Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:20]3[CH:21]=[N:22][N:23]([CH2:25][CH:26]4[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:28][CH2:27]4)[CH:24]=3)=[CH:7][N:8]2[S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[CH:4][CH:3]=1.Cl.[F:40]C1C=C2C(=CC=1F)N(S(C1C=CC=CC=1)(=O)=O)C=C2C1C=NNC=1>>[F:40][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:2]=1[F:1])[N:8]([S:11]([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)(=[O:12])=[O:13])[CH:7]=[C:6]2[C:20]1[CH:21]=[N:22][N:23]([CH2:25][CH:26]2[CH2:27][CH2:28][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:30][CH2:31]2)[CH:24]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Cn2cc(-c3cn(S(=O)(=O)c4ccccc4)c4cc(F)ccc34)cn2)CC1
Reactant: O=S(=O)(c1ccccc1)n1cc(-c2cn[nH]c2)c2cc(F)c(F)cc21
Agent: Cl
Product: CC(C)(C)OC(=O)N1CCC(Cn2cc(-c3cn(S(=O)(=O)c4ccccc4)c4cc(F)c(F)cc34)cn2)CC1
Yield: 78 %

Procedure:
Following the general method as outlined in Intermediate 20, starting from 5,6-difluoro-1-(phenylsulfonyl)-3-(1H-pyrazol-4-yl)-1H-indole hydrochloride (Intermediate 30; 300 mg; 0.76 mmol), 330 mg (78%) of the title compound was obtained as a yellow solid after purification by a silica gel chromatography(petroleum ether/EtOAc=5/1).
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([C:6]([C:8]2[CH:25]=[CH:24][C:11]([CH2:12][N:13]3[C:17]4[C:18](=[O:23])[NH:19][N:20]=[C:21]([Cl:22])[C:16]=4[N:15]=[CH:14]3)=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[C:28](=O)([O-])[O-].[K+].[K+].CI.O>CN(C=O)C>[Cl:1][C:2]1[CH:27]=[CH:26][C:5]([C:6]([C:8]2[CH:25]=[CH:24][C:11]([CH2:12][N:13]3[C:17]4[C:18](=[O:23])[N:19]([CH3:28])[N:20]=[C:21]([Cl:22])[C:16]=4[N:15]=[CH:14]3)=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(c1ccc(Cl)cc1)c1ccc(Cn2cnc3c(Cl)n[nH]c(=O)c32)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CI
Solvent: CN(C)C=O
Product: Cn1nc(Cl)c2ncn(Cc3ccc(C(=O)c4ccc(Cl)cc4)cc3)c2c1=O
Temperature: 25 °C
Reaction time: 65 h
Yield: 65.7 %

Procedure:
In DMF (15 ml) was dissolved 1-[4-(4-chlorobenzoyl)benzyl]-4-chloroimidazo[4,5-d]pyridazin-7(6H)-one (963 mg) followed by addition of potassium carbonate (985 mg). Then, methyl iodide (0.45 ml) was added and the mixture was stirred at room temperature for 65 hours. To this reaction mixture was added water (50 ml) and the resulting crystals were harvested by filtration. This crystal crop was purified by silica gel column chromatography (stationary phase 30 g; dichloromethane: ether=1:0-3:1) to provide 655 mg (66%) of the title compound. 1H-NMR (CDCl3) δ: 3.86(3H,s), 5.81(2H,s), 7.45(2H,d,J=7.8Hz), 7.46(2H,d,J=8.6Hz), 7.73(2H,d,J=8.6Hz), 7.78(2H,d,J=8.2Hz), 8.01(1H,s).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([O:9][CH3:10])=[O:8].[Br:11]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:11][CH2:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([O:9][CH3:10])=[O:8]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1sccc1C
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1sccc1CBr
Temperature: 90 °C
Yield: 63.1 %

Procedure:
To a solution of methyl 3-methylthiophene-2-carboxylate (10.0 g, 64.0 mmol) in CCl4 (100 mL) was added AlBN (180 mg, 1.1 mmol) and N-bromosuccinimide (11.4 g, 64.0 mmol). The reaction mixture was refluxed for 10 min, and then an additional portion of AlBN (460 mg, 2.8 mmol) was added. This reaction was heated overnight at 90° C. under a reflux condenser. At completion, the reaction was filtered over a short plug of silica gel (100% DCM eluent). The filtrate was concentrated and purified by flash chromatography over silica gel (2% EtOAc/hexane eluent) to afford methyl 3-(bromomethyl)thiophene-2-carboxylate (9.5 g, 63% yield) as a white solid. 1H NMR (400 MHz, METHANOL-d4) δ ppm 7.66 (d, J=5.0 Hz, 1H), 7.23 (d, J=5.0 Hz, 1H), 4.95 (s, 2H), 3.89 (s, 3H); MS (EI) m/z=236.1 [M+1]+.
Reaction SMILES: [C:1]1(=[O:8])[CH2:6][CH2:5][CH2:4][C:3](=[O:7])[CH2:2]1.[Br:9]Br>>[Br:9][CH:2]1[C:3](=[O:7])[CH2:4][CH2:5][CH2:6][C:1]1=[O:8]
Reactant: O=C1CCCC(=O)C1
Reactant: BrBr
Product: O=C1CCCC(=O)C1Br
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Cyclohexane-1,3-dione (11.2 g, 0.1 mol) was suspended in ice water (70 mL) and bromine (5.16 mL, 0.1 mol) was added dropwise over 5 minutes. The resulting suspension was stirred at room temperature for 3 hours. The suspension was filtered and the solid was stirred in water (200 mL) for 30 minutes. The solid was collected by vacuum filtration, rinsed with water, and dried to render crude product. The crude product was recrystallized from ethanol to produce the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:13]([C:14]([NH2:16])=[O:15])=[C:12]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=3)[NH:11][N:10]=2)=[CH:4][CH:3]=1.[Cl:26][C:27]1[C:28]2[CH:38]=[CH:37][C:36]([F:39])=[CH:35][C:29]=2[S:30][C:31]=1[C:32](Cl)=[O:33]>CN(C=O)C>[Cl:26][C:27]1[C:28]2[CH:38]=[CH:37][C:36]([F:39])=[CH:35][C:29]=2[S:30][C:31]=1[C:32]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]2[C:13]([C:14]([NH2:16])=[O:15])=[C:12]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=3)[NH:11][N:10]=2)=[CH:6][CH:7]=1)=[O:33]
Reactant: NC(=O)c1c(Nc2ccc(N)cc2)n[nH]c1NCc1ccc(O)cc1
Reactant: O=C(Cl)c1sc2cc(F)ccc2c1Cl
Solvent: CN(C)C=O
Product: NC(=O)c1c(Nc2ccc(NC(=O)c3sc4cc(F)ccc4c3Cl)cc2)n[nH]c1NCc1ccc(O)cc1
Reaction time: 0.25 h
Yield: 4.9 %

Procedure:
3-((4-aminophenyl)amino)-5-((4-hydroxybenzyl)amino)-1H-pyrazole-4-carboxamide (100 mg) was dissolved in 3.0 mL of DMF and TEA (125 μL, 3.0 eq.) was then added to the reaction vessel. Reaction was then stirred on an ice bath for 15 min and 3-Chloro-6-fluorobenzo[b]thiophene-2-carbonyl chloride (75 mg, 1.00 eq.) dissolved in DMF (2.0 mL) was slowly added into the reaction. The reaction continued stirring for 18 hrs and allowed to reach room temperature. The reaction was tracked via HPLC, once completed and no traces of starting material is present, the solvent was then removed via vacuo and column chromatography was used to purify the compound. A gradient of 0 to 20% MeOH in dichloromethane was used and the desired fractions were combined, evaporated and triturated with diisoproyl ether then filtered to yield product as an off white powder (0.008 g, 6.0% yield).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([C:11]([NH:13][C@H:14]([C:16]2[NH:20][C:19]3[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:18]=3[N:17]=2)[CH3:15])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)CC)(C)C.[S:57]1[CH2:61][CH2:60][NH:59][CH2:58]1.BrCl>CN(C)C=O.ClCCl.C(O)C>[Br:1][C:2]1[CH:10]=[C:9]([CH:8]=[CH:7][C:3]=1[C:4]([N:59]1[CH2:60][CH2:61][S:57][CH2:58]1)=[O:5])[C:11]([NH:13][C@H:14]([C:16]1[NH:20][C:19]2[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:18]=2[N:17]=1)[CH3:15])=[O:12]
Reactant: C1CSCN1
Reactant: C[C@H](NC(=O)c1ccc(C(=O)O)c(Br)c1)c1nc2cc(Cl)ccc2[nH]1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: ClBr
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Solvent: CN(C)C=O
Product: C[C@H](NC(=O)c1ccc(C(=O)N2CCSC2)c(Br)c1)c1nc2cc(Cl)ccc2[nH]1
Yield: 43 %

Procedure:
Prepared analogously to Example 1g from (1S)-2-bromo-4-{N-[1-(5-chloro-1H-benzimidazol-2-yl)ethyl]aminocarbonyl}benzoic acid, TBTU, diisopropylethylamine and thiazolidine in dimethylformamide. Yield: 43%; Rf value: 0.40 (silica gel: dichloromethane/ethanol=9:1); C20H18BrClN4O2S (493.813); mass spectrum: (M−H)−=493/495/497 (bromo-chlorine isotope).
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[N:17][N:18]([CH2:20][CH2:21][CH2:22][OH:23])[CH:19]=2)=[CH:11][C:3]=1[C:4]([N:6]([CH2:9]C)CC)=[O:5].N[C:25]1C(C(NC)=O)=C(C)C(Br)=CC=1.NC1C=CC(Br)=CC=1C(N(CC)CC)=O>>[NH2:1][C:2]1[C:3]([C:4]([NH:6][CH3:9])=[O:5])=[C:11]([CH3:25])[C:12]([C:15]2[CH:16]=[N:17][N:18]([CH2:20][CH2:21][CH2:22][OH:23])[CH:19]=2)=[CH:13][CH:14]=1
Reactant: CNC(=O)c1c(N)ccc(Br)c1C
Reactant: CCN(CC)C(=O)c1cc(-c2cnn(CCCO)c2)ccc1N
Agent: CCN(CC)C(=O)c1cc(Br)ccc1N
Product: CNC(=O)c1c(N)ccc(-c2cnn(CCCO)c2)c1C

Procedure:
Prepared analogously to Compound 3C substituting 6-amino-3-bromo-2-methyl-N-methylbenzamide (Compound 29D) for 2-amino-5-bromo-N,N-diethylbenzamide (Compound 3D). MS (ESI): m/z=289.29 [M+H]+. UPLC: tR=2.33 min (ZQ3: polar—5 min).
Reaction SMILES: [Br:1][C:2]1[O:6][C:5]([C:7]([OH:9])=O)=[CH:4][CH:3]=1.[NH2:10][C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][C:19]#[N:20])[CH:14]=[CH:15][CH:16]=1>>[C:19]([CH:18]=[CH:17][C:13]1[CH:12]=[C:11]([NH:10][C:7]([C:5]2[O:6][C:2]([Br:1])=[CH:3][CH:4]=2)=[O:9])[CH:16]=[CH:15][CH:14]=1)#[N:20]
Reactant: O=C(O)c1ccc(Br)o1
Reactant: N#CC=Cc1cccc(N)c1
Product: N#CC=Cc1cccc(NC(=O)c2ccc(Br)o2)c1

Procedure:
5-Bromo-furan-2-carboxylic acid (716 mg, 3.75 mmol) was coupled to aniline (88) (540 mg, 3.75 mmol) using Method C. The residue was purified by column chromatography eluting with 20% EtOAc in heptane, to give the title compound.
Reaction SMILES: [NH:1]([C:3]([CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH:13]2[O:25][CH2:26][C:27]2[CH:36]=[CH:35][C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH:28]=2)=[CH:8][CH:7]=1)=[O:4])[NH2:2].CCO[C:40](OCC)(OCC)[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>C(O)C>[CH:28]1[C:29]2[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:35]=[CH:36][C:27]=1[CH2:26][O:25][CH:13]1[CH:12]([C:9]2[CH:10]=[CH:11][C:6]([CH2:5][C:3]3[O:4][C:40]([C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=4)=[N:2][N:1]=3)=[CH:7][CH:8]=2)[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14]1
Reactant: CCOC(OCC)(OCC)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(CC(=O)NN)cc2)C(OCc2ccc3ccccc3c2)C1
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(Cc3nnc(-c4ccccc4)o3)cc2)C(OCc2ccc3ccccc3c2)C1

Procedure:
A mixture of 60 mg (0.12 mmol) of tert-butyl (3RS,4RS)-4-(4-hydrazinocarbonylmethyl-phenyl)-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate and 27.7 gl (0.12 mmol) of triethyl orthobenzoate in 5 ml of ethanol was boiled under reflux for 18 hours. After cooling the mixture was evaporated under reduced pressure and the residue was chromatographed on silica gel using a 2:1 mixture of hexane and ethyl acetate as the eluent. There were obtained 30 mg (44% of theory) or tert-butyl (3RS,4RS)-3-(naphthalen-2-ylmethoxy)-4-[4-(5-phenyl-[1,3,4]oxadiazol-2-ylmethyl)-phenyl]-piperidine-1-carboxylate as a colourless foam; MS: 575 (M+H)+.
Reaction SMILES: [CH:1]([C:3]1[C:18]([OH:19])=[C:17]([C:20]([O:22]C)=[O:21])[CH:16]=[CH:15][C:4]=1[O:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([O:12]CC)=[O:11])=[O:2].Cl>[OH-].[Na+]>[CH:1]([C:3]1[C:18]([OH:19])=[C:17]([C:20]([OH:22])=[O:21])[CH:16]=[CH:15][C:4]=1[O:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[O:2]
Reactant: CCOC(=O)CCCCOc1ccc(C(=O)OC)c(O)c1C=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=Cc1c(OCCCCC(=O)O)ccc(C(=O)O)c1O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Ethyl 5-(2-formyl-3-hydroxy-4-methoxycarbonylphenoxy)pentanoate (0.5 g, 0.0015 M) was added to 10% sodium hydroxide solution (10 ml) and stirred at room temperature for 2 hours. The reaction mixture was acidified with concentrated hydrochloric acid and the resulting solid was filtered, sucked dry, and washed with a little ethanol, then dried in a desiccator over phosphorus pentoxide to give 5-(2-formyl-3-hydroxy-4-carboxyphenoxy)pentanoic acid, 0.38 g, 90%, m.p. 165°-166° C.
Reaction SMILES: [SH:1][CH2:2][CH2:3][OH:4].[Na].Br[CH:7]([CH2:19][CH2:20][CH2:21][CH:22]([O:28][C:29](=[O:31])[CH3:30])[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15]>CO>[OH:4][CH2:3][CH2:2][S:1][CH:7]([CH2:19][CH2:20][CH2:21][CH:22]([O:28][C:29](=[O:31])[CH3:30])[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: OCCS
Reactant: CCCCCC(CCCC(Br)CCCCCCC(=O)OCC)OC(C)=O
Agent: [Na]
Solvent: CO
Product: CCCCCC(CCCC(CCCCCCC(=O)OCC)SCCO)OC(C)=O

Procedure:
2-Mercaptoethanol (31.2 g., 0.4 mole) is dissolved in a solution of sodium (9.2 g., 0.4 mole) in methanol (300 ml.). Ethyl 8-bromo-12-acetoxy-heptadecanoate (Example 1, Step E) (43.5 g., 0.1 mole) is added and the resulting solution is heated at feflux for 5 hours. Most of the methanol is then removed by evaporation in vacuo. Water (350 ml.) is added to the residue and the oily product taken up in ether, washed with water and brine and dried over sodium sulfate. Evaporation of the ether leaves the title compound as a yellow residual oil which is used in the next step without further purification.
Reaction SMILES: Br[C:2](Br)=[CH:3][CH:4]1[CH2:7][CH:6]([CH2:8][CH:9]([CH2:12][CH3:13])[CH2:10][CH3:11])[CH2:5]1.C([Li])CCC.[Si:20]([O:37][CH2:38][CH2:39][CH:40]([C:49](=[O:54])NCOC)[CH2:41][C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])([C:33]([CH3:36])([CH3:35])[CH3:34])([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[Cl-].[NH4+]>O1CCCC1>[Si:20]([O:37][CH2:38][CH2:39][CH:40]([C:49](=[O:54])[C:2]#[C:3][CH:4]1[CH2:7][CH:6]([CH2:8][CH:9]([CH2:12][CH3:13])[CH2:10][CH3:11])[CH2:5]1)[CH2:41][C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])([C:33]([CH3:34])([CH3:36])[CH3:35])([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: CCC(CC)CC1CC(C=C(Br)Br)C1
Reactant: COCNC(=O)C(CCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)CC(=O)OC(C)(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCC(CC)CC1CC(C#CC(=O)C(CCO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)CC(=O)OC(C)(C)C)C1
Temperature: 25 °C
Yield: 75.8 %

Procedure:
1-(2,2-Dibromovinyl)-3-(2-ethylbutyl)cyclobutane (9.78 g) and tetrahydrofuran (100 mL) were mixed. To the mixture was added dropwise n-butyllithium (1.65 M in hexane) (39 mL) at −78° C. The mixture was stirred under ambient temperature. To the mixture was added dropwise a solution of tert-butyl 5-(tert-butyldiphenylsilanyloxy)-3-methoxymethylcarbamoylvalerate (10.6 g) in tetrahydrofuran (30 mL) at ice temperature. After stirring at ice temperature for 2 hr., saturated aqueous ammonium chloride (150 mL) was added to the reaction mixture. The mixture was extracted with ethyl acetate (150 mL, 100 mL). The combined organic layer was washed with water (75 mL) and brine (75 mL, 50 mL), then dried over sodium sulfate. The sodium sulfate was filtered off and the filtrate was concentrated in vacuo. The resultant residue was purified by silica gel column chromatography (Eluent: ethyl acetate/hexane=1/40→1/30→1/20) to give the title compound (9.70 g).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[C:5]([C:8]1[C:13](Cl)=[N:12][CH:11]=[CH:10][N:9]=1)([CH3:7])[CH3:6])[CH3:2].[C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1C(F)(F)F)#[CH:17].C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[CH2:1]([O:3][C:4](=[O:15])[C:5]([CH3:7])([C:8]1[C:13]([C:17]#[C:16][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[N:12][CH:11]=[CH:10][N:9]=1)[CH3:6])[CH3:2]
Reactant: CCOC(=O)C(C)(C)c1nccnc1Cl
Reactant: C#Cc1ccccc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CCOC(=O)C(C)(C)c1nccnc1C#Cc1ccccc1
Temperature: 25 °C
Yield: 57.7 %

Procedure:
To a solution of 2-(3-Chloro-pyrazin-2-yl)-2-methyl-propionic acid ethyl ester (0.70 g) in acetonitrile (7.0 ml) was added 1-ethynyl-2-trifluoromethylbenzene (0.781 g) and caesium carbonate (“Cs2CO3”) (2.99 g) and nitrogen bubbled through the solution for 20 min. To this solution was added as 4,5-(bisdiphenylphosphino)-9,9-dimethylxanthene (“Xantphos”) (0.133 g) and (1,1′-bis(diphenylphosphino)-ferrocene)dichloro palladium(2) (0.125 g) and the reaction mixture heated to reflux for 30 min. The reaction mixture was cooled to ambient temperature then filtered and concentrated. The residue was purified by chromatography on silica gel (eluent 5-95% ethyl acetate in isohexane) to give 2-methyl-2-(3-phenylethynyl-pyrazin-2-yl)-propionic acid ethyl ester (compound B1 of Table B) (0.52 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]=[C:10]2[CH2:18][CH:19]2[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][NH:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[N+:34]([O-])=O)[CH2:21][CH2:20]2)=[CH:4][CH:3]=1.S1C=CC=C1.[H][H]>CO.[Pd]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]=[C:10]2[CH2:18][CH:19]2[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][NH:27][C:28]3[C:29]([NH2:34])=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH2:21][CH2:20]2)=[CH:4][CH:3]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccccc1NCCN1CCC(Cc2nc3ccccc3n2Cc2ccc(F)cc2)CC1
Agent: [Pd]
Solvent: c1ccsc1
Solvent: CO
Product: Nc1ccccc1NCCN1CCC(Cc2nc3ccccc3n2Cc2ccc(F)cc2)CC1
Yield: 90 %

Procedure:
A mixture of 7 parts of 4-[[1-[(4-fluorophenyl]methyl]-1H-benzimidazol-2-yl]methyl]-N-(2-nitrophenyl)-1-piperidineethanamine, 1 part of a solution of thiophene in methanol 4% and 200 parts of methanol was hydrogenated at normal pressure and at 50° C. with 2 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated, yielding 6 parts (90%) of N1 -[2-[4-[[1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-yl]methyl]-1-piperidinyl]ethyl]-1,2-benzenediamine (506).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[CH2:5][N:6]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:7]1[CH:12]=[C:11]([C:13]([NH:15][NH:16][C:17]([O:19]C)=[O:18])=O)[CH:10]=[CH:9][C:8]=1[CH3:21])[CH3:2].P(Cl)(Cl)(Cl)=O>>[CH2:1]([O:3][C:4](=[O:28])[CH2:5][N:6]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:7]1[CH:12]=[C:11]([C:13]2[O:19][C:17](=[O:18])[NH:16][N:15]=2)[CH:10]=[CH:9][C:8]=1[CH3:21])[CH3:2]
Reactant: CCOC(=O)CN(CC(=O)OCC)c1cc(C(=O)NNC(=O)OC)ccc1C
Solvent: O=P(Cl)(Cl)Cl
Product: CCOC(=O)CN(CC(=O)OCC)c1cc(-c2n[nH]c(=O)o2)ccc1C
Temperature: 110 °C
Reaction time: 2.5 h
Yield: 59.3 %

Procedure:
To the compound (3.67 g, 9.28 mmol) obtained in step A was added phosphorus oxychloride (30 g), and the mixture was stirred at 110° C. for 2.5 hr. After cooling to room temperature, the reaction mixture was poured into ice water, and the solution was extracted with ethyl acetate. The organic layer was washed with water, saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the solution was concentrated under reduced pressure to give the title compound (2.00 g, yield 59%) as a colorless solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH:23]4[CH2:25][CH2:24]4)=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([N:26]2[CH2:30][CH2:29][CH2:28][S:27]2(=[O:32])=[O:31])[CH:3]=1.[CH3:33][C:34]1([CH3:40])[O:38][C:37](=[O:39])[N:36]=[CH:35]1>>[CH:23]1([C:19]2[CH:20]=[C:21]([CH3:22])[C:16]([N:13]3[CH2:14][CH2:15][N:10]([C:8]([C:5]4[CH:6]=[CH:7][C:2]([N:36]5[CH2:35][C:34]([CH3:40])([CH3:33])[O:38][C:37]5=[O:39])=[CH:3][C:4]=4[N:26]4[CH2:30][CH2:29][CH2:28][S:27]4(=[O:32])=[O:31])=[O:9])[CH2:11][CH2:12]3)=[N:17][CH:18]=2)[CH2:25][CH2:24]1
Reactant: CC1(C)C=NC(=O)O1
Reactant: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(Br)cc2N2CCCS2(=O)=O)CC1
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(N3CC(C)(C)OC3=O)cc2N2CCCS2(=O)=O)CC1
Yield: 50.6 %

Procedure:
By reaction and treatment in the same manner as in Example 110 and using [4-bromo-2-(1,1-dioxoisothiazolidin-2-yl)phenyl][4-(5-cyclopropyl-3-methylpyridin-2-yl)piperazin-1-yl]methanone (779 mg) described in Preparation Example 179 and 5,5-dimethyloxazolin-2-one (207 mg) described in Preparation Example 43, the title compound (420 mg) was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:35]=[CH:36][CH:37]=1)[CH2:6][CH2:7][O:8][C:9]1[CH:10]=[C:11]([B:26]2[O:30]C(C)(C)C(C)(C)[O:27]2)[CH:12]=[CH:13][C:14]=1[O:15][CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[CH:19]=1.I([O-])(=O)(=O)=O.[Na+].C([O-])(=O)C.[NH4+].Cl>CC(C)=O.CCOC(C)=O.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:35]=[CH:36][CH:37]=1)[CH2:6][CH2:7][O:8][C:9]1[CH:10]=[C:11]([B:26]([OH:30])[OH:27])[CH:12]=[CH:13][C:14]=1[O:15][CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[CH:19]=1
Reactant: COc1cccc(CCOc2ccc(B3OC(C)(C)C(C)(C)O3)cc2OCCc2cccc(OC)c2)c1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [NH4+]
Solvent: O
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: COc1cccc(CCOc2ccc(B(O)O)cc2OCCc2cccc(OC)c2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 87.3 %

Procedure:
To a solution of 2-(3,4-bis(3-methoxyphenethoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (40 mg, 0.079 mmol) in Acetone (5 mL)/Water (2.500 mL) was added sodium periodate (50.9 mg, 0.238 mmol) and ammonium acetate (18.34 mg, 0.238 mmol) and the resulting mixture was stirred at room temp for 16 h. Then, 1N HCl (1 mL) was added and the mixture was stirred for 1 h. The mixture was diluted with EtOAc (10 mL) and washed with brine (5 mL), dried (Na2SO4), filtered and concentrated to afford (3,4-bis(3-methoxyphenethoxy)phenyl)boronic acid (29 mg, 0.069 mmol, 87% yield) as white solid. 1H NMR (400 MHz, CDCl3)) δ 7.82 (dd, J=8.0, 1.3 Hz, 1H), 7.69 (d, J=1.3 Hz, 1H), 7.28-7.22 (m, 2H), 7.02 (s, 1H), 6.96-6.90 (m, 4H), 6.85-6.77 (m, 2H), 4.31 (q, J=7.3 Hz, 4H), 3.83 (s, 3H), 3.80 (s, 3H), 3.17 (dt, J=14.0, 7.2 Hz, 4H).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[NH2:15][C:16]1[N:17]=[CH:18][C:19]([C:35]2[CH:36]=[N:37][N:38]([CH:40]3[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]3)[CH:39]=2)=[C:20]2[CH:24]=[C:23]([C:25]3[C:33]4[C:28](=[CH:29][N:30]=[C:31]([OH:34])[CH:32]=4)[S:27][CH:26]=3)[O:22][C:21]=12.C1C[O:49][CH2:48][CH2:47]1.C(N(CC)CC)C.C(OC(=O)C)(=O)C>CN(C=O)C>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[NH2:15][C:16]1[N:17]=[CH:18][C:19]([C:35]2[CH:36]=[N:37][N:38]([CH:40]3[CH2:45][CH2:44][N:43]([C:48](=[O:49])[CH3:47])[CH2:42][CH2:41]3)[CH:39]=2)=[C:20]2[CH:24]=[C:23]([C:25]3[C:33]4[C:28](=[CH:29][N:30]=[C:31]([OH:34])[CH:32]=4)[S:27][CH:26]=3)[O:22][C:21]=12
Reactant: Nc1ncc(-c2cnn(C3CCNCC3)c2)c2cc(-c3csc4cnc(O)cc34)oc12
Reactant: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Solvent: CC(=O)OC(C)=O
Product: CC(=O)N1CCC(n2cc(-c3cnc(N)c4oc(-c5csc6cnc(O)cc56)cc34)cn2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 5 %

Procedure:
To a mixture of 3-{7-amino-4-[1-(piperidin-4-yl)-1H-pyrazol-4-yl]furo[2,3-c]pyridin-2-yl}thieno[2,3-c]pyridin-5-ol bis(trifluoroacetate) (40 mg, 0.061 mmol), THF (3 mL), and DMF (1.5 mL) was added triethylamine (72 μl, 0.52 mmol) followed by acetic anhydride (5.9 μl, 0.61 mmol). After stirring at RT for 1 h, the reaction mixture was concentrated in vacuo, and was then purified by MDP to afford 2.0 mg (5%) of the title compound as a yellow paste. 1H NMR (400 MHz, DMSO-d6): δ 13.72 (br s, 1 H), 8.86 (s, 1 H), 8.74 (s, 1 H), 8.56 (br s, 2 H), 8.48 (d, J=0.8 Hz, 1 H), 8.12 (d, J=0.8 Hz, 1 H), 7.96 (s, 1 H), 7.88 (s, 1 H), 7.67 (s, 1 H), 4.48-4.58 (m, 2 H), 3.94-4.01 (m, 1 H), 3.22-3.31 (m, 1 H), 2.73-2.82 (m, 1 H), 2.07-2.18 (m, 2 H), 2.07 (s, 3 H), 1.79-2.02 (m, 2 H); MS (ESI): 475.14 [M+H]+; HPLC tR=0.96 min (TOF: polar—3 min).