Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Br:13])[CH:8]=1.[F:14][C:15]([F:25])([F:24])[C:16]1[C:17]([CH:22]=[O:23])=[N:18][CH:19]=[CH:20][CH:21]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>ClCCl.C1COCC1>[Br:13][C:9]1[CH:8]=[C:7]([CH:22]([C:17]2[C:16]([C:15]([F:25])([F:14])[F:24])=[CH:21][CH:20]=[CH:19][N:18]=2)[OH:23])[CH:12]=[CH:11][CH:10]=1
Reactant: Brc1cccc(Br)c1
Reactant: O=Cc1ncccc1C(F)(F)F
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li]CCCC
Solvent: ClCCl
Solvent: C1CCOC1
Product: OC(c1cccc(Br)c1)c1ncccc1C(F)(F)F
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 55.5 %

Procedure:
25 mL of anhydrous THF was placed under nitrogen and cooled to −78° C. 2.2 ml (5.5 mmol) of a 2.5 M solution of n-butyl lithium in hexanes were added. To the resulting solution was slowly added 0.7 mL (1.4 g, 5.8 mmol) of 1,3-dibromobenzene. Upon complete addition the resulting solution was stirred at −78° C. for 90 min. 1.00 g (5.71 mmol) of 3-trifluoromethyl-pyridine-2-carbaldehyde was added rapidly. The dark solution was warmed to −20° C. and stirred for 20 min at that temperature. The resulting mixture was distributed between 10% aqueous citric acid and dichloromethane. The phases were separated and the aqueous layer extracted three times with dichloromethane. The combined organic phases were dried over sodium sulfate and the solvent completely evaporated. The resulting residue was purified by flash chromatography on silica gel using a gradient of ethyl acetate in hexanes to afford 1.053 g (3.171 mmol, 58%) of (3-bromo-phenyl)-(3-trifluoromethyl-pyridin-2-yl)-methanol as a yellow oil. 1H NMR (500 MHz, DMSO-d6) δ 8.84 (m, 1H), 8.18 (dd, 1H), 7.63 (m, 1H), 7.53 (dd, 1H), 7.42 (m, 1H), 7.26-7.24 (m, 2H), 6.31 (d, 1H), 6.02 (d, 1H); MS: m/z 332.0+334.0 (M+H+).
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[C:7]([C:24]#[N:25])[C:8]2[C:9](=[O:23])[N:10]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:11]=[CH:12][C:13]=2[C:14]=1[OH:15])=[O:4].[NH2:26][CH2:27][CH2:28][CH2:29][C:30]([OH:32])=[O:31].C[O-].[Na+]>>[CH2:16]([N:10]1[C:9](=[O:23])[C:8]2[C:7]([C:24]#[N:25])=[N:6][C:5]([C:3]([NH:26][CH2:27][CH2:28][CH2:29][C:30]([OH:32])=[O:31])=[O:4])=[C:14]([OH:15])[C:13]=2[CH:12]=[CH:11]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: NCCCC(=O)O
Reactant: COC(=O)c1nc(C#N)c2c(=O)n(Cc3ccccc3)ccc2c1O
Agent: C[O-]
Agent: [Na+]
Product: N#Cc1nc(C(=O)NCCCC(=O)O)c(O)c2ccn(Cc3ccccc3)c(=O)c12
Temperature: 25 °C
Yield: 87.5 %

Procedure:
A mixture of 7-benzyl-1-cyano-4-hydroxy-8-oxo-7,8-dihydro-[2,7]naphthyridine-3-carboxylic acid methyl ester (30 mg, 0.090 mmol), 4-aminobutyric acid (185 mg, 1.79 mmol) and NaOMe solution (2.7 mL, 1.34 mmol, 0.5 M in MeOH) was refluxed for 24 h. After the mixture was cooled to r.t., solvent was evaporated in vacuo. The residue was partitioned between EtOAc and water. 1 M HCl was added with vigorous stirring until pH was about 1. The organic layer was dried over MgSO4 and concentrated to give 32 mg of the title compound as an off-white solid. MS: (+) m/z 407.31 (M+1).
Reaction SMILES: [C:1]1([OH:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.O.[C:13]1(C)[CH:18]=[CH:17][C:16](S(O)(=O)=O)=[CH:15][CH:14]=1.C1CCC=CC=1>C1(C)C=CC=CC=1>[CH:9]1[C:10]2[C:1]3[O:11][C:14]4[CH2:15][CH2:16][CH2:17][CH2:18][C:13]=4[C:2]=3[CH:3]=[CH:4][C:5]=2[CH:6]=[CH:7][CH:8]=1
Reactant: Oc1cccc2ccccc12
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1=CCCC=C1
Solvent: Cc1ccccc1
Solvent: O
Product: c1ccc2c(c1)ccc1c3c(oc12)CCCC3
Temperature: 25 °C
Yield: 25 %

Procedure:
144 g of 1-naphthol, 190 g of p-toluenesulfonic acid monohydrate, 80.1 g of 1,3-cyclohexadiene and 4 L of toluene were placed in a flask. The resulting mixture was stirred under reflux for 24 hours. After cooling to room temperature, the reaction solution was washed with 600 mL of water. After drying an organic phase with magnesium sulfate, the solvent was distilled off under reduced pressure. Residues were purified by silica gel column chromatography, whereby 55.5 g (yield: 25%) of 7,8,9,10-tetrahydrobenzo[b]naphtho[2,1-d]furan was obtained.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][N:5]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:13][CH:12]=2)[C:6]=1[C:7]([NH2:9])=[O:8].[F:21][C:22]([F:33])([F:32])[C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=1)[C:26](Cl)=[O:27]>>[C:17]([C:14]1[CH:15]=[CH:16][C:11]([CH2:10][N:5]2[C:6]([C:7]([NH2:9])=[O:8])=[C:2]([NH:1][C:26](=[O:27])[C:25]3[CH:29]=[CH:30][CH:31]=[C:23]([C:22]([F:21])([F:32])[F:33])[CH:24]=3)[N:3]=[CH:4]2)=[CH:12][CH:13]=1)([CH3:20])([CH3:19])[CH3:18]
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Reactant: CC(C)(C)c1ccc(Cn2cnc(N)c2C(N)=O)cc1
Product: CC(C)(C)c1ccc(Cn2cnc(NC(=O)c3cccc(C(F)(F)F)c3)c2C(N)=O)cc1
Yield: 70 %

Procedure:
An amidation reaction and post-treatment were carried out under the same conditions as in Example 1, using 1.91 g (7.01 mmol) of 4-amino-1-(4-t-butylbenzyl)-5-imidazole carboxamide which was prepared in the same manner as in Example 57 and 3-trifluoromethylbenzoyl chloride instead of benzoyl chloride to obtain 2.17 g of 1-(4-t-butylbenzyl)-4-(3-trifluoromethylbenzoylamino)-5-imidazolecarboxamide (yield 70%).
Reaction SMILES: [CH3:1][C:2]1([CH3:8])[CH2:7][CH2:6][CH2:5][NH:4][CH2:3]1.C(N(CC)CC)C.[Br:16][CH2:17][C:18](Br)=[O:19].O>ClCCl>[Br:16][CH2:17][C:18]([N:4]1[CH2:5][CH2:6][CH2:7][C:2]([CH3:8])([CH3:1])[CH2:3]1)=[O:19]
Reactant: O=C(Br)CBr
Reactant: CC1(C)CCCNC1
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(C)CCCN(C(=O)CBr)C1
Temperature: 0 °C
Reaction time: 18 h

Procedure:
A mixture of 3,3-dimethylpiperidine (10 g) and triethylamine (12.3 ml) in dry dichloromethane (50 ml) was added dropwise to an ice-cold solution of bromoacetyl bromide (7.7 ml) in dry dichloromethane (100 ml). The mixture was stirred at 23° for 18 h then recooled to 0°. Iced water (200 ml) was added and the layers separated. The aqueous layer was further extracted with dichloromethane (2×200 ml) then the combined extracts were washed with 2N HCl (200 ml) and saturated brine (200 ml), dried and evaporated to give the title compound (17.28 g) as a brown oil.
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:3]=1[CH2:4][NH:5][C:6]1[CH:11]=[CH:10][N:9]=[CH:8][C:7]=1[N+:12]([O-])=O.[ClH:20]>O>[NH2:12][C:7]1[C:8]([Cl:20])=[N:9][CH:10]=[CH:11][C:6]=1[NH:5][CH2:4][C:3]1[C:2]([F:1])=[CH:18][CH:17]=[CH:16][C:15]=1[F:19]
Reactant: Cl
Reactant: O=[N+]([O-])c1cnccc1NCc1c(F)cccc1F
Solvent: O
Product: Nc1c(NCc2c(F)cccc2F)ccnc1Cl
Temperature: 90 °C

Procedure:
A 3-neck 5-L flask, equipped with a thermometer, reflux condenser, nitrogen inlet and a mechanical stirrer was charged with 4-[(2,6-difluorobenzyl)amino]3-nitropyridine(146g, 0.55mol) and concentrated hydrochloric acid(1.4L, 16.8mol). The solution was heated on a steam bath to 90° C. and stannous chloride dihydrate(659g, 2.92mol) was added portionwise. After heating the suspension at 90° C. for 1.5 hours, the condenser was replaced with a distillation apparatus and approximately 1.5L of H2O removed by distillation at 100mm Hg. The remaining suspension was cooled in an ice bath and neutralized to pH 7 with concentrated ammonium hydroxide. The pasty solid was collected by filtration and dried overnight on a Buechner funnel. The still damp solid was transferred to a 12-L flask equipped with a mechanical stirrer and reflux condenser and charged with ethyl acetate. With rapid stirring, the suspension was heated at reflux for 3.5 hours on a steam bath, cooled slightly, filtered using positive nitrogen pressure, and the filtrate concentrated in vacuo. The resulting oily solid was slurried in ethyl ether, solids collected by filtration and dried overnight on a Buechner funnel to yield 123g (83.1%) of 3-amino-2-chloro-4-[(2,6-difluorobenzyl)amino]pyridine. TLC (silica gel, EtOAc/ether, 1:1) Rf =0.71; mp=221°-2230° C.; 1H NMR (DMSO-d6): 4.36(d,J=5.1 Hz, 2H, CH2), 4.84 (s, 2H, NH2), 6.06(t, J=5.1 Hz, 1H, NH), 6.54(d,J=5.4Hz, 1H, C-5H), 7.01-7.65 (m, 3H, C-3'H, C-4'H, C-5'H), 7.44 (d, J=5.3 Hx, 1H, C-6H).
Reaction SMILES: [CH:1]1(/[CH:4]=[CH:5]/[C:6]2[N:11]=[CH:10][N:9]=[C:8]([NH:12]C(=O)OC(C)(C)C)[CH:7]=2)[CH2:3][CH2:2]1.FC(F)(F)C(O)=O>ClCCl>[CH:1]1(/[CH:4]=[CH:5]/[C:6]2[N:11]=[CH:10][N:9]=[C:8]([NH2:12])[CH:7]=2)[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)Nc1cc(/C=C/C2CC2)ncn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1cc(/C=C/C2CC2)ncn1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of tert-butyl N-[6-[(E)-2-cyclopropylvinyl]pyrimidin-4-yl]carbamate (3, 350 mg, 1.34 mmol) in dichloromethane (10 mL) at 0° C., trifluoroacetic acid (1.5 mL, 1.34 mmol) was added and stirred at 25° C. for 16 h. The solvent was removed under reduced pressure and the mixture made basic with the residue with aqueous ammonia. Filtration and washing with diethyl ether provided (6-[(E)-2-cyclopropylvinyl]pyrimidin-4-amine (4) as a brown solid. Yield: 170 mg, 79%; MS (ESI) m/z 162.10 [M+1]+; 1H NMR (400 MHz, DMSO-d6) δ 8.19 (s, 1H), 6.70 (brs, 2H), 6.32-6.27 (m, 2H), 6.17 (s, 1H), 1.60 (m, 1H), 0.84 (m, 2H), 0.55 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([Cl:10])[C:8]=1[CH3:9])N.N([O-])=O.[Na+].C(OCC)(=O)C.[BrH:21]>O>[Br:21][C:4]1[CH:6]=[C:7]([Cl:10])[C:8]([CH3:9])=[C:2]([Cl:1])[CH:3]=1
Reactant: Br
Reactant: Cc1c(Cl)cc(N)cc1Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1c(Cl)cc(Br)cc1Cl
Temperature: 25 °C
Yield: 45 %

Procedure:
Suspend the 3,5-dichloro-4-methylaniline in 48% HBr (5 mL) and water (5 mL) and heat with a heat gun until the mixture is near the boiling point. Cool the slurry to room temperature and then cool to 0° C. with an ice/brine bath. Add a solution of sodium nitrite (109 mg, 1.58 mmol) in water (2 mL) dropwise. After the addition is complete, stir the reaction an additional 15 min in the cold bath. Add a solution of CuBr (1.08 g, 7.53 mmol) in 48% HBr (2 mL) and heat the rapidly stirring reaction to 50° C. for 1 hour. Cool the reaction to room temperature, dilute the reaction with ethyl acetate and discard the aqueous layer. Wash the organic layer with water and brine, dry with MgSO4, filter through celite and concentrate to an orange residue. Purify the residue by silica gel chromatography eluting with hexanes to afford 164 mg (45%) of the product as a yellow solid.
Reaction SMILES: Cl.Cl.[C:3]1([CH:9]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[O:10][CH:11]2[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][CH2:19][CH2:20][C:21]3[CH:22]=[CH:23][C:24]4[N:25]([CH:27]=[C:28]([C:30]([CH3:37])([CH3:36])[C:31]([O:33]CC)=[O:32])[N:29]=4)[N:26]=3)[CH2:13][CH2:12]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[OH-].[Na+:45]>C(O)C>[C:38]1([CH:9]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[O:10][CH:11]2[CH2:12][CH2:13][N:14]([CH2:17][CH2:18][CH2:19][CH2:20][C:21]3[CH:22]=[CH:23][C:24]4[N:25]([CH:27]=[C:28]([C:30]([CH3:37])([CH3:36])[C:31]([O-:33])=[O:32])[N:29]=4)[N:26]=3)[CH2:15][CH2:16]2)[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.[Na+:45]
Reactant: CCOC(=O)C(C)(C)c1cn2nc(CCCCN3CCC(OC(c4ccccc4)c4ccccc4)CC3)ccc2n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C(=O)[O-])c1cn2nc(CCCCN3CCC(OC(c4ccccc4)c4ccccc4)CC3)ccc2n1

Procedure:
631 mg of ethyl 2-[6-[4-[4-(diphenylmethoxy)piperidino]butyl]imidazo[1,2-b]pyridazin-2-yl]-2-methylpropionate dihydrochloride was dissolved in 4 ml of ethanol; 5.5 ml of a 1 N aqueous solution of sodium hydroxide was added, followed by thermal refluxing for 3 hours. After cooling, the mixture was concentrated under reduced pressure. The residue was diluted with water and adjusted to pH 5.5 by the addition of 1 N hydrochloric acid. Acetone was added to cause crystallization; the crystal precipitated was washed with water-acetone (2:1) and dried to yield 345 mg of the title compound.
Reaction SMILES: Br[C:2]1[NH:3][C:4]2[C:9]([C:10]=1[C:11]([O:13][CH3:14])=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2.[C:15]1(B(O)O)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:15]1([C:2]2[NH:3][C:4]3[C:9]([C:10]=2[C:11]([O:13][CH3:14])=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=3)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: OB(O)c1ccccc1
Reactant: COC(=O)c1c(Br)[nH]c2ccccc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1c(-c2ccccc2)[nH]c2ccccc12
Yield: 80.6 %

Procedure:
Methyl 2-bromo-1H-indole-3-carboxylate (200 mg, 0.79 mmol), phenylboronic acid (122 mg, 1 mmol), tetrakis(triphenylphosphine)palladium (231 mg, 0.2 mmol) and cesiumcarbonate (652 mg, 2 mmol) in dioxane/water (20 mL/5 mL) were stirred at room temperature 15 hours. Filterated the solid and the solvent was concentrated in vacuum. The resulted residue was purified by silica gel column (ethyl acetate: petroleum ether=1:2) to obtain methyl 2-phenyl-1H-indole-3-carboxylate as a pale yellow solid (160 mg, 80%) LRMS (M+H+) m/z: calcd 251.1 found 251.
Reaction SMILES: Br.[NH2:2][C@@H:3]1[C:20](=[O:21])[N:5]2[C:6]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[C:7]([CH2:11][Br:12])[CH2:8][S:9](=[O:10])[C@H:4]12.[C:22]([C:25]12[CH2:32][CH2:31][N:28]([CH2:29][CH2:30]1)[CH2:27][CH2:26]2)(=[O:24])[NH2:23].C(OCC)C>CN(C)C=O>[Br-:12].[NH2:2][C@@H:3]1[C:20](=[O:21])[N:5]2[C:6]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[C:7]([CH2:11][N+:28]34[CH2:31][CH2:32][C:25]([C:22](=[O:24])[NH2:23])([CH2:30][CH2:29]3)[CH2:26][CH2:27]4)[CH2:8][S:9](=[O:10])[C@H:4]12
Reactant: NC(=O)C12CCN(CC1)CC2
Reactant: CC(C)(C)OC(=O)C1=C(CBr)CS(=O)[C@@H]2[C@H](N)C(=O)N12
Agent: Br
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(C)(C)OC(=O)C1=C(C[N+]23CCC(C(N)=O)(CC2)CC3)CS(=O)[C@@H]2[C@H](N)C(=O)N12
Product: [Br-]
Temperature: 25 °C
Reaction time: 14 h

Procedure:
t-Butyl 7β-amino-3-bromomethyl-3-cephem-4-carboxylate 1-oxide hydrobromide (600 mg) was dissolved in N,N-dimethylformamide (6 ml), and 4-carbamoylquinuclidine (456 mg) was added thereto, and the mixture was stirred in argon gas stream at room temperature for 14 hours. To the reaction solution was added diethyl ether (120 ml), the resulting precipitate was filtered and washed with n-hexane, whereby the desired product (580 mg) was obtained.
Reaction SMILES: [H-].[Na+].[CH2:3]([CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:15][CH3:16])[CH:11]=2)[C:6]1=[O:17])[CH3:4].[CH2:18](I)[CH:19]=C.[CH3:22]N(C=O)C>>[CH2:3]([C:5]1([CH2:18][CH3:19])[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:15][CH3:16])[CH:11]=2)[C:6]1=[O:17])[CH:4]=[CH2:22]
Reactant: CN(C)C=O
Reactant: CCC1CCc2cc(OC)ccc2C1=O
Reactant: C=CCI
Agent: [H-]
Agent: [Na+]
Product: C=CCC1(CC)CCc2cc(OC)ccc2C1=O
Temperature: 2.5 °C
Reaction time: 0.75 h

Procedure:
NaH (0.31 g of a 60% dispersion in mineral oil, 7.6 mmol) was added to an ice-cold solution of 2-ethyl-6-methoxy-3,4-dihydro-1(2H)-naphthalenone (1.48 g, 7.2 mmol) in anhydrous DMF (14.4 mL). The mixture was purged with N2 and stirred at 0-5° C. for 45 minutes. Allyl iodide (1.0 mL, 10.9 mmol) was added and, after a few minutes, the cooling bath was removed. After stirring overnight at room temperature, the mixture was partitioned between EtOAc and water, and the aqueous phase was back-extracted several times with EtOAc. The combined organics were washed with brine, dried over MgSO4, filtered, and concentrated under vacuum. The residue was purified by Biotage™ (Charlottesville, Va.) flash chromatography to afford 2-allyl-2-ethyl-6-methoxy-3,4-dihydro-1(2H)-naphthalenone as an oil.
Reaction SMILES: [C:1](O)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:10][C:11]1[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[CH:14][C:12]=1[S-:13].[Na+].[OH-].[Na+]>O>[C:2]1([C:1]2[S:13][C:12]3[CH:14]=[CH:15][C:16]([N+:18]([O-:20])=[O:19])=[CH:17][C:11]=3[N:10]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccccc1
Reactant: Nc1cc([N+](=O)[O-])ccc1[S-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=[N+]([O-])c1ccc2sc(-c3ccccc3)nc2c1
Temperature: 117.5 °C

Procedure:
PPA (210 g) is added to benzoic acid (12.96 g, 0.104 mol) and sodium 2-amino-4-nitrothiophenoxide (19.98 g, 0.104 mol) (V. L. Guarda, Heterocyclic Comm., 2000, 1.6, 49-54). The mixture is heated at 115-120° C. for 10 minutes, cooled, and water (200 ml) is added dropwise, followed by addition of 32 percent NaOH (pH=5). The product is filtered off and suspended in NaHCO3 ss, filtered off, washed with water and recrystallized from isopropyl ether. Yield: 17.0 g (64%); IR (KBr): 1515, 1341 cm−1; 1H-NMR (d6-DMSO) 8.77 (d, 1H); 8.39 (d, 1H); 8.25 (dd, 1H); 8.11 (dd, 1H); 7.61 (m, 4H).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH:10]([S:29][CH2:30][CH2:31][C:32](O)=[O:33])[C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]3[CH:28]=[CH:27][C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:20]=3)=[CH:13][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC[N:37](CC)CC>C(Cl)Cl.CC#N>[C:1]1([CH2:7][CH2:8][CH2:9][CH:10]([S:29][CH2:30][CH2:31][C:32]([NH2:37])=[O:33])[C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]3[CH:28]=[CH:27][C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:20]=3)=[CH:13][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)CCSC(CCCc1ccccc1)c1ccc(OCc2ccc3ccccc3n2)cc1
Reactant: CCN(CC)CC
Solvent: CC#N
Solvent: ClCCl
Product: NC(=O)CCSC(CCCc1ccccc1)c1ccc(OCc2ccc3ccccc3n2)cc1
Reaction time: 1.25 h

Procedure:
To a solution of the title acid of Example 2 (200 mg) in CH2Cl2 (3 mL) and CH3CN (1 mL) at 0° C. was added Et3N (120 μL) followed by 2-chlorol-methylpyridinium iodide (220 mg). After stirring for 75 mins. at 0° C., an excess of NH3 was slowly bubbled into the mixture and the reaction was allowed to stir at RT for 12 h. It was then diluted with ethyl acetate and washed successively with aq. NH4OAc (x2) and brine. After drying, the organic solution was concentrated and the residue was purified on a column of silica to afford the title compound.
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[C:9]2[C:4]=1[N:5]=[C:6]([O:18]C)[C:7]([O:16]C)=[N:8]2.[CH2:20]([NH:27][CH3:28])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(#N)C>[BrH:1].[O:16]=[C:7]1[C:6](=[O:18])[NH:5][C:4]2[C:9](=[CH:10][C:11]([N+:13]([O-:15])=[O:14])=[CH:12][C:3]=2[CH2:2][N:27]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH3:28])[NH:8]1
Reactant: CNCc1ccccc1
Reactant: COc1nc2cc([N+](=O)[O-])cc(CBr)c2nc1OC
Solvent: CC#N
Product: Br
Product: CN(Cc1ccccc1)Cc1cc([N+](=O)[O-])cc2[nH]c(=O)c(=O)[nH]c12

Procedure:
200 mg of 5-bromomethyl-2,3-dimethoxy-7-nitro-quinoxaline and 0.016 ml (2.2 equiv.) of N-benzyl-methylamine are dissolved in 10 ml of acetonitrile, and the solution is stirred at reflux for 20 hours. The mixture is concentrated by evaporation, and the residue is dissolved in ethyl acetate and washed in aqueous 5% sodium carbonate solution and brine. The organic phase is dried over magnesium sulfate and the solvent is concentrated by evaporation.
Reaction SMILES: [C:1]([O:9][C@H:10]1[CH2:33][C@H:32]([O:34][C:35](=[O:38])[NH:36][CH3:37])[C@@:31]2([CH3:39])[C@@:12](O)([CH:13]=[CH:14][C@@H:15]3[C@@H:30]2[CH2:29][CH2:28][C@@:27]2([CH3:40])[C@H:16]3[CH2:17][CH2:18][C@@H:19]2[CH:20]([CH3:26])[CH:21]([O:24][CH3:25])[O:22][CH3:23])[CH2:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC(Cl)C(O)=O.[C:48](=[O:53])([O:51]C)[O:49][CH3:50]>>[C:1]([O:9][C@H:10]1[CH2:33][C@H:32]([O:34][C:35](=[O:38])[NH:36][CH3:37])[C@@:31]2([CH3:39])[C:12](=[CH:13][C@@H:14]([O:53][C:48]([O:49][CH3:50])=[O:51])[C@@H:15]3[C@@H:30]2[CH2:29][CH2:28][C@@:27]2([CH3:40])[C@H:16]3[CH2:17][CH2:18][C@@H:19]2[CH:20]([CH3:26])[CH:21]([O:24][CH3:25])[O:22][CH3:23])[CH2:11]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)OC
Reactant: CNC(=O)O[C@H]1C[C@H](OC(=O)c2ccccc2)C[C@]2(O)C=C[C@H]3[C@@H]4CC[C@H](C(C)C(OC)OC)[C@@]4(C)CC[C@@H]3[C@@]12C
Agent: O=C(O)C(Cl)Cl
Product: CNC(=O)O[C@H]1C[C@H](OC(=O)c2ccccc2)CC2=C[C@@H](OC(=O)OC)[C@H]3[C@@H]4CC[C@H](C(C)C(OC)OC)[C@@]4(C)CC[C@@H]3[C@]21C

Procedure:
In 10 ml of dimethyl carbonate was dissolved 350 mg of 3β-benzoyloxy-21,21-dimethoxy-20-methyl-1α-(N-methylcarbamoyl)oxypregn-6-en-5α-ol, followed by addition of 50 mg of dichloroacetic acid, and the mixture was heated in an atmosphere of argon gas for 12 hours. The reaction mixture-was then worked up in the same manner as Example 132 to give 90 mg of 3β-benzoyloxy-21,21-dimethoxy-20-methyl-1α-(N-methylcarbamoyl)oxy-7α-(methoxycarbonyl)oxypregn-5-ene showing the following physical properties.
Reaction SMILES: [OH-].[K+].[CH3:3][C:4]1[C:13]2[C:8](=[C:9]([C:18](=[O:20])[CH3:19])[C:10]([O:14][CH2:15][CH:16]=[CH2:17])=[CH:11][CH:12]=2)[O:7][C:6](=[O:21])[CH:5]=1.[CH:22](=O)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(O)C.O>[CH3:3][C:4]1[C:13]2[C:8](=[C:9]([C:18](=[O:20])[CH:19]=[CH:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[C:10]([O:14][CH2:15][CH:16]=[CH2:17])=[CH:11][CH:12]=2)[O:7][C:6](=[O:21])[CH:5]=1
Reactant: C=CCOc1ccc2c(C)cc(=O)oc2c1C(C)=O
Reactant: O=Cc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: C=CCOc1ccc2c(C)cc(=O)oc2c1C(=O)C=Cc1ccccc1
Temperature: 25 °C
Yield: 42.3 %

Procedure:
A solution of KOH 50% (3 ml) is added to an equimolar solution of 4-methyl-7-allyloxy-8-acetylcoumarin (1.93 g, 0.0075 mol) and benzaldehyde (0.8 g, 0.0075 mol) in ethanol 95%; the addition is performed under energetic stirring at room temperature. The reaction is left under stirring for one night and then diluted with water and acidified. The precipitate is separated by filtration and dried under vacuum. The compound is crystallized by methanol to give 1.1 g of product m.p. 136-139° C., 1H-NMR (CDCl3) δ: 2.43 (s, 3H); 4.65 (d, 2H, J=5.1 Hz); 4.25-4.55 (m, 2H); 5.15-5.35 (m, 1H); 6,16 (s, 1H); 6.93 (d, 1H, J=8.9 Hz); 7.03 (d, 1H) J=16 Hz); 7.04-7.15 (m, 3H); 7.15-7.26 (m, 2H); 7.33 (d, 1H, J=16 Hz); 7.64 (d, 1H, J=8.9 Hz).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:12])=[N:4][NH:5][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8].C([O-])([O-])=O.[Cs+].[Cs+].[CH3:19][N:20]([CH:22]=O)C>O>[Br:1][C:2]1[C:3]([CH3:12])=[N:4][N:5]([CH2:6][C:2]2[CH:3]=[N:4][N:20]([CH3:19])[CH:22]=2)[C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)c1[nH]nc(C)c1Br
Reactant: CN(C)C=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Product: CCOC(=O)c1c(Br)c(C)nn1Cc1cnn(C)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 23 %

Procedure:
To ethyl 4-bromo-3-methyl-1H-pyrazole-5-carboxylate (2.56 g, 10.98 mmol) in DMF (30 mL) were added Cs2CO3 (8.94 g, 27.4 mmol) and 4-(chloromethyl)-1-methyl-1H-pyrazole, HCl (2.2 g, 13.17 mmol). The reaction mixture was stirred at room temperature for 20 hours and then diluted with water. The product was extracted into EtOAc. The organic phase was dried over Na2SO4 and concentrated. The crude residue was purified by CombiFlash® chromatography (120 g, column) eluting with a gradient of 10-100% EtOAc in heptane over a period of 180 minutes. The product-containing fractions were combined and concentrated to give the title compound (0.82 g, 23%) and a regioisomer, ethyl 4-bromo-5-methyl-1-((1-methyl-1H-pyrazol-4-yl)methyl)-1H-pyrazole-3-carboxylate (1.32 g, 36.8%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[NH:13][C:12](=[O:14])[CH2:11][N:10]=[C:9]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:8]=2[CH:21]=1)([O-:3])=[O:2].Cl.[NH2:23][OH:24]>N1C=CC=CC=1.C(Cl)Cl>[NH2:10][CH2:11][C:12]([NH:13][C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:21][C:8]=1[C:9](=[N:23][OH:24])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:14]
Reactant: O=C1CN=C(c2ccccc2)c2cc([N+](=O)[O-])ccc2N1
Reactant: NO
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: NCC(=O)Nc1ccc([N+](=O)[O-])cc1C(=NO)c1ccccc1

Procedure:
A solution of 10 g (35.55 mmol) of 1,3-dihydro-7-nitro-5-phenyl-2H-1,4-benzodiazepin-2-one and 3.7 g (53.3 mmol) of hydroxylamine hydrochloride in 80 ml of pyridine is heated under reflux for 1 hour. After cooling, the mixture is taken up in methylene chloride, washed with water, dried and evaporated. The residual pyridine is removed in vacuo azeotropically with toluene. The solid crude product is suspended in hot tert.-butyl methyl ether and filtered off. There is obtained 2-amino-2'-[α-(hydroxyimino)-benzyl]-4'-nitro-acetanilide of melting point 167° (decomposition).