Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:10][CH2:9][O:8][C:7]2[CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=[CH:14][C:6]1=2)=[O:4].C([O-])([O-])=O.[K+].[K+].Cl.[CH2:25]([NH2:27])[CH3:26]>C(#N)C>[CH2:25]([NH:27][CH2:2][C:3]([N:5]1[CH2:10][CH2:9][O:8][C:7]2[CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=[CH:14][C:6]1=2)=[O:4])[CH3:26]
Reactant: O=C(CCl)N1CCOc2cc([N+](=O)[O-])ccc21
Reactant: CCN
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCNCC(=O)N1CCOc2cc([N+](=O)[O-])ccc21
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 75.5 %

Procedure:
A solution of 2-chloro-1-(7-nitro-2H-benzo[b][1,4]oxazin-4(3H)-yl)ethanone (9.9 g, 38.6 mmol) in anhydrous acetonitrile (250 mL) under positive argon pressure was treated with K2CO3 (42.7 g, 309 mmol) to give a yellow suspension. The mixture was cooled to 0° C. and treated with ethanamine hydrochloride (15.7 g, 193 mmol). The reaction was brought to room temperature and stirred for 2.5 hours. The mixture was then filtered through a pad of Celite, washed with CH2Cl2 (500 mL), and concentrated. The residue was subjected to flash chromatography on silica gel using EtOAc, followed by 2.5:97.5 (2M NH3 in MeOH):CH2Cl2 to give a yellow solid (7.73 g, 76%). 1H-NMR (DMSO-d6) δ 8.29 (d, J=9.0 Hz, 1H), 7.80 (dd, J=2.7, 9.3 Hz, 1H), 7.71 (d, J=2.7 Hz, 1H), 4.36 (t, J=4.2 Hz, 2H), 3.93 (t, J=4.8 Hz, 2H), 3.71 (s, 2H), 2.62 (q, J=7.2 Hz, 2H), 1.05 (t, J=7.2 Hz, 3H). ESI-MS (m/z, %): 266.1 (MH+, 100).
Reaction SMILES: [I:1][C:2]1[CH:19]=[CH:18][C:5]([NH:6][C:7]2[S:8][C:9]3[N:17]=[CH:16][CH:15]=[CH:14][C:10]=3[C:11](=[O:13])[N:12]=2)=[CH:4][CH:3]=1.[H-].[Li+].[CH2:22](Br)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH2:22]([N:12]1[C:11](=[O:13])[C:10]2[CH:14]=[CH:15][CH:16]=[N:17][C:9]=2[S:8][C:7]1=[N:6][C:5]1[CH:18]=[CH:19][C:2]([I:1])=[CH:3][CH:4]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=c1nc(Nc2ccc(I)cc2)sc2ncccc12
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Li+]
Product: O=c1c2cccnc2sc(=Nc2ccc(I)cc2)n1Cc1ccccc1
Yield: 61 %

Procedure:
The reaction procedure of Example 11 was followed except that 901 mg (2.36 mmol) of 2-(4-iodoanilino)-4H-pyrido[3,2-e]-1,3-thiazin-4-one, 23 mg of lithium hydride and 458 mg of benzyl bromide were used. The resulting residue was then purified through silica gel column chromatography (eluant: chloroform) to obtain 678 mg of 3-benzyl-2,3-dihydro-2-[(4-iodophenyl)imino]-4H-pyrido[3,2-e]-1,3-thiazin-4-one (61%, recrystallized from a mixture of ether and hexane).
Reaction SMILES: [OH-].[Na+].[N+:3]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[CH:7]=1)([O-:5])=[O:4].[C:15]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([CH3:28])([CH3:27])[CH3:26])[C:20]=1[OH:29])([CH3:18])([CH3:17])[CH3:16].Cl>CS(C)=O>[C:25]([C:21]1[CH:22]=[C:23]([C:9]2[CH:10]=[CH:11][C:6]([N+:3]([O-:5])=[O:4])=[CH:7][C:8]=2[N+:12]([O-:14])=[O:13])[CH:24]=[C:19]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:20]=1[OH:29])([CH3:28])([CH3:27])[CH3:26]
Reactant: CC(C)(C)c1cccc(C(C)(C)C)c1O
Reactant: O=[N+]([O-])c1cccc([N+](=O)[O-])c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CC(C)(C)c1cc(-c2ccc([N+](=O)[O-])cc2[N+](=O)[O-])cc(C(C)(C)C)c1O
Temperature: 80 °C
Yield: 40.5 %

Procedure:
A mixture of 30 mg (0.75 mmol) of powdered sodium hydroxide, 100 mg (0.59 mmol) of 1,3-dinitrobenzene, 155 mg (0.75 mmol) of 2,6-di-t-butylphenol, and 1.0 mL of dimethylsulfoxide was heated at 80° C. for one hour and poured into 10 mL of 1N HCl, and the resulting aqueous mixture was extracted with three 10 mL portions of diethyl ether. The ether layers were combined, dried over magnesium sulfate, and concentrated. Purification of the residue by preparative thin layer chromatography (PTLC) and crystallization afforded 89 mg (40% yield) of 2,6-di-t-butyl-4-(2',4'-dinitrophenyl)phenol.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:3][CH2:2]1.[CH3:21][CH:22]([CH3:32])[CH2:23][CH:24]([C:26]1[N:27]=[N:28][CH:29]=[CH:30][CH:31]=1)[NH2:25]>>[CH3:21][CH:22]([CH3:32])[CH2:23][CH:24]([NH:25][C:12]([C:10]1[CH:9]=[CH:8][C:7]([N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)=[C:6]([O:5][CH2:4][CH:1]2[CH2:2][CH2:3]2)[N:11]=1)=[O:14])[C:26]1[N:27]=[N:28][CH:29]=[CH:30][CH:31]=1
Reactant: CC(C)CC(N)c1cccnn1
Reactant: O=C(O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Product: CC(C)CC(NC(=O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1)c1cccnn1

Procedure:
In analogy to the procedure described in Example 293, 6-(cyclopropylmethoxy)-5-(3,3-difluoroazetidin-1-yl)picolinic acid (Example 69 b) and 3-methyl-1-(pyridazin-3-yl)butan-1-amine were condensed to the title product. MS (EI): m/e=432.4 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][N:14]=[CH:13][C:12]=2[C:17](OC)=[O:18])=[O:9])=[CH:6][C:5]([C:21]2[S:22][C:23]([CH2:26][N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)=[CH:24][CH:25]=2)=[CH:4][N:3]=1.[CH3:33][NH2:34]>C1COCC1>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:21]2[S:22][C:23]([CH2:26][N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)=[CH:24][CH:25]=2)=[CH:6][C:7]=1[C:8]([NH:10][C:11]1[CH:16]=[CH:15][N:14]=[CH:13][C:12]=1[C:17](=[O:18])[NH:34][CH3:33])=[O:9]
Reactant: COC(=O)c1cnccc1NC(=O)c1cc(-c2ccc(CN3CCOCC3)s2)cnc1N
Reactant: CN
Solvent: C1CCOC1
Product: CNC(=O)c1cnccc1NC(=O)c1cc(-c2ccc(CN3CCOCC3)s2)cnc1N
Temperature: 25 °C
Reaction time: 2 h

Procedure:
100 mg of methyl 4-[[2-amino-5-[5-(morpholinomethyl)-2-thienyl]pyridine-3-carbonyl]amino]pyridine-3-carboxylate (MSC 2392368) are dissolved in 4 ml THF and 4 ml of methylamine (40% in water) are added. The mixture is stirred for 2 h at room temperature. The mixture is evaporated and treated with petrol ether and ethyl acetate. After filtration 79 mg of a yellow solid is obtained;
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1.[O:10]=[CH:11][C:12]1[CH:20]=[CH:19][C:17](O)=[C:14]([O:15][CH3:16])[CH:13]=1>>[CH3:16][O:15][C:14]1[CH:13]=[C:12]([CH:20]=[CH:19][C:17]=1[O:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1)[CH:11]=[O:10]
Reactant: OCCN1CCOCC1
Reactant: COc1cc(C=O)ccc1O
Product: COc1cc(C=O)ccc1OCCN1CCOCC1

Procedure:
3-Methoxy-4-(2-morpholin-4-yl-ethoxy)-benzaldehyde was prepared from N-(2-hydroxyethyl)morpholine (Aldrich) and vanillin (Aldrich) by method H above.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].CON(C)[C:10]([CH:12]1[CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])[CH2:13]1)=[O:11]>C1COCC1>[CH:10]([CH:12]1[CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20][CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[O:19])[CH2:13]1)=[O:11]
Reactant: CON(C)C(=O)C1CCCN(C(=O)OCc2ccccc2)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O=CC1CCCN(C(=O)OCc2ccccc2)C1
Reaction time: 0.75 h
Yield: 14.9 %

Procedure:
To a cooled (−78° C.) suspension of lithium aluminum hydride (0.70 g, 18.4 mmol) in dry THF (100 mL) under an argon atmosphere was added dropwise a solution of benzyl 3-{[methoxy(methyl)amino]carbonyl}-1-piperidinecarboxylate (4.5 g, 14.7 mmol) in THF (30 mL), and the stirring was continued at −78° C. for 45 min. The reaction mixture was quenched with 0.5N KHSO4 (130 mL), and then extracted with ether. The separated organic phase was dried over MgSO4, filtered, and concentrated under reduced pressure to give benzyl 3-formyl-1-piperidinecarboxylate as a colorless oil (0.54 g, yield; 82%).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N+:9]([O-])=O)[CH3:2].[C:12]([Mg]Br)([CH3:14])=[CH2:13].[Na+].[Cl-]>C1COCC1>[CH3:14][C:12]1[NH:9][C:4]2[C:5]([CH:13]=1)=[CH:6][CH:7]=[CH:8][C:3]=2[CH2:1][CH3:2]
Reactant: CCc1ccccc1[N+](=O)[O-]
Reactant: C=C(C)[Mg]Br
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCc1cccc2cc(C)[nH]c12
Temperature: -20 °C
Reaction time: 2 h

Procedure:
A solution of 36.5 g of 2-ethylnitrobenzene in 250 ml of THF is added dropwise at −20° C. to 1.6 l of 0.5M isopropenylmagnesium bromide in THF. The reaction medium is maintained at −20° C. with stirring for 2 hours and then the medium is poured onto 800 ml of saturated NaCl solution. The mixture is allowed to separate by settling and then extraction is carried out with ether. The ether extract is dried and evaporated and then the residue is chromatographed on silica while eluting with an AcOEt/cyclohexane (1/9, v/v) mixture. 23.75 g of the expected compound are obtained.
Reaction SMILES: [OH-].[Na+].C(#N)C.[NH2:6][C:7]1[NH:8][C:9]2[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=2[N:11]=1.[CH3:16][N:17]([CH3:22])[S:18](Cl)(=[O:20])=[O:19]>O>[CH3:16][N:17]([CH3:22])[S:18]([C:12]1[C:10]2[NH:11][C:7]([NH2:6])=[N:8][C:9]=2[CH:15]=[CH:14][CH:13]=1)(=[O:20])=[O:19]
Reactant: Nc1nc2ccccc2[nH]1
Reactant: CN(C)S(=O)(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Product: CN(C)S(=O)(=O)c1cccc2nc(N)[nH]c12
Temperature: 25 °C
Yield: 92.5 %

Procedure:
To a solution of sodium hydroxide (1.8 g) in water (9 mL) add acetonitrile (44 mL). To this solution, add 2-aminobenzimidazole (3.0 g, 22.5 mmol) and dimethylsulfamoyl chloride (2.4 mL, 22.5 mmol). Stir the reaction mixture at room temperature, overnight. Then, cool the mixture at 0° C. and the product crystallized from solution. Filter the product and dry it in vacuum to provide 5.0 g (90% yield) of the title compound as a white solid. MS (ES+): m/z=241.1 (M+H)+
Reaction SMILES: [NH2:1][C@H:2]([C:6]([OH:8])=[O:7])[CH:3]([CH3:5])[CH3:4].[OH-].[Na+].[C:11]1([CH2:17][C:18](Cl)=[O:19])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[C:11]1([CH2:17][C:18]([NH:1][C@H:2]([C:6]([OH:8])=[O:7])[CH:3]([CH3:5])[CH3:4])=[O:19])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: CC(C)[C@H](N)C(=O)O
Agent: [Na+]
Agent: [OH-]
Product: CC(C)[C@H](NC(=O)Cc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 18 h
Yield: 75 %

Procedure:
To a stirred solution of 5.15 g (44 mmol) of valine (Bachem) in 50 mL (100 mmol) of 2N NaOH cooled to 0° C. was added dropwise 5.3 mL (40 mmol) of phenylacetyl chloride (Aldrich). A colorless oil precipitated. The reaction mixture was allowed to warm to room temperature and stirred for 18 hours, washed with 50 mL diethyl ether, acidified to pH 2-3 with aqueous HCl. The white precipitate formed was filtered off, washed thoroughly with water, followed by diethyl ether to give 7.1 g (30 mmol, 69% yield) of the title compound.
Reaction SMILES: [C:1]([NH:4][CH2:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[CH:8][CH:7]=1)(=[O:3])[CH3:2].Cl.[CH3:16]O>>[C:1]([NH:4][CH2:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([O:12][CH3:16])=[O:11])=[CH:8][CH:7]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)NCc1ccc(C(=O)O)cc1
Reactant: CO
Agent: Cl
Product: COC(=O)c1ccc(CNC(C)=O)cc1
Temperature: 40 °C
Reaction time: 3.5 h

Procedure:
4-Acetamidomethylbenzoic acid (4.0 g) was dissolved in 0.5% hydrogen chloride-methanol solution (100 ml). The mixture was stirred at 40° C. for 3.5 hr and poured into ice water (300 ml) and extracted with ethyl acetate. The extract was washed with a saturated aqueous sodium hydrogencarbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated to give a pale-yellow solid (4.3 g). The obtained solid was crystallized from ethyl acetate (50 ml) to give the title compound (3.2 g) as a pale-yellow white crystals, m.p.=110-111° C.
Reaction SMILES: [Si]([O:8][C:9]1[CH:14]=[CH:13][C:12]([S:15]([C:18]2[CH:31]=[CH:30][C:21]3[O:22][C:23]([CH3:29])([CH3:28])[C@@:24]4([CH3:27])[O:26][C@H:25]4[C:20]=3[CH:19]=2)(=[O:17])=[O:16])=[CH:11][CH:10]=1)(C(C)(C)C)(C)C.[CH3:32][N:33]1[C:38](=[O:39])[CH:37]=[CH:36][C:35]([OH:40])=[N:34]1.N1C=CC=CC=1>O1CCOCC1>[CH3:32][N:33]1[C:38](=[O:39])[CH:37]=[CH:36][C:35]([O:40][C@H:25]2[C@@:24]([OH:26])([CH3:27])[C:23]([CH3:28])([CH3:29])[O:22][C:21]3[CH:30]=[CH:31][C:18]([S:15]([C:12]4[CH:11]=[CH:10][C:9]([OH:8])=[CH:14][CH:13]=4)(=[O:16])=[O:17])=[CH:19][C:20]2=3)=[N:34]1
Reactant: CC1(C)Oc2ccc(S(=O)(=O)c3ccc(O[Si](C)(C)C(C)(C)C)cc3)cc2[C@@H]2O[C@@]21C
Reactant: Cn1nc(O)ccc1=O
Solvent: C1COCCO1
Solvent: c1ccncc1
Product: Cn1nc(O[C@@H]2c3cc(S(=O)(=O)c4ccc(O)cc4)ccc3OC(C)(C)[C@@]2(C)O)ccc1=O
Yield: 21.2 %

Procedure:
(3S,4S)-6-(4-tert-Butyidimethylsilyloxyphenyl)sulphonyl-3,4-dihydro-3,4-epoxy-2,2,3-trimethyl-2H-benzo[b]pyran (1.618 g) (see Preparation 14) and 2,3-dihydro-2-methyl-3-oxo-6-hydroxypyridazine (1.33 g) (see J.Org.Chem, 1971, 36, 3372) were suspended in dry 1,4-dioxane (15 ml), pyridine (0.275 ml) was added and the mixture was heated under reflux (a calcium chloride drying tube was attached to the flask) for 3 days. The solvent was removed under reduced pressure and the residue was partitioned between ethyl acetate and water. The organic phase was separated and dried (anhydrous sodium sulphate), the solvent was removed under reduced pressure and the crude product was chromatographed on silica using. 1:99 methanol: ethyl acetate as the eluent to yield (3S,4R)-3,4-dihydro-4-(2,3-dihydro-2-methyl-3-oxopyridazin-6-yl)oxy-3-hydroxy-6-(4-hydroxyphenyl)sulphonyl-2,2,3-trimethyl-2H-benzo[b]pyran (0.352 g) as a white solid. Found: C,58.13; H,5.00; N,5.70. C23H24N2O7S requires C,58.46; H,5.12; N,5.93%.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[C@H:5]([CH2:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[NH2:6])[CH3:2].[NH2:15][C:16]1[NH:25][C:24](=[O:26])[C:23]2[C:22]3[CH:27]=[C:28]([NH:31][S:32]([C:35]4[CH:43]=[CH:42][C:38]([C:39](O)=[O:40])=[CH:37][CH:36]=4)(=[O:34])=[O:33])[CH:29]=[CH:30][C:21]=3[CH:20]=[CH:19][C:18]=2[N:17]=1.O.ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O>[NH2:15][C:16]1[NH:25][C:24](=[O:26])[C:23]2[C:22]3[CH:27]=[C:28]([NH:31][S:32]([C:35]4[CH:43]=[CH:42][C:38]([C:39]([NH:6][C@H:5]([C:4]([O:3][CH2:1][CH3:2])=[O:14])[CH2:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:40])=[CH:37][CH:36]=4)(=[O:34])=[O:33])[CH:29]=[CH:30][C:21]=3[CH:20]=[CH:19][C:18]=2[N:17]=1
Reactant: Nc1nc2ccc3ccc(NS(=O)(=O)c4ccc(C(=O)O)cc4)cc3c2c(=O)[nH]1
Reactant: CCOC(=O)CC[C@H](N)C(=O)OCC
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CC[C@H](NC(=O)c1ccc(S(=O)(=O)Nc2ccc3ccc4nc(N)[nH]c(=O)c4c3c2)cc1)C(=O)OCC
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of L-glutamic acid diethyl ester (0.81 g, 4.0 mmoles) and 4-(((3-amino-1,2-dihydro-1-oxobenzo[f]quinazolin-9-yl)amino)sulfonyl)benzoic acid (0.43 g, 0.9 mmoles) in dry dimethylformamide (20 ml) was added 1-hydroxybenzotriazole monohydrate (0.43 g, 3.2 mmoles) and dicyclohexylcarbodiimide (0.66 g, 3.2 mmoles). The solution was stirred at room temperature under a nitrogen atmosphere for 20 hrs, after which time the solvent was removed under reduced pressure. The residue was recrystallized successively from methylene chloride:methanol/9:1 and methanol to give diethyl N-(4-(((3-amino-1,2-dihydro-1-oxobenzo[f]quinazolin-9-yl)amino)sulfonyl)benzoyl)-L-glutamate as a white solid. (0.215 g, 36%). 1HNMR(DMSO-d6, 300 MHz) δ: 1.12(t, J=7 Hz, 3H, ester-CH3); 1.15(t, J=7 Hz, 3H, ester-CH3); 1.89-2.13(m, 2H, glu-CH2); 2.40(t, J=7.6 Hz, 2H, glu-CH2); 4.00(q, J=7 Hz, 2H, ester-CH2); 4.08(q, J=7 Hz, 2H, ester-CH2); 6.55(br s, 2H, NH2); 7.16(d, J=8.9 Hz, 1H, Ar); 7.23(dd, J=8.7, 2 Hz, 1H, Ar); 7.73(d, J=8.7 Hz, 1H, Ar); 7.89(d, J=8.9 Hz, 1H, Ar); 7.96(m, 4H, Ar); 8.89(d, J=7.4 Hz, 1H, glu-NH); 9.48(d, J=2 Hz, 1H, Ar); 10.67(s, 1H, NH); 11.08(s, 1H, NH). Anal. Calculated for C28H29N5O8S: C, 56.46; H, 4.91; N, 11.7.6; S, 5.38. Found: C, 56.45; H, 4.94; N, 11.75; S, 5.43.
Reaction SMILES: C([Li])CCC.[CH3:6][P:7](=[O:12])([O:10][CH3:11])[O:8][CH3:9].O1CCCC1.[CH3:18][CH:19]([CH2:25][CH2:26][CH2:27][CH3:28])[C:20](OCC)=[O:21]>C(O)(=O)C>[O:21]=[C:20]([CH:19]([CH3:18])[CH2:25][CH2:26][CH2:27][CH3:28])[CH2:6][P:7](=[O:12])([O:10][CH3:11])[O:8][CH3:9]
Reactant: CCCCC(C)C(=O)OCC
Reactant: COP(C)(=O)OC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCCCC(C)C(=O)CP(=O)(OC)OC

Procedure:
n-Butyllithium (150 ml.) is added slowly to a solution of dimethyl methylphosphonate (25.6 g.) in 475 ml. of tetrahydrofuran (THF) at about -65° C. To the mixture is added a solution of racemic ethyl 2-methylhexanoate (18.4 g.) in 50 ml. of THF, and the resulting mixture is stirred at -70° C. for 2 hrs. Then, 16 ml. of acetic acid is added, and the mixture is concentrated under reduced pressure. The residue is mixed with dichloromethane (about 400 ml.) and water (about 50 ml.), shaken, and separated. The organic phase is dried over magnesium sulfate and concentrated. Distillation yields the title compound, 16.7 g., b.p. 126°-129° C./1 mm.
Reaction SMILES: [ClH:1].[NH2:2][CH:3]([CH2:7][NH2:8])[C:4]([OH:6])=[O:5].Cl.[CH3:10]O>>[ClH:1].[ClH:1].[CH3:10][O:5][C:4](=[O:6])[CH:3]([NH2:2])[CH2:7][NH2:8]
Reactant: CO
Reactant: NCC(N)C(=O)O
Agent: Cl
Product: COC(=O)C(N)CN
Temperature: 0 °C
Reaction time: 48 h

Procedure:
2,3-Diaminopropionic acid monohydrochloride (2.0 g, 14.3 mmol) is suspended in dry methanol (80 ml) and cooled on 0° C. Dry HCl gas is introduced into the solution for 30 min. Stirring is carried out at room temperature for 48 h, and the solvent is then removed in vacuo. The desired compound is obtained as a colorless solid and used directly for the next reaction.
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:5]2[C:6]([CH3:12])=[C:7]([C:9]([OH:11])=[O:10])[O:8][C:4]=2[CH:3]=1.O=S(Cl)Cl.[CH3:19]O>>[Br:1][C:2]1[CH:14]=[CH:13][C:5]2[C:6]([CH3:12])=[C:7]([C:9]([O:11][CH3:19])=[O:10])[O:8][C:4]=2[CH:3]=1
Reactant: CO
Reactant: Cc1c(C(=O)O)oc2cc(Br)ccc12
Solvent: O=S(Cl)Cl
Product: COC(=O)c1oc2cc(Br)ccc2c1C
Temperature: 25 °C

Procedure:
To a suspension of 6-bromo-3-methylbenzofuran-2-carboxylic acid (5 g, 19.6 mmol) in 196 mL of MeOH was added SOCl2 (2.9 mL, 39.2 mmol). After the mixture was heated to reflux for 1 hr, the reaction solution became clear, and the color changed to green. The mixture was concentrated to remove part of solvent, and the color of the solution changed to yellow. After cooling to room temperature a white PPT formed, and the suspension was filtered, and the solid was washed with small amounts of EtOAc. The solid was dried under vacuum at 50° C. to give pure methyl 6-bromo-3-methylbenzofuran-2-carboxylate (3.56 g). LCMS retention time=1.58 minutes (LC method 3); MS (m+1)=270.9. 1H NMR (400 MHz, CHLOROFORM-d) δ 2.59 (s, 3H), 3.99 (s, 3H), 7.41-7.47 (m, 1H), 7.48-7.53 (m, 1H), 7.72 (d, J=1.5 Hz, 1H).
Reaction SMILES: [F:1][C:2]([F:16])([CH2:12][CH2:13][CH2:14][CH3:15])[C:3](=[O:11])[CH2:4]P(=O)(OC)OC.O.[OH-].[Li+].[C:20]([O:23][C@@H:24]1[C@H:28]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]([O:37][CH3:38])=[O:36])[C@@H:27]([CH:39]=O)[C@H:26]([O:41][CH:42]2[CH2:47][CH2:46][CH2:45][CH2:44][O:43]2)[CH2:25]1)(=[O:22])[CH3:21]>O1CCOCC1.O>[C:20]([O:23][C@@H:24]1[C@H:28]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]([O:37][CH3:38])=[O:36])[C@@H:27](/[CH:39]=[CH:4]/[C:3](=[O:11])[C:2]([F:1])([F:16])[CH2:12][CH2:13][CH2:14][CH3:15])[C@H:26]([O:41][CH:42]2[CH2:47][CH2:46][CH2:45][CH2:44][O:43]2)[CH2:25]1)(=[O:22])[CH3:21]
Reactant: COC(=O)CCCCCC[C@@H]1[C@@H](C=O)[C@H](OC2CCCCO2)C[C@@H]1OC(C)=O
Reactant: CCCCC(F)(F)C(=O)CP(=O)(OC)OC
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CCCCC(F)(F)C(=O)/C=C/[C@@H]1[C@@H](CCCCCCC(=O)OC)[C@@H](OC(C)=O)C[C@H]1OC1CCCCO1
Temperature: 25 °C
Reaction time: 1.2 h
Yield: 55.8 %

Procedure:
To a solution of dimethyl (3,3-difluoro-2-oxoheptyl)phosphonate (1) (1.052 g, 4.074 mmol) in 1,4-dioxane (16 ml), lithium hydroxide monohydrate (0.160 g, 3.81 mmol) was added and stirred for approximately 1.2 hours at room temperature. A solution of methyl 7-[(1R,2R,3R,5S)-5-acetoxy-2-formyl-3-(2-tetrahydropyranyloxy)cyclopentyl]heptanate (2) (0.902 g, 2.26 mmol) in 1,4-dioxane (3 ml) and water (0.57 ml) were added thereto, and the mixed solution was heat refluxed for approximately 48 hours. After cooling to room temperature, approximately half of the solvent was evaporated under reduced pressure. Ethyl acetate and water were added to the residue and the solution was stirred, let to stand and then separated into two layers. The aqueous layer was extracted twice with ethyl acetate. The organic layers were combined, sequentially washed with 3% aqueous sodium chloride and saturated aqueous sodium chloride, and then dried with anhydrous magnesium sulfate. After concentration under reduced pressure, the residue was purified by silica gel column chromatography (Fuji Silysia BW-300SP: 36 g; ethyl acetate:hexane=1:4). The fractions containing impurities were re-purified by silica gel column chromatography (Fuji Silysia BW-300SP: 6 g; ethyl acetate:hexane=1:4) to give methyl 7-[(1R,2R,3R,5S)-5-acetoxy-2-((E)-4,4-difluoro-3-oxo-1-octenyl)-3-(2-tetrahydropyranyloxy)cyclopentyl]heptanate (3) (0.671 g; 1.26 mmol; yield: 55.9%).
Reaction SMILES: [H-].[Na+].[CH:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[CH2:13][C:14]#[N:15].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>COCCOC>[CH:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[CH:13]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:14]#[N:15]
Reactant: N#CCc1ccc2ccccc2c1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: N#CC(Cc1ccccc1)c1ccc2ccccc2c1
Temperature: 25 °C
Yield: 39.9 %

Procedure:
To a refluxing solution of NaH (3.00 g, 75 mmol, 60% dispersion) in DME (150 mL) was added a solution of 2-naphthaleneacetonitrile (12.5 g, 75 mmol) and benzyl bromide (12.8 g, 75 mmol) in DME (75 mL) dropwise over 50 minutes. The resulting solution was kept at reflux for 3 hours and then cooled to room temperature. The volatiles were removed in vacuo and the residue was partitioned between Et2O (100 mL) and H2O (100 mL). The aqueous phase was washed with Et2O (1×150 mL), the organics were dried (MgSO4) and concentrated in vacuo. This residue was purified by preparative HPLC (SiO2 : gradient hexane/EtOAc) to give the title compound as a white solid (7.71 g, 40%).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:3]=1[CH2:4]O.[CH3:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH2:19][C:20](O)=[O:21]>CO>[Cl:10][C:8]1[CH:9]=[C:2]2[C:3]([CH:4]=[C:19]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[O:12][CH3:11])[C:20](=[O:21])[NH:1]2)=[CH:6][CH:7]=1
Reactant: COc1ccccc1CC(=O)O
Reactant: Nc1cc(Cl)ccc1CO
Solvent: CO
Product: COc1ccccc1-c1cc2ccc(Cl)cc2[nH]c1=O

Procedure:
2-Amino-4-chlorobenzyl alcohol (2 g, 12.86 mmol) and 2-methoxyphenylacetic acid (4.70 g, 28.3mol) were reacted in a similar manner as described in Example 19 to give 7-chloro-3-(2-methoxyphenyl)-2(1H)-quinolone as fine white needles mp 235°-236° C. (MeOH). (Found: C, 67.49; H, 4.22; N, 4.93. C16H12ClNO2 requires C, 67.26; H, 4.23; N, 4.90%); δH (360 MHz, d6 -DMSO) 3.73 (1H, s, CH3) 6.97 (1H, dt, J=0.8 and 7.4 Hz, 5'-H) 7.08 (1H, d, J=8.3 Hz, 3'-H) 7.22 (1H, dd, J=8.4 and 2.1 Hz, 6-H) 2.27 (1H, dd, J=7.5 and 1.7 Hz, 6'-H) 7.34 (1H, d, J=1.8 Hz, 8-H) 7.37 (1H, dt, J=1.7 and 8.2 Hz, 4'-H) 7.70 (1H, d, J=8.4 Hz, 5-H) 7.87 (1H, s, 4-H) 11.87 (1H, br s, NH); m/z (EI+) 285 (M+). The quinolone (300 mg) and boron tribromide (3.15 ml, 1N solution in CH2Cl2) were reacted as described in Example 20 to give 286 mg of 7-chloro-3-(2-hydroxyphenyl)-2(1H)-quinolone as a yellow crystalline solid; mp 246°-248° C. (dec) (methanol). (Found: C, 66.43; H, 3.70; N, 5.17. C15H10ClNO2 requires C, 66.31; H, 3.71; N, 5.15%); δH (360 MHz, DMSO-d6) 6.87 (1H, t, J=8.2 Hz, 5'-H), 6.90 (1H, d, J=7.8 Hz, 3'-H), 7.22 (1H, dt, J=1.7 and 7.8 Hz, 4'-H), 7.26 (1H, dd, J=8.4 and 2.1 Hz, 6-H), 7.31 (1H, dd, J=8.2 and 1.7 Hz, 6'-H), 7.39 (1H, d, J=2.1 Hz, 8-H), 7.77 (1H, d, J=8.4 Hz, 5-H), 8.03 (1H, s, 4-H), 9.56 (1H, br s, OH), 12.14 (1H, br s, NH); m/z (EI+) 271 (M+).