Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:19][CH2:18][C:11]2([C:15](=[O:16])[NH:14][C:13](=[O:17])[CH2:12]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH2:21][CH2:22][O:23][CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][O:25]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11]2([C:15](=[O:16])[N:14]([CH2:21][CH2:22][O:23][CH:24]3[CH2:29][CH2:28][CH2:27][CH2:26][O:25]3)[C:13](=[O:17])[CH2:12]2)[CH2:18][CH2:19]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CC(=O)NC2=O
Reactant: BrCCOC1CCCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CC(=O)N(CCOC1CCCCO1)C2=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 109.1 %

Procedure:
To a suspension of 1,3-dioxo-2,8-diaza-spiro[4.5]decane-8-carboxylic acid tert-butyl ester (1.0 g, 3.7 mmol) in DMF (12 ml), 2-(2-bromoethoxy)-tetrahydro-2H-pyrane (0.62 ml, 4.1 mmol) and potassium carbonate (0.62 g, 4.5 mmol) are added at ambient temperature and the mixture is stirred for overnight at room temperature. The reaction mixture is quenched with water and extracted with ethyl acetate. The combined extracts are washed with brine and dried over sodium sulfate, filtrated. The solvent is evaporated down to give 1.6 g of crude 1,3-dioxo-2-[2-(tetrahydro-pyran-2-yloxy)-ethyl]-2,8-diaza-spiro[4.5]decane-8-carboxylic acid tert-butyl ester.
Reaction SMILES: C([O:3][C:4]([CH2:6][O:7][C:8]1[CH:17]=[CH:16][C:15]([Br:18])=[C:14]2[C:9]=1[CH2:10][CH2:11][C:12](=[O:19])[NH:13]2)=[O:5])C.O.[OH-].[K+]>C(O)C>[C:4]([CH2:6][O:7][C:8]1[CH:17]=[CH:16][C:15]([Br:18])=[C:14]2[C:9]=1[CH2:10][CH2:11][C:12](=[O:19])[NH:13]2)([OH:5])=[O:3]
Reactant: CCOC(=O)COc1ccc(Br)c2c1CCC(=O)N2
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)COc1ccc(Br)c2c1CCC(=O)N2

Procedure:
3.6 Grams of 5-ethoxycarbonylmethoxy-8-bromo-3,4-dihydrocarbostyril is dissolved in 150 ml of ethanol, and to this solution is added a 50 ml water solution of 5 g of potassium hydroxide, and the mixture is refluxed for 5 hours. The solvent is distilled off and the residue is dissolved in water and then made acidic with hydrochloric acid. The precipitate is filtered out and recrystallized from aqueous ethanol to obtain 2.5 g of 5-carboxymethoxy-8-bromo-3,4-dihydrocarbostyril in the form of colorless needle-like crystals, m.p., 255°-256° C. (decomposed).
Reaction SMILES: C(N(CC)CC)C.[O:8]=[C:9]1[N:15]([CH:16]2[CH2:21][CH2:20][N:19]([C:22]([O:24][C@@H:25]([C:39]([OH:41])=O)[CH2:26][C:27]3[CH:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[C:30]([NH2:37])=[C:29]([Cl:38])[CH:28]=3)=[O:23])[CH2:18][CH2:17]2)[CH2:14][CH2:13][C:12]2[CH:42]=[CH:43][CH:44]=[CH:45][C:11]=2[NH:10]1.[CH3:46][N:47]1[CH2:52][CH2:51][CH:50]([N:53]2[CH2:58][CH2:57][NH:56][C@H:55]([C:59]([O:61][CH2:62][CH3:63])=[O:60])[CH2:54]2)[CH2:49][CH2:48]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[NH2:37][C:30]1[C:31]([C:33]([F:36])([F:35])[F:34])=[CH:32][C:27]([CH2:26][C@@H:25]([O:24][C:22]([N:19]2[CH2:20][CH2:21][CH:16]([N:15]3[CH2:14][CH2:13][C:12]4[CH:42]=[CH:43][CH:44]=[CH:45][C:11]=4[NH:10][C:9]3=[O:8])[CH2:17][CH2:18]2)=[O:23])[C:39]([N:56]2[CH2:57][CH2:58][N:53]([CH:50]3[CH2:51][CH2:52][N:47]([CH3:46])[CH2:48][CH2:49]3)[CH2:54][C@H:55]2[C:59]([O:61][CH2:62][CH3:63])=[O:60])=[O:41])=[CH:28][C:29]=1[Cl:38]
Reactant: CCOC(=O)[C@@H]1CN(C2CCN(C)CC2)CCN1
Reactant: Nc1c(Cl)cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)O)cc1C(F)(F)F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)[C@@H]1CN(C2CCN(C)CC2)CCN1C(=O)[C@@H](Cc1cc(Cl)c(N)c(C(F)(F)F)c1)OC(=O)N1CCC(N2CCc3ccccc3NC2=O)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
0.30 mL (2.16 mmol) triethylamine were added to a mixture of 700 mg (1.26 mmol) (R)-2-(4-amino-3-chloro-5-trifluoromethyl-phenyl)-1-carboxy-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate (Example 1f), 430 mg (1.41 mmol) ethyl(S)-4-(1-methyl-piperidin-4-yl)-piperazine-2-carboxylate (Example A11b) and 450 mg (1.40 mmol) TBTU in 7 mL DMF and the reaction mixture was stirred for 18 h at RT. It was evaporated down i. vac., the residue was stirred with saturated NaHCO3 solution, extracted exhaustively with EtOAc and the combined organic phases were dried over Na2SO4. After elimination of the desiccant and solvent the residue was purified by HPLC; the fractions containing the product were combined and lyophilised.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[OH:11].[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH2:12]([O:11][C:3]1[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=1[I:1])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: BrCc1ccccc1
Reactant: O=[N+]([O-])c1ccc(I)c(O)c1
Product: O=[N+]([O-])c1ccc(I)c(OCc2ccccc2)c1
Yield: 90.4 %

Procedure:
According to the method described in example 4.1., starting from 20.8 g (78.5 mmol) of 2-iodo-5-nitrophenol and 9.3 mL (78.5 mmol) of benzyl bromide, we obtain 25.2 g of 2-(benzyloxy)-1-iodo-4-nitrobenzene in the form of oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:30]=[CH:31][C:32]=1[Cl:33])[C:5]([NH:7][CH2:8][C:9]([N:11]1[CH2:15][CH2:14][CH:13]([N:16]2[CH2:21][CH2:20][CH:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[O:28]C)[CH2:18][CH2:17]2)[CH2:12]1)=[O:10])=[O:6].B(Br)(Br)Br>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:30]=[CH:31][C:32]=1[Cl:33])[C:5]([NH:7][CH2:8][C:9]([N:11]1[CH2:15][CH2:14][CH:13]([N:16]2[CH2:21][CH2:20][CH:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[OH:28])[CH2:18][CH2:17]2)[CH2:12]1)=[O:10])=[O:6]
Reactant: COc1ccccc1C1CCN(C2CCN(C(=O)CNC(=O)c3ccc(Cl)c(Cl)c3)C2)CC1
Agent: BrB(Br)Br
Product: O=C(NCC(=O)N1CCC(N2CCC(c3ccccc3O)CC2)C1)c1ccc(Cl)c(Cl)c1
Reaction time: 0.05 h
Yield: 85.9 %

Procedure:
3,4-Dichloro-N-(2-(3-(4-(2-methoxyphenyl)piperidin-1-yl)pyrrolidin-1-yl)-2-oxoethyl)benzamide (0.035 g, 0.071 mmol) and boron tribromide (1M solution in DCM, 0.357 mL, 0.357 mmol) was stirred at about 0° C. for about 1 hour. The precipitate was collected by filtration, rinsed with DCM. The residue was purified by preparative RP-HPLC (15% acetonitrile/0.05M aqueous ammonium acetate buffered to pH 4.5 for 3 min then 15% to 60% acetonitrile/0.05M aqueous ammonium acetate buffered to pH 4.5 over 6 min at 25 mL/min; APCI positive mode detection; Xterra prep. MS C18 19×50 mm column) to yield 3,4-dichloro-N-(2-(3-(4-(2-hydroxyphenyl)piperidin-1-yl)pyrrolidin-1-yl)-2-oxoethyl)benzamide (0.029 g, 0.061 mmol). RP-HPLC (Table 1, Method a) Rt 1.91 min; m/z: (M+H)+ 476.
Reaction SMILES: [CH2:1]([N:7]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:8]([CH:10]1[CH2:19][C:18](=O)[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[S:11]1)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[C:27]1([NH:33]N)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[CH2:1]([N:7]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[C:8]([CH:10]1[C:19]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[NH:33][C:18]=2[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[S:11]1)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: NNc1ccccc1
Reactant: CCCCCCN(CCCCCC)C(=O)C1CC(=O)c2ccccc2S1
Product: CCCCCCN(CCCCCC)C(=O)C1Sc2ccccc2-c2[nH]c3ccccc3c21
Temperature: 170 °C
Reaction time: 0.08 h

Procedure:
N,N-Dihexyl-(4-oxo-thiochroman-2-yl)-carboxamide (1.00 g) and phenylhydrazine (0.26 ml) were stirred at 100° C. for 30 minutes, and the reaction mixture was dried under reduced pressure at 50° C. for 30 minutes. The residue, after addition of 1.44 g of anhydrous zinc chloride, was stirred at 170° C. for 5 minutes, and cooled to room temperature. To the reaction mixture was added ice water, followed by extracting with ethyl acetate. The extract was washed with 1N hydrochloric acid, a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution, and dried over anhydrous sodium sulfate. After removal of the drying agent by filtration, the filtrate was concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give 0.79 g of N,N-dihexyl-6,11-dihydro-5-thia-11-aza-benzo[a]fluoren-6-carboxamide.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([OH:13])[C@H:10](Br)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:15]([NH2:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>[OH-].[Na+]>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([OH:13])[C@H:10]([NH:22][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1C[C@@H](O)[C@H](Br)C1
Reactant: NCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Product: CC(C)(C)OC(=O)N1C[C@@H](O)[C@H](NCc2ccccc2)C1
Temperature: 0 °C
Yield: 60.7 %

Procedure:
Stir a mixture of crude rac-trans-3-bromo-4-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester (75.0 g) and aqueous 1 N sodium hydroxide (400 mL) at room temperature for 2 h. Add benzylamine (0.86 mol, 80.0 g,), stir at 65° C. for 4.5 h and then cool to 0° C. Collect the resultant precipitates by filtration, wash with water and isopropyl ether and dry to obtain the title compound as a white solid (50.0 g, 63%). 1H NMR (300 MHz, CDCl3) δ 7.21-7.38 (m, 5H), 4.06-4.15 (m, 1H), 3.84 (d, J=5.0 Hz, 2H), 3.57-3.75 (m, 2H), 3.10-3.35 (m, 3H), 1.65 (br s, 2H), 1.46 (s, 9H).
Reaction SMILES: [CH2:1]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]#N)=[CH:14][CH:13]=2)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5].[H-].C([Al+]CC(C)C)C(C)C.S(=O)(=O)(O)[OH:31].O>C1(C)C=CC=CC=1>[CH2:1]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([CH:18]=[O:31])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCc1ccc(-c2ccc(C#N)cc2)cc1
Reactant: O=S(=O)(O)O
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCCc1ccc(-c2ccc(C=O)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 10 g of 4-pentyl-4'-cyanobiphenyl in 150 ml of toluene was treated dropwise at 0° C. with 65 ml of a 1M solution of diisobutylaluminium hydride in toluene while gassing with nitrogen. The reaction mixture was stirred at room temperature overnight, then treated dropwise with 340 ml of 1N sulphuric acid, stirred at room temperature for 1 hour, poured into 1,000 ml of water and then extracted three times with 100 ml of ethyl acetate each time. The combined organic phases were washed twice with 50 ml of saturated sodium chloride solution each time, dried over magnesium sulphate, filtered and subsequently concentrated. Chromatographic purification of the residue on silica gel with hexane/ethyl acetate (vol. 9:1) gave 10.1 g of 4-pentyl-4'-biphenylcarboxaldehyde.
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[NH2:23][C:24]1[C:29]2=[C:30]([C:43]3[CH:48]=[CH:47][C:46]([NH:49][C:50]([NH:52][C:53]4[CH:58]=[C:57]([C:59]([F:62])([F:61])[F:60])[CH:56]=[CH:55][N:54]=4)=[O:51])=[CH:45][CH:44]=3)[C:31]([CH:40]([OH:42])[CH3:41])=[C:32]([CH2:33][N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)[N:28]2[N:27]=[CH:26][N:25]=1.C([O-])(O)=O.[Na+].CCOC(C)=O>CS(C)=O.O>[C:40]([C:31]1[C:30]([C:43]2[CH:48]=[CH:47][C:46]([NH:49][C:50]([NH:52][C:53]3[CH:58]=[C:57]([C:59]([F:60])([F:61])[F:62])[CH:56]=[CH:55][N:54]=3)=[O:51])=[CH:45][CH:44]=2)=[C:29]2[N:28]([C:32]=1[CH2:33][N:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1)[N:27]=[CH:26][N:25]=[C:24]2[NH2:23])(=[O:42])[CH3:41]
Reactant: CC(O)c1c(-c2ccc(NC(=O)Nc3cc(C(F)(F)F)ccn3)cc2)c2c(N)ncnn2c1CN1CCOCC1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: O
Product: CC(=O)c1c(-c2ccc(NC(=O)Nc3cc(C(F)(F)F)ccn3)cc2)c2c(N)ncnn2c1CN1CCOCC1
Yield: 33.3 %

Procedure:
Dess-Martin periodinane (342.9 mg, 0.809 mmol) was added to a stirring solution of N-{4-[4-amino-6-(1-hydroxyethyl)-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]-triazin-5-yl]phenyl}-N′-[4-(trifluoromethyl)-pyridin-2-yl]urea (300 mg, 0.54 mmol) in DMSO (3 mL). The reaction was allowed to stir until complete by HPLC. Saturated aq. NaHCO3 solution (0.25 volumes) was added until a lot of solid had crashed out. Then 2 volumes of EtOAc and 0.5 volumes of H2O was added. This was allowed to stir overnight and the next day the excess liquid was removed via pipette. Careful addition of 5-10 mL of Et2O and 2 mL of CH2Cl2 provided an off white suspension. This was filtered to give a the title compound (100 mg, 0.18 mmol, 31% yield, 2 steps) as pure white powder. 1H-NMR (DMSO-d6). δ 10.20 (s, 1H), 10.04 (s, 1H), 8.67 (d, J=5.1 Hz, 1H), 8.20 (s, 1H), 8.10 (s, 1H), 7.78 (d, J=8.7 Hz, 2H), 7.52-7.48 (m, 3H), 4.19 (s, 2H), 3.63-3.60 (m, 4H), 2.56-2.53 (m, 4H), 2.19 (s, 3H). MS [M+H]+=555; LCMS RT=2.51 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([NH2:20])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:4][CH:3]=1.[CH3:21][C:22]1[O:23][C:24]([C:28](O)=[O:29])=[C:25]([CH3:27])[N:26]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([NH:20][C:28]([C:24]3[O:23][C:22]([CH3:21])=[N:26][C:25]=3[CH3:27])=[O:29])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:17])([F:18])[F:19])=[CH:6][CH:7]=1
Reactant: Cc1nc(C)c(C(=O)O)o1
Reactant: Nc1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1
Product: Cc1nc(C)c(C(=O)Nc2cnc(OCC(F)(F)F)c(-c3ccc(Cl)cc3)c2)o1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-(4-chloro-phenyl)-6-(2,2, 2-trifluoro-ethoxy)-pyridin-3-ylamine and 2,4-dimethyl-5-oxazolecarboxylic acid, as starting materials, MS (LC/MS): 426.2 (M+H).
Reaction SMILES: [Si]([O:18][CH2:19][C:20]1[C:24]([CH2:25][NH:26][S:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[N+:36]([O-:38])=[O:37])(=[O:29])=[O:28])=[N:23][N:22]([CH2:39][C@@H:40]2[C@H:43]([NH:44][C:45](=[O:54])[O:46][CH2:47][C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)[C:42](=[O:55])[N:41]2[CH2:56][C:57]2[CH:62]=[CH:61][C:60]([O:63][CH3:64])=[CH:59][C:58]=2[O:65][CH3:66])[N:21]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.CCOC(C)=O>[CH3:66][O:65][C:58]1[CH:59]=[C:60]([O:63][CH3:64])[CH:61]=[CH:62][C:57]=1[CH2:56][N:41]1[C:42](=[O:55])[C@@H:43]([NH:44][C:45](=[O:54])[O:46][CH2:47][C:48]2[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=2)[C@H:40]1[CH2:39][N:22]1[N:21]=[C:20]([CH2:19][OH:18])[C:24]([CH2:25][NH:26][S:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[N+:36]([O-:38])=[O:37])(=[O:28])=[O:29])=[N:23]1
Reactant: COc1ccc(CN2C(=O)[C@@H](NC(=O)OCc3ccccc3)[C@H]2Cn2nc(CNS(=O)(=O)c3ccccc3[N+](=O)[O-])c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)n2)c(OC)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccc(CN2C(=O)[C@@H](NC(=O)OCc3ccccc3)[C@H]2Cn2nc(CO)c(CNS(=O)(=O)c3ccccc3[N+](=O)[O-])n2)c(OC)c1
Reaction time: 2.6 h
Yield: 87.8 %

Procedure:
To a solution of benzyl ((2R,3S)-2-((4-(((tert-butyldiphenylsilyl)oxy)methyl)-5-((2-nitrophenylsulfonamido)methyl)-2H-1,2,3-triazol-2-yl)methyl)-1-(2,4-dimethoxybenzyl)-4-oxoazetidin-3-yl)carbamate (252 mg, 0.270 mmol) in THF (2.8 mL) at 0° C. was added TBAF (1.0 M in THF, 270 μL, 0.270 mmol). After stirring for 2.6 h, the solution was diluted with EtOAc and partially concentrated in vacuo. Additional EtOAc was added along with KHSO4 (2%, aq) and water. The layers were separated and the aqueous layer was extracted with EtOAc (3×). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo. The crude residue was purified via silica gel chromatography (EtOAc-Heptane, 0-100%), affording the title compound (165 mg, 88%) as a white solid. Rt=0.83 min, m/z=696.3 (M+1) Method 2m_acidic.
Reaction SMILES: C(OC([N:8]([C:17]1([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:21][C:20](=[O:22])[NH:19][C:18]1=[O:23])NC(OC(C)(C)C)=O)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH2:8][C:17]1([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:21][C:20](=[O:22])[NH:19][C:18]1=[O:23]
Reactant: CCOC(=O)C1(N(NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)CC(=O)NC1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)C1(N)CC(=O)NC1=O
Temperature: 25 °C
Reaction time: 6 h
Yield: 64.9 %

Procedure:
To a solution of the compound of Example 4 (970 mg) in dichloromethane (8 ml) was added trifluoroacetic acid (4 ml) and the mixture was stirred at room temperature for 6 hours. The reaction mixture was concentrated and to the resulting residue was added toluene to remove azeotropically the residual trifluoroacetic acid and then the mixture was concentrated again. The residue was dissolved in ethanol (25 ml) and thereto was added an appropriate amount of Raney nickel. This mixture was stirred vigorously at 40° C. under hydrogen (atmospheric pressure) for 24 hours. To the reaction mixture was added water (20 ml) and the mixture was filtered through a Celite pad and then the Celite was washed with ethanol. The mixture of the filtrate combined with the washers was adjusted to pH 7-8 with sodium bicarbonate and then thereto was added pH 7.4 phosphate buffer solution. This mixture was extracted with ethyl acetate and the extract was dried over magnesium sulfate and filtered. The filtrate was concentrated to give an oil which was then purified by a flash column chromatography (chloroform:methanol=20:1→10:1) to give the desired product (292 mg, 65%) as crystal.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=1[CH3:11].C(=O)([O-])[O-].[Cs+].[Cs+].Br[C:19]([CH3:26])([CH3:25])[C:20]([O:22][CH2:23][CH3:24])=[O:21]>C(#N)C.C(OCC)(=O)C>[C:8]([C:5]1[CH:6]=[CH:7][C:2]([O:1][C:19]([CH3:26])([CH3:25])[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:3]([CH3:11])[CH:4]=1)(=[O:10])[CH3:9]
Reactant: CC(=O)c1ccc(O)c(C)c1
Reactant: CCOC(=O)C(C)(C)Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C)(C)Oc1ccc(C(C)=O)cc1C
Temperature: 25 °C
Reaction time: 0.03 h

Procedure:
A suspension of 1-(4-hydroxy-3-methylphenyl)ethanone (20.1 g) in acetonitrile (200 ml) was added to a suspension of cesium carbonate (86.6 g) in acetonitrile (400 ml) and the mixture stirred under nitrogen at room temperature for 2 minutes. ethyl 2-bromo-2-methylpropanoate (33 g) was added and the mixture stirred for 25 hours, further ethyl 2-bromo-2-methylpropanoate (33 g) was added and the mixture stirred for a further 16 hours. The mixture was filtered and the filtrate concentrated to give an orange oil, the oil was dissolved in ethyl acetate and the solution washed thrice with 1M sodium hydroxide and brine. The organic layer was separated, dried over sodium sulfate, filtered and the filtrate concentrated; the resulting oil was purified by Biotage® chromatography eluting with cyclohexane:ethyl acetate (9:1) to give the title compound as a clear oil.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]1[CH2:12][CH2:11][NH:10][C:9]1=[O:13].Br[C:15]1[CH:16]=[CH:17][C:18]([F:23])=[C:19]([CH:22]=1)[CH:20]=[O:21].N[C@@H]1CCCC[C@H]1N.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu](I)I.O1CCOCC1>[F:23][C:18]1[CH:17]=[CH:16][C:15]([N:10]2[CH2:11][CH2:12][N:8]([C:3]3[CH:4]=[N:5][CH:6]=[CH:7][C:2]=3[CH3:1])[C:9]2=[O:13])=[CH:22][C:19]=1[CH:20]=[O:21]
Reactant: O=Cc1cc(Br)ccc1F
Reactant: Cc1ccncc1N1CCNC1=O
Agent: I[Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: Cc1ccncc1N1CCN(c2ccc(F)c(C=O)c2)C1=O
Yield: 70.1 %

Procedure:
Using the same reaction conditions as in Example 14, 1-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (I-14b: 200 mg, 1.12 mmol) was reacted with 5-bromo-2-fluoro-benzaldehyde (272 mg, 1.34 mmol), 1,4-dioxane (20 mL), copper iodide (18 mg, 0.098 mmol), trans-1,2-diamino cyclohexane (0.05 mL, 0.294 mmol) and potassium phosphate (520 mg, 2.54 mmol) to afford the crude product which was purified by column chromatography on silica gel (2-3% MeOH in CHCl3). The residue was washed with DCM and hexane in dry ice and dried to afford 235 mg of 2-Fluoro-5-[3-(4-methyl-pyridin-3-yl)-2-oxo-imidazolidin-1-yl]-benzaldehyde (70.35% yield).
Reaction SMILES: [C:1]12([NH:11][C:12]3[N:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[C:15]([C:22]([N:24]4[CH2:29][CH2:28][CH:27]([C:30]([O:32]CC)=[O:31])[CH2:26][CH2:25]4)=[O:23])=[CH:14][N:13]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.CO.[OH-].[Na+].Cl>O.O1CCCC1>[C:1]12([NH:11][C:12]3[N:17]=[C:16]([C:18]([F:20])([F:21])[F:19])[C:15]([C:22]([N:24]4[CH2:29][CH2:28][CH:27]([C:30]([OH:32])=[O:31])[CH2:26][CH2:25]4)=[O:23])=[CH:14][N:13]=3)[CH2:2][CH:3]3[CH2:4][CH:5]([CH2:6][CH:7]([CH2:9]3)[CH2:8]1)[CH2:10]2
Reactant: CCOC(=O)C1CCN(C(=O)c2cnc(NC34CC5CC(CC(C5)C3)C4)nc2C(F)(F)F)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)C1CCN(C(=O)c2cnc(NC34CC5CC(CC(C5)C3)C4)nc2C(F)(F)F)CC1
Temperature: 60 °C
Reaction time: 2 h
Yield: 91.7 %

Procedure:
To a mixture of ethyl 1-{[2-(adamantan-1-ylamino)-4-(trifluoromethyl)pyrimidin-5-yl]carbonyl}piperidine-4-carboxylate (220 mg), methanol (3 mL) and tetrahydrofuran (3 mL) was added a 1 M aqueous sodium hydroxide solution (1.37 mL) at room temperature, followed by stirring at 60° C. for 2 hours. To the reaction mixture were added 1 M hydrochloric acid and water, followed by stirring at room temperature for 30 minutes. The solvent was evaporated under reduced pressure, to the obtained residue was added water, followed by stirring for 30 minutes, and then the precipitate was collected by filtration and washed with water to obtain 1-{[2-(adamantan-1-ylamino)-4-(trifluoromethyl)pyrimidin-5-yl]carbonyl}piperidine-4-carboxylic acid (190 mg) as a white powder.
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.[C:5]([C:8]1[CH:13]=[N:12][N:11]2[CH:14]=[C:15]([C:17]3[O:18][C:19](S(C)=O)=[N:20][N:21]=3)[CH:16]=[C:10]2[C:9]=1[NH:25][C@@H:26]1[CH2:31][CH2:30][N:29](C(OC(C)(C)C)=O)[CH2:28][C:27]1([CH3:40])[CH3:39])(=[O:7])[NH2:6]>>[CH:1]1([NH:4][C:19]2[O:18][C:17]([C:15]3[CH:16]=[C:10]4[C:9]([NH:25][C@@H:26]5[CH2:31][CH2:30][NH:29][CH2:28][C:27]5([CH3:40])[CH3:39])=[C:8]([C:5]([NH2:6])=[O:7])[CH:13]=[N:12][N:11]4[CH:14]=3)=[N:21][N:20]=2)[CH2:3][CH2:2]1
Reactant: CS(=O)c1nnc(-c2cc3c(N[C@@H]4CCN(C(=O)OC(C)(C)C)CC4(C)C)c(C(N)=O)cnn3c2)o1
Reactant: NC1CC1
Product: CC1(C)CNCC[C@H]1Nc1c(C(N)=O)cnn2cc(-c3nnc(NC4CC4)o3)cc12
Temperature: 25 °C
Reaction time: 22 h

Procedure:
Cyclopropanamine (0.067 mL, 0.966 mmol) was added to a crude solution of (4R)-tert-butyl 4-((3-carbamoyl-6-(5-(methylsulfinyl)-1,3,4-oxadiazol-2-yl)pyrrolo[1,2-b]pyridazin-4-yl)amino)-3,3-dimethylpiperidine-1-carboxylate (⅙ of the total volume from Step 5, 0.097 mmol maximum). After 22 h at room temperature, the reaction was complete. The mixture was concentrated in vacuo. The crude material was dissolved in dichloromethane (0.5 mL) and treated with trifluoroacetic acid (0.100 mL). After stirring overnight at room temperature, the Boc-deprotection was approximately 50% complete. Additional trifluoroacetic acid (0.185 mL) was added. After 30 min at room temperature, the deprotection was complete. The mixture was concentrated and triturated with ether. The ether layer was decanted. The solid residue was used in the next reaction without purification.