Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [PH4+].[O:2]1[CH2:6][CH2:5][CH:4]=P1.[C:7]1(C)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>>[O:2]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:4]=[CH:5][CH2:6]1
Reactant: Cc1ccccc1
Reactant: C1=POCC1
Agent: [PH4+]
Product: C1=Cc2ccccc2OC1

Procedure:
The cyclisation is effected by dropwise addition of a solution of sodium t-amylate in toluene to the aforementioned phosphonium salt in suspension in the same solvent heated under reflux. After each addition, the yellow colouring of the phosphorane appears and then disappears almost immediately. After filtration of the sodium bromide, the toluene is evaporated and the 3-methyl chrom-3-ene is separated from the triphenyl phosphine oxide by a treatment with pentane.
Reaction SMILES: CN(C)[C:3]1[S:4][C:5]2[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=[CH:25][C:6]=2[C:7]=1[C:8]([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][N:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)=[CH:12][CH:11]=1)=[O:9].[CH3:32][O:33][C:34]1[CH:39]=[C:38]([O:40][CH3:41])[CH:37]=[CH:36][C:35]=1[Mg]Br.CCCCCC.C(OCC)(=O)C>C1COCC1.CO>[CH3:32][O:33][C:34]1[CH:39]=[C:38]([O:40][CH3:41])[CH:37]=[CH:36][C:35]=1[C:3]1[S:4][C:5]2[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=[CH:25][C:6]=2[C:7]=1[C:8]([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][N:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)=[CH:12][CH:11]=1)=[O:9]
Reactant: COc1ccc([Mg]Br)c(OC)c1
Reactant: COc1ccc2c(C(=O)c3ccc(OCCN4CCCCC4)cc3)c(N(C)C)sc2c1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COc1ccc(-c2sc3cc(OC)ccc3c2C(=O)c2ccc(OCCN3CCCCC3)cc2)c(OC)c1
Yield: 58.5 %

Procedure:
By the method described in Example 1, [2-dimethylamino-6-methoxybenzothien-3-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]-methanone (2.0 g, 4.6 mmol) in THF (17 mL) was treated with a 1.8 M THF solution of 2,4-dimethoxyphenylmagnesium bromide (12.5 mL, 22.5 mmol) (prepared from 2,4-dimethoxybromobenzene, catalytic iodine, and magnesium turnings) to provide, after chromatography (silica gel, 1:1 hexane:ethyl acetate, 0-10% MeOH) 1.43 g (58%) of the title compound as a pale green, fluffy solid: 1H NMR d 1.44 (m, 2H), 1.60 (m, 4H), 2.49 (m, 4H), 2.74 (t, J=6.0 Hz, 2H), 3.49 (s, 3H), 3.75 (s, 3H), 3.87 (s, 3H), 4.07 (t, J=6.0 Hz, 2H), 6.21 (d, J=2.2 Hz, 1H), 6.42 (dd, J=2.3, 8.5 Hz, 1H), 6.74 (d, J=8.8 Hz, 2H), 6.95 (dd, J=2.3, 8.9 Hz, 1H), 7.30-7.33 (m, 2H), 7.63 (d, J=8.9 Hz, 1H), 7.74 (d, J=8.7 Hz, 2H); 13C NMR d 24.2, 26.0, 54.7, 55.2, 55.5, 55.7, 57.9, 66.3, 98.6, 104.4, 104.8, 113.8, 114.7, 115.7, 124.6, 130.7, 131.4, 132.0, 132.2, 133.7, 140.1, 140.4, 157.1, 157.5, 161.5, 162.5, 192.0; IR (CHCl3) 1644, 1601 cm-1 ; MS (FD) m/e 531 (M+); Anal. calc'd. for C31H33NO5S: C, 70.03; H, 6.26; N, 2.63. Found: C, 70.24; H, 6.35; N, 2.66.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1/[C:6](=[CH:14]/[C:15]1[C:23]2[C:18](=[CH:19][C:20]([Cl:25])=[CH:21][C:22]=2[Cl:24])[N:17]([S:26]([C:29]2[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=2)(=[O:28])=[O:27])[C:16]=1[C:36]([O:38][CH2:39][CH3:40])=[O:37])/[C:7]([O:9]C(C)(C)C)=[O:8]>C(O)=O>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1/[C:6](=[CH:14]/[C:15]1[C:23]2[C:18](=[CH:19][C:20]([Cl:25])=[CH:21][C:22]=2[Cl:24])[N:17]([S:26]([C:29]2[CH:30]=[CH:31][C:32]([CH3:35])=[CH:33][CH:34]=2)(=[O:28])=[O:27])[C:16]=1[C:36]([O:38][CH2:39][CH3:40])=[O:37])/[C:7]([OH:9])=[O:8]
Reactant: CCOC(=O)c1c(/C=C(\C(=O)OC(C)(C)C)c2cccs2)c2c(Cl)cc(Cl)cc2n1S(=O)(=O)c1ccc(C)cc1
Solvent: O=CO
Product: CCOC(=O)c1c(/C=C(\C(=O)O)c2cccs2)c2c(Cl)cc(Cl)cc2n1S(=O)(=O)c1ccc(C)cc1
Reaction time: 2 h

Procedure:
Combine (E)-2-(thien-2-yl)-3-(1-p-toluenesulfonyl-2-carboethoxy-4,6-dichloroindol-3-yl)propenoic acid, t-butyl ester and formic acid (96%, 20 mL). After 2 hours, evaporate in vacuo to obtain a residue. Triturate with pentane containing a small amount of diethyl ether to obtain a solid. Recrystallize the solid from cyclohexane/ethyl acetate/acetone, filter, and dry to give the title compound: mp 184-187° C. (dec). 1H NMR (DMSO-d6) δ 13.2 (br s, 1H), 7.92 (d, 1H, J=1.7 Hz), 7.80 (d, 2H, J=8.4 Hz), 7.60 (s, 1H), 7.57 (d, 1H, J=1.7 Hz), 7.44 (d, 2H, J=8.4 Hz), 7.40 (dd, 1H, J=4.7, 1.5 Hz), 6.84-6.8 (m, 2H), 4.14 (q, 2H, J=7.1 Hz), 2.37 (s, 3H), 1.13 (t, 3H, J=7.1 Hz). Elemental Analysis calculated for C25H19Cl2NO6S2: C, 53.20; H, 3.39; N, 2.48. Found: C, 53.30; H, 3.40; N, 2.41.
Reaction SMILES: C([O:5][C:6]([CH2:8][N:9]1[CH2:17][CH2:16][N:15]([CH2:18][CH:19]([NH:56][CH2:57][C:58]([O:60]C(C)(C)C)=[O:59])[CH2:20][C:21]2[CH:26]=[CH:25][C:24]([NH:27][C:28](=[O:55])[CH2:29][CH2:30][CH:31]([CH:33]3[C:49]4([CH3:50])[CH:36]([CH:37]5[CH:46]([CH2:47][CH:48]4[OH:51])[C:45]4([CH3:52])[CH:40]([CH2:41][CH:42]([OH:53])[CH2:43][CH2:44]4)[CH2:39][CH:38]5[OH:54])[CH2:35][CH2:34]3)[CH3:32])=[CH:23][CH:22]=2)[CH2:14][CH2:13][N:12]([CH2:65][C:66]([O:68]C(C)(C)C)=[O:67])[CH2:11][CH2:10]1)=[O:7])(C)(C)C.Cl.CCOCC>O1CCOCC1>[C:6]([CH2:8][N:9]1[CH2:17][CH2:16][N:15]([CH2:18][CH:19]([NH:56][CH2:57][C:58]([OH:60])=[O:59])[CH2:20][C:21]2[CH:26]=[CH:25][C:24]([NH:27][C:28](=[O:55])[CH2:29][CH2:30][CH:31]([CH:33]3[C:49]4([CH3:50])[CH:36]([CH:37]5[CH:46]([CH2:47][CH:48]4[OH:51])[C:45]4([CH3:52])[CH:40]([CH2:41][CH:42]([OH:53])[CH2:43][CH2:44]4)[CH2:39][CH:38]5[OH:54])[CH2:35][CH2:34]3)[CH3:32])=[CH:23][CH:22]=2)[CH2:14][CH2:13][N:12]([CH2:65][C:66]([OH:68])=[O:67])[CH2:11][CH2:10]1)([OH:7])=[O:5]
Reactant: CC(CCC(=O)Nc1ccc(CC(CN2CCN(CC(=O)OC(C)(C)C)CCN(CC(=O)OC(C)(C)C)CC2)NCC(=O)OC(C)(C)C)cc1)C1CCC2C3C(O)CC4CC(O)CCC4(C)C3CC(O)C12C
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: CC(CCC(=O)Nc1ccc(CC(CN2CCN(CC(=O)O)CCN(CC(=O)O)CC2)NCC(=O)O)cc1)C1CCC2C3C(O)CC4CC(O)CCC4(C)C3CC(O)C12C
Temperature: 25 °C
Reaction time: 24 h
Yield: 112.8 %

Procedure:
To a solution of Compound 3 (20 mg, 0.02 mmol) in a ice-bath was added 4M HCl in 1,4-dioxane (5 mL). After the addition, the reaction mixture was gradually increased to room temperature and stirred for 24 h. To this solution, ether (30 mL) was added and continuously stirred for 30 min. The resulting mixture was placed in the freezer for 2 h. Solid residue was quickly filtered, washed with ethyl ether (5 mL), immediately dissolved in H2O and CH3OH, and lypophilized to provide pure Compound 4 as a light brownish solid (19 mg, 97%). 1H NMR (CD3OD) 0.71 (s, 3H), 0.58-0.95 (m, 6H), 0.96-1.17 (m, 5H), 1.21-2.05 (m, 26H), 2.10-2.52 (m, 5H), 2.55-3.09 (m, 4H), 3.15-4.12 (m, 10H), 7.27 (d, 2H), 7.56 (d, 2H). HRMS (Positive ion FAB) Calcd for C45H72N5O10 [M+H]+ m/z 842.5279. Found: [M+H]+ m/z 842.5265.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:12]=1[OH:13])=[CH:10][CH:9]=[CH:8][CH:7]=2.[C:14](OC(=O)CC)(=O)[CH2:15][CH3:16].[OH-].[Na+]>O>[CH2:15]([C:16]1[O:13][C:12]2[C:11]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[N:5]=[CH:4][C:3]=2[N:2]=1)[CH3:14]
Reactant: CCC(=O)OC(=O)CC
Reactant: Nc1cnc2ccccc2c1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCc1nc2cnc3ccccc3c2o1

Procedure:
3-Aminoquinolin-4-ol hydrochloride (6 g) was refluxed with propanoic anhydride (8 eq.) until analysis by thin layer chromatography indicated that the reaction was complete. The reaction mixture was cooled, diluted with ice and water, made basic with 10% sodium hydroxide and then extracted with dichloromethane. The extract was washed with water and brine, dried over magnesium sulfate and then concentrated under vacuum. The residue was purified by column chromatography (silica gel eluting with methanol/ethyl acetate) to provide 4.0 g of 2-ethyloxazolo[4,5-c]quinoline.
Reaction SMILES: [CH2:1]([NH2:9])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.Cl.[F:18][C:19]([F:53])([F:52])[C:20]1[CH:25]=[C:24]([C:26]2[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][CH:27]=2)[N:23]=[C:22]([C:36]2[CH:41]=[CH:40][N:39]=[C:38]([C:42]3[CH:43]=[C:44]([S:48](Cl)(=[O:50])=[O:49])[CH:45]=[CH:46][CH:47]=3)[CH:37]=2)[N:21]=1>C1COCC1>[CH2:1]([NH:9][S:48]([C:44]1[CH:45]=[CH:46][CH:47]=[C:42]([C:38]2[CH:37]=[C:36]([C:22]3[N:21]=[C:20]([C:19]([F:18])([F:52])[F:53])[CH:25]=[C:24]([C:26]4[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:33])[F:34])=[CH:28][CH:27]=4)[N:23]=3)[CH:41]=[CH:40][N:39]=2)[CH:43]=1)(=[O:49])=[O:50])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=S(=O)(Cl)c1cccc(-c2cc(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)ccn2)c1
Reactant: NCCc1ccccc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=S(=O)(NCCc1ccccc1)c1cccc(-c2cc(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)ccn2)c1
Temperature: 0 °C
Yield: 90.7 %

Procedure:
To a cooled (ice-water bath) and stirred mixture of phenethylamine (0.36 g, 3.0 mmol), triethylamine (0.29 ml, 2.1 mmol) and THF (4 ml) was added drop wise a solution of 3-{4-[4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyrimidin-2-yl]-pyridin-2-yl}-benzenesulfonyl chloride hydrochloride (example I.1) (0.58 g, 1.0 mmol) in THF (6 ml). The mixture was allowed to stir at room temperature for 16 h. Purification of the reaction mixture by flash chromatography on silica gel (ethyl acetate/heptane) and crystallization (dichloromethane/MeOH/hexane) yielded the title compound as a white solid (0.57 g, 97%). MS (ISP) 628.8 [(M+H)+]; mp 201° C.
Reaction SMILES: [C:1]12([C:11]3[CH:35]=[CH:34][C:14]([O:15][C:16]4[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[C:18]([N:25]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH3:26])[CH:17]=4)=[CH:13][CH:12]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2>[Pd].CO>[C:1]12([C:11]3[CH:35]=[CH:34][C:14]([O:15][C:16]4[CH:21]=[CH:20][C:19]([NH2:22])=[C:18]([N:25]([C:27]([O:29][C:30]([CH3:31])([CH3:32])[CH3:33])=[O:28])[CH3:26])[CH:17]=4)=[CH:13][CH:12]=3)[CH2:8][CH:7]3[CH2:9][CH:3]([CH2:4][CH:5]([CH2:6]3)[CH2:10]1)[CH2:2]2
Reactant: CN(C(=O)OC(C)(C)C)c1cc(Oc2ccc(C34CC5CC(CC(C5)C3)C4)cc2)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: CN(C(=O)OC(C)(C)C)c1cc(Oc2ccc(C34CC5CC(CC(C5)C3)C4)cc2)ccc1N
Temperature: 25 °C
Reaction time: 2 h
Yield: 51.1 %

Procedure:
A mixture of 4-(4-adamantan-1-ylphenoxy)-2-(N-t-butoxycarbonyl-N-methylamino)nitrobenzene (14 g), palladium on carbon (1.50 g, 10%) and methanol (300 ml) was stirred at room temperature under a hydrogen atmosphere for 2 hours and then 50° C. for 2 hours, allowed to stand at room temperature overnight and then stirred at 50° C. for 2 hours. The insoluble material of the reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was chromatographed on a silica gel column using hexane:ethyl acetate=3:1 as the eluant to afford the title compound (6.70 g, mp 85-90° C.).
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH2:16]([O:23][C:24]1[C:29]([F:30])=[CH:28][C:27]([CH:31]2[CH2:33][CH:32]2[C:34](Cl)=[O:35])=[CH:26][C:25]=1[F:37])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[NH4+].[Cl-]>C1COCC1>[CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:34]([CH:32]1[CH2:33][CH:31]1[C:27]1[CH:26]=[C:25]([F:37])[C:24]([O:23][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:29]([F:30])[CH:28]=1)=[O:35])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)C1CC1c1cc(F)c(OCc2ccccc2)c(F)c1
Reactant: O=C1N[C@H](Cc2ccccc2)CO1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: O=C1OC[C@@H](Cc2ccccc2)N1C(=O)C1CC1c1cc(F)c(OCc2ccccc2)c(F)c1
Reaction time: 0.5 h

Procedure:
After (R)-4-benzyl-oxazolidin-2-on (52 mg, 0.295 mmol) was dissolved in anhydrous THF (2 ml), NaH (60%, 14 mg, 0.344 mmol) was added thereto, and the mixture was stirred for 30 minutes. Next, 2-(4-benzyloxy-3,5-difluoro-phenyl)-cyclopropanecarnoyl chloride obtained in Step A was added thereto at −78° C., and the mixture was stirred for 15 minutes, and then stirred at room temperature for 1 hour. After the termination of the reaction, NH4Cl solution was added thereto and the mixture was extracted with ethyl acetate. The organic layer was separated, dried with anhydrous magnesium sulfate, concentrated under reduced pressure, and purified by column chromatography (eluent, EtOAc/Hex=1/2) to obtain each title compound [(more polar, 41 mg, 36%), (less polar, 44 mg, 38%)].
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:8]=[CH:7][C:6]([C@:9]23[CH2:14][C@H:13]2[CH2:12][NH:11][CH2:10]3)=[CH:5][CH:4]=1.Cl[CH2:18][CH2:19][CH2:20][CH2:21][N:22]1[CH:27]=[C:26]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:25]=[N:24][C:23]1=[O:34].C(N(CC)CC)C>CN(C)C=O>[C:28]1([C:26]2[CH:25]=[N:24][C:23](=[O:34])[N:22]([CH2:21][CH2:20][CH2:19][CH2:18][N:11]3[CH2:12][C@H:13]4[C@:9]([C:6]5[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:15])[F:16])=[CH:8][CH:7]=5)([CH2:14]4)[CH2:10]3)[CH:27]=2)[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: O=c1ncc(-c2ccccc2)cn1CCCCCl
Reactant: FC(F)(F)c1ccc([C@@]23CNC[C@@H]2C3)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=c1ncc(-c2ccccc2)cn1CCCCN1C[C@@H]2C[C@]2(c2ccc(C(F)(F)F)cc2)C1
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
To a solution of (1S,5R)-1-[4-(trifluoromethyl)phenyl]-3-azabicyclo[3.1.0]hexane (52 mg, 0.23 mmol, prepared with a similar procedure to that reported in WO 2005080382) in N,N-dimethylformamide (DMF) (3 ml) were added at room temperature 1-(4-chlorobutyl)-5-phenyl-2(1H)-pyrimidinone (Prep51, 60.1 mg, 0.23 mmol, D1) and triethylamine (0.064 ml, 0.46 mmol). The reaction mixture was heated at 100° C. for 24 hours, then passed through a SCX cartridge (10 g) (eluting with methanol followed by 2N ammonia solution in methanol). The crude obtained was then purified by column chromatography on silica gel eluting with DCM/methanol 96/4. After evaporation of the solvent the compound recovered (20 mg, 0.044 mmol) was dissolved in DCM (1 ml) and treated with HCl (1.1 eq of a 1.25 M solution in methanol, 0.048 mmol). The resulting mixture was stirred at room temperature for 0.5 hour. Evaporation of the solvent and trituration with diethyl ether (2×3 ml) gave the hydrochloride salt of the title compound. The recovered material was passed through SCX (2 g) cartridge (eluting with methanol followed by 2N ammonia solution in methanol) to recover (6 mg, 0.013 mmol) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:21]=[C:11]3[NH:12][C:13](=[O:20])[C:14]4[C:19]([N:10]3[N:9]=2)=[CH:18][CH:17]=[CH:16][CH:15]=4)[CH:5]=[CH:6][CH:7]=1.Br[CH2:23][CH2:24][N:25]([CH3:27])[CH3:26].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:26][N:25]([CH3:27])[CH2:24][CH2:23][NH:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:21]=[C:11]3[NH:12][C:13](=[O:20])[C:14]4[C:19]([N:10]3[N:9]=2)=[CH:18][CH:17]=[CH:16][CH:15]=4)[CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)CCBr
Reactant: Nc1cccc(-c2cc3[nH]c(=O)c4ccccc4n3n2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CN(C)CCNc1cccc(-c2cc3[nH]c(=O)c4ccccc4n3n2)c1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
A solution of EXAMPLE 12 (0.04 g, 0.1 mmol) and (2-bromoethyl) dimethylamine (0.02 g, 0.1 mmol) in acetonitrile (1 mL) was treated with potassium carbonate (0.04 g, 0.3 mmol). The mixture was stirred overnight at 50° C. and filtered. The filtrate was concentrated and purified by flash chromatography on silica gel with 10% methanol/dichloromethane to provide the title compound. 1H NMR (DMSO-d6) δ 8.12-8.18 (m, 2H), 7.86-7.95 (m, 1H), 7.49 (t, J=7.6 Hz, 1H), 7.12-7.20 (m, 3H), 6.64 (s, 1H), 6.27 (s, 1H), 3.23-3.26 (m, 3H), 2.57-2.65 (m, 1H), 2.31 (s, 6H), 1.24 (s, 1H), 0.85 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][C:9](F)=[CH:8][CH:7]=1)=[O:5].[S:18]1[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[N:20]=[C:19]1[SH:27].C(=O)([O-])[O-].[K+].[K+]>O>[Cl:1][C:2]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][C:9]([S:27][C:19]2[S:18][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[N:20]=2)=[CH:8][CH:7]=1)=[O:5]
Reactant: O=C(c1ccc(F)cc1)c1cc(Cl)ccc1Cl
Reactant: Sc1nc2ccccc2s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: O=C(c1ccc(Sc2nc3ccccc3s2)cc1)c1cc(Cl)ccc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.2 %

Procedure:
269.1 g (1.000 mol) of 2,5-dichloro-4′-fluorobenzophenon, 175.6 g (1.050 mol) of 2-benzothiazolethiol, 152.0 g (1.100 mol) of potassium carbonate, and 1.500 ml of N,N′-dimethylacetamide were added into a 3 L three-necked flask equipped with a stirrer, thermometer, cooling pipe, and nitrogen inlet tube, and dehydrated. The reaction solution was heated by use of an oil bath and was allowed to react at 110 degrees C. in a nitrogen atmosphere for 2 hours. After the disappearance of material was confirmed by a thin layer chromatography, the mixture was cooled to ambient temperature. Then, the reaction solution was gradually poured into 3 L of water to cause coagulation. The resulting product by filtration was dissolved into 4 L of toluene. The organic layer was washed by brine to be neutral. After the organic layer was dried by magnesium sulfate, the solvent was removed by an evaporator. The rough yield was 350.3 g. By using 1.5 L of toluene heated at 80 degrees C., the dried product was recrystallized for isolation to obtain 325.4 g of the refining material in 78.2% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-])=O)[CH:13]=1)[C:6]([CH3:22])([CH3:21])[CH2:5]2>C(O)C.Cl.[Fe]>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]([C:12]1[CH:13]=[C:14]([NH2:18])[CH:15]=[CH:16][CH:17]=1)[C:6]([CH3:22])([CH3:21])[CH2:5]2
Reactant: CC1(C)Cc2cc(Cl)ccc2NC1c1cccc([N+](=O)[O-])c1
Agent: [Fe]
Agent: Cl
Solvent: CCO
Product: CC1(C)Cc2cc(Cl)ccc2NC1c1cccc(N)c1
Temperature: 95 °C
Reaction time: 3 h
Yield: 82.4 %

Procedure:
To a mixture of 6-chloro-3,3-dimethyl-2-(3-nitro-phenyl)-1,2,3,4-tetrahydro-quinoline (10.5 g, 33 mmol) in ethanol 95% (150 mL) and 10% hydrochloric acid (10 mL) was added iron (3.72 g, 66 mmol). The reaction mixture was stirred at 95° C. for 3 h. Then the insoluble solid was filtered off and the filtrate was concentrated in vacuo and the residue was extracted with ethyl acetate (2×200 mL), washed with 30% sodium hydroxide in water (2×100 mL), dried over anhydrous sodium sulfate and concentrated in vacuo to afford 3-(6-chloro-3,3-dimethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenylamine (7.8 g, 82%) as a yellow solid: LC/MS m/e calcd for C17H19ClN2 (M+H)+: 287.81, observed: 287.0.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:23]=[CH:22][C:6]([CH2:7][O:8][C:9]2[C:14]([N:15]3[CH2:20][CH2:19][C:18](=[O:21])[CH2:17][CH2:16]3)=[CH:13][CH:12]=[CH:11][N:10]=2)=[CH:5][CH:4]=1.CO[CH:26](OC)[N:27]([CH3:29])[CH3:28]>>[CH3:26][N:27]([CH:29]=[C:17]1[C:18](=[O:21])[CH2:19][CH2:20][N:15]([C:14]2[C:9]([O:8][CH2:7][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:23][CH:22]=3)=[N:10][CH:11]=[CH:12][CH:13]=2)[CH2:16]1)[CH3:28]
Reactant: COc1ccc(COc2ncccc2N2CCC(=O)CC2)cc1
Reactant: COC(OC)N(C)C
Product: COc1ccc(COc2ncccc2N2CCC(=O)C(=CN(C)C)C2)cc1

Procedure:
A solution of 2′-(4-methoxybenzyloxy)-2,3,5,6-tetrahydro[1,3′]bipyridinyl-4-one (962 mg, 3.08 mmol) in N,N-dimethylformamide-dimethylacetal (7.0 ml, 52.28 mmol) was heated at 75° C. for 21 hours. The solvent was removed in vacuo and the residue was eluted through a flash column (silica gel 60, 230-400 mesh, 8% methanol in EtOAc) to give the title compound as an orange, viscous oil (628 mg, 56%).
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH:9]2[CH:14]3[CH2:15][CH2:16][CH:10]2[CH2:11][NH:12][CH2:13]3)[CH:6]=[CH:7][CH:8]=1.Br.[OH-].[Na+].Cl.CCOC(C)=O>CC(O)=O>[CH:10]12[CH:9]([C:5]3[CH:4]=[C:3]([OH:2])[CH:8]=[CH:7][CH:6]=3)[CH:14]([CH2:15][CH2:16]1)[CH2:13][NH:12][CH2:11]2
Reactant: COc1cccc(C2C3CCC2CNC3)c1
Agent: Br
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: Oc1cccc(C2C3CCC2CNC3)c1
Yield: 100.2 %

Procedure:
8-(3-Methoxy-phenyl)-3-aza-bicyclo[3.2.1]octane (162 mg, 0.638 mmol) was dissolved in glacial HOAc (2 mL), charged with hydrobromic acid (48%, 2 mL), then heated to a gentle reflux overnight (or until judged complete by TLC). The reaction was carefully poured onto 1N NaOH (30 mL); pH 14 was achieved. The product was extracted with n-butanol/toluene (3/1, 6×6 mL), washed with saturated aqueous NaCl solution (1×10 mL), dried over Na2SO4, and concentrated to yield a yellow semi-solid. To this was added 2.5N HCl/EtOAc (4 mL), then azeotroped from MeOH (2×10 mL) to yield the title compound as a yellow solid (130 mg, 85%). (TLC 10% MeOH/CH2Cl2, (NH3) Rf 0.10); 1H NMR (400 MHz, CD3OD, HCl salt) δ 7.05 (t, J=7.9 Hz, 1H), 6.67 (d, J=7.9 Hz, 1H), 6.54 (s, 1H), 6.53 (dd, J=7.9, 2.3 Hz, 1H), 3.27 (ddd, J=3.3, 3.3, 1.7 Hz, 1H), 2.85 (d, J=12.9 Hz, 2H), 2.80 (dd, J=12.9, 3.1 Hz, 2H), 2.39 (br s, 2H), 1.67 (m, 2H), 1.57 (m, 2H); GCMS m/z 203 (M)+; LCMS m/z 204.3 (M+1)+.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:11][C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][C:21]=3[F:22])[N:18]=[CH:17][CH:16]=[CH:15]4)=[CH:9][N:10]=2)[N:7]=1.[NH:23]1[CH2:28][CH2:27][NH:26][CH2:25][C:24]1=[O:29].[F-].[K+]>CN1C(=O)CCC1.CCOC(C)=O>[F:22][C:21]1[CH:20]=[C:19]2[C:14]([CH:15]=[CH:16][CH:17]=[N:18]2)=[CH:13][C:12]=1[CH2:11][C:8]1[N:6]2[N:7]=[C:2]([N:26]3[CH2:27][CH2:28][NH:23][C:24](=[O:29])[CH2:25]3)[CH:3]=[CH:4][C:5]2=[N:10][CH:9]=1
Reactant: O=C1CNCCN1
Reactant: Fc1cc2ncccc2cc1Cc1cnc2ccc(Cl)nn12
Agent: [F-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: O=C1CN(c2ccc3ncc(Cc4cc5cccnc5cc4F)n3n2)CCN1
Temperature: 180 °C
Reaction time: 5 h

Procedure:
The title compound was prepared using 6-(6-chloro-imidazo[1,2-b]pyridazin-3-ylmethyl)-7-fluoro-quinoline (Intermediate J, 50 mg, 0.160 mmol), piperazin-2-one (80 mg, 0.799 mmol) and KF (27.9 mg, 0.480 mmol) were suspended in NMP (1.0 mL). The RM was stirred at 180° C. for 5 h. The mixture was diluted with EtOAc and washed with 1M NaHCO3 (1×) and water (2×). The combined organic layers were dried over Na2SO4, filtered and concentrated. The residue was purified by flash chromatography and afforded the title compound as a foam (tR 2.88 min (conditions 5), MH+=377, 1H-NMR in DMSO-d6: 8.85 (d, 1H); 8.33 (d, 1H); 8.07 (s, 1H); 7.98 (d, 1H); 7.83 (d, 1H); 7.74 (m, 1H); 7.5 (s, 2H); 7.11 (d, 1H); 4.41 (s, 2H); 4.00 (s, 2H); 3.67 (m, 2H); 3.26 (m, 2H)).
Reaction SMILES: CN(C)C=O.Cl[C:7]1[CH:12]=[C:11]([O:13][CH2:14][C:15]#[C:16][CH3:17])[N:10]=[CH:9][N:8]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:24][CH:25]1[CH2:29][CH2:28][CH2:27][NH:26]1>C(OCC)(=O)C>[CH2:14]([O:13][C:11]1[CH:12]=[C:7]([N:26]2[CH2:27][CH2:28][CH2:29][CH:25]2[CH3:24])[N:8]=[CH:9][N:10]=1)[C:15]#[C:16][CH3:17]
Reactant: CC1CCCN1
Reactant: CC#CCOc1cc(Cl)ncn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC#CCOc1cc(N2CCCC2C)ncn1
Temperature: 60 °C
Reaction time: 7 h
Yield: 89.7 %

Procedure:
Into 2 ml of N,N-dimethylformamide was resolved 183 mg of 4-chloro-6-(2-butynyloxy)pyrimidine, 166 mg of potassium carbonate and 85 mg of 2-methylpyrrolidine was added therein, and the mixture was stirred for 7 hours at 60° C. The reaction mixture was cooled to near room temperature, ethyl acetate was added therein, and the mixture was washed with a saturated sodium chloride aqueous solution three times. The organic layers were dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to obtain 207 mg of 4-(2-butynyloxy)-6-(2-methyl-pyrrolidin-1-yl)pyrimidine (hereinafter, referred to as Compound (21)).