Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[CH2:2][C:3]1[N:4]([CH2:9][CH2:10][CH3:11])[C:5]([CH3:8])=[CH:6][N:7]=1.S(Cl)([Cl:14])=O>>[ClH:14].[Cl:14][CH2:2][C:3]1[N:4]([CH2:9][CH2:10][CH3:11])[C:5]([CH3:8])=[CH:6][N:7]=1
Reactant: CCCn1c(C)cnc1CO
Reactant: O=S(Cl)Cl
Product: CCCn1c(C)cnc1CCl
Product: Cl
Temperature: 90 °C

Procedure:
To 2-hydroxymethyl-5-methyl-1-propylimidazole (2.11 g) was added thionyl chloride (25 ml) at 0° C., and the mixture was heated for 30 minutes under nitrogen atmosphere at 90° C. The mixture was allowed to be at room temperature. The solvent was distilled off under reduced pressure and the obtained residue was dissolved in methanol, and the solvent was distilled off again under reduced pressure. The obtained solid was recrystallized from ethyl acetate, to give 2-chloromethyl-5-methyl-1-propylimidazole hydrochloride (1.04 g) as colorless crystals.
Reaction SMILES: [C:1]([NH:4][CH:5]([CH3:15])[CH2:6][C:7]1[CH:14]=[CH:13][C:10]([CH:11]=O)=[CH:9][CH:8]=1)(=[O:3])[CH3:2].C(O)(=O)[CH2:17][C:18]([OH:20])=[O:19]>>[C:1]([NH:4][CH:5]([CH3:15])[CH2:6][C:7]1[CH:14]=[CH:13][C:10]([CH:11]=[CH:17][C:18]([OH:20])=[O:19])=[CH:9][CH:8]=1)(=[O:3])[CH3:2]
Reactant: O=C(O)CC(=O)O
Reactant: CC(=O)NC(C)Cc1ccc(C=O)cc1
Product: CC(=O)NC(C)Cc1ccc(C=CC(=O)O)cc1

Procedure:
The ester hydrochloride used as starting material is prepared in the following manner: N-acetyl-4-acetylamphetamine (m.p. 99°-100° C.) is oxidized to 4-(2-acetamidopropyl)-benzoic acid (m.p. 207°-208° C.), this is reduced to give 4-(2-acetamidopropyl)-benzyl alcohol (oil) which is then oxidized to 4-(2-acetamidopropyl)-benzaldehyde (m.p. 84°-86° C.) and this is condensed with malonic acid to give 4-(2-acetamidopropyl)-cinnamic acid (m.p. 207°-208° C.) which is hydrogenated to give β-[4-(2-acetamidopropyl)-phenyl]-propionic acid (m.p. 93°-96° C.). Subsequent acid hydrolysis gives the hydrochloride of β-[4-(2-aminopropyl)-phenyl]-propionic acid which is esterified to give the above-mentioned ethyl ester hydrochloride.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][CH:13]([N:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([CH3:21])[CH:3]=1.BrC1C=CC(C(O)=O)=C(C)C=1.N1(C2CCNCC2)CCCC1.BrC1C(C)=C(C(N2CCC(N3CCCC3)CC2)=O)C=CC=1.[F:65][C:66]([F:77])([F:76])[C:67]1[CH:68]=[C:69](B(O)O)[CH:70]=[CH:71][CH:72]=1>>[CH3:21][C:4]1[CH:3]=[C:2]([C:71]2[CH:70]=[CH:69][CH:68]=[C:67]([C:66]([F:77])([F:76])[F:65])[CH:72]=2)[CH:7]=[CH:6][C:5]=1[C:8]([N:10]1[CH2:15][CH2:14][CH:13]([N:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[CH2:12][CH2:11]1)=[O:9]
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Reactant: Cc1cc(Br)ccc1C(=O)N1CCC(N2CCCC2)CC1
Agent: C1CCN(C2CCNCC2)C1
Agent: Cc1c(Br)cccc1C(=O)N1CCC(N2CCCC2)CC1
Agent: Cc1cc(Br)ccc1C(=O)O
Product: Cc1cc(-c2cccc(C(F)(F)F)c2)ccc1C(=O)N1CCC(N2CCCC2)CC1

Procedure:
In analogy to the procedure described for example 1, (4-bromo-2-methyl-phenyl)-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone (prepared from 4-bromo-2-methyl-benzoic acid and 4-pyrrolidin-1-yl-piperidine in analogy to the procedure described for the preparation of intermediate 2) was reacted with 3-trifluoromethyl-phenyl boronic acid to give the title compound as off-white amorphous solid. MS: 417.4 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[O:12].CN(C)C=O.Br[CH2:19][C:20]([O:22][CH3:23])=[O:21]>O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[C:6](=[O:11])[C:5]2=[O:12]
Reactant: COC(=O)CBr
Reactant: O=C1Nc2ccc(Cl)cc2C1=O
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)CN1C(=O)C(=O)c2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 76 %

Procedure:
To a solution of 5-chloroisatin, compound VIII, (10.0 g, 55.07 mmol) in anhydrous N,N-dimethylformamide (100 ml) potassium carbonate (9.87 g, 71.59 mmol) was added portionwise at 0-5° C. After stirring at 0-5° C. for further 10 minutes and at ambient temperature for one additional hour methyl bromoacetate (8.25 ml, 60.58 mmol) was added dropwise at such a rate that the internal temperature did not exceed 35° C. The resulting orange suspension was allowed to stir at ambient temperature overnight. Water was added (350 ml) and the product was extracted with ethyl acetate (5×100 ml). The combined organic extracts were washed with brine (100 ml), dried (MgSO4) and evaporated under reduced pressure to give the title compound (10.83 g, 76%) as orange solid (HPLC purity 98%). MS (ESI+): 254.1; MS (ESI−): 252.1
Reaction SMILES: C([O:8][C:9]1[CH:37]=[CH:36][C:12]2[CH:13]=[C:14]([C:16]([C:21]3[CH:34]=[CH:33][C:24]([O:25][CH2:26][C:27](=[O:32])[C:28]([CH3:31])([CH3:30])[CH3:29])=[C:23]([CH3:35])[CH:22]=3)([CH2:19][CH3:20])[CH2:17][CH3:18])[O:15][C:11]=2[CH:10]=1)C1C=CC=CC=1>CCOC(C)=O.CO.[Pd]>[CH2:17]([C:16]([C:21]1[CH:34]=[CH:33][C:24]([O:25][CH2:26][C:27](=[O:32])[C:28]([CH3:29])([CH3:31])[CH3:30])=[C:23]([CH3:35])[CH:22]=1)([C:14]1[O:15][C:11]2[CH:10]=[C:9]([OH:8])[CH:37]=[CH:36][C:12]=2[CH:13]=1)[CH2:19][CH3:20])[CH3:18]
Reactant: CCC(CC)(c1ccc(OCC(=O)C(C)(C)C)c(C)c1)c1cc2ccc(OCc3ccccc3)cc2o1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CCC(CC)(c1ccc(OCC(=O)C(C)(C)C)c(C)c1)c1cc2ccc(O)cc2o1
Reaction time: 2 h
Yield: 90.2 %

Procedure:
A solution of 1-{4-[1-(6-benzyloxy-benzofuran-2-yl)-1-ethyl-propyl]-2-methyl-phenoxy}-3,3-dimethyl-butan-2-one (5.90 g, 11.8 mmol) in EtOAc (20.0 mL) is added a slurry of Pd—C (590 mg, 10%) in MeOH (20.0 mL) at RT. The resulting mixture is stirred under hydrogen balloon pressure for 2 h. The mixture is filtered through a pad of celite and the filtrate is concentrated, the residue is purified with 20-30% EtOAc/Hex to afford the title compound (4.35 g, 90%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]3[C:17]4[C:22]([CH:23]=[CH:24][C:9]2=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:4][CH:3]=1.[CH:25]([C:28]1[CH:33]=[CH:32][C:31]([S:34](Cl)(=[O:36])=[O:35])=[CH:30][CH:29]=1)([CH3:27])[CH3:26]>N1C=CC=CC=1>[O:16]=[C:12]1[NH:11][C:10]2[C:17]3[C:22]([CH:23]=[CH:24][C:9]=2[N:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:1][S:34]([C:31]4[CH:32]=[CH:33][C:28]([CH:25]([CH3:27])[CH3:26])=[CH:29][CH:30]=4)(=[O:36])=[O:35])=[CH:3][CH:4]=2)[C:14](=[O:15])[CH2:13]1)=[CH:21][CH:20]=[CH:19][CH:18]=3
Reactant: CC(C)c1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Solvent: c1ccncc1
Product: CC(C)c1ccc(S(=O)(=O)Nc2ccc(N3C(=O)CC(=O)Nc4c3ccc3ccccc43)cc2)cc1
Yield: 56.9 %

Procedure:
5-(4-Aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (32 mg, 0.102 mmol) obtained in Example 1, (3), and 4-isopropylbenzenesulfonyl chloride (33 mg, 0.150 mmol) were treated by heating in pyridine (2.0 mL). After the disappearance of the starting materials was confirmed, the same treatment as that of Example 145 was performed to give the title compound (29 mg, yield 58%) as white crystals.
Reaction SMILES: Cl.[C:2]([O:6][C:7](=[O:13])[C@H:8]([CH:10]([CH3:12])[CH3:11])[NH2:9])([CH3:5])([CH3:4])[CH3:3].CN1CCOCC1.[Br:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:33]=[CH:32][C:31]([S:34](Cl)(=[O:36])=[O:35])=[CH:30][CH:29]=2)=[CH:24][CH:23]=1>ClCCl>[C:2]([O:6][C:7](=[O:13])[C@@H:8]([NH:9][S:34]([C:31]1[CH:30]=[CH:29][C:28]([C:25]2[CH:26]=[CH:27][C:22]([Br:21])=[CH:23][CH:24]=2)=[CH:33][CH:32]=1)(=[O:35])=[O:36])[CH:10]([CH3:11])[CH3:12])([CH3:5])([CH3:4])[CH3:3]
Reactant: O=S(=O)(Cl)c1ccc(-c2ccc(Br)cc2)cc1
Reactant: CC(C)[C@H](N)C(=O)OC(C)(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CC(C)[C@H](NS(=O)(=O)c1ccc(-c2ccc(Br)cc2)cc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 60.3 %

Procedure:
To a solution of L-valine-tert-butyl ester hydrochloride (15.7 g, 0.075 mol) and N-methylmorpholine (15.2 g, 0.15 mol) in dichloromethane (250 mL) was added in one portion 4'-bromobiphenyl-4-sulfonyl chloride (25 g, 0.075 mol). The solution was stirred at room temperature for 16 hours, filtered, and the filtrate was concentrated in vacuo. The residue was diluted with ethyl acetate (250 mL) and washed with HCl (1N), saturated sodium chloride, and dried over magnesium sulfate. The drying agent was filtered, and the filtrate was concentrated in vacuo leaving a cream-colored solid. The crude product was purified using silica gel chromatography (elution with chloroform) to give the title compound (21.2 g, 60%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][CH2:6][C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][CH:8]=1)=[O:4].[NH2:16][CH2:17][C@H:18]([NH:26][C:27]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:28])[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20].F[B-](F)(F)F.C(C(=NOC(N(C)C)=[N+](C)C)C(OCC)=O)#N.C(N(C(C)C)CC)(C)C>CN(C)C=O>[CH2:30]([O:29][C:27]([NH:26][C@@H:18]([CH2:17][NH:16][C:11](=[O:13])[C:10]1[CH:9]=[CH:8][C:7]([CH2:6][CH2:5][C:3]([O:2][CH3:1])=[O:4])=[CH:15][CH:14]=1)[C:19]([O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:20])=[O:28])[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: CC(C)(C)OC(=O)[C@H](CN)NC(=O)OCc1ccccc1
Reactant: COC(=O)CCc1ccc(C(=O)O)cc1
Agent: CCOC(=O)C(C#N)=NOC(N(C)C)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CCc1ccc(C(=O)NC[C@H](NC(=O)OCc2ccccc2)C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 7 h

Procedure:
354 mg (1.7 mmol) of 4-(2-methoxycarbonylethyl)benzoic acid and 500 mg (1.7 mmol) of tert-butyl (2S)-3-amino-2-benzyloxycarbonylaminopropionate were dissolved in 3 ml of dimethylformamide and treated with 557 mg (1.7 mmol) of O-((cyano-(ethoxycarbonyl)-methylidene)amino)-1,1,3,3-tetramethyluronium tetrafluoroborate (TOTU) and 204 mg (1.7 mmol) of diisopropylethylamine and the mixture was stirred at room temperature for 7 h at pH 7-8. The solvent was removed in vacuo, the residue was dissolved in ethyl acetate and the solution was washed three times each with KHSO4 solution and NaHCO3 solution until neutral. The organic phase was separated off and dried and the solvent was removed by distillation in vacuo. Yield: 770 mg (93%).
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][C:5]([Cl:9])=[CH:4][N:3]=1.O.[NH2:11][NH2:12]>C(O)C>[Cl:8][C:7]1[C:2]([NH:11][NH2:12])=[N:3][CH:4]=[C:5]([Cl:9])[CH:6]=1
Reactant: Clc1cnc(Cl)c(Cl)c1
Reactant: NN
Solvent: O
Solvent: CCO
Product: NNc1ncc(Cl)cc1Cl
Yield: 70.9 %

Procedure:
A reaction flask was loaded with 2,3,5-trichloropyridine (9.1 g) and ethanol (25 ml), followed by dropwise addition of hydrazine monohydrate (3 g) to the flask in 5 minutes with stirring. The resultant mixture was heated and stirred at 50 to 60° C. for 5 hours. Thereafter, the heating was stopped, and the reaction mixture was left to cool. The precipitated white crystals were filtrated for collection and dried to give 3,5-dichloro-2-hydrazinopyridine (6.3 g).
Reaction SMILES: Cl.[CH3:2][O:3][N:4]1[C:8](=[O:9])[CH2:7][C:6]2([CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[C:5]1=[O:15].C(N(CC)CC)C.[C:23](OC([O-])=O)([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24]>CN(C)C=O>[C:26]([O:25][C:23]([N:12]1[CH2:13][CH2:14][C:6]2([C:5](=[O:15])[N:4]([O:3][CH3:2])[C:8](=[O:9])[CH2:7]2)[CH2:10][CH2:11]1)=[O:24])([CH3:29])([CH3:28])[CH3:27]
Reactant: CON1C(=O)CC2(CCNCC2)C1=O
Reactant: CC(C)(C)OC(=O)OC(=O)[O-]
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CON1C(=O)CC2(CCN(C(=O)OC(C)(C)C)CC2)C1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-methoxy-2,8-diazaspiro[4,5]decane-1,3-dione hydrochloride (1.5 g) in dimethylformamide (100 ml) was added triethylamine (1 ml), followed by tert-butyl dicarbonate (2.05 ml), and this was followed by stirring at room temperature for 1 hour. The solvent was evaporated off under reduced pressure. To the residual oil dichloromethane (50 ml) was added, after which it was washed with a 10% aqueous solution of citric acid, then with water. After drying the organic layer with anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure. The resulting residual solid was recrystallized with ethyl ether to obtain 1.4 g of a colorless crystal having a melting point of 117° C.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:14][CH2:13][C:12]3([CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[C:11]2=[O:20])=[CH:6][CH:5]=1.O=C(Cl)[O:25][C:26](Cl)(Cl)Cl.[CH2:31]([NH:33][C:34]1[CH:35]=[C:36]([CH3:40])[CH:37]=[CH:38][CH:39]=1)[CH3:32]>>[CH2:31]([N:33]([C:34]1[CH:35]=[C:36]([CH3:40])[CH:37]=[CH:38][CH:39]=1)[C:26]([N:17]1[CH2:16][CH2:15][C:12]2([C:11](=[O:20])[N:10]([C:7]3[CH:8]=[CH:9][C:4]([O:3][C:2]([F:1])([F:21])[F:22])=[CH:5][CH:6]=3)[CH2:14][CH2:13]2)[CH2:19][CH2:18]1)=[O:25])[CH3:32]
Reactant: CCNc1cccc(C)c1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCNCC2
Product: CCN(C(=O)N1CCC2(CC1)CCN(c1ccc(OC(F)(F)F)cc1)C2=O)c1cccc(C)c1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
This material was prepared in analogy to example 251 step B) from 2-(4-trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decan-1-one, diphosgene and ethyl-m-tolyl-amine. The reaction mixture was stirred for 1 h at room temperature, 2 h at 50° C. and 1 h at 80° C. before subjecting to work-up and purification. MS (ESI): 467.4 (MH+).
Reaction SMILES: [CH3:1][C:2]([O-])(C)[CH3:3].[K+].[C:7](=[N:20][CH:21]1[CH2:26][CH2:25][CH2:24][N:23]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[C:22]1=[O:35])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(Br)C#C.C1(C)C=CC=CC=1>C1COCC1>[C:7](=[N:20][C:21]1([CH2:3][C:2]#[CH:1])[CH2:26][CH2:25][CH2:24][N:23]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:32])([CH3:34])[CH3:33])[C:22]1=[O:35])([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CC(C)(C)[O-]
Reactant: C[Si](C)(C)CCOCN1CCCC(N=C(c2ccccc2)c2ccccc2)C1=O
Agent: C#CCBr
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: C#CCC1(N=C(c2ccccc2)c2ccccc2)CCCN(COCC[Si](C)(C)C)C1=O
Reaction time: 0.67 h
Yield: 32.8 %

Procedure:
KOtBu 1.7M in THF (4.32 mL, 7.34 mmol) was added dropwise to a solution of 3-(benzhydrylideneamino)-1-(2-trimethylsilylethoxymethyl)piperidin-2-one (which may be prepared as described in Description 22) (2.5 g, 6.12 mmol) and propargyl bromide 80 wt % in toluene (0.95 mL, 8.57 mmol) in THF (100 mL) at 0° C. under N2. The reaction was stirred for 40 mins. The reaction was quenched by the addition of satd. aq. NaHCO3 and then diluted with EtOAc. The phases were separated, the organic layer was dried (Na2SO4) and the solvent was evaporated to afford an oil. The material was purified by SP4, 100 g SNAP, 0 to 50% EtOAc/i-hexane to afford product: 3-(benzhydrylideneamino)-3-prop-2-ynyl-1-(2-trimethylsilylethoxymethyl)-piperidin-2-one (D23) (897 mg, 2.0082 mmol, 32.8% yield) as a pale yellow oil.
Reaction SMILES: C(C[O:4][C:5]1[C:10]([C:11]([O:13][CH3:14])=[O:12])=[C:9]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:8]([C:19]([O:21][CH3:22])=[O:20])=[C:7]([C:23]([F:26])([F:25])[F:24])[N:6]=1)#N.BrCC#N.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[OH:4][C:5]1[C:10]([C:11]([O:13][CH3:14])=[O:12])=[C:9]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:8]([C:19]([O:21][CH3:22])=[O:20])=[C:7]([C:23]([F:25])([F:24])[F:26])[N:6]=1
Reactant: COC(=O)c1c(OCC#N)nc(C(F)(F)F)c(C(=O)OC)c1CC(C)C
Agent: N#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1c(O)nc(C(F)(F)F)c(C(=O)OC)c1CC(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
This example illustrates the preparation of Compound 80, namely, dimethyl 2-(cyanomethoxy)-4-(2-methylpropyl)-6-(trifluoromethyl)-3,5-pyridine-dicarboxylate. A solution of 6.38 g (0.019 mol) of dimethyl 2-hydroxy-4-(2-methylpropyl)-6-(trifluoromethyl)-3,5-pyridinedicarboxylate (Compound 1) in 50 mL of dimethylformamide was prepared and to it was added 7.2 g (0.06 mol) of bromoacetonitrile and 8.3 g (0.06 mol) of anhydrous potassium carbonate. The mixture was stirred at room temperature overnight then suction filtered The filtrate was diluted with 400 mL of water and extracted with four 50 mL portions of methylene chloride. The combined extracts were dried with magnesium sulfate and the solvent was removed by rotary evaporation giving 7.09 g (98.9% yield) of a dark amber oil. Silica gel chromatography with 10% ethyl acetate, 90% cyclohexane gave 3.51 g (49%) of Compound 80 as a clear colorless oil.
Reaction SMILES: [CH3:1][C:2]([NH:5][S:6]([C:9]1[N:10]([CH3:14])[CH:11]=[CH:12][CH:13]=1)(=[O:8])=[O:7])([CH3:4])[CH3:3].C([Li])CCC.Cl[C:21]([O:23][CH3:24])=[O:22]>C1COCC1.C(OCC)(=O)C>[CH3:4][C:2]([NH:5][S:6]([C:9]1[N:10]([CH3:14])[CH:11]=[CH:12][C:13]=1[C:21]([O:23][CH3:24])=[O:22])(=[O:8])=[O:7])([CH3:1])[CH3:3]
Reactant: Cn1cccc1S(=O)(=O)NC(C)(C)C
Reactant: COC(=O)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)c1ccn(C)c1S(=O)(=O)NC(C)(C)C
Reaction time: 0.5 h
Yield: 14.3 %

Procedure:
To a solution of 2.5 g (11.5 mmol) of N-(1,1-dimethylethyl)-1-methyl-1H-pyrrole-2-sulfonamide in 50 mL THF under nitrogen atmosphere cooled to below -70° C. was added dropwise 13 mL (32.5 mmol) of 2.5M n-butyllithium at such a rate as to keep the temperature below -58° C. After stirring at -20° C. to -10° C. for 30 min then 1 h at 0° C., the mixture was recooled to -70° C. and treated with a solution of 1.63 g (17.3 mmol) of methyl chloroformate in 6 mL THF causing an exotherm to -57° C. The reaction mixture was stirred overnight at ambient temperature then diluted with 200 mL of ethyl acetate. This solution was washed successively with two 60 mL portions of 1N HCl, brine, then dried (Na2SO4) and evaporated to a dark oil. The crude product was purified by chromatography on silica gel (30% ethyl acetate/70% hexanes) then collected from hexanes to afford 0.45 g of the title compound, m.p. 105°-108° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([NH:11][C:12]([NH:14][CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])=[O:13])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[C:21]([O-])([O-])=O.[K+].[K+].CI>CC(C)=O>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:11]([CH3:21])[C:12](=[O:13])[N:14]([CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])[C:7](=[O:9])[C:6]=2[CH:10]=1
Reactant: COC(=O)CCNC(=O)Nc1ncc(Br)cc1C(=O)O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COC(=O)CCn1c(=O)c2cc(Br)cnc2n(C)c1=O
Temperature: 40 °C
Yield: 34.3 %

Procedure:
To a solution of 5-bromo-2-(3-(3-methoxy-3-oxopropyl)ureido)nicotinic acid (15 g, 43.5 mmol) in acetone (150 mL) was added K2CO3 (18 g, 130.4 mmol) followed by CH3I (18 mL, 263.1 mmol). The reaction was heated in a sealed flask at 40° C. for 24 h, cooled to RT, concentrated then diluted with EA (200 mL) and water (100 ml). The organic layer was washed with brine (100 mL), dried over Na2SO4, filtered and concentrated to a residue which was purified by chromatography PE/EA eluted with (10:1 to 2:1) to give methyl 3-(6-bromo-1-methyl-2,4-dioxo-1,2-dihydropyrido[2,3-d]pyrimidin-3(4H)-yl)propanoate (5.1 g, 34.4% yield) as a white solid. LCMS: MH+ 342 and TR=1.266 min. Used without further purification.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][CH:8]([C:12](=[NH:21])[NH:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH:9]([CH3:11])[CH3:10])([CH3:4])([CH3:3])[CH3:2].C([O:25][CH:26]=[C:27]([C:33](OCC)=O)[C:28]([O:30][CH2:31][CH3:32])=[O:29])C>CO>[CH2:31]([O:30][C:28]([C:27]1[C:26](=[O:25])[N:13]([CH2:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:12]([CH:8]([NH:7][C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:22])[CH:9]([CH3:11])[CH3:10])=[N:21][CH:33]=1)=[O:29])[CH3:32]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: CC(C)C(NC(=O)OC(C)(C)C)C(=N)NCc1ccccc1
Solvent: CO
Product: CCOC(=O)c1cnc(C(NC(=O)OC(C)(C)C)C(C)C)n(Cc2ccccc2)c1=O
Temperature: 100 °C

Procedure:
Following the procedure of Veale, J. Org. Chem., 58, 4490 (1993), to [1-(N-Benzyl-carbamimidoyl)-2-methyl-propyl]-carbamic acid tert-butyl ester (10.86 g, 35.6 mmol) in methanol (160 mL) was added diethyl ethoxymethylenemalonate (7.7 g, 35.6 mmol). The reaction is equipped with a Dean-Stark trap. The reaction was heated at 100° C. until all solvent was removed. The residue was dissolved in methylene chloride, washed with 1 N HCl and water, dried (Na2SO4), and concentrated. The resulting pale yellow syrup was used in the next step without further purification.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[CH:6]1([C:9]2[O:13][C:12]([C:14]3[C:15](O)=[N:16][C:17]([S:20][CH3:21])=[N:18][CH:19]=3)=[N:11][N:10]=2)[CH2:8][CH2:7]1.C(=O)([O-])O.[Na+]>>[Cl:3][C:15]1[C:14]([C:12]2[O:13][C:9]([CH:6]3[CH2:8][CH2:7]3)=[N:10][N:11]=2)=[CH:19][N:18]=[C:17]([S:20][CH3:21])[N:16]=1
Reactant: CSc1ncc(-c2nnc(C3CC3)o2)c(O)n1
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: CSc1ncc(-c2nnc(C3CC3)o2)c(Cl)n1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 79 %

Procedure:
Phosphorus oxychloride (15 mL) was added to 5-(5-cyclopropyl[1,3,4]oxadiazol-2-yl)-4-hydroxy-2-methylthiopyrimidine (6.26 g) obtained in Step 6, and the mixture was stirred at 60° C. for 30 minutes. After completion of the reaction was confirmed by thin-layer chromatography, the reaction mixture was added to a saturated aqueous sodium hydrogencarbonate solution, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. Diethyl ether was added to the residue to precipitate crystals. The resulting crystals were collected by filtration and dried thoroughly under reduced pressure to give 4-chloro-5-(5-cyclopropyl[1,3,4]oxadiazol-2-yl)-2-methylthiopyrimidine (5.31 g, yield 79%).
Reaction SMILES: [CH2:1]([NH:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([OH:24])=O)=[CH:20][CH:19]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].C(=O)([O-])[O-].[Na+].[Na+].[C:33](Cl)([O:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)=[O:34].S(Cl)([Cl:46])=O>O.C(Cl)(Cl)Cl>[C:33]([N:17]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[C:18]1[CH:19]=[CH:20][C:21]([C:22]([Cl:46])=[O:24])=[CH:25][CH:26]=1)([O:35][CH2:36][C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1)=[O:34]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CCCCCCCCCCCCCCCCNc1ccc(C(=O)O)cc1
Reactant: O=S(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCCCCCN(C(=O)OCc1ccccc1)c1ccc(C(=O)Cl)cc1
Temperature: 40 °C
Reaction time: 2 h

Procedure:
To 15 g. (41.5 m moles) 4-(hexadecylamino)benzoic acid in 200 ml. warm chloroform is added 15 g. sodium carbonate in 150 ml. water. To the vigorously stirred solution is added 10 g. (59 m moles) carbobenzyloxy chloride. After 2 hours stirring at 40° C., the layers are separated, washed three times with 1 N hydrochloric acid, dried, and evaporated to an oil. The oil is dissolved in 300 ml. toluene, treated with 15 ml. (5 eq) thionyl chloride and the solution is refluxed for 5 hours. The solvents are evaporated and the residue is dissolved three times in toluene, evaporating each time to yield a viscous, orange oil.