Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:10]([C:11]([C:13]2[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=2)=[O:12])[C:9]2[CH:8]=[CH:7][C:6]([O:20][CH3:21])=[CH:5][C:4]=2[C:3]=1[CH2:22][C:23]([OH:25])=O.[C:26]([O:30][C:31](=[O:37])[NH:32][CH2:33][CH2:34][CH2:35][NH2:36])([CH3:29])([CH3:28])[CH3:27].Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[Cl:19][C:16]1[CH:15]=[CH:14][C:13]([C:11]([N:10]2[C:9]3[C:4](=[CH:5][C:6]([O:20][CH3:21])=[CH:7][CH:8]=3)[C:3]([CH2:22][C:23]([NH:36][CH2:35][CH2:34][CH2:33][NH:32][C:31](=[O:37])[O:30][C:26]([CH3:28])([CH3:27])[CH3:29])=[O:25])=[C:2]2[CH3:1])=[O:12])=[CH:18][CH:17]=1
Reactant: COc1ccc2c(c1)c(CC(=O)O)c(C)n2C(=O)c1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)NCCCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)c(CC(=O)NCCCNC(=O)OC(C)(C)C)c(C)n2C(=O)c1ccc(Cl)cc1
Yield: 70 %

Procedure:
an Indo-Coumarinyl Analog: Compound 27gg, N-[3-{7-(N,N-Diethylamino)coumarin-3-carboxylamido}butyl]-2-{1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl}acetamide was synthesized by the method depicted in FIG. 8. Briefly, indomethacin was complexed with tert-Butyl-3-aminopropylcarbamate for 16 hours at room temperature in the presence of 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (EDCl), 1-hydroxybenzotriazole (HOBt), N,N-diisopropylethylamine (DIPEA), and N,N-dimethylformamide (DMF). tert-Butyl 3-[2-{1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl}acetamido]propylcarbamate was produced as a pale yellow solid at 70% yield. This product was then dissolved in dichloromethane and treated with HCl (gas) for 2 hours at room temperature, producing N-(4-qminobutyl)-2-{1-(4-chlorobenzoyl)-5-methoxy-2-methyl-1H-indol-3-yl}acetamide hydrochloride as a brown solid with a yield of 98%, which was reacted with triethylamine (TEA) in dimethyl sulfoxide (DMSO) for 5 minutes at room temperature prior to the addition of 7-(N,N-Diethylamino)coumarin-3-carboxylic acid succinimidyl ester. The reaction proceeded for 16 hours at room temperature and produced Compound 27gg as a yellow solid (66% yield).
Reaction SMILES: [BH4-].[Na+].[Te].C(O)(=O)C.[CH3:8][O:9][C:10](=[O:26])[CH:11]=[C:12]1[S:24][C:15]2=[N:16][C:17]3[C:22]([CH2:23][N:14]2[C:13]1=[O:25])=[CH:21][CH:20]=[CH:19][CH:18]=3>C(O)C>[CH3:8][O:9][C:10](=[O:26])[CH2:11][CH:12]1[S:24][C:15]2=[N:16][C:17]3[C:22]([CH2:23][N:14]2[C:13]1=[O:25])=[CH:21][CH:20]=[CH:19][CH:18]=3
Reactant: COC(=O)C=c1sc2n(c1=O)Cc1ccccc1N=2
Agent: [BH4-]
Agent: [Na+]
Agent: [Te]
Solvent: CCO
Solvent: CC(=O)O
Product: COC(=O)CC1SC2=Nc3ccccc3CN2C1=O
Temperature: -20 °C
Reaction time: 0.08 h
Yield: 32.3 %

Procedure:
A suspension of sodium borohydride (3.03 g, 0.08 mol) and 4.38 g (0.034 mol) tellurium powder in 135 ml anhydrous ethanol was heated under nitrogen atmosphere for 15 min. After cooling to -20° C., 8.08 ml glacial acetic acid in 33.65 ml anhydrous ethanol was added dropwise, and the mixture was stirred at that temperature for 5 min, followed by the addition of 3.50 g (0.013 mol) of (3-oxo-5H-thiazolo[2,3-b]quinazolin-2(3H)-ylidene)acetic acid methyl ester in 13.5 ml anhydrous ethanol. The reaction mixture was allowed to warm up to ambient temperature and stirred overnight. Then, the mixture was filtered through celite, and evaporated under reduced pressure. The residue was taken up in water and extracted with chloroform. The organic extract was dried over anhydrous magnesium sulfate and evaporated under reduced pressure, yielding 1.16 g of 2,3-dihydro-3-oxo-5H-thiazolo[2,3-b]quinazoline-2-acetic acid methyl ester. Mp 143°-144° C. after recrystallization from ethyl acetate.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([I:10])[CH:7]=[C:6]([C:11]([F:14])([F:13])[F:12])[C:5]=1[CH2:15][C:16]([O:18]C)=O)([O-])=O>CO>[F:12][C:11]([F:14])([F:13])[C:6]1[CH:7]=[C:8]([I:10])[CH:9]=[C:4]2[C:5]=1[CH2:15][C:16](=[O:18])[NH:1]2
Reactant: COC(=O)Cc1c([N+](=O)[O-])cc(I)cc1C(F)(F)F
Solvent: CO
Product: O=C1Cc2c(cc(I)cc2C(F)(F)F)N1
Temperature: 25 °C
Reaction time: 3 h
Yield: 77.6 %

Procedure:
To methyl [2-nitro-4-iodo-6-(trifluoromethyl)phenyl]acetate (33.11 g, 85.1 mmol) in MeOH (1000 mL) at 0° C. was added aqueous 20% TiCl3 (815 g, 12.4 eq). The cooling bath was removed and the resulting mixture stirred at room temperature for 3 hours and then left overnight. To the mixture was then added aqueous 6N HCl (900 mL) and the mixture extracted with EtOAc:toluene (1:1, 3×1000 mL) and EtOAc:toluene (2:1, 3×900 mL and 3×500 mL). The extracts were combined and dried (anhydrous MgSO4). After filtration, the solvent was removed in vacuo to give a light brown solid. Purification was carried out by crystallization from EtOH (300 mL) to give the title compound as a light brown crystalline solid (21.588 g, 78%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C@H:13]([CH3:17])[C:14]([OH:16])=[O:15])[CH:7]=[CH:6]2.O[CH2:19][P:20](=[O:27])([O:24][CH2:25][CH3:26])[O:21][CH2:22][CH3:23].Cl.CN(C)CCCN=C=NCC.Cl>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C@H:13]([CH3:17])[C:14]([O:16][CH2:19][P:20]([O:24][CH2:25][CH3:26])([O:21][CH2:22][CH3:23])=[O:27])=[O:15])[CH:7]=[CH:6]2
Reactant: CCOP(=O)(CO)OCC
Reactant: COc1ccc2cc([C@H](C)C(=O)O)ccc2c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: CCOP(=O)(COC(=O)[C@@H](C)c1ccc2cc(OC)ccc2c1)OCC

Procedure:
A solution of (2S)-2-(6-methoxy(2-naphthyl))propanoic acid (4.8 g, 20.85 mmol), diethyl (hydroxymethyl)phosphonate (3.76 g, 22.36 mmol), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (4.29 g, 22.38 mmol) and 4-(dimethylamino)pyridine (catalytic amount) in CH2Cl2 (125 mL) were stirred at room temperature for 2 hours. The reaction was taken up with 0.3 N HCl (150 mL) and extracted with CH2Cl2 (3×50 mL). The combined extracts were washed with water (2×50 mL), dried over Na2SO4, and evaporated under reduced pressure. The product was purified by silica gel column chromatography eluting with 2:1 EtOAc:Hex to obtained the title compound as a viscous oil, 5.23 g (66%). 1H NMR (300 MHz, CDCl3) δ 7.70-7.68 (mult, 3H), 7.43-7.37 (mult, 1H), 7.15-7.09 (mult, 2H), 4.38 (d, JH-P=8.6 Hz, 2H), 4.05-3.85 (mult, 5H), 3.95 (s, 3H), 1.60 (d, J=7.2 Hz, 3H), 1.25-1.1 (mult, 6H); 13C NMR (75 MHz, CDCl3) δ 173.5 (d, JC-P=7.9 Hz), 157.7, 134.9, 133.7, 129.1, 128.8, 127.1, 126.1, 119.0, 105.5, 62.71, 62.62, 62.61, 62.52, 57.1 (d, JC-P=167.0 Hz), 55.2, 45.1, 18.3, 16.20, 16.18, 16.12, 16.11; mass spectrum (API-TIS) m/z 381 (M+H). Anal Calcd for C19H25O6P: C, 60.0; H, 6.62. Found: C, 59.83; H, 6.41.
Reaction SMILES: [N+:1]([C:4]1[O:8][C:7]([C:9]([OH:11])=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[CH:42]1[C:54]2[NH:53][C:52]3[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=3)[C:46]=2[C:45]([O:55][CH2:56][CH:57]([OH:65])[CH2:58][N:59]2[CH2:64][CH2:63][NH:62][CH2:61][CH2:60]2)=[CH:44][CH:43]=1>CN(C=O)C.C(Cl)Cl>[CH:42]1[C:54]2[NH:53][C:52]3[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=3)[C:46]=2[C:45]([O:55][CH2:56][CH:57]([OH:65])[CH2:58][N:59]2[CH2:64][CH2:63][N:62]([C:9]([C:7]3[O:8][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=3)=[O:11])[CH2:61][CH2:60]2)=[CH:44][CH:43]=1
Reactant: OC(COc1cccc2[nH]c3ccccc3c12)CN1CCNCC1
Reactant: O=C(O)c1ccc([N+](=O)[O-])o1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(c1ccc([N+](=O)[O-])o1)N1CCN(CC(O)COc2cccc3[nH]c4ccccc4c23)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 51 %

Procedure:
To a solution of 5-Nitrofuroic acid (1.56 g, 9.9 mmol) in DMF (30 mL) was added DIPEA (4.3 mL, 24.8 mmol), EDCI (3.18 g, 16.5 mmol), HOBt (0.44 g, 3.3 mmol) followed by the 1-(9H-carbazol-4-yloxy)-3-piperazin-1-ylpropan-2-ol (2.7 g, 8.3 mmol, prepared following the procedure described above in step 11, example 26). The reaction mixture was stirred at room temperature for 12 hours and was diluted with DCM (100 mL), washed with water and brine solution. The organic layer was dried on anhydrous Na2SO4, concentrated and purified by silica gel column chromatography, using hexane/EtOAc (4:6) to afford the title compound as yellow colored solid (2.0 g, 51% yield) with m.p: 178-181° C. 1H NMR (400 MHz, DMSO): δ 2.30-2.60 (m, 4H), 2.67-2.69 (m, 2H), 3.63-3.69 (m, 4H), 4.13-4.21 (m, 3H), 5.08 (s, 1H), 6.69 (d, 1H, J=8.0 Hz), 7.06 (d, 1H, J=8.0 Hz), 7.14 (t, 1H, J=8.0 Hz), 7.24-7.36 (m, 3H), 7.44 (d, 1H, J=8.0 Hz), 7.66 (d, 1H, J=4.0 Hz), 8.22 (d, 1H, 8.0 Hz), and 11.25 (s, 1H). MS m/z: 464.8 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[C:5]([CH3:12])[S:4][C:3]=1C(O)=O.Cl>CC(O)=O>[Cl:1][C:2]1[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[C:5]([CH3:12])[S:4][CH:3]=1
Reactant: CCOC(=O)c1c(C)sc(C(=O)O)c1Cl
Agent: Cl
Solvent: CC(=O)O
Product: CCOC(=O)c1c(Cl)csc1C
Temperature: 25 °C

Procedure:
To a stirred solution of 3-chloro-4-(ethoxycarbonyl)-5-methylthiophene-2-carboxylic acid (F-5) (7.79 g, 31.3 mmol, 1.0 eq) in AcOH (150 mL) at RT, HgO (7.46 g, 34.4 mmol, 1.1 eq) is added and the resulting mixture is stirred at reflux for 1 h. The reaction mixture is cooled to 50° C.-60° C. and then aqueous HCl (750 mL, 2.4 M, 1.8 mol) is added. The resulting mixture is stirred at reflux for an additional 1 h. The mixture is allowed to cool to RT and extracted with methyl text-butyl ether (3×200 mL). The combined organic layers are washed with sat. NaHCO3 solution (3×200 mL), H2O (200 mL) and brine H2O (200 mL) sequentially. The organic layer is dried over anhydrous Na2SO4 and filtered. The filtrate is concentrated in vacuo and the residue is purified by flash column chromatography on silica gel (2% ethyl acetate-petroether) to afford the product, ethyl 4-chloro-2-methylthiophene-3-carboxylate (F-6).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][N:9]=[CH:10][C:3]=12.[H-].[Na+].[C:13](Cl)([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CN(C)C=O>[I:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([C:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[N:9]=[CH:10][C:3]=12
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Ic1ccnc2[nH]ncc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Ic1ccnc2c1cnn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 5 °C
Reaction time: 2 h
Yield: 46 %

Procedure:
4-iodo-1H-pyrazolo[3,4-b]pyridine (15 g, 61.22 mmol) was dissolved in dimethylformamide (300 mL) and the solution was cooled down in an ice bath to 5° C. Sodium hydride (60%, 2.938 g, 73.46 mmol) was added portionwise and left to stir at this temperature for 2 hours. After this time a solution of trityl chloride (18.77 g, 67.34 mmol) in dimethylformamide (150 mL) was added dropwise over 30 minutes. After an additional 2 hours of stirring, the solvent was removed by evaporation, and the residue was partitioned between ethyl acetate and saturated bicarbonate (2×100 ml). The organic layer was further washed with brine (100 ml), dried over magnesium sulfate and concentrated in vacuo to give a brown oil. This residue was purified on silica gel by flash column chromatography to afford the title compound as a white solid (less polar fraction: 2-regioisomer, 13.71 g, 46% yield; more polar fraction: 3-regioisomer, pale yellow solid, 8.06 g, 27% yield).
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][CH2:11][N:12]1[CH2:17][CH2:16][N:15]([CH2:18][C:19]([O:21][CH:22]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:20])[C:14](=[O:35])[C:13]1=[O:36])=O)(C)(C)C.[ClH:37]>C(OCC)(=O)C.O1CCOCC1>[ClH:37].[NH2:8][CH2:9][CH2:10][CH2:11][N:12]1[CH2:17][CH2:16][N:15]([CH2:18][C:19]([O:21][CH:22]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[O:20])[C:14](=[O:35])[C:13]1=[O:36]
Reactant: CC(C)(C)OC(=O)NCCCN1CCN(CC(=O)OC(c2ccccc2)c2ccccc2)C(=O)C1=O
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: NCCCN1CCN(CC(=O)OC(c2ccccc2)c2ccccc2)C(=O)C1=O

Procedure:
In 3 ml of ethyl acetate was dissolved 0.50 g of diphenylmethyl [4-[3-(tert-butoxycarbonylamino)-propyl]-2,3-dioxopiperazin-1-yl]acetate, followed by adding thereto 3.3 ml of a 1.5N solution of hydrochloric acid in dioxane, and the resulting mixture was stirred at room temperature for 3 hours. After completion of the reaction, the solvent was distilled off under reduced pressure to obtain 0.43 g of diphenylmethyl [4-(3-aminopropyl)-2,3-dioxopiperazin-1-yl]acetate hydrochloride as a yellow oil.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]([CH:15]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH3:28])[CH:22]=1)[C:16]([O:18][CH2:19][CH3:20])=[O:17])#[N:14].Br[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>O1CCCC1>[C:13]([C:15]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([O:27][CH3:28])[CH:22]=1)([CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:16]([O:18][CH2:19][CH3:20])=[O:17])#[N:14]
Reactant: CCOC(=O)C(C#N)c1cccc(OC)c1
Reactant: BrCc1ccccc1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCOC(=O)C(C#N)(Cc1ccccc1)c1cccc(OC)c1
Temperature: -40 °C
Reaction time: 1 h

Procedure:
To a solution of diisopropylamine (7.80 ml, 54.7 mmol) in 100 ml dry tetrahydrofuran at −78° C. was added n-butyl lithium (34.2 ml, 54.7 mmol) and stirred for 1 h while the reaction mixture was allowed to warm up to −40° C. A solution of ethyl 2-cyano-2-(3-methoxyphenyl)acetate (10 g, 45.6 mmol) in 100 ml dry tetrahydrofuran was added and the mixture stirred for 30 min. Then (bromomethyl)benzene (8.13 ml, 68.4 mmol) was added and the reaction was stirred over night. The solvent was evaporated and the residue dissolved in ethyl acetate, which was washed with 10% citric acid, water and brine. The combined organic layers were dried over sodium bicarbonate, filtered and the solvent evaporated to obtain a yellow-orange oil. Purification on 120 g SiO2 using 20% ethyl acetate in cyclohexene afforded a clear colourless oil m=9.4 g (66.6%).
Reaction SMILES: [N:1]1[C:6]2[C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[CH2:9][CH2:10][CH2:11][C:5]=2[C:4](=[O:16])[NH:3][CH:2]=1.[C:17]1([CH3:27])[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1.C(N(CC)CC)C>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:27][C:17]1[CH:22]=[CH:21][C:20]([S:23]([O:16][C:4]2[C:5]3[CH2:11][CH2:10][CH2:9][C:8]4[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=4[C:6]=3[N:1]=[CH:2][N:3]=2)(=[O:25])=[O:24])=[CH:19][CH:18]=1
Reactant: O=c1[nH]cnc2c1CCCc1ccccc1-2
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)Oc2ncnc3c2CCCc2ccccc2-3)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
The product from Example 118B (154 mg, 0.72 mmol), p-toluenesulfonyl chloride (278 mg, 1.44 mmol), DMAP (17 mg, 0.14 mmol) in CH2Cl2 (20 mL) was treated with triethylamine (0.25 mL, 1.8 mmol) and stirred at room temperature for 16 hours. The mixture was concentrated under reduced pressure and the residue was chromatographed on silica gel eluting with 40% EtOAc/hexanes to provide the title compound. 1H NMR (CDCl3) δ 2.18-2.40 (m, 4H), 2.48 (d, 3H), 2.51-2.58 (m, 2H), 7.25-7.29 (m, 1H), 7.35-7.45 (m, 4H), 7.66-7.73 (m, J=17.63 Hz, 1H), 8.07 (dd, J=15.60, 8.48 Hz, 2H), 8.85 (d, J=8.48 Hz, 1H). MS (M+H)+ m/z 367
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:4]=[C:5]([CH:24]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:26]=1)[CH2:6][O:7][CH2:8][C:9]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:16][CH2:15][CH2:14][NH:13][C:12](=O)[CH2:11][CH2:10]1.B.C1COCC1.CO.Cl>C1COCC1>[F:31][C:2]([F:1])([F:32])[C:3]1[CH:4]=[C:5]([CH:24]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:26]=1)[CH2:6][O:7][CH2:8][C:9]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:10][CH2:11][CH2:12][NH:13][CH2:14][CH2:15][CH2:16]1
Reactant: O=C1CCC(COCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)(c2ccccc2)CCCN1
Agent: B
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: FC(F)(F)c1cc(COCC2(c3ccccc3)CCCNCCC2)cc(C(F)(F)F)c1
Temperature: 65 °C

Procedure:
To a solution of 5-((3,5-bis(trifluoromethyl)benzyloxy)methyl)-5-phenylazocan-2-one (16 mg) in THF (0.10 mL) at room temperature was added borane-THF complex (1.50 M solution in THF, 93 μL) and the resulting solution was heated at 65° C. in a sealed vial for 3 h. The solution was cooled to room temperature, and methanol (0.10 mL) was added slowly followed by 1N hydrochloric acid (0.10 mL), and the reaction mixture was heated at 65° C. for 2 h. The solvents were removed in vacuo, dichloromethane and 1N sodium hydroxide were added, and the aqueous layer was extracted with dichloromethane. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was evaporated in vacuo to give the title compound as an oil. 1H NMR (400 MHz, CDCl3) δ 1.57 (4H, m), 1.87 (1H, broad, s), 2.09 (4H, m), 2.72 (2H, m), 2.88 (2H, m), 3.43 (2H, s), 4.41 (2H, s), 7.21 (1H, m), 7.39 (4H, m), 7.54 (2H, s), and 7.21 (1H, s). HPLC retention time (1.87 min, column: 4.6×50 mm XTERRA C18 S5, flow rate: 5 mL/min, gradient: 0-100% MeOH/H2O 0.1% TFA over 2 min). MS: 446 (MH+).
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][C:6]1[CH:14]=[CH:13][C:9]([C:10](O)=[O:11])=[CH:8][CH:7]=1)[CH3:2].S(Cl)([Cl:17])=O.N1C=CC=CC=1>C1(C)C=CC=CC=1>[CH2:1]([O:3][CH2:4][CH2:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([Cl:17])=[O:11])=[CH:8][CH:7]=1)[CH3:2]
Reactant: CCOCCc1ccc(C(=O)O)cc1
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CCOCCc1ccc(C(=O)Cl)cc1

Procedure:
4-(Ethoxyethyl)benzoic acid (1.4 g, 7.2 mmol) was mixed with thionyl chloride (1.3 g, 10.8 mmol), pyridine (0.1 ml) and toluene (4 ml), followed by reacting them at 80° C. for 2 hours, distilling superfluous thionyl chloride and toluene under reduced pressure, to obtain raw 4-(ethoxy-ethyl)benzoyl chloride.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[C:5]([C:13]([OH:15])=O)[CH:4]=[N:3]1.C(Cl)(=O)C(Cl)=O.CN(C)C=O.[NH2:27][C:28]1[CH:29]=[C:30]([CH:49]=[CH:50][CH:51]=1)[O:31][C:32]1[CH:46]=[CH:45][C:35]2[N:36]=[C:37]([NH:39][C:40]([CH:42]3[CH2:44][CH2:43]3)=[O:41])[S:38][C:34]=2[C:33]=1[C:47]#[N:48]>O1CCCC1.C(OCC)(=O)C>[C:47]([C:33]1[C:34]2[S:38][C:37]([NH:39][C:40]([CH:42]3[CH2:43][CH2:44]3)=[O:41])=[N:36][C:35]=2[CH:45]=[CH:46][C:32]=1[O:31][C:30]1[CH:29]=[C:28]([NH:27][C:13]([C:5]2[CH:4]=[N:3][N:2]([CH3:1])[C:6]=2[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:15])[CH:51]=[CH:50][CH:49]=1)#[N:48]
Reactant: Cn1ncc(C(=O)O)c1-c1ccccc1
Reactant: N#Cc1c(Oc2cccc(N)c2)ccc2nc(NC(=O)C3CC3)sc12
Agent: O=C(Cl)C(=O)Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Cn1ncc(C(=O)Nc2cccc(Oc3ccc4nc(NC(=O)C5CC5)sc4c3C#N)c2)c1-c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.3 %

Procedure:
To a solution of 1-methyl-5-phenyl-1H-pyrazole-4-carboxylic acid (55 mg, 0.271 mmol) in tetrahydrofuran (10 mL) were added oxalyl chloride (58 μL, 0.676 mmol) and N,N-dimethylformamide (20 μL), and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in N,N-dimethylacetamide (2 mL). N-[6-(3-Aminophenoxy)-7-cyano-1,3-benzothiazol-2-yl]cyclopropanecarboxamide (80 mg, 0.228 mmol) produced in Example 3(vi) was added to the solution, and the mixture was stirred at room temperature for 12 hr. The reaction mixture was diluted with ethyl acetate (25 mL), washed successively with 5% aqueous sodium hydrogen carbonate solution (15 mL) and saturated brine (15 mL), and dried over anhydrous sodium sulfate. Insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/n-hexane=40/60→100/0), and the obtained solution was concentrated under reduced pressure. The residue was recrystallized from ethyl acetate/n-hexane to give the title compound (82 mg, 67%) as a white powder.
Reaction SMILES: N1C=CC=CC=1.[C:7](Cl)(=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH3:16][O:17][C:18](=[O:41])[CH:19]1[CH:24]=[C:23]([N:25]2[CH:29]=[CH:28][CH:27]=[CH:26]2)[C:22]([S:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[C:21]([NH2:37])[C:20]1=[S:38](=[O:40])=[O:39]>CC(C)=O.O1CCOCC1.C(Cl)Cl>[CH3:16][O:17][C:18](=[O:41])[CH:19]1[CH:24]=[C:23]([N:25]2[CH:26]=[CH:27][CH:28]=[CH:29]2)[C:22]([S:30][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)=[C:21]([NH:37][C:7](=[O:14])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:20]1=[S:38](=[O:40])=[O:39]
Reactant: COC(=O)C1C=C(n2cccc2)C(Sc2ccccc2)=C(N)C1=S(=O)=O
Reactant: O=C(Cl)c1ccccc1
Solvent: CC(C)=O
Solvent: C1COCCO1
Solvent: ClCCl
Product: COC(=O)C1C=C(n2cccc2)C(Sc2ccccc2)=C(NC(=O)c2ccccc2)C1=S(=O)=O
Temperature: 40 °C
Yield: 59 %

Procedure:
1.4 ml of pyridine, and a solution of 7.2 g of benzoyl chloride in 30 ml of acetone, are added to 5 g of 3-amino-4-phenylthio-5-pyrrol-1-yl-sulfonylbenzoic acid methyl ester, dissolved in 25 ml of anhydrous dioxane, and the mixture is stirred at room temperature and subsequently at 40° C. The solvent is stripped off under reduced pressure, the residue is taken up in methylene chloride and the solution is washed with dilute sodium bicarbonate solution. After drying the solution over sodium sulfate, the solvent is stripped off on a rotary evaporator and the residue is recrystallized from methanol/methylene chloride. 3-Benzoylamino-4-phenylthio-5-pyrrol-1-yl-sulfonylbenzoic acid methyl ester of melting point 210°-211° C. is obtained. Yield: 59%.
Reaction SMILES: [ClH:1].O1CCOCC1.[Br:8][C:9]1[S:13][C:12]([C:14]([N:16]2[CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][CH:17]2[CH2:29][O:30][C:31]2[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=2)=[O:15])=[CH:11][CH:10]=1>CO>[ClH:1].[ClH:1].[Br:8][C:9]1[S:13][C:12]([C:14]([N:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH:17]2[CH2:29][O:30][C:31]2[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=2)=[O:15])=[CH:11][CH:10]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccc(Br)s2)C(COc2cccnc2)C1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: O=C(c1ccc(Br)s1)N1CCNCC1COc1cccnc1
Reaction time: 1 h
Yield: 59 %

Procedure:
4 M HCl in 1,4-dioxane (6 mL, 24 mmol) was added to a solution of tert-butyl 4-(5-bromothiophene-2-carbonyl)-3-((pyridin-3-yloxy)methyl)piperazine-1-carboxylate (192.6 mg, 0.399 mmol) in MeOH (1 mL). After 1 h, the reaction mixture was concentrated under reduced pressure and purified by HPLC (5 to 50% MeCN/0.1% TFA in H2O/0.1% TFA gradient). The desired chromatography fractions were concentrated under reduced pressure, dissolved in MeOH (1 mL), and treated with 4 M HCl in 1,4-dioxane (6 mL). This was concentrated under reduced pressure, yielding 108 mg (59%) of the desired product as a white solid. LC-MS: RT=4.16 min, [M+H]+=382.0.
Reaction SMILES: O.[CH3:2][N:3]1[C:11](=[O:12])[C:9](=O)[C:7](=[O:8])[N:6]([CH3:13])[C:4]1=[O:5].S(=O)(=O)(O)O.[CH:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>[Hg]>[CH3:13][N:6]1[C:7](=[O:8])[C:9]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:11](=[O:12])[N:3]([CH3:2])[C:4]1=[O:5]
Reactant: c1ccccc1
Reactant: CN1C(=O)C(=O)C(=O)N(C)C1=O
Agent: O=S(=O)(O)O
Agent: [Hg]
Solvent: O
Product: CN1C(=O)N(C)C(=O)C(c2ccccc2)(c2ccccc2)C1=O

Procedure:
In a 500 cc. 3-necked flask fitted with a reflux condenser, a mercury seal stirrer and a thermometer in a well, were placed 18 g. of 1,3-dimethylalloxan monohydrate and 60 g. of sulfuric acid, sp. gr. 1.84. Then 75 cc. of benzene were added through the reflux condenser and the mixture heated in an oil-bath, with stirring, for four and one-half hours at 75°-80°. After this time the reaction mixture was cooled, most of the benzene layer decanted, and the sirupy sulfuric acid layer poured into 150 cc. of cold water. The precipitated material was filtered and washed in a beaker with 100 cc. of water and refiltered. After drying in a vacuum this material was chromatographed on silica to furnish the pure product.