Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:15])=[C:10](F)[C:11]=2[F:13])[C:6](=[O:16])[C:5]([C:17]([OH:19])=[O:18])=[CH:4]1)[CH3:2].[CH2:20]([NH:22][CH2:23][CH:24]1[CH2:28][CH2:27][NH:26][CH2:25]1)[CH3:21].N12CCCN=C1CCCCC2>C(#N)C>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:15])=[C:10]([N:26]3[CH2:27][CH2:28][CH:24]([CH2:23][NH:22][CH2:20][CH3:21])[CH2:25]3)[C:11]=2[F:13])[C:6](=[O:16])[C:5]([C:17]([OH:19])=[O:18])=[CH:4]1)[CH3:2]
Reactant: CCNCC1CCNC1
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(F)c(F)c21
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CCNCC1CCN(c2c(F)cc3c(=O)c(C(=O)O)cn(CC)c3c2F)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.6 %

Procedure:
A mixture of 22.50 g (83.03 mmole) 1-ethyl-1,4-dihydro-4-oxo-6,7,8-trifluoro-3-quinolinecarboxylic acid, 225 ml acetonitrile, 11.25 g (87.08 mmole) N-ethyl-3-pyrrolidinemethanamine and 12.6 g (83.03 mmole) 1,8-diazabicyclo[5.4.0]undec-7-ene was refluxed 1 hour then was stirred at room temperature overnight. The solid was filtered and washed with ether to give 26.33 g of 1-ethyl-7-[3-[(ethylamino)methyl]-1-pyrrolidinyl]-6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, mp 208°-210° C.
Reaction SMILES: CO.[OH-].[Na+].C([O:7][C:8]([C:10]1([C:17]([O:19]CC)=[O:18])[CH2:15][CH:14]2[CH2:16][CH:11]1[CH:12]=[CH:13]2)=[O:9])C>O1CCCC1>[C:17]([C:10]1([C:8]([OH:9])=[O:7])[CH2:15][CH:14]2[CH2:16][CH:11]1[CH:12]=[CH:13]2)([OH:19])=[O:18]
Reactant: CCOC(=O)C1(C(=O)OCC)CC2C=CC1C2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)C1(C(=O)O)CC2C=CC1C2
Temperature: 25 °C
Reaction time: 24 h
Yield: 89.6 %

Procedure:
A mixture of methanol (12 ml), 10% aqueous sodium hydroxide (12 ml), tetrahydrofuran (12 ml) and 2,2-bisethoxycarbonyl-5-norbornene (2.38 g) was stirred at room temperature for 24 hours and concentrated under reduced pressure. The residue was diluted with water, made acidic with 10% hydrochloric acid (HCl) solution and extracted with ether. The extract was washed with water and dried. Removal of the solvent gave as an oil 2,2-dicarboxy-5-norbornene (Compound No. 2-1) (1.63 g). IRνmaxfilm (cm-1): 2990, 1710, 1340.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[C:13]([N+:21]([O-:23])=[O:22])[CH:12]=2)[C:8](O)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[NH2:58][C:59]1[CH:68]=[CH:67][C:66]2[C:61](=[CH:62][CH:63]=[CH:64][CH:65]=2)[N:60]=1>C(Cl)Cl>[CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[C:13]([N+:21]([O-:23])=[O:22])[CH:12]=2)[C:8]([NH:58][C:59]2[CH:68]=[CH:67][C:66]3[C:61](=[CH:62][CH:63]=[CH:64][CH:65]=3)[N:60]=2)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: Nc1ccc2ccccc2n1
Reactant: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)O)cc1[N+](=O)[O-]
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)Nc2ccc3ccccc3n2)cc1[N+](=O)[O-]
Yield: 13.6 %

Procedure:
A solution of 3-cyclopentyl-2-(4-methanesulfonyl-3-nitrophenyl)-propionic acid (prepared as in Example 32, 150 mg, 0.439 mmol), triethylamine (0.184 mL, 1.32 mmol), benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (291 mg, 0.659 mmol), and 2-aminoquinoline (95 mg, 0.659 mmol) in methylene chloride (4 mL) was stirred at 25° C. overnight. The crude reaction mixture was directly purified by Biotage chromatography (FLASH 40M, Silica, 1/1 hexanes/ethyl acetate) to afford 3-cyclopentyl-2-(4-methanesulfonyl-3-nitro-phenyl)-N-quinolin-2-yl-propionamide (28 mg, 13.6%) as a white foam: mp 102-106° C. (foam to gel); EI-HRMS m/e calcd for C24H25N3O5S (M+) 467.1515, found 467.1513.
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[C:4]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)=[N:3]1.[CH2:12]([N:14]([CH2:23][CH3:24])[C:15]1[CH:22]=[CH:21][C:18]([CH:19]=[O:20])=[CH:17][CH:16]=1)[CH3:13].O>C1C=CC=CC=1>[CH2:23]([N:14]([CH2:12][CH3:13])[C:15]1[CH:22]=[CH:21][C:18]([CH:19]2[O:20][C:2]([CH3:1])([CH3:11])[N:3]=[C:4]2[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=2)=[CH:17][CH:16]=1)[CH3:24]
Reactant: CC1(C)N=C1c1ccccc1
Reactant: CCN(CC)c1ccc(C=O)cc1
Solvent: O
Solvent: c1ccccc1
Product: CCN(CC)c1ccc(C2OC(C)(C)N=C2c2ccccc2)cc1
Yield: 38.3 %

Procedure:
4 g of 2,2-dimethyl-3-phenyl-2H-azirine and 5 g of 4-diethylaminobenzaldehyde were exposed to light in 350 ml of benzene at 230° C. for 4 hours under an atmosphere of argon with a mercury high-pressure lamp of 150 watt in a water-cooled ring-mantle vessel through a 3 mm thick filter of Pyrex glass. After removing the solvent in a water-jet vacuum, the residue was crystallized from n-hexane/acetone and then a second time from n-pentane/acetone. The crystalline product was then dried at 60° C. in the water-jet vacuum, and there were obtained 3,4 g of 5-[p-(diethylamino)-phenyl]-2,2-dimethyl-4-phenyl-3-oxazoline having a melting point of 104°-105° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[C:5](=O)[CH2:6][C:7]([C:9]1[O:10][CH:11]=[CH:12][CH:13]=1)=O)[CH3:2].[Cl:16][C:17]1[S:21][C:20]([C:22]2[O:26][N:25]=[C:24]([CH2:27][NH:28][NH2:29])[CH:23]=2)=[CH:19][CH:18]=1>C(O)(=O)C.O>[CH2:1]([O:3][C:4]([C:5]1[CH:6]=[C:7]([C:9]2[O:10][CH:11]=[CH:12][CH:13]=2)[N:28]([CH2:27][C:24]2[CH:23]=[C:22]([C:20]3[S:21][C:17]([Cl:16])=[CH:18][CH:19]=3)[O:26][N:25]=2)[N:29]=1)=[O:15])[CH3:2]
Reactant: NNCc1cc(-c2ccc(Cl)s2)on1
Reactant: CCOC(=O)C(=O)CC(=O)c1ccco1
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)c1cc(-c2ccco2)n(Cc2cc(-c3ccc(Cl)s3)on2)n1

Procedure:
A solution of 550 mg 4-Furan-2-yl-2,4-dioxo-butyric acid ethyl ester and 601 mg [5-(5-Chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-hydrazine in 10 ml acetic acid was heated to 80° C. for 2 h. Then the reaction mixture was diluted with 20 ml water and extracted with ethyl acetate (3×100 ml). The combined organic layers were dried over MgSO4. The solvents were removed under reduced pressure and the residue was purified by silica gel chromatography eluting with a n-heptane:ethyl acetate gradient 100%->50%.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5](CCC)[N:4]=1)#[N:2].[Na].[C:13](O)(=[O:15])C>C[O-].[Na+].CO>[N:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[C:1](=[NH:2])[O:15][CH3:13]
Reactant: CC(=O)O
Reactant: CCCc1cccc(C#N)n1
Agent: C[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CO
Product: COC(=N)c1ccccn1
Reaction time: 8 h
Yield: 618.6 %

Procedure:
2-Cyano-6-n-propylpyridine (10 g) was dissolved in a solution of sodium methoxide in methanol prepared from methanol (100 ml) and metallic sodium (0.32 g). After standing overnight, acetic acid (0.82 g) was added thereto, followed by concentration under reduced pressure. The resulting residue was dissolved in ether (200 ml) and insoluble materials were filtered out. The filtrate was concentrated under reduced pressure to obtain methyl 2-picolineimidate (11.5 g, yield: 94 %).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][C@@H:2]1[C:11]([OH:13])=O.C1(N=C=NC2CCCCC2)CCCCC1.ON1C2C=CC=CC=2N=N1.[N:39]1([C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1>C(#N)C>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][C@@H:2]1[C:11]([N:42]1[CH2:41][CH2:40][N:39]([C:45]([O:47][C:48]([CH3:51])([CH3:50])[CH3:49])=[O:46])[CH2:44][CH2:43]1)=[O:13]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=C(O)[C@H]1COc2ccccc2O1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCN(C(=O)[C@H]2COc3ccccc3O2)CC1
Reaction time: 12 h

Procedure:
5 g of (2R)-2,3-dihydro-1,4-benzodioxin-2-carboxylic acid (27.8 mmol) are dissolved in 300 ml of acetonitrile. 6 g of N,N′-dicyclohexylcarbodiimide (29.1 mmol) and then 4.1 g of 1-hydroxybenzotriazole (30.6 mmol) are added. Finally, 6.2 g of tert-butyl piperazine-1-carboxylate (33.4 mmol) are added and stirring is carried out for 12 hours at ambient temperature. The reaction mixture is subsequently filtered and the filtrate is then evaporated to dryness. The oil thereby obtained is purified by flash chromatography on silica (eluant: toluene/ethyl acetate 80/20) to yield the expected product in the form of an oil.
Reaction SMILES: C([C:5]1[C:6]([CH2:18][O:19][SiH](C)C)=[C:7]([N:11]2[CH2:14][C:13]([F:16])([F:15])[C:12]2=[O:17])[CH:8]=[CH:9][CH:10]=1)(C)(C)C.O.C([O-])(O)=O.[Na+]>C(#N)C>[OH:19][CH2:18][C:6]1[CH:5]=[CH:10][CH:9]=[CH:8][C:7]=1[N:11]1[CH2:14][C:13]([F:15])([F:16])[C:12]1=[O:17]
Reactant: C[SiH](C)OCc1c(N2CC(F)(F)C2=O)cccc1C(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: O=C1N(c2ccccc2CO)CC1(F)F
Temperature: 25 °C

Procedure:
0.19 mmole of compound 3a is dissolved in 1 ml of acetonitrile and this solution is added dropwise to a 40% H2O/HF mixture corresponding to 3 eq. Stirring is maintained for 5 min. at ambient temperature, followed by the neutralization of the excess HF by a 5% aqueous NaHCO3 solution.
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[CH3:11])[NH:4][C:3]1=[O:12].Cl[CH2:15][CH2:16][O:17]C1CCCCO1>>[OH:17][CH2:16][CH2:15][N:4]1[C:5]2[C:10](=[C:9]([CH3:11])[CH:8]=[CH:7][CH:6]=2)[C:2]([CH3:13])([CH3:1])[C:3]1=[O:12]
Reactant: ClCCOC1CCCCO1
Reactant: Cc1cccc2c1C(C)(C)C(=O)N2
Product: Cc1cccc2c1C(C)(C)C(=O)N2CCO

Procedure:
Prepared from 3,3,4-trimethyl-1,3-dihydro-2H-indol-2-one (prepared by the method of Endler and Becker; Organic Syntheses Coll. vol.4, page 657) and 2-(2-chloroethoxy)tetrahydro-2H-pyran as described above.
Reaction SMILES: FC(F)(F)S([O-])(=O)=O.[Sm+3].FC(F)(F)S([O-])(=O)=O.FC(F)(F)S([O-])(=O)=O.[CH3:26][NH:27][C:28](=[O:38])[C@H:29]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[NH2:30].[CH3:39][C:40]1[O:46][C:43]([CH:44]=O)=[CH:42][CH:41]=1>O1CCCC1>[CH2:31]([C@@H:29]1[NH:30][C@H:44]([C:43]2[O:46][C:40]([CH3:39])=[CH:41][CH:42]=2)[N:27]([CH3:26])[C:28]1=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: CNC(=O)[C@@H](N)Cc1ccccc1
Reactant: Cc1ccc(C=O)o1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Sm+3]
Solvent: C1CCOC1
Product: Cc1ccc([C@H]2N[C@@H](Cc3ccccc3)C(=O)N2C)o1
Temperature: 25 °C
Reaction time: 29 h
Yield: 46 %

Procedure:
In an inert atmosphere glovebox, samarium (III) trifluoromethanesulfonate (1.20 g, 2.0 mmol) was added to a flame-dried 250 mL 3-neck round bottom flask fitted with a glass stopper, a septum, and a vacuum hose adapter followed by powdered 4 Å molecular sieves (4.0 g). Following removal from the glove-box, the reaction was placed under nitrogen and (S)-phenylalanine methyl amide (8.91 g, 50 mmol) was added as a solution in 80 mL of tetrahydrofuran immediately followed by freshly distilled (77° C., 14 mmHg, Vigreaux collumn) clear, colorless 5-methylfurfural (3.98 mL, 40 mmol). After stirring for 29 hours at room temperature, the reaction mixture was filtered through a plug of silica with dichloromethane, concentrated and purified by silica gel chromatography (1:1 ethyl acetate:hexanes) to afford the title compound as a clear, colorless oil in 46% yield (4.93 g, 18.2 mmol) and the faster eluting (2R, 5S) isomer as a pale yellow oil in 38% yield (4.10 g, 15.2 mmol). IR (film) 3482, 3325, 2922, 2862, 1695, 1563, 1495, 1477, 1453, 1402, 1326, 1267, 1218, 1098, 1021, 1006, 956.8, 938.9, 791.1, 734.4, 701.5 cm−1; 1H NMR (300 MHz, CDCl3) δ 7.26 (m, 5H, PhH), 6.11 (m, 1H, CHCHCCH3), 5.89 (m, 1H, CHCHCCH3 ), 5.19 (s, 1H, NCHN), 3.79 (dd, J=7.2, 4.5 Hz, 1H, CHCONMe), 3.26 (dd, J=14.4, 4.5 Hz, 1H, one of CH2Ph), 3.09 (dd, J=14.1, 7.5 Hz, 1H, one of CH2Ph), 2.64 (s, 3H, NCH3), 2.21 (s, 3H, ArCH3), 2.10 (br s, 1H, NH); 13C NMR (75 MHz, CDCl3) δ 173.9, 153.5, 148.5, 137.3, 129.6, 128.9, 127.0, 111.2, 106.6, 71.3, 60.5, 37.8, 27.4, 14.0; HRMS (CI) exact mass calc'd for (C16H18N2O2) requires m/z 270.1368, found m/z 270.1368. [α]D=−156.5 (g=1.0, CHCl3). The enantiopurity of the catalyst was confirmed (>99% ee) by HPLC analysis (AD column, 5% isopropanol in hexanes, 1 mL/min, 254 nm); (2S, 5S) isomer tr=22.9 min, (2S, 5R) isomer tr=25.7 min. The relative stereochemistry of catalyst 5 was confirmed by NOE studies.
Reaction SMILES: FC(F)(F)[C:3](O)=[O:4].[CH2:8]([O:11][C:12]([N:14]1[C@H:18]([C:19]2[N:20]=[C:21]([CH2:24][NH:25]OC(C)(C)C)[S:22][CH:23]=2)[CH2:17][C@@H:16]([O:31][S:32]([CH3:35])(=[O:34])=[O:33])[CH2:15]1)=[O:13])[CH:9]=[CH2:10]>>[CH2:8]([O:11][C:12]([N:14]1[C@H:18]([C:19]2[N:20]=[C:21]([CH2:24][NH:25][CH:3]=[O:4])[S:22][CH:23]=2)[CH2:17][C@@H:16]([O:31][S:32]([CH3:35])(=[O:33])=[O:34])[CH2:15]1)=[O:13])[CH:9]=[CH2:10]
Reactant: C=CCOC(=O)N1C[C@H](OS(C)(=O)=O)C[C@H]1c1csc(CNOC(C)(C)C)n1
Reactant: O=C(O)C(F)(F)F
Product: C=CCOC(=O)N1C[C@H](OS(C)(=O)=O)C[C@H]1c1csc(CNC=O)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Trifluoroacetic acid (4 ml) is added to 1.26 g of (3R,5S)-1-allyloxycarbonyl-5-[2-(t-butoxyaminomethyl)thiazol-4-yl]-3-methanesulfonyloxypyrrolidine, and the mixture is stirred at room temperature for one hr. The reaction mixture is concentrated under reduced pressure. A saturated aqueous sodium hydrogencarbonate solution (30 ml) and 20 ml of dichloromethane are added to the residue, a mixed acid anhydride prepared from 1.0 ml of formic acid and 0.75 ml of acetic acid are added dropwise thereto, and the mixture is stirred at room temperature for one hr. The reaction mixture is subjected to separation, and the organic layer is washed with saturated saline and dried over anhydrous magnesium sulfate. The solvent is removed by evaporation under reduced pressure. The residue is purified by column chromatography on silica gel (methanol:ethyl acetate=5:95) to give 0.81 g of (3R,5S)-1-allyloxycarbonyl-5-(2-formylaminomethylthiazol-4-yl)-3-methanesulfonyloxypyrrolidine.
Reaction SMILES: C(C1C=CC(OCC2ON=C(CC3C=C(C=CC=3)[C:19]([OH:21])=[O:20])N=2)=C(C)C=1O)(=O)C.[OH:29][C:30]1[C:35]([CH3:36])=[C:34]([O:37][CH2:38][C:39]2[O:43][N:42]=[C:41]([CH2:44][C:45]3[CH:50]=[CH:49][C:48](I)=[CH:47][CH:46]=3)[N:40]=2)[CH:33]=[CH:32][C:31]=1[C:52](=[O:54])[CH3:53]>>[C:52]([C:31]1[CH:32]=[CH:33][C:34]([O:37][CH2:38][C:39]2[O:43][N:42]=[C:41]([CH2:44][C:45]3[CH:50]=[CH:49][C:48]([C:19]([OH:21])=[O:20])=[CH:47][CH:46]=3)[N:40]=2)=[C:35]([CH3:36])[C:30]=1[OH:29])(=[O:54])[CH3:53]
Reactant: CC(=O)c1ccc(OCc2nc(Cc3cccc(C(=O)O)c3)no2)c(C)c1O
Reactant: CC(=O)c1ccc(OCc2nc(Cc3ccc(I)cc3)no2)c(C)c1O
Product: CC(=O)c1ccc(OCc2nc(Cc3ccc(C(=O)O)cc3)no2)c(C)c1O

Procedure:
The title compound is prepared essentially as described for 3-[5-(4-acetyl-3-hydroxy-2-methyl-phenoxymethyl)-[1,2,4]oxadiazol-3-ylmethyl]-benzoic acid of Example 146, employing 1-{2-hydroxy-4-[3-(4-iodo-benzyl)-[1,2,4]oxadiazol-5-ylmethoxy]-3-methyl-phenyl}-ethanone. 1H NMR (DMSO-d6) δ 12.84 (s, 1H), 12.80 (s, 1H), 7.86 (m. 2H), 7.78 (d, 1H), 7.38 (d, 2H), 6.67 (d, 1H), 5.60 (s, 2H), 4.19 (s, 2H), 2.55 (s, 3H), 1.99 (s, 3H). LC-MS (m/e): 381 (M−1).
Reaction SMILES: OC[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11](=[O:20])[N:12]([CH3:19])[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:6][CH:5]=1.[OH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1.N1C=CC=CC=1OCCC1C=CC(OC(=O)N(C)C2C=CC=CC=2)=CC=1>>[O:21]=[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]1[CH2:3][C:4]1[CH:5]=[CH:6][C:7]([O:10][C:11](=[O:20])[N:12]([CH3:19])[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[CH:8][CH:9]=1
Reactant: CN(C(=O)Oc1ccc(CCO)cc1)c1ccccc1
Reactant: Oc1ccccn1
Agent: CN(C(=O)Oc1ccc(CCOc2ccccn2)cc1)c1ccccc1
Product: CN(C(=O)Oc1ccc(Cn2ccccc2=O)cc1)c1ccccc1
Yield: 29 %

Procedure:
The title compound was prepared in 29% yield as an oil using methyl-phenyl-carbamic acid 4-(2-hydroxy-ethyl)-phenyl ester and 2-hydroxypyridine. In addition 50% of the isomeric methyl-phenyl-carbamic acid 4-[2-(pyridin-2-yloxy)-ethyl]-phenyl ester was isolated, see characterization below. 1H NMR (400 MHz; CDCl3): δ 3.05 (t, 2H), 3.41 (br s, 3H), 4.14 (s, 2H), 6.08 (t, 1H), 6.66 (d, 1H), 6.90 (dd, 1H), 7.02 (br s, 2H), 7.10 (d, 2H), 7.25-7.42 (m, 6H); HPLC-MS: m/z=349.2 (M+1); Rt=3.04 min.
Reaction SMILES: Br[C:2]1[S:10][C:9]2[C:8](=[O:11])[NH:7][C:6]([CH3:13])([CH3:12])[N:5]([CH3:14])[C:4]=2[CH:3]=1.[CH2:15]([C:17]1[N:21]([S:22]([N:25]([CH3:27])[CH3:26])(=[O:24])=[O:23])[N:20]=[CH:19][C:18]=1B1OC(C)(C)C(C)(C)O1)[CH3:16].C(=O)([O-])[O-].[Cs+].[Cs+].COCCOC>O>[CH2:15]([C:17]1[N:21]([S:22]([N:25]([CH3:27])[CH3:26])(=[O:24])=[O:23])[N:20]=[CH:19][C:18]=1[C:2]1[S:10][C:9]2[C:8](=[O:11])[NH:7][C:6]([CH3:13])([CH3:12])[N:5]([CH3:14])[C:4]=2[CH:3]=1)[CH3:16]
Reactant: CN1c2cc(Br)sc2C(=O)NC1(C)C
Reactant: CCc1c(B2OC(C)(C)C(C)(C)O2)cnn1S(=O)(=O)N(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: COCCOC
Product: CCc1c(-c2cc3c(s2)C(=O)NC(C)(C)N3C)cnn1S(=O)(=O)N(C)C
Temperature: 90 °C
Reaction time: 1 h
Yield: 69.9 %

Procedure:
A mixture of 6-bromo-1,2,2-trimethyl-2,3-dihydrothieno[3,2-d]pyrimidin-4(1H)-one (138 mg, 0.50 mmol), 5-ethyl-N,N-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-sulfonamide (329 mg, 1.00 mmol), cesium carbonate (815 mg, 2.50 mmol), 1,2-dimethoxyethane (5 mL) and water (1.25 mL) was purged with argon. Then, 1,1′-bis(diphenylphosphino) ferrocenepalladium (II) dichloride dichloromethane adduct (40.8 mg, 0.050 mmol) was added, and the mixture was purged with argon again. The mixture was stirred at 90° C. for 1 h. The mixture was poured into water (100 mL) and EtOAc (200 mL). The insoluble materials were filtered off, and the organic layer was collected from the filtrate. This organic layer was washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure. The residual oil was purified by column chromatography (Purif, silica gel, 95:5 hexane/EtOAc to EtOAc) to afford the title compound (139 mg, 70%) as a yellow solid:
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=[O:15])=[C:12]([F:19])[CH:11]=1.N12CCCN=C1CCCCC2>C(#N)C>[Br:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([O:16][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:15])=[C:12]([F:19])[CH:11]=1
Reactant: O=C(O)c1ccc(Br)cc1F
Reactant: BrCc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: O=C(OCc1ccccc1)c1ccc(Br)cc1F
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Benzyl bromide (0.86 g, 5.0 mmol, 1.1 eq.) was added neat to a solution of 4-bromo-2-fluorobenzoic acid (1.0 g, 4.6 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (1.36 mL, 9.2 mmol, 2.0 eq.) in anhydrous acetonitrile (20 mL). The reaction was stirred at room temperature for 18 hours before removing the solvent in vacuo. The residue was diluted with ether and washed with water, saturated aqueous sodium bicarbonate, saturated aqueous ammonium chloride, and brine. The organic layer was dried (MgSO4) and concentrated in vacuo to provide the title compound as a pale yellow oil that crystallized into long needles upon standing (1.4 g, 99%): 1H NMR (300 MHz, CDCl3) δ7.82 (t, 1 H), 7.42-7.31 (m, 7 H), 5.35 (s, 2 H); GC/MS m/z 308/310 (M+ and M+2).
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]1[NH:12][C:13]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([S:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=1)=[O:14].ClC1C=C(C=CC=1)C(OO)=[O:32]>C(Cl)(Cl)Cl.ClCCl>[O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]1[NH:12][C:13]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([S:22]([C:23]([F:26])([F:25])[F:24])=[O:32])=[CH:18][CH:17]=1)=[O:14]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=C(Nc1ccc(SC(F)(F)F)cc1)Nn1cnc2ccccc2c1=O
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: O=C(Nc1ccc(S(=O)C(F)(F)F)cc1)Nn1cnc2ccccc2c1=O
Temperature: 0 °C
Reaction time: 3 h

Procedure:
A mixture of 1-(3,4-dihydro-4-oxo-3-quinazolinyl)-3-{p-[(trifluoromethyl)thio]phenyl}urea (1.0 g, 2.63 mmol) in chloroform is cooled with an ice-water bath, treated with a solution of 3-chloroperoxybenzoic acid (0.57 g, 80% real, 2.64 mmol) in chloroform, stirred for 3 hours at 0° C., stirred for 32 hours at room temperature, cooled to 0° C., treated with additional 3-chloroperoxybenzoic acid (0.114 g, 0.53 mmol) in chloroform, stirred for 36 hours at room temperature, diluted with dichloromethane, washed sequentially with saturated sodium sulfite solution, saturated sodium hydrogen carbonate solution and brine, dried over anhydrous MgSO4 and concentrated in vacuo to obtain a yellow solid. Chromatography of the solid using silica gel and a 4:1 ethyl acetate/hexanes solution gives the title product as a white solid, 0.50 g, mp 148°-150° C., which is identified by 1HNMR spectral analysis.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH2:13][C:14]1[N:15]=[CH:16][NH:17][CH:18]=1)[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:19]([O:11][C:10](=[O:12])[CH:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:13][C:14]1[N:15]=[CH:16][N:17]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:18]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CC(C)(C)OC(=O)NC(Cc1c[nH]cn1)C(=O)O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC(Cc1cn(Cc2ccccc2)cn1)C(=O)OCc1ccccc1
Yield: 30273.2 %

Procedure:
2-tert-Butoxycarbonylamino-3-(1H-imidazol-4-yl)-propionic acid (25 g, 97.92 mmol), benzyl bromide (17.59 g, 12.2 mL, 0.103 mmol) and potassium carbonate (16.9 g, 0.122 mol) in DMF (250 mL) were stirred overnight under argon. The solvent was removed and the residue taken up into water and CH2Cl2. The organic layer was washed with water and brine, dried and filtered. The solvent was removed and the residue subject to column chromatography (silica gel, 75% EA/PE to afford 3-(1-benzyl-1H-imidazol-4-yl)-2-tert-butoxycarbonylamino-propionic acid benzyl ester (6.79 g, 16%) Rf 0.6, followed by 10% MeOH/EA to afford the title compound (15.832 g, 47%) Rf 0.1). ESMS 346 (M+H+) Mpt 100.5-101.7° C. 1H NMR (500 MHz, CDCl3) δ 1.42 (9H, s), 3.02 (2H, m), 4.51 (1H, m), 5.19 (1H, d, J=12.1 Hz), 5.08 (1H, d, J=12.1 Hz), 5.81 (1H, m), 7.35 (5H, m), 7.47 (1H, s). 13C NMR (CDCl3) δ 28.22, 29.48, 53.67, 66.88, 79.88, 116.23, 126.63, 128.26, 128.45, 133.61, 135.19, 135.39, 155.59, 171.97.
Reaction SMILES: C1(C(=[N:14][C:15]2[CH:16]=[C:17]([C:25]([CH:27]3[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]3)=[O:26])[CH:18]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:20]=2)C2C=CC=CC=2)C=CC=CC=1.Cl.CCOC(C)=O>C1COCC1>[NH2:14][C:15]1[CH:16]=[C:17]([C:25]([CH:27]2[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]2)=[O:26])[CH:18]=[C:19]([C:21]([F:22])([F:23])[F:24])[CH:20]=1
Reactant: CN1CCC(C(=O)c2cc(N=C(c3ccccc3)c3ccccc3)cc(C(F)(F)F)c2)CC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CN1CCC(C(=O)c2cc(N)cc(C(F)(F)F)c2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 58 %

Procedure:
Dissolve (3-(diphenylmethyleneamino)-5-(trifluoromethyl)phenyl)(1-methylpiperidin-4-yl)methanone (210 mg, 0.47 mmol) in THF (2 mL) in an ice-bath, add hydrochloric acid (4N, 0.5 mL), then stir it at room temperature for one hour. TLC (PE:EtOAc=1:1) shows the reaction is complete. Partition the mixture between EtOAc and water. Collect the aqueous layer, adjust pH=9 with sodium hydroxide solution, extract with ethyl acetate three times, combine the organic layers, dry over anhydrous sodium sulfate, concentrate to yield the crude product (78 mg, 59%). MS: (M+1): 287.1.