Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCN(CC)CC.[C:8]([O:16][CH2:17][C:18]#[CH:19])(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[CH:20](=[N:22]/[OH:23])\[CH3:21]>C(Cl)(Cl)Cl>[C:8]([O:16][CH2:17][C:18]1[O:23][N:22]=[C:20]([CH3:21])[CH:19]=1)(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: C#CCOC(=O)c1ccccc1
Reactant: C/C=N/O
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: Cc1cc(COC(=O)c2ccccc2)on1
Reaction time: 8 h

Procedure:
To a solution of chloroform, Et3N (0.435 mL, 3.12 mmol), prop-2-ynyl benzoate (1 g, 6.24 mmol), and (E)-acetaldehyde oxime (0.571 mL, 9.37 mmol) at 0° C. was added bleach (23.12 mL, 18.73 mmol). The reaction was stirred overnight before the layers were separated and the aqueous extracted with DCM. The combined organics were dried over Na2SO4, filtered, and concentrated. The crude residue was purified via Biotage (EtOAc/hex) to afford (3-methylisoxazol-5-yl)methyl benzoate. LC/MS m/z 218 [M+H]+.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]1([C:12]2[CH:13]=[N:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=2)[CH2:10][C:9](=O)[NH:8][CH2:7]1)C.[H-].[Al+3].[Li+].[H-].[H-].[H-].S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCCC1>[CH3:19][O:18][C:15]1[N:14]=[CH:13][C:12]([C:6]2([CH2:5][CH2:4][OH:3])[CH2:10][CH2:9][NH:8][CH2:7]2)=[CH:17][CH:16]=1
Reactant: CCOC(=O)CC1(c2ccc(OC)nc2)CNC(=O)C1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: COc1ccc(C2(CCO)CCNC2)cn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 34.2 %

Procedure:
1.50 g (5.39 mmol) of ethyl[3-(6-methoxypyridin-3-yl)-5-oxopyrrolidin-3-yl]acetate obtained in stage 4.2, in solution in 90 ml of anhydrous tetrahydrofuran, are introduced into a 250 ml round-bottomed flask at ambient temperature. 2.046 g (53.90 mmol) of lithium aluminum hydride are added portionwise and the resulting mixture is subsequently stirred at ambient temperature for 3 hours. The mixture is subsequently hydrolyzed with a saturated aqueous sodium sulfate solution, filtered through celite and concentrated under reduced pressure. The residue obtained is purified by chromatography on a column of silica gel, elution being carried out with a mixture of chloroform, methanol and aqueous ammonia in the proportions 90/10/1, to provide 0.41 g of the desired compound in the form of a yellow wax.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]([C:12]([O:14][CH3:15])=[O:13])[N:7]([S:16]([C:19]1[CH:24]=[CH:23][C:22]([O:25][C:26]3[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=3)=[CH:21][CH:20]=1)(=[O:18])=[O:17])[CH2:6][CH2:5]2.[CH2:34]([N:36]([CH2:40][CH3:41])[CH2:37][CH2:38]O)[CH3:35].FC1C=CC(OC2C=CC(S(N3CCC4C(=CC=C(OCCCN5CCN(C)CC5)C=4)C3C(OC)=O)(=O)=O)=CC=2)=CC=1>>[CH2:34]([N:36]([CH2:40][CH3:41])[CH2:37][CH2:38][O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]([C:12]([O:14][CH3:15])=[O:13])[N:7]([S:16]([C:19]1[CH:24]=[CH:23][C:22]([O:25][C:26]3[CH:27]=[CH:28][C:29]([O:32][CH3:33])=[CH:30][CH:31]=3)=[CH:21][CH:20]=1)(=[O:17])=[O:18])[CH2:6][CH2:5]2)[CH3:35]
Reactant: COC(=O)C1c2ccc(O)cc2CCN1S(=O)(=O)c1ccc(Oc2ccc(OC)cc2)cc1
Reactant: CCN(CC)CCO
Agent: COC(=O)C1c2ccc(OCCCN3CCN(C)CC3)cc2CCN1S(=O)(=O)c1ccc(Oc2ccc(F)cc2)cc1
Product: CCN(CC)CCOc1ccc2c(c1)CCN(S(=O)(=O)c1ccc(Oc3ccc(OC)cc3)cc1)C2C(=O)OC

Procedure:
Methyl 6-hydroxy-2-[4-(4-methoxyphenoxy)benzenesulfonyl]-1,2,3,4-tetrahydroiso-quinoline-1-carboxylate (13B) is reacted with 2-diethylaminoethanol by the method described under 3C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[O:19][C:18]([CH2:20][NH2:21])=[N:17][N:16]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:22][C:23]1[CH:24]=[C:25]([CH:37]=[CH:38][CH:39]=1)[O:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH:32]([OH:36])[C:33](O)=[O:34].CN(C)CCCN=C=NCC.CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.C([O-])(O)=O.[Na+]>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[O:19][C:18]([CH2:20][NH:21][C:33](=[O:34])[CH:32]([OH:36])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][O:26][C:25]3[CH:37]=[CH:38][CH:39]=[C:23]([F:22])[CH:24]=3)=[N:17][N:16]=2)=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NCc1nnc(-c2ccc(OCc3ccccc3)cc2)o1
Reactant: O=C(O)C(O)CCCCCOc1cccc(F)c1
Agent: CCN=C=NCCCN(C)C
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NCc1nnc(-c2ccc(OCc3ccccc3)cc2)o1)C(O)CCCCCOc1cccc(F)c1

Procedure:
A solution of methyl 2-(((benzyloxy)carbonyl)amino)acetimidate (600 mg, 2.7 mmol) and 4-(benzyloxy)benzohydrazide (654 mg, 2.7 mmol) in methanol (45 mL) was heated at 80° C. in a sealed tube for 3 h. The solvent was removed under reduced pressure and the resulting residue was purified by chromatography (silica gel, heptane-ethyl acetate) to yield benzyl ((5-(4-(benzyloxy)phenyl)-1,3,4-oxadiazol-2-yl)methyl)carbamate. A solution of benzyl ((5-(4-(benzyloxy)phenyl)-1,3,4-oxadiazol-2-yl)methyl)carbamate (480 mg, 1.12 mmol) in 33% HBr in acetic acid (5 mL) was stirred for 1 h. Diethyl ether was added, and the supernatant was decanted. The process was repeated, and the resulting solid was collected by filtration to yield (5-(4-(benzyloxy)phenyl)-1,3,4-oxadiazol-2-yl)methanamine. A solution of (5-(4-(benzyloxy)phenyl)-1,3,4-oxadiazol-2-yl)methanamine (155 mg, 0.43 mmol), 7-(3-fluorophenoxy)-2-hydroxyheptanoic acid (110 mg, 0.43 mmol), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide (99 mg, 0.52 mmol), DIPEA (0.224 mL, 1.3 mmol) and HOBt (70 mg, 0.52 mmol) in DMF (20 mL) was stirred overnight. The resulting mixture was diluted with NaHCO3 (saturated, aqueous) and extracted twice with ethyl acetate. The combined extracts were washed with brine, dried (Na2SO4) and concentrated to yield N-((5-(4-(benzyloxy)phenyl)-1,3,4-oxadiazol-2-yl)methyl)-7-(3-fluorophenoxy)-2-hydroxyheptanamide, which was in the next step used without further purification. To a solution of N-((5-(4-(benzyloxy)phenyl)-1,3,4-oxadiazol-2-yl)methyl)-7-(3-fluorophenoxy)-2-hydroxyheptanamide (190 mg, 0.37 mmol) in methylene chloride (5 mL) was added 1,1,1-tris(acetyloxy)1,1-dihydro-1,2-benziodoxol-3-(1H)-one (233 mg, 0.55 mmol) and the resulting mixture was stirred overnight, then quenched with excess sodium thiosulfate in saturated aqueous sodium bicarbonate. The mixture was then extracted twice with ethyl acetate and the combined organic extracts were washed with brine, dried (Na2SO4) and concentrated. The residue was purified by chromatography (silica gel, heptane-ethyl acetate) to yield the title compound. 1H NMR (400 MHz, CDCl3) δ 6.60-8.10 (overlapping m, 14H), 5.15 (s, 2H), 4.75-4.85 (m, 2H), 3.85-4.00 (m, 2H), 2.90-3.10 (m, 2H), 1.50-1.90 (m, 6H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])[CH:5]=[CH:6][C:7]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.O.[S:21]([C:25]1[CH:31]=[CH:30][C:28]([CH3:29])=[CH:27][CH:26]=1)([OH:24])(=[O:23])=[O:22].O>C1(C)C=CC=CC=1.C(O)C1C=CC=CC=1>[S:21]([C:25]1[CH:31]=[CH:30][C:28]([CH3:29])=[CH:27][CH:26]=1)([OH:24])(=[O:23])=[O:22].[NH2:1][C:2]1[CH:3]=[C:4]([CH2:14][CH2:15][CH2:16][C:17]([O:19][CH2:29][C:28]2[CH:30]=[CH:31][CH:25]=[CH:26][CH:27]=2)=[O:18])[CH:5]=[CH:6][C:7]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: Nc1cc(CCCC(=O)O)ccc1-c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: OCc1ccccc1
Solvent: Cc1ccccc1
Solvent: O
Product: Nc1cc(CCCC(=O)OCc2ccccc2)ccc1-c1ccccc1
Yield: 171.2 %

Procedure:
To a suspension of 4-(3-Amino-4-phenylphenyl)butyric acid (21.6 g, 84.6 mmol) in toluene (300 mL), benzyl alcohol (50 mL) and tosylic acid hydrate (17.7 g, 93.0 mmol) were added, and the mixture was heated under reflux for 5 hours with water removed by a Dean-Stark trap. The reaction solution was concentrated under reduced pressure and a solid obtained was washed with a mixed solvent of hexane-ethyl acetate (4:1). The solid was collected by filtration and dried under reduced pressure to obtain benzyl 4-(3-amino-4-phenylphenyl)butyrate tosylate (41.2 g).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][NH2:5].[CH3:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]=[C:18]=S)=[CH:13][CH:12]=1>>[N:1]1[C:2]2[C:3](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][NH:5][C:18]=1[NH:17][C:14]1[CH:15]=[CH:16][C:11]([CH3:10])=[CH:12][CH:13]=1
Reactant: NCc1ccccc1N
Reactant: Cc1ccc(N=C=S)cc1
Product: Cc1ccc(NC2=Nc3ccccc3CN2)cc1

Procedure:
The title compound (MS: m/e=238.3 [M+H+]) was prepared in analogy to example 1 from 2-aminobenzylamine and 4-methylphenylisothiocyanate.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][CH:8]=2)[O:6][CH2:5][CH2:4][O:3]1>CO>[CH3:1][C:2]1([CH:7]2[CH2:12][CH2:11][CH:10]([NH2:13])[CH2:9][CH2:8]2)[O:3][CH2:4][CH2:5][O:6]1
Reactant: CC1(c2ccc([N+](=O)[O-])cc2)OCCO1
Solvent: CO
Product: CC1(C2CCC(N)CC2)OCCO1

Procedure:
8.37 g (40 mmol) of 2-methyl-2-(4-nitrophenyl)-[1,3]dioxolane is placed in 160 mL of methanol and hydrogenated with 1.00 g of Nishimura catalyst at ambient temperature under a pressure of 50 psi. Then the catalyst is filtered off and the filtrate is concentrated by evaporation. The residue is dissolved in cyclohexane, filtered to remove insoluble matter, and the filtrate is evaporated to dryness. Yield: 7.00 g (94%), cis/trans ratio 77:23; NMR: LG201616.
Reaction SMILES: [CH3:1][C:2]([C:13]1[CH:18]=[CH:17][C:16]([C:19]([C:21]2[CH:30]=[CH:29][C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:22]=2)=[O:20])=[CH:15][CH:14]=1)(C(OCC)=O)[C:3]([O:5]CC)=[O:4].[OH-].[Na+]>O>[CH:22]1[C:23]2[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:29]=[CH:30][C:21]=1[C:19]([C:16]1[CH:17]=[CH:18][C:13]([CH:2]([CH3:1])[C:3]([OH:5])=[O:4])=[CH:14][CH:15]=1)=[O:20]
Reactant: CCOC(=O)C(C)(C(=O)OCC)c1ccc(C(=O)c2ccc3ccccc3c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C(=O)O)c1ccc(C(=O)c2ccc3ccccc3c2)cc1
Reaction time: 8 h

Procedure:
A mixture of 9.1 parts of diethyl 2-methyl-2-[p-(2-naphthoyl)phenyl]malonate, 6 parts of sodium hydroxide and 150 parts of water is stirred and refluxed for 8 hours. The reaction mixture is allowed to stand overnight at room temperature. The whole is diluted with water and the product is extracted with ether. The organic layer is separated and discarded. The aqueous phase is degassed on a rotavapor, filtered and acidified with hydrochloric acid solution; an oil is separated which solidifies on standing. The latter is extracted with ether and the extract is washed with water, dried and evaporated. The residue is crystallized from acetonitrile. The product is filtered off, washed with acetonitrile and dried, yielding p-(2-naphthoyl)hydratropic acid; m.p. 149.7° C.
Reaction SMILES: [OH:1][C:2]1[N:7]=[C:6]([S:8][CH2:9][C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=2)[N:5]=[C:4]([C:20]([OH:22])=[O:21])[CH:3]=1.[CH2:23](O)[CH3:24]>CN(C=O)C>[CH2:23]([O:21][C:20]([C:4]1[CH:3]=[C:2]([OH:1])[N:7]=[C:6]([S:8][CH2:9][C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=2)[N:5]=1)=[O:22])[CH3:24]
Reactant: O=C(O)c1cc(O)nc(SCc2ccc3ccccc3c2)n1
Reactant: CCO
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(O)nc(SCc2ccc3ccccc3c2)n1
Reaction time: 1.5 h
Yield: 88 %

Procedure:
A solution of 6-hydroxy-2-(2-naphthylmethylthio)-pyrimidine-4-carboxylic acid (2.50 g, 8.0 mmol) and 1,1-carbonyldiimidazole (1.94 g, 12 mmol) in DMF (30 ml) were stirred for 30 min, then treated with abs ethanol (8.0 ml). After 1.5 hrs of stirring, the reaction was poured onto water, stirred for 20 min, then filtered and dried to give 2.371 g (88%) of 6-hydroxy-2-(2-naphthylmethylthio)-pyrimidine-4-carboxylic acid ethyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9](Cl)(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:13][O:14][C:15]1[CH:28]=[CH:27][C:18]([CH2:19][C@@H:20]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[NH2:21])=[CH:17][CH:16]=1>C(Cl)Cl.C(=O)([O-])[O-].[K+].[K+]>[Cl:1][C:2]1[CH:3]=[C:4]([S:9]([NH:21][C@H:20]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:19][C:18]2[CH:17]=[CH:16][C:15]([O:14][CH3:13])=[CH:28][CH:27]=2)(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=S(=O)(Cl)c1ccc(Cl)c(Cl)c1
Reactant: CCOC(=O)[C@@H](N)Cc1ccc(OC)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CCOC(=O)[C@H](Cc1ccc(OC)cc1)NS(=O)(=O)c1ccc(Cl)c(Cl)c1
Yield: 92.4 %

Procedure:
5 g of 3,4-dichlorophenylsulphonyl chloride are introduced, with stirring, into a mixture of 3,8 g of ethyl O-methyltyrosinate in 35 ml of CH2Cl2 and 50 ml of a saturated aqueous potassium carbonate solution. After one night, the solid is removed, the organic phase separated and the aqueous phase reextracted with CH2Cl2. The dried organic phases are concentrated and the residue is chromatographed on a silica column, eluting with a mixture of CH2Cl2 and CH3OH (95/5-V/V). 6.8 g of racemic ethyl N-(3,4-dichlorophenylsulphonyl)-O-methyltyrosinate are obtained, which product melts at 99° C. This ester is hydrolysed in 100 ml of C2H5OH containing 9.5 ml of a 5N aqueous KOH solution to give, after acidification, 5.5 g of the corresponding acid which melts at 183° C.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1.F[C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:19])[CH3:18])=[CH:12][C:11]=1[N+:20]([O-:22])=[O:21]>CCO>[N+:20]([C:11]1[CH:12]=[C:13]([NH:16][C:17](=[O:19])[CH3:18])[CH:14]=[CH:15][C:10]=1[NH:1][CH2:2][CH:3]1[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1)([O-:22])=[O:21]
Reactant: CC(=O)Nc1ccc(F)c([N+](=O)[O-])c1
Reactant: NCC1CCOCC1
Solvent: CCO
Product: CC(=O)Nc1ccc(NCC2CCOCC2)c([N+](=O)[O-])c1
Reaction time: 8 h

Procedure:
4-Aminomethyl tetrahydropyran (13.7 g, 0.119 mol) was added to a solution of N-(4-Fluoro-3-nitrophenyl)acetamide (20.2 g, 0.102 mol) and TEA (20.9 mL, 15.2 g, 0.15 mol) in EtOH (350 mL). The reaction mixture was stirred overnight at reflux. The orange-red solid was collected by filtration, washed with water and dried in vacuo. The filtrate was concentrated. The residue was dissolved in EtOAc, washed with H2O, brine and dried over anhydrous Na2SO4. The crude product was purified by silica gel flash chromatography using EtOAc as eluent. Total yield: 28.9 g (97%). 1H NMR (400 MHz, CHLOROFORM-D) δ 1.4 (m, 2 H), 1.7 (m, 2 H), 1.89-2.00 (m, 1 H), 2.18 (s, 3 H), 3.22 (dd, J=6.44, 5.66 Hz, 2 H), 3.42 (dt, J=11.86, 2.05 Hz, 2 H), 4.02 (dd, J=10.94, 3.71 Hz, 2 H), 6.84 (d, J=9.37 Hz, 1 H), 7.20 (br.s, 1 H), 7.81 (dd, J=9.37, 2.54 Hz, 1 H), 8.09 (d, J=2.54 Hz, 1 H), 8.10-8.12 (m, 1 H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:12])[C:5]([OH:7])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)CC)(C)C.[Cl:49][C:50]1[CH:67]=[CH:66][C:53]2[NH:54][C:55]([C@@H:57]([NH2:65])[CH2:58][CH2:59][C:60]3[NH:64][N:63]=[N:62][N:61]=3)=[N:56][C:52]=2[CH:51]=1.ClCCl.C(O)C.N.ClCl>O1CCCC1>[Cl:49][C:50]1[CH:67]=[CH:66][C:53]2[NH:54][C:55]([C@@H:57]([NH:65][C:5](=[O:7])[C:4]3[CH:8]=[CH:9][C:10]([C:11]([N:13]4[CH2:17][CH2:16][CH2:15][CH2:14]4)=[O:12])=[C:2]([CH3:1])[CH:3]=3)[CH2:58][CH2:59][C:60]3[NH:64][N:63]=[N:62][N:61]=3)=[N:56][C:52]=2[CH:51]=1
Reactant: Cc1cc(C(=O)O)ccc1C(=O)N1CCCC1
Reactant: N[C@@H](CCc1nnn[nH]1)c1nc2cc(Cl)ccc2[nH]1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: ClCl
Agent: F[B-](F)(F)F
Solvent: CCO
Solvent: C1CCOC1
Solvent: ClCCl
Product: Cc1cc(C(=O)N[C@@H](CCc2nnn[nH]2)c2nc3cc(Cl)ccc3[nH]2)ccc1C(=O)N1CCCC1
Yield: 37 %

Procedure:
Prepared analogously to Example 1g from 3-methyl-4-(pyrrolidin-1-ylcarbonyl)benzoic acid, TBTU, diisopropylethylamine, and (1S)-1-(5-chloro-1H-benzimidazol-2-yl)-3-(1H-tetrazol-5-yl)propylamine in tetrahydrofuran. Yield: 37%; Rf value: 0.25 (silica gel: dichloromethane/ethanol/ammonia=9:1:0.1); C24H25ClN8O2 (492.97); mass spectrum: (M+H)+=493/495 (chlorine isotope).
Reaction SMILES: Cl.[CH2:2]([O:12][CH2:13][CH2:14][CH2:15][C:16]1([C:21]2[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=2)OCC[O:17]1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]>C1COCC1>[CH2:2]([O:12][CH2:13][CH2:14][CH2:15][C:16]([C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=1)=[O:17])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: CCCCCCCCCCOCCCC1(c2ccc(C)cc2)OCCO1
Agent: Cl
Solvent: C1CCOC1
Product: CCCCCCCCCCOCCCC(=O)c1ccc(C)cc1

Procedure:
This compound was synthesized as described under 5.c) with 4.4 ml of HCl (1N) and 4.33 g (11.9 mmol) of 2-[3-(decyloxy)propyl]-2-(4-methylphenyl)-1,3-dioxolane obtained under b) in 100 ml of THF to give 3.82 g (99%) of a slightly yellow oil that solidifies at 4°.
Reaction SMILES: [NH2:1][C:2]1[N:7]2[N:8]=[CH:9][C:10]([C:11]3[CH:12]=[N:13][C:14]4[C:19]([CH:20]=3)=[CH:18][CH:17]=[CH:16][CH:15]=4)=[C:6]2[N:5]=[C:4]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([CH2:28][C:29]([O:31]C)=[O:30])=[CH:24][CH:23]=2)[C:3]=1[Br:33].[Li+].[OH-]>C1COCC1>[NH2:1][C:2]1[N:7]2[N:8]=[CH:9][C:10]([C:11]3[CH:12]=[N:13][C:14]4[C:19]([CH:20]=3)=[CH:18][CH:17]=[CH:16][CH:15]=4)=[C:6]2[N:5]=[C:4]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([CH2:28][C:29]([OH:31])=[O:30])=[CH:24][CH:23]=2)[C:3]=1[Br:33]
Reactant: COC(=O)Cc1ccc(Cc2nc3c(-c4cnc5ccccc5c4)cnn3c(N)c2Br)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Nc1c(Br)c(Cc2ccc(CC(=O)O)cc2)nc2c(-c3cnc4ccccc4c3)cnn12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Crude Methyl 2-(4-((7-amino-6-bromo-3-(quinolin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)methyl)phenyl)acetate from step F was dissolved in THF (5 mL) and LiOH (1N, 1 mL) was added. The mixture was stirred at room temperature overnight. The solvent was removed under vacuo, and the resulting residue was taken over with water and the pH value was adjusted to 5˜6. The solid was collected with filtration and purified with HPLC gave the product 2-(4-((7-amino-6-bromo-3-(quinolin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)methyl)phenyl)acetic acid. HPLC-MS tR=1.53 min (UV254 nm); mass calculated for formula C24H18BrN5O2 487.1, observed LCMS m/z 487.9 (M+H).
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:7])=[C:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:4]([CH3:13])=[C:3]1[C:14](=[O:18])[CH2:15][C:16]#[N:17].[C:19]1([N:25]=[C:26]=[O:27])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C1(C)C=CC=CC=1.C(N(CC)CC)C>[CH3:1][N:2]1[C:6]([CH3:7])=[C:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:4]([CH3:13])=[C:3]1[C:14](=[O:18])[CH:15]([C:26](=[O:27])[NH:25][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:16]#[N:17]
Reactant: CCOC(=O)c1c(C)c(C(=O)CC#N)n(C)c1C
Reactant: O=C=Nc1ccccc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1c(C)c(C(=O)C(C#N)C(=O)Nc2ccccc2)n(C)c1C

Procedure:
To the solution of 1.6 g of 1,3,5-trimethyl-4-ethoxycarbonyl-β-oxo-2-pyrrolpropionitrile in 30 ml of dry toluene and 0.8 g of anhydrous triethylamine, 0.8 g of phenylisocyanate are added while stirring. The mixture is allowed to stand 10 minues at the steam cone and at room temperature overnight. It is evaporated, the residue taken up in methanol and the solution treated with 2 ml of 5 N hydrochloric acid and 200 ml of water. The crystals formed are collected, washed with water, triturated with methanol-ethanol and recrystallized from methanol, to yield the 1,3,5-trimethyl-4-ethoxycarbonyl-β-oxo-α-phenylcarbamoyl-2-pyrrolpropionitrile melting at 164°-166°.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([S:20][CH3:21])[C:10]([S:11]([C:14]3[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=3)(=[O:13])=[O:12])=[C:6]2[N:5]=[C:4]([CH3:22])[CH:3]=1.[NH3:23]>CO>[CH3:22][C:4]1[CH:3]=[C:2]([NH2:23])[N:7]2[N:8]=[C:9]([S:20][CH3:21])[C:10]([S:11]([C:14]3[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=3)(=[O:13])=[O:12])=[C:6]2[N:5]=1
Reactant: CSc1nn2c(Cl)cc(C)nc2c1S(=O)(=O)c1cccnc1
Reactant: N
Solvent: CO
Product: CSc1nn2c(N)cc(C)nc2c1S(=O)(=O)c1cccnc1

Procedure:
In an analogous manner to that described in Example 4), from 7-chloro-5-methyl-2-methylsulphanyl-3-(pyridine-3-sulphonyl)-pyrazolo[1,5-a]pyrimidine and NH3 in MeOH there was obtained 5-methyl-2-methylsulphanyl-3-(pyridine-3-sulphonyl) -pyrazolo[1,5-a]pyrimidin-7-ylamine as colorless crystals, m.p. 226.8 -227.5°.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9](Cl)(=[O:11])=[O:10].[CH2:13]([CH2:15][NH2:16])[OH:14]>C(Cl)Cl.[OH-].[Na+]>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9]([NH:16][CH2:15][CH2:13][OH:14])(=[O:11])=[O:10]
Reactant: NCCO
Reactant: O=S(=O)(Cl)c1ccc(F)cc1F
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: O=S(=O)(NCCO)c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 20 h
Yield: 15.7 %

Procedure:
2,4-Difluorobenzenesulfonyl chloride (4 g, 18.81 mmol) in DCM (10 mL) was added slowly to a solution of ethanolamine (1.25 mL, 20.70 mmol) in DCM (200 mL) and 10% sodium hydroxide solution (200 mL) at 0° C. The reaction was allowed to warm to RT and stirred for 20 hours. The DCM layer was separated and the aqueous re-extracted into DCM (2×50 mL) then the combined organics discarded. The aqueous layer was acidified and extracted into DCM (4×100 mL) the combined organics washed with brine, dried (MgSO4), filtered and reduced in vacuo to give the desired compound as a white solid (0.7 g). 1H NMR δ (CDCl3): 1.75 (s, 1H), 3.17 (q, 2H), 3.72-3.73 (m, 2H), 5.16 (s, 1H), 6.94-7.03 (m, 2H), 7.90-7.97 (m, 1H); m/z 236 (M−H)−
Reaction SMILES: [Na+].[OH:2][C@@H:3]([C@H:5]1[C:11](=[O:12])[N:10]2[C@@H:6]1[CH2:7][C:8]([C:16]1[CH:21]=[CH:20][C:19]([C:22]([NH:24][CH3:25])=[O:23])=[CH:18][CH:17]=1)=[C:9]2[C:13]([O-:15])=[O:14])[CH3:4].[C:26]([O:32][CH2:33]I)(=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28].C(OCC)(=O)C>CN(C)C=O>[OH:2][C@@H:3]([C@H:5]1[C:11](=[O:12])[N:10]2[C@@H:6]1[CH2:7][C:8]([C:16]1[CH:17]=[CH:18][C:19]([C:22]([NH:24][CH3:25])=[O:23])=[CH:20][CH:21]=1)=[C:9]2[C:13]([O:15][CH2:33][O:32][C:26](=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28])=[O:14])[CH3:4]
Reactant: CC(C)(C)C(=O)OCI
Reactant: CNC(=O)c1ccc(C2=C(C(=O)[O-])N3C(=O)[C@H]([C@@H](C)O)[C@H]3C2)cc1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CNC(=O)c1ccc(C2=C(C(=O)OCOC(=O)C(C)(C)C)N3C(=O)[C@H]([C@@H](C)O)[C@H]3C2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 42.8 %

Procedure:
A solution of (5R,6S)-6-[(1R)-1-hydroxyethyl]-3-{4-[(methylamino)carbonyl]phenyl}-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid sodium salt (50 mg) in dry dimethylformamide (1 ml) was cooled with ice, and thereto was added pivaloyloxymethyl iodide (53 mg). The mixture was stirred at the same temperature for 1 hour. To the reaction solution were added ethyl acetate and ice-water, and separated. The organic layer was washed successively with a saturated brine (four times), an aqueous sodium hydrogen carbonate solution, an aqueous sodium thiosulfate solution, and a saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel thin layer chromatography (chloroform/methanol=9/1) to give [(2,2-dimethyl-propanoyl)oxy]methyl (5R,6S)-6-[(1R)-1-hydroxyethyl]-3-{4-[(methylamino)carbonyl]phenyl}-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate (27 mg).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:20]([OH:22])=O)[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O[N:24]1[C:28](=O)CC[C:25]1=O.C1(N=C=NC2CCCCC2)CCCCC1.CNC>C(Cl)(Cl)Cl>[CH3:25][N:24]([CH3:28])[C:20](=[O:22])[C@H:12]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[NH:11][C:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:10]
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)O)OCc1ccccc1
Reactant: O=C1CCC(=O)N1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CNC
Solvent: ClC(Cl)Cl
Product: CN(C)C(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1
Temperature: -10 °C
Reaction time: 0.17 h

Procedure:
20 mmoles (5.99 grams) of N-benzyloxycarbonyl-(L)-phenylalanine and 24 mmoles (2.76 grams) of N-hydroxysuccinimide are dissolved in 30 ml of chloroform and treated under ice cooling and stirring with 22 mmoles (4.34 grams) of dicyclohexylcarbodiimide dissolved in about 10 ml of chloroform. After 10 minutes stirring the mixture was cooled in an ice-salt bath to -10° C. and 20 mmoles (0.90 grams) of condensed, dry dimethylamine (boiling point +7° C.) added. Stirring was carried out for 24 hours, whereby the cooling bath was allowed to slowly melt. The precipitate formed was filtered off and the filtrate washed successively with each 20 ml 2N hydrochloric acid, saturated NaHCO3 solution and water. After drying over sodium sulfate and drawing off the solvent in a vacuum there was obtained an oily product. It was distilled at 240° C. air bath temperature in a high vacuum (10-4Torr). Colorless, very viscous oil.