Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([O:13][Si](C(C)(C)C)(C)C)[C@H:9]1[C@@H:21](O)[C:22]([F:25])([F:24])[F:23])=[O:7])(C)(C)C.[N:27]([C:30]1[CH:37]=[CH:36][C:33]([C:34]#[N:35])=[C:32]([C:38]([F:41])([F:40])[F:39])[C:31]=1[CH3:42])=C=O>>[F:39][C:38]([F:40])([F:41])[C:32]1[C:31]([CH3:42])=[C:30]([N:27]2[C@H:21]([C:22]([F:23])([F:24])[F:25])[C@@H:9]3[C@H:10]([OH:13])[CH2:11][CH2:12][N:8]3[C:6]2=[O:7])[CH:37]=[CH:36][C:33]=1[C:34]#[N:35]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1[C@@H](O)C(F)(F)F
Reactant: Cc1c(N=C=O)ccc(C#N)c1C(F)(F)F
Product: Cc1c(N2C(=O)N3CC[C@@H](O)[C@H]3[C@H]2C(F)(F)F)ccc(C#N)c1C(F)(F)F

Procedure:
The title compound was prepared from (2R,3R)-3-(tert-butyl-dimethylsilanyloxy)-2-[(1R)-(2,2,2-trifluoro-1-hydroxyethyl)]pyrrolidine-1-carboxylic acid tert-butyl ester (66A) and isocyanate 18E following procedures analogous to those found in Example 72. LCMS: m/z 394 [M+H]+
Reaction SMILES: [SH:1][CH2:2][C:3](OCC)=[O:4].[H-].[Na+].[NH2:10][C:11]1[N:16]=[C:15]([C:17]([O:19][CH3:20])=[O:18])[CH:14]=[CH:13][C:12]=1Br>CN(C=O)C.CCOC(C)=O>[O:4]=[C:3]1[CH2:2][S:1][C:12]2[CH:13]=[CH:14][C:15]([C:17]([O:19][CH3:20])=[O:18])=[N:16][C:11]=2[NH:10]1
Reactant: COC(=O)c1ccc(Br)c(N)n1
Reactant: CCOC(=O)CS
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc2c(n1)NC(=O)CS2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of ethyl 2-mercaptoacetate (1.47 mL) in DMF (48 mL) was ice-cooled and treated with sodium hydride (540 mg of a 60% dispersion in oil). After 1 h methyl 6-amino-5-bromopyridine-2-carboxylate (3 g) (T. R. Kelly and F. Lang, J. Org. Chem. 61, 1996, 4623-4633) was added and the mixture stirred for 16 h at room temperature. The solution was diluted with EtOAc (1 L), washed with water (3×300 mL), dried and evaporated to about 10 mL. The white solid was filtered off and washed with a little EtOAc to give the ester (0.95 g); LC/MS (APCI−) m/z 223 ([M−H]−, 100%).
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:38])/[CH:23]=[C:24](\[C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([C:36]#[N:37])[CH:31]=2)/[C:25]2[O:26][CH:27]=[CH:28][CH:29]=2)=[CH:17][CH:16]=1)(=[O:8])=[O:7])(C)(C)C.C(OCC)(=O)C.C([O-])(=O)C.[NH4+:49]>CO>[O:26]1[CH:27]=[CH:28][CH:29]=[C:25]1/[C:24](/[C:30]1[CH:31]=[C:32]([C:36]([NH2:37])=[NH:49])[CH:33]=[CH:34][CH:35]=1)=[CH:23]/[C:22](=[O:38])[NH:21][C:18]1[CH:19]=[CH:20][C:15]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[S:6](=[O:8])(=[O:7])[NH2:5])=[CH:16][CH:17]=1
Reactant: [NH4+]
Reactant: CC(C)(C)NS(=O)(=O)c1ccccc1-c1ccc(NC(=O)/C=C(\c2cccc(C#N)c2)c2ccco2)cc1
Agent: CC(=O)[O-]
Solvent: CO
Solvent: CCOC(C)=O
Product: N=C(N)c1cccc(/C(=C\C(=O)Nc2ccc(-c3ccccc3S(N)(=O)=O)cc2)c2ccco2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (2E)-N-[4-(2-{[(tert-butyl)amino]sulfonyl}phenyl)phenyl]-3-(3-cyanophenyl)-3-(2-furyl)prop-2-enamide (176 mg, 0.336 mmol) in 10 ml 1:1 ethyl acetate:anhydrous methanol cooled to −78° C. was bubbled HCl gas until saturation was achieved. Reaction was allowed to warm to room temperature and stirred overnight. The reaction was then concentrated in vacuo and dried under hi vacuum. The dried methyl imidate residue was dissolved in 5 ml anhydrous methanol to which ammonium acetate (144 mg, 2 mmol) was added and the reaction heated to reflux for 2 hours. The reaction was concentrated, treated with trifluoroacetic acid (10 ml) for 2 hrs, concentrated and purified on a 2×25 cm Vydac C18 HPLC column to give 3-((1E)-1-(2-furyl)-2-{N-[4-(2-sulfamoylphenyl)phenyl]carbamoyl}vinyl)benzenecarboxamidine (60 mg, (37%) as a fluffy off-white powder after lyophilization. ES-MS (MA+H+): 487.15
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2([C:14]([OH:16])=O)[CH2:13][CH2:12]2)=[O:10])=[CH:4][CH:3]=1.[CH3:17][O:18][C:19]1[CH:41]=[CH:40][C:22]([CH2:23][NH:24][C:25]2[CH:30]=[C:29]([O:31][C:32]3[CH:37]=[CH:36][C:35]([NH2:38])=[C:34]([F:39])[CH:33]=3)[CH:28]=[CH:27][N:26]=2)=[CH:21][CH:20]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:17][O:18][C:19]1[CH:20]=[CH:21][C:22]([CH2:23][NH:24][C:25]2[CH:30]=[C:29]([O:31][C:32]3[CH:37]=[CH:36][C:35]([NH:38][C:14]([C:11]4([C:9]([NH:8][C:5]5[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=5)=[O:10])[CH2:12][CH2:13]4)=[O:16])=[C:34]([F:39])[CH:33]=3)[CH:28]=[CH:27][N:26]=2)=[CH:40][CH:41]=1
Reactant: COc1ccc(CNc2cc(Oc3ccc(N)c(F)c3)ccn2)cc1
Reactant: O=C(O)C1(C(=O)Nc2ccc(F)cc2)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc(CNc2cc(Oc3ccc(NC(=O)C4(C(=O)Nc5ccc(F)cc5)CC4)c(F)c3)ccn2)cc1
Yield: 57 %

Procedure:
1-((4-Fluorophenyl)carbamoyl)cyclopropanecarboxylic acid (see Example B1, 171 mg, 0.77 mmol), N-(4-methoxybenzyl)-4-(4-amino-3-fluorophenoxy)pyridin-2-amine (see PCT Publication No. WO 2008/046003, 200 mg, 0.59 mmol), TBTU (284 mg, 0.88 mol) and DIEA (0.12 ml, 0.73 mmol) were combined in DMF (1.5 mL) and the resultant mixture was stirred overnight. The reaction mixture was partitioned between saturated aqueous NaHCO3 (20 mL) and EtOAc (20 mL). The organic was washed with water (10 mL), brine (10 mL), and 5% aqueous lithium chloride solution (10 mL), and was then dried over MgSO4 and concentrated in vacuo. Dichloromethane was added to the residue and the resultant slurry was filtered. The collected precipitate was washed with CH2Cl2 and dried in vacuo to provide N-(4-(2-(4-methoxybenzylamino)pyridin-4-yloxy)-2-fluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (137 mg) as a white solid. The filtrate was concentrated and a second crop (46 mg, total yield 57%) was collected. MS (ESI) m/z: 545.1 (M+H+).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[O:3][C:4]1[CH:5]=[C:6]([CH:15]=[CH:16][CH:17]=1)[CH2:7][NH:8][CH:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1.[CH3:20][N:21]1[CH:25]=[C:24]([C:26](O)=[O:27])[N:23]=[CH:22]1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>C(#N)C>[CH3:20][N:21]1[CH:25]=[C:24]([C:26]([N:8]([CH:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[CH2:7][C:6]2[CH:15]=[CH:16][CH:17]=[C:4]([O:3][C:2]([F:18])([F:1])[F:19])[CH:5]=2)=[O:27])[N:23]=[CH:22]1
Reactant: Cn1cnc(C(=O)O)c1
Reactant: FC(F)(F)Oc1cccc(CNC2CCOCC2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC#N
Product: Cn1cnc(C(=O)N(Cc2cccc(OC(F)(F)F)c2)C2CCOCC2)c1
Temperature: 25 °C
Yield: 14.4 %

Procedure:
A mixture of N-[3-(trifluoromethoxy)benzyl]tetrahydro-2H-pyran-4-amine (450 mg), 1-methyl-1H-imidazole-4-carboxylic acid (210 mg), EDC.HCl (320 mg), HOBt (250 mg) and acetonitrile (5 mL) was stirred at room temperature for an hour. Acetonitrile was distilled off under reduced pressure and an aqueous solution of 6 M sodium hydroxide was added. Extraction was conducted with ethyl acetate and the solvent was concentrated. The residue was purified by column chromatography (NH silica gel cartridge; ethyl acetate) to give the titled compound (90 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH3:13])[C:11]([C:14]#[N:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[C:16](Cl)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[C:14]([C:11]1[N:12]([CH3:13])[C:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:1][C:16](=[O:23])[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:3][CH:4]=2)=[CH:9][CH:10]=1)#[N:15]
Reactant: O=C(Cl)c1ccccc1
Reactant: Cn1c(C#N)ccc1-c1ccc(N)cc1
Product: Cn1c(C#N)ccc1-c1ccc(NC(=O)c2ccccc2)cc1

Procedure:
The title compound was prepared according to the general procedure for acylation of 5-(4-aminophenyl)-1-methyl-1H-pyrrole-2-carbonitrile using benzoyl chloride (64 μL, 0.55 mmol) to provide N-[4-(5-cyano-1-methyl-1H-pyrrol-2-yl)phenyl]benzamide (0.035 g).
Reaction SMILES: N1([C:7]2[C:8](=[O:13])[CH2:9][CH2:10][CH2:11][CH:12]=2)CCOCC1.[CH:14]([C:17]1[CH:23]=[CH:22][CH:21]=[C:20]([CH:24]([CH3:26])[CH3:25])[C:18]=1[NH2:19])([CH3:16])[CH3:15].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH:24]([C:20]1[CH:21]=[CH:22][CH:23]=[C:17]([CH:14]([CH3:16])[CH3:15])[C:18]=1[NH:19][C:7]1[C:8](=[O:13])[CH2:9][CH2:10][CH2:11][CH:12]=1)([CH3:26])[CH3:25]
Reactant: O=C1CCCC=C1N1CCOCC1
Reactant: CC(C)c1cccc(C(C)C)c1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)c1cccc(C(C)C)c1NC1=CCCCC1=O
Temperature: 80 °C
Yield: 96.2 %

Procedure:
A 250-mL three-necked round-bottomed flask equipped with a condenser, gas inlet and septas is placed under N2 atmosphere. The flask is charged with 2-(morpholin-4-yl)-2-cyclohexen-1-one (7.0046 g, 38.65 mmol; Preparation 2), toluene (74.0 mL) and 2,6-diisopropylaniline (6.8521 g, 38.65 mmol). To the yellow solution is added p-toluenesulfonic acid monohydrate (7.3520 g, 38.65 mmol; p-TsOH.H2O). The reaction mixture became very thick with a lot of precipitate. The mixture is heated to 80° C. (oil bath temperature) and allowed to stir. Another 5.0 mL of toluene are added to facilitate stirring. The mixture is stirred for 2 hours. Reaction mixture is allowed to reach room temperature. The mixture is filtered. The filtrate is concentrated under high vacuum to afford 10.09 g of a yellow solid. The solid is dissolved in hot hexanes (about 30 mL) and filtered. The solution is allowed to cool to room temperature, seeded and place on the freezer. The solution is filtered while most of the solid is left behind on the flask. The flask is placed on an ice bath. The solid is rinsed with two about 6 mL portions of cold hexanes. The yellow solid is allowed to dry, transfer to a vial and left to dry overnight under vacuum (first crop: 4.0550 g). Mother liquor is concentrated and recrystallization is repeated two more times. The second crop is left in the freezer for 5 hours (second crop: 1.0785 g) and third crop is left overnight (third crop: 0.6919 g). The combined yield of title compound of Preparation 3 is 5.8254 g (55.54%).
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C(N(CC)CC)C.[Br:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[N:22]=[C:21](Cl)[CH:20]=[C:19]2[CH3:27]>O1CCOCC1>[Br:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[N:22]=[C:21]([N:5]1[CH2:6][CH2:7][CH:2]([CH3:1])[CH2:3][CH2:4]1)[CH:20]=[C:19]2[CH3:27]
Reactant: Cc1cc(Cl)nc2ccc(Br)cc12
Reactant: CC1CCNCC1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: Cc1cc(N2CCC(C)CC2)nc2ccc(Br)cc12

Procedure:
0.24 mL (2.0 mmol) of 4-methylpiperidine and 0.28 mL (2.0 mmol) of triethylamine are added to a solution of 0.51 g (2.0 mmol) of 6-bromo-2-chloro-4-methylquinoline in 15 mL of 1,4-dioxane and the reaction mixture is refluxed overnight. After cooling, the precipitate is filtered off, the filtrate is evaporated down, the residue is combined with acetonitrile and MTBE, filtered to remove insoluble ingredients, and the filtrate is evaporated down again. Yield: 0.69 g (100% of theoretical); C16H19BrN2 (M=319.240); calc.: molpeak (M+H)+: 319/321 (Br); found: molpeak (M+H)+: 319/321 (Br); HPLC-MS: 4.7 min (method B).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.Cl.[CH2:11]([OH:13])[CH3:12]>ClCCl>[OH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6](=[NH:7])[O:13][CH2:11][CH3:12])=[CH:4][CH:3]=1
Reactant: CCO
Reactant: N#Cc1ccc(O)cc1
Agent: Cl
Solvent: ClCCl
Product: CCOC(=N)c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 64 h

Procedure:
A stirred, 0° C. solution of 4-hydroxybenzonitrile (50.7 g, 426 mmol) in 1400 mL of dichloromethane and 75 mL anhydrous ethanol is treated with anhydrous hydrogen chloride gas (110 g) over 1.5 hours. This solution is stirred a room temperature for 64 hours and the resulting solids collected and washed with 500 mL diethyl ether and 2×1000 mL of ethyl acetate. The remaining solids (60.4 g) are dissolved in 1200 mL of water and the residual solids filtered. To the filtrate is added a solution of sodium hydroxide (12.57 g) in 150 mL water. The resulting white solid is filtered and washed with water to afford ethyl 4-hydroxybenzenecarboximidoate.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH3:11])(=[O:10])=[O:9])=[CH:4][C:3]=1[C:12](=[O:14])[CH3:13].[C:15]([N:18]1[CH2:23][CH2:22][C:21](=O)[CH2:20][CH2:19]1)(=[O:17])[CH3:16]>>[C:15]([N:18]1[CH2:23][CH2:22][C:21]2([CH2:13][C:12](=[O:14])[C:3]3[CH:4]=[C:5]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:6]=[CH:7][C:2]=3[O:1]2)[CH2:20][CH2:19]1)(=[O:17])[CH3:16]
Reactant: CC(=O)c1cc(S(C)(=O)=O)ccc1O
Reactant: CC(=O)N1CCC(=O)CC1
Product: CC(=O)N1CCC2(CC1)CC(=O)c1cc(S(C)(=O)=O)ccc1O2

Procedure:
2'-Hydroxy-5'-methanesulfonylacetophenone and 1-acetyl-4-piperidone were condensed according to the method of Example 434 to give the ketone as a white solid, m.p. 105°-110° C.
Reaction SMILES: [NH2:1][C:2]1[C:21]([C:22]2[CH:23]=[CH:24][C:25]3[O:38][CH2:37][N:28]4[C:29]5[CH:30]=[CH:31][CH:32]=[C:33]([F:36])[C:34]=5[CH:35]=[C:27]4[C:26]=3[N:39]=2)=[CH:20][C:5]2[C:6]([C:16]([NH:18][CH3:19])=[O:17])=[C:7]([C:9]3[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=3)[O:8][C:4]=2[CH:3]=1.CCN(CC)CC.[Cl:47][CH2:48][CH2:49][CH2:50][S:51](Cl)(=[O:53])=[O:52]>C(Cl)Cl>[Cl:47][CH2:48][CH2:49][CH2:50][S:51]([NH:1][C:2]1[C:21]([C:22]2[CH:23]=[CH:24][C:25]3[O:38][CH2:37][N:28]4[C:29]5[CH:30]=[CH:31][CH:32]=[C:33]([F:36])[C:34]=5[CH:35]=[C:27]4[C:26]=3[N:39]=2)=[CH:20][C:5]2[C:6]([C:16]([NH:18][CH3:19])=[O:17])=[C:7]([C:9]3[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=3)[O:8][C:4]=2[CH:3]=1)(=[O:53])=[O:52]
Reactant: O=S(=O)(Cl)CCCCl
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N)c(-c3ccc4c(n3)-c3cc5c(F)cccc5n3CO4)cc12
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(NS(=O)(=O)CCCCl)c(-c3ccc4c(n3)-c3cc5c(F)cccc5n3CO4)cc12
Temperature: 12 °C
Reaction time: 16 h
Yield: 104.4 %

Procedure:
To a solution of 6-amino-5-(11-fluoro-6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indol-2-yl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide (70 mg, 0.13 mmol) and Et3N (0.1 mL) in CH2Cl2 (2 mL) was added 3-chloropropane-1-sulfonyl chloride (140 mg, 0.92 mmol) dropwise at 0° C. The reaction mixture was stirred at 12° C. for 16 hours. The reaction mixture was concentrated to provide 6-(3-chloropropylsulfonamido)-5-(11-fluoro-6H-pyrido[2′,3′:5,6][1,3]oxazino[3,4-a]indol-2-yl)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide (90 mg, yield: 100%), which was used directly in the next step without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][C:14]=1[CH3:15])[C:5]([NH:7][N:8]=[C:9]([CH3:11])[CH3:10])=[O:6].[C:16](OC(=O)C)(=[O:18])[CH3:17]>>[Br:1][C:2]1[CH:3]=[C:4]([C:5]2[O:6][C:9]([CH3:11])([CH3:10])[N:8]([C:16](=[O:18])[CH3:17])[N:7]=2)[CH:12]=[CH:13][C:14]=1[CH3:15]
Reactant: CC(C)=NNC(=O)c1ccc(C)c(Br)c1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)N1N=C(c2ccc(C)c(Br)c2)OC1(C)C
Temperature: 25 °C

Procedure:
A mixture of 3-bromo-4-methyl-N′-(propan-2-ylidene)benzohydrazide (2.0 g, 7.46 mmol), as obtained hereinbefore, and acetic anhydride (30 mL) was refluxed for one hour. The excess of acetic anhydride was removed under vacuum after cooling the reaction mixture to room temperature and the crude residue obtained was triturated with hexane to remove traces of acetic anhydride present in the reaction mixture. The crude product was purified by flash column chromatography (silica gel, 100-200 mesh, 13% ethyl acetate in hexane) to afford 800 mg of the desired product as an oil. 1HNMR (400 MHz, CDCl3) δ 7.97 (s, 1H), 7.65 (d, J=8.0 Hz, 1H), 7.28 (d, J=8.0 Hz, 1H), 2.44 (s, 3H), 2.29 (s, 3H), 1.85 (s, 6H); ESI-MS (m/z) 311, 313 [(MH)+, Br79,81].
Reaction SMILES: [I-:1].[OH:2][C:3]1[CH:4]=[C:5]([C@@H:9]([N+:11]([CH3:21])([CH3:20])[C@H:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH3:13])[CH3:10])[CH:6]=[CH:7][CH:8]=1.C(#N)C.C(=O)([O-])[O-].[K+].[K+].[CH2:31]([N:33]([CH3:37])[C:34](Cl)=[O:35])[CH3:32]>C(O)CO>[I-:1].[CH2:31]([N:33]([CH3:37])[C:34]([O:2][C:3]1[CH:4]=[C:5]([C@@H:9]([N+:11]([CH3:21])([CH3:20])[C@H:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH3:13])[CH3:10])[CH:6]=[CH:7][CH:8]=1)=[O:35])[CH3:32]
Reactant: CCN(C)C(=O)Cl
Reactant: C[C@@H](c1ccccc1)[N+](C)(C)[C@@H](C)c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: OCCO
Solvent: CC#N
Product: CCN(C)C(=O)Oc1cccc([C@H](C)[N+](C)(C)[C@@H](C)c2ccccc2)c1

Procedure:
Mix 7.9 g (0.02 mol) (S)-1-(3-hydroxyphenyl)-N,N-dimethyl-N—((S)-1-phenylethyl)ethanaminium iodide (formula VIII) with 180 ml of acetonitrile, 4.1 g (0.03 mol) of potassium carbonate, 3.6 g (0.03 mol) ethyl(methyl)carbamic chloride and 0.1 g of macrogol 400 at room temperature, let it react at 20° C. for 16 hours. Filter it and reduce the pressure to recover 9.8 g of red-brown liquid to be directly used in the next reaction.
Reaction SMILES: C([Li])CCC.CCCCCC.[O:12]([C:30]1[CH:35]=[C:34]([O:36][CH3:37])[CH:33]=[C:32]([O:38][CH3:39])[CH:31]=1)[Si:13]([C:26]([CH3:29])([CH3:28])[CH3:27])([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.CN(C)[CH:42]=[O:43].[Cl-].[NH4+]>C(OCC)C>[O:12]([C:30]1[CH:35]=[C:34]([O:36][CH3:37])[C:33]([CH:42]=[O:43])=[C:32]([O:38][CH3:39])[CH:31]=1)[Si:13]([C:26]([CH3:28])([CH3:29])[CH3:27])([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CN(C)C=O
Reactant: COc1cc(OC)cc(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: CCOCC
Product: COc1cc(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)cc(OC)c1C=O
Temperature: 0 °C
Yield: 41.3 %

Procedure:
Under nitrogen, a 1.60 M solution of n-butyl lithium in hexane (31 mL, 49 mmol) was added to a solution of 1-t-butyldiphenylsiloxy-3,5-dimethoxybenzene (14.68 g, 39.0 mmol) in anhydrous diethyl ether (200 mL) stirred in an ice bath. The reaction mixture was stirred at 35° C. for 3 hours and cooled in the ice bath, followed by the addition of dimethylformamide (9.21 mL, 119.4 mmol). After stirring at room temperature for 1 hour, saturated aqueous ammonium chloride was added, and the mixture was extracted with diethyl ether. The organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel to yield 4-t-butyldiphenylsiloxy-2,6-dimethoxybenzaldehyde as a colorless crystalline powder (melting point: 177.5-120.0° C.) (6.77 g, yield: 41%).
Reaction SMILES: N[C@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4][C:5]([OH:7])=[O:6].Cl.N([O-])=O.[Na+]>O.CCOC(C)=O>[O:9]=[C:8]1[O:10][C@H:4]([C:5]([OH:7])=[O:6])[CH2:3][CH2:2]1
Reactant: N[C@@H](CCC(=O)O)C(=O)O
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: O=C1CC[C@@H](C(=O)O)O1
Temperature: 25 °C
Reaction time: 12 h
Yield: 91.6 %

Procedure:
To a solution of L-glutamic acid (10.07 g, 0.068 mol, J&K CHEMICA) in 20 ml of concd. HCl and 40 mL H2O was added a solution of NaNO2 (7.0 g, 0.102 mol, Shantou Xilong chemical factory) in H2O (20 mL) slowly at −5° C. The mixture was continued to stir for 12 hrs at room temperature. The reaction mixture was evaporated in vacuo below 50° C. to give yellow oil, which was dissolved in EtOAc. The solid formed was filtered and washed with EtOAc. The filtrate and washing solution were combined, dried over Na2SO4. The solvent was concentrated in vacuo to give (S)-tetrahydro-5-oxofuran-2-carboxylic acid as pale yellow oil (8.1 g, 91.6%)1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH2:24]([O:31][C:32](=[O:43])[CH:33]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:34](O)=[O:35])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(CC)CC>CN(C=O)C>[CH2:24]([O:31][C:32](=[O:43])[CH:33]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:34]([N:11]([C:5]1[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1)[CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([F:22])([F:21])[F:23])=[CH:16][CH:15]=1)=[O:35])[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: COc1ccc(NCCc2ccc(C(F)(F)F)cc2)cc1OC
Reactant: O=C(O)C(C(=O)OCc1ccccc1)c1ccccc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1ccc(N(CCc2ccc(C(F)(F)F)cc2)C(=O)C(C(=O)OCc2ccccc2)c2ccccc2)cc1OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 28.9 %

Procedure:
A mixture of 0.7 g (2.1 mmol) (3,4-Dimethoxy-phenyl)-[2-(4-trifluoromethyl-phenyl)-ethyl]-amine, 0.58 g (2.1 mmol) 2-phenyl-malonic acid monobenzylester (commercially available), 0.83 g (2.5 mmol) TBTU and 0.43 g (4.3 mmol) NEt3 in 15 mL DMF was stirred at room temperature for 16 h. After evaporation to dryness the residue was treated with HCl aq. and DCM. The combined organic phases were washed with HCl aq., dried with MgSO4 and evaporated to dryness. The residue was purified by flash column chromatography on silica eluting with a gradient formed from ethyl acetate and heptane. The product containing fractions were combined and evaporated to dryness to yield 0.35 g (29%) of the title compound. MS(m/e): 578.3 (MH+).
Reaction SMILES: [K:1].CC(C)([O-:5])C.[O:7]([C:14]1[CH:19]=[CH:18][C:17](O)=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>CS(C)=O>[K:1].[O:7]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[O-:5])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC(C)(C)[O-]
Reactant: Oc1ccc(Oc2ccccc2)cc1
Agent: [K]
Solvent: CS(C)=O
Product: [O-]c1ccccc1Oc1ccccc1
Temperature: 0 °C

Procedure:
13.2 g of potassium-tert.-butoxide is added portionwise, with slight external cooling (ice water) and with the introduction of nitrogen, to a solution of 20.4 g of 4-phenoxyphenol in 200 ml of dimethylsulphoxide. After potassium-phenoxy-phenolate has formed, with complete dissolving of the potassium-tert.-butoxide, there is added dropwise to the phenolate within 30 minutes at 20°-22° C., with stirring, 21.5 g of 1-bromo-3-phenoxypropane, and the whole is stirred at 30° C. for a further 16 hours. In further processing, the reaction mixture is poured, with stirring, into 800 ml of ice water, and the mixture is repeatedly extracted with dichloromethane. The combined dichloromethane phases are thereupon repeatedly washed with ice-cold 10% potassium hydroxide solution, water and saturated sodium chloride solution; they are then dried over sodium sulphate and the solvent is completely removed in vacuo. The 1-phenoxy-4-(3-phenoxy)-1-propoxy-benzene then solidifying in crystalline form is further purified by recrystallisation in isopropanol; m.p. 69°-71° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12](=[O:13])[NH:11][C:10](=[O:14])[O:9]2)[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[F:22][C:23]1[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[C:24]=1[C:25](Cl)=[O:26]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12](=[O:13])[N:11]([C:25](=[O:26])[C:24]3[C:23]([F:22])=[CH:31][CH:30]=[CH:29][C:28]=3[F:32])[C:10](=[O:14])[O:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=c1[nH]c(=O)n(-c2cccc(Cl)c2)o1
Reactant: O=C(Cl)c1c(F)cccc1F
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=C(c1c(F)cccc1F)n1c(=O)on(-c2cccc(Cl)c2)c1=O
Reaction time: 24 h

Procedure:
2-(3-Chlorophenyl)-1,2,4-oxadiazolidin-3,5-dione (0.03 mole), toluene (100 ml) and triethylamine (5 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. 2,6-Difluorobenzoyl chloride (0.03 mole) dissolved in toluene (20 ml) is then added to the reaction flask and the resulting mixture is heated at reflux with stirring for a period of about 24 hours. After this time the reaction mixture is filtered and the filtrate is washed with water, dilute hydrochloric acid and with aqueous sodium bicarbonate. The washed solution is then dried over anhydrous magnesium sulfate. The dried solution is stripped of solvent under reduced pressure leaving a solid residue. The residue is recrystallized to yield the desired product 2-(3-chlorophenyl)-4-(2,6-difluorobenzoyl)-1,2,4-oxadiazolidin-3,5-dione.