Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:4]=1[O:10][CH2:11][CH2:12][CH2:13][O:14][CH3:15].[Br:16]N1C(=O)CCC1=O>CC#N>[Br:16][C:6]1[CH:5]=[C:4]([O:10][CH2:11][CH2:12][CH2:13][O:14][CH3:15])[C:3]([O:2][CH3:1])=[CH:8][C:7]=1[CH3:9]
Reactant: O=C1CCC(=O)N1Br
Reactant: COCCCOc1ccc(C)cc1OC
Solvent: CC#N
Product: COCCCOc1cc(Br)c(C)cc1OC
Reaction time: 2 h

Procedure:
To a solution of 2-methoxy-1-(3-methoxy-propoxy)-4-methyl-benzene (2.00 g, 9.51 mmol) in MeCN (30 mL) is added N-bromosuccinimide (1.96 g, 10.5 mmol) at room temperature. Stirring is continued for 2 hrs, followed by evaporation of the solvent. The title compound is obtained after flash chromatography on silica gel (hexane/AcOEt 6:1) as an oil. MS: 289.0/291.0 [M]+. tR (HPLC, Nucleosil C18HD column, 20-100% CH3CN/H2O/6 min, 100% CH3CN/2 min, CH3CN and H2O containing 0.1% TFA, flow: 1 mL/min): 5.04 min. 1H-NMR (CDCl3): δ 2.13 (m, 2H), 2.36 (s, 3H), 3.39 (s, 3H), 3.58 (m, 2H), 3.87 (s, 3H), 4.12 (m, 2H), 6.77 (s,1H), 7.08 (s, 1H) ppm.
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[NH:7][C@H:8]1[C@H:12]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[CH2:11][N:10]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].I[CH2:31][CH3:32]>CN(C=O)C>[C:1]([O:5][C:6](=[O:27])[N:7]([C@H:8]1[C@H:12]([C:13]2[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=2)[CH2:11][N:10]([CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:9]1)[CH2:31][CH3:32])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CN(Cc2ccccc2)C[C@H]1c1ccc(Cl)cc1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN(C(=O)OC(C)(C)C)[C@@H]1CN(Cc2ccccc2)C[C@H]1c1ccc(Cl)cc1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
A mixture of 4.2 g (10.9 mmol) [(3S,4R)-1-Benzyl-4-(4-chloro-phenyl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester, 521 mg (13 mmol) NaH (60%) and 2.54 g (16.3 mmol) iodoethane in 40 mL DMF was stirred for 1 h at 60° C. and evaporated to dryness. The residue was taken up in ethyl acetate and water and extracted further with ethyl acetate. The combined organic layers were washed with brine, dried with Na2SO4, filtered and evaporated to dryness. The residue was purified by column chromatography on silica eluting with a gradient formed from ethyl acetate and heptane to yield after evaporation of the product containing fractions 2.5 g (55%) of the title compound as light yellow viscous oil. MS m/e: 415.3 [M+H]+.
Reaction SMILES: B1(C)OC(C2C=CC=CC=2)(C2C=CC=CC=2)[C@@H]2N1CCC2.S(C)C.[C:25]([C:28]1[CH:37]=[CH:36][C:31]([C:32]([O:34][CH3:35])=[O:33])=[CH:30][CH:29]=1)(=[O:27])[CH3:26].CO>C1(C)C=CC=CC=1.C1COCC1>[OH:27][C@H:25]([C:28]1[CH:37]=[CH:36][C:31]([C:32]([O:34][CH3:35])=[O:33])=[CH:30][CH:29]=1)[CH3:26]
Reactant: COC(=O)c1ccc(C(C)=O)cc1
Agent: CB1OC(c2ccccc2)(c2ccccc2)[C@H]2CCCN12
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1ccc([C@H](C)O)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of (R)-2-methyl-CBS-oxazaborolidine (7.5 mL of a 1 M soln in toluene, 7.5 mmol) in toluene (200 mL) was cooled in ice-salt bath (bath temp: −10° C.) under N2. To the solution was added BH3.SMe2 (17.1 mL, 180 mmol) over 3 min. Methyl 4-acetylbenzoate (26.4 g, 148 mmol) in THF (180 mL) was then added over 3 h via syringe pump. The bath temp remained at −10° C. throughout the addition. The reaction mixture was stirred for an additional 30 min, and then MeOH (100 mL) was added over 30 min (bath temp: −10° C.). The ice in the bath was allowed to melt and the reaction mixture was stirred overnight at RT. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with EtOAc (500 mL). The organic solution was washed with 0.1 N HCl aq. (300 mL×4), 5% NaHCO3 (300 mL×2), saturated NaCl (300 mL×2) and dried over Na2SO4. Evaporation of the solvent afforded the title compound. MS (m/z): 181.1 (m+H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([C:10]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH:20]4[CH2:22][O:21]4)=[CH:14][CH:13]=3)=[O:11])[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[C:23]([NH2:27])([CH3:26])([CH3:25])[CH3:24]>C(O)C>[CH3:24][C:23]([NH:27][CH2:22][CH:20]([OH:21])[CH2:19][O:18][C:15]1[CH:14]=[CH:13][C:12]([C:10]([C:5]2[CH:6]=[CH:7][CH:8]=[C:9]3[C:4]=2[CH:3]=[CH:2][NH:1]3)=[O:11])=[CH:17][CH:16]=1)([CH3:26])[CH3:25]
Reactant: O=C(c1ccc(OCC2CO2)cc1)c1cccc2[nH]ccc12
Reactant: CC(C)(C)N
Solvent: CCO
Product: CC(C)(C)NCC(O)COc1ccc(C(=O)c2cccc3[nH]ccc23)cc1

Procedure:
A solution of 4.65 g of the product of Step A, 100 ml of ethanol and 9.94 ml of tert-butylamine was stirred at reflux for 2 hours and the solution was distilled to dryness. The 6.83 g of residue were chromatographed on silica (eluant: ethyl acetate triethylamine (9-1)) to obtain 4.77 g of the desired product.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:12]([O:14]C)=[O:13])[C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10]=2[CH:11]=1.[Li+].[OH-].O>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([C:12]([OH:14])=[O:13])[C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10]=2[CH:11]=1
Reactant: COC(=O)c1cc(F)cc2c1CCCC2
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cc(F)cc2c1CCCC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.9 %

Procedure:
A mixture of methyl 3-fluoro-5,6,7,8-tetrahydronaphthalene-1-carboxylate (37 mg, 0.18 mmol), LiOH (27 mg, 1.1 mmol), water (2 mL) and THF (1 mL) was stirred at room temperature overnight and then partitioned between ether and water. The aqueous layer was extracted thrice with ether and then repeatedly with ethyl acetate. The combined organic solutions were dried over MgSO4 and the solvent was removed by evaporation. There was obtained 15 mg (43%) of 3-fluoro-5,6,7,8-tetrahydronaphthalene-1-carboxylic acid as a white solid. 1H NMR (500 MHz, CD3CO CD3): 1.8 (m, 4H), 2.8 (m, 2H), 3.1 (m, 2H), 7.0 (m, 1H), 7.6 (m, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:12][CH3:13])[C:9](O)=[O:10])=[CH:4][CH:3]=1.CCOC(C)=O>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([CH2:12][CH3:13])[CH2:9][OH:10])=[CH:6][CH:7]=1
Reactant: CCC(C(=O)O)c1ccc(Br)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCC(CO)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 93.8 %

Procedure:
To a solution of 75B (96 mg, 0.4 mmol) in 3 mL THF was added BH3 (2M in THF, 0.5 mL, 1 mmol). The solution was stirred at rt for 16 h. EtOAc (20 mL) was added, and the organic phase washed with 1M H3PO4, sat. NaHCO3 and brine, dried (Na2SO4), and concentrated. Purification via flash chromatography (0-30% EtOAc in hexanes) gives 75C (86 mg, 96%). MS (ESI) m/z 211.2(M−H2O)+.
Reaction SMILES: C(=O)([O-])O.[Na+].CS(C)=O.Cl.[OH:11][NH2:12].[CH2:13]([C:17]1[N:18]=[C:19]([CH3:45])[N:20]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][N:40]=2)[C:21](=[O:38])[C:22]=1[CH2:23][C:24]1[CH:25]=[CH:26][C:27]([C:30]2[CH:37]=[CH:36][CH:35]=[CH:34][C:31]=2[C:32]#[N:33])=[N:28][CH:29]=1)[CH2:14][CH2:15][CH3:16]>C(OCC)(=O)C.O>[CH2:13]([C:17]1[N:18]=[C:19]([CH3:45])[N:20]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][N:40]=2)[C:21](=[O:38])[C:22]=1[CH2:23][C:24]1[CH:25]=[CH:26][C:27]([C:30]2[CH:37]=[CH:36][CH:35]=[CH:34][C:31]=2[C:32](=[N:12][OH:11])[NH2:33])=[N:28][CH:29]=1)[CH2:14][CH2:15][CH3:16]
Reactant: NO
Reactant: CCCCc1nc(C)n(-c2ccccn2)c(=O)c1Cc1ccc(-c2ccccc2C#N)nc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CS(C)=O
Product: CCCCc1nc(C)n(-c2ccccn2)c(=O)c1Cc1ccc(-c2ccccc2C(N)=NO)nc1
Temperature: 40 °C
Reaction time: 1 h
Yield: 93 %

Procedure:
Process 2: Sodium hydrogen carbonate (2.02 mg, 24.0 mmol) was added to a dimethyl sulfoxide (20 mL) solution of hydroxyl amine hydrochloride (1.42 g, 20.4 mmol), and the reaction solution was stirred at 40° C. for 1 hour. The reaction solution was added a dimethyl sulfoxide (3 mL) solution of 2-{5-{[4-butyl-2-methyl-6-oxo-1-(pyridin-2-yl)-1,6-dihydropyrimidin-5-yl]methyl}pyridin-2-yl}benzonitrile (430 mg, 0.987 mmol), and stirred at 90° C. for 19 hours. The reaction solution was added water and extracted with ethyl acetate. The organic layer was combined, washed with water and brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residues obtained were subjected to silica gel column chromatography (ethyl acetate), to obtain 2-{5-{[4-butyl-2-methyl-6-oxo-1-(pyridin-2-yl)-1,6-dihydropyrimidin-5-yl]methyl}pyridin-2-yl}-N′-hydroxybenzimidamide (430 mg, 93%) as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[F:10][CH2:11][CH2:12]I.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[F:10][CH2:11][CH2:12][O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6]
Reactant: O=Cc1cccc(O)c1
Reactant: FCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1cccc(OCCF)c1
Temperature: 70 °C

Procedure:
A mixture of commercially available 3-hydroxybenzaldehyde (2.000 g; 16.40 mmol), 1-fluoro-2-iodoethane (3.849 g; 22.10 mmol), and K2CO3 (4.527 g; 32.80 mmol) in anh. DMF (30 ml) was heated to 70° C., under nitrogen, for 3 h. After cooling to rt, the reaction mixture was filtered over a pad of celite. Et2O was added and the organic layer was washed with water, dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure affording 3-(2-fluoroethoxy)benzaldehyde as a green oil. LC-MS (conditions A): tR=0.62 min.; no ionisation.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8]>CO>[OH:1][C@H:2]1[CH2:3][NH:4][CH2:5][C@@H:6]([C:7]([O:9][CH3:10])=[O:8])[CH2:11]1
Reactant: COC(=O)c1cncc(O)c1
Solvent: CO
Product: COC(=O)[C@@H]1CNC[C@H](O)C1

Procedure:
A solution of methyl 5-hydroxynicotinate (1.50 g) in MeOH (30 ml) was hydrogenated (ca. 4 atm) for 3 days in a Parr low-pressure hydrogenation apparatus with a 5 wt. % Rh on Al2O3 catalyst (300 mg) at 70° C. Rh on Al2O3 catalyst was filtered off and the filtrate was concentrated in vacuo to give the crude methyl cis-5-hydroxypiperidine-3-carboxylate as a pale yellow oil.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([CH3:12])[CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:13][C:14]2[CH:18]=[C:17]([CH3:19])[NH:16][N:15]=2)[N:3]=1.[CH3:20][OH:21]>>[CH3:20][O:21][C:2]1[C:11]2[C:6](=[C:7]([CH3:12])[CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:13][C:14]2[CH:18]=[C:17]([CH3:19])[NH:16][N:15]=2)[N:3]=1
Reactant: Cc1cc(Nc2cc3c(C)cccc3c(Cl)n2)n[nH]1
Reactant: CO
Product: COc1nc(Nc2cc(C)[nH]n2)cc2c(C)cccc12

Procedure:
Similar procedure as described in example 10 was used, starting from methanol and (1-chloro-5-methyl-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine to give (1-methoxy-5-methyl-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS m/e 271(MH+).
Reaction SMILES: C([O:8][C:9]([C@H:11]1[CH2:15][CH2:14][CH2:13][C@@H:12]1[C:16]([N:18]1[CH2:23][CH2:22][N:21]([C:24]2[CH:29]=[CH:28][C:27]([NH:30][C:31]([C:33]3[N:34]=[C:35]([C:42]4[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=4)[O:36][C:37]=3[C:38]([F:41])([F:40])[F:39])=[O:32])=[C:26]([F:48])[CH:25]=2)[CH2:20][CH2:19]1)=[O:17])=[O:10])C1C=CC=CC=1>CO.[OH-].[Li+].O>[F:48][C:26]1[CH:25]=[C:24]([N:21]2[CH2:22][CH2:23][N:18]([C:16]([C@H:12]3[CH2:13][CH2:14][CH2:15][C@@H:11]3[C:9]([OH:10])=[O:8])=[O:17])[CH2:19][CH2:20]2)[CH:29]=[CH:28][C:27]=1[NH:30][C:31]([C:33]1[N:34]=[C:35]([C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=2)[O:36][C:37]=1[C:38]([F:40])([F:41])[F:39])=[O:32]
Reactant: O=C(Nc1ccc(N2CCN(C(=O)[C@H]3CCC[C@@H]3C(=O)OCc3ccccc3)CC2)cc1F)c1nc(-c2ccccc2)oc1C(F)(F)F
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(Nc1ccc(N2CCN(C(=O)[C@H]3CCC[C@@H]3C(=O)O)CC2)cc1F)c1nc(-c2ccccc2)oc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To the solution of (1S,2S)-2-(4-{3-fluoro-4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-phenyl}-piperazine-1-carbonyl)-cyclopentanecarboxylic acid benzyl ester in methanol, lithium hydroxide and water were added. The so formed mixture was stirred at 25° C. overnight. Solvent was removed and the residue was resuspended in ethyl acetate and water. Citric acid was added to acidify the mixture. Organic layer was concentrated and the residue was purified on a reverse phase HPLC system to give (1S,2S)-2-(4-{3-fluoro-4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-phenyl}-piperazine-1-carbonyl)-cyclopentanecarboxylic acid as a white solid. LCMS calcd for C28H26F4N4O5 (m/e) 574, obsd 575 (M+H).
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[NH:10][C:11]1[N:12]=[CH:13][C:14]2[CH2:20][N:19]([C:21]([O:23][CH2:24][CH2:25][CH2:26]Cl)=[O:22])[CH2:18][CH2:17][C:15]=2[N:16]=1.[C-:28]#[N:29].[Na+]>CN(C)C=O.ClCCl>[CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[NH:10][C:11]1[N:12]=[CH:13][C:14]2[CH2:20][N:19]([C:21]([O:23][CH2:24][CH2:25][CH2:26][C:28]#[N:29])=[O:22])[CH2:18][CH2:17][C:15]=2[N:16]=1
Reactant: O=C(OCCCCl)N1CCc2nc(NC3Cc4ccccc4C3)ncc2C1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: N#CCCCOC(=O)N1CCc2nc(NC3Cc4ccccc4C3)ncc2C1
Temperature: 25 °C

Procedure:
Heat a solution of 3-chloropropyl 2-(indan-2-ylamino)-7,8-dihydro-5H-pyrido[4,3-d]pyrimidine-6-carboxylate (0.42 g; 1.0 equiv; 1.09 mmoles) and and sodium cyanide (0.085 g; 1.6 equiv; 1.73 mmoles) in dimethylformamide (3 mL) to 100° C. for 2 hours. Cool the mixture to ambient temperature, dilute with dichloromethane (20 mL) and wash the reaction mixture with water (25 mL). Extract the aqueous layer with dichloromethane (2×20 mL). Dry the combined organic extracts over sodium sulfate, filter, and concentrate to afford crude product. Combine the crude product and purify by column chromatography (0 to 10% methanol in dichloromethane) to afford 3-cyanopropyl 2-(2,3-dihydro-1H-inden-2-ylamino)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate as a light brown oil and used in next step. MS (m/z): 378 (M+1).
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=1)[C:11]([NH2:13])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[O:1]([C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=1)[CH2:11][NH2:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC(=O)c1cccc(Oc2ccccc2)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: NCc1cccc(Oc2ccccc2)c1
Temperature: -5 °C
Yield: 97.1 %

Procedure:
A solution of the product from step (a) (6.5 g) in THF (75 ml) was added under N2 over 15 minutes to a stirred suspension of LAH (2.3 g) in THF (100 ml). After addition was complete, the mixture was refluxed for 5.5 hours, then cooled to -5° C., excess LAH destroyed by the careful addition of 15% w/v aqu. NaOH (100 ml), and the mixture taken up in water (150 ml) and ether (200 ml). The aqueous phase was separated, extracted with ether and the combined ether solutions washed with 2N aqu. NaOH (2×100 ml) and water (2×200 ml), dried over Na2SO4 and evaporated in vacuo to give the desired product as a colourless oil (5.9 g). The 200 MHz 1H NMR was consistent with the proposed structure.
Reaction SMILES: C[O:2][C:3](=O)[C:4]([C:25]([F:28])([F:27])[F:26])=[C:5]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)=[CH:14][CH:13]=1)[C:6](=O)[CH2:7][CH2:8][CH2:9][CH3:10].O.[NH2:31][NH2:32]>C(O)(=O)C>[CH2:7]([C:6]1[C:5]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)=[CH:14][CH:13]=2)=[C:4]([C:25]([F:28])([F:27])[F:26])[C:3](=[O:2])[NH:31][N:32]=1)[CH2:8][CH2:9][CH3:10]
Reactant: CCCCC(=O)C(=C(C(=O)OC)C(F)(F)F)c1ccc(OC2CCCCC2)cc1
Reactant: NN
Solvent: O
Solvent: CC(=O)O
Product: CCCCc1n[nH]c(=O)c(C(F)(F)F)c1-c1ccc(OC2CCCCC2)cc1
Temperature: 100 °C
Yield: 119.3 %

Procedure:
To a stirred solution of 3-(4-cyclohexyloxy-phenyl)-4-oxo-2-trifluoromethyl-oct-2-enoic acid methyl ester (3.40 mmol, 1.4 g) in glacial acetic acid (3 mL) was added hydrazine hydrate (61.7 mmol, 3 mL) and the reaction was heated at 100° C. for 12 h. After cooling, the volatiles were under reduced pressure to give 1.6 g of crude 6-butyl-5-(4-cyclohexyloxy-phenyl)-4-trifluoromethyl-2H-pyridazin-3-one. The ketone was treated with phosphorous oxychloride (21.8 mmol, 2.0 mL) and heated at 90° C. for 1 hour with stirring. The reaction mixture was cooled to room temperature and the volatiles were removed under reduced pressure. The residue was dissolved in ethyl acetate (30 mL) and shaken with water (30 mL). The layers were separated and the organic layer was washed with saturated NaHCO3 (2×30 mL), brine (30 mL), dried (Na2SO4) filtered and concentrated under reduced pressure. The residue was purified on a 40 g SiO2 cartridge eluting with ethyl acetate/hexanes gradient to afford 3-butyl-6-chloro-4-(4-cyclohexyloxy-phenyl)-5-trifluoromethyl-pyridazine (0.65 g).
Reaction SMILES: C(O[C:4]([CH2:6][N:7]1[C:14]2[N:10]([N:11]=[CH:12][CH:13]=2)[CH:9]=[CH:8]1)=[O:5])C.[CH3:15][NH:16][CH3:17]>C(O)C>[CH3:15][N:16]([CH3:17])[C:4]([CH2:6][N:7]1[C:14]2[N:10]([N:11]=[CH:12][CH:13]=2)[CH:9]=[CH:8]1)=[O:5]
Reactant: CCOC(=O)Cn1ccn2nccc12
Reactant: CNC
Solvent: CCO
Product: CN(C)C(=O)Cn1ccn2nccc12
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 1-ethoxycarbonylmethyl-1H-imidazo-[1,2-b]pyrazole (7.0 g) in ethanol (35 ml) was added 50% dimethylamine aqueous solution (17 ml). The mixture was stirred at room temperature for 5 hours. The reaction mixture was evaporated in vacuo. The resultant crude powder was subjected to column chromatography on silica gel using a mixture of ethyl acetate and methanol as an eluent. Fractions containing the object compound were combined and evaporated in vacuo. The resultant precipitate was collected and washed with diisopropyl ether to give 1-(N,N-dimethylcarbamoylmethyl)-1H-imidazo[1,2-b]-pyrazole (1.6 g).
Reaction SMILES: [NH2:1][C:2]([CH3:17])([CH2:5][N:6]1[CH:14]=[C:13]2[C:8]([C:9]([Cl:16])=[CH:10][C:11]([Cl:15])=[CH:12]2)=[N:7]1)[C:3]#[N:4].[O:18]([C:25]1[CH:33]=[CH:32][C:28]([C:29](Cl)=[O:30])=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[C:3]([C:2]([NH:1][C:29](=[O:30])[C:28]1[CH:27]=[CH:26][C:25]([O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:33][CH:32]=1)([CH3:17])[CH2:5][N:6]1[CH:14]=[C:13]2[C:8]([C:9]([Cl:16])=[CH:10][C:11]([Cl:15])=[CH:12]2)=[N:7]1)#[N:4]
Reactant: O=C(Cl)c1ccc(Oc2ccccc2)cc1
Reactant: CC(N)(C#N)Cn1cc2cc(Cl)cc(Cl)c2n1
Product: CC(C#N)(Cn1cc2cc(Cl)cc(Cl)c2n1)NC(=O)c1ccc(Oc2ccccc2)cc1

Procedure:
Using a procedure similar to that described in Example 1, except using 2-amino-2-methyl-3-(5,7-dichloro-2H-indazol-2-yl)propionitrile (60 mg, described in Example 98) and 4-phenoxybenzoyl chloride, the title compound was isolated as a white solid (90 mg, 87%). MS (ES): M/Z [M+H]=465. 1H NMR: (400 MHz, DMSO-d6): 1.71 (s, 3H), 5.12 (d, 1H), 5.21 (d, 1H), 7.04-7.13 (m, 4H), 7.23 (t, J=7.4 Hz, 1H), 7.41-7.51 (m, 3H), 7.85-7.92 (m, 3H), 8.52 (s, 1H) and 8.80 (s, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@:10]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)([C:14]([OH:16])=[O:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(OC(N1CCC[C@@](CC2C=CC=CC=2)(C(O)=O)C1)=O)(C)(C)C>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C:10]([CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)([C:14]([OH:16])=[O:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC[C@](Cc2ccccc2)(C(=O)O)C1
Agent: CC(C)(C)OC(=O)N1CCC[C@@](Cc2ccccc2)(C(=O)O)C1
Product: CC(C)(C)OC(=O)N1CCCC(Cc2ccccc2)(C(=O)O)C1

Procedure:
3-Benzylpiperidine-1,3-dicarboxylic acid 1-tert-butyl ester (76 g, 238 mmol) was dissolved in EtOAc (3,0 L) in a one neck flask (5 L) equipped with magnetic stirring. Then H2O (30 ml), R(+)-1-phenethylamine (18,2 ml, 143 mmol) and Et3N (13,2 ml, 95 mmol) were added and the mixture was stirred overnight at room temperature resulting in precipitation of white crystals (41,9 g), which were removed by filtration, washed with EtOAc and dried in vacuo. The precipitate was dissolved in a mixture of aqueous NaHSO4 (300 ml, 10%) and EtOAc (600 ml), layers were separated and the aqueous layer re-extracted with EtOAc (100 ml). The combined organic layers were washed with brine (100 ml), dried over MgSO4 and filtered. The solvent was removed in vacuo to afford a colorless oil, which was dissolved in EtOAc(1):heptane(10) and aged overnight. The crystals that had been formed were removed by filtration, washed with heptane and dried in vacuo to give one compound which is either (3R)-3-benzylpiperidine-1,3-dicarboxylic acid 1-tert-butyl ester or (3S)-3-benzylpiperidine-1,3-dicarboxylic acid 1-tert-butyl ester (27,8 g).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH:10]([C:15]1[CH:20]=[C:19]([Br:21])[CH:18]=[CH:17][C:16]=1[Cl:22])[CH2:9][C:8]2([CH3:24])[CH3:23])=[O:4].[OH-].[Na+].Cl>CO.O1CCCC1.O>[Br:21][C:19]1[CH:18]=[CH:17][C:16]([Cl:22])=[C:15]([CH:10]2[CH2:9][C:8]([CH3:24])([CH3:23])[C:7]3[C:12](=[CH:13][CH:14]=[C:5]([C:3]([OH:4])=[O:2])[CH:6]=3)[NH:11]2)[CH:20]=1
Reactant: COC(=O)c1ccc2c(c1)C(C)(C)CC(c1cc(Br)ccc1Cl)N2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CC1(C)CC(c2cc(Br)ccc2Cl)Nc2ccc(C(=O)O)cc21
Temperature: 60 °C
Reaction time: 6 h
Yield: 98.9 %

Procedure:
To a stirred mixture solution of 2-(5-bromo-2-chloro-phenyl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid methyl ester (1.5 g, 3.56 mmol) in methanol (20 mL) and tetrahydrofuran (20 mL) was added 30% sodium hydroxide in water (10 mL). The reaction mixture was stirred at 60° C. for 6 h. The mixture was neutralized with a 3 N aqueous hydrochloric acid solution and extracted with ethyl acetate (2×100 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo to afford 2-(5-bromo-2-chloro-phenyl)-4,4-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (1.39 g, 99%) as a light white solid which was used for next step without further purification: MS (ESI) M+1=394.0.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[H-].[Na+].[Cl:10][CH2:11][CH2:12][CH2:13][CH2:14]I.[Na+].[Cl-]>CN(C)C=O.O>[Cl:10][CH2:11][CH2:12][CH2:13][CH2:14][O:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: ClCCCCI
Reactant: Oc1cccnc1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: ClCCCCOc1cccnc1
Temperature: 25 °C
Yield: 100.8 %

Procedure:
Under a nitrogen atmosphere, a solution of 3-hydroxypyridine (3.50 g, 36.8 mmol) in N,N-dimethylformamide (DMF) (10 mL) was added drop-wise over 5 min to a cold (0-5° C.), stirring slurry of sodium hydride (1.16 g of an 80% dispersion in mineral oil, 38.6 mmol) in DMF (40 mL). The mixture was allowed to stir and warm to ambient temperature over 1 h. The mixture was then cooled to 0-5° C., and 1-chloro-4-iodobutane (9.67 g, 44.2 mmol) was added drop-wise over 5 min. The resulting dark-brown mixture was stirred at ambient temperature for 2 h. Water (25 mL) was added, followed by saturated NaCl solution (25 mL), and the mixture was extracted with ether (4×50 mL). The combined ether extracts were dried (Na2SO4), filtered, and concentrated by rotary evaporation to a residue that was dried briefly under high vacuum to give 6.89 g (quantitative yield) of an oil.