Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:3](OC2C=C(C#N)C=C(C#N)C=2)=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1[F:8].[C:23]([NH:27][C:28]([C:30]1[CH:31]=[C:32]([O-:43])[CH:33]=[C:34]([C:36](=[O:42])[NH:37][C:38]([CH3:41])([CH3:40])[CH3:39])[CH:35]=1)=[O:29])([CH3:26])([CH3:25])[CH3:24].[Na+].FC1C(F)=C(F)C=CC=1[N+]([O-])=O>>[F:1][C:2]1[C:3]([O:43][C:32]2[CH:31]=[C:30]([C:28](=[O:29])[NH:27][C:23]([CH3:26])([CH3:24])[CH3:25])[CH:35]=[C:34]([C:36](=[O:42])[NH:37][C:38]([CH3:41])([CH3:40])[CH3:39])[CH:33]=2)=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: N#Cc1cc(C#N)cc(Oc2c([N+](=O)[O-])ccc(F)c2F)c1
Reactant: CC(C)(C)NC(=O)c1cc([O-])cc(C(=O)NC(C)(C)C)c1
Agent: O=[N+]([O-])c1ccc(F)c(F)c1F
Agent: [Na+]
Product: CC(C)(C)NC(=O)c1cc(Oc2c([N+](=O)[O-])ccc(F)c2F)cc(C(=O)NC(C)(C)C)c1

Procedure:
In another embodiment of the present invention there is provided a process for the preparation of a compound according to formula III wherein R2 is 3,5-dicyano-phenyl which process further comprises (i) contacting sodium 3,5-bis-tert-butylcarbamoyl-phenolate with 2,3,4-trifluoronitrobenzene in an appropriate solvent at temperatures from about −30° C. up to about 40° C. to afford a 3,4-difluoro-2-(3,5-bis-tert-butylcarbamoyl-phenoxy)nitrobenzene; and (ii) contacting 3,4-difluoro-2-(3,5-bis-tert-butylcarbamoyl-phenoxy)nitrobezene with phosphorus oxychloride or a similar dehydrating agent to afford 3,4-difluoro-2-(3,5-dicyano-phenoxy)nitrobenzene III (R2=3,5-dicyanophenyl). The ether can be convert to IV (R2=3,5-dicyanophenyl) as described below.
Reaction SMILES: [C:1]1([CH2:7][C:8]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:17]1([C:23](=O)[C:24]([C:26]2[CH:31]=[CH:30][C:29]([C:32](=O)[C:33]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=O)=[CH:28][CH:27]=2)=O)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[CH2:43]([OH:45])[CH3:44].[OH-].[K+]>O>[C:29]1([C:32]2[C:33]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[C:43](=[O:45])[C:44]=2[C:12]2[CH:11]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:30]=[CH:31][C:26]([C:24]2[C:23]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[C:8](=[O:9])[C:10]=2[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[CH:27][CH:28]=1
Reactant: O=C(Cc1ccccc1)Cc1ccccc1
Reactant: CCO
Reactant: O=C(C(=O)c1ccc(C(=O)C(=O)c2ccccc2)cc1)c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: O=C1C(c2ccccc2)=C(c2ccccc2)C(c2ccc(C3=C(c4ccccc4)C(=O)C(c4ccccc4)=C3c3ccccc3)cc2)=C1c1ccccc1

Procedure:
1,3-Diphenylacetone (1.23 g, 0.00584 mol), 1,4-bis(phenylglyoxaloyl)benzene, commercially available as Bis-PGB from Ken Seika Corporation (1.000 g, 0.00292 mol) and ethanol (50 mL) are added to a 100 mL 3-necked round bottom flask fitted with a reflux condenser/nitrogen inlet. The reaction mixture is heated to reflux and an aqueous KOH solution (0.112 g, 0.002 mol) in water (2.25 mL) is added. Additional KOH is added until the solution turns dark and stays dark. The mixture is refluxed for 45 minutes and then allowed to cool. A dark solid which precipitates is collected by filtration and analyzed by 1H-NMR, 13C-NMR, HPLC and FT-IR. All data is consistent with the formation of Compound B.
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[C:9]=1[CH:8]=[C:7]([C:10]1[CH:15]=[CH:14][N:13]([CH2:16][CH2:17][CH2:18][N:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)[C:12](=[O:25])[CH:11]=1)[CH:6]=[N:5]2.[Br:26]N1C(=O)CCC1=O>CN(C=O)C.CCOC(C)=O>[Br:26][C:3]1[N:4]2[N:5]=[CH:6][C:7]([C:10]3[CH:15]=[CH:14][N:13]([CH2:16][CH2:17][CH2:18][N:19]4[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]4)[C:12](=[O:25])[CH:11]=3)=[CH:8][C:9]2=[N:1][CH:2]=1
Reactant: O=c1cc(-c2cnn3ccnc3c2)ccn1CCCN1CCCCC1
Reactant: O=C1CCC(=O)N1Br
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=c1cc(-c2cnn3c(Br)cnc3c2)ccn1CCCN1CCCCC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
4-Imidazo[1,2-b]pyridazin-7-yl-1-(3-piperidin-1-yl-propyl)-1H-pyridin-2-one (1 eq, 0.122 mmol, 41.3 mg) is dissolved in DMF (10 ml) and N-bromosuccinimide (1.1 eq, 0.135 mmol, 24.2 mg) is added. The reaction mixture is then stirred at 0° C. for 30 min. The reaction is diluted with EtOAc and washed with NaHCO3 and brine. The organic phase is then dried over MgSO4, filtered and evaporated to dryness to give 4-(3-bromo-imidazo[1,2-b]pyridazin-7-yl)-1-(3-piperidin-1-yl-propyl)-1H-pyridin-2-one as a brown solid which did not require any further purification; [M+H]+=417
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8](O)=[CH:7][CH:6]=1)([CH3:4])(C)C.[OH-:12].[Na+].C=O.S(=O)(=O)(O)O.[CH2:21](O)[C:22]1OC=CC=1>C1(C)C(C)=CC=CC=1>[CH2:1]([C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:10]=1[OH:12])[CH2:4][CH2:21][CH3:22]
Reactant: [OH-]
Reactant: CC(C)(C)c1ccc(O)cc1
Reactant: OCc1ccco1
Agent: C=O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: Cc1ccccc1C
Product: CCCCc1ccccc1O

Procedure:
1 200 Parts of p-tert-butylphenol, 800 parts of xylene, 240 parts of sodium hydroxide solution and 1 296 parts of 37% aqueous formaldehyde are reacted as in Example 1 in the apparatus of Example 1 until the formaldehyde content is 1.7%. Then, as in Example 1, the pH is adjusted to 5.5 with 25% sulphuric acid, followed by working up. 1 568 Parts of furfuryl alcohol are then added and 450 ml of aqueous phase is azeotropically distilled off at maximum temperature of 177° C. as in Example 1. After distilling off the entrainer at 130° C./100 mbar, 1 225 parts of furfuryl alcohol are added and 3 890 parts of a furan resin solution are obtained having a residue of 60% (1 hour/170° C.) and a viscosity of 4 750 mPa.s/20° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2].Cl.Cl.[NH:27]1[CH2:30][CH:29]([N:31]2[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]2)[CH2:28]1>>[OH:14][C:13]1[N:12]([C:15]2[CH:23]=[CH:22][C:18]([C:19]([N:27]3[CH2:30][CH:29]([N:31]4[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]4)[CH2:28]3)=[O:21])=[CH:17][N:16]=2)[N:11]=[CH:10][C:9]=1[C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][C:5]=1[CH3:24]
Reactant: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)O)cn2)c1O
Reactant: C1CCN(C2CNC2)CC1
Agent: Cl
Product: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)N3CC(N4CCCCC4)C3)cn2)c1O

Procedure:
The title compound was prepared in a manner similar to Example 112 using 6-(4-(4-cyano-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and 1-(azetidin-3-yl)piperidine dihydrochloride. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.36 (d, J=4.80 Hz, 2 H) 1.41-1.54 (m, 4 H) 2.23-2.34 (m, 3 H) 2.36 (s, 3 H) 3.13-3.21 (m, 1 H) 3.86 (dd, J=9.47, 4.67 Hz, 1 H) 4.05 (t, J=8.46 Hz, 1 H) 4.20 (d, J=4.80 Hz, 1 H) 4.28-4.43 (m, 1 H) 7.55 (dd, J=8.08, 1.52 Hz, 1 H) 7.62 (s, 1 H) 7.78 (d, J=8.08 Hz, 1 H) 8.03 (s, 1 H) 8.15 (dd, J=8.72, 2.40 Hz, 1 H) 8.35 (d, J=8.84 Hz, 1 H) 8.65 (dd, J=2.27, 0.76 Hz, 1 H) 12.19-13.21 (m, 1 H); ESI-MS m/z [M+H]+ 443.3
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[N:14]([CH3:35])[C:15](=[O:34])[C:16]2[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[C:18]([S:26][CH2:27][CH2:28][NH:29][S:30]([CH3:33])(=[O:32])=[O:31])[CH:17]=2)=[C:4]([O:36][CH3:37])[CH:3]=1.[OH:38]OS([O-])=O.[K+].[O-]S([O-])(=S)=O.[Na+].[Na+].CCOC(C)=O.[OH2:57]>CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[N:14]([CH3:35])[C:15](=[O:34])[C:16]2[CH:21]=[C:20]([C:22]([F:24])([F:25])[F:23])[CH:19]=[C:18]([S:26]([CH2:27][CH2:28][NH:29][S:30]([CH3:33])(=[O:32])=[O:31])(=[O:38])=[O:57])[CH:17]=2)=[C:4]([O:36][CH3:37])[CH:3]=1
Reactant: O
Reactant: COc1cc(F)ccc1-c1ccncc1N(C)C(=O)c1cc(SCCNS(C)(=O)=O)cc(C(F)(F)F)c1
Reactant: O=S([O-])OO
Agent: O=S([O-])([O-])=S
Agent: [K+]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: COc1cc(F)ccc1-c1ccncc1N(C)C(=O)c1cc(C(F)(F)F)cc(S(=O)(=O)CCNS(C)(=O)=O)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To an ice-cold solution of N-(4-(4-fluoro-2-methoxyphenyl)pyridin-3-yl)-N-methyl-3-(2-(methylsulfonamido)ethylthio)-5-(trifluoromethyl)benzamide (0.105 g, 188 μmol, example 262) in MeOH (3 mL) and water (0.6 mL) was added Oxone® (289 mg, 471 μmol) and the white suspension was stirred at room temperature for 4 hours. The reaction mixture was poured on 10% aqueous Na2S2O3 solution and EtOAc and the layers were separated. The aqueous layer was extracted twice with EtOAc. The organic layers were washed once with brine, dried over MgSO4, filtered, treated with silica gel and evaporated. The crude product was purified by preparative HPLC (Gemini NX column) using a gradient of MeOH:water (containing 0.1% formic acid) (20:80 to 98:2). Colorless foam (0.094 g; 84%). MS (ESI): m/z=590.10 [M+H]+.
Reaction SMILES: [CH3:1][C@@H:2]([C@@H:9]1[C@@:13]2([CH3:35])[CH2:14][CH2:15][C@@H:16]3[C@@:21]4([CH3:34])[CH2:22][CH2:23][C@H:24]([O:26]C(CCC(O)=O)=O)[CH2:25][C:20]4=[CH:19][CH2:18][C@H:17]3[C@@H:12]2[CH2:11][CH2:10]1)[CH2:3][CH2:4][CH2:5][CH:6]([CH3:8])[CH3:7].C(N(CCCC)CCCC)CCC.ClC(OCC(C)C)=O.[OH-].[Na+]>O1CCOCC1.O>[CH3:8][CH:6]([CH2:5][CH2:4][CH2:3][C@H:2]([C@@H:9]1[C@:13]2([CH3:35])[C@H:12]([C@H:17]3[C@H:16]([CH2:15][CH2:14]2)[C@:21]2([CH3:34])[C:20]([CH2:25][C@H:24]([CH2:23][CH2:22]2)[OH:26])=[CH:19][CH2:18]3)[CH2:11][CH2:10]1)[CH3:1])[CH3:7]
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OC(=O)CCC(=O)O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: CC(C)COC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Solvent: CCCCN(CCCC)CCCC
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Reaction time: 6 h

Procedure:
20.25 Grams (41.8 mmoles) of cholesteryl hydrogen succinate (sold by Aldrich Chemicals) and 19.8 ml (83.4 mmoles) of tributylamine were dissolved in 540 ml of Dioxane. The solution was cooled and treated with 5.3 ml (5.7 g, 41.7 mmoles) of isobutyl chloroformate. The reaction was permitted to proceed in the cold for 30 minutes, and then the mixture was added in one portion to a stirred, cooled solution of 50.0 g (41.7 mmoles) of bovine serum albumin in 1100 ml of water, 750 ml of p-dioxane, and 50 ml of 1 N NaOH. Stirring and cooling was continued for 6 hours. The material was then dialyzed against water and lyophilized to yield a stable white powder useful as a cholesterol standard.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([CH:9]=O)=[C:4](Cl)[N:3]=1.C(O)(=O)C(O)=O.[CH2:18]([NH:20][NH2:21])[CH3:19].C(N(CC)CC)C.Cl.[CH:30]12[O:37][CH:34]([CH2:35][CH2:36]1)[CH2:33][NH:32][CH2:31]2>C(Cl)(Cl)Cl>[Cl:1][C:2]1[N:3]=[C:4]2[N:20]([CH2:18][CH3:19])[N:21]=[CH:9][C:5]2=[C:6]([N:32]2[CH2:31][CH:30]3[O:37][CH:34]([CH2:35][CH2:36]3)[CH2:33]2)[N:7]=1
Reactant: CCNN
Reactant: O=Cc1c(Cl)nc(Cl)nc1Cl
Reactant: C1CC2CNCC1O2
Agent: Cl
Agent: O=C(O)C(=O)O
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCn1ncc2c(N3CC4CCC(C3)O4)nc(Cl)nc21
Temperature: 25 °C

Procedure:
To a cloudy solution of 2,4,6-trichloro-pyrimidine-5-carbaldehyde (1.1 g, 5.2 mmol) in chloroform (50 mL) cooled to −78° C. was added ethylhydrazine oxalate (0.78 g, 5.2 mmol) in two portions, followed by triethylamine (2.7 mL). The cooling bath was then removed and ethanol (10 mL) was added to the reaction mixture, which was allowed to warm to room temperature. 8-Oxa-3-azabicyclo[3.2.1]octane hydrochloride (0.69 g, 4.6 mmol) was added to the mixture. The mixture was concentrated under reduced pressure and the residue was partitioned between ethyl acetate and water. The aqueous phase was extracted three times with ethyl acetate. The combined organics were washed successively with 5% aqueous potassium hydrogen sulfate solution, water, saturated aqueous sodium hydrogen carbonate solution, and saturated aqueous sodium chloride solution. Organics were dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to provide 3-(6-chloro-1-ethyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-8-oxa-3-azabicyclo[3.2.1]octane. MS (ES+): 293.9, 295.9 (M+H)+
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[Li+].CC([N-]C(C)C)C.[C:23](N1C=CN=C1)(=[O:25])[CH3:24]>C1COCC1>[C:23]([CH:7]1[C:2](=[O:1])[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6]1)(=[O:25])[CH3:24]
Reactant: CC(=O)n1ccnc1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(=O)C1CN(C(=O)OC(C)(C)C)CCC1=O
Temperature: -78 °C
Reaction time: 2 h
Yield: 41 %

Procedure:
To a solution of tert-butyl 4-oxopiperidine-1-carboxylate (6.00 g) in THF was added LDA (16 mL, 1 M) dropwise at −78° C. The mixture was stirred at −78° C. for 2 h. To this, a solution of N-acetylimidazole (3.50 g) in THF was added, and the reaction mixture was stirred at −78° C. for another 7 h, then quenched with 10 mL of ice-water and extracted with CH2Cl2 (50 mL×3). The combined organic phases were dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuo and the residue was chromatographed with a silica gel column (eluting agent: 3:1 (v/v) PE/EA) to give the title compound as yellow oil (2.98 g, 41.00%), HPLC: 89.00%. The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 242.4 (M+1); 1H NMR (400 MHz, CDCl3) δ: 1.47 (s, 9H), 2.13 (s, 3H), 2.28 (s, 1H), 2.44 (t, J=4.0 Hz, 2H), 3.58 (t, J=8.0 Hz, 2H), 3.97 (s, 2H) ppm.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])/[CH:5]=[C:6](\[NH:14]OC)/[C@H:7]([CH3:13])[C@H:8]([CH3:12])[CH2:9][CH2:10][CH3:11])[CH3:2].[H][H]>[Ni].CO>[CH2:1]([O:3][C:4](=[O:17])/[CH:5]=[C:6](\[NH2:14])/[C@H:7]([CH3:13])[C@H:8]([CH3:12])[CH2:9][CH2:10][CH3:11])[CH3:2]
Reactant: [H][H]
Reactant: CCC[C@@H](C)[C@@H](C)/C(=C/C(=O)OCC)NOC
Agent: [Ni]
Solvent: CO
Product: CCC[C@@H](C)[C@@H](C)/C(N)=C/C(=O)OCC
Yield: 100.1 %

Procedure:
A reactor vessel charged with 171 g of (4R,5R)-3-methoxyamino-4,5-dimethyl-(Z)-oct-2-enoic acid ethyl ester, 1600 mL of MeOH, and 65 g of Raney nickel (Ra—Ni) catalyst. The methoxyamino ester was reacted with hydrogen at 50 psig to 55 psig. During the hydrogenation, additional Ra—Ni was added at reaction times of 8 hours (20 g), 21 hours (20 g), and 37 hours (8 g). After the reaction was completed (51 hours), the Ra—Ni was filtered off and the filtrate was concentrated under reduced pressure to give 150 g (>99% yield) of the titled compound as an oil: 1H NMR (400 MHz, CHLOROFORM-D): 0.86 (t, J=4.5 Hz, 3 H), 0.88 (d, J=4.9 Hz, 3 H), 1.05–1.50 (m, 6 H), 1.10 (d, J=7.0 Hz, 3 H), 1.24 (t, J=7.2 Hz, 3 H), 1.87 (m, 1 H), 3.45 (s, 2 H) 4.08 (q, J=7.0 Hz, 2 H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:26])[C:7]=1[NH:8][C:9]1[NH:10][C:11]2[C:17]3[CH2:18][C:19]([CH3:22])([CH3:21])[O:20][C:16]=3[C:15]([C:23]([OH:25])=O)=[CH:14][C:12]=2[N:13]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CN1CCOCC1.[Br:61][C:62]1[CH:68]=[CH:67][C:65]([NH2:66])=[CH:64][CH:63]=1>C1COCC1.CN(C=O)C>[Br:61][C:62]1[CH:68]=[CH:67][C:65]([NH:66][C:23]([C:15]2[C:16]3[O:20][C:19]([CH3:22])([CH3:21])[CH2:18][C:17]=3[C:11]3[NH:10][C:9]([NH:8][C:7]4[C:2]([Cl:1])=[CH:3][N:4]=[CH:5][C:6]=4[Cl:26])=[N:13][C:12]=3[CH:14]=2)=[O:25])=[CH:64][CH:63]=1
Reactant: CC1(C)Cc2c(c(C(=O)O)cc3nc(Nc4c(Cl)cncc4Cl)[nH]c23)O1
Reactant: Nc1ccc(Br)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: CC1(C)Cc2c(c(C(=O)Nc3ccc(Br)cc3)cc3nc(Nc4c(Cl)cncc4Cl)[nH]c23)O1
Yield: 10.3 %

Procedure:
The title compound was prepared following the procedure as described for Example-1 using 2-[(3,5-dichloropyridin-4-yl)amino]-7,7-dimethyl-7,8-dihydro-1H-furo[3,2-e]benzimidazole-5-carboxylic acid (Intermediate-3, 0.070 g, 0.177 mmol), benzotriazole-1-yl-oxy-tris-(dimethylamino)-phosphonium hexafluorophosphate (0.157 g, 0.355 mmol), N-methyl morpholine (0.5 mL), DMF (1.0 mL), THF (5.0 mL) and 4-bromo aniline (0.092 g, 0.531 mmol) to afford 0.010 g of the desired product. 1HNMR (DMSO-d6): δ 1.23 (s, 3H), 1.57 (s, 3H), 3.06 (s, 2H), 7.24 (s, 1H), 7.52 (d, J=8.7 Hz, 2H), 7.68 (d, J=8.7 Hz, 2H), 8.44 (s, 2H), 9.72 (s, 1H), 10.98 (s, 1H), 11.52 (s, 1H); MS [M−H]−: 546.22.
Reaction SMILES: [C:1]1([C:7]2[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:10][O:9][C:8]=2[C:18]([O:20]C)=[O:19])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].C(O)C>O>[C:1]1([C:7]2[C:11]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)=[CH:10][O:9][C:8]=2[C:18]([OH:20])=[O:19])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)c1occ(-c2ccccc2)c1-c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1occ(-c2ccccc2)c1-c1ccccc1
Yield: 54.8 %

Procedure:
Methyl 3,4-diphenyl-2-furancarboxylate (10.00 g) and sodium hydroxide (1.73 g) in a mixed solution of ethanol (20 ml) and water (20 ml) were heated at reflux for 3 hours while stirring. After evaporating the solvent under reduced pressure, 1 M hydrochloric acid was added, and the thus-precipitated crystals were filtered, thereby giving 5.20 g of the desired compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C@@:15]3([CH2:19][O:18][C:17]([NH2:20])=[N:16]3)[C:14]3[CH:13]=[C:12](Cl)[N:11]=[C:10]([F:22])[C:9]=3[O:8][C:5]2=[CH:6][CH:7]=1.[F:23][C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[N:28][CH:29]=1.[NH:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1>>[F:22][C:10]1[C:9]2[O:8][C:5]3[C:4]([C@@:15]4([CH2:19][O:18][C:17]([NH2:20])=[N:16]4)[C:14]=2[CH:13]=[C:12]([N:33]2[CH2:38][CH2:37][O:36][CH2:35][CH2:34]2)[N:11]=1)=[CH:3][C:2]([C:26]1[CH:27]=[N:28][CH:29]=[C:24]([F:23])[CH:25]=1)=[CH:7][CH:6]=3
Reactant: NC1=N[C@@]2(CO1)c1cc(Br)ccc1Oc1c2cc(Cl)nc1F
Reactant: OB(O)c1cncc(F)c1
Reactant: C1COCCN1
Product: NC1=N[C@@]2(CO1)c1cc(-c3cncc(F)c3)ccc1Oc1c2cc(N2CCOCC2)nc1F

Procedure:
The titled compound was synthesized by steps analogous to those described in Method CC4 above using (S)-7-bromo-3-chloro-1-fluoro-5′H-spiro[chromeno[2,3-c]pyridine-5,4′ oxazol]-2′-amine (prepared as described in Method BB33), 5-fluoropyridin-3-ylboronic acid, and morpholine. MS m/z=452.1 [M+H]+. Calculated for C23H19F2N5O3: 451.1.
Reaction SMILES: [Cl-].[C:2]1([CH2:8][C@H:9]([NH2+:11][CH2:12][C:13]#[CH:14])[CH3:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:18][CH2:19][F:20]>CN(C=O)C.O>[F:20][CH2:19][CH2:18][N:11]([C@H:9]([CH3:10])[CH2:8][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:12][C:13]#[CH:14]
Reactant: C#CC[NH2+][C@H](C)Cc1ccccc1
Reactant: FCCBr
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C#CCN(CCF)[C@H](C)Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of N-[(2R)-1-phenylpropan-2-yl]prop-2-yn-1-aminium chloride (Sigma 100 mg, 0.578 mmol) in dry DMF (2 mL) was added sodium hydride (48.0 mg, 2 mmol). The reaction mixture was stirred at room temperature for 30 min, after which 1-bromo-2-fluoro ethane (0.85 mg, 0.603 mmol) was added. The reaction mixture was stirred over night, diluted with water (10 mL) and extracted with CH2Cl2 (3×15 mL). The organic phase was separated and washed with saturated NaHCO3 (15 ml) and brine (15 ml) and dried over MgSO4 and filtered. The solvent was removed under reduced pressure to obtain the crude product as light yellow oil. The crude product was purified by silica-gel column chromatography (hexane/ether 80:20) and analyzed by NMR, HPLC and LC-MS.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5]1[N:6]=[C:7]([C:14]([C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)=[O:15])[C:8]2[S:13][CH:12]=[CH:11][C:9]=2[N:10]=1.[OH2:21].[CH3:22][N:23]([CH:25]=[O:26])C>>[S:17]1[CH:18]=[CH:19][CH:20]=[C:16]1[C:14]([C:7]1[C:8]2[S:13][CH:12]=[CH:11][C:9]=2[N:10]=[C:5]([NH:4][CH2:3][CH2:22][NH:23][C:25]([NH:1][CH2:2][CH2:3][NH:4][C:5]2[N:6]=[C:7]([C:14]([C:16]3[S:17][CH:18]=[CH:19][CH:20]=3)=[O:15])[C:8]3[S:13][CH:12]=[CH:11][C:9]=3[N:10]=2)=[O:26])[N:6]=1)=[O:21]
Reactant: O
Reactant: CN(C)C=O
Reactant: NCCNc1nc(C(=O)c2cccs2)c2sccc2n1
Product: O=C(NCCNc1nc(C(=O)c2cccs2)c2sccc2n1)NCCNc1nc(C(=O)c2cccs2)c2sccc2n1
Reaction time: 2 h
Yield: 31 %

Procedure:
A solution of 2-(2-aminoethylamino)thieno[3,2-d]pyrimidin-4-yl 2-thienylmethanone (0.10 g, 0.33 mmol) in anhydrous DMF (4 mL) under argon was treated with 1,1-carbonyldiimidazole (0.05 g, 0.33 mmol), stirred for 2 h, treated with 2-(2-aminoethylamino)thieno[3,2-d]pyrimidin-4-yl 2-thienylmethanone (0.10 g, 0.33 mmol), stirred at room temperature for 4 h and then at 60° C. for 16 h, cooled, poured into water (25 mL) and the resulting orange suspension filtered and dried in vacuo to give the title compound (0.13 g, 31%) as an orange solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[N:5][C:6]2[C:11]([CH:12]=1)=[C:10]([N+:13]([O-:15])=[O:14])[CH:9]=[CH:8][CH:7]=2.[CH3:16][C:17]1[CH:22]=[CH:21][C:20]([S:23]([O:26]C)(=[O:25])=[O:24])=[CH:19][CH:18]=1>C(#N)C>[CH3:16][C:17]1[CH:18]=[CH:19][C:20]([S:23]([O-:26])(=[O:25])=[O:24])=[CH:21][CH:22]=1.[CH3:1][O:2][C:3]1[CH:4]=[N+:5]([CH3:16])[C:6]2[C:11]([CH:12]=1)=[C:10]([N+:13]([O-:15])=[O:14])[CH:9]=[CH:8][CH:7]=2
Reactant: COc1cnc2cccc([N+](=O)[O-])c2c1
Reactant: COS(=O)(=O)c1ccc(C)cc1
Solvent: CC#N
Product: COc1cc2c([N+](=O)[O-])cccc2[n+](C)c1
Product: Cc1ccc(S(=O)(=O)[O-])cc1

Procedure:
A mixture of 3-methoxy-5-nitroquinoline and methyl 4-methylbenzenesulfonate in acetonitrile is refluxed. After cooling, the precipitate is collected by filtration to provide 3-methoxy-1-methyl-5-nitroquinolinium 4-methylbenzenesulfonate.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])/[C:5](/[C:14]#[N:15])=[CH:6]/[C:7]1[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][CH:8]=1)[CH3:2].Br[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:24]([F:27])([F:26])[F:25]>>[CH2:1]([O:3][C:4](=[O:16])[CH:5]([C:14]#[N:15])[CH:6]([C:7]1[CH:8]=[CH:9][C:10]([Br:13])=[CH:11][CH:12]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:24]([F:27])([F:26])[F:25])[CH3:2]
Reactant: FC(F)(F)c1ccccc1Br
Reactant: CCOC(=O)/C(C#N)=C/c1ccc(Br)cc1
Product: CCOC(=O)C(C#N)C(c1ccc(Br)cc1)c1ccccc1C(F)(F)F

Procedure:
In analogy to example 74, step 2, from (E)-3-(4-bromo-phenyl)-2-cyano-acrylic acid ethyl ester and 2-bromobenzotrifluoride (CAS RN: [392-83-6]) was prepared the title compound as a brown oil, MS (ESI−): m/z=424.0 ([M−H]−, 1Br).
Reaction SMILES: [Na+:1].[Na+].[N+:3]([C:6]1[CH:32]=[CH:31][C:9]([C:10]([NH:12][C:13]2[C:22]3[C:21]([S:23]([O-:26])(=[O:25])=[O:24])=[CH:20][CH:19]=[CH:18][C:17]=3[C:16]([S:27]([O-:30])(=[O:29])=[O:28])=[CH:15][CH:14]=2)=[O:11])=[CH:8][CH:7]=1)([O-])=O.[H][H]>[Pd].O>[Na+:1].[Na+:1].[NH2:3][C:6]1[CH:7]=[CH:8][C:9]([C:10]([NH:12][C:13]2[C:22]3[C:21]([S:23]([O-:26])(=[O:25])=[O:24])=[CH:20][CH:19]=[CH:18][C:17]=3[C:16]([S:27]([O-:30])(=[O:29])=[O:28])=[CH:15][CH:14]=2)=[O:11])=[CH:31][CH:32]=1
Reactant: O=C(Nc1ccc(S(=O)(=O)[O-])c2cccc(S(=O)(=O)[O-])c12)c1ccc([N+](=O)[O-])cc1
Reactant: [H][H]
Agent: [Pd]
Agent: [Na+]
Solvent: O
Product: Nc1ccc(C(=O)Nc2ccc(S(=O)(=O)[O-])c3cccc(S(=O)(=O)[O-])c23)cc1

Procedure:
A mixture of 10.0 g of 4-p-nitrobenzamido-1,5-naphthalenedisulfonic acid disodium salt (prepared as in Example 3), 200 ml of water and 1.0 g of 10% palladium on charcoal is hydrogenated in a Parr shaker for 11/2 hours at room temperature with an initial pressure of 46 pounds of hydrogen. During this time a total of 4.5 pounds of hydrogen is absorbed. The mixture is heated to dissolve some precipitated product and is filtered hot to remove the catalyst. The filtrate is then evaporated to a small volume in vacuo at about 60° C. and a copious amount of absolute ethyl alcohol is added. The product is collected by filtration and is washed with absolute ethyl alcohol followed by ether. After air drying the material is oven dried at 120° C. overnight.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([CH2:9][OH:10])[C:5]([F:11])=[C:4]([F:12])[C:3]=1[CH2:13]O.[ClH:15]>C1(C)C=CC=CC=1>[Cl:15][CH2:13][C:3]1[C:2]([F:1])=[C:7]([F:8])[C:6]([CH2:9][OH:10])=[C:5]([F:11])[C:4]=1[F:12]
Reactant: Cl
Reactant: OCc1c(F)c(F)c(CO)c(F)c1F
Solvent: Cc1ccccc1
Product: OCc1c(F)c(F)c(CCl)c(F)c1F
Temperature: 90 °C

Procedure:
2,3,5,6-Tetrafluoro-1,4-benzene dimethanol (1 g; 4.8 m.mol) was added to hydrochloric acid 36°Tw (10 ml; 115 m.mol) at 20° C., followed by toluene (10 ml). The mixture was then stirred and warmed to 90° C. and maintained at this temperature for 7 hours to complete the reaction.