Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C:3]([C@H:5]1[NH:8][C:7](=[O:9])[C@@H:6]1[C@H:10]([O:12][C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[CH3:11])=[CH2:4].CO[C:25](OC)([CH3:27])[CH3:26].B(F)(F)F.CCOCC>ClCCl>[O:9]=[C:7]1[N:8]2[C@H:5]([C:3](=[CH2:4])[CH2:2][O:1][C:25]2([CH3:27])[CH3:26])[C@H:6]1[C@H:10]([O:12][C:13]([O:15][CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)=[O:14])[CH3:11]
Reactant: COC(C)(C)OC
Reactant: C=C(CO)[C@H]1NC(=O)[C@@H]1[C@@H](C)OC(=O)OCc1ccccc1
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: C=C1COC(C)(C)N2C(=O)[C@H]([C@@H](C)OC(=O)OCc3ccccc3)[C@@H]12

Procedure:
A solution of (3S,4S)-4-(1-hydroxymethylethenyl)-3-(1-(R)-benzyloxycarbonyloxyethyl)-2-azetidinone (3.7 g) and 2,2-dimethoxypropane (1.45 g) in dry dichloromethane (26 ml) was treated with boron trifluoride-etherate (0.14 ml) at room temperature for 1.5 hours. The reaction mixture was washed successively with saturated sodium bicarbonate (15 and water (20 ml×2), and dried over anhydrous sodium sulfate. Filtration and concentration of the filtrate in vacuo gave an oily residue, which was purified by silica gel chromatography to yield (6S,7S)-8-oxo-2,2-dimethyl-5-methylidene-7-(1-(R)-benzyloxycarbonyloxyethyl)-3-oxa-1-azabicyclo[4.2.0]octane.
Reaction SMILES: [Cl:1]C(OC(Cl)C)=O.[F:8][C:9]1[CH:32]=[CH:31][C:12]([C:13]([NH:15][C:16]2[CH:17]=[C:18]([CH:28]=[CH:29][CH:30]=2)[C:19]([CH:21]2[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]2)=[O:20])=[O:14])=[CH:11][CH:10]=1>ClCCCl>[ClH:1].[F:8][C:9]1[CH:10]=[CH:11][C:12]([C:13]([NH:15][C:16]2[CH:17]=[C:18]([CH:28]=[CH:29][CH:30]=2)[C:19]([CH:21]2[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]2)=[O:20])=[O:14])=[CH:31][CH:32]=1
Reactant: CC(Cl)OC(=O)Cl
Agent: CN1CCC(C(=O)c2cccc(NC(=O)c3ccc(F)cc3)c2)CC1
Solvent: ClCCCl
Product: Cl
Temperature: 25 °C

Procedure:
1-Chloroethyl chloroformate (435 μl, 4.0 mmol) was added dropwise to a 0° C. solution of 4-[3-(4-fluorobenzamidyl)benzoyl]-1-methylpiperidine (686 mg, 2.0 mmol) in 1,2-dichloroethane (15 ml). The reaction mixture was warmed to room temperature then heated to reflux for 1.5 h. An additional quantity of 1-chloroethyl chloroformate (400 μl, 3.7 mmol) was added and the reaction mixture was refluxed for 50 min. The reaction mixture was concentrated in vacuo. The residue was dissolved in methanol (15 mL) and heated to reflux for 2 h. The solvent was removed under vacuum to give 780 mg of a brown oil. Purification by radial chromatography (silica gel, 2000 micron rotor, methylene chloride:methanol:ammonium hydroxide, 95:5:0.5 then methylene chloride:methanol:ammonium hydroxide, 92.5:7.5:0.75) gave 220 mg (33%) of a white foam. Crystallization as the hydrochloride salt from ethyl acetate/ethanol gave a white solid. Mp>225° C. MS(m/e): 327(M+1).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:24])[N:9]3[CH2:23][CH2:22][CH2:21][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[C-:25]#N.[K+]>C(O)C=C>[Cl:1][C:2]1[C:7]2[C:8](=[O:24])[N:9]3[CH2:23][CH2:22][CH2:21][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([O:18][CH2:19][CH:20]=[CH2:25])=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1ncn2c1[C@@H]1CCCN1C(=O)c1c(Cl)cccc1-2
Reactant: [C-]#N
Agent: [K+]
Solvent: C=CCO
Product: C=CCOC(=O)c1ncn2c1[C@@H]1CCCN1C(=O)c1c(Cl)cccc1-2

Procedure:
A mixture of 6.9 g (0.02 mmol) of ethyl (S)-8-chloro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxylate, 100 ml of allyl alcohol and 0.5 g of potassium cyanide is heated to boiling ii under reflux for 4 hours, then concentrated to half of the volume, 50 ml of allyl alcohol are added and the resulting mixture is heated to boiling under reflux for a further 10 hours. The mixture is evaporated, the residue is dissolved in chloroform, the chloroform solution is washed with water, the chloroform phase is dried over magnesium sulphate and evaporated. The residue is chromatographed on silica gel while eluting with ethyl acetate and then crystallized from ethyl acetate/hexane. There is obtained allyl (S)-8-chloro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxylate of melting point 122-123°.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[CH:3]([C:9]([F:12])([F:11])[F:10])[CH:4]([C:6]([OH:8])=[O:7])[NH2:5].[Si](C=[N+]=[N-])(C)(C)[CH3:16].CO>C(Cl)Cl.CO.C(Cl)(Cl)Cl>[F:1][C:2]([F:13])([F:14])[CH:3]([C:9]([F:11])([F:10])[F:12])[CH:4]([C:6]([O:8][CH3:16])=[O:7])[NH2:5]
Reactant: NC(C(=O)O)C(C(F)(F)F)C(F)(F)F
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: COC(=O)C(N)C(C(F)(F)F)C(F)(F)F
Temperature: 25 °C
Reaction time: 19 h

Procedure:
A solution of 4,4,4,4′,4′,4′-hexafluoro-dl-valine (1.1 g, 4.88 mmol) in CH2Cl2-MeOH (4:1, 25 mL) was stirred under nitrogen at 0° C. TMS-diazomethane (2.0 M in hexane, 20 mL, 19.55 mL) was added dropwise and the resulting neon greenish solution stirred for 19 h at 25° C. After this time period, the reaction was complete by TLC (10% MeOH in chloroform). After concentration, the resulting residue of methyl 4,4,4,4′,4′,4′-hexafluoro-dl-valinate (1.1 g) was used directly in the next step without further purification. Mass Spectrum (−ESI): 238 (M−H)−.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[N+:11]([O-])[CH:12]=[C:13]([Br:15])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O=P(Cl)(Cl)[Cl:19]>>[CH2:1]([O:8][C:9]1[C:10]([Cl:19])=[N:11][CH:12]=[C:13]([Br:15])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [O-][n+]1cc(Br)cc(OCc2ccccc2)c1
Reactant: O=P(Cl)(Cl)Cl
Product: Clc1ncc(Br)cc1OCc1ccccc1
Temperature: 25 °C
Yield: 40 %

Procedure:
A solution of 3-(benzyloxy)-5-bromopyridine N-oxide (2.0 g, 7.1 mmol) in POCl3 (20 mL) was stirred at 100° C. for 7 hours, cooled to room temperature, concentrated, treated with ethyl acetate (50 mL), washed with brine, dried (MgSO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 10% ethyl acetate/hexane to provide the desired product (1.0 g, 40%). MS (DCI/NH3) m/e 299 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C@H:4]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:5][C:6]1[CH:16]=[CH:15][C:9]([O:10][CH2:11][C:12]([OH:14])=O)=[CH:8][CH:7]=1)[CH3:2].Cl.[F:23][C:24]1[CH:39]=[C:38]([F:40])[CH:37]=[CH:36][C:25]=1[CH2:26][NH:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35].C(N(CC)C(C)C)(C)C.Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[F:23][C:24]1[CH:39]=[C:38]([F:40])[CH:37]=[CH:36][C:25]=1[CH2:26][N:27]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[C:12](=[O:14])[CH2:11][O:10][C:9]1[CH:8]=[CH:7][C:6]([CH2:5][C@H:4]([O:3][CH2:1][CH3:2])[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:16][CH:15]=1
Reactant: CCOC(=O)[C@H](Cc1ccc(OCC(=O)O)cc1)OCC
Reactant: CCCCCCCCNCc1ccc(F)cc1F
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCCCCCCN(Cc1ccc(F)cc1F)C(=O)COc1ccc(C[C@H](OCC)C(=O)OCC)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 38.4 %

Procedure:
To a solution of {4-[(2S)-2,3-diethoxy-3-oxopropyl]phenoxy}acetic acid (0.120 g, 0.40 mmol) in methylene chloride (5.0 mL) were added N-(2,4-difluorobenzyl)-N-octylamine hydrochloride (0.165 g, 0.57 mmol), DMAP (0.054 g, 0.45 mmol) and N,N-diisopropylethylamine (0.078 mL, 0.45 mmol) followed by 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.085 g, 0.45 mmol) and the reaction mixture was stirred at room temperature overnight. The resulting solution was diluted with methylene chloride (50 mL) and the organic phase was washed with 5% HCl (3×25 mL), aqueous NaHCO3 (25 mL), and brine (25 mL), dried over anhydrous Na2SO4, and concentrated in vacuo. Purification on a prepacked column of silica gel (Isolute® SPE Column, 5 g Si/25 mL) with methanol (0-1% gradient) in methylene chloride as the eluent afforded 0.082 g (38%) of a colourless oil.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([CH3:9])[N:3]=1.[CH3:10][O:11][C:12]([C:14]1[S:15][CH:16]=[CH:17][C:18]=1[S:19]([N:22]=[C:23]=[O:24])(=[O:21])=[O:20])=[O:13]>C(Cl)Cl>[CH3:9][C:4]1[N:5]=[C:6]([CH3:8])[N:7]=[C:2]([NH:1][C:23]([NH:22][S:19]([C:18]2[CH:17]=[CH:16][S:15][C:14]=2[C:12]([O:11][CH3:10])=[O:13])(=[O:20])=[O:21])=[O:24])[N:3]=1
Reactant: Cc1nc(C)nc(N)n1
Reactant: COC(=O)c1sccc1S(=O)(=O)N=C=O
Solvent: ClCCl
Product: COC(=O)c1sccc1S(=O)(=O)NC(=O)Nc1nc(C)nc(C)n1
Temperature: 25 °C
Yield: 62.5 %

Procedure:
To 1.23 g of 2-amino-4,6-dimethyl-1,3,5-triazine in 30 ml of anhydrous methylene chloride was added with stirring 2.7 g of 2-methoxycarbonyl-3-thiophenesulfonylisocyanate. The mixture was heated to the boiling point and allowed to cool and stir at ambient temperature for sixteen hours. The solid thus obtained was removed by filtration to yield 2.3 g of the crude desired product melting at 158°-178°. The product showed peaks at 1720 and 1710 cm-1, by infrared absorption spectroscopy, consistent for the desired product.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[C:13]([CH:14]=[O:15])=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:16][CH3:17])[CH:10]=2)[N:5]=1)[CH3:2]>C1COCC1>[CH2:1]([NH:3][C:4]1[C:13]([CH2:14][OH:15])=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:16][CH3:17])[CH:10]=2)[N:5]=1)[CH3:2]
Reactant: CCNc1nc2ccc(OC)cc2cc1C=O
Solvent: C1CCOC1
Product: CCNc1nc2ccc(OC)cc2cc1CO
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.6 %

Procedure:
To a stirred solution of SLA 28162 (1.495 g, 6.49 mmol) in THF (120 mL) in a 250 mL round-bottomed flask equipped with a magnetic stirrer was added sodium borohydride NaBH4 (0.246 g, 6.50 mmol) and the mixture was stirred overnight at RT then cooled in an ice bath before quenching by addition of a 1 N aq. HCl solution (40 mL). After stirring for 15 min at RT, the mixture was basified to pH=9 with a 2 N aq. NaOH solution. THF was then removed at 40° C. under vacuum and the solution was extracted with CH2Cl2 (200 mL), washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under at 40° C. under vacuum to give (2-(ethylamino)-6-methoxyquinolin-3-yl)methanol SLA 28164 as an orange oil (1.17 g, 78% yield).
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]=[O:9])=[C:6]([Cl:10])[N:5]=[CH:4][N:3]=1.[CH3:11][NH2:12]>C1COCC1>[Cl:10][C:6]1[C:7]([CH:8]=[O:9])=[C:2]([NH:12][CH3:11])[N:3]=[CH:4][N:5]=1
Reactant: CN
Reactant: O=Cc1c(Cl)ncnc1Cl
Solvent: C1CCOC1
Product: CNc1ncnc(Cl)c1C=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4,6-dichloro-pyrimidine-5-carbaldehyde Compound 2a (0.5 g), methylamine (88 mg) and THF (50 mL) were added to a flask. The mixture was stirred at rt overnight, then concentrated and the residue was purified by flash chromatography (silica gel, hexane:EtOAc/5:5) to afford 4-chloro-6-methylamino-pyrimidine-5-carbaldehyde Compound 2b (0.40 g, 82%). 1H NMR (300 MHz, CDCl3) δ 10.38 (s, 1H), 9.15 (s, 1H), 8.45 (s, 1H), 3.15 (d, 3 H). MS (ESI) m/z: 172 (M+H+).
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[CH2:10][CH2:9][N:8]([C:11]3[N:16]=[CH:15][C:14]([C:17]4[CH:24]=[CH:23][C:20]([C:21]#N)=[CH:19][CH:18]=4)=[CH:13][CH:12]=3)[CH2:7][CH2:6]2)[CH2:3][CH2:2]1.CC(C[AlH]CC(C)C)C.C[OH:35].[OH-].[Na+]>C1COCC1.O>[CH:1]1([CH2:4][N:5]2[CH2:10][CH2:9][N:8]([C:11]3[N:16]=[CH:15][C:14]([C:17]4[CH:24]=[CH:23][C:20]([CH:21]=[O:35])=[CH:19][CH:18]=4)=[CH:13][CH:12]=3)[CH2:7][CH2:6]2)[CH2:3][CH2:2]1
Reactant: N#Cc1ccc(-c2ccc(N3CCN(CC4CC4)CC3)nc2)cc1
Reactant: CO
Agent: CC(C)C[AlH]CC(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=Cc1ccc(-c2ccc(N3CCN(CC4CC4)CC3)nc2)cc1
Temperature: -40 °C
Reaction time: 2 h
Yield: 51 %

Procedure:
To a solution of 4-[6-(4-cyclopropylmethyl-piperazin-1-yl)-pyridin-3-yl]-benzonitrile (2.0 g 6.3 mmol) dissolved in THF (40 mL) was added DIBAL-H (25 mL, 1 N) at −40° C. The mixture was stirred 2 h at −40° C. and then CH3OH (15 mL), water (100 mL) and 1 N NaOH (15 mL) was added at −40° C. The mixture was extracted with EtOAc (3×300 mL). The combined organic extracts were washed with water (3×50 mL), dried (Na2SO4) and concentrated under reduced pressure to give 1.7 g (51%) of 4-[6-(4-cyclopropylmethyl-piperazin-1-yl)-pyridin-3-yl]-benzaldehyde.
Reaction SMILES: [N+:1]([C:4]1[CH:24]=[CH:23][C:7]([C:8]([C:10]2[N:14]([CH3:15])[C:13]([CH2:16][C:17]([O:19]CC)=[O:18])=[CH:12][C:11]=2[CH3:22])=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].C(I)CCCCC>>[CH2:16]([C:13]1[N:14]([CH3:15])[C:10]([C:8](=[O:9])[C:7]2[CH:23]=[CH:24][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)=[C:11]([CH3:22])[CH:12]=1)[CH3:17].[CH2:13]([CH2:16][C:17]([O-:19])=[O:18])[CH2:12][CH2:11][CH2:10][CH2:8][CH3:7]
Reactant: CCOC(=O)Cc1cc(C)c(C(=O)c2ccc([N+](=O)[O-])cc2)n1C
Solvent: CCCCCCI
Product: CCCCCCCC(=O)[O-]
Product: CCc1cc(C)c(C(=O)c2ccc([N+](=O)[O-])cc2)n1C

Procedure:
The alkylation procedure of Example 77A is performed upon ethyl 5-(p-nitrobenzoyl)-1,4-dimethylpyrrole-2-acetate (from Example 85), using an equivalent quantity of n-hexyl iodide instead of methyl iodide used in Example 77A to yield ethyl 5-(p-nitrobenzoyl)-1,4-dimethylpyrrole-2-(α-n-hexyl)-acetate.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Cl)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[F:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][C:21]([CH3:26])=[C:20]2[C:27]1[C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=2[S:30](=[O:38])(=[O:37])[NH:29][N:28]=1.Br[CH2:40][C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42]>CC#N.O.C(Cl)Cl>[C:44]([O:43][C:41](=[O:42])[CH2:40][N:22]1[C:23]2[C:19](=[CH:18][C:17]([F:16])=[CH:25][CH:24]=2)[C:20]([C:27]2[C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=3[S:30](=[O:37])(=[O:38])[N:29]([CH2:6][C:5]3[CH:8]=[CH:9][C:2]([Cl:1])=[CH:3][CH:4]=3)[N:28]=2)=[C:21]1[CH3:26])([CH3:47])([CH3:46])[CH3:45]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: Cc1[nH]c2ccc(F)cc2c1C1=NNS(=O)(=O)c2ccccc21
Reactant: ClCc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Solvent: CC#N
Product: Cc1c(C2=NN(Cc3ccc(Cl)cc3)S(=O)(=O)c3ccccc32)c2cc(F)ccc2n1CC(=O)OC(C)(C)C
Temperature: 80 °C
Reaction time: 8 h

Procedure:
4-Chlorobenzyl chloride (11 mg, 67 μmol) and K2CO3 (10 mg, 72 μmol) were added to a solution of 4-(5-fluoro-2-methyl-1H-indol-3-yl)-2H-benzo[e][1,2,3]thiadiazine 1,1-dioxide (20 mg, 61 μmol) in CH3CN (1 mL), and stirred overnight at 80° C. An additional amount of K2CO3 (10 mg, 72 μmol) and tert-butyl bromoacetate (14 μL, 92 μmol) was added, and the reaction mixture stirred an additional 2 h at 80° C. The reaction mixture was diluted with H2O and CH2Cl2, and filtered through an Extrelut column. The Extrelut column was washed with CH2Cl2, and the filtrate was concentrated to afford the sub-title compound, which was carried onto the next step without further purification or characterization.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:21][CH3:22])=[C:4]([C:10]([CH2:13][S:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:11][CH:12]=1)[C:5]([O:7][CH2:8]C)=[O:6].BrC1C(OC)=C(C(CBr)=CC=1)C(OC)=O.[Cl:38]C1C=C(S)C=CC=1>>[Br:1][C:2]1[C:3]([O:21][CH3:22])=[C:4]([C:10]([CH2:13][S:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:38])[CH:16]=2)=[CH:11][CH:12]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: CCOC(=O)c1c(CSc2ccccc2)ccc(Br)c1OC
Reactant: Sc1cccc(Cl)c1
Agent: COC(=O)c1c(CBr)ccc(Br)c1OC
Product: COC(=O)c1c(CSc2cccc(Cl)c2)ccc(Br)c1OC

Procedure:
Prepared by proceeding in a similar manner to Intermediate 73, starting from methyl 3-bromo-6-bromomethyl-2-methoxybenzoate (Intermediate 89) and 3-chlorothiophenol.
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:18].[CH:19]1([CH2:24][C:25](O)=[O:26])[CH2:23][CH2:22][CH2:21][CH2:20]1>>[CH:19]1([CH2:24][C:25]([NH:1][N:2]2[N:11]=[C:10]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]2=[O:18])=[O:26])[CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: Nn1nc(N2CCOCC2)c2ccccc2c1=O
Reactant: O=C(O)CC1CCCC1
Product: O=C(CC1CCCC1)Nn1nc(N2CCOCC2)c2ccccc2c1=O

Procedure:
The product of Example 1B and 2-cyclopentylacetic acid were treated using a method similar to that described in Example 111 to give the title compound. 1H NMR (500 MHz, DMSO-d6/Deuterium Oxide) δ ppm 8.31 (dd, J=7.9, 1.3 Hz, 1H), 8.03 (d, J=8.0 Hz, 1H), 7.97-8.00 (m, 1H), 7.91 (td, J=7.5, 1.3 Hz, 1H), 3.81-3.84 (m, 4H), 3.05-3.14 (m, 4H), 2.29 (d, J=7.5 Hz, 2H), 2.13-2.23 (m, 1H), 1.75-1.84 (m, 2H), 1.49-1.66 (m, 4H), 1.21-1.29 (m, 2H); MS (ESI−) M/Z 355 (M−H)−.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[O:9]=[C:10]1[NH:19][CH:18]([C:20]2[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][CH:21]=2)[C:17]2[C:16](=[O:28])[CH2:15][CH2:14][CH2:13][C:12]=2[N:11]1[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:38])([F:37])[F:36])[CH:30]=1.[CH2:39](I)[CH2:40][CH2:41][CH3:42]>CN(C)C=O>[CH2:39]([N:19]1[CH:18]([C:20]2[CH:21]=[CH:22][C:23]([C:24]#[N:25])=[CH:26][CH:27]=2)[C:17]2[C:16](=[O:28])[CH2:15][CH2:14][CH2:13][C:12]=2[N:11]([C:29]2[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:38])([F:36])[F:37])[CH:30]=2)[C:10]1=[O:9])[CH2:40][CH2:41][CH3:42]
Reactant: CCCCI
Reactant: N#Cc1ccc(C2NC(=O)N(c3cccc(C(F)(F)F)c3)C3=C2C(=O)CCC3)cc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CN(C)C=O
Product: CCCCN1C(=O)N(c2cccc(C(F)(F)F)c2)C2=C(C(=O)CCC2)C1c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Lithium diisopropylamide (2.0 M in tetrahydrofuran, 135 μL, 0.27 mmol) is added at 0° C. to a solution of 4-(2,5-dioxo-1-(3-(trifluoromethyl)phenyl)-1,2,3,4,5,6,7,8-octahydroquinazolin-4-yl)-benzonitrile (example 1, 100 mg, 0.243 mmol) in N,N-dimethylformamide (5 mL). n-Butyl iodide (30 μL, 0.264 mmol) is added, and the mixture is warmed to room temperature and stirred for 2 h. Another portion of n-Butyl iodide (15 μL, 0.132 mmol) is added and the mixture is stirred over night and purified by reversed phase HPLC (Waters Xbridge™-C18, gradient of acetonitrile in water, 0.1% TFA). Yield: 28 mg; ESI mass spectrum [M+H]+=468; Retention time HPLC: 1.47 min (V001—006).
Reaction SMILES: [C:1]1([CH:7]2[NH:13][CH2:12][CH2:11][NH:10][C:9](=[O:14])[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH3:22][C:23]1[CH:24]=[C:25]([CH:29]=[C:30]([CH3:32])[CH:31]=1)[C:26](Cl)=[O:27]>ClCCl>[CH3:22][C:23]1[CH:24]=[C:25]([CH:29]=[C:30]([CH3:32])[CH:31]=1)[C:26]([N:13]1[CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:8][C:9](=[O:14])[NH:10][CH2:11][CH2:12]1)=[O:27]
Reactant: Cc1cc(C)cc(C(=O)Cl)c1
Reactant: O=C1CC(c2ccccc2)NCCN1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(C)cc(C(=O)N2CCNC(=O)CC2c2ccccc2)c1
Yield: 98.5 %

Procedure:
3.0 g hexahydro-7-phenyl-1,4-diazepin-5-one (for preparation see Example 1C)) in 40 ml dichloromethane were reacted with 4.0 g triethylamine and 2.9 g 3,5-dimethylbenzoyl chloride according to the method given above in Example 1F). 5.01 g amorphous 1-(3,5-dimethylbenzoyl)-hexahydro-7-phenyl-1,4-diazepin-5-one were obtained, which was reacted without further purification.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].Cl.[C:16]([O:20][C:21](=[O:24])[CH2:22][NH2:23])([CH3:19])([CH3:18])[CH3:17].C([O-])(O)=O.[Na+].O>CS(C)=O>[N+:12]([C:3]1[CH:4]=[C:5]([C:8]([F:11])([F:10])[F:9])[CH:6]=[CH:7][C:2]=1[NH:23][CH2:22][C:21]([O:20][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:24])([O-:14])=[O:13]
Reactant: CC(C)(C)OC(=O)CN
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1F
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)CNc1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Temperature: 65 °C
Reaction time: 8 h
Yield: 79.3 %

Procedure:
A mixture of 4-fluoro-3-nitrobenzotrifluoride (209 mg, 1 mmol), glycine tert-butyl ester hydrochloride (201 mg, 1.2 mmol) and NaHCO3 (128 mg, 2 mmol) in dry DMSO (1 ml) is stirred overnight at 50 or 65° C. In case the reaction is not complete a further heating at 85° C. to 100° C. for 3 h is necessary. The reaction is then cooled to rt and water is added. The yellow to orange solid formed is filtered over a fritted funnel, rinsed thoroughly with water and dried under high vacuum. This yields the title compound (254 mg) in 79% as a yellow solid: tR=1.08 min (LC-3), ESI-MS (pos.): m/z 403.2 [M+2AcCN]+, m/z 321.56 [M+H]+, 1H-NMR (DMSO-d6): δ (ppm) 1.44 (s, 9H, tBu), 4.23 (d, 2H, NHCH2CO2), 7.08 (d, 1H, Harom), 7.80 (dd, 1H, H, m), 8.34 (br. s, 1H, Harom), 8.65 (t, 1H, NH).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=1)[CH3:2].[H-].[Na+].Br[CH2:19][CH2:20]Br.O>CN(C)C=O>[N+:12]([C:9]1[CH:10]=[CH:11][C:6]([C:5]2([C:4]([O:3][CH2:1][CH3:2])=[O:15])[CH2:20][CH2:19]2)=[CH:7][CH:8]=1)([O-:14])=[O:13]
Reactant: BrCCBr
Reactant: CCOC(=O)Cc1ccc([N+](=O)[O-])cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C1(c2ccc([N+](=O)[O-])cc2)CC1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of ethyl(4-nitrophenyl)acetate (5.0 g) in N,N-dimethylformamide (100 mL) was added sodium hydride (60% in mineral oil, 1.9 g) in an ice bath, and the mixture was stirred at room temperature for 20 min. To the reaction mixture was added 1,2-dibromoethane (4.1 mL) in an ice bath, and the mixture was stirred at the same temperature for 30 min, and the at room temperature for 1 hr. The reaction mixture was colled to 0° C., water was added thereto, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (3.0 g).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:28]4[CH:33]=[CH:32][CH:31]=[C:30](Br)[N:29]=4)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[N:35]1[CH:40]=[CH:39][C:38](B(O)O)=[CH:37][CH:36]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:28]4[N:29]=[C:30]([C:38]5[CH:39]=[CH:40][N:35]=[CH:36][CH:37]=5)[CH:31]=[CH:32][CH:33]=4)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cccc(Br)n4)cc3)cc2)CC1
Reactant: OB(O)c1ccncc1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cccc(-c5ccncc5)n4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 42, Step 2, using 1-{4′-[4-(6-bromo-pyridin-2-ylamino)-3-methyl-isoxazol-5-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid ethyl ester and pyridine-4-boronic acid.
Reaction SMILES: FC(F)(F)C([N:5]1[CH2:15][CH:14]2[CH2:16][CH:7]([C:8]3[CH:9]=[CH:10][C:11]([OH:17])=[CH:12][C:13]=32)[CH2:6]1)=O.C([O-])([O-])=O.[Na+].[Na+].C(OCC)(=O)C.[ClH:32]>CO.O>[ClH:32].[CH:14]12[CH2:16][CH:7]([CH2:6][NH:5][CH2:15]1)[C:8]1[CH:9]=[CH:10][C:11]([OH:17])=[CH:12][C:13]2=1
Reactant: O=C(N1CC2CC(C1)c1cc(O)ccc12)C(F)(F)F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: CCOC(C)=O
Product: Oc1ccc2c(c1)C1CNCC2C1
Temperature: 65 °C

Procedure:
2,2,2-Trifluoro-1-(4-hydroxy-10-aza-tricyclo[6.3.1.02,7]dodeca-2(7),3,5-trien-10-yl)-ethanone (50 mg, 0.184 mmol) was dissolved in methanol/H2O (3/1, 5 mL), treated with Na2CO3(s) (40 mg, 0.369 mmol) and warmed to 65° C. for 2 hours. The mixture was concentrated, diluted with H2O and extracted with CH2Cl2 (3×20 mL) then dried through a cotton plug. Filtration through a Silica gel plug provided an oil (10% methanol/CH2Cl2) which was treated with 3N HCl ethyl acetate (3 mL) then concentrated, dissolved in a minimum of methanol which was saturated with Et2O and stirred. After 18 hours the white crystalline product was collected by filtration (10 mg, 26%). 1H NMR (400 MHz, CDOD3)7.16 (d, J=8.0 Hz, 1H), 6.80 (d, J=2.0 Hz, 1H), 6.72 (dd, J=8.0, 2.0 Hz, 1H), 3.32–3.28 (4H), 3.09 (dd, J=14.5, 12.0 Hz, 2H), 2.32 (m, 1H), 2.03 (d, J=11.0 Hz, 1H). APCI MS m/e 176.2 [(M+1)+]. M.p. 308 (dec.)° C.