Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12](=O)[CH2:13][N:14]2[C:18](=[O:19])[C:17]3=[CH:20][CH:21]=[CH:22][CH:23]=[C:16]3[C:15]2=[O:24])=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.Cl.[NH2:27][OH:28].N1C=CC=CC=1.O>C(O)C>[Cl:1][C:2]1[C:3]([C:12](=[N:27][OH:28])[CH2:13][N:14]2[C:18](=[O:19])[C:17]3=[CH:20][CH:21]=[CH:22][CH:23]=[C:16]3[C:15]2=[O:24])=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1
Reactant: NO
Reactant: O=C(CN1C(=O)c2ccccc2C1=O)c1ncc(C(F)(F)F)cc1Cl
Agent: Cl
Solvent: CCO
Solvent: O
Solvent: c1ccncc1
Product: O=C1c2ccccc2C(=O)N1CC(=NO)c1ncc(C(F)(F)F)cc1Cl
Temperature: 25 °C
Reaction time: 24 h
Yield: 66.4 %

Procedure:
To a solution of 0.47 g of N-[2-[3-chloro-5-(trifluoromethyl)pyridin-2-yl]-2-oxoethyl]phthalimide and 0.54 g of hydroxylamine hydrochloride in 5 ml of ethanol, 0.94 g of pyridine was added, and the mixture was stirred at room temperature for 24 hours. After completion of the reaction, the reaction mixture was mixed with 5 ml of water and extracted with ethyl acetate (5 ml×3), the resulting organic layers were combined, dried over saturated aqueous sodium chloride and then anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was purified by preparative medium pressure liquid chromatography (preparative medium pressure chromatograph: YFLC-Wprep manufactured by Yamazen Science, Inc.) using ethyl acetate-hexane (with a gradient of from 1:3 to 2:2) as the eluent to obtain 325 mg of the desired product as white crystals.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][CH:3]=1.S(Cl)([Cl:17])(=O)=O.C(OCC)C>C(Cl)Cl>[Cl:17][C:7]1[CH:6]=[C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:4]=[CH:3][C:2]=1[OH:1]
Reactant: O=S(=O)(Cl)Cl
Reactant: CCOC(=O)Cc1ccc(O)cc1
Solvent: CCOCC
Solvent: ClCCl
Product: CCOC(=O)Cc1ccc(O)c(Cl)c1
Temperature: 15 °C
Reaction time: 0.5 h
Yield: 59.2 %

Procedure:
To a stirred solution of ethyl 2-(4-hydroxyphenyl)acetate (25 g, 138 mmol) in 375 ml of DCM, sulfuryl chloride (9.48 mL 118 mmol) was slowly added at 0° C. over a period of 30 min. Diethyl ether (19.6 mL) was slowly added reaction mixture at 0° C. and stirring was continued for 30 min at 0° C. The reaction mixture was slowly warmed to 15° C. for 1 h. After completion of reaction, the mixture was poured onto crushed ice and extracted with DCM (×2). The combined organic layers were washed with 10% NaHCO3 solution followed by water. The organic layer was dried over Na2SO4, filtered and evaporated under vacuum to give compound ethyl 2-(3-chloro-4-hydroxyphenyl)acetate (15 g) as a thick oil.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([S:38][CH2:39][C:40]5[N:41]([CH2:45][CH2:46][CH2:47][C:48]([O:50][CH2:51][CH3:52])=[O:49])[CH:42]=[CH:43][N:44]=5)=[CH:34][CH:33]=4)=[O:30])=[CH:20][C:19]=3[CH:53]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:62])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:27])[CH3:28])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([S:38]([CH2:39][C:40]5[N:41]([CH2:45][CH2:46][CH2:47][C:48]([O:50][CH2:51][CH3:52])=[O:49])[CH:42]=[CH:43][N:44]=5)=[O:62])=[CH:34][CH:33]=4)=[O:30])=[CH:20][C:19]=3[CH:53]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(SCc4nccn4CCCC(=O)OCC)cc2)CCN3CC(C)C)cc1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(S(=O)Cc4nccn4CCCC(=O)OCC)cc2)CCN3CC(C)C)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 89.2 %

Procedure:
To a solution of ethyl 4-[2-[[[4-[[[7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-2,3-dihydro-1H-1-benzazepin-4-yl]carbonyl]amino]phenyl]thio]methyl]-1H-imidazol-1-yl]butanoate (1.0 g) in dichloromethane (10 ml) was added dropwise a solution of 3-chloroperbenzoic acid (70%, 0.50 g) in dichloromethane (10 ml) at −78° C. The mixture was stirred for 1 hour at −78° C., an aqueous solution of sodium thiosulfate was added to the mixture, and the mixture was stirred at room temperature for 10 minutes. The mixture was extracted with ethyl acetate, and the organic layer was washed with sodium bicarbonate solution and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was separated and purified by column chromatography (basic silica gel, ethyl acetate), to give ethyl 4-[2-[[[4-[[[7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-2,3-dihydro-1H-1-benzazepine-4-yl]carbonyl]amino]phenyl]sulfinyl]methyl]-1H-imidazol-1-yl]butanoate (Preparation of Compound 414) (911 mg) as yellow crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[CH2:9][O:10][C:11]1[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][CH:12]=1.[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1.O>C(Cl)Cl.N1C=CC=CC=1>[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([S:28]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=2[CH2:9][O:10][C:11]2[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][CH:12]=2)(=[O:30])=[O:29])=[CH:24][CH:23]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: COC(=O)c1ccc(OCc2cc(Cl)ccc2N)cc1
Solvent: ClCCl
Solvent: O
Solvent: c1ccncc1
Product: COC(=O)c1ccc(OCc2cc(Cl)ccc2NS(=O)(=O)c2ccc(Cl)cc2)cc1
Reaction time: 21 h
Yield: 43.1 %

Procedure:
To a solution of methyl 4-(2-amino-5-chlorophenylmethoxy)benzoate (450 mg; prepared in Reference Example 10.) in methylene chloride (4 ml), pyridine (0.24 ml) and 4-chlorobenzenesulfonylchloride (380 mg) were added. The mixture was stirred for 21 hour. To the reaction mixture, water was added. The mixture was extracted with ethyl acetate. The organic layer was washed, dried over and concentrated under the reduced pressure. The residue was purified by recrystallization from hexane-AcOEt mixture solvent to give the title compound (310 mg) having the following physical data.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6](Cl)=[N:7]2.[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH2:18]Br.[NH2:23][C@H:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:26][CH2:25]1>>[C@H:24]1([NH:23][C:6]2[CH:5]=[CH:4][C:3]3[C:8](=[CH:9][CH:10]=[CH:11][C:2]=3[O:1][CH2:18][C:17]3[CH:20]=[CH:21][CH:22]=[C:15]([O:14][CH3:13])[CH:16]=3)[N:7]=2)[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:26][CH2:25]1
Reactant: N[C@@H]1CCc2ccccc21
Reactant: COc1cccc(CBr)c1
Reactant: Oc1cccc2nc(Cl)ccc12
Product: COc1cccc(COc2cccc3nc(N[C@@H]4CCc5ccccc54)ccc23)c1

Procedure:
The title compound, MS: m/e=397.5 (M+H+), was prepared in accordance with the general method of example 2 from 5-hydroxy-2-chloroquinoline, 3-methoxy-benzylbromide and (R)-1-aminoindane.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH2:11][CH:12]([O:16][CH2:17][CH3:18])[O:13][CH2:14][CH3:15])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[C:19]([C:23]1[CH:24]=[C:25]([N:29]=[C:30]=[O:31])[CH:26]=[CH:27][CH:28]=1)([O:21][CH3:22])=[O:20]>ClCCl>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH:11]=[CH:12][N:29]([C:25]3[CH:24]=[C:23]([CH:28]=[CH:27][CH:26]=3)[C:19]([OH:21])=[O:20])[C:30]2=[O:31])=[CH:8][CH:9]=1)([CH3:2])[CH3:3].[CH3:22][O:21][C:19](=[O:20])[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([NH:29][C:30]([N:10]([CH2:11][CH:12]([O:13][CH2:14][CH3:15])[O:16][CH2:17][CH3:18])[C:7]2[CH:8]=[CH:9][C:4]([CH:1]([CH3:2])[CH3:3])=[CH:5][CH:6]=2)=[O:31])[CH:24]=1
Reactant: COC(=O)c1cccc(N=C=O)c1
Reactant: CCOC(CNc1ccc(C(C)C)cc1)OCC
Solvent: ClCCl
Product: CC(C)c1ccc(-n2ccn(-c3cccc(C(=O)O)c3)c2=O)cc1
Product: CCOC(CN(C(=O)Nc1cccc(C(=O)OC)c1)c1ccc(C(C)C)cc1)OCC
Temperature: 25 °C
Reaction time: 8 h
Yield: 170.4 %

Procedure:
A solution of N-(4-isopropylphenyl)-2,2-diethoxyethylamine (0.50 g, 2.0 mmol) prepared above and 3-carbomethoxyphenyl isocyanate (0.36 g, 2.05 mmol) in dry dichloromethane (10 mL) was stirred at room temperature overnight. The solution was then chromatographed (silica gel, hexanes:ethyl acetate, 8:2) to give the pure urea, 3-[3-(2,2-diethoxyethyl)-3-(4-isopropylphenyl)ureido]benzoic acid methyl ester as a colorless oil (0.73 g, 85.3%). MS (ES−) m/z: 427. This was then stirred with HCl (0.5 M, 50 mL) at 80° C. for 4 h. After cooling to room temperature, the white precipitate formed was collected and purified by chromatography (silica gel, dichloromethane:ethyl acetate, 9:1) to give pure methyl 3-[3-(4-isopropylphenyl)-2-oxo-2,3-dihydroimidazol-1-yl]benzoate as white solid [0.42 g, 73.7%, MS (ES+) m/z: 337]. The solid was then treated with boron tribromide in dichloromethane (1.0 M, 4.0 mL) at, room temperature overnight. The volatiles were removed in vacuum and the residue was suspended in water and stirred for 30 min. The solid was collected by filtration and washed with water to furnish 3-[3-(4-isopropylphenyl)-2-oxo-2,3-dihydroimidazol-1-yl]benzoic acid (0.40 g, 100%). m.p. 283-285° C. 1H NMR (CDCl3, 300 MHz) δ (ppm) 1.24 (d, 6H), 2.84-3.00 (m, 1H), 6.69 (d, 1H), 6.74 (d, 1H, 7.26 (d, 2H), 7.45-7.54 (m, 3H), 7.91 (d, 1H), 8.02 (d, 1H), 8.12 (s, 1H). MS (ES−) m/z: 321.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[C:14]([C:15]#[CH:16])=[C:13]([CH3:17])[O:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].Br[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[C:14]([C:15]#[C:16][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)=[C:13]([CH3:17])[O:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: Brc1ccccn1
Reactant: C#Cc1c(-c2ccc(OC)c(Cl)c2)noc1C
Product: COc1ccc(-c2noc(C)c2C#Cc2ccccn2)cc1Cl
Yield: 72 %

Procedure:
As described for example 11c, 3-(3-chloro-4-methoxy-phenyl)-4-ethynyl-5-methyl-isoxazole (134 mg, 0.50 mmol) instead of 4-ethynyl-5-methyl-3-phenyl-isoxazole was converted (using 2-bromopyridine instead of 2-chloro-4-iodopyridine) to the title compound (SiO2, heptane:ethyl acetate=95:5 to 0:100, 117 mg, 72%) which was obtained as a white solid. MS: m/e=325.2 [M+H]+.
Reaction SMILES: [CH3:1][Si:2]([CH3:29])([CH3:28])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[C:8]1[N:13]2[N:14]=[CH:15][CH:16]=[C:12]2[N:11]=[C:10]([C:17](=O)[CH3:18])[CH:9]=1.Cl.[NH2:31][OH:32]>CCO.N1C=CC=CC=1>[CH3:29][Si:2]([CH3:28])([CH3:1])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[C:8]1[N:13]2[N:14]=[CH:15][CH:16]=[C:12]2[N:11]=[C:10]([C:17](=[N:31][OH:32])[CH3:18])[CH:9]=1
Reactant: NO
Reactant: CC(=O)c1cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n2nccc2n1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: CC(=NO)c1cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n2nccc2n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 109.1 %

Procedure:
A solution of 1-[7-(bis{[2-(trimethylsilyl)ethoxy]methyl}amino)pyrazolo[1,5-a]pyrimidin-5-yl]ethanone (4.34 g, 9.94 mmol) in 1:1 EtOH/pyridine (50 mL) was treated with hydroxylamine hydrochloride (3.45 g, 49.7 mmol). The resulting mixture was stirred at room temperature for 1.5 h and then concentrated under reduced pressure to remove most solvent. The residue was partitioned between EtOAc (100 mL) and water (60 mL), the layers were separated, and the organic phase was washed with water (60 mL) and brine (20 mL), dried over Na2SO4 and concentrated under reduced pressure to give the title compound, 1-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)ethanone oxime (4.90 g, 85% purity, 93% yield) as an off-white semisolid: MS (ESI+) for C20H37N5O3Si2 m/z 452 (M+H)+.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[Br:11][C:12]1[CH:13]=[N:14][CH:15]=[C:16](Br)[CH:17]=1.[OH-].[Na+]>CN(C=O)C.O>[Br:11][C:12]1[CH:13]=[N:14][CH:15]=[C:16]([O:10][C:7]2[CH:8]=[CH:9][C:4]([F:3])=[CH:5][CH:6]=2)[CH:17]=1
Reactant: Oc1ccc(F)cc1
Reactant: Brc1cncc(Br)c1
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: Fc1ccc(Oc2cncc(Br)c2)cc1
Temperature: 25 °C
Yield: 20.9 %

Procedure:
Sodium hydride (1.53 g of 80% in mineral oil, 51 mmol) was slowly added to a solution of 4-fluorophenol (5.6 g, 50 mmol) in DMF (100 mL) as it was stirred and cooled (ice water bath) under a nitrogen atmosphere. The resulting mixture was warmed to ambient temperature and stirred for 1 h. 3,5-Dibromopyridine (5.9 g, 25 mmol) was added and the mixture was then heated at 90° C. (bath temperature) for 62 h. The mixture was cooled, diluted with water (150 mL), poured into 5N sodium hydroxide (150 mL), and extracted with diethyl ether (2×150 mL). The combined ether extracts were washed with water, dried (MgSO4), filtered and concentrated by rotary evaporation. The residue was purified by flash chromatography on silica gel, using 5% ethyl acetate: hexane as eluent, to yield 1.4 g (21%) of a colorless oil.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][NH2:8].C(N(CC)CC)C.[C:16](Cl)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C(Cl)Cl.C(OCC)(=O)C>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][NH:8][C:16](=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: NOC1CCCCO1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C(NOC1CCCCO1)c1ccccc1
Reaction time: 1 h
Yield: 76.7 %

Procedure:
To a solution of 1.00 g (8.55 mmol) of O-tetrahydropyran-2-ylhydroxylamine (prepared as described in U.S. Pat. No. 4,607,053, Example 2, Part A) and 1.4 ml (10 mmol) of sieve-dried triethylamine in 15 ml of dry CH2Cl2 cooled to -20 was added a solution of 1.50 g (10.7 mmol) of benzoyl chloride in 5 ml of CH2Cl2 over 10 minutes. The reaction mixture was stirred for 1 hour then diluted with 15 ml of ethyl acetate. The resulting slurry was filtered and the filtrate concentrated in vacuo to give a solid. Recrystallization (EtOAc/petroleum ether) of the solid afforded 1.45 g (77%) of title compound as white crystals, m.p. 130°-134°.
Reaction SMILES: [H-].[Na+].[CH2:3]([N:10]1[C:18]2[C:17]([S:19][C:20]3[C:25]([CH3:26])=[CH:24][C:23]([CH3:27])=[CH:22][C:21]=3[CH3:28])=[N:16][C:15](F)=[N:14][C:13]=2[CH:12]=[CH:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C[N:31]1[C:35](=O)[CH2:34][CH2:33][CH2:32]1>O>[CH2:3]([N:10]1[C:18]2[C:17]([S:19][C:20]3[C:25]([CH3:26])=[CH:24][C:23]([CH3:27])=[CH:22][C:21]=3[CH3:28])=[N:16][C:15]([NH:10][C:3]3[CH:32]=[CH:33][C:34]([C:35]#[N:31])=[CH:5][CH:4]=3)=[N:14][C:13]=2[CH:12]=[CH:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: Cc1cc(C)c(Sc2nc(F)nc3ccn(Cc4ccccc4)c23)c(C)c1
Reactant: CN1CCCC1=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: Cc1cc(C)c(Sc2nc(Nc3ccc(C#N)cc3)nc3ccn(Cc4ccccc4)c23)c(C)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 11 %

Procedure:
To a stirred suspension of NaH (30 mg, 1.25 mmol) in dry NMP (1.5 mL) was added 4-aminobenzylnitrile (87.4 mg, 0.74 mmol) and stirred at room temperature for 30 min under argon. The reaction mixture was added to a solution of 5-benzyl-2-fluoro-4-(mesitylthio)-5H-pyrrolo[3,2-d]pyrimidine (93 mg, 0.25 mmol) in dry NMP (1 mL) and stirred at room temperature for 2 h. After completion of the reaction, the resulting mixture was diluted with water and washed with EtOAc×3. The combined organic layers were washed with water, NH4Cl, water×2, brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by preparative TLC, eluting with Hexanes:Ethyl acetate (1.5:1) afforded the product as a tan solid (12.6 mg, 11%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][OH:8])=[CH:5][CH:4]=1.[H-].[Na+].Br[C:14]1[C:19]([O:20][CH2:21][CH2:22][CH3:23])=[CH:18][CH:17]=[C:16]([I:24])[N:15]=1.O>CN(C)C=O>[I:24][C:16]1[N:15]=[C:14]([O:8][CH2:7][C:6]2[CH:9]=[CH:10][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[C:19]([O:20][CH2:21][CH2:22][CH3:23])=[CH:18][CH:17]=1
Reactant: COc1ccc(CO)cc1
Reactant: CCCOc1ccc(I)nc1Br
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCOc1ccc(I)nc1OCc1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
4-Methoxybenzyl alcohol (689 mg) was added to a solution of sodium hydride (200 mg) in N,N-dimethylformamide (4 mL) under ice-cooling, and the mixture was stirred at room temperature for 15 minutes. A solution of 2-bromo-6-iodo-3-propoxypyridine in N,N-dimethylformamide (2 mL) was added thereto, and the mixture was stirred at 85° C. for six hours. The reaction solution was poured into water, followed by extraction with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and filtered. The solvent was then evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:1→1:1) to give the title compound as a colorless powder (670 mg).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:11]2[CH:12]=[C:13]([C:17]([N:19]([CH:33]([CH3:35])[CH3:34])[C@@H:20]3[CH2:25][CH2:24][CH2:23][N:22]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:21]3)=[O:18])[C:14]([CH3:16])=[CH:15][C:10]=2[O:9][C:8]([CH3:37])([CH3:36])[C:7]1=[O:38].[H-].[Na+].CN(C)C=O.Br[CH:47]1[CH2:49][CH2:48]1>O>[CH:47]1([O:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]2[C:11]3[CH:12]=[C:13]([C:17]([N:19]([CH:33]([CH3:34])[CH3:35])[C@@H:20]4[CH2:25][CH2:24][CH2:23][N:22]([C:26]([O:28][C:29]([CH3:30])([CH3:31])[CH3:32])=[O:27])[CH2:21]4)=[O:18])[C:14]([CH3:16])=[CH:15][C:10]=3[O:9][C:8]([CH3:36])([CH3:37])[C:7]2=[O:38])[CH2:49][CH2:48]1
Reactant: BrC1CC1
Reactant: Cc1cc2c(cc1C(=O)N(C(C)C)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1)N(CCCCO)C(=O)C(C)(C)O2
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc2c(cc1C(=O)N(C(C)C)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1)N(CCCCOC1CC1)C(=O)C(C)(C)O2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To tert-butyl (3R)-3-[{[4-(4-hydroxybutyl)-2,2,7-trimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}(isopropyl)amino]piperidine-1-carboxylate (200 mg) were added sodium hydride (60 mg) and N,N-dimethylformamide (3 ml) under ice-cooling, and the mixture was stirred at room temperature for 30 minutes. Then, to the mixture was added bromocyclopropane (0.30 ml), and the mixture was stirred at 150° C. for 6 hours. After the reaction was complete, water was added to the reaction solution, and the mixture was extracted with ethyl acetate solution. The obtained ethyl acetate solution was washed with water and an aqueous sodium chloride solution, dried over magnesium sulfate, filtered and concentrated. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/2) to give the title compound (30 mg) as a colorless liquid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH2:20]([O:22][CH2:23][C:24](Cl)=O)[CH3:21].C(N(CC)CC)C.C(O)C>ClCCl>[CH2:20]([O:22][CH2:23][C:24]1[N:12]([CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:11]2[C:10]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:4]=[CH:3][C:2]=2[N:1]=1)[CH3:21]
Reactant: CCOCC(=O)Cl
Reactant: CCOC(=O)CCNc1c(N)cnc2ccccc12
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOCc1nc2cnc3ccccc3c2n1CCC(=O)OCC
Reaction time: 1.5 h
Yield: 98.8 %

Procedure:
Ethyl N-(3-aminoquinolin-4-yl)-β-alaninate (20.0 g, 77.3 mmol, prepared in Parts A and B of Example 22) was treated with ethoxyacetyl chloride (11.29 g, 92.5 mmol) according to a modification the method described in Part A of Example 12. The reaction in dichloromethane (300 mL) was stirred for 1.5 hours, and after the addition of triethylamine (43.08 mL, 309.1 mmol) and ethanol (300 mL), the reaction was heated at reflux for four hours and then subjected to the work-up procedure to provide 25.0 g of ethyl 3-(2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)propanoate.
Reaction SMILES: P(N=[N+]=[N-])([O:10][C:11]1C=CC=CC=1)(OC1C=CC=CC=1)=O.[CH3:20][C@@H:21]1[CH2:26][CH2:25][CH2:24][CH2:23][C@@H:22]1[NH:27][C:28]1[C:33](C(O)=O)=[CH:32][N:31]=[C:30]2[NH:37][CH:38]=[CH:39][C:29]=12.C([N:42](CC)CC)C>C(O)(C)(C)C>[CH3:20][C@@H:21]1[CH2:26][CH2:25][CH2:24][CH2:23][C@@H:22]1[N:27]1[C:28]2=[C:29]3[CH:39]=[CH:38][NH:37][C:30]3=[N:31][CH:32]=[C:33]2[NH:42][C:11]1=[O:10]
Reactant: CCN(CC)CC
Reactant: [N-]=[N+]=NP(=O)(Oc1ccccc1)Oc1ccccc1
Reactant: C[C@@H]1CCCC[C@@H]1Nc1c(C(=O)O)cnc2[nH]ccc12
Solvent: CC(C)(C)O
Product: C[C@@H]1CCCC[C@@H]1n1c(=O)[nH]c2cnc3[nH]ccc3c21
Temperature: 100 °C
Reaction time: 4 h

Procedure:
Diphenyl azidophosphate (0.083 mL) was added to 4-{[(1S,2R)-2-methylcyclohexyl]amino}-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid (56 mg) and triethylamine (0.075 mL) in tert-butanol (1.5 mL) and the mixture was stirred at 100° C. for 4 hours. tert-butanol was removed under reduced pressure, then chloroform and water were added, and the organic layer was separated, washed with brine, and dried over MgSO4. After removal of MgSO4 and solvent, the residue was purified by column chromatography on silica gel with chloroform and methanol (98:2 to 90:10) to give 1-[(1S,2R)-2-methylcyclohexyl]-3,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridin-2(1H)-one (53 mg) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[CH2:14][N:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:12]([CH3:23])([CH3:22])[C:4]=2[N:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:6]=1.[F:24][C:25]1[CH:26]=[C:27]([N:31]=[C:32]=[O:33])[CH:28]=[CH:29][CH:30]=1>C1COCC1>[F:24][C:25]1[CH:26]=[C:27]([NH:31][C:32]([NH:1][C:2]2[C:3]3[CH2:14][N:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:12]([CH3:22])([CH3:23])[C:4]=3[N:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:6]=2)=[O:33])[CH:28]=[CH:29][CH:30]=1
Reactant: CCOC(=O)n1nc(N)c2c1C(C)(C)N(C(=O)OC(C)(C)C)C2
Reactant: O=C=Nc1cccc(F)c1
Solvent: C1CCOC1
Product: CCOC(=O)n1nc(NC(=O)Nc2cccc(F)c2)c2c1C(C)(C)N(C(=O)OC(C)(C)C)C2
Reaction time: 8 h
Yield: 71.5 %

Procedure:
5-tert-Butyl 1-ethyl 3-amino-6,6-dimethyl-4,6-dihydropyrrolo[3,4-c]pyrazole-1,5-dicarboxylate (3.0 g, 9.24 mmol) was dissolved in anhydrous THF: (50 ml), treated at room temperature with 3-fluorophenyl-isocyanate (1.4 g, 10.21 mmol, 1.1 eq) and stirred overnight. The following day the reaction mixture was evaporated, taken up with DCM and washed with brine. The organic phase was dried over sodium sulfate and evaporated to dryness. Purification by flash chromatography (CH2Cl2/MeOH 90/10) afforded 3.05 g (yield 71%) of the title compound.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([OH:9])=O)=[CH:5][C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:3]1.[NH2:16][C:17]1[CH:18]=[CH:19][C:20]([O:25][CH2:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[C:21]([CH:24]=1)[C:22]#[N:23].C(N(CC)CC)C.P(C#N)(OCC)(OCC)=O>O.CN(C)C=O>[C:22]([C:21]1[CH:24]=[C:17]([NH:16][C:7]([C:6]2[N:2]([CH3:1])[N:3]=[C:4]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH:5]=2)=[O:9])[CH:18]=[CH:19][C:20]=1[O:25][CH2:26][C:27]([CH3:29])([CH3:28])[CH3:30])#[N:23]
Reactant: Cn1nc(-c2ccccc2)cc1C(=O)O
Reactant: CC(C)(C)COc1ccc(N)cc1C#N
Agent: CCOP(=O)(C#N)OCC
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: Cn1nc(-c2ccccc2)cc1C(=O)Nc1ccc(OCC(C)(C)C)c(C#N)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 19.7 %

Procedure:
1-Methyl-3-phenylpyrazole-5-carboxylic acid (0.8 g), 5-amino-2-neopentyloxybenzonitrile (0.8 g), triethylamine (1.2 g) and diethyl cyanophosphate (1.0 g) were added to dimethylformamide (10 ml) and the mixture was stirred at room temperature for 1 h. The reaction mixture was added into water and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, after which the solvent was evaporated under reduced pressure. n-Hexane was added to the residue to allow crystallization. The crystals were recrystallized from hydrous methanol to give the title compound (0.3 g), melting point: 223–224° C.