Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2](=[N:6][OH:7])[C:3](=[O:5])[CH3:4].[F:8][C:9]([F:19])([F:18])[C:10]1[CH:17]=[CH:16][C:13]([CH:14]=O)=[CH:12][CH:11]=1.Cl.O1CCOCC1>C(OCC)C.C(O)(=O)C>[CH3:1][C:2]1[N+:6]([O-:7])=[C:14]([C:13]2[CH:12]=[CH:11][C:10]([C:9]([F:8])([F:18])[F:19])=[CH:17][CH:16]=2)[O:5][C:3]=1[CH3:4]
Reactant: CC(=O)C(C)=NO
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CC(=O)O
Solvent: CCOCC
Product: Cc1oc(-c2ccc(C(F)(F)F)cc2)[n+]([O-])c1C
Temperature: 0 °C
Yield: 34.3 %

Procedure:
A 100 mL pear-shaped flask was charged with butane-2,3-dione monooxime (2.1 g, 20.4 mmol), 4-(trifluoromethyl)benzaldehyde (3.0 mL, 22.4 mmol), and acetic acid (20 mL). The mixture was cooled to 0° C. A solution of 4N HCl in dioxane (7.0 mL, 28.0 mmol) was added dropwise to the reaction and the resultant mixture was stirred at 0° C. for 20 minutes. Diethyl ether (30 mL) was added to the reaction and the mixture was allowed to warm to room temperature overnight. The solvent was removed under reduced pressure and the resulting residue was taken up in water (300 mL). Conc. NH4OH(aq) was added to adjust the pH to 9.0. The mixture was extracted with ethyl acetate (2×75 mL), and the combined organic layers were washed with water (100 mL), followed by saturated brine (100 mL). The organic layer was dried (Na2SO4) and the solvent removed under reduced pressure. The resulting residue was purified via radial chromatography (3% MeOH in DCM) to yield 1.8 g (35%) of 4,5-dimethyl-2-(4-trifluoromethyl-phenyl)-oxazole-3-oxide as a white solid. LC/MSD m/e: 258.1 (M+H); 1H NMR (400 MHz) (Acetone-d6) δ 8.68 (d, 2H, J=8.0 Hz), 7.89 (d, 2H, J=8.0 Hz), 2.45 (s, 3H), 2.16 (s, 3H).
Reaction SMILES: Cl(O)(=O)(=O)=O.[CH3:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][C@@H:22]3[O:31][C@H:25]4[O:26]C(C)(C)[O:28][C@H:24]4[C@H:23]3[CH2:32][CH2:33][N:34]3[C:39](=[O:40])[C:38]4[CH:41]=[CH:42][CH:43]=[CH:44][C:37]=4[N:36]=[N:35]3)=[CH:16][CH:15]=2)=[CH:10][CH:9]=1>C(#N)C.C(OCC)(=O)C.O>[OH:28][C@@H:24]1[C@H:25]([OH:26])[O:31][C@@H:22]([CH2:21][CH2:20][C:17]2[CH:18]=[CH:19][C:14]([C:11]3[CH:10]=[CH:9][C:8]([O:7][CH3:6])=[CH:13][CH:12]=3)=[CH:15][CH:16]=2)[C@@H:23]1[CH2:32][CH2:33][N:34]1[C:39](=[O:40])[C:38]2[CH:41]=[CH:42][CH:43]=[CH:44][C:37]=2[N:36]=[N:35]1
Reactant: COc1ccc(-c2ccc(CC[C@@H]3O[C@H]4OC(C)(C)O[C@H]4[C@H]3CCn3nnc4ccccc4c3=O)cc2)cc1
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CC#N
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ccc(-c2ccc(CC[C@@H]3O[C@@H](O)[C@@H](O)[C@H]3CCn3nnc4ccccc4c3=O)cc2)cc1
Temperature: 55 °C

Procedure:
Perchloric acid (0.2 mL) was added to a solution of the compound obtained from step f above (0.6 g) in acetonitrile (50 mL) and water (10 mL) at room temperature. The reaction mixture was heated to 55° C. for 30 minutes. The reaction mixture was then quenched using a sodium hydrogen carbonate solution. The solvents were evaporated at reduced pressure. The residue thus obtained was taken in ethyl acetate and water. The organic layer was separated, washed with water and brine solution, and dried over anhydrous sodium sulphate. The solvent was concentrated under reduced pressure to yield the title compound (0.6 g).
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:19])[CH2:15][O:16][CH2:17][CH3:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)S(O)(=O)=O.C(BCCCC)CCC.[CH:37]([C:39]1[CH:44]=[CH:43][C:42]([C:45]2[CH:50]=[CH:49][CH:48]=[C:47]([CH2:51][N:52]([CH3:61])[C:53](=[O:60])[C:54]3[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=3)[CH:46]=2)=[CH:41][CH:40]=1)=[O:38].OO>ClCCl.CO.O>[CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:19])[C@@H:15]([O:16][CH2:17][CH3:18])[C@@H:37]([C:39]1[CH:44]=[CH:43][C:42]([C:45]2[CH:50]=[CH:49][CH:48]=[C:47]([CH2:51][N:52]([CH3:61])[C:53](=[O:60])[C:54]3[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=3)[CH:46]=2)=[CH:41][CH:40]=1)[OH:38])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOCC(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Reactant: CN(Cc1cccc(-c2ccc(C=O)cc2)c1)C(=O)c1ccccc1
Agent: CCCCBCCCC
Agent: O=S(=O)(O)C(F)(F)F
Agent: OO
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: CCO[C@H](C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1)[C@H](O)c1ccc(-c2cccc(CN(C)C(=O)c3ccccc3)c2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 47.8 %

Procedure:
1.8 g (6.7 mmol) of (S)-4-benzyl-3-(2-ethoxy-ethanoyl) oxazolidin-2-one amd 15 ml of dichloromethane are introduced into a three-necked flask under argon. 7.3 ml (8 mmol) of dibutylborane trifluoromethane-sulfonate and 1.3 ml (8 mmol) of diisopropylethylamineare successively added dropwise at 0° C., and the mixture is stirred for one hour. At −78° C., a solution of 2 g (6 mmol) of N-(4′-formylbiphenyl-3-ylmethyl)-N-methylbenzamide (prepared in Example 1(e)) in 25 ml of dichloromethane is added and the mixture is stirred for one hour. The mixture is allowed to warm to 0° C. and is treated with a pH 7 buffer solution (16 ml) in 45 ml of methanol and then with aqueous hydrogen peroxide solution (16 ml) in 45 ml of methanol and stirred for one hour at 0° C. The reaction medium is poured into water and extracted with dichloromethane, and the organic phase is separated out after settling of the phases has taken place, dried over magnesium sulfate and evaporated. The residue obtained is purified by chromatography on a column of silica eluted with a mixture of heptane and ethyl acetate (60/40). 1.7 g (48%) of N-{4′-[(1R,2S)-3-((S)-4-benzyl-2-oxo-oxazolidin-3-yl)-2-ethoxy-1-hydroxy-3-oxopropyl]biphenyl-3-ylmethyl}-N-methylbenzamide are obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[C:9]([OH:11])=O)=[CH:4][CH:3]=1.[NH2:19][CH2:20][CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][CH:26]([C:29]2[CH:30]=[C:31]([NH:35][C:36](=[O:40])[N:37]([CH3:39])[CH3:38])[CH:32]=[CH:33][CH:34]=2)[CH2:25][CH2:24]1>>[CH3:39][N:37]([CH3:38])[C:36]([NH:35][C:31]1[CH:30]=[C:29]([CH:26]2[CH2:27][CH2:28][N:23]([CH2:22][CH2:21][CH2:20][NH:19][C:9](=[O:11])[CH:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)[CH2:24][CH2:25]2)[CH:34]=[CH:33][CH:32]=1)=[O:40]
Reactant: CN(C)C(=O)Nc1cccc(C2CCN(CCCN)CC2)c1
Reactant: O=C(O)C(c1ccc(F)cc1)c1ccc(F)cc1
Product: CN(C)C(=O)Nc1cccc(C2CCN(CCCNC(=O)C(c3ccc(F)cc3)c3ccc(F)cc3)CC2)c1

Procedure:
Example 139 was prepared from bis(4-fluorophenyl)acetic acid and N′-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}-N,N-dimethylurea according to the procedures described in Scheme 9: ESMS m/e: 535.4 (M+H)+.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][C@@H:5]([C@H:7]([C@@H:9]([C@@H:11]([CH2:13][OH:14])O)[OH:10])[OH:8])[OH:6])[CH3:2].Cl.C(NC[C@@H]1O[C@](O)(CO)[C@@H](O)[C@@H]1O)C>O>[CH3:2][CH2:1][N:3]1[C@H:11]([CH2:13][OH:14])[C@@H:9]([OH:10])[C@H:7]([OH:8])[C@@H:5]([OH:6])[CH2:4]1
Reactant: CCNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: CCNC[C@@H]1O[C@](O)(CO)[C@@H](O)[C@@H]1O
Agent: Cl
Solvent: O
Product: CCN1C[C@H](O)[C@@H](O)[C@H](O)[C@H]1CO
Reaction time: 24 h
Yield: 60 %

Procedure:
1.0 gram of N-ethylglucamine is suspended in 50 mL water and titrated to pH 5.0 with concentrated HCl (simultaneously dissolving the aminosugar). This solution is placed in a 500 mL shaker flask. To this solution is added 2.0 grams (wet weight) of washed Gluconobacter oxydans cells and the solution agitated at 100-120 rpm. After 24 hours, HPLC analysis indicates that 70% of the initial charge of N-ethylglucamine has been converted to 6-ethylamino-6-deoxy-α-L-sorbofuranose, and after 48 hours, at least 90% has been converted. After 72 hours, the supernatant is separated from the cells and sterile filtered. An aliquot (10 mL) of the supernatant is adjusted to pH 9.0 with concentrated NH4OH, chilled in an ice bath, and 100 mg NaBH4 is added. After standing in the ice bath overnight, the samples are acetylated and assayed by gas chromatography (GC)-mass spectroscopy. GC-mass spectroscopy indicates a 60% yield of N-ethyl-1-deoxynojirimycin from 6-ethylamino-6-deoxy-α-L-sorbofuranose (Chemical ionization mass spectroscopy of the acetylated product indicates that the GC peak corresponding to the reduced cyclized product has a parent peak mass of 360 (M+H), corresponding to tetraacetylated N-ethyl-1-deoxynojirimycin).
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][N:20]=3)=[CH:13][C:12]2=[O:26])=[CH:7][CH:6]=1.[Si:27]([O:34][C@H:35]1[CH2:39][CH2:38][NH:37][CH2:36]1)([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28].C(N(C(C)C)C(C)C)C.CN(C=O)C>O>[Si:27]([O:34][C@H:35]1[CH2:39][CH2:38][N:37]([CH2:2][CH2:3][O:4][C:5]2[CH:10]=[CH:9][C:8]([N:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]4[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][N:20]=4)=[CH:13][C:12]3=[O:26])=[CH:7][CH:6]=2)[CH2:36]1)([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28]
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CCNC1
Reactant: O=c1cc(OCc2ccc(Cl)cn2)ccn1-c1ccc(OCCBr)cc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CC(C)(C)[Si](C)(C)O[C@H]1CCN(CCOc2ccc(-n3ccc(OCc4ccc(Cl)cn4)cc3=O)cc2)C1
Temperature: 60 °C
Reaction time: 14 h
Yield: 72.1 %

Procedure:
A mixture of 1-[4(2-bromoethoxy)phenyl]-4-[(5-chloro-2-pyridinyl)methoxy]-1H-pyridin-2-one (300.7 mg, 0.69 mmol), (3S)-3-{[tert-butyl(dimethyl)silyl]oxy}pyrrolidine (417 mg, 2.1 mmols), ethyl (diisopropyl)amine (0.132 mL, 0.76 mmol) and DMF (3.5 mL) was stirred at 60° C. for 14 hours. Adding water, the reaction liquid was filtered. Thus obtained crude title compound was purified on silica gel column chromatography (KP-Sil FLASH 25+M, chloroform:methanol=1:0→10:1) to provide the title compound (276.6 mg, 72%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([O:8]CC[Si](C)(C)C)[N:3]=1.[CH3:15][O:16][C@@H:17]1[C@H:30]([O:31][C:32](=[O:39])[C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C@@H:29]([CH2:40][O:41][C:42](=[O:49])[C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[O:28][C@@H:18]1OC(=O)C1C=CC=CC=1.FC(F)(F)S(O[Si](C)(C)C)(=O)=O>C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]([C@@H:18]2[O:28][C@H:29]([CH2:40][O:41][C:42](=[O:49])[C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[C@@H:30]([O:31][C:32](=[O:39])[C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)[C@H:17]2[O:16][CH3:15])[C:4](=[O:8])[N:3]=1
Reactant: C[Si](C)(C)CCOc1nccc(Cl)n1
Reactant: CO[C@H]1[C@@H](OC(=O)c2ccccc2)O[C@H](COC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CC#N
Product: CO[C@@H]1[C@H](OC(=O)c2ccccc2)[C@@H](COC(=O)c2ccccc2)O[C@H]1n1ccc(Cl)nc1=O
Reaction time: 1.5 h
Yield: 90.9 %

Procedure:
4-Chloro-2-trimethylsilylethoxy-pyrimidine (3.5 g, 15.2 mmole) and 2-O-methyl-1,3,5-tri-O-benzoyl-α-D-ribose (7.0 g, 15.2 mmole) were dissolved in acetonitrile (100 ml). This solution was treated with trimethylsilyl trifluoromethanesulfonate (2.8 g, 15.2 mmole) and stirred for 1.5 hours. The reaction mixture was concentrated to an oil and redissolved in 300 ml CH2Cl2. The CH2Cl2 solution was washed with cold concentrated sodium bicarbonate, dried over magnesium sulfate, filtered, and evaporated to an oil. The oil was coevaporated with acetonitrile and dried to a brown foam to give 6.70 g (91%) crude product.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH:5]([C@H:8]([NH:10][C:11]2[N:16]=[C:15]([C:17]3[C:25]4[C:20](=[N:21][CH:22]=[C:23]([C:26]([F:29])([F:28])[F:27])[CH:24]=4)[N:19]([S:30]([C:33]4[CH:39]=[CH:38][C:36]([CH3:37])=[CH:35][CH:34]=4)(=[O:32])=[O:31])[CH:18]=3)[C:14]([C:40]#[N:41])=[CH:13][N:12]=2)[CH3:9])[CH2:4][CH2:3]1.C([O-])(=O)C.[NH4+:46].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO.ClCCl>[NH2:46][CH:2]1[CH2:7][CH2:6][CH:5]([C@H:8]([NH:10][C:11]2[N:16]=[C:15]([C:17]3[C:25]4[C:20](=[N:21][CH:22]=[C:23]([C:26]([F:29])([F:28])[F:27])[CH:24]=4)[N:19]([S:30]([C:33]4[CH:39]=[CH:38][C:36]([CH3:37])=[CH:35][CH:34]=4)(=[O:32])=[O:31])[CH:18]=3)[C:14]([C:40]#[N:41])=[CH:13][N:12]=2)[CH3:9])[CH2:4][CH2:3]1
Reactant: [NH4+]
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3nc(N[C@H](C)C4CCC(=O)CC4)ncc3C#N)c3cc(C(F)(F)F)cnc32)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: Cc1ccc(S(=O)(=O)n2cc(-c3nc(N[C@H](C)C4CCC(N)CC4)ncc3C#N)c3cc(C(F)(F)F)cnc32)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 90.3 %

Procedure:
2-((R)-1-(4-oxocyclohexyl)ethylamino)-4-(1-tosyl-5-(trifluoromethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidine-5-carbonitrile (105 mg, 0.1802 mmol) was disolved in methanol (5 mL) and dichloromethane (5 mL). Ammonium acetate (138.9 mg, 118.7 μL, 1.802 mmol), followed by sodium triacetoxyborohydride (38.19 mg, 0.1802 mmol) were added and the reaction mixture was stirred for 4 hours at room temperature. The mixture was partitioned between dichloromethane and a saturated solution of sodium bicarbonate. The aqueous phase was extracted with dichloromethane. The organic layer was dried over magnesium sulfate, filtered and concentrated to dryness to afford the desired product as a yellow solid (95 mg, 90% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[C:11]([C:19]2[O:23][N:22]=[C:21]([C:24]3[CH:31]=[CH:30][C:27]([CH:28]=O)=[CH:26][CH:25]=3)[N:20]=2)[N:10]=[N:9]1.F[C:33]1([F:39])[CH2:38][CH2:37][NH:36][CH2:35]C1>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[C:11]([C:19]2[O:23][N:22]=[C:21]([C:24]3[CH:31]=[CH:30][C:27]([CH2:28][N:36]4[CH2:37][CH2:38][C@@H:33]([F:39])[CH2:35]4)=[CH:26][CH:25]=3)[N:20]=2)[N:10]=[N:9]1
Reactant: O=Cc1ccc(-c2noc(-c3nnn(-c4ccccc4F)c3-c3ccncc3)n2)cc1
Reactant: FC1(F)CCNCC1
Product: Fc1ccccc1-n1nnc(-c2nc(-c3ccc(CN4CC[C@@H](F)C4)cc3)no2)c1-c1ccncc1

Procedure:
The title compound was prepared following the procedure described for Example 94, but starting from 4-(5-(1-(2-fluorophenyl)-5-(pyridin-4-yl)-1H-1,2,3-triazol-4-yl)-1,2,4-oxadiazol-3-yl)benzaldehyde, obtained as described in Example 113, Step 1, (200 mg; 0.48 mmol) and 4,4-difluoropiperidine (168 mg; 0.97 mmol) to give Example 161 as a white solid. 1H NMR: (CDCl3, 400 MHz) δ 8.72 (2H, dd, J=4.5, 1.7 Hz), 8.05 (2H, d, J=8.1 Hz), 7.63-7.52 (2H, m), 7.45 (2H, d, J=8.0 Hz), 7.40-7.34 (3H, m), 7.22-7.15 (1H, m), 3.61 (2H, s), 2.57 (4H, t, J=5.4 Hz), 2.07-1.94 (4H, m). LC/MS (Method C): 518 (M+H)+. HPLC (Method I) Rt 15.55 min (Purity: 97.6%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[CH2:5][C:6]1[C:7]([F:24])=[CH:8][C:9]2[C:13](=O)[CH:12](C(OC(C)(C)C)=O)[S:11][C:10]=2[C:22]=1[F:23])[CH3:2].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O.B.[Na]>C1(C)C=CC=CC=1.CO>[F:24][C:7]1[C:6]([CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:25])=[C:22]([F:23])[C:10]2[S:11][CH:12]=[CH:13][C:9]=2[CH:8]=1
Reactant: CCOC(=O)Cc1c(F)cc2c(c1F)SC(C(=O)OC(C)(C)C)C2=O
Agent: B
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CO
Product: CCOC(=O)Cc1c(F)cc2ccsc2c1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 15 %

Procedure:
In 60 mL of toluene is dissolved 19.2 g of tert-butyl 6-(2-ethoxy-2-oxoethyl)-5,7-difluoro-3-oxo-2,3-dihydrobenzo[b]thiophene-2-carboxylate, to which is added 0.96 g of p-toluenesulfonic acid monohydrate. The mixture is heated under reflux for 2.5 hours. Water is added to the reaction mixture, and the organic layer is separated. The organic layer is washed with water, saturated aqueous solution of sodium bicarbonate and saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The residue thus obtained is dissolved in 100 ml of methanol, 0.97 g of sodium boron hydride is added, and the mixture thus formed is stirred at ambient temperature for 30 minutes. Then, 5.88 g of p-toluenesulfonic acid monohydrate is added and the mixture thus formed is heated under reflux for one hour. The reaction mixture is concentrated under reduced pressure, water and ethyl acetate are added to the residue, and the organic layer is separated. The organic layer is washed with water, saturated aqueous solution of sodium bicarbonate and saturated aqueous solution of sodium chloride successively and dried over anhydrous magnesium sulfate, the solvent is distilled off under reduced pressure, and the residue is purified by column chromatography (eluent: hexane:ethyl acetate=50:1 to 20:1) to obtain 1.98 g of ethyl 2-(5,7-difluorobenzo[b]thiophen-6-yl)acetate as an oily product.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:12]2[N:11]=[C:10]3[N:13]([C:17]4[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=4[Cl:24])[CH2:14][CH2:15][CH2:16][N:9]3[C:8]=2[C:7]([C:25]([CH:30]2[CH2:32][CH2:31]2)([CH:27]2[CH2:29][CH2:28]2)[OH:26])=[CH:6][CH:5]=1.[CH3:33]I>CN(C)C=O.O>[Cl:3][C:4]1[C:12]2[N:11]=[C:10]3[N:13]([C:17]4[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=4[Cl:24])[CH2:14][CH2:15][CH2:16][N:9]3[C:8]=2[C:7]([C:25]([CH:30]2[CH2:32][CH2:31]2)([CH:27]2[CH2:29][CH2:28]2)[O:26][CH3:33])=[CH:6][CH:5]=1
Reactant: OC(c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl)(C1CC1)C1CC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl)(C1CC1)C1CC1
Reaction time: 0.08 h
Yield: 57.9 %

Procedure:
Sodium hydride (60% in oil, 17.5 mg, 0.438 mmol) was added to a stirred solution of [9-chloro-1-(2,4-dichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl](dicyclopropyl)methanol (100 mg, 0.216 mmol) in N,N-dimethylformamide (1.0 mL) at room temperature. After stirring 5 min, methyl iodide (61.3 mg, 0.422 mmol) was added to the mixture, and the mixture was stirred at room temperature for 6 hr. The mixture was diluted with water, and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 10-40% ethyl acetate/n-hexane gradient mixture. The filtrate was concentrated in vacuo to give the solid, which was recrystallized from ethyl acetate/n-hexane to give the title compound as a colorless crystal (59.4 mg, 0.125 mmol, 58%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH:10]([C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=1)[C:18](O)=[O:19])[C:9]([CH3:25])([CH3:24])[CH2:8]2)=[O:4].C(N1C=CN=C1)(N1C=CN=C1)=O.[CH:38]1([S:41]([NH2:44])(=[O:43])=[O:42])[CH2:40][CH2:39]1.N12CCCN=C1CCCCC2>O1CCCC1.C(OCC)(=O)C>[CH:38]1([S:41]([NH:44][C:18]([C:17]2[CH:16]=[C:15]([CH:10]3[C:9]([CH3:25])([CH3:24])[CH2:8][C:7]4[C:12](=[CH:13][CH:14]=[C:5]([C:3]([O:2][CH3:1])=[O:4])[CH:6]=4)[NH:11]3)[CH:23]=[CH:22][CH:21]=2)=[O:19])(=[O:43])=[O:42])[CH2:40][CH2:39]1
Reactant: NS(=O)(=O)C1CC1
Reactant: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(C(=O)O)c1)N2
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCOC(C)=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(C(=O)NS(=O)(=O)C3CC3)c1)N2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 110.9 %

Procedure:
A solution of 3-(6-(methoxycarbonyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinolin-2-yl)benzoic acid (150 mg, 0.44 mmol) and 1,1′-carbonyldiimidazole (214 mg, 1.32 mmol) in tetrahydrofuran (3 mL) was heated to 60° C. for 1.5 h, then was cooled to room temperature and treated with cyclopropanesulfonamide (69.1 mg, 0.57 mmol). After stirring for 10 min, the reaction mixture was treated with dropwise addition of a solution of 1,8-diazabicyclo[5.4.0]undec-7-ene (221 mg, 1.45 mmol) in tetrahydrofuran (1 mL). Upon completion of addition, the resultant mixture was stirred for an additional 3 h, Thin layer chromatography (petroleum ether:ethyl acetate=1:1) showed the reaction was complete. The reaction mixture was quenched with brine and acidified with 1N hydrochloric acid solution to pH=6, extracted with ethyl acetate (twice). The combined organic layers were washed with brine for 3 times, dried over anhydrous magnesium sulfate. Removal of the solvent in vacuo gave 216 mg of methyl 2-(3-(cyclopropylsulfonylcarbamoyl)phenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate as a white solid, which was pure enough for next step without further purification. MS (ESI+APCI) M+1=443.2.
Reaction SMILES: [Br:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][C:5]([Br:11])=[CH:4][N:3]=1.O.O.[Sn](Cl)Cl>CCOC(C)=O>[Br:1][C:2]1[C:7]([NH2:8])=[CH:6][C:5]([Br:11])=[CH:4][N:3]=1
Reactant: O=[N+]([O-])c1cc(Br)cnc1Br
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCOC(C)=O
Product: Nc1cc(Br)cnc1Br
Temperature: 90 °C
Reaction time: 2 h

Procedure:
To a stirred mixture of 2,5-dibromo-3-nitropyridine (0.99 g, 3.50 mmol) in EtOAc (30.0 mL) was added tin(II) chloride dihydrate (4.02 g, 17.80 mmol) in portions. Upon complete addition of the reducing agent, the mixture was carefully heated to 90° C. After 2 h, the reaction was cooled to rt and diluted with ethyl acetate, then washed with 1M NaOH, water, and brine. After drying over anhydrous sodium sulfate and filtration, the organic solvent was removed under reduced pressure. The residue was identified as 2,5-dibromopyridin-3-amine. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.65 (1H, d, J=2.5 Hz), 7.27 (1H, d, J=2.5 Hz), 5.82 (2H, br, s).
Reaction SMILES: [Br:1][C:2]1[CH:16]=[CH:15][C:5]([NH:6][C:7]2[C:12]([Cl:13])=[CH:11][N:10]=[C:9]([Cl:14])[N:8]=2)=[CH:4][CH:3]=1.[F:17][C:18]([F:24])([F:23])[CH2:19][CH2:20][CH2:21]Br.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Br:1][C:2]1[CH:16]=[CH:15][C:5]([N:6]([C:7]2[C:12]([Cl:13])=[CH:11][N:10]=[C:9]([Cl:14])[N:8]=2)[CH2:21][CH2:20][CH2:19][C:18]([F:24])([F:23])[F:17])=[CH:4][CH:3]=1
Reactant: Clc1ncc(Cl)c(Nc2ccc(Br)cc2)n1
Reactant: FC(F)(F)CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: FC(F)(F)CCCN(c1ccc(Br)cc1)c1nc(Cl)ncc1Cl
Temperature: 25 °C
Reaction time: 12 h
Yield: 43.6 %

Procedure:
A mixture of 4-(4-bromoanilino)-2,5-dichloropyrimidine (Method 24; 315 mg, 1.0 mmol), 4,4,4-trifluoro-1-bromobutane (228 mg, 1.20 mmol) and potassium carbonate (165 mg, 1.20 mmol) in DMF (3 ml) was stirred at room temperature for 12 hours. Silica (2.5 g) was added and volatile material was removed by evaporation. The residue was purified by column chromatography, eluting with 0-40% ethyl acetate in isohexane, to give the product (187 mg). NMR: (373K); 1.84 (m, 2H), 2.28 (m, 2H), 3.99 (t, 2H), 7.22 (d, 2H), 7.58 (d, 2H), 8.23 (s, 1H); MS (MH+): 428.2, 430.2, 432.2.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][C:6](=[O:8])[CH:5]=[C:4](B2OC(C)(C)C(C)(C)O2)[CH2:3]1.Cl[C:19]1[CH:24]=[CH:23][N:22]=[CH:21][C:20]=1[N+:25]([O-:27])=[O:26].O>O1CCOCC1.C([O-])([O-])=O.[Na+].[Na+].CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][CH:2]1[CH2:7][C:6](=[O:8])[CH:5]=[C:4]([C:19]2[CH:24]=[CH:23][N:22]=[CH:21][C:20]=2[N+:25]([O-:27])=[O:26])[CH2:3]1
Reactant: CC1CC(=O)C=C(B2OC(C)(C)C(C)(C)O2)C1
Reactant: O=[N+]([O-])c1cnccc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: CC1CC(=O)C=C(c2ccncc2[N+](=O)[O-])C1
Temperature: 120 °C
Reaction time: 0.17 h

Procedure:
To a solution of 5-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-2-enone (1.0 equiv.) in degassed dioxane and 2M Na2CO3 was added 4-chloro-3-nitropyridine (1.2 equiv.) and Pd(PPh3)4 (0.05 equiv.). The reaction was heated in an oil bath to 120° C. for 2 h. (reaction can also be carried out in the microwave for 10 min at 120° C.). Cooled to room temperature, then diluted with EtOAc, added H2O—dark solution, lots of emulsions. Filtered to get rid of the solids, then extracted the organic phase, dried with Na2SO4, and concentrated. The crude was purified via silica gel chromatography to yield 5-methyl-3-(3-nitropyridin-4-yl)cyclohex-2-enone. LC/MS=233.2 (M+H); Rt=0.69 min, LC=2.70 min.