Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]#[C:8][C:9]1[C:17]2[C:12](=[CH:13][C:14]([NH:18][C:19]3[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=3[C:21](O)=[O:22])=[CH:15][CH:16]=2)[NH:11][N:10]=1.[CH2:28]([NH2:31])[C:29]#[CH:30].C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH2:28]([NH:31][C:21](=[O:22])[C:20]1[CH:24]=[CH:25][CH:26]=[CH:27][C:19]=1[NH:18][C:14]1[CH:13]=[C:12]2[C:17]([C:9](/[CH:8]=[CH:7]/[C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)=[N:10][NH:11]2)=[CH:16][CH:15]=1)[C:29]#[CH:30]
Reactant: O=C(O)c1ccccc1Nc1ccc2c(C#Cc3ccccn3)n[nH]c2c1
Reactant: C#CCN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C#CCNC(=O)c1ccccc1Nc1ccc2c(/C=C/c3ccccn3)n[nH]c2c1
Reaction time: 8 h
Yield: 58.7 %

Procedure:
A solution of 2-(3-Pyridin-2-ylethynyl-1H-indazol-6-ylamino)-benzoic acid (41 mg, 0.117 mmol), propargylamine (24 μL, 0.35 mmol), triethylamine (81 μl, 0.58 mmol), dissolved in DMF (0.5 mL), was treated with HATU (89 mg, 0.233 mmol). The mixture was stirred overnight, then purified by reverse phase HPLC yielding 27 mg (59%) of the title compound as a yellow solid. 1H NMR (DMSO-d6): δ 9.78 (1H, s), 8.99 (1H, m), 8.61 (1H, d, J=2.1), 7.88 (1H, s), 7.72 (3H, m), 7.43 (4H, m), 7.29 (1H, s), 7.04 (1H, d, J=7.3), 6.91 (1H, t, J=5.2), 4.04 (2H, s), 3.04 (1H, s). ESIMS (M+H+): 392.1.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[CH3:11][N:12]1[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[C:14]([C:20](OC)=[O:21])=[N:13]1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1(C)C=CC=CC=1.C1COCC1>[CH3:11][N:12]1[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[C:14]([CH2:20][OH:21])=[N:13]1
Reactant: COC(=O)c1nn(C)cc1[N+](=O)[O-]
Agent: CC(C)C[Al+]CC(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: Cn1cc([N+](=O)[O-])c(CO)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Diisobutyl aluminum hydride (34.2 ml of a 1 M solution in toluene) was added to a solution of methyl 1-methyl-4-nitro-pyrazole-3-carboxylate (2.92 g) in anhydrous THF (100 ml) at −20° C. over a period of 5 minutes. The reaction was stirred at room temperature overnight and then poured into sat. citric acid (100 ml). The organic phase was separated and the aqueous washed with EtOAc (4×100 ml). The combined organic phases were washed with brine (100 ml), dried, filtered and concentrated in vacuo. The crude material was columned on silica (50 g), eluting with EtOAc. The product fractions were combined and washed with sat. aq. potassium sodium L-tartrate solution (3×100 ml) and brine (100 ml). The solvent was removed in vacuo to yield (1-methyl-4-nitropyrazol-3-yl)methanol as a pale yellow solid, 2.0 g, 74%.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:24]=[CH:23][C:12]([O:13][C:14]3[CH:19]=[CH:18][N:17]=[C:16]([C:20]([OH:22])=O)[CH:15]=3)=[CH:11][CH:10]=2)[CH:5]=[C:4]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:3]=1.[CH3:31][O:32][CH2:33][CH2:34][NH2:35]>>[NH2:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:24]=[CH:23][C:12]([O:13][C:14]3[CH:19]=[CH:18][N:17]=[C:16]([C:20]([NH:35][CH2:34][CH2:33][O:32][CH3:31])=[O:22])[CH:15]=3)=[CH:11][CH:10]=2)[CH:5]=[C:4]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:3]=1
Reactant: COCCN
Reactant: Nc1nc(Nc2ccc(Oc3ccnc(C(=O)O)c3)cc2)cc(-c2ccccc2)n1
Product: COCCNC(=O)c1cc(Oc2ccc(Nc3cc(-c4ccccc4)nc(N)n3)cc2)ccn1

Procedure:
This material was prepared by a method analogous to that described for Example 21, starting from 4-{4-[(2-amino-6-phenylpyrimidin-4-yl)amino] phenoxy}pyridine-2-carboxylic acid and 2-methoxyethylamine.
Reaction SMILES: Br[CH2:2][C:3](=[CH2:9])[C:4]([O:6][CH2:7][CH3:8])=[O:5].[NH:10]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:21]([O:20][C:18]([N:10]([CH2:2][C:3](=[CH2:9])[C:4]([O:6][CH2:7][CH3:8])=[O:5])[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:19])([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)(C)OC(=O)NC(=O)OC(C)(C)C
Reactant: C=C(CBr)C(=O)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C=C(CN(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(=O)OCC
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To ethyl 2-(bromomethyl)acrylate (104.4 g) in an acetonitrile (900 ml) solution, di-tert-butyl imino dicarboxylate (122.4 g) and potassium carbonate was added, and the mixture was stirred at room temperature for 2 days. The reaction solution was concentrated in vacuo. To the residue, ethyl acetate (1.4 liter) and water (700 ml) were added, and the layers were separated. The organic layer was washed with water (350 ml), dried over sodium sulfate, then concentrated to obtain ethyl 2-{[di(tert-butoxycarbonyl)amino]methyl}acrylate (compound S62a) as a crude product (182.7 g).
Reaction SMILES: [C:1](=O)([O:5]CC)[O:2][CH2:3][CH3:4].CCOCC.[CH3:14][C:15]1([CH2:20][CH2:21][CH2:22][C:23](=[O:25])[CH3:24])[O:19][CH2:18][CH2:17][O:16]1>C(O)C>[CH2:3]([O:2][C:1](=[O:5])[CH2:24][C:23](=[O:25])[CH2:22][CH2:21][CH2:20][C:15]1([CH3:14])[O:16][CH2:17][CH2:18][O:19]1)[CH3:4]
Reactant: CCOC(=O)OCC
Reactant: CC(=O)CCCC1(C)OCCO1
Solvent: CCOCC
Solvent: CCO
Product: CCOC(=O)CC(=O)CCCC1(C)OCCO1

Procedure:
11.8 Grams (0.1 moles) of diethyl carbonate in 12.5 ml. of anhydrous ether was added to 4.55 g. (0.1 moles) of a 53 percent dispersion of sodium hydride in mineral oil which was washed with anhydrous hexane and dried under nitrogen. This mixture was stirred under nitrogen and 8.6 g. (0.05 mole) of the ketal ketone, 5-(2-methyl-1,3-dioxolan-2-yl)-2-pentanone was added dropwise over a period of 2 hours. A gentle reflux was maintained throughout the addition and the refluxing was continued for an additional period of approximately 11/2 hours. The solution was then cooled with an ice bath, 20 ml. of anhydrous ether and 2 ml. of absolute ethyl alcohol was added and it was stirred for 45 minutes to destroy any unreacted sodium hydride. The suspension was diluted with an equal volume of ether and the ice cold suspension was then added to a rapidly agitated mixture of 6 ml. of glacial acetic acid and 200 ml. of ice water. The etheral layer was separated, and the aqueous layer was additionally extracted twice with ether. The extract was washed with saturated sodium bicarbonate and with a saturated sodium chloride, dried with sodium sulfate, filtered and evaporated in vacuo to give the crude β-keto ester, 6-(2-methyl-1,3-dioxolan-2-yl)-3-oxo-hexanoic acid ethyl ester, b.p. 110°-112° C at 0.2 mm., Analysis calculated for C12H20O5 : C, 59.00; H, 8.25. Found: C, 58.92; H, 8.38.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[N:11]1([CH2:17][CH2:18][CH2:19][NH2:20])[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1>CS(C)=O.Cl>[N:11]1([CH2:17][CH2:18][CH2:19][NH:20][C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=2)[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1
Reactant: NCCCN1CCOCC1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: Cl
Solvent: CS(C)=O
Product: O=[N+]([O-])c1ccc(NCCCN2CCOCC2)nc1
Temperature: 50 °C

Procedure:
2-chloro-5-nitro-pyridine Compound 16a1 (6.06 g, 38.2 mmol) and 3-morpholin-4-yl-propylamine Compound 9a (6.27 mL, 42.1 mmol) were combined in DMSO (100 mL) and heated to 50° C. After 2.5 hours the reaction mixture was diluted with 0.5 M HCl and washed with ethyl ether. The aqueous layer was adjusted to pH 11 with NaOH and extracted with EtOAc. The combined organic layers were dried over MgSO4 and concentrated to provide (3-morpholin-4-yl-propyl)-(5-nitro-pyridin-2-yl)-amine Compound 19a1. Using the procedure of Example 1, Compound 19a1 was used in place of Compound 1n3 with AcOH (30 mL) replacing EtOAc as solvent. 10% Pd/C (3.1 g) was added to the solution and the reaction was carried forward to provide N2-(3-morpholin-4-yl-propyl)-pyridine-2,5-diamine Compound 19a. 1H NMR (CDCl3) δ 7.67 (d, J=3.0 Hz, 1H); 6.95 (dd, J=8.6, 3.0 Hz, 1H); 6.31(d, J=8.6 Hz, 1H); 3.77-3.66 (m, 4H); 2.52-2.38 (m, 8H); 2.08.(p, J=6.8Hz, 2H). MS 267 (MH+).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=[CH:7][C:6]=1[O:15][C@H:16]([CH3:20])[C:17](O)=[O:18])([CH3:4])([CH3:3])[CH3:2].C(Cl)(=O)C([Cl:24])=O>CN(C)C=O.C(Cl)Cl>[C:1]([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=[CH:7][C:6]=1[O:15][C@H:16]([CH3:20])[C:17]([Cl:24])=[O:18])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(Cl)C(=O)Cl
Reactant: C[C@@H](Oc1ccc(C(C)(C)C)cc1C(C)(C)C)C(=O)O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: C[C@@H](Oc1ccc(C(C)(C)C)cc1C(C)(C)C)C(=O)Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 99 %

Procedure:
To a mixture of 675 m9 (2.2 mmol) of (2R)-2-(2,4-di-t-butylphenyloxy)propanoic acid (18) and 4 drops of N,N-dimethylformamide in methylene chloride (20 mL) at 0° C. under a nitrogen atmophere was added 1.21 mL (2.4 mmol) of a 2M solution of oxalyl chloride in methylene chloride dropwise over a 10 min period. The reaction mixture was allowed to stir at room temperature overnight. The solvent and any excess oxalyl chloride was removed by rotary evaporation and dried (under vacuum) to afford 715 mg (99%) of (2R)-2-(2,4-di-t-butylphenyloxy)propanoyl chloride (16) as a crude yellow liquid: 1H NMR (CDCl3) δ1.29 (s, 9 H), 1.42 (s, 9 H), 1.76-1.79 (d, 3 H), 4.94-5.00 (q, 1 H), 6.50-6.(d, 1 H), 7.12-7.16 (d, 1 H), 7.36 (s, 1 H); 13C NMR (CDCl3) δ175.0, 152.8, 144.1, 137.4, 124.6, 123.4, 110.6, 78.6, 35.1, 34.3, 1.5, 30.0, 18.0.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[CH:5][C:4]=1[C:9]1[NH:10][C:11]2[C:16]([CH:17]=1)=[CH:15][C:14]([C:18]#[N:19])=[CH:13][CH:12]=2.[H-].[Na+].IC.[C:24]([O-])(O)=O.[Na+]>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[CH:5][C:4]=1[C:9]1[N:10]([CH3:24])[C:11]2[C:16]([CH:17]=1)=[CH:15][C:14]([C:18]#[N:19])=[CH:13][CH:12]=2
Reactant: O=C([O-])O
Reactant: COc1ccncc1-c1cc2cc(C#N)ccc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: COc1ccncc1-c1cc2cc(C#N)ccc2n1C
Reaction time: 0.5 h

Procedure:
To a solution of 2-(4-methoxy-pyridin-3-yl)-1H-indole-5-carbonitrile (Example 90, 178 mg, 0.649 mmol) in DMF (4 mL) is added 60% sodium hydride in mineral oil (78 mg, 1.95 mmol) and the suspension is stirred for 30 min. Iodomethane (138 mg, 0.97 mmol) is then added to the reaction mixture which is stirred at ambient temperature for 1 h. Aqueous NaHCO3 (3 mL) is added to quench the reaction and the mixture is filtered and purified by HPLC using an Xbridge C18 with a gradient of acetonitrile in 0.1% NH4OH to afford 2-(4-methoxy-pyridin-3-yl)-1-methyl-1H-indole-5-carbonitrile as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 3.59 (s, 3H), 3.89 (s, 3H), 6.67 (s, 1H), 7.27 (d, J=5.8 Hz, 1H), 7.54 (dd, J=8.6, 1.5 Hz, 1H), 7.70 (d, J=8.6 Hz, 1H), 8.11 (d, J=1.1 Hz, 1H), 8.42 (s, 1H), 8.60 (d, J=5.8 Hz, 1H). HRMS (ESI) m/z 264.1138 [(M+H) calcd for C16H14N3O: 264.1137].
Reaction SMILES: [CH2:1]=[C:2]1[O:6][C:4](=[O:5])[CH2:3]1.[CH:7]1([NH:13][C:14]2[CH:23]=[C:22]3[C:17]([C:18](=[O:35])[C:19]([O:29][CH2:30][C:31](=[N:33][OH:34])[NH2:32])=[CH:20][N:21]3[CH:24]3[CH2:28][CH2:27][CH2:26][CH2:25]3)=[CH:16][C:15]=2[F:36])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1>C(Cl)(Cl)Cl>[C:4]([O:34][N:33]=[C:31]([NH2:32])[CH2:30][O:29][C:19]1[C:18](=[O:35])[C:17]2[C:22](=[CH:23][C:14]([NH:13][CH:7]3[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]3)=[C:15]([F:36])[CH:16]=2)[N:21]([CH:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)[CH:20]=1)(=[O:5])[CH2:3][C:2]([CH3:1])=[O:6]
Reactant: NC(COc1cn(C2CCCC2)c2cc(NC3CCCCC3)c(F)cc2c1=O)=NO
Reactant: C=C1CC(=O)O1
Solvent: ClC(Cl)Cl
Product: CC(=O)CC(=O)ON=C(N)COc1cn(C2CCCC2)c2cc(NC3CCCCC3)c(F)cc2c1=O

Procedure:
40 μl of diketene was added dropwise under ice-cooling to a 8 ml chloroform solution of 800 mg of 2-{[7-(cyclohexylamino)-1-cyclopentyl-6-fluoro-4-oxo-1,4-dihydroquinolin-3-yl]oxy}-N′-hydroxyethanimidamide, followed by stirring under ice-cooling for 6 hours. By evaporating the solvent under a reduced pressure, 180 mg of N′-(acetoacetyloxy)-2-{[7-(cyclohexylamino)-1-cyclopentyl-6-fluoro-4-oxo-1,4-dihydroquinolin-3-yl]oxy}ethanimidamide was obtained.
Reaction SMILES: [Cl:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([CH:12]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8].[F:14][C:15]([F:19])([F:18])[CH2:16][OH:17].C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>C1COCC1>[Cl:1][C:2]1[C:3]([O:17][CH2:16][C:15]([F:19])([F:18])[F:14])=[N:4][CH:5]=[C:6]([CH:12]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: OCC(F)(F)F
Reactant: CCOC(=O)c1cnc(Cl)c(Cl)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)c1cnc(OCC(F)(F)F)c(Cl)c1
Temperature: -73 °C
Reaction time: 0.5 h
Yield: 92.9 %

Procedure:
To a solution of ethyl 5,6-dichloronicotinate (6.28 g, 28.5 mmol) and 2,2,2-trifluoroethanol (2.71 ml, 37.1 mmol) in THF (90 ml) at −73° C. was added NaHMDS (37.1 ml, 37.1 mmol). The reaction was stirred at −73° C. for 30 minutes, then at 0° C. for 5 hours. The reaction was quenched with 30 mL saturated NH4Cl solution. The reaction mixture was then poured into 50 mL brine and phases were separated. The aqueous layer was extracted with DCM (2×100 mL). The combined organics were dried (Na2SO4) and concentrated. Silica gel chromatography with 100% heptane to 30% EtOAc in heptane provided final product (7.51 g). LCMS m/z 284.1 (M+H)+, Rt 1.07 min.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20]2[C:29](=O)[C:28]3[C:27]([C:31](OC)=[O:32])=[CH:26][CH:25]=[CH:24][C:23]=3[NH:22][CH:21]2[C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[CH:16][CH:15]=1)[CH3:12])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[NH2:42][NH2:43]>CO>[CH3:12][N:11]([CH2:13][C:14]1[CH:15]=[CH:16][C:17]([CH:20]2[C:29]3=[N:42][NH:43][C:31](=[O:32])[C:27]4[CH:26]=[CH:25][CH:24]=[C:23]([C:28]=43)[NH:22][CH:21]2[C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[CH:18][CH:19]=1)[C:9](=[O:10])[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1cccc2c1C(=O)C(c1ccc(CN(C)C(=O)OCc3ccccc3)cc1)C(c1ccccc1)N2
Reactant: NN
Solvent: O
Solvent: CO
Product: CN(Cc1ccc(C2c3n[nH]c(=O)c4cccc(c34)NC2c2ccccc2)cc1)C(=O)OCc1ccccc1
Temperature: 40 °C
Reaction time: 24 h
Yield: 16 %

Procedure:
A mixture of methyl 3-(4-(((benzyloxycarbonyl)(methyl)amino)methyl)phenyl)-4-oxo-2-phenyl-1,2,3,4-tetrahydroquinoline-5-carboxylate (220 mg, 0.94 mmol) in hydrazine monohydrate (50 mL) and methanol (5 mL) was stirred at 40° C. for 24 hr. The mixture was cooled to room temperature and filtered to give the crude product. The crude product was purified by chromatography (silica gel, petroleum ether/ethyl acetate=3:1) to give benzyl methyl(4-(3-oxo-8-phenyl-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazin-9-yl)benzyl)carbamate (80 mg, yield 16%). LC-MS (ESI) m/z: 517(M+1)+.
Reaction SMILES: [C:1]1([C:7]2([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[O:11][C:10]3[CH:12]=[CH:13][C:14]([S:16](Cl)(=[O:18])=[O:17])=[CH:15][C:9]=3[O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.[C:27](#[N:29])[CH3:28].O>N1C=CC=CC=1>[CH2:7]([CH:20]1[CH2:21][CH2:22][N:29]([S:16]([C:14]2[CH:13]=[CH:12][C:10]3[O:11][C:7]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[O:8][C:9]=3[CH:15]=2)(=[O:18])=[O:17])[CH2:27][CH2:28]1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(=O)(Cl)c1ccc2c(c1)OC(c1ccccc1)(c1ccccc1)O2
Reactant: CC#N
Solvent: c1ccncc1
Solvent: O
Product: O=S(=O)(c1ccc2c(c1)OC(c1ccccc1)(c1ccccc1)O2)N1CCC(Cc2ccccc2)CC1
Temperature: 60 °C

Procedure:
2,2-Diphenyl-benzo[1,3]dioxole-5-sulfonyl chloride (93 mg, 0.25 mmol) was dissolved in pyridine (1 ml). The appropriate amine (0.25 mmol) was added and the reaction was heated to 60° C. overnight. Water was added and solids respectively oils separated. The aqueous phase was decanted and the residue was stirred with acetonitrile. A solution was obtained, which was subjected to preparative reversed phase chromatography (gradient of acetonitrile/water containing 0.1% formic acid as the eluant) to yield the product after evaporation of the eluant and drying.
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](C4C=CN=CC=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.CC1(C)C(C)(C)OB(C2C=NN([C:44]3[CH:45]=[N:46][CH:47]=[CH:48][CH:49]=3)C=2)O1>>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:20]3[CH:21]=[N:22][N:23]([C:44]4[CH:45]=[N:46][CH:47]=[CH:48][CH:49]=4)[CH:24]=3)=[CH:7][N:8]2[S:11]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)(=[O:12])=[O:13])=[CH:4][CH:3]=1
Reactant: O=S(=O)(c1ccccc1)n1cc(-c2cnn(-c3ccncc3)c2)c2ccc(F)cc21
Reactant: CC1(C)OB(c2cnn(-c3cccnc3)c2)OC1(C)C
Product: O=S(=O)(c1ccccc1)n1cc(-c2cnn(-c3cccnc3)c2)c2ccc(F)cc21
Yield: 96 %

Procedure:
Following the general method as outlined in Intermediate 10, starting from 3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)pyridine (Intermediate 11; 485 mg; 1.80 mmol), 362 mg (96%) of the title compound was obtained as a brown solid after purification by a silica gel chromatography (petroleum ether/EtOAc=1/1).
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C:6]1[N:7]=[C:8]2[CH:13]=[CH:12][C:11]([S:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:15])=[CH:10][N:9]2[CH:22]=1)=[O:4].FC(F)(F)C(OO)=[O:26].FC(F)(F)C(OC(=O)C(F)(F)F)=O.OO>C(Cl)Cl>[CH3:1][O:2][C:3]([NH:5][C:6]1[N:7]=[C:8]2[CH:13]=[CH:12][C:11]([S:14]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)(=[O:26])=[O:15])=[CH:10][N:9]2[CH:22]=1)=[O:4]
Reactant: O=C(OO)C(F)(F)F
Reactant: COC(=O)Nc1cn2cc(S(=O)c3ccccc3)ccc2n1
Agent: OO
Solvent: ClCCl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: COC(=O)Nc1cn2cc(S(=O)(=O)c3ccccc3)ccc2n1

Procedure:
Portionwise, with cooling, 0.500 g. (0.0015 mole) of 2(methoxycarbonylamino)-6-(phenylsulfinyl) imidazo [1,2-a] pyridine is added to 5 ml. of a methylene chloride solution of trifluoroperacetic acid prepared from 415 μl. trifluoroacetic anhydride and 65 μl. of 90% hydrogen peroxide. The solution is heated at reflux for 20 hours. The cooled reaction mixture is washed with 10 ml. of a saturated aqueous sodium bicarbonate solution, the organic layer is separated and chromatographed on silica gel. Elution with 50% ethyl acetate-methylene chloride yields 2-(methoxycarbonylamino) 6-(phenylsulfonyl) imidazo [1,2-a] pyridine, m.p. 300° C.
Reaction SMILES: [CH2:1]([O:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]2[O:13][C:12](B(O)O)=[CH:11][C:10]=2[CH:17]=1)[CH3:2].[C:18]([O:22][C:23](=[O:36])[N:24]([C:26]1[C:27]([N+:33]([O-:35])=[O:34])=[N:28][C:29](Br)=[CH:30][CH:31]=1)[CH3:25])([CH3:21])([CH3:20])[CH3:19].CCN(CC)CC>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>[C:18]([O:22][C:23](=[O:36])[N:24]([C:26]1[C:27]([N+:33]([O-:35])=[O:34])=[N:28][C:29]([C:12]2[O:13][C:9]3[CH:8]=[CH:7][C:6]([O:5][CH2:4][O:3][CH2:1][CH3:2])=[CH:17][C:10]=3[CH:11]=2)=[CH:30][CH:31]=1)[CH3:25])([CH3:21])([CH3:19])[CH3:20]
Reactant: CCOCOc1ccc2oc(B(O)O)cc2c1
Reactant: CN(C(=O)OC(C)(C)C)c1ccc(Br)nc1[N+](=O)[O-]
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOCOc1ccc2oc(-c3ccc(N(C)C(=O)OC(C)(C)C)c([N+](=O)[O-])n3)cc2c1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 84.3 %

Procedure:
To a degassed solution of 5-ethoxymethoxy-benzofuran boronic acid (4) (140 mg, 0.593 mmol) in ethanol (10 mL), (6-bromo-2-nitro-pyridin-3-yl)-methyl-carbamic acid tert-butyl ester (7) (151 mg, 0.455 mmol), Pd(PPh3)2Cl2 (42 mg, 0.059 mmol) and Et3N (127 μL, 0.909 mmol) were added. The reaction mixture was stirred at 100° C. for 30 minutes in a microwave reactor. Volatiles were removed under reduced pressure. The residue was diluted with water (15 mL) and the mixture was extracted with ethyl acetate (3×50 mL). The combined organic extracts were washed with water, brine, dried over Na2SO4, and concentrated under reduced pressure. The crude product was purified by flash column chromatography using 20% ethyl acetate in hexane. Evaporation of solvent gave title compound 8 (170 mg) as a pale yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[C:5]2[O:9][C:8]([C:10]([N:12]([CH3:14])[CH3:13])=[O:11])=[CH:7][C:6]=2[CH:15]=1.Br[CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1.Br.C(N(CC)CC)C>>[F:1][C:2]1[CH:3]=[C:4]([N:16]2[CH2:21][CH2:20][N:19]([CH2:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=3)[CH2:18][CH2:17]2)[C:5]2[O:9][C:8]([C:10]([N:12]([CH3:14])[CH3:13])=[O:11])=[CH:7][C:6]=2[CH:15]=1
Reactant: BrCCc1ccccn1
Reactant: CN(C)C(=O)c1cc2cc(F)cc(N3CCNCC3)c2o1
Agent: Br
Solvent: CCN(CC)CC
Product: CN(C)C(=O)c1cc2cc(F)cc(N3CCN(CCc4ccccn4)CC3)c2o1

Procedure:
A reaction mixture of 5-fluoro-N,N-dimethyl-7-(piperazin-1-yl)benzofuran-2-carboxamide (0.10 g, 0.35 mmol), 2-(2-bromoethyl)pyridine:HBr (0.132 g, 0.49 mmol) and triethylamine (0.12 mL, 0.88 mmol) was heated at 80° C. over night. The product was purified by preparative HPLC to give the title compound. Yield: 0.091 g (65%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:20][CH2:19][CH:18]([C:21]([OH:23])=O)[CH2:17][CH2:16]2)=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[CH3:37][NH:38][O:39][CH3:40]>ClCCl>[CH3:40][O:39][N:38]([CH3:37])[C:21]([CH:18]1[CH2:17][CH2:16][N:15]([C:12]2[CH:11]=[CH:10][C:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[CH:14][CH:13]=2)[CH2:20][CH2:19]1)=[O:23]
Reactant: CC(C)(C)OC(=O)Nc1ccc(N2CCC(C(=O)O)CC2)cc1
Reactant: CNOC
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: CON(C)C(=O)C1CCN(c2ccc(NC(=O)OC(C)(C)C)cc2)CC1
Reaction time: 0.5 h
Yield: 100.7 %

Procedure:
To a suspension of 1-{4-[(tert-butoxycarbonyl)amino]phenyl}piperidine-4-carboxylic acid (1.3 g, 4.1 mmol) in dichloromethane (40 mL) is added carbonyldiimidazole (0.79 g, 4.9 mmol) and the mixture is stirred at room temperature for 30 minutes before N,O-dimethylhydroxylamine hydrochloride (1.0 g, 10 mmol) is added. After stirring for 30 minutes, the reaction mixture is concentrated under reduced pressure. The residue is partitioned between diethyl ether and water. The ethereal phase is washed 2× with water and once with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to provide tert-butyl [4-(4-{[methoxy(methyl)amino]carbonyl}piperidin-1-yl)phenyl]carbamate as a pale yellow solid (1.5 g, 100%).
Reaction SMILES: [CH2:1]([O:8][C:9]([C@H:11]1[CH2:16][N:15]([C:17](=[S:19])[NH2:18])[CH2:14][CH2:13][N:12]1[S:20]([C:23]1[CH:28]=[CH:27][C:26]([O:29][C:30]([F:33])([F:32])[F:31])=[CH:25][CH:24]=1)(=[O:22])=[O:21])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:34]([O:38][C:39](=[O:45])[CH:40](Br)[C:41](=O)[CH3:42])([CH3:37])([CH3:36])[CH3:35]>C(#N)C>[CH2:1]([O:8][C:9]([C@H:11]1[CH2:16][N:15]([C:17]2[S:19][C:40]([C:39]([O:38][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:45])=[C:41]([CH3:42])[N:18]=2)[CH2:14][CH2:13][N:12]1[S:20]([C:23]1[CH:24]=[CH:25][C:26]([O:29][C:30]([F:33])([F:31])[F:32])=[CH:27][CH:28]=1)(=[O:21])=[O:22])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)C(Br)C(=O)OC(C)(C)C
Reactant: NC(=S)N1CCN(S(=O)(=O)c2ccc(OC(F)(F)F)cc2)[C@@H](C(=O)OCc2ccccc2)C1
Solvent: CC#N
Product: Cc1nc(N2CCN(S(=O)(=O)c3ccc(OC(F)(F)F)cc3)[C@@H](C(=O)OCc3ccccc3)C2)sc1C(=O)OC(C)(C)C
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 67.4 %

Procedure:
A mixture of the compound (2.12 g) obtained in Step 4 and 2-bromo-3-oxobutyric acid tert-butyl ester (2.0 g) in acetonitrile (20 ml) was stirred at 80° C. for 30 min. The reaction mixture was concentrated under reduced pressure, and the residue was partitioned by adding ethyl acetate and saturated aqueous sodium carbonate solution. The organic layer was washed successively with saturated aqueous sodium carbonate solution and saturated brine, dried over anhydrous sodium sulfate, filtrated, and concentrated under reduced pressure. The residue was purified by column chromatography (ethyl acetate:n-hexane=1:2) to give the title compound (1.82 g).