Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.CCN(CC)CC.[CH3:16][Si:17](Cl)([CH3:20])[CH2:18][CH3:19]>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[O:8][CH2:19][CH2:18][SiH:17]([CH3:20])[CH3:16]
Reactant: CC[Si](C)(C)Cl
Reactant: Oc1cccc(Br)c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C[SiH](C)CCOc1cccc(Br)c1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a stirred solution of 3-bromophenol (0.60 g, 3.47 mmol) in dry THF (15 mL) under nitrogen was added Et3N (0.48 mL, 3.47 mmol). A clear yellow solution formed immediately; after cooling to 0° C., dimethylethylsilyl chloride (0.43 g, 0.49 mL, 3.47 mmol) was added by syringe over a period of 10 minutes. The yellow color disappeared in 10 min, and a white cloudy solution formed. After 3 hr the thick reaction mixture was filtered, washed with 15 mL of hexane, and filtered again. Concentration gave a clear oil (quantitative weight recovery) that was used in the next step without any purification.
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[C:11]([C:19]3[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=3)[N:10]=2)[CH2:5][CH2:4]1)[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35].O>CN(C)C=O>[CH2:1]([N:3]1[CH2:4][CH2:5][N:6]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[C:11]([C:19]3[CH:20]=[CH:21][C:22]([O:25][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])=[CH:23][CH:24]=3)[N:10]=2)[CH2:7][CH2:8]1)[CH3:2]
Reactant: CCOC(=O)CBr
Reactant: CCN1CCN(c2nc(-c3ccc(O)cc3)cc3ccccc23)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)COc1ccc(-c2cc3ccccc3c(N3CCN(CC)CC3)n2)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
The resulting 1-(4-ethylpiperazin-1-yl)-3-(4-hydroxyphenyl)isoquinoline (0.57 g) was dissolved in N,N-dimethylformamide (5 ml), to which were added potassium carbonate (0.24 g) and ethyl bromoacetate (210 ml), and the mixture was stirred at room temperature for 2 days. Water was added to the reaction solution, followed by the extraction with ethyl acetate. The extract was washed with water and brine, and dried over magnesium sulfate. The solvent was evaporated, and the resulting residue was purified by silica gel column chromatography (chloroform/methanol system), to give obtain 1-(4-ethylpiperazin-1-yl)-3-[4-(ethoxycarbonylmethoxy)phenyl]isoquinoline (0.57 g) as a pale yellow viscous oil.
Reaction SMILES: [NH2:1][C@H:2]1[C:10]2[C:5](=[C:6]([C:11]3[N:15]=[C:14]([C:16]4[CH:17]=[CH:18][C:19]([O:24][CH:25]([CH3:27])[CH3:26])=[C:20]([CH:23]=4)[C:21]#[N:22])[O:13][N:12]=3)[CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3]1.[S:28](N)([NH2:31])(=[O:30])=[O:29]>O1CCOCC1>[C:21]([C:20]1[CH:23]=[C:16]([C:14]2[O:13][N:12]=[C:11]([C:6]3[CH:7]=[CH:8][CH:9]=[C:10]4[C:5]=3[CH2:4][CH2:3][C@H:2]4[NH:1][S:28]([NH2:31])(=[O:30])=[O:29])[N:15]=2)[CH:17]=[CH:18][C:19]=1[O:24][CH:25]([CH3:27])[CH3:26])#[N:22]
Reactant: NS(N)(=O)=O
Reactant: CC(C)Oc1ccc(-c2nc(-c3cccc4c3CC[C@H]4N)no2)cc1C#N
Solvent: C1COCCO1
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c3CC[C@H]4NS(N)(=O)=O)no2)cc1C#N
Temperature: 110 °C
Reaction time: 14 h
Yield: 25.8 %

Procedure:
Prepared using General Procedure 22: To a stirred solution of (R)-5-(3-(1-amino-2,3-dihydro-1H-inden-4-yl)-1,2,4-oxadiazol-5-yl)-2-isopropoxybenzonitrile 49 (50 mg, 0.14 mmol) in dioxane (1.5 mL) was added sulfamide (66 mg, 0.69 mmol) and the mixture was heated to 110° C. After 14 h of stirring, the solvent was evaporated and the residue was purified by column chromatography. Additional purification by recrystallization from MeOH provided 15.9 mg (26%) of (R)-N-(4-(5-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl)sulfamide 248. LCMS-ESI (m/z) calculated for C21H21N5O4S: 439.5. found 440.1 [M+H]+, tR=3.42 min. 1H NMR (400 MHz, CDCl3) δ 8.41 (d, J=2.1 Hz, 1H), 8.33 (dd, J=8.9, 2.2 Hz, 1H), 8.13 (d, J=7.6 Hz, 1H), 7.65 (d, J=7.6 Hz, 1H), 7.43 (t, J=7.7 Hz, 1H), 7.12 (d, J=9.0 Hz, 1H), 5.08 (dd, J=16.1, 7.9 Hz, 1H), 4.80 (dt, J=12.1, 6.1 Hz, 1H), 4.65 (s, 1H), 4.59 (d, J=8.4 Hz, 1H), 3.50 (ddd, J=17.5, 8.8, 3.7 Hz, 1H), 3.30-3.09 (m, 1H), 2.87-2.67 (m, 1H), 2.07 (dt, J=21.3, 8.2 Hz, 1H), 1.47 (t, J=6.3 Hz, 6H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]([C:8]2[CH:9]=[CH:10][C:11]3[N:15]=[C:14]([CH:16]4[CH2:18][CH2:17]4)[N:13]([CH3:19])[C:12]=3[CH:20]=2)[C:4](=[O:21])[CH:3]=1.[O:22]1[C:26]2[CH:27]=[CH:28][C:29]([CH2:31][OH:32])=[CH:30][C:25]=2[CH2:24][CH2:23]1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C=O)C>O>[CH:16]1([C:14]2[N:13]([CH3:19])[C:12]3[CH:20]=[C:8]([N:5]4[CH:6]=[CH:7][C:2]([O:32][CH2:31][C:29]5[CH:28]=[CH:27][C:26]6[O:22][CH2:23][CH2:24][C:25]=6[CH:30]=5)=[CH:3][C:4]4=[O:21])[CH:9]=[CH:10][C:11]=3[N:15]=2)[CH2:18][CH2:17]1
Reactant: OCc1ccc2c(c1)CCO2
Reactant: Cn1c(C2CC2)nc2ccc(-n3ccc(Cl)cc3=O)cc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1c(C2CC2)nc2ccc(-n3ccc(OCc4ccc5c(c4)CCO5)cc3=O)cc21
Temperature: 100 °C
Yield: 29 %

Procedure:
A mixture of 4-chloro-1-(2-cyclopropyl-1-methyl-1H-benzimidazol-6-yl)pyridin-2(1H)-one (100 mg), (2,3-dihydrobenzofuran-5-yl)methanol (100 mg), cesium carbonate (326 mg) and DMF (3 ml) was heated at 100° C. overnight. The mixture was poured into water, and extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4, concentrated in vacuo, and purified by NH silica gel column chromatography (hexane/EtOAc) to give the title compound (40 mg) as a white solid.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[OH:6][CH2:7][CH2:8][O:9][CH:10]1[CH2:27][CH2:26][C:13]2([CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]2)[CH2:12][CH2:11]1.CCN(CC)CC>>[CH3:1][S:2]([O:6][CH2:7][CH2:8][O:9][CH:10]1[CH2:27][CH2:26][C:13]2([CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:20])[CH2:17][CH2:18]2)[CH2:12][CH2:11]1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC2(CCC(OCCO)CC2)CC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC2(CCC(OCCOS(C)(=O)=O)CC2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 99 %

Procedure:
Methanesulfonyl chloride (5.43 mmol, 2.0 eq.) was added dropwise to a stirred solution of tert-butyl 9-(2-hydroxyethoxy)-3-azaspiro[5.5]undecane-3-carboxylate (2.71 mmol, 1.0 eq.) and Et3N (9.485 mmol, 3.5 eq.) in MC (30 ml) at 0° C. and the resulting reaction mixture was stirred at 25° C. for 3 h. The reaction mixture was diluted with MC (150 ml), washed with water (100 ml) and brine (100 ml) and dried over sodium sulfate. The solvent was evaporated under reduce pressure to give the crude product as a yellow sticky solid which was used in the next step reaction without further purification. Yield: 99%
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]3[C:15]4[CH2:16][NH:17][CH2:18][CH2:19][C:14]=4[NH:13][N:12]=3)=[CH:8][CH:9]=2)[CH:4]=[N:3]1.[N:20]([CH:23]1[CH2:29][CH2:28][CH:27]2[N:30]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH:24]1[CH2:25][CH2:26]2)=[C:21]=[O:22].C(N(C(C)C)CC)(C)C>CN(C)C=O>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]3[C:15]4[CH2:16][N:17]([C:21]([NH:20][CH:23]5[CH2:29][CH2:28][CH:27]6[N:30]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH:24]5[CH2:25][CH2:26]6)=[O:22])[CH2:18][CH2:19][C:14]=4[NH:13][N:12]=3)=[CH:8][CH:9]=2)[CH:4]=[N:3]1
Reactant: CC(C)(C)OC(=O)N1C2CCC(N=C=O)C1CC2
Reactant: Cn1ncc2cc(-c3n[nH]c4c3CNCC4)ccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cn1ncc2cc(-c3n[nH]c4c3CN(C(=O)NC3CCC5CCC3N5C(=O)OC(C)(C)C)CC4)ccc21
Temperature: 70 °C
Reaction time: 16 h

Procedure:
Dimethylformamide (0.7133 mL) was added to a flask containing 3-(1-methyl-1H-indazol-5-yl)-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine (54.2 mg, 0.214 mmol) and tert-butyl 2-isocyanato-8-azabicyclo[3.2.1]octane-8-carboxylate (45 mg, 0.178 mmol). Diisopropylethylamine (0.1474 mL, 0.856 mmoL) was added to the flask, and the reaction was allowed to stir at 70° C. for 16 hrs. The reaction was quenched with water and was extracted using ethyl acetate three times. The ethyl acetate layers were combined, dried over sodium sulfate, filtered, and concentrated. The crude was purified using flash chromatography (methanol in dichloromethane 0-20%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH3:11])[C:5]([OH:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].C([O-])([O-])=O.[K+].[K+].[CH2:18]([O:20][CH:21]([O:24][CH2:25][CH3:26])[CH2:22]Br)[CH3:19]>CN(C=O)C>[CH2:18]([O:20][CH:21]([O:24][CH2:25][CH3:26])[CH2:22][O:10][C:5]1[C:4]([CH3:11])=[CH:3][C:2]([F:1])=[CH:9][C:6]=1[CH:7]=[O:8])[CH3:19]
Reactant: Cc1cc(F)cc(C=O)c1O
Reactant: CCOC(CBr)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(COc1c(C)cc(F)cc1C=O)OCC
Yield: 20 %

Procedure:
To a stirred suspension containing 5-fluoro-2-hydroxy-3-methylbenzaldehyde (1.0 g, 6.49 mmol) and K2CO3 (980 mg, 7.10 mmol) in DMF (8 mL), bromoacetaldehyde diethyl acetal (1.10 mL, 7.15 mmol) was added dropwise. The mixture was refluxed for 4 h. After cooling, the precipitate was filtered off and the solvent was evaporated in vacuo. The crude residue was adsorbed on silica gel and purified by flash chromatography. The product was eluted with hexane/EtOAc (4:1) to give 20 (350 mg, 20%) as an oil, 1H NMR (500 MHz, CDCl3): δ: 10.40 (1H, s, CHO), 7.32 (1H, d, J=7.30 Hz, ArH), 7.14 (1H, d, J=7.75 Hz, ArH), 4.85 (1H, s, CH), 3.95 (2H, s, CH2), 3.75 (2H, t, J=7.15 Hz, CH2CH3), 3.61 (2H, t, J=7.20 Hz, CH2CH3), 2.36 (3H, s, CH3), 1.24 (6H, t, J=5.65 Hz, 2×CH3).
Reaction SMILES: [OH:1][C:2]1[CH:14]=[CH:13][C:5]2[N:6]([CH3:12])[C:7](=[S:11])[CH:8]([CH3:10])[O:9][C:4]=2[CH:3]=1.[Cl:15][C:16]1[CH:17]=[C:18]([C:24]([F:27])([F:26])[F:25])[CH:19]=[C:20]([F:23])[C:21]=1F.C(=O)([O-])[O-].[K+].[K+].O>CS(C)=O>[Cl:15][C:16]1[CH:17]=[C:18]([C:24]([F:25])([F:26])[F:27])[CH:19]=[C:20]([F:23])[C:21]=1[O:1][C:2]1[CH:14]=[CH:13][C:5]2[N:6]([CH3:12])[C:7](=[S:11])[CH:8]([CH3:10])[O:9][C:4]=2[CH:3]=1
Reactant: Fc1cc(C(F)(F)F)cc(Cl)c1F
Reactant: CC1Oc2cc(O)ccc2N(C)C1=S
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CC1Oc2cc(Oc3c(F)cc(C(F)(F)F)cc3Cl)ccc2N(C)C1=S
Temperature: 80 °C
Reaction time: 1 h

Procedure:
First, 7-hydroxy-2,4-dimethyl-2H-1,4-benzoxazine-3 (4H)-thione (0.2 g) and 3-chloro-4,5-difluorotrifluoromethylbenzene (0.3 g) were dissolved in DMSO (5 ml), potassium carbonate (0.2 g) was added thereto, and the mixture was stirred at 80° C. for one hr. Water (10 ml) was added thereto to terminate the reaction, and the reaction mixture was extracted with ethyl acetate (20 ml×2), washed with water and a saturated saline solution and dried over anhydrous magnesium sulfate. The solvent was distilled off in vacuo, and the residue was purified by silica gel chromatography (developing solvent: n-hexane/ethyl acetate=5/1) to prepare the title compound (0.2 g) as a colorless crystal.
Reaction SMILES: Br[C:2]1[CH:20]=[CH:19][CH:18]=[CH:17][C:3]=1[O:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:8]=1[NH:14]C=O.C(=O)([O-])[O-].[K+].[K+].C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1>[Cu]>[Cl:13][C:10]1[CH:11]=[CH:12][C:7]2[O:6][CH2:5][O:4][C:3]3[CH:17]=[CH:18][CH:19]=[CH:20][C:2]=3[NH:14][C:8]=2[CH:9]=1
Reactant: O=CNc1cc(Cl)ccc1OCOc1ccccc1Br
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccc(-c2ccccc2)cc1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: Clc1ccc2c(c1)Nc1ccccc1OCO2
Reaction time: 8 h

Procedure:
A suspension of 1.4 g. (0.004 moles) of (2-bromophenoxy)-(2-formamido-4-chlorophenoxy)-methane (m.p.: 98° to 100° C.), 0.6 g. (0.0042 moles) of potassium carbonate, 0.2 g. of copper powder and 12 ml. of Dowtherm® is heated up to 180° C. and is vigorously stirred at this temperature for 8 hours. The reaction mixture is filtered while hot, then the solvent is evaporated in vacuo. The remaining dark tar is hydrolyzed by boiling in a mixture of 20 ml. of ethanol and 2 ml. of a 20% aqueous sodium hydroxide solution for one hour. The reaction mixture is cooled and neutralized with a 37% aqueous hydrogen chloride solution. The solvent is evaporated and the brown solid residue is extracted with 10 ml. of hot benzene. Thereafter the solvent is eliminated and the residue is crystallized from benzine.
Reaction SMILES: [CH2:1]([N:8]=[C:9]=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:11]([N:14]([C:25]1[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=1)[N:15]1[C:23]2[C:18](=[CH:19][C:20]([OH:24])=[CH:21][CH:22]=2)[CH:17]=[CH:16]1)[CH2:12][CH3:13].C(=O)([O-])[O-].[K+].[K+]>O1CCCC1>[C:2]1([CH2:1][NH:8][C:9](=[O:10])[O:24][C:20]2[CH:19]=[C:18]3[C:23](=[CH:22][CH:21]=2)[N:15]([N:14]([CH2:11][CH2:12][CH3:13])[C:25]2[CH:30]=[CH:29][N:28]=[CH:27][CH:26]=2)[CH:16]=[CH:17]3)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C=NCc1ccccc1
Reactant: CCCN(c1ccncc1)n1ccc2cc(O)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCCN(c1ccncc1)n1ccc2cc(OC(=O)NCc3ccccc3)ccc21
Temperature: 25 °C
Yield: 101.1 %

Procedure:
Benzyl isocyanate (2 g) was added to a solution of 1-(propyl-4-pyridinylamino)-1H-indol-5-ol (3.3 g) in 75 mL tetrahydrofuran containing potassium carbonate (milled, 3 g). After stirring twenty hours at ambient temperature, the mixture was filtered and the filtrate was concentrated. The residue was eluted through silica with ethyl acetate via flash column chromatography to yield 5 g of the product as a solid, m.p. 156°-158° C. The product was recrystallized from acetonitrile to yield 3.8 g of crystals, m.p. 162°-164° C.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH2:6]2.[C:13](Cl)(=[O:15])[CH3:14].[Al+3].[Cl-].[Cl-].[Cl-]>ClCCCl>[C:13]([C:11]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:12])[NH:8]2)=[CH:4][C:3]=1[OH:2])(=[O:15])[CH3:14]
Reactant: CC(=O)Cl
Reactant: COc1ccc2c(c1)CC(=O)N2
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: CC(=O)c1cc2c(cc1O)CC(=O)N2
Reaction time: 8 h
Yield: 52.4 %

Procedure:
The procedure described in Example 33a was followed with 1,3-dihydro-5-methoxy-2H-indol-2-one (4.4 g, 26.96 mmol), acetyl chloride (4.8 mL, 67.41 mmol), and AlCl3 (14.4 g, 107.8 mmol) in 1,2-dichloroethane (210 mL) for 6 hours. After aqueous work-up and overnight stirring, a precipitate was obtained. This yellow solid was collected by filtration and dried to give the title compound (2.7 g, 52%).
Reaction SMILES: I[C:2]1[C:14]2[S:13][C:12]3[CH:15]=[CH:16][CH:17]=[CH:18][C:11]=3[C:10]=2[C:9]([C:19]2[CH:24]=[CH:23][C:22]([O:25][S:26]([CH3:29])(=[O:28])=[O:27])=[CH:21][CH:20]=2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[CH:7]2.[CH3:30][Sn](C)(C)C.O>CN(C)C=O.C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:30][C:2]1[C:14]2[S:13][C:12]3[CH:15]=[CH:16][CH:17]=[CH:18][C:11]=3[C:10]=2[C:9]([C:19]2[CH:24]=[CH:23][C:22]([O:25][S:26]([CH3:29])(=[O:27])=[O:28])=[CH:21][CH:20]=2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[CH:7]2
Reactant: CS(=O)(=O)Oc1ccc(-c2c3ccccc3c(I)c3sc4ccccc4c23)cc1
Reactant: C[Sn](C)(C)C
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c2ccccc2c(-c2ccc(OS(C)(=O)=O)cc2)c2c1sc1ccccc12
Temperature: 103 °C
Reaction time: 8 h
Yield: 86 %

Procedure:
A suspension of methanesulfonic acid 4-(6-iodo-benzo[b]naphtho[2,3-d]thiophen-11-yl)-phenyl ester (1.65 g, 3.11 mmole), tetramethyltin (3.58, 25.8 mmole), and bis(triphenylphosphine)palladium II chloride (0.218 g, 0.311 mmole 10 mole %) in dry N,N dimethylformamide (16 mL) was heated in a sealed vessel under argon at 103° C. for 4 hours and left at room temperature overnight. The reaction mixture was added to water (200 mL) and extracted with ether. Silica gel (40 mL) was added and the solvent removed. The adsorbate was flash chromatographed (85:15 Petroleum ether:ethyl acetate) to give the title compound as a pale yellow solid (1.12 g, 86%): mp 172-173° C.; NMR (CDCl3); δ 8.18 (ddd, J=8, 1, 1 Hz, 1H), 7.81 (ddd, J=1, 1, 8 Hz, 1H), 7.62-7.55 (m, 3H), 7.50-7.48 (m, 2H), 7.44-7.34 (m, 2H), 7.06 (ddd, J=8, 7, 1 Hz, 1H), 6.64 (ddd, J=8, 1, 1 Hz), 3.32 (s, 3H), 2.99 (s, 3H); MS: EI [m/z] 418 (100%); Anal. Calcd. for C24H18O3S2: C, 68.87, H, 4.34, N, 0.00. Found: C, 68.60, H, 4.26, N, 0.02.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[CH:4]([CH2:11][CH:12]=O)[CH2:3][CH2:2]1.Cl.[O:15]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[CH:17]=[C:16]1[C:24]([NH:26][CH:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)=[O:25]>>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[CH:4]([CH2:11][CH2:12][N:30]2[CH2:29][CH2:28][CH:27]([NH:26][C:24]([C:16]3[O:15][C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=4[CH:17]=3)=[O:25])[CH2:32][CH2:31]2)[CH2:3][CH2:2]1
Reactant: O=CCC1CCOc2ccccc21
Reactant: O=C(NC1CCNCC1)c1cc2ccccc2o1
Agent: Cl
Product: O=C(NC1CCN(CCC2CCOc3ccccc32)CC1)c1cc2ccccc2o1
Reaction time: 8 h
Yield: 25.7 %

Procedure:
To a stirred solution of 2-(3,4-dihydro-2H-1-benzopyran-4-yl)ethanal (875 mg, 5 mmol) and 4-(2-benzofurancarboxamido)piperidine hydrochloride (1.4 g, 5 mmol)under a nitrogen atmosphere, borane/pyridine complex (0.5 ml, excess) was added. The reaction was stirred overnight (ca 15 h) and evaporated to an oily gum which was neutralized by careful addition of 10% hydrochloric acid. The acidic solution was extracted with diethyl ether. The diethyl ether extracts were discarded. The acidic aqueous layer was basified by dropwise addition of 50% sodium hydroxide. The ethyl acetate layer was washed with distilled water, dried (Na2SO4), filtered and evaporated to afford an oily gum (520 mg). The resulting gum was purified by chromatography on silica (eluant: chloroform/ethanol/ammonium hydroxide; 85/14/1) to afford an oil (260 mg) which was crystallized from diethyl ether to afford the title compound (150 mg, 7%), mp=146°-8°. Anal: C25H28N2O3 0.5 H2O, Calc. C, 72.62; H, 7.07; N, 6.77; Found C,72.40; H, 6.94; N, 6.83.
Reaction SMILES: C1(COC([N:11]2[CH2:19][C@@H:18]([N:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[CH2:17][C@H:12]2[C:13]([O:15][CH3:16])=[O:14])=O)C=CC=CC=1.[H][H]>CO.[Pd].O>[N:20]1([C@@H:18]2[CH2:19][NH:11][C@H:12]([C:13]([O:15][CH3:16])=[O:14])[CH2:17]2)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]1
Reactant: [H][H]
Reactant: COC(=O)[C@@H]1C[C@H](N2CCCCC2)CN1C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: O
Product: COC(=O)[C@@H]1C[C@H](N2CCCCC2)CN1

Procedure:
A solution of 10.0 g of [4S]-1-[(phenylmethoxy)-carbonyl]-4-(1-piperidinyl)-L-proline, methyl ester in 100 ml of methanol is treated with a suspension of 2 g of 5% palladium on charcoal in 10 ml of water and placed under 3 atmospheres of hydrogen. After an equivalent quantity of hydrogen is consumed, the suspension is filtered and the solvent evaporated to give the title compound.
Reaction SMILES: [ClH:1].C(O[C:5](=[NH:14])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]#[N:13])C.C(O[CH:18](OCC)[CH2:19][NH2:20])C>CO>[ClH:1].[NH:20]1[CH:19]=[CH:18][N:14]=[C:5]1[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]#[N:13]
Reactant: CCOC(CN)OCC
Reactant: CCOC(=N)c1ccccc1C#N
Agent: Cl
Solvent: CO
Product: N#Cc1ccccc1-c1ncc[nH]1
Yield: 3.6 %

Procedure:
A solution of 2-cyano-benzimidic acid ethyl ester hydrochloride (43 g, 0.20 mol) and 2,2-diethoxy-ethylamine (30 ml, 0.21 mol) in methanol (430 ml) was aged at room temperature for 1 h. The reaction mixture was concentrated to remove methanol and conc. sulfuric acid (110 ml) was added. After heating on a steam bath for 1.5 h, the reaction mixture was diluted with water (700 ml) and extracted with chloroform. The aqueous phase was made strongly basic with sodium hydroxide and extracted with chloroform. hydrochloric acid (12N) was added to give pH 3–4, tar was filtered and the filtrate was concentrated. The resultant brown solid was sublimed at 200–220° C. The purified solid was dissolved in hydrochloric acid solution (6N, 110 ml), byproducts filtered and the filtrate concentrated. The residue was diluted with ethanol (100–120 ml) containing hydrochloric acid (12N, 1 ml), boiled briefly and filtered. Further concentration and cooling of the filtrate gave 2-(1H-imidazol-2-yl)benzonitrile hydrochloride (1.5 g). The filtrate was concentrated further and diluted with acetone. Filtration gave 2-(1H-imidazol-2-yl)-benzoic acid hydrochloride (7.3 g). Dilution of the filtrate with acetone and filtration of the resultant solid gave additional 2-(1H-imidazol-2-yl)-benzonitrile hydrochloride; mp 200–204° C.; IR 4.5 μ.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1.N[CH:13]([CH2:21][NH:22][C:23]1[C:28]([CH3:29])=[C:27]([N:30]2[CH2:35][CH2:34][CH:33]([C:36]3[CH:45]=[CH:44][C:43]4[CH2:42][CH2:41][CH2:40][NH:39][C:38]=4[N:37]=3)[CH2:32][CH2:31]2)[N:26]=[CH:25][N:24]=1)[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15]>ClCCl.N1C=CC=CC=1>[CH3:29][C:28]1[C:23]([NH:22][CH2:21][CH:13]([C:7](=[O:8])[C:6]2[CH:10]=[CH:11][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[N:24][CH:25]=[N:26][C:27]=1[N:30]1[CH2:35][CH2:34][CH:33]([C:36]2[CH:45]=[CH:44][C:43]3[CH2:42][CH2:41][CH2:40][NH:39][C:38]=3[N:37]=2)[CH2:32][CH2:31]1
Reactant: Cc1c(NCC(N)C(=O)OC(C)(C)C)ncnc1N1CCC(c2ccc3c(n2)NCCC3)CC1
Reactant: COc1ccc(C(=O)Cl)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccc(C(=O)C(CNc2ncnc(N3CCC(c4ccc5c(n4)NCCC5)CC3)c2C)C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.7 %

Procedure:
40 mg (0.233 mmoles) of 4-methoxy-benzoyl chloride in solution in 3 ml of dichloromethane is added to a mixture of 109 mg (0.233 mmoles) of tert-butyl 2-amino-3-{5-methyl-6-[4-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-piperidin-1-yl]-pyrimidin-4-ylamino}-propionate in solution in 6 ml of dichloromethane and 650 μl of pyridine. The reaction mixture is stirred at ambient temperature for 1 hour. Then, the solvent is evaporated off under reduced pressure (2 kPa) and the residue is chromatographed on silica gel with the following eluent: ethyl acetate-dichloromethane 50-50, ethyl acetate-dichloromethane/methanol (95/5) 50-50 then finishing with ethyl acetate-dichloromethane/methanol (9/1) 50-50. 98 mg of expected product is obtained.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[C:8](Cl)[N:7]=[CH:6][N:5]=1)([OH:3])=[O:2].[CH3:11][NH:12][CH3:13]>>[C:1]([C:4]1[CH:9]=[C:8]([N:12]([CH3:13])[CH3:11])[N:7]=[CH:6][N:5]=1)([OH:3])=[O:2]
Reactant: O=C(O)c1cc(Cl)ncn1
Reactant: CNC
Product: CN(C)c1cc(C(=O)O)ncn1
Reaction time: 72 h

Procedure:
A 40% aqueous dimethylamine solution (2000 cc) is added to 4-carboxy-6-chloropyrimidine (93.6 g). The mixture is allowed to stand for 3 days and then concentrated to dryness under reduced pressure. The residue is dissolved in water (300 cc). The solution is made alkaline by the addition of sodium bicarbonate powder to a pH of 8 to 9. The solution is then extracted with diisopropyl ether (1000 cc). The aqueous phase is acidified with 12N hydrochloric acid to a pH of 2 to 3. The precipitate is filtered off, washed with ice-water (30 cc) and then with isopropanol (120 cc). 4-Carboxy-6-dimethylaminopyrimidine (73.6 g), melting at 250° C., is obtained.