Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)(=[O:4])[CH2:2][OH:3].[C:13](Cl)(Cl)=[O:14].N1C=CC=CC=1.[C:23]([O:27][C:28]([NH:30][C@H:31]1[C@H:34]([CH3:35])[NH:33][C:32]1=[O:36])=[O:29])([CH3:26])([CH3:25])[CH3:24].ClC([O-])=O.N1CCC1=O>C(N(CC)CC)C>[C:23]([O:27][C:28]([NH:30][C@H:31]1[C@H:34]([CH3:35])[N:33]([C:32]([O:3][CH2:2][C:1]([O:5][CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[O:4])=[O:36])[C:13]1=[O:14])=[O:29])([CH3:25])([CH3:24])[CH3:26]
Reactant: O=C(Cl)Cl
Reactant: C[C@@H]1NC(=O)[C@H]1NC(=O)OC(C)(C)C
Reactant: O=C(CO)OCc1ccccc1
Agent: O=C([O-])Cl
Agent: O=C1CCN1
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: C[C@H]1[C@H](NC(=O)OC(C)(C)C)C(=O)N1C(=O)OCC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 664 mg (4.0 mmol) of benzyl glycolate was added 5.8 ml of 12.5% phosgene (in toluene) at 0° C. To this solution at 0° C. was added pyridine (0.372 ml, 4.6 mmol) dropwise. The reaction was allowed to stir at room temperature for 2 hours and was then filtered under argon. Most of the volatiles were removed under vacuum without external heating, and the residual chloroformate was dissolved in methylene chloride (8 ml). Approximately half of this solution was added to (3S-trans)-3-[[(t-butyloxy)carbonyl]amino]-4-methyl-2-azetidinone (440 mg, 2.0 mmol), and the resulting solution was cooled to -20° C. Triethylamine (0.293 ml, 2.1 mmol) was then added dropwise. After 2 hours at -20° C., the remaining chloroformate was added to the azetidinone reaction mixture followed by 0.293 ml of triethylamine. After 3 hours at -20° C., the product was extracted from aqueous KH2PO4 with three portions of ethyl acetate. The combined organic layers were dried over sodium sulfate, and the volatiles were removed. The residue was subjected to column chromatography on silica gel (eluting with 35% ethyl acetate-hexane) to yield 488 mg of the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]([O:6][CH2:7][C:8]([OH:10])=[O:9])=[CH:4][CH:3]=1.Cl.[CH3:14]O>>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH2:7][C:8]([O:10][CH3:14])=[O:9])=[CH:11][CH:12]=1
Reactant: O=C(O)COc1ccc(O)cc1
Reactant: CO
Agent: Cl
Product: COC(=O)COc1ccc(O)cc1
Reaction time: 8 h

Procedure:
A solution of 4-hydroxyphenoxyacetic acid (33.6 g) in methanol was treated with hydrogen chloride gas and left to stand at ambient temperature overnight. The solvent was removed in vacuo and the residue taken up in ethyl acetate. This solution was washed sequentially with saturated sodium hydrogen carbonate solution (2×100 ml) and brine (100 ml), then dried (MGSO4) and the solvent evaporated to give methyl 4-hydroxyphenoxyacetate as a colourless crystalline mass, m.p. 112°-114° C.; NMR: 3.8 (s, 3H, CH3), 4.55 (s, 2H, CH2), 6.75 (s, 4H, phenyl-H) 6.8-7.8 (broad s, 1H, OH); m/e 200 (M+NH4)+.
Reaction SMILES: [NH:1]1[CH2:5][C:4](=[O:6])[NH:3][C:2]1=[O:7].[CH2:8]([C:11]1[C:19]2[O:18][N:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[C:15]=2[CH:14]=[CH:13][C:12]=1[O:24][CH2:25][CH2:26][CH2:27]Br)[CH2:9][CH3:10]>CCOCC>[CH2:8]([C:11]1[C:19]2[O:18][N:17]=[C:16]([C:20]([F:21])([F:23])[F:22])[C:15]=2[CH:14]=[CH:13][C:12]=1[O:24][CH2:25][CH2:26][CH2:27][N:3]1[C:4](=[O:6])[CH2:5][NH:1][C:2]1=[O:7])[CH2:9][CH3:10]
Reactant: O=C1CNC(=O)N1
Reactant: CCCc1c(OCCCBr)ccc2c(C(F)(F)F)noc12
Solvent: CCOCC
Product: CCCc1c(OCCCN2C(=O)CNC2=O)ccc2c(C(F)(F)F)noc12

Procedure:
3-(3-{[7-Propyl-3-(trifluoromethyl)-1,2-benzisoxazol-6-yl]oxy}propyl)imidazolidine-2,4-dione was prepared as for Example 10 from imidazolidine-2,4-dione and the bromide from Example 7. After aqueous ether work-up and silica gel chromatography, the title compound was obtained.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH2:17][C:18]([F:21])([F:20])[F:19])[C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([C:13]([F:16])([F:15])[F:14])[CH:6]=1.O[C:23]1[N:28]=[CH:27][C:26]([NH:29][C:30](=[O:32])[CH3:31])=[CH:25][CH:24]=1>COCCOC>[C:9]([C:8]1[CH:11]=[CH:12][C:5]([N:4]([CH2:17][C:18]([F:19])([F:20])[F:21])[CH2:3][CH2:2][O:1][C:23]2[N:28]=[CH:27][C:26]([NH:29][C:30](=[O:32])[CH3:31])=[CH:25][CH:24]=2)=[CH:6][C:7]=1[C:13]([F:15])([F:16])[F:14])#[N:10]
Reactant: CC(=O)Nc1ccc(O)nc1
Reactant: N#Cc1ccc(N(CCO)CC(F)(F)F)cc1C(F)(F)F
Solvent: COCCOC
Product: CC(=O)Nc1ccc(OCCN(CC(F)(F)F)c2ccc(C#N)c(C(F)(F)F)c2)nc1

Procedure:
Synthesized as described in Example 27B from 4-[(2-hydroxyethyl)(2,2,2-trifluoroethyl)amino]-2-(trifluoromethyl)benzonitrile (Example 15B) and N-(6-hydroxy-3-pyridinyl)acetamide, using dry DME as the reaction solvent: MS (ESI) m/z 447 (M+1).
Reaction SMILES: CO[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=[O:13])[CH2:7][CH2:6]2.Cl[CH2:15][CH2:16][CH2:17]I.C([O-])([O-])=O.[Cs+].[Cs+].C([O-])([O-])=O.[K+].[K+].[CH2:31]([CH:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1)[CH2:32][CH2:33][CH3:34]>C(#N)C.O>[CH2:31]([CH:35]1[CH2:40][CH2:39][N:38]([CH2:15][CH2:16][CH2:17][N:9]2[C:10]3[C:5](=[CH:4][CH:3]=[CH:12][CH:11]=3)[CH2:6][CH2:7][C:8]2=[O:13])[CH2:37][CH2:36]1)[CH2:32][CH2:33][CH3:34]
Reactant: COc1ccc2c(c1)CCC(=O)N2
Reactant: CCCCC1CCNCC1
Reactant: ClCCCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CCCCC1CCN(CCCN2C(=O)CCc3ccccc32)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
6-Methoxy-3,4-dihydro-1H-quinolin-2-one (108 mg, 0.61 mmol), 1-chloro-3-iodopropane (64 μl, 0.6 mmol) and Cs2CO3 (290 mg, 0.9 mmol) in acetonitrile (2 mL) were shaken at 60° C. for 14 h then the reaction was cooled to room temperature. Water (5 mL) was added and the product was extracted with ethyl acetate (2×10 mL). The organic layer was dried (Na2SO4), filtered and concentrated in vacuo. The syrup was dissolved in acetonitrile (4 mL). KI (83 mg, 3.6 mmol), K2CO3 (100 mg, 0.6 mmol) and 4-butylpiperidine (83 μl, 0.5 mmol) were added and the reaction mixture was shaken at 60° C. for 16 h. Water (5 mL) was added and the product was extracted with ethyl acetate (2×10 mL). The organic layer was dried (Na2SO4) and concentrated in vacuo. The product was purified by column chromatography (eluent: 20% methanol in ethyl acetate) to yield the title compound. Yield: 24.8 mg, 11.3%. HPLC-MS: M+1+=359.5 (UV/MS (%)=90/78). 1H NMR (400 MHz, CDCl3): δ=0.89 (3H, t), 1.12-1.34 (9H, m), 1.67 (2H, broad d), 1.85 (2H, quin.), 1.93 (2H, broad t), 2.39 (2H, t), 2.59 (2H, dd), 2.83 (2H, t), 2.90 (2H, broad d), 3.76 (3H, s), 3.94 (2H, t), 6.70 (1H, d), 6.74 (1H, dd), 7.01 (1H, d). 13C NMR (CDCl3): d 14.3, 23.0, 25.0, 26.1, 29.2, 32.1, 32.5 (2C), 35.9, 36.4, 40.8, 54.3 (2C), 55.8, 56.3, 112.2, 114.2, 116.2, 128.3, 133.4, 155.4, 169.9
Reaction SMILES: C(Cl)(=[O:3])C.[N:5]1([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]3[N:22]=[C:21]([C:23]4[CH:28]=[C:27]([NH:29][C:30]5[CH:35]=CC=CC=5)[CH:26]=[C:25]([N:36]5[CH2:41][CH2:40][O:39][CH2:38][CH2:37]5)[CH:24]=4)[CH:20]=[CH:19][N:18]=3)=[CH:12][CH:11]=2)[CH:9]=[CH:8][N:7]=[N:6]1>C(Cl)Cl>[N:5]1([C:10]2[CH:11]=[CH:12][C:13]([NH:16][C:17]3[N:22]=[C:21]([C:23]4[CH:28]=[C:27]([NH:29][C:30](=[O:3])[CH3:35])[CH:26]=[C:25]([N:36]5[CH2:37][CH2:38][O:39][CH2:40][CH2:41]5)[CH:24]=4)[CH:20]=[CH:19][N:18]=3)=[CH:14][CH:15]=2)[CH:9]=[CH:8][N:7]=[N:6]1
Reactant: CC(=O)Cl
Reactant: c1ccc(Nc2cc(-c3ccnc(Nc4ccc(-n5ccnn5)cc4)n3)cc(N3CCOCC3)c2)cc1
Solvent: ClCCl
Product: CC(=O)Nc1cc(-c2ccnc(Nc3ccc(-n4ccnn4)cc3)n2)cc(N2CCOCC2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of acetyl chloride (0.02 mL, 0.28 mmol) in CH2Cl2 (1 mL) was added to N-(4-(1H-1,2,3-triazol-1-yl)phenyl)-4-(3-morpholino-5-(phenylamino)phenyl)pyrimidin-2-amine (0.11 g, 0.28 mmol) in CH2Cl2 (3 mL) drop wise at 0° C. The reaction was warmed to room temperature, stirred for 30 min, concentrated, and purified by chromatography on silica gel (ethyl acetate/hexanes) to afford N-(3-(2-(4-(1H-1,2,3-triazol-1-yl)phenylamino)pyrimidin-4-yl)-5-morpholinophenyl)acetamide. MS (ESI) 457 (M+H).
Reaction SMILES: [C:1]1([N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([CH:16]=[O:17])=[C:8]2[N:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:24]([CH:26]1[O:28][CH2:27]1)Br.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[O:28]1[CH2:27][CH:26]1[CH2:24][N:21]1[CH2:22][CH2:23][N:18]([C:8]2[N:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[C:15]3[C:10]([C:9]=2[CH:16]=[O:17])=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:19][CH2:20]1
Reactant: BrCC1CO1
Reactant: O=Cc1c(N2CCNCC2)n(-c2ccccc2)c2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=Cc1c(N2CCN(CC3CO3)CC2)n(-c2ccccc2)c2ccccc12
Yield: 41 %

Procedure:
A stirred mixture of 1-phenyl-2-(piperazin-1-yl)-1H-indole-3-carboxaldehyde (438 mg, 1.37 mmol), epibromohydrin (188 mg, 1.37 mmol), potassium carbonate (758 mg, 5.49 mmol) and acetonitrile (20 ml) is heated at reflux for 2.5 hr. The reaction is cooled and the solids are removed by filtration. The filtrate is concentrated and the residue is purified by chromatography eluting with dichloromethane-1 to 5% methanol. Fractions containing the desired product are combined and concentrated to afford 2-(4-oxiranylmethylpiperazin-1-yl)-1-phenyl-1H-indole-3-carboxaldehyde (41% yield) as a yellow solid. LC/MS: MS 376 (M+H); RT 2.65 min; NMR (CDCl3): 10.28 (1H, s), 8.26 (1H, d), 7.43-7.65 (3H, m), 7.17-7.42 (3H, m), 7.13 (1H, t), 6.96 (1H, d), 3.49 (4H, m), 3.03 (1H, m), 2.56-2.86 (4H, m), 2.30-2.50 (2H, m), 1.74 (2H, m), 1.56 (2H, s).
Reaction SMILES: Br[C:2]([CH2:4][Br:5])=[CH2:3].[CH2:6]([Mg]Br)[CH2:7][CH2:8][CH2:9]C.Cl.[CH2:14](OCC)C>>[Br:5][C:4]([CH2:2][CH2:3][CH2:6][CH2:7][CH2:8][CH3:9])=[CH2:14]
Reactant: CCOCC
Reactant: C=C(Br)CBr
Reactant: CCCCC[Mg]Br
Agent: Cl
Product: C=C(Br)CCCCCC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 9.42 ml (0.0728 mol) of 2,3-dibromopropene in 70 ml diethylether was placed under a nitrogen atmosphere by use of a Firestone valve. While cooling in an ice water bath, a solution of 0.091 mol of pentylmagnesium bromide in 70 ml diethyl ether was added slowly via addition funnel. After stirring for 2 hours while warming to room temperature, there was then added via syringe 50 ml of 1 N hydrochloric acid to the reaction cooling in an ice water bath. The resulting mixture was transferred to a separatory funnel and the phases were separated. The organic layer was dried over MgSO4 and filtered. The solvent was removed from the filtrate in vacuo to yield 15.0 g (85.7% of theory) of 81% pure 2-bromo-oct-1-ene as an oil.
Reaction SMILES: CON(C)[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1)=[O:5].[F:13][C:14]1[C:19]([C:20]([F:23])([F:22])[F:21])=[CH:18][CH:17]=[CH:16][C:15]=1[Mg]Br>C1COCC1.C(OCC)(=O)C.[Cl-].[NH4+]>[F:13][CH:14]1[CH:15]([C:4]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=2)=[O:5])[CH:16]=[CH:17][CH:18]=[C:19]1[C:20]([F:21])([F:22])[F:23]
Reactant: CON(C)C(=O)c1ccccn1
Reactant: Fc1c([Mg]Br)cccc1C(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(c1ccccn1)C1C=CC=C(C(F)(F)F)C1F

Procedure:
Then a solution of pyridine-2-carboxylic acid methoxy-methyl-amide (1.5 g, 9 mmoles) was allowed to react with 2-flouro-3-trifluoromethylphenylmagnesium bromide (2.72 g, 10 mmoles) in THF (30 mL) at 60° C. overnight. The reaction mixture was cooled and diluted with ethyl acetate and ammonium chloride. The organic portion was washed with brine and dried over MgSO4 and stripped to afford a crude product, which was purified by chromatography with CH2Cl2 to give (6-fluoro-5-trifluoromethyl-cyclohexa-2,4-dienyl)-pyridin-2-yl-methanone as a colorless liquid (1.6 gr., 65%).
Reaction SMILES: C([NH:3][C@@H:4]1[C:21](=[O:22])[N:6]2[C:7]([C:13]([O:15][CH2:16][C:17]([Cl:20])([Cl:19])[Cl:18])=[O:14])=[C:8]([CH:11]=[CH2:12])[CH2:9][S:10][C@H:5]12)=O>CO>[ClH:18].[NH2:3][C@@H:4]1[C:21](=[O:22])[N:6]2[C:7]([C:13]([O:15][CH2:16][C:17]([Cl:19])([Cl:18])[Cl:20])=[O:14])=[C:8]([CH:11]=[CH2:12])[CH2:9][S:10][C@H:5]12
Reactant: C=CC1=C(C(=O)OCC(Cl)(Cl)Cl)N2C(=O)[C@@H](NC=O)[C@H]2SC1
Solvent: CO
Product: C=CC1=C(C(=O)OCC(Cl)(Cl)Cl)N2C(=O)[C@@H](N)[C@H]2SC1
Product: Cl
Reaction time: 0.5 h
Yield: 168.8 %

Procedure:
2,2,2-Trichloroethyl 7β-formamido-3-vinylceph-3-em-4-carboxylate (0.88 g., 2.3 mmole) was treated with dry methanol (5 ml.), when some solid crystallised. The suspension was cooled to ca. 5° and stirred while phosphorus oxychloride (0.53 ml.) was added dropwise. The reaction mixture was kept at ca. 5° for 30 minutes and diluted with ether (20 ml.); no solid separated. The solvents were evaporated and the residual oil was treated with ether (ca. 10 ml.) to give a white solid. The solid was filtered off, washed with ether, and dried to give the title hydrochloride (0.765 g., 85%), λmax. (MeOH) 295 nm (ε 10,150), νmax. (Nujol), ca. 2590 (N+H3), 1788 (azetidin-2-one), 1730 (CO2R), and 946 cm-1 (=CH2), τ (Me2SO-d6), 2.86 (1H, dd, J 11 and 17.5 Hz; CH=CH2), 4.13 (1 H, d, J 17.5 Hz) and 4.45 (1H, d, J 11 Hz) (CH=CH2), 4.64 (1H, d, J 5 Hz; C7 -H), 4.78 (1H, d, J 5 Hz; C6 -H), 4.81 and 4.98 (2H, AB-q, J 12 Hz; CH2CCl3), 5.92 and 6.24 (2H, AB-q, J 17 Hz; C2 -H2), 6.31 (ca 1H, d, JP-H 11 Hz; ca. 0.1 M trimethyl phosphate) (Found: P, 0.78%).
Reaction SMILES: [C:1]([NH:20][C:21]1[S:22][CH:23]=[C:24]([CH2:26][C:27](O)=[O:28])[N:25]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN1CCOCC1.ClC(OCC(C)C)=O.[CH3:45][C:46]([O:48][CH2:49][C:50]1[CH2:59][S:58][C@@H:53]2[C@H:54]([NH2:57])[C:55](=[O:56])[N:52]2[C:51]=1[C:60]([OH:62])=[O:61])=[O:47]>O1CCCC1.O>[C:46]([O:48][CH2:49][C:50]1[CH2:59][S:58][C@@H:53]2[C@H:54]([NH:57][C:27](=[O:28])[CH2:26][C:24]3[N:25]=[C:21]([NH:20][C:1]([C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)([C:8]4[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=4)[C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[S:22][CH:23]=3)[C:55](=[O:56])[N:52]2[C:51]=1[C:60]([OH:62])=[O:61])(=[O:47])[CH3:45]
Reactant: O=C(O)Cc1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: CC(C)COC(=O)Cl
Solvent: O
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)Cc3csc(NC(c4ccccc4)(c4ccccc4)c4ccccc4)n3)[C@H]2SC1
Temperature: -20 °C
Yield: 88.7 %

Procedure:
A mixture of 801 mg of 2-tritylamino-4-thiazolylacetic acid, 10 ml of dry tetrahydrofuran and 2 ml of a molar solution of N-methyl-morpholine in tetrahydrofuran was stirred at -20° C. and 2 ml of a molar solution of isobutyl chloroformate in tetrahydrofuran were slowly added thereto. The mixture was stirred and a solution of 544 mg of 7-amino-cephalosporanic acid in 10 ml of water and 2.4 ml of a molar solution of N-methyl-morpholine in tetrahydrofuran was added thereto. The mixture was stirred with reheating and the solvent was evaporated. The residue was diluted with water and 2 ml of 2 N hydrochloric acid were added. The mixture was vacuum filtered and the product was dried to obtain 1.16 g of 3-acetoxymethyl-7β-[2-(2-tritylamino-4-thiazolyl)-acetamido]-ceph-3-eme-4-carboxylic acid.
Reaction SMILES: [C:1]1([CH:7]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:8][NH:9][C:10]2[N:18]=[C:17]([C:19](O)=[O:20])[N:16]=[C:15]3[C:11]=2[N:12]=[CH:13][N:14]3[CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][O:23]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:34]1([CH2:40][CH2:41][NH2:42])[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1.O>O1CCCC1>[C:1]1([CH:7]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:8][NH:9][C:10]2[N:18]=[C:17]([C:19]([NH:42][CH2:41][CH2:40][N:34]3[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]3)=[O:20])[N:16]=[C:15]3[C:11]=2[N:12]=[CH:13][N:14]3[CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][O:23]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)c1nc(NCC(c2ccccc2)c2ccccc2)c2ncn(C3CCCCO3)c2n1
Reactant: NCCN1CCCCC1
Solvent: C1CCOC1
Solvent: O
Product: O=C(NCCN1CCCCC1)c1nc(NCC(c2ccccc2)c2ccccc2)c2ncn(C3CCCCO3)c2n1
Temperature: 25 °C

Procedure:
To a suspension of 6-[(2,2-diphenylethyl)amino]-9-(tetrahydro-2H-pyran-2-yl) 9H-purine-2-carboxylic acid (249 g, 0.561 moles) (Preparation 21) in anhydrous tetrahydrofuran (2500 ml) was added N,N′-carbonyldiimidazole (109 g, 0.672 moles) in two portions over 10 minutes. The resulting mixture was stirred at ambient temperature under an atmosphere of nitrogen whereupon the solid gradually dissolved to give a cloudy pale orange solution. After stirring for 2.5 h, the reaction mixture was cooled in an ice-bath, and a solution of 2-(1-piperidinyl)ethylamine (86.4 g, 0.674 moles) in anhydrous tetrahydrofuran (100 ml) was added over a period of 55 minutes during which time a clear orange solution formed. The reaction mixture was stirred at room temperature for a further 17.5 hours. Deionised water (10 ml) was then added and the reaction mixture was then distilled at atmospheric pressure until approximately 2400 ml of distillate had collected. To the resultant amber oil was added isopropanol (2000 ml) and distillation at atmospheric pressure was continued until approximately 50 ml of distillate had collected. The resultant dark orange solution was allowed to cool to ambient temperature and further isopropanol (600 ml) was added to give a solution of the title compound in isopropanol that may be used directly without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][C:7]([C:13]([OH:15])=[O:14])=[CH:6]2.CO[C:18]([C@H:20]1[CH2:25][CH2:24][C@H:23]([NH:26][CH2:27][CH2:28][S:29][C:30]2[S:31][CH:32]=[CH:33][CH:34]=2)[CH2:22][CH2:21]1)=O>>[S:31]1[CH:32]=[CH:33][CH:34]=[C:30]1[S:29][CH2:28][CH2:27][NH:26][C@H:23]1[CH2:24][CH2:25][C@H:20]([CH2:18][O:14][C:13]([C:7]2[CH:8]=[N:9][C:10]3[C:5]([CH:6]=2)=[N:4][C:3]([O:2][CH3:1])=[CH:12][CH:11]=3)=[O:15])[CH2:21][CH2:22]1
Reactant: COC(=O)[C@H]1CC[C@H](NCCSc2cccs2)CC1
Reactant: COc1ccc2ncc(C(=O)O)cc2n1
Product: COc1ccc2ncc(C(=O)OC[C@H]3CC[C@H](NCCSc4cccs4)CC3)cc2n1

Procedure:
The title compound is prepared as an off-white viscous oil following Scheme 2 and in analogy to Example 28 using 6-methoxy-[1,5]naphthyridine-3-carboxylic acid and trans-4-[2-(thiophen-2-ylsulfanyl)-ethylamino]-cyclohexanecarboxylic acid methyl ester as starting materials.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[CH:6][C:5]=1[OH:11])(=[O:3])[CH3:2].Cl[C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]([CH2:23][C:24]2[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=2)=[N:15][N:14]=1.N.ClCCl>CN1C(=O)N(C)CC1>[C:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]([CH2:23][C:24]3[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=3)=[N:15][N:14]=2)=[CH:6][C:5]=1[OH:11])(=[O:3])[CH3:2]
Reactant: Clc1nnc(Cc2ccncc2)c2ccccc12
Reactant: CC(=O)c1ccc(N)cc1O
Agent: N
Solvent: ClCCl
Solvent: CN1CCN(C)C1=O
Product: CC(=O)c1ccc(Nc2nnc(Cc3ccncc3)c3ccccc23)cc1O

Procedure:
302 mg (2.0 mmol) 2-acetyl-5-aminophenol (Maybridge) and 256 mg (1.00 mmol) 1-chloro-4-(4-pyridylmethyl)phthalazine (Example 67A.1) in 2 ml DMEU are heated for 3-18 h to 100° C. The reaction mixture is stirred with 10 ml NH3 solution (10% in water) and 25 ml ethyl actetate (or dichloromethane) and filtered via Celite. The organic phase of the filtrate is dried (Na2SO4), evaporated, and chromatographed (SiO2; ethyl acetate/CH3OH 40:1→10:1) Crystallization from acetonitrile yields the title compound: m.p.: 234-236° C.; HPLC: tRet(Grad5-40)=9.5; FAB MS (M+H)+=371.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[CH:3][C:2]=1[O:11][C:12]1[CH:23]=[CH:22][C:15]([O:16][CH:17]([CH3:21])[C:18](O)=[O:19])=[CH:14][CH:13]=1.S(Cl)(Cl)=O>ClCCCC>[CH2:2]([N:1]([CH2:10][CH3:9])[C:18](=[O:19])[CH:17]([O:16][C:15]1[CH:22]=[CH:23][C:12]([O:11][C:2]2[CH:3]=[N:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:1]=2)=[CH:13][CH:14]=1)[CH3:21])[CH3:3]
Reactant: CC(Oc1ccc(Oc2cnc3ccccc3n2)cc1)C(=O)O
Solvent: CCCCCl
Solvent: O=S(Cl)Cl
Product: CCN(CC)C(=O)C(C)Oc1ccc(Oc2cnc3ccccc3n2)cc1

Procedure:
The title compound can be prepared by interaction of 2-[4-(2-quinoxalinyloxy)phenoxy]propionic acid with thionyl chloride in a suitable solvent such as chlorobutane. Add a solution of 3.3 g (0.01 mole) 2-[4-(2-quinoxalinyloxy)phenoxy]propionyl chloride in 30 cc methylene chloride to a cold (5° C.) solution of 1.8 g (0.025 mole) diethylamine in 30 cc methylene chloride. Stir the mixture at room temperature overnight. Wash the methylene chloride solution with water and dry over magnesium sulfate. Remove the methylene chloride under vacuum to yield N,N-diethyl-2-[4-(quinoxalinyloxy)phenoxy]propanamide.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:27][CH3:28])=[C:10]([O:13][C@H:14]3[CH2:19][CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15]3)[CH:11]=2)[N:6]=[CH:5][N:4]=1.[Cl:29][C:30]1[C:31]([F:37])=[C:32]([CH:34]=[CH:35][CH:36]=1)[NH2:33]>C(#N)C>[ClH:2].[Cl:29][C:30]1[C:31]([F:37])=[C:32]([CH:34]=[CH:35][CH:36]=1)[NH:33][C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:27][CH3:28])=[C:10]([O:13][C@H:14]3[CH2:19][CH2:18][CH2:17][NH:16][CH2:15]3)[CH:11]=2)[N:6]=[CH:5][N:4]=1
Reactant: Nc1cccc(Cl)c1F
Reactant: COc1cc2ncnc(Cl)c2cc1O[C@H]1CCCN(C(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: CC#N
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1O[C@H]1CCCNC1
Temperature: 60 °C
Yield: 65.8 %

Procedure:
HCl (1.0 ml, 4M solution in dioxane) was added to 4-chloro-7-methoxy-6-[(3S)-1-(tert-butoxycarbonyl)piperidin-3-yloxy]quinazoline (0.786 g) and 3-chloro-2-fluoroaniline (0.304 g) dissolved in acetonitrile (25 ml). The mixture was heated to 60° C. for 2 hours, cooled and the precipitate collected to give 4-(3-chloro-2-fluoroanilino)-7-methoxy-6-[(3S)-piperidin-3-yloxy]quinazoline hydrochloride as a white solid (0.577 g, 66%); 1H NMR Spectrum: (DMSOd6) 1.70-1.95 (m, 2H), 1.95-2.10 (m, 1H); 2.10-2.25 (m, 1H), 2.95-3.10 (m, 1H), 3.10-3.30 (m, 2H), 3.45-3.65 (m, 1H); 4.03 (s, 3H); 4.95-5.10 (m, 1H); 7.30-7.45 (m, 1H); 7.45-7.60 (m, 2H); 7.60-7.73 (m, 1H), 8.85 (s, 1H); 8.90 (s, 1H); 9.15 (bs, 2H); 12.3 (bs, 1H); Mass Spectrum: (M+H): 403.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[C:7]1([C:13]2[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=2)[C:16]([OH:18])=O)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH:22]1([CH2:28][NH2:29])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>C1COCC1.CN(C=O)C>[CH:22]1([CH2:28][NH:29][C:16](=[O:18])[C:15]2[CH:19]=[CH:20][CH:21]=[C:13]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH:14]=2)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: O=C(O)c1cccc(-c2ccccc2)c1
Reactant: NCC1CCCCC1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: O=C(NCC1CCCCC1)c1cccc(-c2ccccc2)c1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
Oxalyl chloride (132 μL, 1.5 mmol) was added over a 10 minute period to a mixture of 3-phenylbenzoic acid (200 mg, 1 mmol) dissolved in a mixture THF/DMF (3.5 mL/58 μL). After the addition, the reaction was stirred at room temperature for 2.5 hours. Cyclohexylmethylamine (325 μL, 2.5 mmol) was then added into half of the acid chloride solution at 0° C. The reaction mixture was then stirred at room temperature for 18 hours. The reaction mixture was concentrated and water was added to the residue. The aqueous phase was extracted 3 times with CH2Cl2. The combined organic layers were washed with 2N HCl, saturated NaHCO3, brine, dried over Na2SO4 and concentrated. Diethyl ether was added to the residue and a white solid precipitated which was collected by filtration and rinsed with a small amount of diethyl ether. The white solid was then dried under vacuum (115 mg, 78%). NMR 1H (ppm, CDCl3): 7.95 (s, 1H), 7.69 (d, J3=7.80 Hz, 2H), 7.59 (d, J3=8.22 Hz, 2H), 7.50-7.33 (m, 4H), 6.22 (br. s., 1H), 3.31 (t, J3=6.29 Hz, 2H), 1.80-1.53 (m, 6H), 1.31-1.10 (m, 3H), 1.05-0.84 (m, 2H).
Reaction SMILES: Cl.[CH2:2]([S:9][C:10]1[S:11][CH:12](O)[C:13](C)(O)[N:14]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:18]([OH:20])C>>[CH2:2]([S:9][C:10]1[S:11][C:12]([CH2:18][OH:20])=[CH:13][N:14]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CCO
Reactant: CC1(O)N=C(SCc2ccccc2)SC1O
Agent: Cl
Product: OCc1cnc(SCc2ccccc2)s1
Temperature: 50 °C
Reaction time: 12 h

Procedure:
0.2 ml of concentrated hydrochloric acid is added to 3.0 g of 2-benzylsulfanyl-5-hydroxy-methyl-4,5-dihydrothiazol-4-ol in 25 ml of ethanol. The mixture is stirred at 50° C. for 12 hours, the solvent is removed in vacuo, and the residue is chromatographed on silica gel (ethethexane; 1:1). The title compound is obtained in the form of a yellow oil (compound 3.1).