Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:4]=[C:5]=[O:6])[CH2:2][CH3:3].[C:7]([CH2:9][C:10]([NH:12][CH2:13][CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:11])#[N:8]>C1(C)C=CC=CC=1>[NH2:8][C:7]1[N:4]([CH2:1][CH2:2][CH3:3])[C:5](=[O:6])[N:12]([CH2:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[C:10](=[O:11])[CH:9]=1.[C:7]([CH2:9][C:5]([N:4]([CH2:1][CH:2]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:3]1)[C:10]([NH:12][CH2:13][CH2:14][CH3:15])=[O:11])=[O:6])#[N:8]
Reactant: CCCN=C=O
Reactant: N#CCC(=O)NCC1CCCCC1
Solvent: Cc1ccccc1
Product: CCCNC(=O)N(CC1CCCCC1)C(=O)CC#N
Product: CCCn1c(N)cc(=O)n(CC2CCCCC2)c1=O

Procedure:
6-Amino-3-(cyclohexylmethyl)-1-propyluracil was prepared by the method of V. Papesh, J. Org. Chem. 1951, 16, 1879-1889. A solution of propyl isocyanate (Aldrich, 10.92 mL, 116.5 mmol) and 2-cyano-N-(cyclohexylmethyl)acetamide (from step (a), 14.00 g, 77.7 mmol) in anhydrous toluene (100 mL) was stirred at reflux (heating mantle) under nitrogen for 24 h. Volatiles were then removed at 20 Torr and 50° C., and the resulting orange oil was chromatographed on silica gel. 1-(2-Cyanoacetyl)-1-cyclohexylmethyl-3-propylurea eluted with hexane/ethyl acetate (5:2) as a yellow oil, which solidified upon standing (2.708 g). Unreacted 2-cyano-N-(cyclohexylmethyl)acetamide eluted with hexane/ethylacetate (1:1) as a white crystalline solid (12.02 g), which was resubmitted to the reaction conditions described above. This process was repeated twice to provide 1-(2-cyanoacetyl)-1-cyclohexylmethyl-3-propylurea (total for the three runs: 7.101 g, 34%), 1H-NMR (DMSO-d6) consistent with structure. Unreacted 2-cyano-N-(cyclohexylmethyl)acetamide was also recovered (7.108 g, 51%).
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([I:20])=[CH:16][C:15]=1[Cl:21].[C:22](=[O:24])=[O:23]>C1COCC1.O>[Cl:21][C:15]1[C:14]([Cl:13])=[CH:19][CH:18]=[C:17]([I:20])[C:16]=1[C:22]([OH:24])=[O:23]
Reactant: O=C=O
Reactant: Clc1ccc(I)cc1Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: CC(C)NC(C)C
Product: O=C(O)c1c(I)ccc(Cl)c1Cl
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
n-Butyllithium (1.45M solution in hexane, 19.4 mmol, 13.4 ml) was added dropwise to a stirred solution of diisopropylamine (21.4 mmol, 3.0 ml) in THF (90 ml) at 0° C. After 30 minutes, the solution was cooled to -78° C. and a solution of 1,2-dichloro-4-iodobenzene (5.30 g, 19.4 mmol) in THF (10 ml) was added dropwise. After 10 minutes, solid carbon dioxide was added cautiously and the mixture allowed to warm to room temperature over 16 h. The mixture was diluted with water and extracted twice with ethyl acetate. The aqueous layer was acidified with dilute aqueous hydrochloric acid and then extracted twice with ethyl acetate. The extracts were dried over sodium sulphate and evaporated to give the title compound as a yellow solid (3.59 g). 300 MHz 1H NMR (d6 -DMSO) 11.5 (1H, br.s), 7.82 (1H, d, J 8.4 Hz), 7.44 (1H, d, J 8.4 Hz).
Reaction SMILES: [CH3:1][C:2]1[C:3]([NH:15][CH:16]2[CH2:23][CH:19]3[CH2:20][NH:21][CH2:22][CH:18]3[CH2:17]2)=[N:4][C:5]([NH:8][C:9]2[CH:10]=[N:11][N:12]([CH3:14])[CH:13]=2)=[N:6][CH:7]=1.C(N(CC)CC)C.[CH3:31][S:32](Cl)(=[O:34])=[O:33]>C(Cl)Cl>[CH3:1][C:2]1[C:3]([NH:15][CH:16]2[CH2:23][CH:19]3[CH2:20][N:21]([S:32]([CH3:31])(=[O:34])=[O:33])[CH2:22][CH:18]3[CH2:17]2)=[N:4][C:5]([NH:8][C:9]2[CH:10]=[N:11][N:12]([CH3:14])[CH:13]=2)=[N:6][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: Cc1cnc(Nc2cnn(C)c2)nc1NC1CC2CNCC2C1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cnc(Nc2cnn(C)c2)nc1NC1CC2CN(S(C)(=O)=O)CC2C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 42.4 %

Procedure:
To a suspension of 5-methyl-N2-(1-methyl-1H-pyrazol-4-yl)-N4-(octahydrocyclopenta[c]pyrrol-5-yl)pyrimidine-2,4-diamine (122.4 mg, 0.39 mmol) and N,N-diethylethanamine (103.9 mg, 1.03 mmol) in DCM (10 mL) was added methanesulfonyl chloride (98.4 mg, 0.86 mmol). The reaction mixture was stirred at rt for 2 h, quenched with H2O (30 mL) and extracted with DCM (100 mL×3). The combined organic phases were washed with brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (MeOH/DCM (v/v)=1/20) to give the title compound as a beige solid (64.8 mg, 42.4%).
Reaction SMILES: C(O[CH:4]=[CH:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])C.BrN1C(=O)CCC1=O.[C:19]([CH:22]1[CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24][CH2:23]1)(=[S:21])[NH2:20].[OH-].[NH4+]>O1CCOCC1.O>[NH:25]1[CH2:26][CH2:27][CH:22]([C:19]2[S:21][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][N:20]=2)[CH2:23][CH2:24]1
Reactant: CC(C)(C)OC(=O)N1CCC(C(N)=S)CC1
Reactant: CCOC=CC(=O)OCC
Agent: O=C1CCC(=O)N1Br
Agent: [NH4+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)c1cnc(C2CCNCC2)s1
Temperature: -10 °C
Reaction time: 1 h

Procedure:
Ethyl 3-ethoxyacrylate (1.50 g, 10.38 mml) was dissolved in dioxane/water and chilled to −10° C. N-Bromosuccinimide (2.03 g, 11.42 mmol) was added and the mixture was stirred 1 hour at room temperature. tert-Butyl 4-carbamothioylpiperidine-1-carboxylate (2.54 g, 10.38 mmol) was added and the mixture was heated at 100° C. for 1 hour. The reaction mixture was poured into 25 mL saturated ammonium hydroxide and extracted with dichloromethane. The combined organic layers were washed with brine, dried with sodium sulfate, filtered, and concentrated. Normal phase chromatography provided the title compound.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[N:3]=1.[NH2:18][C:19]1[N:24]=[C:23]([O:25][CH3:26])[CH:22]=[C:21]([O:27][CH3:28])[N:20]=1>>[CH3:28][O:27][C:21]1[CH:22]=[C:23]([O:25][CH3:26])[N:24]=[C:19]([NH:18][C:2]2[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]3[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=3)[N:3]=2)[N:20]=1
Reactant: FC(F)(F)c1cc(Cl)nc(-c2cccnc2)n1
Reactant: COc1cc(OC)nc(N)n1
Product: COc1cc(OC)nc(Nc2cc(C(F)(F)F)nc(-c3cccnc3)n2)n1

Procedure:
The title compound was prepared from 4-chloro-2-(3-pyridinyl)-6-trifluoromethylpyrimidine (50 mg, 0.192 mmol) and 2-amino-4,6-dimethoxypyrimidine (27 mg, 0.288 mmol) similar to Example 190 and was isolated as a solid. 1H NMR (CDCl3): 9.65 (brs, 1H), 8.71-8.70 (m, 2H), 7.54 (brs, 1H), 7.44 (dd, J=7.8, 4.8 Hz, 1H), 7.25 (s, 1H), 7.04 (s, 1H), 6.07 (t, J=5.4 Hz, 1H).
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[C:5]2[CH:13]=[CH:14][CH:15]=[CH:16][C:4]=2[NH:3]1.Br[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20].C(N(CC)C(C)C)(C)C>C(#N)C>[O:1]=[C:2]1[N:6]([CH:7]2[CH2:8][CH2:9][N:10]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:11][CH2:12]2)[C:5]2[CH:13]=[CH:14][CH:15]=[CH:16][C:4]=2[NH:3]1
Reactant: O=c1[nH]c2ccccc2n1C1CCNCC1
Reactant: CCOC(=O)CBr
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCOC(=O)CN1CCC(n2c(=O)[nH]c3ccccc32)CC1
Yield: 94.6 %

Procedure:
A solution of 4-(2-keto-1-benzimidazolinyl)piperidine (10.0 g, 46 mmol), ethyl bromoacetate (5.1 mL, 46 mmol) and N,N-diisopropylethylamine (8.8 mL, 50.6 mmol) in acetonitrile (200 mL) was heated at reflux for 1 hour. The solvent was evaporated in vacuo, and the residue was suspended in water (˜200 mL). The suspension was made basic with the addition of a saturated aqueous solution of sodium bicarbonate. The resultant solid was collected by filtration, washed with water and dried in vacuo to give the ethyl (4-(2-keto-1-benzimidazolinyl)piperidin-1-yl)acetate as a colorless solid (13.2 g, 94%). MS m/z 304 (MH+); NMR(CDCl3): δ 1.32 (t, 3 H), 1.84 (br d, 2 H), 2.40-2.66 (m, 4 H), 3.13 (br d, 2 H), 3.31 (s, 2 H), 4.23 (q, 2 H), 4.45-4.49 (m, 1 H), 6.99-7.10 (m, 2 H), 7.12-7.19 (m, 1 H), 7.27-7.34 (m, 1 H) and 10.54 (br s, 1 H).
Reaction SMILES: [CH2:1]([S:3][C:4]1[N:5]=[C:6]([NH:9][C:10](=[O:38])[C@@H:11]([N:20]2[C:24](=[O:25])[C@@H:23]([C:26]3[CH:31]=[CH:30][C:29]([O:32][CH2:33][CH2:34][O:35][CH3:36])=[CH:28][CH:27]=3)[NH:22][C:21]2=[O:37])[C@H:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH3:13])[S:7][CH:8]=1)[CH3:2].ClC1C=CC=C(C(OO)=[O:47])C=1>O1CCCC1>[CH2:1]([S:3]([C:4]1[N:5]=[C:6]([NH:9][C:10](=[O:38])[C@@H:11]([N:20]2[C:24](=[O:25])[C@@H:23]([C:26]3[CH:31]=[CH:30][C:29]([O:32][CH2:33][CH2:34][O:35][CH3:36])=[CH:28][CH:27]=3)[NH:22][C:21]2=[O:37])[C@H:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH3:13])[S:7][CH:8]=1)=[O:47])[CH3:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCSc1csc(NC(=O)[C@H]([C@@H](C)c2ccccc2)N2C(=O)N[C@H](c3ccc(OCCOC)cc3)C2=O)n1
Solvent: C1CCOC1
Product: CCS(=O)c1csc(NC(=O)[C@H]([C@@H](C)c2ccccc2)N2C(=O)N[C@H](c3ccc(OCCOC)cc3)C2=O)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75.2 %

Procedure:
(2S,3S)-N-(4-Ethylsulfanyl-thiazol-2-yl)-2-{(R)-4-[4-(2-methoxy-ethoxy)-phenyl]-2,5-dioxo-imidazolidin-1-yl}-3-phenyl-butyramide (0.135 g, 0.24 mmole) (prepared as described in Example 16) was dissolved in anhydrous tetrahydrofuran (15 mL). To this solution was added a solution of m-chloroperbenzoic acid (0.066 g, 0.27 mmole) in tetrahydrofuran (8 mL). After stirring at room temperature for 30 minutes, the reaction was concentrated. The residue was dissolved in cold methylene chloride and washed twice with saturated sodium bicarbonate and twice with brine. Each aqueous phase was backwashed with a second portion of methylene chloride. The two organic phases were combined, dried over sodium sulfate and concentrated. The crude material was purified by chromatography over silica gel eluted with a gradient of 50-100% v/v ethyl acetate in hexanes followed by 5% v/v methanol in ethyl acetate to yield (2S,3S)-N-(4-ethanesulfinyl-thiazol-2-yl)-2-{(R)-4-[4-(2-methoxy-ethoxy)-phenyl]-2,5-dioxo-imidazolidin-1-yl}-3-phenyl-butyramide (0.103 g, 75%). This material was combined with another batch of material, dissolved in methylene chloride and added to hexanes to precipitate the product, (2S,3S)-N-(4-ethanesulfinyl-thiazol-2-yl)-2-{(R)-4-[4-(2-methoxy-ethoxy)-phenyl]-2,5-dioxo-imidazolidin-1-yl}-3-phenyl-butyramide (0.117 g).
Reaction SMILES: [Cl:1][C:2]1[C:12]([Cl:13])=[C:11]([C:14]([C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)=[O:15])[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C:6]([OH:8])=[O:7].O.[NH2:22][CH:23]([CH2:27][CH2:28][CH2:29][CH2:30][NH2:31])[C:24]([OH:26])=[O:25]>C(O)C>[Cl:1][C:2]1[C:12]([Cl:13])=[C:11]([C:14]([C:16]2[S:17][CH:18]=[CH:19][CH:20]=2)=[O:15])[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C:6]([OH:8])=[O:7].[NH2:22][C@H:23]([C:24]([OH:26])=[O:25])[CH2:27][CH2:28][CH2:29][CH2:30][NH2:31]
Reactant: NCCCCC(N)C(=O)O
Agent: O=C(O)COc1ccc(C(=O)c2cccs2)c(Cl)c1Cl
Solvent: O
Solvent: CCO
Product: NCCCC[C@H](N)C(=O)O
Reaction time: 0.17 h

Procedure:
16.55 g 2,3-Dichloro-4-(2-thienylcarbonyl)-phenoxyacetic acid and 35 ml water were added to a solution of 7.3 g 2,6-diaminohexanoic acid in 150 ml anhydrous ethanol at about 45° C. The reaction mixture was held at about 100° C. for 10 minutes and then the mixture was cooled. The cooled mixture was filtered to isolate 16 g precipitated salt. M.Pt. 225° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:8]([CH2:9][CH2:10][C:11]([O:13]CC)=[O:12])=[CH:7][N:6]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]3[N:26]=[C:27]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[O:28][C:29]=3[CH3:30])=[C:19]([O:37][CH2:38][CH3:39])[CH:18]=2)[N:5]=1)[CH3:2].[OH-].[Na+].O1CCCC1.Cl>C(O)C>[CH2:1]([O:3][C:4]1[C:8]([CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:7][N:6]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]3[N:26]=[C:27]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[O:28][C:29]=3[CH3:30])=[C:19]([O:37][CH2:38][CH3:39])[CH:18]=2)[N:5]=1)[CH3:2]
Reactant: CCOC(=O)CCc1cn(Cc2ccc(OCc3nc(-c4ccccc4)oc3C)c(OCC)c2)nc1OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOc1cc(Cn2cc(CCC(=O)O)c(OCC)n2)ccc1OCc1nc(-c2ccccc2)oc1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 90.4 %

Procedure:
After a mixture of ethyl 3-[3-ethoxy-1-[3-ethoxy-4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-1H-pyrazol-4-yl]propionate (544 mg), 1N aqueous sodium hydroxide solution (3 ml), tetrahydrofuran (6 ml) and ethanol (6 ml) was stirred at room temperature for 3 hours, 1N hydrochloric acid (3 ml) was added to the mixture, and then the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4) and concentrated. The resulting colorless crystals were collected by filtration to obtain 3-[3-ethoxy-1-[3-ethoxy-4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-1H-pyrazol-4-yl]propionic acid (466 mg, yield: 90%) This was recrystallized from ethanol-hexane. Melting point: 105–106° C.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:10]([NH:13][C:14]([NH2:16])=[O:15])=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH3:17][CH2:18][O:19][C:20]([CH:22]1[C:26](=O)[CH2:25][CH2:24][CH2:23]1)=[O:21].O>C1C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Cl:1][C:2]1[CH:12]=[CH:11][C:10]([NH:13][C:14]([NH:16][C:23]2[CH2:24][CH2:25][CH2:26][C:22]=2[C:20]([O:19][CH2:18][CH3:17])=[O:21])=[O:15])=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)c1cc(NC(N)=O)ccc1Cl
Reactant: CCOC(=O)C1CCCC1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: CCOC(=O)C1=C(NC(=O)Nc2ccc(Cl)c(C(=O)OCC)c2)CCC1

Procedure:
48.4 g of ethyl 2-chloro-5-ureido-benzoate and 31.2 g of ethyl cyclopentanone-2-carboxylate are heated at reflux temperature for 6 hours in 500 ml of benzene and 2 g of toluene-4-sulphonic acid monohydrate. The water formed is removed by means of a water separator. The reaction mixture is subsequently evaporated to dryness. the residue is dissolved in 700 ml of diethyl ether and the solution is filtered. The filtrate is evaporated to dryness and the residue is purified by chromatography on 1.5 kg of silica gel using diethyl ether/n-hexane (1:2) as the eluent. Ethyl 2-chloro-5-[3-(2-ethoxycarbonyl-1-cyclopenten-1-yl)-ureido]-benzoate is obtained as colourless crystals. The product is recrystallized from diethyl ether/n-hexane, m.p. 110°-112° C.
Reaction SMILES: [CH:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=O)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].C(N(CC)CC)C.C(OC(Cl)=O)C(C)C.[NH:28]([CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[NH2:29]>ClCCl.C1COCC1>[CH2:34]([O:33][C:31](=[O:32])[CH2:30][NH:28][NH:29][C:8](=[O:10])[C:7]1[CH:6]=[CH:5][C:4]([CH:1]([CH3:2])[CH3:3])=[CH:12][CH:11]=1)[CH3:35]
Reactant: CC(C)c1ccc(C(=O)O)cc1
Reactant: CCOC(=O)CNN
Agent: CC(C)COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCOC(=O)CNNC(=O)c1ccc(C(C)C)cc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 91.7 %

Procedure:
At 0° C., to a solution of 4-isopropylbenzoic acid (3.28 g, 20.0 mmol), triethylamine (2.12 g, 2.93 mL, 21.0 mmol) in dichloromethane/THF (15 mL/5 mL), is added isobutylchloroformate (2.87 g, 2.72 mL, 21.0 mmol). The mixture is stirred at 0° C. for 20 min. with warming to room temperature over 2 hr., and then treated with ethyl hydrazinoacetate (2.18 g, 21.0 mmol) and stirred overnight. The mixture is then washed with water, brine and dried over Na2SO4. The crude product obtained after the removal of the solvent is chromatographed (silica gel, 5:1 dichloromethane-ethyl acetate) to provide ethyl[2-(4-isopropylbenzoyl)hydrazino]acetate (4.85 g, 97%). MS (ES+): m/e 251.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([C:11](=[S:13])[NH2:12])[N:4]=1.Br[CH2:15][C:16](=O)[C:17]([F:20])([F:19])[F:18].CC[OH:24]>>[CH3:10][O:9][C:7]1([OH:24])[CH:8]=[C:3]([O:2][CH3:1])[N:4]=[C:5]([C:11]2[S:13][CH:15]=[C:16]([C:17]([F:20])([F:19])[F:18])[N:12]=2)[NH:6]1
Reactant: CCO
Reactant: O=C(CBr)C(F)(F)F
Reactant: COc1cc(OC)nc(C(N)=S)n1
Product: COC1=CC(O)(OC)NC(c2nc(C(F)(F)F)cs2)=N1
Temperature: 90 °C
Reaction time: 16 h
Yield: 12 %

Procedure:
To a solution of compound 287 (14 g, 1 eq.) in EtOH (140 mL) was added 3-bromo-1,1,1-trifluoroacetone (8.8 mL, 1.2 eq.). The mixture was stirred at 90° C. for 16 hrs and concentrated in vacuo. DCM (20 mL) and water (20 mL) were added. Organics were dried over Na2SO4, filtered, concentrated under reduced pressure, and flushed on a silica gel column with 5% MeOH/DCM to yield compound 288 as a beige compound in 12% yield. MS (ESI, EI+): m/z=292 (MH+).
Reaction SMILES: C1(OC)C=CC=CC=1.[C:9]([O:12][CH2:13][C:14]1[CH2:15][S:16][C@@H:17]2[C@H:37]([NH:38][C:39](=[O:49])[C:40](=[N:46][O:47][CH3:48])[C:41]3[O:42][CH:43]=[CH:44][CH:45]=3)[C:36](=[O:50])[N:18]2[C:19]=1[C:20]([O:22]C(C1C=CC=CC=1)C1C=CC=CC=1)=[O:21])(=[O:11])[NH2:10]>FC(F)(F)C(O)=O>[C:9]([O:12][CH2:13][C:14]1[CH2:15][S:16][C@@H:17]2[C@H:37]([NH:38][C:39](=[O:49])[C:40](=[N:46][O:47][CH3:48])[C:41]3[O:42][CH:43]=[CH:44][CH:45]=3)[C:36](=[O:50])[N:18]2[C:19]=1[C:20]([OH:22])=[O:21])(=[O:11])[NH2:10]
Reactant: CON=C(C(=O)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(COC(N)=O)CS[C@H]12)c1ccco1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CON=C(C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(COC(N)=O)CS[C@H]12)c1ccco1
Reaction time: 0.17 h
Yield: 97.2 %

Procedure:
Trifluoroacetic acid (20ml) was added slowly to a mixture of anisole (5ml) and diphenylmethyl 3-carbamoyloxymethyl-7β-[2-methoxyimino-2-(fur-2-yl)acetamido]-ceph-3-em-4-carboxylate (syn isomer) (4.7g, 8 mmole) which had been cooled in an ice-bath. The flask was shaken occasionally during the next 10 minutes to ensure complete solution of the solid. It was then removed from the ice-bath and excess trifluoroacetic acid was removed on a rotary-evaporator. Trituration of the residue with ethyl acetate (5ml) gave 3-carbamoyloxymethyl-7β-[2-methoxyimino-2-(fur-2-yl)acetamido]-ceph-3-em-4-carboxylic acid (syn isomer) (3.3g, 94%) as a solid which was filtered off and washed with diethyl ether.
Reaction SMILES: CN(C)C=O.[NH2:6][C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][N:8]=1.Br.Br[CH2:18][CH2:19][CH2:20][N:21]([CH2:24][CH3:25])[CH2:22][CH3:23].C(=O)([O-])[O-].[K+].[K+]>C(Cl)(Cl)Cl.O>[CH2:22]([N:21]([CH2:24][CH3:25])[CH2:20][CH2:19][CH2:18][NH:6][C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][N:8]=1)[CH3:23]
Reactant: Nc1n[nH]c2ccccc12
Reactant: CCN(CC)CCCBr
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCN(CC)CCCNc1n[nH]c2ccccc12
Temperature: 80 °C
Reaction time: 24 h
Yield: 64.7 %

Procedure:
To 80 ml of anhydrous N,N-dimethylformamide were added 5.0 g of 3-aminoindazole, 8.30 g of 3-bromopropyldiethylamine hydrobromide and 8.3 g of anhydrous potassium carbonate. The mixture was stirred for 24 hours at 80° C. and condensed under reduced pressure. The condensed residue was added with 100 ml of chloroform and 50 ml of water. The chloroform layer was dried over anhydrous sodium sulfate, and chloroform was removed under reduced pressure. The residue thus obtained was subjected to an alumina-column chromatography(alumina: 200 g) using chloroform as the development solvent to give 4.81 g of 3-(3-diethylaminopropylamino)indazole having the following analytical values in a yield of 52%.
Reaction SMILES: O.C([O:5][CH2:6][C:7]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:8]=1[O:9][C:10](=[CH:15][O:16][CH3:17])[C:11]([O:13][CH3:14])=[O:12])(=O)C.C(=O)([O-])[O-].[Na+].[Na+].C(OCC)(=O)C>CO>[OH:5][CH2:6][C:7]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:8]=1[O:9][C:10](=[CH:15][O:16][CH3:17])[C:11]([O:13][CH3:14])=[O:12]
Reactant: COC=C(Oc1ccc(Cl)cc1COC(C)=O)C(=O)OC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: O
Product: COC=C(Oc1ccc(Cl)cc1CO)C(=O)OC
Temperature: 25 °C
Yield: 84.5 %

Procedure:
Water was added to a solution of 1.42 g of methyl 2-(2-acetyloxymethyl-4-chlorophenoxy)-3-methoxyacrylate in methanol, and stirred at room temperature. Sodium carbonate (0.53 g) was added. After a further 0.5 hour water and ethyl acetate were added. The organic phase was dried with anhydrous sodium sulfate, evaporated and the residue purified by silica gel column chromatography to give methyl 2-(2-hydroxymethyl-4-chlorophenoxy)-3-methoxyacrylate (1.04 g).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:15]=[C:14]2[C:9]([C:10]([O:16][C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][C:18]=3[C:24]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:25])=[CH:11][CH:12]=[N:13]2)=[CH:8][C:7]=1[O:32][CH3:33].[CH3:34][N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:33][O:32][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][C:6]=1[O:5][CH2:4][CH2:3][CH2:2][N:38]1[CH2:39][CH2:40][N:35]([CH3:34])[CH2:36][CH2:37]1)[N:13]=[CH:12][CH:11]=[C:10]2[O:16][C:17]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][C:18]=1[C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:25]
Reactant: COc1cc2c(Oc3ccc(C)cc3C(=O)c3ccccc3)ccnc2cc1OCCCCl
Reactant: CN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc(C)cc3C(=O)c3ccccc3)ccnc2cc1OCCCN1CCN(C)CC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 69.8 %

Procedure:
(2-{[7-(3-Chloropropoxy)-6-methoxy-4-quinolyl]oxy}-5-methylphenyl)(phenyl)methanone (68 mg), 4-methylpiperazine (42 mg), and potassium carbonate (95 mg) were suspended in N,N-dimethylformamide (3 ml), and the suspension was stirred at 80° C. overnight. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using methanol-chloroform to give the title compound (54 mg, yield 75%).
Reaction SMILES: [N+:1]([O-])([O-])=O.[Na+].Cl.[F:7][C:8]1[CH:9]=[C:10]([CH:12]=[CH:13][C:14]=1[F:15])[NH2:11].[C:16]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])#[N:17].C([O-])(=O)C.[Na+]>CCO>[C:16]([CH:18]([N:1]=[N:11][C:10]1[CH:12]=[CH:13][C:14]([F:15])=[C:8]([F:7])[CH:9]=1)[C:19]([O:21][CH2:22][CH3:23])=[O:20])#[N:17]
Reactant: CCOC(=O)CC#N
Reactant: O=[N+]([O-])[O-]
Reactant: Nc1ccc(F)c(F)c1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(C#N)N=Nc1ccc(F)c(F)c1
Reaction time: 1.5 h

Procedure:
An aqueous solution of sodium nitrate was added dropwise to an aqueous hydrochloric acid solution of 3,4-difluoroaniline under ice cooling, for stirring at the same temperature for 1.5 hours. The resulting reaction mixture was added dropwise to an aqueous EtOH solution of ethyl cyanoacetate and sodium acetate as prepared in a separate reaction flask, for stirring at ambient temperature for 2 hours, to obtain ethyl cyano[(3,4-difluorophenyl)diazenyl]acetate.
Reaction SMILES: [CH3:1][CH:2]([CH3:38])[C@H:3]([NH:33][C:34](=[O:37])[O:35][CH3:36])[C:4](=[O:32])[N:5]1[CH2:9][CH2:8][CH2:7][C@H:6]1[C:10]1[NH:14][C:13]2[C:15]3[C:20]([CH:21]=[CH:22][C:12]=2[N:11]=1)=[CH:19][C:18](B1OC(C)(C)C(C)(C)O1)=[CH:17][CH:16]=3.[Br:39][C:40]1[CH:41]=[CH:42][C:43]2[CH:47]=[C:46](I)[S:45][C:44]=2[CH:49]=1.C([O-])([O-])=O.[K+].[K+]>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:39][C:40]1[CH:41]=[CH:42][C:43]2[CH:47]=[C:46]([C:18]3[CH:19]=[C:20]4[C:15](=[CH:16][CH:17]=3)[C:13]3[NH:14][C:10]([C@@H:6]5[CH2:7][CH2:8][CH2:9][N:5]5[C:4](=[O:32])[C@@H:3]([NH:33][C:34](=[O:37])[O:35][CH3:36])[CH:2]([CH3:38])[CH3:1])=[N:11][C:12]=3[CH:22]=[CH:21]4)[S:45][C:44]=2[CH:49]=1
Reactant: Brc1ccc2cc(I)sc2c1
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc2ccc3cc(B4OC(C)(C)C(C)(C)O4)ccc3c2[nH]1)C(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc2ccc3cc(-c4cc5ccc(Br)cc5s4)ccc3c2[nH]1)C(C)C
Temperature: 85 °C
Yield: 152.1 %

Procedure:
To a solution of methyl (S)-3-methyl-1-oxo-1-((S)-2-(7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-naphtho[1,2-d]imidazol-2-yl)pyrrolidin-1-yl)butan-2-ylcarbamate (251 mg, 0.48 mmol) in DME (5 mL) was added 6-bromo-2-iodobenzo[b]thiophene (82 mg, 0.24 mmol), Pd(PPh3)4 (28 mg, 0.024 mmol), and K2CO3 (2M in H2O, 0.8 mL, 1.58 mmol). The solution was degassed with N2 for 10 min, then heated to 85° C. for 24 h. The mixture was cooled to rt, diluted with EtOAc, and washed with sat. NaHCO3, brine, dried with MgSO4, and concentrated. The residue was purified by silica gel chromatography to yield product (221 mg).