Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[CH3:15][O:16][C:17]([C:19]([CH3:42])([CH3:41])[CH2:20][C:21]1[CH:26]=[C:25]([CH3:27])[C:24]([C:28]2[NH:29][C:30]3[CH:36]=[C:35]([C:37](O)=[O:38])[CH:34]=[CH:33][C:31]=3[N:32]=2)=[C:23]([CH3:40])[CH:22]=1)=[O:18].[CH3:43][C:44]1[CH:53]=[CH:52][CH:51]=[CH:50][C:45]=1[C:46]([NH:48][NH2:49])=O.CC[N+](S(N=C(OC)[O-])(=O)=O)(CC)CC>CN(C=O)C.CCOC(C)=O>[CH3:15][O:16][C:17](=[O:18])[C:19]([CH3:41])([CH3:42])[CH2:20][C:21]1[CH:22]=[C:23]([CH3:40])[C:24]([C:28]2[NH:29][C:30]3[CH:36]=[C:35]([C:37]4[O:38][C:46]([C:45]5[CH:50]=[CH:51][CH:52]=[CH:53][C:44]=5[CH3:43])=[N:48][N:49]=4)[CH:34]=[CH:33][C:31]=3[N:32]=2)=[C:25]([CH3:27])[CH:26]=1
Reactant: Cc1ccccc1C(=O)NN
Reactant: COC(=O)C(C)(C)Cc1cc(C)c(-c2nc3ccc(C(=O)O)cc3[nH]2)c(C)c1
Agent: CC[N+](CC)(CC)S(=O)(=O)N=C([O-])OC
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)C(C)(C)Cc1cc(C)c(-c2nc3ccc(-c4nnc(-c5ccccc5C)o4)cc3[nH]2)c(C)c1

Procedure:
Add EDC (380 mg, 1.98 mmol) and HOBt (268 mg, 1.98 mmol) to a stirring solution of 2-[4-(2-methoxycarbonyl-2-methyl-propyl)-2,6-dimethyl-phenyl]-3H-benzoimidazole-5-carboxylic acid (626 mg, 1.65 mmol) and 2-methyl-benzoic acid hydrazide (248 mg, 1.65 mmol) in DMF (6 mL) under N2. Upon disappearance of the carboxylic acid by LC/MS, dilute the reaction with EtOAc (60 mL) and extract with water (20 mL) followed by brine (10 mL). Dry the organic phase over Na2SO4 and evaporate the solvent. Dissolve the residue in DMF (6 mL) and add Burgess reagent (1.18 g, 4.95 mmol). Heat the mixture my microwave irradiation to 150° C. for 15 min. Dilute the reaction with EtOAc (100 mL) and extract with water (25 mL). Extract the organic phase with saturated NaHCO3 (2×25 mL) followed by brine (20 mL). Dry the organic phase over Na2SO4 and evaporate the solvent. Purify the residue by silica gel chromatography (10-45% ACN/DCM) to afford the title compound as a yellow oil: (M+H)+ 495.3.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:3]=1.[NH2:18][CH2:19][CH:20]([OH:23])[CH2:21][NH2:22]>>[ClH:1].[NH2:18][CH2:19][CH:20]([OH:23])[CH2:21][NH:22][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:3]=1
Reactant: NCC(O)CN
Reactant: Clc1cc(-c2ccccc2)nc2ccccc12
Product: Cl
Product: NCC(O)CNc1cc(-c2ccccc2)nc2ccccc12

Procedure:
The title compound, m.p. 291-294° C., MS: m/e=294.3 (M+H+), was prepared from 4-chloro-2-phenyl-quinoline and 1,3-diamino-2-propanol.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[CH:12][C:13]1[N:14]=[CH:15][NH:16][CH:17]=1.C[Si]([N:22]=[C:23]=[O:24])(C)C.O1CCC[CH2:26]1>>[NH:1]([C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[C:12]([C:13]1[N:14]=[CH:15][NH:16][CH:17]=1)[CH3:26])[C:23]([NH2:22])=[O:24]
Reactant: C[Si](C)(C)N=C=O
Reactant: C1CCOC1
Reactant: Nc1ccc2c(c1)C(=Cc1c[nH]cn1)C(=O)N2
Product: CC(=C1C(=O)Nc2ccc(NC(N)=O)cc21)c1c[nH]cn1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
5-amino-3-[(imidazol-4-yl)methylene]indolin-2-one (0.3 g, 1.3 mmol) was suspended in tetrahydrofuran (100 mL) and trimethylsilylisocyanate (0.5 mL, 3.75 mmol) was added. The reaction mixture was stirred at ambient temperature for three days. The reaction mixture was concentrated and dissolved in acetonitrile/water/TFA. Soluble solids were collected by filtration, dissolved in DMSO and purified with HPLC to afford 80 mg of 5-ureido-3-[1-(imidazol-4-yl)ethylidene]indolin-2-one; as an orange solid, 1H NMR (400 MHz, DMSO-d6) δ 2.6 (s, 3H), 5.8 (s, 2H), 6.8 (d, 1H), 7.3 (m, 1H), 7.9 (s, 1H), 8.3 (s, 1H), 8.5 (s, 1H), 8.9 (s, 1H), 11.1 (s, 1H) ppm.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]([O:10][CH3:11])=[O:9])[S:5][C:6]=1[Cl:7].[CH3:12][N:13]1[C:17](B2OC(C)(C)C(C)(C)O2)=[C:16]([CH3:27])[CH:15]=[N:14]1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.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:7][C:6]1[S:5][C:4]([C:8]([O:10][CH3:11])=[O:9])=[CH:3][C:2]=1[C:17]1[N:13]([CH3:12])[N:14]=[CH:15][C:16]=1[CH3:27]
Reactant: Cc1cnn(C)c1B1OC(C)(C)C(C)(C)O1
Reactant: COC(=O)c1cc(Br)c(Cl)s1
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: O
Solvent: C1COCCO1
Product: COC(=O)c1cc(-c2c(C)cnn2C)c(Cl)s1
Temperature: 85 °C
Yield: 24.4 %

Procedure:
To a 350 mL sealed flask reactor was added methyl 4-bromo-5-chloro-2-thiophenecarboxylate (409 mg, 1.60 mmol) [prepared according to the procedure of Example 95], 1,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (388 mg, 1.75 mmol) [prepared according to the procedure of Preparation 17], K2CO3 (676 mg, 4.89 mmol) and Pd(PtBu3)2 (32 mg, 0.06 mmol) in 1,4-Dioxane (6 mL) and water (1.5 mL). The reaction was heated at 85° C. for 3 hours. The reaction was partitioned between CHCl3/H2O and the pH of the aqueous layer was adjusted to ˜3 with 6N HCl. The separated organic layer was dried with Na2SO4, adsorbed onto silica and purified via column chromatography (10-65% EtOAc/Hexanes) affording the title compound (106 mg, 0.39 mmol, %); LC-MS (ES) m/z=271 (M+H)+.
Reaction SMILES: [CH:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8]Cl)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[Cl:12][C:13]1[CH:14]=[C:15]([CH2:20][C:21]([O:23]C)=[O:22])[CH:16]=[CH:17][C:18]=1[OH:19]>CO.O>[Cl:12][C:13]1[CH:14]=[C:15]([CH2:20][C:21]([OH:23])=[O:22])[CH:16]=[CH:17][C:18]=1[O:19][CH2:8][C:7]1[CH:10]=[CH:11][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:5][CH:6]=1
Reactant: CC(C)c1ccc(CCl)cc1
Reactant: COC(=O)Cc1ccc(O)c(Cl)c1
Solvent: CO
Solvent: O
Product: CC(C)c1ccc(COc2ccc(CC(=O)O)cc2Cl)cc1

Procedure:
3-chloro-4-(4'-isopropylbenzyloxy) phenylacetic acid was prepared in accordance with the procedure designated (f) above by reacting 4-isopropylbenzyl chloride with methyl 3-chloro-4-hydroxyphenylacetate. The resultant product evidenced a melting point of 146.5°-148° C. in a methanol-water 2:1 mixture.
Reaction SMILES: [CH2:1]([N:8]1[C:20]2[C:19]([O:21][CH3:22])=[CH:18][CH:17]=[C:16]([C:23](OC3C=CC([N+]([O-])=O)=CC=3)=[O:24])[C:15]=2[C:14]2[C:9]1=[CH:10][CH:11]=[C:12]([Cl:35])[CH:13]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:36][C:37]1[CH:38]=[N:39][CH:40]=[C:41]([Cl:44])[C:42]=1[NH2:43].[H-].[Na+].Cl>CN(C=O)C.O>[Cl:36][C:37]1[CH:38]=[N:39][CH:40]=[C:41]([Cl:44])[C:42]=1[NH:43][C:23]([C:16]1[C:15]2[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([Cl:35])[CH:13]=3)[N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C:20]=2[C:19]([O:21][CH3:22])=[CH:18][CH:17]=1)=[O:24]
Reactant: COc1ccc(C(=O)Oc2ccc([N+](=O)[O-])cc2)c2c3cc(Cl)ccc3n(Cc3ccccc3)c12
Reactant: Nc1c(Cl)cncc1Cl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)Nc2c(Cl)cncc2Cl)c2c3cc(Cl)ccc3n(Cc3ccccc3)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 46.1 %

Procedure:
To a solution of 4-Nitrophenyl 9-benzyl-6-chloro-1-methoxy-4-carbazole carboxylate (124 mg, 0.255 mmoles) in dry DMF (3 ml) under nitrogen atmosphere, 3,5-dichloro-4-amino pyridine (41.5 mg, 0.255 mmoles) was added followed by sodium hydride (60% suspension, 16.7 mg, 0.382 mmoles) and the reaction mixture was stirred at room temperature for one hour. Ice pieces were added to the reaction mixture, diluted with water (15 ml) and neutralized with 1N HCl. The precipitated product was filtered, washed with water, dried and purified by column chromatography to give 60 mg of the title compound as an off white solid, m. p: 210-213° C.
Reaction SMILES: [C:1]([O:4][CH:5]1[C:9]2=[N:10][CH:11]=[C:12]([NH2:29])[C:13]([N:14]3[CH2:19][C@H:18]([CH3:20])[CH2:17][C@H:16]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:15]3)=[C:8]2[CH2:7][CH2:6]1)(=[O:3])[CH3:2].[F:30][C:31]1[CH:36]=[C:35]([CH2:37][O:38][CH3:39])[CH:34]=[C:33]([F:40])[C:32]=1[C:41]1[N:46]=[C:45]([C:47](O)=[O:48])[CH:44]=[CH:43][C:42]=1[F:50].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[C:1]([O:4][CH:5]1[C:9]2=[N:10][CH:11]=[C:12]([NH:29][C:47]([C:45]3[CH:44]=[CH:43][C:42]([F:50])=[C:41]([C:32]4[C:31]([F:30])=[CH:36][C:35]([CH2:37][O:38][CH3:39])=[CH:34][C:33]=4[F:40])[N:46]=3)=[O:48])[C:13]([N:14]3[CH2:19][C@H:18]([CH3:20])[CH2:17][C@H:16]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:15]3)=[C:8]2[CH2:7][CH2:6]1)(=[O:3])[CH3:2]
Reactant: COCc1cc(F)c(-c2nc(C(=O)O)ccc2F)c(F)c1
Reactant: CC(=O)OC1CCc2c1ncc(N)c2N1C[C@H](C)C[C@H](NC(=O)OC(C)(C)C)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COCc1cc(F)c(-c2nc(C(=O)Nc3cnc4c(c3N3C[C@H](C)C[C@H](NC(=O)OC(C)(C)C)C3)CCC4OC(C)=O)ccc2F)c(F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 3-amino-4-{(3S,5R)-3-[(tert-butoxycarbonyl)amino]-5-methylpiperidin-1-yl}-6,7-dihydro-5H-cyclopenta[b]pyridin-7-yl acetate (256 mg, 0.633 mmol), 6-[2,6-difluoro-4-(methoxymethyl)phenyl]-5-fluoropyridine-2-carboxylic acid (188 mg, 0.633 mmol), HATU (481 mg, 1.26 mmol) in DMF (1 mL) and DIPEA (0.330 mL, 1.90 mmol) was stirred at room temperature for 2 h. The reaction mixture was quenched with water and then extracted with EtOAc (2 times). The combined organic extracts were washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel using CombiFlash® apparatus eluting with EtOAc/hexanes (50-100%) to yield 4-{(3S,5R)-3-[(tert-butoxycarbonyl)amino]-5-methylpiperidin-1-yl}-3-[({6-[2,6-difluoro-4-(methoxymethyl)phenyl]-5-fluoropyridin-2-yl}carbonyl)amino]-6,7-dihydro-5H-cyclopenta[b]pyridin-7-yl acetate as an intermediate.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:4](=[O:18])[C:3]=1[C:19]([O:21][CH2:22][CH3:23])=[O:20].[NH2:24][C:25]1[C:26]([CH3:31])=[CH:27][CH:28]=[CH:29][CH:30]=1>C(Cl)(Cl)Cl>[CH3:31][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[NH:24][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:4](=[O:18])[C:3]=1[C:19]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: CCOC(=O)c1c(Cl)c2ccccc2n(-c2ccccc2)c1=O
Reactant: Cc1ccccc1N
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1c(Nc2ccccc2C)c2ccccc2n(-c2ccccc2)c1=O
Yield: 69.4 %

Procedure:
A mixture consisting of 1.0 g (3.05 mmol) of ethyl 4-chloro-2-oxo-1-phenyl-1,2-dihydroquinoline-3-carboxylate and 6.5 g (60.7 mmol) of o-toluidine was reacted at 100° C. for 5 hours. After the reaction, chloroform was added, and the resultant mixture was washed with a 5% aqueous solution of potassium hydrogensulfate and was then dried. The solvent was distilled off under reduced pressure, and the residue so obtained was purified by chromatography on a silica gel and was then recrystallized from ethanol/water, whereby 0.844 g of ethyl 4-(2-methylphenylamino)-2-oxo-1-phenyl-1,2-dihydroquinoline-3-carboxylate (Compound No. 33) was obtained (yield: 69.5%).
Reaction SMILES: O1CCCC1.Cl.[F:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH2:15][CH2:16][NH:17][CH2:18][CH:19]=2)=[CH:10][CH:9]=1.C(=O)([O-])[O-].[Na+].[Na+].[Cl:26][C:27]1[N:32]=[C:31](Cl)[N:30]=[CH:29][N:28]=1>C(OCC)(=O)C.O>[Cl:26][C:27]1[N:32]=[C:31]([N:17]2[CH2:16][CH2:15][C:14]([C:11]3[CH:12]=[CH:13][C:8]([F:7])=[CH:9][CH:10]=3)=[CH:19][CH2:18]2)[N:30]=[CH:29][N:28]=1
Reactant: Clc1ncnc(Cl)n1
Reactant: Fc1ccc(C2=CCNCC2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: Fc1ccc(C2=CCN(c3ncnc(Cl)n3)CC2)cc1
Yield: 84.6 %

Procedure:
To a tetrahydrofuran (10 mL)-water (4.0 mL) solution of 4-(4-fluorophenyl)-1,2,3,6-tetrahydropyridine hydrochloride (1.43 g, 6.67 mmol) and sodium carbonate (1.56 g, 14.7 mol), 2,4-dichloro-1,3,5-triazine (1.00 g, 6.67 mmol) was added at 0° C. and the resultant mixture was stirred for 1 hour. After completion of the reaction, ethyl acetate was added to the reaction solution and the resultant mixture was washed with each of saturated ammonium chloride aqueous solution and saturated sodium chloride aqueous solution. The obtained organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform) to obtain the title compound (1.64 g, yield 85%).
Reaction SMILES: [CH3:1][N:2]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:25]=[C:24]([N+]([O-])=O)[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:17]=2)=[CH:12][CH:11]=1)[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6].[F-:29].[K+]>>[F:29][C:24]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:17]=[C:16]([C:13]2[CH:14]=[CH:15][C:10]([N:2]([CH3:1])[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6])=[CH:11][CH:12]=2)[CH:25]=1
Reactant: CN(C(=O)OC(C)(C)C)c1ccc(-c2cc([N+](=O)[O-])c3ccccc3n2)cc1
Reactant: [F-]
Agent: [K+]
Product: CN(C(=O)OC(C)(C)C)c1ccc(-c2cc(F)c3ccccc3n2)cc1

Procedure:
tert-Butyl methyl(4-(4-fluoroquinolin-2-yl)phenyl)carbamate was prepared using general procedure M from tert-butyl methyl(4-(4-nitroquinolin-2-yl)phenyl)carbamate (10 mg, 0.026 mmol) and KF (60 mg, 1 mmol). tert-butyl (4-(4-fluoroquinolin-2-yl)phenyl)(methyl)carbamate was isolated as a clear oil (4.5 mg, 49%). 1H NMR (400 MHz, CDCl3): δ 8.16 (m, 1H), 8.12-8.07 (m, 3H), 7.78 (m, 1H), 7.59-7.54 (m, 2H), 7.41 (m, 1H), 3.32 (s, 3H), 1.48 (s, 9H); MS (ESI): 353 (M+H+).
Reaction SMILES: Br[CH:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3](Cl)=[O:4].[S:12]1[C:16]2[C:17](=[S:21])[NH:18][CH2:19][CH2:20][C:15]=2[CH:14]=[CH:13]1.C(N(CC)CC)C>C(Cl)(Cl)Cl.O>[OH-:4].[OH:4][C:3]1[N+:18]2[CH2:19][CH2:20][C:15]3[CH:14]=[CH:13][S:12][C:16]=3[C:17]=2[S:21][C:2]=1[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=C(Cl)C(Br)c1ccccc1
Reactant: S=C1NCCc2ccsc21
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: O
Product: Oc1c(-c2ccccc2)sc2[n+]1CCc1ccsc1-2
Product: [OH-]
Reaction time: 0.5 h

Procedure:
aa) Method A: 29.4 g of α-bromophenylacetyl chloride were added dropwise while stirring to a solution of 23.3 g of 4,5-dihydrothieno[2,3-c]pyridine-7(6H)-thione in 630 ml of chloroform, whereby care was taken that the temperature did not exceed 25°. After 30 minutes, the mixture was treated with 25.45 g of triethylamine and stirred for an additional 3 hours. The mixture was diluted with water, the organic phase was separated, washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate, evaporated and the residue was chromatographed on silica gel (elution agent toluene/ethanol 95:5). There was obtained 5,6-dihydro-3-hydroxy-2 -phenylthiazolo[3.2-a]thieno[2,3-c]pyridinium hydroxide (internal salt) of m.p. 225° (dec.) (from dioxane/acetonitrile).
Reaction SMILES: [Br:1][C:2]1[CH:13]=[CH:12][C:5]2[N:6]=[C:7]([CH2:9][CH2:10][OH:11])[S:8][C:4]=2[CH:3]=1.[S:14](Cl)([CH3:17])(=[O:16])=[O:15]>C(N(CC)CC)C>[Br:1][C:2]1[CH:13]=[CH:12][C:5]2[N:6]=[C:7]([CH2:9][CH2:10][O:11][S:14]([CH3:17])(=[O:16])=[O:15])[S:8][C:4]=2[CH:3]=1
Reactant: OCCc1nc2ccc(Br)cc2s1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCc1nc2ccc(Br)cc2s1

Procedure:
Compounds of formula (22) can be prepared from 6-bromobenzothiazolone as shown in Scheme 3. 6-Bromobenzothiazolone is heated in the presence of NaOH base to provide a mixture of 2-amino-5-bromothiophenol (15) and its disulfide (16). The mixture is treated with chlorocarbonyl-acetic acid ethyl ester to provide 6-bromo-benzothiazol-2-yl-acetic acid ethyl ester (17) and 7-bromo-3-hydroxy-4H-benzo[1,4]thiazine-2-carboxylic acid ethyl ester (18), which can undergo rearrangement by treatment with zinc and ethyl acetate to provide compound (17). Compound (17) is reduced with NaBH4 to provide 2-(6-bromo-benzothiazol-2-yl)-ethanol (19). Compound (19) is treated with mesyl chloride in the presence of triethyl amine to afford the corresponding methanesulfonic acid 2-(6-bromo-benzothiazol-2-yl)-ethyl ester (20), which is treated with an amine of formula HNRaRb, wherein Ra and Rb each is as defined for R4 and R5, to provide compounds of formula (21). Compounds of formula (21) can be treated with a boronic acid, wherein Rc is aryl or heteroaryl, to provide compounds of formula (22).
Reaction SMILES: [C:1](Cl)(=[O:6])[CH2:2][CH2:3][CH2:4][CH3:5].[C:8]([O:12][C:13](=[O:45])[CH:14]([CH2:40][CH2:41][CH2:42][CH2:43][OH:44])[CH2:15][C:16]1([C:21](=[O:39])[NH:22][C@H:23]2[CH2:28][CH2:27][C@@H:26]([C:29]([O:31][CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[O:30])[CH2:25][CH2:24]2)[CH2:20][CH2:19][CH2:18][CH2:17]1)([CH3:11])([CH3:10])[CH3:9].Cl>N1C=CC=CC=1>[C:8]([O:12][C:13](=[O:45])[CH:14]([CH2:40][CH2:41][CH2:42][CH2:43][O:44][C:1](=[O:6])[CH2:2][CH2:3][CH2:4][CH3:5])[CH2:15][C:16]1([C:21](=[O:39])[NH:22][C@H:23]2[CH2:28][CH2:27][C@@H:26]([C:29]([O:31][CH2:32][C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)=[O:30])[CH2:25][CH2:24]2)[CH2:20][CH2:19][CH2:18][CH2:17]1)([CH3:10])([CH3:9])[CH3:11]
Reactant: CC(C)(C)OC(=O)C(CCCCO)CC1(C(=O)N[C@H]2CC[C@@H](C(=O)OCc3ccccc3)CC2)CCCC1
Reactant: CCCCC(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Product: CCCCC(=O)OCCCCC(CC1(C(=O)N[C@H]2CC[C@@H](C(=O)OCc3ccccc3)CC2)CCCC1)C(=O)OC(C)(C)C
Reaction time: 8 h

Procedure:
Valeryl chloride (0.2 ml, 1.98 mmole) was added dropwise to a stirred, ice cold solution of 3-{1-[(cis-4-benzyloxycarbonylcyclohexyl)carbamoyl]cyclopentyl}-2-(4-hydroxybutyl)propanoic acid t-butyl ester (0.7 g, 1.32 mmole) in dry pyridine (5 ml). The mixture was allowed to stand overnight at room temperature and ice was added, the pH was adjusted to 3 by the addition of 2N hydrochloric acid and the mixture was extracted with diethyl ether. The organic extract was dried (Na2SO4) and evaporated to give a gum which was chromatographed on silica eluting with hexane containing increasing proportions of diethyl ether to give the title product as a gum (. . . g . . . %). Found: C,70.06; H,8.91; N,2.58. C36H55NO7 requires C,70.44; H,9.03; N,2.28%.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13].NC(N)=[S:17].[OH-].[Na+].S(=O)(=O)(O)O>O>[SH:17][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13]
Reactant: O=C(O)CCCCCCCCCCBr
Reactant: NC(N)=S
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)CCCCCCCCCCS
Yield: 94.1 %

Procedure:
4 g (15.09 mmol) 11-bromoundecanoic acid is added along with 1.505 g thiourea (19.82 mmol) and 15 ml water to a round botton flask, and the mixture is refluxed for 3 hours. 10.2 ml 3M sodium hydroxide (30.6 mmol) was then added and the mixture was refluxed for one additional hour. The reaction mixture was cooled in an ice bath, and dilute sulfuric acid was added dropwise until the solution had a pH of about 2. The cloudy solution was then extracted with ether (2×25 ml), dried over anhydrous MgSO4, and concentrated under reduced pressure to give a white solid (3.1 g, 94%). 1H-NMR (300 MHz, CDCl3) 1.28, m, 10 H; 1.60, m, 7 H; 2.35, t, 2 H, J=7.3 Hz; 2.50, q, 2 H, J =7.5 Hz.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:22]([CH3:23])=[CH:21][C:19]([NH2:20])=[C:18]([CH3:24])[CH:17]=1.C1(C)C=CC=CC=1.C(N(CC)CC)C.Cl[C:40](Cl)([O:42]C(=O)OC(Cl)(Cl)Cl)Cl.[F:51][C:52]1[CH:60]=[C:59]([F:61])[C:58]([F:62])=[CH:57][C:53]=1[CH:54]([OH:56])[CH3:55]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[C:22]([CH3:23])=[CH:21][C:19]([NH:20][C:40](=[O:42])[O:56][CH:54]([C:53]2[CH:57]=[C:58]([F:62])[C:59]([F:61])=[CH:60][C:52]=2[F:51])[CH3:55])=[C:18]([CH3:24])[CH:17]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2nccc(Oc3cc(C)c(N)cc3C)c2cc1OC
Reactant: CC(O)c1cc(F)c(F)cc1F
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COc1cc2nccc(Oc3cc(C)c(NC(=O)OC(C)c4cc(F)c(F)cc4F)cc3C)c2cc1OC
Temperature: 25 °C
Yield: 51.1 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,5-dimethylaniline (82 mg) was added to toluene/triethylamine=10/1 (8 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (130 mg) in methylene chloride was then added to the solution, and the mixture was heated under reflux for 15 min. Subsequently, 2,4,5-trifluoro-α-methylbenzyl alcohol (80 mg) was added thereto, and the mixture was further stirred with heating under reflux for 2 hr. After the completion of the reaction, the reaction solution was allowed to cool to room temperature before distilled water was added thereto. The mixture was subjected to separatory extraction with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution and saturated brine. The washed solution was dried over sodium sulfate and was concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (68 mg, yield 48%).
Reaction SMILES: Cl[C:2]1[C:3](=[O:15])[N:4](C2CCCCO2)[N:5]=[CH:6][C:7]=1Cl.[N:16]1[CH:21]=[CH:20][CH:19]=[C:18]([OH:22])[CH:17]=1.C[O:24][C:25](=[O:34])[CH:26](Br)[CH2:27][CH:28]1[CH2:32][CH2:31][CH2:30][CH2:29]1>>[CH:28]1([CH2:27][CH:26]([N:4]2[C:3](=[O:15])[CH:2]=[C:7]([O:22][C:18]3[CH:17]=[N:16][CH:21]=[CH:20][CH:19]=3)[CH:6]=[N:5]2)[C:25]([OH:24])=[O:34])[CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: O=c1c(Cl)c(Cl)cnn1C1CCCCO1
Reactant: COC(=O)C(Br)CC1CCCC1
Reactant: Oc1cccnc1
Product: O=C(O)C(CC1CCCC1)n1ncc(Oc2cccnc2)cc1=O
Yield: 72 %

Procedure:
In an analogous manner to the stepwise sequence outlined in intermediate 19, starting from 4,5-dichloro-2-(tetrahydropyran-2-yl)-2H-pyridazin-3-one (Intermediate 20) and pyridin-3-ol and alkylating with 2-bromo-3-cyclopentyl-propionic acid methyl ester (Intermediate 10) afforded 3-cyclopentyl-2-[6-oxo-4-(pyridin-3-yloxy)-6H-pyridazin-1-yl]-propionic acid (10.5 g, 72%) as a solid; ESI-MS 330 [M+H+]; HPLC: >96% (purity). 1H-NMR (300 MHz, DMSO-d6): δ 1.11 (m, 2H), 1.52 (m, 7H), 2.01 (m, 1H), 2.22 (m, 1H), 5.32 (m, 1H), 5.89 (s, 1H), 7.56 (m, 1H), 7.84 (m, 1H), 8.15 (s, 1H), 8.59 (m, 2H), 13.00 (brs, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[N:12]1[CH:16]=[CH:15][CH:14]=[CH:13]1.N1C=CC=CC=1.[C:23](OC(=O)C)(=[O:25])[CH3:24].C(=O)([O-])[O-].[K+].[K+]>ClCCl.O>[C:23]([O:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[N:12]1[CH:16]=[CH:15][CH:14]=[CH:13]1)(=[O:25])[CH3:24]
Reactant: CC(=O)OC(C)=O
Reactant: COC(=O)c1ccc(O)c(-n2cccc2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccncc1
Solvent: O
Solvent: ClCCl
Product: COC(=O)c1ccc(OC(C)=O)c(-n2cccc2)c1

Procedure:
A solution of methyl 4-hydroxy-3-(pyrrol-1-yl)benzoate (15.0 g), pyridine (8.4 ml) and acetic anhydride (9.8 ml) in dichloromethane (75 ml) was stirred for 15 hours at ambient temperature. To the reaction mixture was added the mixture of dichloromethane and water and the mixture was adjusted to pH 8 with 20% aqueous potassium carbonate solution. The separated organic layer was washed with 1N-hydrochloric acid and water respectively. The organic layer was dried over magnesium sulfate and evaporated in vacuo to give methyl 4-acetoxy-3-(pyrrol-1-yl)benzoate (15.9 g).