Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:58])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]1[NH:17][C:18]([C:21]2[CH:26]=[CH:25][C:24]([C:27]#[C:28][C:29]3[CH:34]=[CH:33][C:32]([C:35]4[NH:36][C:37]([CH:40]5[CH2:44][C:43](F)(F)[CH2:42][N:41]5[C:47](=[O:57])[CH:48]([NH:52][C:53]([O:55][CH3:56])=[O:54])[CH:49]([CH3:51])[CH3:50])=[N:38][CH:39]=4)=[CH:31][CH:30]=3)=[CH:23][CH:22]=2)=[CH:19][N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7].CO[C:61](=O)[NH:62]C(C(N1CCCC1C1NC(C2C=CC(Br)=CC=2)=CN=1)=O)C(C)C.COC(=O)N[CH:91](C(N1C(C2NC(C3C=CC(C#C)=CC=3)=CN=2)CC2(CC2)C1)=O)[CH:92](C)C.COC(=O)NC(C(N1CC(F)(F)CC1C1NC(C2C=CC(C#C)=CC=2)=CN=1)=O)C(C)C>>[CH3:1][O:2][C:3](=[O:58])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH:14]([C:61]#[N:62])[CH2:13][CH:12]1[C:16]1[NH:17][C:18]([C:21]2[CH:26]=[CH:25][C:24]([C:27]#[C:28][C:29]3[CH:34]=[CH:33][C:32]([C:35]4[NH:36][C:37]([CH:40]5[CH2:44][C:43]6([CH2:92][CH2:91]6)[CH2:42][N:41]5[C:47](=[O:57])[CH:48]([NH:52][C:53]([O:55][CH3:56])=[O:54])[CH:49]([CH3:51])[CH3:50])=[N:38][CH:39]=4)=[CH:31][CH:30]=3)=[CH:23][CH:22]=2)=[CH:19][N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7]
Reactant: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc(C#Cc3ccc(-c4cnc(C5CC(F)(F)CN5C(=O)C(NC(=O)OC)C(C)C)[nH]4)cc3)cc2)[nH]1)C(C)C
Reactant: C#Cc1ccc(-c2cnc(C3CC4(CC4)CN3C(=O)C(NC(=O)OC)C(C)C)[nH]2)cc1
Reactant: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc(Br)cc2)[nH]1)C(C)C
Agent: C#Cc1ccc(-c2cnc(C3CC(F)(F)CN3C(=O)C(NC(=O)OC)C(C)C)[nH]2)cc1
Product: COC(=O)NC(C(=O)N1CC(C#N)CC1c1ncc(-c2ccc(C#Cc3ccc(-c4cnc(C5CC6(CC6)CN5C(=O)C(NC(=O)OC)C(C)C)[nH]4)cc3)cc2)[nH]1)C(C)C

Procedure:
Title compound was prepared according to the method employed to prepare [1-(2-{5-[4-(4-{2-[4,4-Difluoro-1-(2-methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenylethynyl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester (Example AB1), substituting (1-{2-[5-(4-Bromo-phenyl)-1H-imidazol-2-yl]-4-cyano-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester for (1-{2-[5-(4-bromo-phenyl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (400 mg, 0.89 mmol), and (1-{6-[5-(4-Ethynyl-phenyl)-1H-imidazol-2-yl]-5-aza-spiro[2.4]heptane-5-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester for (1-{2-[5-(4-Ethynyl-phenyl)-1H-imidazol-2-yl]-4,4-difluoro-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester. 1H NMR (MeOH-d4, 400 MHz) δ: 7.78-7.66 (m, 4H), 7.52-7.37 (m, 4H), 5.29 (m, 1H), 5.17 (m, 1H), 4.59 (m, 1H), 4.17-4.09 (m, 3H), 4.01 (m, 1H), 3.93-3.80 (m, 2H), 3.65 (s, 6H), 3.50-3.42 (m, 2H), 2.88-2.81 (m, 1H), 2.66-2.52 (m, 2H), 2.36-2.31 (m, 1H), 2.18-2.13 (m, 1H), 2.05-1.94 (m, 3H), 1.01-0.87 (m, 12H), 0.82-0.63 (m, 4H); MS (ESI) m/z 814 [M+H]+.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C@H:11]2[CH2:16][CH2:15][C@H:14]([OH:17])[CH2:13][CH2:12]2)=[CH:7][CH:6]=1)[CH3:3].[CH:18]1([C:21](Cl)=[O:22])[CH2:20][CH2:19]1.C(N(CC)CC)C>>[CH:18]1([C:21]([O:17][C@H:14]2[CH2:15][CH2:16][C@H:11]([C:8]3[CH:9]=[CH:10][C:5]([CH2:4][N:2]([CH3:1])[CH3:3])=[CH:6][CH:7]=3)[CH2:12][CH2:13]2)=[O:22])[CH2:20][CH2:19]1
Reactant: CN(C)Cc1ccc([C@H]2CC[C@H](O)CC2)cc1
Reactant: O=C(Cl)C1CC1
Solvent: CCN(CC)CC
Product: CN(C)Cc1ccc([C@H]2CC[C@H](OC(=O)C3CC3)CC2)cc1

Procedure:
from trans-4-(4-dimethylaminomethylphenyl)-cyclohexanol and cyclopropane carboxylic acid chloride/triethylamine. Colourless wax.
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9](=[O:12])[O:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:13](=[CH:20][C:21](=[O:23])[CH3:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.CS(O)(=O)=O.O>C(#N)C.C(OCC)(=O)C>[O:23]=[C:21]([CH3:22])[CH2:20][CH:13]([C:11]1[O:10][C:9](=[O:12])[NH:8][C:7]=1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=c1[nH]c(-c2ccccc2)co1
Reactant: CC(=O)C=Cc1ccccc1
Agent: CS(=O)(=O)O
Solvent: O
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC(=O)CC(c1ccccc1)c1oc(=O)[nH]c1-c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.3 %

Procedure:
4-Phenyl-2-oxo-4-oxazoline (1.61 g) and benzalacetone (1.46 g) were dissolved in acetonitrile (20 mL), and methanesulfonic acid (0.96 mL) was added. The obtained mixture was stirred at room temperature for 1 h and water (100 mL) and ethyl acetate (100 mL) were added to the reaction mixture. The organic layer was separated, washed twice with water (50 mL), and concentrated under reduced pressure to give an oily substance. The obtained oily substance was subjected to silica gel column chromatography and eluted with n-hexane-ethyl acetate (1:1). The solvent was evaporated and isopropyl ether (50 mL) was added to the obtained oily substance to allow crystallization and the mixture was stirred at room temperature for 1 h. The crystals were collected by filtration and washed with isopropyl ether (20 mL) to give the title compound (2.65 g; yield 86.3%) as white crystals.
Reaction SMILES: [CH:1]1([CH2:7][OH:8])[CH2:6][CH2:5][CH:4]=[CH:3][CH2:2]1.C(N(CC)C(C)C)(C)C.[C:18]([Si:22]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)Cl)([CH3:21])([CH3:20])[CH3:19]>CN(C)C1C=CN=CC=1>[Si:22]([O:8][CH:7]=[C:1]1[CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]1)([C:18]([CH3:21])([CH3:20])[CH3:19])([C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: OCC1CC=CCC1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)[Si](OC=C1C=CCCC1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a mixture of 3-cyclohexene-1-methanol (Aldrich, 13.0 mL, 0.11 mol), N,N-diisopropylethylamine (43 mL, 0.244 mol) and 4-dimethylaminopyridine (2.70 g., 0.022 mol) in 375 mL of dry CH2CI2 under B2 at 25° C. was added tert-butyldiphenylchlorosilane (32 mL, 0.123 mol). The mixture was stirred at 25° C. for 48 hours. The reaction mixture was washed sequentially with 150 mL portions of 1N HCl, water, brine and dried over anhydrous MgSO4. The solvent was evaporated. The residue was loaded onto a 4"×4" column of silica and slowly eluted using hexanes as eluant. 3-(tert-butyldiphenylsilyloxymethylene)-1-cyclohexene, 33.6 g (86%), was obtained as a colorless oil which was homogenous by TLC (Rf=0.4, hexanes).
Reaction SMILES: I[C:2]1[CH:3]=[N:4][N:5]([CH3:7])[CH:6]=1.[Li]CCCC.[N:13](/[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[N:14]/[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16]>CCOCC.CCCCCC>[CH3:7][N:5]1[CH:6]=[C:2]([N:13]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[NH:14][C:15]([O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:16])[CH:3]=[N:4]1
Reactant: Cn1cc(I)cn1
Reactant: CC(C)(C)OC(=O)/N=N\C(=O)OC(C)(C)C
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: Cn1cc(N(NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)cn1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 30 %

Procedure:
To a solution of 4-iodo-1-methyl-1H-pyrazole (21 g, 0.12 mol) in dry ether (200 mL) at −78° C. was added n-BuLi (84.5 mL of a 2.5 M solution in hexane, 0.18 mol) over a period of 30 min and the mixture stirred for a further 30 min. A solution of di-tert-butyl(Z)-diazene-1,2-dicarboxylate (30.4 g, 0.12 mol) in ether (100 ml) was added to the reaction mixture over a period of 10 min and the resultant mixture stirred at −78° C. for 1 hour. The reaction was warmed to 0° C. and quenched with ice-water and extracted with ether (3×100 mL). The organic layer was separated, dried (Na2SO4) and evaporated in vacuo. The crude material was washed with hexane and then dried under vacuum to give the title compound in 30% yield, 11.2 g.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH:17]([CH2:24][CH:25]([CH3:27])[CH3:26])[C:18]([CH3:23])([CH3:22])[C:19](O)=[O:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[S:28]1[CH:32]=[N:31][N:30]=[C:29]1[NH2:33]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH:17]([CH2:24][CH:25]([CH3:26])[CH3:27])[C:18]([CH3:23])([CH3:22])[C:19]([NH:33][C:29]4[S:28][CH:32]=[N:31][N:30]=4)=[O:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1
Reactant: CC(C)CC(c1ccc2c(cnn2-c2ccc(F)cc2)c1)C(C)(C)C(=O)O
Reactant: Nc1nncs1
Product: CC(C)CC(c1ccc2c(cnn2-c2ccc(F)cc2)c1)C(C)(C)C(=O)Nc1nncs1
Yield: 12.2 %

Procedure:
To a solution of 3-(1-(4-fluorophenyl)-1H-indazol-5-yl)-2,2,5-trimethylhexanoic acid (220 mg, 0.6 mmol) from Example 33(c) was coupled to 1,3,4-thiadiazol-2-amine (60 mg, 0.6 mmol) using General Coupling Method B. The product was purified by HPLC to give 33 mg (24%) of the desired product Example 34. MS found: (M+H)+=452. NMR(CDCl3) δ 8.73 (s, 1H); 8.11 (s, 1H); 7.8-8.4 (bs, 1H) 7.55-7.61 (m, 3H); 7.49-7.51 (d, 1H); 7.28-7.30 (d, 1H); 7.14-7.19 (m, 3H); 3.31-3.36 (dd, 1H), 1.88-1.95 (dt, 1H); 1.26 (s, 3H); 1.15 (s, 3H); 0.6-0.8 (dd, 6H).
Reaction SMILES: [OH:1][C:2]1[CH:13]=[CH:12][C:5]([O:6][CH2:7][CH2:8][CH2:9][CH2:10][OH:11])=[CH:4][CH:3]=1.[F:14][C:15]([F:25])([F:24])[O:16][C:17]1[CH:22]=[CH:21][C:20](Br)=[CH:19][CH:18]=1.C([O-])([O-])=O.[K+].[K+]>>[F:14][C:15]([F:24])([F:25])[O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[O:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH2:7][CH2:8][CH2:9][CH2:10][OH:11])=[CH:12][CH:13]=1
Reactant: FC(F)(F)Oc1ccc(Br)cc1
Reactant: OCCCCOc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: OCCCCOc1ccc(Oc2ccccc2OC(F)(F)F)cc1
Temperature: 90 °C

Procedure:
A mixture of 3.13 g of 4-(4-hydroxyphenoxy) butan-1-ol, 4.97 g of 4-(trifluoromethoxy)bromobenzene, and 4.75 g of K2CO3 are placed in a flask and flushed with N2 gas. To this are added 17 ml of pyridine and, after heating to 90° C.., 3.42 g of CuO. The reaction mixture is heated at reflux for 2 days, and then cooled and poured into an ice/3N HCl mixture. This mixture is extracted twice with ether; and after separating, the combined ether extracts are washed with saturated NaHCO3, followed by brine, and then dried over MgSO4. Filtration and evaporation yields an oily residue which is purified by flash chromatography on silica gel, using 2:1 hexane/EtOAc as eluant. After evaporation, 4-[4-(4-(trifluoromethoxyphenoxy)phenoxy]butan-1-ol is obtained as a white solid.
Reaction SMILES: [O:1]=[CH:2][C:3]1[CH:11]=[CH:10][C:8]([OH:9])=[C:5]([O:6][CH3:7])[CH:4]=1.C(N(CC)CC)C.[C:19](OC(=O)C)(=[O:21])[CH3:20]>CN(C)C1C=CN=CC=1.C(Cl)Cl.CCOCC>[C:19]([O:9][C:8]1[CH:10]=[CH:11][C:3]([CH:2]=[O:1])=[CH:4][C:5]=1[O:6][CH3:7])(=[O:21])[CH3:20]
Reactant: CC(=O)OC(C)=O
Reactant: COc1cc(C=O)ccc1O
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOCC
Product: COc1cc(C=O)ccc1OC(C)=O

Procedure:
A solution of vanillin (60.8 g), triethylamine (60 ml), acetic anhydride (44 ml), and 4-dimethylaminopyridine (1.0 g) in methylene chloride (800 ml) is stirred at room temperature for about 30 minues, and the volume then reduced by 50% in vacuo. The residue is diluted with ether and the solution washed with water, brine, dried over magnesium sulfate, filtered and concentrated in vacuo to give the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([NH2:9])[CH:3]=1.[N+:10]([C:13]1[C:14]([NH2:20])=[C:15]([NH2:19])[CH:16]=[CH:17][CH:18]=1)([O-:12])=[O:11].Cl.Cl.[C:23](=N)(OCC)[CH2:24][C:25](=N)OCC>C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]2[NH:8][C:23]([CH2:24][C:25]3[NH:19][C:15]4[CH:16]=[CH:17][CH:18]=[C:13]([N+:10]([O-:12])=[O:11])[C:14]=4[N:20]=3)=[N:9][C:4]=2[CH:3]=1
Reactant: Nc1cccc([N+](=O)[O-])c1N
Reactant: CCOC(=N)CC(=N)OCC
Reactant: Nc1ccc(Cl)cc1N
Agent: Cl
Solvent: CC(=O)O
Product: O=[N+]([O-])c1cccc2[nH]c(Cc3nc4cc(Cl)ccc4[nH]3)nc12
Temperature: 25 °C
Yield: 34.9 %

Procedure:
To a flame-dried 100 mL round-bottom flask equipped with a stir bar and a reflux condenser were added 4-chloro-1,2-phenylenediamine (1 g; 7.0 mmoles), 3-nitro-1,2-phenylenediamine (1.07 g; 7.0 mmoles), diethyl malonimidate dihydrochloride (1.62 g; 7.0 mmoles) and ultra pure acetic acid (ca. 35 mL; from Aldrich) under a nitrogen atmosphere. The mixture was refluxed for 2 hours and then cooled to room temperature, and the acetic acid was removed (via roto-vap). The residue was suspended and sonicated (ca. 5 minutes) in 0.5 M HCl, and the remaining precipitate was removed by filtration and dried (P2O5 and high-vacuum). This procedure gave 0.8 g of the desired 2-[(5-chloro-1H-benzimidazol-2-yl)methyl]4-nitro-1H-benzimidazole as a dark brown solid in 35% yield. It gave one major peak by HPLC and had mass spec (FB+): m/z=328.0 [M+].
Reaction SMILES: F[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=CC(=O)[NH:9]2)=[CH:4][CH:3]=1.CN.O.C[CH2:17][OH:18].C[N:20]1C(=O)CCC1>>[NH2:9][C:10]1[CH:11]=[CH:2][CH:3]=[C:4]([O:18][CH3:17])[C:5]=1[C:6]#[N:20]
Reactant: O=c1ccc2ccc(F)cc2[nH]1
Reactant: CCO
Reactant: CN1CCCC1=O
Agent: CN
Solvent: O
Product: COc1cccc(N)c1C#N

Procedure:
A 7-Fluoroquinolinone derivative in a 8 M solution of MeNH2 in EtOH:NMP (1:1), was submitted to microwave irradiation 4 times for 5 minutes at 220° C. After cooling, water was added, and the mixture was extracted with EtOAc. The organic extracts were collected and dried over Na2SO4. Evaporation of the solvent under reduced pressure and purification of the residue by reverse phase preparative HPLC afforded the desired product. Other primary and secondary amines were used neat, 1:1 with NMP.
Reaction SMILES: C([O:3][C:4](=[O:28])[CH2:5][S:6][C:7]1[S:11][C:10]([NH:12][C:13]([N:15]([CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)[CH:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)=[O:14])=[N:9][CH:8]=1)C.C(N1CCCCC1=O)(OC(C)(C)C)=O.C1(N)CCCCC1.C(OC(=O)CSC1SC(N)=NC=1)C.[N:63]1([C:69](Cl)=[O:70])[CH2:68][CH2:67][O:66][CH2:65][CH2:64]1>>[CH:22]1([N:15]([CH:16]2[CH2:21][CH2:20][N:19]([C:69]([N:63]3[CH2:68][CH2:67][O:66][CH2:65][CH2:64]3)=[O:70])[CH2:18][CH2:17]2)[C:13](=[O:14])[NH:12][C:10]2[S:11][C:7]([S:6][CH2:5][C:4]([OH:3])=[O:28])=[CH:8][N:9]=2)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: O=C(Cl)N1CCOCC1
Reactant: CCOC(=O)CSc1cnc(NC(=O)N(C2CCCCC2)C2CCNCC2)s1
Agent: CC(C)(C)OC(=O)N1CCCCC1=O
Agent: CCOC(=O)CSc1cnc(N)s1
Solvent: NC1CCCCC1
Product: O=C(O)CSc1cnc(NC(=O)N(C2CCCCC2)C2CCN(C(=O)N3CCOCC3)CC2)s1

Procedure:
{2-[3-Cyclohexyl-3-piperidin-4-yl-ureido]-thiazol-5-ylsulfanyl}-acetic acid ethyl ester was pre-pared in a similar manner to the synthesis of example 12 from N-Boc piperidone, cyclohexylamine and (2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester, Boc deprotection, reaction with 4-morpholine carbonyl chloride and hydrolysis of the ester moiety as described in general procedure (I) gave the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-])=O)[C:3]=1[OH:11].[C:12](OC(=O)C)(=[O:14])[CH3:13].[H][H]>C(O)(=O)C.[C].[Pd]>[C:12]([NH:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[OH:11])(=[O:14])[CH3:13]
Reactant: [H][H]
Reactant: O=[N+]([O-])c1cccc(F)c1O
Reactant: CC(=O)OC(C)=O
Agent: [Pd]
Solvent: CC(=O)O
Product: CC(=O)Nc1cccc(F)c1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.1 %

Procedure:
In 290 ml of acetic acid were dissolved 26.4 g (0.168 mole) of 2-fluoro-6-nitrophenol and 17.2 g (0.168 mole) of acetic anhydride, and 3.0 g of 5% palladium carbon was added thereto. Hydrogen gas was passed through the mixture, with stirring, at room temperature for 2 hours. After the reaction mixture had been filtered and the filtrate concentrated under reduced pressure, the residue was extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was applied to silica gel column chromatography (the eluent used was a mixture of ethyl acetate:toluene=1:2) to obtain 25.9 g of 2-acetylamino-6-fluorophenol as brown crystals.
Reaction SMILES: Cl.[C:2]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][NH:12][C:13]([C:15]2[CH:19]=[C:18]([CH3:20])[N:17]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)[C:16]=2[CH3:28])=[O:14])=[CH:7][CH:6]=1)(=[NH:4])[NH2:3].C(=O)([O-])[O-].[K+].[K+].Cl[C:36]([O:38][CH2:39][CH3:40])=[O:37]>O.O1CCCC1>[NH2:4]/[C:2](=[N:3]\[C:36](=[O:37])[O:38][CH2:39][CH3:40])/[C:5]1[CH:10]=[CH:9][C:8]([CH2:11][NH:12][C:13]([C:15]2[CH:19]=[C:18]([CH3:20])[N:17]([C:21]3[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=3)[C:16]=2[CH3:28])=[O:14])=[CH:7][CH:6]=1
Reactant: CCOC(=O)Cl
Reactant: Cc1cc(C(=O)NCc2ccc(C(=N)N)cc2)c(C)n1-c1ccc(F)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)/N=C(\N)c1ccc(CNC(=O)c2cc(C)n(-c3ccc(F)cc3)c2C)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
130 mg of N-[(4-carbamimidoylphenyl)methyl]-1-(4-fluorophenyl)-2,5-dimethyl-pyrrole-3-carboxamide hydrochloride and 130 mg of potassium carbonate were dissolved in 1.6 ml of water and 8 ml of tetrahydrofuran. The mixture was stirred at room temperature, and 0.031 ml of ethyl chloroformate (Sigma-Aldrich) added. Stirring was continued for 1 h, following which the organic layer is removed, and dried in vacuo to obtain the synthetic target. The mass of the compound was verified using LC/MS/MS.
Reaction SMILES: [F:1][C:2]([F:12])([C:8]([F:11])([F:10])[F:9])/[CH:3]=[CH:4]/[C:5]([OH:7])=O.C(Cl)(=O)C(Cl)=O.[CH3:19][C:20]1[CH:25]=[CH:24][N:23]=[C:22]([NH:26][CH2:27][CH2:28][NH2:29])[CH:21]=1.C(N(C(C)C)CC)(C)C>CN(C=O)C.C(OCC)(=O)C>[F:12][C:2]([F:1])([C:8]([F:11])([F:10])[F:9])/[CH:3]=[CH:4]/[C:5]([NH:29][CH2:28][CH2:27][NH:26][C:22]1[CH:21]=[C:20]([CH3:19])[CH:25]=[CH:24][N:23]=1)=[O:7]
Reactant: Cc1ccnc(NCCN)c1
Reactant: O=C(O)/C=C/C(F)(F)C(F)(F)F
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccnc(NCCNC(=O)/C=C/C(F)(F)C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
(E)-4,4,5,5,5-Pentafluoropent-2-enoic acid (29 mg, 0.15 mmol) was dissolved in DMF (1 ml), oxalyl chloride was added (13 μl, 0.15 mmol) and the solution was stirred at room temperature for 5 minutes. To this solution was added a solution of N′-(4-methyl-2-pyridyl)ethane-1,2-diamine (19 mg, 0.1 mmol) in DMF (0.5 ml) and diisopropylethylamine (51 μl, 0.3 mmol) and the resulting mixture was stirred at room temperature for two hours. The reaction mixture was diluted with ethyl acetate, washed with sat. sodium bicarbonate solution and brine and dried over magnesium sulfate. The volatiles were removed under reduced pressure and the residue obtained was purified by preparative HPLC (Waters XBridge, gradient of water containing 0.1% NH3 and 10% to 100% acetonitrile) to yield 18.5 mg (0.057 mmol, 57%).
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[CH2:6][O:5][C:4]([C:7]2[C:8]([CH3:14])=[C:9]([NH2:13])[CH:10]=[CH:11][CH:12]=2)=[N:3]1.C(N(CC)CC)C.[CH3:23][C:24]1[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][C:25]=1[O:26][CH2:27][CH2:28][CH2:29][C:30]([CH3:35])([CH3:34])[C:31](Cl)=[O:32]>ClCCl>[CH3:1][C:2]1([CH3:15])[CH2:6][O:5][C:4]([C:7]2[C:8]([CH3:14])=[C:9]([NH:13][C:31](=[O:32])[C:30]([CH3:34])([CH3:35])[CH2:29][CH2:28][CH2:27][O:26][C:25]3[CH:36]=[C:37]([CH3:40])[CH:38]=[CH:39][C:24]=3[CH3:23])[CH:10]=[CH:11][CH:12]=2)=[N:3]1
Reactant: Cc1ccc(C)c(OCCCC(C)(C)C(=O)Cl)c1
Reactant: Cc1c(N)cccc1C1=NC(C)(C)CO1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(C)c(OCCCC(C)(C)C(=O)Nc2cccc(C3=NC(C)(C)CO3)c2C)c1
Yield: 59.6 %

Procedure:
To a solution of 10.2 g (0.05 mol) of 3-(4,5-dihydro-4,4-dimethyl-2-oxazolyl)-2-methylbenzenamine and 10 ml of triethylamine in dichloromethane is added 13.4 g (0.05 mol) of 5-(2,5-dimethylphenoxy)-2,2-dimethylpentanoyl chloride (U.S. Pat. No. 4,285,951). The mixture is worked up, chromatographed over silica gel and eluted with toluene-diethyl ether (2:1) to give 13 g of N-[3-(4,5-dihydro-4,4-dimethyl-2-oxazolyl)-2-methylphenyl]-5-(2,5-dimethylphenoxy)-2,2-dimethylpentanamide; mp 51°-52° C.
Reaction SMILES: [C:1]1([CH2:11][CH:12]([CH2:16][C:17](=[O:25])[N:18]([CH3:24])[CH2:19][C:20]([O:22][CH3:23])=[O:21])[C:13](O)=[O:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.Cl.Cl.[NH2:28][C@H:29]([C:36]([NH:38][C@@H:39]([CH2:48][CH:49]([CH3:51])[CH3:50])[CH:40]([OH:47])[C:41]([O:43][CH:44]([CH3:46])[CH3:45])=[O:42])=[O:37])[CH2:30][C:31]1[N:35]=[CH:34][NH:33][CH:32]=1.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.C(N(CC)CC)C>CN(C)C=O>[C:1]1([CH2:11][CH:12]([CH2:16][C:17](=[O:25])[N:18]([CH3:24])[CH2:19][C:20]([O:22][CH3:23])=[O:21])[C:13]([NH:28][C@H:29]([C:36]([NH:38][C@@H:39]([CH2:48][CH:49]([CH3:51])[CH3:50])[CH:40]([OH:47])[C:41]([O:43][CH:44]([CH3:45])[CH3:46])=[O:42])=[O:37])[CH2:30][C:31]2[N:35]=[CH:34][NH:33][CH:32]=2)=[O:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)CN(C)C(=O)CC(Cc1cccc2ccccc12)C(=O)O
Reactant: CC(C)C[C@H](NC(=O)[C@@H](N)Cc1c[nH]cn1)C(O)C(=O)OC(C)C
Agent: Cl
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)CN(C)C(=O)CC(Cc1cccc2ccccc12)C(=O)N[C@@H](Cc1c[nH]cn1)C(=O)N[C@@H](CC(C)C)C(O)C(=O)OC(C)C
Yield: 10.3 %

Procedure:
To a solution of 50 mg of 2-(1-naphthylmethyl)-3-(N-methyl-N-methoxycarbonylmethylcarbamoyl)propionic acid and 70 mg of isopropyl(2RS,3S)-3-(L-histidyl)amino-2-hydroxy-5-methylhexanoate dihydrochloride in 4 ml of N,N-dimethylformamide were added 0.036 ml of diphenylphosphoryl azide and 0.064 ml of triethylamine with stirring under ice-cooling, and the mixture was stirred overnight. The reaction mixture was concentrated under reduced pressure, and a 5% aqueous sodium bicarbonate solution was added to the residue. The mixture was extracted with ethyl acetate, and the ethyl acetate layer was washed with water, dried over anhydrous magnesium sulfate, concentrated under reduced pressure. The residue was purified by preparative silica gel thin layer chromatography (developing solvent: chloroform/methanol=5/1 by volume; Rf2 =0.36) to obtain 10 mg of isopropyl(2RS,3S)-3-{N-[2-(1-naphthylmethyl)-3-(N-methyl-N-methoxycarbonylmethylcarbamoyl)propionyl]-L-histidyl}amino-2-hydroxy-5-methylhexanoate as a white powder.
Reaction SMILES: C(O[C:4]([C:6]1([CH2:12][CH2:13]OC)[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5])C.[Cl:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[S:23](Cl)(=[O:25])=[O:24].[CH3:27][N:28]1[C:36]2[C:31](=[CH:32][C:33]([NH2:37])=[CH:34][CH:35]=2)[CH:30]=[N:29]1>>[Cl:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[S:23]([N:9]1[CH2:8][CH2:7][C:6]2([C:4](=[O:5])[N:37]([C:33]3[CH:32]=[C:31]4[C:36](=[CH:35][CH:34]=3)[N:28]([CH3:27])[N:29]=[CH:30]4)[CH2:13][CH2:12]2)[CH2:11][CH2:10]1)(=[O:25])=[O:24]
Reactant: CCOC(=O)C1(CCOC)CCNCC1
Reactant: O=S(=O)(Cl)c1ccccc1Cl
Reactant: Cn1ncc2cc(N)ccc21
Product: Cn1ncc2cc(N3CCC4(CCN(S(=O)(=O)c5ccccc5Cl)CC4)C3=O)ccc21

Procedure:
Light brown crystalline solid. MS (ESI): 459.4 (MH+). This example was prepared in analogy to example 1 step C) to D) from 4-(2-methoxy-ethyl)-piperidine-4-carboxylic acid ethyl ester (example 1 step B)), 2-chlorobenzenesulfonyl chloride and 1-methyl-1H-indazol-5-ylamine (synthesis: Fries et al, Justus Liebigs Annalen der Chemie; 454; 1927; 306).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:19])=[C:6]([C@:8]2([CH3:18])[C:14]([F:16])([F:15])[CH2:13][O:12][CH2:11][C:10]([NH2:17])=[N:9]2)[CH:7]=1.[C:20]([C:23]1[CH:24]=[C:25]([F:32])[C:26]([C:29]([OH:31])=[O:30])=[N:27][CH:28]=1)(=[O:22])[NH2:21]>>[CH:29]([OH:31])=[O:30].[NH2:17][C:10]1[CH2:11][O:12][CH2:13][C:14]([F:15])([F:16])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:29]([C:26]3[C:25]([F:32])=[CH:24][C:23]([C:20]([NH2:21])=[O:22])=[CH:28][N:27]=3)=[O:30])[CH:3]=[CH:4][C:5]=2[F:19])([CH3:18])[N:9]=1
Reactant: C[C@]1(c2cc(N)ccc2F)N=C(N)COCC1(F)F
Reactant: NC(=O)c1cnc(C(=O)O)c(F)c1
Product: C[C@]1(c2cc(NC(=O)c3ncc(C(N)=O)cc3F)ccc2F)N=C(N)COCC1(F)F
Product: O=CO

Procedure:
The coupling of (R)-5-(5-amino-2-fluorophenyl)-6,6-difluoro-5-methyl-2,5,6,7-tetrahydro-1,4-oxazepin-3-amine (intermediate A9B) and 5-carbamoyl-3-fluoro-pyridine-2-carboxylic acid (prepared according to Hori, A. et al., Int. Patent Application Publ. No. WO2009151098) yielded the title compound as an off-white amorphous material. MS (ISP): m/z=440.2 [M+H]+.