Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:17]=[C:16]([C:18]2[N:27]=[CH:26][CH:25]=[C:24]3[C:19]=2[CH:20]=[CH:21][N:22]=[C:23]3[NH2:28])[C:15]2[C:10](=[N:11][CH:12]=[CH:13][CH:14]=2)[N:9]=1.[C:29](OC(=O)C)(=[O:31])[CH3:30]>C(O)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:17]=[C:16]([C:18]2[N:27]=[CH:26][CH:25]=[C:24]3[C:19]=2[CH:20]=[CH:21][N:22]=[C:23]3[NH:28][C:29](=[O:31])[CH3:30])[C:15]2[C:10](=[N:11][CH:12]=[CH:13][CH:14]=2)[N:9]=1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1nccc2c(-c3cc(-c4ccccc4F)nc4ncccc34)nccc12
Solvent: CC(=O)O
Product: CC(=O)Nc1nccc2c(-c3cc(-c4ccccc4F)nc4ncccc34)nccc12
Temperature: 80 °C
Reaction time: 18 h

Procedure:
A solution of 37 mg (0.10 mmol) 5-[2-(2-fluoro-phenyl)-[1,8]naphthyridin-4-yl]-[2,6]naphthyridin-1-ylamine in 0.5 ml acetic acid was treated with 20.4 mg (0.20 mmol) acetic acid anhydride and heated to 80° C. The reaction mixture was stirred at this temperature for 18 hours. The reaction mixture was cooled to room temperature and partitioned between 25% aqueous ammonia and dichloromethane. The organic phase was dried over sodium sulphate and evaporated. The residue was triturated with tert-butyl-methylether yielding N-{5-[2-(2-fluoro-phenyl)-[1,8]naphthyridin-4-yl]-[2,6]naphthyridin-1-yl}-acetamide as brown crystals; HPLC/MS (A) 1.64 min, [M+H] 410.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8](=[O:10])[CH3:9])[CH2:3][CH2:2]1.C([O-])([O-])=O.[K+].[K+].F[C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1.O>CN(C=O)C>[N+:24]([C:21]1[CH:22]=[CH:23][C:18]([N:1]2[CH2:6][CH2:5][CH:4]([NH:7][C:8](=[O:10])[CH3:9])[CH2:3][CH2:2]2)=[CH:19][CH:20]=1)([O-:26])=[O:25]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: CC(=O)NC1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)NC1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Temperature: 80 °C
Reaction time: 24 h

Procedure:
To a solution of N-(piperidin-4-yl)acetamide (341 mg, 2.4 mmol) in DMF (15 mL) was added K2CO3 (331 mg, 2.4 mmol) and 1-fluoro-4-nitrobenzene (282 mg, 2 mmol) at room temperature. The reaction was stirred at 80° C. for 24 hours. After that, the reaction was poured into 50 mL of water and extracted with EA (3×25 mL), washed with H2O (25 mL) and brine (25 mL), dried over Na2SO4 and concentrated to give yellow solid. MS (m/z): 264 (M+H)+
Reaction SMILES: [S:1](Br)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].CCN(CC)CC.C[O:20][C:21](=[O:36])[CH2:22][O:23][C:24]1[CH:29]=[C:28]([C:30]([CH3:33])([CH3:32])[CH3:31])[C:27]([SH:34])=[CH:26][C:25]=1[CH3:35]>C(Cl)(Cl)(Cl)Cl.C(Cl)Cl>[C:30]([C:28]1[C:27]([S:34][S:1]([C:4]2[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=2)(=[O:3])=[O:2])=[CH:26][C:25]([CH3:35])=[C:24]([CH:29]=1)[O:23][CH2:22][C:21]([OH:36])=[O:20])([CH3:33])([CH3:32])[CH3:31]
Reactant: Cc1ccc(S(=O)(=O)Br)cc1
Reactant: COC(=O)COc1cc(C(C)(C)C)c(S)cc1C
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)Sc2cc(C)c(OCC(=O)O)cc2C(C)(C)C)cc1
Reaction time: 8 h

Procedure:
1.86 g (7.9 mmol, 2 equivalents) tosyl bromide and 1.05 mL (7.9 mmol) NEt3 were combined in 200 mL CCl4 and the mixture chilled in an ice bath under nitrogen. To this mixture was added a solution of 1.06 g (3.95 mmol) of (5-tert-butyl-4-mercapto-2-methyl-phenoxy)acetic acid methyl ester (prepared in Example MMMM) in 125 mL of CCl4 over 3 hours, and the reaction was allowed to come to ambient temperature overnight. The mixture was then diluted with CH2Cl2, washed with aqueous ammonium chloride and aqueous sodium chloride, and dried (Na2SO4). Concentration gave a residue which was chromatographed on silica gel eluting with 3:1 hexanes:EtOAc to yield the title compound. 1H NMR (CDCl3) δ 1.25 (s, 9 H), 2.14 (s, 3 H), 2.43 (s, 3 H), 3.82 (s, 3 H), 4.68 (s, 2 H), 6.75 (s, 1 H), 7.14 (s, 1 H), 7.25 (d, 2 H), 7.50 (d, 2 H).
Reaction SMILES: N1(C2C=CC([C:13]3[NH:21][C:16]4=NC=CN=[C:15]4[C:14]=3[CH2:22][CH2:23][C:24]([NH:26]C)=O)=CC=2)CCOCC1.[C:28]1([Mg]Br)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.O>O1CCCC1>[C:28]1([C:22]2[CH:23]=[CH:24][N:26]=[C:13]3[NH:21][CH:16]=[CH:15][C:14]=23)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: Br[Mg]c1ccccc1
Reactant: CNC(=O)CCc1c(-c2ccc(N3CCOCC3)cc2)[nH]c2nccnc12
Solvent: O
Solvent: C1CCOC1
Product: c1ccc(-c2ccnc3[nH]ccc23)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A suspension of 1-(2,6-dimethyl-1,4-dihydropyridin-4-one)-1H-pyrrolo[2,3-b]pyridinium tetrafluoroborate (Reference Example 43, 1.0 g) in tetrahydrofuran (100 mL) was treated with a solution of phenylmagnesium bromide in tetrahydrofuran (9.6 mL, 1M) and stirred at room temperature for 72 hours before adding water ((100 mL) and the tetrahydrofuran removed in vacuo. The residue was extracted with chloroform (3×100 mL), and the combined organics dried over sodium sulfate and evaporated. The residue was subjected to flash chromatography on silica eluting with a mixture of dichloromethane and methanol (99:1 v/v) to give the title compound (83 mg) as a white solid. MS: 195 (MH+). 1H NMR [(CD3)2SO]: δ 8.27 (1H, d, J=4.1 Hz); 7.78 (2H, d, J=8.2 Hz); 7.57 (3H, m); 7.48 (1H, t, J=8.2 Hz); 7.19 (1H, d, J=3.5 Hz); 6.60 (1H, s).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13]2[CH:18]=[CH:17][N:16]3[N:19]=[CH:20][C:21]([NH2:22])=[C:15]3[N:14]=2)[CH:5]=[CH:6][CH:7]=1.C1N=CN([C:28]([N:30]2[CH:34]=N[CH:32]=[CH:31]2)=[O:29])C=1.N1CC[O:38][CH2:37]C1>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([C@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13]2[CH:18]=[CH:17][N:16]3[N:19]=[CH:20][C:21]([NH:22][C:28]([N:30]4[CH2:31][CH2:32][O:38][CH2:37][CH2:34]4)=[O:29])=[C:15]3[N:14]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cnn2ccc(N3CCC[C@@H]3c3cccc(F)c3)nc12
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: C1COCCN1
Solvent: ClCCl
Product: O=C(Nc1cnn2ccc(N3CCC[C@@H]3c3cccc(F)c3)nc12)N1CCOCC1
Reaction time: 2 h
Yield: 98.9 %

Procedure:
To a DCM (0.8 mL) solution of (R)-5-(2-(3-fluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-amine (50 mg, 0.17 mmol) was added CDI (41 mg, 0.25 mmol) at ambient temperature in one portion. After stirring two hours, morpholine (22 mg, 0.25 mmol) was added in one portion. The reaction was stirred for 5 minutes before it was concentrated and directly purified by reverse-phase column chromatography, eluting with 5 to 54% acetonitrile/water to yield the final product as a yellowish foamy powder (69 mg, 100% yield). MS (apci) m/z=411.2 (M+H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][N:4]=1)#[N:2].C(O)C.N>[Ni].O1CCOCC1.Cl.C(OCC)C>[NH2:2][CH2:1][C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][N:4]=1
Reactant: N#Cc1ccc(F)cn1
Agent: [Ni]
Agent: Cl
Agent: N
Solvent: CCO
Solvent: CCOCC
Solvent: C1COCCO1
Product: NCc1ccc(F)cn1
Reaction time: 16 h

Procedure:
Combine a mixture of 2-cyano-5-fluoropyridine (63.2 g, 0.52 mol), 22.5 g of Raney nickel, and ethanol (1.5 L) saturated with ammonia and hydrogenate at 500 p.s.i. and 70° C. for 16 h. Chromatograph the dark purple liquid over flash silica gel (methylene chloride/methanol/ammonia hydroxide—95:4.5:0.5) to give, after concentration at 25-30° C., a yellow liquid of the pure desired free base, 25.0 g (44%); 1H NMR (DMSO-d6) δ 8.43 (d, J=2.9 Hz, 1H), 7.66 (m, 1H), 7.50 (m, 1H), 3.77 (s, 2H), 2.10 (br, 2H); MS (ESI) m/z 127 (m+H). Add to a solution of the free base (20.0 g, 159.0 mmol) in 150 ml of 1,4-dioxane, 4N HCl in dioxane (150 mL, 3.8 eq.) and a white solid separates immediately. Dilute the solid with ethyl ether (300 mL) and filter. Dry the product at 20 mm Hg, 60° C., to give the pure dihydrochloride title compound, 30.0 g (95%); 1H NMR (DMSO-d6) δ 8.61 (d, J=2.9 Hz, 1H), 8.50 (brs, 3H), 7.82 (m, 1H), 7.62 (m, 1H), 7.50 (br, 1H), 4.18 (m, 2H); MS (ESI) m/z 127 (m+H, free base).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][NH:11][S:12]([CH3:15])(=[O:14])=[O:13])=[CH:6][CH:5]=1)([O-])=O.[H][H]>C(O)C.C(OCC)(=O)C.[Pd]=O>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][NH:11][S:12]([CH3:15])(=[O:14])=[O:13])=[CH:6][CH:5]=1
Reactant: [H][H]
Reactant: CS(=O)(=O)NCc1ccc([N+](=O)[O-])cc1
Agent: O=[Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CS(=O)(=O)NCc1ccc(N)cc1

Procedure:
A solution of N-[(4-nitrophenyl)methyl]methanesulphonamide (2.5 g) in a mixture of ethanol (90 ml) and ethyl acetate (90 ml) was hydrogenated at room temperature and pressure over palladium oxide on charcoal (10%; 50% paste with water, 1 g) until uptake of hydrogen ceased (15 min., 820 ml).
Reaction SMILES: [CH3:1][CH:2]([CH3:6])[C:3]([NH2:5])=O.F[B-](F)(F)F.C([O+](CC)CC)C.N[C:20]1[C:21]([NH:29][C@@H:30]2[CH2:35][O:34][C@@H:33]([CH2:36][OH:37])[CH2:32][CH2:31]2)=[C:22]2[S:28][CH:27]=[CH:26][C:23]2=[N:24][CH:25]=1>C1COCC1.C(O)C.CO>[CH:2]([C:3]1[N:29]([C@@H:30]2[CH2:35][O:34][C@@H:33]([CH2:36][OH:37])[CH2:32][CH2:31]2)[C:21]2=[C:22]3[S:28][CH:27]=[CH:26][C:23]3=[N:24][CH:25]=[C:20]2[N:5]=1)([CH3:6])[CH3:1]
Reactant: Nc1cnc2ccsc2c1N[C@H]1CC[C@H](CO)OC1
Reactant: CC(C)C(N)=O
Agent: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Solvent: CO
Solvent: CCO
Product: CC(C)c1nc2cnc3ccsc3c2n1[C@H]1CC[C@H](CO)OC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 2-methylpropanamide (71.4 mg, 0.820 mmol) and triethyloxonium tetrafluoroborate (154 mg, 0.812 mmol) in THF (2 mL) was stirred at room temperature for 2 h. The solvent was removed and the residue dissolved in ethanol (0.5 mL) and added to a suspension of {(2R,5S)-5-[(6-aminothieno[3,2-b]pyridin-7-yl)amino]tetrahydro-2H-pyran-2-yl}methanol (69.2 mg, 0.248 mmol) in ethanol (1.7 mL). The mixture was stirred at 80° C. for 1 h. The reaction mixture was cooled to room temperature, diluted with methanol, and purified with prep-LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 60 mL/min) to give the desired product. LCMS calculated for C17H22N3O2S (M+H)+: m/z=332.1. Found: 332.1.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[CH:10][CH:9]=2)=[CH:4][N:3]=1.S(=O)(=O)(O)O.[C:22](=O)(O)[O-].[Na+].O>CO.C(OCC)(=O)C>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([O:14][CH3:22])=[O:13])=[CH:10][CH:9]=2)=[CH:4][N:3]=1
Reactant: O=C([O-])O
Reactant: Nc1ccc(-c2ccc(C(=O)O)cc2)cn1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1ccc(-c2ccc(N)nc2)cc1

Procedure:
The resulting 4-(2-aminopyridin-5-yl)benzoic acid (684 mg) was dissolved in methanol (50 ml) at room temperature, followed by the addition of concentrated sulfuric acid (1 ml). After heating under reflux for 2 hours, the reaction mixture was made weakly alkaline with an aqueous solution of sodium bicarbonate. Water and ethyl acetate were added to the resulting mixture to separate the organic layer. The organic layer was then dried over anhydrous magnesium sulfate. The solvent was distilled off. Hexane was added to the residue for crystallization, whereby the title compound (243 mg, 23%) was obtained.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Br[CH2:10][CH:11]([CH3:13])[CH3:12].C([O-])([O-])=O.[K+].[K+].CN(C=O)C>O>[I:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:10][CH:11]([CH3:13])[CH3:12])=[CH:4][CH:3]=1
Reactant: CC(C)CBr
Reactant: Oc1ccc(I)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)COc1ccc(I)cc1
Temperature: 80 °C
Reaction time: 4 h

Procedure:
3.0 g (13.64 mmol) 4-iodophenol, 1.6 mL (15.00 mmol) 1-bromo-2-methylpropane and 7.5 g (54.54 mmol) K2CO3 are added to 30 mL DMF and stirred at 80° C. for 4 h. Afterwards the reaction mixture is diluted with water and extracted with EtOAc. The organic layer is washed with diluted aq. NaOH (2×) and water (2×), dried with MgSO4 and the solvent is removed in vacuo. The crude product is used without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:6]([C:7]2[C:12]([Cl:13])=[CH:11][CH:10]=[CH:9][C:8]=2[Cl:14])=[N:5][S:4][N:3]=1.C(N(CC)CC)C.[CH3:22][N:23]([CH3:27])[C:24](Cl)=[O:25].O>CN(C)C=O>[Cl:14][C:8]1[CH:9]=[CH:10][CH:11]=[C:12]([Cl:13])[C:7]=1[C:6]1[C:2]([NH:1][C:24]([N:23]([CH3:27])[CH3:22])=[O:25])=[N:3][S:4][N:5]=1
Reactant: Nc1nsnc1-c1c(Cl)cccc1Cl
Reactant: CN(C)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)C(=O)Nc1nsnc1-c1c(Cl)cccc1Cl
Temperature: 120 °C
Yield: 30.1 %

Procedure:
To a solution of 0.49 g of 3-amino-4-(2,6-dichlorophenyl)-1,2,5-thiadiazole and 0.22 g of triethylamine in N,N-dimethylformamide, 0.24 g of dimethylcarbamoyl chloride was added and the mixture was heated at 120° C. for 12 hours. After allowing to cool, the mixture was poured into water and was extracted with ether. The ether layer was washed twice with dilute hydrochloric acid, twice with water and twice with saturated aqueous sodium chloride solution. The resultant was dried over anhydrous sodium sulfate, concentrated and purified by silica gel column chromatography to obtain 0.19 g of 3-(2,6-dichlorophenyl)-4(3,3-dimethylureido)-1,2,5-thiadiazole.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:7]([Br:10])=[CH:6][C:3]=1[CH:4]=[O:5].C1COCC1.[C:16]1(=O)[O:21][C:19](=[O:20])[C:18]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:17]12>C1(C)C=CC=CC=1>[Br:10][C:7]1[CH:8]=[CH:9][C:2]([N:1]2[C:19](=[O:20])[C:18]3[C:17](=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:16]2=[O:21])=[C:3]([CH:6]=1)[CH:4]=[O:5]
Reactant: Nc1ccc(Br)cc1C=O
Reactant: O=C1OC(=O)c2ccccc21
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: O=Cc1cc(Br)ccc1N1C(=O)c2ccccc2C1=O
Temperature: 100 °C
Yield: 35.1 %

Procedure:
To a vial charged with 2-amino-5-bromobenzaldehyde (commercially available from Matrix Scientific, Columbia, S.C.) (0.500 g, 2.500 mmol) were added THF (4.17 mL), toluene (4.17 mL), TEA (0.871 mL, 6.25 mmol) and phthalic anhydride (0.849 mL, 8.75 mmol). The mixture was heated at 100° C. overnight. LC-MS indicated that the product was present as a component of a complex mixture. The resulting mixture was passed through a 10 g SCX-2 column with much solid sticking to the top of the column and some product eluting through indicating a solubility issue in MeOH. The solid and filtrate were dissolved in DCM:MeOH and the crude residue was adsorbed onto silica gel with drying under reduced pressure. The adsorbed material was purified with a 50 g SNAP column ramping EtOAc in heptane from 0-45%, then isocratic at 45% to elute 5-bromo-2-(1,3-dioxoisoindolin-2-yl)benzaldehyde (0.290 g, 0.878 mmol, 35.1% yield) as a yellow solid. m/z (ESI) 330.0/332.0 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[Br:12]N1C(=O)CCC1=O.CCCCCC>C(Cl)(Cl)(Cl)Cl.C(OCC)(=O)C.N(C(C)(C)C#N)=NC(C)(C)C#N>[Br:12][CH2:11][C:9]1[CH:8]=[CH:7][C:3]([C:4]([OH:6])=[O:5])=[C:2]([F:1])[CH:10]=1
Reactant: Cc1ccc(C(=O)O)c(F)c1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: O=C(O)c1ccc(CBr)cc1F
Temperature: 100 °C
Reaction time: 2.5 h
Yield: 53.9 %

Procedure:
To a solution of 2-fluoro-4-methylbenzoic acid (1.029 g, 6.678 mmol) in carbon tetrachloride (10 ml) were added N-bromosuccinimide (1.189 g, 6.682 mmol) and 2,2′-azobisisobutyronitrile (43.9 mg, 0.267 mmol). After stirring at 90° C. for 30 min and at 100° C. for 2.5 hr, the mixture was cooled to 0° C. The precipitate was collected by filtration and washed with hexane and water to give a crude product. The crude product was dissolved in ethyl acetate (5 ml), and hexane (10 ml) was added. The precipitated solid was collected by filtration, and dried under reduced pressure to give 4-(bromomethyl)-2-fluorobenzoic acid (838.6 mg, 3.599 mmol, yield 53.9%) as a slightly yellow solid.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][N:5]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[C:6]=1[C:7]([NH2:9])=[O:8].[C:18]([O:22][C:23]([N:25]([CH2:27][C:28](O)=[O:29])[CH3:26])=[O:24])([CH3:21])([CH3:20])[CH3:19]>>[C:18]([O:22][C:23]([N:25]([CH2:27][C:28]([NH:1][C:2]1[N:3]=[CH:4][N:5]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[C:6]=1[C:7]([NH2:9])=[O:8])=[O:29])[CH3:26])=[O:24])([CH3:21])([CH3:20])[CH3:19]
Reactant: NC(=O)c1c(N)ncn1Cc1ccc(F)cc1
Reactant: CN(CC(=O)O)C(=O)OC(C)(C)C
Product: CN(CC(=O)Nc1ncn(Cc2ccc(F)cc2)c1C(N)=O)C(=O)OC(C)(C)C
Yield: 72 %

Procedure:
An amidation reaction and post-treatment were carried out following the conditions of Example 17, using 2.12 g (9.01 mmol) of 4-amino-1-(4-fluorobenzyl)-5-imidazolecarboxamide prepared in the same manner as in Example 58 and 2-(N-t-butyloxycarbonyl-N-methylamino)acetic acid instead of 3-pyridylacetic acid hydrochloride to obtain 2.63 g of 4-(2-(N-t-butyloxycarbonyl-N-methylamino)acetylamino)-1-(4-fluorobenzyl)-5-imidazolecarboxamide (yield 72%).
Reaction SMILES: [NH:1]=[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[CH3:8].[CH2:9]([O:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]=[C:24]=[O:25])=[CH:19][CH:18]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C1C=CC=CC=1>[CH2:9]([O:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:24]([N:1]=[C:2]2[CH2:7][CH2:6][CH2:5][CH2:4][N:3]2[CH3:8])=[O:25])=[CH:19][CH:18]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: O=C=Nc1ccc(OCc2ccccc2)cc1
Reactant: CN1CCCCC1=N
Solvent: c1ccccc1
Product: CN1CCCCC1=NC(=O)Nc1ccc(OCc2ccccc2)cc1
Reaction time: 6 h

Procedure:
The hydrochloride salt of 2-imino-1-methylpiperidine (7.43 g.; 0.05 mole) is converted to the free base in benzene in the usual manner. After drying over K2CO3 and filtering, a benzene solution of 0.05 mole of p-benzyloxyphenylisocyanate is added dropwise with stirring. After addition is complete, further stirring is continued for about 6 hours at room temperature. The benzene is evaporated in vacuo and the solid residue is recrystallized from methanol to give the product 1-(4-benzyloxyphenyl)-3-(1-methyl-2-piperidylidene)urea.
Reaction SMILES: [CH2:1]([NH:5][CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][CH2:3][CH3:4].Cl[CH2:11][CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18](/[CH:21]=[CH:22]/[C:23]2[O:24][C:25]3[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][C:26]=3[N:27]=2)=[CH:17][CH:16]=1>>[CH2:1]([N:5]([CH2:11][CH2:12][CH2:13][O:14][C:15]1[CH:16]=[CH:17][C:18](/[CH:21]=[CH:22]/[C:23]2[O:24][C:25]3[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][C:26]=3[N:27]=2)=[CH:19][CH:20]=1)[CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][CH2:3][CH3:4]
Reactant: Cc1ccc2oc(/C=C/c3ccc(OCCCCl)cc3)nc2c1
Reactant: CCCCNCCCC
Product: CCCCN(CCCC)CCCOc1ccc(/C=C/c2nc3cc(C)ccc3o2)cc1
Yield: 22 %

Procedure:
Reaction of this product (2.2 g, 6.8 mmol) with dibutylamine produced 0.65 g (22% yield) of the title compound as the HCl salt, mp 143°-144° C. IR(KBr): 1600 cm-1. MS: 421(MH+). 1H NMR (CDCl3): δ 7.21-6.87 (m, 10H), 4.16 (t, J=5.6 Hz, 2H), 3.11 (m, 6H), 2.51 (s, 3H), 2.51-0.88 (m, 16H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:12]([OH:14])=O)=[CH:8][C:9]=1[C:10]#[N:11])=[O:4].C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.[NH2:56][CH2:57][C:58]1[CH:59]=[C:60]([OH:64])[CH:61]=[CH:62][CH:63]=1>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:12](=[O:14])[NH:56][CH2:57][C:58]2[CH:63]=[CH:62][CH:61]=[C:60]([OH:64])[CH:59]=2)=[CH:8][C:9]=1[C:10]#[N:11])=[O:4]
Reactant: COC(=O)c1sc(C(=O)O)cc1C#N
Reactant: NCc1cccc(O)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)c1sc(C(=O)NCc2cccc(O)c2)cc1C#N
Temperature: 25 °C
Reaction time: 15 h
Yield: 16.8 %

Procedure:
To a solution of 3-Cyano-thiophene-2,5-dicarboxylic acid 2-methyl ester (130 mg, 0.62 mmol) in anhydrous DMF (8 mL) was added triethylamine (0.26 mL, 1.86 mmol), HBTU (0.28 g, 0.74 mmol), HOBT (100 mg, 0.74 mmol), and 3-Aminomethyl-phenol (114 mg, 0.92 mmol). The mixture was stirred at room temperature 15 h, then quenched by pouring into EtOAc. The organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by flash chromatography with 0-50% EtOAc in hexane to afford the desired product (0.033 g, 17% yield).
Reaction SMILES: C(N(CC)C(=O)O[CH2:6][N:7]1[CH2:11][CH:10]([CH2:12][CH2:13][CH3:14])[CH2:9][C:8]1=[O:15])C.[CH3:19][S:20][C:21]1[NH:22][C:23]2[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=2[N:25]=1>C(#N)C>[CH3:19][S:20][C:21]1[N:22]([CH2:6][N:7]2[CH2:11][CH:10]([CH2:12][CH2:13][CH3:14])[CH2:9][C:8]2=[O:15])[C:23]2[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=2[N:25]=1
Reactant: CCCC1CC(=O)N(COC(=O)N(CC)CC)C1
Reactant: CSc1nc2ccccc2[nH]1
Solvent: CC#N
Product: CCCC1CC(=O)N(Cn2c(SC)nc3ccccc32)C1
Yield: 40.3 %

Procedure:
A solution of (2-oxo-4-propylpyrrolidin-1-yl)methyl diethylcarbamate a26 (1 eq, 3.18 mmol, 0.5 g) and 2-(methylthio)-benzimidazole (1.25 eq, 3.90 mmol, 0.64 g) in acetonitrile (4 ml) was heated under reflux for 42 h. The solvent was evaporated under reduce pressure and purification by preparative chromatography on reverse phase afforded 390 mg of 1-{[2-(methylthio)-1H-benzimidazol-1-yl]methyl}-4-propylpyrrolidin-2-one 90 (HPLC purity (U.V.): 85%; Yield: 40.3%).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][CH2:21][CH:20]([OH:24])[CH:19]1[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:17])([CH3:14])([CH3:13])[CH3:12].C(N(CC)CC)C>ClCCl>[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][CH2:21][C:20](=[O:24])[CH:19]1[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)OC(=O)N1CCCC(O)C1c1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCCC(=O)C1c1ccccc1
Temperature: -60 °C
Reaction time: 0.33 h

Procedure:
To a cooled (-60° C.) solution of oxalyl chloride (0.68 ml, 7.8 mmol) in dichloronmethane (17 ml) was added dimethyl sulphoxide (0.69 ml, 9.8 mmol) for 10 minutes before addition of (±)1-tert-butoxycarbonyl-3-hydroxy-2-phenylpiperidine (1.8 g, 6.5 mmol; prepared by the method described in European Patent Specification number 0 528 495-A) in dichloromethane (7 ml). The solution was stirred at -60° C. for 20 minutes, warmed to -30° C. and triethylamine (2.5 ml) added. The solution was warmed to room temperature then was washed with ice cold 10% aqueous citric acid solution (40 ml, twice), water and dried (MgSO4). After evaporation the residue was purified by chromatography on silica gel (eluting with hexane containing an increasing proportion of ethyl acetate up to 20%) to give the title compound.
Reaction SMILES: [O:1]1CCC[CH2:3][CH:2]1[O:7][CH2:8][CH2:9][N:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]=[C:11]1[CH2:19][C:20]1[CH:37]=[CH:36][C:23]([C:24]([N:26]2[CH2:30][CH2:29][C@H:28]([N:31]3[CH2:35][CH2:34][CH2:33][CH2:32]3)[CH2:27]2)=[O:25])=[CH:22][CH:21]=1.Cl.C([O:41][CH2:42][CH3:43])C.C([OH:46])C>>[C:42]([OH:41])(=[O:46])/[CH:43]=[CH:3]/[C:2]([OH:7])=[O:1].[N:31]1([C@H:28]2[CH2:29][CH2:30][N:26]([C:24]([C:23]3[CH:36]=[CH:37][C:20]([CH2:19][C:11]4[N:10]([CH2:9][CH2:8][OH:7])[C:14]5[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=5[N:12]=4)=[CH:21][CH:22]=3)=[O:25])[CH2:27]2)[CH2:32][CH2:33][CH2:34][CH2:35]1
Reactant: CCOCC
Reactant: O=C(c1ccc(Cc2nc3ccccc3n2CCOC2CCCCO2)cc1)N1CC[C@H](N2CCCC2)C1
Reactant: CCO
Agent: Cl
Product: O=C(O)/C=C/C(=O)O
Product: O=C(c1ccc(Cc2nc3ccccc3n2CCO)cc1)N1CC[C@H](N2CCCC2)C1
Temperature: 25 °C

Procedure:
Using essentially the same procedure described for Examples 217-222 and employing methyl 4-((1H-benzo[d]imidazol-2-yl)methyl)benzoate and 2-(2-bromoethoxy)tetrahydro-2H-pyran as starting materials, (3′S)-1′-{4-[(1-(2-(tetrahydro-pyran-2-yloxy)-ethyl)-1H-benzimidazol-2-yl)methyl]benzoyl}-1,3′-bipyrrolidine was obtained, [M+H] 503.2. A portion of (3′S)-1′-{4-[(1-(2-(tetrahydro-pyran-2-yloxy)-ethyl)-1H-benzimidazol-2-yl)methyl]benzoyl}-1,3′-bipyrrolidine was treated with hydrogen chloride in diethyl ether/ethanol, stirred at room temperature and concentrated in vacuo. The resultant residue was partitioned between aqueous potassium carbonate (1.0 M) and dichloromethane. The organic phase was separated, washed with water, dried over sodium sulfate and concentrated under reduced pressure. This residue was treated with fumaric acid in dichloromethane/methanol to give the title product. 1H NMR (300 MHz, DMSO-d6+TFA): 7.94 (m, 1 H), 7.79 (m, 1 H), 7.57 (d, 2 H), 7.57 (m, 2 H), 7.49 (d, 2 H), 6.65 (s, 2 H), 4.74 (s, 2 H), 4.58 (t, 2 H), 3.92 (m, 2 H), 3.80 (t, 2 H), 3.74 (m, 2 H), 3.51 (m, 2 H), 3.44-3.06 (br. s, 3 H), 2.33 (m, 1 H), 2.21 (m, 1 H), 1.99 (m, 4 H). [M+H] 419.17.