Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([O:5][C:6]2[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][C:7]=2[C:8]([OH:10])=O)[CH2:4][CH2:3][CH2:2]1.C(Cl)Cl.[NH2:19][C:20]1([C:29]#[N:30])[CH2:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:21]1.CCN(C(C)C)C(C)C>CC(O)C.C(Cl)Cl>[C:29]([C:20]1([NH:19][C:8](=[O:10])[C:7]2[CH:11]=[CH:12][CH:13]=[C:14]([CH3:15])[C:6]=2[O:5][CH:1]2[CH2:2][CH2:3][CH2:4]2)[CH2:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:21]1)#[N:30]
Reactant: Cc1cccc(C(=O)O)c1OC1CCC1
Reactant: N#CC1(N)Cc2ccccc2C1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cccc(C(=O)NC2(C#N)Cc3ccccc3C2)c1OC1CCC1
Reaction time: 0.08 h

Procedure:
A 30 mL vial is charged with 2-cyclobutoxy-3-methyl-benzoic acid (734 mg, 3.56 mmol) and dry DCM (10 mL). A stirring bar is added and stirring is initiated. After 5 min, HTBU (1.35 g, 3.56 mmol) is added. After 5 min, 2-amino-indane-2-carbonitrile. (308, 563 mg, 3.56 mmol) is added followed by DIPEA (1.5 mL, 8.95 mmol). The reaction is allowed to stir for 38 h. Analysis of the reaction mixture by tlc (silica, 15% iPrOH/DCM) indicates complete consumption of the starting amine. The contents of the reaction flask are transferred to a separatory funnel and diluted with EtOAc (60 mL). This is washed saturated aqueous NaHCO3 (2×20 mL) and brine (20 mL), dried over MgSO4, filtered and evaporated in vacuo to provide 1.2 g of thick black oil. This material is dissolved in 10 mL of DCM. This material is purified utilizing an ISCO Companion with a 40 g cartridge of silica. The gradient is 10% EtOAc in heptanes over 4 column volumes followed by a linear gradient to 50% EtOAc over 8 column volumes and then 90% EtOAc in heptanes for 2 column volumes. 17 mL fractions of UV active eluent are collected. Fractions 27 through 30 are combined and evaporated in vacuo to give white solid (0.51 g, 41%).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[NH2:11][C:12]1[CH:21]=[C:20]2[C:15]([CH:16]=[CH:17][CH:18]=[N:19]2)=[CH:14][CH:13]=1>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:11][C:12]2[CH:21]=[C:20]3[C:15]([CH:16]=[CH:17][CH:18]=[N:19]3)=[CH:14][CH:13]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccc(Br)cc1
Reactant: Nc1ccc2cccnc2c1
Product: O=C(Nc1ccc2cccnc2c1)c1ccc(Br)cc1

Procedure:
This material was prepared analogous to the procedure described for Example 1(c). 4-Bromo-benzoyl chloride (2.19 g, 10 mmol, Aldrich) reacted with 7-amino-quinoline (1.22 g, 8.5 mmol, prepared according to the procedure described in WO03099284) to give the title compound. MS (ESI, pos. ion) m/z: 328 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[CH2:5][C@@H:6]([NH:13][C:14]1[C:19]([N+:20]([O-])=O)=[CH:18][N:17]=[C:16]([CH:23]2[CH2:25][CH2:24]2)[N:15]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:2]>C(OCC)(=O)C.[Pd]>[CH2:1]([O:3][C:4](=[O:26])[CH2:5][C@@H:6]([NH:13][C:14]1[C:19]([NH2:20])=[CH:18][N:17]=[C:16]([CH:23]2[CH2:24][CH2:25]2)[N:15]=1)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)[CH3:2]
Reactant: CCOC(=O)C[C@@H](Nc1nc(C2CC2)ncc1[N+](=O)[O-])c1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)C[C@@H](Nc1nc(C2CC2)ncc1N)c1ccccc1
Reaction time: 1 h

Procedure:
(R)-3-(2-cyclopropyl-5-nitro-pyrimidine-4-ylamino)-3-phenyl-propionic acid ethyl ester (1.42 g, 4 mmol) was dissolved in ethyl acetate (30 ml). To the solution Pd/C (200 mg) was added and the mixture was stirred under hydrogen at 1 atm for 1 hour. The reaction mixture was filtered and evaporated to dryness to give oil. The residue was used as such for the next step.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].Cl[C:8]1[C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:16][C:15]2[C:10](=[CH:11][C:12]([F:24])=[C:13]([F:23])[CH:14]=2)[N:9]=1.[CH:25]1([NH:28][CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH2:27][CH2:26]1.O>C1(C)C=CC=CC=1.C(O)(=O)C>[CH2:21]([O:20][C:18]([C:17]1[C:8]([N:28]([CH:25]2[CH2:26][CH2:27]2)[CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])=[N:9][C:10]2[C:15]([CH:16]=1)=[CH:14][C:13]([F:23])=[C:12]([F:24])[CH:11]=2)=[O:19])[CH3:22]
Reactant: CCOC(=O)c1cc2cc(F)c(F)cc2nc1Cl
Reactant: CCOC(=O)CCNC1CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)CCN(c1nc2cc(F)c(F)cc2cc1C(=O)OCC)C1CC1
Temperature: 20 °C
Reaction time: 15 h
Yield: 65.6 %

Procedure:
3 g of sodium carbonate are added to a solution of 3.48 g of 2-chloro-3-ethoxycarbonyl-6,7-difluoroquinoline, prepared as described in Application Example 1, and 3 g of N-cyclopropyl-N-(b-ethoxycarbonylethyl)amine in 10 cm3 of toluene. The suspension obtained is heated to reflux and then stirred for 15 hours at this temperature. The reaction mixture is then cooled to approximately 20° C. and 30 cm3 of water and 4.5 cm3 of acetic acid are thereafter added. After settling has taken place, the reaction mixture is separated and washed with twice 10 cm3 of water. The organic phase is concentrated to dryness under reduced pressure (20 kPa) at approximately 50° C. 3.3 g of crude 3-ethoxycarbonyl-6,7-difluoro-2-[N-cyclopropyl-N-(b-ethoxycarbonylethyl)amino]quinoline are obtained in the form of an oil, which is used without further purification for the subsequent step.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]=[C:9]=[O:10])[CH:5]=[CH:6][CH:7]=1.[C:11]1([C:17]([OH:24])([C:21]([NH2:23])=[O:22])[C:18]([NH2:20])=[O:19])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(OCC)(=O)C.CCCCCCCC([O-])=O.CCCCCCCC([O-])=O.[Zn+2]>[C:11]1([C:17]([O:24][C:9]([NH:8][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)=[O:10])([C:21]([NH2:23])=[O:22])[C:18]([NH2:20])=[O:19])[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: NC(=O)C(O)(C(N)=O)c1ccccc1
Reactant: O=C=Nc1cccc(Cl)c1
Agent: CCCCCCCC(=O)[O-]
Agent: [Zn+2]
Solvent: CCOC(C)=O
Product: NC(=O)C(OC(=O)Nc1cccc(Cl)c1)(C(N)=O)c1ccccc1
Reaction time: 0.5 h
Yield: 55.6 %

Procedure:
0.5 g of zinc octoate and 4.45 g of 3-chlorophenyl isocyanate were added to 8.2 g of phenylhydroxymalonic acid diamide in 30 ml of ethyl acetate and the mixture was kept at 50° C. for 30 minutes. After cooling, the precipitate was filtered off with suction and recrystallised from acetone. 5.6 g of phenyl-(3-chlorophenylaminocarbonyloxy)-malonic acid diamide of melting point 196°-198° C. were obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH:13]([NH:14][CH3:15])[CH2:12][N:11]([C:16]([CH:18]3[CH2:23][CH2:22][N:21]([C:24]([C:26]4([CH3:29])[CH2:28][CH2:27]4)=[O:25])[CH2:20][CH2:19]3)=[O:17])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[Cl:30][C:31]1[CH:32]=[CH:33][C:34]([C:37]([OH:39])=O)=[N:35][CH:36]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:10][N:11]([C:16]([CH:18]3[CH2:19][CH2:20][N:21]([C:24]([C:26]4([CH3:29])[CH2:27][CH2:28]4)=[O:25])[CH2:22][CH2:23]3)=[O:17])[CH2:12][CH:13]2[N:14]([CH3:15])[C:37]([C:34]2[CH:33]=[CH:32][C:31]([Cl:30])=[CH:36][N:35]=2)=[O:39])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CNC1CN(C(=O)C2CCN(C(=O)C3(C)CC3)CC2)CC1c1ccc(Cl)c(Cl)c1
Reactant: O=C(O)c1ccc(Cl)cn1
Product: CN(C(=O)c1ccc(Cl)cn1)C1CN(C(=O)C2CCN(C(=O)C3(C)CC3)CC2)CC1c1ccc(Cl)c(Cl)c1

Procedure:
In analogy to the procedure described for the synthesis of example 97, the title compound 5-chloro-pyridine-2-carboxylic acid {(3RS,4SR)-4-(3,4-dichloro-phenyl)-1-[1-(1-methyl-cyclopropanecarbonyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-methyl-amide was prepared from {4-[(3SR,4RS)-3-(3,4-dichloro-phenyl)-4-methylamino-pyrrolidine-1-carbonyl]-piperidin-1-yl}-(1-methyl-cyclopropyl)-methanone using 5-chloro-2-pyridinecarboxylic acid instead of 4-chloro-3-(trifluoromethyl)benzoic acid and was obtained as a light brown oil. MS m/e: 577.2 [M]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([O:11][C:12]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([O:34][CH3:35])[N:29]=3)[C:13]=2[C:14]([O:16]CC2C=CC=CC=2)=[O:15])[N:4]=1.[H][H]>C(OCC)C.[Pd]>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([O:11][C:12]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([O:34][CH3:35])[N:29]=3)[C:13]=2[C:14]([OH:16])=[O:15])[N:4]=1
Reactant: COc1cccc(-c2cccc(Oc3nc(OC)cc(OC)n3)c2C(=O)OCc2ccccc2)n1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOCC
Product: COc1cccc(-c2cccc(Oc3nc(OC)cc(OC)n3)c2C(=O)O)n1

Procedure:
1.57 g of benzyl 2-(4,6-dimethoxypyrimidin-2-yloxy)-6-(6-methoxypyridin-2-yl)benzoate and 560 mg of palladium on active carbon (10%) in 100 ml of diethyl ether are hydrogenated at room temperature for 10 h at a hydrogen pressure of 50 bar. A further 300 mg of catalyst are then added and the mixture is hydrogenated at room temperature for another 10 h at a hydrogen pressure of 50 bar. The mixture is filtered through Celite® (Aldrich) and concentrated under reduced pressure. Yield: 0.99 g of a solid of m.p. 158°-160° C.
Reaction SMILES: [CH2:1]([N:7]=[C:8]=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].C[O:11][C:12](=O)[C:13]1[CH:18]=[CH:17][CH:16]=[N:15][C:14]=1[NH2:19]>N1C=CC=CC=1>[CH2:1]([N:7]1[C:12](=[O:11])[C:13]2[CH:18]=[CH:17][CH:16]=[N:15][C:14]=2[NH:19][C:8]1=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCN=C=O
Reactant: COC(=O)c1cccnc1N
Solvent: c1ccncc1
Product: CCCCCCn1c(=O)[nH]c2ncccc2c1=O
Yield: 30.8 %

Procedure:
17.46 g (137.3 mmol, 20 ml)n-hexyl isocyanate was added to a suspension of 5.31 g (34.9 mmol) 2-aminonicotinic acid methyl ester in 130 ml dry pyridine. The mixture was refluxed for 24 hours. The pyridine was removed under reduced pressure and the residue was treated with 160 ml ethanol. The mixture was refluxed for 10 minutes. The crude 3-hexyl-1H-pyrido[2,3-d]pyrimidine-2,4-dione crystallized from the medium and was purified by preparative column chromatography on straight phase silica (eluent:ethyl acetate:cyclohexane 1:2). 3-hexyl-1H-pyrido[2,3-d]pyrimidine-2,4-dione crystallized upon evaporation of the eluent. 2.66 g (310) of 3-hexyl-1H-pyrido[2,3-d]pyrimidine-2,4-dione was isolated (m.p. 166-168° C.)
Reaction SMILES: [C@H:1]1([NH:11][C:12]2[O:13][CH2:14][C:15]3[CH:21]=[C:20]([NH2:22])[CH:19]=[CH:18][C:16]=3[N:17]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.O=C1CCC(=O)N1[O:30][C:31](=O)[CH2:32][Cl:33]>C(#N)C>[Cl:33][CH2:32][C:31]([NH:22][C:20]1[CH:19]=[CH:18][C:16]2[N:17]=[C:12]([NH:11][C@H:1]3[C:10]4[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=4)[CH2:4][CH2:3][CH2:2]3)[O:13][CH2:14][C:15]=2[CH:21]=1)=[O:30]
Reactant: Nc1ccc2c(c1)COC(N[C@@H]1CCCc3ccccc31)=N2
Reactant: O=C(CCl)ON1C(=O)CCC1=O
Solvent: CC#N
Product: O=C(CCl)Nc1ccc2c(c1)COC(N[C@@H]1CCCc3ccccc31)=N2
Temperature: 23 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
A mixture of (R)-N2-(1,2,3,4-tetrahydro-naphthalen-1-yl)-4H-benzo[d][1,3]oxazine-2,6-diamine (Example 33) (293 mg, 1 mmol) and chloro-acetic acid 2,5-dioxo-pyrrolidin-1-yl ester (CAS 27243-15-8) (192 mg, 1 mmol) in acetonitrile (2 ml) was stirred at 23° C. for 1 h. Poured onto water and extracted with ethyl acetate, dried the combined organic layers over sodium sulfate, filtered off and evaporated totally to give the title compound as a light red oil (370 mg, 100%, HPLC 1.185 min), MS (ISP) m/e=370.1 [(M+H)+] and 372 [(M+2+H)+].
Reaction SMILES: [CH3:1][C:2]1([CH3:35])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[C:11]3[C:32](=[CH:33][CH:34]=2)[C:15]2[NH:16][C:17]([C@@H:19]4[CH2:24][C@@H:23]5[C@@H:21]([CH2:22]5)[N:20]4[C:25]([O:27]C(C)(C)C)=O)=[N:18][C:14]=2[CH:13]=[CH:12]3)[O:3]1.Cl.[CH3:37][O:38][C:39]([NH:41][C@@H:42]([CH:46]([CH3:48])[CH3:47])C(O)=O)=[O:40].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl.CO>[CH3:47][CH:46]([CH3:48])[C@H:42]([NH:41][C:39](=[O:40])[O:38][CH3:37])[C:25](=[O:27])[N:20]1[C@H:19]([C:17]2[NH:16][C:15]3[C:32]4[C:11]([CH:12]=[CH:13][C:14]=3[N:18]=2)=[CH:10][C:9]([B:4]2[O:3][C:2]([CH3:1])([CH3:35])[C:6]([CH3:7])([CH3:8])[O:5]2)=[CH:34][CH:33]=4)[CH2:24][C@@H:23]2[C@H:21]1[CH2:22]2
Reactant: COC(=O)N[C@H](C(=O)O)C(C)C
Reactant: CC(C)(C)OC(=O)N1[C@@H]2C[C@@H]2C[C@H]1c1nc2ccc3cc(B4OC(C)(C)C(C)(C)O4)ccc3c2[nH]1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Solvent: ClCCl
Product: COC(=O)N[C@H](C(=O)N1[C@@H]2C[C@@H]2C[C@H]1c1nc2ccc3cc(B4OC(C)(C)C(C)(C)O4)ccc3c2[nH]1)C(C)C
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 86.7 %

Procedure:
To a solution of (1R,3S,5R)-tert-butyl 3-(7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-naphtho[1,2-d]imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate (0.60 g, 1.3 mmol) in a mixture of CH2Cl2 (12.0 mL) and MeOH (2.5 mL) was added HCl (4M in 1,4-dioxane, 9.4 mL, 37.6 mmol). The solution was stirred at room temperature for 2.5 h and concentrated to dryness. The crude intermediate was suspended in CH2Cl2 (12 mL). (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (0.25 g, 1.4 mmol), HATU (0.58 g, 1.5 mmol), and DIPEA (0.7 mL, 4.0 mmol) were sequentially added to the reaction. The homogenous solution was then stirred at room temperature for 1.5 h. The solution was diluted with CH2Cl2 and washed with HCl (aqueous, 1N) and aqueous bicarbonate (sat.). The aqueous layers were back extracted with CH2Cl2 and the combined organic layers were dried over Na2SO4 and concentrated. The crude oil was then purified by silica gel chromatography (30 to 100% EtOAc (5% MeOH)/Hexanes) to provide methyl (S)-3-methyl-1-oxo-1-((1R,3S,5R)-3-(7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-naphtho[1,2-d]imidazol-2-yl)-2-azabicyclo[3.1.0]hexan-2-yl)butan-2-ylcarbamate (0.60 g, 89%). LCMS-ESI+: calc'd for C29H37BN4O5: 532.29 (M+); Found: 533.11 (M+H+).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([N:11]2[CH2:22][CH2:21][C:14]3[N:15]=[C:16]([S:19][CH3:20])[N:17]=[CH:18][C:13]=3[CH2:12]2)[N:6]=1)=[O:4].[OH-].[Na+]>O1CCOCC1>[CH3:20][S:19][C:16]1[N:17]=[CH:18][C:13]2[CH2:12][N:11]([C:7]3[N:6]=[C:5]([C:3]([OH:4])=[O:2])[CH:10]=[CH:9][CH:8]=3)[CH2:22][CH2:21][C:14]=2[N:15]=1
Reactant: COC(=O)c1cccc(N2CCc3nc(SC)ncc3C2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CSc1ncc2c(n1)CCN(c1cccc(C(=O)O)n1)C2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of methyl-6-[2-(methylthio)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-6-yl]pyridine-2-carboxylate (2.76 g, 8.72 mmol) in 1,4-dioxane (50 ml) was treated with 1.0N NaOH(aq.) (13.09 ml, 13.09 mmol) and the reaction mixture was stirred at room temperature for 2 hours. The solvent was removed in vacuo and the residue was diluted with water. The aqueous phase was washed with diethyl ether and acidified to pH ˜5-6 with 1.0N HCl(aq.). The precipitate was collected, washed with water, ethyl acetate, and dried to give the title compound as a yellow, amorphous solid (2.52 g, 96%).
Reaction SMILES: [CH3:1][C:2]1[C:6]([N+:7]([O-:9])=O)=[C:5]([CH3:10])[O:4][N:3]=1.N1CC[CH2:14][CH2:13][CH2:12]1.C(=O)CC>CCO>[CH3:1][C:2]1[C:6]2=[N+:7]([O-:9])[C:13]([CH3:14])=[CH:12][CH:10]=[C:5]2[O:4][N:3]=1
Reactant: Cc1noc(C)c1[N+](=O)[O-]
Reactant: C1CCNCC1
Solvent: CCC=O
Solvent: CCO
Product: Cc1noc2ccc(C)[n+]([O-])c12
Temperature: 90 °C
Yield: 225 %

Procedure:
3,5-dimethyl-4-nitroisoxazole (2.50 g, 17.6 mmol) in 25 mL EtOH was dissolved. Piperidine (0.174 mL, 1.76 mmol) was added followed by propionaldehyde (1.52 mL, 21.1 mmol). The solution was heated at 90° C. overnight. The solution was concentrated and chromatographed using EtOAc to obtain the title compound (0.650 g, 22.5% yield).
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[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][C:17]=1[CH3:23].[F:24][C:25]1[CH:30]=[CH:29][C:28]([N:31]2[C:36](=[O:37])[C:35]([C:38](O)=[O:39])=[CH:34][N:33]([CH:41]([CH3:43])[CH3:42])[C:32]2=[O:44])=[CH:27][CH:26]=1>>[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[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:38]([C:35]2[C:36](=[O:37])[N:31]([C:28]3[CH:27]=[CH:26][C:25]([F:24])=[CH:30][CH:29]=3)[C:32](=[O:44])[N:33]([CH:41]([CH3:43])[CH3:42])[CH:34]=2)=[O:39])=[CH:18][C:17]=1[CH3:23]
Reactant: CC(C)n1cc(C(=O)O)c(=O)n(-c2ccc(F)cc2)c1=O
Reactant: COc1cc2nccc(Oc3ccc(N)cc3C)c2cc1OC
Product: COc1cc2nccc(Oc3ccc(NC(=O)c4cn(C(C)C)c(=O)n(-c5ccc(F)cc5)c4=O)cc3C)c2cc1OC

Procedure:
This compound was synthesized using 4-(6,7-Dimethoxy-quinolin-4-yloxy)-3-methyl-phenylamine and 3-(4-fluorophenyl)-1-isopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid using the procedure for example 1. mp=238-240° C.; LCMS m/z=585 (M+1); 1H NMR (DMSO-d6) δ: 10.92 (s, 1H), 8.65 (s, 1H), 8.44 (d, 1H, J=6 Hz), 7.73-7.67 (m, 2H), 7.55 (s, 1H), 7.45-7.41 (m, 2H), 7.39-7.34 (m, 3H), 7.17 (d, 1H, J=8 Hz), 6.31 (d, 1H, J=4.5 Hz), 4.78 (p, 1H, J=6 Hz), 3.95 (s, 6H), 2.09 (s, 3H), 1.43 (d, 6H, J=7 Hz).
Reaction SMILES: [CH:1]1[C:6]([CH2:7][C:8]2[CH:13]=[CH:12][C:11](I)=[CH:10][CH:9]=2)=[CH:5][CH:4]=[C:3](I)[CH:2]=1.[C:16]([Si:18]([CH3:21])([CH3:20])[CH3:19])#[CH:17]>>[CH3:19][Si:18]([C:16]#[C:17][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([C:17]#[C:16][Si:18]([CH3:21])([CH3:20])[CH3:19])=[CH:10][CH:9]=2)=[CH:1][CH:2]=1)([CH3:21])[CH3:20]
Reactant: Ic1ccc(Cc2ccc(I)cc2)cc1
Reactant: C#C[Si](C)(C)C
Product: C[Si](C)(C)C#Cc1ccc(Cc2ccc(C#C[Si](C)(C)C)cc2)cc1

Procedure:
In Step II, 4,4'-diiododiphenylmethane [Compound (2)] was then coupled with ethynyltrimethylsilane [Compound (3)] to form an end-protected bis(4 trimethylsilylethynylphenyl) methane [Compound (4)] by forming a solution comprising 8.40 g (20.0 mmoles) of 4,4'-diiododiphenylmethane and 2.50 g (25.5 mmoles) of ethynyltrimethylsilane in 150 ml of 2:1 triethylamine toluene deaerated with argon. This solution was subsequently treated with a catalyst mixture comprising 50 mg of dichlorobis(triphenylphosphine)palladium[II], 150 mg of triphenylphosphine and 50 mg of copper[I] iodide. The yellow solution thus obtained was stirred and warmed to 80°-90° C. over 1 hour and kept in this temperature range for 4 hours. A copious white precipitate was formed which was filtered off after cooling to 25° C. and diluting with 150 ml of ether. The yield of triethylamine hydroiodide [Compound (5)] was quantitative. The filtrate was concentrated to a thick oil, dissolved in 200 ml of ether and washed with 200 ml each of 10% aqueous hydrochloric acid, water, saturated aqueous sodium bicarbonate, and water again. The ethereal phase was dried over magnesium sulfate and concentrated to an oil which crystallized on standing. The solid was taken up in 100 ml of 1:1 hexane/dichloromethane and filtered through a bed of silica gel. The filtrate was evaporated down to half of the original volume and cooled at -78° C. to precipitate 7.20 g (20.0 mmoles; 100%) of a crystalline solid. Recrystallization from hexane yielded pure, lustrous crystals in 81% recovery: mp 110°-111° C.; IR (KBr) 2970 (strong, sharp, SiCH3), 2160 (strong, sharp, C≡C), 1505 (strong, sharp, C=C), 1250 (strong, sharp, SiCH3) and 840 cm (very strong, broad, Si--C bending); NMR (CDCl3) δ0.28 (s, 18H, SiCH3), 3.92 (s, 2H, CH2), 7.37 and 7.40 ppm (q, 8H, JAB =8.0 Hz, aromatic).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([C:15]([OH:17])=O)=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:5][CH:4]=1.C(Cl)(=O)C(Cl)=O.[NH:26]1[CH2:34][CH2:33][CH:29]([C:30]([NH2:32])=[O:31])[CH2:28][CH2:27]1.C(N(CC)CC)C.C(=O)([O-])O.[Na+]>CN(C)C=O.ClCCl>[F:18][C:2]([F:1])([F:19])[C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:15]([N:26]2[CH2:34][CH2:33][CH:29]([C:30]([NH2:32])=[O:31])[CH2:28][CH2:27]2)=[O:17])=[CH:7][CH:8]=1
Reactant: O=C(O)c1ccccc1-c1ccc(C(F)(F)F)cc1
Reactant: NC(=O)C1CCNCC1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: NC(=O)C1CCN(C(=O)c2ccccc2-c2ccc(C(F)(F)F)cc2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 82.1 %

Procedure:
4′-(Trifluoromethyl)-2-biphenylcarboxylic acid (20.5 g; 77 mmol) is dissolved in 340 ml of dimethylformamide and 200 ml of dichloromethane. The reaction medium is placed at 0° C. and oxalyl chloride (1.8 eq.; 138.6 mmol; 12 ml) is added. The reaction medium is stirred at room temperature for 3 hours and then evaporated to dryness. The crude product is taken up in 270 ml of dichloromethane, followed by addition of a solution of isonipecotamide (0.97 eq.; 74.7 mmol; 9.57 g) and triethylamine (2.7 eq.; 207.9 mmol; 29 ml) in 270 ml of dichloromethane, placed at 0° C. The mixture is allowed to warm to room temperature over 12 hours, saturated aqueous sodium hydrogen carbonate solution is then added (in a 1/1 proportion) and the resulting mixture is stirred for 30 minutes. The organic phase is washed with 1M sodium hydroxide solution and then with water, dried over sodium sulfate and evaporated to dryness. The crude product is dispersed in diisopropyl ether and then filtered off and dried to give 23.09 g of coupling product.
Reaction SMILES: C1(=O)[N:5]([C:6]2[C:11]([N:12]3C(=O)C4=CC=CC=C4C3=O)=[N:10][C:9]3=[N:23][S:24][N:25]=[C:8]3[N:7]=2)C(=O)C2=CC=CC=C12.NN>>[NH2:12][C:11]1[C:6]([NH2:5])=[N:7][C:8]2=[N:25][S:24][N:23]=[C:9]2[N:10]=1
Reactant: O=C1c2ccccc2C(=O)N1c1nc2nsnc2nc1N1C(=O)c2ccccc2C1=O
Agent: NN
Product: Nc1nc2nsnc2nc1N

Procedure:
The cyclization reaction of o-diaminobenzene (compound II) in an aqueous solution of glyoxal and sodium hydrogen sulfite gives quinoxaline (compound III; See R. G. Jones et al., Org. Syn. Collective Vol. IV, page 824). Quinoxaline is in turn oxidized by an aqueous solution of potassium permanganate to produce 2,3-pyrazinedicarboxylic acid (compound IV; See R. G. Jones et al., Org. Syn. Collective Vol. IV, page 824). 2,3-pyrazinedicarboxylic acid is then chlorinated with phosphorus pentachloride at 300° C. to produce 2,3,5,6-tetrachloropyrazine (compound V; See C. G. Allison et al., J. Chem. Soc. (C), 1970, page 1023). The reaction of 2,3,5,6-tetrachloropyrazine with ammonium chloride at a temperature of 120° C. gives 2,3-diamino-5,6-dichloropyrazine (compound VI; See Palamidess et al., Ed. Sc. XXI-fasc, 11, 1966, page 810). The cyclization reaction of 2,3-diamino-5,6-dichloropyrazine with thionyl chloride in the presence of pyridine in xylene produces 5,6-dichloro-[1,2,5]thiadiazolo[3,4-b]pyrazine (compound VII; See Y. C. Tong, J. Heterocyclic Chem., 12, 1975, page 451 ). The 5,6-dichloro-[1,2,5]thiadiazolo[3,4-b]pyrazine is reacted with potassium phthalimide in the presence of dimethyl formamide (DMF) at a temperature of 60° C. to produce 5,6-diphthalimido[1,2,5]thiadiazolo[3,4-b]pyrazine (compound VIII; See Example 1). The 5,6-diphthalimido-[1,2,5]thiadiazolo[3,4-b]pyrazine is then reacted with an aqueous solution of hydrazine at 0° C. to produce 5,6-diamino-[1,2,5]thiadiazolo[3,4-b]pyrazine (compound IX; See Example 2). Finally the cyclization reaction of 5,6-diamino[1,2,5]thiadiazolo[3,4-b]pyrazine with thionyl chloride in the presence of pyridine in methylene chloride gives bis[1,2,5]thiadiazolo[3,4-b:3',4'-e]pyrazine (compound I; See Example 3).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[O:10][C:11]3[CH:17]=[C:16]([O:18][CH2:19][C@@H:20]([NH:22][C:23](=[O:25])[CH3:24])[CH3:21])[CH:15]=[CH:14][C:12]=3[N:13]=2)[CH:5]=[CH:6][C:7]=1[OH:8].[F:26][C:27]([F:32])([F:31])[CH2:28][CH2:29]I>>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[O:10][C:11]3[CH:17]=[C:16]([O:18][CH2:19][C@@H:20]([NH:22][C:23](=[O:25])[CH3:24])[CH3:21])[CH:15]=[CH:14][C:12]=3[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:29][CH2:28][C:27]([F:32])([F:31])[F:26]
Reactant: CC(=O)N[C@@H](C)COc1ccc2nc(-c3ccc(O)c(F)c3)oc2c1
Reactant: FC(F)(F)CCI
Product: CC(=O)N[C@@H](C)COc1ccc2nc(-c3ccc(OCCC(F)(F)F)c(F)c3)oc2c1

Procedure:
Using N-((2S)-1-((2-(3-fluoro-4-hydroxyphenyl)-1,3-benzoxazol-6-yl)oxy)propan-2-yl)acetamide and 1,1,1-trifluoro-3-iodopropane, and in the same manner as in Example 5, the title compound was obtained.