Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:4][C:5](=[O:23])[C@H:6]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1)[NH:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH:2]=[CH2:3].Cl[C:25]([O:27][C:28]1[CH:33]=[CH:32][C:31]([N+:34]([O-:36])=[O:35])=[CH:30][CH:29]=1)=[O:26].C(N(CC)CC)C>CN(C)C1C=CN=CC=1.ClCCl>[CH2:1]([O:4][C:5](=[O:23])[C@H:6]([CH2:15][C:16]1[CH:17]=[CH:18][C:19]([O:22][C:25]([O:27][C:28]2[CH:29]=[CH:30][C:31]([N+:34]([O-:36])=[O:35])=[CH:32][CH:33]=2)=[O:26])=[CH:20][CH:21]=1)[NH:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CCOC(=O)[C@H](Cc1ccc(OC(=O)Oc2ccc([N+](=O)[O-])cc2)cc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
36.7 g (114.3 mmol) N-Boc-L-tyrosine allyl ester, 23.0 g (114.3 mmol) 4-nitrophenyl chloroformate, 17.5 ml (125.7 mmol) triethylamine and 1.40 g (11.4 mmol) 4-dimethylamino pyridine were combined in 1000 ml dichloromethane and stirred at room temperature for 2 h. The reaction mixture was extracted with approx. 500 ml water and with approx. 250 ml brine and dried over approx. 100 g sodium sulfate. The solvent was removed by rotary evaporation (approx. 40° C., approx. 200 mbar, approx. 30 min.) and the product was dissolved in warm diethyl ether and crystallized over night at 4° C. The crystals were filtered of, washed with cold diethyl ether and dried in high vacuum (approx. 0.1 mbar, 18 h). The yield was 29.86 g, (59.6 mmol, 52% of theory) of the desired product.
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([CH2:17][C@H:18]([NH:22][C:23](=[O:36])[C:24]4[CH:29]=[CH:28][C:27]([O:30][CH:31]([CH3:33])[CH3:32])=[C:26]([C:34]#[N:35])[CH:25]=4)[CH2:19][CH2:20][OH:21])=[CH:13][CH:12]=3)[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:37][C:38]1[C:42](B(O)O)=[C:41]([CH3:46])[O:40][N:39]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[C:34]([C:26]1[CH:25]=[C:24]([CH:29]=[CH:28][C:27]=1[O:30][CH:31]([CH3:32])[CH3:33])[C:23]([NH:22][C@@H:18]([CH2:17][C:14]1[CH:15]=[CH:16][C:11]([C:9]2[N:10]=[C:3]3[C:2]([C:42]4[C:38]([CH3:37])=[N:39][O:40][C:41]=4[CH3:46])=[CH:7][CH:6]=[CH:5][N:4]3[CH:8]=2)=[CH:12][CH:13]=1)[CH2:19][CH2:20][OH:21])=[O:36])#[N:35]
Reactant: Cc1noc(C)c1B(O)O
Reactant: CC(C)Oc1ccc(C(=O)N[C@H](CCO)Cc2ccc(-c3cn4cccc(Br)c4n3)cc2)cc1C#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1noc(C)c1-c1cccn2cc(-c3ccc(C[C@@H](CCO)NC(=O)c4ccc(OC(C)C)c(C#N)c4)cc3)nc12
Temperature: 100 °C
Reaction time: 22 h
Yield: 21.8 %

Procedure:
To a solution of N-((1S)-1-{[4-(8-bromoimidazo[1,2-a]pyridin-2-yl)phenyl]methyl)-3-hydroxypropyl)-3-cyano-4-[(1-methylethyl)oxy]benzamide (200 mg, 0.366 mmol) in dry DMF (2 mL) were added 3,5-dimethyl-isoxazole-4-boronic acid (63 mg, 0.439 mmol), tetrakistriphenylphosphine palladium(0) (21 mg, 0.018 mmol) and 2.0 M aqueous K2CO3 (0.46 mL) successively at rt. The reaction mixture was purged with argon and heated to 100° C., stirred for 22 h, cooled to rt, filtered and purified directly by reverse phase HPLC (MeCN/H2O with 0.1% TFA). The clean fractions were adjusted to pH ˜8 with saturated aqueous NaHCO3 and extracted with 3% MeOH/EtOAc (3×30 mL). The extracts were dried (Na2SO4), filtered and concentrated under reduced pressure to give 45 mg (22%) of the title compound as an off-white solid. LC/MS (ES) m/e 564.2 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][C:14]([NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23]([OH:25])=O)=O.Cl.[NH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.CN(C)C=O>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][C:14]1[N:27]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:23](=[O:25])[C:18]2[C:17](=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:16]=1
Reactant: Nc1ccccc1
Reactant: COc1ccc2[nH]cc(CCC(=O)Nc3ccccc3C(=O)O)c2c1
Agent: Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COc1ccc2[nH]cc(CCc3nc4ccccc4c(=O)n3-c3ccccc3)c2c1
Yield: 39.9 %

Procedure:
To a solution of 3-(5-methoxyindol-3-yl)-N-(2-carboxyphenyl)propionamide (4.0 g, 11.8 mmol) in 50 ml of THF at room temperature was added 1,1-carbonyldiimidazole (1.92 g, 11.8 mmol). The reaction mixture was stirred for one hour after which aniline hydrochloride (3.06 g, 23.6 mmol) and 25 ml of dimethylformamide were added. The reaction mixture was stirred at reflux under a drying tube for two days, allowed to cool, and concentrated in vacuo to dryness. The residue was partitioned between lN hydrochloric acid and ethyl acetate. The organic layer was washed (water, lN sodium hydroxide, and brine), dried over anhydrous sodium sulfate, and concentrated in vacuo to dryness. Crystallization of the product from ethyl acetate/trace methanol provided 1.86 g of 2-[2-(5-methoxyindol-3-yl)-ethyl]-3-phenyl-4-(3H)quinazolinone as a white powder: mp 220°-221° C.; EIMS: 395 (M+)
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:16]=[CH:15][C:7]2[O:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:6]=2[CH:5]=1.CS(O[CH2:22][CH2:23][F:24])(=O)=O>CN(C)C=O>[F:24][CH2:23][CH2:22][O:3][C:4]1[CH:16]=[CH:15][C:7]2[O:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:6]=2[CH:5]=1
Reactant: Oc1ccc2oc3ccccc3c2c1
Reactant: CS(=O)(=O)OCCF
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: FCCOc1ccc2oc3ccccc3c2c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 85.2 %

Procedure:
To a suspension of sodium hydride (60% oil dispersion; 4.0 g) in N,N-dimethylformamide (100 ml), 2-hydroxydibenzofuran (18.4 g) was added at a temperature of 0 to 5° C., and the resultant suspension was stirred at room temperature for 1 hour. 2-Fluoroethyl methanesulfonate (14.2 g) was added thereto. The resulting mixture was stirred at room temperature for 12 hours. The reaction mixture was poured into ice-water and extracted with ethyl acetate. The extract was washed with aqueous potassium carbonate solution, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was distilled under reduced pressure to give 2-(2-fluoroethoxy)-dibenzofuran (Compound No. 35) (19.6 g). b.p., 180°-185° C./5 mmHg.
Reaction SMILES: [N:1]1[C:10]2[C:9](=[O:11])[CH:8]=[CH:7][C:6](=[O:12])[C:5]=2[N:4]=[CH:3][CH:2]=1.[CH2:13]([O:15][C:16]([N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)=[O:17])[CH3:14]>O1CCOCC1>[CH2:13]([O:15][C:16]([N:18]1[CH2:19][CH2:20][N:21]([C:8]2[C:9](=[O:11])[C:10]3[N:1]=[CH:2][CH:3]=[N:4][C:5]=3[C:6](=[O:12])[CH:7]=2)[CH2:22][CH2:23]1)=[O:17])[CH3:14]
Reactant: CCOC(=O)N1CCNCC1
Reactant: O=C1C=CC(=O)c2nccnc21
Solvent: C1COCCO1
Product: CCOC(=O)N1CCN(C2=CC(=O)c3nccnc3C2=O)CC1
Reaction time: 3 h
Yield: 47.5 %

Procedure:
A mixture of 160 mg of 5,8-quinoxalinedione and 316 mg of 1-piperazinecarboxylic acid ethyl ester in 10 ml of dioxane was stirred for 3 hours. The resulting solid was collected, washed with ether and dried, giving 150 mg of the desired product as a red solid, mp 180°-195° C. (dec.).
Reaction SMILES: [CH2:1]([S:4][C:5]1[N:10]=[C:9]([OH:11])[CH:8]=[C:7]([OH:12])[N:6]=1)[CH2:2][CH3:3].O.[N+:14]([O-])([OH:16])=[O:15]>>[N+:14]([C:8]1[C:7]([OH:12])=[N:6][C:5]([S:4][CH2:1][CH2:2][CH3:3])=[N:10][C:9]=1[OH:11])([O-:16])=[O:15]
Reactant: O=[N+]([O-])O
Reactant: CCCSc1nc(O)cc(O)n1
Solvent: O
Product: CCCSc1nc(O)c([N+](=O)[O-])c(O)n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 48 %

Procedure:
A solution of 2-(propylthio)pyrimidine-4,6-diol (3 g, 16.11 mmol, 1.00 equiv.) in nitric acid (65%) (10 mL) was stirred at ambient temperature for about 2 hours. After adding water (10 mL), the mixture was stirred at about 0° C. for about 30 minutes. The resulting solids were collected by filtration to afford the title product as a yellow solid (1.8 g; yield=48%). 1H NMR (300 MHz, DMSO-d6) δ: 3.17 (t, J=7.2 Hz, 2H), 1.62-1.75 (m, 2H), 0.95-1.02, (t, J=7.2 Hz, 3H).
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]1([CH:14]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[CH2:15][CH2:16][N:17]([C:31]([NH:33][C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([C:40]([F:43])([F:42])[F:41])[CH:35]=2)=[O:32])[CH:18]2[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][CH2:19]2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>ClCCl>[C:44]1([CH:14]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:15][CH2:16][N:17]([CH:18]2[CH2:19][CH2:20][NH:21][CH2:22][CH2:23]2)[C:31]([NH:33][C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([C:40]([F:42])([F:41])[F:43])[CH:35]=2)=[O:32])[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1
Reactant: CC(C)(C)OC(=O)N1CCC(N(CCC(c2ccccc2)c2ccccc2)C(=O)Nc2cccc(C(F)(F)F)c2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1cccc(C(F)(F)F)c1)N(CCC(c1ccccc1)c1ccccc1)C1CCNCC1
Reaction time: 1.5 h
Yield: 97.8 %

Procedure:
1.6 ml (21 mmol, 20 eq.) of trifluoroacetic acid is added to a solution of tert-butyl 4-((3,3-diphenylpropyl) {[3-(trifluoromethyl)anilino]carbonyl}amino)-1-piperidine carboxylate (600 mg, 1.04 mmol) in dichloromethane. The reaction medium is agitated for 90 minutes then concentrated. Dichloromethane is added and the organic phase is washed with a saturated solution of sodium bicarbonate, dried over magnesium sulphate, filtered and concentrated under vacuum in order to isolate 490 mg (yield=98%) of a white foam.
Reaction SMILES: C(OC([NH:8][CH2:9][C:10]1[CH:11]=[C:12]([NH:16][C:17]2[S:18][C:19]([CH3:22])=[CH:20][N:21]=2)[CH:13]=[CH:14][CH:15]=1)=O)(C)(C)C.FC(F)(F)C(O)=O>>[NH2:8][CH2:9][C:10]1[CH:11]=[C:12]([NH:16][C:17]2[S:18][C:19]([CH3:22])=[CH:20][N:21]=2)[CH:13]=[CH:14][CH:15]=1
Reactant: Cc1cnc(Nc2cccc(CNC(=O)OC(C)(C)C)c2)s1
Solvent: O=C(O)C(F)(F)F
Product: Cc1cnc(Nc2cccc(CN)c2)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.8 %

Procedure:
A mixture of the compound (73 mg) obtained in Example 507 and trifluoroacetic acid (5 ml) was stirred at room temperature for 1 h and concentrated under reduced pressure. The resulting residue was purified by basic silica gel column chromatography (eluent, methylene chloride:methanol=95:5) to give 34.5 mg of the titled compound (yield, 67%).
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[NH:14][CH:13]=[CH:12]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[K+].[NH2:20]OS(O)(=O)=O.O>CN(C)C=O>[C:1]1([CH2:7][O:8][C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[N:14]([NH2:20])[CH:13]=[CH:12]3)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(COc2ccc3[nH]ccc3c2)cc1
Reactant: NOS(=O)(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: Nn1ccc2cc(OCc3ccccc3)ccc21
Reaction time: 1 h
Yield: 133.1 %

Procedure:
To 5-phenylmethoxyindole (50 g) in 300 ml of dimethylformamide at ice bath temperature was added milled potassium hydroxide (62.72 g). Then hydroxylamine-O-sulfonic acid (32.93 g) was added portionwise, keeping the internal temperature below 20° C. After the addition was complete, the mixture was stirred for one hour, then poured into water and extracted with ethyl acetate. The organic layer was washed with water and dried (sat. NaCl, anhy. MgSO4). After filtration, the solvent was evaporated to yield an oil (71 g), which was eluted with dichloromethane on silica gel columns via HPLC. The desired fractions were concentrated to yield a solid (21.15 g). Of this material, 3.0 g was triturated with ether to yield a solid, 2.4 g, m.p. 126°-128° C.
Reaction SMILES: Cl.[NH:2]1[CH:6]=[C:5]([CH2:7][CH2:8][C:9]([O:11][CH3:12])=[O:10])[N:4]=[CH:3]1.C(N(CC)CC)C.[C:20]1([C:26](Cl)([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(Cl)(Cl)Cl>[C:20]1([C:26]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[N:2]2[CH:6]=[C:5]([CH2:7][CH2:8][C:9]([O:11][CH3:12])=[O:10])[N:4]=[CH:3]2)[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: COC(=O)CCc1c[nH]cn1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COC(=O)CCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of methyl 3-(imidazol-4-yl)propionate hydrochloride, as described above in Step B, (20.2 g, 106 mmol) in dry CHCl3 (500 mL) were added triethylamine (44 mL, 318 mmol), then a solution of triphenylmethyl chloride (29.5 g, 106 mmol) in CHCl3 (100 mL). The mixture was stirred at ambient temperature for 18 hours, then washed with H2O (250 mL). The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure to yield the product as a pale solid.
Reaction SMILES: [O:1]1[C:5]2=[CH:6][CH:7]=[CH:8][C:9]([OH:10])=[C:4]2[CH:3]=[CH:2]1.[F:11][C:12]1[CH:13]=[C:14]([N+:19]([O-:21])=[O:20])[CH:15]=[CH:16][C:17]=1F.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[F:11][C:12]1[CH:13]=[C:14]([N+:19]([O-:21])=[O:20])[CH:15]=[CH:16][C:17]=1[O:10][C:9]1[C:4]2[CH:3]=[CH:2][O:1][C:5]=2[CH:6]=[CH:7][CH:8]=1
Reactant: Oc1cccc2occc12
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccc(Oc2cccc3occc23)c(F)c1
Temperature: 50 °C
Reaction time: 5 h

Procedure:
2.40 g (5.37 mmol) of 1-benzofuran-4-ol (from example XXI), 0.90 g (5.64 mmol) of 3,4-difluoronitrobenzene and 1.48 g (10.7 mmol) of potassium carbonate are suspended in 20 ml of anhydrous dimethylformamide, and the mixture is stirred at 50° C. for 5 hours. The reaction solution is then diluted with water and extracted twice with ethyl acetate. The combined organic phases are dried over sodium sulfate. The solvent is removed under reduced pressure. The crude product is purified on a silica gel column (mobile phase: cyclohexane:ethyl acetate (10:1)).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=1.[CH2:17]([NH2:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[ClH:25]>O>[ClH:25].[F:16][C:13]1[CH:14]=[CH:15][C:10]([CH2:9][CH2:8][O:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][NH:24][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:11][CH:12]=1
Reactant: NCc1ccccc1
Reactant: Fc1ccc(CCOCCCCCBr)cc1
Agent: Cl
Solvent: O
Product: Fc1ccc(CCOCCCCCNCc2ccccc2)cc1
Reaction time: 3.5 h

Procedure:
1-[2-[(5-Bromopentyl)oxy]ethyl]-4-fluorobenzene (7.95 g) was added dropwise over 10 min to benzylamine (24 ml) at 125° under nitrogen. The reaction mixture was stirred for 3.5 h at 120° and the hot reaction mixture was poured into 2N aqueous hydrochloric acid (170 ml) and water (220 ml). After stirring for 15 min the precipitate was collected by filtration to give the title compound as a white solid (7.41 g) m.p. 112°.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].[CH3:11]O>S(=O)(=O)(O)O>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([O:7][CH3:11])=[O:6]
Reactant: O=C(O)c1cccc(Br)c1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1cccc(Br)c1
Temperature: 25 °C
Yield: 92.5 %

Procedure:
A solution of 3-bromobenzoic acid (50 g, 248.73 mmol, 1.00 equiv.) in methanol (500 mL) and 98% sulfuric acid (5 mL) was heated at reflux for about 15 hours. After cooling to ambient temperature, the solution was concentrated in vacuo and water (300 mL) was added to the resulting residue. The pH of the solution was adjusted to about 9 by adding sodium carbonate. Standard extractive workup with dichloromethane (3×200 mL) gave a residue that was then dried in an oven to give the title product as an off-white solid (49.5 g; yield=92.5%). 1H NMR (300 MHz, CDCl3) δ: 8.20 (t, J=1.8 Hz, 1H), 7.97-8.01 (m, 1H), 7.69-7.73 (m, 1H), 7.32 (t, J=8.1 Hz, 1H), 3.95 (s, 3H).
Reaction SMILES: Cl.[CH2:2]([O:4][NH2:5])[CH3:3].C(=O)([O-])[O-].[K+].[K+].[Cl:12][C:13]1[C:22]([CH:23]=O)=[C:21]([S:25]([CH3:28])(=[O:27])=[O:26])[CH:20]=[CH:19][C:14]=1[C:15]([O:17][CH3:18])=[O:16]>CO>[Cl:12][C:13]1[C:22]([CH:23]=[N:5][O:4][CH2:2][CH3:3])=[C:21]([S:25]([CH3:28])(=[O:27])=[O:26])[CH:20]=[CH:19][C:14]=1[C:15]([O:17][CH3:18])=[O:16]
Reactant: CCON
Reactant: COC(=O)c1ccc(S(C)(=O)=O)c(C=O)c1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CCON=Cc1c(S(C)(=O)=O)ccc(C(=O)OC)c1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.3 %

Procedure:
1.90 g (0.0195 mol) of O-ethylhydroxylamine hydrochloride and 1.35 g (0.0097 mol) of finely powdered potassium carbonate were stirred for 1 hour at room temperature in 60 ml of dry methanol, and 4.90 g (0.0177 mol) of methyl 2-chloro-3-formyl-4-methylsulfonylbenzoate were then added. After stirring for 8 hours at room temperature, the solvent was removed, the residue was taken up in ethyl acetate and the organic phase was washed with water until neutral, dried and concentrated under reduced pressure. 5.00 g of methyl 2-chloro-3-ethoxyiminomethyl-4-methylsulfonylbenzoate were obtained. (Yield 88%).
Reaction SMILES: [CH2:1]([N:4]([CH2:12][C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=O)[C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8])[CH:2]=[CH2:3].Cl.[NH2:22][OH:23].C([O-])(=O)C.[Na+]>C(O)C.O>[CH2:1]([N:4]([CH2:12][C:13](=[N:22][OH:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8])[CH:2]=[CH2:3]
Reactant: C=CCN(CC(=O)c1ccccc1)C(=O)OC(C)(C)C
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: C=CCN(CC(=NO)c1ccccc1)C(=O)OC(C)(C)C
Temperature: 70 °C
Reaction time: 18 h

Procedure:
A mixture of tert-butyl N-allyl-N-phenacyl-carbamate (3.2 g, 11.6 mmol), hydroxylamine hydrochloride (1.2 g, 17.4 mmol) and sodium acetate (1.4 g, 17.4 mmol) in ethanol (46 mL) is stirred at 70° C. for 18 hours. The reaction is cooled, diluted with water and extracted with dichloromethane. The organic layers are combined, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound as a mixture of E and Z isomers which is used without further purification (3.16 g, 94%). ES/MS (m/e): 191 (M+H-100).
Reaction SMILES: [CH3:1][Mg]Br.C[C:5]1([C:12]([OH:21])([C:17]([F:20])([F:19])[F:18])[C:13]([F:16])([F:15])[F:14])[CH2:10][CH2:9][CH2:8][CH2:7][C:6]1=[O:11]>O1CCCC1>[F:20][C:17]([F:18])([F:19])[C:12]([CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][C:6]1([CH3:1])[OH:11])([OH:21])[C:13]([F:15])([F:14])[F:16]
Reactant: C[Mg]Br
Reactant: CC1(C(O)(C(F)(F)F)C(F)(F)F)CCCCC1=O
Solvent: C1CCOC1
Product: CC1(O)CCCCC1C(O)(C(F)(F)F)C(F)(F)F
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a flame-dried, nitrogen-purged, 250 mL 3-neck roundbottom flask with 50 mL, pressure-equalized addition funnel and stirbar was added 48 mL of methyl magnesium bromide (143 mmol, 2.1 eq., 3 M in ethyl ether). A degassed solution of 18 g methyl 2-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)cyclohexanone (IX) (68 mmol, 1 eq.) in 60 mL anhydrous tetrahydrofuran was charged to the addition funnel and added dropwise to the reaction over the course of 1 hour at room temperature. The reaction was stirred at room temperature for 14 hours, after which it was cooled to 0° C. and carefully quenched with dilute hydrochloric acid solution until the pH was less than 5.0. The reaction solution was neutralized with saturated aqueous sodium bicarbonate until the pH was greater than 8. The product was extracted into ethyl ether and the organic phase washed with brine and dried over magnesium sulfate, filtered, concentrated in vacuo, and stored over a small amount of sodium bicarbonate. Crude .sup.1H and .sup.19F NMR indicated only 42% conversion to a single isomer. The reaction was repeated again and the conversion driven to 69% by NMR. The crude product was taken on to the next step without further purification.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH:11]=O)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[NH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.[BH3-]C#N.[Na+].C(O)(=O)C>ClCCCl>[I:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([CH2:11][N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[CH2:9][CH2:10]2)=[CH:6][CH:7]=1
Reactant: O=CC1(c2ccc(I)cc2)CC1
Reactant: C1COCCN1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: Ic1ccc(C2(CN3CCOCC3)CC2)cc1
Reaction time: 0.17 h

Procedure:
To a solution of 1-(4-iodophenyl)cyclopropanecarbaldehyde (7 g, 0.025 mol) in 1,2-Dichloroethane (100 mL) is added morpholine (4.5 mL, 0.051 mol) in drops at 0° C. . After 10 min, NaBH3CN (3.2 g, 30 mmol) is added in a portion wise fashion at 0° C. followed by acetic acid (500 μL). The reaction mixture is stirred for another 1 h at same temperature and then at Rt for 10 h. After this time, the reaction mixture is quenched with 10% sodium bicarbonate and extracted with EtOAc. The combined organic layer is washed with water, brine, dried over sodium sulphate and evaporated. The crude product is purified by column chromatography (pet ether and EtOAc) to afford the title compound as colourless liquid. 1H NMR (DMSO-d6, 400 MHz) δ 7.60-7.56 (m, 2H), 7.13-7.08 (m, 2H), 3.47-3.43 (m, 4H), 2.50-2.46 (m, 2H), 2.34 (bs, 4H) 0.0.80-0.77 (m, 2H),0.72-00.69 (m, 2H).
Reaction SMILES: Cl.[CH2:2]([C:4]1[C:8]2[CH:9]=[C:10]([NH:13]N)[CH:11]=[CH:12][C:7]=2[S:6][CH:5]=1)[CH3:3].[CH2:15]([N:17]1[CH2:22][CH2:21][C:20](=O)[CH2:19][CH2:18]1)[CH3:16]>C(O)CO>[CH2:2]([C:4]1[C:8]2=[C:9]3[C:10](=[CH:11][CH:12]=[C:7]2[S:6][CH:5]=1)[NH:13][C:20]1[CH2:21][CH2:22][N:17]([CH2:15][CH3:16])[CH2:18][C:19]3=1)[CH3:3]
Reactant: CCN1CCC(=O)CC1
Reactant: CCc1csc2ccc(NN)cc12
Agent: Cl
Solvent: OCCO
Product: CCc1csc2ccc3[nH]c4c(c3c12)CN(CC)CC4

Procedure:
The compound is formed analogously to that described in Example 36, from 8.0 g of 3-ethyl-5-hydrazinobenzothiophene hydrochloride and 6.0 g of 1-ethyl-4-piperidone, by cyclisation under the influence of heat at 165°-170° C. in ethylene glycol for 3 hours.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6](/[C:10](=[N:12]/[S@:13]([C:15]([CH3:18])([CH3:17])[CH3:16])=[O:14])/[CH3:11])[CH:7]=[CH:8][CH:9]=1)([CH3:3])[CH3:2].O.[BH4-].[Na+]>C1COCC1>[CH:1]([C:4]1[CH:5]=[C:6]([C@@H:10]([NH:12][S@:13]([C:15]([CH3:18])([CH3:16])[CH3:17])=[O:14])[CH3:11])[CH:7]=[CH:8][CH:9]=1)([CH3:3])[CH3:2]
Reactant: C/C(=N\[S@@](=O)C(C)(C)C)c1cccc(C(C)C)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)c1cccc([C@H](C)N[S@@](=O)C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of (S,E)-N-(1-(3-isopropylphenyl)ethylidene)-2-methylpropane-2-sulfinamide (9.5 g, 0.036 mol) in THF (98 mL)/H2O (2 mL) was added NaBH4, the mixture was stirred at room temperature for 16 hours. The mixture was then partitioned between EtOAc and water, the layers were separated and the organic layer was washed with water, brine, dried over Na2SO4, and concentrated. The residue was purified by column chromatography to give the titled compound.
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3]([O:5]CC)=O.[CH3:10][C:11]([CH3:22])([O:13][C:14]([N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1)=[O:15])[CH3:12]>>[F:9][C:2]([F:1])([F:8])[C:3]([N:19]1[CH2:18][CH2:17][N:16]([C:14]([O:13][C:11]([CH3:22])([CH3:12])[CH3:10])=[O:15])[CH2:21][CH2:20]1)=[O:5]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CCOC(=O)C(F)(F)F
Product: CC(C)(C)OC(=O)N1CCN(C(=O)C(F)(F)F)CC1
Temperature: 40 °C
Reaction time: 2 h
Yield: 86.6 %

Procedure:
Ethyl trifluoroacetate (3.9 g, 0.027 mole) was added over 10 minutes to a warm (40° C.) stirred melt of 5.2 g (0.028 mole) 1-[1,1-dimethylethoxycarbonyl]piperazine. The mixture was heated at 120° C. for 2 hours, cooled to room temperature, treated with 1.0 g (0.007 mole) ethyl trifluoroacetate, and reheated for an additional 2 hours. The mixture was allowed to stand 18 hours at room temperature and then was evaporated in vacuo. The residue was dissolved in ether, passed through an alumina-packed column (2.2×16 cm), the eluent collected, washed with dilute aqueous HCl, dried (MgSO4), filtered, and evaporated in vacuo to yield 6.6 g yellow oil which solidified on standin g Recrystallization from hexane gave 6.0 g of white, crystalline solid, m.p. 66°-68° C. Calc. for C11H17F3N2O3 (282.26): C, 46.81; H, 6.07; N, 9.92. Found: C, 46.76; H, 6.40; N, 10.12.