Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH:4]1[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1.C(N(CC)CC)C.[N:17]1[O:18][N:19]=[C:20]2[CH:25]=[C:24]([C:26](Cl)=[O:27])[CH:23]=[CH:22][C:21]=12>ClCCl>[CH3:1][N:2]([CH2:3][CH:4]1[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1)[C:26]([C:24]1[CH:23]=[CH:22][C:21]2=[N:17][O:18][N:19]=[C:20]2[CH:25]=1)=[O:27]
Reactant: CNCC1CCOCC1
Reactant: O=C(Cl)c1ccc2nonc2c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(CC1CCOCC1)C(=O)c1ccc2nonc2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Methyl tetrahydro-2H-pyran-4-carboxylate (5 ml, 40.0 mmol) was added to a solution of methylamine (generated by heating a mixture of methylamine hydrochloride and sodium hydroxide pellets) in THF (30 ml) and the mixture heated at 110° C. in a bomb reactor overnight. The solvents were evaporated, the residue dissolved in THF (100 ml), and LiAlH4 (4.6 g, 121 mmol) added, and the mixture heated at 70° C. for 1 h. The mixture was cooled to 0° C., concentrated NaOH solution added and the THF evaporated. Chloroform (100 ml) was added to the residue and the resulting solid was filtered off and the filtrate concentrated under vacuum to give N-methyl-N-tetrahydro-2H-pyran-4-ylmethylamine as a pale brown oil. The preceding amine (1 g, 7.8 mmol) was dissolved in dichloromethane (50 ml), and triethylamine (4 ml) and [2,1,3]-benzoxadiazole-5-carbonylchloride (1.7 g, 9.3 mmol), as a solution in dichloromethane (20 ml), were added, slowly. The mixture was stirred at room temperature for 1 h, the mixture washed with 1N HCl (20 ml), and saturated sodium bicarbonate solution (20 ml), dried (MgSO4) and evaporated. The residue was purified by silica gel chromatography eluting with ethyl acetate/chloroform (3:1) to give the title compound as a pale brown oil. 1H NMR (300 MHz, CDCl3, 2-rotamers) δ 7.93 (d, J=9.3 Hz, 1H), 7.83 (br s, 1H), 7.38-7.45 (m, 1H), 4.10-3.90 (m, 2H), 3.52-3.20 (m, 4H), 3.13 and 3.05 (both s, total 3H), 2.18-1.80 (m, 1H), 1.73-1.40 ppm (m, 4H).
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH3:15][N:16]1[CH2:21][CH2:20][NH:19][CH2:18][C:17]1=[O:22].[O:23]1[C:27]2([CH2:32][CH2:31][C:30](=O)[CH2:29][CH2:28]2)[O:26][CH2:25][CH2:24]1.[OH-].[Na+]>ClCCl.C(O)(=O)C>[CH3:15][N:16]1[CH2:21][CH2:20][N:19]([CH:30]2[CH2:31][CH2:32][C:27]3([O:26][CH2:25][CH2:24][O:23]3)[CH2:28][CH2:29]2)[CH2:18][C:17]1=[O:22]
Reactant: CN1CCNCC1=O
Reactant: O=C1CCC2(CC1)OCCO2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CN1CCN(C2CCC3(CC2)OCCO3)CC1=O

Procedure:
26.18 g Sodium triacetoxyborohydride are added at 5° C. to a solution of 10.0 g 4-methyl-3-oxo-piperazine, 13.51 g 1,4-dioxa-spiro[4,5]decan-8-one, 5.65 ml acetic acid and 200 ml dichloromethane. After 23 hours stirring at ambient temperature 100 ml dichloromethane and 100 ml 4N sodium hydroxide solution are added. The phases are separated and the organic phase is evaporated down. The residue is purified by chromatography.
Reaction SMILES: Cl[C:2]1[C:3]([N+:13]([O-:15])=[O:14])=[C:4]([CH3:12])[C:5]([CH3:11])=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[CH:16]([NH2:20])([CH2:18][CH3:19])[CH3:17]>C1(C)C(C)=CC=CC=1>[CH:16]([NH:20][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([CH3:11])=[C:4]([CH3:12])[C:3]=1[N+:13]([O-:15])=[O:14])([CH2:18][CH3:19])[CH3:17]
Reactant: CCC(C)N
Reactant: Cc1cc([N+](=O)[O-])c(Cl)c([N+](=O)[O-])c1C
Solvent: Cc1ccccc1C
Product: CCC(C)Nc1c([N+](=O)[O-])cc(C)c(C)c1[N+](=O)[O-]

Procedure:
A mixture of 4-chloro-3,5-dinitro-o-xylene (140 grams, 0.61 mole), sec-butylamine (184 ml, 1.82 moles), and xylene (1400 ml) is brought to reflux. After refluxing overnight, the reaction mixture is cooled and filtered. The precipitate is washed with petroleum ether. The filtrate and washings are combined, washed with 500 ml. of 10% hydrochloric acid, and finally with 2 liters of water. The organic layer is separated and dried. Removal of the drying agent and the solvent leaves an orange oil which crystallizes with the addition of petroleum ether. A yellow orange solid (150.6 grams, 86.5%) with melting point 42° C. to 43° C. is collected.
Reaction SMILES: [Mg].[I-].[Li+].[CH3:4][O:5][C:6]1[CH:13]=[CH:12][C:9]([CH2:10]Cl)=[CH:8][CH:7]=1.[CH:14]1[C:27]2[C:26]3([CH2:29][N:30]4[CH2:35][CH2:34][C:33](=[O:36])[CH2:32][CH2:31]4)[CH2:28][CH:19]([C:20]4[C:25]3=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:18]=2[CH:17]=[CH:16][CH:15]=1>O1CCCC1.C(OCC)C>[CH:24]1[C:25]2[C:26]3([CH2:29][N:30]4[CH2:35][CH2:34][C:33]([CH2:10][C:9]5[CH:12]=[CH:13][C:6]([O:5][CH3:4])=[CH:7][CH:8]=5)([OH:36])[CH2:32][CH2:31]4)[CH2:28][CH:19]([C:18]4[C:27]3=[CH:14][CH:15]=[CH:16][CH:17]=4)[C:20]=2[CH:21]=[CH:22][CH:23]=1
Reactant: O=C1CCN(CC23CC(c4ccccc42)c2ccccc23)CC1
Reactant: COc1ccc(CCl)cc1
Agent: [I-]
Agent: [Li+]
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1ccc(CC2(O)CCN(CC34CC(c5ccccc53)c3ccccc34)CC2)cc1
Reaction time: 18 h
Yield: 68.1 %

Procedure:
Magnesium turnings (0.32 g, 1.32 mmol, 1.3 eq) were stirred in the absence of solvent for 15 min under nitrogen. Diethyl ether (20 mL) and catalytic lithium iodide were added, and the suspension was stirred vigorously for an additional 15 min at which time 4-methoxybenzyl chloride (1.08 mL, 7.0 mmol, 8 eq) was syringed into the reaction flask in portions. The reaction was refluxed for 3 h to assure Grignard formation and recooled to room temperature. 1-(9,10-Dihydro-9,10-methanoanthracen-9-ylmethyl)-4-piperidinone (described in example 5d) (0.30 g, 1.00 mmol) was added dropwise as a tetrahydrofuran solution (25 mL). After stirring for 18 h, the reaction was quenched with water (10 mL). The aqueous phase was extracted with ethyl acetate (200 mL). The organic extract was washed with water (2×100 mL), dried with anhydrous sodium sulfate, filtered, and reduced to an oil. The reaction mixture was purified by flash chromatography over silica gel (25 mL, eluent: 20% ethyl acetate in hexane) to yield 0.29 g (69%) of the title compound as a white solid. 1H NMR (CDCl3, 300 MHz) 7.23 (m, 2H), 7.13 (m 4H), 6.88 (m, 6H), 4.25 (s, 1H), 3.78 (s, 3H), 3.41 (s, 2H), 2.76 (m, 2H), 2.66 (s, 2H), 2.57 (d, J=1.2 Hz, 2H), 2.52 (m, 2H), 1.67 (m, 2H), 1.47 (m, 2H), 1.57 (s, 1H) MS (CI, CH4) m/z 426 (M+1,100), 454 (M+29,13), 408 (20). The free base was dissolved in methanol and methylene chloride, acidified with ethereal HCl and the salt precipitated with ether dilution. The hydrochloride salt was filtered, rinsed with fresh ether, and dried in vacuo (50° C. 10 pascal 18 h) to yield a white solid, mp 267°-268° C. (dec).
Reaction SMILES: [CH:1]1([CH2:7][O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]2[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:22]([C:24]1([C:27](O)=[O:28])[CH2:26][CH2:25]1)#[N:23]>>[C:22]([C:24]1([C:27]([NH:19][C:18]2[CH:20]=[CH:21][C:15]([CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][O:8][CH2:7][CH:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)=[CH:16][CH:17]=2)=[O:28])[CH2:26][CH2:25]1)#[N:23]
Reactant: Nc1ccc(CCCCCCOCC2CCCCC2)cc1
Reactant: N#CC1(C(=O)O)CC1
Product: N#CC1(C(=O)Nc2ccc(CCCCCCOCC3CCCCC3)cc2)CC1
Yield: 99.2 %

Procedure:
General procedure E was used to convert 1.30 mmol of 13b and 1.95 mmol of 1-cyanocyclopropanecarboxylic acid to 1.29 mmol (99%) of the title compound.
Reaction SMILES: C(O)C.[C:4]1([C:10]2[CH:11]=[CH:12][C:13]([NH:19][C:20]([C:22]3[CH:27]=[CH:26][C:25]([CH:28]4[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]4)=[CH:24][CH:23]=3)=[O:21])=[C:14]([CH:18]=2)[C:15]([OH:17])=[O:16])[CH2:9][CH2:8][CH2:7][CH2:6][CH:5]=1>[Pd].CN(C=O)C>[CH:4]1([C:10]2[CH:11]=[CH:12][C:13]([NH:19][C:20]([C:22]3[CH:27]=[CH:26][C:25]([CH:28]4[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]4)=[CH:24][CH:23]=3)=[O:21])=[C:14]([CH:18]=2)[C:15]([OH:17])=[O:16])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9]1
Reactant: O=C(Nc1ccc(C2=CCCCC2)cc1C(=O)O)c1ccc(C2CCCCC2)cc1
Agent: [Pd]
Solvent: CCO
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(C2CCCCC2)cc1C(=O)O)c1ccc(C2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 90 %

Procedure:
22 mg of 10% Pd—C was added to an ethanol (11 mL)/DMF (1 mL) solution comprising 216 mg (0.54 mmol) of 5-(cyclohex-1-en-1-yl)-2-{[(4-cyclohexylphenyl)carbonyl]amino}benzoic acid obtained in Example 81, and the mixture was stirred under hydrogen atmosphere at room temperature for 72 hours. The reaction mixture was filtered using filter paper, and the filtrate was condensed, thereby giving 195 mg of the target 5-cyclohexyl-2-{[(4-cyclohexylphenyl)carbonyl]amino}benzoic acid (yield: 90%).
Reaction SMILES: [CH2:1]([O:4][C@@H:5]([CH3:11])[CH2:6][CH2:7][C@@H:8]([OH:10])[CH3:9])[CH2:2][CH3:3].[Na].Cl[C:14]1[N:15]=[N:16][C:17]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[CH:22][CH:21]=2)=[CH:18][CH:19]=1.O>C1(C)C=CC=CC=1>[CH3:9][C@H:8]([O:10][C:14]1[N:15]=[N:16][C:17]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[CH:22][CH:21]=2)=[CH:18][CH:19]=1)[CH2:7][CH2:6][C@@H:5]([O:4][CH2:1][CH2:2][CH3:3])[CH3:11]
Reactant: CCCO[C@@H](C)CC[C@H](C)O
Reactant: CCCCCCCCOc1ccc(-c2ccc(Cl)nn2)cc1
Agent: [Na]
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCCCCCOc1ccc(-c2ccc(O[C@@H](C)CC[C@H](C)OCCC)nn2)cc1
Temperature: 25 °C
Yield: 21.5 %

Procedure:
320 mg (2.0 mM) of the (2S,5S)-5-propoxy-2-hexanol obtained in Reference Example 1 was dissolved in 15 ml of anhydrous toluene. Thereto was added metallic sodium with stirring at room temperature. To the mixture was added 478 g (1.5 mM) of 3-chloro-6-(4-octyloxyphenyl)pyridazine. The resulting mixture was refluxed for 3 hours. The reaction mixture was cooled and mixed with water and toluene. The toluene layer was separated and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography [eluting solvent: n-hexane-ethyl acetate (4:1)] to obtain 190 mg of the title compound.
Reaction SMILES: C(N(CC)CC)C.[Br:8][C:9]1[N:10]=[C:11]([C:30]#[CH:31])[C:12]([N:15]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[N:13][CH:14]=1.[OH:32][N:33]=[C:34](Cl)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>C1COCC1>[Br:8][C:9]1[N:10]=[C:11]([C:30]2[O:32][N:33]=[C:34]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[CH:31]=2)[C:12]([N:15]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C:16](=[O:22])[O:17][C:18]([CH3:20])([CH3:21])[CH3:19])=[N:13][CH:14]=1
Reactant: ON=C(Cl)c1ccccc1
Reactant: C#Cc1nc(Br)cnc1N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1ncc(Br)nc1-c1cc(-c2ccccc2)no1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70 %

Procedure:
Triethylamine (50.82 mg, 70.00 μL, 0.5022 mmol) was added to a solution of tert-butyl N-(5-bromo-3-ethynyl-pyrazin-2-yl)-N-tert-butoxycarbonyl-carbamate (200 mg, 0.5022 mmol) and N-hydroxybenzimidoyl chloride (78.13 mg, 0.5022 mmol) in THF (16.00 mL) and the reaction mixture stirred at RT for 1 hour. After this time the reaction mixture was heated under reflux for 3 hours, cooled to RT and concentrated in vacuo. The residue was purified by column chromatography eluting with 10% EtOAc/ Petroleum ether to give the product as a colourless oil that crystallised on standing (182 mg, 70% Yield). 1H NMR (400.0 MHz, DMSO) d 1.41 (18H, s), 7.37 (1H, s), 7.52 (3H, m), 7.90 (2H, m), 8.68 (1H, s); MS (ES+) 519.05
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[CH:4]=1.C1C(=O)N([Br:17])C(=O)C1>C(Cl)(Cl)(Cl)Cl>[Br:17][CH2:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: COc1cccc(C)c1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: COc1cccc(CBr)c1
Temperature: 25 °C
Yield: 75.8 %

Procedure:
To a solution of 122 g (1.0 mol) of 1-methoxy-3-methylbenzene in 900 ml of CCl4, 178 g (1.0 mol) of NBS and 1.0 g of (PhCO2)2 were added at room temperature. This mixture was refluxed for 3 h, cooled to room temperature, and the formed succinimide was filtered off. Succinimide was additionally washed by 2×150 ml of CCl4. The combined filtrate was evaporated to dryness, and the residue was distilled in vacuum, b.p. 112-125° C./8 mm Hg. This procedure gave 152.5 g of 1-(bromomethyl)-3-methoxybenzene contaminated with ca. 25% of the isomeric product, i.e. 1-bromo-4-methoxy-2-methylbenzene.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)=[C:9]([CH:13]=1)[C:10]([OH:12])=[O:11])(=[O:4])=[O:3].Cl[C:20]1C=CC(S(C)(=O)=O)=CC=1C(O)=O.N1CCCCC1>>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([N:14]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:20]2)=[C:9]([CH:13]=1)[C:10]([OH:12])=[O:11])(=[O:3])=[O:4]
Reactant: CS(=O)(=O)c1ccc(N2CCCC2)c(C(=O)O)c1
Reactant: CS(=O)(=O)c1ccc(Cl)c(C(=O)O)c1
Solvent: C1CCNCC1
Product: CS(=O)(=O)c1ccc(N2CCCCC2)c(C(=O)O)c1
Yield: 78 %

Procedure:
The title compound was synthesised according to the procedure described for the synthesis of 5-Methanesulfonyl-2-pyrrolidin-1-yl-benzoic acid (Example Y) from 2-Chloro-5-methanesulfonyl-benzoic acid and piperidine and obtained in 78% yield. MS (m/e): 282.0 (M−H+ 100%)
Reaction SMILES: N[C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][CH2:4][CH2:5]NC(=N)N.N[C@H:14]([C:20](O)=[O:21])CCCCN>>[C:10]([OH:12])(=[O:11])[C:2]1[C:20](=[CH:14][CH:5]=[CH:4][CH:3]=1)[OH:21]
Reactant: N=C(N)NCCC[C@H](N)C(=O)O
Reactant: NCCCC[C@H](N)C(=O)O
Product: O=C(O)c1ccccc1O
Reaction time: 2 h

Procedure:
To characterize MS59 further its amino acid sequence was partially determined. Therefore, MS59 was separated in the presence of 0.1 mM thioglycolate in the upper reservoir buffer and SDS on a 12.5% polyacrylamide gel, which was prerun for 2 hours at 50 V with 0.05 mM glutathione in the upper reservoir buffer. The gel was stained with 5% (w/v) Serva Blue G in 45% (v/v) methanol and 10% acetic acid for 30 minutes and destained in 20% (v/v) acetic acid for 30 minutes and the 59 kDa band was cut out and sequenced using Edman degradation on an Applied Biosystems 477A protein sequencer according to the protocol provided by the manufacturer. N-terminal amino acid sequencing of MS59 revealed that the N-terminus was blocked. To obtain internal sequences, MS59 was digested with trypsin. Trypsin cleaves protein at arginine and lysine residues. The digestion products were separated on a reversed-phase column and analyzed by Edman degradation. Two tryptic fragments were sequenced: Pep1 and Pep2. Of Pep1 25 amino acid residues were identified: S-I-N-V-D-I-E-Q-E-T-A-W-V-Q-A-G-A-T-L-G-E-V-Y-Y-R (SEQ ID NO: 1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=2)[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)=[CH:5][C:4]=1[NH2:26].[C:27]([N:35]=[C:36]=[S:37])(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>CC(C)=O.C(OCC)(=O)C>[C:27]([NH:35][C:36]([NH:26][C:4]1[CH:5]=[C:6]([N:9]([CH2:18][C:19]2[CH:20]=[CH:21][C:22]([CH3:25])=[CH:23][CH:24]=2)[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)[CH:7]=[CH:8][C:3]=1[O:2][CH3:1])=[S:37])(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=C(N=C=S)c1ccccc1
Reactant: COc1ccc(N(Cc2ccc(C)cc2)Cc2ccc(C)cc2)cc1N
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: COc1ccc(N(Cc2ccc(C)cc2)Cc2ccc(C)cc2)cc1NC(=S)NC(=O)c1ccccc1
Reaction time: 0.5 h
Yield: 54.6 %

Procedure:
To a stirred solution of 400 mg (1.15 mmol) 4-methoxy-N1,N1-bis-(4-methyl-benzyl)-benzene-1,3-diamine in 8 ml acetone was added dropwise a solution of 0.18 ml (1.34 mmol) benzoyl isothiocyanate in 4 ml acetone and stirring continued for 30 minutes at room temperature. The mixture was then diluted with ethyl acetate and washed with water and then with brine. The organic phase was dried over sodium sulfate and concentrated in vacuo. Flash chromatography (1/9 ethyl acetate/hexane) afforded 320 mg (80%) 1-benzoyl-3-{5-[bis-(4-methyl-benzyl)-amino]-2-methoxy-phenyl}-thiourea as a yellow oil. ES-MS m/e (%): 510 (M+H+, 100).
Reaction SMILES: C([C:3]1[C:11]2[O:10][CH2:9][CH:8]([C:12]3[CH:17]=[CH:16][C:15]([CH:18]([CH3:20])[CH3:19])=[CH:14][CH:13]=3)[C:7]=2[C:6]([CH3:21])=[C:5]([NH:22][CH:23]=[O:24])[C:4]=1[CH3:25])=O.[OH2:26]>>[CH:23]([NH:22][C:5]1[C:4]([CH3:25])=[C:3](/[CH:7]=[CH:8]/[C:9]([O:10][CH2:11][CH3:3])=[O:26])[C:11]2[O:10][CH2:9][CH:8]([C:12]3[CH:13]=[CH:14][C:15]([CH:18]([CH3:20])[CH3:19])=[CH:16][CH:17]=3)[C:7]=2[C:6]=1[CH3:21])=[O:24]
Reactant: Cc1c(C=O)c2c(c(C)c1NC=O)C(c1ccc(C(C)C)cc1)CO2
Reactant: O
Product: CCOC(=O)/C=C/c1c(C)c(NC=O)c(C)c2c1OCC2c1ccc(C(C)C)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To the reaction solution was added (7-formyl-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)formamide obtained in Example 60 (3.0 g, 8.89 mmol), and the mixture was stirred at room temperature for 30 minutes. Water was added to the reaction solution, and the product was extracted with diisopropyl ether. The combined extract was washed with water, dried over magnesium sulfate, and then concentrated under reduced pressure to obtain the crude product of oily ethyl (2E)-3-(5-(formylamino)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-7-yl)-2-propenoate. A mixture of said compound with 10%—palladium carbon (50% hydrous, 300 mg) and ammonium formate (1.26 g, 20 mmol) in ethanol (50 mL), was heated under reflux for 2 hours. The solid material was removed and the filtrate was concentrated under reduced pressure. Water and ethyl acetate were added to the residue to separate the organic layer, and the aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with water and was dried over magnesium sulfate and then concentrated under reduced pressure. The solvent was distilled off under reduced pressure to obtain the crude product of ethyl 3-(5-(formylamino)-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-7-yl)propanoate. A mixture of said compound with concentrated hydrochloric acid (10 mL)-ethanol (30 mL), was heated under reflux for 1.5 hours. The solvent was distilled off under reduced pressure and the obtained residue was neutralized with a 12 N aqueous sodium hydroxide solution. The product was extracted with ethyl acetate.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([N:18]3[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH:20]([C:31]([OH:33])=[O:32])[CH2:19]3)=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH3:34][Si](C=[N+]=[N-])(C)C>C1(C)C=CC=CC=1.CO>[CH3:34][O:32][C:31]([CH:20]1[CH2:19][N:18]([C:16]([O:15][CH2:14][CH:12]2[C:13]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=3[C:6]3[C:11]2=[CH:10][CH:9]=[CH:8][CH:7]=3)=[O:17])[CH2:23][CH2:22][N:21]1[C:24]([O:26][C:27]([CH3:29])([CH3:30])[CH3:28])=[O:25])=[O:33]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)OCC2c3ccccc3-c3ccccc32)CC1C(=O)O
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: Cc1ccccc1
Product: COC(=O)C1CN(C(=O)OCC2c3ccccc3-c3ccccc32)CCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of piperazine-1,2,4-tricarboxylic acid 1-tert-butyl ester 4-(9H-fluoren-9-ylmethyl)ester (2.21 mmol) in toluene: methanol (9:1) was added equimolar trimethylsilyldiazomethane (2.0 M in hexanes) and the resulting mixture was stirred overnight at room temperature. The reaction mixture was concentrated in vacuo and purified using gradient elution from hexane/ethyl acetate (5%) to hexane/ethyl acetate (30%). ESI-MS m/z: 467 (M+1), UV retention time: 3.04 min.
Reaction SMILES: Br[C:2]1[N:6]=[CH:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([O:13][C:14]([F:20])([F:19])[C:15]([F:18])([F:17])[F:16])=[CH:9][CH:8]=2)[N:3]=1.CC1(C)C(C)(C)OB([C:29]2[CH:34]=[CH:33][C:32]([CH2:35][C:36]([O:38][CH3:39])=[O:37])=[CH:31][CH:30]=2)O1>>[F:19][C:14]([F:20])([O:13][C:10]1[CH:11]=[CH:12][C:7]([N:4]2[CH:5]=[N:6][C:2]([C:29]3[CH:34]=[CH:33][C:32]([CH2:35][C:36]([O:38][CH3:39])=[O:37])=[CH:31][CH:30]=3)=[N:3]2)=[CH:8][CH:9]=1)[C:15]([F:18])([F:17])[F:16]
Reactant: FC(F)(F)C(F)(F)Oc1ccc(-n2cnc(Br)n2)cc1
Reactant: COC(=O)Cc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Product: COC(=O)Cc1ccc(-c2ncn(-c3ccc(OC(F)(F)C(F)(F)F)cc3)n2)cc1

Procedure:
The title compound was prepared as described in Example 3 using 3-bromo-1-(4-(perfluoroethoxy)phenyl)-1H-1,2,4-triazole (C1a) and methyl 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetate (C2) and isolated as a white solid (3.57 g, 59%): 1H NMR (400 MHz, DMSO-d6) δ 9.42 (s, 1H), 8.18-8.04 (m, 4H), 7.68-7.58 (m, 2H), 7.48-7.38 (m, 2H), 3.78 (s, 2H), 3.65 (s, 3H); 19F NMR (376 MHz, DMSO-d6) δ −85.20 (d, J=2.9 Hz), −86.93; ESIMS m/z 428 ([M+H]+).
Reaction SMILES: [N+](=[CH2:3])=[N-].[O:4]=[C:5]1[CH:12]2[CH2:13][C:8]3([NH:15][C:16](=[O:18])[CH3:17])[CH2:9][CH:10]([CH2:14][CH:6]1[CH2:7]3)[CH2:11]2.[OH-].[K+]>CO.O>[O:4]=[C:5]1[CH2:3][CH:12]2[CH2:13][C:8]3([NH:15][C:16](=[O:18])[CH3:17])[CH2:9][CH:10]([CH2:14][CH:6]1[CH2:7]3)[CH2:11]2
Reactant: CC(=O)NC12CC3CC(C1)C(=O)C(C3)C2
Reactant: C=[N+]=[N-]
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(=O)NC12CC3CC(=O)C(CC(C3)C1)C2
Temperature: 25 °C
Yield: 90.6 %

Procedure:
A solution of diazomethane (Diazald, 2.70 g) in MeOH (15 mL) was added dropwise to a mixture of ketone 1A (997 mg) and KOH (3.81 g) in MeOH (10 mL) and water (1.8 mL) at 0° C. over a period of 1.5 h. The reaction mixture was allowed to warm to rt and was maintained for 16 h. The resulting suspension was concentrated and was diluted with water (50 mL). The resulting aqueous suspension was extracted with ether (1×), then with DCM (2×), and the combined organic layers were dried (Na2SO4) and concentrated. The residue was purified by silica gel chromatography (0/100 to 10/90 MeOH/EtOAc) to provide 964 mg of ketone 8A as a white solid. Data: LC/MS (ESR) m/z 222 [M+1]+, 244 [M+Na]+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:29][C:30]1[CH:35]=[C:34]([F:36])[C:33]([F:37])=[CH:32][C:31]=1[F:38])[CH2:10][C:11]([N:13]1[CH2:18][CH2:17][N:16]2[C:19]([C:25]([F:28])([F:27])[F:26])=[N:20][C:21]([C:22]([OH:24])=O)=[C:15]2[CH2:14]1)=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:39][N:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1.O=C1N([ClH]P([ClH]N2CCOC2=O)=O)CCO1.C(N(CC)CC)C>ClCCl>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]([CH2:29][C:30]1[CH:35]=[C:34]([F:36])[C:33]([F:37])=[CH:32][C:31]=1[F:38])[CH2:10][C:11]([N:13]1[CH2:18][CH2:17][N:16]2[C:19]([C:25]([F:28])([F:27])[F:26])=[N:20][C:21]([C:22]([N:43]3[CH2:44][CH2:45][N:40]([CH3:39])[CH2:41][CH2:42]3)=[O:24])=[C:15]2[CH2:14]1)=[O:12])([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCn2c(C(F)(F)F)nc(C(=O)O)c2C1)Cc1cc(F)c(F)cc1F
Reactant: CN1CCNCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN1CCN(C(=O)c2nc(C(F)(F)F)n3c2CN(C(=O)C[C@@H](Cc2cc(F)c(F)cc2F)NC(=O)OC(C)(C)C)CC3)CC1
Yield: 46.8 %

Procedure:
(R)-7-[3-tert-Butoxycarbonylamino-4-(2,4,5-trifluoro-phenyl)-butyryl]-3-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine-1-carboxylic acid 2a (150 mg, 0.27 mmol), 1-methylpiperazine (54 mg, 0.54 mmol) and bis(2-oxo-3-oxazolidinyl)phosphonic chloride (0.138 g, 0.54 mmol) were dissolved in 8 mL of dichloromethane under stirring, and triethylamine (0.25 mL, 1.62 mmol) was then added to the solution. The reaction mixture was reacted at room temperature overnight and monitored by thin layer chromatography until the disappearance of the starting materials. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (R)-[3-[1-(4-methyl-piperazine-1-carbonyl)-3-trifluoromethyl-5,6-dihydro-8H-imidazo[1,5-a]pyrazin-7-yl]-3-oxo-1-(2,4,5-trifluoro-benzyl)-propyl]-carbamic acid tert-butyl ester 5a (80 mg, yield 49%) as a white solid.