Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([NH2:4])([CH3:3])[CH3:2].Cl.C([BH3-])#N.[Na+].O[CH:11]1[NH:16][C:15](=[O:17])[C:14]2([C:29]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[C:23]3[C:18]2=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:13][CH2:12]1>C(#N)C>[C:15]([C:14]1([CH2:13][CH2:12][CH2:11][NH:4][CH:1]([CH3:3])[CH3:2])[C:29]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[C:23]2[C:18]1=[CH:19][CH:20]=[CH:21][CH:22]=2)(=[O:17])[NH2:16]
Reactant: CC(C)N
Reactant: O=C1NC(O)CCC12c1ccccc1-c1ccccc12
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC#N
Product: CC(C)NCCCC1(C(N)=O)c2ccccc2-c2ccccc21
Temperature: 10 °C

Procedure:
The general procedure thus described was repeated when a solution of isopropylamine (45.0 ml) in acetonitrile (250 ml) was cooled to 10° C. and hydrogen chloride gas introduced into the solution keeping the temperature below 15° to pH 8.5±0.3. The resultant slurry was allowed to warm to room temperature and sodium cyanoborohydride (12.0 g) added in one portion and the pH readjusted to 8.5 if necessary. 6'-Hydroxyspiro-(9H-fluorene-9,3'-piperidine)-2'-one (30.0 g) was then added and the reaction mixture heated to reflux for 2 hours. The mixture was allowed to cool to room temperaure and dilute hydrochloric acid added to pH 1-2 to destroy any excess cyanoborohydride. The acetonitrile was removed under reduced pressure and the residue basified with sodium hydroxide solution (pH 11) and extracted with dichloromethane (3×100 ml) and the combined organic layers washed with sodium hydroxide solution, dried with anhydrous sodium sulphate and evaporated to give the crystalline free amine.
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[C:7]2[CH2:8][CH2:9][CH2:10][C:6]=2[C:5]2[C:11]([OH:24])=[CH:12][C:13]([CH:15]([CH:17]([CH3:23])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH3:16])=[CH:14][C:4]=2[O:3]1.C1(N=C=NC2CCCCC2)CCCCC1.[ClH:41].[N:42]1([CH2:48][CH2:49][C:50](O)=[O:51])[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]1.Cl>CCOCC.C(Cl)Cl>[ClH:41].[CH3:25][C:2]1([CH3:1])[C:7]2[CH2:8][CH2:9][CH2:10][C:6]=2[C:5]2[C:11]([O:24][C:50](=[O:51])[CH2:49][CH2:48][N:42]3[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]3)=[CH:12][C:13]([CH:15]([CH:17]([CH3:23])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH3:16])=[CH:14][C:4]=2[O:3]1
Reactant: O=C(O)CCN1CCCCC1
Reactant: CCCCCC(C)C(C)c1cc(O)c2c(c1)OC(C)(C)C1=C2CCC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Product: CCCCCC(C)C(C)c1cc(OC(=O)CCN2CCCCC2)c2c(c1)OC(C)(C)C1=C2CCC1

Procedure:
2.8 g. (8.2 mmoles) of 4,4-dimethyl-9-hydroxy-7-(3-methyl-2-octyl)-1,2,3,4-tetrahydrocyclopenta[c] [l] benzopyran, 1.77 g. (8.6 mmoles) of dicyclohexylcarbodiimide and 1.65 g. (8.5 mmoles) of β-piperidinopropionic acid hydrochloride (m.p. 216°-220°, J. Am. Chem. Soc. 73, 3168 (1951)) were combined with 125 ml. of methylene chloride and stirred at room temperature for about 20 hours. The reaction mixture was filtered and the methylene chloride removed using a rotary evaporator. The residue was treated with benzene and filtered to remove a small quantity of insoluble material. The benzene was evaporated and the dark viscous residue was chromatographed using 100 g. of 60-100 mesh Florisil activated magnesium silicate and methanol/chloroform graded solvent mixtures. Chromatography gave a small quantity of orange oil which was dissolved in ether and treated with a solution of ethereal HCl. The desired compound appeared as white crystals which were filtered and washed with additional ether. The colorless crystals (86 mg., m.p. 106°-107°) were pure by thin layer chromatography (10% MeOH/CHCl3) and the nmr and infrared spectra are in agreement with the proposed structure.
Reaction SMILES: [F:1][C:2](=[CH2:7])[C:3]([O:5][CH3:6])=[O:4].[CH2:8]([N:15]([CH2:19][Si](C)(C)C)[CH2:16]OC)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:8]([N:15]1[CH2:16][CH2:7][C:2]([F:1])([C:3]([O:5][CH3:6])=[O:4])[CH2:19]1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: C=C(F)C(=O)OC
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)C1(F)CCN(Cc2ccccc2)C1
Temperature: 0 °C
Reaction time: 16 h
Yield: 42.6 %

Procedure:
A 0.3 M solution of methyl 2-fluoroacrylate (4.37 g, 41.99 mmol) and DCM (140 mL) was stirred under nitrogen and cooled to 0° C. The reaction mixture was then treated with N-benzyl-1-methoxy-N-((trimethylsilyl)methyl)methanamine (10.47 g, 44.09 mmol) followed by TFA (1.56 mL, 20.99 mmol). The reaction mixture was warmed to RT and stirred for 16 h. The reaction mixture was then concentrated in vacuo. The crude product was purified by SiO2 Biotage chromatography (hexanes/acetone) to afford 4.24 g (42.6%) of methyl 1-benzyl-3-fluoropyrrolidine-3-carboxylate (72a): 1H NMR (400 MHz, DMSO-d6) δ=7.35-7.23 (m, 5H), 3.72 (s, 3H), 3.63 (s, 2H), 2.97-2.80 (m, 3H), 2.54-2.48 (m, 1H), 2.43-2.30 (m, 1H), 2.18-2.04 (m, 1H).
Reaction SMILES: [CH2:1]([C:9]1[C:13]([C:14](Cl)=[O:15])=[C:12]([CH3:17])[O:11][N:10]=1)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[OH-].[NH4+:19]>C(OCC)C>[CH2:1]([C:9]1[C:13]([C:14]([NH2:19])=[O:15])=[C:12]([CH3:17])[O:11][N:10]=1)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: [NH4+]
Reactant: Cc1onc(CCc2ccccc2)c1C(=O)Cl
Agent: [OH-]
Solvent: CCOCC
Product: Cc1onc(CCc2ccccc2)c1C(N)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 24.9 g. (0.10 mole) 3-phenethyl-5-methyl-isoxazole-4-carboxylic acid chloride in 100 ml. diethyl ether is added to 7.7 g. (0.2 mole) of concentrated ammonium hydroxide while maintaining the temperature at 0° to 10° C. The mixture is stirred at room temperature overnight and filtered. The resulting solid is washed with water and dried to give 3-phenethyl-5-methyl-isoxazole-4-carboxamide; m.p. 135° to 136° C.
Reaction SMILES: [NH2:1][C:2]1[C:6]2[C:7](=[O:23])[N:8]([C:11]3[C:16]([F:17])=[CH:15][C:14]([NH:18][C:19](=[O:21])[CH3:20])=[CH:13][C:12]=3[F:22])[CH:9]=[CH:10][C:5]=2[NH:4][N:3]=1.[Br:24]Br>C(O)(=O)C>[BrH:24].[NH2:1][C:2]1[C:6]2[C:7](=[O:23])[N:8]([C:11]3[C:12]([F:22])=[CH:13][C:14]([NH:18][C:19](=[O:21])[CH3:20])=[CH:15][C:16]=3[F:17])[CH:9]=[C:10]([Br:24])[C:5]=2[NH:4][N:3]=1
Reactant: CC(=O)Nc1cc(F)c(-n2ccc3[nH]nc(N)c3c2=O)c(F)c1
Reactant: BrBr
Solvent: CC(=O)O
Product: Br
Product: CC(=O)Nc1cc(F)c(-n2cc(Br)c3[nH]nc(N)c3c2=O)c(F)c1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To a mixture of N-(4-(3-amino-4-oxo-1H-pyrazolo[4,3-c]pyridin-5(4H)-yl)-3,5-difluorophenyl)acetamide obtained in Step D (0.67 g) and acetic acid (30 mL) was slowly added bromine (0.21 mL) at 80° C., and the reaction mixture was stirred at 80° C. for 2 hr. The solvent was evaporated under reduced pressure, and the residue was recrystallized from acetic acid to give the title compound (0.65 g).
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]([C:16]([OH:18])=O)[S:10][C:11]=2[C:12]([F:15])([F:14])[F:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.[Si:33]([O:40][CH2:41][CH2:42][N:43]([C@H:51]1[C:59]2[C:54](=[C:55]([C:60](=[NH:63])[NH:61]O)[CH:56]=[CH:57][CH:58]=2)[CH2:53][CH2:52]1)[C:44](=[O:50])[O:45][C:46]([CH3:49])([CH3:48])[CH3:47])([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34]>CN(C=O)C>[Si:33]([O:40][CH2:41][CH2:42][N:43]([C@H:51]1[C:59]2[C:54](=[C:55]([C:60]3[N:63]=[C:16]([C:9]4[S:10][C:11]([C:12]([F:13])([F:14])[F:15])=[C:7]([C:1]5[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=5)[CH:8]=4)[O:18][N:61]=3)[CH:56]=[CH:57][CH:58]=2)[CH2:53][CH2:52]1)[C:44](=[O:50])[O:45][C:46]([CH3:49])([CH3:48])[CH3:47])([C:36]([CH3:37])([CH3:38])[CH3:39])([CH3:35])[CH3:34]
Reactant: O=C(O)c1cc(-c2ccccc2)c(C(F)(F)F)s1
Reactant: CC(C)(C)OC(=O)N(CCO[Si](C)(C)C(C)(C)C)[C@@H]1CCc2c(C(=N)NO)cccc21
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N(CCO[Si](C)(C)C(C)(C)C)[C@@H]1CCc2c(-c3noc(-c4cc(-c5ccccc5)c(C(F)(F)F)s4)n3)cccc21
Temperature: 85 °C
Reaction time: 0.5 h
Yield: 40 %

Procedure:
Prepared using General Procedure 2. To a solution of 4-phenyl-5-(trifluoromethyl)thiophene-2-carboxylic acid (0.109 g, 0.4 mmol) in DMF (3.0 mL) was added HOBt (0.088 g, 0.57 mmol) and EDC (0.109 g, 0.57 mmol) at room temperature. The reaction mixture was stirred for 0.5 h until the complete formation of the HOBt-acid complex. (R)-tert-butyl 2-(tert-butyldimethylsilyloxy)ethyl(4-(N-hydroxycarbamimidoyl)-2,3-dihydro-1H-inden-1-yl)carbamate INT-61 (0.200 g, 0.44 mmol) was added and the mixture was stirred at room temperature for 0.5 h until the formation of the intermediate (R)-tert-butyl 2-(tert-butyldimethylsilyloxy)ethyl(4-(N-(4-phenyl-5-(trifluoromethyl)thiophene-2-carbonyloxy) carbamimidoyl)-2,3-dihydro-1H-inden-1-yl) carbamate was observed. The reaction mixture was heated at 85° C. for 4 h. Upon cooling, the mixture was extracted with DCM and brine. The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure to produce a brown oil. The crude product was purified by silica gel flash chromatography (MeOH/DCM) to yield 0.108 g (40%) of (R)-tert-butyl 2-(tert-butyldimethylsilyloxy)ethyl(4-(5-(4-phenyl-5-(trifluoromethyl)thiophen-2-yl)-1,2,4-oxa-diazol-3-yl)-2,3-dihydro-1H-inden-1-yl)carbamate INT-63 as a light yellow oil. LCMS-ESI (m/z) calculated for C35H42F3N3O4SSi: 685.9; found 411.0 [M+H−tert-butyl 2-(tert-butyldimethylsilyloxy)ethylcarbamate]+, tR=4.01 min.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:17][OH:18])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:19][S:20](Cl)(=[O:22])=[O:21]>ClCCl>[CH3:19][S:20]([O:18][CH2:17][C@H:9]([NH:8][C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:7])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=[O:22])=[O:21]
Reactant: CC(C)(C)OC(=O)N[C@@H](CO)Cc1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](COS(C)(=O)=O)Cc1ccccc1
Reaction time: 0.5 h

Procedure:
To a solution of N-tert-butoxycarbonyl-D-Phenylalaninol (754 mg) and TEA (0.5 ml) in dichloromethane was added methanesulfonyl chloride (0.28 ml) at 0°-5° C. The reaction mixture was stirred at 0°-5° C. for 30 min, quenched with water, and extracted with dichloromethane.
Reaction SMILES: CC([O:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1)=O.[NH:14]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:17](=O)[C:15]1=[O:16].C(=O)([O-])[O-].[Na+].[Na+].O>CO>[CH:21]1[CH:22]=[CH:23][C:24]2[NH:14][C:15]([OH:16])=[C:17]([C:6]3[C:5](=[O:4])[C:13]4[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=4[N:7]=3)[C:19]=2[CH:20]=1
Reactant: O=C1Nc2ccccc2C1=O
Reactant: CC(=O)Oc1c[nH]c2ccccc12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: O=C1C(c2c(O)[nH]c3ccccc23)=Nc2ccccc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 69 %

Procedure:
Argon gas was blown into a suspension of indoxyl acetate (1.75 g, 10 mmol) and isatin (1.47 g, 10 mmol) in anhydrous methanol (20 mL) for 5 minutes. Sodium carbonate (2.12 g, 20 mmol) was added to the reaction liquid and stirred at room temperature for 18 hours. The reaction liquid was then poured into water (1 L). The precipitated crude crystals were collected by suction filtration. The resulting crude crystals were recrystallized from 1,4-dioxane/hexane to give purple needle-shaped crystals of indirubin (1.81 g, 69%).
Reaction SMILES: Br[CH:2]([C:9](=O)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:3][CH2:4][C:5]([O:7][CH3:8])=[O:6].[CH2:17]([NH:20][C:21]([NH2:23])=[S:22])[CH2:18][CH3:19]>CO>[C:10]1([C:9]2[N:23]=[C:21]([NH:20][CH2:17][CH2:18][CH3:19])[S:22][C:2]=2[CH2:3][CH2:4][C:5]([O:7][CH3:8])=[O:6])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: COC(=O)CCC(Br)C(=O)c1ccccc1
Reactant: CCCNC(N)=S
Solvent: CO
Product: CCCNc1nc(-c2ccccc2)c(CCC(=O)OC)s1
Yield: 70.3 %

Procedure:
A mixture of methyl 4-bromo-5-oxo-5-phenylpentanoate (5.00 g), N-propylthiourea (2.01 g) and methanol (50 ml) was refluxed for 2 hrs. The reaction solvent was removed under reduced pressure, and the residue was dissolved in ethyl acetate. The obtained solution was washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate, and concentrated to give methyl 3-[4-phenyl-2-[N-(1-propyl)amino]-5-thiazolyl]propionate (3.64 g, yield 70%) as colorless crystals. The crystals were recrystallized from ethyl acetate-hexane. melting point: 67–68° C.
Reaction SMILES: C1(NC2C=CC=CC=2)C=CC=CC=1.NC1C=CC=CC=1.P(=O)(O)(O)O.C(OCC)(=O)C.[O:32]=[CH:33][C@@H:34]([C@H:36]([C@@H:38]([C@@H:40]([CH2:42][OH:43])[OH:41])[OH:39])[OH:37])[OH:35]>>[CH2:42]([OH:43])[C@@H:40]([OH:41])[C@@H:38]([OH:39])[C@H:36]([OH:37])[C:34]([CH:33]=[O:32])=[O:35]
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: O=P(O)(O)O
Agent: c1ccc(Nc2ccccc2)cc1
Solvent: Nc1ccccc1
Solvent: CCOC(C)=O
Product: O=CC(=O)[C@@H](O)[C@H](O)[C@H](O)CO
Temperature: 100 °C

Procedure:
Thin layer chromatography (TLC). Avicel coated glass plates are developed with an 8:8:2:4 (by volume); isopropanol:pyridine:acetic acid:water solvent system. Glucose and fructose have Rf 's 0.5-0.6; D-glucosone has an Rf 0.4-0.5 streak. (Rf =the distance substance migrates from origin/solvent front distance from origin). When the plates are sprayed with triphenyltetrazolium chloride (2% TTC in 0.5 N NaOH), both D-glucosone and fructose instantly yield red spots; glucose yields a red spot only upon heating for ten minutes at 100° C. When the plates are sprayed with diphenylamine/aniline/phosphoric acid/ethyl acetate reagent, (0.15 g/0.8 ml/11 ml/100ml), glucose yields a brown spot; D-glucosone yields a purple streak; and fructose yields a yellow spot upon heating for 10 minutes at 95° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH:5]([O:17][CH2:18][CH3:19])[CH2:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]=[C:10]2[CH3:16])[CH3:2].Cl[CH2:22][C:23]1[N:24]=[C:25]([C:29]2[CH:34]=[CH:33][C:32]([CH:35]([CH3:37])[CH3:36])=[CH:31][CH:30]=2)[O:26][C:27]=1[CH3:28].[H-].[Na+]>CN(C)C=O.O>[CH2:1]([O:3][C:4](=[O:20])[CH:5]([O:17][CH2:18][CH3:19])[CH2:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH2:22][C:23]1[N:24]=[C:25]([C:29]3[CH:30]=[CH:31][C:32]([CH:35]([CH3:37])[CH3:36])=[CH:33][CH:34]=3)[O:26][C:27]=1[CH3:28])[CH:11]=[C:10]2[CH3:16])[CH3:2]
Reactant: Cc1oc(-c2ccc(C(C)C)cc2)nc1CCl
Reactant: CCOC(=O)C(Cc1ccc2[nH]cc(C)c2c1)OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C(Cc1ccc2c(c1)c(C)cn2Cc1nc(-c2ccc(C(C)C)cc2)oc1C)OCC
Temperature: 25 °C
Reaction time: 48 h
Yield: 65.5 %

Procedure:
0.28 g (1.0 mmol) rac-2-ethoxy-3-(3-methyl-1H-indol-5-yl)-propionic acid ethyl ester (preparation 4) and 0.30 g (1.2 mmol) 4-chloromethyl-2-(4-isopropyl-phenyl)-5-methyl-oxazole were dissolved under argon in 5.0 ml N,N-dimethylformamide; 0.048 g (1.1 mmol) sodium hydride (55% in mineral oil) were added and the reaction mixture then stirred for 48 hours at ambient temperature. It was then diluted with water and extracted with ether. The combined organic phases were dried over MgSO4 and evaporated. The residue formed was purified by flash-chromatography (silica gel; eluent: gradient of hexane and ethyl acetate) to give 0.32 g (67%) of rac-2-ethoxy-3-{1-[2-(4-isopropyl-phenyl)-5-methyl-oxazol-4-ylmethyl]-3-methyl-1H-indol-5-yl}-propionic acid ethyl ester as colorless oil.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=O)#[N:2].[C:11]([OH:17])(=[O:16])[CH2:12]C(O)=O.C([O-])(=O)C.[NH4+:22]>C(O)C>[C:1]([C:3]1[CH:4]=[C:5]([CH:6]([NH2:22])[CH2:12][C:11]([OH:17])=[O:16])[CH:8]=[CH:9][CH:10]=1)#[N:2]
Reactant: O=C(O)CC(=O)O
Reactant: N#Cc1cccc(C=O)c1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CCO
Product: N#Cc1cccc(C(N)CC(=O)O)c1

Procedure:
Part A. The 3-cyano benzaldehyde (2.0 gm, 15.3 mmol), malonic acid (1.6 gm, 15.3 mmol) and ammonium acetate (2.37 gm, 30.75 mmol) were combined in 35 mLs ethanol under a nitrogen atmosphere. The reaction mixture was heated over night to become a thick slurry. The slurry was filtered and the solids were washed with additional ethanol. The 3-(cyano)-beta-(amino)benzene propanoic acid was isolated as a white powder 1.58 gm (55%) MS 191(M+H)+ 1 H NMR (DMSO-d6): 8.11(s, 1H), 7.96(d, 1H), 7.90(d, 1H), 7.46(t,1H), 5.7(s,4H), 4.66(m, 1H), 3.61(dd, 1H), 3.06(dd, 1H).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[O:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH:8]1[O:13][CH2:14][C:15]#[C:16][CH:17]([OH:27])[CH2:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1.C(OCC)(=O)C>CCOCC>[O:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH:8]1[O:13][CH2:14]/[CH:15]=[CH:16]/[CH:17]([OH:27])[CH2:18][O:19][C:20]1[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=1
Reactant: OC(C#CCOC1CCCCO1)COc1ccc(F)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: OC(/C=C/COC1CCCCO1)COc1ccc(F)cc1
Reaction time: 1.5 h

Procedure:
Lithium aluminum hydride (7.6 g., 0.2 mole) is dissolved in ether (225 ml.) and 1-(2-tetrahydropyranyloxy)-4-hydroxy-5-(4-fluorophenoxy)-2-pentyne (35.2 g., 0.12 mole) is added dropwise with stirring during 1.5 hour. The resulting mixture is stirred at 25° for 21 hours and then heated at reflux for 4 hours. The mixture is cooled and treated dropwise with ethyl acetate to consume excess lithium aluminum hydride. It is then poured into 600 ml. of ice-cold 20% aqueous potassium hydroxide solution. The oily product is taken up in ether, washed with water and brine, and dried over magnesium sulfate. Removal of solvent under vacuum leaves the title compound as a yellow residual oil.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[CH:12]=[C:13]([CH:18]=[CH:19][CH:20]=3)[C:14]([O:16]C)=[O:15])[CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:21]1[CH:22]=[C:23]([CH:28]=[CH:29][CH:30]=1)[C:24]([O:26]C)=[O:25]>C1COCC1.CO.[OH-].[Na+]>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[CH:12]=[C:13]([CH:18]=[CH:19][CH:20]=3)[C:14]([OH:16])=[O:15])[CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:21]1[CH:22]=[C:23]([CH:28]=[CH:29][CH:30]=1)[C:24]([OH:26])=[O:25]
Reactant: COC(=O)c1cccc(-c2ccc3ccc(-c4cccc(C(=O)OC)c4)cc3c2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1cccc(-c2ccc3ccc(-c4cccc(C(=O)O)c4)cc3c2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2.0 g of dimethyl 3,3′-(naphthalene-2,7-diyl)dibenzoate was dissolved in 60 mL of mixed solvent of THF and MeOH (v/v=1:1), 20 mL of 2N NaOH aqueous solution was added. The mixture was stirred at room temperature overnight. After the organic phase was removed, the aqueous phase was acidified with dilute hydrochloric acid to give white precipitate, which was filtered and washed with water several times. Yield: 1.71 g, 92%. 1H NMR (300 MHz, DMSO-d6): δ 7.65 (t, 2H), 7.92 (d, 2H), 7.98 (d, 2H), 8.09 (m, 4H), 8.38 (m, 2H), 8.43 (d, 2H).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([C:8]([NH:10][CH3:11])=[O:9])=[N:6][CH:7]=1.[CH2:12]([O:19][C:20](=[O:23])[CH:21]=[CH2:22])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CCCC)CCCC)CCC>CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH2:12]([O:19][C:20](=[O:23])[CH:21]=[CH:22][C:2]1[CH:3]=[N:4][C:5]([C:8](=[O:9])[NH:10][CH3:11])=[N:6][CH:7]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: C=CC(=O)OCc1ccccc1
Reactant: CNC(=O)c1ncc(Br)cn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCCCN(CCCC)CCCC
Solvent: CN(C)C=O
Product: CNC(=O)c1ncc(C=CC(=O)OCc2ccccc2)cn1
Temperature: 110 °C

Procedure:
To a solution of 5-bromo-N-methylpyrimidine-2-carboxamide (0.14 g, 0.64 mmol) in DMF (5 mL) was added acrylic acid benzyl ester (0.13 g, 0.78 mmol), Pd(OAc)2 (14.3 mg), tri-o-tolyl phosphine (49 mg, 0.16 mmol), tributyl amine (0.48 g, 2.59 mmol). The reaction mixture was heated in microwave oven at 110° C. for 1 h. The reaction mixture was cooled to room temperature, partitioned in water (50 mL) and ethyl acetate (50 mL). Ethyl acetate layer was separated, dried (MgSO4), concentrated to give 3-(2-methylcarbamoyl-pyrimidin 5-yl)acrylic acid benzyl ester as a solid, this was washed with hexanes and dried to give the 0.122 g of the product. LCMS (APCI) 298 (M+)
Reaction SMILES: [H-].[Na+].[CH3:3][S:4]([CH:7]([CH3:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9])(=[O:6])=[O:5].[Br:14][CH2:15][CH2:16]Br>CCCCCC.CN(C=O)C>[Br:14][CH2:15][CH2:16][C:7]([CH3:13])([S:4]([CH3:3])(=[O:5])=[O:6])[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: BrCCBr
Reactant: CCOC(=O)C(C)S(C)(=O)=O
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(CCBr)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 50 %

Procedure:
Sodium hydride (60% dispersion in mineral oil, 2.33 g, 58.3 mmol) was washed with hexane (2×10 mL) in a 100 mL two neck round bottom flask under nitrogen then suspended in DMF (30 mL). The suspension was treated dropwise with ethyl 2-(methylsulfonyl)propanoate (10.0 g, 55.49 mmol) in DMF (10 mL). The mixture was stirred 30 min at RT, cooled to 0° C., and treated dropwise with 1,2-dibromoethane (5.17 mL, 58.8). The mixture was allowed to warm to room temperature while stirring overnight. The mixture was quenched with saturated ammonium chloride (100 mL) and the mixture was extracted with diethyl ether (4×50 mL). Combined organics were washed with 50% saturated sodium chloride (4×50 mL), dried (MgSO4), filtered and the filtrate concentrated in vacuo. Crude material was chromatographed over silica gel (350 g, 230-400 mesh) eluting with 10-20% EtOAc/hexane to afford the title compound as a pale yellow oil (7.9 g, 50%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.33 (t, J=7.05 Hz, 3 H) 1.64 (s, 3 H) 2.49-2.59 (m, 1 H) 2.78 (ddd, J=13.89, 10.16, 6.64 Hz, 1 H) 3.05 (s, 3 H) 3.33-3.41 (m, 1 H) 3.46-3.54 (m, 1 H) 4.22-4.37 (m, 2 H).
Reaction SMILES: [CH3:1][N:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1C)[NH2:3].C(O[C:14](=[NH:22])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=1)C.Cl.[Na].[CH2:25](O)[CH3:26]>>[CH3:1][N:2]1[C:4]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:25]=2[CH3:26])=[N:22][C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=2)=[N:3]1
Reactant: CCOC(=N)c1cccc(Cl)c1
Reactant: Cc1ccccc1N(C)N
Reactant: CCO
Agent: Cl
Agent: [Na]
Product: Cc1ccccc1-c1nc(-c2cccc(Cl)c2)nn1C
Temperature: 65 °C
Reaction time: 18 h
Yield: 66 %

Procedure:
A mixture of 6.85 g. of 1-methyl-1-(o-toluyl)-hydrazine, 13.8 g. of m-chlorobenzimidic acid ethyl ester and 1.8 g. of the hydrochloride of m-chlorobenzimidic acid ethyl ester is heated with stirring under vacuum for 18 hours and simultaneously ethanol and m-chlorobenzonitrile are distilled off. Then, maintaining the temperature at about 65° C., 40 ml. of ethanol are added followed by a sodium ethylate solution prepared from 0.336 g. of sodium and 20 ml. of ethanol. The mixture is refluxed for 6 hours and after standing over night, the insoluble precipitate is filtered off. The filtrate is evaporated to dryness. The residue is dissolved in 100 ml. of diethyl ether and after washing the organic layer successively with aqueous 5% Na2CO3, 5% HCl and water, the solution is dried over sodium sulfate. The crude product obtained by evaporation of the diethyl ether solution is crystallized from ethanol. Yield 66%. M.p. 77°-78° C.
Reaction SMILES: [CH:1]1[C:14]2[CH2:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[O:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[Cl:15][CH2:16][CH2:17][CH2:18][C:19](Cl)=[O:20].[Cl-:22].[Al+3].[Cl-].[Cl-]>C(Cl)Cl>[Cl:15][CH2:16][CH2:17][CH2:18][C:19]([C:10]1[CH:9]=[CH:8][C:7]2[O:6][C:5]3[C:14](=[CH:1][C:2]([C:5](=[O:6])[CH2:4][CH2:3][CH2:2][Cl:22])=[CH:3][CH:4]=3)[CH2:13][C:12]=2[CH:11]=1)=[O:20]
Reactant: [Cl-]
Reactant: c1ccc2c(c1)Cc1ccccc1O2
Reactant: O=C(Cl)CCCCl
Agent: [Al+3]
Solvent: ClCCl
Product: O=C(CCCCl)c1ccc2c(c1)Cc1cc(C(=O)CCCCl)ccc1O2
Temperature: -20 °C

Procedure:
To a mixture of 91.1 g (0.5 mole) xanthene, 176.3 g (1.25 moles) of 4-chlorobutyryl chloride and 3 liters of dried methylene chloride cooled to -20°C. was added slowly over 1/2 hour 146.7 g (1.1moles) of aluminum chloride, maintaining a temperature below -10°C. The reaction mixture was allowed to warm slowly to room temperature and then refluxed for 4 hours and cooled to room temperature. The mixture was decomposed by pouring cautiously into 2 liters of ice water, and the layers were separated. The aqueous layer was extracted again with methylene chloride. The methylene chloride layers were combined and evaporated to a small volume and cooled. The resulting solid was filtered off and recrystallized from acetone to give the desired product. M.P. 131°-132°C.