Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]([O:6][CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH:14]([O:19][CH3:20])[C:15]([NH:17][NH2:18])=[O:16])=[C:4]([CH3:23])[CH:3]=1.[CH:24]([O-])([O-])OCC.C1C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>O>[Cl:1][C:2]1[CH:22]=[CH:21][C:5]([O:6][CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH:14]([C:15]2[O:16][CH:24]=[N:18][N:17]=2)[O:19][CH3:20])=[C:4]([CH3:23])[CH:3]=1
Reactant: COC(C(=O)NN)c1ccccc1COc1ccc(Cl)cc1C
Reactant: CCOC([O-])[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: COC(c1nnco1)c1ccccc1COc1ccc(Cl)cc1C
Yield: 13.5 %

Procedure:
To 0.50 g (1.5 mmol) of 2-(4-chloro-2-methylphenoxymethyl)phenyl-2-methoxyacetic acid hydrazide was added 1.5 ml of ethyl orthoformate, stirred under reflux for 3 hours, and thereafter concentrated under reduced pressure. To the residue thus obtained, 4.5 ml of benzene and 0.03 g (0.15 mmol) of p-toluenesulfonic acid monohydrate were added and stirred under reflux for an hour. After completion of the reaction, 100 ml of water was added and extracted twice with 50 ml of dichloromethane. The dichloromethane layer was dried over anhydrous magnesium and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate/n-hexane) to give 2-[2-(4-chloro-2-methylphenoxymethyl)-α-methoxybenzyl]-1,3,4-oxadiazole (0.07 g, 13.5%) as colorless crystals. mp. 68-70° C.
Reaction SMILES: [CH2:1]([N:8]([CH2:18][CH2:19][O:20][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22])[C:9](=[O:17])[C:10]1[CH:15]=[CH:14][N:13]=[CH:12][C:11]=1[F:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:36])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>C1COCC1>[CH2:1]([N:8]([CH2:18][CH2:19][O:20][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:22])[CH3:23])[C:9](=[O:17])[C:10]1[CH:15]=[CH:14][N+:13]([O-:36])=[CH:12][C:11]=1[F:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[Si](C)(C)OCCN(Cc1ccccc1)C(=O)c1ccncc1F
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCCN(Cc1ccccc1)C(=O)c1cc[n+]([O-])cc1F
Temperature: 25 °C
Reaction time: 4 h
Yield: 69.7 %

Procedure:
To a solution of the compound (26.2 g) obtained in step 1 in THF (135 mL) was added 70% m-chloroperbenzoic acid (m-CPBA) (16.2 g) at 0° C., and the mixture was stirred at room temperature for 4 hr. m-CPBA (16.2 g) was further added, and the mixture was stirred at room temperature for 4 hr. The reaction mixture was poured into aqueous sodium thiosulfate solution, and the mixture was extracted three times with ethyl acetate. The organic layer was washed with brine, and concentrated. The residue was purified by silica gel column chromatography (solvent gradient; 10→80% ethyl acetate/hexane) to give N-benzyl-N-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-3-fluoroisonicotinamide 1-oxide (19.0 g, 70%) as a pale-yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([Cl:11])[CH:5]=1.[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:6]([Cl:11])[CH:5]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)c1ccc(O)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OCc2ccccc2)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 3-chloro-4-hydroxy benzoic acid methyl ester (4.665 g, 25 mmol), benzyl bromide (5.13 g, 30 mmol) and potassium carbonate (6.91 g, 50 mmol) in N,N-dimethylformamide (50 mL) was stirred overnight at room temperature. The reaction mixture was poured onto crushed ice (ca. 300 g) and the product was extracted with ethyl acetate (2×100 mL). The combined organic layers were dried over sodium sulphate and concentrated under reduced pressure. The residue was dissolved in dichloromethane and precipitated by addition of hexane. Yield: 6.47 g (94%) white powder. 1H-NMR (400 MHz, CDCl3) δ=3.90 (s, 3H, —OCH3); 5.23 (s, 2H, —CH2Ar), 6.99 (d, J=9.0 Hz, 1H), 7.31-7.48 (m, 5H), 7.89 (dd, J=9.0, 2.3 Hz, 1H), 8.08 (d, J=2.3 Hz, 1H).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[C:7]([CH2:9][C:10]2[C:11](=[O:17])[NH:12][C:13](=[S:16])[NH:14][CH:15]=2)[CH:6]=[CH:5][N:4]=1.Cl>C(O)(=O)C>[O:2]=[C:3]1[CH:8]=[C:7]([CH2:9][C:10]2[C:11](=[O:17])[NH:12][C:13](=[S:16])[NH:14][CH:15]=2)[CH:6]=[CH:5][NH:4]1
Reactant: COc1cc(Cc2c[nH]c(=S)[nH]c2=O)ccn1
Agent: Cl
Solvent: CC(=O)O
Product: O=c1cc(Cc2c[nH]c(=S)[nH]c2=O)cc[nH]1
Temperature: 150 °C
Yield: 75.9 %

Procedure:
5-(2-Methoxy-pyridin-4-ylmethyl)-2-thioxo-2,3-dihydro-1H-pyrimidin-4-one (900 mg, 3.61 mmol, 1 eq) was refluxed in an acetic acid, glacial (12 ml)/HCl conc. (12 ml) mixture for 7 hours. (150° C. on display of heating device). Solvent from the mixture was evaporated as much as possible. In the mixture was added 20 ml of water. pH of the mixture was adjusted to 4-5. The resulting precipitate was collected and was dried. It was obtained 5-(2-oxo-1,2-dihydro-pyridin-4-ylmethyl)-2-thioxo-2,3-dihydro-1H-pyrimidin-4-one (645 mg, yield=72.1%, purity=95%) in form of white powder. MS: [M+H]+=236.15 1H NMR (300 MHz; DMSO-d6) δ/ppm 3.36 (s, 2H), 6.06 (dd, J=6.81 Hz, J=1.60 Hz, 1H), 6.11(s, 1H), 7.24 (d, J=6.81 Hz, 1H), 7.43 (d, J=5.66 Hz, 1H), 11.36 (br.s, 1H), 12.30 (d, J=4.89 Hz, 1H), 12.52 (br.s, 1H)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[C:6]([NH2:11])[C:5]=1[OH:12].[C:14](C1NC=CN=1)(C1NC=CN=1)=[O:15]>O1CCCC1>[CH3:1][O:2][C:3]([C:4]1[C:5]2[O:12][C:14](=[O:15])[NH:11][C:6]=2[CH:7]=[C:8]([Cl:10])[CH:9]=1)=[O:13]
Reactant: COC(=O)c1cc(Cl)cc(N)c1O
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: C1CCOC1
Product: COC(=O)c1cc(Cl)cc2[nH]c(=O)oc12
Temperature: 25 °C
Yield: 90.9 %

Procedure:
3-Amino-5-chloro-2-hydroxy-benzoic acid methyl ester 8 g (39.6 mmol) is dissolved in tetrahydrofuran 100 mL and carbonyl diimidazole (12.9 g, 79.3 mmol) is added. The reaction is heated to reflux for 2 hours and then cooled to room temperature. The reaction is evaporated in vacuo and then taken up in dichloromethane (200 mL) and then washed with HCl (2N, 50 mL 2×) and water (2×50 mL). The organic layer is dried (Na2SO4) filtered and evaporated in vacuo to give the title compound (8.2 g, 36 mmol, 91%). LCMS (ESMS): m/z 228.9 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:34]=[CH:35][CH:36]=1)[CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][N:16]1[CH2:20][C@@H:19]([C:21]2[CH:32]=[CH:31][C:24]3[O:25][C:26]([CH3:30])([CH3:29])[O:27][CH2:28][C:23]=3[CH:22]=2)[O:18][C:17]1=[O:33].[C:37]1([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[CH:42]=[CH:41][C:40]([N:43]=[C:44]=[O:45])=[CH:39][CH:38]=1.C(O)(C)C>ClCCl>[C:37]1([C:46]2[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=2)[CH:38]=[CH:39][C:40]([NH:43][C:44]([NH:1][C:2]2[CH:36]=[CH:35][CH:34]=[C:4]([CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][N:16]3[CH2:20][C@@H:19]([C:21]4[CH:32]=[CH:31][C:24]5[O:25][C:26]([CH3:30])([CH3:29])[O:27][CH2:28][C:23]=5[CH:22]=4)[O:18][C:17]3=[O:33])[CH:3]=2)=[O:45])=[CH:41][CH:42]=1
Reactant: CC1(C)OCc2cc([C@@H]3CN(CCCCCCOCCOCc4cccc(N)c4)C(=O)O3)ccc2O1
Reactant: O=C=Nc1ccc(-c2ccccc2)cc1
Solvent: CC(C)O
Solvent: ClCCl
Product: CC1(C)OCc2cc([C@@H]3CN(CCCCCCOCCOCc4cccc(NC(=O)Nc5ccc(-c6ccccc6)cc5)c4)C(=O)O3)ccc2O1
Temperature: 20 °C
Reaction time: 19 h
Yield: 42.3 %

Procedure:
A solution of (5R)-3-(6-{2-[(3-aminobenzyl)oxy]ethoxy}hexyl)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-1,3-oxazolidin-2-one (0.202 g) in dichloromethane (4 ml) was treated with 4-biphenylyl isocyanate (0.126 g) and the mixture stirred under nitrogen at 20° C. for 19 h. Isopropanol (15 ml) was added to quench excess isocyanate, and the mixture stirred for 2 h. The solvents were removed in vacuo to give a residue which was purified by Biotage. Elution with 6:4 EtOAc/cyclohexane followed by solvent evaporation in vacuo gave the title compound (0.119 g). LCMS RT=4.09 min, ES+ve 694 (MH)+.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([C@H:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]2[N:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[CH:6]=[CH:7][CH:8]=1.B(Br)(Br)Br.O>ClCCl>[OH:2][C:3]1[CH:4]=[C:5]([C@H:9]2[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]2[N:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc([C@H]2CCCC[C@H]2N2CCCC2)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: Oc1cccc([C@H]2CCCC[C@H]2N2CCCC2)c1
Temperature: 0 °C
Reaction time: 18 h
Yield: 84.6 %

Procedure:
(2) A solution of cis-2-(3-methoxyphenyl)-1-pyrrolidinocyclohexane (2.5g) in dichloromethane was added cautiously to an ice-cold solution of boron tribromide (3 ml) in dichloromethane (15 ml). The mixture was set aside at room temperature for 18 hours and was hydrolysed with water. The aqueous layer was collected, made alkaline with ammonia and extracted with ether. The ether extracts were washed, dried (Na2SO4) and evaporated. The residue was crystallised from aqueous ethanol to give cis-2-(3-hydroxyphenyl)-1-pyrrolidinocyclohexane (2.0g), m.p. 125° to 127° C, identical to (b)(1) above.
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][CH2:12][CH:13]([C:20]([F:23])([F:22])[F:21])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])(=O)=O)=CC=1.[OH:25][C:26]1[CH:36]=[CH:35][C:29]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:28][CH:27]=1.[H-].[Na+]>CN(C=O)C>[F:21][C:20]([F:22])([F:23])[CH:13]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:12][CH2:11][O:25][C:26]1[CH:27]=[CH:28][C:29]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:35][CH:36]=1
Reactant: CCCCCCC(CCOS(=O)(=O)c1ccc(C)cc1)C(F)(F)F
Reactant: CCOC(=O)c1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCC(CCOc1ccc(C(=O)OCC)cc1)C(F)(F)F
Temperature: 130 °C
Yield: 60.4 %

Procedure:
345 mg of 3-trifluoromethylnonyl p-toluenesulfonate obtained in Step (1), 166 mg of ethyl p-hydroxybenzoate and 1 ml of dimethylformamdie (DMF) were placed in a round-bottomed flask, and 80 mg of sodium hydride (60%) was added thereto together with DMF, followed by 6 hours of stirring at 130° C. After the reaction, DMF was distilled off under a reduced pressure, and water was added, followed by extraction with methylene chloride. The methylene chloride solution was dried with magnesium sulfate, followed by distilling-off of the solvent and purification by thin layer chromatography with benzene as the developer to obtain 205 mg of ethyl p-(3-trifluoromethylnonyloxy)benzoate (yield: 60.5%).
Reaction SMILES: [C:1]([C:4]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:8][N:7]([CH2:16][CH3:17])[C:6](=[O:18])[C:5]=1[N+:19]([O-])=O)(=[O:3])[CH3:2].N[C:23]1[N:28]=[CH:27][CH:26]=[CH:25][N:24]=1>C(O)C>[C:1]([C:4]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:8][N:7]([CH2:16][CH3:17])[C:6](=[O:18])[C:5]=1[NH:19][C:23]1[N:28]=[CH:27][CH:26]=[CH:25][N:24]=1)(=[O:3])[CH3:2]
Reactant: Nc1ncccn1
Reactant: CCn1nc(-c2ccccc2)c(C(C)=O)c([N+](=O)[O-])c1=O
Solvent: CCO
Product: CCn1nc(-c2ccccc2)c(C(C)=O)c(Nc2ncccn2)c1=O
Temperature: 50 °C
Reaction time: 120 h
Yield: 36 %

Procedure:
To a stirred solution of 100 mg (0.348 mmol) of 5-acetyl-2-ethyl-4-nitro-6-phenylpyridazin-3(2H)-one (Dal Piaz, V et al, J. Med. Chem. 1997, 40, 1417) in 5 ml of ethanol, 430 mg (4.524 mmol) of 2-aminopyrimidine was added. The resulting mixture was stirred at 50° C. during five days and the final product was collected by filtration and washed with diethylether to yield the title compound (42 mg, 35.6% yield).
Reaction SMILES: [Cl:1][CH:2]([Cl:21])[C:3]([N:5]1[C@H:9]([CH2:10][F:11])[C@@H:8]([C:12]2[CH:17]=[CH:16][C:15](I)=[CH:14][CH:13]=2)[O:7][C:6]1([CH3:20])[CH3:19])=[O:4].[OH:22][CH2:23][C:24]1[N:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1>>[Cl:1][CH:2]([Cl:21])[C:3]([N:5]1[C@H:9]([CH2:10][F:11])[C@@H:8]([C:12]2[CH:17]=[CH:16][C:15]([C:27]3[CH:28]=[N:29][C:24]([CH2:23][OH:22])=[CH:25][CH:26]=3)=[CH:14][CH:13]=2)[O:7][C:6]1([CH3:20])[CH3:19])=[O:4]
Reactant: OCc1ccc(B(O)O)cn1
Reactant: CC1(C)O[C@H](c2ccc(I)cc2)[C@@H](CF)N1C(=O)C(Cl)Cl
Product: CC1(C)O[C@H](c2ccc(-c3ccc(CO)nc3)cc2)[C@@H](CF)N1C(=O)C(Cl)Cl

Procedure:
Following the general procedure of Example 1—Step 1 and making non-critical variations but using 2,2-dichloro-1-((4S,5R)-4-(fluoromethyl)-5-(4-iodophenyl)-2,2-dimethyloxazolidin-3-yl)ethanone and (6-(hydroxymethyl)pyridin-3-yl)boronic acid as starting materials the title compound is obtained (800 mg): m/z (Cl) M−H 426.1.
Reaction SMILES: [NH2:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]3[N:11]([CH:13]=[C:14]([NH:16][C:17]([CH:19]4[CH2:21][CH2:20]4)=[O:18])[N:15]=3)[CH:12]=2)=[C:4]([F:24])[CH:3]=1.[Br:25][C:26]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=1[N:33]1[C:38]([CH3:39])=[CH:37][CH:36]=[C:35]([C:40](O)=[O:41])[C:34]1=[O:43].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>CN(C)C=O>[Br:25][C:26]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=1[N:33]1[C:38]([CH3:39])=[CH:37][CH:36]=[C:35]([C:40]([NH:1][C:2]2[CH:23]=[CH:22][C:5]([O:6][C:7]3[CH:8]=[CH:9][C:10]4[N:11]([CH:13]=[C:14]([NH:16][C:17]([CH:19]5[CH2:21][CH2:20]5)=[O:18])[N:15]=4)[CH:12]=3)=[C:4]([F:24])[CH:3]=2)=[O:41])[C:34]1=[O:43]
Reactant: Nc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3c2)c(F)c1
Reactant: Cc1ccc(C(=O)O)c(=O)n1-c1ccc(F)cc1Br
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(C(=O)Nc2ccc(Oc3ccc4nc(NC(=O)C5CC5)cn4c3)c(F)c2)c(=O)n1-c1ccc(F)cc1Br
Temperature: 25 °C
Reaction time: 72 h
Yield: 53.5 %

Procedure:
A mixture of N-[6-(4-amino-2-fluorophenoxy)imidazo[1,2-a]pyridin-2-yl]cyclopropanecarboxamide (150 mg, 0.459 mmol), 1-(2-bromo-4-fluorophenyl)-6-methyl-2-oxo-1,2-dihydropyridine-3-carboxylic acid (146 mg, 0.448 mmol), HATU (262 mg, 0.689 mmol), N,N-diisopropylethylamine (160 μl, 0.919 mmol) and N,N-dimethylformamide (3 mL) was stirred at room temperature for 3 days. After dilution with ethyl acetate, the mixture was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate and filtered. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (NH silica gel, 30 g, ethyl acetate/hexane=2/98→100/0) and preparative HPLC (acetonitrile/water=40/60→50/50, containing 0.1% trifluoroacetic acid) to give the title compound (152 mg, 52%) as a white solid.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[Cl:5][CH2:6][CH2:7][CH2:8][C:9](Cl)=[O:10].[C:12]1([CH3:18])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[Cl:5][CH2:6][CH2:7][CH2:8][C:9]([C:15]1[CH:16]=[CH:17][C:12]([CH3:18])=[CH:13][CH:14]=1)=[O:10]
Reactant: O=C(Cl)CCCCl
Reactant: Cc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Product: Cc1ccc(C(=O)CCCCl)cc1
Temperature: 3 °C
Reaction time: 0.25 h
Yield: 95 %

Procedure:
suspended anhydrous AlCl3 (156 g, 1.15 mol) in toluene (1500 mL) and cool to 2-4° C. Add, by slow addition, a solution of 4-chlorobutyryl chloride (165.5 g, 1.15 mol) in toluene (300 mL). Stir for 15 minutes and pour into stirring ice-water (2.5L). Stir for 30 hours, decant the toluene and extract the aqueous phase with toluene (700 mL). Combine the organic layers and wash three times with water (1L, 1L. 500 mL). Evaporate the solvent in vacuo to give the title compound as a pale yellow oil (292.3 g, 95%).
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]2[N:14]3[N:15]=[CH:16][C:17]([C:18]#[N:19])=[C:13]3[N:12]=[CH:11][CH:10]=2)[CH:4]=1.C([BH3-])#N.[Na+]>C(O)(=O)C>[F:20][C:2]([F:1])([F:21])[C:3]1[CH:4]=[C:5]([C:9]2[N:14]3[N:15]=[CH:16][C:17]([C:18]#[N:19])=[C:13]3[NH:12][CH2:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: N#Cc1cnn2c(-c3cccc(C(F)(F)F)c3)ccnc12
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Product: N#Cc1cnn2c1NCC=C2c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 6.0 g of 7-(α,α,α-trifluoro-m-tolyl)pyrazolo[1,5-a]pyrimidine-3-carbonitrile (Ex. 3, U.S. Pat. No. 4,236,005) in 100 ml of glacial acetic acid, was added in portions, 3.0 g of sodium cyanoborohydride at room temperature under nitrogen. The mixture was stirred at room temperature for 2 hours. The precipitate was collected by filtration, washed with water, then dissolved in dichloromethane. The organic solution was neutralized with a saturated solution of sodium bicarbonate, then dried over anhydrous sodium sulfate and filtered. The filtrate was evaporated in vacuo and gave the desired product as a white solid. The product was recrystallized from isopropyl alcohol, mp 175°-177° C.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:10][C:9]=1[NH:20][C:21](=[O:30])[CH2:22][C:23](=O)[C:24]1[CH:28]=[CH:27][S:26][CH:25]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:14]1([C:11]2[CH:12]=[CH:13][C:8]3[N:7]=[C:23]([C:24]4[CH:28]=[CH:27][S:26][CH:25]=4)[CH2:22][C:21](=[O:30])[NH:20][C:9]=3[CH:10]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccccc2)cc1NC(=O)CC(=O)c1ccsc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1CC(c2ccsc2)=Nc2ccc(-c3ccccc3)cc2N1
Yield: 66.6 %

Procedure:
Prepared from [3-(3-oxo-3-thiophen-3-yl-propionylamino)-biphenyl-4-yl]-carbamic acid tert.-butyl ester (Example K14) (110 mg, 0.25 mmol) by treatment with TFA in CH2Cl2 according to the general procedure M. Obtained as a light yellow solid (53 mg).
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([N:8]2[CH2:10][CH2:9]2)=[O:7])=[C:4]([O:13][CH3:14])[CH:3]=1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2([OH:28])[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[CH:18][CH:17]=1.CO>C1C=CC=CC=1>[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2([OH:28])[CH2:23][CH2:24][N:25]([CH2:9][CH2:10][NH:8][C:6](=[O:7])[C:5]3[CH:11]=[CH:12][C:2]([F:1])=[CH:3][C:4]=3[O:13][CH3:14])[CH2:26][CH2:27]2)=[CH:18][CH:17]=1
Reactant: COc1cc(F)ccc1C(=O)N1CC1
Reactant: OC1(c2ccc(Cl)cc2)CCNCC1
Solvent: CO
Solvent: c1ccccc1
Product: COc1cc(F)ccc1C(=O)NCCN1CCC(O)(c2ccc(Cl)cc2)CC1
Temperature: 25 °C

Procedure:
A mixture of 8 parts of 1-(4-fluoro-2-methoxybenzoyl)-aziridine, 3.7 parts of 4-(4-chlorophenyl)-4-piperidinol, 54 parts of benzene and 8 parts of methanol is stirred and refluxed for 1.50 hours. The reaction mixture is cooled to room temperature and 90 parts of benzene are added. The whole is washed with water and the layers are separated. The organic phase is dried, filtered and evaporated. The residue is crystallized from 2-propanone. The product is filtered off and dried, yielding 3.5 parts of N-{2-[4-(4-chlorophenyl)-4- hydroxy-1-piperidinyl]ethyl}-4-fluoro-2-methoxybenzamide; mp. 156.7° C.
Reaction SMILES: [OH:1][C:2]([CH3:34])([CH3:33])[CH2:3][C@@:4]1([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]#[C:20][C:21]([CH3:26])([CH3:25])[C:22](O)=[O:23])=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.C[CH2:36][N:37](C(C)C)[CH:38](C)C.N(C)C.C1COCC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[OH:1][C:2]([CH3:34])([CH3:33])[CH2:3][C@@:4]1([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]#[C:20][C:21]([CH3:26])([CH3:25])[C:22]([N:37]([CH3:38])[CH3:36])=[O:23])=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1
Reactant: CCN(C(C)C)C(C)C
Reactant: C[C@@H](c1ccc(C#CC(C)(C)C(=O)O)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CNC
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: ClCCl
Product: C[C@@H](c1ccc(C#CC(C)(C)C(=O)N(C)C)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 19 %

Procedure:
To a stirred solution of 4-(4-((S)-1-((S)-6-(2-hydroxy-2-methylpropyl)-2-oxo-6-phenyl-1,3-oxazinan-3-yl)ethyl)phenyl)-2,2-dimethylbut-3-ynoic acid (5.0 mg, 0.011 mmol) and i-Pr2NEt (0.01 mL) in CH2Cl2 (1 mL) were added 2 M Me2NH in THF (0.1 mL, 0.2 mmol) and solid HATU (8.5 mg, 0.022 mmol). The mixture was stirred overnight at rt, concentrated and the residue purified by prep HPLC to afford 4-(4-((S)-1-((S)-6-(2-hydroxy-2-methylpropyl)-2-oxo-6-phenyl-1,3-oxazinan-3-yl)ethyl)phenyl)-N,N,2,2-tetramethylbut-3-ynamide (1.0 mg, 19%). LC-MS Method 1 tR=1.65 min, m/z=491, 433; 1H NMR (CDCl3) 1.13 (s, 3H), 1.18 (s, 3H), 1.52 (d, 3H), 1.55 (s, 6H), 2.10-2.40 (5H), 2.82 (m, 1H), 5.64 (q, 1H), 6.88 (d, 2H), 7.13 (d, 2H), 7.30-7.40 (5H)
Reaction SMILES: C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl.[NH2:15][CH2:16][C:17]([CH:19]1[CH:24]2[CH2:25][CH2:26][N:21]([CH2:22][CH2:23]2)[CH2:20]1)=[O:18].[C:27](Cl)(=[O:29])[CH3:28].N1C=CC=CC=1>C(Cl)(Cl)Cl>[C:27]([NH:15][CH2:16][C:17]([CH:19]1[CH:24]2[CH2:23][CH2:22][N:21]([CH2:26][CH2:25]2)[CH2:20]1)=[O:18])(=[O:29])[CH3:28]
Reactant: NCC(=O)C1CN2CCC1CC2
Reactant: CC(=O)Cl
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: CC(=O)NCC(=O)C1CN2CCC1CC2
Temperature: 25 °C
Yield: 57.6 %

Procedure:
A suspension of the dihydrochloride salt of (±) 3-(α-aminoacetyl)-1-azabicyclo[2.2.2]octane (D14) (0.8 g; 0.0033 mole) in absolute chloroform (30 ml) was treated with acetyl chloride (0.76 g, 0.01 mole) and pyridine (4.58 g, 0.058 mole) at 0° C. for 1/2 h. The reaction was allowed to warm to room temperature for 15 h and then concentrated in vacuo. The residue was partitioned between chloroform and saturated aqueous potassium carbonate solution. The organic phase was separated, dried over sodium sulphate and concentrated in vacuo to a gum, which was chromatographed on neutral alumina in 10% methanol in ethyl acetate. This afforded the title compound as an oil (0.4 g, 58%).
Reaction SMILES: [CH:1]1([C:7]2[C:8]([O:16][CH2:17][C:18]([F:21])([F:20])[F:19])=[N:9][CH:10]=[C:11]([CH:15]=2)[C:12]([OH:14])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N:22]1[CH:27]=[CH:26][C:25]([NH2:28])=[N:24][CH:23]=1>>[CH:1]1([C:7]2[C:8]([O:16][CH2:17][C:18]([F:21])([F:20])[F:19])=[N:9][CH:10]=[C:11]([CH:15]=2)[C:12]([NH:28][C:25]2[CH:26]=[CH:27][N:22]=[CH:23][N:24]=2)=[O:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Nc1ccncn1
Reactant: O=C(O)c1cnc(OCC(F)(F)F)c(C2CCCCC2)c1
Product: O=C(Nc1ccncn1)c1cnc(OCC(F)(F)F)c(C2CCCCC2)c1

Procedure:
This compound was prepared following the same procedure as described in Example 11 using 5-cyclohexyl-6-(2,2,2-trifluoro-ethoxy)-nicotinic acid (Example 4b) (100 mg, 0.33 mmol) and 4-pyrimidinamine (CAN 591-54-8, 31.4 mg, 0.33 mmol) as starting materials; off white solid (50 mg, 39.8%). MS (ESI): 381.4 (M+H)+.
Reaction SMILES: [O:1]([CH2:8][C:9]([NH:11][CH:12]1[C:37](=[O:38])[N:14]2[C:15]([C:21]([O:23][CH:24]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[O:22])=[C:16]([CH2:19][OH:20])[CH2:17][S:18][C@H:13]12)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:39]([C:41]1[CH:42]=[C:43](O)[CH:44]=[CH:45][CH:46]=1)#[N:40]>>[C:39]([C:41]1[CH:46]=[C:45]([CH:44]=[CH:43][CH:42]=1)[O:20][CH2:19][C:16]1[CH2:17][S:18][C@@H:13]2[CH:12]([NH:11][C:9](=[O:10])[CH2:8][O:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:37](=[O:38])[N:14]2[C:15]=1[C:21]([O:23][CH:24]([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:22])#[N:40]
Reactant: O=C(COc1ccccc1)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CO)CS[C@H]12
Reactant: N#Cc1cccc(O)c1
Product: N#Cc1cccc(OCC2=C(C(=O)OC(c3ccccc3)c3ccccc3)N3C(=O)C(NC(=O)COc4ccccc4)[C@H]3SC2)c1

Procedure:
The procedure described in Example 1(a), was repeated, but using 2.00 g of diphenylmethyl 7-phenoxyacetamido-3-hydroxymethyl-3-cephem-4-carboxylate and m-cyanophenol, to afford 490 mg of the title compound as a powder.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][OH:6].[CH3:7][C:8]([CH3:10])=O>C(O)C.[Pt](=O)=O>[CH:8]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][OH:6])([CH3:10])[CH3:7]
Reactant: CC(C)=O
Reactant: NCCCCO
Agent: O=[Pt]=O
Solvent: CCO
Product: CC(C)NCCCCO
Reaction time: 48 h

Procedure:
100.40 g of 4-amino-1-butanol was dissolved in a mixed solvent of 108 ml of acetone and 160 ml of ethanol and, after adding 2.1 g of platinum (IV) oxide, hydrogenation was carried out under the pressure of 2 to 3 atms for 48 hours. A catalyst was removed by filtering the reaction solution and the filtrated was concentrated to obtain 147.64 g of the desired compound as a colorless oily substance.