Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1([C:12](O)=[O:13])[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].ClC(OCC(C)C)=O.CN1CCOCC1.[BH4-].[Na+]>O1CCCC1.O>[OH:13][CH2:12][C:9]1([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:3])([CH3:2])[CH3:4])[CH2:10][CH2:11]1
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CC1
Agent: CC(C)COC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CN1CCOCC1
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1(CO)CC1
Reaction time: 0.33 h
Yield: 91.1 %

Procedure:
A solution of 1-(N-tert-butoxycarbonylamino)cyclopropanecarboxylic acid (5 g) in tetrahydrofuran was cooled to −20° C. Isobutyl chloroformate (3.24 ml) and N-methylmorpholine (2.74 ml) were added thereto, and the mixture was stirred at the same temperature as above for 20 minutes. Then, sodium borohydride (1.12 g) and water (1 ml) were added thereto, and the mixture was further stirred at room temperature for 40 minutes. Water was added to the reaction solution, followed by extraction with ethyl acetate. The extract was washed with water and saturated saline in this order and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane-ethyl acetate) to obtain the title compound (4.24 g).
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][C:3]=1[C:4]([NH:6][NH2:7])=[O:5].[Cl:13][CH2:14][C:15](OCC)(OCC)OCC>>[Cl:13][CH2:14][C:15]1[O:5][C:4]([C:3]2[CH:8]=[C:9]([CH3:12])[CH:10]=[CH:11][C:2]=2[F:1])=[N:6][N:7]=1
Reactant: Cc1ccc(F)c(C(=O)NN)c1
Reactant: CCOC(CCl)(OCC)OCC
Product: Cc1ccc(F)c(-c2nnc(CCl)o2)c1
Yield: 66 %

Procedure:
2-Fluoro-5-methyl-benzoic acid hydrazide (320 mg, 1.9 mmol) and 2-chloro-1,1,1-triethoxy-ethane (1.9 ml) were heated in a sealed vial at 120° C. for 30 min. The reaction mixture was place directly onto a flash column (silica gel) and purified by using 0-5% ethyl acetate in hexanes to afford 2-chloromethyl-5-(2-fluoro-5-methyl-phenyl)-[1,3,4]oxadiazole (284.5 mg, 66%). 1H NMR (CDCl3) d (ppm): 7.89 (q, 1H), 7.36 (m, 1H), 7.16 (t, 1H), 4.81 (s, 2H), 2.43 (s, 3H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[CH:4][C:3]=1[NH:14][C:15]1[C:24]2[C:19](=[CH:20][C:21]([F:26])=[CH:22][C:23]=2[F:25])[N:18]=[C:17]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=2)[C:16]=1[CH3:33].[O:34]1[CH2:39][CH:38]=[C:37](B2OC(C)(C)C(C)(C)O2)[CH2:36][CH2:35]1.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>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].O.O1CCOCC1>[O:34]1[CH2:35][CH:36]=[C:37]([C:2]2[CH:7]=[CH:6][C:5]([N:8]3[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)=[CH:4][C:3]=2[NH:14][C:15]2[C:24]3[C:19](=[CH:20][C:21]([F:26])=[CH:22][C:23]=3[F:25])[N:18]=[C:17]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=3)[C:16]=2[CH3:33])[CH2:38][CH2:39]1
Reactant: Cc1c(-c2ccccn2)nc2cc(F)cc(F)c2c1Nc1cc(N2CCOCC2)ccc1Cl
Reactant: CC1(C)OB(C2=CCOCC2)OC1(C)C
Agent: [Pd]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: Cc1c(-c2ccccn2)nc2cc(F)cc(F)c2c1Nc1cc(N2CCOCC2)ccc1C1=CCOCC1
Temperature: 90 °C
Reaction time: 19 h

Procedure:
N-(2-Chloro-5-morpholinophenyl)-5,7-difluoro-3-methyl-2-(pyridin-2-yl)quinolin-4-amine (33.9 mg, 0.073 mmol), 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (22.8 mg, 0.11 mmol), tricyclohexylphosphine (3.9 mg, 0.014 mmol), and tris(dibenzylideneacetone)dipalladium (0) (4.1 mg, 4.5 μmol) were added to a flask then degassed and backfilled with argon. To the flask, 1,4-dioxane (1.0 mL) and aq. 1.3M potassium phosphate tribasic (0.12 mL, 0.16 mmol) were added by syringe. The resulting reaction was heated to 90° C. and monitored with TLC and LC-MS. After 19 h, the reaction was cooled to rt then poured into water. After extracting twice with EtOAc and twice with DCM, the combined organic extractions were dried over anhydrous magnesium sulfate. After filtration and concentration, the residue was purified on silica gel (0-100% EtOAc in hexanes) to afford an impure orange residue. The light orange film was further purified with HPLC (10-90% of 0.1% TFA acetonitrile solution in 0.1% TFA water solution). The desired fractions were cond then diluted with EtOAc. After washing twice with satd aq. sodium bicarbonate solution and once with brine, the solvent was removed under reduced pressure to yield a brown solid as N-(2-(3,6-dihydro-2H-pyran-4-yl)-5-morpholinophenyl)-5,7-difluoro-3-methyl-2-(pyridin-2-yl)quinolin-4-amine. 1H NMR (400 MHz, CDCl3) δ ppm 8.70 (1H, dt, J=4.8, 1.3 Hz), 8.00 (3H, m), 7.75 (1H, m), 7.48 (1H, m), 7.13 (1H, d, J=8.4 Hz), 7.05 (1H, ddd, J=13.9, 8.3, 2.4 Hz), 6.66 (1H, dd, J=8.4, 2.3 Hz), 6.39 (1H, d, J=2.3 Hz), 5.92 (1H, m), 4.29 (2H, d, J=2.5 Hz), 3.94 (6H, m), 3.23 (4H, m), 2.44 (2H, m), 2.06 (3H, s). Mass Spectrum (pos.) m/e: 515.2 (M+1).
Reaction SMILES: ClC1C(Cl)=NC2C(=CC=C([N+]([O-])=O)C=2)N=1.Cl[C:17]1[C:26](Cl)=[N:25][C:24]2[C:19](=[CH:20][CH:21]=[C:22]([C:28]([F:31])([F:30])[F:29])[CH:23]=2)[N:18]=1.[K][S:33][C:34](=[C:37]([C:40]#[N:41])[C:38]#[N:39])[S:35][K]>>[F:29][C:28]([F:31])([F:30])[C:22]1[CH:23]=[C:24]2[C:19](=[CH:20][CH:21]=1)[N:18]=[C:17]1[S:33][C:34](=[C:37]([C:40]#[N:41])[C:38]#[N:39])[S:35][C:26]1=[N:25]2
Reactant: N#CC(C#N)=C(S[K])S[K]
Reactant: FC(F)(F)c1ccc2nc(Cl)c(Cl)nc2c1
Agent: O=[N+]([O-])c1ccc2nc(Cl)c(Cl)nc2c1
Product: N#CC(C#N)=C1Sc2nc3ccc(C(F)(F)F)cc3nc2S1
Yield: 88 %

Procedure:
The process of Example 13 is followed except that the 2,3-dichloro-6-nitroquinoxaline is replaced by 0.50 g of 2,3-dichloro-6-trifluoromethylquinoxaline and 0.49 g of the di(potassiomercapto)methylenemalononitrile is used. The recovered material is a dark yellow powder weighing 0.56 g with a calculated overall yield of 88 percent and has a melting point of 197° to 199° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[C:5]([O:7][CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:6].[CH:24](O)=[O:25]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH:24]([NH:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[C:5]([O:7][CH:8]1[CH2:9][CH2:10][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:12][CH2:13]1)=[O:6])=[O:25]
Reactant: O=CO
Reactant: Nc1cccc(C(=O)OC2CCN(Cc3ccccc3)CC2)c1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: O=CNc1cccc(C(=O)OC2CCN(Cc3ccccc3)CC2)c1
Yield: 91.7 %

Procedure:
0.26 g (0.000838 mol) of 1-benzyl-piperidin-4-yl 3-amino-benzoate was dissolved in 8.5 ml of toluene, treated with 0.84 ml (0.0222 mol) of formic acid and boiled at reflux for 12 hrs. The mixture was freed from solvent and the residue was taken up in ethyl acetate and washed with sat. carbonate solution and sodium chloride solution. It was dried over sodium sulfate. 0.26 g (92%) of 1-benzyl-piperidin-4-yl 3-formamido-benzoate was obtained as a brownish oil. MS: me/e=339 (C20H23N2 O3 +).
Reaction SMILES: [C:1]1([CH:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:8][N:9]2[CH2:14][CH2:13][C:12](=[O:15])[CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:22][Mg]Br>O1CCCC1>[CH3:22][C:12]1([OH:15])[CH2:13][CH2:14][N:9]([CH2:8][CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:10][CH2:11]1
Reactant: O=C1CCN(CC(c2ccccc2)c2ccccc2)CC1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: CC1(O)CCN(CC(c2ccccc2)c2ccccc2)CC1
Reaction time: 8 h

Procedure:
To a stirred solution of 0.28 parts of 1-(2,2-diphenylethyl)-4-piperidinone in 5 parts by volume of tetrahydrofuran under nitrogen atmosphere is added 2 parts by volume of 3 M solution of methylmagnesium bromide. The resultant mixture is stirred for about 2.5 hours and then quenched with the careful addition of 5 parts by volume of 10% ammonium chloride. The mixture is left standing overnight, partitioned between water and ethyl acetate, and the organic layer separated. The organic layer is then dried with brine and magnesium sulfate, and concentrated to give 4-methyl-1-(2,2-diphenylethyl)-4-piperidinol, as yellow solid. This compound is represented by the following structural formula ##STR40##
Reaction SMILES: C(=O)([O-])[O-].[Ca+2].[NH2:6][C:7]1[CH:11]=[C:10]([CH3:12])[NH:9][N:8]=1.[C:13](Cl)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>O1CCOCC1>[C:13]([NH:6][C:7]1[CH:11]=[C:10]([CH3:12])[NH:9][N:8]=1)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Cc1cc(N)n[nH]1
Reactant: O=C(Cl)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: C1COCCO1
Product: Cc1cc(NC(=O)c2ccccc2)n[nH]1
Yield: 24.8 %

Procedure:
103 g (1 mol) of calcium carbonate were added with stirring to a solution of 50 g (0.5 mol) of 3-amino-5-methyl-1H-pyrazole in 100 cm3 of dioxane. 73 cm3 (0.6 mol) of benzoyl chloride were added dropwise to this solution at 65° C. The temperature was brought to 80° C. and maintained for 1 hour. The solution was subsequently brought back to 10° C. A beige solid formed during the reaction was pulled dry on sintered glass and was then taken up again with stirring in 400 cm3 of methanol. The solution was filtered and the filtrate was concentrated under vacuum. A beige solid crystallized and was pulled dry on sintered glass and then washed with 50 cm3 of isopropyl ether. After drying under vacuum at 40° C., 25 g of the expected product were obtained in the form of beige crystals, the melting point of which was between 218 and 220° C.
Reaction SMILES: [ClH:1].[CH3:2][C:3]1[N:4]=[CH:5][NH:6][C:7]=1[CH2:8]O.[NH2:10][CH2:11][CH2:12][SH:13]>Cl>[ClH:1].[ClH:1].[CH3:2][C:3]1[N:4]=[CH:5][NH:6][C:7]=1[CH2:8][S:13][CH2:12][CH2:11][NH2:10]
Reactant: NCCS
Reactant: Cc1nc[nH]c1CO
Agent: Cl
Product: Cc1nc[nH]c1CSCCN
Yield: 166.3 %

Procedure:
30 g of 4-methyl-5-hydroxymethylimidazole hydrochloride and 23 g of cysteamine in 450 ml of concentrated hydrochloric acid are refluxed for 17 hours. The solution is evaporated to dryness under reduced pressure. The residue (61 g) is recrystallized from 500 ml of alcohol. 41 g of 4-methyl-5-[(2-aminoethyl)-thiomethyl]-imidazole dihydrochloride (corresponding to a yield of 84.0% of theory), of melting point 184°-191° C., are obtained.
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([NH2:8])=[CH:4][CH:3]=1.[F:9][C:10]([F:21])([F:20])[C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1.[F-].[Cs+].C(N(CC)CC)C>C(O)CC.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O>[F:9][C:10]([F:21])([F:20])[C:11]1[CH:16]=[CH:15][C:14]([C:2]2[N:7]=[N:6][C:5]([NH2:8])=[CH:4][CH:3]=2)=[CH:13][CH:12]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: Nc1ccc(Cl)nn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Cs+]
Solvent: CCCO
Solvent: O
Solvent: CCN(CC)CC
Product: Nc1ccc(-c2ccc(C(F)(F)F)cc2)nn1
Yield: 27 %

Procedure:
To a solution of 6-chloropyridazin-3-amine (3.00 g, 23.2 mmol), 4-(trifluoromethyl)phenylboronic acid (5.72 g, 30.1 mmol), cesium fluoride (9.15 g, 60.2 mmol), triethylamine (4.84 mL, 34.7 mmol) in n-propanol (100 mL) degassed with argon was added dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium (II) dichloromethane adduct (0.953 g, 1.16 mmol), and the reaction was heated to reflux for 3 hours. Water was added to precipitate solids, which were collected by filtrations. The solids were purified on a SP1 system (0-10% MeOH in EtOAc) to yield 6-(4-(trifluoromethyl)phenyl)pyridazin-3-amine (1.5 g, 6.27 mmol, 27.1% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]2[N:6]=[C:7]([Cl:9])[S:8][C:4]=2[CH:3]=1.[CH:12](=O)[CH3:13].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClC(Cl)C.O>[Cl:9][C:7]1[S:8][C:4]2[CH:3]=[C:2]([NH:1][CH2:12][CH3:13])[CH:11]=[CH:10][C:5]=2[N:6]=1
Reactant: Nc1ccc2nc(Cl)sc2c1
Reactant: CC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: CCNc1ccc2nc(Cl)sc2c1
Reaction time: 2 h

Procedure:
To a solution of (29) (0.2 mmol, 36.8 mg) in 2 ml dichloroethane was added 0.2 mmol acetaldehyde, followed by 63.6 mg sodium triacetoxyborohydride, and 12 μl acetic acid. After 2 h, the solution was poured into water and extracted with ethyl acetate. The combined extracts were washed with water, dried over sodium sulfate, and the solvent removed by rotary evaporation.
Reaction SMILES: [CH3:1][C:2]([CH3:36])([CH3:35])[C@H:3]([NH:10][C:11]([C:13]1[N:14]=[C:15]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[N:16]2[CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][C:17]=12)=[O:12])[C:4]1[O:8][N:7]=[C:6]([CH3:9])[N:5]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][C:2]([CH3:36])([CH3:35])[C@H:3]([NH:10][C:11]([C:13]1[N:14]=[C:15]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[N:16]2[CH2:21][CH2:20][NH:19][CH2:18][C:17]=12)=[O:12])[C:4]1[O:8][N:7]=[C:6]([CH3:9])[N:5]=1
Reactant: Cc1noc([C@@H](NC(=O)c2nc(-c3ccccc3)n3c2CN(C(=O)OC(C)(C)C)CC3)C(C)(C)C)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1noc([C@@H](NC(=O)c2nc(-c3ccccc3)n3c2CNCC3)C(C)(C)C)n1
Reaction time: 2 h
Yield: 93.2 %

Procedure:
Intermediate 22D (170 mg, 0.34 mmol) was dissolved in DCM (2 mL) and TFA (0.5 mL) was added. The resulting mixture was stirred for 2 h. The mixture was concentrated, neutralized with NaHCO3 saturated solution and extracted several times with EtOAc. The combined organic extracts were washed successively with water and brine, dried over anhydrous Na2SO4, filtered and concentrated to give of Compound 282 (125 mg, 87%). 1H-NMR (400 MHz, CDCl3-d) δ: 1.09 (s, 9H), 2.40 (s, 3H), 3.78 (m, 2H), 4.11 (m, 2H), 5.01 (m, 2H), 5.37 (d, 1H), 7.35 (m, 3H), 7.64 (m, 2H), 7.78 (d, 1H), LCMS (+ESI) m/z 395.0 [M+H]+.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:10]2[N:11]=[C:12]([O:15][CH:16]([CH2:22][CH3:23])[C:17]([O:19]CC)=[O:18])[CH:13]=[CH:14][C:9]2=[N:8][N:7]=1.[OH-].[Na+]>O1CCOCC1>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:10]2[N:11]=[C:12]([O:15][CH:16]([CH2:22][CH3:23])[C:17]([OH:19])=[O:18])[CH:13]=[CH:14][C:9]2=[N:8][N:7]=1
Reactant: CCOC(=O)C(CC)Oc1ccc2nnc(-c3cccs3)n2n1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CCC(Oc1ccc2nnc(-c3cccs3)n2n1)C(=O)O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of ethyl 2-((3-(thiophen-2-yl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)oxy)butanoate. (1 mmol) in dioxane (3 mL) was added 0.5 ml of sodium hydroxide (2N), and the reaction mixture was stirred at room temperature. After 2 hours, the mixture was evaporated to dryness, and the obtained residue dissolved in water (2 mL) and then acidified with a hydrochloric acid solution. The resulting precipitate was filtered, washed with water, and dried to give 2-((3-(thiophen-2-yl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)oxy)butanoic acid.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[O:20][C:7]2([CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]2)[CH2:6][NH:5][CH2:4]1.Cl[C:22]1[N:27]=[CH:26][CH:25]=[CH:24][N:23]=1.C(=O)([O-])[O-].[Na+].[Na+].C(OCC)(=O)C.CCCCCC>CS(C)=O.C(OCC)(=O)C>[OH:1][CH2:2][CH:3]1[O:20][C:7]2([CH2:8][CH2:9][N:10]([C:13]([O:15][C:16]([CH3:17])([CH3:19])[CH3:18])=[O:14])[CH2:11][CH2:12]2)[CH2:6][N:5]([C:22]2[N:27]=[CH:26][CH:25]=[CH:24][N:23]=2)[CH2:4]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CNCC(CO)O2
Reactant: Clc1ncccn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CN(c1ncccn1)CC(CO)O2
Yield: 80.8 %

Procedure:
A solution of tert-butyl 10-(hydroxymethyl)-11-oxa-3,8-diazaspiro[5.5]undecane-3-carboxylate (3.10 g, 10.8 mmol), 2-chloropyrimidine (1.86 g, 16.2 mmol) and sodium carbonate (2.30 g, 21.7 mmol) in DMSO (15 mL) was heated at 110° C. for 1 h. The reaction mixture was diluted with ethyl acetate (200 mL), washed with water (4×100 mL), dried over Na2SO4, and concentrated in vacuo. Silica gel column chromatography (0-60% ethyl acetate/hexane) provided tert-butyl 10-(hydroxymethyl)-8-pyrimidin-2-yl-11-oxa-3,8-diazaspiro[5.5]undecane-3-carboxylate (3.18 g, 8.73 mmol, 80%). ESI-MS m/z calc. 364.2. found 365.3 (M+1)+; Retention time: 1.21 minutes (3 min run). 1H NMR (400 MHz, CDCl3) δ 8.29 (d, J=4.7 Hz, 2H), 6.50 (t, J=4.7 Hz, 1H), 4.64 (ddd, J=16.0, 8.5, 1.5 Hz, 2H), 3.90-3.80 (m, 1H), 3.79-3.56 (m, 4H), 3.44-3.22 (m, 1H), 3.13 (t, J=10.6 Hz, 1H), 2.90-2.71 (m, 2H), 2.19 (d, J=8.9 Hz, 1H), 1.98 (dd, J=10.6, 3.6 Hz, 1H), 1.69-1.58 (m, 2H), 1.45 (s, 9H).
Reaction SMILES: C[O:2][C:3](=[O:17])[C:4]1[CH:9]=[C:8]([Cl:10])[C:7]([NH:11][C:12](=[O:14])[CH3:13])=[CH:6][C:5]=1[O:15][CH3:16].[Li+].[OH-]>CO>[C:12]([NH:11][C:7]1[C:8]([Cl:10])=[CH:9][C:4]([C:3]([OH:17])=[O:2])=[C:5]([O:15][CH3:16])[CH:6]=1)(=[O:14])[CH3:13]
Reactant: COC(=O)c1cc(Cl)c(NC(C)=O)cc1OC
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: COc1cc(NC(C)=O)c(Cl)cc1C(=O)O
Temperature: 25 °C
Reaction time: 6 h
Yield: 47.2 %

Procedure:
4-Acetylamino-5-chloro-2-methoxy-benzoic acid methyl ester (2.09 g, 8.11 mmol) was dissolved in MeOH (110 ml) and LiOH solution (25.48 mmol in 30 ml, 1:1 MeOH:H2O) added and the solution stirred at room temperature for 6 hours. The solvent was concentrated in vacuo, EtOAc added and the organic phase was washed with 0.5N HCl then extracted with saturated NaHCO3 (2×) . The aqueous phase was acidified with 12N HCl to pH 1 and the resulting precipitate extracted into CH2Cl2. The combined extracts were dried over anhydrous Na2SO4, filtered and evaporated to give the title compound as a white solid (0.933 g, 50% yield). 1H-NMR (500 MHz, CDCl3) δ 2.31 (s, 3H), 4.10 (s, 3H), 7.78-7.92 (br s, 1H), 8.17 (s, 1H), 8.45 (s, 1H). Analytical HPLC 5.62 min.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[N:15]([CH2:20][CH2:21][OH:22])[CH:16]=[C:17](Br)[N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:23][C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][C:29]=1[CH3:30].C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O.C(P(CCCC)CCCC)CCC.C(P(CCCC)CCCC)CCC.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[N:15]([CH2:20][CH2:21][OH:22])[CH:16]=[C:17]([C:27]3[CH:26]=[CH:25][C:24]([F:23])=[C:29]([CH3:30])[CH:28]=3)[N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(B(O)O)cc1F
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(Br)cn2CCO)CC1
Agent: [Pd]
Agent: CCCCP(CCCC)CCCC
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: Cc1cc(-c2cn(CCO)c(C3CCN(C(=O)OC(C)(C)C)CC3)n2)ccc1F
Temperature: 70 °C
Reaction time: 5 h
Yield: 69.6 %

Procedure:
A mixture of 4-[4-bromo-1-(2-hydroxyethyl)-1H-imidazol-2-yl]-piperidine-1-carboxylic acid tert-butyl ester (1600.00 mg; 4.27 mmol; 1.00 eq.), 3-fluoro-4-methyl phenyl boronic acid (855.55 mg; 5.56 mmol; 1.30 eq.), palladium bis(tributylphosphine) (436.95 mg; 0.85 mmol; 0.20 eq.) and Cesium carbonate (4178.60 mg; 12.82 mmol; 3.00 eq.) in 1,4-Dioxane (10.0 mL) and water (1.50 mL) in the sealed vial was stirred at 70° C. for 5 hours. The crude was purified through flash chromatography (EtOAc in Hexanes 30% to 80%) to provide the title compound (1.2 g, 70%).
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.C[N:13]1[CH2:22][CH2:21][C:20]2([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[CH:24]=3)[C:15]([CH3:32])([CH2:16][CH2:17][CH:18](N)[CH2:19]2)[CH2:14]1.ClC(OC(Cl)C)=O>ClCCCl>[C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[NH2:5][CH:14]1[C:15]2([CH3:32])[C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[CH:24]=3)([CH2:19][CH2:18][CH2:17][CH2:16]2)[CH2:21][CH2:22][NH:13]1
Reactant: COc1cccc(C23CCN(C)CC2(C)CCC(N)C3)c1
Agent: CC(Cl)OC(=O)Cl
Agent: O=C1NC(=O)c2ccccc21
Solvent: ClCCCl
Product: COc1cccc(C23CCCCC2(C)C(N)NCC3)c1
Temperature: 25 °C
Yield: 19.1 %

Procedure:
To a solution of 21 (2.09 g, 0.05 mol) in anhydrous 1,2-dichloroethane (100 mL) at reflux was added 1-chloroethyl chloroformate (0.82 mL, 7.47 mmol) drop wise. The resulting solution was heated under reflux for 5 h and then cooled to room temperature. This was then washed 1 time with saturated bicarbonate solution, 1× with water and then organic layer was evaporated and the resulting carbamate (foamy white solid, almost quantitative yield) was dissolved immediately in methanol (100 mL) and then refluxed overnight. After cooling to room temperature, methanol was removed under reduced pressure and the residue was treated with saturated sodium bicarbonate solution. This was then extracted with 3:1, CH2Cl2/THF, and the combined organic extracts were washed once with water. Removal of solvent under reduced pressure afforded 2.01 g (99%) of 22 as a white foamy solid: LCMS (APCI): m/z 405.2 (M+H)+; 1H NMR (CDCl3, 300 MHz) δ 7.80-7.83 [m, 2H], 7.68-7.71 [m, 2H], 7.23-7.28 [m, 3H], 6.78-6.81 [m, 1H], 4.84 [m, 1H], 3.86 [s, 1H], 3.75-3.80 [m, 2H], 3.32 [t, J=12 Hz, 1H], 3.03-3.15 [m, 2H], 2.90 [br s, 1H], 2.61-2.67 [m, 1H], 2.45 [d, J=12 Hz, 1H], 2.27-2.31 [m, 1H], 1.83-1.93 [m, 2H], 1.64 [dd, J1=15 Hz, J2=6 Hz, 2H], 1.31-1.48 [m, 3H], 1.24 [s, 3H]; 13C NMR (CDCl3, 300 MHz) δ 167.5, 158.1, 147.0, 132.9, 131.1, 127.5, 122.1, 120.5, 114.7, 109.8, 67.0, 54.3, 53.2, 46.5, 43.5, 41.8, 35.2, 34.8, 33.9, 32.9, 29.4, 24.7, 24.1, 22.9.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[C:18](Cl)=[C:13]3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:23][CH:24]1[CH2:32][CH:31]2[CH:27]([CH2:28][C:29](=[O:44])[N:30]2[CH2:33][C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][C:35]=2[O:42][CH3:43])[CH2:26][CH2:25]1.C(N(C(C)C)CC)(C)C>CC(O)C>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[C:18]([NH:23][CH:24]4[CH2:32][CH:31]5[CH:27]([CH2:28][C:29](=[O:44])[N:30]5[CH2:33][C:34]5[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][C:35]=5[O:42][CH3:43])[CH2:26][CH2:25]4)=[C:13]3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=[N+]([O-])c1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1Cl
Reactant: COc1ccc(CN2C(=O)CC3CCC(N)CC32)c(OC)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: COc1ccc(CN2C(=O)CC3CCC(Nc4c([N+](=O)[O-])cnc5c4ccn5S(=O)(=O)c4ccccc4)CC32)c(OC)c1
Temperature: 120 °C
Yield: 71 %

Procedure:
A mixture of 1-benzenesulfonyl-4-chloro-5-nitro-1H-pyrrolo[2,3-b]pyridine (137.2 mg, 0.4062 mmol), 6-amino-1-(2,4-dimethoxy-benzyl)-octahydro-indol-2-one (107.8 mg, 0.3542 mmol), and diisopropylethylamine (0.10 mL, 0.57 mmol) in propan-2-ol (1.5 ml) was heated in a microwave reactor at 120° C. for 20 minutes. The solvent was evaporated in vacuo and then purified by column chromatography on silica gel (gradient: 0 to 100% ethyl acetate in dichloromethane) affording 152.3 mg (71%) of 6-(1-benzenesulfonyl-5-nitro-1H-pyrrolo[2,3-b]pyridin-4-ylamino)-1-(2,4-dimethoxy-benzyl)-octahydro-indol-2-one. LCMS (Method E, ESI): RT=1.81 min, m+H=606.0.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13]([CH3:14])=[CH:12][C:11](=[O:15])[C:10]([C:16]([OH:18])=O)=[N:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH2:26]([NH:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH2:27][CH2:28][CH3:29].O>C1(C)C=CC=CC=1>[CH2:26]([N:30]([CH2:31][CH2:32][CH2:33][CH3:34])[C:16]([C:10]1[C:11](=[O:15])[CH:12]=[C:13]([CH3:14])[N:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[N:9]=1)=[O:18])[CH2:27][CH2:28][CH3:29]
Reactant: Cc1cc(=O)c(C(=O)O)nn1-c1ccc(Cl)cc1
Reactant: CCCCNCCCC
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCCCN(CCCC)C(=O)c1nn(-c2ccc(Cl)cc2)c(C)cc1=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 73.2 %

Procedure:
To an ice cooled suspension of 5.29 g (0.02 mol) 1-(4-chlorophenyl)-1,4-dihydro-4-oxo-6-methyl pyridazine-3-carboxylic Acid (see Example 12) and 2.02 g (0.02 mol) of triethylamine in 100 ml of toluene there is added dropwise 2.17 g (0.02 mol) of ethyl chlorofomate. The suspension formed is stirred at room temperature for 15 min. and is cooled to 5° C. To the suspension is added 2.59 g (0.02 mol) di-n-butylamine and the mixture is stirred at room temperature for 18 hrs. To the mixture is added 100 ml of water and the suspension formed is stirred at room temperature for 1 hr. The toluene layer is isolated, dried over magnesium sulfate and concentrated in vacuo. The residue oil is dissolved in 25 ml of ether and to it there is added 25 ml of hexane. The mixture is allowed to stand at room temperature for 30 minutes and is vacuum filtered. The filter cake is washed with hexane and air dried to afford 5.5 g (73% yield) of product, mp 101°-105° C.