Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[CH3:47][C:48](=[CH:50][CH2:51][CH2:52]/[C:53](=[CH:55]/[CH2:56][OH:57])/[CH3:54])[CH3:49].[H][H]>CO>[CH3:47][C:48](=[CH:50][CH2:51][CH2:52][C@H:53]([CH2:55][CH2:56][OH:57])[CH3:54])[CH3:49]
Reactant: CC(C)=CCC/C(C)=C/CO
Reactant: [H][H]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: CO
Product: CC(C)=CCC[C@@H](C)CCO
Temperature: 25 °C
Reaction time: 12 h
Yield: 97.2 %

Procedure:
Under an inert gas atmosphere, 2.4 mg of [RuCl2(C6H6)]2 (corresponding to 0.01 μmol of Ru) were dissolved in 75 ml of methanol, 6.0 mg (80.01 μmol) of (S)-BINAP were added and the mixture was stirred for 12 h at room temperature until the resulting solution was clear. The catalyst solution was transferred to an autoclave fitted with a gas dispersion stirrer and a further 75 ml of methanol and 14.8 g of geraniol (0.096 mol, purity 95%) were added. The mixture was stirred for 24 h at a hydrogen pressure of 100 bar and a temperature of 40° C. A conversion of 98.3% was then determined by gas chromatography. A yield of 97.2% of (R)-citronellol with an enantiomeric purity of 95.2% ee was obtained.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([S:13]([NH:16][C:17]3([C:21]([OH:23])=[O:22])[CH2:20][CH2:19][CH2:18]3)(=[O:15])=[O:14])=[CH:10][CH:11]=2)[C:6]([NH:24][C:25]([NH2:27])=[NH:26])=[N:5][CH:4]=1.Cl.NC(N)=N.Cl[C:34]1[C:43]2C(=CC=C(S(NC3(C(OCC)=O)CCC3)(=O)=O)C=2)C(Cl)=CN=1.O>CS(C)=O>[Cl:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([S:13]([NH:16][C:17]3([C:21]([O:23][CH2:34][CH3:43])=[O:22])[CH2:20][CH2:19][CH2:18]3)(=[O:14])=[O:15])=[CH:10][CH:11]=2)[C:6]([NH:24][C:25]([NH2:27])=[NH:26])=[N:5][CH:4]=1
Reactant: CCOC(=O)C1(NS(=O)(=O)c2ccc3c(Cl)cnc(Cl)c3c2)CCC1
Reactant: N=C(N)Nc1ncc(Cl)c2ccc(S(=O)(=O)NC3(C(=O)O)CCC3)cc12
Agent: Cl
Agent: N=C(N)N
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)C1(NS(=O)(=O)c2ccc3c(Cl)cnc(NC(=N)N)c3c2)CCC1
Temperature: 60 °C
Yield: 68 %

Procedure:
1-{[(4-Chloro-1-guanidino-7-isoquinolinyl)sulphonyl]amino}cyclobutanecarboxylic acid hydrochloride ##STR47## NaH (37 mg, 80% dispersion by wt in mineral oil, 1.24 mmol) was added in one portion to a stirred solution of guanidine hydrochloride (189 mg, 1.98 mmol) in DMSO (6 mL) and the mixture was heated at 60° C. under N2 for 30 min. Ethyl 1-{[(1,4-dichloro-7-isoquinolinyl)sulphonyl]amino)-cyclobutanecarboxylate (200 mg, 0.50 mmol) was added in one portion and the mixture heated at 80° C. for 10 h. The cooled mixture was poured into water, extracted with EtOAc (2×50 mL) and the combined organic extracts were dried (MgSO4) and evaporated in vacuo. The residue was purified by column chromatography upon silica gel using pentane-EtOAc (50:50 to 0:100) as eluant to give ethyl 1-{[(4-chloro-1-guanidino-7-isoquinolinyl)sulphonyl]amino)cyclobutanecarboxylate (150 mg, 0.34 mmol) as a yellow powder.
Reaction SMILES: [OH:1][CH2:2][C:3]([N:6]1[C:11](=[O:12])[CH:10]=[CH:9][C:8]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[CH:7]1)([CH3:5])[CH3:4].N1C2C(=CC=C3C=2N=CC=C3)C=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].I[C:42]1[C:51]2[C:46](=[CH:47][C:48]([O:52][CH3:53])=[CH:49][CH:50]=2)[N:45]=[CH:44][CH:43]=1>CN(C=O)C.[Cu]I>[CH3:53][O:52][C:48]1[CH:47]=[C:46]2[C:51]([C:42]([O:1][CH2:2][C:3]([N:6]3[C:11](=[O:12])[CH:10]=[CH:9][C:8]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[CH:7]3)([CH3:5])[CH3:4])=[CH:43][CH:44]=[N:45]2)=[CH:50][CH:49]=1
Reactant: COc1ccc2c(I)ccnc2c1
Reactant: CC(C)(C)OC(=O)Nc1ccc(=O)n(C(C)(C)CO)c1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1ccc2c(OCC(C)(C)n3cc(NC(=O)OC(C)(C)C)ccc3=O)ccnc2c1
Temperature: 100 °C

Procedure:
A suspension of tert-butyl 1-(1-hydroxy-2-methylpropan-2-yl)-6-oxo-1,6-dihydropyridin-3-ylcarbamate (275 mg, 974 μmol), 1,10-phenanthroline (35 mg, 195 μmol), cesium carbonate (635 mg, 1948 μmol), copper(I) iodide (19 mg, 97 μmol), and 4-iodo-7-methoxyquinoline in DMF (4 mL) was heated to 100° C. for 2 h. The reaction mixture was partitioned between CH2Cl2 (50 mL) and 5% NaHCO3 (25 mL). The aqueous was extracted twice with CH2Cl2 (5 mL). The combined extracts were concentrated onto dry silica (10 g) and purified on 80 grams of silica eluting with 0-6% 2M NH3 in MeOH/CH2Cl2. MS (ESI pos. ion) m/z (MH+): 440. Calc'd exact mass for C24H29N3O5: 439.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:11][C:10](=[O:12])[C:9]2(Cl)Cl)=[C:4]([O:15][CH3:16])[CH:3]=1.[Cl-].[NH4+]>[Zn]>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:9][C:10](=[O:12])[CH2:11]2)=[C:4]([O:15][CH3:16])[CH:3]=1
Reactant: COc1cc(Br)ccc1C1CC(=O)C1(Cl)Cl
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Product: COc1cc(Br)ccc1C1CC(=O)C1
Temperature: 23 °C
Yield: 72.6 %

Procedure:
In a 50 mL round-bottom flask equipped with a reflux condenser is placed 3-(4-bromo-2-methoxyphenyl)-2,2-dichlorocyclobutanone (300 mg, 1.08 mmol) and activated zinc (280 mg, 4.30 mmol), in a saturated methanolic ammonium chloride solution (2 ml), the suspension is refluxed for 6 hr, then cooled to 23° C. and filtered through celite and rinsed with petroleum ether (10 mL), and organics are rinsed with water (10 mL), sat sodium bicarbonate (10 mL) and brine (10 ml), dried over sodium sulfate and concentrated under reduced pressure, the crude material was purified by silica gel chromatography to give the title compound (200 mg, 85%).
Reaction SMILES: C[O:2][C:3](=[O:28])[C@@H:4]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[CH:8][CH:7]=1.Cl>CO.[OH-].[Na+].CCOCC>[CH3:26][C:24]([CH3:27])([O:23][C:21]([NH:20][C@@H:4]([CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[CH:8][CH:7]=1)[C:3]([OH:28])=[O:2])=[O:22])[CH3:25]
Reactant: COC(=O)[C@H](Cc1ccc(CC(=O)OC(C)(C)C)cc1)NC(=O)OC(C)(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CO
Product: CC(C)(C)OC(=O)Cc1ccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)O)cc1
Yield: 77.9 %

Procedure:
A solution of 1.471 g of (S)-alpha-[[(1,1-dimethylethoxy)carbonyl]amino]-4-[2-(1,1-dimethylethoxy) -2-oxoethyl]benzenepropanoic acid methyl ester in 25 mL of methanol and 5 mL of 1N sodium hydroxide solution was stirred at room temperature for 2 hours. The mixture was acidified with a slight excess of hydrochloric acid, was diluted with 100 mL of ether, and was washed with water and saturated sodium chloride solution. The residue obtained after filtration and evaporation was chromatographed over 100 g of silica gel, eluting with 40:59:0.5 ethyl acetate-hexane-acetic acid. The product containing fractions were combined evaporated, diluted with toluene and evaporated finally under high vacuum to give 1.105 g of (S)-alpha-[[(1,1-dimethylethoxy) carbonyl]amino]-4-[2-(1,1-dimethylethoxy)-2-oxoethyl]benzene-propanoic acid [a]D +21.41 (ethanol).
Reaction SMILES: C([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:20][NH:21][C:22](=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1)=[O:19])C1C=CC=CC=1>CO.[Pd]>[OH:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:20][NH:21][C:22](=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1)=[O:19]
Reactant: O=C(NNC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1)c1ccccn1
Agent: [Pd]
Solvent: CO
Product: O=C(NNC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2O)c1ccccn1
Reaction time: 3 h
Yield: 99.1 %

Procedure:
A mixture of (2S,5R)-6-(benzyloxy)-7-oxo-NE-picolinoyl-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide 216 (0.30 g, 0.76 mmol) and Pd/C (0.40 g) in methanol (100 mL) was hydrogenated at 1 atm at room temperature for 3 h. The mixture was filtered through Celite pad and concentrated to provide 217 (0.23 g, quant. yield) as a white foam.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][C@@H:9]2[CH3:14])[CH:5]=[C:4]([C:15]([S:18]([CH3:21])(=[O:20])=[O:19])([CH3:17])[CH3:16])[N:3]=1.CC1(C)C(C)(C)OB([C:30]2[CH:36]=[CH:35][C:33]([NH2:34])=[CH:32][CH:31]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.COCCOC.C(O)C.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:14][C@H:9]1[CH2:10][O:11][CH2:12][CH2:13][N:8]1[C:6]1[CH:5]=[C:4]([C:15]([S:18]([CH3:21])(=[O:20])=[O:19])([CH3:17])[CH3:16])[N:3]=[C:2]([C:30]2[CH:36]=[CH:35][C:33]([NH2:34])=[CH:32][CH:31]=2)[N:7]=1
Reactant: C[C@H]1COCCN1c1cc(C(C)(C)S(C)(=O)=O)nc(Cl)n1
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CN(C)C=O
Solvent: O
Product: C[C@H]1COCCN1c1cc(C(C)(C)S(C)(=O)=O)nc(-c2ccc(N)cc2)n1
Temperature: 80 °C
Reaction time: 3 h
Yield: 67.6 %

Procedure:
Dichlorobis(triphenylphosphine)palladium(II) (0.287 g, 0.41 mmol) was added to 2-chloro-4-[(3S)-3-methylmorpholin-4-yl]-6-(2-methylsulfonylpropan-2-yl)pyrimidine (2.73 g, 8.18 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (2.329 g, 10.63 mmol) and 2M aqueous sodium carbonate (15 mL, 29.44 mmol) in DMF (15 mL), DME (15 mL), ethanol (15 mL) and water (37.5 mL) at RT under nitrogen. The reaction was purged with nitrogen for 15 minutes and the resulting mixture was stirred at 80° C. for 3 hours. The reaction mixture was diluted with ethyl acetate (300 mL) and washed sequentially twice with water (150 mL) and saturated brine (150 mL). The organic layer was dried (MgSO4), filtered and evaporated to afford crude product as a dark brown gum. The crude product was purified by flash silica chromatography, eluting with 0 to 20% ethyl acetate in DCM, to give the desired material as a white solid (2.16 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([C:12]2[C:16]([CH2:17][OH:18])=[N:15][O:14][N:13]=2)=[O:11])[CH:5]=[CH:6][C:7]=1[F:8].N1C(C)=CC=CC=1C.O([Si:35]([CH:42]([CH3:44])[CH3:43])([CH:39]([CH3:41])[CH3:40])[CH:36]([CH3:38])[CH3:37])S(C(F)(F)F)(=O)=O>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([C:12]2[C:16]([CH2:17][O:18][Si:35]([CH:42]([CH3:44])[CH3:43])([CH:39]([CH3:41])[CH3:40])[CH:36]([CH3:38])[CH3:37])=[N:15][O:14][N:13]=2)=[O:11])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CC(C)[Si](OS(=O)(=O)C(F)(F)F)(C(C)C)C(C)C
Reactant: O=C(Nc1ccc(F)c(Cl)c1)c1nonc1CO
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: CC(C)[Si](OCc1nonc1C(=O)Nc1ccc(F)c(Cl)c1)(C(C)C)C(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 91 %

Procedure:
To a stirred solution of N-(3-chloro-4-fluorophenyl)-4-(hydroxymethyl)-1,2,5-oxadiazole-3-carboxamide (3.2 g, 0.012 mol) in dichloromethane (DCM) (23 mL) at 0° C. was added 2,6-lutidine (3.4 mL, 0.029 mol) followed by triisopropylsilyl triflate (4.1 mL). The solution was stirred at 0° C. for 30 min and then the reaction was warmed to rt overnight. The reaction was concentrated and chromatographed on a silica column eluting with 15% ethyl acetate/hexane to yield a colorless oil (4.59 g, 91%). 1H NMR (400 MHz, DMSO-d6) δ: 11.03 (s, 1H), 8.01 (dd, J=6.7, 2.6 Hz, 1H), 7.67 (ddd, J=9.1, 4.3, 2.6 Hz, 1H), 7.44 (dd, J=9.1, 9.1 Hz, 1H), 5.2 (s, 2H), 1.09 (m, 3H), 0.99 (d, J=7.1 Hz, 18H); MF═C19H27ClFN3O3Si; LCMS calculated for C19H28ClFN3O3Si(M+H)+: m/z=428.157.
Reaction SMILES: O.CO.[C:4]1([C@H:10]2[N:14]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=3)(=[O:18])=[O:17])[C@@H:13]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C@H:12]([C:34]([O:36]C)=[O:35])[O:11]2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(=O)([O-])[O-].[K+].[K+]>C1COCC1>[C:4]1([C@H:10]2[N:14]([NH:15][S:16]([C:19]3[CH:20]=[CH:21][C:22]([N+:25]([O-:27])=[O:26])=[CH:23][CH:24]=3)(=[O:18])=[O:17])[C@@H:13]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[C@H:12]([C:34]([OH:36])=[O:35])[O:11]2)[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: COC(=O)[C@@H]1O[C@@H](c2ccccc2)N(NS(=O)(=O)c2ccc([N+](=O)[O-])cc2)[C@H]1c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)[C@@H]1O[C@@H](c2ccccc2)N(NS(=O)(=O)c2ccc([N+](=O)[O-])cc2)[C@H]1c1ccccc1
Reaction time: 5 h

Procedure:
Water (8 ml), methanol (8 ml) and THF (8 ml) are added to (2S,4S,5R)-2,4-diphenyl-3-(4-nitrobenzenesulfonamido)-5-methoxycarbonyl-1,3-oxazolidine (III, EXAMPLE 12A, 1.50 g 3.19 mmol). Potassium carbonate (1.018 g, 7.71 mmol) is then added. The resulting mixture is stirred at 20-25° until complete by TLC. After 5 hr the reaction is complete and the reaction mixture is extracted with basic methylene chloride (2×). The aqueous phase is then acidified with hydrochloric acid and extracted with ethyl acetate. The ethyl acetate phase is then washed with water, saline and dried over magnesiuim sulfate. Concentration of the organic phase (ethyl acetate) gives the title compound, mp=61-65°.
Reaction SMILES: [OH:1][C:2]1([C:15]([O:17][CH3:18])=[O:16])[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[H-].[Na+].Cl[CH2:22][CH2:23][O:24][CH3:25]>CN(C=O)C>[CH3:25][O:24][CH2:23][CH2:22][O:1][C:2]1([C:15]([O:17][CH3:18])=[O:16])[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9])[CH2:6][CH2:7]1
Reactant: COCCCl
Reactant: COC(=O)C1(O)CCN(C(=O)OC(C)(C)C)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCCOC1(C(=O)OC)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1-tert-butyl 4-methyl 4-hydroxypiperidine-1,4-dicarboxylate (360 mg, 1.39 mmol) in DMF (5.6 mL) was carefully added sodium hydride (60% dispersion in mineral oil, 84 mg, 2.08 mmol). The mixture was stirred for 30 minutes at room temperature. 1-Chloro-2-methoxyethane (0.38 mL, 4.17 mmol) was added, and the reaction was stirred at 60° C. for 72 hours. The reaction was quenched with 25 mL of water. The aqueous layer was extracted with ethyl acetate (3×25 mL). The combined organic layers were washed with brine, dried with MgSO4, and concentrated under vacuum. Silica gel chromatography (20-35% ethyl acetate:hexanes) provided the title compound and starting material as a mixture that was carried forward (150 mg, 1:2 product:starting material).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:16][C:17]([C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][C:28]([C:31]4[N:35]=[C:34]([CH3:36])[O:33][N:32]=4)=[CH:27][C:26]=3[CH3:37])=[CH:21][CH:20]=2)=[O:18])[CH:5]=[CH:6][C:7]=1[S:8][CH2:9][C:10]1[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=1.CI.[BH4-].[Na+].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([NH:16][C:17]([C:19]2[CH:20]=[CH:21][C:22]([C:25]3[CH:30]=[CH:29][C:28]([C:31]4[N:35]=[C:34]([CH3:36])[O:33][N:32]=4)=[CH:27][C:26]=3[CH3:37])=[CH:23][CH:24]=2)=[O:18])[CH:5]=[CH:6][C:7]=1[S:8][CH2:9][C:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH:11]=1
Reactant: Cc1nc(-c2ccc(-c3ccc(C(=O)Nc4ccc(SCc5ccncc5)c(Br)c4)cc3)c(C)c2)no1
Agent: O=C([O-])[O-]
Agent: [BH4-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: Cc1nc(-c2ccc(-c3ccc(C(=O)Nc4ccc(SCC5=CCNCC5)c(Br)c4)cc3)c(C)c2)no1
Temperature: 0 °C
Reaction time: 60 h
Yield: 48 %

Procedure:
A stirred solution of N-[3-bromo-4-(pyrid-4-ylmethylthio)phenyl]-2'-methyl-4'-(5-methyl-1,2,4-oxadiazol-3-yl)biphenyl-4-carboxamide (D 16) (1.41 g, 2.46 mmol) in dry DMF (15 ml) was treated with methyl iodide (0.184 ml, 2.95 mmol). After 60 h, the reaction mixture was evaporated under reduced pressure and the residue was triturated with ethyl acetate. The resultant brown solid was filtered off and dried in vacuo. It was redissolved in a mixture of ethanol (150 ml) and water (75 ml), cooled to 0° C. and treated with sodium borohydride (0.165 g, 4.35 mmol) slowly with stirring. After 1 h, the reaction mixture was treated with potassium carbonate solution (50 ml). The resultant suspension was extracted with dichloromethane (3×100 ml) and the combined organic layers were dried (Na2SO4) and evaporated under reduced pressure to give a brown solid, which was purified by silica gel chromatography (10% MeOH/CH2Cl2 as eluant) to give the title compound as a yellow oil (0.680 g, 47%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([N:9]2[C:13]3=[N:14][C:15]([CH3:31])=[CH:16][C:17]([N:18]4[CH2:23][CH2:22][CH:21]([CH2:24][CH2:25]OS(C)(=O)=O)[CH2:20][CH2:19]4)=[C:12]3[C:11]([CH3:32])=[CH:10]2)=[C:4]([CH3:33])[CH:3]=1.[Na+].[I-:35].O>CC(C)=O>[Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([N:9]2[C:13]3=[N:14][C:15]([CH3:31])=[CH:16][C:17]([N:18]4[CH2:23][CH2:22][CH:21]([CH2:24][CH2:25][I:35])[CH2:20][CH2:19]4)=[C:12]3[C:11]([CH3:32])=[CH:10]2)=[C:4]([CH3:33])[CH:3]=1
Reactant: Cc1cc(N2CCC(CCOS(C)(=O)=O)CC2)c2c(C)cn(-c3c(C)cc(Br)cc3C)c2n1
Reactant: [I-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: Cc1cc(N2CCC(CCI)CC2)c2c(C)cn(-c3c(C)cc(Br)cc3C)c2n1
Temperature: 25 °C
Yield: 87.6 %

Procedure:
A mixture of methanesulfonic acid 2-{1-[1-(4-bromo-2,6-dimethyl-phenyl)-3,6-dimethyl-1H-pyrrolo[2,3-b]pyridin-4-yl]-piperidin-4-yl}-ethyl ester (0.70 g) and NaI (0.59 g) in acetone (14 mL) was heated at reflux for 3 hours. After cooling to room temperature, water was added and the mixture was extracted with ethyl acetate. The organic phase was washed with water, dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure. The residue was purified with column chromatography (silica gel: Wako gel C200, eluent: hexane:ethyl acetate=10/1) to obtain 1-(4-bromo-2,6-dimethyl-phenyl)-4-[4-(2-iodo-ethyl)-piperidin-1-yl]-3,6-dimethyl-1H-pyrrolo[2,3-b]pyridine (0.65 g) as a white crystal.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([C:12]#[N:13])[C:9]([F:14])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[NH2:15][OH:16]>CCO>[NH2:13][C:12](=[N:15][OH:16])[C:10]1[C:9]([F:14])=[CH:8][C:3]([C:4]([O:6][CH3:7])=[O:5])=[C:2]([Cl:1])[CH:11]=1
Reactant: COC(=O)c1cc(F)c(C#N)cc1Cl
Reactant: NO
Solvent: CCO
Product: COC(=O)c1cc(F)c(C(N)=NO)cc1Cl
Temperature: 25 °C
Reaction time: 6 h

Procedure:
Methyl 2-chloro-4-cyano-5-fluorobenzoate (1.65 g; 7.72 mmol; 1 eq.) was suspended in EtOH (33 mL). Hydroxylamine (1.14 mL; 38.62 mmol; 5 eq.) was added in one portion. The reaction mixture was stirred at RT for 6 hours. The obtained suspension was filtered affording the title compound as a beige solid. 1H NMR (DMSO-d6, 300 MHz) δ 9.98 (br s, 1H), 7.74-7.67 (m, 2H), 6 (hr s, 2H), 3.87 (s, 3H). LC/MS (Method B): 247.0 (M+H)+; 245.1 (M−H)−. HPLC (Method A) Rt 1.80 min (Purity: 90.4%).
Reaction SMILES: COC(C1C=C(O)N(C2C=CC=CC=2F)N=1)=O.C(=O)([O-])[O-].[Cs+].[Cs+].BrCC1C=CC=CC=1C#N.C[O:35][C:36]([C:38]1[CH:42]=[C:41]([O:43][CH2:44][C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=2[C:51]#[N:52])[N:40]([C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][C:54]=2[F:59])[N:39]=1)=[O:37].[OH-].[Li+]>CN(C=O)C.C1COCC1.O>[C:51]([C:46]1[CH:47]=[CH:48][CH:49]=[CH:50][C:45]=1[CH2:44][O:43][C:41]1[N:40]([C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][C:54]=2[F:59])[N:39]=[C:38]([C:36]([OH:37])=[O:35])[CH:42]=1)#[N:52]
Reactant: COC(=O)c1cc(OCc2ccccc2C#N)n(-c2ccccc2F)n1
Agent: COC(=O)c1cc(O)n(-c2ccccc2F)n1
Agent: N#Cc1ccccc1CBr
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1ccccc1COc1cc(C(=O)O)nn1-c1ccccc1F
Temperature: 60 °C
Reaction time: 5 h
Yield: 86.4 %

Procedure:
1-(2-Fluoro-phenyl)-5-hydroxy-1H-pyrazole-3-carboxylic acid methyl ester (200 mg, 0.847 mmol) were dissolved in 5 ml of DMF and cesium carbonate (552 mg, 1.7 mmol) and 2-bromomethyl-benzonitrile (166 mg, 0.85 mmol) were added. The mixture was stirred for 5 h at 60° C., filtrated and the solvent was removed in vacuo. The obtained residue of crude 5-(2-cyano-benzyloxy)-1-(2-fluoro-phenyl)-1H-pyrazole-3-carboxylic acid methyl ester (235 mg, 79%) was dissolved in a mixture of THF, MOH and water (3 ml each), lithium hydroxide (64.1 mg, 2.7 mmol) was added, and the mixture was stirred overnight at room temperature. After evaporation of the solvent the residue was subjected to column chromatography (silica gel, DCM/MOH 9:1) to give 195 mg (86%) of the title compound.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH3:6][C:7]1[O:11][C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:9][C:8]=1[CH2:18][CH2:19][OH:20]>C(Cl)Cl>[CH3:6][C:7]1[O:11][C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:9][C:8]=1[CH2:18][CH2:19][O:20][S:2]([CH3:1])(=[O:4])=[O:3]
Reactant: Cc1oc(-c2ccccc2)nc1CCO
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Product: Cc1oc(-c2ccccc2)nc1CCOS(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
TEA (4.98 g, 49.2 mmol) and methanesulfonyl chloride (3.38 g, 29.5 mmol) is added to a solution of 2-(5-methyl-2-phenyl-oxazol-4-yl)-ethanol (5 g, 24.6 mmol) in 100 mL of DCM at 0° C. The resulting mixture is stirred at RT overnight. The mixture is then washed with water and brine, and the organic solution is dried over anhydrous magnesium sulfate and concentrated to give methanesulfonic acid 2-(5-methyl-2-phenyl-oxazol-4-yl)-ethyl ester as a yellow solid.
Reaction SMILES: [C:1]([C:4]1[C:5]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[NH:32][C:33](=[O:39])[O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[N:6][C:7]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:13][C:12]=2[O:23][CH3:24])=[N:8][CH:9]=1)(=O)[CH3:2].Cl.[NH2:41][OH:42]>>[OH:42]/[N:41]=[C:1](/[C:4]1[C:5]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[NH:32][C:33](=[O:39])[O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[N:6][C:7]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:13][C:12]=2[O:23][CH3:24])=[N:8][CH:9]=1)\[CH3:2]
Reactant: COc1cc(N2CCOCC2)ccc1Nc1ncc(C(C)=O)c(Nc2ccccc2NC(=O)OC(C)(C)C)n1
Reactant: NO
Agent: Cl
Product: COc1cc(N2CCOCC2)ccc1Nc1ncc(/C(C)=N/O)c(Nc2ccccc2NC(=O)OC(C)(C)C)n1

Procedure:
This intermediate was prepared in the same way as for Intermediate 3 in Example 298 in Example 299, using hydroxylamine hydrochloride instead of methoxylamine hydrochloride. MS: m/z 550.4 (ES+).
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[C:3]1[O:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]2[C:26](=[O:27])[NH:25][C:24]3[C:19]2=[N:20][CH:21]=[N:22][CH:23]=3)=[CH:14][CH:13]=1.I[CH2:29][CH3:30].C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[CH2:29]([N:25]1[C:24]2[C:19](=[N:20][CH:21]=[N:22][CH:23]=2)[N:18]([C:15]2[CH:16]=[CH:17][C:12]([O:11][C:3]3[N:2]([CH3:1])[C:6]4[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=4[N:4]=3)=[CH:13][CH:14]=2)[C:26]1=[O:27])[CH3:30]
Reactant: CCI
Reactant: Cn1c(Oc2ccc(-n3c(=O)[nH]c4cncnc43)cc2)nc2ccccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCn1c(=O)n(-c2ccc(Oc3nc4ccccc4n3C)cc2)c2ncncc21
Temperature: 50 °C
Reaction time: 4 h

Procedure:
A mixture of 9-{4-[(1-methyl-1H-benzimidazol-2-yl)oxy]phenyl}-7,9-dihydro-8H-purin-8-one (56 mg), iodoethane (20 μL) and cesium carbonate (120 mg) in DMF (3 mL) was stirred at 50° C. for 4 h. The mixture was poured into water, and the mixture was extracted with AcOEt. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residual crystals were recrystallized from AcOEt to give 7-ethyl-9-{4-[(1-methyl-1H-benzimidazol-2-yl)oxy]phenyl}-7,9-dihydro-8H-purin-8-one (40 mg) as white crystals.