Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:24])([CH3:23])[C@@H:11]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:12]([OH:14])=[O:13])(=[O:7])=[O:6].C(Cl)(=O)C(Cl)=O.[CH:31](O)([CH3:33])[CH3:32].N1C=CC=CC=1>ClCCl>[Cl:1][CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:24])([CH3:23])[C@@H:11]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:12]([O:14][CH:31]([CH3:33])[CH3:32])=[O:13])(=[O:6])=[O:7]
Reactant: CC(C)O
Reactant: CC(C)(COS(=O)(=O)CCCCl)[C@@H](OCc1ccccc1)C(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)OC(=O)[C@H](OCc1ccccc1)C(C)(C)COS(=O)(=O)CCCCl
Yield: 76.3 %

Procedure:
Following the general procedure for the preparation of carboxylic esters from carboxylic acids of Description 15, (2R)-4-[(3-chloropropyl)sulfonyloxy]-3,3-dimethyl-2-(phenylmethoxy)butanoic acid (11) (0.73 g, 1.9 mmol) dissolved in 20 mL of anhydrous dichloromethane (DCM) was reacted with 1.1 mL (2.2 mmol) of oxalyl chloride (2.0 M in DCM). After completion of the reaction, a solution of 2 mL (1.57 g, 26.1 mmol) of isopropanol (iPrOH) and 0.16 mL of pyridine (0.15 g, 1.9 mmol) in 10 mL of anhydrous dichloromethane (DCM) was added to the acid chloride. After work-up, the crude material was purified by silica gel column chromatography using a mixture of ethyl acetate (EtOAc) and hexane (Hxn) (EtOAc/Hxn=1:2) as eluent to provide 0.61 g (75% yield) of the title compound (25a) as a colorless oil. Rf=0.67 (EtOAc/Hxn=1:2). 1H NMR (400 MHz, CDCl3): δ=1.06 (s, 3H), 1.08 (s, 3H), 1.30-1.32 (m, 3H), 2.25-2.32 (m, 2H), 3.65 (t, J=5.6 Hz, 2H), 3.81 (s, 1H), 3.98 (d, J=9.2 Hz, 1H), 4.23 (d, J=9.2 Hz, 1H), 4.35 (d, J=11.2 Hz, 1H), 4.62 (d, J=11.2 Hz, 1H), 5.14 (m, 1H), 7.33-7.36 (m, 5H) ppm. MS (ESI) m/z 420.94 (M+H)+, 442.95 (M+Na)+. The analytical data was consistent with the proposed structure.
Reaction SMILES: [OH-:1].[Na+].OO.[C:5]([C:7]1[N:12]=[CH:11][C:10]([NH:13][C@@H:14]2[CH2:19][CH2:18][CH2:17][CH2:16][C@@H:15]2[NH:20]C(=O)OC(C)(C)C)=[CH:9][C:8]=1[NH:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([N:35]2[N:39]=[CH:38][CH:37]=[N:36]2)[N:30]=1)#[N:6].[C:40]([OH:46])([C:42]([F:45])([F:44])[F:43])=[O:41]>C(Cl)Cl.CS(C)=O>[OH:46][C:40]([C:42]([F:45])([F:44])[F:43])=[O:41].[NH2:20][C@H:15]1[CH2:16][CH2:17][CH2:18][CH2:19][C@H:14]1[NH:13][C:10]1[CH:9]=[C:8]([NH:28][C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([N:35]3[N:39]=[CH:38][CH:37]=[N:36]3)[N:30]=2)[C:7]([C:5]([NH2:6])=[O:1])=[N:12][CH:11]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1Nc1cnc(C#N)c(Nc2cccc(-n3nccn3)n2)c1
Reactant: [OH-]
Agent: OO
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC(=O)c1ncc(N[C@@H]2CCCC[C@@H]2N)cc1Nc1cccc(-n2nccn2)n1
Reaction time: 0.5 h

Procedure:
Dioxane (1.06 mL), 6-(2H-1,2,3-triazol-2-yl)pyridin-2-amine (51 mg, 0.32 mmol) and cesium carbonate (311 mg, 0.955 mmol) were added to tert-butyl {(1S,2R)-2-[(5-bromo-6-cyanopyridin-3-yl)amino]cyclohexyl}carbamate (PrepEx 1.1) (94 mg, 0.32 mmol) in a scintillation vial. The vial was purged and flushed with argon three times before Pd2 dba3 (29 mg, 0.032 mmol) and Xantphos (28 mg, 0.048 mmol) were added. The vial was purged and flushed 3 times with argon before the vial was sealed and heated to 80° C. After 16 hours, the reaction mixture was cooled to room temperature, filtered through CELITE (washed with dichloromethane), and diluted with water. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (10-70% acetone in hexanes, linear gradient) to afford tert-butyl {(1S,2R)-2-[(6-cyano-5-{[6-(2H-1,2,3-triazol-2-yl)pyridin-2-yl]amino}pyridin-3-yl)amino]cyclohexyl}carbamate. The isolated solids were dissolved in DCM (1 mL) and TFA (1 mL), and stirred at room temperature. After 30 minutes, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in DMSO (1 mL). To this solution was added sodium hydroxide (4.0 M in water, 0.1 mL, 0.4 mmol) and hydrogen peroxide (30 wt % in water, 0.050 mL, 0.49 mmol). The reaction mixture was stirred at room temperature until complete conversion of the nitrile intermediate was observed by LCMS. The reaction mixture was diluted with DMSO and filtered. The filtrate was purified directly by reverse phase HPLC (acetonitrile/water with 0.1% TFA, linear gradient) to afford 5-{[(1R,2S)-2-aminocyclohexyl]amino}-3-{[6-(2H-1,2,3-triazol-2-yl)pyridin-2-yl]amino}pyridine-2-carboxamide TFA salt. MS ESI calc'd. for C19H24N9O [M+H]+ 394. found 394. 1H NMR (500 MHz, CD3OD) δ 9.20 (s, 1H), 8.07 (s, 2H), 7.83 (t, J=8.0 Hz, 1H), 7.80 (d, J=2.5 Hz, 1H), 7.55 (d, J=7.5 Hz, 1H), 6.87 (d, J=7.8 Hz, 1H), 4.38 (s, 1H), 3.75-3.67 (m, 1H), 2.01-1.66 (m, 6), 1.66-1.51 (m, 2H).
Reaction SMILES: COC1C=CC(C[O:8][C:9]2[CH:27]=[CH:26][C:12]([CH2:13][N:14]([CH3:25])[S:15]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)(=[O:17])=[O:16])=[CH:11][C:10]=2[C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:36])[F:35])[CH:29]=2)=CC=1>C(O)(C(F)(F)F)=O.C(Cl)Cl>[F:37][C:34]([F:35])([F:36])[C:30]1[CH:29]=[C:28]([C:10]2[CH:11]=[C:12]([CH:26]=[CH:27][C:9]=2[OH:8])[CH2:13][N:14]([CH3:25])[S:15]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)(=[O:17])=[O:16])[CH:33]=[CH:32][CH:31]=1
Reactant: COc1ccc(COc2ccc(CN(C)S(=O)(=O)c3ccc(F)cc3)cc2-c2cccc(C(F)(F)F)c2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(Cc1ccc(O)c(-c2cccc(C(F)(F)F)c2)c1)S(=O)(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 63.7 %

Procedure:
Intermediate 35 (700 mg, 1.25 mmol) was dissolved in TFA/DCM (1/1) and stirred at room temperature for 1 h. Solvent was removed in vacuo and the residue was purified via silica gel chromatography (0-40% EtOAc/hexane) to afford 350 mg (64%) of N-(3-(3-trifluoromethylphenyl)-4-hydroxybenzyl)-4-fluoro-N-methylbenzenesulfonamide (36). 1HNMR (CD3OD, 400 MHz): δ 7.91 (m, 2H), 7.80 (s, 1H), 7.65 (m, 2H), 7.59 (d, 1H), 7.15-7.25 (m, 4H), 6.94 (d, 1H), 4.97 (s, 1H), 4.13 (s, 2H), 2.64 (s, 3H). MS (ESI): MH+=440.1. HPLC (Method B) tR=3.45 min.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][NH2:10])=[CH:5][CH:4]=1.[C:11]([O-])(=O)[CH3:12].[Na+].C(=O)C>O.C(O)C>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][N:10]=[CH:11][CH3:12])=[CH:5][CH:4]=1
Reactant: CC(=O)[O-]
Reactant: NNc1ccc(Cl)cc1
Agent: CC=O
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC=NNc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4-Chlorophenylhydrazine hydrochloride (5.0 g) and 3.4 g of sodium acetate were dissolved in a mixture of 50 ml of water and 25 ml of ethanol, to which 1.69 g of 80% acetaldhyde aqueous solution were added dropwise at room temperature, and the resulting mixture was stirred for 30 minutes at room temperature. After adding 50 ml of water, the reaction mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated sodium chloride solution, dried and distilled off to give acetaldehyde 4-chlorophenylhydrazone as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:12])=[C:6]([CH2:8][C:9](O)=[O:10])[CH:7]=1.C(Cl)(=O)C([Cl:16])=O>ClCCl.CN(C)C=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:12])=[C:6]([CH2:8][C:9]([Cl:16])=[O:10])[CH:7]=1
Reactant: O=C(O)Cc1cc(Br)ccc1Cl
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)Cc1cc(Br)ccc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5-Bromo-2-chlorophenylacetic acid (2.0 g) obtained in Reference Example 125-(3) was dissolved in dichloromethane (40 ml), and thereto were added oxalyl chloride (0.77 ml) and N,N-dimethylformamide (one drop) at 0° C. The mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure to give 5-bromo-2-chlorophenylacetyl chloride, which was used in the subsequent step without further purification.
Reaction SMILES: [CH3:1][NH:2][C:3]1[S:4][C:5]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)=[C:6]([CH:8]=O)[N:7]=1.[OH2:16].Cl.[O:18]1[CH2:22]C[CH2:20][CH2:19]1>>[CH3:1][NH:2][C:3]1[S:4][C:5]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)=[C:6]([CH:8]=[CH:20][C:19]([O:18][CH3:22])=[O:16])[N:7]=1
Reactant: CNc1nc(C=O)c(-c2ccncc2)s1
Reactant: O
Reactant: C1CCOC1
Agent: Cl
Product: CNc1nc(C=CC(=O)OC)c(-c2ccncc2)s1
Reaction time: 2.5 h

Procedure:
A mixture of 2-methylamino-4-formyl-5-(4-pyridyl)thiazole (1.1 g) and triphenylphosphinecarbomethoxymethylene (3.34 g) in tetrahydrofuran (80 ml) was stirred at 40° to 45° C. for 2.5 hours. The reaction mixture was poured into water and the resultant solution was acidified to pH 1.0 with 10% hydrochloric acid. The acidified solution was washed with ethyl acetate. The aqueous solution was adjusted to pH 7.0 with 20% aqueous potassium carbonate and extracted with ethyl acetate. The organic extract was washed with brine and dried over magnesium sulfate. The solvent was evaporated in vacuo and the residue was subjected to column chromatography on silica gel eluting with a mixture of ethyl acetate and tetrahydrofuran (8:2). The fractions containing the desired compound were combined and evaporated in vacuo to give methyl 2-methylamino-5-(4-pyridyl)-4-thiazoleacrylate (trans isomer) (0.66 g). mp 166°-167° C.
Reaction SMILES: [Cl-].[Cl-].[CH:3]1([Ti+2:8][CH:9]2[CH:13]=[CH:12][CH:11]=[CH:10]2)[CH:7]=[CH:6][CH:5]=[CH:4]1.[F:14][C:15]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=1[CH2:22][CH2:23][CH2:24][N:25]1[CH:29]=[CH:28][CH:27]=[CH:26]1.[CH:30]([N-:33][CH:34]([CH3:36])C)([CH3:32])C.[Li+]>>[CH:9]1([Ti:8]([CH:3]2[CH:4]=[CH:5][CH:6]=[CH:7]2)([C:20]2[C:19]([F:21])=[CH:18][CH:17]=[C:16]([CH2:22][CH2:23][CH2:24][N:33]3[CH:30]=[CH:32][CH:36]=[CH:34]3)[C:15]=2[F:14])[C:20]2[C:19]([F:21])=[CH:18][CH:17]=[C:16]([CH2:22][CH2:23][CH2:24][N:25]3[CH:29]=[CH:28][CH:27]=[CH:26]3)[C:15]=2[F:14])[CH:13]=[CH:12][CH:11]=[CH:10]1
Reactant: Fc1ccc(CCCn2cccc2)c(F)c1
Reactant: CC(C)[N-]C(C)C
Reactant: C1=CC([Ti+2]C2C=CC=C2)C=C1
Agent: [Cl-]
Agent: [Li+]
Product: Fc1ccc(CCCn2cccc2)c(F)c1[Ti](c1c(F)ccc(CCCn2cccc2)c1F)(C1C=CC=C1)C1C=CC=C1
Yield: 37.2 %

Procedure:
Analogously to Example 19, 2.5 g (0.010 mol) of bis(cyclopentadienyl)titanium dichloride and 4.9 g (0.022 mol) of 1-[3-(2,4-difluorophenyl)propyl]-1H-pyrrole are reacted with 0.022 mol of lithium diisopropylamide solution. The brown-orange oil is purified by means of flash chromatography using hexane/ethyl acetate (9:1) as solvent. 2.3 g of an orange glassy resin are obtained.
Reaction SMILES: [Cl:1][SiH:2]([CH2:4][Si:5]([Cl:8])([Cl:7])[Cl:6])[Cl:3].Cl[Si](C[Si](Cl)(Cl)Cl)(Cl)Cl.[CH2:18]([Cl:22])[C:19](=[CH2:21])[CH3:20]>O1CCCC1.[H+].[H+].Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl>[Cl:6][Si:5]([Cl:8])([Cl:7])[CH2:4][Si:2]([Cl:3])([Cl:1])[CH2:20][CH:19]([CH3:21])[CH2:18][Cl:22]
Reactant: Cl[SiH](Cl)C[Si](Cl)(Cl)Cl
Reactant: C=C(C)CCl
Agent: Cl[Pt-2](Cl)(Cl)(Cl)(Cl)Cl
Agent: Cl[Si](Cl)(Cl)C[Si](Cl)(Cl)Cl
Agent: [H+]
Solvent: C1CCOC1
Product: CC(CCl)C[Si](Cl)(Cl)C[Si](Cl)(Cl)Cl
Temperature: 110 °C
Yield: 60 %

Procedure:
A 2-L flask equipped with magnetic stirring, pot thermometer, addition funnel and condenser was charged with a mixture of 1455 g (2.05 mol) containing approximately 46% (dichlorosilylmethyl)trichlorosilane and 54% bis(trichlorosilyl)methane [molar ratio 1:1]. To the addition funnel were added 186 g (2.05 mol) of methallyl chloride. The reaction mixture was heated to 110° C. and 20 g of the olefin and 0.5 mL of a 5% solution of chloroplatinic acid in tetrahydrofuran were added to the reaction mixture to initiate the reaction. The remainder of the olefin was added to the reaction mixture at an appropriate rate to maintain the reaction temperature between 110 and 120° C. After completion of the olefin addition, the reaction mixture was heated to 130° C. for an additional 3 hours. Distillation of the product directly from the reaction mixture yielded 412 g (60%) of the title dipodal silane, bp 89-91° C./0.4 mm Hg, density @ 20° C. 1.380.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[NH:5]1[CH:9]=[CH:8][NH:7][C:6]1=[O:10].[S:11]1[CH:15]=[CH:14][CH:13]=[C:12]1[C:16](Cl)=[O:17]>[N+](C1C=CC=CC=1)([O-])=O>[S:11]1[CH:15]=[CH:14][CH:13]=[C:12]1[C:16]([C:9]1[NH:5][C:6](=[O:10])[NH:7][CH:8]=1)=[O:17]
Reactant: O=c1[nH]cc[nH]1
Reactant: O=C(Cl)c1cccs1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=[N+]([O-])c1ccccc1
Product: O=C(c1c[nH]c(=O)[nH]1)c1cccs1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
In 50 ml of nitrobenzene is combined 13.3 g of aluminum chloride, 4.2 g of 1,3-dihydro-2H-imidazol-2-one and 8.1 g of thienoyl chloride. The mixture is stirred at 60° C. for 3 hours and poured over ice water. The solids are filtered, washed with ether and recrystallized twice from ethanol-water to afford the title compound. M.P. 339°-42° C.
Reaction SMILES: C(O[C:4](=[O:13])[C:5](=[O:12])[CH2:6][C:7](=[O:11])[CH:8]([CH3:10])[CH3:9])C.[CH3:14][O:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20][NH2:21])=[CH:18][CH:17]=1.[Cl:24][C:25]1[CH:32]=[CH:31][C:28]([CH:29]=O)=[C:27]([CH3:33])[CH:26]=1>C(O)(=O)C.C(#N)C>[Cl:24][C:25]1[CH:32]=[CH:31][C:28]([CH:29]2[N:21]([CH2:20][C:19]3[CH:22]=[CH:23][C:16]([O:15][CH3:14])=[CH:17][CH:18]=3)[C:4](=[O:13])[C:5]([OH:12])=[C:6]2[C:7](=[O:11])[CH:8]([CH3:9])[CH3:10])=[C:27]([CH3:33])[CH:26]=1
Reactant: CCOC(=O)C(=O)CC(=O)C(C)C
Reactant: COc1ccc(CN)cc1
Reactant: Cc1cc(Cl)ccc1C=O
Solvent: CC#N
Solvent: CC(=O)O
Product: COc1ccc(CN2C(=O)C(O)=C(C(=O)C(C)C)C2c2ccc(Cl)cc2C)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 73 %

Procedure:
5-Methyl-2,4-dioxo-hexanoic acid ethyl ester (5.6 g, 36.4 mmol) was added to a solution of 4-methoxybenzyl amine (5 g, 36.4 mmol) in acetic acid (40 mL). The mixture was stirred for 10 min at rt. 4-Chloro-2-methylbenzaldehyde (6.77 g, 36.4 mmol) was added. The reaction mixture was heated to 120° C., stirred at this temperature overnight, allowed to cool to rt and diluted with acetonitrile. The resulting precipitate was collected by vacuum filtration and dried to provide 11 g of the title compound. tR: 1.80 min (LC-MS 2); ESI-MS: 414 [M+H]+ (LC-MS 2).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[N:11]([CH:19]([CH3:21])[CH3:20])[C:12](=[O:18])[N:13]([CH3:17])[C:14]=2[CH2:15]O)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[C:22]1([OH:28])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>O1CCCC1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[N:11]([CH:19]([CH3:21])[CH3:20])[C:12](=[O:18])[N:13]([CH3:17])[C:14]=2[CH2:15][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[OH:28])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CC(C)n1c(Sc2cc(Cl)cc(Cl)c2)c(CO)n(C)c1=O
Reactant: Oc1ccccc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)n1c(Sc2cc(Cl)cc(Cl)c2)c(Cc2ccccc2O)n(C)c1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 13.1 %

Procedure:
To a solution of 100 mg of 4-(3,5-dichlorophenylthio)-5-(hydroxymethyl)-3-isopropyl-1-methyl-1,3-dihydro-2-imidazolone, 30 mg of phenol and 100 mg of triphenylphosphine in 5 mL of tetrahydrofuran at 0° C. was added 70 μL of diisopropylazodicarboxylate in 5 mL of tetrahydrofuran over 20 min. The reaction was stirred overnight warming to room temperature. The mixture was then diluted with ethyl acetate and washed with 0.5N hydrochloric acid solution then 0.5N sodium hydroxide solution, dried, concentrated and purified by flash chromatography eluting with 3:1 hexane: ethyl acetate to give 16 mg of a colourless oil. Mass spectrum (ES) m/z 423 [M+H]+.
Reaction SMILES: [OH-:1].[Na+].Cl[C:4]1[C:9]([N:10]2[CH2:15][CH2:14][N:13]([CH:16]([CH3:18])[CH3:17])[CH2:12][CH2:11]2)=[N:8][CH:7]=[CH:6][N:5]=1>O.CS(C)=O>[CH:16]([N:13]1[CH2:14][CH2:15][N:10]([C:9]2[C:4](=[O:1])[NH:5][CH:6]=[CH:7][N:8]=2)[CH2:11][CH2:12]1)([CH3:18])[CH3:17]
Reactant: CC(C)N1CCN(c2nccnc2Cl)CC1
Reactant: [OH-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)N1CCN(c2ncc[nH]c2=O)CC1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To a solution of NaOH (5.4 g, 125 mmol) in a mixture of water/DMSO (1: 1; 15 mL) was added 2-chloro-3-(4-isopropylpiperazin-1-yl)pyrazine (2.66 g, 12 mmol; from Step 1). After being stirred at 80° C. for 2 h, the dark red solution was cooled to room temperature, extracted with EtOAc overnight to give, after drying and solvent removal in vacuo, 2.6 g (70%) of the title compound as a white solid. HPLC purity: 87%. MS m/z 223 (M+H)+. HRMS m/z calcd for C11H18N4O (M)+ 222.1481, found 222.1489.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[F:10][C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][C:12]=1B1OC(C)(C)C(C)(C)O1>>[F:10][C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][C:12]=1[C:2]1[C:3]([C:4]#[N:5])=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CC1(C)OB(c2cc([N+](=O)[O-])ccc2F)OC1(C)C
Reactant: N#Cc1ccccc1Br
Product: N#Cc1ccccc1-c1cc([N+](=O)[O-])ccc1F
Yield: 100 %

Procedure:
A mixture of 2-bromobenzonitrile (34.6 g, 190 mmol) and 2-(2-fluoro-5-nitrophenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (76.1 g, 285 mmol) were coupled as described in Example 2 to afford 2′-fluoro-5′-nitrobiphenyl-2-carbonitrile as a beige solid (46 g, 100%): δH (360 MHz, CDCl3) 7.37-7.42 (1H, m), 7.53 (1H, d, J 8), 7.59 (1H, td, J 8 and 1), 7.75 (1H, td, J 8 and 1), 7.83 (1H, dd, J 8 and 1), 8.35-8.39 (2H, m).
Reaction SMILES: [K].[CH3:2][N:3]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]1[CH:11]([CH3:13])[CH3:12].[O:14]=O.Cl>C(O)(C)(C)C.C(OP(OCC)OCC)C.O=P(N(C)C)(N(C)C)N(C)C>[OH:14][C:11]([C:4]1[N:3]([CH3:2])[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=1)([CH3:13])[CH3:12]
Reactant: CC(C)c1ncc([N+](=O)[O-])n1C
Reactant: O=O
Agent: CCOP(OCC)OCC
Agent: Cl
Agent: [K]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CC(C)(C)O
Product: Cn1c([N+](=O)[O-])cnc1C(C)(C)O
Temperature: 0 °C
Yield: 74 %

Procedure:
A total of 21.5 g of potassium were dissolved in 450 ml of tert.-butanol with vigorous stirring and the solution heated to reflux. 300 ml of hexametapol were added to the cooled solution. The mixture was then cooled to -25°, a solution of 42.5 g of 1-methyl-2-isopropyl-5-nitroimidazole in 60 ml of triethylphosphite and 150 ml of hexametapol was added and dry oxygen was conducted through the mixture for 5 hours at -20° to -25° with vigorous stirring. The mixture was poured into a mixture of 1.5 liter of ice-water and 45 ml of 36% hydrochloric acid and extracted six times with 400 ml portions of ether. The combined ether extracts were washed twice with 250 ml portions of water and evaporated. The crude 2-(2-hydroxy-2-propyl)-1-methyl-5-nitroimidazole (40.5 g; 87%) was purified by crystallization from 300 ml of water. There were obtained 30.2 g of pure 2-(2-hydroxy-2-propyl)-1-methyl-5-nitroimidazole, melting point 106°-108° and a second crop of 4.2 g, melting point 102°-105° (total yield 74%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([NH2:16])([C:14]#[N:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:17][C:18]1[CH:26]=[CH:25][C:21]([C:22](Cl)=[O:23])=[CH:20][CH:19]=1.[OH-].[Na+]>ClCCl.C(N(CC)CC)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11]([NH:16][C:22](=[O:23])[C:21]2[CH:25]=[CH:26][C:18]([Cl:17])=[CH:19][CH:20]=2)([C:14]#[N:15])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(N)(C#N)CC1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(C#N)(NC(=O)c2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-amino-4-cyano-piperidine-1-carboxylic acid tert-butyl ester (1.25 g, 5.55 mmol, 1.0 equiv; prepared as described in WO 03/104 236 A1 (Bristol-Myers Squibb Company); [CAS RN 331281-25-5]) in dichlormethane (30 mL) and triethylamine (1.20 mL) was added 4-chloro-benzoyl chloride (1.09 g, 6.21 mmol, 1.12 equiv; commercially available) and the reaction stirred at rt overnight. A solution of 1 M NaOH (10 mL) was added and the reaction mixture extracted with ethyl acetate. The combined organic phases were washed with water and a sat. solution of NaCl, dried over MgSO4 and concentrated by evaporation under reduced pressure. The crude material was crystallized from a mixture of hexane/ethyl acetate yielding 0.71 g (44%) of the title compound as white crystals. 1H NMR (300 MHz, CDCl3): δ 1.46 (s, 9H), 1.85 (t, J=10.2 Hz, 2H), 2.45 (br s, 2H), 3.24 (t, J=11.8 Hz, 2H), 3.99 (br d, J=13.5 Hz, 2H), 6.87 (s, 1H), 7.36 (d, J=8.4 Hz, 2H), 7.69 (d, J=8.4 Hz, 2H). MS (ISP): 364.4 [M+H]+.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([CH:23]=[CH:24][CH:25]=1)[O:7][C:8]1[C:13]([CH2:14][C:15]([O:17][CH3:18])=[O:16])=[C:12]([N:19]([CH3:21])[CH3:20])[N:11]=[C:10]([CH3:22])[N:9]=1)([CH3:3])[CH3:2].C([O:30][N:31]=O)(C)(C)C>COCCOC>[CH:1]([C:4]1[CH:5]=[C:6]([CH:23]=[CH:24][CH:25]=1)[O:7][C:8]1[C:13]([C:14](=[N:31][OH:30])[C:15]([O:17][CH3:18])=[O:16])=[C:12]([N:19]([CH3:21])[CH3:20])[N:11]=[C:10]([CH3:22])[N:9]=1)([CH3:3])[CH3:2]
Reactant: COC(=O)Cc1c(Oc2cccc(C(C)C)c2)nc(C)nc1N(C)C
Reactant: CC(C)(C)ON=O
Solvent: COCCOC
Product: COC(=O)C(=NO)c1c(Oc2cccc(C(C)C)c2)nc(C)nc1N(C)C
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of methyl 4-(3-isopropylphenoxy)-6-dimethylamino-2-methyl-pyrimidin-5-yl-acetate (28 g, 0.08 mol) in t-butylnitrite (40 ml) and 1,2-dimethoxyethane (40 ml) is added at -30° C. to a solution of potassium tert. butylate (14 g, 0.12 mol) in 1,2-dimethoxyethane (50 ml). The reaction mixture is allowed to warm to 0° C. and is the quenched with a solution of ammonium chloride. After stirring for 2 hours at room temperature the product is extracted with diethylether. Drying (MgSO4) and evaporation of the solvent gives crude methyl 2-[4-(3 -isopropylphenoxy)-6-dimethylamino-2-methyl-pyrimidin-5-yl-]-2-hydroximino-acetate (30 g).
Reaction SMILES: [OH:1][C:2]([C:5]([CH3:11])([CH:9]=[CH2:10])[C:6]([OH:8])=[O:7])([CH3:4])[CH3:3].N1C(C)=CC=CC=1C.[C:20]([Si:24]([CH3:27])([CH3:26])Cl)([CH3:23])([CH3:22])[CH3:21]>ClCCl>[C:20]([Si:24]([CH3:27])([CH3:26])[O:1][C:2]([C:5]([CH3:11])([CH:9]=[CH2:10])[C:6]([OH:8])=[O:7])([CH3:4])[CH3:3])([CH3:23])([CH3:22])[CH3:21]
Reactant: C=CC(C)(C(=O)O)C(C)(C)O
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: C=CC(C)(C(=O)O)C(C)(C)O[Si](C)(C)C(C)(C)C
Reaction time: 1 h
Yield: 95.8 %

Procedure:
A cooled (0° C.) solution of 2-(1-hydroxy-1-methyl-ethyl)-2-methyl-but-3-enoic acid (2.0 g, 12.6 mmol) and 2,6-lutidine (13.5 g, 126.4 mmol) in dichloromethane (150 mL) was treated with tert-butyldimethylchlorosilane (16.7 g, 63.2 mmol). After stirring for 1 h, the volatiles were removed in vacuo, the residue was taken in methanol (100 mL) and water (50 mL) and treated with potassium carbonate (20 g). After stirring for 16 h, the volatiles were removed in vacuo, the residue was diluted with water (50 mL), acidified to pH 2 with potassium hydrogen sulfate, and extracted with dichloromethane (3×25 mL). All the organics were combined and the volatiles were removed in vacuo to afford the title compound (3.288 g, 95%) as a clear oil. 1H NMR (300 MHz, CDCl3) δ 0.24 (s, 3H), 0.25 (s, 3H), 0.94 (s, 9H), 1.34 (s, 3H), 1.37 (s, 3H), 1.38 (s, 3H), 5.29 (m, 2H), 6.17 (dd, J=17.6, 10.9 Hz, 1H), 10.99 (br s, 1H).