Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([C:13]#[N:14])=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]=1[C:15]([O:17]C)=[O:16].O[Li].O.O.CO>C(=O)(O)[O-].[Na+]>[CH3:1][O:2][C:3]1[C:12]([C:13]#[N:14])=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]=1[C:15]([OH:17])=[O:16]
Reactant: COC(=O)c1c(OC)c(C#N)cc2ccccc12
Agent: O=C([O-])O
Agent: [Li]O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1c(C#N)cc2ccccc2c1C(=O)O

Procedure:
A solution of methyl 2-methoxy-3-cyano-1-naphthoate (0.113 g) and LiOH.H2O (0.0196 g) THF (3 mL), water (1 mL) and methanol (1 mL) was stirred overnight at room temperature. The solution was diluted with saturated sodium bicarbonate and extracted with Et2O. The aqueous layer was acidified to pH 2 by addition of 1N HCl and extracted with Et2O. The organic layer was washed with water (30 mL) and brine (40 mL), dried (sodium sulfate), filtered, and concentrated to a white solid. 1H NMR (DMSO-d6): δ14.06 (broad, 1 H), 8.08-8.02 (m, 1 H), 7.83-7.76 (m, 2 H), 7.69-7.63 (m, 1 H), 4.02 (s, 3 H); MS m/z: 226 (M−1).
Reaction SMILES: [H-].[Na+].[NH2:3][CH:4]=[CH:5][C:6](=[O:11])[C:7]([F:10])([F:9])[F:8].CO[CH:14]=[CH:15][C:16]#[N:17].Cl>CN(C)C=O.O>[F:8][C:7]([F:10])([F:9])[C:6](=[O:11])[CH:5]=[CH:4][NH:3][CH:14]=[CH:15][C:16]#[N:17]
Reactant: NC=CC(=O)C(F)(F)F
Reactant: COC=CC#N
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: N#CC=CNC=CC(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h
Yield: 43.1 %

Procedure:
Sodium hydride (60% dispersion in mineral oil suspension, 4.00 g, 100 mmol) was added and washed with hexane twice. Into this flask, N,N-dimethylformamide (100 ml) was added and then a solution prepared by dissolving 4-amino-1,1,1-trifluoro-3-buten-2-one (13.9 g, 100 mmol) and 3-methoxyacrylonitrile (8.30 g, 100 mmol) in N,N-dimethylformamide (50 ml) was added dropwise under ice-cooling. After stirring the mixture at room temperature for 3 hours, the reaction mixture was poured into water (500 ml). This mixture was acidified with concentrated hydrochloric acid under ice-cooling, the precipitate was collected by filtration and then washed with cold water. The obtained precipitate was dried under reduced pressure to obtain 8.20 g (yield 43.1%) of a mixture of compounds (IIa) and (IIb).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.Br[CH2:16][CH2:17][O:18][CH3:19].[H-].[Na+]>C1COCC1>[CH3:19][O:18][CH2:17][CH2:16][N:12]1[CH:13]=[C:9]([B:4]2[O:5][C:6]([CH3:7])([CH3:8])[C:2]([CH3:14])([CH3:1])[O:3]2)[CH:10]=[N:11]1
Reactant: COCCBr
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCCn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Temperature: 25 °C

Procedure:
A mixture of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (200 mg, 1.03 mmol), 1-bromo-2-methoxyethane (280 mg, 2.01 mmol), and NaH (200 mg, 4 mmol) in THF (15 mL) was stirred at reflux for 24 hours, cooled to the ambient temperature, and concentrated in vacuo. The residue was treated with HCl(aq) and extracted with EtOAc. The insoluble solid was removed by filtration, and the organic solution was concentrated to give the title compound. MS (m/z): 253 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:10]=[N:11][NH:12][CH:13]=2)[O:3]1.Br[CH2:16][CH2:17][O:18][CH3:19].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH3:19][O:18][CH2:17][CH2:16][N:12]1[CH:13]=[C:9]([B:4]2[O:5][C:6]([CH3:7])([CH3:8])[C:2]([CH3:14])([CH3:1])[O:3]2)[CH:10]=[N:11]1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COCCn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (19.4 g, 0.10 mol), 1-bromo-2-methoxy-ethane (14.18 ml, 0.15 mol), and caesium carbonate (32.58 g, 0.1 mol) are dissolved in DMF (200 ml). The suspension is stirred for 16 h at 80° C., filtered and the solvent is removed in vacuum. The residue is treated with tert-butyl methyl ether (200 ml), filtered over Celite and then the solvent is removed in vacuum; yield: 25.4 g 1-(2-methoxy-ethyl)-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole; HPLC/MS: 1.82 min, [M+H]=253.
Reaction SMILES: [Br:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][C@@:7]23[CH2:14][C@H:13]([O:15]C(=O)C)[CH2:12][N:11]2[C:10](=[O:19])[N:9]([C:20]2[CH:25]=[C:24]([Cl:26])[CH:23]=[C:22]([Cl:27])[CH:21]=2)[C:8]3=[O:28])=[CH:4][CH:3]=1.O.[Li+].[OH-]>C1COCC1.CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C@@:7]23[CH2:14][C@H:13]([OH:15])[CH2:12][N:11]2[C:10](=[O:19])[N:9]([C:20]2[CH:21]=[C:22]([Cl:27])[CH:23]=[C:24]([Cl:26])[CH:25]=2)[C:8]3=[O:28])=[CH:29][CH:30]=1
Reactant: CC(=O)O[C@@H]1CN2C(=O)N(c3cc(Cl)cc(Cl)c3)C(=O)[C@]2(Cc2ccc(Br)cc2)C1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=C1N(c2cc(Cl)cc(Cl)c2)C(=O)[C@]2(Cc3ccc(Br)cc3)C[C@H](O)CN12
Reaction time: 4 h
Yield: 47.4 %

Procedure:
To a solution of (5S,7S)-5-(4-bromobenzyl)-3-(3,5-dichlorophenyl)-7-acetoxy-1,3-diazabicyclo[3.3.0]octane-2,4-dione (0.10 g) in THF (5 in L), MeOH (0.10 mL), and water (0.10 mL) was added 2N LiOH (0.11 mL). After 4 hours, the mixture was quenched with acetic acid (0.10 mL) and concentrated. Purification by chromatography (Silica gel: 4% methanol/CH2Cl2, Chromatotron) afforded the titled compound (0.0435 g). MS (m/z) 469 (MH+), mp 88.3° C.
Reaction SMILES: [C:1]1([C:7]2([C:13]#[N:14])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[C:1]1([C:7]2([CH2:13][NH2:14])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N#CC1(c2ccccc2)CCCCC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: NCC1(c2ccccc2)CCCCC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of 1-phenyl-cyclohexanecarbonitrile (11.0 g; 59 mmol) in tetrahydrifuran (100 mL) was cooled to 0° C. and treated with lithium aluminum hydride (11 g, 289 mmol) in several portions over the course of 0.5 h. When the addition of lithium aluminum hydride was complete the cooling bath was removed and the reaction mixture was allowed to stir at room temperature for 12 h. The reaction mixture was cooled back to 0° C. and carefully quenched by dropwise addition of 2 N NaOH (approximately 20 mL), diluted with ethyl ether, filtered through a celite plug and dried (magnesium sulfate). C-(1-Phenyl-cyclohexyl)-methylamine was obtained as a colorless oil which was used without further purification. LCMS m/z=190.2 (M+H)+
Reaction SMILES: [OH:1][CH2:2][C:3]1[S:7][CH:6]=[N:5][CH:4]=1.CN1CCOCC1.Cl[C:16]([O:18][C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=1)=[O:17]>C(Cl)Cl.C(Cl)(Cl)Cl>[CH:23]1[C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=[C:19]([O:18][C:16]([O:1][CH2:2][C:3]2[S:7][CH:6]=[N:5][CH:4]=2)=[O:17])[CH:24]=1
Reactant: OCc1cncs1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: ClC(Cl)Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: O=C(OCc1cncs1)Oc1ccc([N+](=O)[O-])cc1
Reaction time: 1 h
Yield: 78 %

Procedure:
A solution of 3.11 g (27 mmol) of 5-(hydroxymethyl)thiazole and excess N-methyl morpholine in 100 ml of methylene chloride was cooled to 0° C. and treated with 8.2 g (41 mmol) of 4-nitrophenyl chloroformate. After being stirred for 1 h, the reaction mixture was diluted with CHCl3, washed successively with 1N HCl, saturated aqueous NaHCO3, and saturated brine, dried over NaSO4, and concentrated in vacuo. The residue was purified by silica gel chromatography (SiO2, 1-2% MeOH/CHCl3, Rf=0.5 in 4% MeOH/CHCl3) to yield 5.9 g (78%) of the desired compound as a yellow solid. NMR (CDCl3) δ5.53 (s, 2H), 7.39 (dt, J=9, 3 Hz, 2H), 8.01 (s, 1H), 8.29 (dt, J=9, 3 Hz, 2H), 8.90 (s, 1H). Mass spectrum: (M+H)+ =281.
Reaction SMILES: N[C:2]1[C:3]([F:13])=[C:4]([CH:8]=[C:9]([F:12])[C:10]=1[F:11])[C:5]([OH:7])=[O:6].[ClH:14].N([O-])=O.[Na+]>O>[Cl:14][C:2]1[C:3]([F:13])=[C:4]([CH:8]=[C:9]([F:12])[C:10]=1[F:11])[C:5]([OH:7])=[O:6]
Reactant: Cl
Reactant: Nc1c(F)c(F)cc(C(=O)O)c1F
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: O=C(O)c1cc(F)c(F)c(Cl)c1F
Yield: 83 %

Procedure:
3-Amino-2,4,5-trifluorobenzoic acid (Example 2), 0.52 g, and 3 g of cupric chloride are added to 10 ml of a 3% aqueous solution of hydrochloric acid and the mixture is stirred with ice bath cooling. A solution of 0.32 g of sodium nitrite in 4 ml of water is added to the reaction mixture in portions over a one-hour period while maintaining the reaction at 0°-5° C. The ice bath is then removed and the mixture is stirred for two hours at room temperature. Toluene, 20 ml, and 15 ml of water are added with stirring. The layers are separated and the aqueous layer extracted with 20 ml of toluene. The combined toluene extracts are extracted with 4 ml of a 36% aqueous solution of hydrochloric acid and then concentrated to a solid under reduced pressure to give 0.48 g (83%) of 3-chloro-2,4,5-trifluorobenzoic acid as a tan solid; GC (98.4%); HPLC (89.2%); recrystallization from heptanes gives 0.40 g (70%) of 3-chloro-2,4,5-trifluorobenzoic acid; mp 109°-111° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:16]([OH:18])=O)[CH2:10][C:11]1[N:15]=[CH:14][NH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:19]([O:21][C:22]([N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)=[O:23])[CH3:20].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>C1COCC1.C(OCC)(=O)C>[CH2:19]([O:21][C:22]([N:24]1[CH2:25][CH2:26][N:27]([C:16]([CH:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:10][C:11]2[N:15]=[CH:14][NH:13][CH:12]=2)=[O:18])[CH2:28][CH2:29]1)=[O:23])[CH3:20]
Reactant: CCOC(=O)N1CCNCC1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1c[nH]cn1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)N1CCN(C(=O)C(Cc2c[nH]cn2)NC(=O)OC(C)(C)C)CC1
Reaction time: 8 h

Procedure:
To a solution of N-t-butoxycarbonylhistidine (2 g, 7.05 mmol) in THF (30 mL) was added 1-ethoxycarbonylpiperazine (1.36 mL, 1.3 eq.), EDCI (1.65 g, 1.2 eq. ), HOBt (1.2 g, 1.1 eq.) and the reaction mixture was stirred overnight. The reaction mixture was evaporated in vacuo to afford a crude product, which was dissolved in ethyl acetate, washed with saturated NaHCO3, 1M NaHSO4 and brine. The organic layer was evaporated. Flash column chromatography with 2%–6% MeOH in CH2Cl2 afforded 4-ethoxycarbonyl-1-(1-(t-butoxycarbonyl)amino-2-(imidazol-4-yl)ethyl)carbonylpiperazine (820 mg). 4-Ethoxycarbonyl-1-(1-(t-butoxycarbonyl)amino-2-(imidazol-4-yl)ethyl)carbonylpiperazine (200 mg, 0.5 mmol) was treated with trifluoroacetic acid/methylene chloride (1:1, 2.0 mL) with stirring at ambient temperture for 1 hour. Evaporation gave 4-ethoxycarbonyl-1-(1-amino-2-(imidazol-4-yl)ethyl)carbonylpiperazine, which was treated with methylene chloride and triethylamine (0.5 mL), and the solvents evaporated to again afford 4-ethoxycarbonyl-1-(1-amino-2-(imidazol-4-yl)ethyl)carbonylpiperazine. To a solution of 2-carboxy-4-methoxyquinoline (124 mg, 0.61 mmol) in THF (4 mL) was added a mixture of 4-ethoxycarbonyl-1-(1-amino-2-(imidazol-4-yl)ethyl)carbonylpiperazine, THF (2 mL), and triethylamine (0.1 mL), followed by addition of EDCI (136 mg, 1.4 eq.), HOBt (98 mg, 1.4 eq.). The resulting mixture was stirred overnight. The crude product (245 mg, foam) was isolated from the reaction mixture by the same methods employed above. Flash column chromatography with 25%–6% MeOH in methylene chloride afforded 2-[1-(4-(ethoxycarbonyl)piperazin-1-yl)carbonyl-2-(imidazol-4-yl)ethyl]aminocarbonyl-4-methoxyquinoline; NMR (CDCl3) 1.25 (t, 3), 3.10–3.30 (m, 2), 3.20–3.65 (m, 9), 4.10 (m, 5), 5.40 (m, 1), 6.90 (s, 1), 7.55–7.60 (m, 3), 7.70 (t, 1), 8.02 (d, 1), 8.20 (d, 1), 9.0 (d, 1) ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[O:10])=[CH:4][CH:3]=1.[C:11](OC)(=[O:19])[C:12]1[C:13](=[CH:15][CH:16]=[CH:17][CH:18]=1)[NH2:14].C[O-].[Na+]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:11](=[O:19])[C:12]3[C:13](=[CH:15][CH:16]=[CH:17][CH:18]=3)[NH:14][C:9]2=[O:10])=[CH:4][CH:3]=1
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: COC(=O)c1ccccc1N
Agent: C[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: O=c1[nH]c2ccccc2c(=O)n1-c1ccc(Cl)cc1
Temperature: 90 °C
Reaction time: 2 h
Yield: 98.3 %

Procedure:
A solution of p-chlorophenyl isocyanate (15.3 g, 0.10 mol) in toluene (50 ml) is metered at room temperature into a solution of methyl anthranilate (15.1 g, 0.10 mol) in toluene (100 ml). After addition is complete, the mixture is stirred at 90° C. for 2 hours. 1.80 ml of a 30% strength solution of methanolic sodium methoxide (0.010 mol) are metered in and the mixture is stirred at 90° C. for a further 1 hour, methanol being distilled off. After cooling, the product is filtered off with suction and washed with 3×20 ml of toluene. The toluene-moist precipitate is treated with dilute sulfuric acid and the residual toluene is removed by azeotropic distillation. The product is then filtered off with suction, washed with water and dried. 26.8 g of 3-(4-chlorophenyl)-2,4(1H,3H)-quinazolinedione (yield: 98.3% of theory) of melting point 290° to 292° C. are obtained.
Reaction SMILES: C[O:2][C:3](=[O:22])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=2)=[CH:6][CH:5]=1.[OH-].[Na+].Cl>O1CCCC1.CO.[Cl-].[Na+].O>[N:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:20]=[CH:21][C:12]=1[CH2:11][O:10][C:7]1[CH:8]=[CH:9][C:4]([C:3]([OH:22])=[O:2])=[CH:5][CH:6]=1
Reactant: COC(=O)c1ccc(OCc2ccc3ccccc3n2)cc1
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1ccc(OCc2ccc3ccccc3n2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 97.5 %

Procedure:
To a solution of 4-(Quinolin-2-ylmethoxy)-benzoic acid methyl ester (500 mg, 1.7 mmole) in tetrahydrofuran (8.5 ml) and methanol (3 ml) was added 1N NaOH (3.4 ml, 2 eq.). The reaction mixture was stirred at ambient temperature for 16 h. To the reaction mixture was added 50 ml of brine and the pH was adjusted to 3 with 1 N HCl to provide a white precipitate which was filtered and dried to provide the title compound as a white solid (463 mg, 98%). 1H NMR (400 MHz, DMSO) δ 8.39 (d, J=8.3 Hz, 1H), 7.99 (m, 2H), 7.81 (M, 2H), 7.76 (dt, J=8.3, 1.7 Hz, 1H), 7.64 (d, J=8.3 Hz, 1H), 7.60 (dt, J=7.9, 1.3 Hz, 1H), 7.12 (M, 2H), 5.41 (s, 2H); MS: (M+H m/z=280.2).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[CH3:10])[C:5]#[N:6].[Br:11]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N.O>C(Cl)(Cl)(Cl)Cl>[Br:11][CH2:10][C:9]1[CH:8]=[CH:7][C:4]([C:5]#[N:6])=[CH:3][C:2]=1[Cl:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(C#N)cc1Cl
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: O
Solvent: ClC(Cl)(Cl)Cl
Product: N#Cc1ccc(CBr)c(Cl)c1
Yield: 98.1 %

Procedure:
A mixture of 3-chloro-4-methylbenzonitrile (7.5 g, 50 mmol, 1.0 equiv), N-bromosuccinimide (9.14 g, 52 mmol, 1.1 equiv), and azobisisobutyronitrile (AIBN, 0.82 g, 5 mmol, 0.1 equiv) in carbon tetrachloride was heated to reflux temperature for 25 h. Water (50 mL) was added, and the product was extracted with CH2Cl2. The organic layers were washed with water, dried with MgSO4, and evaporated to provide 11.3 g of the title compound. This material was used in the next step without purification.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9].CN(C)[CH:13]=[O:14]>>[CH3:13][O:14][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9]
Reactant: O=C(O)CCCCCCBr
Reactant: CN(C)C=O
Product: COCCCCCCC(=O)O

Procedure:
The title compound was prepared by the method of Example 1 using 7-bromoheptanoic acid (50 g, 239 mmol) instead of 12-bromoundecanoic acid and dimethylformamide (300 mL) instead of methanol as the solvent. Concentration afforded the title compound (30 g) as a pale yellow liquid and the structure verified by NMR.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([S:8][CH3:9])[CH:3]=1.[Br:10]Br>ClCCl.[Fe]>[Br:10][C:7]1[CH:6]=[CH:5][C:4]([S:8][CH3:9])=[CH:3][C:2]=1[CH3:1]
Reactant: BrBr
Reactant: CSc1cccc(C)c1
Agent: [Fe]
Solvent: ClCCl
Product: CSc1ccc(Br)c(C)c1
Temperature: 3 °C
Reaction time: 0.17 h
Yield: 40 %

Procedure:
Combine iron (25 mg, 0.45 mmol) and 1-methyl-3-methylsulfanyl-benzene (204 mg, 1.47 mmol) in dichloromethane (DCM, 2 mL). Cool the slurry to 3° C. and add Br2 (74 μL, 1.44 mmol) over 5 minutes. Stir at 3° C. for 10 minutes and remove the external cooling bath. Stir at room temperature for 4 hours, then quench with 10% aqueous Na2SO3 solution. Dilute the reaction with dichloromethane (10 mL) and separate. Wash the organic layer with brine, concentrate and chromatograph with dichloromethane in hexanes (0 to 5%) to give 125 mg of 1-bromo-2-methyl-4-methylsulfanyl-benzene (53%).
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Br:13])[N:8]=1.CN([CH:17]=[O:18])C.[NH4+].[Cl-]>C(OCC)(=O)C.CCCCCC.C1COCC1>[Br:13][C:9]1[N:8]=[C:7]([CH:17]=[O:18])[CH:12]=[CH:11][CH:10]=1
Reactant: Brc1cccc(Br)n1
Reactant: CN(C)C=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=Cc1cccc(Br)n1
Temperature: -70 °C
Reaction time: 0.25 h
Yield: 38.2 %

Procedure:
A three necked 100 mL round-bottomed flask with magnetic stirring, an immersion thermometer, and an addition funnel was charged with THF (30 mL) and cooled to −78° C. n-butyllithium (1.35 g, 21.10 mmol) was carefully added to the reaction maintaining an internal temperature of −70° C. After the addition of 2,6-dibromopyridine (5.0 g, 21.10 mmol), the resulting dark green solution was stirred for 15 min, then neat DMF (2.31 g, 31.66 mmol) was added over a period of 30 seconds. The reaction mass was stirred for 15 min at −70° C. The progress of the reaction was monitored by TLC analysis on silica gel with ethyl acetate:hexane (3:7) as mobile phase. Reaction mixture was poured into saturated NH4Cl (50 mL) and extracted with EtOAc (3×50 mL). The combined organic layers were washed with brine solution (3×50 mL), dried over MgSO4, filtered, and concentrated by rotary evaporation to afford 5.0 g of crude compound which was purified by chromatography. Product elute at 3% ethyl acetate in hexane to give 1.5 g of pure product (Yield 38.4%).
Reaction SMILES: [C:1]([NH:8][C:9]([NH2:11])=[S:10])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[Cl:12][CH2:13][C:14]([CH2:16]Cl)=O.C([O-])(O)=O.[Na+].CCOC(C)=O.CCCCCCC>CC(C)=O>[C:1]([NH:8][C:9]1[S:10][CH:16]=[C:14]([CH2:13][Cl:12])[N:11]=1)([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2]
Reactant: O=C(CCl)CCl
Reactant: CC(C)(C)OC(=O)NC(N)=S
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)Nc1nc(CCl)cs1
Temperature: 25 °C
Reaction time: 72 h
Yield: 68.2 %

Procedure:
To a solution of Intermediate VII (3.0 g, 17 mmol) in acetone (75 mL) was added 1,3-dichloroacetone (2.4 g, 18.7 mmol) at once. The mixture was stirred at room temperature for 72 h. The reaction mixture was treated with NaHCO3 (3 g) and stirred for 15 min. The solids were removed by filtration and the filtrate was concentrated in vacuo. Column chromatography (EtOAc/Heptane, 4/1) afforded N-Boc-4-(chloromethyl)thiazol-2-amine (2.9 g, 11.6 mmol, 68%) as a white solid.
Reaction SMILES: [NH:1]1[CH:8]=[CH:7][C:5](=[O:6])[NH:4][C:2]1=[O:3].[CH2:9]=[O:10].[OH-].[K+]>O>[OH:10][CH2:9][C:7]1[C:5](=[O:6])[NH:4][C:2](=[O:3])[NH:1][CH:8]=1
Reactant: O=c1cc[nH]c(=O)[nH]1
Reactant: C=O
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: O=c1[nH]cc(CO)c(=O)[nH]1
Temperature: 50 °C
Yield: 81 %

Procedure:
A mixture of uracil (9 g, 80.3 mmol), paraformaldehyde (3 g) and 0.42N potassium hydroxide (125 mL) was heated 90 hours at 50° C. The reaction mixture was diluted with water (350 mL), stirred with Dowex® 50 ion-exchange resin (30 g, H form, 100-200 mesh), filtered, concentrated in vacuo to a volume of 20 mL and refrigerated. The solids were collected and recrystallized from water (50 mL) to give 5-hydroxymethyl-2,4(1H,3H)-pyrimidinedione (9.5 g, 65.04 mmol), m.p. 260°-300° C. (dec).
Reaction SMILES: [C:1]([N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][CH:12]=2)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].O.O.[Sn](Cl)Cl.Cl>CO>[C:1]([N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:12]=[CH:13][C:14]([NH2:17])=[CH:15][CH:16]=2)[CH2:7][CH2:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)N1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CO
Product: CC(C)(C)N1CCN(c2ccc(N)cc2)CC1
Temperature: 40 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
1-tert-Butyl-4-(4-nitro-phenyl)-piperazine (348 mg, 1.32 mmol) is dissolved in MeOH (10 mL) and tin (II) dichloride dihydrate (1.08 g, 4.79 mmol) is added. The mixture is cooled using a water bath and conc. HCl is added (3 mL). The reaction is stirred at 40° C. overnight. After removing the methanol, the resultant solution is basified using conc. NaOH (pH 11). The water phase is extracted with diethyl ether (3×) and the organic layers combined, dried over MgSO4, filtered, concentrated in vacuo to afford the title compound (308 mg, 99%) which is used in the next step without further purification. LCMS: Rt 2.16 min (87%)
Reaction SMILES: [Mg].[C:2]([O:10][CH2:11][CH3:12])(=[O:9])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].C(=O)=O.CC(C)=O.[F:20][C:21]1[C:29]([F:30])=[C:28]([F:31])[C:27]([F:32])=[CH:26][C:22]=1[C:23](Cl)=[O:24].S(=O)(=O)(O)O>C(O)C.C1(C)C=CC=CC=1.C(Cl)(Cl)(Cl)Cl>[F:20][C:21]1[C:29]([F:30])=[C:28]([F:31])[C:27]([F:32])=[CH:26][C:22]=1[C:23]([CH:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[C:2]([O:10][CH2:11][CH3:12])=[O:9])=[O:24]
Reactant: O=C(Cl)c1cc(F)c(F)c(F)c1F
Reactant: CCOC(=O)CC(=O)OCC
Agent: O=C=O
Agent: O=S(=O)(O)O
Agent: [Mg]
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCO
Solvent: CC(C)=O
Product: CCOC(=O)C(C(=O)OCC)C(=O)c1cc(F)c(F)c(F)c1F
Temperature: 0 °C
Reaction time: 1 h
Yield: 99.7 %

Procedure:
24.3 g of magnesium turnings are suspended in 50 ml of anhydrous ethanol. 5 ml of carbon tetrachloride are added and, when the reaction has started, a mixture of 160 g of diethyl malonate, 100 ml of absolute ethanol and 400 ml of anhydrous toluene are added dropwise at 50°-60° C. The mixture is then heated at 50°-60° C. for a further 1 hour, cooled with dry ice/acetone to -5° C. to -10° C. and a solution of 212.5 g of 2,3,4,5-tetrafluorobenzoyl chloride in 80 ml of absolute toluene is slowly added dropwise at this temperature. The mixture is stirred at 0° to -5° C. for 1 hour, allowed to reach room temperature overnight, and is then run into a mixture of 400 ml of ice-water and 25 ml of concentrated sulphuric acid while cooling in ice. The phases are separated and two further extractions with toluene are carried out. The combined toluene solutions are washed with saturated NaCl solution, dried with Na2SO4, and the solvent is removed in vacuo. 335 g of diethyl 2,3,4,5-tetrafluorobenzoylmalonate are obtained as a crude product.
Reaction SMILES: [CH:1]1([C:4]2[N:14]([CH2:15][C:16]3[S:20][C:19]([C:21]4([C:26]([OH:28])=[O:27])[CH2:25][CH:24]=[CH:23][CH2:22]4)=[CH:18][CH:17]=3)[C:7]3=[N:8][C:9]([CH3:13])=[CH:10][C:11]([CH3:12])=[C:6]3[N:5]=2)[CH2:3][CH2:2]1.[F:29][C:30]([F:36])([F:35])[S:31]([NH2:34])(=[O:33])=[O:32]>>[F:29][C:30]([F:36])([F:35])[S:31]([NH2:34])(=[O:33])=[O:32].[CH:1]1([C:4]2[N:14]([CH2:15][C:16]3[S:20][C:19]([C:21]4([C:26]([OH:28])=[O:27])[CH2:25][CH:24]=[C:23]=[CH:22]4)=[CH:18][CH:17]=3)[C:7]3=[N:8][C:9]([CH3:13])=[CH:10][C:11]([CH3:12])=[C:6]3[N:5]=2)[CH2:2][CH2:3]1
Reactant: Cc1cc(C)c2nc(C3CC3)n(Cc3ccc(C4(C(=O)O)CC=CC4)s3)c2n1
Agent: NS(=O)(=O)C(F)(F)F
Product: Cc1cc(C)c2nc(C3CC3)n(Cc3ccc(C4(C(=O)O)C=C=CC4)s3)c2n1

Procedure:
The title compound was prepared from the product of Example 3, by the method of Example 25, except that trifiuoromethanesulfonamide was used in place of benzenesulfonamide.