Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](N1C=CN=C1)(=[O:3])[CH3:2].[CH3:9][C:10]([NH:13][CH2:14][CH:15]([OH:26])[CH2:16][O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:24]#[CH:25])([CH3:12])[CH3:11]>C1COCC1>[C:1]([O:26][CH:15]([CH2:16][O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:24]#[CH:25])[CH2:14][NH:13][C:10]([CH3:9])([CH3:11])[CH3:12])(=[O:3])[CH3:2]
Reactant: CC(=O)n1ccnc1
Reactant: C#Cc1ccccc1OCC(O)CNC(C)(C)C
Solvent: C1CCOC1
Product: C#Cc1ccccc1OCC(CNC(C)(C)C)OC(C)=O
Reaction time: 1 h

Procedure:
A 4.8 g (42.8 mmole) sample of 1-acetylimidazole was added to a solution of 5.14 g (20.8 mmole) of 1-[(1,1-dimethylethyl)amino]-3-(2-ethynylphenoxy)-2-propanol in 28 ml THF. The mixture was stirred under N2 for one hour. The mixture was partitioned between water and ether. The ether layer was washed with brine, dried (K2CO3) and the solvent evaporated in vacuo to give the title compound as an oil, 6.14 g.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[N:5][C:6]([N:9]2[CH2:14][CH2:13][CH:12]([C@H:15]3[CH2:17][C@H:16]3[CH2:18][CH2:19][O:20][C:21]3[CH:26]=[CH:25][C:24]([CH2:27][C:28]([O:30]C)=[O:29])=[C:23]([F:32])[CH:22]=3)[CH2:11][CH2:10]2)=[N:7][CH:8]=1)[CH3:2].CO.[OH-].[Li+].Cl>O1CCCC1.O>[CH2:1]([C:3]1[CH:4]=[N:5][C:6]([N:9]2[CH2:14][CH2:13][CH:12]([C@H:15]3[CH2:17][C@H:16]3[CH2:18][CH2:19][O:20][C:21]3[CH:26]=[CH:25][C:24]([CH2:27][C:28]([OH:30])=[O:29])=[C:23]([F:32])[CH:22]=3)[CH2:11][CH2:10]2)=[N:7][CH:8]=1)[CH3:2]
Reactant: CCc1cnc(N2CCC([C@H]3C[C@H]3CCOc3ccc(CC(=O)OC)c(F)c3)CC2)nc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CCc1cnc(N2CCC([C@H]3C[C@H]3CCOc3ccc(CC(=O)O)c(F)c3)CC2)nc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl [4-(2-{(1S,2R)-2-[1-(5-ethylpyrimidin-2-yl)piperidin-4-yl]cyclopropyl}ethoxy)-2-fluorophenyl]acetate (0.300 g, 0,679 mmol) in 6 ml anhydrous tetrahydrofuran was added by 2 ml methanol and 2 ml water. Lithium hydroxide (81.0 mg, 3.40 mmol) was added, and the mixture stirred at RT overnight. 1 M hydrochloric acid was added and the pH adjusted to 4. The volatiles were removed under reduced pressure, and the aqueous phase extracted with dichloromethane (3×20 ml). The organics were combined, dried over magnesium sulphate, filtered, and the filtrate concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (50 g silica gel) using a gradient eluent of 0-70% ethyl acetate in hexanes (700 ml) to afford the title compound. LC/MS (m/z) 428.2 (M+H)+.
Reaction SMILES: [Br-].[F:2][C:3]1([F:34])[C:7]([F:9])([F:8])[C:6]2[CH:10]=[CH:11][CH:12]=[C:13]([CH2:14][P+](C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[C:5]=2[O:4]1.C([Li])CCC.[CH2:40]1[O:50][C:43]2([CH2:48][CH2:47][C:46](=O)[CH2:45][CH2:44]2)[O:42][CH2:41]1>O1CCCC1>[F:34][C:3]1([F:2])[C:7]([F:8])([F:9])[C:6]2[CH:10]=[CH:11][CH:12]=[C:13]([CH:14]=[C:46]3[CH2:47][CH2:48][C:43]4([O:50][CH2:40][CH2:41][O:42]4)[CH2:44][CH2:45]3)[C:5]=2[O:4]1
Reactant: FC1(F)Oc2c(C[P+](c3ccccc3)(c3ccccc3)c3ccccc3)cccc2C1(F)F
Reactant: O=C1CCC2(CC1)OCCO2
Agent: [Br-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: FC1(F)Oc2c(C=C3CCC4(CC3)OCCO4)cccc2C1(F)F

Procedure:
This compound is prepared in a manner analogous to that of Step B of Example 2, using 20.1 grams (0.039 mole) of (2,2,3,3-tetrafluoro-2,3-dihydrobenzofuran-7-ylmethyl)triphenylphosphonium bromide, 15.4 mL (0.039 mole) of n-butyllithium (2.5M in hexanes), and 5.0 grams (0.032 mole) of 1,4-cyclohexanedione mono-ethylene ketal in about 55 mL of dry tetrahydrofuran, yielding 8-(2,2,3,3-tetrafluoro-2,3-dihydrobenzofuran-7-ylmethylene)-1,4-dioxaspiro[4.5]decane.
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)[CH:10]=2)[CH2:3]1.C(N(CC)CC)C.[CH3:27][S:28](Cl)(=[O:30])=[O:29].C(=O)([O-])O.[Na+]>ClCCl>[CH3:27][S:28]([O:1][C@H:2]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N:15]3[CH2:16][CH2:17][CH2:18][CH2:19]3)[CH:10]=2)[CH2:3]1)(=[O:30])=[O:29]
Reactant: CS(=O)(=O)Cl
Reactant: O[C@H]1CCN(CCc2cccc(N3CCCC3)c2)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)O[C@H]1CCN(CCc2cccc(N3CCCC3)c2)C1
Reaction time: 8 h

Procedure:
(S)-3-Hydroxy-1-(3-pyrrolidinophenethyl)pyrrolidine (1.04 g, 4.00 mmol) was dissolved in dichloromethane (10 ml). Triethylamine (0.76 ml, 5.49 mmol) and methanesulfonyl chloride (0.39 ml, 5.03 mmol) were added to the obtained solution at 0° C. and they were stirred overnight. The reaction mixture was distributed into 5% aqueous sodium hydrogencarbonate solution and dichloromethane. The organic layer was dried and the solvent was evaporated under reduced pressure. The residue was subjected to the silica gel column chromatography. After the elution with chloroform and methanol (95:5), suitable fractions were collected and the solvent was evaporated under reduced pressure to obtain (S)-3-methanesulfonyloxy-1-(3-pyrrolidinophenethyl)pyrrolidine in the form of a light yellow oily substance (1.30 g, 96%).
Reaction SMILES: [F:1][C:2]1[C:24]([CH3:25])=[CH:23][C:5]2[N:6]([CH:10]3[CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12][CH2:11]3)[C:7](=[O:9])[NH:8][C:4]=2[CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[F:1][C:2]1[C:24]([CH3:25])=[CH:23][C:5]2[N:6]([CH:10]3[CH2:11][CH2:12][NH:13][CH2:14][CH2:15]3)[C:7](=[O:9])[NH:8][C:4]=2[CH:3]=1
Reactant: Cc1cc2c(cc1F)[nH]c(=O)n2C1CCN(C(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc2c(cc1F)[nH]c(=O)n2C1CCNCC1
Reaction time: 1 h
Yield: 94.1 %

Procedure:
1,1-Dimethylethyl 4-(5-fluoro-6-methyl-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)-1-piperidine-carboxylate (D29) (0.68 mmol, 239 mg) in dichloromethane (5 mL) was treated under argon at room temperature with trifluoroacetic acid (1 mL) and allowed to stir for 1 h. The mixture was concentrated, treated with 10% Na2CO3 aqueous solution, extracted 3 times with ethyl acetate. Organics were combined, dried on MgSO4, and concentrated under vacuum to give the title compound (0.64 mmol, 160 mg, 94% yield). M+H=250.2.
Reaction SMILES: CS([O:5][C:6]1[CH:11]=[C:10]([CH2:12][CH2:13][CH3:14])[CH:9]=[CH:8][C:7]=1[O:15][C:16]1[CH:17]=[N:18][C:19]([NH:22][S:23]([CH3:26])(=[O:25])=[O:24])=[CH:20][CH:21]=1)(=O)=O.[OH-].[K+]>O>[OH:5][C:6]1[CH:11]=[C:10]([CH2:12][CH2:13][CH3:14])[CH:9]=[CH:8][C:7]=1[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][S:23]([CH3:26])(=[O:24])=[O:25])=[N:18][CH:17]=1
Reactant: CCCc1ccc(Oc2ccc(NS(C)(=O)=O)nc2)c(OS(C)(=O)=O)c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CCCc1ccc(Oc2ccc(NS(C)(=O)=O)nc2)c(O)c1
Yield: 100 %

Procedure:
To a solution of 2-({6-[(methylsulfonyl)amino]pyridin-3-yl}oxy)-5-propylphenyl methanesulfonate (0.09 mmol; 30 mg), under argon, in water (0.5 mL), was added KOH (0.26 mmol; 15 mg). The reaction mixture was refluxed for 4 hr. After quenching with NH4Cl (1 mL), extraction with ethyl acetate (3*3 mL), combined organic phases were washed with water (3 mL), dried over MgSO4, concentrated in vacuo, to yield the title compound as a white solid (37 mg; 0.09 mmol; 77%).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([OH:12])=[CH:6][C:3]=1[CH:4]=[O:5].[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:13]([O:12][C:7]1[C:8]([O:10][CH3:11])=[CH:9][C:2]([Br:1])=[C:3]([CH:6]=1)[CH:4]=[O:5])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: BrCc1ccccc1
Reactant: COc1cc(Br)c(C=O)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(Br)c(C=O)cc1OCc1ccccc1

Procedure:
B2 is benzylated with benzyl bromide and potassium carbonate in DMF to obtain 5-benzyloxy-2-bromo-4-methoxybenzaldehyde (B3).
Reaction SMILES: [S:1]1[C:13]2[C:12]3[C:11](=[O:14])[NH:10][CH2:9][CH2:8][C:7]=3[CH:6]=[CH:5][C:4]=2[N:3]=[CH:2]1.I[C:16]1[CH:17]=[N:18][CH:19]=[CH:20][C:21]=1[CH3:22].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.[Cu](I)I>[CH3:22][C:21]1[CH:20]=[CH:19][N:18]=[CH:17][C:16]=1[N:10]1[CH2:9][CH2:8][C:7]2[CH:6]=[CH:5][C:4]3[N:3]=[CH:2][S:1][C:13]=3[C:12]=2[C:11]1=[O:14]
Reactant: Cc1ccncc1I
Reactant: O=C1NCCc2ccc3ncsc3c21
Agent: I[Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: Cc1ccncc1N1CCc2ccc3ncsc3c2C1=O
Yield: 20.3 %

Procedure:
7,8-Dihydrothiazolo[4,5-h]isoquinolin-9(6H)-one (I-66c: 0.13 g, 0.0006 mol) was reacted with 3-iodo-4-methylpyridine (0.15 g, 0.0007 mol), copper iodide (0.036 g, 0.00019 mol), trans-N,N′-dimethyl-cyclohexyl-1,2-diamine (0.027 g, 0.00019 mol) and potassium phosphate (0.45 g, 0.0015 mol) in 1,4-dioxane (10 mL) to afford the crude product. Purification by column chromatography on silica gel (2% methanol in DCM) afforded 36 mg of the product (20.2% yield).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][C:11](O)=[O:12])=[CH:9][C:4]=2[O:3][CH2:2]1.CO>O1CCCC1>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][CH2:11][OH:12])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: O=C(O)Cc1ccc2c(c1)OCO2
Solvent: C1CCOC1
Solvent: CO
Product: OCCc1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 84.4 %

Procedure:
A solution of benzo[1,3]dioxol-5-yl-acetic acid (2.5 g, 13.9 mmol) in tetrahydrofuran (15 ml) under argon at −10° C. was treated dropwise with borane-dimethylsulfide complex (1.45 ml, 15.3 mmol). The mixture was stirred at ambient temperature for 1.5 hours (CAUTION—exothermic reaction). The orange solution was cooled to ˜5° C. (ice bath) and methanol (1.4 ml) was added. After 0.5 hour at room temperature, the mixture was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution. The organic extract was dried and evaporated to give a yellow oil (1.95 g, 84%).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([NH:13][C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([C:20]#[CH:21])[CH:15]=3)=[N:8][CH:9]=[N:10]2)=[CH:5][C:4]=1[N+:22]([O-])=O.S(S([O-])=O)([O-])=O.[Na+].[Na+].CO>C(O)=O>[ClH:2].[NH2:22][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][C:3]=1[Cl:2])[N:10]=[CH:9][N:8]=[C:7]2[NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]#[CH:21])[CH:15]=1
Reactant: C#Cc1cccc(Nc2ncnc3cc(Cl)c([N+](=O)[O-])cc23)c1
Agent: Cl
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CO
Solvent: O=CO
Product: C#Cc1cccc(Nc2ncnc3cc(Cl)c(N)cc23)c1
Reaction time: 16 h

Procedure:
(7-Chloro-6-nitro-quinazolin-4-yl)-(3-ethynyl-phenyl)-amine hydrochloride (166 mg, 0.295 mmol) and sodium dithionite (207 mg, 1.19 mmol) were stirred in 1.5 mL of formic acid for 4 hours at room temperature. 45 mL of methanol were added to the reaction mixture which was set aside for 16 hours at room temperature. The precipitate thus obtained was filtered, triturated with 3% sodium bicarbonate for 0.5 hours and refiltered. The solid was dissolved in 20 mL of 1N HCl in methanol and precipitated with 200 mL of ethyl ether. This was filtered and dried in vacuo at 70° C. to afford the title product, 72 mg (83%); mp 260°-265° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[CH3:9][NH:10][CH3:11]>>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([N:10]([CH3:11])[CH3:9])=[N:3][CH:4]=1
Reactant: Brc1ccc(Br)nc1
Reactant: CNC
Product: CN(C)c1ccc(Br)cn1

Procedure:
A solution of 2,5-dibromopyridine (10 g, 42.3 mmol) in aqueous dimethylamine (50 mL) was refluxed overnight. The volatiles were removed in vacuo, and the residue was treated with EtOAc/PE. The precipitates were collected by filtration and dried to give the title compound. MS (m/z): 201 (M+H)+, 203 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:46]=[CH:45][CH:44]=[CH:43][C:3]=1[C:4]([C:6]1[CH:10]=[C:9]([CH2:11][CH3:12])[S:8][C:7]=1[N:13]1[C:17]([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)=[N:16][N:15]=[C:14]1[CH2:24][NH:25][C:26]([C:28]1[N:29]([CH2:37][C:38]([O:40]CC)=[O:39])[C:30]2[C:35]([CH:36]=1)=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:27])=[O:5].[OH-].[Na+]>C(O)C>[Cl:1][C:2]1[CH:46]=[CH:45][CH:44]=[CH:43][C:3]=1[C:4]([C:6]1[CH:10]=[C:9]([CH2:11][CH3:12])[S:8][C:7]=1[N:13]1[C:17]([CH:18]2[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]2)=[N:16][N:15]=[C:14]1[CH2:24][NH:25][C:26]([C:28]1[N:29]([CH2:37][C:38]([OH:40])=[O:39])[C:30]2[C:35]([CH:36]=1)=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:27])=[O:5]
Reactant: CCOC(=O)Cn1c(C(=O)NCc2nnc(C3CCCCC3)n2-c2sc(CC)cc2C(=O)c2ccccc2Cl)cc2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCc1cc(C(=O)c2ccccc2Cl)c(-n2c(CNC(=O)c3cc4ccccc4n3CC(=O)O)nnc2C2CCCCC2)s1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 47 %

Procedure:
Ethyl 2-(4-(3-(2-chlorobenzoyl)-5-ethylthiophen-2-yl)-5-cyclohexyl[1,2,4]triazol-3-ylmethylcarbamoyl)indole-1-acetate (0.8 g) and a solution of sodium hydroxide (0.08 g) in ethanol was added to ethanol (10 ml), and the mixture was stirred at 50° C. for 30 minutes. The solvent was evaporated, and the residue was dissolved in water. Toluene was added to the solution for washing. The aqueous layer was taken out, and 2M hydrochloric acid was added to adjust the solution to pH 2. The solution was extracted with chloroform and the extract was dried over magnesium sulfate. The solvent was evaporated, and the residue was recrystallized from ethyl acetate-hexane to give 0.36 g of 2-(4-(3-(2-chlorobenzoyl)-5-ethylthiophen-2-yl)-5-cyclohexyl[1,2,4]triazol-3-ylmethylcarbamoyl)indole-1-acetic acid.
Reaction SMILES: [F:1][C:2]([F:44])([F:43])[O:3][C:4]1[CH:5]=[C:6]([C@@H:10]([NH:12][C:13]([C:15]2[C:23]3[C:18](=[N:19][CH:20]=[C:21]([C:24]4[C:32]5[C:27](=[CH:28][C:29]([F:33])=[CH:30][CH:31]=5)[N:26]([CH3:34])[N:25]=4)[N:22]=3)[N:17](COCC[Si](C)(C)C)[CH:16]=2)=[O:14])[CH3:11])[CH:7]=[CH:8][CH:9]=1.FC(F)(F)C(O)=O.C(N)CN>ClCCl>[F:44][C:2]([F:1])([F:43])[O:3][C:4]1[CH:5]=[C:6]([C@@H:10]([NH:12][C:13]([C:15]2[C:23]3[C:18](=[N:19][CH:20]=[C:21]([C:24]4[C:32]5[C:27](=[CH:28][C:29]([F:33])=[CH:30][CH:31]=5)[N:26]([CH3:34])[N:25]=4)[N:22]=3)[NH:17][CH:16]=2)=[O:14])[CH3:11])[CH:7]=[CH:8][CH:9]=1
Reactant: C[C@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(F)ccc34)nc12)c1cccc(OC(F)(F)F)c1
Solvent: O=C(O)C(F)(F)F
Solvent: NCCN
Solvent: ClCCl
Product: C[C@H](NC(=O)c1c[nH]c2ncc(-c3nn(C)c4cc(F)ccc34)nc12)c1cccc(OC(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 57.3 %

Procedure:
In a 10 ml round-bottomed flask, 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(S)-1-(3-trifluoromethoxy-phenyl)-ethyl]-amide (123 mg, 0.196 mmol) was dissolved in dichloromethane (1 ml) and trifluoroacetic acid (0.6 ml, 7.9 mmol) was added. The light yellow reaction was stirred at room temperature for 2 h then concentrated. The residue was dissolved in dichloromethane (1 ml) and ethylenediamine (0.80 ml, 11.8 mmol) was added. The yellow reaction mixture was stirred at room temperature for 1 h then quenched with water and diluted with ethyl acetate. The resulting suspension was filtered and washed with hot water and ethyl acetate and the solid collected was dried under high vacuum to provide 56 mg (57%) of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(S)-1-(3-trifluoromethoxy-phenyl)-ethyl]-amide as a light yellow powder. MS: (M+Na)+=521; 1H NMR (DMSO-d6, 400 MHz): δ (ppm) 12.85 (br. s., 1H), 9.11 (s, 1H), 8.53 (d, J=7.8 Hz, 1H), 8.45 (s, 1H), 8.36 (dd, J=9.2, 5.2 Hz, 1H), 7.67 (dd, J=9.7, 1.9 Hz, 1H), 7.39-7.54 (m, 3H), 7.24 (d, J=7.1 Hz, 1H), 6.98 (td, J=9.0, 2.1 Hz, 1H), 5.27-5.43 (m, 1H), 4.14 (s, 3H), 1.65 (d, J=7.1 Hz, 3H).
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([Cl:21])=[CH:5][C:6]([F:20])=[C:7]([C:9]2[C:13]([Cl:14])=[C:12]([C:15]([F:18])([F:17])[F:16])[N:11]([CH3:19])[N:10]=2)[CH:8]=1.C([O-])(=[O:24])C.[Na+].O>CN(C=O)C>[Cl:21][C:4]1[CH:5]=[C:6]([F:20])[C:7]([C:9]2[C:13]([Cl:14])=[C:12]([C:15]([F:18])([F:17])[F:16])[N:11]([CH3:19])[N:10]=2)=[CH:8][C:3]=1[CH2:2][OH:24]
Reactant: Cn1nc(-c2cc(CBr)c(Cl)cc2F)c(Cl)c1C(F)(F)F
Reactant: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1nc(-c2cc(CO)c(Cl)cc2F)c(Cl)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 12 h
Yield: 99.9 %

Procedure:
To a solution of 7.1 g (0.0175 mole) 3-[5-(bromomethyl)-4-chloro-2-fluorophenyl]-4-chloro-1-methyl-5-(trifluoromethyl)-1H-pyrazole in 20 mL DMF was added 1.5 g (0.018 mole) sodium acetate. The mixture was stirred for 12 hours at 25° C. The mixture was poured into 100 mL cold water and the solid filtered and dried. The product was recrystallized from ethanol/-water to give 6.0 g (90%) of 2-chloro-5-(4-chloro-1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl)-4-fluorobenzenemethanol, acetate (ester), mp 90° C. The acetate was dissolved in 10 mL 1,4-dioxane and 10 mL water and 6.3 mL (0.0158 mole) 10% NaOH solution was added. After 30 minutes the solution was neutralized with concentrated HCl, filtered and the solid dried. The solid was recrystallized from ethanol/water to give 5.4 g (99%) of 2-chloro-5-[4-chloro-1-methyl-5-(trifluoromethyl)-1H-pyrazol-3-yl]-4-fluorobenzenemethanol as a white solid; mp 103° C.
Reaction SMILES: I[CH2:2][CH3:3].[C:4]([O:8][C:9]([NH:11][CH2:12][C@H:13]([NH:18]CC)[C:14]([O:16][CH3:17])=[O:15])=[O:10])([CH3:7])([CH3:6])[CH3:5]>>[C:4]([O:8][C:9]([NH:11][CH2:12][C@@:13]([NH2:18])([CH2:2][CH3:3])[C:14]([O:16][CH3:17])=[O:15])=[O:10])([CH3:7])([CH3:6])[CH3:5]
Reactant: CCN[C@@H](CNC(=O)OC(C)(C)C)C(=O)OC
Reactant: CCI
Product: CC[C@](N)(CNC(=O)OC(C)(C)C)C(=O)OC

Procedure:
In a manner similar to Example 1-1, starting from 500 mg (2 mmol) of methyl (S)-2-amino-3-tert-butoxy-carbonyl-aminopropanoate hydrochloride and from 870 mg (6.3 mmol) of iodoethane, 192 mg (40%) of methyl (S)-3-tert-butoxycarbonylamino-2-ethylaminopropanoate are obtained in the form of a yellow oil.
Reaction SMILES: [NH:1](C(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O)[C@H:2]([C:27](O)=[O:28])[CH2:3][CH2:4][C:5](=[O:26])[NH:6][C:7]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C.[NH2:83][C@H:84]([C:88]([NH:90][C@H:91]([C:96]([OH:98])=[O:97])[CH2:92][CH:93]([CH3:95])[CH3:94])=[O:89])[C@@H:85]([CH3:87])[OH:86]>CN(C=O)C>[NH2:1][C@H:2]([C:27]([NH:83][C@H:84]([C:88]([NH:90][C@H:91]([C:96]([OH:98])=[O:97])[CH2:92][CH:93]([CH3:94])[CH3:95])=[O:89])[C@@H:85]([CH3:87])[OH:86])=[O:28])[CH2:3][CH2:4][C:5](=[O:26])[NH:6][C:7]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CC(C)C[C@H](NC(=O)[C@@H](N)[C@@H](C)O)C(=O)O
Reactant: O=C(CC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)C[C@H](NC(=O)[C@@H](NC(=O)[C@@H](N)CCC(=O)NC(c1ccccc1)(c1ccccc1)c1ccccc1)[C@@H](C)O)C(=O)O
Reaction time: 0.03 h

Procedure:
In an RBF were mixed Fmoc-Gln(Trt)-OH (44.7 g, 73.2 mmol), BOP (40.4 g, 91.5 mmol) and 250 ml of DMF. The mixture was stirred for 2 min and then DIPEA (18.9 g, 146.4 mmol) was added. The resulting mixture was added in one portion to the pre-swollen H-Thr-Leu-Resin and the reaction mixture was stirred for 2.5 h, the Kaiser test was negative, then the reaction was considered to be complete and the reaction medium was removed via filtration.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:5]([O:6][CH2:7][C:8]([CH3:10])=[CH2:9])=[CH:4][CH:3]=1.CC(C)([O-])C.[K+]>O>[Cl:1][C:2]1[CH:12]=[CH:11][C:5]([O:6][CH:7]=[C:8]([CH3:9])[CH3:10])=[CH:4][CH:3]=1
Reactant: C=C(C)COc1ccc(Cl)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Product: CC(C)=COc1ccc(Cl)cc1

Procedure:
Seven grams of 3-(4-chlorophenoxy)2-methyl-1-propene and 0.35 g of potassium t-butoxide are heated at 150° under nitrogen for 3 days. The mixture is then worked up with water and extracted with ether. The organic phase is washed with dilute acid, water and brine, dried over magnesium sulfate and solvent is removed to yield 3-(4-chlorophenoxy)-2-methyl-2-propene.
Reaction SMILES: [NH2:1][C@H:2]([C:10]([NH:12][C@H:13]([C:21]([NH:23][C@H:24]([C:26]([NH:28][C@H:29]([C:35]([NH:37][C@H:38]([C:43]([NH:45][C@H:46]([C:54]([NH:56][C@H:57]([C:61]([NH:63][C@H:64]([C:70]([NH:72][C@H:73]([C:84]([NH:86][C@H:87]([C:92]([NH:94][C@H:95]([C:101]([NH:103][C@H:104]([C:109]([NH:111][C@H:112]([C:116]([OH:118])=[O:117])[C@@H:113]([CH3:115])[OH:114])=[O:110])[CH2:105][C:106](=[O:108])[NH2:107])=[O:102])[CH2:96][CH2:97][S:98]([CH3:100])=O)=[O:93])[CH2:88][CH:89]([CH3:91])[CH3:90])=[O:85])[CH2:74][C:75]1[C:83]2[C:78](=[CH:79][CH:80]=[CH:81][CH:82]=2)[NH:77][CH:76]=1)=[O:71])[CH2:65][CH2:66][C:67](=[O:69])[NH2:68])=[O:62])[CH:58]([CH3:60])[CH3:59])=[O:55])[CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)=[O:44])[CH2:39][C:40](=[O:42])[OH:41])=[O:36])[CH2:30][CH2:31][C:32](=[O:34])[NH2:33])=[O:27])[CH3:25])=[O:22])[CH2:14][CH2:15][CH2:16][NH:17][C:18](=[NH:20])[NH2:19])=[O:11])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:9])[NH2:8]>C(O)(=O)CS>[NH2:1][C@H:2]([C:10]([NH:12][C@H:13]([C:21]([NH:23][C@H:24]([C:26]([NH:28][C@H:29]([C:35]([NH:37][C@H:38]([C:43]([NH:45][C@H:46]([C:54]([NH:56][C@H:57]([C:61]([NH:63][C@H:64]([C:70]([NH:72][C@H:73]([C:84]([NH:86][C@H:87]([C:92]([NH:94][C@H:95]([C:101]([NH:103][C@H:104]([C:109]([NH:111][C@H:112]([C:116]([OH:118])=[O:117])[C@@H:113]([CH3:115])[OH:114])=[O:110])[CH2:105][C:106](=[O:108])[NH2:107])=[O:102])[CH2:96][CH2:97][S:98][CH3:100])=[O:93])[CH2:88][CH:89]([CH3:90])[CH3:91])=[O:85])[CH2:74][C:75]1[C:83]2[C:78](=[CH:79][CH:80]=[CH:81][CH:82]=2)[NH:77][CH:76]=1)=[O:71])[CH2:65][CH2:66][C:67](=[O:69])[NH2:68])=[O:62])[CH:58]([CH3:60])[CH3:59])=[O:55])[CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)=[O:44])[CH2:39][C:40](=[O:41])[OH:42])=[O:36])[CH2:30][CH2:31][C:32](=[O:34])[NH2:33])=[O:27])[CH3:25])=[O:22])[CH2:14][CH2:15][CH2:16][NH:17][C:18](=[NH:19])[NH2:20])=[O:11])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:8])[NH2:9]
Reactant: CC(C)C[C@H](NC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(=O)O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](C)NC(=O)[C@H](CCCNC(=N)N)NC(=O)[C@@H](N)CCCNC(=N)N)C(C)C)C(=O)N[C@@H](CCS(C)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@H](C(=O)O)[C@@H](C)O
Agent: O=C(O)CS
Product: CSCC[C@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(=O)O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](C)NC(=O)[C@H](CCCNC(=N)N)NC(=O)[C@@H](N)CCCNC(=N)N)C(C)C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@H](C(=O)O)[C@@H](C)O
Reaction time: 24 h

Procedure:
In 3 ml of 5% thioglycolic acid-50% aqueous acetic acid was dissolved 30 mg of H-Arg-Arg-Ala-Gln-Asp-Phe-Val-Gln-Trp-Leu-Met(O)-Asn-Thr-OH and reduction was carried out at 45° C. for 24 hours. Then, the reaction mixture was run onto a column (2.4×122 cm) of Sephadex G-25 and elution was carried out with 30% aqueous acetic acid. The fractions from 180 ml to 250 ml were pooled and lyophilized. Yield 29 mg; [α]D21 -41.9° (c=0.4%, 0.1 N-HCl); Rf3 0.55(Avicel®); amino acid analysis: Trp 0.69(1); Arg 2.25(2); Asp 2.13(2); Thr 0.97(1); Glu 2.16(2); Ala 1.00(1); Val 1.01(1); Met 0.97(1); Leu 1.01(1); Phe 1.05(1); (peptide content 78%)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C@H:4]([CH2:6][C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][CH:8]=1)[NH2:5].[CH:17]1[C:22]([CH:23]=O)=[CH:21][C:20]2[O:25][CH2:26][O:27][C:19]=2[CH:18]=1>>[CH3:1][O:2][C:3]([C@H:4]1[NH:5][C@H:23]([C:22]2[CH:17]=[CH:18][C:19]3[O:27][CH2:26][O:25][C:20]=3[CH:21]=2)[C:8]2[NH:9][C:10]3[C:15]([C:7]=2[CH2:6]1)=[CH:14][CH:13]=[CH:12][CH:11]=3)=[O:16]
Reactant: O=Cc1ccc2c(c1)OCO2
Reactant: COC(=O)[C@@H](N)Cc1c[nH]c2ccccc12
Product: COC(=O)[C@@H]1Cc2c([nH]c3ccccc23)[C@@H](c2ccc3c(c2)OCO3)N1

Procedure:
The same method but starting from L-tryptophan methyl ester and piperonal gave the cis and trans isomers of the title compound.