Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:17]([O:20][CH2:21][CH2:22][NH2:23])[CH2:18][CH3:19]>>[C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]([NH:23][CH2:22][CH2:21][O:20][CH2:17][CH2:18][CH3:19])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCCOCCN
Reactant: O=C(Cl)C(c1ccccc1)c1ccccc1
Product: CCCOCCNC(=O)C(c1ccccc1)c1ccccc1

Procedure:
The title compound, white solid, m.p. 77.8-78.9° C. and MS: m/e=297 (M+) was prepared in accordance with the general method of example 1 from diphenylacetyl chloride and 2-propoxy-ethylamine.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][N:7]1[C:19]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:12]=[C:11]([NH2:20])[C:10]=2[N:9]=[C:8]1[CH2:21][O:22][CH2:23][CH3:24].[CH:25]1([N:31]=[C:32]=[O:33])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>C(Cl)Cl>[NH2:20][C:11]1[C:10]2[N:9]=[C:8]([CH2:21][O:22][CH2:23][CH3:24])[N:7]([CH2:6][CH2:5][O:4][CH2:3][CH2:2][NH:1][C:32]([NH:31][CH:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)=[O:33])[C:19]=2[C:18]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N:12]=1
Reactant: CCOCc1nc2c(N)nc3ccccc3c2n1CCOCCN
Reactant: O=C=NC1CCCCC1
Solvent: ClCCl
Product: CCOCc1nc2c(N)nc3ccccc3c2n1CCOCCNC(=O)NC1CCCCC1
Reaction time: 0.5 h
Yield: 29.5 %

Procedure:
A solution of the compound of Example 47, 1-[2-(2-aminoethoxy)ethyl]-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-4-amine (980 mg, 2.98 mmol) in 20 mL of CH2Cl2 was chilled in an ice water bath. With vigorous stirring, the solution was treated with cyclohexyl isocyanate (0.400 mL, 3.13 mmol). After 30 min, the reaction was concentrated to yield a yellow foam. Purification by column chromatography (SiO2, 95:5:0.5 CHCl3:MeOH:NH4OH) followed by recrystallization from acetonitrile gave 400 mg of N-(2-{2-[4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]ethoxy}ethyl)-N′-cyclohexylurea as an off white solid.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3](=[O:10])[NH:2]1.[CH2:11]([N:23]=[C:24]=[O:25])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]>>[CH2:11]([NH:23][C:24]([N:2]1[C:3](=[O:10])[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[S:1]1)=[O:25])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCCCCCCCCN=C=O
Reactant: O=c1[nH]sc2ccccc12
Product: CCCCCCCCCCCCNC(=O)n1sc2ccccc2c1=O

Procedure:
Following the synthetic procedure of 6a as described in Example 1, compound 6g (78% yield) was synthesized from benzo[d]isothiazol-3-one and dodecyl isocyanate as a white solid. mp 66-67° C.; IR(CHCl3) 3279, 1709, 1660, 1536 cm−1; 1H-NMR (CDCl3) δ0.87 (t, J=6.8 Hz, 3H), 1.20-1.39 (m, 18H), 1.59-1.66 (m, 2H), 3.40-3.46 (m, 2H), 7.42 (t, J=7.6 Hz, 1H), 7.57 (d, J=7.6 Hz, 1H), 7.69 (t, J=7.6 Hz, 1H), 8.01 (d, J=7.6 Hz, 1H), 8.87 (br s, 1H); ESIMS m/e 363 (M++1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10](B3OC(C)(C)C(C)(C)O3)=[CH:9][N:8](S(C3C=CC(C)=CC=3)(=O)=O)[C:5]2=[N:6][CH:7]=1.Cl[C:31]1[N:36]=[C:35]([NH:37][CH2:38][C@H:39]2[CH2:44][CH2:43][CH2:42][N:41]([C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[CH2:40]2)[C:34]([F:52])=[CH:33][N:32]=1.C([O-])([O-])=O.[K+].[K+]>C1COCC1.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:31]3[N:36]=[C:35]([NH:37][CH2:38][C@H:39]4[CH2:44][CH2:43][CH2:42][N:41]([C:45]([O:47][C:48]([CH3:50])([CH3:49])[CH3:51])=[O:46])[CH2:40]4)[C:34]([F:52])=[CH:33][N:32]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(B3OC(C)(C)C(C)(C)O3)c3cc(Cl)cnc32)cc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](CNc2nc(Cl)ncc2F)C1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC[C@H](CNc2nc(-c3c[nH]c4ncc(Cl)cc34)ncc2F)C1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a degassed solution of 5-chloro-1-(p-tolylsulfonyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrrolo[2,3-b]pyridine (0.71 g, 1.65 mmol), (R)-tert-butyl 3-((2-chloro-5-fluoropyrimidin-4-ylamino)methyl)-piperidine-1-carboxylate, 11a, (1.19 g, 3.60 mmol) and aqueous K2CO3 (2.48 mL of 2 M solution, 4.97 mmol) in THF (30 mL) was added bis(tri-tert-butylphosphine)palladium(0) (0.17 g, 0.33 mmol). The reaction mixture was degassed for an additional 15 min. The mixture was stirred at room temperature for 4 hours, concentrated in vacuo, and the resulting crude residue was purified by silica gel chromatography (10%-80% EtOAc/hexanes) to afford the desired product, 11b.
Reaction SMILES: [CH:1]([C:4]1[C:9](S(C2C=CC(C)=CC=2)(=O)=O)=[CH:8][C:7]([C:20]2[N:21]=[CH:22][S:23][CH:24]=2)=[C:6]([O:25][CH3:26])[CH:5]=1)([CH3:3])[CH3:2].C([O-])([O-])=[O:28].[K+].[K+]>CO>[CH:1]([C:4]1[CH:5]=[C:6]([O:25][CH3:26])[C:7]([C:20]2[N:21]=[CH:22][S:23][CH:24]=2)=[CH:8][C:9]=1[OH:28])([CH3:3])[CH3:2]
Reactant: COc1cc(C(C)C)c(S(=O)(=O)c2ccc(C)cc2)cc1-c1cscn1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: COc1cc(C(C)C)c(O)cc1-c1cscn1

Procedure:
A mixture of 4-[4-Isopropyl-2-methoxy-5-(toluene-4-sulfonyl)-phenyl]-thiazole (1.0 g, 2.27 mmol) and K2CO3 (1.6 g, 11.34 mmol) in anhydrous MeOH (10 ml) was refluxed for 8 hrs. Solvent was removed in vacuo and the residue was partitioned between methylene chloride and water. The combined organic extract was dried over Na2SO4, filtered, and concentrated to give 2-Isopropyl-4-methoxy-5-thiazol-4-yl-phenol.
Reaction SMILES: Cl[CH2:2][CH:3]([CH3:19])[CH:4]([C:6]1[CH:18]=[CH:17][C:9]([CH2:10][C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)=[CH:8][CH:7]=1)[OH:5].[C:20]([O-:23])(=[O:22])[CH3:21].[Na+].[Cl-].[Na+].C(OCC)(=O)C>CN(C)C=O>[C:20]([O:23][CH2:2][CH:3]([CH3:19])[CH:4]([C:6]1[CH:18]=[CH:17][C:9]([CH2:10][C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)=[CH:8][CH:7]=1)[OH:5])(=[O:22])[CH3:21]
Reactant: CC(CCl)C(O)c1ccc(Cc2cccnc2)cc1
Reactant: CC(=O)[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)OCC(C)C(O)c1ccc(Cc2cccnc2)cc1
Yield: 36.7 %

Procedure:
In 11 ml of N,N-dimethylformamide was dissolved 2.29 g of 3-[p-(3-chloro-1-hydroxy-2-methylpropyl)benzyl]pyridine, and to the resulting solution was added 1.36 g of sodium acetate, after which the resulting mixture was subjected to reaction under reflux for 2 hours. The solvent was removed by distillation under reduced pressure, and to the residue thus obtained were added 20 ml of a saturated aqueous sodium chloride solution and 20 ml of ethyl acetate. The organic layer was separated, washed with 10 ml of water, and then dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, and the residue thus obtained was purified by a column chromatography [Wako Silica Gel C-200, eluant: chloroform] to obtain 910 mg (yield 36.7%) of colorless, oily 3-[p-(3-acetoxy-1-hydroxy-2-methylpropyl)benzyl]pyridine.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH:10][C:11]([NH:13][C:14]2[N:19]=[CH:18][C:17]3[CH:20]=[N:21][N:22](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[C:16]=3[CH:15]=2)=[O:12])[CH3:9])=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O.C([SiH](CC)CC)C>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([NH:10][C:11]([NH:13][C:14]2[N:19]=[CH:18][C:17]3[CH:20]=[N:21][NH:22][C:16]=3[CH:15]=2)=[O:12])[CH3:9])=[CH:4][CH:3]=1
Reactant: C[C@@H](NC(=O)Nc1cc2c(cn1)cnn2C(c1ccccc1)(c1ccccc1)c1ccccc1)c1ccc(F)cc1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H](NC(=O)Nc1cc2[nH]ncc2cn1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 11.7 %

Procedure:
A solution of (R)-1-(1-(4-fluorophenyl)ethyl)-3-(1-trityl-1H-pyrazolo[4,3-c]pyridin-6-yl)urea (157 mg, 0.291 mmol) in DCM (0.8 mL) was treated with TFA (0.2 mL) and triethylsilane (0.1 mL). The mixture was stirred at room temperature for 1.5 h. Additional TFA (0.2 mL) and triethylsilane (0.1 mL) were added and the mixture was stirred for 1.5 h and then evaporated in vacuo to afford a residue, which was purified by MS-directed reverse phase preparative-HPLC (C-18 stationary phase, eluting with a H2O/MeCN gradient with 0.1% TFA), to yield (R)-1-(1-(4-fluorophenyl)ethyl)-3-(1H-pyrazolo[4,3-c]pyridin-6-yl)urea (14 mg, 0.034 mmol, 12%). MS ESI calc'd. for C15H15FN5O [M+H]+ 300, found 300. 1H NMR (600 MHz, DMSO-d6) δ 9.22 (s, 1H), 8.15 (s, 1H), 7.92 (s, 1H), 7.32 (dd, J=8.5, 5.6 Hz, 2H), 7.12 (t, J=8.9 Hz, 2H), 7.07 (s, 1H), 6.78 (s, 1H), 4.79 (m, 1H), 1.35 (d, J=7.0 Hz, 3H).
Reaction SMILES: [OH:1][C:2]1[C:16]([O:17][C:18]2[CH:19]=[N:20][C:21]([S:24]([CH2:27][CH3:28])(=[O:26])=[O:25])=[CH:22][CH:23]=2)=[CH:15][C:5]2[NH:6][C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=3)=[N:8][C:4]=2[CH:3]=1.[F:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]#[N:37])[C:31]=1F>>[F:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]#[N:37])[C:31]=1[O:1][C:2]1[C:16]([O:17][C:18]2[CH:19]=[N:20][C:21]([S:24]([CH2:27][CH3:28])(=[O:25])=[O:26])=[CH:22][CH:23]=2)=[CH:15][C:5]2[NH:6][C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=3)=[N:8][C:4]=2[CH:3]=1
Reactant: CCS(=O)(=O)c1ccc(Oc2cc3[nH]c(-c4ccccn4)nc3cc2O)cn1
Reactant: N#Cc1cccc(F)c1F
Product: CCS(=O)(=O)c1ccc(Oc2cc3[nH]c(-c4ccccn4)nc3cc2Oc2c(F)cccc2C#N)cn1

Procedure:
The entitled compound was obtained as a pale green solid in the same method as in Example 251 or in accordance with the method or by combining it with an ordinary method but using 5-hydroxy-2-pyridin-2-yl-6-(6-ethanesulfonyl-pyridin-3-yloxy)-1H-benzimidazole obtained in Example 397 and 1,2-difluoro-3-cyano-benzene.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].S(=O)(=O)(O)O.O.[C:11]1([C:17]23[CH2:25][CH:21]4[CH2:22][CH:23]([CH2:24]2)[C:19]([C:26](=[O:28])[CH3:27])([CH2:20]4)[CH2:18]3)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>[N+](C)([O-])=O>[N+:1]([C:14]1[CH:15]=[CH:16][C:11]([C:17]23[CH2:25][CH:21]4[CH2:22][CH:23]([CH2:24]2)[C:19]([C:26](=[O:28])[CH3:27])([CH2:20]4)[CH2:18]3)=[CH:12][CH:13]=1)([O-:4])=[O:2]
Reactant: O=[N+]([O-])O
Reactant: CC(=O)C12CC3CC1CC(c1ccccc1)(C3)C2
Agent: O=S(=O)(O)O
Solvent: O
Solvent: C[N+](=O)[O-]
Product: CC(=O)C12CC3CC1CC(c1ccc([N+](=O)[O-])cc1)(C3)C2
Reaction time: 2 h
Yield: 87.6 %

Procedure:
Nitration mixture (1 mL) [the nitration mixture was prepared by mixing of 10.5 g of nitric acid (d 1.375 at 22° C.), 180.0 g of conc. sulphuric acid (d 1.84 at 22° C.), and 16 g of H2O) was added drop wise to a stirred solution of 1-(1-phenyltricyclo[3.3.1.03,7]non-3-yl)ethanone (240 mg, 1.0 mmol) obtained in preparation 1, in nitromethane (4 mL) at 0° C. After stirring for 2 h, the reaction mixture was poured into ice cold water and extracted with EtOAc, the combined organic layers were washed with brine and dried over Na2SO4. The solvent was evaporated under reduced pressure and the crude product was purified by column chromatography to obtain 1-[1-(4-nitrophenyl)tricyclo[3.3.1.03,7]non-3-yl]ethanone as an off-white solid (250 mg) in 88% yield. M.R: 61.3-66.6° C. m/z (M+1) 286; IR cm−1 2953, 1697, 1598, 1519, 1217, 1110, 852, 768. 1H NMR (CDCl3) 300 MHz δ 8.17 (d, J=8.7 Hz, 2H), 7.43 (d, J=8.7 Hz, 2H), 2.87-2.80 (m, 1H), 2.61-2.55 (m, 1H), 2.34-2.26 (m, 1H), 2.23 (s, 3H), 2.13-1.98 (m, 4H), 1.90-1.71 (m, 5H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:14]([CH2:15][CH2:16][C:17]([O:19]CC)=[O:18])[C:13]2[C:22]([N:26]([CH2:29][CH3:30])[CH2:27][CH3:28])=[CH:23][CH:24]=[CH:25][C:12]=2[N:11]=1.[OH-].[Na+].Cl>O1CCCC1.CO>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:14]([CH2:15][CH2:16][C:17]([OH:19])=[O:18])[C:13]2[C:22]([N:26]([CH2:27][CH3:28])[CH2:29][CH3:30])=[CH:23][CH:24]=[CH:25][C:12]=2[N:11]=1
Reactant: CCOC(=O)CCn1c(Nc2ccc(Cl)cc2Cl)nc2cccc(N(CC)CC)c21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCN(CC)c1cccc2nc(Nc3ccc(Cl)cc3Cl)n(CCC(=O)O)c12
Yield: 78 %

Procedure:
To a solution of ethyl 3-[2-[(2,4-dichlorophenyl)amino]-7-(diethylamino)-1H-benzimidazol-1-yl]propanoate (Reference Example 28; 100 mg, 0.223 mmol) in a mixture of tetrahydrofuran (2 mL) and methanol (1 mL) was added 1N sodium hydroxide solution (0.446 mL, 0.446 mmol) at 0° C. After the resultant mixture was stirred at room temperature for 1 hr, the mixture was neutralized with 1N hydrochloric acid and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with ethyl acetate to give the title compound as a solid (73.3 mg, 0.174 mmol, 78%).
Reaction SMILES: [NH2:1][C@H:2]1[C:7]2[CH:8]=[C:9]([C:12]#[N:13])[CH:10]=[CH:11][C:6]=2[O:5][C:4]([CH3:15])([CH3:14])[C@@H:3]1[OH:16].[CH3:17][S:18][C:19](SC)=[N:20][C:21]#[N:22]>N1C=CC=CC=1>[C:21]([N:20]=[C:19]([S:18][CH3:17])[NH:1][C@H:2]1[C:7]2[CH:8]=[C:9]([C:12]#[N:13])[CH:10]=[CH:11][C:6]=2[O:5][C:4]([CH3:14])([CH3:15])[C@@H:3]1[OH:16])#[N:22]
Reactant: CSC(=NC#N)SC
Reactant: CC1(C)Oc2ccc(C#N)cc2[C@H](N)[C@H]1O
Solvent: c1ccncc1
Product: CSC(=NC#N)N[C@H]1c2cc(C#N)ccc2OC(C)(C)[C@@H]1O

Procedure:
A solution of (3R,4S)-4-amino-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-6-carbonitrile (2.40 g) and dimethyl N-cyanoimidodithiocarbonate [(CH2C=C--N--] (1.61 g) in pyridine (12 ml) was stirred at 80° C. for 10 hours, and then concentrated in vacuo. The residue was dissolved in ethyl acetate and washed with 5% aqueous hydrochloric acid, and brine. The organic layer was dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was subjected to column chromatography on silica gel (48 g) and eluted with a mixture of chloroform and methanol (20:1). The fractions containing the object compound were combined and concentrated in vacuo to give (3R,4S)-4-(3-cyano-2-methyl-1-isothioureido)-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-6-carbonitrile (2.17 g).
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[N:15]=[C:14]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[S:13][N:12]=3)[CH:9]=2)[NH:4][CH:3]=1.[H-].[Na+].[CH3:26][C:27]1[CH:32]=[CH:31][C:30]([S:33](Cl)(=[O:35])=[O:34])=[CH:29][CH:28]=1>CN(C=O)C>[I:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[N:15]=[C:14]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:20])([CH3:22])[CH3:21])[S:13][N:12]=3)[CH:9]=2)[N:4]([S:33]([C:30]2[CH:31]=[CH:32][C:27]([CH3:26])=[CH:28][CH:29]=2)(=[O:35])=[O:34])[CH:3]=1
Reactant: CC(C)(C)OC(=O)Nc1nc(-c2ccc3[nH]cc(I)c3c2)ns1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(-c4nsc(NC(=O)OC(C)(C)C)n4)ccc32)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 46.6 %

Procedure:
To a solution of tert-butyl (3-(3-iodo-1H-indol-5-yl)-1,2,4-thiadiazol-5-yl)carbamate (80 mg, 0.18 mmol) in DMF (2.5 mL) at 0° C. was added 60% NaH (80 mg, 0.199 mmol) at 0° C. and the reaction was stirred at RT. After 5 min, the mixture was again cooled to 0° C. and 4-methylbenzene sulfonyl chloride (38 mg, 0.199 mmol) in DMF (2.5 mL) was added dropwise. The reaction was stirred at RT for 1 h, then treated with ice cold water (5 mL) and extracted with EtOAc (10 mL). The aqueous layer was back extracted with EtOAc (10 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated. The crude was purified by silica-gel column Chromatography (eluent: 15% EtOAc in petroleum ether) to give tert-butyl (3-(3-iodo-1-tosyl-1H-indol-5-yl)-1,2,4-thiadiazol-5-yl)carbamate (50 mg, 46.7%) as an off white solid. MS (ESI, pos. ion) m/z: 540.9 (M+1) (carbamic acid mass). 1H NMR (400 MHz, DMSO-d6) δ 12.45 (brs, 1H), 8.22-8.19 (m, 1H), 8.15 (s, 1H), 8.11-8.07 (m, 2H), 7.95 (d, J=8.4 Hz, 2H), 7.41 (d, J=8 Hz, 2H), 2.31 (s, 3H), 1.51 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].CCO[C:12]([C:14]1[C:23](=[O:24])[O:22][C:21]2[C:16](=[CH:17][C:18]3C[CH2:30][CH2:29][N:28]4[C:19]=3[C:20]=2C[CH2:26][CH2:27]4)[CH:15]=1)=O.C1(OC2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1>[CH3:30][CH2:29][N:28]([C:19]1[CH:18]=[CH:17][C:16]2[CH:15]=[C:14]([C:12]3[S:8][C:3]4[C:2](=[CH:7][CH:6]=[CH:5][CH:4]=4)[N:1]=3)[C:23]([O:22][C:21]=2[CH:20]=1)=[O:24])[CH2:27][CH3:26]
Reactant: CCOC(=O)c1cc2cc3c4c(c2oc1=O)CCCN4CCC3
Reactant: Nc1ccccc1S
Solvent: Cc1ccccc1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCN(CC)c1ccc2cc(-c3nc4ccccc4s3)c(=O)oc2c1
Temperature: 25 °C

Procedure:
The diphenyl analog of coumarin 6 was prepared by the thermal condensation of 2-aminothiophenol with the diphenyl analog of coumarin 314. 7.5 g of the diphenyl analog of coumarin 314 prepared according to Example 1, 2.45 g of 2-aminothiophenol, 15 g diphenyl, and 15 g phenyl ether were placed in a 50 ml round bottom flask and taken to reflux for 30 minutes. After cooling to room temperature, 50 ml of toluene was added and the product was isolated by filtration, washed with ether, dried in vacuum, and recrystallized from methylene chloride/ethyl acetate.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:27])[C:9]([C:15]2[CH:16]=[CH:17][C:18]3[O:23][CH2:22][C:21](=[O:24])[N:20]([CH3:25])[C:19]=3[CH:26]=2)([OH:14])[C:10]([F:13])([F:12])[F:11])=[C:4]([Cl:28])[CH:3]=1.[CH3:29][O:30][C:31]1[CH:32]=[C:33](B(O)O)[CH:34]=[CH:35][C:36]=1[C:37]([O:39][CH3:40])=[O:38]>>[CH3:40][O:39][C:37]([C:36]1[CH:35]=[CH:34][C:33]([C:2]2[CH:7]=[CH:6][C:5]([CH:8]([CH3:27])[C:9]([OH:14])([C:15]3[CH:16]=[CH:17][C:18]4[O:23][CH2:22][C:21](=[O:24])[N:20]([CH3:25])[C:19]=4[CH:26]=3)[C:10]([F:13])([F:12])[F:11])=[C:4]([Cl:28])[CH:3]=2)=[CH:32][C:31]=1[O:30][CH3:29])=[O:38]
Reactant: COC(=O)c1ccc(B(O)O)cc1OC
Reactant: CC(c1ccc(Br)cc1Cl)C(O)(c1ccc2c(c1)N(C)C(=O)CO2)C(F)(F)F
Product: COC(=O)c1ccc(-c2ccc(C(C)C(O)(c3ccc4c(c3)N(C)C(=O)CO4)C(F)(F)F)c(Cl)c2)cc1OC

Procedure:
In analogy to Example 17, step 2, 6-[2-(4-bromo-2-chloro-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-4-methyl-4H-benzo[1,4]oxazin-3-one (Example 22, step 3) was reacted with 3-methoxy-4-methoxycarbonylphenylboronic acid to give the title compound as an off-white solid. MS (m/e, ISP neg. ion)=562.2 [M−H+].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[NH:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.Cl[C:17]1[N:22]=[C:21]([CH3:23])[CH:20]=[CH:19][N:18]=1>>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[N:13]([C:17]3[N:22]=[C:21]([CH3:23])[CH:20]=[CH:19][N:18]=3)[CH:14]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Cc1nc(C#Cc2ccnc(Cl)c2)c[nH]1
Reactant: Cc1ccnc(Cl)n1
Product: Cc1ccnc(-n2cc(C#Cc3ccnc(Cl)c3)nc2C)n1

Procedure:
The title compound, MS: m/e=310.4 (M+H+), was prepared in accordance with the general method of example 3 from 2-chloro-4-(2-methyl-1H-imidazol-4-ylethynyl)-pyridine and 2-chloro-4-methyl-pyrimidine.
Reaction SMILES: [I:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[C:4]([OH:10])[CH:3]=1.Cl[CH2:12][C:13]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=1[Cl:22])=[O:14].C([O-])([O-])=O.[K+].[K+]>CN(C)C=O>[Cl:22][C:16]1[CH:17]=[C:18]([Cl:21])[CH:19]=[CH:20][C:15]=1[C:13]([C:12]1[O:10][C:4]2[CH:3]=[C:2]([I:1])[CH:9]=[CH:8][C:5]=2[CH:6]=1)=[O:14]
Reactant: O=Cc1ccc(I)cc1O
Reactant: O=C(CCl)c1ccc(Cl)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(c1cc2ccc(I)cc2o1)c1ccc(Cl)cc1Cl
Reaction time: 48 h

Procedure:
To a solution of 4-iodo-2-hydroxy-benzaldehyde (5.4 g, 22 mmol) and 2-chloro-1-(2,4dichlorophenyl)ethanone (11.2 g, 50.0 mmol) in anhydrous N,N-dimethylformamide (100 mL) was added K2CO3 (12.0 g, 86.9 mmol). The dark brown reaction mixture was stirred at 90 C for 48 h, then poured onto water (150 mL) and extracted with ethyl acetate. The solvent was removed under reduced pressure and the residue was purified by column chromatography, eluting with 50% hexanes in dichloromethane. The desired product was obtained as an orange solid (2.06 g, 23%). 1H-NMR (CDCl3) δ 7.98 (s, 1H), 7.70 (dd, J=8.3, 1.3 Hz, 1H), 7.54-7.21 (m, 5H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:8]([CH2:9][CH2:10][C:11]([O:13]CC)=[O:12])=[CH:7][N:6]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]3[N:26]=[C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([O:33][CH2:34][CH3:35])[N:28]4[CH:36]=3)=[CH:19][CH:18]=2)[N:5]=1)[CH3:2].[OH-].[Na+].O1CCCC1.Cl>C(O)C>[CH2:1]([O:3][C:4]1[C:8]([CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:7][N:6]([CH2:16][C:17]2[CH:18]=[CH:19][C:20]([O:23][CH2:24][C:25]3[N:26]=[C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([O:33][CH2:34][CH3:35])[N:28]4[CH:36]=3)=[CH:21][CH:22]=2)[N:5]=1)[CH3:2]
Reactant: CCOC(=O)CCc1cn(Cc2ccc(OCc3cn4c(OCC)cccc4n3)cc2)nc1OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOc1nn(Cc2ccc(OCc3cn4c(OCC)cccc4n3)cc2)cc1CCC(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 80.6 %

Procedure:
After a mixture of ethyl 3-[3-ethoxy-1-[4-(5-ethoxyimidazo[1,2-a]pyridin-2-ylmethoxy)benzyl]-1H-pyrazol-4-yl]propionate (441 mg), 1N aqueous sodium hydroxide solution (2 ml), tetrahydrofuran (4 ml) and ethanol (4 ml) was stirred at room temperature for 3 hours, 1N hydrochloric acid (2 ml) was added to the mixture, and then the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4) and concentrated. The resulting colorless crystals were collected by filtration to obtain 3-[3-ethoxy-1-[4-(5-ethoxyimidazo[1,2-a]pyridin-2-ylmethoxy)benzyl]-1H-pyrazol-4-yl]propionic acid (335 mg, yield: 81%). This was recrystallized from ethanol-hexane. Melting point: 197–198° C.
Reaction SMILES: [Br:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][NH:7][C:8]2[C:9]([NH2:26])=[CH:10][C:11]([O:14][CH2:15][C:16]3[CH:25]=[CH:24][C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[N:17]=3)=[CH:12][CH:13]=2)=[CH:4][CH:3]=1.[C:29]1(=[O:39])[C@@H:37]2[C@@H:32]([CH2:33][CH2:34][CH2:35][CH2:36]2)[C:31](=O)[O:30]1.Cl>C(#N)C>[Br:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:8]3[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]4[CH:25]=[CH:24][C:23]5[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=5)[N:17]=4)=[CH:10][C:9]=3[N:26]=[C:31]2[C@H:32]2[CH2:33][CH2:34][CH2:35][CH2:36][C@H:37]2[C:29]([OH:39])=[O:30])=[CH:4][CH:3]=1
Reactant: Nc1cc(OCc2ccc3ccccc3n2)ccc1NCc1ccc(Br)cc1
Reactant: O=C1OC(=O)[C@@H]2CCCC[C@H]12
Agent: Cl
Solvent: CC#N
Product: O=C(O)[C@@H]1CCCC[C@@H]1c1nc2cc(OCc3ccc4ccccc4n3)ccc2n1Cc1ccc(Br)cc1
Temperature: 90 °C
Reaction time: 3 h
Yield: 45.3 %

Procedure:
To a 100 mL round-bottomed flask was added N1-(4-bromobenzyl)-4-(quinolin-2-ylmethoxy)benzene-1,2-diamine (1.3 g, 2.9 mmol), cis-hexahydroisobenzofuran-1,3-dione (0.5 g, 2.9 mmol) and acetonitrile (27 mL). The resulting solution was heated to 90° C. After 3 h, the reaction was cooled to RT and HCl (15 mL, 6 N) was added and the mixture was heated to 90° C. for 15 h. The resulting mixture was cooled to RT and concentrated to dryness. The residue was partitioned between water (100 mL) and DCM (100 mL) and the mixture was stirred vigorously while the pH was adjusted to 4-5 using sat. NaHCO3. The organic layer was separated and the aqueous layer was further extracted with DCM (2×100 mL). The combine organic layers were dried with magnesium sulfate, filtered, and concentrated to dryness. The residue was subjected to FCC to give the title compound (750 mg, 44%). MS (ESI): mass calcd. for C31H28BrN3O3, 569.13; m/z found, 570.1 [M+H]+. 1H NMR (500 MHz, CD3OD) δ 8.36 (d, J=8.5, 1H), 8.05 (d, J=8.5, 1H), 7.93 (d, J=8.2, 1H), 7.78 (ddd, J=8.4, 6.9, 1.4, 1H), 7.74 (d, J=8.5, 1H), 7.60 (ddd, J=8.1, 7.0, 1.1, 1H), 7.47-7.41 (m, 2H), 7.29 (d, J=2.3, 1H), 7.19 (d, J=8.8, 1H), 7.05 (d, J=8.5, 2H), 7.01 (dd, J=8.8, 2.4, 1H), 5.53-5.41 (m, 2H), 5.39 (s, 2H), 3.60-3.51 (m, 1H), 2.88-2.76 (m, 1H), 2.43-2.29 (m, 1H), 2.00-1.93 (m, 1H), 1.92-1.69 (m, 4H), 1.52-1.36 (m, 2H).