Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH2:15][OH:16])[C:7]2[CH2:8][C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=3[C:6]=2[CH2:5][CH2:4][O:3]1.FC(F)(F)C(O)=O.N1C=CC=CC=1.C(O)(=O)C(O)=O>CS(C)=O.C1C=CC=CC=1.CCOCC.CO.O>[CH3:1][C:2]1([CH:15]=[O:16])[C:7]2[CH2:8][C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=3[C:6]=2[CH2:5][CH2:4][O:3]1
Reactant: CC1(CO)OCCC2=C1Cc1ccccc12
Agent: O=C(O)C(=O)O
Solvent: CS(C)=O
Solvent: c1ccccc1
Solvent: O
Product: CC1(C=O)OCCC2=C1Cc1ccccc12
Temperature: 25 °C
Reaction time: 5 h

Procedure:
N,N-Dicyclohexylcarbodiimide (2.87 g) is added to a cooled, stirred solution of the primary alcohol, 1-methyl-1,3,4,9-tetrahydroindeno[2,1-c]pyran-1-methanol (1.09 g), described in Example 462, in 10 ml of dimethyl sulfoxide-benzene (2:1) containing trifluoroacetic acid (0.18 ml) and pyridine (0.38 ml). The reaction is stirred at room temperature under nitrogen for 5 hr. The reaction mixture is now diluted with 100 ml of ether, followed by the dropwise addition of a solution of oxalic acid (1.26 g) in 6 ml of methanol. After thirty minutes, water (100 ml) is added and the insoluble material is collected. The organic phase is washed with water (2X), 5% aqueous sodium bicarbonate (2X) and water (2X). After drying (MgSO4) the organic phase is evaporated to yield an oil. The oil is purified by chromatography on silica gel. Elution with 10% ether in benzene affords the title compound as an oil νmaxCHCl3 1720 cm-1.
Reaction SMILES: [CH:1]([C:4]1([CH3:23])[C:8](=[O:9])[NH:7][C:6]([C:10]2[N:19]=[CH:18][C:17]([CH:20]=[CH:21][CH3:22])=[CH:16][C:11]=2[C:12]([O:14]C)=[O:13])=[N:5]1)([CH3:3])[CH3:2].[OH-].[Na+].Cl>CO>[CH:1]([C:4]1([CH3:23])[C:8](=[O:9])[NH:7][C:6]([C:10]2[N:19]=[CH:18][C:17]([CH:20]=[CH:21][CH3:22])=[CH:16][C:11]=2[C:12]([OH:14])=[O:13])=[N:5]1)([CH3:3])[CH3:2]
Reactant: CC=Cc1cnc(C2=NC(C)(C(C)C)C(=O)N2)c(C(=O)OC)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC=Cc1cnc(C2=NC(C)(C(C)C)C(=O)N2)c(C(=O)O)c1

Procedure:
A mixture of 1.5 g methyl 2-(4-isopropyl-4-methyl-5-oxo-2-imidazolin-2-yl)-5-propenylnicotinate and 3.2 mL of 2N sodium hydroxide in 15 mL methanol is stirred under nitrogen and heated at 45° for 31/2 hours. The reaction is cooled to 10°, acidified to pH 3 with 2N hydrochloric acid, and concentrated in vacuo. The residue is partitioned between methylene chloride and water, and the aqueous phase is further extracted with methylene chloride. The combined organic phases are dried and concentrated in vacuo to a solid. Recrystallization from methylene chloride-hexanes gives a solid, mp 175°-176°.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8]Br)[N:3]=1.[CH3:10][S-:11].[Na+]>CN(C=O)C.C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][S:11][CH3:10])[N:3]=1
Reactant: BrCc1cccc(Br)n1
Reactant: C[S-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CSCc1cccc(Br)n1
Temperature: 80 °C

Procedure:
2-Bromo-6-(bromomethyl)pyridine (Example 190, Step 1) (0.20 g, 0.80 mmol) and sodium thiomethoxide (0.072 g, 1.04 mmol) were taken up in DMF (12.1 mL) heated at 80° C. for 3 hours. The reaction was then cooled to ambient temperature, diluted with ethyl acetate, washed with water, dried over magnesium sulfate, filtered and concentrated. The crude residue was purified by silica gel chromatography to yield the title compound. 1H NMR (600 MHz, CDCl3): 7.53 (t, J=9.0 Hz, 1H), 7.37 (d, J=9.0 Hz, 1H), 7.36 (d, J=9.0 Hz, 1H), 3.77 (s, 2H), 2.08 (2, 3H).
Reaction SMILES: Cl[CH2:2][CH2:3]Cl.C(=O)([O-])[O-].[K+].[K+].[C:11]([O:18][CH3:19])(=[O:17])[CH2:12][C:13]([O:15][CH3:16])=[O:14]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O>[C:12]1([C:11]([O:18][CH3:19])=[O:17])([C:13]([O:15][CH3:16])=[O:14])[CH2:3][CH2:2]1
Reactant: ClCCCl
Reactant: COC(=O)CC(=O)OC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: O
Product: COC(=O)C1(C(=O)OC)CC1
Yield: 87 %

Procedure:
319.6 g of 1,2-dichloroethane (3.23 mol), 5 g of polyethylene glycol (mean molar mass 600 g/mol) and 168.0 g of potassium carbonate (1.2 mol) were initially introduced, and the reaction mixture was heated until the 1,2-dichloroethane refluxes. 132.1 g of dimethyl malonate (1 mol) and 1.25 g of tetrabutylammonium bromide (3.88 mmol) were then added at the boil. The mixture was stirred using a paddle stirrer for 6 hours. Water formed during the reaction was removed by azeotropic distillation with 1,2-dichloroethane throughout the reaction. Further work-up was carried out analogously to Comparative Example 2. The yield was 87%.
Reaction SMILES: [CH2:1]([C@H:6]1[CH2:11][CH2:10][C@H:9]([C@H:12]2[CH2:17][CH2:16][C@H:15]([C:18]([OH:20])=[O:19])[CH2:14][CH2:13]2)[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH:4]=[CH2:5].[F:21][C:22]1[CH:27]=[CH:26][C:25](O)=[CH:24][CH:23]=1.C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl.CN(C)C1C=CN=CC=1>[F:21][C:22]1[CH:27]=[CH:26][C:25]([O:19][C:18]([C@H:15]2[CH2:14][CH2:13][C@H:12]([C@H:9]3[CH2:10][CH2:11][C@H:6]([CH2:1][CH2:2][CH2:3][CH:4]=[CH2:5])[CH2:7][CH2:8]3)[CH2:17][CH2:16]2)=[O:20])=[CH:24][CH:23]=1
Reactant: C=CCCC[C@H]1CC[C@H]([C@H]2CC[C@H](C(=O)O)CC2)CC1
Reactant: Oc1ccc(F)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: C=CCCC[C@H]1CC[C@H]([C@H]2CC[C@H](C(=O)Oc3ccc(F)cc3)CC2)CC1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A solution of 996 mg of trans-4-[trans-4-(4-pentenyl)cyclohexyl]cyclohexanecarboxylic acid in 80 ml of methylene chloride was treated with 752 mg of p-fluorophenol, 61 mg of 4-(dimethylamino)pyridine and 1.03 g of dicyclohexylcarbodiimide and stirred at room temperature for 15 hours. The reaction mixture was subsequently filtered. The filtrate was evaporated and the residue obtained was purified by chromatography on silica gel with ethyl acetate/petroleum ether (vol. 3:97). Crystallization of the product obtained (1.24 g) from 40 ml of hexane gave 757 mg of pure trans-4-[trans-4-(4-pentenyl)cyclohexyl]cyclohexanecarboxylic acid 4-fluorophenyl ester with m.p. (C--N) 70.3° C. and cl.p. (N--I) 158.7° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH:27]4[CH2:29][O:28]4)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH2:30]([NH2:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.CN1CCCC1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH:27]([OH:28])[CH2:29][NH:37][CH2:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:7][CH2:8]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4C4CO4)cc3)cc2)CC1
Reactant: NCc1ccccc1
Agent: CN1CCCC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4C(O)CNCc4ccccc4)cc3)cc2)CC1
Temperature: 85 °C
Reaction time: 8 h

Procedure:
1-[4′-(3-Methyl-4-oxiranyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester (0.100 g, 0.26 mmol), benzylamine (0.034 mL, 0.31 mmol) and N-methylpyrrolidine (5 mL) were combined in a flask and stirred at 85° C. overnight. An additional portion of benzylamine (0.050 mL) was added and the reaction continued to stir at 85° C. for 48 hours. The reaction mixture was cooled and submitted to standard aqueous workup to give the title compound.
Reaction SMILES: C([O-])(O)=O.[Na+].O.[CH2:7]([O:14][C:15]([NH:17][C@@H:18]([C:22]([SH:25])([CH3:24])[CH3:23])[C:19]([OH:21])=[O:20])=[O:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.F[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[N+:33]([O-:35])=[O:34]>CCO>[CH2:7]([O:14][C:15]([NH:17][C@@H:18]([C:22]([CH3:23])([S:25][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[N+:33]([O-:35])=[O:34])[CH3:24])[C:19]([OH:21])=[O:20])=[O:16])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: CC(C)(S)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC(C)(Sc1ccccc1[N+](=O)[O-])[C@H](NC(=O)OCc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 67.2 %

Procedure:
NaHCO3 (14.5 g, 172 mmol, Eq: 2.5) and H2O (210 mL) were added to a slurry of (R)-2-(benzyloxycarbonylamino)-3-mercapto-3-methylbutanoic acid (19.5 g, 68.8 mmol, Eq: 1.00) in EtOH (70.0 mL). After 20 min. the mixture became homogeneous, 1-fluoro-2-nitrobenzene (9.71 g, 7.00 mL, 68.8 mmol, Eq: 1.00) was added and the mixture heated to reflux for 6 h. The mixture was cooled to RT, poured into H2O (300 mL) and extracted with MTBE. The aqueous layer was acidified to pH 5 with 1 N HCl and extracted with Et2O. The combined organic extracts were dried over Na2SO4 filtered and concentrated to give (R)-2-(benzyloxycarbonylamino)-3-methyl-3-(2-nitrophenylthio)butanoic acid (18.7 g, 67.2%) as a light yellow oil which was used without purification.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:19]([CH3:20])=[CH:18][CH:17]=[C:16]2[C:21]2[CH:40]=[CH:39][C:24]([O:25][C@H:26]([CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:27]([O:29]CC)=[O:28])=[CH:23][CH:22]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[OH-].[K+].Cl>C1COCC1.CO>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([N:15]2[C:19]([CH3:20])=[CH:18][CH:17]=[C:16]2[C:21]2[CH:22]=[CH:23][C:24]([O:25][C@H:26]([CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:27]([OH:29])=[O:28])=[CH:39][CH:40]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCCOc1ccc(-n2c(C)ccc2-c2ccc(O[C@H](Cc3ccccc3)C(=O)OCC)cc2)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCCCCCCOc1ccc(-n2c(C)ccc2-c2ccc(O[C@H](Cc3ccccc3)C(=O)O)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.2 %

Procedure:
To a mixed solution of ethyl (2R)-2-{4-[1-(4-heptyloxyphenyl)-5-methyl-1H-pyrrol-2-yl]phenoxy}-3-phenylpropanoate (235 mg, 0.435 mmol) in THF (7 ml) and methanol (7 ml) was added 1N aqueous potassium hydroxide solution (2 ml, 2 mmol) and the mixture was stirred for 1 hour at room temperature. The reaction solution was neutralized with 1N hydrochloric acid and extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate anhydride and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to give the object compound as an oily substance. 210 mg (yield: 94.2%)
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][C:27]([O:36][CH3:37])=[C:28]([O:31][CH2:32][CH2:33][CH2:34]Cl)[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:38]1[CH2:43][CH2:42][S:41](=[O:45])(=[O:44])[CH2:40][CH2:39]1.CCN(C(C)C)C(C)C.O>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C=O)C>[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][C:27]([O:36][CH3:37])=[C:28]([O:31][CH2:32][CH2:33][CH2:34][N:38]5[CH2:43][CH2:42][S:41](=[O:45])(=[O:44])[CH2:40][CH2:39]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: COc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)c2cc1OCCCCl
Reactant: O=S1(=O)CCNCC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)c2cc1OCCCN1CCS(=O)(=O)CC1
Temperature: 60 °C
Yield: 19.5 %

Procedure:
The intermediate 1-(5-tert-butylisoxazol-3-yl)-3-(3-(6-(3-chloropropoxy)-7-methoxyquinazolin-4-yloxy)phenyl)urea (200 mg, 0.38 mmol) from Example 21B was treated with thiomorpholine-1,1-dioxide (154 mg, 1.14 mmol), tetrabutylammonium iodide (140 mg, 0.38 mmol) and N,N′-diisopropylethylamine (135 μL, 0.76 mmol) in N,N′-dimethylformamide (2 mL). The mixture was heated to 60° C. for 56 h and cooled to room temperature. Water was added and the solid filtered off and dried. The crude solid was purified by preparative HPLC (Phenomenex phenylhexyl reverse phase column) and the obtained solid triturated with water and drops of methanol, then filtered off and dried under high vacuum to afford 1-(5-tert-butyl-isoxazol-3-yl)-3-(3-{6-[3-(1,1-dioxo-thiomorpholin-4-yl)-propoxy]-7-methoxy-quinazolin-4-yloxy}-phenyl)-urea (46.40 mg, 20%) as a solid. 1H NMR (300 MHz, DMSO-d6) δ 9.62 (bs, 1H), 9.04 (bs, 1H), 8.56 (s, 1H), 7.57 (d, 2H), 7.40-7.37 (m, 2H), 7.25 (d, 1H), 6.97 (d, 1H), 6.47 (s, 1H), 4.25-4.21 (m, 2H), 4.00 (s, 3H), 3.34 (bs, 4H), 2.93 (bs, 4H), 2.68-2.64 (m, 2H), 1.99-1.96 (m, 2H), 1.18 (s, 9H); LC-MS (ESI) m/z 625 (M+H)+.
Reaction SMILES: [CH:1]1([NH:11][CH2:12][CH2:13][CH2:14][N:15]2[C:19](=[O:20])[C:18]3=[CH:21][CH:22]=[CH:23][CH:24]=[C:17]3[C:16]2=[O:25])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].Br[CH2:35][CH2:36][CH2:37][C:38]#[N:39]>CC#N>[C:19]1(=[O:20])[N:15]([CH2:14][CH2:13][CH2:12][N:11]([CH:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH2:4][CH2:3][CH2:2]2)[CH2:35][CH2:36][CH2:37][C:38]#[N:39])[C:16](=[O:25])[C:17]2=[CH:24][CH:23]=[CH:22][CH:21]=[C:18]12
Reactant: O=C1c2ccccc2C(=O)N1CCCNC1CCCc2ccccc21
Reactant: N#CCCCBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: N#CCCCN(CCCN1C(=O)c2ccccc2C1=O)C1CCCc2ccccc21
Reaction time: 18 h
Yield: 49.2 %

Procedure:
To a mixture of N-[3-(1,2,3,4-tetrahydro-1-naphthylamino)propyl]phthalimide (569 mg, 1.7 mmol), potassium carbonate (709 mg, 5.1 mmol) and potassium iodide (280 mg, 1.7 mmol) in CH3CN (20 ml) was added 4-bromobutyronitrile (754 mg, 5.1 mmol). The mixture was refluxed under stirring for 18 h, and then filtered. The filtrate was concentrated under vacuum to dryness, and the residue was chromatographed on silica gel (eluting with 20% ethyl acetate/chloroform) to afford 4-[[(3-phthalimido)propyl](1,2,3,4-tetrahydro-1-naphthyl)amino]butyronitrile (336 mg, 50%): MS(ES+) m/e 402 [M+H]+; 1H NMR (400 MHz, CDCl3) δ 7.82 (dd, J=5.4, 2.9 Hz, 2H), 7.70 (m, 2H), 7.60 (d, J=7.6 Hz, 1H), 7.11 (m, 1H), 7.02 (m, 2H), 3.95 (m, 1H), 3.78 (m, 1H), 3.59 (m, 1H), 2.73 (m, 2H), 2.64 (m, 1H), 2.51 (m, 4H), 2.35 (m, 1H), 1.98 (m, 2H), 1.83 (m, 4H), 1.63 (m, 2H).
Reaction SMILES: [NH2:1][N:2]1[CH:6]=[N:5][N:4]=[CH:3]1.[C:7]1([CH3:14])[C:8]([CH3:13])=[CH:9][CH:10]=[CH:11][CH:12]=1>O>[CH:8](=[C:6]1[N:2]([NH2:1])[CH:3]=[N:4][NH:5]1)[CH2:7][CH2:12][CH2:11][CH2:13][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:7][CH3:14]
Reactant: Nn1cnnc1
Reactant: Cc1ccccc1C
Solvent: O
Product: CCCCCCCCCCCC=C1NN=CN1N

Procedure:
4-amino-1,2,4-triazole (8.4g.), didecyl aldehyde (18.4g.) and xylene (125 ml.) were heated in a Dean Stack apparatus until the evolution of water ceased. Concentration on the rotary afforded the product as a viscous oil which solidified upon cooling. Yield = 25g. m.p. 40°-3°.
Reaction SMILES: Cl[C:2]1[C:3]2[N:4]([C:8]([C:11]3[CH:16]=[CH:15][N:14]=[C:13]([S:17][CH3:18])[N:12]=3)=[CH:9][N:10]=2)[CH:5]=[CH:6][N:7]=1.[O:19]1[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][NH2:27])[CH2:21][CH2:20]1.C(N(C(C)C)CC)(C)C>CC(O)C>[CH3:18][S:17][C:13]1[N:12]=[C:11]([C:8]2[N:4]3[CH:5]=[CH:6][N:7]=[C:2]([NH:27][CH2:26][CH2:25][N:22]4[CH2:23][CH2:24][O:19][CH2:20][CH2:21]4)[C:3]3=[N:10][CH:9]=2)[CH:16]=[CH:15][N:14]=1
Reactant: CSc1nccc(-c2cnc3c(Cl)nccn23)n1
Reactant: NCCN1CCOCC1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CSc1nccc(-c2cnc3c(NCCN4CCOCC4)nccn23)n1

Procedure:
To a solution of 8-chloro-3-(2-methylsulfanyl-pyrimidin-4-yl)-imidazo[1,2-a]pyrazine (from Example 44 supra) (400 mg, 1.44 mmol) in iPrOH (20 mL) was added 2-morpholino-ethanamine (244 mg, 1.88 mmol) followed by diisopropylethylamine (242 mg, 1.88 mmol). The reaction mixture was stirred at reflux for 15 hours and the solvent was removed under reduced pressure. The residue was extracted with dichloromethane (150 mL) and washed with water (3×25 mL), dried over anhydrous sodium sulfate and concentrated to afford [3-(2-methylsulfanyl-pyrimidin-4-yl)-imidazo[1,2-a]pyrazin-8-yl]-(2-morpholin-4-yl-ethyl)-amine. (Yield 410 g, 76.8%). LC-MS: [M+H]+ 372.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N:8]2[C:13](=[O:14])[NH:12][C:11](=[O:15])[CH:10]=[N:9]2)[CH:5]=[C:4]([Cl:16])[C:3]=1[CH:17]([C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=1)[C:18]#[N:19].[C:27](=O)([O-])[O-].[K+].[K+].IC>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([N:8]2[C:13](=[O:14])[N:12]([CH3:27])[C:11](=[O:15])[CH:10]=[N:9]2)[CH:5]=[C:4]([Cl:16])[C:3]=1[CH:17]([C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=1)[C:18]#[N:19]
Reactant: O=C([O-])[O-]
Reactant: N#CC(c1ccc(Cl)cc1)c1c(Cl)cc(-n2ncc(=O)[nH]c2=O)cc1Cl
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: Cn1c(=O)cnn(-c2cc(Cl)c(C(C#N)c3ccc(Cl)cc3)c(Cl)c2)c1=O
Temperature: 40 °C
Reaction time: 1.5 h
Yield: 59.2 %

Procedure:
To a stirred mixture of 4 parts of 2,6-dichloro-α-(4-chlorophenyl)-4-(4,5-dihydro-3,5-dioxo-1,2,4-triazin-2(3H)-yl)benzeneacetonitrile, 1.4 parts of potassium carbonate and 22.5 parts of N,N-dimethylformamide were added 2.84 parts of iodomethane at room temperature. The reaction mixture was stirred for 1.5 hours at 40° C. After evaporation in vacuo, the residue was taken up in water. The precipitated product was filtered off and washed with water. After crystallization from acetonitrile, the product was filtered off, washed with 2,2'-oxybispropane and dried, yielding 2.5 parts (59.2%) of 2,6-dichloro-α-(4-chlorophenyl)-4-(4,5-dihydro-4-methyl-3,5-dioxo-1,2,4-triazin-2(3H)-yl)benzeneacetonitrile; mp. 159.7° C. (intermediate 46).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[C:22]([CH3:23])=[N:21][O:20][C:7]=3[CH2:8][N:9]=[C:10]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[C:11]=2[N:12]=1.BrC1C(C(O)=O)=CC(Cl)=NC=1.BrC1C(C(O)=O)=NC(Cl)=CC=1>>[Cl:1][C:2]1[N:12]=[CH:11][C:5]2[C:6]3[C:22]([CH3:23])=[N:21][O:20][C:7]=3[CH2:8][N:9]=[C:10]([C:13]3[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=3)[C:4]=2[CH:3]=1
Reactant: Cc1noc2c1-c1ccc(Cl)nc1C(c1ccc(Cl)cc1)=NC2
Agent: O=C(O)c1cc(Cl)ncc1Br
Agent: O=C(O)c1nc(Cl)ccc1Br
Product: Cc1noc2c1-c1cnc(Cl)cc1C(c1ccc(Cl)cc1)=NC2

Procedure:
A sequence similar to 8-chloro-6-(4-chlorophenyl)-1-methyl-4H-isoxazolo[5,4-c]pyrido[3,2-e]azepine (Compound 240) was followed, except that 5-bromo-2-chloroisonicotinic acid was used as commercially available starting material instead of 3-bromo-6-chloropicolinic acid. LC/MS m/z 344 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ 8.93 (d, J=0.80 Hz, 1H), 7.49 (td, J=2.10, 8.70 Hz, 2H), 7.46-7.42 (m, 3H), 4.77 (br. s, 2H), 2.57 (s, 3H).
Reaction SMILES: [CH3:1][Mg]Cl.[C:4]([C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19]([CH:21]2[O:25][N:24]=[C:23]([C:26]3[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=3)[CH2:22]2)=[O:20])=[CH:14][CH:13]=1)(=[O:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.O>C1COCC1>[OH:11][C:4]([C:12]1[CH:13]=[CH:14][C:15]([NH:18][C:19]([CH:21]2[O:25][N:24]=[C:23]([C:26]3[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=3)[CH2:22]2)=[O:20])=[CH:16][CH:17]=1)([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH3:1]
Reactant: O=C(c1ccccc1)c1ccc(NC(=O)C2CC(c3cccnc3)=NO2)cc1
Reactant: C[Mg]Cl
Solvent: O
Solvent: C1CCOC1
Product: CC(O)(c1ccccc1)c1ccc(NC(=O)C2CC(c3cccnc3)=NO2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 50 %

Procedure:
) CH3MgCl, 22% (w/w)/THF (0.003 mol) was added dropwise to a cooled (0° C.) solution of (±)-N-(4-benzoylphenyl)-4,5-dihydro-3-(3-pyridinyl)-5-isoxazolecarboxamide (0.003 mol) in THF (50 ml). The reaction mixture was stirred for 30 minutes at 0° C. More CH3MgCl, 22% w/w/THF (0.003 mol) was added and the mixture was stirred for 30 minutes at 0° C. Extra CH3MgCl, 22% (w/w)/THF (0.003 mol) was added and the reaction mixture was stirred for 30 minutes at 0° C. The mixture was allowed to warm to RT for 30 minutes, then cooled again to 0° C. Water was added. This mixture was extracted with CH2Cl2. The separated organic layer was dried (MgSO4), filtered and the solvent evaporated under reduced pressure. The crude oil was crystallized from EtOAc. The precipitate was filtered off, washed with EtOAc, and dried, yielding 0.5 g(50%) of (±)4,5-dihydro-N-[4-(1-hydroxy-1-phenylethyl)phenyl]-3-(3-pyridinyl)-5-isoxazolecarboxamide (compound 51).
Reaction SMILES: [CH2:1]([C:5]1[N:10]=[N:9][C:8]([C:11]([OH:13])=O)=[CH:7][C:6]=1[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:16][CH:15]=1)[CH2:2][CH2:3][CH3:4].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:51]([O:55][C:56]([N:58]1[CH2:62][C@H:61]([CH2:63][NH2:64])[O:60][C:59]1([CH3:66])[CH3:65])=[O:57])([CH3:54])([CH3:53])[CH3:52].CCN(C(C)C)C(C)C>CN(C=O)C.CCOCC.O>[C:51]([O:55][C:56]([N:58]1[CH2:62][C@H:61]([CH2:63][NH:64][C:11]([C:8]2[N:9]=[N:10][C:5]([CH2:1][CH2:2][CH2:3][CH3:4])=[C:6]([C:14]3[CH:15]=[CH:16][C:17]([O:20][CH:21]4[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]4)=[CH:18][CH:19]=3)[CH:7]=2)=[O:13])[O:60][C:59]1([CH3:66])[CH3:65])=[O:57])([CH3:54])([CH3:53])[CH3:52]
Reactant: CCCCc1nnc(C(=O)O)cc1-c1ccc(OC2CCCCC2)cc1
Reactant: CC(C)(C)OC(=O)N1C[C@H](CN)OC1(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCCCc1nnc(C(=O)NC[C@H]2CN(C(=O)OC(C)(C)C)C(C)(C)O2)cc1-c1ccc(OC2CCCCC2)cc1

Procedure:
To a mixture of 6-butyl-5-(4-cyclohexyloxy-phenyl)-pyridazine-3-carboxylic acid (Example 93, 0.34 mmol, 0.12 g), HBTU (0.34 mmol, 0.13 g) and (S)-5-aminomethyl-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (0.34 mmol, 0.05 mL) in DMF was added DIEA (1.0 mmol, 0.17 mL). Upon completion of the reaction, the mixture was diluted with ether, and then poured into water. The resulting mixture was extracted, the organic layer was dried. The solvent was removed, and the resulting residue was chromatographed with 4:1 hexane/EtOAc to provide (S)-5-({[6-butyl-5-(4-cyclohexyloxy-phenyl)-pyridazine-3-carbonyl]-amino}-methyl)-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester was used as is in the next step. LCMS: m/z 566.9 [M+1].
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH2:3][CH2:2]1.[CH2:8]([OH:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C1(C)C=CC=CC=1>[CH2:8]([O:15][C:4]([CH2:3][CH2:2][C:1]([OH:6])=[O:7])=[O:5])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C1CCC(=O)O1
Reactant: OCc1ccccc1
Solvent: Cc1ccccc1
Product: O=C(O)CCC(=O)OCc1ccccc1

Procedure:
A solution of succinic anhydride (16.0 g, 160 mmol) and benzyl alcohol (17.1 g, 158 mmol) in toluene (200 mL) was heated at reflux for 3.5 hr. At this time, the solvent was removed in vacuo to leave 3-(benzyloxycarbonyl)propanoic acid as a white solid.
Reaction SMILES: [F:1][C:2]([F:14])([CH3:13])[CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[CH:11]=[C:10]([NH2:12])[CH:9]=[N:8]1.[F:15][C:16]([F:29])([F:28])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1/[CH:23]=[CH:24]/[C:25](O)=[O:26]>>[F:14][C:2]([F:1])([CH3:13])[CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[CH:11]=[C:10]([NH:12][C:25](=[O:26])/[CH:24]=[CH:23]/[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[C:16]([F:28])([F:29])[F:15])[CH:9]=[N:8]1
Reactant: CC(F)(F)CCCCn1cc(N)cn1
Reactant: O=C(O)/C=C/c1ccccc1C(F)(F)F
Product: CC(F)(F)CCCCn1cc(NC(=O)/C=C/c2ccccc2C(F)(F)F)cn1

Procedure:
Following general procedure B, starting from 1-(5,5-difluoro-hexyl)-1H-pyrazol-4-ylamine and (E)-3-(2-trifluoromethyl-phenyl)-acrylic acid. LC-MS-conditions 05b: tR=1.12 min; [M+H]+=402.11.