Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:7][N:8]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=3)[N:10]=[CH:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:20][CH3:21]>C(#N)C>[Br-:20].[OH:19][C:16]1[CH:15]=[CH:14][C:13]([C:11]2[N:10]([CH3:21])[CH2:9][NH+:8]([CH2:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH:12]=2)=[CH:18][CH:17]=1
Reactant: CBr
Reactant: Oc1ccc(-c2cn(Cc3ccccc3)cn2)cc1
Solvent: CC#N
Product: CN1C[NH+](Cc2ccccc2)C=C1c1ccc(O)cc1
Product: [Br-]
Reaction time: 2 h

Procedure:
Through a stirred and refluxing mixture of 5.5 parts of 4-[1-(phenylmethyl)-1H-imidazol-4-yl]phenol and 120 parts of acetonitrile, gaseous bromomethane is bubbled till the solution is clear. Stirring at reflux is continued for 2 hours while gaseous bromomethane is still introduced. The solvent is evaporated and the solid residue is triturated in 2-propanone. The product is filtered off and dried, yielding 7.5 parts of 4-(4-hydroxyphenyl)-3-methyl-1-(phenylmethyl)-1H-imidazolium bromide.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([NH:8][C:9]2[S:10][CH:11]=[C:12]([CH2:14][C:15]([OH:17])=O)[N:13]=2)=[O:7])=[CH:4][CH:3]=1.[CH3:20][N:21]1[CH2:26][CH2:25][CH:24]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[CH2:23][CH2:22]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:8][C:9]2[S:10][CH:11]=[C:12]([CH2:14][C:15]([N:30]3[CH2:29][CH2:28][N:27]([CH:24]4[CH2:25][CH2:26][N:21]([CH3:20])[CH2:22][CH2:23]4)[CH2:32][CH2:31]3)=[O:17])[N:13]=2)=[O:7])=[CH:18][CH:19]=1
Reactant: O=C(O)Cc1csc(NC(=O)c2ccc(Cl)cc2)n1
Reactant: CN1CCC(N2CCNCC2)CC1
Product: CN1CCC(N2CCN(C(=O)Cc3csc(NC(=O)c4ccc(Cl)cc4)n3)CC2)CC1

Procedure:
In analogy to example 1.3, [2-(4-chloro-benzoylamino)-thiazol-4-yl]-acetic acid (example 1.2) was coupled with 1-(N-methylpiperidin-4-yl)piperazine to give 4-chloro-N-(4-{2-[4-(1-methyl-piperidin-4-yl)-piperazin-1-yl]-2-oxo-ethyl}-thiazol-2-yl)-benzamide, using general procedure C. Off-white solid. MS 462.3 ([M+H]+)
Reaction SMILES: C([O:3][C:4](=O)[C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:22]=[CH:21][S:20][CH:19]=3)=[CH:14][CH:13]=2)=[CH:7][CH:6]=1)C.[H-].[H-].[H-].[H-].[Li+].[Al+3]>>[S:20]1[CH:21]=[CH:22][C:18]([C:15]2[CH:16]=[CH:17][C:12]([O:11][C:8]3[CH:9]=[CH:10][C:5]([CH2:4][OH:3])=[CH:6][CH:7]=3)=[CH:13][CH:14]=2)=[CH:19]1
Reactant: CCOC(=O)c1ccc(Oc2ccc(-c3ccsc3)cc2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: OCc1ccc(Oc2ccc(-c3ccsc3)cc2)cc1
Yield: 96.6 %

Procedure:
The title compound (300 mg, 99%) was prepared from the product of step 3 (0.35 g, 1.1 mmol) and LiAlH4 (82 mg, 2.2 mmol) using the procedure of Example 156, step 2.
Reaction SMILES: [CH:1](/O)=[CH:2]/[CH:3]=[CH:4]\[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCCCCC.C(Cl)(Cl)(Cl)[Cl:39]>>[Cl:39][CH2:1]/[CH:2]=[CH:3]\[CH2:4]/[CH:5]=[CH:6]\[CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: ClC(Cl)(Cl)Cl
Reactant: CCCCCCC/C=C\C=C/O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCCC
Product: CCCCC/C=C\C/C=C\CCl
Temperature: 23 °C
Reaction time: 9 h
Yield: 92 %

Procedure:
A mixture of (Z,Z)-undecadien-1-ol (3.42 g, 20.4 mmol) and triphenylphosphine (7.5 g, 28.6 mmol) in dry CCl4 (25 ml) was refluxed with stirring for 9 h. The reaction mixture was allowed to cool to 23° C., hexane (60 ml) was added, and stirring was continued for an additional 10 minutes. The precipitate of triphenylphosphine oxide was filtered and washed with hexane. The solvent was removed from the combined filtrate at 40° C./~30 mmHg. Evaporation distillation of the resulting residue at 125°-130° C./0.3 mmHg gave 3.5 g (92%) of (Z,Z)-1-chloro-2,5-undecadiene as a colorless liquid.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4]Cl.[C:10]([CH2:13]C(=O)C)(=[O:12])[CH3:11].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[F:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][CH2:11][C:10](=[O:12])[CH3:13]
Reactant: CC(=O)CC(C)=O
Reactant: Fc1ccccc1CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CC(=O)CCc1ccccc1F
Yield: 65.8 %

Procedure:
A stirred mixture of 2-fluorobenzyl chloride (22.47 g), acetylacetone (17.10 g), anhydrous potassium carbonate (21.5 g) and ethanol (155 ml) was heated at reflux for 18 hr. The solvent was evaporated and the residue was partitioned between water (200 ml) and ether (150 ml). The aqueous layer was washed with ether (3×150 ml). The extracts were combined, washed with brine (200 ml), dried (MgSO4) and evaporated. Distillation of the residue under reduced pressure gave the product (17 g) b.p. 58°-66°/0.5-0.6 mm.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH:11]=O)=[CH:3][CH:2]=1.[S:13]1[CH:17]=[CH:16][C:15]([CH2:18][C:19]#[N:20])=[CH:14]1>>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](/[CH:11]=[C:18](/[C:15]2[CH:16]=[CH:17][S:13][CH:14]=2)\[C:19]#[N:20])=[CH:3][CH:2]=1
Reactant: O=Cc1ccnc2ccccc12
Reactant: N#CCc1ccsc1
Product: N#C/C(=C\c1ccnc2ccccc12)c1ccsc1
Yield: 30.9 %

Procedure:
4-Quinolinecarboxaldehyde (157 mg) was condensed with 3-thiopheneacetonitrile (123 mg) through Method B (production step 3), to thereby yield the target product (yield: 81 mg, 31%).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]1(=[O:30])[NH:24][C:23](=[O:25])[C:22]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:21]12.[C:31]([NH:39][C:40]1[C:41]2[N:42]=[CH:43][N:44]([C:53]=2[N:54]=[CH:55][N:56]=1)[C@@H:45]1[O:52][C@H:49]([CH2:50][OH:51])[C@@H:47]([OH:48])[CH2:46]1)(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[C:20]1(=[O:30])[N:24]([CH:50]([OH:51])[C@H:49]2[O:52][C@@H:45]([N:44]3[C:53]4[N:54]=[CH:55][N:56]=[C:40]([NH:39][C:31](=[O:38])[C:32]5[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=5)[C:41]=4[N:42]=[CH:43]3)[CH2:46][C@@H:47]2[OH:48])[C:23](=[O:25])[C:22]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:21]12
Reactant: O=C1NC(=O)c2ccccc21
Reactant: O=C(Nc1ncnc2c1ncn2[C@H]1C[C@H](O)[C@@H](CO)O1)c1ccccc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C(Nc1ncnc2c1ncn2[C@H]1C[C@H](O)[C@@H](C(O)N2C(=O)c3ccccc3C2=O)O1)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 29.9 %

Procedure:
13.11 g (50 mmol) triphenylphosphine, 6.99 g (47.5 mmol) phthalimide and 17.77 g (50 mmol) N6-benzoyl-2′-deoxyadenosine were stirred in 400 mL dry THF, and added 9.84 mL (50 mmol) of diisopropyl azodicarboxylate under a nitrogen atmosphere. After stirring in an ice-water bath for 2 h and at the ambient temperature for 4 h, the reaction mixture was concentrated and the residue was added 100 mL dichloromethane. The precipitates thus formed were removed by filtration and the filtrate was concentrated and flashed through a silica gel column with 2:1 dichloromethane-THF and 19:1 dichloromethane-methanol to give 7.1 g of 5′-phthalimido-N6-benzoyl-2′-deoxyadenosine.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH3:7].[CH2:8]([Li])[CH2:9]CC.[CH2:13]1[CH2:17][O:16][CH2:15][CH2:14]1>>[CH:13]1([C:17](=[O:16])[CH2:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[CH2:14][CH2:15][CH2:9][CH2:8]1
Reactant: [Li]CCCC
Reactant: Cc1ccccn1
Reactant: C1CCOC1
Product: O=C(Cc1ccccn1)C1CCCC1
Temperature: -78 °C
Reaction time: 1 h
Yield: 77 %

Procedure:
A 100 mL round bottom flask was charged with 2-picoline (2.97 mL, 30.05 mmol) and anhydrous THF (30 mL). The solution was cooled to −78° C. and n-butyllithium (20.7 mL of a 1.6 M solution in THF, 33.1 mmol) was added dropwise. The reaction mixture was slowly warmed to room temperature and then stirred for one hour. The reaction mixture was then cooled back to −78° C. and N-methoxy-N-methyl-cyclopentyl amide (5.0 g, 31.85 mmol) was added. The reaction mixture was allowed to warm to room temperature overnight with stirring and then quenched with 0.1 N HCl to pH 9. The mixture was then extracted with methylene chloride, the organic extracts were combined, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The residue was purified by flash chromatography (ethyl acetate:hexane, 3:7, silica gel) to provide 1-cyclopentyl-2-(2-pyridyl)ethan-1-one (4.35 g, 77%).
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[C:13]2[NH:15][C:16](=[O:38])[C:17]3([CH:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=4[F:29])[CH:20]([C:30](O)=[O:31])[NH:19][CH:18]3[CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:12]2=[CH:11][CH:10]=1.C(N(C(C)C)CC)(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[CH3:63][CH:64]1[CH2:69][N:68]([C:70]2[CH:76]=[CH:75][C:73]([NH2:74])=[C:72]([O:77][CH3:78])[CH:71]=2)[CH2:67][CH:66]([CH3:79])[O:65]1>>[CH3:63][CH:64]1[O:65][CH:66]([CH3:79])[CH2:67][N:68]([C:70]2[CH:76]=[CH:75][C:73]([NH:74][C:30]([CH:20]3[NH:19][CH:18]([CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:17]4([C:12]5[C:13](=[CH:14][C:9]([Cl:8])=[CH:10][CH:11]=5)[NH:15][C:16]4=[O:38])[CH:21]3[C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=3[F:29])=[O:31])=[C:72]([O:77][CH3:78])[CH:71]=2)[CH2:69]1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Reactant: COc1cc(N2CC(C)OC(C)C2)ccc1N
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(N2CC(C)OC(C)C2)ccc1NC(=O)C1NC(CC(C)(C)C)C2(C(=O)Nc3cc(Cl)ccc32)C1c1cccc(Cl)c1F
Yield: 37.4 %

Procedure:
In a manner similar to the method described in Example 5, rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid trifluoroacetic acid prepared in Example 4 (0.25 g, 0.43 mmol), was reacted with diisopropylethylamine (0.29 g, 2.2 mmol), diphenylphosphinic chloride (0.21 g, 0.89 mmol), then reacted with 4-(2,6-dimethylmorpholino)-2-methoxyaniline (Bionet) (0.11 g, 0.44 mmol) to give rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid [4-(2,6-dimethyl-morpholin-4-yl)-2-methoxy-phenyl]-amide as a white solid (Yield 0.11 g, 37%).
Reaction SMILES: [O:1]=[C:2]1[C:7]2([CH2:11][CH2:10][CH2:9][CH2:8]2)[NH:6][CH2:5][CH2:4][CH:3]1C(OCC)=O.Cl>O>[CH2:11]1[C:7]2([C:2](=[O:1])[CH2:3][CH2:4][CH2:5][NH:6]2)[CH2:8][CH2:9][CH2:10]1
Reactant: CCOC(=O)C1CCNC2(CCCC2)C1=O
Agent: Cl
Solvent: O
Product: O=C1CCCNC12CCCC2

Procedure:
A mixture of ethyl 10-oxo-6-azaspiro[4.5]decan-9-carboxylate (7.6 g), concentrated hydrochloric acid (35 ml) and water (35 ml) was heated at 90°-95° C. for 8 hours. The solvent was removed in vacuo and the residue diluted with ice-water (35 ml) and basified by the addition of an excess of 5M aqueous sodium hydroxide solution. The product was extracted into ethyl acetate and the extracts were washed with brine, dried over magnesium sulphate and the solvent removed in vacuo to give 6-azaspiro[4.5]decan-10-one. Yield 3.1 g.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.Br[CH:10]1[C:16](=[O:17])[CH2:15][CH2:14][N:13]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:12][CH2:11]1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH:10]2[C:16](=[O:17])[CH2:15][CH2:14][N:13]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:12][CH2:11]2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)N1CCC(=O)C(Br)CC1
Reactant: Sc1ccc(Br)cc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)N1CCC(=O)C(Sc2ccc(Br)cc2)CC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
60.5 g (320 mmol) 4-bromothiophenol in 300 mL chloroform are added to a solution of 84.5 g (320 mmol) ethyl 4-bromo-5-oxo-azepan-1-carboxylate and 32.4 g (320 mmol) triethylamine in 80 mL chloroform over 45 min, so that the internal temperature does not exceed 40° C. The reaction solution is stirred for 1.5 h at RT. The reaction mixture is washed twice with dilute ammonia solution and twice with water. The organic phase is dried over Na2SO4 and K2CO3 and the solvent is eliminated i.vac. The purification is carried out by repeated column chromatography on silica gel.
Reaction SMILES: [CH2:1]([N:3]([CH2:20]C)[CH2:4][C:5]([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)[CH2:6][NH2:7])[CH3:2].[CH3:22][O:23]CCNC>>[CH3:22][O:23][CH2:2][CH2:1][N:3]([CH3:20])[CH2:4][C:5]([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)[CH2:6][NH2:7]
Reactant: CNCCOC
Reactant: CCN(CC)CC(CN)(c1ccccc1)c1ccccc1
Product: COCCN(C)CC(CN)(c1ccccc1)c1ccccc1

Procedure:
The title material was prepared as described for the synthesis of N1,N1-diethyl-2,2-diphenylpropane-1,3-diamine (Example Q) in using 2-methoxy-N-methylethanamine LC/MS (M+H)+: 299. HPLC ret. time (Condition B): 1.480 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]([OH:12])=[O:11].I[CH2:14][CH3:15]>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH2:14][CH3:15])[C:10]([OH:12])=[O:11]
Reactant: CCI
Reactant: O=C(O)Cc1ccc(Cl)cc1Cl
Product: CCC(C(=O)O)c1ccc(Cl)cc1Cl

Procedure:
prepared from 2,4-dichlorophenylacetic acid and iodoethane;
Reaction SMILES: [CH2:1]([C:5]1[N:10]=[C:9]([Cl:11])[N:8]=[C:7](Cl)[CH:6]=1)[CH2:2][CH2:3][CH3:4].Cl.[CH2:14]([O:16][CH2:17][CH2:18][CH2:19][NH:20][C:21](=[O:28])[C@H:22]([CH2:24][CH:25]([CH3:27])[CH3:26])[NH2:23])[CH3:15].C(N(CC)C(C)C)(C)C>CS(C)=O.C(OCC)(=O)C>[CH2:14]([O:16][CH2:17][CH2:18][CH2:19][NH:20][C:21](=[O:28])[CH:22]([NH:23][C:7]1[CH:6]=[C:5]([CH2:1][CH2:2][CH2:3][CH3:4])[N:10]=[C:9]([Cl:11])[N:8]=1)[CH2:24][CH:25]([CH3:26])[CH3:27])[CH3:15]
Reactant: CCCCc1cc(Cl)nc(Cl)n1
Reactant: CCOCCCNC(=O)[C@@H](N)CC(C)C
Agent: Cl
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCCc1cc(NC(CC(C)C)C(=O)NCCCOCC)nc(Cl)n1
Temperature: 25 °C

Procedure:
6-Butyl-2,4-dichloropyrimidine (1.0 g), L-leucine-3-ethoxypropylamide hydrochloride (17 mL of a 0.32 M solution in DMSO), and N,N-diisopropylethylamine (3.0 mL) were stirred for 24 h in 20 mL methyl sulfoxide at 60 C. The solution was cooled to room temperature and diluted with ethyl acetate (100 mL), then washed 4 times with 100 mL aliquots of a saturated aqueous solution of sodium chloride. Silica gel chromatography (gradient: 20–40–50–100% ethyl acetate in hexanes) followed by semi-preparative HPLC purification of mixed fractions provided 1.24 g of 2-(6-butyl-2-chloropyrimidin-4-ylamino)-4-methypentanoic acid (3-ethoxypropyl)amide as a colorless oil.
Reaction SMILES: [P:1]([O-:6])([O:4][CH3:5])[O:2][CH3:3].[CH:7](=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[F-].[K+]>C(Cl)Cl>[OH:14][CH:7]([P:1](=[O:6])([O:4][CH3:5])[O:2][CH3:3])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: COP([O-])OC
Reactant: O=Cc1ccccc1
Agent: [F-]
Agent: [K+]
Solvent: ClCCl
Product: COP(=O)(OC)C(O)c1ccccc1
Reaction time: 0.08 h
Yield: 102.3 %

Procedure:
Dimethyl phosphite (1.86 mL, 20.3 mmol, 1.03 eq) was added to benzaldehyde (2 mL, 19.8 mmol, 1 eq) and stirred for 5 min. KF (5.75 g, 99.0 mmol, 5 eq) was then added and the reaction mixture was stirred until it solidified (˜20 min). The crude product was then dissolved in DCM, filtered, and the solvent evaporated yielding 4 as a white powder (4.38 g, 100%). The product was dried under high vacuum over P2O5. No further purification was required. 1H NMR (400 MHz CDCl3) δ 7.53-7.45 (m, 2H), 7.43-7.23 (m, 3H), 5.05 (d, J=11.1 Hz, 1H), 3.67 (dd, J=14.3, 10.4 Hz, 6H). 13C NMR (101 MHz, CDCl3) δ 136.66 (s), 128.64 (s), 128.49 (s), 127.28 (d, JC-P=5.7 Hz), 70.86 (d, JC-P=159.6 Hz), 54.02 (dd, JC-P=28.4, 7.0 Hz). 31P NMR (162 MHz CDCl3) δ 24.71 (s). ESIMS calculated for C9H13O4PNa [M+Na]+239.06, found: 239.04; mp 85-86° C.
Reaction SMILES: [OH:1][CH:2]([CH2:14][OH:15])[CH2:3][N:4]1[C:8](=[O:9])[C:7]([CH3:11])([CH3:10])[NH:6][C:5]1([CH3:13])[CH3:12].C(O[Cl:21])(C)(C)C>CO>[Cl:21][N:6]1[C:7]([CH3:10])([CH3:11])[C:8](=[O:9])[N:4]([CH2:3][CH:2]([OH:1])[CH2:14][OH:15])[C:5]1([CH3:13])[CH3:12]
Reactant: CC(C)(C)OCl
Reactant: CC1(C)NC(C)(C)N(CC(O)CO)C1=O
Solvent: CO
Product: CC1(C)C(=O)N(CC(O)CO)C(C)(C)N1Cl
Temperature: 0 °C
Reaction time: 1 h
Yield: 85.1 %

Procedure:
To a 0° C. solution of 3-(2,3-dihydroxypropyl)-2,2,5,5-tetramethylimidazolidin-4-one (250 mg, 1.2 mmol) in methanol (150 ml) was added tert-butylhypochlorite (150 mg, 1.4 mmol). The mixture was stirred for 1 hour at 0° C. The reaction mixture was concentrated in vacuo, and crude material is purified by silica gel flash chromatography (0 to 10% methanol in dichloromethane) to give 256 mg (88%) of the title compound. 1H NMR (400 MHz, D2O) δ 4.06-3.98 (m, 1H), 3.62 (dd, J=12.0, 4.0 Hz, 1H), 3.56-3.44 (m, 2H), 3.36 (dd, J=14.8, 8.4 Hz, 1H), 1.54 (s, 6H), 1.38-1.37 (m, 6H). 13C NMR (100 MHz, D2O) δ 175.5, 83.9, 69.4, 66.0, 63.4, 43.6, 24.2, 23.9, 22.72, 22.4. LRMS (ESI/APCI) m/z 251 [M+H]+.
Reaction SMILES: C(O)(=O)C.[CH2:5]([N:12]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:13](=[O:33])[CH2:14][CH2:15][CH2:16][O:17][C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][CH:27]=1)[N:24]=[C:23]1[NH:28][C:29](=[O:32])[C:30](=C)[N:22]1[CH2:21]2)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[S:41](=[O:45])(=[O:44])([OH:43])[OH:42]>O>[S:41]([OH:45])([OH:44])(=[O:43])=[O:42].[CH2:34]([N:12]([CH2:5][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)[C:13](=[O:33])[CH2:14][CH2:15][CH2:16][O:17][C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][CH:27]=1)[N:24]=[C:23]1[NH:28][C:29](=[O:32])[CH2:30][N:22]1[CH2:21]2)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: C=c1c(=O)[nH]c2n1Cc1cc(OCCCC(=O)N(Cc3ccccc3)Cc3ccccc3)ccc1N=2
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: O=C1CN2Cc3cc(OCCCC(=O)N(Cc4ccccc4)Cc4ccccc4)ccc3N=C2N1

Procedure:
N,N-dibenzyl-4-(2-oxo-3-methylene-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxybutanamide acetate (1.0 g) is dissolved in 50 ml water containing a stoichiometric equivalent of sulfuric acid, and the solution evaporated to dryness. The product is suspended in ethanol and filtered, air dried and recrystallized from methanol/acetone to yield N,N-dibenzyl-4-(2-oxo-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxybutanamide sulfate.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[CH3:9][S:10](Cl)=[O:11]>>[Cl:8][C:5]1[N:6]=[CH:7][C:2]([NH:1][S:10]([CH3:9])=[O:11])=[CH:3][N:4]=1
Reactant: Nc1cnc(Cl)nc1
Reactant: CS(=O)Cl
Product: CS(=O)Nc1cnc(Cl)nc1

Procedure:
The title compound is prepared from 5-amino-2-chloropyrimidine and methanesulfinyl chloride following a procedure analogous to that described for Intermediate 3 (Step 1). The reaction mixture is cooled in an ice bath for the entire reaction time. LC (method 1): tR=0.49 min; Mass spectrum (ESI+): m/z=192 [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:13]=[CH:12][NH:11][N:10]=2)[O:3]1.[H-].[Na+].[CH3:17][Si:18]([CH2:21][CH2:22][O:23][CH2:24]Cl)([CH3:20])[CH3:19]>C1COCC1.O>[CH3:1][C:2]1([CH3:14])[C:6]([CH3:7])([CH3:8])[O:5][B:4]([C:9]2[CH:13]=[CH:12][N:11]([CH2:24][O:23][CH2:22][CH2:21][Si:18]([CH3:20])([CH3:19])[CH3:17])[N:10]=2)[O:3]1
Reactant: CC1(C)OB(c2cc[nH]n2)OC1(C)C
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC1(C)OB(c2ccn(COCC[Si](C)(C)C)n2)OC1(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
At 0° C., 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (388 mg, 2 mmoL) was added to NaH (160 mg, 60%, 4 mmoL) in THF (12 mL). After stirring at room temperature for 30 min, the mixture was cooled to 0° C. and SEMCl (705.7 μL, 4 mmoL) was added. The mixture was stirred at room temperature overnight, diluted with H2O and then extracted with ethyl acetate (×2). The combined organic layers were washed with brine and dried with Na2SO4. Evaporation afforded crude 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]([C:18]3[C:19](=[O:31])[N:20]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[N:21]([CH3:24])[C:22]=3[CH3:23])=[O:17])=[CH:11][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[C:32]1([O:38][C:39](Cl)=[O:40])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>C(Cl)Cl.N1C=CC=CC=1.C(Cl)Cl>[CH3:24][N:21]1[C:22]([CH3:23])=[C:18]([C:16]([NH:15][C:12]2[CH:11]=[CH:10][C:9]([O:8][C:6]3[CH:5]=[CH:4][N:3]=[C:2]([NH:1][C:39](=[O:40])[O:38][C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[CH:7]=3)=[CH:14][CH:13]=2)=[O:17])[C:19](=[O:31])[N:20]1[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Cc1c(C(=O)Nc2ccc(Oc3ccnc(N)c3)cc2)c(=O)n(-c2ccccc2)n1C
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1c(C(=O)Nc2ccc(Oc3ccnc(NC(=O)Oc4ccccc4)c3)cc2)c(=O)n(-c2ccccc2)n1C
Temperature: 0 °C
Reaction time: 2 h
Yield: 42.4 %

Procedure:
A suspension of N-(4-((2-aminopyridin-4-yl)oxy)phenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide (600 mg, 1.44 mmol) in DCM/pyridine (30 mL/20 mL) was cooled to 0° C., then a solution of phenylcarbonochloridate (565 mg, 3.61 mmol) in DCM (10 mL) was added to the mixture slowly over 1 hour. The reaction was stirred at rt for 2 hours, then diluted with DCM (200 mL). The mixture was washed with water (140 mL×4), followed by washing with brine (150 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by a silica gel column chromatography (DCM/EtOAc (v/v)=2/1) to give the title compound as a white solid (327 mg, 42%).
Reaction SMILES: C([Si]([O:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH2:26][C@@H:27]2[CH2:29][O:28]2)=[CH:21][CH:20]=1)(C1C=CC=CC=1)C1C=CC=CC=1)(C)(C)C.[CH3:30][N:31]1[CH:35]=[C:34]([S:36]([N:39]2[CH2:44][CH2:43][CH:42]([CH2:45][NH2:46])[CH2:41][CH2:40]2)(=[O:38])=[O:37])[N:33]=[CH:32]1>>[OH:28][C@@H:27]([CH2:29][NH:46][CH2:45][CH:42]1[CH2:41][CH2:40][N:39]([S:36]([C:34]2[N:33]=[CH:32][N:31]([CH3:30])[CH:35]=2)(=[O:38])=[O:37])[CH2:44][CH2:43]1)[CH2:26][O:25][C:22]1[CH:21]=[CH:20][C:19]([OH:18])=[CH:24][CH:23]=1
Reactant: Cn1cnc(S(=O)(=O)N2CCC(CN)CC2)c1
Reactant: CC(C)(C)[Si](Oc1ccc(OC[C@@H]2CO2)cc1)(c1ccccc1)c1ccccc1
Product: Cn1cnc(S(=O)(=O)N2CCC(CNC[C@H](O)COc3ccc(O)cc3)CC2)c1
Yield: 10.6 %

Procedure:
Prepared from t-butyl-[4-(2S)-oxiranylmethoxy-phenoxy]-diphenylsilane (0.404 g, 1.0 mmol) and [1-(1-methyl-1H-imidazole-4-sulfonyl)-piperidin-4-ylmethyl amine (0.650 g, 1.8 mmol) according to the procedure used in example 37 to give 0.045 g of the title compound as a white solid.
Reaction SMILES: [C:1]([C:4]1[CH:8]([CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[N:7]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)[C:6](=[O:22])[C:5]=1O)(=[O:3])[CH3:2].C([O-])=O.[NH4+:27].O>C(O)C>[C:1]([C:4]1[CH:8]([CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[N:7]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)[C:6](=[O:22])[C:5]=1[NH2:27])(=[O:3])[CH3:2]
Reactant: CC(=O)C1=C(O)C(=O)N(c2ccc(C)cc2)C1C1CCCCC1
Reactant: [NH4+]
Agent: O=C[O-]
Solvent: O
Solvent: CCO
Product: CC(=O)C1=C(N)C(=O)N(c2ccc(C)cc2)C1C1CCCCC1

Procedure:
A reaction mixture of 4-acetyl-5-cyclohexyl-3-hydroxy-1-(4-methylphenyl)-1,5-dihydro-2H-pyrrol-2-one (139 mg, 0.44 mmol) and ammonium formate (342 mg, 4.44 mmol) in ethanol (0.2M, 2.2 ml) is heated at reflux for 16 hours. The solvent is removed in vacuo to give a white residue. Water is added to the residue to dissolve some of the white solid leaving a sandy-coloured precipitate. This mixture is then filtered, washed with a small amount of diethyl ether and dried under high vacuum at room temperature to give a pale brown solid.