Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].Br[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]3[O:17][CH2:18][O:19][C:13]=3[CH:12]=2)=[CH:7][CH:6]=1.[OH2:20].[ClH:21].[CH3:22][N:23]([CH:25]=O)[CH3:24]>CC(C)=O.CCOCC>[ClH:21].[O:17]1[C:14]2[CH:15]=[CH:16][C:11]([C:8]3[CH:9]=[CH:10][C:5]([CH2:4][O:20][CH:4]4[CH:5]5[CH2:10][CH2:22][N:23]([CH2:24][CH2:6]5)[CH2:25]4)=[CH:6][CH:7]=3)=[CH:12][C:13]=2[O:19][CH2:18]1
Reactant: O
Reactant: BrCc1ccc(-c2ccc3c(c2)OCO3)cc1
Reactant: CN(C)C=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CCOCC
Product: c1cc(-c2ccc3c(c2)OCO3)ccc1COC1CN2CCC1CC2
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a suspension of 0.14 g (3.44 m mole) of 60% sodium hydride in 20 ml of anhydrous DMF is added a solution of 0.48 g (3.44 m mole) of 3-quinuclidinol borane complex in 10 ml of DMF dropwise over 3 minutes. The mixture is stirred at room temperature for 15 minutes and a solution of 1.0 g (3.44 m moles) of 4-bromomethyl-3', 4'-methylenedioxy-1,1-biphenyl in 10 ml of DMF was added dropwise over 5 minutes. The mixture is stirred at room temperature for 2 hours and poured into 75 ml of water and extracted with 150 ml of ether. The ether is washed with water, dried over magnesium sulfate and filtered. The filtrate is evaporated and the residue purified by flash chromatography using 4:1 hexane:ethyl acetate to give a solid with 100°-3° mp. This solid is suspended in 10 ml of acetone and ethanolic hydrochloric acid is added to pH1. The mixture is stirred at room temperature for 15 minutes and then diluted with ether to precipitate 3-[4-(1,3-benzodioxol-5-yl) benzyloxy]-1-azabicyclo[2.2.21octane hydrochloride (m.p. 195°-8°).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]2[O:8][CH2:9][C:10]([CH2:12][O:13][C:4]=2[CH:3]=1)=[O:11].[Br:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][CH:16]=1>>[Br:14][C:15]1[CH:22]=[CH:21][C:18](/[CH:19]=[C:9]2/[C:10](=[O:11])/[C:12](=[CH:19]/[C:18]3[CH:21]=[CH:22][C:15]([Br:14])=[CH:16][CH:17]=3)/[O:13][C:4]3[CH:3]=[C:2]([CH3:1])[CH:7]=[CH:6][C:5]=3[O:8]/2)=[CH:17][CH:16]=1
Reactant: Cc1ccc2c(c1)OCC(=O)CO2
Reactant: O=Cc1ccc(Br)cc1
Product: Cc1ccc2c(c1)O/C(=C\c1ccc(Br)cc1)C(=O)/C(=C/c1ccc(Br)cc1)O2

Procedure:
Calone is reacted with 4-bromobenzaldehyde analogously to the reaction conditions of Example 1, giving 2,4-bis[1-(4-bromophenyl)meth-(Z)-ylidene]-7-methylbenzo[b]-1,4-dioxepin-3-one.
Reaction SMILES: CCN(C(C)C)C(C)C.[F:10][C:11]([F:27])([F:26])[C:12]1[CH:17]=[CH:16][C:15]([C:18]2[NH:22][N:21]=[C:20]([C:23]([OH:25])=O)[CH:19]=2)=[CH:14][CH:13]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.[NH2:51][CH2:52][C:53]([N:55]1[CH2:60][CH2:59][CH:58]([O:61][C:62]2[CH:67]=[CH:66][CH:65]=[CH:64][C:63]=2[Cl:68])[CH2:57][CH2:56]1)=[O:54]>CN(C=O)C.O>[Cl:68][C:63]1[CH:64]=[CH:65][CH:66]=[CH:67][C:62]=1[O:61][CH:58]1[CH2:57][CH2:56][N:55]([C:53](=[O:54])[CH2:52][NH:51][C:23]([C:20]2[CH:19]=[C:18]([C:15]3[CH:14]=[CH:13][C:12]([C:11]([F:10])([F:27])[F:26])=[CH:17][CH:16]=3)[NH:22][N:21]=2)=[O:25])[CH2:60][CH2:59]1
Reactant: O=C(O)c1cc(-c2ccc(C(F)(F)F)cc2)[nH]n1
Reactant: NCC(=O)N1CCC(Oc2ccccc2Cl)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC(=O)N1CCC(Oc2ccccc2Cl)CC1)c1cc(-c2ccc(C(F)(F)F)cc2)[nH]n1
Reaction time: 8 h
Yield: 48.2 %

Procedure:
DIPEA (150 mg, 1.15 mmol) was added to a stirred solution of 5-(4-trifluoromethyl-phenyl)-1H-pyrazole-3-carboxylic acid (84 mg, 0.33 mmol) (prepared by the method used for the synthesis of Intermediate 29, starting from (p-trifluoromethyl)acetophenone) in DMF (2 mL) followed by HOBt (46 mg, 0.34 mmol) and EDCI.HCl (66 mg, 0.34 mmol). After 2 minutes 2-amino-1-[4-(2-chloro-phenoxy)-piperidin-1-yl]-ethanone hydrochloride (prepared according to Step 1 and 5 of the General Scheme) (100 mg, 0.33 mmol) was added to the reaction mixture and stirring was continued at ambient temperature overnight. The reaction mixture was diluted with cold water, extracted with ethyl acetate and dried over sodium sulfate. The organic layer was concentrated under reduced pressure to afford the residue. The residue was purified by washing with mixture of ethyl acetate and methanol to afford 80 mg (48.2% Yield) of 5-(4-trifluoromethyl-phenyl)-1H-pyrazole-3-carboxylic acid {2-[4-(2-chloro-phenoxy)-piperidin-1-yl]-2-oxo-ethyl}-amide. LC/MS [M+H]+: 507, 92.02%. 1H NMR (300 MHz, DMSO-d6): δ13.7 (d, 1H), 8.0 (m, 3H), 7.8 (m, 2H), 7.44 (d, 1H), 7.24 (m, 3H), 6.96 (m, 1H), 4.7 (m, 1H), 4.2 (d, 2H), 3.7 (m, 2H), 3.4 (m, 2H), 1.9 (m, 2H), 1.6 (m, 2H).
Reaction SMILES: C([O:5][NH:6][C:7](=[O:31])[C@H:8]([N:12]([S:20]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1)(=[O:22])=[O:21])[CH2:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1)[CH:9]([CH3:11])[CH3:10])(C)(C)C.C(O)C.[Cl:35]C(Cl)C>>[ClH:35].[OH:5][NH:6][C:7](=[O:31])[C@H:8]([N:12]([S:20]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1)(=[O:22])=[O:21])[CH2:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1)[CH:9]([CH3:11])[CH3:10]
Reactant: CC(Cl)Cl
Reactant: COc1ccc(S(=O)(=O)N(Cc2cccnc2)[C@@H](C(=O)NOC(C)(C)C)C(C)C)cc1
Solvent: CCO
Product: COc1ccc(S(=O)(=O)N(Cc2cccnc2)[C@@H](C(=O)NO)C(C)C)cc1
Product: Cl
Temperature: -10 °C
Reaction time: 48 h

Procedure:
(a) N-(t-Butyloxy)-2(R)-[[4-methoxybenzenesulfonyl](3-picolyl)amino]-3-methylbutanamide (4.1 g, 9.13 mmol) is dissolved in dichloroethane (150 mL) containing ethanol (0.53 ml, 9.13 mmol) in a round bottom flask, and the reaction is cooled to -10° C. Hydrochloric acid gas (from a lecture bottle) is bubbled through for 30 minutes. The reaction is sealed, allowed to slowly warm to room temperature, and stirred for 2 days. The solvent is reduced to 1/3 volume by evaporation and triturated with ether. The mixture is filtered, filter cake removed, and dried in vacuo to provide N-hydroxy-2(R)-[[4-methoxybenzenesulfonyl](3-picolyl)amino]-3-methylbutanamide hydrochloride as a white solid, m.p. 169°-170° C. (dec), and having the following structure: ##STR12##
Reaction SMILES: [CH2:1]([O:3][C:4](/[C:6](=[CH:11]/[C:12]1[O:13][C:14]([CH3:17])=[CH:15][CH:16]=1)/[CH2:7][C:8]([OH:10])=O)=[O:5])[CH3:2].[C:18](OC(=O)C)(=[O:20])[CH3:19].C([O-])(=O)C.[Na+]>>[C:18]([O:10][C:8]1[C:16]2[CH:15]=[C:14]([CH3:17])[O:13][C:12]=2[CH:11]=[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH:7]=1)(=[O:20])[CH3:19]
Reactant: CCOC(=O)/C(=C/c1ccc(C)o1)CC(=O)O
Reactant: CC(=O)OC(C)=O
Agent: CC(=O)[O-]
Agent: [Na+]
Product: CCOC(=O)c1cc(OC(C)=O)c2cc(C)oc2c1
Temperature: 25 °C
Yield: 152.7 %

Procedure:
To a vigorously stirred solution of (E)-3-(ethoxycarbonyl)-4-(5-methylfuran-2-yl)but-3-enoic acid (I-1a: 326.6 g, 1.371 mol) in acetic anhydride (1.77 L, 18.72 mol) at room temperature was added sodium acetate (193 g, 2350 mmol) in one portion. The reaction mixture was then heated at reflux for 2.5 hours. After cooling to room temperature, the mixture was concentrated in vacuo (all batches were combined at this point). The resulting residue was suspended in dichloromethane (1.5 L) and filtered, washing the solids with dichloromethane (3×500 mL). The combined filtrate and washings were then washed with sodium hydrogencarbonate (2×1 L of a saturated aqueous solution) and brine (2 L), then concentrated in vacuo to give desired ethyl 4-acetoxy-2-methylbenzofuran-6-carboxylate (I-1b: 549.03 g, quantitative). 1H NMR (CDCl3, 300 MHz) δ ppm 8.00-7.99 (m, 1H), 7.64 (d, 1H), 6.32-6.32 (m, 1H), 4.38 (q, 2H), 2.47 (d, 3H), 2.37 (s, 3H), 1.39 (t, 3H).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][C@@H:2]1[C:6]([OH:8])=O.C(C1NC=CN=1)(C1NC=CN=1)=O.[CH3:21][NH:22][CH2:23][C:24]1[N:28]=[C:27]([NH2:29])[S:26][N:25]=1>CN(C=O)C.O>[NH2:29][C:27]1[S:26][N:25]=[C:24]([CH2:23][N:22]([CH3:21])[C:6]([C@H:2]2[CH2:3][CH2:4][CH2:5][O:1]2)=[O:8])[N:28]=1
Reactant: O=C(O)[C@H]1CCCO1
Reactant: CNCc1nsc(N)n1
Agent: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: CN(C)C=O
Solvent: O
Product: CN(Cc1nsc(N)n1)C(=O)[C@H]1CCCO1
Temperature: 25 °C
Reaction time: 2 h
Yield: 56.6 %

Procedure:
To a solution of (R)-tetrahydrofuran-2-carboxylic acid (5.0 g, 43 mmol) in DMF (100 mL) was added carbonyl diimidazole (7.68 g, 47 mmol) at 0 C under N2. After 2 hours agitation at 0 C, the product obtained from Step 1 (7.0 g, 49 mmol) in DMF (20 mL) was added and the mixture was stirred at room temperature overnight. The reaction mixture was then diluted with water (800 mL), extracted with EA (10×200 mL). The combined organic layers were washed twice with brine (100 mL) and concentrated. The residue was purified by silica gel column chromatography (PE:EA=1:3) to afford (R)-tetrahydro-furan-2-carboxylic acid (5-amino-[1,2,4]thiadiazol-3-ylmethyl)-methyl-amide (5.9 g, yield: 59%) as a red syrup. LC-MS (m/z): 243.1 [M+H]+.
Reaction SMILES: [CH3:1][C:2]([CH3:10])([CH3:9])[CH2:3][CH2:4][CH2:5][C:6]([OH:8])=[O:7].S(Cl)(Cl)=O.CCCCCC.[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[C:29](=[O:44])[N:30]([CH2:42]O)[CH:31]=[C:32]3[C:37]=2[NH:36][C:35]2[CH:38]=[CH:39][CH:40]=[CH:41][C:34]=2[S:33]3)=[CH:24][CH:23]=1>N1C=CC=CC=1>[Cl:21][C:22]1[CH:23]=[CH:24][C:25]([C:28]2[C:29](=[O:44])[N:30]([CH2:42][O:7][C:6](=[O:8])[CH2:5][CH2:4][CH2:3][C:2]([CH3:10])([CH3:9])[CH3:1])[CH:31]=[C:32]3[C:37]=2[NH:36][C:35]2[CH:38]=[CH:39][CH:40]=[CH:41][C:34]=2[S:33]3)=[CH:26][CH:27]=1
Reactant: O=c1c(-c2ccc(Cl)cc2)c2c(cn1CO)Sc1ccccc1N2
Reactant: CC(C)(C)CCCC(=O)O
Solvent: c1ccncc1
Solvent: CCCCCC
Solvent: O=S(Cl)Cl
Product: CC(C)(C)CCCC(=O)OCn1cc2c(c(-c3ccc(Cl)cc3)c1=O)Nc1ccccc1S2
Reaction time: 16 h
Yield: 59 %

Procedure:
A mixture of 3.0 g. of 5,5-dimethylhexanoic acid (23.0 mmol.) and 2.5 ml. of thionyl chloride (34.3 mmol.) was allowed to stand at room temperature for 16 hours. Upon addition of 20 ml. of Skellysolve B, the resulting solution was refluxed for 1 hour, then the solvent was removed in vacuo. The remaining residue was azeotroped twice with Skellysolve B to yield a pale yellow liquid which was added dropwise to a suspension of 3.0 g. of 4-(4-chlorophenyl)-2-(hydroxymethyl)-5H-pyrido[3,4-b][1,4]benzothiazin-3(2H)-one (8.4 mmol.) in 30 ml. of cold pyridine. After stirring in an ice-bath for 35 minutes, the reaction mixture was poured onto ice-water resulting in the formation of a solid product which was filtered, washed with water, and purified using flash chromotography on silica gel, using a mixture of 5% ethyl acetate: 95% methylene chloride as the eluent. Fractions containing product were combined and triturated with diethyl ether to yield 4 -(4-chlorophenyl)-2-[(5,5-dimethyl-1-oxohexyloxy)methyl]-5H-pyrido[3,4-b][1,4]-benzothiazin-3(2H)-one as a yellow solid (2.4 g; 59% yield) having the structural formula, ##STR15## a melting point in the range of 143°-145° C. and the following elemental analysis:
Reaction SMILES: [CH:1]1[C:11]2[CH:10]([CH2:12][OH:13])[C:9]3[CH:14]=[CH:15][CH:16]=[CH:17][C:8]=3[CH2:7][O:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.C([N:20]([CH2:23]C)[CH2:21][CH3:22])C.[OH2:25]>ClCCl>[CH:1]1[C:11]2[CH:10]([CH2:12][O:13][C:23](=[O:25])[NH:20][C:21]3[C:22]([CH:8]([CH3:17])[CH3:7])=[CH:3][CH:2]=[CH:1][C:11]=3[CH:10]([CH3:12])[CH3:9])[C:9]3[CH:14]=[CH:15][CH:16]=[CH:17][C:8]=3[CH2:7][O:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: O
Reactant: OCC1c2ccccc2COc2ccccc21
Reactant: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)c1cccc(C(C)C)c1NC(=O)OCC1c2ccccc2COc2ccccc21
Temperature: 25 °C
Reaction time: 15 h

Procedure:
1.1 g of 6,11-dihydrodibenz[b,e]oxepin-11-methanol was dissolved in 30 ml of dichloromethane, and 2.7 ml of triethylamine and 2.3 ml of 2,6-diisopropyl isocyanate were added thereto with cooling on ice. The mixture was stirred for 15 hours at room temperature, and 100 ml of water was added to the reaction mixture, and then extracted with dichloromethane. The thus obtained organic layer was washed first with 1N hydrochloric acid and then with a saturated saline solution, dried and concentrated to dryness under reduced pressure. The solid residue was purified by silica gel column chromatography (using an eluting solvent of 1/9 (v/v) ethyl acetate/toluene). The crude product was recrystallized from ethyl acetate to obtain 0.97 g of Compound 6.
Reaction SMILES: I[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1/[C:4](=[CH:12]/[C:13]1[NH:14][CH:15]=[CH:16][CH:17]=1)/[C:5](=[O:11])[NH:6]2.C([O-])([O-])=O.[Na+].[Na+].[CH3:24][O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1B(O)O>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.COCCOC>[CH3:24][O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1/[C:4](=[CH:12]/[C:13]1[NH:14][CH:15]=[CH:16][CH:17]=1)/[C:5](=[O:11])[NH:6]2
Reactant: COc1ccccc1B(O)O
Reactant: O=C1Nc2cccc(I)c2/C1=C/c1ccc[nH]1
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: [Na+]
Solvent: COCCOC
Product: COc1ccccc1-c1cccc2c1/C(=C/c1ccc[nH]1)C(=O)N2
Temperature: 100 °C

Procedure:
A solution of (Z)-1,3-dihydro-4-iodo-3-[(1H-pyrrol-2-yl)methylene]-2H-indol-2-one (50 mg, 0.149 mmol) (Starting Material 1), 2M aqueous Na2CO3 solution (149 μL , 0.298 mmol), (Ph3P)4Pd (5 mg, 0.004 mmol) (Aldrich), and 2-methoxyphenylboronic acid (25 mg, 0.164 mmol) (Aldrich) in 4 mL of a 2:1 mixture of 1,2-dimethoxyethane:distilled water was heated at 100° C. under a nitrogen atmosphere for 18 h. The reaction mixture was allowed to cool to room temperature and then directly purified by flash chromatography (Merck Silica gel 60, 230-400 mesh, 20% ethyl acetate-hexanes elution) to provide a crude yellow solid. Recrystallization from chloroform-pentane yielded pure (Z)-1,3-dihydro-4-(2-methoxyphenyl)-3-[(1H-pyrrol-2-yl)methylene]-2H-indol-2-one (Yield 37 mg, 79%) as yellow crystals (mp 223-225° C.).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6](F)[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[F:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17][NH2:18])=[CH:15][CH:14]=1.C(N(CC)CC)C>CS(C)=O>[NH2:1][C:2]1[CH:7]=[C:6]([N:18]=[CH:17][C:16]2[CH:19]=[CH:20][C:13]([F:12])=[CH:14][CH:15]=2)[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: NCc1ccc(F)cc1
Reactant: Nc1cc(F)ccc1[N+](=O)[O-]
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: Nc1cc(N=Cc2ccc(F)cc2)ccc1[N+](=O)[O-]
Reaction time: 30 h

Procedure:
A solution of 15.6 g (100 mmol) 2-amino-4-fluoronitrobenzene, 22.5 g (180 mmol) 4-fluorobenzylamine and 20.2 g (220 mmol) triethylamine in 150 ml dimethylsulfoxide is heated with stirring and under an inert gas atmosphere for 30 hours to 60°-70° C. When the reaction time is completed, the solvent is distilled off in a vacuum, the residue is taken up in 500 ml 0.5N hydrochloric acid and the mixture is stirred intensively at room temperature for 30 minutes. The precipitated solid is suction filtered and subjected to hot steam extraction with toluene. The product crystallizing out of the toluene after the mixture has been allowed to stand for twelve hours at 0°-4° C. is suction filtered and dried in a vacuum. 22.2 g (85 % of theory) are obtained. After being left to stand for 12 hours at 0°-4° C., 2-amino-4-(4-fluorobenzylamino)-nitrobenzene crystallizes out of the toluene phase as orange-yellow crystals.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([OH:10])=[O:9])[N:6]=1.[C:11]([N+:15]#[C-:16])([CH3:14])([CH3:13])[CH3:12].[CH3:17][O:18][C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[CH:21]=O>Cl(O)(=O)(=O)=O>[C:11]([NH:15][C:16]1[N:6]2[C:2]([S:3][CH:4]=[C:5]2[CH2:7][C:8]([OH:10])=[O:9])=[N:1][C:21]=1[C:20]1[CH:23]=[CH:24][CH:25]=[CH:26][C:19]=1[O:18][CH3:17])([CH3:14])([CH3:13])[CH3:12]
Reactant: COc1ccccc1C=O
Reactant: [C-]#[N+]C(C)(C)C
Reactant: Nc1nc(CC(=O)O)cs1
Agent: [O-][Cl+3]([O-])([O-])O
Product: COc1ccccc1-c1nc2scc(CC(=O)O)n2c1NC(C)(C)C

Procedure:
Compound 33 was prepared in accordance with the general synthesis instructions from 1.0 ml (0.1 mmol) (2-aminothiazol-4-yl)acetic acid solution (0.1 M, MC), 0.575 ml (0.115 mmol) tert-butylisonitrile solution (0.2 M, MC), 0.500 ml (0.15 mmol) 2-methoxybenzaldehyde solution (0.3 M, MC) and 10 μl perchloric acid (w=20%) in a substance library.
Reaction SMILES: [OH:1][C:2]1[C:11]([CH2:12][CH2:13][CH3:14])=[C:10]2[C:5]([C:6](=[O:20])[CH:7]=[C:8]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[O:9]2)=[CH:4][CH:3]=1.[CH2:21]([C:24]1[CH:36]=[CH:35][CH:34]=[CH:33][C:25]=1[O:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]Br)[CH2:22][CH3:23]>>[C:15]([C:8]1[O:9][C:10]2[C:5]([C:6](=[O:20])[CH:7]=1)=[CH:4][CH:3]=[C:2]([O:1][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][O:26][C:25]1[CH:33]=[CH:34][CH:35]=[CH:36][C:24]=1[CH2:21][CH2:22][CH3:23])[C:11]=2[CH2:12][CH2:13][CH3:14])([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CCCc1ccccc1OCCCCCBr
Reactant: CCCc1c(O)ccc2c(=O)cc(C(=O)OCC)oc12
Product: CCCc1ccccc1OCCCCCOc1ccc2c(=O)cc(C(=O)OCC)oc2c1CCC
Yield: 79.9 %

Procedure:
Using essentially the method of Example 2, 2.76 g (10 mmole) of ethyl 7-hydroxy-8-n-propylchromone-2-carboxylate and 8.18 g (11 mmole) of 5-(2-n-propylphenoxy)-1-bromopentane, gave 3.84 g (80%) of the title compound, mp 73°-75°. Calc: C, 72.48; H, 7.55; Found: C, 72.24; H, 7.63.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:31]=[CH:32][CH:33]=1)[CH2:5][O:6][C:7]1[CH:16]=[C:15]2[C:10]([CH2:11][CH:12]([CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[C:13](=[O:24])[N:14]2C(OC(C)(C)C)=O)=[CH:9][CH:8]=1.Cl.O1CCOCC1.CC(O)C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:31]=[CH:32][CH:33]=1)[CH2:5][O:6][C:7]1[CH:16]=[C:15]2[C:10]([CH2:11][CH:12]([CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[C:13](=[O:24])[NH:14]2)=[CH:9][CH:8]=1
Reactant: CCOC(=O)CC1Cc2ccc(OCc3cccc(Cl)c3)cc2N(C(=O)OC(C)(C)C)C1=O
Agent: Cl
Solvent: CC(C)O
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Product: CCOC(=O)CC1Cc2ccc(OCc3cccc(Cl)c3)cc2NC1=O
Temperature: 25 °C

Procedure:
To crude tert-butyl 7-((3-chlorobenzyl)oxy)-3-(2-ethoxy-2-oxoethyl)-2-oxo-3,4-dihydroquinoline-1(2H)-carboxylate (115.7 g, 244.1 mmol) was added a 4.0 M 1,4-dioxane hydrochloride solution (200 mL, 0.8 mol) in an ice bath. After addition, the ice bath was removed and the reaction was warmed to ambient temperature. The reaction was concentrated to a yellow oil and azeotroped with toluene (2×250 mL) to furnish a brown oil. The oil was diluted in toluene (400 mL) followed by 2-propanol (400 mL). The resulting white ppt that was formed was filtered and washed with 2-propanol to furnish the desired product as a white solid. The mother liquor was concentrated to a brown solid that was triturated with 2-propanol (400 mL), filtered and washed with 2-propanol to furnish a second crop of product (38.3 g). The two crops were combined to give (50.3 g, 55%) of the title compound. 1H NMR (400 MHz, CDCl3) δ 7.88 (s, 1H), 7.43 (s, 1H), 7.35-7.29 (m, 3H), 7.06 (d, J=8.3 Hz, 1H), 6.59 (dd, J=8.3, 2.4 Hz, 1H), 6.39 (d, J=2.4 Hz, 1H), 5.02 (s, 2H), 4.23-4.15 (m, 2H), 3.12-2.92 (m, 3H), 2.92-2.77 (m, 1H), 2.48 (dd, J=16.2, 7.5 Hz, 1H), 1.29 (t, J=7.1 Hz, 3H). [M+H]=374.2.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:7]([NH:9][C:10]2[C:15]([CH3:16])=[CH:14][CH:13]=[CH:12][C:11]=2[Cl:17])=[O:8])=[CH:5][N:6]=1.[Cl:18][C:19]1[CH:24]=[C:23](Cl)[N:22]=[C:21]([CH3:26])[N:20]=1.CC(C)([O-])C.[Na+].Cl>C1COCC1>[Cl:18][C:19]1[N:20]=[C:21]([CH3:26])[N:22]=[C:23]([NH:1][C:2]2[S:3][C:4]([C:7]([NH:9][C:10]3[C:15]([CH3:16])=[CH:14][CH:13]=[CH:12][C:11]=3[Cl:17])=[O:8])=[CH:5][N:6]=2)[CH:24]=1
Reactant: Cc1cccc(Cl)c1NC(=O)c1cnc(N)s1
Reactant: Cc1nc(Cl)cc(Cl)n1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1nc(Cl)cc(Nc2ncc(C(=O)Nc3c(C)cccc3Cl)s2)n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 90.1 %

Procedure:
To a stirring solution of compound 5C (5.00 g, 18.67 mmol) and 4,6-dichloro-2-methylpyrimidine (3.65 g 22.4/mmol) in THF (65 mL) was added a 30% wt. solution of sodium t-butoxide in THF (21.1 g, 65.36 mmol) slowly with cooling to keep the temperature at 10-20° C. The mixture was stirred at room temperature for 1.5 h and cooled to 0-5° C. Hydrochloric acid, 2N (21.5 mL) was added slowly and the mixture stirred 1.75 h at 0-5° C. The solid was collected by vacuum filtration, washed with water (15 mL) and dried to give 6.63 g (86.4% yield) of compound 5D. 1H NMR (400 MHz, DMSO-d6) δ 2.23 (s, 3H), 2.58 (s, 3H), 6.94 (s, 1H), 7.18-7.34, (m, 2H, J=7.5), 7.34-7.46 (d, 1H, J=7.5), 8.31 (s, 1H), 10.02 (s, 1H), 12.25 (s, 1H).
Reaction SMILES: [CH2:1]([CH:9]([C:15](OCC)=O)[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[OH-].[K+]>C(O)C>[CH2:15]=[C:9]([CH2:1][CH2:2][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1)[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC(=O)C(CCc1ccccc1)C(=O)OCC
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: C=C(CCc1ccccc1)C(=O)OCC
Temperature: 25 °C
Reaction time: 15 h

Procedure:
26.6 g (0.1 mole) of diethyl phenethylmalonate were added dropwise in the course of an hour, with stirring, to 5.6 g of KOH in 65 ml of absolute ethanol, the mixture was stirred at room temperature for 15 hours and then boiled for 5 minutes. The ethanol was removed in vacuo, ice-water was added and the mixture was extracted with ether. The aqueous phase was acidified with 2N hydrochloric acid and extracted with ether. The second extract was dried and evaporated and then neutralized with 8.8 ml of diethylamine. 12 ml of 30% strength formaldehyde solution were added, the mixture was stirred for 3 hours, then saturated with potassium carbonate, extracted with ether, the extract was washed with dilute hydrochloric acid, dried and evaporated.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C@H:10](OS(C)(=O)=O)/[CH:11]=[CH:12]/[C:13]([O:15][CH3:16])=[O:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl-].[NH4+]>O1CCCC1>[CH2:22]([C@H:12](/[CH:11]=[CH:10]/[C@@H:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:13]([O:15][CH3:16])=[O:14])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: COC(=O)/C=C/[C@@H](OS(C)(=O)=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COC(=O)[C@@H](/C=C/[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C)Cc1ccccc1
Temperature: 30 °C
Reaction time: 0.17 h
Yield: 167.3 %

Procedure:
Cuprous cyanide (5 mg) was placed in a flask which was flushed with N2 gas. Anhydrous tetrahydrofuran (0.5 ml) was added, and the mixture was cooled under N2 to 30° C. A solution of benzylmagnesium chloride (0.18 ml, 1.0M in diethyl ether) was added, and the mixture was stirred for 10 min to produce a yellow slurry. A solution of 30 mg (0.073 mmol) of the resultant compound of Example 7 in 1 ml of anhydrous tetrahydrofuran was subsequently added, and the resulting solution was stirred and allowed to warm to -10° C. over a period of 30 min. After addition of aqueous ammonium chloride, the mixture was extracted with ethyl acetate, washed with saturated brine, dried over Na2SO4, and concentrated in vacuo. Chromatography on silica gel using 6:1 hexane:ethyl acetate provided 25 mg (84%) of the desired compound (Rf 0.71, 2:1 hexane:ethyl acetate). 1H NMR (CDCl3) δ 1.41 (s, 9 H), 2.2-2.3 (m, 3 H), 3.04 (dd, J=13, 7 Hz, 1 H), 3.25 (q, J=7 Hz, 1 H), 3.61 (s, 3 H), 4.37 (m, 2 H), 5.39 (dd, J=15, 5 Hz, 1 H), 5.55 (dd, J=15, 8 Hz, 1 H), 7.05-7.15 (m, 4 H), 7.2-7.3 (m, 6 H). Mass spectrum: (M+NH4)+ =427.