C@@H](C)CN1
Reactant: [OH-]
Agent: [Na+]
Solvent: O
Product: CC1CN(S(=O)(=O)c2cccc(C(=O)O)c2)C(C)CN1S(=O)(=O)c1cccc(C(=O)O)c1

Procedure:
Binder 15 was prepared as follows: Trans-2,5-dimethylpiperazine in water at 50° C. was treated with slightly more than two molar equivalents of m-chlorosulfonylbenzoic acid and five molar equivalents of aqueous sodium hydroxide. Acidification gave 1,4-bis(m-carboxyphenylsulfonyl)-2,5-dimethylpiperazine which was recrystallized from aqueous ethanol. The dimethyl ester was made by boiling the acid for 24 hours in methanol to which some hydrogen chloride has been added. Recrystallization from 2:1 dioxane: water gave a product which melted at 223°-227° C. Anal. Calc'd for C22H26N2O8S2 : C, 51.7; H, 5.1; N, 5.5. Found: C, 51.6; H, 5.4; N, 5.7. The polymer was then made from this ester and ethylene glycol as described for Binder 6.
Reaction SMILES: [C:1]([C:3]1[O:7][C:6]([S:8]([N:11]2[C:15]([C:16]3[C:17]([F:22])=[N:18][CH:19]=[CH:20][CH:21]=3)=[C:14]([F:23])[C:13]([CH2:24][N:25](C)[C:26](=O)OC(C)(C)C)=[CH:12]2)(=[O:10])=[O:9])=[CH:5][CH:4]=1)#[N:2].[C:34]([O:37]CC)(=[O:36])[CH3:35].Cl.[C:41]([O:44]CC)(=[O:43])[CH3:42]>CC(O)C>[C:41]([OH:44])(=[O:43])/[CH:42]=[CH:35]/[C:34]([OH:37])=[O:36].[F:23][C:14]1[C:13]([CH2:24][NH:25][CH3:26])=[CH:12][N:11]([S:8]([C:6]2[O:7][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)(=[O:10])=[O:9])[C:15]=1[C:16]1[C:17]([F:22])=[N:18][CH:19]=[CH:20][CH:21]=1
Reactant: CCOC(C)=O
Reactant: CN(Cc1cn(S(=O)(=O)c2ccc(C#N)o2)c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CC(C)O
Product: CNCc1cn(S(=O)(=O)c2ccc(C#N)o2)c(-c2cccnc2F)c1F
Product: O=C(O)/C=C/C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 23 %

Procedure:
To a solution of tert-butyl {[1-[(5-cyano-2-furyl)sulfonyl]-4-fluoro-5-(2-fluoropyridin-3-yl)-1H-pyrrol-3-yl]methyl}methylcarbamate (253 mg) in ethyl acetate (2 mL) and 2-propanol (1 mL) was added 4 mol/L hydrogen chloride-ethyl acetate solution (3 mL), and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with saturated aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The separated aqueous layer was extracted again with ethyl acetate. The combined organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. A solution of the residue in ethyl acetate (2 mL) was added dropwise to a solution of fumaric acid (27.6 mg) in ethanol (2 mL) and the mixture was concentrated under reduced pressure. The residue was recrystallized from ethanol to give the title compound as a white solid (yield 59.3 mg, 23%).
Reaction SMILES: Cl[C:2]1[C:3]([C:9]#[N:10])=[N:4][C:5]([Cl:8])=[CH:6][N:7]=1.[CH2:11]([O:18][C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C)C=O.O>[CH2:11]([O:18][C:19]1[CH:20]=[CH:21][C:22]([O:25][C:2]2[C:3]([C:9]#[N:10])=[N:4][C:5]([Cl:8])=[CH:6][N:7]=2)=[CH:23][CH:24]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: Oc1ccc(OCc2ccccc2)cc1
Reactant: N#Cc1nc(Cl)cnc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: N#Cc1nc(Cl)cnc1Oc1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.1 %

Procedure:
In 25 mL of dimethylformamide was dissolved 2.5 g of 3,6-dichloro-2-pyrazinecarbonitrile. After adding 3.2 g of 4-(benzyloxy)phenol and 3.0 g of potassium carbonate, the mixture was stirred at room temperature for one hour. A mixture of 25 ml of ethyl acetate and 100 mL of water was added to the reaction mixture, and the organic layer was separated. The organic layer thus obtained was washed successively with water and saturated aqueous solution of sodium chloride and dried on anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. Diisopropyl ether was added to the residue, the insoluble matter was filtered off, and the filtrate was concentrated. The residue thus obtained was washed with n-hexane to obtain 3.84 g of 3-[(4-(benzyloxy)phenoxy)]-6-chloro-2-pyrazinecarbonitrile as a light brown-colored solid product.
Reaction SMILES: [CH:1]([C:3]1[N:4]=[C:5]2[C:10]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)=[CH:9][CH:8]=[N:7][N:6]2[C:17]=1[C:18]1[CH:30]=[CH:29][C:21]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[CH:20][CH:19]=1)=O.[C:31]([O-])([O-])=O.[K+].[K+].[N+](=C(P(=O)(OC)OC)C(=O)C)=[N-]>CO.C(Cl)Cl>[C:1]([C:3]1[N:4]=[C:5]2[C:10]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)=[CH:9][CH:8]=[N:7][N:6]2[C:17]=1[C:18]1[CH:30]=[CH:29][C:21]([C:22]([O:24][C:25]([CH3:27])([CH3:26])[CH3:28])=[O:23])=[CH:20][CH:19]=1)#[CH:31]
Reactant: CC(C)(C)OC(=O)c1ccc(-c2c(C=O)nc3c(N4CCOCC4)ccnn23)cc1
Reactant: O=C([O-])[O-]
Agent: COP(=O)(OC)C(=[N+]=[N-])C(C)=O
Agent: [K+]
Solvent: ClCCl
Solvent: CO
Product: C#Cc1nc2c(N3CCOCC3)ccnn2c1-c1ccc(C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a suspension of compound 5f (0.30 g, 0.73 mmol, Example 5) in MeOH (5 mL) was added K2CO3 (0.30 g, 2.2 mmol) and a solution of dimethyl (1-diazo-2-oxopropyl)phosphonate (0.18 g, 0.96 mmol) in MeOH (2 mL). The reaction mixture was stirred at rt for 2 days, and concentrated under reduced pressure. The residue obtained was dissolved in DCM (20 mL) and washed with water (20 mL). The aqueous layer was extracted with DCM (3×10 mL). The combined organic extracts were washed with brine, and dried over MgSO4. The mixture was filtered and concentrated to give a residue, which was purified by flash column chromatography on silica gel (20-60% EtOAc/heptane) to give the compound 17a as an off-white solid. Mass Spectrum (LCMS, ESI pos.): Calcd. for C23H24N4O3: 405.2 (M+H). found: 405.2.