Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:4](=[O:11])[NH:3][S:2]1(=[O:13])=[O:12].[OH-].[K+].Cl[CH2:17][CH2:18][C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:20].CN(C)C=O>CO>[O:20]=[C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:18][CH2:17][N:3]1[C:4](=[O:11])[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[CH2:1][S:2]1(=[O:12])=[O:13]
Reactant: O=C(CCCl)c1ccccc1
Reactant: O=C1NS(=O)(=O)Cc2ccccc21
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CO
Product: O=C(CCN1C(=O)c2ccccc2CS1(=O)=O)c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 67.5 %

Procedure:
1H-2,3-Benzothiazin-4(3H)-one 2,2-dioxide (1 g, 5.08 mmol.) was added to a solution of powdery potassium hydroxide (334 mg, 5.08 mmol.) in methanol (4 mL). The mixture was then stirred at room temperature for 15 min. The solution was placed under reduced pressure to distill the solvent off to dryness. To the dried product were added 3-chloropropiophenone (856 mg, 5.08 mmol.) and dimethylformamide (8 mL). The mixture was heated to 120° C. for 6 hours under stirring. The reaction liquid was placed under reduced pressure to distill the solvent off. To the resulting residue was added water, and it was extracted with ethyl acetate. The extract solution was washed with an aqueous saturated sodium chloride solution, and dried over anhydrous sodium sulfate. The dried extract solution was placed under reduced pressure to distill the solvent off. The resulting oil was treated by silica gel column chromatography (chloroform) to give the desired compound (1.13 g, yield 68%) as a white solid.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1/[CH:10]=[CH:11]/[CH:12]=[C:13](\[O:17][CH3:18])/[C:14]([OH:16])=O.[NH2:19][CH:20]1[CH2:25][C:24]([CH3:27])([CH3:26])[N:23]([CH3:28])[C:22]([CH3:30])([CH3:29])[CH2:21]1.O.ON1C2N=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>CN(C=O)C>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1/[CH:10]=[CH:11]/[CH:12]=[C:13](\[O:17][CH3:18])/[C:14]([NH:19][CH:20]1[CH2:21][C:22]([CH3:29])([CH3:30])[N:23]([CH3:28])[C:24]([CH3:27])([CH3:26])[CH2:25]1)=[O:16]
Reactant: CO/C(=C\C=C\c1cc2ccccc2o1)C(=O)O
Reactant: CN1C(C)(C)CC(N)CC1(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: O
Solvent: CN(C)C=O
Product: CO/C(=C\C=C\c1cc2ccccc2o1)C(=O)NC1CC(C)(C)N(C)C(C)(C)C1
Yield: 42.8 %

Procedure:
A solution of (2Z,4E)-5-(benzofuran-2-yl)-2-methoxy-2,4-pentadienoic acid (122 mg, 0.5 mmol), 4-amino-1,2,2,6,6-pentamethylpiperidine (85 mg, 0.5 mmol), 1-hydroxy-7-azabenzotriazole hydrate (65 mg, 0.5 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (95 mg, 0.5 mmol) in DMF (2 ml) was stirred at RT overnight. After the same work-up described in example 3 the residue was triturated with isopropyl ether to produce a solid that was recovered and dried to give pure title compound (85 mg, 0.214 mmol, yield 42.8%) as yellow crystals, m.p.=152°.
Reaction SMILES: Cl.[CH2:2]([N:9]1[C:16](=O)[C@@H:15]2[C@@H:11]([CH2:12][NH:13][CH2:14]2)[C:10]1=O)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].O.[OH-].[Na+]>C1COCC1>[CH2:2]([N:9]1[CH2:10][C@@H:11]2[C@@H:15]([CH2:14][NH:13][CH2:12]2)[CH2:16]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=C1[C@H]2CNC[C@H]2C(=O)N1Cc1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: c1ccc(CN2C[C@H]3CNC[C@H]3C2)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 84.1 %

Procedure:
3-Benzyl-3,7-diazabicyclo[3.3.0]octan-2,4-dione hydrochloride (73.8 g, 275 mmol; from step (b) above) was added in portions to a suspension of LiAlH4 (83.5 g, 2.26 mol) in THF at 0° C. The reaction was slowly warmed to reflux. After refluxing for 16 h the reaction was cooled to 0° C. To the cold reaction there was added dropwise sequentially H2O (84 mL), 3 M NaOH (84 mL) and H2O (250 mL). The reaction was then stirred for an additional 15 minutes and filtered through a pad of Celite® to remove the inorganic salts. The filtrate was concentrated in vacuo to afford the crude product. Kugelrohr distillation (95–115° C./66.5 Pa (0.5 mm Hg)) provided 46.8 g (84%) of the sub-title compound as a colourless oil.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][CH:10]([NH:13][C:14]2[N:19]=[CH:18][C:17](/[CH:20]=[CH:21]/[C:22]([OH:24])=O)=[CH:16][CH:15]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH:26]1[O:31][NH2:32].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C.C(OCC)(C)=O.O>[CH2:1]([N:8]1[CH2:12][CH2:11][CH:10]([NH:13][C:14]2[N:19]=[CH:18][C:17](/[CH:20]=[CH:21]/[C:22]([NH:32][O:31][CH:26]3[CH2:27][CH2:28][CH2:29][CH2:30][O:25]3)=[O:24])=[CH:16][CH:15]=2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NOC1CCCCO1
Reactant: O=C(O)/C=C/c1ccc(NC2CCN(Cc3ccccc3)C2)nc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(/C=C/c1ccc(NC2CCN(Cc3ccccc3)C2)nc1)NOC1CCCCO1
Temperature: 25 °C
Reaction time: 15 h
Yield: 32.5 %

Procedure:
A mixture of (2E)-3-{6-[(1-benzyl-3-pyrrolidinyl)amino]-3-pyridyl}acrylic acid (400 mg), O-(tetrahydro-2H-pyran-2-yl)hydroxylamine (159 mg), HOBt (175 mg) and EDCI (202 mg) in DMF (10 ml) was stirred at ambient temperature for 15 hours. The reaction mixture was poured into a mixture of AcOEt-H2O and the organic layer was washed with brine and dried over MgSO4— The solvent was evaporated in vacuo and the residue was chromatographed on silicagel eluting with AcOEt-MeOH (9:1). The eluted fractions containing the desired product were collected and evaporated in vacuo to give (2E)-3-{6-[(1-benzyl-3-pyrrolidinyl)amino]-3-pyridyl}-N-(tetrahydro-2H-pyran-2-yloxy)acrylamide (170 mg)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([NH:11][C:12]([C:14]1[C:15]([CH3:27])=[N:16][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=3)=[N:18][CH:19]=1)=[O:13])[CH:6]=[CH:5]2.ClS([N:32]=[C:33]=O)(=O)=O.CCN(CC)CC>C1COCC1.[Cl-].[Na+].O>[C:33]([C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=2)[N:7]([NH:11][C:12]([C:14]2[C:15]([CH3:27])=[N:16][C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=3)=[N:18][CH:19]=2)=[O:13])[CH:6]=1)#[N:32]
Reactant: Cc1nc(-c2cccc(F)c2)ncc1C(=O)Nn1ccc2cc(F)ccc21
Reactant: O=C=NS(=O)(=O)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1nc(-c2cccc(F)c2)ncc1C(=O)Nn1cc(C#N)c2cc(F)ccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 37.6 %

Procedure:
A solution of 2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid (5-fluoro-indol-1-yl)-amide (300 mg, 0.82 mmol) in THF (8 mL) is cooled to 0° C., treated with chlorosulfonyl isocyanate (86 μL, 0.99 mmol) and the mixture is stirred at rt for 1 h. The mixture is treated with Et3N (138 μL, 0.99 mmol) and stirred for 1 h. The mixture is diluted with brine, extracted with EtOAc. The organic layer is separated, dried (Na2SO4), filtered and concentrated in vacuo. The residue is purified by silica gel chromatography eluting with 25% -35% EtOAc in heptane to afford 2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid (3-cyano-5-fluoro-indol-1-yl)-amide (120 mg, 38%). MS: 390 (M+H); 1H NMR (300 MHz, DMSO-d6): δ 2.78 (s, 3H), 7.32 (m, 1H), 7.46 (m, 1H), 7.55 (m, 1H), 7.66 (m, 1H), 7.77 (m, 1H), 8.20 (m, 1H), 8.35 (m, 1H), 8.65 (s, 1H), 9.28 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[C:11](=O)[CH2:12][N:13]1[CH2:17][CH2:16][CH2:15][CH:14]1[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH2:25][CH2:26][CH2:27][N:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)[CH:19]=1.N>CO.C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[C@H:11]1[C:23]2[C:18](=[CH:19][C:20]([O:24][CH2:25][CH2:26][CH2:27][N:28]3[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)=[CH:21][CH:22]=2)[C@@H:14]2[CH2:15][CH2:16][CH2:17][N:13]2[CH2:12]1
Reactant: COc1ccc(OC)c(C(=O)CN2CCCC2c2cccc(OCCCN3CCCCC3)c2)c1
Agent: N
Solvent: ClCCl
Solvent: CO
Product: COc1ccc(OC)c([C@@H]2CN3CCC[C@H]3c3cc(OCCCN4CCCCC4)ccc32)c1
Yield: 78 %

Procedure:
1-(2,5-Dimethoxy-phenyl)-2-{2-[3-(3-piperidin-1-yl-propoxy)-phenyl]-pyrrolidin-1-yl}-ethanone. Prepared as described in Example 8, Step 1, on a 3.47 mmol scale, to give 1.27 g (78%) of the desired product as a pale yellow oil after chromatography (NH3 in MeOH/CH2Cl2). MS: exact mass calcd for C28H38N2O4, 466.3; m/z found, 467.5 [M+H]+. 1H NMR (MeOH-d4): 7.14 (m, 1H), 7.09 (d, J=3.2, 1H), 6.97 (dd, J=3.2, 9.0, 1H), 6.93 (d, J=1.6, 1H), 6.88 (m, 1H), 6.75 (m, 1H), 4.03 (d, J=18.4, 1H), 3.91 (m, 2H), 3.69 (s, 3H), 3.63 (s, 3H), 3.43 (m, 3H), 2.40 (m, 6H), 2.30 (m, 1H), 2.15 (m, 1H), 1.90 (m, 3H), 1.80 (m, 1H), 1.75 (m, 3H), 1.55 (m, 4H), 1.41 (m, 2H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[C:16](=[O:34])[N:17]([CH2:30][CH:31]3[CH2:33][CH2:32]3)[N:18]=[C:19]([C:21]3[CH:22]=[CH:23][C:24]4[O:28][CH2:27][CH2:26][C:25]=4[CH:29]=3)[CH:20]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.O.C(=O)([O-])[O-].[K+].[K+]>FC(F)(F)C(O)=O>[CH:31]1([CH2:30][N:17]2[C:16](=[O:34])[C:15]([CH2:14][N:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)=[CH:20][C:19]([C:21]3[CH:22]=[CH:23][C:24]4[O:28][CH2:27][CH2:26][C:25]=4[CH:29]=3)=[N:18]2)[CH2:33][CH2:32]1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2cc(-c3ccc4c(c3)CCO4)nn(CC3CC3)c2=O)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: O=c1c(CN2CCNCC2)cc(-c2ccc3c(c2)CCO3)nn1CC1CC1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
4-(4-tert-Butoxycarbonyl-1-piperazinyl)methyl-2-cyclopropylmethyl-6-(2,3-dihydro-1-benzofuran-5-yl)-2H-pyridazin-3-one (121 mg, 0.26 mmol) was dissolved in trifluoroacetic acid (1.1 mL) under cooling with ice-water, and the solution was stirred for 15 minutes at the same temperature. Water (10 mL) was added to the reaction mixture, and the resultant mixture was made alkaline with potassium carbonate, followed by extraction with chloroform. The organic layer was washed with saturated brine (20 mL) and dried over sodium sulfate anhydrate, and the solvent was removed under reduced pressure, to thereby yield 83 mg (87.4%) of the title compound as a yellow oil.
Reaction SMILES: [O:1]1CCO[CH:2]1[C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([NH2:20])=[O:19])[CH:13]=2)=[CH:8][C:7]=1[C:21]([F:24])([F:23])[F:22].CC(O)=O.C([O-])(O)=O.[Na+]>O>[CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([NH2:20])=[O:19])[CH:13]=2)=[CH:8][C:7]=1[C:21]([F:22])([F:23])[F:24])=[O:1]
Reactant: NC(=O)c1cccc(-c2ccc(C3OCCO3)c(C(F)(F)F)c2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: NC(=O)c1cccc(-c2ccc(C=O)c(C(F)(F)F)c2)c1
Temperature: 65 °C
Reaction time: 1 h

Procedure:
4′-(1,3-Dioxolan-2-yl)-3′-(trifluoromethyl)-1,1′-biphenyl-3-carboxamide (0.177 g; 0.525 mmol) was added to a solution of HOAc (4 mL) and water (1 mL) and the mixture was stirred at 65° C. in a sealed vial for 1 h. Upon cooling, the mixture was poured into satd NaHCO3 and extracted with EtOAc (×3). Combined organics were washed (water, brine), dried over Na2SO4 and concentrated in vacuo affording the title compound, which was used without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:18](C(O)=O)=[C:17]3[N:12]([N:13]=[CH:14][CH:15]=[CH:16]3)[N:11]=2)=[CH:6][CH:5]=1)[CH3:2].[I:22]N1C(=O)CCC1=O.C(=O)(O)[O-].[Na+]>CN(C=O)C>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:18]([I:22])=[C:17]3[N:12]([N:13]=[CH:14][CH:15]=[CH:16]3)[N:11]=2)=[CH:6][CH:5]=1)[CH3:2]
Reactant: O=C1CCC(=O)N1I
Reactant: CCOc1ccc(-c2nn3ncccc3c2C(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOc1ccc(-c2nn3ncccc3c2I)cc1
Reaction time: 4 h
Yield: 46.9 %

Procedure:
A mixture of 2-(4-ethoxy-phenyl)-pyrazolo[1,5-b]pyridazine-3-carboxylic acid (710 mg), N-iodosuccinimide (678 mg) and sodium bicarbonate (717 mg) in DMF (8 ml) was stirred for 4 h. A further quantity of N-iodosuccinimide(100 mg) was added and stirring continued for 2 h. Aqueous workup gave a dark brown solid which was purified by SPE with dichloromethane as eluant. This gave the title compound as an orange-brown solid (429 mg, 47%).
Reaction SMILES: [CH3:1][N:2]1[C:6]([N+:7]([O-:9])=[O:8])=[CH:5][N:4]=[C:3]1[C:10]1[CH:14]=[C:13]([C:15]([O:17]CC)=O)[O:12][N:11]=1.[NH3:20]>CO>[CH3:1][N:2]1[C:6]([N+:7]([O-:9])=[O:8])=[CH:5][N:4]=[C:3]1[C:10]1[CH:14]=[C:13]([C:15](=[O:17])[NH2:20])[O:12][N:11]=1
Reactant: N
Reactant: CCOC(=O)c1cc(-c2ncc([N+](=O)[O-])n2C)no1
Solvent: CO
Product: Cn1c([N+](=O)[O-])cnc1-c1cc(C(N)=O)on1

Procedure:
3 g. of the compound prepared in Example 12 is dissolved in hot methanol. The solution is saturated with ammonia. A precipitate is formed and the mixture is cooled by placing in the refrigerator. After filtration and purification, the pure product having a melting point of 235°-238° C. is recovered. This product is identified as 1-methyl-2-(5-carbamoyl-isoxazol-3-yl)-5-nitroimidazole.
Reaction SMILES: Cl.[CH:2]1([CH2:5][N:6]2[CH2:23][CH2:22][C@@:13]34[C:14]5[CH:15]=[C:16](O)[CH:17]=[CH:18][C:19]=5[CH2:20][C@@H:7]2[C@@H:8]3[CH2:9][C:10]([CH3:25])([CH3:24])[O:11][CH2:12]4)[CH2:4][CH2:3]1.Cl.[C:27](Cl)(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[N:30][CH:29]=1.N1C=CC=CC=1>C(Cl)Cl>[CH:2]1([CH2:5][N:6]2[CH2:23][CH2:22][C@@:13]34[C:14]5[CH:15]=[C:16]([C:27](=[O:34])[C:28]6[CH:33]=[CH:32][CH:31]=[N:30][CH:29]=6)[CH:17]=[CH:18][C:19]=5[CH2:20][C@@H:7]2[C@@H:8]3[CH2:9][C:10]([CH3:25])([CH3:24])[O:11][CH2:12]4)[CH2:4][CH2:3]1
Reactant: O=C(Cl)c1cccnc1
Reactant: CC1(C)C[C@H]2[C@H]3Cc4ccc(O)cc4[C@@]2(CCN3CC2CC2)CO1
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC1(C)C[C@H]2[C@H]3Cc4ccc(C(=O)c5cccnc5)cc4[C@@]2(CCN3CC2CC2)CO1

Procedure:
Equimolar amounts of 17-cyclopropylmethyl-7,7-dimethyl-3-hydroxy-6-oxamorphinan (XIV, prepared in Example 5), nicotinoyl chloride hydrochloride and pyridine are mixed together in dry methylene chloride and heated at reflux temperature for 3 hours to produce the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[CH:17]([OH:19])[CH3:18].Cl[C:21]1[CH:22]=[CH:23][C:24]2[N:25]([C:27]([CH2:30][NH:31][C:32]3[C:41]4[C:36](=[CH:37][C:38]([O:42][CH3:43])=[CH:39][N:40]=4)[N:35]=[CH:34][CH:33]=3)=[N:28][N:29]=2)[N:26]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O>[Cl:1][C:2]1[CH:7]=[C:6]([C:21]2[CH:22]=[CH:23][C:24]3[N:25]([C:27]([CH2:30][NH:31][C:32]4[C:41]5[C:36](=[CH:37][C:38]([O:42][CH3:43])=[CH:39][N:40]=5)[N:35]=[CH:34][CH:33]=4)=[N:28][N:29]=3)[N:26]=2)[CH:5]=[CH:4][C:3]=1[CH:17]([OH:19])[CH3:18]
Reactant: CC(O)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1Cl
Reactant: COc1cnc2c(NCc3nnc4ccc(Cl)nn34)ccnc2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: COc1cnc2c(NCc3nnc4ccc(-c5ccc(C(C)O)c(Cl)c5)nn34)ccnc2c1
Temperature: 100 °C

Procedure:
A suspension of 1-(2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethanol (228 mg, 807 μmol), N-((6-chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl)-7-methoxy-1,5-naphthyridin-4-amine (197 mg, 576 μmol), dichloro[1,1 bis(diphenylphoshino)ferrocene]palladium(ii)dichloromethane adduct (127 mg, 173 μmol), cesium carbonate (751 mg, 2306 μmol) in dioxane (3 mL) and water (0.6 mL) was sparged with argon for 5 min then heated to 100° C. for 6 h. Reaction cooled then partitioned between 9:1 CHCl3/IPA (20 mL) and 1M NaOH (15 mL). Aqueous further extracted with 9:1 CHCl3/IPA (2×10 mL). The combined organics dried over MgSO4. concentrated, then purified on 40 g silica eluting with an isocratic 7% 2M NH3 in MeOH/DCM. Product further purified prep HPLC eluting with water/ACN (0.1% TFA). After collected fractions were reduced to a clear the residue was dissolved in 1:1 ACN/water and pH adjusted to 9 with 1M NaOH (3-4 drops). Resulting solid collected by filtration and solid washed with water (2 mL). MS (ESI pos. ion) m/z: 462 (MH+). Calc'd exact mass for C23H20ClN7O2: 461.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[N:7]1[CH2:12][CH2:11][N:10]([CH2:13][C:14]#[C:15][CH2:16][N:17]2[C:26](=[O:27])[CH2:25][C:20]3([CH2:24][CH2:23][CH2:22][CH2:21]3)[CH2:19][C:18]2=[O:28])[CH2:9][CH2:8]1.[H][H].C1C2(CC(=O)NC(=O)C2)CCC1>S1C=CC=C1.[Pd]>[N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[N:7]1[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][CH2:15][CH2:16][N:17]2[C:26](=[O:27])[CH2:25][C:20]3([CH2:24][CH2:23][CH2:22][CH2:21]3)[CH2:19][C:18]2=[O:28])[CH2:9][CH2:8]1
Reactant: [H][H]
Reactant: O=C1CC2(CCCC2)CC(=O)N1CC#CCN1CCN(c2ncccn2)CC1
Agent: [Pd]
Agent: O=C1CC2(CCCC2)CC(=O)N1
Solvent: c1ccsc1
Product: O=C1CC2(CCCC2)CC(=O)N1CCCCN1CCN(c2ncccn2)CC1
Reaction time: 0 h
Yield: 100.1 %

Procedure:
A solution of 100 g (0.26 mole) of 8-[4-[4-(pyrimidine-2-yl)-piperazine-1-yl]-but-2-inyl]-8-aza-spiro[4.5]decane-7,9-dione in 50 ml thiophen-free benzene is added to a suspension of 2 g of a palladium/carbon catalyst (palladium content about 5% by weight) and 50 ml of thiophen-free benzene under vigorous stirring at 20°-40° C. under the introduction of hydrogen under a pressure of 1 bar at such a rate that the hydrogen uptake of the unsaturated 8-[4-[4-pyrimidine-2-yl)-piperazine-1-yl]-but-2-inyl]-8-aza-spiro[4.5]decane-7,9-dione added is substantially identical with the calculated hydrogen consumption continuously measured with the aid of a gas burette. This practically means that when the addition of the active ingredient is stopped, the hydrogen consumption ceases within 5-10 seconds. The reaction temperature is 20°-40° C. and the reaction time is 1-4 hours. When the reduction has been terminated, the catalyst is filtered off. The catalyst can be directly used in the next hydrogenating operations without any further treatment. The filtrate is evaporated and the residue is suspended in isopropanol and filtered. Thus in the form of white crystals 100.3 g of 8-[4-[4-(pyrimidine-2yl)-piperazine-1-yl]-butyl]-8-aza-spiro[4.5]decane-7.9-dione base are obtained, yield: about 100%.Mp.:105°-106° C. (according to prior art 90°-98° C.). Content: (on the base) 99.8-100.1%. According to HPLC analysis the product contains only 0.1% of contaminations.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[CH:11][C:12]3[O:18][CH2:17][CH2:16][NH:15][C:14](=[O:19])[C:13]=3[CH:20]=2)=[CH:5][CH:4]=1.[H-].[Na+].Cl[CH2:26][C:27]1[N:28]=[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][N:30]2[CH:35]=1.C(OCC)(=O)C>C1COCC1>[N:28]1[C:27]([CH2:26][N:15]2[C:14](=[O:19])[C:13]3[CH:20]=[C:9]([C:6]4[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:21])[F:22])=[CH:8][CH:7]=4)[CH:10]=[CH:11][C:12]=3[O:18][CH2:17][CH2:16]2)=[CH:35][N:30]2[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=12
Reactant: O=C1NCCOc2ccc(-c3ccc(C(F)(F)F)cc3)cc21
Reactant: ClCc1cn2ccccc2n1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C1c2cc(-c3ccc(C(F)(F)F)cc3)ccc2OCCN1Cc1cn2ccccc2n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
7-(4-(trifluoromethyl)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one (50 mg) was dissolved in dry THF and the NaH suspension (6 mg, 60% in oil) was added, followed shortly by 2-(chloromethyl)imidazo[1,2-a]pyridine (29 mg) and stirred overnight at room temperature. Worked up with ethyl acetate and pH 7 buffer organic layer dried over MgS(O)4 and concentrated. Purification was conducted on normal phase (CH2Cl2/10% EtOH in ethyl acetate gradient) followed by reverse-phase (ACN/H2O, 0.1% TFA). Resulting glassy solid was dissolved in dioxane, diluted 10-fold with 0.1N HCl and lyophilized resulting in 4-(imidazo[1,2-a]pyridin-2-ylmethyl)-7-(4-(trifluoromethyl)phenyl)-3,4-dihydrobenzo[f][1,4]oxazepin-5(2H)-one hydrochloride salt as a white solid (42.2 mg).
Reaction SMILES: [CH:1]([Li])([CH3:3])[CH3:2].[CH:5]([O:8][B:9](OC(C)C)[O:10][CH:11]([CH3:13])[CH3:12])([CH3:7])[CH3:6]>>[CH:1]([B:9]([O:10][CH:11]([CH3:13])[CH3:12])[O:8][CH:5]([CH3:7])[CH3:6])([CH3:3])[CH3:2]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: [Li]C(C)C
Product: CC(C)OB(OC(C)C)C(C)C
Temperature: 80 °C

Procedure:
The title compound was prepared following the procedure of Example 1, from isopropyllithium (177 mL, 101 mmol) and triisopropoxyborane (19.0 g, 101 mmol). Solvent was removed at 0° C. and 15 mm Hg. The oil bath was heated to 80° C. Yield: 16.3 g (94.2 mmol, 93%), bp 138° C. (749 mm Hg); n20D 1.3853; proton NMR (CDCl3) δ4.40 (septet, J=18 Hz, 2H); 1.13 (d, J=18 Hz, 12H), 0.93 (bs, 7H); boron NMR (neat) δ+30.5 ppm (s). Anal. Calcd. for C9H21BO2 : C, 62.80; H, 12.22; B, 6.29. Found: C, 62.59; H, 12.59; B, 5.93.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:14]3[CH:15]=[CH:16][S:17][C:13]=3[CH2:12][CH2:11][NH:10]2)=[CH:5][CH:4]=1.C(N(C(C)C)CC)(C)C.[C:29](Cl)(=[O:38])[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([O:36][CH3:37])[CH:31]=1>ClCCl>[F:19][C:2]([F:1])([F:18])[C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[C:14]3[CH:15]=[CH:16][S:17][C:13]=3[CH2:12][CH2:11][N:10]2[C:29]([C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([O:36][CH3:37])[CH:31]=2)=[O:38])=[CH:7][CH:8]=1
Reactant: FC(F)(F)c1ccc(C2NCCc3sccc32)cc1
Reactant: COc1cccc(C(=O)Cl)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cccc(C(=O)N2CCc3sccc3C2c2ccc(C(F)(F)F)cc2)c1
Reaction time: 8 h

Procedure:
4-(4-Trifluoromethylphenyl)-4,5,6,7-tetrahydro-thieno[3,2-c]pyridine (100 mg, 0.35 mmol) was dissolved in dichloromethane (1 mL) and diisopropylethylamine (0.5 mL) was added. To this solution m-anisoyl chloride (50 μL, 0.35 mmol) was added. The mixture was shaken overnight and evaporated to afford the title compound.
Reaction SMILES: [C:1]1([CH:7]2[O:11][N:10]=[C:9]([C:12]3[N:13]=[C:14]([CH:17]4[CH2:22][CH2:21][N:20]([C:23]([NH:25][C:26]5[CH:31]=[C:30]([CH3:32])[CH:29]=[CH:28][C:27]=5[CH3:33])=O)[CH2:19][CH2:18]4)[S:15][CH:16]=3)[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:35]>ClCCl>[C:1]1([CH:7]2[O:11][N:10]=[C:9]([C:12]3[N:13]=[C:14]([CH:17]4[CH2:22][CH2:21][N:20]([C:23]([Cl:35])=[N:25][C:26]5[CH:31]=[C:30]([CH3:32])[CH:29]=[CH:28][C:27]=5[CH3:33])[CH2:19][CH2:18]4)[S:15][CH:16]=3)[CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: Cc1ccc(C)c(NC(=O)N2CCC(c3nc(C4=NOC(c5ccccc5)C4)cs3)CC2)c1
Solvent: ClCCl
Product: Cc1ccc(C)c(N=C(Cl)N2CCC(c3nc(C4=NOC(c5ccccc5)C4)cs3)CC2)c1
Temperature: 40 °C

Procedure:
To a mixture of 4-[4-(4,5-dihydro-5-phenyl-3-isoxazolyl)-2-thiazolyl]-N-(2,5-dimethylphenyl)-1-piperidinecarboxamide (i.e. the product of Step A) (0.406 g, 0.88 mmol) in dichloromethane (10 mL) was added phosphorus pentachloride (0.208 g, 1.0 mmol). The reaction mixture was heated at 40° C. for 16 h, and then concentrated under reduced pressure to provide the title compound as a foamy white solid (0.52 g).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8]C(=O)C)=[C:4](F)[CH:3]=1.O.[NH2:14][NH2:15].C([O-])(O)=O.[Na+]>C(O)C>[NH:14]1[C:4]2[C:5](=[CH:6][CH:7]=[CH:2][CH:3]=2)[CH:8]=[N:15]1
Reactant: CC(=O)Cc1ccc(Br)cc1F
Reactant: NN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: c1ccc2[nH]ncc2c1
Temperature: 162.5 °C
Yield: 148.8 %

Procedure:
A solution of 4-bromo-2-fluoro-N-methoxy-N-methyl-benzamide (CAS [801303-33-3]) (24.9 g, 95.0 mmol) in THF (100 mL) at −78° C. was treated with a 3 N solution of ethyl magnesium bromide in diethyl ether (33.25 mL, 115 mmol) and allowed to warm to 0 C and stir for a 6 h period, after which time the reaction mixture was quenched with a half saturated aqueous solution of NH4Cl (200 mL) and EtOAc (100 mL). The mixture was separated and the organic component, washed with brine (2×50 mL), dried over MgSO4, filtered, and evaporated to an oil which was purified by silica gel flash chromatography with 20% EtOAc/hexanes as eluant to afford 1-(4-bromo-2-fluorophenyl)-propanone as a pale yellow solid (16.25 g, 74%). The propanone (21.15 g, 91.6 mmol) was then dissolved in ethanol (100 mL), treated with hydrazine hydrate (4.9 mL, 100.7 mmol), and heated at reflux for 4 h. The reaction mixture was then evaporated and dissolved in ethylene glycol (100 mL) and heated at 160-165° C. for 8 h after which time the cooled reaction mixture was poured onto water (500 mL) with stirring. The aqueous mixture was neutralized, with rapid stirring, using a small amount of an aqueous saturated solution of NaHCO3 to afford a pale yellow precipitate. The solids were filtered, washed with water, and air dried to afford cyclized indazole product (16.1 g, 78%).