Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([N:3]1[CH2:8][CH2:7][N:6]([CH2:9][CH2:10]O)[CH2:5][CH2:4]1)=[O:2].[SH:12][C:13]1[NH:14][C:15]2[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=2[N:17]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>CN(C)C=O.O>[CH:1]([N:3]1[CH2:8][CH2:7][N:6]([CH2:9][CH2:10][S:12][C:13]2[NH:14][C:15]3[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=3[N:17]=2)[CH2:5][CH2:4]1)=[O:2]
Reactant: Sc1nc2ccccc2[nH]1
Reactant: O=CN1CCN(CCO)CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: O
Product: O=CN1CCN(CCSc2nc3ccccc3[nH]2)CC1
Yield: 75.4 %

Procedure:
To a solution containing 1-formyl-4-(2-hydroxyethyl)piperazine (1.58 g, 10 mmol), 2-mercaptobenzimidazole (5.56 g, 37 mmol), and triphenylphosphine (9.26 g, 35.3 mmol) in dimethylformamide (100 mL), diethyl azodicarboxylate (5.19 g, 29.8 mmol) was added dropwise over 5 minutes with ice-cooling and stirring under argon. The mixture was stirred for 80 minutes at room temperature, and then water (2 mL) was added to the mixture so as to deactivate the reagent. The reaction mixture was concentrated under reduced pressure, and chloroform (200 mL) was added to the residue. Insoluble material was removed through filtration, and the filtrate was concentrated under reduced pressure. 2N Hydrochloric acid (20 mL) and ethyl acetate (100 mL) were added to the residue, and the liquid was partitioned. The organic layer was extracted with 2N hydrochloric acid (20 mL×2). The aqueous extract and the aqueous layer were combined, and the mixture was washed with chloroform (50 mL×2) . The pH of the mixture was adjusted to about 9 through addition of potassium carbonate, followed by extraction with chloroform (50 mL×3), washing the organic layer with saturated brine, drying over sodium sulfate anhydrate, and removing the solvent. The thus-formed crude product was crystallized from acetone-diethyl ether, thereby yielding 2.19 g of 1-formyl-4-[2-(benzimidazol-2-ylthio)ethyl]piperazine (yield: 76%) as a colorless crystalline powder. The crystallization mother liquor was concentrated under reduced pressure, and the residue was purified through silica gel column chromatography (eluent: chloroform:methanol=50:1 to 20:1), thereby yielding 0.42 g of 1-formyl-4-[2-(benzimidazol-2-ylthio)ethyl]piperazine (yield: 14%) as a colorless crystalline powder. The overall yield was 90%.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([O:6][C:7](=[CH:10][NH:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:8]=O)=[CH:4][CH:3]=1>C(O)CO>[Cl:1][C:2]1[CH:19]=[CH:18][C:5]([O:6][C:7]2[CH:8]=[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[NH:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)CNC=C(C=O)Oc1ccc(Cl)cc1
Solvent: OCCO
Product: CCOC(=O)c1cc(Oc2ccc(Cl)cc2)c[nH]1
Temperature: 25 °C
Yield: 5.3 %

Procedure:
2-(4-Chlorophenoxy)-3-carbethoxymethylaminoacrylaldehyde (2 g.) was boiled in 5 ml. of ethylene glycol for 15 minutes. The reaction was cooled to room temperature, diluted with 10 ml. of water and product extracted into 10 ml. of ethyl acetate. The ethyl acetate was back-washed with water and concentrated to an oil (1.5 g.). The oil chromatographed on approximately 100 ml. of silica gel with ethyl acetate-1/hexane-1 as eluant, monitored by thin layer chromatography. Evaporation of middle fractions gave ethyl 4-(4-chlorophenoxy)pyrrole-2-carboxylate (100 mg., oil, m/e 281, Rf 0.65 on silica gel thin layer chromatography with ethyl acetate-1/hexane-1/5% acetic acid as eluant; Rf 0.3 with ethyl acetate-1/hexane-1 as eluant). Repeat on a 5.5 g. scale gave an additional 400 mg. of product.
Reaction SMILES: [C:1]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(=[O:13])[CH2:2][C:3]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4].Br[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]Br.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.O>[C:2]1([C:1]([O:14][CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[O:13])([C:3]([O:5][CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[O:4])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: BrCCCCCBr
Reactant: O=C(CC(=O)OCc1ccccc1)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: O=C(OCc1ccccc1)C1(C(=O)OCc2ccccc2)CCCCC1

Procedure:
A solution of dibenzyl malonate (40 g, 161 mmol), 1,5-dibromopentane (22 mL, 161 mmol) and potassium carbonate (56 g, 402 mmol) in 300 mL of DMSO was stirred for 48 h in an oil bath at 50° C. The mixture was diluted with water and extracted with ethyl acetate (2×). The combined organic portions were dried over magnesium sulfate and concentrated. Flash chromatography (400 g silica, 15/1 hexane/EtOAc) gave the desired product. 1H NMR (500 MHz, CDCl3) δ1.4-1.5 (m, 1H), 1.52-1.6 (m, 5H), 2.03-2.1 (m, 4H), 5.13 (s, 4H), 7.22-7.38 (m, 10H).
Reaction SMILES: Br[C:2]1[C:3]2[C:4]3[CH:17]=[CH:16][S:15][C:5]=3[C:6](=[O:14])[NH:7][C:8]=2[CH:9]=[CH:10][C:11]=1[O:12][CH3:13].[CH2:18]([N:20]([CH:28]([C:30]1[CH:35]=[CH:34][C:33](B2OC(C)(C)C(C)(C)O2)=[CH:32][CH:31]=1)[CH3:29])[C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH3:19]>>[CH2:18]([N:20]([CH:28]([C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][C:35]=1[C:2]1[C:3]2[C:4]3[CH:17]=[CH:16][S:15][C:5]=3[C:6](=[O:14])[NH:7][C:8]=2[CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[CH3:29])[C:21](=[O:27])[O:22][C:23]([CH3:24])([CH3:25])[CH3:26])[CH3:19]
Reactant: COc1ccc2[nH]c(=O)c3sccc3c2c1Br
Reactant: CCN(C(=O)OC(C)(C)C)C(C)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Product: CCN(C(=O)OC(C)(C)C)C(C)c1ccccc1-c1c(OC)ccc2[nH]c(=O)c3sccc3c12
Yield: 37.6 %

Procedure:
Following General Procedure B, 9-bromo-8-methoxythieno[2,3-c]quinolin-4(5H)-one (770 mg, 2.5 mmol) was reacted with tert-butyl ethyl(1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)carbamate (1.4 g, 3.7 mmol) to afford the desired product (450 mg, 40%) as a light brown solid: ESI MS m/z 479 [C27H30N2O4S+H]+.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[NH:11]1[CH2:16][CH2:15][CH2:14][C@H:13]([NH:17][C:18](=[O:27])[O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:12]1.CCN(C(C)C)C(C)C>C(O)CCC>[N+:8]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:2]=1[N:11]1[CH2:16][CH2:15][CH2:14][C@H:13]([NH:17][C:18](=[O:27])[O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:12]1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1cnccc1Cl
Reactant: O=C(N[C@H]1CCCNC1)OCc1ccccc1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: O=C(N[C@H]1CCCN(c2ccncc2[N+](=O)[O-])C1)OCc1ccccc1
Yield: 95.9 %

Procedure:
To a 20 mL microwave vial containing 4-chloro-3-nitropyridine (Aldrich, 1.373 g, 8.660 mmol) and benzyl (3S)-piperidin-3-ylcarbamate (MolBridge, 2.077 g, 8.865 mmol), 1-butanol (10.0 mL) was added followed by DIPEA (1.836 g, 14.20 mmol). The mixture was irradiated with microwaves at 130° C. for 1 h. The mixture was then concentrated under reduced pressure, and the resulting residue was purified by flash chromatography on silica gel (0-30% MeOH in DCM) to give the sub-title compound as a yellow solid (2.96 g, 96%). LCMS calc. for C18H21N4O4 (M+H)+: m/z=357.2. found 357.1.
Reaction SMILES: [C:1]([O:4][C:5]1[C:14]([CH3:15])=[CH:13][C:12](/[CH:16]=[CH:17]\[CH2:18][OH:19])=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8])(=[O:3])[CH3:2]>[Pd].CCOC(C)=O>[C:1]([O:4][C:5]1[C:14]([CH3:15])=[CH:13][C:12]([CH2:16][CH2:17][CH2:18][OH:19])=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8])(=[O:3])[CH3:2]
Reactant: COC(=O)c1cc(/C=C\CO)cc(C)c1OC(C)=O
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(CCCO)cc(C)c1OC(C)=O
Reaction time: 8 h

Procedure:
A suspension of 10% palladium on carbon (146 mg, 0.137 mmol) in a solution of methyl 2-(acetyloxy)-5-[(1Z)-3-hydroxyprop-1-en-1-yl]-3-methylbenzoate (362 mg, 1.370 mmol) in EtOAc (17.2 mL) was shaken in a Parr shaker under H2 at 40 psi overnight. The reaction mixture was filtered through a plug of Celite and washed through with EtOAc. The filtrate was concentrated in vacuo to afford the crude product. This was purified by flash chromatography (Biotage Horizon, 25M, Si, ˜20 mL/min, 100% hexanes for 144 mL, gradient to 60% EtOAc in hexanes over 1125 mL) to afford methyl 2-(acetyloxy)-5-(3-hydroxypropyl)-3-methylbenzoate, as a colorless oil. LCMS calc.=289.1; found=288.9 (M+Na)+. 1H NMR (500 MHz, CHCl3): δ 7.65 (d, J=2.2 Hz, 1 H); 7.25 (d, J=2.2 Hz, 1 H); 3.84 (s, 3 H); 3.64 (t, J=6.4 Hz, 2 H); 2.67 (t, J=7.8 Hz, 2 H); 2.35 (s, 3 H); 2.18 (s, 3 H); 1.89-1.82 (m, 2 H).
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[NH:16][C:15](=[O:20])[NH:14][CH2:13]3)=[O:9])[CH:3]=1.CO.[OH-].[Na+].[BH4-].[Na+]>O.C(O)(=O)C>[OH:9][CH:8]([C:4]1[CH:3]=[N:2][CH:7]=[CH:6][CH:5]=1)[C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[NH:16][C:15](=[O:20])[NH:14][CH2:13]2
Reactant: O=C1NCc2cc(C(=O)c3cccnc3)ccc2N1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Solvent: O
Product: O=C1NCc2cc(C(O)c3cccnc3)ccc2N1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.6 %

Procedure:
To a mixture of 4.35 parts of intermediate 2, namely 3,4-dihydro-6-(3-pyridinylcarbonyl)-2(1H)-quinazolinone monohydrochloride, 63.2 parts of methanol, 1.2 parts of sodium hydroxide and 15 parts of water were added portionwise 0.6 parts of sodium tetrahydroborate. After stirring for 2 hours at room temperature, there was added a mixture of 2.1 parts of acetic acid in 25 parts of water. The precipitate was filtered off, washed with water, 2-propanol and 1,1'-oxybisethane and dried, yielding 3.7 parts (96.6%) of 3,4-dihydro-6-[hydroxy(3-pyridinyl)methyl]-2(1H)-quinazolinone; mp. 272.0° C. (interm. 27).
Reaction SMILES: [CH2:1]([NH:4][CH:5]([CH3:10])[C:6]([O:8]C)=O)[C:2]#[CH:3].[Cl:11][C:12]1[CH:13]=[C:14]([N:19]=[C:20]=[O:21])[CH:15]=[C:16]([Cl:18])[CH:17]=1>C1(C)C=CC=CC=1.CCCCC(C([O-])=O)CC.CCCCC(C([O-])=O)CC.[Sn+2]>[Cl:11][C:12]1[CH:13]=[C:14]([N:19]2[C:6](=[O:8])[CH:5]([CH3:10])[N:4]([CH2:1][C:2]#[CH:3])[C:20]2=[O:21])[CH:15]=[C:16]([Cl:18])[CH:17]=1
Reactant: O=C=Nc1cc(Cl)cc(Cl)c1
Reactant: C#CCNC(C)C(=O)OC
Agent: CCCCC(CC)C(=O)[O-]
Agent: [Sn+2]
Solvent: Cc1ccccc1
Product: C#CCN1C(=O)N(c2cc(Cl)cc(Cl)c2)C(=O)C1C
Yield: 86.5 %

Procedure:
To a solution of 10 g (0.07 mole) of methyl 2-propargylaminopropionate in 100 ml of toluene with 2 drops of stannous octoate is added 14.5 g (0.077 mole) of 3,5-dichlorophenylisocyanate in small portions. The resulting mixture is heated at 100° for 3 hours. It is then washed with water twice and dried over sodium sulfate. Solvent is evaporated to give a thick yellow oil. Material is further purified by passing it through a silica gel column using 30/70 ethyl acetate/hexane as solvent to give 18 g of a light yellow oil which solidifies on standing. The solids are triturated in boiling hexane and collected by filtration, mp 105°-6°. NMR and elemental analysis confirm the desired structure.
Reaction SMILES: [C:1]1([C:7]2[O:8][CH:9]=[C:10]([CH2:12][CH2:13][O:14][C:15]3[CH:20]=[CH:19][C:18]([CH2:21][C:22]4[NH:26]C(=O)[O:24][N:23]=4)=[CH:17][CH:16]=3)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.NO.Cl.N=O>CO>[OH:24][NH:23][C:22](=[NH:26])[CH2:21][C:18]1[CH:17]=[CH:16][C:15]([O:14][CH2:13][CH2:12][C:10]2[N:11]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[O:8][CH:9]=2)=[CH:20][CH:19]=1
Reactant: O=c1[nH]c(Cc2ccc(OCCc3coc(-c4ccccc4)n3)cc2)no1
Agent: Cl
Agent: N=O
Agent: NO
Solvent: CO
Product: N=C(Cc1ccc(OCCc2coc(-c3ccccc3)n2)cc1)NO
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Preparation of: 3-[(4-(2-(2-Phenyl-4-oxazolyl)ethoxy)phenyl)methyl]1,2,4-oxadiazolin-5-one. ##STR28## Part A Preparation of: ##STR29## To a cooled (0° C.) solution of 0.88 g of Na in 80 mL of anhydrous MeOH was added 2.67 g of NH2OH HCl followed by a solution of the iminoether of Example 12 Part C Method 2 in 100 mL of anhydrous MeOH. The reaction mixture was allowed to warm to 25° C. and was stirred for 18 hours. The residue, after removal of solvent, was partitioned between 200 mL of H2O and 700 mL of EtOAc. The solid was removed by filtration and washed with H2O and EtOAc. The combined organic phases were washed with H2O and combined with the solid. After removal of the solvent, the residue was recrystallized from MeOH. The filtrate was diluted with Et2O and the resulting solid was filtered to give 4.14 g of crude N-hydroxy-4-[2-(2-phenyl-4-oxazolyl)ethoxy]benzeneethanimidamide. FD-MS: m/e 337.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[N:11]1[CH:16]=[CH:15][C:14](=[O:17])[CH2:13][CH2:12]1.C(O)(=O)C.[H][H]>C1COCC1.[Pd].C([O-])([O-])=O.[Ca+2]>[NH2:8][C:6]1[CH:5]=[CH:4][C:3]([N:11]2[CH:12]=[CH:13][C:14](=[O:17])[CH2:15][CH2:16]2)=[C:2]([F:1])[CH:7]=1
Reactant: [H][H]
Reactant: O=C1C=CN(c2ccc([N+](=O)[O-])cc2F)CC1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: Nc1ccc(N2C=CC(=O)CC2)c(F)c1

Procedure:
In a 500 ml Parr bottle, the nitrophenyl compound from step 3 (35 g, 148.3 mmol), Pd/CaCO3 (3.5 g, 10 wt %) and acetic acid (17 ml, 297 mmol) are combined in THF (350 ml). The mixture is hydrogenated at 40° C. under 15 psi hydrogen for 6 h at which time the reaction is complete by HPLC. The reaction mixture is filtered through a GF/F filter and the catalyst cake washed with THF (350 ml). The filtrate is partitioned between 500 ml of NaHCO3 and 500 ml of ethyl acetate. The organic layer is washed again with 500 ml of NaHCO3. The organic layer is separated and dried over MgSO4. The mixture is filtered, and the filtrated is concentrated in vacuo to afford 29.0 g (95% recovery) of crude title compound. MS (ESI−) for C11H11FN2O m/z 205.0 (M−H)−; 1H NMR (MeOD) δ 7.37 (d, J=7.5, 1 H), 7.02 (t, J=9.0, 1 H), 6.47 (m, 3 H), 5.07 (d, J=7.4, 1 H), 3.84 (t, J=7.8, 2 H), 2.58 (t, J=7.8, 1 H); 13C NMR (MeOD) δ 195.1, 160.1, 157.7, 157.1, 151.2, 127.9, 124.0, 122.9, 112.2, 103.5, 103.2, 100.2, 51.4, 36.8.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:15]=[C:14]3[C:10]([CH2:11][C:12](=[O:16])[NH:13]3)=[CH:9][CH:8]=2)[CH:2]=1.[CH3:17][N:18]([CH3:34])[CH2:19][CH2:20][CH2:21][NH:22][C:23]([C:25]1[C:29]([CH3:30])=[C:28]([CH:31]=O)[NH:27][C:26]=1[CH3:33])=[O:24]>>[CH3:34][N:18]([CH3:17])[CH2:19][CH2:20][CH2:21][NH:22][C:23]([C:25]1[C:29]([CH3:30])=[C:28]([CH:31]=[C:11]2[C:10]3[C:14](=[CH:15][C:7]([C:3]4[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=4)=[CH:8][CH:9]=3)[NH:13][C:12]2=[O:16])[NH:27][C:26]=1[CH3:33])=[O:24]
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)NCCCN(C)C
Reactant: O=C1Cc2ccc(-c3cccnc3)cc2N1
Product: Cc1[nH]c(C=C2C(=O)Nc3cc(-c4cccnc4)ccc32)c(C)c1C(=O)NCCCN(C)C
Yield: 75.9 %

Procedure:
6-Pyridin-3-yl-1,3-dihydroindol-2-one (42 mg, 0.2 mmol) was condensed with 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (3-dimethylaminopropyl)amide (50 mg) to give 67 mg (75%) of the title compound as yellow-brown solid.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:24])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:23])=[CH:10][CH:9]=1)[NH2:6].[Cl:25][C:26]1[N:34]=[CH:33][CH:32]=[CH:31][C:27]=1[C:28](O)=[O:29].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1>C(Cl)Cl>[CH3:2][O:3][C:4](=[O:24])[C@H:5]([CH2:7][C:8]1[CH:9]=[CH:10][C:11]([O:14][CH2:15][C:16]2[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:23])=[CH:12][CH:13]=1)[NH:6][C:28](=[O:29])[C:27]1[CH:31]=[CH:32][CH:33]=[N:34][C:26]=1[Cl:25]
Reactant: COC(=O)[C@@H](N)Cc1ccc(OCc2c(Cl)cccc2Cl)cc1
Reactant: O=C(O)c1cccnc1Cl
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Solvent: ClCCCl
Product: COC(=O)[C@H](Cc1ccc(OCc2c(Cl)cccc2Cl)cc1)NC(=O)c1cccnc1Cl

Procedure:
A solution of O-(2,6-dichlorobenzyl)-L-tyrosine methyl ester hydrochloride, (1.11 g, 2.84 mmol), 2-chloronicotinic acid (0.45 g, 2.84 mmol), EDC (0.60 g, 3.13 mmol), HOBT (0.46 g, 3.41 mmol) and NMM (0.467 ml, 0.43 g, 4.26 mmol) in DCM (25 ml) was stirred at room temperature for 24 h. The reaction mixture was partitioned between DCM (50 ml) and 10% NaHCO3 solution (30 ml). The organic layer was separated, dried over MgSO4 and the solvent removed under vacuum to give a pale yellow solid that was recrystallized from EtOAc/hexane to give the title compound as an off white solid (1.14 g, 81%), δH (CDCl3) 8.46 (1H, dd, J 2.0, 4.7Hz), 8.05 (1H, dd, J 2.0, 7.6Hz), 7.34 (2H, m), 7.25 (2H, m), 7.11 (2H, m), 6.96 (3H, m), 5.24 (2H, s), 5.06 (1H, m), 3.80 (3H, s) and 3.24 (2H, m).
Reaction SMILES: [CH3:1]O.[CH3:3][O:4][C:5]1[CH:10]=[C:9]([C:11]([OH:20])([C:16]([F:19])([F:18])[F:17])[C:12]([F:15])([F:14])[F:13])[CH:8]=[CH:7][C:6]=1[CH2:21][CH2:22][C:23]([OH:25])=[O:24].S(=O)(=O)(O)O>C1(C)C=CC=CC=1>[CH3:3][O:4][C:5]1[CH:10]=[C:9]([C:11]([OH:20])([C:16]([F:17])([F:18])[F:19])[C:12]([F:15])([F:14])[F:13])[CH:8]=[CH:7][C:6]=1[CH2:21][CH2:22][C:23]([O:25][CH3:1])=[O:24]
Reactant: CO
Reactant: COc1cc(C(O)(C(F)(F)F)C(F)(F)F)ccc1CCC(=O)O
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Product: COC(=O)CCc1ccc(C(O)(C(F)(F)F)C(F)(F)F)cc1OC

Procedure:
To a solution of 50 ml of methanol in 50 ml toluene are added 7.0 g (0.02 mole) of 2-methoxy-4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]benzenepropanoic acid and 1 ml of concentrated sulfuric acid. The resulting solution is stirred, heated at reflux for 18 hours, then concentrated to 20 ml at reduced pressure, and extracted with ether. The resulting ether solution is washed with 5% sodium bicarbonate solution and water. The solution is dried with anhydrous magnesium sulfate, filtered and concentrated at reduced pressure to obtain a residual solid which is recrystallized from petroleum ether to give 5.5 g of methyl 2-methoxy-4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]benzenepropanoate having a melting point of 78°-80°.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[CH:12][C:5]([C:6](N(OC)C)=[O:7])=[C:4]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:3]=1.[CH2:21]([Mg]Br)[CH3:22].CCCCCC.C(OCC)(=O)C>C1COCC1>[Cl:1][C:2]1[CH:13]=[CH:12][C:5]([C:6](=[O:7])[CH2:21][CH3:22])=[C:4]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:3]=1
Reactant: CON(C)C(=O)c1ccc(Cl)cc1Nc1ccccc1
Reactant: CC[Mg]Br
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCC(=O)c1ccc(Cl)cc1Nc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.9 %

Procedure:
To a solution of 4-chloro-N-methoxy-N-methyl-2-phenylamino-benzamide (5.0 g, 17.2 mmol) in THF (60 mL) was added ethylmagnesium bromide (1M solution in THF, 70 mL, 70 mmol) dropwise at 0° C. under nitrogen. The mixture was slowly warmed to room temperature and stirred for 2 hr. Completion of the reaction was monitored by silica TLC (mobile phase; hexane:ethyl acetate=4:1; Rf=0.5). Reaction was quenched with an aqueous solution of 1N HCl (50 mL) at 0° C. and was extracted with ethyl acetate (2×300 mL). The combined organic layers were washed with water (100 mL), brine (100 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude material was purified using silica gel (100-200 mesh) column chromatography, using gradient polarity mobile phase (ethyl acetate:hexane=1:91:4), to give 1-(4-chloro-2-phenylamino-phenyl)-propan-1-one (4.15 g, 92.9% yield) as a yellow oil. 1H NMR (DMSO-d6) δ ppm 10.53 (s, 1H) 8.00 (d, J=8.7 Hz, 1H) 7.34-7.51 (m, 2H) 7.28 (d, J=7.7 Hz, 2H) 7.13-7.23 (m, 1H) 7.07 (d, J=1.8 Hz, 1H) 6.82 (dd, J=8.6, 1.9 Hz, 1H) 3.07 (q, J=7.2 Hz, 2H) 1.09 (t, J=7.3 Hz, 3H).
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]([N:11]2[CH2:20][CH2:19][N:18]3[CH:13]([CH2:14][O:15][C:16]4[CH:24]=[C:23]([N+:25]([O-])=O)[CH:22]=[CH:21][C:17]=43)[CH2:12]2)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])=O.[NH4+].C(=O)([O-])[O-].[K+].[K+].[CH2:38]([O:45][C:46](Cl)=[O:47])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>O1CCCC1.CO.[Pd]>[C:1]1([CH2:7][O:8][C:9]([N:11]2[CH:20]=[CH:19][N:18]3[C:13](=[CH:14][O:15][C:16]4[CH:24]=[C:23]([NH:25][C:46]([O:45][CH2:38][C:39]5[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=5)=[O:47])[CH:22]=[CH:21][C:17]=43)[CH2:12]2)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: O=C(OCc1ccccc1)N1CCN2c3ccc([N+](=O)[O-])cc3OCC2C1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: O=C[O-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(Nc1ccc2c(c1)OC=C1CN(C(=O)OCc3ccccc3)C=CN12)OCc1ccccc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a flask containing 1, 2, 4a, 5-tetrahydro-8-nitro-pyrazino[2, 1-c] [1, 4]benzoxazine-3(4 H)-carboxylic acid phenylmethyl ester (Step 6, 2.75 g, 7.45 mmol) in tetrahydrofuran (100 mL) and methanol (50 mL) is added 10% palladium on carbon (2.00 g) and ammonium formate (4.69 g, 74.45 mmol), heated to reflux for 2 hours and stirred at ambient temperature for 15 hours. The mixture is filtered through celite and concentrated in vacuo. To the residue dissolved in water (15 mL) and acetone (15 mL) cooled to 0° C. is added potassium carbonate (2.27 g, 16.39 mmol) followed by benzyloxycarbonylchloride (2.34 mL, 16.39 mmol). The reaction is slowly warmed to ambient temperature, stirred for 64 hours, concentrated in vacuo, diluted with ethyl acetate (100 mL), washed with water (2×25 mL) and saline, dried over Na2SO4, concentrated in vacuo and chromatographed on silica gel (230-400 mesh, 200 mL), eluting with hexane/ethyl acetate (75/25). The appropriate fractions are combined (Rf =0.46, TLC, hexane/ethyl acetate, 50/50) and concentrated in vacuo to give the title compound, mp 118-120° C.
Reaction SMILES: C=CC1C=CC=CC=1.[C:9]1([C:15]#[C:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[C:23]([O-:33])(=[O:32])[CH:24]=[CH:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[C:23]([OH:33])(=[O:32])[CH:24]=[CH:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1.[C:9]1([C:15]#[C:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C([O-])C=Cc1ccccc1
Agent: C(#Cc1ccccc1)c1ccccc1
Solvent: C=Cc1ccccc1
Product: O=C(O)C=Cc1ccccc1

Procedure:
The ethyl bromocinnamate 9F is treated with diisobutylaluminum hydride (DIBAL) to give the alcohol, which is then coupled with an alkyl bromide to give the styrene ether 9G. This ether is then coupled with alkyne 9E, again using a palladium catalyst, to give the tolane styrene 1H. Alternatively, the alkyne can be coupled with the original cinnamate to give a tolane cinnamate. If desired, the ester group can be derivatized by sequential hydrolysis, conversion to an acid chloride, and reaction with an alkanol to give the tolane cinnamate 9I.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:12]=[C:11](O)[C:10]2[C:5](=[CH:6][C:7]([O:14][CH3:15])=[CH:8][CH:9]=2)[N:4]=1.O=P(Cl)(Cl)[Cl:18]>>[Cl:18][C:11]1[C:10]2[C:5](=[CH:6][C:7]([O:14][CH3:15])=[CH:8][CH:9]=2)[N:4]=[C:3]([O:2][CH3:1])[N:12]=1
Reactant: COc1ccc2c(O)nc(OC)nc2c1
Reactant: O=P(Cl)(Cl)Cl
Product: COc1ccc2c(Cl)nc(OC)nc2c1
Yield: 36.1 %

Procedure:
A solution of 2,7-dimethoxyquinazolin-4-ol (155 mg, 0.752 mmol) in POCl3 (2 ml, 21.46 mmol) was refluxed for 4 h. The reaction mixture was concentrated. The residue was dissolved in DCM and the pH was adjusted to 7 with 4N NaOH. The organic phase was collected and dried over sodium sulfate, filtered, then concentrated under vacuum. The crude material was purified by silica gel chromatography using 50% DCM in hexanes. The product fractions were collected and the solvent removed under vacuum to give 4-chloro-2,7-dimethoxyquinazoline (61 mg, 36% yield). MS: MS m/z 225.1 (M++1).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][O:35]C(=O)C)=[CH:14][CH:13]=2)=[CH:8][CH:7]=1)=[O:5])C.[OH-].[Na+].C(O)C>O>[OH:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][O:18][C:15]1[CH:14]=[CH:13][C:12]([C:9]2[CH:10]=[CH:11][C:6]([C:4]([OH:5])=[O:3])=[CH:7][CH:8]=2)=[CH:17][CH:16]=1
Reactant: CCOC(=O)c1ccc(-c2ccc(OCCCCCCCCCCCCCCCCOC(C)=O)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1ccc(-c2ccc(OCCCCCCCCCCCCCCCCO)cc2)cc1
Yield: 95.6 %

Procedure:
30 m moles (15.7 g) of the above 4'-(16-acetyloxyhexadecyloxy)biphenyl-4-carboxylic acid ethyl ester and 10 g of sodium hydroxide were stirred for 10 min. at 70° C. in a mixed solution of 40 ml of ethanol and 80 ml of water. After the reaction, the reaction solution was concentrated to obtain 13.0 g of 4'-(16-hydroxyhexadecyloxy)biphenyl-4-carboxylic acid. (yield: 95%)