Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[CH2:8][NH:7][CH2:6]2.[O:14]=[C:15]1[C:19]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:18][CH2:17][N:16]1[CH2:32][C:33](O)=[O:34].Cl.C(N=C=NCCCN(C)C)C>ClCCl>[O:34]=[C:33]([N:7]1[CH2:6][C:5]2[C:9](=[CH:10][CH:11]=[C:3]([C:2]([F:1])([F:12])[F:13])[CH:4]=2)[CH2:8]1)[CH2:32][N:16]1[CH2:17][CH2:18][C:19]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:15]1=[O:14]
Reactant: O=C(O)CN1CCC(c2ccccc2)(c2ccccc2)C1=O
Reactant: FC(F)(F)c1ccc2c(c1)CNC2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: O=C(CN1CCC(c2ccccc2)(c2ccccc2)C1=O)N1Cc2ccc(C(F)(F)F)cc2C1
Reaction time: 8 h

Procedure:
A solution of 5-(trifluoromethyl)isoindoline (0.035 g, 0.186 mmol), 2-(2-oxo-3,3-diphenylpyrrolidin-1-yl)acetic acid (0.050 g, 0.169 mmol) and N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (0.049 g, 0.254 mmol) in dichloromethane (0.5 mL) was stirred at room temperature. After stirring overnight, the reaction was loaded directly onto a SF15-12 silica gel column (Analogix®, Burlington, Wis.), and the title compound was eluted using a gradient of 5% to 100% ethyl acetate/hexanes over 20 minutes (flow=30 mL/minute). 1H NMR (300 MHz, CDCl3) δ ppm 7.54-7.61 (m, 1H), 7.20-7.49 (m, 12H), 4.82-4.88 (m, 4H), 4.24 (s, 2H), 3.61 (td, J=6.5, 1.6 Hz, 2H), 2.85 (t, J=6.6 Hz, 2H); MS (ESI+) m/z 465 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([OH:10])[CH2:7][C@H:6]1[C:11](=[O:24])[NH:12][C@H:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:14][CH2:15][CH3:16])=[O:4].[C:25]1([C:31]2[CH:40]=[C:39](O)[C:38]3[C:33](=[CH:34][C:35]([O:42][CH3:43])=[CH:36][CH:37]=3)[N:32]=2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@H:8]([O:10][C:39]2[C:38]3[C:33](=[CH:34][C:35]([O:42][CH3:43])=[CH:36][CH:37]=3)[N:32]=[C:31]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:40]=2)[CH2:7][C@H:6]1[C:11](=[O:24])[NH:12][C@H:13]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:14][CH2:15][CH3:16])=[O:4]
Reactant: CCC[C@H](NC(=O)[C@@H]1C[C@H](O)C[C@H]1C(=O)OC)C(=O)OC(C)(C)C
Reactant: COc1ccc2c(O)cc(-c3ccccc3)nc2c1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCC[C@H](NC(=O)[C@@H]1C[C@@H](Oc2cc(-c3ccccc3)nc3cc(OC)ccc23)C[C@H]1C(=O)OC)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.5 %

Procedure:
Compound 42 (249 mg, 0.725 mmol), 2-phenyl-7-methoxy-4-quinolinol (310 mg, 1.23 mmol) and PPh3 (580 mg, 2.21 mmol) were dissolved in dry THF and the temperature was lowered to 0° C. DIAD (435 uL. 2.21 mmol) dissolved in 2 mL dry THF, was added to the mixture during five minutes. After two hours the temperature was raised to room temperature and the solution was stirred overnight. Evaporation and purification by flash column chromatography (toluene/EtOAc gradient 6:1 to 4:1) gave 43 (324 mg, 78%).
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[F:14])=[CH:6][N:7]=1.O.[NH2:16][NH2:17]>N1C=CC=CC=1>[F:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[C:5]1[N:4]=[N:3][C:2]([NH:16][NH2:17])=[N:7][CH:6]=1
Reactant: NN
Reactant: Fc1ccccc1-c1cnc(Cl)nn1
Solvent: c1ccncc1
Solvent: O
Product: NNc1ncc(-c2ccccc2F)nn1
Temperature: 60 °C

Procedure:
A 17.9 g. portion of 3-chloro-6-(o-fluorophenyl)-1,2,4-triazine is dissolved in 120 ml. of pyridine and cooled in an ice bath. An 8.5 g. portion of hydrazine hydrate is added and the mixture is heated at 60° C. for one hour and then cooled, poured into ice water and filtered giving 6-(o-fluorophenyl)-3-hydrazino-1,2,4-triazine as yellow plates.
Reaction SMILES: [NH2:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][NH:7][C:8](=[O:24])[C:9]2[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:10]=2[NH:18][CH:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:34](Cl)(=[O:36])[CH3:35]>ClCCl>[C:34]([NH:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][NH:7][C:8](=[O:24])[C:9]2[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:10]=2[NH:18][CH:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)=[CH:4][CH:3]=1)(=[O:36])[CH3:35]
Reactant: Nc1ccc(CNC(=O)c2cc([N+](=O)[O-])ccc2NC2CCCC2)cc1
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Nc1ccc(CNC(=O)c2cc([N+](=O)[O-])ccc2NC2CCCC2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.8 %

Procedure:
To a mixture of N-(4-aminobenzyl)-2-(cyclopentylamino)-5-nitrobenzamide (126 mg) and triethylamine (0.119 mL) in anhydrous dichloromethane (20 mL) was added acetyl chloride (33.5 mg). After stirring for 2 hours at ambient temperature, the mixture was washed with an aqueous saturated sodium bicarbonate solution, water and brine. The resultant was dried over magnesium sulfate and evaporated in vacuo. The residue was purified by a silica gel column chromatography eluting with 10% methanol in chloroform. The obtained product was triturated with diisopropyl ether to give N-(4-acetamidobenzyl)-2-(cyclopentylamino)-5-nitrobenzamide as yellow powders (135 mg).
Reaction SMILES: [CH3:1][N:2]=[C:3]=[S:4].[F:5][C:6]1[CH:7]=[CH:8][C:9]([O:33][CH3:34])=[C:10]([CH:32]=1)[C:11]([NH:13][CH:14]1[CH2:23][C:22]2[C:17](=[CH:18][C:19]([O:28][CH3:29])=[C:20]([S:24](=[O:27])(=[O:26])[NH2:25])[CH:21]=2)[O:16][C:15]1([CH3:31])[CH3:30])=[O:12].C(=O)([O-])[O-].[K+].[K+].C>CS(C)=O>[F:5][C:6]1[CH:7]=[CH:8][C:9]([O:33][CH3:34])=[C:10]([CH:32]=1)[C:11]([NH:13][CH:14]1[CH2:23][C:22]2[C:17](=[CH:18][C:19]([O:28][CH3:29])=[C:20]([S:24]([NH:25][C:3]([NH:2][CH3:1])=[S:4])(=[O:27])=[O:26])[CH:21]=2)[O:16][C:15]1([CH3:31])[CH3:30])=[O:12]
Reactant: CN=C=S
Reactant: COc1ccc(F)cc1C(=O)NC1Cc2cc(S(N)(=O)=O)c(OC)cc2OC1(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CNC(=S)NS(=O)(=O)c1cc2c(cc1OC)OC(C)(C)C(NC(=O)c1cc(F)ccc1OC)C2
Temperature: 80 °C
Reaction time: 0.42 h

Procedure:
0.26 g (3.5 mmol) of methyl isothiocyanate was added to a suspension of 1.1 g (2.5 mmol) of 3-(5-fluoro-2-methoxybenzamido)-2,2-dimethyl-7-methoxy-6-sulfamoyl-chroman and 1.04 g (7.5 mmol) of finely powdered potassium carbonate in 10 ml of DMSO. After the mixture had been stirred at 80° C. for 25 minutes, it was cooled, introduced into ice/water, clarified with charcoal and acidified to pH 1. The precipitate was filtered off with suction and recrystallized from ethanol/DMF. The product had a melting point of 222° C.
Reaction SMILES: C([O:5]O)(C)(C)C.[Cl:7][C:8]1[CH:9]=[C:10]([CH:15]=[CH:16][C:17]=1[Cl:18])[CH:11]=[CH:12][CH2:13][OH:14]>C(Cl)Cl>[Cl:7][C:8]1[CH:9]=[C:10]([C@@H:11]2[O:5][C@H:12]2[CH2:13][OH:14])[CH:15]=[CH:16][C:17]=1[Cl:18]
Reactant: CC(C)(C)OO
Reactant: OCC=Cc1ccc(Cl)c(Cl)c1
Solvent: ClCCl
Product: OC[C@@H]1O[C@H]1c1ccc(Cl)c(Cl)c1
Temperature: -20 °C
Reaction time: 1 h
Yield: 65.3 %

Procedure:
To a suspension of powdered 4 Å molecular sieves (3.2 g) in DCM (144 mL) was added Ti(O-iPr)4 (0.864 mL, 2.93 mmol), (+)-L-diisopropyl tartrate (0.924 mL, 4.39 mmol), and t-BuOOH (5.5 M in decane, 10.8 mL, 59.4 mmol). The mixture was cooled to −20° C. stirred for 1 h. A solution of 3,4-dichlorocinnamyl alcohol (6.0 g, 29.5 mmol) in DCM (30 mL) was added via cannula. After 18 h at −20° C., the reaction was quenched by addition of 10% aq. NaOH and brine (10%, 4 mL). The cooling bath was removed, and after stirring for 20 min, Et2O (30 mL) was added followed by MgSO4 (8 g) and diatomaceous earth (8 g). The mixture was stirred rapidly for 15 min then was filtered through a pad of diatomaceous earth, washing with excess Et2O. The filtrate was concentrated, and the desired epoxide was crystallized from the yellow residue with a warm DCM/hexanes mixture to afford 4.22 g (65%) of pale yellow crystals. The epoxide was determined to be >95% ee by 1H NMR analysis of both the R- and S-Mosher ester derivatives. 1H NMR (400 MHz, CDCl3): 7.42 (d, J=8.3, 1H), 7.37 (d, J=2.0, 1H), 7.13 (dd, J=8.3, 2.0, 1H), 4.04 (dd, J=12.9, 2.2, 1H), 3.91 (d, J=2.0, 1H), 3.82 (dd, J=12.9, 3.4, 1H), 3.18-3.11 (m, 1H), 1.80 (br s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[O:4][C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[C:7]([F:12])[C:6]=1[F:13].[N+:15]([O-])([OH:17])=[O:16]>S(=O)(=O)(O)O>[CH3:1][O:2][C:3](=[O:14])[O:4][C:5]1[CH:10]=[C:9]([N+:15]([O-:17])=[O:16])[C:8]([CH3:11])=[C:7]([F:12])[C:6]=1[F:13]
Reactant: O=[N+]([O-])O
Reactant: COC(=O)Oc1ccc(C)c(F)c1F
Agent: O=S(=O)(O)O
Product: COC(=O)Oc1cc([N+](=O)[O-])c(C)c(F)c1F
Temperature: 0 °C
Reaction time: 1 h
Yield: 49 %

Procedure:
To a suspension of carbonic acid 2,3-difluoro-4-methyl-phenyl ester methyl ester (3.85 g, 19.04 mmol) in sulfuric acid (2.23 ml) at 0° C. was added nitric acid (2.23 ml). The mixture was stirred at 0° C. for one hour. Ice-water was added and the mixture was extracted with dichloromethane. The combined extracts were washed with water and brine, dried over MgSO4, filtered and concentrated to dryness under reduced pressure. Purification of the crude product by flash chromatography (hexanes:EtOAc 95:5) gave 2.3 g (49%) of carbonic acid 2,3-difluoro-4-methyl-5-nitro-phenyl ester methyl ester a clear oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]([CH2:7][NH:8]C=O)=[CH:5][C:4]=1[C:13]([F:16])([F:15])[F:14].[ClH:17].C(OCC)C>C(O)C>[ClH:17].[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]([CH2:7][NH2:8])=[CH:5][C:4]=1[C:13]([F:14])([F:15])[F:16]
Reactant: COc1ccc(CNC=O)cc1C(F)(F)F
Agent: Cl
Solvent: CCOCC
Solvent: CCO
Product: COc1ccc(CN)cc1C(F)(F)F

Procedure:
3.8 g of N-[4-methoxy-3-(trifluoromethyl)benzyl]formamide was dissolved in 20 ml ethanol, 2 ml conc. hydrochloric acid was added thereto, and the mixture was heated under reflux for 3 hr. After cooling, diethyl ether was added thereto, and the resulting crystals were collected by filtration to give 2.5 g of 4-methoxy-3-(trifluoromethyl)benzylamine hydrochloride.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.C(=O)(O)[O-].[Na+].[C:21](Cl)(Cl)=[S:22]>C(Cl)(Cl)Cl.O>[N:15]([C:12]1[CH:13]=[CH:14][C:9]([O:8][CH2:7][CH2:6][N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)=[CH:10][CH:11]=1)=[C:21]=[S:22]
Reactant: Nc1ccc(OCCn2ccnc2)cc1
Reactant: S=C(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: S=C=Nc1ccc(OCCn2ccnc2)cc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 116.8 %

Procedure:
To an ice-cooled stirred biphasic solution of 4-[2-(1H-imidazol-1-yl)ethoxy]benzenamine (1.00 g; 4.92 mmol) and sodium bicarbonate (2.07 g; 24.6 mmol) in chloroform (100 mL) and water (50 mL) was added a solution of thiophosgene (452 μL; 5.90 mmol) in chloroform (10 mL) over 5 min. The mixture was stirred at ice-bath temperature for 20 min, and then the aqueous and organic phases were separated and the aqueous phase extracted with chloroform (50 mL). The combined chloroform layers were washed with brine, then dried over magnesium sulfate and concentrated under reduced pressure to give 1-[2-(4-isothiocyanatophenoxy)ethyl]-1H-imidazole (1.41 g) as a yellow oil.
Reaction SMILES: [C:1]([O:7][CH2:8]Cl)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[CH3:10][N:11]1[CH:15]=[CH:14][N:13]=[C:12]1[SH:16].Cl>C1COCC1>[CH3:10][N:11]1[CH:15]=[CH:14][N:13]=[C:12]1[S:16][CH2:8][O:7][C:1](=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(C)(C)C(=O)OCCl
Reactant: Cn1ccnc1S
Agent: Cl
Solvent: C1CCOC1
Product: Cn1ccnc1SCOC(=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 81 %

Procedure:
To 1.53 g (0.01 mole) of pivalyloxymethyl chloride dissolved in 30 ml of THF was added 1.14 g (0.01 mole) of 1-methyl-2-mercaptoimidazole. The clear yellow solution that resulted was stirred at room temperature overnight. The solution was concentrated to give a glass which was triturated twice with 100 ml of ether. The suspension was filtered and the residue was dried to give 1.85 g (mp 128°-132°, 67% yield) of the desired product as its hydrochloride. IR (KBr) 2800-2200 cm-1 ; (broad, s) (N+H), 1730 cm-1 (s) (C=O) and 1870 and 1820 cm-1 ; 1H NMR (CDCl3) δ7.60 (broad s, 2, N--CH=CH--N), 5.85 (s, 2, CO2CH2S), 3.57 (s, 3, N--CH3) and 1.18 (s, 9, (CH3)3C).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:5]=[C:4]([NH:14][C:15]2[CH:19]=[C:18]([CH:20]3[CH2:22][CH2:21]3)[NH:17][N:16]=2)[N:3]=1.[CH3:23][O:24][C@@H:25]1[CH2:29][NH:28][C@H:27]([C:30]([OH:32])=[O:31])[CH2:26]1>>[CH:20]1([C:18]2[NH:17][N:16]=[C:15]([NH:14][C:4]3[N:5]=[C:6]([N:8]4[CH2:13][CH2:12][O:11][CH2:10][CH2:9]4)[N:7]=[C:2]([N:28]4[CH2:29][C@@H:25]([O:24][CH3:23])[CH2:26][C@H:27]4[C:30]([OH:32])=[O:31])[N:3]=3)[CH:19]=2)[CH2:22][CH2:21]1
Reactant: Clc1nc(Nc2cc(C3CC3)[nH]n2)nc(N2CCOCC2)n1
Reactant: CO[C@@H]1CN[C@H](C(=O)O)C1
Product: CO[C@H]1C[C@@H](C(=O)O)N(c2nc(Nc3cc(C4CC4)[nH]n3)nc(N3CCOCC3)n2)C1

Procedure:
Compound 112B was prepared from 112A and (2S,4S)-4-methoxypyrrolidine-2-carboxylic acid as described for 1. LC/MS [M+H]+: 431; Ret time (Method F): 2.27 min.
Reaction SMILES: [Mn]([O-])(=O)(=O)=O.[K+].C[C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][C:9]=1[S:17]([OH:20])(=[O:19])=[O:18].[C:21](=O)([O-:23])[O-:22].[K+].[K+]>O>[C:21]([C:10]1[C:11]([N+:14]([O-:16])=[O:15])=[CH:12][CH:13]=[CH:8][C:9]=1[S:17]([OH:20])(=[O:18])=[O:19])([OH:23])=[O:22]
Reactant: Cc1ccc([N+](=O)[O-])cc1S(=O)(=O)O
Reactant: O=C([O-])[O-]
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: O
Product: O=C(O)c1c([N+](=O)[O-])cccc1S(=O)(=O)O

Procedure:
400.0 g (2.53 mol) of potassium permanganate are added in portions at 80° C. over a period of 2 h to a solution of 106.0 g (0.40 mol) of 2-methyl-5-nitrobenzenesulfonic acid and 80.0 g (0.58 mol) of potassium carbonate in 1300 ml of water. The reaction temperature is maintained at between 80° and 95° C.
Reaction SMILES: C([O:4][CH:5]1[C:14]2[N:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH2:8][CH2:7][CH2:6]1)(=O)C.C([O-])([O-])=O.[K+].[K+].O>CO>[OH:4][CH:5]1[C:14]2[N:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH2:8][CH2:7][CH2:6]1
Reactant: CC(=O)OC1CCCc2cccnc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: OC1CCCc2cccnc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.5 %

Procedure:
To a solution of 8-acetoxy-5,6,7,8-tetrahydroquinoline (99.2 g) in methanol (450 mL) was added K2CO3 (144 g, 1.04 mol) and the mixture was stirred at room temperature overnight. The mixture was poured into water (500 mL) and extracted with CHCl3(3×500 mL) and the combined organic extracts were dried (Na2SO4), and concentrated to provide 71.6 g of 8-hydroxy-5,6,7,8-tetrahydroquinoline as a brown oil. A purified sample (silica gel, 25:1 CH2Cl2—CH3OH) exhibited the following spectral properties: 1H NMR (CDCl3) δ 1.75-1.89 (m, 2H), 1.96-2.06 (m, 1H), 2.25-2.33 (m, 1H), 2.74-2.90 (m, 2H), 4.23 (br s, 1H, OH), 4.72 (dd, 1H, J=7.8, 6.3 Hz), 7.12 (dd, 1H, J=7.5, 4.8 Hz), 7.41 (d, 1H, J=7.5 Hz), 8.41 (d, 1H, J=4.8 Hz); 13C NMR (CDCl3) δ 19.66, 28.84, 31.27, 68.87, 122.74, 132.19, 137.40, 147.06, 158.50. ES-MS m/z 150 (M+H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([N:11]([CH3:13])[CH3:12])=[O:10])=[CH:4][CH:3]=1.CC1C=CC(S(O[CH2:25][CH2:26][CH2:27][NH:28][C:29]2[C:30](=[O:46])[N:31]([C:42]([CH3:45])([CH3:44])[CH3:43])[S:32](=[O:41])(=[O:40])[C:33]=2[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)(=O)=O)=CC=1>>[C:42]([N:31]1[C:30](=[O:46])[C:29]([NH:28][CH2:27][CH2:26][CH2:25][O:1][C:2]2[CH:3]=[CH:4][C:5]([CH2:8][C:9]([N:11]([CH3:12])[CH3:13])=[O:10])=[CH:6][CH:7]=2)=[C:33]([C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[S:32]1(=[O:40])=[O:41])([CH3:43])([CH3:44])[CH3:45]
Reactant: Cc1ccc(S(=O)(=O)OCCCNC2=C(c3ccccc3)S(=O)(=O)N(C(C)(C)C)C2=O)cc1
Reactant: CN(C)C(=O)Cc1ccc(O)cc1
Product: CN(C)C(=O)Cc1ccc(OCCCNC2=C(c3ccccc3)S(=O)(=O)N(C(C)(C)C)C2=O)cc1
Yield: 59 %

Procedure:
The title compound was prepared as described for Example 12 from 2-(4-hydroxyphenyl)-N,N-dimethylacetamide and 3-[(2-tert-butyl-1,1-dioxido-3-oxo-5-phenyl-2,3-dihydroisothiazol-4-yl)amino]propyl 4-methylbenzenesulfonate. The reaction mixture was evaporated, purified twice by silica gel column chromatography (Horizons Biotage) using 75-85% EtOAc in petroleum ether 40-60° C. and then 50% DCM in EtOAc as eluent to give the title compound (0.072 g, 59%). 1H NMR (500 MHz CDCl3): δ 7.54-7.49 (m, 2H), 7.46-7.42 (m, 3H), 7.18 (d, 2H), 6.82 (d, 2H), 5.76 (t, 1H), 3.87 (t, 2H), 3.66 (s, 2H), 3.08 (m, 2H), 3.01 (s, 3H), 2.98 (s, 3H), 1.83 (m, 2H), 1.74 (s, 9H); 13C NMR (CDCl3): δ 171.5, 159.8, 157.4, 135.3, 131.8, 130.1, 129.7, 128.8, 127.8, 125.3, 114.8, 107.1, 66.1, 61.7, 42.5, 40.3, 37.9, 35.9, 28.9, 27.8; Mass Spectrum M+H+ 500.
Reaction SMILES: Br[CH2:2][C:3]1[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:22])([F:21])[F:20])=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[Cl:23])[N:4]=1.CN(C=O)C.[N-:29]=[N+:30]=[N-:31].[Na+]>>[N:29]([CH2:2][C:3]1[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:22])([F:21])[F:20])=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[Cl:23])[N:4]=1)=[N+:30]=[N-:31]
Reactant: FC(F)(F)c1ccccc1-c1nc2c(Cl)cccc2nc1CBr
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCc1nc2cccc(Cl)c2nc1-c1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirring solution of 2-(bromomethyl)-5-chloro-3-(2-(trifluoromethyl)phenyl)-quinoxaline (0.7173 g, 1.786 mmol) in DMF (8.930 mL, 1.786 mmol) was added sodium azide (0.2322 g, 3.572 mmol) at room temperature and the mixture was stirred at room temperature. After 30 min, the mixture was partitioned between EtOAc (100 mL) and H2O (100 mL). The organic layer was washed with brine (50 mL×1), dried over Na2SO4, filtered, and concentrated under reduced pressure to give bluish-brown syrup. The bluish-brown syrup was purified by silica gel column chromatography on a 40 g of Redi-Sep™ column using 0 to 50% gradient of EtOAc in hexane over 14 min, then 50% isocratic of EtOAc for 5 min as eluent to give 2-(azidomethyl)-5-chloro-3-(2-(trifluoromethyl)phenyl)quinoxaline: 1H NMR (400 MHz, DMSO-d6) δ ppm 8.20 (1H, dd, J=8.6, 1.2 Hz), 8.10-8.14 (1H, m), 7.99 (1H, d, J=7.8 Hz), 7.95 (1H, dd, J=8.4, 7.6 Hz), 7.79-7.91 (3H, m), 4.41-4.67 (2H, m); LC-MS (ESI) major peak of m/z 364.0 [M+H]+. The crude product was carried on crude without purification for the next step. To a solution of 2-(azidomethyl)-5-chloro-3-(2-(trifluoromethyl)phenyl)-quinoxaline (0.5736 g, 1.58 mmol) in methanol (17.500 mL, 1.58 mmol) was added palladium, 10 wt. % on activated carbon (0.0839 g, 0.0789 mmol). After repeating three times of evacuation of air in the flask by house vacuum and filling the flask with H2, the mixture was stirred under H2. After 45 min, the mixture was filtered through a pad of Celite™ and rinsed the pad with MeOH. The filtrate was concentrated under reduced pressure to give blue syrup. The blue syrup was purified by column chromatography on a 80 g of Redi-Sep™ column using 0 to 12% gradient of CH2Cl2:MeOH:NH4OH (89:9:1) in CH2Cl2 over 3 min, 12% isocratic of CH2Cl2:MeOH:NH4OH (89:9:1) in CH2Cl2 for 4 min, 12% to 100% gradient of CH2Cl2:MeOH:NH4OH (89:9:1) in CH2Cl2 over 22 min as eluent to give (5-chloro-3-(2-(trifluoromethyl)phenyl)quinoxalin-2-yl)methanamine as a blue syrupy solid: 1H NMR (500 MHz, DMSO-d6) δ ppm 8.15 (1H, dd, J=8.6, 1.2 Hz), 8.04 (1H, dd, J=7.6, 1.2 Hz), 7.97 (1H, d, J=7.6 Hz), 7.74-7.92 (4H, m), 3.62-3.91 (2H, m), 1.98 (2H, br. s.); LC-MS (ESI) m/z 338.0 [M+H]+.
Reaction SMILES: [NH2:1]C(N)=S.[C:5]([NH:13][C:14](=[O:16])[O-])(=[O:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>C(N(CC)CC)C>[C:14]([NH:13][C:5](=[O:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)(=[O:16])[NH2:1]
Reactant: NC(N)=S
Reactant: O=C([O-])NC(=O)c1ccccc1
Solvent: CCN(CC)CC
Product: NC(=O)NC(=O)c1ccccc1
Reaction time: 2 h

Procedure:
In Scheme 3, step L, substep 1, the fluorinated primary alcohol (prepared in Scheme 1, step H) is deprotected under standard conditions followed by neutralization, thiourea formation and cyclization in substeps 2a and 2b to provide the protected bicyclic aminooxazine. For example, in substep 1, the fluorinated primary alcohol is dissolved in a suitable organic solvent, such as ethyl acetate or dichloromethane and treated with an excess of a suitable acid such as hydrochloric acid (4 M in 1,4-dioxane) or trifluoroacetic acid. The reaction is stirred at room temperature for about 2 hours to overnight. The deprotected amine is then isolated with techniques well known in the art such as filtration as a salt. Alternatively for substep 1, ethanol is added drop wise to a solution of excess acetyl chloride in ethyl acetate at about 0° C. and stirring for about 30 minutes. The fluorinated primary alcohol, (Scheme 1, step H) is added and the reaction is stirred overnight at room temperature. The deprotected amine salt is then isolated with techniques well known in the art such as filtration. Then, for the neutralization and thiourea formation for substep 2a, the deprotected amine salt is dissolved in a suitable organic solvent, such as acetonitrile or tetrahydrofuran and treated with about 1.1 equivalents of a suitable organic amine, such as triethylamine to neutralize the amine, and about 1.05 equivalents of benzoyl isothiocyanate is added to form the intermediate thiourea. The reaction is then stirred at 5° C. for about 1 hour or heated to about 70° for 2 hours. To cyclize and form the protected bicyclic aminooxazine in substep 2b, about 1.1 equivalents of trimethylsilyl chloride and DMSO are added and stirring is continued for about 2 hours. The reaction is quenched with potassium phosphate dibasic (20%) to adjust the pH to 7-8 and the product is isolated using techniques well known in the art to give the protected bicyclic aminooxazine product of step L. Alternatively, the amine salt can be neutralized with triethylamine as described above for step L, step 2a, and treated with benzoylcarbamate to form an N-carbamoyl benzamide intermediated that is then cyclized with diethylaminosulfur trifluoride in an organic solvent such as dichloromethane at about −78° C. and warmed to about room temperature over 1 hour. The product is isolated using techniques well known in the art to give the protected bicyclic aminooxazine product of step L.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[CH3:11][C@H:12]1[CH2:17][O:16][CH2:15][CH2:14][NH:13]1>CO>[CH3:11][C@H:12]1[CH2:17][O:16][CH2:15][CH2:14][N:13]1[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1
Reactant: C[C@H]1COCCN1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Solvent: CO
Product: C[C@H]1COCCN1c1ccc([N+](=O)[O-])cn1
Temperature: 150 °C
Yield: 97.9 %

Procedure:
A mixture of 1 g (6.18 mmol) of 2-chloro-5-nitropyridine and 1.31 g (12.36 mmol) of (S)-3-methylmorpholine is heated in a Biotage microwave machine for 1 hour at 150° C. The reaction medium is taken up in MeOH and then evaporated under reduced pressure. The residue is chromatographed on silica gel, eluting with a DCM/MeOH mixture from (100/0 v/v) up to (95/5 v/v) to give 1.35 g of (S)-3-methyl-4-(5-nitropyridin-2-yl)morpholine.