Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:16]=[C:17]([CH:22]=[CH:23][N:24]=2)[C:18]([O:20]C)=[O:19])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>CO>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:16]=[C:17]([CH:22]=[CH:23][N:24]=2)[C:18]([OH:20])=[O:19])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1ccnc(NC2CCN(C(=O)OC(C)(C)C)CC2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(Nc2cc(C(=O)O)ccn2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.4 %

Procedure:
To a solution of methyl 2-((1-(tert-butoxycarbonyl)piperidin-4-yl)amino)isonicotinate (230 g, 0.69 mol) in MeOH (1500 mL) was added aq.NaOH (56 g, in 200 mL of water) over 20 min at 0° C. After addition, the mixture was stirred at room temperature for 2 h. MeOH was then removed under reduced pressure and the aqueous solution then pH adjusted to pH=6 by acidifying with the addition of 4N HCl. The resulting precipitate was collected by filtration, washed with water and dried to give the crude product. Three batches were run in parallel and produced a combined crude product weight of 590 g, yield: 89.4%. This crude was used in next step without further purification. LCMS (m/z): 322.2 (M+1).
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][CH:12]=2)[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)C(Cl)=O.[C:27]([O:31][N:32]=[C:33]([C:35]1[CH:40]=[N:39][C:38]([NH2:41])=[CH:37][N:36]=1)[CH3:34])([CH3:30])([CH3:29])[CH3:28].N1C(C)=CC=CC=1C>C(Cl)Cl.CN(C)C=O.O1CCCC1>[C:27]([O:31][N:32]=[C:33]([C:35]1[N:36]=[CH:37][C:38]([NH:41][C:8](=[O:10])[C@@H:7]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][CH:12]=2)[CH2:6][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)=[N:39][CH:40]=1)[CH3:34])([CH3:28])([CH3:29])[CH3:30]
Reactant: CC(=NOC(C)(C)C)c1cnc(N)cn1
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)O)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC(=NOC(C)(C)C)c1cnc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)cc2)cn1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 54.9 %

Procedure:
A solution of 3-cyclopentyl-2(R)-(4-methanesulfonylphenyl)-propionic acid (prepared as in Example 3, 500.0 mg, 1.687 mmol) in methylene chloride (4.2 mL) was cooled to 0° C. The reaction mixture was treated with N,N-dimethylformamide (1 drop) and oxalyl chloride (294 μL, 3.374 mmol). The reaction mixture was stirred at 0° C. for 15 min and then slowly allowed to warm to 25° C. where it was stirred for 3 h. The solution was then concentrated in vacuo. The resulting residue was dissolved in methylene chloride (8.4 mL) and then cooled to 0° C. This cooled solution was then treated dropwise with a solution of 1-(5-amino-pyrazin-2-yl)-ethanone O-tert-butyl-oxime (prepared as in Example 28, 351.4 mg, 1.687 mmol) and 2,6-lutidine (246 μL, 2.109) in tetrahydrofuran (8.4 mL). The reaction mixture was stirred at 0° C. for 30 min and then was allowed to warm to 25° C. where it was stirred overnight. The reaction mixture was then concentrated in vacuo, diluted with ethyl acetate (250 mL), and washed with a 1N aqueous hydrochloric acid solution (3×100 mL) and a saturated aqueous sodium chloride solution (1×300 mL). The organic layer was then dried over sodium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40L, Silica, 1/4 ethyl acetate/hexanes) afforded the N-[5-(1-tert-butoxyimino-ethyl)-pyrazin-2-yl]-3-cyclopentyl-2(R)-(4-methanesulfonyl-phenyl)-propionamide (451.1 mg, 55%) as a yellow foam. This material was re-purified via Biotage chromatography (FLASH 40L, Silica, 5% ethyl acetate/methylene chloride) to afford N-[5-(1-tert-butoxyimino-ethyl)-pyrazin-2-yl]-3-cyclopentyl-2(R)-(4-methanesulfonyl-phenyl)-propionamide (380.4 mg, 46%) as a white foam: mp 81–83° C. (foam to gel); (ES)+-HRMS m/e calcd for C25H34N4O4S (M+H)+ 487.2374, found 487.2377.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][NH:7][CH:8]=1)([O-:3])=[O:2].[O:9]1[CH2:13][CH2:12]OC1=O.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C=O.C(OCC)(=O)C>[N+:1]([C:4]1[CH:5]=[N:6][N:7]([CH2:12][CH2:13][OH:9])[CH:8]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cn[nH]c1
Reactant: O=C1OCCO1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1cnn(CCO)c1
Temperature: 100 °C

Procedure:
A solid mixture of 4-nitro-1H-pyrazole (1 g, 8.84 mmol), 1,3-dioxolan-2-one (3.89 g, 44.2 mmol) and cesium carbonate (2.88 g, 8.84 mmol) was suspended in 20 ml dimethylformamide and the resulting suspension was slowly heated to 100° C. overnight. The mixture was added to 100 ml water and 40 ml ethyl acetate; the separated aqueous layer was extracted with ethyl acetate (30 ml), and the combined organic layers were washed with brine (30 ml), dried with magnesium sulfate, filtered and concentrated. The residue was flash chromatographed (50 mm; 2% methanol/methylene chloride then 4% methanol/methylene chloride) to give the title compound with some residual DMF.
Reaction SMILES: [CH3:1][C:2]([CH3:11])([CH2:7][C:8]([OH:10])=O)[CH2:3][C:4]([OH:6])=[O:5].N1C(C)=CC=[CH:14][C:13]=1C>O1CCCC1.[Pd]>[CH:8]([CH2:7][C:2]([CH3:1])([CH3:11])[CH2:3][C:4]([O:6][CH2:13][CH3:14])=[O:5])=[O:10]
Reactant: Cc1cccc(C)n1
Reactant: CC(C)(CC(=O)O)CC(=O)O
Agent: [Pd]
Solvent: C1CCOC1
Product: CCOC(=O)CC(C)(C)CC=O

Procedure:
40 g of the acid chloride ethyl ester of 3,3-dimethylglutaric acid, prepared in Example 28, are dissolved in 400 ml of tetrahydrofuran. 2 g of 5% palladium-on-charcoal and 22.8 ml of 2,6-lutidine are added and the mixture is hydrogenated at normal pressure and room temperature. When the absorption of hydrogen has ceased, the catalyst is filtered off and the solvent is evaporated off under vacuum. The residue is taken up with water and extracted with ether. The ether phase is washed with a dilute solution of hydrochloric acid in the cold, washed with a solution of sodium bicarbonate in the cold, dried over magnesium sulfate and evaporated under vacuum to give, after distillation of the residue, 18 g of ethyl 4-formyl-3,3-dimethylbutanoate in the form of a liquid with a boiling point b.p.20 of 112°-118° C.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH:7]=O)=[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[O:4][N:3]=1.C(OP([CH2:23][C:24]([O:26]CC)=[O:25])(OCC)=O)C.[H-].[Na+].Cl>CN(C)C=O>[CH3:1][C:2]1[C:6](/[CH:7]=[CH:23]/[C:24]([OH:26])=[O:25])=[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[O:4][N:3]=1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: Cc1noc(-c2ccccc2)c1C=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1noc(-c2ccccc2)c1/C=C/C(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 66.5 %

Procedure:
To a mixture of 3-methyl-5-phenylisoxazole-4-carbaldehyde (4.94 g), ethyl diethylphosphonoacetate (6.53 g) and N,N-dimethylformamide (70 ml) was added sodium hydride (60%, oil, 1.13 g) at 0° C., and the mixture was stirred at room temperature for 3 hr. The reaction mixture was poured into dilute hydrochloric acid, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and a yellow oil was obtained from a fraction eluted with ethyl acetate-hexane (1:4, volume ratio). A mixture of the obtained yellow oil, 2N hydrochloric acid (50 ml) and acetic acid (50 ml) was refluxed for 3 hr. The reaction mixture was concentrated, and water was added to the residue. The obtained colorless crystals were filtrated to give (E)-3-(3-methyl-5-phenyl-4-isoxazolyl)propenoic acid (4.02 g, yield 93%). The crystals were recrystallized from ethyl acetate-hexane. melting point: 173–174° C.
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]2[CH:8]=[C:9]([C:11]3[CH:12]=[N:13][N:14]([CH3:16])[CH:15]=3)[NH:10][C:4]=2[CH:3]=1.Br[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1>CN(C=O)C.C(OCC)(=O)C.O>[Br:1][C:2]1[N:7]=[CH:6][C:5]2[CH:8]=[C:9]([C:11]3[CH:12]=[N:13][N:14]([CH3:16])[CH:15]=3)[N:10]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[C:4]=2[CH:3]=1
Reactant: Cn1cc(-c2cc3cnc(Br)cc3[nH]2)cn1
Reactant: Fc1ccc(CBr)cc1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: Cn1cc(-c2cc3cnc(Br)cc3n2Cc2ccc(F)cc2)cn1
Temperature: 60 °C
Yield: 72.1 %

Procedure:
6-bromo-2-(1-methyl-1H-pyrazol-4-yl)-1H-pyrrolo[3,2-c]pyridine (Preparation 22, 50 mg, 0.18 mmol) was dissolved in dry DMF (1 ml). The solution was degassed and a solution of sodium bis(trimethylsilyl)amide (0.27 ml of a 1M solution in THF, 0.27 mmol) was added. After 20 minutes reaction, 1-(bromomethyl)-4-fluorobenzene (51 mg, 0.27 mmol) was added and the reaction heated to 60° C. for 3 hours. The reaction was cooled to room temperature and diluted with ethyl acetate and water. The organic solution was washed with brine, dried over sodium sulphate and concentrated in vacuum. The crude product was purified on silica gel column chromatography eluting with 20% hexane in ethyl acetate to afford the title compound as white foam (50 mg, 71.9%). 1H-NMR (500 MHz, CDCl3) 3.92 (s, 3H), 5.31 (s, 2H), 6.62 (s, 1H), 6.93 (m, 2H), 7.02 (m, 2H), 7.27 (s, 1H), 7.39 (s, 1H), 7.51 (s, 1H), 8.63 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([S:15]([CH3:18])(=[NH:17])=[O:16])=[CH:11][CH:10]=2)=[N:6][CH:7]=1.C(N(CC)CC)C.[SH:27][CH:28]([CH2:31][CH3:32])[CH2:29][OH:30]>CN(C)C=O>[Br:1][C:2]1[C:3]([S:27][CH:28]([CH2:29][OH:30])[CH2:31][CH3:32])=[N:4][C:5]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([S:15]([CH3:18])(=[NH:17])=[O:16])=[CH:11][CH:10]=2)=[N:6][CH:7]=1
Reactant: CS(=N)(=O)c1ccc(Nc2ncc(Br)c(Cl)n2)cc1
Reactant: CCC(S)CO
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCC(CO)Sc1nc(Nc2ccc(S(C)(=N)=O)cc2)ncc1Br
Temperature: 25 °C
Reaction time: 18 h
Yield: 59.1 %

Procedure:
362 mg of (RS)-S-{4-[(5-bromo-4-chloropyrimidin-2-yl)amino]phenyl}-S-methyl sulfoximide is dissolved in 1.5 ml of dimethylformamide, mixed with 0.5 ml of triethylamine and 320 mg of (RS)-2-mercapto-butan-1-ol and stirred for 18 hours at room temperature. The mixture is evaporated to the dry state in a vacuum and purified by flash chromatography (dichloromethane/ethanol). 255 mg of the product with a melting point of 175-180° C. is obtained.
Reaction SMILES: [I-].[CH3:2][C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[C:6]([O:12][CH3:13])=[CH:5][C:4]=1[C:14]1[CH:19]=[CH:18][N+:17]([CH2:20][CH2:21][CH3:22])=[CH:16][CH:15]=1.[BH4-].[Na+]>CO.CCOC(C)=O>[CH3:2][C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[C:6]([O:12][CH3:13])=[CH:5][C:4]=1[C:14]1[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][CH3:22])[CH2:16][CH:15]=1
Reactant: CCC[n+]1ccc(-c2cc(OC)c([N+](=O)[O-])cc2C)cc1
Agent: [BH4-]
Agent: [I-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: CCCN1CC=C(c2cc(OC)c([N+](=O)[O-])cc2C)CC1
Reaction time: 2 h
Yield: 96 %

Procedure:
To 4-[2-methyl-5-(methyloxy)-4-nitrophenyl]-1-propylpyridinium iodide (1.04 g, 2.51 mmol) in 25 mL of MeOH at 0° C. was added, NaBH4 (0.284 g, 7.53 mmol) over 1 h. The mixture was allowed to come to rt over 2 h. The solvent was reduced to approximately 5 mL and then diluted with EtOAc, washed with conc. NaHCO3, dried (Na2SO4), filtered, rotovaped down, and purified by flash chromatography to give the title compound of step C (0.7 g, 2.41 mmol, 96%). 1H NMR (400 MHz, DMSO-d6) δ ppm 7.71 (s, 1H), 7.00 (s, 1H), 5.61-5.67 (m, 1H), 3.87 (s, 3H), 2.98-3.07 (m, 2H), 2.60 (t, J=5.50 Hz, 2H), 2.28-2.37 (m, 4H), 2.20 (s, 3H), 1.43-1.53 (m, 2H), 0.87 (t, J=7.52 Hz, 3H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH:12]=[C:11]([CH2:13][NH:14][C:15]([C:17]3[S:18][C:19]([Cl:22])=[CH:20][CH:21]=3)=[O:16])[N:10]=[CH:9]2)=[N:6][CH:7]=1.[OH:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1.CNCCNC.C([O-])([O-])=O.[K+].[K+]>CS(C)=O.O1CCOCC1.[Cu]I>[Cl:22][C:19]1[S:18][C:17]([C:15]([NH:14][CH2:13][C:11]2[N:10]=[CH:9][N:8]([C:5]3[CH:4]=[CH:3][C:2]([N:25]4[CH:26]=[CH:27][CH:28]=[CH:29][C:24]4=[O:23])=[CH:7][N:6]=3)[CH:12]=2)=[O:16])=[CH:21][CH:20]=1
Reactant: O=C(NCc1cn(-c2ccc(Br)cn2)cn1)c1ccc(Cl)s1
Reactant: Oc1ccccn1
Agent: [Cu]I
Agent: CNCCNC
Agent: O=C([O-])[O-]
Solvent: CS(C)=O
Solvent: C1COCCO1
Product: O=C(NCc1cn(-c2ccc(-n3ccccc3=O)cn2)cn1)c1ccc(Cl)s1
Temperature: 110 °C
Yield: 6.6 %

Procedure:
A mixture of N-((1-(5-bromopyridin-2-yl)-1H-imidazol-4-yl)methyl)-5-chlorothiophene-2-carboxamide (42 mg, 0.11 mmol), 2-hydroxypyridine (40 mg, 0.42 mmol), N,N′-dimethylethylenediamine (0.035 mL, 0.32 mmol) and K2CO3 (52 mg, 0.38 mmol) in DMSO (1 mL) and dioxane (1 mL) was degassed with Argon before being charged with CuI (23 mg, 0.12 mmol). The mixture was heated at 110° C. overnight in a sealed tube. It was then purified by HPLC to give the title compound (3 mg). MS found for C19H14ClN5O2S: 412.2 and 414.2 (M+H, Cl pattern).
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]2[C:3]1=[O:12].Br[CH2:14][CH:15]=[CH:16][C:17]1[CH:22]=[CH:21][C:20]([Br:23])=[CH:19][CH:18]=1>CN1CCCC1=O>[Br:23][C:20]1[CH:21]=[CH:22][C:17]([CH:16]=[CH:15][CH2:14][O:1][N:2]2[C:3](=[O:12])[C:4]3=[CH:11][CH:10]=[CH:9][CH:8]=[C:5]3[C:6]2=[O:7])=[CH:18][CH:19]=1
Reactant: BrCC=Cc1ccc(Br)cc1
Reactant: O=C1c2ccccc2C(=O)N1O
Solvent: CN1CCCC1=O
Product: O=C1c2ccccc2C(=O)N1OCC=Cc1ccc(Br)cc1
Temperature: 20 °C
Reaction time: 96 h
Yield: 86.8 %

Procedure:
18.5 g (0.11 mol) of N-hydroxyphthalimide and 31.4 g (0.11 mol) of 1-bromo-[3-(4-bromophenyl)]-prop-2-ene were added in succession to 350 ml of dry N-methylpyrrolidone, after which 12.1 g (0.12 mol) of triethylaminewere added dropwise at room temperature. The reaction mixture was stirred for four days at 20° C. and then poured onto 1.5 l of ice water, and the product was filtered off and washed with water and isopropanol. Yield: 86.8%; mp.: 161°-162° C.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([P:8](=[O:15])([O:12][CH2:13][CH3:14])[O:9][CH2:10][CH3:11])[CH:5]=[CH:6][CH:7]=1.[OH:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O.CCOC(C)=O>[CH2:10]([O:9][P:8]([C:4]1[CH:3]=[C:2]([C:21]2[CH:22]=[CH:23][C:18]([CH2:17][OH:16])=[CH:19][CH:20]=2)[CH:7]=[CH:6][CH:5]=1)(=[O:15])[O:12][CH2:13][CH3:14])[CH3:11]
Reactant: CCOP(=O)(OCC)c1cccc(I)c1
Reactant: OCc1ccc(B(O)O)cc1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Product: CCOP(=O)(OCC)c1cccc(-c2ccc(CO)cc2)c1
Reaction time: 18 h

Procedure:
To the product of Step 1 (680 mg, 2 mmol) in toluene (10 mL)—H2O (3 mL)—n Propanol (3 mL) were added 4-hydroxymethyl phenyl boronic acid (607 mg, 4 mmol), tris(dibenzylidene acetone)dipalladium (92 mg, 0.1 mmol), triphenylphosphine (209 mg, 0.8 mmol) and EtNH (175 mg, 2.4 mmol). After a period of 18 h at 90° C., the reaction mixture was partionned between EtOAc and H2O. The organic phase was separated, dried over NaSO4, filtered and evaporated under reduced pressure. The title compound was obtained after flash chromatography (446 mg, 69%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:32])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:23]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:22][C:21]([NH2:30])=[C:20]([OH:31])[N:19]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.Cl[CH2:43][C:44](Cl)=[O:45]>C(Cl)Cl>[C:1]([O:5][C:6](=[O:32])[NH:7][C:8]1([C:12]2[CH:13]=[CH:14][C:15]([C:18]3[C:23]([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)=[CH:22][C:21]4[NH:30][C:44](=[O:45])[CH2:43][O:31][C:20]=4[N:19]=3)=[CH:16][CH:17]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc(O)c(N)cc3-c3ccccc3)cc2)CCC1
Reactant: O=C(Cl)CCl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)NC(=O)CO4)cc2)CCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 42 %

Procedure:
To a solution of tert-butyl(1-(4-(5-amino-6-hydroxy-3-phenylpyridin-2-yl)phenyl)cyclobutyl)carbamate (1.8 g, 4.17 mmol), DIPEA (3.63 ml, 20 mmol) in DCM (100 ml) at 0° C. was added a solution of chloroacetyl chloride (0.465 ml) in DCM (20 ml). The resulting mixture was stirred at room temperature for 16 h. The reaction mixture was concentrated to dryness under reduced pressure. To the residue was added MIBK (120 ml) and saturated sodium bicarbonate (120 ml). The resulting mixture was heated at 115° C. for 16 h. After cooled down to room temperature, the MIBK was removed under reduced pressure. The residue was extracted with ethyl acetate (75 ml). The layers were separated and the aqueous phase extracted into ethyl acetate (2×50 ml). The combined organic phases were washed with water (150 ml) and brine (150 ml), dried over Na2SO4, filtered and concentrated to dryness under reduced pressure. The resulting residue was purified by Biotage silica gel chromatography (gradient 0 to 2% methanol in DCM) to give the title compound (0.82 g, 42%). LCMS (Method A): RT=6.55 min, M+1=472. 1H NMR (500 MHz, CDCl3): 7.3-7.0 (10H, m), 4.96 (1H, br), 4.82 (2H, s), 2.55-2.25 (4H, m), 2.1-1.9 (1H, m), 1.8-1.65 (1H, m), 1.35-1.1 (9H, br).
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([O:11][CH:12]([CH3:14])[CH3:13])[C:8]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)=[C:7]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=2[Cl:29])[N:6]=1)(=O)=O.[H-].[Na+].[F:32][C:33]1[CH:34]=[C:35]([CH:38]=[CH:39][C:40]=1[F:41])[CH2:36][OH:37]>>[F:32][C:33]1[CH:34]=[C:35]([CH:38]=[CH:39][C:40]=1[F:41])[CH2:36][O:37][C:5]1[N:10]=[C:9]([O:11][CH:12]([CH3:14])[CH3:13])[C:8]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)=[C:7]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=2[Cl:29])[N:6]=1
Reactant: OCc1ccc(F)c(F)c1
Reactant: CC(C)Oc1nc(S(C)(=O)=O)nc(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Product: CC(C)Oc1nc(OCc2ccc(F)c(F)c2)nc(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1

Procedure:
2-(Methylsulfonyl)-4-isopropyloxy-5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)pyrimidine (LRf from Example 126) was reacted with 2 equivalents each of sodium hydride and 3,4-difluorobenzyl alcohol by the procedure described in Example 16 to afford the title compound: HPLC/MS: m/e=535 (M++1); Rt=4.99 min. 1H-NMR 500 MHz (CDCl3): δ 1.45 (d, J=8 Hz, 6H), 5.28-5.35 (m, 1H), 5.22 (s, 2H), 7.02-7.21 (m, 9H), 7.35 (d, J=2 Hz, 1H).
Reaction SMILES: CO.[OH-].[Na+].[CH3:5][C:6]1([CH3:17])[CH:8]([CH2:9][C:10](Cl)([Cl:12])[Cl:11])[CH:7]1[C:14]([OH:16])=[O:15]>O>[CH3:5][C:6]1([CH3:17])[CH:8]([CH:9]=[C:10]([Cl:12])[Cl:11])[CH:7]1[C:14]([OH:16])=[O:15]
Reactant: CC1(C)C(CC(Cl)(Cl)Cl)C1C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC1(C)C(C=C(Cl)Cl)C1C(=O)O
Yield: 86.2 %

Procedure:
To 120 ml of methanol solution containing 4.8 g of sodium hydroxide were added 11.1 g of 2,2-dimethyl-3-(2',2',2'-trichloroethyl)-cyclopropanecarboxylic acid (purity: 91.8%, cis/trans ratio: 82.8/17.2) to heat the resulting mixture for 37 hours under reflux. The mixture was diluted with water and neutral part was removed by extraction with ether. The water layer was acidified with conc. hydrochloric acid and extracted with ether. The ether layer was concentrated to obtain 8.15 g of 2,2-dimethyl-3-(2',2'-dichlorovinyl)-cyclopropanecarboxylic acid, cis/trans ratio 79.8/20.2, purity 92.4%, yield 86.8%.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:13]=[C:14]4[C:20]([C:21](O)=[O:22])=[CH:19][NH:18][C:15]4=[N:16][CH:17]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.Cl.[NH2:25][C:26]1([CH3:40])[CH2:31][CH2:30][CH:29]([NH:32][C:33](=[O:39])[O:34][C:35]([CH3:38])([CH3:37])[CH3:36])[CH2:28][CH2:27]1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C1C=CN=CC=1)C.CN(C=O)C>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:13]=[C:14]4[C:20]([C:21]([NH:25][C:26]5([CH3:40])[CH2:31][CH2:30][CH:29]([NH:32][C:33](=[O:39])[O:34][C:35]([CH3:37])([CH3:36])[CH3:38])[CH2:28][CH2:27]5)=[O:22])=[CH:19][NH:18][C:15]4=[N:16][CH:17]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1
Reactant: CC1(N)CCC(NC(=O)OC(C)(C)C)CC1
Reactant: Cn1nc(-c2cnc3[nH]cc(C(=O)O)c3n2)c2ccc(F)cc21
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1nc(-c2cnc3[nH]cc(C(=O)NC4(C)CCC(NC(=O)OC(C)(C)C)CC4)c3n2)c2ccc(F)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.9 %

Procedure:
A mixture of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (0.08 g, 0.26 mmol), tert-butyl 4-amino-4-methylcyclohexylcarbamate hydrochloride (0.07 g, 0.26 mmol), EDCI (0.076 g, 0.4 mmol), DMAP (0.05 g, 0.4 mmol), HOBT (0.054 g, 0.4 mmol) and DIPEA (0.206 g, 1.6 mmol) in 20 mL of DMF was stirred at room temperature overnight. The solvent was removed under reduced pressure and the residue was passed through a pad of silica gel (200-300 mesh, eluting with a mixture of petroleum ether and ethyl acetate (4:1, v/v) to give tert-butyl 4-(2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamido)-4-methylcyclohexylcarbamate (0.065 g, 49%) as a white solid which was used for the next step without further purification. MS: (M+H)+=522.2.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]2[C:8](I)=[N:9][N:10]([C:11]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:4]=2[CH:3]=1.C(CC(=O)C)(=O)C.C(=O)([O-])[O-].[Cs+].[Cs+].[OH-].[NH4+:45]>CN(C=O)C.[Cl-].[Na+].O.CC(CC(C)=O)=O.CC(CC(C)=O)=O.[Cu].CCOC(C)=O>[Cl:1][C:2]1[N:7]=[CH:6][C:5]2[C:8]([NH2:45])=[N:9][N:10]([C:11]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:4]=2[CH:3]=1
Reactant: [NH4+]
Reactant: Clc1cc2c(cn1)c(I)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: CC(=O)CC(C)=O
Solvent: CCOC(C)=O
Product: Nc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(Cl)ncc12
Temperature: 60 °C

Procedure:
A mixture of 6-chloro-3-iodo-1-trityl-1H-pyrazolo[4,3-c]pyridine (Intermediate 1C; 5.0 g, 9.58 mmol), acetylacetone (0.979 mL, 9.58 mmol), cupric acetylacetonate (0.251 g, 0.958 mmol), and cesium carbonate (6.24 g, 19.17 mmol) in DMF (25.2 mL) were charged in a sealed vessel. The system was degassed and ammonium hydroxide (13.33 mL, 96 mmol) was added. The reaction was heated at 60° C. for 16 h. The reaction was then poured into a solution of 10% NH4OH aq. (150 mL), brine (50 mL), and EtOAc (75 mL). The layers were separated and the aqueous phase was extracted with EtOAc (75 mL). The combined organic layers were washed with brine, dried over Na2SO4, and evaporated in vacuo. The residue was purified by flash chromatography (0-45% EtOAc/Hexanes) to afford 6-chloro-1-trityl-1H-pyrazolo[4,3-c]pyridin-3-amine. MS ESI calc'd. for C25H19ClN4 [M+1]+ 411. found 411.
Reaction SMILES: [CH2:1]([C:3]1[N:8]=[CH:7][N:6]=[C:5](O)[C:4]=1[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH3:2].P(Cl)(Cl)([Cl:17])=O.[OH-].[Na+]>O>[Cl:17][C:5]1[C:4]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:3]([CH2:1][CH3:2])[N:8]=[CH:7][N:6]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)c1c(O)ncnc1CC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCOC(=O)c1c(Cl)ncnc1CC
Temperature: 90 °C
Reaction time: 3 h
Yield: 43.8 %

Procedure:
Ethyl 6-ethyl-4-hydroxypyrimidine-5-carboxylate (7.30 g, 37.21 mmol) was stirred under ice-cooling. Phosphorus oxychloride (11.41 g, 74.41 mmol) was added dropwise to it. After the addition, the mixture was stirred at 90° C. for 3 hours. After cooling to room temperature, the mixture was poured into ice-cooled water and adjusted to pH 10 with an aqueous solution of sodium hydroxide. The resulting mixture was extracted with methylene chloride and dried over magnesium sulfate, and the solvent was evaporated. The residue was purified by column chromatography on silica gel eluting with n-hexane/ethyl acetate (=8/2) to give the desired ethyl 4-chloro-6-ethylpyrimidine-5-carboxylate (3.50 g, 44%).