Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[C:3]([C:5]1[S:6][C:7]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)=[CH:8][C:9]=1[N:10]=[CH:11][N:12]([CH3:14])C)=[O:4].[CH3:22][N:23]1[CH2:28][CH2:27][CH2:26][C:25]([CH2:30][O:31][C:32]2[CH:33]=[C:34](CN)[CH:35]=[CH:36][CH:37]=2)([CH3:29])[CH2:24]1>CO>[Cl:21][C:18]1[CH:17]=[CH:16][C:15]([C:7]2[S:6][C:5]3[C:3](=[O:4])[N:12]([CH2:14][C:36]4[CH:35]=[CH:34][CH:33]=[C:32]([O:31][CH2:30][C:25]5([CH3:29])[CH2:26][CH2:27][CH2:28][N:23]([CH3:22])[CH2:24]5)[CH:37]=4)[CH:11]=[N:10][C:9]=3[CH:8]=2)=[CH:20][CH:19]=1
Reactant: COC(=O)c1sc(-c2ccc(Cl)cc2)cc1N=CN(C)C
Reactant: CN1CCCC(C)(COc2cccc(CN)c2)C1
Solvent: CO
Product: CN1CCCC(C)(COc2cccc(Cn3cnc4cc(-c5ccc(Cl)cc5)sc4c3=O)c2)C1
Temperature: 25 °C

Procedure:
5-(4-Chloro-phenyl)-3-(dimethylamino-methyleneamino)-thiophene-2-carboxylic acid methyl ester (0.16 g, 0.5 mmol), 1-{3-[(1,3-dimethylpiperidin-3-yl)methoxy]phenyl}methanamine (0.10 g, 0.4 mmol) in MeOH (2 mL) were heated by microwave at 120° C. for 20 minutes. The reaction mixture was allowed to cool to room temperature and the precipitate was filtered off and washed with MeOH to give the title compound as a solid. Yield: 0.12 g (49%). 1H NMR (400 MHz, CDCl3) δ 8.09 (s, 1H), 7.61 (d, 2H, J=8.91 Hz), 7.45 (s, 1H), 7.43 (d, 2H, J=8.91 Hz), 7.21-7.25 (m, 1H), 6.84-6.92 (m, 3H), 5.17 (s, 2H), 3.72-3.83 (m, 2H), 2.34 (m, 2H), 2.18 (s, 3H), 2.06 (m, 1H), 1.49-1.64 (m, 4H), 1.18 (m, 1H), 1.04 (s, 3H). MS (ESI+) 494.06 (M+1H+).
Reaction SMILES: CS(O[CH:6]([C:24]1[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=1)[CH2:7][CH2:8][CH:9](OS(C)(=O)=O)[C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=1)(=O)=O.[F:33][C:34]1[CH:40]=[CH:39][C:37]([NH2:38])=[CH:36][CH:35]=1>>[F:33][C:34]1[CH:40]=[CH:39][C:37]([N:38]2[CH:9]([C:10]3[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=3)[CH2:8][CH2:7][CH:6]2[C:24]2[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=2)=[CH:36][CH:35]=1
Reactant: CS(=O)(=O)OC(CCC(OS(C)(=O)=O)c1ccc([N+](=O)[O-])cc1)c1ccc([N+](=O)[O-])cc1
Reactant: Nc1ccc(F)cc1
Product: O=[N+]([O-])c1ccc(C2CCC(c3ccc([N+](=O)[O-])cc3)N2c2ccc(F)cc2)cc1
Temperature: 50 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
The product from Example 1C (0.6 gm, 1.228 mmol) and 4-fluoroaniline (2.0 ml, 20.82 mmol) were combined and stirred at 50° C. overnight. The resulting mixture was partitioned between 0.2 N HCl (50 ml) and ethyl acetate (3×50 ml), and the combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by chromatography on silica gel using a solvent gradient of 0-40% ethyl acetate in hexane to give the title compound as a mixture of cis and trans isomers (0.5 gm, 100% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:9][C:10]2[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=2[C:12](O)=[O:13])[CH:6]=[CH:7][CH:8]=1.[H-].COCCO[Al+]OCCOC.[Na+].[H-]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:9][C:10]2[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=2[CH2:12][OH:13])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(Sc2ccccc2C(=O)O)c1
Agent: COCCO[Al+]OCCOC
Agent: [H-]
Agent: [Na+]
Product: COc1cccc(Sc2ccccc2CO)c1
Yield: 87.6 %

Procedure:
2-(3-Methoxyphenylsulfanyl)benzoic acid was reduced with sodium bis-(methoxyethyoxy)-aluminum hydride to provide in 87.6% yield 2-(3-methoxyphenylsulfanyl)benzyl alcohol. This compound was without purification treated with thionyl chloride to provide in 91.0% yield 2-(3-methoxyphenylsulfanyl)benzyl chloride which treated with sodium cyanide provided nearly quantitatively 2-(3-methoxyphenylsulfanyl)phenylacetonitrile. Alkaline hydrolysis of this crude nitrile provided after work-up 65.1% yield of 2-(3-methoxyphenylsulfanyl)phenylacetic acid, m.p. 63-65° C. Corresponding 4-(4-hydroxyphenylsulfanyl)phenylacetic acid, m.p. 163-165° C., was obtained in 76.5% yield. For C14H12O3S (260.3) calculated: 64.60% C, 4.65% H, 12.32% S; found: 64.30% C, 4.85% H, 12.10% S. This acid was esterified with methanol in the presence of sulfuric acid to give the required ester in 78.9% yield, m.p. 54-56° C. For C15H14O3S (274.3) calculated: 65.69% C, 5.15% H, 11.67% S; found: 64.79% C, 5.25% H, 11.45% S. 1H NMR spectrum (CDCl3): H(O) 5.60 bs; CH2 3.85 s; aromatic H on the phenolic nucleus: H(2) 6.54 dd, J=1.6, 2.5 Hz; H(5) 7.08 dd, J=7.9, 8.2 Hz; H(6) 6.72 ddd, J=1.0, 1.6, 7.9 Hz.
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][N:8]([C:11]3[CH:16]=[CH:15][C:14]([C:17]4[NH:21][NH:20][C:19](=[O:22])[CH:18]=4)=[CH:13][CH:12]=3)[CH2:7][CH2:6]2)[O:4]CC1.S(=O)(=O)(O)O.O>CC(C)=O>[O:22]=[C:19]1[NH:20][NH:21][C:17]([C:14]2[CH:15]=[CH:16][C:11]([N:8]3[CH2:9][CH2:10][C:5](=[O:4])[CH2:6][CH2:7]3)=[CH:12][CH:13]=2)=[CH:18]1
Reactant: O=c1cc(-c2ccc(N3CCC4(CC3)OCCO4)cc2)[nH][nH]1
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Solvent: O
Product: O=C1CCN(c2ccc(-c3cc(=O)[nH][nH]3)cc2)CC1
Temperature: 25 °C
Reaction time: 96 h
Yield: 116.6 %

Procedure:
To a suspension of 5-[4-(1,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-phenyl]-1,2-dihydro-pyrazol-3-one (which was obtained in Example 144) (0.15 g, 0.5 mmol) in acetone (5 mL) was added 5 mL of 10% sulfuric acid. The resulting solution was stirred at room temperature for 4 days. Water (5 mL) was then added, and the acetone was evaporated. The aqueous residue was treated with sodium carbonate until pH 8, and the resulting suspension was filtered. The precipitate was washed with water and ether, and dried in vacuo to give 0.15 g of tan solid; 1H NMR (DMSO-d6) δ 2.41 (t, 4 H), 3.64 (t, 4 H), 5.74 (s, 1 H), 7.04 (d, 2 H), 7.53 (d, 2 H), 9.55 (brs, 1 H), 11.80 (brs, 1 H); MS (ES) m/z: 258 (MH+).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:3][CH2:2]1.Br[CH2:23][CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][O:25]1>>[O:25]1[CH2:26][CH2:27][CH2:28][CH2:29][CH:24]1[CH2:23][N:1]1[CH2:2][CH2:3][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:5][CH2:6]1
Reactant: O=C1C(=O)c2ccccc2C2=C1SCC1(CCNCC1)O2
Reactant: BrCC1CCCCO1
Product: O=C1C(=O)c2ccccc2C2=C1SCC1(CCN(CC3CCCCO3)CC1)O2

Procedure:
Compound 119 was synthesized using spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione, 2-(bromomethyl)tetrahydro-2H-pyran and conditions outlined in procedure V. M.p.=135-137° C.; 400 MHz 1H NMR (CDCl3) δ: 8.05 (d, 1H), 7.8 (d, 1H), 7.65 (t, 1H), 7.5 (t, 1H), 4.0 (d, 1H), 3.5 (dt, 2H), 2.9 (m, 3H), 2.65-2.3 (m, 4H), 2.1 (m, 2H), 1.9 (m, 3H), 1.5 (m, 4H), 1.3 (m, 2H); LCMS: 400 [M+H].
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH:6]([CH3:8])[CH2:5][N:4]([S:9]([C:12]2[CH:25]=[CH:24][C:23]3[N:22]([CH3:26])[C:21]4[C:16](=[CH:17][C:18]([S:27]([N:30]5[CH2:35][CH:34]([CH3:36])[CH2:33][CH:32]([CH3:37])[CH2:31]5)(=[O:29])=[O:28])=[CH:19][CH:20]=4)[C:15](=S)[C:14]=3[CH:13]=2)(=[O:11])=[O:10])[CH2:3]1.Cl.[NH2:40][OH:41]>N1C=CC=CC=1>[CH3:37][CH:32]1[CH2:33][CH:34]([CH3:36])[CH2:35][N:30]([S:27]([C:18]2[CH:19]=[CH:20][C:21]3[N:22]([CH3:26])[C:23]4[C:14](=[CH:13][C:12]([S:9]([N:4]5[CH2:5][CH:6]([CH3:8])[CH2:7][CH:2]([CH3:1])[CH2:3]5)(=[O:11])=[O:10])=[CH:25][CH:24]=4)[C:15](=[N:40][OH:41])[C:16]=3[CH:17]=2)(=[O:28])=[O:29])[CH2:31]1
Reactant: NO
Reactant: CC1CC(C)CN(S(=O)(=O)c2ccc3c(c2)c(=S)c2cc(S(=O)(=O)N4CC(C)CC(C)C4)ccc2n3C)C1
Agent: Cl
Solvent: c1ccncc1
Product: CC1CC(C)CN(S(=O)(=O)c2ccc3c(c2)c(=NO)c2cc(S(=O)(=O)N4CC(C)CC(C)C4)ccc2n3C)C1
Temperature: 100 °C
Reaction time: 8 h
Yield: 85.3 %

Procedure:
To a solution of 2,7-bis(3,5-dimethylpiperidin-1-ylsulfonyl)-10-methylacridine-9(10H)-thione (290 mg, 0.5 mmole) in pyridine (5 mL) was added hydroxylamine hydrochloride (210 mg, 30 mmole) and the mixture was stirred at 100° C. for 8 hrs. Solvent was removed and the residue was treated with water to remove excess of hydroxylamine. Crude material was crystallized from methanol-water to give 245 mg (85%) of the title compound. MS 575 (MH+).
Reaction SMILES: [NH2:1][C:2]1[C:7](=[O:8])[NH:6][C:5]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:4]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:3]=1.C(O[C:22](OCC)(OCC)[CH2:23][CH3:24])C.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[CH2:23]([C:24]1[O:8][C:7]2[C:2]([N:1]=1)=[CH:3][C:4]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:5]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[N:6]=2)[CH3:22]
Reactant: CCOC(CC)(OCC)OCC
Reactant: CCOC(=O)c1cc(N)c(=O)[nH]c1C(=O)OCC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CCOC(=O)c1cc2nc(CC)oc2nc1C(=O)OCC
Yield: 84.8 %

Procedure:
Diethyl 5-amino-1,6-dihydro-6-oxo-pyridine-2,3-dicarboxylate (7.57 g, 0.030 mol), is suspended in mL triethylorthopropionate (TEOP 0.30 mol). A small amount of p-toluenesulfonic acid is added and the mixture is heated at reflux for 65 hours. The triethylorthopropionate is removed in vacuo and the resulting oil is purified by column chromatography. The tractions containing the pure desired product are combined and stripped to a honey-colored oil weighing 7.38 g, yield 84.8%.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=2)[C:5]([Cl:15])=[CH:4][N:3]=1.CO.C(N(CC)CC)C.[C]=O.C[CH2:28][O:29][C:30](C)=[O:31]>C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].CC([O-])=O.CC([O-])=O.[Pd+2]>[Cl:15][C:5]1[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=2)=[CH:7][C:2]([C:30]([O:29][CH3:28])=[O:31])=[N:3][CH:4]=1
Reactant: CCOC(C)=O
Reactant: Fc1cccc(-c2cc(Cl)ncc2Cl)c1
Agent: [Fe+2]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: CO
Product: COC(=O)c1cc(-c2cccc(F)c2)c(Cl)cn1
Temperature: 100 °C
Reaction time: 17 h

Procedure:
To a mixture of 2,5-dichloro-4-(3-fluorophenyl)pyridine (0.604 g, 2.5 mmol), 1,1′-bis(diphenylphosphino)ferrocene (dppf) (0.105 g, 0.19 mmol), and Pd(OAc)2 (0.025 g, 0.11 mmol) was added MeOH (3.5 mL) and triethylamine (0.365 mL, 2.6 mmol). The nitrogen atmosphere was replaced with carbon monoxide (3.4 atm) and the reaction mixture was heated to 100° C. in a sealed tube. After 17 h, the reaction mixture was diluted with EtOAc, washed with saturated NaHCO3 (1×), brine (1×), dried over MgSO4, filtered, and concentrated. Purification by flash column chromatography on silica gel (5% to 20% EtOAc in hexanes) gave methyl 5-chloro-4-(3-fluorophenyl)picolinate.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([C:12]2[CH:13]=[N:14][CH:15]=[C:16](Br)[CH:17]=2)[O:9][N:8]=1.[O:19]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20]1.C(=O)([O-])[O-].[Na+].[Na+]>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.COCCOC>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([C:12]2[CH:13]=[N:14][CH:15]=[C:16]([C:21]3[CH:22]=[CH:23][O:19][CH:20]=3)[CH:17]=2)[O:9][N:8]=1
Reactant: Brc1cncc(-c2nc(-c3ccccn3)no2)c1
Reactant: OB(O)c1ccoc1
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: COCCOC
Product: c1ccc(-c2noc(-c3cncc(-c4ccoc4)c3)n2)nc1
Yield: 32.4 %

Procedure:
In a similar fashion, 3-(2-pyridyl)-5-(5-bromo-pyrid-3-yl)-1,2,4-oxadiazole (152 mg, 0.5 mmol), 3-furylboronic acid (111.9 mg, 1.0 mmole) and Pd(PPh3)4 (57.8 mg, 0.05 mmole) in a solution of 2M sodium carbonate (3 mL) and ethylene glycol dimethyl ether (3 mL) was heated overnight at 105° C. Standard work up afforded 47 mg (32%) of 3-(2-pyridyl)-5-[5-(3-furyl)-pyrid-3-yl ]-1,2,4-oxadiazole.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][C@H:11]1[CH2:15][CH2:14][O:13][CH2:12]1)[C:5]#[N:6].[NH2:16][OH:17]>CCO>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][C@H:11]1[CH2:15][CH2:14][O:13][CH2:12]1)/[C:5](=[N:16]/[OH:17])/[NH2:6]
Reactant: N#Cc1ccc(O[C@H]2CCOC2)c(Cl)c1
Reactant: NO
Solvent: CCO
Product: N/C(=N\O)c1ccc(O[C@H]2CCOC2)c(Cl)c1
Yield: 41.2 %

Procedure:
Under an atmosphere of nitrogen, (S)-3-chloro-4-(tetrahydrofuran-3-yloxy)benzonitrile (11.2 g, 50.1 mmol) and 50% aqueous hydroxylamine (3.31 g, 50.1 mmol) in EtOH (150.0 mL) was heated at 60° C. for 18 hr. Solvents removed in vacuo and the residue was azeotroped with MeOH. The residual solid was purified by precipitation from an ethyl acetate/30-60° C. pet/ether mixture (1:2) to give (S,Z)-3-chloro-N′-hydroxy-4-(tetrahydrofuran-3-yloxy)benzimidamide (5.3 g) LCMS (Table 1, Method b) Rt=1.52 min, m/z 257.09 (M+H)+.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([OH:7])[CH2:3][CH2:2]1.[CH3:8][C:9]([C:11]1[CH:12]=[CH:13][C:14](O)=[CH:15][C:16]=1[OH:17])=[O:10].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOCC>C(Cl)Cl>[OH:17][C:16]1[CH:15]=[C:14]([O:7][CH:4]2[CH2:5][CH2:6][O:1][CH2:2][CH2:3]2)[CH:13]=[CH:12][C:11]=1[C:9](=[O:10])[CH3:8]
Reactant: OC1CCOCC1
Reactant: CC(=O)c1ccc(O)cc1O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCOCC
Product: CC(=O)c1ccc(OC2CCOCC2)cc1O
Temperature: 20 °C
Reaction time: 20 h
Yield: 31.3 %

Procedure:
A mixture of tetrahydro-4H-pyran-4-ol (1.53 g, 15 mmol), 2,4-dihydroxyacetophenone (1.52 g, 10 mmol), and triphenyiphosphine, polymer-bound (5 g, 3 mmol P/g resin, 15 mmol) in CH2Cl2 (150 mL) was treated with diethyilazodicarboxylate (2.61 g, 15 mmol) and stirred at 20° C. for 20 h. The reaction mixture was treated with ether (200 mL) and the resin was filtered off and discarded. The filtrate was concentrated irn vacuo and purified by flash chromatography (silica gel, 4×7.5 cm, eluted with 25% ether in hexanes) to yield the white solid product (0.74 g, 31%).
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:3]=1[CH2:4][O:5][C:6]1[C:7]2[N:8]([C:13]([C:17]([OH:19])=O)=[C:14]([CH3:16])[N:15]=2)[CH:9]=[C:10]([F:12])[CH:11]=1.F[B-](F)(F)F.N1(O[C+](N(C)C)N(C)C)C2C=CC=CC=2N=N1.CN1CCOCC1.[NH2:54][CH2:55][C:56]([NH2:59])([CH3:58])[CH3:57]>CN(C=O)C.O>[NH2:59][C:56]([CH3:58])([CH3:57])[CH2:55][NH:54][C:17]([C:13]1[N:8]2[CH:9]=[C:10]([F:12])[CH:11]=[C:6]([O:5][CH2:4][C:3]3[C:2]([F:1])=[CH:23][CH:22]=[CH:21][C:20]=3[F:24])[C:7]2=[N:15][C:14]=1[CH3:16])=[O:19]
Reactant: CC(C)(N)CN
Reactant: Cc1nc2c(OCc3c(F)cccc3F)cc(F)cn2c1C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CN(C)[C+](On1nnc2ccccc21)N(C)C
Agent: F[B-](F)(F)F
Solvent: CN1CCOCC1
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nc2c(OCc3c(F)cccc3F)cc(F)cn2c1C(=O)NCC(C)(C)N
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
45 mg of 8-[(2,6-difluorobenzyl)oxy]-6-fluoro-2-methylimidazo[1,2-a]pyridine-3-carboxylic acid Example 11A, 0.13 mmol, 1 equivalent), 65 mg of (benzotriazol-1-yloxy)bisdimethylaminomethylium fluoroborate (TBTU, 0.2 mmol, 1.5 equivalents) and 54 mg of 4-methylmorpholine (0.54 mmol, 4 equivalents) were initially charged in 0.9 ml of DMF. After 10 min at RT, 24 mg of 1,2-diamino-2-methylpropane (0.27 mmol, 2 equivalents) were added and the mixture was stirred at RT overnight. Another 22 mg equivalents of TBTU (0.07 mmol, 0.5 equivalents) and 12 mg of 1,2-diamino-2-methylpropane (0.13 mmol, 1 equivalent) were added and the reaction was stirred at RT for 2 h. Water was added and the reaction solution was purified by preparative HPLC (RP18 column, mobile phase: acetonitrile/water gradient with addition of 0.1% TFA). The residue was taken up in dichloromethane and washed twice with saturated aqueous sodium bicarbonate solution. The aqueous phase was extracted twice with dichloromethane and the combined organic phases were dried over sodium sulphate. The mixture was filtered and concentrated and the crude product obtained was purified by thick-layer chromatography (mobile phase: dichloromethane/2 N ammonia in methanol: 10:0.5). This gave 31 mg of the title compound (55% of theory; purity 98%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH2:4][C:5]1[C:9]2[CH:10]=[CH:11][C:12]([OH:15])=[C:13]([Cl:14])[C:8]=2[O:7][CH:6]=1.C([O-])([O-])=O.[K+].[K+].[Cl:23][C:24]1[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:25]=1[CH2:26]Cl>CN(C=O)C>[CH3:1][O:2][C:3](=[O:16])[CH2:4][C:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:15][CH2:26][C:25]3[CH:28]=[CH:29][C:30]([Cl:32])=[CH:31][C:24]=3[Cl:23])=[C:13]([Cl:14])[C:8]=2[O:7][CH:6]=1
Reactant: ClCc1ccc(Cl)cc1Cl
Reactant: COC(=O)Cc1coc2c(Cl)c(O)ccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)Cc1coc2c(Cl)c(OCc3ccc(Cl)cc3Cl)ccc12
Temperature: 60 °C
Reaction time: 1.5 h

Procedure:
To a mixture of methyl(7-chloro-6-hydroxy-1-benzofuran-3-yl)acetate (200 mg) and DMF (dry) (8.0 mL) were added K2CO3 (172 mg) and 2,4-dichlorobenzyl chloride (0.138 mL). The mixture was stirred at 60° C. for 1.5 h. The mixture was quenched with water. The precipitate was collected by filtration and washed with water and hexane to give the title compound (272 mg) as a solid. The solid was crystallized from EtOAc-hexane to give the title compound.
Reaction SMILES: [NH2:1][NH2:2].Cl[C:4]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=2)[N:7]=[C:6]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[CH:5]=1>CC(O)CC>[N:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[C:8]1[CH:9]=[C:4]([NH:1][NH2:2])[CH:5]=[C:6]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[N:7]=1
Reactant: Clc1cc(-c2ccccn2)nc(-c2ccccn2)c1
Reactant: NN
Solvent: CCC(C)O
Product: NNc1cc(-c2ccccn2)nc(-c2ccccn2)c1

Procedure:
4 ml (126 mmol) of hydrazine are added to 600 mg (2.2 mmol) of 4′-chloro-[2,2′;6′,2″]-terpyridine in 12 ml of 2-butanol. The mixture is heated at reflux for 17 hours and cooled, and [2,2′;6′,2″]terpyridin-4′-yl-hydrazine is filtered off in the form of a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:12](Cl)(=O)C(Cl)=O>C(Cl)(Cl)Cl.CN(C)C=O>[CH3:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH3:12])=[O:5]
Reactant: Cc1ccc(C(=O)O)c(C)c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(C)cc1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2,4-dimethylbenzoic acid (20.0 g) was suspended in chloroform (100 ml), and thereto were added oxalyl chloride (6.8 ml) and N,N-dimethylformamide (2 drops). The mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure, and the residue was dissolved in methanol (200 ml). The mixture was stirred at room temperature for 3 hours. The solvent was evaporated under reduced pressure, and the residue was dissolved in ethyl acetate. The mixture was washed successively with a saturated aqueous sodium hydrogen carbonate solution and brine, and dried over sodium sulfate. The solvent was evaporated under reduced pressure to give methyl 2,4-dimethylbenzoate as pale yellow oil, which was used in the subsequent step without further purification. (2) To a mixture of the above methyl 2,4-dimethylbenzoate (19.75 g) and activated aluminum neutral oxide (120 g) was added dropwise bromine (9.25 ml) while stirring at room temperature. The mixture was stirred at room temperature for 8 hours, and diluted with diethyl ether (1000 ml). Insoluble materials were filtered off, and washed with diethyl ether (500 ml). The combined filtrate was washed successively with 10% aqueous sodium thiosulfate solution, a saturated aqueous sodium hydrogen carbonate solution and brine. The filtrate was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was crystallized from methanol (40 ml) to give methyl 5-bromo-2,4-dimethylbenzoate (6.34 g) as colorless crystals. APCI-Mass m/Z 243/245 (M+H). (3) The above methyl 5-bromo-2,4-dimethylbenzoate was treated in a manner similar to Reference Example 4-(1) to give 5-bromo-2,4-dimethylbenzoic acid as colorless crystals. ESI-Mass m/Z 227/229 (M−H) (4) The above 5-bromo-2,4-dimethylbenzoic acid and 2-phenylthiophene were treated in a manner similar to Reference Example 5 to give 5-bromo-2,4-dimethyl-1-(5-phenyl-2-thienylmethyl)benzene as colorless crystals. APCI-Mass m/Z 357/359 (M+H).
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[N:7]=[CH:8][N:9]([C:11]2[N:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:14]=[C:13]([C:21]3[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=3)[N:12]=2)[CH:10]=1)CCC.[C:39]([NH:43][S:44]([C:47]1[S:51][C:50](Cl)=[N:49][CH:48]=1)(=[O:46])=[O:45])([CH3:42])([CH3:41])[CH3:40].[F-].[K+].O>C1(C)C=CC=CC=1.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>[C:39]([NH:43][S:44]([C:47]1[S:51][C:50]([C:6]2[N:7]=[CH:8][N:9]([C:11]3[N:16]=[C:15]([C:17]([F:18])([F:20])[F:19])[CH:14]=[C:13]([C:21]4[CH:26]=[CH:25][C:24]([C:27]([F:28])([F:29])[F:30])=[CH:23][CH:22]=4)[N:12]=3)[CH:10]=2)=[N:49][CH:48]=1)(=[O:45])=[O:46])([CH3:42])([CH3:40])[CH3:41]
Reactant: CC(C)(C)NS(=O)(=O)c1cnc(Cl)s1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn(-c2nc(-c3ccc(C(F)(F)F)cc3)cc(C(F)(F)F)n2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [F-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(C)NS(=O)(=O)c1cnc(-c2cn(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)cn2)s1

Procedure:
A stirred mixture of 2-(4-tributylstannanyl-imidazol-1-yl)-4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyrimidine (Example G.1) (0.265 g, 0.41 mmol), 2-chloro-thiazole-5-sulfonic acid tert-butylamide (Example H.1) (0.115 g, 0.45 mmol), tetrakis(triphenylphosphine)palladium (0.028 g, 0.024 mmol) in toluene (5 mL) was heated under reflux conditions for 15 h. The mixture was poured into saturated potassiumfluoride solution (5 mL), water (20 mL) was added and the water layer was extracted with ethyl acetate (2×30 mL). The combined organic layers were washed with brine (30 mL), dried (MgSO4) and evaporated. The crude product was purified by flash chromatography (heptane/ethyl acetate) and crystallization (THF/hexane) to yield N-tert-butyl-2-{1-[4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)pyrimidin-2-yl]-1H-imidazol-4-yl}-thiazole-5-sulfonamide (0.081) as a light brown solid. Mp 281° C.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[Cl:22])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:23]([CH2:27][CH3:28])[CH:24]([OH:26])[CH3:25])=[CH:4][CH:3]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(#N)C.C(=O)(O)[O-].[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[Cl:22])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:23]([CH2:27][CH3:28])[C:24](=[O:26])[CH3:25])=[CH:4][CH:3]=1
Reactant: CCC(c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl)C(C)O
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: CC#N
Product: CCC(C(C)=O)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Yield: 88.2 %

Procedure:
To a solution of 3-[9-chloro-1-(2,4-dichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl]pentan-2-ol (234 mg, 0.533 mmol) in acetonitrile (5 mL) was added Dess-Martin reagent (271 mg, 0.639 mmol) at 0° C., and the resultant mixture was stirred at room temperature for 1 h and diluted with aqueous sodium bicarbonate and aqueous sodium thiosulfate. The resultant mixture was extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 20-50% ethyl acetate/n-hexane gradient mixture to give the title compound as a colorless amorphous solid (205 mg, 0.470 mmol, 88%).