Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]#[N:4].[Na+].[C:6]1([CH3:15])[CH:11]=[CH:10][CH:9]=[C:8]([S:12]([O-:14])=[O:13])[CH:7]=1>CN(C=O)C>[C:6]1([CH3:15])[CH:11]=[CH:10][CH:9]=[C:8]([S:12]([CH2:2][C:3]#[N:4])(=[O:14])=[O:13])[CH:7]=1
Reactant: Cc1cccc(S(=O)[O-])c1
Reactant: N#CCCl
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cccc(S(=O)(=O)CC#N)c1
Reaction time: 1 h
Yield: 25.1 %

Procedure:
2.65 ml (42 mmol) of chloroacetonitrile were added to a suspension of 7.5 g (42 mmol) of toluene-3-sulphinic acid sodium salt in 80 ml of DMF and stirred at 100° for 1 hr. The reaction solution was evaporated, the residue was partitioned between H2O and CH2Cl2. The aqueous phase was washed three times with CH2Cl2. The combined organic phases were washed once with H2O, dried (MgSO4). filtered and evaporated. Chromatography (SiO2, CH2Cl2) yielded 2.06 g (25%) of (toluene-3-sulphonyl)-acetonitrile as a colorless oil.
Reaction SMILES: C[C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12](O)=[O:13])=[CH:9][CH:10]=2)[N:5]=[C:4]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([S:22](=[O:25])(=[O:24])[NH2:23])=[CH:18][CH:17]=2)[N:3]=1.CN.C[CH2:29][N:30](C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>>[CH3:29][NH:30][C:12]([C:8]1[CH:7]=[C:6]2[C:11]([CH:2]=[N:3][C:4]([NH:15][C:16]3[CH:17]=[CH:18][C:19]([S:22](=[O:25])(=[O:24])[NH2:23])=[CH:20][CH:21]=3)=[N:5]2)=[CH:10][CH:9]=1)=[O:13]
Reactant: Cc1nc(Nc2ccc(S(N)(=O)=O)cc2)nc2cc(C(=O)O)ccc12
Reactant: CCN(C(C)C)C(C)C
Agent: CN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: CNC(=O)c1ccc2cnc(Nc3ccc(S(N)(=O)=O)cc3)nc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50 %

Procedure:
To methyl 2-(4-sulfamoylphenylamino)quinazolin-7-carboxylic acid (1 eq) was added methylamine (2 eq) and DIEA (4 eq) and HBTU (2 eq) and the mixture was stirred at RT overnight. The coupling went to completion and the mixture was concentrated and partitioned between ethyl acetate and water. The organic layers were concentrated and purified on the prep HPLC to give N-methyl-2-(4-sulfamoylphenylamino)quinazoline-7-carboxamide in 50% yield. ES/MS m/z 358 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](Cl)=[O:6].[C:11]([O:15][C:16](=[O:38])[CH2:17][N:18]1[C:22]2[CH:23]=[CH:24][C:25]([NH:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:26][C:21]=2[N:20]=[C:19]1[CH2:35][CH2:36][CH3:37])([CH3:14])([CH3:13])[CH3:12].CCN(C(C)C)C(C)C>CN(C1C=CN=CC=1)C.C(Cl)Cl.Cl>[C:11]([O:15][C:16](=[O:38])[CH2:17][N:18]1[C:22]2[CH:23]=[CH:24][C:25]([N:27]([CH2:28][C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[C:5](=[O:6])[C:4]3[CH:8]=[CH:9][CH:10]=[C:2]([Cl:1])[CH:3]=3)=[CH:26][C:21]=2[N:20]=[C:19]1[CH2:35][CH2:36][CH3:37])([CH3:14])([CH3:13])[CH3:12]
Reactant: O=C(Cl)c1cccc(Cl)c1
Reactant: CCCc1nc2cc(NCc3ccccc3)ccc2n1CC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCc1nc2cc(N(Cc3ccccc3)C(=O)c3cccc(Cl)c3)ccc2n1CC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-Chloro-benzoyl chloride (46 μL, 0.36 mmol) was added to a solution of (5-benzylamino-2-propyl-benzoimidazol-1-yl)-acetic acid tert-butyl ester (45 mg, 0.12 mmol), DIEA (41 μL, 0.24 mmol) and DMAP (15 mg, 0.12 mmol) in CH2Cl2 (1 mL), and stirred overnight at room temperature. The reaction solution was diluted with aqueous HCl (1.0 M) and filtered through an Extrelut column. The Extrelut column was washed with CH2Cl2, and the filtrate was concentrated to afford the subtitle compound that was used without further purification. MS calculated for C30H32ClN3O3+H: 518, observed: 518.
Reaction SMILES: Br[C:2]1[C:3]([F:12])=[C:4]([CH:8]=[C:9]([F:11])[CH:10]=1)[CH:5]([OH:7])[CH3:6].[C:13]([Cu])#[N:14].CN(C=O)C.[C-]#N.[Na+]>O>[F:12][C:3]1[C:4]([CH:5]([OH:7])[CH3:6])=[CH:8][C:9]([F:11])=[CH:10][C:2]=1[C:13]#[N:14]
Reactant: N#C[Cu]
Reactant: CC(O)c1cc(F)cc(Br)c1F
Agent: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(O)c1cc(F)cc(C#N)c1F
Yield: 95.4 %

Procedure:
A mixture of 9.39 g of 3-bromo-2,5-difluoro-α-methylbenzyl alcohol, 3.82 g of CuCN and 117 mL of DMF is stirred and heated at reflux for 7 hours under N2. When the mixture has cooled, 100 mL of 5% aqueous NaCN is added followed by 350 mL of H2O 30 minutes later. The black solution is extracted with 4×150 mL of CH2Cl2 and these combined extracts washed with H2O, saturated NaHCO3 and H2O (150 mL each) and stripped in vacuo to furnish 6.92 g (95% yield) of 2,5-difluoro-3-(1-hydroxyethyl)-benzonitrile as a brown oil. The product exhibits an M+1 ion at 184 in the mass spectrum and appropriate infrared and N.M.R. spectral data.
Reaction SMILES: [CH:1]1([NH:7][C:8]2[S:9][CH:10]=[C:11]([CH:13]=O)[N:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[S:15]1[CH2:21][C:19](=[O:20])[N:18]([CH2:22][C:23]([OH:25])=[O:24])[C:16]1=[S:17].[Cl-].[NH4+].N>C(O)C>[CH:1]1([NH:7][C:8]2[S:9][CH:10]=[C:11]([CH:13]=[C:21]3[S:15][C:16](=[S:17])[N:18]([CH2:22][C:23]([OH:25])=[O:24])[C:19]3=[O:20])[N:12]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=Cc1csc(NC2CCCCC2)n1
Reactant: O=C(O)CN1C(=O)CSC1=S
Agent: N
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: O=C(O)CN1C(=O)C(=Cc2csc(NC3CCCCC3)n2)SC1=S

Procedure:
The reaction described in Example 1 was repeated, but using 3.0 g of 2-cyclohexylaminothiazole-4-carbaldehyde, 2.27 g of rhodanine-3-acetic acid, 1.7 g of ammonium chloride, 1.7 ml of 28% v/v aqueous ammonia and 60 ml of ethanol giving the title compound as yellowish-brown needles.
Reaction SMILES: C[O:2][C:3](=[O:31])[CH2:4][CH:5]([C:25]1[N:29]([CH3:30])[N:28]=[N:27][N:26]=1)[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH:14]2[CH2:19][CH2:18][CH2:17][C:16]3([CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)[CH2:15]2)=[CH:8][CH:7]=1.O1CCCC1.[OH-].[Na+].Cl>O.CO>[CH3:30][N:29]1[C:25]([CH:5]([C:6]2[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH:14]3[CH2:19][CH2:18][CH2:17][C:16]4([CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]4)[CH2:15]3)=[CH:8][CH:7]=2)[CH2:4][C:3]([OH:31])=[O:2])=[N:26][N:27]=[N:28]1
Reactant: COC(=O)CC(c1ccc(OCC2CCCC3(CCCCC3)C2)cc1)c1nnnn1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: Cn1nnnc1C(CC(=O)O)c1ccc(OCC2CCCC3(CCCCC3)C2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 98.4 %

Procedure:
To a solution of 3-(1-methyl-1H-tetrazol-5-yl)-3-[4-(spiro[5.5]undec-2-ylmethoxy)-phenyl]-propionic acid methyl ester (41 mg) obtained in Step 8 in a mixed solvent of tetrahydrofuran (1 mL)-methanol (0.5 mL)-water (0.5 mL) was added 2N aqueous sodium hydroxide solution (0.144 mL), followed by stirring the reaction mixture at room temperature for 18 hours. Then, after addition of 1N aqueous hydrochloric acid solution (0.3 mL), the reaction mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried and concentrated. The residue was purified by thin-layer column chromatography on silica gel (acetic acid:ethyl acetate:chloroform (volume ratio)=0.1:1:10) to give 3-(1-methyl-1H-tetrazol-5-yl)-3-[4-(spiro[5.5]undec-2-ylmethoxy)-phenyl]-propionic acid (39 mg) as the desired compound.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[CH2:11](Br)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[CH2:11]([O:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=[N+]([O-])c1cccc(O)c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cccc(OCc2ccccc2)c1
Temperature: 100 °C
Yield: 97.1 %

Procedure:
3-Nitro-phenol (1.00 g, 7.189 mmol) was treated with benzyl bromide (1.352 g, 7.91 mmol), and K2CO3 (1.242 g, 8.986 mmol) in DMF. The reaction mixture was heated to 100° C. for 1 hr at which time the reaction mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate. Dried over Na2SO4, filtered and concentrated under vacuum giving the title compound (1.6 g, 97%).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:20][C:21]1[CH:22]=[C:23]([OH:28])[CH:24]=[C:25]([F:27])[CH:26]=1.O[CH:30]1[CH2:35][CH2:34][N:33]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:32][CH2:31]1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>C1COCC1>[Br:20][C:21]1[CH:22]=[C:23]([CH:24]=[C:25]([F:27])[CH:26]=1)[O:28][CH:30]1[CH2:35][CH2:34][N:33]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:32][CH2:31]1
Reactant: Oc1cc(F)cc(Br)c1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2cc(F)cc(Br)c2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70 %

Procedure:
To a mixture of triphenylphosphine (1.75 g, 6.66 mmol) and 3-bromo-5-fluorophenol (795 mg, 4.16 mmol) and tert-butyl 4-hydroxypiperidine-1-carboxylate (922 mg, 4.58 mmol) in THF (20. mL) was added di-tert-butyl azodicarboxylate (1.53 g, 6.66 mmol) (DBAD) at 0° C. The reaction was stirred overnight at room temperature. The solvent was removed and the residue was dissolved in methanol and purified by preparative-LCMS (C18 column eluting with a gradient of ACN/H2O containing 0.15% NH4OH) to give the desired product (1.09 g, 70%). LCMS (M+Na)+: 396.0, 398.0.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]([O:10][C:11]1[C:16]([O:17][CH3:18])=[C:15]([O:19][CH3:20])[C:14]([O:21]C(=O)C)=[CH:13][C:12]=1[CH3:25])(=[O:9])[CH3:8].Cl>CO>[C:7]([O:10][C:11]1[C:12]([CH3:25])=[CH:13][C:14]([OH:21])=[C:15]([O:19][CH3:20])[C:16]=1[O:17][CH3:18])(=[O:9])[CH3:8]
Reactant: COc1c(OC(C)=O)cc(C)c(OC(C)=O)c1OC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: COc1c(O)cc(C)c(OC(C)=O)c1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.5 %

Procedure:
An aqueous solution (150 ml) of potassium carbonate (9.8 g) was added to a solution of 1,4-diacetoxy-5,6-dimethoxy-2-methylbenzene (31 g) in methanol (200 ml), and the mixture was stirred under an atmosphere of argon at room temperature for 1 hour. The reaction mixture was ice-cooled, made acidic by addition of hydrochloric acid (11 ml) and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain the title compound (26 g, 90%) as an oil.
Reaction SMILES: C[O:2][C:3](=[O:12])[CH:4]([OH:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[CH3:13][N:14]([CH3:18])[C:15](Cl)=[O:16]>C1COCC1.CN(C1C=CN=CC=1)C.C(OCC)(=O)C>[CH3:13][N:14]([CH3:18])[C:15]([O:11][CH:4]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[C:3]([OH:2])=[O:12])=[O:16]
Reactant: COC(=O)C(O)c1ccccc1
Reactant: CN(C)C(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CN(C)C(=O)OC(C(=O)O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83 %

Procedure:
To hydroxyl-phenyl-acetic acid methyl ester (500 mg) in THF (10 mL) were added dimethylcarbamoyl chloride (304 μl), TEA (503 μl), and DMAP (37 mg). After stirring for overnight at room temperature, the mixture was taken up in ethyl acetate (150 mL). The organic phase was washed with 1 N HCl (1×100 mL) and saturated sodium bicarbonate (1×100 mL), and dried over sodium sulfate. After the solvent was removed, the resulting solid was dissolved in THF (6 mL). To the solution was added 2 M LiOH (3 mL). After stirring for 90 min. at room temperature, the reaction mixture was acidified with 2 N HCl (3.2 mL). The mixture was extracted with ethyl acetate (50 mL). The organic phase was dried over sodium sulfate. The solvent was removed under reduced pressure to provide dimethylcarbamoyloxy-phenyl-acetic acid (561 mg, 83%) as an off-white solid.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][C:6](=[O:8])[CH2:5][CH:4]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:3]1.C(N(CC)CC)C.[C:21](Cl)(=[O:24])[CH2:22][CH3:23]>ClCCl>[O:8]=[C:6]1[CH:7]([C:21](=[O:24])[CH2:22][CH3:23])[C:2](=[O:1])[CH2:3][CH:4]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:5]1
Reactant: CCOC(=O)C1CC(=O)CC(=O)C1
Reactant: CCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C1CC(=O)C(C(=O)CC)C(=O)C1
Temperature: 25 °C
Yield: 45.6 %

Procedure:
4.2 g of ethyl 3,5-dioxocyclohexanecarboxylate and 3.4 g of triethylamine were dissolved in 50 ml of dichloromethane, to which was added dropwise 2.9 g of propionyl chloride under stirring at room temperature. The resultant mixture was allowed to react at ambient temperature for 2 hours, after which the reaction solution was washed with water and admixed with a dilute aqueous sodium bicarbonate solution to remove the acidic matters from the reaction solution. The organic layer was then separated from the aqueous phase, dried and concentrated to a small volume. The concentrated solution was taken up in 20 ml of toluene, followed by addition of 0.5 g of 4-N,N-dimethylaminopyridine and heating the mixture at 85° C. for 3 hours. Thereafter, the toluene was removed from the reaction solution by distillation under reduced pressure, and the residue was chromatographed on silica gel using benzene as developing solvent to afford 2.5 g of the title compound (Compound No. 9 of Table 1) as colorless flakes having a melting point of 55°- 56° C.
Reaction SMILES: C([O:8][C:9]1[C:10]([CH:33]([CH3:35])[CH3:34])=[CH:11][C:12]([C:29]([F:32])([F:31])[F:30])=[C:13]([NH:15][C:16]([C:18]2[C:27](=[O:28])[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[NH:20][CH:19]=2)=[O:17])[CH:14]=1)C1C=CC=CC=1>[Pd]>[OH:8][C:9]1[C:10]([CH:33]([CH3:35])[CH3:34])=[CH:11][C:12]([C:29]([F:32])([F:30])[F:31])=[C:13]([NH:15][C:16]([C:18]2[C:27](=[O:28])[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[NH:20][CH:19]=2)=[O:17])[CH:14]=1
Reactant: CC(C)c1cc(C(F)(F)F)c(NC(=O)c2c[nH]c3ccccc3c2=O)cc1OCc1ccccc1
Agent: [Pd]
Product: CC(C)c1cc(C(F)(F)F)c(NC(=O)c2c[nH]c3ccccc3c2=O)cc1O
Reaction time: 8 h

Procedure:
A flask charged with N-[5-benzyloxy-4-isopropyl-2-(trifluoromethyl)phenyl]-4-oxo-1H-quinoline-3-carboxamide (118 mg, 0.25 mmol) and Pd/C (12 mg, 0.11 mmol) was evacuated under vacuum, followed by purging with N2. Methanol (2 mL) was added under inert atmosphere, followed by evacuating under vacuum. The reaction was stirred overnight under an atmosphere of hydrogen, filtered through a plug of celite and concentrated to give N-[5-hydroxy-4-isopropyl-2-(trifluoromethyl)phenyl]-4-oxo-1H-quinoline-3-carboxamide. 1H NMR (400.0 MHz, DMSO-d6) δ 12.93 (s, 1H), 12.59 (s, 1H), 10.29 (s, 1H), 8.87 (s, 1H), 8.32 (dd, J=1.0, 8.1 Hz, 1H), 7.95 (s, 1H), 7.83-7.74 (m, 2H), 7.52 (t, J=8.0 Hz, 1H), 7.36 (s, 1H), 3.20 (qn, J=6.9 Hz, 1H) and 1.24-1.19 (m, 6H) ppm. LC/MS: m/z 391.36 (M+H)+ at 1.77 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][S:4][CH2:3][CH2:2]1.[C:7](Cl)([Cl:9])=[O:8]>C1(C)C=CC=CC=1>[N:1]1([C:7]([Cl:9])=[O:8])[CH2:6][CH2:5][S:4][CH2:3][CH2:2]1
Reactant: C1CSCCN1
Reactant: O=C(Cl)Cl
Solvent: Cc1ccccc1
Product: O=C(Cl)N1CCSCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 10 g (97 mmol) of thiomorpholine in 200 ml of toluene is added dropwise at 0° to a solution of 85 ml (165 mmol) of 20% phosgene in toluene and the white suspension is stirred for 1 h at RT. Excess phosgene is driven off by introducing nitrogen, the suspension is filtered, and the filtrate is concentrated by evaporation. The title compound is obtained in the form of a yellow oil. IR (CH2Cl2, cm-1): 1735, 1450, 1440, 1405, 1370, 1290, 1180.
Reaction SMILES: [C:1]([OH:10])([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[C:11]1([CH:17]([CH3:19])[CH3:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[C:1]([OH:10])([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[CH3:19][C:17]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[CH2:18]
Reactant: CC(C)c1ccccc1
Agent: CC(C)(O)c1ccccc1
Product: C=C(C)c1ccccc1

Procedure:
The conversion step is a step for obtaining cumene by subjecting cumyl alcohol obtained in the epoxidation step to hydrogenation-containing reaction and recycling the cumene to the oxidation step. As a method for converting cumyl alcohol into cumene, a method of first dehydrating cumyl alcohol to obtain α-methylstyrene and then hydrogenating α-methylstyrene to convert into cumene (dehydration-hydrogenation method), and a method of subjecting cumyl alcohol to hydrogenolysis to directly convert into cumene, can be illustrated.
Reaction SMILES: [F:1][CH2:2][C:3]1([CH2:20][F:21])[CH:8]=[C:7]([C:9]([NH:11][CH3:12])=O)[C:6]2[CH:13]=[C:14]([N+:17]([O-:19])=[O:18])[CH:15]=[CH:16][C:5]=2[O:4]1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:31])=CC=1>C1C=CC=CC=1>[F:1][CH2:2][C:3]1([CH2:20][F:21])[CH:8]=[C:7]([C:9](=[S:31])[NH:11][CH3:12])[C:6]2[CH:13]=[C:14]([N+:17]([O-:19])=[O:18])[CH:15]=[CH:16][C:5]=2[O:4]1
Reactant: CNC(=O)C1=CC(CF)(CF)Oc2ccc([N+](=O)[O-])cc21
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: c1ccccc1
Product: CNC(=S)C1=CC(CF)(CF)Oc2ccc([N+](=O)[O-])cc21
Yield: 152.3 %

Procedure:
A mixture of 0.08 g of 2,2-bis(fluoromethyl)-N-methyl-6-nitro-2H-1-benzopyran-4-carboxamide, 0.06 g of a Lawesson's reagent and 2 ml of benzene was refluxed with heating for 1 hour. The solvent was distilled. The resultant residue was purified according to silica gel column chromatography (developing solution:CH2Cl2) and further recrystallized by a mixed solvent of ethyl acetate and hexane to obtain 71 mg of 2,2-bis(fluoromethyl)-N-methyl-6-nitro-2H-1-benzopyran-4-carbothioamide with a melting point of 134°-135° C.
Reaction SMILES: [C:1](OC([O-])=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH2:12]([NH2:15])[CH2:13][NH2:14]>O1CCOCC1>[C:4]([O:3][C:1]([NH:14][CH2:13][CH2:12][NH2:15])=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)OC(=O)OC(=O)[O-]
Reactant: NCCN
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)NCCN
Reaction time: 24 h

Procedure:
This compound was prepared as described previously (Krapcho et al., 1990, Synthetic Commun. 20: 2559-2564). Briefly, a solution of tert.butyl dicarbonate (5.0 g, 0.023 mol) in dioxane (50 ml) was slowly added to ethylenediamine (11.0 ml, 0.165 mol) in dioxane (60 ml). After 24 hrs of stirring the solvent was evaporated and the residue was dissolved in water (80 ml), insoluble byproduct was filtered off and the filtrate was extracted with dichloromethane (3×100 ml). After evaporation of the solvent the product was crystallized from solvent mixture of diethylether--petroleum ether or ethyl acetate--petroleum ether. Yield 2.6 g (71%). NMR (300 MHz, DMSO-d6, 25° C.) d: 1.39 (s, 9H, tBu), 2.83 (m, 2H, Ca H2), 3.16 (q, 2H, CbH2), 6.93 (t, 1H, NH), 7.77 (br, 2H, NH2). M.p. 75° C.
Reaction SMILES: [NH2:1][C@H:2]1[C@@H:7]([NH:8][C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:6][CH2:5][N:4]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:3]1.[C:26](=O)([O:35][CH2:36][CH2:37][Si:38]([CH3:41])([CH3:40])[CH3:39])[O:27]N1C(=O)CCC1=O.C(N(CC)CC)C>O1CCOCC1.O.C(OCC)(=O)C>[CH2:12]([O:11][C:9]([NH:8][C@H:7]1[CH2:6][CH2:5][N:4]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:3][C@H:2]1[NH:1][C:26]([O:35][CH2:36][CH2:37][Si:38]([CH3:41])([CH3:40])[CH3:39])=[O:27])=[O:10])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](NC(=O)OCc2ccccc2)[C@H](N)C1
Reactant: C[Si](C)(C)CCOC(=O)ON1C(=O)CCC1=O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CC[C@H](NC(=O)OCc2ccccc2)[C@H](NC(=O)OCC[Si](C)(C)C)C1
Yield: 82.4 %

Procedure:
A solution of cis-tert-butyl 3-amino-4-(benzyloxycarbonylamino)piperidine-1-carboxylate (3.0 g, 8.6 mmol), 2,5-dioxopyrrolidin-1-yl 2-(trimethylsilyl)ethyl carbonate (2.5 g, 9.5 mmol) and triethylamine in dioxane/water (40 mL, v/v=1/1) was stirred at room temperature for 4 hours. After that, the solution was diluted with ethyl acetate (200 mL), and washed by 1 M hydrochloric acid (50 mL), saturated sodium bicarbonate solution (50 mL) and brine (50 mL). The organic layer was dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate=4/1) to afford the title compound (3.5 g, 83%) as a white solid. MS (ES+) C24H39N3O6Si requires: 493, found: 516 [M+23]+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].F[B-](F)(F)F.C[N+](C)=C(N(C)C)O.C(N(CC)CC)C.[N:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[N:39]([CH2:51][CH2:52][C:53]([O:55][CH2:56][CH3:57])=[O:54])[C:40](=[O:50])[C:41]1[CH:46]=[CH:45][C:44]([NH:47][CH3:48])=[C:43]([NH2:49])[CH:42]=1>CN(C)C=O>[N:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[N:39]([CH2:51][CH2:52][C:53]([O:55][CH2:56][CH3:57])=[O:54])[C:40](=[O:50])[C:41]1[CH:46]=[CH:45][C:44]([NH:47][CH3:48])=[C:43]([NH:49][C:10](=[O:12])[CH2:9][NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH:42]=1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: CCOC(=O)CCN(C(=O)c1ccc(NC)c(N)c1)c1ccccn1
Agent: CN(C)C(O)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)CCN(C(=O)c1ccc(NC)c(NC(=O)CNC(=O)OC(C)(C)C)c1)c1ccccn1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
19.2 g (0.11 mol) of N-tert-butyloxycarbonylglycine were dissolved in 175 mL of dimethylformamide, mixed with 35.2 g (0.11 mol) of O-benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate, 11.0 g of triethylamine, and 34.2 g (0.10 mol) of 3-amino-4-methylaminobenzoic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)amide and stirred for 2.5 hours at ambient temperature. Then the reaction solution was mixed with 5 l of ice water and stirred for 2 hours. The grey precipitate formed was filtered off, washed with water, dried, and recrystallized from ethyl acetate with the addition of activated charcoal. Yield: 39.85 g (80% of theory), C25H33N5O6 (499.6); Rf value: 0.55 (silica gel; methylene chloride/ethanol=19:1).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][C:6]2[O:9][CH2:10][O:11][C:5]=2[CH:4]=1.[C:12](Cl)([Cl:14])=[O:13]>>[CH3:1][N:2]([C:3]1[CH:8]=[CH:7][C:6]2[O:9][CH2:10][O:11][C:5]=2[CH:4]=1)[C:12]([Cl:14])=[O:13]
Reactant: O=C(Cl)Cl
Reactant: CNc1ccc2c(c1)OCO2
Product: CN(C(=O)Cl)c1ccc2c(c1)OCO2

Procedure:
By following the procedure described in example 1A N-methyl-3,4-methylenedioxyaniline (N. J. Houlihan et al., J.Het. Chem. 19, 1453 (1982)) (3.02 g, 20 mmol) was reacted with phosgene to give 3.0 g N-methyl-N -(3,4-methylenedioxyphenyl)carbamoylchloride. M.p. 71°-73° C.
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[NH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[N:8]1([CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: CCOC(=O)CBr
Reactant: C1CCNCC1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCOC(=O)CN1CCCCC1
Reaction time: 2 h
Yield: 63.6 %

Procedure:
Ethyl bromoacetate (8.5 g, 50.9 mmol) was added dropwise to a stirred solution of piperidine (4.3 g, 50.5 mmol) and triethylamine (5.5 g, 54.4 mmol) in chloroform (20 ml) at such a rate as to maintain a gentle reflux. After the addition was complete stirring was continued for 2 hours and the reaction mixture washed with water (20 m×3). The choroform layer was dried (MgSO4) filtered and the solvent evaporated to leave a yellow oil. This oil was passed through a short column of silica eluting with a CH2Cl2/Pet Ether 40:60 mixture (1:1). Removal of the solvent from the resulting solution gave the required product as a pale yellow oil (Yield 5.5 g,64%).