Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:7]2[N:15]=[C:14]3[C:10]([NH:11][CH:12]=[N:13]3)=[C:9]([N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)[N:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[H-].[Na+].[CH3:24][Si:25]([CH3:32])([CH3:31])[CH2:26][CH2:27][O:28][CH2:29]Cl.O>CN(C=O)C.C(OCC)(=O)C>[N:1]1([C:7]2[N:15]=[C:14]3[C:10]([N:11]([CH2:29][O:28][CH2:27][CH2:26][Si:25]([CH3:32])([CH3:31])[CH3:24])[CH:12]=[N:13]3)=[C:9]([N:16]3[CH2:17][CH2:18][O:19][CH2:20][CH2:21]3)[N:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: C[Si](C)(C)CCOCCl
Reactant: c1nc2nc(N3CCOCC3)nc(N3CCOCC3)c2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: C[Si](C)(C)CCOCn1cnc2nc(N3CCOCC3)nc(N3CCOCC3)c21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78.4 %

Procedure:
As shown in Scheme 5 above, 2,6-dicloropyrimidine (1 g, 5.29 mmol) was dissolved in morpholine (5 mL) in a sealed tube. The tube was heated to 120° C. for 5 hours then cooled to room temperature. Water (100 mL) was added and the resulting precipitate was filtered and washed with water to give 2,6-di-morpholin-4-yl-7H-purine (1.33 g, 87%). 2,6-Di-morpholin-4-yl-7H-purine (1.33 g, 4.58 mmol) was dissolved in DMF (50 mL). NaH (0.22 g, 5.50 mmol, 60% dispersion in oil) was added and the reaction was stirred at room temperature for 30 min. 2-(Trimethylsilyl)ethoxymethyl chloride (0.92 g, 5.50 mmol) was added dropwisely and the reaction was stirred for 18 h at room temperature. Water (200 mL) then ethyl aceate (200 mL) were added. The ethyl acetate extracts were washed with water (3×100 mL), dried over MgSO4, filtered and evaporated to dryness. The resulting residue was purified by silicagel column chromatography eluting with a gradient of 1:1 ethyl aceate to ethyl acetate to produce 2,6-Di-morpholin-4-yl-7-(2-trimethylsilanylethoxymethyl)-7H-purine (1.51 g, 78% yield).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][CH2:18][C:19]([OH:21])=O)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN1CCOCC1.C(OC(Cl)=O)C(C)C.[CH2:37]([O:39][C:40](=[O:56])[CH2:41][CH2:42][NH:43][C:44]([CH:46]1[CH2:55][C:54]2[C:49](=[CH:50][CH:51]=[CH:52][CH:53]=2)[NH:48][CH2:47]1)=[O:45])[CH3:38]>CN(C)C=O.O1CCCC1.O>[CH2:37]([O:39][C:40](=[O:56])[CH2:41][CH2:42][NH:43][C:44]([CH:46]1[CH2:55][C:54]2[C:49](=[CH:50][CH:51]=[CH:52][CH:53]=2)[N:48]([C:19](=[O:21])[CH2:18][CH2:17][CH:14]2[CH2:13][CH2:12][N:11]([C:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)=[O:10])[CH2:16][CH2:15]2)[CH2:47]1)=[O:45])[CH3:38]
Reactant: CCOC(=O)CCNC(=O)C1CNc2ccccc2C1
Reactant: O=C(O)CCC1CCN(C(=O)OCc2ccccc2)CC1
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Solvent: O
Product: CCOC(=O)CCNC(=O)C1Cc2ccccc2N(C(=O)CCC2CCN(C(=O)OCc3ccccc3)CC2)C1
Temperature: -15 °C
Yield: 53 %

Procedure:
To a solution of 3-(1-benzyloxycarbonyl-4-piperidyl)propionic acid (0.18 g) in N,N-dimethylformamide (3 ml) was added N-methylmorpholine (0.09 ml) and isobutylchloroformate (0.1 ml) under stirring at −15° C. After stirring at −15° C. for 2 hours, N-[(1,2,3,4-tetrahydro-3-quinolyl)carbonyl]-β-alanine ethyl ester (0.22 g) and N-methylmorpholine (0.12 ml) in tetrahydrofuran (2 ml) was added. After stirring at 0° C. for 2 hours and ambient temperature for overnight, the mixture was poured into water, and extracted with ethyl acetate. The extract was washed with 5% KHSO4 aqueous solution saturated NaHCO3 aqueous solution and brine, and dried over MgSO4, and evaporated in vacuo. The residue was purified by chromatography on silica gel eluting with (CHCl3:MeOH=100:1) to give N-[1-{3-(1-benzyloxycarbonyl-4-piperidyl)propionyl}-1,2,3,4-tetrahydro-3-quinolylcarbonyl]-β-alanine ethyl ester as an oil (0.18 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([S:21](=[O:39])(=[O:38])[NH:22][C:23]2[CH:24]=[CH:25][C:26]3[CH:27]4[CH2:37][CH:28]4[CH2:29][O:30][C:31]=3[C:32]=2[C:33]([O:35][CH3:36])=[O:34])=[C:6]([CH2:8][CH2:9][CH:10]2[CH2:13][N:12]([C:14](OC(C)(C)C)=O)[CH2:11]2)[CH:7]=1.[CH2:40](Cl)Cl>FC(F)(F)C(O)=O>[CH2:14]([N:12]1[CH2:13][CH:10]([CH2:9][CH2:8][C:6]2[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=2[S:21]([NH:22][C:23]2[C:32]([C:33]([O:35][CH3:36])=[O:34])=[C:31]3[C:26]([CH:27]4[CH2:37][CH:28]4[CH2:29][O:30]3)=[CH:25][CH:24]=2)(=[O:39])=[O:38])[CH2:11]1)[CH3:40]
Reactant: ClCCl
Reactant: COC(=O)c1c(NS(=O)(=O)c2ccc(F)cc2CCC2CN(C(=O)OC(C)(C)C)C2)ccc2c1OCC1CC21
Solvent: O=C(O)C(F)(F)F
Product: CCN1CC(CCc2cc(F)ccc2S(=O)(=O)Nc2ccc3c(c2C(=O)OC)OCC2CC32)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of tert-butyl (1aRS,7bSR)-3-{2-[5-fluoro-2-(4-methoxycarbonyl-1,1a,2,7b-tetrahydrocyclopropa[c]chromen-5-ylsulfamoyl)phenyl]ethyl}azetidine-1-carboxylate (Intermediate 184, 0.397 g) in DCM (5 mL) and trifluoroacetic acid (5 mL) was left at room temperature for 30 minutes then evaporated in vacuo and the residue was dissolved in toluene and re-evaporated. The residue was dissolved in DCM (15 mL) and acetaldehyde (0.063 g) was added followed by sodium triacetoxyborohydride (0.301 g). The mixture was stirred at room temperature for 2 hours then diluted with ethyl acetate and water and the organic layer was dried (Na2SO4) and filtered. The filtrate was concentrated in vacuo and the residue was purified by chromatography on silica, eluting with a mixture of methanol and DCM with a gradient of 0-25% to give methyl (1aRS,7bSR)-5-{2-[2-(1-ethylazetidin-3-yl)ethyl]-4-fluorobenzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate (0.312 g) as a white foam.
Reaction SMILES: [OH:1][CH:2]1[CH2:5][CH:4]([CH2:6][N:7]2[CH2:15][C:14]3[C:9](=[CH:10][CH:11]=[C:12]([C:16]4[N:17]=[N:18][N:19]([C:22]5[C:23]([F:28])=[N:24][CH:25]=[CH:26][CH:27]=5)[C:20]=4[CH3:21])[CH:13]=3)[C:8]2=[O:29])[CH2:3]1.C(N(CC)CC)C>CS(C)=O.C(OCC)(=O)C>[O:1]=[C:2]1[CH2:3][CH:4]([CH2:6][N:7]2[CH2:15][C:14]3[C:9](=[CH:10][CH:11]=[C:12]([C:16]4[N:17]=[N:18][N:19]([C:22]5[C:23]([F:28])=[N:24][CH:25]=[CH:26][CH:27]=5)[C:20]=4[CH3:21])[CH:13]=3)[C:8]2=[O:29])[CH2:5]1
Reactant: Cc1c(-c2ccc3c(c2)CN(CC2CC(O)C2)C3=O)nnn1-c1cccnc1F
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: Cc1c(-c2ccc3c(c2)CN(CC2CC(=O)C2)C3=O)nnn1-c1cccnc1F
Reaction time: 1 h
Yield: 60.3 %

Procedure:
20 mg of 4-[2-(3-hydroxy-cyclobutylmethyl)-1-oxo-isoindoline-5-yl]-1-(2-fluoropyridine-3-yl)-5-methyl-1H-[1,2,3]triazole obtained in Example 132 was dissolved in 1 ml of dimethylsulfoxide, and 100 μl of triethylamine followed by 40 mg of sulfur trioxide/pyridine complex were added at room temperature and the mixture was stirred for 1 hour. The reaction solution was diluted with ethyl acetate, washed with water and saturated saline solution, and dried with anhydrous sodium sulfate. The solvents were distilled outunder reduced pressure, and the residues were purified by preparative thin-layer silicagel chromatography (chloroform:methanol=20:1) to obtain 12 mg of the above compound as a white solid.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[Si:7]([O:14][C@@H:15]1[C@@H:19]([F:20])[CH2:18][C@@H:17]([C:21](OCC)=[O:22])[CH2:16]1)([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8]>C1COCC1>[Si:7]([O:14][C@@H:15]1[C@@H:19]([F:20])[CH2:18][C@@H:17]([CH2:21][OH:22])[CH2:16]1)([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8]
Reactant: CCOC(=O)[C@H]1C[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](F)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)O[C@H]1C[C@H](CO)C[C@@H]1F
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 76 %

Procedure:
A slurry of LiAlH4 (2.99 g, 78.5 mmol, 2.0 equiv) in THF (100 mL) was cooled to −78° C. A solution of the above (1S,3S,4S)-ethyl 3-(tert-butyldimethylsilyloxy)-4-fluorocyclopentanecarboxylate in THF (50 mL) was added over 20 min, and the mixture was stirred at −78° C. for 0.5 h. Analysis by tlc showed consumption of the ester. The mixture was allowed to warm to 0° C., then brine (10 mL) was added dropwise over a 15 min, followed by ˜20 g of Celite. The thick slurry was diluted with EtOAc and allowed to stir for 0.5 h. The mixture was filtered through a pad of Celite. The filter cake was washed with additional EtOAc. The resulting clear solution was dried over Na2SO4, filtered, and evaporated. This afforded ((1S,3S,4S)-3-(tert-butyldimethylsilyloxy)-4-fluorocyclopentyl)methanol 7.24 g (76% yield).
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4](=[S:16])[C:5]([C:14]#[N:15])=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:7]=1.[CH2:17](Br)[CH2:18][CH2:19][CH3:20].CC[O-].[Na+]>C(O)C>[NH2:1][C:2]1[N:3]=[C:4]([S:16][CH2:17][CH2:18][CH2:19][CH3:20])[C:5]([C:14]#[N:15])=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:7]=1
Reactant: N#Cc1c(-c2ccccc2)nc(N)[nH]c1=S
Reactant: CCCCBr
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCCCSc1nc(N)nc(-c2ccccc2)c1C#N

Procedure:
From 2-amino-4-phenyl-6-thioxo-1,6-dihydro-pyrimidine-5-carbonitrile, butyl bromide and sodium ethylate in ethanol. EI-MS m/e (%): 284 (M+, 48), 283 ([M—H]+, 100), 241 (([M—C3H7]+, 95), 228 (([M—C2H5CH═CH2]+, 92).
Reaction SMILES: Br[C@@H:2]1[C@@H:8]([OH:9])[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[N:10]1[C:18](=[O:19])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]1=[O:20].C([SnH](CCCC)CCCC)CCC.N(C(C)(C)C#N)=NC(C)(C)C#N>C1(C)C=CC=CC=1.CO>[OH:9][C@H:8]1[CH2:7][CH2:6][CH2:5][CH2:4][C@@H:3]([N:10]2[C:11](=[O:20])[C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:18]2=[O:19])[CH2:2]1
Reactant: O=C1c2ccccc2C(=O)N1[C@@H]1CCCC[C@H](O)[C@H]1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: CCCC[SnH](CCCC)CCCC
Solvent: CO
Solvent: Cc1ccccc1
Product: O=C1c2ccccc2C(=O)N1[C@@H]1CCCC[C@H](O)C1
Yield: 80.8 %

Procedure:
To a solution of 2-((1R,2S,3S)-2-bromo-3-hydroxycycloheptyl)isoindoline-1,3-dione (4.2 g, 12.42 mmol) in toluene (69 mL) and methanol (6.9 mL) was added tributyltin hydride (4.34 mL, 16.14 mmol) via syringe over 10 minutes under nitrogen followed by 2,2′-azobis(2-methylpropanenitrile) (0.204 g, 1.242 mmol) in one portion. The reaction was then heated to reflux overnight under a nitrogen atmosphere. The reaction mixture was concentrated to dryness under reduced pressure to afford a residue that was purified by silica gel chromatography (0-50% ethyl acetate in hexanes). Fractions containing the desired product were concentrated under reduced pressure to afford the title compound (2.6 g, 10.03 mmol, 81% yield) as a solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.72-7.98 (m, 4H), 4.58 (d, J=4.29 Hz, 1H), 4.14 (br. s., 1H), 3.67 (dt, J=6.25, 3.90 Hz, 1H), 2.24-2.40 (m, 1H), 2.04-2.19 (m, 1H), 1.81-1.95 (m, 2H), 1.39-1.80 (m, 6H). MS (ESI) m/z 259.9 [M+H]+.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[Si:11]([O:18][C@@H:19]1[CH2:23][C@H:22]([CH2:24][OH:25])[C@@H:21]([CH2:26][C:27]#[CH:28])[C@H:20]1/[CH:29]=[CH:30]/[C@@H:31]([O:37][Si:38]([C:41]([CH3:44])([CH3:43])[CH3:42])([CH3:40])[CH3:39])[CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12].C(N(CC)CC)C.C(O)(=O)C.[Cl-].[NH4+]>ClCCl>[Si:11]([O:18][C@@H:19]1[CH2:23][C@H:22]([CH:24]=[O:25])[C@H:21]([CH2:26][C:27]#[CH:28])[C@H:20]1/[CH:29]=[CH:30]/[C@@H:31]([O:37][Si:38]([C:41]([CH3:42])([CH3:44])[CH3:43])([CH3:40])[CH3:39])[CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12]
Reactant: C#CC[C@@H]1[C@@H](CO)C[C@@H](O[Si](C)(C)C(C)(C)C)[C@@H]1/C=C/[C@H](CCCCC)O[Si](C)(C)C(C)(C)C
Agent: O=C(Cl)C(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CS(C)=O
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Product: C#CC[C@@H]1[C@@H](/C=C/[C@H](CCCCC)O[Si](C)(C)C(C)(C)C)[C@H](O[Si](C)(C)C(C)(C)C)C[C@@H]1C=O
Temperature: -50 °C
Reaction time: 0.5 h

Procedure:
Oxalyl chloride (5.08 g; 40 mmoles) and 60 ml of dichloromethane were taken into a nitrogen-purged 500 ml eggplant-shaped flask, and cooled to -50° C. A solution of 6.24 g (80 mmoles) of dimethyl sulfoxide in 20 ml of dichloromethane was added, and the mixture was stirred for 30 minutes. A solution of 9.09 g (17.9 mmoles) of (1R,2R,3R,4S)-1-t-butyldimethylsilyloxy-2-[(E,3S)-3-t-butyldimethylsilyloxy-1-octenyl]-4-hydroxymethyl-3-(2-propynyl)cyclopentane (32) in 40 ml of dichloromethane was added, and the mixture was stirred at -50° C. for 30 minutes. Subsequently, 10.1 g (100 mmoles) of triethylamine was added, and the mixture was stirred at -50° C. for 30 minutes. Acetic acid (7.2 g; 120 mmoles) was added, and the mixture was stirred for 10 minutes. The reaction mixture was poured into saturated aqueous ammonium chloride solution and extracted with dichloromethane. The organic layer was washed successively with saturated aqueous potassium hydrogensulfate and saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give 9.05 g (yield of the crude product 100%) of (1R,2R,3R,4S)-1-t-butyldimethylsilyloxy-2-[(E,3S)-3-t-butyldimethylsilyloxy-1-octenyl]-4-formyl-3-(2-propynyl)cyclopentane (20).
Reaction SMILES: CON(C)[C:4](=[O:9])[CH2:5][CH2:6][CH2:7][CH3:8].[CH2:11]([Mg]Cl)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.Cl>C1COCC1>[C:12]1([CH2:11][C:4](=[O:9])[CH2:5][CH2:6][CH2:7][CH3:8])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Cl[Mg]Cc1ccccc1
Reactant: CCCCC(=O)N(C)OC
Agent: Cl
Solvent: C1CCOC1
Product: CCCCC(=O)Cc1ccccc1
Yield: 70.6 %

Procedure:
Part B: To a magnetically stirred solution of pentanoic acid methoxy-methyl-amide (8.6 g, 59.3 mmol) at 0° C. in anhydrous THF (100 ml) was slowly added benzylmagnesium chloride (2 M solution in THF, 45 ml, 90 mmol) and the resulting mixture was reacted for 20 hours in a nitrogen atmosphere at room temperature. The reaction mixture was poured in excess of a cold (0° C.) aqueous hydrochloric acid (4 N solution) and extracted with MTBE. The organic layer was dried over Na2SO4, filtered and concentrated to give crude product. This crude product was further purified using Sepacore equipment: Gradient: (petroleum ether/diethyl ether=98/2 (v/v))=>(petroleum ether/diethyl ether=95/5 (v/v)) to give 1-phenylhexan-2-one (Intermediate II-1) (7.38 gram, 71% yield) as a colorless oil; 1H-NMR (400 MHz, CDCl3) δ 0.86 (t, J=7, 3H), 1.21-1.31 (m, 2H), 1.48-1.58 (m, 2H), 2.41-2.47 (m, 2H), 3.68 (s, 2H), 7.18-7.36 (m, 5H).
Reaction SMILES: Cl[CH:2]([C:4]1[CH:16]=[CH:15][C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH2:7][C:6]=2[CH:5]=1)[CH3:3].[NH:17]1[CH:21]=[CH:20][N:19]=[CH:18]1>CN(C)C=O>[CH:5]1[C:6]2[CH2:7][C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:14]=2[CH:15]=[CH:16][C:4]=1[CH:2]([N:17]1[CH:21]=[CH:20][N:19]=[CH:18]1)[CH3:3]
Reactant: CC(Cl)c1ccc2c(c1)Cc1ccccc1-2
Reactant: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(c1ccc2c(c1)Cc1ccccc1-2)n1ccnc1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
The thus obtained 2-(1-chloroethyl)-9H-fluorene was dissolved in 20 ml of N,N-dimethylformamide, and the solution was mixed with imidazole (2.72 g), followed by stirring at 100° C. for 2 hours. The solvent was evaporated under a reduced pressure, and water was added to the resulting residue, followed by extraction with chloroform. The chloroform layer was washed with water and dried over anhydrous magnesium sulfate, the solvent was evaporated under a reduced pressure and then the resulting residue was purified by silica gel column chromatography to obtain crude crystals from the eluate of a mixed solvent of chloroform and methanol (200:1). By recrystallizing the crude crystals from a mixed solvent of ethyl acetate and ether, 0.6 g of 1-[1-(9H-fluoren-2-yl) ethyl]-1H-imidazole was obtained.
Reaction SMILES: N#N.[C:3]([C:6]1[N:7]=[C:8]([CH2:11]OS(C)(=O)=O)[O:9][CH:10]=1)(=[O:5])[CH3:4].[N+:17]([C:20]1[CH:24]=[N:23][NH:22][N:21]=1)([O-:19])=[O:18].CCN(C(C)C)C(C)C>CN(C=O)C.CC(=O)OCC.O>[N+:17]([C:20]1[CH:24]=[N:23][N:22]([CH2:11][C:8]2[O:9][CH:10]=[C:6]([C:3](=[O:5])[CH3:4])[N:7]=2)[N:21]=1)([O-:19])=[O:18]
Reactant: O=[N+]([O-])c1cn[nH]n1
Reactant: CC(=O)c1coc(COS(C)(=O)=O)n1
Agent: N#N
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(=O)c1coc(Cn2ncc([N+](=O)[O-])n2)n1
Temperature: 50 °C
Reaction time: 20 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of methanesulfonic acid 4-acetyl-oxazol-2-ylmethyl ester (116 mg, 0.53 mmol) in DMF (3.0 mL) was added to a solution of 4-nitro-2H-[1,2,3]triazole (62 mg, 0.53 mmol) in DMF (2.0 mL) pre-treated for 30 min with DIPEA (0.20 mL, 1.17 mmol) and the reaction mixture was stirred for 20 h at 50° C. Water (10 mL), followed by EA (10 mL) were added. The aq. layer was extracted with EA (10 mL) and the combined org. extracts were dried over NaSO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (3:1 to 1:1 hept-EA) gave the title compound as a yellow solid. TLC:rf (1:2 hept-EA)=0.49. LC-MS-conditions 01: tR=0.76 min.
Reaction SMILES: [NH:1]([C:8]([NH:10][C:11]1[CH:39]=[CH:38][C:14]([O:15][C:16]2[CH:21]=[CH:20][N:19]=[C:18]([NH:22][C:23]([CH:25]3[CH2:30][CH2:29][N:28]([C:31](OC(C)(C)C)=O)[CH2:27][CH2:26]3)=[O:24])[CH:17]=2)=[CH:13][C:12]=1[Cl:40])=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.C(=O)(O)[O-].[Na+].[OH-].[Na+]>FC(F)(F)C(O)=O>[NH:1]([C:8]([NH:10][C:11]1[CH:39]=[CH:38][C:14]([O:15][C:16]2[CH:21]=[CH:20][N:19]=[C:18]([NH:22][C:23]([CH:25]3[CH2:26][CH2:27][N:28]([CH3:31])[CH2:29][CH2:30]3)=[O:24])[CH:17]=2)=[CH:13][C:12]=1[Cl:40])=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)Nc2cc(Oc3ccc(NC(=O)Nc4ccccc4)c(Cl)c3)ccn2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CN1CCC(C(=O)Nc2cc(Oc3ccc(NC(=O)Nc4ccccc4)c(Cl)c3)ccn2)CC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 78.6 %

Procedure:
After dissolving 120 mg of t-butyl 4-{[(4-{4-[(anilinocarbonyl)amino]-3-chlorophenoxy}-2-pyridyl)amino]carbonyl}-1-piperidine carboxylate in 5 ml of trifluoroacetic acid, the solution was stirred at room temperature for 5 minutes. Sodium bicarbonate water and 5N aqueous sodium hydroxide were added and extraction was performed with ethyl acetate. The extract was washed with brine and dried over sodium sulfate. The drying agent was filtered off, and the solvent was distilled off under reduced pressure. After adding 5 ml of tetrahydrofuran, 26 mg of acetic acid, 92 mg of sodium triacetoxyborohydride and 0.5 ml of formaldehyde (37% in water) to the residue, the mixture was stirred at room temperature for 10 minutes. Sodium bicarbonate water and 5N aqueous sodium hydroxide were added to the reaction solution, and extraction was performed with ethyl acetate. The extract was washed with brine and then passed through a glass filter coated with NH type silica gel. The silica gel was washed thoroughly with ethyl acetate, the ethyl acetate layers were combined and subjected to distillation under reduced pressure, and the residue was solidified with ethyl acetate and hexane to obtain 80 mg of a colorless powder.
Reaction SMILES: [NH:1]1[CH2:71][CH2:70][CH2:69][CH2:68][C@H:2]1[C:3]([NH:5][C@@H:6]([C:17]([NH:19][C@H:20]([C:28]([NH:30][C@@H:31]([C:49]([NH:51][C@H:52]([C:57]([NH:59][C@H:60]([C:65]([NH2:67])=[O:66])[CH2:61][CH2:62][S:63][CH3:64])=[O:58])[CH2:53][CH:54]([CH3:56])[CH3:55])=[O:50])[CH2:32][CH2:33][CH2:34][NH:35][C:36](=[NH:48])[NH:37]S(C1C=CC(C)=CC=1)(=O)=O)=[O:29])[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:18])[CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][CH:9]=1)=[O:4].F.C1(OC)C=CC=CC=1>>[NH:1]1[CH2:71][CH2:70][CH2:69][CH2:68][C@H:2]1[C:3]([NH:5][C@@H:6]([C:17]([NH:19][C@H:20]([C:28]([NH:30][C@@H:31]([C:49]([NH:51][C@H:52]([C:57]([NH:59][C@H:60]([C:65]([NH2:67])=[O:66])[CH2:61][CH2:62][S:63][CH3:64])=[O:58])[CH2:53][CH:54]([CH3:55])[CH3:56])=[O:50])[CH2:32][CH2:33][CH2:34][NH:35][C:36](=[NH:37])[NH2:48])=[O:29])[CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)=[O:18])[CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][CH:9]=1)=[O:4]
Reactant: CSCC[C@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](CCCNC(=N)NS(=O)(=O)c1ccc(C)cc1)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H](Cc1c[nH]c2ccccc12)NC(=O)[C@@H]1CCCCN1)C(N)=O
Agent: F
Solvent: COc1ccccc1
Product: CSCC[C@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](CCCNC(=N)N)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H](Cc1c[nH]c2ccccc12)NC(=O)[C@@H]1CCCCN1)C(N)=O

Procedure:
Condensation of BocPro-DTrp-PheOH (Example 33, 658 mg.) and HDArg(Tos)-Leu-MetNH2 (630 mg.) using dicyclohexylcarbodiimide and 1-hydroxybenzotriazole gave BocPro-DTrp-Phe-DArg(Tos)-Leu-MetNH2 in 46% yield. De-t-butoxycarbonylation of BocPro-DTrp-Phe-DArg(Tos)-Leu-MetNH2 (524 mg.) using trifluoroacetic acid in dimethyl sulfide and ethanedithiol gave HPro-DTrp-Phe-DArg(Tos)-Leu-MetNH2 in 78% yield. De-p-toluenesulfonylation of HPro-DTrp-Phe-DArg(Tos)-Leu-MetNH2 (420 mg.) using liquid hydrogen fluoride with anisole gave HPro-DTrp-Phe-DArg-Leu-MetNH2, which was isolated as the amorphous off-white solid dihydrochloride acetate (2:1) salt hydrate (2:5) in 61% yield.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=O)[CH2:10][N:11]2[CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[CH2:13][C@@H:12]2[CH3:23])[CH:5]=[CH:6][CH:7]=1.COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:34]2)=CC=1>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=[S:34])[CH2:10][N:11]2[CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[CH2:13][C@@H:12]2[CH3:23])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccc(NC(=O)CN2CCN(c3ccccn3)C[C@@H]2C)c1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: Cc1cccc(NC(=S)CN2CCN(c3ccccn3)C[C@@H]2C)c1
Temperature: 65 °C
Yield: 163.9 %

Procedure:
A solution of the product from Example 214 (200 mg, 0.62 mmol) in dry toluene (6 mL) was treated with 2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulphide (Lawesson's reagent, 125 mg, 0.31 mmol) and heated at 65° C. for 1 hour. The mixture was allowed to cool to room temperature and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (elution with 75% hexanes:ethyl acetate) to provide 173 mg (82% yield) of the title compound as a yellow oil. 1H NMR (300 MHz, CDCl3) δ 1.17 (d, J=6.1 Hz, 3H) 2.39 (s, 3H) 2.75 (dd, J=12.4, 9.8 Hz, 1H) 2.81 (m, 1H) 2.96 (m, 2H) 3.26 (t, J=5.5 Hz, 1H) 3.56 (d, J=17.6 Hz, 1H) 3.88 (d, J=17.6 Hz, 1H) 4.04 (m, 2H) 6.67 (t, J=6.1 Hz, 1H) 6.69 (d, J=8.5 Hz, 1H) 7.08 (d, J=7.5 Hz, 1H) 7.30 (t, J=7.8 Hz, 1H) 7.52 (ddd, J=8.7, 7.0, 2.0 Hz, 1H) 7.67 (s, 1H) 7.74 (d, J=8.1 Hz, 1H) 8.22 (dd, J=4.9, 1.9 Hz, 1H) 11.25 (s, 1H); MS (DCI/NH3) m/e 341.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2([C:27]([F:30])([F:29])[F:28])[CH2:14][C:13]([C:15]3[CH:22]=[CH:21]C(C#N)=[C:17]([C:23]([F:26])([F:25])[F:24])[CH:16]=3)=[N:12][CH2:11]2)[CH:5]=[C:6]([Cl:9])[C:7]=1[Cl:8].O.[CH3:32][C:33]([OH:35])=[O:34]>OS(O)(=O)=O.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:10]2([C:27]([F:28])([F:30])[F:29])[CH2:14][C:13]([C:15]3[CH:22]=[CH:21][C:32]([C:33]([OH:35])=[O:34])=[C:17]([C:23]([F:24])([F:25])[F:26])[CH:16]=3)=[N:12][CH2:11]2)[CH:5]=[C:6]([Cl:9])[C:7]=1[Cl:8]
Reactant: N#Cc1ccc(C2=NCC(c3cc(Cl)c(Cl)c(Cl)c3)(C(F)(F)F)C2)cc1C(F)(F)F
Reactant: CC(=O)O
Agent: O=S(=O)(O)O
Solvent: O
Product: O=C(O)c1ccc(C2=NCC(c3cc(Cl)c(Cl)c(Cl)c3)(C(F)(F)F)C2)cc1C(F)(F)F
Yield: 82 %

Procedure:
4-[3-(3,4,5-Trichlorophenyl)-3-(trifluoromethyl)-3,4-dihydro-2H-pyrrol-5-yl]-2-(trifluoromethyl)benzonitrile (0.82 g, 1.68 mmol) was dissolved in AcOH and suspended in conc. H2SO4—H2O mixture. The reaction mixture was stirred vigorously and refluxed for 26 hours. The reaction mixture was then poured to a mixture of ice and water. The resulting mixture was then extracted with EtOAc and the organic layer was washed with brine and dried over Na2SO4. The solvent was evaporated to obtain the product (0.70 g, 82%).