Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH2:10])=[CH:4][CH:3]=1.C([O:13][C:14]([C:16]1[N:17]=[C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH2:29][CH2:28][N:27]([C:30](=[O:42])[C:31]4[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:32]=4[C:38]([F:41])([F:40])[F:39])[CH2:26][CH2:25]3)=[N:20][N:19]2[CH:43]=1)=O)C>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH:10][C:14]([C:16]2[N:17]=[C:18]3[CH:23]=[CH:22][C:21]([N:24]4[CH2:29][CH2:28][N:27]([C:30](=[O:42])[C:31]5[CH:36]=[C:35]([F:37])[CH:34]=[CH:33][C:32]=5[C:38]([F:39])([F:41])[F:40])[CH2:26][CH2:25]4)=[N:20][N:19]3[CH:43]=2)=[O:13])=[CH:4][CH:3]=1
Reactant: NCCc1ccc(F)cc1
Reactant: CCOC(=O)c1cn2nc(N3CCN(C(=O)c4cc(F)ccc4C(F)(F)F)CC3)ccc2n1
Product: O=C(NCCc1ccc(F)cc1)c1cn2nc(N3CCN(C(=O)c4cc(F)ccc4C(F)(F)F)CC3)ccc2n1
Yield: 42 %

Procedure:
Following the procedure as described in Example 1, making variations only as required to use 2-(4-fluorophenyl)ethylamine in place of isoamylamine to react with 6-[4-(5-fluoro-2-trifluoromethylbenzoyl)piperazin-1-yl]imidazo[1,2-b]pyridazine-2-carboxylic acid ethyl ester, the title compound was obtained as a white solid in 42% yield. 1H NMR (300 MHz, CDCl3) δ 8.15 (d, J=3.0 Hz, 1H), 7.76-7.7 (m, 1H), 7.65 (d, J=9.9 Hz, 1H), 7.33 (t, J=6.0 Hz, 1H), 7.27-7.12 (m, 3H), 7.09-7.02 (m, 1H), 7.0-6.91 (m, 2H), 6.87 (d, J=9.9 Hz, 1H), 4.04-3.92 (m, 1H), 3.91-3.79 (m, 1H), 3.71-3.53 (m, 4H), 3.51-3.4 (m, 2H), 3.36-3.28 (m, 2H), 2.88 (t, J=7.2 Hz, 2H). 13C NMR (75 MHz, CDCl3) δ 165.9, 163.2, 162.4, 160.0, 154.8, 138.1, 135.6, 134.6, 134.58, 130.3, 130.1, 129.7, 129.6, 129.57, 129.5, 126.4, 118.3, 116.8, 116.5, 115.5, 115.2, 114.9, 114.6, 111.9, 46.2, 45.6, 41.3, 40.5, 35.2. MS (ES+) m/z 559 (M+1).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[S:11]([Cl:15])(=O)(=[O:13])[OH:12]>O>[Cl:15][S:11]([C:6]1[CH:7]=[CH:8][C:9]2[C:4](=[CH:3][C:2](=[O:10])[N:1]=2)[CH:5]=1)(=[O:13])=[O:12]
Reactant: O=S(=O)(O)Cl
Reactant: O=C1Cc2ccccc2N1
Solvent: O
Product: O=C1C=c2cc(S(=O)(=O)Cl)ccc2=N1
Temperature: 25 °C
Reaction time: 1 h
Yield: 65.3 %

Procedure:
1,3-Dihydro-indol-2-one 64a (13.3 g, 100 mmol) was added slowly with chlorosulfuric acid (26.6 ml, 400 mmol) in an ice-water bath. Upon completion of the addition, the reaction mixture was stirred for 1 hour in an ice-water bath, for another 1 hour at room temperature, and heated to 68° C. for 1 hour. The reaction mixture was cooled down to room temperature, added slowly with water (400 ml), stirred and yellow precipitates were formed. After standing for 1 hour at room temperature, the filter cake was washed with water (20 ml×4) and dried to obtain the title compound 5-chlorosulfonyl-indol-2-one 64b (15.0 g, yield 65%) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([NH2:8])=[CH:4][C:3]=1[CH2:9][CH3:10].ClC1C(CC)=C(N)N=NC=1.C([O-])(O)=O.[Na+].[Br:26]Br>CO.CCOC(C)=O>[Br:26][C:4]1[C:3]([CH2:9][CH3:10])=[C:2]([Cl:1])[N:7]=[N:6][C:5]=1[NH2:8]
Reactant: CCc1cc(N)nnc1Cl
Reactant: BrBr
Agent: CCc1c(Cl)cnnc1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: CCc1c(Cl)nnc(N)c1Br
Temperature: 25 °C
Reaction time: 24 h

Procedure:
The mixture of 6-Chloro-5-ethylpyridazin-3-amine and chloro-4-ethylpyridazin-3-amine (3.50 g, 0.022 mol) from 1b and NaHCO3 (3.73 g, 0.044 mol, 2 eq) were suspended in MeOH (20 mL) and treated with Br2 (1.25 mL, 0.024 mol). The mixture was stirred at room temperature for 24 h, then filtered. The filtrate was condensed in vacuo. The resulting residue was resuspended in EtOAc (100 mL) and washed sequentially with sat. aqueous NaHCO3 solution (2×20 mL) and aqueous NaCl solution (1×20 mL). The solution was dried over sodium sulfate. The solvent was removed in vacuo to give crude 4-bromo-6-chloro-5-ethylpyridazin-3-amine. LC/MS, m/e 236 (M+1). HPLC Rt, 2.15 min. Waters Sunfire C18 column (4.6×50 mm). 0%-100% B. Solvent B: (90% MeOH, 10% H2O, 0.1% TFA). Solvent A: (10% MeOH, 90% H2O, 0.1% TFA). Gradient, start % B=0, final % B=100, gradient time 4 min, hold at 100% B 1 min, flow rate 4 mL/min.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][CH2:10]O)[CH:5]=[CH:6][CH:7]=1.N1C=CC=CC=1.[Br:18]P(Br)Br>C(OCC)C>[Br:18][CH2:10][C:9]#[C:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=1
Reactant: BrP(Br)Br
Reactant: OCC#Cc1cccc(F)c1
Solvent: CCOCC
Solvent: c1ccncc1
Product: Fc1cccc(C#CCBr)c1
Temperature: -2.5 °C
Reaction time: 3 h
Yield: 126 %

Procedure:
3-(3-Fluoro-phenyl)-prop-2-yn-1-ol (0.750 g, 0.005 mol) was taken in diethyl ether (10 ml) containing catalytic amount of pyridine (0.05 ml). The reaction mixture was then cooled to −5-0° C. Tribromo phosphine (0.26 ml, 0.003 mol) was added slowly at −5-0° C. and stirred at the same temperature for 3 hrs. The reaction mixture was quenched with saturated NaHCO3 solution and extracted with ethyl acetate. The organic layer was washed with saturated brine solution, dried over Na2SO4, and evaporated under vacuum to get 1-(3-bromo-prop-1-ynyl)-3-fluoro benzene (0.805 gm, 76%).
Reaction SMILES: [C:1]1([CH:7]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:24]=[C:23]4[C:19]([CH2:20][NH:21][C:22]4=[O:25])=[CH:18][CH:17]=3)[CH2:12][CH2:11]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+:32]([C:35]1[CH:36]=[C:37]([CH:40]=[CH:41][CH:42]=1)[CH2:38]Br)([O-:34])=[O:33]>>[C:26]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:8][CH2:9][N:10]2[CH2:11][CH2:12][N:13]([C:16]3[CH:24]=[C:23]4[C:19]([CH2:20][N:21]([CH2:38][C:37]5[CH:40]=[CH:41][CH:42]=[C:35]([N+:32]([O-:34])=[O:33])[CH:36]=5)[C:22]4=[O:25])=[CH:18][CH:17]=3)[CH2:14][CH2:15]2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=[N+]([O-])c1cccc(CBr)c1
Reactant: O=C1NCc2ccc(N3CCN(CCC(c4ccccc4)c4ccccc4)CC3)cc21
Product: O=C1c2cc(N3CCN(CCC(c4ccccc4)c4ccccc4)CC3)ccc2CN1Cc1cccc([N+](=O)[O-])c1
Yield: 57.2 %

Procedure:
In the same manner as in Example 51, the title compound (38 mg) was prepared from the compound (50 mg) obtained in Example 50 and 3-nitro benzyl bromide (39 mg).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.Br[C:22]1[C:23](=[O:30])[N:24]([CH3:29])[CH:25]=[C:26]([Br:28])[CH:27]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[Br:28][C:26]1[CH:27]=[C:22]([NH:1][C:2]2[N:7]=[CH:6][C:5]([C:8]3[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH:9]=3)=[CH:4][CH:3]=2)[C:23](=[O:30])[N:24]([CH3:29])[CH:25]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(N)nc2)CC1
Reactant: Cn1cc(Br)cc(Br)c1=O
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: Cn1cc(Br)cc(Nc2ccc(C3=CCN(C(=O)OC(C)(C)C)CC3)cn2)c1=O
Temperature: 100 °C
Yield: 60.2 %

Procedure:
A 100-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged 200b (2.0 g, 7.2 mmol), 3,5-dibromo-1-methylpyridin-2(1H)-one (1.9 g, 7.2 mmol), cesium carbonate (4.7 g, 14.4 mmol), and 1,4-dioxane (50 mL). After bubbling nitrogen through the resulting mixture for 30 min, Xantphos (418 mg, 0.72 mmol) and tris(dibenzylideneacetone)dipalladium(0) (661 mg, 0.72 mmol) were added. The reaction mixture was subject to three cycles of vacuum/argon flush and heated at 100° C. for 6 h. After this time the reaction was cooled to room temperature and filtered. The filtrate was partitioned between ethyl acetate (120 mL) and water (60 mL). The aqueous layer was separated and extracted with ethyl acetate (3×80 mL). The combined organic layer was washed with brine (30 mL) and dried over sodium sulfate. The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by silica-gel column chromatography eluting with 1:4 ethyl acetate/petroleum ether to afford 200c (2.0 g, 61%) as a yellow solid. MS-ESI: [M+H]+ 463.2
Reaction SMILES: C1COCC1.[NH2:6][C:7]1[C:12]2=[C:13]([C:27]3[CH:32]=[CH:31][C:30]([NH:33][C:34]([NH:36][C:37]4[CH:42]=[C:41]([C:43]([F:46])([F:45])[F:44])[CH:40]=[CH:39][N:38]=4)=[O:35])=[CH:29][CH:28]=3)[C:14]([C:16]([NH:18][C@H:19]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:20]O)=[O:17])=[CH:15][N:11]2[N:10]=[CH:9][N:8]=1.CCN(S(F)(F)F)CC.C([O-])([O-])=O.[K+].[K+]>CCOC(C)=O.C(Cl)Cl.CCOC(C)=O.CO>[NH2:6][C:7]1[C:12]2=[C:13]([C:27]3[CH:28]=[CH:29][C:30]([NH:33][C:34]([NH:36][C:37]4[CH:42]=[C:41]([C:43]([F:45])([F:46])[F:44])[CH:40]=[CH:39][N:38]=4)=[O:35])=[CH:31][CH:32]=3)[C:14]([C:16]3[O:17][CH2:20][CH:19]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[N:18]=3)=[CH:15][N:11]2[N:10]=[CH:9][N:8]=1
Reactant: CCOC(=O)[C@H](CO)NC(=O)c1cn2ncnc(N)c2c1-c1ccc(NC(=O)Nc2cc(C(F)(F)F)ccn2)cc1
Agent: CCN(CC)S(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCOC(=O)C1COC(c2cn3ncnc(N)c3c2-c2ccc(NC(=O)Nc3cc(C(F)(F)F)ccn3)cc2)=N1
Temperature: -78 °C
Reaction time: 1 h
Yield: 17.8 %

Procedure:
To a solution of THF (2 mL) was added ethyl N-[(4-amino-5-{4-[({[4-(trifluoromethyl)pyridin-2-yl]amino}carbonyl)amino]phenyl}pyrrolo[2,1-f][1,2,4]triazin-6-yl)carbonyl]serinate (Example 221) (50 mg, 0.09 mmol) which was cooled to −78° C. DAST (13 μL, 0.10 mmol) was added and the reaction proceeded for 1 h while stirring under N2. Anhydrous K2CO3 was then added and the solution was allowed to warm to rt over the following 30 min. The reaction mixture was transferred to a separatory funnel, diluted with EtOAc (20 mL), washed with aq saturated NaHCO3 (20 mL) and H2O (20 mL). The organic was collected, dried (MgSO4), and evaporated in vacuo. The crude material was purified by preparative HPLC (10-90% ACN/H2O with 0.1% TFA). The fractions were left overnight resulting in the partial formation of a new product. The two products were separated by column chromatography 5:4:1 v/v/v DCM/EtOAc/MeOH resulting in the isolation of 9 mg of the title compound (0.016 mmol, 18%). 1H-NMR (DMSO-d6) δ 9.91 (s, 1H), 9.78 (s, 1H), 8.54 to 8.53 (d, J=5.0 Hz, 1H), 8.08 (s, 1H), 8.05 (s, 1H), 7.91 (s, 1H), 7.58 to 7.56 (d, J=8.6 Hz, 2H), 7.37 to 7.36 (d, J=5.1 Hz, 1H), 7.34 to 7.32 (d, J=8.6 Hz, 2H), 4.75 to 4.71 (m, 1H), 4.38 to 4.29 (m, 2H), 4.13 to 4.08 (q, J=7.1 Hz, 2H), 1.21 to 1.18 (t, J=7.0 Hz, 3H); MS [M+H]+=555.1; LCMS RT=2.84 min.
Reaction SMILES: [C:1]1(=[O:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:7](=O)([O:11]CC)[O:8][CH2:9][CH3:10].[H-].[Na+]>C1COCC1>[O:6]=[C:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[C:7]([O:8][CH2:9][CH3:10])=[O:11]
Reactant: CCOC(=O)OCC
Reactant: O=C1CCCC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C1CCCC1=O

Procedure:
Similarly, compounds of this invention can be prepared as illustrated by the exemplary reaction in Scheme 3. Reaction of cyclopentanone with diethyl carbonate in THF in the presence of NaH produced ethyl 2-oxocyclopentanecarboxylate. Reaction of ethyl 2-oxocyclopentanecarboxy late with urea at 175-185° C. produced 6,7-dihydro-1H-cyclopenta[d]pyrimidine-2,4(3H,5H)-dione. Reaction of 6,7-dihydro-1H-cyclopenta[d]pyrimidine-2,4(3H,5H)-dione with hexamethyldisilazane (HMDS) in toluene in the presence of concentrated sulfuric acid, produced the intermediate 2,4-di(trimethylsilyloxy)-6,7-dihydro-5H-cyclopenta[d]pyrimidine. Reaction of 2,4-di(trimethylsilyloxy)-6,7-dihydro-5H-cyclopenta[d]pyrimidine with methyl 3-(bromomethyl)benzoate in DMF, followed by treatment with 1,4-dioxane and methanol, produced 1-(3-methoxycarbonylbenzyl)-6,7-dihydro-1H-cyclopenta[d]pyrimidine-2,4(3H,5H)-dione. Treatment of the ester with NaOH in water-methanol produced 1-(3-carboxybenzyl)-6,7-dihydro-1H-cyclopenta[d]pyrimidine-2,4(3H,5H)-dione. Coupling of the acid with a substituted amine, such as 1-(pyrimidin-2-yl)piperazine, in the presence of coupling agents, such as HATU and DIPEA in DMF, produced the targeted compound 1-(3-(4-(pyrimidin-2-yl)piperazine-1-carbonyl)benzyl)-6,7-dihydro-1H-cyclopenta[d]pyrimidine-2,4(3H,5H)-dione.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[CH:11]=[C:12]([CH2:25][CH2:26][C:27]2[CH:28]=[C:29](/[C:33](/[CH2:47][CH3:48])=[CH:34]/[CH:35]=[CH:36]/[C:37]([C:43]([F:46])([F:45])[F:44])([OH:42])[C:38]([F:41])([F:40])[F:39])[CH:30]=[CH:31][CH:32]=2)[CH:13]=[CH:14][C:15]=1[CH2:16][O:17][Si](C(C)(C)C)(C)C)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>>[OH:8][CH2:9][C:10]1[CH:11]=[C:12]([CH2:25][CH2:26][C:27]2[CH:28]=[C:29](/[C:33](/[CH2:47][CH3:48])=[CH:34]/[CH:35]=[CH:36]/[C:37]([C:38]([F:39])([F:40])[F:41])([OH:42])[C:43]([F:45])([F:46])[F:44])[CH:30]=[CH:31][CH:32]=2)[CH:13]=[CH:14][C:15]=1[CH2:16][OH:17]
Reactant: CC/C(=C\C=C\C(O)(C(F)(F)F)C(F)(F)F)c1cccc(CCc2ccc(CO[Si](C)(C)C(C)(C)C)c(CO[Si](C)(C)C(C)(C)C)c2)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: CC/C(=C\C=C\C(O)(C(F)(F)F)C(F)(F)F)c1cccc(CCc2ccc(CO)c(CO)c2)c1

Procedure:
In a manner analogous to example 2m, by reaction of 1.2 g (1.67 mmol) of (3E,5E)-6-(3-{2-[3,4-bis(tert-butyldimethylsilanyloxymethyl)phenyl]ethyl}phenyl)-1, 1,1-trifluoro-2-trifluoromethylocta-3,5-dien-2-ol with 4 ml (4 mmol) of a 1.0 M solution of tetrabutylammonium fluoride. A white solid is obtained (m.p.=104° C.; m=715 mg; Y=87%).
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].Cl[C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([O:18][CH3:19])[CH:16]=2)[N:11]=[CH:10][CH:9]=1.[CH2:20](B(CC)CC)[CH3:21].CCCCCC>[Pd].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1>[CH2:20]([C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([O:18][CH3:19])[CH:16]=2)[N:11]=[CH:10][CH:9]=1)[CH3:21]
Reactant: COc1ccc2nccc(Cl)c2c1
Reactant: CCB(CC)CC
Agent: [Pd]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: CCc1ccnc2ccc(OC)cc12
Temperature: 90 °C
Reaction time: 96 h

Procedure:
A mixture of toluene (17 mL) and 2 M aqueous sodium carbonate (5 mL) was degassed by bubbling nitrogen for 20 minutes. To the mixture was added 4-chloro-6-methoxy-quinoline (500 mg, 2.58 mmol) and tetrakis(triphenylphosphine)palladium(0) (90 mg, 0.0774 mmol), followed by 1 M triethylborane solution in hexane (15.5 mL, 15.5 mmol). The reaction mixture was stirred at 90° C. for 4 days, periodically adding more palladium catalyst (270 mg total) and triethylborane solution (30 mL total) to drive the reaction. The reaction mixture was cooled to room temperature and partitioned between water and ethyl acetate. The organic layer was separated, dried over sodium sulfate, filtered, and adsorbed on silica gel. Purification by flash chromatography using a gradient of 0-70% ethyl acetate/hexane afforded 579 mg of impure 4-ethyl-6-methoxy-quinoline as a waxy off white solid. The solid was treated with concentrated sulfuric acid (6 mL) and water (4 mL). The reaction mixture was stirred at reflux for 5 h and poured onto ice. Ammonium hydroxide was added until pH 9 and the aqueous layer was extracted with ethyl acetate (2×). Combined organics were adsorbed on silica gel. Purification by flash chromatography using a gradient of 0-80% ethyl acetate/hexane afforded 195 mg of 4-ethyl-quinolin-6-ol as an off white solid (44% yield): 1H NMR (DMSO-d6) δ 1.30 (t, 3H), 2.96 (q, 2H), 7.25 (d, 1H), 7.28 (m, 2H), 7.86 (d, 1H), 8.56 (d, 1H), 9.98 (broad s, 1H); MS (m/z) 174 [M+H]+.
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[N:13]3[CH:14]=[N:15][CH:16]=[C:12]3[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.N([O-])=O.[Na+].[Cu][C:22]#[N:23]>Cl.O>[C:22]([C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[N:13]3[CH:14]=[N:15][CH:16]=[C:12]3[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1)#[N:23]
Reactant: N#C[Cu]
Reactant: Nc1ccc(C2CCCc3cncn32)cc1
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: N#Cc1ccc(C2CCCc3cncn32)cc1
Temperature: 0 °C

Procedure:
A solution of 2.13 g of 5-(p-aminophenyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyridine in 4 ml of concentrated hydrochloric acid and 10 ml of water is added in an ice-bath and a solution of 0.78 g of sodium nitrite in 2 ml of water is added slowly. The solution is added via dropping funnel to an ice cooled solution of 3.0 g of copper(I) cyanide in 10 ml of water, keeping the temperature between 30°-40°. The reaction mixture is heated on a steam bath for 1 hr, cooled and brought to pH 9. The organic extracts are dried over sodium sulfate and evaporated and the residue is chromatographed on silica gel with ethyl acetate to yield the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1([OH:12])[CH2:11][CH2:10][CH2:9]1.[F:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:21]=[C:22]3[C:27](=[CH:28][CH:29]=2)[CH:26]=[C:25]([S:30]([O-:32])=[O:31])[CH:24]=[CH:23]3)=[CH:16][CH:15]=1.[Na+]>>[F:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:21]=[C:22]3[C:27](=[CH:28][CH:29]=2)[CH:26]=[C:25]([S:30]([C:2]2[CH:3]=[N:4][CH:5]=[CH:6][C:7]=2[C:8]2([OH:12])[CH2:11][CH2:10][CH2:9]2)(=[O:32])=[O:31])[CH:24]=[CH:23]3)=[CH:16][CH:15]=1
Reactant: OC1(c2ccncc2Br)CCC1
Reactant: O=S([O-])c1ccc2cc(-c3ccc(F)cc3)ccc2c1
Agent: [Na+]
Product: O=S(=O)(c1ccc2cc(-c3ccc(F)cc3)ccc2c1)c1cnccc1C1(O)CCC1

Procedure:
Prepared according to the method of Example 6 Step 4 using 1-(3-bromopyridin-4-yl)cyclobutanol and sodium 6-(4-fluorophenyl)naphthalene-2-sulfinate. 1H NMR (500 MHz, CDCl3): δ 8.91 (1H, s), 8.77 (1H, d, J=4.9 Hz), 8.54 (1H, s), 8.08-8.02 (3H, m), 7.88-7.82 (2H, m), 7.69 (2H, dd, J=5.2, 8.7 Hz), 7.42 (1H, d, J=5.1 Hz), 7.21 (2H, t, J=8.6 Hz), 4.74 (1H, s), 2.59-2.45 (4H, m), 2.35-2.27 (1H, m), 1.76-1.68 (1H, m). m/z (ES+) 434 [MH+].
Reaction SMILES: [Cl:1][S:2]([C:5]1[S:6][C:7]([Cl:10])=[CH:8][CH:9]=1)(=[O:4])=[O:3].[N+:11]([O-])([OH:13])=[O:12]>>[Cl:1][S:2]([C:5]1[S:6][C:7]([Cl:10])=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=1)(=[O:4])=[O:3]
Reactant: O=S(=O)(Cl)c1ccc(Cl)s1
Reactant: O=[N+]([O-])O
Product: O=[N+]([O-])c1cc(S(=O)(=O)Cl)sc1Cl
Temperature: 50 °C
Reaction time: 2 h

Procedure:
2--Chlorosulphonyl-5-chlorothiophene (19.8 parts) was added to fuming nitric acid (80 parts), allowing to exotherm to 35° C. Heated to 50° C. and stirred under these conditions for 2 hours. Cooled to room temperature then poured onto ice/water with vigorous stirring. The white solid was filtered off and dried to yield the product 2-chlorosulphonyl-4-nitro-5-chlorothiophene (19 parts).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7](F)=[CH:6][CH:5]=1)([O-:3])=[O:2].[C@H:11]1([NH2:18])[CH2:16][CH2:15][C@H:14]([NH2:17])[CH2:13][CH2:12]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C(=O)C>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:17][C@H:14]2[CH2:15][CH2:16][C@H:11]([NH2:18])[CH2:12][CH2:13]2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: N[C@H]1CC[C@H](N)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: N[C@H]1CC[C@H](Nc2ccc([N+](=O)[O-])cc2)CC1
Temperature: 144 °C
Reaction time: 72 h

Procedure:
A N,N-dimethylacetamide (30 ml) solution containing 4-nitrofluorobenzene (1.69 g) and trans-1,4-cyclohexanediamine (4.1 g) was stirred at 144° C. for 3 days. After cooling, an aqueous saturated potassium carbonate solution was added to the reaction solution, and the reaction mixture was extracted with ethyl acetate. The extract was dried over anhydrous potassium carbonate, and then, the solvent was removed under reduced pressure. The residue was purified by silica gel flash column chromatography (solvent: chloroform-methanol-ammonia (90:10:1)), and the solvent was removed to obtain trans-N-(4-nitrophenyl)-1,4-cyclohexanediamine (Reference Example 3-41 in Table 5) (2.31 g).
Reaction SMILES: [CH3:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:11].[H-].[Na+].[CH3:14]I.O>CN(C=O)C>[CH3:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[O:11][CH3:14]
Reactant: Cc1c(O)cccc1[N+](=O)[O-]
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cccc([N+](=O)[O-])c1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 86.1 %

Procedure:
To a solution of 2-methyl-3-nitrophenol (15.3 g, 100 mmol) in DMF (150 mL) was added sodium hydride (60% in mineral oil, 2.6 g, 110 mmol) at 0° C. and the mixture was stirred for 30 minutes at room temperature. Methyl iodide (28.4 g, 200 mmol) was added and the mixture was heated to 80° C. for 5 hours. Water (100 mL) was added and the mixture was extracted with ethyl acetate (3 times 100 mL). The combined ethyl acetate phases were dried over sodium sulphate and concentrated under vacuum to give a residue, which was purified by column chromatography on silica gel (PE:EtOAc=5:1). Evaporation afforded the title compound as a yellow solid (14.4 g).
Reaction SMILES: [Cl:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([CH3:8])[C:3]=1[C:9]([OH:11])=O.[CH3:12][CH:13]([C:19]1[CH:25]=[C:24]([CH:26]([C:31]([F:34])([F:33])[F:32])[C:27]([F:30])([F:29])[F:28])[CH:23]=[CH:22][C:20]=1[NH2:21])[CH2:14][CH2:15][CH:16]([CH3:18])[CH3:17].C(N(CC)CC)C>S(Cl)(Cl)=O.O1CCCC1.C(OCC)(=O)C>[CH3:12][CH:13]([C:19]1[CH:25]=[C:24]([CH:26]([C:27]([F:30])([F:29])[F:28])[C:31]([F:32])([F:33])[F:34])[CH:23]=[CH:22][C:20]=1[NH:21][C:9]([C:3]1[C:4]([CH3:8])=[N:5][N:6]([CH3:7])[C:2]=1[Cl:1])=[O:11])[CH2:14][CH2:15][CH:16]([CH3:17])[CH3:18]
Reactant: Cc1nn(C)c(Cl)c1C(=O)O
Reactant: CC(C)CCC(C)c1cc(C(C(F)(F)F)C(F)(F)F)ccc1N
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: Cc1nn(C)c(Cl)c1C(=O)Nc1ccc(C(C(F)(F)F)C(F)(F)F)cc1C(C)CCC(C)C
Yield: 20.1 %

Procedure:
5-Chloro-1,3-dimethylpyrazole-4-carboxylic acid (349 mg, 2 mmol) was dissolved in thionyl chloride (10 ml), and the solution was stirred at reflux temperature for 2 hours. After concentration under reduced pressure, the resulting acid chloride was added to a solution of 2-(1,4-dimethylpentyl)-4-[2,2,2-trifluoro-1-(trifluoromethyl)ethyl]aniline (682 mg, 2 mmol) and triethylamine (300 mg, 3 mmol) in tetrahydrofuran (20 ml) under ice-cooling, and the resulting mixture was stirred at reflux temperature for 2 hours. The reaction mixture was diluted with ethyl acetate and then washed with water. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure, and the resulting residue was separated and purified by silica gel column chromatography (hexane:ethyl acetate=2:3) to obtain 200 mg of the desired compound.
Reaction SMILES: [CH3:1][C:2]1[O:3][CH:4]=[CH:5][C:6]=1[CH2:7][OH:8].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:28]1([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:33]=[CH:32][C:31](O)=[CH:30][CH:29]=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C(OCC)C>[C:28]1([C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH:33]=[CH:32][C:31]([O:8][CH2:7][C:6]2[CH:5]=[CH:4][O:3][C:2]=2[CH3:1])=[CH:30][CH:29]=1
Reactant: Oc1ccc(-c2ccccc2)cc1
Reactant: Cc1occc1CO
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Product: Cc1occc1COc1ccc(-c2ccccc2)cc1
Temperature: 25 °C
Yield: 59.4 %

Procedure:
A solution of (2-methyl-furan-3-yl)-methanol (1)(5.0 g) in diethyl ether (75 mL) was cooled to 0° C. with stirring and treated with triphenylphosphine (12.85 g) and biphenyl-4-ol (7.59 g). The resulting solution was then treated drop-wise with diisopropylazodicarboxylate (9.75 mL). After stirring for 10 minutes at 0° C. the reaction mixture was allowed to warm to room temperature and then stirred for a further 3 hours. The reaction mixture was then filtered and concentrated in vacuo. The residue was purified by flash chromatography, eluting with diethyl ether/petroleum ether (1:19 by volume), to give compound 44 as a white solid (7.0 g). LC/MS System A: Rt=4.38 mins.