Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][NH:5][C:4](=[O:8])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].I[CH2:16][CH2:17][CH3:18].O>CN(C=O)C>[I:1][C:2]1[CH:7]=[CH:6][N:5]([CH2:16][CH2:17][CH3:18])[C:4](=[O:8])[CH:3]=1
Reactant: O=c1cc(I)cc[nH]1
Reactant: CCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCn1ccc(I)cc1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of 2.0 g (9.05 mmol) 4-iodo-1H-pyridin-2-one and 3.13 g (22.6 mmol) potassium carbonate in 10 mL DMF are added 1.05 mL (10.9 mmol) 1-iodopropane. The mixture is stirred for 2 h at rt. Subsequently the mixture is poured into water and extracted with ethyl acetate (2×). The combined organic layers are washed with sat. NaHCO3-solution. After drying over sodium sulphate, the solvent is removed in vacuo and the residue is purified by HPLC (column: Agilent Stablebond C18, 7 μM; eluent A: water+0.15% HCOOH, eluent B: MeOH) to yield the desired product.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:35]=[CH:34][C:8]([CH2:9][N:10]2[CH:19]=[CH:18][C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:20]4[CH:21]=[C:22]([CH:29]=[CH:30][C:31]=4[CH3:32])[C:23]([NH:25][CH:26]4[CH2:28][CH2:27]4)=[O:24])[CH:16]=3)[C:11]2=[O:33])=[CH:7][CH:6]=1.[CH3:36][NH2:37]>>[CH:26]1([NH:25][C:23](=[O:24])[C:22]2[CH:29]=[CH:30][C:31]([CH3:32])=[C:20]([C:15]3[CH:16]=[C:17]4[C:12](=[CH:13][CH:14]=3)[C:11](=[O:33])[N:10]([CH2:9][C:8]3[CH:34]=[CH:35][C:5]([O:4][CH2:3][CH2:2][NH:37][CH3:36])=[CH:6][CH:7]=3)[CH:19]=[CH:18]4)[CH:21]=2)[CH2:28][CH2:27]1
Reactant: CN
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(Cc3ccc(OCCCl)cc3)ccc2c1
Product: CNCCOc1ccc(Cn2ccc3cc(-c4cc(C(=O)NC5CC5)ccc4C)ccc3c2=O)cc1

Procedure:
The title compound was prepared according to the method of Example 32 step (iii) using the product of Example 32 step (ii) and methylamine.
Reaction SMILES: [OH:1][C@H:2]1[CH2:23][CH2:22][C@@:21]2([CH3:24])[CH:4]([CH2:5][CH2:6][C:7]3[C:8]4[C@:17]([CH3:25])([CH2:18][CH2:19][C:20]=32)[C@@H:11]([C@@H:12]([CH3:16])[CH2:13][CH:14]=O)[CH2:10][CH:9]=4)[C:3]1([CH3:27])[CH3:26].[CH3:28][NH:29][CH3:30].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[CH3:28][N:29]([CH2:14][CH2:13][C@@H:12]([C@@H:11]1[C@:17]2([CH3:25])[C:8]([C:7]3[CH2:6][CH2:5][C@@H:4]4[C@:21]([C:20]=3[CH2:19][CH2:18]2)([CH3:24])[CH2:22][CH2:23][C@H:2]([OH:1])[C:3]4([CH3:26])[CH3:27])=[CH:9][CH2:10]1)[CH3:16])[CH3:30]
Reactant: CNC
Reactant: C[C@@H](CC=O)[C@H]1CC=C2C3=C(CC[C@@]21C)[C@@]1(C)CC[C@H](O)C(C)(C)C1CC3
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: C[C@@H](CCN(C)C)[C@H]1CC=C2C3=C(CC[C@@]21C)[C@@]1(C)CC[C@H](O)C(C)(C)[C@@H]1CC3

Procedure:
(20S)-3β-hydroxy-4,4,20-trimethyl-pregna-8,14-dien-21-carbaldehyde was treated with N,N-dimethylamin and sodium tris(acetoxy)borohydride as described in Example 9d). (20S)-20-[(N,N-dimethylamino)ethyl]-4,4-dimethyl-5α-pregna-8,14-dien-3β-ol was isolated as a white solid.
Reaction SMILES: [CH:1]([NH2:4])([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C.[Cl:14][C:15]1[N:20]=[C:19](Cl)[C:18]([N+:22]([O-:24])=[O:23])=[CH:17][N:16]=1>ClCCl>[Cl:14][C:15]1[N:20]=[C:19]([NH:4][CH:1]([CH3:3])[CH3:2])[C:18]([N+:22]([O-:24])=[O:23])=[CH:17][N:16]=1
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Reactant: CC(C)N
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)Nc1nc(Cl)ncc1[N+](=O)[O-]
Yield: 90.4 %

Procedure:
Isopropylamine (4.5 ml) and N,N-diisopropylethylamine (13.2 ml) were dissolved into 150 ml dichloromethane. The mixture was added dropwise to a solution of 2,4-dichloro-5-nitropyrimidine (10.0 g) in dichloromethane (30 ml) at 0° C. After the completion of the dropwise addition, the mixture was kept at the same temperature to react for half an hour. Purification was conducted by a column chromatography to obtain a bright-yellow solid (10.1 g) in a yield of 90.4%. 1H NMR (400 MHz, CDCl3): δ 9.03 (s, 1H), 8.24 (s, 1H), 4.53 (m, 1H), 1.34 (d, J=6.8 Hz, 6H) ppm.
Reaction SMILES: C([O:8][C:9]1[C:14](=[O:15])[CH:13]=[C:12]([CH2:16][NH:17][S:18]([C:21]2[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=2)(=[O:20])=[O:19])[N:11]([CH3:28])[C:10]=1[C:29]([OH:31])=[O:30])C1C=CC=CC=1.C1(S(C(N)C2N(C)C(C(O)=O)=C(O)C(=O)C=2)(=O)=O)C=CC=CC=1>>[OH:8][C:9]1[C:14](=[O:15])[CH:13]=[C:12]([CH2:16][NH:17][S:18]([C:21]2[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=2)(=[O:19])=[O:20])[N:11]([CH3:28])[C:10]=1[C:29]([OH:31])=[O:30]
Reactant: Cc1ccc(S(=O)(=O)NCc2cc(=O)c(OCc3ccccc3)c(C(=O)O)n2C)cc1
Agent: Cn1c(C(N)S(=O)(=O)c2ccccc2)cc(=O)c(O)c1C(=O)O
Product: Cc1ccc(S(=O)(=O)NCc2cc(=O)c(O)c(C(=O)O)n2C)cc1
Yield: 9.4 %

Procedure:
3-Hydroxy-1-methyl-4-oxo-6-[(toluene-4-sulfonylamino)-methyl]-1,4-dihydro-pyridine-2-carboxylic acid (14-06) (30.0 mg, 9.41%, purified by Prep-HPLC) was synthesized as an off white solid from 3-benzyloxy-1-methyl-4-oxo-6-[(toluene-4-sulfonylamino)-methyl]-1,4-dihydro-pyridine-2-carboxylic acid (13-06) 400.0 mg, 0.905 mmol) following the procedure described for 6-(benzenesulfonylamino-methyl)-3-hydroxy-1-methyl-4-oxo-1,4-dihydro-pyridine-2-carboxylic acid (14-01).
Reaction SMILES: [Br:1]Br.ClCCl.[C:6]1([C:12]2[CH:16]=[CH:15][O:14][C:13]=2[C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>C(Cl)(Cl)Cl>[Br:1][C:15]1[O:14][C:13]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[C:12]([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:16]=1
Reactant: BrBr
Reactant: CCOC(=O)c1occc1-c1ccccc1
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1oc(Br)cc1-c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Bromine (1.29 ml) was added to a dichloromethane (40 ml) solution of ethyl 3-phenyl-2-furancarboxylate (3.60 g) at 0° C. and stirred overnight at 25° C. The reaction solution was diluted with chloroform and washed with saturated aqueous sodium hydrogencarbonate solution, 20% aqueous sodium thiosulphate solution, and saturated brine. The organic layer was dried over MgSO4, and the solvent was evaporated under reduced pressure, thereby giving 3.50 g of ethyl 5-bromo-3-phenyl-2-furancarboxylate.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C@H:7]1[CH2:11][CH2:10][N:9]([C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[CH2:18][NH:17][CH2:16][CH2:15]3)[CH2:8]1.Br[C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][N:24]=1>>[Cl:29][C:26]1[CH:27]=[CH:28][C:23]([N:17]2[CH2:16][CH2:15][C:14]3[C:19](=[CH:20][CH:21]=[C:12]([N:9]4[CH2:10][CH2:11][C@H:7]([N:3]5[CH2:4][CH2:5][CH2:6][C@@H:2]5[CH3:1])[CH2:8]4)[CH:13]=3)[CH2:18]2)=[N:24][CH:25]=1
Reactant: Clc1ccc(Br)nc1
Reactant: C[C@H]1CCCN1[C@H]1CCN(c2ccc3c(c2)CCNC3)C1
Product: C[C@H]1CCCN1[C@H]1CCN(c2ccc3c(c2)CCN(c2ccc(Cl)cn2)C3)C1

Procedure:
The title compound was synthesized in substantially the same way as Example 1 by condensation of 6-((2S,3′S)-2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-1,2,3,4-tetrahydro-isoquinoline with 2-bromo-5-chloro-pyridine.
Reaction SMILES: C1(=O)N([N:6]2[CH:14]=[CH:13][CH:12]=[C:8]([C:9]([O-:11])=O)[CH2:7]2)C(=O)CC1.[CH2:17]([CH2:19][NH2:20])[OH:18].C(N(C(C)C)CC)(C)C.C(N)C.CN(C=O)C.C([O-])(=O)C1C=CC=NC=1.ON1C(=O)CCC1=O>CN(C=O)C>[OH:18][CH2:17][CH2:19][NH:20][C:9](=[O:11])[C:8]1[CH:12]=[CH:13][CH:14]=[N:6][CH:7]=1
Reactant: O=C([O-])C1=CC=CN(N2C(=O)CCC2=O)C1
Reactant: NCCO
Agent: CCN
Agent: O=C([O-])c1cccnc1
Agent: O=C1CCC(=O)N1O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCCO)c1cccnc1
Reaction time: 0.25 h

Procedure:
The N-succinimidyl-nicotinate compound described in Example 1 was reacted with the hydrochloric salt of ethanolamine, available commercially in its radioactive form. The ethanolamine salt was dissolved in dried DMF and chilled in an ice bath. To the mixture was added an equimolar of diisopropylethylamine (DIEA) and stirred for 15 minutes. An equimolar solution of N-succinimidyl-nicotinate was added to the ethylamine-DMF mixture dropwise under a nitrogen atmosphere. As the nicotinate was added the mixture turned milky and was slurried for at least another half hour. The milky substance was the N-hydroxy-succinimide precipitating, which was filtered off. The DMF-mixture was washed with ether to remove any precipitant. The solvent mixture was removed under high vaccum. The oily mixture was triturated with ether to yield a precipitant, N-(2-hydroxyethyl)nicotinamide. The radioactive compound was isolated and identified by its TLC.
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:5][CH:4]=1.S(Cl)([Cl:18])=O>C(Cl)Cl>[Cl:18][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:5][CH:4]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1ccc(Sc2ccccc2)cc1
Solvent: ClCCl
Product: ClCc1ccc(Sc2ccccc2)cc1
Reaction time: 1 h

Procedure:
The 1-hydroxymethyl-4-phenylthiobenzene (3.0 g) is dissolved in methylene chloride (15 ml), and thereto is added with stirring thionyl chloride (1.5 ml) under ice cooling. The mixture is stirred for one hour, and the reaction mixture is washed with ice water (10 ml×3), and thereto is added methylene chloride (50 ml). The mixture is washed in order with 5% aqueous sodium hydrogen carbonate solution (5 ml×3) and saturated aqueous sodium chloride solution (30 ml×2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 1-chloromethyl-4-phenylthiobenzene (3.0 g).
Reaction SMILES: CCOC(/N=N/C(OCC)=O)=O.O[C:14]1([CH2:27][CH2:28][CH2:29][OH:30])[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[O:30]1[C:14]2([CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:24])([CH3:25])[CH3:26])=[O:21])[CH2:18][CH2:19]2)[CH2:27][CH2:28][CH2:29]1
Reactant: CC(C)(C)OC(=O)N1CCC(O)(CCCO)CC1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC2(CCCO2)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 74 %

Procedure:
A solution of diethyl diazenedicarboxylate (3.35 mL, 21.3 mmol) in tetrahydrofuran (50 mL) was added over 15 minutes to a stirred, cooled (0° C.) solution of 1,1-dimethylethyl 4-hydroxy-4-(3-hydroxypropyl)-1-piperidinecarboxylate (Description 73, 4.6 g, 17.8 mmol) and triphenylphosphine (5.58 g, 21.3 mmol) in tetrahydrofuran (150 mL) and the mixture was stirred at 0° C. for 1 hour, then at room temperature for 24 hours. The solvent was evaporated under reduced pressure and the residue was purified by flash column chromatography on silica gel, eluting with isohexane/EtOAc (75:25 increasing to 50:50), to give the title compound (3.18 g, 70%). m/z (ES+) 242 (M+1).
Reaction SMILES: N#N.[N+:3]([C:6]1[NH:10][N:9]=[CH:8][CH:7]=1)([O-:5])=[O:4].[CH3:11][O:12][C:13]([C:15]1[O:16][C:17]([CH2:20]Cl)=[CH:18][CH:19]=1)=[O:14].C([O-])([O-])=O.[K+].[K+].[Br-]>CC(C)=O.CC(=O)OCC.O>[CH3:11][O:12][C:13]([C:15]1[O:16][C:17]([CH2:20][N:9]2[CH:8]=[CH:7][C:6]([N+:3]([O-:5])=[O:4])=[N:10]2)=[CH:18][CH:19]=1)=[O:14]
Reactant: O=[N+]([O-])c1ccn[nH]1
Reactant: COC(=O)c1ccc(CCl)o1
Agent: N#N
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Solvent: O
Product: COC(=O)c1ccc(Cn2ccc([N+](=O)[O-])n2)o1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 5-nitro-1H-pyrazole (10.95 g, 96.89 mmol) in dry acetone (219 mL) was treated with 5-chloromethyl-furan-2-carboxylic acid methyl ester (17.80 g, 96.89 mmol) followed by K2CO3 (67.61 g, 484.29 mmol) and TBA bromide (6.24 g, 19.37 mmol). The reaction mixture was stirred at rt overnight. Water (500 mL) was added followed by EA (1000 mL). The aq. layer was extracted with EA (2×500 mL) and the combined org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (50:50 hept-EA) gave the title compound as a yellow oil. TLC: rf (50:50 hept-EA)=0.26. LC-MS-conditions 02: tR=0.84 min. 1H NMR (400 MHz, CDCl3) δ 3.90 (s, 3H), 5.44 (s, 2H), 6.58 (d, J=3.5 Hz, 1H), 6.93 (d, J=2.5 Hz, 1H), 7.15 (d, J=3.5 Hz, 1H), 7.60 (d, J=2.3 Hz, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7](/[CH:10]=[CH:11]/[C:12]2[N:13]=[C:14]([NH:23][C:24](=[O:26])[CH3:25])[S:15][C:16]=2[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:6][CH:5]=1)([O-])=O.[N+](C1C=CC(/C=C\C2N=C(NC(=O)C)SC=2C2C=CC=CC=2)=CC=1)([O-])=O.CO.C1COCC1>[C].[Pd].CC(O)=O>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][C:12]2[N:13]=[C:14]([NH:23][C:24](=[O:26])[CH3:25])[S:15][C:16]=2[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:6][CH:5]=1
Reactant: CC(=O)Nc1nc(/C=C/c2ccc([N+](=O)[O-])cc2)c(-c2ccccc2)s1
Agent: [Pd]
Agent: CC(=O)Nc1nc(/C=C\c2ccc([N+](=O)[O-])cc2)c(-c2ccccc2)s1
Solvent: CO
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC(=O)Nc1nc(CCc2ccc(N)cc2)c(-c2ccccc2)s1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
A mixture of N-{4-[(E)-2-(4-nitrophenyl)vinyl]-5-phenyl-1,3-thiazol-2-yl}acetamide and N-{4-[(Z)-2-(4-nitrophenyl)vinyl]-5-phenyl-1,3-thiazol-2-yl}acetamide (E:Z=2:1) (600 mg), 10% palladium carbon (657 mg), MeOH (6 ml), THF (6 ml) and AcOH (1 ml) were combined. The reaction mixture was stirred under 3 atm H2 at r.t. for 3.5 hours, and filtered through a celite pad. The filtrate was concentrated in vacuo. 1N—NaOH was added to the residue, and the mixture was extracted with AcOEt. The organic layer was washed with water and brine, dried over MgSO4, and concentrated in vacuo to give N-{4-[2-(4-aminophenyl)ethyl]-5-phenyl-1,3-thiazol-2-yl}acetamide (528.6 mg) as a pale brown amorphous substance.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([CH3:11])([CH3:10])[CH2:8][OH:9].[O:12]1[CH:17]=[CH:16][CH2:15][CH2:14][CH2:13]1>ClCCl.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([CH3:11])([CH3:10])[CH2:8][O:9][CH:13]1[CH2:14][CH2:15][CH2:16][CH2:17][O:12]1
Reactant: C1=COCCC1
Reactant: CC(C)(CO)CCCCCBr
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Product: CC(C)(CCCCCBr)COC1CCCCO1
Temperature: 25 °C
Yield: 56.3 %

Procedure:
To a solution of 7-bromo-2,2-dimethylheptan-1-ol (36.0 g, 133.0 mmol) in dichloromethane (60 mL) was added p-toluenesulfonic acid (0.28 g, 1.3 mmol) and 3,4-dihydro-2H-pyran (18.54 g, 213 mmol) at 5-10° C. under cooling with an ice-water bath. The mixture was stirred and allowed to warm to room temperature overnight. The reaction solution was filtered through neutral alumina (200 g), which was rinsed with dichloromethane (500 mL). Concentration of the solvent gave the crude product as a brown oil, which was subjected to column chromatography on silica gel (240 g) using hexanes:ethyl acetate (50:1) as eluent to yield 2-(7-bromo-2,2-dimethylheptyloxy)-tetrahydropyran as a colorless oil (23.0 g, 48%). 1H NMR (300 MHz, CDCl3/TMS): δ (ppm): 4.54 (t, 1H, J=3.0 Hz), 3.84 (m, 1H), 3.51-3.39 (m, 4H), 2.98 (d, 1H, J=9.3 Hz), 1.89-1.80 (m, 3H), 1.70-1.40 (m, 7H), 1.29-1.22 (m, 4H), 0.89 (s, 6H). 13C NMR (75 MHz, CDCl3/TMS): δ (ppm): 99.3, 76.6, 62.1, 39.3, 34.3, 34.2, 33.0, 30.8, 29.2, 25.7, 24.7, 23.2, 19.6. HRMS (LSIMS, nba): Calcd. for C14H27BrO2: 307.1272, found: 307.1245.
Reaction SMILES: [CH:1]([S:4]([N:7]1[C:11]2[CH:12]=[C:13]([C:16](O)([CH2:23][C:24]([O:26]C(C)(C)C)=[O:25])[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[NH2:32])(=[O:6])=[O:5])([CH3:3])[CH3:2].C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[CH:1]([S:4]([N:7]1[C:11]2[CH:12]=[C:13]([C:16](=[CH:23][C:24]([OH:26])=[O:25])[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[NH2:32])(=[O:5])=[O:6])([CH3:3])[CH3:2]
Reactant: CC(C)S(=O)(=O)n1c(N)nc2ccc(C(O)(CC(=O)OC(C)(C)C)c3ccccc3)cc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CC(C)S(=O)(=O)n1c(N)nc2ccc(C(=CC(=O)O)c3ccccc3)cc21
Temperature: 25 °C

Procedure:
A solution of 1.89 g. of 1-isopropylsulfonyl-2-amino-6-(α-hydroxy-α-tert.-butoxycarbonylmethylbenzyl)benzimidazole (from Example 6) and 1.2 g. of p-toluenesulfonic acid in 100 ml. of chloroform was heated at reflux for two hours and then cooled to room temperature. The solution was extraced three times with aqueous sodium bicarbonate solution. The aqueous extracts were combined, washed with fresh chloroform and then neutralized to pH 7.0 by the addition of 1 N hydrochloric acid. The acidic solution next was extracted several times with ethyl acetate. The extracts were combined, washed with water and dried. Removal of the solvent by evaporation under reduced pressure provided 1-isopropylsulfonyl-2-amino-6-(α-hydroxycarbonylmethylenebenzyl)benzimidazole.
Reaction SMILES: [C:1]([N:3]=[C:4]1[NH:8][CH2:7][CH2:6][N:5]1[C@@H:9]1[C:14]2[CH:15]=[C:16]([C:19]#[N:20])[CH:17]=[CH:18][C:13]=2[O:12][C:11]([CH3:22])([CH3:21])[C@H:10]1[OH:23])#[N:2].[C:24](OC(=O)C)(=[O:26])[CH3:25]>N1C=CC=CC=1.C(OCC)(=O)C>[C:24]([O:23][C@H:10]1[C@H:9]([N:5]2[CH2:6][CH2:7][NH:8][C:4]2=[N:3][C:1]#[N:2])[C:14]2[CH:15]=[C:16]([C:19]#[N:20])[CH:17]=[CH:18][C:13]=2[O:12][C:11]1([CH3:21])[CH3:22])(=[O:26])[CH3:25]
Reactant: CC1(C)Oc2ccc(C#N)cc2[C@@H](N2CCNC2=NC#N)[C@@H]1O
Reactant: CC(=O)OC(C)=O
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CC(=O)O[C@H]1[C@H](N2CCNC2=NC#N)c2cc(C#N)ccc2OC1(C)C
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of trans-4-(2-cyanoiminoimidazolidin-1-yl)-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-6-carbonitrile (0.62 g) and acetic anhydride (0.47 ml) in dry pyridine (3.1 ml) was stirred at room temperature for 3 days. The mixture was diluted with ethyl acetate (30 ml) and washed with 5% hydrochloric acid (20 ml×2), brine (20 ml), saturated aqueous sodium bicarbonate (20 ml) and brine (20 ml), successively. The organic layer was dried over anhydrous magnesium sulfate and evaporated in vacuo. The residue was subjected to column chromatography on silica gel (50 g) and eluted with a mixture of chloroform and methanol (50:1). The fractions containing the object compound were combined and concentrated under reduced pressure. The residue was recrystallized from a mixture of dichloromethane and n-hexane to give trans-3-acetoxy-4-(2-cyanoiminoimidazolidin-1-yl)-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-6-carbonitrile (0.44 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:20]#[N:21])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]([CH:14]([CH3:18])[C:15]([OH:17])=O)[C:10](=[O:19])[CH:9]=2)[CH:7]=1.[NH:22]1[CH:26]=[CH:25][N:24]=[C:23]1[C:27]1[CH:33]=[CH:32][C:30]([NH2:31])=[CH:29][CH:28]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:20]#[N:21])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]([CH:14]([CH3:18])[C:15]([NH:31][C:30]3[CH:29]=[CH:28][C:27]([C:23]4[NH:24][CH:25]=[CH:26][N:22]=4)=[CH:33][CH:32]=3)=[O:17])[C:10](=[O:19])[CH:9]=2)[CH:7]=1
Reactant: Nc1ccc(-c2ncc[nH]2)cc1
Reactant: CC(C(=O)O)n1ccc(-c2cc(Cl)ccc2C#N)cc1=O
Product: CC(C(=O)Nc1ccc(-c2ncc[nH]2)cc1)n1ccc(-c2cc(Cl)ccc2C#N)cc1=O

Procedure:
71 mg (0.23 mmol) of 2-[4-(5-chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]propanoic acid (racemate) (Example 2.2B) and 40 mg (0.25 mmol) of 4-(1H-imidazol-2-yl)aniline (Example 1.2A) were reacted according to General Method 1. Yield: 4 mg (4% of theory)
Reaction SMILES: C([O:8][C:9](=[O:17])[CH2:10][NH:11][C:12](=[O:16])[C:13]([CH3:15])=[O:14])C1C=CC=CC=1>O>[C:12]([NH:11][CH2:10][C:9]([OH:17])=[O:8])(=[O:16])[C:13]([CH3:15])=[O:14]
Reactant: CC(=O)C(=O)NCC(=O)OCc1ccccc1
Solvent: O
Product: CC(=O)C(=O)NCC(=O)O

Procedure:
Preferably in this method of synthesis, the thionyl chloride or oxalyl chloride is added to a suspension of sodium pyruvate to yield the pyruvyl chloride to which is added the of glycine benzyl ester hydrochloride. The yield a pyruvyl-glycine benzyl ester. The yielding of the pyruvyl-glycine benzyl ester occurs after warming, the addition of water, separation, washing, drying, evaporation, precipitation, filtering, and drying again. The pyruvyl-glycine benzyl ester is then charged in a hydrogen pressure vessel in a solvent and a palladium on carbon catalyst, with the hydrogen pressure being approximately 60 psi such that hydrogen is digested whereby following filtering, concentration, precipitation, filtering, and drying there is yielded pyruvyl-glycine.
Reaction SMILES: Cl.Cl.[N:3]1([C:9]2[C:10]3[CH2:17][CH2:16][CH:15]([OH:18])[C:11]=3[N:12]=[CH:13][N:14]=2)[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.[C:19]([O:23][C:24]([N:26]([CH:39]([CH3:41])[CH3:40])[CH2:27][CH:28]([C:32]1[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=1)[C:29](O)=[O:30])=[O:25])([CH3:22])([CH3:21])[CH3:20].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[Cl:38][C:35]1[CH:36]=[CH:37][C:32]([CH:28]([C:29]([N:6]2[CH2:5][CH2:4][N:3]([C:9]3[C:10]4[CH2:17][CH2:16][CH:15]([OH:18])[C:11]=4[N:12]=[CH:13][N:14]=3)[CH2:8][CH2:7]2)=[O:30])[CH2:27][N:26]([CH:39]([CH3:40])[CH3:41])[C:24](=[O:25])[O:23][C:19]([CH3:21])([CH3:20])[CH3:22])=[CH:33][CH:34]=1
Reactant: OC1CCc2c1ncnc2N1CCNCC1
Reactant: CC(C)N(CC(C(=O)O)c1ccc(Cl)cc1)C(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: CC(C)N(CC(C(=O)N1CCN(c2ncnc3c2CCC3O)CC1)c1ccc(Cl)cc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.3 %

Procedure:
To a solution of 4-(piperazin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-ol dihydrochloride (40 mg, 0.14 mmol) in DCM (20 mL) and TEA (2 mL) was added 3-(tert-butoxycarbonyl(isopropyl)amino)-2-(4-chlorophenyl)propanoic acid (47 mg, 0.14 mmol) and HBTU (52 mg, 0.14 mmol). The mixture was stirred at room temperature for 1 hour. The solvent was removed and the residue was subject to chromatography on silica gel, eluted by ethyl acetate to afford the tert-butyl 2-(4-chlorophenyl)-3-(4-(7-hydroxy-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-oxopropyl(isopropyl)carbamate (49 mg, 66%). MS (APCI+) [M+H]+544.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[CH:7][CH:8]=1)#[N:2].Br[C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[NH:19][C:18](=[O:23])[CH2:17][C:16]2([CH3:25])[CH3:24].C(=O)([O-])[O-].[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1.O>[CH3:24][C:16]1([CH3:25])[C:15]2[C:20](=[CH:21][CH:22]=[C:13]([C:5]3[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=3)[C:1]#[N:2])[CH:14]=2)[NH:19][C:18](=[O:23])[CH2:17]1
Reactant: CC1(C)CC(=O)Nc2ccc(Br)cc21
Reactant: N#Cc1cccc(B(O)O)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: CC1(C)CC(=O)Nc2ccc(-c3cccc(C#N)c3)cc21

Procedure:
Prepared by coupling 3-cyanophenylboronic acid with an equivalent amount of 6-bromo-4,4-dimethyl-3,4-dihydo-1H-quinolin-2-one using a catalytic amount of tetrakis(triphenylphosphine)palladium (0) as a catalyst with overnight refluxing in toluene containing an equivalent amount of potassium carbonate dissolved in water in the usual manner followed by recrystallization from ethanol gave a gray solid: mp. 190-192° C.; 1H-NMR (DMSO-d6) δ 10.29 (s, 1H), 8.17 (s, 1H), 8.00 (d, 1H, J=7.9 Hz), 7.77 (d, 1H, J=6.4 Hz), 7.65 (m, 2H), 7.55 (d, 1H, J=8.2 Hz), 6.97 (d, 1H, J=8.3 Hz), 2.40 (s, 2H), 1.30 (s, 6H); MS (APCI (−)) m/z 275 [M−H]− Anal. Calc. For C18H16N2O 0.25H2O: C, 75.77, H, 6.01, N, 9.82. Found: C, 75.45, H, 5.65, N 9.20.