Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]2[NH:8][C:9]([NH:11][C:12]3[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:19])=[N:10][C:6]=2[CH:5]=[C:4]([C:20]([O:22][CH3:23])=[O:21])[C:3]=1[OH:24].Cl.[CH:26]1([C:29](=N)OCC)[CH2:28][CH2:27]1>C(Cl)Cl>[CH:26]1([C:29]2[O:24][C:3]3[C:4]([C:20]([O:22][CH3:23])=[O:21])=[CH:5][C:6]4[N:10]=[C:9]([NH:11][C:12]5[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=5[Cl:19])[NH:8][C:7]=4[C:2]=3[N:1]=2)[CH2:28][CH2:27]1
Reactant: COC(=O)c1cc2nc(Nc3c(Cl)cccc3Cl)[nH]c2c(N)c1O
Reactant: CCOC(=N)C1CC1
Agent: Cl
Solvent: ClCCl
Product: COC(=O)c1cc2nc(Nc3c(Cl)cccc3Cl)[nH]c2c2nc(C3CC3)oc12
Temperature: 2.5 °C
Reaction time: 24 h
Yield: 34.2 %

Procedure:
Under N2 atmosphere to a cold solution of methyl 7-amino-2-[(2,6-dichlorophenyl)amino]-6-hydroxy-1H-benzimidazole-5-carboxylate (0.400 g, 1.05 mmol) in DCM (25 mL) was added HCl salt of ethyl cyclopropanecarboximidate (Intermediate-57, 0.234 g, 1.57 mmol) at 0° C. The reaction mass was stirred at 0-5° C. for 1 h and at RT for 24 h. The obtained crude was purified by column chromatography on neutral alumina eluting with 1.0-2.0% MeOH:DCM to afford 0.150 g of the desired product. (DMSO-d6): δ 1.06-1.14 (m, 4H), 3.88 (s, 3H), 2.3 (m, 1H), 7.41 (s, 1H), 7.62 (d, J=7.8 Hz, 2H), 7.69 (s, 1H), 9.47 (s, 1H), 11.55 (s, 1H).
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41](O)=[O:42])[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH:47]([O:50][CH2:51][CH2:52][NH:53][CH2:54][CH2:55][O:56][CH:57]([CH3:59])[CH3:58])([CH3:49])[CH3:48]>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41]([N:53]([CH2:52][CH2:51][O:50][CH:47]([CH3:49])[CH3:48])[CH2:54][CH2:55][O:56][CH:57]([CH3:58])[CH3:59])=[O:42])[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:26]=[CH:27][C:28]([Cl:31])=[CH:29][CH:30]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)OCCNCCOC(C)C
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)O)CC1
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)N(CCOC(C)C)CCOC(C)C)CC1

Procedure:
In a manner analogous to the method described in example 163, {1-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperidin-4-yl}-acetic acid was coupled with bis-(isopropoxy-ethyl)-amine (TCI-US) to give the title compound. HR-MS (ES, m/z) calculated for C46H63Cl2N5O5 [(M+H)+] 836.4279, observed 836.4274.
Reaction SMILES: [CH3:1][N:2]([C:12]1[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=1)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][NH:8][CH2:7][C:6]1=[O:11].[Cl:18][C:19]1[CH:20]=[CH:21][C:22]2[CH:26]=[C:25]([S:27](Cl)(=[O:29])=[O:28])[S:24][C:23]=2[CH:31]=1>>[Cl:18][C:19]1[CH:20]=[CH:21][C:22]2[CH:26]=[C:25]([S:27]([N:8]3[CH2:9][CH2:10][N:5]([CH2:4][CH2:3][N:2]([CH3:1])[C:12]4[CH:13]=[CH:14][N:15]=[CH:16][CH:17]=4)[C:6](=[O:11])[CH2:7]3)(=[O:29])=[O:28])[S:24][C:23]=2[CH:31]=1
Reactant: O=S(=O)(Cl)c1cc2ccc(Cl)cc2s1
Reactant: CN(CCN1CCNCC1=O)c1ccncc1
Product: CN(CCN1CCN(S(=O)(=O)c2cc3ccc(Cl)cc3s2)CC1=O)c1ccncc1

Procedure:
A portion (˜50%) of the crude 1-[2-{(Methyl)-(pyridin-4-yl)-amino}-ethyl]-piperazin-2-one, EXAMPLE 93 is reacted with 6-chloro-benzo[b]thiophene-2-sulfonyl chloride (54 mg, 0.20 mmol), EXAMPLE 1, using same procedure as described in EXAMPLE 719. The residue obtained after HPLC purification is subjected to silica gel chromatography using NH4OH/MeOH/CH2Cl2 (1:4:95) as eluant to give title compound (30 mg, 0.064 mmol) as a white solid. MS m/z 465, 457 (M+1); 1H NMR (CDCl3, 300 MHz) δ8.15 (d, 2H), 7.88 (s, 1H), 7.85 (d, 1H), 7.79 (s, 1H), 7.47 (d, 1H), 6.47 (d. 2H), 3.80 (s, 2H), 3.50 (m, 4H), 3.43 (d, 2H), 3.30 (d, 2H), 2.98 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:23]=[CH:24][CH:25]=1)[O:5][C:6]1[CH:20]=[CH:19][C:9]2[N:10]=[C:11]([NH:13][C:14]([CH:16]3[CH2:18][CH2:17]3)=[O:15])[S:12][C:8]=2[C:7]=1[C:21]#[N:22].[F:26][C:27]([F:42])([F:41])[C:28]1[CH:29]=[C:30]([CH:34]=[CH:35][C:36]=1[C:37]([F:40])([F:39])[F:38])[C:31](O)=[O:32].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.N1C=CC=CC=1>C(OCC)(=O)C>[C:21]([C:7]1[C:8]2[S:12][C:11]([NH:13][C:14]([CH:16]3[CH2:18][CH2:17]3)=[O:15])=[N:10][C:9]=2[CH:19]=[CH:20][C:6]=1[O:5][C:4]1[CH:3]=[C:2]([NH:1][C:31](=[O:32])[C:30]2[CH:34]=[CH:35][C:36]([C:37]([F:38])([F:39])[F:40])=[C:28]([C:27]([F:26])([F:41])[F:42])[CH:29]=2)[CH:25]=[CH:24][CH:23]=1)#[N:22]
Reactant: O=C(O)c1ccc(C(F)(F)F)c(C(F)(F)F)c1
Reactant: N#Cc1c(Oc2cccc(N)c2)ccc2nc(NC(=O)C3CC3)sc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: N#Cc1c(Oc2cccc(NC(=O)c3ccc(C(F)(F)F)c(C(F)(F)F)c3)c2)ccc2nc(NC(=O)C3CC3)sc12
Temperature: 60 °C
Reaction time: 12 h
Yield: 70.7 %

Procedure:
A mixture of N-[6-(3-aminophenoxy)-7-cyano-1,3-benzothiazol-2-yl]cyclopropanecarboxamide (100 mg, 0.285 mmol) produced in Example 3(vi), 3,4-bis(trifluoromethyl)benzoic acid (88 mg, 0.340 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (129 mg, 0.340 mmol) and pyridine (3 mL) was stirred at 60° C. for 12 hr. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (15 mL), washed successively with 5% aqueous sodium hydrogen carbonate solution (10 ml) and saturated brine (10 mL), and dried over anhydrous sodium sulfate. Insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/n-hexane=30/70→80/20), and the obtained solution was concentrated under reduced pressure. The residue was crystallized from ethyl acetate/n-hexane to give the title compound (119 mg, 71%) as a white powder.
Reaction SMILES: [OH:1][C:2]1[C:7]2[C:8]([CH3:14])([CH3:13])[O:9][C:10](=[O:12])[NH:11][C:6]=2[CH:5]=[CH:4][CH:3]=1.[Cl:15][C:16]1[CH:17]=[C:18]([S:23]([CH2:25][CH2:26][CH2:27][CH2:28]Br)=[O:24])[CH:19]=[CH:20][C:21]=1[Cl:22]>>[Cl:15][C:16]1[CH:17]=[C:18]([S:23]([CH2:25][CH2:26][CH2:27][CH2:28][O:1][C:2]2[C:7]3[C:8]([CH3:14])([CH3:13])[O:9][C:10](=[O:12])[NH:11][C:6]=3[CH:5]=[CH:4][CH:3]=2)=[O:24])[CH:19]=[CH:20][C:21]=1[Cl:22]
Reactant: O=S(CCCCBr)c1ccc(Cl)c(Cl)c1
Reactant: CC1(C)OC(=O)Nc2cccc(O)c21
Product: CC1(C)OC(=O)Nc2cccc(OCCCCS(=O)c3ccc(Cl)c(Cl)c3)c21

Procedure:
Prepared analogously to Example 4 from 5-hydroxy-4,4-dimethyl-4H-3,1-benzoxazin-2-one and 4-(3,4-dichloro-phenylsulfinyl)-butylbromide.
Reaction SMILES: [H-].[Na+].N1C=[CH:6][N:5]=[N:4]1.[F:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=1[C:16]1([C@H:19]([O:21][CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][O:23]2)[CH3:20])[CH2:18][O:17]1.[CH3:28][N:29](C=O)C>>[F:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=1[C:16]([OH:17])([C@H:19]([O:21][CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][O:23]1)[CH3:20])[CH2:18][N:5]1[CH:6]=[N:29][CH:28]=[N:4]1
Reactant: C[C@@H](OC1CCCCO1)C1(c2cc(F)ccc2F)CO1
Reactant: CN(C)C=O
Reactant: c1c[nH]nn1
Agent: [H-]
Agent: [Na+]
Product: C[C@@H](OC1CCCCO1)C(O)(Cn1cncn1)c1cc(F)ccc1F
Temperature: 25 °C

Procedure:
To a suspension of NaH (38.5 g, 60% in mineral oil, 0.962 mol, washed with hexane three times) in DMF (1 L) cooled in an ice-bath was added triazole (133 g, 1.92 mol) portionwise over a period of 30 min. After completion of the addition, the mixture was warmed to room temperature. The above crude 2-(2,5-Difluorophenyl)-2-[(1R)-1-(3,4,5,6,-tetrahydro-2H-pyran-2-yloxy)ethyl]oxirane was added and the mixture was heated at 70° C. for 8 h. After cooling to room temperature, the reaction mixture was quenched with water (1 L) and the mixture was extracted with EtOAc (1 L×3). The EtOAc layer was combined and washed with water and brine, dried over MgSO4, and evaporated under reduced pressure. The portion of residue was chromatographed on silicagel for analysis (n-hexane: EtOAc=4:1˜1:5) to give pure (3R)-2-(2,5-difluorophenyl)-3-(3,4,5,6-tetrahydro-2H-pyran-2-yloxy)-1-(1H-1,2,4-triazol-1-yl)-2-butanol.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:5]=1[OH:14])([O-])=O.Cl[Sn]Cl>CCO>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([C:10]([F:11])([F:12])[F:13])=[CH:6][C:5]=1[OH:14]
Reactant: O=[N+]([O-])c1ccc(C(F)(F)F)cc1O
Agent: Cl[Sn]Cl
Solvent: CCO
Product: Nc1ccc(C(F)(F)F)cc1O

Procedure:
2-Amino-5-trifluoromethylphenol was prepared by treating 2-nitro-5-trifluoromethylphenol (500 mg, 2.41 mmol) with a solution of SnCl2 (3.5g, mmol) in EtOH at 23° C. for 12 h. The mixture was concentrated to 50 mL and adjusted to pH 7 using saturated sodium bicarbonate. The reaction mixture was partitioned between H2O and EtOAc. The aqueous layer was separated and extracted with EtOAc. The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo. The resulting colorless oil(370 mg, 87%) was used without further purification. 1H NMR (CDCl3): 7.6 (s, 1H), 7.39(d, 1H, J =8.5 Hz), 7.08(d, 1H, J=8.5 Hz)
Reaction SMILES: [BrH:1].C(O)(=O)C.[N:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:36])[C:14]2[CH:19]=[CH:18][C:17]([C@H:20]([NH:22]C(OCC3C=CC=CC=3)=O)[CH3:21])=[C:16]([N+:33]([O-:35])=[O:34])[CH:15]=2)=[CH:8][CH:7]=1>>[BrH:1].[BrH:1].[N:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:36])[C:14]2[CH:19]=[CH:18][C:17]([C@H:20]([NH2:22])[CH3:21])=[C:16]([N+:33]([O-:35])=[O:34])[CH:15]=2)=[CH:8][CH:7]=1
Reactant: C[C@@H](NC(=O)OCc1ccccc1)c1ccc(C(=O)Nc2ccncc2)cc1[N+](=O)[O-]
Agent: Br
Solvent: CC(=O)O
Product: C[C@@H](N)c1ccc(C(=O)Nc2ccncc2)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A 25% hydrogen bromide-acetic acid solution (4 ml) was added to (R)-N-(4-pyridyl)-4-(1-benzyloxycarbonylaminoethyl)-3-nitrobenzamide (400 mg), and the mixture was stirred at room temperature for 1 hour. After the reaction, the reaction mixture was evaporated under reduced pressure. The obtained crystals were washed with ethyl acetate, and recrystallized from methanol to give 153 mg of (R)-(-)-N-(4-pyridyl)-4-(1-aminoethyl)-3-nitrobenzamide dihydrobromide 1/2 hydrate having a melting point of 275° C. (dec.).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](Cl)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].C(N(CC)CC)C.[N+:20]([C:23]1[CH:29]=[CH:28][C:26]([NH2:27])=[CH:25][CH:24]=1)([O-:22])=[O:21].O>CN(C1C=CN=CC=1)C.O1CCCC1>[N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([NH:27][C:26]2[CH:28]=[CH:29][C:23]([N+:20]([O-:22])=[O:21])=[CH:24][CH:25]=2)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: Nc1ccc([N+](=O)[O-])cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: O=C(Nc1ccc([N+](=O)[O-])cc1)c1ccc([N+](=O)[O-])cc1
Temperature: 24 °C
Reaction time: 2 h

Procedure:
4-Nitrobenzoyl chloride (111.34 grams, 0.60 mole), triethylamine (72.86 grams, 0.72 mole), 4-(N,N'-dimethylamino)pyridine (1.94 grams, 1.0% wt. of the 4-nitrobenzoyl chloride and 4-nitroaniline used) and tetrahydrofuran (250 milliliters) are added to a reactor and stirred under a nitrogen atmosphere with cooling to provide a 5° C. solution. Dropwise addition of a solution of 4-nitroaniline (82.88 grams, 0.60 mole) in tetrahydrofuran (400 milliliters) commenced and is completed over the next 30 minutes while maintaining a reaction temperature of 5° C. to 8° C. After completion of addition of the 4-nitroaniline and tetrahydrofuran solution the reaction temperature is allowed to increase to room temperature (24° C.) over a 106 minute period. After the reaction is held at room temperature for two hours, the reactor contents are added to deionized water (1.5 gallons). The resultant precipitated product is recovered by filtration then washed with deionized water (500 milliliters). The wet filter cake is added to acetone (500 milliliters) and heated to boiling with stirring. The acetone suspension is held at 2° C. overnight followed by filtration to recover the crystalline precipitate. The recovered filter cake is dried in a vacuum oven at 110° C. and 5 mm Hg to a constant weight of 84.7 grams. The product is light yellow in color with a brilliant appearance. Additional solids precipitated from the acetone mother liquor from the initial filtration upon concentration by rotary evaporation, but no attempt is made to recover and process this material. Fourier transform infrared spectrophotometric analysis of a nujol mull of the product on a sodium chloride plate confirms the product structure (1538 and 1336 cm-1 absorbances observed for the conjugated nitro group, secondary amide N--H stretching (solid state) absorbance observed at 3368 cm-1, and secondary amide carbonyl stretching (solid state) absorbance observed at 1686 cm-1). Proton nuclear magnetic resonance spectroscopy further confirms the product structure.
Reaction SMILES: [Br:1][CH:2]([CH2:6][CH2:7][CH2:8][Br:9])[C:3](Br)=[O:4].[C:10]([O:13][CH:14]([CH2:43][O:44][C:45](=[O:47])[CH3:46])[CH2:15][NH:16][C:17]([C:19]1[C:24]([I:25])=[C:23]([NH2:26])[C:22]([I:27])=[C:21]([C:28]([NH:30][CH2:31][CH:32]([O:38][C:39](=[O:41])[CH3:40])[CH2:33][O:34][C:35](=[O:37])[CH3:36])=[O:29])[C:20]=1[I:42])=[O:18])(=[O:12])[CH3:11]>CN(C)C(=O)C>[C:10]([O:13][CH:14]([CH2:43][O:44][C:45](=[O:47])[CH3:46])[CH2:15][NH:16][C:17]([C:19]1[C:24]([I:25])=[C:23]([NH:26][C:3](=[O:4])[CH:2]([Br:1])[CH2:6][CH2:7][CH2:8][Br:9])[C:22]([I:27])=[C:21]([C:28]([NH:30][CH2:31][CH:32]([O:38][C:39](=[O:41])[CH3:40])[CH2:33][O:34][C:35](=[O:37])[CH3:36])=[O:29])[C:20]=1[I:42])=[O:18])(=[O:12])[CH3:11]
Reactant: CC(=O)OCC(CNC(=O)c1c(I)c(N)c(I)c(C(=O)NCC(COC(C)=O)OC(C)=O)c1I)OC(C)=O
Reactant: O=C(Br)C(Br)CCCBr
Solvent: CC(=O)N(C)C
Product: CC(=O)OCC(CNC(=O)c1c(I)c(NC(=O)C(Br)CCCBr)c(I)c(C(=O)NCC(COC(C)=O)OC(C)=O)c1I)OC(C)=O
Reaction time: 1 h
Yield: 95.5 %

Procedure:
2,5-Dibromopentanoyl bromide (11 g, 34 mmol ) was added dropwise to a stirred solution of N,N'-bis[2,3bis(acetyloxy)propyl]-5-amino-2,4,6-triiodo-1,3-benzenedicarboxamide (23.0 g, 26.3 mmol) in N,N-dimethylacetamide (240 ml) at 0°. After the addition, the reaction mixture was stirred at 0° for 1 hour, and then at room temperature for 20 hours. The solvent was removed in vacuo at 45° and the resulting solid was dissolved in ethyl acetate (400 ml). The organic layer was washed with saturated aqueous sodium bicarbonate (1×70 ml), water (1×70 ml) and saturated sodium chloride (1×70 ml). After drying over magnesium sulfate, the solvent was removed in vacuo to obtain a yellow residue (28 g). Purification by column chromatography over silica gel furnished pure N,N'-bis[2,3-bis(acetyloxy)propyl]-5-[(2,5-dibromo-1-oxopentyl)amino]-2,4,6-triiodo-1,3-benzenedicarboxamide as an off-white crystalline compound (20.2 g, yield 69%).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[C:9]([CH:16]=[CH:17][C:18]=2[CH3:19])[C:10]([NH:12][CH:13]2[CH2:15][CH2:14]2)=[O:11])[N:5]=[CH:4][C:3]=1[C:20](=[O:29])[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH:27]=O)[CH:22]=1.[CH3:30][N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1.CC(O)=O.[OH-].[Na+]>ClCCl.ClCCCl>[NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[C:9]([CH:16]=[CH:17][C:18]=2[CH3:19])[C:10]([NH:12][CH:13]2[CH2:14][CH2:15]2)=[O:11])[N:5]=[CH:4][C:3]=1[C:20](=[O:29])[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27][N:34]2[CH2:35][CH2:36][N:31]([CH3:30])[CH2:32][CH2:33]2)[CH:22]=1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-n1ncc(C(=O)c2cccc(C=O)c2)c1N
Reactant: CN1CCNCC1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCCl
Solvent: CC(=O)O
Solvent: ClCCl
Product: Cc1ccc(C(=O)NC2CC2)cc1-n1ncc(C(=O)c2cccc(CN3CCN(C)CC3)c2)c1N
Temperature: 25 °C
Reaction time: 2 h
Yield: 67 %

Procedure:
To a mixture of 3-[5-amino-4-(3-formyl-benzoyl)-pyrazol-1-yl]-N-cyclopropyl-4-methyl-benzamide 6 (Example 9, 1.0 eq) and 1-methyl-piperazine (1.09 eq) in equal volume of 1,2-dichloroethane and dichloromethane was added AcOH (0.96 eq) Sodium triacetoxyborohydride (1.5 eq) was then added. The reaction mixture was stirred at room temperature for 2 h. Aqueous NaOH was added to quench the reaction and the mixture was extracted with ethyl acetate. The organic layer was separated and washed with water and saturated NaCl solution. The organic layer was then dried over Na2SO4, filtered and concentrated to give a residue that could be purified by silica gel chromatography (eluent: 9/1 CH2Cl2/methanol then 9/1/0.05 CH2Cl2/MeOH/NH3H2O). Yield 67%. MS m/z 473.3 [M+H]+; 1H NMR (300 MHz, CDCl3) δ0.61 (m, 2H), 0.86 (m, 2H), 2.26 (s, 3H), 2.30 (s, 3H), 2.52 (brs, 8H), 2.90 (m, 1H), 3.60 (s, 2H), 5.87 (brs, 1H), 6.30 (brs, 2H), 7.45 (m, 3H), 7.70 (m, 2H), 7.83 (m, 3H) ppm.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])[C:5]#[N:6].C(=O)=O.C(O)(C)C.C1([Mg]Br)C=CC=CC=1.[CH:28](=[O:32])[CH:29]([CH3:31])[CH3:30]>O1CCCC1>[C:5]([C:4]1[CH:7]=[CH:8][C:9]([N+:10]([O-:12])=[O:11])=[C:2]([CH:28]([OH:32])[CH:29]([CH3:31])[CH3:30])[CH:3]=1)#[N:6]
Reactant: CC(C)C=O
Reactant: N#Cc1ccc([N+](=O)[O-])c(I)c1
Agent: Br[Mg]c1ccccc1
Agent: O=C=O
Solvent: CC(C)O
Solvent: C1CCOC1
Product: CC(C)C(O)c1cc(C#N)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 22.7 %

Procedure:
To a solution of 3-iodo-4-nitrobenzonitrile (314 mg, 1.14 mmol) in anhydrous tetrahydrofuran (5.5 mL) cooled at minus 45° C. (dry ice-isopropanol bath) under nitrogen atmosphere, phenylmagnesium bromide (2 M in THF, 3.16 mL, 6.32 mmol) was added at a rate to keep the temperature at or below minus 40° C. Upon completion of the addition the mixture was stirred for five minutes, then isobutyraldehyde (0.957 mL, 10.54 mmol) was added. The mixture was allowed to gradually warm up to room temperature, then quenched with saturated NH4Cl (2 mL) and poured into water (50 mL)/dichloromethane (50 mL). The organic layer was separated; aqueous layer was extracted three times with dichloromethane (25 mL each). Combined organic extract was dried over anhydrous Na2SO4, concentrated under reduced pressure, and purified by silica gel column chromatography to yield racemic (RS)-1-(5-cyano-2-nitrophenyl)-2-methyl-1-propanol (57 mg, 23%) as a light yellow oil. 1H NMR (400 MHz, CDCl3): δ 7.93 (d, 1H, J=8.1 Hz, Ph-H), 7.74 (s, 1H, Ph-H), 7.21 (d, 1H, J=8.1 Hz, Ph-H), 4.72 (d, 1H, J=3.6 Hz, Ph-CH), 2.33 (br. s, 1H, OH), 2.03 (m, 1H, CHCH(CH3)2), 1.04 (d, 3H, J=6.8 Hz, CH3), 0.89 (d, 3H, J=6.6 Hz, CH3); 13C NMR (100 MHz, CDCl3): δ 147.78 (C), 140.25 (CH), 131.40 (CH), 131.24 (CH), 118.36 (C), 112.27 (CN), 103.82 (C), 80.80 (CH), 33.56 (CH), 19.70 (CH3), 15.62 (CH3).
Reaction SMILES: O(P(O[C:18]1[C@H:19]([CH3:35])[C@H:20]2[C@@H:30]([C@H:31]([OH:33])[CH3:32])[C:29](=[O:34])[N:21]2[C:22]=1[C:23]([O:25][CH2:26][CH:27]=[CH2:28])=[O:24])(OC1C=CC=CC=1)=O)C1C=CC=CC=1.[CH2:36]([O:39][C:40]([N:42]1[CH2:46][C@@H:45]([SH:47])[CH2:44][C@H:43]1/[CH:48]=[CH:49]/[C:50]([NH2:52])=[O:51])=[O:41])[CH:37]=[CH2:38].C(N(CC)C(C)C)(C)C>C(#N)C>[CH2:36]([O:39][C:40]([N:42]1[CH2:46][C@@H:45]([S:47][C:18]2[C@H:19]([CH3:35])[C@@H:20]3[C@@H:30]([C@H:31]([OH:33])[CH3:32])[C:29](=[O:34])[N:21]3[C:22]=2[C:23]([O:25][CH2:26][CH:27]=[CH2:28])=[O:24])[CH2:44][C@H:43]1/[CH:48]=[CH:49]/[C:50]([NH2:52])=[O:51])=[O:41])[CH:37]=[CH2:38]
Reactant: C=CCOC(=O)C1=C(OP(=O)(Oc2ccccc2)Oc2ccccc2)[C@H](C)[C@H]2[C@@H]([C@@H](C)O)C(=O)N12
Reactant: C=CCOC(=O)N1C[C@@H](S)C[C@H]1/C=C/C(N)=O
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: C=CCOC(=O)C1=C(S[C@H]2C[C@@H](/C=C/C(N)=O)N(C(=O)OCC=C)C2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Temperature: 5 °C
Reaction time: 16 h
Yield: 82.8 %

Procedure:
To a solution of allyl (1R,5S,6S)-2-diphenoxyphosphoryloxy-6-[(R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate (27.0 g, 54.06 mmol) and (E)-3-[(2S,4S)-N-allyloxycarbonyl-4-mercaptopyrrolidin-2-yl]acrylamide (16.63 g, 64.88 mmol) in acetonitrile (405 ml) was dropwise added N,N-diisopropylethylamine (9.42 ml, 54.06 mmol) at -30° C. over 15 minutes. The reaction mixture was stirred at -30° C. for 4 hours and at 5° C. for another 16 hours, partitioned between ethyl acetate (400 ml) and water (400 ml), and the each layer separated. The aqueous layer was treated with ethyl acetate (200 ml) for back extraction, the combined organic layer washed successively with saturated aqueous sodium bicarbonate (300 ml) and saturated aqueous sodium chloride (300 ml), dried over anhydrous sodium sulfate and concentrated. The residue was purified by flash column chromatography on silica gel (Wakogel® C-300, 400 ml; elution with ethyl acetate-acetone 7:3) to afford allyl (1R,5S,6S)-2-[(2S,4S)-N-allyloxycarbonyl-2-[(E)-2-(aminocarbonyl)vinyl]pyrrolidin-4-ylthio]-6-[(R)-1hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate (22.64 g, 82.8% yield) as a foam powder.
Reaction SMILES: [CH2:1]([N:4]([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:32])[C:17]2[CH:22]=[CH:21][C:20]([CH2:23][NH:24][CH2:25][C:26]3[N:27]([CH3:31])[CH:28]=[CH:29][N:30]=3)=[CH:19][CH:18]=2)=[CH:11][CH:10]=1)[CH2:5][CH2:6][CH3:7])[CH2:2][CH3:3].C([BH3-])#N.[Na+].C(O)(=O)C.[CH2:41]([C:43]1[CH:44]=[CH:45][C:46]([CH:49]=O)=[N:47][CH:48]=1)[CH3:42]>CO>[CH2:41]([C:43]1[CH:44]=[CH:45][C:46]([CH2:49][N:24]([CH2:23][C:20]2[CH:21]=[CH:22][C:17]([C:16]([NH:15][C:12]3[CH:11]=[CH:10][C:9]([CH2:8][N:4]([CH2:5][CH2:6][CH3:7])[CH2:1][CH2:2][CH3:3])=[CH:14][CH:13]=3)=[O:32])=[CH:18][CH:19]=2)[CH2:25][C:26]2[N:27]([CH3:31])[CH:28]=[CH:29][N:30]=2)=[N:47][CH:48]=1)[CH3:42]
Reactant: CCCN(CCC)Cc1ccc(NC(=O)c2ccc(CNCc3nccn3C)cc2)cc1
Reactant: CCc1ccc(C=O)nc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCCN(CCC)Cc1ccc(NC(=O)c2ccc(CN(Cc3ccc(CC)cn3)Cc3nccn3C)cc2)cc1
Yield: 91.2 %

Procedure:
The compound (191 mg) obtained in Example 15-5 was dissolved in anhydrous methanol (4.0 ml) and added with sodium cyanoborohydride (41.5 mg), acetic acid (0.50 ml), and the compound (71.4 mg) obtained in Example 16-1 and the whole was stirred at room temperature for 2 days under a nitrogen atmosphere. After completion of the reaction, the solvent was distilled off. The resultant was dissolved in chloroform and added with a 1 mol/l sodium hydroxide aqueous solution, followed by stirring for a while. Then, the solution was subjected to extraction with chloroform and washed with a saturated aqueous sodium hydrogen carbonate solution and a saturated saline solution. The organic layer was dried with anhydrous sodium sulfate and the solvent was distilled off. The residue was purified through silica gel column chromatography (chloroform/ethyl acetate) and treated with hydrochloric acid, thereby obtaining a hydrochloride (222 mg) of the subject compound as a white solid.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[NH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[C:18](#[N:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.O>C1COCC1>[C:12]1([NH:11][C:18](=[NH:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: N#Cc1ccccc1
Reactant: Nc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: N=C(Nc1ccccc1)c1ccccc1
Reaction time: 0.33 h

Procedure:
To NaHMDS (49 mL, 48.5 mmol, 1.0 M solution in THF) was added dropwise a solution of aniline (compound 11a, 4.5 mL, 48.5 mmol) in anhydrous THF (10 mL) under N2. After 20 min, a solution of benzonitrile (compound 21, 5.0 mL, 48.5 mmol) in anhydrous THF (10 mL) was slowly added. The reaction mixture was stirred for 12 hrs, poured into cold water and extracted with EtOAc. The organic layer was dried over anhydrous MgSO4, filtered, and concentrated in vacuo.