Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:10]=[C:11]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:12]=1[OH:13])[CH:8]=O)([CH3:4])([CH3:3])[CH3:2].[S:18]1[CH2:22][C:21](=[O:23])[NH:20][C:19]1=[O:24].C([O-])(=O)C.[Na+]>C(O)(=O)C>[CH3:16][C:14]([C:11]1[CH:10]=[C:7]([CH:8]=[C:22]2[S:18][C:19](=[O:24])[NH:20][C:21]2=[O:23])[CH:6]=[C:5]([C:1]([CH3:3])([CH3:2])[CH3:4])[C:12]=1[OH:13])([CH3:15])[CH3:17]
Reactant: CC(C)(C)c1cc(C=O)cc(C(C)(C)C)c1O
Reactant: O=C1CSC(=O)N1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(C)(C)c1cc(C=C2SC(=O)NC2=O)cc(C(C)(C)C)c1O
Temperature: 25 °C
Reaction time: 5 h
Yield: 64.5 %

Procedure:
To a flask containing 41.7 g (0.18 moles) of 3,5-di-tert-butyl-4-hydroxybenzaldehyde, 25 g (0.21 moles) of 2,4-thiazolidinedione and 29.5 g (0.36 moles) of anhydrous sodium acetate were added. To these solids 175 ml of glacial acetic acid was added and the mixture was stirred and refluxed for 18 hours. The mixture was allowed to cool to room temperature and the precipitated solid was collected by filtration. The precipitate was rinsed with 1:1 water/ethanol then dried. The dried solid was slurried in 300 ml of methylene chloride for five hours, then collected and dried to yield 38.7 g of the sub-titled intermediate.
Reaction SMILES: [C:1]([O:5][C:6](=[O:9])[CH2:7][NH2:8])([CH3:4])([CH3:3])[CH3:2].[C:10]([Si:14]([CH3:28])([CH3:27])[O:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][C:21]([CH3:26])([CH3:25])[CH2:22][CH:23]=O)([CH3:13])([CH3:12])[CH3:11]>C(Cl)Cl>[C:1]([O:5][C:6](=[O:9])[CH2:7]/[N:8]=[CH:23]/[CH2:22][C:21]([CH3:25])([CH3:26])[CH2:20][CH2:19][O:18][CH2:17][CH2:16][O:15][Si:14]([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:27])[CH3:28])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(CC=O)CCOCCO[Si](C)(C)C(C)(C)C
Reactant: CC(C)(C)OC(=O)CN
Solvent: ClCCl
Product: CC(C)(C/C=N/CC(=O)OC(C)(C)C)CCOCCO[Si](C)(C)C(C)(C)C
Yield: 99.6 %

Procedure:
Step C In a manner similar to the method described in Example 1a, glycine tert-butyl ester (0.13 g, 1 mmol) was reacted with 5-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-3,3-dimethyl-pentanal (0.27 g, 1 mmol) in CH2Cl2 at room temperature for 18 h to give [5-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-3,3-dimethyl-pent-(E)-ylideneamino]-acetic acid tert-butyl ester as a colorless oil (0.4 g, 100%).
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][CH2:5][NH:4][C:3]1=[O:7].[Br:8][C:9]1[N:14]=[CH:13][C:12](O)=[CH:11][CH:10]=1>>[Br:8][C:9]1[N:14]=[CH:13][C:12]([O:1][C@@H:2]2[CH2:6][CH2:5][NH:4][C:3]2=[O:7])=[CH:11][CH:10]=1
Reactant: Oc1ccc(Br)nc1
Reactant: O=C1NCC[C@@H]1O
Product: O=C1NCC[C@H]1Oc1ccc(Br)nc1

Procedure:
Typical Procedure 3 was followed. Reaction of (S)-3-hydroxy-pyrrolidin-2-one with 6-bromo-pyridin-3-ol provided the subtitle compound. MS ESI+: m/z=257 [M+H]+.
Reaction SMILES: [CH:1]([C:4](=[CH2:19])[C:5]([C:7]1[S:8][CH:9]=[C:10]([C:12]2[CH:17]=[C:16](C)[CH:15]=[CH:14][CH:13]=2)[CH:11]=1)=[O:6])([CH3:3])[CH3:2].[CH3:20]S(O)(=O)=O.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>O>[CH3:20][C:9]1[S:8][C:7]2[C:5](=[O:6])[CH:4]([CH:1]([CH3:2])[CH3:3])[CH2:19][C:11]=2[C:10]=1[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CS(=O)(=O)O
Reactant: C=C(C(=O)c1cc(-c2cccc(C)c2)cs1)C(C)C
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: O
Product: Cc1sc2c(c1-c1ccccc1)CC(C(C)C)C2=O
Temperature: 90 °C
Reaction time: 0.17 h
Yield: 70 %

Procedure:
A mixture of 2-(isopropyl)-1-(5-methyl-4-phenyl(2-thienyl))prop-2-en-1-one (98 g crude product) and Eaton's reagent (200 mL) was heated to 90° C. with stirring. After 10 minutes, the reaction mixture was poured slowly into water (500 mL). The product was extracted with dichloromethane, washed with a saturated aqueous solution of NaHCO3, and dried (MgSO4). Rotoevaporation of solvent gave 98 g of crude product (˜70% product by GC/MS). A portion of the product was further refined by chromatography on silica. 1H-NMR δ (CDCl3): 7.15–7.4 (m, 5H), 2.7 (m, 2H), 2.5 (m, 1H), 2.38 (s, 3H), 2.3 (m, 1H), 0.9 (d, 3H). EIMS: m/z (%) 270 (M+, 10), 255 (4), 228 (100), 213 (5), 195 (5), 184 (10), 165 (7), 152 (6).
Reaction SMILES: [CH:1](OCC)(OCC)OCC.[NH2:11][C:12]1[C:13]([Cl:35])=[N:14][C:15]2[C:20]([C:21]=1[NH:22][CH2:23][CH2:24][CH2:25][CH2:26][NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[CH:19][CH:18]=[CH:17][CH:16]=2>>[C:31]([O:30][C:28]([NH:27][CH2:26][CH2:25][CH2:24][CH2:23][N:22]1[C:21]2[C:20]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[N:14]=[C:13]([Cl:35])[C:12]=2[N:11]=[CH:1]1)=[O:29])([CH3:32])([CH3:34])[CH3:33]
Reactant: CC(C)(C)OC(=O)NCCCCNc1c(N)c(Cl)nc2ccccc12
Reactant: CCOC(OCC)OCC
Product: CC(C)(C)OC(=O)NCCCCn1cnc2c(Cl)nc3ccccc3c21
Temperature: 100 °C
Reaction time: 8 h
Yield: 83.6 %

Procedure:
0.32 ml (1.92 mmol)of Triethyl ortho-formate was added to 0.14 g (0.384 mmol) of 3-amino-4-[4-(tert-butoxycarbonylamino)butylamino]-2-chloroquinoline. The mixture was heated at 100° C. and stirred overnight. The reaction mixture was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography (chloroform:methanol=150:1 to 100:1 (v/v)) to obtain 0.12 g (0.321 mmol) of 1-[4-(tert-butoxycarbonylamino)butyl]-4-chloro-1H-imidazo[4,5-c]quinoline as pale orange powder (mp: 148-150° C.). ##STR43## Its spectroscopic data are as follows: IR (KBr) cm-1 : 1695, 1510.
Reaction SMILES: CN(C)C=O.[C:6]([O:10][C:11](=[O:46])[N:12]([CH:24]1[CH2:29][CH2:28][N:27]([CH2:30][CH2:31][N:32]2[C:41]3[C:36](=[C:37](Br)[CH:38]=[C:39]([O:42][CH3:43])[CH:40]=3)[CH:35]=[CH:34][C:33]2=[O:45])[CH2:26][CH2:25]1)[CH2:13][C:14]1[CH:23]=[CH:22][C:17]2[O:18][CH2:19][CH2:20][O:21][C:16]=2[CH:15]=1)([CH3:9])([CH3:8])[CH3:7].[C:47]([O:51][CH2:52][CH3:53])(=[O:50])[CH:48]=[CH2:49]>CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C.C(N(CC)CC)C>[C:6]([O:10][C:11]([N:12]([CH2:13][C:14]1[CH:23]=[CH:22][C:17]2[O:18][CH2:19][CH2:20][O:21][C:16]=2[CH:15]=1)[CH:24]1[CH2:29][CH2:28][N:27]([CH2:30][CH2:31][N:32]2[C:41]3[C:36](=[C:37](/[CH:49]=[CH:48]/[C:47]([O:51][CH2:52][CH3:53])=[O:50])[CH:38]=[C:39]([O:42][CH3:43])[CH:40]=3)[CH:35]=[CH:34][C:33]2=[O:45])[CH2:26][CH2:25]1)=[O:46])([CH3:9])([CH3:8])[CH3:7]
Reactant: C=CC(=O)OCC
Reactant: COc1cc(Br)c2ccc(=O)n(CCN3CCC(N(Cc4ccc5c(c4)OCCO5)C(=O)OC(C)(C)C)CC3)c2c1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)/C=C/c1cc(OC)cc2c1ccc(=O)n2CCN1CCC(N(Cc2ccc3c(c2)OCCO3)C(=O)OC(C)(C)C)CC1
Temperature: 90 °C

Procedure:
To 4.0 mL of an N,N-dimethylformamide solution containing 0.15 g of tert-butyl(1-(2-(5-bromo-7-methoxy-2-oxoquinolin-1(2H)-yl)ethyl)piperidin-4-yl)(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)carbamate, 39 μl of ethyl acrylate, 50 μL of triethylamine and 6.1 mg of bis(tri-tert-butylphosphine)palladium(0) were added and heated under nitrogen atmosphere at 90° C. for 1.5 hours. The reaction mixture was cooled to the room temperature, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [eluent; chloroform:methanol=20:1] to give 0.15 g of ethyl (2E)-3-(1-(2-(4-((tert-butoxycarbonyl)(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino)piperidin-1-yl)ethyl)-7-methoxy-2-oxo-1,2-dihydroquinolin-5-yl)acrylate as a light brown foam.
Reaction SMILES: [OH:1][CH2:2][C:3]([CH3:12])([CH3:11])[C:4]([NH:6][CH2:7][CH2:8][O:9][CH3:10])=[O:5].[N+:13]([C:16]1[CH:23]=[CH:22][CH:21]=[C:20]([N+]([O-])=O)[C:17]=1[C:18]#[N:19])([O-:15])=[O:14]>>[C:18]([C:17]1[C:16]([N+:13]([O-:15])=[O:14])=[CH:23][CH:22]=[CH:21][C:20]=1[O:1][CH2:2][C:3]([CH3:12])([CH3:11])[C:4]([NH:6][CH2:7][CH2:8][O:9][CH3:10])=[O:5])#[N:19]
Reactant: N#Cc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Reactant: COCCNC(=O)C(C)(C)CO
Product: COCCNC(=O)C(C)(C)COc1cccc([N+](=O)[O-])c1C#N
Yield: 55 %

Procedure:
Prepared as in Example 197c from 3-hydroxy-N-(2-methoxyethyl)-2,2-dimethylpropanamide (Example 204d) and 2,6-dinitrobenzonitrile in 55% yield. MS 322 (MH+).
Reaction SMILES: I/[CH:2]=[CH:3]/[C@@H:4]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][O:19]2)=[CH:13][CH:12]=1)[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7].[Br-].[CH2:25]([Zn+])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.O>C1COCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:26]1([CH2:25]/[CH:2]=[CH:3]/[C@H:4]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][O:19]3)=[CH:13][CH:12]=2)[CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CCOC(=O)C[C@@H](/C=C/I)c1ccc(OC2CCCCO2)cc1
Reactant: [Zn+]Cc1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)C[C@H](/C=C/Cc1ccccc1)c1ccc(OC2CCCCO2)cc1
Reaction time: 17.5 h

Procedure:
To a stirred solution of 83.4 (571.9 mg, 1.33 mmol, 1 eq., MW 430.29) in THF (15 mL) at 23° C. was added Pd(PPh3)4 (153.6 mg, 0.133 mmol, 0.1 eq., MW 1155.58) followed by dropwise addition of benzylzinc bromide solution (3.2 mL, 1.6 mmol, 1.2 eq., 0.5 M). After 17.5 hours, water (10 mL) was added to quench the reaction. The mixture was extracted with EtOAc (2×50 mL), dried with MgSO4, and filtered. The organic layer was concentrated in vacuo. The residue was then purified by flash chromatography (SiO2 gel 60, eluted with 0 to 20% EtOAc in hexanes). Fractions containing the desired product were combined and concentrated providing a colorless oil that was used without further purification.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[CH2:11]([N:14]1[C:18](=[O:19])[NH:17][N:16]=[N:15]1)[CH2:12][CH3:13].C(=O)([O-])[O-].[Na+].[Na+].CS(C)=O>O>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([N:17]2[C:18](=[O:19])[N:14]([CH2:11][CH2:12][CH3:13])[N:15]=[N:16]2)=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: CCCn1nn[nH]c1=O
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CCCn1nnn(-c2ccc([N+](=O)[O-])cc2)c1=O
Temperature: 120 °C
Yield: 74 %

Procedure:
A mixture of 38 parts of 1-fluoro-4-nitrobenzene, 32 parts of 1,4-dihydro-1-propyl-5H-tetrazol-5-one, 14 parts of sodium carbonate and 200 parts of dimethyl sulfoxide was stirred and heated for 4 hours at 120° C. The reaction mixture was cooled and poured into water. The precipitated product was filtered off and crystallized from 2-propanol, yielding 46 parts (74%) of 1,4-dihydro-1-(4-nitrophenyl)-4-propyl-5H-tetrazol-5-one; mp. 91.1° C. (int. 31).
Reaction SMILES: C[O:2][C:3]1[C:38]([CH3:39])=[C:37]([CH3:40])[C:36]([O:41]C)=[C:35]([CH3:43])[C:4]=1[CH2:5][N:6]1[C:12](=[O:13])[C@H:11]2[CH2:14][CH2:15][CH2:16][C@H:10]2[N:9]([C:17](=[O:30])[CH2:18][N:19]2[C:23](=[O:24])[C:22]3=[CH:25][CH:26]=[CH:27][CH:28]=[C:21]3[C:20]2=[O:29])[C:8]2[CH:31]=[CH:32][CH:33]=[CH:34][C:7]1=2.[N+]([O-])([O-])=O.[Ce+4].[NH4+].[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O>C(#N)C.O>[C:20]1(=[O:29])[N:19]([CH2:18][C:17]([N:9]2[C@@H:10]3[CH2:16][CH2:15][CH2:14][C@@H:11]3[C:12](=[O:13])[N:6]([CH2:5][C:4]3[C:3](=[O:2])[C:38]([CH3:39])=[C:37]([CH3:40])[C:36](=[O:41])[C:35]=3[CH3:43])[C:7]3[CH:34]=[CH:33][CH:32]=[CH:31][C:8]2=3)=[O:30])[C:23](=[O:24])[C:22]2=[CH:25][CH:26]=[CH:27][CH:28]=[C:21]12
Reactant: COc1c(C)c(C)c(OC)c(CN2C(=O)[C@H]3CCC[C@H]3N(C(=O)CN3C(=O)c4ccccc4C3=O)c3ccccc32)c1C
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Solvent: O
Solvent: CC#N
Product: CC1=C(C)C(=O)C(CN2C(=O)[C@H]3CCC[C@H]3N(C(=O)CN3C(=O)c4ccccc4C3=O)c3ccccc32)=C(C)C1=O
Yield: 63.2 %

Procedure:
In a mixture of acetonitrile (3 mL) and water (2 mL) was suspended (3aR*,10aS*)-9-(2,5-dimethoxy-3,4,6-trimethylbenzyl)-4-(phthalimidoacetyl)-2,3,3a,4,9,10a-hexahydrobenzo[b]cyclopenta[e][1,4]diazepin-10(1H)-one (0.5 g, 0.86 mmol). To the suspension was added, while stirring, a solution of ammonium cerium (IV) nitrate (1.4 g, 2.55 mmol) in a mixture of acetonitrile (2 mL) and water (2 mL). The reaction mixture was stirred for one hour, which was diluted with water, followed by extraction with chloroform. The extract was washed with water and dried, then the solvent was distilled off. The residue was crystallized from ethyl acetate to give 300 mg (yield 63%) of the titled compound, m.p. 258°-260° C.
Reaction SMILES: [H-].[Na+].[CH:3]1([NH2:9])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.Cl[C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][N:12]=1>O1CCCC1>[CH:3]1([NH:9][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][N:12]=2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: NC1CCCCC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(NC2CCCCC2)nc1
Temperature: 22 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (60% dispersion in mineral oil, 1.99 g, 49.8 mmol) was washed 3× with hexanes then a solution of cyclohexylamine (3.8 mL, 33.2 mmol) dissolved in tetrahydrofuran (50 mL) was added. After stirring for 30 minutes at 22° C., 2-chloro-5-nitropyridine (5.00 g, 31.5 mmol) was added and the reaction mixture was heated to reflux for 3 hours. The solution was cooled to ambient temperature, quenched with saturated aqueous NH4Cl and concentrated in vacuo. The residue was redissolved in ethyl acetate then washed 2× with saturated NaHCO3, saturated NaCl, dried over anhydrous Na2SO4 and concentrated in vacuo. The product was recovered as a brown oil.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=1)(=O)[CH3:2].[C:10]1([N:16]2[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[N:18]=[C:17]2[NH:25][NH2:26])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>CO.C(O)(=O)C>[C:10]1([N:16]2[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[N:18]=[C:17]2[NH:25][N:26]=[C:1]([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][N:5]=2)[CH3:2])[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: NNc1nc2ccccc2n1-c1ccccc1
Reactant: CC(=O)c1ccccn1
Solvent: CO
Solvent: CC(=O)O
Product: CC(=NNc1nc2ccccc2n1-c1ccccc1)c1ccccn1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 2-acetyl pyridine (1.00 g, 8.26 mmol) and 1-phenyl-2-hydrazinobenzimidazole (1.85 g, 8.26 mmol) in 20 ml of methanol is stirred at room temperature for 2 days after the addition of 6 drops of glacial acetic acid. The reaction is monitored by means of thin layer chromatography (Polygram Sil G/UV254 prefabricated foils; eluting agent: CH2Cl2:MeOH (12:1)). Subsequently, the reaction mixture is diluted with distilled water until a precipitate forms and stored for 24 hours in the refrigerator at approximately 5° C. The precipitate is filtered, washed several times with 50% methanol, and dried. The product is recrystallized from a mixture of methanol and water. Yield: 1.35 g (50% of theory).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10](=[O:18])[CH:11]=[C:12]([C:15]([OH:17])=[O:16])O[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].Cl.[F:22][C:23]([F:27])([F:26])[CH2:24][NH2:25]>>[CH2:1]([O:8][C:9]1[C:10](=[O:18])[CH:11]=[C:12]([C:15]([OH:17])=[O:16])[N:25]([CH2:24][C:23]([F:27])([F:26])[F:22])[CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1cc(=O)c(OCc2ccccc2)co1
Reactant: NCC(F)(F)F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)c1cc(=O)c(OCc2ccccc2)cn1CC(F)(F)F
Temperature: 70 °C
Reaction time: 17 h
Yield: 42.9 %

Procedure:
5-(Benzyloxy)-4-oxo-4H-pyran-2-carboxylic acid (10.5 g, 42.7 mmol) was dissolved in sodium hydroxide solution (1.71 g, 42.7 mmol in 77 mL de-ionized water). 2,2,2-Trifluoroethylamine hydrochloride (23.1 g, 171 mmol) was added and the resulting suspension was stirred at 70° C. (oil-bath temperature) in the sealed flask for 17 hours. The reaction mixture was then filtered and the off-white solid was washed with de-ionized water (20 mL×5) to give 5-(benzyloxy)-4-oxo-1-(2,2,2-trifluoroethyl)-1,4-dihydropyridine-2-carboxylic acid (6.00 g). Yield=43%; 1H NMR (MeOD-D4, 90 MHz) δ 7.30 (s, 1H), 6.76-7.09 (m, 5H), 6.71 (s, 1H), 4.93 (d, J=8.4 Hz, 2H) and 4.65 (s, 2H); MS m/z 328 [M+1]+. (b) 5-(Benzyloxy)-4-oxo-1-(2,2,2-trifluoroethyl)-1,4-dihydropyridine-2-carboxylic acid (4.70 g, 14.4 mmol) was mixed with DMF (25 mL) and heated to 130° C. (bath temperature) for 3 hours. The mixture was concentrated under reduced pressure using a rotary evaporator and the residue was mixed with ethyl acetate (50 mL). It was then stirred for 2 hours at room temperature and filtered. The filtrate was concentrated to give 3-(benzyloxy)-1-(2,2,2-trifluoroethyl)pyridin-4(1H)-one (3.58 g). Yield=69%; 1H NMR (DMSO-D6, 400 MHz) δ (ppm) 7.57-7.84 (m, 2H), 7.22-7.57 (m, 5H), 6.25 (br. s, 1H) and 4.69-5.28 (m, 4H); MS m/z 284 [M+1]+. (c) 3-(Benzyloxy)-1-(2,2,2-trifluoroethyl)pyridin-4(1H)-one (1.2 g, 4.2 mmol) was mixed with 10% Palladium on charcoal (wet, 0.12 g) in ethanol (70 mL). The resulting mixture was hydrogenated at 15 psi of hydrogen pressure for 1.5 hours. Palladium was removed by filtration through a layer of Celite™ and the Celite™ cake was washed with methanol (5 mL×3). The filtrate was evaporated to give 3-hydroxy-1-(2,2,2-trifluoroethyl)pyridin-4(1H)-one (0.78 g) as white solid. Yield=95%; 1H NMR (DMSO-D6, 400 MHz) δ (ppm) 7.60 (d, J=7.1 Hz, 1H), 7.46 (s, 1H), 6.23 (d, J=7.1 Hz, 1H) and 4.80-5.00 (m, 2H); MS m/z 194 [M+1]+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:18])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1.B(F)(F)F.[CH3:23]COCC.CS(Cl)(=O)=O>CN(C=O)C>[OH:8][C:6]1[CH:7]=[C:2]2[C:3]([C:9](=[O:18])[C:10]([C:11]3[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=3)=[CH:23][O:1]2)=[CH:4][CH:5]=1
Reactant: O=C(Cc1ccc(O)cc1)c1ccc(O)cc1O
Reactant: CCOCC
Agent: CS(=O)(=O)Cl
Agent: FB(F)F
Solvent: CN(C)C=O
Product: O=c1c(-c2ccc(O)cc2)coc2cc(O)ccc12
Temperature: 50 °C

Procedure:
In a solution of 1-(2,4-dihydroxyphenyl)-2-(4-hydroxyphenyl)-ethanone (2 mmol) in DMF (6 mL), freshly distilled BF3.OEt2 (6.3 mL) was added under argon. The mixture was heated at 50° C., and a solution of methanesulphonyl chloride (1 mL) in dry DMF (1.5 mL) was added slowly. After reaction at 80° C. for 1 h, the mixture was cooled to rt and poured into a large volume of ice cold aq. sodium acetate (12 g/100 mL), then extracted with EtOAc, and the organic layer was dried and concentrated. The residue was purified by column chromatography on silica gel using a mixture of DCM and MeOH to give 7-hydroxy-3-(4-hydroxyphenyl)-chromen-4-one.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([F:15])([F:14])[F:13])=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.C(N(CC)CC)C>[Pd].CO>[F:15][C:12]([F:13])([F:14])[C:8]1[CH:7]=[C:6]2[C:11]([CH:2]=[CH:3][CH:4]=[N:5]2)=[CH:10][CH:9]=1
Reactant: FC(F)(F)c1ccc2c(Cl)ccnc2c1
Agent: [Pd]
Solvent: CO
Solvent: CCN(CC)CC
Product: FC(F)(F)c1ccc2cccnc2c1
Reaction time: 3.5 h

Procedure:
4-Chloro-7-(trifluoromethyl)quinoline (9.35 g, 0.0404 mol) was hydrogenated in the presence of 5% palladium on carbon (4 g) in methanol (180 mL) in the presence of triethylamine (6 mL). The solution was stirred for 3.5 hours, and then filtered through Celite. The filtrate was concentrated under reduced pressure, and the residue was treated with ethyl acetate and water. The organic layer was separated, washed with water (2×75 mL), dried over MgSO4, filtered, and concentrated under reduced pressure to a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[CH2:6]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:33]N1C(=O)CCC1=O.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[CH2:6][Cl:33]
Reactant: COc1cc(CO)ccc1[N+](=O)[O-]
Reactant: O=C1CCC(=O)N1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1cc(CCl)ccc1[N+](=O)[O-]
Temperature: 0 °C
Yield: 83.5 %

Procedure:
To a solution of 3-methoxy-4-nitrobenzyl alcohol (3.0 g, 16.4 mmol) in 150 mL of dichloromethane was added triphenylphosphine (5.6 g, 21.3 mmol). The reaction was cooled to 0° C. and N-chlorosuccinimide (2.8 g, 21.3 mmol) was added. The reaction was warmed to room temperature and then heated gently to 50° C. for 2 h. The reaction was poured into aqueous sodium carbonate solution and the aqueous layer was extracted with dichloromethane and then ethyl acetate. Combined organics were dried over anhydrous MgSO4, filtered, concentrated onto silica gel and purified by flash chromatography with ethyl acetate/hexanes as the eluent to afford 3-methoxy-4-nitrobenzyl chloride (2.76 g, 84%). 1H NMR (400 MHz, CDCl3) δ ppm 7.88 (d, J=8.2 Hz, 1H), 7.44 (d, J=1.6 Hz, 1H), 7.17 (d, J=8.2, 1.7 Hz, 1H), 4.81 (s, 2H), 3.91 (s, 3H).
Reaction SMILES: S(=O)(=O)(O)O.[Br:6][C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[CH2:14][C:15]([OH:17])=[O:16].[C:18]([O-])([O-])=O.[Na+].[Na+]>CO>[Br:6][C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[CH2:14][C:15]([O:17][CH3:18])=[O:16]
Reactant: O=C(O)Cc1ccc(F)cc1Br
Reactant: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COC(=O)Cc1ccc(F)cc1Br
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Sulfuric acid (1.50 mL) was added cautiously to a solution of 2-bromo-4-fluorophenylacetic acid (1.00 g, 4.29 mmol) in MeOH (25 mL) and the resulting mixture stirred overnight at room temperature. Saturated aqueous Na2CO3 solution was added until the pH of the mixture was 14, then the aqueous layer was extracted with DCM (2×100 mL). The combined organics were dried over MgSO4 then the volatiles were removed in vacuo to yield the title compound A48 as a clear oil (1.00 g, 94%); 1H NMR (400 MHz, CDCl3) δ 7.34 (dd, J=8.2, 2.6 Hz, 1H), 7.29 (dd, J=8.5, 6.0 Hz, 1H), 7.03 (td, J=8.3, 2.6 Hz, 1H), 3.79 (s, 2H), 3.74 (s, 3H). LCMS-A: rt 5.911 min.
Reaction SMILES: C([O:3][C:4](=O)[NH:5][CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([Cl:15])[CH:9]=1)C.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>O=P(Cl)(Cl)Cl>[Cl:15][C:10]1[CH:9]=[C:8]2[C:13](=[CH:12][C:11]=1[Cl:14])[C:4](=[O:3])[NH:5][CH2:6][CH2:7]2
Reactant: CCOC(=O)NCCc1ccc(Cl)c(Cl)c1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: O=P(Cl)(Cl)Cl
Product: O=C1NCCc2cc(Cl)c(Cl)cc21
Yield: 12.1 %

Procedure:
Using an analogous reaction procedure and workup as described in Example 1, [2-(3,4-dichloro-phenyl)-ethyl]-carbamic acid ethyl ester (I-41c: 3.5 g, 13.409 mmol) in POCl3 (35 mL) was reacted with P2O5 (3.80 g, 26.819 mmol) at 120° C. for 1 hour to afford the crude product. Purification by column chromatography on silica gel (30% ethylacetate in hexane) afforded 0.350 g of the crude product which was used in the next step without further purification.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[O:9][CH3:10])#[CH:2].Br[C:12]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:13]=1[CH:14]=[O:15].C(N(CC)CC)C>CN(C)C=O>[CH3:10][O:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[C:1]#[C:2][C:12]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][C:13]=1[CH:14]=[O:15]
Reactant: C#Cc1ccccc1OC
Reactant: COc1ccc(Br)c(C=O)c1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1ccc(C#Cc2ccccc2OC)c(C=O)c1
Yield: 67.3 %

Procedure:
The resulting 2-ethynylanisole (0.79 g) and 2-bromo-5-methoxybenzaldehyde (1.14 g) were reacted in dimethylformamide (50 ml) in the presence of dichloro-bis-triphenylphosphine palladium (1.0 g), cuprous iodide (0.5 g) and triethylamine (15 ml), in nitrogen atmosphere at 50° C. for 6 hr. The resulting reaction solution was evaporated, and to the resulting residue were added ethyl acetate and water. The resulting organic layer was washed with water and brine, and dried over magnesium sulfate. The solvent was evaporated, and the resulting residue was purified by silica gel column chromatography (ethyl acetate/hexane system), to give 0.95 g of the title compound as a pale yellow oil.