Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[CH2:10]([O:12][C:13](=[O:24])[C:14](=[CH:20]OCC)[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH3:11].CCCCCC>C1(C)C=CC=CC=1>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([NH:1][CH:20]=[C:14]([C:13]([O:12][CH2:10][CH3:11])=[O:24])[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:3][CH:4]=1)#[N:7]
Reactant: N#Cc1ccc(N)cc1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: CCOC(=O)C(=CNc1ccc(C#N)cc1)C(=O)OCC
Yield: 87.5 %

Procedure:
To 5.00 g (42.3 mmol) 4-aminobenzonitrile (Aldrich, 98%) was added 10.1 g (9.41 mL, 46.6 mmol, 1.1 eq) diethylethoxymethylenemalonate (Aldrich, 99%), and the mixture was dissolved in 50 mL toluene (HPLC grade). The solution was refluxed for four hours with a condensor open to the air. The solution was then poured into 200 mL hexane, and the resulting white precipitate was filtered and washed well with more hexane to yield 10.62 g (37.0 mmol, 85% yield) of the title compound as a slightly off-white solid (per LC/MS and 1H NMR). LC [MH+] 289, 97% purity.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:12][CH2:13][CH2:14][CH2:15][OH:16])[CH:9]([CH3:11])[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(C)([O-])C.[K+].[F:23][C:24]1[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=1[CH2:26]Br>O1CCCC1.C(Cl)Cl>[F:23][C:24]1[CH:31]=[CH:30][CH:29]=[CH:28][C:25]=1[CH2:26][O:16][CH2:15][CH2:14][CH2:13][CH2:12][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH:9]([CH3:11])[CH3:10]
Reactant: Fc1ccccc1CBr
Reactant: CC(C)N(CCCCO)C(=O)OC(C)(C)C
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(C)N(CCCCOCc1ccccc1F)C(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 0.67 h
Yield: 77.1 %

Procedure:
A solution of N-(t-butoxycarbonyl)-4-hydroxy-N-isopropylbutylamine (539 mg, 2.33 mmol) in tetrahydrofuran (11 ml) at −40° C. was treated with potassium t-butoxide (1 M in tetrahydrofuran, 2.54 ml, 2.54 mmol). After 40 minutes, the suspension was cooled to −78° C. and treated with a solution of 2-fluorobenzyl bromide (400 mg, 2.12 mmol) in tetrahydrofuran (4 ml). The reaciton was slowly warmed to room temperature and stirred for about five hours. The reaction was diluted with methylene chloride and washed with 1 M potassium carbonate and brine. The organic fraction was dried over sodium sulfate, filtered, and concentrated. The crude oil was purified by liquid chromatography to yield 555 mg (77%) of the title intermediate as a clear oil.
Reaction SMILES: [Br:1][C:2]1[CH:20]=[C:19]([C:21]2[C:30]3[C:31]4[CH:37]=[CH:36][CH:35]=[CH:34][C:32]=4[S:33][C:29]=3[C:28]([O:38][CH2:39][C:40]([OH:42])=[O:41])=[C:27]3[C:22]=2[CH:23]=[CH:24][CH:25]=[CH:26]3)[CH:18]=[C:17]([Br:43])[C:3]=1[O:4][C@H:5]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:6]([O:8]C)=[O:7].[OH-]>O1CCCC1.CO>[Br:1][C:2]1[CH:20]=[C:19]([C:21]2[C:30]3[C:31]4[CH:37]=[CH:36][CH:35]=[CH:34][C:32]=4[S:33][C:29]=3[C:28]([O:38][CH2:39][C:40]([OH:42])=[O:41])=[C:27]3[C:22]=2[CH:23]=[CH:24][CH:25]=[CH:26]3)[CH:18]=[C:17]([Br:43])[C:3]=1[O:4][CH:5]([CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[C:6]([OH:8])=[O:7]
Reactant: COC(=O)[C@@H](Cc1ccccc1)Oc1c(Br)cc(-c2c3ccccc3c(OCC(=O)O)c3sc4ccccc4c23)cc1Br
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)COc1c2ccccc2c(-c2cc(Br)c(OC(Cc3ccccc3)C(=O)O)c(Br)c2)c2c1sc1ccccc12
Reaction time: 3.5 h
Yield: 87.2 %

Procedure:
To a solution of (R)-2-[2,6-dibromo-4-(6-carboxymethoxy-benzo [b]naphtho[2,3-d]thiophen-11-yl)-phenoxy]-3-phenyl-propionic acid, methyl ester (0.436 g, 0.594 mmol) in tetrahydrofuran (9 mL) and methanol (3 mL) was added an aqueous solution of potassuim hydroxide (1 N, 2.37 mL, 2.37 mmol, 4 eq) dropwise at room temperature. After stirring 3.5 hours the solvents were removed and the residue was combined with water. The suspension was acidified with 10% aqueous hydrochloric acid and diethyl ether was added. The biphasic mixture was shaken well before the layers were separated. The organic phase was washed with water and concentrated. The residue was triturated with petroleum ether and dried in vacuo to provide the title compound as a white solid (0.366 g, 87%): mp 110-120° C.; [a]25/D =+49.620 (10.076 mg/mL, methanol); NMR (DMSO-d6): δ13.21 (broad s, 2 H), 8.40 (d, J=8 Hz, 1H), 8.03 (d, J=8 Hz, 1H), 7.74 (dd, J=2, 8 Hz, 2 H), 7.68 (ddd, J=8, 7, 1 Hz, 1 H), 7.57 (ddd, J=8, 7, 1 Hz, 1H), 7.52 - 7.45 (m, 2 H), 7.43 - 7.38 (m, 2 H), 7.37 -7.11 (m, 2 H), 7.10-7.20 (m, 2 H), 6.69 (d, J=8Hz, 1H), 5.30 (t, J=7 Hz, 1 H), 4.90 (s, 2 H), 3.41 (d, J=7 Hz, 2 H); MS (+FAB): [M+], 2 bromine isotope pattern, 704 (9%), 706 (22%), 708 (22%); Anal. Calc. for C33212Br2O6S: C, 56.11, H, 3.14, N, 0.00. Found: C, 55.93, H, 3.28, N, 0.09.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:24]=[C:23]([S:25][CH3:26])[CH:22]=[CH:21][C:16]=2[C:17]([O:19]C)=[O:18])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>[Li+].[OH-].CO.C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:24]=[C:23]([S:25][CH3:26])[CH:22]=[CH:21][C:16]=2[C:17]([OH:19])=[O:18])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)c1ccc(SC)cc1OC1CCN(C(=O)OC(C)(C)C)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CSc1ccc(C(=O)O)c(OC2CCN(C(=O)OC(C)(C)C)CC2)c1
Reaction time: 8 h
Yield: 85.6 %

Procedure:
The methyl 2-(1-tert-butoxycarbonylpiperidin-4-yloxy)-4-(methylthio)benzoate (504 mg, 1.32 mmol) was dissolved in a mixture of 1 M LiOH (2 mL), MeOH (2 mL), and THF (6 mL) and left to stir overnight. The mixture was concentrated in vacuo to remove MeOH and THF. The residue was diluted with dichloromethane (50 mL), washed with saturated aqueous citric acid (2×5 mL) and water (2×5 mL), dried over sodium sulfate, filtered, and concentrated to give the desired product as a yellow solid (417 mg, 1.13 mmol, 86%).
Reaction SMILES: [OH:1][C:2]1[CH:18]=[CH:17][C:5]([CH:6]=[C:7]2[C:12](=[O:13])[O:11][C:10]([CH3:15])([CH3:14])[O:9][C:8]2=[O:16])=[CH:4][CH:3]=1.[CH:19]1([Mg]Br)[CH2:21][CH2:20]1>C1COCC1>[CH:19]1([C:6]([C:5]2[CH:4]=[CH:3][C:2]([OH:1])=[CH:18][CH:17]=2)=[C:7]2[C:8](=[O:16])[O:9][C:10]([CH3:15])([CH3:14])[O:11][C:12]2=[O:13])[CH2:21][CH2:20]1
Reactant: CC1(C)OC(=O)C(=Cc2ccc(O)cc2)C(=O)O1
Reactant: Br[Mg]C1CC1
Solvent: C1CCOC1
Product: CC1(C)OC(=O)C(=C(c2ccc(O)cc2)C2CC2)C(=O)O1
Temperature: 0 °C
Reaction time: 2 h
Yield: 42.76 %

Procedure:
To a 250 mL RB flask fitted with magnetic stirrer was charged 6 mL of dry THF under argon atmosphere. To the stirred solvent was added 5-(4-hydroxybenzylidene)-2,2-dimethyl-1,3-dioxane-4,6-dione (0.6 g, 2.41 mmol). The resulting mixture was cooled to 0° C. and was added cyclopropylmagnesium bromide (25 mL, 0.5 M in THF, 7.25 mmol). The resulting mixture was stirred at ambient temperatures for 2 h. Then, the reaction mass was quenched with 20 mL of 1N HCl then, ethyl acetate (50 mL) was added, stirred well and the layers were separated. The organic layer was washed with water (100 mL×3), brine solution. Then the organic layer was dried over anhydrous Na2SO4. The solvent was removed under reduced pressure, and the resulting crude compound is purified by column chromatography on silica gel (60-120 meshes) using petroleum ether (60-80) and ethyl acetate as eluent. The product was obtained as yellow solid. Yield: 42.76% (0.3 g) MS (ESI, 120 ev): m/z=291.1 (M+1). (300 MHz, DMSO-d6): δ 9.16 (s, 1H), 6.95-6.98 (d, 2H), 6.53-6.56 (d, 2H), 4.42-4.43 (d, 1H), 2.54-2.59 (m, 1H), 1.61 (s, 4H), 1.29 (s, 3H), 0.40-0.49 (m, 2H), 0.23-0.28 (m, 1H), 0.03-0.01 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:17](I)=[CH:16][N:15]([CH2:19][C:20]3[C:25]([CH3:26])=[C:24]([O:27][CH3:28])[C:23]([CH3:29])=[CH:22][N+:21]=3[O-:30])[C:4]=2[N:5]=[C:6]([NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])[N:7]=1>C(O)CC#C>[Cl:1][C:2]1[C:3]2[C:17]([C:19]#[C:20][CH2:25][CH2:24][OH:27])=[CH:16][N:15]([CH2:19][C:20]3[C:25]([CH3:26])=[C:24]([O:27][CH3:28])[C:23]([CH3:29])=[CH:22][N+:21]=3[O-:30])[C:4]=2[N:5]=[C:6]([NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])[N:7]=1
Reactant: COc1c(C)c[n+]([O-])c(Cn2cc(I)c3c(Cl)nc(NC(=O)C(C)(C)C)nc32)c1C
Agent: C#CCCO
Product: COc1c(C)c[n+]([O-])c(Cn2cc(C#CCCO)c3c(Cl)nc(NC(=O)C(C)(C)C)nc32)c1C
Yield: 194.4 %

Procedure:
Sonogashira coupling of 2-((4-chloro-5-iodo-2-pivalamido-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-4-methoxy-3,5-dimethylpyridine 1-oxide (335 mg) with but-3-yn-1-ol (200 μL) according to the general procedure A gave crude 2-((4-chloro-5-(4-hydroxybut-1-ynyl)-2-pivalamido-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-4-methoxy-3,5-dimethylpyridine 1-oxide (291 mg).
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCCCCCCCCCCCCCCC[CH2:25][CH2:26][O:27][C:28]([CH2:30][CH2:31]C1C=C(C(C)(C)C)[C:35]([OH:42])=[C:34]([C:43](C)(C)C)[CH:33]=1)=[O:29].CO>C1C2C(CCCC2)CCC1.CC([O-])C.CC([O-])C.CC([O-])C.CC([O-])C.[Ti+4]>[C:28]([O:27][CH2:26][CH3:25])(=[O:29])[C:30]([CH3:31])=[CH2:1].[C:35]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)(=[O:42])[C:34]([CH3:43])=[CH2:33]
Reactant: CCCCCCCCCCCCCCCCCCOC(=O)CCc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reactant: OCc1ccccc1
Agent: [Ti+4]
Agent: CC(C)[O-]
Solvent: C1CCC2CCCCC2C1
Solvent: CO
Product: C=C(C)C(=O)OCC
Product: C=C(C)C(=O)OCc1ccccc1

Procedure:
350 grams (3.5 mole) of polymethylmethacrylate (Plexiglass VO 44 from Rohm & Haas), 378 grams of benzyl alcohol (3.5 mole) and 0.54 gram (0.1 mole %) of an antioxidant Irganox 1076 were heated to 180° C. to dissolve them in 550 cc of decalin. 13.86 grams of tetraisopropyl titanate was added and the temperature was maintained at 180°-190° C. for 14 hours, and during this time 23 ml of distillate containing methanol was collected and the reaction was stopped. The polymer was precipitated in methanol then washed with hexane. After drying at 55° C. overnight in an vacuum oven, 404 gram of polymer were recovered with a DSC melting point of 93°-94° C. NMR analysis showed a 22.6% conversion of methyl ester to benzyl ester.
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]([O:10]CC)=[O:9])=[CH:6][N:5]=[C:4]2[S:13][C:14]3[CH2:19][CH2:18][CH2:17][CH2:16][C:15]=3[C:3]=12.[OH-].[K+].[CH2:22](O)[CH3:23].C(I)C>O>[CH2:22]([N:5]1[CH:6]=[C:7]([C:8]([OH:10])=[O:9])[C:2](=[O:1])[C:3]2[C:15]3[CH2:16][CH2:17][CH2:18][CH2:19][C:14]=3[S:13][C:4]1=2)[CH3:23]
Reactant: CCOC(=O)c1cnc2sc3c(c2c1O)CCCC3
Reactant: CCO
Agent: [K+]
Agent: [OH-]
Solvent: CCI
Solvent: O
Product: CCn1cc(C(=O)O)c(=O)c2c3c(sc21)CCCC3

Procedure:
A mixture of 1.38 parts of ethyl 4-hydroxy-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridine-3-carboxylate, 11 parts by volume of 10 percent aqueous potassium hydroxide, 44 parts by volume of ethanol and 45 parts by volume of water and 1.5 parts by volume of ethyl iodide is refluxed for 4 hours and the product is isolated in a manner similar to that described in Example 13, whereby 1-ethyl-1,4,5,6,7,8-hexahydro-4-oxo[1]benzothieno[2,3-b]pyridine-3-carboxylic acid is obtained as crystals. Recrystallization from ethanol and, then, from tetrahydrofuran gives colorless needles melting at 218°-221° C.
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[C:12]2[N:11]=[CH:10][N:9]([C:13](=[O:19])[C:14]([CH3:18])([CH3:17])[CH2:15][CH3:16])[C:8]=2[C:7](=[O:20])[NH:6][C:5]1=[O:21].Br[CH2:23][CH2:24][CH2:25][CH2:26][CH:27]=[CH2:28].O>CS(C)=O.C(OCC)(=O)C>[CH2:28]([N:6]1[C:7](=[O:20])[C:8]2[N:9]([C:13](=[O:19])[C:14]([CH3:17])([CH3:18])[CH2:15][CH3:16])[CH:10]=[N:11][C:12]=2[N:4]([CH3:3])[C:5]1=[O:21])[CH2:27][CH2:26][CH2:25][CH:24]=[CH2:23]
Reactant: CCC(C)(C)C(=O)n1cnc2c1c(=O)[nH]c(=O)n2C
Reactant: C=CCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: C=CCCCCn1c(=O)c2c(ncn2C(=O)C(C)(C)CC)n(C)c1=O
Reaction time: 0.25 h
Yield: 69.8 %

Procedure:
Sodium hydride (86 mg, 3.6 mmol) was added to a stirring solution of 3-methyl-7-(methylpivaloyl)xanthine 1404 (1.00 g, 3.6 mmol) in dimethyl sulfoxide (25 mL). After 15 minutes, 6-bromo-1-hexene (589 mg, 3.6 mmol) was added and stirring continued for 72 hours. The reaction mixture was then poured into water (70 mL) and extracted with dichloromethane (2×100 mL) and 20% ethanol/dichloromethane (1×100 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution (50 mL) and dried over magnesium sulfate. The solvent was evaporated under vacuum to give a thick oil. Chromotograpy of the resulting thick oil using silica and ethyl acetate yielded 870 mg (67% yield) 1-(5-hexenyl)-3-methyl-7-(methylpivaloyl)xanthine (inventive compound no. 1441)
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[O:6][CH:5]([CH2:7][O:8][C:9]2[C:18](C)=[CH:17][C:12]([C:13]([NH:15][OH:16])=[NH:14])=[CH:11][C:10]=2C)[CH2:4][O:3]1.[Cl:22]C1C=C(C=C(OC)C=1O)C#N.CC1(C)O[C@H]([CH2:40][OH:41])CO1>>[Cl:22][C:18]1[CH:17]=[C:12]([CH:11]=[C:10]([O:41][CH3:40])[C:9]=1[O:8][CH2:7][C@@H:5]1[CH2:4][O:3][C:2]([CH3:1])([CH3:21])[O:6]1)[C:13]([NH:15][OH:16])=[NH:14]
Reactant: CC1(C)OC[C@@H](CO)O1
Reactant: Cc1cc(C(=N)NO)cc(C)c1OCC1COC(C)(C)O1
Reactant: COc1cc(C#N)cc(Cl)c1O
Product: COc1cc(C(=N)NO)cc(Cl)c1OC[C@@H]1COC(C)(C)O1

Procedure:
The title compound is prepared in analogy to rac-4-(2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-N-hydroxy-3,5-dimethyl-benzamidine starting from 3-chloro-4-hydroxy-5-methoxy-benzonitrile and L-α,β-isopropylidene glycerol. LC-MS: tR=0.42 min, [M+H]+=331.17; 1H NMR (D6-DMSO): δ 1.30 (s, 3H), 1.34 (s, 3H), 3.86 (s, 3H), 3.87-3.93 (m, 2H), 4.00-4.12 (m, 2H), 4.36 (quint, J=5.8 Hz, 1H), 5.90 (s, 2H), 7.32 (d, J=2.0 Hz, 1H), 7.34 (d, J=2.0 Hz, 1H), 9.71 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:10]([Cl:11])=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1OC.C(N(CC)CC)C.Cl[C:22](OCC)=[O:23].[NH2:27][C@H:28]1[CH2:33][CH2:32][N:31]([C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH2:30][C@H:29]1[O:39][CH3:40]>O1CCCC1>[NH2:1][C:2]1[C:10]([Cl:11])=[CH:9][C:5]([C:6]([NH:27][C@H:28]2[CH2:33][CH2:32][N:31]([C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH2:30][C@H:29]2[O:39][CH3:40])=[O:8])=[C:4]([O:23][CH3:22])[CH:3]=1
Reactant: CCOC(=O)Cl
Reactant: CCOC(=O)N1CC[C@H](N)[C@H](OC)C1
Reactant: COc1cc(C(=O)O)cc(Cl)c1N
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)N1CC[C@H](NC(=O)c2cc(Cl)c(N)cc2OC)[C@H](OC)C1
Reaction time: 1.5 h

Procedure:
To a mixture of 33.3 g of 4-amino-5-chloro-3-methoxybenzoic acid, 27.0 ml of triethylamine, and 450 ml of tetrahydrofuran, 16.2 ml of ethyl chloroformate was added dropwise with stirring under ice-cooling. Stirring was continued for 1.5 hours under ice-cooling, a solution of 35.0 g of ethyl cis-(4-amino-3-methoxypiperidino)formate in 50 ml of tetrahydrofuran was added dropwise. After being stirred for 20 hours at room temperature, the reaction mixture was concentrated under reduced pressure. Water was added to the residue, and the mixture was extracted with dichloromethane. The extract was washed with aqueous potassium carbonate solution, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was washed with diethyl ether to give 44.5 g of colorless crystals.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[C:10]([C:12]1[CH:17]=[CH:16][C:15]([CH2:18][NH2:19])=[CH:14][N:13]=1)#[N:11].[NH:20]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[C@@H:21]([C:29]([N:31]1[CH2:38][CH2:37][CH2:36][C@H:32]1[C:33](O)=[O:34])=[O:30])[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(Cl)Cl>[C:10]([C:12]1[N:13]=[CH:14][C:15]([CH2:18][NH:19][C:33](=[O:34])[C@@H:32]2[CH2:36][CH2:37][CH2:38][N:31]2[C:29](=[O:30])[C@@H:21]([CH2:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[NH:20][C:39]([O:41][C:42]([CH3:45])([CH3:43])[CH3:44])=[O:40])=[CH:16][CH:17]=1)#[N:11]
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)C(=O)N1CCC[C@H]1C(=O)O
Reactant: N#Cc1ccc(CN)cn1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)C(=O)N1CCC[C@H]1C(=O)NCc1ccc(C#N)nc1
Reaction time: 2 h

Procedure:
8.12 g of diisopropylethylamine, and subsequently 11 ml (15 mmol) of propanephosphonic anhydride (50% strength solution in ethyl acetate), were added dropwise to a solution of 2.11 g (12.5 mmol) of 2-cyano-5-(aminomethyl)pyridine and 4.5 g (12.5 mmol) of Boc-D-Phe-Pro-OH in 70 ml of CH2Cl2 at -5° C. The mixture was then stirred for 2 h, allowing the temperature to rise from -5° to 20° C. The organic phase was washed with water, 5% strength sodium bicarbonate and 5% strength citric acid solutions, dried over Na2SO4 and evaporated to dryness, a pale yellowish crystalline residue was obtained, melting point 167-170° C., which was used in the next reaction without further purification.
Reaction SMILES: CC(O[CH2:5][C:6]1[CH2:15][S:14][C@@H:9]2[C@H:10]([NH2:13])[C:11](=[O:12])[N:8]2[C:7]=1[C:16]([OH:18])=[O:17])=O.[OH:19][C:20]1[CH:21]=[C:22]([C:27]2[C:28](=[S:39])[NH:29][C:30]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[N:31][CH:32]=2)[CH:23]=[CH:24][C:25]=1[OH:26].B(F)(F)F.CCOCC>ClCCl.S1(CCCC1)(=O)=O>[NH2:13][C@@H:10]1[C:11](=[O:12])[N:8]2[C@@H:9]1[S:14][CH2:15][C:6]([CH2:5][S:39][C:28]1[C:27]([C:22]3[CH:23]=[CH:24][C:25]([OH:26])=[C:20]([OH:19])[CH:21]=3)=[CH:32][N:31]=[C:30]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[N:29]=1)=[C:7]2[C:16]([OH:18])=[O:17]
Reactant: Oc1ccc(-c2cnc(-c3ccccc3)[nH]c2=S)cc1O
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: FB(F)F
Solvent: CCOCC
Solvent: O=S1(=O)CCCC1
Solvent: ClCCl
Product: N[C@@H]1C(=O)N2C(C(=O)O)=C(CSc3nc(-c4ccccc4)ncc3-c3ccc(O)c(O)c3)CS[C@H]12
Yield: 81.9 %

Procedure:
7-Aminocephalosporanic acid (162 mg) (0.6 mmol) and 216 mg (0.66 mmol) of 5-(3,4-dihydroxyphenyl)-2-phenyl-4(3H)-pyrimidinethione are suspended in 7 ml of dichloromethane/sulpholane (1:1 v/v). 4 ml of boron trifluoride diethyl etherate are added thereto while stirring. After 16 hours the mixture is concentrated in a high vacuum at room temperature, the residue is washed with diethyl ether and dissolved in about 3 ml of water. Sodium hydrogen carbonate is added thereto until the pH is adjusted to 5. Then, 1 ml of diethyl ether and 0.5 ml of ethanol are added thereto. The precipitated product is filtered off under suction, washed in succession with water, ethanol and ether and dried in a high vacuum at room temperature. There are obtained 250 mg of (6R,7R)-7-amino-3-[[[5-(3,4-dihydroxyphenyl)-2-phenyl-4-pyrimidinyl]thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid as a beige powder.
Reaction SMILES: N[C:2]1C=CC=C[CH:3]=1.[NH2:8][C:9]1[C:10]([CH3:15])=[CH:11][CH:12]=[CH:13][CH:14]=1.[CH3:16][O:17][C:18]1[C:19]([NH2:24])=[CH:20][CH:21]=[CH:22][CH:23]=1>>[CH3:15][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:9]=1[NH:8][CH:3]=[CH:2]2.[CH3:16][O:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:19]=1[NH:24][CH:3]=[CH:2]2
Reactant: Cc1ccccc1N
Reactant: Nc1ccccc1
Reactant: COc1ccccc1N
Product: COc1cccc2cc[nH]c12
Product: Cc1cccc2cc[nH]c12

Procedure:
Reaction was carried out in the same manner as described in Example 1, except that the aniline was replaced by o-toluidine or o-anisidine. As a result, 7-methylindole and 7-methoxyindole were obtained in 32% and 26% yields, respectively.
Reaction SMILES: F[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[O:9][C:10]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:11]=2[N:12]=1.[K].[C:22]1(=[O:32])[NH:26][C:25](=[O:27])[C:24]2=[CH:28][CH:29]=[CH:30][CH:31]=[C:23]12.CN(C=O)C>O>[F:18][C:17]([F:20])([F:19])[C:14]1[CH:15]=[CH:16][C:10]2[O:9][C:8]([C:7]3[CH:6]=[CH:5][N:4]=[CH:3][C:2]=3[N:26]3[C:25](=[O:27])[C:24]4=[CH:28][CH:29]=[CH:30][CH:31]=[C:23]4[C:22]3=[O:32])=[N:12][C:11]=2[CH:13]=1
Reactant: Fc1cnccc1-c1nc2cc(C(F)(F)F)ccc2o1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1c2ccccc2C(=O)N1c1cnccc1-c1nc2cc(C(F)(F)F)ccc2o1
Temperature: 120 °C
Reaction time: 6 h
Yield: 61.6 %

Procedure:
A mixture of 1.41 g of 2-(3-fluoropyridin-4-yl)-5-(trifluoromethyl)benzoxazole, 1.85 g of phthalimide potassium and 8 ml of DMF was stirred while heating at 120° C. After six hours, 0.92 g of phthalimide potassium was added and stirred while heating at 140° C. for further one hour. The reaction mixture was cooled to room temperature, and then water was added to the reaction mixture, which followed by extraction with ethyl acetate twice. The combined organic layers were washed with water and a saturated sodium chloride solution, sequentially, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 1.26 g of N-{4-[5-(trifluoromethyl)benzoxazole-2-yl]pyridin-3-yl}phthalimide.
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]([C:15]([F:18])([F:17])[F:16])=[C:10]([C:12]([OH:14])=O)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)(=O)C(Cl)=O.[C:25]([O:29][C:30]([N:32]1[CH2:37][CH2:36][N:35]([C:38]2[N:43]=[CH:42][C:41]([NH2:44])=[CH:40][N:39]=2)[CH2:34][CH2:33]1)=[O:31])([CH3:28])([CH3:27])[CH3:26].N1C=CC=CC=1>C(Cl)Cl.CN(C)C=O>[C:25]([O:29][C:30]([N:32]1[CH2:33][CH2:34][N:35]([C:38]2[N:43]=[CH:42][C:41]([NH:44][C:12]([C:10]3[N:11]=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[O:8][C:9]=3[C:15]([F:18])([F:17])[F:16])=[O:14])=[CH:40][N:39]=2)[CH2:36][CH2:37]1)=[O:31])([CH3:28])([CH3:26])[CH3:27]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncc(N)cn2)CC1
Reactant: O=C(O)c1nc(-c2ccccc2)oc1C(F)(F)F
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CCN(c2ncc(NC(=O)c3nc(-c4ccccc4)oc3C(F)(F)F)cn2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.7 %

Procedure:
To a suspension of 2-phenyl-5-trifluoromethyloxazole-4-carboxylic acid (771 mg, 3 mmol) in methylene chloride (10 mL) was added oxalyl chloride (2M, 3 mL, 6.0 mmol) and one drop of N,N-dimethylformamide. The mixture was stirred at room temperature for 1 hr and the solvents were evaporated. The residue was treated with benzene (5 mL) and the solvents were again evaporated. The oily residue was dried in vacuum and then dissolved in methylene chloride (10 mL). The solution was cooled in an ice bath. To this solution was added a methylene chloride solution of 4-(5-amino-pyrimidin-2-yl)-piperazine-1-carboxylic acid tert-butyl ester (3 mmol) and pyridine (0.73 mL). The mixture was stirred at 0° C. for 10 minutes and room temperature for 2 hrs. After concentration, the residue was partitioned between methylene chloride and water. The organic layer was washed with aqueous citric acid solution and dried over sodium sulfate. The solvents were evaporated and the residue was dried in vacuum. The resulting material was triturated with ethyl acetate and the precipitate was filtered to give 4-{5-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-pyrimidin-2-yl}-piperazine-1-carboxylic acid tert-butyl ester (1.38 g). LC-MS calcd for C24H25F3N6O4 (m/e) 518.5, obsd 519.1 (M+H). The NMR spectrum obtained on the sample is compatible with its structure.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]([O:28][C:29]2[CH:34]=[CH:33][C:32]([C:35]3[C:36]4[CH:43]([CH3:44])[CH2:42][CH2:41][C:37]=4[N:38]=[CH:39][N:40]=3)=[CH:31][CH:30]=2)[CH2:16][N:17]([CH:25]([CH3:27])[CH3:26])C(=O)OC(C)(C)C)=[CH:11][CH:10]=1>C(Cl)Cl>[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]([O:28][C:29]2[CH:34]=[CH:33][C:32]([C:35]3[C:36]4[CH:43]([CH3:44])[CH2:42][CH2:41][C:37]=4[N:38]=[CH:39][N:40]=3)=[CH:31][CH:30]=2)[CH2:16][NH:17][CH:25]([CH3:27])[CH3:26])=[CH:11][CH:10]=1.[C:3]([OH:5])([C:2]([F:7])([F:6])[F:1])=[O:4]
Reactant: CC1CCc2ncnc(-c3ccc(O[C@@H](CN(C(=O)OC(C)(C)C)C(C)C)c4ccc(Cl)cc4)cc3)c21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)NC[C@H](Oc1ccc(-c2ncnc3c2C(C)CC3)cc1)c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
Trifluoroacetic acid (0.5 mL) was added dropwise to a solution of (R)-tert-butyl 2-(4-chlorophenyl)-2-(4-(5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)phenoxy)ethyl(isopropyl)carbamate (26 mg, 0.0498 mmol) in methylene chloride (1.0 mL) at 0° C. The mixture was stirred at 0° C. for 10 minutes and then at room temperature for 2 hours. The contents were concentrated. The resulting residue was purified by reverse-phase HPLC to give (R)—N-(2-(4-chlorophenyl)-2-(4-(5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)phenoxy)ethyl)propan-2-amine as TFA salt (7.5 mg, 23%). 1H NMR (d6-DMSO, 500 MHz) δ (ppm): 8.9 (s, 1H), 8.7 (s, br, 2H), 7.8 (t, 2H), 7.5 (m, 4H), 7.1 (d, 2H), 5.7 (d, 1H), 3.8 (m, 1H), 3.4-3.5 (m, 2H), 3.3-3.4 (m, 1H), 3.0-3.1 (m, 1H), 2.9 (m, 1H), 2.3 (m, 1H), 1.7 (m, 1H), 1.3 (dd, 6H), 0.9 (dd, 3H). MS (422.3, M+1).