Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:3]([CH2:21][CH3:22])[CH:4]([C:6]1[N:10]([S:11]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)(=[O:13])=[O:12])[N:9]=[CH:8][CH:7]=1)O)[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.C1(P([N:68]=[N+:69]=[N-:70])(C2C=CC=CC=2)=O)C=CC=CC=1>C1COCC1>[N:68]([CH:4]([C:6]1[N:10]([S:11]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)(=[O:13])=[O:12])[N:9]=[CH:8][CH:7]=1)[CH:3]([CH2:21][CH3:22])[CH2:1][CH3:2])=[N+:69]=[N-:70]
Reactant: CCC(CC)C(O)c1ccnn1S(=O)(=O)c1ccc(C)cc1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCC(CC)C(N=[N+]=[N-])c1ccnn1S(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 96.2 %

Procedure:
To 2-ethyl-1-{1-[(4-methylphenyl)sulfonyl]-1H-pyrazol-5-yl}butan-1-ol (0.250 g, 0.778 mmol) in THF (10 mL) at 0° C. was added triphenylphosphine (0.307 g, 1.17 mmol), diethyl azodicarboxylate (0.18 mL, 1.2 mmol), and diphenylphosphoryl azide (0.25 mL, 1.2 mmol). The reaction mixture was warmed to room temperature and stirred for 20 h. The solvent was removed in vacuo and the resulting residue was purified by column chromatography (EtOAc/hexanes, 15:85) to give 0.260 g (97%) of 5-(1-azido-2-ethylbutyl)-1-[(4-methylphenyl)sulfonyl]-1H-pyrazole with an aromatic impurity as judged by 1H NMR. This compound was used in the next step without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:13]=[CH:12][C:5]([O:6][CH2:7][C:8]([NH:10][CH3:11])=[O:9])=[CH:4][CH:3]=1.Br[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[F:22].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[F:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[CH2:15][O:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH2:7][C:8]([NH:10][CH3:11])=[O:9])=[CH:12][CH:13]=1
Reactant: Fc1ccccc1CBr
Reactant: CNC(=O)COc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CNC(=O)COc1ccc(OCc2ccccc2F)cc1

Procedure:
In analogy to the procedure described in Example 3b), the alkylation of 2-(4-hydroxy-phenoxy)-N-methyl-acetamide [Example 3a)] with 1-bromomethyl-2-fluoro-benzene in 2-butanone using potassium carbonate as the base yielded the 2-[4-(2-fluoro-benzyloxy)-phenoxy]-N-methyl-acetamide as white crystals; MS: m/e=290 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:10])=[C:6]([CH:9]=1)[C:7]#[N:8].[CH:11]1([C:14]#[CH:15])[CH2:13][CH2:12]1>C(N(CC)CC)C.C(Cl)Cl.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH:11]1([C:14]#[C:15][C:2]2[CH:3]=[CH:4][C:5]([F:10])=[C:6]([CH:9]=2)[C:7]#[N:8])[CH2:13][CH2:12]1
Reactant: N#Cc1cc(Br)ccc1F
Reactant: C#CC1CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: N#Cc1cc(C#CC2CC2)ccc1F
Temperature: 60 °C

Procedure:
5-Bromo-2-fluorobenzonitrile (3.06 g, 15.3 mmol), dichlorobis(triphenylphosphine)palladium(II) (478 mg, 0.681 mmol), and copper(I) iodide (165 mg, 0.866 mmol) were combined in triethylamine (15 mL) under an inert atmosphere of nitrogen. Cyclopropylacetylene (1.8 mL) was added, and the mixture was heated to 60° C. until it turned to a black solid. The mixture was diluted with methylene chloride and washed with 1 N hydrochloric acid. The organic layer was absorbed on silica gel and purified by silica gel chromatography eluting with a gradient of 5-40% ethyl acetate in hexanes to afford the title compound. MS (ESI+) m/z 319.0 (M+H)+.
Reaction SMILES: [CH:1]1[C:6]([NH2:7])=[CH:5][CH:4]=[C:3]([NH2:8])[CH:2]=1.[CH:9]1[C:21]2[CH:20]([CH2:22][O:23][C:24](ON3C(=O)CCC3=O)=[O:25])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]=2[CH:12]=[CH:11][CH:10]=1>O1CCOCC1.O>[CH:9]1[C:21]2[CH:20]([CH2:22][O:23][C:24]([NH:7][C:6]3[CH:5]=[CH:4][C:3]([NH2:8])=[CH:2][CH:1]=3)=[O:25])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]=2[CH:12]=[CH:11][CH:10]=1
Reactant: Nc1ccc(N)cc1
Reactant: O=C(OCC1c2ccccc2-c2ccccc21)ON1C(=O)CCC1=O
Solvent: O
Solvent: C1COCCO1
Product: Nc1ccc(NC(=O)OCC2c3ccccc3-c3ccccc32)cc1

Procedure:
4-((9-Fluorenylmethyloxycarbonyl)amino)aniline is prepared from p-phenylenediamine (2.16 g, 0.02 mole) and N-(9-fluorenylmethoxycarbonyloxy)succinimide (6.75 g, 0.02 mole) in dioxane-water (1:1). Purification is achieved by crystallization. This product is coupled to BOC-L-Glu-α-O-Benzyl using HOBT/DCC. After the usual work-up, the fully-protected amino acid derivative is dissolved in MeOH and treated with hydrogen gas at 1 atmosphere pressure in the presence of palladium-on-carbon catalyst until hydrogen consumption is complete (about 2 hours). Following the usual workup, the starting material:
Reaction SMILES: C[O:2][C:3]([C:5]1[C:9]([NH:10][C:11]([C:13]2[C:18]([NH:19][C:20]3[CH:21]=[N:22][CH:23]=[N:24][CH:25]=3)=[CH:17][CH:16]=[C:15]([CH:26]3[CH2:28][CH2:27]3)[N:14]=2)=[O:12])=[CH:8][N:7]([CH3:29])[N:6]=1)=[O:4].[OH-].[Na+]>CO.O>[CH:26]1([C:15]2[N:14]=[C:13]([C:11]([NH:10][C:9]3[C:5]([C:3]([OH:4])=[O:2])=[N:6][N:7]([CH3:29])[CH:8]=3)=[O:12])[C:18]([NH:19][C:20]3[CH:25]=[N:24][CH:23]=[N:22][CH:21]=3)=[CH:17][CH:16]=2)[CH2:28][CH2:27]1
Reactant: COC(=O)c1nn(C)cc1NC(=O)c1nc(C2CC2)ccc1Nc1cncnc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cn1cc(NC(=O)c2nc(C3CC3)ccc2Nc2cncnc2)c(C(=O)O)n1
Temperature: 25 °C
Reaction time: 12 h
Yield: 49.3 %

Procedure:
To a stirred solution of 4-{[6-cyclopropyl-3-(pyrimidin-5-ylamino)-pyridine-2-carbonyl]-amino}-1-methyl-1H-pyrazole-3-carboxylic acid methyl ester (example 27, step 4; 300 mg, 0.76 mmol) in MeOH (7 ml) was added a solution of NaOH (49 mg, 1.2 mmol) in water (2 ml) while keeping the internal bath temperature below 5° C. The reaction mixture was stirred for 12 h at rt, then concentrated. The residue was dissolved in water (10 ml), and the aqueous layer was washed with EtOAc. The aqueous phase was acidified with aqueous 1N HCl solution (pH˜4-5), then saturated with sodium chloride, and extracted with EtOAc. Combined organic layers were washed with brine, dried (Na2SO4), and filtered. The organic layer was concentrated to give the title compound (142 mg, 45%) as yellowish sticky solid, which was directly used for next step.
Reaction SMILES: C1COCC1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[CH2:24]([O:31][C:32]1[CH:37]=[CH:36][N:35]([C:38]2[CH:43]=[CH:42][C:41]([O:44][Si](C(C)(C)C)(C)C)=[CH:40][CH:39]=2)[C:34](=[O:52])[CH:33]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(OCC)(=O)C>[CH2:24]([O:31][C:32]1[CH:37]=[CH:36][N:35]([C:38]2[CH:39]=[CH:40][C:41]([OH:44])=[CH:42][CH:43]=2)[C:34](=[O:52])[CH:33]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(-n2ccc(OCc3ccccc3)cc2=O)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=c1cc(OCc2ccccc2)ccn1-c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98.8 %

Procedure:
A THF solution (0.7 mL) of 1N tetrabutylammonium fluoride was added to a THF solution (2 mL) of 4-benzyloxy-1-{4-[tert-butyl(dimethyl)silyloxy]phenyl}-1H-pyridin-2-one (234 mg, 0.573 mmol) and stirred for 30 minutes at room temperature. Ethyl acetate was added to the reaction liquid, the organic layer was washed with water and saturated brine and dried over anhydrous magnesium sulfate. Concentrating the solvent under reduced pressure, the title compound (166 mg, 99%) was obtained.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[CH2:5]([N:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]2[CH:17]=[C:18]([C:20]#[N:21])[CH:19]=[C:9]2[C:8]1=[O:22])[CH3:6].[Cl-].[NH4+].CN(C)C=O>O>[CH2:5]([N:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]2[CH:17]=[C:18]([C:20]3[NH:21][N:3]=[N:2][N:1]=3)[CH:19]=[C:9]2[C:8]1=[O:22])[CH3:6]
Reactant: CCn1c(=O)c2cc(C#N)cn2c2ccccc21
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCn1c(=O)c2cc(-c3nnn[nH]3)cn2c2ccccc21
Reaction time: 12 h
Yield: 48 %

Procedure:
0.48 g (7.4 mmole) of sodium azide were added to a suspension of 1.3 g (5.5 mmole) of the product of Step B, 0.425 g (8.0 mmole) of ammonium chloride and 50 ml of dimethylformamide and the mixture was stirred at 130°-140° C. for 12 hours and was then cooled. 200 ml of water were added thereto and the mixture was filtered. The recovered product was crystallized from a methanol-ethyl acetate mixture to obtain 0.74 g (48% yield) of 5-ethyl-2-(1H-tetrazol-5-yl)-pyrrolo-[1,2-a]-quinoxaline-4(5H)-one in the form of off-white crystals melting at 295°-297° C. with decomposition.
Reaction SMILES: IC.[O:3]([CH2:6][CH3:7])CC.[Li].[C:9]1([NH:15][C:16]2(C(O)=O)[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:18][CH2:17]2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>O>[C:9]1([NH:15][C:16]2([C:6](=[O:3])[CH3:7])[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:18][CH2:17]2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C(O)C1(Nc2ccccc2)CCN(CCc2ccccc2)CC1
Reactant: CCOCC
Agent: [Li]
Solvent: O
Solvent: CI
Product: CC(=O)C1(Nc2ccccc2)CCN(CCc2ccccc2)CC1
Reaction time: 0.5 h

Procedure:
To start the reaction, a small amount of a solution of 78.1 parts of iodomethane in 70 parts of dry 1,1'-oxybisethane is dropped to a stirred solution of 6.9 parts of lithium in 70 parts of dry 1,1'-oxybisethane. After the addition of 70 parts of dry 1,1'-oxybisethane, the remainder of the solution is added dropwise at reflux temperature. Stirring at reflux is continued for 30 minutes. Then there were added portionwise 16.2 parts of 4-(phenylamino)-1-(2-phenylethyl)-4-piperidinecarboxylic acid (a violent reaction occurs whereby reflux temperature is maintained). Upon completion, stirring at reflux is continued for 1h. 30. The reaction mixture is decomposed by the dropwise addition of 300 parts of water. The organic phase is separated, washed with water, dried, filtered and evaporated. The residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and 5% of methanol as eluent. The first fraction is collected and the eluent is evaporated. The residue is crystallized from 14 parts of 2,2'-oxybispropane, yielding 1-[4-(phenylamino)-1-(2-phenylethyl)-4-piperidinyl]ethanone; mp. 100.6° C.
Reaction SMILES: [F:1][C:2]([C:5]1[CH:6]=[C:7]([CH:22]=[CH:23][CH:24]=1)[CH2:8][CH:9]1[CH:13]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[O:12]C(=O)[NH:10]1)([F:4])[CH3:3].[OH-].[Na+]>C(O)C.O>[NH2:10][CH:9]([CH2:8][C:7]1[CH:22]=[CH:23][CH:24]=[C:5]([C:2]([F:4])([F:1])[CH3:3])[CH:6]=1)[CH:13]([C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)[OH:12]
Reactant: CC(F)(F)c1cccc(CC2NC(=O)OC2c2ccc(F)cc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(F)(F)c1cccc(CC(N)C(O)c2ccc(F)cc2)c1
Yield: 79.7 %

Procedure:
To a solution of (4RS,5SR)-4-[3-(1,1-difluoroethyl)benzyl]-5-(4-fluorophenyl)-1,3-oxazolidin-2-one (3.83 g, 12.5 mmol) in ethanol (100 ml) was added 8N aqueous sodium hydroxide solution (7.8 ml, 39.0 mmol), and the mixture was heated under reflux for 5 hrs. After completion of the reaction, the mixture was diluted with water, and extracted with ethyl acetate. The organic layers were combined, washed with saturated brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was recrystallized from (hexane-ethyl acetate) to give (1RS,2SR)-2-amino-3-[3-(1,1-difluoroethyl)phenyl]-1-(4-fluorophenyl)-1-propanol (3.08 g, 88%) as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][N:5]=[C:4]2[NH:9][CH:10]=[CH:11][C:3]=12.[I:12]N1C(=O)CCC1=O>CN(C)C=O>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][N:5]=[C:4]2[NH:9][CH:10]=[C:11]([I:12])[C:3]=12
Reactant: O=C1CCC(=O)N1I
Reactant: Fc1cnc2[nH]ccc2c1Cl
Solvent: CN(C)C=O
Product: Fc1cnc2[nH]cc(I)c2c1Cl

Procedure:
To a solution of 4-chloro-5-fluoro-1H-pyrrolo[2,3-b]pyridine (1.8 g, 10.5 mmol) in N,N-dimethylformamide (25 mL) at 0° C. was added N-iodosuccinimide (2.37 g, 10.55 mmol). The mixture was slowly brought to room temperature, quenched with brine and extracted with ethyl acetate (twice). The organic phase was concentrated and purified by column chromatography (silica gel, 30% ethyl acetate in hexane) to afford the title compound. MS (ESI+) m/z 297 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([NH:11]C(=O)OC(C)(C)C)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.Cl>CO.C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([NH2:11])[CH2:9][CH2:10]2)=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(Br)cc2)CC1
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: NC1(c2ccc(Br)cc2)CC1
Temperature: 35 °C
Reaction time: 17 h

Procedure:
To a solution of tert-butyl [1-(4-bromophenyl)-cyclopropyl]-carbamate (Intermediate 115, 1.08 g, 3.40 mmols) in 20 mL MeOH and 20 mL THF was added 20 mL of 3M aqueous HCl. The solution was warmed to 35° C. for 3 hours and then stirred for 17 h at 25° C. The reaction was quenched by adjusting the pH of the solution to 12 with 3M aqueous NaOH. The mixture was extracted with Et2O and the combined organic layers were washed with H2O and saturated aqueous NaCl before being dried (MgSO4) and concentrated under reduced pressure. The title compound 613 mg (85%) was used without further purification.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]([CH3:44])([CH3:43])[CH2:7][N:8]([S:32]([C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([NH:41][CH3:42])[CH:36]=1)(=[O:34])=[O:33])[CH2:9][C@@H:10]([OH:31])[C@@H:11]([NH:19][C:20](=[O:30])[O:21][C@@H:22]1[C@H:29]2[C@H:25]([O:26][CH2:27][CH2:28]2)[O:24][CH2:23]1)[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)C(C)C)(C)C.[CH3:54][N:55]([CH3:59])[C:56](Cl)=[O:57]>C1COCC1>[CH2:12]([C@H:11]([NH:19][C:20](=[O:30])[O:21][C@@H:22]1[C@H:29]2[C@H:25]([O:26][CH2:27][CH2:28]2)[O:24][CH2:23]1)[C@H:10]([OH:31])[CH2:9][N:8]([CH2:7][C:6]([CH3:44])([CH3:43])[CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:56]([N:55]([CH3:59])[CH3:54])=[O:57])[S:32]([C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([NH:41][CH3:42])[CH:36]=1)(=[O:34])=[O:33])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CNc1cccc(S(=O)(=O)N(C[C@@H](O)[C@H](Cc2ccccc2)NC(=O)O[C@H]2CO[C@H]3OCC[C@H]32)CC(C)(C)CCCCN)c1
Reactant: CN(C)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CNc1cccc(S(=O)(=O)N(C[C@@H](O)[C@H](Cc2ccccc2)NC(=O)O[C@H]2CO[C@H]3OCC[C@H]32)CC(C)(C)CCCCNC(=O)N(C)C)c1
Temperature: 25 °C
Yield: 80 %

Procedure:
A solution of 55 mg (0.087 mmol) of (3R,3aS,6aR)hexahydrofuro[2,3-b]furan-3-yl N-[(1S,2R)-3-((6-amino-2,2-dimethylhexyl)[3-(methylamino)phenyl]sulfonylamino)-1-benzyl-2-hydroxypropyl]carbamate and 17 μL (0.091 mmol) of N,N-diisopropylethylamine in 4 mL of anhydrous THF at 0° C. was treated with 8.4 μL (0.091 mmol) of N,N-dimethylcarbamyl chloride. The solution was allowed to warm to RT with stirring. After 18 hours the solution was concentrated in vacuo and the residue was subjected to flash chromatography (SiO2, 95:5 CH2Cl2/2M NH3 in MeOH) to afford 49 mg (80%) of the desired compound as a white foam.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH3:12])=[C:6]([B:8]([OH:10])[OH:9])[CH:7]=1.[CH3:13][C:14]([CH2:18]O)([CH2:16]O)[CH3:15]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH3:12])=[C:6]([B:8]2[O:9][CH2:15][C:14]([CH3:18])([CH3:16])[CH2:13][O:10]2)[CH:7]=1
Reactant: CC(C)(CO)CO
Reactant: COc1ccc(Cl)cc1B(O)O
Product: COc1ccc(Cl)cc1B1OCC(C)(C)CO1
Yield: 86 %

Procedure:
The title compound (86%, oil) was prepared from 5-chloro-2-methoxyphenylboronic acid and neopentylglycol.
Reaction SMILES: CS[C:3]1[N:8]=[C:7]2[N:9]=[C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[O:20][CH2:21][CH2:22][CH3:23])[NH:11][C:12](=[O:13])[C:6]2=[CH:5][N:4]=1.[NH3:24]>>[NH2:24][C:3]1[N:8]=[C:7]2[N:9]=[C:10]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[O:20][CH2:21][CH2:22][CH3:23])[NH:11][C:12](=[O:13])[C:6]2=[CH:5][N:4]=1
Reactant: N
Reactant: CCCOc1ccccc1-c1nc2nc(SC)ncc2c(=O)[nH]1
Product: CCCOc1ccccc1-c1nc2nc(N)ncc2c(=O)[nH]1
Reaction time: 8 h

Procedure:
7-Methylthio-4-oxo-2-(2-propoxyphenyl)-3,4-dihydropyrimido[4,5-d]pyrimidine (1.55 g) was heated in ethanolic ammonia (50 ml) in a pressure vessel for 8 hours at 90° C. and then for 8 hours at 145° C. After cooling a grey solid (0.64 g) was collected and was recrystallized from ethanol (with charcoal) to yield a crude product (0.47 g) which was recrystallized from ethanol to yield the title compound, 0.29 g, m.p. 261-262° C.
Reaction SMILES: [C:1]1([C:7]2([CH3:14])[O:13][CH:8]2[C:9]([O:11][CH3:12])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(=O)(=O)(O)O.[CH2:20]([OH:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH2:20]([O:27][C:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)([CH3:14])[CH:8]([OH:13])[C:9]([O:11][CH3:12])=[O:10])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COC(=O)C1OC1(C)c1ccccc1
Reactant: OCc1ccccc1
Agent: O=S(=O)(O)O
Product: COC(=O)C(O)C(C)(OCc1ccccc1)c1ccccc1
Temperature: 50 °C
Reaction time: 6 h

Procedure:
9.6 g (50 mmol) of methyl 3-phenyl-2,3-epoxybutyrate are dissolved in 150 ml of benzyl alcohol, and 0.5 ml of concentrated sulfuric acid is added. The mixture is stirred at 50° C. for 6 hours and allowed to cool to room temperature. After neutralization with sodium bicarbonate solution, the excess benzyl alcohol is removed by distillation under high vacuum, and the residue is purified by flash chromatography on silica gel with 9:1 n-hexane/ethyl acetate. After removal of the solvent by distillation, 6.5 g of a colorless oil remain.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.[CH3:10][C:11]([CH3:13])=[O:12].[OH-].[Na+].O>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:10][C:11](=[O:12])[CH:13]=[CH:5][C:4]2[CH:7]=[CH:8][CH:9]=[C:2]([Cl:1])[CH:3]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: CC(C)=O
Reactant: O=Cc1cccc(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(C=Cc1cccc(Cl)c1)C=Cc1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 90.3 %

Procedure:
3-Chlorobenzaldehyde (1y, 2.00 ml, 17.7 mmol) and acetone (19, 0.65 ml, 8.8 mmol) were combined in ethanol (20 ml) and stirred for 15 min at room temperature. A solution of sodium hydroxide (1.00 g, 25.0 mmol) and water (20 ml) was added and the mixture stirred for 2 hr at room temperature. The resulting precipitate was filtered and recrystallized from ethyl acetate to give 2.41 g (90%) of a yellow solid: mp 125-127° C. [expected mp 120-121° C.]; 1H NMR: δ 7.03 (d, 2H, J=15.9 Hz), 7.33 (m, 4H), 7.45 (d, 2H, J=6.6 Hz), 7.58 (m, 2H), 7.64 (d, 2H, J=15.9 Hz); 13C NMR: δ 126.3, 126.6, 127.9, 130.1, 130.3, 134.9, 136.5, 141.8, 188.0.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:30]=[CH:29][CH:28]=[CH:27][C:4]=1[CH2:5][N:6]1[CH:10]=[CH:9][N:8]=[C:7]1[C@@H:11]([NH:19]C(=O)OC(C)(C)C)[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.Cl>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:30]=[CH:29][CH:28]=[CH:27][C:4]=1[CH2:5][N:6]1[CH:10]=[CH:9][N:8]=[C:7]1[C@@H:11]([NH2:19])[CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: COc1ccccc1Cn1ccnc1[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: ClCCl
Product: COc1ccccc1Cn1ccnc1[C@@H](N)Cc1ccccc1
Reaction time: 3 h

Procedure:
(S)-tert-butyl 1-(1-(2-methoxybenzyl)-1H-imidazol-2-yl)-2-phenylethylcarbamate was dissolved in DCM and treated with 4 N HCl in dioxanes. The reaction was stirred for 3 hr. Solvents were removed in vacuo to provide the desired product. MS (m/z) 308.1 [M+H]+.
Reaction SMILES: [C:1]([NH:9][C:10]1[CH:19]=[C:18]2[C:13]([CH:14]=[CH:15][CH:16]=[C:17]2[N:20]2[CH2:25][CH2:24][N:23](C)[CH2:22][CH2:21]2)=[CH:12][CH:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC(OC(Cl)C)=O.CO>C(Cl)Cl>[C:1]([NH:9][C:10]1[CH:19]=[C:18]2[C:13]([CH:14]=[CH:15][CH:16]=[C:17]2[N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[CH:12][CH:11]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN1CCN(c2cccc3ccc(NC(=O)c4ccccc4)cc23)CC1
Agent: CC(Cl)OC(=O)Cl
Solvent: CO
Solvent: ClCCl
Product: O=C(Nc1ccc2cccc(N3CCNCC3)c2c1)c1ccccc1
Temperature: 0 °C
Yield: 66.6 %

Procedure:
The title product from Example 1 (0.50 g, 1.45 mmol) was dissolved in methylene chloride (10 mL) and chilled to 0° C. 1-chloroethyl chloroformate (0.156 mL, 1.45 mmol) was added via syringe. The mixture was allowed to come to room temperature and then refluxed 3 hours. Additional 1-chloroethyl chloroformate (0.1 mL, 0.93 mmol) was added and the mixture was further refluxed overnight. Methanol (10mL) was added and the reaction was refluxed for 2 hours. The mixture was concentrated and the residue was taken up in methylene chloride and extracted with 1N NaOH and brine. The organic phase was dried, concentrated onto silica gel, and flash chromatographed (1×4 inches silica gel). Gradient elution with ethyl acetate/hexane of from 1: 1 to 100% ethyl acetate followed by elution with 2 to 10% ethanol/0.1% ammonium hydroxide/ethyl acetate gave recovered unweighed starting material. Continued elution with 15% methanol/0.1% ammonium hydroxide/ethyl acetate gave 0.32 g of the title product as a clear colorless oil which partially crystallized on standing. Trituration with ether gave 0.13 g (27%) of the title compound as white crystals: mp 141.5°-144° C.; 1H NMR δ 8.58 (br s, 1H), 8.04 (br s, 1H), 7.95 (dd, J=8, 1.5 Hz, 2H), 7.84 (d, J=9 Hz, 1H), 7.68 (dd, J=2, 9 Hz, 1H), 7.62-7.49 (m, 4H), 7.37 (t, J=8 Hz, 1H), 7.12 (d, J=7 Hz, 1H), 3.32-3.22 (m, 5H), 3.16 (br s, 3H), 2.40 (br s, 1H, exchanges with D2O). HRMS m/e calculated for C21H21N3O: 331.1680. Observed m/e: 331.1682.
Reaction SMILES: [CH2:1]([C:8]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([OH:15])[C:9]([O:11][CH2:12][CH:13]=[CH2:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:22]Cl>CN(C)C=O>[CH2:1]([C:8]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([O:15][CH3:22])[C:9]([O:11][CH2:12][CH:13]=[CH2:14])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=CCOC(=O)C(O)(Cc1ccccc1)c1ccccc1
Reactant: CCl
Solvent: CN(C)C=O
Product: C=CCOC(=O)C(Cc1ccccc1)(OC)c1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Into a suspension of 0.75 g of 66% sodium hydride-paraffin in 20 cc of dimethylformamide was added a solution of 5.6 g of allyl α-benzyl-α-hydroxyphenylacetate in 10 cc of dimethylformamide under cooling, and the mixture was stirred for 1 hour. Successively, methyl chloride was introduced into the mixture. The reaction mixture was poured in ice-water and the resultant was subjected to extraction with ether. The ether extract was washed with an aqueous solution saturated with sodium chloride, and dried over sodium sulfate. Thereafter, ether was distilled out and paraffin was removed, whereby, 5.1 g oily allyl α-benzyl-α-methoxyphenylacetate, nD25 1.5488 was obtained.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][C:12]([C:15]([C:17]([CH3:40])([CH3:39])[CH2:18][C:19]3[CH:38]=[CH:37][C:22]4[N:23]([CH3:36])[C:24]([CH2:26][NH:27][C:28]5[CH:33]=[CH:32][C:31]([C:34]#[N:35])=[CH:30][CH:29]=5)=[N:25][C:21]=4[CH:20]=3)=[O:16])([CH3:14])[CH3:13])=[CH:10][C:5]=2[N:4]=[C:3]1[CH2:41][NH:42][C:43]1[CH:48]=[CH:47][C:46]([C:49]#[N:50])=[CH:45][CH:44]=1.[ClH:51].C(=O)([O-])[O-].[NH4+:56].[NH4+:57]>C(O)C>[ClH:51].[CH3:36][N:23]1[C:22]2[CH:37]=[CH:38][C:19]([CH2:18][C:17]([C:15]([C:12]([CH3:14])([CH3:13])[CH2:11][C:9]3[CH:8]=[CH:7][C:6]4[N:2]([CH3:1])[C:3]([CH2:41][NH:42][C:43]5[CH:48]=[CH:47][C:46]([C:49](=[NH:56])[NH2:50])=[CH:45][CH:44]=5)=[N:4][C:5]=4[CH:10]=3)=[O:16])([CH3:40])[CH3:39])=[CH:20][C:21]=2[N:25]=[C:24]1[CH2:26][NH:27][C:28]1[CH:33]=[CH:32][C:31]([C:34](=[NH:57])[NH2:35])=[CH:30][CH:29]=1
Reactant: Cn1c(CNc2ccc(C#N)cc2)nc2cc(CC(C)(C)C(=O)C(C)(C)Cc3ccc4c(c3)nc(CNc3ccc(C#N)cc3)n4C)ccc21
Reactant: [NH4+]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCO
Product: Cn1c(CNc2ccc(C(=N)N)cc2)nc2cc(CC(C)(C)C(=O)C(C)(C)Cc3ccc4c(c3)nc(CNc3ccc(C(=N)N)cc3)n4C)ccc21

Procedure:
Prepared analogously to Example 25d from 1-methyl-2-[N-(4-cyanophenyl)aminomethyl]benzimidazol-5-yl-tert-butyl ketone, ethanolic hydrochloric acid, ethanol, and ammonium carbonate.