Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]([C:11]2[N:12]=[C:13]([CH3:17])[S:14][C:15]=2[NH2:16])=[O:10])[CH:5]=[CH:4][N:3]=1.[CH:18]1([CH:21]=O)[CH2:20][CH2:19]1.C(O)C.C([BH3-])#N.[Na+]>O>[CH3:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]([C:11]2[N:12]=[C:13]([CH3:17])[S:14][C:15]=2[NH:16][CH2:21][CH:18]2[CH2:20][CH2:19]2)=[O:10])[CH:5]=[CH:4][N:3]=1
Reactant: O=CC1CC1
Reactant: Cc1cc(NC(=O)c2nc(C)sc2N)ccn1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cc1cc(NC(=O)c2nc(C)sc2NCC2CC2)ccn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 45.1 %

Procedure:
5-Amino-2-methyl-thiazole-4-carboxylic acid (2-methyl-pyridin-4-yl)-amide (0.200 g, 0.806 mmol) was treated with cyclopropanecarboxaldehyde (0.230 g, 3.22 mmol) and tetraisopropyl-orthotitanate (0.916 g, 3.22 mmol) and stirred at room temperature overnight. Ethanol (5 mL) and sodium cyanoborohydride (0.213 g, 3.22 mmol) were added and the reaction mixture was stirred for 5 h. Water (0.5 mL) was added to the reaction mixture and the solvent was evaporated. The residue was purified by flash chromatography on silica gel with ethyl acetate/methanol 100:0→90:10 gradient to yield the title compound (0.110 g, 45%) as a light yellow solid, MS (ISP): m/e=303.1 (M+H+).
Reaction SMILES: Cl[C:2]1[C:3]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=2.[NH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1.[CH2:29](O)[CH2:30][CH2:31]C>>[F:22][C:19]1[CH:20]=[CH:21][C:16]([C:3]2[C:2]([N:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)=[N:11][C:10]3[C:5](=[CH:6][CH:7]=[C:8]([C:12]([O:14][CH2:15][CH2:29][CH2:30][CH3:31])=[O:13])[CH:9]=3)[N:4]=2)=[CH:17][CH:18]=1
Reactant: COC(=O)c1ccc2nc(-c3ccc(F)cc3)c(Cl)nc2c1
Reactant: CCCCO
Reactant: C1CCNCC1
Product: CCCCOC(=O)c1ccc2nc(-c3ccc(F)cc3)c(N3CCCCC3)nc2c1
Temperature: 110 °C
Reaction time: 8 h

Procedure:
Into a 10-mL sealed tube, was placed methyl 3-chloro-2-(4-fluorophenyl)quinoxaline-6-carboxylate (150 mg, 0.47 mmol, 1.00 equiv), piperidine (403 mg, 4.74 mmol, 10.00 equiv), butan-1-ol (2 mL). The resulting solution was stirred for overnight at 110° C. in an oil bath. The resulting mixture was concentrated under vacuum. This resulted in 150 mg (crude) of butyl 2-(4-fluorophenyl)-3-(piperidin-1-yl)quinoxaline-6-carboxylate as a yellow solid.
Reaction SMILES: [CH3:1][N:2]1[CH2:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[C:5](=[O:13])[C:4]2[CH:14]=[C:15]([CH2:18][C:19]([O:21][CH3:22])=[O:20])[CH:16]=[CH:17][C:3]1=2.[H-].[Na+].O.C(O)(=O)C.[CH3:30][C:31]1([CH3:38])[O:35][CH:34](CO)[CH2:33][O:32]1>>[CH3:30][C:31]1([CH3:38])[O:35][CH2:34][CH:33]([CH2:22][O:21][C:19](=[O:20])[CH2:18][C:15]2[CH:16]=[CH:17][C:3]3[N:2]([CH3:1])[CH2:8][C:7]4[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=4[C:5](=[O:13])[C:4]=3[CH:14]=2)[O:32]1
Reactant: COC(=O)Cc1ccc2c(c1)C(=O)c1ccccc1CN2C
Reactant: CC1(C)OCC(CO)O1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CN1Cc2ccccc2C(=O)c2cc(CC(=O)OCC3COC(C)(C)O3)ccc21

Procedure:
Methyl 5,6-dihydro-5-methyl-11-oxodibenz[b,e]azepine-2-acetate (1.5 g) was dissolved in Solketal (20 ml), and 50% oily sodium hydride (0.2 g) was added. The mixture was maintained at 80°-100° C. under reduced pressure using an aspirator. The reaction mixture was poured into water (150 ml) and acetic acid (0.5 ml), and the system was extracted with dichloromethane. The extract was dried over MgSO4, and then, the solvent was distilled off. The residual oily matter was subjected to liquid column chromatography using 100 g of Wakogel C-200 to afford the desired compound as a yellow oily material (0.950 g) eluted with a mixed liquid of benzene-dichloromethane (1:1).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][C@@H:11]([C:13]2([NH:16]C(OC(C)(C)C)=O)[CH2:15][CH2:14]2)[C@H:10]([CH2:24][OH:25])[CH2:9]1)[C:2]1[CH:7]=CC=C[CH:3]=1.[NH2:26][C:27]1[C:36]([F:37])=C(F)C(C)=C2[C:28]=1[C:29](=[O:46])[C:30]([C:43]([OH:45])=[O:44])=[CH:31][N:32]2[CH:40]1[CH2:42][CH2:41]1.C(N(CC)CC)C>C(O)C.CS(C)=O.[OH-].[Pd+2].[OH-]>[NH2:26][C:27]1[C:36]([F:37])=[C:1]([N:8]2[CH2:12][C@@H:11]([C:13]3([NH2:16])[CH2:14][CH2:15]3)[C@H:10]([CH2:24][OH:25])[CH2:9]2)[C:2]([CH3:7])=[C:3]2[C:28]=1[C:29](=[O:46])[C:30]([C:43]([OH:45])=[O:44])=[CH:31][N:32]2[CH:40]1[CH2:42][CH2:41]1
Reactant: Cc1c(F)c(F)c(N)c2c(=O)c(C(=O)O)cn(C3CC3)c12
Reactant: CC(C)(C)OC(=O)NC1([C@@H]2CN(Cc3ccccc3)C[C@H]2CO)CC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: CCO
Solvent: CS(C)=O
Product: Cc1c(N2C[C@@H](CO)[C@H](C3(N)CC3)C2)c(F)c(N)c2c(=O)c(C(=O)O)cn(C3CC3)c12
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 24 %

Procedure:
Trans-1-benzyl-4-(1-tert-butoxycarbonylaminocyclopropyl)-3-hydroxymethylpyrrolidine (1.10 g, 3.18 mmol) was dissolved in ethanol (50 ml), and the solution was mixed with palladium hydroxide (500 mg) and stirred for 1.5 hours at room temperature under a hydrogen atmosphere. The reaction suspension was subjected to celite filtration (ethanol washing) and the solvent was evaporated. The resulting residue and 5-amino-1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methyl-4-oxoquinoline-3-carboxylic acid (471 mg, 1.60 mmol) were dissolved in dimethyl sulfoxide (20 ml) and, under a nitrogen atmosphere, the solution was mixed with triethylamine (5 ml) and stirred at 150° C. for 19 hours. After evaporating the solvent, the resulting residue was mixed with 10% citric acid aqueous solution (50 ml) and extracted with chloroform (50 ml×2), and the extract was dried over anhydrous sodium sulfate. After evaporating the solvent, the resulting residue was mixed with concentrated hydrochloric acid (5 ml) and stirred for 1 hour. This was mixed with water (50 ml) and washed with chloroform (50 ml×2). The aqueous layer was adjusted to pH 12.00 with a sodium hydroxide aqueous solution and washed with chloroform (50 ml×2). Finally, the aqueous layer was adjusted to pH 7.40 with 1 N hydrochloric acid and extracted with chloroform (300 ml×5). The extract was dried over anhydrous sodium sulfate, the solvent was evaporated and then the resulting residue was recrystallized from ethanol to obtain 165 mg (38%) of the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.[CH3:12][C@@H:13](O)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].[N+](C1C=CC=CC=1O)([O-])=O>>[CH3:12][C@H:13]([O:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: Cc1ccc(O)cc1[N+](=O)[O-]
Reactant: CCCCCC[C@@H](C)O
Agent: O=[N+]([O-])c1ccccc1O
Product: CCCCCC[C@H](C)Oc1ccc(C)c([N+](=O)[O-])c1

Procedure:
4-Methyl-3-nitrophenol (Compound 33, Scheme VI) was coupled with (R)-2-octanol using the same procedure as that given for alkylation of phenol 9, Scheme I, to give (S)-4-(1-methylheptyloxy)-2-nitro-toluene (Compound 34, Scheme VI, R1 =(S)-OCH(CH3)C6H13) as a yellow liquid; Rf [Hexanes/ethyl acetate 99/1]: 0.26; 1H NMR (300 MHz, CDCl3): δ 0.87(t, 3H, J=6.6 Hz), 1.16-1.65(m, 12H), 1.70(m, 1H), 2.50(s, 3H), 4.37(m, 1H), 7.02(dd, 1H ,J=2.7 Hz, J=8.5 Hz), 7.19(d, 1H, J=8.5 Hz), 7.47(d, 1H, J=2.7 Hz); 13C NMR (300 MHz, CDCl3): δ 13.97, 19.41, 19.63, 22.51, 25.32, 29.14, 31.69, 36.20, 74.72, 111.05, 121.44, 125.12, 133.44, 149.5, 156.77; IR (CHCl3): 3020, 2940, 2850, 1620, 1550, 1525, 1490, 1375, 1300, 1240, 1220, 1110, 1050, 975, 860, 825 cm-1 ; Mass spectrum, m/z(rel.intensity): 265(M+ 11), 153(33), 136(100), 112(21), 71(40), 57(70), 51(11), 43(78), 41(66).
Reaction SMILES: [CH2:1]([N:4]1[C:10]2[CH:11]=[N:12][CH:13]=[CH:14][C:9]=2[N:8]([CH3:15])[N:7]2[CH:16]=[CH:17][CH:18]=[C:6]2[CH2:5]1)[C:2]#[CH:3].[CH3:19][O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1.[CH2:33]=O>Cl[Cu].O1CCOCC1>[CH3:19][O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[N:27]1[CH2:32][CH2:31][N:30]([CH:1]([N:4]2[C:10]3[CH:11]=[N:12][CH:13]=[CH:14][C:9]=3[N:8]([CH3:15])[N:7]3[CH:16]=[CH:17][CH:18]=[C:6]3[CH2:5]2)[C:2]#[C:3][CH3:33])[CH2:29][CH2:28]1
Reactant: COc1ccccc1N1CCNCC1
Reactant: C=O
Reactant: C#CCN1Cc2cccn2N(C)c2ccncc21
Agent: Cl[Cu]
Solvent: C1COCCO1
Product: CC#CC(N1CCN(c2ccccc2OC)CC1)N1Cc2cccn2N(C)c2ccncc21
Temperature: 80 °C
Reaction time: 3 h

Procedure:
To 150 ml of p-dioxane were added 11-(2-propynyl)-10,11-dihydro-5-methyl-5H-pyrido[3,4-f]pyrrolo[1,2-b][1,2,5]triazepine (2.3 g), 4-(2-methoxyphenyl)piperazine (2.1 g), paraformaldehyde (2.0 g), and CuCl (0.02 g). After stirring at 80° C. for three hours, the mixture was concentrated to 6.9 g of brown oil, which was eluted on a silica gel column with 5% methanol/DCM via HPLC. The desired fraction was concentrated to 4.3 g of 11-[1-[4-(2-methoxyphenyl)piperazin-1-yl]-2-butynyl]-10,11-dihydro-5-methyl-5H-pyrido[3,4-f]pyrrolo[1,2-b][1,2,5]triazepine, as a light brown oil; MS(EI)M+ @ 442 (6.7%), IR(CHCl3)--C≡CH @ 3300 cm-1.
Reaction SMILES: [F:1][C:2]1[CH:28]=[CH:27][C:5]([O:6][C:7]2[S:13][CH:12]3[N:9]([CH2:10][CH2:11]3)[C:8]=2[C:14]([O:16]CC2C=CC([N+]([O-])=O)=CC=2)=[O:15])=[CH:4][CH:3]=1.C(=O)(O)[O-:30].[Na+:33]>O1CCOCC1.O.[Pd]>[F:1][C:2]1[CH:28]=[CH:27][C:5]([O:6][C:7]2[S:13][CH:12]3[N:9]([C:10](=[O:30])[CH2:11]3)[C:8]=2[C:14]([O-:16])=[O:15])=[CH:4][CH:3]=1.[Na+:33]
Reactant: O=C(OCc1ccc([N+](=O)[O-])cc1)C1=C(Oc2ccc(F)cc2)SC2CCN12
Reactant: O=C([O-])O
Agent: [Pd]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: O=C([O-])C1=C(Oc2ccc(F)cc2)SC2CC(=O)N12
Yield: 95.5 %

Procedure:
A mixture of a solution of 500 mg of 4-nitrobenzyl 3-(4-fluorophenoxy)-4-thia-1-azabicyclo[3,2,0]hept-2-ene-2-carboxylate in dioxan and 101 mg of sodium bicarbonate in water, and 10% palladium/charcoal was hydrogenated at 50 psi at 25° for 60 minutes. Then the reaction mixture was filtered through Celite, and then lyophilised to yield 348 mg of the title compound as a pale yellow crystalline solid (95% of the theoretical yield).
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]([N:15]1[CH2:20][CH2:19][CH2:18][CH:17]([CH2:21][N:22]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:23](=[O:26])[CH2:24][CH3:25])[CH2:16]1)(OC(C)(C)C)=O.[C:33]1([CH2:39]C=O)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[CH2:8]([N:15]1[CH2:20][CH2:19][CH2:18][CH:17]([CH2:21][N:22]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:23](=[O:26])[CH2:24][CH3:25])[CH2:16]1)[CH2:39][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: CCC(=O)N(CC1CCCN(C(=O)OC(C)(C)C)C1)c1ccccc1
Reactant: O=CCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCC(=O)N(CC1CCCN(CCc2ccccc2)C1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Trifluoroacetic acid (5 mL) was added dropwise to a solution of N-(1-Boc-piperidin-3-ylmethyl)-N-phenyl-propionamide 5 (1.21 g, 3.49 mmol) in 5 mL of dry CH2Cl2 at 0° C. (ice-water). The reaction mixture was stirred at room temperature for 30 minutes. TLC showed the reaction was complete. After removal of the solvents, the residue was dried under vacuum for 3 hrs. The crude compound was dissolved in DMF (5.0 mL) and phenylacetaldehyde (5.3 mL, 2M/in DMF, 5.3 mmol) was added. The mixture was stirred at room temperature for 30 min. NaB(OAc)3H (95%, 1.18 g, 5.3 mmol.) was introduced in one portion, and the mixture was stirred at room temperature overnight. The mixture was quenched with 10 mL of aqueous potassium carbonate (sat.), then extracted with ethyl acetate (3×60 mL). The extracts were combined and washed with aqueous NaHCO3 (sat., 2×10 mL), brine (30 mL), and dried over anhydrous sodium sulfate. After the solvent was removed, the remaining oily residue was purified by a flash column chromatography to give 6. IR (film, cm−1) 3060, 3026, 2934, 2854, 2800, 2765, 1662, 1495, 1452, 1401, 1262, 1203, 1150, 1106, 966, 1033, 775, 749; LRMS 351.
Reaction SMILES: [CH2:1]([N:3]1[C:9]2[N:10]=[CH:11][CH:12]=[CH:13][C:8]=2[C:7](=[O:14])[N:6]([CH3:15])[C:5]2[CH:16]=[CH:17][C:18](OS(C(F)(F)F)(=O)=O)=[N:19][C:4]1=2)[CH3:2].[CH3:28][C:29]1[C:33]([Sn](CCCC)(CCCC)CCCC)=[CH:32][NH:31][N:30]=1>>[CH2:1]([N:3]1[C:9]2[N:10]=[CH:11][CH:12]=[CH:13][C:8]=2[C:7](=[O:14])[N:6]([CH3:15])[C:5]2[CH:16]=[CH:17][C:18]([C:33]3[C:29]([CH3:28])=[N:30][NH:31][CH:32]=3)=[N:19][C:4]1=2)[CH3:2]
Reactant: CCCC[Sn](CCCC)(CCCC)c1c[nH]nc1C
Reactant: CCN1c2ncccc2C(=O)N(C)c2ccc(OS(=O)(=O)C(F)(F)F)nc21
Product: CCN1c2ncccc2C(=O)N(C)c2ccc(-c3c[nH]nc3C)nc21

Procedure:
The title compound (mp 113°-115° C.) was prepared from 5,11-dihydro-11-ethyl-5-methyl-2-trifluoromethanesulfonyloxy-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one and 3-methyl-4-(tributylstannyl)pyrazole in a manner analogous to that described in Example 1.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]2[N:22]=[C:21]([Cl:23])C(C(F)(F)F)=CN=2)=[CH:12][CH:11]=1)(=[O:8])[O:5][CH2:6][CH3:7])C.O=P1(CC2C=CC(N)=CC=2)OCCCO1.ClC1N=C(Cl)[C:47]([C:51]([F:54])([F:53])[F:52])=[CH:46][N:45]=1>>[Cl:23][C:21]1[N:22]=[C:17]([NH:16][C:13]2[CH:12]=[CH:11][C:10]([CH2:9][P:4]3(=[O:8])[O:3][CH2:1][CH2:7][CH2:6][O:5]3)=[CH:15][CH:14]=2)[C:47]([C:51]([F:54])([F:53])[F:52])=[CH:46][N:45]=1
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)cc1)OCC
Reactant: FC(F)(F)c1cnc(Cl)nc1Cl
Agent: Nc1ccc(CP2(=O)OCCCO2)cc1
Product: O=P1(Cc2ccc(Nc3nc(Cl)ncc3C(F)(F)F)cc2)OCCCO1

Procedure:
The title compound was prepared according to the procedure for diethyl(4-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}benzyl)phosphonate using 4-[(2-oxido-1,3,2-dioxaphosphinan-2-yl)methyl]aniline (Compound 230C) and 2,4-dichloro-5-trifluoromethylpyrimidine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9]2[CH:10]=[C:11]([NH:15][C:16]([NH2:18])=[S:17])[CH:12]=[CH:13][CH:14]=2)[CH:4]=1.[ClH:19].[C:20](OCC)(=O)[CH3:21]>CN(C)C=O.O1CCOCC1.ICC>[ClH:19].[ClH:19].[CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9]2[CH:10]=[C:11]([NH:15][C:16](=[NH:18])[S:17][CH2:20][CH3:21])[CH:12]=[CH:13][CH:14]=2)[CH:4]=1
Reactant: COc1ccnc(-c2cccc(NC(N)=S)c2)c1
Reactant: CCOC(C)=O
Agent: Cl
Solvent: CN(C)C=O
Solvent: C1COCCO1
Solvent: CCI
Product: CCSC(=N)Nc1cccc(-c2cc(OC)ccn2)c1
Temperature: 50 °C
Reaction time: 1.5 h

Procedure:
To a suspension of N-(3-(4-methoxypyridin-2-yl)phenyl)thiourea (171 mg) in N,N-dimethylformamide (4 ml) were added a solution of hydrogen chloride in 1,4-dioxane (4N, 0.33 ml) and iodoethane (0.263 ml), and the mixture was stirred at 50° C. for 1.5 hours. Ethyl acetate (100 ml) was added to the mixture, and the mixture was cooled. The precipitate was collected by filtration. The precipitate was dissolved in water, and to the solution was added a saturated aqueous sodium hydrogencarbonate solution and extracted with dichloromethane. The organic layer was washed with brine, dried over sodium sulfate and evaporated under reduced pressure. The residue was dissolved in ethyl acetate, and to the solution was added a solution of hydrogen chloride in 1,4-dioxane (4N, 0.5 ml). The precipitate was collected by filtration and dried under reduced pressure to give N-(3-(4-methoxypyridin-2-yl)phenyl)-S-ethylisothiourea dihydrochloride (204 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([CH:14]3[C:18](=[O:19])[CH2:17][CH2:16][C:15]3=[O:20])[C:11]([CH3:21])=[CH:10][N:9]=2)=[CH:4][CH:3]=1.[C:22](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O>CC(C)=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[C:12]([C:14]3[C:18](=[O:19])[CH2:17][CH2:16][C:15]=3[O:20][CH3:22])[C:11]([CH3:21])=[CH:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: Cc1cnc(-c2ccc(Cl)cc2)nc1C1C(=O)CCC1=O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: COC1=C(c2nc(-c3ccc(Cl)cc3)ncc2C)C(=O)CC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 77.3 %

Procedure:
2-[2-(4-Chloro-phenyl)-5-methyl-pyrimidin-4-yl]-cyclopentane-1,3-dione (650 mg, 2.16 mmol) was slurried in acetone (20 ml) and potassium carbonate (300 mg, 2.16 mmol) was added. After stirring at room temperature for 5 minutes, dimethyl sulphate (0.20 ml, 2.16 ml) was added in one portion and the reaction was heated to reflux. After 3 hours at reflux the reaction was complete and subsequently cooled to room temperature, before stripping to dryness. The resulting orange solid was re-solubilised in ethyl acetate (20 ml) and 1M sodium hydroxide (20 ml) and the biphasic mixture separated. The aqueous layer was further extracted with ethyl acetate (2×10 ml) before combining the organic layers, drying over magnesium sulphate, filtering and stripping to dryness to isolate a brown solid. This was purified by normal phase chromatography (gradient system of 100% dichloromethane−5% methanol:dichloromethane) to isolate 2-[2-(4-Chloro-phenyl)-5-methyl-pyrimidin-4-yl]-3-methoxy-cyclopent-2-enone as a yellow foam (526 mg, 1.67 mmol, 77% yield).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[N:14]3[N:15]=[C:16]([CH:18]([CH3:20])[CH3:19])[N:17]=[C:13]3[NH:12][C:11]([CH3:21])=[C:10]2[C:22]#[N:23])=[CH:5][CH:4]=1)#[N:2].ClCCl.[F:27][C:28]([F:39])([F:38])[C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][CH:34]=1.C(N(CC)CC)C>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.N1C=CC=CC=1>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[N:14]3[N:15]=[C:16]([CH:18]([CH3:20])[CH3:19])[N:17]=[C:13]3[N:12]([C:33]3[CH:32]=[CH:31][CH:30]=[C:29]([C:28]([F:39])([F:38])[F:27])[CH:34]=3)[C:11]([CH3:21])=[C:10]2[C:22]#[N:23])=[CH:5][CH:4]=1)#[N:2]
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Reactant: CC1=C(C#N)C(c2ccc(C#N)cc2)n2nc(C(C)C)nc2N1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC1=C(C#N)C(c2ccc(C#N)cc2)n2nc(C(C)C)nc2N1c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Under an atmosphere of argon protective gas, (rac)-7-(4-cyanophenyl)-5-methyl-2-(1-methylethyl)-4,7-dihydro[1,2,4]triazolo[1,5-a]pyrimidine-6-carbonitrile (63 mg, 207 μmol) was stirred in abs. dichloromethane (50 ml) with molecular sieve (0.5 g, 4 Å) for 1 h. 3-(Trifluoromethyl)phenylboronic acid (118 mg, 621 μmol, 3 eq.), anhydrous copper(II) acetate (113 mg, 621 μmol, 3 eq.), abs. pyridine (1390 μl) and triethylamine (63 mg, 621 μmol, 3 eq.) were then added, and the mixture was stirred at RT for 12 h. More molecular sieve (0.5 g, 4 Å), 3-(trifluoromethyl)phenylboronic acid (39 mg, 207 μmol, 1 eq.), anhydrous copper(II) acetate (38 mg, 207 μmol, 1 eq.) and abs. pyridine (500 μl) were then added, and the mixture was stirred at RT for a further 3 d. The reaction mixture was then filtered through kieselguhr, the filter residue was washed with dichloromethane and pyridine and the filtrate was concentrated to dryness. The residue was purified by preparative HPLC (Gromsil C18 column, 10 μm; mobile phase: acetonitrile/water+0.1% TFA 10:90→90:10). The product was obtained as a colorless solid (29.8 mg, 64% of theory).
Reaction SMILES: Cl[CH2:2][O:3][CH2:4][C:5]1[CH:9]=[N:8][S:7][N:6]=1.Cl.[Cl:11][C:12]1[CH:13]=[N:14][C:15](=[O:18])[NH:16][CH:17]=1.C(N(CC)CC)C>ClCCl>[S:7]1[N:8]=[CH:9][C:5]([CH2:4][O:3][CH2:2][N:16]2[CH:17]=[C:12]([Cl:11])[CH:13]=[N:14][C:15]2=[O:18])=[N:6]1
Reactant: ClCOCc1cnsn1
Reactant: O=c1ncc(Cl)c[nH]1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=c1ncc(Cl)cn1COCc1cnsn1
Temperature: 40 °C
Reaction time: 2 h

Procedure:
3-(Chloromethyl)oxymethyl-1,2,5-thiadiazole (see Preparation 10) (0.18 mmol) in dichloromethane (1 ml) was added dropwise with stirring at room temperature to a solution of 5-chloropyrimidin-2-one hydrochloride (18 mmol) and triethylamine (0.36 mmol) in dichloromethane (3 ml). The mixture was stirred for 11/2 hours at 40° C. before the solvent was distilled off. The residue was triturated with water, extracted into chloroform and the dried (MgSO4) solution evaporated. Trituration of the residue with ether left the title compound in 20% (11 mg) yield, m.p. 106° C. 1H NMR (CDCl3): δ5.00 (CH2Het), 5.40 (OCH2), 7.73 and 8.47 (H-4, H-6, J 3 Hz), 8.50 (H-31).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[N:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.CO.[F:13][CH:14]([F:28])[O:15][C:16]1[CH:17]=[C:18]([CH:21]=[C:22]([O:24][CH:25]([F:27])[F:26])[CH:23]=1)[CH:19]=[O:20].[OH-].[K+]>O>[F:13][CH:14]([F:28])[O:15][C:16]1[CH:17]=[C:18]([CH:19]([C:5]2[C:4]3[C:8](=[N:9][CH:10]=[C:2]([Br:1])[CH:3]=3)[NH:7][CH:6]=2)[OH:20])[CH:21]=[C:22]([O:24][CH:25]([F:26])[F:27])[CH:23]=1
Reactant: O=Cc1cc(OC(F)F)cc(OC(F)F)c1
Reactant: Brc1cnc2[nH]ccc2c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: OC(c1cc(OC(F)F)cc(OC(F)F)c1)c1c[nH]c2ncc(Br)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 36.7 %

Procedure:
To 5-bromo-7-azaindole (67, 86.4 mg, 0.000438 mol) methanol (10.0 mL) were added 3,5-bis-difluoromethoxy-benzaldehyde (529, 110.0 mg, 0.46 mmol) and potassium hydroxide (200.0 mg, 3.6 mmol) under art atmosphere of nitrogen. The reaction was stirred at room temperature overnight. The reaction was poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 20% ethyl acetate in hexane to give the compound as a white solid (530, 70 mg, 35%). MS (ESI) [M+H+]+=435.1, 437.1.
Reaction SMILES: C1[C@H](N)[C@@H]([O:8][C@H]2O[C@H](CN)[C@@H](O)[C@H](O)[C@H]2N)[C@H](O[C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)[C@@H](O)[C@@H]1N.FC(F)(F)C([O-])=O.[CH:39]1([N:45]=[C:46]=[N:47][CH:48]2[CH2:53][CH2:52][CH2:51][CH2:50][CH2:49]2)[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]1.C1[C@H](N)[C@@H](O[C@H]2O[C@H](CN)[C@@H](O)[C@H](O)[C@H]2N)[C@H](O[C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)[C@@H](O)[C@@H]1N.C(O)(=O)C>O1CCCC1.CN(C)C=O>[C:46]([NH:45][CH:39]1[CH2:40][CH2:41][CH2:42][CH2:43][CH2:44]1)([NH:47][CH:48]1[CH2:53][CH2:52][CH2:51][CH2:50][CH2:49]1)=[O:8]
Reactant: NC[C@H]1O[C@H](O[C@H]2[C@H](O[C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)[C@@H](O)[C@H](N)C[C@@H]2N)[C@H](N)[C@@H](O)[C@@H]1O
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C([O-])C(F)(F)F
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: O=C(NC1CCCCC1)NC1CCCCC1
Reaction time: 0.5 h

Procedure:
2 g of the ribostamycin trifluoroacetate prepared in the same manner as in Example 1 was taken and dissolved in 35 ml of a liquid mixture of tetrahydrofuran and dimethylformamide (10:1 by volume). This solution was admixed with a solution of 1.74 g of (S)-α-hydroxy-δ-N-phthalimido-n-valeric acid in 16 ml tetrahydrofuran. A solution of 3.62 g. of dicyclohexylcarbodiimide in 16 ml of tetrahydrofuran was added thereto under ice-cooling. The mixture was agitated for 30 minutes under ice-cooling and agitated at ambient temperature for 1 hour 25 minutes to effect the esterification of the hydroxyl groups of the ribostamycin with the substituted valeric acid. The reaction mixture was admixed with 0.8 ml of glacial acetic acid and allowed to stand at ambient temperature overnight to decompose the excess of dicyclohexylcarbodiimide. The dicylcohexylurea by-produced which precipitated was removed by filtration. The filtrate was concentrated to give a solid comprising mixed trifluoroacetic acid salts of O-((S)-α-hydroxy-δ-N-phthalimido-n-valeryl)-ribostamycins.