Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6](=[O:10])[CH2:7][C:8]#[N:9])[CH3:4].F[C:12]1[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][C:13]=1[N+:20]([O-:22])=[O:21].Cl>CN(C=O)C.C(OCC)(=O)C>[CH2:3]([O:5][C:6](=[O:10])[CH:7]([C:8]#[N:9])[C:12]1[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][C:13]=1[N+:20]([O-:22])=[O:21])[CH3:4]
Reactant: CCOC(=O)CC#N
Reactant: N#Cc1ccc(F)c([N+](=O)[O-])c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)C(C#N)c1ccc(C#N)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of sodium hydride (0.96 g, 60% in mineral oil, 24 mmol) in DMF (6 mL) at 0° C. was added ethylcyanoacetate (2.72 g, 24 mmol) in DMF (2 mL) under an atmosphere of nitrogen. The reaction mixture was stirred at room temperature for 30 minutes then 4-fluoro-3-nitro-benzonitrile (2.05 g, 22.7 mmol) in DMF (5 mL) was added dropwise. 1M HCl and ethyl acetate were added to the reaction mixture after 1 hour. The organic layer was washed with water and brine, then dried over sodium sulphate and concentrated to give a brown oil which was purified by flash column chromatography to give the title compound. 1H NMR (DMSO-d6) δ 8.79 (1H), 8.38 (1H), 7.95 (1H, d, J=2), 6.38 (1H), 4.21 (2H), 1.19 (3H, t).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([O:12][CH3:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:14]([F:17])([F:16])[F:15])[CH:3]=1.CCN(CC)CC>CCO.[Pd]>[CH3:13][O:12][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:6]=1[N:5]=[C:4]([C:14]([F:17])([F:15])[F:16])[CH:3]=[CH:2]2
Reactant: COc1cccc2c(Cl)cc(C(F)(F)F)nc12
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CCO
Product: COc1cccc2ccc(C(F)(F)F)nc12
Reaction time: 0.75 h

Procedure:
To a solution of 4-chloro-8-methoxy-2-trifluoromethylquinoline (0.57 g) in 5 mL absolute EtOH is added 10% Pd/C (125 mg) and NEt3 (0.3 mL). The reaction is hydrogenated under atmospheric pressure for 0.75 h. The reaction is then filtered over Celite and the filtrate is evaporated. The residue is taken up in Et2O and the triethylamine hydrochloride salt is filtered. The desired product is obtained as a light yellow solid by evaporation of the Et2O filtrate (0.38 g).
Reaction SMILES: C1(O[C@@H:8]2[C@@H:15]([OH:16])[C@H:14]([CH:17]=S)[O:13][C@@:10](C=O)([O:11][CH3:12])[C@@H:9]2[OH:21])C=CC=CC=1.CC(N=NC(C#N)(C)C)(C#N)C.[SnH](CCCC)(CCCC)CCCC>C1(C)C=CC=CC=1>[O:11]([CH3:12])[C@@H:10]1[O:13][C@@H:14]([CH3:17])[C@H:15]([OH:16])[CH2:8][C@H:9]1[OH:21]
Reactant: CO[C@]1(C=O)O[C@@H](C=S)[C@H](O)[C@@H](Oc2ccccc2)[C@H]1O
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: CCCC[SnH](CCCC)CCCC
Solvent: Cc1ccccc1
Product: CO[C@@H]1O[C@@H](C)[C@H](O)C[C@H]1O
Reaction time: 0.33 h

Procedure:
To a solution of methyl 6-deoxy-3-O-phenylthiono-formyl-α-L-mannopyranoside, 2,4-O-dibenzoate (3.5 g, 6.7 mmol) in toluene (120 mL) is added AIBN (55 mg, 0.34 mmol) and n-Bu3SnH (2.6 mL, 13.4 mmol). The solution is deoxygenated by passing through N2 gas for 20 min. The reaction flask is placed in an oil bath (120° C.). After 1.5 h TLC indicates that the reaction is complete. Evaporation of the solvent yields a residue. Purification by chromatography (eluting with hexane/ethyl acetate in gradient from 500:20 to 500:50) yields methyl 3,6-dideoxy-α-L-mannopyranoside, 2,4-O-dibenzoate (1.8 g, 70% in two steps from 6-deoxy-α-L-mannopyranoside, 2,4-O-dibenzoate).
Reaction SMILES: C(OC([N:11]1[CH:16]([CH3:17])[CH2:15][N:14]([CH2:18][C:19]2[CH:28]=[C:27]3[C:22]([C:23]([Cl:29])=[CH:24][CH:25]=[N:26]3)=[CH:21][CH:20]=2)[C:13](=[O:30])[C@@H:12]1[CH3:31])=O)C1C=CC=CC=1.I[Si](C)(C)C>C(#N)C>[Cl:29][C:23]1[C:22]2[C:27](=[CH:28][C:19]([CH2:18][N:14]3[CH2:15][CH:16]([CH3:17])[NH:11][C@@H:12]([CH3:31])[C:13]3=[O:30])=[CH:20][CH:21]=2)[N:26]=[CH:25][CH:24]=1
Reactant: CC1CN(Cc2ccc3c(Cl)ccnc3c2)C(=O)[C@H](C)N1C(=O)OCc1ccccc1
Agent: C[Si](C)(C)I
Solvent: CC#N
Product: CC1CN(Cc2ccc3c(Cl)ccnc3c2)C(=O)[C@H](C)N1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.5 %

Procedure:
(2S, 6RS)-4-(4-Chloro-quinolin-7-ylmethyl)-2,6-dimethyl-3-oxo-piperazine-1-carboxylic acid benzyl ester (417 mg, 1.0 mmol) is taken up in 7 mL of acetonitrile, and iodotrimethyl-silane (0.43 mL, 3.0 mmol) is added. The resulting mixture is stirred for one hour at room temperature before quenched with methanol (1 mL). The residue after concentration is taken up in 2N hydrochloric acid (3 mL) and is extracted with ether (2×30 mL). The aqueous layer is condensed to dryness and the residue is recrystalized from isopropanol and ether to give a mixture (1:4 ratio) of (3S, 5RS)-1-(4-chloro-quinolin-7-ylmethyl)-3,5-dimethyl-piperazin-2-one as a yellow solid (290 mg). The two epimers are separated using a flash column (SiO2, 1% triethylamine/3% methanol/methylene chloride). C16H18ClN3O MS m/z: 304, 306. The minor isomer (3S, 5R)-1-(4-chloro-quinolin-7-ylmethyl)-3,5-dimethyl-piperazin-2-one.is (3S, 5R)-1-(4-chloro-quinolin-7-ylmethyl)-3,5-dimethyl-piperazin-2-one while the major isomer is (3S, 5S)-1-(4-chloro-quinolin-7-ylmethyl)-3,5-dimethyl-piperazin-2-one. Alternatively, (3S, 5R)-1-(4-chloro-quinolin-7-ylmethyl)-3,5-dimethyl-piperazin-2-one and (3S, 5S)-1-(4-chloro-quinolin-7-ylmethyl)-3,5-dimethyl-piperazin-2-one can be made via the same chemistry shown below from pure (2S, 6S)-2,6-dimethyl-3-oxo-piperazine-1-carboxylic acid benzyl ester and (2S, 6RS)-4-(4-chloro-quinolin-7-ylmethyl)-2,6-dimethyl-3-oxo-piperazine-1-carboxylic acid benzyl ester, respectively.
Reaction SMILES: [CH3:1][CH:2]1[CH:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:6](=[O:13])[NH:5][C:4]([S:14][CH3:15])=[N:3]1.BrN1C(=O)CCC1=O.C(=O)([O-])[O-].[K+].[K+]>C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C(Cl)(Cl)(Cl)Cl>[CH3:1][C:2]1[N:3]=[C:4]([S:14][CH3:15])[NH:5][C:6](=[O:13])[C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)C1C(=O)NC(SC)=NC1C
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1c(C)nc(SC)[nH]c1=O
Temperature: 25 °C
Yield: 73.8 %

Procedure:
A round bottom flask was charged with ethyl 4-methyl-2-(methylthio)-6-oxo-1,4,5,6-tetrahydro-5-pyrimidinecarboxylate (11.2 g, 48.7 mmol), N-bromo succinimide (8.67 g, 48.7 mmol), benzoyl peroxide (0.65 g, 2.7 mmol), potassium carbonate (67 g, 487 mmol) and carbon tetrachloride (700 mL). The reaction was heated to reflux for 45 min and cooled to room temperature. The reaction was quenched with to water (500 mL) and washed with methylene chloride. Aqueous phase was acidified by dropwise addition of conc. HCl and extracted with methylene chloride. The extract was dried over MgSO4, filtered, and evaporated under vacuum to afford the product (8.2 g, 78% yield).
Reaction SMILES: [OH-].[Na+].[N+:3]([C:6]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:7]=1[N:13]=[N:14][C:15]1[CH:20]=[C:19]([CH3:21])[CH:18]=[C:17]([C:22]([CH3:25])([CH3:24])[CH3:23])[C:16]=1[OH:26])([O-])=O.ClC1C(=O)C2C(C(=[O:39])C=1Cl)=CC=CC=2.O=C[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O.N(C1C=CC=CC=1)=NC1C=CC=CC=1>CO>[OH:26][C:16]1[C:17]([C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:18][C:19]([CH3:21])=[CH:20][C:15]=1[N:14]1[N+:13]([O-:39])=[C:7]2[CH:8]=[CH:9][C:10]([Cl:12])=[CH:11][C:6]2=[N:3]1
Reactant: O=C1C(Cl)=C(Cl)C(=O)c2ccccc21
Reactant: Cc1cc(N=Nc2ccc(Cl)cc2[N+](=O)[O-])c(O)c(C(C)(C)C)c1
Agent: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1cc(-n2nc3cc(Cl)ccc3[n+]2[O-])c(O)c(C(C)(C)C)c1
Temperature: 65 °C
Reaction time: 0.5 h

Procedure:
97% sodium hydroxide 8.2 g was added to methanol 100 ml, and the mixture was stirred at 65° C. for 30 minutes. After cooling to 50° C., 2-nitro-4-chloro-2'-hydroxy-3'-t-butyl-5'-methylazobenzene 11.6 g was added to the resultant mixture over 30 minutes, and thereafter 2,3-dichloro-1,4-naphthoquinone 0.7 g was added. Glucose 4 g was then added to the resultant mixture at 40° to 45° C. over one hour, and the mixture was further stirred for one hour at 40° to 45° C. As this result, almost all of the azobenzene disappeared to produce 2-(2'-hydroxy-3'-t-butyl-5'-methylphenyl)-5-chlorobenzotriazole-N-oxide.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:11]=1[CH2:12][NH:13][C:14](=[O:20])[C@@H:15]1[CH2:19][CH2:18][CH2:17][NH:16]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:26]1([CH:32]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH2:33][C:34](O)=[O:35])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C1C=C2N=NN(O)C2=CC=1.O.C(Cl)CCl.C(N(C(C)C)CC)(C)C>CN(C=O)C>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:11]=1[CH2:12][NH:13][C:14](=[O:20])[C@@H:15]1[CH2:19][CH2:18][CH2:17][N:16]1[C:34](=[O:35])[CH2:33][CH:32]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCc1ccc(Cl)cc1CNC(=O)[C@@H]1CCCN1
Reactant: O=C(O)CC(c1ccccc1)c1ccccc1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCc1ccc(Cl)cc1CNC(=O)[C@@H]1CCCN1C(=O)CC(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 105.8 %

Procedure:
To a stirred solution of L-prolin-N-(2-(tert-butyloxycarbonylaminomethyl)-5-chlorobenzyl)amide (0.030 g, 0.082 mmol), 3,3-diphenylpropanoic acid (20 mg, 0.090 mmol), and HOBT hydrate (13 mg, 0.098 mmol) in DMF (1 mL) was added EDC (0.023 g, 0.122 mmol). Diisopropylethylamine (0.0142 mL, 0.082 mmol) was added and the mixture was stirred at ambient temperature for 3 hours, at which time HPLC analysis indicated complete consumption of the proline starting material. The DMF was removed under reduced pressure and the residue was partitioned between EtOAc (50 mL) and 1N HCl. The EtOAc layer was separated, washed with water, 10% aqueous Na2CO3 and brine, dried over anhydrous MgSO4, and filtered. The filtrate solvent was removed under reduced pressure and the residue was purified by chromatography on a 10 g ISCO column using 10-100% EtOAc/hexanes over 40 min. The product-containing fractions were combined and the solvents were removed under reduced pressure to give N-(2-{[(tert-butoxycarbonyl)amino]methyl}-5-chlorobenzyl)-1-(3,3-diphenylpropanoyl)-L-prolinamide as an oil (0.050 g, 99%). HPLC RT=2.9 min, Method B; LC-MS M+H=576, 578.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[C:15]([C:16]2[C:25]3[C:20](=[CH:21][C:22]([OH:26])=[CH:23][CH:24]=3)[N:19]=[CH:18][CH:17]=2)=[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][N:9]2[N:8]=1.CN(C=O)C.Br[CH2:33][CH2:34][Cl:35].C(=O)([O-])[O-].[Cs+].[Cs+]>CO>[Cl:35][CH2:34][CH2:33][O:26][C:22]1[CH:21]=[C:20]2[C:25]([C:16]([C:15]3[C:7]([C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=4)=[N:8][N:9]4[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=34)=[CH:17][CH:18]=[N:19]2)=[CH:24][CH:23]=1
Reactant: ClCCBr
Reactant: Oc1ccc2c(-c3c(-c4ccccn4)nn4ccccc34)ccnc2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CO
Product: ClCCOc1ccc2c(-c3c(-c4ccccn4)nn4ccccc34)ccnc2c1
Temperature: 60 °C
Reaction time: 8 h
Yield: 30 %

Procedure:
4-(2-Pyridin-2-yl-pyrazolo[1,5-a]pyridin-3-yl)-quinolin-7-ol in a solution of DMF and MeOH was treated with 1-bromo-2-chloroethane (3 equiv) and cesium carbonate (2 equiv). The reaction was heated to 60° C. and stirred overnight. As described above, the desired product was then obtained upon chromatographic purification (EtOAc, followed by MeOH, then 2 M NH3 in MeOH). Yield; 30% overall from Prep. 90. MS ES+ m/e 401.0 (M+1).
Reaction SMILES: [NH2:1][CH:2]([CH3:15])[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([O:13][CH3:14])[CH:6]=1)[OH:4].[C:16](C1NC=CN=1)(C1NC=CN=1)=[O:17]>C(Cl)(Cl)Cl>[CH3:14][O:13][C:7]1[CH:6]=[C:5]([CH:3]2[O:4][C:16](=[O:17])[NH:1][CH:2]2[CH3:15])[CH:10]=[CH:9][C:8]=1[O:11][CH3:12]
Reactant: COc1ccc(C(O)C(C)N)cc1OC
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: ClC(Cl)Cl
Product: COc1ccc(C2OC(=O)NC2C)cc1OC
Reaction time: 8 h
Yield: 24 %

Procedure:
5.5 mmol of 2-amino-(3,4-dimethoxyphenyl)-propanol is dissolved in 50 ml. of chloroform and stirred with 1.05 g. (6.5 mmol) of carbonyl diimidazole for 2 hours under the exclusion of moisture. After allowing the reaction mixture to stand overnight, the mixture is extracted with the use of 50 ml. of distilled water, dried, filtered, and concentrated. After chromatography of the residue over 50 g. of silica gel with chloroform/methanol (95:5) as the eluent and recrystallization from ethyl acetate/petroleum ether, a 24% yield is obtained of 5-(3,4-dimethoxyphenyl)-4-methyl-2-oxazolidinone, m.p. 98°-99°.
Reaction SMILES: C([O:5][C:6](=[O:49])[CH2:7][CH:8]([NH:16][S:17]([C:20]1[CH:25]=[CH:24][C:23]([NH:26][C:27](=[O:29])[CH3:28])=[CH:22][C:21]=1[O:30][CH2:31][CH2:32][C:33]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[C:36]([C:43]([NH:45][N:46]([CH3:48])[CH3:47])=[O:44])=[CH:35][CH:34]=1)(=[O:19])=[O:18])[CH:9](OCC)[O:10]CC)(C)(C)C.C(O)(C(F)(F)F)=O.C(#N)C.O>C(Cl)Cl.O>[C:27]([NH:26][C:23]1[CH:24]=[CH:25][C:20]([S:17]([NH:16][CH:8]([CH:9]=[O:10])[CH2:7][C:6]([OH:49])=[O:5])(=[O:19])=[O:18])=[C:21]([O:30][CH2:31][CH2:32][C:33]2[C:42]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=3)[C:36]([C:43]([NH:45][N:46]([CH3:48])[CH3:47])=[O:44])=[CH:35][CH:34]=2)[CH:22]=1)(=[O:29])[CH3:28]
Reactant: CCOC(OCC)C(CC(=O)OC(C)(C)C)NS(=O)(=O)c1ccc(NC(C)=O)cc1OCCc1ccc(C(=O)NN(C)C)c2ccccc12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CC(=O)Nc1ccc(S(=O)(=O)NC(C=O)CC(=O)O)c(OCCc2ccc(C(=O)NN(C)C)c3ccccc23)c1
Yield: 35.3 %

Procedure:
3-(4-Acetylamino-2-{2-[4-(N′,N′-dimethyl-hydrazinocarbonyl)-naphthalen-1-yl]-ethoxy}-benzenesulfonylamino)-4,4-diethyoxy-butyric acid tert-butyl ester (0.12 g, 0.17 mmol) was stirred in 12 mL of a solution of 17% TFA in CH2Cl2 at room temperature for 2 h. Analytical HPLC indicated the reaction was complete. The reaction mixture was concentrated. Residual TFA was azeotroped with toluene. Half of the product was lyophilized to give (0.06 g, 54%). The second half of the crude product was stirred with 22 mL of a solution of 10% TFA in 1:1 acetonitrile/water for 16 h. Analytical HPLC indicated that reaction was complete. The reaction mixture was diluted with H2O and lyopholyzed. The crude product was purified by preparative-scale reverse phase HPLC (0 to 30% acetonitrile in H2O with 0.1% TFA over 2 h at 15 mL/min on Vydac #218TP152022-2.5×25 cm C18 column) and then lyophilized to give (0.035 g, 0.06 mmol, 36%) of 3-(4-Acetylamino-2-{2-[4-(N′,N′-dimethyl-hydrazinocarbonyl)-naphthalen-1-yl]-ethoxy}-benzenesulfonylamino)-4-oxo-butyric acid as a fluffy white solid. MS m/z 571 (M+1).
Reaction SMILES: N=[C:2]1[C:6]2([CH2:11][CH2:10][S:9][CH2:8][CH2:7]2)[NH:5][C:4](=[O:12])[N:3]1[C:13]1[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[C:15]([C:21]([F:24])([F:23])[F:22])[CH:14]=1.C[OH:26].Cl>C(Cl)(Cl)Cl>[O:12]=[C:4]1[N:3]([C:13]2[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[C:15]([C:21]([F:24])([F:23])[F:22])[CH:14]=2)[C:2](=[O:26])[C:6]2([CH2:11][CH2:10][S:9][CH2:8][CH2:7]2)[NH:5]1
Reactant: N#Cc1ccc(N2C(=N)C3(CCSCC3)NC2=O)cc1C(F)(F)F
Reactant: CO
Agent: Cl
Solvent: ClC(Cl)Cl
Product: N#Cc1ccc(N2C(=O)NC3(CCSCC3)C2=O)cc1C(F)(F)F

Procedure:
Using the procedure of Example 2, 2.34 g of the product of Example 12, 25 ml of methanol and 5 ml of chloroform were reacted and 4.5 ml of 2N hydrochloric acid were added. The reaction medium was refluxed for one hour and after purification on silica with methylene chloride-acetone: 95-5 as eluant, crystallization from isopropanol was carried out to obtain 368 mg of the expected product (white crystals) melting at 209-210° C.
Reaction SMILES: Cl.[NH2:2][OH:3].C([O-])(=O)C.[Na+].[Br:9][C:10]1[CH:22]=[C:21]2[C:13]([C:14]3[C:15](=O)[CH2:16][CH2:17][CH2:18][C:19]=3[N:20]2[CH3:23])=[CH:12][CH:11]=1>CCO.O>[Br:9][C:10]1[CH:22]=[C:21]2[C:13]([C:14]3[C:15](=[N:2][OH:3])[CH2:16][CH2:17][CH2:18][C:19]=3[N:20]2[CH3:23])=[CH:12][CH:11]=1
Reactant: NO
Reactant: Cn1c2c(c3ccc(Br)cc31)C(=O)CCC2
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cn1c2c(c3ccc(Br)cc31)C(=NO)CCC2
Temperature: 40 °C
Yield: 69.7 %

Procedure:
Hydroxylamine hydrochloride (3.21 g, 46.5 mmol) and sodium acetate (3.81 g, 46.5 mmol) were added to a suspension of 7-bromo-9-methyl-2,3-dihydro-1H-carbazol-4(9H)-one (8.61 g, 30.9 mmol) in EtOH (79.0 mL) and H2O (27.0 mL), and the resulting suspension was heated at reflux for 20 h. The reaction was cooled to ˜40° C., and the solids were collected by filtration. The solids were washed with H2O and EtOH. The solids were divided into two batches of 3.93 g and 4.08 g and recrystallized in CH3CN (500 mL per batch). The material was allowed to crystallize for two days the resulting crystals were collected by filtration to afford the title compound (6.31 g, 70%) as an off-white crystalline solid: 1H NMR (500 MHz, DMSO-d6) δ 10.33 (s, 1H), 7.82 (d, J=8.5 Hz, 1H), 7.70 (d, J=2.0 Hz, 1H), 7.20 (dd, J=8.0, 1.5 Hz, 1H), 3.66 (s, 3H), 2.81 (t, J=6.0 Hz, 2H), 2.66 (t, J=6.0 Hz, 2H), 1.94-1.91 (m, 2H). Additional material was obtained by concentrating the filtrate to 200 mL and collecting the resulting solids to afford the title compound (1.22 g, 13%) as an off-white powder.
Reaction SMILES: O=[C:2]1[NH:12][CH2:11][CH:10]2[CH2:13][CH:3]1[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:9]=12.[BH4-].[Na+].B(F)(F)F.CCOCC.Cl.O.[C:27]1([CH3:37])[CH:32]=[CH:31][C:30]([S:33]([OH:36])(=[O:35])=[O:34])=[CH:29][CH:28]=1>O1CCCC1.C(O)(C)C.CO>[S:33]([C:30]1[CH:31]=[CH:32][C:27]([CH3:37])=[CH:28][CH:29]=1)([OH:36])(=[O:35])=[O:34].[CH:3]12[CH2:13][CH:10]([CH2:11][NH:12][CH2:2]1)[C:9]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]2=1
Reactant: O=C1NCC2CC1c1ccccc12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Agent: FB(F)F
Solvent: CC(C)O
Solvent: C1CCOC1
Solvent: O
Product: c1ccc2c(c1)C1CNCC2C1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1.38 g of 9-oxo-10-aza-tricyclo[6.3.1.02,7]dodeca-2(7),3,5-triene (8.00 mmol, 1 equivalent) in 8 mL of tetrahydrofuran was added 603 mg of sodium borohydride (16.0 mmol, 2.0 equivalent) followed by slow addition of 2.77 mL of boron trifluoride diethyl etherate (21.6 mmol, 2.7 equivalent). Once the effervescence subsided, the reaction mixture was heated to 50° C. for 5 hours. The reaction was then cooled to room temperature for addition of 10 mL of methanol (added dropwise at first) and 0.125 mL of concentrated hydrochloric acid. Heating was resumed at a reflux for 12 hours. The reaction mixture was then cooled to room temperature and concentrated in vacuo. The residue was diluted with 20 mL of 20% aqueous sodium hydroxide followed by 30 mL of methyl-tert-butyl ether. The mixture was stirred for 30 minutes and then the aqueous layer was extracted with another 30 mL of methyl-tert-butyl ether. The combined organic layers were washed with 40 mL of a saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. After concentrating in vacuo, 1.67 g of p-toluenesulfonic acid monohydrate (8.80 mmol, 1.1 equivalent) was added with 20 mL of isopropanol. The solution was heated until homogeneous and then allowed to gradually cool to room temperature with stirring. White crystals of the title compound formed and were collected by filtration (2.17 g, 81%). mp: 207-208° C.; 1H NMR (400 MHz, CD3OD): δ 7.69 (d, J=7.9 Hz, 2H), 7.43-7.32 (m, 4H), 7.23 (d, J=7.9 Hz, 2H), 3.37 (d, J=11.2 Hz, 4H), 3.30 (bs, 2H), 3.15 (d, J=12.4 Hz, 2H), 2.36 (s, 3H), 2.40-2.35 (m, 1H), 2.08 (d, J=11.2 Hz, 1H); 13C NMR (100 MHz, CD3OD): δ 140.8, 140.5, 139.1, 127.2, 127.2, 124.3, 122.3, 45.1, 39.7, 37.3, 18.7; IR (KBr, cm−1): 3438, 3021, 2958, 2822, 2758, 2719, 2683, 2611, 2424, 1925, 1606, 1497, 1473, 1428, 1339, 1302, 1259, 1228, 1219, 1176, 1160, 1137, 1122, 1087, 1078, 945, 914, 876, 847, 829, 818, 801, 710, 492; Anal. Calcd for C18H21NO3S: C, 65.23; H, 6.39; N, 4.23; Found: C, 65.05; H, 6.48; N, 4.26.
Reaction SMILES: [O:1]1[C:13]([CH3:15])([CH3:14])[C:2]1([CH3:16])[CH2:3][CH2:4][C:5]([CH3:12])=[CH:6][CH2:7][CH2:8]C(=O)C.[CH2:17]([O:19][C:20](=[O:30])[C:21]([CH2:28][CH3:29])(CC)P(O)(O)=O)[CH3:18].[Na]>C(O)C>[CH2:17]([O:19][C:20](=[O:30])[CH:21]=[C:28]([CH3:29])[CH2:8][CH2:7][CH:6]=[C:5]([CH3:12])[CH2:4][CH2:3][C:2]1([CH3:16])[O:1][C:13]1([CH3:15])[CH3:14])[CH3:18]
Reactant: CCOC(=O)C(CC)(CC)P(=O)(O)O
Reactant: CC(=O)CCC=C(C)CCC1(C)OC1(C)C
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)C=C(C)CCC=C(C)CCC1(C)OC1(C)C
Reaction time: 14 h

Procedure:
To a solution of 25 g. of 9,10-epoxy-6,9,10-trimethyl-undec-5-en-2-one and 24.8 g. of diethyl phosphonoacetic acid ethyl ester in 160 ml. of absolute ethanol, there was added dropwise while cooling with ice, a solution containing 2.56 g. of sodium in 65 ml. of absolute ethyl alcohol. The mixture was allowed to stand for 14 hours at room temperature and evaporated subsequently under vacuum. The residue was poured into a standard aqueous sodium chloride solution, exhaustively extracted with diethyl ether, washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate and evaporated. Fractional distillation at high vacuum gave 10,11-epoxy-3,7,10,11-tetramethyl-2,6-dodecadienoic acid ethyl ester; b.p. 110°-113°C./0.01 mmHg; nD20 = 1.4792.
Reaction SMILES: [C:1]([C:4]1[CH:5]([C:23]2[CH:31]=[CH:30][C:29]([C:32]#[N:33])=[CH:28][C:24]=2[C:25](O)=[O:26])[N:6]([CH3:22])[C:7](=[O:21])[N:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)[C:9]=1[CH3:10])(=[O:3])[CH3:2].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.[N:48]1(OC(N(C)C)=[N+](C)C)[C:52]2N=CC=[CH:56][C:51]=2N=N1>CN(C)C=O>[C:1]([C:4]1[CH:5]([C:23]2[CH:31]=[CH:30][C:29]([C:32]#[N:33])=[CH:28][C:24]=2[C:25]([NH:48][CH2:52][C:51]#[CH:56])=[O:26])[N:6]([CH3:22])[C:7](=[O:21])[N:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:18])([F:19])[F:20])[CH:12]=2)[C:9]=1[CH3:10])(=[O:3])[CH3:2]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)C(=O)N(C)C1c1ccc(C#N)cc1C(=O)O
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C#CCNC(=O)c1cc(C#N)ccc1C1C(C(C)=O)=C(C)N(c2cccc(C(F)(F)F)c2)C(=O)N1C
Reaction time: 0.08 h

Procedure:
2-[5-Acetyl-3,6-dimethyl-2-oxo-1-(3-trifluoromethyl-phenyl)-1,2,3,4-tetrahydro-pyrimidin-4-yl]-5-cyano-benzoic acid (intermediate 6) (70 mg, 0.15 mmol) and triethylamine (35 μL, 0.25 mmol) are suspended in N,N-dimethylformamide (1.5 mL) and the mixture is shaken for 5 min. A solution of O-(7-azabenzotriazole-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (61.1 mg, 0.16 mmol) in N,N-dimethylformamide (0.5 mL) and triethylamine (35 μL, 0.25 mmol) is added and the reaction mixture is shaken for 1.5 h at room temperature. The product is purified by reversed phase HPLC. Yield 48 mg; ESI mass spectrum [M+H]+=495; Retention time HPLC: 0.99 min (HPLC method Z011_S03).