Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:5])(=O)[CH:2]=[O:3].[CH2:6]([NH:13][C:14]([NH2:16])=[O:15])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.O>C(O)(=O)C>[CH2:6]([N:13]1[CH:1]([OH:5])[C:2](=[O:3])[NH:16][C:14]1=[O:15])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=CC(=O)O
Reactant: NC(=O)NCc1ccccc1
Solvent: CC(=O)O
Solvent: O
Product: O=C1NC(=O)N(Cc2ccccc2)C1O
Temperature: 100 °C
Reaction time: 1 h

Procedure:
3000 parts by weight of 50% strength aqueous glyoxylic acid solution and 500 parts by weight of acetic acid (100% strength) are placed in a heatable, stirred apparatus and heated to 100° C. A mixture of 3000 parts by weight of benzylurea, 1300 parts by weight of water and 1500 parts by weight of acetic acid having a temperature of 80° C. is added to this solution over a period of one hour. The total reaction mixture is subsequently stirred at an internal temperature of 100° C. for another hour. 4500 parts by weight of an acetic acid/water mixture are then distilled off to a pressure of 200 mbar and a temperature at the bottom of 100° C. The remaining liquid residue is admixed at 90° C. with 900 parts by weight of water and 12.5 parts by weight of acetic acid, cooled to 35° C., admixed with 3000 parts by weight of methylene chloride and stirred at 25° C. for 12 hours. The temperature is then held at 3° C. for 1 hour by cooling.
Reaction SMILES: [NH3:1].[CH2:2]([O:4][C:5]([C:7]1[C:8]2[S:16][CH:15]=[C:14]([CH2:17][O:18][C:19]3[CH:24]=[C:23]([C:25]4[O:29][N:28]=[C:27]([CH3:30])[N:26]=4)[CH:22]=[CH:21][C:20]=3[CH3:31])[C:9]=2[C:10](Cl)=[N:11][CH:12]=1)=[O:6])[CH3:3]>CC(O)C>[CH2:2]([O:4][C:5]([C:7]1[C:8]2[S:16][CH:15]=[C:14]([CH2:17][O:18][C:19]3[CH:24]=[C:23]([C:25]4[O:29][N:28]=[C:27]([CH3:30])[N:26]=4)[CH:22]=[CH:21][C:20]=3[CH3:31])[C:9]=2[C:10]([NH2:1])=[N:11][CH:12]=1)=[O:6])[CH3:3]
Reactant: CCOC(=O)c1cnc(Cl)c2c(COc3cc(-c4nc(C)no4)ccc3C)csc12
Reactant: N
Solvent: CC(C)O
Product: CCOC(=O)c1cnc(N)c2c(COc3cc(-c4nc(C)no4)ccc3C)csc12
Temperature: 140 °C

Procedure:
Ammonia gas was bubbled into a solution of 4-chloro-3-[2-methyl-5-(3-methyl-[1,2,4]oxadiazol-5-yl)-phenoxymethyl]-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester (0.42 g, 0.95 mmol) (from Example 53 supra) in 2-propanol (30 mL) for 20 minutes. The mixture was heated in a microwave reactor at 140° C. for 2 hours. The reaction mixture was concentrated. The residue washed with hot methanol, filtered and dried to give 4-amino-3-[2-methyl-5-(3-methyl-[1,2,4]oxadiazol-5-yl)-phenoxymethyl]-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester as a white powder. (Yield 0.33 g, 83%).
Reaction SMILES: [CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:30]([NH2:32])=[O:31])[CH:17]=[C:18](B4OC(C)(C)C(C)(C)O4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:5])=[O:4])[CH3:2].C(=O)([O-])[O-].[Na+].[Na+].Br[C:40]1[CH:41]=[C:42]([O:50][CH3:51])[C:43]([O:48][CH3:49])=[C:44]([CH:47]=1)[CH:45]=[O:46]>O1CCOCC1.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>[CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:30]([NH2:32])=[O:31])[CH:17]=[C:18]([C:40]4[CH:41]=[C:42]([O:50][CH3:51])[C:43]([O:48][CH3:49])=[C:44]([CH:45]=[O:46])[CH:47]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:5])=[O:4])[CH3:2]
Reactant: COc1cc(Br)cc(C=O)c1OC
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(B4OC(C)(C)C(C)(C)O4)cc23)CC1
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: O
Solvent: C1COCCO1
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cc(C=O)c(OC)c(OC)c4)cc23)CC1
Temperature: 120 °C
Yield: 59.1 %

Procedure:
To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-7-carboxamide (500 mg, 1.09 mmol) in dioxane (9.0 mL) and H2O (3.0 mL) was added sodium carbonate (690 mg, 6.51 mmol), and 5-bromo-2,3-bis(methyloxy)benzaldehyde (7.95 mg, 3.25 mmol). The reaction mixture was flushed under Argon for 10 min before addition of tetrakis(triphenylphosphine)palladium (0) (63 mg, 0.054 mmol). The reaction was then heated in a microwave at 120° C. for 30 min. All solvent was then concentrated and an aqueous wash was performed with EtOAc and H2O. The desired compound then precipitated and was filtered to give 322 mg of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-formyl-4,5-bis(methyloxy)phenyl]-1H-indole-7-carboxamide (59%).
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]2[C:3]1=[O:12].[CH2:13](O)[CH2:14][CH3:15]>>[CH2:13]([O:1][N:2]1[C:3](=[O:12])[C:4]2=[CH:11][CH:10]=[CH:9][CH:8]=[C:5]2[C:6]1=[O:7])[CH2:14][CH3:15]
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: CCCO
Product: CCCON1C(=O)c2ccccc2C1=O

Procedure:
The desired product was prepared using the method described in Example 1176A starting with N-hydoxyphthalimide and 1-propanol. m/e (DCI) 223 (MH+NH3+)
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]1[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:10]=1[C@H:16]1[CH2:22][N:21]([CH2:23][CH2:24][S:25]([CH3:28])(=[O:27])=[O:26])[C:20](=[O:29])[C@H:19]([NH:30]C(=O)OC(C)(C)C)[CH2:18][CH2:17]1>ClCCl>[NH2:30][C@@H:19]1[CH2:18][CH2:17][C@@H:16]([C:10]2[CH:11]=[CH:12][CH:13]=[C:14]([F:15])[C:9]=2[F:8])[CH2:22][N:21]([CH2:23][CH2:24][S:25]([CH3:28])(=[O:26])=[O:27])[C:20]1=[O:29]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CC[C@@H](c2cccc(F)c2F)CN(CCS(C)(=O)=O)C1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CS(=O)(=O)CCN1C[C@H](c2cccc(F)c2F)CC[C@@H](N)C1=O
Reaction time: 4 h

Procedure:
Trifluoroacetic acid (1 mL) was added to a solution of tert-butyl (3R,6S)-6-(2,3-difluorophenyl)-1-[2-(methylsulfonyl)ethyl]-2-oxoazepan-3-ylcarbamate (23.7 mg, 0.053 mmol) in dichloromethane (2 mL). After 4 h, the solution was concentrated. Saturated aqueous sodium bicarbonate solution was added and the mixture was extracted with dichloromethane (3×). The combined organic extracts were washed with saturated brine, dried over magnesium sulfate, filtered and concentrated to give the title compound. MS 347 (M+1).
Reaction SMILES: Cl[C:2]1[S:6][N:5]=[C:4]([S:7][CH2:8][O:9][CH2:10][CH3:11])[N:3]=1.[CH3:12][C:13]1([CH3:20])[O:17][CH:16]([CH2:18][OH:19])[CH2:15][O:14]1.[H-].[Na+].[Cl-].[Na+]>C(OC)(C)(C)C.CN(C)C=O>[CH3:12][C:13]1([CH3:20])[O:17][CH:16]([CH2:18][O:19][C:2]2[S:6][N:5]=[C:4]([S:7][CH2:8][O:9][CH2:10][CH3:11])[N:3]=2)[CH2:15][O:14]1
Reactant: CCOCSc1nsc(Cl)n1
Reactant: CC1(C)OCC(CO)O1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: COC(C)(C)C
Solvent: CN(C)C=O
Product: CCOCSc1nsc(OCC2COC(C)(C)O2)n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 75.7 %

Procedure:
To 3 g of N,N-dimethylformamide, 300 mg of 5-chloro-3-ethoxymethylthio-1,2,4-thiadiazole and 188 mg of 2,2-dimethyl-1,3-dioxolane-4-methanol were dissolved, and added 62 mg of sodium hydride (60% in oil) at about 0° C., followed by stirring at about 0° C. for 30 minutes and standing at room tempareture for about 1 day. Then, to the reaction mixture, t-butylmethylether and saturated sodium chloride aqueous solution were added, and separeted to two layers. The organic layer was dried by anhydrous sodium salfate, and concentrated. The residue obtaind was subjected to column chromatography to obtain 330 mg of 5-(2,2-dimethyl-1,3-dioxolane-4-yl)methoxy-3-ethoxymethylthio-1,2,4-thiadiazole.
Reaction SMILES: [C:1]1([CH3:17])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[C:9]1[C:10]([CH3:16])=[C:11]([CH:13]=[CH:14][CH:15]=1)[NH2:12].[C:18]([CH:21]1[CH2:26][CH2:25][O:24][C:22]1=[O:23])(=O)[CH3:19]>C(O)C>[C:1]1([CH3:17])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[C:9]1[C:10]([CH3:16])=[C:11]([CH:13]=[CH:14][CH:15]=1)[NH:12][C:18](=[C:21]1[CH2:26][CH2:25][O:24][C:22]1=[O:23])[CH3:19]
Reactant: Cc1cc(C)c(-c2cccc(N)c2C)c(C)c1
Reactant: CC(=O)C1CCOC1=O
Solvent: CCO
Product: CC(Nc1cccc(-c2c(C)cc(C)cc2C)c1C)=C1CCOC1=O
Yield: 95.9 %

Procedure:
A solution of 3-mesityl-2-methylaniline (5.0 g, 22 mmol) and α-acetyl-γ-butyrolactone (14.2 g, 0.11 mol) in ethanol (100 mL) was heated at reflux for three days. The mixture was evaporated, and the residue was purified by silica gel column chromatography (10% ethyl acetate/hexane), to give the title compound (7.08 g) as white crystals.
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].[C:4]([NH:11][CH2:12][CH2:13][CH2:14][C:15]([OH:17])=O)([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5]>C(Cl)Cl>[C:7]([O:6][C:4](=[O:5])[NH:11][CH2:12][CH2:13][CH2:14][C:15](=[O:17])[NH:3][CH2:1][CH3:2])([CH3:8])([CH3:9])[CH3:10]
Reactant: CC(C)(C)OC(=O)NCCCC(=O)O
Reactant: CCN
Solvent: ClCCl
Product: CCNC(=O)CCCNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
An aqueous solution of ethylamine (70%, 41 ml) was added into an ice cold solution of benzotriazole derivative 2 (50 g, 156 mmol) in CH2Cl2 (500 ml), stirred for 1 h at room temperature, diluted 2 times with CH2Cl2, washed with H2O, then brine, dried (Na2SO4), concentrated and dried in vacuo. Yield 32.845 g (91%). mp: 82-83° C. 1H NMR (CDCl3): 1.15 (t, J=7.27, 3H), 1.44 (s, 9H), 1.75-1.85 (m, 2H), 2.20 (t, J=7.10, 2H), 3.17 (q, J=6.49, 2H), 3.24-3.34 (m, 2H), 4.82 (s, 1H), 6.13 (bs, 1H). 13C NMR (CDCl3): 14.72, 24.91, 26.33, 28.35, 33.66, 33.92, 34.32, 39.78, 79.21, 156.44, 172.43. ESI-MS: 483.4 (M2Na+), 461.4 (M2H+), 321.2 (MH+).
Reaction SMILES: C([N:8]([CH2:13][CH2:14][CH3:15])[O:9][CH2:10][CH2:11][CH3:12])(OC(C)(C)C)=O.[ClH:16].O1CCOCC1>>[ClH:16].[CH2:13]([NH:8][O:9][CH2:10][CH2:11][CH3:12])[CH2:14][CH3:15]
Reactant: CCCON(CCC)C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: CCCNOCCC
Temperature: 25 °C
Reaction time: 7 h

Procedure:
N-Boc-N-propyl-N-propoxyamine (5.8 g) was dissolved in 4N HCl/dioxane (10 mL) and stirred at room temperature for 7 hours. The solvent was removed in vacuo and the residue triturated with diethyl ether. The resulting yellow solid (2.1 g) was collected by filtration and washed with diethyl ether.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([OH:19])=[C:13]([CH:18]=1)[C:14]([O:16][CH3:17])=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:20](=O)([O-])[O-].[Cs+].[Cs+].CI>CC(C)=O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([O:19][CH3:20])=[C:13]([CH:18]=1)[C:14]([O:16][CH3:17])=[O:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1cc(OCc2ccccc2)ccc1O
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CI
Solvent: CC(C)=O
Product: COC(=O)c1cc(OCc2ccccc2)ccc1OC
Temperature: 50 °C
Reaction time: 6 h
Yield: 90.2 %

Procedure:
To a suspended solution of methyl 5-benzyloxy-2-hydroxybenzoate (3.91 g) and cesium carbonate (6.41 g) in acetone (100 ml) was added methyl iodide (1.41 ml), and the mixture was stirred at 50° C. for 6 hr. The reaction mixture was concentrated, dissolved again in ethyl acetate and washed with saturated brine. The organic layer was dried (over MgSO4), and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography (Biotage cartridge 40+M, ethyl acetate:n-hexane=15:85→1:4) to give methyl 5-benzyloxy-2-methoxybenzoate (3.72 g, 90%) as colorless crystals.
Reaction SMILES: [C:1]1(=[O:17])[N:5]([CH2:6][CH2:7][O:8][CH2:9][CH2:10][OH:11])[C:4](=[O:12])[C:3]2=[CH:13][CH:14]=[CH:15][CH:16]=[C:2]12.[H-].[Na+].[CH2:20](Br)[C:21]#[CH:22].CO>CN(C)C=O>[C:4]1(=[O:12])[N:5]([CH2:6][CH2:7][O:8][CH2:9][CH2:10][O:11][CH2:22][C:21]#[CH:20])[C:1](=[O:17])[C:2]2=[CH:16][CH:15]=[CH:14][CH:13]=[C:3]12
Reactant: O=C1c2ccccc2C(=O)N1CCOCCO
Reactant: C#CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: C#CCOCCOCCN1C(=O)c2ccccc2C1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 36.6 %

Procedure:
To a stirred solution of compound 15 (1.39 g, 5.91 mmol) in N,N-dimethylformamide (25 mL) was added NaH (0.33 g, 80%) dropwise. After complete NaH addition, stirring was continued for 0.5 h at room temperature and then cooled to 0° C. Propargyl bromide 4 (1.24 mL, 11.13 mmol) was added, and stirring was continued for 0.5 h at 0° C., then for 2 h at room temperature. After careful addition of methanol to decompose excess NaH, the solvent was evaporated and crude product was purified by flash column chromatography (3:2 to 1:1 to 2:3 hexane-ethyl acetate) to give compound 16 as a solid (591 mg, 36.6%) having an RF of 0.41 (solvent 3:2 hexane-ethyl acetate). See FIG. 9.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C@H:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH3:10])[CH:5]=[N:4][CH:3]=1.[OH:17][CH2:18][CH2:19][NH:20][C:21]([C:23]1[CH:31]=[CH:30][C:26]2[N:27]=[CH:28][NH:29][C:25]=2[CH:24]=1)=[O:22]>>[C:11]1([C@@H:9]([NH:8][C:6]2[N:7]=[C:2]([N:27]3[C:26]4[CH:30]=[CH:31][C:23]([C:21]([NH:20][CH2:19][CH2:18][OH:17])=[O:22])=[CH:24][C:25]=4[N:29]=[CH:28]3)[CH:3]=[N:4][CH:5]=2)[CH3:10])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: C[C@H](Nc1cncc(Cl)n1)c1ccccc1
Reactant: O=C(NCCO)c1ccc2nc[nH]c2c1
Product: C[C@H](Nc1cncc(-n2cnc3cc(C(=O)NCCO)ccc32)n1)c1ccccc1

Procedure:
In a procedure analogous to example 12, reaction of 6-chloro-N-[(1S)-1-phenylethyl]pyrazin-2-amine (91 mg, 0.39 mmol) and benzimidazole 5-carboxylic acid (2-hydroxyethyl)amide (88 mg, 0.43 mmol) furnished the product which was purified by column chromatography (22 mg, 14%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([C:12]([F:15])([F:14])[F:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1)=[O:17].[Cl:24][C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1>>[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([C:2]2[C:11]3[C:6](=[C:7]([C:12]([F:14])([F:13])[F:15])[CH:8]=[CH:9][CH:10]=3)[N:5]=[CH:4][C:3]=2[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)=[O:17])=[CH:27][CH:26]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: O=C(c1ccccn1)c1cnc2c(C(F)(F)F)cccc2c1Cl
Product: O=C(c1ccccn1)c1cnc2c(C(F)(F)F)cccc2c1-c1ccc(Cl)cc1

Procedure:
This compound was prepared using the procedure of Example 1, step 5 using (4-chloro-8-trifluoromethyl-quinolin-3-yl)-pyridin-2-yl-methanone in place of [4-chloro-8-(trifluoromethyl)quinolin-3-yl](phenyl)methanone and 4-chlorophenylboronic acid in place of phenyl boronic acid; MS (ESI) m/z 413/415 ([M+H]+); Anal. Calcd for C22H12ClF3N2O: C, 64.01; H, 2.93; N, 6.79. Found: C, 63.66; H, 3.03; N, 6.60.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][CH:10]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:5]=[CH:6][C:7]=1[OH:8].O[CH2:24][CH2:25][NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1(C)C=CC=CC=1>[C:29]([O:28][C:27]([NH:26][CH2:25][CH2:24][O:8][C:7]1[CH:6]=[CH:5][C:4]([CH2:9][CH:10]([O:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:3][C:2]=1[Cl:1])=[O:33])([CH3:32])([CH3:31])[CH3:30]
Reactant: CCOC(=O)C(Cc1ccc(O)c(Cl)c1)Oc1ccccc1
Reactant: CC(C)(C)OC(=O)NCCO
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)C(Cc1ccc(OCCNC(=O)OC(C)(C)C)c(Cl)c1)Oc1ccccc1
Yield: 93.6 %

Procedure:
In a similar manner to that described in Example 122, a reaction was carried out using ethyl 3-(3-chloro-4-hydroxyphenyl)-2-phenoxypropionate (761 mg), which is the product of Reference example 51(a), t-butyl 2-hydroxyethylcarbamate (0.96 g), triphenylphosphine (1.55 g) and solution of diethylazodicarboxylate in toluene (40%, 2.69 ml) and the reaction mixture was treated to afford the desired compound (1.03 g) as a colorless oil.
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4][C:5]1[C:20]([C:21](=[O:29])[C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)=[CH:19][CH:18]=[CH:17][C:6]=1[CH2:7][CH:8]([C:14]([O-:16])=[O:15])[C:9]([O:11]CC)=[O:10]>O.CO>[CH3:3][O:4][C:5]1[C:20]([C:21](=[O:29])[C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)=[CH:19][CH:18]=[CH:17][C:6]=1[CH2:7][CH:8]([C:14]([OH:16])=[O:15])[C:9]([OH:11])=[O:10]
Reactant: CCOC(=O)C(Cc1cccc(C(=O)c2ccc(Cl)cc2)c1OC)C(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1c(CC(C(=O)O)C(=O)O)cccc1C(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Yield: 45.6 %

Procedure:
A solution of 86.4 g of sodium hydroxide in 180 ml of water was added with stirring to a suspension of 226.6 g of ethyl 2-methoxy-3-(p-chlorobenzoyl)-benzyl-malonate in 2.8 liters of methanol and the mixture was refluxed for 3 hours and then was cooled to room temperature. The mixture was filtered and the precipitate recovered was washed with methanol, then with ether and dried. The residue was dissolved in 800 ml of water and the solution was washed with ether and acidified to a pH of 1 by addition of 0.5N hydrochloric acid. The acid precipitate formed was extracted with ether and the combined organic phases were washed with water, dried over magnesium sulfate, treated with activated carbon, filtered and evaporated to dryness under reduced pressure. The residue was crystallized from benzene to obtain 96.2 g of 2-methoxy-3-(p-chlorobenzoyl)-benzyl-malonic acid in the form of colorless crystals which melted at 142° C after crystallization from benzene.
Reaction SMILES: C[O:2][C:3]1[CH:11]=[C:10]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=[O:6].CCO.O.B(Br)(Br)Br>Cl>[CH2:12]([C:10]1[CH:11]=[C:3]([OH:2])[C:4](=[CH:8][CH:9]=1)[C:5]([OH:7])=[O:6])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCCCCCCc1ccc(C(=O)O)c(OC)c1
Agent: BrB(Br)Br
Agent: Cl
Solvent: CCO
Solvent: O
Product: CCCCCCCCCc1ccc(C(=O)O)c(O)c1
Temperature: -10 °C
Yield: 22.9 %

Procedure:
A solution of 2-methoxy-4-nonyl benzoic acid (600 mg; 2.15 mmol) was refluxed overnight in 6 M HCl [50% (w/w) EtOH/H2O; 35 mL). The reaction mixture was extracted with EtOAc (3×) dried (MgSO4), filtered and evaporated to dryness. The crude ester was dissolved in CH2Cl2 (10 mL), cooled to −10° C. and then added 1 M BBr3 (CH2Cl2; 10 mL; 10 mmol). The reaction mixture was allowed to warm to room temperature overnight and then poured onto H2O. Succeeding extraction with EtOAc, drying (MgSO4), filtering, evaporation to dryness and column chromatography (SiO2) yielded 130 mg (23%) product. Mp. 94-97° C.
Reaction SMILES: [H-].[Na+].[C:3](#[N:7])[CH2:4][C:5]#[N:6].I[C:9]1[CH:14]=[C:13]([CH3:15])[C:12]([C:16]2[C:21]([CH3:22])=[CH:20][N:19]=[CH:18][C:17]=2[CH3:23])=[C:11]([CH3:24])[CH:10]=1.Cl>COCCOC>[CH3:22][C:21]1[CH:20]=[N:19][CH:18]=[C:17]([CH3:23])[C:16]=1[C:12]1[C:11]([CH3:24])=[CH:10][C:9]([CH:4]([C:3]#[N:7])[C:5]#[N:6])=[CH:14][C:13]=1[CH3:15]
Reactant: Cc1cncc(C)c1-c1c(C)cc(I)cc1C
Reactant: N#CCC#N
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: Cc1cncc(C)c1-c1c(C)cc(C(C#N)C#N)cc1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.3 %

Procedure:
To an ice-cooled suspension of NaH (0.12 g, 5.0 mmol) in anhydrous 1,2-dimethoxyethane (8 mL) was added dropwise via syringe a solution of malononitrile (0.165 g, 2.50 mmol) in anhydrous 1,2-dimethoxyethane (2 mL) under N2. The mixture was stirred for 1 h at room temperature under N2. Next, 11 (0.674 g, 2.00 mmol) and tetrakis(triphenyphosphine)palladium(0) (0.232 g, 0.200 mmol) were added to the resulting pink suspension under an N2 flow. The reaction mixture was next stirred at 85° C. under N2 for 5 h. The solvent was then removed under reduced pressure. The resulting solid was washed with benzene (20 mL), dissolved in water, and filtered to give a dark-yellow aqueous solution. This solution was neutralized with 5% HCl to pH=7, and the resulting yellow precipitate was collected by filtration to give an orange solid. The crude product was purified by flash chromatography on silica gel eluting with 1:1 hexane: ethyl acetate, to give 0.525 g (95.5%) of the title compound as red solid: mp 58-60° C.; 1H NMR (400 MHz, CDCl3): δ 8.412 (s, 2H), 7.286 (s, 2H), 5.100 (s, 1H), 1.946 (s, 6H), 1.895 (s, 6H); 13C NMR (100 MHz, CDCl3): δ 149.066, 146.564, 139.513, 137.283, 130.441, 126.692, 125.518, 112.024, 28.059, 19.988, 16.704; Anal. Calcd. for C18H17N3.H2O: C, 73.69; H, 6.53; N, 14.32. Found; C, 73.36; H, 6.35; N, 14.07.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[C:12](=[O:13])[CH2:11][C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=3[S:8][C:7]=2[CH:18]=1.[C-:19]#[N:20].[Na+]>CN(C)C=O>[C:19]([CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[C:12](=[O:13])[CH2:11][C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=3[S:8][C:7]=2[CH:18]=1)#[N:20]
Reactant: [C-]#N
Reactant: O=C1Cc2ccccc2Sc2cc(CBr)ccc21
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CCc1ccc2c(c1)Sc1ccccc1CC2=O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Dissolve 6.4 gm. of the bromide of Step 2 in 75 cc. of dimethylformamide and add 2.95 gm. of sodium cyanide. Stir the mixture at room temperature for 1.5 hours. Dilute with 600 cc. of water and extract three times with ether. Wash the combined organics with water, dry and strip to a solid residue. Triturate in hexane and recover the solid by filtration.
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8]Br)=[CH:6][CH:5]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].[CH3:18][NH:19][CH3:20]>C(#N)C>[CH3:18][N:19]([CH3:20])[CH2:8][C:7]1[CH:10]=[CH:11][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1
Reactant: CNC
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CN(C)Cc1ccc([N+](=O)[O-])cc1
Reaction time: 1 h
Yield: 84 %

Procedure:
To a mixture of 4-nitrobenzyl bromide (4 g, 18.5 mmol) and potassium carbonate (7.65 g, 55.5 mmol) in acetonitrile (50 ml) at 0-5° C. was added 40% aqueous dimethyl amine solution (1.5 eq). After 1 hr at room temperature, the solvent was evaporated; the crude material was dissolved in water and extracted with ethyl acetate. The organic layer was dried and concentrated to give dimethyl-(4-nitro-benzyl)-amine (2.8 g, 84%)
Reaction SMILES: N1CCCC1.[F:6][C:7]1[C:8]([OH:16])=[C:9]([C:13](=[O:15])[CH3:14])[CH:10]=[CH:11][CH:12]=1.[O:17]1[CH2:22][CH2:21][C:20](=O)[CH2:19][CH2:18]1.Cl>C1(C)C=CC=CC=1>[F:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:8]=1[O:16][C:20]1([CH2:21][CH2:22][O:17][CH2:18][CH2:19]1)[CH2:14][C:13]2=[O:15]
Reactant: CC(=O)c1cccc(F)c1O
Reactant: O=C1CCOCC1
Agent: Cl
Solvent: C1CCNC1
Solvent: Cc1ccccc1
Product: O=C1CC2(CCOCC2)Oc2c(F)cccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 47.8 %

Procedure:
Pyrrolidine (4.8 ml, 58 mmol) was added to a stirred solution of 1-(3-fluoro-2-hydroxyphenyl)ethanone (28) (5.9 g, 39 mmol) and tetrahydro-4h-pyran-4-one (4.6 ml, 50 mmol) in toluene (40 mL) at rt. After the exotherm subsided, the reaction mixture was stirred at rt for 1 h. then subjected to Dean-Stark reflux conditions for 6 h. The reaction mixture was cooled, poured into ice and 2 N HCl aqueous solution, and extracted with EtOAc (2×). The combined organics were washed with 2 N HCl aqueous solution (1×), 2 N NaOH aqueous solution (2×), brine (1×), and dried over Na2SO4. Concentration in vacuo gave 8-fluoro-2′,3′,5′,6′-tetrahydrospiro[chromene-2,4′-pyran]-4(3H)-one (29) (4.4 g, 48% yield) which was taken onto the next step without further purification. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.51-7.60 (2H, m), 7.00-7.07 (1H, m), 3.60-3.73 (4H, m), 2.93 (2H, s), 1.71-1.92 (4H, m).