Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[CH:9]=[CH:8][C:7]([C:10]3[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][CH:11]=3)=[N:6]2)[CH2:3][CH2:2]1>CO.Cl.[Pd]>[CH:1]1([CH2:4][N:5]2[CH:9]=[CH:8][C:7]([C:10]3[CH:11]=[CH:12][C:13]([CH2:14][NH2:15])=[CH:16][CH:17]=3)=[N:6]2)[CH2:3][CH2:2]1
Reactant: N#Cc1ccc(-c2ccn(CC3CC3)n2)cc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: NCc1ccc(-c2ccn(CC3CC3)n2)cc1
Yield: 79.2 %

Procedure:
Bubble nitrogen into a solution of 4-(1-cyclopropylmethyl-1H-pyrazol-3-yl)-benzonitrile (256 mg, 1.15 mmol) in methanol (48 mL) with 5 drops of concentrated hydrochloric acid for 10 min. Add 10% Pd/C (Degussa type, 48 mg) and submit the mixture to hydrogenation at atmospheric pressure overnight. Filter the mixture over Celite® and concentrate in vacuo. Add saturated aqueous NaHCO3 and extract twice with AcOEt. Dry the combined organic extracts over MgSO4, filter and concentrate in vacuo to give the title compound as a yellow oil (207 mg, 80%). MS (ES+) m/z: 228 (M+H)+.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH:10]([NH:20][C:21]([CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][N:24]2[C:29]([CH:31]2[CH2:36][CH2:35][CH2:34][CH2:33][N:32]2C(OC(C)(C)C)=O)=[O:30])=[O:22])[CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[C:1]1([CH2:7][CH2:8][CH2:9][CH:10]([NH:20][C:21]([CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][N:24]2[C:29]([CH:31]2[CH2:36][CH2:35][CH2:34][CH2:33][NH:32]2)=[O:30])=[O:22])[CH2:11][CH2:12][CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CCCCC1C(=O)N1CCCCC1C(=O)NC(CCCc1ccccc1)CCCc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(NC(CCCc1ccccc1)CCCc1ccccc1)C1CCCCN1C(=O)C1CCCCN1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
1-[1-(tert-Butoxycarbonyl)piperidine-2-carbonyl]-piperidine-2-carboxylic acid [4-phenyl-1-(3-phenyl-propyl)-butyl]-amide (32) (1.05 g; 1.78 mmol) is dissolved in methylene chloride (40 mL) at ambient temperature. Trifluoroacetic acid (20 mL) is added in a slow stream, and the solution is stirred for 4 hours at ambient temperature. The solution is concentrated in vacuo at 40° C. The residue is dissolved in methylene chloride (200 mL) and poured onto saturated sodium bicarbonate solution. The pH is adjusted to 9 with saturated potassium carbonate solution. The mixture is shaken and the layers separated. The water layer is extracted with methylene chloride (3×50 mL). The combined organic extracts are washed with water, dried over MgSO4, filtered, and concentrated in vacuo affording the desired product as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][C:3]=1[C:12]([F:15])([F:14])[F:13].[Br:16][C:17]1[C:22]([NH2:23])=[CH:21][C:20]([Cl:24])=[CH:19][N:18]=1>N1C=CC=CC=1>[Br:16][C:17]1[C:22]([NH:23][S:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([C:12]([F:15])([F:14])[F:13])[CH:4]=2)(=[O:10])=[O:9])=[CH:21][C:20]([Cl:24])=[CH:19][N:18]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)c(C(F)(F)F)c1
Reactant: Nc1cc(Cl)cnc1Br
Solvent: c1ccncc1
Product: O=S(=O)(Nc1cc(Cl)cnc1Br)c1ccc(Cl)c(C(F)(F)F)c1
Temperature: 60 °C

Procedure:
A mixture of 4-chloro-3-trifluoromethyl-benzenesulfonyl chloride (1.5 g, 5.3 mmol) and 2-bromo-5-chloro-pyridin-3-ylamine (500 mg, 2.4 mmol) dissolved in pyridine (20 mL) was heated at 60° C. for 16 h. The solvent was evaporated and the residue suspended in a 1:1 mixture of 2 M NaOH and methanol (20 mL) and heated at 70° C. for 30 min. The methanol was evaporated under reduced pressure and the residue diluted with 15 mL water. The solution was cooled on ice bath and the pH was adjusted to 3 by drop wise addition of concentrated HCl. The solid formed was collected by filtration and the product was purified by flash chromatography on silica gel column to afford the desired product. MS m/z: 450.8 (M+H).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:15]=[CH:14][C:8]([CH:9]=[CH:10][C:11]([OH:13])=O)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].NC1C=CC(C=CC(O)=O)=CC=1.P(Cl)(OCC)(OCC)=O.[CH3:37][N:38]([CH3:49])[CH2:39][CH2:40][NH:41][C@H:42]1[CH2:47][CH2:46][C@H:45]([CH3:48])[CH2:44][CH2:43]1>CN(C)C1C=CN=CC=1.C(Cl)Cl.C(N(CC)CC)C>[CH3:37][N:38]([CH3:49])[CH2:39][CH2:40][N:41]([C@H:42]1[CH2:43][CH2:44][C@H:45]([CH3:48])[CH2:46][CH2:47]1)[C:11](=[O:13])[CH:10]=[CH:9][C:8]1[CH:7]=[CH:6][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[CH:15][CH:14]=1
Reactant: CC(=O)Nc1ccc(C=CC(=O)O)cc1
Reactant: CN(C)CCN[C@H]1CC[C@H](C)CC1
Agent: CCOP(=O)(Cl)OCC
Agent: CN(C)c1ccncc1
Agent: Nc1ccc(C=CC(=O)O)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Nc1ccc(C=CC(=O)N(CCN(C)C)[C@H]2CC[C@H](C)CC2)cc1

Procedure:
Using 2.0 g of 4-acetylaminocinnamic acid derived from 4-aminocinnamic acid by the acetylation thereof, 1.9 ml of diethyl chlorophosphate, 3.5 ml of triethylamine, 60 ml of methylene chloride, 2.3 ml of N-(2-dimethylaminoethyl)-trans-4-methylcyclohexylamine (Example 78), and 0.04 g of 4-dimethylaminopyridine, a reaction similar to that conducted in Example 81 was carried out. As a result, 2.08 g of N-(2-dimethylaminoethyl)-N-(trans-4-methylcyclohexyl)-4-acetylaminocinnamamide (a compound of the present invention) was obtained as white crystal, which had the following physiochemical properties:
Reaction SMILES: Br[CH2:2][C:3]1[C:8]([CH2:9][CH2:10][CH3:11])=[C:7]([Cl:12])[N:6]=[CH:5][N:4]=1.[CH2:13]([NH2:18])[CH2:14][CH:15]([CH3:17])[CH3:16].C([O-])([O-])=O.[K+].[K+]>C(#N)C>[Cl:12][C:7]1[N:6]=[CH:5][N:4]=[C:3]([CH2:2][NH:18][CH2:13][CH2:14][CH:15]([CH3:17])[CH3:16])[C:8]=1[CH2:9][CH2:10][CH3:11]
Reactant: CC(C)CCN
Reactant: CCCc1c(Cl)ncnc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCc1c(Cl)ncnc1CNCCC(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 4-bromomethyl-5-propyl-6-chloro-pyrimidine (10 mmol) and isoamylamine (4.35 g, 50 mmol) in acetonitrile (30 mL) is added excess K2CO3 (6.9 g). The mixture is stirred at room temperature overnight. The solvent is removed in vacuo and water (10mL) and DCM (15 mL) are added. The layers are separated and the aqueous layer is extracted with DCM (2×15 mL). The combined extracts are washed with brine (10 ML) and dried (Na2SO4) and solvent evaporated to provide the title product as an oil.
Reaction SMILES: C([O:8][C:9]1[CH:22]=[C:21]([CH2:23][CH3:24])[CH:20]=[CH:19][C:10]=1[O:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[N:13]=1)C1C=CC=CC=1>C(O)C.[Pd]>[CH2:23]([C:21]1[CH:20]=[CH:19][C:10]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[N:13]=2)=[C:9]([OH:8])[CH:22]=1)[CH3:24]
Reactant: CCc1ccc(Oc2cccc(F)n2)c(OCc2ccccc2)c1
Agent: [Pd]
Solvent: CCO
Product: CCc1ccc(Oc2cccc(F)n2)c(O)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-[2-(benzyloxy)-4-ethylphenoxy]-6-fluoropyridine (28 mg; 0.09 mmol) was dissolved in ethanol (4 mL), under argon. Palladium on charcoal (4 mg; 0.02 mmol) was added and the reaction was flushed twice with hydrogen, then left to stir overnight at room temperature. The reaction mixture was filtered on celite, then rinsed with methanol (3*3 mL). Concentration yielded a white solid (25 mg; 98%) of title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:31]=[CH:32][C:33]=1[O:34][CH3:35])[CH2:6][CH:7]1[C:16]2[C:11](=[C:12]([OH:19])[CH:13]=[CH:14][C:15]=2[O:17][CH3:18])[CH2:10][CH2:9][N:8]1[CH2:20][C:21]([NH:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1)=[O:22].Br[CH2:37][CH2:38][F:39]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:31]=[CH:32][C:33]=1[O:34][CH3:35])[CH2:6][CH:7]1[C:16]2[C:11](=[C:12]([O:19][CH2:37][CH2:38][F:39])[CH:13]=[CH:14][C:15]=2[O:17][CH3:18])[CH2:10][CH2:9][N:8]1[CH2:20][C:21]([NH:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1)=[O:22]
Reactant: COc1ccc(CC2c3c(OC)ccc(O)c3CCN2CC(=O)NCc2ccccn2)cc1OC
Reactant: FCCBr
Product: COc1ccc(CC2c3c(OC)ccc(OCCF)c3CCN2CC(=O)NCc2ccccn2)cc1OC

Procedure:
prepared by reaction of 2-[1-(3,4-dimethoxy-benzyl)-5-hydroxy-8-methoxy-3,4-dihydro-1H-isoquinolin-2-yl]-N-(pyridin-2-yl-methyl)-acetamide with 1-bromo-2-fluoro-ethane
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][N:6]=[CH:5][C:4]=2[CH:3]=[CH:2]1.[H-].[Na+].[C:12]1([S:18](Cl)(=[O:20])=[O:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C1COCC1>[C:12]1([S:18]([N:1]2[C:9]3[CH:8]=[CH:7][N:6]=[CH:5][C:4]=3[CH:3]=[CH:2]2)(=[O:20])=[O:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: c1cc2[nH]ccc2cn1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=S(=O)(c1ccccc1)n1ccc2cnccc21
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 59.5 %

Procedure:
A 100 mL round-bottomed flask was charged with a solution of 1H-pyrrolo[3,2-c]pyridine (1.0 g, 8.4 mmol) in anhydrous THF (50 mL). NaH (60% in mineral oil, 0.41 g, 10.2 mmol) was added and the reaction mixture was stirred for 5 min at room temperature. To this solution was added dropwise, at 0° C., benzenesulfonyl chloride (1.35 mL, 10.2 mmol) and the resulting mixture was stirred at room temperature for 2 h. The reaction mixture was quenched with water (30 mL) and extracted with EtOAc (3×100 mL). The organic layers were combined, dried (Na2SO4) and concentrated in vacuo to give the title compound as a white solid (1.29 g, 55%). 1H NMR (DMSO, 300 MHz): δ 8.95 (s, 1 H); 8.49 (d, J=5.8 Hz, 1 H); 8.13-8.05 (m, 2 H); 8.02-7.94 (m, 2 H); 7.79-7.71 (m, 1 H); 7.69-7.59 (m, 2 H); 7.01 (dd, J=3.7, 0.9 Hz, 1 H).
Reaction SMILES: Br[C:2]1[C:7]2[N:8]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:9]([C@@H:11]([NH:13][C:14]3[N:22]=[CH:21][N:20]=[C:19]4[C:15]=3[N:16]=[CH:17][N:18]4C3CCCCO3)[CH3:12])=[N:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH3:35][N:36](C=O)C>C(Cl)Cl.[C-]#N.[Zn+2].[C-]#N.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:29]1([N:8]2[C:7]3[C:2]([C:35]#[N:36])=[CH:3][CH:4]=[CH:5][C:6]=3[N:10]=[C:9]2[C@@H:11]([NH:13][C:14]2[N:22]=[CH:21][N:20]=[C:19]3[C:15]=2[N:16]=[CH:17][NH:18]3)[CH3:12])[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: C[C@H](Nc1ncnc2c1ncn2C1CCCCO1)c1nc2cccc(Br)c2n1-c1ccccc1
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: ClCCl
Product: C[C@H](Nc1ncnc2[nH]cnc12)c1nc2cccc(C#N)c2n1-c1ccccc1
Temperature: 150 °C
Yield: 73 %

Procedure:
[(S)-1-(7-Bromo-1-phenyl-1H-benzoimidazol-2-yl)ethyl][9-(tetrahydropyran-2-yl)-9H-purin-6-yl]amine (300 mg, 0.58 mmol) was dissolved in DMF (1 mL) in a microwave vial and zinc cyanide (68 mg, 0.58 mmol) and Pd(PPh3)4 (67 mg, 0.058 mmol) added. The vial was sealed and evacuated and purged with argon (×3). The vial was heated at 150° C. by microwave irradiation for 15 min. The resulting colourless solution was poured onto a mixture of EtOAc and water. A white solid precipitated and was dispersed between the 2 phases. The solid was isolated by filtration and dissolved in DCM and the resulting solution washed with NaHCO3 (satd. aq. soln.). The DCM fraction was passed through a PTFE cartridge. The DCM was removed in vacuo and the residue purified by passage through an SCX cartridge. The cartridge was washed with MeOH and the product eluted with 2M NH3 in MeOH. The product fractions were combined and evaporated and the residue purified by chromatography (Si—PCC) eluting with 0-8% MeOH in DCM. The product fractions were concentrated in vacuo to give white solid. This was triturated in ether, filtered and dried in vacuo to give 279 as a white solid (160 mg, 73%). 1H NMR (DMSO-d6, 400 MHz) δ: 8.09 (1H, br s), 8.03 (1H, s), 7.98 (2H, d, J=8.2 Hz), 7.66-7.59 (3H, m), 7.56-7.37 (4H, m), 7.33 (1H, t, J=7.9 Hz), 5.35-5.21 (1H, m), 1.54 (3H, d, J=6.9 Hz). LCMS (Method K): RT 3.07 min; m/z 381 [M+H]+
Reaction SMILES: [CH3:1][C:2]([S:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([CH3:7])[C:3](OC)=[O:4].CC(C[AlH]CC(C)C)C.Cl>ClCCl.C1(C)C=CC=CC=1>[CH3:7][C:2]([S:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([CH3:1])[CH2:3][OH:4]
Reactant: COC(=O)C(C)(C)Sc1ccccc1
Agent: CC(C)C[AlH]CC(C)C
Agent: Cl
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CC(C)(CO)Sc1ccccc1
Temperature: 25 °C

Procedure:
A −78° C. solution of Example 103B (860 mg, 4.1 mmol) in dichloromethane (10 mL) was treated with 1.0M DIBAL-H in toluene (11 mL), warmed to room temperature over 4 hours, poured into a mixture of 3M HCl (15 mL) and ice (˜10 g), and extracted with ethyl acetate (100 mL). The combined extracts were washed with 1M HCl (10 mL) and brine (10 mL), dried (MgSO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 10-30% ethyl acetate/hexanes to provide the desired product. MS (DCI) m/e 183 (M+H)+.
Reaction SMILES: C[O:2][CH:3](OC)[C:4]1[CH:9]=[CH:8][C:7]([C:10]2([OH:23])[CH2:15][CH2:14][N:13]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:12][CH2:11]2)=[CH:6][C:5]=1[O:24][CH3:25].C1(C)C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C(N(CC)CC)C>[CH2:16]([N:13]1[CH2:12][CH2:11][C:10]([C:7]2[CH:8]=[CH:9][C:4]([CH:3]=[O:2])=[C:5]([O:24][CH3:25])[CH:6]=2)([OH:23])[CH2:15][CH2:14]1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: COc1cc(C2(O)CCN(Cc3ccccc3)CC2)ccc1C(OC)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: O
Product: COc1cc(C2(O)CCN(Cc3ccccc3)CC2)ccc1C=O
Yield: 39.2 %

Procedure:
To 10.0 g of 4-(1-benzyl-4-hydroxypiperidin-4-yl)-2-methoxybenzaldehyde dimethyl acetal were added 100 ml of toluene and 6.15 g of p-toluenesulfonic acid monohydrate and the resulting mixture was heated under reflux for 1 hour. To the reaction mixture were added water and triethylamine followed by extraction with ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography (eluted with dichloromethane/methanol) to thereby give 3.43 g of the title compound as a pale brown oily substance.
Reaction SMILES: [Cl-:1].[NH2:2][C:3]([NH:5][N:6]=[CH:7][C:8]1[C:13]([C:14](=[O:18])[N:15]([CH3:17])[CH3:16])=[C:12]([OH:19])[CH:11]=[C:10](C)[N+:9]=1[CH3:21])=[O:4].OC1C(C=O)=NC=CC=1.OC1C(C=O)=NC(C)=CC=1.[Cl-].NC(NN=CC1C(O)=CC(C(=O)N(C)C)=C[N+]=1C)=O.C(C1C=CC(O)=CN=1)=O>>[Cl-:1].[NH2:2][C:3]([NH:5][N:6]=[CH:7][C:8]1[C:13]([C:14](=[O:18])[N:15]([CH3:16])[CH3:17])=[C:12]([OH:19])[CH:11]=[CH:10][N+:9]=1[CH3:21])=[O:4]
Reactant: Cc1cc(O)c(C(=O)N(C)C)c(C=NNC(N)=O)[n+]1C
Agent: CN(C)C(=O)c1cc(O)c(C=NNC(N)=O)[n+](C)c1
Agent: Cc1ccc(O)c(C=O)n1
Agent: O=Cc1ccc(O)cn1
Product: CN(C)C(=O)c1c(O)cc[n+](C)c1C=NNC(N)=O

Procedure:
2-[[(Aminocarbonyl)hydrazono]methyl]-3-(N,N-dimethylcarbamoyl)hydroxy-1,6-dimethyl pyridinium chloride can be made by the same procedure replacing 3-hydroxy-2-pyridine aldehyde in the above example with 3-hydroxy-6-methyl-2-pyridine aldehyde. 2-[[(Aminocarbonyl)hydrazono]methyl]-5-(N,N-dimethylcarbamoyl)hydroxy-1-methyl pyridinium chloride can be made by the same procedure replacing 3-hydroxy-2-pyridine aldehyde in the above example with 2-formyl-5-hydroxy pyridine.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:29][C:30]1[CH:35]=[C:34]([F:36])[C:33]([F:37])=[CH:32][C:31]=1[F:38])[CH2:10][C:11]([N:13]1[CH2:18][CH2:17][N:16]2[C:19]([C:25]([F:28])([F:27])[F:26])=[N:20][C:21]([C:22]([OH:24])=[O:23])=[C:15]2[CH2:14]1)=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:39](=[O:47])([O:44][CH2:45][CH3:46])[O:40][CH:41](Cl)[CH3:42].[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>O.CN(C)C=O>[CH2:41]([O:40][C:39]([O:44][CH2:45][CH2:46][O:23][C:22]([C:21]1[N:20]=[C:19]([C:25]([F:27])([F:28])[F:26])[N:16]2[CH2:17][CH2:18][N:13]([C:11](=[O:12])[CH2:10][C@H:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:29][C:30]3[CH:35]=[C:34]([F:36])[C:33]([F:37])=[CH:32][C:31]=3[F:38])[CH2:14][C:15]=12)=[O:24])=[O:47])[CH3:42]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCn2c(C(F)(F)F)nc(C(=O)O)c2C1)Cc1cc(F)c(F)cc1F
Reactant: CCOC(=O)OC(C)Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)OCCOC(=O)c1nc(C(F)(F)F)n2c1CN(C(=O)C[C@@H](Cc1cc(F)c(F)cc1F)NC(=O)OC(C)(C)C)CC2
Temperature: 25 °C
Yield: 78 %

Procedure:
(R)-7-[3-tert-Butoxycarbonylamino-4-(2,4,5-trifluoro-phenyl)-butyryl]-3-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine-1-carboxylic acid 2a (0.275 g, 0.5 mmol) and 4 mL of N,N-dimethylformamide were added into the reaction tube, and then 1-chloroethyl ethyl carbonate (0.092 g, 0.6 mmol), potassium iodide (0.0415 g, 0.25 mmol) and potassium carbonate (0.083 g, 0.6 mmol) were added successively under stirring. Then the reaction tube was sealed up. The reaction mixture was reacted at 65° C. in an oil bath for 2 hours and monitored by thin layer chromatography until the disappearance of the starting materials. After cooling to room temperature, 40 mL of water was added to the reaction tube. The reaction mixture was extracted with ethyl acetate (25 mL×3), and the combined organic phase was washed with water (20 mL×2), dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound, (R)-7-[3-tert-butoxycarbonylamino-4-(2,4,5-trifluoro-phenyl)-butyryl]-3-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine-1-carboxylic acid (1-ethoxycarbonyloxy)-ethyl ester 34a (0.26 g, yield 78.1%) as a white solid.
Reaction SMILES: Cl.[C:2]([C:5]1[NH:9][CH:8]=[C:7]([C:10]([OH:12])=[O:11])[C:6]=1[C:13]1[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][CH:14]=1)(=[O:4])[NH2:3].[F:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][C:22]=1[N:31]=[C:32]=[O:33].C(N(CC)CC)C>O1CCCC1.CCCCC>[C:2]([C:5]1[NH:9][CH:8]=[C:7]([C:10]([OH:12])=[O:11])[C:6]=1[C:13]1[CH:18]=[CH:17][C:16]([NH:19][C:32]([NH:31][C:22]2[CH:23]=[C:24]([C:27]([F:28])([F:30])[F:29])[CH:25]=[CH:26][C:21]=2[F:20])=[O:33])=[CH:15][CH:14]=1)(=[O:4])[NH2:3]
Reactant: O=C=Nc1cc(C(F)(F)F)ccc1F
Reactant: NC(=O)c1[nH]cc(C(=O)O)c1-c1ccc(N)cc1
Agent: Cl
Solvent: CCCCC
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: NC(=O)c1[nH]cc(C(=O)O)c1-c1ccc(NC(=O)Nc2cc(C(F)(F)F)ccc2F)cc1
Temperature: 20 °C
Reaction time: 5 h
Yield: 46.9 %

Procedure:
To 0.14 g (0.497 mmol) of 5-carbamoyl-4-(4-aminophenyl)-1H-pyrrole-3-carboxylic acid hydrochloride dissolved in 18 cm3 of tetrahydrofuran are added, at a temperature in the region of 20° C. under an argon atmosphere, 0.072 cm3 (0.497 mmol) of 2-fluoro-5-trifluoromethylphenyl isocyanate and 0.07 cm3 (0.497 mmol) of triethylamine. After stirring for 5 hours at a temperature in the region of 20° C., the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa) to give a residue, which is purified by flash chromatography [eluent: dichloromethane/methanol/acetonitrile (gradient of from 90/5/5 to 80/10/10 by volume)]. After concentrating the fractions under reduced pressure, a solid is obtained, which is then stirred in 5 cm3 of pentane for 3 hours. After filtering through a No. 3 sinter funnel, the solid is washed with twice 1 cm3 of pentane and then dried under reduced pressure (2.7 kPa) at a temperature in the region of 30° C. for 15 hours to give 0.105 g of 5-carbamoyl-4-{4-[3-(2-fluoro-5-trifluoromethylphenyl)ureido]-phenyl}-1H-pyrrole-3-carboxylic acid in the form of a yellow solid melting at 194° C.; 1H NMR (400 MHz, DMSO d6, δ in ppm): 5.37 (broad m, 1H); 7.23 (d, J=8.5 Hz, 2H); 7.23 (masked m, 1H); 7.39 (m, 1H); 7.42 (d, J=3.0 Hz, 1H); 7.49 (d, J=8.5 Hz, 2H); 7.50 (partially masked m, 1H); 8.64 (dd, J=2.5 and 7.5 Hz, 1H); 8.97 (d, J=2.0 Hz, 1H); 9.35 (s, 1H); 11.6 (broad m, 1H); 12.05 (broad s, 1H); ES+: m/z=451: [M+H]+; ES−: m/z=449: [M−H]−.
Reaction SMILES: O.C(OC([NH:9][C@H:10]([C:21]([NH:23][C@H:24]([C:29]([NH:31][C@H:32]([C:37]([NH:39][C@@H:40]([C:42]([NH2:44])=[O:43])[CH3:41])=[O:38])[CH2:33][C:34](=[O:36])[OH:35])=[O:30])[CH2:25][CH2:26][S:27][CH3:28])=[O:22])[CH2:11][C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[NH:14][CH:13]=1)=O)(C)(C)C.C(O)(=O)C.SCCO.[ClH:53]>O1CCOCC1>[ClH:53].[NH2:9][C@H:10]([C:21]([NH:23][C@H:24]([C:29]([NH:31][C@H:32]([C:37]([NH:39][C@@H:40]([C:42]([NH2:44])=[O:43])[CH3:41])=[O:38])[CH2:33][C:34](=[O:35])[OH:36])=[O:30])[CH2:25][CH2:26][S:27][CH3:28])=[O:22])[CH2:11][C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[NH:14][CH:13]=1
Reactant: CSCC[C@H](NC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)OC(C)(C)C)C(=O)N[C@@H](CC(=O)O)C(=O)N[C@H](C)C(N)=O
Agent: Cl
Agent: OCCS
Solvent: CC(=O)O
Solvent: O
Solvent: C1COCCO1
Product: CSCC[C@H](NC(=O)[C@@H](N)Cc1c[nH]c2ccccc12)C(=O)N[C@@H](CC(=O)O)C(=O)N[C@H](C)C(N)=O
Reaction time: 0.08 h

Procedure:
to a solution of N-t-butoxycarbonyl-L-tryptophanyl-L-methionyl-L-aspartyl-D-alanine amide hydrate in 11.6 parts by volume glacial acetic acid and 0.12 part by volume 2-mercaptoethanol is added 5.8 parts by volume of a 6.04 M solution of hydrochloric acid in dioxane. After stirring for approximately five minutes, the solvent is removed under reduced pressure. The residue is triturated with ethyl ether, filtered and vacuum-dried to afford L-tryptophanyl-L-methionyl-L-aspartyl-D-alanine amide hydrochloride. This compound is represented by the following formula.
Reaction SMILES: N[C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[C:3]=1[C:4]#[N:5].N([O-])=O.[Na+].[I-:17].[K+].O>OS(O)(=O)=O.C(O)(=O)C>[I:17][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[C:3]=1[C:4]#[N:5]
Reactant: N#Cc1c(N)cccc1[N+](=O)[O-]
Reactant: [I-]
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Product: N#Cc1c(I)cccc1[N+](=O)[O-]
Temperature: 45 °C
Reaction time: 1.5 h
Yield: 53.2 %

Procedure:
2-Amino-6-nitrobenzonitrile (Example 130e) (4.32 g, 26.5 mmol) was added in small portions to a suspension of sodium nitrite (2.19 g, 31.7 mmol) in concentrated H2SO4 (43 mL) and acetic acid (43 mL) at 45° C. The reaction was heated at 45° C. for 1 h and then added in small portions to a solution of potassium iodide (7.47 g, 45.0 mmol) in H2SO4 (1 M, 43 mL). After stirring at room temperature for 1.5 h, iced water was added to the reaction and the precipitated product was collected by filtration. The product was purified by chromatography on silica gel eluting with CH2Cl2, to give 2-iodo-6-nitrobenzonitrile (3.86 g, 53%) as a yellow solid. 1H-NMR (400 MHz, DMSO-d6) δ 8.46-8.52 (m, 1H), 8.34-8.38 (m, 1H), 7.66-7.71 (m, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[N:9][NH:10]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].Cl.Cl[CH2:21][CH2:22][N:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1>CN(C)C=O>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[C:11]([CH:12]=1)=[N:10][N:9]([CH2:21][CH2:22][N:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1)[CH:8]=2)([O-:3])=[O:2]
Reactant: ClCCN1CCCC1
Reactant: O=[N+]([O-])c1ccc2cn[nH]c2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc2cn(CCN3CCCC3)nc2c1
Temperature: 60 °C

Procedure:
6-Nitroindazole (2.00 g, 12.3 mmol) was treated with potassium carbonate (5.00 g 36.2 mmol) in N,N-dimethylformamide (40 mL) for 30 minutes and then 1-(2-chloro-ethyl)-pyrrolidine hydrochloride (3.20 g 18.8 mmol) was added. The reaction mixture was heated to 60° C. for 6 hours, then cooled to room temperature. The reaction mixture was filtered through a plug of silica gel and rinsed with triethylamine/ethyl acetate (1/4). The filtrate was concentrated in vacuo and purified by flash chromatography (silica gel, triethylamine/ethyl acetate 1/30) to afford the title compound. 1H NMR (300 MHz, DMSO-d6) ppm 1.65 (m, 4H) 2.48 (m, 4H), 3.00 (t, 2H, J=6.44), 4.64 (t, 2H, J=6.44), 7.80 (m, 1H), 7.97 (m, 1H), 8.62 (s, 1H), 8.68 (s, 1H); MS (DCI/NH3) m/z 261 [M+H]+.