Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][N:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1)=[O:5])[CH3:2].C(N(CC)CC)C.[C:20](Cl)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>O1CCCC1>[CH2:1]([O:3][C:4](=[O:5])[CH2:6][N:7]1[CH2:8][CH2:9][N:10]([C:20](=[O:27])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:11][CH2:12]1)[CH3:2]
Reactant: O=C(Cl)c1ccccc1
Reactant: CCOC(=O)CN1CCNCC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)CN1CCN(C(=O)c2ccccc2)CC1
Reaction time: 4 h

Procedure:
1-(Ethoxycarbonylmethyl)piperazine (5.1 g) was dissolved in tetrahydrofuran (300 ml) under a nitrogen atmosphere, and triethylamine (8.25 ml) and benzoyl chloride (3.44 ml) was added thereto with cooling in an ice water bath. The reaction mixture was brought to room temperature, followed by stirring for 4 hours. The reaction mixture was partitioned between ethyl acetate (200 ml) and a saturated aqueous solution of sodium hydrogencarbonate (100 ml). The separated organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate (100 ml), water (100 ml) and brine (100 ml), and dried over sodium sulfate. The solvent was distilled off under reduced pressure to give the title compound (8.19 g, quant.) as a colorless oil.
Reaction SMILES: [C:1]([O:9][C:10]1[C:20](=[O:21])[N:14]2[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:13]2=[N:12][C:11]=1[C:22]([O:24][CH3:25])=[O:23])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:26]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[C:1]([O:9][C:10]1[C:20](=[O:21])[N:14]2[CH2:15][CH2:16][CH2:17][CH2:18][CH:19]([Br:26])[C:13]2=[N:12][C:11]=1[C:22]([O:24][CH3:25])=[O:23])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1nc2n(c(=O)c1OC(=O)c1ccccc1)CCCCC2
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1nc2n(c(=O)c1OC(=O)c1ccccc1)CCCCC2Br
Temperature: 25 °C

Procedure:
A mixture of methyl 3-(benzoyloxy)-4-oxo-4,6,7,8,9,10-hexahydropyrimido[1,2-a]azepine-2-carboxylate, N-bromo-succinimide (2 eq.) and α,α′-azoisobutyronitrile (0.45 eq.) in carbon tetrachloride was stirred under reflux for 14 hour. The mixture was cooled to room temperature, the succinimide was filtered off and the solvent was removed under reduced pressure. Methyl 3-(benzoyloxy)-10-bromo-4-oxo-4,6,7,8,9,10-hexahydropyrimido[1,2-a]azepine-2-carboxylate was obtained after flash chromatography (eluents petroleum ether/ethyl acetate, 8:2) as a pale yellow solid.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:25]/[O:26][CH2:27][C:28]([O:30]C(C)(C)C)=[O:29])/[C:8]([NH:10][C@@H:11]2[C:23](=[O:24])[N:13]3[C:14]([C:20]([O-:22])=[O:21])=[C:15]([CH2:18]O)[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.[Na+:35].[C:36]([CH2:39][S:40][C:41]1[C:45]([C:46]#[N:47])=[C:44]([SH:48])[S:43][N:42]=1)(=[NH:38])[NH2:37]>CN(C=O)C>[C:36]([CH2:39][S:40][C:41]1[C:45]([C:46]#[N:47])=[C:44]([S:48][CH2:18][C:15]2[CH2:16][S:17][C@@H:12]3[C@H:11]([NH:10][C:8](=[O:9])/[C:7](/[C:5]4[N:6]=[C:2]([NH2:1])[S:3][CH:4]=4)=[N:25]\[O:26][CH2:27][C:28]([OH:30])=[O:29])[C:23](=[O:24])[N:13]3[C:14]=2[C:20]([O-:22])=[O:21])[S:43][N:42]=1)(=[NH:37])[NH2:38].[Na+:35]
Reactant: CC(C)(C)OC(=O)CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)[O-])=C(CO)CS[C@H]12)c1csc(N)n1
Reactant: N#Cc1c(SCC(=N)N)nsc1S
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1c(SCC(=N)N)nsc1SCC1=C(C(=O)[O-])N2C(=O)[C@@H](NC(=O)/C(=N\OCC(=O)O)c3csc(N)n3)[C@H]2SC1
Temperature: -20 °C
Yield: 50.7 %

Procedure:
To a solution of sodium 7β-[2-(2-aminothiazol-4-yl) -(Z)-2-(tert-butoxycarbonylmethoxyimino)acetamido]-3-hydroxymethyl-3-cephem-4-carboxylate (554 mg) and 3-amidinomethylthio-4-cyano-5-mercaptoisothiazole (345 mg) in 7 ml of DMF was added 1.2 g of ethyl o-phenylenephosphate under stirring at -20° C. After stirring under ice-cooling for 2 hours, the reaction mixture was subjected to a column chromatography on silica gel (150 g), being washed with acetonitrile and eluted with acetonitrile/water (6:1). The eluate was concentrated. The resultant precipitate was collected by filtration and dissolved in 40 ml of trifluoroacetic acid under ice-cooling. The mixture was stirred at room temperature for an hour and distilled to remove the solvent. The residue was dissolved in a mixture of water and THF and then adjusted to pH 6 with an aqueous sodium hydrogencarbonate solution. The solution was washed with ethyl acetate, concentrated under reduced pressure and subjected to a column chromatography on XAD-II (150 ml), being washed with water and eluted with 20% aqueous ethanol. The eluate was concentrated under reduced pressure and lyophilized to give 363 mg of the title compound as a pale yellow powder.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[O:11][C:10]2[C:5](=[CH:6][C:7]([C:12]#[N:13])=[CH:8][CH:9]=2)[C@@H:4]2[O:14][C@H:3]12.[N:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19]([OH:26])=[N:18][CH:17]=1>>[OH:14][C@H:3]1[C@H:4]([O:26][C:19]2[C:20]3[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=3)[N:16]=[CH:17][N:18]=2)[C:5]2[C:10](=[CH:9][CH:8]=[C:7]([C:12]#[N:13])[CH:6]=2)[O:11][C:2]1([CH3:15])[CH3:1]
Reactant: CC1(C)Oc2ccc(C#N)cc2[C@@H]2O[C@@H]21
Reactant: Oc1ncnc2ccccc12
Product: CC1(C)Oc2ccc(C#N)cc2[C@@H](Oc2ncnc3ccccc23)[C@@H]1O

Procedure:
Following the procedure in Example 1, using (S,S)-2,2-dimethyl-1a,7 b-dihydro-2H-1,3-dioxa-cyclopropa[a]naphthalene-6-carbonitrile and quinazolin-4-ol as starting material, the title compound was prepared as a white solid.
Reaction SMILES: [N-:1]=[N+]=[N-].[Na+].OS(O)(=O)=O.[Br:10][C:11]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:12]=1[CH2:13][CH2:14][C:15]2=[O:20].[OH-].[Na+]>O.C(Cl)(Cl)Cl>[Br:10][C:11]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:12]=1[CH2:13][CH2:14][C:15](=[O:20])[NH:1]2
Reactant: O=C1CCc2c(Br)cccc21
Reactant: [N-]=[N+]=[N-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: O
Product: O=C1CCc2c(Br)cccc2N1
Temperature: 0 °C
Reaction time: 2.5 h

Procedure:
To a stirred mixture of sodium azide (862 mg, 13.3 mmol) in H2O (1.7 mL) and CHCl3 (6.5 mL) was added conc. H2SO4 (0.23 mL, 4.14 mmol). The reaction mixture was stirred vigorously at 0° C. for 2.5 h. The CHCl3 layer was separated, dried over Na2SO4, and added to a solution of 4-bromo-1-indanone (1.12 g, 5.31 mmol) in CHCl3 (20 mL). To this mixture was added conc. H2SO4 (1.75 mL, 31.5 mmol) dropwise over 10 min. The reaction mixture was heated at 45 C for 1 h then poured into ice-water, neutralized with 20% aqueous NaOH, and extracted with CH2Cl2 (100 mL). The organic extract was dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography, eluting with a gradient of CH2Cl2:EtOAc—100:0 to 80:20, to give the title compound. MS: m/z=226 (M+1).
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[CH2:4][N:5]1[C:13]2[CH2:12][CH2:11][N:10]([C:14](=[O:16])[CH3:15])[CH2:9][C:8]=2[C:7]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=2)=[N:6]1.[Cl:27][C:28]1[CH:42]=[CH:41][C:31]2[N:32]=[C:33]([N:35]3[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]3)[S:34][C:30]=2[CH:29]=1>CCO>[Cl:27][C:28]1[CH:42]=[CH:41][C:31]2[N:32]=[C:33]([N:35]3[CH2:40][CH2:39][N:38]([CH2:3][CH:2]([OH:1])[CH2:4][N:5]4[C:13]5[CH2:12][CH2:11][N:10]([C:14](=[O:16])[CH3:15])[CH2:9][C:8]=5[C:7]([C:17]5[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=5)=[N:6]4)[CH2:37][CH2:36]3)[S:34][C:30]=2[CH:29]=1
Reactant: CC(=O)N1CCc2c(c(-c3ccc(C(F)(F)F)cc3)nn2CC2CO2)C1
Reactant: Clc1ccc2nc(N3CCNCC3)sc2c1
Solvent: CCO
Product: CC(=O)N1CCc2c(c(-c3ccc(C(F)(F)F)cc3)nn2CC(O)CN2CCN(c3nc4ccc(Cl)cc4s3)CC2)C1
Temperature: 60 °C
Yield: 91.1 %

Procedure:
To a stirred solution of 144 mg (0.39 mmol) of 1-[1-oxiranylmethyl-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone in 4 mL of EtOH was added 100 mg (0.39 mmol) 6-chloro-2-piperazin-1-yl-benzothiazole. The solution was heated to 60° C. overnight. The solvent was then removed by rotary evaporation and the crude product was purified by column chromatography (silica, 0-10% MeOH/EtOAc) to afford 220 mg (90%) of a white solid. MS (electrospray): exact mass calculated for C29H30ClF3N6O2S: 618.18; m/z found, 619.2 [M+H]+. HPLC (reverse phase conditions 40-90%): tR=8.27 min. 1H NMR (CDCl3, 400 MHz, a mixture of amide rotamers): 7.70 (d, J=8.34 Hz, 1H), 7.62 (m, 2H), 7.57 (d, J=8.59 Hz, 1H), 7.48 (d, J=2.53 Hz, 1H), 7.36 (d, J=8.59 Hz, 1H), 7.16 (dd, J=8.59, 2.53 Hz, 1H), 4.80 and 4.68 (A and B of AB quartet, J=15.92 Hz, 1H), 4.58 (s, 1H), 4.18-4.08 (m, 2H), 4.01-3.89 (m, 2H), 3.85-3.60 (m, 2H), 3.59-3.47 (m, 4H), 2.94-2.75 (m, 2H), 2.72-2.62 (m, 2H), 2.55-2.47 (m, 2H), 2.46-2.39 (m, 2H), 2.13 (s, 1.5H), 2.08 (s, 1.5H).
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:2].[CH2:10](O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.P(OC1C=CC=CC=1)(OC1C=CC=CC=1)OC1C=CC=CC=1>O>[CH2:1]([N:3]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:2]
Reactant: OCc1ccccc1
Reactant: CCNc1ccccc1
Agent: c1ccc(OP(Oc2ccccc2)Oc2ccccc2)cc1
Solvent: O
Product: CCN(Cc1ccccc1)c1ccccc1
Temperature: 210 °C
Yield: 87 %

Procedure:
182 parts of N-ethylaniline, 170 parts of benzyl alcohol and 10 parts of triphenyl phosphite are mixed whilst stirring and next heated to an internal temperature of 184° C, at which the elimination of water commences. The mixture is then heated to an internal temperature of 210° C in the course of 8 hours. During this time, 25 parts of water have distilled off and the condensation has ended. The excess ethylaniline and unconverted benzyl alcohol are then distilled off. 276 parts of N-ethyl-N-benzyl-aniline, corresponding to a yield of 87% of theory, distil at a boiling point of 140° - 144° C/5 mm Hg.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[NH:4][C:5]1[S:6][C:7]2[C:13]([C:14]3[N:15]=[C:16]([CH2:19][NH:20]C(OC(C)(C)C)=O)[S:17][CH:18]=3)=[CH:12][CH:11]=[C:10]([O:28][CH3:29])[C:8]=2[N:9]=1.[ClH:31].CO>>[ClH:31].[CH3:1][O:2][C:3](=[O:30])[NH:4][C:5]1[S:6][C:7]2[C:13]([C:14]3[N:15]=[C:16]([CH2:19][NH2:20])[S:17][CH:18]=3)=[CH:12][CH:11]=[C:10]([O:28][CH3:29])[C:8]=2[N:9]=1
Reactant: COC(=O)Nc1nc2c(OC)ccc(-c3csc(CNC(=O)OC(C)(C)C)n3)c2s1
Agent: Cl
Solvent: CO
Product: COC(=O)Nc1nc2c(OC)ccc(-c3csc(CN)n3)c2s1
Temperature: 25 °C

Procedure:
0.075 g of {7-[2-(tert-butoxycarbonylamino-methyl)-thiazol-4-yl]-4-methoxy-benzothiazol-2-yl}-carbamic acid methyl ester (0.00017 Mol) were stirred in 2 ml of 2.5 M HCl/MeOH for 4 hrs. Upon cooling to room temperature a precipitate formed, which was filtered off, washed with hexane and dried. The title compound was obtained as a white solid (70%), F.p.: 220-230° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([C:9]#[N:10])[CH:6]=[CH:5][C:4]=1[OH:11].C([O-])([O-])=O.[K+].[K+].[CH2:18](Br)[CH2:19][CH2:20][CH3:21]>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH:6]=[CH:5][C:4]=1[O:11][CH2:18][CH2:19][CH2:20][CH3:21])[C:9]#[N:10]
Reactant: COc1cc(C#N)ccc1O
Reactant: CCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCOc1ccc(C#N)cc1OC
Temperature: 37 °C
Yield: 105.3 %

Procedure:
2-methoxy-4-cyano-phenol (0.25 g, 1.67 mmol) and anhydrous DMF (2.00 mL) were added into a flask, then cooled in a water bath while stirring. Several batches of K2CO3 (0.347 g, 2.50 mmol) were added to the mixture and stirred at 20° C. to react for 1 h. n-butyl bromine (0.23 ml, 2.14 mmol) was added into the mixture, which was stirred at room temperature overnight, then heated at 37° C. to react for 6 h. Poured the solution into a mixture of ice/H2O (25 mL), then stirred for 10 min, a precipitate was formed. Filtered, washed with H2O, and air-dried to yield 0.361 g of white solid product with a recovery rate of 92%.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[CH2:12][OH:13].C(=O)([O-])[O-].[K+].[K+].[CH2:20](Br)[CH2:21][CH3:22]>CC(=O)CC>[OH:13][CH2:12][C:3]1[C:2](=[O:1])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]([CH2:20][CH2:21][CH3:22])[CH:4]=1
Reactant: OCc1cnc2ccccc2c1O
Reactant: CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCCn1cc(CO)c(=O)c2ccccc21

Procedure:
A mixture of 4-hydroxy-3-hydroxymethylquinoline (5.0 g.), anhydrous potassium carbonate (1.6 g.), propyl bromide (2.6 ml.) and 2-butanone (500 ml.) was stirred and boiled under reflux for 18 hours. Additional propyl bromide (2 ml.) was added and the mixture boiled under reflux for 23 hours. The solvent was evaporated and the residue treated with water (100 ml.) and basified with 5 N aqueous sodium hydroxide. The solution was extracted with dichloromethane (4×100 ml.). The extract was dried and evaporated to give an oil. This oil was triturated with petroleum ether:ethyl acetate:industrial methylated spirit 12:1:1 to give the novel compound 3-hydroxymethyl-1-propyl-4-quinolone, m.p. 88°-91°.
Reaction SMILES: Br[C:2]1[O:6][C:5]([CH3:7])=[C:4]([C:8]([O:10][CH3:11])=[O:9])[CH:3]=1.[Cl:12][C:13]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=1B(O)O>>[Cl:12][C:13]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=1[C:2]1[O:6][C:5]([CH3:7])=[C:4]([C:8]([O:10][CH3:11])=[O:9])[CH:3]=1
Reactant: COC(=O)c1cc(Br)oc1C
Reactant: OB(O)c1ccc(Cl)cc1Cl
Product: COC(=O)c1cc(-c2ccc(Cl)cc2Cl)oc1C
Yield: 53.5 %

Procedure:
An operation similar to that in Example 49 (2) was performed using methyl 5-bromo-2-methyl-3-furoate (3.3 g) and 2,4-dichlorophenylboronic acid (3.4 g) to give the title compound (2.3 g, 54%) as a yellow crystal.
Reaction SMILES: [C:1]([OH:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].[CH3:11][O:12][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]([CH:23]=O)=[CH:15][CH:14]=1>>[CH3:11][O:12][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]([CH2:23][NH:4][C:3]2[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=2[C:1]([OH:10])=[O:9])=[CH:15][CH:14]=1
Reactant: COc1ccc(C=O)c2ccccc12
Reactant: Nc1ccccc1C(=O)O
Product: COc1ccc(CNc2ccccc2C(=O)O)c2ccccc12

Procedure:
Prepared by a similar procedure as described for preparation 1A, starting from anthranilic acid and 4-methoxy-1-naphthaldehyde (Aldrich). 13C-NMR (DMSO-d6) δ 169.9, 154.4, 150.7, 134.4, 131.8, 131.6, 126.7, 125.8, 125.7, 125.2, 125.1, 123.3, 122.0, 114.4, 111.6, 110.1, 103.7, 55.4, 43.9.
Reaction SMILES: [Cl:1][C:2]1[C:12]2[O:11][C:10]3[CH:13]=[CH:14][CH:15]=[CH:16][C:9]=3[NH:8][C:7](=O)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[NH:18]1[CH2:24][CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1>C1(C)C=CC=CC=1.C1(OC)C=CC=CC=1.[Ti](Cl)(Cl)(Cl)Cl>[Cl:1][C:2]1[C:12]2[O:11][C:10]3[CH:13]=[CH:14][CH:15]=[CH:16][C:9]=3[N:8]=[C:7]([N:18]3[CH2:24][CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=C1Nc2ccccc2Oc2c(Cl)cccc21
Reactant: C1CNCCNC1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: Cc1ccccc1
Solvent: COc1ccccc1
Product: Clc1cccc2c1Oc1ccccc1N=C2N1CCCNCC1

Procedure:
In a like manner as Example 1, 4-Chloro-10,11-dihydro-dibenz[b,f][1,4]oxazepine-11-one (2.46 g, 10.0 mmol) was reacted with homopiperazine (7.41 g, 74.0 mmol) in the presence of titanium tetrachloride (2.09 g, 11.0 mmol) in toluene (55.0 mL) and anisole (2.00 mL) to produce 4-Chloro-11-(1-homopiperazinyl)dibenz[b,f][1,4]oxazepine; viscous oil; yield, 0.92 g (28%). This crude product (0.26 g, 0.79 mmol) was reacted with 1-bromohexane (0.13 mL, 0.16 g, 0.95 mmol) in the presence of sodium hydride (0.044 mg, 60% in oil, 1.11 mmol) in DMF (10.0 mL) to produce 4-Chloro-11-(4-hexylhomopiperazinyl)dibenz[b,f][1,4]oxazepine; viscous oil; yield, 0.17 g (52%).
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[O:19]=[C:20]1[C:29]2[NH:30][CH:31]=[CH:32][C:28]=2[C:27]2[CH:26]=[C:25]([C:33]#[C:34][Si](C)(C)C)[CH:24]=[CH:23][C:22]=2[NH:21]1.[CH2:39]([C:41]([O-:43])=[O:42])[CH3:40]>O1CCCC1>[C:33]([C:25]1[CH:24]=[CH:23][C:22]2[NH:21][C:20](=[O:19])[C:29]3[NH:30][CH:31]=[CH:32][C:28]=3[C:27]=2[CH:26]=1)#[CH:34].[CH2:39]([C:41]([O-:43])=[O:42])[CH3:40]
Reactant: C[Si](C)(C)C#Cc1ccc2[nH]c(=O)c3[nH]ccc3c2c1
Agent: CCC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C#Cc1ccc2[nH]c(=O)c3[nH]ccc3c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 50.3 %

Procedure:
1.2 ml (1.2 mmol) of a 1M solution of tetrabutylammonium fluoride in tetrahydrofuran is added to a solution of 398 mg (1.13 mmol) of 4-oxo-8-trimethylsilanylethynyl-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate in 10 ml of tetrahydrofuran, then the mixture is stirred for 1 hour at room temperature. The solvent is evaporated and the product is extracted with ethyl acetate. The organic phase is washed with a 1M aqueous solution of hydrochloric acid, a saturated solution of sodium chloride, dried over magnesium sulfate, filtered and evaporated. The product is crystallized in a methanol/acetone mixture (4/1) to give 160 mg (50%) of 8-ethynyl-4-oxo-4,5-dihydro-3H-pyrrolo[2,3-c]quinoline-1-ethyl carboxylate in the form of a white solid.
Reaction SMILES: [Cl:1][CH2:2][C:3]([N:5]([C:12]1[C:17]([CH3:18])=[CH:16][CH:15]=[CH:14][C:13]=1[CH3:19])[CH:6]([CH3:11])[C:7](=[N:9][OH:10])[CH3:8])=[O:4].[CH3:20][N:21]=[C:22]=[O:23]>C(Cl)Cl.C(N(CC)CC)C>[CH3:20][NH:21][C:22]([O:10][N:9]=[C:7]([CH:6]([N:5]([C:12]1[C:13]([CH3:19])=[CH:14][CH:15]=[CH:16][C:17]=1[CH3:18])[C:3](=[O:4])[CH2:2][Cl:1])[CH3:11])[CH3:8])=[O:23]
Reactant: CN=C=O
Reactant: CC(=NO)C(C)N(C(=O)CCl)c1c(C)cccc1C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CNC(=O)ON=C(C)C(C)N(C(=O)CCl)c1c(C)cccc1C
Temperature: 25 °C
Yield: 96 %

Procedure:
3-(N-chloroacetyl-2,6-dimethylphenylamino)-2-butanone oxime (2.6 g) was dissolved in 75 ml methylene chloride and 5 drops of triethylamine were added. To this mixture was added 2.6 g methylisocyanate and the solution was stirred at room temperature. The solution was refluxed for 5 minutes and solvent was stripped. The oil was crystallized in ethanol-water to yield 3 g tan product. This product is tabulated as Compound No. 17 in Table I.
Reaction SMILES: [OH-].[Na+].[CH2:3]([O:10][CH2:11][CH2:12][CH2:13][O:14][C:15]1[C:16]([B:24]2[O:28][C:27]([CH3:30])(C)C(C)(C)[O:25]2)=[C:17]([C:20]([F:23])=[CH:21][CH:22]=1)C=O)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C[N+:34]([O-:36])=[O:35].Cl>O>[CH2:3]([O:10][CH2:11][CH2:12][CH2:13][O:14][C:15]1[C:16]2[B:24]([OH:25])[O:28][CH:27]([CH2:30][N+:34]([O-:36])=[O:35])[C:17]=2[C:20]([F:23])=[CH:21][CH:22]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: C[N+](=O)[O-]
Reactant: CC1(C)OB(c2c(OCCCOCc3ccccc3)ccc(F)c2C=O)OC1(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=[N+]([O-])CC1OB(O)c2c(OCCCOCc3ccccc3)ccc(F)c21
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 26.7 %

Procedure:
NaOH (48 mg, 1.20 mmol) was added to 3-(3-benzyloxy-propoxy)-6-fluoro-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzaldehyde (500 mg, 1.2 mmol) in H2O (3 mL) at rt, and the reaction mixture was stirred at rt for 5 min. MeNO2 (219 mg, 3.6 mmol) was added dropwise and the mixture was stirred at rt for 16 h. The reaction mixture was acidified with 2 N HCl and extracted with EtOAc. The organic fraction was washed with H2O then brine, dried (MgSO4), and concentrated in vacuo. Purification was accomplished by flash chromatography (10-40% EtOAc/hexane) to give 120 mg of the title compound by 1H NMR spectrum. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.40-7.22 (m, 5H), 7.11 (t, J=8.8 Hz, 1H), 6.81 (t, J=8.6 Hz, 1H), 5.93 (dd, J=9.0, 2.3 Hz, 1H), 4.99 (dd, J=13.1, 2.5 Hz, 1H), 4.62-4.53 (m, 2H), 4.43 (dd, J=12.9, 9.0 Hz, 1H), 4.19-4.01 (m, 2H), 3.66 (dt, J=15.9, 5.7 Hz, 2H), 2.18-1.94 (m, 2H); 19F NMR (376 MHz, CHLOROFORM-d) δ ppm −72.81 (s, 1F); MS (ESI) m/z=374 (M−1, negative).
Reaction SMILES: [H-].[Na+].[O:3]1[C:7]2([CH2:12][CH2:11][CH2:10][CH2:9][CH:8]2[CH2:13][OH:14])OCC1.[CH2:15](Br)[CH:16]=[CH2:17]>C1COCC1>[CH2:17]([O:14][CH2:13][CH:8]1[CH2:9][CH2:10][CH2:11][CH2:12][C:7]1=[O:3])[CH:16]=[CH2:15]
Reactant: OCC1CCCCC12OCCO2
Reactant: C=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCOCC1CCCCC1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of NaH (1.14 g, 60% oil dispersion, 28.6 mmol) in dry THF (45 mL) at 0° C. was added 1,4-dioxaspiro[4.5]dec-6-ylmethanol (2.46 g, 14.3 mmol) in dry THF (5 mL). The mixture was allowed to warm to rt and stirred for 1 hr. The mixture was then cooled to 0° C. and allyl bromide (2.10 mL, 24.28 mmol) was added in one portion. The mixture was then allowed to warm to rt and stirred for 1 hr. The mixture was then heated to 60° C. overnight. It was cooled to 0° C. and quenched with 50 mL of 10% aq HCl. This mixture was stirred for 1 hr at rt. The resulting mixture was cooled to 0° C. and neutralized carefully with solid Na2CO3 and then extracted with Et2O. The combined organics were dried, filtered, and concentrated. The residue was purified by column chromatography to give the title compound. 1H NMR (500 MHz, CDCl3) δ 5.86-5.95 (m, 1H), 5.28 (d, 1H, J=1.7 Hz), 5.25 (d, 1H, J=1.5 Hz), 5.17 (d, 1H, J=10.5 Hz), 3.94-4.03 (m, 2H), 3.79 (dd, 1H, J=5.1 Hz, 9.8 Hz), 3.38 (dd, 1H, J=7.33 Hz, 9.53 Hz), 2.56-2.65 (m, 1H), 2.26-2.43 (m, 3H), 2.02-2.10 (m, 1H), 1.85-1.93 (m, 1H), 1.61-1.74 (m, 2H), 1.39-1.49 (m, 1H).
Reaction SMILES: [C:1]1([CH2:11][CH2:12][C:13]([OH:15])=[O:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH2:16](O)[CH3:17]>S(=O)(=O)(O)O>[C:1]1([CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: CCO
Reactant: O=C(O)CCc1cccc2ccccc12
Agent: O=S(=O)(O)O
Product: CCOC(=O)CCc1cccc2ccccc12

Procedure:
A stirred solution of 50 grams (0.25 mole) of 3-(naphth-1-yl)propanoic acid and 20 drops (catalyst) of concentrated sulfuric acid in 250 mL of ethanol was heated at reflux for about 24 hours. After this time the reaction mixture was concentrated under reduced pressure to a residue. The residue was dissolved in diethyl ether, and the solution was washed with two 150 mL portions of an aqueous solution saturated with sodium bicarbonate and then with 150 mL of an aqueous solution saturated with sodium chloride. The organic layer was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, yielding 56.0 grams of ethyl 3-(naphth-1-yl)propanoate. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([Cl:28])[CH:21]=2)[C:10]2[C:15]([Cl:16])=[C:14]([CH3:17])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([Cl:28])[CH:21]=3)[C:10]3[C:15]([Cl:16])=[C:14]([CH3:17])[S:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: COc1ccc(CNc2nc(Cl)nc3sc(C)c(Cl)c23)cc1Cl
Reactant: c1cn[nH]c1
Product: COc1ccc(CNc2nc(-n3cccn3)nc3sc(C)c(Cl)c23)cc1Cl

Procedure:
Following the procedure of Example 97, the reaction of pyrazole with 2,5-dichloro-6-methyl-4-(3-chloro-4-methoxybenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(pyrazol-1-yl)-5-chloro-6-methyl-4-(3-chloro-4-methoxybenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: Br[CH:2]([C:8]1[CH:13]=[CH:12][C:11]([CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[C:10]([Cl:20])[CH:9]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[F-:21].[K+].C(O)CO>O>[F:21][CH:2]([C:8]1[CH:13]=[CH:12][C:11]([CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[C:10]([Cl:20])[CH:9]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CCOC(=O)C(Br)c1ccc(C2CCCCC2)c(Cl)c1
Reactant: [F-]
Agent: [K+]
Solvent: O
Solvent: OCCO
Product: CCOC(=O)C(F)c1ccc(C2CCCCC2)c(Cl)c1

Procedure:
A mixture of 118 g. (0.33 moles) of ethyl α-bromo-3-chloro-4-cyclohexylphenylacetate is vigorously stirred at 130°-140° C with 29 g. (0.5 moles) of potassium fluoride in 100 ml. of ethylene glycol for 12 hours. The reaction mixture is cooled and 400 ml. of water is added and the crude product separates. The aqueous glycol mixture is extracted with ether, the ether is then dried, evaporated to dryness and upon distillation results in ethyl α-fluoro-3-chloro-4-cyclohexylphenylacetate.