Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8].C(=O)([O-])[O-].[K+].[K+].Cl[C:17]([O:19][CH3:20])=[O:18].Cl>O.O1CCOCC1>[CH3:20][O:19][C:17]([N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8])=[O:18]
Reactant: COC(=O)Cl
Reactant: CNCCCCC(=O)O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)N(C)CCCCC(=O)O
Temperature: 25 °C
Yield: 88.4 %

Procedure:
1-methyl-2-piperidone (5 ml, 44.1 mmol) was combined with barium hydroxide (3.8 g, 26.95 mmol) and water (55 ml). The suspension was warmed to 110° C. for 6 hours then cooled over an ice bath. Gaseous carbon dioxide was bubbled through the solution for 20 minutes. The suspension was filtered through a celite pad and the filtrate was concentrated to dryness. The residue was triturated with acetonitrile, collected, rinsed with ether and dried in vacuo to yield 5-(methylamino)pentanoic acid as a white solid (2.95 g). 5-(Methylamino)pentanoic acid (2 g, 15.3 mmol), and potassium carbonate (13 g, 94 mmol) were suspended in water (30 ml) and dioxane (10 ml) then cooled to 0° C. Methyl chloroformate (5 ml, 65 mmol) was added over 30 seconds, then the mixture was stirred and allowed to warm slowly to room temperature for 16 hours. Conc. HCl (20 ml) was added then the mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, evaporated and dried in vacuo to give 5-[(methoxycarbonyl)(methyl)amino]pentanoic acid as a thick clear oil (2.56 g).
Reaction SMILES: [C:1]1([C:7]2[CH:14]=[CH:13][C:10]([CH:11]=O)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:15]([OH:21])(=[O:20])[CH2:16]C(O)=O.C([O-])(=O)C.[NH4+:26]>COC(O)C>[NH2:26][CH:11]([C:10]1[CH:13]=[CH:14][C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:8][CH:9]=1)[CH2:16][C:15]([OH:21])=[O:20]
Reactant: [NH4+]
Reactant: O=Cc1ccc(-c2ccccc2)cc1
Reactant: O=C(O)CC(=O)O
Agent: CC(=O)[O-]
Agent: COC(C)O
Product: NC(CC(=O)O)c1ccc(-c2ccccc2)cc1
Temperature: 80 °C

Procedure:
18.2 g of 4-phenylbenzaldehyde, 10.4 g of malonic acid and 15.4 g of ammonium acetate in 150 ml of methoxyethanol are mixed together. After heating overnight at 80° C., the mixture is cooled and the product formed is then washed with ethanol, with ether and then dried. After washing again with water, the product is recrystallized from a methanol/water mixture with a small amount of HCl. A mixture of the expected product and of the methyl ester hydrochloride of 3-amino-3-biphenyl-4-ylpropionic acid is obtained, which is used without further purification in the following step.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH:14]3[CH2:16][CH2:15]3)=[C:10]([CH:17]=[C:18]3[C:22]([CH3:24])([CH3:23])[O:21][C:20]([CH3:26])([CH3:25])[C:19]3=[O:27])[CH:9]=2)=[C:4]([F:28])[CH:3]=1.[OH-:29].[Li+]>CO.OO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH:14]3[CH2:16][CH2:15]3)=[C:10]([CH:17]3[C:18]4([C:19](=[O:27])[C:20]([CH3:26])([CH3:25])[O:21][C:22]4([CH3:23])[CH3:24])[O:29]3)[CH:9]=2)=[C:4]([F:28])[CH:3]=1
Reactant: CC1(C)OC(C)(C)C(=Cc2cc(-c3ccc(Cl)cc3F)ccc2C2CC2)C1=O
Reactant: [OH-]
Agent: OO
Agent: [Li+]
Solvent: CO
Product: CC1(C)OC(C)(C)C2(OC2c2cc(-c3ccc(Cl)cc3F)ccc2C2CC2)C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 438.7 %

Procedure:
To a solution of 4-[1-(4′-chloro-4-cyclopropyl-2′-fluorobiphenyl-3-yl)methylidene]-2,2,5,5-tetramethyldihydrofuran-3-one (19.80 g, 0.050 mol) in methanol (830 ml) at 35° C. is added 50% aqueous hydrogen peroxide (5.00 ml, 0.075 mmol), followed immediately by 2M lithium hydroxide (5.00 ml, 0.01 mol) solution. The mixture is stirred at this temperature for a further 2 hours, then allowed to cool to room temperature. Then reaction mixture is quenched with 10% sodium metabisulfite (negative KI-starch indicator test) then diluted with diethyl ether. Most of the methanol is removed under vacuum, and the crude mixture is partitioned between distilled water and diethyl ether. The aqueous phase is further extracted with diethyl ether (×2), then all organics are combined and washed with saturated sodium bicarbonate (×2) then brine. After anhydrousing over magnesium sulfate the suspension is filtered and the filtrate concentrated in vacuo to afford 2-(4′-chloro-4-cyclopropyl-2′-fluorobiphenyl-3-yl)-4,4,6,6-tetramethyl-1,5-dioxa-spiro[2.4]heptan-7-one (18.2 g) as an orange foam. This material is of sufficient purity to use directly in the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:12]=[N:13][C:14](I)=[C:10]3[CH2:9][N:8]([CH3:16])[C:7](=[O:17])[C:6]=2[CH:18]=1.[C:19]([Si:21]([CH3:24])([CH3:23])[CH3:22])#[CH:20]>C(NCC)C.C(Cl)CCl.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.[Cu]I>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:12]=[N:13][C:14]([C:20]#[C:19][Si:21]([CH3:24])([CH3:23])[CH3:22])=[C:10]3[CH2:9][N:8]([CH3:16])[C:7](=[O:17])[C:6]=2[CH:18]=1
Reactant: CN1Cc2c(I)ncn2-c2ccc(F)cc2C1=O
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: ClCCCl
Solvent: CCNCC
Product: CN1Cc2c(C#C[Si](C)(C)C)ncn2-c2ccc(F)cc2C1=O

Procedure:
67.8 g (190 mmol) of 8-fluoro-4,5-dihydro-3-iodo-5-methyl-6H-imidazo[1,5-a][1,4]benzodiazepin-6-one was heated to boiling under reflux for 8 hours with 23.4 g (238 mmol) of ethynyltrimethylsilane, 300 mg of bis-(triphenylphosphine)-palladium(II) dichloride and 70 mg of copper(I) iodide in 280 ml of diethylamine and 25 ml of ethylene chloride. The reaction mixture was evaporated and the residue was chromatographed on silica gel while eluting with chloroform/ethyl acetate (3:1). By recrystallization from ethyl acetate there was obtained 8-fluoro-4,5-dihydro-5-methyl-3-[(trimethylsilyl)ethynyl]-6H-imidazo-[1,5-a][1,4]benzodiazepin-6-one of melting point 184°-185°.
Reaction SMILES: [OH-].[Na+].Cl.[CH2:4]([O:6][NH2:7])[CH3:5].[OH:8][C:9]1[CH2:14][CH:13]([C:15]2[CH:20]=[CH:19][C:18]3[O:21][CH2:22][O:23][C:17]=3[CH:16]=2)[CH2:12][C:11](=[O:24])[C:10]=1[C:25](=O)[CH2:26][CH3:27].ClCCl>O.C(O)C>[CH2:4]([O:6][N:7]=[C:25]([C:10]1[C:9](=[O:8])[CH2:14][CH:13]([C:15]2[CH:20]=[CH:19][C:18]3[O:21][CH2:22][O:23][C:17]=3[CH:16]=2)[CH2:12][C:11]=1[OH:24])[CH2:26][CH3:27])[CH3:5]
Reactant: CCON
Reactant: CCC(=O)C1=C(O)CC(c2ccc3c(c2)OCO3)CC1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCO
Solvent: O
Product: CCON=C(CC)C1=C(O)CC(c2ccc3c(c2)OCO3)CC1=O
Temperature: 25 °C

Procedure:
A solution of sodium hydroxide (0.15 g) in water and then ethoxyamine hydrochloride (0.37 g) were added to a solution of 3-hydroxy-5-(3,4-methylenedioxyphenyl)-2-propionylcyclohex-2-en-1-one (1.0 g) in ethanol (40 ml) The mixture was stirred at room temperature and the progress of the reaction was monitored by thin layer chromatography (eluant dichloromethane). On completion of the reaction the solvent was removed by distillation under reduced pressure. The residue was dissolved in dichloromethane and the organic phase was washed with water and dried over anhydrous sodium sulphate. The solvent was evaporated to give 2-[1-(ethoxyimino)propyl]-3-hydroxy-5-(3,4-methylenedioxyphenyl)cyclohex-2-en-1-one as an oil.
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]([CH3:16])=[CH:5][CH2:6][CH2:7][C:8](=[O:15])[CH2:9][C:10]([O:12]CC)=O.[C:17](O)(=[O:19])[CH3:18].C(=O)C(C)=O>O.C(Cl)Cl>[OH:12][CH:10]([CH2:9][C:8](=[O:15])[CH2:7][CH2:6][CH:5]=[C:4]([CH3:3])[CH3:16])[C:17](=[O:19])[CH3:18]
Reactant: CCOC(=O)CC(=O)CCC=C(C)C
Reactant: CC(=O)O
Agent: CC(=O)C=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: CC(=O)C(O)CC(=O)CCC=C(C)C
Temperature: 25 °C
Reaction time: 20 h

Procedure:
97 ml of 10 N sodium hydroxide solution were added over one hour at less than 33° C. to a suspension of 175 g of ethyl 7-methyl-3-oxo-6-octenoate in 875 ml of water and the mixture was stirred at room temperature for 20 hours and 25 ml of acetic acid were added thereto to obtain a pH of 7. An aqueous solution containing 396 g of pyruvaldehyde (16.8% by weight) was added to the mixture at 20° to 25° C. while maintaining a pH of 7 and the mixture was stirred for 20 hours at room temperature during which 30 ml of acetic acid were added to keep the pH at 7. 1000 ml of methylene chloride were added thereto and the mixture was stirred for 10 minutes. The decanted aqueous phase was extracted with methylene chloride and the combined organic phases were dried over sodium sulfate and evaporated to dryness under reduced pressure to obtain 175 g of 3-hydroxy-9-methyl-8-decene-2,5-dione.
Reaction SMILES: [O:1]=[C:2]([CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:3][C:4]([O:6][CH3:7])=[O:5].[C:15]([C:17]1[C:26]2[C:21](=[CH:22][C:23]([O:27][CH3:28])=[CH:24][CH:25]=2)[CH2:20][CH2:19][CH:18]=1)#[N:16].C1CCN2C(=NCCC2)CC1>C(#N)C>[O:1]=[C:2]([CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH:3]([CH:18]1[CH2:19][CH2:20][C:21]2[C:26](=[CH:25][CH:24]=[C:23]([O:27][CH3:28])[CH:22]=2)[CH:17]1[C:15]#[N:16])[C:4]([O:6][CH3:7])=[O:5]
Reactant: COc1ccc2c(c1)CCC=C2C#N
Reactant: COC(=O)CC(=O)Cc1ccccc1
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: COC(=O)C(C(=O)Cc1ccccc1)C1CCc2cc(OC)ccc2C1C#N
Temperature: 25 °C
Reaction time: 2 h
Yield: 64.6 %

Procedure:
Methyl 3-oxo-4-phenylbutyrate (29.33 g, 153 mmol) and 1-cyano-6-methoxy-3,4-dihydronaphthalene (25.7, 139 mmol), the product of Step 2 of Example 1, were dissolved in 25 mL of acetonitrile. DBU (1.5 mL) was added and the reaction mixture was stirred for 2 h at ambient temperature. A second aliquot of DBU (1.5 mL) was then added and stirring continued overnight. The reaction mixture was partitioned between diethyl ether and 1N aqueous hydrochloric acid solution (4:1) and the aqueous layer was extracted with diethyl ether. The combined organic layers were washed with 1N aqueous hydrochloric acid and brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was chromatographed on silica gel eluted with hexane/ethyl acetate (6:1) to give 33.9 g (65% yield) of the title compound; MS DCI-NH3M/Z: 395 (M+NH4)+.
Reaction SMILES: [Br:1][C:2]1[C:3]([NH2:14])=[N:4][CH:5]=[C:6]([CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[N:7]=1.CCN(C(C)C)C(C)C.Cl[C:25]([O:27][CH3:28])=[O:26]>C(Cl)Cl>[NH2:14][C:3]1[N:4]=[CH:5][C:6]([CH:8]2[CH2:9][CH2:10][N:11]([C:25]([O:27][CH3:28])=[O:26])[CH2:12][CH2:13]2)=[N:7][C:2]=1[Br:1]
Reactant: Nc1ncc(C2CCNCC2)nc1Br
Reactant: COC(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)N1CCC(c2cnc(N)c(Br)n2)CC1
Reaction time: 0.5 h

Procedure:
To a solution of 3-bromo-5-(piperidin-4-yl)pyrazin-2-amine (60 mg, 0.233 mmol) in DCM (2 mL) in ice bath was added DIEA (408 μl, 2.333 mmol) and methyl chloroformate (18.07 μl, 0.233 mmol). The reaction mixture was stirred under ice bath for 30 min. The reaction mixture was partitioned between DCM and water. The organic layer was separated and washed with brine, dried over sodium sulfate, filtered off, and evaporated in vacuo. The crude methyl 4-(5-amino-6-bromopyrazin-2-yl)piperidine-1-carboxylate was used for next step. LCMS (m/z): 315.0/317.0 (MH+), 0.647 min.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]1[C:9](=[O:10])[N:8]2[C:11]([CH3:15])=[CH:12][CH:13]=[CH:14][C:7]2=[N:6][C:5]=1[CH3:16].[Cl:17][C:18]1[CH:19]=[C:20]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH:21]=[CH:22][CH:23]=1>C1(C)C=CC=CC=1>[Cl:17][C:18]1[CH:19]=[C:20]([N:24]2[CH2:29][CH2:28][N:27]([CH2:2][CH2:3][C:4]3[C:9](=[O:10])[N:8]4[C:11]([CH3:15])=[CH:12][CH:13]=[CH:14][C:7]4=[N:6][C:5]=3[CH3:16])[CH2:26][CH2:25]2)[CH:21]=[CH:22][CH:23]=1
Reactant: Clc1cccc(N2CCNCC2)c1
Reactant: Cc1nc2cccc(C)n2c(=O)c1CCCl
Solvent: Cc1ccccc1
Product: Cc1nc2cccc(C)n2c(=O)c1CCN1CCN(c2cccc(Cl)c2)CC1
Yield: 34.8 %

Procedure:
A mixture of 2.4 g of 3-(2-chloroethyl)-2,6-dimethy-4H-pyrido[1,2-a]pyrimidin-4-one, 5.9 g of 1-(m-chlorophenyl)piperazine and 25 ml of toluene was refluxed with heating for 30 hours. The reaction mixture was then treated in the same manner as in Example 1, and the obtained crude crystals were recrystallized from isopropyl alcohol to give 1.4 g of the desired compound as pale yellow needles, m.p. 116.5° - 117.5°C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([C:12]2[CH:17]=[C:16]([C:18]#[N:19])[CH:15]=[C:14](Br)[CH:13]=2)[O:9][N:8]=1.[NH2:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][CH:27]=1.COCCOC.C(=O)([O-])[O-].[Na+].[Na+]>CCCCCC.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(OCC)(=O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([C:12]2[CH:13]=[C:14]([C:26]3[CH:25]=[CH:24][CH:23]=[C:22]([NH2:21])[CH:27]=3)[CH:15]=[C:16]([C:18]#[N:19])[CH:17]=2)[O:9][N:8]=1
Reactant: Nc1cccc(B(O)O)c1
Reactant: N#Cc1cc(Br)cc(-c2nc(-c3ccccn3)no2)c1
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+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Solvent: CCCCCC
Product: N#Cc1cc(-c2cccc(N)c2)cc(-c2nc(-c3ccccn3)no2)c1
Yield: 44.9 %

Procedure:
In a similar fashion, 3-(2-pyridyl)-5-(3-bromo-5-cyanophenyl)-1,2,4-oxadiazole (70 mg, 0.21 mmol), 3-aminophenylboronic acid (66 mg, 0.43 mmol), and Pd(PPh3)4 (25 mg, 0.021 mmol), in a solution of ethylene glycol dimethyl ether (3 mL) and 2M sodium carbonate (3 mL) was heated in a sealed vial at 100° C. for 1 hour. Standard work up and silica gel chromatography using a gradient of 30% ethyl acetate in hexane to 100% ethyl acetate, followed by trituration with 50% ethyl acetate in hexane afforded 32mg (45%) of 3-(2-pyridyl)-5-(3-cyano-5-(3-aminophenyl)phenyl)-1,2,4-oxadiazole: 1H NMR (CDCl3):δ-8.82 (d, 1H), 8.57 (s, 2H), 8.40 (s, 1H), 8.22 (d, 1H), 8.08 (t, 1H), 7.66 (m, 1H), 7.20 (t, 1H), 7.00 (m, 2H), 6.69 (d, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Cl[CH2:10][CH2:11][C:12]#[N:13].[OH-].[Na+].C1COCC1>CN(C=O)C.O>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:10][CH2:11][C:12]#[N:13])=[CH:4][CH:3]=1
Reactant: Oc1ccc(O)cc1
Reactant: N#CCCCl
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: O
Product: N#CCCOc1ccc(O)cc1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
A mixture of 1.43 g (0.013 mol) 1,4-dihydroxybenzene, 1.15 g (0.013 mol) 3-chloropropionitrile and 15 ml (2N, NaOH) in 15 ml DMF anmd 50 ml THF is stirred overnight at 60° C. bath temperature. The reaction mixture is poured into water and extracted with ether. The ether extract is washed with water, dried and concentrated to dryness under reduced pressure. The residue is passed through a silica gel column using hexane/ethylacetate (3:1) as eluent. Evaporation of eluent gives the desired product which is used directly in the next step.
Reaction SMILES: C(O)(C(F)(F)F)=O.[NH:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[C:17]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([S:32]([CH3:35])(=[O:34])=[O:33])[CH:27]=3)[CH:24]=2)[N:19](C2CCCCO2)[N:18]=1>C(Cl)Cl>[NH:10]1[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:8]=[C:9]1[C:17]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([S:32]([CH3:35])(=[O:34])=[O:33])[CH:27]=3)[CH:24]=2)[NH:19][N:18]=1
Reactant: CS(=O)(=O)c1cccc(-c2ccc3c(c2)c(-c2nc4ccccc4[nH]2)nn3C2CCCCO2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)c1cccc(-c2ccc3[nH]nc(-c4nc5ccccc5[nH]4)c3c2)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 68.7 %

Procedure:
TFA (0.5 mL, 6.490 mmol) was added to a solution 3-(1H-benzo[d]imidazol-2-yl)-5-(3-(methylsulfonyl)phenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (7 mg, 0.015 mmol) in CH2Cl2 (4 mL). The reaction mixture was stirred at room temperature for 24 h, and then the solvent was removed in vacuo. Purification by flash chromatography (6% CH3OH/CH2Cl2) afforded the title compound (4 mg) as an off-white solid. 1H NMR (400 MHz, CD3OD): δ 8.84 (s, 1H), 8.39 (m, 1H), 7.17 (m, 1H), 7.95 (m, 1H), 7.85 (m, 2H), 7.78-7.73 (m, 3H), 7.28 (m, 2H); ESI-MS [M+H]+: 389.3.
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[N:6][NH:7]2.[O:12]1[CH:17]=[CH:16][CH2:15][CH2:14][CH2:13]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>C1COCC1>[Br:1][CH2:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[N:6][N:7]2[CH:13]1[CH2:14][CH2:15][CH2:16][CH2:17][O:12]1
Reactant: C1=COCCC1
Reactant: BrCc1cccc2[nH]ncc12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: BrCc1cccc2c1cnn2C1CCCCO1
Yield: 86.9 %

Procedure:
A solution of 4-bromomethyl-1H-indazole (2.0 g, 9.476 mmol), 3,4-dihyro-2H-pyran (4.0 mL, 43.84 mmol), p-toluenesulfonic acid monohydrate (2.0 g, 10.51 mmol) and anhydrous THF (20 mL) was heated at 60° C. for 1 h. The reaction mixture was cooled, added to aqueous saturated sodium carbonate solution (50 mL) and extracted with ethyl acetate (200 mL). The organic layer was washed with brine (50 mL), dried over MgSO4, filtered and concentrated under reduced pressure. The resulting crude compound was purified by flash chromatography (20% EtOAc in hexanes) to give 4-bromomethyl-1-(tetrahydro-pyran-2-yl)-1H-indazole (2.43 g, 86.9%) as an off white solid. MS m/e 296.2 (M+H+).
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:13]=[CH:12][C:11]([CH3:14])=[C:10]2[C:5]=1[CH:6]([C:23]1[CH:24]=[CH:25][CH:26]=[C:27]3[C:32]=1[O:31][C:30]([CH3:33])=[CH:29][C:28]3=[O:34])[C:7]([C:16]([O:18]CCC#N)=[O:17])=[C:8]([CH3:15])[NH:9]2)[CH3:2].[OH-].[Na+].C(OCC)C>COCCOC.O>[CH2:1]([O:3][C:4]1[N:13]=[CH:12][C:11]([CH3:14])=[C:10]2[C:5]=1[CH:6]([C:23]1[CH:24]=[CH:25][CH:26]=[C:27]3[C:32]=1[O:31][C:30]([CH3:33])=[CH:29][C:28]3=[O:34])[C:7]([C:16]([OH:18])=[O:17])=[C:8]([CH3:15])[NH:9]2)[CH3:2]
Reactant: CCOc1ncc(C)c2c1C(c1cccc3c(=O)cc(C)oc13)C(C(=O)OCCC#N)=C(C)N2
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Solvent: COCCOC
Product: CCOc1ncc(C)c2c1C(c1cccc3c(=O)cc(C)oc13)C(C(=O)O)=C(C)N2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
640 mg (1.39 mmol) of the compound from Example 40A are dissolved in 30 ml of 1,2-dimethyoxyethane/water (2:1 v/v), mixed with 2.76 ml (2.76 mmol) of 1 N sodium hydroxide solution and stirred at room temperature for 30 min. The reaction mixture is then mixed with 20 ml of diethyl ether. The aqueous phase is separated off, adjusted to a pH of 4-5 with 1 N hydrochloric acid and extracted three times with ethyl acetate. The organic phases are combined and dried with magnesium sulfate. The volatile components are removed in a rotary evaporator. Drying in vacuo results in 335 mg (56% of theory) of the title compound in a purity of 94% (LC-MS).
Reaction SMILES: [F:1][C:2]([F:12])([C:7]1[CH:11]=[CH:10][NH:9][N:8]=1)[C:3]([F:6])([F:5])[F:4].[OH-].[Na+].[Br:15]Br>O>[Br:15][C:11]1[C:7]([C:2]([F:1])([F:12])[C:3]([F:6])([F:5])[F:4])=[N:8][NH:9][CH:10]=1
Reactant: BrBr
Reactant: FC(F)(F)C(F)(F)c1cc[nH]n1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: FC(F)(F)C(F)(F)c1n[nH]cc1Br
Temperature: 0 °C
Reaction time: 7 h
Yield: 103.6 %

Procedure:
9.30 g of 3-(pentafluoroethyl)-1H-pyrazole was suspended to 90 ml of water, and 6.0 g of 50% aqueous solution of sodium hydroxide was added to the suspension. The mixture was cooled to 0° C., then 8.79 g of bromine was added to the mixture, followed by stirring at room temperature for 7 hours. The reaction mixture was extracted by ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium salfate, filtered, and concentrated under reduced pressure to obtain 13.72 g of 4-bromo-3-(pentafluoroethyl)-1H-pyrazole.
Reaction SMILES: Cl.[CH:2]([C:5]1[CH:10]=[CH:9][C:8]([NH:11]N)=[CH:7][CH:6]=1)([CH3:4])[CH3:3].[C:13]1(=O)[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][CH2:14]1.Cl.C(O)C.O>C(O)C>[CH:2]([C:5]1[CH:10]=[CH:9][C:8]2[NH:11][C:15]3[C:16]4[C:21]([CH2:13][C:14]=3[C:7]=2[CH:6]=1)=[CH:20][CH:19]=[CH:18][CH:17]=4)([CH3:4])[CH3:3]
Reactant: CC(C)c1ccc(NN)cc1
Reactant: O=C1CCc2ccccc21
Agent: Cl
Solvent: CCO
Solvent: O
Product: CC(C)c1ccc2[nH]c3c(c2c1)Cc1ccccc1-3
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 4-isopropylphenylhydrazine hydrochloride (6.3 g, 34 mmol) and 1-indanone (4.5 g, 34 mmol) were heated to reflux in ethanol (40 cm3) containing concentrated hydrochloric acid (2 cm3). Heating was continued for 4 hours, and then the reaction mixture was cooled to room temperature during which time the product crystallised out of solution as colourless crystals. This compound was filtered off, dried in a vacuum oven, and recrystallised from ethanol/water to yield colourless prisms. Yield: 6.59 g, (79%). M.p. 193° C. (from ethanol/water). 1H NMR (DMSO-d6) δ: 1.27 (6H, d,), 2.96 (1H, septet,), 3.65 (2H, s,), 6.9-7.6 (7H, m,), 11.2 (1H, br,).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[S:12][C:11]2[CH2:13][CH2:14][C:15](=[CH:18]N(C)C)[C:16](=O)[C:10]=2[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[NH:23]([C:27]1[CH:28]=[C:29]([S:33]([NH2:36])(=[O:35])=[O:34])[CH:30]=[CH:31][CH:32]=1)[C:24]([NH2:26])=[NH:25].[OH-].[Na+]>C(O)(C)C.O>[C:1]([O:5][C:6]([C:8]1[S:12][C:11]2[CH2:13][CH2:14][C:15]3[CH:18]=[N:25][C:24]([NH:23][C:27]4[CH:32]=[CH:31][CH:30]=[C:29]([S:33](=[O:34])(=[O:35])[NH2:36])[CH:28]=4)=[N:26][C:16]=3[C:10]=2[CH:9]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: N=C(N)Nc1cccc(S(N)(=O)=O)c1
Reactant: CN(C)C=C1CCc2sc(C(=O)OC(C)(C)C)cc2C1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: CC(C)(C)OC(=O)c1cc2c(s1)CCc1cnc(Nc3cccc(S(N)(=O)=O)c3)nc1-2
Temperature: 25 °C
Yield: 53.1 %

Procedure:
5-Dimethylaminomethylene-4-oxo-4,5,6,7-tetrahydro-benzo[b]thiophene-2-carboxylic acid tert-butyl ester (6.21 g, 20.20 mmol), 3-guanidinophenylsulphonamide hydrochloride (5.07 g, 20.20 mmol) and sodium hydroxide (0.81 g, 20.20 mmol) were suspended in isopropanol (250 mL) and stirred at reflux overnight. The reaction was allowed to cool to room temperature and diluted with water (˜200 mL). The resulting precipitate was isolated by filtration and the solid obtained was washed with water (1×100 mL), isopropanol (1×50 mL), diethyl ether (2×50 mL) and pentane (3×100 mL). Air drying gave an ochre powder (4.92 g, 53% yield). MS (ES+)459. δH (d6 DMSO) 1.5-1.6 (9H, s), 2.9-3.0 (2H, m), 3.1-3.2 (2H, m), 7.2-7.3 (2H, br s), 7.3-7.5 (2H, m), 7.7-7.8 (1H, m), 8.1 (1H, s), 8.4 (1H, s), 8.6 (1H, s), 9.9 (1H, s).
Reaction SMILES: Cl[C:2]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][C:12]=1[OH:13])[NH:9][N:8]=[C:7]2[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[C:17](C)C=1)=[O:3].[CH3:22][NH:23][CH2:24][CH2:25][CH2:26][CH3:27].[CH2:28](N(C(C)C)C(C)C)C>C1COCC1>[CH2:24]([N:23]([CH3:22])[C:2]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][C:12]=1[OH:13])[NH:9][N:8]=[C:7]2[C:14]1[CH:15]=[CH:20][CH:19]=[C:18]([CH3:17])[CH:28]=1)=[O:3])[CH2:25][CH2:26][CH3:27]
Reactant: CCCCNC
Reactant: CCN(C(C)C)C(C)C
Reactant: Cc1cccc(Cc2n[nH]c3cc(O)c(C(=O)Cl)cc23)c1
Solvent: C1CCOC1
Product: CCCCN(C)C(=O)c1cc2c(-c3cccc(C)c3)n[nH]c2cc1O
Reaction time: 1 h

Procedure:
4.7 A solution of 52 mg of “4f” in 1 ml of THF is added dropwise to a solution of 18.65 mg of N-methylbutylamine and 88.2 μl of N-ethyldiisopropylamine in 2 ml of THF. The mixture is stirred for a further 1 hour and subjected to conventional work-up. For further purification, the residue is chromatographed over an RP18 silica-gel column, giving 18.8 mg of 5-(N-butyl-N-methylaminocarbonyl)-3-(3-methylphenyl)-6-hydroxy-1H-indazole (“A25”)