Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:12][CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([Br:13])[CH:9]=2)[C:4]1=[O:14].C(N(C(C)C)CC)(C)C.[C:24](Cl)(=[O:30])[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]>ClCCl>[Br:13][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[C:4](=[O:14])[CH:3]([NH:2][C:24](=[O:30])[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])[CH2:12][CH2:11]2
Reactant: CCCCCC(=O)Cl
Reactant: NC1CCc2cc(Br)ccc2C1=O
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCCCC(=O)NC1CCc2cc(Br)ccc2C1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 89.2 %

Procedure:
To 2-amino-6-bromo-3,4-dihydronaphthalen-1(2H)-one hydrochloride (Preparation 82B, 1.1 g, 3.98 mmol) in dichloromethane (5 mL) was added diisopropylethylamine (1.737 mL, 9.94 mmol) at 0° C. under a nitrogen atmosphere. To the homogenous solution was added hexanoyl chloride (0.602 mL, 4.38 mmol) dropwise over a period of 3 min. The reaction mixture was allowed to come to room temperature (˜5 min.) and was stirred at room temperature for 3 h. The reaction mixture was partitioned between dichloromethane (30 mL) and 1N HCl (10 mL). The dichloromethane layer was separated, washed with sat. aq. NaHCO3 (20 mL), dried over sodium sulfate and concentrated to yield N-(6-bromo-1-oxo-1,2,3,4-tetrahydronaphthalen-2-yl)hexanamide (1.2 g, 3.55 mmol, 89% yield) as an off-white solid. LC/MS M+1 339.
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:17]([CH3:18])[C:16]([C:19]34[CH2:26][CH2:25][C:22]([CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])([CH2:23][CH2:24]3)[CH2:21][CH2:20]4)=[N:15][N:14]=2)=[C:9]([CH3:32])[CH:8]=1>C(Cl)Cl>[CH3:32][C:9]1[CH:8]=[C:7]([OH:6])[CH:12]=[CH:11][C:10]=1[C:13]1[N:17]([CH3:18])[C:16]([C:19]23[CH2:24][CH2:23][C:22]([CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])([CH2:25][CH2:26]2)[CH2:21][CH2:20]3)=[N:15][N:14]=1
Reactant: CCCCCC12CCC(c3nnc(-c4ccc(OC)cc4C)n3C)(CC1)CC2
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCCCCC12CCC(c3nnc(-c4ccc(O)cc4C)n3C)(CC1)CC2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Boron tribromide (1M/CH2Cl2, 3.21 mL, 3.21 mmol) was added to a solution of 3-(4-methoxy-2-methylphenyl)-4-methyl-5-(4-pentylbicyclo[2.2.2]oct-1-yl)-4H-1,2,4-triazole (2-F) (410 mg, 1.07 mmol) in methylene chloride (6 mL) at 0° C. The mixture was stirred at room temperature for 2 h. The solution was washed with water, 10% NaHCO3, dried (MgSO4) and concentrated in vacuo. The residue was purified by preparative TLC (silica gel, MeOH:methylene chloride, 5:95) to provide 3-methyl-4-[4-methyl-5-(4-pentylbicyclo[2.2.2]oct-1-yl)-4H-1,2,4-triazol-3-yl]phenol (2-G). Mass spectrum: 393 (M+1); 1H NMR (500 MHz, CDCl3): δ 0.93 (t, 3H); 1.27 (m, 8H); 1.56 (m, 6H); 1.97 (s 3H); 2.12 (m, 6H); 3.50 (s, 3H); 6.65 (m, 2H); 6.98 (d, 1H) ppm.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][NH:8]2)=[C:4]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[N:3]=1.[CH3:17]I>>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH3:17])=[C:4]([N:11]2[CH2:12][CH2:13][O:14][CH2:15][CH2:16]2)[N:3]=1
Reactant: Clc1nc(N2CCOCC2)c2nc[nH]c2n1
Reactant: CI
Product: Cn1cnc2c(N3CCOCC3)nc(Cl)nc21

Procedure:
4-(2-Chloro-9H-purin-6-yl)morpholine (510 mg) was reacted with methyl iodide via General Procedure C to give 4-(2-chloro-9-methyl-9H-purin-6-yl)morpholine. 4-(2-Chloro-9-methyl-9H-purin-6-yl)morpholine (100 mg) was cooled in 1.5 mL of anhydrous THF to −78° C. before adding 2 eq of a 2.5 M solution of n-butyl lithium. The reaction was stirred for 1 hour at −78° C. upon which 3 eq of DMF were added. The reaction was subsequently warmed to 0° C. after 30 minutes. The reaction was quenched into a cold 0.25 M aqueous solution of HCl and the orange solid was filtered, collected and dried to give 48 mg crude intermediate 2-chloro-9-methyl-6-morpholino-9H-purine-8-carbaldehyde.
Reaction SMILES: [CH2:1]([N:8](C)[C:9]1[CH:10]=[C:11]([CH:21]=[CH:22][CH:23]=1)[CH2:12][NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])C1C=CC=CC=1>CCO.[OH-].[OH-].[Pd+2]>[CH3:1][NH:8][C:9]1[CH:10]=[C:11]([CH:21]=[CH:22][CH:23]=1)[CH2:12][NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:17])[CH3:18]
Reactant: CN(Cc1ccccc1)c1cccc(CNC(=O)OC(C)(C)C)c1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CNc1cccc(CNC(=O)OC(C)(C)C)c1
Reaction time: 8 h

Procedure:
20% Pd(OH)2 0.076 g) was added to a stirred suspension of tert-butyl 3-(benzyl(methyl)amino)benzylcarbamate (0.248 g, 0.76 mmol, 1 eq) in 10 ml EtOH. A H2 balloon was added. After stirring overnight the mixture was filtered through Celite. The filter cake was rinsed with EtOAc (×3). The organics were combined and the solvent was removed in vacuo to yield tert-butyl 3-(methylamino)benzylcarbamate.
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH2:16][CH:17]([CH3:19])[CH3:18])[CH3:15])[C:11]([C:20]([F:23])([F:22])[F:21])=[CH:10][C:9]=1[NH2:24])([CH3:4])([CH3:3])[CH3:2].C([O:30][C:31](=O)[CH2:32][C:33](=[O:53])[C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([N:40]2[C:44]([CH2:45][O:46][CH:47]3[CH2:52][CH2:51][CH2:50][CH2:49][O:48]3)=[CH:43][N:42]=[N:41]2)[CH:35]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:25])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH2:16][CH:17]([CH3:19])[CH3:18])[CH3:15])[C:11]([C:20]([F:23])([F:22])[F:21])=[CH:10][C:9]=1[NH:24][C:31](=[O:30])[CH2:32][C:33](=[O:53])[C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([N:40]2[C:44]([CH2:45][O:46][CH:47]3[CH2:52][CH2:51][CH2:50][CH2:49][O:48]3)=[CH:43][N:42]=[N:41]2)[CH:35]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-n2nncc2COC2CCCCO2)c1
Reactant: CC(C)CN(C)c1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Product: CC(C)CN(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-n3nncc3COC3CCCCO3)c2)cc1C(F)(F)F

Procedure:
The title compound was prepared from [2-amino-5-(isobutyl-methyl-amino)-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example J36) (370 mg, 1.02 mmol) and (RS)-3-oxo-3-{3-[5-(tetrahydro-pyran-2-yloxymethyl)-[1,2,3]triazol-1-yl]-phenyl}-propionic acid tert-butyl ester (Example K5) (411 mg, 1.02 mmol) according to the general procedure M. Obtained as a light brown foam (520 mg, 74%).
Reaction SMILES: [F:1][C:2]([F:12])([C:8]([F:11])([F:10])[F:9])[CH2:3][CH2:4][C:5]([OH:7])=O.Cl.[Cl:14][C:15]1[CH:16]=[CH:17][C:18]([CH2:21][NH2:22])=[N:19][CH:20]=1.C(Cl)CCl.CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:14][C:15]1[CH:16]=[CH:17][C:18]([CH2:21][NH:22][C:5](=[O:7])[CH2:4][CH2:3][C:2]([F:1])([F:12])[C:8]([F:11])([F:10])[F:9])=[N:19][CH:20]=1
Reactant: NCc1ccc(Cl)cn1
Reactant: O=C(O)CCC(F)(F)C(F)(F)F
Agent: Cl
Solvent: ClCCl
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CCC(F)(F)C(F)(F)F)NCc1ccc(Cl)cn1

Procedure:
To a solution of 4,4,5,5,5-pentafluoropentanoic acid (6.44 g, 33.5 mmol) and the intermediate from Step E (5.0 g, 27.9 mmol) in DCM (100 mL) was added EDC (7.49 g, 39.1 mmol) followed by DIEA (24.4 mL, 140 mmol). After stirring the reaction at room temperature for 2 hours, it was diluted with DCM (100 mL), and washed with water (2×). The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give a colorless oil. m/z=316.8 (M+H).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[OH-].[K+].Cl[CH2:14][CH2:15][OH:16].CCOC(C)=O>CS(C)=O>[I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:14][CH2:15][OH:16])[CH:6]=[CH:5]2
Reactant: Ic1ccc2[nH]ccc2c1
Reactant: OCCCl
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: OCCn1ccc2cc(I)ccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Under an N2 atmosphere 30 g (121 mmol) 5-iodoindole are added to a suspension of 27.1 g (484 mmol) KOH in 150 mL DMSO. The reaction mixture is kept for 1 h at RT, cooled to 0° C. with ice water, 9.7 mL (145 mmol) of 2-chloroethanol in 30 mL DMSO are slowly added dropwise and stirred for 4.5 h at RT. The reaction mixture is combined with 1 L EtOAc, washed four times with in each case 800 mL water and once with 400 mL saturated NaCl solution and the organic phase is dried over Na2SO4. After the desiccant and solvent have been eliminated the residue is purified by chromatography (silica gel, cyc/EtOAc 3:1).
Reaction SMILES: [O:1]1CCCC1.S(=O)(=O)(O)O.[OH:11][C:12]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([CH:15]([CH3:17])[CH3:16])[C:13]#[CH:14]>O>[OH:11][C:12]([C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)([CH:15]([CH3:17])[CH3:16])[C:13](=[O:1])[CH3:14]
Reactant: C#CC(O)(c1ccccc1)C(C)C
Reactant: C1CCOC1
Agent: O=S(=O)(O)O
Solvent: O
Product: CC(=O)C(O)(c1ccccc1)C(C)C
Temperature: 60 °C
Reaction time: 0.08 h

Procedure:
To a refluxing mixture of tetrahydrofuran (70 ml), water (5 ml), and conc. sulfuric acid (1.5 g) is added 1 g of red mercuric oxide and the reflux is continued for 5 min. Then, the inside temperature is adjusted to 60°-62° C. and 10 g of 3-hydroxy-4-methyl-3-phenyl-1-pentyne (described in Example 1) is added. The reaction is exothermic (spontaneous mild reflux) and there is a noticeable clearing of the mixture. Another 1 g of mercuric oxide is added, and the solution is refluxed for 30 min. The reaction mixture is stirred at 60° C. for an additional 3 hr, during which time the precipitation of a mercury sludge occurred. After cooling, the slurry is diluted with 100 ml of diethyl ether and filtered through diatomaceous earth. The filter cake is washed with 200 ml of diethyl ether, and the combined filtrates are washed repeatedly with water, dried over magneisum sulfate, filtered, and evaporated to give 10.6 g of the title product, ir (CDCl3) 3470 and 1715-1710 cm-1 and nmr (CDCl3) δ 0.91(d), 2.15(s), 2.79(heptuplet), 4.39(s) and 7.20-7.65(m).
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[C:16]([F:18])[C:15]([N:19]2[C:23](=[O:24])[N:22]([CH3:25])[C:21]([CH:26]([F:28])[F:27])=[N:20]2)=[CH:14][C:3]=1[O:4][CH:5]([CH3:13])[C:6]([O:8]C(C)(C)C)=[O:7].FC(F)(F)C(O)=O>>[Cl:1][C:2]1[CH:17]=[C:16]([F:18])[C:15]([N:19]2[C:23](=[O:24])[N:22]([CH3:25])[C:21]([CH:26]([F:28])[F:27])=[N:20]2)=[CH:14][C:3]=1[O:4][CH:5]([CH3:13])[C:6]([OH:8])=[O:7]
Reactant: CC(Oc1cc(-n2nc(C(F)F)n(C)c2=O)c(F)cc1Cl)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: CC(Oc1cc(-n2nc(C(F)F)n(C)c2=O)c(F)cc1Cl)C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 68.4 %

Procedure:
A mixture of 0.8 g (0.002 mole) of tert-butyl 2-[2-chloro-4-fluoro-5-(3-difluoromethyl-4,5-dihydro-4-methyl-5-oxo-1H-1,2,4-triazol-1-yl)phenoxy]propionate and 59.2 g (0.52 mole) of trifluoroacetic acid was stirred at room temperature for two hours. Most of the trifluoroacetic acid was removed from the mixture by distillation under reduced pressure leaving a residue. This residue was partitioned between methylene chloride and water. The organic phase was dried over anhydrous magnesium sulfate and filtered. The filtrate was evaporated under reduced pressure to yield 0.5 g of 2-[2-chloro-4-fluoro-5-(3-difluoromethyl-4,5-dihydro-4-methyl-5-oxo-1H-1,2,4-triazol-1-yl)phenoxy]propionic acid as an oil.
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:45]([O:47]C)=[O:46])=[CH:12][C:13]=3[N:14]3[CH2:20][CH:19]([N:21]([CH3:40])[CH2:22][CH2:23][N:24]([CH3:39])[CH2:25][CH2:26][CH2:27][S:28](=[O:38])(=[O:37])[NH:29]C(=O)OC(C)(C)C)[CH2:18][C:17]4[CH:41]=[CH:42][CH:43]=[CH:44][C:16]=4[C:15]=23)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[K+].Cl>C(Cl)Cl.C(O)(C(F)(F)F)=O>[NH2:29][S:28]([CH2:27][CH2:26][CH2:25][N:24]([CH3:39])[CH2:23][CH2:22][N:21]([CH3:40])[CH:19]1[CH2:18][C:17]2[CH:41]=[CH:42][CH:43]=[CH:44][C:16]=2[C:15]2=[C:7]([CH:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[C:8]3[CH:9]=[CH:10][C:11]([C:45]([OH:47])=[O:46])=[CH:12][C:13]=3[N:14]2[CH2:20]1)(=[O:38])=[O:37]
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(N(C)CCN(C)CCCS(=O)(=O)NC(=O)OC(C)(C)C)Cc1ccccc1-3
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(CCCS(N)(=O)=O)CCN(C)C1Cc2ccccc2-c2c(C3CCCCC3)c3ccc(C(=O)O)cc3n2C1
Temperature: 65 °C
Reaction time: 4 h

Procedure:
Methyl 13-cyclohexyl-6-[methyl(3,11,11-trimethyl-7,7-dioxido-9-oxo-10-oxa-7-thia-3,8-diazadodec-1-yl)amino]-6,7-dihydro-5H-indolo[2,1-a][2]benzazepine-10-carboxylate was dissolved in DCM/TFA 3:1 (0.03M) and the mixture was left standing at RT. After 45 min all volatiles were evaporated in vacuo. The residue was dissolved in MeOH (0.07M) and 1M aqueous KOH solution (9 eq.) was added. The mixture was stirred at 65° C. for 4h. After cooling to 0° C. the pH of the solution was adjusted with 1 M aqueous HCl to pH 6. The resulting suspension was extracted with EtOAc. The combined organic phases were washed with brine and dried over Na2SO4. All volatiles were evaporated in vacuo. The residual material was used without further purification in the next reaction. (ES+) m/z 567 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[OH:15].C([O-])([O-])=O.[Cs+].[Cs+].CN(C=O)C.F[C:28]1[CH:33]=[CH:32][C:31]([N+:34]([O-:36])=[O:35])=[CH:30][C:29]=1[F:37]>CC#N>[F:37][C:29]1[CH:30]=[C:31]([N+:34]([O-:36])=[O:35])[CH:32]=[CH:33][C:28]=1[O:15][C:6]1[C:5]2[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=2)[N:9]=[CH:8][CH:7]=1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Reactant: COc1cc2nccc(O)c2cc1OC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CC#N
Product: COc1cc2nccc(Oc3ccc([N+](=O)[O-])cc3F)c2cc1OC
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 51.3 %

Procedure:
A solution of 6,7-dimethoxyquinolin-4-ol (50 g, 0.244 mol) and Cs2CO3 (159 g, 0.488 mol) in CH3CN (300 mL)/DMF (300 mL) was stirred at room temperature for 30 min. 1,2-Difluoro-4-nitrobenzene (42.7 g, 0.268 mol) was then added dropwise. After stirring at rt for 3.5 h, the reaction solution was concentrated in vacuo. Ice (500 mL) was added to the residual suspension and the mixture was stirred overnight for precipitation. The solid was collected by filtration and further purified by a silica gel column chromatography (EtOAc) to give the title compound as a pale yellow powder (43.1 g, 51.2%).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([C:14]2[CH:18]=[C:17]([CH3:19])[N:16]([C:20]3[CH:25]=[CH:24][C:23]([Br:26])=[CH:22][C:21]=3[C:27]([F:30])([F:29])[F:28])[C:15]=2[CH3:31])=[O:13])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[F:32][C:33]([F:48])([F:47])[C:34]1[CH:42]=[C:41]([C:43]([F:46])([F:45])[F:44])[CH:40]=[CH:39][C:35]=1[C:36]([NH2:38])=[O:37].C([O-])([O-])=O.[K+].[K+].NCCN.[OH-].[Na+].C(N(CC(O)=O)CC(O)=O)CN(CC(O)=O)CC(O)=O>[Cu]I.C(OCC)(=O)C.C1(C)C=CC=CC=1>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([C:14]2[CH:18]=[C:17]([CH3:19])[N:16]([C:20]3[CH:25]=[CH:24][C:23]([Br:26])=[CH:22][C:21]=3[C:27]([F:29])([F:30])[F:28])[C:15]=2[CH3:31])=[O:13])=[CH:7][CH:6]=1)(=[O:3])=[O:4].[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([C:14]2[CH:18]=[C:17]([CH3:19])[N:16]([C:20]3[CH:25]=[CH:24][C:23]([NH:38][C:36](=[O:37])[C:35]4[CH:39]=[CH:40][C:41]([C:43]([F:45])([F:46])[F:44])=[CH:42][C:34]=4[C:33]([F:32])([F:47])[F:48])=[CH:22][C:21]=3[C:27]([F:30])([F:29])[F:28])[C:15]=2[CH3:31])=[O:13])=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: NC(=O)c1ccc(C(F)(F)F)cc1C(F)(F)F
Agent: [Cu]I
Agent: Cc1cc(C(=O)Nc2ccc(S(C)(=O)=O)cc2)c(C)n1-c1ccc(Br)cc1C(F)(F)F
Agent: O=C(O)CN(CCN(CC(=O)O)CC(=O)O)CC(=O)O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: NCCN
Product: Cc1cc(C(=O)Nc2ccc(S(C)(=O)=O)cc2)c(C)n1-c1ccc(NC(=O)c2ccc(C(F)(F)F)cc2C(F)(F)F)cc1C(F)(F)F
Temperature: 110 °C
Reaction time: 18 h
Yield: 39.9 %

Procedure:
1-[4-Bromo-2-(trifluoromethyl)phenyl]-2,5-dimethyl-1H-pyrrole-3-carboxylic acid [4-(methanesulfonyl)phenyl]-amide was prepared as described in Example 1G. Into an oven-dried 1 dram vial was added 1-[4-Bromo-2-(trifluoromethyl)phenyl]-2,5-dimethyl-1H-pyrrole-3-carboxylic acid [4-(methanesulfonyl)phenyl]-amide (26 mg, 50 μmol), 2,4-Bis(Trifluoromethyl)benzamide (13 mg, μmol) Copper (1) Iodide (50 mg, 260 μmol), K2CO3 (50 mg, 360 μmol), N,N′-Dimethylenediamine (9 mg, 100 μmol), and 0.4 mL of Toluene. The vial was sealed and stirred for 18 h at 110° C. The reaction was worked up by addition of a 1:1 solution of 2.0 M NaOH: 0.5M EDTA (1 ml) and Ethyl Acetate (1 ml). The vial was vortexed and the Ethyl Acetate was removed and dried in Vacuo. The crude material was purified by reverse-phase chromatography (C18 column), eluting with 0.05% TFA in MeCN/H2O (30:70 to 90:10) to yield the title compound (6.9 mg, 10%) as a white solid. 1H-NMR (DMSO-d6): δ11.24 (1H, s), 9.78 (1H, s), 8.28 (1H, d, J=2 Hz), 8.22 (1H, d, J=8 Hz), 8.19 (1H, s), 8.02 (4H, m), 7.76 (2H, d, J=9 Hz), 7.44 (2H, d, J=9 Hz), 6.59 (1H, s), 3.09 (3H, s), 2.10 (3H, s), 1.84 (3H, s); MS (ESI): 692 (MH+).
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[Cl:9][C:10]1[CH:15]=[N:14][CH:13]=[C:12]([Cl:16])[N:11]=1.[C:17](=[O:19])=[O:18]>C1COCC1>[Cl:9][C:10]1[C:15]([C:17]([OH:19])=[O:18])=[N:14][CH:13]=[C:12]([Cl:16])[N:11]=1
Reactant: Clc1cncc(Cl)n1
Reactant: O=C=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(O)c1ncc(Cl)nc1Cl
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 22 %

Procedure:
To a solution of lithium diisopropylamide (2.0 M heptane/tetrahydrofuran/ethylbenzene, 11.10 mL, 22.20 mmol) in THF (75 mL) at −78° C. was added a solution of 2,6-dichloropyrazine (1.44 g, 9.67 mmol) in THF (20 mL) at room temperature over 20 min. The reaction mixture was stirred at −78° C. for 1.5 h and added via cannula to a 3-neck flask containing dry ice at −78° C. The reaction mixture was warmed from −78° C. to room temperature over 21 h and quenched with 5 M HCl. The mixture was partitioned between brine and EtOAc. The aqueous phase was acidified to pH 3.5 with 5 M HCl. The aqueous phase was extracted with EtOAc (6×) and the combined organic extracts were washed with brine (1×), dried over MgSO4, filtered, and concentrated. Purification by flash column chromatography on silica gel (5% to 10% MeOH in DCM) gave 3,5-dichloropyrazine-2-carboxylic acid (0.408 g, 2.11 mmol, 22% yield) as a light brown solid. LC/MS (ESI+) m/z=193.0 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[O:11]C.C(Cl)Cl.B(Br)(Br)Br.OP([O-])(O)=O.[K+]>O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[OH:11]
Reactant: COc1cc([N+](=O)[O-])ccc1Br
Agent: BrB(Br)Br
Agent: O=P([O-])(O)O
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: O=[N+]([O-])c1ccc(Br)c(O)c1
Temperature: -44 °C
Reaction time: 20 h
Yield: 100 %

Procedure:
A mixture of 29.1 g (125.6 mmol) of 2-bromo-5-nitroanisole and 250 mL CH2Cl2 was stirred at −44° C. in a dry ice acetonitrile bath under a nitrogen atmosphere. Boron tribromide (18 mL) was added dropwise to the reaction mixture. The resulting black reaction was stirred while allowing the cooling bath to slowly rise to room temperature over 20 h. TLC analysis indicated complete reaction, so the reaction mixture was transferred to an addition funnel and added cautiously to a mixture of ice, water and 75 g solid KH2PO4. The layers were separated, the aqueous layer was washed with CH2Cl2, the combined organic extracts were washed with brine, dried over anhydrous magnesium sulfate, filtered, concentrated to give 27.4 g (125.6 mmol, 100%) of 2-bromo-5-nitrophenol as a black solid. 1H NMR (400 MHz) CDCl3 7.85 (s, 1H), 7.62-7.70 (m, 2H), 5.88 (s, 1H).
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=[O:9])C=1.[CH2:12]([O:19][C:20]1[CH:29]=[CH:28][C:27]2[N:26]=[CH:25][C:24]3[N:30]=[C:31]([CH2:46][O:47][CH2:48][CH3:49])[N:32]([CH2:33][C:34]([NH:37][C:38]([CH:40]4[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]4)=[O:39])([CH3:36])[CH3:35])[C:23]=3[C:22]=2[CH:21]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(Cl)(Cl)Cl>[CH2:12]([O:19][C:20]1[CH:29]=[CH:28][C:27]2[N+:26]([O-:9])=[CH:25][C:24]3[N:30]=[C:31]([CH2:46][O:47][CH2:48][CH3:49])[N:32]([CH2:33][C:34]([NH:37][C:38]([CH:40]4[CH2:41][CH2:42][CH2:43][CH2:44][CH2:45]4)=[O:39])([CH3:36])[CH3:35])[C:23]=3[C:22]=2[CH:21]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCOCc1nc2cnc3ccc(OCc4ccccc4)cc3c2n1CC(C)(C)NC(=O)C1CCCCC1
Solvent: ClC(Cl)Cl
Product: CCOCc1nc2c[n+]([O-])c3ccc(OCc4ccccc4)cc3c2n1CC(C)(C)NC(=O)C1CCCCC1
Reaction time: 2 h
Yield: 111 %

Procedure:
mCPBA (60% pure, 1.34 g) was added to a solution of N-{2-[8-(benzyloxy)-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]-1,1-dimethylethyl}cyclohexanecarboxamide (2.34 g, 4.55 mmol) in chloroform (100 mL). The reaction was stirred for 2 hours and quenched by adding 50 mL of aqueous 2% sodium carbonate. The layers were separated and the aqueous fraction was extracted with two portions of chloroform. The combined organic fractions were washed with brine, dried over sodium sulfate, filtered, and concentrated to give 2.68 g of crude N-{2-[8-(benzyloxy)-2-(ethoxymethyl)-5-oxido-1H-imidazo[4,5-c]quinolin-1-yl]-1,1-dimethylethyl}cyclohexanecarboxamide as an orange foam.
Reaction SMILES: FC(F)(F)C([N:5]1[CH:10]2[CH2:11][CH2:12][CH:6]1[CH2:7][C:8]1([O:17][C:16]3[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=3[N:14]3[CH:22]=[CH:23][CH:24]=[C:13]13)[CH2:9]2)=O.[OH-].[Na+]>CO>[CH:6]12[NH:5][CH:10]([CH2:11][CH2:12]1)[CH2:9][C:8]1([O:17][C:16]3[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=3[N:14]3[CH:22]=[CH:23][CH:24]=[C:13]13)[CH2:7]2
Reactant: O=C(N1C2CCC1CC1(C2)Oc2ccccc2-n2cccc21)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: c1ccc2c(c1)OC1(CC3CCC(C1)N3)c1cccn1-2
Temperature: 70 °C

Procedure:
To a solution of 2: 2,2,2-trifluoro-1-(8′-azaspiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,3′-bicyclo[3.2.1]octane]-8′-yl)ethanone (469 mg, 1.29 mmol) in MeOH (5 mL) was added NaOH (1.3 mL of 2.0 M, 2.6 mmol). The solution was heated at 70° C. overnight. The reaction was then cooled to room temperature and the organics were extracted with EtOAc (3×100 mL), combined, and dried over Na2SO4. The organic layer was then filtered and concentrated to provide 8′-azaspiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,3′-bicyclo[3.2.1]octane] as an opaque oil in quantitative yield. 1H NMR (400 MHz, CDCl3) δ 7.28 (d, J=7.7 Hz, 1H), 7.09-6.96 (m, 4H), 6.26 (t, J=3.2 Hz, 1H), 5.97 (d, J=3.4 Hz, 1H), 3.58 (s, 2H), 2.40-2.29 (m, 2H), 2.21-2.15 (m, 2H), 2.09 (dd, J=15.0, 3.1 Hz, 2H), 1.86-1.77 (m, 2H). ESI-MS m/z calc. 266.3. found 267.3 (M+1)+; Retention time: 1.04 minutes (3 min run).
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][C@@H:5]([CH2:8][C:9](OCC)=[O:10])[C@@H:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:3]1.[H-].C([Al+]CC(C)C)C(C)C>C1(C)C=CC=CC=1>[O:1]=[C:2]1[CH2:7][CH2:6][C@@H:5]([CH2:8][CH:9]=[O:10])[C@@H:4]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:3]1
Reactant: CCOC(=O)C[C@@H]1CCC(=O)C[C@@H]1c1ccccc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Product: O=CC[C@@H]1CCC(=O)C[C@@H]1c1ccccc1
Temperature: -70 °C
Reaction time: 0.58 h
Yield: 94.4 %

Procedure:
A stirred solution of the ethylene ketal of ethyl (4-keto-2-phenyl-cis-cyclohexyl)acetate (5.0 g.) in dry toluene (100 ml.), cooled at -70° C. under argon, was treated dropwise with a 1M solution of diisobutylaluminium hydride in toluene (18 ml.). The mixture was stirred at -70° C. for 35 minutes, quenched by addition of ethanol (5 ml.) and allowed to warm up to ambient temperature. Water (100 ml.) was then added and the subsequent mixture was extracted with ether (4×100 ml.). The combined extracts were washed successively with water (2×100 ml.) and brine (1×100 ml.), dried (MgSO4) and evaporated. The residue obtained was purified by flash chromatography on silica, eluting with ether/hexane (3:7 v/v), to give the ethylene ketal of (4-keto-2-phenyl-cis-cyclohexyl)acetaldehyde (3.92 g.) which was used immediately in the Wittig reaction.