Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[CH2:11]([NH2:14])[CH2:12][CH3:13]>CCO>[N+:8]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:2]=1[NH:14][CH2:11][CH2:12][CH3:13])([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1cnccc1Cl
Reactant: CCCN
Solvent: CCO
Product: CCCNc1ccncc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-chloro-3-nitro-pyridine (18.0 g, 114 mmol) in EtOH(300 ml) is added n-propylamine (46.9 ml, 568 mmol) slowly at 0° C. and the resulting yellow mixture is warmed to room temp. After stirring for 2 h, the reaction is concentrated in vacuo. The residue is purified by flash chromatography (eluent 50% Hex/EtOAc) to give (3-nitro-pyridin-4-yl)-propyl-amine as a yellow solid. 1H NMR (CDCl3) δ 9.16 (s, 1H), 8.25 (d, J=6 Hz, 1H), 8.15 (br s, 1H), 6.68 (d, J=6 Hz, 1H), 3.29 (q, J=6.8 Hz, 2H), 1.74 (sextet, J=7.2 Hz, 2H), 1.02 (t, J=7.6 Hz, 3H). LRMS calcd 181.19. found 182.5 (MH+).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:11])[CH3:10].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:19][CH:20]=[C:21]([CH3:23])[CH3:22].Cl>O1CCCC1>[OH:1][C:2]1[C:7]([CH2:19][CH:20]=[C:21]([CH3:23])[CH3:22])=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:11])[CH3:10]
Reactant: CC(=O)c1ccc(O)cc1O
Reactant: CC(C)=CCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(=O)c1ccc(O)c(CC=C(C)C)c1O
Temperature: 25 °C
Reaction time: 120 h
Yield: 45.4 %

Procedure:
In 750 ml of tetrahydrofuran was dissolved 149.95 g of 2',4'-dihydroxyacetophenone, and 409.26 g of anhydrous potassium carbonate and 150 ml of 1-chloro-3-methyl-2-butene were added to the solution and the mixture was stirred at room temperature in a nitrogen current for 5 days. After the reaction, 3 N hydrochloric acid was added to the reaction liquid under cooling to make the aqueous layer acidic, and the aqueous layer was extracted with ether. The ether extract was washed with water and dried with anhydrous sodium sulfate and the solvent was removed by distillation. Then, 800 ml of hexane was added to the obtained residue and the hexane-soluble substances were removed by decantation to obtain 98.55 g (yield=45.4%) of 2',4'-dihydroxy-3'-(3-methyl-2-butenyl)acetophenone in the form of a colorless solid.
Reaction SMILES: [CH2:1]([OH:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].OO.C(=[O:20])CCCCCCC>[Pt]>[C:1]([OH:20])(=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCO
Reactant: CCCCCCCC=O
Agent: [Pt]
Agent: OO
Product: CCCCCCCC(=O)O
Temperature: 90 °C
Reaction time: 0.17 h
Yield: 19 %

Procedure:
Platinum black (19.5 mg, 0.100 mmol) and 1-octanol (1.6 ml, 10 mmol) were mixed and stirred at 90° C. for 10 minutes. A 30% aqueous hydrogen peroxide solution (1.3 ml, 12 mmol) was gradually added dropwise to the mixed solution, followed by stirring at 90° C. for 5 hours, and then the reaction solution was cooled to room temperature. As a result of measurement by GLC, it was found that 1-octanal was obtained in yield of 18%, and 1-octanoic acid was obtained in yield of 19%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]([N+:14]([O-:16])=[O:15])=[CH:10][C:11]=1[O:12][CH3:13])[C:6]([OH:8])=O.[CH:17]1([C:23]([CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[O:24])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.C(N(CC)CC)C>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]([N+:14]([O-:16])=[O:15])=[CH:10][C:11]=1[O:12][CH3:13])[C:6]([N:28]1[CH2:27][CH2:26][CH:25]([C:23]([CH:17]2[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]2)=[O:24])[CH2:30][CH2:29]1)=[O:8]
Reactant: COc1cc(C(=O)O)c([N+](=O)[O-])cc1OC
Reactant: O=C(C1CCCCC1)C1CCNCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(C(=O)N2CCC(C(=O)C3CCCCC3)CC2)c([N+](=O)[O-])cc1OC

Procedure:
10.3 g of 3,4-dimethoxy-6-nitrobenzoic acid was converted to the corresponding acid chloride as described in Example 43. It was added to a solution containing 8.83 g of 4-cyclohexylcarbonylpiperidine and 4.58 g of triethylamine in 300 ml of dichloromethane. Yield 16.4 g (90%), m.p. 120°-125° C.
Reaction SMILES: CCO.[C:4]1([C:10]2[CH:15]=[C:14]([C:16]([O:18][CH3:19])=[O:17])[CH:13]=[C:12]([O:20]CC3C=CC=CC=3)[N:11]=2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[H][H]>[C].[Pd].C1COCC1>[O:20]=[C:12]1[CH:13]=[C:14]([C:16]([O:18][CH3:19])=[O:17])[CH:15]=[C:10]([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:11]1
Reactant: COC(=O)c1cc(OCc2ccccc2)nc(-c2ccccc2)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: COC(=O)c1cc(-c2ccccc2)[nH]c(=O)c1

Procedure:
In a nitrogen atmosphere, 10% palladium-carbon (3.2 g) was added to an EtOH (50 mL)-THF (5 mL) mixed solution of methyl 2-phenyl-6-benzyloxypyridine-4-carboxylate (5.3 g), and in a hydrogen atmosphere, this was stirred at room temperature for 9 hours. The reaction liquid was filtered through Celite, concentrated under reduced pressure, and a mixed solution of hexane/ethyl acetate=2/1 was added thereto. The precipitate was taken out through filtration, washed with that solution, and dried to obtain the title compound as a white powder. The filtrate was concentrated, and the residue was purified through silica gel column chromatography (from hexane/ethyl acetate to chloroform/methanol), and combined with the previous powder to obtain the title compound as a white powder.
Reaction SMILES: [NH2:1][C:2]1[N:6]=[C:5]([C:7]2[S:8][CH:9]=[CH:10][C:11]=2[Cl:12])[O:4][N:3]=1.[Cl:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][CH:15]=1>C1(C)C=CC=CC=1>[Cl:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=[N:1][C:2]2[N:6]=[C:5]([C:7]3[S:8][CH:9]=[CH:10][C:11]=3[Cl:12])[O:4][N:3]=2)=[CH:16][CH:15]=1
Reactant: Nc1noc(-c2sccc2Cl)n1
Reactant: O=Cc1ccc(Cl)cc1
Solvent: Cc1ccccc1
Product: Clc1ccc(C=Nc2noc(-c3sccc3Cl)n2)cc1

Procedure:
Compounds of this invention with a linker between middle ring and Ar2 may be prepared as illustrated by the exemplary reaction in Scheme 11. Reaction of 3-chloro-thiophene-2-carbonyl chloride with cyanamide produces N-cyano-3-chloro-thiophene-2-carboxylic acid amide, followed by treating with hydroxyamine to give 3-amino-5-(3-chloro-2-thienyl)-1,2,4-oxadiazole. The amine was refluxed with 4-chlorobenzaldehyde in toluene to produce (4-chloro-benzylidene)-[5-(3-chloro-thiophen-2-yl)-[1,2,4]-oxadiazol-3-yl]-amine.
Reaction SMILES: [CH3:1][S:2]([CH2:5][CH2:6][O:7][C:8]1[CH:9]=[C:10]([C:19]2[N:20]=[C:21]3[C:27]([C:28](=[O:33])[C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:26][N:25](COCC[Si](C)(C)C)[C:22]3=[N:23][CH:24]=2)[CH:11]=[C:12]([N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)[CH:13]=1)(=[O:4])=[O:3].CO.Cl.C([O-])(O)=O.[Na+]>CCOC(C)=O>[CH3:1][S:2]([CH2:5][CH2:6][O:7][C:8]1[CH:9]=[C:10]([C:19]2[N:20]=[C:21]3[C:27]([C:28](=[O:33])[C:29]([CH3:31])([CH3:30])[CH3:32])=[CH:26][NH:25][C:22]3=[N:23][CH:24]=2)[CH:11]=[C:12]([N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)[CH:13]=1)(=[O:4])=[O:3]
Reactant: CC(C)(C)C(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3cc(OCCS(C)(=O)=O)cc(N4CCCC4)c3)nc12
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)(C)C(=O)c1c[nH]c2ncc(-c3cc(OCCS(C)(=O)=O)cc(N4CCCC4)c3)nc12
Reaction time: 0.83 h
Yield: 62.1 %

Procedure:
To a flask containing 1-[2-[3-(2-methanesulfonyl-ethoxy)-5-pyrrolidin-1-yl-phenyl]-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-2,2-dimethyl-propan-1-one (75 mg, 0.13 mmol) was added methanol (1 ml) and aqueous 6N HCl (1.5 ml). The flask was capped and placed in a heated oil bath (90° C.). After stirring for 50 minutes the mixture was cooled to ambient and the volatiles were stripped (rotovap/pump). The remainder was taken up in EtOAc (15 ml) and 5% aqueous NaHCO3 (15 ml) and stirred for 5 minutes. The material was partitioned and the organic phase collected and washed with brine (15 ml). The aqueous phases were back extracted with EtOAc (2×15 ml). The organics were combined, dried (MgSO4), filtered and stripped to provide a crude semi-solid. The material was purified by crystallization from hot CH2Cl2/hexanes (containing 4 drops of methanol) to afford 38 mg of 1-{2-[3-(2-methanesulfonyl-ethoxy)-5-pyrrolidin-1-yl-phenyl]-5H-pyrrolo[2,3-b]pyrazin-7-yl}-2,2-dimethyl-propan-1-one as a yellow solid. MP 230-232° C., M+H=471.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([C:9]([F:12])([F:11])[F:10])[CH:3]=1.Cl[CH2:14][CH2:15][N:16]([CH2:27][CH2:28]Cl)S(C1C=CC(C)=CC=1)(=O)=O>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:28][CH2:27][NH:16][CH2:15][CH2:14]2)=[C:4]([C:9]([F:10])([F:11])[F:12])[CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)N(CCCl)CCCl)cc1
Reactant: Cc1ccc(N)c(C(F)(F)F)c1
Product: Cc1ccc(N2CCNCC2)c(C(F)(F)F)c1
Yield: 26.4 %

Procedure:
Using 4-methyl-2-trifluoromethylphenylamine (1 g) and N,N-bis(2-chloroethyl)-p-toluenesulfonamide (1.69 g) and by the reaction and treatment in the same manner as in Preparation Example 95, the title compound (368 mg) was obtained.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6]1[C:10]([CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:9][N:8]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=2)[N:7]=1)[CH3:4].Cl[CH2:27][C:28]1[N:29]=[C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([O:36][CH2:37][CH3:38])[N:31]2[CH:39]=1.O>CN(C)C=O>[CH2:3]([O:5][C:6]1[C:10]([CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:9][N:8]([CH2:18][C:19]2[CH:20]=[CH:21][C:22]([O:25][CH2:27][C:28]3[N:29]=[C:30]4[CH:35]=[CH:34][CH:33]=[C:32]([O:36][CH2:37][CH3:38])[N:31]4[CH:39]=3)=[CH:23][CH:24]=2)[N:7]=1)[CH3:4]
Reactant: CCOc1cccc2nc(CCl)cn12
Reactant: CCOC(=O)CCc1cn(Cc2ccc(O)cc2)nc1OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCc1cn(Cc2ccc(OCc3cn4c(OCC)cccc4n3)cc2)nc1OCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 59.8 %

Procedure:
Sodium hydride (60%, oily, 60.0 mg) was added to a solution of ethyl 3-[3-ethoxy-1-(4-hydroxybenzyl)-1H-pyrazol-4-yl]propionate (478 mg) and 2-chloromethyl-5-ethoxyimidazo[1,2-a]pyridine (316 mg) in N,N-dimethylformamide (10 ml) at 0° C., and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl 3-[3-ethoxy-1-[4-(5-ethoxyimidazo[1,2-a]pyridin-2-ylmethoxy)benzyl]-1H-pyrazol-4-yl]propionate (442 mg, yield: 60%) as a colorless oily substance from the fraction eluted with ethyl acetate.
Reaction SMILES: [CH:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1)=O.[CH3:16][CH2:17][O:18][C:19](/[C:21](/P(OCC)(OCC)=O)=[CH:22]\[CH3:23])=[O:20].O[Li].O>C1COCC1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[CH2:17]([O:18][C:19](=[O:20])/[CH:21]=[CH:22]/[CH:23]=[CH:1]/[CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1)[CH3:16]
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Reactant: C/C=C(\C(=O)OCC)P(=O)(OCC)OCC
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)/C=C/C=C/C1CCN(C(=O)OC(C)(C)C)CC1
Yield: 95.3 %

Procedure:
A mixture of the above aldehyde (21) (2.10 g, 10 mmol), triethyl trans-4-phosphono-2-butenoate (3.0 g, 12 mmol), LiOH—H2O (510 mg, 12 mmol) and 4A molecular sieve (5 g) in THF (100 mL) was heated at reflux 1.5 hours. The molecular sieve was filtered through a short pad of Celite and washed with EtOAc (100 mL) and the filtrate concentrated to give sticky brown oil. The oily residue was diluted with 5% citric acid and extracted thrice with 100 mL of EtOAc. The combined extracts were washed with NaHCO3, brine, then dried over Na2SO4 and concentrated. Purification by flash chromatography (EtOAc:Hexanes=1:5) gave a white solid (22) (2.95 g, 95%) of the desired compound. 1H NMR (500 MHz, CDCL3) δ 7.24 (dd, J=15.5, 10.5 Hz, 1H), 6.16 (dd, J=15.5, 10.5 Hz, 1H), 6.04 (dd, J=15.5, 7.0 Hz, 1H), 5.82 (d, J=15.5 Hz, 1H), 4.20 (q, J=7.0 Hz, 2H), 4.10 (m, 2H), 2.75 (m, 2H), 2.25 (m, 1H), 1.71 (m, 2H), 1.46 (s, 9H), 1.34 (m, 2H), 1.29 (t, J=7.0 Hz, 3H); MS (ESI+) m/z 210.75 (M+H+-boc).
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:18][CH2:19][CH3:20])[CH2:5][N:6]1[C:10]([NH2:11])=[CH:9][C:8]([C:12]2[CH:17]=[N:16][CH:15]=[CH:14][N:13]=2)=[N:7]1)[CH3:2].Br[C:22]1[CH:27]=[C:26]([N+:28]([O-:30])=[O:29])[CH:25]=[CH:24][C:23]=1[CH3:31]>>[CH2:19]([O:18][CH:4]([O:3][CH2:1][CH3:2])[CH2:5][N:6]1[C:10]([NH:11][C:22]2[CH:27]=[C:26]([N+:28]([O-:30])=[O:29])[CH:25]=[CH:24][C:23]=2[CH3:31])=[CH:9][C:8]([C:12]2[CH:17]=[N:16][CH:15]=[CH:14][N:13]=2)=[N:7]1)[CH3:20]
Reactant: Cc1ccc([N+](=O)[O-])cc1Br
Reactant: CCOC(Cn1nc(-c2cnccn2)cc1N)OCC
Product: CCOC(Cn1nc(-c2cnccn2)cc1Nc1cc([N+](=O)[O-])ccc1C)OCC

Procedure:
Analogously to Example 13A/Step 1, 1.16 g (4.18 mmol) of the compound of Example 59A and 994 mg (4.60 mmol) of 2-Bromo-4-nitrotoluene gave 1.64 g (86% of theory) of the title compound.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.CC(C)([O-])C.[K+].Cl[C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[N:21][CH:22]=2)[CH:17]=[CH:16][N:15]=1>C(O)(C)(C)C>[N:1]1([C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[N:21][CH:22]=3)[CH:17]=[CH:16][N:15]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1
Reactant: C1CNCCN1
Reactant: Clc1nccc2ccncc12
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: c1cc2ccnc(N3CCNCC3)c2cn1
Reaction time: 8 h
Yield: 63.9 %

Procedure:
A solution of piperazine (5.5 g, 64 mmol) in t-butanol (50 mL) was treated with potassium t-butoxide (0.9 g, 8 mmol) in one portion. After stirring for 10 minutes at 40° C. a solution of 1-chloro-2,7-naphthyridine (1.2 g, 7.3 mmol) in 10 mL of t-butanol was added. Stirring was continued overnight at 40° C. after which the solvent was removed in vacuo. The residue was purified by flash chromatography (silica gel 60 Merck, methylene chloride-methanol-ammonia 9:1:0.125) to give the product (1.0 g, 64%) as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:7][C@H:6]1[C:8]([OH:10])=O)=[O:4].[B-](F)(F)(F)F.CCOC(C(C#N)=NOC(N(C)C)=[N+](C)C)=O.CN1CCOCC1.[CH3:40][C@H:41]1[CH2:46][CH2:45][C@H:44]([NH2:47])[CH2:43][CH2:42]1>CN(C=O)C>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:7][C@H:6]1[C:8](=[O:10])[NH:47][CH:44]1[CH2:45][CH2:46][CH:41]([CH3:40])[CH2:42][CH2:43]1)=[O:4]
Reactant: COC(=O)[C@@H]1C[C@H]1C(=O)O
Reactant: C[C@H]1CC[C@H](N)CC1
Agent: CCOC(=O)C(C#N)=NOC(N(C)C)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: COC(=O)[C@@H]1C[C@H]1C(=O)NC1CCC(C)CC1
Reaction time: 3 h
Yield: 95.6 %

Procedure:
Stir a solution of trans-cyclopropane-1,2-dicarboxylic acid monomethyl ester (Example 3a) (3.0 g, 20.8 mmol) and TOTU (8.5 g, 26 mmol) in DMF (300 mL) at ambient temperature for 20 min at which time add N-methylmorpholine (2.4 mL 22.9 mmol) and trans 4-methylcyclohexylamine 3.06 g, 27.0 mmol). After 3 h, remove the solvent and dissolve the residue in H2O/EtOAc. Extract the aqueous layer 3 more times with EtOAc and combine the extracts. Wash the extract with saturated NaHCO3 solution, brine and dry over MgSO4. Concentrate the solvent to afford the crude product, and purify by column chromatography over silica gel to give 4.76 g (95%) of colorless crystals, m/z=240 (M+H)+.
Reaction SMILES: C[O:2][C:3](=[O:35])[C@@H:4]([NH:13][C:14](=[O:34])[C:15]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:16]=1[NH:22][CH2:23][C:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26][CH:25]=1)[CH2:5][C:6]1[CH:11]=[CH:10][C:9](Br)=[CH:8][CH:7]=1.[O:36]([C:43]1[CH:48]=[CH:47][C:46](B(O)O)=[CH:45][CH:44]=1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C(Cl)Cl.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>[Cl:21][C:19]1[CH:18]=[CH:17][C:16]([NH:22][CH2:23][C:24]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=[CH:26][CH:25]=2)=[C:15]([CH:20]=1)[C:14]([NH:13][C@@H:4]([CH2:5][C:6]1[CH:7]=[CH:8][C:9]([C:46]2[CH:47]=[CH:48][C:43]([O:36][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)=[CH:44][CH:45]=2)=[CH:10][CH:11]=1)[C:3]([OH:2])=[O:35])=[O:34]
Reactant: COC(=O)[C@H](Cc1ccc(Br)cc1)NC(=O)c1cc(Cl)ccc1NCc1cccc2ccccc12
Reactant: OB(O)c1ccc(Oc2ccccc2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: O=C(N[C@@H](Cc1ccc(-c2ccc(Oc3ccccc3)cc2)cc1)C(=O)O)c1cc(Cl)ccc1NCc1cccc2ccccc12
Temperature: 80 °C
Yield: 52.3 %

Procedure:
(S)-3-(4-Bromo-phenyl)-2-{5-chloro-2-[(naphthalen-1-ylmethyl)-amino]-benzoylamino}-propionic acid methyl ester (150 mg, 0.36 mmol), Pd (PPh3)4 (84 mg, 0.072 mmol), and 4-phenoxyphenylboronic acid (233 mg, 1.09 mmol) were dissolved in 5 mL of toluene, a 1M Na2CO3 solution (0.9 mL, 0.91 mmol) added and the mixture heated at 80° C. for 12 h. The reaction mixture was diluted with 5 mL of CH2Cl2 and filtered, all volatiles are removed under vaccum and the ester product was hydrolyzed according to Procedure C, and purified over silica gel (ethyl acetate:hexanes) to give the title compound(118 mg) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][N:3]=1.[CH3:12][C:13]1([CH3:29])[C:17]([CH3:19])([CH3:18])[O:16][B:15]([C:20]2[CH:28]=[CH:27][C:23]([C:24](Cl)=[O:25])=[CH:22][CH:21]=2)[O:14]1>CN(C)C1C=CN=CC=1.C(#N)C>[CH3:18][C:17]1([CH3:19])[C:13]([CH3:12])([CH3:29])[O:14][B:15]([C:20]2[CH:28]=[CH:27][C:23]([C:24]([NH:1][C:2]3[CH:7]=[C:6]([C:8]([F:9])([F:11])[F:10])[CH:5]=[CH:4][N:3]=3)=[O:25])=[CH:22][CH:21]=2)[O:16]1
Reactant: CC1(C)OB(c2ccc(C(=O)Cl)cc2)OC1(C)C
Reactant: Nc1cc(C(F)(F)F)ccn1
Agent: CN(C)c1ccncc1
Solvent: CC#N
Product: CC1(C)OB(c2ccc(C(=O)Nc3cc(C(F)(F)F)ccn3)cc2)OC1(C)C

Procedure:
To the stirred solution of 2-amino-4-(trifluoromethyl)pyridine (10.79 g, 66.6 mmol) and 4-dimethylaminopyridine (7.39 g, 60.5 mmol) in Acetonitrile (125.00 ml) was added a solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoyl chloride (16.12 g, 60.50 mmol) in Acetonitrile (75.00 ml) dropwise at room temperature. The solution turned into suspension after about half an hour and was stirred at r. t. overnight. The reaction mixture was concentrated and partitioned between 250 ml 0.2 N HCl and 250 ml CH2Cl2. The organic phase was separated and washed with 2×250 ml 0.2N HCl. The organic phase was dried over MgSO4 and evaporated to dryness. The crude was purified on RediSep 220 g silica cartridge and eluted with 1 lt Hexane, 4 lt 10% EtOAc/Hexane, 4 lt 20% EtOAc/Hexane gave white solid product 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-N-(4-(trifluoromethyl)pyridin-2-yl)benzamide. 1HNMR (CD3Cl, 500 MHz, δ): 8.83 (1H, br), 8.71 (1H, s), 8.45 (1H, d), 7.93 (4H, m), 7.30 (1H, d), 1.38 (12H, s).
Reaction SMILES: Br[C:2]1[S:3][C:4]2[CH2:5][C:6]3[C:12]([C:13]4[CH:18]=[CH:17][C:16]([N:19]5[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]5)=[CH:15][CH:14]=4)=[N:11][N:10]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[C:7]=3[C:8]=2[CH:9]=1.CC1(C)C(C)(C)OB([C:42]2[CH:43]=[N:44][CH:45]=[CH:46][CH:47]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:25][N:22]1[CH2:21][CH2:20][N:19]([C:16]2[CH:17]=[CH:18][C:13]([C:12]3[C:6]4[CH2:5][C:4]5[S:3][C:2]([C:42]6[CH:43]=[N:44][CH:45]=[CH:46][CH:47]=6)=[CH:9][C:8]=5[C:7]=4[N:10]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:31])[CH3:32])[N:11]=3)=[CH:14][CH:15]=2)[CH2:24][CH2:23]1
Reactant: CN1CCN(c2ccc(-c3nn(COCC[Si](C)(C)C)c4c3Cc3sc(Br)cc3-4)cc2)CC1
Reactant: CC1(C)OB(c2cccnc2)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CN1CCN(c2ccc(-c3nn(COCC[Si](C)(C)C)c4c3Cc3sc(-c5cccnc5)cc3-4)cc2)CC1
Temperature: 100 °C
Yield: 67 %

Procedure:
A mixture of the corresponding 2-Bromo-6-[4-(4-methyl-piperazin-1-yl)-phenyl]-4-(2-trimethylsilanyl-ethoxymethyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalene (1.25 g, 2.3 mmol), 3-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine (0.70 g, 3.4 mmol), Na2CO3 (2 M, 5.0 mL), and Pd(PPh3)2Cl2 (260 mg, 0.23 mmol) in toluene/ethanol (1:1, 15 mL) was heated at 100° C. for 8 hr. The solution was cooled to room temperature and extracted with ethyl acetate. The target product was purified by gravity column chromatography (50% EtOAc in hexane) to give the corresponding intermediate 6-[4-(4-Methyl-piperazin-1-yl)-phenyl]-2-pyridin-3-yl-4-(2-trimethylsilanyl-ethoxymethyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalene as brown solid in 67% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([F:14])=[C:12]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([O:22]C)=[CH:18][CH:17]=3)[CH:11]=[C:10]([CH:24]([O:28][CH2:29][CH3:30])[O:25][CH2:26][CH3:27])[N:9]=2)=[CH:4][CH:3]=1.[Cl:31]N1C(C)(C)C(=O)N(Cl)C1=O>C(#N)C.O>[Cl:31][C:11]1[C:10]([CH:24]([O:28][CH2:29][CH3:30])[O:25][CH2:26][CH3:27])=[N:9][C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)=[C:13]([F:14])[C:12]=1[N:15]=[C:16]1[CH:21]=[CH:20][C:19](=[O:22])[CH:18]=[CH:17]1
Reactant: CC1(C)C(=O)N(Cl)C(=O)N1Cl
Reactant: CCOC(OCC)c1cc(Nc2ccc(OC)cc2)c(F)c(-c2ccc(Cl)cc2)n1
Solvent: O
Solvent: CC#N
Product: CCOC(OCC)c1nc(-c2ccc(Cl)cc2)c(F)c(N=C2C=CC(=O)C=C2)c1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 30.3 %

Procedure:
A mixture of 2-(4-chlorophenyl)-6-(diethoxymethyl)-3-fluoro-N-(4-methoxy-phenyl)pyridin-4-amine (0.862 g, 2 mmol) and 1,3-dichloro-5,5-dimethylimidazolidine-2,4-dione (0.788 g, 4.00 mmol) in 1:1 acetonitrile/water (20 mL) was stirred at room temperature. After 2 h, the orange solid was collected by filtration, washed with 1:1 acetonitrile/water (5 mL), dried at room temperature and recrystallized from ether/hexane. 4-((3-Chloro-6-(4-chlorophenyl)-2-(diethoxymethyl)-5-fluoropyridin-4-yl)imino)cyclohexa-2,5-dienone (0.272 g, 30% yield) was isolated as orange crystals: mp 134-136° C.; 1H NMR (400 MHz, CDCl3) δ 7.96 (m, 2H), 7.44 (m, 3H), 6.76 (m, 2H), 6.58 (dd, J=10.2, 2.1 Hz, 1H), 5.79 (s, 1H), 3.90 (m, 2H), 3.72 (m, 2H), 1.31 (t, J=7.1 Hz, 6H); 19F NMR (376 MHz, CDCl3) δ −134.18; HRMS-ESI (m/z) [M+H]+ calcd for C22H19Cl2FN2O3, 448.0757; found, 448.0761.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:17]([CH2:18][C:19](O)=[O:20])[C:12]3=[N:13][CH:14]=[CH:15][CH:16]=[C:11]3[N:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].C(N1C=CN=C1)(N1C=CN=C1)=O.[NH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:17]([CH2:18][C:19](=[O:20])[N:34]3[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]3)[C:12]3=[N:13][CH:14]=[CH:15][CH:16]=[C:11]3[N:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: C1CCNCC1
Reactant: O=C(O)Cn1c(-c2ccc(Cl)c(Cl)c2)nc2cccnc21
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: O=C(Cn1c(-c2ccc(Cl)c(Cl)c2)nc2cccnc21)N1CCCCC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Under nitrogen bubbling, a mixture of 2-(3,4-dichlorophenyl)3H-imidazo[4,5-b]pyridine-3-acetic acid (3.5 g, 0.011 mole) and 1,1'-carbonyldiimidazole (1.95 g, 0.011 mole) in 150 ml of tetrahydrofuran was stirred at room temperature for 4 hrs. Piperidine (1.87 g, 0.022 mole) was added and the reaction was allowed to stir at room temperature overnight.