Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C:3](C)([CH3:6])[CH:4]=O.[CH:8]([O:13][CH3:14])([O:11][CH3:12])OC.Cl.O1CCOCC1.O(C)[Na]>CO>[CH3:14][O:13][CH:8]([O:11][CH3:12])[C:3]([CH3:6])([CH3:4])[CH2:2][OH:1]
Reactant: COC(OC)OC
Reactant: CC(C)(C=O)CO
Agent: CO[Na]
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: COC(OC)C(C)(C)CO
Reaction time: 8 h

Procedure:
A solution of 24.4 g (0.24 mol) of 3-hydroxy-2,2-dimethylpropanal (Aldrich), 26 g (0.25 mol) of trimethyl orthoformate, and 0.5 mL of 6.8 N HCl/dioxane in 300 mL of methanol was allowed to stand at room temperature overnight. A slight excess of NaOCH3 was added and the solvent evaporated at reduced pressure. The residue was dissolved in ether and the mixture filtered. After evaporation of solvent and fractionation twice through a 15 cm Vigreux column, the product was obtained as a water white oil, bp 43°-48°/0.2mm, 18.5 g (52%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]=[C:12]=[S:13].[NH2:14][CH:15]([CH:17]1[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1)[CH3:16].Cl[CH2:24][C:25](O)=[O:26]>>[CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]=[C:12]1[N:14]([CH:15]([CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[CH3:16])[C:25](=[O:26])[CH2:24][S:13]1
Reactant: O=C(O)CCl
Reactant: CC(N)C1CCCCC1
Reactant: Cc1cc([N+](=O)[O-])ccc1N=C=S
Product: Cc1cc([N+](=O)[O-])ccc1N=C1SCC(=O)N1C(C)C1CCCCC1

Procedure:
2-Methyl-4-nitrophenyl isothiocyanate was reacted with I -amino-1-cyclohexylethane followed by chloroacetic acid according to Method C8a to afford 2-(2-methyl-4-nitrophenylimino)-3-(1-cyclohexylethyl)-1,3-thiazolidin4-one.
Reaction SMILES: [C:1]1([OH:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([OH:11])[CH:2]=1.N1C(C)=CC=CC=1C.[Cl:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[S:28](Cl)(=[O:30])=[O:29]>O1CCCC1>[OH:12][C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([O:11][S:28]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[Cl:21])(=[O:30])=[O:29])[CH:2]=1
Reactant: Oc1cc(O)c2ccccc2c1
Reactant: O=S(=O)(Cl)c1ccccc1Cl
Solvent: Cc1cccc(C)n1
Solvent: C1CCOC1
Product: O=S(=O)(Oc1cc(O)c2ccccc2c1)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 13.3 %

Procedure:
At 0° C. to 1.0 g (6.24 mmol) of 1,3-naphthalenediol in tetrahydrofuran (20 mL) containing 1.5 mL of 2,6-lutidine was added 1.35 g (6.40 mmol) of 2-chlorobenzenesulfonyl chloride. The reaction mixture was stirred to ambient temperature overnight, quenched with 3 N hydrochloric acid, extracted into methylene chloride, and dried (MgSO4). Purification by flash chromatography (2% ethyl acetate/methylene chloride) gave 277 mg (13% yield) of the title compound as a colorless solid. 1H-NMR (300 MHz, DMSO-d6) δ 10.75 (s, 1 H), 8.06 (d, 1 H, J=1.7 Hz), 7.78-7.95 (m, 4 H), 7.43-7.57 (m, 3 H), 7.11 (d, 1 H, J=2 Hz), and 6.63 (d, 1 H, J=2 Hz).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:9][CH:10]([NH:21][C:22](=[S:30])[NH:23][CH2:24][CH2:25][O:26]C(=O)C)[C:11]2[C:20]3[CH2:19][CH2:18][CH2:17][CH2:16][C:15]=3[CH:14]=[CH:13][CH:12]=2)[CH:5]=[C:6]([CH3:8])[CH:7]=1.[OH-].[Li+].C(OCC)(=O)C>C1COCC1.O>[CH3:1][C:2]1[CH:3]=[C:4]([CH2:9][CH:10]([NH:21][C:22]([NH:23][CH2:24][CH2:25][OH:26])=[S:30])[C:11]2[C:20]3[CH2:19][CH2:18][CH2:17][CH2:16][C:15]=3[CH:14]=[CH:13][CH:12]=2)[CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: CC(=O)OCCNC(=S)NC(Cc1cc(C)cc(C)c1)c1cccc2c1CCCC2
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1cc(C)cc(CC(NC(=S)NCCO)c2cccc3c2CCCC3)c1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of acetic acid 2-{3-[2-(3,5-dimethyl-phenyl)-1-(5,6,7,8-tetrahydro-naphthalen-1-yl)-ethyl]-thioureido}-ethyl ester (2.60 g) in THF (30 ml) was added a solution of lithium hydroxide (294 mg) in water (30 ml) and the mixture stirred for 6 hours at room temperature. The reaction mixture was poured into ethyl acetate (300 ml) and washed with potassium carbonate solution (5 wt % in water). The solution was dried over sodium sulphate. Removal of the solvent in vacuo yielded 1-[2-(3,5-dimethylphenyl)-1-(5,6,7,8-tetrahydronaphthalen-1-yl)-ethyl]-3-(2-hydroxyethyl)-thiourea in 2.28 g (97%) yield.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[C:18]([O:20][CH2:21][CH:22]=[C:23]([Cl:25])[Cl:24])[CH:17]=[C:16]([Cl:26])[C:3]=1[O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][CH2:11][C:12](=[N:14][OH:15])[CH3:13].[H-].[Na+].[H][H].Cl[CH2:32][C:33]#[N:34].Cl>COC(C)(C)C>[C:33]([CH2:32][O:15][N:14]=[C:12]([CH2:11][O:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][O:4][C:3]1[C:2]([Cl:1])=[CH:19][C:18]([O:20][CH2:21][CH:22]=[C:23]([Cl:25])[Cl:24])=[CH:17][C:16]=1[Cl:26])[CH3:13])#[N:34]
Reactant: N#CCCl
Reactant: CC(COCCCCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl)=NO
Reactant: [H][H]
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: COC(C)(C)C
Product: CC(COCCCCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl)=NOCC#N
Temperature: 25 °C

Procedure:
First, 0.45 g of 5-(2,6-dichloro-4-(3,3-dichloro-2-propenyloxy)phenoxy)pentyloxyacetone oxime and 10 ml of tert-butyl methyl ether are placed in a reaction vessel, to which 48 mg of 60% sodium hydride (in oil) is slowly added with stirring at room temperature in a stream of nitrogen gas. The mixture is stirred at room temperature until the evolution of hydrogen gas ceases, to which 0.11 g of chloroacetonitrile is added at room temperature, and the mixture is further stirred with heating under reflux. After completion of the reaction, the reaction mixture is poured into diluted hydrochloric acid, and extracted twice with diethyl ether. The diethyl ether layers are combined, washed with water, dried over anhydrous magnesium sulfate, and concentrated to give a crude product. This crude product is subjected to silica gel chromatography, which affords 5-(2,6-dichloro-4-(3,3-dichloro-2-propenyloxy)phenoxy)pentyloxyacetone O-cyanomethyloxime.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]([C:11]([OH:13])=O)[CH2:7][CH:8]([OH:10])[CH:9]=1)=[O:4].[C:14]([O:18][C:19]([C@@:21]1([NH2:26])[CH2:23][C@H:22]1[CH:24]=[CH2:25])=[O:20])([CH3:17])([CH3:16])[CH3:15]>>[CH3:1][O:2][C:3]([C:5]1[CH:6]([C:11](=[O:13])[NH:26][C:21]2([C:19]([O:18][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:20])[CH2:23][CH:22]2[CH:24]=[CH2:25])[CH2:7][CH:8]([OH:10])[CH:9]=1)=[O:4]
Reactant: C=C[C@@H]1C[C@]1(N)C(=O)OC(C)(C)C
Reactant: COC(=O)C1=CC(O)CC1C(=O)O
Product: C=CC1CC1(NC(=O)C1CC(O)C=C1C(=O)OC)C(=O)OC(C)(C)C

Procedure:
Reaction of compound the acid 23c (50 mg, 37 mmol) with (1R,2S)-1-amino-2-vinyl-cyclopropane carboxylic acid tert-butyl ester according to the method described in Example 1 step j, provided the title compound as a slightly yellow oil (50 mg, 38%). 1H-NMR (300 MHz, CDCl3): δ [(1.38 & 1.42) s, 9H], 1.75-1.83 (m, 1H), 2.00-2.21 (m, 3H), 3.55-3.63 (m, 1H), [(3.77 & 3.82) s, 3H], 4.20-4.38 (m, 1H), 4.65-4.80 (m, 1H), 5.13-5.20 (m, 1H), 5.22-5.38 (m, 1H), 5.60-5.82 (m, 1H), 6.95-6.96 (m, 2H). Inhibitors of the invention are achieved from the title compound by coupling of the afforded cyclopentenol derivative to a desired pyrimidinol for example as described in Example 3 step f, followed by hydrolysis of the methyl ester using a reagent like LiOH; coupling of a desired alkenylamine and macrocyclisation as described in Example 3 step h and i; hydrolysis of the tert. butyl ester by treatment with for example TFA and finally coupling of a desired sulphone amide derivative for example as described in Example 3, step k.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH:3]([CH2:7][CH2:8][CH2:9][OH:10])[CH2:2]1.C(N(CC)CC)C.[S:18](Cl)([CH3:21])(=[O:20])=[O:19]>ClCCl>[CH3:21][S:18]([O:10][CH2:9][CH2:8][CH2:7][CH:3]1[CH2:4][CH2:5][CH2:6][O:1][CH2:2]1)(=[O:20])=[O:19]
Reactant: CS(=O)(=O)Cl
Reactant: OCCCC1CCCOC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCCC1CCCOC1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a solution of 3-(tetrahydro-2H-pyran-3-yl)-1-propanol (2.64 g) in dry dichloromethane (78 ml) at 0° C. was added triethylamine (6.21 ml) followed by mesyl chloride (1.85 ml). The reaction mixture was allowed to warm to room temperature as the ice melted and allowed to stir for three hours. The reaction mixture was washed with sodium hydrogen carbonate. The organic layer was separated, dried by passing through a hydrophobic frit and concentrated in vacuo. to give a yellow oil (4.42 g). The product was purified by silica chromatography (80 g) (ISCO) using a gradient elution of 0-50% cyclohexane:ethyl acetate to afford the title compound as a clear oil (3.79 g).
Reaction SMILES: [F:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][O:7][CH2:8][C@@H:9]2[N:14]3[C:15]4[C:24]5[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=5)[N+:18]([O-])=[CH:17][C:16]=4[N:26]=[C:13]3[CH2:12][O:11][CH2:10]2)=[CH:4][CH:3]=1.[NH4+:29].[OH-].C1(C)C=CC(S(Cl)(=O)=O)=CC=1.O>C(Cl)Cl.C(Cl)(Cl)Cl>[F:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][O:7][CH2:8][C@@H:9]2[N:14]3[C:15]4[C:24]5[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=5)[N:18]=[C:17]([NH2:29])[C:16]=4[N:26]=[C:13]3[CH2:12][O:11][CH2:10]2)=[CH:4][CH:3]=1
Reactant: [O-][n+]1cc2nc3n(c2c2ccccc21)[C@@H](COCc1ccc(F)cc1)COC3
Reactant: [NH4+]
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Solvent: O
Product: Nc1nc2ccccc2c2c1nc1n2[C@@H](COCc2ccc(F)cc2)COC1

Procedure:
(11S)-11-{[(4-Fluorobenzyl)oxy]methyl}-10,11-dihydro-8H-[1,4]oxazino[4′,3′:1,2]imidazo[4,5-c]quinoline 5-oxide (732 mg, 1.93 mmol) was dissolved in 50 mL of CH2Cl2 and treated with 5 mL of concentrated NH4OH solution. The mixture was stirred rapidly and then p-toluenesulfonyl chloride (370 mg, 1.93 mmol) was carefully added. Rapid stirring continued overnight. The reaction mixture was treated with 5 mL of H2O, and the layers were separated. The organic portion was washed with saturated NaHCO3 (2×50 mL) followed by brine (50 mL). The organic layer was then dried over Na2SO4, filtered, and concentrated under reduced pressure to give a crude orange solid. Chromatography (SiO2, 10-30% CMA/CHCl3) gave 236 mg of (11S)-11-{[(4-fluorobenzyl)oxy]methyl}-10,11-dihydro-8H-[1,4]oxazino[4′,3′:1,2]imidazo[4,5-c]quinolin-6-amine as a tan solid, mp 134-137° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[C:10]([OH:12])=O)[CH:3]=[CH:2]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)C(C)C)(C)C.[C:44]([C:48]1[CH:67]=[CH:66][C:51]([CH2:52][NH:53][CH2:54][CH2:55][C:56]2[CH:61]=[CH:60][CH:59]=[C:58]([C:62]([F:65])([F:64])[F:63])[CH:57]=2)=[CH:50][CH:49]=1)([CH3:47])([CH3:46])[CH3:45]>CN(C=O)C.O>[C:44]([C:48]1[CH:67]=[CH:66][C:51]([CH2:52][N:53]([CH2:54][CH2:55][C:56]2[CH:61]=[CH:60][CH:59]=[C:58]([C:62]([F:65])([F:63])[F:64])[CH:57]=2)[C:10]([C:8]2[CH:7]=[CH:6][CH:5]=[C:4]3[C:9]=2[NH:1][CH:2]=[CH:3]3)=[O:12])=[CH:50][CH:49]=1)([CH3:47])([CH3:45])[CH3:46]
Reactant: CC(C)(C)c1ccc(CNCCc2cccc(C(F)(F)F)c2)cc1
Reactant: O=C(O)c1cccc2cc[nH]c12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CC(C)(C)c1ccc(CN(CCc2cccc(C(F)(F)F)c2)C(=O)c2cccc3cc[nH]c23)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 86.4 %

Procedure:
To a solution of 48 mg (0.3 mmol) of 1H-indole-7-carboxylic acid and 96 mg of TBTU (0.3 mmol) in 4 ml DMF, were added 0.26 ml (1.5 mmol) of N,N-diisopropylethyl amine. After stirring for 5 min at rt, 101 mg (0.3 mmol) of (4-tert-butyl-benzyl)-[2-(3-trifluoromethyl-phenyl)-ethyl]-amine in 1 ml DMF were added. After 2.5 h stirring at rt, the reaction mixture was diluted with 50 ml water and extracted with 2×50 ml EtOAc. The combined organic phases were washed with water and brine, dried with magnesium sulfate, filtered and concentrated in vacuo. The yellow solid foam was purified by column chromatography (8 g silica gel; heptane/EtOAc 9:1) to give 124 mg (84%) of a colorless gum. MS (ISP) 479.5 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:15]=[CH:14][C:7]([CH2:8][C@@H:9]([C:11]([OH:13])=[O:12])[NH2:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].S(Cl)([Cl:18])=O.[CH2:20](O)[CH3:21]>>[ClH:18].[CH2:20]([O:12][C:11](=[O:13])[C@H:9]([CH2:8][C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:15][CH:14]=1)[NH2:10])[CH3:21]
Reactant: N[C@@H](Cc1ccc([N+](=O)[O-])cc1)C(=O)O
Reactant: CCO
Reactant: O=S(Cl)Cl
Product: CCOC(=O)[C@@H](N)Cc1ccc([N+](=O)[O-])cc1
Product: Cl
Reaction time: 1 h

Procedure:
4-nitrophenylalanine (5 g, 1 eq, mmol) was added in portions to a solution of dry ethanol (mL) and thionylchloride (mL) at −5° C. It was stirred at that temperature for another one hour, followed by stirring at RT for 16 h. The reaction mixture was condensed on rotavapour, azeotroped with toluene, and then dried over high vaccum pump to obtain 4-nitrophenylalanine ethyl ester hydrochloride as white solid (quantitative yield).
Reaction SMILES: C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1.[I:34][C:35]1[O:36][CH:37]=[CH:38][C:39]=1[C:40]([OH:42])=O.[CH3:43][CH:44]([C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][C:50]=1[NH2:55])[CH2:45][CH:46]([CH3:48])[CH3:47]>C(#N)C.O>[CH3:43][CH:44]([C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][C:50]=1[NH:55][C:40]([C:39]1[CH:38]=[CH:37][O:36][C:35]=1[I:34])=[O:42])[CH2:45][CH:46]([CH3:47])[CH3:48]
Reactant: O=C(O)c1ccoc1I
Reactant: CC(C)CC(C)c1ccccc1N
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CC(C)CC(C)c1ccccc1NC(=O)c1ccoc1I
Temperature: 25 °C
Reaction time: 24 h
Yield: 19.2 %

Procedure:
Under protective gas (argon), 0.56 ml (3.38 mmol) of N,N-diisopropylethylamine and 1.18 g (2.5 mmol) of bromotrispyrrolidinophosphonium hexafluorophosphate (PyBrop) are added to a solution of 483 mg (2.02 mmol) of 2-iodofuran-3-carboxylic acid and 300 mg (1.7 mmol) of 2-(1,3-dimethylbutyl)phenylamine in 10 ml of acetonitrile. The reaction mixture is stirred at room temperature for 24 hours and, for work-up, added to water, extracted with ethyl acetate, dried over sodium sulphate and concentrated under reduced pressure. Column chromatography (cyclohexane/ethyl acetate gradient) gives 130 mg (18% of theory) of N-[2-(1,3-dimethylbutyl)phenyl]-2-iodo-3-furamide [log P (pH 2.3)=3.88].
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][C:7](Br)=[CH:8][CH:9]=2)[N:4]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[N:3]=1.CC1(C)C(C)(C)OB([C:27]2[CH:32]=[CH:31][C:30]([C:33]3[NH:37][C:36]([C@@H:38]4[CH2:42][CH2:41][CH2:40][N:39]4[C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])=[N:35][CH:34]=3)=[CH:29][CH:28]=2)O1.C([O-])(O)=O.[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([C:27]3[CH:28]=[CH:29][C:30]([C:33]4[NH:37][C:36]([C@@H:38]5[CH2:42][CH2:41][CH2:40][N:39]5[C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])=[N:35][CH:34]=4)=[CH:31][CH:32]=3)=[CH:8][CH:9]=2)[N:4]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[N:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1c1ncc(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)[nH]1
Reactant: CC(C)(C)OC(=O)n1nc(N)c2ccc(Br)cc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Product: CC(C)(C)OC(=O)N1CCC[C@H]1c1ncc(-c2ccc(-c3ccc4c(N)nn(C(=O)OC(C)(C)C)c4c3)cc2)[nH]1
Temperature: 80 °C
Yield: 40.3 %

Procedure:
A mixture of tert-butyl 3-amino-6-bromo-1H-indazole-1-carboxylate (1.17 g, 3.73 mmol), (S)-tert-butyl 2-(5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (1.62 g, 3.68 mmol), NaHCO3 (0.96 g, 11 mmol) and Pd(PPh3)4 (212 mg, 0.184 mmol) was degassed and then heated at 80° C. After heating for 24 h the reaction mixture was poured into EtOAc/H2O (500/100 mL) and the mixture was shaken and the layers separated. The aq phase was extracted once more with EtOAc and the combined organic layers were washed (H2O, brine), dried (Na2SO4), and concentrated in vacuo. The residue was purified by BIOTAGE® (40+M, TLC 2:1 EtOAc:hex) affording a light yellow foam (807.8 mg) which was repurified by BIOTAGE® (TLC 6:3.5:0.5 hex:EtOAc:MeOH) to give the title compound as a light yellow solid (413.9 mg, 36%). 1H NMR (400 MHz, DMSO-d6) δ 11.86-12.22 (m, 1H), 8.20 (s, 1H), 7.85-7.92 (m, 3H), 7.75-7.76 (m, 1H), 7.68 (d, J=8.1 Hz, 1H), 7.53-7.62 (m, 2H), 6.35 (s, 2H), 4.75-4.86 (m, 1H), 3.49-3.58 (m, 1H), 3.35-3.39 (m, 1H), 2.10-2.26 (m, 1H), 1.80-2.01 (m, 3H), 1.60 (s, 9H), 1.40 and 1.15 (s, 9H, rotamers). LCMS: Anal. Calcd. for C30H36N6O4: 544; found: 545 (M+H)+.
Reaction SMILES: F[C:2]1[C:3]([C:15]#[N:16])=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[CH:9]=[N:10][CH:11]=[CH:12][C:13]=1[CH3:14].[OH:17][NH:18]C(=O)C.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[CH3:14][C:13]1[CH:12]=[CH:11][N:10]=[CH:9][C:8]=1[C:7]1[CH:6]=[CH:5][N:4]=[C:3]2[C:15]([NH2:16])=[N:18][O:17][C:2]=12
Reactant: CC(=O)NO
Reactant: Cc1ccncc1-c1ccnc(C#N)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccncc1-c1ccnc2c(N)noc12
Temperature: 80 °C
Reaction time: 3 h
Yield: 77.2 %

Procedure:
A mixture of 3′-fluoro-4-methyl-3,4′-bipyridine-2′-carbonitrile (0.057 g, 0.267 mmol), N-hydroxyacetamide (0.060 g, 0.802 mmol), and potassium carbonate (0.222 g, 1.604 mmol) in DMF (Ratio: 7.0, Volume: 1.170 ml) and water (Ratio: 1.000, Volume: 0.167 ml) was stirred at 80° C. for 3 hr. The reaction mixture was filtered through a disposable fritted funnel. The filter cake was washed with EtOAc. Layers in the filtrate were separated and the aqueous phase was extracted with EtOAc (3×). The organic phases were combined, dried over Na2SO4, filtered, concentrated, and further dried under high vacuum to afford the title compound as a brown solid (49 mg, 0.206 mmol, 77% yield). ESI MS (M+H)+=227.1.
Reaction SMILES: [CH2:1]([N:8]1[CH2:31][CH2:30][C:11]2([O:19][C:18]3[C:14](=[N:15][N:16](CC4C=CC(OC)=CC=4)[CH:17]=3)[C:13](=[O:29])[CH2:12]2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCCl>[CH2:1]([N:8]1[CH2:31][CH2:30][C:11]2([O:19][C:18]3[CH:17]=[N:16][NH:15][C:14]=3[C:13](=[O:29])[CH2:12]2)[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(Cn2cc3c(n2)C(=O)CC2(CCN(Cc4ccccc4)CC2)O3)cc1
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1CC2(CCN(Cc3ccccc3)CC2)Oc2cn[nH]c21
Temperature: 25 °C
Yield: 91.7 %

Procedure:
Dissolved 1-benzyl-2′-(4-methoxybenzyl)-2′H-spiro[piperidine-4,5′-pyrano[3,2-c]pyrazol]-7′(6′H)-one (428 mg, 1.02 mmol) in 20 mL 1,2-dichloroethane and treated with 10 mL trifluoroacetic acid. The resultant mixture was heated for 18 h at 90° C. The reaction was cooled to ambient temperature and concentrated to dryness under reduced pressure. The resultant residue was taken up in 50 mL saturated aqueous sodium bicarbonate and extracted with 2×50 mL ethyl acetate. The organic extracts were combined and dried over sodium sulfate, filtered and concentrated under reduced pressure. The resultant oil was flash chromatographed (25 g silica, step gradient 5 column volumes 50% ethyl acetate/heptane, 10 CV 100% ethyl acetate) to yield 278 mg (91%) of 1-benzyl-1′H-spiro[piperidine-4,5′-pyrano[3,2-c]pyrazol]-7′(6′H)-one as a pale yellow solid. 1H NMR (400 MHz, CD3OD) δ ppm 7.27 (m, 6H), 3.55 (s, 2H), 2.64 (m, 4H), 2.45 (td, J=11.7, 2.5 Hz, 2H), 2.06 (d, J=12.1 Hz, 2H), 1.74 (m, 2H); m/z (M+1)=298.5.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][C:11]([F:14])([F:13])[F:12])=[CH:6][C:3]=1[CH:4]=O.Cl.[NH2:16][OH:17].C([O-])(=O)C.[Na+]>C(O)C>[F:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][C:11]([F:14])([F:13])[F:12])=[CH:6][C:3]=1/[CH:4]=[N:16]/[OH:17]
Reactant: O=Cc1cc(OC(F)(F)F)ccc1F
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: O/N=C/c1cc(OC(F)(F)F)ccc1F
Yield: 87.8 %

Procedure:
A solution of 2-fluoro-5-trifluoromethoxy-benzaldehyde (9.78 g, 47 mmol) in ethanol (50 ml) was treated with hydroxylamine HCl (3.59 g, 52 mmol) and sodium acetate (4.27 g, 52 mmol). The mixture was refluxed for 2 h, the solvent was evaporated and the residue stirred with water (50 ml). The precipitate was filtered, dried and chromatographed (SiO2, heptanes:Ethyl acetate=100:0 to 80:2) and afforded the title compound (9.21 g, 88%) as a white solid. MS: m/e=223.0 [M]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:13]3=[N:14][CH:15]=[CH:16][CH:17]=[C:12]3[C:11](=[O:18])CO2)[CH:5]=[CH:6][CH:7]=1.[C:19]([O-])(=O)C.[NH4+:23]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]3[N:14]=[CH:15][CH:16]=[CH:17][C:12]=3[C:11](=[O:18])[NH:23][CH:19]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: [NH4+]
Reactant: CC(=O)[O-]
Reactant: O=C1COC(c2cccc(Cl)c2)c2ncccc21
Solvent: CN(C)C=O
Product: O=c1[nH]cc(-c2cccc(Cl)c2)c2ncccc12
Temperature: 50 °C
Yield: 87.5 %

Procedure:
To a solution of 8-(3-chlorophenyl)pyrano [3,4-b]pyridin-5-one (1.25 g., 4.9 mmoles) in 20 ml DMF was added solid ammonium acetate (0.56 g., 7.29 mmoles). The reaction was heated at 50° C. under nitrogen for one hour, cooled and concentrated under vacuum. The solid was triturated with ether to give 1.1 grams (88% yield) 8-(3-chlorophenyl)-1,6-naphthyridin-5-one as a white solid. Characteristic analytical data are as follows: mp 252°-252.5° C.; 1H NMR (DMSO-d6, 300 MHz) δ7.37-7.66 (m, 6H), 8.58 (dd, 1H, J=8.2, 2.1), 8.94 (dd, 1H, J=4.69, 1.68), 11.85 (bs, 1H); 13C NMR (75 MHz, DMSO-d6) δ161.74, 154.04, 151.91, 137.69, 135.62, 132.47, 132.26, 129.68, 129.55, 128.43, 126.64, 121.85, 121.60, 116.87; IR (KBr) vmax 3437, 3173, 3032, 2951, 2878, 1672, 1630, 1593, 1566, 1477, 1462, 1417, 1340, 1236, 821, 794, 692, 671, 603, 555 cm-1 ; mass spectrum (EI), m/e 256. Anal. (C14H9ClN2O) Calcd.: C, 65.51; H, 3.53; N, 10.91; C1, 13.81. Found: C, 65.67; H, 3.34; N, 10.98; C1, 13.91.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[N:4][C:5]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:6][C:7]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[Br:20][CH2:21][CH2:22][CH2:23][C:24]#[N:25]>CN(C)C=O>[Br-:20].[NH2:1][C:2]1[N:3]([CH2:21][CH2:22][CH2:23][C:24]#[N:25])[NH2+:4][C:5]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[CH:6][C:7]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: N#CCCCBr
Reactant: Nc1nnc(-c2ccccc2)cc1-c1ccccc1
Solvent: CN(C)C=O
Product: N#CCCCN1[NH2+]C(c2ccccc2)=CC(c2ccccc2)=C1N
Product: [Br-]
Temperature: 60 °C

Procedure:
2.47 g of 3-amino-4,6-diphenylpyridazine are dissolved in 5 ml of dimethylformamide, and 1.63 g of 4-bromobutyronitrile are added. The mixture is heated at 60° C. for 2 hours and left to cool. The crystals formed are filtered off and recrystallised from isopropanol. Melting point=202°-204° C.
Reaction SMILES: [Cl-].[NH4+].[F:3][C:4]1[CH:5]=[C:6]([S:11][C:12]2[CH:13]=[C:14]3[C:20]([NH:21][C:22](=[O:33])[CH2:23][C:24]4[CH:29]=[CH:28][C:27]([N+:30]([O-])=O)=[CH:26][CH:25]=4)=[N:19][NH:18][C:15]3=[N:16][CH:17]=2)[CH:7]=[C:8]([F:10])[CH:9]=1>O.C(O)C.O.C(O)(=O)C.[Fe]>[NH2:30][C:27]1[CH:28]=[CH:29][C:24]([CH2:23][C:22]([NH:21][C:20]2[C:14]3[C:15](=[N:16][CH:17]=[C:12]([S:11][C:6]4[CH:5]=[C:4]([F:3])[CH:9]=[C:8]([F:10])[CH:7]=4)[CH:13]=3)[NH:18][N:19]=2)=[O:33])=[CH:25][CH:26]=1
Reactant: O=C(Cc1ccc([N+](=O)[O-])cc1)Nc1n[nH]c2ncc(Sc3cc(F)cc(F)c3)cc12
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Solvent: CC(=O)O
Product: Nc1ccc(CC(=O)Nc2n[nH]c3ncc(Sc4cc(F)cc(F)c4)cc23)cc1
Temperature: 60 °C
Yield: 4.9 %

Procedure:
A solution of 152 mg (2.72 mmol) of iron and 70 mg (1.3 mmol) of ammonium chloride in 100 μl of water is added to a solution of 0.24 g (0.544 mmol) of N-(5-(3,5-difluorophenylthio)-1H-pyrazolo[3,4-b]pyridin-3-yl)-2-(4-nitrophenyl)acetamide in 10 ml of a 2:1 ethanol/water mixture. Several drops of acetic acid are added to this mixture and it is heated at 60° C. for 4 hours. After cooling and concentration of the solvents, the crude reaction product is extracted with ethyl acetate and is washed with saturated sodium bicarbonate solution. The organic phases are combined, dried on magnesium sulfate and then concentrated. The crude product is purified by silica gel chromatography (DCM/MeOH) to yield 11 mg (4%) of 2-(4-aminophenyl)-N-(5-(3,5-difluorophenylthio)-1H-pyrazolo[3,4-b]pyridin-3-yl) acetamide in the form of a brown solid.