Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].[C:3]1([CH3:9])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C[NH:11][NH2:12]>O>[NH:11]1[CH:9]=[CH:3][CH:4]=[N:12]1.[C:3]1([CH3:9])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CNN
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: c1cn[nH]c1
Temperature: -10 °C

Procedure:
A 2000-ml three-neck flask was equipped with a dropping funnel and a thermometer and sealed under a nitrogen balloon. Into this flask, 36.0 g of water, 6.4 g of sodium hydroxide, 400 ml of toluene and 24.0 g (0.52 mol) of monomethylhydrazine were placed. The resulting solution was cooled, with stirring, to −10° C. or lower in a low-temperature thermostat whose temperature was set to −15° C. Then, 375 g of the water-washed DFAAE-toluene solution (DFAAE: 0.11 mol) was gradually dropped into the flask through the dropping funnel in such a manner that the inside temperature of the flask did not exceed −10° C. After completion of the dropping, the solution was kept stirred for 1 hour at −12° C. The inside temperature of the flask was then raised to 0° C. The thus-obtained solution was separated with the addition of 400 ml of water. The organic phase was recovered by a separatory funnel and washed with 400 ml of water, thereby yielding 702 g of 9.7 mass % pyrazole-toluene solution.
Reaction SMILES: [CH2:1]([C:6]1[N:11]=[CH:10][C:9]([NH:12][C:13]([C@@H:15]2[CH2:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:17][N:16]2C(OC(C)(C)C)=O)=[O:14])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([C:6]1[N:11]=[CH:10][C:9]([NH:12][C:13]([C@@H:15]2[CH2:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:17][NH:16]2)=[O:14])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCc1ccc(NC(=O)[C@@H]2Cc3ccccc3CN2C(=O)OC(C)(C)C)cn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCCc1ccc(NC(=O)[C@@H]2Cc3ccccc3CN2)cn1
Reaction time: 1.5 h

Procedure:
The crude product from step 1 was dissolved in methylene chloride (6.4 mL) and treated with trifluoroacetic acid (3.6 mL). After stirring for 1.5 hours the reaction was concentrated and the residue was partitioned between methylene chloride and aqueous sodium bicarbonate solution. The organic layer was dried (sodium sulfate) and concentrated to afford a gray-green solid.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([NH:6][C:7](=[O:17])[N:8]2[CH:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[C:4]([C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)[N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.Br[C:77]1[CH:82]=[C:81]([Cl:83])[CH:80]=[CH:79][C:78]=1[N+:84]([O-:86])=[O:85]>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2].CS(C)=O>[Cl:83][C:81]1[CH:80]=[CH:79][C:78]([N+:84]([O-:86])=[O:85])=[C:77]([NH:1][C:2]2[N:10]=[C:9]3[C:5]([NH:6][C:7](=[O:17])[N:8]3[CH:11]3[CH2:12][CH2:13][O:14][CH2:15][CH2:16]3)=[C:4]([C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)[N:3]=2)[CH:82]=1
Reactant: Nc1nc(-c2ccncc2)c2[nH]c(=O)n(C3CCOCC3)c2n1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1Br
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: CS(C)=O
Product: O=c1[nH]c2c(-c3ccncc3)nc(Nc3cc(Cl)ccc3[N+](=O)[O-])nc2n1C1CCOCC1
Temperature: 170 °C
Reaction time: 0.33 h
Yield: 10.7 %

Procedure:
To an oven-dried vial was added 2-amino-6-(pyridin-4-yl)-9-(tetrahydro-2H-pyran-4-yl)-7H-purin-8(9H)-one (68 mg, 0.22 mmol, 1 equiv.) in anhydrous toluene (1 mL), then freshly grounded cesium carbonate (99.4 mg, 0.31 mmol, 1.4 equiv.) with stirring at room temperature under Ar. After 20 min, Pd(OAc)2 (15 mg, 0.02 mmol, 0.1 equiv.), racemic BINAP (20.5 mg, 0.03 mmol, 0.15 equiv.) and 1-bromo-5-chloro-2-nitrobenzene (WO 02/053545 A1) (67.6 mg, 0.29 mmol, 1.3 equiv.) were added as solids, followed by anhydrous DMSO (1 mL). The vial was purged with Ar for 3 min, then closed and heated in a microwave oven at 170° C. for 45 min. The reaction mixture was cooled to room temperature, diluted with ethyl acetate/methylene chloride, filtered through a Nylon 0.45 μm filter, and the filtrate was concentrated in vacuo. The resulting residue was purified using preparative TLC (silica gel, 7.5% methanol in methylene chloride) to give the desired product as a brown solid (11 mg, 11% yield). 1H NMR (300 MHz, CDCl3+CD3OD) δ, ppm: 9.13 (s, 1H), 8.63 (br m, 2H), 8.13 (d, J=8.9 Hz, 1H), 7.83 (br m, 2H), 6.91 (d, J=8.6 Hz, 1H), 4.70-4.50 (m, 1H), 4.10-4.03 (m, 2H), 3.51-3.43 (m, 2H), 2.68-2.65 (m, 2H), 1.71-1.66 (m, 2H); MS (EI) m/z 468.4 (MH)+.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([CH2:11][OH:12])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[CH2:13]([O:20][C:21]1[CH:22]=[C:23](O)[CH:24]=[CH:25][CH:26]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[CH2:13]([O:20][C:21]1[CH:26]=[C:25]([CH:24]=[CH:23][CH:22]=1)[O:12][CH2:11][CH:8]1[CH2:9][CH2:10][C:5]2([O:4][CH2:3][CH2:2][O:1]2)[CH2:6][CH2:7]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: OCC1CCC2(CC1)OCCO2
Reactant: Oc1cccc(OCc2ccccc2)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: c1ccc(COc2cccc(OCC3CCC4(CC3)OCCO4)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.8 %

Procedure:
To a solution of 1,4-dioxaspiro[4.5]dec-8-ylmethanol (946 mg), 3-(benzyloxy)phenol (1 g), and triphenylphosphine (1.57 g) in THF (15 mL) was added azodicarboxylate diethyl (944 μL) under ice-cooling, and the mixture was stirred at room temperature overnight. The reaction liquid was concentrated under reduced pressure, benzene was added to the residue, and insolubles were removed by filtration. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=92/8-85/15) to obtain 8-{[3-(benzyloxy)phenoxy]methyl}-1,4-dioxaspiro[4.5]decane (846 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[NH:10][C:9](=[O:11])[N:8]([C@@H:12]3[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13]3)[C:5]2=[N:6][CH:7]=1.[H-].[Na+].[CH3:26]I>C1COCC1.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[N:10]([CH3:26])[C:9](=[O:11])[N:8]([C@@H:12]3[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13]3)[C:5]2=[N:6][CH:7]=1
Reactant: CI
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](n2c(=O)[nH]c3cc(Cl)cnc32)C1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cn1c(=O)n([C@@H]2CCN(C(=O)OC(C)(C)C)C2)c2ncc(Cl)cc21
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 93.6 %

Procedure:
To a stirred solution of (R)-tert-butyl 3-(6-chloro-2-oxo-1H-imidazo[4,5-b]pyridin-3(2H)-yl)pyrrolidine-1-carboxylate (110 mg, 0.33 mmol) in dry THF (5 mL) was added 60% NaH in oil (20 mg, 0.5 mmol). The mixture was stirred at rt for 5 min and MeI (0.02 mL, 0.33 mmol) was added. The mixture was stirred overnight, diluted with EtOAc (100 mL), washed with brine (2×10 mL) and dried over Na2SO4. Removal of the solvent left an oil (118 mg) which was applied to a 2-g silica SPE cartridge. The cartridge was eluted sequentially with 0, 25, 50, 75 and 100% EtOAc in hexanes (15 mL of each) to afford 5 fractions. Fractions 2 & 3 were pooled and concentrated to give (R)-tert-butyl 3-(6-chloro-1-methyl-2-oxo-1H-imidazo[4,5-b]pyridin-3(2H)-yl)pyrrolidine-1-carboxylate (109 mg, 95%) as a red oil. LC-MS Method 1 tR=1.82 min, m/z=353, 279.
Reaction SMILES: [C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:32]/[O:33][CH2:34][CH2:35]O)/[C:27]([O:29]CC)=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(S(F)(F)[F:43])CC)C>>[C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:32]/[O:33][CH2:34][CH2:35][F:43])/[C:27]([OH:29])=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)/C(=N\OCCO)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: CCN(CC)S(F)(F)F
Product: O=C(O)/C(=N\OCCF)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1

Procedure:
N.m.r. in solvent C: 2.9 (s, 3H), 3.5 (t, 2H), 4.5 t, 2H , 6.65 s, 1H , 7.3 (s, 15H). 6. N.m.r. in solvent C: 3 0 (s, 3H), 3.5-3.7 (m, 4H), 4.3 (m, 2H), 4.7 (m, 2H), 5.1 (d, 1H), 5.9 (d, 1H) 6.8 (s, 1H), 7.4 (s, 15H). 7. N.m.r. in solvent A: 3.4 (s, 2H), 3.9 (d, 1H), 4.4 (d, 1H), 4.8 (s, 2H , 4.9 (d, 1H), 5.7 (d, 1H), 6.8 (s, 1H), 7.2 (s, 15H). 8. The starting material may be prepared as follows. Reaction of ethyl 2-(2-tritylaminothiazol-4-yl)-2-[(Z)-2-hydroxyethoxyimino]acetate with diethylamino sulphur trifluoride and hydrolysis of the resulting ester gave 2-(2-tritylaminothiazol-4-yl)-2[(Z)-2-fluoroethoxyimino]acetic acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[C:8]([CH:10]2[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]2)[CH:7]=[CH:6][C:4]=1[NH2:5].[CH3:17][C:18]1[C:27]2[CH:26]=[N:25][C:24](S(C)=O)=[N:23][C:22]=2[N:21]([C:31]2[CH:32]=[C:33]([NH:37][C:38](=[O:41])[CH:39]=[CH2:40])[CH:34]=[CH:35][CH:36]=2)[C:20](=[O:42])[CH:19]=1.C(N(C(C)C)CC)(C)C.C(O)(C(F)(F)F)=O.CC#N>C(O)(C)(C)C.C(O)(C(F)(F)F)=O.O>[CH3:1][O:2][C:3]1[CH:9]=[C:8]([CH:10]2[CH2:15][CH2:14][N:13]([CH3:16])[CH2:12][CH2:11]2)[CH:7]=[CH:6][C:4]=1[NH:5][C:24]1[N:25]=[CH:26][C:27]2[C:18]([CH3:17])=[CH:19][C:20](=[O:42])[N:21]([C:31]3[CH:32]=[C:33]([NH:37][C:38](=[O:41])[CH:39]=[CH2:40])[CH:34]=[CH:35][CH:36]=3)[C:22]=2[N:23]=1
Reactant: COc1cc(C2CCN(C)CC2)ccc1N
Reactant: C=CC(=O)Nc1cccc(-n2c(=O)cc(C)c3cnc(S(C)=O)nc32)c1
Solvent: CC(C)(C)O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: C=CC(=O)Nc1cccc(-n2c(=O)cc(C)c3cnc(Nc4ccc(C5CCN(C)CC5)cc4OC)nc32)c1
Temperature: 100 °C
Yield: 5.2 %

Procedure:
To a suspension of 2-methoxy-4-(1-methylpiperidin-4-yl)aniline (19b, 363 mg, 1.65 mmol) and N-(3-(5-methyl-2-(methylsulfinyl)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)acrylamide (5b, 300 mg, 0.81 mmol) in tert-butanol (15 mL) at RT was added diisopropylethylamine (0.43 mL, 2.443 mmol). The mixture was heated at 100° C. for 48 h. The reaction mixture was concentrated on the rotovap and the crude residue was suspended in Et2O and filtered. The resulting light yellow amorphous solid was washed with Et2O (3×50 mL) and chromatographed on an ISCO Combiflash RF (40 g Thomson SingleStep column, using a gradient of 0-15% MeOH in DCM) affording enriched product. It was repurifed on a Gilson (Gemini Phenomenex; 30×150 mm, 5 u, 10-95% 0.1% TFA/CH3CN in 0.1% TFA/water), concentrated in the genevac overnight and then passed through a Silicycle SPE-R66030B-20× SiliaSep OT, 5 g/25 mL carbonate column using 20% MeOH/DCM to remove any residual salt then dried under vacuum affording N-(3-(2-((2-methoxy-4-(1-methylpiperidin-4-yl)phenyl)amino)-5-methyl-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)acrylamide (22 mg) as a light yellow solid. m/z (ESI, +ve ion) 525.0 (M+H)+. 1H NMR (400 MHz, DMSO6) δ ppm 10.34 (1H, s), 8.85 (1H, s), 8.16 (1H, s), 7.85 (1H, d, J=9.2 Hz), 7.63 (1H, s), 7.48-7.56 (1H, m), 7.36 (1H, d, J=8.4 Hz), 7.00 (1H, d, J=7.8 Hz), 6.80 (1H, d, J=1.4 Hz), 6.38-6.47 (1H, In), 6.30-6.38 (2H, m), 6.19-6.29 (1H, m), 5.70-5.78 (1H, m), 3.80 (3H, s), 2.84 (2H, d, J=11.2 Hz), 2.47 (3H, s), 2.25-2.36 (1H, m), 2.19 (3H, s), 1.92 (2H, td, J=11.1, 3.7 Hz), 1.52-1.69 (4H, m).
Reaction SMILES: [Si:1]([O:18][CH:19]1[CH2:22][N:21]([C:23]2[O:24][CH:25]=[C:26]([CH2:28][OH:29])[N:27]=2)[CH2:20]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(Cl)Cl.[O-2].[O-2].[Mn+4]>[Si:1]([O:18][CH:19]1[CH2:22][N:21]([C:23]2[O:24][CH:25]=[C:26]([CH:28]=[O:29])[N:27]=2)[CH2:20]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC(C)(C)[Si](OC1CN(c2nc(CO)co2)C1)(c1ccccc1)c1ccccc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: CC(C)(C)[Si](OC1CN(c2nc(C=O)co2)C1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 80 %

Procedure:
To a solution of 3-t-butyldiphenylsilyloxy-1-(4-hydroxymethyl-1,3-oxazol-2-yl)azetidine (3.88 g, 9.50 mmol) (obtained as described in Reference Example 70(9)) in methylene chloride (190 ml) was added activated manganese dioxide (19.4 g) and the mixture was stirred at room temperature for 2 hours. After checking the completion of the reaction, the mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using n-hexane:ethyl acetate (3:1) as the eluant to afford 3-t-butyldiphenylsilyloxy-1-(4-formyl-1,3-oxazol-2-yl)azetidine (3.09 g, yield 80%) as pale yellow crystals.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[S:4][CH2:3][CH:2]1[CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][CH:16]([N:19]2[CH2:23][CH2:22][NH:21][C:20]2=[O:24])[CH2:15][CH2:14]1.I([O-])(=O)(=O)=[O:26].[Na+]>O1CCOCC1.CO.O>[O:26]=[S:4]1[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[O:1][CH:2]([CH2:11][CH2:12][N:13]2[CH2:14][CH2:15][CH:16]([N:19]3[CH2:23][CH2:22][NH:21][C:20]3=[O:24])[CH2:17][CH2:18]2)[CH2:3]1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: O=C1NCCN1C1CCN(CCC2CSc3ccccc3O2)CC1
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Solvent: CO
Product: O=C1NCCN1C1CCN(CCC2CS(=O)c3ccccc3O2)CC1
Temperature: 25 °C

Procedure:
To the solution of 3.47 g of 1-[1-[2-(1,4-benzoxathian-2-yl)-ethyl]-4-piperidyl]-2-imidazolidinone (Example 5, No. 8) in 10 ml of dioxane and 10 ml of methanol, the solution of 2.8 g of sodium metaperiodate in 20 ml of water is added dropwise while stirring at room temperature. After 2 hours the mixture is evaporated, the residue taken up in water and the mixture extracted with methylene chloride. The extract is washed with saturated aqueous sodium chloride, dried, evaporated and the residue recrystalized from isopropanol, to yield the 1-[1-[2-(4-oxo-1,4-benzooxathian-2-yl)-ethyl]-4-piperidyl]-2-imidazolidinone; m.p. 145°.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.Br[CH2:16][C:17]([NH2:19])=[O:18].C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[CH3:1][C:2]1([CH3:14])[C:6]([CH3:7])([CH3:8])[O:5][B:4]([C:9]2[CH:13]=[N:12][N:11]([CH2:16][C:17]([NH2:19])=[O:18])[CH:10]=2)[O:3]1
Reactant: NC(=O)CBr
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CC1(C)OB(c2cnn(CC(N)=O)c2)OC1(C)C

Procedure:
A mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (50 mg, 0.2 mmol), 2-Bromoacetamide (43 mg, 0.31 mmol, Aldrich, Cat. No. 301272), and cesium carbonate (250 mg, 0.77 mmol) in acetonitrile (1 mL) was stirred at 90° C. for 2 h. After cooling it was quenched with water, extracted with ethyl acetate. The extract was washed with water twice, brine once; dried over Na2SO4. After filtration the filtrate was concentrated to yield 45 mg of the product which was directly used in the next step reaction without further purification. LCMS (M+H)+: m/z=252.1
Reaction SMILES: N(C(C)C)C(C)C.C([Li])CCC.[CH3:13][Si:14]([CH3:57])([CH3:56])[CH2:15][CH2:16][O:17][CH2:18][O:19][C:20]1[CH:25]=[C:24]([O:26][CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[CH:23]=[CH:22][C:21]=1[C:35]1[C:36](=[O:55])[O:37][C:38]2[C:43]([C:44]=1[CH3:45])=[CH:42][CH:41]=[C:40]([O:46][CH2:47][O:48][CH2:49][CH2:50][Si:51]([CH3:54])([CH3:53])[CH3:52])[CH:39]=2.[Br:58]Br.C([O-])(O)=O.[Na+].[O-]S([O-])=O.[Na+].[Na+]>CCCCCC.C1COCC1.CCOC(C)=O>[CH3:57][Si:14]([CH3:56])([CH3:13])[CH2:15][CH2:16][O:17][CH2:18][O:19][C:20]1[CH:25]=[C:24]([O:26][CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:32])([CH3:33])[CH3:34])[CH:23]=[CH:22][C:21]=1[C:35]1[C:36](=[O:55])[O:37][C:38]2[C:43]([C:44]=1[CH2:45][Br:58])=[CH:42][CH:41]=[C:40]([O:46][CH2:47][O:48][CH2:49][CH2:50][Si:51]([CH3:54])([CH3:53])[CH3:52])[CH:39]=2
Reactant: BrBr
Reactant: Cc1c(-c2ccc(OCOCC[Si](C)(C)C)cc2OCOCC[Si](C)(C)C)c(=O)oc2cc(OCOCC[Si](C)(C)C)ccc12
Agent: O=C([O-])O
Agent: O=S([O-])[O-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: CCOC(C)=O
Product: C[Si](C)(C)CCOCOc1ccc(-c2c(CBr)c3ccc(OCOCC[Si](C)(C)C)cc3oc2=O)c(OCOCC[Si](C)(C)C)c1
Temperature: -10 °C
Reaction time: 0.25 h

Procedure:
A 250 mL 3-neck round bottom flask was equipped with a magnetic stirrer, a rubber stopper and an argon inlet/outlet adapter. This vessel was charged with THF (20 mL) via syringe, iPr2NH (1.8 mL, 14.0 mmol) via syringe and cooled to −10° C. in an ice/methanol bath. n-Butyl lithium (1.85 M (titrated) via syringe, 6.3 mL, 11.7 mmol) in hexane was added dropwise via syringe at −10° C., stirred for 15 min at −10° C. To the solution was added 3-[2,4-bis-(2-trimethylsilanyl-ethoxymethoxy)-phenyl]-4-methyl-7-(2-trimethylsilanyl-ethoxymethoxy)-chromen-2-one (5.1 g, 7.8 mol) in THF (20 mL) drop-wise via syringe. The mixture was stirred at −10° C. for 2.5 h. This mixture was added dropwise via syringe to a solution of Br2 (0.76 mL, 2 eq) in −78° C. THF (100 mL) via syringe that was contained in a 1-L 3-neck round bottom flask equipped with mechanical stirrer and septum under N2. After the addition was complete, the mixture was stirred for 5 min at −78° C. and then diluted with EtOAc (0.5 L) via syringe, saturated NaHCO3 (50 mL) via syringe and saturated Na2SO3 (100 mL) via syringe. The dry ice/acetone bath was removed and the mixture was allowed to warm to room temperature while stirring. The organic phase was separated and the aqueous phase was back-extracted with EtOAc (2×0.2 L). The combined organic phase was washed with brine (2×0.5 L) and concentrated in vacuo to yield the title compound as a crude semi-solid.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][N:10]=[N:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.ClC1C=CC=C(C(OO)=[O:21])C=1>ClCCl.[Ni].C(O)C>[N:10]1[CH:11]=[CH:12][C:7]([C@H:1]2[CH2:6][CH2:5][CH2:4][CH2:3][C@@H:2]2[OH:21])=[CH:8][N:9]=1
Reactant: C1=C(c2ccnnc2)CCCC1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: [Ni]
Solvent: ClCCl
Solvent: CCO
Product: O[C@H]1CCCC[C@@H]1c1ccnnc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 20.9 %

Procedure:
To a solution of the 4-(cyclohex-1-en-1-yl)pyridazine (0.15 g, 0.94 mmol) prepared in Example 53a in dichloromethane (9.4 mL), 3-chloroperbenzoic acid (0.76 g, 3.09 mmol) was added with cooling on ice, and the reaction solution was stirred at room temperature for 4 hours. A highly polar compound was removed with a silica gel pad (dichloromethane) to yield crude epoxide. A solution of the crude epoxide and Raney nickel in ethanol (3.0 mL) was stirred at 70° C. for 3 hours under a hydrogen atmosphere. The reaction solution was filtered, and the residue was then purified with silica gel chromatography to yield the title compound (35 mg, 31%) as a colorless amorphous solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[N:12][C:11]([N:14]3[CH2:19][CH2:18][CH:17]([N:20](C)[C:21](=O)OC(C)(C)C)[CH2:16][CH2:15]3)=[C:10]([CH3:29])[C:9]=2[CH3:30])=[CH:4][CH:3]=1.Cl>O1CCOCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[N:12][C:11]([N:14]3[CH2:19][CH2:18][CH:17]([NH:20][CH3:21])[CH2:16][CH2:15]3)=[C:10]([CH3:29])[C:9]=2[CH3:30])=[CH:4][CH:3]=1
Reactant: Cc1c(-c2ccc(F)cc2)nnc(N2CCC(N(C)C(=O)OC(C)(C)C)CC2)c1C
Agent: Cl
Solvent: C1COCCO1
Product: CNC1CCN(c2nnc(-c3ccc(F)cc3)c(C)c2C)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.3 %

Procedure:
Treat a solution of tert-butyl 1-(6-(4-fluorophenyl)-4,5-dimethylpyridazin-3-yl)piperidin-4-yl(methyl)carbamate (1.04 g, 2.51 mmol) in 1,4-dioxane (10 mL) with 4 M HCl in 1,4-dioxane (15.0 mL). Stir the resulting mixture at ambient temperature for 2 h. Concentrate the reaction mixture under reduced pressure. Dissolve the residue in MeOH, and pour onto an SCX column (Varian, 10 g). Rinse the column with MeOH and CH2Cl2, and elute the product with a 1:1 mixture of CH2Cl2 and 2 M NH3/MeOH. Concentrate under reduced pressure to afford the title compound as an off-white solid (784 mg, 99%). ES/MS m/z 315.2 (M+1).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].C(O/[CH:12]=[CH:13]/[C:14]1[C:19]([CH3:20])=[CH:18][N:17]=[C:16]([Cl:21])[N:15]=1)CCC.[I-].[NH2:23][N+:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(Cl)Cl>CN(C=O)C.CCOC(C)=O>[Cl:21][C:16]1[N:15]=[C:14]([C:13]2[CH:12]=[N:23][N:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=23)[C:19]([CH3:20])=[CH:18][N:17]=1
Reactant: N[n+]1ccccc1
Reactant: CCCCO/C=C/c1nc(Cl)ncc1C
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1cnc(Cl)nc1-c1cnn2ccccc12
Temperature: 25 °C
Reaction time: 72 h
Yield: 29.6 %

Procedure:
K2CO3 (10.60 g, 76.68 mmol) was added to a mixture of 4-[(E)-2-butoxyethenyl]-2-chloro-5-methylpyrimidine (Intermediate 6, 6.95 g, 30.67 mmol) and 1-aminopyridinium iodide (9.19 g, 41.40 mmol) in DMF (40 mL) at r.t. The resulting dark blue suspension was stirred at r.t. for 3 days (became deep red color) and was then heated at 110° C. for 3 h. The mixture was then cooled, diluted with EtOAc (100 mL) plus a little CH2Cl2. This solution was washed with water (100 mL) and the aqueous wash solution was extracted with EtOAc (100 mL). The combined organic solutions were washed with water (4×100 mL) and sat. brine (50 mL), dried (MgSO4) and concentrated in vacuo. The residue was dissolved in THF (100 mL) and filtered through a 30 g silica pad. The eluted solution was concentrated in vacuo and the residue was washed with −70° C. CH3OH to give the title compound (2.223 g, 30%) as a beige crystalline solid; 1H NMR: 2.53 (3H, s), 7.22 (1H, m), 7.64 (1H, m), 8.53-8.59 (2H, m), 8.70 (1H, s), 8.90 (1H, d); m/z: ES+ MH+ 245.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([CH3:12])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C1C(=O)N([Cl:20])C(=O)C1>C(#N)C>[Cl:20][C:9]1[C:10]([CH3:12])=[CH:11][C:2]([OH:1])=[C:3]([CH:8]=1)[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1ccc(C)cc1O
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC#N
Product: COC(=O)c1cc(Cl)c(C)cc1O
Temperature: 100 °C
Reaction time: 2 h
Yield: 100.2 %

Procedure:
To a solution of methyl 2-hydroxy-4-methylbenzoate (2 g, 12.04 mmol) in acetonitrile (30 mL) was added NCS (1.688 g, 12.64 mmol). The solution was stirred at 100° C. for 2 hours and then cooled. The solvent was removed in vacuo. The residue was redissolved in DCM (20 mL), washed with water (10 mL) and NaHCO3 solution (15 mL), dried over MgSO4 and the solvent removed in vacuo. Purification by column (Si, Isolute, 5% EtOAc/Cyclohexane) gave the title product as a solid (2.42 g, 100% yield).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]([CH:10]=1)=[N:8][N:7]([C:11]1[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=1)[C:6]=2Cl.[OH-:22].[K+]>CO>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6](=[O:22])[N:7]([C:11]3[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=3)[NH:8]2)=[CH:4][CH:3]=1
Reactant: FC(F)(F)c1ccc(-n2nc3cc(Br)ccc3c2Cl)cc1
Reactant: [OH-]
Agent: [K+]
Solvent: CO
Product: O=c1c2ccc(Br)cc2[nH]n1-c1ccc(C(F)(F)F)cc1
Yield: 44 %

Procedure:
A solution of the product of Step 3 (2.4 g, 0.0064 mol) in 1M KOH in MeOH (16 mL) was heated at 150° C. in a sealed tube via microwave irradiation for 15 min. The mixture was then concentrated, diluted with H2O, acidified with 1N HCl and the resulting precipitate collected by filtration to give 1.0 g (44% yield) of product. 1H NMR (360 MHz, CDCl3): 7.37 (1H, dd, J 1.4 and 8.5 Hz), 7.66 (1H, d, 1.4 Hz), 7.73 (1H, d, 8.5 Hz), 7.89 (2H, d, 8.5 Hz), 8.13 (2H, d, 8.5 Hz), 11.0 (1H, s).