Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=2)[O:11][CH2:12][CH2:13][CH2:14][NH2:15])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Br[C:20]1[CH2:25][C:24](=[O:26])[CH:23]=[CH:22][N:21]=1>Cl>[N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=2)[O:11][CH2:12][CH2:13][CH2:14][NH:15][C:22]2[CH2:23][C:24](=[O:26])[CH:25]=[CH:20][N:21]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C1C=CN=C(Br)C1
Reactant: NCCCOc1cccc(CN2CCCCC2)c1
Agent: Cl
Product: O=C1C=CN=C(NCCCOc2cccc(CN3CCCCC3)c2)C1
Yield: 58.8 %

Procedure:
3-[3-(Piperidinomethyl)phenoxy]propylamine (14.84 g) and 2-bromopyrid-4-one (5.20 g) were stirred together at 165°-170° C. for 4 hours. The reaction mixture was cooled to give a dark orange glassy solid which was dissolved in 2N hydrochloric acid to give a solution having a pH of 4.5. This solution was washed thoroughly with diethyl ether (8×) and chloroform (4×) to remove residual 2-bromopyrid-4-one and some by-product. The aqueous phase was taken to pH 9-10 with 2N sodium hydroxide and extracted into chloroform (9×). The chloroform extracts were combined, dried and evaporated under reduced pressure to afford a dark orange oil. This oil was subjected to medium pressure column chromatography on silica gel using gradient elution; ethyl acetate→10% methanol:90% ethyl acetate. The desired fractions were collected, combined and evaporated under reduced pressure to give the title compound (6.0 g) as a yellow-orange oil which was washed with diethyl ether.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]1[C:21]([C:22]([OH:24])=[O:23])=[C:20]2[C:15]([CH:16]3[CH2:25][CH:17]3[CH2:18][O:19]2)=[CH:14][CH:13]=1)(=[O:10])=[O:9].[CH2:26]([N:28]1[CH2:31][CH:30]([CH2:32][NH2:33])[CH2:29]1)[CH3:27]>CS(C)=O>[CH2:26]([N:28]1[CH2:31][CH:30]([CH2:32][NH:33][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[S:8]([NH:11][C:12]2[C:21]([C:22]([OH:24])=[O:23])=[C:20]3[C:15]([CH:16]4[CH2:25][CH:17]4[CH2:18][O:19]3)=[CH:14][CH:13]=2)(=[O:10])=[O:9])[CH2:29]1)[CH3:27]
Reactant: O=C(O)c1c(NS(=O)(=O)c2ccccc2F)ccc2c1OCC1CC21
Reactant: CCN1CC(CN)C1
Solvent: CS(C)=O
Product: CCN1CC(CNc2ccccc2S(=O)(=O)Nc2ccc3c(c2C(=O)O)OCC2CC32)C1

Procedure:
A mixture of (1aRS,7bSR)-5-(2-fluorobenzenesulfonylamino)-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylic (Intermediate 67, 0.07 g) and (1-ethylazetidin-3-yl)methylamine (Intermediate 149, 0.7 g) in DMSO (1.4 mL) was divided evenly between 7 microwave vials and each was irradiated in the microwave at 130° C. for 4 hours. After cooling, the combined mixture was concentrated under vacuum and the residue was purified by chromatography on silica, eluting with a mixture of methanol and DCM (10%). The product was repurified by HPLC (C18) to give (1aRS,7bSR)-5-{2-[(1-ethylazetidin-3-ylmethyl)amino]benzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylic acid (0.012 g) as an off-white solid.
Reaction SMILES: [Cl-].[NH3+:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([C:9]1[CH:10]=[NH+:11][CH:12]=[CH:13][CH:14]=1)=O.[Cl-].[Cl:16][C:17]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:18]=1[C:24]1[O:30][C:27]([CH:28]=O)=[CH:26][CH:25]=1>C(O)(C)C>[Cl:16][C:17]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:18]=1[C:24]1[O:30][C:27]([CH:28]=[C:6]2[CH2:5][CH2:4][CH2:3][N:2]=[C:7]2[C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)=[CH:26][CH:25]=1
Reactant: [NH3+]CCCCC(=O)c1ccc[nH+]c1
Reactant: O=Cc1ccc(-c2ccc(Cl)cc2Cl)o1
Agent: [Cl-]
Solvent: CC(C)O
Product: Clc1ccc(-c2ccc(C=C3CCCN=C3c3cccnc3)o2)c(Cl)c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 45.2 %

Procedure:
3-(5-Ammoniopentanoyl)pyridinium chloride (103 mg, 0.41 mmol) and 5-(2,4-dichlorophenyl)furfural (128 mg, 0.53 mmol) were combined in a reaction vessel and treated with isopropanol (6 mL). The reaction vessel was sealed and the reaction was heated to 80° C. with stirring overnight. The reaction was then cooled to room temperature, concentrated under reduced pressure and treated with saturated NaHCO3(aq). This mixture was then extracted three times with EtOAc. The EtOAc extracts were washed with brine, combined, dried over Na2SO4, filtered and concentrated under reduced pressure. The recovered material was eluted through a 20 gram column of silica gel with 10.5:7:7:0.5:0.05 (700 mL) and with 7:7:7:1:0.1 (440 mL) hexane:MtBE:CH2Cl2:MeOH:NH4OH (step gradient). One sample was recovered that slowly solidified. This solid material was re-crystallized from a mixture of hot isopropanol and hexane. The crystals were recovered by vacuum filtration, washed with 20% isopropanol in hexane and then with ether, then dried under vacuum giving 71 mg (45%) of a yellow crystalline solid. LC-MS: RT=6.17 min, [M+H]+=383.0.
Reaction SMILES: B(Br)(Br)Br.[CH2:5]([C:7]1([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21]C)[CH:16]=2)[CH2:13][CH2:12][CH2:11][CH2:10][NH:9][C:8]1=O)[CH3:6]>C(Cl)Cl>[CH2:5]([C:7]1([C:15]2[CH:16]=[C:17]([OH:21])[CH:18]=[CH:19][CH:20]=2)[CH2:13][CH2:12][CH2:11][CH2:10][NH:9][CH2:8]1)[CH3:6]
Reactant: CCC1(c2cccc(OC)c2)CCCCNC1=O
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCC1(c2cccc(O)c2)CCCCNC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A 1M solution of BBr3(2.56 mL, 2.56 mmol) in CH2Cl2 was added to 3-ethyl-3-(3-methoxy-phenyl)-azepane (as described in Example 8, Step A) (0.300 g, 0.1.28 mmol) dissolved in anhydrous CH2Cl2 (10 mL) at −78° C. After 20 h of stirring at room temperature, the reaction was quenched with sat. NaHCO3 solution, extracted with CH2Cl2 (3×), dried (MgSO4) and concentrated to give the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][CH:11]=[CH:10][CH2:9]2)=[CH:4][CH:3]=1.C(=O)([O-])[OH:14].[K+].OO.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(OCC)(=O)C.C(#N)C.CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:12][CH:11]3[CH:10]([O:14]3)[CH2:9]2)=[CH:6][CH:7]=1
Reactant: O=C([O-])O
Reactant: Fc1ccc(N2CC=CC2)cc1
Agent: O=S([O-])([O-])=S
Agent: OO
Agent: [K+]
Solvent: CO
Solvent: CC#N
Solvent: CCOC(C)=O
Product: Fc1ccc(N2CC3OC3C2)cc1
Temperature: 25 °C
Reaction time: 10 h
Yield: 22.8 %

Procedure:
To a methanol (5 mL) solution of 1-(4-fluorophenyl)-2,5-dihydro-1H-pyrrole (300 mg) synthesized according to the method described in The Journal of Organic Chemistry vol. 25, p. 2230, 1960, acetonitrile (0.8 mL), potassium hydrogen carbonate (221 mg) and 20% hydrogen peroxide (0.8 mL) were added one by one, and the reaction solution was agitated at room temperature for 10 hours. Ethyl acetate and saturated sodium thiosulfate solution were added to the reaction solution, and the organic layer was partitioned. After the obtained organic layer was washed with a saturated sodium bicarbonate water, it was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. 75 mg of the title compound was obtained by purifying the residue by silica gel chromatography (heptane:elution solvent;ethyl acetate=3:1). The physical properties of the compound are as follows.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=[N:7]1.[C:15]1([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][CH:16]=1.C(N(C(C)C)CC)(C)C.[I-].[K+]>C(#N)C>[C:15]1([N:25]2[CH2:30][CH2:29][N:28]([CH2:2][CH2:3][CH2:4][CH2:5][N:6]3[C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=4[N:8]=[N:7]3)[CH2:27][CH2:26]2)[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][CH:16]=1
Reactant: ClCCCCn1nnc2ccccc21
Reactant: c1ccc2c(N3CCNCC3)cccc2c1
Agent: [I-]
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: c1ccc2c(N3CCN(CCCCn4nnc5ccccc54)CC3)cccc2c1
Temperature: 25 °C
Yield: 59.7 %

Procedure:
1-(4-chlorobutyl)-1H-benzotriazole (7.55 g, 0.036 mol) was dissolved into 100 ml of acetonitrile, 4-(1-naphthyl)piperazine (6.4 g, 0.03 mol), diisopropylethylamine (15.5 g, 0.12 mol) and potassium iodide (5.0 g, 0.03 mol) were respectively added. The mixture was stirred and mixed, then heated and refluxed to react for 20 hours. The mixture was cooled down to ambient temperature and filtered. The filtrate was concentrated to produce oily products, and treated by chromatography with neutral Al2O3 and purified, eluted with dichloromethane to produce 6.9 g compound (I-47) with a yield of 60.1%. ESI-MS [M+H]+: m/z 385.2.
Reaction SMILES: [OH:1][C@@H:2]([C@H:8]([OH:25])[C:9](=[O:24])[NH:10][C@H:11]([C:16](=[O:23])[NH:17][CH2:18][CH2:19][CH:20]([CH3:22])[CH3:21])[CH2:12][CH:13]([CH3:15])[CH3:14])[C:3]([O:5][CH2:6][CH3:7])=[O:4].C([C@@]1(C([O-])=O)[C@@H](C(=O)N[C@H](C(=O)NCCC(C)C)CC(C)C)[O:31][S:30](=O)[O:29]1)C.C(#N)C.I([O-])(=O)(=O)=O.[Na+]>O.O.[Ru](Cl)(Cl)Cl.C(OCC)C.C(Cl)(Cl)(Cl)Cl>[CH3:14][CH:13]([CH3:15])[CH2:12][C@H:11]([NH:10][C:9]([C@H:8]1[O:25][S:30](=[O:31])(=[O:29])[O:1][C@@H:2]1[C:3]([O:5][CH2:6][CH3:7])=[O:4])=[O:24])[C:16](=[O:23])[NH:17][CH2:18][CH2:19][CH:20]([CH3:22])[CH3:21]
Reactant: CCOC(=O)[C@@H](O)[C@H](O)C(=O)N[C@@H](CC(C)C)C(=O)NCCC(C)C
Reactant: CC[C@]1(C(=O)[O-])OS(=O)O[C@@H]1C(=O)N[C@@H](CC(C)C)C(=O)NCCC(C)C
Agent: Cl[Ru](Cl)Cl
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Solvent: CCOCC
Product: CCOC(=O)[C@H]1OS(=O)(=O)O[C@@H]1C(=O)N[C@@H](CC(C)C)C(=O)NCCC(C)C
Temperature: 25 °C

Procedure:
Following the same procedures as in Example 3, ethyl (2S,3S)-2,3-dihydroxy-3-[(S)-3-methyl-1-(3-methylbutylcarbamoyl)butylcarbamoyl]propionate (200 mg) was converted into ethyl-(4S,5S)-5-[(S)-3-methyl-1-(3-methylbutylcarbamoyl) butylcarbamoyl]-1,3,2-dioxathiolane-4-carboxylate-2-oxide. Acetonitrile (3 ml) was added to the reaction solution (carbon tetrachloride; 3 ml) without isolating or purifying the product, and the resultant solution was stirred at room temperature. Subsequently, a solution prepared by dissolving sodium periodate (252 mg) and ruthenium trichloride hydrate (catalytic amount) in water (4.5 ml) was added, and the resultant solution was stirred at room temperature for 20 hours. Diethylether was added to the reaction solution, and the ether layer of the solution was sequentially washed with water, saturated sodium bicarbonate solution, and saturated sodium chloride solution. The resultant layer was dried with magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain a crude product. This crude product was purified by silica gel column chromatography (a developing solvent; hexane:ethyl acetate=2:1) to obtain 117 mg of a target compound as a white powder. NMR data, IR data, and SIMS data of the compound were as follows.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:19])[O:10][CH:11]1[CH:16]2[CH2:17][CH2:18][N:13]([CH2:14][CH2:15]2)[CH2:12]1.[CH3:20][O:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][CH:27]=1>>[CH3:20][O:21][C:22]1[CH:27]=[C:26]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[NH:8][C:9](=[O:19])[O:10][CH:11]2[CH:16]3[CH2:17][CH2:18][N:13]([CH2:14][CH2:15]3)[CH2:12]2)[CH:25]=[CH:24][CH:23]=1
Reactant: COc1cccc(B(O)O)c1
Reactant: O=C(Nc1ccccc1Br)OC1CN2CCC1CC2
Product: COc1cccc(-c2ccccc2NC(=O)OC2CN3CCC2CC3)c1
Yield: 85 %

Procedure:
Using general procedure E, quinuclidin-3-yl 2-bromophenylcarbamate, 3-methoxyphenylboronic acid and [PdCl2(pddf)]CH2Cl2 gave the title compound as a white solid (120 mg, 85%). 1H NMR (500 MHz, CDCl3) δ 8.08 (br s, 1H), 7.40 (t, J=7.5 Hz, 1H), 7.36 (t, J=7.5 Hz, 1H), 7.23 (dd, J=7.5, 1.5 Hz, 1H), 7.13 (td, J=7.5, 1.5 Hz, 1H), 6.96 (dd, J=8.0, 2.0 Hz, 2H), 6.91 (t, J=1.5 Hz, 1H), 6.73 (br s, 1H), 4.79 (m, 1H), 3.84 (s, 3H), 3.24 (m, 1H), 2.90-2.70 (m, 5H), 2.05 (m, 1H), 1.80-1.70 (m, 2H), 1.62-1.52 (m, 1H), 1.41-1.32 (m, 1H) ppm. 13C NMR (125 MHz, CDCl3) δ 160.1, 153.4, 139.5, 134.7, 131.5, 130.1, 130.1, 128.5, 123.5, 121.4, 119.9, 114.7, 113.6, 72.1, 55.3, 55.3, 47.3, 46.5, 25.3, 24.5, 19.4 ppm. Purity: >98% LCMS (214 nm & 254 nm); retention time 1.48 min; (M+1) 353
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:8].[CH3:9][Si:10]([C:13]#[CH:14])([CH3:12])[CH3:11].Cl>C(N(CC)CC)C.[Cu]I.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:9][Si:10]([CH3:12])([CH3:11])[C:13]#[C:14][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:8]
Reactant: C#C[Si](C)(C)C
Reactant: Cc1ccccc1I
Agent: [Cu]I
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: Cc1ccccc1C#C[Si](C)(C)C
Temperature: 25 °C
Yield: 94.6 %

Procedure:
2-Iodotoluene (81.5 ml, 0.64 mol) and trimethylsilylacetylene (99 ml, 0.71 mol) were dissolved in triethylamine (250 ml). Triphenylphosphine (0.427 g, 1.6 mmol), copper (I) iodide (0.3 g, 1.6 mmol) and bistriphenyphosphinepalladium (II) dichloride (0.53 g, 0.71 mmol) were added and the mixture was heated under reflux for 18 h. The mixture was cooled to ambient temperature and carefully added to 10% hydrochloric acid (480 ml) and the product was extracted into hexane (3×200 ml). The extracts were washed with 10% hydrochloric acid (200 ml) and water (2×200 ml) then dried (MgSO4) and evaporated in vacuo to give trimethyl-(2-methylphenyl)ethynylsilane (114.06 g) as a yellow oil, which was used without further purification.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][OH:5].C(N(CC)CC)C.Cl[C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1)=[O:15]>C1COCC1>[N+:24]([C:21]1[CH:20]=[CH:19][C:18]([CH2:17][O:16][C:14]([NH:1][CH2:2][CH2:3][CH2:4][OH:5])=[O:15])=[CH:23][CH:22]=1)([O-:26])=[O:25]
Reactant: NCCCO
Reactant: O=C(Cl)OCc1ccc([N+](=O)[O-])cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(NCCCO)OCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Yield: 314.7 %

Procedure:
To a solution stirred under argon at room temperature of 3-amino-1-propanol (0.77 g, 1.1 mmol) and triethylamine (2.85 mL, 7 mmol) in THF (5 mL) was added a suspension of 4-nitrobenzyl chloroformate (2 g, 1 mmol) in THF (20 mL). The resulting mixture was allowed to stir at room temperature over the weekend, then was concentrated. The residue was purified by chromatography on silica gel (0%-2% MeOH/CH2Cl2) to give the title compound (0.80 g, 34%) as a pale yellow oil: MS (ES) m/e 254.3 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[CH3:55][N:56]1[CH:60]=[C:59]([NH2:61])[CH:58]=[N:57]1>CN(C=O)C>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([NH:61][C:59]2[CH:58]=[N:57][N:56]([CH3:55])[CH:60]=2)=[O:21])=[CH:17][N:16]=1
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)O)cn1
Reactant: Cn1cc(N)cn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)Nc2cnn(C)c2)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 40.9 %

Procedure:
To a solution of 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (100 mg, 0.32 mmol) in DMF (2 mL) were added 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (114 mg, 0.35 mmol), N,N-diisopropyl ethyl amine (275 μL, 1.6 mmol) and 1-methyl-1H-pyrazol-4-ylamine (1 M solution in MeOH, 0.35 mmol). The resulting reaction mixture was stirred overnight at room temperature. Concentration and purification by chromatography (SiO2, heptane:ethyl acetate=100:0 to 1:1) afforded the title compound (51 mg, 41%) which was obtained as a white solid. MS: m/e=388.1 [M−H]−.
Reaction SMILES: [Cl:1][C:2]1[C:3](Cl)=[C:4]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)=[CH:13][CH:12]=3)[NH:8][C:5]2=[N:6][CH:7]=1.[CH2:27]([N:29]([CH2:37][CH3:38])[C:30]1[CH:35]=[CH:34][C:33]([NH2:36])=[CH:32][CH:31]=1)[CH3:28]>COC(C)(C)C>[Cl:1][C:2]1[C:3]([NH:36][C:33]2[CH:32]=[CH:31][C:30]([N:29]([CH2:37][CH3:38])[CH2:27][CH3:28])=[CH:35][CH:34]=2)=[C:4]2[NH:10][C:9]([C:11]3[CH:12]=[CH:13][C:14]([O:17][CH2:18][CH2:19][N:20]4[CH2:21][CH2:22][O:23][CH2:24][CH2:25]4)=[CH:15][CH:16]=3)=[N:8][C:5]2=[N:6][CH:7]=1
Reactant: CCN(CC)c1ccc(N)cc1
Reactant: Clc1cnc2[nH]c(-c3ccc(OCCN4CCOCC4)cc3)nc2c1Cl
Solvent: COC(C)(C)C
Product: CCN(CC)c1ccc(Nc2c(Cl)cnc3nc(-c4ccc(OCCN5CCOCC5)cc4)[nH]c23)cc1
Yield: 56 %

Procedure:
6,7-Dichloro-2-[4-(2-morpholin-4-ylethoxy)phenyl]-3H-imidazo[4,5-b]pyridine (Example 206) (0.020 g, 0.051 mmol) and N,N-diethyl-1,4-phenylenediamine (0.1 g) were heated to 180° C. for 2 h. The reaction mixture was diluted with tert-butyl methyl ether (5 ml) and extracted with 2M HCl (20 ml). The aqueous phase was basified with 10M NaOH and extracted with EtOAc. The organic phase was evaporated in vacuo and the residue was dissolved in CH3CN (2 ml) and purified by HPLC-C18, giving the title product (56%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([O:10][CH3:11])[CH:3]=1.[N+:12]([O-])([OH:14])=[O:13]>C(OC(=O)C)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([O:10][CH3:11])[C:5]([N+:12]([O-:14])=[O:13])=[C:6]([O:8][CH3:9])[CH:7]=1
Reactant: COc1cc(Br)cc(OC)c1
Reactant: O=[N+]([O-])O
Solvent: CC(=O)OC(C)=O
Product: COc1cc(Br)cc(OC)c1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 3 h
Yield: 25.2 %

Procedure:
1-Bromo-3,5-dimethoxybenzene (10.9 g, 50 mmol) was dissolved in 100 mL of acetic anhydride and cooled to 0° C. A cooled solution of 70% HNO3 (6.4 mL, 100 mmol) in 20 mL of acetic anhydride was added dropwise and the resulting mixture was stirred for 1 hour at 0° C. and for 3 hours at room temperature. The reaction mixture was poured into ice-water with strong stirring and the yellow solid was filtered and washed with water. The solid as a mixture of two isomers was separated by silica gel column (ISCO, hexane/EtOAc, 0-30%, 40 min) to give 3.3 g (25%) of pure 5-bromo-1,3-dimethoxy-2-nitro-benzene as an yellow solid. 1H-NMR (DMSO-d6, 400 MHz): δ 7.17 (s, 2H), 3.89 (s, 6H).
Reaction SMILES: [F:1][C@H:2]1[CH2:6][N:5]([C:7]2([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[O:28][CH3:29])[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([O:16][C:17]([F:20])([F:19])[F:18])[CH:14]=3)[NH:9][C:8]2=[O:21])[C@H:4]([C:30]([N:32]([CH3:34])[CH3:33])=[O:31])[CH2:3]1.[CH3:35][O:36][C:37]1[CH:42]=[CH:41][C:40]([S:43](Cl)(=[O:45])=[O:44])=[C:39]([O:47][C:48]([F:51])([F:50])[F:49])[CH:38]=1>>[F:1][C@H:2]1[CH2:6][N:5]([C:7]2([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[O:28][CH3:29])[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([O:16][C:17]([F:20])([F:19])[F:18])[CH:14]=3)[N:9]([S:43]([C:40]3[CH:41]=[CH:42][C:37]([O:36][CH3:35])=[CH:38][C:39]=3[O:47][C:48]([F:49])([F:50])[F:51])(=[O:45])=[O:44])[C:8]2=[O:21])[C@H:4]([C:30]([N:32]([CH3:33])[CH3:34])=[O:31])[CH2:3]1
Reactant: COc1ccccc1C1(N2C[C@H](F)C[C@H]2C(=O)N(C)C)C(=O)Nc2ccc(OC(F)(F)F)cc21
Reactant: COc1ccc(S(=O)(=O)Cl)c(OC(F)(F)F)c1
Product: COc1ccc(S(=O)(=O)N2C(=O)C(c3ccccc3OC)(N3C[C@H](F)C[C@H]3C(=O)N(C)C)c3cc(OC(F)(F)F)ccc32)c(OC(F)(F)F)c1
Yield: 51.7 %

Procedure:
With 200 mg of the compound obtained in Step 20-1 (Isomer B) and 133 mg of 4-methoxy-2-(trifluoromethoxy)benzene sulfonyl chloride as starting material, 158 mg of the title compound (colorless amorphous) was obtained by a similar method to Example 2.
Reaction SMILES: [CH3:1][CH:2]([C:8]1[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=1[NH2:10])[CH2:3][CH2:4][CH:5]([CH3:7])[CH3:6].[F:15][C:16](I)([C:21]([F:24])([F:23])[F:22])[C:17]([F:20])([F:19])[F:18].C(=O)([O-])O.[Na+].S(S([O-])=O)([O-])=O.[Na+].[Na+]>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.CCCCCC.O.COC(C)(C)C>[CH3:1][CH:2]([C:8]1[CH:14]=[C:13]([C:16]([F:15])([C:21]([F:24])([F:23])[F:22])[C:17]([F:20])([F:19])[F:18])[CH:12]=[CH:11][C:9]=1[NH2:10])[CH2:3][CH2:4][CH:5]([CH3:6])[CH3:7]
Reactant: CC(C)CCC(C)c1ccccc1N
Reactant: FC(F)(F)C(F)(I)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: O=S(=O)([O-])O
Solvent: COC(C)(C)C
Solvent: O
Solvent: CCCCCC
Product: CC(C)CCC(C)c1cc(C(F)(C(F)(F)F)C(F)(F)F)ccc1N
Yield: 97.1 %

Procedure:
The 2-(1,4-dimethylpentyl)aniline (1.8 g, 9.4 mmol) obtained in Example 3-2 was dissolved in a solution (50 ml) consisting of t-butyl methyl ether and water in the ratio of 1:1. To the resulting solution were added 1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl iodide (2.78 g, 9.4 mmol), tetra-n-butylammonium hydrogensulfate (318 mg, 0.94 mmol), sodium hydrogencarbonate (795 mg, 9.4 mmol) and then sodium dithionite (1.63 g, 9.4 mmol), and the resulting mixture was stirred at room temperature for 12 hours. The reaction mixture was diluted with hexane and washed twice with 3N hydrochloric acid and then with an aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution. The organic layer was dried over magnesium sulfate and then concentrated under reduced pressure to obtain 3.28 g of the desired compound.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:17]([F:20])([F:19])[F:18])=[CH:7][C:6]=1[NH2:21])=O.C(O)(=O)C.[CH:26](N)=[NH:27]>COCCO.[OH-].[Na+]>[F:18][C:17]([F:20])([F:19])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[C:8]1[CH:7]=[C:6]2[C:5]([C:3](=[O:2])[NH:27][CH:26]=[N:21]2)=[CH:10][CH:9]=1
Reactant: N=CN
Reactant: COC(=O)c1ccc(-c2ccccc2C(F)(F)F)cc1N
Agent: [Na+]
Agent: [OH-]
Solvent: COCCO
Solvent: CC(=O)O
Product: O=c1[nH]cnc2cc(-c3ccccc3C(F)(F)F)ccc12

Procedure:
Heat a solution of 3-amino-2′-trifluoromethyl-biphenyl-4-carboxylic acid methyl ester (5.0 g, 0.0169 mol) and formamidine acetate (2.8 g, 0.0203 mol) in 2-methoxyethanol at reflux for 8 hours. Cool the mixture and concentrate under reduced pressure to give a dark oil. Dissolve the residue in 10% NaOH and wash the aqueous with ether (3X). Bring the aqueous layer to pH ˜4 using 12N HCl to produce a milky solution. Extract the solution with EtOAc, wash the EtOAc with brine, dry (Na2SO4) and concentrate under reduced pressure to give 7-(2-Trifluoromethyl-phenyl)-3H-quinazolin-4-one as a beige solid.
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([C:7]2[S:11][C:10]([NH2:12])=[N:9][C:8]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[O:4][N:3]=1.[C:19](Cl)(=[O:21])[CH3:20]>>[CH3:1][C:2]1[N:6]=[C:5]([C:7]2[S:11][C:10]([NH:12][C:19](=[O:21])[CH3:20])=[N:9][C:8]=2[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[O:4][N:3]=1
Reactant: CC(=O)Cl
Reactant: Cc1noc(-c2sc(N)nc2-c2ccccc2)n1
Product: CC(=O)Nc1nc(-c2ccccc2)c(-c2nc(C)no2)s1

Procedure:
Prepared from 5-(3-methyl-[1,2,4]oxadiazol-5-yl)-4-phenyl-thiazol-2-ylamine and acetyl chloride.
Reaction SMILES: O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[Br:13][C:14]1[C:22]2[N:21]=[N:20][N:19]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C:18]=2[CH:17]=[CH:16][C:15]=1N.N([O-])=O.[Na+].[I-:33].[K+].C(=O)(O)[O-].[Na+].[O-]S([O-])(=S)=O.[Na+].[Na+]>C(#N)C.O>[Br:13][C:14]1[C:22]2[N:21]=[N:20][N:19]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C:18]=2[CH:17]=[CH:16][C:15]=1[I:33]
Reactant: [I-]
Reactant: CC(C)(C)Cn1nnc2c(Br)c(N)ccc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: O=N[O-]
Solvent: CC#N
Solvent: O
Product: CC(C)(C)Cn1nnc2c(Br)c(I)ccc21
Temperature: 12.5 °C
Reaction time: 0.17 h

Procedure:
To a solution of para-toluenesulfonic acid monohydrate (510 mg, 2.68 mmol) in acetonitrile (3.5 mL), was added 4-bromo-1-(2,2-dimethylpropyl)-1H-1,2,3-benzotriazol-5-amine (253 mg, 0.893 mmol). The resulting suspension was cooled to 10-15° C. and treated with an aqueous solution of sodium nitrite (537 μl, 1.787 mmol) and potassium iodide (536 μl, 2.23 mmol). The mixture was stirred for 10 minutes at 0° C. and then warmed to ambient temperature. The mixture was diluted with water and treated with sodium bicarbonate (1 M, aqueous) until the mixture was adjusted to pH 9-10, which was followed by treatment of a 3 M aqueous solution of Na2S2O3 (6 mL). The solid was collected by filtration and washed with cold diethyl ether and hexane. The residue was purified via silica gel chromatography (ethyl acetate/hexane gradient), providing the titled compound: 1H NMR (500 MHz, CDCl3) 7.86 (d, 1H, J=8.7 Hz), 7.25 (d, 1H, J=9.0 Hz), 4.36 (s, 2H), 1.04 (s, 9H) ppm. LRMS m/z (M+H) 393.8 and 395.8 found, 393.9 and 395.9 required.