Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][CH2:5][CH:6](Br)[C:7]1[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][C:8]=1[F:14])(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Cl.[CH:23]1([N:26]2[CH2:31][C:30]3([CH2:36][CH2:35][NH:34][CH2:33][CH2:32]3)[O:29][CH2:28][C:27]2=[O:37])[CH2:25][CH2:24]1>CN(C)C=O.O>[C:1]([O:4][CH2:5][CH:6]([C:7]1[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][C:8]=1[F:14])[N:34]1[CH2:35][CH2:36][C:30]2([O:29][CH2:28][C:27](=[O:37])[N:26]([CH:23]3[CH2:24][CH2:25]3)[CH2:31]2)[CH2:32][CH2:33]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCC(Br)c1ccc(Br)cc1F
Reactant: O=C1COC2(CCNCC2)CN1C1CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)OCC(c1ccc(Br)cc1F)N1CCC2(CC1)CN(C1CC1)C(=O)CO2
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.5 %

Procedure:
A solution of 2-bromo-2-(4-bromo-2-fluorophenyl)ethyl acetate (0.971 mmol) in N,N-dimethylformamide (5 mL) was treated with potassium carbonate (2.91 mmol) and 4-cyclopropyl-1-oxa-4,9-diazaspiro[5.5]undecan-3-one hydrochloride (1.019 mmol). The reaction was allowed to stir at room temperature overnight. The reaction solution was then diluted with water (50 mL) and was extracted four times with ethyl acetate. The combined organic layer was washed four times with water, twice with brine, dried over sodium sulfate, filtered and concentrated in vacuo to afford the title compound as an oil (385 mg, 76% yield). MS(ES)+ m/e 469.1/471.2 [M+H]+ (bromide isotope pattern).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[C:17](=[O:18])[N:16]2[C:19]([CH2:25][O:26][CH3:27])([C:22]([OH:24])=O)[CH2:20][CH2:21][C:15]2=[N:14][CH:13]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:28]([O:32][C:33](=[O:45])[NH:34][C:35]([C:37]1[CH:42]=[CH:41][C:40]([CH2:43][NH2:44])=[CH:39][CH:38]=1)=[NH:36])([CH3:31])([CH3:30])[CH3:29]>>[CH2:1]([O:8][C:9](=[O:10])[NH:11][C:12]1[C:17](=[O:18])[N:16]2[C:19]([C:22](=[O:24])[NH:44][CH2:43][C:40]3[CH:41]=[CH:42][C:37]([C:35]([NH:34][C:33]([O:32][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:45])=[NH:36])=[CH:38][CH:39]=3)([CH2:25][O:26][CH3:27])[CH2:20][CH2:21][C:15]2=[N:14][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COCC1(C(=O)O)CCc2ncc(NC(=O)OCc3ccccc3)c(=O)n21
Reactant: CC(C)(C)OC(=O)NC(=N)c1ccc(CN)cc1
Product: COCC1(C(=O)NCc2ccc(C(=N)NC(=O)OC(C)(C)C)cc2)CCc2ncc(NC(=O)OCc3ccccc3)c(=O)n21
Yield: 100 %

Procedure:
According to the procedure for the preparation of intermediate 19c, intermediate 23b (57.8 mg, 0.155 mmol) was coupled with [(4-aminomethyl-phenyl)-imino-methyl]-carbamic acid tert-butyl ester to afford 94 mg (100%) of intermediate 23c.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH3:17])[CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1)=[CH:7]2.[CH2:18]([N:20]=[C:21]=[O:22])[CH3:19]>>[CH2:18]([NH:20][C:21]([NH:1][C:2]1[CH:3]=[C:4]([CH3:17])[CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1)=[CH:7]2)=[O:22])[CH3:19]
Reactant: CCN=C=O
Reactant: Cc1cc(N)c2[nH]c(-c3ccccn3)cc2c1
Product: CCNC(=O)Nc1cc(C)cc2cc(-c3ccccn3)[nH]c12

Procedure:
7-Amino-5-methyl-2-(pyridin-2-yl)-1H-indole prepared in Step A of Example 1 and ethylisocyanate were reacted according to the same procedure as Example 22 to give the title compound.
Reaction SMILES: Br[C:2]1[CH:18]=[C:17]2[C:5]([CH2:6][CH2:7][C@@:8]32[C:13]([F:15])([F:14])[CH2:12][O:11][C:10]([NH2:16])=[N:9]3)=[CH:4][CH:3]=1.[Cl:19][C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[C:24]([Cl:26])[CH:25]=1.COCCOC>O>[Cl:19][C:20]1[CH:21]=[C:22]([C:2]2[CH:18]=[C:17]3[C:5]([CH2:6][CH2:7][C@@:8]43[C:13]([F:15])([F:14])[CH2:12][O:11][C:10]([NH2:16])=[N:9]4)=[CH:4][CH:3]=2)[CH:23]=[C:24]([Cl:26])[CH:25]=1
Reactant: OB(O)c1cc(Cl)cc(Cl)c1
Reactant: NC1=N[C@@]2(CCc3ccc(Br)cc32)C(F)(F)CO1
Solvent: COCCOC
Solvent: O
Product: NC1=N[C@@]2(CCc3ccc(-c4cc(Cl)cc(Cl)c4)cc32)C(F)(F)CO1
Yield: 15 %

Procedure:
In a manner analogous to that described in Example 1, the cross-coupling reaction of (R)-6-bromo-5′,5′-difluoro-2,3,5′,6′-tetrahydrospiro[indene-1,4′-[1,3]oxazin]-2′-amine (intermediate A6.5) with 3,5-dichlorophenylboronic acid in a 3:1-mixture of 1,2-dimethoxyethane and water as the solvent yielded the title compound (15% yield) as an off-white solid. MS (ISP): m/z=382.8 [M+H]+.
Reaction SMILES: [NH2:1][C:2]([C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][C:22]2[C:26]3[C:27]([OH:31])=[CH:28][CH:29]=[CH:30][C:25]=3[O:24][CH:23]=2)=[CH:16][CH:15]=1)=[N:3][C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5].[C:32]([O:35][C@@H:36]1[C@@H:48]([O:49][C:50](=[O:52])[CH3:51])[C@H:47]([O:53][C:54](=[O:56])[CH3:55])[C@@H:46]([CH2:57][O:58][C:59](=[O:61])[CH3:60])[O:45][C@@H:37]1OC(=N)C(Cl)(Cl)Cl)(=[O:34])[CH3:33].C(=O)([O-])O.[Na+]>ClCCl>[C:32]([O:35][C@@H:36]1[C@@H:48]([O:49][C:50](=[O:52])[CH3:51])[C@H:47]([O:53][C:54](=[O:56])[CH3:55])[C@@H:46]([CH2:57][O:58][C:59](=[O:61])[CH3:60])[O:45][C@H:37]1[O:31][C:27]1[C:26]2[C:22]([CH2:21][CH2:20][C:17]3[CH:18]=[CH:19][C:14]([C:2]([NH2:1])=[N:3][C:4]([O:6][CH2:7][C:8]4[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=4)=[O:5])=[CH:15][CH:16]=3)=[CH:23][O:24][C:25]=2[CH:30]=[CH:29][CH:28]=1)(=[O:34])[CH3:33]
Reactant: CC(=O)OC[C@H]1O[C@H](OC(=N)C(Cl)(Cl)Cl)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: NC(=NC(=O)OCc1ccccc1)c1ccc(CCc2coc3cccc(O)c23)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(=O)OC[C@H]1O[C@@H](Oc2cccc3occ(CCc4ccc(C(N)=NC(=O)OCc5ccccc5)cc4)c23)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 72 h
Yield: 77.9 %

Procedure:
To a mixture of 3-(2-{4-[1-amino-1-(benzyloxycarbonylimino)methyl]phenyl}ethyl)-4-hydroxybenzofuran (30 mg) and 2,3,4,6-tetra-O-acetyl-1-O-trichloroacetoimidoyl-α-D-glucopyranose (43 mg) in dichloromethane (3 mL) was added boron trifluoride-diethyl ether complex (0.009 mL), and the mixture was stirred at room temperature for 3 days. The reaction mixture was poured into a saturated aqueous sodium hydrogen carbonate solution, and the resulting mixture was extracted with ethyl acetate. The extract was washed with brine and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=1/1-2/3) to give 4-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-3-(2-{4-[1-amino-1-(benzyloxycarbonylimino)methyl]phenyl}ethyl)benzofuran (42 mg). This material was dissolved in methanol (3 mL). To the solution was added sodium methoxide (28% methanol solution, 0.02 mL), and the mixture was stirred at room temperature for 1 hour. To the reaction mixture was added a saturated aqueous sodium hydrogen carbonate solution, and the resulting mixture was extracted with ethylacetate. The extract was washed with brine and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: dichloromethane/methanol=10/1) to give 3-(2-{4-[1-amino-1-(benzyloxycarbonylimino)methyl]phenyl}ethyl)-4-(β-D-glucopyranosyloxy)benzofuran (20 mg). This material was dissolved in methanol (3 mL). To the solution was added 10% palladium-carbon powder (10 mg), and the mixture was stirred at room temperature under a hydrogen atmosphere for 2 hours. The insoluble material was removed by filtration. The solvent of the filtrate was removed under reduced pressure to give the title compound (13 mg).
Reaction SMILES: [Br:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([N+:9]([O-:11])=[O:10])=[C:4](F)[CH:3]=1.Cl.Cl.[O:15]1[CH2:20][CH2:19][CH:18]([N:21]2[CH2:26][CH2:25][CH:24]([NH2:27])[CH2:23][CH2:22]2)[CH2:17][CH2:16]1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[Br:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([N+:9]([O-:11])=[O:10])=[C:4]([NH:27][CH:24]2[CH2:23][CH2:22][N:21]([CH:18]3[CH2:19][CH2:20][O:15][CH2:16][CH2:17]3)[CH2:26][CH2:25]2)[CH:3]=1
Reactant: O=[N+]([O-])c1cc(F)c(Br)cc1F
Reactant: NC1CCN(C2CCOCC2)CC1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1cc(F)c(Br)cc1NC1CCN(C2CCOCC2)CC1
Temperature: 200 °C
Yield: 107.7 %

Procedure:
A mixture of 4-bromo-2,5-difluoro-1-nitrobenzene (1 g, 4.2 mmol), 1-(tetrahydro-2H-pyran-4yl)piperidin-4-amine dihydrochloride salt (D40, 1.08 g, 4.2 mmol), and di-iso-propylethylamine (2.2 ml, 1.26 mmol) in dimethylformamide (10 ml) was heated in microwave reactor for 5 min at 200° C. The mixture was washed with water, then extracted with dichloromethane and the extract dried over MgSO4 and concentrated under vacuum. The crude material was purified on silica column (100 g of silica, ethyl acetate/methanol: 1.0% to 0%, 3CV; 2.0% to 100% 2CV 3. 100% to 100% 5CV) to leave 1.82 g (96%) of a mixture of title compound and an unknown impurity (˜3:1 by HPLC).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([NH2:12])[S:11][C:7]=2[C:6]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[CH:5][CH:4]=1.[CH3:19][O:20][CH2:21][C:22](Cl)=[O:23]>>[CH3:19][O:20][CH2:21][C:22]([NH:12][C:10]1[S:11][C:7]2[C:6]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[C:8]=2[N:9]=1)=[O:23]
Reactant: COCC(=O)Cl
Reactant: COc1ccc(N2CCOCC2)c2sc(N)nc12
Product: COCC(=O)Nc1nc2c(OC)ccc(N3CCOCC3)c2s1

Procedure:
Using 4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl-amine and methoxyacetyl chloride the title compound was obtained as a light yellow solid (37%), MS: m/e=338 (M+H+).
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[C:8]2[C:17](=[O:18])[NH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:19]([F:22])([F:21])[F:20])[CH:14]=3)[N:9]2[C:23]=1[CH2:24][N:25]1[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27][CH2:26]1)=[O:5])C>Br>[C:4]([C:6]1[N:7]=[C:8]2[C:17](=[O:18])[NH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:19]([F:21])([F:22])[F:20])[CH:14]=3)[N:9]2[C:23]=1[CH2:24][N:25]1[CH2:26][CH2:27][N:28]([CH3:31])[CH2:29][CH2:30]1)([OH:5])=[O:3]
Reactant: CCOC(=O)c1nc2c(=O)[nH]c3cc(C(F)(F)F)ccc3n2c1CN1CCN(C)CC1
Agent: Br
Product: CN1CCN(Cc2c(C(=O)O)nc3c(=O)[nH]c4cc(C(F)(F)F)ccc4n23)CC1
Yield: 73 %

Procedure:
A solution of 2-ethoxycarbonyl-1-(4-methyl-1-piperazinyl)methyl-7-trifluoromethylimidazo[1,2-a]quinoxalin-4(5H)-one (Example 11) (380 mg, 0.87 mmol) in hydrobromic acid (48% in water) (20 ml) was stirred at 80° C. for 30 h. The mixture was concentrated in vacuo and the residue stirred with ether. The product which was isolated by filtration was recrystallized from methanol/ether to afford 260 mg (57%) of the title compound as a HBr salt. M.p. >240° C.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1.[OH-].[Na+].O=C1CCC(=O)N1[O:21][C:22](=O)[CH2:23][CH2:24][CH2:25][O:26][C:27]1[CH:47]=[CH:46][C:30]2[CH:31]([CH2:40][CH2:41][CH2:42][N:43]([CH3:45])[CH3:44])[C:32]3[CH:39]=[CH:38][CH:37]=[CH:36][C:33]=3[CH2:34][CH2:35][C:29]=2[CH:28]=1.Cl>O.C1COCC1>[CH3:45][N:43]([CH3:44])[CH2:42][CH2:41][CH2:40][CH:31]1[C:30]2[CH:46]=[CH:47][C:27]([O:26][CH2:25][CH2:24][CH2:23][C:22]([NH:1][CH2:2][C:3]3[CH:4]=[CH:5][C:6]([C:7]([OH:9])=[O:8])=[CH:10][CH:11]=3)=[O:21])=[CH:28][C:29]=2[CH2:35][CH2:34][C:33]2[CH:36]=[CH:37][CH:38]=[CH:39][C:32]1=2
Reactant: NCc1ccc(C(=O)O)cc1
Reactant: CN(C)CCCC1c2ccccc2CCc2cc(OCCCC(=O)ON3C(=O)CCC3=O)ccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CN(C)CCCC1c2ccccc2CCc2cc(OCCCC(=O)NCc3ccc(C(=O)O)cc3)ccc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 81 %

Procedure:
A mixture of 32 mg (0.212 mmol) of 4-(aminomethyl)benzoic acid in 2 ml of H2O and 4 ml of THF was treated with approximately 0.1 ml of 2 N NaOH such that the pH of the mixture was about 9. This was then treated with a solution of 100 mg (0.209 mmol) of the TCA NHS ester 9 in 4.5 ml of THF. The pH was adjusted to about 8.5-9.0 with 2 N NaOH and the reaction was stirred at room temperature for 15 minutes. The reaction was neutralized to pH 6 with 2 N HCl, then extracted twice with CH2Cl2. The CH2Cl2 portions were combined, dried over anhydrous Na2SO4 and concentrated in vacuo to give 87 mg (81%) of the acid 15 as a pale yellow oil. This was used in the next step without further purification.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([OH:22])[C:8]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].O[CH2:24][NH:25][C:26](=[O:29])[CH2:27][Cl:28].FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:28][CH2:27][C:26]([NH:25][CH2:24][C:6]1[C:7]([OH:22])=[C:8]([C:15]2[CH:16]=[CH:17][C:18]([Cl:21])=[CH:19][CH:20]=2)[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:10][C:5]=1[C:1]([CH3:2])([CH3:3])[CH3:4])=[O:29]
Reactant: CC(C)(C)c1cc(O)c(-c2ccc(Cl)cc2)c(C(C)(C)C)c1
Reactant: O=C(CCl)NCO
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)c1cc(C(C)(C)C)c(-c2ccc(Cl)cc2)c(O)c1CNC(=O)CCl
Reaction time: 8 h

Procedure:
To a solution of 3.0 g (9.5 mmol) of the product of Step B and 1.25 g (10.1 mmol) of N-hydroxymethyl-2-chloroacetamide in 20 mL CH2Cl2 was added 25 mL of trifluoroacetic acid. The reaction mixture was stirred under a nitrogen atmosphere overnight and then concentrated in vacuo. The residue was partitioned between EtOAc and excess saturated aqueous NaHCO3. The aqueous layer was separated and re-extracted with EtOAc. The organic layers were then combined, dried (Na2SO4), filtered and evaporated in vacuo to afford the title compound.
Reaction SMILES: [C:1]1([CH:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Br.[CH2:19]([O:21][C:22](=[O:32])[C@@H:23]1[CH2:28][CH2:27][CH2:26][N:25]([CH2:29][CH2:30]Br)[CH2:24]1)[CH3:20]>C1(C)C=CC=CC=1>[CH2:19]([O:21][C:22]([C@@H:23]1[CH2:28][CH2:27][CH2:26][N:25]([CH2:29][CH2:30][O:9][CH:8]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:24]1)=[O:32])[CH3:20]
Reactant: O=CC(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)[C@@H]1CCCN(CCBr)C1
Agent: Br
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCOC(=O)[C@@H]1CCCN(CCOC=C(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69.6 %

Procedure:
Diphenylacetaldehyde (4.9 g, 0.025 mole) was added dropwise to a mixture of sodium hydride (1.5 g, 0.05 mole, 80% oil dispersion) and dry toluene (25 ml) at 0° C. This mixture was stirred at room temperature for 0.5 h, heated to 50° C. and allowed to cool to room temperature. The above (R)-1-(2-bromoethyl)nipecotic acid ethyl ester hydrobromide (8.6 g, 0.025 mole) was added portionwise whilst the temperature was kept below 30° C. with an ice-water bath. After being stirred for 1 h the reaction mixture was filtered, and the filtrate was evaporated to dryness. Flash chromatography of the residue on silica gel (200 g) using a mixture of heptane and tetrahydrofuran (4/1) as eluent provided the title compound (6.6 g, 69%) as an oil. Tlc: rf 0.24 (SiO2 ; heptane/THF 7/3).
Reaction SMILES: [CH3:1][C:2]1[C:3](=O)[NH:4][C:5]([S:8][CH3:9])=[N:6][CH:7]=1.O=P(Cl)(Cl)[Cl:13]>O1CCOCC1>[Cl:13][C:3]1[C:2]([CH3:1])=[CH:7][N:6]=[C:5]([S:8][CH3:9])[N:4]=1
Reactant: CSc1ncc(C)c(=O)[nH]1
Reactant: O=P(Cl)(Cl)Cl
Solvent: C1COCCO1
Product: CSc1ncc(C)c(Cl)n1
Yield: 89 %

Procedure:
A mixture of 5-methyl-2-methylsulfanyl-3H-pyrimidin-4-one (6.86 g, 44 mmol) and POCl3 (14 ml) in dioxane (60 ml) was refluxed for 2 hours. The solvent was removed under vacuum and the residue was quenched with ice and extracted with diethylether. The organic phase was dried (Na2SO4) and evaporated to give 6.8 g of the title compound as oil that was used in the next step without further purification. (89% yield)
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[CH:10][C:11](=[O:14])[NH:12][CH:13]=2)=[CH:4][CH:3]=1.[N+:15]([C:18]1[CH:26]=[CH:25][C:21]([C:22](Cl)=[O:23])=[CH:20][CH:19]=1)([O-:17])=[O:16]>[OH-].[Na+]>[N+:15]([C:18]1[CH:19]=[CH:20][C:21]([C:22]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]3[N:9]=[CH:10][C:11](=[O:14])[NH:12][CH:13]=3)=[CH:6][CH:7]=2)=[O:23])=[CH:25][CH:26]=1)([O-:17])=[O:16]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: Nc1ccc(-c2c[nH]c(=O)cn2)cc1
Agent: [Na+]
Agent: [OH-]
Product: O=C(Nc1ccc(-c2c[nH]c(=O)cn2)cc1)c1ccc([N+](=O)[O-])cc1
Yield: 49.1 %

Procedure:
A solution of 5-(4-aminophenyl)-2(1H)-pyrazinone (1.7 g) in sodium hydroxide was reacted with 4-nitrobenzoyl chloride (1.8 g) in a manner similar to that described in Example 9 to give 5-[4-(4-nitrobenzamido)phenyl]-2(1H)-pyrazinone (1.5 g, m.p. 298°-300° C.).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[N:9]1[CH:13]=[CH:12][C:11]([C:14](=O)[CH3:15])=[CH:10]1.Cl.[NH2:18][OH:19].N1C=CC=CC=1>CO>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[N:9]1[CH:13]=[CH:12][C:11]([C:14](=[N:18][OH:19])[CH3:15])=[CH:10]1
Reactant: CC(=O)c1ccn(-c2c(C)cccc2C)c1
Reactant: NO
Agent: Cl
Solvent: CO
Solvent: c1ccncc1
Product: CC(=NO)c1ccn(-c2c(C)cccc2C)c1

Procedure:
A mixture of 1-(2,6-dimethylphenyl)-3-acetyl-1H-pyrrole (20.0 g), hydroxylamine hydrochloride (25.0 g), pyridine (130 ml) in 100 ml of methanol is heated under reflux for 20 hours. Workup in the usual manner yields 1-(2,6-dimethylphenyl)-3-acetyl-1H-pyrrole oxime.
Reaction SMILES: C([O:3][C:4](=[O:14])[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[OH:13])C.[OH-].[K+]>C(O)C.O>[OH:13][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1/[CH:6]=[CH:5]/[C:4]([OH:14])=[O:3]
Reactant: CCOC(=O)C=Cc1ccccc1O
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)/C=C/c1ccccc1O
Yield: 51.9 %

Procedure:
To a solution of 100.0 g 3-(2-hydroxy-phenyl)-acrylic acid ethyl ester in 500 ml of ethanol, a solution of 50.9 g potassium hydroxide in 500 ml of water was dropped in at room temperature. After stirring at reflux for 28 hours, the reaction mixture was concentrated. The residue was diluted with 500 ml HCl 2N and extracted with ether. The organic phase was washed with 2N HCl and water, dried and evaporated to dryness. The resulting solid was recrystallized to yield 44.3 g of colourless crystals.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH:12]2[CH2:14][CH:9]1[CH2:10][N:11]2[C:15]1[CH:20]=[CH:19][C:18](Cl)=[CH:17][CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:22]S([O-])=O.[Na+]>Cl.O>[CH2:1]([N:8]1[CH2:13][CH:12]2[CH2:14][CH:9]1[CH2:10][N:11]2[C:15]1[CH:20]=[CH:19][C:18]([OH:22])=[CH:17][CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S([O-])O
Reactant: Clc1ccc(N2CC3CC2CN3Cc2ccccc2)cc1
Agent: Cl
Agent: [Na+]
Solvent: O
Product: Oc1ccc(N2CC3CC2CN3Cc2ccccc2)cc1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
To a solution of 1.17 g (122) in 17 mL concentrated HCl 0.35 g NaNO2 in 5 mL water were added slowly dropwise, so that the temperature remained below 5° C. The solution was agitated for 2 hours at 60° C., neutralized with NaHSO3 and extracted with ether (4×50 mL). The combined organic phases were dried with Na2SO4, evaporated and distilled in a bulb tube (Kp: 0.05 mbar; 140° C.): 0.1 g (123) (123) as colorless oil. DC: CHCl3/methanol (9:1).
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([C:9]([NH2:11])=[O:10])[CH2:2]2.C1(=O)O[CH:15]=[CH:14]O1>>[O:10]1[CH:15]=[CH:14][N:11]=[C:9]1[CH:3]1[CH:4]2[CH2:7][CH2:8][N:1]([CH2:6][CH2:5]2)[CH2:2]1
Reactant: O=c1occo1
Reactant: NC(=O)C1CN2CCC1CC2
Product: c1coc(C2CN3CCC2CC3)n1
Yield: 27.7 %

Procedure:
A stirred mixture of (±) 1-azabicyclo[2.2.2]octane-3-carboxamide (D2) (2.3 g; 0.015 moles) and vinylene carbonate (1.33 g; 0.016 moles) in polyphosphoric acid was placed in an oil bath at 120° and the temperature was raised to 180° over a period of 45 min. After cooling the reaction was treated with ice and washed with ether (100 ml). The pH of the aqueous solution was adjusted to 9 with 40% sodium hydroxide and potassium carbonate was then added until saturation point. Extraction with ether (4×100 ml) followed by drying (Na2SO4) and concentration in vacuo afforded a crude oil (1.45 g). Purification on neutral alumina (Brockmann grade 1) using a graded eluant of 2%-6% methanol in ethyl acetate produced the title compound as a pale yellow oil (0.74 g; 28%) which was converted into the oxalate salt, m.p. 98°-101° C. (acetone-methanol).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]([O:14][CH3:15])=[O:13])[CH:8]=[CH:7]2.[C:16](=O)([O-])[O-].[K+].[K+].IC>CC(C)=O>[CH3:16][O:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]([O:14][CH3:15])=[O:13])[CH:8]=[CH:7]2
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1ccc2cccc(O)c2n1
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COC(=O)c1ccc2cccc(OC)c2n1
Temperature: 25 °C
Reaction time: 48 h
Yield: 100.6 %

Procedure:
Methyl 8-hydroxyquinoline-2-carboxylate (1.6 g), acetone (15 ml), potassium carbonate (1.3 g) and iodomethane (0.6 ml) were combined and stirred at room temperature for 48 h. The solvents were removed in vacuo and the resulting white residue suspended in water (25 ml) which was extracted with ethyl acetate (3×25 ml). The combined organic layers were dried (magnesium sulphate) and the solvents removed in vacuo to give the title compound as a white solid (1.72 g).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6]([O:9][CH2:10][CH3:11])([OH:8])[CH3:7])[CH3:4].[CH2:12](Cl)[C:13](=[CH2:15])[CH3:14]>C1COCC1>[CH2:12]([O:8][C:6]([O:9][CH2:10][CH3:11])([O:5][CH2:3][CH3:4])[CH3:7])[C:13](=[CH2:15])[CH3:14]
Reactant: CCOC(C)(O)OCC
Reactant: C=C(C)CCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=C(C)COC(C)(OCC)OCC
Yield: 90 %

Procedure:
To a cold (0° C.) suspension of NaH (2.68 g, 60%) in THF (150 mL) was added a solution of 1,1-diethoxyethanol [which was prepared according to the literature procedure of Zirkle, C. L. et. al. J. Org. Chem. 1961, 26, 395-407] (9.00 g) in THF (20 mL), and the reaction mixture was stirred at room temperature for 1 hour before adding methallyl chloride (8.0 mL). The reaction mixture was heated to reflux overnight, cooled and filtered through a plug of celite. Solvent was removed by rotary evaporation, and the residue purified by column chromatography (silica, 20% ether/hexane) to give 1,1-diethoxyethyl methallyl ether (11.5, 90%). Ozonolysis of a chilled (-30° C.) solution of this ether (6.00 g) in EtOAc (80 mL) was carried out until no starting material was detectable by TLC (1 hour). At this time, the reaction was purged with oxygen, treated with Pd(OH)2 (150 mg) and stirred under an atmosphere of hydrogen overnight. The catalyst was filtered away, and the filtrate was concentrated by rotary evaporation. The resulting residue was purified by column chromatography (silica, 20% EtOAc/hexane) to afford the title compound (4.53 g, 82%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:13])[C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1.[CH2:14]([O:16][P:17]([O-:21])[O:18][CH2:19][CH3:20])[CH3:15].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH2:14]([O:16][P:17]([C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:13])[C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1)([O:18][CH2:19][CH3:20])=[O:21])[CH3:15]
Reactant: COC(=O)C(C)c1ccc(Br)cc1
Reactant: CCOP([O-])OCC
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCOP(=O)(OCC)c1ccc(C(C)C(=O)OC)cc1
Temperature: 110 °C

Procedure:
To a solution of methyl 2-(4-bromophenyl)propanoate, 7-e, (500 mg, 2.06 mmol), diethylphosphite (994 mg, 7.20 mmol) and triethylamine (681 mg, 6.7 mmol) in toluene (5 mL) was added [1,1′-bis(diphenylphosphino) ferrocene]dicholoropalladium (54 mg). The resulting reaction mixture was heated at 110° C. under nitrogen overnight. The cooled reaction mixture was filtrated (washed with DCM, 3×10 mL), and the filtrate was concentrated to afford the crude product which was purified by column chromatography to give the title compound, 7-f, as yellow brown oil (500 mg, 99%). 1H NMR (300 MHz, CDCl3) δ1.30-1.39 (m, 6H), 1.51 (d, J=7.2 Hz, 3H), 3.67 (s, 3H), 3.77 (q, J=7.2 Hz, 1H), 4.05-4.20 (m, 4H), 7.37-7.41 (m, 2H), 7.72-7.79 (m, 2H). LC-MS (M+H)+ 301.