Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:3]2[CH:11]=[CH:10][NH:9][C:4]=2[N:5]=[C:6]([NH2:8])[N:7]=1.[O:12]1[CH:16]=[CH:15][CH:14]=[C:13]1[C:17]([NH:19][NH2:20])=[O:18]>C(O)CCC>[NH2:8][C:6]1[N:7]=[C:2]([NH:20][NH:19][C:17]([C:13]2[O:12][CH:16]=[CH:15][CH:14]=2)=[O:18])[C:3]2[CH:11]=[CH:10][NH:9][C:4]=2[N:5]=1
Reactant: Nc1nc(Cl)c2cc[nH]c2n1
Reactant: NNC(=O)c1ccco1
Solvent: CCCCO
Product: Nc1nc(NNC(=O)c2ccco2)c2cc[nH]c2n1
Temperature: 120 °C
Reaction time: 2 h

Procedure:
4-Chloro-7H-pyrrolo[2,3-d]pyrimidin-2-amine (0.5 g, 2 96 mmol) and 2-furoic acid hydrazide (0.76 g, 6.0 mmol) are taken into 30 mL of n-butanol. The mixture is stirred at 120° C. under N2 for 2 h. The solvent is evaporated in vacuum and the residue is triturated with water and filtered to afford compound N′-(2-amino-7H-pyrrolo[2,3-d]pyrimidin-4-yl)furan-2-carbohydrazide: LC/MS (M+1=259.32). This material is used in the next step without further purification.
Reaction SMILES: [N:1]1(C(OC(C)(C)C)=O)[CH2:40][CH2:39][CH2:38][C@H:2]1[C:3]([NH:5][C@H:6]([C:8]([NH:10][C@H:11]([C:28]([O:30]CC1C=CC=CC=1)=[O:29])[CH2:12][CH2:13][CH2:14][CH2:15][NH:16]C(OCC1C=CC=CC=1Cl)=O)=[O:9])[CH3:7])=[O:4].C1(OC)C=CC=CC=1>>[NH:1]1[CH2:40][CH2:39][CH2:38][C@H:2]1[C:3]([NH:5][C@H:6]([C:8]([NH:10][C@H:11]([C:28]([OH:30])=[O:29])[CH2:12][CH2:13][CH2:14][CH2:15][NH2:16])=[O:9])[CH3:7])=[O:4]
Reactant: C[C@H](NC(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C)C(=O)N[C@@H](CCCCNC(=O)OCc1ccccc1Cl)C(=O)OCc1ccccc1
Solvent: COc1ccccc1
Product: C[C@H](NC(=O)[C@@H]1CCCN1)C(=O)N[C@@H](CCCCN)C(=O)O
Temperature: 0 °C
Reaction time: 1 h
Yield: 76.3 %

Procedure:
The solution of 280 mg (0.417 mmol) of Boc-Pro-Ala-Lys(ClZ)-OBzl, 1 ml of anisole and 2 ml of HF was stirred at 0° C. for 2 h. The reaction mixture was evaporated under reduced pressure to remove HF. To the residue 2 ml of HF were added and the solution was stirred at 0° C. for another 1 h. The reaction mixture was evaporated under reduced pressure to remove HF. The residue was triturated with ether and the resulted solid was purified on the Sephadex G-10 column. The collected fractions were lyophilized to provide 100 mg (75%) of the title compound. Mp. 150–152° C., FAB-MS (m/e) 315[M+H]+.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[OH:6][CH2:7][CH2:8][N:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([CH3:18])=[C:10]1[C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1.C(N(CC)CC)C>C(Cl)Cl>[CH3:1][S:2]([O:6][CH2:7][CH2:8][N:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([CH3:18])=[C:10]1[C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1c(-c2cccnc2)n(CCO)c2ccccc12
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1c(-c2cccnc2)n(CCOS(C)(=O)=O)c2ccccc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Methanesulfonyl chloride (2.70 ml) is added dropwise to a solution of 7.5 g 1-(2-hydroxyethyl)-2-(3-pyridyl)-3-methylindole and 10.34 ml of triethylamine in 150 ml of methylene chloride at -10°. This mixture is stirred at room temperature for 0.5 hour and poured into 600 ml of ice water. The resulting slurry is extracted with methylene chloride and the extract is washed with saturated NaHCO3 solution, dried over MgSO4 and evaporated in vacuo. There is obtained 1-(2-methylsulfonyloxyethyl)-2-(3-pyridyl)-3-methylindole which is used directly in the above reaction.
Reaction SMILES: [NH:1](C(OCC1C=CC=CC=1)=O)[C@H:2]([C:11]([NH:13][C@H:14]([C:24]([NH:26][C@H:27]([C:30]([NH:32][C@H:33]([C:35]([NH:37][C@H:38]([C:48]([NH:50][C@H:51]([C:53]([NH:55][C@H:56]([C:64]([N:66]1[CH2:109][CH2:108][CH2:107][C@H:67]1[C:68]([NH:70][C@H:71]([C:76]([NH:78][C@H:79]([C:89]([NH:91][C@H:92]([C:100]([O:102][C:103]([CH3:106])([CH3:105])[CH3:104])=[O:101])[CH2:93][C:94]1[CH:99]=[CH:98][CH:97]=[CH:96][CH:95]=1)=[O:90])[CH2:80][CH2:81][C:82](=[O:88])[O:83][C:84]([CH3:87])([CH3:86])[CH3:85])=[O:77])[CH2:72][CH:73]([CH3:75])[CH3:74])=[O:69])=[O:65])[CH2:57][C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=1)=[O:54])[CH3:52])=[O:49])[CH2:39][CH2:40][C:41](=[O:47])[O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:36])[CH3:34])=[O:31])[CH2:28][OH:29])=[O:25])[CH2:15][CH2:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:12])[CH2:3][C:4](=[O:10])[O:5][C:6]([CH3:9])([CH3:8])[CH3:7]>[Pd].C(O)(=O)C>[NH2:1][C@H:2]([C:11]([NH:13][C@H:14]([C:24]([NH:26][C@H:27]([C:30]([NH:32][C@H:33]([C:35]([NH:37][C@H:38]([C:48]([NH:50][C@H:51]([C:53]([NH:55][C@H:56]([C:64]([N:66]1[CH2:109][CH2:108][CH2:107][C@H:67]1[C:68]([NH:70][C@H:71]([C:76]([NH:78][C@H:79]([C:89]([NH:91][C@H:92]([C:100]([O:102][C:103]([CH3:104])([CH3:106])[CH3:105])=[O:101])[CH2:93][C:94]1[CH:95]=[CH:96][CH:97]=[CH:98][CH:99]=1)=[O:90])[CH2:80][CH2:81][C:82](=[O:88])[O:83][C:84]([CH3:85])([CH3:86])[CH3:87])=[O:77])[CH2:72][CH:73]([CH3:75])[CH3:74])=[O:69])=[O:65])[CH2:57][C:58]1[CH:59]=[CH:60][CH:61]=[CH:62][CH:63]=1)=[O:54])[CH3:52])=[O:49])[CH2:39][CH2:40][C:41](=[O:47])[O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:36])[CH3:34])=[O:31])[CH2:28][OH:29])=[O:25])[CH2:15][CH2:16][C:17](=[O:23])[O:18][C:19]([CH3:21])([CH3:22])[CH3:20])=[O:12])[CH2:3][C:4](=[O:10])[O:5][C:6]([CH3:9])([CH3:8])[CH3:7]
Reactant: CC(C)C[C@H](NC(=O)[C@@H]1CCCN1C(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](C)NC(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)[C@H](C)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)[C@H](CC(=O)OC(C)(C)C)NC(=O)OCc1ccccc1)C(=O)N[C@@H](CCC(=O)OC(C)(C)C)C(=O)N[C@@H](Cc1ccccc1)C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CC(=O)O
Product: CC(C)C[C@H](NC(=O)[C@@H]1CCCN1C(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](C)NC(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)[C@H](C)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)[C@@H](N)CC(=O)OC(C)(C)C)C(=O)N[C@@H](CCC(=O)OC(C)(C)C)C(=O)N[C@@H](Cc1ccccc1)C(=O)OC(C)(C)C

Procedure:
67.25 g. (42.15 mmoles) of Z-29-39-OtBu are dissolved in 1300 ml. of 80 % acetic acid, and the mixture is hydrogenated in the presence of palladium-on-carbon. At the end of the reaction the catalyst is filtered off, and the filtrate is evaporated to dryness. The residue is triturated with ether, the solid is filtered off, and dried. 63.8 g. (95%) of H-29-39OtBu are obtained. M.p.: 128°-132° C (under decomposition), Rf5 = 0.3.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9](=[O:14])[C:10]([F:13])([F:12])[F:11].[C:15]([O:21][C@H:22]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:23](Cl)=[O:24])(=[O:20])[C:16]([CH3:19])([CH3:18])[CH3:17].CN(C)C1C=CC=CC=1.Cl>ClCCl>[C:15]([O:21][C@H:22]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:23]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9](=[O:14])[C:10]([F:13])([F:11])[F:12])=[O:24])(=[O:20])[C:16]([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)C(=O)O[C@@H](C(=O)Cl)c1ccccc1
Reactant: Nc1ccc(Cl)cc1C(=O)C(F)(F)F
Agent: Cl
Solvent: ClCCl
Solvent: CN(C)c1ccccc1
Product: CC(C)(C)C(=O)O[C@@H](C(=O)Nc1ccc(Cl)cc1C(=O)C(F)(F)F)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
1-(2-amino-5-chlorophenyl)-2,2,2-trifluoroethanone (2, 5.0 g, 22.4 mmol) was dissolved in dichloromethane (50 mL) and (R)-2-chloro-2-oxo-1-phenylethyl pivalate (8.54 g, 33.5 mmol) was added. To this mixture N,N-dimethylaniline (2.8 mL, 22.4 mmol) was added. The reaction mixture was stirred at room temperature for 3 hours. The mixture was diluted with dichloromethane (50 mL), treated with 1N HCl, washed with brine and the organic layer was separated and evaporated to give (R)-2-(4-chloro-2-(2,2,2-trifluoroacetyl)-phenylamino)-2-oxo-1-phenylethyl pivalate (12) as an brown oil.
Reaction SMILES: Cl.Cl.[N:3]1([C:8]2[CH:22]=[CH:21][C:11]([C:12]([N:14]3[CH2:19][CH2:18][CH:17]([NH2:20])[CH2:16][CH2:15]3)=[O:13])=[CH:10][CH:9]=2)[CH:7]=[CH:6][N:5]=[CH:4]1.[CH3:23][C:24]1[CH:32]=[CH:31][CH:30]=[C:29]([CH3:33])[C:25]=1[C:26](Cl)=[O:27]>>[N:3]1([C:8]2[CH:9]=[CH:10][C:11]([C:12]([N:14]3[CH2:19][CH2:18][CH:17]([NH:20][C:26](=[O:27])[C:25]4[C:29]([CH3:33])=[CH:30][CH:31]=[CH:32][C:24]=4[CH3:23])[CH2:16][CH2:15]3)=[O:13])=[CH:21][CH:22]=2)[CH:7]=[CH:6][N:5]=[CH:4]1
Reactant: NC1CCN(C(=O)c2ccc(-n3ccnc3)cc2)CC1
Reactant: Cc1cccc(C)c1C(=O)Cl
Agent: Cl
Product: Cc1cccc(C)c1C(=O)NC1CCN(C(=O)c2ccc(-n3ccnc3)cc2)CC1

Procedure:
In a manner similar to that described in Example 10, 1-[4-(1H-imidazol-1-yl)benzoyl]-4-piperidinamine dihydrochloride and 2,6-dimethylbenzoyl chloride are reacted to give the title compound.
Reaction SMILES: [CH3:1][N:2]1[C:10]([CH3:11])=[C:9]2[C:4]([CH:5]=[CH:6][C:7]([N:12]3[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][C:13]3=[O:19])=[CH:8]2)=[N:3]1.[F:20][C:21]([F:30])([F:29])[C:22]1[S:26][CH:25]=[C:24]([CH2:27]O)[CH:23]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>O1CCCC1>[CH3:1][N:2]1[C:10]([CH3:11])=[C:9]2[C:4]([CH:5]=[CH:6][C:7]([N:12]3[CH:17]=[CH:16][C:15]([O:18][CH2:27][C:24]4[CH:23]=[C:22]([C:21]([F:30])([F:29])[F:20])[S:26][CH:25]=4)=[CH:14][C:13]3=[O:19])=[CH:8]2)=[N:3]1
Reactant: OCc1csc(C(F)(F)F)c1
Reactant: Cc1c2cc(-n3ccc(O)cc3=O)ccc2nn1C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: Cc1c2cc(-n3ccc(OCc4csc(C(F)(F)F)c4)cc3=O)ccc2nn1C
Reaction time: 3 h
Yield: 42.6 %

Procedure:
To a suspension of 1-(2,3-dimethyl-2H-indazol-5-yl)-4-hydroxypyridin-2(1H)-one (50 mg), [5-(trifluoromethyl)thiophen-3-yl]methanol (71 mg) and triphenylphosphine (154 mg) in tetrahydrofuran (5 ml) was added bis(2-methoxyethyl)azodicarboxylate (138 mg) at room temperature, and the mixture was stirred at the same temperature for 3 hr. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate/methanol) and recrystallized from ethanol-hexane to give the title compound (35 mg).
Reaction SMILES: [CH3:1][CH:2]([OH:4])[CH3:3].[H-].[Na+].Cl[C:8]1[N:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:9]=1[C:10]([NH2:12])=[O:11]>CN(C=O)C>[Cl:17][C:15]1[CH:14]=[CH:13][C:9]([C:10]([NH2:12])=[O:11])=[C:8]([O:4][CH:2]([CH3:3])[CH3:1])[N:16]=1
Reactant: NC(=O)c1ccc(Cl)nc1Cl
Reactant: CC(C)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)Oc1nc(Cl)ccc1C(N)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 52.3 %

Procedure:
To a solution of propan-2-ol (2.94 mL, 39.26 mmol) in DMF (15 mL) at 0° C. was added sodium hydride (95% in mineral oil, 0.94 g, 39.26 mmol) in portions and stirred for 1 h at room temperature. This mixture was slowly added to a solution of 2,6-dichloro-nicotinamide (5.0 g, 26.17 mmol) in DMF (25 mL) at 0° C. The reaction mixture was stirred at room temperature overnight. DMF was removed under reduced pressure, and the resulting mixture was diluted with EtOAc (50 mL), washed with water (2×20 mL) and brine (2×10 mL) solution, dried over anhydrous Na2SO4, filtered, and concentrated to give yellow oil. Purification was accomplished by flash chromatography on silica gel using 5-50% EtOAc/hexanes gradient elution to yield the title compound (2.94 g, 64%) as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm 8.45 (d, J=8.2 Hz, 1 H), 7.73 (br. s., 1 H), 7.03 (d, J=7.8 Hz, 1 H), 5.84 (br. s., 1 H), 5.64-5.47 (m, 1 H), 1.45 (d, J=6.3 Hz, 6 H).
Reaction SMILES: [Li+].[C:2]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH:19]([CH3:23])[C:20]([O-:22])=O)[CH2:14][CH2:13]2)=[CH:8][CH:7]=1)([CH3:5])([CH3:4])[CH3:3].F[P-](F)(F)(F)(F)F.CN(C)C(ON1C2C=CC=CC=2N=N1)=[N+](C)C.Cl.[N+:49]([C:52]1[CH:57]=[CH:56][C:55]([NH:58][CH:59]2[CH2:64][CH2:63][NH:62][CH2:61][CH2:60]2)=[CH:54][C:53]=1[C:65]([F:68])([F:67])[F:66])([O-:51])=[O:50].C(N(C(C)C)CC)(C)C.[O-2].[Al+3].[O-2].[O-2].[Al+3]>CN(C)C=O.O1CCCC1>[C:2]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH:19]([CH3:23])[C:20]([N:62]3[CH2:63][CH2:64][CH:59]([NH:58][C:55]4[CH:56]=[CH:57][C:52]([N+:49]([O-:51])=[O:50])=[C:53]([C:65]([F:66])([F:67])[F:68])[CH:54]=4)[CH2:60][CH2:61]3)=[O:22])[CH2:14][CH2:13]2)=[CH:8][CH:7]=1)([CH3:3])([CH3:4])[CH3:5]
Reactant: O=[N+]([O-])c1ccc(NC2CCNCC2)cc1C(F)(F)F
Reactant: CC(CN1CCN(c2ccc(C(C)(C)C)cc2)CC1)C(=O)[O-]
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(CN1CCN(c2ccc(C(C)(C)C)cc2)CC1)C(=O)N1CCC(Nc2ccc([N+](=O)[O-])c(C(F)(F)F)c2)CC1
Reaction time: 4 h
Yield: 50 %

Procedure:
3-[4-(4-tert-Butyl-phenyl)-piperazin-1-yl]-2-methyl-propionic acid lithium salt (15 mg; 0.05 mmol, prepared in accordance with Example 129) and tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate (19 mg; 0.05 mmol) are diluted in a 2 to 1 mixture of dimethylformamide and tetrahydrofuran (0.75 mL). A solution of (4-nitro-3-trifluoromethyl-phenyl)-piperidin-4-yl-amine hydrochloride (16 mg; 0.05 mmol, prepared in accordance with Example 8) in dimethylformamide (0.25 mL) and diisopropylethyl amine (25 μL; 0.15 mmol) are added and the reaction is then stirred. After 4 hours at room temperature, aluminium oxide (90 active basic) is added and stiffing is continued for 40 minutes. The solids are removed by filtration and the filtrate is concentrated under high vacuum. The obtained residue is purified by preparative HPLC to afford the desired compound (15 mg; 0.025 mmol). The structure was confirmed using Protocol I-D. Calculated mass=576; observed mass=576; HPLC retention time=1.61 min.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:11]([CH3:12])=[C:10]([CH3:13])[S:9][C:8]=2[F:14])[N:5]=[C:4]([OH:15])[CH:3]=1.[C:16](Cl)(=[O:18])[CH3:17]>C1(C)C=CC=CC=1>[C:16]([NH:1][C:2]1[N:6]([C:7]2[C:11]([CH3:12])=[C:10]([CH3:13])[S:9][C:8]=2[F:14])[N:5]=[C:4]([OH:15])[CH:3]=1)(=[O:18])[CH3:17]
Reactant: CC(=O)Cl
Reactant: Cc1sc(F)c(-n2nc(O)cc2N)c1C
Solvent: Cc1ccccc1
Product: CC(=O)Nc1cc(O)nn1-c1c(F)sc(C)c1C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Then, the obtained pyrazole derivative was dissolved in 50 mL of toluene, and to this solution, 6.0 g of acetyl chloride was added, followed by reflux with heating for 12 hours. After cooling to room temperature, the solvent was distilled off under reduced pressure, the residue was dissolved in 30 mL of ethanol, and 20 mL of a 25mass % ammonia water was added, followed by stirring at room temperature for 30minutes. The solvent was distilled off under reduced pressure, and the obtained solid was washed with diisopropyl ether to obtain 5.2 g of 5-acetylamino-1-(2-fluoro-4-methyl-5-methylthiophenyl)-3-hydroxypyrazole in the form of pale yellow crystals (melting point: 204-205° C.).
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([C:21]3[N:22]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[C:23]([C:26]4[CH:31]=[CH:30][C:29]([CH:32]=[O:33])=[CH:28][N:27]=4)=[CH:24][CH:25]=3)[CH2:14][CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.[BH4-].[Na+].C(=O)([O-])O.[Na+]>C(O)C>[CH:1]1([S:4]([C:7]2[CH:8]=[CH:9][C:10]([CH:13]([C:21]3[N:22]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[C:23]([C:26]4[CH:31]=[CH:30][C:29]([CH2:32][OH:33])=[CH:28][N:27]=4)=[CH:24][CH:25]=3)[CH2:14][CH:15]3[CH2:16][CH2:17][O:18][CH2:19][CH2:20]3)=[CH:11][CH:12]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(C=O)cn2)ccc1C(CC1CCOCC1)c1ccc(S(=O)(=O)C2CC2)cc1
Agent: O=C([O-])O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)OC(=O)n1c(-c2ccc(CO)cn2)ccc1C(CC1CCOCC1)c1ccc(S(=O)(=O)C2CC2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 99.6 %

Procedure:
To a solution of tert-butyl 2-{1-[4-(cyclopropylsulfonyl)phenyl]-2-(tetrahydro-2H-pyran-4-yl)ethyl}-5-(5-formylpyridin-2-yl)-1H-pyrrole-1-carboxylate (3 g) in ethanol (10 mL) was added sodium borohydride (221 mg), and the mixture was stirred at room temperature for 10 min. Saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (3 g, yield 100%) was obtained as a pale-yellow amorphous solid from a fraction eluted with hexane-ethyl acetate (1:1, volume ratio). MS: 567 (MH+).
Reaction SMILES: [CH3:1][Si:2]([CH3:20])([CH3:19])[CH2:3][CH2:4][O:5][CH2:6][N:7]1[C:11]([C:12]([O:14]C)=[O:13])=[CH:10][C:9]2[S:16][CH:17]=[CH:18][C:8]1=2.[Li+].[OH-]>CCO>[CH3:1][Si:2]([CH3:20])([CH3:19])[CH2:3][CH2:4][O:5][CH2:6][N:7]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[S:16][CH:17]=[CH:18][C:8]1=2
Reactant: COC(=O)c1cc2sccc2n1COCC[Si](C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Product: C[Si](C)(C)CCOCn1c(C(=O)O)cc2sccc21
Temperature: 75 °C
Yield: 93.2 %

Procedure:
Methyl 4-(2-trimethylsilanyl-ethoxymethyl)-4H-thieno[3,2-b]pyrrole-5-carboxylate (2.89 g, 9.27 mmol) was dissolved in 60 mL EtOH. A 2.0 M solution of LiOH (46 mL) was added and the reaction was heated to 75° C. for 30 min. EtOH was removed with a N2 stream. The residue was taken up in 300 mL water and acidified to pH 2 with conc. HCl, which gave a white precipitate. The precipitate was extracted into EtOAc. The solution was dried (Na2SO4), filtered and evaporated in vacuo to give 4-(2-trimethylsilanyl-ethoxymethyl)-4H-thieno[3,2-b]pyrrole-5-carboxylic acid (2.57 g, 93% yield). 1H NMR (400 MHz, (CD3)2CO) δ ppm −0.08 (s, 9H) 0.77-0.91 (m, 2H) 3.55 (t, 2H) 5.96 (s, 2H) 7.23 (d, J=5.37 Hz, 1H) 7.31 (s, 1H) 7.55 (d, J=5.37 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[N:5]=[C:4]([CH:9]([CH3:11])[CH3:10])[N:3]=1.Cl.[F:13][C:14]([F:28])([F:27])[C:15]1[CH:16]=[C:17]([CH:24]=[CH:25][CH:26]=1)[O:18][CH2:19][CH:20]([NH2:23])[CH2:21][CH3:22].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[NH2:1][C:2]1[N:3]=[C:4]([CH:9]([CH3:11])[CH3:10])[N:5]=[C:6]([NH:23][CH:20]([CH2:21][CH3:22])[CH2:19][O:18][C:17]2[CH:24]=[CH:25][CH:26]=[C:15]([C:14]([F:13])([F:27])[F:28])[CH:16]=2)[N:7]=1
Reactant: CC(C)c1nc(N)nc(Cl)n1
Reactant: CCC(N)COc1cccc(C(F)(F)F)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCC(COc1cccc(C(F)(F)F)c1)Nc1nc(N)nc(C(C)C)n1
Temperature: 80 °C
Yield: 75.8 %

Procedure:
2.6 g (0.015 mol) of 2-amino4-chloro-6-isopropyl-1,3,5-triazine, 4.0 g (0.015 mol) of 1-(3-trifluoromethylphenoxy)-2-aminobutane hydrochloride and 6.2 g (0.045 mol) of potassium carbonate were added to 50 ml of dimethylformamide (DMF). The mixture was heated at 80° C. for 3 hours, added into water and extracted with ethyl acetate. The organic phase was washed with water, dried over magnesium sulfate and filtered and the solvent was evaporated under reduced pressure. Purification by silica gel column chromatography using ethyl acetate/petroleum ether (1:1) gave 4.2 g (76%) of the title compound.
Reaction SMILES: C(OC([CH:8]1[CH:12]2[CH2:13][N:14]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]4[S:25][C:26]5[CH:32]=[CH:31][CH:30]=[CH:29][C:27]=5[N:28]=4)=[CH:19][CH:18]=3)[CH2:15][CH:11]2[CH2:10][N:9]1[S:33]([NH2:36])(=[O:35])=[O:34])=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl.CO.CS(C)=O>[S:25]1[C:26]2[CH:32]=[CH:31][CH:30]=[CH:29][C:27]=2[N:28]=[C:24]1[O:23][C:20]1[CH:19]=[CH:18][C:17]([CH2:16][N:14]2[CH2:15][CH:11]3[CH2:10][N:9]([S:33]([NH2:36])(=[O:34])=[O:35])[CH2:8][CH:12]3[CH2:13]2)=[CH:22][CH:21]=1
Reactant: CC(C)(C)OC(=O)C1C2CN(Cc3ccc(Oc4nc5ccccc5s4)cc3)CC2CN1S(N)(=O)=O
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NS(=O)(=O)N1CC2CN(Cc3ccc(Oc4nc5ccccc5s4)cc3)CC2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.7 %

Procedure:
To a stirred solution tert-butoxy carbonyl-5-[4-(benzothiazol-2-yloxy)-benzyl]-hexahydro-pyrrolo[3,4-c]pyrrole-2-sulfonic acid amide (108 mg, 0.20 mmol) in CH2Cl2 (5 mL) was added trifluoroacetic acid (1 mL). The homogeneous reaction mixture was allowed to stir overnight at rt. The crude reaction mixture was blown down to dryness and dissolved in CH3OH/DMSO (2:1) and purified via reverse phase preparative HPLC to afford the title compound as fluffy white powder (60 mg, 70%). MS (ESI): mass calcd. for C20H22N4O3S2, 430.6; m/z found, 431.1 [M+H]+; 1H NMR (500 MHz, CD3OD): 7.79 (d, J=8.0 Hz, 1H), 7.67 (d, J=8.1 Hz, 1H), 7.52-7.46 (m, 2H), 7.46-7.39 (m, 1H), 7.37-7.27 (m, 3H), 3.68 (s, 2H), 3.24 (dd, J=9.5, 7.0 Hz, 2H), 3.06 (dd, J=9.4, 2.6 Hz, 2H), 2.93-2.87 (m, 2H), 2.87-2.78 (m, 2H), 2.40 (dd, J=8.5, 3.6 Hz, 2H).
Reaction SMILES: [CH3:1]C1N=CN2C=1C=NNC2=S.[CH3:12][C:13]1[N:14]=[C:15]([CH2:23][CH2:24][CH3:25])[N:16]2[C:21]=1[CH:20]=[N:19][NH:18][C:17]2=[S:22]>C1CCCCC1>[CH3:12][C:13]1[N:14]=[C:15]([CH2:23][CH2:24][CH3:25])[N:16]2[C:21]=1[CH:20]=[N:19][N:18]=[C:17]2[S:22][CH3:1]
Reactant: Cc1ncn2c(=S)[nH]ncc12
Reactant: CCCc1nc(C)c2cn[nH]c(=S)n12
Solvent: C1CCCCC1
Product: CCCc1nc(C)c2cnnc(SC)n12

Procedure:
Repeating the procedure of Example 59 in every detail except that in lieu of 8-methylimidazo[1,5-d]-as-triazine-4(3H)-thione, 8-methyl-6-propylimidazo[1,5-d]-as-triazine-4(3H)-thione is employed, there is obtained the desired above-noted product having a melting point equal to 74°-78° C (cyclohexane).
Reaction SMILES: [F:1][C:2]([F:48])([F:47])[CH:3]([NH:36]C(=O)OCC1C=CC=CC=1)[C:4]([NH:6][C@@:7]([C:22]1[CH:27]=[C:26]([O:28][C:29]([F:34])([F:33])[CH:30]([F:32])[F:31])[CH:25]=[C:24]([F:35])[CH:23]=1)([C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1)[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:5].[Si](I)(C)(C)C>C(Cl)Cl>[NH2:36][CH:3]([C:2]([F:47])([F:48])[F:1])[C:4]([NH:6][C@@:7]([C:22]1[CH:27]=[C:26]([O:28][C:29]([F:34])([F:33])[CH:30]([F:32])[F:31])[CH:25]=[C:24]([F:35])[CH:23]=1)([C:15]1[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=1)[CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)=[O:5]
Reactant: O=C(NC(C(=O)N[C@](Cc1ccccc1)(c1ccc(F)cc1)c1cc(F)cc(OC(F)(F)C(F)F)c1)C(F)(F)F)OCc1ccccc1
Agent: C[Si](C)(C)I
Solvent: ClCCl
Product: NC(C(=O)N[C@](Cc1ccccc1)(c1ccc(F)cc1)c1cc(F)cc(OC(F)(F)C(F)F)c1)C(F)(F)F
Temperature: 25 °C
Reaction time: 20 h
Yield: 64.9 %

Procedure:
To a solution of benzyl 1,1,1-trifluoro-3-((R)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethylamino)-3-oxopropan-2-ylcarbamate (10 mg, 0.014 mmol) in CH2Cl2 (0.5 mL) was added TMSI (18 mg, 0.094 mmol). The reaction mixture was sealed and stirred at rt for 20 h. The reaction mixture was concentrated under reduced pressure and the residue was purified by prep HPLC (Phenomenex Luna AXIA 5μ 21.2×100 mm, 10%-90% ACN/H2O containing 0.1% TFA, flow rate 20 mL/min, gradient time 10 min) to yield 2-amino-3,3,3-trifluoro-N—((R)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-(4-fluorophenyl)-2-phenylethyl)propanamide (Example 324) as a white solid (5 mg, 65% yield). HPLC: RT=1.90 min [M+H] 551.5 (Phenomenex Luna C18 column, 4.6×50 mm eluting with 10-90% MeOH/H2O over 2 minutes containing 0.1% TFA; 5 mL/min, monitoring at 220 nm); 1H NMR (400 MHz, CDCl3) δ ppm 7.82-7.85, m, 1H, 7.19-7.23, m, 1H, 7.11-7.17, m, 2H, 7.07-7.11, m, 1H, 6.98-7.03, m, 3H, 6.89-6.93, m, 2H, 6.80-6.86, m, 1H, 6.61-6.64, m, 2H, 5.73-5.99, t, J=52, 1H, 4.00-4.03, J=12, d, 1H, 3.98, m, 1H, 3.63-3.67, d, J=12, 1H;