Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:29]=[CH:28][C:27]([C:30]([O:32][CH3:33])=[O:31])=[CH:26][C:9]=3[N:10]3[C:16]=2[C:15]2[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=2[O:13][CH:12]([C:21]([O:23]CC)=[O:22])[CH2:11]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O.[OH-].[Li+].Cl>O1CCCC1.CO.O>[CH:1]1([C:7]2[C:8]3[CH:29]=[CH:28][C:27]([C:30]([O:32][CH3:33])=[O:31])=[CH:26][C:9]=3[N:10]3[C:16]=2[C:15]2[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=2[O:13][CH:12]([C:21]([OH:23])=[O:22])[CH2:11]3)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCOC(=O)C1Cn2c(c(C3CCCCC3)c3ccc(C(=O)OC)cc32)-c2ccccc2O1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(C(=O)O)Oc1ccccc1-3
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of 6-ethyl 9-methyl 12-cyclohexyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-6,9-dicarboxylate (270 mg, 0.60 mmol) in tetrahydrofuran (1 ml), methanol (1 ml) and water (1 ml) was added lithium hydroxide monohydrate (30 mg, 0.71 mmol) under ice-cooling, and the mixture was stirred at room temperature for 20 hr. 1N Hydrochloric acid was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure to give 12-cyclohexyl-9-methoxycarbonyl-6,7-dihydro-5-oxa-7a-azadibenzo[a,e]azulene-6-carboxylic acid as a crude product. The obtained crude product was used in Example 3-3 without further purification.
Reaction SMILES: [N+:1]([C:4]1[C:12]2[NH:11][C:10](=O)[NH:9][C:8]=2[CH:7]=[C:6]([C:14]([F:17])([F:16])[F:15])[CH:5]=1)([O-:3])=[O:2].O=P(Cl)(Cl)[Cl:20]>>[Cl:20][C:10]1[NH:9][C:8]2[CH:7]=[C:6]([C:14]([F:17])([F:16])[F:15])[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[C:12]=2[N:11]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]c2cc(C(F)(F)F)cc([N+](=O)[O-])c2[nH]1
Product: O=[N+]([O-])c1cc(C(F)(F)F)cc2[nH]c(Cl)nc12

Procedure:
The benzoimidazol-2-one from step (b) above (1.8 g, 7.3 mmol) reacted with POCl3 under the conditions of Example 1c to give the title compound as a yellow solid. MS (ESI, pos. ion) m/z: 266 (M+1).
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:13]([O:15][CH:16]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[C:17]1[C:25]([F:26])=[CH:24][C:20]([C:21]([OH:23])=O)=[CH:19][C:18]=1[F:27])[CH3:14].[CH2:33]([NH2:37])[CH:34]([CH3:36])[CH3:35].CCOC(C)=O>C1COCC1>[CH2:31]([O:30][C:28](=[O:29])[CH:16]([C:17]1[C:18]([F:27])=[CH:19][C:20]([C:21](=[O:23])[NH:37][CH2:33][CH:34]([CH3:36])[CH3:35])=[CH:24][C:25]=1[F:26])[O:15][CH2:13][CH3:14])[CH3:32]
Reactant: CCOC(=O)C(OCC)c1c(F)cc(C(=O)O)cc1F
Reactant: CC(C)CN
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)C(OCC)c1c(F)cc(C(=O)NCC(C)C)cc1F
Reaction time: 3 h
Yield: 67.3 %

Procedure:
1,1′-Carbonyldiimidazole (88 mg) was dissolved in THF (1 ml) and a solution of (RS)-4-(ethoxy-ethoxycarbonyl-methyl)-3,5-difluoro-benzoic acid (156 mg) in THF (1 ml) was added. After 30 min stirring at rt isobutylamine (41 mg) was added and the mixture was stirred 3 h. AcOEt (20 ml) was added and the solution was washed with 1 N HCl (20 ml). The aqueous layer was extracted with two more portions AcOEt (20 ml), the the combined organic layers were dried (Na2SO4) and the solvent was evaporated. CC (Hept/AcOET 3:1) afforded 125 mg (67%) of (RS)-(2,6-difluoro-4-isobutylcarbamoyl-phenyl)-ethoxy-acetic acid ethyl ester. White solid.
Reaction SMILES: [O:1]1[CH2:5][C@H:4]([OH:6])[C@H:3]2[O:7][CH2:8][C@H:9]([OH:10])[C@@H:2]12.[O:11]1[CH:16]=[CH:15][CH2:14][CH2:13][CH2:12]1>C(Cl)Cl>[O:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]1[O:6][C@@H:4]1[C@H:3]2[O:7][CH2:8][C@H:9]([OH:10])[C@H:2]2[O:1][CH2:5]1
Reactant: O[C@H]1CO[C@H]2[C@@H]1OC[C@@H]2O
Reactant: C1=COCCC1
Solvent: ClCCl
Product: O[C@H]1CO[C@H]2[C@@H]1OC[C@@H]2OC1CCCCO1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of (3S,3aR,6S,6aR)-hexahydrofuro[3,2-b]furan-3,6-diol (0.57 g, 3.90 mmol) and 3,4-dihydro-2H-pyran (0.41 g, 4.88 mmol) in DCM (15 ml), toluene-4-solfonic acid monohydrate (0.0074 g, 0.039 mmol) was added and the mixture was stirred at room temperature for 3 hrs. Then the reaction mixture was washed with a saturated solution of NaHCO3 and brine. The organic extract was dried over sodium sulfate and the solvent, was evaporated under reduced pressure. The residue was purified by flash chromatography (Biotage SP1, EtOAc/n-hexane from 30 to 100%), affording the title product as a white solid.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:42]([F:43])=[CH:41][C:17]3[N:18]=[C:19]([CH2:33][O:34][C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[N:20]([CH2:21][C:22]4[CH:27]=[CH:26][C:25]([O:28][C:29]([F:32])([F:31])[F:30])=[CH:24][CH:23]=4)[C:16]=3[CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>O>[F:43][C:42]1[C:14]([N:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[CH:15][C:16]2[N:20]([CH2:21][C:22]3[CH:23]=[CH:24][C:25]([O:28][C:29]([F:30])([F:31])[F:32])=[CH:26][CH:27]=3)[C:19]([CH2:33][O:34][C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)=[N:18][C:17]=2[CH:41]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cc3c(cc2F)nc(COc2ccccc2)n3Cc2ccc(OC(F)(F)F)cc2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: Fc1cc2nc(COc3ccccc3)n(Cc3ccc(OC(F)(F)F)cc3)c2cc1N1CCNCC1

Procedure:
4.6 g of 4-[6-fluoro-2-phenoxymethyl-3-(4-trifluoromethoxy-benzyl)-3H-benzoimidazol-5-yl]-piperazine-1-carboxylic acid tert-butyl ester (7.6 mmol) were stirred in 51 ml trifluoroacetic acid (661 mmol) for 2 h at rt. The reaction mixture was diluted with 500 ml water and the pH adjusted to 8 with solid sodium bicarbonate. The mixture was extracted twice with ethyl acetate and the combined organic phases were washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was then suspended in 70 ml water, the pH adjusted to 9 with ammonium hydroxide, extracted with ethylacetate, washed with water and brine, dried over magnesium sulfate, filtered and concentrated in vacuo., leading to 3.67 g of 5-fluoro-2-phenoxymethyl-6-piperazin-1-yl-1-(4-trifluoromethoxy-benzyl)-1H-benzoimidazole as a light yellow solid (95%). MS(ISP): 500.3 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[N:13]2[CH:14]=[N:15][CH:16]=[C:12]2[CH:11]([CH3:17])[CH2:10][CH2:9]1.[C:18]1(B(O)O)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:2]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[N:13]2[CH:14]=[N:15][CH:16]=[C:12]2[CH:11]([CH3:17])[CH2:10][CH2:9]1
Reactant: CC1CCC(c2ccccc2Br)n2cncc21
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CC1CCC(c2ccccc2-c2ccccc2)n2cncc21

Procedure:
To a solution of 5-(2-bromophenyl)-8-methyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyridine (573 mg, 1.97 mmol) in DME (10 mL) is added phenylboronic acid (480 mg, 3.94 mmol), aqueous Na2CO3 (2M, 4 mL, 8.0 mmol), and Pd(PPh3)4 (500 mg). The reaction mixture is stirred at reflux overnight. The mixture is partitioned between EtOAc and brine. The organic layer is washed by brine, dried over Na2SO4 and concentrated to give an oil, which is subjected to flash chromatography (silica gel) eluting with MeOH:CH2Cl2 to yield the desired compound. MS (ESI) m/z 289 (M+H)
Reaction SMILES: Br[C:2]1[C:15]2[CH2:14][CH2:13][N:12]3[C:8](=[N:9][C:10]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)=[CH:11]3)[CH:7]([O:22][CH:23]3[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]3)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH2:30](B1OC(C)(C)C(C)(C)O1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:30]([C:2]1[C:15]2[CH2:14][CH2:13][N:12]3[C:8](=[N:9][C:10]([C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=4)=[CH:11]3)[CH:7]([O:22][CH:23]3[CH2:24][CH2:25][N:26]([CH3:29])[CH2:27][CH2:28]3)[C:6]=2[CH:5]=[CH:4][CH:3]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: CC1(C)OB(Cc2ccccc2)OC1(C)C
Reactant: CN1CCC(OC2c3cccc(Br)c3CCn3cc(-c4ccccc4)nc32)CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: CN1CCC(OC2c3cccc(Cc4ccccc4)c3CCn3cc(-c4ccccc4)nc32)CC1
Temperature: 95 °C
Reaction time: 20 h

Procedure:
To a solution of 8-bromo-4-(1-methyl-piperidin-4-yloxy)-2-phenyl-9,10-dihydro-4H-3,10a-diaza-benzo[f]azulene (example 231) (150 mg) in toluene/dioxane/water 10/1/1 (6 mL) in a screw-capped vial are added benzylboronic pinacol ester (151 mg), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (50 mg) and potassium carbonate (137 mg). The vial is evacuated and filled with argon. The reaction mixture is stirred at 95° C. for 20 hours. Water is added to the reaction mixture, and the aqueous phase is extracted three times with dichloromethane. Pooled organic extracts are dried over magnesium sulphate, filtered and the solvent is removed under reduced pressure. The residue is purified by preparative HPLC-MS (Waters AutoPurification HPLC/MS System, Sunfire Prep C18 5 μm OBD 30×150 mm column, eluents: water/0.1% formic acid (A) and acetonitrile/0.1% formic acid (B), focus gradient from 23% (B) to 33% (B) in 10 minutes) to afford 8-benzyl-4-(1-methylpiperidin-4-yloxy)-2-phenyl-9,10-dihydro-4H-3,10a-diaza-benzo[f]azulene melting at 66° C.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH:5]([N:8]2[C:16](=[O:17])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]2=[O:18])[CH2:4][CH2:3]1.[CH3:19][O:20][C:21]1[C:29](O)=[CH:28][CH:27]=[C:26]2[C:22]=1[CH:23]=[N:24][NH:25]2.C(C=P(CCCC)(CCCC)CCCC)#N.[OH-].[Na+]>C1(C)C=CC=CC=1.O>[CH3:19][O:20][C:21]1[C:29]([O:1][CH:2]2[CH2:3][CH2:4][CH:5]([N:8]3[C:9](=[O:18])[C:10]4[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=4)[C:16]3=[O:17])[CH2:6][CH2:7]2)=[CH:28][CH:27]=[C:26]2[C:22]=1[CH:23]=[N:24][NH:25]2
Reactant: O=C1c2ccccc2C(=O)N1C1CCC(O)CC1
Reactant: COc1c(O)ccc2[nH]ncc12
Agent: CCCCP(=CC#N)(CCCC)CCCC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Product: COc1c(OC2CCC(N3C(=O)c4ccccc4C3=O)CC2)ccc2[nH]ncc12
Temperature: 25 °C
Yield: 65.8 %

Procedure:
Under nitrogen, the 2-(4-hydroxycyclohexyl)-1H-isoindole-1,3(2H)-dione (1.23 g, 5.01 mmol) obtained in Example 385, (b), the 4-methoxy-1H-indazol-5-ol (0.906 g, 5.52 mmol) obtained in Example 469 and 90%-cyanomethylenetri-n-butylphosphorane (161 g, 6.02 mmol) were dissolved in toluene (20 ml), and the resulting solution was heated under reflux for 5 hours. The reaction solution was cooled to room temperature and water and a 1N-aqueous sodium hydroxide solution were added thereto. The resulting solution was separated by the addition of toluene and the desired compound was extracted from the aqueous layer with toluene. The combined toluene layer was washed with a saturated aqueous sodium chloride solution, dried by the addition of anhydrous magnesium sulfate, and then filtered. The solvent was distilled off under reduced pressure and the concentration residue thus obtained was purified by a silica gel column chromatography (eluent: n-hexane/ethyl acetate=2/1, 1/1) to obtain 2-[4-[(4-methoxy-1H-indazol-5-yl)oxy]cyclohexyl]-1H-isoindole-1,3(2H)-dione (1.29 g, yield 66%).
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[C:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=4)[C:15]=3[O:14]2)(=O)=O)=CC=1.[N-:32]=[N+:33]=[N-:34].[Na+]>>[N:32]([CH2:12][CH:13]1[CH2:17][C:16]2[CH:18]=[CH:19][CH:20]=[C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=3)[C:15]=2[O:14]1)=[N+:33]=[N-:34]
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cccc(-c4cccc(C(F)(F)F)c4)c3O2)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Product: [N-]=[N+]=NCC1Cc2cccc(-c3cccc(C(F)(F)F)c3)c2O1

Procedure:
Treatment of (±)-{7-[3-(trifluoromethyl)phenyl]-2,3-dihydro-1-benzofuran-2-yl}methyl 4-methylbenzenesulfonate (5.2 g, 11.57 mmol) with sodium azide (3.01 g, 46.3 mmol) generally according to the procedure described for Intermediate 98 gave (±)-2-(azidomethyl)-7-[3-(trifluoromethyl)phenyl]-2,3-dihydro-1-benzofuran. Treatment of the azide with palladium on carbon (0.375 g, 10 wt. %) generally according to the procedure described for Example 1 provided 2.64 g (69%) of (±)-1-{7-[3-(trifluoromethyl)phenyl]-2,3-dihydro-1-benzofuran-2-yl}methanamine as a white solid, hydrochloride salt. mp 172-174° C.; Anal. calcd. for C16H14F3NOHCl: C, 58.28; H, 4.59; N, 4.25. Found: C, 58.09; H, 4.6; N, 4.03.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C@H:3]([NH:6][C:7]2[N:16]=[C:15]([N:17]3[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]3)[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]=2)[CH2:2]1.[Cl:30][C:31]1[CH:36]=[CH:35][C:34]([CH2:37][C:38](O)=[O:39])=[CH:33][CH:32]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.C(=O)([O-])O.[Na+]>O.C(Cl)(Cl)Cl>[Cl:30][C:31]1[CH:36]=[CH:35][C:34]([CH2:37][C:38]([N:1]2[CH2:5][CH2:4][C@H:3]([NH:6][C:7]3[N:16]=[C:15]([N:17]4[CH2:18][CH2:19][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:21][CH2:22]4)[C:14]4[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=4)[N:8]=3)[CH2:2]2)=[O:39])=[CH:33][CH:32]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2nc(N[C@H]3CCNC3)nc3ccccc23)CC1
Reactant: O=C(O)Cc1ccc(Cl)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: ClC(Cl)Cl
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(c2nc(N[C@H]3CCN(C(=O)Cc4ccc(Cl)cc4)C3)nc3ccccc23)CC1
Yield: 69.9 %

Procedure:
To a mixture of t-butyl 4-(2-((S)-pyrrolidin-3-ylamino)quinazolin-4-yl)piperazine-1-carboxylate (0.30 g), p-chlorophenylacetic acid (0.13 g), and chloroform (5 mL) were added HOBt.H2O (0.18 g) and EDC.HCl (0.18 g), and the mixture was stirred at room temperature for 2 days. To the reaction mixture was added saturated aqueous sodium hydrogencarbonate, and the mixture was extracted with chloroform. The organic layer was dried with anhydrous sodium sulfate, the desiccant was removed by filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (NH silica gel, hexane/ethyl acetate=3:2) to obtain t-butyl 4-(2-((S)-1-(2-(4-chlorophenyl)ethanoyl)pyrrolidin-3-ylamino)quinazolin-4-yl)piperazine-1-carboxylate (0.29 g). (2) To a solution of t-butyl 4-(2-((S)-1-(2-(4-chlorophenyl)ethanoyl)pyrrolidin-3-ylamino)quinazolin-4-yl)piperazine-1-carboxylate (0.28 g) in methanol (5 mL) was added a solution (1.3 mL) of 4 M HCl in ethyl acetate, and the mixture was stirred overnight. The solvent was evaporated under reduced pressure, and the residue was crystallized in diethyl ether to obtain the title compound (0.15 g).
Reaction SMILES: [OH-].[Na+].C([O:6][C:7]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:8]=1[CH:9]=[CH:10][C:11]([S:17]([NH:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)(=[O:19])=[O:18])=[CH:12]2)(=O)C.Cl>C(O)C>[CH2:21]([NH:20][S:17]([C:11]1[CH:10]=[CH:9][C:8]2[C:13](=[CH:14][CH:15]=[CH:16][C:7]=2[OH:6])[CH:12]=1)(=[O:19])=[O:18])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CC(=O)Oc1cccc2cc(S(=O)(=O)NCc3ccccc3)ccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=S(=O)(NCc1ccccc1)c1ccc2c(O)cccc2c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 100.1 %

Procedure:
Ethanol (3 ml) and 2N aqueous sodium hydroxide (0.1 ml) were added to 5-acetyloxy-N-benzylnaphthalene-2-sulfonamide (Compound No. 3-1; 62.0 mg, 0.17 mmol), and the mixture was stirred at room temperature for 5 minutes. The reaction mixture was poured into diluted hydrochloric acid and extracted with ethyl acetate. After the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, the residue obtained by evaporation of the solvent under reduced pressure was purified by column chromatography on silica gel (eluent; n-hexane: ethyl acetate=1:1) to give the title compound as a yellow white crystal (53.3 mg, 100%).
Reaction SMILES: [C:1]([CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][C:5]1([CH:11]=[CH:12][CH3:13])[OH:10])([CH3:3])=[CH2:2].C(OCC)C>O1CCCC1>[CH3:13][CH:12]1[CH2:3][C:1]([CH3:2])=[CH:4][CH2:9][CH2:8][CH2:7][CH2:6][C:5](=[O:10])[CH2:11]1
Reactant: C=C(C)C1CCCCC1(O)C=CC
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC1=CCCCCC(=O)CC(C)C1

Procedure:
A mixture of 2-isopropenyl-1-propenylcyclohexan-1-ol (0.090 g; 5.10-4 mol) and dichloro-bis-(benzonitrile)-palladium(II) (0.008 g; 0.2.10-4 mol) in tetrahydrofuran (5cc) is kept at a temperature of the order of 20° C. under an inert atmosphere. After a reaction time of 6 hours, diethyl ether (75 cc) is added and the mixture is then washed with water (5×15 cc). After drying with magnesium sulphate, filtration and evaporation of the solvent under reduced pressure (20 mm Hg; 2.7 kPa), alcohol starting material (0.050 g) is obtained together with 3,5-dimethylcyclodec-5-en-1-one (0.023 g), which has the following characteristics:
Reaction SMILES: [C:1]1([OH:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].[CH2:14]([CH:16]1[O:18][CH2:17]1)Cl.C(O)C>O>[O:18]1[CH:16]([CH2:14][O:11][C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH:2]=2)[CH2:17]1
Reactant: ClCC1CO1
Reactant: Oc1cccc2ccccc12
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: c1ccc2c(OCC3CO3)cccc2c1
Yield: 93 %

Procedure:
Into a 500 mL three-necked round bottom flask, 10.03 g 1-naphthol, 3.1 g NaOH, 20.4 g epichlorohydrin (SIR) and 0.5 g KI were added, then 330 mL ethanol was added. The flask was then placed in a microwave reactor. The reaction was performed at 30° C. under stirring and 300 W microwave irradiation for 12 min. The reaction mixture was then removed and suction filtrated, and the filtrate was concentrated to obtain an oily substance. H2O was added to the oily substance, and the mixture was extracted with ethyl ether. The ethyl ether layers were combined and washed with a solution of NaOH, then washed with H2O once. The ether layer was dried using anhydrous magnesium sulfate and concentrated to obtain 12.95 g of the product in a yield of 93.2%.
Reaction SMILES: [Cl-].[Cl-].[Cl-].[In+3].Cl[SiH](C1C=CC=CC=1)C1C=CC=CC=1.[CH2:19]([N:26]1[CH2:33][CH:32]2[CH:28]([CH:29](O)[C:30]3[CH:36]=[CH:35][S:34][C:31]=32)[CH2:27]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>ClC(Cl)C>[CH2:19]([N:26]1[CH2:33][CH:32]2[CH:28]([CH2:29][C:30]3[CH:36]=[CH:35][S:34][C:31]=32)[CH2:27]1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: OC1c2ccsc2C2CN(Cc3ccccc3)CC12
Agent: Cl[SiH](c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [In+3]
Solvent: CC(Cl)Cl
Product: c1ccc(CN2CC3Cc4ccsc4C3C2)cc1
Temperature: 60 °C
Yield: 57 %

Procedure:
Indiumtrichloride (973 mg, 4.40 mmol) and chlorodiphenylsilane (2888 mg, 13.20 mmol) were added to a solution of the product from step f) (1192 mg, 4.40 mmol) in 20 mL of dichloroethane. The reaction mixture was heated at 60° C. overnight and then was cooled to room temperature and quenched with saturated NaHCO3 (50 ml). The reaction mixture was extracted with ethylacetate (2×50 mL). The combined organic extracts were washed with brine (50 ml), dried with MgSO4 and solvent evaporated in vacuo to afford the subtitle compound (638 mg, yield: 57%) that was used without further purification. MS calculated C16H17NS +H: 256, observed: 256.
Reaction SMILES: N[C:2]1[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[C:5]2[N:6]([C:10]3[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=3)[C:7](=[O:9])[NH:8][C:4]=2[CH:3]=1.[C:23]([Cu])#[N:24].N(OC(C)(C)C)=O>CS(C)=O.[Cl-].[Na+].O>[Cl:16][C:13]1[CH:12]=[CH:11][C:10]([N:6]2[C:5]3[C:17]([C:19]([F:21])([F:22])[F:20])=[CH:18][C:2]([C:23]#[N:24])=[CH:3][C:4]=3[NH:8][C:7]2=[O:9])=[CH:15][CH:14]=1
Reactant: N#C[Cu]
Reactant: Nc1cc(C(F)(F)F)c2c(c1)[nH]c(=O)n2-c1ccc(Cl)cc1
Agent: CC(C)(C)ON=O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: N#Cc1cc(C(F)(F)F)c2c(c1)[nH]c(=O)n2-c1ccc(Cl)cc1
Temperature: 55 °C
Reaction time: 4 h
Yield: 23.2 %

Procedure:
5-Amino-1-(4-chlorophenyl)-7-(trifluoromethyl)-1,3-dihydro-2H-benzimidazol-2-one (0.7398 g) was dissolved in dimethyl sulfoxide (35 ml), and to the solution was added CuCN (0.6065 g). The mixture was heated at 55° C. At the same temperature, t-butyl nitrite (0.792 ml) was added dropwise during 1.5 hours. After the addition was completed, the mixture was stirred at 60° C. for 4 hours. After allowing to cool, to the reaction mixture was added saturated brine, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo. The resultant residue was purified by silica gel column (100 g, CHCl3:methanol=25:1) and then by silica gel column (70 g, hexane:ethyl acetate=1:1) to give the title compound (0.1767 g, 23%).
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[C:6]([CH3:16])=[C:7]([NH:12][C:13](=[O:15])[CH3:14])[C:8]([CH3:11])=[CH:9][CH:10]=1)=[O:4].Cl.[N:18]1([C:24]2[C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=3[S:26][N:25]=2)[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1>>[S:26]1[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[C:24]([N:18]2[CH2:19][CH2:20][N:21]([CH2:2][C:3]([C:5]3[C:6]([CH3:16])=[C:7]([NH:12][C:13](=[O:15])[CH3:14])[C:8]([CH3:11])=[CH:9][CH:10]=3)=[O:4])[CH2:22][CH2:23]2)=[N:25]1
Reactant: c1ccc2c(N3CCNCC3)nsc2c1
Reactant: CC(=O)Nc1c(C)ccc(C(=O)CCl)c1C
Agent: Cl
Product: CC(=O)Nc1c(C)ccc(C(=O)CN2CCN(c3nsc4ccccc34)CC2)c1C
Yield: 64.4 %

Procedure:
Starting with N-[3-(2-chloro-acetyl)-2,6-dimethyl-phenyl]-acetamide (0.250 g, 1.04 mmol), and 3-piperazin-1-yl-benzo[d]isothiazole hydrochloride (0.290 g, 1.15 mmol) and following the procedure as outlined in Example 517, N-{3-[2-(4-benzo[d]isothiazol-3-yl-piperazin-1-yl)-acetyl]-2,6-dimethyl-phenyl}-acetamide (0.285 g, 0.67 mmol) was obtained as its hydrochloride salt from treatment with dioxane/HCl(gas). Yield=65%. 100% purity at 254 nM. 1H NMR (400 MHz, DMSO-d6) δ 9.29 (s, 2H), 8.00 (d, J=8.04 Hz, 2H), 7.55–7.47 (m, 2H), 7.38 (t, J=8.04 Hz, 1H), 7.14 (t, J=8.04 Hz, 1H), 3.76 (s, 2H), 4.13–3.99 (m, 2H), 3.42–3.36 (m, 4H), 3.28 (s, H2O), 2.45 (p, DMSO), 2.14–2.11 (m, 6H), 2.01 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([NH:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:10]=[C:9]([C:20]#[N:21])[N:8]=2)[N:5]=[C:4]([NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:3]=1.C([O-])([O-])=[O:30].[K+].[K+]>CS(C)=O.OO>[NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([NH:13][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:10]=[C:9]([C:20]([NH2:21])=[O:30])[N:8]=2)[N:5]=[C:4]([NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:3]=1
Reactant: O=C([O-])[O-]
Reactant: N#Cc1nc(Nc2ccccc2)cc(-n2nc(Nc3ccccc3)nc2N)n1
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Product: NC(=O)c1nc(Nc2ccccc2)cc(-n2nc(Nc3ccccc3)nc2N)n1
Reaction time: 0.17 h
Yield: 61 %

Procedure:
To (20 mg; 0.054 mMol) of 4-(5-amino-3-phenylamino-[1,2,4]triazol-1-yl)-6-phenylamino-pyrimidine-2-carbonitrile in 500 μL of DMSO was added, at ambient temperature, (5 mg; 0.036 mMol) of anhydrous K2CO3, followed by 10 drops of 30% aqueous H2O2. The reaction was stirred for 10 min and quenched with water. The aqueous layer was extracted with EtOAc (2×). The organic fractions were combined and washed with water, brine, and then dried (Na2SO4), filtered and concentrated. The solid was triturated with hot 2-propanol, allowed to cool and the solid was collected via suction filtration, washed with 2-propanol, and MTBE, and air-dried to provide an off white powder (61% yield).