Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:6][C:7]3[C:12]([C:13]=2[CH:14]=1)=[CH:11][C:10]([O:15][CH3:16])=[CH:9][CH:8]=3.C([O:19][CH:20]=[C:21]([C:27](OCC)=O)[C:22]([O:24][CH2:25][CH3:26])=[O:23])C>C1(C)C(C)=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]3[CH:27]=[C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:20](=[O:19])[C:8]4[CH:9]=[C:10]([O:15][CH3:16])[CH:11]=[C:12]([C:13]=2[CH:14]=1)[C:7]3=4
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: COc1ccc2[nH]c3ccc(Br)cc3c2c1
Solvent: Cc1ccccc1C
Product: CCOC(=O)c1cn2c3ccc(Br)cc3c3cc(OC)cc(c1=O)c32
Yield: 50 %

Procedure:
3-bromo-6-methoxycarbazole (2.5 g) produced in Example 1, step 1 and diethyl ethoxymethylenemalonate (9.16 ml) were dissolved in xylene, and the solution was heated under reflux in an argon atmosphere for 120 hours, and allowed to cool. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (eluent: chloroform) to obtain the title compound (2 g, 50%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[CH:26]=[C:25]([C:27](=[O:36])[NH:28][C:29]5([C:32](=[NH:35])[NH:33][OH:34])[CH2:31][CH2:30]5)[C:24]([O:37][CH3:38])=[CH:23][C:22]=4[CH3:39])=[CH:17][C:11]=3[C:12]=2[C:13]([NH:15][CH3:16])=[O:14])=[CH:4][CH:3]=1.[C:40]1(C)C=CC=C[CH:41]=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[CH:26]=[C:25]([C:27](=[O:36])[NH:28][C:29]5([C:32]6[N:35]=[C:40]([CH3:41])[O:34][N:33]=6)[CH2:30][CH2:31]5)[C:24]([O:37][CH3:38])=[CH:23][C:22]=4[CH3:39])=[CH:17][C:11]=3[C:12]=2[C:13]([NH:15][CH3:16])=[O:14])=[CH:4][CH:3]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)NC4(C(=N)NO)CC4)c(OC)cc3C)cc12
Reactant: Cc1ccccc1
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)NC4(c5noc(C)n5)CC4)c(OC)cc3C)cc12

Procedure:
2-(4-Fluorophenyl)-5-(4-methoxy-2-methyl-5-(1-(5-methyl-1,2,4-oxadiazol-3-yl)cyclopropylcarbamoyl)phenyl)-N-methylbenzofuran-3-carboxamide was prepared from 2-(4-fluorophenyl)-5-(5-(1-(N-hydroxycarbamimidoyl)cyclopropylcarbamoyl)-4-methoxy-2-methylphenyl)-N-methylbenzofuran-3-carboxamide under similar conditions as described but using PhMe as a solvent. The crude mixture was purified by preparative TLC (20×20 cm×500 um plates, 5% MeOH/CH2Cl2) to give the product, which was further purified by Shimadzu-VP preparative reverse phase HPLC using the separation method: Solvent A=10% MeOH-90% H2O-0.1% TFA, Solvent B=90% MeOH-10% H2O-0.1% TFA, Start % B=50, Final % B=100, Gradient time=10 min, Stop time=12 min, Flow Rate=25 mL/min, Column: Waters-Sunfire 19×100 mm S5, Fraction Collection: 7.95-8.47 min. (UV detection at 220 nm). Analytical TLC Rf=0.38 (5% MeOH/CH2Cl2). 1H NMR (500 MHz, CD3OD) δ 7.97 (dd, J=7.93, 5.49, 2H), 7.87 (s, 1H), 7.62 (d, J=8.24, 1H), 7.58 (s, 1H), 7.33 (d, J=8.55, 1H), 7.27 (t, J=8.39, 2H), 7.11 (s, 1H), 4.05 (s, 3H), 2.96 (s, 3H), 2.54 (s, 3H), 2.36 (s, 3H), 1.60 (m, 2H), 1.45 (m, 2H). LC/MS were performed by using Shimadzu-VP instrument with UV detection at 220 nm and Waters Micromass. HPLC method: Solvent A=10% MeOH-90% H2O-0.1% TFA, Solvent B=90% MeOH-10% H2O-0.1% TFA, Start % B=0, Final % B=100, Gradient time=2 min, Stop time=3 min, Flow Rate=5 ml/min, Column: Phenomenex-Luna, 3.0×50 mm, S10; (ES+) m/z (M+H)+=555.34, HPLC Rt=1.735 min. Analytical HPLC were performed by using Shimadzu-VP instrument with UV detection at 220 nm and 254 nm. Analytical HPLC method: Solvent A=5% MeCN-95% H2O-0.1% TFA, Solvent B=95% MeCN-5% H2O-0.1% TFA, Start % B=50, Final % B=100, Gradient time=15 min, Stop time=18 min, Flow Rate=1 ml/min, Column: Sunfire C18, 3.5 um, 4.6×150 mm, Rt=7.75 min; Column: Xbridge Phenyl 3.5 um, 4.6×150 mm, Rt=5.93 min. Analytical HPLC method: Solvent A=5% MeOH-95% H2O-10 mM NH4HCO3, Solvent B=95% MeOH-5% H2O-10 mM NH4HCO3, Start % B=50, Final % B=100, Gradient time=15 min, Stop time=18 min, Flow Rate=1 ml/min, Column: Xbridge Phenyl 3.5 um, 4.6×150 mm, Rt=11.98 min.
Reaction SMILES: [CH:1]1([CH2:6][NH2:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:8]([C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][CH:15]=[CH:14]2)(O)=[O:9].Cl.CN(C)CCCN=C=NCC>CN(C)C1C=CN=CC=1.ClCCl>[CH:1]1([CH2:6][NH:7][C:8]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][CH:15]=[CH:14]3)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NCC1CCCC1
Reactant: O=C(O)c1ccc2[nH]ccc2c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: O=C(NCC1CCCC1)c1ccc2[nH]ccc2c1
Yield: 79.5 %

Procedure:
A solution of cyclopentylmethylamine (2.66 g), 5-carboxyindole (4.76 g), 4-(dimethylamino)-pyridine (3.60 g) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (5.67 g) in dichloromethane (60 ml) was stirred for 12 hours under an atmosphere of nitrogen. The amber solution was diluted with dichloromethane (150 ml), washed successively with 10% (w/v) aqueous sodium carbonate, 10% (v/v) hydrochloric acid, water, and brine, dried (MgSO4), and evaporated. The residual amber oil was purified by flash chromatography on silica gel (700 ml), eluting with 1:3 v/v ethyl acetate:chloroform, to yield 5-(N-cyclopentylmethylcarbamoyl)indole (A) (5.17 g, 80%) as a white crystalline solid; mp 110°-112° C.; NMR (80 MHz, CDCl3): 1.0-2.4(broad m, 9H, cyclopentyl), 3.4(dd, 2H, CH2N), 6.2(broad, 1H, NH), 6.6(m, 1H, H3 -indole), 7.3(t, 1H, H2 -indole), 7.4(d, 1H, H7 -indole), 8.5(broad, 1H, CONH).
Reaction SMILES: C(C1N=C(N2CCOCC2)C2N=NN(CC3C=CC=CC=3Cl)C=2N=1)(C)(C)C.[C:28]([C:32]1[N:33]=[C:34](Cl)[C:35]2[N:40]=[N:39][N:38]([CH2:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=3[Cl:48])[C:36]=2[N:37]=1)([CH3:31])([CH3:30])[CH3:29].C(O)(=O)C(O)=O.[CH2:56]1[C:59]2([CH2:63][CH2:62][NH:61][CH2:60]2)[CH2:58][O:57]1>>[C:28]([C:32]1[N:33]=[C:34]([N:61]2[CH2:62][CH2:63][C:59]3([CH2:56][O:57][CH2:58]3)[CH2:60]2)[C:35]2[N:40]=[N:39][N:38]([CH2:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=3[Cl:48])[C:36]=2[N:37]=1)([CH3:31])([CH3:30])[CH3:29]
Reactant: C1CC2(CN1)COC2
Reactant: CC(C)(C)c1nc(Cl)c2nnn(Cc3ccccc3Cl)c2n1
Agent: CC(C)(C)c1nc(N2CCOCC2)c2nnn(Cc3ccccc3Cl)c2n1
Agent: O=C(O)C(=O)O
Product: CC(C)(C)c1nc(N2CCC3(COC3)C2)c2nnn(Cc3ccccc3Cl)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-3-(2-chloro-benzyl)-7-morpholin-4-yl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 1, step c), the title compound was prepared from 5-tert-butyl-7-chloro-3-(2-chlorobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 2-oxa-6-azaspiro[3.4]octane oxalate and isolated as colorless gum (2.6 mg, 13%). MS (m/e): 413.4 (MH+).
Reaction SMILES: [CH3:1][S:2]([CH3:4])=[O:3].[H-].[Na+].C1COCC1.[O:12]1[CH:16]=[CH:15][CH:14]=[C:13]1[C:17](OC)=[O:18]>O>[O:12]1[CH:16]=[CH:15][CH:14]=[C:13]1[C:17](=[O:18])[CH2:1][S:2]([CH3:4])=[O:3]
Reactant: COC(=O)c1ccco1
Reactant: CS(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CS(=O)CC(=O)c1ccco1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
DMSO (35 ml., dry, distilled from CaH2) and NaH (3.08 g., 0.076 mol as a 60% suspension in oil) was heated under nitrogen until evolution of H2 was complete, cooled to 0° C., and diluted with 35 ml. THF. Methyl furan-2-carboxylate (5 ml., 5.89 g., 0.047 mol) was added, the mixture warmed to ambient temperature, stirred 2 hours, poured into an equal volume of water, and extracted with one half volume of ether. The aqueous layer was adjusted to pH3 with 6N HCl and extracted 3×150 ml. CHCl3. The CHCl3 extracts were combined, dried and evaporated to an oil which crystallized on standing in vacuum. The latter was slurried in minimal 1:1 CHCl3 :hexane and recovered by filtration, 2.84 g.; tlc Rf 0.7 (3:1 ethyl acetate:methanol); 1H-nmr 2.75 (s, 3H), 4.21 (ABq, 2H), 6.58 (dd, 1H), 7.32 (d, 1H), 7.62 (d, 1H).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4](=[O:9])[CH2:5][C:6](=[O:8])[CH3:7].Br[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][C:13]=1[Cl:22]>CN(C)C=O.O>[Cl:22][C:13]1[CH:14]=[C:15]([S:18]([CH3:21])(=[O:20])=[O:19])[CH:16]=[CH:17][C:12]=1[CH2:11][CH:5]([C:4](=[O:9])[CH3:3])[C:6](=[O:8])[CH3:7]
Reactant: CC(=O)CC(C)=O
Reactant: CS(=O)(=O)c1ccc(CBr)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)C(Cc1ccc(S(C)(=O)=O)cc1Cl)C(C)=O
Temperature: 5 °C
Reaction time: 0.33 h

Procedure:
Sodium hydride (60% in oil, 0.30 g) was added portionwise to a stirred solution of pentane-2,4-dione (0.92 g) in N,N-dimethylformamide (8.0 mL) at 0-10° C. The resulting mixture was stirred at 0-10° C. for 20 minutes and then a solution of 1-bromomethyl-2-chloro-4-methanesulfonylbenzene (2.0 g) in N,N-dimethylformamide (3.0 mL) was added dropwise. The resulting mixture was stirred at room temperature for 5 hours, and then diluted with water and this mixture was extracted with ethyl acetate. The combined extracts were washed with water and saturated aqueous sodium chloride solution and then dried over magnesium sulfate. The solvent was removed under reduced pressure and purification of the residue by column chromatography on silica gel, eluting with a mixture of ethyl acetate and cyclohexane (1:4 to 3:7 by volume) gave title compound as a white solid, 1.2 g.
Reaction SMILES: [CH:1]([NH:3][CH:4]([C:11]1([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[CH2:14][CH2:13][CH2:12]1)[CH2:5][CH2:6][CH2:7][O:8][CH2:9][CH3:10])=O.[H-].COCCO[Al+]OCCOC.[Na+].[H-].COCCO[AlH2-]OCCOC.[Na+].[OH-].[Na+].[C:50]([OH:57])(=[O:56])/[CH:51]=[CH:52]\[C:53]([OH:55])=[O:54]>C1(C)C=CC=CC=1.O>[C:50]([OH:57])(=[O:56])/[CH:51]=[CH:52]\[C:53]([OH:55])=[O:54].[CH3:1][NH:3][CH:4]([C:11]1([C:15]2[CH:16]=[CH:17][C:18]([Cl:21])=[CH:19][CH:20]=2)[CH2:14][CH2:13][CH2:12]1)[CH2:5][CH2:6][CH2:7][O:8][CH2:9][CH3:10]
Reactant: CCOCCCC(NC=O)C1(c2ccc(Cl)cc2)CCC1
Agent: COCCO[Al+]OCCOC
Agent: COCCO[AlH2-]OCCOC
Agent: O=C(O)/C=C\C(=O)O
Solvent: O
Solvent: Cc1ccccc1
Product: CCOCCCC(NC)C1(c2ccc(Cl)cc2)CCC1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
A solution of N-formyl-1-[1-(4-chlorophenyl)-cyclobutyl]-4-ethoxybutylamine (1.6 g) in dry toluene (40 ml) was added dropwise to a stirred 70% solution of sodium bis-(2-methoxyethoxy)aluminium hydride in toluene sold under the trade name Red-Al (6 ml) in dry toluene (15 ml) at ambient temperature, under nitrogen. The mixture was stirred at 50° C. for 3 hours then cooled and water (20 ml) and then 5N sodium hydroxide solution (15 ml) were added. The mixture was extracted with ether and the extracts dried and evaporated to give an oil which was treated with an ethereal solution of maleic acid to give a salt which was recrystallised from propan-2-ol to give N-methyl-1-[1-(4-chlorophenyl)cyclobutyl)-4-ethoxybutylamine maleate (m.p. 102-103° C.).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:27]=[C:28]([C:31]([CH3:34])([CH3:33])[CH3:32])[C:29]=1[OH:30])[C:8]([NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[NH:17][C:18](=[O:26])OC1C=CC=CC=1)=[O:9])([CH3:4])([CH3:3])[CH3:2].[CH2:35]([NH:42][CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>C1C=CC=CC=1>[CH2:43]([N:42]([CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:18](=[O:26])[NH:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[NH:10][C:8](=[O:9])[C:7]1[CH:6]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[C:29]([OH:30])=[C:28]([C:31]([CH3:34])([CH3:33])[CH3:32])[CH:27]=1)[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1
Reactant: c1ccc(CNCc2ccccc2)cc1
Reactant: CC(C)(C)c1cc(C(=O)Nc2ccccc2NC(=O)Oc2ccccc2)cc(C(C)(C)C)c1O
Solvent: c1ccccc1
Product: CC(C)(C)c1cc(C(=O)Nc2ccccc2NC(=O)N(Cc2ccccc2)Cc2ccccc2)cc(C(C)(C)C)c1O
Reaction time: 2 h
Yield: 24 %

Procedure:
Phenyl N-[2-(3,5-di-t-butyl-4-hydroxybenzoylamino)phenyl]carbamate (1.6 g) and dibenzylamine (0.7 g) were dissolved in benzene (10 ml) and stirred at 70°-80°0 C. for 2 hrs. The reaction solution was washed with 2N sodium hydroxide, saturated ammonium chloride solution, dried over anhydrous NaSO4 and the solvent was distilled off. Purification of the residue by a silica gel column chromatography followed by crystallization from ether afforded N-[2-(3,3-dibenzylureido )phenyl]-3,5-di-t-butyl-4-hydroxybenzamide (0.47 g, 23%).
Reaction SMILES: O.[OH-].[Li+].[CH3:4][C:5]1([C:42]([O:44]C)=[O:43])[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[NH:14][C:15](=[O:41])[CH:16]([C:21]2[CH:26]=[CH:25][C:24]([CH2:27][N:28]3[C:33](=[O:34])[CH2:32][O:31][C:30]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)=[N:29]3)=[CH:23][CH:22]=2)[CH:17]([CH3:20])[CH2:18][CH3:19])[CH2:6]1>C1COCC1.O>[CH3:4][C:5]1([C:42]([OH:44])=[O:43])[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[NH:14][C:15](=[O:41])[CH:16]([C:21]2[CH:26]=[CH:25][C:24]([CH2:27][N:28]3[C:33](=[O:34])[CH2:32][O:31][C:30]([C:35]4[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=4)=[N:29]3)=[CH:23][CH:22]=2)[CH:17]([CH3:20])[CH2:18][CH3:19])[CH2:6]1
Reactant: CCC(C)C(C(=O)Nc1cccc2c1CC(C)(C(=O)OC)C2)c1ccc(CN2N=C(c3ccccc3)OCC2=O)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCC(C)C(C(=O)Nc1cccc2c1CC(C)(C(=O)O)C2)c1ccc(CN2N=C(c3ccccc3)OCC2=O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
100 mg (2.39 mmol) of lithium hydroxide monohydrate were added to a solution of 339 mg (0.60 mmol) of methyl 2-methyl-4-[(3-methyl-2-{4-[(5-oxo-2-phenyl-5,6-dihydro-4H-1,3,4-oxadiazin-4-yl)methyl]phenyl}pentanoyl)amino]-2,3-dihydro-1H-indene-2-carboxylate (Example 160A) in 12 ml of THF and 6 ml of water, and the mixture was stirred at room temperature overnight. After the reaction had gone to completion, the THF was removed under reduced pressure and the reaction solution was diluted with water and then adjusted to pH 2 with 1 M hydrochloric acid. The precipitated solid was filtered off, washed with water and dried under reduced pressure at 45° C. overnight. This gave 305 mg (0.55 mmol, 92% of theory) of the title compound as a mixture of isomers.
Reaction SMILES: N1C=CC=CC=1.[C:7]([O:11][C:12]([N:14]1[CH2:19][CH2:18][CH:17]([C:20]([NH:22][NH:23][C:24]([C@@H:26]2[CH2:32][CH2:31][C@@H:30]3[CH2:33][N:27]2[C:28](=[O:42])[N:29]3[O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=O)=[O:21])[CH2:16][CH2:15]1)=[O:13])([CH3:10])([CH3:9])[CH3:8].O(S(C(F)(F)F)(=O)=O)S(C(F)(F)F)(=O)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH2:35]([O:34][N:29]1[C:28](=[O:42])[N:27]2[CH2:33][C@H:30]1[CH2:31][CH2:32][C@H:26]2[C:24]1[O:21][C:20]([CH:17]2[CH2:16][CH2:15][N:14]([C:12]([O:11][C:7]([CH3:10])([CH3:8])[CH3:9])=[O:13])[CH2:19][CH2:18]2)=[N:22][N:23]=1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)NNC(=O)[C@@H]2CC[C@@H]3CN2C(=O)N3OCc2ccccc2)CC1
Agent: O=C([O-])O
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(c2nnc([C@@H]3CC[C@@H]4CN3C(=O)N4OCc3ccccc3)o2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 82.6 %

Procedure:
Pyridine (2.6 mL, 35.0 mmol) was added to a solution of tert-butyl-4-(2-((2S,5R)-6-(benzyloxy)-7-oxo-1,6-diaza-bicyclo[3.2.1]octane-2-carbonyl) hydrazinecarbonyl)piperidine-1-carboxylate (901 mg, 1.8 mmol) in DCM (200 mL). Then, (CF3SO2)2O (2.6 mL, 9.0 mmol) was added slowly at −10° C. The reaction mixture was stirred at rt for 3 hrs then saturated NaHCO3 was added very slowly at −10° C. The organic layer was separated and the aqueous layer was exacted with EtOAc (3×). The combined organic layer was dried over Na2SO4, and concentrated. The crude product was purified by silica gel column chromatography (2:1 EtOAc/hexanes) to give tert-butyl 4-(5-((2S,5R)-6-(benzyloxy)-7-oxo-1,6-diaza-bicyclo[3.2.1]octan-2-yl)-1,3,4-oxadiazol-2-yl)piperidine-1-carboxylate (719 mg, 82%) as a slight yellow solid. ESI-MS (EI+, m/z): 484.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([OH:16])=O)=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].[OH:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26][NH2:27])=[CH:24][CH:23]=1>>[Cl:20][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:27][CH2:26][C:25]2[CH:28]=[CH:29][C:22]([OH:21])=[CH:23][CH:24]=2)=[O:16])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18]
Reactant: NCc1ccc(O)cc1
Reactant: O=C(O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Product: O=C(NCc1ccc(O)cc1)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1

Procedure:
Prepared according to the procedure described for example 44 from 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-nitro-thiophene-2-carboxylic acid (35 mg, 0.1 mmol) and 4-hydroxylbenzylamine (14.5 mg, 0.12 mmol). The title compound was obtained as a solid (23.1 mg, 51% yield). MS m/z: 455.96, 457.96 [M+H]+.
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[NH:12][C:13]3[CH:18]=[CH:17][N:16]=[CH:15][C:14]=3[N:19]=2)=[C:7]([O:20][CH3:21])[CH:6]=1)(=O)C.[OH-].[Na+]>CO>[OH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[NH:12][C:13]3[CH:18]=[CH:17][N:16]=[CH:15][C:14]=3[N:19]=2)=[C:7]([O:20][CH3:21])[CH:6]=1
Reactant: COc1cc(OC(C)=O)ccc1-c1nc2cnccc2[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1cc(O)ccc1-c1nc2cnccc2[nH]1
Reaction time: 16 h

Procedure:
A mixture of 10 g of 2-(4-acetoxy-2-methoxyphenyl)imidazo(4,5-c)pyridine, 100 ml of methanol and 100 ml of 2N aqueous NaOH solution is allowed to stand at 20° for 16 hours. After the usual work-up, 2-(4-hydroxy-2-methoxyphenyl)imidazo(4,5-c)pyridine is obtained; fumarate, m.p. 255°.
Reaction SMILES: [B-](F)(F)(F)F.C1C=CN=CC=1.C1C=CN=CC=1.[IH2+:18].[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([CH:27]([C:37]2[CH:42]=[CH:41][C:40]([O:43][C:44](=[O:49])[C:45]([CH3:48])([CH3:47])[CH3:46])=[CH:39][CH:38]=2)[CH:28]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:29]=[CH2:30])=[CH:23][CH:22]=1.[Cl-].[NH4+]>C(Cl)Cl>[I:18][CH:29]1[CH:28]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:27]([C:37]2[CH:38]=[CH:39][C:40]([O:43][C:44](=[O:49])[C:45]([CH3:48])([CH3:47])[CH3:46])=[CH:41][CH:42]=2)[C:24]2[C:23](=[CH:22][C:21]([O:20][CH3:19])=[CH:26][CH:25]=2)[CH2:30]1
Reactant: [IH2+]
Reactant: C=CC(c1ccccc1)C(c1ccc(OC)cc1)c1ccc(OC(=O)C(C)(C)C)cc1
Agent: F[B-](F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ccc2c(c1)CC(I)C(c1ccccc1)C2c1ccc(OC(=O)C(C)(C)C)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 71 %

Procedure:
Bis(pyridine)iodonium tetrafluoroborate (65.8 mg, 0.177 mmol) was suspended in methylene chloride (3.4 mL), and cooled in a dry ice-acetone bath to −78° C. To this, a methylene chloride (1.8 mL) solution of 1-(4-methoxyphenyl)-2-phenyl-1-(4-pivaloyloxyphenyl)-3-butene (4, 56.0 mg, 0.135 mmol) was added, and further, boron tribromide diethyl ether complex (0.015 mL, 0.118 mmol) was added divided into 3 portions. After this, and after stirring for 1 hr at −78° C., the reaction was stopped by adding a saturated ammonium chloride solution (5 mL), and after returning to room temperature, extraction was performed three times with diethyl ether (10 mL). The organic layers were combined and washed with a saturated sodium chloride solution (10 mL), dried with anhydrous sodium sulfate, and concentrated. The residue was purified with thin layer chromatography (toluene), and the subject compound (5, 51.6 mg) was obtained as a slightly yellow oily substance (yield 71%).
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][CH3:16])[N:11]=[CH:10][N:9]=[C:8]2[O:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][C:25]([NH:27][CH2:28][CH2:29][CH3:30])=[O:26])=[C:20]([Cl:31])[CH:19]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:38][N:39]1[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1>CN(C)C=O>[Cl:31][C:20]1[CH:19]=[C:18]([O:17][C:8]2[C:7]3[C:12](=[CH:13][C:14]([O:15][CH3:16])=[C:5]([O:4][CH2:3][CH2:2][N:42]4[CH2:43][CH2:44][N:39]([CH3:38])[CH2:40][CH2:41]4)[CH:6]=3)[N:11]=[CH:10][N:9]=2)[CH:23]=[CH:22][C:21]=1[NH:24][C:25]([NH:27][CH2:28][CH2:29][CH3:30])=[O:26]
Reactant: CCCNC(=O)Nc1ccc(Oc2ncnc3cc(OC)c(OCCBr)cc23)cc1Cl
Reactant: CN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCNC(=O)Nc1ccc(Oc2ncnc3cc(OC)c(OCCN4CCN(C)CC4)cc23)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 44 %

Procedure:
N-{2-Chloro-4-[(6-hydroxy-7-methoxy-4-quinazolinyl)oxy]phenyl}-N′-propylurea (500 mg), potassium carbonate (857 mg), and 1,3-dibromopropane (0.5 ml) were dissolved in N,N-dimethylformamide (5 ml), and the solution was stirred at room temperature for 3 hr. The solvent was removed by distillation under the reduced pressure. Water was added to the residue, and the mixture was extracted with chloroform/2-propanol (4/1). The organic layer was dried over anhydrous sodium kp sulfate. The solvent was removed by distillation under the reduced pressure. The residue was washed with ether to give 451 mg (yield 71%) of N-(4-{[6-(2-bromoethoxy)-7-methoxy-4-quinazolinyl]oxy}-2-chlorophenyl}-N′-propyl-urea. N-(4-{[6-(2-Bromoethoxy)-7-methoxy-4-quinazolinyl]oxy}-2-chlorophenyl}-N′-propylurea (50 mg), (3 potassium carbonate (40 mg), and N-methylpiperazine (50 μl) were dissolved in N,N-dimethylformamide (1 ml), and the solution was stirred at room temperature overnight. The solvent was removed by distillation under the reduced pressure. A saturated aqueous sodium hydrogencarbonate solution was added to the residue, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure. The residue was purified by chromatography on silica gel by development with chloroform/methanol to give 20 mg (yield 44%) of the title compound.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]3[C:13](=[C:14]([C:16]([NH2:18])=[O:17])[CH:15]=2)[NH:12][CH:11]=[C:10]3[CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:25]([NH:28][C:29]1[S:30][C:31]([S:35](Cl)(=[O:37])=[O:36])=[C:32]([CH3:34])[N:33]=1)(=[O:27])[CH3:26].C(N(CC)CC)C>>[C:25]([NH:28][C:29]1[S:30][C:31]([S:35]([N:22]2[CH2:23][CH2:24][CH:19]([C:10]3[C:9]4[C:13](=[C:14]([C:16]([NH2:18])=[O:17])[CH:15]=[C:7]([C:1]5[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=5)[CH:8]=4)[NH:12][CH:11]=3)[CH2:20][CH2:21]2)(=[O:36])=[O:37])=[C:32]([CH3:34])[N:33]=1)(=[O:27])[CH3:26]
Reactant: CC(=O)Nc1nc(C)c(S(=O)(=O)Cl)s1
Reactant: NC(=O)c1cc(-c2ccccc2)cc2c(C3CCNCC3)c[nH]c12
Solvent: CCN(CC)CC
Product: CC(=O)Nc1nc(C)c(S(=O)(=O)N2CCC(c3c[nH]c4c(C(N)=O)cc(-c5ccccc5)cc34)CC2)s1

Procedure:
Following the general procedure in example 267, 5-(phenyl)-3-(4-piperidinyl)-1H-indole-7-carboxamide (32 mg, 0.1 mmol), 2-(acetylamino)-4-methyl-1,3-thiazole-5-sulfonyl chloride (38.2 mg, 0.15 mmol) and triethylamine (0.06 mL, 0.3 mmol) were reacted to form the desired product which was purified by Gilson HPLC (CH3CN/Water, 0.1% TFA) (4.0 mg, 7.5%).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:6]=1.[Cl:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[C:16]([CH3:21])[C:15]=1[S:22](Cl)(=[O:24])=[O:23]>>[Cl:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[C:16]([CH3:21])[C:15]=1[S:22]([NH:1][C:2]1[S:3][CH:4]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:6]=1)(=[O:24])=[O:23]
Reactant: Nc1nc(-c2ccccc2)cs1
Reactant: Cc1cc(Cl)cc(Cl)c1S(=O)(=O)Cl
Product: Cc1cc(Cl)cc(Cl)c1S(=O)(=O)Nc1nc(-c2ccccc2)cs1

Procedure:
The title compound was prepared from 2-amino-4-phenylthiazole and 2,4-dichloro-6-methylbenzenesulfonyl chloride as described in the synthetic METHOD B to give a white solid (49.2 mg) with purity >90%. MS (pos) m/z 399.1,401.1.