Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14](=[O:15])[CH:13]=[CH:12]O[C:10]=1[CH3:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC1C(=O)C=COC=1C)C1C=CC=CC=1.C([N:36]1C=CC(=O)[C:38]([OH:43])=[C:37]1C)(=O)C.OCCN.[OH-].[Na+].Cl>O.C(O)C>[CH2:1]([O:8][C:9]1[C:14](=[O:15])[CH:13]=[CH:12][N:36]([CH2:37][CH2:38][OH:43])[C:10]=1[CH3:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1occc(=O)c1OCc1ccccc1
Reactant: CC(=O)n1ccc(=O)c(O)c1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: NCCO
Solvent: CCO
Solvent: O
Product: Cc1c(OCc2ccccc2)c(=O)ccn1CCO
Temperature: 25 °C
Reaction time: 144 h

Procedure:
3-Benzyloxy-2-methyl-4-pyrone (4.8 g), prepared as described under (J), and 2-hydroxyethylamine (1.22 g) are dissolved in water (220 ml) and ethanol (100 ml) containing sodium hydroxide (2 g) is added. The mixture is stirred at room temperature for 6 days and is then acidified with concentrated hydrochloric acid to pH 2, and evaporated to dryness. The resulting colourless solid is washed with water and extracted into chloroform (2×50 ml). The chloroform extracts are combined, dried over magnesium sulphate, and evaporated to yield 3-benzyloxy-1-(2'-hydroxyethyl)-2-methylpyrid-4-one, as a white solid (3.4 g), m.p. 198°-199° C.
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][C@H:24]([CH2:27][OH:28])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[NH:29]1[CH:33]=[CH:32][C:31](B(O)O)=[N:30]1>>[OH:28][CH2:27][C@H:24]1[CH2:25][CH2:26][N:22]([C:3]2[C:2]([C:31]3[NH:30][N:29]=[CH:33][CH:32]=3)=[CH:21][C:6]([C:7]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=3)=[O:8])=[CH:5][N:4]=2)[CH2:23]1
Reactant: OB(O)c1cc[nH]n1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC[C@H](CO)C2)c(Br)c1
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC[C@H](CO)C2)c(-c2ccn[nH]2)c1

Procedure:
The title compound was prepared in an analogous fashion to that of Example 2 using (S)-5-bromo-6-(3-(hydroxymethyl)pyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 7.1) and (1H-pyrazol-3-yl)boronic acid to afford a white solid. UPLC-MS (Condition 1) tR=1.89 min, m/z=448.0 [M+H]+, m/z=446.1 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.48-1.64 (m, 1H) 1.77-1.90 (m, 1H) 2.15-2.28 (m, 1H) 3.03 (dd, J=11.25, 6.85 Hz, 1H) 3.22 (br. s, 2H) 3.25-3.31 (m, 2H) 3.34-3.39 (m, 1H) 4.62 (br. s, 1H) 6.39 (br. s, 1H) 7.34 (d, J=8.56 Hz, 2H) 7.51-7.84 (m, 1H) 7.83-7.90 (m, 2H) 8.03 (s, 1H) 8.68-8.79 (m, 1H) 10.19 (s, 1H) 12.87-13.12 (m, 1H).
Reaction SMILES: C[N:2](C)/C=C/C(C1SC(N2CCN(CC3C=CC(C(F)(F)F)=CC=3)C2=O)=NC=1C)=O.C[N:32](C)/[C:33](/[CH3:60])=[CH:34]/[C:35]([C:37]1[S:41][C:40]([N:42]2[CH2:46][CH2:45][N:44]([CH2:47][C:48]3[CH:53]=[CH:52][C:51]([C:54]([F:57])([F:56])[F:55])=[CH:50][CH:49]=3)[C:43]2=[O:58])=[N:39][C:38]=1[CH3:59])=O.O.NN>>[CH3:59][C:38]1[N:39]=[C:40]([N:42]2[CH2:46][CH2:45][N:44]([CH2:47][C:48]3[CH:49]=[CH:50][C:51]([C:54]([F:56])([F:55])[F:57])=[CH:52][CH:53]=3)[C:43]2=[O:58])[S:41][C:37]=1[C:35]1[CH:34]=[C:33]([CH3:60])[NH:32][N:2]=1
Reactant: Cc1nc(N2CCN(Cc3ccc(C(F)(F)F)cc3)C2=O)sc1C(=O)/C=C/N(C)C
Reactant: C/C(=C\C(=O)c1sc(N2CCN(Cc3ccc(C(F)(F)F)cc3)C2=O)nc1C)N(C)C
Agent: NN
Solvent: O
Product: Cc1cc(-c2sc(N3CCN(Cc4ccc(C(F)(F)F)cc4)C3=O)nc2C)n[nH]1
Yield: 67 %

Procedure:
Following the procedure as described in Example 38, making variations as required to replace (E)-1-(5-(3-(dimethylamino)acryloyl)-4-methylthiazol-2-yl)-3-(4-(trifluoromethyl)benzyl)imidazolidin-2-one with (E)-1-(5-(3-(dimethylamino)but-2-enoyl)-4-methylthiazol-2-yl)-3-(4-(trifluoromethyl)benzyl)imidazolidin-2-one to react with hydrazine monohydrate, the title compound was obtained as a colorless solid in 67% yield: mp 238-239° C. (ethyl acetate); 1H NMR (300 MHz, CDCl3) δ 7.53 (d, J=7.8 Hz, 2H), 7.34 (d, J=7.8 Hz, 2H), 6.08 (s 1H), 4.52 (s, 2H), 4.04-3.99 (m, 2H), 3.42-3.36 (m, 2H), 2.36 (s, 3H), 2.24 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 156.8, 155.8, 143.1, 139.9, 130.3, 129.9, 128.3, 125.8, 125.7, 122.1, 103.6, 47.5, 41.9, 41.8, 16.0, 10.8; MS (ES+) m/z 422.1 (M+1).
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:13][C:14]2[CH:15]=[C:16]3[C:21](=[CH:22][CH:23]=2)[N:20]=[C:19]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[C:30]([O:32]C)=[O:31])[CH:18]=[C:17]3[C:34]([O:36]C)=[O:35])[C:7]([CH2:11][OH:12])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+].O>C(O)C>[CH2:1]([C:5]1[N:6]([CH2:13][C:14]2[CH:15]=[C:16]3[C:21](=[CH:22][CH:23]=2)[N:20]=[C:19]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[C:30]([OH:32])=[O:31])[CH:18]=[C:17]3[C:34]([OH:36])=[O:35])[C:7]([CH2:11][OH:12])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(Cl)c(CO)n1Cc1ccc2nc(-c3ccccc3C(=O)OC)cc(C(=O)OC)c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCCc1nc(Cl)c(CO)n1Cc1ccc2nc(-c3ccccc3C(=O)O)cc(C(=O)O)c2c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 92.3 %

Procedure:
50.6 mg (0.0969 mmol) of methyl 6-[(2-butyl-4-chloro-5-hydroxymethyl-1H-imidazol-1-yl)methyl]-2-(2-methoxycarbonylphenyl)-4-quinolinecarboxylate obtained in Example 8 was mixed with 33.5 mg (0.388 mmol) of sodium hydroxide, 1 ml of water and 0.3 ml of ethanol and the mixture was stirred at the room temperature for 24 hours. After concentrated under reduced pressure, the concentrate was partitioned between water and ether. The aqueous layer was acidified with 1N hydrochloric acid and extracted with ethyl acetate to obtain 44.2 mg of 6-[(2-butyl-4-chloro-5-hydroxymethyl-1H-imidazol-1-yl)methyl]-2-(2-carboxyphenyl)-4-quinolinecarboxylic acid. NMR (270 MHz, CD3OD):
Reaction SMILES: [C:1]([O:4][C@H:5]1[CH2:10][CH2:9][C@H:8]2[C@H:11]3[C@H:20]([CH2:21][CH2:22][C@:6]12[CH3:7])[C:19]1C[CH2:17][C:16]2([O:26][CH2:25][CH2:24][O:23]2)[CH2:15][C:14]=1[CH2:13][CH2:12]3)(=[O:3])[CH3:2].C([O-])([O-])=O.[Ca+2].[Br:32]N1C(=O)CCC1=O.CN(C)[CH:42]=[O:43]>O>[C:1]([O:4][C@H:5]1[CH2:10][CH2:9][C@H:8]2[C@H:11]3[C@H:20]([CH2:21][CH2:22][C@:6]12[CH3:7])[C@:19]1([Br:32])[C@:42]([OH:43])([CH2:17][C:16]2([O:26][CH2:25][CH2:24][O:23]2)[CH2:15][CH2:14]1)[CH2:13][CH2:12]3)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@H]1CC[C@H]2[C@@H]3CCC4=C(CCC5(C4)OCCO5)[C@H]3CC[C@]12C
Reactant: O=C1CCC(=O)N1Br
Reactant: CN(C)C=O
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: O
Product: CC(=O)O[C@H]1CC[C@H]2[C@@H]3CC[C@@]4(O)CC5(CC[C@]4(Br)[C@H]3CC[C@]12C)OCCO5
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a suspension of 8.5 g of 17β-acetoxy-3,3-ethylenedioxy-estr-5(10)-ene in 130 ml of dimethylformamide and 40 ml of water, 2.35 g of powdered CaCO3 and 8.39 g of N-bromosuccinimide are added at room temperature. After stirring for 4 hours at room temperature, the yellow suspension is poured into ice-water and the precipitate filtered on buckner; the precipitate is dissolved in methylene chloride and the insoluble residue is filtered off; the filtrate is washed with water and dried over anhydrous sodium sulphate. Evaporation of the solvent yields 10.7 g of 17β-acetoxy-3,3-ethylenedioxy-5α-hydroxy-10β-bromo-estrane as a white solid material,
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([S:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[Cl:16])=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:17][C:18]#N.[OH-:20].[K+].[OH2:22]>C(O)C>[CH3:1][O:2][C:3]1[C:8]([S:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[Cl:16])=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:17][C:18]([OH:22])=[O:20]
Reactant: O
Reactant: COc1c(CC#N)cccc1Sc1ccccc1Cl
Reactant: [OH-]
Agent: [K+]
Solvent: CCO
Product: COc1c(CC(=O)O)cccc1Sc1ccccc1Cl

Procedure:
A mixture of 2-[2-methoxy-3-(2-chlorophenylthio)phenyl]acetonitrile (1.5 g) and potassium hydroxide (870 mg) in ethanol (40 ml) and water (20 ml) was refluxed under heating for 24 hours. The reaction mixture was evaporated under reduced pressure and the residue was dissolved in water. The aqueous solution was washed with diethyl ether, acidified with dil. hydrochloric acid and extracted with diethyl ether. The extract was washed with water, dried and then evaporated to give oily 2-[2-methoxy-3-(2-chlorophenylthio)phenyl]acetic acid (1.4 g).
Reaction SMILES: [C:1]([O:10][CH3:11])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].[OH-].[Na+].[C:14](Cl)(=[O:23])[C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1.C(O)(=O)C>C(Cl)Cl.O>[C:14]([NH:4][C:3]1[C:2](=[CH:8][CH:7]=[CH:6][CH:5]=1)[C:1]([O:10][CH3:11])=[O:9])(=[O:23])[C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: COC(=O)c1ccccc1N
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)c1ccccc1NC(=O)c1ccc(OC)cc1
Temperature: 23 °C
Yield: 96 %

Procedure:
A solution of 529.8 g (3.505 mole) methyl anthranilate and 294.4 g 50 weight percent NaOH (3.68 mole) in 3.6 L CH2Cl2 and 1.8 L H2O was stirred in an ice-bath as 627.8 g (3.680 mole) p-anisoyl chloride was added at such rate that the temperature did not exceed 10° C. (time required was 1.25 hr). The mixture was allowed to warm to 23° C. Acetic acid (50 mL) was added to adjust the pH to 5. The layers were separated and the organic layer was washed with 10% aqueous NaHCO3 (1×0.8 L) and brine (1×0.8 L). The solvent was removed in vacuo. The residual white solid was recrystallized from 7.0 L boiling methanol. The product (III) was dried in vacuo at 70° C. for 24 hr to yield 959.7 g (96.0%) white crystalline solid, m.p. 122.5°-124.5° C.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[C:9]([CH3:11])[C:8]([Br:12])=[C:7]([CH2:13]Br)[CH:6]=1)(=[O:3])[CH3:2].[C:15]([O-:18])(=[O:17])[CH3:16].[Na+].C(OCC)(=O)C>CN(C)C=O>[C:15]([O:18][CH2:13][C:7]1[CH:6]=[C:5]([O:4][C:1](=[O:3])[CH3:2])[CH:10]=[C:9]([CH3:11])[C:8]=1[Br:12])(=[O:17])[CH3:16]
Reactant: CC(=O)Oc1cc(C)c(Br)c(CBr)c1
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(=O)OCc1cc(OC(C)=O)cc(C)c1Br
Temperature: 70 °C
Reaction time: 4 h
Yield: 66.7 %

Procedure:
To a solution of 4-bromo-3-(bromomethyl)-5-methylphenyl acetate (11.7 g, 36.3 mmol) in N,N-dimethylformamide (60 mL) was added sodium acetate (5.96 g, 72.6 mmol), and the mixture was stirred at 70° C. for 4 hr under nitrogen atmosphere. Ethyl acetate was added to the reaction mixture, and the mixture was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=0:100-25:75) to give the title compound (7.29 g, yield 67%) as a pale-yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5](B2OC(C)(C)C(C)(C)O2)=[C:6]2[C:10]=1[C@H:9]([O:11][C:12]1[CH:25]=[CH:24][C:15]3[C@H:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:17][O:18][C:14]=3[CH:13]=1)[CH2:8][CH2:7]2.Br[C:36]1[C:49]([CH3:50])=[CH:48][C:39]([O:40][CH2:41][CH2:42][NH:43][S:44]([CH3:47])(=[O:46])=[O:45])=[CH:38][C:37]=1[CH3:51].BrC1C=CC(F)=C2C=1CC[C@H]2OC1C=CC2[C@H](CC(OC)=O)COC=2C=1>>[CH3:51][C:37]1[CH:38]=[C:39]([O:40][CH2:41][CH2:42][NH:43][S:44]([CH3:47])(=[O:45])=[O:46])[CH:48]=[C:49]([CH3:50])[C:36]=1[C:5]1[CH:4]=[CH:3][C:2]([F:1])=[C:10]2[C:6]=1[CH2:7][CH2:8][C@H:9]2[O:11][C:12]1[CH:25]=[CH:24][C:15]2[C@H:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:17][O:18][C:14]=2[CH:13]=1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(B5OC(C)(C)C(C)(C)O5)ccc(F)c43)ccc21
Reactant: Cc1cc(OCCNS(C)(=O)=O)cc(C)c1Br
Agent: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Br)ccc(F)c43)ccc21
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5c(C)cc(OCCNS(C)(=O)=O)cc5C)ccc(F)c43)ccc21

Procedure:
The title compound is prepared from methyl 2-((S)-6-((R)-7-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-yloxy)-2,3-dihydrobenzofuran-3-yl)acetate and N-(2-(4-bromo-3,5-dimethylphenoxy)ethyl)methanesulfonamide following a procedure analogous to that described in Step 5 of Intermediate 1. LC (method 8): tR=0.59 min; Mass spectrum (ESI+): m/z=584 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:11])[N:3]=1.[NH2:12][C:13]1[CH:21]=[C:20]2[C:16]([CH:17]=[N:18][NH:19]2)=[CH:15][CH:14]=1.C(N(CC)CC)C.O>C(#N)C>[Cl:11][C:4]1[N:3]=[C:2]([NH:12][C:13]2[CH:21]=[C:20]3[C:16]([CH:17]=[N:18][NH:19]3)=[CH:15][CH:14]=2)[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=1
Reactant: Nc1ccc2cn[nH]c2c1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1Cl
Solvent: CC#N
Solvent: O
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1ccc(Cl)nc1Nc1ccc2cn[nH]c2c1
Yield: 73.3 %

Procedure:
To the solution of 2,6-dichloro-3-nitropyridine (4 g) and 6-aminoindazole (2.8 g) in acetonitrile (50 ml) was added triethylamine (3.2 ml), and then the solution was reacted at 35-40° C. for 12 hr. The reaction mixture was cooled at room temperature with slowly adding H2O (20 ml), and then reacted at 20-25° C. for 1 hr. The reaction mixture was filtered, washed with acetonitrile (6 ml) and H2O (15 ml), and then dried at 50° C. in vacuo to obtain the desired compound (4.4 g, 73%).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[O:26][C@H:25]([CH2:27][OH:28])[C@@H:23]([OH:24])[C@H:12]2[O:13][CH2:14][CH2:15][CH2:16][CH2:17][N:18]2[CH:22]=[CH:21][N:20]=[CH:19]2)=[C:4](N)[N:3]=1.NC1N=C2C(N=CN2[C@@H]2O[C@H](CO)[C@@H](OCCCCN3C=CN=C3)[C@H]2[OH:42])=C(N)N=1.[C@@H]1(N2C3N=CN=C(N)C=3N=C2)O[C@H](CO)[C@@H](O)[C@H]1O>>[N:18]1([CH2:17][CH2:16][CH2:15][CH2:14][O:13][C@@H:12]2[C@H:23]([OH:24])[C@@H:25]([CH2:27][OH:28])[O:26][C@H:11]2[N:8]2[C:9]3[N:10]=[C:2]([NH2:1])[NH:3][C:4](=[O:42])[C:5]=3[N:6]=[CH:7]2)[CH:22]=[CH:21][N:20]=[CH:19]1
Reactant: Nc1nc(N)c2ncn([C@@H]3O[C@H](CO)[C@@H](OCCCCn4ccnc4)[C@H]3O)c2n1
Reactant: Nc1nc(N)c2ncn([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3OCCCCn3ccnc3)c2n1
Agent: Nc1ncnc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Product: Nc1nc2c(ncn2[C@@H]2O[C@H](CO)[C@@H](O)[C@H]2OCCCCn2ccnc2)c(=O)[nH]1

Procedure:
A mixture of the 2,6-diamino-9-[2'-O-(imidazol-1-yl)butyl-β-D-ribofuranosyl]purine and 2,6-diamino-9-[3'-O-(imidazol-1-yl)butyl-β-D-ribofuranosyl]purine isomers in 0.1M tris buffer (pH 7.4), 0.1M NaSO4 buffer (pH 7.4) and DMS0 is treated with adenosine deaminase at RT for 5 days as per the procedure of Example 3. The product containing fractions are purified by silica gel chromatography and the product containing fraction evaporated to give the product.
Reaction SMILES: O1CCCC1.[Si]([O:23][CH2:24][C:25]1[CH:26]=[C:27]([F:41])[C:28]([CH:31]([C:33]2[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:34]=2[F:40])[OH:32])=[N:29][CH:30]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.CCCCCC>C(OCC)(=O)C>[F:40][C:34]1[CH:35]=[CH:36][C:37]([F:39])=[CH:38][C:33]=1[CH:31]([C:28]1[C:27]([F:41])=[CH:26][C:25]([CH2:24][OH:23])=[CH:30][N:29]=1)[OH:32]
Reactant: CC(C)(C)[Si](OCc1cnc(C(O)c2cc(F)ccc2F)c(F)c1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: OCc1cnc(C(O)c2cc(F)ccc2F)c(F)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 91.1 %

Procedure:
To a tetrahydrofuran (7 ml) solution of [5-(t-butyldiphenylsilyloxymethyl)-3-fluoropyridin-2-yl](2,5-difluorophenyl)methanol (853 mg, 1.68 mmol) was added a tetrahydrofuran solution (1.04 ml, 1.04 mmol) of tetrabutylammonium fluoride. The mixture was stirred at room temperature for 5 hours. After the reaction mixture was concentrated under reduced pressure, the residue thus obtained was dissolved in ethyl acetate. The resulting solution was washed with a saturated aqueous solution of sodium bicarbonate. The organic layer was dried over anhydrous sodium sulfate and then, filtered. The filtrate was concentrated under reduced pressure. The residue thus obtained was subjected to flash silica gel chromatography. The fraction obtained from the hexane:ethyl acetate=1:1 eluate was concentrated under reduced pressure to give the title compound (413 mg, 1.53 mmol, 91%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6](N=[CH:8][CH:9]=[N:10]2)=[C:5]([N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[CH:4]=1.[C:19]([C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[N:26]([CH3:30])[CH:25]=[C:24]2[CH:31]1[CH2:36][CH2:35][C:34](=O)[CH2:33][CH2:32]1)#[N:20].[C:38](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClC(Cl)C>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:38]=[CH:8][CH:9]=[N:10]2)=[C:5]([N:13]2[CH2:14][CH2:15][N:16]([C@@H:34]3[CH2:35][CH2:36][C@H:31]([C:24]4[C:23]5[C:27](=[CH:28][CH:29]=[C:21]([C:19]#[N:20])[CH:22]=5)[N:26]([CH3:30])[CH:25]=4)[CH2:32][CH2:33]3)[CH2:17][CH2:18]2)[CH:4]=1
Reactant: Cn1cc(C2CCC(=O)CC2)c2cc(C#N)ccc21
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: COc1cc(N2CCNCC2)c2nccnc2c1
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: COc1cc(N2CCN([C@H]3CC[C@@H](c4cn(C)c5ccc(C#N)cc54)CC3)CC2)c2cccnc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 7-methoxy-5-piperazin-1-yl-quinoxaline (160 mg, 0.66 mmol), 4-(5-cyano-1-methyl-1H-indol-3-yl)-cyclohexanone (170 mg, 0.66 mmol), and sodium triacetoxyborohydride (210 mg, 0.98 mmol) in dichloroethane (30 mL) was added acetic acid (0.1 mL, 1.3 mmol) and stirred overnight at room temperature. The reaction was quenched with 1 M NaOH (100 mL) then extracted in CH2Cl2 (75 mL) and EtOAc (100 mL). The organic fractions were combined, dried over Na2SO4, concentrated, filtered and chromatographed (5% MeOH/EtOAc) affording 120 mg (38%) of the cis isomer as a bright yellow solid: mp 226-229° C.
Reaction SMILES: C([O-])([O-])[O:2][CH2:3][CH3:4].[C:7]1(C)C=CC(S(O)(=O)=O)=C[CH:8]=1.[CH2:18]([NH:22][C:23]([O:25][C:26]1[CH:27]=[C:28]([CH:36]=[CH:37][CH:38]=1)[NH:29][C:30](=[O:35])[CH2:31][C:32](=[O:34])[CH3:33])=[O:24])[CH2:19][CH2:20][CH3:21].N1C2C(=CC=CC=2)C=CC=1>CO>[CH2:18]([NH:22][C:23]([O:25][C:26]1[CH:27]=[C:28]([CH:36]=[CH:37][CH:38]=1)[NH:29][C:30](=[O:35])[CH2:31][C:32]([O:2][CH2:3][CH3:4])([O:34][CH2:7][CH3:8])[CH3:33])=[O:24])[CH2:19][CH2:20][CH3:21]
Reactant: CCCCNC(=O)Oc1cccc(NC(=O)CC(C)=O)c1
Reactant: CCOC([O-])[O-]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccc2ncccc2c1
Solvent: CO
Product: CCCCNC(=O)Oc1cccc(NC(=O)CC(C)(OCC)OCC)c1
Temperature: 25 °C
Reaction time: 7 h
Yield: 939.8 %

Procedure:
52 g of ethyl orthoformate and 1 g of p-toluene sulfonic acid were added to a solution of 59 g of the product of Step A in 180 ml of methanol and the mixture was stirred at room temperature for 7 hours. The mixture was then allowed to stand for 18 hours and 1 ml of quinoline was added thereto. The solvent was evaporated and the residue was chromatographed over silica gel. Elution with an 8-2 methylene chloride-acetone mixture gave 20 g of m-(n-butylcarbamoyloxy)-3,3-diethoxy-butyranilide melting at 130°C.
Reaction SMILES: [F:1][CH:2]([F:33])[C:3]([N:5]1[C@H:9]([CH2:10][F:11])[C@@H:8]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:19]=[CH:20][C:21]([CH:24](OS(C)(=O)=O)[CH3:25])=[N:22][CH:23]=3)=[CH:14][CH:13]=2)[O:7][C:6]1([CH3:32])[CH3:31])=[O:4].C(N(C(C)C)CC)(C)C.[NH:43]1[CH2:48][CH2:47][O:46][CH2:45][CH2:44]1>C(#N)C>[F:33][CH:2]([F:1])[C:3]([N:5]1[C@H:9]([CH2:10][F:11])[C@@H:8]([C:12]2[CH:13]=[CH:14][C:15]([C:18]3[CH:23]=[N:22][C:21]([CH:24]([N:43]4[CH2:48][CH2:47][O:46][CH2:45][CH2:44]4)[CH3:25])=[CH:20][CH:19]=3)=[CH:16][CH:17]=2)[O:7][C:6]1([CH3:32])[CH3:31])=[O:4]
Reactant: C1COCCN1
Reactant: CC(OS(C)(=O)=O)c1ccc(-c2ccc([C@H]3OC(C)(C)N(C(=O)C(F)F)[C@@H]3CF)cc2)cn1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(c1ccc(-c2ccc([C@H]3OC(C)(C)N(C(=O)C(F)F)[C@@H]3CF)cc2)cn1)N1CCOCC1
Temperature: 60 °C
Reaction time: 16 h
Yield: 68.4 %

Procedure:
To a stirred solution of Methanesulfonic acid 1-(5-{4-[(4S,5R)-3-(2,2-difluoro-acetyl)-4-fluoromethyl-2,2-dimethyl-oxazolidin-5-yl]-phenyl}-pyridin-2-yl)-ethyl ester (0.150 g, 0.309 mmol) in acetonitrile (2 mL) is added diisopropylethylamine (0.161 mL, 0.926 mmol) and morphline (0.054 mL, 0.617 mmol). Reaction mixture is stirred at 60° C. for 16 h. The solvent is evaporated in vacuo and the crude material is purified by combiflash using 1% methanol:CH2Cl2 as an eluent to afford the title compound (0.101 g). 1H NMR (400 MHz, CDCl3) δ 1.33 (d, J=6.48 Hz, 3H), 1.53 (s, 3H), 1.60 (s, 3H), 2.32-2.33 (m, 2H), 2.45-2.50 (m, 2H), 3.53-3.58 (m, 4H), 3.60-3.63 (m, 1H), 4.54-4.58 (m, 0.5H), 4.66-4.72 (m, 1H), 4.80-4.84 (m, 0.5H), 4.90-4.94 (m, 1H) 5.26 (d, J=4 Hz, 1H), 6.64 (t, J=52.32, 1H), 7.50 (d, J=8.2 Hz, 2H), 7.59 (d, J=8.12 Hz, 2H), 7.78 (d, J=8.24 Hz, 2H), 8.06-8.10 (dd, J1=8.8 Hz, J2=6.48 Hz, 1H), 8.83 (d, J=2.24 Hz, 1H). LCMS—not ionized.
Reaction SMILES: [I:1][C:2]1[C:10]2[CH2:9][O:8][C:7](=[O:11])[C:6]=2[CH:5]=[CH:4][C:3]=1[CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1.OCCC1C(I)=CC2C(=O)OCC=2C=1>>[I:1][C:2]1[C:3]([CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:25])([CH3:24])[CH3:26])=[O:21])[CH2:16][CH2:15]2)=[CH:4][C:5]2[CH2:9][O:8][C:7](=[O:11])[C:6]=2[CH:10]=1
Reactant: CC(C)(C)OC(=O)N1CCN(CCc2ccc3c(c2I)COC3=O)CC1
Agent: O=C1OCc2cc(CCO)c(I)cc21
Product: CC(C)(C)OC(=O)N1CCN(CCc2cc3c(cc2I)C(=O)OC3)CC1

Procedure:
tert-Butyl 4-[2-(6-iodo-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazine-1-carboxylate was prepared in an analogous fashion to that described for the preparation of tert-butyl 4-[2-(4-iodo-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazine-1-carboxylate above starting from 5-(2-hydroxyethyl)-6-iodo-2-benzofuran-1(3H)-one. LC-MS (IE, m/z): 473 [M+1]+.
Reaction SMILES: [OH-].[Li+].CO.O.[F:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][O:14][C:15]2[CH:31]=[CH:30][C:29]([CH:32]=[O:33])=[CH:28][C:16]=2[C:17]([O:19]CC2C=CC(F)=CC=2)=[O:18])=[CH:9][CH:8]=1>O1CCCC1>[F:6][C:7]1[CH:8]=[CH:9][C:10]([CH2:13][O:14][C:15]2[CH:31]=[CH:30][C:29]([CH:32]=[O:33])=[CH:28][C:16]=2[C:17]([OH:19])=[O:18])=[CH:11][CH:12]=1
Reactant: O=Cc1ccc(OCc2ccc(F)cc2)c(C(=O)OCc2ccc(F)cc2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=Cc1ccc(OCc2ccc(F)cc2)c(C(=O)O)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Lithium hydroxide (0.75 g, 31.4 mmol), methanol (25 ml) and water (25 ml) were added to a solution of (4-fluorophenyl)methyl 2-{[(4-fluorophenyl)methyl]oxy}-5-formylbenzoate (may be prepared as described in Description 104; 4 g, 10.46 mmol) in tetrahydrofuran (100 ml). The mixture was stirred at room temperature overnight. The mixture was evaporated to half volume, diluted with water (100 ml) and acidified with 1M aqueous hydrochloric acid to adjust the pH to 1. The mixture was stirred at room temperature and the solid formed was filtered, washed with water (50 ml) and air dried under vacuum to yield the title compound as a white solid. 2.85 g.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]([N:16]2[CH2:22][C:21]3([CH3:24])[CH2:23][CH:17]2[CH2:18][C:19]([CH3:26])([CH3:25])[CH2:20]3)=[O:15])=[CH:10][CH:9]=1)(C)(C)C.[H-].[Na+].C([O:34][C:35](=[O:38])[CH2:36]Br)(C)(C)C>CN(C=O)C>[CH3:24][C:21]12[CH2:23][CH:17]([N:16]([C:14]([C:11]3[CH:10]=[CH:9][C:8]([NH:7][CH2:36][C:35]([OH:38])=[O:34])=[CH:13][CH:12]=3)=[O:15])[CH2:22]1)[CH2:18][C:19]([CH3:25])([CH3:26])[CH2:20]2
Reactant: CC1(C)CC2CC(C)(CN2C(=O)c2ccc(NC(=O)OC(C)(C)C)cc2)C1
Reactant: CC(C)(C)OC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(C)CC2CC(C)(CN2C(=O)c2ccc(NCC(=O)O)cc2)C1
Reaction time: 0.5 h
Yield: 74.4 %

Procedure:
To a solution of [4-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]octane-6-carbonyl)-phenyl]carbamic acid tert-butyl ester (5.0 g, 13.42 mmol) in dry DMF (75 ml) was added sodium hydride (750 mg, 33.3 mmol in 60% mineral oil) and the mixture was stirred for 30 min. Bromo-acetic acid tert-butyl ester (3.14 g, 16.11 mmol) was added and the stirring was continued for an additional 1 hr. at 50° C. The reaction was quenched by addition of water (50 ml) and extracted with diethyl ether (2×50 ml). The combined organic phases were dried (Na2SO4), filtered and evaporated in vacuo. The residue was dissolved in DCM (75 ml) and TFA (40 ml) was added. The resulting mixture was stirred for 16 hrs. at room temperature and evaporated in vacuo. To the residue was added water (75 ml) and diethyl ether (25 ml) and the precipitate was filtered off, washed with diethyl ether and dried in vacuo at 50° C. affording 3.3 g (74%) of [4-(1,3,3-trimethyl-6-aza-bicyclo[3.2.1]-octane-6-carbonyl)-phenylamino]-acetic acid an solid.