Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:5][CH2:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16](=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18])=[C:11]([OH:22])[CH:10]=1)=[O:8])([CH3:4])([CH3:3])[CH3:2].C[O-].[Na+].C1([O-])C=CC=CC=1.[Na+].[CH3:34][O:35][C:36]1[CH:37]=[C:38]([CH:42]=[C:43]([O:47][CH3:48])[C:44]=1[O:45][CH3:46])[C:39](Cl)=[O:40]>>[C:1]([NH:5][CH2:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([O:15][C:16](=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18])=[C:11]([O:22][C:39](=[O:40])[C:38]2[CH:37]=[C:36]([O:35][CH3:34])[C:44]([O:45][CH3:46])=[C:43]([O:47][CH3:48])[CH:42]=2)[CH:10]=1)=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1cc(C(=O)Cl)cc(OC)c1OC
Reactant: CC(C)(C)NCC(=O)c1ccc(OC(=O)C(C)(C)C)c(O)c1
Agent: C[O-]
Agent: [Na+]
Agent: [O-]c1ccccc1
Product: COc1cc(C(=O)Oc2cc(C(=O)CNC(C)(C)C)ccc2OC(=O)C(C)(C)C)cc(OC)c1OC

Procedure:
Following a procedure similar to that described in Example 30A above, when 3-hydroxy-4-(pivalyloxy)phenyl tert-butylaminomethyl ketone is interacted with one equivalent of sodium methoxide and the resulting sodium phenolate salt is reacted with 3,4,5-trimethoxybenzoyl chloride there is obtained 3-(3,4,5-trimethoxybenzoyloxy)-4 -(pivalyloxy)phenyl tert-butylaminomethyl ketone which reacts with hydrochloric acid to yield the hydrochloride salt. When this hydrochloride is catalytically hydrogenated, using the procedure described above in Example 30B, there is obtained 3-(3,4,5-trimethoxy benzoyloxy)-4-(pivalyloxy)-alpha-(tert-butylaminomethyl)benzyl alcohol hydrochloride.
Reaction SMILES: [CH3:1][N:2]([CH3:18])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[N:10][CH2:11][CH2:12][C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)=[CH:5][CH:4]=1>C(O)(C(F)(F)F)=O>[CH3:18][N:2]([CH3:1])[C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[C:17]3[CH:16]=[CH:15][S:14][C:13]=3[CH2:12][CH2:11][NH:10]2)=[CH:7][CH:8]=1
Reactant: CN(C)c1ccc(C=NCCc2cccs2)cc1
Solvent: O=C(O)C(F)(F)F
Product: CN(C)c1ccc(C2NCCc3sccc32)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 95.3 %

Procedure:
The above dimethyl-{4-[(2-thiophen-2-yl-ethylimino)-methyl]-phenyl}-amine (1 g, 3.9 mmol) was added TFA (20 mL) at once (strongly exothermic reaction). The reaction mixture was stirred at room temperature for 72 hours, then evaporated in vacuo. The crude oil was suspended in dichloromethane (75 ml) and extracted with 1 N hydrochloric acid (50 ml). The aqueous phase was added 2 N sodium hydroxide to pH=10, then extracted with dichloromethane (3×125 ml). The organic phase was dried with MgSO4, filtered, evaporated in vacuo to afford 0.96 g (95%) of the title compound.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:8]=[CH:7][C:6]=1[OH:15])([CH3:4])([CH3:3])[CH3:2]>O>[C:11]([C:9]1[CH:8]=[C:7]([C:7]2[C:6]([OH:15])=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:10]=[C:9]([C:11]([CH3:12])([CH3:13])[CH3:14])[CH:8]=2)[C:6]([OH:15])=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:10]=1)([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)c1ccc(O)c(C(C)(C)C)c1
Solvent: O
Product: CC(C)(C)c1cc(-c2cc(C(C)(C)C)cc(C(C)(C)C)c2O)c(O)c(C(C)(C)C)c1
Yield: 39 %

Procedure:
A mixture of 24 g (0.1 mol) of 3,3',5,5'-tetramethyldipheno-4,4'-quinone obtained in Example 2 and 52 g (0.25 mol) of 2,4-di-t-butylphenol was boiled in 150 ml of water for 4 hours. The reaction mixture was filtered and dried. Formation of 2,2',6,6'-tetramethyl-4,4'-biphenol and 4,4',6,6'-tetra-t-butyl-2,2'-biphenol was confirmed by GPC and liquid chromatography. 20 g of pure 4,4',6,6'-tetra-t-butyl-2,2'-biphenol were isolated by extraction of hot isooctane and washing by methanol.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[N:4]=[C:5]2[CH2:10][NH:9][CH2:8][CH2:7][N:6]2[CH:11]=1.CCN(C(C)C)C(C)C.[Cl:23][C:24]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:25]=1[C:26](Cl)=[O:27]>ClCCl>[Cl:23][C:24]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:25]=1[C:26]([N:9]1[CH2:8][CH2:7][N:6]2[CH:11]=[C:3]([C:2]([F:12])([F:1])[F:13])[N:4]=[C:5]2[CH2:10]1)=[O:27]
Reactant: O=C(Cl)c1ccc(F)cc1Cl
Reactant: FC(F)(F)c1cn2c(n1)CNCC2
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1ccc(F)cc1Cl)N1CCn2cc(C(F)(F)F)nc2C1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
2-(Trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine (I4) (287 mg, 1.5 mmol) and DIPEA (0.314 mL, 1.800 mmol) were dissolved at 0° C. in dichloromethane (DCM) (15 mL). 2-chloro-4-fluorobenzoyl chloride (290 mg, 1.500 mmol, commercially available from e.g. Sigma-Aldrich, Maybridge or Apollo) dissolved in DCM (5 mL) was added dropwise and the solution stirred to room temperature over 4 h. Solvents were removed in vacuo and the residue was partitioned between dichloromethane (50 mL) and saturated sodium bicarbonate solution (25 mL). The aqueous phase was extracted with dichloromethane (3×50 mL) and the combined extracts were washed with water (50 mL), brine (50 mL), dried over anhydrous sodium sulfate and concentrated in vacuo to afford a crude oil (759 mg). The crude product was purified by flash chromatography (Isolera, 25 g, 0-100% 2M ammonia in methanol:dichloromethane (1:9)/dichloromethane) to afford crude product. Concentration of the waste afforded material which was also identified as product. Samples were combined to afford crude product. This was purified by MDAP, product containing fractions concentrated and loaded directly on to an SCX cartridge (Varian, 10 g). The column was washed with methanol and the product eluted with 2M ammonia methanol. The solvents were evaporated in vacuo to afford the desired product in 318 mg.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([C:14]2[S:23][C:22]3[C:21]4[N:24]=[C:25]([C:28]#[C:29][CH:30]([OH:32])[CH3:31])[CH:26]=[CH:27][C:20]=4[O:19][CH2:18][CH2:17][C:16]=3[CH:15]=2)=[N:12][CH:11]=[N:10]1.ClC1C=CC2OCCC3C=C(C4N(C5C=CC(F)=CC=5F)N=CN=4)SC=3C=2N=1.CC(O)C#C>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([C:14]2[S:23][C:22]3[C:21]4[N:24]=[C:25]([CH2:28][CH2:29][CH:30]([OH:32])[CH3:31])[CH:26]=[CH:27][C:20]=4[O:19][CH2:18][CH2:17][C:16]=3[CH:15]=2)=[N:12][CH:11]=[N:10]1
Reactant: CC(O)C#Cc1ccc2c(n1)-c1sc(-c3ncnn3-c3ccc(F)cc3F)cc1CCO2
Agent: C#CC(C)O
Agent: Fc1ccc(-n2ncnc2-c2cc3c(s2)-c2nc(Cl)ccc2OCC3)c(F)c1
Product: CC(O)CCc1ccc2c(n1)-c1sc(-c3ncnn3-c3ccc(F)cc3F)cc1CCO2
Yield: 38 %

Procedure:
Following the procedures for 246, 4-{2-[2-(2,4-Difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulen-9-yl}-but-3-yn-2-ol was prepared (Yield: 93%. 1H NMR (DMSO-d6, 400 MHz): δ8.32 (s, 1H), 7.93 (dd, J=5.6, 8.4 Hz, 1H), 7.74-7.69 (m, 1H), 7.45-7.40 (m, 2H), 7.33 (d, J=8.0 Hz, 1H), 6.95 (s, 1H), 5.59 (d, J=5.2 Hz, 1H), 4.64 (q, J=5.6, 6.8 Hz, 1H), 4.32 (t, J=4.0 Hz, 2H), 3.13 (t, J=4.4 Hz, 2H), 1.42 (d, J=6.4 Hz, 3H), ESI− MS: (m/z)=451 [M+H]+) from 9-Chloro-2-[2-(2,4-difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1-thia-10-aza-benzo[e]azulene and but-3-yn-2-ol, and hydrogenated to give 244 Yield: 38%. 1H NMR (DMSO-d6, 400 MHz): δ8.26 (s, 1H), 7.89-7.84 (m, 1H), 7.70-7.65 (m, 1H), 7.40 (t, J=8.0 Hz, 1H), 7.28 (d, J=8.4 Hz, 1H), 7.07 (d, J=8.4 Hz, 1H), 7.00 (s, 1H), 4.44 (s, 1H), 4.23 (t, =4.8 Hz, 2H), 3.58-3.56 (m, 1H), 3.13 (t, J=4.8 Hz, 2H), 2.71-2.63 (m, 2H), 1.69-1.61 (m, 2H), 1.05 (d, J=6.4 Hz, 3H). LC-MS (ESI): m/z=455 [M+H]+
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[C:9]([Cl:11])[C:8]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH3:21])=[CH:15][CH:14]=2)=[CH:7][C:6]=1[C@@H:22]1[O:27][C@H:26]([CH2:28][OH:29])[C@@H:25]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C@H:24]([O:38][CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[C@H:23]1[O:46][CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)[CH:2]=[CH2:3].[H-].[Na+].Br[CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][O:62][Si:63]([C:76]([CH3:79])([CH3:78])[CH3:77])([C:70]1[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=1)[C:64]1[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=1>CN(C)C=O>[CH2:1]([O:4][C:5]1[CH:10]=[C:9]([Cl:11])[C:8]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([O:19][CH2:20][CH3:21])=[CH:17][CH:18]=2)=[CH:7][C:6]=1[C@@H:22]1[O:27][C@H:26]([CH2:28][O:29][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][O:62][Si:63]([C:76]([CH3:77])([CH3:79])[CH3:78])([C:70]2[CH:75]=[CH:74][CH:73]=[CH:72][CH:71]=2)[C:64]2[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=2)[C@@H:25]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C@H:24]([O:38][CH2:39][C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)[C@H:23]1[O:46][CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)[CH:2]=[CH2:3]
Reactant: C=CCOc1cc(Cl)c(Cc2ccc(OCC)cc2)cc1[C@@H]1O[C@H](CO)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Reactant: CC(C)(C)[Si](OCCCCCBr)(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCOc1cc(Cl)c(Cc2ccc(OCC)cc2)cc1[C@@H]1O[C@H](COCCCCCO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 41.7 %

Procedure:
To a solution of ((2R,3R,4R,5S,6S)-6-(2-(allyloxy)-4-chloro-5-(4-ethoxybenzyl)phenyl)-3,4,5-tris(benzyloxy)tetrahydro-2H-pyran-2-yl)methanol (16, 1.1 g, 1.51 mmol) in N,N-dimethylformamide (25 mL) was added sodium hydride (60% dispersion in mineral oil, 120.4 mg, 3.01 mmol) at 0° C., and the reaction mixture was stirred at ambient temperature for 0.5 h. After 1 h at room temperature, the reaction mixture was re-cooled to 0° C. and (5-Bromopentyloxy)(tert-butyl)diphenylsilane (27, 980 mg, 2.42 mmol) was added dropwise, and the mixture was stirred with gradual warming to ambient temperature over 5 h. After re-cooling to 0° C., the reaction mixture was quenched by addition of water (25 mL). The mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, filtered and evaporated in vacuo. The resulting crude residue was purified on a Biotage® purification apparatus (silica gel, 5 to 20% tetrahydrofuran in hexanes gradient) to yield the title compound (28, 664 mg, 0.63 mmol, 42%) as yellowish oil.
Reaction SMILES: [Cl:1][C@H:2]1[C@H:6]([CH2:7]/[CH:8]=[CH:9]\[CH2:10][CH2:11][CH2:12][C:13]([O:15][CH2:16][CH:17]=[CH2:18])=[O:14])[C@@H:5]([CH2:19][OH:20])[C@H:4]([O:21][CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][O:23]2)[CH2:3]1.C1C=C[NH+]=CC=1.[O-][Cr](Cl)(=O)=O.C([O-])(=O)C.[Na+]>ClCCl>[Cl:1][C@H:2]1[C@H:6]([CH2:7]/[CH:8]=[CH:9]\[CH2:10][CH2:11][CH2:12][C:13]([O:15][CH2:16][CH:17]=[CH2:18])=[O:14])[C@@H:5]([CH:19]=[O:20])[C@H:4]([O:21][CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][O:23]2)[CH2:3]1
Reactant: C=CCOC(=O)CCC/C=C\C[C@@H]1[C@@H](CO)[C@H](OC2CCCCO2)C[C@H]1Cl
Agent: O=[Cr](=O)([O-])Cl
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: ClCCl
Product: C=CCOC(=O)CCC/C=C\C[C@@H]1[C@@H](C=O)[C@H](OC2CCCCO2)C[C@H]1Cl
Yield: 72.9 %

Procedure:
A solution of 690 mg (1.72 mmol) of alcohol 4 in 4 mL of dichloromethane was added via pipette to a mixture of PCC (650 mg, 3.0 mmol), sodium acetate (325 mg, 3.96 mmol), and Celite (1.23 g) in 7 mL of DCM. The pipette was rinsed with an additional 3 mL of DCM to complete the transfer. The mixture was stirred sealed at 25° C. for 3 h. The mixture was worked up by filtration through 25 g of silica gel and washed with 200 mL of 1:4 EA:hexanes. The filtrate was concentrated in vacuo to yield 500 mg (72% yield) of crude aldehyde 5 as an oil; 1H NMR (CDCl3): 1.45-1.85 (m, 10H), 2.04-3.00 (m, 10H), 3.51 (m, 1H), 3.81 (m, 1H), 4.07 (m, 1H), 4.59 (m, 4H), 5.26 (m, 1H), 5.45 (m, 1H), 5.92 (m, 1H), 9.75 (dd, J=2.1, 9 Hz, 1H).
Reaction SMILES: [C:1]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:5][C:4]([CH:7]=O)=[CH:3][CH:2]=1.FC(F)(F)C([O-])=O.[C:22]([C:25]1[C:26]([NH:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)=[N:27][N:28]([C:30]2([CH2:36][C:37]#[N:38])[CH2:35][CH2:34][NH2+:33][CH2:32][CH2:31]2)[CH:29]=1)(=[O:24])[NH2:23].C(O)(C(F)(F)F)=O>CN(C=O)C>[C:1]1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:5][C:4]([CH2:7][N:33]2[CH2:34][CH2:35][C:30]([N:28]3[CH:29]=[C:25]([C:22]([NH2:23])=[O:24])[C:26]([NH:39][C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)=[N:27]3)([CH2:36][C:37]#[N:38])[CH2:31][CH2:32]2)=[CH:3][CH:2]=1
Reactant: N#CCC1(n2cc(C(N)=O)c(Nc3ccccc3)n2)CC[NH2+]CC1
Reactant: O=Cc1ccc(-c2ccccc2)cc1
Agent: O=C([O-])C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: N#CCC1(n2cc(C(N)=O)c(Nc3ccccc3)n2)CCN(Cc2ccc(-c3ccccc3)cc2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Biphenyl-4-carbaldehyde (12 mg, 0.070 mmol) was treated with a solution of 4-[4-carbamoyl-3-(phenylamino)-1H-pyrazol-1-yl]-4-(cyanomethyl)piperidinium trifluoroacetate (Intermediate #38-2) (20 mg, 0.050 mmol) and TFA (0.020 mL, 0.23 mmol) in DMF (0.65 mL). The resulting solution was then treated with MP-(OAc)3BH (80 mg, 0.16 mmol). The resulting mixture was shaken at ambient temperature for 16 hours on an orbital shaker. The mixture was then filtered through a 0.45 micron fit and the fit was washed with DMSO (1.0 mL). The filtrate was then purified directly by reverse-phase preparative HPLC (using a gradient elution of 5-95% MeCN/water, with 0.1% v/v NH4OH modifier). Desired fractions were identified, combined, and concentrated in vacuo to afford the title compound, Example #21-1.
Reaction SMILES: F[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.[NH:13]1[CH2:17][CH2:16][CH:15]([CH2:18][OH:19])[CH2:14]1>>[OH:19][CH2:18][CH:15]1[CH2:16][CH2:17][N:13]([C:2]2[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=2)[CH2:14]1
Reactant: CCOC(=O)c1ccc(F)cc1
Reactant: OCC1CCNC1
Product: CCOC(=O)c1ccc(N2CCC(CO)C2)cc1

Procedure:
Ethyl 4-fluorobenzoate and pyrrolidin-3-ylmethanol were coupled following the procedure outlined in example 28 to give ethyl 4-[3-(hydroxymethyl)pyrrolidin-1-yl]benzoate. MS (ESI): 250.0 (M+H). A similar reaction sequence as outlined in example 26 was followed using the above alcohol. 1H NMR (500 MHz, DMSO) δ 12.03 (br s, 1H), 7.76 (d, 2H), 7.25 (d, 1H), 7.21 (d, 1H), 6.89 (d, 1H), 6.56 (d, 2H), 6.38 (d, 1H), 4.05-3.95 (m, 2H), 3.90 (s, 2H), 3.56 (dd, 1H), 3.49-3.42 (m, 1H), 3.38 (dd, 1H), 3.27 (dd, 1H), 2.86-2.78 (m, 1H), 2.77 (t, 2H), 2.26-2.17 (m, 1H), 2.00-1.92 (m, 1H), 1.64-1.53 (m, 2H), 0.92 (s, 9H), 0.91 (t, 3H). MS (ESI): 449.1 (M+H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:23][CH2:24][CH2:25][O:26][CH2:27][CH2:28]O)=[C:17]([N+:20]([O-])=O)[CH:18]=3)[N:13]=[CH:12][N:11]=2)=[C:4]([F:30])[CH:3]=1.O.O.NN>CCO.[Ni]>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:23][CH2:24][CH2:25][O:26][CH2:27][CH3:28])=[C:17]([NH2:20])[CH:18]=3)[N:13]=[CH:12][N:11]=2)=[C:4]([F:30])[CH:3]=1
Reactant: O=[N+]([O-])c1cc2c(Nc3cc(Cl)c(Cl)cc3F)ncnc2cc1OCCOCCO
Agent: [Ni]
Agent: NN
Solvent: CCO
Solvent: O
Product: CCOCCOc1cc2ncnc(Nc3cc(Cl)c(Cl)cc3F)c2cc1N
Reaction time: 1 h

Procedure:
Compound 29a is dissolved in a 9:1 mixture of EtOH:H2O at 85° C., a solution of hydrazine monohydrate in a Ra—Ni solution is added and the reaction mixture is stirred for 1 hour. The obtained solution is cooled and thereafter filtered over Celite®. The filtrate is evaporated under reduced pressure to afford Compound 41a.
Reaction SMILES: Br[C:2]1[CH:41]=[N:40][C:5]2[O:6][C:7]([CH3:39])([CH3:38])[C:8](=[O:37])[N:9]([CH:10]3[CH2:15][CH2:14][N:13]([C:16]([C:18]4[CH:23]=[CH:22][C:21]([C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=5[O:30][C@H:31]([CH3:35])[CH2:32][CH2:33][OH:34])=[CH:20][C:19]=4[F:36])=[O:17])[CH2:12][CH2:11]3)[C:4]=2[CH:3]=1.C(=O)([O-])O.[Na+].[CH3:47][N:48](C)C=O>C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].[Zn].[C-]#N.[Zn+2].[C-]#N.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]>[F:36][C:19]1[CH:20]=[C:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[O:30][C@H:31]([CH3:35])[CH2:32][CH2:33][OH:34])[CH:22]=[CH:23][C:18]=1[C:16]([N:13]1[CH2:12][CH2:11][CH:10]([N:9]2[C:8](=[O:37])[C:7]([CH3:39])([CH3:38])[O:6][C:5]3[N:40]=[CH:41][C:2]([C:47]#[N:48])=[CH:3][C:4]2=3)[CH2:15][CH2:14]1)=[O:17]
Reactant: C[C@H](CCO)Oc1ccccc1-c1ccc(C(=O)N2CCC(N3C(=O)C(C)(C)Oc4ncc(Br)cc43)CC2)c(F)c1
Reactant: CN(C)C=O
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: C[C@H](CCO)Oc1ccccc1-c1ccc(C(=O)N2CCC(N3C(=O)C(C)(C)Oc4ncc(C#N)cc43)CC2)c(F)c1
Temperature: 130 °C
Reaction time: 3 h

Procedure:
To an N,N-dimethylformamide solution (3.0 ml) of 7-bromo-1-{1-[(3-fluoro-2′-{[(1R)-3-hydroxy-1-methylpropyl]oxy}biphenyl-4-yl)carbonyl]piperidin-4-yl}-3,3-dimethyl-1H-pyrido[2,3-b][1,4]oxazin-2(3H)-one (135 mg) were added at room temperature 1,1′-bis(diphenylphosphino)ferrocene (239 mg), zinc powder (1.7 mg), zinc cyanide (15.5 mg) and tris(dibenzylideneacetone)dipalladium (19.8 mg), followed by stirring at 130° C. for 3 hours. The reaction solution was poured into a saturated aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The organic layer was washed sequentially with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to afford 1-{1-[(3-fluoro-2′-{[(1R)-3-hydroxy-1-methylpropyl]oxy}biphenyl-4-yl)carbonyl]piperidin-4-yl}-3,3-dimethyl-2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-7-carbonitrile (111 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:17]=[C:16]([C:18](O)=[O:19])[O:15][N:14]=2)=[CH:9][CH:8]=1.C([N:27](C(C)C)CC)(C)C.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.[NH4+].[Cl-]>C(Cl)Cl.CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:17]=[C:16]([C:18]([NH2:27])=[O:19])[O:15][N:14]=2)=[CH:9][CH:8]=1
Reactant: O=C(O)c1cc(-c2ccc(OCc3cccc(F)c3)cc2)no1
Reactant: CCN(C(C)C)C(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCl
Product: NC(=O)c1cc(-c2ccc(OCc3cccc(F)c3)cc2)no1
Temperature: 25 °C
Yield: 20.8 %

Procedure:
3-[4-(3-Fluoro-benzyloxy)-phenyl]-isoxazole-5-carboxylic acid (which may be prepared as described in Preparation of Intermediate 5; 313 mg, 1.0 mmol) and diisopropylethylamine (275 μL, 1.6 mmol) were dissolved in CH2Cl2 (6 mL). N′-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride (160 mg, 3 mmol), 1-hydroxybenzotriazole (180 mg, 1.16 mmol), and NH4Cl (53.5 mg, 3 mmol) were added. The reaction mixture was stirred at room temperature. DMF (6 mL) was added to the heterogeneous reaction mixture and the resulting solution was stirred at room temperature for 48 h. Additional equivalents of NH4Cl, 1-hydroxybenzotriazole, N′-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride, and diisopropylethylamine were added. The reaction mixture was stirred for an additional 48 h, and then purified by chromatography, eluting with 45% EtOAc/hexanes, to give 3-[4-(3-fluoro-benzyloxy)-phenyl]-isoxazole-5-carboxylic acid amide (65 mg, 21%), mp 221-222° C. LRMS (ESI+): m/z [M+H]+ 313.0. Impurity observed at m/z=423. 1H NMR (300 MHz, DMSO-d6) δ ppm 8.34 (s, 1H), 7.98 (s, 1H), 7.84 (d, J=9.2 Hz, 2H), 7.52 (s, 1H), 7.42 (dd, J=8.1, 5.9 Hz, 1H), 7.29 (d, J=7.3 Hz, 2H), 7.15 (d, J=8.8 Hz, 3H), 5.20 (s, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=1[N+:23]([O-])=O.[H][H]>C(N(CC)CC)C.CN(C)C=O.[OH-].[Pd+2].[OH-]>[NH2:23][C:17]1[CH:18]=[C:19]([CH3:22])[CH:20]=[CH:21][C:16]=1[O:15][C:6]1[C:5]2[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=2)[N:9]=[CH:8][CH:7]=1
Reactant: [H][H]
Reactant: COc1cc2nccc(Oc3ccc(C)cc3[N+](=O)[O-])c2cc1OC
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc2nccc(Oc3ccc(C)cc3N)c2cc1OC
Yield: 54.8 %

Procedure:
6,7-Dimethoxy-4-(4-methyl-2-nitrophenoxy)quinoline (480 mg) was dissolved in triethylamine/N,N-dimethylformamide (2 ml/10 ml), and palladium hydroxide (1.2 g) was added to the solution. The mixture was stirred at room temperature in a hydrogen gas atmosphere overnight. The reaction solution was filtered through Celite, and the solvent was removed therefrom by distillation under the reduced pressure. Water was added to the residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by column chromatography using acetone-chloroform to give 4-(2-amino-4-methylphenoxy)-6,7-dimethoxyquinoline (240 mg, yield 55%).
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[C:10]([CH2:15][CH2:16][CH3:17])[CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:18][CH2:19][CH2:20][CH2:21]Br.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[C:2]1([O:1][C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:21][CH2:20][CH2:19][Br:18])=[C:10]([CH2:15][CH2:16][CH3:17])[CH:9]=2)[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCc1cc(Oc2ccccc2)ccc1O
Reactant: BrCCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCCc1cc(Oc2ccccc2)ccc1OCCCBr

Procedure:
A solution of 4-phenoxy-2-propylphenol (12.0 g, 52.60 mmol), 1,3-dibromopropane (31.86 g, 157.81 mmol) and cesium carbonate (18.0 g, 55.23 mmol) in dry DMF (110 mL) was stirred at room temperature overnight. The reaction mixture was partitioned between ethyl acetate and 0.2N HCl. The organic was washed twice with water, then dried over sodium sulfate. The organic was filtered and evaporated to an oil which was chromatographed over silica gel with methylene chloride/hexane (1:1) to afford the title compound.
Reaction SMILES: [OH:1][CH:2]1[NH:6][C:5](=[O:7])[CH2:4][CH2:3]1.[CH2:8](O)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]>>[CH2:8]([O:1][CH:2]1[NH:6][C:5](=[O:7])[CH2:4][CH2:3]1)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: O=C1CCC(O)N1
Reactant: CCCCCCCO
Product: CCCCCCCOC1CCC(=O)N1
Temperature: 60 °C
Reaction time: 4 h

Procedure:
A mixture of 8 g of 5-hydroxy-pyrrolidin-2-one, 100 cm3 of n-heptanol and 4 g of Amberlite IR 120 H is agitated at 60° C. for 4 hours. After filtering and distilling to dryness, 11.9 g of the expected product is obtained, m.p. 52°-54° C., crystallized from hexane.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][CH:8]1[CH2:13][CH2:12][C:11](=[CH2:14])[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].ClC1C=CC=C(C(OO)=[O:24])C=1>>[C:1]([O:5][C:6](=[O:15])[NH:7][CH:8]1[CH2:9][CH2:10][C:11]2([O:24][CH2:14]2)[CH2:12][CH2:13]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C=C1CCC(NC(=O)OC(C)(C)C)CC1
Reactant: O=C(OO)c1cccc(Cl)c1
Product: CC(C)(C)OC(=O)NC1CCC2(CC1)CO2
Yield: 93 %

Procedure:
(4-Methylene-cyclohexyl)-carbamic acid tert-butyl ester (Raju, B. et al, Bioorganic and Medicinal Chemistry Letters 2004, 14(12), 3103-3107) (2.3 g, 10.9 mmol) was treated with 3-chloroperbenzoic acid (70% purity, 3.76 g, 21.8 mmol, uncorrected) according to the method of Example 7 Step B. After work up the title compound was obtained (2.3 g, 93% yield) as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]3[CH2:17][CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13]3)[N:9]=[C:10]([I:11])[C:3]=12.[ClH:25]>CC(C)=O>[ClH:25].[ClH:25].[I:11][C:10]1[C:3]2[C:4](=[N:5][CH:6]=[N:7][C:2]=2[NH2:1])[N:8]([CH:12]2[CH2:17][CH2:16][CH2:15][NH:14][CH2:13]2)[N:9]=1
Reactant: CC(C)(C)OC(=O)N1CCCC(n2nc(I)c3c(N)ncnc32)C1
Agent: Cl
Solvent: CC(C)=O
Product: Nc1ncnc2c1c(I)nn2C1CCCNC1
Temperature: 45 °C
Reaction time: 1.5 h

Procedure:
To a mixture of tert-butyl 3-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-1-piperidinecarboxylate (1.2 g, 0.0027 mol) in acetone (20 mL) was added an aqueous 6N solution of hydrogen chloride (8 mL) at room temperature. The mixture was stirred at 45° C. for 1.5 hours, and then room temperature for 16 hours. The precipitate was filtered and washed with acetone. The solid was dried to give 3-iodo-1-(3-piperidyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine dihydrochloride (1 g, 0.0024 mol). TLC (methanol/dichloromethane=5:95) Rf 0.14 MS: MH+ 345