Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([C:9]2[C:10](=[O:18])[N:11]([CH3:17])[C:12](=[S:16])[N:13]([CH3:15])[N:14]=2)=[C:4]([F:19])[CH:3]=1.Cl[C:21]1[N:26]=[CH:25][CH:24]=[CH:23][N:22]=1.C(=O)([O-])[O-].[K+].[K+].CC(=O)CC>CS(C)=O>[Cl:1][C:2]1[C:7]([O:8][C:21]2[N:26]=[CH:25][CH:24]=[CH:23][N:22]=2)=[CH:6][C:5]([C:9]2[C:10](=[O:18])[N:11]([CH3:17])[C:12](=[S:16])[N:13]([CH3:15])[N:14]=2)=[C:4]([F:19])[CH:3]=1
Reactant: Clc1ncccn1
Reactant: Cn1nc(-c2cc(O)c(Cl)cc2F)c(=O)n(C)c1=S
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCC(C)=O
Product: Cn1nc(-c2cc(Oc3ncccn3)c(Cl)cc2F)c(=O)n(C)c1=S
Yield: 83.4 %

Procedure:
A mixture 6-(4-chloro-2-fluoro-5-hydroxyphenyl)-2,4-dimethyl-5-oxo-3-thioxo-2,3,4,5-tetrahydro-1,2,4-triazine (0.200 g), 2-chloropyrimidine (0.084 g), potassium carbonate (0.113 g), 2-butanone (10 ml), and dimethyl sulfoxide (2.5 ml) was heated at refluxed for 10 hours. The reaction was partitioned between water and ethyl acetate and the aqueous phase extracted with ethyl acetate (3×25 ml). The combined organic layers were dried over anhydrous magnesium sulfate and concentrated to afford the desired material (0.21 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][CH:9]1[C:17](O)=[O:18])=[O:7])([CH3:4])([CH3:3])[CH3:2].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C.Br.[NH2:55][C:56]1[S:57][CH:58]=[C:59]([C:61]2[C:66]([CH3:67])=[CH:65][C:64]([CH3:68])=[CH:63][C:62]=2[CH3:69])[N:60]=1>CN(C)C=O>[CH3:67][C:66]1[CH:65]=[C:64]([CH3:68])[CH:63]=[C:62]([CH3:69])[C:61]=1[C:59]1[N:60]=[C:56]([NH:55][C:17]([CH:9]2[CH2:10][C:11]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[N:8]2[C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])=[O:18])[S:57][CH:58]=1
Reactant: Cc1cc(C)c(-c2csc(N)n2)c(C)c1
Reactant: CC(C)(C)OC(=O)N1c2ccccc2CC1C(=O)O
Agent: Br
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1cc(C)c(-c2csc(NC(=O)C3Cc4ccccc4N3C(=O)OC(C)(C)C)n2)c(C)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 95 %

Procedure:
21 g of 1-tert-butoxycarbonyl-indoline-2-carboxylic acid, then 35.2 g of 1-benzotriazolyl-oxytris (dimethylamino)phosphonium hexafluorophosphate (BOP) and the 24.2 g of triethylamine are added successively to a solution of 23.5 g of 2-amino-4-(2,4,6-trimethylphenyl)thiazole hydrobromide in 250 ml of dimethylformamide. The reaction mixture is stirred at ambient temperature for 12 h. The solvent is then evaporated under reduced pressure and 150 ml of ethyl acetate are poured onto the residue. The organic solution is washed with a saturated aqueous NaCl solution and dried over anhydrous magnesium sulphate. The solid obtained after evaporation of the solvent is washed with diisopropyl ether. Yield: 95%.
Reaction SMILES: Cl.[N+](C1C=C[C:8]([O:11][C:12](=[O:33])[NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH:20]3[C:29]4[C:24](=[C:25]([Cl:31])[CH:26]=[C:27]([Cl:30])[CH:28]=4)[CH2:23][N:22]([CH3:32])[CH2:21]3)[CH:15]=2)=[CH:7]C=1)([O-])=O.[CH3:34][N:35](C)[CH2:36]CO.O.C(=O)([O-])[O-].[K+].[K+]>ClCCl>[ClH:30].[CH3:34][N:35]([CH3:36])[CH2:7][CH2:8][O:11][C:12](=[O:33])[NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH:20]2[C:29]3[C:24](=[C:25]([Cl:31])[CH:26]=[C:27]([Cl:30])[CH:28]=3)[CH2:23][N:22]([CH3:32])[CH2:21]2)[CH:15]=1
Reactant: CN(C)CCO
Reactant: CN1Cc2c(Cl)cc(Cl)cc2C(c2cccc(NC(=O)Oc3ccc([N+](=O)[O-])cc3)c2)C1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: CN(C)CCOC(=O)Nc1cccc(C2CN(C)Cc3c(Cl)cc(Cl)cc32)c1
Yield: 73.9 %

Procedure:
Under stirring and argon atmosphere [3(6,8-dichloro-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-phenyl]-carbamic acid 4-nitro-phenyl ester—hydrochloride salt (15 mg, example 151, intermediate 1) was suspended in dichloromethane (1.5 ml) and 2-dimethylamino-ethanol (3 mg) dissolved in dichloromethane (0.5 ml) was added. After stirring for 6 h and standing over night dichloromethane, water and saturated potassium carbonate solution were added. The organic layer was separated, washed three times with saturated potassium carbonate solution, dried over magnesium sulphate, filtered and concentrated in vacuo. The crude material was purified by preparative HPLC. The product containing fractions were combined and the acetonitrile was removed in vaccuo. After addition of sodium bicarbonate the aqueous phase was extracted with ethyl acetate. The organic layer was separated, dried (magnesium sulphate), filtered and concentrated in vaccuo. The residue was dissolved in water/2N hydrochloric acid and freeze dried to give 5 mg of the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]=[CH:10][C@H:9]1[C:13]([OH:15])=[O:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]=[CH:10][C@H:9]1[C:13]([O:15][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:14])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CC=C[C@H]1C(=O)O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC=C[C@H]1C(=O)OCc1ccccc1
Temperature: 25 °C

Procedure:
To a solution of (S)-1-(tert-butoxycarbonyl)-2,5-dihydro-1H-pyrrole-2-carboxylic acid (10 g, 46.9 mmol) in DMF (249 mL) cooled at 0° C. were added cesium carbonate (16.8 g, 51.6 mmol) then benzyl bromide (6.69 mL, 56.3 mmol) and the mixture was allowed to warm up to RT overnight. The reaction mixture was quenched with water (500 mL) and extracted with ethyl acetate (3×200 mL). The organic layers were combined and washed with brine, dried (Na2SO4), filtered and concentrated. The crude residue was purified by flash column chromatography on silica gel (c-hexane to c-hexane/EtOAc 4:1) to give the desired material. TLC, Rf (c-hexane/EtOAc 4:1)=0.25; MS (UPLC): 326 [M+Na]+, 204 [MH−Boc]+; tR (HPLC conditions f): 2.35 min.
Reaction SMILES: [C:1]([OH:20])(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[CH:21]1[C:26]([NH2:27])=[CH:25][CH:24]=[C:23]([NH2:28])[CH:22]=1>>[C:1]([NH:27][C:26]1[CH:21]=[CH:22][C:23]([NH2:28])=[CH:24][CH:25]=1)(=[O:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: Nc1ccc(N)cc1
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)O
Product: CCCCCCCC/C=C\CCCCCCCC(=O)Nc1ccc(N)cc1
Yield: 76.6 %

Procedure:
Oleic acid (2.82 g) and p-phenylenediamine (1.62 g) were reacted in the same manner as in Reference Example 11 to obtain 2.85 g of the objective compound (yield: 77%).
Reaction SMILES: [C:1]1([OH:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.Br[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15].C([O-])([O-])=O.[K+].[K+]>CC#N>[C:1]1([O:11][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)CBr
Reactant: Oc1cccc2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)COc1cccc2ccccc12
Temperature: 80 °C
Reaction time: 4 h
Yield: 95 %

Procedure:
To a stirred mixture of naphthalen-1-ol (196 mg, 1.35 mmol) in MeCN (5 mL) was added ethyl bromoacetate (269 mg, 1.62 mmol) and K2CO3 (372 mg, 2.70 mmol). The mixture was stirred at 80° C. for 4 hours. The mixture was filtered and the filtrate concentrated. The residue was used directly for the next step without further purification (300 mg, Yield 95%).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]([N:10]=O)[CH2:6][C@@H:5]1[CH3:12])(=[O:3])[CH3:2]>O.C(O)(=O)C.[Zn]>[C:1]([N:4]1[CH2:9][CH2:8][N:7]([NH2:10])[CH2:6][C@@H:5]1[CH3:12])(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCN(N=O)C[C@@H]1C
Agent: [Zn]
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)N1CCN(N)C[C@@H]1C
Temperature: 55 °C
Reaction time: 2 h
Yield: 99.6 %

Procedure:
To a mixture of (S)-1-acetyl-2-methyl-4-nitrosopiperazine (350 mg) in water (2 ml) and acetic acid (0.59 ml) was added zinc powder (401 mg) as portions during the period of 2 hours at 8-13° C. (exothermic reaction) with ice-water cooling bath. After removal of the bath, the temperature was raised till 55° C. and the reaction mixture was additionally stirred at 45° C. for 2 hours. The zinc residue was filtered off and washed with methanol (10 ml) on the Celite. The combined filtrate was added into dichloromethane (40 ml) and sodium hydroxide (409 mg) in water (6 ml) below 35° C. The resulting precipitate was filtered off with Celite and the residue was washed with chloroform (50 ml). The combined filtrate was washed with water, dried over magnesium sulfate and concentrated to give (S)-1-acetyl-4-amino-2-methylpiperazine (320 mg). This product was used for next step without purification.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]([C:7]1[NH:8][C:9]2[C:14]([CH:15]=1)=[C:13]([F:16])[C:12]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[CH:11][CH:10]=2)=[O:6].[Cl:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][C:33]=1[Cl:34])[CH2:29]Cl>CN(C)C=O>[CH3:3][O:4][C:5]([C:7]1[N:8]([CH2:29][C:28]2[CH:31]=[CH:32][C:33]([Cl:34])=[C:26]([Cl:25])[CH:27]=2)[C:9]2[C:14]([CH:15]=1)=[C:13]([F:16])[C:12]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[CH:11][CH:10]=2)=[O:6]
Reactant: COC(=O)c1cc2c(F)c(OCc3ccccc3)ccc2[nH]1
Reactant: ClCc1ccc(Cl)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc2c(F)c(OCc3ccccc3)ccc2n1Cc1ccc(Cl)c(Cl)c1
Reaction time: 0.5 h

Procedure:
Sodium hydride (60% in mineral oil, 589 mg) was added to a solution of methyl-4-fluoro-5-benzyloxyindole-2-carboxylate (4 g) in dimethylformamide (100 ml) and the mixture was stirred under an argon atmosphere for 30 minutes. 3,4-dichlorobenzyl chloride (2.22 ml) was added and the mixture stirred overnight. The reaction mixture was concentrated in vacuo and the residue partitioned between diethyl ether (100 ml) and water (100 ml). Organic extracts were washed with water (100 ml), dried (MgSO4), concentrated in vacuo and purified by flash column chromatography; using iso-hexane followed by 5% ethyl acetate/iso-hexane as eluent, to give the product as a yellow crystalline solid (4.61 g) 1H NMR (DMSO-d6) δ 3.80(s, 3H), 5.15(s, 2H), 5.80(s, 2H), 6.85(m, 1H), 7.25-7.52(m, 10H); M/z(+) 458.2 (MH+)
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1.[C:14]([O:18][C:19](=[O:46])[CH2:20][N:21]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[Sn](C)(C)C)[C:22](=[O:35])[CH2:23][NH:24][C:25]([NH:27][C:28]1[CH:29]=[C:30]([CH3:34])[CH:31]=[CH:32][CH:33]=1)=[O:26])([CH3:17])([CH3:16])[CH3:15].O>C1(C)C=CC=CC=1>[C:14]([O:18][C:19](=[O:46])[CH2:20][N:21]([C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][C:41]=1[C:7](=[O:8])[C:6]1[CH:10]=[CH:11][C:3]([C:2]([F:13])([F:12])[F:1])=[CH:4][CH:5]=1)[C:22](=[O:35])[CH2:23][NH:24][C:25]([NH:27][C:28]1[CH:29]=[C:30]([CH3:34])[CH:31]=[CH:32][CH:33]=1)=[O:26])([CH3:17])([CH3:15])[CH3:16]
Reactant: Cc1cccc(NC(=O)NCC(=O)N(CC(=O)OC(C)(C)C)c2ccccc2[Sn](C)(C)C)c1
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1cccc(NC(=O)NCC(=O)N(CC(=O)OC(C)(C)C)c2ccccc2C(=O)c2ccc(C(F)(F)F)cc2)c1
Temperature: 50 °C
Reaction time: 0.33 h
Yield: 45.4 %

Procedure:
To a solution of 4-trifluoromethylbenzoyl chloride (53 μl, 0.36 mmol) in toluene (4 ml) is added dichlorobisacetonitrile palladium (12.5 mg, 0.036 mmol) at room temperature. Then, tert-butyl((2-trimethylstannylphenyl)-(2-(3-m-tolylureido)acetyl)amino)acetate (compound 25) (200 mg, 0.36 mmol) is added, and the mixture is stirred at 50° C. for 20 minutes. After addition of dichlorobisacetonitrile palladium (6.2 mg, 0.018 mmol), stirring is confinated for additional 10 minutes. To the reaction solution is added ice-cooled water. After stirring, the aqueous layer is extracted twice with ethyl acetate. The organic layer is washed with saturated brine, dried over anhydrous magnesium sulfate and then concentrated. The residue is purified by subjecting to silica gel column chromatography to obtain the objective compound 26a (93 mg). Yield 46%.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[H-].[Na+].[Cl:10][CH2:11][CH2:12][CH2:13]I.O>CN(C)C=O.[Na+].[Cl-]>[Cl:10][CH2:11][CH2:12][CH2:13][O:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1cccnc1
Reactant: ClCCCI
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: ClCCCOc1cccnc1
Temperature: 25 °C
Yield: 87242 %

Procedure:
Under a nitrogen atmosphere, a solution of 3-hydroxypyridine (35.00 g, 0.368 mmol) in N,N-dimethylformamide (DMF) (150 mL) was slowly added drop-wise over 15 min to a cold (0-5° C.), stirring slurry of sodium hydride (17.64 g of an 80% dispersion in mineral oil, 0.588 mol) in DMF (250 mL). The mixture was allowed to stir and warm to ambient temperature over 1 h. The gray slurry was cooled to 0-5° C., and 1-chloro-3-iodopropane (90.3 g, 0.442 mol) was added drop-wise over 30 min. The resulting dark-brown mixture was allowed to stir and warm to ambient temperature over 16 h. Water (500 mL) was added and the mixture was divided into equal parts. Each half was diluted with saturated NaCl solution (200 mL) and extracted with ether (5×200 mL). All ether extracts were combined and concentrated to give 55.1 g (87.3%) of a dark-brown oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7]([C:12]1[N:13]=[CH:14][C:15]3[C:20]([CH:21]=1)=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:6][C:5]2=O.Cl.[C:24]([O:28][NH2:29])([CH3:27])([CH3:26])[CH3:25]>CO>[C:24]([O:28][N:29]=[C:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([Br:1])[CH:3]=2)[O:8][C:7]([C:12]2[N:13]=[CH:14][C:15]3[C:20]([CH:21]=2)=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:6]1)([CH3:27])([CH3:26])[CH3:25]
Reactant: O=c1cc(-c2cc3ccccc3cn2)oc2ccc(Br)cc12
Reactant: CC(C)(C)ON
Agent: Cl
Solvent: CO
Product: CC(C)(C)ON=c1cc(-c2cc3ccccc3cn2)oc2ccc(Br)cc12
Yield: 75.9 %

Procedure:
6-bromo-2-isoquinolin-3-yl-chromen-4-one O-tert-butyl oxime was prepared using the method D (step 1) illustrated in example 1B. 6-bromo-2-isoquinolin-3-yl-chromen-4-one (600 mg, 1.7 mmol) was treated with O-tert-butyl-hydroxylamine hydrochloride (427 mg, 3.4 mmol) in methanol (10 ml) under microwave irradiation to yield 6-bromo-2-isoquinolin-3-yl-chromen-4-one O-tert-butyl oxime (546 mg, 76%) as a yellow solid.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[CH2:13]([O:15][C:16](=[O:31])[CH:17]([C:28](=O)C)[CH2:18][CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[Cl:27])[CH3:14]>O1CCCC1>[CH2:13]([O:15][C:16](=[O:31])[C:17](=[CH2:28])[CH2:18][CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[Cl:27])[CH3:14]
Reactant: CCOC(=O)C(CCCc1ccccc1Cl)C(C)=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: C=C(CCCc1ccccc1Cl)C(=O)OCC
Reaction time: 8 h
Yield: 40.2 %

Procedure:
A mixture of 104 ml of 15% strength butyl-lithium (in hexane), 19 g of diisopropylamine and 400 ml of tetrahydrofuran is stirred together at -78°; 39 g of 5-(2-chlorophenyl)-2-acetylvaleric acid ethyl ester [prepared from 3-(2-chlorophenyl)propyltosylate and ethyl acetoacetate] are added dropwise to the resulting admixture. The mixture thus obtained is stirred for a further 20 minutes. After removing the cooling bath, 19.4 g of paraformaldehyde (anhydrous) are added in portions to the mixture. After stirring the mixture for 1 hour, it is heated under reflux for 5 hours and left to stand overnight. The solid constituents are filtered off, and the filtrate is concentrated in a rotary evaporator. 500 ml of saturated sodium bicarbonate solution are added to the residue, and the mixture is stirred for 30 minutes. Extraction with methylene chloride and evaporation of the solvent yield (after purification by distillation) 14 g of 5-(2-chlorophenyl)-2-methylenevaleric acid ethyl ester of b.p. 95° to 98° C. under 0.005 mm Hg. The title compound is obtained analogously to Example 4a by oxidation.
Reaction SMILES: O[C@@H](C1C=CC=CC=1)C([O:5][C@@H:6]1[C@@H:11]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[C@H:10]([CH2:20][O:21][C:22]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:9][N:8]([CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[CH2:7]1)=O.C(=O)([O-])[O-].[Na+].[Na+]>O.C(OCC)(=O)C>[CH2:41]([N:8]1[CH2:9][C@@H:10]([CH2:20][O:21][C:22]([C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C@H:11]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[C@@H:6]([OH:5])[CH2:7]1)[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1
Reactant: COc1ccc([C@H]2[C@H](COC(c3ccccc3)(c3ccccc3)c3ccccc3)CN(Cc3ccccc3)C[C@@H]2OC(=O)[C@@H](O)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ccc([C@H]2[C@H](COC(c3ccccc3)(c3ccccc3)c3ccccc3)CN(Cc3ccccc3)C[C@@H]2O)cc1

Procedure:
33.3 (46.13 mmol) of (3R,4R,5S)-1-benzyl-4-(4-methoxy-phenyl)-5-trityloxymethyl-piperidin-3-ol (S)-hydroxy-phenyl-acetate were treated with a cold aqueous solution of 7.3 g (69.2 mmol) of sodium carbonate in 100 ml water and 600 ml of ethyl acetate. The aqueous phase was separated and extracted twice with 200 ml of ethyl acetate. The combined organic phases were dried over sodium sulfate and evaporated under reduced pressure to yield 25 g of (3R,4R,5S)-1-benzyl-4-(4-methoxy-phenyl)-5-trityloxymethyl-piperidin-3-ol as a colorless oil which was directly used without further purification.
Reaction SMILES: [N:1]1([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:31][CH2:30][CH2:29][C@H:2]1[C:3]([NH:5][C@@H:6]([C:14]([NH:16][C@H:17]([C:25]([NH:27]N)=[O:26])[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:15])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:4].N[C@@H:40]([C:48]([NH:50][C@H:51]([C:56]([NH:58][C@H:59]([C:64]([NH2:66])=[O:65])[CH2:60][CH2:61][CH2:62][CH3:63])=[O:57])[CH2:52][CH:53]([CH3:55])[CH3:54])=[O:49])[CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1.Cl>>[N:1]1([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:31][CH2:30][CH2:29][C@H:2]1[C:3]([NH:5][C@@H:6]([C:14]([NH:16][C@H:17]([C:25]([NH:27][C@@H:40]([C:48]([NH:50][C@H:51]([C:56]([NH:58][C@H:59]([C:64]([NH2:66])=[O:65])[CH2:60][CH2:61][CH2:62][CH3:63])=[O:57])[CH2:52][CH:53]([CH3:54])[CH3:55])=[O:49])[CH2:41][C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1)=[O:26])[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:15])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:4]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)N[C@H](Cc1ccccc1)C(=O)N[C@@H](Cc1ccccc1)C(=O)NN
Reactant: CCCC[C@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@H](N)Cc1ccccc1)C(N)=O
Agent: Cl
Product: CCCC[C@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](Cc1ccccc1)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H](Cc1ccccc1)NC(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C)C(N)=O
Yield: 51 %

Procedure:
Condensation of BocPro-DPhe-PheNHNH2 (Example 23, 0.717 g.) and HDPhe-Leu-NleNH2 hydrochloride salt (0.585 g.) by the acyl azide method (Yajima et al., Chem. Pharm. Bull., vol. 19, p. 1900, 1971) gave BocPro-DPhe-Phe-DPhe-Leu-NleNH2 in 51% yield. De-t-butoxycarbonylation of BocPro-Dphe-Dphe-Leu-NleNH2 (0.500 g.) using hydrogen chloride in acetic acid gave HPro-DPhe-Phe-DPhe-Leu-NleNH2, which was isolated as the amorphous white solid hydrochloride salt trihydrate in 36% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([OH:13])=O)=[CH:5]2.[NH2:14][CH:15]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[CH:25]=1)[C:16]([N:18]1[CH2:22][CH2:21][S:20][CH2:19]1)=[O:17]>>[Cl:30][C:26]1[CH:25]=[C:24]([CH:29]=[CH:28][CH:27]=1)[CH2:23][CH:15]([NH:14][C:11]([C:6]1[NH:7][C:8]2[C:4]([CH:5]=1)=[CH:3][C:2]([Cl:1])=[CH:10][CH:9]=2)=[O:13])[C:16](=[O:17])[N:18]1[CH2:22][CH2:21][S:20][CH2:19]1
Reactant: O=C(O)c1cc2cc(Cl)ccc2[nH]1
Reactant: NC(Cc1cccc(Cl)c1)C(=O)N1CCSC1
Product: O=C(NC(Cc1cccc(Cl)c1)C(=O)N1CCSC1)c1cc2cc(Cl)ccc2[nH]1

Procedure:
From 5-chloro-1H-indole-2-carboxylic acid and (±)-2-amino-3-(3-chloro-phenyl)-1-thiazolidin-3-yl-propan-1-one.
Reaction SMILES: [C:1]([O:4][CH:5]=[CH:6][CH:7]1[NH:10][C:9](=[O:11])[CH2:8]1)(=[O:3])[CH3:2]>[Pd].C(OC(=O)C)C>[C:1]([O:4][CH2:5][CH2:6][CH:7]1[NH:10][C:9](=[O:11])[CH2:8]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC=CC1CC(=O)N1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(=O)OCCC1CC(=O)N1
Reaction time: 0.17 h
Yield: 101.9 %

Procedure:
A mixture of 4-(2-acetoxyvinyl)-azetidin-2-one (3.00 g), 10% Pd/C (0.15 g) and ethylacetate (EtOAc) (120 ml) is hydrogenated in a 500 ml glass bomb on a Parr shaker at an initial pressure of 39 psi. After shaking 10 mins (final pressure of 20 psi), the mixture is filtered through a pad of MgSO4 to remove the catalyst. The filtrate is concentrated in vacuo and the residue stripped with anhydrous benzene to provide 4-(2-acetoxyethyl)-azetidin-2-one (3.098 g) as a clear oil: ir (neat) 3.01, 5.66, 5.75, 7.28, 8.05, and 9.61 cm-1 ; nmr (CDCl3) δ1.95 (m, 2), 2.07 (s, 3), 2.60 (m, 1), 3.12 (m, 1), 3.70 (m, 1), 4.15 (m, 2), and 6.77 (br s, 1).
Reaction SMILES: C(O[C:4](=O)[C:5]1[CH:10]=[CH:9][CH:8]=[C:7](OCCN2CCOCC2)[CH:6]=1)C.[NH2:21][C:22]1[N:26]([C:27]2[CH:28]=[C:29]([CH:36]=[CH:37][C:38]=2[CH3:39])[C:30]([NH:32][CH:33]2[CH2:35][CH2:34]2)=[O:31])[N:25]=[CH:24][C:23]=1[C:40](=[O:49])C1C=CC=C(CO)C=1.C(N(C(C)C)CC)(C)C>C(O)C>[NH2:21][C:22]1[N:26]([C:27]2[CH:28]=[C:29]([CH:36]=[CH:37][C:38]=2[CH3:39])[C:30]([NH:32][CH:33]2[CH2:35][CH2:34]2)=[O:31])[N:25]=[CH:24][C:23]=1[C:40](=[O:49])[C:8]1[CH:9]=[CH:10][C:5]([CH3:4])=[CH:6][CH:7]=1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-n1ncc(C(=O)c2cccc(CO)c2)c1N
Reactant: CCOC(=O)c1cccc(OCCN2CCOCC2)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: Cc1ccc(C(=O)c2cnn(-c3cc(C(=O)NC4CC4)ccc3C)c2N)cc1
Temperature: 65 °C
Yield: 21.9 %

Procedure:
A mixture of 2-(4-methyl-benzoyl)-3-phenylamino-acrylonitrile 2 (205 mg, 0.78 mmol), N-cyclopropyl-3-hydrazino-4-methyl-benzamide trifluoroacetic acid salt 7 (Example 6C, 250 mg, 0.78 mmol) and diisopropylethylamine (0.14 mL, 0.78 mmol) in 8 mL of ethanol was heated at 65° C. in for 18 h. Solvent was removed and the residue was purified by silica gel column chromatography (EtOAc/hexanes, gradient from 1/3 to 3/1). The product can be further purified by trituration with Et2O to give 3-[5-amino-4-(4-methyl-benzoyl)-pyrazol-1-yl]-N-cyclopropyl-4-methyl-benzamide 3 as a white solid (64 mg, 22%). HPLC (4 minute gradient) tR 2.26 min; MS m/z 375.2 [M+H]+; 1H NMR (300 MHz, DMSO-d6) δ 8.51 (d, J=4.0, 1H), 7.93 (d, J=8.0, 1H), 8.51 (d, J=4.0, 1H), 7.83 (bs, 1H), 7.82 (s, 1H), 7.70 (d, J=7.9, 2 H), 7.53 (d, J=8.0, 1H), 7.35 (d, J=7.9, 2 H), 6.95 (bs, 2H), 2.86 (m, 1H), 2.40 (s, 3H), 2.14 (s, 3H), 0.68 (m, 2H), 0.56 (m, 2H); 13C NMR (300 MHz, DMSO-d6) δ 187.4, 166.0, 151.9, 141.3, 141.1, 139.2, 136.9, 135.6, 133.0, 131.2, 129.1, 128.3, 128.0, 126.5, 102.6, 23.1, 21.0, 17.2, 5.6 ppm.