Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[CH:4]=[CH:5][C:6]2[O:10][N:9]=[C:8]([NH:11][CH2:12][C:13]([O:15]C(C)(C)C)=[O:14])[C:7]=2[CH:20]=1.FC(F)(F)C(O)=O>ClCCl>[F:22][C:2]([F:1])([F:21])[C:3]1[CH:4]=[CH:5][C:6]2[O:10][N:9]=[C:8]([NH:11][CH2:12][C:13]([OH:15])=[O:14])[C:7]=2[CH:20]=1
Reactant: CC(C)(C)OC(=O)CNc1noc2ccc(C(F)(F)F)cc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)CNc1noc2ccc(C(F)(F)F)cc12
Temperature: 25 °C
Reaction time: 5 h
Yield: 89.4 %

Procedure:
Preparation I7, Step 5: A solution of tert-butyl 2-(5-(trifluoromethyl)benzo[d]isoxazol-3-ylamino)acetate (367 mg) in dichloromethane (20 mL) at 0° C. was treated with trifluoroacetic acid (2 mL) and stirred at rt for 5 h. The mixture was concentrated under vacuum, and the residue was purified by column chromatography on silica gel, eluting with 10% to 50% (v/v) ethyl acetate-hexane, to provide 2-(5-(trifluoromethyl)benzo[d]isoxazol-3-ylamino)acetic acid (270 mg) as an off-white solid. MS found: (M+H)+=261.
Reaction SMILES: [OH-].[Na+].[Cl:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]([CH2:16]Cl)[C:11]=1[CH3:18].ClCC1C(C)=C(OCCOCCO)C=CN=1.OCC1C(C)=C(OCCOCCO)C=CN=1.[SH:51][C:52]1[NH:56][C:55]2[CH:57]=[CH:58][CH:59]=[CH:60][C:54]=2[N:53]=1>>[Cl:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]([CH2:16][S:51][C:52]2[NH:56][C:55]3[CH:57]=[CH:58][CH:59]=[CH:60][C:54]=3[N:53]=2)[C:11]=1[CH3:18]
Reactant: Cc1c(OCCOCCCl)ccnc1CCl
Reactant: Sc1nc2ccccc2[nH]1
Agent: Cc1c(OCCOCCO)ccnc1CCl
Agent: Cc1c(OCCOCCO)ccnc1CO
Agent: [Na+]
Product: Cc1c(OCCOCCCl)ccnc1CSc1nc2ccccc2[nH]1
Temperature: 60 °C
Reaction time: 1.5 h

Procedure:
0.54 g of sodium hydroxide was added to an ethanolic solution of 3.1 g of a crude mixture comprising 4-[2-(2-chloroethoxy)ethoxy]-2-chloromethyl-3-methylpyridine and 2-chloromethyl-4-[2-(2-hydroxyethoxy)ethoxy]-3-methylpyridine which has been prepared by the chlorination of 2-hydroxymethyl-4-[2-(2-hydroxyethoxy)ethoxy]-3-methylpyridine and 2.0 g of 2-mercapto-1H-benzimidazole to obtain a mixture. This mixture was stirred at 60° C. for 1.5 hour, cooled and distilled under a reduced pressure to remove the ethanol. The obtained residue was chromatographed over a silica gel column and eluted with ethyl acetate/n-hexane and then with methanol/ethyl acetate to obtain 1.0 g of 2-[{4-(2-(2-chloroethoxy)ethoxy)-3-methylpyridine-2-yl}methylthio]-1H-benzimidazole
Reaction SMILES: [P:1]([O:13][CH2:14][N:15]1[CH:19]=[N:18][C:17]([C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:27]=[N:28][N:29]4[CH:34]=[CH:33][C:32]([N:35]5[C@@H:39]([C:40]6[CH:45]=[CH:44][CH:43]=[CH:42][N:41]=6)[CH2:38][O:37][C:36]5=[O:46])=[N:31][C:30]=34)=[CH:22][C:21]=2[F:47])=[N:16]1)([O:8]C(C)(C)C)([O:3]C(C)(C)C)=[O:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[P:1]([OH:3])([OH:8])([O:13][CH2:14][N:15]1[CH:19]=[N:18][C:17]([C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:27]=[N:28][N:29]4[CH:34]=[CH:33][C:32]([N:35]5[C@@H:39]([C:40]6[CH:45]=[CH:44][CH:43]=[CH:42][N:41]=6)[CH2:38][O:37][C:36]5=[O:46])=[N:31][C:30]=34)=[CH:22][C:21]=2[F:47])=[N:16]1)=[O:2]
Reactant: CC(C)(C)OP(=O)(OCn1cnc(-c2ccc(-c3cnn4ccc(N5C(=O)OC[C@@H]5c5ccccn5)nc34)cc2F)n1)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1OC[C@H](c2ccccn2)N1c1ccn2ncc(-c3ccc(-c4ncn(COP(=O)(O)O)n4)c(F)c3)c2n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 53.1 %

Procedure:
To a stirred solution of (S)-di-tert-butyl (3-(2-fluoro-4-(5-(2-oxo-4-(pyridin-2-yl)oxazolidin-3-yl)pyrazolo[1,5-a]pyrimidin-3-yl)phenyl)-1H-1,2,4-triazol-1-yl)methyl phosphate (50 mg, 0.075 mmol) in DCM (0.5 mL) cooled to 0° C. was added TFA (0.1 mL) and the reaction stirred at 0° C. for 1 hour. The reaction was concentrated under vacuum and azeotroped with DCM/Hexanes. The remaining material was taken up in water. The aqueous layer was made basic (pH 9) by the addition of saturated NaHCO3. HCl (0.1 N) was then slowly added to the solution to adjust the pH to 2. The precipitated solid was collected by filtration, washed with acetone and diethyl ether, and dried under vacuum to give (S)-(3-(2-fluoro-4-(5-(2-oxo-4-(pyridin-2-yl)oxazolidin-3-yl)pyrazolo[1,5-a]pyrimidin-3-yl)phenyl)-1H-1,2,4-triazol-1-yl)methyl dihydrogen phosphate (22 mg, 53% yield) as a yellow solid. 1H-NMR (400 MHz, DMSO-d6) δ 9.11 (d, J=7.6 Hz, 1H), 8.79 (s, 1H), 8.73 (s, 1H), 8.52 (d, J=4.0 Hz, 1H), 7.99 (m, 2H), 7.84 (t, J=7.6 Hz, 1H), 7.72 (m, 3H), 7.31 (t, J=6.4 Hz, 1H), 6.06 (d, J=6.0 Hz, 1H), 5.95 (d, J=10.8 Hz, 2H), 4.91 (t, J=8.4 Hz, 1H), 4.32 (dd, J=8.4 Hz, 2.8 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[NH:10][CH:9]=[CH:8][C:6]=2[N:7]=1.C1C(=O)N([Br:18])C(=O)C1>CN(C=O)C.CCOC(C)=O>[Br:18][C:8]1[C:6]2[N:7]=[C:2]([Cl:1])[N:3]=[CH:4][C:5]=2[NH:10][CH:9]=1
Reactant: Clc1ncc2[nH]ccc2n1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Clc1ncc2[nH]cc(Br)c2n1
Reaction time: 1 h
Yield: 75.3 %

Procedure:
A solution of 2-chloro-5H-pyrrolo[3,2-d]pyrimidine (1.54 g, 10 mmol) in DMF (10 mL) was added NBS (2.00 g, 11 mmol) at room temperature. The resulting solution was stirred for 1 h and diluted with EtOAc. The resulting solution was washed with a sat. aq. solution of NaHCO3, H2O and brine. The EtOAc layer was dried (Na2SO4), concentrated and purified by ISCO to provide the desired product (1.75 g, 75%). 1H NMR (400 MHz, CD3OD) δ 8.53 (s, 1H), 7.60 (s, 1H); MS m/z 234.0 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[C:11]3[CH:17]=[CH:16][NH:15][C:12]3=[N:13][CH:14]=2)[O:3]1.[H-].[Na+].Cl[Si:22]([CH:29]([CH3:31])[CH3:30])([CH:26]([CH3:28])[CH3:27])[CH:23]([CH3:25])[CH3:24].[Cl-].[Na+]>O1CCCC1>[CH3:8][C:6]1([CH3:7])[C:2]([CH3:18])([CH3:1])[O:3][B:4]([C:9]2[CH:10]=[C:11]3[CH:17]=[CH:16][N:15]([Si:22]([CH:29]([CH3:31])[CH3:30])([CH:26]([CH3:28])[CH3:27])[CH:23]([CH3:25])[CH3:24])[C:12]3=[N:13][CH:14]=2)[O:5]1
Reactant: CC1(C)OB(c2cnc3[nH]ccc3c2)OC1(C)C
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)[Si](C(C)C)(C(C)C)n1ccc2cc(B3OC(C)(C)C(C)(C)O3)cnc21
Yield: 92 %

Procedure:
3.00 g of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine are suspended in 40 ml of tetrahydrofuran in a flask. 0.73 g of sodium hydride (60% in paraffin oil) are added in portions with ice-cooling. 3.94 ml of chlorotriisopropylsilane is subsequently added dropwise at about 25° C., and the mixture is heated at 40° C. (bath temperature) under nitrogen until the boronic acid ester has reacted completely (HPLC check, about 5 hours). The excess sodium hydride is deactivated using 10 ml of saturated sodium chloride solution. The solvent is removed in vacuo. The residue is diluted with about 50 ml of water and extracted three times with diethyl ether. The combined organic phases are dried over sodium sulfate and purified by means of column chromatography (gradient heptane: EA 5-100% in 15 min.), giving 4.55 g of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine as white solid (yield 92%, content 92%); MS-FAB (M+H+)=401.2; Rf (nonpolar method): 3.61 min.
Reaction SMILES: [CH3:1][N:2]([CH3:10])[C:3]([C@@H:5]1[CH2:9][CH2:8][CH2:7][NH:6]1)=[O:4].Br[CH2:12][CH2:13][CH2:14][OH:15].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[OH:15][CH2:14][CH2:13][CH2:12][N:6]1[CH2:7][CH2:8][CH2:9][C@H:5]1[C:3](=[O:4])[N:2]([CH3:10])[CH3:1]
Reactant: CN(C)C(=O)[C@@H]1CCCN1
Reactant: OCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CN(C)C(=O)[C@@H]1CCCN1CCCO
Yield: 48.3 %

Procedure:
A mixture of (S)-2(N,N-dimethylcarbamoyl)pyrrolidine (426 mg, 3 mmol), (Chem. pharm. Bull. 1973, 21, 2112-2116), 3-bromo-1-propanol (0.41 ml, 4.5 mmol) and potassium carbonate (829 mg, 6 mmol) in acetonitrile (6 ml) was heated at reflux for 8 hours. The mixture was allowed to cool and was partitioned between methylene chloride and water. The organic layer was separated, washed with brine, dried (MgSO4) and the solvent removed by evaporation. The residue was purified by column chromatography, eluting with methylene chloride/methanol (a gradient from 90/10 to 60/40) to give (S)-1-(3-hydroxypropyl)-2(N,N-dimethylcarbamoyl)pyrrolidine (290 mg, 48%).
Reaction SMILES: C([Li])CCC.[F:6][C:7](F)([F:20])[CH2:8][O:9][S:10]([C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1)(=[O:12])=[O:11].C(O)(=O)C.C(OCC)(=O)C>C1COCC1>[F:20][C:7]([F:6])=[CH:8][O:9][S:10]([C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1)(=[O:11])=[O:12]
Reactant: Cc1ccc(S(=O)(=O)OCC(F)(F)F)cc1
Agent: [Li]CCCC
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)OC=C(F)F)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 47.1 %

Procedure:
Add n-butyllithium (1.6 M in hexanes, 4.9 mL, 7.8 mmol) dropwise over 5 min to a solution of 2,2,2-trifluoroethyl-p-toluene sulfonate (1.0 g, 3.9 mmol) in THF (20 mL) at −78° C. Stir for 30 min, add acetic acid (225 μL, 3.9 mmol) and stir for 30 min. Warm to room temperature, add ethyl acetate and extract with saturated aqueous ammonium chloride, and saturated aqueous sodium bicarbonate. Dry (magnesium sulfate), concentrate and purify (silica gel chromatography, eluting with 0:100 to 15:85 ethyl acetate:hexanes) to give the title compound as an oil (430 mg, 47%).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:3]=1[CH:4]=[O:5].C([O-])(=O)C.[Na+].[Br:17]Br.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(O)(=O)C>[Br:17][C:9]1[C:2]([OH:1])=[C:3]([CH:6]=[C:7]([O:10][CH3:11])[CH:8]=1)[CH:4]=[O:5]
Reactant: COc1ccc(O)c(C=O)c1
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC(=O)O
Product: COc1cc(Br)c(O)c(C=O)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 59.9 %

Procedure:
To 2-hydroxy-5-methoxybenzaldehyde (4.1 mL, 32.86 mmol) in acetic acid (150 mL) were added sodium acetate (4.0 g, 49.3 mmol) and bromine (2.2 mL, 42.7 mmol) and the mixture was stirred at rt for 2 h. Aqueous sodium thiosulfate was added and the mixture was concentrated by rotary evaporation. The solid was dissolved in dichloromethane and washed with water. The organic phase was separated, dried over MgSO4, filtered and the solvent removed by rotary evaporation. The solid residue was recrystallized from ethanol to yield 3-bromo-2-hydroxy-5-methoxybenzaldehyde (4.55 g, 60%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH2:19][CH2:18][CH:17]([O:20][C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([Cl:28])[CH:22]=3)[CH2:16][CH2:15]2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[Cl:28][C:23]1[CH:22]=[C:21]([CH:26]=[CH:25][C:24]=1[Cl:27])[O:20][CH:17]1[CH2:16][CH2:15][N:14]([CH:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)[CH2:19][CH2:18]1
Reactant: CC(C)(C)OC(=O)N1CCC(N2CCC(Oc3ccc(Cl)c(Cl)c3)CC2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Clc1ccc(OC2CCN(C3CCNCC3)CC2)cc1Cl

Procedure:
The product of Step 2 (10.15 g, 23.6 mmol) was dissolved in dichloromethane (150 ml) and trifluoroacetic acid (40 ml, 519 mmol) added and the resultant solution stirred. After 90 minutes the dichloromethane and trifluoroacetic acid were removed on a rotary evaporator. The resultant oil was partitioned between ethyl acetate (100 ml) and 2M aq NaOH (100 ml). The layers were separated and the organics extracted with 10% aq citric acid (100 ml). The layers were separated and the aqueous basified with 2M aq NaOH and extracted with ethyl acetate (200 ml). The organics were dried (MgSO4), filtered and the solvent removed to give the sub-titled product as a pale oil which solidified on standing (4.62 g, 59%; MS: (M+H) 329).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]([C:10]2[C:14]3[CH:15]=[N:16][CH:17]=[C:18]([F:19])[C:13]=3[N:12]([C:20]([CH3:31])([CH3:30])[CH2:21][O:22][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24])[CH:11]=2)=[O:9])[CH:5]=[N:6][CH:7]=1.[F:32][C:33]([F:45])([F:44])[C:34]1[CH:35]=[C:36]([CH2:40][C:41](O)=[O:42])[CH:37]=[CH:38][CH:39]=1.CCN(C(C)C)C(C)C.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>C1COCC1>[C:26]([Si:23]([CH3:24])([CH3:25])[O:22][CH2:21][C:20]([N:12]1[C:13]2[C:18]([F:19])=[CH:17][N:16]=[CH:15][C:14]=2[C:10]([C:8]([C:4]2[CH:3]=[C:2]([NH:1][C:41](=[O:42])[CH2:40][C:36]3[CH:37]=[CH:38][CH:39]=[C:34]([C:33]([F:44])([F:32])[F:45])[CH:35]=3)[CH:7]=[N:6][CH:5]=2)=[O:9])=[CH:11]1)([CH3:31])[CH3:30])([CH3:29])([CH3:28])[CH3:27]
Reactant: O=C(O)Cc1cccc(C(F)(F)F)c1
Reactant: CC(C)(CO[Si](C)(C)C(C)(C)C)n1cc(C(=O)c2cncc(N)c2)c2cncc(F)c21
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(CO[Si](C)(C)C(C)(C)C)n1cc(C(=O)c2cncc(NC(=O)Cc3cccc(C(F)(F)F)c3)c2)c2cncc(F)c21
Temperature: 25 °C
Reaction time: 18 h
Yield: 86.6 %

Procedure:
To a solution of (5-amino-pyridin-3-yl)-{1-[2-(tert-butyl-dimethyl-silanyloxy)-1,1-dimethyl-ethyl]-7-fluoro-1H-pyrrolo[3,2-c]pyridin-3-yl}-methanone (Preparation 29, 35 mg, 79 μmol), (3-trifluoromethyl-phenyl)-acetic acid (21.8 mg, 106 μmol) and DIPEA (48.94 μL, 277 μmol) in THF (3 mL), T3P (160 μL, 277 μmol) was added and the mixture stirred at 25° C. for 18 hours. The reaction was evaporated under reduced pressure, the residue partitioned between water and ethyl acetate, the organic extracts washed with saturated sodium bicarbonate solution, dried over sodium sulphate, evaporated in vacuo and triturated with pentane-ether to afford the title compound as a white solid (87%, 43 mg).
Reaction SMILES: B.CSC.[CH2:5]1[O:17][CH:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH:15]=[CH2:16])[O:7][CH2:6]1.[OH-:18].[Na+].OO>C1COCC1.O>[CH2:6]1[O:7][CH:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH2:15][CH2:16][OH:18])[O:17][CH2:5]1
Reactant: C=Cc1ccccc1C1OCCO1
Reactant: [OH-]
Agent: B
Agent: OO
Agent: [Na+]
Solvent: CSC
Solvent: C1CCOC1
Solvent: O
Product: OCCc1ccccc1C1OCCO1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
Borane-dimethyl sulphide complex (2.0M in THF, 7.67 ml, 15.3 mmol) was added dropwise to 2-vinylbenzaldehyde ethylene acetal (2.7 g, 15.3 mmol) in THF (80 ml) at 0° C. Stirring was continued at room temperature for 4 h, cooled to 0° C. and 10% aqueous sodium hydroxide (3 ml) added dropwise, followed by hydrogen peroxide (30% by volume, 1.8 ml). After 1 h at room temperature, the mixture was diluted with water, extracted with ethyl acetate, dried over sodium sulphate and evaporated to give a colourless viscous gum (2.2 g), MS (+EI) 194 (M+), 1H NMR (CDCl3) 7.48 (1H, d, J6 Hz), 7.3-7.1 (3H, m), 5.91 (1H, s), 4.1-3.9 (4H, m), 3.78 (2H, t, J6.5 Hz), 2.93 (2H, t, J6.5 Hz).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C@H:4]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1)[NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].[C:22]1([S:28](Cl)(=[O:30])=[O:29])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:21])[C@H:4]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][S:28]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)(=[O:30])=[O:29])=[CH:16][CH:15]=1)[NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:10])[CH3:11])=[O:7]
Reactant: COC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](Cc1ccc(OS(=O)(=O)c2ccccc2)cc1)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 3 h
Yield: 99.9 %

Procedure:
N-Boc-L-tyrosine methyl ester 3 (3.0 g, 0.01 mol) and benzenesulfonyl chloride (1.8 g, 0.01 mol) were dissolved in toluene (14.8 g) and then cooled to 0° C. To the mixture was added dropwise triethylamine (1.0 g, 0.01 mol) at 0° C. over 35 min. The mixture was further kept at 0° C. for 3 hrs. The reaction mass was washed with 5% hydrochloric acid (7.3 g) and 5% aqueous sodium bicarbonate (8.4 g) and then concentrated under reduced pressure with a rotary evaporator to give N-Boc-O-benzenesulfonyl-L-tyrosine methyl ester 5 (4.35 g, yield 100%) as white solid.
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]1[CH2:10][CH2:9][CH:8]([N:11]2[CH2:16][CH2:15][CH:14]([N:17]3[C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=4[NH:19][C:18]3=[O:26])[CH2:13][CH2:12]2)[CH2:7][CH2:6]1)=[O:4].[H-].[Na+].[CH2:29](Br)[C:30]#[CH:31].C(=O)(O)[O-].[Na+]>CN(C)C=O.C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]([N:5]1[CH2:10][CH2:9][CH:8]([N:11]2[CH2:16][CH2:15][CH:14]([N:17]3[C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=4[N:19]([CH2:31][C:30]#[CH:29])[C:18]3=[O:26])[CH2:13][CH2:12]2)[CH2:7][CH2:6]1)=[O:4]
Reactant: COC(=O)N1CCC(N2CCC(n3c(=O)[nH]c4ccccc43)CC2)CC1
Reactant: C#CCBr
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: C#CCn1c(=O)n(C2CCN(C3CCN(C(=O)OC)CC3)CC2)c2ccccc21
Reaction time: 0.5 h

Procedure:
1-[1-(1-Methoxycarbonylpiperidin-4-yl)piperidin-4-yl]-1,3-di-hydro-2H-benzimidazol-2-one (28 mg) as synthesized by the method of Referential Example 1 was dissolved in 5 ml of dimethylformamide, and to which 2.0 mg of sodium hydride was added under cooling with ice, followed by 30 minutes' stirring. Ten(10) mg of propargyl bromide was added to the reaction liquid which was stirred for further 3 hours at room temperature. After adding saturated aqueous sodium bicarbonate solution and concentrating the reaction liquid, the resulting residue was distributed between saturated aqueous sodium bicarbonate solution and chloroform. The organic layer was dried over anhydrous sodium sulfate, concentrated, and the resulting residue was purified by silica gel column chromatography (chloroform/methanol=20/1). Thus 11.3 mg of the title compound was obtained as a colorless oil.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=O.[C:8]([CH2:10][C:11]([NH2:13])=[S:12])#[N:9].CN1CCOCC1>C(O)C>[C:8]([C:10](=[CH:6][C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)[C:11]([NH2:13])=[S:12])#[N:9]
Reactant: N#CCC(N)=S
Reactant: O=Cc1cccs1
Solvent: CCO
Solvent: CN1CCOCC1
Product: N#CC(=Cc1cccs1)C(N)=S
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.6 %

Procedure:
To a mixture of 2-thiophencarbaldehyde (22.4 g, 0.2 mol) and 2-cyanothioacetamide (22 g, 0.22 mol) in 250 ml of ethanol was added N-methylmorpholine (30.3 g, 0.3 mol) at room temperature. The resulting mixture was stirred at room temperature overnight. The solid was filtered and washed with ethanol to give 28.2 g (72%) of product as a yellow solid after drying in vacuo. 1H-NMR (300 MHz, DMSO-d6): δ 10.0 (brs, 1H), 9.45 (brs, 1H), 8.37 (s, 1H), 8.12 (d, J=4.8 Hz, 1H), 7.88 (d, J=3.3 Hz, 1H), 7.32 (dd, J=3.3, 4.8 Hz, 1H). ES MS m/z 195 (M+H)+, 193(M−H)−.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[CH:6][CH:7]=1.[Cl:11][C:12]1[C:13]([C:19]#[N:20])=[N:14][CH:15]=[C:16](Cl)[CH:17]=1.C([O-])([O-])=O.[K+].[K+].CN(C)C=O>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(OCC)(=O)C.CO.O>[F:1][C:2]1[CH:3]=[C:4]([C:16]2[CH:17]=[C:12]([Cl:11])[C:13]([C:19]#[N:20])=[N:14][CH:15]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: N#Cc1ncc(Cl)cc1Cl
Reactant: OB(O)c1cccc(F)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: N#Cc1ncc(-c2cccc(F)c2)cc1Cl
Temperature: 45 °C
Reaction time: 18 h

Procedure:
To a 100 mL round bottom flask that is adapted for magnetic stirring and equipped with a nitrogen inlet is charged (3-fluorophenyl)boronic acid (4.48 g, 32 mmol), 3,5-dichloro-2-cyanopyridine (5.8 g, 34 mmol), K2CO3 (5.5 g, 40 mmol), [1,1′-bis(diphenyphosphino)ferrocene]dichloro-palladium(II) [PdCl2(dppf)] (0.1 g, 0.13 mmol), dimethylformamide (50 mL) and water (5 mL). The reaction solution is agitated and heated to 45° C. and held at that temperature for 18 hours after which the completeness of the reaction can be determined by the absence of the starting material 3,5-dichloro-2-cyanopyridine via TLC using ethyl acetate/methanol (4:1) as the mobile phase and UV 435 nm to visualize any remaining starting material. The reaction solution is then cooled to room temperature and the contents partitioned between ethyl acetate (250 mL) and saturated aqueous NaCl (100 mL). The organic phase is isolated and washed a second time with saturated aqueous NaCl (100 mL). The organic phase is dried for 4 hours over MgSO4, the MgSO4 is removed by filtration and the solvent is removed under reduced pressure. The residue that remains is then slurried in methanol (50 mL) at room temperature for 20 hours. The resulting solid is collected by filtration and washed with cold methanol (50 mL) then hexanes (60 mL) and dried to afford desired product.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][C:2]1=O.C(O[CH:11](OCC)[CH2:12][NH2:13])C>C1(C)C=C(C)C=C(C)C=1.[Ti](Cl)(Cl)(Cl)Cl>[N:13]1[CH:12]=[CH:11][N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][C:2]=12
Reactant: O=C1CCCCN1
Reactant: CCOC(CN)OCC
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: Cc1cc(C)cc(C)c1
Product: c1cn2c(n1)CCCC2
Temperature: 140 °C
Reaction time: 70 h
Yield: 20.3 %

Procedure:
1.5 g of 2-piperidone was dissolved in 75 mL of mesitylene, 248 μL of titanium tetrachloride was added thereto, and heated at 140° C. A solution obtained by dissolving 4.02 g of aminoacetoaldehyde diethyl acetal to 45 mL of mesitylene was prepared, and was added dropwise to the previous mesitylene solution over 3 hours. The mixture was stirred at 140° C. for 70 hours, then cooled back to room temperature, and was extracted with a 2N aqueous solution of hydrochloric acid. The obtained aqueous layer was basified with a 5N aqueous solution of sodium hydroxide, and then was extracted with chloroform. The organic layer was washed with saturated brine, and then dried over anhydrous sodium sulfate. The insolubles were filtered, the filtrate was concentrated under reduced pressure, and then the purification was carried out by distillation under reduced pressure (3 mmHg, 120° C.), to obtain 375 mg of 5,6,7,8-tetrahydroimidazo[1,2-a]pyridine [44-1] as a pale yellow oily product.
Reaction SMILES: Cl.[NH2:2][N:3]1[C:7]([CH3:8])=[N:6][N:5]=[C:4]1[NH:9][NH2:10].[Cl:11][C:12]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:13]=1[CH:14]=O.Cl>C(O)C>[ClH:11].[NH2:2][N:3]1[C:7]([CH3:8])=[N:6][N:5]=[C:4]1[NH:9][N:10]=[CH:14][C:13]1[C:12]([Cl:11])=[CH:19][CH:18]=[CH:17][C:16]=1[Cl:20]
Reactant: O=Cc1c(Cl)cccc1Cl
Reactant: Cc1nnc(NN)n1N
Agent: Cl
Solvent: CCO
Product: Cc1nnc(NN=Cc2c(Cl)cccc2Cl)n1N

Procedure:
To a solution of 5.25 g (0.032 mole) of 4-amino-3-hydrazino-5-methyl-1,2,4-triazole hydrochloride in 100 ml of 75 percent ethanol was added 5.6 g (0.032 mole) of 2,6-dichlorobenzaldehyde and 0.5 ml of concentrated hydrochloric acid. The mixture was stirred and heated at reflux for 16 hours. After cooling, the precipitate was collected and washed with chilled ethanol and ether. Yield: 7.0 g, m.p. 244°-245° (D).
Reaction SMILES: [Cl:1][C:2]1[CH:38]=[CH:37][C:5]2[NH:6][C:7]([C@@H:9]([NH:11][C:12](=[O:36])[C:13]3[CH:18]=[CH:17][C:16]([C:19]([N:21]4[CH2:25][CH2:24][CH2:23][C@H:22]4[CH2:26][NH:27]C(OC(C)(C)C)=O)=[O:20])=[C:15]([Cl:35])[CH:14]=3)[CH3:10])=[N:8][C:4]=2[CH:3]=1.FC(F)(F)C(O)=O.ClCCl.CO.N.ClCl>>[Cl:1][C:2]1[CH:38]=[CH:37][C:5]2[NH:6][C:7]([C@@H:9]([NH:11][C:12](=[O:36])[C:13]3[CH:18]=[CH:17][C:16]([C:19]([N:21]4[CH2:25][CH2:24][CH2:23][C@H:22]4[CH2:26][NH2:27])=[O:20])=[C:15]([Cl:35])[CH:14]=3)[CH3:10])=[N:8][C:4]=2[CH:3]=1
Reactant: C[C@H](NC(=O)c1ccc(C(=O)N2CCC[C@H]2CNC(=O)OC(C)(C)C)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1
Agent: ClCl
Agent: N
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@H](NC(=O)c1ccc(C(=O)N2CCC[C@H]2CN)c(Cl)c1)c1nc2cc(Cl)ccc2[nH]1
Yield: 91 %

Procedure:
Prepared analogously to Example 17 from N-[(1S)-1-(5-chloro-1H-benzimidazol-2-yl)ethyl]-3-chloro-4-[(2S)-2-(N-tert-butoxycarbonylaminomethyl)pyrrolidin-1-ylcarbonyl]benzamide and trifluoroacetic acid. Yield: 91%; Rf value: 0.10 (silica gel; dichloromethane/methanol/ammonia=9:1:0.1); C22H23Cl2N5O2 (460.36); mass spectrum: (M+H)+=460/462 (chlorine isotope) and (M−H)−=458/460 (chlorine isotope).