Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[CH:3][C:2]=1[C:11]1[CH:12]=[C:13]([NH2:17])[CH:14]=[CH:15][CH:16]=1.CCN(C(C)C)C(C)C.[Cl:27]CCC(Cl)=O.[CH2:33]1[CH2:37][O:36][CH2:35][CH2:34]1>C(OCC)(=O)C>[Cl:27][CH2:35][CH2:34][CH2:33][C:37]([NH:17][C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([C:2]2[CH:3]=[N:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:1]=2)[CH:12]=1)=[O:36]
Reactant: Nc1cccc(-c2cnc3ccccc3n2)c1
Reactant: O=C(Cl)CCCl
Reactant: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: O=C(CCCCl)Nc1cccc(-c2cnc3ccccc3n2)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 26 %

Procedure:
To a solution of (3-quinoxalin-2-ylphenyl)amine (128 mg, 0.578 mmol) and DIEA (115 μL, 0.694 mmol) in THF (5 mL), 3-chloropropionyl chloride (61 μL, 0.636 mmol) was added and the mixture was stirred at room temperature for 48 hrs. The reaction mixture was diluted with ethyl acetate (20 mL), the organic phase was washed with water (10 mL) and then brine (10 mL), dried over MgSO4, and the solvent evaporated in vacuo to afford a light yellow solid. The light yellow solid was triturated with diethyl ether, dried and submitted to preparative LCMS for further purification, to afford 4-chloro-N-[3-(quinoxalin-2-yl)phenyl]butanamide (50 mg, 26% yield). LCMS calculated for C18H16ClN3O (M+H): 326.79. found 326.00. 1H-NMR (DMSO-d6, 400 Mhz) δH: 10.20 (1H, br. S), 9.50 (1H, s), 8.55 (1H, m), 8.20-8.15 (2H, m), 8.04 (1H, m), 7.95-7.85 (m, 3H), 7.54 (1H, m), 3.62 (2H, t, 0.1=7 Hz), 2.60 (2H, m), 2.1 (2H, m).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]=1[CH:13]([O:17]C(=O)C)[C:14](=[O:16])[CH3:15].[CH3:21][O:22][C:23]1[CH:32]=[CH:31][C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:24]=1[C:33](=[O:40])[CH:34]([O:36]C(=O)C)[CH3:35]>>[OH:16][CH:14]([CH3:15])[C:13]([C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:11]=[CH:12][C:3]=1[O:2][CH3:1])=[O:17].[OH:40][CH:33]([C:24]1[C:25]2[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:31]=[CH:32][C:23]=1[O:22][CH3:21])[C:34](=[O:36])[CH3:35]
Reactant: COc1ccc2ccccc2c1C(=O)C(C)OC(C)=O
Reactant: COc1ccc2ccccc2c1C(OC(C)=O)C(C)=O
Product: COc1ccc2ccccc2c1C(=O)C(C)O
Product: COc1ccc2ccccc2c1C(O)C(C)=O
Yield: 59 %

Procedure:
2-hydroxy-1-(2-methoxy-naphthalen-1-yl)-propan-1-one and 1-hydroxy-1-(2-methoxy-naphthalen-1-yl)-propan-2-one (4.5:1 mixture) (580 mg, 59%) were prepared from acetic acid 1-(2-methoxy-naphthalen-1-yl)-2-oxo-propyl ester and acetic acid 2-(2-methoxy-naphthalen-1-yl)-1-methyl-2-oxo-ethyl ester (3:1 mixture) according to the method in Example 16A(c) as an orange solid, 1H NMR (CDCl3): 1.3 (3H, d, J=7.2 Hz), 2.0 (3H, s), 3.75 (1H, d, J=5.0 Hz), 3.9 (3H, s), 3.95 (3H, s), 4.2 (1H, d, J=3.5 Hz), 5.0 (1H, m), 5.9 (1H, d, J=3.5 Hz), 7.25-7.30 (2H, m), 7.35-7.40 (2H, m), 7.45-7.50 (2H, m), 7.6 (1H, d, J=7.7 Hz), 7.75 (2H, m), 7.85 (1H, d, J=9.0 Hz), 7.90-7.95 (2H, m).
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C:15]3([C:22]#[C:23][C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([NH:30]C(=O)C(F)(F)F)[CH:25]=4)[CH2:20][CH2:19][CH2:18][C:17](=[O:21])[CH2:16]3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+]>CO.O>[NH2:30][C:26]1[CH:25]=[C:24]([C:23]#[C:22][C:15]2([C:9]3[CH:10]=[CH:11][C:12]([O:13][CH3:14])=[C:7]([O:6][CH:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)[CH:8]=3)[CH2:20][CH2:19][CH2:18][C:17](=[O:21])[CH2:16]2)[CH:29]=[CH:28][CH:27]=1
Reactant: COc1ccc(C2(C#Cc3cccc(NC(=O)C(F)(F)F)c3)CCCC(=O)C2)cc1OC1CCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: COc1ccc(C2(C#Cc3cccc(N)c3)CCCC(=O)C2)cc1OC1CCCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 77.9 %

Procedure:
To a solution of 3-(3-cyclopentyloxy-4- methoxyphenyl)-3-(3-trifluoroacetamidophenylethynyl)cyclohexan-1-one (0.62 g, 1.24 mmol) in 95:5 methanol/water (10 mL) under an argon atmosphere was added potassium carbonate (0.86 g, 6.2 mmol). The mixture was refluxed for 6 h and was stirred for 18 h at room temperature. The solid precipitate was collected and purified by trituration from ethyl acetate/hexanes to provide the title compound as a white solid (0.39 g, 77%), m.p. 100°-102° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([CH3:23])[C:17]=1[CH3:24].C(N(CC)CC)C.[C:32](Cl)(Cl)=[S:33].[CH3:36][N:37]([CH3:41])[CH2:38][CH2:39][NH2:40]>CN(C)C=O.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:32]([NH:40][CH2:39][CH2:38][N:37]([CH3:41])[CH3:36])=[S:33])=[C:18]([CH3:23])[C:17]=1[CH3:24]
Reactant: S=C(Cl)Cl
Reactant: COc1cc2nccc(Oc3ccc(N)c(C)c3C)c2cc1OC
Reactant: CN(C)CCN
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc2nccc(Oc3ccc(NC(=S)NCCN(C)C)c(C)c3C)c2cc1OC
Temperature: 25 °C
Reaction time: 7 h
Yield: 16.8 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,3-dimethylaniline (51 mg) was dissolved in N,N-dimethylformamide (2 ml) and triethylamine (1 ml) to prepare a solution. Thiophosgene (51 mg) was then added to the solution, and the mixture was stirred at room temperature for 7 hr. Next, N,N-dimethylethylenediamine (50 mg) was added thereto, and the mixture was further stirred at room temperature for 13 hr. Ethyl acetate was added to the reaction solution, followed by washing with water and saturated brine in that order. The organic layer was then dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by HPLC using chloroform/methanol for development to give the title compound (12 mg, yield 17%).
Reaction SMILES: [BH4-].[Na+].[F:3][C:4]1[C:15]([F:16])=[C:14]([F:17])[CH:13]=[CH:12][C:5]=1[NH:6][C@@H:7]([CH3:11])[C:8]([O-])=[O:9].CO.O>C(Cl)Cl>[F:3][C:4]1[C:15]([F:16])=[C:14]([F:17])[CH:13]=[CH:12][C:5]=1[NH:6][C@@H:7]([CH3:11])[CH2:8][OH:9]
Reactant: C[C@H](Nc1ccc(F)c(F)c1F)C(=O)[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CO
Product: C[C@@H](CO)Nc1ccc(F)c(F)c1F
Reaction time: 1 h

Procedure:
At room temperature, sodium borohydride (35.7 mg) was suspended in methylene chloride (0.2 ml). Then a solution (0.8 ml) of methyl. (2S)-2-(2,3,4-trifluoroanilino)propionate (200 mg, 99.8% ee) in metylene chloride was added to the solution. After adding methanol (137.4 mg), the liquid reaction mixture was stirred for 1 hour. Then water was added to the liquid reaction mixture followed by extraction with ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of ammonium chloride and dried over anhydrous magnesium sulfate. After evaporating the solvent, the obtained residue was subjected to silica gel column chromatography to thereby give 159.8 mg (99.8% ee) of the title compound as an oily substance. The 1H-NMR and IR spectral data of this product was identical with those of the compound obtained in Example 51.
Reaction SMILES: [CH2:1]([NH:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[CH2:2][CH2:3][CH2:4][CH3:5].[C:12](=[S:14])=[S:13]>>[CH2:7]([N:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[C:12](=[S:13])[S-:14])[CH2:8][CH2:9][CH2:10][CH3:11].[CH2:7]([NH2+:6][CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: S=C=S
Reactant: CCCCCNCCCCC
Product: CCCCCN(CCCCC)C(=S)[S-]
Product: CCCCC[NH2+]CCCCC
Temperature: 40 °C

Procedure:
Diamyl amine (75.13 grams, 0.478 moles) was charged into a 3-neck, round-bottom flask fitted with agitator, condenser, and thermometer. The reactor was placed in cold-water bath, and the CS2 (46.30 grams, 0.608 moles) was added drop-wise through addition funnel while maintaining the reaction temperature under 40° C. The reaction was then placed aspirator vacuum to remove excess CS2.
Reaction SMILES: [CH3:1][C:2]([CH3:4])=[O:3].O[CH2:6][C:7]([C@H:9]([C@@H:11]([C@H:13]([CH2:15][OH:16])[OH:14])[OH:12])[OH:10])=[O:8].I.N1C=C[CH:21]=[CH:20][CH:19]=1>>[CH3:1][C:2]1([CH3:4])[O:10][C@H:9]2[C@@H:11]3[O:12][C:20]([CH3:21])([CH3:19])[O:14][C@:13]3([CH2:15][OH:16])[O:8][C@H:7]2[CH2:6][O:3]1
Reactant: CC(C)=O
Reactant: O=C(CO)[C@@H](O)[C@H](O)[C@@H](O)CO
Reactant: c1ccncc1
Agent: I
Product: CC1(C)OC[C@@H]2O[C@@]3(CO)OC(C)(C)O[C@H]3[C@@H]2O1
Temperature: 60 °C
Reaction time: 6 h
Yield: 84 %

Procedure:
To 200 ml of acetone were added 10.0 g of L-sorbose and 223 mg of hydriodic acid (57%) and the mixture was refluxed with stirring in a water bath at 60° C. for 6 hours. During this reaction, the refluxing solvent was dried with 20 g of Molecular Sieves 3A interposed between the reaction vessel and the cooling jacket. After completion of the reaction, a small amount of pyridine was added. The acetone was then distilled off under reduced pressure and the residue was dissolved in benzene. The benzene solution was washed with aqueous sodium bicarbonate and water and dried over anhydrous magnesium sulfate. The benzene was distilled off under reduced pressure to give 12.13 g (84.0%) of 2,3:4,6-di-O-isopropylidene-L-sorbofuranose (purity ≥98%). Melting point: 77°-78° C. (recrystallized from petroleum ether).
Reaction SMILES: [C:1]([CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][CH:5]=1)#N.[H-].[Cl-].[Na+].[OH:16]S(O)(=O)=O>CCCCCC.C1COCC1.C1(C)C=CC=CC=1>[CH:4]1([CH2:3][CH:1]=[O:16])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5]1
Reactant: O=S(=O)(O)O
Reactant: N#CCC1=CCc2ccccc21
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=CCC1C=Cc2ccccc21

Procedure:
3-Cyanomethylindene (3.84 g, 0.025 mol), prepared as described in example 14, was dissolved in a mixture of hexane and THF and stirred under nitrogen at -78°. Dissobutylaluminum hydride (DIBAL) (19.2 ml of a 1.5M solution in toluene; 0.029 mmol) was added and the mixture stirred at ambient temperature 2.5 hours. Saturated sodium chloride solution (220 ml) was added and the mixture stirred another 20 minutes. 5% H2SO4 (90 ml) was added and the solution immediately extracted with ether. The ether layer was dried over sodium sulfate, filtered, and evaporated to dryness in vacuo. The residue was chromatographed on a silica gel column eluted with 8% Et2O in hexane. The product fraction was evaporated to dryness to provide 2-(1H-indene-1-yl)acetaldehyde.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([C:13]([F:16])([F:15])[F:14])=[C:10]([C:17](Cl)=[O:18])[CH:9]=2)=[CH:4][CH:3]=1.[F:20][C:21]1[CH:22]=[C:23]([NH2:31])[CH:24]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:26]=1.C(N(CC)C(C)C)(C)C.Cl.C([O-])(O)=O.[Na+]>ClCCl>[F:20][C:21]1[CH:22]=[C:23]([NH:31][C:17]([C:10]2[CH:9]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[O:12][C:11]=2[C:13]([F:16])([F:15])[F:14])=[O:18])[CH:24]=[C:25]([C:27]([F:29])([F:30])[F:28])[CH:26]=1
Reactant: O=C(Cl)c1cc(-c2ccc(Cl)cc2)oc1C(F)(F)F
Reactant: Nc1cc(F)cc(C(F)(F)F)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(Nc1cc(F)cc(C(F)(F)F)c1)c1cc(-c2ccc(Cl)cc2)oc1C(F)(F)F
Temperature: 25 °C
Reaction time: 24 h
Yield: 26.1 %

Procedure:
5-(4-Chloro-phenyl)-2-trifluoromethyl-furan-3-carbonyl chloride (0.200 g) was added to a solution of 3-fluoro-5-trifluoromethyl-phenylamine (0.105 g) and N,N-diisopropylethylamine (0.102 mL) in dichloromethane (5 mL). After stirring at room temperature for 1 day, the reaction underwent an aqueous acidic (dilute HCl, 2×15 mL) and basic (dilute NaHCO3, 2×15 mL) workup followed by washing with brine (saturated NaCl, 2×15 mL), drying over MgSO4, and concentration. The crude compound was triturated with hexanes/ethyl ether (1:1) to afford the title compound (0.069 g, 24% yield). 1H NMR (CDCl3) δ 7.69 (d, 1H, J=0.02 Hz), 7.68 (s, 1H), 7.67 (d, 2H, J=0.017 Hz), 7.53 (s, 1H), 7.47 (d, 2H, J=0.017 Hz), 7.16 (d, 1H. J=0.02 Hz), 7.02 (s, 1H). ES-MS negative Q1 (m/z) 451.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C:10]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH2:13][CH2:14][OH:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:29][S:30](Cl)(=[O:32])=[O:31]>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C:10]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)([CH2:13][CH2:14][O:15][S:30]([CH3:29])(=[O:32])=[O:31])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(CCO)(c2ccccc2)C1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(CCOS(C)(=O)=O)(c2ccccc2)C1
Reaction time: 16 h

Procedure:
Combine 1-(t-butoxycarbonyl)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine (30 mmol) and triethylamine (8.2 mL, 59.2 mmol) in dichloromethane (150 mL). Cool in an ice-bath. Add methanesulfonyl chloride (2.5 mL, 32.6 mmol). After 16 hours, dilute the reaction mixture with dichloromethane and extract with brine. Dry the organic layer over MgSO4, filter, and evaporate in vacuo to give residue. Chromatograph the residue on silica gel to give 1-(t-butoxycarbonyl)-3-phenyl-3-(2-methanesulfonyloxyethyl)pyrrolidine.
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])(OCC)=O)C.[F:17][C:18]1[CH:26]=[CH:25][C:24]2[C:20](=[CH:21][N:22]([CH3:27])[N:23]=2)[C:19]=1[CH:28]=O.O>O1CCCC1>[F:17][C:18]1[CH:26]=[CH:25][C:24]2[C:20](=[CH:21][N:22]([CH3:27])[N:23]=2)[C:19]=1/[CH:28]=[CH:11]/[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: Cn1cc2c(C=O)c(F)ccc2n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)/C=C/c1c(F)ccc2nn(C)cc12
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 98.3 %

Procedure:
To a suspension of sodium hydride (0.88 g, 21.9 mmol) in tetrahydrofuran (20 mL) was added a solution of ethyl diethylphosphonoacetate (4.38 mL, 21.9 mmol) in tetrahydrofuran (5 mL) at 0° C., and the mixture was stirred for 20 min. To the reaction mixture was added a solution of 5-fluoro-2-methyl-2H-indazole-4-carbaldehyde (3.0 g, 16.8 mmol) in tetrahydrofuran (8.7 mL), and the mixture was warmed to room temperature over 4 hr. Water was added and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by flash silica gel column chromatography (ethyl acetate/hexane=1/3) to give the title compound (4.10 g, yield 98%)
Reaction SMILES: N1C(C)=CC=CC=1C.[CH2:9]([C:11]([C:30]1[CH:35]=[CH:34][C:33]([C:36]#[C:37][C:38]2([OH:44])[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]2)=[C:32]([CH3:45])[CH:31]=1)([C:14]1[CH:19]=[CH:18][C:17]([B:20]2[O:24][C:23]([CH3:26])([CH3:25])[C:22]([CH3:28])([CH3:27])[O:21]2)=[C:16]([CH3:29])[CH:15]=1)[CH2:12][CH3:13])[CH3:10].O([Si:54]([CH3:57])([CH3:56])[CH3:55])S(C(F)(F)F)(=O)=O.C(=O)(O)[O-].[Na+]>ClCCl>[CH2:9]([C:11]([C:14]1[CH:19]=[CH:18][C:17]([B:20]2[O:24][C:23]([CH3:25])([CH3:26])[C:22]([CH3:27])([CH3:28])[O:21]2)=[C:16]([CH3:29])[CH:15]=1)([C:30]1[CH:35]=[CH:34][C:33]([C:36]#[C:37][C:38]2([O:44][Si:54]([CH3:57])([CH3:56])[CH3:55])[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]2)=[C:32]([CH3:45])[CH:31]=1)[CH2:12][CH3:13])[CH3:10]
Reactant: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: CCC(CC)(c1ccc(C#CC2(O)CCCCC2)c(C)c1)c1ccc(B2OC(C)(C)C(C)(C)O2)c(C)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: CCC(CC)(c1ccc(C#CC2(O[Si](C)(C)C)CCCCC2)c(C)c1)c1ccc(B2OC(C)(C)C(C)(C)O2)c(C)c1
Reaction time: 1 h
Yield: 96.3 %

Procedure:
2,6-Lutidine (0.16 g, 1.49 mmol) was added to a solution of 1-(4-{1-ethyl-1-[3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-propyl}-2-methyl-phenylethynyl)-cyclohexanol (Example 35-(3); 0.15 g, 0.29 mmol) in dichloromethane (1.5 mL). Trimethylsilyl triflate (0.13 mL, 0.71 mmol) was added at 0° C., and the mixture was stirred at the same temperature for one hour. A saturated aqueous sodium bicarbonate solution was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (3% ethyl acetate/hexane) to give the title compound (0.16 g, 93%).
Reaction SMILES: CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.Cl.Cl[CH2:33][C@@H:34]([CH3:54])[CH2:35]/[C:36](=[CH:40]\[C:41]1[CH:46]=[CH:45][C:44]([N:47]2[CH:51]=[C:50]([CH3:52])[N:49]=[CH:48]2)=[C:43]([F:53])[CH:42]=1)/[C:37]([OH:39])=O.Cl.[NH2:56][C@H:57]([C:61]1[CH:66]=[C:65]([F:67])[C:64]([F:68])=[C:63]([F:69])[CH:62]=1)[C@H:58]([OH:60])[CH3:59]>CN(C=O)C.C(OCC)(=O)C>[F:53][C:43]1[CH:42]=[C:41](/[CH:40]=[C:36]2/[C:37](=[O:39])[N:56]([C@H:57]([C:61]3[CH:62]=[C:63]([F:69])[C:64]([F:68])=[C:65]([F:67])[CH:66]=3)[C@H:58]([OH:60])[CH3:59])[CH2:33][C@@H:34]([CH3:54])[CH2:35]/2)[CH:46]=[CH:45][C:44]=1[N:47]1[CH:51]=[C:50]([CH3:52])[N:49]=[CH:48]1
Reactant: Cc1cn(-c2ccc(/C=C(\C[C@H](C)CCl)C(=O)O)cc2F)cn1
Reactant: C[C@@H](O)[C@H](N)c1cc(F)c(F)c(F)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cn(-c2ccc(/C=C3\C[C@H](C)CN([C@H](c4cc(F)c(F)c(F)c4)[C@@H](C)O)C3=O)cc2F)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 53.9 %

Procedure:
DIEA (0.47 mL), WSC (257 mg), and HOBT (181 mg) were added to a suspension of (E)-(S)-5-chloro-2-{1-[3-fluoro-4-(4-methyl-1H-imidazol-1-yl)phenyl]methylidene}-4-methylvaleric acid hydrochloride (250 mg) and (1R,2R)-1-amino-1-(3,4,5-trifluorophenyl)propan-2-ol hydrochloride (243 mg) in DMF (5 mL) at room temperature, and the reaction solution was stirred at room temperature for one hour. Ethyl acetate was added to the reaction solution, which was then sequentially washed with saturated sodium bicarbonate water, water, a saturated ammonium chloride solution, and brine. The resulting organic layer was dried over magnesium sulfate and then concentrated under reduced pressure. The residue was dissolved DMF (8 mL). 60% sodium hydride (32 mg) was added at 0° C., and the reaction solution was stirred at 0° C. for one hour. Ethyl acetate was added to the reaction solution, which was then sequentially washed with saturated sodium bicarbonate water, water, a saturated ammonium chloride solution, and brine. The resulting organic layer was dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (carrier: Chromatorex NH; elution solvent: heptane-ethyl acetate system->ethyl acetate-methanol system) to obtain 176 mg of the title compound. The property values of the compound are as follows.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[Br:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[CH:21]([CH3:25])[NH:20][CH2:19][CH2:18]2>>[Br:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[CH:21]([CH3:25])[N:20]([C:11]([C:9]1[CH:10]=[C:5]3[N:4]=[CH:3][C:2]([Br:1])=[CH:7][N:6]3[N:8]=1)=[O:13])[CH2:19][CH2:18]2
Reactant: CC1NCCc2cc(Br)ccc21
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Product: CC1c2ccc(Br)cc2CCN1C(=O)c1cc2ncc(Br)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 6-Bromo-1-methyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([NH:12][C:13]1[C:14]([S:20][CH3:21])=[N:15][C:16]([CH3:19])=[CH:17][CH:18]=1)=[O:11].[SH:22][C:23]1[O:24][C:25]2[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=2[N:27]=1.C1OCCOCCOCCOCCOCCOC1.C(=O)([O-])[O-].[K+].[K+]>O.CN(C=O)C>[O:24]1[C:25]2[CH:31]=[CH:30][CH:29]=[CH:28][C:26]=2[N:27]=[C:23]1[S:22][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([NH:12][C:13]1[C:14]([S:20][CH3:21])=[N:15][C:16]([CH3:19])=[CH:17][CH:18]=1)=[O:11]
Reactant: CSc1nc(C)ccc1NC(=O)CCCCCCCCBr
Reactant: Sc1nc2ccccc2o1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CSc1nc(C)ccc1NC(=O)CCCCCCCCSc1nc2ccccc2o1
Temperature: 80 °C
Reaction time: 3 h
Yield: 79.2 %

Procedure:
To a DMF (1.5 ml) solution of this amide (131 mg, 0.35 mmol) and 2-mercaptobenzoxazole (58 mg, 0.385 mmol) were added 18-crown-6 (,9 mg, 0.035 mmol) and potassium carbonate (58 mg, 0.42 mmol), and the mixture was stirred at 80° C. for 3 hours. The reaction mixture was diluted with water, and then extracted with ethyl acetate. The organic layer was washed with water and then with a saturated aqueous solution of sodium chloride, and dried over sodium sulfate. Subsequently, the solvent was distilled off, and the resulting crude product was purified through silica gel chromatography (silica gel 30 g, eluent—hexane:ethyl acetate=4:1→3:1) to obtain 123 mg (yield 79%) of the desired compound as a colorless needle crystal.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[CH2:9][C:7](=[O:8])[CH2:6][C:4](=[O:5])[CH2:3]1.C1(N=C=NC2CCCCC2)CCCCC1.[Cl:26][C:27]1[C:35]([CH:36]=[N:37][O:38][CH2:39][CH3:40])=[C:34]([S:41]([CH3:44])(=[O:43])=[O:42])[CH:33]=[CH:32][C:28]=1[C:29](O)=[O:30].CC(C)(O)C#N.C(N(CC)CC)C>C(#N)C.O>[Cl:26][C:27]1[C:35]([CH:36]=[N:37][O:38][CH2:39][CH3:40])=[C:34]([S:41]([CH3:44])(=[O:43])=[O:42])[CH:33]=[CH:32][C:28]=1[C:29]([CH:6]1[C:4](=[O:5])[CH2:3][C:2]([CH3:10])([CH3:1])[CH2:9][C:7]1=[O:8])=[O:30]
Reactant: CCON=Cc1c(S(C)(=O)=O)ccc(C(=O)O)c1Cl
Reactant: CC1(C)CC(=O)CC(=O)C1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CC(C)(O)C#N
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: O
Product: CCON=Cc1c(S(C)(=O)=O)ccc(C(=O)C2C(=O)CC(C)(C)CC2=O)c1Cl
Temperature: 25 °C
Reaction time: 12 h

Procedure:
1.26 g (0.009 mol) of dimedone and 1.90 g (0.009 mol) of dicyclohexylcarbodiimide were added to a solution of 2.95 g (0.009 mol) of 2-chloro-3-ethoxyiminomethyl-4-methylsulfonyl-benzoic acid in 130 ml of anhydrous acetonitrile. After stirring for 12 hours at room temperature, 0.42 g (0.005 mol) of acetone cyanohydrin and 3.27 g (0.032 mol) of triethylamine in 10 ml of absolute acetonitrile were added dropwise. The reaction mixture was then stirred for a further 2 hours at room temperature. With stirring, the reaction mixture was poured into 200 ml of water, the precipitate was filtered off with suction and the filtrate was added to 100 ml of 5% strength potassium carbonate solution. The aqueous phase was washed with ethyl acetate, the pH was adjusted to 2 using 10% strength hydrochloric acid and the mixture was extracted with ethyl acetate. The combined organic phases were washed with water until neutral, dried and concentrated under reduced pressure. This gave 2.52 g of crude product which was recrystallized from toluene. (mp.: 156-157° C.)
Reaction SMILES: N(C(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O)[C@H](C(O)=O)CCCNC(=N)N[S:9]([C:12]1[C:25]([CH3:26])=[C:23]([CH3:24])[C:22]2[O:21][C:18]([CH3:20])([CH3:19])[CH2:17][CH2:16][C:15]=2[C:13]=1[CH3:14])(=[O:11])=[O:10].[NH:48]([C:63]([O:65][CH2:66][CH:67]1[C:79]2[C:74](=[CH:75][CH:76]=[CH:77][CH:78]=2)[C:73]2[C:68]1=[CH:69][CH:70]=[CH:71][CH:72]=2)=[O:64])[C@H:49]([C:60]([OH:62])=[O:61])[CH2:50][C:51]1[C:59]2[C:54](=[CH:55][CH:56]=[CH:57][CH:58]=2)[NH:53][CH:52]=1>C(O)(C(F)(F)F)=O>[NH:48]([C:63]([O:65][CH2:66][CH:67]1[C:68]2[C:73](=[CH:72][CH:71]=[CH:70][CH:69]=2)[C:74]2[C:79]1=[CH:78][CH:77]=[CH:76][CH:75]=2)=[O:64])[C@H:49]([C:60]([OH:62])=[O:61])[CH2:50][C:51]1[C:59]2[C:54](=[CH:55][CH:56]=[CH:57][CH:58]=2)[NH:53][C:52]=1[S:9]([C:12]1[C:25]([CH3:26])=[C:23]([CH3:24])[C:22]2[O:21][C:18]([CH3:20])([CH3:19])[CH2:17][CH2:16][C:15]=2[C:13]=1[CH3:14])(=[O:10])=[O:11]
Reactant: O=C(N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O)OCC1c2ccccc2-c2ccccc21
Reactant: Cc1c(C)c(S(=O)(=O)NC(=N)NCCC[C@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)O)c(C)c2c1OC(C)(C)CC2
Solvent: O=C(O)C(F)(F)F
Product: Cc1c(C)c(S(=O)(=O)c2[nH]c3ccccc3c2C[C@H](NC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)O)c(C)c2c1OC(C)(C)CC2
Temperature: 30 °C

Procedure:
Fmoc-Arg(Pmc)-OH (0.5 g, 0.75 mmol) and Fmoc-Trp-OH (0.43 g, 0.1 mmol) was dissolved in 10 ml 100% TFA and heated at 30° C. for 1.5 hours. After evaporation of TFA, Fmoc-Arg-OH was removed by column chromatography on silica gel with heptane/ethyl acetate 2:1 as mobile phase. Fmoc-Trp(2Pmc)-OH was isolated by preparative HPLC (C18, 70-100% B in 15 min., tR 14.8 min, (A: H2O+0.1% TFA; B: CH3CN+0.1% TFA)). Isolated yield 130 mg (0.19 mmol, 25%).