Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@H:6]([C:10]([N:12]1[C@@H:16]([CH3:17])[CH2:15][CH2:14][C@H:13]1[C:18]1[NH:22][C:21]2[C:23]3[C:28]([CH:29]=[CH:30][C:20]=2[N:19]=1)=[CH:27][C:26]1[C:31]2[C:36]([CH2:37][O:38][C:25]=1[CH:24]=3)=[CH:35][C:34]([C:39]1[NH:43][C:42]([C@@H:44]3[CH2:48][C@H:47]([CH2:49][O:50][CH3:51])[CH2:46][N:45]3C(OC(C)(C)C)=O)=[N:41][CH:40]=1)=[CH:33][CH:32]=2)=[O:11])[CH:7]([CH3:9])[CH3:8])=[O:4].[CH3:59][O:60][C@H:61]([CH3:71])[C@H:62]([NH:66][C:67]([O:69][CH3:70])=[O:68])[C:63]([OH:65])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>Cl.CCO.CN(C=O)C>[CH3:59][O:60][C@@H:61]([CH3:71])[C@H:62]([NH:66][C:67]([O:69][CH3:70])=[O:68])[C:63]([N:45]1[CH2:46][C@@H:47]([CH2:49][O:50][CH3:51])[CH2:48][C@H:44]1[C:42]1[NH:43][C:39]([C:34]2[CH:35]=[C:36]3[CH2:37][O:38][C:25]4[CH:24]=[C:23]5[C:28]([CH:29]=[CH:30][C:20]6[N:19]=[C:18]([C@@H:13]7[CH2:14][CH2:15][C@H:16]([CH3:17])[N:12]7[C:10](=[O:11])[C@@H:6]([NH:5][C:3](=[O:4])[O:2][CH3:1])[CH:7]([CH3:9])[CH3:8])[NH:22][C:21]=65)=[CH:27][C:26]=4[C:31]3=[CH:32][CH:33]=2)=[CH:40][N:41]=1)=[O:65]
Reactant: COC[C@H]1C[C@@H](c2ncc(-c3ccc4c(c3)COc3cc5c(ccc6nc([C@@H]7CC[C@H](C)N7C(=O)[C@@H](NC(=O)OC)C(C)C)[nH]c65)cc3-4)[nH]2)N(C(=O)OC(C)(C)C)C1
Reactant: COC(=O)N[C@H](C(=O)O)[C@@H](C)OC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCO
Solvent: CN1CCOCC1
Product: COC[C@H]1C[C@@H](c2ncc(-c3ccc4c(c3)COc3cc5c(ccc6nc([C@@H]7CC[C@H](C)N7C(=O)[C@@H](NC(=O)OC)C(C)C)[nH]c65)cc3-4)[nH]2)N(C(=O)[C@@H](NC(=O)OC)[C@H](C)OC)C1
Reaction time: 3 h
Yield: 58.6 %

Procedure:
Tert-butyl (2S,4S)-2-[5-(2-{(2S,5S)-1-[N-(methoxycarbonyl)-L-valyl]-5-methylpyrrolidin-2-yl}-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-9-yl)-1H-imidazol-2-yl]-4-(methoxymethyl)pyrrolidine-1-carboxylate (119 mg, 0.15 mmol) in 1.25 N HCl in EtOH (3 mL) was heated to 50° C. for 3h and then concentrated under reduced pressure. The crude residue was treated with (2S,3R)-3-methoxy-2-(methoxycarbonylamino)butanoic acid (43 mg, 0.23 mmol), HATU (63 mg, 0.17 mmol) and DMF (2 mL), then N-methylmorpholine (0.050 mL, 0.45 mmol) was added dropwise. After 3 hr, the mixture was quenched with 1N HCl (0.100 mL) and then purified by HPLC to afford methyl {(2S)-1-[(2S,5S)-2-(9-{2-[(2S,4S)-1-{(2S,3S)-3-methoxy-2-[(methoxycarbonyl)amino]butanoyl}-4-(methoxymethyl)pyrrolidin-2-yl]-1H-imidazol-5-yl}-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl)-5-methylpyrrolidin-1-yl]-3-methyl-1-oxobutan-2-yl}carbamate (76 mg, 59%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5](I)=[C:4]([CH3:10])[N:3]=1.[CH3:11][O:12][C:13]1[CH:18]=[C:17]([CH2:19][C:20]#[CH:21])[CH:16]=[C:15]([O:22][CH3:23])[C:14]=1[O:24][CH3:25]>>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([C:21]#[C:20][CH2:19][C:17]2[CH:16]=[C:15]([O:22][CH3:23])[C:14]([O:24][CH3:25])=[C:13]([O:12][CH3:11])[CH:18]=2)=[C:4]([CH3:10])[N:3]=1
Reactant: C#CCc1cc(OC)c(OC)c(OC)c1
Reactant: Cc1nc(N)nc(N)c1I
Product: COc1cc(CC#Cc2c(C)nc(N)nc2N)cc(OC)c1OC
Yield: 85.3 %

Procedure:
2,4-Diamino-5-iodo-6-methylpyrimidine (250 mg) was allowed to react with 1,2,3-Trimethoxy-5-(prop-2-ynyl)benzene (412 mg) as per the general procedure to afford 2,4-Diamino-5-(3-(3,4,5-trimethoxyphenyl)prop-1-ynyl)-6-methylpyrimidine as a white powder (280 mg, 85%): Rf=0.31 (9:1, CHCl3:MeOH); mp=164-166° C.; 1H NMR (DMSO-d6) δ 6.72 (s, 2H), 6.42 (s, 2H), 3.85 (s, 2H), 3.76 (s, 6H), 3.63 (s, 3H), 2.24 (s, 3H); 13C NMR (DMSO-d6) δ 165.0, 164.3, 159.7, 152.8, 135.9, 132.8, 105.0, 96.3, 89.3, 75.8, 60.0, 55.8, 25.7, 21.7; HRFAB[M+Li]335.1679 (calculated C17H20N4O3Li: 335.1695).
Reaction SMILES: [CH3:1][N:2]=[C:3]=[O:4].[Cl:5][C:6]([O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[S:16]([NH2:19])(=[O:18])=[O:17])=[CH:7][Cl:8].C(N(CC)CC)C>C(Cl)Cl>[Cl:5][C:6]([O:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[S:16]([NH:19][C:3]([NH:2][CH3:1])=[O:4])(=[O:17])=[O:18])=[CH:7][Cl:8]
Reactant: CN=C=O
Reactant: NS(=O)(=O)c1ccccc1OC(Cl)=CCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CNC(=O)NS(=O)(=O)c1ccccc1OC(Cl)=CCl
Yield: 96 %

Procedure:
1.9 g of methyl isocyanate are added to a suspension of 6.7 g of 2-(1,2-dichlorovinyloxy)phenylsulfonamide in 50 ml of methylene chloride. 3.3 g of triethylamine are added dropwise to this mixture at 20° to 25° C. in the course of 10 minutes, a clear solution being formed. Stirring of this solution is continued for a further hour, and the solution is then evaporated to dryness. The residue is dissolved in 5% aqueous sodium carbonate solution and acidified with 10% hydrochloric acid, whereupon the product precipitates as crystals. After filtration and drying, 7.8 g of N-[2-(1,2-dichlorovinyloxy)phenylsulfonyl]-N'-methylurea are obtained. Melting point: 228°-229° C.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].C([O-])([O-])=O.[K+].[K+].[C:15]([C:17]1[CH:18]=[C:19]([S:24]([NH:27][C:28]2[S:32][N:31]=[CH:30][N:29]=2)(=[O:26])=[O:25])[CH:20]=[CH:21][C:22]=1F)#[N:16].Cl>CN(C=O)C>[C:15]([C:17]1[CH:18]=[C:19]([S:24]([NH:27][C:28]2[S:32][N:31]=[CH:30][N:29]=2)(=[O:26])=[O:25])[CH:20]=[CH:21][C:22]=1[O:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[I:1])#[N:16]
Reactant: Oc1ccccc1I
Reactant: N#Cc1cc(S(=O)(=O)Nc2ncns2)ccc1F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1cc(S(=O)(=O)Nc2ncns2)ccc1Oc1ccccc1I
Temperature: 80 °C
Yield: 88.7 %

Procedure:
To a solution of 2-iodophenol (6.0 mmol, 1320 mg) and K2CO3 (10.5 mmol, 1450 mg) in DMF (15.0 mL) was added 3-cyano-4-fluoro-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide (Preparation 65, 4.5 mmol, 1280 mg). The reaction mixture was heated at 80° C. for 24 hours. The reaction was cooled to room temperature and the mixture was poured into 1 N aqueous HCl (100 mL) to obtain a white solid. The afforded solid was washed with heptane and the solid was dried in vacuo to furnish 1.932 g of the title compound. LCMS Rt=1.67 minutes MS m/z 485 [MH]+
Reaction SMILES: [N+:1]([C:4]1[O:8][C:7]([C:9](Cl)=[O:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH:12]([C:14]1[S:15][C:16]2[CH:22]=[C:21]([CH3:23])[CH:20]=[CH:19][C:17]=2[N:18]=1)[NH2:13]>>[CH3:23][C:21]1[CH:20]=[CH:19][C:17]2[N:18]=[C:14]([NH:12][NH:13][C:9]([C:7]3[O:8][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=3)=[O:10])[S:15][C:16]=2[CH:22]=1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])o1
Reactant: Cc1ccc2nc(NN)sc2c1
Product: Cc1ccc2nc(NNC(=O)c3ccc([N+](=O)[O-])o3)sc2c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
The compound 4b was prepared according to above described method by using 5-nitro-2-furancarboxylic acid chloride (300 mg, 1 mmol) and 2-hydrazino-6-methylbenzothiazole (179 mg, 1 mmol) which stirred for 1 h at 0° C. and stirring continued at 25° C. for 11 h (yield 216 mg, 85%).
Reaction SMILES: [CH3:1][N:2]([CH:10]1[CH2:15][CH2:14][N:13]([CH2:16][C:17]2[CH:22]=[CH:21][N:20]=[C:19]([N:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:18]=2)[CH2:12][CH2:11]1)C(=O)OC(C)(C)C.C([Cl:31])(=O)C>C(O)C>[ClH:31].[CH3:1][NH:2][CH:10]1[CH2:15][CH2:14][N:13]([CH2:16][C:17]2[CH:22]=[CH:21][N:20]=[C:19]([N:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:18]=2)[CH2:12][CH2:11]1
Reactant: CC(=O)Cl
Reactant: CN(C(=O)OC(C)(C)C)C1CCN(Cc2ccnc(N3CCCC3)c2)CC1
Solvent: CCO
Product: CNC1CCN(Cc2ccnc(N3CCCC3)c2)CC1
Product: Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 99 %

Procedure:
tert-Butyl methyl(1-((2-(pyrrolidin-1-yl)pyridin-4-yl)methyl)piperidin-4-yl)carbamate (1.469 mmol, 1.0 eq) was dissolved in ethanol (5 ml), and acetyl chloride (7.345 mmol, 5 eq) was added, while cooling with ice. The reaction mixture was stirred for 16 h at RT. TLC monitoring showed that the reaction was incomplete. Acetyl chloride (1 eq) was metered in, and the reaction mixture was stirred for 1 h at 50° C. A solid precipitated. Ethanol was concentrated slightly, and the precipitate was filtered off, washed with diethyl ether and dried. Yield: >99%
Reaction SMILES: [CH2:1]([C:3]1[CH:9]=[C:8]([CH3:10])[CH:7]=[C:6]([CH2:11][CH3:12])[C:4]=1N)[CH3:2].N([O-])=O.[Na+].S(=O)(=O)(O)N.[ClH:22]>O>[CH2:1]([C:3]1[CH:9]=[C:8]([CH3:10])[CH:7]=[C:6]([CH2:11][CH3:12])[C:4]=1[Cl:22])[CH3:2]
Reactant: CCc1cc(C)cc(CC)c1N
Reactant: Cl
Agent: NS(=O)(=O)O
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: CCc1cc(C)cc(CC)c1Cl
Temperature: 50 °C
Reaction time: 0.08 h

Procedure:
To an initial charge of 65 ml of 36% aqueous HCl are added, in portions, 16.33 g [0.1 mol] of 2,6-diethyl-4-methylaniline. The resulting thick suspension is stirred at 50° C. for 5 minutes. It is then cooled to −10° C., and a solution of 8 g [0.116 mol] of NaNO2 in 35 ml of water is added dropwise within approx. 1 h at such a rate that the temperature does not exceed −5° C. 80 mg of sulphamic acid are added. Then the suspension of the diazonium salt, cooled to −10° C., is metered within about 30 minutes into a solution, heated to 65° C., of 4.18 g [0.025 mol] of FeCl3 in 65 ml of 36% aqueous HCl. The reaction mixture is then stirred at 65° C. for another 1 hour, allowed to cool to room temperature and admixed with 200 ml of water, the phases are separated and the aqueous phase is extracted three times with 50 ml each time of methylene chloride. The combined organic phases are washed twice with 25 ml each time of water, dried and concentrated under reduced pressure. This gives 17.9 g of an oil which, according to GC, contains 93.1% 2,6-diethyl-4-methylchlorobenzene (91% of theory).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N-:11][C:12]([CH3:15])([CH3:14])[CH3:13])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[C:16](=O)([O-])[O-].[K+].[K+].IC.O>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH3:16])(=[O:10])=[O:9])=[CH:6][CH:7]=1
Reactant: CC(C)(C)[N-]S(=O)(=O)c1ccc(Br)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: O
Product: CN(C(C)(C)C)S(=O)(=O)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 73.5 %

Procedure:
4-Bromo-N-(tert-butyl)benzenesulfonyl amide (100 mg, 0.342 mmol) and potassium carbonate (95 mg, 0.684 mmol) were dissolved in DMF (2 ml), followed by addition of iodomethane (0.043 ml, 0.684 mmol), and then the resulting liquid was stirred at room temperature for 18 hours. Distilled water (10 ml) was added to the resulting reaction liquid, followed by extraction with EtOAc (10 ml×3). The organic layer was dried over anhydrous sodium sulfate, followed by filtration and concentration, and then the residue thus obtained was subjected to MPLC (20% EtOAc/Hexanes), to obtain 77 mg of yellow oil (73%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[C:9](=[N:11][OH:12])[CH3:10])=[CH:4][CH:3]=1.[NH2:14][NH:15][C:16]([NH2:18])=[S:17].CO>C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[N:14][NH:15][C:16]([NH2:18])=[S:17])[C:9](=[N:11][OH:12])[CH3:10])=[CH:4][CH:3]=1
Reactant: CC(=NO)C(=O)c1ccc(Cl)cc1
Reactant: NNC(N)=S
Solvent: CC(=O)O
Solvent: CO
Product: CC(=NO)C(=NNC(N)=S)c1ccc(Cl)cc1
Yield: 86.5 %

Procedure:
A mixture of 4'-chloro-2-hydroxyiminopropiophenone (252.3 g), thiosemicarbazide (151.3 g), methanol (650 ml) water (300 ml), and acetic acid (9 ml) was refluxed for 31 hours with stirring. After cooling, the resulting precipitates were collected by filtration, washed successively with methanol, water and methanol, and then dried to give 4'-chloro-2-hydroxyiminopropiophenone thiosemicarbazone (298.88 g).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][CH:6]=[C:7]([CH:10]=1)[C:8]#[N:9])#[CH:2].[F:11][C:12]1[CH:17]=[CH:16][C:15](I)=[CH:14][C:13]=1[OH:19].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.C(NCC)C>O1CCOCC1.C(OCC)C.[Cu]I>[OH:19][C:13]1[CH:14]=[C:15]([C:2]#[C:1][C:3]2[CH:4]=[N:5][CH:6]=[C:7]([CH:10]=2)[C:8]#[N:9])[CH:16]=[CH:17][C:12]=1[F:11]
Reactant: Oc1cc(I)ccc1F
Reactant: C#Cc1cncc(C#N)c1
Agent: [Cu]I
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Solvent: CCOCC
Solvent: C1COCCO1
Solvent: CCNCC
Product: N#Cc1cncc(C#Cc2ccc(F)c(O)c2)c1
Temperature: 60 °C
Reaction time: 0.17 h
Yield: 42 %

Procedure:
Add bis(phenylnitrile)palladium (II) chloride (115 mg, 0.3 mmol) to a suspension of copper (I) iodide (38 mg, 0.2 mmol) in anhydrous 1,4-dioxane (1 mL) under nitrogen and stir for 10 min. Sequentially add 5-ethynyl-nicotinonitrile (1.28 g, 10 mmol), (prepared essentially as described in PREPARATION 4), 2-fluoro-5-iodophenol, (prepared essentially as described in PREPARATION 15), (2.37 g, 10 mmol) and tri-tert-butylphosphine (121 mg, 0.6 mmol) in 1,4-dioxane (5 mL) and diethylamine (2.1 mL, 12 mmol) to the reaction mixture and heat at 60° C. for 16 h. Cool to room temperature, dilute with diethyl ether, stir for 10 min and filter through diatomaceous earth. Wash the filtrate sequentially with water and an aqueous saturated solution of sodium chloride. Dry (magnesium sulfate), concentrate and purify by silica gel chromatography, eluting with 0:100 to 35:100 ethyl acetate:hexanes, to give the title compound (1.0 g, 42%) as a yellow solid.
Reaction SMILES: Br[C:2]1[CH:33]=[CH:32][C:5]([CH2:6][CH:7]2[C:16]3[C:11](=[CH:12][C:13]([O:17][CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[CH:14][CH:15]=3)[CH2:10][CH2:9][N:8]2[C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)=[CH:4][CH:3]=1.[CH3:34][N:35]([CH3:55])[C:36]1[CH:41]=[CH:40][C:39]([Sn](CCCC)(CCCC)CCCC)=[CH:38][N:37]=1>>[CH3:34][N:35]([CH3:55])[C:36]1[N:37]=[CH:38][C:39]([C:2]2[CH:3]=[CH:4][C:5]([CH2:6][CH:7]3[C:16]4[C:11](=[CH:12][C:13]([O:17][CH2:18][C:19]5[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=5)=[CH:14][CH:15]=4)[CH2:10][CH2:9][N:8]3[C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)=[CH:32][CH:33]=2)=[CH:40][CH:41]=1
Reactant: Fc1ccc(N2CCc3cc(OCc4ccccc4)ccc3C2Cc2ccc(Br)cc2)cc1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(N(C)C)nc1
Product: CN(C)c1ccc(-c2ccc(CC3c4ccc(OCc5ccccc5)cc4CCN3c3ccc(F)cc3)cc2)cn1
Yield: 90 %

Procedure:
The title compound was prepared as described in Example 135, using 1-(4-bromobenzyl)-2-(4-fluorophenyl)-6-(phenylmethoxy)-1,2,3,4-tetrahydroisoquinoline (0.60 g, 0.12 mmol) and 2-(dimethylamino)-5-(tributylstannyl)pyridine to provide the title compound (0.581 g, 90% yield): 1H NMR (CDCl3) 8.42 (dd, 1H), 7.68 (dd, 1H), 7.32-7.45 (m, 7H), 7.06 (d, 2H), 6.91 (m, 2H), 6.72-6.80 (m, 5H), 6.58 (d, 1H), 5.04 (s, 2H), 4.77 (t, 1H), 3.62 (m 1H), 3.48 (m, 1H), 3.19 (dd, 1H), 3.13 (s, 6H), 2.96 (m, 2H), 2.72 (dt, 1H); ES-MS m/z 544 [M+H]+.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[O:17][N:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.[O:31]1C[CH:32]1[CH2:34][N:35]1[C:43]2[CH2:42][CH2:41][N:40]([C:44](=[O:46])[CH3:45])[CH2:39][C:38]=2[C:37]([C:47]2[CH:52]=[CH:51][C:50]([C:53]([F:56])([F:55])[F:54])=[CH:49][CH:48]=2)=[N:36]1>C(Cl)Cl>[O:17]1[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[C:15]([O:14][CH:11]2[CH2:10][CH2:9][N:8]([CH2:6][CH:32]([OH:31])[CH2:34][N:35]3[C:43]4[CH2:42][CH2:41][N:40]([C:44](=[O:46])[CH3:45])[CH2:39][C:38]=4[C:37]([C:47]4[CH:52]=[CH:51][C:50]([C:53]([F:56])([F:55])[F:54])=[CH:49][CH:48]=4)=[N:36]3)[CH2:13][CH2:12]2)=[N:16]1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2noc3ccccc23)CC1
Reactant: CC(=O)N1CCc2c(c(-c3ccc(C(F)(F)F)cc3)nn2CC2CO2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)N1CCc2c(c(-c3ccc(C(F)(F)F)cc3)nn2CC(O)CN2CCC(Oc3noc4ccccc34)CC2)C1
Temperature: 60 °C
Reaction time: 1 h
Yield: 68.5 %

Procedure:
A solution of 176 mg (0.55 mmol) of 4-(benzo[d]isoxazol-3-yloxy)-piperidine-1-carboxylic acid tert-butyl ester in CH2Cl2(2 mL) was treated with trifluoroacetic acid (0.5 mL) at room temperature overnight. The solvent was then removed and the crude product dissolved in methanol and stirred over 100 mg of sodium bicarbonate for 1 h, the solid was then filtered off and the filtrate concentrated. The crude piperidine was then dissolved in 4 mL EtOH and treated with 202 mg (0.55 mmol) of 1-[1-oxiranylmethyl-3-(4-trifluoromethyl-phenyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone The solution was heated to 60° C. overnight. The solvent was then removed by rotary evaporation and the crude product was purified by column chromatography (silica, 0-10% MeOH/EtOAc) to afford 220 mg (68%) of a white solid. MS (electrospray): exact mass calculated for C30H32F3N5O4, 583.24. m/z found, 584.2 [M+H]+. 1H NMR (CDCl3, 400 MHz, a mixture of amide rotamers): 7.77 (d, J=8.22 Hz, 1H), 7.69 (m, 2H), 7.66-7.61 (m, 2H), 7.54-7.49 (m, 1H), 7.41 (d, J=8.41 Hz, 1H), 7.28-7.23 (m, 1H), 4.93 (br m, 1H), 4.88 and 4.75 (A and B of AB quartet, J=15.65 Hz, 1H), 4.65 (br s, 1H), 4.24-4.18 (m, 0.75H), 4.18-4.09 (m, 1.25H), 4.07-3.98 (m, 1.5H), 3.91-3.79 (m, 0.5H), 3.79-3.67 (m, 1H), 3.02-2.85 (m, 2.4H), 2.85-2.70 (m, 1.6H), 2.61-2.52 (m, 1H), 2.51-2.40 (m, 2H), 2.39-2.30 (m, 1H), 2.24-2.12 (br m, 2H), 2.20 (s, 1.5H), 2.16 (s, 1.5H), 2.02-1.86 (m, 2H).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][NH:3][C:2]1=[O:6].C([O-])([O-])=O.[K+].[K+].[CH:13](Cl)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O>CS(C)=O>[C:14]1([CH:13]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:1]2[CH2:5][CH2:4][NH:3][C:2]2=[O:6])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C1NCCN1
Reactant: ClC(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: O=C1NCCN1C(c1ccccc1)c1ccccc1
Reaction time: 0.3 h
Yield: 43 %

Procedure:
A 21.5 g (0.25 mole) portion of 2-imidazolidinone in 250 ml of dimethylsulfoxide was treated with 34.5 g (0.25 mole) of K2CO3, 20 g (0.12 mole) of KI and 50.8 g (0.25 mole) of benzhydryl chloride. The reaction mixture was heated with rapid stirring to 100° over 0.3 hr, held at 100° for 1.5 hours and poured into 1.5 l of H2O. The aqueous mixture was extracted with 1.3 l of chloroform. The chloroform extract was washed with 500 ml of H2O, dried over MgSO4 overnight and filtered. The filtrate was concentrated to dryness under reduced pressure leaving 27 g (43%) of a semi-solid. The crude product was washed with 100 ml of ether, air dried and dried at 60° for 2 hours to give 19 g (30%) of a white solid, m.p. 200°-202°. Recrystallization from acetonitrile provided an analytical sample, m.p. 201°-203°.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:14]([C:15]([NH:17][NH2:18])=[O:16])=[CH:13][N:12]3[CH:19]=[CH:20][N:21]=[C:11]3[C:10]=2[Cl:22])=[C:4]([F:23])[CH:3]=1.[N:24]#[C:25]Br.C(=O)(O)[O-].[Na+]>O1CCOCC1.O.C(OCC)(=O)C>[NH2:24][C:25]1[O:16][C:15]([C:14]2[C:9]([NH:8][C:5]3[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=3[F:23])=[C:10]([Cl:22])[C:11]3[N:12]([CH:19]=[CH:20][N:21]=3)[CH:13]=2)=[N:17][N:18]=1
Reactant: N#CBr
Reactant: NNC(=O)c1cn2ccnc2c(Cl)c1Nc1ccc(Br)cc1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: Nc1nnc(-c2cn3ccnc3c(Cl)c2Nc2ccc(Br)cc2F)o1
Temperature: 25 °C
Reaction time: 16 h
Yield: 91.6 %

Procedure:
7-(4-Bromo-2-fluoro-phenylamino)-8-chloro-imidazo[1,2-a]pyridine-6-carboxylic acid hydrazide (100 mg, 0.25 mmol) was suspended in dioxane (2 mL). Cyanogen bromide (27 mg, 0.253 mmol) was added, followed by a solution of sodium bicarbonate (21 mg, 0.25 mmol) in H2O (1.2 mL). The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with ethyl acetate and washed with water and saturated aqueous NaCl, dried over Na2SO4 and concentrated to yield the desired product (97 mg, 91%) as a white solid. MS ESI (+) m/z 423, 425 (M+, Cl, Br pattern) detected. 1H NMR (400 MHz, CH3OD) δ 8.98 (s, 1H), 7.95 (s, 1H), 7.61 (s, 1H), 7.33 (d, 1H), 7.17 (d, 1H), 6.78 (t, 1H). 19F (376 MHz, CD3OD) −128.6 (t).
Reaction SMILES: [CH2:1](Br)[CH2:2][C@H:3]([CH2:5][CH2:6][CH:7]=[C:8]([CH3:10])[CH3:9])[CH3:4].[Li+].[Cl-].[CH3:14][Mg]Cl.[Cl-].[NH4+]>C1COCC1>[CH3:9][C:8](=[CH:7][CH2:6][CH2:5][C@H:3]([CH3:4])[CH2:2][CH2:1][CH3:14])[CH3:10]
Reactant: C[Mg]Cl
Reactant: CC(C)=CCC[C@H](C)CCBr
Agent: [Cl-]
Agent: [Li+]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCC[C@@H](C)CCC=C(C)C
Temperature: 25 °C

Procedure:
To (S)-citronellyl bromide (50 g, 0.228 mol) in THF (800 mL) at 0° C. was added LiCl (4.3 g) followed by CuCl2 (6.8 g). After 30 minutes methylmagnesium chloride (152 mL of a 3 M solution in THF, Aldrich) was added and the solution warmed to room temperature. After 10 hours the solution was cooled to 0° C. and a saturated aqueous solution of ammonium chloride carefully added. The resultant two layers were separated and the aqueous phase extracted with ether. The combined organic phases were dried (MgSO4) and concentrated to give an oil. 32.6 g; 93%. Used without further purification. 13C NMR (100 MHz; CDCl3) 131.13, 125.28, 39.50, 37.35, 32.35, 25.92, 25.77, 20.31, 19.74, 17.81, 14.60.
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:7]([N:30]2[CH2:42][CH2:41][N:33]3[C:34]4[CH2:35][CH2:36][CH2:37][CH2:38][C:39]=4[CH:40]=[C:32]3[C:31]2=[O:43])=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[C:16]([NH:18][C:19]2[CH:27]=[C:22]3[CH2:23][NH:24][CH2:25][CH2:26][N:21]3[N:20]=2)[C:15](=[O:28])[N:14]([CH3:29])[CH:13]=1)(=O)C.[OH-].[Li+]>C(O)(C)C.C1COCC1.O>[OH:4][CH2:5][C:6]1[C:7]([N:30]2[CH2:42][CH2:41][N:33]3[C:34]4[CH2:35][CH2:36][CH2:37][CH2:38][C:39]=4[CH:40]=[C:32]3[C:31]2=[O:43])=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[C:16]([NH:18][C:19]2[CH:27]=[C:22]3[CH2:23][NH:24][CH2:25][CH2:26][N:21]3[N:20]=2)[C:15](=[O:28])[N:14]([CH3:29])[CH:13]=1
Reactant: CC(=O)OCc1c(-c2cc(Nc3cc4n(n3)CCNC4)c(=O)n(C)c2)ccnc1N1CCn2c(cc3c2CCCC3)C1=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Solvent: C1CCOC1
Product: Cn1cc(-c2ccnc(N3CCn4c(cc5c4CCCC5)C3=O)c2CO)cc(Nc2cc3n(n2)CCNC3)c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 46.2 %

Procedure:
A mixture of 205f (165 mg, 0.28 mmol) and lithium hydroxide (67 mg, 2.80 mmol) in i-propanol/THF (1:1, 4 mL) and water (1 mL) was stirred at room temperature for 1 h. The mixture was evaporated in vacuo and diluted with water (4 mL). It was then extracted with ethyl acetate (10 mL×2). The combined ethyl acetate extract was concentrated under reduced pressure and the residue was purified by reverse-phase prep-HPLC to afford 205 (70 mg, 46%) as a white solid. MS-ESI: [M+H]+ 541.2. 1H NMR (500 MHz, CDCl3) δ 8.48 (d, J=5.0 Hz, 1H), 7.96 (d, J=2.0 Hz, 1H), 7.72 (d, J=2.0 Hz, 1H), 7.43 (s, 1H), 7.35 (d, J=5.5 Hz, 1H), 6.90 (s, 1H), 5.70 (s, 1H), 5.01 (s, 1H), 4.64-4.61 (m, 1H), 4.50 (s, 1H), 4.34 (s, 1H), 4.16-3.99 (m, 6H), 3.89-3.87 (m, 1H), 3.71 (s, 3H), 3.30 (t, J=5.5 Hz, 2H), 2.63-2.57 (m, 4H), 1.92-1.89 (m, 2H), 1.80-1.78 (m, 3H).
Reaction SMILES: O=[C:2]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH2:3][O:4][C:5]1[CH:25]=[CH:24][C:8]([CH2:9][O:10][C:11]2[N:16]=[CH:15][C:14](/[CH:17]=[CH:18]/[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1.[N:32]1C=CC=CC=1.C[CH2:39][OH:40]>>[CH3:39][O:40]/[N:32]=[C:2](/[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)\[CH2:3][O:4][C:5]1[CH:25]=[CH:24][C:8]([CH2:9][O:10][C:11]2[N:16]=[CH:15][C:14]([CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1
Reactant: c1ccncc1
Reactant: CCOC(=O)/C=C/c1ccc(OCc2ccc(OCC(=O)c3ccccc3)cc2)nc1
Reactant: CCO
Product: CCOC(=O)CCc1ccc(OCc2ccc(OC/C(=N\OC)c3ccccc3)cc2)nc1
Temperature: 80 °C
Yield: 23 %

Procedure:
To a solution of ethyl (2E)-3-(6-{[4-(2-oxo-2-phenylethoxy)benzyl]oxy}pyridin-3-yl)prop-2-enoate (0.13 g, 0.3 mmol) in ethanol was added pyridine (0.038 g, 0.45 mmol) and O-Methoxylamine hydrochloride, the resulting mass was refluxed at 80° C. for 3 h. Reaction quenched with water and extracted with ethyl acetate, organic layer was washed with water and brine solution dried over anhydrous Na2SO4 and concentrated to colourless oil (0.03 g, Yield: 23%); MS (ESI, 120 eV): m/z=449 (M+H)+.