Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:24][CH3:25])[N:12]2[CH2:15][CH2:16][CH2:17][NH:18][C@@H:19]2[CH2:23][CH2:22][CH2:21]O2)=[C:8]([NH2:26])[N:7]=1)[CH2:2][CH2:3][CH3:4].F[C:28](F)(F)[C:29](O)=[O:30].C(OC1NC(N)=C2C(N=1)=NC(OC)=N2)CCC>>[CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:24][CH3:25])[N:12]2[CH2:15][CH2:16][CH2:17][NH:18][CH2:19][CH:23]2[CH2:22][CH2:21][CH2:28][CH2:29][O:30]2)=[C:8]([NH2:26])[N:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: O=C(O)C(F)(F)F
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCCN[C@@H]3CCCO3)c2n1
Agent: CCCCOc1nc2nc(OC)nc-2c(N)[nH]1
Product: CCCCOc1nc(N)c2nc(OC)n(CCCNCC3CCCCO3)c2n1

Procedure:
Prepared similarly to Intermediate 14 from 2-(butyloxy)-8-(methyloxy)-1H-purin-6-amine trifluoroacetate and (tetrahydro-2H-pyran)-2-ylmethyl)amine hydrochloride.
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[C:18]=3[C:28]([F:31])([F:30])[F:29])[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:3](O)=[O:4].[NH2:32][CH2:33][C:34]([NH:36][CH3:37])=[O:35].CN1CCOCC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[OH:1][CH:2]([C:6]1[CH:7]=[CH:8][C:9]([C:12]2[N:16]=[C:15]([C:17]3[O:21][N:20]=[C:19]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[C:18]=3[C:28]([F:31])([F:29])[F:30])[O:14][N:13]=2)=[CH:10][CH:11]=1)[C:3]([NH:32][CH2:33][C:34]([NH:36][CH3:37])=[O:35])=[O:4]
Reactant: O=C(O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reactant: CNC(=O)CN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CNC(=O)CNC(=O)C(O)c1ccc(-c2noc(-c3onc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reaction time: 1 h
Yield: 18 %

Procedure:
2-Hydroxy-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetic acid (Int-Va, 60 mg, 0.139 mmol), 2-amino-N-methylacetamide (12.26 mg, 0.139 mmol), 4-methylmorpholine (56.3 mg, 0.556 mmol), and HATU (68.8 mg, 0.181 mmol) were added to DMF (1 mL). The mixture was stirred for 1 h before it was purified by prep HPLC (PHENOMENEX® Luna 5u 21×250 mm, gradient elution with Method 1—MeOH/water containing 0.1% trifluoroacetic acid as defined above, 0% B to 100% B over 30 min, 25 mL/min, 220 nM, product retention=29.4 min) to provide 2-hydroxy-N-(2-(methylamino)-2-oxoethyl)-2-(4-(5-(3-phenyl-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamide (13 mg, 0.025 mmol, 18.02% yield) as a single enantiomer. LCMS=502.2 [M+H]+; 1H NMR (400 MHz, methanol-d4) δ ppm 8.10-8.25 (2 H, m), 7.53-7.82 (7 H, m), 5.20 (1 H, s), 3.77-4.01 (2 H, m), 2.75 (3 H, s); HPLC peak RT=8.4 min (Method A).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([OH:16])[CH:12]=[C:13]([CH3:15])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.[F:26][C:27]([F:39])([F:38])[C:28]1[CH:29]=[C:30]([S:34](Cl)(=[O:36])=[O:35])[CH:31]=[CH:32][CH:33]=1>C(Cl)Cl.O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([O:16][S:34]([C:30]2[CH:31]=[CH:32][CH:33]=[C:28]([C:27]([F:26])([F:38])[F:39])[CH:29]=2)(=[O:36])=[O:35])[CH:12]=[C:13]([CH3:15])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1cccc(C(F)(F)F)c1
Reactant: Cc1cc(O)cc(OCc2ccccc2)c1
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(OCc2ccccc2)cc(OS(=O)(=O)c2cccc(C(F)(F)F)c2)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 84 %

Procedure:
A solution of 3-benzyloxy-5-methylphenol (400 mg, 2.0 mmol), as prepared in step a of Example 3, in methylene chloride (10 mL) at 0° C. was treated with N,N-diisopropylethylamine (0.4 mL) and 3-trifluoromethylbenzenesulfonyl chloride (489 mg, 2.0 mmol). The reaction mixture was stirred at 0° C. for 2 h and at room temperature for 2 h. The reaction mixture was diluted with methylene chloride (200 ml,) and water (50 mL). The organic extract was washed sequentially with saturated NaHCO3 (2×50 mL) and brine (2×50 mL), dried over Na2SO4, and concentrated in vacuo. The residue was purified by flash column chromatography (1:1 hexane:methylene chloride) to give the title compound as a colorless liquid (710 mg, 85%). 1H-NMR (300 MHz, CDCl3) δ 2.25 (s, 3H), 4.94 (s, 2H), 6.41 (s, 2H), 6.72 (s, 1H), 7.37 (m, 5H), 7.68 (t, 1H), 7.91 (d, 1H), 8.03 (d, 1H), 8.09 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([CH3:13])=[N:10][C:9]=2[C:14]([OH:16])=O)=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[F:50][C:51]1[C:59]2[N:58]=[C:57]([CH2:60][CH:61]3[CH2:66][CH2:65][CH2:64][CH2:63][NH:62]3)[NH:56][C:55]=2[CH:54]=[CH:53][C:52]=1[F:67]>CN(C=O)C>[F:50][C:51]1[C:59]2[N:58]=[C:57]([CH2:60][CH:61]3[CH2:66][CH2:65][CH2:64][CH2:63][N:62]3[C:14]([C:9]3[N:10]=[C:11]([CH3:13])[S:12][C:8]=3[C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)=[O:16])[NH:56][C:55]=2[CH:54]=[CH:53][C:52]=1[F:67]
Reactant: Cc1nc(C(=O)O)c(-c2ccc(F)cc2)s1
Reactant: Fc1ccc2[nH]c(CC3CCCCN3)nc2c1F
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: Cc1nc(C(=O)N2CCCCC2Cc2nc3c(F)c(F)ccc3[nH]2)c(-c2ccc(F)cc2)s1
Reaction time: 16 h
Yield: 85 %

Procedure:
A solution of 5-(4-fluoro-phenyl)-2-methyl-thiazole-4-carboxylic acid (1.00 g, 4.2 mmol), HATU (1.60 g, 4.2 mmol) and N,N-diisopropylethylamine (2.00 ml, 11.6 mmol) in DMF (20 ml) was stirred at room temperature under argon for 2 min. The mixture was then treated with (RS)-4,5-difluoro-2piperidin-2-ylmethyl-1H-benzoimidazole, D21 (1.06 g, 4.2 mmol) and stirring was continued for 16 h. The solvent was removed in vacuo and the residue was washed with water then was triturated with ethyl acetate to afford the title compound as an off-white solid (1.68 g, 85%).
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:8])[CH2:6][NH2:7])[CH3:3].C([O-])(O)=O.[Na+].[Cl:14][CH2:15][C:16](Cl)=[O:17]>>[CH2:2]([O:4][C:5](=[O:8])[CH2:6][NH:7][C:16](=[O:17])[CH2:15][Cl:14])[CH3:3]
Reactant: O=C(Cl)CCl
Reactant: CCOC(=O)CN
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: CCOC(=O)CNC(=O)CCl
Temperature: 0 °C

Procedure:
Twenty-seven and nine-tenths grams (g) (0.2 mole) of glycine ethyl ester --HCl was combined with about 100 grams of ice in a reaction flask. Solid NaHCO3 (33.6 g) (0.4 mole) was then added to this mixture followed by dropwise addition of 23.0 g (0.2 mole) of chloroacetyl chloride with stirring. The temperature of the reaction mixture was maintained between -10° and -5° C. by ice addition. The solid precipitate that formed was separated from the reaction mixture by filtration, washed with ice water and air dried. The yield was 15 g (41.7%) of a solid having a melting point of 60°-62° C. which was identified as the title compound by infrared (IR) spectroscopy analysis.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][NH:7][CH2:8][CH2:9][NH2:10].[CH2:11]([N:13]=[C:14]=[S:15])[CH3:12]>>[CH2:11]([NH:13][C:14]([NH:10][CH2:9][CH2:8][NH:7][CH2:6][C:2]1[S:1][CH:5]=[CH:4][N:3]=1)=[S:15])[CH3:12]
Reactant: CCN=C=S
Reactant: NCCNCc1nccs1
Product: CCNC(=S)NCCNCc1nccs1

Procedure:
Reacting N-(2-thiazolylmethyl)ethylenediamine with ethyl isothiocyanate by the procedure of Example 3(b) and then chromatographing gives N-ethyl-N'-[2-(2-thiazolylmethylamino)ethyl]thiourea. Reacting this thiourea with lead cyanamide by the procedure of Example 3(b) gives N-cyano-N'-ethyl-N"-[2-(2-thiazolylmethylamino)ethyl]- guanidine.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15]O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N1C=CN=C1.[I:41]I>C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][I:41])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: II
Reactant: CC(C)(C)OC(=O)N1CCC(CCO)CC1
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(CCI)CC1
Reaction time: 8 h
Yield: 82.5 %

Procedure:
To a solution of 1-(tert-butoxycarbonyl)-4-(2-hydroxyethyl)piperidine (458 mg, 2.0 mmol), Ph3P (785 mg, 3.0 mmol, 1.5 equiv.) and imidazole (204 mg, 3.0 mmol, 1.5 equiv.) in toluene (10 mL) was added I2 (761 mg, 3.0 mmol, 1.5 equiv.) at 0° C. The mixture was allowed to stand at room temperature overnight, before it was quenched with saturated Na2S2O3 solution. The product was extracted into CH2Cl2, and the organic layer was washed with brine and dried over Na2SO4. After concentration, the residue was purified by CC (SiO2, hexane/EtOAc 8:1, then 4:1). After removal of the solvents, 1-(tert-butoxycarbonyl)-4-(2-iodoethyl)piperidine (560 mg, 83%) was obtained as a colorless oil. 1H NMR (CDCl3, 400 MHz) δ 4.09 (br, 2H), 3.21 (t, 2H, J=7.2 Hz), 2.70 (t, 2H, J=12.0 Hz), 1.77 (q, 2H, J=7.2 Hz), 1.65 (d, 2H, J=12.8 Hz), 1.56 (m, 1H), 1.45 (s, 9H), 1.11 (m, 2H).
Reaction SMILES: [H-].[Na+].[C:3]([O:6][C:7]1[CH:8]=[C:9]([CH:30]([O:33][CH3:34])[O:31][CH3:32])[CH:10]=[C:11]2[C:19]=1[CH:18]([CH2:20][O:21][C:22](=[O:24])[NH2:23])[C:17]1([O:26][C:27](=[O:29])[CH3:28])[O:25][N:12]2[CH2:13][CH:14]2[CH:16]1[NH:15]2)(=[O:5])[CH3:4].CI.[C:37](O)(=O)C>O1CCCC1>[C:3]([O:6][C:7]1[CH:8]=[C:9]([CH:30]([O:31][CH3:32])[O:33][CH3:34])[CH:10]=[C:11]2[C:19]=1[CH:18]([CH2:20][O:21][C:22](=[O:24])[NH2:23])[C:17]1([O:26][C:27](=[O:29])[CH3:28])[O:25][N:12]2[CH2:13][CH:14]2[CH:16]1[N:15]2[CH3:37])(=[O:5])[CH3:4]
Reactant: COC(OC)c1cc(OC(C)=O)c2c(c1)N1CC3NC3C(OC(C)=O)(O1)C2COC(N)=O
Reactant: CC(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Product: COC(OC)c1cc(OC(C)=O)c2c(c1)N1CC3C(N3C)C(OC(C)=O)(O1)C2COC(N)=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a suspension of sodium hydride (60% in oil, 4 mg) in tetrahydrofuran (0.5 ml) was added a solution of B-isomer of 8-carbamoyloxymethyl-4-dimethoxymethyl-14-oxa-1,11-diazatetracyclo[7.4.1.02,7.010,12 ]tetradeca-2,4,6-trien-6,9-diyl diacetate (20 mg) in tetrahydrofuran (2.0 mg) in an ice-water bath. To this solution was added methyl iodide (0.4 ml) in an ice-water bath. After stirring for 3 hours at ambient temperature, acetic acid (0.1 ml) was added to the reaction mixture in an ice-water bath. The resultant mixture was evaporated in vacuo and the residual oil was subjected to preparative thin layer chromatography, which was developed with a mixture of chloroform and methanol (8:1, v/v) to afford 8-carbamoyloxymethyl-4-dimethoxymethyl-11-methyl-14-oxa-1,11-diazatetracyclo[7.4.1.02,7.010,12 ]tetradeca-2,4,6-trien-6,9-diyl diacetate (11 mg).
Reaction SMILES: C1(C)C=CC=CC=1.C(=O)([O-])O.[Na+].I[C:14]1[C:19]([O:20][C:21]2[C:30]3[C:25](=[CH:26][C:27]([O:33][CH3:34])=[C:28]([O:31][CH3:32])[CH:29]=3)[N:24]=[CH:23][CH:22]=2)=[CH:18][CH:17]=[C:16]([CH3:35])[N:15]=1.[OH:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=1B(O)O>O>[CH3:32][O:31][C:28]1[CH:29]=[C:30]2[C:25](=[CH:26][C:27]=1[O:33][CH3:34])[N:24]=[CH:23][CH:22]=[C:21]2[O:20][C:19]1[C:14]([C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=2[OH:36])=[N:15][C:16]([CH3:35])=[CH:17][CH:18]=1
Reactant: OB(O)c1ccccc1O
Reactant: COc1cc2nccc(Oc3ccc(C)nc3I)c2cc1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(C)nc3-c3ccccc3O)c2cc1OC
Temperature: 80 °C
Reaction time: 8 h
Yield: 97.8 %

Procedure:
Toluene (1 ml) and a saturated aqueous sodium hydrogencarbonate solution (0.5 ml) were added to 4-(2-iodo-6-methyl-pyridin-3-yloxy)-6,7-dimethoxy-quinoline (compound 116) (50 mg), tetrakistriphenylphosphine palladium (14 mg), and 2-hydroxyphenylboronic acid (81 mg) under an argon atmosphere, and the mixture was stirred at 80° C. overnight. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with chloroform. The chloroform layer was then washed with water and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-methanol to give the title compound (45 mg, yield 93%).
Reaction SMILES: Br[C:2]1[C:3]([C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)=[N:4][C:5]([NH:8][CH3:9])=[N:6][CH:7]=1.C(N(CC)CC)C.[C:22]([Si:24]([CH3:27])([CH3:26])[CH3:25])#[CH:23]>[Cu]I.C(#N)C>[CH3:9][NH:8][C:5]1[N:4]=[C:3]([C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)[C:2]([C:23]#[C:22][Si:24]([CH3:27])([CH3:26])[CH3:25])=[CH:7][N:6]=1
Reactant: C#C[Si](C)(C)C
Reactant: CNc1ncc(Br)c(-c2cccs2)n1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CNc1ncc(C#C[Si](C)(C)C)c(-c2cccs2)n1
Temperature: 90 °C

Procedure:
A 75 mL thick wall glass tube with a teflon screw cap was charged with 5-bromo-N-methyl-4-(thiophen-2-yl)pyrimidin-2-amine (0.995 g, 3.68 mmol), acetonitrile (9 mL), triethylamine (3.00 ml, 3.68 mmol), dichlorobistriphenylphosphine palladium(II) (0.259 g, 0.368 mmol), copper(I) iodide (0.0351 g, 0.184 mmol), and ethynyltrimethylsilane (0.362 g, 3.68 mmol). The tube was capped and heated to 90° C. for 2 hours. The reaction mixture was cooled to room temperature and concentrated. The residue was purified via column chromatography on silica gel (gradient elution with 0-100% ethyl acetate-hexane) to afford N-methyl-4-(thiophen-2-yl)-5-(2-(trimethylsilyl)ethynyl)pyrimidin-2-amine. MS m/z=288 [M+H]+. Calc'd for C14H17N3SSi: 287.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C:13]1[N:14]=[C:15]([C:24]([CH3:28])([CH3:27])[CH2:25]N)[NH:16][C:17]=1[C:18]1[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=1)[CH:7]=[CH:6]2.O1CCCC1.CC[N:36](C(C)C)C(C)C.[CH3:43][S:44](Cl)(=[O:46])=[O:45]>O.ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C:13]1[N:14]=[C:15]([C:24]([CH3:27])([CH3:28])[CH2:25][CH2:43][S:44]([NH2:36])(=[O:46])=[O:45])[NH:16][C:17]=1[C:18]1[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=1)[CH:7]=[CH:6]2
Reactant: CS(=O)(=O)Cl
Reactant: CCN(C(C)C)C(C)C
Reactant: COc1ccc2cc(-c3nc(C(C)(C)CN)[nH]c3-c3ccncc3)ccc2c1
Solvent: O
Solvent: C1CCOC1
Solvent: ClCCl
Product: COc1ccc2cc(-c3nc(C(C)(C)CCS(N)(=O)=O)[nH]c3-c3ccncc3)ccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 44.4 %

Procedure:
A solution of the product of Example 2 (15 mg, 0.04 mmol) in a 1:1 mixture of tetrahydrofuran and dichloromethane (2 mL) containing Hunig's base (9 μL, 0.05 mmol) was treated with methanesulfonyl chloride (4 μL, 0.05 mmol) and stirred at room temperature for 8 hours. The mixture was diluted with water and extracted with dichloromethane. The aqueous layer was separated and extracted with additional dichloromethane, the organic layers were combined, dried over anhydrous magnesium sulphate, filtered and concentrated at reduced pressure. The residue was chromatographed on a Gilson HPLC to give the title compound (8 mg, 44%) as a yellow solid; MS(ES) m/e. 451 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[O:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1.C1(P(=[CH:33][CH:34]=[O:35])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1>[F:1][C:2]([F:13])([F:12])[O:3][C:4]1[CH:11]=[CH:10][C:7](/[CH:8]=[CH:33]/[CH:34]=[O:35])=[CH:6][CH:5]=1
Reactant: O=Cc1ccc(OC(F)(F)F)cc1
Reactant: O=CC=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: O=C/C=C/c1ccc(OC(F)(F)F)cc1
Yield: 59.7 %

Procedure:
570 mg (3.0 mmol) of 4-(trifluoromethoxy)benzaldehyde and 913 mg (3.0 mmol) of (triphenylphosphoranylidene)acetaldehyde were heated under reflux in 7.5 ml of toluene under nitrogen atmosphere for 1 hour and 45 minutes. The toluene was distilled off under reduced pressure and the thus obtained residue was purified over column chromatography using 20 g of silica gel. The fractions eluted with a mixed solvent of acetic acid-hexane (1:10) were collected to obtain 387 mg (yield: 60%) of the title compound as an oil.
Reaction SMILES: [OH:1][C:2]1[C:7](=[O:8])[N:6]2[CH2:9][CH2:10][N:11]([CH2:12][CH2:13][OH:14])[C:5]2=[N:4][C:3]=1[C:15]([O:17]CC)=O.[F:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25][NH2:26])=[CH:23][CH:22]=1>C(O)C.C(OCC)(=O)C>[F:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25][NH:26][C:15]([C:3]2[N:4]=[C:5]3[N:11]([CH2:12][CH2:13][OH:14])[CH2:10][CH2:9][N:6]3[C:7](=[O:8])[C:2]=2[OH:1])=[O:17])=[CH:23][CH:22]=1
Reactant: CCOC(=O)c1nc2n(c(=O)c1O)CCN2CCO
Reactant: NCc1ccc(F)cc1
Solvent: CCOC(C)=O
Solvent: CCO
Product: O=C(NCc1ccc(F)cc1)c1nc2n(c(=O)c1O)CCN2CCO
Yield: 81.6 %

Procedure:
A solution of ethyl 6-hydroxy-1-(2-hydroxyethyl)-5-oxo-1,2,3,5-tetrahydroimidazo[1,2-a]pyrimidine-7-carboxylate (0.110 g, 0.408 mmol) and 4-fluorobenzylamine (0.200 g, 1.6 mmol) in anhydrous ethanol (5 ml) was heated under reflux for 6 h. The reaction mixture was then diluted with ethyl acetate, washed successively with 0.1 N hydrochloric acid and brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Crystallization of the residual solid from ethanol gave 0.116 g (82% yield) of the title amide as white cubes; mp 203° C. 1HNMR 400 MHz (CDCl3) δ (ppm): 3.54 (2H, t, J=5.0 Hz, CH2), 3.80 (2H, t, J=8.5 Hz, CH2), 3.89 (2H, t, J=5.0 Hz, CH2), 4.15 (2H, t, J=8.5 Hz, CH2), 4.57 (2H, d, J=6.0 Hz, NCH2), 7.07 (2H, m, aromatics), 7.34 (2H, m, aromatics), 7.92 (1H, broad t, NH), 11.68 (1H, s, OH). Anal. Calcd for C16H17FN4O4: C, 55.17; H, 4.92; N, 16.08. Found: C, 55.22; H, 5.06; N, 15.89.
Reaction SMILES: [I:1]([OH:5])(=[O:4])(=[O:3])=[O:2].[O-2:6].[O-2].[O-2].[Cr+6:9].[C:10]([O:14][C@@H:15]([C:18]1[C:43]([CH3:44])=[CH:42][C:21]2[N:22]=[C:23]([N:25]3[CH2:30][CH2:29][CH2:28][N:27]([C:31]4[CH:32]=[C:33]5[C:37](=[CH:38][CH:39]=4)[N:36]([CH3:40])[N:35]=[CH:34]5)[C:26]3=[O:41])[S:24][C:20]=2[C:19]=1[C:45]1[CH:50]=[CH:49][C:48]([Cl:51])=[CH:47][CH:46]=1)[CH2:16][OH:17])([CH3:13])([CH3:12])[CH3:11]>C(#N)C>[I:1]([OH:5])(=[O:4])(=[O:3])=[O:2].[O-2:14].[O-2:6].[O-2:2].[Cr+6:9].[C:10]([O:14][C@@H:15]([C:18]1[C:43]([CH3:44])=[CH:42][C:21]2[N:22]=[C:23]([N:25]3[CH2:30][CH2:29][CH2:28][N:27]([C:31]4[CH:32]=[C:33]5[C:37](=[CH:38][CH:39]=4)[N:36]([CH3:40])[N:35]=[CH:34]5)[C:26]3=[O:41])[S:24][C:20]=2[C:19]=1[C:45]1[CH:46]=[CH:47][C:48]([Cl:51])=[CH:49][CH:50]=1)[C:16]([OH:6])=[O:17])([CH3:13])([CH3:11])[CH3:12]
Reactant: Cc1cc2nc(N3CCCN(c4ccc5c(cnn5C)c4)C3=O)sc2c(-c2ccc(Cl)cc2)c1[C@@H](CO)OC(C)(C)C
Agent: [Cr+6]
Agent: [O-2]
Agent: [O-][I+3]([O-])([O-])O
Solvent: CC#N
Product: Cc1cc2nc(N3CCCN(c4ccc5c(cnn5C)c4)C3=O)sc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O

Procedure:
A stock solution of periodic acid/chromium trioxide was prepared according to WO 99/52850 by dissolving periodic acid (11.4 g, 50.0 mmol) and chromium trioxide (23 mg, 1.2 mol %) in wet acetonitrile (0.75% H2O, 114 mL). To a solution of (S)-1-(6-(1-tert-butoxy-2-hydroxyethyl)-7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-2-yl)-3-(1-methyl-1H-indazol-5-yl)tetrahydropyrimidin-2(1H)-one (16 mg) in wet acetonitrile (1.0 mL, 0.75% H2O) at 0° C. was added the above stock solution (0.6 mL) at 0° C. Filtration and purification by reverse phase HPLC gave (S)-2-tert-butoxy-2-(7-(4-chlorophenyl)-5-methyl-2-(3-(1-methyl-1H-indazol-5-yl)-2-oxotetrahydropyrimidin-1(2H)-yl)benzo[d]thiazol-6-yl)acetic acid. LCMS-ESI+: calc'd for C32H32ClN5O4S: 618.2 (M+H+); Found: 618.3 (M+H+), 615.8 (M+H+); 1H-NMR 400 MHz, (CD3OD) δ 7.99 (s, 1H), 7.70 (s, 1H), 7.62-7.50 (m, 3H), 7.50-7.47 (m, 3H), 7.37 (m, 1H), 5.20 (s, 1H), 4.40 (m, 2H), 4.07 (s, 3H), 3.85 (m, 2H), 2.55 (s, 3H), 2.34 (m, 2H), 0.94 (s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:4]=1[CH2:5][NH:6][CH:7]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:8]([O:10][CH2:11][CH3:12])=[O:9].C(N(CC)CC)C.Br[CH:32]([CH2:36][CH3:37])[C:33](Cl)=[O:34]>C1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:4]=1[CH2:5][N:6]1[C:33](=[O:34])[CH:32]([CH2:36][CH3:37])[C:7]1([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: CCC(Br)C(=O)Cl
Reactant: CCOC(=O)C(NCc1ccc(OC)cc1OC)C(=O)OCC
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(=O)C1(C(=O)OCC)C(CC)C(=O)N1Cc1ccc(OC)cc1OC
Reaction time: 6 h
Yield: 87 %

Procedure:
30 g (0.092 mole) of diethyl N-(2,4-dimethoxybenzyl)-amino-malonate prepared according to paragraph (b) of Example 1 are dissolved in a mixture of 90 ml of benzene and 15.6 ml (11.2 g, 0.111 mole) of triethyl amine and thereafter 20.5 g (0.111 mole) of 2-bromo butyric acid chloride are added dropwise under external ice-cooling. The reaction mixture is stirred under cooling for half an hour and thereafter at room temperature for half an hour. The precipitated crystalline substance is filtered off and washed twice with 20 ml of benzene. To the combined benzene mother liquor 31.2 g (22.4 g, 0.222 mole) of triethyl amine are added and the mixture is boiled for 6 hours. The precipitated crystalline substance is cooled and filtered. The mother liquor is extracted successively with 100 ml of water, twice with 100 ml of diluted hydrochloric acid each (a mixture of 90 ml of water and 10 ml of hydrochloric acid) and twice with 100 ml of water each. The organic layer is dried over anhydrous magnesium sulfate, filtered and the filtrate is evaporated. The residual oil is made crystalline by rubbing with petrolether. Thus 31.5 g of diethyl 1-(2,4-dimethoxy-benzyl)-3-ethyl-4-oxo-2,2-azetidinedicarboxylate are obtained. M.p.: 69° C. (from a mixture of benzene and petrolether).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([S:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([OH:25])=O)[NH:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:26]([NH2:33])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32].B(F)(F)F.CCOCC>C1(C)C=CC=CC=1>[C:1]1([C:7]2[N:8]=[C:9]([S:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([NH:33][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[O:25])[NH:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCCCCCCN
Reactant: O=C(O)CCCCSc1nc(-c2ccccc2)c(-c2ccccc2)[nH]1
Agent: FB(F)F
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CCCCCCCNC(=O)CCCCSc1nc(-c2ccccc2)c(-c2ccccc2)[nH]1
Yield: 87.7 %

Procedure:
Part C, Method 2. To a solution of 5-(4,5-diphenyl-1H-imidazol-2-ylthio)pentanoic acid (2.0 g, 0.0057 mol) in toluene (35 mL) was added heptylamine (1.63 mL, 1.27 g, 0.011 mol) and then boron trifluoride etherate (1.35 mL, 1.56 g, 0.011 mol) and the reaction mixture was stirred at reflux for 120 hours using a Dean-Stark moisture trap. The reaction mixture was cooled, extracted with 0.1N NaOH, 0.1N HCl, and water, and the combined organic extracts were dried over magnesium sulfate and concentrated under vacuum. The residue was chromatographed and worked-up as described in Part C, Method 1, to give 5-(4,5-diphenyl-1H-imidazol-2-ylthio)-N-heptylpentanamide (2.35 g, 0.005 mol) as a white solid.