Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]([CH3:10])([CH3:9])[CH3:8])[O:4][N:3]=1.[CH2:11]([N:13]([CH2:17][CH3:18])[C:14](Cl)=[O:15])[CH3:12]>>[CH2:11]([N:13]([CH2:17][CH3:18])[C:14]([NH:1][C:2]1[CH:6]=[C:5]([C:7]([CH3:10])([CH3:9])[CH3:8])[O:4][N:3]=1)=[O:15])[CH3:12]
Reactant: CCN(CC)C(=O)Cl
Reactant: CC(C)(C)c1cc(N)no1
Product: CCN(CC)C(=O)Nc1cc(C(C)(C)C)on1
Yield: 98.2 %

Procedure:
Using 3-amino-5-t-butylisoxazole and N,N-diethylcarbamoyl chloride, the reaction is effected as in Example 1, whereby 1,1-diethyl-3-(5-t-butyl-3-isoxazolyl)urea is obtained. Yield is 98.2%. Melting point is 122.0° to 123.5° C.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C@H:3]([NH:6][C:7]([C:9]23[CH2:18][CH:13]4[CH2:14][CH:15]([CH2:17][CH:11]([CH2:12]4)[CH2:10]2)[CH2:16]3)=[O:8])[CH2:2]1.C1(C)C=CC(S(O[CH2:29][CH2:30][CH2:31][C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=2)(=O)=O)=CC=1>>[F:38][C:35]1[CH:36]=[CH:37][C:32]([CH2:31][CH2:30][CH2:29][N:1]2[CH2:5][CH2:4][C@H:3]([NH:6][C:7]([C:9]34[CH2:18][CH:13]5[CH2:14][CH:15]([CH2:17][CH:11]([CH2:12]5)[CH2:10]3)[CH2:16]4)=[O:8])[CH2:2]2)=[CH:33][CH:34]=1
Reactant: Cc1ccc(S(=O)(=O)OCCCc2ccc(F)cc2)cc1
Reactant: O=C(N[C@H]1CCNC1)C12CC3CC(CC(C3)C1)C2
Product: O=C(N[C@H]1CCN(CCCc2ccc(F)cc2)C1)C12CC3CC(CC(C3)C1)C2
Yield: 19.4 %

Procedure:
(S)-N-(Pyrrolidin-3-yl)-1-adamantanecarboxamide (0.5 g) and 3-(4-fluorophenyl)propyl p-toluenesulfonate (0.92 g) were reacted under the same conditions as in Example 6 to give (S)-N-(1-(3-(4-fluorophenyl)propyl)pyrrolidin-3-yl)-1-adamantanecarboxamide (0.15 g), melting point 114-115° C.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]O)=[CH:11][CH:10]=1.O.P(Br)(Br)[Br:30]>C(Cl)(Cl)(Cl)Cl>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][Br:30])=[CH:11][CH:10]=1
Reactant: OCCCCCCCCCCCOc1ccc(-c2cccc(F)c2F)cc1
Reactant: BrP(Br)Br
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Product: Fc1cccc(-c2ccc(OCCCCCCCCCCCBr)cc2)c1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 120.5 %

Procedure:
First, 8 g of 2,3-difluoro-4'-(11-hydroxyundecyl)oxybiphenyl and 100 ml of carbon tetrachloride were placed in a 200 ml flask. A solution in which 2.3 g of phosphorus tribromide was dissolved in 50 ml of carbon tetrachloride was added dropwise to the reaction mixture under ice water cooling, and the resultant reaction mixture was stirred at room temperature for 3 hours and under reflux for 2 hours. The reaction mixture was poured into water, and an organic layer was extracted with ether. The ether layer was washed with water and dried over anhydrous sodium sulfate. Thereafter, the solvent was distilled away. The residue was purified by silica gel column chromatography (eluent: toluene/hexane=1/9) and recrystallized from hexane to obtain 4.5 g of 2,3-difluoro-4'-(11-bromoundecyl)oxybiphenyl (Y: 47.8%). The compound thus obtained had a purity of 95.3% by GC.
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][C@@H:11]([NH:25][C:26]1[CH:33]=[CH:32][C:29]([C:30]#[N:31])=[C:28]([Cl:34])[C:27]=1[CH3:35])[C:12]1[O:13][C:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[CH:19][CH:18]=2)=[N:15][N:16]=1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.CCOC(C)=O>[Cl:34][C:28]1[C:27]([CH3:35])=[C:26]([NH:25][C@@H:11]([C:12]2[O:13][C:14]([C:17]3[CH:18]=[CH:19][C:20]([C:23]#[N:24])=[CH:21][CH:22]=3)=[N:15][N:16]=2)[CH2:10][CH2:9][OH:8])[CH:33]=[CH:32][C:29]=1[C:30]#[N:31]
Reactant: Cc1c(N[C@H](CCO[Si](C)(C)C(C)(C)C)c2nnc(-c3ccc(C#N)cc3)o2)ccc(C#N)c1Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1c(N[C@H](CCO)c2nnc(-c3ccc(C#N)cc3)o2)ccc(C#N)c1Cl
Temperature: -40 °C
Yield: 0 %

Procedure:
To a 25 mL round bottom flask equipped with a magnetic stirrer and a septum was added (R)-4-(3-(tert-butyldimethylsilyloxy)-1-(5-(4-cyanophenyl)-1,3,4-oxadiazol-2-yl)propylamino)-2-chloro-3-methylbenzonitrile (900 mg, 177 mmol), which was then dissolved in anhydrous THF (50 mL) under an atmosphere of nitrogen and cooled to −40° C. To this was added the tetrabutylammonium fluoride as a 1M solution in THF (2.13 mL, 2.13 mmol) producing an instant color change to yellow. The mixture was then allowed to warm to −20° C. over a period of 2 h, at which point TLC analysis suggested the reaction was complete. The solvent was then removed under reduced pressure to yield a dark brown residue. This residue was taken up in EtOAc (40 mL) and washed with water (2×25 mL), brine (1×25 mL) and dried over Na2SO4. The solution was then filtered and concentrated under reduced pressure using rotary evaporation to reveal a yellow solid (1.08 g). Purification by flash column chromatography [EtOAc-hexanes (1:1) as eluent] afforded the title compound as a white crystalline solid (0.605 mg, 87%): 1H NMR (400 MHz, Acetone-d6, δ in ppm) 8.21 (d, J=9 Hz, 2H), 7.99 (d, J=9 Hz, 2H), 7.48 (d, J=9 Hz, 1H), 6.92 (d, J=9 Hz, 1H), 6.41 (d, J=9 Hz, 1H), 5.4 (m, 1H), 4.28-4.26 (m, 1H), 3.97-3.77 (m, 1H), 2.58-2.38 (m, 2H), 2.37.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH3:11])=[CH:4][CH:3]=1.[Mg].[CH:13]1[C:34]2[C:17](=[CH:18][C:19]3[C:20](=O)[C:21]4[C:30](C(=O)[C:32]=3[CH:33]=2)=[CH:29]C2[C:23](=[CH:24][CH:25]=CC=2)[CH:22]=4)[CH:16]=[CH:15][CH:14]=1.[I-].[K+]>O1CCCC1.C(O)(=O)C>[CH2:25]([C:24]1[CH:23]=[CH:22][C:21]([C:20]2[C:7]3[C:2](=[CH:3][C:4]4[C:5]([CH:6]=3)=[CH:8][CH:9]=[CH:10][CH:11]=4)[C:13]([C:34]3[CH:33]=[CH:32][C:19]([CH2:20][CH2:21][CH2:22][CH3:23])=[CH:18][CH:17]=3)=[C:18]3[C:19]=2[CH:32]=[C:33]2[C:34](=[CH:17]3)[CH:13]=[CH:14][CH:15]=[CH:16]2)=[CH:30][CH:29]=1)[CH2:16][CH2:15][CH3:14]
Reactant: CCCCc1ccc(Br)cc1
Reactant: O=C1c2cc3ccccc3cc2C(=O)c2cc3ccccc3cc21
Agent: [I-]
Agent: [K+]
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCCCc1ccc(-c2c3cc4ccccc4cc3c(-c3ccc(CCCC)cc3)c3cc4ccccc4cc23)cc1
Temperature: 60 °C
Reaction time: 2 h
Yield: 94.4 %

Procedure:
6,13-bis(4-butylphenyl)pentacene was synthesized as follows. A solution of 1-bromo-4-butylbenzene (about 5.09 grams, about 32.40 mmol) in about 20 milliliters of anhydrous tetrahydrofuran (THF) was added over a period of about 1 hour to a stirred suspension of magnesium turnings (about 0.79 grams, about 32.40 mmol) in about 10 milliliters of THF in a 250 milliliter round-bottomed flask under an inert argon atmosphere. The resultant mixture was stirred at about 60° C. for about 2 hours. A solution of 6,13-pentacenequinone (about 1.0 grams, about 3.24 mmol) in about 20 milliliters of THF was added and the resulting mixture was stirred at about 60° C. for about 2 hours. Subsequently, the reaction mixture was cooled to about 22° C. to about 25° C. and quenched with ice. The reaction mixture was extracted with toluene and the organic layer was separated and dried with anhydrous magnesium sulfate (MgSO4). The solvent was removed and a solution of potassium iodide (KI) (about 2.00 grams, about 12.0 mmol) in about 50 milliliters acetic acid (AcOH) was added to the solid residue. The resultant mixture was then refluxed for about 1 hour and then cooled to about 22° C. to about 25° C. A purple precipitate, obtained after filtration, was washed with water and methanol, yielding about 0.83 grams of 6,13-bis(4-butylphenyl)pentacene as a dark purple solid (about 47% yield). Further purification was conducted by sublimation. An overview of this process is set forth below in Scheme 1.
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:27])([F:26])[S:5]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][C:17]=1[OH:18])[CH2:14][CH:13]([N:19]([CH2:23][CH2:24][CH3:25])[CH2:20][CH2:21][CH3:22])[CH2:12]2)(=[O:7])=[O:6].[CH2:28](Br)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>CCCCCC.CN(C=O)C>[F:27][C:4]([F:26])([F:3])[S:5]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][C:17]=1[O:18][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH2:14][CH:13]([N:19]([CH2:23][CH2:24][CH3:25])[CH2:20][CH2:21][CH3:22])[CH2:12]2)(=[O:6])=[O:7]
Reactant: BrCc1ccccc1
Reactant: CCCN(CCC)C1Cc2cc(O)c(OS(=O)(=O)C(F)(F)F)cc2C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: CCCN(CCC)C1Cc2cc(OCc3ccccc3)c(OS(=O)(=O)C(F)(F)F)cc2C1
Reaction time: 0.5 h

Procedure:
Sodium hydride (0.96 g, 24 mmol) was washed with hexane under nitrogen and suspended in DMF (10 mL). 2-(Dipropylamino)-2,3-dihydro-6-hydroxy-1H-inden-5-yl trifluoromethanesulfonate (69, 7.6 g, 20 mmol) in DMF (30 mL) was added dropwise at 0-5° C. over 30 min and the mixture stirred 30 min. Benzyl bromide (5.13 g, 30 mmol) in DMF (5 mL) was added and the resulting mixture was stirred 1 h. The reaction was quenched with saturated NaHCO3 and extracted with EtOAc. The organic layer was washed with water, brine, dried (MgSO4), filtered and concentrated to give the crude product. Chromatographic purification yielded pure product 70 as an oil that was converted into the HCl salt and crystallized from EtOAc/MeOH/hexane to give a white solid (mp 162-163° C.).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([NH2:7])=[N:3][CH:2]=1.C[Si](CCOCCl)(C)C.[CH3:17][O:18][C:19]1[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[CH:21][C:20]=1[C:29]1[C:38]2[C:33](=[CH:34][C:35]([S:39](Cl)(=[O:41])=[O:40])=[CH:36][CH:37]=2)[N:32]=[CH:31][N:30]=1.CN1C=CN=C1>CC#N>[CH3:17][O:18][C:19]1[CH:24]=[C:23]([C:25]([F:26])([F:27])[F:28])[CH:22]=[CH:21][C:20]=1[C:29]1[C:38]2[C:33](=[CH:34][C:35]([S:39]([NH:7][C:4]3[CH:5]=[CH:6][N:1]=[CH:2][N:3]=3)(=[O:41])=[O:40])=[CH:36][CH:37]=2)[N:32]=[CH:31][N:30]=1
Reactant: Nc1ccncn1
Reactant: COc1cc(C(F)(F)F)ccc1-c1ncnc2cc(S(=O)(=O)Cl)ccc12
Agent: C[Si](C)(C)CCOCCl
Agent: Cn1ccnc1
Solvent: CC#N
Product: COc1cc(C(F)(F)F)ccc1-c1ncnc2cc(S(=O)(=O)Nc3ccncn3)ccc12
Temperature: 110 °C
Reaction time: 1 h

Procedure:
A solution of pyrimidin-4-amine (0.029 g, 0.300 mmol) in 3 mL of MeCN was treated with SEM-Cl (0.053 ml, 0.300 mmol), and the reaction mixture was allowed to stir for one hour. 4-(2-methoxy-4-(trifluoromethyl)phenyl)quinazoline-7-sulfonyl chloride (Intermediate DDDD; 0.110 g, 0.273 mmol) was added as a solution in 3 mL of MeCN, followed by 1-methylimidazole (0.054 ml, 0.546 mmol). After stirring at room temperature for an additional hour, the reaction mixture was concentrated and then dissolved in 1 mL of THF. 4N HCl dioxanes (1.024 ml, 4.10 mmol) was added, and the reaction mixture was heated to 110° C. for one hour. The reaction mixture was concentrated and purification of the crude residue by reverse phase column chromatography [C18 50 g, 10 to 100% (0.1% NH4OH in MeOH)/(0.1% NH4OH in water)] yielded 4-(2-methoxy-4-(trifluoromethyl)phenyl)-N-(pyrimidin-4-yl)quinazoline-7-sulfonamide. 1H NMR (acetonitrile-d3) δ ppm: 9.44 (s, 1H), 8.63 (s, 1H), 8.44 (s, 1H), 8.18 (br. s., 1H), 8.03 (d, J=8.8 Hz, 1H), 7.79 (d, J=8.8 Hz, 1H), 7.58 (d, J=7.4 Hz, 1H), 7.43-7.51 (m, 2H), 7.07 (br. s., 1H), 3.75 (s, 3H). m/z (ESI) 462.0 (M+H)+
Reaction SMILES: [C:1](=[O:23])(OC1C=CC=CC=1)[O:2][CH2:3][C:4](=O)[C:5]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][CH:6]=1.C([O-])(=O)C.[NH4+:28]>C(O)(=O)C>[F:12][C:11]([F:14])([F:13])[C:8]1[CH:9]=[CH:10][C:5]([C:4]2[NH:28][C:1](=[O:23])[O:2][CH:3]=2)=[CH:6][CH:7]=1
Reactant: [NH4+]
Reactant: O=C(OCC(=O)c1ccc(C(F)(F)F)cc1)Oc1ccccc1
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Product: O=c1[nH]c(-c2ccc(C(F)(F)F)cc2)co1
Yield: 84.9 %

Procedure:
A mixture of 2-oxo-2-(4-trifluoromethylphenyl)ethyl phenyl carbonate (18.0 g), ammonium acetate (20 g) and acetic acid (100 ml) was stirred with heating under reflux for 1 hour. The reaction mixture was concentrated, and poured into ice water (200 ml). The solid precipitates were filtered, washed with water, and air-dried to give crystals of 4-(4-trifluoromethylphenyl)-2-oxazolone (10.8 g, 85%).
Reaction SMILES: [CH3:1][C:2]1[C:7]2[CH:8]([C:11]3[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=3)[CH2:9][O:10][C:6]=2[C:5]([CH3:18])=[C:4]([CH3:19])[C:3]=1[NH2:20].C([O:24][CH2:25][CH3:26])(=O)C>>[CH3:1][C:2]([CH3:7])([CH3:3])[CH2:26][C:25]([NH:20][C:3]1[C:4]([CH3:19])=[C:5]([CH3:18])[C:6]2[O:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=3)[C:7]=2[C:2]=1[CH3:1])=[O:24]
Reactant: Cc1ccc(C2COc3c(C)c(C)c(N)c(C)c32)cc1
Reactant: CCOC(C)=O
Product: Cc1ccc(C2COc3c(C)c(C)c(NC(=O)CC(C)(C)C)c(C)c32)cc1
Yield: 80 %

Procedure:
Using 4,6,7-trimethyl-3-(4-methylphenyl)-2,3-dihydro-1-benzofuran-5-amine obtained in Reference Example 307, the title compound was synthesized in the same manner as in Example 1. Yield: 80%. Melting point: 176-177° C. (ethyl acetate).
Reaction SMILES: [F:1][C:2]([F:34])([C:30]([F:33])([F:32])[F:31])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][N:12]2[CH2:18][CH2:17][CH2:16][N:15]([CH2:19][C:20]3[CH:29]=[CH:28][C:23]([C:24]([O:26]C)=[O:25])=[CH:22][CH:21]=3)[CH2:14][CH2:13]2)=[CH:7][CH:6]=1.C1COCC1.[OH-].[Na+]>CO>[F:34][C:2]([F:1])([C:30]([F:31])([F:32])[F:33])[CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([CH2:11][N:12]2[CH2:18][CH2:17][CH2:16][N:15]([CH2:19][C:20]3[CH:29]=[CH:28][C:23]([C:24]([OH:26])=[O:25])=[CH:22][CH:21]=3)[CH2:14][CH2:13]2)=[CH:9][CH:10]=1
Reactant: COC(=O)c1ccc(CN2CCCN(Cc3ccc(OCC(F)(F)C(F)(F)F)cc3)CC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1ccc(CN2CCCN(Cc3ccc(OCC(F)(F)C(F)(F)F)cc3)CC2)cc1
Reaction time: 16 h
Yield: 79.4 %

Procedure:
A solution of methyl 4-[[hexahydro-4-[[4-(2,2,3,3,3-pentafluoropropoxy)-phenyl]methyl]-1H-1,4-diazepin-1-yl]methyl]benzoate (0.35 g, 0.72 mmol) in a 1 to 1 mixture of THF and methanol (20 mL) was stirred as an aqueous 2N sodium hydroxide solution (9.8 mL, 27 eq) was added. After 16 h, the reaction mixture was concentrated. The residue was suspended in water (5 mL) and acidified to a pH of 6 with an aqueous 2N HCl solution. The resulting solid was collected by filtration and dried to afford 0.27 g of 4-[[hexahydro-4-[[4-(2,2,3,3,3-pentafluoropropoxy)phenyl]methyl]-1H-1,4-diazepin-1-yl]methyl]benzoic acid; 1H NMR (400 MHz, CD3OD) δ 7.92 (d, 2H), 7.40 (d, 4H), 7.05 (d, 2H), 4.60 (t, 2H), 4.02 (s, 2H), 3.92 (s, 2H), 3.20 (m, 2H), 3.05 (m, 2H), 2.98 (m, 4H), 2.0 (m, 2H) ppm.
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[C:6](=[O:7])[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=2)=[C:4]([C:15]2[CH:20]=[CH:19][C:18](S(C)(=O)=O)=[CH:17][CH:16]=2)[O:3]1.FC1C=C(CC(C2C=C[C:39]([S:42](C)(=[O:44])=[O:43])=CC=2)=O)C=CC=1.[H-].[Na+].BrC(C)(C)C(C#N)=O>C1COCC1>[CH3:1][C:2]1([CH3:25])[C:6](=[O:7])[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=2)=[C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[S:42]([CH3:39])(=[O:44])=[O:43])[O:3]1
Reactant: CS(=O)(=O)c1ccc(C(=O)Cc2cccc(F)c2)cc1
Reactant: CC1(C)OC(c2ccc(S(C)(=O)=O)cc2)=C(c2cccc(F)c2)C1=O
Agent: CC(C)(Br)C(=O)C#N
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC1(C)OC(c2ccccc2S(C)(=O)=O)=C(c2cccc(F)c2)C1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Another variation to prepare 2,2-dimethyl-4-(3-fluorophenyl)-5-{4-(methylsulfonyl)phenyl}-3(2H)-furanone was performed starting from 2-(3-fluorophenyl)-1-{4-(methylsulfonyl)phenyl}-ethanone as follows: To a stirred solution of 2-(3-fluorophenyl)-1-(4-methylsulfonylphenyl)-ethanone (1 g) in 10 ml of THF, was added 0.23 g of 95% sodium hydride at 0° C. The reaction solution was stirred for 1 hour at the same temperature. Then 0.64 g of a-bromo-isobutyric cyanide was added dropwise to the reaction mixture at 0° C. The reaction mixture was stirred for another 7 hours while being allowed to warm to room temperature. Then the reaction was quenched with 5 ml of water. The mixture was concentrated in vacuo, and was dissolved in 50 ml of water. The aqueous solution was extracted with ethylacetate (100 ml). The organic layer was washed with brine, concentrated in vacuo. Then the resulting residue was purified by column chromatography (hexane/ethylacetate) to afford 0.75 g of 2,2-dimethyl-4-(3-fluorophenyl)-5-{(methylsulfonyl)phenyl}-3(2H)-furanone.
Reaction SMILES: [CH2:1]([C@H:3]1[N:12]([C:13](=[O:22])[C:14]2[CH:19]=[CH:18][C:17]([O:20]C)=[CH:16][CH:15]=2)[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([F:23])[CH:10]=2)[N:5]([CH:24]([CH3:26])[CH3:25])[C:4]1=[O:27])[CH3:2].C([C@H]1N(C(=O)C2C=CC(O)=CC=2)C2C(=CC(F)=CC=2)N(C)C1=O)C>>[CH2:1]([C@H:3]1[N:12]([C:13](=[O:22])[C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([F:23])[CH:10]=2)[N:5]([CH:24]([CH3:26])[CH3:25])[C:4]1=[O:27])[CH3:2]
Reactant: CC[C@@H]1C(=O)N(C(C)C)c2ccc(F)cc2N1C(=O)c1ccc(OC)cc1
Agent: CC[C@@H]1C(=O)N(C)c2cc(F)ccc2N1C(=O)c1ccc(O)cc1
Product: CC[C@@H]1C(=O)N(C(C)C)c2ccc(F)cc2N1C(=O)c1ccc(O)cc1
Yield: 92 %

Procedure:
(3R)-3-Ethyl-6-fluoro-4-(4-methoxybenzoyl)-1-isopropyl-3,4-dihydroquinoxalin-2(1H)-one was treated according to the procedure for the preparation of (3R)-3-ethyl-7-fluoro-4-(4-hydroxybenzoyl)-1-methyl-3,4-dihydroquinoxalin-2(1H)-one (see Example 1) to yield (3R)-3-ethyl-6-fluoro-4-(4-hydroxybenzoyl)-1-isopropyl-3,4-dihydroquinoxalin-2(1H)-one (92%). [α]D25=−309° (c=0.0099 G/ML, CHCl3); MS (ESI) m/z 357 ([M+H]+); MS (ESI) m/z 355 ([M−H]−); HRMS: calcd for C20H21FN2O3, 356.1536; found (ESI_FT), 357.16064.
Reaction SMILES: [CH3:1][CH:2]([CH3:22])[CH2:3][CH:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1)[NH2:5].Cl[C:24]1[N:25]=[CH:26][C:27]([C:30]([O:32][CH3:33])=[O:31])=[N:28][CH:29]=1.C(N(C(C)C)CC)(C)C>CC(O)C>[CH3:1][CH:2]([CH3:22])[CH2:3][CH:4]([NH:5][C:24]1[N:25]=[CH:26][C:27]([C:30]([O:32][CH3:33])=[O:31])=[N:28][CH:29]=1)[C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:19])([F:20])[F:21])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1
Reactant: CC(C)CC(N)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Reactant: COC(=O)c1cnc(Cl)cn1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cnc(NC(CC(C)C)c2ccc(-c3ccc(C(F)(F)F)cc3)cc2)cn1
Temperature: 25 °C
Yield: 52 %

Procedure:
A solution of 3-methyl-1-(4′-(trifluoromethyl)biphenyl-4-yl)butan-1-amine (0.200 g, 0.651 mmol), methyl 5-chloropyrazine-2-carboxylate (124 mg, 0.716 mmol), and diisopropylethylamine (168 mg, 1.30 mmol) in 2-propanol (5 mL) was heated in a microwave reactor at 100° C. for 2 h. The mixture was cooled to room temperature and concentrated. The mixture was concentrated and purified by column chromatography to give methyl 5-(3-methyl-1-(4′-(trifluoromethyl)biphenyl-4-yl)butylamino)pyrazine-2-carboxylate (150 mg, 52%). 1H NMR (400 MHz, CDCl3, δ): 8.75 (s, 1H), 7.87 (s, 1H), 7.68 (d, J=8.8 Hz, 2H), 7.64 (d, J=8.8 Hz, 2H), 7.55 (d, J=8.0 Hz, 2H), 7.43 (d, J=8.0 Hz, 2H), 5.46 (s, 1H), 5.04 (t, 1H), 4.12 (s, 3H), 1.87-1.80 (m, 1H), 1.80-1.60 (m, 2H), 1.02 (d, J=6.4 Hz, 3H), 0.98 (d, J=6.4 Hz, 3H).
Reaction SMILES: [S:1]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8](O)=[O:9])(=[O:4])(=[O:3])[NH2:2].S(Cl)([Cl:16])=O>>[S:1]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([Cl:16])=[O:9])(=[O:4])(=[O:3])[NH2:2]
Reactant: O=S(Cl)Cl
Reactant: NS(=O)(=O)c1cccc(C(=O)O)c1
Product: NS(=O)(=O)c1cccc(C(=O)Cl)c1

Procedure:
10 g of ground 3-sulfamoylbenzoic acid were reacted as prescribed in Example 70b), the thionyl chloride was distilled off and the residue was crystallized under a mixture of petroleum ether and diethyl ether (1:1). Melting point: 123° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:26])[N:9]3[CH2:25][CH2:24][CH2:23][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([O:18][C:19]([CH3:22])(C)[CH3:20])=[O:17])[C:6]=2[CH:5]=[CH:4][C:3]=1[F:27].[CH:28]1(O)[CH2:33]CCC[CH2:29]1>CCO.CCO.CCO.CCO.[Ti]>[Cl:1][C:2]1[C:7]2[C:8](=[O:26])[N:9]3[CH2:25][CH2:24][CH2:23][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([O:18][CH:19]3[CH2:22][CH2:33][CH2:28][CH2:29][CH2:20]3)=[O:17])[C:6]=2[CH:5]=[CH:4][C:3]=1[F:27]
Reactant: OC1CCCCC1
Reactant: CC(C)(C)OC(=O)c1ncn2c1[C@@H]1CCCN1C(=O)c1c-2ccc(F)c1Cl
Agent: [Ti]
Solvent: CCO
Product: O=C(OC1CCCCC1)c1ncn2c1[C@@H]1CCCN1C(=O)c1c-2ccc(F)c1Cl
Reaction time: 8 h

Procedure:
A mixture of 4.0 g (10 mmol) of tert.butyl (S)-8-chloro-7-fluoro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxylate, 0.8 g (3 mmol) of tetraethyl orthotitanate and 15 ml of cyclohexanol is stirred at 120° overnight, evaporated to dryness, the residue is taken up in methylene chloride, the solution obtained is washed successively with 40 ml of 5N hydrochloric acid, water and saturated sodium bicarbonate solution, dried over magnesium sulphate and evaporated. There is obtained cyclohexyl (S)-8-chloro-7-fluoro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxylate of melting point 163°-166°.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[C:19]([N:20]4[CH2:25][CH2:24][N:23]([C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=5)[CH2:22][C@@H:21]4[CH3:32])=[N:18][C:17]4[C:12](=[CH:13][CH:14]=[C:15]([C:33]([O:35]C)=[O:34])[CH:16]=4)[N:11]=3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[OH-].[Na+].Cl>CO.O>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[C:19]([N:20]4[CH2:25][CH2:24][N:23]([C:26]5[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=5)[CH2:22][C@@H:21]4[CH3:32])=[N:18][C:17]4[C:12](=[CH:13][CH:14]=[C:15]([C:33]([OH:35])=[O:34])[CH:16]=4)[N:11]=3)=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: COC(=O)c1ccc2nc(-c3ccc4[nH]ncc4c3)c(N3CCN(c4ccccn4)C[C@@H]3C)nc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: C[C@H]1CN(c2ccccn2)CCN1c1nc2cc(C(=O)O)ccc2nc1-c1ccc2[nH]ncc2c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 85.9 %

Procedure:
To a solution of (S)-methyl 2-(1H-indazol-5-yl)-3-(2-methyl-4-(pyridin-2-yl)piperazin-1-yl)quinoxaline-6-carboxylate (47 mg, 0.10 mmol) in methanol (15 ml) was added NaOH (15.6 mg, 0.39 mmol) and water (1 mL). After stirring 6 h at room temperature, the reaction mixture was concentrated under reduced pressure to afford a residue, which was dissolved in water (10 ml), adjusted to pH 6 with HCl (3N). The solids were filtered to give (S)-2-(1H-indazol-5-yl)-3-(2-methyl-4-(pyridin-2-yl)piperazin-1-yl)quinoxaline-6-carboxylic acid as a yellow solid (40 mg, 88%).
Reaction SMILES: ClC(Cl)C.[F:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]1[C:18]2[CH:19]=[C:20]([N:23]=[C:24]=[O:25])[CH:21]=[CH:22][C:17]=2[N:16]([CH3:26])[C:15](=[O:27])[CH2:14][N:13]=1.NC1C=CC2N(C)C(=O)CN=C(C3C=CC=CC=3F)C=2C=1.[NH2:49][CH2:50][CH:51]([OH:53])[CH3:52]>ClCCCl>[F:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]1[C:18]2[CH:19]=[C:20]([NH:23][C:24]([NH:49][CH2:50][CH:51]([OH:53])[CH3:52])=[O:25])[CH:21]=[CH:22][C:17]=2[N:16]([CH3:26])[C:15](=[O:27])[CH2:14][N:13]=1
Reactant: CC(O)CN
Reactant: CN1C(=O)CN=C(c2ccccc2F)c2cc(N=C=O)ccc21
Agent: CN1C(=O)CN=C(c2ccccc2F)c2cc(N)ccc21
Solvent: ClCCCl
Solvent: CC(Cl)Cl
Product: CC(O)CNC(=O)Nc1ccc2c(c1)C(c1ccccc1F)=NCC(=O)N2C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A dichloroethane solution of [5-(o-fluorophenyl)-2,3-dihydro-1-methyl-2-oxo-1H-1,4-benzodiazepin-7-yl]isocyanate, prepared as described in paragraph (a) of Example 1 from 12.5 g (0.044 M) of 7-amino-5-(o-fluorophenyl)-1,3-dihydro-1-methyl-2H-1,4-benzodiazepin-2-one, is added to a solution of 8 g of 1-amino-2-propanol in 100 ml of 1,2-dichloroethane, the mixture is stirred at room temperature for 15 minutes and then concentrated. The residue is purified on a 300 g silica gel column using methylene chloride and then acetone as the eluting agent. This operation is repeated once using ethyl acetate as the eluting agent. After crystallisation from ethyl acetate, there is obtained rac-1-[5-(o-fluorophenyl)-2,3-dihydro-1-methyl-2-oxo-1H-1,4-benzodiazepin-7-yl]-3-(2-hydroxypropyl)urea which melts at 149°-151° C. with decomposition.