Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:41])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=4[O:23][C:24]([C:27]([O:29]CC)=[O:28])([CH3:26])[CH3:25])[CH2:14][C:13](=[O:32])[NH:12][CH:11]3[C:33]3[CH:38]=[C:37]([Cl:39])[CH:36]=[CH:35][C:34]=3[F:40])[C:5]2=[CH:4][CH:3]=1.[OH-].[Na+].O>CO>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:41])[C:10]3([CH:15]([C:16]4[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=4[O:23][C:24]([C:27]([OH:29])=[O:28])([CH3:25])[CH3:26])[CH2:14][C:13](=[O:32])[NH:12][CH:11]3[C:33]3[CH:38]=[C:37]([Cl:39])[CH:36]=[CH:35][C:34]=3[F:40])[C:5]2=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(Cl)cc1C1CC(=O)NC(c2cc(Cl)ccc2F)C12C(=O)Nc1cc(Cl)ccc12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)(Oc1ccc(Cl)cc1C1CC(=O)NC(c2cc(Cl)ccc2F)C12C(=O)Nc1cc(Cl)ccc12)C(=O)O
Temperature: 80 °C
Yield: 84.9 %

Procedure:
A mixture of racemic (2′R,3S,4′R)-6-chloro-4′-[5-chloro-2-(1-ethoxycarbonyl-1-methyl-ethoxy)-phenyl]-2′-(5-chloro-2-fluoro-phenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (185 mg), NaOH (120 mg), H2O (15 mL) and methanol (5 mL) was heated at 80° C. for 2 h. Then the mixture was concentrated. The remaining aqueous solution was acidified to “pH” 1 by concentrated aqueous HCl solution. The white precipitate was collected by filtration to give title compound as a white solid (150 mg).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:26]=[CH:25][C:12]([CH2:13][C:14]2[NH:18][C:17]3[CH:19]=[CH:20][C:21]([CH:23]=O)=[CH:22][C:16]=3[N:15]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].Cl.[NH2:28][CH2:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31].[Na]>C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:26]=[CH:25][C:12]([CH2:13][C:14]2[NH:18][C:17]3[CH:19]=[CH:20][C:21]([CH2:23][NH:28][CH2:29][C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])=[CH:22][C:16]=3[N:15]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCCOc1ccc(Cc2nc3cc(C=O)ccc3[nH]2)cc1
Reactant: CC(C)(C)OC(=O)CN
Agent: Cl
Agent: [Na]
Solvent: ClCCl
Product: CCCCCCCOc1ccc(Cc2nc3cc(CNCC(=O)OC(C)(C)C)ccc3[nH]2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 30 %

Procedure:
To a stirred solution of 2-(4-(heptyloxy)benzyl)-1H-benzo[d]imidazole-5-carbaldehyde INT-47 (571 mg, 1.63 mmol) in DCM (6 mL) was added tert-butyl 2-aminoacetate hydrochloride (328 mg, 1.96 mmol). After 1 h, sodium triacetoxyhydroborate (691 mg, 3.26 mmol) was added. After stirring at room temperature for 18 h, the reaction mixture was quenched with NaHCO3 (10 mL), stirred for 10 min and split through a hydrophobic frit and evaporated. The crude product was purified by column chromatography (MeOH/EA) to give 228 mg (30%) of tert-butyl 2-(((2-(4-(heptyloxy)benzyl)-1H-benzo[d]imidazol-5-yl)methyl)amino)acetate INT-48 as a pale yellow oil. LCMS-ESI (m/z) calculated for C28H39N3O3: 465; found 466 [M+H]+, tR=1.17 min (Method 3).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:13][CH2:12][CH2:11][CH:10]2[C:14]2[CH:15]=[C:16]([C:31](O)=[O:32])[CH:17]=[C:18]3[C:23]=2[O:22][C:21]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)=[CH:20][C:19]3=[O:30])[CH:5]=[C:6]([F:8])[CH:7]=1.[NH:34]1[CH2:39][CH2:38][CH:37]([OH:40])[CH2:36][CH2:35]1>>[F:8][C:6]1[CH:5]=[C:4]([N:9]2[CH2:13][CH2:12][CH2:11][CH:10]2[C:14]2[CH:15]=[C:16]([C:31]([N:34]3[CH2:39][CH2:38][CH:37]([OH:40])[CH2:36][CH2:35]3)=[O:32])[CH:17]=[C:18]3[C:23]=2[O:22][C:21]([N:24]2[CH2:25][CH2:26][O:27][CH2:28][CH2:29]2)=[CH:20][C:19]3=[O:30])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: O=C(O)c1cc(C2CCCN2c2cc(F)cc(F)c2)c2oc(N3CCOCC3)cc(=O)c2c1
Reactant: OC1CCNCC1
Product: O=C(c1cc(C2CCCN2c2cc(F)cc(F)c2)c2oc(N3CCOCC3)cc(=O)c2c1)N1CCC(O)CC1
Yield: 66.2 %

Procedure:
Title compound was prepared using an analogous procedure to that described in Example 1.01. 8-(1-(3,5-difluorophenyl)pyrrolidin-2-yl)-2-morpholino-4-oxo-4H-chromene-6-carboxylic acid (105 mg, 0.21 mmol) was reacted with piperidin-4-ol (22.48 mg, 0.22 mmol) to afford 8-(1-(3,5-difluorophenyl)pyrrolidin-2-yl)-6-(4-hydroxypiperidine-1-carbonyl)-2-morpholino-4H-chromen-4-one (75 mg, 66%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[NH:9][CH:8]=[C:7]([C:15]([OH:17])=O)[C:6]2=[O:18].C(N(CC)CC)C.P(Cl)(OC1C=CC=CC=1)(OC1C=CC=CC=1)=O.[NH2:43][N:44]1[CH2:48][CH2:47][NH:46][C:45]1=[O:49]>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[NH:9][CH:8]=[C:7]([C:15]([NH:43][N:44]1[CH2:48][CH2:47][NH:46][C:45]1=[O:49])=[O:17])[C:6]2=[O:18]
Reactant: NN1CCNC1=O
Reactant: COc1cc2[nH]cc(C(=O)O)c(=O)c2cc1OC
Agent: O=P(Cl)(Oc1ccccc1)Oc1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc2[nH]cc(C(=O)NN3CCNC3=O)c(=O)c2cc1OC
Temperature: 0 °C
Reaction time: 6 h
Yield: 43.6 %

Procedure:
To a suspension of 1,4-dihydro-6,7-dimethoxy-4-oxo-3-quinolinecarboxylic acid (39.9 g, 0.160 mol) in 3.2 l of N,N-dimethylformamide, triethylamine (32.4 g, 0.320 mol) was added. At 0° C. and under nitrogen protection, diphenyl chlorophosphate (43.0 g, 0.160 mol) was added dropwise and the mixture was stirred for 6 hours at 0° C. A solution of N-amino-imidazolidine-2-one (16.2 g, 0.160 mol) in N,N-dimethylformamide was added and stirring was continued at 0° C. overnight. The triethyl ammonium salt (26 g) was filtered off and the filtrate evaporated in vacuo. The residual oil was triturated with 1 l of ethyl acetate and 1 l of water. The resulting solid was filtered off, washed with water and ethyl acetate and dried in vacuo. The crude product was stirred with 270 ml of 0.2N sodium hydroxide solution of 2 days, filtered off, washed with water and dried in vacuo to give 23.2 g of the title compound, melting point>300° C.
Reaction SMILES: BrBr.[C:3]([O:6][C:7](Br)=[C:8]([Br:16])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])(=O)C.[CH3:18][OH:19]>C(Cl)(Cl)(Cl)Cl.O>[CH3:3][O:6][CH:7]([O:19][CH3:18])[CH:8]([Br:16])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CCCCCCCC(Br)=C(Br)OC(C)=O
Reactant: CO
Agent: BrBr
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Product: CCCCCCCC(Br)C(OC)OC
Reaction time: 48 h

Procedure:
The oil is mixed with 200 ml of carbon tetrachloride and cooled in an ice bath. Bromine, diluted with an equal volume of carbon tetrachloride, is added slowly with agitation while maintaining the temperature below 10°C. Bromine addition is stopped when the bromine is no longer decolorized. To the brominated mixture, containing 1,2-dibromononen-1-yl acetate, is added 500 ml of methyl alcohol with shaking and cooling. The mixture is allowed to stand two days with occasional shaking and then diluted with 1.5 liters of water. The separated oil is washed with 5% sodium carbonate solution until free of acid and then fractionally distilled in the presence of a small amount of sodium carbonate to yield 2-bromo-nonanal dimethyl acetal.
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([O:17][CH:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[C:14](O)=[O:15])=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.[NH2:24][C:25]1[N:30]=[C:29]([CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH:28]=[CH:27][CH:26]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.CN1CCOCC1>CN(C=O)C>[CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([O:17][CH:18]3[CH2:19][CH2:20][O:21][CH2:22][CH2:23]3)[C:14]([NH:24][C:25]3[N:30]=[C:29]([CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH:28]=[CH:27][CH:26]=3)=[O:15])=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1
Reactant: CCOC(=O)Cc1cccc(N)n1
Reactant: O=C(O)C(OC1CCOCC1)c1ccc(S(=O)(=O)C2CC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1cccc(NC(=O)C(OC2CCOCC2)c2ccc(S(=O)(=O)C3CC3)cc2)n1
Yield: 46.2 %

Procedure:
The compound of example A9 was obtained by similar method described in example A1 using 2-(4-cyclopropanesulfonyl-phenyl)-2-[(tetrahydro-pyran-4-yloxy)]-acetic acid (Preparation 4; 0.990 g, 2.91 mmol), ethyl 2-(6-amino-2-pyridyl)acetate (0.35 g, 1.94 mmol), HOBt (0.65 g, 4.81 mmol), and EDCl (0.92 g, 4.81 mmol), N-methyl morpholine (0.64 mL, 5.83 mmol) in DMF (25 mL) to provide the title compound (0.45 g).
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][C:6]([CH2:9][O:10][CH3:11])=[CH:5][C:3]=1[NH2:4].Cl[CH2:13][CH:14]=[O:15].C(=O)([O-])[O-].[Na+].[Na+]>>[CH3:1][C:2]1[CH:8]=[CH:7][C:6]([CH2:9][O:10][CH3:11])=[CH:5][C:3]=1[NH:4][CH2:13][CH:14]=[O:15]
Reactant: COCc1ccc(C)c(N)c1
Reactant: O=CCCl
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: COCc1ccc(C)c(NCC=O)c1
Temperature: 150 °C

Procedure:
2-Methyl-5-methoxymethylaniline )0.3 mole), the dimethyl acetal of 2-chloroacetaldehyde (0.3 mole) and sodium carbonate (20 grams) are charged into a glass reaction flask equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture is heated to about 150°C for a period of about 8 hours. After this time the mixture is filtered and the filtrate is distilled to yield the desired product the dimethyl acetal of 2-(2-methyl-5-methoxymethylanilino)acetaldehyde.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[NH:7][CH2:6][C:5]=12.C(N(CC)C(C)C)(C)C.[C:24]1([CH2:30][C:31]2[CH:48]=[CH:47][CH:46]=[CH:45][C:32]=2[C:33]([NH:35][C:36]2[CH:44]=[CH:43][C:39]([C:40](Cl)=[O:41])=[CH:38][CH:37]=2)=[O:34])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[Si]([O-])([O-])([O-])[O-].[Mg+2].[Mg+2]>C(Cl)Cl>[CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[N:7]([C:40]([C:39]3[CH:38]=[CH:37][C:36]([NH:35][C:33](=[O:34])[C:32]4[CH:45]=[CH:46][CH:47]=[CH:48][C:31]=4[CH2:30][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:44][CH:43]=3)=[O:41])[CH2:6][C:5]=12
Reactant: c1ccc2c(c1)Cn1cccc1CN2
Reactant: O=C(Cl)c1ccc(NC(=O)c2ccccc2Cc2ccccc2)cc1
Agent: [Mg+2]
Agent: [O-][Si]([O-])([O-])[O-]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(Nc1ccc(C(=O)N2Cc3cccn3Cc3ccccc32)cc1)c1ccccc1Cc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 97.3 %

Procedure:
To a solution of 0.75 g of 10, 11-dihydro-5H-pyrrolo [2, 1-c][1, 4]benzodiazepine and 0.57 g of N, N-diisopropylethylamine in 50 ml of methylene chloride is added 1.53 g of 4-[[2-(phenylmethyl)benzoyl]amino]-benzoyl chloride followed by stirring at room temperature for 18 hours. The reaction mixture is washed with water and saturated aqueous NaHCO3 and the organic layer dried(Na2SO4). The organic layer is passed through hydrous magnesium silicate and the filtrate concentrated in vacuo to give a residue which is dissolved in methylene chloride and passed through hydrous magnesium silicate two additional times to give upon concentration in vacuo to give 1.97 g of the desired product as an amorphous solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[CH:14][C:13]2[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[CH2:6][C:5]=2[CH:4]=1.C([Li])CCC.[C:21]([O:24]CC)(=[O:23])C>C1COCC1.O>[CH3:1][O:2][C:3]1[CH:15]=[CH:14][C:13]2[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[CH:6]([C:21]([OH:24])=[O:23])[C:5]=2[CH:4]=1
Reactant: COc1ccc2c(c1)Cc1ccccc1-2
Reactant: CCOC(C)=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc2c(c1)C(C(=O)O)c1ccccc1-2
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 66.7 %

Procedure:
A solution of 2-methoxyfluorene (2.7 g, 13.8 mmol) in 50 mL of THF at -78° C. was charged with n-butyl lithium (0.93 g, 14.5 mmol). The reaction mixture was stirred for 15 min then CO, gaseous (5 g, 113.6 mmol) was introduced via cannula over a period of 15 min at -78° C. The reaction mixture was warmed up to room temperature and stirred for additional 2 hr until a colorless solution was obtained. The reaction mixture was diluted with 100 mL of water and 100 mL of ethyl acetate. The layers were separated, the aqueous phase was washed with ethyl acetate (5×25 mL) and acidified to pH 1 with concentrated hydrochloric acid. The precipitate was filtered off, washed with water and dried to afford 2.2 g (66.7%) of 2-methoxy-9-fluorenecarboxylic acid as colorless solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:15]([NH2:17])=[N:14][CH:13]=[N:12][C:11]=3[S:10][CH:9]=2)=[CH:4][CH:3]=1.[F:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][C:20]=1[N:29]=[C:30]=[O:31]>ClCCl>[NH2:17][C:15]1[C:16]2[C:8]([C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:30]([NH:29][C:20]4[CH:21]=[C:22]([C:25]([F:26])([F:28])[F:27])[CH:23]=[CH:24][C:19]=4[F:18])=[O:31])=[CH:7][CH:6]=3)=[CH:9][S:10][C:11]=2[N:12]=[CH:13][N:14]=1
Reactant: O=C=Nc1cc(C(F)(F)F)ccc1F
Reactant: Nc1ccc(-c2csc3ncnc(N)c23)cc1
Solvent: ClCCl
Product: Nc1ncnc2scc(-c3ccc(NC(=O)Nc4cc(C(F)(F)F)ccc4F)cc3)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.9 %

Procedure:
A suspension of Example 58D (0.04 g, 0.165 mmol) in dichloromethane (3 mL) under nitrogen was cooled to 0° C., treated with 1-fluoro-2-isocyanato-4-(trifluoromethyl)benzene (0.024 mL, 0.165 mmol), and stirred overnight while gradually warming to room temperature. The suspension was filtered and the filter cake was dried in a vacuum oven to provide 0.056 g of the desired product. MS(ESI(+)) m/e 448 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ 9.40 (s, 1H); 8.98 (d, J=2.7 Hz, 1H); 8.63 (dd, J=7.2 Hz, 2.1 Hz, 1H); 8.35 (s, 1H); 7.63 (d, J=8.7 Hz, 2H); 7.55-7.39 (m, 5H).
Reaction SMILES: [SH:1][C:2]1[N:7]=[C:6]([OH:8])[CH:5]=[C:4]([C:9]([F:12])([F:11])[F:10])[N:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:20][C:21]1[C:22]([CH2:29][CH3:30])=[N:23][CH:24]=[CH:25][C:26]=1[CH2:27][CH3:28]>CN(C=O)C>[CH2:29]([C:22]1[C:21]([CH2:20][S:1][C:2]2[N:7]=[C:6]([OH:8])[CH:5]=[C:4]([C:9]([F:12])([F:10])[F:11])[N:3]=2)=[C:26]([CH2:27][CH3:28])[CH:25]=[CH:24][N:23]=1)[CH3:30]
Reactant: Oc1cc(C(F)(F)F)nc(S)n1
Reactant: CCc1ccnc(CC)c1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCc1ccnc(CC)c1CSc1nc(O)cc(C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.5 %

Procedure:
2-sulfanyl-6-(trifluoromethyl)pyrimidin-4-ol (592 mg, 3.0 mmol) was dissolved in anhydrous DMF (25 mL), and then potassium carbonate (1.25 g, 9.0 mmol) and 3-(bromomethyl)-2,4-diethylpyridine (3.6 mmol) in DMF (10 mL) were added. The mixture was stirred overnight at room temperature. The solid was removed by filtration and washed with methanol, and the filtrate was evaporated. The residue was dissolved in DCM/MeOH and purified on silica gel using 3-12% DCM/MeOH to afford 2-{[(2,4-diethylpyridin-3-yl)methyl]sulfanyl}-6-(trifluoromethyl)pyrimidin-4-ol (860 mg, 69% yield for 2 steps); 1H NMR (400 MHz, DMSO-d6): δ 1.13-1.20 (m, 6H), 2.67 (q, J=7.5 Hz, 2H), 2.81 (q, J=7.5 Hz, 2H), 4.54 (s, 2H), 6.67 (s, 1H), 7.10 (d, J=5.1 Hz, 1H), 8.34 (d, J=5.1 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:14][C@@H:13]3[C@H:9]2[CH2:10][NH:11][CH2:12]3)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[C:22]([CH3:28])([CH3:27])[C:23]([O:25][CH3:26])=[O:24]>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:14][C@@H:13]3[C@H:9]2[CH2:10][N:11]([C:22]([CH3:28])([CH3:27])[C:23]([O:25][CH3:26])=[O:24])[CH2:12]3)=[CH:4][CH:3]=1
Reactant: Clc1ccc([C@@H]2C[C@H]3CNC[C@H]32)cc1
Reactant: COC(=O)C(C)(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)C(C)(C)N1C[C@@H]2C[C@@H](c3ccc(Cl)cc3)[C@@H]2C1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
To a solution of (1R*,5S*,6R*)-6-(4-chlorophenyl)-3-azabicyclo[3.2.0]heptane (Steiner, G., et al., Heterocycles, 1995, 40, 319-330) (1.0 g, 1.3 mmol) in N,N-dimethylformamide (40 mL) were added potassium carbonate (1.0 g, 7.5 mmol) and methyl 2-bromo-2-methylpropanoate (0.4 mL, 3.0 mmol, Aldrich). After stirring at 80° C. for 16 hours, the reaction mixture was cooled and quenched with water (30 mL). The aqueous layer was extracted with ethyl acetate (3×50 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was then purified by column chromatography using an Analogix® Intelliflash280™ (SiO2, 0-50% of ethyl acetate in hexanes) to obtain the titled compound. MS (ESI+) m/z 308 (M+H)+.
Reaction SMILES: [CH3:1][NH:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]2[CH:18]=[CH:17][C:12]3[NH:13][C:14](=[O:16])[O:15][C:11]=3[CH:10]=2)[CH2:5][CH2:4]1.[Cl:19][C:20]1[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:21]=1[CH2:27][CH2:28][CH:29]=O.Cl>>[Cl:19][C:20]1[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:21]=1[CH2:27][CH2:28][CH2:29][N:2]([CH3:1])[C@H:3]1[CH2:4][CH2:5][C@H:6]([C:9]2[CH:18]=[CH:17][C:12]3[NH:13][C:14](=[O:16])[O:15][C:11]=3[CH:10]=2)[CH2:7][CH2:8]1
Reactant: CN[C@H]1CC[C@H](c2ccc3[nH]c(=O)oc3c2)CC1
Reactant: O=CCCc1ccc(Cl)cc1Cl
Agent: Cl
Product: CN(CCCc1ccc(Cl)cc1Cl)[C@H]1CC[C@H](c2ccc3[nH]c(=O)oc3c2)CC1

Procedure:
Condensation of 15 (550 mg, 1.9 mmol) and 3-(2,4-dichlorophenyl)-propionaldehyde (390 mg, 1.9 mmol) following the procedure described in Example 45, Step 2, followed by conversion to the HCl salt, gave 6-(trans-4-{[3-(2,4-dichlorophenyl)propyl]methylamino}cyclohexyl)-3H-benzoxazol-2-one (446 mg, 50%), as an off-white solid: mp 273-279° C.; IR (KBr): 2949, 1775, 1500, 1474 cm−1; 1H NMR(500 MHz, DMSO-d6): δ 11.49 (s, 1H), 10.01 (s, 1H), 7.61 (d, J=2 Hz, 1H), 7.47-7.41 (m, 2H), 7.17 (s, 1H), 7.00 (s, 2H), 3.34-3.29 (m, 1H), 3.22-3.17 (m, 1H), 3.11-3.03 (m, 1H), 2.79-2.73 (m, 2H), 2.71 (d, J=5 Hz, 3H), 2.59-2.48 (m, 1H), 2.14-2.06 (m, 2H), 2.03-1.97 (m, 2H), 1.94-1.88 (m, 2H), 1.69-1.50 (m, 4H); ESI (m/z): 433 [M+H]+; HPLC: method A, 6.78 minutes (>99%); Anal. Calcd for C23H26Cl2N2O2.HCl: C, 58.80; H, 5.79; N, 5.96. Found: C, 58.62; H, 5.76; N, 5.89.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:22]3[C:21](=O)[CH2:20][CH2:19][CH2:18][C:17]=3[NH:16][C:15]3[CH2:14][CH2:13][CH2:12][C:11](=[O:24])[C:10]2=3)[CH:5]=[CH:6][C:7]=1[F:8].[BH4-].[Na+].C(O)C>N1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:10]3[C:11](=[O:24])[CH2:12][CH2:13][CH2:14][C:15]=3[NH:16][C:17]3[CH2:18][CH2:19][CH2:20][CH2:21][C:22]2=3)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=C1CCCC2=C1C(c1ccc(F)c(Br)c1)C1=C(CCCC1=O)N2
Agent: [BH4-]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CCO
Product: O=C1CCCC2=C1C(c1ccc(F)c(Br)c1)C1=C(CCCC1)N2
Temperature: 70 °C
Yield: 63.4 %

Procedure:
A mixture of 9-(3-bromo-4-fluorophenyl)-3,4,6,7,9,10-hexahydro-1,8(2H,5H)-acridinedione (1.8 g), sodium borohydride (1.74 g), ethanol (40 mL) and pyridine (14 mL) was heated at 70° C. for three and one half hours. The solvent was removed, the residue partitioned between water and ethyl acetate, the organic layer dried and the solvent removed. Chromatography (methylene chloride/ethyl acetate; 7/3) gave the title compound (1.1 g), as a yellow solid, mp 254°-257° C.; NMR: 1.41-1.51 (m,3, CH2), 1.60-1.88 (m,5, CH2), 2.03-2.13 (m,4, CH2), 2.38-2.44 (m,2, CH2), 4.18 (s,1, CH), 7.13-7.24 (m,2, Ar), 7.38 (dd,1, J=6.9, 2.0, Ar), 8.45 (s,1, NH); (CI, CH4) MS: m/z=378(M+1). Analysis for C19H19FBr: Calculated C, 60.65; H, 5.09; N, 3.72; Found: C, 60.68; H, 5.09; N, 3.65.
Reaction SMILES: [OH-].[K+].[NH2:3][C:4]1[C:9]([C:10]([O:12]C)=[O:11])=[CH:8][C:7]([C:14]2[CH:15]=[N:16][N:17]([CH:19]3[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]3)[CH:18]=2)=[CH:6][N:5]=1.Cl>CO.O>[NH2:3][C:4]1[C:9]([C:10]([OH:12])=[O:11])=[CH:8][C:7]([C:14]2[CH:15]=[N:16][N:17]([CH:19]3[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]3)[CH:18]=2)=[CH:6][N:5]=1
Reactant: COC(=O)c1cc(-c2cnn(C3CCN(C)CC3)c2)cnc1N
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CN1CCC(n2cc(-c3cnc(N)c(C(=O)O)c3)cn2)CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 77.1 %

Procedure:
Potassium hydroxide (0.773 g) was added to a cold solution of methyl 2-amino-5-[1-(1-methyl-4-piperidyl)pyrazol-4-yl]pyridine-3-carboxylate (2.172 g) in methanol (50 ml) and water (5 ml). The resulting mixture was stirred at room temperature during 48 hours. A 2N aqueous hydrochloric acid solution (6.89 ml) was added. The mixture was evaporated to dryness, dried, diluted with water (50 ml) and purified on OASIS resine (ion exchange resin Oasis, HLB 30 μM, Waters) (150 ml). The salts were eluted with water and the product was eluted with 50% Methanol/water. The solvents were evaporated to dryness. The residue was dried at 50° C. to give 2-amino-5-[1-(1-methyl-4-piperidyl)pyrazol-4-yl]pyridine-3-carboxylic acid (1.600 g). NMR Spectrum: (DMSO-d6) 2.02-2.13 (m, 4H), 2.27-2.38 (m, 2H), 2.35 (s, 3H), 2.97-3.06 (m, 2H), 4.13-4.22 (m, 1H), 7.21 (bs, 2H), 7.80 (s, 1H), 8.18 (s, 1H), 8.19 (d, 1H), 8.39 (d, 1H); Mass spectrum: M+H+ 302
Reaction SMILES: [OH-].[Li+].[C:3]([O:7][C:8]([N:10]1[CH2:15][CH:14]([C:16]2[CH:21]=[C:20]([F:22])[CH:19]=[C:18]([F:23])[CH:17]=2)[N:13]([CH2:24][C:25]([O:27]C)=[O:26])[C:12](=[O:29])[C@@H:11]1[CH2:30][CH:31]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1)=[O:9])([CH3:6])([CH3:5])[CH3:4]>O.C1COCC1>[C:3]([O:7][C:8]([N:10]1[CH2:15][CH:14]([C:16]2[CH:21]=[C:20]([F:22])[CH:19]=[C:18]([F:23])[CH:17]=2)[N:13]([CH2:24][C:25]([OH:27])=[O:26])[C:12](=[O:29])[C@@H:11]1[CH2:30][CH:31]1[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37]1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: COC(=O)CN1C(=O)[C@H](CC2CCCCCC2)N(C(=O)OC(C)(C)C)CC1c1cc(F)cc(F)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CC(c2cc(F)cc(F)c2)N(CC(=O)O)C(=O)[C@@H]1CC1CCCCCC1

Procedure:
10 mg (0.42 mmol) lithium hydroxide in 800 μl water were added to 105 mg (0.21 mmol) (2S)-tert-butyl-2-(cycloheptylmethyl)-5-(3,5-difluorophenyl)-4-(2-methoxy-2-oxoethyl)-3-oxopiperazine-1-carboxylate in 2 ml THF. After 2 h tetrahydrofuran was distilled off and the aqueous solution was neutralised with hydrochloric acid. The aqueous phase was extracted with ethyl acetate. The ethyl acetate phase was dried and evaporated down.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:9]2[O:13][C:12](=[O:14])[N:11]([CH3:15])[N:10]=2)[CH:5]=[CH:6][C:7]=1[CH3:8].C[Sn](C)(C)[C:18]1[N:19]=[CH:20][C:21]([NH2:24])=[N:22][CH:23]=1.NC1C=NC(Br)=CN=1>C1COCC1.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>[NH2:24][C:21]1[N:22]=[CH:23][C:18]([C:2]2[CH:3]=[C:4]([C:9]3[O:13][C:12](=[O:14])[N:11]([CH3:15])[N:10]=3)[CH:5]=[CH:6][C:7]=2[CH3:8])=[N:19][CH:20]=1
Reactant: C[Sn](C)(C)c1cnc(N)cn1
Reactant: Cc1ccc(-c2nn(C)c(=O)o2)cc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Nc1cnc(Br)cn1
Solvent: C1CCOC1
Product: Cc1ccc(-c2nn(C)c(=O)o2)cc1-c1cnc(N)cn1
Temperature: 75 °C

Procedure:
To a solution of 5-(3-bromo-4-methylphenyl)-3-methyl-1,3,4-oxadiazol-2(3H)-one (500 mg, 1.76 mmol) and 5-(trimethyl stannyl)-pyrazine-2-amine (683 mg, 2.65 mmol, prepared from 2-amino-5-bromopyrazine by following the procedure described in Chem. Eur. J. 2000, 6, 4132) in THF (10 mL) was added Pd(PPh3)4 (100 mg, 0.088 mmol). The resulting mixture was thoroughly deoxygenated by subjecting to vacuum/nitrogen cycle three times and the reaction mixture was heated at 75° C. for 15 h under nitrogen atmosphere. The resulting mixture was cooled to room temperature and filtered through celite. The filtrate was concentrated under vacuum and the crude product was purified by flash column chromatography over silica gel using ethyl acetate-hexane mixture as eluent to afford 250 mg of the intermediate 15b as a white solid. 1HNMR (400 MHz, DMSO-d6) δ 8.07 (s, 1H), 7.99 (s, 1H), 7.69 (d, J=2.0 Hz, 1H), 7.64 (dd, J=8.0, 2.0 Hz, 1H), 7.44 (d, J=8.0 Hz, 1H), 6.62 (s, 2H, D2O exchangeable), 3.36 (s, 3H), 2.35 (s, 3H); ESI-MS (m/z) 284 (MH)+.