Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8]/[N:9]=[CH:10]/[C:11]2[C:16]([F:17])=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:18])=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:20]>C1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][N:9]=[C:10]([Cl:20])[C:11]2[C:16]([F:17])=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:18])=[CH:6][CH:7]=1
Reactant: Fc1cccc(Cl)c1/C=N/Nc1ccc(Br)cc1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: c1ccccc1
Product: Fc1cccc(Cl)c1C(Cl)=NNc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 23 %

Procedure:
To a solution of (2E)-1-(4-bromophenyl)-2-(2-chloro-6-fluorobenzylidene)hydrazine (0.300 g, 1.32 mmol) in benzene (10 mL) was added PCl5 (0.330 g, 1.58 mmol). The reaction mixture was stirred at RT for 18 h. The reaction mass was quenched in water, neutralized with NaHCO3 and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulphate and concentrated to afford 0.110 g of the desired product. 1H NMR (300 MHz, DMSO d6): δ 7.17 (d, J=8.7 Hz, 2H), 7.41 (d, J=8.7 Hz, 3H), 7.45-7.61 (m, 2H), 10.26 (s, 1H). MS (m/z): 361.34 (M−H)−.
Reaction SMILES: [CH:1]([N:14]1[CH2:17][CH:16](OS(C)(=O)=O)[CH2:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:23]1[CH2:33][CH2:32][CH2:31][CH:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:24]1>CN(C)C=O.O>[CH2:29]([O:28][C:26]([CH:25]1[CH2:31][CH2:32][CH2:33][N:23]([CH:16]2[CH2:17][N:14]([CH:1]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:15]2)[CH2:24]1)=[O:27])[CH3:30]
Reactant: CCOC(=O)C1CCCNC1
Reactant: CS(=O)(=O)OC1CN(C(c2ccccc2)c2ccccc2)C1
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C1CCCN(C2CN(C(c3ccccc3)c3ccccc3)C2)C1
Temperature: 110 °C

Procedure:
Methanesulfonic acid 1-benzhydryl-azetidin-3-yl ester (A. G. Anderson, Jr. and R. Lok, J. Org. Chem., 1972, 37, 3953)(2.22 g, 7 mmol) and ethyl nipecotate (1.0 g, 6.37 mmol) were dissolved in dimethylformamide (3 mL) and heated at 110° C. for 1 hr. The mixture was cooled to ambient temperature, diluted with water and extracted with dichloromethane (3×15 mL). The extract was dried over anhydrous magnesium sulfate and the solvent removed under vacuum to give an impure sample of 1-(1-benzhydryl-azetidin-3-yl)-piperidine-3-carboxylic acid ethyl ester (2.91 g).
Reaction SMILES: [CH2:1]([C:4]1[C:5]([O:16][CH2:17][O:18][CH3:19])=[C:6]([CH:11]=[CH:12][C:13]=1[O:14][CH3:15])[C:7]([O:9]C)=[O:8])[CH:2]=[CH2:3].[OH-].[Na+].C(OCC)(=O)C.S([O-])(O)(=O)=O.[Na+]>CO>[CH2:1]([C:4]1[C:5]([O:16][CH2:17][O:18][CH3:19])=[C:6]([CH:11]=[CH:12][C:13]=1[O:14][CH3:15])[C:7]([OH:9])=[O:8])[CH:2]=[CH2:3]
Reactant: C=CCc1c(OC)ccc(C(=O)OC)c1OCOC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: C=CCc1c(OC)ccc(C(=O)O)c1OCOC
Yield: 95.2 %

Procedure:
1.32 g of methyl 3-allyl-4-methoxy-2-(methoxymethoxy)benzoate was dissolved in 12 ml of methanol, and the obtained mixture was then stirred while cooling on ice. Thereafter, 2.97 ml of a 5 N sodium hydroxide aqueous solution was added to the reaction mixture, and the obtained mixture was then stirred at room temperature overnight. The reaction solution was cooled on ice, and ethyl acetate was added thereto. Then, the obtained mixture was adjusted to be approximately pH 5 with addition of a 5% sodium hydrogen sulfate aqueous solution. An organic layer was separated, and a water layer was extracted with ethyl acetate. The obtained organic layers were gathered. The combined organic layer was washed with water and a saturated sodium chloride solution, and then dried over anhydrous magnesium sulfate. After removing the drying agent by filtration, the organic layer was concentrated under a reduced pressure, so as to obtain 1.19 g of the subject compound. This compound was used in the following reaction without further purification.
Reaction SMILES: Cl.[NH2:2][CH:3]([CH:8]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:4]([O:6][CH3:7])=[O:5].C(=O)([O-])[O-].[Na+].[Na+].Cl[C:28]([O:30][CH2:31][CH3:32])=[O:29]>C(Cl)(Cl)Cl>[CH2:31]([O:30][C:28]([NH:2][CH:3]([CH:8]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[C:4]([O:6][CH3:7])=[O:5])=[O:29])[CH3:32]
Reactant: CCOC(=O)Cl
Reactant: COC(=O)C(N)C(c1ccccc1)c1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCOC(=O)NC(C(=O)OC)C(c1ccccc1)c1ccccc1
Reaction time: 18 h

Procedure:
To a solution of methyl 2-amino-3,3-diphenylpropanoate hydrochloride (Example 1a, 28.0 g, 96 mmol), chloroform (250 ml), and 1.0M sodium carbonate (250 ml) was added ethyl chloroformate (9.20 ml, 96 mmol). After the solution had been stirred for 18 h the organic phase was separated, washed with 10% citric acid, water, saturated brine and dried (MgSO4). After removal of the solvent in vacuo the residue was recrystallised from hot methanol to give methyl 2-ethoxycarbonylamino-3,3-diphenylpropanoate, m.p.=107°-109° C. 1H NMR (250 MHz, CDCl3) δ7.18-7.33 (10H, m), 5.12 (1H, br t, J=8.5 Hz), 4.95 (1H, br d, J=8.5 Hz), 4.40 (1H, d, J=8.0 Hz), 4.06 (2H, q, J=7.0 Hz), 3.50 (3H, s), 1.17 (3H, t, J=7.0 Hz). m/z (CI+) 328(MH).
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:12]([SH:16])[CH:13]([SH:15])[CH3:14].[CH3:17][C:18](=[CH:20][CH2:21][CH2:22][C:23](=[CH:25][CH:26]=O)[CH3:24])[CH3:19]>C1CCCCC1>[CH3:24][C:23]([CH2:22][CH2:21][CH:20]=[C:18]([CH3:19])[CH3:17])=[CH:25][CH:26]1[S:15][CH:13]([CH3:14])[CH2:12][S:16]1
Reactant: CC(S)CS
Reactant: CC(C)=CCCC(C)=CC=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: C1CCCCC1
Product: CC(C)=CCCC(C)=CC1SCC(C)S1

Procedure:
Into a 100 ml reaction flask equipped with spin bar, reflux condenser, heating mantle and hot plate with magnetic stirring apparatus is placed 0.5 grams para-toluenesulfonic acid, 5.0 ml cyclohexane and 5.4 grams (0.05 moles) of 1,2-propanedithiol. 7.6 grams (0.05 moles) of citral is then added to the reaction mass over a period of 30 minutes. After the addition of the citral, the reaction mass is heated to reflux and refluxed for a period of 10 hours while removing water of reaction. After the 10 hour reflux period, the reaction mass is cooled and transferred to a separatory funnel. The reaction mass is then washed with one 50 ml portion of saturated sodium chloride solution followed by drying over anhydrous sodium sulfate and filtration. The resulting filtrate is distilled on a Microvigreux column yielding the following fractions:
Reaction SMILES: [C:1]([N:5]1[CH:9]=[C:8]([CH2:10][CH2:11][CH2:12][CH3:13])[C:7](=[NH:14])[S:6]1)([CH3:4])([CH3:3])[CH3:2].[C:15]1([C:21]2([C:26](O)=[O:27])[CH2:25][CH2:24][CH2:23][CH2:22]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH2:10]([C:8]1=[CH:9][N:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[S:6]/[C:7]/1=[N:14]\[C:26]([C:21]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:25][CH2:24][CH2:23][CH2:22]1)=[O:27])[CH2:11][CH2:12][CH3:13]
Reactant: O=C(O)C1(c2ccccc2)CCCC1
Reactant: CCCCc1cn(C(C)(C)C)sc1=N
Product: CCCCc1cn(C(C)(C)C)s/c1=N\C(=O)C1(c2ccccc2)CCCC1

Procedure:
The product from Example 92B and 1-phenylcyclopentanecarboxylic acid (Aldrich) were processed using the method described in Example 92C to afford the title compound. 1H NMR (DMSO-d6) δ 0.90 (t, J=7.3 Hz, 3H), 1.23-1.35 (m, 2H), 1.54 (s, 9H), 1.54-1.69 (m, 6H), 1.78-1.87 (m, 2H), 2.61-2.66 (m, 2H), 2.86-2.93 (m, 2H), 7.10-7.16 (m, 1H), 7.21-7.26 (m, 2H), 7.31-7.38 (m, 2H), 8.50 (s, 1H). MS (ESI+) m/z 385 (M+H)+. Anal. calcd. for C23H32N2OS: C, 71.83; H, 8.39; N, 7.28. Found: C, 71.58; H, 8.21; N, 7.05.
Reaction SMILES: [CH3:1][C:2]1[CH:20]=[C:19]([CH2:21]O)[CH:18]=[C:17]([CH3:23])[C:3]=1[O:4][CH:5]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=1)[C:6]([O:8][CH3:9])=[O:7].P(Br)(Br)[Br:25]>C(Cl)(Cl)(Cl)Cl>[Br:25][CH2:21][C:19]1[CH:20]=[C:2]([CH3:1])[C:3]([O:4][CH:5]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C:6]([O:8][CH3:9])=[O:7])=[C:17]([CH3:23])[CH:18]=1
Reactant: COC(=O)C(Oc1c(C)cc(CO)cc1C)c1cccc(Cl)c1
Reactant: BrP(Br)Br
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)C(Oc1c(C)cc(CBr)cc1C)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 81.2 %

Procedure:
To a solution of 0.560 g (1.62 mmol) of the product of Step B dissolved in 5.0 mL of carbon tetrachloride was added 154 μL (1.62 mmol) of phosphorous tribromide and the reaction mixture was stirred at room temperature for 5 minutes. Carbon tetrachloride was evaporated from the reaction mixture several times to remove the hydrogen bromide, then the residue was purified on a silica gel flash chromatography column eluted with 5% EtOAc-hexane. The purified fractions were evaporated in vacuo affording 0.523 g (81%) of the title compound.
Reaction SMILES: [H-].[Na+].[C:3]1([N:9]=[C:10]=[O:11])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.O.Br[CH2:14][C:15](=[O:26])[CH2:16][C:17]([NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:18]>O1CCOCC1>[O:26]=[C:15]1[CH2:14][O:11][C:10]([NH:9][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)=[C:16]1[C:17]([NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:18]
Reactant: O=C=Nc1ccccc1
Reactant: O=C(CBr)CC(=O)Nc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: O=C1COC(Nc2ccccc2)=C1C(=O)Nc1ccccc1
Reaction time: 5 h

Procedure:
Under a nitrogen atmosphere, sodium hydride (97%; 0.633 g, 25.61 mmol) was weighed into a dry reaction vessel and covered with 55 ml of anhydrous dioxane. A solution of phenyl isocyanate (1.39 ml, 12.81 mmol) in 5 ml of anhydrous dioxane was then added over a 5-10 minute period at room temperature (cooling with cold water). Next, the 4-bromoacetoacetanilide (3.28 g, 12.8 mmol) was added portionwise over a 20-minute period. The reaction mixture was stirred at 20°-25° C. for 5 hours, filtered under nitrogen atmosphere, and poured into 300 ml of ice-cold water. After acidifying (pH 5-6) with several drops of concentrated hydrochloric acid, the crude product was filtered off and crystallized from ethanol to provide 2.8 g. of amide product, m.p. 182°-184° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]=[C:10](Cl)[C:11]([F:14])([F:13])[F:12].[N-:16]=[N+:17]=[N-:18].[Na+].Cl.C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[C:10]([C:11]([F:14])([F:13])[F:12])=[N:18][N:17]=[N:16]1
Reactant: COc1ccccc1N=C(Cl)C(F)(F)F
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: COc1ccccc1-n1nnnc1C(F)(F)F
Temperature: 25 °C
Yield: 97.8 %

Procedure:
Four grams (16.8 mmol) of N-(2-methoxyphenyl)-2,2,2-trifluoroacetimidoyl chloride obtained in Example 9, 1.98 g (30.2 mmol) of sodium azide, 1.16 g (8.42 mmol) of triethylamine hydrochloride, and 40 ml of toluene were introduced into a 100 ml flask and reacted at 80° C. for 14 hours. After the reaction, the reaction solution was cooled to room temperature and washed with water (30 ml×2). The organic phase was dried over anhydrous magnesium sulfate for 1 hour, filtered, and then subjected to solvent removal by evaporation. The crude product thus obtained was purified by column chromatography (silica gel, ethyl acetate:hexane=3:7), resulting in 4.01 g of 1-(2-methoxyphenyl)-5-(trifluoromethyl)-1H-tetrazole as a pale yellow oil (yield: 97.6%).
Reaction SMILES: [C:1]1([CH3:12])[CH:6]=[CH:5][C:4]([O:7][CH2:8][C:9](O)=O)=[CH:3][CH:2]=1.[CH3:13][NH2:14]>>[C:1]1([CH3:12])[CH:6]=[CH:5][C:4]([O:7][CH2:8][CH2:9][NH:14][CH3:13])=[CH:3][CH:2]=1
Reactant: Cc1ccc(OCC(=O)O)cc1
Reactant: CN
Product: CNCCOc1ccc(C)cc1

Procedure:
Synthesized according to typical procedures C and D from 2-p-tolyloxyacetic acid and methylamine.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[C:8]([O:10][CH2:11][CH2:12][CH2:13][O:14][CH3:15])[CH:7]=[C:6]([O:16][CH3:17])[CH:5]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].O>C1COCC1>[CH3:17][O:16][C:6]1[CH:5]=[C:4]([CH2:3][OH:2])[CH:9]=[C:8]([O:10][CH2:11][CH2:12][CH2:13][O:14][CH3:15])[CH:7]=1
Reactant: COCCCOc1cc(OC)cc(C(=O)OC)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: COCCCOc1cc(CO)cc(OC)c1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
A mixture of 3-Methoxy-5-(3-methoxy-propoxy)-benzoic acid methyl ester (5 g, 19.7 mmol) and LAH (528 mg, 20 mmol) in THF (110 mL) is stirred under N2 at 0° C. for 3 h. After adding H2O, the reaction mixture is extracted with EtOAc. The combined organic phases are washed with H2O, brine and dried (Na2SO4). Concentration under reduced pressure and silica gel flash chromatography give the title compound as colorless oil. MS: 227 [M+H]+; tR (HPLC, CombiScreen ODS-AM 50×4.6 mm; 5-100% CH3CN+0.1% TFA/H2O+0.1% TFA for 5 min then 100% CH3CN+0.1% TFA for 2 min, flow 2.0 ml/min): 2.85 min.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10])=[O:2].Br[C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.C(O)C>[CH3:10][O:9][C:8]1[CH:7]=[CH:6][C:5]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)=[CH:4][C:3]=1[CH:1]=[O:2]
Reactant: COc1ccc(B(O)O)cc1C=O
Reactant: Brc1cccnc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1ccc(-c2cccnc2)cc1C=O
Yield: 32 %

Procedure:
N1 is prepared according to a method similar to Method A. Commercially available 3-formyl-4-methoxyphenylboronic acid (1.66 g, 9.22 mmol) is dissolved in 56 mL toluene and 14 mL ethanol. 3-Bromopyridine (0.98 mL, 10.2 mmol) is added followed by cesium carbonate (3.0 g, 9.21 mmol). Nitrogen is bubbled through the mixture for 10 minutes, then palladium tetrakistriphenylphosphine (0.53 g, 0.46 mmol) is added and nitrogen bubbling is resumed for another ten minutes. The mixture is heated to reflux for 5 hours. The mixture is allowed to cool and is filtered through Celite. The Celite pad is washed with ethyl acetate and methylene chloride. The filtrate is pumped dry and the residue is chromatographed on silica gel using a gradient elution of methanol/methylene chloride. 2-Methoxy-5-pyridin-3-yl-benzaldehyde (N1) is obtained (0.635 g, 2.98 mmol; 32% yield).
Reaction SMILES: C([NH:18][C@H:19]([C:24]([NH:26][C@@H:27]([CH2:35][OH:36])[CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:25])[C@H:20]([CH2:22][CH3:23])[CH3:21])(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O.[CH:37]1[C:49]2[CH:48]([CH2:50][O:51][C:52]([NH:54][C@H:55]([C:60](O)=[O:61])[CH2:56][CH:57]([CH3:59])[CH3:58])=[O:53])[C:47]3[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=3)[C:41]=2[CH:40]=[CH:39][CH:38]=1.C1CCC(N=C=NC2CCCCC2)CC1.C1C=CC2N(O)N=NC=2C=1>N1CCCCC1.CN(C=O)C>[C:52]([NH:54][C@H:55]([C:60]([NH:18][C@H:19]([C:24]([NH:26][C@@H:27]([CH2:35][OH:36])[CH2:28][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)=[O:25])[C@H:20]([CH2:22][CH3:23])[CH3:21])=[O:61])[CH2:56][CH:57]([CH3:59])[CH3:58])([O:51][CH2:50][CH:48]1[C:47]2[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=2)[C:41]2[C:49]1=[CH:37][CH:38]=[CH:39][CH:40]=2)=[O:53]
Reactant: CC(C)C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Reactant: CC[C@H](C)[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)N[C@@H](CO)Cc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: C1CCNCC1
Product: CC[C@H](C)[C@H](NC(=O)[C@H](CC(C)C)NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)N[C@@H](CO)Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 48.8 %

Procedure:
Dipeptide Fmoc-NH-L-Ile-D-Phe-CH2OH (1a) (520 mg, 1.06 mmol) was taken in 20% piperidine in DMF (2 mL) and stirred for 15 minutes at 25° C., TLC examination showed complete removal of the Fmoc protecting group (NH2-L-Ile-D-Phe-CH2OH), further confirmed by LC/MS examination, which showed M+−1 (263.3) peak. The reaction mixture was concentrated in vacuo, excess of the piperidine was removed by co-evaporating with toluene (2×10 mL), the free amino dipeptide was further dried over high vacumn for 30 minutes, and then redissolved in dry DMF (2 mL) and added to the mixture of N-(9-fluorenylmethoxycarbonyl)-L-leucine (38.1 mg, 1.06 mmol), DCC (262.0 mg, 1.27 mmol) and HOBt (171.4 mg, 1.27 mmol) in dry DMF (20 mL) at 25° C. The stirring was further continued for 14 h at 25° C. After 14 h white colored crystals precipitated out (DCU), which was filtered. The filterate was checked on TLC (3% MeOH: CH2Cl2) which showed formation of a new compound at higher Rf (0.5), LC/MS also showed molecular ion peak corresponding to the tripeptide 2a with other impurities peaks. The crude product was chromatographed on silica gel (Silica gel 60, 63-200μ) column and eluted with 3% MeOH: CH2Cl2 to give 310 mg of the tripeptide Fmoc-NH-L-Leu-L-Ile-D-Phe-CH2OH (2a) as a white solid. Checked on LC/MS which showed M++1 (600.3) and M++Na (622.3).
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([NH:14][C:15]([C:17]2[CH:18]=[N:19][N:20]3[CH:25]=[CH:24][C:23](Cl)=[N:22][C:21]=23)=[O:16])=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[CH3:13])[N:6]=1.[NH3:27]>CC(O)C>[CH3:1][C:2]1[S:3][C:4]([NH:14][C:15]([C:17]2[CH:18]=[N:19][N:20]3[CH:25]=[CH:24][C:23]([NH2:27])=[N:22][C:21]=23)=[O:16])=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[CH3:13])[N:6]=1
Reactant: Cc1nc(-c2ccccc2C)c(NC(=O)c2cnn3ccc(Cl)nc23)s1
Reactant: N
Solvent: CC(C)O
Product: Cc1nc(-c2ccccc2C)c(NC(=O)c2cnn3ccc(N)nc23)s1
Temperature: 120 °C
Yield: 16 %

Procedure:
A mixture of 5-chloro-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (2-methyl-4-o-tolyl-thiazol-5-yl)-amide (74.0 mg, 0.19 mmol, 1.0 equiv) and 2M ammonia in propan-2-ol (3 mL) was sealed and heated in a microwave reactor at 120° C. for 1 hour. The solvent was removed under vacuum, and the resultant residue purified by flash column chromatography on silica gel (gradient: 0 to 5% methanol in dichloromethane) to afford 11.0 mg (16%) of 5-amino-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (2-methyl-4-o-tolyl-thiazol-5-yl)-amide. LCMS (ESI) m+H=365.1; 1H NMR (400 MHz, DMSO-d6) δ: 10.35 (s, 1H), 8.66 (d, 1H), 8.23 (s, 1H), 7.47-7.37 (m, 4H), 6.38 (d, 1H), 2.61 (s, 3H), 2.20 (s, 3H).
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[C:16]([NH:26][C@H:27]([C:31]([OH:33])=[O:32])[CH:28]([CH3:30])[CH3:29])([O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[O:17].O[CH2:35][CH2:36][C@@H:37]([CH2:50][O:51][C:52](=[O:70])[CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH3:69])[CH2:38][N:39]1[CH:47]=[N:46][C:45]2[C:44](=[O:48])[NH:43][C:42]([NH2:49])=[N:41][C:40]1=2>C1COCC1.CN(C)C1C=CN=CC=1>[CH2:19]([O:18][C:16]([NH:26][C@H:27]([C:31]([O:33][CH2:35][CH2:36][C@@H:37]([CH2:50][O:51][C:52](=[O:70])[CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH3:69])[CH2:38][N:39]1[CH:47]=[N:46][C:45]2[C:44](=[O:48])[NH:43][C:42]([NH2:49])=[N:41][C:40]1=2)=[O:32])[CH:28]([CH3:29])[CH3:30])=[O:17])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CCCCCCCCCCCCCCCCCC(=O)OC[C@H](CCO)Cn1cnc2c(=O)[nH]c(N)nc21
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCCCC(=O)OC[C@H](CCOC(=O)[C@@H](NC(=O)OCc1ccccc1)C(C)C)Cn1cnc2c(=O)[nH]c(N)nc21
Temperature: 20 °C

Procedure:
A solution of dicyclohexylcarbodiimide (1500 g, 7.27 moles) in THF (7 L) was added to a reactor containing a mixture of N-carbobenzyloxy-L-valine (3630 g, 14.5 moles) in THF (20 L). The resulting mixture was stirred at 20±5° C. for 1–2 hours. The product of Example 30, step e) (2500 g, 4.81 moles) and 4-dimethylaminopyridine (59 g, 0.48 moles) were charged to a second reactor. To this second reactor was filtered the THF mixture from the first reactor, followed with a rinse of THF (15 L). The resulting mixture was stirred at 20±5° C. for 1–3 hours. Water (600 mL) was added and the solution was concentrated under vacuum at not more than 45° C. The residual oil was taken up in ethyl acetate (14 L) and filtered. The filtrate was washed successively with 10% aqueous sodium bicarbonate (2×14 L) and 10% brine (14 L). The organic phase was concentrated under vacuum and the residue was dissolved in methanol (10 kg) at 50–60° C. The warm solution was added gradually to a mixture of acetonitrile (30 kg) and water (13 kg) at ambient temperature. The mixture was stirred 1 hour at 15° C., then filtered to isolate the crude product, which was dried at 40° C. under vacuum to provide the desired product as a white solid (3.9 kg).
Reaction SMILES: [NH2:1][C:2]1[C:19]([F:20])=[C:18]([F:21])[C:5]2[N:6]([C:10]3[CH:15]=[CH:14][C:13]([Br:16])=[CH:12][C:11]=3[F:17])[C:7](=[O:9])[NH:8][C:4]=2[C:3]=1[OH:22].[CH2:23](OC(OCC)(OCC)C)[CH3:24].C1(C)C=CC(S(O)(=O)=O)=CC=1>>[Br:16][C:13]1[CH:14]=[CH:15][C:10]([N:6]2[C:5]3[C:18]([F:21])=[C:19]([F:20])[C:2]4[N:1]=[C:23]([CH3:24])[O:22][C:3]=4[C:4]=3[NH:8][C:7]2=[O:9])=[C:11]([F:17])[CH:12]=1
Reactant: CCOC(C)(OCC)OCC
Reactant: Nc1c(F)c(F)c2c([nH]c(=O)n2-c2ccc(Br)cc2F)c1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: Cc1nc2c(F)c(F)c3c([nH]c(=O)n3-c3ccc(Br)cc3F)c2o1
Yield: 54.68 %

Procedure:
Intermediate I-17a was prepared from 5-amino-1-(4-bromo-2-fluoro-phenyl)-6,7-difluoro-4-hydroxy-1,3-dihydro-benzoimidazol-2-one (I-14a: 600 mg, 1.6 mmol), 1,1,1-triethoxy-ethane (5 mL) and p-toluene sulfonic acid (100 mg) using procedures analogous to those described above for Intermediate I-16a to afford 350 mg of the product (54.68% yield). H1NMR (DMSO-d6, 300 MHz): δ 12.40 (s, 1H), 7.90 (dd, 1H), 7.72-7.60 (m, 2H), 2.68 (s, 3H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([CH:9]([CH2:12][CH2:13][CH2:14][CH3:15])[CH2:10][NH2:11])[CH3:8].[CH:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][C:17]=1[O:26][CH2:27][CH2:28]Cl>CS(C)=O.O>[CH2:7]([CH:9]([CH2:12][CH2:13][CH2:14][CH3:15])[CH2:10][NH:11][CH2:28][CH2:27][O:26][C:17]1[CH:18]=[CH:19][C:20]2[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:16]=1)[CH3:8]
Reactant: CCCCC(CC)CN
Reactant: ClCCOc1ccc2ccccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CCCCC(CC)CNCCOc1ccc2ccccc2c1
Temperature: 140 °C

Procedure:
A mixture of anhydrous potassium carbonate (10 gm, in excess) and 2-ethyl n-hexylamine (0.37 ml, 0.003 mole) was taken in dry DMSO(40 ml). Now 2-(2-naphthyloxy)-1-chloroethane (0.5 gm, 0.002 mole) was added in it. Reaction mixture was refluxed at 140° C. for 7 hrs and the reaction was completed as checked by TLC. Reaction mixture was poured in distilled water (60 ml) and extracted with ethyl acetate thrice. The organic layer was separated and concentrated to get oily compound which was later crystallized by benzene hexane to get N-(2-ethyl-n-hexyl)-(2-(naphthalen-2-yloxy)ethyl]amine, solid, m.p. 92° C., (yield 0.62 gm, 83.6%).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]2[CH:12]=[C:11]([C:13]#[C:14][C:15]3[CH:20]=[CH:19][N:18]=[C:17]([Cl:21])[CH:16]=3)[N:10]=[C:9]2[CH3:22])[CH:5]=[CH:4][N:3]=1.[OH-:23].[K+]>C(O)(C)(C)C>[Cl:21][C:17]1[CH:16]=[C:15]([C:14]#[C:13][C:11]2[N:10]=[C:9]([CH3:22])[N:8]([C:6]3[CH:5]=[CH:4][NH:3][C:2](=[O:23])[CH:7]=3)[CH:12]=2)[CH:20]=[CH:19][N:18]=1
Reactant: Cc1nc(C#Cc2ccnc(Cl)c2)cn1-c1ccnc(Cl)c1
Reactant: [OH-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: Cc1nc(C#Cc2ccnc(Cl)c2)cn1-c1cc[nH]c(=O)c1

Procedure:
The title compound, white crystalline solid, MS: m/e=311.2, 313.2 (M+H+), was prepared in accordance with the general method of example 1a by treatment of 2-chloro-4-[4-(2-chloro-pyridin-4-ylethynyl)-2-methyl-imidazol-1-yl]-pyridine with 50% KOH in tert-butanol
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]2[CH:7]=[C:8]([C:26]([O:28]C(C)(C)C)=[O:27])[N:9]([CH2:14][C:15]3[CH:19]=[C:18]([C:20]4[S:21][C:22]([Cl:25])=[CH:23][CH:24]=4)[O:17][N:16]=3)[C:10]=2[CH:11]=[CH:12][CH:13]=1)=[O:4].C1(C)C=CC=CC=1>FC(F)(F)C(O)=O>[CH3:1][O:2][C:3]([C:5]1[C:6]2[CH:7]=[C:8]([C:26]([OH:28])=[O:27])[N:9]([CH2:14][C:15]3[CH:19]=[C:18]([C:20]4[S:21][C:22]([Cl:25])=[CH:23][CH:24]=4)[O:17][N:16]=3)[C:10]=2[CH:11]=[CH:12][CH:13]=1)=[O:4]
Reactant: COC(=O)c1cccc2c1cc(C(=O)OC(C)(C)C)n2Cc1cc(-c2ccc(Cl)s2)on1
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1cccc2c1cc(C(=O)O)n2Cc1cc(-c2ccc(Cl)s2)on1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4.1 g 1-[5-(5-Chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-1H-indole-2,4-dicarboxylic acid 2-tert-butyl ester 4-methyl ester were dissolved in 100 ml trifluoro-acetic acid and stirred for 1 h at RT. Then 100 ml toluene was added and the solvents were removed under reduced pressure. This procedure was repeated three times, then the residue was dried in vacuo.