Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[F:10][C:11]([Si](C)(C)C)([F:13])[F:12].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:4]([CH:5]([OH:6])[C:11]([F:13])([F:12])[F:10])[CH:3]=1
Reactant: O=Cc1cccc(Cl)c1
Reactant: C[Si](C)(C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: OC(c1cccc(Cl)c1)C(F)(F)F
Yield: 136.1 %

Procedure:
According to Reference Example 8-12, by use of 3-chlorobenzaldehyde (500 mg, 3.56 mmol), (trifluoromethyl)trimethylsilane (631 μL, 4.27 mmol), tetrabutylammonium fluoride (a 1.0 mol/L solution in tetrahydrofuran, 360 μL, 0.360 mmol) and tetrahydrofuran (10 mL), the mixture was stirred and reacted at room temperature for 3 hours. Thus, 1-chloro-3-(2,2,2-trifluoro-1-hydroxyethyl)benzene (Compound DB) (1.02 g, yield: quantitative) was obtained.
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][S:6]([C:9]1[N:13]=[CH:12][NH:11][N:10]=1)(=[O:8])=[O:7])[CH3:2].[CH2:14]([N:17]([CH2:21][CH:22]=[CH2:23])[C:18](Cl)=[O:19])[CH:15]=[CH2:16].C(N(CC)CC)C>O1CCCC1>[CH2:14]([N:17]([CH2:21][CH:22]=[CH2:23])[C:18]([N:11]1[CH:12]=[N:13][C:9]([S:6]([CH2:5][CH2:4][O:3][CH2:1][CH3:2])(=[O:8])=[O:7])=[N:10]1)=[O:19])[CH:15]=[CH2:16]
Reactant: C=CCN(CC=C)C(=O)Cl
Reactant: CCOCCS(=O)(=O)c1nc[nH]n1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C=CCN(CC=C)C(=O)n1cnc(S(=O)(=O)CCOCC)n1

Procedure:
A solution of 4.1 g. 3-(2-ethoxyethylsulphonyl)-1,2,4-triazole, 3.5 g. diallylcarbamoyl chloride and 4 ml. triethylamine in 40 ml. dry tetrahydrofuran was refluxed under anhydrous conditions for 15 hours. The cooled reaction mixture was filtered to remove triethylamine hydrochloride and the filtrate was evaporated to remove solvent. The residue was triturated with petroleum ether (b.p. 40° - 60°C.) to give a solid product. This product was collected and recrystallised from ether/petroleum ether b.p. 40° - 60°C. to give 1-diallylcarbamoyl-3-(2-ethoxyethylsulphonyl)-1,2,4-triazole, m.p. 62° - 63°C. Elemental analysis satisfactory.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#N)=[CH:4][CH:3]=1.[OH-].[Na+].[N+:13]([C:16]1C=[CH:20][CH:19]=[CH:18][CH:17]=1)([O-])=[O:14]>CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:14][N:13]=[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:9]=23)=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1ccccc1
Reactant: N#CCc1ccc(F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Fc1ccc(-c2onc3ccccc23)cc1
Temperature: 25 °C
Reaction time: 9 h

Procedure:
A total of 50.7 g (0.375 mol) of 4-fluorophenyl-acetonitrile is slowly added to a vigorously stirred, room-temperature solution of 150 g (3.75 mol) of sodium hydroxide in 750 ml of absolute methanol. After solution is complete, 46 g (0.374 mol) of nitrobenzene is slowly added. The resulting solution is warmed to 65°-70° C. and held at this temperature for 9 hours. The dark slurry is cooled to room temperature, diluted with 250 ml of 50% methanol, and cooled in an ice bath. The resulting dark precipitate is filtered and washed with cold methanol until the methanol washings were clear. The product (16) is recrystallized from toluene.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[C:10](=[O:27])[N:11]3[C:15]([CH2:18][C:19]4[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=4)([C:16]=2[OH:17])[CH2:14][CH2:13][CH2:12]3)[CH:5]=[C:6]([Cl:8])[CH:7]=1.P(OC)(OC)(O[CH3:31])=O.C([O-])([O-])=O.[K+].[K+]>O>[Cl:8][C:6]1[CH:5]=[C:4]([C:9]2[C:10](=[O:27])[N:11]3[C:15]([CH2:18][C:19]4[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=4)([C:16]=2[O:17][CH3:31])[CH2:14][CH2:13][CH2:12]3)[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: N#Cc1ccc(CC23CCCN2C(=O)C(c2cc(Cl)cc(Cl)c2)=C3O)cc1
Reactant: COP(=O)(OC)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: COC1=C(c2cc(Cl)cc(Cl)c2)C(=O)N2CCCC12Cc1ccc(C#N)cc1
Temperature: 25 °C

Procedure:
4-[6-(3,5-Dichloro-phenyl)-7-hydroxy-5-oxo-2,3-dihydro-1H,5H-pyrrolizin-7a-ylmethyl]-benzonitrile (24), (60 mg, 0.15 mmol) Trimethyl phosphate (4 ml) and K2CO3 were stirred under reflux for 10 hours then cooled to RT and diluted with water. The precipitate was filtered to afford after HPLC purification 4-[6-(3,5-Dichloro-phenyl)-7-methoxy-5-oxo-2,3-dihydro-1H,5H-pyrrolizin-7a-ylmethyl]-benzonitrile XII (18mg) as a white solid.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C@@H:9]12[C:15](=O)[O:14][C:12](=[O:13])[C@@H:10]1[CH2:11]2>>[CH2:1]([N:8]1[C:12](=[O:13])[CH:10]2[CH:9]([CH2:11]2)[C:15]1=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccccc1
Reactant: O=C1OC(=O)[C@@H]2C[C@H]12
Product: O=C1C2CC2C(=O)N1Cc1ccccc1
Temperature: 180 °C

Procedure:
Benzylamine (8.8 mmol, 9.97 ml) was added dropwise to ice cooled cis-1,2-cyclopropanedicarboxylic acid anhydride (8.8 mmol, 0.99 g). After that the mixture was heated to 180° C. for 2 h on an oil bath. After cooling to r.t. the resulting solid oil was recrystallised from isopropanol.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[N:11]=[CH:10][C:9]3[CH:12]=[N:13][N:14]([C:15]4[N:20]=[C:19]([N:21]5[CH2:27][CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23][CH2:22]5)[CH:18]=[CH:17][CH:16]=4)[C:8]=3[CH:7]=2)[CH:3]=[N:2]1.Br[CH2:36][CH2:37][F:38]>>[N:21]1([C:19]2[N:20]=[C:15]([N:14]3[C:8]4[CH:7]=[C:6]([C:4]5[CH:5]=[N:1][N:2]([CH2:36][CH2:37][F:38])[CH:3]=5)[N:11]=[CH:10][C:9]=4[CH:12]=[N:13]3)[CH:16]=[CH:17][CH:18]=2)[CH2:27][CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1
Reactant: FCCBr
Reactant: CC(C)(C)OC(=O)N1CCCN(c2cccc(-n3ncc4cnc(-c5cn[nH]c5)cc43)n2)CC1
Product: FCCn1cc(-c2cc3c(cn2)cnn3-c2cccc(N3CCCNCC3)n2)cn1
Yield: 87.5 %

Procedure:
Following the procedures as described in Example 61 and starting with tert-butyl 4-(6-(6-(1H-pyrazol-4-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)pyridin-2-yl)-1,4-diazepane-1-carboxylate and 1-bromo-2-fluoroethane, 153 was obtained as a yellow solid (60 mg, 87.5%) over two steps. 1H NMR (500 MHz, DMSO-d6) δ (ppm) 9.12 (s, 1H), 8.63 (s, 1H), 8.51 (s, 1H), 8.28 (s, 1H), 7.95 (s, 1H), 7.49-7.66 (m, 1H), 7.13-7.15 (d, J=7.5 Hz, 1H), 6.55-6.57 (d, J=8.5 Hz, 1H), 4.88-4.90 (m, 1H), 4.73-4.80 (m, 1H), 4.54-4.58 (m, 1H), 4.49-4.52 (m, 1H), 3.77-3.83 (m, 4H), 2.97-2.99 (m, 2H), 2.70-2.72 (m, 2H), 1.87-1.89 (m, 2H); MS (ESI) m/z: 407 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.C([Mg]Cl)(C)C.[Br:13][C:14]1[CH:15]=[CH:16][C:17]([F:22])=[C:18]([CH:21]=1)[CH:19]=[O:20]>C1COCC1>[Br:13][C:14]1[CH:15]=[CH:16][C:17]([F:22])=[C:18]([CH:19]([C:2]2[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=2)[OH:20])[CH:21]=1
Reactant: Brc1cccnc1
Reactant: O=Cc1cc(Br)ccc1F
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: OC(c1cccnc1)c1cc(Br)ccc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To an oven-dried flask was added anhydrous THF (20 mL) and 3-bromopyridine (2 mL, 20 mmol). Isopropylmagnesium chloride in THF (11 mL, 2.0 M solution) was then added dropwise over several minutes. The mixture was stirred at room temperature for 1 hour, and then 5-bromo-2-fluorobenzaldehyde (2.4 mL, 20 mmol) was added. After stirring for 1 further hour at room temperature, the reaction was quenched with saturated aqueous NH4Cl. The aqueous layer was extracted with EtOAc, dried over MgSO4, and purified by column chromatography (gradient 0 to 50% EtOAc in hexanes) to afford the product. 1H NMR (400 MHz, CDCl3) δ 8.51 (d, J=1.9 Hz, 1H), 8.41 (dd, J=4.8, 1.5 Hz, 1H), 7.78-7.68 (m, 2H), 7.38 (ddd, J=8.7, 4.6, 2.6 Hz, 1H), 7.27 (dd, J=8.6, 4.2 Hz, 1H), 6.95-6.85 (m, 1H), 6.10 (s, 1H), 4.22 (br s, 1H).
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]3[C:30]4[C:25](=[CH:26][CH:27]=[C:28](I)[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1.C([O-])([O-])=O.[Cs+].[Cs+]>COCCOC.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]3[C:30]4[C:25](=[CH:26][CH:27]=[C:28]([N:32]5[CH2:37][CH2:36][O:35][CH2:34][CH2:33]5)[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cc(NC(=O)Nc2cccc(Oc3ncnc4ccc(I)cc34)c2)no1
Reactant: C1COCCN1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: COCCOC
Product: CC(C)(C)c1cc(NC(=O)Nc2cccc(Oc3ncnc4ccc(N5CCOCC5)cc34)c2)no1
Temperature: 70 °C
Yield: 3.4 %

Procedure:
A mixture of 1-(5-tert-butylisoxazol-3-yl)-3-[3-(6-iodoquinazolin-4-yloxy)phenyl]urea from Example 92A (0.225 g, 0.425 mmol), morpholine (0.5 mL), xamtphhos (0.087 g, 0.15 mmol), tris(dibenzylideneacetone)dipalladium (0) (0.046 g, 0.05 mmol), and Cs2CO3 (0.489 g, 1.5 mmol) in 1,2-dimethoxyethane (8 mL) was heated at 70° C. for 4 hours. It was quenched with water and extracted with CH2Cl2. Extracts were dried over MgSO4 and concentrated under reduced pressure. It was purified by silica gel chromatophraphy with 30-100% EtOAc/hexane and 5% MeOH/EtOAc as eluants, and by preparative HPLC(C18) with 60-80% CH3CN/H2O (0.05% AcOH) to afford 1-(5-tert-butylisoxazol-3-yl)-3-[3-(6-morpholinoquinazolin-4-yloxy)phenyl]urea as a solid (0.007 g, 3.4%). 1H NMR (300 MHz, CD3CN) δ 9.48 (br, 1H), 8.39 (s, 1H), 7.78 (m, 4H), 7.67 (dd, 1H), 7.44 (m, 3H), 7.03 (d, 1H), 3.76 (t, 4H), 3.23 (t, 4H), 1.11 (s, 9H); LC-MS (ESI) m/z 489 (M+H)+.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[O:8][C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:6][C:5]=1[CH2:15][OH:16].Cl[C:18]1[N:23]=[C:22]([C:24]([O:26][CH3:27])=[O:25])[CH:21]=[CH:20][CH:19]=1.O>O1CCCC1>[CH3:3][C:4]1[O:8][C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:6][C:5]=1[CH2:15][O:16][C:18]1[N:23]=[C:22]([C:24]([O:26][CH3:27])=[O:25])[CH:21]=[CH:20][CH:19]=1
Reactant: COC(=O)c1cccc(Cl)n1
Reactant: Cc1oc(-c2ccccc2)nc1CO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1cccc(OCc2nc(-c3ccccc3)oc2C)n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 50.8 %

Procedure:
Sodium hydride (60%, oily, 1.80 g) was added to a solution of 5-methyl-2-phenyl-4-oxazolylmethanol (8.51 g) in tetrahydrofuran (100 ml) at 0° C., which was stirred at room temperature for 15 minutes. A solution of methyl 6-chloro-2-pyridinecarboxylate (7.72 g) in tetrahydrofuran (75 ml) was added to the mixture. After being stirred at 40° C. for 5 hours, the reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated to obtain methyl 6-(5-methyl-2-phenyl-4-oxazolylmethoxy)-2-pyridinecarboxylate (7.41 g, yield 51%) as yellow crystals. This was recrystallized from ethyl acetate-hexane. Melting point: 97–98° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([C:10]3[N:11]=[C:12]([N:26]4[CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)[C:13]4[S:18][C:17]([CH2:19][N:20]5[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]5)=[CH:16][C:14]=4[N:15]=3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[CH2:32]([O:36][CH2:37][CH2:38][CH2:39][CH3:40])[CH:33]1[O:35][CH2:34]1>CN(C)C=O>[CH2:37]([O:36][CH2:32][CH:33]([OH:35])[CH2:34][N:23]1[CH2:22][CH2:21][N:20]([CH2:19][C:17]2[S:18][C:13]3[C:12]([N:26]4[CH2:27][CH2:28][O:29][CH2:30][CH2:31]4)=[N:11][C:10]([C:5]4[CH:6]=[CH:7][CH:8]=[C:9]5[C:4]=4[CH:3]=[CH:2][NH:1]5)=[N:15][C:14]=3[CH:16]=2)[CH2:25][CH2:24]1)[CH2:38][CH2:39][CH3:40]
Reactant: c1cc(-c2nc(N3CCOCC3)c3sc(CN4CCNCC4)cc3n2)c2cc[nH]c2c1
Reactant: CCCCOCC1CO1
Solvent: CN(C)C=O
Product: CCCCOCC(O)CN1CCN(Cc2cc3nc(-c4cccc5[nH]ccc45)nc(N4CCOCC4)c3s2)CC1

Procedure:
To a stirred solution of 2-(1H-indol-4-yl)-4-morpholin-4-yl-6-piperazin-1-ylmethyl-thieno[3,2-d]pyrimidine (50 mg) in N,N-dimethylformamide (3 mL) at r.t. was added 0.1 M Na2HPO4 pH 6.8 buffer (0.5 mL) and butyl glycidyl ether (18 μL) and the resulting cloudy mixture was heated at 55° C. for 3 days with 2 extra equivalents of butyl glycidyl ether (18 μL) added during this time. The reaction mixture was partitioned between EtOAc (15 mL) and brine (15 mL), the organic layer was dried (Na2SO4), concentrated and the residue purified by flash chromatography (silica; 96:4 EtOAc/MeOH as eluent) to give an off-white solid (38 mg).
Reaction SMILES: [F:1][CH:2]([F:29])[C:3]1[CH:7]=[C:6]([CH:8]([F:10])[F:9])[N:5]([CH2:11][C:12]([N:14]2[CH2:19][CH2:18][CH:17]([C:20]3[N:25]=[C:24]([C:26]([OH:28])=[O:27])[CH:23]=[CH:22][CH:21]=3)[CH2:16][CH2:15]2)=[O:13])[N:4]=1.[CH:30]1(O)[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1.C(N=C=NCCCN(C)C)C.O>ClCCl.CN(C)C1C=CN=CC=1>[F:29][CH:2]([F:1])[C:3]1[CH:7]=[C:6]([CH:8]([F:9])[F:10])[N:5]([CH2:11][C:12]([N:14]2[CH2:19][CH2:18][CH:17]([C:20]3[N:25]=[C:24]([C:26]([O:28][CH:30]4[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]4)=[O:27])[CH:23]=[CH:22][CH:21]=3)[CH2:16][CH2:15]2)=[O:13])[N:4]=1
Reactant: OC1CCCCC1
Reactant: O=C(O)c1cccc(C2CCN(C(=O)Cn3nc(C(F)F)cc3C(F)F)CC2)n1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: ClCCl
Product: O=C(OC1CCCCC1)c1cccc(C2CCN(C(=O)Cn3nc(C(F)F)cc3C(F)F)CC2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 6-(1-{[3,5-bis(difluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)-pyridine-2-carboxylic acid (157 mg) in dichloromethane (5 ml) are added, at room temperature, cyclohexanol (42 mg), 4-dimethylaminopyridine (4.6 mg) and 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide (80 mg). The mixture is stirred at room temperature overnight, and then water is added. The aqueous phase is removed and extracted with ethyl acetate. The combined organic phases are dried over sodium sulphate and concentrated under reduced pressure. The residue is purified by chromatography. This gives cyclohexyl 6-(1-{[3,5-bis(difluoromethyl)-1H-pyrazol-1-yl]acetyl}piperidin-4-yl)pyridine-2-carboxylate (87 mg).
Reaction SMILES: [CH2:1]([C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]([CH2:17][CH:18]=O)[CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:21][OH:22].N1C=CC=CC=1>CCO>[CH2:1]([C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]([CH2:17][CH:18]=[N:21][OH:22])[CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=CCn1cc(Cc2ccccc2)c2ccccc21
Reactant: NO
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: ON=CCn1cc(Cc2ccccc2)c2ccccc21
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a solution of the aldehyde from Step 2 (390 mg, 1.57 mmol) in EtOH (6 mL) there was added hydroxylamine hydrochloride (435 mg, 6.26 mmol), then pyridine (3 mL). The mixture was stirred at r.t. for 45 minutes, then it was evaporated to dryness. The residue was partitioned between Et2O and H2O, and by evaporation of the ethereal fraction the title oxime was obtained as a soft solid.
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][CH2:5][C:4](=[O:8])[C:3]2[CH:9]=[CH:10][CH:11]=[CH:12][C:2]1=2.N1C=CC=CC=1.[CH:19]([O:22][C:23](Cl)=[O:24])([CH3:21])[CH3:20]>ClCCl>[CH:19]([O:22][C:23]([N:1]1[CH2:7][CH2:6][CH2:5][C:4](=[O:8])[C:3]2[CH:9]=[CH:10][CH:11]=[CH:12][C:2]1=2)=[O:24])([CH3:21])[CH3:20]
Reactant: O=C1CCCNc2ccccc21
Reactant: CC(C)OC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)OC(=O)N1CCCC(=O)c2ccccc21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a cooled (0° C.) solution of 1,2,3,4-Tetrahydro-benzo[b]azepin-5-one (1.5 g, 9.3 mmol) and pyridine (2.26 ml, 27.9 mmol) in dichloromethane (30 ml) was added 1M isopropylchloroformate (solution in toluene) dropwise over 10 minutes. After addition was completed, the mixture was removed from the cold bath and stirred for 18 hours at room temperature. The mixture was cooled to 0° C., then treated with aqueous 1N NaOH and stirred for 30 minutes. After layer separation, the aqueous layer was extracted with dichloromethane. The combined organic phases were washed with 1N HCl, saturated aqueous NaHCO3, brine, then dried (Na2SO4) and concentrated to an oil. Purification by silica gel chromatography (eluent, 3:1 n-hexanes:ethyl acetate) provided 5-Oxo-2,3,4,5-tetrahydro-benzo[b]azepine-1-carboxylic acid isopropyl ester (1.91 g).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH2:19])(C)(C)C.C(O[C:26](=[O:43])[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]2[CH:41]=[CH:40][N:39]=[C:38]([CH3:42])[N:37]=2)[CH:31]=1)=O)(C)(C)C>>[CH3:14][C:12]1[C:11]([C:15]([F:16])([F:17])[F:18])=[CH:10][C:9]2[NH:19][C:26](=[O:43])[CH2:27][C:28]([C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([C:36]4[CH:41]=[CH:40][N:39]=[C:38]([CH3:42])[N:37]=4)[CH:31]=3)=[N:7][C:8]=2[CH:13]=1
Reactant: Cc1nccc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)n1
Reactant: Cc1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Product: Cc1nccc(-c2cccc(C3=Nc4cc(C)c(C(F)(F)F)cc4NC(=O)C3)c2)n1

Procedure:
The title compound was prepared from (2-amino-5-methyl-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J20) (87 mg, 0.3 mmol) and 3-[3-(2-methyl-pyrimidin-4-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K42) (112 mg, 0.36 mmol) according to the general procedure M and subsequent treatment of the crude product according to the general procedure N. Obtained as a light yellow solid (41 mg).
Reaction SMILES: [CH3:1][C:2]([CH3:24])([CH3:23])[C@@H:3]([N:5]1[CH2:10][CH2:9][C@@:8]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)([CH2:11][CH2:12][CH2:13][OH:14])[O:7][C:6]1=[O:22])[CH3:4].CC(C)=[O:27].OS(O)(=O)=O.O=[Cr](=O)=O>CC(C)=O>[CH3:24][C:2]([CH3:23])([CH3:1])[C@@H:3]([N:5]1[CH2:10][CH2:9][C@:8]([CH2:11][CH2:12][C:13]([OH:27])=[O:14])([C:15]2[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=2)[O:7][C:6]1=[O:22])[CH3:4]
Reactant: C[C@H](N1CC[C@](CCCO)(c2ccc(F)cc2)OC1=O)C(C)(C)C
Reactant: CC(C)=O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Product: C[C@H](N1CC[C@](CCC(=O)O)(c2ccc(F)cc2)OC1=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 32 %

Procedure:
To a solution of (R)-3-((S)-3,3-dimethylbutan-2-yl)-6-(4-fluorophenyl)-6-(3-hydroxypropyl)-1,3-oxazinan-2-one (150 mg, 0.45 mmol) in acetone (10 mL) was added Jones reagent (2.5 mol/L, 0.5 mL) at 0° C., and the mixture was stirred at rt for 1 h. The reaction mixture was concentrated, and the mixture was extracted with EtOAc. The combined organic phase was concentrated to give the crude product, which was purified by preparative TLC to give 3-((R)-3-((S)-3,3-dimethylbutan-2-yl)-6-(4-fluorophenyl)-2-oxo-1,3-oxazinan-6-yl)propanoic acid (50 mg, 32%).
Reaction SMILES: [CH2:1]1[CH:8]2[C:4]3([C:10]([OH:12])=[O:11])[CH2:5][CH:6]([CH2:9][CH:2]1[CH2:3]3)[CH2:7]2.C(N1C=CN=C1)(N1C=CN=C1)=O.C(=O)=O.[N:28]1[CH:33]=[CH:32][CH:31]=[N:30][C:29]=1[N:34]1[CH2:39][CH2:38][N:37]([CH2:40][CH2:41]O)[CH2:36][CH2:35]1>C(Cl)(Cl)Cl>[N:28]1[CH:33]=[CH:32][CH:31]=[N:30][C:29]=1[N:34]1[CH2:39][CH2:38][N:37]([CH2:40][CH2:41][O:11][C:10]([C:4]23[CH2:5][CH:6]4[CH2:9][CH:2]([CH2:1][CH:8]2[CH2:7]4)[CH2:3]3)=[O:12])[CH2:36][CH2:35]1
Reactant: O=C(O)C12CC3CC(CC1C3)C2
Reactant: OCCN1CCN(c2ncccn2)CC1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: O=C=O
Solvent: ClC(Cl)Cl
Product: O=C(OCCN1CCN(c2ncccn2)CC1)C12CC3CC(CC1C3)C2
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a stirred solution of hexahydro-2,5-methanopentalene-3a[1H]-carboxylic acid (1.0 g, 6.0×10-3 mol) in 25 ml of chloroform under a dry nitrogen atmosphere, was added carbonyldiimidazole (0.98 g, 6.0×10-3 mol). The resulting solution was stirred at ambient temperature for three hours, during which time a gas (CO2) was evolved. A solution of 2-[1-(2-pyrimidyl)-4-piperazinyl]ethanol (1.25 g, 6.0×10-3 mol) in 25 ml of chloroform was then added, and the resulting reaction mixture was stirred under nitrogen at ambient temperature for two days. The mixture was diluted to 150 ml with chloroform, washed with three-one hundred ml portions of water, dried over anhydrous sodium sulfate, and concentrated on a rotary evaporator. The desired product (TLC on silica using a 30% methanol in ethyl acetate solvent system, Rf=0.45) was isolated by gravity chromatography on silica gel and converted to the hydrochloride salt with isopropanolic HCl (1.76 g, 61% yield), mp.=219°-220° C.
Reaction SMILES: [ClH:1].O1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[CH2:4][CH2:3]1.Cl.[CH3:14][NH:15][CH3:16].C=O>C(O)C>[ClH:1].[CH3:14][N:15]([CH3:16])[CH2:3][CH2:4][C:5]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:12]
Reactant: CNC
Reactant: O=C1CCOc2ccccc21
Agent: C=O
Agent: Cl
Solvent: CCO
Product: CN(C)CCC(=O)c1ccccc1
Yield: 55 %

Procedure:
Concentrated hydrochloric acid (0.2 ml) was dropwise added to a solution of 4-chromanone (10 g), dimethylamine hydrochloride (7.1 g) and paraformaldehyde (2.6 g) dissolved in ethanol (20 ml). The mixture was refluxed for 2 hours with heating. The mixture was allowed to cool. The resulting crystals were collected by filtration, washed with acetone and dried to obtain 9 g of β-dimethylaminopropiophenone hydrochloride (yield: 55%).
Reaction SMILES: [CH3:1][C:2]1[C:7]([N:8]2[CH2:12][CH:11]([C:13]([O:15]C(C)(C)C)=[O:14])[N:10]([CH3:20])[C:9]2=[O:21])=[CH:6][CH:5]=[C:4]([CH3:22])[N:3]=1.[C:23]([OH:29])([C:25]([F:28])([F:27])[F:26])=[O:24].C(Cl)Cl>>[OH:29][C:23]([C:25]([F:28])([F:27])[F:26])=[O:24].[CH3:1][C:2]1[C:7]([N:8]2[CH2:12][CH:11]([C:13]([OH:15])=[O:14])[N:10]([CH3:20])[C:9]2=[O:21])=[CH:6][CH:5]=[C:4]([CH3:22])[N:3]=1
Reactant: Cc1ccc(N2CC(C(=O)OC(C)(C)C)N(C)C2=O)c(C)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc(N2CC(C(=O)O)N(C)C2=O)c(C)n1

Procedure:
A solution of 1,1-dimethylethyl 3-methyl-2-oxo-4-imidazolidinecarboxylate (600 mg, 3.00 mmol) (prepared as described in step (iii) of Example 13, starting from (4S)-2-oxo-3-{[(phenylmethyl)oxy]carbonyl}-4-imidazolidinecarboxylic acid) and 3-bromo-2,6-dimethylpyridine (557 mg, 3.00 mmol) in 1,4-dioxane (20 ml) was treated with cesium carbonate (1464 mg, 4.49 mmol), Xantphos™ (130 mg, 0.225 mmol) and tris(dibenzylideneacetone)dipalladium(0) (68.6 mg, 0.075 mmol) and the mixture was heated at reflux under argon for 3 hours. After cooling to room temperature, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic layers were combined, washed with water and brine and evaporated in vacuo. The residue was purified by silica gel chromatography eluting with 0-10% methanol in dichloromethane. The residue was dissolved in methanol and applied to a SCX ion exchange cartridge and washed with methanol and then 2M ammonia in methanol. The basic fractions were combined and evaporated to give 1,1-dimethylethyl 1-(2,6-dimethyl-3-pyridinyl)-3-methyl-2-oxo-4-imidazolidinecarboxylate (493 mg, 54%). LC/MS [M+H]+=306. (ii) A solution of 1,1-dimethylethyl 1-(2,6-dimethyl-3-pyridinyl)-3-methyl-2-oxo-4-imidazolidinecarboxylate (0.489 g, 1.6 mmol) in TFA/DCM (1:2, 9 ml) was stirred at room temperature for 16 hours. The solution was evaporated and the residue was co-evaporated with toluene and dried to give crude 1-(2,6-dimethyl-3-pyridinyl)-3-methyl-2-oxo-4-imidazolidinecarboxylic acid TFA salt, (assume ˜1.6 mmol) which was used in the next step. LC/MS [M+H]+=250.