Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH:6]([O:9][C:10]1[CH:11]=[C:12]([CH2:16][C:17]([N:19]([CH2:24][CH:25]([C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[C:31]([Cl:36])[CH:30]=2)[CH2:26][CH2:27][OH:28])[CH2:20][CH2:21][O:22][CH3:23])=[O:18])[CH:13]=[CH:14][CH:15]=1)([CH3:8])[CH3:7].C(N(CC)CC)C>ClCCl>[CH:6]([O:9][C:10]1[CH:11]=[C:12]([CH2:16][C:17]([N:19]([CH2:24][CH:25]([C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[C:31]([Cl:36])[CH:30]=2)[CH2:26][CH2:27][O:28][S:2]([CH3:1])(=[O:4])=[O:3])[CH2:20][CH2:21][O:22][CH3:23])=[O:18])[CH:13]=[CH:14][CH:15]=1)([CH3:8])[CH3:7]
Reactant: COCCN(CC(CCO)c1ccc(Cl)c(Cl)c1)C(=O)Cc1cccc(OC(C)C)c1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCCN(CC(CCOS(C)(=O)=O)c1ccc(Cl)c(Cl)c1)C(=O)Cc1cccc(OC(C)C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.2 %

Procedure:
0.526 g of methanesulfonyl chloride are added to a mixture of 1.8 g of the product obtained in step 4 and 0.46 g of triethylamine in 40 ml of dichloromethane. The reaction mixture is stirred at ambient temperature for 1 h and is then concentrated under vacuum. The residue is taken up with ethyl acetate, washed with water, dried over Na2SO4 and concentrated under vacuum to give 2 g of the expected product
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][CH2:9][C:10]1[N:15]=[C:14]([C:16]2[S:17][C:18]3[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=3[C:20](=[O:22])[N:21]=2)[CH:13]=[CH:12][CH:11]=1.[CH3:27][S:28](Cl)(=[O:30])=[O:29].C(=O)([O-])O.[Na+]>C(OCC)(=O)C.O>[O:22]=[C:20]1[C:19]2[CH:23]=[CH:24][CH:25]=[CH:26][C:18]=2[S:17][C:16]([C:14]2[N:15]=[C:10]([CH2:9][NH:8][S:28]([CH3:27])(=[O:30])=[O:29])[CH:11]=[CH:12][CH:13]=2)=[N:21]1
Reactant: CS(=O)(=O)Cl
Reactant: NCc1cccc(-c2nc(=O)c3ccccc3s2)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)NCc1cccc(-c2nc(=O)c3ccccc3s2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 23 %

Procedure:
2-[6-(Aminomethyl)-2-pyridyl]-4H-1,3-benzothiazine-4-one trifluoroacetic acid salt (450 mg, 1.1 mmol) and methanesulfonyl chloride (205 mg, 1.7 mmol) were dissolved in ethyl acetate (10 ml) and water (5 ml), and sodium hydrogen carbonate (250 mg, 3.0 mmol) was added thereto. The mixture was stirred at room temperature for 1 hr. The reaction mixture was combined with ethyl acetate and water. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was subjected to a silica gel column chromatography. The fractions eluted with ethyl acetate-methanol (20:1, v/v) were collected, concentrated and recrystallized from hexane-tetrahydrofuran to give the titled compound (88 mg, 21%) as white crystals.
Reaction SMILES: Br[C:2]1[C:6]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=2)=[CH:5][S:4][CH:3]=1.[C:15]([C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[C:19]([CH3:26])[CH:18]=1)#[N:16].C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1>C(O)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>[CH3:14][O:13][C:10]1[CH:11]=[CH:12][C:7]([C:6]2[C:2]([C:20]3[CH:21]=[CH:22][C:17]([C:15]#[N:16])=[CH:18][C:19]=3[CH3:26])=[CH:3][S:4][CH:5]=2)=[CH:8][CH:9]=1
Reactant: COc1ccc(-c2cscc2Br)cc1
Reactant: Cc1cc(C#N)ccc1B(O)O
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: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: COc1ccc(-c2cscc2-c2ccc(C#N)cc2C)cc1
Temperature: 80 °C
Reaction time: 5 h
Yield: 69.5 %

Procedure:
To a mixture of 3-bromo-4-(4-methoxyphenyl)thiophene (Scheme I, 2, X1=4-methoxyphenyl) (1.7 g, 6.316 mmol), 4-cyano-2-methylphenylboronic acid (Scheme I, 2A, X2=4-cyano-2-methylphenyl) (1.535 g, 6.316 mmol), sodium carbonate (1.34 g, 12.63 mmol), toluene (60 mL) in a mixture of ethanol (36 mL) and water (24 mL) under nitrogen was added Pd(PPh3)4 (0.7 g, 0.606 mmol). The mixture was stirred at 80° C. for 5 h, poured into water (50 mL), and extracted with ethyl acetate (50 mL×3). The organic extracts were dried over anhydrous magnesium sulfate (6 g), evaporated, and purified by column chromatography on silica gel (petroleum ether/ethyl acetate=50:1) to give 4-(4-(4-methoxyphenyl)thiophen-3-yl)-3-methylbenzonitrile (Scheme I, 3, X1=4-methoxyphenyl, X2=4-cyano-2-methylphenyl) (1.34 g, yield 69.4%). 1H NMR (DMSO-d6 400 MHz): δ 7.68-7.65 (m, 3H), 7.58 (d, J=3.2 Hz, 1H), 7.33 (d, J=8.0 Hz, 1H), 6.98 (d, J=8.8 Hz, 2H), 6.80 (d, J=8.8 Hz, 2H), 3.70 (s, 3H), 1.79 (s, 3H).
Reaction SMILES: [F:1][C:2]1[C:7](B(O)O)=[CH:6][CH:5]=[CH:4][N:3]=1.Br[C:12]1[CH:13]=[C:14]2[C@@:26]3([CH2:30][O:29][C:28]([NH2:31])=[N:27]3)[C:25]3[C:20](=[N:21][CH:22]=[C:23]([CH2:32][O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[CH:24]=3)[O:19][C:15]2=[CH:16][C:17]=1[F:18].C(=O)([O-])[O-].[K+].[K+].O>O1CCOCC1.CCOC(C)=O>[C:34]([O:33][CH2:32][C:23]1[CH:24]=[C:25]2[C@:26]3([CH2:30][O:29][C:28]([NH2:31])=[N:27]3)[C:14]3[C:15](=[CH:16][C:17]([F:18])=[C:12]([C:7]4[C:2]([F:1])=[N:3][CH:4]=[CH:5][CH:6]=4)[CH:13]=3)[O:19][C:20]2=[N:21][CH:22]=1)([CH3:37])([CH3:35])[CH3:36]
Reactant: CC(C)(C)OCc1cnc2c(c1)[C@]1(COC(N)=N1)c1cc(Br)c(F)cc1O2
Reactant: OB(O)c1cccnc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC(C)(C)OCc1cnc2c(c1)[C@]1(COC(N)=N1)c1cc(-c3cccnc3F)c(F)cc1O2
Temperature: 100 °C
Yield: 41.8 %

Procedure:
A solution of pd(Ph3P)4 (0.019 g, 0.017 mmol), 2-fluoropyridin-3-ylboronic acid (0.047 g, 0.34 mmol), (S)-7-bromo-3-(tert-butoxymethyl)-8-fluoro-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazol]-2′-amine (0.073 g, 0.17 mmol), and potassium carbonate (0.12 g, 0.84 mmol) in 1 mL dioxane, was treated with 0.4 mL water and was heated to 100° C. overnight. The reaction mixture was diluted with EtOAc, dried over MgSO4, and concentrated. Purification of the crude residue by column chromatography [0-100% (9:1 DCM:MeOH)/DCM] gave (4′S)-3-(tert-butoxymethyl)-8-fluoro-7-(2-fluoropyridin-3-yl)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazol]-2′-amine (0.032 g, 0.071 mmol, 42.3% yield). [M+H]+=453.0
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([OH:7])=O.[NH2:12][C:13]1[N:17]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)[N:16]=[C:15]([CH3:25])[CH:14]=1.C(N(CC)C(C)C)(C)C.O>S(Cl)(Cl)=O.C(Cl)Cl>[I:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([NH:12][C:13]1[N:17]([C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)[N:16]=[C:15]([CH3:25])[CH:14]=1)=[O:7]
Reactant: Cc1ccc(C(=O)O)cc1I
Reactant: Cc1ccc(-n2nc(C)cc2N)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O=S(Cl)Cl
Solvent: O
Product: Cc1ccc(-n2nc(C)cc2NC(=O)c2ccc(C)c(I)c2)cc1
Temperature: 80 °C
Reaction time: 1.75 h
Yield: 85.8 %

Procedure:
3-Iodo-4-methylbenzoic acid (1.00 g, 3.89 mmol) was dissolved in thionyl chloride (12.5 mL) and was stirred at 80° C. for 1.75 hours, then thionyl chloride was evaporated under reduced pressure. The reaction mixture was dissolved in methylene chloride (10.0 mL) and the solution was added with a solution of 5-amino-3-methyl-1-(p-tolyl)pyrazole (0.728 g, 3.89 mmol) and N,N-diisopropylethylamine (0.678 mL, 3.89 mmol) in methylene chloride (10.0 mL), followed by stirring at room temperature overnight. After the reaction mixture was added with water and extracted with ethyl acetate, the organic layer was washed with saturated aqueous sodium hydrogencarbonate solution, saturated aqueous ammonium chloride solution and water, followed by drying over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=1/4) to obtain 3-iodo-4-methyl-N-[5-methyl-2-(p-tolyl)-2H-pyrazol-3-yl]benzamide (1.44 g, 86%).
Reaction SMILES: [CH:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1)=O.C(OP([CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])(OCC)=O)C.[H-].[Na+].OS([O-])(=O)=O.[K+]>COCCOC.CC(C)=O>[C:24]([O:23][C:21](=[O:22])/[CH:20]=[CH:1]/[C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1)([CH3:27])([CH3:26])[CH3:25]
Reactant: O=Cc1ccc(C(=O)O)cc1
Reactant: CCOP(=O)(CC(=O)OC(C)(C)C)OCC
Agent: O=S(=O)([O-])O
Agent: [H-]
Agent: [K+]
Solvent: COCCOC
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)/C=C/c1ccc(C(=O)O)cc1
Reaction time: 1 h
Yield: 100 %

Procedure:
A solution of 4-formylbenzoic acid (223) (306 mg, 2.04 mmol) and tert-butyl 2-(diethoxyphosphoryl)acetate (0.8 mL, 3.23 mmol) in ethyleneglycol dimethylether (15 mL) was stirred at 0° C. then treated with sodium hydride (60% in oil, 312 mg, 7.8 mmol), further stirred for 1 h then at room temperature for 3 h. The reaction mixture was diluted with acetone, stirred 10 min then treated with 5% aqueous KHSO4, extracted with DCM. The extract was dried over MgSO4, filtered and concentrated to provide title compound 224 as a white solid (811.5 mg, >100% yield, crude, used in the next step without additional purification).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH3:9])=[CH:4][N:3]=1.Br[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([O:18][CH3:19])[CH:12]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C(Cl)Cl.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([NH:8][C:6]2[C:5]([CH3:9])=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=2)=[CH:12][C:13]=1[O:18][CH3:19]
Reactant: Cc1cnc(Cl)nc1N
Reactant: COc1cc(Br)ccc1Cl
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: ClCCl
Product: COc1cc(Nc2nc(Cl)ncc2C)ccc1Cl
Temperature: 25 °C
Yield: 55.3 %

Procedure:
A mixture of 2-chloro-5-methyl-pyrimidin-4-ylamine (0.50 g, 3.5 mmol), 4-bromo-1-chloro-2-methoxy-benzene (0.65 mL, 4.8 mmol), Pd2(dba)3 (0.17 g, 0.19 mmol), Xantphos (0.22 g, 0.38 mmol) and cesium carbonate (2.3 g, 7.1 mmol) was suspended in dioxane (20 mL) and heated at reflux under the argon atmosphere for 5 h. The reaction mixture was cooled to room temperature and diluted with DCM (30 mL). The mixture was filtered and the filtrate concentrated in vacuo. The residue was purified by Hash chromatography on silica gel (hexanes to 40% EtOAc/hexanes) to afford the title compound (0.55 g, 55%) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[CH:19][CH:20]=[C:21]4[C:25]=3[N:24]([CH3:26])[CH:23]=[C:22]4[CH2:27][NH:28][CH2:29][C:30]([O:32]CC)=[O:31])[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].[OH-].[Na+]>O1CCCC1.C(O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[CH:19][CH:20]=[C:21]4[C:25]=3[N:24]([CH3:26])[CH:23]=[C:22]4[CH2:27][NH:28][CH2:29][C:30]([OH:32])=[O:31])[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:10])[CH3:11]
Reactant: CCOC(=O)CNCc1cn(C)c2c(-c3noc(-c4ccc(OC(C)C)c(Cl)c4)n3)cccc12
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c(CNCC(=O)O)cn(C)c34)no2)cc1Cl
Temperature: 20 °C
Reaction time: 8 h
Yield: 56.3 %

Procedure:
To a solution of ethyl N-{[7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1-methyl-1H-indol-3-yl]methyl}glycinate (D77) (283 mg) in tetrahydrofuran (5 mL) and ethanol (5 mL) stirred at 20° C. was added a solution of sodium hydroxide (40 mg) in water (5 mL) in one charge. The reaction mixture was stirred at 20° C. overnight. The reaction mixture was concentrated to about 5 mL and then H2SO4 (0.1 M) solution was added dropwise until no further white precipitate was formed. The solid was filtered and washed with EtOAc. The solid was collected and then was suspended in methanol (5 mL). The mixture was acidified with HCl (1 M) solution to pH around 1 to form a clear solution. After most of the solvent was evaporated off, the residue was freeze-dried to afford N-{[7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1-methyl-1H-indol-3-yl]methyl}glycine (E56) (150 mg) as a hydrochloride salt. δH (DMSO-d6, 400 MHz): 1.37 (6H, d), 3.72 (3H, s), 3.85 (2H, s), 4.39 (2H, s), 4.87-4.93 (1H, m), 7.30 (1H, t), 7.47 (1H, d), 7.52 (1H, d), 7.62 (1H, s), 8.05 (1H, s), 8.14 (1H, dd), 8.21 (1H, d), 9.23 (1H, br s). MS (ES): C23H23ClN4O4 requires 454; found 380.1 (M—NHCH2COOH+).
Reaction SMILES: [NH:1]([C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[NH:23](C(OCC1C=CC=CC=1)=O)[C@@H:24](C(O)=O)[CH2:25]C1C=CC=CC=1>C(N(CC)CC)C.ClCC#N>[NH:1]([C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[C@H:2]([C:10]([O:12][CH2:25][C:24]#[N:23])=[O:11])[CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=C(N[C@H](Cc1ccccc1)C(=O)O)OCc1ccccc1
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)O)OCc1ccccc1
Agent: N#CCCl
Solvent: CCN(CC)CC
Product: N#CCOC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1 gram of Z-L-Phe-OH or Z-D-Phe-OH was dissolved in 2 mL of triethylamine and 2 mL of chloroacetonitrile. The reaction was stirred for two hours at room temperature. The reaction was concentrated under vacuum and the residue taken up in 5 mL ethyl acetate. The ethyl acetate was then washed with 2% Na2CO3 (3x), water (2x), 1 N HCl (2x), water (2x), and 0.5 M or higher saline (1x). The organic phase was dried over MgSO4, and concentrated to dryness. The residue was recrystallized from CH2Cl2 /hexanes. Yield for Z-L-Phe-OCH2CN was 1.0 g (89%). M.P. 53°-55° C. [α]d (c 2, DMF)+6.6°. 1H-NMR (CDCl3) 3.1 (d, 2H, Phe βH), 4.7 (m, 3H, αH and cyanomethyl), 5.1 (s, 2H, CBZ βH), 5.2 (d, 1H, amide), 7.3 (m, 10 H, Phe and CBZ phenyl). Z-D-Phe-OCH2CH, yield 0.88 g (78%). M.P. 53°-54° C. [α]d (c, 2, DMF)-6.1°.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]([C:18]2[NH:19][CH:20]=[CH:21][CH:22]=2)=[O:17])=[CH:11][CH:10]=1)C1C=CC=CC=1.OC1C=CC(NC(C2C=CC=CN=2)=O)=CC=1>>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([NH:15][C:16]([C:18]2[NH:19][CH:20]=[CH:21][CH:22]=2)=[O:17])=[CH:13][CH:14]=1
Reactant: O=C(Nc1ccc(OCc2ccccc2)cc1)c1ccc[nH]1
Agent: O=C(Nc1ccc(O)cc1)c1ccccn1
Product: O=C(Nc1ccc(O)cc1)c1ccc[nH]1

Procedure:
This compound was prepared from 1H-pyrrole-2-carboxylic acid (4-benzyloxyphenyl)-amide (2.5 g, 8.55 mmol), using the same method used to prepare of pyridine-2-carboxylic acid (4-hydroxyphenyl)amide. The product was purified by flash chromatography, on silica gel, eluted with 5 to 7.5% methanol in DCM, to give the product as a colorless solid, 1.47 g (85%). MS m/z 203 (MH+). 1H NMR(DMSO-d6) δ 6.14 (m, 1H), 6.72 (d, 2H), 6.92 (m, 1H), 6.99 (d, 1H), 7.47 (d, 2H), 9.19 (s, 1H). Anal. calcd for C11H10N2O2: C, 65.34; H, 4.98; N, 13.85. Found: C, 65.15; H, 4.83; N, 13.81.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][S:10]([C:13]1[CH:18]=[CH:17][C:16]([C:19]([O:21]C)=[O:20])=[CH:15][CH:14]=1)(=[O:12])=[O:11].[OH-].[Na+]>C(O)C.O1CCCC1>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][S:10]([C:13]1[CH:18]=[CH:17][C:16]([C:19]([OH:21])=[O:20])=[CH:15][CH:14]=1)(=[O:12])=[O:11]
Reactant: COCCCCCCCS(=O)(=O)c1ccc(C(=O)OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: COCCCCCCCS(=O)(=O)c1ccc(C(=O)O)cc1
Temperature: 80 °C
Reaction time: 5 h
Yield: 98.3 %

Procedure:
A mixture of 7-methoxyheptyl-[4-(methoxycarbonyl)phenyl]sulfone (0.85 g) and 1N-aqueous sodium hydroxide (5 ml) in a mixture of ethanol (20 ml) and tetrahydrofuran (10 ml) was stirred at 80° C. for 5 hours. The reaction mixture was concentrated under reduced pressure and the residue was triturated with water. The solution was adjusted to pH 1.0 using diluted hydrochloric acid. The precipitates were collected by filtration, washed with water and dried in vacuo to give 7-methoxyheptyl-(4-carboxyphenyl)sulfone (0.8 g) white solid.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1.Cl.[NH2:13][OH:14]>C(O)C>[Cl:1][CH2:2][CH2:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[N:13][OH:14])=[CH:6][CH:5]=1
Reactant: O=Cc1ccc(CCCl)cc1
Reactant: NO
Agent: Cl
Solvent: CCO
Product: ON=Cc1ccc(CCCl)cc1
Temperature: 50 °C
Reaction time: 2 h
Yield: 94.5 %

Procedure:
4-(2-Chloroethyl)benzaldehyde (1.70 g, 10.08 mmol) was dissolved in ethanol (35 ml), hydroxylamine hydrochloride (1.05 g, 15.11 mmol) was added, and the mixture was stirred at 50° C. for 2 hours. Ethanol was evaporated under reduced pressure, and water was added. The mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give the title compound (1.75 g, 95%).
Reaction SMILES: S(=O)(=O)(O)O.[CH2:6]([O:13][C@:14]1([CH3:38])[C@H:18]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C@@H:17]([CH2:27][O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[O:16][C@@H:15]1[O:36]C)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(OCC)(=O)C>C(O)(=O)C.O>[CH2:6]([O:13][C@:14]1([CH3:38])[C@H:18]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C@@H:17]([CH2:27][O:28][CH2:29][C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[O:16][C@@H:15]1[OH:36])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CO[C@H]1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@@]1(C)OCc1ccccc1
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: O
Product: C[C@@]1(OCc2ccccc2)[C@H](OCc2ccccc2)[C@@H](COCc2ccccc2)O[C@@H]1O
Temperature: 70 °C
Reaction time: 3 h
Yield: 63.1 %

Procedure:
4.9 g of concentrated sulfuric acid was added dropwise to a solution of 9.0 g of (2S,3R,4R,5R)-3,4-bis(benzyloxy)-5-((benzyloxy)methyl)-2-methoxy-3-methyloxolane in 80 mL of acetic acid and 20 mL of water at room temperature, and the obtained mixture was then stirred at 70° C. for 3 hours. Thereafter, the reaction mixture was cooled to 30° C., and 200 mL of water and 200 mL of ethyl acetate were then added to the mixture. The organic layer was fractionated, and it was successively washed with 200 mL of 1 mol/L hydrochloric acid and 200 mL of a saturated sodium chloride aqueous solution. The solvent was distilled away under reduced pressure. The obtained residue was purified by silica gel column chromatography, so as to obtain 5.5 g of (2S,3R,4R,5R)-3,4-bis(benzyloxy)-5-((benzyloxy)methyl)-3-methyloxolan-2-ol in the form of a colorless oily product.
Reaction SMILES: C(N[C:5]1[CH:6]=[C:7]([C:11]2[C:16]3[N:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH:18]=[N:19][C:15]=3[CH:14]=[C:13]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH:12]=2)[CH:8]=[CH:9][CH:10]=1)(=O)C.[CH2:31]([O:33]C(C1C=C(I)C2N(C3C=CC=CC=3)C=NC=2C=1)=O)C.OCC1C=C(B(O)O)C=CC=1.C(O)CCO.C(=O)([O-])[O-].[K+].[K+]>C(COC)OC.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:29]([O:28][C:26]([C:13]1[CH:12]=[C:11]([C:7]2[CH:8]=[CH:9][CH:10]=[C:5]([CH2:31][OH:33])[CH:6]=2)[C:16]2[N:17]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:18]=[N:19][C:15]=2[CH:14]=1)=[O:27])[CH3:30]
Reactant: CCOC(=O)c1cc(I)c2c(c1)ncn2-c1ccccc1
Reactant: CCOC(=O)c1cc(-c2cccc(NC(C)=O)c2)c2c(c1)ncn2-c1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: OCc1cccc(B(O)O)c1
Solvent: COCCOC
Solvent: OCCCO
Solvent: O
Product: CCOC(=O)c1cc(-c2cccc(CO)c2)c2c(c1)ncn2-c1ccccc1

Procedure:
This was prepared analogously to 7-(3-acetamidophenyl)-5-ethoxycarbonyl-1-phenylbenzimidazole from 5-ethoxycarbonyl-7-iodo-1-phenylbenzimidazole (2.7 g, 6.89 mmol), 3-(hydroxymethyl)phenylboronic acid (1.57 g, 10.3 mmol), 1,3-propanediol (2.5 ml, 34.4 mmol), potassium carbonate (4.75 g, 34.4 mmol) and bis(triphenylphosphin)palladium dichloride (100 mg, 0.14 mmol) in a mixture of dimethoxyethane (30 ml) and water (15 ml). The title product was obtained as an off-white solid (2.1 g, 82%) m/z, 373.2 (M+H)+.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([SH:14])[CH:11]=[CH:12][CH:13]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:22][CH2:23][CH2:24][C:25]#[N:26].O>CN(C)C=O>[N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([S:14][CH2:22][CH2:23][CH2:24][C:25]#[N:26])[CH:11]=[CH:12][CH:13]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Sc1cccc(CN2CCCCC2)c1
Reactant: N#CCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: N#CCCCSc1cccc(CN2CCCCC2)c1
Reaction time: 0.5 h

Procedure:
A stirred suspension of 3-piperidinomethylthiophenol (0.36 g) in dry dimethylformamide (4 ml) was treated with anhydrous potassium carbonate (0.5 g) and stirred for 30 minutes. 4-Bromobutyronitrile (0.18 ml) was then added to the reaction mixture with dimethylformamide (1 ml) and the resultant suspension stirred at room temperature for 48 hours. The resulting product was poured into 5 volumes of water and extracted with ethyl acetate; the extracts were washed with water, dried and evaporated to give 4-(3-piperidinomethylphenylthio)butyronitrile as an orange-red oil.
Reaction SMILES: CC(C)([O-])C.[K+].[Cl:7][C:8]1[NH:9][C:10]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=2)=[C:11]([Cl:15])[C:12]=1[C:13]#[N:14].[CH2:24]([O:26][CH2:27]Cl)[CH3:25].N1C=CC=C1>CCCCCC.C(OCC)(=O)C.O1CCCC1>[Cl:7][C:8]1[N:9]([CH2:27][O:26][CH2:24][CH3:25])[C:10]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=2)=[C:11]([Cl:15])[C:12]=1[C:13]#[N:14]
Reactant: CCOCCl
Reactant: N#Cc1c(Cl)[nH]c(-c2ccc(Cl)c(Cl)c2)c1Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: c1cc[nH]c1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOCn1c(Cl)c(C#N)c(Cl)c1-c1ccc(Cl)c(Cl)c1
Yield: 89.4 %

Procedure:
To a mixture of potassium tert-butoxide (0.62 g, 0.0055 mol) and tetrahydrofuran (50 mL) is added 2,4-dichloro-5-(3,4-dichlorophenyl)pyrrole-3-carbonitrile (1.3 g, 0.0043 mol) followed by chloromethyl ethyl ether (0.52 g, 0.0055 mol). After stirring the reaction mixture overnight, TLC (1:1 hexane/ethyl acetate shows no remaining starting pyrrole and the reaction is concentrated in vacuo. Addition of water to the residue affords a solid which is collected and dried to give the title compound as a brown solid (1.4 g, 90%, mp 106°-109° C.) which is indentified by IR and NMR spectral analyses.
Reaction SMILES: [NH2:1][C:2]1[O:21][C:6]2[N:7]([CH3:20])[N:8]=[C:9]([C:10]3[CH:15]=[CH:14][C:13](OC)=[C:12](OC)[CH:11]=3)[C:5]=2[CH:4]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[C:3]=1[C:29]#[N:30].F[C:32]1[CH:39]=[CH:38]C(C=O)=[CH:34][CH:33]=1.C(#N)CC#N.C(N(CC)CC)C.COC1C=C(C2CC(=O)N(C)N=2)C=CC=1OC>C(O)C>[NH2:1][C:2]1[O:21][C:6]2[N:7]([C:20]3[CH:38]=[CH:39][CH:32]=[CH:33][CH:34]=3)[N:8]=[C:9]([C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:5]=2[CH:4]([C:22]2[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=2)[C:3]=1[C:29]#[N:30]
Reactant: COc1ccc(-c2nn(C)c3c2C(c2ccc(F)cc2)C(C#N)=C(N)O3)cc1OC
Reactant: O=Cc1ccc(F)cc1
Agent: COc1ccc(C2=NN(C)C(=O)C2)cc1OC
Solvent: CCN(CC)CC
Solvent: N#CCC#N
Solvent: CCO
Product: N#CC1=C(N)Oc2c(c(-c3ccccc3)nn2-c2ccccc2)C1c1ccc(F)cc1
Reaction time: 0.02 h
Yield: 67 %

Procedure:
6-amino-3-(3,4-dimethoxyphenyl)-4-(4-fluorophenyl)-1-methyl-1,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile UC-E21: A mixture of 4-fluorobenzaldehyde (300 μL, 2.87 mmol, 1.0 equ.), malononitrile (190 mg, 2.87 mmol, 1.0 equ.) and triethylamine (400 μL, 2.87 mmol, 1.0 equ.) in ethanol (10 mL) was stirred for 1 min, followed by the addition of 3-(3,4-dimethoxyphenyl)-1-methyl-1H-pyrazol-5(4H)-one (672 mg, 2.87 mmol, 1 equ.). The precipitate formed was filtered out and washed with ethanol and hexanes, and re-crystallized from ethanol to give 6-amino-4-(4-fluorophenyl)-1,3-diphenyl-1,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile (782 mg, 1.93 mmol, 67%) as a white powder. 1H-NMR (400 MHz) DMSO: 7.20-7.18 (m, 2H), 7.09-7.03 (m, 5H), 6.96-6.95 (d, 1H), 6.80-6.78 (d, 2H), 5.02 (s, 1H), 3.77 (s, 3H), 3.69 (s, 3H), 3.62 (s, 3H) 13C-NMR (100 MHz) DMSO: 162.6, 159.0, 148.7, 146.0, 144.6, 141.0, 141.0, 129.8, 129.7, 125.9, 120.4, 119.0, 115.7, 115.4, 111.8, 109.8, 94.7, 55.8, 55.7, 37.3, 34.4; LC/MS-MS: 407.1→341.1 m/z; GS1 and GS2 at 30, DP=71, CE=33, CXP=22, tR=3.86 min.