Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O1CCCCC1[O:7][CH2:8][CH2:9][CH2:10][C:11]([C:13]1[N:14]=[CH:15][N:16](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:17]=1)=[O:12].Cl.C(=O)(O)[O-].[Na+]>O1CCCC1>[OH:7][CH2:8][CH2:9][CH2:10][C:11]([C:13]1[N:14]=[CH:15][NH:16][CH:17]=1)=[O:12]
Reactant: O=C(CCCOC1CCCCO1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(CCCO)c1c[nH]cn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 102.6 %

Procedure:
4-(Tetrahydro-2H-pyran-2-yloxy)-1-(1-trityl-1H-imidazol-4-yl)butan-1-one (28.51 g) and 6 N hydrochloric acid (17.5 ml) were dissolved in tetrahydrofuran (200 ml) and the mixture was stirred at room temperature for 3 h. Sodium bicarbonate (8.82 g) was added to the reaction mixture, and after removal of the precipitate by filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent; ethyl acetate:methanol=4:1) and recrystallized from methanol/ethyl acetate/diethyl ether to give the title compound (9.38 g) as a pale yellow powder.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:5]=2[N:6]=1.[CH3:12][C:13]1[S:17][C:16]([C:18](Cl)=[O:19])=[CH:15][CH:14]=1>N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[F:11][C:7]1[C:5]2[N:6]=[C:2]([NH:1][C:18]([C:16]3[S:17][C:13]([CH3:12])=[CH:14][CH:15]=3)=[O:19])[S:3][C:4]=2[CH:10]=[CH:9][CH:8]=1
Reactant: Nc1nc2c(F)cccc2s1
Reactant: Cc1ccc(C(=O)Cl)s1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: Cc1ccc(C(=O)Nc2nc3c(F)cccc3s2)s1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-Amino-4-flourobenzothiazol (84 mg, 0.50 mmol) is dissolved in pyridine (3 ml) and treated with 4-dimethylaminopyridine (1 mg) and 5-methyl-thiophene-2-carbonyl chloride (161 mg, 1.0 mmol). After stirring for 1 h at ambient temperature, the reaction mixture was evaporated to dryness. Flash chromatography on silica (eluent diethyl ether/cyclohexane 1:1 containing 0.5% of 25% aqueous ammonia) and final recrystallization from ethyl acetate affords the product as off-white solid. (34 mg, 69%). MS: m/e=292 (M+).
Reaction SMILES: [C:1]1([NH:11][C:12](=[O:20])OC2C=CC=CC=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.[CH3:21][CH:22]1[CH2:27][CH2:26][N:25]([C:28]2[C:33]([CH2:34][NH2:35])=[CH:32][CH:31]=[C:30]([C:36]([F:39])([F:38])[F:37])[N:29]=2)[CH2:24][CH2:23]1.C(N(CC)CC)C>CS(C)=O.O>[C:1]1([NH:11][C:12]([NH:35][CH2:34][C:33]2[C:28]([N:25]3[CH2:26][CH2:27][CH:22]([CH3:21])[CH2:23][CH2:24]3)=[N:29][C:30]([C:36]([F:39])([F:37])[F:38])=[CH:31][CH:32]=2)=[O:20])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1
Reactant: CC1CCN(c2nc(C(F)(F)F)ccc2CN)CC1
Reactant: O=C(Nc1nccc2ccccc12)Oc1ccccc1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: O
Product: CC1CCN(c2nc(C(F)(F)F)ccc2CNC(=O)Nc2nccc3ccccc23)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 34.6 %

Procedure:
Phenyl isoquinolin-1-ylcarbamate (80 mg, 0.30 mmol) and (2-(4-methylpiperidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl)methanamine (87 mg, 0.32 mmol) was dissolved in dimethyl sulfoxide. Then triethylamine (0.08 mL, 0.61 mmol) was added to it. The mixture was stirred at room temperature for 12 h. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was concentrated under reduced pressure. The crude was purified by column chromatography to give 1-(isoquinolin-1-yl)-3-((2-(4-methylpiperidin-1-yl)-6-(trifluoromethyl)pyridin-3-yl)methyl)urea (example compound 20) (46 mg, 34%).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].ClCCl.C(OC(=O)[NH:17][C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([NH:27][C:28](=[O:44])[C:29]([N:31]3[CH2:36][CH2:35][CH:34]([CH2:37][C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)[CH2:33][CH2:32]3)=[O:30])=[CH:26][C:20]=2[N:19]=1)(C)(C)C>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:17][C:18]1[NH:19][C:20]2[CH:26]=[C:25]([NH:27][C:28](=[O:44])[C:29]([N:31]3[CH2:36][CH2:35][CH:34]([CH2:37][C:38]4[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=4)[CH2:33][CH2:32]3)=[O:30])[CH:24]=[CH:23][C:21]=2[N:22]=1
Reactant: CC(C)(C)OC(=O)Nc1nc2cc(NC(=O)C(=O)N3CCC(Cc4ccccc4)CC3)ccc2[nH]1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1nc2ccc(NC(=O)C(=O)N3CCC(Cc4ccccc4)CC3)cc2[nH]1
Temperature: 20 °C
Reaction time: 48 h
Yield: 97.1 %

Procedure:
To a solution of 5 ml of 5% trifluoroacetic acid in dichloromethane 0.8 g (1.67 mmol) of {5-[2-(4-benzyl-piperidin-1-yl)-2-oxo-acetylamino]-1H-benzimidazol-2-yl}-carbamic acid tert-butyl ester is added. The reaction mixture is stirred for 48 hours at 20° C. The precipitated crystals are filtered off and washed with dichloromethane to yield 0.8 g (97.1%) of the title compound. Melting Point: 121° C.
Reaction SMILES: [CH:1]([Mg]Br)=[CH2:2].[Cl:5][C:6]1[C:11]([N+:12]([O-])=O)=[CH:10][CH:9]=[C:8]([CH3:15])[N:7]=1.C(=O)=O.[Cl-].[NH4+]>C1COCC1>[Cl:5][C:6]1[N:7]=[C:8]([CH3:15])[CH:9]=[C:10]2[CH:2]=[CH:1][NH:12][C:11]=12
Reactant: Cc1ccc([N+](=O)[O-])c(Cl)n1
Reactant: C=C[Mg]Br
Agent: O=C=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1cc2cc[nH]c2c(Cl)n1
Reaction time: 18 h
Yield: 44 %

Procedure:
Vinylmagnesium bromide solution (1 M in THF, 111 mL, 111 mmol) was added dropwise at −78° C. to a solution of 2-chloro-3-nitro-6-picoline (6.19 g, 35.2 mmol) in THF (200 mL). The dry ice cooling bath was replaced by an ice/NaCl cooling bath, and the reaction mixture was allowed to reach RT over 18 h, then the reaction mixture was carefully treated with 20% aq. ammonium chloride solution (210 mL). The reaction mixture was extracted with ethyl acetate, the organic layer was dried (MgSO4), and evaporated. Chromatography of the residue (SiO2, heptane/ethyl acetate gradient) afforded the title compound (2.58 g, 44%). Orange solid, MS (EI) 166.1 (100, M+).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Br[C:21]1[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][CH:22]=1.[CH2:31]([OH:35])[CH2:32][C:33]#[CH:34]>C(NCC)C.[Pd](Cl)Cl.[Cu]I>[OH:35][CH2:31][CH2:32][CH2:33][CH2:34][C:21]1[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][CH:22]=1
Reactant: C#CCCO
Reactant: COC(=O)c1ccc(Br)cc1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCNCC
Product: COC(=O)c1ccc(CCCCO)cc1
Yield: 75.8 %

Procedure:
To a mixture of 0.082 g (0.005 eq) of palladium chloride, and 0.244 g (0.01 eq) of triphenylphosphine, and 20.00 g (1.0 eq) of methyl 4-bromobenzoate in diethylamine which is stirred under nitrogen is added 0.178 g (0.01 eq) of copper (I) iodide and 6.52 g (1.0 eq) of 3-butyn-1-ol. The reaction mixture is stirred under nitrogen at room temperature (about 25° C.) for eighteen hours. Diethylamine is then removed under reduced pressure, water is added, and the mixture extracted with benzene. The benzene extracts are filtered through silica to remove the metal residue and the filtrate concentrated under reduced pressure to yield methyl 4-(4-hydroxybut-1-yl)benzoate. Recrystallization from a mixture of benzene and hexane yields pure material in 75.8% yield, m.p. 95.5°-96.0° C.; IR (KBr) νmax 3310, 2955, 1718, 1604, 1433, 1275, 1177, 1108, 1040, 955, 852, and 769 cm-1 ; 1H NMR (CDCl3) delta 7.98 (d, J=8.3 Hz, 2H, Ar), 7.49 (d, J=8.3 Hz, 2H, Ar), 3.93 (s, 3H, --CH3), 3.87 (m, 2H, --CH2OH), 2.74 (t, J=6.2 Hz, 2H, --yl--CH2 --), 1.88 (m, 1H, --OH).
Reaction SMILES: [CH3:1][O:2][C:3]1[S:4][CH:5]=[C:6]([O:8][CH3:9])[N:7]=1.C1(N(C)[CH:17]=[O:18])C=CC=CC=1.P(Cl)(Cl)(Cl)=O.C(Cl)(Cl)=O.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O>ClCCl>[CH3:1][O:2][C:3]1[S:4][C:5]([CH:17]=[O:18])=[C:6]([O:8][CH3:9])[N:7]=1
Reactant: COc1csc(OC)n1
Reactant: CN(C=O)c1ccccc1
Agent: O=C(Cl)Cl
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: O=P(Cl)(Cl)Cl
Product: COc1nc(OC)c(C=O)s1

Procedure:
To a stirred solution of 2,4-dimethoxythiazole (0.01 mol), which may be prepared as described in Step (a) above, in dichloromethane is added N-phenyl-N-methylformamide (0.01 mol) and phosphorous oxychloride (POCl3, 0.01 mol), or optionally phosgene or trifluoromethanesulfonic acid anhydride instead of POCl3, and the mixture is stirred. Reaction progress may be followed by TLC or HPLC. When a sufficient amount of the desired product is formed, the mixture is partitioned between ethyl acetate and water. The organic layer is washed with brine, dried over sodium sulfate, and rotary evaporated to give 2,4-dimethoxythiazole-5-carboxaldehyde, which may be purified, if needed or desired, by chromatography on silica gel or crystallization.
Reaction SMILES: [CH2:1]([N:4]1[CH:8]([CH2:9][CH2:10][CH3:11])[CH2:7][O:6][S@:5]1=[O:12])[CH2:2][CH3:3].I([O-])(=O)(=O)=[O:14].[Na+]>C(OCC)(=O)C.O.[Ru](Cl)(Cl)Cl>[CH2:1]([N:4]1[C@H:8]([CH2:9][CH2:10][CH3:11])[CH2:7][O:6][S:5]1(=[O:14])=[O:12])[CH2:2][CH3:3]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: CCCC1CO[S@@](=O)N1CCC
Agent: Cl[Ru](Cl)Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: CCC[C@@H]1COS(=O)(=O)N1CCC
Temperature: 3 °C
Yield: 93 %

Procedure:
Ruthenium trichloride hydrate (10 mg) was added to a solution of (R)-3,4-dipropyl-1,2,3-oxathiazolidine 2-oxide (11.09 g) in ethyl acetate (58 mL) under stirring at 3° C. A cold saturated aqueous sodium periodate solution (200 mL) was added to the solution. The resulting suspension was stirred under ice-cooling for 10 minutes and then further stirred at room temperature for 1 hour. The suspension was filtered, and the insoluble matter was washed twice with ethyl acetate (15 mL). The filtrate and the washings were combined. The organic layer was separated, washed with a saturated aqueous sodium hydrogen carbonate solution (15 mL), dried over anhydrous sodium sulfate and then concentrated under reduced pressure. Tetrahydrofuran (13.5 mL) was added to the residue, and the mixture was concentrated under reduced pressure. The concentration was repeated three times. (R)-3,4-Dipropyl-1,2,3-oxathiazolidine 2,2-dioxide (11.22 g, 93% yield) was obtained as a brown oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[NH:7][C:6](=[O:12])[CH2:5]2.[CH3:13]O>[Ni]>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[NH:7][C:6](=[O:12])[CH:5]2[CH3:13]
Reactant: O=C1Cc2cc(F)c(F)cc2N1
Reactant: CO
Agent: [Ni]
Product: CC1C(=O)Nc2cc(F)c(F)cc21

Procedure:
1.5 g (9.0 mmol) 5,6-difluoro-1,3-dihydro-indol-2-one were stirred with 1.0 g Raney nickel in 50 mL methanol 3 h at 200° C. in an autoclave. The catalyst was filtered off and the filtrate was concentrated to dryness by rotary evaporation.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][OH:10])[CH:5]=[CH:4][N:3]=1.C(N(CC)CC)C.[CH3:18][S:19](Cl)(=[O:21])=[O:20].O>C(OCC)(=O)C>[CH3:18][S:19]([O:10][CH2:9][CH2:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([F:1])[CH:7]=1)(=[O:21])=[O:20]
Reactant: CS(=O)(=O)Cl
Reactant: OCCc1ccnc(F)c1
Solvent: CCN(CC)CC
Solvent: O
Solvent: CCOC(C)=O
Product: CS(=O)(=O)OCCc1ccnc(F)c1
Yield: 74.8 %

Procedure:
To a solution of compound 42 (6.50 g, 46.1 mmol) in anhydrous ethyl acetate (250 mL) were added successively at 0° C., under argon, triethylamine (6.40 mL, 46.0 mmol) and dropwise methanesulfonyl chloride (3.60 mL, 46.5 mmol). The mixture was stirred at 0° C. for 10 min before addition of water (200 mL) at room temperature. The mixture was extracted with ethyl acetate (3×200 mL). The organic layers were combined, dried on magnesium sulfate, filtered and evaporated under vacuum. The residue was chromatographed (Al2O3, CH2Cl2) to give sulfonate 43 (7.56 g, 34.5 mmol) as a yellow oil. Yield 75%; Rf (Al2O3, CH2Cl2) 0.52; IR (CCl4) ν 1179, 1352, 1414, 1613 cm−1; 1H NMR (200 MHz, CDCl3) δ 2.95 (s, 3H), 3.09 (t, 2H, J=6.4 Hz), 4.45 (t, 2H, J=6.4 Hz), 6.82 (s, 1H), 7.07 (d, 1H, J=5.1 Hz), 8.15 (d, 1H, J=5.1 Hz); MS m/z 219 (M+, 3), 123 (100), 111 (30), 83 (14), 79 (53), 57 (11).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C@@H:6]1[C@H:10]([O:11][Si](C(C)(C)C)(C)C)[C@@H:9]([C@@H:19]([CH3:21])[OH:20])[O:8][C@H:7]1[N:22]1[CH:29]=[C:28]([CH3:30])[C:26](=[O:27])[NH:25][C:23]1=[O:24].[CH3:31][O:32][C:33]1[CH:54]=[CH:53][C:36]([C:37](Cl)([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[C:38]2[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[CH:40][CH:39]=2)=[CH:35][CH:34]=1.F.F.F.C(N(CC)CC)C.C(N(CC)CC)C>C1COCC1.CCOC(C)=O>[CH3:45][O:44][C:41]1[CH:40]=[CH:39][C:38]([C:37]([O:20][C@H:19]([CH3:21])[C@H:9]2[O:8][C@@H:7]([N:22]3[CH:29]=[C:28]([CH3:30])[C:26](=[O:27])[NH:25][C:23]3=[O:24])[C@H:6]([O:5][CH2:4][CH2:3][O:2][CH3:1])[C@@H:10]2[OH:11])([C:46]2[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=2)[C:36]2[CH:53]=[CH:54][C:33]([O:32][CH3:31])=[CH:34][CH:35]=2)=[CH:43][CH:42]=1
Reactant: COCCO[C@@H]1[C@H](O[Si](C)(C)C(C)(C)C)[C@@H]([C@@H](C)O)O[C@H]1n1cc(C)c(=O)[nH]c1=O
Reactant: COc1ccc(C(Cl)(c2ccccc2)c2ccc(OC)cc2)cc1
Agent: F
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COCCO[C@@H]1[C@H](O)[C@@H]([C@@H](C)OC(c2ccccc2)(c2ccc(OC)cc2)c2ccc(OC)cc2)O[C@H]1n1cc(C)c(=O)[nH]c1=O
Temperature: 45 °C
Reaction time: 18 h
Yield: 72.4 %

Procedure:
Compound 11 (0.42 g, 0.96 mmol) was mixed with 4,4′-dimethoxytrityl chloride (0.82 g, 2.41 mmol) and dried over P2O5 under reduced pressure. The mixture was dissolved in anhydrous pyridine (3 mL) and stirred at 45° C. for 18 h under an atmosphere of argon. The reaction mixture was cooled to room temperature and diluted with EtOAc (40 mL) and washed with saturated aqueous NaHCO3 (60 mL) and brine (40 mL), dried over Na2SO4, filtered and concentrated. The residue obtained was purified by silica gel column chromatography and eluted first with 50% EtOAc in hexanes and then with 5% methanol in CH2Cl2. The product obtained was dissolved in a mixture of triethylamine trihydrofluoride (1.38 mL, 8.44 mmol) and triethylamine (0.58 mL, 4.22 mmol) in THF (8.4 mL). After 72 h the mixture was diluted with EtOAc (60 mL), washed with water (40 mL), saturated aqueous NaHCO3 (40 mL) and brine (40 mL) then dried over Na2SO4, filtered and evaporated. The residue obtained was purified by silica gel column chromatography and eluted with 70% EtOAc in hexanes to yield Compound 12 (0.44 g, 73%). ES MS m/z 631.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([OH:9])=O)=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[B-](F)(F)(F)F.CCOC(C(C#N)=NOC(N(C)C)=[N+](C)C)=O.Cl.[CH3:42][O:43][C:44](=[O:56])[C@@H:45]([NH:48][C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])[CH2:46][NH2:47]>C(Cl)Cl>[CH3:42][O:43][C:44](=[O:56])[C@@H:45]([NH:48][C:49]([O:51][C:52]([CH3:54])([CH3:53])[CH3:55])=[O:50])[CH2:46][NH:47][C:7]([C:5]1[S:6][C:2]([Cl:1])=[CH:3][CH:4]=1)=[O:9]
Reactant: O=C(O)c1ccc(Cl)s1
Reactant: COC(=O)[C@H](CN)NC(=O)OC(C)(C)C
Agent: CCOC(=O)C(C#N)=NOC(N(C)C)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@H](CNC(=O)c1ccc(Cl)s1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5-Chloro-thiophene-2-carboxylic acid (16.26 g, 0.1 mol) in 500 ml DCM was stirred with DIPEA (51.04 ml, 0.3 mol) and TOTU (32.8 g, 0.1 mmol) at RT for 5 min. Commercially available (S)-3-amino-2-tert-butoxycarbonylamino-propionic acid methyl ester hydrochloride (25.4 g, 0.1 mol) were added and the reaction mixture was stirred at RT overnight and then evaporated. The resulting solid was suspended in 400 ml DCM and washed subsequently with sat. aq NaHCO3, 1N HCl and brine. The organic layer was dried with MgSO4, filtered and evaporated. The crude material was triturated with DCM and the solid filtered off. One obtained 18.4 g white, amorphous solid which was used in the next step without further purification.
Reaction SMILES: [N:1]1([C:7]2[S:8][N:9]=[C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=23)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Br[CH2:17][CH2:18][CH2:19][CH2:20][N:21]1[C:30](=[O:31])[CH2:29][C:24]2([CH2:28][CH2:27][CH2:26][CH2:25]2)[CH2:23][C:22]1=[O:32].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(#N)C>[N:9]1[S:8][C:7]([N:1]2[CH2:6][CH2:5][N:4]([CH2:17][CH2:18][CH2:19][CH2:20][N:21]3[C:22](=[O:32])[CH2:23][C:24]4([CH2:28][CH2:27][CH2:26][CH2:25]4)[CH2:29][C:30]3=[O:31])[CH2:3][CH2:2]2)=[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=12
Reactant: O=C1CC2(CCCC2)CC(=O)N1CCCCBr
Reactant: c1ccc2c(N3CCNCC3)snc2c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: O=C1CC2(CCCC2)CC(=O)N1CCCCN1CCN(c2snc3ccccc23)CC1
Yield: 93 %

Procedure:
Title product dihydrochloride dihydrate. A mixture of 3-(1-piperazinyl)-2,1-benzisothiazole (4.0 g., 0.018 mole) and 8-(4-bromobutyl)-8-azaspiro[4.5]decane-7,9-dione (5.5 g., 0.018 mole), anhydrous potassium carbonate (4.98 g., 0.036 mole) and potassium iodide (0.83 g., 0.005 mole) in 100 ml. of acetonitrile is stirred at reflux temperature for a period of 20 hr. The reaction mixture is filtered, concentrated in vacuo and residual material triturated with ether to afford 7.38 g., (93% yield) of the title product free base. Conversion of the free base to the hydrochloride salt in ethanol with ethanolic hydrogen chloride and crystallization from ethanol affords 5.34 g. (57% yield) of analytically pure 8-[4-[4-(2,1-benzisothiazol-3-yl)-1-piperazinyl]butyl]-8-azaspiro-[4.5]decane-7,9-dione dihydrochloride hemihydrate, m.p. 225°-227° C. (dec.).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N:10]2[CH:14]=[C:13]([CH3:15])[N:12]=[CH:11]2)=[C:6]([CH:9]=1)[C:7]#[N:8].[Cl:16][C:17]1[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[C:18]=1[CH2:19][C:20]1[O:24][N:23]=[C:22]([NH2:25])[N:21]=1>>[Cl:30][C:26]1[CH:27]=[CH:28][CH:29]=[C:17]([Cl:16])[C:18]=1[CH2:19][C:20]1[O:24][N:23]=[C:22]([NH:25][C:2]2[CH:3]=[CH:4][C:5]([N:10]3[CH:14]=[C:13]([CH3:15])[N:12]=[CH:11]3)=[C:6]([CH:9]=2)[C:7]#[N:8])[N:21]=1
Reactant: Nc1noc(Cc2c(Cl)cccc2Cl)n1
Reactant: Cc1cn(-c2ccc(Br)cc2C#N)cn1
Product: Cc1cn(-c2ccc(Nc3noc(Cc4c(Cl)cccc4Cl)n3)cc2C#N)cn1

Procedure:
Prepared in analogy to example 1b) starting with 5-bromo-2-(4-methyl-imidazol-1-yl)-benzonitrile and 5-(2,6-dichloro-benzyl)-[1,2,4]oxadiazol-3-ylamine (M. J. Dimsdale, J. Heterocyclic Chem. 1981, 18, 37-41). The title compound was obtained as a white solid (Yield=17%). MS ISP (m/e): 425.1 & 426.9 (100 & 84) [(M+H)+].
Reaction SMILES: [CH:1]1([N:5]2[CH2:11][CH2:10][CH2:9][N:8]([C:12]([N:14]3[CH2:17][CH:16]([CH2:18][OH:19])[CH2:15]3)=[O:13])[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[F-].[Cs+].Br[C:25]1[CH:26]=[CH:27][C:28]([C:31]([F:34])([F:33])[F:32])=[N:29][CH:30]=1>CS(C)=O.ClCCl>[CH:1]1([N:5]2[CH2:11][CH2:10][CH2:9][N:8]([C:12]([N:14]3[CH2:15][CH:16]([CH2:18][O:19][C:25]4[CH:30]=[N:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=4)[CH2:17]3)=[O:13])[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1
Reactant: FC(F)(F)c1ccc(Br)cn1
Reactant: O=C(N1CCCN(C2CCC2)CC1)N1CC(CO)C1
Agent: [Cs+]
Agent: [F-]
Agent: [H-]
Solvent: ClCCl
Solvent: CS(C)=O
Product: O=C(N1CCCN(C2CCC2)CC1)N1CC(COc2ccc(C(F)(F)F)nc2)C1
Temperature: 85 °C
Yield: 45.9 %

Procedure:
To a solution of {1-[(4-cyclobutyl-1,4-diazepan-1-yl)carbonyl]azetidin-3-yl}methano 1 (20 mg, 74 μmol) in DMSO (1 ml) was added NaH (6 mg of a 60% dispersion in mineral oil, 0.15 mmol). After 30 minutes CsF (12 mg, 74 μmol) and 5-bromo-2-trifluoromethylpyridine (34 mg, 0.15 mmol) were added and the mixture was heated at 85° C. for 2 hours. The reaction was cooled to room temperature, diluted with dichloromethane (20 ml), washed with water (20 ml), dried (MgSO4), filtered and concentrated at reduced pressure. The residue was purified by preparative HPLC to give the title compound (14 mg, 45%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:11][C:12](=[O:14])[CH3:13])[CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1.[N:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[OH:21].C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.[Cu]I>[N+:8]([C:6]1[CH:5]=[C:4]([NH:11][C:12](=[O:14])[CH3:13])[CH:3]=[C:2]([N:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]2=[O:21])[CH:7]=1)([O-:10])=[O:9]
Reactant: Oc1ccccn1
Reactant: CC(=O)Nc1cc(Br)cc([N+](=O)[O-])c1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CC(=O)Nc1cc(-n2ccccc2=O)cc([N+](=O)[O-])c1
Temperature: 100 °C
Yield: 95 %

Procedure:
To a solution of N-(3-bromo-5-nitrophenyl)acetamide (1 g, 3.85 mmol), pyridin-2-ol (0.4 g, 4.24 mmol, 1.1 eq.), potassium carbonate (1 g, 1.3 mmol, 1.0 eq.) and copper(I) iodide (10 mg) in toluene (20 ml) was added trans cyclohexyl diamine (5 mg, 0.039 mmol, 0.01 eq.) and the mixture was heated at 100° C. for 16 h. The mixture was quenched and extracted as in Example 1(d). The solvent was distilled off and the residue was purified by column chromatography (60-120 silica gel, 50% ethyl acetate in hexane) to give the product in 95% yield (1 g).
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH2:20]([C:23]1[CH:30]=[CH:29][C:26]([CH:27]=O)=[CH:25][CH:24]=1)[CH2:21][CH3:22]>>[CH2:20]([C:23]1[CH:30]=[CH:29][C:26]([CH2:27][N:4]2[CH2:3][CH2:2][N:1]([C:7]3[CH:8]=[CH:9][C:10]4[N:11]([C:13]([C:16]([F:17])([F:18])[F:19])=[N:14][N:15]=4)[N:12]=3)[CH2:6][CH2:5]2)=[CH:25][CH:24]=1)[CH2:21][CH3:22]
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Reactant: CCCc1ccc(C=O)cc1
Product: CCCc1ccc(CN2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc1

Procedure:
Reductive amination of 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with 4-propylbenzaldehyde was carried out according to General Synthetic Method 7. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column, 5μ silica, 30 mm diameter, 100 mm length eluted with decreasingly polar mixtures of water (containing 0.1% aqueous ammonia) and acetonitrile as eluents to give 6-[4-[(4-propylphenyl)methyl]piperazin-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: C([BH3-])#N.[Na+].[N+:5]([C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=1)[CH:11]=[N:12][OH:13])([O-:7])=[O:6].C(OCC)(=O)C.[OH-].[K+]>C(O)(=O)C>[N+:5]([C:8]1[CH:9]=[C:10]([CH2:11][NH:12][OH:13])[CH:14]=[CH:15][CH:16]=1)([O-:7])=[O:6]
Reactant: O=[N+]([O-])c1cccc(C=NO)c1
Agent: [BH3-]C#N
Agent: [K+]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: O=[N+]([O-])c1cccc(CNO)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 67.8 %

Procedure:
N-{(3-Nitrophenyl)methyl}hydroxylamine can be obtained in the following manner: 3.78 g of sodium cyanoborohydride are added in portions in the course of two hours at a temperature near to 25° C. to a solution of 5 g of 3-nitrobenzaldoxime in 120 cm3 of acetic acid. The reaction mixture is stirred for 16 hours at a temperature near to 25° C., and then poured into a mixture of 500 cm3 of ethyl acetate and 150 cm3 of a 30% aqueous solution of potassium hydroxide. The organic phase is separated by decantation and the aqueous phase is extracted with three times 500 cm3 of ethyl acetate. The organic phases are combined, dried over magnesium sulphate and concentrated under reduced pressure. The residue is purified by chromatography on 200 cm3 of silica [eluent dichloromethane/methanol (98:2 by volume)]. The fractions containing the expected product are combined and concentrated under reduced pressure. 3.43 g of N-{(3-nitrophenyl)methyl}hydroxylamine are thus obtained in the form of an oil which is used as such in the subsequent syntheses.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]2[S:9][CH:8]=[CH:7][C:5]=2[CH:6]=1.[Br:10][C:11]1[CH:12]=[CH:13][C:14]([O:19][CH2:20][CH3:21])=[C:15]([CH:18]=1)[CH:16]=O>>[S:9]1[C:8]([CH2:16][C:15]2[CH:18]=[C:11]([Br:10])[CH:12]=[CH:13][C:14]=2[O:19][CH2:20][CH3:21])=[CH:7][C:5]2[CH:6]=[CH:1][CH:2]=[CH:3][C:4]1=2
Reactant: c1ccc2sccc2c1
Reactant: CCOc1ccc(Br)cc1C=O
Product: CCOc1ccc(Br)cc1Cc1cc2ccccc2s1

Procedure:
Thianaphthene and 5-bromo-2-ethoxybenzaldehyde were treated in a manner similar to Reference Example 7 to give the target compound.