Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][O:3][C:4](=[O:29])[NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[CH:21]=[N:20][C:19]3[C:18]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)=[N:17][C:16]([Cl:28])=[N:15][C:14]=3[CH:13]=2)[CH:7]=1.[C:30]([OH:33])(=[O:32])[CH3:31]>C(Cl)(Cl)Cl>[C:30]([O:33][CH2:2][O:3][C:4](=[O:29])[NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[CH:21]=[N:20][C:19]3[C:18]([N:22]4[CH2:23][CH2:24][O:25][CH2:26][CH2:27]4)=[N:17][C:16]([Cl:28])=[N:15][C:14]=3[CH:13]=2)[CH:7]=1)(=[O:32])[CH3:31]
Reactant: O=C(Nc1cccc(-c2cnc3c(N4CCOCC4)nc(Cl)nc3c2)c1)OCCl
Reactant: CC(=O)O
Solvent: ClC(Cl)Cl
Product: CC(=O)OCOC(=O)Nc1cccc(-c2cnc3c(N4CCOCC4)nc(Cl)nc3c2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 87 %

Procedure:
To a 100 mL round bottom flask, chloromethyl(3-(2-chloro-4-morpholinopyrido[3,2-d]pyrimidin-7-yl)phenyl)carbamate (1.2 g, 0.0028 mol) and acetic acid (20 mL) were added. To the reaction mixture was added mercuric acetate (0.968 g, 0.0031 mol) and the mixture was stirred at room temperature for 4 hours. The reaction mixture was diluted with chloroform and washed with water. The organic layer was washed with brine, dried over anhydrous sodium sulphate and evaporated under reduced pressure to provide the title compound as a yellow solid (1.1 g, 87%). 1H NMR (400 MHz, DMSO-d6): δ 10.25 (br s, 1H), 9.05 (d, J=1.6 Hz, 1H), 8.19 (d, J=1.2 Hz, 1H), 7.93 (s, 1H), 7.59-7.48 (m, 3H), 5.77 (s, 2H), 4.64-3.98 (br s, 4H), 3.81 (t, J=4.4 Hz, 4H), 2.10 (s, 3H). LC-MS (ESI): Calculated mass: 457.12; Observed mass [M+H]+: 457.9 (RT: 1.57 min).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([Cl:17])[CH:10]=2)[N:5]=[C:4]([NH:18][CH:19]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[N:3]=1.[C:26]([O-])([O-])=[O:27].[K+].[K+]>CO>[CH3:26][O:27][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([Cl:17])[CH:10]=2)[N:5]=[C:4]([NH:18][CH:19]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[N:3]=1
Reactant: O=C([O-])[O-]
Reactant: COc1ccc(Nc2nc(Cl)nc(NC3CCCCCC3)n2)cc1Cl
Agent: [K+]
Solvent: CO
Product: COc1nc(Nc2ccc(OC)c(Cl)c2)nc(NC2CCCCCC2)n1

Procedure:
To 6-chloro-N-(3-chloro-4-methoxyphenyl)-N′-cycloheptyl-[1,3,5]triazine-2,4-diamine (5 g) dissolved in methanol was added K2CO3 (3.2 g) and refluxed for about 6–8 h. TLC was monitored. After the completion of the reaction, the reaction mass was filtered through vacuum and the filtrate was evaporated to yield the title compound. (Wt. 4.7 g Y: 95%)
Reaction SMILES: Cl.[OH:2][CH:3]1[O:11][C@H:10]([CH2:12][OH:13])[C@@H:8]([OH:9])[C@H:6]([OH:7])[C@H:4]1[NH2:5].[S:14]([O-:18])([OH:17])(=[O:16])=[O:15].[Na+:19].C(O)(C)C>O>[Na+:19].[S:14]([O-:18])([O-:17])(=[O:16])=[O:15].[OH:2][CH:3]1[O:11][C@H:10]([CH2:12][OH:13])[C@@H:8]([OH:9])[C@H:6]([OH:7])[C@H:4]1[NH2:5].[Na+:19]
Reactant: O=S(=O)([O-])O
Agent: Cl
Agent: N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Product: O=S(=O)([O-])[O-]
Reaction time: 4 h

Procedure:
Glucosamine hydrochloride (6.45 g, 0.03 mol) and sodium hydrogen sulphate (1.8 g, 0.015 mol) were taken in a flask and dissolved in water (25 ml). The resulting solution was added dropwise to vigorously stirred isopropanol(150 ml) at room temperature over a period of one hour. The contents in the flask were further stirred for 4 hrs and then kept at 0° C.-5° C. for 16 hrs. The precipitate was filtered under vacuum (150 mm Hg). The product was washed twice (each time with 25 ml of isopropanol).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5](Br)=[CH:4][CH:3]=1.[CH3:9][Si:10]([C:13]#[CH:14])([CH3:12])[CH3:11]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I.C1COCC1>[CH3:9][Si:10]([C:13]#[C:14][C:2]1[CH:7]=[CH:6][C:5]([C:14]#[C:13][Si:10]([CH3:12])([CH3:11])[CH3:9])=[CH:4][CH:3]=1)([CH3:12])[CH3:11]
Reactant: C#C[Si](C)(C)C
Reactant: Brc1ccc(Br)cc1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C[Si](C)(C)C#Cc1ccc(C#C[Si](C)(C)C)cc1
Temperature: 45 °C
Yield: 92 %

Procedure:
40 mL THF was transferred to a flame-dried Schlenk flask. 1,4-dibromobenzene (2.5 mmol, 0.060 g), Pd(PPh3)4 (0.1 mmol 0.12 g), and CuI (0.2 mmol, 0.004 g) were added. Trimethylsilylacetylene (6 mmol, 0.87 mL) and 10 mL DIPA was added via syringe. The mixture was heated to 45° C. for 24 hrs. under nitrogen. The resulting suspension was filtered and filtrate was concentrated under reduced pressure. The residual solid was dissolved in dichloromethane and washed with an aqueous ammonium chloride solution. The organic layer was concentrated and crude product was subjected to column chromatography (silica, hexanes) to afford a white solid (2.3 mmol, 0.61 g, 90% yield). 1H NMR (400 MHz, CDCl3) δ: 7.37 (s, 4H), 0.22 (s, 18H).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[OH:9][C:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]=[CH:12][CH:11]=1.C(=O)([O-])O.[Na+].S([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C>[Br:1][C:11]1[CH:12]=[N:13][C:14]2[C:19]([C:10]=1[OH:9])=[CH:18][CH:17]=[CH:16][CH:15]=2
Reactant: Oc1ccnc2ccccc12
Reactant: O=C1CCC(=O)N1Br
Agent: O=C([O-])O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Oc1c(Br)cnc2ccccc12
Temperature: 25 °C
Reaction time: 15 h
Yield: 71.3 %

Procedure:
N-Bromosuccinimide(1.3 g) was added to a DMF solution (15 ml) of 4-hydroxy quinoline(1.0 g) and the mixture was stirred at room temperature for 15 hours. A sodium hydrogencarbonate aqueous solution of 25% sodium sulfite was added to the mixture. The mixture was stirred and the precipitated insoluble matter was separated. The filtrate was dissolved in a mixture of ethyl acetate and methanol, and an insoluble matter was removed by filtration. The filtrate was condensed under reduced pressure, and the residue was washed with ethyl acetate and dried to give the title compound(1.1 g) as a white powder.
Reaction SMILES: [O:1]=[C:2]1[C:7]([CH2:8][N:9]2C(=O)C3C(=CC=CC=3)C2=O)=[N:6][N:5]=[CH:4][NH:3]1.NN>C(Cl)Cl.CCO>[NH2:9][CH2:8][C:7]1[C:2](=[O:1])[NH:3][CH:4]=[N:5][N:6]=1
Reactant: O=C1c2ccccc2C(=O)N1Cc1nnc[nH]c1=O
Agent: NN
Solvent: CCO
Solvent: ClCCl
Product: NCc1nnc[nH]c1=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A slurry of 2-(5-oxo-4,5-dihydro-[1,2,4]triazin-6-ylmethyl)-isoindole-1,3-dione (4 g, 15.6 mmol) in DCM/EtOH (1:1) (150 mL ) was charged with anhydrous hydrazine (1.23 mL, 39.0 mmol) and stirred at rt for 18 h. The reaction mixture was concentrated in vacuo and the off-white solid was triturated with warm CHCl3 and filtered through a fritted funnel. The solid was then triturated with hot boiling methanol (MeOH) and filtered through a fritted funnel resulting in an off-white solid. The material was triturated a second time as before and dried overnight resulting in the title compound as a white solid, which was taken on to the next step without further purification; 1H NMR (DMSO-d6, 400 MHz) δ 3.88 (s, 2H), 8.31 (2, 1H); MS (ES+): m/z 127.07 (100) [MH+], HPLC: tR=0.34 min (MicromassZQ, polar—5 min).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]1[NH:15][C:14](=[O:16])[C:13]2=[C:17]([CH3:21])[N:18]=[C:19]([CH3:20])[N:12]2[N:11]=1)[CH3:2].[Cl:22][S:23](O)(=[O:25])=[O:24]>>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([S:23]([Cl:22])(=[O:25])=[O:24])=[CH:6][C:5]=1[C:10]1[NH:15][C:14](=[O:16])[C:13]2=[C:17]([CH3:21])[N:18]=[C:19]([CH3:20])[N:12]2[N:11]=1)[CH3:2]
Reactant: O=S(=O)(O)Cl
Reactant: CCOc1ccccc1-c1nn2c(C)nc(C)c2c(=O)[nH]1
Product: CCOc1ccc(S(=O)(=O)Cl)cc1-c1nn2c(C)nc(C)c2c(=O)[nH]1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
7.25 g (25.5 mmol) of 2-(2-ethoxyphenyl)-5,7-dimethyl-3H-imidazo[5,1-f][1,2,4]-triazin-4-one are initially charged, and 26.74 g (0.23 mol) of chlorosulphonic acid are added with ice-cooling. The mixture is stirred at room temperature overnight and poured into ice-water, and the crystals are filtered off with suction and dried in a vacuum desiccator.
Reaction SMILES: [CH3:1][S:2]([N:5]([S:7]([NH:10][C:11]([NH:13]N(S(C)(=O)=O)C)=[O:12])(=[O:9])=[O:8])[CH3:6])(=[O:4])=[O:3].N[C:21]1[N:26]=[C:25]([O:27][CH3:28])[CH:24]=[C:23]([O:29][CH3:30])[N:22]=1>ClC1C=CC=CC=1>[CH3:1][S:2]([N:5]([S:7]([NH:10][C:11]([NH:13][C:21]1[N:26]=[C:25]([O:27][CH3:28])[CH:24]=[C:23]([O:29][CH3:30])[N:22]=1)=[O:12])(=[O:8])=[O:9])[CH3:6])(=[O:3])=[O:4]
Reactant: CN(NC(=O)NS(=O)(=O)N(C)S(C)(=O)=O)S(C)(=O)=O
Reactant: COc1cc(OC)nc(N)n1
Solvent: Clc1ccccc1
Product: COc1cc(OC)nc(NC(=O)NS(=O)(=O)N(C)S(C)(=O)=O)n1
Temperature: 80 °C
Yield: 103.2 %

Procedure:
32.3 g of 1-[(N-methylsulfonyl-N-methylamino)-sulfonyl]-3-(N-methylsulfonyl-N-methylamino)urea are slurried in 500 ml of chlorobenzene, 15.5 g of 2-amino-4,6-di-methoxypyrimidine are added at 80° C. with stirring, and the mixture is heated for 3 hours at 80° C. After cooling to 20° C., the precipitate is filtered off and washed with 100 ml of chlorobenzene. 36.4 g of the desired product are obtained with a purity of 98.1%, corresponding to a yield of 96.8% of theory. The melting point for the product is 183°-185° C. 5.1 g of N-methylmethanesulfonamide are recovered from the liltrate by distillation, corresponding to a yield of 92.7% of theory.
Reaction SMILES: [OH:1][C:2]1[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][N:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:3]=1.[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH2:18]([O:1][C:2]1[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][N:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:3]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)c1cn(-c2ccccc2)nc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(-c2ccccc2)nc1OCc1ccccc1
Temperature: 50 °C
Reaction time: 8 h
Yield: 77 %

Procedure:
A mixture of ethyl 3-hydroxy-1-phenyl-1H-pyrazole-4-carboxylate (7.76 g), benzyl bromide (3.97 ml), potassium carbonate (6.91 g) and N,N-dimethylformamide (75 ml) was stirred overnight at 50° C. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The ethyl acetate layer was dilute hydrochloric acid, and then washed successively with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and ethyl 3-benzyloxy-1-phenyl-1H-pyrazole-4-carboxylate (8.29 g, yield 77%) was obtained as colorless crystals from a fraction eluted with ethyl acetate-hexane (1:1, volume ratio). The crystals were recrystallized from ethyl acetate-hexane. melting point: 113–114° C.
Reaction SMILES: [K].[C:2]1(=[O:12])[NH:6][C:5](=[O:7])[C:4]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:3]12.CN(C)C=O.[Cl:18][C:19]1[C:20]([C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=2)=[C:21]2[C:29]3[CH2:30][CH2:31][S:32][CH2:33][C:28]=3[S:27][C:22]2=[N:23][C:24]=1[CH2:25]Cl>O>[Cl:18][C:19]1[C:20]([C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=2)=[C:21]2[C:29]3[CH2:30][CH2:31][S:32][CH2:33][C:28]=3[S:27][C:22]2=[N:23][C:24]=1[CH2:25][N:6]1[C:2](=[O:12])[C:3]2[C:4](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:5]1=[O:7]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: COc1ccc(-c2c(Cl)c(CCl)nc3sc4c(c23)CCSC4)cc1
Agent: [K]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(-c2c(Cl)c(CN3C(=O)c4ccccc4C3=O)nc3sc4c(c23)CCSC4)cc1
Temperature: 62.5 °C
Reaction time: 1 h
Yield: 99.4 %

Procedure:
To a mixture of phthalimide potassium (6.2 kg) and dimethylformamide (110.74 L) was added 3-chloro-2-chloromethyl-5,8-dihydro-4-(4-methoxyphenyl)-6H-thiopyrano-[4′,3′:4,5]thieno[2,3-b]pyridine (11.055 kg) obtained in Reference Example 27 and the mixture was stirred at 60 to 65° C. for 1 hour. After cooling to 25° C., water (36.91 L) was added dropwise thereto and the mixture was stirred at the same temperature for 1 hour. The crystals deposited was filtered off and washed with water (29.14 L) to obtain the titled compound (14.057 kg, 99.4%). 1H-NMR (CDCl3) δ: 2.14 (2H, t, J=5.7 Hz), 2.64 (2H, t, J=5.7 Hz), 3.80 (2H, s), 3.89 (3H, s), 5.20 (2H, s), 6.98–7.13 (2H, s), 6.98–7.13 (3H, m), 7.75–7.78 (2H, m), 7.79–7.794 (2H, m).
Reaction SMILES: I[C:2]1[CH:14]=[CH:13][C:5]2[C:6](=[O:12])[CH2:7][CH2:8][C:9](=[O:11])[NH:10][C:4]=2[CH:3]=1.CCOC(C)=O.O.[CH3:22][N:23](C=O)C>[C-]#N.[C-]#N.[Zn+2].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:22]([C:2]1[CH:14]=[CH:13][C:5]2[C:6](=[O:12])[CH2:7][CH2:8][C:9](=[O:11])[NH:10][C:4]=2[CH:3]=1)#[N:23]
Reactant: CN(C)C=O
Reactant: O=C1CCC(=O)c2ccc(I)cc2N1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: O
Solvent: CCOC(C)=O
Product: N#Cc1ccc2c(c1)NC(=O)CCC2=O
Temperature: 80 °C
Reaction time: 3.5 h
Yield: 70 %

Procedure:
To a solution of 8-iodo-3,4-dihydro-1H-1-benzazepine-2,5-dione (0.3 g, 1.0 mmol) in DMF (5 mL) was added Zn(CN)2 (0.12 g, 1.0 mmol) and Pd(PPh3)4 (116 mg, 0.1 mmol). The reaction mixture was allowed to stir at 80° C. for 3.5 h. After being allowed to cool to rt, EtOAc (20 mL) and H2O (20 mL) were added, the organic solution was separated, and the aqueous solution was extracted with EtOAc (2×50 mL). The organic solutions were combined, washed with H2O and brine, dried over MgSO4, filtered and concentrated. The residue was purified by column chromatography to provide 8-cyano-3,4-dihydro-1H-1-benzazepine-2,5-dione (140 mg, 70%).
Reaction SMILES: [CH3:1][C:2]1([CH3:35])[O:7][CH2:6][C:5]([N+:32]([O-:34])=[O:33])([C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([O:18][C:19]4[CH:24]=[CH:23][C:22]([O:25]C5C=CC=CC=5)=[CH:21][CH:20]=4)[CH:14]=3)[CH:9]=2)[CH2:4][O:3]1.[CH2:36](OC1C=CC(O)=CC=1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>>[CH2:36]([O:25][C:22]1[CH:23]=[CH:24][C:19]([O:18][C:13]2[CH:14]=[C:15]3[C:10](=[CH:11][CH:12]=2)[CH:9]=[C:8]([C:5]2([N+:32]([O-:34])=[O:33])[CH2:6][O:7][C:2]([CH3:35])([CH3:1])[O:3][CH2:4]2)[CH:17]=[CH:16]3)=[CH:20][CH:21]=1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: Oc1ccc(OCc2ccccc2)cc1
Reactant: CC1(C)OCC(c2ccc3cc(Oc4ccc(Oc5ccccc5)cc4)ccc3c2)([N+](=O)[O-])CO1
Product: CC1(C)OCC(c2ccc3cc(Oc4ccc(OCc5ccccc5)cc4)ccc3c2)([N+](=O)[O-])CO1
Yield: 41 %

Procedure:
5-(6-(4-(benzyloxy)phenoxy)naphthalen-2-yl)-2,2-dimethyl-5-nitro-1,3-dioxane was synthesized as per 2,2-dimethyl-5-nitro-5-(6-(4-phenoxyphenoxy)naphthalen-2-yl)-1,3-dioxane (Example 243) in 41% yield using 4-(benzyloxy)phenol as the reagent.
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[CH:3]([C:18]1[CH:23]=[C:22]([Cl:24])[C:21]([Cl:25])=[C:20]([Cl:26])[CH:19]=1)/[CH:4]=[CH:5]/[C:6]1[CH:11]=[CH:10][C:9]([CH2:12][NH2:13])=[C:8]([C:14]([F:17])([F:16])[F:15])[CH:7]=1.[N:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[CH:35]=O.[BH4-].[Na+]>CO>[N:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[CH2:35][NH:13][CH2:12][C:9]1[CH:10]=[CH:11][C:6](/[CH:5]=[CH:4]/[CH:3]([C:18]2[CH:19]=[C:20]([Cl:26])[C:21]([Cl:25])=[C:22]([Cl:24])[CH:23]=2)[C:2]([F:1])([F:27])[F:28])=[CH:7][C:8]=1[C:14]([F:16])([F:17])[F:15]
Reactant: NCc1ccc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)cc1C(F)(F)F
Reactant: O=Cc1ccccn1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: FC(F)(F)c1cc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)ccc1CNCc1ccccn1
Reaction time: 1 h
Yield: 39.7 %

Procedure:
(E)-(4-(4,4,4-Trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)-2-(trifluoromethyl)phenyl)methanamine (0.46 g, 1 mmol) was dissolved in CH3OH (3 mL). To this was added pyridine-2-carbaldehyde (0.107 g, 1 mmol). The reaction mixture was stirred for 1 h. After 1 h, NaBH4 (0.076 g, 2 mmol) was added and left at ambient temperature for 3 h. The reaction mixture was concentrated to give an oily residue. Purification by flash column chromatography (SiO2, 100-200 mesh; 30-50% EtOAc in hexane) afforded the title compound as a pale yellow liquid (0.22 g, 40%): 1H NMR (400 MHz, CDCl3) δ 8.58 (d, J=4.8 Hz, 1H), 7.74 (m, 1H), 7.62 (m, 2H), 7.52 (m, 1H), 7.4 (s, 2H), 7.3 (m, 1H), 7.2 (m, 2H), 6.60 (d, J=16.0 Hz, 1H), 6.38 (dd, J=16.0, 8.0 Hz, 1H), 4.10 (m, 1H), 4.02 (s, 2H), 3.96 (s, 2H); ESIMS m/z 552.95 ([M+H]+); IR (thin film) 3338, 1114, 808 cm−1.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=2)[O:11][CH2:12][CH2:13][CH2:14][NH2:15])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:23]=[CH:22][CH:21]=1>Cl>[N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=2)[O:11][CH2:12][CH2:13][CH2:14][NH:15][C:20]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[N:23]=[CH:22][CH:21]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Clc1ccnc2ccccc12
Reactant: NCCCOc1cccc(CN2CCCCC2)c1
Agent: Cl
Product: c1cc(CN2CCCCC2)cc(OCCCNc2ccnc3ccccc23)c1
Temperature: 155 °C
Reaction time: 2 h

Procedure:
3-[3-(Piperidinomethyl)phenoxy]propylamine (13.51 g) and 4-chloroquinoline (4.45 g) were heated with stirring at 155° C. for 21/2 hours. The cooled reaction mixture was dissolved in 2 Normal hydrochloric acid to pH 3-4 and the acidic solution was extracted with ethyl acetate. The aqueous solution was then basified to pH greater than 9 and was extracted with chloroform several times. The combined chloroform extracts were dried and evaporated to dryness to give the title compound as an oil. This was treated with maleic acid in ethanol to afford 4-[3-[3-(piperidinomethyl)phenoxy] propylamino]quinoline dimaleate (8.9 g), m.p. 127°-127.5° C. (recrystallised from isopropanol).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([C:9](=[O:11])[CH3:10])[CH:6]=[CH:5][C:4]=1[N:12]1[CH:16]=[C:15]([CH3:17])[N:14]=[CH:13]1.C(NC(C)C)(C)C.[Li].C([Li])CCC.C(NC(C)C)(C)C.[Cl:38][CH2:39][CH2:40][CH2:41][CH:42]([C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=1[C:52]([F:55])([F:54])[F:53])[C:43](Cl)=[O:44]>O1CCCC1>[Cl:38][CH2:39][CH2:40][CH2:41][CH:42]([C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=1[C:52]([F:53])([F:54])[F:55])[C:43](=[O:44])[CH2:10][C:9]([C:7]1[CH:6]=[CH:5][C:4]([N:12]2[CH:16]=[C:15]([CH3:17])[N:14]=[CH:13]2)=[C:3]([O:2][CH3:1])[N:8]=1)=[O:11]
Reactant: O=C(Cl)C(CCCCl)c1ccccc1C(F)(F)F
Reactant: COc1nc(C(C)=O)ccc1-n1cnc(C)c1
Agent: [Li]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COc1nc(C(=O)CC(=O)C(CCCCl)c2ccccc2C(F)(F)F)ccc1-n1cnc(C)c1
Reaction time: 0.5 h

Procedure:
A solution of 1-[6-methoxy-5-(4-methylimidazol-1-yl)pyridin-2-yl]ethanone obtained in Preparation Example 1-8 (412 mg) in tetrahydrofuran (10 ml) was added at −30° C. to a lithium diisopropylamine solution prepared from n-butyllithium (1.4 mL) and diisopropylamine (528 μL) in tetrahydrofuran (30 mL). After stirring at the same temperature for 30 minutes, 5-chloro-2-(2-trifluoromethylphenyl)valeric acid chloride (532 mg) was added and the mixture was stirred for 1.5 hours. After further stirring at room temperature for 30 minutes, the reaction was terminated with water, followed by dilution with ethyl acetate. The organic layer was washed with brine and dried over magnesium sulfate. The oil after concentration under reduced pressure was purified by silica gel chromatography (mobile phase:ethyl acetate/heptane=0 to 100%) to obtain the title compound (90 mg).
Reaction SMILES: [NH2:1]C1SC2C=C([N+]([O-])=O)C=CC=2N=1.[C:14](Cl)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.O>N1C=CC=CC=1>[C:14]([NH2:1])(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Nc1nc2ccc([N+](=O)[O-])cc2s1
Reactant: O=C(Cl)c1ccccc1
Solvent: O
Solvent: c1ccncc1
Product: NC(=O)c1ccccc1
Temperature: 25 °C
Yield: 86 %

Procedure:
To a suspension of 2-amino-6-nitrobenzothiazole (Sigma Aldrich, 2.93 g, 15 mmol) in pyridine (20 mL), benzoyl chloride (1.74 mL, 15 mmol) was added. After stirring over-night at r.t., additional benzoyl chloride (1.74 mL, 15 mmol) was added and the mixture was stirred at 60° C. After completion of the reaction, the mixture was poured into water (250 mL) and stirred overnight at r.t. Separation of the resulting precipitate yielded N-6-nitrobenzotihiazol-2-yl)benzamide (3.87 g, 12.9 mmol, 86%) as a yellow solid. LC/ESI-MS: m/z=300 [M+H]+; m/z=298 [M−H]−; Rt=3.93 min.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([CH:13]=[CH:14][C:15]=2[OH:16])[CH:11]=[O:12])=[CH:4][C:3]=1[S:17]([CH3:20])(=[O:19])=[O:18].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30]>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([CH:11]=[O:12])[CH:13]=[CH:14][C:15]=2[O:16][CH2:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[CH:4][C:3]=1[S:17]([CH3:20])(=[O:18])=[O:19]
Reactant: CS(=O)(=O)c1cc(-c2cc(C=O)ccc2O)ccc1F
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)COc1ccc(C=O)cc1-c1ccc(F)c(S(C)(=O)=O)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 51 %

Procedure:
To a solution of 3-(4-fluoro-3-(methylsulfonyl)phenyl)-4-hydroxybenzaldehyde (28) (315 mg, 1.1 mmol, 1 eq.) in DMF (10 mL) was added Cs2CO3 (715 mg, 2.2 mmol, 2 eq.) and t-butyl 2-bromoacetate (236 mg, −1.2 mmol, 1.2 eq.). After stirring at room temperature, for 16 h, the solvent was removed in vacuo, and the resultant residue was extracted between EtOAc and H2O (3×20 mL). The organic layer was dried (Na2SO4), and concentrated in vacuo. The resultant residue was purified by column chromatography (eluent: PE:EA=1:1) to give 250 mg (57%) of t-butyl 2-(2-(4-fluoro-3-(methylsulfonyl)phenyl)-4-formylphenoxy)acetate (29) as oil.
Reaction SMILES: [OH:1][CH:2]([CH3:9])[CH2:3][CH2:4][CH2:5][C:6]([OH:8])=[O:7].S(=O)(=O)(O)O.[CH3:15]O>>[CH3:15][O:7][C:6](=[O:8])[CH2:5][CH2:4][CH2:3][CH:2]([OH:1])[CH3:9]
Reactant: CO
Reactant: CC(O)CCCC(=O)O
Agent: O=S(=O)(O)O
Product: COC(=O)CCCC(C)O
Yield: 78 %

Procedure:
5-Hydroxy hexanoic acid 3 (1 g, 7.69 mmoles) is dissolved in 30 mL of methanol, mixed with a catalytic amount of sulfuric acid and heated until the reaction is completed. Subsequently, the solvent is removed under vacuum and the residue distilled under the vacuum of an oil pump. 870 mg (6.00 mmoles) of methyl-5-hydroxyhexanoate 4 is obtained which represents a yield of 78%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([CH2:11]Cl)[N:10]=2)[CH:7]=1.Cl.Cl.[CH3:15][O:16][C:17]1[CH:18]=[C:19]([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[CH:20]=[CH:21][CH:22]=1.C(N(CC)CC)C>C(O)CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([CH2:11][N:26]3[CH2:25][CH2:24][N:23]([C:19]4[CH:20]=[CH:21][CH:22]=[C:17]([O:16][CH3:15])[CH:18]=4)[CH2:28][CH2:27]3)[N:10]=2)[CH:7]=1
Reactant: ClCc1cn2cc(Cl)ccc2n1
Reactant: COc1cccc(N2CCNCC2)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: OCCO
Product: COc1cccc(N2CCN(Cc3cn4cc(Cl)ccc4n3)CC2)c1
Yield: 72.7 %

Procedure:
Following the general procedure of Example 11 and making noncritical variations, 6-chloro-2-(chloromethyl)imidazo[1,2-a]pyridine (Example 4, Step 1; 0.409 g), 1-(3-methoxyphenyl)piperazine dihydrochloride (Aldrich; 0.450 g), triethylamine (Aldrich; 0.686 g), and ethylene glycol (2 mL) give 0.440 g of the title compound after chromatography (silica gel, methanol/dichloromethane, 4/96) and crystallization from dichloromethane/ethyl ether/hexane; mp 132-133.5° C.; MS m/z 356; IR (mineral oil) 805, 2817, 1198, 1171, 1580, 1502 cm-1. 1H NMR (CDCl3) δ2.74, 3.24, 3.78, 6.41, 6.46, 6.55, 7.11-7.19, 7.52, 7.56, 8.14.