Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][N:3]([CH3:13])[C:4]([C:6]1[C:11]([OH:12])=[CH:10][CH:9]=[CH:8][N:7]=1)=[O:5].[C:14](=O)([O-])[O-].[K+].[K+].CI>CN(C)C=O>[CH3:1][O:2][N:3]([CH3:13])[C:4]([C:6]1[C:11]([O:12][CH3:14])=[CH:10][CH:9]=[CH:8][N:7]=1)=[O:5]
Reactant: O=C([O-])[O-]
Reactant: CON(C)C(=O)c1ncccc1O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COc1cccnc1C(=O)N(C)OC
Yield: 28.2 %

Procedure:
3-Hydroxy-pyridine-2-carboxylic acid methoxy-methyl-amide (5.21 g, 28.60 mmol), N,N-dimethylformamide (500 ml), potassium carbonate (15.91 g), and methyl iodide (3.6 ml, 57.70 mmol) were stirred for 18 hours at room temperature. The reaction was concentrated. Water and ethyl acetate was added. The organic layer was separated, dried over sodium sulfate, and concentrated. The crude material was purified by flash chromatography (0-70% [10% methanol in ethyl acetate] in hexanes) to give 1.58 g (28%) of 3-methoxy-pyridine-2-carboxylic acid methoxy-methyl-amide. 1H NMR (250 MHz, CDCl3) δ 8.20-8.11 (m, 1H), 7.32-7.18 (m, 2H), 3.83 (s, 3H), 3.51 (s, 3H), 3.35 (s, 3H); MS: m/z 310.6+197.1 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[N:7][NH:8]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[N+:23]([C:26]1[CH:33]=[CH:32][C:29]([CH2:30]Br)=[CH:28][CH:27]=1)([O-:25])=[O:24]>O1CCCC1>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[N:7][N:8]2[CH2:30][C:29]2[CH:32]=[CH:33][C:26]([N+:23]([O-:25])=[O:24])=[CH:27][CH:28]=2)=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: CCOC(=O)Cc1n[nH]c2cc(F)ccc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: CCOC(=O)Cc1nn(Cc2ccc([N+](=O)[O-])cc2)c2cc(F)ccc12
Temperature: 25 °C
Yield: 41.3 %

Procedure:
Ethyl 2-(6-fluoro-1H-indazol-3-yl)acetate (2.08 g, 9.36 mmol) was dissolved in anhydrous tetrahydrofuran (30 mL). Cesium carbonate (9.15 g, 28.1 mmol) was added, and stirred at room temperature for half an hour. Then p-nitro benzyl bromide (2.02 g, 9.35 mmol) was added, and reacted for 16 hours. Then the solid was filtered. The filtrate was concentrated, chromatographed on a silica gel column (petroleum ether:ethyl acetate=2:1) to obtain a yellow solid 1.38 g, at a yield of 41.2%.
Reaction SMILES: [O:1]=[C:2]1[C:11](=[O:12])[NH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:13]([OH:15])=O)[CH:8]=2)[NH:3]1.C(Cl)(=O)C([Cl:19])=O.CN(C=O)C>C(Cl)Cl>[O:1]=[C:2]1[C:11](=[O:12])[NH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:13]([Cl:19])=[O:15])[CH:8]=2)[NH:3]1
Reactant: O=C(O)c1ccc2[nH]c(=O)c(=O)[nH]c2c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccc2[nH]c(=O)c(=O)[nH]c2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2,3-dioxo-1,2,3,4-tetrahydroquinoxaline-6-carboxylic acid (0.300 g, 1.455 mmol) in DCM (3 mL) was added oxalyl chloride (0.387 mL, 4.37 mmol) and a drop of DMF (anhydrous). The resulting mixture was then stirred at room temperature for 2 h, then the mixture was concentrated in vacuo to give 2,3-dioxo-1,2,3,4-tetrahydroquinoxaline-6-carbonyl chloride. A solution of (S)-4-(3-fluoro-4-(trifluoromethoxy)phenyl)-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-amine hydrochloride (50 mg, 0.137 mmol) in DCM (1 mL) at 0° C. was added 2,3-dioxo-1,2,3,4-tetrahydroquinoxaline-6-carbonyl chloride (326 mg, 1.453 mmol), and DIEA (0.072 mL, 0.411 mmol). The resulting mixture was stirred at 0° C. for 30 min and then at room temperature for overnight. The reaction was diluted with H2O (5 mL) and EtOAc (7 mL). The mixture was then stirred at room temperature for 30 min. The mixture was then filtered and the organic layer was dried over MgSO4, and concentrated in vacuo. The residue was dissolved in DMSO (2 mL) and solution was purified by preparative HPLC (0-100% MeCN 0.1% TFA/H2O 0.1% TFA) to give the title compound as a white solid. MS (ESI, positive ion) m/z: 517.0 (MH+). 1H NMR (400 MHz, d4-MeOH) δ: 8.27 (dd, J=4.8, 1.3 Hz, 1H), 7.60-7.69 (m, 3H), 7.51-7.58 (m, 1H), 7.42-7.48 (m, 2H), 7.24 (d, J=8.4 Hz, 2H), 4.45-4.59 (m, 1H), 4.16-4.35 (m, 1H), 3.07-3.27 (m, 1H), 2.84-3.05 (m, 1H).
Reaction SMILES: [CH2:1]([S:3][C:4]1[N:9]=[C:8]([N:10]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[N:12]=[CH:11]2)[C:7]([CH3:19])=[CH:6][N:5]=1)[CH3:2].CO.S([O-])(O[O-])(=O)=[O:23].[K+].[K+].[OH2:30]>>[CH2:1]([S:3]([C:4]1[N:9]=[C:8]([N:10]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[N:12]=[CH:11]2)[C:7]([CH3:19])=[CH:6][N:5]=1)(=[O:23])=[O:30])[CH3:2]
Reactant: O
Reactant: O=S(=O)([O-])O[O-]
Reactant: CCSc1ncc(C)c(-n2cnc3ccccc32)n1
Agent: [K+]
Solvent: CO
Product: CCS(=O)(=O)c1ncc(C)c(-n2cnc3ccccc32)n1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 2-Ethylthio-4-(benzimidazol-1-yl)-5-methylpyrimidine (127.5 mg, 0.47 mmol) in methanol (1.2 mmol) at 0° C. was added slurry of potassium peroxymonosulfate (Oxone®) (870 mg, 1.41 mmol) in H2O (1.2 mL). The mixture was stirred at room temperature for 4 h, and was then diluted with H2O. The aqueous layer was extracted with CH2Cl2, and the combined organic layer was washed with H2O followed by brine. The organic extract was dried over Na2SO4 then purified (20 mg of crude material) by preparative thin layer chromatography eluting with 1:1 acetone:hexane system to give the title compound. Mass spectrum 303 (ESI, M+1).
Reaction SMILES: Br[CH2:2]/[CH:3]=[CH:4]/[C:5]([O:7][CH3:8])=[O:6].C(N(CC)CC)C.[CH2:16]([NH:23][CH2:24][CH2:25][NH:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C1(C)C=CC=CC=1>[CH2:16]([N:23]1[CH2:24][CH2:25][N:26]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:2][CH:3]1[CH2:4][C:5]([O:7][CH3:8])=[O:6])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: c1ccc(CNCCNCc2ccccc2)cc1
Reactant: COC(=O)/C=C/CBr
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COC(=O)CC1CN(Cc2ccccc2)CCN1Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.2 %

Procedure:
Methyl 4-bromocrotonate (Aldrich, 5.53 mL, 40 mmol) was added dropwise with stirring to an ice-cooled solution of triethylamine (11.15 mL, 80 mmol) and N,N′-dibenzylethylenediamine (Aldrich, 9.67 mL, 40 mmol) in toluene (200 mL). The solution was stirred with ice cooling for 1 hour, then allowed to warm gradually to room temperature and stirred 25 hours longer. The mixture was filtered through a pad of diatomaceous earth with an ethyl acetate (20 mL) rinse. The filtrate was concentrated to an oil, which was mixed with 10% aqueous HCl (240 mL). After 5 minutes, the mixture was filtered and the cake was rinsed with water (2×10 mL). The filtrate was washed with ethyl acetate (2×80 mL) and the aqueous phase was made basic (pH˜9-10) by portionwise addition of solid K2CO3 (26 g), then 25% aqueous NaOH (10 mL). The turbid mixture was extracted with ethyl acetate (3×120 mL) and the combined extracts were washed with brine (100 mL), dried (MgSO4) and concentrated under vacuum to leave the title compound as an oil (9.78 g): 1H NMR (300 MHz, CDCl3) δ ppm 2.30-2.47 (m, 4H), 2.49-2.73 (m, 4H), 3.06-3.18 (m, 1H), 3.43 (d, J=13.2 Hz, 2H), 3.53 (d, J=13.2 Hz, 1H), 3.60 (s, 3H), 3.76 (d, J=13.6 Hz, 1H), 7.14-7.36 (m, 10H); MS (DCI) m/z 339 (M+H)+.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7](I)[CH3:8].Cl.Cl.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([NH:19][C:20]2[C:29]3[C:24](=[CH:25][C:26]([O:32][CH3:33])=[C:27]([O:30][CH3:31])[CH:28]=3)[N:23]=[C:22]([N:34]3[CH2:39][CH2:38][CH:37]([N:40]([CH3:48])[C:41](=[O:47])[C@@H:42]4[CH2:46][CH2:45][CH2:44][NH:43]4)[CH2:36][CH2:35]3)[N:21]=2)=[C:15]([F:49])[CH:14]=1>C(#N)C>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([NH:19][C:20]2[C:29]3[C:24](=[CH:25][C:26]([O:32][CH3:33])=[C:27]([O:30][CH3:31])[CH:28]=3)[N:23]=[C:22]([N:34]3[CH2:35][CH2:36][CH:37]([N:40]([CH3:48])[C:41](=[O:47])[C@@H:42]4[CH2:46][CH2:45][CH2:44][N:43]4[CH2:7][CH3:8])[CH2:38][CH2:39]3)[N:21]=2)=[C:15]([F:49])[CH:14]=1
Reactant: CCI
Reactant: COc1cc2nc(N3CCC(N(C)C(=O)[C@@H]4CCCN4)CC3)nc(Nc3ccc(Cl)cc3F)c2cc1OC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCN1CCC[C@H]1C(=O)N(C)C1CCN(c2nc(Nc3ccc(Cl)cc3F)c3cc(OC)c(OC)cc3n2)CC1
Temperature: 50 °C
Reaction time: 19 h

Procedure:
Potassium carbonate (62 mg) and ethyl iodide (36 μl) were added in that order to an acetonitrile (5 mL) solution of N-(1-{4-[(4-chloro-2-fluorophenyl)amino]-6,7-dimethoxyquinazolin-2-yl}piperidin-4-yl)-N-methyl-L-prolinamide dihydrochloride (250 mg), followed by stirring at room temperature for 2 hours and at 50° C. for 19 hours. The solvent was evaporated, and a saturated sodium bicarbonate aqueous solution was added to the resulting residue, followed by extraction with chloroform. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. Then, the solvent was evaporated. By purifying the resulting residue by a silica gel column chromatography (chloroform-MeOH), N-(1-{4-[(4-chloro-2-fluorophenyl)amino]-6,7-dimethoxyquinazolin-2-yl}piperidin-4-yl)-1-ethyl-N-methyl-L-prolinamide was obtained. This compound was dissolved in MeOH (3 mL), 4 M HCl/ethyl acetate solution (198 μl) was added thereto, and the solvent was evaporated. By recrystallizing the resulting crude crystals from isopropanol-diisopropyl ether, N-(1-{4-[(4-chloro-2-fluorophenyl)amino]-6,7-dimethoxyquinazolin-2-yl}piperidin-4-yl)-1-ethyl-N-methyl-L-prolinamide dihydrochloride (101 mg) was obtained as pale yellow crystals.
Reaction SMILES: COC(=O)[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH:10][C:11](=[O:38])[CH2:12][N:13]2[N:19]=[C:18]([CH:20]3C[CH2:24][CH2:23][CH2:22][CH2:21]3)[C:17]3[CH:26]=[CH:27][CH:28]=[CH:29][C:16]=3[N:15]([CH2:30][C:31](=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33])[C:14]2=[O:37])[CH:5]=1.NC1C=C([C:47]2[N:48]=[N:49][N:50]([CH2:52][O:53][C:54](=[O:59])[C:55]([CH3:58])([CH3:57])[CH3:56])[N:51]=2)C=CC=1>>[CH:20]1([C:18]2[C:17]3[CH:16]=[CH:29][CH:28]=[CH:27][C:26]=3[N:15]([CH2:30][C:31](=[O:36])[C:32]([CH3:33])([CH3:35])[CH3:34])[C:14](=[O:37])[N:13]([CH2:12][C:11]([NH:10][C:6]3[CH:5]=[C:4]([C:47]4[N:48]=[N:49][N:50]([CH2:52][O:53][C:54](=[O:59])[C:55]([CH3:57])([CH3:56])[CH3:58])[N:51]=4)[CH:9]=[CH:8][CH:7]=3)=[O:38])[N:19]=2)[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: COC(=O)c1cccc(NC(=O)CN2N=C(C3CCCCC3)c3ccccc3N(CC(=O)C(C)(C)C)C2=O)c1
Reactant: CC(C)(C)C(=O)OCn1nnc(-c2cccc(N)c2)n1
Product: CC(C)(C)C(=O)CN1C(=O)N(CC(=O)Nc2cccc(-c3nnn(COC(=O)C(C)(C)C)n3)c2)N=C(C2CCCC2)c2ccccc21

Procedure:
The title compound was obtained by the method used in the preparation of 3-{2-[5-cyclohexyl-1-(3,3-dimethyl-2-oxo-butyl)-2-oxo-1,2-dihydro-3H-1,3,4-benzotriazepin-3-yl]-acetylamino}-benzoic acid methyl ester (Example 1) except that 2,2-dimethyl-propionic acid 5-(3-amino-phenyl)-tetrazol-2-ylmethyl ester was used in place of 3-amino-benzoic acid methyl ester in step e, followed by reaction of the product obtained, in place of 2,2-dimethyl-propionic acid 5-(3-{2-[5-cyclopentyl-1-(3,3-dimethyl-2-oxo-butyl)-2-oxo-1,2-dihydro-3H-1,3,4-benzotriazepin-3-yl]-acetylamino}-phenyl)-tetrazol-2-ylmethyl ester (Example 10, step a), according to the method of Example 10, step b. 1H NMR (CDCl3) 8.86 (1H, s), 8.18 (1H, m), 7.79 (1H, m), 7.46-7.24 (6H, m), 6.97 (1H, m), 4.73 (1H, d), 4.63 (1H, d), 4.27 (1H, d), 4.22 (1H, d), 2.77 (1H, m), 1.97-1.68 (6H, m), 1.24-1.11 (13H, m). The compound was further characterised as the N-methyl-D-glucamine salt. Found: C, 55.36; H, 7.36; N, 16.01%; C29H34N8O3.C7H17NO5.2.5H2O requires: C, 55.23; H, 7.21; N, 16.10%.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][CH2:11][CH2:12][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([F:23])[CH:21]=2)[NH:16][C:15](=[O:24])[CH:14]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Br:25][C:26]1[CH:27]=[C:28]([CH:31]=[C:32]([Br:35])[C:33]=1[Br:34])[CH2:29]Br>CN(C)C=O.O>[CH2:3]([O:10][CH2:11][CH2:12][C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([F:23])[CH:21]=2)[N:16]([CH2:29][C:28]2[CH:27]=[C:26]([Br:25])[C:33]([Br:34])=[C:32]([Br:35])[CH:31]=2)[C:15](=[O:24])[CH:14]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: BrCc1cc(Br)c(Br)c(Br)c1
Reactant: O=c1cc(CCOCc2ccccc2)c2cc(F)ccc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=c1cc(CCOCc2ccccc2)c2cc(F)ccc2n1Cc1cc(Br)c(Br)c(Br)c1
Temperature: 40 °C
Reaction time: 1 h

Procedure:
To a suspension of sodium hydride (0.675 g. of 80% w/w suspension; freed of mineral oil as in Example 1) in dimethylformamide (100 ml.) under a nitrogen atmosphere was added 4-(2-benzyloxyethyl)-6-fluoro-1,2-dihydro-2-oxoquinoline (6.0 g.). The mixture was stirred at 40° C. for one hour and then treated at this temperature with 3,4,5-tribromobenzylbromide (9.1 g.). The mixture was stirred overnight at ambient temperature and then diluted with water (200 ml.) and the product extracted with ethyl acetate (3×150 ml.). The combined organic extracts were washed with water (2×100 ml.), dried (MgSO4), and evaporated. The residue was a mixture of O- and N-substituted products. Chromatography of this residue on silica gel using a 50:50 v/v mixture of ether and petroleum ether (b.p. 40°-60° C.) as eluant gave 4-(2-benzyloxyethyl)-6-fluoro-1-(3,4,5-tribromobenzyl)-1,2-dihydro-2-oxoquinoline, as an oil, Infra-Red Spectral Absorption ν max. 1665 cm.-1.
Reaction SMILES: [NH:1]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C@H:2]([C:14]([OH:16])=[O:15])[CH2:3][C:4](=[O:13])[O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C1CCC(N=C=NC2CCCCC2)CC1.[CH3:39][O:40][C:41]1[CH:46]=[CH:45][C:44]([CH2:47][CH2:48][NH2:49])=[CH:43][CH:42]=1>C(Cl)Cl>[NH:1]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C@H:2]([C:14]([OH:16])=[O:15])[CH2:3][C:4](=[O:13])[O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH3:39][O:40][C:41]1[CH:46]=[CH:45][C:44]([CH2:47][CH2:48][NH-:49])=[CH:43][CH:42]=1
Reactant: COc1ccc(CCN)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CC(C)(C)OC(=O)N[C@@H](CC(=O)OCc1ccccc1)C(=O)O
Solvent: ClCCl
Product: COc1ccc(CC[NH-])cc1

Procedure:
Boc-Asp(OBzl)-OH (38.8 g; 0.12 Mole) was dissolved in CH2Cl2 (250 ml) and cooled in a dry ice/acetone bath. DCC (24.75 g; 0.12 Mole) dissolved in CH2Cl2 (50 ml) was added slowly. After stirring for 10 minutes 4-methoxyphenylethyl amine (15.1 g; 0.1 Mole) was added dropwise and stirring was continued for another hour at room temperature. The mixture was filtered and the filtrate was washed with saturated NaHCO3 solution (×50 ml) and 1N HCl (50 ml). The organic phase was dried over sodium sulfate and evaporated to an oil. Yield: 41.5 g; FAB-MS: (M+Li)=463.
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH2:8]O.S(Cl)(Cl)=O.[N-:14]=[N+:15]=[N-:16].[Na+]>>[N:14]([CH2:8][C:7]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[F:1])=[N+:15]=[N-:16]
Reactant: [N-]=[N+]=[N-]
Reactant: OCc1ccncc1F
Agent: [Na+]
Solvent: O=S(Cl)Cl
Product: [N-]=[N+]=NCc1ccncc1F

Procedure:
The product of Example 129B, thionyl chloride and sodium azide were processed according to the method of Example 115A to provide the product. MS (ESI+) m/z 153 (M+H)+.
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]3[C:17]([C:24]4[CH:29]=[CH:28][C:27]([CH:30]([CH3:32])[CH3:31])=[CH:26][CH:25]=4)=[C:18](OC)[CH:19]=[CH:20][CH:21]=3)=[O:15])=[CH:9][CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:33]([O-:36])([O-])=O.[K+].[K+].Br[CH2:40][C:41]([NH2:43])=[O:42]>CC(C)=O>[C:41]([CH2:40][N:4]1[CH2:5][CH2:6][N:1]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]3[C:17]([C:24]4[CH:29]=[CH:28][C:27]([CH:30]([CH3:32])[CH3:31])=[CH:26][CH:25]=4)=[CH:18][CH:19]=[C:20]([O:36][CH3:33])[CH:21]=3)=[O:15])=[CH:9][CH:8]=2)[CH2:2][CH2:3]1)(=[O:42])[NH2:43]
Reactant: COc1cccc(C(=O)Nc2ccc(N3CCNCC3)cc2)c1-c1ccc(C(C)C)cc1
Reactant: NC(=O)CBr
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COc1ccc(-c2ccc(C(C)C)cc2)c(C(=O)Nc2ccc(N3CCN(CC(N)=O)CC3)cc2)c1
Temperature: 25 °C
Yield: 49.5 %

Procedure:
To a solution of 4′-isopropyl-6-methoxy-biphenyl-2-carboxylic acid (4-piperazin-1-yl-phenyl)-amide (214 mg) in acetone (20 mL) containing K2CO3 (206 mg) was added 2-bromo-acetamide (100 mg) and the mixture was heated at reflux for 16 hours. After cooling at room temperature the salts were removed by filtration, washed with acetone and the filtrate was evaporated under reduced pressure. The residue was purified by flash chromatography eluting with CH2Cl2/MeOH (92/8) and the solid obtained was recrystallized from CH2Cl2/diisopropyl ether to give the title compound (120 mg) as white crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:30]=[CH:29][C:5]([O:6][C:7]2[N:12]=[CH:11][N:10]=[C:9]([NH:13][C:14](=[O:28])[N:15]([CH3:27])[CH:16]3[CH2:21][CH2:20][N:19]([CH:22]4[CH2:25][N:24]([CH3:26])[CH2:23]4)[CH2:18][CH2:17]3)[CH:8]=2)=[C:4]([F:31])[CH:3]=1.[C@]12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.[C:47]1([CH2:53][C:54]([N:56]=[C:57]=[S:58])=[O:55])[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1.C(OCC)C>C(O)C.C1(C)C=CC=CC=1>[F:31][C:4]1[CH:3]=[C:2]([NH:1][C:57]([NH:56][C:54](=[O:55])[CH2:53][C:47]2[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=2)=[S:58])[CH:30]=[CH:29][C:5]=1[O:6][C:7]1[N:12]=[CH:11][N:10]=[C:9]([NH:13][C:14](=[O:28])[N:15]([CH3:27])[CH:16]2[CH2:17][CH2:18][N:19]([CH:22]3[CH2:23][N:24]([CH3:26])[CH2:25]3)[CH2:20][CH2:21]2)[CH:8]=1
Reactant: O=C(Cc1ccccc1)N=C=S
Reactant: CN1CC(N2CCC(N(C)C(=O)Nc3cc(Oc4ccc(N)cc4F)ncn3)CC2)C1
Agent: CC1(C)C2CC[C@@]1(CS(=O)(=O)O)C(=O)C2
Solvent: CCO
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CN1CC(N2CCC(N(C)C(=O)Nc3cc(Oc4ccc(NC(=S)NC(=O)Cc5ccccc5)cc4F)ncn3)CC2)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 13.4 %

Procedure:
To a solution of 3-[6-(4-amino-2-fluorophenoxy)pyrimidin-4-yl]-1-methyl-1-[1-(1-methylazetidin-3-yl)piperidin-4-yl]urea (68.0 mg) in ethanol (2.0 ml) was added (1S)-(+)-10-camphorsulfonic acid (70.2 mg), followed by stirring at room temperature for 10 min. A solution of 2-phenylacetyl isothiocyanate in toluene (0.25 M, 1.91 ml) was added to the reaction mixture, followed by stirring at room temperature for 30 min. The reaction mixture was partitioned between ethyl acetate (50 ml) and a saturated aqueous solution of sodium hydrogencarbonate (20 ml). The organic layer was washed with brine, and dried over anhydrous sodium sulfate. The organic layer was concentrated to give a residue, which was then purified by silica gel column chromatography (FUJI Silysia NH, eluent; ethyl acetate, then ethyl acetate:methanol=25:1). Fractions containing the target compound were concentrated to give a residue, which was added diethyl ether (2 ml) to give a precipitate. The precipitate was filtered off, washed with diethyl ether, and dried under aeration to provide the titled compound (12.9 mg, 13.4%) as white powder.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2C=1N[C:11](=[O:14])[C:10]2=[O:15])=O.[N+:16](=[CH2:18])=[N-].[C:19]([OH:22])(=[O:21])C>CCOCC>[OH:15][C:10]1[C:11](=[O:14])[N:16]([C:19]([OH:22])=[O:21])[C:18]2[C:8]([CH:9]=1)=[CH:7][CH:6]=[CH:5][C:3]=2[O:2][CH3:1]
Reactant: COC(=O)c1cccc2c1NC(=O)C2=O
Reactant: C=[N+]=[N-]
Reactant: CC(=O)O
Solvent: CCOCC
Product: COc1cccc2cc(O)c(=O)n(C(=O)O)c12
Reaction time: 3 h

Procedure:
A suspension of 7-methoxycarbonylisatin (2.4 g) in ether (50 ml) was treated at 31 5° C. with a solution of diazomethane (1.5 g) in ether (140 ml). The mixture was stirred for 3 hours and acetic acid (3 ml) added. The mixture was filtered and the filtrate concentrated under reduced pressure to give a residue that was purified by column chromatograph (silica gel eluting with dichloromethane/methanol) to give 3-hydroxy-8-methoxycarboxy-2-(1H)-quinolinone (350 mg). This in methanol (10 ml) was treated with 2N sodium hydroxide (1.75 ml) at room temperature for 2.5 hours. The mixture was acidified with 2N HCl and the precipitate was collected and dried to give 3-hydroxy-8-carboxy-2(1H)-quinolinone (180 mg); NMR (DMSO-d6 /CF3COOD) 7.12-7.30(m,2H); 7.75(d,1H); 8.01(d,1H).
Reaction SMILES: ClCC([NH:5][C:6]1[S:7][CH:8]=[C:9]([C:11](=[N:43][O:44][CH3:45])[C:12]([NH:14][CH:15]2[C:41](=[O:42])[N:17]3[C:18]([C:25]([O:27][CH:28]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[O:26])=[C:19]([CH2:22][O:23][CH3:24])[CH2:20][S:21][C@H:16]23)=[O:13])[N:10]=1)=O.NC(N)=S.C(=O)(O)[O-].[Na+]>CC(N(C)C)=O>[NH2:5][C:6]1[S:7][CH:8]=[C:9]([C:11](=[N:43][O:44][CH3:45])[C:12]([NH:14][CH:15]2[C:41](=[O:42])[N:17]3[C:18]([C:25]([O:27][CH:28]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[O:26])=[C:19]([CH2:22][O:23][CH3:24])[CH2:20][S:21][C@H:16]23)=[O:13])[N:10]=1
Reactant: COCC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)C(=NOC)c3csc(NC(=O)CCl)n3)[C@H]2SC1
Agent: NC(N)=S
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: COCC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)C(=NOC)c3csc(N)n3)[C@H]2SC1
Temperature: 25 °C
Yield: 35.6 %

Procedure:
200 mg of benzhydryl 7-[2-(2-chloroacetamidothiazol-4-yl)-2-methoxyiminoacetamido]-3-methoxymethyl-3-cephem-4-carboxylate, followed by 45 mg of thiourea, were dissolved in 5 ml of dimethylacetamide. The solution was maintained at room temperature for 2 hours, after which a saturated aqueous solution of sodium bicarbonate was added. The reaction mixture was then extracted with 20 ml of ethyl acetate and the extract was washed with water to remove excess thiourea and then dried over anhydrous magnesium sulphate. After the drying agent had been filtered off, the filtrate was concentrated by evaporation under reduced pressure. The resulting residue was chromatographed through 30 g of silica gel (Wacogel C-100), eluted with ethyl acetate, to afford 63 mg of benzhydryl 7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-methoxymethyl-3-cephem-4-carboxylate.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:17])[CH:5]=[CH:6][C:7]=1[CH2:8][CH2:9][CH2:10][CH2:11][N:12]1[CH:16]=[CH:15][N:14]=[N:13]1.[H-].[Na+].Cl[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=2)[N:23]=1.O>CN(C)C=O>[Cl:34][C:31]1[CH:30]=[CH:29][C:28]([C:24]2[CH:25]=[CH:26][CH:27]=[C:22]([CH2:21][O:17][C:4]3[CH:5]=[CH:6][C:7]([CH2:8][CH2:9][CH2:10][CH2:11][N:12]4[CH:16]=[CH:15][N:14]=[N:13]4)=[C:2]([CH3:1])[CH:3]=3)[N:23]=2)=[CH:33][CH:32]=1
Reactant: ClCc1cccc(-c2ccc(Cl)cc2)n1
Reactant: Cc1cc(O)ccc1CCCCn1ccnn1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(OCc2cccc(-c3ccc(Cl)cc3)n2)ccc1CCCCn1ccnn1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 78.6 %

Procedure:
A solution of 97 mg (0.42 mmol) 3-methyl-4-(4-[1,2,3]triazol-1-yl-butyl)phenol in 4.0 ml N,N-dimethylformamide was treated at 0° C. with 17 mg (0.42 mmol) of 60% sodium hydride and stirred at 0° C. for 30 min. Then 100 mg (0.42 mmol) 2-Chloromethyl-6-(4-chloro-phenyl)-pyridine [ZA 6706809] were added and stirred continued at r.t. over night. After addition of 8 ml water, the precipitate was isolated, washed thoroughly with water and n-heptane. The residue was dried at 40° C. to give 143 mg (78%) of the title compound as white powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[C:4]=1[C:5]([O:7]C)=[O:6].CC(C)([O-])C.[K+].CCCCCC.C(OCC)(=O)C.Cl>CS(C)=O>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[C:4]=1[C:5]([OH:7])=[O:6]
Reactant: CCCCCCCCCCCCCCCc1cccc(OC)c1C(=O)OC
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCCCCCCCCCCCCCCc1cccc(OC)c1C(=O)O
Temperature: 70 °C
Yield: 8.7 %

Procedure:
To a stirred solution of Methyl 2-methoxy-6-pentadecylbenzoate (10 g, 240 mmol) in dimethyl sulfoxide (40 mL) was added potassium tert-butoxide (10 g, 890 mmol) in portions. The solution was heated to 70° C. on a water bath for 2 h, and the progress of the reaction was monitored by TLC using a hexane-ethyl acetate (8:2) solvent system. The reaction mass was cooled to 10° C., poured into ice water, and then acidified with 5% dilute hydrochloric acid. The precipitated solid was filtered and washed thoroughly with distilled water, and the crude mass was recrystallized in hexane (50 mL) to yield an off-white solid of 2-Methoxy-6-pentadecylbenzoic Acid (7.6 g, 80%).