Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([NH:8][CH:9]1[CH2:12][CH:11]([CH2:13][O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:10]1[F:22])C1C=CC=CC=1.CCN(CC)CC.[N+](C1C=CC([N:39]([CH2:43][C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[C:40](=[O:42])[O-])=CC=1)([O-])=O>C(Cl)Cl>[CH2:43]([NH:39][C:40]([NH:8][CH:9]1[CH2:12][CH:11]([CH2:13][O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:10]1[F:22])=[O:42])[C:44]1[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=1
Reactant: O=C([O-])N(Cc1ccccc1)c1ccc([N+](=O)[O-])cc1
Reactant: FC1C(COCc2ccccc2)CC1NCc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NCc1ccccc1)NC1CC(COCc2ccccc2)C1F
Reaction time: 0.08 h
Yield: 92.5 %

Procedure:
In a 25 mL flask with benzyl-(3-benzyloxymethyl-2-fluoro-cyclobutyl)-amine (25.8 mg, 0.12 mmol) inside, dry CH2Cl2 2 mL was added under argon at room temperature to give a colorless solution, followed by the addition of Et3N (0.02 mL, 0.14 mmol). After stirring for 5 min, 4-nitrophenyl-N-benzylcarbamate (32.1 mg, 0.12 mmol) was added to give a yellow solution. This was left stirring at room temperature for 10 hr and the reaction was quenched by adding 10 mL CH2Cl2. The organic phase was washed with 1 M NaOH 10 mL, H2O 10 mL and brine 10 mL and was dried over MgSO4. Solvent evaporation gave the crude product 42 mg that is pure enough and crystallization gave the pure product 38 mg (90%) as a white solid. 1H NMR (CDCl3, 400 MHz): δ 1.96-2.01 (m, 2H), 2.65-2.80 (m, 1H), 3.48-3.58 (m, 2H), 4.31-4.36 (m, 3H), 4.52 (s, 2H), 4.82-4.99 (td, 1H, J=54.8, 5.2), 7.19-7.39 (m, 10H). 13C NMR (CDCl3, 100 MHz): δ 27.11-27.19 (d, J=7.6), 41.75-41.96 (d, J=21), 47.92, 48.44-48.51 (d, J=7.0), 71.12-71.16 (d, J=4.0), 74.26, 90.34-92.48 (d, J=214), 128.14, 128.30, 128.84, 128.96, 129.56, 129.62, 139.81, 141.35, 160.85. MS (FAB): expected for C20H23FN2O2 (M+H)+ 343.41. Found 343.18178. IR (neat) νmax 2923, 2851, 1558, 1458, 1378, 1265, 895, 740, 704. The absolute stereochemistry was established by X-ray crystallographic analyses.
Reaction SMILES: [C:1](#[N:3])[CH3:2].C([Li])CCC.C([O:11][C:12](=O)[C:13]1[CH:18]=[C:17]([CH3:19])[CH:16]=[C:15]([CH3:20])[CH:14]=1)C.[OH-].[Na+]>C1COCC1>[CH3:20][C:15]1[CH:14]=[C:13]([C:12](=[O:11])[CH2:2][C:1]#[N:3])[CH:18]=[C:17]([CH3:19])[CH:16]=1
Reactant: CCOC(=O)c1cc(C)cc(C)c1
Reactant: CC#N
Agent: [Li]CCCC
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1cc(C)cc(C(=O)CC#N)c1
Temperature: -78 °C
Reaction time: 8 h

Procedure:
Under Ar(g), a solution of anhydrous acetonitrile (1.6 mL) in 35 mL anhydrous THF is cooled to −78° C. in a dry ice-acetone bath and then slowly treated with 12 mL of a 2.5 M n-butyl lithium in hexanes. The reaction mixture is maintained at −78° C. for an additional 45 min. and then slowly treated with a solution of 5 gms. of 3,5-dimethyl-benzoic acid ethyl ester in 5 mL of anhydrous THF. The resulting solution is then stirred overnight at room temperature. Subsequently, the reaction mixture is treated with 10% NaOH(aq) to dissolve solids, and then is extracted with ethyl acetate. The aqueous layer is acidified (pH 6) with HCl(aq) affording a white precipitate which subsequently is filtered The organic layer is concentrated in vacuo and the residue is triturated with isopropanol resulting in the formation of additional white precipitate. The combined precipitates provide the desired 3-(3,5-dimethyl-phenyl)-3-oxo-propionitrile in the amount of 2.0175 gms.
Reaction SMILES: [CH3:1][N:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5](=[O:12])[N:4]([C:13]2[CH:14]=[CH:15][C:16]3[S:20][N:19]=[C:18]([CH2:21][S:22]([CH3:25])(=[O:24])=[O:23])[C:17]=3[CH:26]=2)[C:3]1=[O:27].[H-].[Na+].I[CH3:31]>O1CCCC1>[CH3:1][N:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5](=[O:12])[N:4]([C:13]2[CH:14]=[CH:15][C:16]3[S:20][N:19]=[C:18]([CH:21]([S:22]([CH3:25])(=[O:24])=[O:23])[CH3:31])[C:17]=3[CH:26]=2)[C:3]1=[O:27]
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc3snc(CS(C)(=O)=O)c3c2)c1=O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(c1nsc2ccc(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)cc12)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 40.7 %

Procedure:
To a suspension of 1-methyl-3-{3-[(methylsulfonyl)methyl]-1,2-benzisothiazol-5-yl}-6-(trifluoromethyl)-2,4(1H,3H)-pyrimidinedione (1.00 g, 0.00238 mol) in tetrahydrofuran is added sodium hydride (60%, 0.120 g, 0.00300 mol). The resultant mixture is stirred one hour at room temperature and treated with iodomethane (0.220 ml, 0.00360 mol). The mixture is stirred two hours at room temperature, partially concentrated in vacuo, diluted with water, and extracted with ethyl acetate. The organic layer is washed with water, filtered through anhydrous magnesium sulfate and concentrated in vacuo to a brown foam. The foam is chromatographed on silica gel with methylene chloride/ether to give the title compound as an off-white solid (0.420 g, 40.4%) which is identified by NMR spectral analysis.
Reaction SMILES: N[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].N([O-])=[O:12].[Na+]>OS(O)(=O)=O>[OH:12][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8]
Reactant: Nc1cncc(C(=O)O)c1
Reactant: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: O=C(O)c1cncc(O)c1

Procedure:
A mixture of 4.00 g (29.0 mmol) of 5-aminonicotinic acid in 400 ml of 0.1N H2SO4 at room temperature was diazotized with 2.2 g (31.8 mmol) of NaNO2 by the method of R. Graf (supra) to afford 5-hydroxynicotinic acid. The intermediate free acid was esterified in anhydrous methanolic HCl by the method of Urban (supra) to afford 2.34 g (53% overall yield) of 5-hydroxy nicotinic acid, methyl ester, mp 186°-187° C. (lit 182°-193° C.; Urban, supra). The IR data gave the characteristic 5-hydroxy band at 2550.
Reaction SMILES: [OH:1][C@@H:2]([C@H:6]([OH:23])[C:7](=[O:22])[NH:8][C@H:9]([C:14](=[O:21])[NH:15][CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19])[CH2:10][CH:11]([CH3:13])[CH3:12])[C:3]([OH:5])=[O:4].C(=O)(O)[O-].[Na+].[CH2:29](Br)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.O>CN(C)C=O>[OH:1][C@@H:2]([C@H:6]([OH:23])[C:7](=[O:22])[NH:8][C@H:9]([C:14](=[O:21])[NH:15][CH2:16][CH2:17][CH:18]([CH3:19])[CH3:20])[CH2:10][CH:11]([CH3:12])[CH3:13])[C:3]([O:5][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:4]
Reactant: BrCc1ccccc1
Reactant: CC(C)CCNC(=O)[C@H](CC(C)C)NC(=O)[C@@H](O)[C@H](O)C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)CCNC(=O)[C@H](CC(C)C)NC(=O)[C@@H](O)[C@H](O)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 63.5 %

Procedure:
(2S,3S)-2,3-dihydroxy-3-[(S)-3-methyl-1-(3-methylbutylcarbamoyl)butylcarbamoyl]propionic acid (1.40 g) obtained in Example 9 and sodium bicarbonate (712 mg) were suspended in dimethylformamide (20 ml). A dimethylformamide (20 ml) solution of benzyl bromide (3.56 g) was added to the resultant suspension, and the suspension was stirred at room temperature for 24 hours. Water was added after the reaction, and then was extracted with ethyl acetate. The organic layer was sequentially washed with water and saturated sodium chloride solution. After the resultant layer was dried with magnesium sulfate, the solvent was distilled off under reduced pressure to obtain a crude product. This crude product was purified by silica gel column chromatography (a developing solvent; hexane:ethyl acetate=1:1→1:3) to obtain 1.13 g of a target compound. NMR data of the compound were as follows.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][Cl:6].[SH:7][C:8]1[N:13]2[CH:14]=[CH:15][N:16]=[C:12]2[CH:11]=[CH:10][CH:9]=1.C(N(CC)CC)C>C(O)C>[Cl:6][CH2:5][CH2:4][CH2:3][CH2:2][S:7][C:8]1[N:13]2[CH:14]=[CH:15][N:16]=[C:12]2[CH:11]=[CH:10][CH:9]=1
Reactant: ClCCCCBr
Reactant: Sc1cccc2nccn12
Solvent: CCO
Solvent: CCN(CC)CC
Product: ClCCCCSc1cccc2nccn12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
In a nitrogen atmosphere, 8.87 ml (77 mmol) of 1-bromo-4-chlorobutane was added to a solution of 10.51 g (70 mmol) of 5-mercaptoimidazo[1,2-a]pyridine and 10.73 ml (77 mmol) of triethylamine in 150 ml of ethanol was added, followed by stirring at room temperature for 16 hours. After the solvent was distilled off, the residue was dissolved in dichloromethane. This solution was washed with saturated aqueous sodium hydrogen carbonate and dried, after which the solvent was distilled off. The residue was purified by column chromatography (eluent: ethyl acetate) to yield 12.93 g (76.7%, light brown oily substance) of the desired product.
Reaction SMILES: [CH2:1]([N:6]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:8]2([CH2:20]C[C:18](=[O:21])[C:17]3[C:9]2=[CH:10][C:11]2[O:15][CH2:14][O:13][C:12]=2[CH:16]=3)[C:7]1=[O:28])[CH2:2][CH2:3][CH2:4][CH3:5].[BH4-].[Na+].O>CO>[OH:21][CH:18]1[C:17]2[C:9](=[CH:10][C:11]3[O:15][CH2:14][O:13][C:12]=3[CH:16]=2)[C:8]2([C:22]3[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=3)[N:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[C:7]2=[O:28])[CH2:20]1
Reactant: CCCCCN1C(=O)C2(CCC(=O)c3cc4c(cc32)OCO4)c2ccccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCCCCN1C(=O)C2(CC(O)c3cc4c(cc32)OCO4)c2ccccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.6 %

Procedure:
To a solution of 1-pentyl-6′H-spiro[indole-3,5′-naphtho[2,3-d][1,3]dioxole]-2,8′(1H,7′H)-dione (0.20 g, 0.55 mmol) in methanol (10.0 mL) was added sodium borohydride (0.03 g, 0.83 mmol). The reaction mixture was stirred at ambient temperature for 2 h and poured into of water (100 mL) and extracted with ethyl acetate (100 mL). The organic layer was washed with water, dried over sodium sulfate and filtered. The filtrate was concentrated in vacuo to dryness. The residue was subjected to flash column chromatography to afford the title compound (0.18 g, 90%) as an oil: 1H NMR (300 MHz, CDCl3) δ 7.36-7.29 (m, 1H), 7.11-6.99 (m, 3H), 6.93 (d, 1H), 5.98 (s, 1H), 5.94-5.87 (m, 2H), 5.16 (d, 1H), 3.80-3.61 (m, 2H), 2.69 (br, 1H), 2.39 (d, 1H), 1.75-1.62 (m, 2H), 1.38-1.22 (m, 4H), 0.87 (t, 3H); 13C NMR (75 MHz, CDCl3) δ 180.5, 148.9, 148.5, 143.7, 140.5, 136.9, 132.1, 128.7, 123.7, 123.3, 108.8, 105.7, 103.2, 101.5, 74.8, 59.6, 40.4, 28.9, 27.0, 22.3, 14.0; MS (ES+) m/z 388.4 (M+23).
Reaction SMILES: [C:1]1([N:7]2[CH:11]=[CH:10][CH:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[S:12](=O)(=[O:15])([OH:14])[OH:13]>>[N:7]1([C:1]2[CH:2]=[CH:3][C:4]([S:12]([OH:15])(=[O:14])=[O:13])=[CH:5][CH:6]=2)[CH:11]=[CH:10][CH:9]=[N:8]1
Reactant: O=S(=O)(O)O
Reactant: c1ccc(-n2cccn2)cc1
Product: O=S(=O)(O)c1ccc(-n2cccn2)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution was prepared by adding 1-phenylpyrazole (1.3 ml, 9.8 mmol) to concentrated sulfuric acid (2 ml). To this solution, fuming sulfuric acid (5 ml, 30% SO3) was added gradually over at least 5 minutes at 0° C. The resultant mixture was heated to 35° C., and this temperature was kept for 1 hour. This mixture then was cooled to 0° C. by pouring it over crushed ice, thereby causing sulfate to precipitate. This sulfate was collected by filtration and then vacuum-dried. Thus, a desired compound, 4-(1H-pyrazole-1-yl)benzenesulfonic acid, was obtained in the form of a white solid (the yield calculated based on 1-phenylpyrazole: 37%). The instrumental analysis values of 4-(1H-pyrazole-1-yl)benzenesulfonic acid are shown below.
Reaction SMILES: [O:1]=[CH:2][C@@H:3]([C@H:5]1[O:12][C:10](=[O:11])[C@@H:8]([OH:9])[C@H:6]1[OH:7])[OH:4].[CH3:13]O.[OH-].[K+]>CS(O)(=O)=O>[O:11]([CH3:13])[C@@H:10]1[O:12][C@@H:5]2[C@@H:3]([C:2]([O:7][C@@H:6]2[C@H:8]1[OH:9])=[O:1])[OH:4]
Reactant: O=C[C@H](O)[C@H]1OC(=O)[C@@H](O)[C@H]1O
Reactant: CO
Agent: CS(=O)(=O)O
Agent: [K+]
Agent: [OH-]
Product: CO[C@@H]1O[C@H]2[C@H](OC(=O)[C@H]2O)[C@H]1O
Yield: 19.3 %

Procedure:
D-Glucurono-6,3-lactone (100.0 g, 0.57 mole), anhydrous methanol (200.0 g, 6.24 moles), and methanesulfonic acid (3 drops) were placed in an oven dried three-necked round bottom flask equipped with mechanical stirrer, thermometer and condenser. The mixture was heated for 24 hours at reflux, cooled and neutralized with 0.1N methanolic KOH. The mixture was filtered and washed with cold methanol (20 ml) yielding 20.9 g of methyl b-D-glucofuranosidurono-6,3-lactone (MbGlucl). By further concentration of the filtrate an additional 28.2 g of MbGlucl was isolated giving a total yield of 49.1 g (45.3%), MP=139° C., purity=99.1% (GC).
Reaction SMILES: [CH2:1]([N:3]([CH2:33][CH3:34])[CH2:4][CH:5]([OH:32])[CH2:6][N:7]1[C:19]2[C:18]3[NH:20][C:21]4[C:22](=[O:27])[CH2:23][CH:24]=[CH:25][C:26]=4[C:17]=3[C:16]3[C:28](=[O:31])O[CH2:30][C:15]=3[C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH3:2].[NH3:35]>C(O)C>[CH2:1]([N:3]([CH2:33][CH3:34])[CH2:4][CH:5]([OH:32])[CH2:6][N:7]1[C:19]2[C:18]3[NH:20][C:21]4[C:22](=[O:27])[CH2:23][CH:24]=[CH:25][C:26]=4[C:17]=3[C:16]3[C:28](=[O:31])[NH:35][CH2:30][C:15]=3[C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH3:2]
Reactant: CCN(CC)CC(O)Cn1c2ccccc2c2c3c(c4c5c([nH]c4c21)C(=O)CC=C5)C(=O)OC3
Reactant: N
Solvent: CCO
Product: CCN(CC)CC(O)Cn1c2ccccc2c2c3c(c4c5c([nH]c4c21)C(=O)CC=C5)C(=O)NC3

Procedure:
285 mg (0.63 mmol) (±)-12-(3-diethylamino-2-hydroxy-1-propyl)-6,7,12,13-tetrahydro-5,1-dioxoindolo-[2,3-a]furano[3,4-c]carbazole are heated in an autoclave for 6 hours at 140° C. in 30 ml of a saturated solution of ammonia in ethanol. The solution is evaporated, the residue is heated in 50 ml diisopropyl ether/tetrahydrofuran (4:1 v/v) and, after cooling, the crystals obtained are filtered off. (±)-12-(3-Diethylamino-2-hydroxy-1-propyl) -6,7,12,13-tetrahydro-5,1-dioxo-5H-indolo[2,3-a]pyrrolo[3,4-c]carbazole is obtained in the form of yellow crystals which decompose from 235° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]2[N:8]=[C:9]([NH2:11])[N:10]=[C:6]2[CH:5]=[C:4]([C:12]([F:15])([F:14])[F:13])[CH:3]=1.Cl.[C:17](Cl)(=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[N:20][CH:19]=1>>[Cl:1][C:2]1[N:7]2[N:8]=[C:9]([NH:11][C:17](=[O:24])[C:18]3[CH:23]=[CH:22][CH:21]=[N:20][CH:19]=3)[N:10]=[C:6]2[CH:5]=[C:4]([C:12]([F:13])([F:15])[F:14])[CH:3]=1
Reactant: Nc1nc2cc(C(F)(F)F)cc(Cl)n2n1
Reactant: O=C(Cl)c1cccnc1
Agent: Cl
Product: O=C(Nc1nc2cc(C(F)(F)F)cc(Cl)n2n1)c1cccnc1

Procedure:
The title compound was prepared following procedure described for intermediate B1, but starting from 5-chloro-7-(trifluoromethyl)[1,2,4]triazolo[1,5-a]pyridin-2-amine ((A7), 2.72 g; 11.5 mmol; 1.0 eq.) and nicotinoyl chloride hydrochloride (2.46 g; 13.8 mmol; 1.2 eq.) as a greenish solid (1.42 g; 36%). HPLC, Rt: 2.16 min. (purity 100%). LC/MS, M+(ESI): 342.2, M−(ESI): 340.2.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4]([OH:7])(=[O:6])=[O:5].Cl[C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10].C(=O)([O-])[O-].[Na+].[Na+]>O>[CH2:12]([O:11][C:9]([NH:1][CH2:2][CH2:3][S:4]([OH:7])(=[O:6])=[O:5])=[O:10])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: NCCS(=O)(=O)O
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=C(NCCS(=O)(=O)O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of taurine (12.5 g, 100 mmol), benzyl chloroformate (15.1 mL, 105 mmol) and sodium carbonate (10.6 g, 100 mmol) in water (250 mL) was stirred at room temperature for overnight. The product mixture was extracted with diethyl ether. The organic extract was concentrated under vacuum to provide 2-{[(benzyloxy)carbonyl]-amino}ethanesulfonic acid. Without further purification, the sulfonic acid was treated with thionyl chloride (15 mL, 206 mmol) with external ice-water bath cooling. The resultant mixture was stirred at room temperature for 1 hour, and poured into ice water. The mixture was extracted with diethyl ether. The organic extract was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under vacuum to provide the title compound as white solid.
Reaction SMILES: Cl.[O:2]=[C:3]1[CH2:8][NH:7][CH2:6][CH2:5][N:4]1[C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH:15]=[C:14]([C:19]#[N:20])[CH:13]=[CH:12]2.[O:21]=[C:22]1[C:26]2[CH:27]=[CH:28][C:29]([CH2:31][CH:32]=O)=[CH:30][C:25]=2[CH2:24][O:23]1.[Na]>C(O)(=O)C.C(Cl)Cl>[O:2]=[C:3]1[CH2:8][N:7]([CH2:32][CH2:31][C:29]2[CH:28]=[CH:27][C:26]3[C:22](=[O:21])[O:23][CH2:24][C:25]=3[CH:30]=2)[CH2:6][CH2:5][N:4]1[C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[CH:15]=[C:14]([C:19]#[N:20])[CH:13]=[CH:12]2
Reactant: O=CCc1ccc2c(c1)COC2=O
Reactant: N#Cc1ccc2cc(N3CCNCC3=O)ccc2c1
Agent: Cl
Agent: [Na]
Solvent: CC(=O)O
Solvent: ClCCl
Product: N#Cc1ccc2cc(N3CCN(CCc4ccc5c(c4)COC5=O)CC3=O)ccc2c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a 25 mL pear shaped flask charged with 6-(2-Oxopiperazin-1-yl)naphthalene-2-carbonitrile hydrochloride [I-5] (30 mg, 0.10 mmol) and a stir bar was added (1-Oxo-1,3-dihydro-2-benzofuran-5-yl)acetaldehyde [I-1] (28 mg, 0.16 mmol), sodium triacetocyborohydride (22 mg, 0.10 mmol), DCM, and a few drops of acetic acid. The mixture was allowed to stir at RT for 16 hours. The title product was purified by mass-directed reverse phase HPLC (AcCN-Water with 0.1% TFA). LC-MS (IE, m/z): 412 [M+1]+.
Reaction SMILES: [CH2:1]([OH:4])[C:2]#[CH:3].Br[C:6]1[CH:7]=[C:8]([CH:13]=[C:14](Br)[C:15]=1[C:16]([O:18][CH3:19])=[O:17])[C:9]([O:11][CH3:12])=[O:10]>C(N(CC)CC)C.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>[OH:4][CH2:1][C:2]#[C:3][C:6]1[CH:7]=[C:8]([CH:13]=[C:14]([C:3]#[C:2][CH2:1][OH:4])[C:15]=1[C:16]([O:18][CH3:19])=[O:17])[C:9]([O:11][CH3:12])=[O:10]
Reactant: C#CCO
Reactant: COC(=O)c1cc(Br)c(C(=O)OC)c(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: COC(=O)c1cc(C#CCO)c(C(=O)OC)c(C#CCO)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 81.3 %

Procedure:
Pd(Ph3P)4 (0.27 g), CuBrSMe2 (0.11 g) and propargyl alcohol (0.72 g, 12.9 mmol) are added successively to a solution of dimethyl 3,5-dibromoterephthalate (Al 15, 2.0 g, 5.7 mmol) in triethylamine (40 ml), and the mixture is stirred at RT for 10 min and then under reflux at 80° C. for 3.5 h. After cooling, the reaction mixture is filtered off with suction through kieselguhr and washed with ethyl acetate (20 ml). The organic phase is concentrated under reduced pressure. Further purification is carried out by chromatography [toluene/acetone (8:2)] on a silica gel column. This gives the title compound (1.4 g) as a colorless solid. TLC, silica gel (glass plates), [toluene/acetone (8:2)], Rf=0.20.
Reaction SMILES: N1C=CN=C1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[I:25]I.[CH2:27]([O:29][C:30]([CH:32]1[C:36](=[O:37])[N:35]([C@H:38]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH3:39])[CH2:34][C@H:33]1[C:46]1([CH2:49]O)[CH2:48][CH2:47]1)=[O:31])[CH3:28]>ClCCl>[CH2:27]([O:29][C:30]([CH:32]1[C:36](=[O:37])[N:35]([C@H:38]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH3:39])[CH2:34][C@H:33]1[C:46]1([CH2:49][I:25])[CH2:48][CH2:47]1)=[O:31])[CH3:28]
Reactant: II
Reactant: CCOC(=O)C1C(=O)N([C@@H](C)c2ccccc2)C[C@H]1C1(CO)CC1
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCOC(=O)C1C(=O)N([C@@H](C)c2ccccc2)C[C@H]1C1(CI)CC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 87.5 %

Procedure:
Imidazole (708 mg, 10.40 mmol), triphenylphosphine (2.727 g, 10.40 mmol), and iodine (2.111 g, 8.32 mmol) were sequentially added to a solution of (3R)-3-[1-(hydroxymethyl)cyclopropan-1-yl]-5-oxo-1-[(1S)-1-phenylethyl]pyrrolidin-4-ylcarboxylic acid ethyl ester (1.378 g, 4.16 mmol) in dichloromethane (50 mL) at room temperature. The mixture was stirred at room temperature for 15 hours. The solvent was evaporated under reduced pressure. Then, the residue was dissolved in ethyl acetate (200 mL) and washed with water (50 mL×2) and brine (50 mL). After drying over anhydrous sodium sulfate and filtration, the solvent was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:9→1:4→1:2) to give 1.606 g (88%) of the title compound as a pale yellow gummy solid.
Reaction SMILES: [Br:1][C:2]1[C:3]([NH:16][N:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)=[N:4][C:5]([N:9]2[C:13]([CH3:14])=[CH:12][CH:11]=[C:10]2[CH3:15])=[N:6][C:7]=1[CH3:8].[C:22](Cl)(=[O:25])[CH:23]=[CH2:24]>C(Cl)Cl.CCN(C(C)C)C(C)C>[Br:1][C:2]1[C:3]([N:16]([N:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[C:22](=[O:25])[CH:23]=[CH2:24])=[N:4][C:5]([N:9]2[C:13]([CH3:14])=[CH:12][CH:11]=[C:10]2[CH3:15])=[N:6][C:7]=1[CH3:8]
Reactant: Cc1nc(-n2c(C)ccc2C)nc(NN2CCCC2)c1Br
Reactant: C=CC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=CC(=O)N(c1nc(-n2c(C)ccc2C)nc(C)c1Br)N1CCCC1
Reaction time: 1 h

Procedure:
To a reaction solution of 5-bromo-2-(2,5-dimethyl-1H-pyrrol-1-yl)-6-methyl-N-(pyrrolidin-1-yl)pyrimidin-4-amine (3.14 g, 8.97 mmol) in anhyrous methylene chloride (120 ml) and hunig's base (4.68 ml) was added slowly a solution of acryloyl chloride (0.80 ml, 9.86 mmol) in methylene chloride (30 ml) dropwise at R.T. After stirring at R.T for 60 mins, the reaction mixture was concentrated under reduced pressure and the residue was purified by 120 g column eluted with 40% ethyl acetate:hexane to give the titled product weighted 3.5 g a white solid 97%
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([CH:13]=[CH:14][CH:15]=1)[CH2:6][CH:7]([CH2:11][CH3:12])[C:8](O)=[O:9].S(Cl)([Cl:20])=O>>[F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([CH:13]=[CH:14][CH:15]=1)[CH2:6][CH:7]([CH2:11][CH3:12])[C:8]([Cl:20])=[O:9]
Reactant: O=S(Cl)Cl
Reactant: CCC(Cc1cccc(C(F)(F)F)c1)C(=O)O
Product: CCC(Cc1cccc(C(F)(F)F)c1)C(=O)Cl
Yield: 92.2 %

Procedure:
To 1.0 g (4.1 mmol) of 2-(m-trifluoromethylbenzyl)butanoic acid was added 0.98 g (8.2 mol) of thionyl chloride, and the resulting mixture was refluxed for 3 hours. Thionyl chloride was removed by an evaporator to obtain 1.0 g of 2-(m-trifluoromethylbenzyl)butanoic acid chloride as a colorless liquid.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:9][C:10]1[CH:15]=[CH:14][C:13]([S:16]([N:19]2[CH2:24][CH2:23][CH2:22][CH2:21][C@H:20]2[C:25]2[N:29]=[CH:28][NH:27][N:26]=2)(=[O:18])=[O:17])=[CH:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:1]([N:27]1[CH:28]=[N:29][C:25]([C@@H:20]2[CH2:21][CH2:22][CH2:23][CH2:24][N:19]2[S:16]([C:13]2[CH:14]=[CH:15][C:10]([F:9])=[CH:11][CH:12]=2)(=[O:17])=[O:18])=[N:26]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(=O)(c1ccc(F)cc1)N1CCCC[C@H]1c1nc[nH]n1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=S(=O)(c1ccc(F)cc1)N1CCCC[C@H]1c1ncn(Cc2ccccc2)n1
Temperature: 50 °C
Reaction time: 7 h

Procedure:
Benzyl bromide (40 μl) was added to a solution of (2S)-1-[(4-fluorophenyl)sulfonyl]-2-(1H-1,2,4-triazol-3-yl)piperidine (95 mg) [see Preparation 42] and potassium carbonate (47 mg) in dimethylformamide (5 ml). The reaction mixture was stirred at 50° C. for 7 hours, after which time the solvent was removed under reduced pressure and the residue diluted with ethyl acetate. The organic solution was washed with water, dried over magnesium sulphate and the solvent removed under reduced pressure. The crude product was purified by column chromatography on silica gel eluting with 100:0 changing to 50:50, by volume, hexane:ethyl acetate (in 10% increments), to afford (2S)-2-(1-benzyl-1H-1,2,4-triazol-3-yl)-1-[(4-fluorophenyl)sulfonyl]piperidine (35 mg) as a white solid.