Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH2:14][NH2:15])=[CH:4][CH:3]=1.Cl[CH2:17][C:18]([NH2:20])=[O:19].C(=O)(O)[O-].[Na+]>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH2:14][NH:15][CH2:17][C:18]([NH2:20])=[O:19])=[CH:6][CH:7]=1
Reactant: NCc1ccccc1-c1ccc(Cl)cc1
Reactant: NC(=O)CCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: NC(=O)CNCc1ccccc1-c1ccc(Cl)cc1

Procedure:
A reaction vessel was charged with 7.62 g (30 mmole) of [(4-chlorophenyl)phenyl]methylamine dissolved in 150 ml of absolute ethanol. A mixture of 2.34 g (25 mmole) of chloracetamide and 5.46 g (5 mmole) of sodium bicarbonate was added to the vessel and the resulting suspension was brought to reflux and held at reflux for 2 days. The solution was then cooled, filtered and evaporated under reduced pressure. The residue was dissolved in water and extracted with dichloromethane. The organic phase was dried over magnesium sulfate and evaporated under reduced pressure. The oily residue was solidified in pentane and crystallized in toluene.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[OH:25][N:26]1[C:30]2[CH:31]=[C:32]([C:35]([OH:37])=O)[CH:33]=[CH:34][C:29]=2[N:28]=[N:27]1.CN(C=O)C.[C:43]([O:48][CH2:49][O:50][C:51](=[O:71])[C@H:52]([OH:70])[CH2:53][C@H:54]([NH2:69])[CH2:55][C:56]1[CH:61]=[CH:60][C:59]([C:62]2[CH:67]=[CH:66][CH:65]=[C:64]([Cl:68])[CH:63]=2)=[CH:58][CH:57]=1)(=[O:47])[CH2:44][CH2:45][CH3:46].CCN(C(C)C)C(C)C>>[C:43]([O:48][CH2:49][O:50][C:51](=[O:71])[C@H:52]([OH:70])[CH2:53][C@H:54]([NH:69][C:35]([C:32]1[CH:33]=[CH:34][C:29]2[N:28]=[N:27][N:26]([OH:25])[C:30]=2[CH:31]=1)=[O:37])[CH2:55][C:56]1[CH:61]=[CH:60][C:59]([C:62]2[CH:67]=[CH:66][CH:65]=[C:64]([Cl:68])[CH:63]=2)=[CH:58][CH:57]=1)(=[O:47])[CH2:44][CH2:45][CH3:46]
Reactant: O=C(O)c1ccc2nnn(O)c2c1
Reactant: CCCC(=O)OCOC(=O)[C@H](O)C[C@H](N)Cc1ccc(-c2cccc(Cl)c2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCCC(=O)OCOC(=O)[C@H](O)C[C@@H](Cc1ccc(-c2cccc(Cl)c2)cc1)NC(=O)c1ccc2nnn(O)c2c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 10.8 %

Procedure:
HATU (37.9 mg, 99.6 μmol) was added to a solution of 1-hydroxy-1H-1,2,3-benzotriazole-6-carboxylic acid (14.9 mg, 83 μmol) in DMF (0.5 mL, 6.4 mmol) and the resulting mixture was stirred at room temperature for 5 minutes. (2R,4R)-4-Amino-5-(3′-chlorobiphenyl-4-yl)-2-hydroxypentanoic acid butyryloxymethyl ester (27.9 mg, 66.4 mol) was added to the mixture, followed by DIPEA (35 μL, 0.2 mmol) dropwise over 5 minutes, and the mixture was stirred at room temperature for 30 minutes. The mixture was concentrated in vacuo to yield a yellow liquid, which was purified by preparative HPLC to yield the title compound as a white solid (5.2 mg, purity 98.2%). MS m/z [M+H]+ calc'd for C29H29ClN4O7, 581.17. found 581.2.
Reaction SMILES: Cl.[C:2]([NH:5][C:6]1[S:7][CH:8]=[C:9]([C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=2)=[O:12])[N:10]=1)(=[O:4])[CH3:3].[N:21]#[C:22][NH2:23]>COCCO>[C:2]([NH:5][C:6]1[S:7][CH:8]=[C:9]([C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:22]([NH2:23])=[NH:21])=[CH:16][CH:15]=2)=[O:12])[N:10]=1)(=[O:4])[CH3:3]
Reactant: CC(=O)Nc1nc(C(=O)Nc2ccc(N)cc2)cs1
Reactant: N#CN
Agent: Cl
Solvent: COCCO
Product: CC(=O)Nc1nc(C(=O)Nc2ccc(NC(=N)N)cc2)cs1
Temperature: 100 °C
Reaction time: 72 h
Yield: 63.2 %

Procedure:
A mixture of 2-(acetylamino)-N-(4-aminophenyl)-1,3-thiazole-4-carboxamide hydrochloride (70 mg), cyanamide (11 mg) and 2-methoxyethanol (2 ml) was stirred at 100° C. for 72 hours. The reaction mixture was concentrated in vacuo. To the residue was added ethyl acetate (5 ml) and saturated aqueous sodium hydrogen bicarbonate (5 ml). The precipitated solid was filtered and washed with ethyl acetate and water to give 2-(acetylamino)-N-(4-{[amino(imino)methyl]amino}phenyl)-1,3-thiazole-4-carboxamide (45 mg).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:15](=[O:17])[N:14](CCCOC3CCCCO3)[C:13](=[O:28])[N:12]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[C:11]=2[N:10]=[C:9]1Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:38][C:39]([F:49])([F:48])[O:40][C:41]1[CH:42]=[C:43]([OH:47])[CH:44]=[CH:45][CH:46]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:1]([N:8]1[C:16]2[C:15](=[O:17])[NH:14][C:13](=[O:28])[N:12]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:34])([CH3:36])[CH3:35])[C:11]=2[N:10]=[C:9]1[O:47][C:43]1[CH:44]=[CH:45][CH:46]=[C:41]([O:40][C:39]([F:38])([F:48])[F:49])[CH:42]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1cccc(OC(F)(F)F)c1
Reactant: C[Si](C)(C)CCOCn1c(=O)n(CCCOC2CCCCO2)c(=O)c2c1nc(Cl)n2Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1c(=O)[nH]c(=O)c2c1nc(Oc1cccc(OC(F)(F)F)c1)n2Cc1ccccc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 87.3 %

Procedure:
To a solution of 7-benzyl-8-chloro-3-((2-(trimethylsilyl)ethoxy)methyl)-1H-purine-2,6(3H,7H)-dione (500 mg, 1.232 mmol, product of intermediate 18, step 4) in DMF (3 mL) was added 3-(trifluoromethoxy)phenol (280 mg, 1.55 mmol), followed by potassium carbonate (400 mg, 2.90 mmol). The mixture was stirred at 80° C. overnight. The reaction was cooled and partitioned between ethyl acetate and water. The organic phase was washed with brine, dried over sodium sulfate, and concentrated to give 7-benzyl-8-(3-(trifluoromethoxy)phenoxy)-3-((2-(trimethylsilyl)ethoxy)methyl)-1H-purine-2,6(3H,7H)-dione (0.59 g, 87.3% yield) as brown oil. LCMS retention time 2.157 min; LCMS MH+ 549.
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]2[C:6](=[O:10])[CH2:7][CH2:8][O:9][C:4]=2[C:3]=1[CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[CH3:22][O:23][C:24](=[O:44])[CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[O:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38]OS(C)(=O)=O>>[CH3:22][O:23][C:24](=[O:44])[CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[O:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][O:1][C:2]1[CH:12]=[CH:11][C:5]2[C:6](=[O:10])[CH2:7][CH2:8][O:9][C:4]=2[C:3]=1[CH2:13][CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COC(=O)CCc1ccccc1OCCCCCOS(C)(=O)=O
Reactant: O=C1CCOc2c1ccc(O)c2CCCc1ccccc1
Product: COC(=O)CCc1ccccc1OCCCCCOc1ccc2c(c1CCCc1ccccc1)OCCC2=O
Yield: 75.5 %

Procedure:
Using the procedure of example 11 and starting with 1.13 g (4 mmol) of 2,3-dihydro-7-hydroxy-8-(3-phenylpropyl)-4H-1-benzopyran-4-one (from example 194) and 1.38 g (4 mmol) of 2-[[5-[(methylsulfonyl)oxy]pentyl]oxy]benzenepropanoic acid methyl ester (from example 72), 2-[[5-[[3,4-dihydro-4-oxo-8-(3-phenylpropyl)-2H-1-benzopyran-7-yl]oxy]pentyl]oxy]benzenepropanoic acid methyl ester was obtained in 75.5% yield (1.6 g) as a pale-yellow oil. This diester (3 mmol) was saponified with 13.6 mL of 3N aqueous lithium hydroxide in 80 mL of tetrahydrofuran, at room temperature, for 96 hr. Work-up as in example 4 and recrystallization from ethyl acetate gave 0.6 g (38.5%) of the title acid, a colorless solid, mp 98°-99° C.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20](SCC)=[N:19][C:18]4=[O:25])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:28]([F:31])([F:30])[F:29])[CH:3]=1.[CH3:32][NH:33][C:34]([C@@H:36]1[CH2:41][NH:40][CH2:39][CH2:38][NH:37]1)=[O:35]>>[Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20]([N:40]5[CH2:39][CH2:38][NH:37][C@H:36]([C:34]([NH:33][CH3:32])=[O:35])[CH2:41]5)=[N:19][C:18]4=[O:25])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:28]([F:31])([F:30])[F:29])[CH:3]=1
Reactant: CCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Reactant: CNC(=O)[C@@H]1CNCCN1
Product: CNC(=O)[C@@H]1CN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(Cl)cc4C(F)(F)F)c3)S2)CCN1

Procedure:
(2S)-4-[5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-4-oxo-4,5-dihydro-1,3-thiazol-2-yl]-N-methylpiperazine-2-carboxamide was prepared from 5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-one and (2S)-piperazine-2-carboxylic acid methylamide following General Procedure C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[CH:10][CH2:11][NH2:12])=[CH:5][CH:4]=1.[C:21]1([S:27](Cl)(=[O:29])=[O:28])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>N1C=CC=CC=1.C(OCC)(=O)C>[CH3:20][O:19][C:16]1[CH:15]=[CH:14][C:13]([C:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)=[CH:10][CH2:11][NH:12][S:27]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)(=[O:29])=[O:28])=[CH:18][CH:17]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: COc1ccc(C(=CCN)c2ccc(OC)cc2)cc1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: COc1ccc(C(=CCNS(=O)(=O)c2ccccc2)c2ccc(OC)cc2)cc1
Reaction time: 5 h
Yield: 88 %

Procedure:
2.69 g of 3,3-bis-(4-methoxyphenyl)allylamine was dissolved in 5 ml of pyridine. To the obtained solution, 1.9 g of benzenesulfonyl chloride was added under icecooling and the mixture was stirred for five hours. After the completion of the reaction, the reaction mixture was dissolved in ethyl acetate and washed with 5% hydrochloric acid and a saturated saline solution successively. The crude product thus obtained was purified by silica gel chromatography in a conventional manner. Thus 3.6 g of the title compound was obtained in the form of a colorless oily product.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:33])[CH2:5][O:6][C:7]1[C:12]([CH3:13])=[CH:11][C:10]([NH:14][CH2:15][C:16]2[S:20][C:19]([C:21]3[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=3)=[N:18][C:17]=2[CH3:31])=[CH:9][C:8]=1[CH3:32])[CH3:2].[CH2:34](I)[CH3:35].C([O-])([O-])=O.[K+].[K+]>CS(C)=O>[CH2:1]([O:3][C:4](=[O:33])[CH2:5][O:6][C:7]1[C:12]([CH3:13])=[CH:11][C:10]([N:14]([CH2:34][CH3:35])[CH2:15][C:16]2[S:20][C:19]([C:21]3[CH:22]=[CH:23][C:24]([C:27]([F:28])([F:30])[F:29])=[CH:25][CH:26]=3)=[N:18][C:17]=2[CH3:31])=[CH:9][C:8]=1[CH3:32])[CH3:2]
Reactant: CCI
Reactant: CCOC(=O)COc1c(C)cc(NCc2sc(-c3ccc(C(F)(F)F)cc3)nc2C)cc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCOC(=O)COc1c(C)cc(N(CC)Cc2sc(-c3ccc(C(F)(F)F)cc3)nc2C)cc1C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
0.102 g (0.21 mmol) of the above prepared (2,6-dimethyl-4-{[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethyl]-amino}-phenoxy)-acetic acid ethyl ester was dissolved in 1.5 ml of abs. DMSO and treated with 0.066 g (0.43 mmol) of ethyl iodide and 0.032 g (0.23 mmol) of K2CO3. After vigorously stirring for 18 h at ambient temperature, the reaction mixture was poured onto crashed ice/aqueous 10% KHSO4, extracted twice with EtOAc, the organic layer was washed with water and brine, dried over magnesium sulfate, and evaporated to dryness. Flash chromatography (SiO2, hexane/EtOAc=8/2), yielded finally 0.067 g of the title compound as yellow oil, MS: 507.6 (MH)+.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]([C:9]2[O:13][CH:12]=[N:11][C:10]=2[CH3:14])(O)[CH3:7])=[CH:2]1.C[Si]([N:19]=[N+:20]=[N-:21])(C)C.B(F)(F)F.O>C1C=CC=CC=1>[N:19]([C:6]([C:3]1[CH:4]=[CH:5][O:1][CH:2]=1)([C:9]1[O:13][CH:12]=[N:11][C:10]=1[CH3:14])[CH3:7])=[N+:20]=[N-:21]
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: Cc1ncoc1C(C)(O)c1ccoc1
Agent: FB(F)F
Solvent: c1ccccc1
Solvent: O
Product: Cc1ncoc1C(C)(N=[N+]=[N-])c1ccoc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-(3-Furyl)-1-(4-methyl-5-oxazolyl)ethanol (1 g) was suspended in benzene (4 ml). Trimethylsilylazide (822 μl) was added followed by boron trifluoride diethyletherate (770 μl). The mixture was stirred overnight at room temperature, then poured into water and extracted to give the title compound.
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[K].S(O[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][C:41]([O:43][CH3:44])=[O:42])(C1C=CC(C)=CC=1)(=O)=O>CN(C)C=O>[C:1]1(=[O:11])[N:5]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][C:41]([O:43][CH3:44])=[O:42])[C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12
Reactant: COC(=O)CCCCCCCCCCCCCCCCCOS(=O)(=O)c1ccc(C)cc1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Product: COC(=O)CCCCCCCCCCCCCCCCCN1C(=O)c2ccccc2C1=O
Temperature: 110 °C
Reaction time: 2 h

Procedure:
A mixture of potassium phthalimide (2.96 g, 16.0 mmoles) and 100 ml of dried N,N-dimethylformamide was heated at 110° C. To this mixture was added dropwise 80 ml of a solution of methyl 18-tosyloxyoctadecanoate (5.0 g, 10.7 mmoles) in 80 ml of N,N-dimethylformamide, and the mixture was heated with stirring at 110° C. for 2 hours. The reaction mixture was poured into ice water to a total volume of 1.2 1, and stirred for 30 minutes. Thereafter, the precipitates that formed were collected by filtration and dissolved in chloroform. The obtained solution was washed with water and then with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and isolated and purified by silica gel column chromatography [eluent: mixture of benzene and methylene chloride (volume ratio: 2:1)], to give methyl 18-phtahlimideocatadecanoate (4.15 g, 88%) having the following properties.
Reaction SMILES: [NH:1]1[C:5]([C:6]2[CH:7]=[C:8]([CH2:12][OH:13])[CH:9]=[CH:10][CH:11]=2)=[N:4][N:3]=[N:2]1.[CH3:14][S:15](Cl)(=[O:17])=[O:16].C(N(CC)CC)C>ClCCl>[CH3:14][S:15]([O:13][CH2:12][C:8]1[CH:9]=[CH:10][CH:11]=[C:6]([C:5]2[NH:1][N:2]=[N:3][N:4]=2)[CH:7]=1)(=[O:17])=[O:16]
Reactant: CS(=O)(=O)Cl
Reactant: OCc1cccc(-c2nnn[nH]2)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCc1cccc(-c2nnn[nH]2)c1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
50 mg (0.28 mmol) of the compound from Example 49A are dissolved in 5 ml of dry dichloromethane, and 33 μl (0.43 mmol) of methanesulfonyl chloride and 0.06 ml (0.43 mmol) of triethylamine are added. The reaction mixture is stirred at RT for 10 h. The reaction mixture is then diluted with 10 ml of dichloromethane and washed in each case once with in each case 5 ml of water, 1 N hydrochloric acid and saturated aqueous sodium chloride solution. The organic phase is dried over magnesium sulfate. Removal of the solvent on a rotary evaporator gives a solid which is used in the next reaction without further purification.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:11])[C@H:5]([CH2:7][CH2:8][S:9][CH3:10])[NH2:6].[CH3:12][N:13]1[CH2:18][CH2:17][N:16]([C:19]2[S:20][CH:21]=[C:22]([C:24]3[CH:29]=[CH:28][C:27]([C:30]4[O:34][C:33](=[O:35])[C:32]5([CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]5)[N:31]=4)=[CH:26][CH:25]=3)[N:23]=2)[CH2:15][CH2:14]1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH3:2][O:3][C:4](=[O:11])[C@H:5]([CH2:7][CH2:8][S:9][CH3:10])[NH:6][C:33]([C:32]1([NH:31][C:30]([C:27]2[CH:28]=[CH:29][C:24]([C:22]3[N:23]=[C:19]([N:16]4[CH2:15][CH2:14][N:13]([CH3:12])[CH2:18][CH2:17]4)[S:20][CH:21]=3)=[CH:25][CH:26]=2)=[O:34])[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40]1)=[O:35]
Reactant: CN1CCN(c2nc(-c3ccc(C4=NC5(CCCCC5)C(=O)O4)cc3)cs2)CC1
Reactant: COC(=O)[C@@H](N)CCSC
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@H](CCSC)NC(=O)C1(NC(=O)c2ccc(-c3csc(N4CCN(C)CC4)n3)cc2)CCCCC1
Temperature: 80 °C
Reaction time: 15 h
Yield: 33.3 %

Procedure:
200 mg (1.00 mmol) of L-methionine methyl ester hydrochloride was added to a solution of 411 mg (1.00 mmol) of 2-[4-[2-(4-methyl-1-piperazinyl)-4-thiazolyl]phenyl]-3-oxa-1-azaspiro[4.5]dec-1-en-4-one and 258 mg (2.00 mmol) of N,N-diisopropylethylamine in 20 ml of dimethylformamide. After the mixture was stirred at 80° C. for 15 hours, the reaction solution was concentrated under reduced pressure, ethyl acetate was added thereto, and the mixture was successively washed with water, a saturated aqueous sodium hydrogencarbonate solution and saturated brine and dried with anhydrous sodium sulfate. After the solvent was distilled off under reduced pressure, it was purified by silica gel chromatography to obtain 191 mg (33%) of the title compound.
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][CH2:11][N:12]1[C:20](=[O:21])[C:19]2[N:18]([CH2:22][C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)[C:17]([CH:30]([OH:32])[CH3:31])=[N:16][C:15]=2[N:14]([CH3:33])[C:13]1=[O:34])(C(C)(C)C)(C)C.Cl>C(O)C.O>[Cl:29][C:26]1[CH:25]=[CH:24][C:23]([CH2:22][N:18]2[C:19]3[C:20](=[O:21])[N:12]([CH2:11][CH2:10][CH2:9][OH:8])[C:13](=[O:34])[N:14]([CH3:33])[C:15]=3[N:16]=[C:17]2[CH:30]([OH:32])[CH3:31])=[CH:28][CH:27]=1
Reactant: CC(O)c1nc2c(c(=O)n(CCCO[Si](C)(C)C(C)(C)C)c(=O)n2C)n1Cc1ccc(Cl)cc1
Agent: Cl
Solvent: O
Solvent: CCO
Product: CC(O)c1nc2c(c(=O)n(CCCO)c(=O)n2C)n1Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 29.8 %

Procedure:
Step 2 1-(3-((tert-butyldimethysilyl)oxy)propyl)-7-(4-chlorobenzyl)-8-(1-hydroxyethyl)-3-methyl-1H-purine-2,6(3H,7H)-dione (0.052 g, 0.10 mmoL) was dissolved in ethanol (2 mL) and 6N aqueous HCl (0.5 mL) was added. The clear solution was stirred at room temperature for 1 h. The reaction was diluted with water (25 mL) and extracted with DCM (3×25 mL). The combined organic extracts were dried with magnesium sulfate, filtered and the solvent removed under reduced pressure to a golden oil. The oil was purified using a 2000 micron preparative TLC plate eluted with 50% ethyl acetate/hexanes. Target band was extracted with ethyl acetate and the solvent was removed under reduced pressure to give 7-(4-chlorobenzyl)-8-(1-hydroxyethyl)-1-(3-hydroxypropyl)-3-methyl-1H-purine-2,6(3H,7H)-dione (0.012 g, 29% yield) as a clear oil. LCMS retention time=2.429 min and 96% purity, LCMS MH+ 393. 1H NMR (CDCl3) δ 7.25 (dd, 4H, J=8 Hz and 64 Hz), 5.65 (dd, J=12 Hz and 40 Hz), 4.91-4.97 (m, 1H), 4.19 (t, 2H, J=4 Hz), 3.61 (s, 3H), 3.51-3.55 (m, 2H), 2.52 (d, 1H, J=4 Hz), 1.87-1.93 (m, 2H), 1.57 (d, 3H, J=4 Hz).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.Cl[CH2:11][C:12]#[N:13].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:11][C:12]#[N:13])=[CH:5][CH:4]=1
Reactant: COc1ccc(O)cc1
Reactant: N#CCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1ccc(OCC#N)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 4-methoxyphenol (10 g, 80 mmol), chloroacetonitrile (7.0 mL, 111 mmol) and K2CO3 (26 g, 188 mmol) in acetone (150 mL) was stirred at r.t. for 18 h. The mixture was filtered, concentrated and purified by flash chromatography (Hex:EtOAc, 4:1) to yield (4-methoxyphenoxy)acetonitrile as a clear oil.
Reaction SMILES: [I:1]I.[CH3:3][C:4]1([C:11]([OH:13])=[O:12])[CH2:9][CH2:8][C:7](=[CH2:10])[CH2:6][CH2:5]1.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(#N)C>[I:1][CH2:10][C:7]12[CH2:6][CH2:5][C:4]([CH3:3])([CH2:9][CH2:8]1)[C:11](=[O:13])[O:12]2
Reactant: C=C1CCC(C)(C(=O)O)CC1
Reactant: II
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CC#N
Product: CC12CCC(CI)(CC1)OC2=O
Yield: 46.6 %

Procedure:
7.5 g of iodine was added to a solution of 1.3 g of 1-methyl-4-methylene-1-cyclohexanecarboxylic acid in 50 ml of acetonitrile. The solution was reacted for 3 hours at room temperature. After reaction, 100 ml of an aqueous solution of sodium thiosulfate was added to the reaction solution. The solution was extracted five times with 30 ml of ethyl acetate. The organic layer obtained was washed three times with aqueous sodium thiosulfate solution and two times with an aqueous sodium chloride solution, and was dried over magnesium sulfate. The solvent was removed in vacuo. The oily substance obtained was subjected to column chromatography using 10 g of silica gel. From the fraction eluted with hexane and ethyl acetate=1:1, the solvent was removed in vacuo, yielding 1.1 g of 1-iodomethyl-4-methyl-2-oxabicyclo[2.2.2]octan-3-one as a pale yellow oil, which had the following physiochemical properties:
Reaction SMILES: C([O:5][C:6](=[O:36])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH:18]([C:20]3[S:24][C:23]([C:25]4[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=4)=[N:22][C:21]=3[CH3:35])[CH3:19])[CH:15]=2)[CH:10]=[CH:9]1)(C)(C)C.[OH-].[Na+].Cl>C1COCC1.CO>[CH3:35][C:21]1[N:22]=[C:23]([C:25]2[CH:26]=[CH:27][C:28]([C:31]([F:33])([F:34])[F:32])=[CH:29][CH:30]=2)[S:24][C:20]=1[CH:18]([O:17][C:14]1[CH:15]=[C:16]2[C:11]([CH:10]=[CH:9][N:8]2[CH2:7][C:6]([OH:36])=[O:5])=[CH:12][CH:13]=1)[CH3:19]
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1C(C)Oc1ccc2ccn(CC(=O)OC(C)(C)C)c2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1C(C)Oc1ccc2ccn(CC(=O)O)c2c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 89.7 %

Procedure:
To a solution of [rac]-(6-{1-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-ethoxy}-indol-1-yl)-acetic acid tert-butyl ester (30 mg, 58 μmol) in THF/methanol 2/1 (4.5 ml) was added a 1 N aqueous NaOH solution (1.5 ml). The reaction mixture was stirred for 14 h at ambient temperature, neutralized with 1 N aqueous HCl solution under ice cooling and concentrated under reduced pressure. The residue was dissolved in 1 N HCl/ice water 1/1 and ethyl acetate, the layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with ice water/brine 1/1, dried over sodium sulfate and the solvent was evaporated in vacuo to give the title compound (24 mg, 52 μmol, 90%) as light yellow oil.
Reaction SMILES: [C:1]([C:3]([C@H:16]1[CH2:21][CH2:20][CH2:19][NH:18][CH2:17]1)([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)#[N:2].[OH:22][CH2:23][C:24]1[CH:32]=[CH:31][C:27]([CH2:28][CH2:29]Br)=[CH:26][CH:25]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:1]([C:3]([C@H:16]1[CH2:21][CH2:20][CH2:19][N:18]([CH2:29][CH2:28][C:27]2[CH:31]=[CH:32][C:24]([CH2:23][OH:22])=[CH:25][CH:26]=2)[CH2:17]1)([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)#[N:2]
Reactant: OCc1ccc(CCBr)cc1
Reactant: N#CC(c1ccccc1)(c1ccccc1)[C@H]1CCCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: N#CC(c1ccccc1)(c1ccccc1)[C@H]1CCCN(CCc2ccc(CO)cc2)C1

Procedure:
A mixture containing 3-(R)-(+)-(1-cyano-1,1-diphenylmethyl)piperidine (0.28 g), 4-hydroxymethylphenethyl bromide (0.22 g), anhydrous potassium carbonate (0.28 g) and acetonitrile (10 ml) was heated under reflux for 5 hours. The mixture was partitioned between dichloromethane (30 ml) and 10% aqueous potassium carbonate (20 ml), the layers separated, and the aqueous layer extracted with dichloromethane (2×20 ml). The combined dichloromethane extracts were dried (MgSO4) and concentrated in vacuo to give an oil which was purified by column chromatography on silica eluting with hexane containing dichloromethane (30% up to 70%) then dichloromethane containing methanol (0% up to 5%). The product-containing fractions were combined and concentrated in vacuo to give an oil which was crystallised from acetonitrile to give the title compound as colourless rhombs, yield 0.21 g, m.p. 110°-114° C., {α]D25 +16 2° (c 1.0, CH2Cl2).
Reaction SMILES: [CH3:1][N:2]1[C:7]([NH2:8])=[N:6][C:4](=[O:5])[CH2:3]1.[S:9]1[CH:13]=[CH:12][CH:11]=[C:10]1[N:14]=[C:15]=[O:16]>CN(C=O)C.C1(C)C=CC=CC=1>[CH3:1][N:2]1[CH2:3][C:4](=[O:5])[NH:6][C:7]1=[N:8][C:15]([NH:14][C:10]1[S:9][CH:13]=[CH:12][CH:11]=1)=[O:16]
Reactant: O=C=Nc1cccs1
Reactant: CN1CC(=O)N=C1N
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CN1CC(=O)NC1=NC(=O)Nc1cccs1
Temperature: 55 °C
Reaction time: 1 h
Yield: 30.3 %

Procedure:
To 9.4 g (83 mM) of creatinine in 100 ml of anhydrous DMF was added with stirring of solution of 9.2 g (75 mM) 2-thienyl isocyanate in 60 ml of toluene. After the addition was completed, the mixture was stirred at 55° C. for 1 hr., cooled, and the solvents removed in vacuo. The residue was recrystallized first from ethanol and then ethyl acetate (treated with charcoal) to give 5.3 g of the above urea as an off-white solid, m.p. 191°-192° C. (dec.).