Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C:6]1([NH:9][C:10]([C:12]2[C:13]([OH:36])=[C:14]3[C:19](=[CH:20][N:21]=2)[N:18]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17](=[O:29])[C:16]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[CH:15]3)=[O:11])[CH2:8][CH2:7]1)=[O:5])C.[OH-].[Na+].CO.C1COCC1>C([O-])(O)=O.[Na+]>[CH2:22]([N:18]1[C:19]2[C:14](=[C:13]([OH:36])[C:12]([C:10]([NH:9][C:6]3([C:4]([OH:5])=[O:3])[CH2:8][CH2:7]3)=[O:11])=[N:21][CH:20]=2)[CH:15]=[C:16]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:17]1=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CCOC(=O)C1(NC(=O)c2ncc3c(cc(-c4ccccc4)c(=O)n3Cc3ccccc3)c2O)CC1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(NC1(C(=O)O)CC1)c1ncc2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O
Temperature: 25 °C
Reaction time: 16 h
Yield: 39.7 %

Procedure:
A mixture of 1-[(1-benzyl-5-hydroxy-2-oxo-3-phenyl-1,2-dihydro-[1,7]naphthyridine-6-carbonyl)-amino]-cyclopropanecarboxylic acid ethyl ester (40 mg, 0.083 mmol), 2 M NaOH (3 mL), MeOH (3 mL) and THF (3 mL) was stirred at r.t. for 16 h, then concentrated to approximately one-third of its original volume. 1 M HCl was added to acidify the mixture, and the resulting suspension was extracted with EtOAc. The organic layer was dried over MgSO4 and concentrated. The residue was dissolved in saturated NaHCO3 and washes several times with ether. The aqueous layer was acidified to pH about 3, and the resulting precipitate was isolated by filtration. The crude solid was purified by silica gel chromatography (5-60% EtOAc/hexanes+1% AcOH). The product isolated was dissolved in saturated NaHCO3 and washed several times with ether. The aqueous layer was acidified to pH about 3, and the resulting precipitate was isolated by filtration to give 15 mg of the title compound. MS: (+) m/z 456.35 (M+1).
Reaction SMILES: Br[C:2]1[C:3]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[N:4][C:5]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[N:6][CH:7]=1.C([Li])CCC.[CH:23]1[C:33]2[CH:32]=[CH:31][C:30]3[CH:34]=[CH:35][CH:36]=[CH:37][C:29]=3[C:28](=[O:38])[C:27]=2[CH:26]=[CH:25][CH:24]=1.[Cl-].[NH4+]>O1CCCC1.CCCCCC>[CH3:10][C:9]([CH3:12])([O:8][C:5]1[N:4]=[C:3]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[C:2]([C:28]2([OH:38])[C:29]3[CH:37]=[CH:36][CH:35]=[CH:34][C:30]=3[CH:31]=[CH:32][C:33]3[CH:23]=[CH:24][CH:25]=[CH:26][C:27]2=3)=[CH:7][N:6]=1)[CH3:11]
Reactant: CC(C)(C)Oc1ncc(Br)c(OC(C)(C)C)n1
Reactant: O=c1c2ccccc2ccc2ccccc12
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)(C)Oc1ncc(C2(O)c3ccccc3C=Cc3ccccc32)c(OC(C)(C)C)n1
Temperature: -78 °C
Reaction time: 3 h

Procedure:
To a solution of the product of step (i) (50 g) in dry tetrahydrofuran (11) at -78° C. was added n-butyllithium (69 ml of a 2.5M solution in hexane) dropwise such that the internal temperature of the reaction did not rise above -65° C. After 0.5 hours a solution of 5H-dibenzo[a,d]cyclohepten-5-one (44 g) in tetrahydrofuran (100 ml) was added. The reaction mixture was stirred at -78° C. for three hours and then allowed to warm to room temperature overnight. Saturated aqueous ammonium chloride solution (400 ml) was added and the mixture extracted with ethyl acetate. The organic solution was dried (MgSO4) and evaporated under reduced pressure to give the crude 5-{2,4-bis(1,1-dimethylethoxy)pyrimidin-5-yl)-5H-dibenzo[a,d]cyclohepten-5-ol which was used directly. To a stirred solution of this product and triethylsilane (64 ml) in dry dichloromethane (400 ml) cooled in an ice-bath was added trifluoroacetic acid (150 ml) dropwise over ten minutes. The cooling bath was removed and the solution was stirred at room temperature overnight. Toluene (300 ml) was added and solution was evaporated under reduced pressure. The residue was azeotroped with toluene (3 times). The oil was treated with diethyl ether and the precipitated product collected as a white powder. Yield 44 g.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[O:12])[O:10][C:8](=O)[C:7]2=[CH:13][CH:14]=1)([O-:3])=[O:2].[NH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21]>>[N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[O:12])[N:15]([CH2:16][CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21])[C:8](=[O:10])[C:7]2=[CH:13][CH:14]=1)([O-:3])=[O:2]
Reactant: O=C1OC(=O)c2cc([N+](=O)[O-])ccc21
Reactant: NCCCCC(=O)O
Product: O=C(O)CCCCN1C(=O)c2ccc([N+](=O)[O-])cc2C1=O
Yield: 97.4 %

Procedure:
4-nitrophthalic anhydride (0.25 g, 0.0013 mol) and 5-aminopentanoic acid (0.152 g, 0.0013 mol) were refluxed as above overnight. The clear solution was purified as per 120 to yield 0.37 g (98%) 143 as dull white crystals: mp=172° C.; Rf0.93 (A): Rf0.83 (B): Rf0.69 (D): 1H NMR (DMSO-d6) δ1.83 (m, 2H), 2.29 (t, J=7.2 Hz, 2H), 3.64 (t, J=6.7 Hz, 2H), 8.01 (d, J=7.6 Hz, 1H), 8.45 (d, J=1.9 Hz, 1H), 8.59 (dd, J=7.6, 1.9 Hz, 1H); IR (cm−1): 2750-3200 (OH), 3056 (C═CH), 2620 (C—H), 1773 (C═O), 1707 (bs, C═O), 1624 (C═C), 1543 (N═O), 1438 (C═C), 1403 (C—O), 1351 (N═O), 1217 (C—O), 1068 (C—O), 723 (C═CH); MS m/z (rel intensity) 305 (100).
Reaction SMILES: [Mg].[Cl:2][C:3]1[S:4][C:5](Cl)=[CH:6][CH:7]=1.[C:9]1(=[O:15])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.Cl>C1COCC1.C1C=CC=CC=1.O>[Cl:2][C:3]1[S:4][C:5]([C:9]2([OH:15])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)=[CH:6][CH:7]=1
Reactant: Clc1ccc(Cl)s1
Reactant: O=C1CCCCC1
Agent: Cl
Agent: [Mg]
Solvent: c1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: OC1(c2ccc(Cl)s2)CCCCC1
Yield: 81.2 %

Procedure:
To a Grignard reagent prepared from magnesium (26.7 g), 2,5-dichlorothiophene (16.83 g) and anhydrous THF (70 ml) was added dropwise in small portions a solution of cyclohexanone (XIa) (9.815 g) in anhydrous THF (30 ml) with stirring under ice-cooling in nitrogen atmosphere. The mixture was made to react at room temperature for 3 hours and after addition of water and acidification with 5% hydrochloric acid, extracted with chloroform. The extract was washed with water, dried and evaporated. The residue was applied to column chromatography on silica gel (70 g). From the benzene fraction, 1-(5-chloro-2-thienyl)cyclohexanol (Xa) (17.6 g) was obtained as an oil (yield 81.2%).
Reaction SMILES: [CH3:1][N:2]=[C:3]=[O:4].[OH:5][C:6]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][CH3:14])[S:8][N:7]=1.C(N(CC)CC)C>O1CCCC1>[CH3:1][NH:2][C:3]([N:7]1[C:6](=[O:5])[N:10]=[C:9]([O:11][CH2:12][CH2:13][CH3:14])[S:8]1)=[O:4]
Reactant: CCCOc1nc(O)ns1
Reactant: CN=C=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCOc1nc(=O)n(C(=O)NC)s1
Temperature: 20 °C
Reaction time: 20 h

Procedure:
10 ml of methyl isocyanate were added to a solution of 16.01 g of 3-hydroxy-5-n-propoxy-1,2,4-thiadiazole, 0.5 ml of triethylamine and 200 ml of tetrahydrofuran and the mixture was stirred for 20 hours at 20° C. The mixture was evaporated to dryness and the residue was twice crystallized from a 75-25 isopropyl ether-ethyl acetate mixture to obtain 12 g of 2-(N-methylcarbamoyl)-5-n-propoxy-1,2,4-thiadiazole-3-one melting at 112° C.
Reaction SMILES: COC1C=CC(C[N:8]2[C:12]([CH2:13][CH2:14][C:15]3[N:25]=[C:18]4[C:19]([CH3:24])=[N:20][CH:21]=[C:22]([CH3:23])[N:17]4[N:16]=3)=[N:11][C:10]([N:26]3[CH2:30][CH2:29][CH2:28][CH2:27]3)=[N:9]2)=CC=1.FC(F)(F)C(O)=O.C1(OC)C=CC=CC=1>ClCCl>[CH3:23][C:22]1[N:17]2[N:16]=[C:15]([CH2:14][CH2:13][C:12]3[NH:8][N:9]=[C:10]([N:26]4[CH2:30][CH2:29][CH2:28][CH2:27]4)[N:11]=3)[N:25]=[C:18]2[C:19]([CH3:24])=[N:20][CH:21]=1
Reactant: COc1ccc(Cn2nc(N3CCCC3)nc2CCc2nc3c(C)ncc(C)n3n2)cc1
Solvent: COc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ncc(C)n2nc(CCc3nc(N4CCCC4)n[nH]3)nc12
Yield: 67.3 %

Procedure:
2-(2-(1-(4-methoxybenzyl)-3-(pyrrolidin-1-yl)-1H-1,2,4-triazol-5-yl)ethyl)-5,8-dimethyl-[1,2,4]triazolo[1,5-a]pyrazine (13.6 mg, 31.4 μmol, Eq: 1.00) was stirred with trifluoroacetic acid (143 mg, 96.3 μl, 1.26 mmol, Eq: 40) and anisole (61.2 mg, 61.8 μl, 566 μmol, Eq: 18) in Dichloromethane (400 μl) overnight at room-temperature. The reaction mixture was extracted with aq. sodium borohydride sat. and dichloromethane three times, dried over magnesium sulfate, filtered and evaporated to give 5,8-Dimethyl-2-[2-(5-pyrrolidin-1-yl-2H-[1,2,4]triazol-3-yl)-ethyl]-[1,2,4]triazolo[1,5-a]pyrazine (6.6 mg, 67.2%) as off-white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][N:5]([C:27]2[CH:34]=[CH:33][C:30]([C:31]#[N:32])=[CH:29][CH:28]=2)[C:6]=1[C:7]1[C:8](=[O:26])[N:9]([CH3:25])[C:10](=[O:24])[N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)[C:12]=1[CH3:13].C([Sn](CCCC)(CCCC)[C:40]([O:42]CC)=[CH2:41])CCC.Cl.C(OCC)(=O)C>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:40]([C:2]1[CH:3]=[N:4][N:5]([C:27]2[CH:34]=[CH:33][C:30]([C:31]#[N:32])=[CH:29][CH:28]=2)[C:6]=1[C:7]1[C:8](=[O:26])[N:9]([CH3:25])[C:10](=[O:24])[N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)[C:12]=1[CH3:13])(=[O:42])[CH3:41]
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: Cc1c(-c2c(Br)cnn2-c2ccc(C#N)cc2)c(=O)n(C)c(=O)n1-c1cccc(C(F)(F)F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CC(=O)c1cnn(-c2ccc(C#N)cc2)c1-c1c(C)n(-c2cccc(C(F)(F)F)c2)c(=O)n(C)c1=O
Temperature: 120 °C
Reaction time: 1 h

Procedure:
To a solution of 4-(4-bromo-5-(3,6-dimethyl-2,4-dioxo-1-(3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazol-1-yl)benzonitrile (prepared in Example 93) (54.6 mg) in 1,4-dioxane (1.0 ml) were added tetrakis(triphenylphosphine)palladium (23.8 mg) and tributyl(1-ethoxyvinyl)tin (103.4 μl) and the resulting mixture was stirred for one hour with heating in microwave instrument (120° C.). To the reaction mixture were then added 1M hydrochloric acid (1 mL) and ethyl acetate (2 ml) and the resulting mixture was stirred at room temperature for one hour. To the reaction mixture was ethyl acetate (50 ml) and the mixture was washed with 10% aqueous potassium carbonate solution (30 ml) and saturated saline (30 ml), dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate) to afford 4-(4-acetyl-5-(3,6-dimethyl-2,4-dioxo-1-(3-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydropyrimidin-5-yl)-1H-pyrazol-1-yl)benzonitrile (19.0 mg) as white solid.
Reaction SMILES: [F:1][CH:2]([F:31])[CH2:3][N:4]1[CH2:9][CH2:8][N:7]2[N:10]=[C:11]([NH:13][C:14]3[C:15](=[O:30])[N:16]([CH3:29])[CH:17]=[C:18](B4OC(C)(C)C(C)(C)O4)[CH:19]=3)[CH:12]=[C:6]2[CH2:5]1.[C:32]([C:36]1[CH:37]=[C:38]2[C:43](=[C:44]([F:46])[CH:45]=1)[C:42](=[O:47])[N:41]([C:48]1[N:55]=[CH:54][CH:53]=[C:52](Cl)[C:49]=1[CH:50]=[O:51])[N:40]=[CH:39]2)([CH3:35])([CH3:34])[CH3:33].[O-]P([O-])([O-])=O.[K+].[K+].[K+].C([O-])(=O)C.[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(#N)C.O>[C:32]([C:36]1[CH:37]=[C:38]2[C:43](=[C:44]([F:46])[CH:45]=1)[C:42](=[O:47])[N:41]([C:48]1[N:55]=[CH:54][CH:53]=[C:52]([C:18]3[CH:19]=[C:14]([NH:13][C:11]4[CH:12]=[C:6]5[CH2:5][N:4]([CH2:3][CH:2]([F:31])[F:1])[CH2:9][CH2:8][N:7]5[N:10]=4)[C:15](=[O:30])[N:16]([CH3:29])[CH:17]=3)[C:49]=1[CH:50]=[O:51])[N:40]=[CH:39]2)([CH3:35])([CH3:33])[CH3:34]
Reactant: CC(C)(C)c1cc(F)c2c(=O)n(-c3nccc(Cl)c3C=O)ncc2c1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cc(Nc2cc3n(n2)CCN(CC(F)F)C3)c1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: CC#N
Product: Cn1cc(-c2ccnc(-n3ncc4cc(C(C)(C)C)cc(F)c4c3=O)c2C=O)cc(Nc2cc3n(n2)CCN(CC(F)F)C3)c1=O
Temperature: 100 °C
Yield: 37.8 %

Procedure:
A 25-mL round-bottomed flask equipped with a reflux condenser was charged with 135d (200 mg, 0.46 mmol), 2-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-4-chloronicotinaldehyde 103b (166 mg, 0.46 mmol), K3PO4 (195 mg, 0.92 mmol), sodium acetate (75 mg, 0.92 mmol), 1,1′-bis(diphenylphosphino)ferrocenedichloropalladium(II) (17 mg, 0.023 mmol), and acetonitrile/water (8/0.2 mL). After three cycles of vacuum/N2 flush, the mixture was heated at 100° C. for 1 h. Analysis of the reaction mixture by LCMS showed complete conversion to the desired product. The reaction mixture was cooled to room temperature and diluted with dichloromethane (30 mL) and water (15 mL). The water layer was extracted with dichloromethane (2×15 mL). The combined organic extract was dried over Na2SO4, filtered, and concentrated under reduced pressure. The dark residue was purified by silica-gel column chromatography eluting with dichloromethane/methanol (80/1 to 30/1) to afford 135e (110 mg, 38%) as a yellow solid. MS-ESI: [M+H]+ 633.3
Reaction SMILES: [N+:1]([C:4]1[CH:23]=[CH:22][C:7]([C:8]([N:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[C:14](=[O:21])[CH2:13][CH2:12][CH2:11]2)=[O:9])=[CH:6][CH:5]=1)([O-])=O.CN(C)C=O>[Ni].CO>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([C:8]([N:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[C:14](=[O:21])[CH2:13][CH2:12][CH2:11]2)=[O:9])=[CH:22][CH:23]=1
Reactant: O=C1CCCN(C(=O)c2ccc([N+](=O)[O-])cc2)c2ccccc21
Agent: [Ni]
Solvent: CN(C)C=O
Solvent: CO
Product: Nc1ccc(C(=O)N2CCCC(=O)c3ccccc32)cc1

Procedure:
A 19.2 g portion of 1-(4-nitrobenzoyl)-2,3,4,5-tetrahydro-1H-1-benzazepin-5-one was dissolved in a mixed solvent consisting of 200 ml of dimethylformamide and 100 ml of methyl alcohol, and 3 ml of Raney nickel was added to the resulting solution to carry out hydrogenation at normal pressure. After completion of the hydrogen absorption, the reaction solution was filtered and concentrated. The thus obtained residue was dissolved in dichloromethane and then washed with a saturated sodium bicarbonate aqueous solution. The resulting dichloromethane layer was dried over anhydrous magnesium sulfate and then concentrated under a reduced pressure. The thus obtained residue was recrystallized from methyl alcohol to obtain 15.5 g of 1-(4-aminobenzoyl)-2,3,4,5-tetrahydro-1H-1-benzazepin-5-one.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13](=O)[CH:14]=[CH:15][NH:16]2)=[CH:11][C:10]=1[C:20]#[N:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:24])=O>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([Cl:24])=[CH:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[C:20]#[N:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: N#Cc1cc2c(=O)cc[nH]c2cc1OCc1ccccc1
Solvent: CN(C)C=O
Product: N#Cc1cc2c(Cl)ccnc2cc1OCc1ccccc1

Procedure:
A mixture of 7-benzyloxy-6-cyano-1,4-dihydroquinolin-4-one (3.5 g), thionyl chloride (50 ml) and DMF (10 drops) was heated at reflux for 3 hours. The volatiles were removed by evaporation and the residue was partitioned between water and methylene chloride. A saturated solution of sodium hydrogen carbonate was added until the aqueous phase became alkaline. The aqueous phase was extracted with methylene chloride, the organic phases were combined, washed with water and dried by passing through phase separating paper. Removal of the solvent by evaporation gave a solid which was triturated with ether (50 ml) and collected by filtration. The orange solid obtained was dried in a vacuum oven to give 7-benzyloxy-4-chloro-6-cyanoquinoline (2.28 g, 36% over the last two steps).
Reaction SMILES: C(Cl)(=O)C(C)(C)C.[NH:8]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[C@H:9]([C:28]([OH:30])=[O:29])[CH2:10][C:11]1[N:15]=[CH:14][N:13]([C:16]2[CH:27]=[CH:26][C:22]([N+:23]([O-:25])=[O:24])=[CH:21][C:17]=2[N+:18]([O-:20])=[O:19])[CH:12]=1.C(N1CCCCC1)C.[CH:46]1([CH2:52][C@H:53]([NH2:65])[C@@H:54]([OH:64])[CH2:55][CH2:56][CH2:57][C:58]2[CH:63]=[CH:62][CH:61]=[CH:60][N:59]=2)[CH2:51][CH2:50][CH2:49][CH2:48][CH2:47]1.C(N1[C@@H](CC2CCCCC2)C(CCCC2C=CC=CN=2)OC1(C)C)(OC(C)(C)C)=O.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl.N1C=CC=CC=1>[NH:8]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[C@H:9]([C:28]([OH:30])=[O:29])[CH2:10][C:11]1[N:15]=[CH:14][N:13]([C:16]2[CH:27]=[CH:26][C:22]([N+:23]([O-:25])=[O:24])=[CH:21][C:17]=2[N+:18]([O-:20])=[O:19])[CH:12]=1.[CH:46]1([CH2:52][C@H:53]([NH-:65])[C@@H:54]([OH:64])[CH2:55][CH2:56][CH2:57][C:58]2[CH:63]=[CH:62][CH:61]=[CH:60][N:59]=2)[CH2:51][CH2:50][CH2:49][CH2:48][CH2:47]1
Reactant: N[C@@H](CC1CCCCC1)[C@@H](O)CCCc1ccccn1
Agent: CC(C)(C)C(=O)Cl
Agent: CC(C)(C)OC(=O)N1[C@@H](CC2CCCCC2)C(CCCc2ccccn2)OC1(C)C
Agent: CC(C)(C)OC(=O)N[C@@H](Cc1cn(-c2ccc([N+](=O)[O-])cc2[N+](=O)[O-])cn1)C(=O)O
Solvent: c1ccncc1
Solvent: ClCCl
Product: [NH-][C@@H](CC1CCCCC1)[C@@H](O)CCCc1ccccn1
Temperature: -5 °C
Reaction time: 0.17 h

Procedure:
550 μl of pivaloyl chloride are added dropwise, at -5° C., to 1.9 g of Boc-His(DNP)-OH, 360 μl of pyridine and 620 μl of N-ethylpiperidine in 50 ml of CH2Cl2. After 10 minutes at -5° C., the mixture is stirred at +10° C. for 10 minutes. It is again cooled to -5° C. and then 1.3 g of 1(S)-cyclohexylmethyl-2(S)-hydroxy-5-(2-pyridyl)-pentylamine (prepared from 1.7 g of 3-Boc-4(S)-cyclohexylmethyl-2,2-dimethyl-5-(3-(2-pyridyl)propyl)oxazolidine by the process described under b) and subsequent liberation with Na2CO3) in 20 ml of CH2Cl2 are added. After 1 hour at -5° C., the mixture is left to stand at room temperature for 16 hours. 50 ml of saturated Na2CO3 solution are added, and the mixture is extracted 3 times with EA. The combined organic extracts are dried over Na2SO4 and concentrated. Chromatography on silica gel (EA/MeOH 10:1) yields the title compound.
Reaction SMILES: COC(=O)[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH:10][C:11](=[O:38])[CH2:12][N:13]2[N:19]=[C:18]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[C:17]3[CH:26]=[CH:27][CH:28]=[CH:29][C:16]=3[N:15]([CH2:30][C:31](=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33])[C:14]2=[O:37])[CH:5]=1.[C:40]([O:44][C:45](=[O:59])[N:46]([C:52]1C=CC=[C:54](N)[CH:53]=1)CCOCC)([CH3:43])([CH3:42])[CH3:41].C(OC(=O)N(C1C=CC=C(N)C=1)C)(C)(C)C.BrCCOCC.IC.COC(=O)C1C=CC=C(N)C=1>>[C:40]([O:44][C:45](=[O:59])[N:46]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH:10][C:11](=[O:38])[CH2:12][N:13]2[N:19]=[C:18]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[C:17]3[CH:26]=[CH:27][CH:28]=[CH:29][C:16]=3[N:15]([CH2:30][C:31](=[O:36])[C:32]([CH3:35])([CH3:33])[CH3:34])[C:14]2=[O:37])[CH:5]=1)[CH2:52][CH2:53][CH3:54])([CH3:43])([CH3:42])[CH3:41]
Reactant: COC(=O)c1cccc(NC(=O)CN2N=C(C3CCCCC3)c3ccccc3N(CC(=O)C(C)(C)C)C2=O)c1
Reactant: CCOCCN(C(=O)OC(C)(C)C)c1cccc(N)c1
Agent: CCOCCBr
Agent: CN(C(=O)OC(C)(C)C)c1cccc(N)c1
Agent: COC(=O)c1cccc(N)c1
Solvent: CI
Product: CCCN(C(=O)OC(C)(C)C)c1cccc(NC(=O)CN2N=C(C3CCCCC3)c3ccccc3N(CC(=O)C(C)(C)C)C2=O)c1

Procedure:
The title compound was obtained as the hydrochloride salt by the method used in the preparation of 3-{2-[5-cyclohexyl-1-(3,3-dimethyl-2-oxo-butyl)-2-oxo-1,2-dihydro-3H-1,3,4-benzotriazepin-3-yl]-acetylamino}-benzoic acid methyl ester (Example 1), except that (3-amino-phenyl)-2-ethoxyethyl-carbamic acid tert-butyl ester (obtained using the method employed in the preparation of (3-amino-phenyl)-methyl-carbamic acid tert-butyl ester (Example 3, step c) except that 2-bromoethyl-ethyl ether was used in step b instead of iodomethane) was used instead of 3-amino-benzoic acid methyl ester in step e, followed by reaction of the product obtained, in place of (3-{2-[5-cyclohexyl-1-(3,3-dimethyl-2-oxo-butyl)-2-oxo-1,2-dihydro-3H-1,3,4-benzotriazepin-3-yl]-acetylamino}-phenyl)-propyl-carbamic acid tert-butyl ester (Example 41, step a) according to the method of Example 41 step b. 1H NMR (CDCl3) 8.45 (1H, s), 7.61 (1H, s), 7.56-7.47 (2H, m), 7.36 (4H, m), 7.03 (1H, d), 4.70 (2H, dd), 4.26 (2H, dd), 3.73 (2H, br s), 3.51 (4H, m), 2.82 (1H, br s), 2.05-1.65 (6H, m), 1.30-1.17 (16H, m). Found: C, 63.90; H, 7.66; N, 11.58%; C32H43N5O4.HCl.0.25H2O requires: C, 63.77; H, 7.44; N, 11.62%.
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:8]=[C:7]([CH2:9][C:10]2[C:18]3[C:13](=[CH:14][C:15]([O:19][CH3:20])=[CH:16][CH:17]=3)[N:12]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C:11]=2[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:6]=[CH:5][CH:4]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[CH:2]([C:3]1[N:8]=[C:7]([CH2:9][C:10]2[C:18]3[C:13](=[CH:14][C:15]([O:19][CH3:20])=[CH:16][CH:17]=3)[N:12]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[C:11]=2[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:6]=[CH:5][CH:4]=1)=[O:1]
Reactant: COc1ccc2c(Cc3cccc(CO)n3)c(-c3ccccc3)n(C(=O)OC(C)(C)C)c2c1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc2c(Cc3cccc(C=O)n3)c(-c3ccccc3)n(C(=O)OC(C)(C)C)c2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.4 %

Procedure:
To a solution of tert-butyl 3-(6-hydroxymethylpyridin-2-ylmethyl)-6-methoxy-2-phenyl-1H-indole-1-carboxylate (600 mg) in dichloromethane (6 mL) was added Dess-Martin periodinane (744 mg), and the mixture was stirred at room temperature for 2 hours. To the reaction mixture was added 1 mol/L aqueous sodium thiosulfate solution, followed by stirring for 5 minutes. The mixture was extracted with dichloromethane. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and saturated brine successively, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate-hexane) to obtain the title compound (486 mg). 1H-NMR (CDCl3) δ ppm: 1.23 (9H, s), 3.89 (3H, s), 4.15 (2H, s), 6.84 (1H, dd, J=2.3, 8.7 Hz), 7.15-7.21 (1H, m), 7.28-7.44 (6H, m), 7.61-7.69 (1H, m), 7.72-7.77 (1H, m), 7.86 (1H, d, J=2.3 Hz), 10.02-10.05 (1H, m).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:11][CH3:12])[CH:9]=2)[C:4]([C:13]([OH:15])=O)=[C:3]1[CH3:16].[OH:17][CH2:18][CH2:19][CH2:20][NH2:21].C(Cl)(=O)C(Cl)=O.CNC(C1C2C(=CC(OC)=CC=2)N(C)C=1C)=O>>[OH:17][CH2:18][CH2:19][CH2:20][NH:21][C:13]([C:4]1[C:5]2[C:10](=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=2)[N:2]([CH3:1])[C:3]=1[CH3:16])=[O:15]
Reactant: COc1ccc2c(C(=O)O)c(C)n(C)c2c1
Reactant: NCCCO
Agent: CNC(=O)c1c(C)n(C)c2cc(OC)ccc12
Agent: O=C(Cl)C(=O)Cl
Product: COc1ccc2c(C(=O)NCCCO)c(C)n(C)c2c1

Procedure:
This material was prepared by the reaction of 1,2-dimethyl-6-methoxy-1H-indole-3-carboxylic acid 16c with 3-hydroxy-propyl amine and oxalyl chloride in a manner as previously described for 16d. 1H NMR (300 MHz, CD3OD) δ 7.52 (1H, d, J=8.6 Hz), 6.73 (1H, d, J=2.1 Hz), 6.68 (1H, dd, J=2.1, 8.6 Hz), 3.69 (2H, t, J=6.1 Hz), 3.79 (3H, s), 3.63 (3H, s), 3.51 (2H, m), 2.57 (3H, s), 1.85 (2H, m). LCMS (ESI+) [M+H]/z Calc'd 291. found 291.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([N:12]2[C:16](=[O:17])[NH:15][N:14]=[CH:13]2)[S:5][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:25][CH:26]1[CH2:28][C:27]1([F:30])[F:29]>CN(C)C=O>[F:29][C:27]1([F:30])[CH2:28][CH:26]1[CH2:25][N:15]1[C:16](=[O:17])[N:12]([C:4]2[S:5][C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[C:2]([CH3:1])[N:3]=2)[CH:13]=[N:14]1
Reactant: FC1(F)CC1CBr
Reactant: CCOC(=O)c1sc(-n2cn[nH]c2=O)nc1C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1sc(-n2cnn(CC3CC3(F)F)c2=O)nc1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89.4 %

Procedure:
To a solution of ethyl 4-methyl-2-(5-oxo-1H-1,2,4-triazol-4(5H)-yl)thiazole-5-carboxylate (9.36 g, 36.8 mmol) in anhydrous N,N-dimethylformamide (150 mL) was added cesium carbonate (23.90 g, 73.70 mmol). The reaction mixture was stirred at ambient temperature for 30 min, followed by the addition of bromomethyl-2,2-difluorocyclopropane (6.00 g, 35.10 mmol) in N,N-dimethylformamide (50 mL). The reaction mixture was heated at 40° C. for 3 h and filtered. The solid was washed with ethyl acetate (100 mL). The filtrate was concentrated in vacuo to dryness. The residue was triturated with ethyl acetate (50 mL) to afford the title compound as a yellow solid (10.8 g, 98%): mp 146-148° C.; 1H NMR (300 MHz, DMSO-d6) δ 8.74 (s, 1H), 4.23 (t, J=7.1 Hz, 2H), 3.97-3.77 (m, 2H), 2.54 (s, 3H), 2.20-2.04 (m, 1H), 1.73-1.60 (m, 1H), 1.48-1.37 (m, 1H), 1.26 (t, J=7.1 Hz, 3H); 13C NMR (75 MHz, DMSO-d6) δ 161.8, 156.6, 154.0, 149.9, 132.2, 118.2, 114.4 (t), 61.6, 42.8 (d), 20.7 (t), 17.2, 14.9 (t), 14.5; MS (ES+) m/z 345.9 (M+1).