Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: BrP([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C([Li])CCC.[Cl:36][C:37]1[CH:38]=[C:39](/[CH:44]=[CH:45]/[CH:46]=O)[CH:40]=[CH:41][C:42]=1[Cl:43]>C1COCC1>[Cl:43][C:42]1[CH:41]=[CH:40][C:39](/[CH:44]=[CH:45]/[CH:46]=[CH:21][C:22]2[CH:23]=[CH:24][C:25]([N+:28]([O-:30])=[O:29])=[CH:26][CH:27]=2)=[CH:38][C:37]=1[Cl:36]
Reactant: O=[N+]([O-])c1ccc(CP(Br)(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: O=C/C=C/c1ccc(Cl)c(Cl)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(C=C/C=C/c2ccc(Cl)c(Cl)c2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 27.8 %

Procedure:
A mixture of 4-nitro-benzyl bromide (200.0 g, 0.93 mol) and triphenylphosphine (244.0 g, 0.93 mol) in CHCl3 (1.5 L) was heated to reflux for overnight. The reaction mixture was cooled to room temperature, concentrated in vacuo to remove CHCl3 and then suspended in Et2O and stirred rigorously. The suspension was filtered, and the off-white solid was washed with Et2O, dried at 80° C. for 16 hours to give 433.0 g (0.91 mol, 98%) of bromo[(4-nitrophenyl)methyl]triphenylphosphine. A solution of bromo[(4-nitrophenyl)methyl]triphenylphosphine (100.0 g, 0.23 mol) in dry THF (500 mL) was cooled to 5° C. n-Butyl lithium (n-BuLi) (2.4 M, 96 mL, 0.23 mol) was added dropwise to maintain the temperature between 5° C. to 10° C. The cooling bath was then removed, and the reaction mixture was allowed to warm to room temperature. After 4 hours, a solution of (trans)-3-(3,4-dichlorophenyl)-2-propenal (36.2 g, 0.18 mol) in THF (100 mL) was added dropwise, and the resulting mixture was stirred at room temperature for 16 hours. The mixture was filtered, and the filtrate was concentrated in vacuo to give a residue. Purification by flash chromatography (silica gel, 20% EtOAc/hexane) yielded 16.0 g (0.05 mol, 28%) of the desired product. mp 125-135° C.
Reaction SMILES: [C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:30]/[O:31][CH:32]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH3:33])/C(O)=O)[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.ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1.[NH2:66][C@@H:67]1[C:85](=[O:86])[N:69]2[C:70]([C:82]([OH:84])=[O:83])=[C:71]([CH2:74][S:75][C:76]3[N:80]([NH2:81])[N:79]=[N:78][N:77]=3)[CH2:72][S:73][C@H:68]12.C(N(CC)CC)C.NC1C(CSC2N(NC(C)C)N=NN=2)=C([C:112](O)=[O:113])N2C(=O)C[C@H]2S1>CC(N(C)C)=O.O>[C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24](/[C:26](=[N:30]/[O:31][CH:32]([C:34]([O:36][C:37]([CH3:40])([CH3:38])[CH3:39])=[O:35])[CH3:33])/[C:112]([NH:66][C@@H:67]2[C:85](=[O:86])[N:69]3[C:70]([C:82]([OH:84])=[O:83])=[C:71]([CH2:74][S:75][C:76]4[N:80]([NH2:81])[N:79]=[N:78][N:77]=4)[CH2:72][S:73][C@H:68]23)=[O:113])[N:25]=1)([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)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CC(C)Nn1nnnc1SCC1=C(C(=O)O)N2C(=O)C[C@H]2SC1N
Reactant: N[C@@H]1C(=O)N2C(C(=O)O)=C(CSc3nnnn3N)CS[C@H]12
Reactant: CC(O/N=C(\C(=O)O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1)C(=O)OC(C)(C)C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(CC)CC
Solvent: CC(=O)N(C)C
Product: CC(O/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(CSc3nnnn3N)CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 17 h
Yield: 60 %

Procedure:
A solution of 2-(2-tritylaminothiazol-4-yl)-(Z)-2-(1-tert-butoxycarbonylethoxyimino)acetic acid (4.18 g, 7.5 mmol), 1-hydroxybenzotriazole (1.11 g, 8.25 mmol) and N,N'-dicyclohexylcarbodiimide (1.70 g, 8.25 mmol) in dimethylacetamide (35 ml) was stirred at room temperature for 2.5 hours. To the solution was added a solution of 7β-amino-3-[(1-amino-1H-tetrazol-5-yl)thiomethyl]-3-cephem-4-carboxylic acid (2.96 g, 8.98 mmol) and triethylamine (1.82 g, 18 mmol) in dimethylacetamide (18 ml) and water (2.5 ml) and the mixture was stirred at room temperature for 17 hours. Then the mixture was treated in a manner similar to that described in Example 6, (c) to give pale brown powder of 7β-[2-(2-tritylaminothiazol-4-yl)-(Z)-2-(1-tert-butoxycarbonylethoxyimino)acetamido]-3-[(1-amino-1H-tetrazol-5-yl)thiomethyl]-3-cephem-4-carboxylic acid (3.88 g, 60%).
Reaction SMILES: [CH2:1]([O:15][C:16]1[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].C(Cl)(=O)C([Cl:28])=O>CN(C)C=O.C(Cl)Cl>[CH2:1]([O:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]([Cl:28])=[O:21])=[CH:18][CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCCCCCCCCCCOc1ccc(C(=O)O)cc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCOc1ccc(C(=O)Cl)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a room temperature suspension of 15 g of product from Example 2, 160 ml methylene chloride and 5 drops dimethylformamide is added 5.87 ml oxalyl chloride. The reaction mixture is stirred at room temperature for 18 hours, concentrated in vacuo, dissolved in 300 ml of diethyl ether, filtered through diatomaceous earth and the filtrate concentrated in vacuo to give 15.5 g of the desired product.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([NH2:36])[C:5]2[CH:11]=[C:10]([CH2:12][CH2:13][C:14]3[CH:35]=[CH:34][C:17]([C:18]([NH:20][C@H:21]([C:29]([O:31]CC)=[O:30])[CH2:22][CH2:23][C:24]([O:26]CC)=[O:25])=[O:19])=[CH:16][CH:15]=3)[CH:9]=[N:8][C:6]=2[N:7]=1.[OH-].[Na+].C(O)(=O)C>CO>[NH2:1][C:2]1[N:3]=[C:4]([NH2:36])[C:5]2[CH:11]=[C:10]([CH2:12][CH2:13][C:14]3[CH:15]=[CH:16][C:17]([C:18]([NH:20][C@H:21]([C:29]([OH:31])=[O:30])[CH2:22][CH2:23][C:24]([OH:26])=[O:25])=[O:19])=[CH:34][CH:35]=3)[CH:9]=[N:8][C:6]=2[N:7]=1
Reactant: CCOC(=O)CC[C@H](NC(=O)c1ccc(CCc2cnc3nc(N)nc(N)c3c2)cc1)C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Product: Nc1nc(N)c2cc(CCc3ccc(C(=O)N[C@@H](CCC(=O)O)C(=O)O)cc3)cnc2n1
Yield: 44.5 %

Procedure:
A solution of 0.38 g of diethyl N-(4-[2-(2,4-diaminopyrido[2,3-d]pyrimidin-6-yl)ethyl]benzoyl)-L-glutamate in 50 mL of methanol containing 4.6 mL of 0.5N aqueous sodium hydroxide was stirred at room temperature for 72 hours. Acetic acid (5 mL) was added, and the resulting white precipitate collected by filtration. The filter cake was washed well with water, methanol, and ether and was dried under reduced pressure to yield 0.15 g (44%) of the title compound, which can be alternatively named as 5,10-dideazaaminopterin; mp >250° C.; NMR (TFA-d1) delta 2.2-2.7 (m, 2H), 2.28; 2.7-2.95 (m, 2H), 5.0-5.2 (m, 1H), 7.35 and 7.85 (AB q, 4H, J=9 Hz), 8.7 (s, 1H), 9.1 (s, 1H).
Reaction SMILES: [H-].[Na+].[N:3]1([C:8]2[CH:9]=[C:10]([C:18]3[S:22][C:21]([NH2:23])=[N:20][C:19]=3[CH3:24])[CH:11]=[CH:12][C:13]=2[S:14]([CH3:17])(=[O:16])=[O:15])[CH:7]=[CH:6][N:5]=[CH:4]1.[C:25](N1C=CN=C1)([N:27]1[CH:31]=[CH:30][N:29]=[CH:28]1)=[O:26]>CN(C)C=O>[N:3]1([C:8]2[CH:9]=[C:10]([C:18]3[S:22][C:21]([NH:23][C:25]([N:27]4[CH:31]=[CH:30][N:29]=[CH:28]4)=[O:26])=[N:20][C:19]=3[CH3:24])[CH:11]=[CH:12][C:13]=2[S:14]([CH3:17])(=[O:16])=[O:15])[CH:7]=[CH:6][N:5]=[CH:4]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Cc1nc(N)sc1-c1ccc(S(C)(=O)=O)c(-n2ccnc2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1nc(NC(=O)n2ccnc2)sc1-c1ccc(S(C)(=O)=O)c(-n2ccnc2)c1
Temperature: 40 °C

Procedure:
Sodium hydride (60% dispersion in oil, 0.137 g, 3.42 mmol) is added to a stirred suspension of 5-(3-Imidazol-1-yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-ylamine (148) (1.04 g, 3.1 mmol) in dry dimethylformamide (10 ml) at room temperature under argon. 1,1′-Carbonyl diimidazole (0.757 g, 4.67 mmol) is added and the stirred suspension is heated to 40° C. for 1 h. The reaction mixture is cooled and the resulting solid filtered and washed with DCM and ether to afford the title compound.
Reaction SMILES: Br[CH:2]1[C:8](=[O:9])[C:7]2[CH:10]=[CH:11][CH:12]=[CH:13][C:6]=2[O:5][CH:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:3]1.[CH3:20][N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>C1C=CC=CC=1>[CH3:20][N:21]1[CH2:26][CH2:25][N:24]([CH:2]2[C:8](=[O:9])[C:7]3[CH:10]=[CH:11][CH:12]=[CH:13][C:6]=3[O:5][CH:4]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:3]2)[CH2:23][CH2:22]1
Reactant: O=C1c2ccccc2OC(c2ccccc2)CC1Br
Reactant: CN1CCNCC1
Solvent: c1ccccc1
Product: CN1CCN(C2CC(c3ccccc3)Oc3ccccc3C2=O)CC1
Yield: 55.1 %

Procedure:
970 mg (3.1 m moles) of 4-bromo-2-phenyl-2,3,4,5-tetrahydro-1-benzoxepin-5-one (compound R14 of Reference Example 14) was dissolved in 100 ml of benzene, 3.1 g (10 equivalent amount) of N-methylpiperazine was added to the solution, and the whole was heated to reflux for 7 hours. After distilling off the solvent, water was added to the residue, and the mixture was extracted with methylene chloride. The organic phase was washed with water and dried with anhydrous magnesium sulfate. After filtrating off the magnesium sulfate, the filtrate was concentrated to obtain a residue, which was then applied to a silica gel column, and eluted with a mixture of methylene chloride/methanol (90:10) to obtain diastereomers R15a (700 mg; yield 55.1%) and R15b (220 mg; yield 17.3%) of the desired compound.
Reaction SMILES: OC(C(F)(F)F)=O.[NH:8]1[CH2:11][CH:10]([NH:12][C:13](=[O:30])[CH2:14][NH:15][C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([C:25]([F:28])([F:27])[F:26])[CH:23]=3)[N:18]([CH3:29])[N:17]=2)[CH2:9]1.[OH:31][C:32]1([C:39]2[CH:40]=[N:41][C:42]([O:45][CH3:46])=[CH:43][CH:44]=2)[CH2:37][CH2:36][C:35](=O)[CH2:34][CH2:33]1>>[OH:31][C:32]1([C:39]2[CH:40]=[N:41][C:42]([O:45][CH3:46])=[CH:43][CH:44]=2)[CH2:33][CH2:34][CH:35]([N:8]2[CH2:9][CH:10]([NH:12][C:13](=[O:30])[CH2:14][NH:15][C:16]3[C:24]4[C:19](=[CH:20][CH:21]=[C:22]([C:25]([F:27])([F:26])[F:28])[CH:23]=4)[N:18]([CH3:29])[N:17]=3)[CH2:11]2)[CH2:36][CH2:37]1
Reactant: COc1ccc(C2(O)CCC(=O)CC2)cn1
Reactant: Cn1nc(NCC(=O)NC2CNC2)c2cc(C(F)(F)F)ccc21
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(C2(O)CCC(N3CC(NC(=O)CNc4nn(C)c5ccc(C(F)(F)F)cc45)C3)CC2)cn1

Procedure:
The title compound was prepared as a white solid from reaction of N-azetidin-3-yl-2-(1-methyl-5-trifluoromethyl-1H-indazol-3-ylamino)-acetamide TFA salt (as prepared in the previous step) and 4-hydroxy-4-(6-methoxy-pyridin-3-yl)-cyclohexanone using the procedure described in Step E of Example 1.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH2:36][CH2:37][CH3:38])=[C:5]([CH:28]=[CH:29][C:30]=1[C:31]1[N:32]=[CH:33][S:34][CH:35]=1)[O:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:24]=[CH:23][C:14]2[CH2:15][CH2:16][CH:17]([C:19]([O:21]C)=[O:20])[O:18][C:13]=2[C:12]=1[CH2:25][CH2:26][CH3:27].CO.C1COCC1.C(OCC)(=O)C>[OH-].[Li+]>[CH3:1][O:2][C:3]1[C:4]([CH2:36][CH2:37][CH3:38])=[C:5]([CH:28]=[CH:29][C:30]=1[C:31]1[N:32]=[CH:33][S:34][CH:35]=1)[O:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:24]=[CH:23][C:14]2[CH2:15][CH2:16][CH:17]([C:19]([OH:21])=[O:20])[O:18][C:13]=2[C:12]=1[CH2:25][CH2:26][CH3:27]
Reactant: CCCc1c(OCCCOc2ccc(-c3cscn3)c(OC)c2CCC)ccc2c1OC(C(=O)OC)CC2
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CO
Product: CCCc1c(OCCCOc2ccc(-c3cscn3)c(OC)c2CCC)ccc2c1OC(C(=O)O)CC2

Procedure:
The compound of Example 11 (27 mg, 50 mmol) was combined with 2 mL of 4:1 methanol/THF and 0.1 mL of IN lithium hydroxide, and the mixture was allowed to react at room temperature for 3 hr (another 0.05 mL LiOH was added after 1.5 hr). The reaction mixture was poured into ethyl acetate/0.5 M hydrochloric acid, and the ethyl acetate layer was washed with brine, dried over sodium sulfate and concentrated under vacuum to give the product. High resolution mass spectrum, m/e 481.2281 (calculated for C28H35SO4N (M-CO2), 481.2287).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][NH:4][C@H:3]1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Cl[C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[CH2:18]([O:17][C:15]([NH:1][C@H:2]1[CH2:7][CH2:6][CH2:5][NH:4][C@H:3]1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:16])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: N[C@H]1CCCN[C@H]1c1ccccc1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(N[C@H]1CCCN[C@H]1c1ccccc1)OCc1ccccc1
Reaction time: 16 h
Yield: 80.2 %

Procedure:
To a solution of (2S,3S)-(−)-3-amino-2-phenylpiperidine (152 mg, 0.86 mmole) (L-tartaric acid salt, [a]D=−57.1 (EtOH, c=0.1138)) in methylene chloride (10 mL) at room temperature was added benzyl chloroformate (0.123 mL, 0.86 mmole) and diisopropylethylamine (0.45 mL, 2.58 mmole). The reaction was stirred for 16 hours and was then diluted with methylene chloride and quenched by addition of water. The mixture was separated and the aqueous was reextracted with 2 additional aliquots of methylene chloride. The organic layers were successively washed with a portion of brine, dried over sodium sulfate, combined and evaporated. The residue was purified by flash chromatography (5% methanol in methylene chloride) to afford 214 mg (80%) of the title compound. NMR (CDCl3): δ 1.55 (br, d, J=9 Hz, 1 H), 1.6-1.9 (m, 2 H), 2.02 (br. d, J=9 Hz, 1 H), 2.79 (dd, J=9 and 10 Hz, 1 H), 3.22 (dd, J=1 and 10 Hz, 1 H), 3.91 (br. s, 1 H), 4.01 (dd, J=1 and 8 Hz, 1 H), 4.89 (s, 2 H), 5.65 and 5.88 (2 br. s, 1 H), 7.1-7.4 (m, 10 H).
Reaction SMILES: C(C1NC=CN=1)(C1NC=CN=1)=[S:2].[CH2:13]([O:20][C:21]1[CH:22]=[C:23]([CH:25]=[CH:26][CH:27]=1)[NH2:24])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[NH2:28][C:29]1C=CC=CC=1>ClCCl>[CH2:13]([O:20][C:21]1[CH:22]=[C:23]([NH:24][C:29]([NH2:28])=[S:2])[CH:25]=[CH:26][CH:27]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: Nc1ccccc1
Reactant: Nc1cccc(OCc2ccccc2)c1
Reactant: S=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: ClCCl
Product: NC(=S)Nc1cccc(OCc2ccccc2)c1
Reaction time: 2 h

Procedure:
Alternatively thiocarbonyl di-imidazole (1.1 mmol, 196 mg) is added to a solution of 3-benzyloxyaniline (1 mmol, 199 mg) in dichloromethane (5 mL). The reaction is stirred at room temperature until the aniline is consumed, about 1 hour. A solution of methanolic ammonia (2 M, 2 mL) is added and the stirring continued for 2 hours. Solvent is evaporated and the residue purified by chromatography on silica gel to give 150 mg of (3-benzyloxyphenyl)thiourea.
Reaction SMILES: [OH:1][CH2:2][C:3]1[NH:4][C:5]2[CH:10]=[CH:9][N:8]=[CH:7][C:6]=2[N:11]=1.N1C=CN=C1.[Si:17](Cl)([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18]>CN(C)C=O>[Si:17]([O:1][CH2:2][C:3]1[NH:4][C:5]2[CH:10]=[CH:9][N:8]=[CH:7][C:6]=2[N:11]=1)([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18]
Reactant: OCc1nc2cnccc2[nH]1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCc1nc2cnccc2[nH]1

Procedure:
A procedure similar to that described in Preparation 49 was repeated, except that 5.00 g of 2-hydroxymethyl-1H-imidazo[4,5-c]pyridine, 6.85 g of imidazole, 7.58 g of t-butyldimethylsilyl chloride and 100 ml of dimethylformamide were used, to give the title compound as a crude product. This crude product was purified by column chromatography through silica gel, using a 10:1 by volume mixture of ethyl acetate and methanol as the eluent, to give 7.40 g of the title compound, melting at 53°-55° C.
Reaction SMILES: [NH2:1][C@H:2](C(N)=O)[CH2:3][C:4]1C=CC(O)=C[CH:5]=1.Cl.C([N:17]([CH2:20]C)[CH2:18][CH3:19])C.FC(F)(F)C(OC1C(F)=C(F)C(F)=C(F)C=1F)=O>ClCCl>[N:17]1[C:18]2[CH:19]=[CH:5][CH:4]=[CH:3][C:2]=2[NH:1][CH:20]=1
Reactant: NC(=O)[C@@H](N)Cc1ccc(O)cc1
Reactant: CCN(CC)CC
Agent: Cl
Agent: O=C(Oc1c(F)c(F)c(F)c(F)c1F)C(F)(F)F
Solvent: ClCCl
Product: c1ccc2[nH]cnc2c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 193.1 %

Procedure:
To a 0° C. crude solution of compound 2 (4.1 g, 15.34 mmol) and triethylamine (6.4 mL, 46.02 mmol) in dichloromethane (200 mL) was added pentafluorophenyl trifluoroacetate (6.35 mL, 36.82 mmol) via syringe over 3 min. After another 5 min, the ice bath was removed and the reaction mixture stirred while warming to room temperature for another 2 hours. The reaction mixture was concentrated in vacuo, and the resulting residue purified by flash chromatography (silica gel, hexanes/ethyl acetate=1:0, 50:1) to give compound 3 (3.5 g, 50% yield).
Reaction SMILES: [OH:1][CH:2]([CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=1)[C:3]#[CH:4].N1C=CN=C1.Cl[Si:20]([CH3:23])([CH3:22])[CH3:21]>CCCCCC>[F:13][C:10]1[CH:9]=[CH:8][C:7]([O:6][CH2:5][CH:2]([O:1][Si:20]([CH3:23])([CH3:22])[CH3:21])[C:3]#[CH:4])=[CH:12][CH:11]=1
Reactant: C#CC(O)COc1ccc(F)cc1
Reactant: C[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CCCCCC
Product: C#CC(COc1ccc(F)cc1)O[Si](C)(C)C
Temperature: 0 °C
Yield: 87.9 %

Procedure:
To a 0° C. solution of 10 g (55 mmoles) of 3-hydroxy-4-p-fluorophenoxy-1-butyne (Example 157) in 75 ml of dry dimethylformamidee and 88 g (130 mmoles) of imidazole is added dropwise, with stirring, 7.5 g (68 mmoles) of chlorotrimethylsilane. The mixture, while under an argon atmosphere, is stirred at room temperature for 18 hours, and then poured into 150 ml of hexane and 100 ml of ice-water. Thhe organic phase is separated, washed with 50 ml of a brine solution, dried with magnesium sulfate, and evaporated under vacuum. This crude product is distilled under vacuum at 0.1 mm (bp 73°-75° C.), to give 12.2 g (91%) of the subject compound as a colorless oily liquid.
Reaction SMILES: [NH2:1][C@@H:2]([CH3:36])[C:3]([NH:5][C@H:6]1[CH2:12][O:11][C:10]2[CH:13]=[CH:14][CH:15]=[CH:16][C:9]=2[N:8]([CH2:17][C:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[N:20]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[C:33]#[N:34])[N:19]=2)[C:7]1=[O:35])=[O:4].[CH3:37][C:38]1([CH3:41])[CH2:40][O:39]1>CCO>[C:33]([C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[N:20]1[C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:18]([CH2:17][N:8]2[C:7](=[O:35])[C@@H:6]([NH:5][C:3](=[O:4])[C@@H:2]([NH:1][CH2:37][C:38]([OH:39])([CH3:41])[CH3:40])[CH3:36])[CH2:12][O:11][C:10]3[CH:13]=[CH:14][CH:15]=[CH:16][C:9]2=3)=[N:19]1)#[N:34]
Reactant: C[C@H](N)C(=O)N[C@H]1COc2ccccc2N(Cc2nn(-c3ccccc3C#N)c3ccccc23)C1=O
Reactant: CC1(C)CO1
Solvent: CCO
Product: C[C@H](NCC(C)(C)O)C(=O)N[C@H]1COc2ccccc2N(Cc2nn(-c3ccccc3C#N)c3ccccc23)C1=O
Temperature: 100 °C
Reaction time: 2 h
Yield: 59.1 %

Procedure:
(S)-2-Amino-N-((S)-5-((1-(2-cyanophenyl)-1H-indazol-3-yl)methyl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)propanamide (50 mg, 104 μmol, Eq: 1.00), LiClO4 (11.1 mg, 4.56 μl, 104 μmol, Eq: 1.00) and 2,2-dimethyloxirane (1 mL) were mixed with EtOH (7 mL) in a microwave reaction vial, the vial was sealed and heated in the microwave at 100° C. After 2 h, 20 eq of 2,2-dimethyloxirane were added and heating was continued under microwave at 100° C. for 3 h. The mixture was concentrated and the residue was purified by preparative TLC to give the title compound (34 mg, 59.1%) as a solid. MS m/z 553 (MH+)
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([N:9]2[CH2:11][CH:10]2[C:12]([O:14][CH3:15])=[O:13])=[O:8])=[CH:4][CH:3]=1.[CH3:16][O:17][CH2:18][CH2:19][OH:20].B(F)(F)F.CCOCC>C(Cl)Cl>[Cl:1][C:2]1[S:6][C:5]([C:7]([NH:9][CH:10]([CH2:11][O:20][CH2:19][CH2:18][O:17][CH3:16])[C:12]([O:14][CH3:15])=[O:13])=[O:8])=[CH:4][CH:3]=1
Reactant: COC(=O)C1CN1C(=O)c1ccc(Cl)s1
Reactant: COCCO
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: COCCOCC(NC(=O)c1ccc(Cl)s1)C(=O)OC
Reaction time: 3 h

Procedure:
A mixture of 0.30 g (about 1 mmol) methyl N-(5-chlorothiophen-2yl)carbonyl-aziridine-2-carboxylate and 0.29 ml (3.7 mmol) 2-methoxyethanol in 4 ml methylene chloride is slowly combined with 0.16 ml boron trifluoride etherate and stirred for 3 h. The reaction mixture is concentrated and purified by chromatography (silica gel, petroleum ether/ethyl acetate 80/20->40/60). Rf value: 0.05 (silica gel; methylene chloride/methanol 80/20)
Reaction SMILES: [C:1]([O:10]C)(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[SH:4].[CH2:12]([N:19]([C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][N:28]=1)[C:24]#[N:25])[CH3:20])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH2:12]([N:19]([C:21]1[CH:22]=[C:23]([C:24]2[S:4][C:3]3[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=3[C:1](=[O:10])[N:25]=2)[CH:26]=[CH:27][N:28]=1)[CH3:20])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CN(Cc1ccccc1)c1cc(C#N)ccn1
Reactant: COC(=O)c1ccccc1S
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CN(Cc1ccccc1)c1cc(-c2nc(=O)c3ccccc3s2)ccn1
Yield: 30.5 %

Procedure:
Methyl thiosalicylate (0.70 g, 4.2 mmol) and 2-[N-benzyl-N-methylamino]isonicotinonitrile (0.46 g, 2.1 mmol) were dissolved in toluene (2.0 ml), and triethylamine (0.68 ml, 4.9 mmol) was added thereto. The reaction mixture was refluxed for 8 hrs, subjected to silica gel (50 g) column chromatography, eluted with hexane-ethyl-acetate (2:1, v/v) and recrystallized from ethanol to give the titled compound (0.23 g, 15%).
Reaction SMILES: Cl.[C:2](Cl)(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[N:5][CH:4]=1.[CH3:11][O:12][C:13]1[C:18]([OH:19])=[CH:17][CH:16]=[C:15](/[CH:20]=[CH:21]/[C:22]([CH2:24][C:25](/[CH:27]=[CH:28]/[C:29]2[CH:37]=[C:34]([O:35][CH3:36])[C:32]([OH:33])=[CH:31][CH:30]=2)=[O:26])=[O:23])[CH:14]=1.O/C(/C=C/C1C=CC(O)=C(OC)C=1)=C\C(=O)/C=C/C1C=CC(O)=C(OC)C=1.N1C=CC=CC=1>C1COCC1.CCOC(C)=O>[C:2]([O:19][C:18]1[CH:17]=[CH:16][C:15](/[CH:20]=[CH:21]/[C:22](=[O:23])/[CH:24]=[C:25](\[OH:26])/[CH:27]=[CH:28]/[C:29]2[CH:30]=[CH:31][C:32]([OH:33])=[C:34]([O:35][CH3:36])[CH:37]=2)=[CH:14][C:13]=1[O:12][CH3:11])(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[N:5][CH:4]=1
Reactant: COc1cc(/C=C/C(=O)CC(=O)/C=C/c2ccc(O)c(OC)c2)ccc1O
Reactant: O=C(Cl)c1cccnc1
Agent: COc1cc(/C=C/C(=O)/C=C(O)/C=C/c2ccc(O)c(OC)c2)ccc1O
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1cc(/C=C/C(O)=C/C(=O)/C=C/c2ccc(OC(=O)c3cccnc3)c(OC)c2)ccc1O
Temperature: 25 °C
Reaction time: 20 h
Yield: 23 %

Procedure:
To a solution of nicotinoyl chloride hydrochloride [296] (0.725 g, 4.0 mmol, 1.5 eq) in THF (30 ml) was added TEA (1 ml, x mmol, y eq) drop-wise at 0° C. A solution of curcumin, (1E,4Z,6E)-5-hydroxy-1,7-bis(4-hydroxy-3-methoxyphenyl)hepta-1,4,6-trien-3-one [4151] (1.0 g, 2.7 moles, 1.0 eq) and pyridine (1 ml) in THF (10 ml) was then added at the same temperature. The reaction temperature was gradually increased to RT. The reaction mixture was stirred for 20 h at RT. Reaction was monitored by TLC. The reaction mixture was diluted with EtOAc (200 ml), washed by saturated NaHCO3 solution (75 ml) and water (100 ml) successively. The EtOAc layer was separated, dried with sodium sulphate and concentrated under reduced pressure to yield a crude product. The crude product was purified by column chromatography using (2% MeOH: DCM, 100-200 mesh) get the desired product, 4-((1E,4Z,6E)-5-hydroxy-7-(4-hydroxy-3-methoxyphenyl)-3-oxohepta-1,4,6-trien-1-yl)-2-methoxyphenyl nicotinate [307] as yellow solid (0.30 g, 23%).
Reaction SMILES: [O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][C:11]([CH:13]([CH3:17])[C:14]([OH:16])=[O:15])=[CH:12][C:7]=2[CH:6]=[CH:5][C:4]2[CH:18]=[CH:19][CH:20]=[CH:21][C:3]1=2.C(=O)(O)[O-].[Na+:26].O>C1C=CC=CC=1>[O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][C:11]([CH:13]([CH3:17])[C:14]([O-:16])=[O:15])=[CH:12][C:7]=2[CH:6]=[CH:5][C:4]2[CH:18]=[CH:19][CH:20]=[CH:21][C:3]1=2.[Na+:26]
Reactant: CC(C(=O)O)c1ccc2c(=O)c3ccccc3ccc2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O
Product: CC(C(=O)[O-])c1ccc2c(=O)c3ccccc3ccc2c1

Procedure:
0.278 g. of 2-(5-oxo-5H-dibenzo[a,d]cyclohepten-2-yl)-propionic acid is added to a solution of 0.084 g. of sodium bicarbonate in 2 ml. of water. About 20 ml. of benzene is added and the mixture evaporated to dryness. This process is repeated several times, and the residue is recrystallized from methanol/ether to afford sodium 2-(5-oxo-5H-dibenzo[a,d]cyclohepten-2-yl)propionate (m.p. 145°-148° C). By employing 0.327 g. of potassium bicarbonate in place of the sodium bicarbonate above, there is obtained potassium 2-(5-oxo-5H-dibenzo[a,d]cyclohepten-2yl)propionate.