Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:16][C:17](=[O:19])[CH3:18])[CH:5]=[C:6]([C:8]2[C:13]([F:14])=[CH:12][CH:11]=[CH:10][C:9]=2[F:15])[CH:7]=1.[Br:20][C:21]1[CH:22]=[C:23]([N+:28]([O-:30])=[O:29])[C:24](Cl)=[N:25][CH:26]=1.[F-].[K+]>CN(C=O)C>[Br:20][C:21]1[CH:22]=[C:23]([N+:28]([O-:30])=[O:29])[C:24]([NH:1][C:2]2[CH:3]=[C:4]([NH:16][C:17](=[O:19])[CH3:18])[CH:5]=[C:6]([C:8]3[C:13]([F:14])=[CH:12][CH:11]=[CH:10][C:9]=3[F:15])[CH:7]=2)=[N:25][CH:26]=1
Reactant: CC(=O)Nc1cc(N)cc(-c2c(F)cccc2F)c1
Reactant: O=[N+]([O-])c1cc(Br)cnc1Cl
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)Nc1cc(Nc2ncc(Br)cc2[N+](=O)[O-])cc(-c2c(F)cccc2F)c1
Yield: 28 %

Procedure:
A solution of N-(5-amino-2′,6′-difluoro-[1,1′-biphenyl]-3-yl)acetamide (1.4 g, 6.1 mmol), 5-bromo-2-chloro-3-nitropyridine (1.6 g, 6.1 mmol, 1.0 eq.) and potassium fluoride (0.53 g, 9.0 mmol, 1.5 eq.) in DMF (8 ml) was heated at 110° C. for 4 h. The mixture was quenched and extracted as in Example 1(d). The solvent was distilled off to afford the crude product which was purified by column chromatography (60-120 silica gel, 30% Ethyl acetate in hexane) to give the title product in 28% yield (0.8 g).
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@H:2]([C:7]([NH:9][C@H:10]([C:16]([NH:18][NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[O:17])[CH2:11][CH2:12][C:13](=[O:15])[NH2:14])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].[H][H]>CO.[Pd]>[NH2:1][C@H:2]([C:7]([NH:9][C@H:10]([C:16]([NH:18][NH:19][C:20]([O:22][C:23]([CH3:25])([CH3:24])[CH3:26])=[O:21])=[O:17])[CH2:11][CH2:12][C:13](=[O:15])[NH2:14])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5]
Reactant: [H][H]
Reactant: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@@H](CCC(N)=O)C(=O)NNC(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Product: CC(C)C[C@H](N)C(=O)N[C@@H](CCC(N)=O)C(=O)NNC(=O)OC(C)(C)C

Procedure:
2.79 Grams of Z-Leu-Gln-NHNHBoc was suspended in 80 ml of methanol, a small amount of palladium black was added to this suspension and the suspension was stirred for 32 hours under the condition of introducing hydrogen gas. After completion of the reaction, the catalyst was removed by suction filtration, the filtrate was subjected to distillation under a reduced pressure, the residue obtained was dried under a reduced pressure in a desiccator to obtain the desired product.
Reaction SMILES: Cl[C:2]1[C:15]2[C:14](=O)[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[C:5]([CH3:18])=[CH:4][CH:3]=1.O.[NH2:20][NH2:21]>N1C=CC=CC=1>[CH3:18][C:5]1[CH:4]=[CH:3][C:2]2[NH:20][N:21]=[C:14]3[C:15]=2[C:6]=1[C:7](=[O:17])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:13]3=1
Reactant: Cc1ccc(Cl)c2c1C(=O)c1ccccc1C2=O
Reactant: NN
Solvent: O
Solvent: c1ccncc1
Product: Cc1ccc2[nH]nc3c2c1C(=O)c1ccccc1-3
Temperature: 90 °C
Reaction time: 8 h

Procedure:
To a solution of 32.3 g of 1-chloro-4-methyl-9,10-dihydro-9,10-anthracenedione prepared in Example 25-a in 150 ml pyridine was added 15 ml of hydrazine monohydrate [CAS No. 7803-57-8], followed by stirring at 90° C. overnight. After removing the solvent, to the resulting residue was added 65 ml of ethanol to give crystals. The crystals were collected by filtration, sequentially washed with moisture ethanol and ethanol, and dried in vacuo, to give 26.6 g of the title compound as ocher yellow needles.
Reaction SMILES: [C:1]([CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][C:13]=2I)[CH:8]=1)#[N:2].[CH2:18]([C:20]1[N:24]([C:25]2[CH:30]=[CH:29][C:28]([NH2:31])=[CH:27][CH:26]=2)[N:23]=[C:22]([C:32]2[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=2)[CH:21]=1)[CH3:19].O(C(C)(C)C)[Na]>C1(C)C=CC=CC=1.C(OCC)(=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:1]([CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]=1[C:29]1[C:28]([NH2:31])=[CH:27][CH:26]=[C:25]([N:24]2[C:20]([CH2:18][CH3:19])=[CH:21][C:22]([C:32]3[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=3)=[N:23]2)[CH:30]=1)#[N:2]
Reactant: CCc1cc(-c2cccnc2)nn1-c1ccc(N)cc1
Reactant: N#CCCCOc1ccc2c(I)cccc2c1
Agent: [Pd]
Agent: CC(C)(C)O[Na]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCc1cc(-c2cccnc2)nn1-c1ccc(N)c(-c2c(OCCCC#N)ccc3ccccc23)c1
Yield: 90.8 %

Procedure:
A mixture of 2-(3-cyanopropoxy)-5-iodonaphthalene (77.0 mg, 0.228 mmol), with 5-ethyl-3-(3-pyridyl)-1-(4′-aminophenyl)pyrazole (72.4 mg, 1.2 equiv.), NaO-t-Bu (40.8 mg, 1.86 equiv.), Pd2(dba)3 (5.2 mg, 2.5% equiv.) and (−)B1NAP (10.6 mg, 7.5% equiv.) in toluene (1 mL) was heated at 80° C. for 18 h. The mixture was diluted with ethyl acetate, filtered through diatomaceous earth and concentrated. Chromatography on silica gel gave the title compound (98.0 mg, 90.8%). 1H-NMR (CDCl3): 1.30 (t, J=7.4 Hz, 3H), 2.20-2.25 (m, 2H), 2.62-2.74 (m, 4H), 4.22 (t, J=5.4 Hz, 2H), 6.31 (bs, 1H), 6.59 (s, 1H), 6.99 (d, J=8.6 Hz, 2H), 7.17 (d, J=9.1 Hz, 1H), 7.20 (s, 1H), 7.29-7.34 (m, 4H), 7.43 (t, J=8.0 Hz, 1H), 7.56 (d, J=8.2 Hz, 1H), 7.98 (d, J=9.2 Hz, 1H), 8.21 (d, J=7.9 Hz, 1H), 8.56 (d, J=4.2 Hz, 1H), 9.11 (s, 1H).
Reaction SMILES: [CH3:1][N:2]([CH3:5])[CH2:3][CH3:4].[Br:6][CH2:7][CH2:8][CH3:9].[Br:10]Br>O>[Br-:6].[Br-:10].[Br-:6].[CH3:1][N+:2]([CH3:5])([CH2:3][CH3:4])[CH2:7][CH2:8][CH3:9].[CH3:1][N+:2]([CH2:7][CH2:8][CH3:9])([CH2:3][CH3:4])[CH3:5].[CH3:1][N+:2]([CH2:7][CH2:8][CH3:9])([CH2:3][CH3:4])[CH3:5]
Reactant: CCN(C)C
Reactant: BrBr
Reactant: CCCBr
Solvent: O
Product: CCC[N+](C)(C)CC
Product: [Br-]
Temperature: 50 °C

Procedure:
Into a 3-liter flask fitted with a condenser, a 250-ml addition funnel, a thermometer, and a mechanical stirrer were placed N,N-dimethyl-N-ethylamine (256.0 grams, 3.50 moles) and 1000 ml of water. To the stirred solution was added 1-bromopropane (430.5 grams, 3.50 mole) and the two-phase mixture heated to 50° C. with vigorous agitation. After 8.5 hours the 1H-NMR nuclear magnetic resonance spectrum of the upper layer indicated that the N,N-dimethyl-N-ethylamine had been completely consumed. The amber solution was cooled to room temperature, and bromine (560 grams, 3.50 moles) was added dropwise over a period of 1.5 hour with vigorous stirring. The tribromide separated as a dark red lower layer. The layers were separated and the residual water (appx. 25 grams) removed from the tribromide layer by distillation at 50° C. under reduced pressure. The yield of dark red N,N-dimethyl-N-ethyl-N-propylammonium tribromide was 1083.0 grams (87% from N,N-dimethyl-N-ethylamine). Analysis: %Brtot =68.73% (exp), 67.35% (theo); %Brox =47.58% (exp), 44.90% (theo).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:4]=2[N:5]=[CH:6][N:7]=1.C([Li])CCC.[I:26]I>O1CCCC1.CCCCCC>[Cl:1][C:2]1[C:3]2[CH:10]=[C:9]([I:26])[N:8]([S:11]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(Cl)ncnc32)cc1
Reactant: II
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)n2c(I)cc3c(Cl)ncnc32)cc1
Temperature: -78 °C
Reaction time: 3 h
Yield: 20 %

Procedure:
To a solution of 4-chloro-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidine [5.4 g, Reference Example 3], in tetrahydrofuran (96 mL) at −78° C. was added drop wise a solution of butyl lithium in hexane (12.1 mL, 1.6M) under inert atmosphere. The solution was stirred at −78° C. for 3 hours and iodine (8.9 g) was added. The reaction mixture was stirred at −78° C. for 2 hours, and allowed to reach room temperature. The reaction mixture was partitioned between ethyl acetate and aqueous sodium sulfite solution, dried over magnesium sulfate and the solvent was evaporated under reduced pressure. The residue was subjected to flash column chromatography on silica eluting with a gradient of ethyl acetate and cyclohexane (50:50, to 100, v/v) to give the title compound (1.52 g) as an amorphous solid. MS: 434 [MH]+. LCMS (Method B) RT=4.26 minutes.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[Cl:18])=[CH:9][C:8]([CH3:19])=[CH:7][C:6]=2[CH3:20].C([O:24][C:25]1[CH:35]=[CH:34][C:28]([CH:29]=[CH:30][C:31](Cl)=[O:32])=[CH:27][CH:26]=1)(=O)C.O1CCCC1.C(=O)([O-])O.[Na+]>O>[Cl:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[C:11]1[C:10]2[C:5](=[C:6]([CH3:20])[CH:7]=[C:8]([CH3:19])[CH:9]=2)[N:4]=[CH:3][C:2]=1[NH:1][C:31](=[O:32])[CH:30]=[CH:29][C:28]1[CH:34]=[CH:35][C:25]([OH:24])=[CH:26][CH:27]=1
Reactant: CC(=O)Oc1ccc(C=CC(=O)Cl)cc1
Reactant: Cc1cc(C)c2ncc(N)c(-c3ccccc3Cl)c2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(C)c2ncc(NC(=O)C=Cc3ccc(O)cc3)c(-c3ccccc3Cl)c2c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 78.3 %

Procedure:
A mixture of 3-amino-4-(2-chlorophenyl)-6,8-dimethylquinoline (282 mg), 4-acetoxycinnamoyl chloride (250 mg) and tetrahydrofuran (5 ml) was stirred at room temperature for 6 hours. After being diluted with water and made neutral with a sodium hydrogen carbonate saturated solution, the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried (MgSO4). The solvent was removed, and the residue was dissolved in tetrahydrofuran-methanol solution (1:1, 6 ml). Then, 2N-hydrochloric acid was added to the solution which was thereafter stirred at room temperature for 1.5 hours. The resultant solution was diluted with water, adjusted to pH 4 by addition of 2N-hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried (MgSO4). The resultant was removed to give crystals of 4-(2-chlorophenyl)-3-(4-hydroxycinnamoylamino)-6,8-dimethylquinoline (335 mg, 78.3%). The obtained crystals were recrystallized from ethanol to afford colorless needles.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[N+:14]([O-])([OH:16])=[O:15]>OS(O)(=O)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[C:4]([N+:14]([O-:16])=[O:15])[CH:3]=1
Reactant: O=[N+]([O-])O
Reactant: Clc1ccc(C2CCCCC2)cc1
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1cc(Cl)ccc1C1CCCCC1
Reaction time: 1 h

Procedure:
To 1-chloro-4-cyclohexylbenzene (1.7 g) in H2SO4 (10 mL) at 20° C. added HNO3 (2.5 g) in H2SO4 (10 mL) maintaining the temperature below 30° C. The mixture was allowed to stir for 1 h and then partitioned between CH2Cl2 and water. The CH2Cl2 layer was washed well with a saturated NaHCO3 solution, dried (MgSO4), and concentrated in vacuo. The residue was chromatographed on silica gel eluting with 5% EtOAc/hexanes to give 5-chloro-2-cyclohexyl-1-nitrobenzene. This compound was then reduced with iron powder as described above to yield the desired compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:28]=[CH:27][C:6]([C:7]([N:9]([CH2:21][C:22]([O:24]CC)=O)[CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][CH:13]=2)=[O:8])=[C:5]([N+:29]([O-])=O)[C:4]=1[O:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37].C(O)C.[H][H].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[C].[Pd].C1(C)C=CC=CC=1>[NH2:18][C:15]1[CH:16]=[CH:17][C:12]([CH2:11][CH2:10][N:9]2[C:7](=[O:8])[C:6]3[CH:27]=[CH:28][C:3]([O:2][CH3:1])=[C:4]([O:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[C:5]=3[NH:29][C:22](=[O:24])[CH2:21]2)=[CH:13][CH:14]=1
Reactant: CCCCCOc1c(OC)ccc(C(=O)N(CCc2ccc([N+](=O)[O-])cc2)CC(=O)OCC)c1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: CCCCCOc1c(OC)ccc2c1NC(=O)CN(CCc1ccc(N)cc1)C2=O
Yield: 63 %

Procedure:
Ethyl {(4-Methoxy-2-nitro-3-pentyloxybenzoyl)-[2-(4-nitrophenyl)-ethyl]amino}acetate (70.0 mg, 0.135 mmol) and ethanol (2 ml) were mixed, and 10% palladium-carbon catalyst was added. The reaction mixture was stirred in a stream of hydrogen at room temperature for 10.5 hours, and then filtered. The filtrate was concentrated under reduced pressure. Toluene (10 ml) and p-toluene sulfonate monohydrate (1 mg, 0.0053 mmol) were added to the precipitated crude crystals, and the mixture was refluxed under heating for 3.5 hours. Ethyl acetate (20 ml) was added to this reaction mixture, and the organic layer was washed with saturated aqueous sodium hydrogencarbonate solution (5 ml) and saturated brine (5 ml) and dried over anhydrous magnesium sulfate. The drying agent was filtered off and the filtrate was concentrated under reduced pressure. The obtained residue was purified by column chromatography on silica gel (chloroform/methanol=10/1) to give 4-[2-(4-aminophenyl)ethyl]-8-methoxy-9-pentyloxy-3,4-dihydro-1H-benzo[e][1,4]diazepine-2,5-dione (35 mg, 63% in 2 steps) as colorless crystals.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([NH:9][C:10]2[S:11][CH:12]=[CH:13][C:14]=2[C:15]#[N:16])=[C:4]([N+:17]([O-])=O)[CH:3]=1.[ClH:20]>C(O)C>[ClH:20].[F:8][C:7]1[C:2]([F:1])=[CH:3][C:4]2[N:17]=[C:15]([NH2:16])[C:14]3[CH:13]=[CH:12][S:11][C:10]=3[NH:9][C:5]=2[CH:6]=1
Reactant: N#Cc1ccsc1Nc1cc(F)c(F)cc1[N+](=O)[O-]
Agent: Cl
Solvent: CCO
Product: NC1=Nc2cc(F)c(F)cc2Nc2sccc21
Temperature: 25 °C
Yield: 86 %

Procedure:
Suspend 2-(4,5-difluoro-2-nitro-phenylamino)-thiophene-3-carbonitrile (4.02 g, 14.30 mmol) in ethanol (40.0 ml). Dissolve tin(H) chloride (8.14 g, 42.91 mmol) in 5N HCl (40.0 ml) and then add it to the suspension. Heat the reaction at reflux for 5.5 hours and then cool it to ambient temperature. Cool the mixture for 16 hours in a refrigerator. Collect the resulting precipitate by vacuum filtration and then dry it by pulling a vacuum on it to give 3.53 g (86%) of the title compound as a yellow solid: mass spectrum (ion spray): m/z =252.1 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1Br.C([Li])CCC.[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][CH:25]([CH:28]=[O:29])[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16]>O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH:28]([OH:29])[CH:25]1[CH2:26][CH2:27][N:22]([C:20]([O:19][C:15]([CH3:17])([CH3:16])[CH3:18])=[O:21])[CH2:23][CH2:24]1
Reactant: Fc1ccc(F)c(Br)c1
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(C(O)c2cc(F)ccc2F)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 33.7 %

Procedure:
To a solution of 2,5-difluoro-1-bromobenzene (24.5 g, 127 mmol) in anhydrous tetrahydrofuran (400 ml) at −78° C. was added n-butyllithium (1.6M, 80 ml, 128 mmol). The solution was stirred for 15 minutes tert-butyl-4-formyl-piperidine-1-carboxylate (27.0 g, 127 mmol) added slowly in THF (50 ml). The mixture was allowed to warm to room temperature and stirred for 16 hours, quenched with water (200 ml) and extracted with ethyl acetate (3×150 ml). The combined organics were washed with water (50 ml), dried (MgSO4) and concentrated. The residue was purified by flash chromatography eluting with 3 to 10% ethyl acetate in iso hexanes to yield (RS)-tertbutyl 4-[(2,5-difluorophenyl)-hydroxymethyl]-piperidine-1-carboxylate as a colourless oil (14 g, 34%).
Reaction SMILES: F[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[O:11]1[CH2:15][CH2:14][C@@H:13]([OH:16])[CH2:12]1>>[N+:8]([C:7]1[C:2]([O:16][C@@H:13]2[CH2:14][CH2:15][O:11][CH2:12]2)=[N:3][CH:4]=[CH:5][CH:6]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1cccnc1F
Reactant: O[C@@H]1CCOC1
Product: O=[N+]([O-])c1cccnc1O[C@@H]1CCOC1

Procedure:
Prepared analogously to I.1 from 2-fluor-3-nitropyridine and (R)-tetrahydro-furan-3-ol.
Reaction SMILES: C(Br)C1C=CC=CC=1.Br[CH2:10][C:11]1[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][CH:12]=1.[C:21]([C:24]1[S:28][C:27]([N:29]2[CH2:33][CH2:32][NH:31][C:30]2=[O:34])=[N:26][C:25]=1[CH3:35])(=[O:23])[CH3:22]>>[C:21]([C:24]1[S:28][C:27]([N:29]2[CH2:33][CH2:32][N:31]([CH2:10][C:11]3[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][CH:12]=3)[C:30]2=[O:34])=[N:26][C:25]=1[CH3:35])(=[O:23])[CH3:22]
Reactant: CC(=O)c1sc(N2CCNC2=O)nc1C
Reactant: COC(=O)c1ccc(CBr)cc1
Agent: BrCc1ccccc1
Product: COC(=O)c1ccc(CN2CCN(c3nc(C)c(C(C)=O)s3)C2=O)cc1
Yield: 60 %

Procedure:
Following the procedure as described in Example 5, making variations to replace benzyl bromide with methyl 4-(bromomethyl)benzoate to react with 1-(5-acetyl-4-methylthiazol-2-yl)imidazolidin-2-one, the title compound was obtained in 60% yield: mp 174-175° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, CDCl3) δ 8.02 (d, J=7.5 Hz, 2H), 7.35 (d, J=7.5 Hz, 2H), 4.53 (s, 2H), 4.12-4.03 (m, 2H), 3.96 (s, 3H), 3.49-3.44 (m, 2H), 2.60 (s, 3H), 2.39 (s, 3H); MS (ES+) m/z 374.1 (M+1).
Reaction SMILES: [CH:1]1[N:2]=[CH:3][N:4]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[C:8](=[O:15])[N:7]3[CH2:16][CH2:17][CH2:18][C@H:6]3[C:5]=12.[Cl:19]N1C(=O)CCC1=O.O>CN(C)C=O>[Cl:19][C:1]1[N:2]=[CH:3][N:4]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[C:8](=[O:15])[N:7]3[CH2:16][CH2:17][CH2:18][C@H:6]3[C:5]=12
Reactant: O=C1c2ccccc2-n2cncc2[C@@H]2CCCN12
Reactant: O=C1CCC(=O)N1Cl
Solvent: O
Solvent: CN(C)C=O
Product: O=C1c2ccccc2-n2cnc(Cl)c2[C@@H]2CCCN12

Procedure:
2.5 g (10.4 mmol) of (S)-11,12,13,13a-tetrahydro-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepin-9-one in 20 ml of dimethylformamide are stirred at room temperature for 1 hour and at 75° for 20 minutes with 1.40 g (10.4 mmol) of N-chlorosuccinimide. The solution is poured into water and extracted with chloroform. The chloroform extracts are washed several times with water, dried over magnesium sulphate and evaporated. By chromatography of the residue on a silica gel column there is obtained (S)-1-chloro-11,12,13,13a-tetrahydro-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepin-9-one of melting point 233°-234.5°.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:18]=[CH:17][C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:19]([O:27][CH2:28][C:29]1[CH:30]=[C:31]([CH:34]=[CH:35][C:36]=1[CH2:37][O:38][C:39](=[O:46])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[CH2:32]Br)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+]>>[C:20]1([C:19]([O:27][CH2:28][C:29]2[CH:30]=[C:31]([CH:34]=[CH:35][C:36]=2[CH2:37][O:38][C:39]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)=[O:46])[CH2:32][O:1][C:2]2[CH:3]=[C:4]([C:8]3[CH:18]=[CH:17][C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:10][N:9]=3)[CH:5]=[CH:6][CH:7]=2)=[O:26])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CCOC(=O)c1ccc(-c2cccc(O)c2)nc1
Reactant: O=C(OCc1ccc(CBr)cc1COC(=O)c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOC(=O)c1ccc(-c2cccc(OCc3ccc(COC(=O)c4ccccc4)c(COC(=O)c4ccccc4)c3)c2)nc1

Procedure:
In a manner similar to that of Example 1(i), by reaction of 277 mg (1.1 mmol) of ethyl 6-(3-hydroxyphenyl)nicotinate with 500 mg (1.1 mmol) of 3,4-bis(benzoyloxymethyl)benzyl bromide and 166 mg (1.2 mmol) of potassium carbonate. The desired product is obtained in the form of white crystals (m.p.=118-120° C.; m=500 mg; Y=73%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:24]([NH:26][NH2:27])=[O:25])[CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]([F:23])([F:22])[F:21])=[CH:15][CH:14]=1)[CH2:7]2.CO[C:30](OC)(OC)[CH2:31][Cl:32]>>[Cl:32][CH2:31][C:30]1[O:25][C:24]([C:4]2[CH:5]=[C:6]3[C:10](=[C:2]([CH3:1])[CH:3]=2)[C:9](=[O:11])[N:8]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][C:20]([F:21])([F:22])[F:23])=[CH:15][CH:14]=2)[CH2:7]3)=[N:26][N:27]=1
Reactant: COC(CCl)(OC)OC
Reactant: Cc1cc(C(=O)NN)cc2c1C(=O)N(Cc1ccc(OC(F)(F)F)cc1)C2
Product: Cc1cc(-c2nnc(CCl)o2)cc2c1C(=O)N(Cc1ccc(OC(F)(F)F)cc1)C2

Procedure:
7-Methyl-1-oxo-2-(4-trifluoromethoxy-benzyl)-2,3-dihydro-1H-isoindole-5-carboxylic acid hydrazide (200.0 mg, 0.527 mmol) was stirred with trimethoxy chloroethane (2.0 mL) at 120° C. for two hours. The reaction was concentrated and column chromatography (50% EtOAc/Hexanes) provided the title compound as a yellow solid (28.0 mg). 1H NMR (300 MHz, CDCl3): δ 7.94 (s, 2H), 7.38 (d, 2H), 7.21 (d, 2H), 4.81 (s, 4H), 4.34 (s, 2H), 2.85 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[C:16]([NH2:18])[CH:15]=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23](/[CH:26]=[CH:27]/[C:28](O)=[O:29])=[CH:22][CH:21]=1>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[C:16]([NH:18][C:28](=[O:29])/[CH:27]=[CH:26]/[C:23]3[CH:24]=[CH:25][C:20]([Cl:19])=[CH:21][CH:22]=3)[CH:15]=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: O=C(O)/C=C/c1ccc(Cl)cc1
Reactant: CC1(c2ccc(Cn3cc(N)cn3)o2)OCCO1
Product: CC(=O)c1ccc(Cn2cc(NC(=O)/C=C/c3ccc(Cl)cc3)cn2)o1

Procedure:
Following general procedure B followed by T, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-4-ylamine and (E)-3-(4-chloro-phenyl)-acrylic acid. LC-MS-conditions 05b: tR=1.0 min; [M+H]+=371.85.
Reaction SMILES: [OH:1][C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[CH:4]=[N:5][C:6]1[C:11]([CH3:12])=[CH:10][C:9]([OH:13])=[CH:8][C:7]=1[CH3:14].[C:19]([S:23][S:24][N:25]([C:27](F)=[O:28])[CH3:26])([CH3:22])([CH3:21])[CH3:20].C(N(CC)CC)C.FC(NC)=O>C1(C)C=CC=CC=1>[C:19]([S:23][S:24][N:25]([CH3:26])[C:27](=[O:28])[O:13][C:9]1[CH:8]=[C:7]([CH3:14])[C:6]([N:5]=[CH:4][C:3]2[CH:15]=[CH:16][CH:17]=[CH:18][C:2]=2[OH:1])=[C:11]([CH3:12])[CH:10]=1)([CH3:22])([CH3:21])[CH3:20]
Reactant: CN(SSC(C)(C)C)C(=O)F
Reactant: Cc1cc(O)cc(C)c1N=Cc1ccccc1O
Agent: CNC(=O)F
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: Cc1cc(OC(=O)N(C)SSC(C)(C)C)cc(C)c1N=Cc1ccccc1O
Temperature: 50 °C
Reaction time: 3 h

Procedure:
In a manner identical to that described in Example II, Part A, 4-(2-hydroxybenzylideneamino)-3,5-dimethylphenol was prepared. To a 500 milliliter round bottom flask equipped with a water condenser, magnetic stirrer and drying tube was added 4.83 grams (0.020 moles) of 4-(2-hydroxybenzylideneamino)-3,5-dimethylphenol, 3.95 grams (0.020 moles) of N-(tertbutylthiosulfenyl)-N-fluorocarbonyl-N-methylamine, 2.12 grams (0.021 moles) of triethylamine and 200 milliliters of toluene. The resulting reaction mixture was heated to a temperature of 50° C. in an oil batch for 16 hours with continuous stirring. After this heating and stirring period, 1.0 grams (0.0041 moles) of N-tert-butylthiosulfenyl)-N-fluorocarbonyl-N-methylamine and 0.5 grams (0.005 moles) of triethylamine were added to the reaction mixture and heating continued for an additional 3 hours at a temperature of 50° C. with continuous stirring. The reaction mixture was cooled to room temperature and then washed twice with water, twice with a 2% aqueous sodium bicarbonate solution and once with a saturated brine solution. After drying the reaction mixture over magnesium sulfate, it was concentrated under reduced pressure to give a red oil. Purification of the red oil by column chromatography yielded 2.02 grams (0.0048 moles) of 4-(2-hydroxybenzylideneamino)-3,5-dimethylphenyl N-(tert-butylthiosulfenyl)-N-methylcarbamate in the form of a yellow solid having a melting point of 121°-124° C. and the following structural formula: ##STR24##
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]=[CH:8][C:9]1[C:17]2[C:12](=[CH:13][C:14]([NH:18][C:19]3[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=3[C:21](O)=[O:22])=[CH:15][CH:16]=2)[NH:11][N:10]=1.[CH:28]1([NH2:31])[CH2:30][CH2:29]1.C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH:28]1([NH:31][C:21](=[O:22])[C:20]2[CH:24]=[CH:25][CH:26]=[CH:27][C:19]=2[NH:18][C:14]2[CH:13]=[C:12]3[C:17]([C:9](/[CH:8]=[CH:7]/[C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=4)=[N:10][NH:11]3)=[CH:16][CH:15]=2)[CH2:30][CH2:29]1
Reactant: O=C(O)c1ccccc1Nc1ccc2c(C=Cc3ccccn3)n[nH]c2c1
Reactant: NC1CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(NC1CC1)c1ccccc1Nc1ccc2c(/C=C/c3ccccn3)n[nH]c2c1
Reaction time: 8 h
Yield: 35.2 %

Procedure:
A solution of 2-[3-(2-Pyridin-2-yl-vinyl)-1H-indazol-6-ylamino]-benzoic acid (50.0 mg, 0.084 mmol), cyclopropyl amin (11.6 μL, 0.17 mmol), triethylamine (58 μl, 0.25 mmol), dissolved in DMF (0.8 mL), was treated with HATU (48 mg, 0.13 mmol). The mixture was stirred overnight, then purified by reverse phase HPLC yielding 11.7 mg (35%) of the title compound as a yellow solid. 1H NMR (DMSO-d6): δ 9.81 (1H, s), 8.68 (1H, d, J=1.7), 8.51 (1H, s), 8.01 (4H, m), 7.50 (5H, m), 7.24 (1H, s), 7.03 (1H, d, J=5.3), 6.89 (1H, t, J=4.2), 2.84 (1H, m), 0.72 (2H, m), 0.56 (2H, m). ESIMS (M+H+): 396.1.