Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([I:14])=[C:5]([C:9]([I:13])=[CH:10][C:11]=1[I:12])[C:6]([OH:8])=[O:7].[Si](C=[N+]=[N-])(C)(C)[CH3:16].N#N>CCOCC.CO>[CH3:1][O:2][C:3]1[C:4]([I:14])=[C:5]([C:9]([I:13])=[CH:10][C:11]=1[I:12])[C:6]([O:8][CH3:16])=[O:7]
Reactant: COc1c(I)cc(I)c(C(=O)O)c1I
Reactant: C[Si](C)(C)C=[N+]=[N-]
Agent: N#N
Solvent: CCOCC
Solvent: CO
Product: COC(=O)c1c(I)cc(I)c(OC)c1I
Reaction time: 0.5 h

Procedure:
In a 3-neck 250 mL round-bottom flask fitted with a thermometer and a condenser, 3-methoxy-2,4,6-triiodobenzoic acid (10.38 g) was dissolved in a 2:1 mixture of Et2O and methanol at 0° C. A 2.0 M hexanes solution of TMSCHN2 was added dropwise until yellow color persisted and N2 bubbling stopped. The reaction mixture was stirred for 30 minutes and quenched with glacial acetic acid. Solvents and excess AcOH were removed in vacuo for 18 h to give the desired ester as a white solid which was used in the next step without any further purification. Yield 11.07 g (˜100% crude).
Reaction SMILES: [I-].C[S+](C)(C)=O.[CH3:7]C(C)([O-])C.[K+].[F:13][C:14]1[CH:15]=[CH:16][C:17]2[O:22][CH:21]([CH:23]=[O:24])[CH2:20][CH2:19][C:18]=2[CH:25]=1>CS(C)=O>[CH2:20]1[CH:21]([CH:23]2[O:24][CH2:7]2)[O:22][C:17]2[CH:16]=[CH:15][C:14]([F:13])=[CH:25][C:18]=2[CH2:19]1
Reactant: O=CC1CCc2cc(F)ccc2O1
Reactant: CC(C)(C)[O-]
Agent: C[S+](C)(C)=O
Agent: [I-]
Agent: [K+]
Solvent: CS(C)=O
Product: Fc1ccc2c(c1)CCC(C1CO1)O2
Temperature: 30 °C
Reaction time: 1 h

Procedure:
To 234 ml of dimethyl sulfoxide was added 32 g of trimethyl sulfoxonium iodide. To it, potassium tertiary butoxide (16 g) was added and stirred for 1 h at 20-40° C. The reaction mixture was cooled and to it was added a solution of the compound obtained in Example 2 in dimethyl sulfoxide (26 ml.) while maintaining the temperature between 20°-40° C. for 1.5 hr. The reaction mixture was quenched in cold water. The aqueous layer was extracted with ethyl acetate, washed with water, concentrated under reduced pressure followed by product distillation to give 19.6 g of 6-fluoro-3,4-dihydro-2-oxiranyl-2H-1-benzopyran (VII) in the form of a mixture of A and B as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][N:8]2[CH2:11][CH2:12][CH2:13][O:14][CH3:15])=[CH:4][CH:3]=1.[Br:16]N1C(=O)CCC1=O>O1CCCC1>[Br:16][C:6]1[C:5]2[C:9](=[CH:10][C:2]([Br:1])=[CH:3][CH:4]=2)[N:8]([CH2:11][CH2:12][CH2:13][O:14][CH3:15])[CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COCCCn1ccc2ccc(Br)cc21
Solvent: C1CCOC1
Product: COCCCn1cc(Br)c2ccc(Br)cc21
Temperature: -78 °C
Reaction time: 1.7 h

Procedure:
A solution of 10.39 g of 6-bromo-1-(3-methoxypropyl)-1H-indole (building block 5) in 1.5 l of tetrahydrofuran is cooled to −78° C., and 7.05 g of N-bromosuccinimide are added. The mixture is stirred at −78° C. for 1.7 hours and then warmed to room temperature. The reaction mixture is evaporated. The title compound is obtained as an orange oil from the residue by flash chromatography (SiO2 60 F). Rf=0.31 (EtOAc-heptane 1:4); Rt=5.65 (Gradient I).
Reaction SMILES: Cl.[NH2:2][OH:3].[CH2:4]([C:8]12[CH2:14][CH:11]([CH:12]=[CH:13]1)[CH:10]1[C:15]([O:17][C:18](=[O:19])[CH:9]21)=[O:16])[C:5](=[CH2:7])[CH3:6].[OH-].[Na+]>O>[OH:3][N:2]=[C:18]([CH:9]1[CH:10]([C:15]([OH:17])=[O:16])[CH:11]2[CH2:14][C:8]1([CH2:4][C:5](=[CH2:7])[CH3:6])[CH:13]=[CH:12]2)[OH:19]
Reactant: NO
Reactant: C=C(C)CC12C=CC(C1)C1C(=O)OC(=O)C12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: C=C(C)CC12C=CC(C1)C(C(=O)O)C2C(O)=NO

Procedure:
34.75 g of hydroxylamine hydrochloride are dissolved in water, and 109 g of methallylbicyclo[2.2.1]hept-5-ene-2,3-dicarboxylic anhydride are added. There are then added dropwise, with stirring, 40 g of 50% aqueous sodium hydroxide solution, and the mixture is refluxed for 1 hour. All volatile components are afterwards distilled off, the residue is taken up in toluene, the precipitated sodium chloride is filtered off, and the toluene is removed in a rotary evaporator (150° C., 2000 Pa). There are thus obtained 98.5 g of a highly viscous liquid (90% of theory), which is not distillable up to 200° C./2.5 Pa, since the product presumably is in the form of a dimer.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[C@H:4]([NH:15][C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17])[CH2:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH:10]=[CH:9]2.C([OH:31])(C)(C)C>[Zn]>[CH3:1][O:2][C:3](=[O:26])[C@H:4]([NH:15][C:16]([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17])[CH2:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:31])[CH2:9]2
Reactant: CC(C)(C)O
Reactant: COC(=O)[C@@H](Cc1ccc2[nH]ccc2c1)NC(=O)OCc1ccccc1
Agent: [Zn]
Product: COC(=O)[C@@H](Cc1ccc2c(c1)CC(=O)N2)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 41 %

Procedure:
PyHBr3 (1.28 g, 4.02 mmol) was added in small portions over 30 min to a solution of (R)-2-benzyloxycarbonylamino-3-(1H-indol-5-yl)-propionic acid methyl ester (0.47 g, 1.34 mmol) in t-butanol (10 mL) while the reaction temperature was maintained between 25–30° C. The resulting mixture was stirred at room temperature for 3.5 h. The solvent was removed in vacuo, and the residue was extracted with ethyl acetate (2×). The combined organic phases were washed with brine and dried over sodium sulfate. After filtration, solvents were removed and the residue was azeotropically dried with anhydrous ethanol. The residue was dissolved in glacial acetic acid (10 mL) and zinc powder (0.88 g, 13.4 mmol) was added. The mixture was stirred at room temperature overnight. After the acetic acid was removed in vacuo, the residue was purified by flash chromatography on silica gel using ethyl acetate/hexanes [(1:3) first and then (3:2)] as eluent to afford the title compound as a white solid (41% for 2 steps). 1H-NMR (CDCl3, 500 MHz) δ 8.03 (s, 1H), 7.36–7.31 (m, 5H), 6.94 (s, 1H), 6.91 (d, J=8.0 Hz, 1H), 6.73 (d, J=7.5 Hz, 1H), 5.26 (d, J=8.0 Hz, 1H), 5.11 (d, J=12.0 Hz, 1H), 5.05 (d, j=12.5 Hz, 1H), 4.61 (dd, J=13.5, 6.0 hz, 1H), 3.72 (s, 3H), 3.45 (s, 2H), 3.10 (dd, J=14.0, 5.5 Hz, 1H), 3.00 (dd, J=14.0, 6.0 Hz, 1H). 13CNMR (CDCl3, 125 MHz) δ 177.7, 172.2, 155.7, 141.7, 136.3, 129.8, 128.9, 128.6, 128.3, 128.2, 125.8, 125.6, 109.8, 67.1, 55.1, 52.5, 38.0, 36. Mass spec. 369.20 (MH)+.
Reaction SMILES: Br[CH2:2][C:3]([Br:5])=[O:4].[C:6]1([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[Cl-].[Al+3].[Cl-].[Cl-]>C(Cl)Cl>[O:12]([C:13]1[CH:14]=[CH:15][C:16]([CH2:2][C:3]([Br:5])=[O:4])=[CH:17][CH:18]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=C(Br)CBr
Reactant: c1ccc(Oc2ccccc2)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C(Br)Cc1ccc(Oc2ccccc2)cc1
Temperature: 2.5 °C
Reaction time: 4 h
Yield: 37.9 %

Procedure:
A mixture of 3.31 g (0.038 mol) of bromoacetyl bromide, 50 ml of methylene chloride and 5 g (0.029 mol) of diphenyl ether is cooled to 0-5° C. and 4.42 ml (0.033 mol) of aluminum chloride are added. The mixture is stirred at room temperature for 4 hours. It is poured into a-water/ice mixture, the two phases are separated and the organic phase is washed with 1 N hydrochloric acid and with water. The organic phase is dried over sodium sulfate and the solvent is evaporated off under reduced pressure. The residue is purified by chromatography on a silica gel column using a 7/3 cyclohexane/ethyl acetate mixture as the eluent. The fraction of the medium corresponding to 3.2 g of 2-(4-phenoxyphenyl)acetyl bromide is isolated. The resulting oil is mixed with 5.9 ml (0.077 mol) of trifluoroacetic acid and 7.7 ml (0.048 mol) of triethylsilane. The mixture is heated at 80° C. for 4 hours and the residue is taken up with an ethyl ether/sodium bicarbonate mixture. The two phases are separated, the organic phase is dried over sodium sulfate and the solvent is evaporated off under reduced pressure to give 7 g of the title compound.
Reaction SMILES: C([O:5][C:6](=[O:39])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][N:18]([C:31]2[N:36]=[CH:35][C:34]([CH2:37][CH3:38])=[CH:33][N:32]=2)[CH2:19][C:20]2[CH:25]=[CH:24][C:23]([NH:26][C:27](=[O:30])[CH2:28][CH3:29])=[CH:22][CH:21]=2)[N:15]=1)([CH3:9])[CH3:8])(C)(C)C.[ClH:40].C(OCC)(=O)C>C(O)=O>[ClH:40].[CH2:37]([C:34]1[CH:33]=[N:32][C:31]([N:18]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([NH:26][C:27](=[O:30])[CH2:28][CH3:29])=[CH:22][CH:21]=2)[CH2:17][CH2:16][C:14]2[N:15]=[C:11]([S:10][C:7]([CH3:8])([CH3:9])[C:6]([OH:39])=[O:5])[S:12][CH:13]=2)=[N:36][CH:35]=1)[CH3:38]
Reactant: CCC(=O)Nc1ccc(CN(CCc2csc(SC(C)(C)C(=O)OC(C)(C)C)n2)c2ncc(CC)cn2)cc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O=CO
Product: CCC(=O)Nc1ccc(CN(CCc2csc(SC(C)(C)C(=O)O)n2)c2ncc(CC)cn2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-{[4-(2-{(5-Ethylpyrimidin-2-yl)[4-(propionylamino)benzyl]amino}ethyl)-1,3-thiazol-2-yl]thio}-2-methylpropionic acid tert-butyl ester (100 mg) synthesized in Example 439-3 was dissolved in formic acid (2.5 mL), 4 mol/L hydrochloric acid-ethyl acetate (0.5 mL) was added thereto, and the mixture was stirred at room temperature overnight. The reaction solution was evaporated under reduced pressure, and the residue was dried by heating at 60° C. to give the title compound (98 mg) as a white amorphous solid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[CH2:17][CH2:16][CH:15]([CH2:18][C:19]([OH:21])=O)[N:7]3[C:8](=[O:14])[C:9](=[O:13])[NH:10][C:11]([CH:12]=1)=[C:6]23)#[N:2].[NH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[C:1]([C:3]1[CH:4]=[C:5]2[CH2:17][CH2:16][CH:15]([CH2:18][C:19](=[O:21])[NH:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[N:7]3[C:8](=[O:14])[C:9](=[O:13])[NH:10][C:11]([CH:12]=1)=[C:6]23)#[N:2]
Reactant: Nc1ccccc1
Reactant: N#Cc1cc2c3c(c1)[nH]c(=O)c(=O)n3C(CC(=O)O)CC2
Product: N#Cc1cc2c3c(c1)[nH]c(=O)c(=O)n3C(CC(=O)Nc1ccccc1)CC2
Yield: 68 %

Procedure:
A procedure similar to that described in Example 5 was carried out with 9-cyano-5-carboxymethyl-6,7-dihydro-1H, 5H-pyrido[1,2,3-de]quinoxaline-2,3-dione (70 mg, 0.245 mmol) and aniline (70 mg, 0.75 mmol) to give 60 mg of the title compound (68%): mp 171°~176° C. (dec); 1H NMR (270 MHz, DMSO-d6)δ12.22 (bs, 1H), 10.02 (s, 1H), 7.56 (d, 2H, J=7.8 Hz), 7.52 (s, 1H), 7.33 (s, 1H), 7.30 (t, 2H, J=7.8 Hz), 7.05 (t, 1H, J=7.8 Hz), 5.18~5.29 (m, 1H), 3.08 (ddd, 1H, J=17.1, 13.5, 4.5 Hz), 2.87 (dm, 1H, J=17.1 Hz), 2.54~2.70 (m, 2H), 2.12 (dm, 1H, J=13.5 Hz), 1.80~1.97 (m, 1H).
Reaction SMILES: [NH2-].[Na+].CS[C:5](=[S:14])[O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH3:15][O:16][C:17]1[CH:30]=[CH:29][C:20]([C:21]([C:23]2C=CC=CC=2)=[O:22])=[CH:19][CH:18]=1.Cl>C1(C)C=CC=CC=1>[CH2:7]([O:6][C:5](=[S:14])[CH2:23][C:21]([C:20]1[CH:29]=[CH:30][C:17]([O:16][CH3:15])=[CH:18][CH:19]=1)=[O:22])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: COc1ccc(C(=O)c2ccccc2)cc1
Reactant: CSC(=S)OCc1ccccc1
Agent: Cl
Agent: [NH2-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COc1ccc(C(=O)CC(=S)OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.1 %

Procedure:
To a suspension of sodium amide (1.6 g) in toluene (50 mL) was added a mixture of dithiocarbonic acid O-benzyl ester S-methyl ester (4.0 g) and 4-methoxybenzophenone (3.0 g) at room temperature and the mixture was stirred at room temperature overnight. Hydrochloric acid solution (2 mol/L, 80 mL) was added to the reaction mixture and the mixture was extracted with diethyl ether. The organic layer was washed with brine and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: hexane/dichloromethane=5/1-2/1) to give the title compound (3.4 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([NH2:12])[CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2.[C:13]([C:15]1[N:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1)#[N:14].N1C=CC=CC=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([NH:12][S:21]([C:18]3[CH:19]=[N:20][C:15]([C:13]#[N:14])=[CH:16][CH:17]=3)(=[O:22])=[O:23])[CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2
Reactant: N#Cc1ccc(S(=O)(=O)Cl)cn1
Reactant: Nc1cc(F)cc2cccnc12
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: N#Cc1ccc(S(=O)(=O)Nc2cc(F)cc3cccnc23)cn1
Yield: 26.5 %

Procedure:
In a similar fashion using route 14 general procedure 27, 6-fluoroquinolin-8-ylamine (Intermediate 48) (125 mg, 0.77 mmol), 6-cyano-pyridine-3-sulfonyl chloride (Intermediate 19) (187 mg, 0.92 mmol), pyridine (121 mg, 1.54 mmol), DMAP (cat.) and DCM (10 ml) gave the title compound (67 mg, 26%) after purification by column chromatography with n-hexane/DCM (50:50) as the eluent.
Reaction SMILES: [C:1]12([C:11]3[CH:22]=[CH:21][C:14]([O:15][CH:16]=[CH:17][C:18](O)=[O:19])=[CH:13][CH:12]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[CH3:23][O:24][C:25](=[O:33])[C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([NH2:32])[CH:27]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:23][O:24][C:25](=[O:33])[C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([NH:32][C:18](=[O:19])/[CH:17]=[CH:16]/[O:15][C:14]2[CH:13]=[CH:12][C:11]([C:1]34[CH2:10][CH:5]5[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]5)[CH2:2]3)[CH2:8]4)=[CH:22][CH:21]=2)[CH:27]=1
Reactant: O=C(O)C=COc1ccc(C23CC4CC(CC(C4)C2)C3)cc1
Reactant: COC(=O)c1cccc(N)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cccc(NC(=O)/C=C/Oc2ccc(C34CC5CC(CC(C5)C3)C4)cc2)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 10 %

Procedure:
3-(4-Adamantan-1-yl-phenoxy)-acrylic acid (110.6 mg, 0.5 mmol), 3-aminobenzoic acid methyl ester (151.2 mg, 1.0 mmol) and HATU (143.8 mg, 0.75 mmol) were mixed in 5 ml of DMF, to which DIPEA (0.13 ml, 0.75 mmol) was added, followed by stirring for 12 hours at room temperature. The reaction mixture was extracted with ethylacetate and 10% HCl, thereafter the organic layer was washed with NaCl solution and water, dried over anhydrous MgSO4, and concentrated. The residue was purified by silcagel column chromatography (n-Hexane:EtOAc=10:1) to give the target compound as a white solid (21.5 mg, yield: 10.6%).
Reaction SMILES: [CH3:1][Si:2]([CH3:39])([CH3:38])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:37])([CH3:36])[CH3:35])[C:8]1[N:13]2[N:14]=[CH:15][C:16]([I:17])=[C:12]2[N:11]=[C:10]([CH:18]2[CH2:23]C[CH:21]([CH2:24][C:25](OCC)=O)[CH2:20][CH2:19]2)[CH:9]=1.C[Si](C)(C)CCOC[N:46](COCC[Si](C)(C)C)C1N2N=CC=C2N=C(C2CCCC(CC(OCC)=O)C2)C=1.C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)C1N2N=CC=C2N=C(C2CCC(CC(OCC)=O)CC2)C=1>>[CH3:38][Si:2]([CH3:1])([CH3:39])[CH2:3][CH2:4][O:5][CH2:6][N:7]([CH2:30][O:31][CH2:32][CH2:33][Si:34]([CH3:35])([CH3:36])[CH3:37])[C:8]1[N:13]2[N:14]=[CH:15][C:16]([I:17])=[C:12]2[N:11]=[C:10]([CH:18]2[CH2:19][CH2:20][CH:21]([CH2:24][C:25]#[N:46])[CH2:23]2)[CH:9]=1
Reactant: CCOC(=O)CC1CCCC(c2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3nccc3n2)C1
Reactant: CCOC(=O)CC1CCC(c2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3ncc(I)c3n2)CC1
Agent: CCOC(=O)CC1CCC(c2cc(N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)n3nccc3n2)CC1
Product: C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)c1cc(C2CCC(CC#N)C2)nc2c(I)cnn12

Procedure:
2-(3-(7-(Bis((2-(trimethylsilyl)ethoxy)methyl)amino)-3-iodopyrazolo[1,5-a]pyrimidin-5-yl)cyclopentyl)acetonitrile was synthesized in a manner similar to the synthesis of ethyl 2-(4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)-3-iodopyrazolo[1,5-a]pyrimidin-5-yl)cyclohexyl)acetate, but with ethyl 2-(3-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)cyclohexyl)acetate substituted for ethyl 2-(4-(7-(bis((2-(trimethylsilyl)ethoxy)methyl)amino)pyrazolo[1,5-a]pyrimidin-5-yl)cyclohexyl)acetate.
Reaction SMILES: [O:1]([C:3]#[N:4])[K].[N:5]1([CH:10]([C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=2)[CH:11]([CH3:13])[CH3:12])[CH:9]=[CH:8][N:7]=[CH:6]1.[OH-].[Na+]>O.C(O)(=O)C>[N:5]1([CH:10]([C:14]2[CH:15]=[CH:16][C:17]([NH:20][C:3]([NH2:4])=[O:1])=[CH:18][CH:19]=2)[CH:11]([CH3:13])[CH3:12])[CH:9]=[CH:8][N:7]=[CH:6]1
Reactant: N#CO[K]
Reactant: CC(C)C(c1ccc(N)cc1)n1ccnc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: CC(C)C(c1ccc(NC(N)=O)cc1)n1ccnc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 37.7 %

Procedure:
A solution of KOCN (2.25 g) in water was added dropwise at RT to a mixture of 4-[1-(1H-imidazol-1-yl)-2-methylpropyl]benzenamine (0.0278 mol) in acetic acid (4 ml) and water (50 ml) and the mixture was stirred at RT for 1 hour. The mixture was neutralized with NaOH 3N and extracted with CH2Cl2 and CH3OH. The organic layer was washed with water, dried, filtered and the solvent evaporated. The residue was purified by column chromatography over silica gel (eluent: CH2Cl2/CH3O/NH4OH 96/4/0.3). The pure fractions were collected and evaporated. The residue was recrystallized from 2-propanone, yielding 2.7 g (51.4%) (±)-4-[1-(1H-imidazol-1-yl)-2-methylpropyl]phenylurea (compound 266).
Reaction SMILES: [CH2:1]([C:8]1[NH:9][C:10]2[C:15]([CH:16]=1)=[CH:14][C:13]([N+:17]([O-:19])=[O:18])=[CH:12][CH:11]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.Cl[CH2:22][CH2:23][CH:24]1[CH2:28][CH2:27][CH2:26][N:25]1[CH3:29].C(=O)([O-])[O-].[K+].[K+]>>[CH2:1]([C:8]1[N:9]([CH2:22][CH2:23][CH:24]2[CH2:28][CH2:27][CH2:26][N:25]2[CH3:29])[C:10]2[C:15]([CH:16]=1)=[CH:14][C:13]([N+:17]([O-:19])=[O:18])=[CH:12][CH:11]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccc2[nH]c(Cc3ccccc3)cc2c1
Reactant: CN1CCCC1CCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CN1CCCC1CCn1c(Cc2ccccc2)cc2cc([N+](=O)[O-])ccc21
Temperature: 65 °C
Yield: 63.9 %

Procedure:
Compound 3 (165 mg, 0.654 mmol), 2-(2-chloroethyl)-1-methylpyrrolidine hydrochloride (132.4 mg, 0.719 mmol), and powdered potassium carbonate (271.2 mg, 1.962 mmol) were placed in an argon-purged flask. DMF (5 mL, Aldrich sure seal™) was added and the mixture heated to 65° C. in an oil bath for 20 hours. The solution was cooled to room temperature and diluted with water (10 mL) and ethyl acetate (25 mL). The layers were separated and the aqueous phase extracted with ethyl acetate (2×25 mL). The organic extracts were combined, washed with brine (2×10 mL) and dried over magnesium sulfate. The sample was filtered, concentrated, and the resultant crude product purified using dry silica gel column chromatography eluting with 15-20 mL portions of solvent system (2M NH3 in methanol:CH2Cl2, 5:95) to afford a yellow solid 4 (152 mg, 63.9%); 1H NMR (CDCl3) δ 8.50 (d, 1H, J=2.2 Hz), 8.07 (dd, 1H, J=2.2, 9.0 Hz), 7.36-7.17 (m, 6H), 6.44 (s, 1H), 4.16 (d, 2H, J=3.0 Hz), 4.10-3.97 (m, 2H), 3.06 (t, 1H, J=7.1 Hz), 2.21 (s, 3H), 2.15-2.00 (2×m, 2H), 1.97-1.55 (m, 5H), 1.53-1.40 (m, 1H); ESI-MS (m/z, %): 364 (M+1, 100%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@H:10]([C:14]([NH:16][C:17]3[N:21]([CH3:22])[N:20]=[CH:19][CH:18]=3)=[O:15])[CH2:9]2)[CH:5]=[C:4]([C:23]2[CH:28]=[CH:27][C:26]([C:29]#[N:30])=[C:25](F)[CH:24]=2)[N:3]=1.CCN(C(C)C)C(C)C.[NH2:41][NH2:42]>CCO>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@H:10]([C:14]([NH:16][C:17]3[N:21]([CH3:22])[N:20]=[CH:19][CH:18]=3)=[O:15])[CH2:9]2)[CH:5]=[C:4]([C:23]2[CH:24]=[C:25]3[C:26]([C:29]([NH2:30])=[N:41][NH:42]3)=[CH:27][CH:28]=2)[N:3]=1
Reactant: NN
Reactant: Cn1nccc1NC(=O)[C@H]1CCCN(c2cc(-c3ccc(C#N)c(F)c3)nc(N)n2)C1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: Cn1nccc1NC(=O)[C@H]1CCCN(c2cc(-c3ccc4c(N)n[nH]c4c3)nc(N)n2)C1
Temperature: 110 °C
Yield: 44.3 %

Procedure:
Into a microwave tube, (3S)-1-[2-amino-6-(4-cyano-3-fluorophenyl)-4-pyrimidinyl]-N-(1-methyl-1H-pyrazol-5-yl)-3-piperidinecarboxamide (180 mg, 0.428 mmol), 3 mL of EtOH, Hunig's base (0.30 mL, 1.71 mmol), and hydrazine anhydrous (0.081 mL, 2.57 mmol) were added, and the yellow mixture was heated overnight at 110° C. in an oil bath. The solution turned black. LCMS showed mainly product. The black solids were filtered and the yellow filtrate was evaporated. The resulting yellow residue was treated with EtOAc (3 mL) at 50° C. with stirring, and the clear layer of EtOAc solution was poured out. The solid layer was then treated with water (3 mL) at 50° C. with stirring, and the suspension was filtered. The light yellow colored solid was washed by water, and dried to give the title compound (82 mg) as a light yellow solid. LC-MS (ES) m/z=433 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 1.39-1.57 (m, 1H), 1.62-1.84 (m, 2H), 2.04 (m, 1H), 2.55-2.71 (m, 1H), 2.81-2.94 (m, 1H), 2.97-3.11 (m, 1H), 3.67 (s, 3H), 4.39-4.73 (m, 2H), 5.38 (s, 2H), 6.11 (s, 2H), 6.21 (s, 1H), 6.69 (s, 1H), 7.33 (s, 1H), 7.56-7.77 (m, 2H), 7.97 (s, 1H), 10.00 (s, 1H), 11.50 (s, 1H).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][CH2:5][O:6][C:7]1[C:15]2[CH:14]=[C:13]([C:16]3[O:20][C:19](=[O:21])[NH:18][N:17]=3)[O:12][C:11]=2[CH:10]=[CH:9][CH:8]=1.[CH3:22]I>CN(C=O)C>[CH3:3][O:4][CH2:5][O:6][C:7]1[C:15]2[CH:14]=[C:13]([C:16]3[O:20][C:19]([O:21][CH3:22])=[N:18][N:17]=3)[O:12][C:11]=2[CH:10]=[CH:9][CH:8]=1
Reactant: CI
Reactant: COCOc1cccc2oc(-c3n[nH]c(=O)o3)cc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCOc1cccc2oc(-c3nnc(OC)o3)cc12
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a suspension of sodium hydride (0.17 g) in DMF was added dropwise a solution (20 ml) of 5-(4-(methoxymethyloxy)-benzo(b)furan-2-yl)-2,3-dihydro-1,3,4-oxadiazol-2-one (1.0 g) obtained in Starting Material Synthesis Example 116 in DMF at room temperature, and the mixture was stirred for 30 min. Thereto was added methyl iodide (0.26 ml), and the mixture was further stirred for 30 min. The reaction mixture was poured into ice water and extracted with ethyl acetate. The extract was washed with water and dried. The solvent was evaporated under reduced pressure to give the title compound (0.80 g) as pale-yellow crystals.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][C:7]([C:18]2[CH:31]=[CH:30][C:21]([O:22][CH2:23][C:24](=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26])=[C:20]([CH3:32])[CH:19]=2)([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[C:12]([CH3:17])[CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].ClCC(=O)C(C)(C)C.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:47]1[O:49][C@H:48]1[CH2:50][OH:51]>>[C:1]([N:4]1[CH2:9][CH2:8][C:7]([C:18]2[CH:31]=[CH:30][C:21]([O:22][CH2:23][C:24](=[O:29])[C:25]([CH3:26])([CH3:27])[CH3:28])=[C:20]([CH3:32])[CH:19]=2)([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:47][CH:48]([OH:49])[CH2:50][OH:51])=[C:12]([CH3:17])[CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCC(c2ccc(O)c(C)c2)(c2ccc(OCC(=O)C(C)(C)C)c(C)c2)CC1
Reactant: OC[C@H]1CO1
Agent: CC(C)(C)C(=O)CCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CC(=O)N1CCC(c2ccc(OCC(=O)C(C)(C)C)c(C)c2)(c2ccc(OCC(O)CO)c(C)c2)CC1

Procedure:
In a manner similar to that described for Example 6B, 1-{4-[1-acetyl-4-(4-hydroxy-3-methylphenyl)-piperidin-4-yl]-2-methylphenoxy)-3,3-dimethylbutan-2-one was prepared by using 1 equiv of 1-chloropinacolone and cesium carbonate. 1-{4-[1-Acetyl-4-(4-hydroxy-3-methylphenyl)-piperidin-4-yl]-2-methylphenoxy}-3,3-dimethylbutan-2-one was then alkylated with (S)-glycidol as in Example 1H to yield 1-(4-(1-acetyl-4-[4-(2,3-dihydroxypropoxy)-3-methylphenyl]-piperidin-4-yl}-2-methylphenoxy)-3,3-dimethylbutan-2-one.
Reaction SMILES: [CH3:1][Li].[Br:3][C:4]1[CH:5]=[CH:6][C:7]([Cl:12])=[C:8]([CH:11]=1)[CH:9]=[O:10]>C1COCC1>[Br:3][C:4]1[CH:5]=[CH:6][C:7]([Cl:12])=[C:8]([CH:9]([OH:10])[CH3:1])[CH:11]=1
Reactant: [Li]C
Reactant: O=Cc1cc(Br)ccc1Cl
Solvent: C1CCOC1
Product: CC(O)c1cc(Br)ccc1Cl
Reaction time: 15 h
Yield: 89.3 %

Procedure:
Methyl lithium (11.6 mL, 16.3 mmol, 1.4M in ether) was added to a cooled −78° C. solution of 5-bromo-2-chloro-benzaldehyde (2.75 g, 12.5 mmol) dissolved in THF (40 mL). The reaction mixture was stirred for 15 hours and then quenched with saturated NH4Cl and extracted with EtOAc. The organic extracts were washed with 1N HCl, brine, dried over Na2SO4 and concentrated to an oil. The oil was purified by flash column chromatography (0% to 10% EtOAc in hexanes) to give the title compound as a solid (2.63 g, 91%). 1H NMR (400 MHz, CDCl3): δ 6.32 (d, J=6.3 Hz, 3 H), 2.00 (d, J=3.8 Hz, 1 H), 5.24 (m, 1 H), 7.19 (d, J=8.6 Hz, 1 H), 7.33 (dd, J=8.6, 2.5 Hz, 1 H), 7.75 (d, J=2.5 Hz, 1 H).