Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([OH:9])=[O:8].ClC(N(C)C)=C(C)C.O[C@H:19]([C@@H:37]([NH:45][C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[CH2:20][N:21]([CH2:30][CH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1)[NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24].N1C=CC=CC=1C(Cl)=O>C(Cl)Cl.CN(C1C=CN=CC=1)C.N1C=CC=CC=1.C1COCC1>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([O:9][C@H:19]([C@@H:37]([NH:45][C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[CH2:38][C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1)[CH2:20][N:21]([CH2:30][CH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1)[NH:22][C:23]([O:25][C:26]([CH3:29])([CH3:27])[CH3:28])=[O:24])=[O:8]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@@H](O)CN(CC1CCCCC1)NC(=O)OC(C)(C)C
Reactant: O=C(O)c1ccccn1
Agent: CC(C)=C(Cl)N(C)C
Agent: CN(C)c1ccncc1
Agent: O=C(Cl)c1ccccn1
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@H](CN(CC1CCCCC1)NC(=O)OC(C)(C)C)OC(=O)c1ccccn1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
At 0° C. under a nitrogen atmosphere, 500 mg (4.07 mmol) of picolinic acid (Fluka; Buchs/Switzerland) in 25 ml of methylene chloride are converted into the acid chloride with 0.57 ml (4.07 mmol) of 1-chloro-N,N,2-trimethyl-1-propenamine [B. Haveaux, A. Dekoker, M. Rens, A. R. Sidani, J. Toye, L. Ghosez, M. Murakami, M. Yoshioka, and W. Nagata, Organic Syntheses 59, 26 (1980)]. After 45 min, 10 ml of THF, 8.3 ml of pyridine, 10 mg of DMAP and 1.00 g (2.03 mmol) of 1-[2(S)-hydroxy-3(S)-(tert-butoxycarbonyl)amino-4-phenyl-butyl]-1-[cyclohexylmethyl]-2-(tert-butoxycarbonyl)-hydrazine (=Boc-[PheNNCha]-Boc, Example 4) are added and the mixture is stirred for 16 h at RT. Since according to HPLC there is still 1-[2(S)-hydroxy-3(S)-(tert-butoxycarbonyl)amino-4-phenyl-butyl]-1-[cyclohexylmethyl]-2-[tert-butoxycarbonyl]-hydrazine present in the reaction mixture, a further 2 equivalents of picolinic acid chloride (prepared as described above) dissolved in 20 ml of methylene chloride are added. After 18 h at RT the mixture is diluted with methylene chloride and washed twice with saturated NaHCO3 solution, water and brine, and the organic phases are extracted with 2 portions of methylene chloride, dried with Na2SO4 and concentrated by evaporation. The brown residue is dissolved in methylene chloride/ethyl acetate, 10 g of silica gel are added and the mixture is concentrated by evaporation. The resulting powder is applied to a silica gel column (hexane/ethyl acetate 1:1). Elution with hexane/ethyl acetate 1:1 yields the title compound: TLC Rf (N)=0.17; tRet (V)=19.9 min; 1H-NMR (200 MHz, CD3OD): 0.6-1.85 (m, 11H, cyclohexyl), 1.36 and 1.40 (2 s, 18H, 2 Boc), 2.4-3.1 (m, 6H), 4.28 (m, 1H), 5.28 (m, 2H), 7.1-7.3 (m, 5H), 7.72 (m, 1H), 8.08 (m, 1H), 8.28 (d, J=7 Hz, 1H), 8.75 (d, J=5 Hz, 1H).
Reaction SMILES: C([O:8][C:9]([C:11]1[CH:12]=[C:13]([CH2:19][C:20]([CH3:26])([CH3:25])[C:21]([O:23][CH3:24])=[O:22])[CH:14]=[CH:15][C:16]=1[O:17][CH3:18])=[O:10])C1C=CC=CC=1>C(O)C.O1CCCC1.[Pd]>[C:9]([C:11]1[CH:12]=[C:13]([CH2:19][C:20]([CH3:26])([CH3:25])[C:21]([O:23][CH3:24])=[O:22])[CH:14]=[CH:15][C:16]=1[O:17][CH3:18])([OH:10])=[O:8]
Reactant: COC(=O)C(C)(C)Cc1ccc(OC)c(C(=O)OCc2ccccc2)c1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: COC(=O)C(C)(C)Cc1ccc(OC)c(C(=O)O)c1
Reaction time: 5 h
Yield: 125.2 %

Procedure:
Methyl 3-(3-benzyloxycarbonyl-4-methoxyphenyl)-2,2-dimethylpropanoate (310 mg, 0.870 mmol) was dissolved in 7 ml of mixed solvent of ethanol with tetrahydrofuran at a ratio of 1:1, 10% palladium on activated carbon (20 mg) was added thereto, and normal pressure hydrogenation was conducted for 5 hours. After completion of the reaction, catalyst was filtered and the filtrate was concentrated to obtain 290 mg (90%) of the title compound as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9](Cl)[C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=2[Cl:17])=[CH:4][CH:3]=1.C([O:21][C:22]([C:24]1[N:25]=[CH:26][N:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:28]=1[NH2:29])=O)C>ClCCCl.[Ti](Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:22](=[O:21])[C:24]3[N:25]=[CH:26][N:27]([C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=4)[C:28]=3[N:29]=[C:9]2[C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][C:11]=2[Cl:17])=[CH:4][CH:3]=1
Reactant: ClC(=Nc1ccc(Br)cc1)c1ccc(Cl)cc1Cl
Reactant: CCOC(=O)c1ncn(-c2ccccc2)c1N
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCCl
Product: O=c1c2ncn(-c3ccccc3)c2nc(-c2ccc(Cl)cc2Cl)n1-c1ccc(Br)cc1
Temperature: 120 °C
Yield: 36 %

Procedure:
To a solution of N-(4-bromo-phenyl)-2,4-dichloro-benzimidoyl chloride (0.22 mmol) and 5-amino-1-phenyl-1H-imidazole-4-carboxylic acid ethyl ester (65 mg, 0.27 mmol) in 1,2-dichloroethane is added titanium tetrachloride (98 μL, 0.89 mmol) dropwise at room temperature. After addition is completed, the reaction mixture is heated at 120° C. for 18 hours. After the reaction is quenched with water and the aqueous layer is extracted with ethyl acetate. The organic solvents are combined and dried over magnesium sulfate. Filtration and concentration provide a crude product which is purified by column chromatography gave a white solid as product (41 mg, three steps yield 36%). 1H NMR (CDCl3) δ(ppm) 8.04 (s, 1H), 7.58 (d, 2H), 7.47 (t, 2H), 7.38 (m, 3H), 7.22 (d, 1H), 7.15 (b, 1H), 7.07 (m, 2H), 6.91 (b, 1H); HPLC-MS calculated for C23H13BrCl2N40 (M+H+): 511.0. Found: 511.0.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][CH3:15])[N:13]=2)[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CCC(F)(F)C2)C2N=NNC=2N=1)(C)(C)C.[Cl:43][C:44]1[CH:49]=[CH:48][CH:47]=[C:46]([F:50])C=1CCl>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][C:15]3[C:46]([F:50])=[CH:47][CH:48]=[CH:49][C:44]=3[Cl:43])[N:13]=2)[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCn1nc2nc(C(C)(C)C)nc(N3CCC(F)(F)C3)c2n1
Reactant: Fc1cccc(Cl)c1CCl
Agent: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Product: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn(Cc3c(F)cccc3Cl)nc2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoro-pyrrolidin-1-yl)-2-ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 1-chloro-2-(chloromethyl)-3-fluorobenzene and isolated as white solid (5.4 mg, 31%). MS (m/e): 425.4 (MH+).
Reaction SMILES: [CH:1]1([CH2:4][NH:5][C:6](=[O:17])[NH:7][C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=2)[CH2:3][CH2:2]1.[F:18][C:19]([F:44])([F:43])[C:20]([C:26]1[CH:42]=[CH:41][C:29]([CH2:30][N:31]2[CH2:36][CH2:35][NH:34][CH:33]([C:37]([O:39][CH3:40])=[O:38])[CH2:32]2)=[CH:28][CH:27]=1)([OH:25])[C:21]([F:24])([F:23])[F:22].C(N(CC)CC)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>ClCCl>[CH:1]1([CH2:4][NH:5][C:6](=[O:17])[NH:7][C:8]2[CH:9]=[CH:10][C:11]([C:12]([N:34]3[CH2:35][CH2:36][N:31]([CH2:30][C:29]4[CH:41]=[CH:42][C:26]([C:20]([OH:25])([C:21]([F:22])([F:23])[F:24])[C:19]([F:44])([F:18])[F:43])=[CH:27][CH:28]=4)[CH2:32][CH:33]3[C:37]([O:39][CH3:40])=[O:38])=[O:14])=[CH:15][CH:16]=2)[CH2:2][CH2:3]1
Reactant: O=C(NCC1CC1)Nc1ccc(C(=O)O)cc1
Reactant: COC(=O)C1CN(Cc2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2)CCN1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C1CN(Cc2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2)CCN1C(=O)c1ccc(NC(=O)NCC2CC2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 34.3 %

Procedure:
4-(3-(Cyclopropylmethyl)ureido)benzoic acid (0.213 mmol, 0.05 g), methyl 4-(4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)benzyl)piperazine-2-carboxylate (0.213 mmol, 0.085 g) and triethylamine (0.640 mmol, 0.089 mL, 0.065 g) were combined and stirred in dichloromethane. 1-Propanephosphonic acid cyclic anhydride (0.320 mmol, 0.191 mL, 0.204 g) was added and the reaction stirred for 2 hours at room temperature. This was washed with water and the resulting residue purified by acidic prep HPLC to afford the title compound (45 mg). MS (ESI) m/z 617.2 [M+H]+
Reaction SMILES: [CH3:1][NH:2][NH2:3].[CH3:4][O:5][C:6]1[CH:25]=[CH:24][C:9](CCNN2C(=O)C3C(=CC=CC=3)C2=O)=[CH:8][C:7]=1[CH3:26].O1CCC[CH2:28]1>>[CH3:4][O:5][C:6]1[CH:25]=[CH:24][C:9]([CH2:1][N:2]([CH3:28])[NH2:3])=[CH:8][C:7]=1[CH3:26]
Reactant: COc1ccc(CCNN2C(=O)c3ccccc3C2=O)cc1C
Reactant: C1CCOC1
Reactant: CNN
Product: COc1ccc(CN(C)N)cc1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 31 %

Procedure:
Tetrahydrofuran (30 ml) and methylhydrazine (138 mg) were added to 2-[(4-methoxy-3-methylbenzyl)methylamino]isoindole-1,3-dione (621 mg) prepared in the Step 15-1-3, and the mixture was stirred at a room temperature for one hour. Another methylhydrazine (138 mg) was added thereto, the resulting mixture was stirred for 12 hours. The solvent was distilled off under a reduced pressure. Dichloromethane was added to the residue, and the insoluble matter was removed by filtration. The filtrate was concentrated under a reduced pressure and then purified by silica gel column chromatography (dichloromethane:methanol=20:1) to give the title compound (115 mg, 31%).
Reaction SMILES: [C:1]([C:3]1[N:4]=[CH:5][C:6]2[CH:11]=[C:10]([CH2:12][N:13]3[C:18](=[O:19])[CH2:17][N:16](C(O)=O)[CH2:15][C:14]3=[O:23])[N:9]([CH2:24][C:25]([CH3:28])([CH3:27])[CH3:26])[C:7]=2[N:8]=1)#[N:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:26][C:25]([CH3:28])([CH3:27])[CH2:24][N:9]1[C:7]2[N:8]=[C:3]([C:1]#[N:2])[N:4]=[CH:5][C:6]=2[CH:11]=[C:10]1[CH2:12][N:13]1[C:14](=[O:23])[CH2:15][NH:16][CH2:17][C:18]1=[O:19]
Reactant: CC(C)(C)Cn1c(CN2C(=O)CN(C(=O)O)CC2=O)cc2cnc(C#N)nc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)Cn1c(CN2C(=O)CNCC2=O)cc2cnc(C#N)nc21
Temperature: 25 °C
Reaction time: 6 h
Yield: 88.3 %

Procedure:
To a solution of 10.5 g (23.9 mmoles) of 4-[2-cyano-7-(2,2-dimethyl-propyl)-7H-pyrrolo[2,3-d]pyrimidin-6-ylmethyl]-3,5-dioxo-piperazine-1-carboxylic acid .tert.-butyl ester in 300 ml of CH2Cl2, 52 ml (675 mmoles) of TFA is added at 0° C. The reaction mixture is allowed to warm to ambient temperature and stirred for 6 hours. The reaction mixture is concentrated under reduced pressure, neutralized with sat.NaHCO3 and extracted with CH2Cl2. The combined extracts are washed with brine, dried over MgSO4 and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (eluent: CH2CO2:AcOEt=1:3) give 7.18 g of desired 7-(2,2-dimethyl-propyl)-6-(2,6-dioxo-piperazin-1-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile in 88.5% yield.
Reaction SMILES: C(OC([N:11]1[CH2:16][C@@H:15]([C:17](=[O:19])[NH2:18])[N:14]([CH2:20][CH2:21][CH2:22][C:23]([N:25]2[CH2:32][CH2:31][C:28]3([CH2:30][CH2:29]3)[C@H:27]([OH:33])[CH2:26]2)=[O:24])[C:13](=[O:34])[C@@H:12]1[CH3:35])=O)C1C=CC=CC=1.[H][H]>[Pd]>[OH:33][C@@H:27]1[CH2:26][N:25]([C:23](=[O:24])[CH2:22][CH2:21][CH2:20][N:14]2[C:13](=[O:34])[C@H:12]([CH3:35])[NH:11][CH2:16][C@H:15]2[C:17]([NH2:18])=[O:19])[CH2:32][CH2:31][C:28]21[CH2:29][CH2:30]2
Reactant: C[C@H]1C(=O)N(CCCC(=O)N2CCC3(CC3)[C@H](O)C2)[C@H](C(N)=O)CN1C(=O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Product: C[C@@H]1NC[C@@H](C(N)=O)N(CCCC(=O)N2CCC3(CC3)[C@H](O)C2)C1=O

Procedure:
In analogy to the procedure described in the first part of example 120 step E, (2S,5S)-5-carbamoyl-4-[4-((S)-4-hydroxy-6-aza-spiro[2.5]oct-6-yl)-4-oxo-butyl]-2-methyl-3-oxo-piperazine-1-carboxylic acid benzyl ester was treated with 10% palladium on charcoal and the reaction was stirred under 1 atmosphere of hydrogen affording the titled compound in quantitative yield as a colorless foam. MS: 353.4 (MH+).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][O:6][CH2:5][CH2:4][N:3]1[C:8]1[N:9]=[C:10]([N:29]2[CH2:34][CH2:33][O:32][CH2:31][C@@H:30]2[CH3:35])[C:11]2[CH:17]=[CH:16][C:15]([C:18]3[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[C:20]([O:27][CH3:28])[CH:19]=3)=[N:14][C:12]=2[N:13]=1.[CH3:36][N:37](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN.C(N(CC)CC)C>C1COCC1>[CH3:1][C@H:2]1[CH2:7][O:6][CH2:5][CH2:4][N:3]1[C:8]1[N:9]=[C:10]([N:29]2[CH2:34][CH2:33][O:32][CH2:31][C@@H:30]2[CH3:35])[C:11]2[CH:17]=[CH:16][C:15]([C:18]3[CH:26]=[CH:25][C:21]([C:22]([NH:37][CH3:36])=[O:23])=[C:20]([O:27][CH3:28])[CH:19]=3)=[N:14][C:12]=2[N:13]=1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: COc1cc(-c2ccc3c(N4CCOC[C@@H]4C)nc(N4CCOC[C@@H]4C)nc3n2)ccc1C(=O)O
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CNC(=O)c1ccc(-c2ccc3c(N4CCOC[C@@H]4C)nc(N4CCOC[C@@H]4C)nc3n2)cc1OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-[2,4-Bis-((S)-3-methyl-morpholin-4-yl)-pyrido[2,3-d]pyrimidin-7-yl]-2-methoxy-benzoic acid (1 equiv) was dissolved in THF (0.1 M) and HBTU (1.5 equiv) was added. Methylamine in THF (15 equiv) was added dropwise followed by triethylamine (1.5 equiv) and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated in vacuo. The residue was partitioned between water and CH2Cl2. The aqueous phase was extracted with CH2Cl2. Combined organic phases were dried (MgSO4), filtered and concentrated in vacuo. The crude residue was purified by preparative HPLC to give the desired product.
Reaction SMILES: C[O:2][C:3](=[O:25])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH:23]=O)[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1.[CH:26]1([NH2:29])[CH2:28][CH2:27]1.Cl[C:31]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:32]>>[CH2:34]([O:33][C:31]([N:29]([CH2:23][C:14]1[CH:15]=[C:16]([C:19]([F:22])([F:21])[F:20])[CH:17]=[CH:18][C:13]=1[C:7]1[C:8]([O:11][CH3:12])=[CH:9][CH:10]=[C:5]([CH2:4][C:3]([OH:25])=[O:2])[CH:6]=1)[CH:26]1[CH2:28][CH2:27]1)=[O:32])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: NC1CC1
Reactant: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2C=O)c1
Product: COc1ccc(CC(=O)O)cc1-c1ccc(C(F)(F)F)cc1CN(C(=O)OCc1ccccc1)C1CC1

Procedure:
{2′-[(Benzyloxycarbonyl-cyclopropyl-amino)-methyl]-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl}-acetic acid (Compound 1-36) was prepared by following the procedures of Example 1 and using the following starting materials: (2′-formyl-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid methyl ester, cyclopropylamine, and benzyl chloroformate
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([N:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH2:12][N:11]3[CH:19]=[CH:20][CH:21]=[C:10]3[CH2:9]2)=[O:7])=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:31][CH2:32][C:33](Cl)=[O:34]>C(Cl)Cl.CN(C1C=CC=CN=1)C>[Cl:31][CH2:32][C:33]([NH:1][C:2]1[CH:23]=[CH:22][C:5]([C:6]([N:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH2:12][N:11]3[CH:19]=[CH:20][CH:21]=[C:10]3[CH2:9]2)=[O:7])=[CH:4][CH:3]=1)=[O:34]
Reactant: O=C(Cl)CCl
Reactant: Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(CCl)Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 100.1 %

Procedure:
To a stirred solution of 0.91 g of 10,11-dihydro-10-(4-aminobenzoyl)-5H-pyrrolo[2,1-c][1,4]-benzodiazepine in 10 ml of methylene chloride is added 0.46 g of triethylamine and 36 mg of dimethylaminopyridine followed by the slow addition of 0.42 g of chloroacetyl chloride in 5 ml of methylene chloride. The resulting mixture is stirred at room temperature for 3 hours then partitioned with 10 ml of 50% NaHCO3 and the methylene chloride evaporated in vacuo. The remaining suspension is filtered, washed with 50% NaHCO3, H2O, EtOAc (2×2 ml), ether (2×5 ml) and dried in vacuo to give 1.14 g of beige solid. MS(CI): 380(M+H).
Reaction SMILES: [H-].[Na+].O1CCCC1.C(OCC)(=O)[CH2:9][C:10]([CH3:12])=[O:11].F[C:18]1[C:23]([F:24])=[C:22]([F:25])[CH:21]=[CH:20][C:19]=1[N+:26]([O-:28])=[O:27]>C(O)(=O)C>[F:24][C:23]1[C:18]([CH2:9][C:10](=[O:11])[CH3:12])=[C:19]([N+:26]([O-:28])=[O:27])[CH:20]=[CH:21][C:22]=1[F:25]
Reactant: CCOC(=O)CC(C)=O
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1F
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC(=O)Cc1c([N+](=O)[O-])ccc(F)c1F
Reaction time: 1 h
Yield: 90 %

Procedure:
12.1 g (303 mmol) of 60% sodium hydride was added to 45 ml of tetrahydrofuran, and while cooling with a freezing mixture, 90 ml of tetrahydrofuran containing 39.0 g (300 mmol) of ethyl acetoacetate was dropped to the solution below 20° C. through 30 minutes. After the solution was stirred for 1 hour as was, 90 ml of tetrahydrofuran solution containing 26.6 g (150 mmol) of 2,3,4-trifluoronitrobenzene was dropped to the solution below 10° C. through 30 minutes, and the solution was stirred overnight at room temperature. 27 ml of acetic acid was added to the solution, and the solvent was removed by distillation. The solution was extracted with 500 ml of chloroform, and after drying over magnesium sulfate, the solvent was removed by distillation. 30 ml of 4N hydrochloric acid and 25 ml of acetic acid were added to the solution, and the solution was heated at reflux for 24 hours. 550 ml of concentrated hydrochloric acid and 550 ml of acetic acid were added to the solution, and the solution was heated at reflux for 16 hours. After air-cooling, the solution was extracted with 1 l of chloroform and was washed with 500 ml of water two times. The solution was further washed with 300 ml of aqueous saturated sodium hydrogen carbonate solution two times, and after drying over magnesium sulfate, the solvent was removed by distillation. The residue was separated by the column chromatography (silica gel 300 g, eluent solvent; chloroform: n-hexane=1 :3) to obtain 31.2 g of the subject compound (148) in a 90% yield.
Reaction SMILES: Cl[C:2]1[C:10]2[NH:9][C:8]([CH:11]([F:13])[F:12])=[N:7][C:6]=2[C:5]([N+:14]([O-:16])=[O:15])=[CH:4][C:3]=1[N+:17]([O-:19])=[O:18].C(N(CC)CC)C.[C:27]([NH2:31])([CH3:30])([CH3:29])[CH3:28].O>C(O)C>[C:27]([NH:31][C:2]1[C:10]2[NH:9][C:8]([CH:11]([F:13])[F:12])=[N:7][C:6]=2[C:5]([N+:14]([O-:16])=[O:15])=[CH:4][C:3]=1[N+:17]([O-:19])=[O:18])([CH3:30])([CH3:29])[CH3:28]
Reactant: CC(C)(C)N
Reactant: O=[N+]([O-])c1cc([N+](=O)[O-])c2nc(C(F)F)[nH]c2c1Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(C)(C)Nc1c([N+](=O)[O-])cc([N+](=O)[O-])c2nc(C(F)F)[nH]c12

Procedure:
4-Chloro-5,7-dinitro-2-difluoromethylbenzimidazole (1.9 grams), triethylamine (0.7 gram), and tert-butylamine (0.5 gram) were mixed in ethanol and refluxed overnight. The mixture was then poured into water, acidified, and filtered to separate the expected 4-tert-butylamino-5,7-dinitro-2-difluoromethylbenzimidazole product, m.p., 189°-196° C. After recrystallization from ethanol, it melted at 199°-201° C. The identity of the product was confirmed by NMR analysis.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:6]=1[C:7]([OH:9])=O)(=[O:3])[CH3:2].[NH2:15][C:16]1[CH:17]=[C:18]([N:22]2[C:26]([C:27]([F:30])([F:29])[F:28])=[CH:25][C:24]([C:31]([F:34])([F:33])[F:32])=[N:23]2)[CH:19]=[CH:20][CH:21]=1>>[C:1]([O:4][C:5]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:6]=1[C:7]([NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([N:22]2[C:26]([C:27]([F:28])([F:29])[F:30])=[CH:25][C:24]([C:31]([F:34])([F:33])[F:32])=[N:23]2)[CH:17]=1)=[O:9])(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1ccc(Cl)cc1C(=O)O
Reactant: Nc1cccc(-n2nc(C(F)(F)F)cc2C(F)(F)F)c1
Product: CC(=O)Oc1ccc(Cl)cc1C(=O)Nc1cccc(-n2nc(C(F)(F)F)cc2C(F)(F)F)c1
Yield: 84.4 %

Procedure:
Using 2-acetoxy-5-chlorobenzoic acid and 1-(3-aminophenyl)-3,5-bis(trifluoromethyl)pyrazole as the raw materials, the same operation as the Example 24 gave the title compound.
Reaction SMILES: COC([C:5]1[N:9]([C:10]([CH3:29])([CH2:12][CH2:13][N:14](C(OC(C)(C)C)=O)[C:15]([O:17]C(C)(C)C)=O)[CH3:11])[C:8]2[CH:30]=[C:31]([C:34]([O:36][CH2:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)=[O:35])[CH:32]=[CH:33][C:7]=2[N:6]=1)=O.C(O)(C(F)(F)F)=O.C(N(CC)CC)C>C(Cl)Cl>[CH3:11][C:10]1([CH3:29])[N:9]2[C:5](=[N:6][C:7]3[CH:33]=[CH:32][C:31]([C:34]([O:36][CH2:37][C:38]4[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=4)=[O:35])=[CH:30][C:8]=32)[C:15](=[O:17])[NH:14][CH2:13][CH2:12]1
Reactant: COC(=O)c1nc2ccc(C(=O)OCc3ccccc3)cc2n1C(C)(C)CCN(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(C)CCNC(=O)c2nc3ccc(C(=O)OCc4ccccc4)cc3n21
Temperature: 25 °C
Reaction time: 16 h
Yield: 46.8 %

Procedure:
To a stirred solution of crude 1-({4-[bis(tert-butoxycarbonyl)amino]-2-methylbutan-2-yl}-1H-benzimidazole-2,6-dicarboxylic acid 6-benzyl ester 2-methyl ester (289 mg, 0.47 mmol) in CH2Cl2 (5 mL) is added TFA (1 mL). After 1 h the solvent is evaporated, and CH2Cl2 is added and evaporated from the residue three times to remove excess TFA. The residue is dissolved in methanol (10 mL) and triethylamine (0.72 mL, 5.16 mmol) added. The solution is stirred at room temperature for 16 h. The solvent is evaporated and the residue partitioned between H2O and EtOAc. The organic layer is dried (MgSO4) and purified by flash chromatography, eluting with CH2Cl2/methanol to afford the title compound (80 mg, 44%).
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:9]1([C:16]#N)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.Cl.S(=O)(=O)(O)[OH:20]>C(OCC)C>[CH:9]1([C:16]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[O:20])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: O=S(=O)(O)O
Reactant: Br[Mg]c1ccccc1
Reactant: N#CC1CCCCCC1
Agent: Cl
Solvent: CCOCC
Product: O=C(c1ccccc1)C1CCCCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Phenylmagnesium bromide (3.0M solution in diethyl ether) (271 mL), was added dropwise to a stirred (overhead stirrer) solution of cycloheptanecarbonitrile (50 g) in 229 mL diethyl ether under nitrogen at such a rate as to maintain gentle reflux. The reaction mixture was then heated at reflux for 3 hours. TLC indicated no starting material present in the reaction mixture. The reaction mixture was allowed to cool to room temperature and stood under nitrogen overnight. The reaction mixture was cooled to 0° C. and treated dropwise with 102 mL 4N HCl(aq) keeping the temperature below 20° C. 4N sulfuric acid (203 mL) was added dropwise rapidly to start with and then more slowly towards the end. The ice bath was removed and the diethyl ether was distilled off. The reaction mixture was heated at 80-90° C. for 3.5 hours then allowed to cool to room temperature and stood overnight. The mixture was diluted with ether (approx 450 mL) and water (100 mL). The layers were separated and the aqueous layer was extracted with ether (2×400 mL). The organic layers were combined and washed with saturated aqueous sodium hydrogen carbonate (600 mL) and brine (600 mL), dried over magnesium sulphate, filtered and evaporated to give the sub-titled compound as an orange liquid (86.5 g).