Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].O.[SH:4][C:5]1[N:13]=[CH:12][N:11]=[C:10]2[C:6]=1[NH:7][CH:8]=[N:9]2.Cl[CH2:15][CH:16]([OH:37])[CH2:17][N:18]1[CH2:23][CH2:22][N:21]([CH:24]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:20][CH2:19]1>CN(C=O)C>[OH2:37].[OH:37][CH:16]([CH2:17][N:18]1[CH2:19][CH2:20][N:21]([CH:24]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:22][CH2:23]1)[CH2:15][S:4][C:5]1[N:13]=[CH:12][N:11]=[C:10]2[C:6]=1[NH:7][CH:8]=[N:9]2.[OH:37][CH:16]([CH2:17][N:18]1[CH2:19][CH2:20][N:21]([CH:24]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:22][CH2:23]1)[CH2:15][S:4][C:5]1[N:13]=[CH:12][N:11]=[C:10]2[C:6]=1[NH:7][CH:8]=[N:9]2
Reactant: OC(CCl)CN1CCN(C(c2ccccc2)c2ccccc2)CC1
Reactant: Sc1ncnc2nc[nH]c12
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: OC(CSc1ncnc2nc[nH]c12)CN1CCN(C(c2ccccc2)c2ccccc2)CC1
Temperature: 80 °C
Yield: 22.4 %

Procedure:
To DMF (6 mL), sodium hydroxide pellets (200 mg, 5 mmol) and 6-mercaptopurine monohydrate (0.85 g, 5 mmol) were added. The reaction mixture was stirred and heated to 80° C. for 30 min under nitrogen. The almost clear solution was cooled to room temperature and 1-(1-chloro-2-hydroxy-3-propanyl)-4-(diphenylmethyl)piperazine (1.72 g, 5 mmol) in DMF (10 mL) was added within 5 min. After stirring under nitrogen for 72 h, the mixture was filtered through Celite on a sintered glass funnel and the funnel was rinsed with DMF (2×5 mL). Evaporation of the solvent from the filtrate at 1.0 mm Hg at 50° C. gave a residue which was triturated with 10% methanol/methylene chloride. Filtration removed unreacted 6-mercaptopurine (0.5 g). The solution was purified using flash chromatography on silica gel using 10% methanol/methylene chloride as eluant. The product was isolated by concentration of the desired fractions and purified by trituration with n-pentane to give the title compound (0.35 g, 15.0%), mp 105°-110° C. (dec). DCI/MS M+1 461. 100 MHz 1H NMR (DMSO-d6) δ: 8.6 (s, 1H), 8.18 (s, 1H), 7.2-7.4 (m, 10H), 4.21 (s, 1H) 4.20 (m, 1H), 3.5 (m, 2H), 2.6 (m, 2H), 2.5-2.6 (m, 8H).
Reaction SMILES: C([O:3][C:4](=[O:31])[C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH2:15][C:14]([C:20]3[CH:25]=[C:24]([Cl:26])[CH:23]=[C:22]([Cl:27])[CH:21]=3)([C:16]([F:19])([F:18])[F:17])[O:13][N:12]=2)=[CH:7][C:6]=1[N+:28]([O-:30])=[O:29])C.[OH-].[K+].Cl>C(O)C.O>[Cl:27][C:22]1[CH:21]=[C:20]([C:14]2([C:16]([F:18])([F:17])[F:19])[O:13][N:12]=[C:11]([C:8]3[CH:9]=[CH:10][C:5]([C:4]([OH:31])=[O:3])=[C:6]([N+:28]([O-:30])=[O:29])[CH:7]=3)[CH2:15]2)[CH:25]=[C:24]([Cl:26])[CH:23]=1
Reactant: CCOC(=O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1[N+](=O)[O-]
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3 h
Yield: 118.1 %

Procedure:
In a solution of 0.36 g of 4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]-2-nitrobenzoic acid ethyl ester in 8 ml of ethanol, a solution of 0.40 g of potassium hydroxide in 2 ml of water was added, and stirred at room temperature for 3 hours. After the completion of the reaction, the reaction mixture was poured in 15 ml of water, adjusted to pH 4 with concentrated hydrochloric acid, then extracted with ethyl acetate (20 ml×2), the organic phase was washed with water, and then dehydrated with saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure to obtain 0.40 g of crude 4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl]-2-nitro benzoic acid as pale yellow oily substance. The substance was dissolved in 10 ml of chloroform, and 0.24 g of 2-picolylamine, 0.01 g of 4-(N,N-dimethylamino)pyridine and 0.35 g of 1-[3-(diethylamino)propyl]-3-ethylcarbodiimide hydrochloride were added, and stirred at room temperature for 18 hours. After the completion of the reaction, the solvent was distilled off under reduced pressure. The residue was subjected to purification with medium-pressure preparative liquid chromatography (Yamazen Corporation, medium pressure preparative system; YFLC-Wprep) that was eluted with ethyl acetate-hexane (1:1 to 1:0 gradient), and 0.14 g of the aimed product was obtained as colorless resinous substance.
Reaction SMILES: CN(/[CH:4]=[C:5]1\[C:6](=O)[C:7]2[C:12]([C@H:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[F:21])[CH2:14]\1)=[CH:11][CH:10]=[CH:9][CH:8]=2)C.[NH:23]([C:27]1[CH:32]=[CH:31][C:30]([N:33]2[CH2:38][CH2:37][N:36]([C:39]([O:41][CH2:42][C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)=[O:40])[CH2:35][CH2:34]2)=[CH:29][CH:28]=1)[C:24]([NH2:26])=[NH:25]>>[F:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[C@H:13]1[C:12]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[C:6]2[N:26]=[C:24]([NH:23][C:27]3[CH:32]=[CH:31][C:30]([N:33]4[CH2:34][CH2:35][N:36]([C:39]([O:41][CH2:42][C:43]5[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=5)=[O:40])[CH2:37][CH2:38]4)=[CH:29][CH:28]=3)[N:25]=[CH:4][C:5]=2[CH2:14]1
Reactant: N=C(N)Nc1ccc(N2CCN(C(=O)OCc3ccccc3)CC2)cc1
Reactant: CN(C)/C=C1/C[C@@H](c2ccccc2F)c2ccccc2C1=O
Product: O=C(OCc1ccccc1)N1CCN(c2ccc(Nc3ncc4c(n3)-c3ccccc3[C@H](c3ccccc3F)C4)cc2)CC1

Procedure:
This was synthesized by using (R,Z)-2-((dimethylamino)methylene)-4-(2-fluorophenyl)-3,4-dihydronaphthalen-1(2H)-one and benzyl 4-(4-guanidinophenyl)piperazine-1-carboxylate as described in general procedure 1. LCMS m/e 586 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:12]=[CH:13][C:14]=1[O:15]C(=O)CC)[CH:6]=[C:7]([CH3:11])[C:8]([OH:10])=[O:9].N>O1CCOCC1>[OH:15][C:14]1[CH:13]=[CH:12][C:5]([CH:6]=[C:7]([CH3:11])[C:8]([OH:10])=[O:9])=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: CCC(=O)Oc1ccc(C=C(C)C(=O)O)cc1OC
Agent: N
Solvent: C1COCCO1
Product: COc1cc(C=C(C)C(=O)O)ccc1O
Temperature: 50 °C
Reaction time: 2 h
Yield: 280.5 %

Procedure:
To cycloartenyl ester of 3-methoxy-4-propionyloxy-α-methyl-cinnamic acid (84.0 g, 0.125 mole) prepared according to the procedure of Example 113 dissolved in dioxane (1000 ml) was added 25% aqueous ammonia (200 ml) and the solution was stirred at 50° C. for 2 hours. Then, the reaction mixture was concentrated under reduced pressure to remove the solvent, and the residue was dissolved in chloroform. The chloroform solution was washed with saturated brine (500 ml), and the aqueous layer were extracted with chloroform (300 ml×2). The combined chloroform layer was dried, concentrated under reduced pressure, and the residue was recrystallized from methylene chloride-methanol (1:4, v/v), giving cycloartenyl ester of 4-hydroxy-3-methoxy-α-methylcinnamic acid (73.0 g), in a yield 94.8%. m.p.143°-144° C.
Reaction SMILES: [CH:1]#[C:2][CH3:3].[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([C@@H:11]2[N:17]([C@@H:18]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)[CH3:19])[C:16](=[O:27])[C:15]3[CH:28]=[C:29](I)[CH:30]=[CH:31][C:14]=3[NH:13][C:12]2=[O:33])=[CH:7][CH:6]=1.C(N(CC)CC)C>[Cu](I)I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(#N)C>[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([C@@H:11]2[N:17]([C@@H:18]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)[CH3:19])[C:16](=[O:27])[C:15]3[CH:28]=[C:29]([C:1]#[C:2][CH3:3])[CH:30]=[CH:31][C:14]=3[NH:13][C:12]2=[O:33])=[CH:7][CH:6]=1
Reactant: C#CC
Reactant: C[C@H](c1ccc(Cl)cc1)N1C(=O)c2cc(I)ccc2NC(=O)[C@@H]1c1ccc(Cl)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC#Cc1ccc2c(c1)C(=O)N([C@H](C)c1ccc(Cl)cc1)[C@@H](c1ccc(Cl)cc1)C(=O)N2
Temperature: 25 °C
Reaction time: 12 h
Yield: 89 %

Procedure:
Propyne (2 mL) was condensed in a sealed tube at −78° C. Then, (3S)-3-(4-Chlorophenyl)-4-[(R)-1-(4-chlorophenyl)ethyl]-7-iodo-1,4-benzodiazepine-2,5-dione (200 mg, 0.362 mmol), copper iodide (15 mg, 0.0788 mmol), dichlorobis(triphenylphosphine)palladium (II) (39 mg, 0.0556 mmol), triethylamine (2 mL), and acetonitrile (4 mL) were added. The sealed tube was closed and the reaction mixture was allowed warm up to room temperature. After 12 h, the reaction mixture was cooled to −78° C. and the sealed tube was opened and allowed to warm up to room temperature under vigorous stirring. Then, solvents were evaporated in vacuo and the residue was purified by column chromatgraphy on silica (EtOAc/Hexanes, 1:1) to give the title compound as colorless solid (150 mg, 89%): 1H NMR (400 MHz, CDCl3) δ 1.73 (d, J=7.1 Hz, 3H), 2.06 (s, 3H), 5.24 (s, 1H), 6.49 (q, J=7.1 Hz, 1H), 6.62–6.65 (m, 3H), 6.93 (d, J=8.4 Hz, 2H), 7.20 (dd, J=8.0 Hz, J=2.0 Hz, 1H), 7.33 (d, J=8.4 Hz, 2H), 7.53 (d, J=8.8 Hz, 2H), 7.79 (d, J=2.0 Hz, 1H), 8.57 (br s, 1H). Mass spectrum (LCMS, ESI pos.): Calcd for C26H20Cl2N2O2: 463; found: 464 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[C:3]([NH:22][C:23](=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25])=[N:4][CH:5]=[C:6]([C@@H:8]2[CH2:13][CH2:12][CH2:11][C@H:10]([O:14][Si](C(C)(C)C)(C)C)[CH2:9]2)[N:7]=1.[CH3:29][S:30](Cl)(=[O:32])=[O:31].O>C(Cl)Cl>[CH3:29][S:30]([O:14][C@H:10]1[CH2:11][CH2:12][CH2:13][C@@H:8]([C:6]2[CH:5]=[N:4][C:3]([NH:22][C:23](=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25])=[C:2]([Br:1])[N:7]=2)[CH2:9]1)(=[O:32])=[O:31]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)C(=O)Nc1ncc([C@@H]2CCC[C@H](O[Si](C)(C)C(C)(C)C)C2)nc1Br
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)C(=O)Nc1ncc([C@@H]2CCC[C@H](OS(C)(=O)=O)C2)nc1Br
Temperature: 25 °C
Reaction time: 3 h
Yield: 61.5 %

Procedure:
To a mixture of (+/−)-N-(3-bromo-5-((1R,35)-3-((tert-butyldimethylsilyl)oxy)cyclohexyl)pyrazin-2-yl)pivalamide (72 mg, 0.202 mmol) in CH2Cl2 (2021 μL) at 0° C. was added TEA (56.3 μL, 0.404 mmol) and methanesulfonyl chloride (18.90 μL, 0.243 mmol). The resulting mixture was stirred at room temperature for 3h. Another TEA (56.3 μL, 0.404 mmol) and Methanesulfonyl chloride (18.90 μL, 0.243 mmol) was added, and stirred for 6h. Worked up the reaction by adding water. The organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated. The crude product was purified with flash chromatography eluting with 0-100% EtOAc/heptane to provide 54 mg of (+/−)-(1S,3R)-3-(6-bromo-5-pivalamidopyrazin-2-yl)cyclohexyl methanesulfonate in 61.5% yield. LCMS (m/z): 436.1 (MH+), 0.75 min.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:25]=[CH:24][C:6]([O:7][C:8]2[CH:23]=[CH:22][C:11]([O:12][CH:13]([CH3:21])[CH:14]=[CH:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.[NH3:28]>C(O)C>[F:1][C:2]([F:26])([F:27])[C:3]1[CH:4]=[CH:5][C:6]([O:7][C:8]2[CH:23]=[CH:22][C:11]([O:12][CH:13]([CH3:21])[CH:14]([NH2:28])[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:10][CH:9]=2)=[CH:24][CH:25]=1
Reactant: CCOC(=O)C=CC(C)Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1
Reactant: N
Solvent: CCO
Product: CCOC(=O)CC(N)C(C)Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1
Temperature: 25 °C

Procedure:
To a solution of ethyl 4-[4-(4-trifluoromethylphenoxy)phenoxy]-2-pentenoate (0.8 g) in ethanol (25 ml), chilled in an ice bath and under nitrogen, ammonia is flowed over for about 10 minutes while stirring. Reaction is allowed to warm to R.T. The reaction is again chilled and additional ammonia added for about 15 minutes. Reaction is allowed to rise to R.T. and stirring continued over night. Reaction is concentrated under vacuum to an oil. The oily concentrate is purified by prep. thin layer chromatography using ethyl acetate/hexane (1:1) to give ethyl 4-[4-(4-trifluoromethylphenoxy)phenoxy]-3-aminopentanoate (purity 93.7%, structure confirmed by MS).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH2:5]Br.[F:12][C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C(COC)OC>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH2:5][C:16]2[CH:17]=[CH:18][C:13]([F:12])=[CH:14][CH:15]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: COc1ccc(CBr)cc1Br
Reactant: OB(O)c1ccc(F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: CCO
Product: COc1ccc(Cc2ccc(F)cc2)cc1Br
Temperature: 60 °C
Yield: 40.1 %

Procedure:
In a 250 mL round-bottomed flask equipped with a stir bar was placed 3-bromo-4-methoxybenzyl bromide (5.0 g, 17.9 mmol), 4-fluorophenylboronic acid (2.76 g, 19.7 mmol), potassium phosphate (tribasic) (7.60 g, 35.8 mmol), dimethoxyethane (30 mL) and 50% aqueous ethanol (30 mL). The mixture was degassed with nitrogen for 30 minutes and then added tetrakis(triphenylphosphine)palladium(0) (5.17 g, 4.48 mmol). The mixture was heated to 60° C. for 4 hours and then the palladium catalyst was filtered off. To the filtrate were added water (100 mL) and a saturated ammonium chloride solution (150 mL). After extracting with ethyl acetate (3×100 mL), the organic portions were combined, washed with brine (150 mL), dried (MgSO4) and concentrated. The crude material was purified by column utilizing 5% EtOAc/hexanes as the eluent to produce 2.12 g of 2-bromo-4-(4-fluoro-benzyl)-1-methoxy-benzene as a colorless oil in 40% yield.
Reaction SMILES: Cl.[C:2]([C:5]1[S:37][C:8]2[N:9]=[CH:10][N:11]=[C:12]([NH:13][C:14]3[CH:35]=[CH:34][C:33]([F:36])=[CH:32][C:15]=3[O:16][CH:17]3[CH2:22][CH2:21][CH2:20][CH:19]([N:23](C)[C:24](=O)OC(C)(C)C)[CH2:18]3)[C:7]=2[C:6]=1[CH3:38])(=[O:4])[NH2:3].CO>O1CCOCC1>[F:36][C:33]1[CH:34]=[CH:35][C:14]([NH:13][C:12]2[C:7]3[C:6]([CH3:38])=[C:5]([C:2]([NH2:3])=[O:4])[S:37][C:8]=3[N:9]=[CH:10][N:11]=2)=[C:15]([O:16][C@H:17]2[CH2:22][CH2:21][CH2:20][C@@H:19]([NH:23][CH3:24])[CH2:18]2)[CH:32]=1
Reactant: Cc1c(C(N)=O)sc2ncnc(Nc3ccc(F)cc3OC3CCCC(N(C)C(=O)OC(C)(C)C)C3)c12
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: CN[C@@H]1CCC[C@H](Oc2cc(F)ccc2Nc2ncnc3sc(C(N)=O)c(C)c23)C1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
220 μl 4 M HCl in dioxane was added to 0.093 g tert-butyl 3-(2-(6-carbamoyl-5-methylthieno[2,3-d]pyrimidin-4-ylamino)-5-fluorophenoxy)cyclohexyl(methyl)carbamate (cpd. 17.3) in 4 ml dioxane. The reaction mixture was stirred for 1 h at rt when further aliquots of 4 M HCl in dioxane were added. methanol was added and the mixture stirred for 2 days at rt. The mixture was purified by chromatography (gradient: CH2Cl2→20% MeOH/CH2Cl2 using the Biotage SP4).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=O)[CH:10]([CH2:31][C:32]1[CH:40]=[C:39]([CH3:41])[CH:38]2[CH:34]([CH:35]=[N:36][NH:37]2)[CH:33]=1)[CH2:11][C:12](=[O:30])[N:13]1[CH2:18][CH2:17][CH:16]([N:19]2[CH2:28][C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[NH:21][C:20]2=[O:29])[CH2:15][CH2:14]1>ClCCCl.C(O)(=O)C>[NH:1]1[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[N:8]=[C:9]1[CH:10]([CH2:31][C:32]1[CH:40]=[C:39]([CH3:41])[CH:38]2[CH:34]([CH:35]=[N:36][NH:37]2)[CH:33]=1)[CH2:11][C:12]([N:13]1[CH2:14][CH2:15][CH:16]([N:19]2[CH2:28][C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[NH:21][C:20]2=[O:29])[CH2:17][CH2:18]1)=[O:30]
Reactant: CC1=CC(CC(CC(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)C(=O)Nc2ccccc2N)=CC2C=NNC12
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CC1=CC(CC(CC(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)c2nc3ccccc3[nH]2)=CC2C=NNC12

Procedure:
A solution of N-(2-aminophenyl)-2-((7-methyl-3a,7a-dihydro-1H-indazol-5-yl)methyl)-4-oxo-4-(4-(2-oxo-1,2-dihydroquinazolin-3(4H)-yl)piperidin-1-yl)butanamide in 1,2-dichloroethane (8 mL) and acetic acid (1 mL) was heated under nitrogen at 65° C. for 5 h. The solvent was evaporated and the residue taken up in ethyl acetate (20 mL). The ethyl acetate layer was washed with 1M sodium hydroxide (5 mL) and water (2×5 mL), dried, filtered and concentrated. The final product was obtained by flash chromatography using 0% to 10% 2 M ammonia in methanol/methylene chloride. MS(ESI)[M+H]+=550.
Reaction SMILES: [CH2:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][C:4]=1[N+:12]([O-:14])=[O:13])[CH3:2].O=S(Cl)Cl.[CH3:19]O>>[CH2:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([O:9][CH3:19])=[O:8])=[CH:5][C:4]=1[N+:12]([O-:14])=[O:13])[CH3:2]
Reactant: CO
Reactant: CCc1ccc(C(=O)O)cc1[N+](=O)[O-]
Solvent: O=S(Cl)Cl
Product: CCc1ccc(C(=O)OC)cc1[N+](=O)[O-]
Temperature: 50 °C
Reaction time: 1 h
Yield: 98 %

Procedure:
To a suspension of 4-ethyl-3-nitrobenzoic acid (5.76 g, 29.53 mmol) in methanol (30 mL) at 0° C., was added SOCl2 (10.54 g, 88.61 mmol) slowly, stirred at this temperature for 1 h, then heated to 50° C. and stirred at this temperature for 3 h. Cooled to room temperature and removed the solvent, the residue was extracted with ethyl acetate, and concentrated to give 6.05 g of the title compound (98%). 1H NMR (400 MHz, CDCl3): δ 1.31 (3H, t, J=7.2 Hz), 2.97 (2H, q, J=7.2 Hz), 3.96 (3H, s), 7.47 (1H, d, J=8.4 Hz), 8.17 (1H, dd, J=1.6, 8.4 Hz), 8.52 (1H, d, J=1.6 Hz).
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:23])=[C:15]2[CH2:14]1)=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:39](O)[CH3:40].C(N(CC)CC)C.O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1>ClCCl>[CH2:39]([O:23][C:22]([C:21]1[N:20]=[C:19]([C:25]([F:27])([F:28])[F:26])[N:16]2[CH2:17][CH2:18][N:13]([C:11](=[O:12])[CH2:10][C@H:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:29][C:30]3[CH:35]=[C:34]([F:36])[C:33]([F:37])=[CH:32][C:31]=3[F:38])[CH2:14][C:15]=12)=[O:24])[CH3:40]
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: CCO
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1nc(C(F)(F)F)n2c1CN(C(=O)C[C@@H](Cc1cc(F)c(F)cc1F)NC(=O)OC(C)(C)C)CC2
Yield: 59.6 %

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 (0.16 g, 0.29 mmol) was dissolved in 10 mL of dichloromethane under stirring, and ethanol (0.05 mL, 0.87 mmol), triethylamine (0.202 mL, 1.45 mmol) and bis(2-oxo-3-oxazolidinyl)phosphinic chloride (0.148 g, 0.58 mmol) were then added to the solution. The reaction mixture was reacted at room temperature for 5 hours 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)-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 ethyl ester 23a (0.1 g) as a colourness oil.
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@H:2]([C:10]([N:12]([CH3:37])[C@H:13]([C:17]([N:19]([CH3:36])[C@H:20]([C:33]([NH2:35])=[O:34])[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[C:24]([C:29]([CH3:32])([CH3:31])[CH3:30])[CH:23]=1)=[O:18])[CH:14]([CH3:16])[CH3:15])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[H][H]>CO.[C].[Pd]>[NH2:1][C@H:2]([C:10]([N:12]([CH3:37])[C@H:13]([C:17]([N:19]([CH3:36])[C@H:20]([C:33]([NH2:35])=[O:34])[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[C:24]([C:29]([CH3:30])([CH3:32])[CH3:31])[CH:23]=1)=[O:18])[CH:14]([CH3:16])[CH3:15])=[O:11])[CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CC(C)[C@@H](C(=O)N(C)[C@@H](Cc1ccc(O)c(C(C)(C)C)c1)C(N)=O)N(C)C(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(C)[C@@H](C(=O)N(C)[C@@H](Cc1ccc(O)c(C(C)(C)C)c1)C(N)=O)N(C)C(=O)[C@@H](N)Cc1ccccc1

Procedure:
A mixture of Z-Phe-N-Me-Val-N-Me-Tyr(3-tBu)-NH2 (610 mg) and 10% palladium carbon (100 mg) in methanol (15 ml) was stirred at room temperature in a hydrogen atmosphere for 17 hours. The reaction mixture was filtered and washed with methanol. The solvent was distilled off under reduced pressure and the resulting residue was subjected to silica gel column chromatography (eluting solvent; ethyl acetate) to yield Phe-N-Me-Val-N-Me-Tyr(3-tBu)-NH2 in the amount of 431 mg (89%).
Reaction SMILES: [CH2:1]([N:3]([CH2:6][C:7]1[CH:14]=[CH:13][C:10]([CH:11]=O)=[CH:9][CH:8]=1)[CH2:4][CH3:5])[CH3:2].S([O-])([O-])(=O)=O.[Mg+2].[NH2:21][C:22]1[CH:30]=[CH:29][CH:28]=[C:27]2[C:23]=1[CH2:24][O:25][C:26]2=[O:31]>C(#N)C>[CH2:1]([N:3]([CH2:6][C:7]1[CH:14]=[CH:13][C:10](/[CH:11]=[N:21]/[C:22]2[CH:30]=[CH:29][CH:28]=[C:27]3[C:23]=2[CH2:24][O:25][C:26]3=[O:31])=[CH:9][CH:8]=1)[CH2:4][CH3:5])[CH3:2]
Reactant: Nc1cccc2c1COC2=O
Reactant: CCN(CC)Cc1ccc(C=O)cc1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CC#N
Product: CCN(CC)Cc1ccc(/C=N/c2cccc3c2COC3=O)cc1
Yield: 33.6 %

Procedure:
To a stirred mixture of 4-((diethylamino)methyl)benzaldehyde (3.7 g, 19.4 mmol) and anhydrous magnesium sulfate (11.6 g, 96.8 mmol) in anhydrous acetonitrile (100 mL) was added 4-aminoisobenzofuran-1(3H)-one (2.89 g, 19.4 mmol) at 0° C. After the addition the mixture was stirred refluxed for 3 days. The mixture was filtered and the cake was washed with ethyl acetate (50 mL×3). The filtrate was concentrated to give crude product, which was re-crystallized from isopropanol to give the title compound (2.1 g, yield: 32%). LC-MS (ESI) m/z: 323 (M+1)+.
Reaction SMILES: C(O)(=O)C.CC1(C)CO[CH:9]([CH:12]([C@@H:14]2[C@:31]3([CH3:32])[C@H:17]([C:18]4[C@H:28]([CH2:29][CH2:30]3)[C@:26]3([CH3:27])[C:21]([CH2:22][C@@H:23]([O:37][Si:38]([C:41]([CH3:44])([CH3:43])[CH3:42])([CH3:40])[CH3:39])[CH2:24][C@@H:25]3[O:33][CH2:34][O:35][CH3:36])=[CH:20][CH:19]=4)[CH2:16][CH2:15]2)[CH3:13])[O:8]C1>O1CCCC1>[Si:38]([O:37][C@H:23]1[CH2:24][C@H:25]([O:33][CH2:34][O:35][CH3:36])[C@@:26]2([CH3:27])[C:21](=[CH:20][CH:19]=[C:18]3[C@@H:28]2[CH2:29][CH2:30][C@@:31]2([CH3:32])[C@H:17]3[CH2:16][CH2:15][C@@H:14]2[CH:12]([CH:9]=[O:8])[CH3:13])[CH2:22]1)([C:41]([CH3:44])([CH3:43])[CH3:42])([CH3:39])[CH3:40]
Reactant: COCO[C@H]1C[C@H](O[Si](C)(C)C(C)(C)C)CC2=CC=C3[C@@H]4CC[C@H](C(C)C5OCC(C)(C)CO5)[C@@]4(C)CC[C@@H]3[C@]21C
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COCO[C@H]1C[C@H](O[Si](C)(C)C(C)(C)C)CC2=CC=C3[C@@H]4CC[C@H](C(C)C=O)[C@@]4(C)CC[C@@H]3[C@]21C

Procedure:
In 5 ml of tetrahydrofuran was dissolved 20-(5,5-dimethyl-1,3-dioxan-2-yl)-3β-(tert-butyldimethylsilyl)oxy-1α-(methoxymethyl)oxypregna-5,7-diene, followed by addition of 5 ml of 80% acetic acid. The mixture was refluxed in an atmosphere of argon gas for 12 hours. The reaction mixture was then worked up in the same manner as Example 156 to give 50 mg of 3β-(tert-butyldimethylsilyl)oxy-1α-(methoxymethyl)oxypregna-5,7-diene-20-carbaldehyde showing the following physical properties.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1F)[CH:5]=[O:6].[OH:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]([NH2:18])=[O:17])=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+].CC(N(C)C)=O>O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[O:6])[CH:7]=[CH:8][C:9]=1[O:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]([NH2:18])=[O:17])=[CH:14][CH:13]=1
Reactant: NC(=O)c1ccc(O)cc1
Reactant: O=Cc1ccc(F)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: NC(=O)c1ccc(Oc2ccc(C=O)cc2Cl)cc1
Yield: 93.7 %

Procedure:
Mix 3-chloro-4-fluorobenzaldehyde (3.28 g, 20.7 mmol), 4-hydroxybenzamide (3.12 g, 22.7 mmol), potassium carbonate (4.29 g, 31.0 mmol) and dimethylacetamide (80 mL) in a flask. Heat the reaction to 100° C. for 3 hours. Let cool to ambient (room) temperature and pour into water (200 mL). After trituration, filter the solid formed and dry on a vacuum pump to obtain the product (5.35 g, 94%). 1H NMR (DMSO-d6) 9.94 (s, 1H), 8.13 (d, J=1.7 Hz, 1H), 7.98 (bs, 1H), 7.94 (d, J=8.5 Hz, 2H), 7.88 (dd, J=1.7 Hz, 8.5 Hz, 1H), 7.36 (bs, 1H), 7.21 (d, J=8.5 Hz, 1H), 7.14 (d, J=8.5 Hz, 2H).