Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[S:5][CH:6]=[C:7]([C:9]([OH:11])=[O:10])[CH:8]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].[CH2:18](Br)[CH:19]=[CH2:20]>CN(C=O)C.O>[N+:1]([C:4]1[S:5][CH:6]=[C:7]([C:9]([O:11][CH2:20][CH:19]=[CH2:18])=[O:10])[CH:8]=1)([O-:3])=[O:2]
Reactant: C=CCBr
Reactant: O=C(O)c1csc([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCOC(=O)c1csc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.5 %

Procedure:
2-Nitro-4-thiophenecarboxylic acid (2.5 g, 14.45 mmol) was suspended in DMF (25 ml) in the presence of potassium carbonate (4 g, 28.9 mmol) at ambient temperature. Allyl bromide (5 ml, 57.8 mmol) was added to this solution and the mixture stirred at ambient temperature overnight. The mixture was diluted with water and extracted with ethyl acetate. After concentration, the residue was purified by silica gel chromatography using ethyl acetate/petroleum ether as eluant (10:30) to give the title compound (2.45 g, 77%).
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([O:25]C(C)(C)C)=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[CH:31][CH:32]=[C:33]([NH:34][C:35]([NH:37][CH:38]3[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]3)=[O:36])[C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4].FC(F)(F)C(O)=O>>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[C:18]([C:23]([OH:25])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:15][CH:16]=2)[C:8]2[CH:30]=[CH:31][CH:32]=[C:33]([NH:34][C:35]([NH:37][CH:38]3[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]3)=[O:36])[C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2c(NC(=O)NC3CCCCC3)cccc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Product: CCCCc1nc2c(NC(=O)NC3CCCCC3)cccc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared in analogous manner to Example 9 from tert.butyl 4'-[(2-n-butyl-4-cyclohexylaminocarbonylamino-benzimidazol-1-yl)-methyl]biphenyl-2-carboxylate and trifluoroacetic acid.
Reaction SMILES: C([O:8][CH:9]1[CH:13]([NH:14][C:15]([CH2:17][N:18]2[C:24](=[O:25])[CH:23]([NH:26][C:27]([C:29]3[C:38]4[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=4)[CH:32]=[CH:31][N:30]=3)=[O:28])[CH2:22][CH2:21][C:20](=[O:39])[N:19]2[CH2:40][CH2:41][CH3:42])=[O:16])[CH2:12][C:11](=[O:43])[O:10]1)C1C=CC=CC=1.[CH2:44]([N:51]1[C:57](=[O:58])[CH2:56][CH2:55][CH:54]([NH:59][C:60]([C:62]2[C:71]3[C:66](=[CH:67][CH:68]=[CH:69][CH:70]=3)[CH:65]=[CH:64][N:63]=2)=[O:61])[C:53](=[O:72])[N:52]1[CH2:73][C:74]([NH:76][CH:77]([CH:82]=[O:83])[CH2:78][C:79]([OH:81])=[O:80])=[O:75])[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1>>[C:29]1([C:27]([NH:26][CH:23]2[C:24](=[O:25])[N:18]([CH2:17][C:15]([NH:14][CH:13]([CH:9]=[O:8])[CH2:12][C:11]([OH:43])=[O:10])=[O:16])[N:19]([CH2:40][CH2:41][CH3:42])[C:20](=[O:39])[CH2:21][CH2:22]2)=[O:28])[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:32]=[CH:31][N:30]=1.[CH2:44]([N:51]1[C:57](=[O:58])[CH2:56][CH2:55][CH:54]([NH:59][C:60]([C:62]2[C:71]3[C:66](=[CH:67][CH:68]=[CH:69][CH:70]=3)[CH:65]=[CH:64][N:63]=2)=[O:61])[C:53](=[O:72])[N:52]1[CH2:73][C:74]([NH:76][CH:77]([CH:82]=[O:83])[CH2:78][C:79]([OH:81])=[O:80])=[O:75])[C:45]1[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=1
Reactant: CCCN1C(=O)CCC(NC(=O)c2nccc3ccccc23)C(=O)N1CC(=O)NC1CC(=O)OC1OCc1ccccc1
Agent: O=CC(CC(=O)O)NC(=O)CN1C(=O)C(NC(=O)c2nccc3ccccc23)CCC(=O)N1Cc1ccccc1
Product: CCCN1C(=O)CCC(NC(=O)c2nccc3ccccc23)C(=O)N1CC(=O)NC(C=O)CC(=O)O

Procedure:
3-(2-(6-[(Isoquinoline-1-carbonyl)-amino]-3,7-dioxo-2-propyl-[1,2]diazepan-1-yl)-acetylamino)-4-oxo-butyric acid (11b) was prepared from isoquinoline-1-carboxylic acid {2-[(2-benzyloxy-5-oxo-tetrahydro-furan-3-ylcarbamoyl)-methyl]-3,7-dioxo-1-propyl-[1,2]diazepan-4-yl}-amide (10b, diastereomers) (95 mg, 0.16 mmol) by the method used to prepare 11a to afford 28 mg (35% yield) of the title compound. 1H-NMR (500 MHz, CDCl3/CD3OD=0.5 mL/3 drops) δ 0.90-1.00 (t, 3H), 1.65-1.80 (m, 2H), 2.10-2.28 (m, 1H), 2.32-2.40 (m, 1H), 2.47-2.80 (m, 3H), 3.05-3.18 (m, 1H), 3.30-3.51 (m, 2H), 4.00-4.55 (m, 3H), 5.10-5.20 (m, 1H), 7.75-8.05 (m, 4H), 8.49 (s, 1H), 8.90-9.00 (m, 1H). Analytical HPLC: 6.26 min. LC-MS (ES+): m/e=498 (M+H+).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][N:15]2[C:19]([CH:20]([NH:32][C:33]([N:35]3[CH2:40][CH2:39][CH:38]([N:41]4[CH2:50][C:49]5[C:44](=[C:45]([F:51])[CH:46]=[CH:47][CH:48]=5)[NH:43][C:42]4=[O:52])[CH2:37][CH2:36]3)=[O:34])[CH2:21][C:22]3[CH:23]=[C:24]4[C:28](=[C:29]([CH3:31])[CH:30]=3)[NH:27][N:26]=[CH:25]4)=[N:18][N:17]=[N:16]2)[CH2:10][CH2:9]1)=O)(C)(C)C>FC(F)(F)C(O)=O.C(Cl)Cl>[F:51][C:45]1[CH:46]=[CH:47][CH:48]=[C:49]2[C:44]=1[NH:43][C:42](=[O:52])[N:41]([CH:38]1[CH2:37][CH2:36][N:35]([C:33]([NH:32][CH:20]([C:19]3[N:15]([CH2:14][CH:11]4[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]4)[N:16]=[N:17][N:18]=3)[CH2:21][C:22]3[CH:23]=[C:24]4[C:28](=[C:29]([CH3:31])[CH:30]=3)[NH:27][N:26]=[CH:25]4)=[O:34])[CH2:40][CH2:39]1)[CH2:50]2
Reactant: Cc1cc(CC(NC(=O)N2CCC(N3Cc4cccc(F)c4NC3=O)CC2)c2nnnn2CC2CCN(C(=O)OC(C)(C)C)CC2)cc2cn[nH]c12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(CC(NC(=O)N2CCC(N3Cc4cccc(F)c4NC3=O)CC2)c2nnnn2CC2CCNCC2)cc2cn[nH]c12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
tert-Butyl-4-({5-(1-[4-(8-fluoro-2-oxo-1,2-dihydroquinazolin-3[4H]-yl)piperidine-1-carboxamido]-2-(7-methyl-1H-indazol-5-yl)ethyl)-1H-tetrazol-1-yl}methyl)piperidine-1-carboxylate (10 mg, 0.014 mmol) was dissolved in a 1:1 mixture of trifluoroacetic acid and methylene chloride (1.0 mL) and stirred at room temperature for 30 min. The solvent was removed under reduced pressure and the compound dried in vacuo for 2 h to afford 5.9 mg (68%). 1H-NMR (CD3OD, 500 MHz) δ 1.20-1.48 (m, 4H), 1.50-1.79 (m, 5H) 2.24 (dd, J=12.5, 8.6, 1H), 2.50 (s, 3H), 2.57 (dd, J=11.6, 11.3, 1H), 3.18 (bs, 2H), 3.47 (s, 1H), 4.01-4.40 (m, 7H), 5.29 (dd, J=8.2, 7.9, 1H), 6.90-7.15 (m, 4H), 7.37 (s, 1H), 7.98 (s, 1H), 8.00 (s, 1H). Mass spec.: 616.20 (MH)+.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8](F)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH3:11][CH:12]([SH:14])[CH3:13]>>[Cl:1][C:2]1[CH:9]=[C:8]([S:14][CH:12]([CH3:13])[CH3:11])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1ccc(F)cc1Cl
Reactant: CC(C)S
Product: CC(C)Sc1ccc(C#N)c(Cl)c1

Procedure:
2 g of 2-chloro-4-fluorobenzonitrile was used in Procedure Q with 2-propanethiol to afford 2-chloro-4-(isopropylthio)benzonitrile. 1.6 g of 2-chloro-4-(isopropythio)benzonitrile was reacted via Procedure T to give 2-chloro-4-(isopropylthio)benzoic acid. 1 g of 2-chloro-4-(isopropylthio)benzoic acid was reacted via Procedure R to give 2-chloro-4-(isopropylsulfonyl)benzoic acid. 75 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 2-chloro-4-(isopropylsulfonyl)benzoic acid via Procedure G. The product was purified on reverse phase HPLC to yield 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(isopropylsulfonyl)benzamide. MS (Q1) 449.1 (M)+.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=1[NH2:6].[N:11]([O-])=O.[Na+].[OH-].[Na+]>Cl.O>[CH3:1][O:2][CH2:3][C:4]1[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=1[NH:6][NH2:11]
Reactant: O=N[O-]
Reactant: COCc1ccccc1N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COCc1ccccc1NN
Temperature: -10 °C
Yield: 71 %

Procedure:
6.86 g (50 m moles) of 2-methoxymethylaniline was dissolved in 50 ml of concentrated hydrochloric acid. The solution was cooled to −10° C. Thereto was dropwise added a solution of sodium nitrite (4.14 g, 60 m moles) dissolved in water (50 ml) while a temperature of −10° C. to 0° C. was being kept. Then, a solution of 44.6 g (235 m moles) of stannous chloride dissolved in concentrated hydrochloric acid (50 ml) was dropwise added at the above temperature in 1 hour. After the completion of the dropwise addition, stirring was conducted with a gradual temperature increase to about 20° C. Then, a 10% aqueous sodium hydroxide solution was dropped to obtain a pH of 14, after which extraction with toluene was conducted. The toluene layer was washed with water and concentrated under reduced pressure using a rotary evaporator to obtain 5.40 g (35.5 m moles) of liquid 2-methoxymethylphenylhydrazine. Yield: 71%.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[NH:7][N:6]=[C:5]([C:8]2[CH:13]=[CH:12][C:11]([C@H:14]3[CH2:19][CH2:18][C@H:17]([CH2:20][C:21](OCC)=[O:22])[CH2:16][CH2:15]3)=[CH:10][CH:9]=2)[CH:4]=1.[CH3:28][NH:29][CH2:30][C:31]([O:33][CH3:34])=[O:32].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[CH3:28][N:29]([C:21](=[O:22])[CH2:20][C@H:17]1[CH2:16][CH2:15][C@H:14]([C:11]2[CH:12]=[CH:13][C:8]([C:5]3[NH:6][N:7]=[C:3]([C:2]([F:1])([F:26])[F:27])[CH:4]=3)=[CH:9][CH:10]=2)[CH2:19][CH2:18]1)[CH2:30][C:31]([O:33][CH3:34])=[O:32]
Reactant: CNCC(=O)OC
Reactant: CCOC(=O)C[C@H]1CC[C@H](c2ccc(-c3cc(C(F)(F)F)[nH]n3)cc2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CN(C)C(=O)C[C@H]1CC[C@H](c2ccc(-c3cc(C(F)(F)F)n[nH]3)cc2)CC1
Reaction time: 4 h

Procedure:
To a 20 mL scintillation vial was added the product from Example 26B (30 mg, 0.085 mmol), methyl 2-(methylamino)acetate (10.0 mg, 0.097 mmol), and N,N-dimethylformamide (0.85 mL) followed by O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (39.0 mg, 0.102 mmol) and diisopropylethylamine (30 μL, 0.176 mmol). Following 4 hours of stirring, the solvent was evaporated and the residue purified over RP-HPLC to afford the title product. MS (ESI) m/z 438 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[N:34]=[C:5]2[C:6]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=3)=[C:7]([CH3:23])[C:8]([C:10]3[N:14]([C:15]4[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=4)[N:13]=[CH:12][CH:11]=3)=[CH:9][N:4]2[N:3]=1.Cl[C:36]([O:38][CH2:39][CH3:40])=[O:37]>N1C=CC=CC=1>[CH2:39]([O:38][C:36](=[O:37])[NH:1][C:2]1[N:34]=[C:5]2[C:6]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:32])([F:33])[F:31])[CH:25]=3)=[C:7]([CH3:23])[C:8]([C:10]3[N:14]([C:15]4[CH:16]=[CH:17][C:18]([C:19]#[N:20])=[CH:21][CH:22]=4)[N:13]=[CH:12][CH:11]=3)=[CH:9][N:4]2[N:3]=1)[CH3:40]
Reactant: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)cn2nc(N)nc2c1-c1cccc(C(F)(F)F)c1
Reactant: CCOC(=O)Cl
Solvent: c1ccncc1
Product: CCOC(=O)Nc1nc2c(-c3cccc(C(F)(F)F)c3)c(C)c(-c3ccnn3-c3ccc(C#N)cc3)cn2n1
Yield: 20.7 %

Procedure:
A solution of 4-{5-[2-amino-7-methyl-8-(3-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-6-yl]-pyrazol-1-yl}-benzonitrile (Ex. 1, 100 mg, 0.218 mmol) and ethyl chloroformate (104 μL, 1.089 mmol) in pyridine (2.5 mL) was heated at 120° C. for 20 mins using microwave irradiation. The reaction mixture was azeotroped with toluene in vacuo. The resultant residue was subjected to preparative C18 HPLC, eluting with a gradient of 40-80% MeCN in water (+0.1% formic acid) to give the title compound as a white solid (24 mg).
Reaction SMILES: Cl[C:2]1[N:10]([CH2:11][CH:12]=[C:13]([CH3:15])[CH3:14])[C:9]2[C:8](=[O:16])[NH:7][C:6](=[O:17])[N:5]([CH3:18])[C:4]=2[N:3]=1.C(OC([N:26]1[CH2:32][CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)=O)(C)(C)C.[F:33][C:34]([F:39])([F:38])[C:35]([OH:37])=[O:36]>>[F:33][C:34]([F:39])([F:38])[C:35]([OH:37])=[O:36].[N:26]1([C:2]2[N:10]([CH2:11][CH:12]=[C:13]([CH3:15])[CH3:14])[C:9]3[C:8](=[O:16])[NH:7][C:6](=[O:17])[N:5]([CH3:18])[C:4]=3[N:3]=2)[CH2:32][CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1
Reactant: CC(C)=CCn1c(Cl)nc2c1c(=O)[nH]c(=O)n2C
Reactant: CC(C)(C)OC(=O)N1CCCNCC1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)=CCn1c(N2CCCNCC2)nc2c1c(=O)[nH]c(=O)n2C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
8-Chloro-3-methyl-7-(3-methylbut-2-enyl)-3,7-dihydropurine-2,6-dione (40 mg) and 1-homopiperazine carboxylic acid tert-butyl ester (87 μl) were stirred at 140° C. for 1 hour, then trifluoroacetic acid (0.5 ml) was added thereto, and the reaction mixture was stirred at room temperature for 30 minutes. After removing the solvent by distillation at reduced pressure from the reaction mixture, the residue was purified by HPLC with a reversed phase column using water-acetonitrile-trifluoroacetic acid system as eluent to give 46.8 mg of the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([F:15])=[CH:13][C:12]([C:16]2[O:17][C:18]3[CH:23]=[C:22]([O:24][CH2:25][C@@H:26]([NH:28][C:29](=[O:31])[CH3:30])[CH3:27])[N:21]=[CH:20][C:19]=3[N:32]=2)=[CH:11][C:10]=1[F:33])[C:2]1C=CC=[CH:4][CH:3]=1.[F:34]C1(CO)CC1>>[F:33][C:10]1[CH:11]=[C:12]([C:16]2[O:17][C:18]3[CH:23]=[C:22]([O:24][CH2:25][C@@H:26]([NH:28][C:29](=[O:31])[CH3:30])[CH3:27])[N:21]=[CH:20][C:19]=3[N:32]=2)[CH:13]=[C:14]([F:15])[C:9]=1[O:8][CH2:1][C:2]1([F:34])[CH2:4][CH2:3]1
Reactant: CC(=O)N[C@@H](C)COc1cc2oc(-c3cc(F)c(OCc4ccccc4)c(F)c3)nc2cn1
Reactant: OCC1(F)CC1
Product: CC(=O)N[C@@H](C)COc1cc2oc(-c3cc(F)c(OCC4(F)CC4)c(F)c3)nc2cn1

Procedure:
Using N-((2S)-1-((2-(4-(benzyloxy)-3,5-difluorophenyl)[1,3]oxazolo[4,5-c]pyridin-6-yl)oxy)propan-2-yl)acetamide and (1-fluorocyclopropyl)methanol, and in the same manner as in Step A and Step B of Example 4, the title compound was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[N:6]=[C:7]([C:9](=O)[CH2:10][C:11](=O)[CH:12]([F:14])[F:13])[S:8][C:4]=2[CH:3]=1.Cl.[S:20]([C:24]1[CH:29]=[CH:28][C:27]([NH:30][NH2:31])=[CH:26][CH:25]=1)(=[O:23])(=[O:22])[NH2:21]>>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[N:6]=[C:7]([C:9]3[N:30]([C:27]4[CH:26]=[CH:25][C:24]([S:20]([NH2:21])(=[O:23])=[O:22])=[CH:29][CH:28]=4)[N:31]=[C:11]([CH:12]([F:14])[F:13])[CH:10]=3)[S:8][C:4]=2[CH:3]=1
Reactant: NNc1ccc(S(N)(=O)=O)cc1
Reactant: O=C(CC(=O)C(F)F)c1nc2ccc(Cl)cc2s1
Agent: Cl
Product: NS(=O)(=O)c1ccc(-n2nc(C(F)F)cc2-c2nc3ccc(Cl)cc3s2)cc1

Procedure:
The procedure of Example 9 was repeated using 1-(6-chlorobenzothiazol-2-yl)-4,4-difluorobutane-1,3-dione and 4-sulfamoylphenylhydrazine hydrochloride as the starting materials to obtain 4-[5-(6-chlorobenzothiazol-2-yl)-3-difluoromethyl-1H-pyrazol-1-yl]benzenesulfonamide. NMR(DMSO-d6) δ: 7.23 (1H, t, J=54.1 Hz), 7.56 (2H, bs), 7.57 (1H , s), 7.56-7.60 (1H, m), 7.76-7.80 (2H, m), 7.93-7.97 (3H, m), 8.36 (1H, d, J=2.3 Hz); mp 242-244° C. (toluene)
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:44])[CH2:15][C@@H:16]([C:22]1[CH:43]=[CH:42][C:25]([O:26][CH2:27][C:28]2[CH:29]=[C:30]([NH:34]C(=O)OC(C)(C)C)[CH:31]=[CH:32][CH:33]=2)=[CH:24][CH:23]=1)[C:17]1[CH:21]=[CH:20][O:19][N:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:34][C:30]1[CH:29]=[C:28]([CH:33]=[CH:32][CH:31]=1)[CH2:27][O:26][C:25]1[CH:42]=[CH:43][C:22]([C@@H:16]([C:17]2[CH:21]=[CH:20][O:19][N:18]=2)[CH2:15][C:14]([N:9]2[C@@H:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:12][O:11][C:10]2=[O:13])=[O:44])=[CH:23][CH:24]=1
Reactant: CC(C)(C)OC(=O)Nc1cccc(COc2ccc([C@H](CC(=O)N3C(=O)OC[C@@H]3Cc3ccccc3)c3ccon3)cc2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1cccc(COc2ccc([C@H](CC(=O)N3C(=O)OC[C@@H]3Cc3ccccc3)c3ccon3)cc2)c1
Temperature: 25 °C
Yield: 57 %

Procedure:
To a cooled solution (0° C.) of carbamate 27.2 (430 mg, 0.719 mmol) in DCM (4 mL), was slowly added TFA (4 mL). The reaction mixture was allowed to slowly warm to room temperature over three hours. The mixture was then concentrated to dryness under reduced pressure and dissolved in DCM (100 mL). The resulting mixture was extracted with saturated sodium bicarbonate solution (1×30 mL). The aqueous layer was then extracted with DCM (1×50 mL). The organic layers were then combined and washed with brine (1×50 mL) and dried over magnesium sulfate. The filtrate was concentrated, and the residue was purified by medium pressure chromatography (silica gel, 20 to 60% EtOAc:DCM) to give 27.3 (204 mg). MS ESI (pos.) m/e 498.1 (M+H). 1H NMR (400 MHz, CDCl3) δ ppm 8.21 (1 H, d, J=1.6 Hz), 7.09-7.29 (8 H, m), 6.75-6.88 (4 H, m), 6.68 (1 H, dd, J=7.6, 2.2 Hz), 6.06 (1 H, d, J=1.6 Hz), 4.89 (2 H, s), 4.67 (1 H, dd, J=8.2, 6.7 Hz), 4.50-4.58 (1 H, m), 4.01-4.06 (2 H, m), 3.94 (1 H, dd, J=17.6, 8.6 Hz), 3.42-3.49 (1H, m), 3.13 (1 H, dd, J=13.5, 3.3 Hz), 2.68 (1 H, dd, J=13.5, 9.6 Hz).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][C@@H:15]([C:24]([OH:26])=O)[NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:28][C@H:29]([CH2:40][OH:41])[CH2:30][CH2:31][NH:32][C:33](=[O:39])[O:34][C:35]([CH3:38])([CH3:37])[CH3:36].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[CH2:1]([O:8][C:9](=[O:10])[NH:11][CH2:12][CH2:13][CH2:14][C@H:15]([NH:16][C:17]([O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[O:18])[C:24]([NH:28][C@H:29]([CH2:40][OH:41])[CH2:30][CH2:31][NH:32][C:33]([O:34][C:35]([CH3:36])([CH3:38])[CH3:37])=[O:39])=[O:26])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)NCC[C@H](N)CO
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCNC(=O)OCc1ccccc1)C(=O)O
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)NCC[C@@H](CO)NC(=O)[C@H](CCCNC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C

Procedure:
Preparation takes place in analogy to Example 79A from 140 mg (0.38 mmol) of N5-[(benzyloxy)carbonyl]-N2-(tert-butoxycarbonyl)-L-ornithine and 120 mg (0.50 mmol) of tert-butyl [(3S)-3-amino-4-hydroxybutyl]carbamate hydrochloride (Example 88A) in 6 ml of dimethylformamide with the addition of 96 mg (0.50 mmol) of EDC, 16 mg (0.12 mmol) of HOBt and 0.17 ml (1.00 mmol) of diisopropylethylamine. The product is purified by preparative RP-HPLC (mobile phase water/acetonitrile gradient: 90:10→10:90).
Reaction SMILES: C(N(C(C)C)CC)(C)C.[CH3:10][S:11]([O:14]S(C)(=O)=O)(=[O:13])=[O:12].O[CH2:20][C:21]1[N:22]([CH2:35][C:36]2[CH:41]=[CH:40][C:39]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=3[C:48]3[N:52]([C:53]([C:66]4[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=4)([C:60]4[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=4)[C:54]4[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=4)[N:51]=[N:50][N:49]=3)=[CH:38][CH:37]=2)[C:23]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=[C:24]([C:26]([OH:29])([CH3:28])[CH3:27])[N:25]=1.C(=O)([O-])O.[Na+]>O1CCCC1.C(OCC)(=O)C>[OH:29][C:26]([C:24]1[N:25]=[C:21]([CH2:20][O:14][S:11]([CH3:10])(=[O:13])=[O:12])[N:22]([CH2:35][C:36]2[CH:37]=[CH:38][C:39]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=3[C:48]3[N:52]([C:53]([C:54]4[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=4)([C:66]4[CH:67]=[CH:68][CH:69]=[CH:70][CH:71]=4)[C:60]4[CH:61]=[CH:62][CH:63]=[CH:64][CH:65]=4)[N:51]=[N:50][N:49]=3)=[CH:40][CH:41]=2)[C:23]=1[C:30]([O:32][CH2:33][CH3:34])=[O:31])([CH3:28])[CH3:27]
Reactant: CCOC(=O)c1c(C(C)(C)O)nc(CO)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: CS(=O)(=O)OS(C)(=O)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CCOC(=O)c1c(C(C)(C)O)nc(COS(C)(=O)=O)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 109.8 %

Procedure:
0.371 ml of N,N-diisopropyl-N-ethylamine and then 0.371 g of methanesulfonic anhydride were added, under a nitrogen atmosphere, to a solution of 500 mg of ethyl 2-hydroxymethyl-4-(1-hydroxy-1-methylethyl)-1-{4-[2-(trityltetrazol-5-yl)phenyl]phenyl}methylimidazole-5-carboxylate [prepared as described in step (b) above] in 10 ml of tetrahydrofuran. The mixture was then stirred at room temperature for 1.5 hours, after which it was mixed with ethyl acetate and an aqueous solution of sodium hydrogencarbonate. The ethyl acetate layer was separated, dried over anhydrous magnesium sulfate and concentrated by evaporation under reduced pressure, to give 610 mg of the title compound as an amorphous powder. The compound was employed in the subsequent reactions without any further purification.
Reaction SMILES: [CH:1]1([NH2:5])[CH2:4][CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.[C:15]([C:19]1[N:23]([CH2:24][CH:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[C:22]2[CH:31]=[CH:32][C:33]([S:35]([N:38]3[CH:42]=[C:41]([C:43](O)=[O:44])[CH:40]=[N:39]3)(=[O:37])=[O:36])=[CH:34][C:21]=2[N:20]=1)([CH3:18])([CH3:17])[CH3:16].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[C:15]([C:19]1[N:23]([CH2:24][CH:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[C:22]2[CH:31]=[CH:32][C:33]([S:35]([N:38]3[CH:42]=[C:41]([C:43]([NH:5][CH:1]4[CH2:4][CH2:3][CH2:2]4)=[O:44])[CH:40]=[N:39]3)(=[O:37])=[O:36])=[CH:34][C:21]=2[N:20]=1)([CH3:18])([CH3:16])[CH3:17]
Reactant: NC1CCC1
Reactant: CC(C)(C)c1nc2cc(S(=O)(=O)n3cc(C(=O)O)cn3)ccc2n1CC1CCOCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)c1nc2cc(S(=O)(=O)n3cc(C(=O)NC4CCC4)cn3)ccc2n1CC1CCOCC1
Yield: 46.6 %

Procedure:
Following the same procedure in Example 24, Step A, using cyclobutylamine (13 uL, 10 mg, 0.15 mmol), DIPEA (28 uL, 21 mg, 0.16 mmol), 1-{[2-tert-butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5-yl]sulfonyl}-1H-pyrazole-4-carboxylic acid (0.073 mmol) and HATU (44 mg, 0.12 mmol) in DMF (2.5 mL). The crude product was purified by MPLC using Hex/EtOAc (1:2) on silica gel to give 17 mg (47%) of a white solid as the title compound. 1H NMR (400 MHz, METHANOL-D4) δ 1.40-1.56 (m, 4 H), 1.58 (s, 9 H), 1.67-1.79 (m, 2 H), 1.96-2.09 (m, 2 H), 2.22-2.34 (m, 3 H), 3.25-3.34 (m, 2 H), 3.83-3.94 (m, 2 H), 4.34-4.39 (m, 1 H), 4.41 (d, J=7.62 Hz, 2 H), 7.90 (d, J=8.6 Hz, 1 H), 7.97 (dd, J=8.8, 1.8 Hz, 1 H), 8.04 (d, J=0.59 Hz, 1 H), 8.33 (d, J=1.37 Hz, 1 H), 8.77 (d, J=0.59 Hz, 1 H); MS (ESI) (M+H)+=499.8; Anal. Calcd for C25H33N5O4S+0.70 TFA+0.30 EtOAc+0.20H2O (613.09): C, 54.66; H, 6.00; N, 11.42. Found: C, 54.63; H, 5.95; N, 11.51.
Reaction SMILES: C1(P(=[CH:20][C:21]([O:23][CH3:24])=[O:22])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:25]1([CH:31]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[N:32]2[CH2:35][C:34](=O)[CH2:33]2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C1COCC1>[C:25]1([CH:31]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[N:32]2[CH2:35][C:34](=[CH:20][C:21]([O:23][CH3:24])=[O:22])[CH2:33]2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C1CN(C(c2ccccc2)c2ccccc2)C1
Solvent: C1CCOC1
Product: COC(=O)C=C1CN(C(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 45.2 %

Procedure:
Methyl (triphenylphosphoranylidene)acetate (2.77 g, 8.29 mmol) was added to a mixture of 1-(diphenylmethyl)azetidin-3-one (1.64 g, 6.91 mmol) in THF (24 mL) and the resultant mixture was left to stir overnight. The mixture was concentrated under vacuum, then the residue was dissolved in hot 1:4 EtOAc/heptane (40 mL) and allowed to cool to room temperature. The resultant solid was filtered off and the filtrate was concentrated under vacuum. The crude residue was purified by FCC, eluting with 20% EtOAc in heptane, to afford the title compound (917 mg, 44%) as a pale yellow solid. Method B HPLC-MS: MH+ m/z 294, RT 1.43 minutes.