Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(C([O:14][C:15]([C:17]2[N:22]3[C:23](=[O:63])[C@@H:24]([NH:25][C:26](=[O:62])/[C:27](/[C:49]4[N:50]=[C:51]([NH:54]C(OC(C)(C)C)=O)[S:52][CH:53]=4)=[N:28]\[O:29]C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[C@H:21]3[S:20][CH2:19][C:18]=2[CH2:64][S:65][C:66]2[S:70][N:69]=[N:68][CH:67]=2)=[S:16])C2C=CC=CC=2)C=CC=CC=1.[Cl-].[Al+3].[Cl-].[Cl-].Cl>C1(OC)C=CC=CC=1.[N+](C)([O-])=O.O>[NH2:54][C:51]1[S:52][CH:53]=[C:49](/[C:27](=[N:28]/[OH:29])/[C:26]([NH:25][C@@H:24]2[C:23](=[O:63])[N:22]3[C:17]([C:15]([OH:14])=[S:16])=[C:18]([CH2:64][S:65][C:66]4[S:70][N:69]=[N:68][CH:67]=4)[CH2:19][S:20][C@H:21]23)=[O:62])[N:50]=1
Reactant: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC(c2ccccc2)(c2ccccc2)c2ccccc2)C(=O)N[C@@H]2C(=O)N3C(C(=S)OC(c4ccccc4)c4ccccc4)=C(CSc4cnns4)CS[C@H]23)cs1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: COc1ccccc1
Solvent: C[N+](=O)[O-]
Solvent: O
Product: Nc1nc(/C(=N/O)C(=O)N[C@@H]2C(=O)N3C(C(O)=S)=C(CSc4cnns4)CS[C@H]23)cs1
Reaction time: 0.83 h
Yield: 73.6 %

Procedure:
To a solution of 7β-[(Z)-2-(2-t-butoxycarbonylaminothiazol-4-yl)-2-trityloxyiminoacetyl]amino-3-(1,2,3-thiadiazol-5-yl) thiomethylthio-3-cephem-4-carboxylic acid diphenylmethyl ester (1.21 g: 1.16 mMol.) in a mixture of anisole (4 ml) and nitromethane (16 ml) cooling at -30° to -40° C. is added a solution of aluminum chloride (1.23 g: 9.25 mMol.) in anisole (4 ml), and the mixture is stirred at -30° to -40° C. for 50 minutes. To the reaction mixture is added 1N-hydrochloric acid (10 ml), diluted with water, and washed with ethyl acetate. The aqueous layer is concentrated to remove the organic solvents, purified by styrene-divinylbenzene copolymer chromatography (methanol: water=4:1) and the resulting powder is washed with ethyl acetate to give 7β-[(Z)-2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetyl]amino-3-(1,2,3-thiadiazol-5-yl)thiomethylthio-3-cephem-4-carboxylic acid as yellow powder (440 mg). Yield 71%.
Reaction SMILES: Cl[C:2]1[N:6]([CH3:7])[N:5]=[C:4]([CH:8]([F:10])[F:9])[C:3]=1[CH:11]=[O:12].[F:13][C:14]([F:23])([F:22])[C:15]1[CH:16]=[C:17]([OH:21])[CH:18]=[CH:19][CH:20]=1.C(=O)([O-])[O-:25].[K+].[K+]>>[F:9][CH:8]([F:10])[C:4]1[C:3]([C:11]([OH:12])=[O:25])=[C:2]([O:21][C:17]2[CH:18]=[CH:19][CH:20]=[C:15]([C:14]([F:22])([F:23])[F:13])[CH:16]=2)[N:6]([CH3:7])[N:5]=1
Reactant: Cn1nc(C(F)F)c(C=O)c1Cl
Reactant: O=C([O-])[O-]
Reactant: Oc1cccc(C(F)(F)F)c1
Agent: [K+]
Product: Cn1nc(C(F)F)c(C(=O)O)c1Oc1cccc(C(F)(F)F)c1

Procedure:
The title compound was prepared using 5-chloro-3-(difluoromethyl)-1-methyl-1H-pyrazole-4-carbaldehyde and 3-trifluoromethylphenol in the manner similar to the method in Production Example 1 above except potassium carbonate was used instead of potassium hydroxide.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1/[CH:9]=[C:10](/[N+:12]([O-:14])=[O:13])\[CH3:11].Cl.[CH3:16][O:17][NH2:18].C(N(CC)CC)C.O>CO>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([NH:18][O:17][CH3:16])[CH:10]([N+:12]([O-:14])=[O:13])[CH3:11]
Reactant: CON
Reactant: C/C(=C\c1ccc(Cl)cc1Cl)[N+](=O)[O-]
Agent: Cl
Solvent: CO
Solvent: O
Solvent: CCN(CC)CC
Product: CONC(c1ccc(Cl)cc1Cl)C(C)[N+](=O)[O-]
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 82.4 %

Procedure:
To a stirred yellow solution of the 2,4-dichloro-1-((E)-2-nitro-propenyl)-benzene (1.0 mmol, 0.232 g), in methanol (3 ml) under N2 was added at 0° C. O-methylhydroxylamine hydrochloride (2.0 mmol, 0.167 g) and triethylamine (3.0 mmol, 0.30 g). After stirring for 0.5 h at 50° C., the colourless liquid cooled to ambient temperature and water (20 ml) was added. The aqueous solution was extracted with dichloromethane (20 ml), the organic layers were combined, dried (MgSO4), filtered, and evaporated under reduced pressure to afford 0.23 g (82.4% of theory) of N-[1-(2,4-dichloro-phenyl)-2-nitro-propyl]-O-methyl-hydroxylamine in the form of liquid, as a mixture of diastereomeres.
Reaction SMILES: Cl[C:2]1[C:7]([NH:8][C:9](=[O:20])[CH2:10][N:11]2[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][OH:19])[CH2:13][CH2:12]2)=[C:6](Cl)[CH:5]=[C:4]([CH3:22])[N:3]=1.C1OCCOCCOCCOCCOCCOC1.[CH3:41][S-:42].[Na+].O.C[S:46]([CH3:48])=O>>[OH:19][CH2:18][CH2:17][N:14]1[CH2:15][CH2:16][N:11]([CH2:10][C:9]([NH:8][C:7]2[C:2]([S:46][CH3:48])=[N:3][C:4]([CH3:22])=[CH:5][C:6]=2[S:42][CH3:41])=[O:20])[CH2:12][CH2:13]1
Reactant: C[S-]
Reactant: Cc1cc(Cl)c(NC(=O)CN2CCN(CCO)CC2)c(Cl)n1
Reactant: CS(C)=O
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [Na+]
Solvent: O
Product: CSc1cc(C)nc(SC)c1NC(=O)CN1CCN(CCO)CC1
Temperature: 25 °C
Yield: 71 %

Procedure:
N-(2,4-Dichloro-6-methylpyridin-3-yl)-2-[4-(2-hydroxyethyl)piperazin-1-yl]acetamide (58.0 g, 167.0 mmol) and 18-crown-6 (4.41 g, 16.7 mmol) were dissolved in dimethyl sulfoxide (580 mL), and sodium thiomethoxide powder (46.8 g, 667.7 mmol) was added to the solution under stirring and under cooling with ice, followed by stirring for 2.5 hours at an inner temperature of 65-75° C. The reaction mixture was allowed to cool to room temperature, and water was added to the mixture under cooling with ice, followed by extraction with chloroform. The aqueous layer was extracted with chloroform. The combined organic layer was washed with saturated brine and concentrated under reduced pressure. The residue was recrystallized from isopropanol and diisopropyl ether, to thereby yield 43.83 g of 2-[4-(2-hydroxyethyl)piperazin-1-yl]-N-[2,4-bis(methylthio)-6-methylpyridin-3-yl]acetamide (yield: 71%) as colorless crystals.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[C:12]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1)(=[O:14])[CH3:13].C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O.C(OCC)(=O)C>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([O:22][C:19]2[CH:18]=[CH:17][C:16]([NH:15][C:12](=[O:14])[CH3:13])=[CH:21][CH:20]=2)=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1
Reactant: CC(=O)Nc1ccc(O)cc1
Reactant: O=[N+]([O-])c1cc(Cl)ccc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CC(=O)Nc1ccc(Oc2ccc(Cl)cc2[N+](=O)[O-])cc1
Temperature: 90 °C
Yield: 81.2 %

Procedure:
A mixture of 2-Fluoro-5-Chloro Nitro benzene (0.5 g, 2.85 mmol), 4-Acetamidophenol (0.45 g, 3.00 mmol) and cesium carbonate (0.98 g, 3.00 mmol) in DMSO (5 mL) was heated 6 hr at 90° C. The mixture was cooled, diluted with ethyl acetate (100 mL) and the organic layer washed with water, 20% aqueous potassium hydroxide solution and aqueous 10% sodium chloride solution, then dried over anhydrous sodium sulfate. The drying agent was filtered and the solvent concentrated under vacuum leaving the title compound as a tan solid (0.71 g, 81%).
Reaction SMILES: C[N:2](/[CH:4]=[C:5]1/[CH2:6][N:7]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:8][C:9]/1=[O:10])C.O.[NH2:19]N>C1(C)C=CC=CC=1>[OH:10][C:9]12[CH2:8][N:7]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:6][CH:5]1[CH:4]=[N:2][NH:19]2
Reactant: NN
Reactant: CN(C)/C=C1/CN(C(=O)OC(C)(C)C)CC1=O
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(C)OC(=O)N1CC2C=NNC2(O)C1
Temperature: 5 °C
Reaction time: 10 h

Procedure:
To a solution of tert-butyl (3Z)-3-[(dimethylamino)methylene]-4-oxopyrrolidine-1-carboxylate (58.2 kg, 242 mol) in toluene (251 kg) at 35-45° C. was added hydrazine hydrate (14.6 kg, 290 mol) via drop-wise addition over 2 h. The mixture was then stirred for 10 h at this temperature. The batch was then cooled to 0-10° C. and the slurry stirred for 6 h. This slurry was then filtered and the cake washed with n-heptane. The solids were then dried under vacuum overnight at 35-50° C. to give tert-butyl 6a-hydroxy-3a,4,6,6a-tetrahydropyrrol[3,4-c]pyrazole-5(1H)-carboxylate.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1([CH3:18])[CH2:12][C:11]2[NH:10][N:9]=[C:8]([C:13]([F:16])([F:15])[F:14])[C:7]=2[C:6](=[O:17])[CH2:5]1.[Br:19][C:20]1[CH:27]=[C:26](F)[CH:25]=[CH:24][C:21]=1[C:22]#[N:23]>CS(C)=O>[Br:19][C:20]1[CH:27]=[C:26]([N:10]2[C:11]3[CH2:12][C:4]([CH3:18])([CH3:3])[CH2:5][C:6](=[O:17])[C:7]=3[C:8]([C:13]([F:16])([F:15])[F:14])=[N:9]2)[CH:25]=[CH:24][C:21]=1[C:22]#[N:23]
Reactant: N#Cc1ccc(F)cc1Br
Reactant: CC1(C)CC(=O)c2c(C(F)(F)F)n[nH]c2C1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CC1(C)CC(=O)c2c(C(F)(F)F)nn(-c3ccc(C#N)c(Br)c3)c2C1
Temperature: 45 °C
Yield: 63.2 %

Procedure:
Sodium hydride (168 mg, 7.02 mmol, 1.0 eq.) was added to a solution of 6,6-dimethyl-3-trifluoromethyl-1,5,6,7-tetrahydro-indazol-4-one (1.63 g, 7.02 mmol, 1.0 eq.) in 35 mL of anhydrous dimethyl sulfoxide. After 15 min 2-bromo-4-fluorobenzonitrile (2.25 g, 11.23 mmol, 1.6 eq.) was added as a solid. The reaction mixture was heated at 45° C. After 23 h the reaction mixture was cooled to ambient temperature and quenched with 10 mL of saturated aqueous ammonium chloride. The mixture was diluted with water and extracted with ethyl acetate (4×). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified on a Biotage (SiO2, hexanes-ethyl acetate) to afford 2-bromo-4-(6,6-dimethyl-4-oxo-3-trifluoromethyl-4,5,6,7-tetrahydro-indazol-1-yl)-benzonitrile (1.83 g, 63%) as an off-white powder, LC/MS: (M+H)=412.0.
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH2:9][CH:8]([N:11]([CH2:22][C:23]2[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[CH:25][CH:24]=2)[C:12]2[N:16]([CH3:17])[C:15]3[CH:18]=[CH:19][CH:20]=[CH:21][C:14]=3[N:13]=2)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[CH3:32][O:33][C:34](=[O:39])[CH:35]([OH:38])[CH2:36][NH2:37].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.CCN(C(C)C)C(C)C>CN(C=O)C>[C:1]([CH:5]1[CH2:6][CH2:7][CH:8]([N:11]([CH2:22][C:23]2[CH:24]=[CH:25][C:26]([C:27]([NH:37][CH2:36][C@@H:35]([OH:38])[C:34]([O:33][CH3:32])=[O:39])=[O:28])=[CH:30][CH:31]=2)[C:12]2[N:16]([CH3:17])[C:15]3[CH:18]=[CH:19][CH:20]=[CH:21][C:14]=3[N:13]=2)[CH2:9][CH2:10]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)C(O)CN
Reactant: Cn1c(N(Cc2ccc(C(=O)O)cc2)C2CCC(C(C)(C)C)CC2)nc2ccccc21
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: COC(=O)[C@H](O)CNC(=O)c1ccc(CN(c2nc3ccccc3n2C)C2CCC(C(C)(C)C)CC2)cc1

Procedure:
To a solution of the title compound of Example 5 Step A (0.32 mmol, 145 mg), the hydrochloride salt of 2-hydroxy β-alanine methyl ester (0.48 mmol, 74 mg), HOBt (0.8 mmol, 121 mg) and EDC (0.96 mmol, 183 mg) in 2 mL of DMF was added DIEA (1.6 mmol, 0.28 mL). After 3 h the reaction was partitioned into EtOAc/brine. The organic phase was dried with MgSO4 and concentrated under reduced pressure. The product was purified by flash chromatography on silica eluting with 1:25:74 MeOH/EtOAc/DCM, affording the title compound as a foamy solid. 1HNMR (500 MHz, DMSO-d6): δ 8.47 (t, 1H), 7.75 (d, 2H), 7.60 (m, 1H), 7.48 (m, 1H), 7.45 (d, 2H), 7.30-7.37 (overlapping m, 2H), 4.80 (s, 2H), 3.76 (s, 3H), 3.70 (m, 1H), 3.60 (s, 3H), 3.50 (m, 1H), 3.39 (m, 1H), 2.02 (m, 2H), 1.82 (m, 2H), 1.71 (m, 2H), 1.18 (m, 2H), 1.03 (m, 1H), 0.85 (s, 9H). MS (ESI): m/z 521 (M+H). HPLC A: 1.94 min.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:10][C:11]2[CH:20]=[C:19]([CH3:21])[C:18]3[C:13](=[CH:14][C:15]([N:22]4C(=O)C5=CC=CC=C5C4=O)=[CH:16][CH:17]=3)[N:12]=2)=[CH:5][CH:4]=1)#[N:2].CN>C1(C)C=CC=CC=1.CO>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([O:9][CH2:10][C:11]2[CH:20]=[C:19]([CH3:21])[C:18]3[C:13](=[CH:14][C:15]([NH2:22])=[CH:16][CH:17]=3)[N:12]=2)=[CH:7][CH:8]=1)#[N:2]
Reactant: Cc1cc(COc2ccc(C#N)cc2)nc2cc(N3C(=O)c4ccccc4C3=O)ccc12
Agent: CN
Solvent: Cc1ccccc1
Solvent: CO
Product: Cc1cc(COc2ccc(C#N)cc2)nc2cc(N)ccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2.15 g (5.1 mmol) of 2-[(4-cyanophenyl)-oxymethyl]-4-methyl-7-phthalimido-quinoline are dissolved in 75 ml of toluene/methanol (2:1), mixed with 7.5 ml of 40% aqueous methylamine solution and stirred for 2 hours at ambient temperature. Then the solution is concentrated by evaporation in vacuo, the residue is stirred with 2N acetic acid, suction filtered and dried. The crude product is chromatographed on silica gel, eluting first with methylene chloride, later with methylene chloride/ethanol (50:1). The desired fractions are combined, concentrated by evaporation and triturated with ether.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:13]3=[CH:14][C:15]4[O:19][CH2:18][O:17][C:16]=4[CH:20]=[C:12]3[O:11][CH2:10]2)[C:2]1=[O:21].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:29][C:30]1[O:34][C:33]([C:35]([F:38])([F:37])[F:36])=[C:32]([C:39]([O:41][CH2:42][CH3:43])=[O:40])[CH:31]=1>CC(=O)CC>[O:21]=[C:2]1[C:3]2([C:13]3=[CH:14][C:15]4[O:19][CH2:18][O:17][C:16]=4[CH:20]=[C:12]3[O:11][CH2:10]2)[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[N:1]1[CH2:29][C:30]1[O:34][C:33]([C:35]([F:38])([F:36])[F:37])=[C:32]([C:39]([O:41][CH2:42][CH3:43])=[O:40])[CH:31]=1
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCO3
Reactant: CCOC(=O)c1cc(CBr)oc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCC(C)=O
Product: CCOC(=O)c1cc(CN2C(=O)C3(COc4cc5c(cc43)OCO5)c3ccccc32)oc1C(F)(F)F
Temperature: 25 °C
Yield: 61.4 %

Procedure:
To a solution of spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one (4.26 g, 15.10 mmol) in 2-butanone (120 mL) was added cesium carbonate (14.76 g, 45.30 mmol) and ethyl 5-(bromomethyl)-2-(trifluoromethyl)furan-3-carboxylate (Lyalin, V. V.; et al., Zhurnal Organicheskoi Khimii (1984), 20(4):846) (4.80 g, 15.90 mmol). The reaction mixture was heated at 60° C. to 70° C. for 18 h, cooled to ambient temperature and filtered. The solid was washed with ethyl acetate. The filtrate was concentrated in vacuo, the residue was purified by column chromatography with ethyl acetate and hexanes to afford ethyl 5-[(2′-oxospiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-1′(2′H)-yl)methyl]-2-(trifluoromethyl)furan-3-carboxylate (4.65 g, 61%): mp 162-164° C.; 1H NMR (300 MHz, CDCl3) δ 7.23-7.17 (m, 2H), 7.12-7.06 (m, 1H), 6.94 (d, J=7.8 Hz, 1H), 6.76 (s, 1H), 6.50 (s, 1H), 5.86-5.85 (m, 2H), 5.05-4.87 (m, 3H), 4.68-4.64 (m, 1H), 4.31 (q, J=7.2 Hz, 2H), 1.32 (t, J=7.2 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 177.2, 160.4, 155.9, 150.6, 149.1, 143.5, 142.5, 141.1, 132.0, 129.1, 124.2, 124.0, 120.7, 120.0, 119.0, 116.4, 111.1, 108.7, 103.0, 101.6, 93.7, 80.4, 61.7, 58.2, 36.7, 13.9; MS (ES+) m/z 502.1 (M+1).
Reaction SMILES: [F:1][C:2]1([F:11])[CH2:4][CH:3]1[C:5](N(OC)C)=[O:6].Cl[Mg][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[Br-].[Cl-:21].[NH4+]>C1COCC1.C(OCC)C>[Cl:21][C:14]1[CH:19]=[CH:18][C:17]([C:5]([CH:3]2[CH2:4][C:2]2([F:11])[F:1])=[O:6])=[CH:16][CH:15]=1
Reactant: Cl[Mg]c1ccccc1
Reactant: [Cl-]
Reactant: CON(C)C(=O)C1CC1(F)F
Agent: [Br-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=C(c1ccc(Cl)cc1)C1CC1(F)F

Procedure:
A solution of 2.00 g (12.1 mmol) of the compound from Example 120A in 20 ml of THF was added under argon to 2.87 g (13.3 mmol) of a 1N chlorophenylmagnesium bromide solution in diethyl ether in 20 ml of THF at RT, and the mixture was heated under reflux for 2 h. The reaction mixture was added to saturated aqueous ammonium chloride solution and extracted twice with diethyl ether, and the combined organic phases were dried over magnesium sulfate and concentrated. 2.47 g (94% of theory) of the title compound were obtained and were reacted without further purification.
Reaction SMILES: [NH2:1][CH:2]1[CH2:6][N:5]([CH:7]([CH2:11][CH3:12])[C:8]([NH2:10])=[O:9])[C:4](=[O:13])[CH2:3]1.[N-:14]=[N+:15]=[N-:16].[Na+].[CH3:18]C(O)=O>>[O:13]=[C:4]1[CH2:3][CH:2]([N:1]2[CH:18]=[N:16][N:15]=[N:14]2)[CH2:6][N:5]1[CH:7]([CH2:11][CH3:12])[C:8]([NH2:10])=[O:9]
Reactant: CC(=O)O
Reactant: CCC(C(N)=O)N1CC(N)CC1=O
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Product: CCC(C(N)=O)N1CC(n2cnnn2)CC1=O

Procedure:
Alternatively to §5.6, reaction of 2-[4-amino-2-oxo-1-pyrrolidinyl]butanamide with triethyl orthoformiate, NaN3 and AcOH provided 2-[2-oxo-4-(1H-tetrazol-1-yl)-1-pyrrolidinyl]butanamide 67.
Reaction SMILES: [CH:1]1([O:4][S:5](=[O:8])(=[O:7])[NH2:6])[CH2:3][CH2:2]1.[Cl:9][C:10]1[CH:15]=[CH:14][C:13](O)=[CH:12][CH:11]=1>>[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([NH:6][S:5](=[O:8])(=[O:7])[O-:4])=[CH:12][CH:11]=1.[Cl:9][C:10]1[CH:11]=[CH:12][C:1]([O:4][S:5](=[O:8])(=[O:7])[NH2:6])=[CH:3][CH:2]=1
Reactant: NS(=O)(=O)OC1CC1
Reactant: Oc1ccc(Cl)cc1
Product: NS(=O)(=O)Oc1ccc(Cl)cc1
Product: O=S(=O)([O-])Nc1ccc(Cl)cc1

Procedure:
4-Chlorophenylsulfamate was synthesized according to the method presented in the synthesis of Sulfamic acid cyclopropyl ester in Example 1 with the exception of utilizing 4-chlorophenol to obtain sulfamic acid 4-chloro-phenyl ester.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([O:11][C:12]([F:15])([F:14])[F:13])[CH:8]=[CH:7][C:5]=2[N:6]=1.[CH2:16]([Br:19])[CH:17]=[CH2:18]>C(O)C>[BrH:19].[CH2:18]([N:6]1[C:5]2[CH:7]=[CH:8][C:9]([O:11][C:12]([F:15])([F:13])[F:14])=[CH:10][C:4]=2[S:3][C:2]1=[NH:1])[CH:17]=[CH2:16]
Reactant: Nc1nc2ccc(OC(F)(F)F)cc2s1
Reactant: C=CCBr
Solvent: CCO
Product: Br
Product: C=CCn1c(=N)sc2cc(OC(F)(F)F)ccc21
Temperature: 0 °C
Yield: 28.1 %

Procedure:
The procedure is as in Example 15, starting with 2-amino-6-trifluoromethoxybenzothiazole (9.4 g) and allyl bromide (9.6 g) in absolute ethanol (30 cc). The mixture is heated for 48 hours to boiling. After cooling of the mixture to 0° C., the precipitate is filtered off, washed with ethyl ether (200 cc) and recrystallized in boiling 2-propanol (70 cc). 3-Allyl-2-imino-6-trifluoromethoxybenzothiazoline hydrobromide (4 g), m.p. 225° C., is obtained.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH:10]2[CH2:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11]2)[CH:5]=[C:4]([C:23]2[C:28]([O:29]CC3C=CC=CC=3)=[CH:27][CH:26]=[CH:25][C:24]=2[O:37]CC2C=CC=CC=2)[N:3]=1.C(O)(=O)C>C(OCC)(=O)C.C1COCC1.[Pd]>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH:10]2[CH2:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11]2)[CH:5]=[C:4]([C:23]2[C:28]([OH:29])=[CH:27][CH:26]=[CH:25][C:24]=2[OH:37])[N:3]=1
Reactant: CC(C)(C)OC(=O)N1CCCC(c2cc(-c3c(OCc4ccccc4)cccc3OCc3ccccc3)nc(N)c2C#N)C1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCCC(c2cc(-c3c(O)cccc3O)nc(N)c2C#N)C1
Temperature: 25 °C
Reaction time: 48 h
Yield: 75.2 %

Procedure:
A suspension of tert-butyl 3-{2-amino-6-[2,6-bis(benzyloxy)phenyl]-3-cyano-4-pyridinyl}-1-piperidinecarboxylate (3.46 g, 5.9 mmol) and Pd/C (10%, 600 mg) in ethyl acetate (50 mL) including acetic acid (5 mL) was stirred for 2 days at room temperature under a hydrogen atmosphere. The reaction mixture was diluted with THF (200 mL) and filtered through Celite®. The filtrate was concentrated under reduced pressure. The residue was washed with ethyl acetate and hexane, and dried under reduced pressure to give tert-butyl 3-[2-amino-3-cyano-6-(2,6-dihydroxyphenyl)-4-pyridinyl]-1-piperidinecarboxylate (1.82 g, yield; 76%).
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][CH:9]=[CH:8][C:5]=1[CH:6]=O)([O-:3])=[O:2].[CH3:12][O:13][C:14]1[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=1[CH2:16][NH2:17].C(OCC)(OCC)OCC>ClCCl>[CH3:12][O:13][C:14]1[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=1[CH2:16][NH:17][CH2:6][C:5]1[CH:8]=[CH:9][CH:10]=[CH:11][C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: COc1ccccc1CN
Reactant: O=Cc1ccccc1[N+](=O)[O-]
Solvent: CCOC(OCC)OCC
Solvent: ClCCl
Product: COc1ccccc1CNCc1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2.0 g (66.17 mmol) 2-nitrobenzaldehyde, 9.08 g (66.17 mmol) 2-methoxybenzylamine and 100 mL triethyl orthoformate in 100 mL dichloromethane were stirred for approx. 24 hours at room temperature. The residue obtained after evaporation was dissolved in 190 mL ethanol and mixed by portions with a total of 5.02 g NaBH4 while stirring at room temperature. After approx. 1 hour, the mixture was poured into water, extracted three times with dichloromethane; the combined organic phases were dried with MgSO4, filtered and concentrated until dry; 18.36 g yellow oil. ESI-MS [M+H+]=273.15.
Reaction SMILES: [OH:1][N:2]=[C:3]([C:7]1[O:8][CH:9]=[CH:10][CH:11]=1)[C:4]([OH:6])=[O:5].[Cl:12][CH:13]([Cl:17])[C:14](Cl)=[O:15]>C(Cl)Cl>[Cl:12][CH:13]([Cl:17])[C:14]([O:1][N:2]=[C:3]([C:7]1[O:8][CH:9]=[CH:10][CH:11]=1)[C:4]([OH:6])=[O:5])=[O:15]
Reactant: O=C(Cl)C(Cl)Cl
Reactant: O=C(O)C(=NO)c1ccco1
Solvent: ClCCl
Product: O=C(O)C(=NOC(=O)C(Cl)Cl)c1ccco1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 63 %

Procedure:
2-Hydroxyimino-2-(fur-2-yl)acetic acid (1.38 g) mixture was added portionwise to an ice cold solution of dichloroacetyl chloride (2.8 mls.) in dry methylene chloride (14 mls.). After 15 mins stirring a white precipitate was formed which was collected, washed successively with cold dry methylene chloride and petrol (b.p. 40°-60°) and dried to yield 2-dichloroacetoxyimino-2-(fur-2-yl)acetic acid (syn isomer) (1.5 g, 63%).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[Br:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][CH:14]=1.C(O)(=O)C.[C-:25]#[N:26].[K+]>O>[Br:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]([NH:1][C:2]2[CH:11]=[CH:10][CH:9]=[CH:8][C:3]=2[C:4]([O:6][CH3:7])=[O:5])[C:25]#[N:26])=[CH:15][CH:14]=1
Reactant: [C-]#N
Reactant: COC(=O)c1ccccc1N
Reactant: O=Cc1ccc(Br)cc1
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)c1ccccc1NC(C#N)c1ccc(Br)cc1
Reaction time: 19 h

Procedure:
To a stirred mixture of 17.4 parts of methyl 2-aminobenzoate 18.5 parts of 4-bromobenzaldehyde in 200 parts of glacial acetic acid is added dropwise a solution of 8.15 parts of potassium cyanide in 15 parts of water, while keeping the temperature below 16° C. Upon completion, stirring is continued for 19 hours at room temperature. The precipitated product is filtered off, washed with 2,2'-oxybispropane and dried in vacuo, yielding 25 parts of methyl 2-{[(4-bromophenyl)cyanomethyl]amino}benzoate; mp. 111.5° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:18])=[C:6]([C:8](=[O:17])/[CH:9]=[CH:10]/[C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)[CH:7]=1.[OH-].[Na+]>CCO.O.CCOC(C)=O>[Br:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[O:18][CH:10]([C:11]1[CH:12]=[CH:13][N:14]=[CH:15][CH:16]=1)[CH2:9][C:8]2=[O:17]
Reactant: O=C(/C=C/c1ccncc1)c1cc(Br)ccc1O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: CCOC(C)=O
Product: O=C1CC(c2ccncc2)Oc2ccc(Br)cc21
Reaction time: 8 h
Yield: 51.9 %

Procedure:
To a solution of (E)-1-(5-bromo-2-hydroxyphenyl)-3-(pyridin-4-yl)prop-2-en-1-one (20 g, 63.3 mmol) in EtOH (160 mL) and H2O (480 mL) was added NaOH (2.53 g, 63.3 mmol). The reaction mixture was stirred overnight. The mixture was filtered to give a solid residue. The solid residue was dissolved in EtOAc. The resulting solution was dried over Na2SO4 and concentrated in vacuo to give 6-bromo-2-(pyridin-4-yl)chroman-4-one (10 g, 50%). 1H-NMR (CDCl3): 3.00 (t, 2H), 5.51 (dd, 1H), 7.02 (d, 1H), 7.39 (d, 2H), 7.63 (t, 1H), 8.04 (s, 1H), 8.72 (d, 2H).