Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][CH:12]=[C:13]([C:16]([F:19])([F:18])[F:17])[CH2:14][CH3:15])(=O)=O)=CC=1.[F:21][C:22]([F:34])([F:33])[CH2:23][CH2:24][S:25]([CH2:28][C:29]([O:31][CH3:32])=[O:30])(=[O:27])=[O:26].[H-].[Na+].Cl>CN(C)C=O>[F:17][C:16]([F:19])([F:18])[C:13]([CH2:14][CH3:15])=[CH:12][CH2:11][CH:28]([S:25]([CH2:24][CH2:23][C:22]([F:21])([F:33])[F:34])(=[O:26])=[O:27])[C:29]([O:31][CH3:32])=[O:30]
Reactant: CCC(=CCOS(=O)(=O)c1ccc(C)cc1)C(F)(F)F
Reactant: COC(=O)CS(=O)(=O)CCC(F)(F)F
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCC(=CCC(C(=O)OC)S(=O)(=O)CCC(F)(F)F)C(F)(F)F
Temperature: 60 °C
Reaction time: 6 h
Yield: 0 %

Procedure:
To a solution of 3.0 g of 3-trifluoromethyl-2-pentenyl p-toluenesulfonate and 2.3 g of methyl (3,3,3-trifluoropropylsulfonyl)acetate in 50 ml of N,N-dimethylformamide was added 0.4 g of sodium hydride (60% in oil) at room temperature. The reaction mixture was stirred at the same temperature for 10 hours, at 60° C. for 6 hours and then at 90° C. for 1 hour. The reaction mixture was allowed to stand to cool to nearly room temperature. To the reaction mixture was added 10% hydrochloric acid and then extracted with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The obtained residue was subjected to silica gel chromatography to obtain 1.86 μg of methyl 5-trifluoromethyl-2-(3,3,3-trifluoropropylsulfonyl)-4-heptenoate (hereinafter referred to as the present compound (36)) as a mixture of (E) and (Z) isomers.
Reaction SMILES: [F:1][C:2]1[C:7]([S:8][CH3:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:10]1[CH2:11][CH2:12][NH:13][CH2:14][CH:15]=1.C(N(CC)CC)C.Cl[C:24]([O:26][CH3:27])=[O:25]>C(Cl)Cl>[F:1][C:2]1[C:7]([S:8][CH3:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:10]1[CH2:15][CH2:14][N:13]([C:24]([O:26][CH3:27])=[O:25])[CH2:12][CH:11]=1
Reactant: COC(=O)Cl
Reactant: CSc1cccc(C2=CCNCC2)c1F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)N1CC=C(c2cccc(SC)c2F)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 55.8 %

Procedure:
To a solution of 4-[2-fluoro-3-(methylthio)phenyl]-1,2,3,6-tetrahydropyridine (1.35 g, 6.05 mmol) and triethyl amine (1.2 ml, 7.2 mmol) in methylen chloride (20 ml) at 0° C., a solution of methyl chloroformate (0.49 g, 6.6 mmol) in methylen chloride (5 ml), was added dropwise. The mixture was stirred for 15 min at 0° C. and for 1 h at ambient temperature. The reaction was quenched with aqueous sodium carbonate (10%, 50 ml), the phases were separated and the aqueous phase was extracted with methylen chloride (3×50 ml). The combined organic phases was dried (MgSO4), filtered and evaporated to dryness to give the title compound (0.95 g). MS m/z (rel. intensity, 70 eV) 281 (M+, 65), 267 (16), 266 (bp), 147 (27), 146 (25).
Reaction SMILES: CC(O)C.[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([C@@H:12]([CH:17]([C:22]([O:24][CH3:25])=[O:23])[C:18](OC)=[O:19])[CH2:13][N+:14]([O-])=O)=[CH:8][CH:7]=1>[Fe].[Ni].O1CCCC1>[Cl:5][C:6]1[CH:11]=[CH:10][C:9]([C@@H:12]2[CH2:13][NH:14][C:18](=[O:19])[C@H:17]2[C:22]([O:24][CH3:25])=[O:23])=[CH:8][CH:7]=1
Reactant: COC(=O)C(C(=O)OC)[C@@H](C[N+](=O)[O-])c1ccc(Cl)cc1
Agent: [Fe]
Agent: [Ni]
Solvent: CC(C)O
Solvent: C1CCOC1
Product: COC(=O)[C@@H]1C(=O)NC[C@H]1c1ccc(Cl)cc1
Temperature: 8 °C
Yield: 78.5 %

Procedure:
To 2-propanol (250 ml) was added dimethyl (R)-2-(1-(4-chlorophenyl)-2-nitroethyl)malonate (50.0 g, 158 mmol) and iron-containing developed nickel (5.0 g, containing iron 16.6%, aluminum 6.1%, manufactured by Kawaken Fine Chemical K.K.), and the mixture was reacted at 65° C. for 3 hours under a hydrogen pressure of 0.5 MPa (gauge pressure). After completion of the reaction, tetrahydrofuran (175 ml) was added, and the nickel catalyst was filtrated off. The nickel catalyst was washed with tetrahydrofuran (75 ml), and filtrate and washing liquid were combined, and acidic active alumina (5.0 g) was added to this and the mixture was thermally insulated at 50 to 60° C. The active alumina was filtrated off, then, the filtrate was concentrate under reduced pressure. The concentrated filtrate was cooled to 8° C., then, the resultant crystal was filtrated, and dried under reduced pressure, to obtain a title compound (31.4 g, 124 mmol) (yield: 78%). The spectrum data corresponded to the value in Example 2. The optical purity of the resultant compound was measured by HPLC to find a value of 99.73% ee. The content of a by-product obtained by releasing a chlorine atom was 0.06% (conditions are shown below).
Reaction SMILES: CCN(C(C)C)C(C)C.CS(O[CH2:15][CH2:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([CH:24]2[CH2:29][CH2:28][N:27]([C:30]3[CH:31]=[CH:32][C:33]4[N:34]([C:36]([C:39]([F:42])([F:41])[F:40])=[N:37][N:38]=4)[N:35]=3)[CH2:26][CH2:25]2)=[CH:20][CH:19]=1)(=O)=O.[C:43]([N:46]1[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]1)(=[O:45])[CH3:44].[OH-].[Na+]>CC(N(C)C)=O>[C:43]([N:46]1[CH2:51][CH2:50][N:49]([CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][C:21]([CH:24]3[CH2:25][CH2:26][N:27]([C:30]4[CH:31]=[CH:32][C:33]5[N:34]([C:36]([C:39]([F:41])([F:40])[F:42])=[N:37][N:38]=5)[N:35]=4)[CH2:28][CH2:29]3)=[CH:20][CH:19]=2)[CH2:48][CH2:47]1)(=[O:45])[CH3:44]
Reactant: CS(=O)(=O)OCCOc1ccc(C2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc1
Reactant: CC(=O)N1CCNCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: CC(=O)N1CCN(CCOc2ccc(C3CCN(c4ccc5nnc(C(F)(F)F)n5n4)CC3)cc2)CC1
Temperature: 110 °C
Reaction time: 1 h
Yield: 76.6 %

Procedure:
DIPEA (107 mL, 613.00 mmol) was added to 2-(4-{1-[3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl}phenoxy)ethyl methanesulfonate (99 g, 204.33 mmol) and N-acetylpiperazine (28.8 g, 224.77 mmol) in DMA (500 mL). The resulting solution was stirred at 110° C. for 1 hour. The reaction mixture was cooled to room temperature and the solvents were evaporated. The residue was dissolved in ethyl acetate (1 L) and the solution was washed with water (1 L). The aqueous was re-extracted with ethyl acetate (1 L) and the combined organics were washed with brine (1 L), dried over MgSO4, filtered and evaporated to give crude product. The aqueous layer was basified to pH 12 with 2M NaOH, then extracted with ethyl acetate (1 L), washed with brine (1 L), dried over MgSO4, filtered and evaporated to give further crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 3% MeOH in DCM then 5% MeOH in DCM. Pure fractions were evaporated to give 6-[4-[4-[2-(4-acetylpiperazin-1-yl)ethoxy]phenyl]piperidin-1-yl]-3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazine (81 g, 77%) as a solid.
Reaction SMILES: [K].[F:2][C:3]1[CH:25]=[CH:24][C:6]([C:7]([NH:9][C:10]2[CH:23]=[CH:22][CH:21]=[CH:20][C:11]=2[C:12]([C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)=O)=O)=[CH:5][CH:4]=1>C1COCC1.[Cl-].[Ti+3].[Cl-].[Cl-]>[N:17]1[CH:18]=[CH:19][C:14]([C:12]2[C:11]3[C:10](=[CH:23][CH:22]=[CH:21][CH:20]=3)[NH:9][C:7]=2[C:6]2[CH:24]=[CH:25][C:3]([F:2])=[CH:4][CH:5]=2)=[CH:15][CH:16]=1
Reactant: O=C(Nc1ccccc1C(=O)c1ccncc1)c1ccc(F)cc1
Agent: [Ti+3]
Agent: [Cl-]
Agent: [K]
Solvent: C1CCOC1
Product: Fc1ccc(-c2[nH]c3ccccc3c2-c2ccncc2)cc1
Temperature: 23 °C
Reaction time: 0.42 h

Procedure:
Graphite (272 mg, 3.63 mmol) and potassium (100 mg, 0.33 mmol) were warmed to 150° C. under argon in a 250 mL round bottom flask with stirring for 25 min. THF (30 mL) was added via syringe to the hot bronze colored solid followed by a suspension of titanium (III) chloride (254 mg, 1.65 mmol) in THF (20 mL). The resultant black solution was allowed-to reflux for 1 h. 4-(2-(4-fluoro-N-benzoylamino)benzoyl)pyridine (14) (100 mg, 0.33 mmol) and THF (20 mL) were then added to the hot (65° C.) reaction mixture over 5 min. After 1 h at 65° C., the reaction was cooled to 23° C. the filtered through a silica gel pad (20 g). After concentration in vacuo, the residue was purified by flash chromatography (ethyl acetate:methylene chloride 1:1) to afford 3-(4-pyridyl)-2-(4-fluorophenyl)indole (3): Mass spectrum (CI) 289 (MH+).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](O)=[O:6].[Cl:12]CCl.C(Cl)(=O)C(Cl)=O>CN(C)C=O>[Br:1][C:2]1[C:3]([CH3:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([Cl:12])=[O:6]
Reactant: Cc1c(Br)cccc1C(=O)O
Reactant: ClCCl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Product: Cc1c(Br)cccc1C(=O)Cl
Reaction time: 0.05 h

Procedure:
3-Bromo-2-methylbenzoic acid (2000 mg) was added to dichloromethane (50 mL) and N,N-dimethylformamide (1 mL). Oxalyl chloride (649 mg) was added and the solution was stirred for three minutes. The mixture was washed with 1 M aqueous HCl three times, washed with brine, and dried on anhydrous sodium sulfate. After filtration, the solvent was removed under vacuum to yield the product.
Reaction SMILES: S(Cl)([Cl:3])=O.C(O)(=O)C(O)=O.O[CH2:12][C@@H:13]1[C@H:18]([CH2:19][CH2:20][CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[C:29]([O:32][CH3:33])[CH:30]=3)[N:25]=[CH:24][CH:23]=2)[CH2:17][CH2:16][N:15]([CH2:34][CH2:35][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH2:14]1.O>C(Cl)(Cl)Cl>[Cl:3][CH2:12][C@@H:13]1[C@H:18]([CH2:19][CH2:20][CH2:21][C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[C:29]([O:32][CH3:33])[CH:30]=3)[N:25]=[CH:24][CH:23]=2)[CH2:17][CH2:16][N:15]([CH2:34][CH2:35][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH2:14]1
Reactant: COc1ccc2nccc(CCC[C@@H]3CCN(CCCc4ccccc4)C[C@@H]3CO)c2c1
Reactant: O=S(Cl)Cl
Agent: O=C(O)C(=O)O
Solvent: O
Solvent: ClC(Cl)Cl
Product: COc1ccc2nccc(CCC[C@@H]3CCN(CCCc4ccccc4)C[C@@H]3CCl)c2c1
Temperature: 60 °C

Procedure:
3.6 cm3 of thionyl chloride were added dropwise, at a temperature in the region of 20° C., to a stirred solution of 2.9 g of (3R,4R)-3-hydroxymethyl4-[3-(6-methoxyquinolin-4-yl)propyl]-1-(3-phenylpropyl)piperidine oxalate in 20 cm3 of chloroform. The mixture was heated for 2 hours at a temperature in the region of 60° C. and then, after cooling, was poured onto 50 cm3 of water to which 250 g of ice had been added. After separating by settling from the chloroform phase, the mixture was extracted with 100 cm3 of dichloromethane. 5 g of sodium hydrogencarbonate were added to the aqueous phase, which was then extracted with 2 times 200 cm3 of dichloromethane. The organic extracts were dried over magnesium sulfate, filtered, and then evaporated under reduced pressure (5 kPa) at a temperature in the region of 40°. 1.3 g of (3R,4R)-3-chloromethyl-4-[3-(6-methoxyquinolin-4-yl)propyl]-1-(3-phenylpropyl)piperidine were obtained in the form of an oil with a brown color.
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]1[N:7]=[CH:8][N:9]([C:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:10]=1)CCC.Br[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][N:40]=1>C1(C)C=CC=CC=1.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>[N:40]1[CH:41]=[CH:42][CH:43]=[CH:44][C:39]=1[C:6]1[N:7]=[CH:8][N:9]([C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:10]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: Brc1ccccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: c1ccc(C(c2ccccc2)(c2ccccc2)n2cnc(-c3ccccn3)c2)cc1
Yield: 77.9 %

Procedure:
The crude 4-tributylstannyl-1-trityl-1H-imidazole (1.37g) in toluene (10 mL) was treated sequentially with 2-bromopyridine (0.33 mL, 3.43 mmol) and Pd(PPh3)4 (0.26 g, 0.23 mmol). The reaction mixture was heated at reflux under an argon atmosphere for 4 hours. After cooling, the reaction mixture was concentrated in vacuo. The residue was dissolved in chloroform (50 mL) and sequentially washed with aqueous saturated potassium fluoride (75 mL), water (75 mL) and brine (100 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated in-vacuo to afford 0.69 g of crude 4-(2-pyridyl)-1-trityl-1H-imidazole.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][C:10]3[N:14]=[CH:13][N:12]([CH:15]4[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]4)[C:11]=3[CH:21]=2)=[N:4][N:3]=1.C(N(CC)CC)C.[CH3:29][S:30](Cl)(=[O:32])=[O:31]>O1CCCC1>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][C:10]3[N:14]=[CH:13][N:12]([CH:15]4[CH2:20][CH2:19][N:18]([S:30]([CH3:29])(=[O:32])=[O:31])[CH2:17][CH2:16]4)[C:11]=3[CH:21]=2)=[N:4][N:3]=1
Reactant: Cc1nnc(-c2ccc3ncn(C4CCNCC4)c3c2)o1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1nnc(-c2ccc3ncn(C4CCN(S(C)(=O)=O)CC4)c3c2)o1
Temperature: 25 °C
Reaction time: 1 h
Yield: 59.7 %

Procedure:
To a solution of 6-(5-methyl-1,3,4-oxadiazol-2-yl)-1-(4-piperidinyl)-1H-benzimidazole (0.25 g, 0.88 mmol) and triethylamine (0.24 mL, 1.76 mmol) in tetrahydrofuran (5 mL) was added methanesulfonyl chloride (0.10 mL, 1.32 mmol) at 0° C., and the resulting mixture was stirred at room temperature for 1 hr. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate/methanol=1/0-19/1) and recrystallized from diethyl ether/methanol to give the title compound (0.19 g, yield 60%) as colorless crystals.
Reaction SMILES: CN(C)C=O.C(=O)([O-])[O-].[K+].[K+].[CH:12](I)([CH3:14])[CH3:13].[OH:16][C:17]1[C:26]([OH:27])=[C:25]2[C:20]([C:21](=[O:30])[CH2:22][C:23]([CH3:29])([CH3:28])[O:24]2)=[CH:19][CH:18]=1>COCCOCCOC>[CH:12]([O:16][C:17]1[C:26]([OH:27])=[C:25]2[C:20]([C:21](=[O:30])[CH2:22][C:23]([CH3:28])([CH3:29])[O:24]2)=[CH:19][CH:18]=1)([CH3:14])[CH3:13]
Reactant: CC1(C)CC(=O)c2ccc(O)c(O)c2O1
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOCCOC
Solvent: CN(C)C=O
Product: CC(C)Oc1ccc2c(c1O)OC(C)(C)CC2=O
Temperature: 140 °C
Yield: 90 %

Procedure:
In 50 ml of N,N-dimethyl formamide 4.2 g (20 millimoles) of 7.8-dihydroxy-2,2-dimethyl-4-chromanone are dissolved, whereupon 5 ml of diethylene glycol dimethylether, 3.0 g (22 millimoles) of potassium carbonate and 4.2 g (2.5 ml, 25 millimoles) of isopropyl iodide are added. The reaction mixture is heated at 140° C. for 4 hours and worked up according to Example 19. Thus 4.5 g of the desired compound are obtained, yield 90%, mp.: 114°-116° C.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7]O[C:9]2=[O:14])([O-:3])=[O:2].CO.C(N(CC)CC)C.Br.[NH2:25][C@@H:26]([CH3:30])[C:27]([NH2:29])=[O:28]>>[N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][N:25]([C@@H:26]([CH3:30])[C:27]([NH2:29])=[O:28])[C:9]2=[O:14])([O-:3])=[O:2]
Reactant: O=c1occc2c([N+](=O)[O-])cccc12
Reactant: C[C@H](N)C(N)=O
Agent: Br
Solvent: CO
Solvent: CCN(CC)CC
Product: C[C@@H](C(N)=O)n1ccc2c([N+](=O)[O-])cccc2c1=O
Temperature: 50 °C

Procedure:
To a solution of 5-nitro-isochromen-1-one (1.5 g, 0.0078 mol) in methanol (20 mL, 0.4 mol) was added triethylamine (2 mL, 0.02 mol) and (S)-2-aminopropanamide hydrobromide (1.6 g, 0.0094 mol) and the resulting mixture was heated at 50° C. overnight. The reaction mixture was cooled to room temperature wherein the product precipitated out. The precipitate was filtered and dried to yield the pure product as a yellow solid. MS m/z=262.2 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[N:10]=[C:9]2S(C)(=O)=O)=[CH:4][CH:3]=1.O1CCCC1.O.[NH2:29][NH2:30]>[Cl-].[Na+].O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[N:10]=[C:9]2[NH:29][NH2:30])=[CH:4][CH:3]=1
Reactant: NN
Reactant: CS(=O)(=O)c1nc(C(F)(F)F)cc(=O)n1-c1ccc(Cl)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: NNc1nc(C(F)(F)F)cc(=O)n1-c1ccc(Cl)cc1
Temperature: 25 °C

Procedure:
A mixture of 3-(4-chlorophenyl)-3,4-dihydro-2-methanesulfonyl-6-trifluoromethylpyrimidin-4-one (2.0 g) and tetrahydrofuran (20 ml) was added with hydrazine monohydrate (NH2NH2. H2O) (0.5 g). After stirring for 30 minuets at room temperature, the mixture was added with saturated brine (30 ml) and then extracted with ethyl acetate. The extract layer was washed with water and then dried on anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to give the compound of interest (1.5 g) as a milk white solid.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[S:10](=[O:13])(=[O:12])[N:9]=[C:8]([C:14]3[C:15](=[O:30])[N:16]([NH:25][CH2:26][CH:27]([CH3:29])[CH3:28])[C:17]4[C:22]([C:23]=3[OH:24])=[CH:21][CH:20]=[CH:19][CH:18]=4)[NH:7][C:6]=2[CH:5]=[CH:4][C:3]=1[OH:31].[NH2:32][C:33]1[CH:34]=[C:35]([CH:39]=[CH:40][CH:41]=1)[C:36](O)=O>>[NH2:32][C:33]1[CH:34]=[C:35]([C:36]2[O:31][C:3]3[CH:4]=[CH:5][C:6]4[NH:7][C:8]([C:14]5[C:15](=[O:30])[N:16]([NH:25][CH2:26][CH:27]([CH3:29])[CH3:28])[C:17]6[C:22]([C:23]=5[OH:24])=[CH:21][CH:20]=[CH:19][CH:18]=6)=[N:9][S:10](=[O:12])(=[O:13])[C:11]=4[C:2]=3[N:1]=2)[CH:39]=[CH:40][CH:41]=1
Reactant: CC(C)CNn1c(=O)c(C2=NS(=O)(=O)c3c(ccc(O)c3N)N2)c(O)c2ccccc21
Reactant: Nc1cccc(C(=O)O)c1
Product: CC(C)CNn1c(=O)c(C2=NS(=O)(=O)c3c(ccc4oc(-c5cccc(N)c5)nc34)N2)c(O)c2ccccc21
Temperature: 190 °C
Yield: 32 %

Procedure:
A mixture of the product of Example 354 (38 mg, 0.086 mmol) and 3-aminobenzoic acid (13 mg, 0.094 mmol) in polyphosphoric acid (1 mL)was heated to 190° C. for 1 hour. The solution was cooled to 25° C., triturated with water and a 10% solution of sodium carbonate. The solid was filtered, dried, and purified by flash column, eluting with 2% methanol in dichloromethane to yield the title compound (15 mg, 38%). The sodium salt was made by the procedure of Example 1D. MS (ESI−) m/z 543 (M−H)−. 1H NMR (300 MHz, DMSO-d6) δ 1.04 (d, J=6.62 Hz, 6 H) 1.86 (m, 1 H) 2.56 (m, 2 H) 5.53 (s, 2 H) 5.96 (t, J=7.35 Hz, 1 H) 6.82 (ddd, J=8.09, 2.21, 1.10 Hz, 1 H) 7.08 (td, J=7.35, 1.47 Hz, 1 H) 7.27 (m, 2 H) 7.36 (dt, J=7.72, 1.29 Hz, 1 H) 7.57 (m, 3 H) 7.96 (d, J=8.82 Hz, 1 H) 8.10 (dd, J=8.09, 1.47 Hz, 1 H) 16.51 (s, 1 H).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[OH-].[Na+].Br[CH2:11][CH2:12][CH2:13][Cl:14]>CC(C)=O>[Cl:14][CH2:13][CH2:12][CH2:11][N:5]1[CH2:6][CH2:7][CH:2]([OH:1])[CH2:3][CH2:4]1
Reactant: OC1CCNCC1
Reactant: ClCCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: OC1CCN(CCCCl)CC1
Yield: 28.1 %

Procedure:
4-Hydroxypiperidine (3 g, 30 mmol), acetone (60 ml, 20 vol), 5M NaOH solution (7.2 ml) and 1-bromo-3-chloropropane (14.2 g, 90 mmol, 3 eq.) were reacted together according to general procedure A to give the title compound (1.5 g, 28%) as a pale yellow oil.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[Br:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]Br.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[C:1]([N:4]1[CH2:5][CH2:6][N:7]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][Br:17])=[CH:12][CH:11]=2)[CH2:8][CH2:9]1)(=[O:3])[CH3:2]
Reactant: BrCCCCCCBr
Reactant: CC(=O)N1CCN(c2ccc(O)cc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)N1CCN(c2ccc(OCCCCCCBr)cc2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 1-acetyl-4-(4-hydroxyphenyl)piperazine (5.00 g) in N,N-dimethylformamide (50 ml) was treated with 1,6-dibromohexane (10.5 ml) and potassium carbonate (4.71 g), and the mixture was stirred for 18 hours at ambient temperature. To the reaction mixture was added water (200 ml), and the resulting precipitate was collected by filtration, washed with water and n-hexane successively and dried under reduced pressure to give crude 1-acetyl-4-[4-(6-bromohexyloxy)phenyl]piperazine (10.52 g), that was used in the next reaction directly.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:14]([O:15][CH3:16])=[CH:13][C:6]2[S:7][C:8]([C:10](O)=[O:11])=[CH:9][C:5]=2[CH:4]=1.C1(C)C=CC=CC=1.S(Cl)(Cl)=O.[N:28]1C=CC=CC=1>>[CH3:1][O:2][C:3]1[C:14]([O:15][CH3:16])=[CH:13][C:6]2[S:7][C:8]([C:10]([NH2:28])=[O:11])=[CH:9][C:5]=2[CH:4]=1
Reactant: COc1cc2cc(C(=O)O)sc2cc1OC
Reactant: c1ccncc1
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: COc1cc2cc(C(N)=O)sc2cc1OC

Procedure:
A mixture of 5,6-dimethoxy-benzo[b]thiophene-2-carboxylic acid (68.8 g), dry toluene (350 ml), thionyl chloride (126 ml) and pyridine (1.75 ml) was stirred and heated at reflux for 4 hours. The resultant mixture was cooled, evaporated to dryness under vacuum and the residue was purged with dry toluene (3×250 ml). The resulting crude acid chloride was suspended in dioxan (160 ml) then cooled in an ice bath and treated in one portion with concentrated ammonium hydroxide solution (33% w/w, 900 ml). This gave a suspension of brown solid which was stirred for two hours then filtered, washed with water and dried under vacuum over calcium chloride at 60° C. to give 5,6-dimethoxybenzo[b]thiophene-2-carboxamide (62.5 g), m.p. 211°-213° C.
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH3:32])[C:4](=[O:31])[C:5]([C:20]2[CH:21]=[C:22]([CH:29]=O)[N:23]([CH2:25][CH2:26][CH2:27][F:28])[CH:24]=2)([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]3[C:14]([F:19])=[N:15][CH:16]=[CH:17][CH:18]=3)[CH:8]=2)[N:6]=1.Cl.[NH2:34][OH:35]>O1CCCC1>[NH2:1][C:2]1[N:3]([CH3:32])[C:4](=[O:31])[C:5]([C:20]2[CH:21]=[C:22]([CH:29]=[N:34][OH:35])[N:23]([CH2:25][CH2:26][CH2:27][F:28])[CH:24]=2)([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]3[C:14]([F:19])=[N:15][CH:16]=[CH:17][CH:18]=3)[CH:8]=2)[N:6]=1
Reactant: NO
Reactant: CN1C(=O)C(c2cccc(-c3cccnc3F)c2)(c2cc(C=O)n(CCCF)c2)N=C1N
Agent: Cl
Solvent: C1CCOC1
Product: CN1C(=O)C(c2cccc(-c3cccnc3F)c2)(c2cc(C=NO)n(CCCF)c2)N=C1N
Temperature: 45 °C

Procedure:
A solution of 4-{2-amino-4-[3-(2-fluoropyridin-3-yl)phenyl]-1-methyl-5-oxo-4,5-dihydro-1H-imidazol-4-yl}-1-(3-fluoropropyl)-1H-pyrrole-2-carbaldehyde in dry tetrahydrofuran was treated with 1.1 equivalent of hydroxylamine hydrochloride, warmed to 45° C. for 2 hours and concentrated in vacuo. The resultant residue was dissolved in chloroform, washed with water, dried over sodium sulfate and concentrated in vacuo. This residue was purified by HPLC (CN bonded stationary phase, gradient 30% to 60% of (20% MeOH/methylene chloride) and hexane to afford the title compound as a white amorphous solid, mp 119-123° C., identified by NMR and mass spectral analyses.
Reaction SMILES: I.[CH:2]1([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15](=[NH:18])SC)=[CH:10][CH:9]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[NH2:19][CH2:20][CH2:21][CH2:22]N>C(O)CCCC>[CH:2]1([C:8]2[CH:13]=[CH:12][C:11]([N:14]=[C:15]3[NH:18][CH2:22][CH2:21][CH2:20][NH:19]3)=[CH:10][CH:9]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: CSC(=N)Nc1ccc(C2CCCCC2)cc1
Reactant: NCCCN
Agent: I
Solvent: CCCCCO
Product: c1cc(C2CCCCC2)ccc1N=C1NCCCN1

Procedure:
A solution of 3.6 g of N-(4-cyclohexylphenyl)-S-methyl-isothiourea hydroiodide and 1 ml of 1,3-diaminopropane in 15 ml of amyl alcohol is refluxed for 21/2 hours. After distilling off the solvent the residue is taken up in methylene chloride and washed with dilute alkaline solution and water. The methylene chloride is distilled off and the crude final product is recrystallised from acetonitrile. The resulting 2-(4-cyclohexylphenyl)imino-hexahydropyrimidine has a melting point of 179°-181° C.