Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1(O)[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][C:4]([CH3:11])([CH3:10])[CH2:3]1.[OH2:13].N.[C:15](#[N:17])[CH3:16]>>[C:15]([NH:17][C:2]1([CH3:1])[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][C:4]([CH3:11])([CH3:10])[CH2:3]1)(=[O:13])[CH3:16]
Reactant: O
Reactant: CC1(C)CC(C)(C)CC(C)(O)C1
Reactant: CC#N
Agent: N
Product: CC(=O)NC1(C)CC(C)(C)CC(C)(C)C1
Temperature: -50 °C
Reaction time: 6 h
Yield: 60 %

Procedure:
To a vigorously stirred solution of 1,3,3,5,5-pentamethylcyclohexanol (3-13) (3.0 g, 17.65 mmol) in acetonitrile (20 ml) fuming HNO3 (6ml) was added dropwise, keeping temperature below 45° C. The resulting mixture was stirred at -50° C. for 6 h, then it was cooled, poured into water (30 ml) ana neutralised with aqueous NH3. Aqueous phase was extracted with ether (3*30 ml). The combined ether phases were washed with saline (30 ml), then dried over MgSO4, filtered and evaporated. The crude product was crystallised from cold acetonitrile to give 223 g (60%) of 14-2 as a white crystals, m.p. 110° C.
Reaction SMILES: O1CCCCC1[O:7][NH:8][C:9]([C@H:11]([C@@H:21]([CH2:33][CH:34]([CH3:36])[CH3:35])[C:22]([NH:24][N:25]1[C:30](=[O:31])[CH2:29][NH:28][CH2:27][C:26]1=[O:32])=[O:23])[CH2:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:10].O.[C:38]1([CH3:48])[CH:43]=[CH:42][C:41]([S:44]([OH:47])(=[O:46])=[O:45])=[CH:40][CH:39]=1>C(O)(C)C.CO>[C:38]1([CH3:48])[CH:39]=[CH:40][C:41]([S:44]([OH:47])(=[O:45])=[O:46])=[CH:42][CH:43]=1.[OH:7][NH:8][C:9]([C@H:11]([C@@H:21]([CH2:33][CH:34]([CH3:36])[CH3:35])[C:22]([NH:24][N:25]1[C:26](=[O:32])[CH2:27][NH:28][CH2:29][C:30]1=[O:31])=[O:23])[CH2:12][CH2:13][CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)=[O:10]
Reactant: CC(C)C[C@@H](C(=O)NN1C(=O)CNCC1=O)[C@H](CCCc1ccccc1)C(=O)NOC1CCCCO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Solvent: CC(C)O
Product: CC(C)C[C@@H](C(=O)NN1C(=O)CNCC1=O)[C@H](CCCc1ccccc1)C(=O)NO
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.7 %

Procedure:
A solution of 0.072 g of 2(R)-[1(S)-[(tetrahydro-2(RS)-pyranyloxy)carbamoyl]-4-phenylbutyl]-4-methyl-N-(2,6-dioxo-1-piperazinyl)valeramide in a mixture of 5 ml of isopropyl alcohol and 1 ml of methanol was treated with 0.030 g of p-toluenesulphonic acid monohydrate at 0° C. The mixture was left to warm to room temperature and was stirred overnight. Evaporation and trituration of the residue with diethyl ether gave 0.059 g of 2(R)-[1(S)-(hydroxycarbamoyl)-4-phenylbutyl]-4-methyl-N-(2,6-dioxo-1-piperazinyl)valeramide p-toluenesulphonate in the form of an off-white solid.
Reaction SMILES: C=C[C@@H]1[C@@H]2C[C@H]([C@@H:11]([OH:22])[C:12]3C=CN=C4C=CC=CC=34)N(CC2)C1.N1C=CC=CC=1.[CH3:29][NH:30][C:31]([C:33]1[CH:42]=[CH:41][C:40]2[C:35](=[CH:36][CH:37]=[C:38]([C:43]([C:45]3[N:46]=[CH:47][N:48]([C:50]([C:63]4[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=4)([C:57]4[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=4)[C:51]4[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=4)[CH:49]=3)=[O:44])[CH:39]=2)[CH:34]=1)=[O:32].Cl.C[O:71][CH:72]1CCC[CH2:73]1>C(OCC)(=O)C.C1COCC1>[OH:44][C@@:43]([C:38]1[CH:37]=[CH:36][C:35]2[C:40](=[CH:41][CH:42]=[C:33]([C:31]([NH:30][CH3:29])=[O:32])[CH:34]=2)[CH:39]=1)([C:45]1[N:46]=[CH:47][N:48]([C:50]([C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)([C:57]2[CH:58]=[CH:59][CH:60]=[CH:61][CH:62]=2)[C:63]2[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=2)[CH:49]=1)[CH2:73][C:72]([O:22][CH2:11][CH3:12])=[O:71]
Reactant: C=C[C@H]1CN2CC[C@H]1C[C@@H]2[C@@H](O)c1ccnc2ccccc12
Reactant: COC1CCCC1
Reactant: CNC(=O)c1ccc2cc(C(=O)c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)ccc2c1
Agent: Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CCOC(=O)C[C@](O)(c1ccc2cc(C(=O)NC)ccc2c1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reaction time: 0.33 h
Yield: 93 %

Procedure:
75.0 mL (75.0 mmol) of the solution of ethyl bromozincacetate in cyclopentyl methyl ether obtained in Example 65 was added dropwise to 100 mL of THF at −15˜−5° C. 11.0 g (37.5 mmol) of cinchonine was added at −15˜−5° C., 9.7 mL (120 mmol) of pyridine was added dropwise, and the mixture was stirred for 20 minutes. 15.6 g (30.0 mmol) of N-methyl-6-[(1-trityl-1H-imidazol-4-yl)carbonyl]-2-naphthamide was added at once by assisting by 25 mL of flowing THF at −15˜−5° C., and the mixture was stirred at the same temperature for 1 hour. 30.0 mL (30.0 mmol) of the solution of ethyl bromozincacetate in cyclopentyl methyl ether obtained in Example 65 was added dropwise at −15˜−5° C. over 40 minutes, and the mixture was stirred at the same temperature for 1 hour. 420 mL of ethyl acetate and 210 mL of 1N hydrochloric acid were added in this order at −15˜10° C., and the mixture was stirred at 15˜25° C. for 30 minutes. The organic layer was washed with 210 mL of 1N hydrochloric acid, and further 210 mL (×3) of water, 210 mL (×2) of an aqueous saturated sodium bicarbonate solution, and 210 mL of water. After washing, the organic layer was concentrated to about 50 mL under heating and reduced pressure (inner temperature 20˜40° C.). 50 mL of ethyl acetate was added, followed by re-concentration procedure two times. 50 mL of ethyl acetate was added to the residue, the mixture was stirred at room temperature for 1 hour, 50 mL of IPE was added, and the mixture was stirred at room temperature. After stirred at 0˜10° C. for 1 hour, crystals were filtered, washed with 16 mL (×2) of IPE, and dried to obtain 17.0 g of ethyl (3S)-3-hydroxy-3-{6-[(methylamino)carbonyl]-2-naphthyl}-3-(1-trityl-1H-imidazol-4-yl)propanoate (yield 93%, enantiomer excess 94.3% ee).
Reaction SMILES: C(N(CC)CC)C.O.[OH:9][C:10]1[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=1.[C:16](Cl)(=[O:25])[O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].Cl>C(Cl)(Cl)Cl>[CH2:18]([O:17][C:16]([O:9][C:10]1[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=1)=[O:25])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CCCCCCCOC(=O)Cl
Reactant: Oc1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCCCCCCOC(=O)Oc1ccncc1
Temperature: 25 °C

Procedure:
100 ml of chloroform and 7.3 ml (0.052 mol) of triethylamine were added and dissolved in 4.5 g (0.040 mol) of 4-hydroxypyridine-monohydrate and stirred at 25° C. To this was dropwise added 8.9 g (0.050 mol) of heptyl chlorocarbonate. After stirring for 30 minutes, a cold aqueous hydrochloric acid solution was added to the reaction mixture for liquid separation, and the chloroform layer separated was washed two times with cold water and dried with Glauber's salt. After the Glauber's salt was filtrated out, the chloroform was distilled out and the remaining precipitate was purified by column chromatography and crystallized in ethanol. The product had a melting point of from 44° to 50° C. Yield: 7.5 g, 83%.
Reaction SMILES: [ClH:1].[NH2:2][OH:3].C(=O)([O-])[O-].[K+].[K+].[CH2:10]([C@H:17]([NH:26][C:27]([C:29]1[NH:30][C:31]2[C:36]([CH:37]=1)=[CH:35][C:34](Cl)=[CH:33][CH:32]=2)=[O:28])[C:18](=[O:25])[N:19]1[CH2:23][CH2:22][C:21](=O)[CH2:20]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(O)C.O>[CH2:10]([C@H:17]([NH:26][C:27]([C:29]1[NH:30][C:31]2[C:36]([CH:37]=1)=[CH:35][C:34]([Cl:1])=[CH:33][CH:32]=2)=[O:28])[C:18]([N:19]1[CH2:23][CH2:22][C:21](=[N:2][OH:3])[CH2:20]1)=[O:25])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: NO
Reactant: O=C1CCN(C(=O)[C@H](Cc2ccccc2)NC(=O)c2cc3cc(Cl)ccc3[nH]2)C1
Reactant: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: O=C(N[C@@H](Cc1ccccc1)C(=O)N1CCC(=NO)C1)c1cc2cc(Cl)ccc2[nH]1
Reaction time: 48 h

Procedure:
Hydroxylamine hydrochloride (68 mg, 0.82 mmol) and potassium carbonate (136 mg, 0.98 mmol) were added to a solution of 5-chloro-1H-indole-2-carboxylic acid [(1S)-benzyl-2-oxo-2-(3-oxo-pyrrolidin-1-yl)-ethyl]-amide in ethanol (5 ml) and water (1 ml) at 25° C. After 48 hours, the reaction mixture was concentrated and the residue dissolved in ethyl acetate. The resulting solution was washed two times with water and once with brine, dried over Na2SO4, and concentrated. Two substances appearing to be syn/anti oxime isomers separated by chromatography on silica eluted with 2.5%, 5%, and 10% ethanol in dichloromethane.
Reaction SMILES: [OH:1][C:2]1[CH:30]=[CH:29][C:5]([C:6]([C:8]2[CH:28]=[CH:27][C:11]([CH2:12][S:13][C:14]3[N:23]([CH3:24])[C:22](=[O:25])[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][C:20]=4[CH3:26])[N:15]=3)=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[CH2:31]([O:38][C:39]1[CH:46]=[CH:45][C:42]([CH2:43]Cl)=[CH:41][CH:40]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:31]([O:38][C:39]1[CH:40]=[CH:41][C:42]([CH2:43][O:1][C:2]2[CH:3]=[CH:4][C:5]([C:6]([C:8]3[CH:28]=[CH:27][C:11]([CH2:12][S:13][C:14]4[N:23]([CH3:24])[C:22](=[O:25])[C:21]5[C:16](=[CH:17][CH:18]=[CH:19][C:20]=5[CH3:26])[N:15]=4)=[CH:10][CH:9]=3)=[O:7])=[CH:29][CH:30]=2)=[CH:45][CH:46]=1)[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: ClCc1ccc(OCc2ccccc2)cc1
Reactant: Cc1cccc2nc(SCc3ccc(C(=O)c4ccc(O)cc4)cc3)n(C)c(=O)c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cccc2nc(SCc3ccc(C(=O)c4ccc(OCc5ccc(OCc6ccccc6)cc5)cc4)cc3)n(C)c(=O)c12
Yield: 78.1 %

Procedure:
A solution of 2-[4-(4-hydroxybenzoyl)benzylthio]-3,5-dimethyl-4(3H)-quinazolinone (309 mg), 4-benzyloxybenzyl chloride (224 mg) and potassium carbonate (295 mg) in DMF (5 ml) was stirred at room temperature for 14 hours. This reaction mixture was concentrated and the residue was dissolved in chloroform. The solution was washed with water, dried, and concentrated. The residue was recrystallized from chloroform-ethyl acetate to provide the title compound as colorless solid (355 mg).
Reaction SMILES: [Cl:1][C:2]1[C:40]([Cl:41])=[CH:39][C:5]2[NH:6][C:7]([O:9][CH:10]([C:19]3([C:25]4[CH:30]=[CH:29][C:28]([C:31]5[CH:36]=[CH:35][CH:34]=[C:33]([C:37]#[N:38])[CH:32]=5)=[CH:27][CH:26]=4)[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)[CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])=[N:8][C:4]=2[CH:3]=1.[CH3:42][S:43](Cl)(=[O:45])=[O:44].CCN(C(C)C)C(C)C>ClCCl.C(OCC)(=O)C>[Cl:1][C:2]1[C:40]([Cl:41])=[CH:39][C:5]2[NH:6][C:7]([O:9][CH:10]([C:19]3([C:25]4[CH:30]=[CH:29][C:28]([C:31]5[CH:36]=[CH:35][CH:34]=[C:33]([C:37]#[N:38])[CH:32]=5)=[CH:27][CH:26]=4)[CH2:24][CH2:23][N:22]([S:43]([CH3:42])(=[O:45])=[O:44])[CH2:21][CH2:20]3)[CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])=[N:8][C:4]=2[CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: C[Si](C)(C)CCOCC(Oc1nc2cc(Cl)c(Cl)cc2[nH]1)C1(c2ccc(-c3cccc(C#N)c3)cc2)CCNCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: C[Si](C)(C)CCOCC(Oc1nc2cc(Cl)c(Cl)cc2[nH]1)C1(c2ccc(-c3cccc(C#N)c3)cc2)CCN(S(C)(=O)=O)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 128.3 %

Procedure:
To a solution of 0.030 g of 4′-{4-[5,6-dichloro-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazol-2-yloxymethyl]-piperidin-4-yl}-biphenyl-3-carbonitrile (0.05 mmol) 55 in 1 mL of dichloromethane was added methanesulfonyl chloride (0.005 mL, 0.053 mmol, 1.1 eq) and DIEA (0.011 mL, 0.06 mmol, 1.2 eq). The resulting mixture was stirred at room temperature for 16 h, diluted with 5 mL of ethyl acetate, and washed with H2O and saturated brine. The organic extracts were combined and dried over Na2SO4, filtered and concentrated by rotary evaporation to give 0.044 g of 4′-{4-[5,6-dichloro-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazol-2-yloxymethyl]-1-methanesulfonyl-piperidin-4-yl}-biphenyl-3-carbonitrile as a pale foam. MS (ESI): m/z 684.8/686.8 (M+1/M+3).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([C:8](OCC)=[O:9])=[C:4]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[C:16]([CH3:21])[N:15]=2)[CH:3]=1.[NH3:22].CO>>[Cl:1][C:2]1[N:7]=[N:6][C:5]([C:8]([NH2:22])=[O:9])=[C:4]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[C:16]([CH3:21])[N:15]=2)[CH:3]=1
Reactant: N
Reactant: CCOC(=O)c1nnc(Cl)cc1Nc1ccc(C)c(C)n1
Solvent: CO
Product: Cc1ccc(Nc2cc(Cl)nnc2C(N)=O)nc1C
Temperature: 50 °C
Yield: 100 %

Procedure:
A pressure tube was charged with ethyl 6-chloro-4-(5,6-dimethylpyridin-2-ylamino)pyridazine-3-carboxylate (133 mg, 434 μmol) and 7N ammonia in methanol (9.44 g, 12 mL, 84.0 mmol). The mixture was heated in an oil bath at 50° C. for 18 h. After cooling to room temperature the reaction mixture was concentrated in vacuo to afford 6-chloro-4-(5,6-dimethylpyridin-2-ylamino)pyridazine-3-carboxamide (160 mg, 100%) as a yellow solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 11.48 (br. s., 1H) 9.18 (s, 1H) 8.17 (br. s., 1H) 7.43 (d, J=8.34 Hz, 1H) 6.74 (d, J=7.83 Hz, 1H) 5.67 (br. s., 1H) 2.53 (s, 3H) 2.28 (s, 3H); LCMS (EI/CI) m/z: 278 [M+H]. This material was used directly in the next step without further purification.
Reaction SMILES: I([O-])(=O)(=O)=[O:2].[Na+].[F:7][C:8]([F:46])([F:45])[C:9]1[CH:10]=[C:11]([C:19]([CH3:44])([CH3:43])[C:20]([N:22]([CH3:42])[C:23]2[CH:24]=[N:25][C:26]([N:36]3[CH2:41][CH2:40][O:39][CH2:38][CH2:37]3)=[CH:27][C:28]=2[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[CH3:35])=[O:21])[CH:12]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:14]=1>C(Cl)(Cl)(Cl)Cl.O.O.[Ru](=O)=O>[F:46][C:8]([F:7])([F:45])[C:9]1[CH:10]=[C:11]([C:19]([CH3:44])([CH3:43])[C:20]([N:22]([CH3:42])[C:23]2[CH:24]=[N:25][C:26]([N:36]3[CH2:41][CH2:40][O:39][CH2:38][C:37]3=[O:2])=[CH:27][C:28]=2[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[CH3:35])=[O:21])[CH:12]=[C:13]([C:15]([F:18])([F:16])[F:17])[CH:14]=1
Reactant: Cc1ccccc1-c1cc(N2CCOCC2)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Ru]=O
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Product: Cc1ccccc1-c1cc(N2CCOCC2=O)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 34.3 %

Procedure:
To an ice-cooled suspension of 1.2 g (7.1 mmol) ruthenium(IV)oxide hydrate in a mixture of 50 ml carbon tetrachloride and 50 ml water were added 9.0 g (42 mmol) sodium periodate. After stirring for 30 min the organic layer was separated and the aqueous layer was extracted twice with 10-ml portions of carbon tetrachloride. The combined organic layers were filtered over celite, cooled to 0° C. and were added slowly to an ice-cooled solution of 2.0 g (3.54 mmol) 2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-N-(6-morpholin-4-yl-4-o-tolyl-pyridin-3-yl)-isobutyramide in 20 ml carbon tetrachloride. The mixture was stirred for additional 15 min at 0° C., was filtered over celite and was evaporated. The residue was purified by flash-chromatography and gave 704 mg (34%) of the title compound as colourless foam. MS m/e (%): 580 (M+H+, 100).
Reaction SMILES: [OH-].[K+].[CH3:3]C1C=CC(S(N(N=O)C)(=O)=O)=CC=1.C(O)CO.CCOCC.[NH:26]1[C:30]2[CH:31]=[C:32]([N:35]3[CH:39]([C:40]4[CH:45]=[CH:44][CH:43]=[C:42]([F:46])[C:41]=4[F:47])[C:38]([CH2:48][CH3:49])=[C:37]([OH:50])[C:36]3=[O:51])[CH:33]=[CH:34][C:29]=2[N:28]=[CH:27]1>CO>[NH:26]1[C:30]2[CH:31]=[C:32]([N:35]3[CH:39]([C:40]4[CH:45]=[CH:44][CH:43]=[C:42]([F:46])[C:41]=4[F:47])[C:38]([CH2:48][CH3:49])=[C:37]([O:50][CH3:3])[C:36]3=[O:51])[CH:33]=[CH:34][C:29]=2[N:28]=[CH:27]1
Reactant: Cc1ccc(S(=O)(=O)N(C)N=O)cc1
Reactant: CCC1=C(O)C(=O)N(c2ccc3nc[nH]c3c2)C1c1cccc(F)c1F
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: OCCO
Solvent: CCOCC
Product: CCC1=C(OC)C(=O)N(c2ccc3nc[nH]c3c2)C1c1cccc(F)c1F

Procedure:
The compound was synthesized starting from KOH (15 eq in water), diazald (9 eq), ethylene glycol/Et2O (1/5 v/v, 30 ml), 1-(1H-Benzo[d]imidazol-6-yl)-4-ethyl-5-(2,3-difluorophenyl)-3-hydroxy-1H-pyrrol-2(5H)-one (1.2 g, 2.81 mmol, 1 eq) and MeOH (10 ml), the product was further purified by preparative HPLC; yield: 0.085 g (8.2%); MS m/z: 370.1 [M+H]+; 1H-NMR: (400 MHz, DMSO-D6) δ: 1.01 (t, 3H), 1.94 (m, 1H), 2.39 (m, 1H), 3.96 (s, 3H), 6.24 (s, 1H), 7.12 (s, 1H), 7.55-7.26 (m, 3H), 7.67 (s, 1H), 8.17 (s, 1H), 12.43 (s, 1H); HPLC (METHOD [A]): rt 13.32 min (100%)
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].Cl.Cl.[O:10]([C:17]1[C:18]([NH:33][C:34]2[S:35][CH:36]=[C:37]([CH2:39][CH:40]3[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]3)[N:38]=2)=[N:19][CH:20]=[C:21]([S:23][C:24]2[CH:29]=[CH:28][N:27]=[C:26]3[CH:30]=[CH:31][S:32][C:25]=23)[CH:22]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(N(CC)CC)C>C1COCC1>[O:10]([C:17]1[C:18]([NH:33][C:34]2[S:35][CH:36]=[C:37]([CH2:39][CH:40]3[CH2:45][CH2:44][N:43]([C:1](=[O:3])[CH3:2])[CH2:42][CH2:41]3)[N:38]=2)=[N:19][CH:20]=[C:21]([S:23][C:24]2[CH:29]=[CH:28][N:27]=[C:26]3[CH:30]=[CH:31][S:32][C:25]=23)[CH:22]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CC(=O)OC(C)=O
Reactant: c1ccc(Oc2cc(Sc3ccnc4ccsc34)cnc2Nc2nc(CC3CCNCC3)cs2)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)N1CCC(Cc2csc(Nc3ncc(Sc4ccnc5ccsc45)cc3Oc3ccccc3)n2)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 91.2 %

Procedure:
Added acetic anhydride (0.0169 g, 0.165 mmol) to a mixture of 3-phenoxy-N-(4-(piperidin-4-ylmethyl)thiazol-2-yl)-5-(thieno[3,2-b]pyridin-7-ylthio)pyridin-2-amine dihydrochloride (0.100 g, 0.165 mmol), triethylamine (0.0837 g, 0.827 mmol), and THF (5 mL) at 0° C. Warmed to ambient temperature and stirred for 4 hours. Partitioned between ethyl acetate and 2N NaOH, washed with water, brine, dried, and concentrated. The residue was dissolved in dichloromethane (2 mL) and 1N HCl in ether was added. Diluted in hexanes, and concentrated, added hexanes again and concentrated to afford the title compound ((Mixture of rotamers; 0.092 g, 91.2% yield) as a light yellow powder: 1H NMR (d6-DMSO) δ 8.65 (d, 1H); 8.47 (d, 1H), 8.46 (s, 1H), 7.77 (d, 1H), 7.41 (s, 1H), 7.41 (d, 2H), 7.15-7.20 (m, 4H), 6.84 (s, 1H), 0.95-4.36 (m, 1H), 1.97 (s, 3H).
Reaction SMILES: [CH:1]1([O:6][C:7]2[C:12]3[O:13][C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=4[C:11]=3[CH:10]=[CH:9][CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[CH:21]([O:23]C)Cl.[Sn](Cl)(Cl)(Cl)Cl.[K+].[Br-]>>[CH:1]1([O:6][C:7]2[C:12]3[O:13][C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=4[C:11]=3[C:10]([CH:21]=[O:23])=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: c1ccc2c(c1)oc1c(OC3CCCC3)cccc12
Reactant: COC(Cl)Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: [Br-]
Agent: [K+]
Product: O=Cc1ccc(OC2CCCC2)c2oc3ccccc3c12
Yield: 31.5 %

Procedure:
Reaction of 4-cyclopentyloxydibenzo[b,d]furan (1.0 g, 3.96 mmol) with dichloromethylmethylether (456 mg, 3.96 mmol) in presence of tin(IV)chloride (1.55 g, 5.95 mmol), gave 350 mg (31.5%) of the product as white solid, IR (KBr)) 2960, 2730, 1686, 1565, 1276, 1099 cm−1. 1H NMR (300 MHz, CDCl3) δ 1.64-1.75 (m, 2H), 1.85-1.98 (m, 2H), 2.03-2.09 (m, 4H), 5.11 (quint, 1H), 7.07 (d, J=8.2 Hz, 1H), 7.38 (t, J=7.9H, 1H), 7.52 (t, J=7.8 Hz, 1H), 7.63 (d, J=8.4 Hz, 1H), 7.77 (d, J=8.2 Hz, 1H), 8.95 (d, J=8.4 Hz, 1H), 10.17 (s, 1H).
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1)([CH3:3])[CH3:2].[I:11]I>C(O)(=O)C>[I:11][C:7]1[CH:8]=[CH:9][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:5][C:6]=1[OH:10]
Reactant: CC(C)c1cccc(O)c1
Reactant: II
Solvent: CC(=O)O
Product: CC(C)c1ccc(I)c(O)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 160.8 %

Procedure:
A mixture of 3-isopropylphenol (670 mg, 4.92 mmol), KIO3 (210 mg, 0.98 mmol), and I2 (500 mg, 1.97 mmol) in acetic acid was stirred for 3 days at room temperature. The solvent was removed at reduced pressure. The residue was diluted with Et2O and washed with aq. NaHCO3, aq. Na2S2O3, and brine. The organic layer was dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure. The residue was purified with flash column chromatography to give the title compound (830 mg, 64%).
Reaction SMILES: [CH2:1]([N:3]([CH2:6]C)CC)[CH3:2].[NH2:8][C:9]1[C:10]([F:33])=[CH:11][C:12]([F:32])=[C:13]([N:15]2[C:24]3[C:19](=[CH:20][C:21]([F:27])=[C:22](F)[C:23]=3[Cl:25])[C:18](=[O:28])[C:17]([C:29]([OH:31])=[O:30])=[CH:16]2)[CH:14]=1.C(#[N:36])C>>[NH2:36][CH2:2][CH2:1][N:3]([C:22]1[C:23]([Cl:25])=[C:24]2[C:19]([C:18](=[O:28])[C:17]([C:29]([OH:31])=[O:30])=[CH:16][N:15]2[C:13]2[CH:14]=[C:9]([NH2:8])[C:10]([F:33])=[CH:11][C:12]=2[F:32])=[CH:20][C:21]=1[F:27])[CH3:6]
Reactant: Nc1cc(-n2cc(C(=O)O)c(=O)c3cc(F)c(F)c(Cl)c32)c(F)cc1F
Reactant: CC#N
Reactant: CCN(CC)CC
Product: CN(CCN)c1c(F)cc2c(=O)c(C(=O)O)cn(-c3cc(N)c(F)cc3F)c2c1Cl
Temperature: 60 °C

Procedure:
N-Methylenediamine (17 mg) and triethylamine (35 mg) were added to acetonitrile (5 ml), to which 1-(5-amino-2,4-difluorophenyl)-8-chloro-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (100 mg) was added with heating and stirring at 60° C. The resultant mixture was heated under reflux for 2 hours as it was. After the reaction mixture was allowed to cool, solids deposited were collected by filtration and washed with ethanol and diethyl ether to obtain the title compound (40 mg) as a pale brown powder.
Reaction SMILES: [C:1]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:24]=[C:23]3[C:19]([CH2:20][N:21]([C@@H:26]([CH:31]([CH3:33])[CH3:32])[C:27]([O:29][CH3:30])=[O:28])[C:22]3=[O:25])=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.NC1C=CC(C2C=C3C(CN([C@@H](C(C)C)C(OC)=O)C3=O)=CC=2)=CC=1.C1(C(Cl)=O)CCCCC1>>[CH:2]1([C:1]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:24]=[C:23]4[C:19]([CH2:20][N:21]([C@@H:26]([CH:31]([CH3:33])[CH3:32])[C:27]([O:29][CH3:30])=[O:28])[C:22]4=[O:25])=[CH:18][CH:17]=3)=[CH:12][CH:11]=2)=[O:8])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4ccccc4)cc3)cc2C1=O
Agent: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(N)cc3)cc2C1=O
Agent: O=C(Cl)C1CCCCC1
Product: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)C4CCCCC4)cc3)cc2C1=O
Yield: 75.96 %

Procedure:
The compound of example 117 was prepared analogous to compound of example 97 by reaction of compound of example 6 with cyclohexoyl chloride.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5](/[C:8](/[CH3:15])=[CH:9]/[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.[Cl:16][C:17]1[CH:18]=[C:19](B(O)O)[CH:20]=[C:21]([Cl:23])[CH:22]=1>>[Cl:16][C:17]1[CH:18]=[C:19]([C:2]2[CH:7]=[CH:6][C:5](/[C:8](/[CH3:15])=[CH:9]/[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=2)[CH:20]=[C:21]([Cl:23])[CH:22]=1
Reactant: OB(O)c1cc(Cl)cc(Cl)c1
Reactant: CCOC(=O)/C=C(\C)c1ccc(I)cc1
Product: CCOC(=O)/C=C(\C)c1ccc(-c2cc(Cl)cc(Cl)c2)cc1

Procedure:
The colourless solid (E)-ethyl 3-(3′,5′-dichloro-biphenyl-4-yl)-but-2-enoate was prepared from (E)-ethyl 3-(4-iodophenyl)-but-2-enoate (example 91 a) and 3,5-dichlorobenzene boronic acid by a procedure analogous to that described in example 52a.
Reaction SMILES: ON=[C:3]([C:5]1[C:14]2[C:9](=[CH:10][C:11]([OH:17])=[C:12]([O:15][CH3:16])[CH:13]=2)[CH:8]=[CH:7][N:6]=1)[CH3:4].[OH:18][C:19]1[C:26]([O:27][CH3:28])=[CH:25][CH:24]=[CH:23][C:20]=1[CH2:21][Br:22]>>[Br-:22].[OH:17][C:11]1[C:12]([O:15][CH3:16])=[CH:13][C:14]2=[C:5]3[N+:6](=[CH:7][CH:8]=[C:9]2[CH:10]=1)[CH:21]=[C:20]1[C:19]([OH:18])=[C:26]([O:27][CH3:28])[CH:25]=[CH:24][C:23]1=[C:3]3[CH3:4]
Reactant: COc1cc2c(C(C)=NO)nccc2cc1O
Reactant: COc1cccc(CBr)c1O
Product: COc1cc2c(cc[n+]3cc4c(O)c(OC)ccc4c(C)c23)cc1O
Product: [Br-]

Procedure:
The procedure of Example 1 is repeated except that 1-(1-hydroxyiminoethyl)-6-hydroxy-7-methoxyisoquinoline and 2-hydroxy-3-methoxybenzyl bromide are used as the starting materials. m.p. 211°-217° C. (with decomposition).