Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: BrC1C([N:8]([CH2:23][O:24][CH3:25])[S:9]([C:12]2[CH:17]=[CH:16][C:15](Cl)=[C:14]([C:19]([F:22])([F:21])[F:20])[CH:13]=2)(=[O:11])=[O:10])=CC(C)=CN=1.C([Mg]Cl)(C)C.CC1C(C=O)=C(C)C=CN=1>C1COCC1>[CH3:25][O:24][CH2:23][NH:8][S:9]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:19]([F:22])([F:20])[F:21])[CH:13]=1)(=[O:11])=[O:10]
Reactant: COCN(c1cc(C)cnc1Br)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Agent: CC(C)[Mg]Cl
Agent: Cc1ccnc(C)c1C=O
Solvent: C1CCOC1
Product: COCNS(=O)(=O)c1cccc(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 100.9 %

Procedure:
To a solution of N-(2-bromo-5-methyl-pyridin-3-yl)-4-chloro-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide (500 mg, 1.06 mmol) in THF (3 mL) under nitrogen atmosphere at −30° C. was added drop wise isopropylmagnesium chloride (2 M solution in THF, 1.27 mL, 2.54 mmol). The mixture was then stirred for 30 min at 0° C. followed by the addition of a solution of 2,4-dimethyl-pyridine-3-carbaldehyde (271 mg, 2.01 mmol) at −30° C. The mixture was stirred at room temperature for 3 hours, quenched with saturated aqueous NH4Cl solution (5 mL) and extracted with EtOAc (2×25 mL). Combined organic layers were washed with saturated aqueous NH4Cl solution (25 mL), brine (25 mL), dried (anhydrous Na2SO4) and concentrated under reduced pressure. Obtained residue was column purified (SiO2, 50% EtOAc-hexanes) to obtain 4-chloro-N-{2-[(2,4-dimethyl-pyridin-3-yl)-hydroxy-methyl]-5-methyl]-5-methyl-pyridin-3-yl}-N-methoxymethyl-3-trifluoromethyl-benzene sulfonamide (288 mg) as yellow foam in 51% yield. ESMS m/z (relative -intensity): 530 (M+H)+ (100).
Reaction SMILES: [C:1]1([CH:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:8][OH:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[N+]([C:21]1[CH:26]=[CH:25][N+:24]([O-:27])=[CH:23][CH:22]=1)([O-])=O.C1(C)C=CC=CC=1>CN(C)C=O>[C:10]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:8][O:9][C:21]2[CH:26]=[CH:25][N+:24]([O-:27])=[CH:23][CH:22]=2)[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: OCC(c1ccccc1)c1ccccc1
Reactant: O=[N+]([O-])c1cc[n+]([O-])cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: [O-][n+]1ccc(OCC(c2ccccc2)c2ccccc2)cc1

Procedure:
2,2-diphenylethanol (4 g, 0.02 m) was added portionwise to a suspension of sodium hydride (0.48 g, 0.02 m) in dry dimethylformamide (200 ml) under nitrogen. After the reaction had ceased, the mixture was added dropwise to a solution of 4-nitropyridine-1-oxide (2.8 g, 0.02 m) in dry dimethylformamide (100 ml) at 35°-40° C. The mixture was maintained at this temperature for 12 hours and then filtered. The solvent was removed under reduced pressure, leaving a residue that was heated with successive portions of toluene. The toluene solution was evaporated to an oil which was crystallised from a mixture of toluene and 60-80 petrol (1:1). This gave 4-(2,2-diphenylethoxy)pyridine-1-oxide (2.2 g) as orange crystals, m.pt. 134°-138° C.
Reaction SMILES: [C:1]1([CH2:7][C:8]#[N:9])([CH2:4][C:5]#[N:6])[CH2:3][CH2:2]1.[BH4-].[Na+].Cl>CO.O.O.O.O.O.O.[Co](Cl)Cl>[NH2:9][CH2:8][CH2:7][C:1]1([CH2:4][C:5]#[N:6])[CH2:3][CH2:2]1
Reactant: N#CCC1(CC#N)CC1
Agent: Cl[Co]Cl
Agent: Cl
Agent: [BH4-]
Solvent: O
Solvent: CO
Product: N#CCC1(CCN)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 31.5 %

Procedure:
A solution of 5.0 g of cyclopropane-1,1-diacetonitrile in 200 ml of methanol was cooled to -15° C., and 4.95 g of cobalt chloride hexahydrate and 4.15 g of sodium borohydride were added thereto in this order, followed by stirring at that temperature for 15 minutes. The reaction mixture was made acidic by addition of 2N hydrochloric acid and then heated to room temperature, at which the mixture was stirred for 15 minutes, followed by concentration under reduced pressure. Water was added to the residue, and the mixture was extracted with ethyl acetate. The aqueous layer was adjusted to pH 9 with a 5N sodium hydroxide aqueous solution, followed by filtration. Chloroform was added to the filtrate, and the organic layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give 1.63 g of the title compound, which had the following physical properties.
Reaction SMILES: C([O:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C:7](=[CH:8][CH2:9][C@@H:10]3[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C@:11]3([O:25][CH2:26][O:27][CH2:28][CH3:29])[CH:12]=[CH:13][C:14]2=O)[CH2:6]1)(=O)C.[OH-].[Na+]>CO.O>[OH:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C:7](=[CH:8][CH2:9][C@@H:10]3[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C@:11]3([O:25][CH2:26][O:27][CH2:28][CH3:29])[CH:12]=[CH:13][CH2:14]2)[CH2:6]1
Reactant: CCOCO[C@]12C=CC(=O)[C@@]1(C)CC[C@H]1[C@H]2CC=C2C[C@@H](OC(C)=O)CC[C@@]21C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCOCO[C@]12C=CC[C@@]1(C)CC[C@H]1[C@H]2CC=C2C[C@@H](O)CC[C@@]21C
Yield: 94.9 %

Procedure:
A solution of 6.00 g of 3β-acetoxy-14β-ethoxymethoxyandrosta-5,15-dien-17-one and 30 ml of 2 N aq. sodium hydroxide in 120 ml of methanol was kept at room temperature for 24 hrs. The mixture was then diluted with water and extracted with dichloromethane. The organic phase was dried over sodium sulfate and evaporated to dryness to give 4.90 g of the title compound (II-a) as a white solid
Reaction SMILES: [C:1]([Si:5]([CH3:13])([CH3:12])[O:6][CH2:7][CH2:8][CH:9]1[CH2:11][O:10]1)([CH3:4])([CH3:3])[CH3:2].[N-:14]=[N+:15]=[N-:16].[Na+].[NH4+].[Cl-]>CO>[N:14]([CH2:11][CH:9]([OH:10])[CH2:8][CH2:7][O:6][Si:5]([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:13])[CH3:12])=[N+:15]=[N-:16]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)[Si](C)(C)OCCC1CO1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)[Si](C)(C)OCCC(O)CN=[N+]=[N-]
Temperature: 80 °C
Reaction time: 8 h
Yield: 81 %

Procedure:
A solution of 2-[2-[[(tert-butyl)dimethylsilyl]oxy]ethyl]-oxirane (5.0 g; prepared according to WO 2007/144423) in MeOH (150 mL) was reacted with NaN3 (3.95 g) and NH4Cl (2.37 g). The reaction mixture was further stirred at 80° C. overnight. The solvent was evaporated under reduced pressure and the residue was partitioned between EA and water. The org. layer was washed with brine, dried over Na2SO4 and evaporated under reduced pressure, affording a yellow oil (4.9 g; 81% yield).
Reaction SMILES: [S:1]([N:11]1[C:15]2[N:16]=[CH:17][C:18]3[N:19]([C:20]([C:23]45[CH2:30][CH2:29][C:26]([NH2:31])([CH2:27][CH2:28]4)[CH2:25][CH2:24]5)=[N:21][N:22]=3)[C:14]=2[CH:13]=[CH:12]1)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].[CH:32]1([S:35](Cl)(=[O:37])=[O:36])[CH2:34][CH2:33]1>C(Cl)Cl.CN(C=O)C>[S:1]([N:11]1[C:15]2[N:16]=[CH:17][C:18]3[N:19]([C:20]([C:23]45[CH2:30][CH2:29][C:26]([NH:31][S:35]([CH:32]6[CH2:34][CH2:33]6)(=[O:37])=[O:36])([CH2:27][CH2:28]4)[CH2:25][CH2:24]5)=[N:21][N:22]=3)[C:14]=2[CH:13]=[CH:12]1)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2]
Reactant: O=S(=O)(Cl)C1CC1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c2ncc2nnc(C45CCC(N)(CC4)CC5)n23)cc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)n2ccc3c2ncc2nnc(C45CCC(NS(=O)(=O)C6CC6)(CC4)CC5)n23)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 54.3 %

Procedure:
A round bottom flask was charged with 4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)bicyclo[2.2.2]octan-1-amine (0.40 g, 0.92 mmol), TEA (0.51 mL, 3.7 mmol) in DCM (3 mL) and DMF (6 mL). Cyclopropanesulfonyl chloride (0.16 g, 1.1 mmol) was added drop-wise and the resulting suspension was stirred at ambient temperature for about 18 h. The solvent was removed under reduced pressure and DCM (10 mL) was added. The crude material was purified by silica gel chromatography eluting with a gradient of 0-10% MeOH/DCM to give N-(4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)bicyclo[2.2.2]octan-1-yl)cyclopropanesulfonamide (0.27 g, 55%): LC/MS (Table 2, Method a) Rt=2.14 min; MS m/z 541 (M+H)+.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([N:17]2[CH2:22][CH2:21][CH:20]([O:23]C(=O)NCCCCCCOC(=O)NCCCCCC)[CH2:19][CH2:18]2)=[O:16])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(Cl)=O.O(C1C=CC(O)=CC=1)C1C=CC=CC=1.ClC(OC1C=CC([N+]([O-])=O)=CC=1)=O.C(=O)([O-])[O-].OC1CCNCC1>>[O:1]([C:8]1[CH:9]=[CH:10][C:11]([O:14][C:15]([N:17]2[CH2:18][CH2:19][CH:20]([OH:23])[CH2:21][CH2:22]2)=[O:16])=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCCCCNC(=O)OCCCCCCNC(=O)OC1CCN(C(=O)Oc2ccc(Oc3ccccc3)cc2)CC1
Agent: O=C(Cl)Cl
Agent: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Agent: O=C([O-])[O-]
Product: O=C(Oc1ccc(Oc2ccccc2)cc1)N1CCC(O)CC1

Procedure:
A multistep synthesis of 4-[6-(hexylcarbamoyloxy)hexylcarbamoyloxy]-piperidine-1 -carboxylic acid 4-phenoxyphenyl ester (1) as disclosed in the cited European Patent Application is shown in Scheme I where intermediate hydroxy compounds are reacted with phosgene or a phosgene equivalent and the resultant mixed carbonic acid diesters are used to aryloxycarbonylate or alkoxycarbonylate an appropriate amine. Thus, 4-phenoxyphenol (2) is treated with 4-nitrophenyl chloroformate (NPC) and condensation of the corresponding carbonate (3) with 4-hydroxypiperidine affords 4-hydroxy-1-piperidine-carboxylic acid 4 -phenoxyphenyl ester (4). Repeating the NPC activation step with the latter intermediate and the following condensation of carbonate (5) with 6-aminohexanol yield 4-[(6 -hydroxyhexyl)carbamoyloxy]-piperidine-1-carboxylic acid 4phenoxyphenyl ester (6). To complete the synthesis of (1), the alcoholic function of this intermediate is activated again with NPC and treated with hexylamine, or reacted directly with hexylisocyanate. ##STR1##
Reaction SMILES: [F:1][C:2]1[CH:30]=[C:29]([N+:31]([O-])=O)[CH:28]=[CH:27][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([NH:11][C:12]([N:14]2[CH2:19][CH2:18][CH:17]([N:20]3[CH2:25][CH2:24][CH:23]([OH:26])[CH2:22][CH2:21]3)[CH2:16][CH2:15]2)=[O:13])[CH:6]=1>O1CCCC1.[OH-].[Pd+2].[OH-].[C]>[NH2:31][C:29]1[CH:28]=[CH:27][C:3]([O:4][C:5]2[CH:10]=[CH:9][N:8]=[C:7]([NH:11][C:12]([N:14]3[CH2:19][CH2:18][CH:17]([N:20]4[CH2:21][CH2:22][CH:23]([OH:26])[CH2:24][CH2:25]4)[CH2:16][CH2:15]3)=[O:13])[CH:6]=2)=[C:2]([F:1])[CH:30]=1
Reactant: O=C(Nc1cc(Oc2ccc([N+](=O)[O-])cc2F)ccn1)N1CCC(N2CCC(O)CC2)CC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1CCOC1
Product: Nc1ccc(Oc2ccnc(NC(=O)N3CCC(N4CCC(O)CC4)CC3)c2)c(F)c1
Reaction time: 8 h
Yield: 104.4 %

Procedure:
4-(2-Fluoro-4-nitrophenoxy)-2-{[4-(4-hydroxypiperidin-1-yl)piperidin-1-yl]carbonylamino}pyridine (168 mg) was dissolved in tetrahydrofuran (20 ml). After adding 20% palladium hydroxide-carbon (103 mg), the mixture was stirred overnight under a hydrogen atmosphere. The catalyst was filtered and washed with tetrahydrofuran. The filtrate and the washings were combined and concentrated under reduced pressure, and the resultant residue was dried under reduced pressure to provide the title compound (164 mg) as pale yellow powder.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][C:17]=2[Cl:18])=[N:8][O:9][C:10]=1[CH3:11])=[O:5])C.[OH-].[Na+].C(O)C.Cl>O1CCCC1>[Cl:18][C:17]1[CH:16]=[CH:15][N:14]=[CH:13][C:12]=1[C:7]1[C:6]([C:4]([OH:5])=[O:3])=[C:10]([CH3:11])[O:9][N:8]=1
Reactant: CCOC(=O)c1c(-c2cnccc2Cl)noc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1onc(-c2cnccc2Cl)c1C(=O)O

Procedure:
Combine 3-(4-chloro-pyridin-3-yl)-5-methyl-isoxazole-4-carboxylic acid ethyl ester (0.90 g, 0.003 mol) with aqueous sodium hydroxide (2N, 7.0 mL, 0.014 mol), ethanol (2 mL), and tetrahydrofuran (2 mL) and stir overnight at ambient temperature. Adjust the aqueous mixture to approx. pH 2.5 with aqueous hydrochloric acid. Extract with ethyl acetate and dry the combined extracts over sodium sulfate and concentrate in vacuo. Drying nets the desired isoxazole acid as a light solid (0.78 g, 97%). MS(ES): (M+1)+ 239.0, 241.0 m/z.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:15])[CH2:10][CH2:11][C:12]([OH:14])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].C([N+](CCCC)(CCCC)CCCC)CCC.[Cl:34][CH2:35]I>O1CCOCC1>[Cl:34][CH2:35][O:13][C:12](=[O:14])[CH2:11][CH2:10][C:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:15]
Reactant: ClCI
Reactant: O=C(O)CCC(=O)OCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C(CCC(=O)OCc1ccccc1)OCCl
Reaction time: 18 h

Procedure:
Succinic acid monobenzyl ester (4.16 g, 20 mmole) was dissolved in dioxane (20 ml). To the solution was added tetrabutylammonium hydroxide aqueous solution (40%, 11.6 ml, 18 mmole). The solution was dried in vacuo and coevaporated with toluene several times. The residue was dissolved in methylene chloride (60 ml) and then chloroiodomethane (14.5 ml, 200 mmole) was added to the solution. The reaction solution was stirred for 18 hr and then evaporated and the product was isolated with silica gel column chromatography. 3.64 g
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:20][C:21]([N:24]1[N:28]=[N:27][C:26]([CH2:29][C:30]2[CH:35]=[CH:34][C:33]([CH2:36]O)=[CH:32][CH:31]=2)=[N:25]1)([CH3:23])[CH3:22].C(Br)(Br)(Br)[Br:39]>C(OCC)C>[Br:39][CH2:36][C:33]1[CH:34]=[CH:35][C:30]([CH2:29][C:26]2[N:27]=[N:28][N:24]([C:21]([CH3:23])([CH3:22])[CH3:20])[N:25]=2)=[CH:31][CH:32]=1
Reactant: BrC(Br)(Br)Br
Reactant: CC(C)(C)n1nnc(Cc2ccc(CO)cc2)n1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Product: CC(C)(C)n1nnc(Cc2ccc(CBr)cc2)n1
Yield: 62.9 %

Procedure:
Triphenylphosphine (6.5 g, 25 mmol) was added to a solution of 4-[[2-(1,1-dimethylethyl)-2H-tetrazol-5-yl]-methyl]benzenemethanol (3.0 g, 12.4 mmol) and carbon tetrabromide (8.3 g. 25 mmol) in diethyl ether (150 mL). After 3 hours the reaction mixture was concentrated and the residue purified by chromatography on silica gel eluting with a 9:1 mixture of hexane-ethyl acetate to give 5-[[4-(bromomethyl)phenyl]methyl]-2-(1,1-dimethylethyl)-2H-tetrazole (2.4 g. 7.8 mmol) in 63% yield, mp. 73°-74° C.
Reaction SMILES: CCN(C(C)C)C(C)C.Cl.Cl.[F:12][C:13]1[CH:14]=[C:15]([C:19]2[C:20]([N:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)=[C:21]3[CH:27]=[N:26][NH:25][C:22]3=[N:23][CH:24]=2)[CH:16]=[CH:17][CH:18]=1.[C:34]([O:38][C:39]([N:41]([CH:54]([CH3:56])[CH3:55])[CH2:42][C@H:43]([C:47]1[CH:52]=[CH:51][C:50]([Cl:53])=[CH:49][CH:48]=1)[C:44](O)=[O:45])=[O:40])([CH3:37])([CH3:36])[CH3:35].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C(Cl)Cl>[Cl:53][C:50]1[CH:51]=[CH:52][C:47]([C@H:43]([C:44]([N:31]2[CH2:32][CH2:33][N:28]([C:20]3[C:19]([C:15]4[CH:16]=[CH:17][CH:18]=[C:13]([F:12])[CH:14]=4)=[CH:24][N:23]=[C:22]4[NH:25][N:26]=[CH:27][C:21]=34)[CH2:29][CH2:30]2)=[O:45])[CH2:42][N:41]([CH:54]([CH3:55])[CH3:56])[C:39](=[O:40])[O:38][C:34]([CH3:36])([CH3:35])[CH3:37])=[CH:48][CH:49]=1
Reactant: CC(C)N(C[C@@H](C(=O)O)c1ccc(Cl)cc1)C(=O)OC(C)(C)C
Reactant: Fc1cccc(-c2cnc3[nH]ncc3c2N2CCNCC2)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)N(C[C@@H](C(=O)N1CCN(c2c(-c3cccc(F)c3)cnc3[nH]ncc23)CC1)c1ccc(Cl)cc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
DIEA (d 0.742; 0.0790 mL, 0.454 mmol) was added to a solution of 5-(3-fluorophenyl)-4-(piperazin-1-yl)-1H-pyrazolo[3,4-b]pyridine dihydrochloride (0.070 g, 0.113 mmol), (S)-3-(tert-butoxycarbonyl(isopropyl)amino)-2-(4-chlorophenyl)propanoic acid (0.0388 g, 0.113 mmol, see Example B) and TBTU (0.0437 g, 0.136 mmol) in DCM (1 mL) and stirred at room temperature for 18 hours. The mixture was directly loaded onto a silica column and purified by chromatography (hexane:ethyl acetate, 1:1) to give (S)-tert-butyl 2-(4-chlorophenyl)-3-(4-(5-(3-fluorophenyl)-1H-pyrazolo[3,4-b]pyridin-4-yl)piperazin-1-yl)-3-oxopropyl(isopropyl)carbamate as a solid. The solid was dissolved in DCM (1 mL), and TFA (0.2 mL) was added. The mixture was stirred at room temperature for 1 hour and then concentrated to dryness. The resulting residue was dissolved in DCM (0.5 mL), and HCl in ether (1 mL, 2N) was added. The resulting solid was collected by filtration to give (S)-2-(4-chlorophenyl)-1-(4-(5-(3-fluorophenyl)-1H-pyrazolo[3,4-b]pyridin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-one dihydrochloride (0.022 g, 32%). MS APCI (+) m/z 521.4 detected.
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2([C:14](=[N:22]O)[CH2:15][C:16]([CH2:20][CH3:21])([OH:19])[CH2:17][CH3:18])[CH2:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1.O.N>COCCOC.[Ti](Cl)(Cl)(Cl)Cl>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2([C:14](=[NH:22])[CH2:15][C:16]([CH2:20][CH3:21])([OH:19])[CH2:17][CH3:18])[CH2:11][CH2:12][CH2:13]2)=[CH:8][CH:9]=1
Reactant: CCC(O)(CC)CC(=NO)C1(c2ccc(Cl)cc2)CCC1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: N
Agent: [BH4-]
Solvent: COCCOC
Solvent: O
Product: CCC(O)(CC)CC(=N)C1(c2ccc(Cl)cc2)CCC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Titanium (IV) chloride (3.9 ml) was added dropwise to stirred dry 1,2-dimethoxyethane (68 ml) cooled to 0° C. under nitrogen. The temperature was maintained at 0° C. and powdered sodium borohydride (2.7 g) was added. A solution of 1-[1-(4-chlorophenyl)cyclobutyl]-3-ethyl-3-hydroxypentan-1-one oxime (5.2 g) in dry 1,2-dimethoxyethane (17 ml) was then added dropwise under nitrogen and the mixture stirred for 30 minutes at 0° C. and then at ambient temperature for 14 hours. After cooling the mixture to 0° C., water (170 ml) was added dropwise and the mixture basified with aqueous ammonia solution (S.G. 0.880) with cooling. The resulting solution was extracted with ether and the extracts washed with brine and dried. Removal of the solvents by evaporation in vacuo gave an oil which was distilled (b.p. 150/0.05 mm) to give 1-[1-(4-chlorophenyl)cyclobutyl]-3-ethyl-1-iminopentan-3-ol.
Reaction SMILES: FC(F)(F)C([NH:5][C:6]1[N:7]=[C:8]2[CH:13]=[N:12][CH:11]=[CH:10][N:9]2[CH:14]=1)=O>N.CO>[N:7]1[C:6]([NH2:5])=[CH:14][N:9]2[CH:10]=[CH:11][N:12]=[CH:13][C:8]=12
Reactant: O=C(Nc1cn2ccncc2n1)C(F)(F)F
Agent: N
Solvent: CO
Product: Nc1cn2ccncc2n1
Temperature: 68 °C

Procedure:
2,2,2-Trifluoro-N-(imidazo[1,2-a]pyrazin-2-yl)acetamide (prepared as described in WO2004/058266A1, 520 mg) was dissolved in 7N NH3 in methanol (4.0 mL), and heated at 68° C. in a sealed tube for 6 hours. The reaction mixture was then cooled and concentrated to provide the title compound.
Reaction SMILES: [OH:1][C:2]1[C:11]2[N:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]([CH:12]=[O:13])=[CH:4][CH:3]=1.Cl[C:15]1[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[CH:17][N:16]=1.C([O-])([O-])=O.[K+].[K+].O>S1(CCCC1)(=O)=O>[CH:12]([C:5]1[CH:4]=[CH:3][C:2]([O:1][C:15]2[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[CH:17][N:16]=2)=[C:11]2[C:6]=1[CH:7]=[CH:8][CH:9]=[N:10]2)=[O:13]
Reactant: N#Cc1ccc(Cl)nc1
Reactant: O=Cc1ccc(O)c2ncccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=S1(=O)CCCC1
Solvent: O
Product: N#Cc1ccc(Oc2ccc(C=O)c3cccnc23)nc1
Temperature: 90 °C

Procedure:
To a solution of 8-hydroxyquinoline-5-carbaldehyde (692 mg, 4 mmol) in sulfolane (8 mL) was added 2-chloro-5-cyanopyridine (552 mg, 4 mmol) and K2CO3 (1.7 g, 12 mmol). The reaction was heated at 90° C. for 2 h in a microwave. The reaction was cooled to rt and poured into water (100 mL). The resulting solid was filtered, washed with water, ether and air dried to give the title compound: RT=3.02 min; m/z (ES+)=276.0 [M+H]+.
Reaction SMILES: [Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.[CH2:12]([O:19][CH2:20][C:21]1([CH2:27][CH2:28][O:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])[O:25][CH:24]([OH:26])[CH2:23][CH2:22]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(Cl)Cl.CCOCC>[CH2:12]([O:19][CH2:20][C:21]1([CH2:27][CH2:28][O:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])[O:25][C:24](=[O:26])[CH2:23][CH2:22]1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CCCCCCCCCCCCCCCCCCOCCC1(COCc2ccccc2)CCC(O)O1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCOCC
Product: CCCCCCCCCCCCCCCCCCOCCC1(COCc2ccccc2)CCC(=O)O1
Reaction time: 18 h

Procedure:
To a solution of 1.6 g (7.4 mmol) of pyridinium chlorochromate in 25 ml of methylene chloride under a nitrogen atmosphere, was added 13.5 g (6.5 mmol) of the compound prepared in (d) above in 25 ml of methylene chloride. After 18 hours at 25° C., the solution was diluted with 150 ml of ether, filtered through silica gel and the filtrate evaporated to afford an oil. The oil was then flash chromatographed on silica gel employing a mixture of petroleum ether and diethyl ether in a ratio of 7:3 as the eluent to yield colorless oil.
Reaction SMILES: C[Al](C)C.[CH3:5][C:6]1([CH3:23])[NH:11][CH2:10][CH2:9][N:8]([C:12]2[CH:22]=[CH:21][C:15]([C:16]([O:18]CC)=O)=[CH:14][CH:13]=2)[CH2:7]1.[CH3:24][O:25][C:26]1[CH:27]=[C:28]([CH2:34][O:35][C:36]2[CH:37]=[C:38]([NH2:41])[NH:39][N:40]=2)[CH:29]=[C:30]([O:32][CH3:33])[CH:31]=1.S([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.CC(C)=O>[CH3:33][O:32][C:30]1[CH:29]=[C:28]([CH2:34][O:35][C:36]2[CH:37]=[C:38]([NH:41][C:16](=[O:18])[C:15]3[CH:14]=[CH:13][C:12]([N:8]4[CH2:9][CH2:10][NH:11][C:6]([CH3:5])([CH3:23])[CH2:7]4)=[CH:22][CH:21]=3)[NH:39][N:40]=2)[CH:27]=[C:26]([O:25][CH3:24])[CH:31]=1
Reactant: CCOC(=O)c1ccc(N2CCNC(C)(C)C2)cc1
Reactant: COc1cc(COc2cc(N)[nH]n2)cc(OC)c1
Agent: C[Al](C)C
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: Cc1ccccc1
Product: COc1cc(COc2cc(NC(=O)c3ccc(N4CCNC(C)(C)C4)cc3)[nH]n2)cc(OC)c1
Temperature: 20 °C
Reaction time: 24 h
Yield: 10.5 %

Procedure:
A 2M solution of trimethylaluminium in toluene (0.691 mL, 1.38 mmol) was added dropwise to a stirred solution of ethyl 4-(3,3-dimethylpiperazin-1-yl)benzoate (145 mg, 0.55 mmol) and 5-[(3,5-dimethoxyphenyl)methoxy]-2H-pyrazol-3-amine (138 mg, 0.55 mmol) in toluene (5 mL) at 20° C., over a period of 5 mins under nitrogen. The resulting solution was stirred at 20° C. for 24 h. This was diluted with acetone (25 ml) and an excess of damp solid sodium sulphite was added. The mixture was stirred for 1 h and the solid filtered off. The solid was washed with 10% MeOH/DCM and the combined organics evaporated to dryness. The crude product was purified by preparative HPLC, using decreasingly polar mixtures of water (containing 1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford the title compound (27.0 mg, 10.49%) as a colourless gum.
Reaction SMILES: [OH:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1)=[O:4].N1C=CN=C1.[C:19]([Si:23](Cl)([CH3:25])[CH3:24])([CH3:22])([CH3:21])[CH3:20].O>CN(C=O)C>[Si:23]([O:1][CH2:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]([N+:11]([O-:13])=[O:12])=[CH:9][CH:10]=1)=[O:4])([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:25])[CH3:24]
Reactant: O=C(CO)c1ccc([N+](=O)[O-])cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCC(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 98.1 %

Procedure:
Step A To a solution of 2-hydroxy-1-(4-nitrophenyl)ethanone (1 g, 5.52 mmol) in DMF (25 ml) was added imidazole (564 mg, 8.28 mmol), followed by the addition of tert-butylchlorodimethylsilane (915 mg, 6.07 mmol). The reaction mixture was stirred at room temperature for 3 h. The mixture was poured into H2O (25 mL) and extracted with ethyl acetate (3×25 mL). The organic layers were combined, washed with H2O (5×25 mL), brine (1×25 mL), dried over MgSO4 and concentrated in vacuo to give 2-(tert-butyldimethylsilyloxy)-1-(4-nitrophenyl)ethanone as a yellow solid (1.6 g, 98%).