Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[CH:10]=[CH:11]/[C:12]([NH:14][CH2:15][CH2:16][N:17]2[CH2:22][CH2:21][CH:20]([C:23]3[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[NH:25][CH:24]=3)[CH2:19][CH2:18]2)=[O:13])=[CH:4][C:3]=1[O:32][CH3:33].CN1CC[O:38][CH2:37][CH2:36]1.CN(C)C=O.C(Cl)(=O)C>O>[C:37]([O:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[CH:10]=[CH:11]/[C:12]([NH:14][CH2:15][CH2:16][N:17]2[CH2:22][CH2:21][CH:20]([C:23]3[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[NH:25][CH:24]=3)[CH2:19][CH2:18]2)=[O:13])=[CH:4][C:3]=1[O:32][CH3:33])(=[O:38])[CH3:36]
Reactant: CN1CCOCC1
Reactant: COc1cc(/C=C/C=C/C(=O)NCCN2CCC(c3c[nH]c4ccccc34)CC2)ccc1O
Solvent: O
Solvent: CN(C)C=O
Solvent: CC(=O)Cl
Product: COc1cc(/C=C/C=C/C(=O)NCCN2CCC(c3c[nH]c4ccccc34)CC2)ccc1OC(C)=O
Reaction time: 1 h
Yield: 22.6 %

Procedure:
To a mixture of 1-[2-{5-(4-hydroxy-3-methoxyphenyl)(2E, 4E)-2, 4-pentadienoylamino}ethyl]-4-(3-indolyl)piperidine (0.89 g), dry N-methylmorpholine (1.0 g) and dry N, N-dimethylformamide (10 ml) was added slowly acetyl chloride (0.26 g) at 5° to 10° C. After stirring for 1 hour, the reaction mixture was poured into water (50 ml) and stirred for 1 hour. The resulting precipitate was collected, washed with water and then recrystallized from a mixture of ethanol and water (7:3 V/V) to give 1-[2-{5-(4-acetoxy-3-methoxyphenyl)-(2E, 4E)-2, 4-pentadienoylamino}ethyl]-4-(3-indolyl)piperidine (0.22 g).
Reaction SMILES: C([NH:4][C:5]1[N:10]([O:11]C(=O)C)[C:9](=[NH:15])[N:8]=[C:7](OS(C2C=CC(C)=CC=2)(=O)=O)[CH:6]=1)(=O)C.[NH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1>>[NH2:4][C:5]1[N:10]([OH:11])[C:9](=[NH:15])[N:8]=[C:7]([N:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)[CH:6]=1
Reactant: CC(=O)Nc1cc(OS(=O)(=O)c2ccc(C)cc2)nc(=N)n1OC(C)=O
Reactant: C1CCNCC1
Product: N=c1nc(N2CCCCC2)cc(N)n1O
Temperature: 25 °C

Procedure:
76 g (0.2 mole) of 6-acetamido-1-acetoxy-1,2-dihydro-2-imino-4-(4-toluenesulfonyloxy)pyrimidine are added to 760 ml of anhydrous piperidine at a temperature of 0° to 5° C. while stirring. The mixture is stirred at the same temperature for additional 2 hours, then let to warm to room temperature and stirred for additional 24 hours. The piperidine is distilled off under reduced pressure, 500 ml of water are added to the residue, then the mixture is left to stand in the refrigerator overnight. The precipitate is filtered, washed with water and filtered by strong suction. The filter cake is washed by suspending it 3 times with 50 ml of ether each and dried to give the aimed product in a yield of 23.0 g (55%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[C:6]([NH2:11])[CH:5]=1)([O-:3])=[O:2].Cl.[C:13]([CH:15]([C:21]1[N:26]=[C:25]([CH3:27])[CH:24]=[C:23]([C:28]([F:31])([F:30])[F:29])[N:22]=1)[C:16](OCC)=O)#[N:14]>C(O)(=O)C>[CH3:27][C:25]1[CH:24]=[C:23]([C:28]([F:31])([F:29])[F:30])[N:22]=[C:21]([C:15](=[C:16]2[NH:10][C:7]3[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][C:6]=3[NH:11]2)[C:13]#[N:14])[N:26]=1
Reactant: Nc1ccc([N+](=O)[O-])cc1N
Reactant: CCOC(=O)C(C#N)c1nc(C)cc(C(F)(F)F)n1
Agent: Cl
Solvent: CC(=O)O
Product: Cc1cc(C(F)(F)F)nc(C(C#N)=C2Nc3ccc([N+](=O)[O-])cc3N2)n1
Temperature: 100 °C
Yield: 50.9 %

Procedure:
4-Nitro-1,2-phenylenediamine (50 mg; 0.32 mmol) and ethyl 2-cyano-2-[4-methyl-6-(trifluoromethyl)pyrimidin-2-yl]acetate hydrochloride salt (101 mg; 0.32 mmol) were heated at 198° C. in a microwave for 3 min. Acetic acid (1.5 mL) was added to the crude material and the mixture heated at 100° C. for 6 hr. The solid was collected by filtration, washed with acetonitrile, and dried under high vacuum to give 2-[4-methyl-6-(trifluoromethyl)pyrimidin-2-yl]-2-(5-nitro-1H-benzimidazol-2(3H)-ylidene)acetonitrile (59 mg) as a yellow solid. 2-[4-Methyl-6-(trifluoromethyl)pyrimidin-2-yl]-2-(5-nitro-1H-benzimidazol-2(3H)-ylidene)acetonitrile (55 mg; 0.15 mmol) in DMF (3 mL) was hydrogenated over 10% palladium on carbon (11 mg). The mixture was filtered through diatomaceous earth, washing with methanol, and the filtrate was concentrated to give 2-(5-amino-1H-benzimidazol-2(3H)-ylidene)-2-[4-methyl-6-(trifluoromethyl)pyrimidin-2-yl]acetonitrile, which was dissolved in DMF (1 mL) and added to a solution of N-methyl-L-proline (19.3 mg; 0.16 mmol), HBTU (56.8 mg; 0.15 mmol), and DIPEA (104.5 μL; 0.60 mmol) in DMF (1 mL). The mixture was stirred for 5 hr and then partitioned between EA and water. The EA phase was dried and concentrated to give 2-{5-[(S)-(1-methylpyrrolidin-2-yl)carbonylamino]-1H-benzimidazol-2 (3H)-ylidene}-2-[4-methyl-6-(trifluoromethyl)pyrimidin-2-yl]acetonitrile (65 mg) as a brown oil. 2-{5-[(S)-(1-Methylpyrrolidin-2-yl)-carbonylamino]-1H-benzimidazol-2(3H)-ylidene}-2-[4-methyl-6-(trifluoromethyl)pyrimidin-2-yl]-acetonitrile (65 mg) was dissolved in concentrated sulfuric acid and stirred at room temperature overnight. The mixture was diluted with ice-water and acetonitrile and, after coming to room temperature, was purified by reverse phase preparative HPLC using a Peeke Ultro 120, 7 μm, C18Q, 250×30 mm column at a flow rate of 42 mL/min and mobile phases of 95% water, 5% acetonitrile (with 0.01% hydrochloric acid) and 5% water, 95% acetonitrile (with 0.01% hydrochloric acid) to give 2-{5-[(S)-(1-methylpyrrolidin-2-yl)carbonylamino]-1H-benzimidazol-2 (3H)-ylidene}-2-[4-methyl-6-(trifluoromethyl)pyrimidin-2-yl]acetamide hydrochloride salt (18 mg) as a yellow solid.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7].Cl.[O-:15][C:16]#[N:17].[Na+].C(Cl)(Cl)Cl>O>[O:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[C:6]([N:8]1[CH2:9][CH2:10][N:11]([NH:17][CH:16]=[O:15])[CH2:12][CH2:13]1)=[O:7]
Reactant: O=C(C1CCCO1)N1CCNCC1
Reactant: N#C[O-]
Agent: Cl
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: O=CNN1CCN(C(=O)C2CCCO2)CC1
Temperature: 70 °C
Reaction time: 2 h
Yield: 82.3 %

Procedure:
4-(2-Tetrahydrofuroyl)piperazine (33.25 g, 180.7 mmol) (III) is dissolved in 165 mL water. 5N Hydrochloric acid (34.5 mL) is added and the suspension is heated to 70° C. with stirring. Sodium cyanate (13.1 g, 201.15 mmol) is added in small portion to the stirring solution and heating is continued for an additional 2 hours. The reaction mixture is concentrated under reduced pressure to yield a thick oil. Chloroform (100 mL) is added to the oil and the solution is heated to reflux. The hot solution is filtered and the filtrate is dried over Na2SO4. The dried solution is concentrated under reduced pressure to a thick yellow oil. Ether (50 mL) is added to the oil and white crystals precipitated out. The product is filtered, washed with ether (25 mL) and dried. The product is used without further purification (33.8 g, 82.3% yield).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[C:15]([SH:20])=[CH:16][CH:17]=[CH:18][CH:19]=3)=[CH:10][C:9]=2[F:21])=[N:6][CH:7]=1.[Cl:22][C:23]1[CH:28]=[N:27][CH:26]=[CH:25][N:24]=1>>[ClH:22].[F:21][C:9]1[CH:10]=[C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[S:20][C:23]2[CH:28]=[N:27][CH:26]=[CH:25][N:24]=2)[CH:12]=[CH:13][C:8]=1[C:5]1[N:6]=[CH:7][C:2]([NH2:1])=[N:3][CH:4]=1
Reactant: Clc1cnccn1
Reactant: Nc1cnc(-c2ccc(-c3ccccc3S)cc2F)cn1
Product: Cl
Product: Nc1cnc(-c2ccc(-c3ccccc3Sc3cnccn3)cc2F)cn1

Procedure:
The title compound was prepared using analogous conditions to those described in Example 213 utilizing 4′-(5-aminopyrazin-2-yl)-3′-fluoro-[1,1′-biphenyl]-2-thiol and 2-chloropyrazine. MS (ESI): mass calcd. for C20H14FN5S, 375.10; m/z found, 375.9 [M+H]+. 1H NMR (400 MHz, CD3OD) δ 8.26-8.24 (m, 3H), 8.18 (d, J=2.6, 1H), 8.08 (d, J=1.4, 1H), 7.84 (m, 1H), 7.77-7.69 (m, 1H), 7.64-7.55 (m, 1H), 7.55-7.46 (m, 2H), 7.27-7.14 (m, 2H).
Reaction SMILES: [CH3:1][N:2]1[CH2:8][CH2:7][CH:6]([OH:9])[C:5]2[CH:10]=[CH:11][O:12][C:4]=2[CH2:3]1.[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16](F)[C:15]=1[C:21]([F:24])([F:23])[F:22]>>[Cl:13][C:14]1[C:15]([C:21]([F:22])([F:23])[F:24])=[C:16]([O:9][CH:6]2[CH2:7][CH2:8][N:2]([CH3:1])[CH2:3][C:4]3[O:12][CH:11]=[CH:10][C:5]2=3)[CH:17]=[CH:18][CH:19]=1
Reactant: Fc1cccc(Cl)c1C(F)(F)F
Reactant: CN1CCC(O)c2ccoc2C1
Product: CN1CCC(Oc2cccc(Cl)c2C(F)(F)F)c2ccoc2C1

Procedure:
The same method as in Example 1 was conducted using 7-methyl-5,6,7,8-tetrahydro-4H-furo[2,3-c]azepin-4-ol (Reference Example 19) instead of 6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-4-ol (Reference Example 6) and was conducted using 2-chloro-6-fluorobenzotrifluoride instead of 1-fluoronaphthalene to give the objective compound.
Reaction SMILES: C1C=C(CC[CH:9]([C:17]2[C:22]([OH:23])=CC=CC=2)[C:10]2[C:15]([OH:16])=CC=CC=2)C(O)=CC=1.[O:25]1[CH:30]=[CH:29][CH2:28][CH2:27][CH2:26]1>>[O:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH:26]1[O:16][CH:15]1[CH2:10][CH2:9][CH2:17][CH2:22][O:23]1
Reactant: C1=COCCC1
Reactant: Oc1ccccc1CCC(c1ccccc1O)c1ccccc1O
Product: C1CCC(OC2CCCCO2)OC1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
A suspension of triphenol 3 (164 g, 0.672 mol) in 3, 4dihydro-2H-pyran (600 mL) (available from Aldrich Chemical Company Inc., Milwaukee, Wis.) was treated with p-toluenesulfonic add monohydrate (2×10 mg) at 0° C. The reaction mixture was stirred for 1.5 h at 0° C. and then for 1 h after removing the ice bath (the reaction was monitored by TLC; p-toluenesulfonic acid monohydrate was added until starting material and monotetrahydropyranyl ether had disappeared). The mixture was then treated with saturated sodium bicarbonate (250 mL) and ethyl acetate (1 L). The organic phase was washed with saturated sodium bicarbonate (250 mL) and brine (250 mL), dried over magnesium sulfate and evaporated under reduced pressure. The crude compound was triturated with hexanes (2 L) for 3 h with stirring. The resulting suspension was left to stand at 0° C. for 5 h and then at -20° C. for 18 h. The solid was filtered and treated again with hexanes (1 L) with stirring for 1 h to give compound 4 which was filtered and dried (190 g, 69%), mp 109-112° C.: 1H-NMR δ (300 MHz: CDCl3), 1.5-2.1 (12H, m, O CH--CH2 --CH2 --CH2 --CH2 --O), 3.55-3.65 (2H, m, O--CH--CH2 --CH2 --CH2 --CH2O), 3.75-3.95 (2H, m, O--CH--CH2 --CH2 --H2 --CH2O), 4.16 (2H, s, Ph--CH2C=O), 5.40 (1H, t, J=3 Hz, O--CH--CH2 --CH2 --CH2 --CH2 --O), 5.49 (1H, t, J=3 Hz, O--CH--CH2 --CH2 --CH2 --CH2 --O), 6.55 (1H, dd, J=2.5 Hz and 8.5 Hz, CH phenyl), 6.61 (1H, d, J=2.5 Hz, CH phenyl), 7.03 and 7.17 (2H, AB system, J=8.5 Hz, CH phenyl), 7.77 (1H, d, J=8.5 Hz, CH phenyl), 12.60 (1H, s, Ph OH).
Reaction SMILES: S(F)(F)(F)[F:2].[CH2-]C(C)=O.[CH3:10][C:11]1[C:16]([OH:17])=[C:15]([CH2:18][OH:19])[C:14]([CH2:20]O)=[CH:13][N:12]=1.C(=O)=O.CC(C)=O.C(=O)=O.Cl>>[CH3:10][C:11]1[C:16]([OH:17])=[C:15]([CH2:18][OH:19])[C:14]([CH2:20][F:2])=[CH:13][N:12]=1
Reactant: FS(F)(F)F
Reactant: Cc1ncc(CO)c(CO)c1O
Agent: Cl
Agent: O=C=O
Agent: [CH2-]C(C)=O
Solvent: CC(C)=O
Product: Cc1ncc(CF)c(CO)c1O

Procedure:
Sulfur tetrafluoride (41 mg.-mole) is passed into 40 ml. of liquid HF, cooled in a dry-ice-acetone bath, then, acetonide of 2-methyl-3-hydroxy-4-hydroxymethyl-5-hydroxymethyl pyridine, (4.18 g.; 20 mg.-mole) is added under continuing cooling. The dry-ice-acetone bath is not replenished with dry-ice and the mixture is left standing in it overnight. After blowing off the remaining HF at room temperature, conc. aq. HCl is added, evaporated to dryness in vacuo, the residue is redissolved in 20 ml. of 1M aq. HCl, heated on the steam-bath for 15 minutes, (for hydrolysis of the acetonide, charcoaled and evaporated to dryness, redissolved in water, then passed through a Dowex 50 × 2 cation-exchange resin column, washed free of F⃝ with water.
Reaction SMILES: ClC1C=CC(C2(O)CCN(CCC=C3C4C(=NC=CC=4)[O:21]C4C=CC=C(OC(C(OCC)=O)(C)C)C=4C3)CC2)=CC=1.[Cl:42][C:43]1[CH:48]=[CH:47][C:46]([C:49]2([OH:80])[CH2:54][CH2:53][N:52]([CH2:55][CH2:56][CH:57]=[C:58]3[C:68]4[C:63](=[N:64][CH:65]=[CH:66][CH:67]=4)[O:62][C:61]4[CH:69]=[CH:70][CH:71]=[C:72]([C:73]5[O:74][C:75](C=O)=[CH:76][CH:77]=5)[C:60]=4[CH2:59]3)[CH2:51][CH2:50]2)=[CH:45][CH:44]=1>>[Cl:42][C:43]1[CH:44]=[CH:45][C:46]([C:49]2([OH:80])[CH2:50][CH2:51][N:52]([CH2:55][CH2:56][CH:57]=[C:58]3[C:68]4[C:63](=[N:64][CH:65]=[CH:66][CH:67]=4)[O:62][C:61]4[CH:69]=[CH:70][CH:71]=[C:72]([C:73]5[O:74][C:75]([OH:21])=[CH:76][CH:77]=5)[C:60]=4[CH2:59]3)[CH2:53][CH2:54]2)=[CH:47][CH:48]=1
Reactant: O=Cc1ccc(-c2cccc3c2CC(=CCCN2CCC(O)(c4ccc(Cl)cc4)CC2)c2cccnc2O3)o1
Reactant: CCOC(=O)C(C)(C)Oc1cccc2c1CC(=CCCN1CCC(O)(c3ccc(Cl)cc3)CC1)c1cccnc1O2
Product: Oc1ccc(-c2cccc3c2CC(=CCCN2CCC(O)(c4ccc(Cl)cc4)CC2)c2cccnc2O3)o1

Procedure:
The titled compound was prepared by following the procedure of example 199, but replacing the product of example 138 with the product of step 1.
Reaction SMILES: C(=[N:14][C:15]1[CH:16]=[CH:17][C:18]([F:32])=[C:19]([C@:21]2([CH3:31])[C:27]([F:29])([F:28])[CH2:26][O:25][CH2:24][C:23](=[O:30])[NH:22]2)[CH:20]=1)(C1C=CC=CC=1)C1C=CC=CC=1.Cl.C([O-])(O)=O.[Na+]>O1CCOCC1>[NH2:14][C:15]1[CH:16]=[CH:17][C:18]([F:32])=[C:19]([C@:21]2([CH3:31])[C:27]([F:28])([F:29])[CH2:26][O:25][CH2:24][C:23](=[O:30])[NH:22]2)[CH:20]=1
Reactant: C[C@]1(c2cc(N=C(c3ccccc3)c3ccccc3)ccc2F)NC(=O)COCC1(F)F
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: C[C@]1(c2cc(N)ccc2F)NC(=O)COCC1(F)F
Reaction time: 0.5 h
Yield: 90 %

Procedure:
To a solution of (R)-5-[5-(benzhydrylidene-amino)-2-fluoro-phenyl]-6,6-difluoro-5-methyl-[1,4]oxazepan-3-one (intermediate A17D) (308 mg, 0.70 mmol) in dioxane (20 ml) at 23° C. was added 1 M HCl (2.1 ml, 2.1 mmol) was added. After 30 min of stirring, the reaction mixture was poured on sat. NaHCO3-solution and extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and evaporated to give a dark green oil, which was purified by silica gel column chromatography with n-heptane/ethyl acetate to give the (R)-5-(5-amino-2-fluorophenyl)-6,6-difluoro-5-methyl-1,4-oxazepan-3-one (172 mg, 0.63 mmol, 90%) as a yellow foam. MS (ISP): m/z=275.2 [(M+H)+].
Reaction SMILES: [CH3:1][CH:2]([O:5][C:6]1[CH:15]=[CH:14][C:9]([O:10][CH2:11][C:12]#[N:13])=[CH:8][CH:7]=1)[CH2:3][CH3:4].B#B>C1COCC1>[CH3:1][CH:2]([O:5][C:6]1[CH:15]=[CH:14][C:9]([O:10][CH2:11][CH2:12][NH2:13])=[CH:8][CH:7]=1)[CH2:3][CH3:4]
Reactant: CCC(C)Oc1ccc(OCC#N)cc1
Agent: B#B
Solvent: C1CCOC1
Product: CCC(C)Oc1ccc(OCCN)cc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To the above phenoxyacetonitrile (7.21 g, 35.2 mmol) in 60 ml of THF at 8° is added 1M diborane (61.50 g, 61.5 mmol) over 45 min. The reaction is warmed to RT and stirred for 6 hours. The reaction is stirred for 16 hours. The THF-H2O is removed in vacuo and water and ether are added to the while sold, followed by 10% aqueous sodium hydroxide to basify. The product is extracted with ether (3X) and the combined organic phases are washed with water and with brine, dried, filtered and solvent removed to give 2-[4-(1-methylpropoxy)phenoxy]ethylamine.
Reaction SMILES: N#N.C([Si](C)(C)[O:8][CH2:9][C:10]1[S:11][CH:12]=[C:13]([C:15]2([CH3:20])[O:19][CH2:18][CH2:17][O:16]2)[CH:14]=1)(C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.CC(=O)OCC>[CH3:20][C:15]1([C:13]2[CH:14]=[C:10]([CH2:9][OH:8])[S:11][CH:12]=2)[O:16][CH2:17][CH2:18][O:19]1
Reactant: CC1(c2csc(CO[Si](C)(C)C(C)(C)C)c2)OCCO1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: N#N
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC1(c2csc(CO)c2)OCCO1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of tert-butyl-dimethyl-[4-(2-methyl-[1,3]dioxolan-2-yl)-thiophen-2-ylmethoxy]-silane (545 mg, 1.73 mmol) in dry THF (5.0 mL) was treated at 0° C. with TBAF (2.6 mL of a 1M solution in THF, 2.60 mmol). The reaction mixture was stirred at 0° C. for 2 h. The mixture was then diluted with EA (10 mL), washed with brine (3×20 mL), dried over MgSO4, filtered and concentrated under reduced pressure. Purification of the residue by FC (1:5 EA-Hept) gave the title compound as a colorless oil. TLC: rf (1:1 EA-Hept)=0.36. LC-MS-conditions 02: tR=0.70 min.
Reaction SMILES: [C:1]1([C:7](=[C:9]2[N:13]=[C:12]([CH2:14][CH2:15][CH3:16])[N:11]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[C:30]4[N:34](C(C5C=CC=CC=5)(C5C=CC=CC=5)C5C=CC=CC=5)[N:33]=[N:32][N:31]=4)=[CH:20][CH:19]=3)[C:10]2=[O:54])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>O1CCCC1.Cl>[C:1]1([C:7](=[C:9]2[N:13]=[C:12]([CH2:14][CH2:15][CH3:16])[N:11]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[C:30]4[NH:34][N:33]=[N:32][N:31]=4)=[CH:20][CH:19]=3)[C:10]2=[O:54])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCCC1=NC(=C(C)c2ccccc2)C(=O)N1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCCC1=NC(=C(C)c2ccccc2)C(=O)N1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 71.7 %

Procedure:
3,5-dihydro-5-(1-phenylethylidene)-2-propyl-3-[(2'-(triphenylmethyltetrazol-5-yl)(1,1'-biphenyl)-4-yl)methyl]-4H-imidazol-4-one (0.17 g) in tetrahydrofuran (20 mL) and 10% hydrochloric acid (5 mL) was allowed to stir at room temperature for 3.5 hr. The reaction mixture was treated with 50% sodium hydroxide to pH 8, concentrated and cooled in ice bath. The precipitate was filtered and the aqueous solution was adjusted to pH 4-5 using concentrated hydrochloric acid to give white solid which was washed with cold water and dried to give yellow solid (80 mg) as a mixture of the Z and E isomers (8:2). M.S. m/e 463 (M+ +H) NMR (CDCl3 /TMS) δ0.98 (t, 3H, CH3), 1.67 (m, 2H, CH2), 2.39 (t, 2H, CH2), 2.76 (s, 3H, CH3), 4.80 (s, 2H, CH2), 7.04-7.20 (m, 4H, Harom), 7.42-7.61 (m, 2H, Harom), 7.63 (d, 2H, Harom), 7.99 (d, 1H, Harom).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([C:35]3[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][CH:36]=3)[O:14][C:13]3[C:15]4[C:20]([C:21]([C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)=[C:22]([C:23]([O:25][CH2:26][CH2:27][OH:28])=[O:24])[C:12]=3[CH:11]=[CH:10]2)=[CH:19][CH:18]=[CH:17][CH:16]=4)=[CH:5][CH:4]=1.[C:43](Cl)(=[O:46])[CH2:44][CH3:45]>ClCCl.C(N(CC)CC)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2([C:35]3[CH:36]=[CH:37][C:38]([O:41][CH3:42])=[CH:39][CH:40]=3)[O:14][C:13]3[C:15]4[C:20]([C:21]([C:29]5[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=5)=[C:22]([C:23]([O:25][CH2:26][CH2:27][O:28][C:43](=[O:46])[CH2:44][CH3:45])=[O:24])[C:12]=3[CH:11]=[CH:10]2)=[CH:19][CH:18]=[CH:17][CH:16]=4)=[CH:7][CH:8]=1
Reactant: COc1ccc(C2(c3ccc(OC)cc3)C=Cc3c(C(=O)OCCO)c(-c4ccccc4)c4ccccc4c3O2)cc1
Reactant: CCC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(=O)OCCOC(=O)c1c2c(c3ccccc3c1-c1ccccc1)OC(c1ccc(OC)cc1)(c1ccc(OC)cc1)C=C2
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
2,2-Bis(4-methoxyphenyl)-5-(2-hydroxyethoxycarbonyl)-6-phenyl-[2H]-naphtho[1,2-b]pyran (U.S. Pat. No. 6,113,814) (0.50 g, 0.90 mmol) was dissolved in dry dichloromethane (20 ml) together with triethylamine (0.25 ml), under nitrogen. To this solution was added propionyl chloride (0.083 g, 0.90 mmol) and the mixture stirred at RT for 15 minutes. The solvent was evaporated and the crude residue purified by column chromatography (silica gel, EtOAc/hexane, 2:3) giving a pink foamy solid on evaporation of the solvent in vacuo. Analysis of the purified product by 1H NMR gave a spectrum consistent with the structure of 2,2-Bis(4-methoxyphenyl)-5-(2-propionyloxy-ethoxycarbonyl)-6-phenyl-[2H]-naphtho[1,2-b]pyran.
Reaction SMILES: C(N(CC)CC)C.Cl[CH:9]([O:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17]CCOC(Cl)C)[CH3:10].C([O:26]C(Cl)C)C.[C:30]([O:33][CH2:34][CH3:35])(=[O:32])[CH3:31]>CN(C)C=O.O>[OH:32][CH:30]([O:33][CH2:34][CH2:35][O:17][CH2:16][CH2:15][O:14][CH2:13][CH2:12][O:11][CH:9]([OH:26])[CH3:10])[CH3:31]
Reactant: CCOC(C)Cl
Reactant: CC(Cl)OCCOCCOCCOC(C)Cl
Reactant: CCOC(C)=O
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(O)OCCOCCOCCOC(C)O
Reaction time: 0.5 h

Procedure:
The thus obtained partially hydroxycarbonylmethylated polyhydroxystyrene, 90 g, was dissolved in 180 g of N,N-dimethylformamide. With stirring under ice cooling, 49.5 g of triethylamine and then 2. 4 g of triethylene glycol di(1-chloroethyl) ether were added. Reaction was carried out for 30 minutes under ice cooling, 30.0 g of 1-chloroethyl ethyl ether was added, and reaction was carried out for a further 2 hours at room temperature. To the reaction mixture were added 500 g of ethyl acetate and 300 g of water, followed by separation. The ethyl acetate layer was washed twice with 300 g of water and then concentrated in vacuum. The residue was dissolved in 300 g of methanol and added dropwise to 20 liters of water whereupon a powdery solid precipitated. The solid was collected by filtration, washed with 20 liters of water, and dried in vacuum at 40° C. for 24 hours. On 1H--N MR analysis, it was identified to be a polymer in which 31.0 mol % of the hydrogen atoms of hydroxyl groups in polyhydroxystyrene were replaced by 1-ethoxyethyl groups, and the carboxyl group moieties which had been introduced in an amount of 2.0 mol % formed ester bonds with alcoholic hydroxyl groups of triethylene glycol di(1-hydroxyethyl) ether to provide crosslinking. This polymer is designated Polym. 1 whose rational formula is shown at the end of Synthesis Examples.
Reaction SMILES: [CH3:1][CH:2]1[C:14](=[O:15])[C:5]2=[CH:6][C:7]3CCCC[C:12]=3[CH:13]=[C:4]2[CH2:3]1.[CH:16]1C=CC=CC=1>>[CH2:1]([CH:2]1[CH2:3][C:4]2[C:5](=[CH:6][CH:7]=[CH:12][CH:13]=2)[C:14]1=[O:15])[CH3:16]
Reactant: c1ccccc1
Reactant: CC1Cc2cc3c(cc2C1=O)CCCC3
Product: CCC1Cc2ccccc2C1=O

Procedure:
2-Ethyl-indan-1-one is prepared from benzene following analogous procedures to those used for 2-methyl-2,3,5,6,7,8-hexahydro-cyclopenta[b]naphthalen-1-one.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10](=[O:15])[CH2:11][C:12](=[O:14])[CH3:13])=[CH:4][CH:3]=1>C(OCC)(=O)C.[Pd]>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10](=[O:15])[CH2:11][C:12](=[O:14])[CH3:13])=[CH:6][CH:7]=1
Reactant: CC(=O)CC(=O)C=Cc1ccc(O)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(=O)CC(=O)CCc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 79.4 %

Procedure:
To a solution of 6-(4-hydroxyphenyl)hex-5-ene-2,4-dione (1.00 g, 4.90 mmol) in 50 mL of ethyl acetate was added palladium 5% on carbon (200 mg) under nitrogen. After the vessel was purged with hydrogen, the reaction mixture was stirred under 1 atm of hydrogen at room temperature for 12 h. After the vessel was purged with nitrogen, the reaction mixture was filtered to remove palladium 5% on carbon. The filtrate was concentrated in vacuo, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=70/30 to 60/40) to obtain the title compound as a colorless oil (802 mg, 80%) having the following characteristics.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][N:3]=1.[CH3:10][N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.O>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([CH2:6][N:14]2[CH2:15][CH2:16][N:11]([CH3:10])[CH2:12][CH2:13]2)=[CH:8][CH:9]=1
Reactant: O=Cc1ccc(Cl)nc1
Reactant: CN1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CC(=O)O
Product: CN1CCN(Cc2ccc(Cl)nc2)CC1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 84.7 %

Procedure:
6-Chloronicotinaldehyde (10 g, 70.6 mmol, Eq: 1.00) was suspended in 700 ml DCM. 1-Methylpiperazine (8.84 g, 88.3 mmol, Eq: 1.25) and acetic acid (8.48 g, 8.09 ml, 141 mmol, Eq: 2.0) were added. Sodium triacetoxyborohydride (22.5 g, 106 mmol, Eq: 1.5) was added in portions over several minutes. The reaction mixture stirred at room temperature. After 3.5 hrs, there was no sign of starting material. LCMS showed product plus a little reduced starting material. Water was added, followed by DCM and the layers were separated. The DCM layer was washed with saturated ammonium chloride and the aqueous layer was combined with the initial aqueous layer. The aqueous extractions were bacidified with 1M NaOH. The resulting aqueous layer was extracted 3 times with DCM, and then dried, and concentrated to give 13.5 grams of a light yellow oil (84.7%) which was used without further purification.