Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([C:3]([O:24][CH:25]([CH3:27])[CH3:26])([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[C:10]([CH2:15][NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH:9]=1)[C:4]([OH:6])=[O:5])C.I[CH2:29][CH3:30].C(=O)([O-])[O-].[K+].[K+].[C:37](OCC)(=O)[CH3:38]>CN(C)C=O>[C:20]([O:19][C:17]([NH:16][CH2:15][C:10]1[CH:9]=[C:8]([CH2:7][CH:3]([O:24][CH:25]([CH3:26])[CH3:27])[C:4]([O:6][CH2:29][CH3:30])=[O:5])[CH:13]=[CH:12][C:11]=1[O:14][CH2:37][CH3:38])=[O:18])([CH3:22])([CH3:23])[CH3:21]
Reactant: CCOC(C)=O
Reactant: CCC(Cc1ccc(O)c(CNC(=O)OC(C)(C)C)c1)(OC(C)C)C(=O)O
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(Cc1ccc(OCC)c(CNC(=O)OC(C)(C)C)c1)OC(C)C
Temperature: 50 °C
Reaction time: 4 h

Procedure:
795 mg of ethyl 3-(3-[(tertiary butoxycarbonyl)amino]methyl-4-hydroxyphenyl)-2-isopropoxypropionic acid was dissolved in 2 ml N,N-dimethylformamide, and 0.3 ml iodoethane and 200 mg potassium carbonate were successively added. After stirring at 50° C. for 4 hours, the reaction mixture was diluted with ethyl acetate, The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate and the solvent was evapoarated. The residue was purified by silica gel column chromatography, and from fractions eluted with hexane-ethyl acetate (8:1), 185 mg of ethyl 3-(3-[(tertiary butoxycarbonyl)amino]methyl-4-ethoxyphenyl)-2-isopropoxypropionate was obtained.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:13]([CH2:14]O)=[C:12]([C:16]([CH3:18])=[CH2:17])[S:11][N:10]=2)=[CH:5][CH:4]=1)[CH3:2].CS([Cl:23])(=O)=O.C(N(CC)CC)C.O>ClCCl>[Cl:23][CH2:14][C:13]1[C:9]([C:6]2[CH:7]=[CH:8][C:3]([CH2:1][CH3:2])=[CH:4][CH:5]=2)=[N:10][S:11][C:12]=1[C:16]([CH3:18])=[CH2:17]
Reactant: C=C(C)c1snc(-c2ccc(CC)cc2)c1CO
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: C=C(C)c1snc(-c2ccc(CC)cc2)c1CCl
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of [3-(4-ethylphenyl)-5-(prop-1-en-2-yl)-1,2-thiazol-4-yl]methanol (305.3 mg, 1.18 mmol, 1.00 equiv) in dichloromethane (15 mL), MsCl (268.8 mg, 2.00 equiv), triethylamine (297.6 mg, 2.94 mmol, 2.50 equiv). The resulting solution was stirred for 40 min at 25° C. 10.0 mL water was added to the mixture. The organic phase was separated and washed by 10.0 mL brine, dried over anhydrous sodium sulfate. The resulting mixture was concentrated under vacuum and residue used in next step directly without further purification. Mass spectrum (ESI, m/z): Calcd. for C15H16ClNS, 278.8 (M+H). found 278.8.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:41])[C@@H:9]([CH3:40])[C:10]([NH:12][C@@H:13]([CH:37]([CH3:39])[CH3:38])[C:14]([N:16]1[C:20]2=[N:21][CH:22]=[CH:23][CH:24]=[C:19]2[CH2:18][C@H:17]1[CH2:25]OS(C1C=CC(C)=CC=1)(=O)=O)=[O:15])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[N-:42]=[N+:43]=[N-:44].[Na+]>CN(C=O)C>[C:1]([O:5][C:6](=[O:7])[N:8]([C@H:9]([C:10](=[O:11])[NH:12][C@H:13]([C:14]([N:16]1[C:20]2=[N:21][CH:22]=[CH:23][CH:24]=[C:19]2[CH2:18][C@H:17]1[CH2:25][N:42]=[N+:43]=[N-:44])=[O:15])[CH:37]([CH3:39])[CH3:38])[CH3:40])[CH3:41])([CH3:4])([CH3:2])[CH3:3]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2Cc3cccnc3N2C(=O)[C@@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)C(C)C)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)[C@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)C(=O)N1c2ncccc2C[C@H]1CN=[N+]=[N-]
Temperature: 90 °C
Yield: 89.6 %

Procedure:
To a stirred solution of toluene-4-sulfonic acid (S)-1-{(S)-2-[(S)-2-(tert-butoxycarbonyl-methyl-amino)-propionylamino]-3-methyl-butyryl}-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-2-ylmethyl ester (Intermediate 2) (200 mg, 0.34 mmol) in DMF (4 mL) was added NaN3 (26.53 mg, 0.408 mmol) and the resulting mixture was heated at 90° C. for 3 h. The reaction was concentrated in vacuo and the obtained residue was dissolved in ethyl acetate (25 mL) and washed with water and brine, dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by flash chromatography (silica gel, 12% EtOAc in hexanes) to give {(S)-1-[(S)-1-((S)-2-azidomethyl-2,3-dihydro-pyrrolo[2,3-b]pyridine-1-carbonyl)-2-methyl-propylcarbamoyl]-ethyl}-methyl-carbamic acid tert-butyl ester (140 mg), m/z=460 (M+H).
Reaction SMILES: [CH3:1][N:2]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH3:23])[CH2:3][CH:4]([C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=1)O.FC(F)(F)C(OC(=O)C(F)(F)F)=O>FC(F)(F)C(O)=O>[CH3:1][N:2]1[CH2:3][CH:4]([C:6]2[CH:15]=[CH:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH:7]=2)[C:22]2[C:17](=[C:18]([CH3:23])[CH:19]=[CH:20][CH:21]=2)[CH2:16]1
Reactant: Cc1ccccc1CN(C)CC(O)c1ccc2ccccc2c1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Product: Cc1cccc2c1CN(C)CC2c1ccc2ccccc2c1
Reaction time: 24 h
Yield: 62 %

Procedure:
The product from Step A (1.25 g, 4.1 mmol) was dissolved in trifluoroacetic acid (TFA, 7.5 mL), then trifluoroacetic anhydride (TFAA, 7.5 mL) was added. After stirring for 24 h, the solvents were removed in vacuo, the residue was dissolved in MeOH, and the solvent was removed in vacuo. The residue was dissolved in aqueous NH4OH, then extracted twice with CH2Cl2. The extract was dried over Na2SO4, filtered, the solvent was removed in vacuo, and the residue was purified by column chromatography on silica gel (40 g) eluting with 5% to 30% EtOAc/hexanes with 1% Et3N to give 2,8-dimethyl-4-naphthalen-2-yl-1,2,3,4-tetrahydroisoquinoline (0.73 g, 61%) as a clear, dark yellow oil: 1H NMR (300 MHz, CDCl3) δ 7.66-7.88 (m, 4 H), 7.38-7.48 (m, 2 H), 7.26 (dd, J=8.3, 1.6 Hz, 1 H), 6.93-7.04 (m, 2 H), 6.74 (d, J=7.2 Hz, 1 H), 4.45 (t, J=6.9 Hz, 1 H), 3.75 (d, J=15.4 Hz, 1 H), 3.51 (d, J=15.4 Hz, 1 H), 3.06 (ddd, J=11.2, 5.6, 0.9 Hz, 1 H), 2.67 (ddd, J=11.4, 8.5 Hz, 1 H), 2.48 (s, 3 H), 2.27 (s, 3H).
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[CH2:3][N:4]=[C:5]([NH2:22])[NH:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18](=[NH:21])OC)[N:8]=1.[Cl-:25].[NH4+:26].CCOCC>CO>[ClH:25].[F:1][C:2]([F:24])([F:23])[CH2:3][N:4]=[C:5]([NH2:22])[NH:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([NH2:26])=[NH:21])[N:8]=1
Reactant: [NH4+]
Reactant: COC(=N)CCCCOc1nccc(NC(N)=NCC(F)(F)F)n1
Reactant: [Cl-]
Solvent: CCOCC
Solvent: CO
Product: Cl
Product: N=C(N)CCCCOc1nccc(NC(N)=NCC(F)(F)F)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.5 %

Procedure:
Methyl 5-(4-[2-(2,2,2-trifluoroethyl)guanidino]pyrimid-2-yloxy)valerimidate (1.5 g.) in MeOH (15 ml.) was treated with ammonium chloride (0.25 g.) and the solution stirred at room temperature for 2 hours. Ether was added until the solution became cloudy. Continued stirring caused precipitation of a solid which was filtered to give 5-(4-[2-(2,2,2-trifluoroethyl)guanidino]pyrimid-2-yloxy)valeramidine hydrochloride, (1.52 g.), m.p. 156°-158°.
Reaction SMILES: [C:1]1([CH:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][NH2:19])[CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:27]1[CH:28]=[CH:29][C:30]2[N:31]([CH:33]=[C:34]([C:36]([CH3:43])([CH3:42])[C:37]([O:39]CC)=[O:38])[N:35]=2)[N:32]=1.C(=O)(O)[O-].[Na+]>>[C:20]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][NH:19][C:27]3[CH:28]=[CH:29][C:30]4[N:31]([CH:33]=[C:34]([C:36]([CH3:43])([CH3:42])[C:37]([OH:39])=[O:38])[N:35]=4)[N:32]=3)[CH2:11][CH2:10]2)[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CCOC(=O)C(C)(C)c1cn2nc(Cl)ccc2n1
Reactant: NCCCCN1CCC(OC(c2ccccc2)c2ccccc2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Product: CC(C)(C(=O)O)c1cn2nc(NCCCCN3CCC(OC(c4ccccc4)c4ccccc4)CC3)ccc2n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 21.7 %

Procedure:
1.56 g of 4-(diphenylmethoxy)-1-piperidinebutanamine and 617 mg of ethyl 2-(6-chloroimidazo[1,2-b]pyridazin-2-yl)-2-methylpropionate were stirred at 185° C. for 3 hours. After cooling, aqueous sodium bicarbonate was added, followed by extraction with ethyl acetate; the extract was washed with saturated saline, dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate:methanol:triethylamine (50:5:1). The desired fraction was collected, concentrated under reduced pressure and dissolved in 5 ml of ethyl acetate; 0.52 ml of a 4 N hydrogen chloride solution in ethyl acetate was added, followed by concentration. The residue was dissolved in 4 ml of ethanol; 4 ml of a 1 N aqueous solution of sodium hydroxide was added, followed by stirring at room temperature for 4 hours; 1 ml of a 2 N aqueous solution of sodium hydroxide was added, followed by stirring at 50° C. for 16 hours. The mixture was concentrated under reduced pressure. The residue was diluted with water and washed with ethyl acetate; the water layer was adjusted to pH 4.5 by the addition of 4 N hydrochloric acid and extracted with ethyl acetate-tetrahydrofuran (1:1); the extract was washed with saturated saline, dried over magnesium sulfate and concentrated under reduced pressure. The residue was powdered by the addition of ethyl acetate, collected by filtration and dried to yield 271 mg of the title compound.
Reaction SMILES: [NH2:1][CH:2]([C:9]1[C:14]([O:15][CH3:16])=[CH:13][CH:12]=[CH:11][C:10]=1[O:17][CH3:18])[CH2:3][CH2:4][C:5]([O:7]C)=O.[C:19]1([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:24]=[CH:23][C:22]([CH:25]=O)=[CH:21][CH:20]=1>>[C:19]1([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:20]=[CH:21][C:22]([CH2:25][N:1]2[CH:2]([C:9]3[C:14]([O:15][CH3:16])=[CH:13][CH:12]=[CH:11][C:10]=3[O:17][CH3:18])[CH2:3][CH2:4][C:5]2=[O:7])=[CH:23][CH:24]=1
Reactant: COC(=O)CCC(N)c1c(OC)cccc1OC
Reactant: O=Cc1ccc(-c2ccccc2)cc1
Product: COc1cccc(OC)c1C1CCC(=O)N1Cc1ccc(-c2ccccc2)cc1

Procedure:
Prepared according to the described general procedure 2 (GP2) by reaction of methyl 4-amino-4-(2,6-dimethoxyphenyl)butanoate with commercially available [1,1′-biphenyl]-4-carbaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.91 min.; [M+H]+: 388.12 g/mol.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][CH:14]=1)[O:5]C1CCCOC1.[C:15]([C:17]1[CH:18]=[C:19]([CH:27]=[CH:28][CH:29]=1)[O:20]C1CCCOC1)#[CH:16].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(N(CC)CC)C.[Cu]I.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>[OH:20][C:19]1[CH:18]=[C:17]([C:15]#[C:16][C:2]2[CH:14]=[CH:13][CH:12]=[C:4]([OH:5])[CH:3]=2)[CH:29]=[CH:28][CH:27]=1
Reactant: Brc1cccc(OC2CCCOC2)c1
Reactant: C#Cc1cccc(OC2CCCOC2)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: Oc1cccc(C#Cc2cccc(O)c2)c1

Procedure:
Following the above procedure, the reaction was performed with 3-(3-bromophenoxy)tetrahydropyran (2.57 g), 3-(3 -ethynylphenoxy)tetrahydropyran (2.02 g), triphenylphosphine (105 mg), copper(I) iodide (19 mg) and bis(triphenylphosphine)palladium(II) dichloride (70 mg) in triethylamine (40 ml). The crude dark residue obtained after filtration over silica-gel column is dissolved in a mixture of dichloromethane (10 ml) and methanol (40 ml), then treated with 150 mg pyridinium p-toluene sulphonate at 60° C. for 2 h. The transparent reaction solution was then diluted with 100 ml of ether and washed twice with 40 ml of water then with 50 ml of saturated NaCl solution, dried over MgSO4 and evaporated to dryness to afford 1,2-bis-(3-hydroxyphenyl)ethyne as yellowish solid.
Reaction SMILES: C(O)(=O)C.Cl[C:6]1[N:11]=[C:10]([CH3:12])[CH:9]=[CH:8][N:7]=1.[Br:13][C:14]1[CH:15]=[C:16]([CH:18]=[C:19]([CH3:21])[CH:20]=1)[NH2:17]>O1CCOCC1>[Br:13][C:14]1[CH:15]=[C:16]([NH:17][C:6]2[N:11]=[C:10]([CH3:12])[CH:9]=[CH:8][N:7]=2)[CH:18]=[C:19]([CH3:21])[CH:20]=1
Reactant: Cc1ccnc(Cl)n1
Reactant: Cc1cc(N)cc(Br)c1
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: Cc1cc(Br)cc(Nc2nccc(C)n2)c1
Temperature: 120 °C
Yield: 100 %

Procedure:
Acetic acid (0.234 mL, 4.08 mmol) was added to 2-chloro-4-methylpyrimidine (0.5 g, 3.89 mmol) and 3-bromo-5-methylaniline (1.096 g, 3.89 mmol) suspended in dioxane (7.78 mL). The reaction was heated to 120° C. overnight. Then, the reaction was cooled to room temperature and was directly purified by column chromatography on silica gel eluting with ethyl acetate/hexanes to give N-(3-bromo-5-methylphenyl)-4-methylpyrimidin-2-amine (1.08 g, 3.89 mmol, quant.) as a white solid. MS ESI: [M+H]+ m/z 278.0 and 280.0.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[NH2:9][C:10]1[CH:22]=[CH:21][C:13]([CH2:14][C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)=[CH:12][CH:11]=1.O>CN(C)C=O.[Al]>[NH2:9][C:10]1[CH:22]=[CH:21][C:13]([CH2:14][C:15]2[CH:16]=[CH:17][N:18]=[CH:19][CH:20]=2)=[CH:12][C:11]=1[Br:1]
Reactant: Nc1ccc(Cc2ccncc2)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: [Al]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1ccc(Cc2ccncc2)cc1Br
Temperature: 25 °C
Reaction time: 3 h
Yield: 77.3 %

Procedure:
A solution of N-bromosuccinimide (1.4 gm) in 10 mL dimethylformamide was added in a dropwise manner to a solution of 4-(4-aminobenzyl)pyridine (1.5 gm) in 10 mL of dimethylformamide. The reaction flask was wrapped in aluminum foil to prevent exposure of the reagents to light. The reaction mixture was stirred at room temperature for 3 hours. The progress of the reaction was monitored by thin-layer chromatography. When the reaction was completed, the reaction mixture was combined with 100 mL of H2O with stirring. A reddish brown precipitate was formed, filtered out of solution, washed with H2O, and air dried. The solid was dissolved in ethyl acetate, back washed with saturated NaCl, dried over MgSO4 and triturated with ethyl ether. The solid was filtered from the solution and air dried yielding 1.6 gm of 4-(4-amino-3-bromobenzyl)pyridine as reddish/tan crystals.
Reaction SMILES: CN(C)C=O.CS(O[CH2:11][CH2:12][CH:13]1[CH2:22][CH2:21][C:16]2([O:20][CH2:19][CH2:18][O:17]2)[CH2:15][CH2:14]1)(=O)=O.[N-:23]=[N+:24]=[N-:25].[Na+].O>C(OCC)(=O)C>[O:20]1[C:16]2([CH2:21][CH2:22][CH:13]([CH2:12][CH2:11][N:23]=[N+:24]=[N-:25])[CH2:14][CH2:15]2)[O:17][CH2:18][CH2:19]1
Reactant: CS(=O)(=O)OCCC1CCC2(CC1)OCCO2
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: [N-]=[N+]=NCCC1CCC2(CC1)OCCO2
Temperature: 47.5 °C
Reaction time: 0.5 h

Procedure:
To 10 mL of an N,N-dimethylformamide solution containing 1.4 g of 2-(1,4-dioxaspiro(4.5)decan-8-yl)ethyl methanesulfonate, 0.45 g of sodium azide was added at room temperature, and the mixture was stirred at 45 to 50° C. for 1 hour and 30 minutes. Thereto was further added 70 mg of sodium azide, and the mixture was stirred at the same temperature for 2 hours. The reaction mixture was cooled to room temperature, and then water and ethyl acetate were added thereto. The organic layer was separated, washed with an aqueous saturated sodium chloride solution and then dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [eluent; hexane:ethyl acetate=4:1] to obtain 1.0 g of a colorless oily substance, 2-(1,4-dioxaspiro(4.5)decan-8-yl)ethyl azide.
Reaction SMILES: [F:1][C:2]1[C:3]([C:9]2[CH:14]=[C:13]([NH:15][C:16]3[CH:21]=[CH:20][N:19]=[C:18]4[CH:22]=[N:23][NH:24][C:17]=34)[C:12]([CH3:25])=[CH:11][N:10]=2)=[N:4][C:5]([CH3:8])=[CH:6][CH:7]=1.[N:26]([CH2:29][CH3:30])=[C:27]=[O:28]>N1C=CC=CC=1.C(#N)C>[CH2:29]([NH:26][C:27]([N:24]1[C:17]2[C:18](=[N:19][CH:20]=[CH:21][C:16]=2[NH:15][C:13]2[C:12]([CH3:25])=[CH:11][N:10]=[C:9]([C:3]3[C:2]([F:1])=[CH:7][CH:6]=[C:5]([CH3:8])[N:4]=3)[CH:14]=2)[CH:22]=[N:23]1)=[O:28])[CH3:30]
Reactant: CCN=C=O
Reactant: Cc1ccc(F)c(-c2cc(Nc3ccnc4cn[nH]c34)c(C)cn2)n1
Solvent: c1ccncc1
Solvent: CC#N
Product: CCNC(=O)n1ncc2nccc(Nc3cc(-c4nc(C)ccc4F)ncc3C)c21
Temperature: 75 °C

Procedure:
N-(3′-Fluoro-5,6′-dimethyl-2,2′-bipyridin-4-yl)-1H-pyrazolo[4,3-b]pyridin-7-amine (81 mg, 0.242 mmol) was combined with acetonitrile (2.4 mL) and isocyanatoethane (23.78 μl, 0.303 mmol) along with 1 drop of pyridine. The mixture was heated at 75° C. The reaction was then cooled to give a solid which was collected by filtration, rinsed with acetonitrile to give the title compound. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.35 (3H, t, J=7.20 Hz) 2.47 (3H, s) 2.64 (3H, s) 3.51-3.63 (2H, m) 7.17-7.23 (1H, m) 7.33 (1H, d, J=4.55 Hz) 7.43 (1H, dd, J=10.48, 8.46 Hz) 7.51-7.59 (1H, m) 8.08 (1H, br. s.) 8.27 (1H, s) 8.41 (1H, d, J=5.31 Hz) 8.65 (1H, br. s.) 11.00 (1H, br. s.). MS [M+H] found 406.4.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:11]2[C:12]([O:16][CH3:17])=[N:13][CH:14]=[CH:15][C:10]=2[N:9]([C:18]2[C:23]([F:24])=[CH:22][CH:21]=[CH:20][C:19]=2[F:25])[N:8]=1)(=O)=O.CN(C=O)C.CC1(C)C(C)(C)OB([C:41]2[CH:42]=[C:43]([CH2:47][C:48]([O:50]C)=[O:49])[CH:44]=[CH:45][CH:46]=2)O1.C(=O)([O-])[O-].[K+].[K+]>O>[F:24][C:23]1[CH:22]=[CH:21][CH:20]=[C:19]([F:25])[C:18]=1[N:9]1[C:10]2[CH:15]=[CH:14][N:13]=[C:12]([O:16][CH3:17])[C:11]=2[C:7]([C:41]2[CH:42]=[C:43]([CH2:47][C:48]([OH:50])=[O:49])[CH:44]=[CH:45][CH:46]=2)=[N:8]1
Reactant: COc1nccc2c1c(OS(=O)(=O)C(F)(F)F)nn2-c1c(F)cccc1F
Reactant: COC(=O)Cc1cccc(B2OC(C)(C)C(C)(C)O2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1nccc2c1c(-c1cccc(CC(=O)O)c1)nn2-c1c(F)cccc1F
Temperature: 90 °C
Reaction time: 8 h
Yield: 35.4 %

Procedure:
To a solution of 1-(2,6-difluorophenyl)-4-methoxy-1H-pyrazolo[4,3-c]pyridin-3-yl trifluoromethanesulfonate (600 mg) obtained in Step C of Example 35 in a mixed solvent of DMF (5 mL)/water (0.5 mL) were added methyl (3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetate (567 mg), (1,1′-bis(diphenylphosphino)ferrocene)dichloropalladium(II) (60 mg) and potassium carbonate (405 mg). The reaction mixture was stirred overnight at 90° C. The reaction mixture was diluted with water, and the aqueous layer was washed with ethyl acetate. The aqueous layer was neutralized with 1M hydrochloric acid at 0° C., and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (205 mg).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:16]3[C:11](=[N:12][CH:13]=[C:14]([Sn](C)(C)C)[N:15]=3)[NH:10][C:9](=[O:21])[CH2:8]2)[CH2:3][CH2:2]1.Br[C:23]1[CH:24]=[CH:25][C:26]([C:29]2[N:33]=[CH:32][N:31]([CH:34]3[CH2:39][CH2:38][CH2:37][CH2:36][O:35]3)[N:30]=2)=[N:27][CH:28]=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CN(C)C=O>[O:35]1[CH2:36][CH2:37][CH2:38][CH2:39][CH:34]1[N:31]1[CH:32]=[N:33][C:29]([C:26]2[N:27]=[CH:28][C:23]([C:14]3[N:15]=[C:16]4[N:7]([CH:4]5[CH2:5][CH2:6][O:1][CH2:2][CH2:3]5)[CH2:8][C:9](=[O:21])[NH:10][C:11]4=[N:12][CH:13]=3)=[CH:24][CH:25]=2)=[N:30]1
Reactant: C[Sn](C)(C)c1cnc2c(n1)N(C1CCOCC1)CC(=O)N2
Reactant: Brc1ccc(-c2ncn(C3CCCCO3)n2)nc1
Agent: [Pd]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C1CN(C2CCOCC2)c2nc(-c3ccc(-c4ncn(C5CCCCO5)n4)nc3)cnc2N1
Temperature: 95 °C
Yield: 39 %

Procedure:
A mixture of 4-(tetrahydro-2H-pyran-4-yl)-6-(trimethylstannyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one (1 equiv), 5-bromo-2-(1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-3-yl)pyridine (1.2 equiv), tris(dibenzylideneacetone)dipalladium (0.1 equiv), tri-o-tolylphosphine (0.2 equiv), triethylamine (3 equiv) and N,N-dimethylformamide was heated at 95° C. for 3 h under nitrogen. Concentration and chromatography purification give the desired product in 39% yield. MS (ESI) m/z 463.1 [M+1]+.
Reaction SMILES: [CH3:1][N:2]([CH3:26])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[CH:9]=[C:10]([CH:15]=[C:16](OS(C(F)(F)F)(=O)=O)[CH:17]=1)[C:11]([O:13][CH3:14])=[O:12])=[O:7].[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=1B(O)O.C(N(CC)CC)C>CN(C)C=O.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:27][C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=1[C:16]1[CH:17]=[C:8]([C:6](=[O:7])[NH:5][CH2:4][CH2:3][N:2]([CH3:26])[CH3:1])[CH:9]=[C:10]([CH:15]=1)[C:11]([O:13][CH3:14])=[O:12]
Reactant: OB(O)c1cc(Cl)ccc1Cl
Reactant: COC(=O)c1cc(OS(=O)(=O)C(F)(F)F)cc(C(=O)NCCN(C)C)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)c1cc(C(=O)NCCN(C)C)cc(-c2cc(Cl)ccc2Cl)c1
Temperature: 100 °C

Procedure:
A mixture of methyl 3-((2-dimethylaminoethyl)carbamoyl]-5-(trifluoromethylsulfonyloxy)benzoate (2 g), 2,5-dichlorophenyl-dihydroxyborane 1.25 g), tetrakis(triphenylphosphine)palladium(0) (0.17 g) and triethylamine (1.52 g) in N,N-dimethylformamide (40 ml) was heated at 100° C. for 3 hours under nitrogen atmosphere. After evaporating the solvent, the residue was dissolved in a mixture of ethyl acetate (100 ml) and water (100 ml). The organic layer was successively washed with 10% potassium carbonate aqueous solution, brine and dried over magnesium sulfate. The solvent was evaporated in vacuo and the residue was purified by column chromatography on silica gel (100 ml) eluting with a mixture of chloroform and methanol (20:1). The fractions containing the desired products were collected and evaporated in vacuo. The residue was crystallized from diisopropyl ether to afford methyl 5-(2,5-dichlorophenyl)-3-[(2-dimethylaminoethyl)carbamoyl]benzoate.
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[NH:7][C:8]([C:10]1[S:11][C:12]([S:27][CH3:28])=[C:13]([S:15]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20](B(O)O)[CH:19]=2)(=[O:17])=[O:16])[CH:14]=1)=[NH:9])([CH3:4])([CH3:3])[CH3:2].I[C:31]1[C:36]([CH3:37])=[CH:35][C:34]([N+:38]([O-:40])=[O:39])=[CH:33][N:32]=1.O>CN(C=O)C.[Cu]I.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:1]([O:5][C:6](=[O:29])[NH:7][C:8](=[NH:9])[C:10]1[S:11][C:12]([S:27][CH3:28])=[C:13]([S:15]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:31]3[C:36]([CH3:37])=[CH:35][C:34]([N+:38]([O-:40])=[O:39])=[CH:33][N:32]=3)[CH:19]=2)(=[O:17])=[O:16])[CH:14]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc([N+](=O)[O-])cnc1I
Reactant: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(B(O)O)c1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CN(C)C=O
Product: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(-c2ncc([N+](=O)[O-])cc2C)c1
Temperature: 25 °C
Yield: 48 %

Procedure:
A solution of {[4-(3-dihydroxyboranyl-benzenesulfonyl)-5-methylsulfanyl-thiophen-2-yl]-imino-methyl}-carbamic acid tert-butyl ester (0.058 mmol, 40 mg, Example 140: step a), 2-iodo-3-methyl-5-nitropyridine (0.08 mmol, 21.1 mg), CuI (0.01 mmol, 2.2 mg) and (Ph3P)4Pd (0.006 mmol) in DMF (0.6 mL) was heated at 100° under Ar for 3 hr. The reaction mixture was allowed to cool to RT and poured in to water (20 mL). The product was extracted with CH2Cl2 (3×10 mL). CH2Cl2 extracts were combined, dried (Na2SO4) and concentrated in vaccuo. The resulting residue was purified on silica (30% EtOAc:Hexane) to obtain (Imino-{4-[3-(3-methyl-5-nitro-pyridin-2-yl)-benzenesulfonyl]-5-methylsulfanyl-thiophen-2-yl}-methyl)-carbamic acid tert-butyl ester. Yield: 48%; 1H NMR (CDCl3) δ 9.36 (br, 1H), 8.37 and 8.25 (s, 1H each), 8.1 and 7.8 (d, J=2.4 Hz, 1H each), 7.93 (s, 1H), 7.74 (t, J=6.8 Hz, 1H), 2.7 and 2.5 (s, 3H each), 1.35 (s, 9H)