Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH3:16])[CH:5]=[C:6]2[C:10]=1[NH:9][C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7]2.[S:17]1[CH:21]=[CH:20][CH:19]=[C:18]1[S:22](Cl)(=[O:24])=[O:23]>N1C=CC=CC=1>[CH3:16][C:4]1[CH:5]=[C:6]2[C:10](=[C:2]([NH:1][S:22]([C:18]3[S:17][CH:21]=[CH:20][CH:19]=3)(=[O:24])=[O:23])[CH:3]=1)[NH:9][C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:7]2
Reactant: CCOC(=O)c1cc2cc(C)cc(N)c2[nH]1
Reactant: O=S(=O)(Cl)c1cccs1
Solvent: c1ccncc1
Product: CCOC(=O)c1cc2cc(C)cc(NS(=O)(=O)c3cccs3)c2[nH]1
Temperature: 25 °C
Reaction time: 15 h
Yield: 90.8 %

Procedure:
To a mixed solution of ethyl 7-amino-5-methyl-1H-indole-2-carboxylate (0.60 g) and pyridine (10 mL) was added 2-thiophenesulfonyl chloride (0.66 g) under ice-cooling, and the mixture was stirred at room temperature for 15 hr. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with ethyl acetate, washed with aqueous citric acid solution, aqueous sodium hydrogencarbonate solution and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (ethyl acetate:hexane=3:7-5:5), and the obtained crystals were recrystallized from ethyl acetate-hexane to give the title compound (910 mg, yield 91%) as colorless needle crystals. melting point 168-169° C.
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[CH:13]1([NH:16][C:17]([C:19]2[C:20]3[CH:21]=[CH:22][N:23]([CH2:28][O:29][CH2:30][CH3:31])[C:24]=3[CH:25]=[CH:26][CH:27]=2)=[O:18])[CH2:15][CH2:14]1.B(OC(C)C)(OC(C)C)OC(C)C.[Cl:45][C:46]1[N:51]=[C:50](Cl)[C:49]([Cl:53])=[CH:48][N:47]=1>C1COCC1.[Cl-].[Cl-].C1(P([C-]2C=CC=C2)C2C=CC=CC=2)C=CC=CC=1.[CH-]1C=CC=C1.[Fe+2].[Pd+2]>[CH:13]1([NH:16][C:17]([C:19]2[C:20]3[CH:21]=[C:22]([C:48]4[C:49]([Cl:53])=[CH:50][N:51]=[C:46]([Cl:45])[N:47]=4)[N:23]([CH2:28][O:29][CH2:30][CH3:31])[C:24]=3[CH:25]=[CH:26][CH:27]=2)=[O:18])[CH2:15][CH2:14]1
Reactant: CCOCn1ccc2c(C(=O)NC3CC3)cccc21
Reactant: Clc1ncc(Cl)c(Cl)n1
Agent: [Fe+2]
Agent: [Pd+2]
Agent: CC(C)OB(OC(C)C)OC(C)C
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCOCn1c(-c2nc(Cl)ncc2Cl)cc2c(C(=O)NC3CC3)cccc21
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 32.2 %

Procedure:
To a solution of diisopropylamine (DIPA, 147 mL, 1.04 mol) in anhydrous THF (600 mL) is added n-BuLi (2.5 M in hexane, 420 mL, 1.04 mol) at −50 C. After the addition, the mixture is stirred at −20° C. for 30 minutes and then cooled to −70° C. A solution of N-cyclopropyl-1-(ethoxymethyl)-1H-indole-4-carboxamide (60 g, 0.23 mol) and tri(isopropyl) borate (56.4 mL, 0.25 mol) in anhydrous THF (300 mL) is added. The reaction mixture is stirred at −70° C. for 30 min. The reaction is slowly warmed up to ambient temperature, stirred for 1 h and then quenched with aqueous K3PO4.3H2O (195 g, 0.74 mol, in 700 mL of water). The crude reaction mixture is degassed and purged with N2 for three times. 2,4,5-trichloropyrimidine (51 g, 0.27 mol) and palladium diphenylphosphinoferrocene dichloride (PdCl2(dppf).CH2Cl2, 19.2 g, 0.023 mol) are added and stirred under nitrogen at refluxing temperature for 1.5 h. The volatiles are removed in vacuo. The residue is extracted with dichloromethane (DCM, 3×500 mL). The combined extracts are washed with aqueous saturated sodium chloride (3×100 mL), dried over anhydrous Na2SO4, filtered and concentrated. The residue is purified by chromatography on silica gel to give the title compound (30 g, 32%). MS (m/z): 405 [(M+1)+, 35Cl, 35Cl], 407 [(M+1)+, 35Cl, 37Cl] and 409 [(M+1)+, 37Cl, 37Cl].
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH3:11][C:12]1[N:17]=[CH:16][C:15]([C:18]2([CH2:24][NH2:25])[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[CH:14][CH:13]=1>>[CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:25][CH2:24][C:18]1([C:15]2[CH:16]=[N:17][C:12]([CH3:11])=[CH:13][CH:14]=2)[CH2:19][CH2:20][O:21][CH2:22][CH2:23]1)=[O:6]
Reactant: Cc1ccccc1C(=O)O
Reactant: Cc1ccc(C2(CN)CCOCC2)cn1
Product: Cc1ccc(C2(CNC(=O)c3ccccc3C)CCOCC2)cn1

Procedure:
From 2-methylbenzoic acid and C-[4-(6-methylpyridin-3-yl)-tetrahydropyran-4-yl]methylamine. LCMS (MH+): m/z=325.0, tR (minutes, Method B)=0.60
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7]1)C.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCCC1>[OH:3][CH2:4][CH2:5][C@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7]1
Reactant: CCOC(=O)C[C@H]1CCCN(C(=O)OC(C)(C)C)C1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC[C@H](CCO)C1
Reaction time: 0.33 h
Yield: 97.6 %

Procedure:
To a solution of 143 mg of t-butyl(3R)-3-(2-ethoxy-2-oxoethyl)tetrahydropyridine-1(2H)-carboxylate in 5 ml of tetrahydrofuran, 30 mg of litiumaluminum hydride was added under cooling with ice, followed by 20 minutes' stirring at the same temperature. To the reaction liquid sodium sulfate decahydrate was added, stirred for 12 hours and filtered with Celite. Distilling the solvent off under reduced pressure, 118 mg of the title compound was obtained.
Reaction SMILES: Br[CH:2]([S:4]([O-:7])(=[O:6])=[O:5])[CH3:3].[Na+].[CH2:9]([CH2:11][NH2:12])[OH:10]>O.C(O)C>[OH:10][CH2:9][CH2:11][NH:12][CH2:3][CH2:2][S:4]([OH:7])(=[O:6])=[O:5]
Reactant: CC(Br)S(=O)(=O)[O-]
Reactant: NCCO
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: O=S(=O)(O)CCNCCO
Reaction time: 17.5 h

Procedure:
A solution in 2 liters of water of 315 g of sodium bromoethanesulphonate (Organic Synthesis, Coll. Vol. II, p. 558) and 450 g of ethanolamine was heated to 60°-70° C. for 30 minutes. Excess ethanolamine and water were then distilled off under vacuum, and the residue dissolved in 250-270 ml of water. 2.2 Liters of concentrated hydrochloric acid was added and the solution kept in a refrigerator for 15-20 hours. The precipitated sodium chloride was filtered off using a filter pump, and the solution concentrated until a viscous oil was obtained. The oil was diluted with 60 ml of water and ethanol (about 500 ml) then added to precipitate the reaction product. After the mixture has been left one night in a refrigerator, precipitation was almost complete. The product obtained was filtered off with a filter pump. About 130-140 g of crystalline product was obtained, having a melting point of 180°-183° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([C:9]2([CH3:15])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[CH:3]=1.Cl[C:17]([O:19][CH3:20])=[O:18]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:17](=[O:18])([O:19][CH3:20])[O:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=1[C:9]1([CH3:15])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: CC1(c2cc(F)ccc2O)CCCCC1
Reactant: COC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: COC(=O)Oc1ccc(F)cc1C1(C)CCCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.1 %

Procedure:
To a solution of 4-fluoro-2-(1-methylcyclohexyl)phenol (23.5 g, 113 mmol), TEA (31 mL, 226 mmol) and DMAP (700 mg, 5.7 mmol) in CH2Cl2 (250 mL) was added methyl chloroformate dropwise at 0° C. The mixture was allowed to warm to room temperature and stirred for 2 hours. The reaction mixture was poured onto crushed ice and extracted with CH2Cl2 (100 mL×3). The organic layer was washed with brine, dried over MgSO4, evaporated under vacuum. The crude product was purified by chromatography on silica gel diluted with (hexane:ethyl acetate=100:1) to give 4-fluoro-2-(1-methylcyclohexyl)phenyl methyl carbonate as red brown oil (43.9 g, 72.1% yield). 1H NMR (400 MHz, CDCl3) δ 7.10 (dd, J=3.2, 11.2 Hz, 1H), 7.05-7.02 (m, 1H), 6.93-6.88 (m, 1H), 3.91 (s, 3H), 2.02-1.96 (m, 2H), 1.66-1.36 (m, 8H), 1.23 (s, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([C:12]([OH:14])=[O:13])=[CH:7][CH:6]=[CH:5]2.[Cl:15][C:16]1[CH:21]=[C:20](Cl)[CH:19]=[CH:18][N:17]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CS(C)=O>[Cl:15][C:16]1[CH:21]=[C:20]([O:1][C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[C:8]([C:12]([OH:14])=[O:13])=[CH:7][CH:6]=[CH:5]3)[CH:19]=[CH:18][N:17]=1
Reactant: O=C(O)c1cccc2cc(O)ccc12
Reactant: Clc1ccnc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Product: O=C(O)c1cccc2cc(Oc3ccnc(Cl)c3)ccc12
Temperature: 90 °C

Procedure:
6-Hydroxynaphtoic acid (10.0 g, 53.1 mmol), 2,4-dichloropyridine (9.44 g, 63.8 mmol) and cesium carbonate (51.9 g, 159 mmol) were combined in DMSO (266 mL) and the reaction mixture was heated at 90° C. for 16 h. After cooling to RT, water was added and the aqueous layer was acidified to pH=4-5. The title compound was isolated by filtration and dried under vacuum.
Reaction SMILES: [NH2:1][C:2]1[C:3]([O:13][CH3:14])=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([CH3:12])=[CH:7][CH:6]=2.Cl[C:16]([O:18][CH2:19][CH3:20])=[O:17].N1C=CC=CC=1>ClCCl>[CH3:14][O:13][C:3]1[C:2]([NH:1][C:16](=[O:17])[O:18][CH2:19][CH3:20])=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH3:12])[CH:9]=2)[N:4]=1
Reactant: CCOC(=O)Cl
Reactant: COc1nc2ccc(C)cc2nc1N
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)Nc1nc2cc(C)ccc2nc1OC
Temperature: 25 °C
Reaction time: 10 h
Yield: 98 %

Procedure:
3-Amino-2-methoxy-6-methylquinoxaline (568 mg, 3.00 mmol) and ethyl chloroformate (391 mg, 3.60 mmol) were dissolved in dichloromethane (50 ml) at room temperature and thereto pyridine (285 mg, 3.60 mmol) was added. The resulting mixture was stirred at room temperature for 10 hours and concentrated under the reduced pressure to remove the solvent, and purified by SiO2 column chromatography. Extraction of the residue with n-hexane:ethyl acetate (3:1) mixture and concentration gave 768 mg of the titled compound (yield, 98%).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[CH2:3][O:4][C:5]1[CH:6]=[N:7][C:8]2[CH:9]([OH:15])[CH2:10][CH2:11][CH2:12][C:13]=2[CH:14]=1>ClCCl.[O-2].[Mn+4].[O-2]>[F:17][C:2]([F:1])([F:16])[CH2:3][O:4][C:5]1[CH:6]=[N:7][C:8]2[C:9](=[O:15])[CH2:10][CH2:11][CH2:12][C:13]=2[CH:14]=1
Reactant: OC1CCCc2cc(OCC(F)(F)F)cnc21
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: O=C1CCCc2cc(OCC(F)(F)F)cnc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 81 %

Procedure:
A mixture of 3-(2,2,2-trifluoroethoxy)-5,6,7,8-tetrahydroquinolin-8-ol (193 mg, 0.78 mmol) and manganese (IV) oxide (543 mg, 6.3 mmol) in dichloromethane (10 mL) was stirred at room temperature for 3 hours. Then, the mixture was filtered through a pad of Celite, and the filtrate was concentrated in vacuo. The residual solid was washed with diethyl ether to give 155 mg (81% yield) of the title compound as a pale yellow solid:
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:18]=[CH:17][CH:16]=[CH:15][C:6]=1[O:7][CH2:8][CH2:9][N:10]([CH2:13][CH3:14])[CH2:11][CH3:12])=[N+]=[N-]>[Pd]>[NH2:1][CH2:4][C:5]1[CH:18]=[CH:17][CH:16]=[CH:15][C:6]=1[O:7][CH2:8][CH2:9][N:10]([CH2:13][CH3:14])[CH2:11][CH3:12]
Reactant: CCN(CC)CCOc1ccccc1CN=[N+]=[N-]
Agent: [Pd]
Product: CCN(CC)CCOc1ccccc1CN

Procedure:
The product of Example 126A and Pd/C were processed according to the method of Example 115B to provide the product. MS (ESI+) m/z 223 (M+H)+.
Reaction SMILES: [CH:1]1[CH:6]=[C:5]2[CH:7]=[CH:8][S:9][C:4]2=[CH:3][CH:2]=1.[Li+].CCC[CH2-].[C:15](=[O:17])=[O:16]>CCOCC>[CH:1]1[CH:6]=[C:5]2[CH:7]=[C:8]([C:15]([OH:17])=[O:16])[S:9][C:4]2=[CH:3][CH:2]=1
Reactant: c1ccc2sccc2c1
Reactant: O=C=O
Agent: [CH2-]CCC
Agent: [Li+]
Solvent: CCOCC
Product: O=C(O)c1cc2ccccc2s1

Procedure:
Thionaphthene was treated in a carboxylation reaction in accordance with the procedure described by D. A. Shirley and M. D. Cameron, in J. Am. Chem. Soc., 72, 2788, 1950 using N-butyllithium in ether, followed by carbonation with dry ice, and hydrolysis to the acid. The product had a melting point of 238°-239° C.
Reaction SMILES: [C:1]([Si:5]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[O:6][CH:7]1[CH2:12][CH2:11][CH:10]([CH:13]2[CH2:17][CH2:16][NH:15][C:14]2=[O:18])[CH2:9][CH2:8]1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:34][C:35]1[C:40]([Cl:41])=[CH:39][C:38]([O:42][CH2:43][C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)=[CH:37][C:36]=1[Cl:50]>CN(C=O)C.C(OCC)C>[CH2:43]([O:42][C:38]1[CH:37]=[C:36]([Cl:50])[C:35]([CH2:34][N:15]2[CH2:16][CH2:17][CH:13]([CH:10]3[CH2:11][CH2:12][CH:7]([O:6][Si:5]([C:1]([CH3:4])([CH3:2])[CH3:3])([C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=4)[C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH2:8][CH2:9]3)[C:14]2=[O:18])=[C:40]([Cl:41])[CH:39]=1)[C:44]1[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=1
Reactant: CC(C)(C)[Si](OC1CCC(C2CCNC2=O)CC1)(c1ccccc1)c1ccccc1
Reactant: Clc1cc(OCc2ccccc2)cc(Cl)c1CBr
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](OC1CCC(C2CCN(Cc3c(Cl)cc(OCc4ccccc4)cc3Cl)C2=O)CC1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 98.2 %

Procedure:
Treat a solution of 3-[4-(tert-butyl-diphenyl-silanyloxy)-cyclohexyl]-pyrrolidin-2-one (0.75 g, 1.78 mmol) in DMF (25 mL) with 60% sodium hydride (0.11 g, 2.67 mmol) and stir at room temperature for 15 minutes under N2. Cool the reaction to 0° C., treat with 2-bromomethyl-1,3-dichloro-5-benzyloxy-benzene (0.74 g, 2.13 mmol), and stir for 30 minutes at 0° C. Warm to room temperature and stir for 30 minutes under N2. Quench the reaction with water and dilute with diethyl ether. Wash the organic layer with water three times, dry (Na2SO4), and remove the solvent in vacuo to afford crude product. Purify with a 0 to 30% ethyl acetate in hexanes gradient to afford 1.2 g (99%) of the titled product. MS (m/z): 686 (M+).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:11])[C@H:5]([CH2:7][CH:8]([CH3:10])[CH3:9])[NH2:6].[C:12](Cl)(=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH3:2][O:3][C:4](=[O:11])[C@H:5]([CH2:7][CH:8]([CH3:10])[CH3:9])[NH:6][C:12](=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: COC(=O)[C@@H](N)CC(C)C
Agent: Cl
Product: COC(=O)[C@H](CC(C)C)NC(=O)c1ccccc1

Procedure:
Prepared from L-leucine methyl ester HCl and benzoyl chloride according to the procedure from Example 10.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[CH:5]=[C:4]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH:3]=1.CCCCCC.C([Li])CCC.[Cl:27][Si:28](Cl)([Cl:30])[Cl:29]>C(OCC)C>[Cl:27][Si:28]([Cl:30])([Cl:29])[C:2]1[CH:7]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[CH:5]=[C:4]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH:3]=1
Reactant: Cl[Si](Cl)(Cl)Cl
Reactant: CC(C)(C)c1cc(Br)cc(C(C)(C)C)c1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: CC(C)(C)c1cc(C(C)(C)C)cc([Si](Cl)(Cl)Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 57.3 %

Procedure:
Under a nitrogen atmosphere, to a diethyl ether solution (175 mL) of 1-bromo-3,5-di-tert-butylbenzene (35.00 g, 130.00 mmol), a 1.65 M hexane solution of n-butyllithium (88.67 mL, 143.00 mmol) was added dropwise at −78° C. After the mixture was gradually warmed to room temperature, stirring was performed at room temperature for 2 hours. The resultant mixture was added dropwise to a solution of tetrachlorosilane (66.26 g, 390.00 mmol) dissolved in diethyl ether (58 mL) at −78° C. After the mixture was gradually warmed to room temperature, stirring was performed at room temperature for 3 hours. After completion of the reaction, the solvent was removed under reduced pressure. Thereafter, hexane was added to the residue, and insoluble materials were removed by filtration. The solvent was removed from the filtrate under reduced pressure. Purification by distillation under reduced pressure afforded trichloro(3,5-di-tert-butylphenyl)silane (24.11 g, yield 57.3%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH:9]=O)=[N:4][CH:5]=[C:6]([Cl:8])[N:7]=1.[CH2:11]([NH:18][CH2:19][CH2:20][OH:21])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C1COCC1.C(OCC)(=O)C.C(O)(=O)C>[CH2:11]([N:18]([CH2:9][C:3]1[C:2]([Cl:1])=[N:7][C:6]([Cl:8])=[CH:5][N:4]=1)[CH2:19][CH2:20][OH:21])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: OCCNCc1ccccc1
Reactant: O=Cc1ncc(Cl)nc1Cl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: OCCN(Cc1ccccc1)Cc1ncc(Cl)nc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.8 %

Procedure:
To a solution of 3,5-dichloropyrazine-2-carbaldehyde (1.194 g), N-benzylethanolamine (1.02 g) and acetic acid (2.0 mL) in THF (50 mL) was added sodium triacetoxyborohydride (2.87 g), and the mixture was stirred at room temperature overnight. The reaction solution was diluted with ethyl acetate, and basified with saturated aqueous sodium hydrogen carbonate. The organic layer was separated, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (solvent gradient: 5→25% ethyl acetate/hexane) to give the title compound (1.47 g, 70%) as a colorless oil.
Reaction SMILES: [H-].[H-].COCCO[Al+2]OCCOC.C1(C)C=CC=CC=1.[CH2:21]([N:23]1[CH2:27][CH2:26][CH2:25][C@H:24]1[C:28]([NH2:30])=O)[CH3:22].Cl>O>[NH2:30][CH2:28][C@@H:24]1[CH2:25][CH2:26][CH2:27][N:23]1[CH2:21][CH3:22]
Reactant: CCN1CCC[C@H]1C(N)=O
Agent: COCCO[Al+2]OCCOC
Agent: Cl
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: O
Product: CCN1CCC[C@H]1CN
Temperature: 40 °C
Yield: 131.6 %

Procedure:
Bis (2-methoxyethoxy)aluminium dihydride (203.4 g, 0.70 mol, approx. 70% solution in toluene) and toluene (80 ml, dried over molecular sieves Å) were added to a three-necked round-bottomed flask. The temperature in the flask was increased to 40° C. and then (S)-1-ethyl-2-pyrrolidinecarboxamide (21.0 g, 0.147 mol, 95% purity on GC) was added spoonwise during 45 min. In order to maintain the temperature at approx. 40° C., cooling was necessary during the addition. The temperature was decreased below 10° C. 55 min after completed addition. Water (500 ml) was added during 15 min and the pH was adjusted to 1 by adding 115 ml concentrated HCl and 100 ml H2O. After extraction, the phases were separated and 200 ml CH2Cl2 were added to the water phase. The pH was subsequently adjusted to 13-14 by adding NaOH (40%, 50 ml). The organic phase was separated and the water phase was extracted with further portions of CH2Cl2 (200+100 ml). The combined organic phases were dried, filtered and concentrated under vacuo to afford 24.8 g crude title product (83%) in an optical purity of >99%.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[CH:8]=[C:9]([C:11]#[N:12])[N:10]=1)=[O:5])C.[OH-:21].[Na+].[OH-].[K+].Cl>CCO.O>[C:11]([C:9]1[N:10]=[C:6]([C:4]([OH:3])=[O:5])[N:7]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[CH:8]=1)(=[O:21])[NH2:12]
Reactant: [OH-]
Reactant: CCOC(=O)c1nc(C#N)cn1COCC[Si](C)(C)C
Agent: Cl
Agent: [K+]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: C[Si](C)(C)CCOCn1cc(C(N)=O)nc1C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.3 %

Procedure:
To a solution of 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylic acid ethyl ester (prepared in Example 11, step (c))(2.0 g, 6.8 mmol) in 15 mL of EtOH was added 5 N NaOH (2.0 mL, 10 mmol) and the reaction stirred for 8 h at RT. The mixture was concentrated, then water (20 mL) and 2 N KOH (3.4 mL, 6.8 mmol) was added and the mixture heated to 90° C. for 1 h. The mixture was cooled in an ice bath and the pH adjusted to 4 with 3 N HCl and a white ppt collected by filtration and dried under vacuum to give 1.5 g (77%) of the title compound. Mass spectrum (ESI, m/z): Calcd. for C1, H19N3O4Si, 286.1 (M+H), found 285.8.
Reaction SMILES: [S:1](/[CH:4]=[CH:5]\[C:6]([OH:8])=[O:7])[C:2]#[N:3].C1CCN2C(=NCCC2)CC1.[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.O>C(#N)C>[S:1](/[CH:4]=[CH:5]\[C:6]([O:8][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:7])[C:2]#[N:3]
Reactant: BrCc1ccccc1
Reactant: N#CS/C=C\C(=O)O
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Solvent: O
Product: N#CS/C=C\C(=O)OCc1ccccc1
Reaction time: 5 h

Procedure:
To a stirred suspension of compound 2 (3.0 g., 0.023 mole) in dry acetonitrile (40 ml), a solution of DBU (3.54 g., 0.023 mole) in 10 ml of dry acetonitrile was added dropwise, keeping the temperature of the mixture below 25° C. To the resulting solution was added dropwise a solution of benzyl bromide (4.0 g., 0.023 mole) in 15 ml of dry acetonitrile at room temperature. After stirring for 5 hours, the mixture was poured into water, and extracted with ether. The ether extract was washed with water, dried (MgSO4) and concentrated to give an oil which solidified upon standing, 4.3 g. The solid recrystallized from ethanol/hexane mixture as plate-like crystals: mp 48.5°-50.5° C.; IR (KBr) 1695, 2180 cm.-1.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:14](=[O:15])[C:13]3[CH:16]=[CH:17][CH:18]=[N:19][C:12]=3[N:11]=[C:10]2[C@H:20]([NH:22]C(=O)OC(C)(C)C)[CH3:21])=[CH:5][CH:4]=1)#[N:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:22][C@@H:20]([C:10]1[N:9]([C:6]2[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)[C:14](=[O:15])[C:13]2[CH:16]=[CH:17][CH:18]=[N:19][C:12]=2[N:11]=1)[CH3:21]
Reactant: C[C@@H](NC(=O)OC(C)(C)C)c1nc2ncccc2c(=O)n1-c1ccc(C#N)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@@H](N)c1nc2ncccc2c(=O)n1-c1ccc(C#N)cc1
Reaction time: 1.5 h

Procedure:
Compound 16 (1.05 g, 2.68 mmol), prepared as described in Section 7.12, was dissolved in CH2Cl2 (40 mL) and treated with TFA (40 mL). The resulting mixture was stirred for 1.5 h then concentrated in vacuo. The concentrate was re-dissolved in CH2Cl2 (100 mL) and washed with saturated NaHCO3 (100 mL). The aqueous wash was extracted with additional CH2Cl2 (3×50 mL). The combined extracts were dried over Na2SO4, concentrated and dried under high vacuum for 17 h to give P1 (767 mg, 98%), which was suitable for use without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[O:9]=[C:10]1[CH2:15][C:14](=O)[CH2:13][CH2:12][NH:11]1>>[F:1][C:2]1[CH:3]=[C:4]([NH:5][C:14]2[CH2:13][CH2:12][NH:11][C:10](=[O:9])[CH:15]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: Nc1cccc(F)c1
Reactant: O=C1CCNC(=O)C1
Product: O=C1C=C(Nc2cccc(F)c2)CCN1
Yield: 67.1 %

Procedure:
A mixture of 3-fluoroaniline (2 g) and 2,4-dioxopiperidine (2.04 g) was heated at 120° under nitrogen for 1 h. The resultant solid was cooled and purified by FCC eluting with System A (100:8:1) to give the title compound (2.49 g), m.p. 188°-190°.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]2[N:9]([C:11]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]4([NH:24][C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:23][CH2:22][CH2:21]4)=[CH:16][CH:15]=3)[N:13]=2)[CH:10]=1)=[O:4].[OH-].[Na+].Cl>C(O)(C)(C)C.O>[C:28]([O:27][C:25]([NH:24][C:20]1([C:17]2[CH:16]=[CH:15][C:14]([C:12]3[N:13]=[C:8]4[CH:7]=[CH:6][C:5]([C:3]([OH:4])=[O:2])=[CH:10][N:9]4[C:11]=3[C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[CH:19][CH:18]=2)[CH2:21][CH2:22][CH2:23]1)=[O:26])([CH3:31])([CH3:29])[CH3:30]
Reactant: COC(=O)c1ccc2nc(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)n2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)(C)O
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4ccc(C(=O)O)cn4c3-c3ccccc3)cc2)CCC1
Temperature: 70 °C

Procedure:
2-[4-(1-tert-butoxycarbonylamino-cyclobutyl)-phenyl]-3-phenyl-imidazo[1,2-a]pyridine-6-carboxylic acid methyl ester (0.76 g) was suspended in tert-butanol (19.2 mL) and treated with dilute aqueous sodium hydroxide solution (1M, 6.1 mL). The mixture was heated to 70° C. for 3.5 h. On cooling the reaction was diluted with water and the pH adjusted to 5 with dilute aqueous hydrochloric acid. The resulting emulsion was extracted with ethyl acetate and the organic extract washed with brine, dried and concentrated in vacuo to give the crude title compound which was used without further purification.