Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[CH:22][C:21]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1.[C:33](Cl)(=[O:35])[CH3:34]>>[C:33]([NH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[CH:22][C:21]=4[O:28][CH2:29][CH:30]4[CH2:31][CH2:32]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1)(=[O:35])[CH3:34]
Reactant: COc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@H]4CC[C@H](N)CC4)c[nH]c23)c1
Reactant: CC(=O)Cl
Product: COc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@H]4CC[C@H](NC(C)=O)CC4)c[nH]c23)c1

Procedure:
Starting from trans-4-(2-cyclopropylmethoxy-5-methoxy-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (4-amino-cyclohexyl)-amide (example A153) and acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:9][CH2:10][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:12][CH:13]=2)=[CH:4][C:3]=1[N+:21]([O-])=O.[H][H]>C(OCC)(=O)C.CO.[Pd]>[C:17]([O:16][C:14]([N:11]1[CH2:10][CH2:9][CH:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[C:3]([NH2:21])[CH:4]=2)[CH2:13][CH2:12]1)=[O:15])([CH3:20])([CH3:18])[CH3:19]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N1CC=C(c2ccc(F)c([N+](=O)[O-])c2)CC1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(F)c(N)c2)CC1
Reaction time: 72 h
Yield: 80.6 %

Procedure:
A mixture of tert-butyl 4-(4-fluoro-3-nitrophenyl)-3,6-dihydro-1(2H)-pyridinecarboxylate (2.35 g, 8.85 mmol) and 10% Pd/C (400 mg) in ethyl acetate (40.0 mL) and methanol (10.0 mL) was hydrogenated at room temperature for 72 hours using hydrogen bomb (200 psi). The reaction mixture was filtered through Celite and the Celite was washed with EtOAc/MeOH (1:1, 3×50 mL). The filtrate was concentrated in vacuo to afford tert-butyl-4-(3-amino-4-fluorophenyl)-1-piperidinecarboxylate (2.10 g, 98.0%): 1H NMR (400 MHz, CDCl3) δ 6.96-6.76 (m, 1H), 6.67-6.54 (m, 1H), 6.54-6.40 (m, 1H), 4.38-4.09 (br, 2H), 4.09-3.58 (br, 2H), 2.87-2.62 (m, 2H), 2.60-2.39 (m, 1H), 1.85-1.65 (m, 2H), 1.64-1.40 (m, 2H), 1.48 (s, 9H).
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([Br:10])[CH:5]=[C:6]([F:9])[C:7]=1[F:8].[OH-].[K+].[CH2:13]([OH:15])[CH3:14]>>[F:9][C:6]1[CH:5]=[C:4]([Br:10])[CH:3]=[C:2]([O:15][CH2:13][CH3:14])[C:7]=1[F:8]
Reactant: Fc1cc(Br)cc(F)c1F
Reactant: CCO
Agent: [K+]
Agent: [OH-]
Product: CCOc1cc(Br)cc(F)c1F
Reaction time: 3 h

Procedure:
To a 500 ml three neck flask provided with a stirrer, thermometer, and cooling tube were added 25.0 g (118.5 mmol) of 3,4,5-trifluorobromobenzene, 19.9 g (355.5 mmol) of potassium hydroxide, and 20 ml of ethanol, and heated to reflux while being stirred for 3 hours. After finishing of the reaction, unreacted ethanol was distilled off under a reduced pressure, 200 ml of water was added thereto, and it was extracted with 200 ml of diethyl ether. The extract was washed with water (150 ml) thrice and dried over anhydrous magnesium sulfate. The colorless oily product in an amount of 27.8 g which was obtained by distilling off the solvent was purified by silica gel column chromatography (eluent: heptane, Rf=0.36) to obtain 23.3 g of colorless oily 3,4-difluoro-5-ethoxybromobenzene.
Reaction SMILES: Cl.C(OCC)(=O)C.[C:8]1([C:14]2[CH:61]=[CH:60][C:17]([C:18]([N:20]([CH2:45][CH2:46][CH2:47][NH:48][C:49]([NH:51][CH2:52][C:53]3[CH:58]=[CH:57][CH:56]=[CH:55][C:54]=3[F:59])=[O:50])[C:21]3[CH:43]=[CH:42][C:41]([Cl:44])=[CH:40][C:22]=3[O:23][C:24]3[CH:25]=[C:26]([C@@H:30]([NH:32]C(=O)OC(C)(C)C)[CH3:31])[CH:27]=[CH:28][CH:29]=3)=[O:19])=[CH:16][CH:15]=2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C(OCC)(=O)C>[ClH:44].[NH2:32][C@H:30]([C:26]1[CH:25]=[C:24]([CH:29]=[CH:28][CH:27]=1)[O:23][C:22]1[CH:40]=[C:41]([Cl:44])[CH:42]=[CH:43][C:21]=1[N:20]([CH2:45][CH2:46][CH2:47][NH:48][C:49]([NH:51][CH2:52][C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][C:54]=1[F:59])=[O:50])[C:18](=[O:19])[C:17]1[CH:16]=[CH:15][C:14]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:61][CH:60]=1)[CH3:31]
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1cccc(Oc2cc(Cl)ccc2N(CCCNC(=O)NCc2ccccc2F)C(=O)c2ccc(-c3ccccc3)cc2)c1
Agent: Cl
Solvent: CCOC(C)=O
Product: C[C@H](N)c1cccc(Oc2cc(Cl)ccc2N(CCCNC(=O)NCc2ccccc2F)C(=O)c2ccc(-c3ccccc3)cc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 187.8 %

Procedure:
A 4 N hydrochloric acid/ethyl acetate (3 ml) solution was added to an ethyl acetate (3 ml) solution of tert-butyl(1S)-1-[3-[2-[(4-phenylbenzoyl)[3-[[[(2-fluorobenzyl)amino]carbonyl]amino]propyl]amino]-5-chlorophenoxy]phenyl]ethylcarbamate (0.36 g, 0.48 mmols), and stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure. The solid precipitated was taken out through filtration, and washed with ethyl ether to give an amorphous solid of N-[2-[3-[(1S)-1-aminoethyl]phenoxy]-4-chlorophenyl]-N-[3-[[[(2-fluorobenzyl)amino]carbonyl]amino]propyl]-4-phenylbenzamide hydrochloride (0.31 g, 95%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12](=[N:25][O:26][CH2:27][CH3:28])[CH2:13][N:14]2C(=O)C3=CC=CC=C3C2=O)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.O.NN.O>C(O)C>[CH2:27]([O:26][N:25]=[C:12]([C:3]1[C:2]([Cl:1])=[CH:7][C:6]([C:8]([F:11])([F:10])[F:9])=[CH:5][N:4]=1)[CH2:13][NH2:14])[CH3:28]
Reactant: CCON=C(CN1C(=O)c2ccccc2C1=O)c1ncc(C(F)(F)F)cc1Cl
Agent: NN
Solvent: O
Solvent: CCO
Product: CCON=C(CN)c1ncc(C(F)(F)F)cc1Cl
Temperature: 80 °C
Reaction time: 1 h
Yield: 61.9 %

Procedure:
To 111 mg of N-[2-[3-chloro-5-(trifluoromethyl)pyridin-2-yl]-2-(ethoxyimino)ethyl]phthalimide in 3 ml of ethanol, 86 mg of hydrazine monohydrate was added, and the mixture was stirred at 80° C. for 1 hour. After completion of the reaction, the reaction mixture was allowed to cool to room temperature, mixed with 5 ml of water and extracted with ethyl acetate (5 ml×3). The resulting organic layers were combined, dried over saturated aqueous sodium chloride and then anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography using methanol-chloroform (1:10) as the eluent to obtain 47 mg of the desired product as a yellow oil. The oil was used in the next step without further purification.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([B:10]([OH:12])[OH:11])=[CH:6][CH:5]=1)([OH:3])=[O:2].O[N:14]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[N:16]=[N:15]1.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O>[NH:14]1[C:18]2[CH:19]=[CH:20][CH:21]=[C:22]([O:2][C:1]([C:4]3[CH:5]=[CH:6][C:7]([B:10]([OH:12])[OH:11])=[CH:8][CH:9]=3)=[O:3])[C:17]=2[N:16]=[N:15]1
Reactant: O=C(O)c1ccc(B(O)O)cc1
Reactant: On1nnc2ccccc21
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN(C)C=O
Product: O=C(Oc1cccc2[nH]nnc12)c1ccc(B(O)O)cc1

Procedure:
To a solution of 4-carboxy-phenylboronic acid (CPBA, Example 1, 2 g, 0.0121 mol) in N,N-dimethylformamide (DMF) was added 1-hydroxybenzotriazole (HBT, 2.04 g, 0.0151 mol) and N,N'-dicyclohexyl-carbodiimide (DCC, 4.98 g, 0.024 mol) both dissolved in DMF (the total volume was 170 ml DMF). The solution was left to react overnight (approx. 12 hours) under a nitrogen atomosphere and at ambient temperature, and then filtered to remove the insoluble urea byproduct (DCU). The title compound was used in subsequent reactions without further purification.
Reaction SMILES: [OH-].[K+].[OH:3][CH2:4][C:5]1[O:6][C:7]([CH3:13])=[CH:8][C:9](=[O:12])[C:10]=1[OH:11].I[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21]>C(O)C.O>[OH:3][CH2:4][C:5]1[O:6][C:7]([CH3:13])=[CH:8][C:9](=[O:12])[C:10]=1[O:11][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21]
Reactant: Cc1cc(=O)c(O)c(CO)o1
Reactant: CCOC(=O)CCCCCI
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCOC(=O)CCCCCOc1c(CO)oc(C)cc1=O
Yield: 60 %

Procedure:
To a solution of 2.00 g (0.0304 mole) of potassium hydroxide in 33 ml of ethanol and 5 ml of water was added 4.75 g (0.0304 mole) of 2-hydroxymethyl-3-hydroxy-6-methyl-4-pyrone, and the resulting mixture heated to 50°. A 7.8 g (0.029 mole) portion of ethyl 6-iodohexanoate was then added and the resulting clear solution heated at reflux for 7 hr under a nitrogen atmosphere. Removal of the ethanol under reduced pressure left a residue which was dissolved in methylene chloride. The organic solution was washed successively with aqueous NaHCO3 and saturated brine, was dried over magnesium sulfate, and was evaporated to afford a viscous oil. This material was chromatographed on silica gel eluting with ethyl acetate to give 5.4 g (60%) of oily product, 2-hydroxymethyl-6-methyl-3-(5-carboethoxypentyloxy)-4-pyrone. NMR (CDCl3): δ1.22 (3H, t, J=7 Hz), 2.26 (3H, s); 4.61 (2H, m); 6.17 (1H, s).
Reaction SMILES: C[O:2][C:3]1[CH:26]=[CH:25][C:6]([O:7][C:8]2[C:22]([CH3:23])=[CH:21][C:11]3[C:12]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:13][O:14][C:10]=3[C:9]=2[CH3:24])=[CH:5][CH:4]=1.[Cl-].[Al+3].[Cl-].[Cl-].C(S)C>ClCCl>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([O:7][C:8]2[C:22]([CH3:23])=[CH:21][C:11]3[C:12]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:13][O:14][C:10]=3[C:9]=2[CH3:24])=[CH:25][CH:26]=1
Reactant: CCOC(=O)Cc1coc2c(C)c(Oc3ccc(OC)cc3)c(C)cc12
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCS
Product: CCOC(=O)Cc1coc2c(C)c(Oc3ccc(O)cc3)c(C)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.1 %

Procedure:
0.74 g (2.09 mmol) of ethyl 2-[6-(4-methoxyphenoxy)-5,7-dimethyl-1-benzofuran-3-yl]acetate, dissolved in 1 ml of dichloromethane, is [lacuna], at 0° C., to a solution of 0.84 g (6.26 mmol) of aluminum chloride and 0.65 g (10.44 mmol) of ethanethiol in 10 ml of dichloromethane. The reaction mixture is stirred overnight at room temperature, after which the solvent is removed in vacuo and the residue is subjected to chromatographic purification (cyclohexane/ethyl acetate=5.1). 0.52 g (73%) of ethyl 2-[6-(4-hydroxyphenoxy)-5,7-dimethyl-1-benzofuran-3-yl]acetate is obtained.
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.C([N:15]([CH2:26][CH3:27])[C:16](=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:18]=1[CH3:24])C.[Br:28][C:29]1[CH:36]=[CH:35]C(C#N)=[CH:31][CH:30]=1>C1COCC1>[Br:28][C:29]1[CH:36]=[CH:35][C:27]([C:26]2[NH:15][C:16](=[O:25])[C:17]3[C:18]([CH:24]=2)=[C:19]([CH3:23])[CH:20]=[CH:21][CH:22]=3)=[CH:31][CH:30]=1
Reactant: N#Cc1ccc(Br)cc1
Reactant: CCN(CC)C(=O)c1cccc(C)c1C
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: Cc1cccc2c(=O)[nH]c(-c3ccc(Br)cc3)cc12
Reaction time: 0.33 h
Yield: 58.4 %

Procedure:
To N,N-diisopropylamine (2.54 mL, 18 mmol) in anhydrous THF (15 mL), under N2 at −78° C. was added n-BuLi dropwise (2.5M in n-hexanes, 7.2 mL, 18 mmol) and the reaction mixture maintained at this temperature for 30 minutes. A solution of N,N-diethyl-2,3-dimethyl-benzamide (1.23 g, 6 mmol) in anhydrous THF (15 mL) was added dropwise to give a deep red solution. After 20 minutes at −78° C., 4-bromobenzonitrile (1.09 g, 6 mmol) in anhydrous THF (15 mL) was added dropwise and the reaction mixture allowed to stir at this temperature for 2.5 h. The reaction mixture was quenched by adding dropwise onto ice, upon which a pale yellow solid precipitated out. The solid was triturated with iso-hexane/EtOAc (2:1), filtered and dried in vacuo to afford 3-(4-bromo-phenyl)-5-methyl-2H-isoquinolin-1-one as a pale yellow solid (1.1 g, 58%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([OH:11])=[C:4]([O:12][CH3:13])[CH:3]=1.[F:14][C:15]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[C:16]=1[CH2:17]Br.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([O:11][CH2:17][C:16]2[C:19]([O:23][CH3:24])=[CH:20][CH:21]=[CH:22][C:15]=2[F:14])=[C:4]([O:12][CH3:13])[CH:3]=1
Reactant: COc1cccc(F)c1CBr
Reactant: COc1cc(Cl)c([N+](=O)[O-])cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(Cl)c([N+](=O)[O-])cc1OCc1c(F)cccc1OC
Temperature: 25 °C
Reaction time: 72 h
Yield: 94.2 %

Procedure:
To a solution of 4-chloro-2-methoxy-5-nitrophenol (0.67 g) and 2-fluoro-6-methoxy-benzyl bromide (0.66 g) in N,N-dimethylformamide (3 mL) was added potassium carbonate (0.54 g), and the mixture was stirred at room temperature for 3 days. The reaction mixture was poured into water, and the resulting mixture was stirred at room temperature for 30 minutes. The precipitated crystals were collected by filtration. The collected crystals were washed with water and a mixed solvent (diethyl ether/n-hexane=1/3), and dried under reduced pressure to give 5-chloro-2-(2-fluoro-6-methoxybenzyloxy)-4-nitroanisole (0.97 g). This material was dissolved in tetrahydrofuran (15 mL). To the solution were added methanol (15 mL) and nickel(II) bromide (31 mg). To the mixture was added sodium borohydride (0.32 g) under ice-cooling, and the mixture was stirred at the same temperature for 30 minutes, and then stirred at room temperature for 30 minutes. The reaction mixture was poured into a saturated aqueous sodium hydrogen carbonate solution, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=4/1−3/2) to give the title compound (0.79 g).
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10](I)=[N:11][CH:12]=2)=[CH:4][C:3]=1[C:16]([F:19])([F:18])[F:17].[C:20]([O:28][CH2:29][CH3:30])(=[O:27])[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23].N1C=CC=CC=1C(O)=O.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.[Cu]I>[Cl:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]([CH:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:20]([O:28][CH2:29][CH3:30])=[O:27])=[N:11][CH:12]=2)=[CH:4][C:3]=1[C:16]([F:19])([F:18])[F:17]
Reactant: FC(F)(F)c1cc(Oc2ccc(I)nc2)ccc1Cl
Reactant: CCOC(=O)CC(=O)OCC
Agent: [Cu]I
Agent: O=C(O)c1ccccn1
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CCOC(=O)C(C(=O)OCC)c1ccc(Oc2ccc(Cl)c(C(F)(F)F)c2)cn1
Temperature: 80 °C
Reaction time: 10 h
Yield: 196.8 %

Procedure:
To a solution of 5-(4-chloro-3-(trifluoromethyl)phenoxy)-2-iodopyridine (6 g, 7.06 mmol), diethyl malonate (2.261 g, 14.12 mmol) and picolinic acid (0.261 g, 2.117 mmol) in 1,4-dioxane (60 mL) were added Cs2CO3 (6.90 g, 21.17 mmol) and copper(I) iodide (0.134 g, 0.706 mmol). The reaction mixture was stirred at 80° C. for 10 hr. and then concentrated under reduced pressure. The reaction mixture was then extracted with CH2Cl2. The organic layer was separated and concentrated under reduced pressure to provide the diethyl 2-(5-(4-chloro-3-(trifluoromethyl) phenoxy)pyridin-2-yl)malonate (6 g, 77%).
Reaction SMILES: [CH3:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][CH:7]2[CH:9]([C:10]([OH:12])=[O:11])[C:8]2([CH3:14])[CH3:13])=[CH:4][CH:3]=1.CS(O[CH:22]([C:37]#[N:38])[C:23]1[CH:28]=[CH:27][C:26]([F:29])=[C:25]([O:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:24]=1)(=O)=O>>[CH3:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][CH:7]2[CH:9]([C:10]([O:12][CH:22]([C:37]#[N:38])[C:23]3[CH:28]=[CH:27][C:26]([F:29])=[C:25]([O:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[CH:24]=3)=[O:11])[C:8]2([CH3:14])[CH3:13])=[CH:4][CH:3]=1
Reactant: Cc1ccc(OC2C(C(=O)O)C2(C)C)cc1
Reactant: CS(=O)(=O)OC(C#N)c1ccc(F)c(Oc2ccccc2)c1
Product: Cc1ccc(OC2C(C(=O)OC(C#N)c3ccc(F)c(Oc4ccccc4)c3)C2(C)C)cc1

Procedure:
Following the procedure of Example 2, 3-(4-methylphenoxy)-2,2-dimethylcyclopropanecarboxylic acid is reacted with α-cyano-4-fluoro-3-phenoxybenzyl methanesulfonate to yield α-cyano-4-fluoro-3-phenoxybenzyl 3-(4-methylphenoxy)-2,2-dimethylcyclopropanecarboxylate.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C@H:4]([CH:17]([CH3:19])[CH3:18])[NH:5][C:6](=[O:16])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=1.C(O[ClH:26][O-])(C)(C)C.CC(C)([O-])C.[K+]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:20])[C@H:4]([CH:17]([CH3:18])[CH3:19])[N:5]([C:6](=[O:16])[CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([Cl:15])=[CH:13][CH:14]=1)[Cl:26]
Reactant: COC(=O)[C@@H](NC(=O)COc1ccc(Cl)cc1)C(C)C
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: COC(=O)[C@H](C(C)C)N(Cl)C(=O)COc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
After the reaction was completed, the mixture was extracted twice with ethyl ether to eliminate the unreacted acid chloride, and the extracted aqueous phase was acidified with hydrochloric acid to precipitate a product, which was then extracted three times with ethyl acetate, the extract was evaporated to dryness, and the residue was recrystallized from ethyl acetate/benzene/hexane to obtain a color-less crystal of N-(p-chlorophenoxy)acetyl-L-valine. 10 m moles of the crystalline compound was then dissolved in ethyl ether, the resulting solution was added with a solution of an excess amount of diazomethane in ethyl ether, and solvent was distilled off to obtain N-(p-chlorophenoxy)acetyl-L-valine methyl ester. 6.7 m moles of the ester was dissolved in 10 ml of dried toluene, and the resulting solution was added dropwise with 6.7 m moles of tert.-butoxyhypochloride, and then added with potassium tert.-butoxide, and the mixture was stirred for 30 minutes at a room temperature. The reaction mixture was partitioned between chloroform and water, the organic phase was washed with water, and then dried on anhydrous sodium sulfate. The dried solution was evaporated to dryness under reduced pressure to obtain a residue which was purified by middle pressure chromatography with silica gel to obtain N-(p-chlorophenoxy)acetyl-N-chloro-L-valine methyl ester.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:21][C:22](=[O:27])[CH2:23][C:24](=O)[CH3:25])[CH:5]=[CH:6][C:7]=1[N:8]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[NH3:28]>CO>[NH2:28]/[C:24](/[CH3:25])=[CH:23]\[C:22]([NH:21][C:4]1[CH:5]=[CH:6][C:7]([N:8]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])=[C:2]([Br:1])[CH:3]=1)=[O:27]
Reactant: CCCCCCN(CCCCCC)c1ccc(NC(=O)CC(C)=O)cc1Br
Reactant: N
Solvent: CO
Product: CCCCCCN(CCCCCC)c1ccc(NC(=O)/C=C(/C)N)cc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
A mixture of N-(3-bromo-4-(dihexylamino)phenyl)-3-oxobutanamide (5.10 g, 11.6 mmol), MeOH (60 mL) and ammonia (60 mL) was stirred at rt overnight. The mixture was then concentrated in vacuo to give the title compound as black oil (5.10 g, 100%).
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][NH:7][C:8](=[O:22])[C@@H:9]([NH2:21])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=1)(=[O:3])[CH3:2].[F:23][C:24]([F:38])([F:37])[CH2:25][CH2:26][O:27][C:28]1[CH:36]=[CH:35][C:31]([C:32](O)=[O:33])=[CH:30][CH:29]=1>>[C:1]([O:4][CH2:5][CH2:6][NH:7][C:8](=[O:22])[C@@H:9]([NH:21][C:32](=[O:33])[C:31]1[CH:35]=[CH:36][C:28]([O:27][CH2:26][CH2:25][C:24]([F:38])([F:37])[F:23])=[CH:29][CH:30]=1)[CH2:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]([F:19])([F:20])[F:18])=[CH:15][CH:16]=1)(=[O:3])[CH3:2]
Reactant: O=C(O)c1ccc(OCCC(F)(F)F)cc1
Reactant: CC(=O)OCCNC(=O)[C@@H](N)Cc1ccc(C(F)(F)F)cc1
Product: CC(=O)OCCNC(=O)[C@H](Cc1ccc(C(F)(F)F)cc1)NC(=O)c1ccc(OCCC(F)(F)F)cc1

Procedure:
A reaction similar to that described in Example 50 was conducted using 2-({(2S)-2-amino-3-[4-(trifluoromethyl)phenyl]propanoyl}amino)ethyl acetate and 4-(3,3,3-trifluoropropoxy)benzoic acid obtained in the preparation process of Example 33 (33a) to give the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:14]3[CH:15]=[N:16][CH:17]=[C:13]3[CH:12]=[N:11][C:10]=2[C:18]([OH:20])=O)=[C:4]([F:21])[CH:3]=1.Cl.[NH2:23][O:24][CH2:25][C@@H:26]([OH:28])[CH3:27].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.CN1CCOCC1>CN(C=O)C.CCOCC.C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:14]3[CH:15]=[N:16][CH:17]=[C:13]3[CH:12]=[N:11][C:10]=2[C:18]([NH:23][O:24][CH2:25][C@@H:26]([OH:28])[CH3:27])=[O:20])=[C:4]([F:21])[CH:3]=1
Reactant: O=C(O)c1ncc2cncn2c1Nc1ccc(Br)cc1F
Reactant: C[C@H](O)CON
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: C[C@H](O)CONC(=O)c1ncc2cncn2c1Nc1ccc(Br)cc1F
Temperature: 25 °C
Reaction time: 7 h
Yield: 25.5 %

Procedure:
To a solution of 5-(4-bromo-2-fluorophenylamino)imidazo[1,5-a]-pyrazine-6-carboxylic acid (100 mg, 0.28 mmol) in anhydrous DMF (1.5 mL) was added, in order, (S)-1-aminooxy-propan-2-ol hydrochloride (37.4 mg, 0.29 mmol, 1.03 eq.), HOBt (40.4 mg, 0.30 mmol, 1.05 eq.), EDCI (57.3 mg, 0.30 mmol, 1.05 eq.), and 4-methylmorpholine (0.15 mL, 1.36 mmol, 4.8 eq.). The reaction mixture was stirred at room temperature under N2 for 7 h and then diluted with ether (25 mL) and ethyl acetate (25 mL). The organic layer was washed with water and brine, dried (Na2SO4), filtered and concentrated in vacuo. The resultant residue was subjected to flash chromatography (Si-PPC, gradient 0 to 40% methanol in ethyl acetate) to give an oil. Crystallization from DCM ether hexane afforded the desired product as a white solid (30.3 mg, 25.0%). 1H NMR (DMSO-d6, 400 MHz) δ ppm 11.88 (broad s, 1H), 10.29 (broad s, 1H), 8.82 (s, 1H), 7.98 (s, 1H), 7.92 (s, 1H), 7.65 (dd, J=10.6 Hz, 2.2 Hz, 1H), 7.30 (d, J=8.6 Hz, 1H), 6.78 (t, J=8.4 Hz, 1H), 4.80 (d, J=4.0 Hz, 1H), 3.90-3.81 (m, 1H), 3.75-3.62 (m, 2H), 1.05 (d, J=6.4 Hz, 3H); LCMS (method D2): RT=1.516 min, [M+H]+=424/426.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:12]=[N:13][C:14](C4ON=C(CN5C(=O)C6=CC=CC=C6C5=O)N=4)=[C:10]3[CH2:9][N:8]([CH3:32])[C:7](=[O:33])[C:6]=2[CH:34]=1.CN>C(O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:12]=[N:13][CH:14]=[C:10]3[CH2:9][N:8]([CH3:32])[C:7](=[O:33])[C:6]=2[CH:34]=1
Reactant: CN1Cc2c(-c3nc(CN4C(=O)c5ccccc5C4=O)no3)ncn2-c2ccc(F)cc2C1=O
Agent: CN
Solvent: CCO
Product: CN1Cc2cncn2-c2ccc(F)cc2C1=O

Procedure:
10.1 g (22 mmol) of 8-fluoro-5,6-dihydro-5-methyl-3-(3-phthalimidomethyl-1,2,4-oxadiazol-5-yl)-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one were heated to 65° in 220 ml of ethanol, whereupon 150 ml of 33% ethanolic methylamine solution were added dropwise within 100 min. After completion of the addition the solution was heated for a further 17 hrs. and then cooled in an ice bath, whereby white crystals separated. These were filtered off and dried in a vacuum. After recrystallization from ethanol there were obtained 3.05 g of 3-(3-aminomethyl)-1,2,4-oxadiazol-5-yl) -8-fluoro-5,6-dihydro-5-methyl-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one of m.p. 208°-217°. A further 2.5 g of product were obtained by chromatography on silica gel with methylene chloride/methanol 19:1, then 9:1. Total yield: 5.55 g (77%).