Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[C:9]1[CH:10]=[N:11][CH:12]=[N:13][CH:14]=1.N1C=CC=CC=1.[C:21]1([C:34](Cl)=[O:35])[C:33]2[CH2:32][C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:25]=2[CH:24]=[CH:23][CH:22]=1>ClCCl>[CH3:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:34]([C:21]2[C:33]3[CH2:32][C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[C:25]=3[CH:24]=[CH:23][CH:22]=2)=[O:35])=[CH:4][C:3]=1[C:9]1[CH:14]=[N:13][CH:12]=[N:11][CH:10]=1
Reactant: Cc1ccc(N)cc1-c1cncnc1
Reactant: O=C(Cl)c1cccc2c1Cc1ccccc1-2
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc(NC(=O)c2cccc3c2Cc2ccccc2-3)cc1-c1cncnc1
Reaction time: 2 h
Yield: 73.9 %

Procedure:
To a suspension of 4-methyl-3-(pyrimidin-5-yl)aniline (0.111 g) and pyridine (0.15 ml) in dichloromethane (2 ml) was dropwise added a solution of the fluorene-1-carbonyl chloride (0.137 g) in dichloromethane (2 ml) followed by stirring for 2 hours. The mixture was diluted with dichloromethane and washed with an aqueous solution of sodium hydrogen carbonate and brine. The separated organic layer was dried over sodium sulfate and evaporated under reduced pressure. The residue was triturated with methanol. The resulting solid was collected by filtration to give N-(4-methyl-3-(pyrimidin-5-yl)-phenyl)-9H-fluorene-1-carboxamide (0.167 g, 73.9%)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.[C:12]([Si:16]([CH3:26])([CH3:25])[O:17][CH:18]1[CH2:23][CH2:22][CH:21](O)[CH2:20][CH2:19]1)([CH3:15])([CH3:14])[CH3:13].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1.C(OCC)(=O)C.CCCCCC>[C:12]([Si:16]([O:17][CH:18]1[CH2:19][CH2:20][CH:21]([O:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=2[N+:9]([O-:11])=[O:10])[CH2:22][CH2:23]1)([CH3:26])[CH3:25])([CH3:15])([CH3:13])[CH3:14]
Reactant: O=[N+]([O-])c1cc(Cl)ccc1O
Reactant: CC(C)(C)[Si](C)(C)OC1CCC(O)CC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OC1CCC(Oc2ccc(Cl)cc2[N+](=O)[O-])CC1
Temperature: 0 °C
Reaction time: 8 h
Yield: 76.8 %

Procedure:
A solution of diisopropylazadicarboxylate (1.65 g, 8.16 mmol) in anhydrous tetrahydrofuran (5 mL) was added, dropwise, at 0° C., to a solution of 4-chloro-2-nitrophenol (0.75 g, 4.32 mmol), 4-(tert-butyl-dimethyl-silanyloxy)-cyclohexanol (1.2 g, 5.21 mmol) and triphenylphosphine (2.27 g, 8.65 mmol) in anhydrous tetrahydrofuran (10 mL). The resulting mixture was stirred at 0° C. for 1 hour and at room temperature overnight. The reaction mixture was then sonicated for 20 minutes at room temperature and for 30 minutes at 40° C. and then was stirred at room temperature for 24 hours. The solvent was evaporated under reduced pressure and the residue was partitioned between ethyl acetate and an aqueous solution of sodium bicarbonate (5%), the organic layer was separated and the aqueous layer was extracted 3 times with ethyl acetate. The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The yellow oily residue was purified on a silica gel plug (hexane/EtOAc, from 99/1 to 90/10) to give a yellow oil. This material was dissolved in a mixture of ethyl acetate and hexane (1/1) and the resulting solution was washed twice with an aqueous solution of sodium hydroxide (3 M) and once with brine, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to give 1.28 g (79% yield) of tert-butyl-[4-(4-chloro-2-nitro-phenoxy)-cyclohexyloxy]-dimethyl-silane as a light yellow oil.
Reaction SMILES: CN1CCOCC1.ClC(OCC)=O.[C:14]([CH2:17][N:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:21][CH:20]([NH:28][C:29]([C:31]2[NH:35][C:34]3[S:36][C:37]([Cl:39])=[CH:38][C:33]=3[CH:32]=2)=[O:30])[C:19]1=[O:40])([OH:16])=O.O[N:42]=[C:43]([NH2:45])[CH3:44]>C1COCC1.CO.C(Cl)Cl>[Cl:39][C:37]1[S:36][C:34]2[NH:35][C:31]([C:29]([NH:28][CH:20]3[CH2:21][C:22]4[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=4)[N:18]([CH2:17][C:14]4[O:16][N:45]=[C:43]([CH3:44])[N:42]=4)[C:19]3=[O:40])=[O:30])=[CH:32][C:33]=2[CH:38]=1
Reactant: O=C(O)CN1C(=O)C(NC(=O)c2cc3cc(Cl)sc3[nH]2)Cc2ccccc21
Reactant: CC(N)=NO
Agent: CCOC(=O)Cl
Solvent: C1CCOC1
Solvent: CO
Solvent: CN1CCOCC1
Product: Cc1noc(CN2C(=O)C(NC(=O)c3cc4cc(Cl)sc4[nH]3)Cc3ccccc32)n1
Temperature: 25 °C
Reaction time: 72 h
Yield: 61.5 %

Procedure:
N-Methylmorpholine (118 μL, 1.07 mmol) then ethyl chloroformate (103 μL, 1.07 mmol) were added to N-[1-(carboxymethyl)-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl]-2-chloro-6H-thieno[2,3-b]pyrrole-5-carboxamide (Example 2; 431 mg, 1.07 mmol) in anhydrous THF (10 mL) at 0° C. After 20 minutes N′-hydroxyethanimidamide (119 mg, 1.61 mmol) was added and the reaction stirred at ambient temperature for 3 days then at reflux for 5 hours. After evaporation to dryness the residue was suspended in 1,4-dioxane and refluxed for 18 hours. On cooling the mixture was diluted with EtOAc (100 mL) and washed with H2O (25 mL). The aqueous was extracted with DCM (3×50 mL) and the combined organics dried (MgSO4), filtered and evaporated. The residue was purified by column chromatography (DCM to DCM:MeOH (9:1)) to give a yellow solid which was dissolved in MeOH:DCM (1:4) (100 mL) and shaken with macroporous silicate-carbonate scavenger resin (300 mg). Filtration then evaporation gave the title compound (291 mg, 61%) as an off-white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:9][C:8]2([CH2:18][C:17](=[O:19])[C:16]3[C:11](=[CH:12][CH:13]=[C:14](/[CH:20]=[CH:21]/[C:22](O)=[O:23])[CH:15]=3)[O:10]2)[CH2:7]1)=[O:5])[CH3:2].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[NH2:39][O:40][CH:41]1[CH2:46][CH2:45][CH2:44][CH2:43][O:42]1>C(Cl)Cl>[CH2:1]([O:3][C:4]([N:6]1[CH2:9][C:8]2([CH2:18][C:17](=[O:19])[C:16]3[C:11](=[CH:12][CH:13]=[C:14](/[CH:20]=[CH:21]/[C:22]([NH:39][O:40][CH:41]4[CH2:46][CH2:45][CH2:44][CH2:43][O:42]4)=[O:23])[CH:15]=3)[O:10]2)[CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CC2(CC(=O)c3cc(/C=C/C(=O)O)ccc3O2)C1
Reactant: NOC1CCCCO1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: ClCCl
Product: CCOC(=O)N1CC2(CC(=O)c3cc(/C=C/C(=O)NOC4CCCCO4)ccc3O2)C1
Yield: 60.2 %

Procedure:
(E)-3-[1′-Ethyloxycarbonyl-4-oxo-spiro(chromane-2,3′-azetidine)-6-yl]-acrylic acid (200 mg, 0.54 mmol) in DCM (5 ml) was treated with TEA (0.12 ml, 0.90 mmol) and then with EDC (172 mg, 0.900 mmol), HOBt (121 mg, 0.896 mmol) and NH2OTHP (84 mg, 0.72 mmol) following the procedure described in Example 30, Step B, giving (E)-3-[1′-ethyloxycarbonyl-4-oxo-spiro(chromane-2,3′-azetidine)-6-yl]-N-(tetrahydro-pyran-2-yloxy)-acrylamide (140 mg) as a light yellow solid.
Reaction SMILES: [CH:1]([N:4]([CH:17]([CH3:19])[CH3:18])[CH2:5][CH2:6][CH:7]([C:14](=[O:16])N)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:3])[CH3:2].[N+]([O-])(O)=O.[CH2:24]([OH:26])[CH3:25]>>[CH:1]([N:4]([CH:17]([CH3:19])[CH3:18])[CH2:5][CH2:6][CH:7]([C:14]([O:26][CH2:24][CH3:25])=[O:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:3])[CH3:2]
Reactant: CCO
Reactant: CC(C)N(CCC(C(N)=O)c1ccccc1)C(C)C
Solvent: O=[N+]([O-])O
Product: CCOC(=O)C(CCN(C(C)C)C(C)C)c1ccccc1

Procedure:
N,N-Diisopropyl-3-carbamyl-3-phenylpropanamine (26.5 g 0.100 mol) was added into aqueous ethanol (90%, 300 mL) containing conc. HNO3 (13.3 g, 0.21 mol) and refluxed for five days. Most of the solvent was evaporated under reduced pressure and the residue was mixed with water/diethyl ether. The organic phase was washed once with water. The combined aqueous phases were made alkaline (11 M NaOH) and extracted twice with diethyl ether. The combined organic phases were then dried (Na2SO4) and the solvent evaporated. The crude product was chromatographed on silica (petroleum ether-triethylamine, 97/3), to afford the title compound as a colourless liquid, 20.1 g (68.7%): 1H NMR (CDCl3) δ0.96 (m, 12H), 1.21 (t, 3H), 1.81 (m, 1H), 2.22 (m, 1H), 2.40 (t, 2H), 3.66 (dd, 1H), 4.12 (m, 2H), 7.20-7.32 (m, 5H).
Reaction SMILES: B(Br)(Br)Br.COC1C=CC(N2CC[N:16]([CH2:19][C:20]3[CH:21]=[C:22]4[NH:31][C:30](=[O:32])[C:29]5[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=5)[N:23]4[CH:33]=3)CC2)=CC=1>C(Cl)Cl.CO>[O:32]=[C:30]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:23]2[CH:33]=[C:20]([C:19]#[N:16])[CH:21]=[C:22]2[NH:31]1
Reactant: COc1ccc(N2CCN(Cc3cc4[nH]c(=O)c5ccccc5n4c3)CC2)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CO
Product: N#Cc1cc2[nH]c(=O)c3ccccc3n2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 22 %

Procedure:
Under cooling on ice, boron tribromide (0.100 mL, 1.04 mmol) was added to a solution of 2-[4-(4-methoxyphenyl)piperazin-1-ylmethyl]pyrrolo[1,2-a]quinazolin-5(4H)-one (the above Compound 2-16, 200 mg, 0.515 mmol) in methylene chloride (3.0 mL). The reaction solution was stirred at room temperature for 1 hour. The reaction solution was diluted with methanol (2.0 mL) under cooling on ice, and then concentrated under reduced pressure. The obtained residue was dissolved in 1M sodium hydroxide aqueous solution (2.0 mL), and 2M hydrochloric acid was added so that pH of the solution was 7. The precipitate was collected by filtration, and dried under reduced pressure, to obtain title Compound 3-1 (43.2 mg, yield: 22%) as an orange powder.
Reaction SMILES: Cl[CH:2](Cl)[CH3:3].[F:5][C:6]1[CH:11]=[C:10]([F:12])[C:9]([N+:13]([O-:15])=[O:14])=[CH:8][C:7]=1[N:16]1[C:25]2[C:20](=[CH:21][C:22]([F:27])=[C:23]([F:26])[CH:24]=2)[C:19](=[O:28])[C:18]([C:29]([OH:31])=[O:30])=[CH:17]1.C(Cl)(=O)C(Cl)=O>C(O)C>[F:5][C:6]1[CH:11]=[C:10]([F:12])[C:9]([N+:13]([O-:15])=[O:14])=[CH:8][C:7]=1[N:16]1[C:25]2[C:20](=[CH:21][C:22]([F:27])=[C:23]([F:26])[CH:24]=2)[C:19](=[O:28])[C:18]([C:29]([O:31][CH2:2][CH3:3])=[O:30])=[CH:17]1
Reactant: O=C(O)c1cn(-c2cc([N+](=O)[O-])c(F)cc2F)c2cc(F)c(F)cc2c1=O
Reactant: CC(Cl)Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CCO
Product: CCOC(=O)c1cn(-c2cc([N+](=O)[O-])c(F)cc2F)c2cc(F)c(F)cc2c1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 40 ml of dichloroethane was added 4.2 g of 1-(2,4-difluoro-5-nitrophenyl)-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid. With ice cooling, 7 g of oxalyl chloride was added dropwise. After the completion of addition, the solution was stirred for 2 hours at room temperature. Ethanol (15 ml) was added dropwise to the reaction solution, which was stirred overnight at room temperature. The reaction solution was concentrated in vacua, ethanol was added to the residue, and the solid was collected by filtration and washed with diethyl ether to give 3.7 g of the title compound.
Reaction SMILES: [OH-].[K+].[CH3:3][C@H:4]1[CH2:9][N:8]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][CH:12]=2)[CH2:7][CH2:6][N:5]1[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21]>O.CO>[NH2:17][C:14]1[CH:15]=[CH:16][C:11]([CH2:10][N:8]2[CH2:7][CH2:6][N:5]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C@@H:4]([CH3:3])[CH2:9]2)=[CH:12][CH:13]=1
Reactant: C[C@H]1CN(Cc2ccc([N+](=O)[O-])cc2)CCN1C(=O)OC(C)(C)C
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: C[C@H]1CN(Cc2ccc(N)cc2)CCN1C(=O)OC(C)(C)C
Reaction time: 0.29 h
Yield: 93.3 %

Procedure:
To a solution of potassium hydroxide (16.5 g, 0.29 mol) in water (35 mL) was added dry 10% Pd/C catalyst (10 g). MeOH (150 mL) was added and the mixture was hydrogenated at room temperature and atmospheric pressure for 15-20 minutes. 1,1-Dimethylethyl (2S)-2-methyl-4-[(4-nitrophenyl)methyl]-1-piperazinecarboxylate (D21) (10 g, 29.8 mmol) in MeOH (165 mL) was added and the reaction was hydrogenated for a total of 5 hrs. The catalyst was removed by filtration, washed with MeOH and water, and the filtrate/washings were concentrated in vacuo. The residue was partitioned between DCM and water and aqueous layer was further extracted with DCM. The combined organics were washed with brine, dried and concentrated to give the title compound as a colourless gum (8.49 g) which was used in the next step without further purification.
Reaction SMILES: C[O:2][C:3](=[O:37])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:15]([C:16](=[O:29])[NH:17][CH2:18][CH2:19][O:20][C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=3[Cl:28])=[C:14]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[O:13][N:12]=2)=[C:7]([Cl:36])[CH:6]=1.[Li+].[OH-].Cl.C(Cl)Cl>C1COCC1.O>[Cl:36][C:7]1[CH:6]=[C:5]([CH2:4][C:3]([OH:37])=[O:2])[CH:10]=[CH:9][C:8]=1[C:11]1[C:15]([C:16](=[O:29])[NH:17][CH2:18][CH2:19][O:20][C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=2[Cl:28])=[C:14]([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[O:13][N:12]=1
Reactant: COC(=O)Cc1ccc(-c2noc(-c3ccccc3)c2C(=O)NCCOc2ccc(Cl)cc2Cl)c(Cl)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Solvent: C1CCOC1
Product: O=C(O)Cc1ccc(-c2noc(-c3ccccc3)c2C(=O)NCCOc2ccc(Cl)cc2Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The crude (3-Chloro-4-{4-[2-(2,4-dichloro-phenoxy)-ethylcarbamoyl]-5-phenyl-isoxazol-3-yl}-phenyl)-acetic acid methyl ester 36 (0.85 mmol) is dissolved in THF (5 mL). A solution of 1 M LiOH in H2O (2 mL) is added and the mixture is stirred overnight at room temperature. The mixture is acidified with 1 M HCl (3 mL), DCM (50 mL) is added and the organic layer washed with H2O (3×30 mL). The organic layer is dried (MgSO4), filtered, concentrated and purified on reverse phase HPLC (H2O/MeCN gradient) to afford the title compound G1 as a white solid: 1H-NMR (400 MHz, CDCl3) δ=7.93 (dd, J=1.8 Hz, J=7.8 Hz, 2H), 7.52-7.23 (m, 7H), 7.17 (dd, J=8.8 Hz, J=2.5 Hz, 1H), 6.71 (d, J=8.8 Hz, 1H), 6.15 (t, J=5.3 Hz, NH), 3.92 (t, J=4.8 Hz, 2H), 3.72 (q, J=5.3 Hz, 2H), 3.50 (s, 2H). MS calculated for C26H20Cl3N2O5 (M+H+) 545.0, found 545.3.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:21])=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14](=[O:17])[CH2:15][CH3:16])=[CH:10][C:9]=2[CH2:18][CH2:19][CH3:20])[CH:7]=1.[C:22]([O:30][CH2:31][C:32]1[CH:33]=[C:34]([CH:37]=[CH:38][C:39]=1[CH2:40][O:41][C:42](=[O:49])[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[CH2:35]Br)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[C:22]([O:30][CH2:31][C:32]1[CH:33]=[C:34]([CH:37]=[CH:38][C:39]=1[CH2:40][O:41][C:42](=[O:49])[C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1)[CH2:35][O:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:21])=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14](=[O:17])[CH2:15][CH3:16])=[CH:10][C:9]=2[CH2:18][CH2:19][CH3:20])[CH:7]=1)(=[O:29])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CCCc1cc(C(=O)CC)ccc1-c1cc(O)ccc1C
Reactant: O=C(OCc1ccc(CBr)cc1COC(=O)c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCCc1cc(C(=O)CC)ccc1-c1cc(OCc2ccc(COC(=O)c3ccccc3)c(COC(=O)c3ccccc3)c2)ccc1C
Yield: 56 %

Procedure:
1.5 g (5.4 mmol) of 1-(5′-hydroxy-2′-methyl-2-propylbiphenyl-4-yl)-1-propanone, 2.5 g (5.7 mmol) of (3,4-bis(benzoyloxymethyl)benzyl bromide and 750 mg (5.4 mmol) of potassium carbonate are placed in 50 ml of methyl ethyl ketone in a round-bottomed flask and under a stream of nitrogen. The mixture is refluxed overnight and, after cooling, it is filtered through Celite. The filtrate is extracted with water and ethyl acetate. The organic phase is dried over magnesium sulfate, filtered and then evaporated. The residue obtained is purified by chromatography on a column of silica eluted with a mixture of heptane and ethyl acetate (85/15) to give 1.93 g (56%) of the expected product in the form of a dark yellow oil.
Reaction SMILES: [F:1][CH:2]([F:29])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:11][CH:12]=[C:13]([CH2:15][NH:16][C:17](=[O:27])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[O:24][CH2:25][CH3:26])[N:14]=2)=[CH:6][C:5]=1[OH:28].C1CCN2C(=NCCC2)CC1.[CH2:41](Br)[CH:42]([CH3:44])[CH3:43].O>C(O)C.C(OCC)(=O)C>[F:29][CH:2]([F:1])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:11][CH:12]=[C:13]([CH2:15][NH:16][C:17](=[O:27])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[O:24][CH2:25][CH3:26])[N:14]=2)=[CH:6][C:5]=1[O:28][CH2:41][CH:42]([CH3:44])[CH3:43]
Reactant: CCOc1ccccc1C(=O)NCc1coc(-c2ccc(OC(F)F)c(O)c2)n1
Reactant: CC(C)CBr
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Solvent: CCOC(C)=O
Product: CCOc1ccccc1C(=O)NCc1coc(-c2ccc(OC(F)F)c(OCC(C)C)c2)n1
Reaction time: 8 h

Procedure:
A 80 mg quantity of the compound obtained in Example 347 and 0.1 ml of DBU were dissolved in 2 ml of ethanol, 80 mg of isobutyl bromide was then added to the obtained solution, and heating and refluxing were conducted overnight. After cooling, water was added to the obtained reaction mixture, and ethyl acetate extraction was performed. The organic layer was washed twice with water, concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=3:1). The obtained crystals were recrystallized from aqueous 80% ethanol, thereby yielding 30 mg of white powdery N-[2-(4-difluoromethoxy-3-isobutoxyphenyl)oxazol-4-ylmethyl]-2-ethoxybenzamide.
Reaction SMILES: C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1.[CH3:26][O:27][C:28]1[CH:29]=[C:30]([NH2:40])[CH:31]=[CH:32][C:33]=1[N:34]1[CH:38]=[C:37]([CH3:39])[N:36]=[CH:35]1.[CH2:41]([C:48]1[CH:53]=[CH:52][N:51]=[C:50](Cl)[N:49]=1)[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:41]([C:48]1[CH:53]=[CH:52][N:51]=[C:50]([NH:40][C:30]2[CH:31]=[CH:32][C:33]([N:34]3[CH:38]=[C:37]([CH3:39])[N:36]=[CH:35]3)=[C:28]([O:27][CH3:26])[CH:29]=2)[N:49]=1)[C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1
Reactant: COc1cc(N)ccc1-n1cnc(C)c1
Reactant: Clc1nccc(Cc2ccccc2)n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: COc1cc(Nc2nccc(Cc3ccccc3)n2)ccc1-n1cnc(C)c1
Temperature: 20 °C
Reaction time: 0.17 h
Yield: 44.9 %

Procedure:
Palladium acetate (2.7 mg, 0.012 mmol) and 2-(dicyclohexylphosphino)-biphenyl (8.7 mg, 0.024 mmol) were dissolved under an atmosphere of nitrogen in dioxane (1 mL) and stirred for 10 min at 20° C. This solution was added at 20° C. under an atmosphere of nitrogen to a microwave flask containing 3-methoxy-4-(4-methyl-imidazol-1-yl)-phenylamine (61 mg, 0.3 mmol), 4-benzyl-2-chloro-pyrimidine (68 mg, 0.3 mmol) and potassium carbonate (829 mg, 6.0 mmol). The mixture was diluted with dioxane (1.7 mL) and heated for 30 min to 200° C. in a microwave oven. The reaction was poured onto water and extracted twice with ethyl acetate. The combined organic solutions were washed with brine, dried over sodium sulfate, filtered and the residue was purified by column chromatography on silica gel using dichloromethane/methanol (19:1 v/v) as eluent to yield the title compound (50 mg, 45%) as a yellow solid.
Reaction SMILES: OC1C=C2C(=CC=1)N(CC(F)(F)F)C(C(N1CCOCC1)=O)=C2.C([O:26][C:27]([C:29]1[NH:30][C:31]2[C:36]([CH:37]=1)=[CH:35][C:34]([O:38][CH2:39][CH2:40][CH2:41][Cl:42])=[CH:33][CH:32]=2)=[O:28])C>>[Cl:42][CH2:41][CH2:40][CH2:39][O:38][C:34]1[CH:35]=[C:36]2[C:31](=[CH:32][CH:33]=1)[NH:30][C:29]([C:27]([OH:28])=[O:26])=[CH:37]2
Reactant: CCOC(=O)c1cc2cc(OCCCCl)ccc2[nH]1
Agent: O=C(c1cc2cc(O)ccc2n1CC(F)(F)F)N1CCOCC1
Product: O=C(O)c1cc2cc(OCCCCl)ccc2[nH]1

Procedure:
In analogy to the procedure described for the synthesis of intermediate 1, step 3, the title compound was synthesized from 5-(3-chloro-propoxy)-1H-indole-2-carboxylic acid ethyl ester (example 4, step 1). The title compound was obtained in 98% yield as white solid. MS (m/e): 252.9 (M−H−, 100%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[C:6]([NH2:11])[CH:5]=1.C([O:15][C:16](=O)[C:17](OCC)=[O:18])C>>[CH3:1][O:2][C:3]([C:4]1[CH:5]=[C:6]2[C:7](=[CH:8][CH:9]=1)[NH:10][C:16](=[O:15])[C:17](=[O:18])[NH:11]2)=[O:12]
Reactant: COC(=O)c1ccc(N)c(N)c1
Reactant: CCOC(=O)C(=O)OCC
Product: COC(=O)c1ccc2[nH]c(=O)c(=O)[nH]c2c1
Temperature: 23 °C

Procedure:
A mixture of methyl-3,4-diaminobenzoate (4.5 g) in diethyloxalate (50 mL) was heated at reflux for three hrs. After cooling to 23° C., the solid was isolated by filtration, affording 2,3-dioxo-1,2,3,4-tetrahydro-quinoxaline-6-carboxylic acid methyl ester as a light yellow solid. MS (M−H)−=219.1.
Reaction SMILES: C([C:3]1([C:22]([O-])=[O:23])[NH:8][C:7]2[CH2:9][O:10][C:11]3([CH2:14][N:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:12]3)[C:6]=2[CH:5]=[CH:4]1)C.CC(C[AlH]CC(C)C)C.C1(C)C=CC=CC=1>C(Cl)Cl>[CH:22]([C:3]1[N:8]=[C:7]2[CH2:9][O:10][C:11]3([CH2:14][N:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:12]3)[C:6]2=[CH:5][CH:4]=1)=[O:23]
Reactant: CCC1(C(=O)[O-])C=CC2=C(COC23CN(C(=O)OC(C)(C)C)C3)N1
Agent: CC(C)C[AlH]CC(C)C
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CC2(C1)OCc1nc(C=O)ccc12
Temperature: -78 °C
Reaction time: 1 h
Yield: 57.4 %

Procedure:
To the stirred solution of 1-tert-butyl 2′-ethyl-7′H-spiro[azetidine-3,5′-furo[3,4-b]pyridine]-1,2′-dicarboxylate (0.5 g, 1.5 mmol, 1 eq.) in DCM (18 mL) at −78° C. under nitrogen atmosphere was added 25% DIBAL-H in toluene (0.64 g, 2.6 mL, 4.5 mmol, 3 eq.). Resulting reaction mixture was stirred at −78° C. for 1 hour under nitrogen atmosphere. After complete consumption of starting material, reaction mixture was quenched by methanol (1.5 mL) followed by addition of saturated solution of sodium potassium tartarate salt (10 mL) at −78° C. and extracted with DCM (3×75 mL). Combined organic layer was dried over sodium sulphate, concentrated under reduced pressure to afford the title compound as brown solid (0.25 g, crude). Crude compound was used as such for the next reaction. LC-MS (m/z): 291.0 (M+H).
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][N:6]([CH:20]([CH3:22])[CH3:21])[C:7]1[C:16]([N+:17]([O-])=O)=[CH:15][C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:9][N:8]=1)C.P(OC1C=CC=CC=1)(OC1C=CC=CC=1)OC1C=CC=CC=1.[H][H]>ClCCl.[NH4+].[O-][V](=O)=O.[Pt]>[CH:20]([N:6]1[CH2:5][C:4](=[O:3])[NH:17][C:16]2[CH:15]=[C:10]([C:11]([O:13][CH3:14])=[O:12])[CH:9]=[N:8][C:7]1=2)([CH3:22])[CH3:21]
Reactant: CCOC(=O)CN(c1ncc(C(=O)OC)cc1[N+](=O)[O-])C(C)C
Reactant: [H][H]
Agent: O=[V](=O)[O-]
Agent: [Pt]
Agent: [NH4+]
Solvent: ClCCl
Product: COC(=O)c1cnc2c(c1)NC(=O)CN2C(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 92.8 %

Procedure:
Methyl 6-((2-ethoxy-2-oxoethyl)(isopropyl)amino)-5-nitronicotinate (2.39 g, 7.35 mmol) was dissolved in dichloromethane (10 mL). To the yellow solution was added ammonium metavanadate (15.0 mg, 1.13 mmol), triphenyl phosphite (aprox 10 ul, 0.032 mmol), and Pt/C (240 mg, 5% w/w). The reaction mixture was pressurized with hydrogen gas (110 psi) and stirred at room temperature for 16 h. The reaction was then depressurized and diluted with dichloromethane (80 mL) which was then refluxed for 30 min. The hot solution was filtered through a pad of celite and washed with hot dichloromethane (3×20 mL). The filtrate was concentrated to yield the title compound (1.70 g, 93%) as a white solid. [M+H] calc'd for C12H15N3O3, 250; found, 250.
Reaction SMILES: [CH:1]1([C:7]2[CH:20]=[CH:19][C:10]([O:11][CH2:12][C@@H:13]3[O:17][C:16]([NH2:18])=[N:15][CH2:14]3)=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>C(Cl)(Cl)Cl>[CH:1]1([C:7]2[CH:20]=[CH:19][C:10]([O:11][CH2:12][C@@H:13]3[O:17][C:16]4=[N:18][C:10](=[O:11])[CH:9]=[CH:8][N:15]4[CH2:14]3)=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: NC1=NC[C@H](COc2ccc(C3CCCCC3)cc2)O1
Solvent: ClC(Cl)Cl
Product: O=c1ccn2c(n1)O[C@@H](COc1ccc(C3CCCCC3)cc1)C2

Procedure:
The title compound was prepared from (R)-5-(4-cyclohexyl-phenoxymethyl)-4,5-dihydro-oxazol-2-ylamine employing the procedures as set forth in Step 3 of Example 1. [α]D25 +52.40 (c 0.5, CHCl3).