Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br-].[NH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:11][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[N:3]1.[O:31]=[C:32]1[NH:36][CH2:35][C:34](=[O:37])[N:33]1[CH2:38][CH2:39][O:40][C:41]1[CH:48]=[CH:47][C:44]([CH:45]=O)=[C:43]([N+:49]([O-:51])=[O:50])[C:42]=1[O:52][CH3:53].C(=O)([O-])[O-].[K+].[K+].O>CO>[NH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](/[CH:11]=[CH:45]/[C:44]2[CH:47]=[CH:48][C:41]([O:40][CH2:39][CH2:38][N:33]3[C:34](=[O:37])[CH2:35][NH:36][C:32]3=[O:31])=[C:42]([O:52][CH3:53])[C:43]=2[N+:49]([O-:51])=[O:50])=[N:3]1
Reactant: c1ccc([P+](Cc2n[nH]c3ccccc23)(c2ccccc2)c2ccccc2)cc1
Reactant: COc1c(OCCN2C(=O)CNC2=O)ccc(C=O)c1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: COc1c(OCCN2C(=O)CNC2=O)ccc(/C=C/c2n[nH]c3ccccc23)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 28.6 %

Procedure:
(1H-indazol-3-ylmethyl)triphenylphosphonium bromide (0.12 g, 0.26 mmol), 4-[2-(2,5-dioxoimidazolidin-1-yl)ethoxy]-3-methoxy-2-nitrobenzaldehyde (0.08 g, 0.24 mmol) obtained in Step 1 and potassium carbonate (0.07 g, 0.47 mmol) were dissolved in methanol (3.0 mL), followed by stirring at room temperature for 1.0 hour. The reaction mixture was added with water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol=9/1) to obtain (E)-3-(2-{4-[2-(1H-indazol-3-yl)vinyl]-2-methoxy-3-nitrophenoxy}ethyl)imidazolidine 2,4-dione (0.03 g, 32%).
Reaction SMILES: [O:1]1CC[O:3][CH:2]1[CH2:6][CH2:7][CH:8]([C:10]1[CH:15]=[CH:14][C:13]([F:16])=[C:12]([CH3:17])[CH:11]=1)[OH:9].CC(C)=O.OS(O)(=O)=O.O=[Cr](=O)=O.O>CC(C)=O>[F:16][C:13]1[CH:14]=[CH:15][C:10]([C:8](=[O:9])[CH2:7][CH2:6][C:2]([OH:3])=[O:1])=[CH:11][C:12]=1[CH3:17]
Reactant: Cc1cc(C(O)CCC2OCCO2)ccc1F
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(C)=O
Product: Cc1cc(C(=O)CCC(=O)O)ccc1F
Reaction time: 0.5 h

Procedure:
To a solution of 3-(1,3-dioxolan-2-yl)-1-(4-fluoro-3-methylphenyl)propan-1-ol (1.6 g, 6.7 mmol) in 15 ml acetone was added Jones reagent (1.5 mL) dropwise at room temperature. The mixture was stirred for 30 min. and then 50 mL of water was added before extracting with DCM (3×40 mL). The combined DCM layers were washed with water (2×20 mL) and dried over Na2SO4. The solvent was evaporated under reduce pressure and the crude product used for the next step without further purification.
Reaction SMILES: O(C(C)(C)C)[K].[Br:7][C:8]1[CH:13]=[CH:12][C:11]([NH2:14])=[C:10]([C:15]#[C:16][CH2:17][CH2:18][N:19]2[CH2:23][CH2:22][CH2:21][CH:20]2[CH3:24])[CH:9]=1>CN1C(=O)CCC1>[Br:7][C:8]1[CH:9]=[C:10]2[C:11](=[CH:12][CH:13]=1)[NH:14][C:16]([CH2:17][CH2:18][N:19]1[CH2:23][CH2:22][CH2:21][C@H:20]1[CH3:24])=[CH:15]2
Reactant: CC1CCCN1CCC#Cc1cc(Br)ccc1N
Agent: CC(C)(C)O[K]
Solvent: CN1CCCC1=O
Product: C[C@@H]1CCCN1CCc1cc2cc(Br)ccc2[nH]1
Temperature: 25 °C
Reaction time: 3 h
Yield: 61.2 %

Procedure:
To a cooled (0° C.) suspension of KO-tBu (95%, 7.8 g, 66 mmol) in NMP (150 mL) was added a solution of 4-bromo-2-[4-(2-methyl-pyrrolidin-1-yl)-but-1-ynyl]-phenylamine (10 g, 33 mmol) in NMP (50 mL) dropwise keeping the temperature below 5° C. The resulting mixture was then stirred at room temperature for 3 hours under nitrogen. HPLC indicated that all the starting material was consumed. H2O (400 mL) was added slowly to the reaction mixture followed by addition of IPAc (500 mL). The resulting mixture was stirred for 5 min. and the organic layer was separated. The organic layer was then washed with 20% brine (3×200 mL), dried over Na2SO4 and treated with activated carbon. After filtration, the filtrate was concentrated under reduced pressure to give the title compound as a thick oil (6.2 g), which was used in the next coupling reaction without further purification. 1H NMR (400 MHz, CDCl3) δ 10.21 (s, 1H), 7.73 (s, 1H), 7.27 (s, 2H), 6.24 (s, 1H), 3.42–3.50 (m, 1H), 3.21–3.28 (m, 1H), 2.97–3.10 (m, 2H), 2.49–2.60 (m, 2H), 2.33 (q, J=8.78 Hz, 1H), 2.10–2.17 (m, 1H), 1.87–2.02 (m, 2H), 1.58–1.67 (m, 1H), 1.24 (d, J=6.2 Hz, 3H). 13C NMR (400 MHz, CDCl3) δ 140.89, 133.92, 129.91, 122.98, 121.77, 112.16, 111.75, 98.32, 60.47, 53.60, 53.34, 33.19, 26.30, 22.14, 19.56. [M+H]+ at m/z 307.
Reaction SMILES: S(Cl)(Cl)=O.[CH3:5][O:6][C:7]1[CH:8]=[C:9]2[C:12](=[CH:13][C:14]=1[O:15][CH3:16])[C@@H:11]([CH2:17][N:18]([CH3:40])[CH2:19][CH2:20][CH2:21][NH:22][C:23](=[O:39])[CH2:24][C:25]1[CH:30]=[C:29]([O:31][CH3:32])[C:28]([O:33][CH3:34])=[CH:27][C:26]=1[CH2:35][C:36](O)=[O:37])[CH2:10]2.[OH-].[Na+]>C1(C)C=CC=CC=1.ClCCl.ClCCl>[CH3:5][O:6][C:7]1[CH:8]=[C:9]2[C:12](=[CH:13][C:14]=1[O:15][CH3:16])[C@@H:11]([CH2:17][N:18]([CH3:40])[CH2:19][CH2:20][CH2:21][N:22]1[C:23](=[O:39])[CH2:24][C:25]3[CH:30]=[C:29]([O:31][CH3:32])[C:28]([O:33][CH3:34])=[CH:27][C:26]=3[CH2:35][C:36]1=[O:37])[CH2:10]2
Reactant: COc1cc(CC(=O)O)c(CC(=O)NCCCN(C)C[C@H]2Cc3cc(OC)c(OC)cc32)cc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Product: COc1cc2c(cc1OC)CC(=O)N(CCCN(C)C[C@H]1Cc3cc(OC)c(OC)cc31)C(=O)C2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78.7 %

Procedure:
Thionyl chloride (1.68 mmol, 1.68 eq) is added to a suspension of {2-[2-({3-[{[(7S)-3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-yl]methyl}(methyl)amino]propyl}amino)-2-oxo-ethyl]-4,5-dimethoxyphenyl}acetic acid (500 mg, 1 mmol) in a mixture of toluene/dichloro-methane (15 ml, 66/33) at 60° C. After remaining in contact for 3 hours 30 minutes, 0.5 mmol of thionyl chloride dissolved in 5 mL of dichloromethane is added (0.5 eq). After remaining in contact for 1 hour 30 minutes, the reaction mixture is cooled to 25° C. 1N aqueous sodium hydroxide solution (10 mL) and dichloromethane (10 mL) are added to the mixture. The two phases are separated, and the organic phase is subjected to drying over sodium sulphate and is then dried. 0.38 g of a dark red oil is obtained. The product may be purified by flash chromatography on a silica column (eluant: dichloromethane/methanol 95/5).
Reaction SMILES: [NH2:1][C:2]1[NH:7][C:6]([C:9]#[C:10]C(O)C)(C)[CH:5]=[CH:4][N:3]=1.[OH-].[Na+].O1CCOC[CH2:17]1>C1(C)C=CC=CC=1>[NH2:1][C:2]1[N:7]=[C:6]([C:9]#[CH:10])[CH:5]=[C:4]([CH3:17])[N:3]=1
Reactant: C1COCCO1
Reactant: CC(O)C#CC1(C)C=CN=C(N)N1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: C#Cc1cc(C)nc(N)n1

Procedure:
A mixture of 4.44 g of 4-(2-amino-4-methylpyrimidin-4-yl)-3-butyne-2-ol, 1 g of sodium hydroxide, 5 ml of dioxane and 50 ml of toluene was refluxed for two hours. The toluene layer was decanted from the residue, concentrated under reduced pressure and chromatographed on a silica gel dry column. The product band eluted with (2:3:0.05) ethyl acetate/dichloromethane/THF. Extraction with THF and concentration of the solvent gave 0.75 g of the title compound as a solid, 129°-130° dec.; IR(nujol) 2119(w, C≡C) cm-1 ; PMR(60 MHz, CDCl3) δ2,3(s, CH3, 3H), 3.1(s, C≡CH, 1H), 5.3-5.6(bs, NH2, 2H), 6.6(s, Het-H, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[S:4][CH:5]=[CH:6][CH:7]=1.[CH:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][C:9]=1[O:18][CH2:19]CO>C1C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][C:9]=1[O:18][CH2:19][CH2:1][O:2][C:3]1[S:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cccs1
Reactant: OCCOc1ccc2ccccc2c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: c1csc(OCCOc2ccc3ccccc3c2)c1
Yield: 49.6 %

Procedure:
A solution of 2-methoxythiophene (2.28 g) and 2-(2-naphthalenyloxy)ethanol (4.0 g) in benzene (35 mL) containing para-toluenesulfonic acid (0.02 g) was stirred at reflux for 3 days in a flask equipped with a Soxhlet extractor charged with 4 Å molecular sieves. The mixture was cooled, washed with 0.5N sodium hydroxide solution, dried over anhydrous magnesium sulfate (MgSO4) and evaporated. Crystallization of the residual material from ethanol (30 mL) provided 2.68 g of 2-[[2-(2-naphthalenyloxy)ethyl]oxy]thiophene as colorless flakes, mp 129°-130 ° C.
Reaction SMILES: [Br:1]NC(=O)CCC(N)=O.[F:10][CH:11]([F:20])[O:12][C:13]1[C:14]([NH2:19])=[N:15][CH:16]=[CH:17][CH:18]=1>C(#N)C>[Br:1][C:17]1[CH:18]=[C:13]([O:12][CH:11]([F:10])[F:20])[C:14]([NH2:19])=[N:15][CH:16]=1
Reactant: Nc1ncccc1OC(F)F
Reactant: NC(=O)CCC(=O)NBr
Solvent: CC#N
Product: Nc1ncc(Br)cc1OC(F)F
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 98.3 %

Procedure:
N-Bromosuccinamide (1.00 g, 5.62 mmol) was added portionwise over 10 min to a cooled solution of 3-(difluoromethoxy)pyridin-2-amine (1.12 g) in dry acetonitrile (20 ml) at 0° C. The reaction mixture was further stirred at 0° C. for 10 min. The mixture was concentrated, and residue was partitioned between EtOAc/sat. Na2CO3/H2O (30 ml/15 ml/15 ml). The organic phase was sequentially washed with sat. aqueous Na2CO3/H2O (15 ml/15 ml) and brine (30 ml), dried (Na2SO4), and concentrated. The resulting residue was extracted with EtOAc/hexanes (6 ml/30 ml), and the resulting suspension was filtered through Celite, and the resulting filtrate was concentrated to provide 1.32 g (80%) of 5-bromo-3-(difluoromethoxy)pyridine-2-amine. LCMS (m/z, MH+): 238.9, tR=0.52 min; 1H NMR (CDCl3, 400 MHz) δ 7.99 (d, J=2.0 Hz, 1H), 7.41 (m, 1H), 6.50 (t, J=72.8 Hz, 1H), 4.75 (br s, 2H).
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:16]=[CH:15][N:14]([CH2:17][CH2:18][C:19]([CH3:34])([S:30]([CH3:33])(=[O:32])=[O:31])[C:20]([NH:22][O:23]C3CCCCO3)=[O:21])[C:13](=[O:35])[CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)Cl.O.Cl>O1CCOCC1>[CH:1]1([CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:16]=[CH:15][N:14]([CH2:17][CH2:18][C:19]([CH3:34])([S:30]([CH3:33])(=[O:32])=[O:31])[C:20]([NH:22][OH:23])=[O:21])[C:13](=[O:35])[CH:12]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC(CCn1ccc(OCCCC2CCCCC2)cc1=O)(C(=O)NOC1CCCCO1)S(C)(=O)=O
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC(CCn1ccc(OCCCC2CCCCC2)cc1=O)(C(=O)NO)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 54.4 %

Procedure:
4-[4-(3-Cyclohexylpropoxy)-2-oxopyridin-1(2H)-yl]-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide (220 mg, 0.429 mmole) was dissolved in dioxane (4 ml), DCM (4 ml) and water (2 ml). To this was added a 4.0M solution of HCl in dioxane (1.0 ml, 4.29 mmole) and was stirred at RT for 1 hour. The reaction mixture was concentrated in vacuo and azeotroped with IPA (2×5 ml) to afford a white solid (100 mg, 54.4%). MS (LC/MS) m/z 429.1 (M+1) 1H NMR (400 MHz, METHANOL-d4) δ ppm 0.83-1.06 (m, 3H) 1.19-1.40 (m, 6H) 1.41 (s, 2H) 1.64-1.90 (m, 4H) 2.31-2.41 (m, 1H) 2.61-2.79 (m, 1H) 3.08 (s, 3H) 3.60 (s, 1H) 3.63-3.71 (m, 1H) 3.86-3.99 (m, 2H) 4.04 (s, 1H) 4.11 (d, J=8.00 Hz, 3H) 4.25-4.41 (m, 1H) 6.29 (s, 1H) 6.53-6.68 (m, 1H) 7.83-7.93 (m, 1H)
Reaction SMILES: P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1C2C(=O)C(=O)C3N=C(C(O)=O)C=C(C(O)=O)C=3C=2NC=1C(O)=O.[Cl-].[Cl-].[Ca+2].[CH2:36]([OH:47])[C@H:37]([OH:46])[C@@H:38]([OH:45])[C@H:39]([OH:44])[C:40]([CH:42]=[O:43])=[O:41]>O>[OH:44][C:39]1[C@@H:38]([C@@H:37]([OH:46])[CH2:36][OH:47])[O:45][C:42](=[O:43])[C:40]=1[OH:41]
Reactant: O=CC(=O)[C@@H](O)[C@H](O)[C@@H](O)CO
Agent: O=C(O)c1cc(C(=O)O)c2c(n1)C(=O)C(=O)c1cc(C(=O)O)[nH]c1-2
Agent: O=P([O-])([O-])[O-]
Agent: [Ca+2]
Solvent: O
Product: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Reaction time: 1 h

Procedure:
A reaction mixture consisting of 1.0 mM PMS, 25 mM potassium phosphate buffer (pH 7.0), 1.0 μM pyrroloquinoline quinone (PQQ), 1.0 mM CaCl2, 50 mM L-sorbosone and enzyme solution in a final volume of 100 μl with water is prepared just before the assay. The reaction is carried out at 30° C. for 60 min unless otherwise stated. The amount of vitamin C produced is measured at a wavelength of 264 nm by a high performance liquid chromatography (HPLC) which is coupled with a UV detector (TOSOH UV8000; TOSOH Co., Kyobashi 3-2-4, Chuo-ku, Tokyo, Japan), a dualpump (TOSOH CCPE; TOSOH Co.), an integrator (Shimadzu C-R6A; Shimadzu Co., Kuwahara-cho 1, Nishinokyo, Chukyo-ku, Kyoto, Japan) and a column (YMC-Pack Polyamine-II, YMC, Inc., 3233 Burnt Mill Drive Wilimington, N.C. 28403, U.S.A.). The amount of 2-KGA produced is measured by HPLC. One unit of the enzyme activity is defined as the amount of the enzyme that produces 1 mg vitamin C or 2-KGA in 60 min in the reaction mixture.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6](Br)=[CH:5][N:4]=1.[C:10]([O:14][CH2:15][CH3:16])(=[O:13])[CH:11]=[CH2:12].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([CH:12]=[CH:11][C:10]([O:14][CH2:15][CH3:16])=[O:13])=[CH:5][N:4]=1
Reactant: C=CC(=O)OCC
Reactant: COc1ncc(Br)cn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: O
Product: CCOC(=O)C=Cc1cnc(OC)nc1
Temperature: 135 °C
Reaction time: 12 h

Procedure:
A mixture of 2-methoxy-5-bromopyrimidine (75.43 g, 0.399 mol), ethyl acrylate (47.5 ml, 0.439 mol), palladium (II) acetate (1.07 g, 0.0048 mol), tri-o-tolylphosphine (2.92 g, 0.0096 mol) and triethylamine (84 ml) were heated at 135° C. with stirring under argon for 12 h. After allowing to cool the solid mass was dissolved in water and ethyl acetate, filtered, and the aqueous phase separated and further extracted with ethyl acetate. The combined extracts were washed with saturated aqueous ammonium chloride, dried (MgSO4) and evaporated. The solid thus obtained was triturated with ether/light petrol (1:3, 350 ml), filtered, washed and dried, yield 52.41 g (63%). 1H-NMR (CDCl3) δ 1.33 (3H, t), 4.06 (3H, s), 4.28 (2H, q), 6.45 (1H, d), 7.58 (1H, d), 8.67 (2H, s); MS (APCI+) found (M+H)=209; C10H12N2O3 requires 208.
Reaction SMILES: [OH:1][C:2]([C:4]([F:7])([F:6])[F:5])=[O:3].[F:8][CH:9]([F:38])[CH2:10][NH:11][C:12]1[N:13]=[C:14]2[CH2:36][CH:35]([CH3:37])[NH:34][CH2:33][C:15]2=[N:16][C:17]=1[N:18]1[CH2:23][CH2:22][CH:21]([O:24][C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=2[F:32])[CH2:20][CH2:19]1.C=O.CCN(C(C)C)C(C)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.CN(C=O)C>[F:38][CH:9]([F:8])[CH2:10][NH:11][C:12]1[N:13]=[C:14]2[CH2:36][CH:35]([CH3:37])[N:34]([CH3:2])[CH2:33][C:15]2=[N:16][C:17]=1[N:18]1[CH2:19][CH2:20][CH:21]([O:24][C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:26]=2[F:32])[CH2:22][CH2:23]1.[C:2]([OH:3])([C:4]([F:7])([F:6])[F:5])=[O:1]
Reactant: CC1Cc2nc(NCC(F)F)c(N3CCC(Oc4ccc(F)cc4F)CC3)nc2CN1
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC1Cc2nc(NCC(F)F)c(N3CCC(Oc4ccc(F)cc4F)CC3)nc2CN1C
Reaction time: 8 h

Procedure:
A solution of N-(2,2-difluoroethyl)-3-(4-(2,4-difluorophenoxyl)piperidin-1-yl)-7-methyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amine TFA salt (15 mg, 0.027 mmol), formaldehyde (4.0 μL, 0.054 mmol), and DIPEA (4.7 μL, 0.027 mmol) in DCM (136 μL) was stirred for 10 min at room temperature then treated with sodium triacetoxyborohydride (17.2 mg, 0.081 mmol). The resulting reaction mixture was stirred overnight. The crude reaction mixture was diluted in DMF, filtered through a hydrophilic PTFE 0.45 nm filter (Millipore® Millex-LCR), and purified via HPLC Method A to give the title compound as a TFA salt (8 mg) as a clear oil. 1H NMR (400 MHz, methanol-d4) δ ppm 1.39-1.57 (m, 3H), 1.92-2.03 (m, 2H), 2.08-2.18 (m, 2H), 2.82-3.09 (m, 6H), 3.16 (d, J=14.9 Hz, 1H), 3.35-3.44 (m, 2H), 3.67-3.85 (m, 3H), 4.11-4.29 (m, 1H), 4.37-4.44 (m, 1H), 4.44-4.52 (m, 1H), 5.90-6.22 (m, 1H), 6.85-6.91 (m, 1H), 6.98 (ddd, J=11.2, 8.5, 3.0 Hz, 1H), 7.17 (td, J=9.2, 5.3 Hz, 1H); ESI-MS m/z [M+H]+ 453.9.
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=[O:9])C=1.[C@@H:12]1([NH:18][C:19](=[O:24])[C:20]([F:23])([F:22])[F:21])[CH2:17][CH2:16][CH:15]=[CH:14][CH2:13]1>ClC1C=CC=CC=1>[F:21][C:20]([F:22])([F:23])[C:19]([NH:18][C@@H:12]1[CH2:17][CH2:16][C@H:15]2[C@H:14]([O:9]2)[CH2:13]1)=[O:24]
Reactant: O=C(N[C@H]1CC=CCC1)C(F)(F)F
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: Clc1ccccc1
Product: O=C(N[C@@H]1CC[C@@H]2O[C@@H]2C1)C(F)(F)F
Temperature: 22.5 °C
Reaction time: 1 h
Yield: 78.2 %

Procedure:
9.2 g of mCPBA (70%) was charged to a vessel containing a cooled (10-15° C.) solution of 6 g of N-(cyclohex-3-en-1(R)-yl)-2,2,2-trifluoro-acetamide in 60 ml of chlorobenzene maintaining the temperature <30° C., and rinsed through with 3 ml of chlorobenzene. The mixture obtained was stirred at 20 to 25° C. for 1 h and the reaction was followed by TLC until completion. Upon completion of the reaction, the mixture obtained was heated to 38 to 42° C. for 2 h until reaction completion and cooled to 0 to −5° C., stirred for 30 min and the solid precipitate (mCBA) was filtered off and washed through with 2×3 ml of chlorobenzene. The resultant filtrate was washed with 30 ml of 10% sodium thiosulfate solution to remove peroxides, 2×30 ml of 5% NaHCO3 solution to ensure an pH of aqueous phase of >7, and 30 ml of H2O. The mixture obtained was concentrated to dryness. 5.08 g of 2,2,2-Trifluoro-N-(1R,3R,6S)-(7-oxa-bicyclo[4.1.0]hept-3-yl)-acetamide containing ca. 8% of anti (trans) epoxide in the form of a crystalline white solid was obtained.
Reaction SMILES: [CH2:1]([N:8]([CH2:21][CH3:22])[C:9]1[C:10]([CH3:20])=[C:11]([CH:17]=[CH:18][CH:19]=1)[C:12]([O:14]CC)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>C1COCC1.CO>[CH2:1]([N:8]([CH2:21][CH3:22])[C:9]1[C:10]([CH3:20])=[C:11]([CH:17]=[CH:18][CH:19]=1)[C:12]([OH:14])=[O:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cccc(N(CC)Cc2ccccc2)c1C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCN(Cc1ccccc1)c1cccc(C(=O)O)c1C
Temperature: 50 °C
Reaction time: 16 h
Yield: 88.6 %

Procedure:
To a stirred solution of ethyl 3-[benzyl(ethyl)amino]-2-methylbenzoate (370 mg, 1.24 mmol) in THF (20 ml) and MeOH (5 ml) was added 2M NaOH (3.11 ml, 6.22 mmol) and the reaction was stirred at 50° C. for 16 h. The reaction was cooled to room temperature and the solvent removed in vacuo after which the aqueous solution was adjusted to pH1 using 1M HCl. The product was extracted into DCM (3×50 ml), washed with brine (20 ml), dried with Na2SO4 concentrated and filtered to afford the title compound as an orange oil (296 mg, 80%) which was used in the next stage without any further purification. LC-MS 91%, m/z=270.0, 1H NMR (500 MHz, Chloroform-d) δ 7.73 (d, J=7.5 Hz, 1H), 7.34-7.30 (m, 4H), 7.23 (dt, J=15.4, 6.9 Hz, 3H), 4.12 (d, J=13.5 Hz, 2H), 3.04-2.94 (m, 2H), 2.69 (s, 3H), 0.99 (t, J=7.0 Hz, 3H).
Reaction SMILES: C([N:8]1[CH:12]=[C:11]([CH3:13])[N:10]=[C:9]1[CH:14]1[C:19]2=[N:20][NH:21][C:22](=[O:27])[C:23]3[CH:24]=[CH:25][CH:26]=[C:17]([C:18]=32)[NH:16][CH:15]1[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)C1C=CC=CC=1>[OH-].[OH-].[Pd+2].CO>[CH3:13][C:11]1[N:10]=[C:9]([CH:14]2[C:19]3=[N:20][NH:21][C:22](=[O:27])[C:23]4[CH:24]=[CH:25][CH:26]=[C:17]([C:18]=43)[NH:16][CH:15]2[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[NH:8][CH:12]=1
Reactant: Cc1cn(Cc2ccccc2)c(C2c3n[nH]c(=O)c4cccc(c34)NC2c2ccccc2)n1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: Cc1c[nH]c(C2c3n[nH]c(=O)c4cccc(c34)NC2c2ccccc2)n1
Yield: 87.4 %

Procedure:
A mixture of 9-(1-benzyl-4-methyl-1H-imidazol-2-yl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one (40 mg, 0.09 mmol) and palladium hydroxide on carbon catalyst (40 mg, 20% wt) in anhydrous methanol (15 mL) was purged with hydrogen (1 bar) at room temperature for 12 hr. The mixture was filtered and the filtrate was concentrated to give crude product, which was purified by pre-HPLC to give 9-(4-methyl-1H-imidazol-2-yl)-8-phenyl-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one (27 mg, yield 87%). 1H-NMR (400 MHz, CD3OD) δ (ppm): 2.22 (dd, 3H), 4.77-4.86 (m, 2H), 7.06 (s, 1H), 7.20 (d, 1H), 7.36 (t, 5H), 7.55 (d, 1H), 7.62 (t, 1H); LC-MS (ESI) m/z: 344(M+1)+.
Reaction SMILES: [CH2:1]([OH:13])[CH2:2][O:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][OH:12].N#N.[OH-].[Na+].Br[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]>>[CH2:19]([O:12][CH2:11][CH2:10][O:9][CH2:8][CH2:7][O:6][CH2:5][CH2:4][O:3][CH2:2][CH2:1][OH:13])[CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: OCCOCCOCCOCCO
Reactant: CCCCCBr
Agent: N#N
Agent: [Na+]
Agent: [OH-]
Product: CCCCCOCCOCCOCCOCCO
Temperature: 60 °C

Procedure:
Tetraethyleneglycol (1087 g, 5.60 mol) was heated at 100° C. for 30 min with stirring and vigorous N2 bubbling, then cooled to 60° C. A 50% NaOH solution (61.6 g, 0.77 mol) was added and the resulting solution was heated at 100°-105° C. for 30 min with N2 bubbling. The solution was cooled to 60° C., bromopentane (106 g, 0.70 mol) was added, and the reaction was heated at 100°-110° C. for 24 hr. The reaction solution was cooled, added to ice water and extracted twice with methylene chloride. The combined extracts were washed with 10% NaOH, water and brine; dried, and the solvent was removed in vacuo. The product (143 g, 78%) was a pale yellow oil.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:19])=[C:10]([N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[CH:11]=2)[C:6](=[O:20])[C:5]([C:21]([OH:23])=[O:22])=[CH:4]1)[CH3:2].[N:24]([O-])=[O:25].[Na+].O>C(O)(=O)C>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:19])=[C:10]([N:13]3[CH2:18][CH2:17][N:16]([N:24]=[O:25])[CH2:15][CH2:14]3)[CH:11]=2)[C:6](=[O:20])[C:5]([C:21]([OH:23])=[O:22])=[CH:4]1)[CH3:2]
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCNCC3)cc21
Reactant: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCN(N=O)CC3)cc21
Temperature: 25 °C
Yield: 100.5 %

Procedure:
3.2 g (10 millimole) of 1-ethyl-6-fluoro-7-(1-piperazinyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid was dissolved in 30 ml of acetic acid, and 1.4 g (20 millimole) of sodium nitrite was added slowly thereto at room temperature under stirring. After stirring for 30 minutes at room temperature, 50 ml of water was added. The precipitated crystals were collected by filtration, washed successively with water, ethanol and dichloromethane and dried. 3.5 g (quantitative) of 1-ethyl-6-fluoro-7-(4-nitroso-1-piperazinyl)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid was obtained as grayish colorless powders.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][N:14]=2)[C:9](=[O:11])[CH3:10])[CH:5]=[CH:6][CH:7]=1.C([BH-](C(CC)C)C(CC)C)(CC)C.[Li+].Cl>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][N:14]=2)[CH:9]([OH:11])[CH3:10])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)C(Cc1ccc(Cl)cn1)c1cccc(Br)c1
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(O)C(Cc1ccc(Cl)cn1)c1cccc(Br)c1
Temperature: 25 °C

Procedure:
To a solution of 3-(3-bromophenyl)-4-(5-chloro-2-pyridyl)-2-butanone (Step B, 6.7 g, 20 mmol) in 50 mL anhydrous THF at −78° C. was added lithium tri(sec-butyl)borohydride (1.0 M in THF, 30 mL, 30 mmol), and the reaction was allowed to warm to room temperature overnight. The reaction was cooled to 0° C., and was carefully added 2 M hydrochloric acid (50 mL), and the resulting mixture was partitioned between hexane (200 mL) and water (200 mL). The aqueous layer was separated and the organic layer extracted with 2 M hydrochloric acid (2×100 mL). The combined aqueous extracts were neutralized with 5 N aqueous sodium hydroxide (pH>12), and was extracted with EtOAc (2×200 mL). The combined extracts were dried over anhydrous sodium sulfate, filtered, and concentrated to dryness to afford the title compound.