Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([OH:9])=[C:4]([F:10])[CH:3]=1.[N+:11]([O-])([OH:13])=[O:12]>C(O)(=O)C.C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([F:10])[C:5]([OH:9])=[C:6]([N+:11]([O-:13])=[O:12])[C:7]=1[CH3:8]
Reactant: O=[N+]([O-])O
Reactant: Cc1cc(O)c(F)cc1Br
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: Cc1c(Br)cc(F)c(O)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 18 h
Yield: 50 %

Procedure:
To a solution of 4-bromo-2-fluoro-5-methylphenol (1.26 g, 6.15 mmol) in acetic acid (4 mL) and chloroform (2 mL) was added concentrated nitric acid (0.392 mL, 6.15 mmol) at −10° C. and the mixture was stirred at room temperature for 18 hours and then at 50° C. for 20 minutes (−50% desired product). The reaction mixture was diluted with ethyl acetate, then washed with water and saturated brine. The organic layer was separated, dried over anhydrous magnesium sulfate, concentrated and purified on silica gel (0-15% ethyl acetate/n-hexane) to afford 4-bromo-6-fluoro-3-methyl-2-nitrophenol (0.69 g, 2.76 mmol, 44.9% yield) as a yellow solid. 1H NMR (400 MHz, CHLOROFORM-d) d=7.57 (d, 1 H), 2.54 (d, J=1.2 Hz, 3 H); LC/MS (m/z) ES−: 247.96 (M−1).
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14]3=[N:15][C:16]([CH3:20])=[CH:17][C:18]([CH3:19])=[C:13]3[N:12]=[C:11]2[CH2:21][CH3:22])=[CH:6][CH:5]=1.[CH3:23][NH2:24]>O>[CH2:21]([C:11]1[N:10]([C:7]2[CH:8]=[CH:9][C:4]([CH2:3][CH2:2][NH:24][CH3:23])=[CH:5][CH:6]=2)[C:14]2=[N:15][C:16]([CH3:20])=[CH:17][C:18]([CH3:19])=[C:13]2[N:12]=1)[CH3:22]
Reactant: CCc1nc2c(C)cc(C)nc2n1-c1ccc(CCCl)cc1
Reactant: CN
Solvent: O
Product: CCc1nc2c(C)cc(C)nc2n1-c1ccc(CCNC)cc1
Temperature: 130 °C
Yield: 85 %

Procedure:
A mixture of 3-[4-(2-chloroethyl)phenyl]-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine (step 7 of Example 1, 627 mg, 9.0 mmol), a solution of methylamine (40% in methanol, 6 mL) and water (6 mL) was placed in a sealed tube and heated overnight at 130° C. The reaction mixture was partitioned between dichloromethane (50 mL) and water (50 mL). The organic phase was separated and the aqueous phase was extracted with dichloromethane (50 mL). The combined organic extracts were washed with brine (50 mL) and dried (Na2SO4). After removal of solvent, the crude product was purified by flash column chromatography on silica gel eluting with dichloromethane/methanol (5:1) to afford 523 mg (85%) of the title compound as white solids: 1H-NMR (CDCl3) δ 7.41 (2H, d, J=8.3 Hz), 7.31 (2H, d, J=8.3 Hz), 6.90 (1H, s), 4.73 (1H, br.s), 2.93 (4H, s), 2.82 (2H, q, J=7.5 Hz), 2.65 (3H, s), 2.51 (3H, s), 2.49 (3H, s), 1.28 (3H, t, J=7.5 Hz).
Reaction SMILES: [C:1]([C:3]1[C:4]([C:17]([F:20])([F:19])[F:18])=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13](=[NH:16])[NH:14][OH:15])[CH:7]=[CH:6]2)#[N:2].[Cl:21][C:22]1[CH:23]=[CH:24][C:25]([F:31])=[C:26]([CH:30]=1)[C:27](O)=O>>[Cl:21][C:22]1[CH:23]=[CH:24][C:25]([F:31])=[C:26]([C:27]2[O:15][N:14]=[C:13]([CH2:12][N:8]3[C:9]4[C:5](=[C:4]([C:17]([F:19])([F:20])[F:18])[C:3]([C:1]#[N:2])=[CH:11][CH:10]=4)[CH:6]=[CH:7]3)[N:16]=2)[CH:30]=1
Reactant: N#Cc1ccc2c(ccn2CC(=N)NO)c1C(F)(F)F
Reactant: O=C(O)c1cc(Cl)ccc1F
Product: N#Cc1ccc2c(ccn2Cc2noc(-c3cc(Cl)ccc3F)n2)c1C(F)(F)F

Procedure:
Synthesized as described in Example 241 from 2-[5-cyano-4-(trifluoromethyl)-1H-indol-1-yl]-N-hydroxyethanimidamide and 5-chloro-2-fluorobenzoic acid: MS (APCl) m/z 421 (M+1).
Reaction SMILES: Cl.[Si]([O:19][CH2:20][C:21]1[N:22]=[C:23]([N:34]2[CH2:39][CH2:38][N:37]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:36][CH2:35]2)[N:24]([CH2:30][C:31]#[C:32][CH3:33])[C:25]=1[C:26]([S:28][CH3:29])=N)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.[O:47]1CCCC1>>[CH2:30]([N:24]1[C:25]([C:26]([S:28][CH3:29])=[O:47])=[C:21]([CH2:20][OH:19])[N:22]=[C:23]1[N:34]1[CH2:39][CH2:38][N:37]([C:40]([O:42][C:43]([CH3:46])([CH3:44])[CH3:45])=[O:41])[CH2:36][CH2:35]1)[C:31]#[C:32][CH3:33]
Reactant: CC#CCn1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c1C(=N)SC
Reactant: C1CCOC1
Agent: Cl
Product: CC#CCn1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc(CO)c1C(=O)SC
Temperature: 25 °C
Reaction time: 22 h

Procedure:
30 ml of 5N hydrochloric acid was added to a 100 ml tetrahydrofuran solution of 5.05 g of t-butyl 4-[4-(t-butyl diphenylsilanyloxymethyl)-1-(2-butynyl)-5-methylsulfanylcarbonimidoyl-1H-imidazol-2-yl]piperazine-1-carboxylate, and the mixture was stirred at room temperature for 22 hours. The solvent was concentrated under reduced pressure. The residue was dissolved in 100 ml of dichloromethane, and 2.05 g of di-t-butyl dicarbonate was added thereto. The solution was made alkaline with 5N sodium hydroxide, and stirred for 2 hours. The organic layer was dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography. Thus, 2.24 g of the title compound was obtained from the fraction eluted with ethyl acetate-hexane (2:3).
Reaction SMILES: C(N([CH2:10][C:11]1[CH:12]=[C:13]([C:17]2[CH:22]=[CH:21][N:20]=[C:19]([NH:23][CH2:24][CH2:25][C:26]3[CH:31]=[CH:30][C:29](O)=[C:28]([F:33])[CH:27]=3)[N:18]=2)[CH:14]=[CH:15][CH:16]=1)C1CCNCC1)C.FC1[CH:36]=[C:37]([CH2:41][CH2:42][NH2:43])[CH:38]=[CH:39]C=1>>[F:33][C:28]1[CH:27]=[C:26]([CH2:25][CH2:24][NH:23][C:19]2[N:18]=[C:17]([C:13]3[CH:14]=[CH:15][CH:16]=[C:11]([CH2:10][CH2:36][CH:37]4[CH2:41][CH2:42][NH:43][CH2:39][CH2:38]4)[CH:12]=3)[CH:22]=[CH:21][N:20]=2)[CH:31]=[CH:30][CH:29]=1
Reactant: CCN(Cc1cccc(-c2ccnc(NCCc3ccc(O)c(F)c3)n2)c1)C1CCNCC1
Reactant: NCCc1cccc(F)c1
Product: Fc1cccc(CCNc2nccc(-c3cccc(CCC4CCNCC4)c3)n2)c1

Procedure:
Intermediate 92 was coupled with 2-(3-fluoro-phenyl)-ethylamine following procedure F. The resulting product was deprotected following procedure G2. LC-MS showed the product had the expected M+H+ of 406. 1H NMR (Varian 300 MHz, CD3OD, shifts relative to the solvent peak at 3.3 ppm) δ 8.27 (d, 1H), 8.04 (s, 1H), 7.96 (m, 1H), 7.47 (d, 2H), 7.25 (m, 2H), 7.09 (d, 1H), 7.04 (d, 1H), 6.89 (t, 1H), 3.80 (m, 2H), 3.36 (m, 2H), 2.91 (m, 4H), 2.77 (t, 2H), 2.00 (d, 2H), 1.67 (m, 3H), 1.36 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:49]2[CH:54]=[CH:53][C:52]([Cl:55])=[CH:51][CH:50]=2)([OH:48])[CH2:9][NH:10][C:11]2[N:19]=[C:18]([N:20]3[CH2:24][CH2:23][C@@H:22]([NH:25]C(OC(C)(C)C)=O)[CH2:21]3)[N:17]=[C:16]3[C:12]=2[N:13]=[CH:14][N:15]3[C@@H:33]2[CH2:37][C@H:36]([NH:38][C:39]([CH2:41][O:42]C(=O)C)=[O:40])[C@@H:35]([OH:46])[C@H:34]2[OH:47])=[CH:4][CH:3]=1.Cl>CO.O1CCOCC1>[NH2:25][C@@H:22]1[CH2:23][CH2:24][N:20]([C:18]2[N:17]=[C:16]3[C:12]([N:13]=[CH:14][N:15]3[C@@H:33]3[CH2:37][C@H:36]([NH:38][C:39](=[O:40])[CH2:41][OH:42])[C@@H:35]([OH:46])[C@H:34]3[OH:47])=[C:11]([NH:10][CH2:9][C:8]([C:49]3[CH:54]=[CH:53][C:52]([Cl:55])=[CH:51][CH:50]=3)([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[OH:48])[N:19]=2)[CH2:21]1
Reactant: CC(=O)OCC(=O)N[C@H]1C[C@@H](n2cnc3c(NCC(O)(c4ccc(Cl)cc4)c4ccc(Cl)cc4)nc(N4CC[C@@H](NC(=O)OC(C)(C)C)C4)nc32)[C@H](O)[C@@H]1O
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: N[C@@H]1CCN(c2nc(NCC(O)(c3ccc(Cl)cc3)c3ccc(Cl)cc3)c3ncn([C@@H]4C[C@H](NC(=O)CO)[C@@H](O)[C@H]4O)c3n2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of acetic acid {(1S,2R,3S,4R)-4-[6-[2,2-bis-(4-chloro-phenyl)-2-hydroxy-ethylamino]-2-((R)-3-tert-butoxycarbonylamino-pyrrolidin-1-yl)-purin-9-yl]-2,3-dihydroxy-cyclopentylcarbamoyl}-methyl ester (Intermediate Z01) in MeOH (˜0.5M) is treated with an equal volume of 4M HCl in dioxane and stirred at room temperature for 2 hours. The solvent is removed in vacuo and purification is carried out by column chromatography/crystallisation to afford the title compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][OH:8])=[CH:3][CH:2]=1.[Li+].CC([N-]C(C)C)C.[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][N:27]([C:30]2[C:35](Cl)=[N:34][C:33]([C:37]#[N:38])=[C:32]([C:39]#[N:40])[N:31]=2)[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:19])[CH3:18].C(O)(=O)C>C1COCC1>[C:17]([O:21][C:22]([N:24]1[CH2:29][CH2:28][N:27]([C:30]2[C:35]([O:8][CH2:7][C:4]3[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=3)=[N:34][C:33]([C:37]#[N:38])=[C:32]([C:39]#[N:40])[N:31]=2)[CH2:26][CH2:25]1)=[O:23])([CH3:20])([CH3:18])[CH3:19]
Reactant: CC(C)(C)OC(=O)N1CCN(c2nc(C#N)c(C#N)nc2Cl)CC1
Reactant: OCc1ccncc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCN(c2nc(C#N)c(C#N)nc2OCc2ccncc2)CC1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 81.8 %

Procedure:
To a solution of 4-pyridylcarbinol (0.44 mmol, 45 mg) and anhydrous tetrahydrofuran (3 ml) cooled at 0° C. was added LDA (2M, 0.6 mmol, 300 ul). The mixture was stirred at 0° C. for 15 minutes. A solution of 3′-Chloro-5′,6′-dicyano-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-carboxylic acid tert-butyl ester (0.29 mmol, 100 mg) in THF (2 ml) was then added to the cold mixture and stirred at 0° C. for 1 hour. Reaction mixture was poured onto 0.5M acetic acid and extracted with ethyl acetate. The crude product was purified by column chromatograph on silica using 70% EtOAc/hexanes to yield product 5′,6′-Dicyano-3′-(pyridin-4-ylmethoxy)-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-carboxylic acid tert-butyl ester (100 mg).
Reaction SMILES: [OH:1][N:2]=[C:3]([Cl:13])[C@H:4]1[C:8]([CH3:10])([CH3:9])[O:7][C:6]([CH3:12])([CH3:11])[O:5]1.[CH3:14][S:15](Cl)(=[O:17])=[O:16].C(N(CC)CC)C>CCOCC>[CH3:11][C:6]1([CH3:12])[O:5][C@@H:4]([C:3]([Cl:13])=[N:2][O:1][S:15]([CH3:14])(=[O:17])=[O:16])[C:8]([CH3:9])([CH3:10])[O:7]1
Reactant: CS(=O)(=O)Cl
Reactant: CC1(C)O[C@@H](C(Cl)=NO)C(C)(C)O1
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CC1(C)O[C@@H](C(Cl)=NOS(C)(=O)=O)C(C)(C)O1
Reaction time: 0.5 h
Yield: 66.2 %

Procedure:
(R)—N-hydroxy-2,2,5,5-tetramethyl-1,3-dioxolane-4-carbimidoyl chloride (12.4 g, 59.7 mmol) was dissolved in Et2O (200 mL) and cooled in an ice bath. Methanesulfonyl chloride (4.6 ml, 59.7 mmol) was added. Triethylamine (8.3 ml, 59.7 mmol) was added slowly and the reaction was stirred in an ice bath for 30 minutes. The reaction was filtered and concentrated. The residue was purified over silica gel (100% CH2Cl2) to afford (R)-2,2,5,5-tetramethyl-N-(methylsulfonyloxy)-1,3-dioxolane-4-carbimidoyl chloride (11.3 g, 39.55 mmol, 66.22% yield) as a white solid.
Reaction SMILES: [CH:1]1[C:6]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)=[CH:5][CH:4]=[C:3]([F:15])[CH:2]=1.[OH2:16]>O=[Mn]=O>[F:15][C:3]1[CH:2]=[CH:1][C:6]([C:7]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)=[O:16])=[CH:5][CH:4]=1
Reactant: O
Reactant: Fc1ccc(Cc2ccc(F)cc2)cc1
Agent: O=[Mn]=O
Product: O=C(c1ccc(F)cc1)c1ccc(F)cc1
Yield: 95 %

Procedure:
The procedure of Example 1 was used except that 20 g 4,4'-difluorodiphenylmethane, 30 g water, 31 g MnO2 and 50 g H2 SO4 were used. 20 g off-white solids, after toluene removal, afforded 95% pure 4,4'-difluorobenzophenone in a 90% yield.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.[N+:12]([O-])([OH:14])=[O:13].[N+]([O-])(O)=O.C(O)(=O)C>C(O)(=O)C>[N+:12]([C:7]1[CH:6]=[C:5]([CH2:8][C:9]([OH:11])=[O:10])[CH:4]=[CH:3][C:2]=1[OH:1])([O-:14])=[O:13]
Reactant: O=[N+]([O-])O
Reactant: O=C(O)Cc1ccc(O)cc1
Solvent: CC(=O)O
Product: O=C(O)Cc1ccc(O)c([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
In a first step, carried out according to Humel in Synth. Commun. 15, pages 1081-88 (1985), to a magnetically stirred solution of 100 g (0.65 mole) of 4-hydroxyphenyl acetic acid in 250 ml of glacial acetic acid was added dropwise a mixture of 40 ml of nitric acid (1.4 specific gravity) and 60 ml glacial acetic acid. The glacial acetic acid was warmed to about 45° C. to completely dissolve the 4-hydroxyphenyl acetic acid. Following addition of the nitric acid/acetic acid mixture, stirring of the resulting mixture was continued for one hour at 25° C. and then the flask was chilled in ice water for one hour. The resulting crystals were washed with cold water and air-dried at room temperature, the reaction providing 65% of the theoretical yield of 3-nitro 4-hydroxyphenyl acetic acid.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[N:11]([CH3:12])[CH2:10][CH2:9][N:5]2[C:6](=[O:8])[N:7]=1.[H-].[Na+].[F:15][C:16]1[CH:17]=[C:18]([CH2:34][OH:35])[CH:19]=[C:20]([F:33])[C:21]=1[O:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=1>CN(C=O)C>[F:15][C:16]1[CH:17]=[C:18]([CH:19]=[C:20]([F:33])[C:21]=1[O:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:30])([F:31])[F:32])[CH:24]=1)[CH2:34][O:35][C:2]1[CH:3]=[C:4]2[N:11]([CH3:12])[CH2:10][CH2:9][N:5]2[C:6](=[O:8])[N:7]=1
Reactant: OCc1cc(F)c(Oc2cccc(C(F)(F)F)c2)c(F)c1
Reactant: CN1CCn2c1cc(Cl)nc2=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CCn2c1cc(OCc1cc(F)c(Oc3cccc(C(F)(F)F)c3)c(F)c1)nc2=O

Procedure:
Prepared in a manner similar to that described for E1 using 7-chloro-1-methyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one (60 mg, 0.323 mmol), sodium hydride (25.9 mg, 0.647 mmol) and (3,5-difluoro-4-(3-(trifluoromethyl)phenoxy)phenyl)methanol (98 mg, 0.323 mmol) in DMF (2 mL).
Reaction SMILES: C([O:5][C:6](=[O:28])[C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:18][CH2:17][N:16]([C:19](=[O:24])[C:20]([F:23])([F:22])[F:21])[CH2:15][CH2:14]2)=[CH:9][C:8]=1[N+:25]([O-:27])=[O:26])(C)(C)C>ClCCl>[N+:25]([C:8]1[CH:9]=[C:10]([N:13]2[CH2:18][CH2:17][N:16]([C:19](=[O:24])[C:20]([F:23])([F:22])[F:21])[CH2:15][CH2:14]2)[CH:11]=[CH:12][C:7]=1[C:6]([OH:28])=[O:5])([O-:27])=[O:26]
Reactant: CC(C)(C)OC(=O)c1ccc(N2CCN(C(=O)C(F)(F)F)CC2)cc1[N+](=O)[O-]
Solvent: ClCCl
Product: O=C(O)c1ccc(N2CCN(C(=O)C(F)(F)F)CC2)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-nitro-4-[4-(2,2,2-trifluoro-acetyl)-piperazin-1-yl]-benzoic acid tert-butyl ester (1.70 g, 4.22 mmol) in dichloromethane (25 mL) trifluoroacetic acid (5 mL) was added. The mixture was stirred at room temperature for 2 h, and then evaporated to give the title compound as yellow solid. 1H-NMR (400 MHz), ppm, DMSO-d6): 13.21 (bs, 1H), 7.78 (d, J=8.9 Hz, 1H), 7.31 (d, J=2.5 Hz, 1H), 7.17 (dd, J1=8.9 Hz, J2=2.5 Hz, 1H), 3.74 (m, 4H), 3.56 (m, 4H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[C:5]([NH:7][C:8]1[CH:13]=[C:12]([Cl:14])[C:11]([O:15][C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([CH:23]=O)[CH:17]=2)=[C:10]([Cl:25])[CH:9]=1)=[O:6])[CH3:2].[NH2:27][CH:28]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH2:30][CH2:29]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClC(Cl)C>[CH2:1]([O:3][C:4](=[O:26])[C:5]([NH:7][C:8]1[CH:13]=[C:12]([Cl:14])[C:11]([O:15][C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([CH2:23][NH:27][CH:28]3[C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[CH2:30][CH2:29]3)[CH:17]=2)=[C:10]([Cl:25])[CH:9]=1)=[O:6])[CH3:2]
Reactant: NC1CCc2ccccc21
Reactant: CCOC(=O)C(=O)Nc1cc(Cl)c(Oc2ccc(O)c(C=O)c2)c(Cl)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: CCOC(=O)C(=O)Nc1cc(Cl)c(Oc2ccc(O)c(CNC3CCc4ccccc43)c2)c(Cl)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture of N-[3,5-dichloro-4-(3-formyl-4-hydroxy-phenoxy)-phenyl]-oxamic acid ethyl ester (30 mg, 0.08 mmol) and aminoindan (10 mg, 0.08 mmol) in dichloroethane (1.0 mL) was added sodium triacetoxyborohydride (22.4 mg, 0.11 mmol) and acetic acid (4.5 mg, 0.08 mmol) in single portions. After stirring at RT for 3 h, the solution became clear and yellow. The solution was quenched with saturated aqueous NaHCO3 (5 mL) and extracted with Et2O (3×10 mL). The combined extracts were dried over Na2SO4, filtered and concentrated to give the crude product as a yellow glass. The crude product was purified by preparative TLC (5% Et2O in CH2Cl2) to afford the title compound as an off-white solid. NMR (400 MHz, CDCl3) d 8.94 (s, 1H), 7.74 (s, 2H), 7.36-7.37 (d, 1H), 7.19-7.25 (m, 4H), 6.75-6.77 (d, 1H), 6.61-6.64 (dd, 1H), 6.54-6.55 (d, 1H), 4.40-4.46 (q, 2H), 4,30-4.33 (t, 1H), 4.05-4.08 (d, 1H), 3.95-3.98 (d, 1H), 2.98-3.06 (m, 1H), 2.81-2.88 (m, 1H), 2.42-2.51 (m, 1H), 1.88-1.96 (m, 1H), 1.41-1.45 (t, 3H). MS Calc.: 514.20, Found: 513.1 (M−1).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12](Br)=[CH:11][C:10]=1[CH:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li]CCCC.CN([CH:29]=[O:30])C.Cl>O1CCCC1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:29]=[O:30])=[CH:11][C:10]=1[CH:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(C)C=O
Reactant: Brc1ccc(OCc2ccccc2)c(C2CCCC2)c1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=Cc1ccc(OCc2ccccc2)c(C2CCCC2)c1
Temperature: -65 °C
Reaction time: 0.5 h
Yield: 63 %

Procedure:
A stirred solution of 1-benzyloxy-4-bromo-2-cyclopentyl-benzene (1500 mg, 4.53 mmol) in tetrahydrofuran (13.4 mL) was cooled to −65° C. n-BuLi (3.11 mL of 1.6 M, 4.98 mmol) was added dropwise over several minutes. After 30 min, DMF (497 mg, 526.0 μL, 6.79 mmol) was added dropwise over a period of 10 min. Stirring at −65° C. was maintained for 20 min, and then the reaction was quenched by the addition of HCl (9.06 mL of 1 M, 9.06 mmol). The aqueous and organic layers were separated. The organic layer was washed with saturated NaHCO3 (10 mL) and water (10 mL), dried over Na2SO4, filtered and concentrated. Purification by silica gel chromatography (0-10% ethyl acetate/hexanes) provided 4-benzyloxy-3-cyclopentyl-benzaldehyde (800 mg, 63% yield) white solid. 1H NMR (400.0 MHz, DMSO-d6) δ 9.86 (s, 1H), 7.76 (dd, J=2.1, 6.6 Hz, 2H), 7.49-7.29 (m, 5H), 7.26-7.20 (m, 1H), 5.26 (s, 2H), 3.37-3.26 (m, 1H), 2.00-1.90 (m, 2H), 1.73-1.50 (m, 6H).
Reaction SMILES: [C:1]([O:6][CH:7]1[CH:11]2[O:12][C:13](=[O:19])[CH:14]3[CH:15]([C:16](O)=[O:17])[CH:8]1[CH2:9][CH:10]23)(=[O:5])[C:2]([CH3:4])=[CH2:3].C(Cl)(=O)C([Cl:23])=O>C1(C)C=CC=CC=1>[C:1]([O:6][CH:7]1[CH:11]2[O:12][C:13](=[O:19])[CH:14]3[CH:15]([C:16]([Cl:23])=[O:17])[CH:8]1[CH2:9][CH:10]23)(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: O=C(Cl)C(=O)Cl
Reactant: C=C(C)C(=O)OC1C2CC3C1OC(=O)C3C2C(=O)O
Solvent: Cc1ccccc1
Product: C=C(C)C(=O)OC1C2CC3C1OC(=O)C3C2C(=O)Cl
Reaction time: 4 h

Procedure:
Suspended into 135 mL of toluene was 18.0 g of the carboxylic acid (26) obtained in Synthesis Example 1-1-2, and then into the resulting suspension was gradually added 10.3 g of oxalyl chloride at 80° C. After this mixture was stirred for 4 hours, toluene was removed by distillation under reduced pressure to obtain the intended product. The obtained acid chloride was used in the next reaction without further purification.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4](=[O:9])[C:5]([CH3:8])([CH3:7])[CH3:6].[CH3:10][O:11][C:12]1[CH:21]=[CH:20][C:15]([C:16]([O:18]C)=O)=[CH:14][C:13]=1[C:22]([O:24]C)=O.Cl>O1CCCC1>[CH3:10][O:11][C:12]1[CH:21]=[CH:20][C:15]([C:16](=[O:18])[CH2:3][C:4](=[O:9])[C:5]([CH3:8])([CH3:7])[CH3:6])=[CH:14][C:13]=1[C:22](=[O:24])[CH2:3][C:4](=[O:9])[C:5]([CH3:8])([CH3:7])[CH3:6]
Reactant: CC(=O)C(C)(C)C
Reactant: COC(=O)c1ccc(OC)c(C(=O)OC)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(C(=O)CC(=O)C(C)(C)C)cc1C(=O)CC(=O)C(C)(C)C
Yield: 66.3 %

Procedure:
In a 100 ml three-necked flask equipped with a mechanical stirrer, dropping funnel, reflux condenser, and a nitogen-inlet tube, 1.5 gm (38 mmol) of 60% sodium hydride, 3.6 gm (36 mmol) of pinacolone, 3.0 gm (13.4 mmol) of dimethyl 4-methoxyisophthalate, and 30 ml of anhydrous tetrahydrofuran were mixed with stirring under nitrogen stream and refluxed with heating for 5 hours. After cooling the reaction mixture, 10 ml of 2N aqueous hydrochloric acid was added, and the product was extracted with chloroform. The extract was dried over anhydrous sodium sulfate and the solvent was removed by evaporation. The crude product was recrystallized using hexane to obtain 3.2 gm of the target compound as colorless crystals (yield: 66%).
Reaction SMILES: Cl[C:2]1[S:3][C:4]2[CH:11]=[CH:10][C:9]3[CH:12]=[C:13]([Cl:16])[CH:14]=[CH:15][C:8]=3[CH:7]([C:17]3[C:18](=[O:25])[NH:19][C:20](=[O:24])[N:21]([CH3:23])[CH:22]=3)[C:5]=2[N:6]=1.[NH:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1>O1CCOCC1>[Cl:16][C:13]1[CH:14]=[CH:15][C:8]2[CH:7]([C:17]3[C:18](=[O:25])[NH:19][C:20](=[O:24])[N:21]([CH3:23])[CH:22]=3)[C:5]3[N:6]=[C:2]([N:26]4[CH2:30][CH2:29][CH2:28][CH2:27]4)[S:3][C:4]=3[CH:11]=[CH:10][C:9]=2[CH:12]=1
Reactant: Cn1cc(C2c3ccc(Cl)cc3C=Cc3sc(Cl)nc32)c(=O)[nH]c1=O
Reactant: C1CCNC1
Solvent: C1COCCO1
Product: Cn1cc(C2c3ccc(Cl)cc3C=Cc3sc(N4CCCC4)nc32)c(=O)[nH]c1=O

Procedure:
The product from example 44 step (viii) (0.042 g) was treated with pyrrolidine (0.1 ml) in 1,4-dioxane (3 ml) at reflux for 6 h. The volatiles were removed under reduced pressure and the residue triturated with diethyl ether/isohexane mixtures to leave the subtitle product as a pale yellow solid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][CH:7]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:6][CH2:5]1.C1CCN2C(=NCCC2)CC1.CN(C)C=O.[F:33][C:34]1[CH:35]=[C:36]2[C@:43]3([C:47](=[O:48])[NH:46][C:45](=[O:49])[NH:44]3)[CH2:42][C@@H:41]([C:50](Cl)=[O:51])[O:40][C:37]2=[CH:38][CH:39]=1>>[CH2:10]([CH:7]1[CH2:6][CH2:5][N:4]([CH2:3][CH2:2][NH:1][C:50]([C@@H:41]2[CH2:42][C@@:43]3([C:47](=[O:48])[NH:46][C:45](=[O:49])[NH:44]3)[C:36]3[C:37](=[CH:38][CH:39]=[C:34]([F:33])[CH:35]=3)[O:40]2)=[O:51])[CH2:9][CH2:8]1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: O=C1NC(=O)[C@@]2(C[C@@H](C(=O)Cl)Oc3ccc(F)cc32)N1
Reactant: NCCN1CCC(Cc2ccccc2)CC1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: O=C1NC(=O)[C@@]2(C[C@@H](C(=O)NCCN3CCC(Cc4ccccc4)CC3)Oc3ccc(F)cc32)N1
Temperature: -30 °C
Reaction time: 15 h
Yield: 49.9 %

Procedure:
A mixture of N-(2-aminoethyl)-4-benzylpiperidine (13.0 g, 59.6 mmol), 1,8-diazabicyclo[5,4,0]-7-undecene (10.9 g, 71.7 mmol) and N,N-dimethylformamide (90.0 ml, 1.16 mol) was chilled to -30° C. To the mixture was added over 30 minutes a solution of (2S, 4S)-6-fluoro-2',5'-dioxospiro[chroman-4,4'-imidazolidine]-2-carbonyl chloride (Reference Example, 18.0 g, 60.3 mmol) in N,N-dimethylformamide (90.0 ml, 1.16 mol) and the mixture was stirred for 15 hours at temperature of 15°-25° C. After distilling off the solvent, the reaction mixture was chromatographed on silica gel, eluted with CH2Cl2 /MeOH (9/1) and evaporated in vacuo to dryness to give the desired compound (14.3 g, 50.0%) as colorless amorphous substance.
Reaction SMILES: [C:1]([N:4]1[C:8]([CH3:9])=[C:7]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([S:17][CH2:18][CH3:19])=[CH:13][CH:12]=2)[C:6]([O:20][C@@H:21]2[O:29][C@H:28]([CH2:30][OH:31])[C@@H:26]([OH:27])[C@H:24]([OH:25])[C@H:22]2[OH:23])=[N:5]1)(=[O:3])[CH3:2].Cl[C:33]([O:35][CH2:36][CH3:37])=[O:34].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CC1C=C(C)C=C(C)N=1>[C:1]([N:4]1[C:8]([CH3:9])=[C:7]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([S:17][CH2:18][CH3:19])=[CH:13][CH:12]=2)[C:6]([O:20][C@@H:21]2[O:29][C@H:28]([CH2:30][O:31][C:33]([O:35][CH2:36][CH3:37])=[O:34])[C@@H:26]([OH:27])[C@H:24]([OH:25])[C@H:22]2[OH:23])=[N:5]1)(=[O:3])[CH3:2]
Reactant: CCOC(=O)Cl
Reactant: CCSc1ccc(Cc2c(O[C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)nn(C(C)=O)c2C)cc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: Cc1cc(C)nc(C)c1
Product: CCOC(=O)OC[C@H]1O[C@@H](Oc2nn(C(C)=O)c(C)c2Cc2ccc(SCC)cc2)[C@H](O)[C@@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1-acetyl-4-[(4-ethylthiophenyl)-methyl]-3-(β-D-glucopyranosyloxy)-5-methylpyrazole (0.03 g) in 2,4,6-trimethylpyridine (0.5 mL) was added ethyl chloro-formate (0.012 mL), and the mixture was stirred at room temperature overnight. To the reaction mixture was added 10% aqueous citric acid solution (5 mL), and the resulting mixture was stirred at room temperature overnight. The resulting precipitatse were collected by filtration and washed with 10% aqueous citric acid solution and water to give 1-acetyl-3-(6-O-ethoxycarbonyl-β-D-glucopyranosyloxy)-4-[(4-ethylthiophenyl)methyl]-5-methylpyrazole (0.020 g).