Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(C)([O-])C.[K+].[F:7][C:8]([F:18])([F:17])[C:9]1[CH:16]=[CH:15][C:12]([CH2:13][OH:14])=[CH:11][CH:10]=1.Cl[C:20]1[CH:21]=[C:22]([CH3:27])[N+:23]([O-:26])=[CH:24][CH:25]=1.C(O)(C)(C)C>O>[F:7][C:8]([F:17])([F:18])[C:9]1[CH:16]=[CH:15][C:12]([CH2:13][O:14][C:20]2[CH:21]=[C:22]([CH3:27])[N+:23]([O-:26])=[CH:24][CH:25]=2)=[CH:11][CH:10]=1
Reactant: Cc1cc(Cl)cc[n+]1[O-]
Reactant: OCc1ccc(C(F)(F)F)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: O
Product: Cc1cc(OCc2ccc(C(F)(F)F)cc2)cc[n+]1[O-]
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
11.2 g (100 mmol) of potassium tert.-butoxide are added under an N2 atmosphere at 25° C. to 25 ml (183 mmol) of 4-trifluoromethylbenzyl alcohol. 7.2 g (50 mmol) of 4-chloro-2-picoline-N-oxide are subsequently added dropwise, then 10 ml of tert.-butanol are added, and the mixture is stirred for 1 hour at 25° C. and for 30 minutes at 75°-80° C. Water is then added and the mixture is extracted three times using dichloromethane, the extracts are dried and concentrated, and the residue is chromatographed on silica gel using dichloromethane/methanol. The product is obtained from the corresponding fractions, m.p. 113°-115° C.
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([N:11]=[C:12]=[O:13])[CH2:9][CH3:10].[NH2:14][C:15]([NH:17][C:18]1[NH:19][C:20]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[OH:32])=[CH:21][C:22]=1[C:23]([NH2:25])=[O:24])=[O:16]>CN(C)C=O>[NH2:14][C:15]([NH:17][C:18]1[NH:19][C:20]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[O:32][C:12]([NH:11][CH2:8][CH2:9][CH3:10])=[O:13])=[CH:21][C:22]=1[C:23]([NH2:25])=[O:24])=[O:16]
Reactant: CCCN=C=O
Reactant: NC(=O)Nc1[nH]c(-c2ccccc2O)cc1C(N)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCNC(=O)Oc1ccccc1-c1cc(C(N)=O)c(NC(N)=O)[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56 %

Procedure:
Triethylamine (43 μL, 0.31 mmol) and propyl isocyanate (17 μL, 0.18 mmol) were added to a solution of 2-aminocarbonylamino-5-(2-hydroxyphenyl)pyrrole-3-carboxamide (Compound No. 3-1, 40 mg, 0.15 mmol) in anhydrous N,N-dimethylformamide (2 mL), and the mixture was stirred overnight at room temperature. After the reaction solution was concentrated in vacuo, the residue was purified by silica gel column chromatography to give the target compound (29 mg) as a pale blue solid (Yield 54%).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1OS(C(F)(F)F)(=O)=O.[F:27][C:28]1[CH:35]=[C:34]([O:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH:33]=[CH:32][C:29]=1[CH2:30][NH2:31]>>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:13])([F:15])[F:14])[CH2:9][CH2:10][C:4]=2[C:3]=1[NH:31][CH2:30][C:29]1[CH:32]=[CH:33][C:34]([O:36][C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)=[CH:35][C:28]=1[F:27]
Reactant: NCc1ccc(Oc2ccccc2)cc1F
Reactant: O=C(N1CCc2ccc(Cl)c(OS(=O)(=O)C(F)(F)F)c2CC1)C(F)(F)F
Product: O=C(N1CCc2ccc(Cl)c(NCc3ccc(Oc4ccccc4)cc3F)c2CC1)C(F)(F)F

Procedure:
Using method similar to the General Procedure 5-3, couple 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine (1.1 g, 2.5 mmol) with 2-fluoro-4-phenoxy-benzylamine (550 mg, 2.5 mmol). Purify by chromatography on silica gel eluting with hexane/EtOAc (9:1) and then SCX chromatography to obtain 7-chloro-6-(2-fluoro-4-phenoxy-benzylamino)-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine. MS (ES+) m/z: 493 (M+H)+.
Reaction SMILES: [CH:1]1(O)[C:10]2[C:5]3[C:6](=[CH:11][CH:12]=[CH:13][C:4]=3[CH2:3][O:2]1)[CH:7]=[CH:8][CH:9]=2.C[Si]([C:19]#[N:20])(C)C.C([O-])(O)=O.[Na+]>C(#N)C>[CH:1]1([C:19]#[N:20])[C:10]2[C:5]3[C:6](=[CH:11][CH:12]=[CH:13][C:4]=3[CH2:3][O:2]1)[CH:7]=[CH:8][CH:9]=2
Reactant: C[Si](C)(C)C#N
Reactant: OC1OCc2cccc3cccc1c23
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: N#CC1OCc2cccc3cccc1c23
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a solution of 1,3-Dihydrobenzo[de]isochromen-1-ol (100 mg) in acetonitrile (3 mL) at 0° C. was added Zn(II)iodide (86 mg) and suspension was stirred at 0° C. for 10 minutes. Trimethylsilyl cyanide (672 μL) was added and the reaction mixture was stirred at room temperature overnight. Solution of saturated NaHCO3 (10 mL) was added and the mixture was extracted with ethyl acetate (2×15 mL). Combined organic phases were washed with brine and dried with Na2SO4. Evaporation of solvents afforded 110 mg 1,3-dihydrobenzo[de]isochromene-1-carbonitrile that was mixed with ethylene diamine mono-p-toluenesulfonic acid salt (157 mg) and the mixture was heated to 200° C. After 3 hours the reaction mixture was cooled to room temperature and taken to mixture of dichloromethane (10 ml) and aqueous NaHCO3 (1:1 saturated solution/water). Phases were separated and aqueous phase was extracted with dichloromethane (5 mL). Combined organic phases were dried with Na2SO4 and concentrated. The evaporation residue was purified by separation method E (aq.NH3-MeOH-dichloromethane). The obtained 2-(1,3-dihydrobenzo[de]isochromen-1-yl)-4,5-dihydro-1H-imidazole was converted to the title compound using salt formation method A.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][C:3]=1[O:10][CH3:11].[N+:12]([CH3:15])([O-:14])=[O:13].[OH-].[Na+]>C(O)C>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[CH:15][N+:12]([O-:14])=[O:13])=[CH:4][C:3]=1[O:10][CH3:11]
Reactant: COc1cc(C=O)ccc1Cl
Reactant: C[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1cc(C=C[N+](=O)[O-])ccc1Cl
Temperature: 0 °C
Reaction time: 3 h
Yield: 63.7 %

Procedure:
4-Chloro-3-methoxybenzaldehyde (1 g, 5.88 mmol) in ethanol (10 mL) was reacted with nitro methane (358 mg, 5.88 mmol) and 10N NaOH (0.6 mL, 28.11 mmol). The resulting mixture was stirred at 0° C. for 3 hours to afford 800 mg of the product (66.6% yield).
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][CH2:7][CH:8]([O:15]COCCOC)[CH2:9][CH2:10][CH2:11][CH2:12][CH:13]=[O:14])=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.[OH-].[Na+]>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH2:7][CH:8]([OH:15])[CH2:9][CH2:10][CH2:11][CH2:12][CH:13]=[O:14])=[CH:22][CH:23]=1
Reactant: COCCOCOC(CCCCC=O)COc1ccc(F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: O=CCCCCC(O)COc1ccc(F)cc1
Reaction time: 24 h
Yield: 81.9 %

Procedure:
(±)-7-(4-fluorophenoxy)-6-(2-methoxyethoxymethoxy)heptan-1-al 45 (2 g, 6.1 mmol) and 2 ml of trifluoroacetic acid are added to 10 ml of chloroform. The reaction mixture is stirred for 24 hours and then is neutralized with 1% aqueous NaOH. The organic layer is washed with water, brine, dried (Na2SO4), concentrated. The crude trifluoroacetyl-aldehyde 46 is then dissolved in MeOH:H2O (1:1) and solid K2CO3 is added to maintain pH 8. The reaction is complete is approximately 15 minutes, as monitored by TLC (ethyl acetate:hexane 3:7). Methanol is removed in vacuo and remaining solution is extracted with ethyl acetate to give (±)-7-(4-fluorophenoxy)-6-(hydroxy)-heptan-al 47 (1.2 g, 82%).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]2[N:12]3[N:13]=[CH:14][CH:15]=[C:16]([N:17]4[CH2:22][CH2:21][O:20][CH2:19][CH2:18]4)[C:11]3=[N:10][C:9]=2[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[C:35]([O:39][C:40]([N:42]1[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]1)=[O:41])([CH3:38])([CH3:37])[CH3:36]>>[CH2:27]([O:26][C:24](=[O:25])[CH2:23][C:9]1[N:10]=[C:11]2[C:16]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:15][CH:14]=[N:13][N:12]2[C:8]=1[C:5]1[CH:4]=[CH:3][C:2]([N:45]2[CH2:44][CH2:43][N:42]([C:40]([O:39][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:41])[CH2:47][CH2:46]2)=[N:7][CH:6]=1)[CH3:28]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CCOC(=O)Cc1nc2c(N3CCOCC3)ccnn2c1-c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCOC(=O)Cc1nc2c(N3CCOCC3)ccnn2c1-c1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)nc1
Temperature: 130 °C
Reaction time: 72 h

Procedure:
Compound 28d (854 mg, 2.13 mmol), K2CO3 (323 mg, 2.34 mmol), Cu powder (27.0 mg, 0.425 mmol), and 1-(tert-butoxycarbonyl)piperazine (435 mg, 2.34 mmol) were placed in a 40 mL vial equipped with a stir bar. The vessel was evacuated and backflushed with argon and then dry DMF (4 mL) was added via syringe. The reaction was heated to 130° C. and stirred for 3 d. The solvent was removed under reduced pressure and then the residue was partitioned between water (50 mL) and DCM (70 mL). The organic phase was separated and then the aqueous layer was extracted with DCM (2×20 mL). The organic extracts were combined and washed with brine (2×30 mL), and then dried over Na2SO4 and filtered. The solvent was removed under reduced pressure. The crude product was chromatographed on a 40 g SiO2 pre-packed column eluting with 0-80% ACN/DCM to afford compound 28e. 1H-NMR (400 MHz, CDCl3) δ (ppm): 8.42 (d, J=1.7 Hz, 1H), 7.97 (d, J=5.6 Hz, 1H), 7.83 (dd, J=8.8, 2.4 Hz, 1H), 6.78 (d, J=9.0 Hz, 1H), 6.06 (d, J=5.6 Hz, 1H), 4.17 (q, J=7.1 Hz, 2H), 3.94-4.01 (m, 4H), 3.87-3.94 (m, 4H), 3.83 (s, 2H), 3.59-3.67 (m, 4H), 3.50-3.59 (m, 4H), 1.50 (s, 9H), 1.25 (t, J=7.1 Hz, 3H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C28H37N7O5: 552.3 (M+H). Found: 552.2.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][CH3:16])=[C:6](Cl)[N:5]=[C:4]([C:18]2[CH:23]=[CH:22][N:21]=[C:20]([C:24]#[N:25])[CH:19]=2)[N:3]=1.C(N(C(C)C)C(C)C)C.[K].[CH2:36]([NH:43][S:44](=[O:47])(=[O:46])[NH2:45])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CS(C)=O>[Cl:1][C:2]1[N:3]=[C:4]([C:18]2[CH:23]=[CH:22][N:21]=[C:20]([C:24]#[N:25])[CH:19]=2)[N:5]=[C:6]([NH:45][S:44](=[O:46])(=[O:47])[NH:43][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15][CH3:16]
Reactant: COc1ccccc1Oc1c(Cl)nc(-c2ccnc(C#N)c2)nc1Cl
Reactant: NS(=O)(=O)NCc1ccccc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [K]
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: COc1ccccc1Oc1c(Cl)nc(-c2ccnc(C#N)c2)nc1NS(=O)(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 93 %

Procedure:
4-[4,6-Dichloro-5-(2-methoxy-phenoxy)-pyrimidin-2-yl]-pyridine-2-carbonitrile (3.2 g) was dissolved in DMSO (20 ml), N-ethyldiisopropylamine (1.7 ml) and benzylsulfamic acid amide potassium salt (3.52 g) was added. The mixture was stirred for 18 h at rt, poured onto ice/water, acidified with solid citric acid and the precipitate was filtered off and recrystallized form EtOAc to give benzylsulfamic acid [6-chloro-2-(2-cyano-pyridin-4-yl)-5-(2-methoxy-phenoxy)-pyrimidin-4-yl]-amide (4.17 g). LC-MS: tR=5.55; [M+H]+=523.29.
Reaction SMILES: [OH-].[Na+].Cl.[N+:4]([C:7]1[CH:8]=[C:9]([NH:13][NH2:14])[CH:10]=[CH:11][CH:12]=1)([O-:6])=[O:5].C(O)(=O)C.[CH:19](=O)[CH2:20][CH3:21]>C(O)C>[N+:4]([C:7]1[CH:8]=[C:9]([NH:13]/[N:14]=[CH:19]/[CH2:20][CH3:21])[CH:10]=[CH:11][CH:12]=1)([O-:6])=[O:5]
Reactant: NNc1cccc([N+](=O)[O-])c1
Reactant: CCC=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCO
Product: CC/C=N/Nc1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Sodium hydroxide solution (10%, 15 mL) was added slowly to a stirred suspension of (3-nitrophenyl)hydrazine hydrochloride (1.89 g, 10 mmol) in ethanol (20 mL) until pH 6. Acetic acid (5 mL) was added to the mixture followed by propionaldehyde (0.7 g, 12 mmol). After stirring for 3 h at room temperature, the mixture was poured into ice-water and the resulting precipitate was isolated by filtration, washed with water and dried in air to obtain (E)-1-(3-nitrophenyl)-2-propylidenehydrazine, which was used directly in the next step.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]3[C:14](=[O:30])[N:15]([C:18]4[CH:23]=[CH:22][C:21]([C:24]5([CH2:27][NH:28][CH3:29])[CH2:26][CH2:25]5)=[CH:20][CH:19]=4)[CH2:16][CH2:17][C:12]=3[C:11]([C:31]([NH2:33])=O)=[N:10]2)=[CH:5][CH:4]=1>CN(C=O)C.S(Cl)(Cl)=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]3[C:14](=[O:30])[N:15]([C:18]4[CH:23]=[CH:22][C:21]([C:24]5([CH2:27][NH:28][CH3:29])[CH2:25][CH2:26]5)=[CH:20][CH:19]=4)[CH2:16][CH2:17][C:12]=3[C:11]([C:31]#[N:33])=[N:10]2)=[CH:5][CH:4]=1
Reactant: CNCC1(c2ccc(N3CCc4c(C(N)=O)nn(-c5ccc(OC)cc5)c4C3=O)cc2)CC1
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: CNCC1(c2ccc(N3CCc4c(C#N)nn(-c5ccc(OC)cc5)c4C3=O)cc2)CC1
Reaction time: 0.17 h
Yield: 76.4 %

Procedure:
The product of Example 67 (15 mg) was stirred in DMF (0.5 mL) at RT in a capped vial. Two drops of thionyl chloride was added. The reaction was completed in 10 min. The mixture was purified by RP-prep LC-MS (5–98% CH3CN/H2O in a 10-min run) to give pure 1-(4-methoxyphenyl)-6-(4-{1-[(methylamino)methyl]cyclopropyl}phenyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carbonitrile (11 mg, yield: 76.2%). LC/MS (ESI+) 428.4 (M+H)+, tR=4.49 min.
Reaction SMILES: [CH3:1][C:2]([CH3:29])([CH3:28])[CH2:3][O:4][C:5]1([C:8]2[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]3[CH:26]=[CH:25][C:19]([C:20]([O:22]CC)=[O:21])=[CH:18][CH:17]=3)=[CH:10][C:9]=2[CH3:27])[CH2:7][CH2:6]1.[OH-].[Na+]>C(O)C.O1CCCC1>[CH3:1][C:2]([CH3:29])([CH3:28])[CH2:3][O:4][C:5]1([C:8]2[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:16]3[CH:17]=[CH:18][C:19]([C:20]([OH:22])=[O:21])=[CH:25][CH:26]=3)=[CH:10][C:9]=2[CH3:27])[CH2:7][CH2:6]1
Reactant: CCOC(=O)c1ccc(C#Cc2ccc(C3(OCC(C)(C)C)CC3)c(C)c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1cc(C#Cc2ccc(C(=O)O)cc2)ccc1C1(OCC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 44.1 %

Procedure:
Using General Procedure I; a solution of ethyl 4-[4-[1-(2,2-dimethylpropyloxy)-cyclopropyl]-3-methyl-phenylethynyl]-benzoate (Compound 87, 60.0 mg, 0.15 mmol) in ethanol (3 mL) and tetrahydrofuran (3 mL) was treated with NaOH (120.0 mg, 3.0 mmols, 3.0 mL of a 1N aqueous solution) and stirred overnight at room temperature. Work-up afforded 24.0 mg (43%) of the title compound as a colorless solid.
Reaction SMILES: [CH:1]1([N:7]2[C:12]([OH:13])=[C:11]([C:14]([NH:16][CH2:17][C:18]([O:20]CC)=[O:19])=[O:15])[C:10](=[O:23])[NH:9][C:8]2=[O:24])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[CH:31]([C:34]1[CH:41]=[CH:40][C:37]([CH2:38]Cl)=[CH:36][CH:35]=1)([CH3:33])[CH3:32].Cl>CC(N(C)C)=O>[CH:1]1([N:7]2[C:12]([OH:13])=[C:11]([C:14]([NH:16][CH2:17][C:18]([OH:20])=[O:19])=[O:15])[C:10](=[O:23])[N:9]([CH2:38][C:37]3[CH:40]=[CH:41][C:34]([CH:31]([CH3:33])[CH3:32])=[CH:35][CH:36]=3)[C:8]2=[O:24])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CNC(=O)c1c(O)n(C2CCCCC2)c(=O)[nH]c1=O
Reactant: CC(C)c1ccc(CCl)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: CC(C)c1ccc(Cn2c(=O)c(C(=O)NCC(=O)O)c(O)n(C3CCCCC3)c2=O)cc1
Reaction time: 8 h
Yield: 36.3 %

Procedure:
A mixture of ethyl N-[(1-cyclohexyl-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl)carbonyl]glycinate (340 mg, 1.0 mmoles), pulv. Potassium carbonate (1.0 g, 7.24 mmoles) and 4-isopropylbenzyl chloride (250 mg, 1.5 mmoles) in dimethylacetamide (5 mL) was vigorously stirred at 100° C. for 3 hours. The mixture was poured into 1 molar hydrochloric acid and extracted with ethyl acetate. The organic solution was washed with 1 molar hydrochloric acid and evaporated. The residue was purified by flash chromatography (10-50% ethyl acetate in hexane), the required fractions evaporated, dissolved in ethanol (5 mL) and 1 molar sodium hydroxide solution (1.0 mL) and 6 molar sodium hydroxide solution (1.0 mL) added. The mixture was stirred overnight, acidified and extracted with ethyl acetate (×2), the combined extracts washed with 1 molar hydrochloric acid, dried and evaporated to give the title compound (161 mg, 36%). 1H NMR (400 MHz, DMSO-d6) δ ppm 13.10 (s, 1 H), 10.14 (s, 1 H), 7.16-7.24 (m, 4 H), 4.95 (s, 2 H), 4.64 (t, J=11.37 Hz, 1 H), 4.13 (d, J=5.56 Hz, 2 H), 2.79-2.90 (m, J=6.86, 6.86, 6.86, 6.86, 6.86, 6.86 Hz, 1 H), 2.20-2.32 (m, 2 H), 1.78 (d, J=12.88 Hz, 2 H), 1.62 (d, J=11.12 Hz, 3 H), 1.22-1.34 (m, 2 H), 1.09-1.20 (m, 7 H).
Reaction SMILES: Br[CH2:2][CH2:3]Br.Cl.[CH3:6][O:7][C:8](=[O:15])[C@@H:9]([C:11]([SH:14])([CH3:13])[CH3:12])[NH2:10].N12CCCN=C1CCCCC2.C([O-])(O)=O.[Na+]>CN(C=O)C>[CH3:12][C:11]1([CH3:13])[S:14][CH2:3][CH2:2][NH:10][C@H:9]1[C:8]([O:7][CH3:6])=[O:15]
Reactant: BrCCBr
Reactant: COC(=O)[C@H](N)C(C)(C)S
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: COC(=O)[C@@H]1NCCSC1(C)C
Reaction time: 2.5 h
Yield: 87.1 %

Procedure:
To a stirred solution of 5.15 mL (59.8 mmol) of 1,2-dibromoethane in 50 mL of DMF at room temperature was added over 45 min a solution of 10 g (50 mmol) of D-penicillamine methyl ester hydrochloride and 22.5 mL (150.45 mmol) of 1,8-diazabicyclo[5.4.0]undec-7-ene in 100 mL of DMF. The reaction was stirred for 2.5 h, poured into a solution of saturated NaHCO3 and extracted with ethyl acetate. The organics were washed with brine, dried over MgSO4, filtered and concentrated in vacuo to provide 8.24 g (87%) of methyl(3S)-2,2-dimethyl-3-thiomorpholine carboxylate as a pale yellow oil. Electrospray Mass Spec: 190.1 (M+H)+.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:16](Cl)(=[O:22])/[CH:17]=[CH:18]/[C:19](Cl)=[O:20]>C(Cl)Cl>[CH2:9]([N:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:16](=[O:22])/[CH:17]=[CH:18]/[C:19]([N:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:20])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: c1ccc(CNCc2ccccc2)cc1
Reactant: O=C(Cl)/C=C/C(=O)Cl
Solvent: ClCCl
Product: O=C(/C=C/C(=O)N(Cc1ccccc1)Cc1ccccc1)N(Cc1ccccc1)Cc1ccccc1
Reaction time: 0.08 h
Yield: 94.3 %

Procedure:
To a cooled (−5° C.) solution of N,N-dibenzylamine (19.3 mL, 100 mmol) in DCM (200 mL) is added TEA (13.8 mL, 100 mmol). To this solution is added, drop wise over 5 minutes, fumaroyl chloride (4.2 mL, 40 mmol). On complete addition, the cold bath is removed and stirring continued for 1 hr. This solution is diluted with DCM, washed with HCl (approx. 100 mL of 1M aq.) then water (2×), dried over MgSO4 and concentrated. The solid residue is crystallized from hot (109° C.) toluene to give the title compound (17.9 g) as a white solid. ESI-MS (m/z) 475 (MH)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([OH:11])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.[H-].[Na+].Br[C:15]1[CH:16]=[N:17][CH:18]=[C:19]([Br:21])[CH:20]=1>CN(C)C=O>[Br:21][C:19]1[CH:18]=[N:17][CH:16]=[C:15]([O:11][C:5]2[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)[CH:20]=1
Reactant: COc1cc(O)cc(OC)c1
Reactant: Brc1cncc(Br)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(OC)cc(Oc2cncc(Br)c2)c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 98.9 %

Procedure:
Under an argon atmosphere, a solution of 3,5-dimethoxyphenol (6.94 g, 45 mmol) in dimethylformamide (30 mL) was added slowly to a stirred suspension of sodium hydride (1.44 g of a 75% suspension in mineral oil, 0.045 mol) in dimethylformamide (30 mL) at 0–5° C. The icebath was removed and the resulting mixture was stirred for 2.5 h at room temperature. 3,5-Dibromopyridine (7.11 g, 0.03 mol) was added to the mixture, which was then heated to 100° C. for 72 h, then the mixture was cooled to room temperature and successively washed with water (100 mL) and 5 N NaOH solution (10 mL). The mixture was extracted with diethyl ether (3×50 mL). The combined organic phases were dried (MgSO4), filtered and concentrated by rotary evaporation to give 9.2 g of a white solid, which was purified by column chromatography, eluting with cyclohexane/ethyl acetate (90/10, v/v). Selected fractions containing the product were concentrated via rotary evaporation to give 2.5 g (29%) of a yellow oil.
Reaction SMILES: C(OC[N:10]1[C:18]2[C:17](=[O:19])[N:16]([CH3:20])[CH2:15][N:14]([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=3[Cl:28])[C:13]=2[N:12]=[C:11]1[CH2:29][CH3:30])C1C=CC=CC=1.FC(F)(F)C(O)=O>C(Cl)(Cl)Cl>[Cl:28][C:22]1[CH:23]=[C:24]([Cl:27])[CH:25]=[CH:26][C:21]=1[N:14]1[C:13]2[N:12]=[C:11]([CH2:29][CH3:30])[NH:10][C:18]=2[C:17](=[O:19])[N:16]([CH3:20])[CH2:15]1
Reactant: CCc1nc2c(n1COCc1ccccc1)C(=O)N(C)CN2c1ccc(Cl)cc1Cl
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: CCc1nc2c([nH]1)C(=O)N(C)CN2c1ccc(Cl)cc1Cl
Temperature: 80 °C
Yield: 94.8 %

Procedure:
A solution of 7-benzyloxymethyl-3-(2,4-dichlorophenyl)-8-ethyl-1-methyl-1,2,3,7-tetrahydro-6H-purin-6-one (1.3 g, 2.92 mmol), prepared by the method described in example 7, in CHCl3 (2 mL) was treated with trifluoroacetic acid (15 mL). The solution was heated at 80° C. in a pressure tube for 5 h. The mixture was then cooled to rt and was concentrated. The residue was concentrated from heptane (2×), transferred into a separatory funnel containing saturated aqueous NaHCO3 (75 mL), and the aqueous layer was extracted with EtOAc (3×50 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated. The residue was purified by column chromatography on silica gel (3% methanol in CH2Cl2) to furnish 3-(2,4-dichlorophenyl)-8-ethyl-1-methyl-1,2,3,7-tetrahydro-6H-purin-6-one (900 mg, 95% yield) as a colorless solid: mp 200-201° C.; 1H NMR (300 MHz, CDCl3) δ 12.05 (s, 1H), 7.47 (d, J=2.2 Hz, 1H), 7.20 (dd, J=8.8, 2.6 Hz, 1H), 7.12 (d, J=8.4 Hz, 1H), 4.90 (s, 2H), 3.02 (s, 3H), 2.79 (q, J=7.7 Hz, 2H), 1.34 (t, J=7.7 Hz, 3H); LRMS (APCI) m/e 325.0 [(M+H)+, calcd for C14H15N15OCl2 325.1].
Reaction SMILES: [Na].[N:2]1([C:8]([NH2:10])=[NH:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[C:11]([O:15][C:16]([N:18]1[CH2:23][CH2:22][CH:21]([C:24](=O)[CH2:25][C:26](OCC)=[O:27])[CH2:20][CH2:19]1)=[O:17])([CH3:14])([CH3:13])[CH3:12]>C(O)C>[C:11]([O:15][C:16]([N:18]1[CH2:19][CH2:20][CH:21]([C:24]2[CH:25]=[C:26]([OH:27])[N:10]=[C:8]([N:2]3[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]3)[N:9]=2)[CH2:22][CH2:23]1)=[O:17])([CH3:14])([CH3:13])[CH3:12]
Reactant: CCOC(=O)CC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: N=C(N)N1CCCCC1
Agent: [Na]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(c2cc(O)nc(N3CCCCC3)n2)CC1
Temperature: 25 °C
Yield: 44.1 %

Procedure:
Sodium (1 mol) was dissolved in anhydrous ethanol (400 mL). To the obtained solution, Piperidine-1-carboxamidine (0.5 mol) was carefully added in portions. Then 4-(2-ethoxycarbonyl-acetyl)-piperidine-1-carboxylic acid tert-butyl ester (0.5 mol) was added dropwise, and the mixture was stirred at reflux for 4-6 h (monitored by TLC), cooled to room temperature, concentrated, diluted with water (300 mL) and acidified with acetic acid to pH-4. The formed precipitate was collected by filtration, washed with water and dried to afford 4-(6-hydroxy-2-piperidin-1-yl-pyrimidin-4-yl)-piperidine-1-carboxylic acid tertbutyl ester (80 g, 44%).