Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].C([O-])(O)=O.[Na+].[Cl:10][C:11]1[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=1.[BH4-].[Na+]>C1COCC1.CO>[Cl:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15][NH:4][CH2:3][CH2:1][OH:2])=[CH:13][CH:12]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: NCCO
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: OCCNCc1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of ethanolamine (1.2 eq.) in either MeOH or THF were added NaHCO3 (1.5 eq.) and 4-chlorobenzaldehyde (1 eq.). The reaction was refluxed for 4 h, then cooled to 0° C. NaBH4 (1.2 eq.) was added portionwise. The reaction was stirred for 1 h at 0° C., then 15 h at 20° C. The crude was concentrated under reduced pressure then partitioned between water and DCM. The aqueous layer was then extracted twice with DCM. The organic layers were combined, dried over MgSO4, filtered and concentrated under reduced pressure. The crude was purified by chromatography on silica gel (elution with DCM/MeOH: 1/0 to 95/5) to afford 2-(4-chloro-benzylamino)-ethanol.
Reaction SMILES: [OH:1][C:2]1([C:6]2[S:7][C:8]([C:11]3[CH:12]=[C:13]([NH:18][C:19]4[N:24]=[C:23]([O:25][CH:26]5[CH2:31][CH2:30][CH:29]([C:32]([O:34]CC)=[O:33])[CH2:28][CH2:27]5)[CH:22]=[CH:21][N:20]=4)[CH:14]=[C:15]([CH3:17])[CH:16]=3)=[CH:9][N:10]=2)[CH2:5][CH2:4][CH2:3]1.CO.[OH-].[Na+].Cl>O1CCCC1.O>[OH:1][C:2]1([C:6]2[S:7][C:8]([C:11]3[CH:12]=[C:13]([NH:18][C:19]4[N:24]=[C:23]([O:25][CH:26]5[CH2:31][CH2:30][CH:29]([C:32]([OH:34])=[O:33])[CH2:28][CH2:27]5)[CH:22]=[CH:21][N:20]=4)[CH:14]=[C:15]([CH3:17])[CH:16]=3)=[CH:9][N:10]=2)[CH2:3][CH2:4][CH2:5]1
Reactant: CCOC(=O)C1CCC(Oc2ccnc(Nc3cc(C)cc(-c4cnc(C5(O)CCC5)s4)c3)n2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(Nc2nccc(OC3CCC(C(=O)O)CC3)n2)cc(-c2cnc(C3(O)CCC3)s2)c1
Temperature: 25 °C
Yield: 100 %

Procedure:
To a solution of ethyl 4-{[2-({3-[2-(1-hydroxycyclobutyl)-1,3-thiazol-5-yl]-5-methylphenyl}-amino)pyrimidin-4-yl]oxy}cyclohexanecarboxylate (Example 94A-16, 40 mg, 0.08 mmol) in tetrahydrofuran (0.52 mL), water (0.13 mL), and methanol (0.13 mL) was added aqueous sodium hydroxide (1.0 M in H2O, 0.2 mL, 0.2 mmol). The mixture was stirred at room temperature until complete. The reaction was then quenched with aqueous hydrochloric acid (1.0 M in H2O, 0.22 mL, 0.22 mmol). The resulting mixture was extracted with dichloromethane. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure to provide 4-{[2-({3-[2-(1-hydroxycyclobutyl)-1,3-thiazol-5-yl]-5-methylphenyl}amino)pyrimidin-4-yl]oxy}cyclohexanecarboxylic acid (37 mg, 0.08 mmol, 99%) as a pale yellow solid. MS ESI: [M+H]+ m/z 480.8. 1H NMR (500 MHz, DMSO-d6) δ 12.12 (s, 1H), 9.52 (s, 1H), 8.19 (m, 1H), 7.97 (s, 1H), 7.88 (s, 1H), 7.73-7.39 (m, 2H), 7.08 (s, 1H), 6.63-6.41 (m, 1H), 6.36-6.15 (m, 1H), 5.38-4.87 (m, 2H), 2.57-2.50 (m, 1H), 2.40-2.26 (m, 4H), 2.19-2.06 (m, 1H), 1.97-1.79 (m, 3H), 1.79-1.68 (m, 2H), 1.67-1.58 (m, 1H), 1.51-1.36 (m, 1H), 1.30-0.74 (m, 2H). rhSyk activity=+++.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][N+:10]([O-])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[Si]([C:18]#[N:19])(C)C.CN(C)C(Cl)=O>[N+](CC)([O-])=O>[C:18]([C:11]1[CH:12]=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:8]=[CH:9][N:10]=1)#[N:19]
Reactant: C[Si](C)(C)C#N
Reactant: [O-][n+]1ccc(-c2ccccc2)cc1
Agent: CN(C)C(=O)Cl
Solvent: CC[N+](=O)[O-]
Product: N#Cc1cc(-c2ccccc2)ccn1
Temperature: 25 °C
Reaction time: 45 h
Yield: 87 %

Procedure:
4-Phenylpyridine N-oxide (3.13 g, 18.3 mmol) was dissolved in nitroethane (30 ml), and trimethylsilyl cyanide (2.0 g, 20.2 mmol) and N,N-dimethylcarbamoyl chloride (1.7 ml, 18.5 mmol) were added thereto. The reaction mixture was stirred at room temperature for 45 hrs, concentrated under reduced pressure, combined with saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The extract was washed with saturated brine and dried. The solvent was evaporated under reduced pressure. The obtained crystals were collected by filtration, washed with diisopropyl ether and dried to give the titled compound (2.87 g, 89%). 1H-NMR (CDCl3) δ: 7.47-7.65 (5H, m), 7.72 (1H, dd, J=1.8, 5.2 Hz), 7.91 (1H, s), 8.75 (1H, d, J=5.1 Hz).
Reaction SMILES: [C:1]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:6]=[CH:5][C:4]([CH2:7][C@@H:8]([NH:17]C(OC(C)(C)C)=O)[CH2:9][C@:10]([CH2:15][OH:16])([CH3:14])[C:11]([OH:13])=[O:12])=[CH:3][CH:2]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NC[CH2:47][CH2:48][N:49]([CH3:51])[CH3:50].CN(CCO)C.CC#N.Cl.O1CCOCC1>C(Cl)Cl>[CH3:51][N:49]([CH3:50])[CH2:48][CH2:47][O:13][C:11](=[O:12])[C@@:10]([CH2:15][OH:16])([CH3:14])[CH2:9][C@H:8]([NH2:17])[CH2:7][C:4]1[CH:5]=[CH:6][C:1]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[CH:2][CH:3]=1
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccc(-c2ccccc2)cc1)C[C@@](C)(CO)C(=O)O
Reactant: CCN=C=NCCCN(C)C
Agent: CN(C)CCO
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: CC#N
Product: CN(C)CCOC(=O)[C@](C)(CO)C[C@H](N)Cc1ccc(-c2ccccc2)cc1
Reaction time: 0.03 h

Procedure:
(2S,4R)-5-Biphenyl-4-yl-4-t-butoxycarbonylamino-2-hydroxymethyl-2-methyl-pentanoic acid (125 mg, 302 μmol), HOBt (240 mg, 1.8 mmol), and EDCI (320 μL, 1.8 mmol) were dissolved in DCM and stirred for 2 minutes. N,N-Dimethylaminoethanol (304 μL, 3.0 mmol) was added and the resulting mixture was stirred at room temperature for 3 hours. The mixture was diluted with DCM and washed with saturated aqueous NaHCO3 solution. The organic layer was separated, dried, concentrated, then purified (Interchim reverse phase chromatography column; 5-70% MeCN in water with 0.5% TFA). The purified material was combined with MeCN (3.0 mL, 58 mmol) and 4 M HCl in dioxane (0.3 mL, 1.2 mmol) and the resulting mixture was stirred at room temperature for 30 minutes. The solvent was removed and azeotroped with toluene (2×) to yield (2S,4R)-4-amino-5-biphenyl-4-yl-2-hydroxymethyl-2-methyl-pentanoic acid 2-dimethylamino-ethyl ester.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([Mg]Br)=[CH:5][CH:4]=1.[F:11][C:12]([F:18])([F:17])[C:13](OC)=[O:14].Cl>C1COCC1.CCOCC>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:13](=[O:14])[C:12]([F:18])([F:17])[F:11])=[CH:5][CH:4]=1
Reactant: COC(=O)C(F)(F)F
Reactant: COc1ccc([Mg]Br)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1ccc(C(=O)C(F)(F)F)cc1
Reaction time: 2 h

Procedure:
At −60° C., a solution of 10.5 g of 4-methoxyphenylmagnesium bromide in 50 ml of THF was added dropwise over a period of 1 hour to a solution of 7.2 g of methyl trifluoroacetate in 50 ml of ether. Stirring was then continued at −20° C. for 2 hours and at 0° C. for a further hour. The reaction solution was mixed with 25 ml of 2N hydrochloric acid and extracted with ethyl acetate. The extract was dried and concentrated. The residue was distilled under reduced pressure (b.p. 41° C., 4.5×10−1 torr), to give the title product as a colourless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[C:5]([NH2:10])[CH:4]=1.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([CH:18]2[CH2:24][C:23](=O)[O:22][C:20](=[O:21])[CH2:19]2)=[CH:14][CH:13]=1>>[Cl:11][C:12]1[CH:13]=[CH:14][C:15]([CH:18]([CH2:24][C:23]2[NH:10][C:5]3[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=[CH:7][C:6]=3[N:9]=2)[CH2:19][C:20]([OH:22])=[O:21])=[CH:16][CH:17]=1.[ClH:11]
Reactant: O=C1CC(c2ccc(Cl)cc2)CC(=O)O1
Reactant: COc1ccc(N)c(N)c1
Product: COc1ccc2nc(CC(CC(=O)O)c3ccc(Cl)cc3)[nH]c2c1
Product: Cl

Procedure:
By a procedure similar to that of example 1.4, starting from commercial 4-methoxy-1,2-phenylenediamine and 3-(4-chlorophenyl)glutaric anhydride, 3-(4-chlorophenyl)-4-(5-methoxy-2-benzimidazolyl)butanoic acid•HCl was obtained as light red solid, provided that cyclisation of the crude glutaramic acid was carried out with HCl in 1,4-dioxane at reflux for 1.5 h.
Reaction SMILES: [C:1]([NH2:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].[CH:11]1([CH:17]=O)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1>>[CH:11]1([CH:17]2[NH:10][C:1](=[O:9])[C:2]3[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=3)[NH:4]2)[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: NC(=O)c1ccccc1N
Reactant: O=CC1CCCCC1
Product: O=C1NC(C2CCCCC2)Nc2ccccc21

Procedure:
Anthranilamide was transformed by Method G (using cyclohexanecarboxaldehyde). M.p. 172–174° C.
Reaction SMILES: [H-].[Na+].C(O[C:12]1[CH:19]=[C:18]([CH:20]=[CH:21][C:22]2[CH:27]=[CH:26][C:25]([CH:28]=[CH2:29])=[CH:24][CH:23]=2)[C:17]([O:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])=[CH:16][C:13]=1[CH:14]=O)CCCCCCC.[Br-].[CH2:40]([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>>[CH2:31]([O:30][C:17]1[C:16]([O:30][CH2:17][CH2:16][CH2:13][CH2:12][CH2:19][CH2:18][CH2:20][CH3:21])=[C:13]([CH:14]=[CH:40][C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=2)[CH:12]=[CH:19][C:18]=1[CH:20]=[CH:21][C:22]1[CH:23]=[CH:24][C:25]([CH:28]=[CH2:29])=[CH:26][CH:27]=1)[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38]
Reactant: c1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: C=Cc1ccc(C=Cc2cc(OCCCCCCCC)c(C=O)cc2OCCCCCCCC)cc1
Agent: [Br-]
Agent: [H-]
Agent: [Na+]
Product: C=Cc1ccc(C=Cc2ccc(C=Cc3ccccc3)c(OCCCCCCCC)c2OCCCCCCCC)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Solid NaH (300 mg, 12.4 mmol) was added in small portions into a suspension of 2,5-dioctoxy-4-(4′-vinylstyryl)benzaldehyde (1.27 g, 2.59 mmol) and benzyltriphenylphosphonium bromide (1.35 g, 3.11 mmol). The reaction mixture was stirred under nitrogen at room temperature for 24 hours. The reaction was quenched slowly with water, extracted with CH2Cl2, washed with brine, dried over MgSO4 and the solvent was evaporated under reduced pressure. The crude product was purified on a silica gel column (25-40% CHCl3/hexanes) to give a greasy yellow solid which is a mixture of cis and trans isomers. Yield 1.2 g (82%). 1H NMR (CDCl3): δ 7.51 (d, J=9.26 Hz, 2H), 7.47 (d, J=9.25 Hz, 1H), 7.42 (s, 2H), 7.29 (d, J=7.36 Hz, 2H), 7.25 (dd, J1=6.38 Hz, J2=7.36 Hz, 2H), 7.18 (t, J=7.34 Hz, 1H), 7.14 (s, 1H), 6.76 (d, J=11.97 Hz, 1H), 6.72 (dd, J1=17.72 Hz, J2=10.85 Hz, 1H), 6.34 (d, J=12.00 Hz, 1H), 5.78 (d, J=17.72 Hz, 1H), 5.25 (d, J=10.85 Hz, 1H), 4.02 (t, J=6.54 Hz, 2H), 3.55 (t, J=6.87 Hz, 2H), 1.78 (m, 4H), 1.64 (m, 4 H), 1.23-1.42 (m, 16H), 0.90 (m, 6H). 13C NMR (CDCl3): δ 151.34, 150.35, 137.89, 137.79, 136.81, 136.72, 130.24, 129.12, 128.49, 128.36, 127.14, 126.84, 126.73, 126.70, 125.62, 123.74, 114.81, 113.71, 110.37, 69.56, 69.16, 32.06, 29.61, 29.51, 26.33, 22.90, 14.35. FABMS: m/z 564 (M+).
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([Cl:19])[CH:18]=[C:13]3[C:12](I)=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Mg]Cl)(C)C.[C:26]([O:30][C:31](=[O:41])[NH:32][C:33]1[S:34][C:35]([CH:39]=[O:40])=[C:36]([Cl:38])[N:37]=1)([CH3:29])([CH3:28])[CH3:27].[Cl-].[NH4+]>O1CCCC1>[C:26]([O:30][C:31](=[O:41])[NH:32][C:33]1[S:34][C:35]([CH:39]([C:12]2[C:13]3[C:14](=[N:15][CH:16]=[C:17]([Cl:19])[CH:18]=3)[N:10]([S:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)(=[O:9])=[O:8])[CH:11]=2)[OH:40])=[C:36]([Cl:38])[N:37]=1)([CH3:29])([CH3:27])[CH3:28]
Reactant: O=S(=O)(c1ccccc1)n1cc(I)c2cc(Cl)cnc21
Reactant: CC(C)(C)OC(=O)Nc1nc(Cl)c(C=O)s1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1nc(Cl)c(C(O)c2cn(S(=O)(=O)c3ccccc3)c3ncc(Cl)cc23)s1
Temperature: -25 °C
Yield: 60.3 %

Procedure:
To a solution of 1-benzenesulfonyl-5-chloro-3-iodo-1H-pyrrolo[2,3-b]pyridine (581, 4.40 g, 10.5 mmol) in tetrahydrofuran (30.0 mL) at −45° C. under nitrogen, a solution of isopropylmagnesium chloride (2.0 M in tetrahydrofuran, 5.4 mL) was added slowly over 10 minutes. The reaction was allowed to warm to −25° C. over 30 minutes. The reaction was cooled to −65° C., followed by adding the cold deprotonated (4-chloro-5-formyl-thiazol-2-yl)-carbamic acid tert-butyl ester 589, which was prepared in situ by adding isopropylmagnesium chloride (2.0 M in tetrahydrofuran, 5.0 mL) to (4-chloro-5-formyl-thiazol-2-yl)-carbamic acid tert-butyl ester (589, 2.51 g, 9.55 mmol) in tetrahydrofuran (23.0 mL) at −78° C. under an atmosphere of nitrogen. The reaction was allowed to warm to room temperature in 2 hours, then poured into aqueous ammonium chloride, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 25% to 100% ethyl acetate in hexane to give the desired compound (590, 3.70 g, 60.3%). MS (ESI) [M+H+]+=554.2.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[N+:19]([CH:22]([CH3:24])[CH3:23])([O-:21])=[O:20].[CH:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[CH:27][C:26]=1[CH:35]=[O:36].C([Si](C)(C)Cl)(C)(C)C>O1CCCC1.C(N(CC)CC)C>[CH3:23][C:22]([N+:19]([O-:21])=[O:20])([CH3:24])[CH:35]([C:26]1[CH:27]=[CH:28][C:29]2[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:25]=1)[OH:36]
Reactant: O=Cc1ccc2ccccc2c1
Reactant: CC(C)[N+](=O)[O-]
Agent: CC(C)(C)[Si](C)(C)Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C(O)c1ccc2ccccc2c1)[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To tetrabutylammonium fluoride 3 hydrate (2.41 g) was added tetrahydrofuran (20 ml) and the mixture was ice-cooled. To the mixture were added 2-nitropropane (2.7 ml), 2-naphthaldehyde (3.12 g) and triethylamine (2.8 ml) under an argon atmosphere. To the mixture was added a solution of tert-butyldimethylchlorosilane (4.51 g) in tetrahydrofuran (20 ml). The resulting mixture was stirred for 40 min while allowing to warm to room temperature from ice-cooling. After removing insoluble matter by filtration, the filtrate was poured into a solution (500 ml) of diethyl ether-n-hexane=1:3 and the mixture was washed twice with water (40 ml). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was subjected to crystallization from n-hexane to give the title compound (3.78 g).
Reaction SMILES: C(O[CH:4]=[C:5]([C:8]#[N:9])[C:6]#[N:7])C.[CH:10]([O:13][CH2:14][CH2:15][CH2:16][NH2:17])([CH3:12])[CH3:11].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:25][C:26]([O:28][CH3:29])=[O:27]>C(#N)C>[NH2:9][C:8]1[C:5]([C:6]#[N:7])=[CH:4][N:17]([CH2:16][CH2:15][CH2:14][O:13][CH:10]([CH3:12])[CH3:11])[C:25]=1[C:26]([O:28][CH3:29])=[O:27]
Reactant: CCOC=C(C#N)C#N
Reactant: COC(=O)CBr
Reactant: CC(C)OCCCN
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: COC(=O)c1c(N)c(C#N)cn1CCCOC(C)C
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
After dissolving ethoxymethylenemalononitrile (10.2 g) in acetonitrile (200 mL), 3-isopropoxypropylamine (9.8 g) was added thereto and the mixture was stirred for 10 minutes. Cesium carbonate (68 g) and methyl bromoacetate (32 g) were added and the mixture was heated to reflux for 30 minutes. After cooling to room temperature, the supernatant was separated by decantation, and the solvent was distilled off under reduced pressure. The concentrated residue was combined with the solid portion remaining after decantation, ethyl acetate and water were added, and extraction was performed 3 times with ethyl acetate. The organic layer was washed with saturated brine and then dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was dissolved in ethyl acetate and passed through a silica gel, and then ethyl acetate (200 mL) was added for elution. The eluate was concentrated under reduced pressure to obtain a methyl 3-amino-4-cyano-1-[3-(methylethoxy)propyl]pyrrole-2-carboxylate crude product as a brown oil.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C@H:9]([CH2:14][CH:15]=[CH2:16])[C:10]([CH3:13])([CH3:12])[CH3:11])[C:5]([F:17])=[CH:4][N:3]=1.C[N+]1([O-])CC[O:22]CC1.[OH2:26]>C1COCC1.[O-]S([O-])(=S)=O.[Na+].[Na+].[Os](=O)(=O)(=O)=O>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][C@@H:9]([C:10]([CH3:11])([CH3:12])[CH3:13])[CH2:14][CH:15]([OH:22])[CH2:16][OH:26])[C:5]([F:17])=[CH:4][N:3]=1
Reactant: O
Reactant: C=CC[C@@H](Nc1nc(Cl)ncc1F)C(C)(C)C
Reactant: C[N+]1([O-])CCOCC1
Agent: O=[Os](=O)(=O)=O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)[C@@H](CC(O)CO)Nc1nc(Cl)ncc1F
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a solution of (R)-2-chloro-N-(2,2-dimethylhex-5-en-3-yl)-5-fluoropyrimidin-4-amine, 188a, (0.140 g, 0.543 mmol) in THF (10 mL) and H2O (10 mL) was added osmium tetraoxide (0.138 g, 0.014 mmol) and 4-methylmorpholine-4-oxide (0.085 mL, 0.815 mmol). The reaction mixture was stirred at room temperature for 2.5 hours. The mixture was diluted with aqueous saturated Na2S2O3. The resulting mixture was stirred for 20 minutes and extracted with EtOAc. The organic phase was dried over MgSO4, filtered and concentrated in vacuo. The resulting residue was purified by silica gel chromatography (MeOH/CH2Cl2) to afford 90 mg of the first diastereomer, 189a, and 65 mg of the second diastereomer, 190a.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH2:18]([C:20]1[N:21]([CH2:34][C:35]#[CH:36])[C:22]2[C:31]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[N:25]=[C:24](N)[C:23]=2[N:33]=1)[CH3:19]>CN(C=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C(Cl)(Cl)Cl.[Pd].[Pd].[Cu]I>[CH2:18]([C:20]1[N:21]([CH2:34][C:35]#[C:36][C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=2)[C:22]2[C:31]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[N:25]=[CH:24][C:23]=2[N:33]=1)[CH3:19]
Reactant: O=[N+]([O-])c1ccc(I)cc1
Reactant: C#CCn1c(CC)nc2c(N)nc3ccccc3c21
Agent: [Cu]I
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: CCc1nc2cnc3ccccc3c2n1CC#Cc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 37.4 %

Procedure:
Tris(dibenzylideneacetone)dipalladium(0) chloroform adduct (95 mg, 0.03 eq.), 4-iodonitrobenzene (0.84 g, 1.1 eq.), triethylamine (0.92 g, 3 eq.), and copper (I) iodide (35 mg, 0.06, eq.) were added sequentially to a solution of 2-ethyl-1-(2-propynyl)-1H-imidazo[4,5-c]quinolin-4-amine (0.72 g, 3.0 mmol, 1.0 eq.) in DMF. The reaction mixture was stirred at ambient temperature overnight. The reaction mixture was concentrated under reduced pressure and the residue was partitioned between dichloromethane (30 mL) and water (50 mL). The organic layer was separated, washed twice with water, and then concentrated under reduced pressure to a solid. This material was purified by column chromatography (silica gel eluting with 3/97 methanol/dichloromethane) to provide 0.4 g of 2-ethyl-1-[3-(4-nitrophenyl)-2-propynyl]-1H-imidazo[4,5-c]quinoline.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:6][C:7]1[C:14]([OH:15])=[C:13]([F:16])[C:12]([Br:17])=[C:11]([CH3:18])[C:8]=1[C:9]#[N:10].[C:19](=[O:22])([O-])O.[Na+]>C(OCC)(=O)C>[Br:17][C:12]1[C:13]([F:16])=[C:14]([OH:15])[C:7]([NH:6][C:19](=[O:22])[C:8]([CH3:11])([CH3:9])[CH2:7][O:1][CH2:5][C:4]2[CH:14]=[CH:13][CH:12]=[CH:2][CH:3]=2)=[C:8]([C:9]#[N:10])[C:11]=1[CH3:18]
Reactant: O=C([O-])O
Reactant: C1CCOC1
Reactant: Cc1c(Br)c(F)c(O)c(N)c1C#N
Agent: [Na+]
Solvent: CCOC(C)=O
Product: Cc1c(Br)c(F)c(O)c(NC(=O)C(C)(C)COCc2ccccc2)c1C#N
Temperature: 25 °C
Reaction time: 19 h
Yield: 70 %

Procedure:
After cooling, the reaction liquid was concentrated under reduced pressure, and azeotroped with benzene. A tetrahydrofuran solution (7 ml) of the resulting residue was dropwise added to a tetrahydrofuran solution (63 ml) of 2-amino-5-bromo-4-fluoro-3-hydroxy-6-methylbenzonitrile (I-75) (3.13 g, 12.77 mmol) and sodium hydrogencarbonate (2.68 g, 31.93 mmol), followed by stirring at room temperature for 19 hours. Ethyl acetate was added to the reaction liquid, followed by washing with water and saturated brine. The organic layer was concentrated under reduced pressure, the resulting residue was dissolved in ethanol (30 ml), aqueous 1 N sodium hydroxide solution (24 ml) was added, followed by stirring at 50° C. for 23 hours. After cooling, the reaction liquid was concentrated under reduced pressure, diluted with ethyl acetate, neutralized with aqueous 1 N hydrochloric acid, washed with saturated brine. The organic layer was concentrated under reduced pressure to obtain the entitled compound (5.82 g, 70%) as a yellow white solid.
Reaction SMILES: O1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)/[C:4](=[N:11]/[OH:12])/[CH2:3]C1.[N:13]1C=CC=C2C(=O)CCC=12>>[N:13]1[CH:8]=[CH:7][CH:6]=[C:5]2/[C:4](=[N:11]\[OH:12])/[CH2:3][CH2:9][C:10]=12
Reactant: O=C1CCc2ncccc21
Reactant: O/N=C1\CCOc2ccccc21
Product: O/N=C1/CCc2ncccc21

Procedure:
Following the procedure for the preparation of (4E)-2,3-dihydro-4H-chromen-4-one oxime but substituting 6,7-dihydro-5H-cyclopenta[b]pyridin-5-one and making non-critical variations provided the title compound as a oil: 1H NMR (400 MHz, DMSO-d6) δ) 11.11, 8.50, 7.89, 7.27, 3.04, 2.81; HRMS (EI) calcd for C8H8N2O 148.0637, found 148.0628.
Reaction SMILES: [F:1][C:2]1[C:3]([F:15])=[C:4]([F:14])[C:5]([F:13])=[C:6]2[C:11](=[O:12])[O:10][C:8](=O)[C:7]=12.[CH3:16][C@H:17]([NH2:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(Cl)(Cl)Cl>[CH:18]1([C@@H:17]([N:24]2[C:11](=[O:12])[C:6]3[C:7](=[C:2]([F:1])[C:3]([F:15])=[C:4]([F:14])[C:5]=3[F:13])[C:8]2=[O:10])[CH3:16])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: O=C1OC(=O)c2c(F)c(F)c(F)c(F)c21
Reactant: C[C@H](N)c1ccccc1
Solvent: ClC(Cl)Cl
Product: C[C@@H](C1CCCCC1)N1C(=O)c2c(F)c(F)c(F)c(F)c2C1=O
Temperature: 180 °C
Yield: 65.3 %

Procedure:
220 mg of tetrafluorophthalic anhydride and 127 mg of (S)-α-methylbenzylamine were charged in an egg-plant type flask of 50 ml, followed by stirring under heating at a temperature of 180° C. for 1.5 hours. After cooled, the reaction product was dissolved in chloroform, purified by silica gel column chromatography (eluent; methylene chloride:methanol=30:1 v/v), recrystallized from a mixed solvent of n-hexane-ethyl acetate, to obtain 215 mg of the desired product as a colorless powder. Yield: 65%. m.p. 147-148° C.; [α]20D=5.26° (C=0.618 AcOEt); MS(EI+) 329(M)+
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5](=[O:19])[NH:6][CH:7]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1)[CH2:8][CH:9]=[CH2:10].[CH2:20]([O:22][CH2:23]Cl)[CH3:21]>O1CCCC1>[CH3:3][O:4][C:5](=[O:19])[N:6]([CH:7]([CH2:11][C:12]1[CH:13]=[CH:14][C:15]([Cl:18])=[CH:16][CH:17]=1)[CH2:8][CH:9]=[CH2:10])[CH2:23][O:22][CH2:20][CH3:21]
Reactant: C=CCC(Cc1ccc(Cl)cc1)NC(=O)OC
Reactant: CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCC(Cc1ccc(Cl)cc1)N(COCC)C(=O)OC
Temperature: 0 °C
Reaction time: 12 h

Procedure:
A suspension of 10.0 g of sodium hydride (80% in mineral oil, 333 mmol) in dry tetrahydrofuran [THF] is heated at reflux under argon. A solution of 60.5 g (238 mmol) of [1-(4-chloro-benzyl)-but-3-enyl]-carbamic acid methyl ester [McCarty F J, Rosenstock P D, Paolini J P, Micucci D D, Ashton L, Bennetts W W, J. Med. Chem, 1968, 11(3),534] in 50 ml of dry THF is added dropwise thereto in the course of 1 hour. The mixture is then boiled under reflux for 2 hours until the evolution of gas subsides. The mixture is cooled to 0° C. and chloromethyl ethyl ether is added dropwise in such a manner that the reaction temperature does not exceed 5° C. The mixture is then heated slowly to 25° C. and stirred for 12 hours to complete the reaction. Excess sodium hydride is destroyed carefully with 1 ml of water before more water is added. The phases are separated and the aqueous phase is extracted again with tert-butyl methyl ether. The combined organic phases are washed with brine, dried over sodium sulfate, and concentrated by evaporation. The crude product is distilled at 0.1 mbar and has a boiling range of 120-125° C. TLC: ethyl acetate/hexane (1:6) Rf =0.34, FD-MS: M+ =311 (313).