Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5][C:6]([N:8]1[CH2:15][CH:14]2[CH:10]([CH2:11][NH:12][CH2:13]2)[CH2:9]1)=O)(C)(C)C.[ClH:16].[C@H:17]12C[C@H](NC1)CN2C(N)=O>>[ClH:16].[CH2:9]1[CH:10]2[CH2:11][NH:12][CH2:13][CH:14]2[CH2:15][N:8]1[C:6](=[O:5])[CH3:17]
Reactant: NC(=O)N1C[C@@H]2C[C@H]1CN2
Reactant: CC(C)(C)OC(=O)N1CC2CNCC2C1
Agent: Cl
Product: CC(=O)N1CC2CNCC2C1

Procedure:
The title product LL is prepared from hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid tert-butyl ester according to the procedure described for the synthesis of Intermediate P.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.I[CH2:11][CH:12]1[CH2:16][CH2:15][CH2:14][CH:13]1[CH3:17].O>CN(C)P(N(C)C)(N(C)C)=O>[CH3:11][CH:12]1[CH2:16][CH2:15][CH2:14][CH:13]1[CH2:17][NH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1
Reactant: CC1CCCC1CI
Reactant: N#Cc1ccc(N)cc1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: O
Product: CC1CCCC1CNc1ccc(C#N)cc1
Temperature: 120 °C

Procedure:
4-Aminobenzonitrile (11.8 g.) and 1-iodomethyl-2-methylcyclopentane (16.3 g.) are dissolved in hexamethylphosphoramide (100 ml.) and heated under nitrogen in an oil bath maintained at 120° C. for 22 hours. The reaction mixture is cooled to room temperature and water (100 ml.) is added gradually. The mixture is then chilled in an ice bath. The precipitate separated is filtered, washed thoroughly with water, and dried. It is then washed repeatedly with hexane and dried. Recrystallization from ether-hexane affords 4-(2-methylcyclopentylmethylamino)benzonitrile as pale yellow crystals.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15](=[O:19])[N:14]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:13]([CH2:24]Cl)=[C:12]2[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:32]1(=[O:42])[NH:36][C:35](=[O:37])[C:34]2=[CH:38][CH:39]=[CH:40][CH:41]=[C:33]12.[K].O>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15](=[O:19])[N:14]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:13]([CH2:24][N:36]1[C:32](=[O:42])[C:33]3[C:34](=[CH:38][CH:39]=[CH:40][CH:41]=3)[C:35]1=[O:37])=[C:12]2[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CC(C)Cn1c(CCl)c(-c2ccccc2)c2cc(OCc3ccccc3)ccc2c1=O
Agent: [K]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)Cn1c(CN2C(=O)c3ccccc3C2=O)c(-c2ccccc2)c2cc(OCc3ccccc3)ccc2c1=O
Yield: 93.4 %

Procedure:
A solution of 6-benzyloxy-3-chloromethyl-2-isobutyl-4-phenyl-1(2H)-isoquinolinone (2.59 g, 6 mmol) and potassium phthalimide (1.67 g, 9 mmol) in N,N-dimethylformamide (30 mL) was stirred at room temperature for 6 h. The reaction mixture was poured into water and extracted with ethyl acetate. After washing the extract with water, the extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained crystals were recrystallized from ethyl acetate-diisopropyl ether to give 2-[(6-benzyloxy-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-3-isoquinolinyl)methyl]-1H-isoindole-1,3(2H)-dione (3.04 g, 93.5%) as crystals.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)=[C:6]([C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)[N:5]=[C:4]([CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:3]=1.FC1C=CC(C2C3N([CH:61]=[N:62][N:63]=3)C(NC(C3C=CC=CC=3)(C)C)=NC=2C2C=CN=CC=2)=CC=1>>[C:26]1([CH2:25][CH2:24][C:4]2[N:3]3[CH:61]=[N:62][N:63]=[C:2]3[C:7]([C:8]3[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:16])([F:15])[F:17])[CH:9]=3)=[C:6]([C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)[N:5]=2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: FC(F)(F)c1cccc(-c2c(Cl)nc(CCc3ccccc3)nc2-c2ccncc2)c1
Reactant: CC(C)(Nc1nc(-c2ccncc2)c(-c2ccc(F)cc2)c2nncn12)c1ccccc1
Product: FC(F)(F)c1cccc(-c2c(-c3ccncc3)nc(CCc3ccccc3)n3cnnc23)c1

Procedure:
The title compound was synthesized from 4-chloro-2-(2-phenylethyl)-6-(4-pyridyl)-5-(3-(trifluoromethyl)phenyl)pyrimidine in the same manner as 2-(8-(4-fluorophenyl)-7-(4-pyridyl)-1,2,4-triazolo[4,3-c]pyrimidin-5-yl)amino-2-phenylpropane; MS m/z (M+H)+ 446; C25H18F3N5 requir. 445.4.
Reaction SMILES: Cl.[CH3:2][N:3]1[CH:7]=[C:6]([N:8]([CH2:33][CH2:34][C:35]([O:37]CC)=[O:36])[S:9]([C:12]2[CH:32]=[CH:31][C:15]3[N:16]([CH3:30])[C:17]([CH2:19][NH:20][C:21]4[CH:26]=[CH:25][C:24]([C:27](=[NH:29])[NH2:28])=[CH:23][CH:22]=4)=[N:18][C:14]=3[CH:13]=2)(=[O:11])=[O:10])[CH:5]=[N:4]1.[OH-].[Na+]>CO>[CH3:2][N:3]1[CH:7]=[C:6]([N:8]([CH2:33][CH2:34][C:35]([OH:37])=[O:36])[S:9]([C:12]2[CH:32]=[CH:31][C:15]3[N:16]([CH3:30])[C:17]([CH2:19][NH:20][C:21]4[CH:22]=[CH:23][C:24]([C:27](=[NH:28])[NH2:29])=[CH:25][CH:26]=4)=[N:18][C:14]=3[CH:13]=2)(=[O:11])=[O:10])[CH:5]=[N:4]1
Reactant: CCOC(=O)CCN(c1cnn(C)c1)S(=O)(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1)n2C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cn1cc(N(CCC(=O)O)S(=O)(=O)c2ccc3c(c2)nc(CNc2ccc(C(=N)N)cc2)n3C)cn1
Yield: 95 %

Procedure:
Prepared analogously to Example 26 from 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-sulphonic acid-N-(1-methylpyrazol-4-yl)-N-(2-ethoxycarbonylethyl)-amide-hydrochloride and sodium hydroxide solution. Yield: 95% of theory, C23H26N8O4S (510.6) Rf value: 0.53 (Reversed Phase silica gel RP-18, methanol+5% saline solution) ##EQU113##
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][C:8](=[O:11])[CH2:7]2.[OH-].[Na+].S(OC)(O[CH3:18])(=O)=O>O>[F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH3:18])[C:8](=[O:11])[CH2:7]2
Reactant: O=C1Cc2cccc(F)c2N1
Reactant: COS(=O)(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CN1C(=O)Cc2cccc(F)c21
Temperature: 100 °C

Procedure:
This is similar to the procedure described in G. W. Rewcastle, B. D. Palmer, E. M. Dobrusin, D. W. Fry, A. J. Kracker and W. A. Deny, Journal of Medicinal Chemistry, 1994, 37, 2033-2042. A suspension of the 7-fluoro-1,3-dihydro-indol-2-one (9, 1.0 g, 6.62 mmol.) in H2O (30 mL) and NaOH (0.397 g, 9.92 mmol., 1.50 eq.) was treated with dimethyl sulfate (1.24 g, 9.86 mmol., 1.49 eq., 0.933 mL; added all at once) and heated to 100° C. for approx. 10 min. and then allowed to cooled to about 50° C. An additional 1.0 eq. of NaOH (0.265 g) and then additional 1 eq. of dimethyl sulfate (0.835 g, 0.626 mL) were added. Again heated to 100° for approx. 10 min. Then cooled to 0° C. in an ice bath and stirred and then filtered off solids, washed several times with water and dried on buchner funnel under vacuum overnight to yield the title compound as a solid. 1H NMR (400 MHz, CHLOROFORM-D) δ ppm 3.4 (d, J=2.5 Hz, 3H) 3.5 (s, 2H) 6.9 (m, 3H).
Reaction SMILES: O1[CH2:5][CH2:4][C:3]2([S:9][C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[C:6]2=[O:14])C1=O.[Cl-].[Na+]>CS(C)=O>[O:14]=[C:6]1[C:3]2([CH2:4][CH2:5]2)[S:9][C:8]2[CH:10]=[CH:11][CH:12]=[CH:13][C:7]1=2
Reactant: O=C1OCCC12Sc1ccccc1C2=O
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Product: O=C1c2ccccc2SC12CC2
Temperature: 0 °C
Reaction time: 3.5 h
Yield: 81.2 %

Procedure:
A mixture of 8.0 g of 4',5'-dihydrospiro[benzo[b]-thiophene-2(3H),3'(2'H)-furan]-3,2'-dione, 2.3 g of sodium chloride and 20 ml of dimethylsulfoxide is stirred in nitrogen streams at 155°-160° C. for 3.5 hours. The reaction mixture is poured in ice-water, the resultant precipitate recovered by filtration and rinsed, and the residue recrystallized from methanol. By the above procedure there is obtained 5.2 g of 3-oxo-2,3-dihydro[1]benzothiophene-2-spirocyclopropane as colorless platelets melting at 70° C.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:5](=[N:7][NH2:8])[CH3:6].[O:15]1[CH2:20][CH2:19][O:18][C:17]([C:21](=[N:30][O:31][CH3:32])[C:22]2[CH:29]=[CH:28][CH:27]=[CH:26][C:23]=2[CH:24]=O)=[N:16]1.S([O-])([O-])(=O)=O.[Mg+2]>C(O)C>[CH3:1][O:2][N:3]=[C:4]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:5](=[N:7][N:8]=[CH:24][C:23]1[CH:26]=[CH:27][CH:28]=[CH:29][C:22]=1[C:21]([C:17]1[O:18][CH2:19][CH2:20][O:15][N:16]=1)=[N:30][O:31][CH3:32])[CH3:6]
Reactant: CON=C(C1=NOCCO1)c1ccccc1C=O
Reactant: CON=C(C(C)=NN)c1ccccc1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CCO
Product: CON=C(C(C)=NN=Cc1ccccc1C(=NOC)C1=NOCCO1)c1ccccc1
Yield: 41.1 %

Procedure:
1 g (0.0052 mol) of 2-hydrazono-1-phenylpropan-1-one O-methyl oxime is heated under reflux at the boiling point in 5 ml of ethanol with 1.3 g (0.0052 mol) of 2-[(5,6-dihydro-[1,4,2]dioxazin-3-yl)-methoxyimino-methyl]-benzaldehyde and 5 g of anhydrous magnesium sulphate for 1 hour. The reaction mixture is poured onto water and extracted with diethyl ether, the organic phase is dried over sodium sulphate and the solvent is distilled off in vacuo. The residue is stirred with diethyl ether and the crystals formed are filtered off. The solid is chromatographed over silica gel with diethylether/petroleum ether/methylene chloride (2:1:1). 0.9 g (40.8% of theory) of crystalline 2-({2-[(5,6-dihydro-[1,4,2]dioxazin-3-yl)-methoxyimino-methyl]-benzylidene}-hydrazono)-1-phenylpropan-1-one O-methyl oxime of melting point 136° C. is obtained.
Reaction SMILES: [OH-].[Li+].C([O:5][C:6](=[O:29])/[CH:7]=[CH:8]/[C:9]1[C:18]2[C:13](=[CH:14][C:15]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[CH:20]=3)=[CH:16][CH:17]=2)[CH:12]=[CH:11][C:10]=1[O:27][CH3:28])C>C1COCC1.O>[CH3:28][O:27][C:10]1[CH:11]=[CH:12][C:13]2[C:18](=[CH:17][CH:16]=[C:15]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[CH:20]=3)[CH:14]=2)[C:9]=1/[CH:8]=[CH:7]/[C:6]([OH:29])=[O:5]
Reactant: CCOC(=O)/C=C/c1c(OC)ccc2cc(-c3cccc(OC)c3)ccc12
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1cccc(-c2ccc3c(/C=C/C(=O)O)c(OC)ccc3c2)c1
Yield: 99.8 %

Procedure:
Lithium hydroxide (407.7 mg, 9.94 mmol, 6 eq) is added to a solution, cooled at 0° C., of (E)-3-(2-methoxy-6-(3-methoxyphenyl)naphthalene-1-yl)acrylic acid ethyl ester (600 mg, 1.66 mmol, 1 eq) in a mixture of THF/water 3/1 (20 ml), and the reaction mixture is boiled under reflux over night. The solvent is removed in vacuum on a rotary evaporator, and 2 N HCl is added to the residue. This phase is extracted with dichloromethane. The combined organic phases are dried over magnesium sulfate, filtered and concentrated in vacuum on a rotary evaporator. The residual solid is the desired product (quantitative yield, 554 mg).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:8]=[CH:9][C:10]2[CH2:16][CH:15]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:14]3[CH:23]=[CH:24][CH:25]=[CH:26][C:13]=3[CH2:12][C:11]=2[CH:27]=1)(=O)=O.[O:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH:31]1[O:36][CH2:37][CH2:38][C:39]#[C:40][Sn](CCCC)(CCCC)CCCC.[Li+].[Cl-]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCOCC1>[O:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH:31]1[O:36][CH2:37][CH2:38][C:39]#[C:40][C:7]1[CH:8]=[CH:9][C:10]2[CH2:16][CH:15]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:14]3[CH:23]=[CH:24][CH:25]=[CH:26][C:13]=3[CH2:12][C:11]=2[CH:27]=1
Reactant: CCOC(=O)CC1Cc2ccc(OS(=O)(=O)C(F)(F)F)cc2Cc2ccccc21
Reactant: CCCC[Sn](C#CCCOC1CCCCO1)(CCCC)CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Li+]
Solvent: C1COCCO1
Product: CCOC(=O)CC1Cc2ccc(C#CCCOC3CCCCO3)cc2Cc2ccccc21
Reaction time: 1.5 h
Yield: 82.7 %

Procedure:
A mixture of ethyl (±)-10,11-dihydro-3-(trifluoromethanesulfonyloxy)-5H-dibenzo[a,d]cycloheptene-10-acetate (1.34 g, 3.13 mmole), 4-(2-tetrahydropyranyloxy)-1-tributylstannyl-1-butyne (1.66 g, 3.76 mmole), LiCl (398 mg, 9.39 mmole), bis(triphenylphosphine)palladium dichloride (110 mg, 0.094 mmole), and anhydrous dioxane (31 mL) was heated at reflux under argon. After 1.5 hr, the reaction was concentrated to remove most of the dioxane, and the residue was taken up in Et2O (100 mL). 10% KF (50 mL) was added and the mixture was stirred briskly for 0.5 hr. The aqueous layer was removed and the Et2O layer was filtered through a mixture of celite® and MgSO4. The filtrate was concentrated and the residue was chromatographed on silica gel (10% EtOAc/hexanes) to afford the title compound (1.12 g, 83%) as a pale yellow oil: TLC (20% EtOAc/hexanes) Rf0.40; 1H NMR (400 MHz, CDCl3) δ7.21-7.30 (m, 1 H), 7.06-7.20 (m, 5 H), 7.00 (d, J=7.8 Hz, 1 H), 4.69 (t, J=3.6 Hz, 1 H), 4.31 (d, J=15.2 Hz, 1 H), 4.11-4.23 (m, 2 H), 3.76-3.97 (m, 4 H), 3.59-3.68 (m, 1 H), 3.48-3.57 (m, 1 H), 3.34 (dd, J=15.2, 4.1 Hz, 1 H), 2.97 (dd, J=15.2, 9.5 Hz, 1 H), 2.70 (t, J=7.3 Hz, 2 H), 2.65 (dd, J=15.7, 4.8 Hz, 1 H), 2.51 (dd, J=15.7, 9.5 Hz, 1 H), 1.78-1.92 (m, 1 H), 1.68-1.78 (m, 1 H), 1.44-1.68 (m, 4 H), 1.27 (t, J=7.1 Hz, 3 H); MS (ES) m/e 455 (M+Na)+.
Reaction SMILES: [CH3:1][C:2]1[CH:26]=[C:25]([CH3:27])[CH:24]=[C:23]([CH3:28])[C:3]=1[CH2:4][O:5][C:6]1[C:7]([NH:12][C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)=S)=[N:8][CH:9]=[CH:10][CH:11]=1.[NH3:29]>>[CH3:1][C:2]1[CH:26]=[C:25]([CH3:27])[CH:24]=[C:23]([CH3:28])[C:3]=1[CH2:4][O:5][C:6]1[C:7]([NH:12][C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)=[NH:29])=[N:8][CH:9]=[CH:10][CH:11]=1
Reactant: Cc1cc(C)c(COc2cccnc2NC(=S)Nc2ccc(Cl)cc2)c(C)c1
Reactant: N
Product: Cc1cc(C)c(COc2cccnc2NC(=N)Nc2ccc(Cl)cc2)c(C)c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of yellow mercuric oxide (0.95 g, 0.0044 mol), N-[3-(2,4,6-trimethylbenzyloxy)pyrid-2-yl]-N'-(4-chlorophenyl)thiourea (1.5 g, 0.0036 mol) and methanolic ammonia solution (40 ml) was stirred for 2 days at room temperature. The solvent was removed in vacuo and the black residue was boiled with chloroform and filtered hot. Evaporation of the solvent followed by trituration with ether and recrystallisation from acetonitrile gave the desired product. Yield 1.16 g (82%), m.p. 169°-171 ° C.
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][CH:8]=[N:9][C:10]=1[C:11]([CH3:15])([CH3:14])[CH:12]=[CH2:13])=O)C.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>C1COCC1>[CH3:15][C:11]([C:10]1[N:9]=[CH:8][NH:7][C:6]=1[CH2:4][OH:3])([CH3:14])[CH:12]=[CH2:13]
Reactant: C=CC(C)(C)c1nc[nH]c1C(=O)OCC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: C=CC(C)(C)c1nc[nH]c1CO
Temperature: 25 °C
Reaction time: 4 h
Yield: 102.7 %

Procedure:
A solution of 5-(1,1-dimethyl-allyl)-3H-imidazole-4-carboxylic acid ethyl ester (3.13 g, 15.0 mmol) in THF (60 ml) was added dropwise to a suspension of lithium aluminium hydride (95% suspension, 1.00 g, 25.0 mmol) in THF (40 ml) and the mixture was stirred at room temperature for 4 h. Water was added until the evolution of gas ceased, the mixture was stirred for 10 min, then was filtered through a sintered funnel. The precipitate was washed with THF, then with methanol, the filtrate and washings were combined, evaporated, then freeze-dried to afford [5-(1,1-dimethyl-allyl)-3H-imidazol-4-yl]-methanol (2.56 g, 102%). Residual water was removed by azeotroping with chloroform prior to further reaction. (See Hayashi et al., J. Org. Chem., 65:8402-8405 (2000)).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[CH:3](O)O.[CH3:8][N+:9]([O-:11])=[O:10].C([O-])([O-])=O.[Na+].[Na+].O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>O>[F:1][C:2]([F:7])([F:6])[CH:3]=[CH:8][N+:9]([O-:11])=[O:10]
Reactant: OC(O)C(F)(F)F
Reactant: C[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Agent: [Na+]
Solvent: O
Product: O=[N+]([O-])C=CC(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 10 %

Procedure:
A mixture of 2,2,2-trifluoroethane-1,1-diol (75% aq solution, 20 g, 0.13 mol), CH3NO2 (24 g, 0.39 mol) and Na2CO3 (0.85 g, 8 mmol) was stirred overnight at RT. Water (50 mL) was added and the mixture was extracted with diethyl ether (3×30 mL) and dried over Na2SO4. After concentrating the organic extract at low temperature and under reduced pressure, P2O5 (20.0 g, 0.14 mol) was added to the residue oil, which was distilled at atmospheric pressure to give a green-yellow oil (4 g, 50% purity, 10% yield). Boiling point 85-90° C.; 1H NMR (400 MHz, CDCl3) δ ppm 7.09-7.17 (m, 1H), 7.50 (dd, J=2.0 Hz, 12.0 Hz, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:18])[CH:7]=[C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[O:9]2)=[CH:4][CH:3]=1.Br[CH2:20][CH2:21][CH2:22][CH:23]=[CH2:24].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:24]([O:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:18])[CH:7]=[C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[O:9]2)=[CH:4][CH:3]=1)[CH2:23][CH2:22][CH:21]=[CH2:20]
Reactant: O=c1cc(-c2ccccc2)oc2cc(O)ccc12
Reactant: C=CCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCCCOc1ccc2c(=O)cc(-c3ccccc3)oc2c1
Reaction time: 6 h
Yield: 98.6 %

Procedure:
A yellow suspension of 7-hydroxyflavone (25.66 g, 0.108 mol), 5-bromo-1-pentene (17.88 g, 14.2 ml, 0.12 mol), and anhydrous, powdered potassium carbonate (30.40 g, 0.22 mol) in acetone (500 ml) was stirred and heated at reflux for 24 hours. The tlc (thin layer chromatography), on silica gel eluted with 20% of hexane in ether, indicated that the reaction was incomplete. Additional 1.5 ml of 5-bromo-1-pentene was added and refluxing was continued for 6 hours and cooled. The solid was filtered and the filtrate was evaporated under vacuum to give a yellow solid 32.63 g, 97% yield. Recrystallization from isopropyl alcohol gave white crystals, mp 104.5°-106° C.; 55% yield (pure).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[Cl:11])[NH:7][C:6]([S:12]([C:15]([F:20])([F:19])[CH:16]([Cl:18])[F:17])(=[O:14])=[O:13])=[CH:5]2.C([O-])(=O)C.[Na+].[Br:26]Br>C(O)(=O)C>[Br:26][C:5]1[C:4]2[C:8](=[CH:9][C:10]([Cl:11])=[C:2]([Cl:1])[CH:3]=2)[NH:7][C:6]=1[S:12]([C:15]([F:20])([F:19])[CH:16]([Cl:18])[F:17])(=[O:13])=[O:14]
Reactant: O=S(=O)(c1cc2cc(Cl)c(Cl)cc2[nH]1)C(F)(F)C(F)Cl
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: O=S(=O)(c1[nH]c2cc(Cl)c(Cl)cc2c1Br)C(F)(F)C(F)Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 91 %

Procedure:
A mixture of 5,6-dichloro-2[(2-chloro-1,1,2-trifluoroethyl)sulfonyl]indole (0.84 g, 2.29 mmole) and sodium acetate (0.21 g, 2.52 mmole in acetic acid is treated with bromine (0.40 g, 2.52 mmole), stirred for 0.5 hour at room temperature, poured onto water and filtered. The filtercake is air-dried to afford the title product as a white solid, 0.93 g (91% yield), mp 200°-205° C., identified by IR, 1HNMR and 19FNMR spectral analyses.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14](Br)=[CH:13][C:12]([CH3:16])=[N:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH:17]([Sn](CCCC)(CCCC)CCCC)=[CH2:18]>C1COCC1.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>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14]([CH:17]=[CH2:18])=[CH:13][C:12]([CH3:16])=[N:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: Cc1cc(Br)n(-c2ccc([N+](=O)[O-])cc2)n1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C=Cc1cc(C)nn1-c1ccc([N+](=O)[O-])cc1
Yield: 91.7 %

Procedure:
To a solution of 1-(4′-nitrophenyl)-5-bromo-3-methylpyrazole (138 mg, 0.49 mmol) in THF (5 mL) was added Pd(PPh3)4 (21 mg, 0.018 mmol) followed by vinyl tributyltin (0.16 mL, 0.54 mmol). The mixture was heated at reflux for 6 hr under N2, and was then quenched with saturated KF and extracted with EtOAc. The extract was dried over MgSO4 and concentrated. The residue was purified by column chromatography on silica gel (hexane/acetate, 10:1) to give the title compound (103 mg, 92%).
Reaction SMILES: [Na].[CH2:2]([OH:9])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].Cl[CH2:11][CH2:12][C:13]([OH:15])=[O:14]>O>[CH2:2]([O:9][CH2:11][CH2:12][C:13]([OH:15])=[O:14])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: O=C(O)CCCl
Reactant: CCCCCCCO
Agent: [Na]
Solvent: O
Product: CCCCCCCOCCC(=O)O
Temperature: 150 °C
Yield: 53.1 %

Procedure:
25.3 g (1.1 mole) of sodium dissolved in 464.8 g (4 mole) of heptyl alcohol was heated to 150° C and 54 g (0.49 mole) of 3-chloropropionic acid were added thereto dropwise with stirring. The mixture was heated for a further 2 hours and a precipitate appeared. The mixture was cooled and 1.5 liters of water were added. The mixture was extracted with ether and the aqueous phase was acidified with concentrated sulfuric acid. The mixture was extracted with ether and the ether phase was washed with water, dried and was concentrated. The residue was rectified to obtain 49 g (52% yield) of 3-heptyloxy-propionic acid as a colorless oil boiling at 165° C at 15 mm Hg and having a refractive index nD22 = 1.436.
Reaction SMILES: O=C1CCC(=O)N1[O:8][C:9](=O)[C:10]1[CH:15]=[C:14]([O:16][C:17]2[C:22]([Cl:23])=[CH:21][C:20]([N:24]3[C:29](=[O:30])[NH:28][C:27](=[O:31])[CH:26]=[N:25]3)=[CH:19][C:18]=2[Cl:32])[CH:13]=[CH:12][C:11]=1[OH:33].C(N(CC)CC)C.[CH3:42][C@H:43]1[CH2:48][C@@H:47]([CH3:49])[CH2:46][NH:45][CH2:44]1>C(COC)OC>[Cl:32][C:18]1[CH:19]=[C:20]([N:24]2[C:29](=[O:30])[NH:28][C:27](=[O:31])[CH:26]=[N:25]2)[CH:21]=[C:22]([Cl:23])[C:17]=1[O:16][C:14]1[CH:13]=[CH:12][C:11]([OH:33])=[C:10]([C:9]([N:45]2[CH2:46][C@H:47]([CH3:49])[CH2:48][C@H:43]([CH3:42])[CH2:44]2)=[O:8])[CH:15]=1
Reactant: C[C@@H]1CNC[C@H](C)C1
Reactant: O=C(ON1C(=O)CCC1=O)c1cc(Oc2c(Cl)cc(-n3ncc(=O)[nH]c3=O)cc2Cl)ccc1O
Solvent: CCN(CC)CC
Solvent: COCCOC
Product: C[C@@H]1C[C@H](C)CN(C(=O)c2cc(Oc3c(Cl)cc(-n4ncc(=O)[nH]c4=O)cc3Cl)ccc2O)C1
Reaction time: 2 h

Procedure:
To solution of 5-[2,6-dichloro-4-(3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl)-phenoxy]-2-hydroxy-benzoic acid 2,5-dioxo-pyrrolidin-1-yl ester (320 mg) and triethylamine (265 μL) in dimethoxyethane (1.3 mL) was added 3,5-cis-dimethylpiperidine (189 mg). After 2 h, the reaction solution was concentrated in vacuo and flash chromatographed on silica gel (50% ethyl acetate/hexanes) to afford the title compound of this Example as a colorless solid, 130 mg. MS Calc.:505.3 Found:505.2.
Reaction SMILES: [CH2:1]([N:8]([C@@H:16]([CH3:19])[CH:17]=[O:18])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[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][CH3:34]>>[CH2:9]([N:8]([C@H:16]([C@H:17]([OH:18])[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][CH3:21])[CH3:19])[CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CCCCCCCCCCCCCCBr
Reactant: C[C@@H](C=O)N(Cc1ccccc1)Cc1ccccc1
Product: CCCCCCCCCCCCCC[C@@H](O)[C@H](C)N(Cc1ccccc1)Cc1ccccc1

Procedure:
According to the method of Example 26, from aldehyde 4 (309 mg, 1.21 mmol) and 1-bromotetradecane (1.34 g, 4.84 mmol), alcohol 36 was obtained as a colorless oil (270 mg, 49% yield).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[C:3]=1[CH3:18].[O:19]1[CH2:24][CH2:23][N:22]([C:25]2[CH:30]=[CH:29][C:28]([N:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)=[CH:27][C:26]=2[NH2:37])[CH2:21][CH2:20]1.Cl.O1CCOCC1>CN1C(=O)CCC1>[N:22]1([C:25]2[CH:30]=[CH:29][C:28]([N:31]3[CH2:32][CH2:33][O:34][CH2:35][CH2:36]3)=[CH:27][C:26]=2[NH:37][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=[C:4]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=3)[C:3]=2[CH3:18])[CH2:23][CH2:24][O:19][CH2:20][CH2:21]1
Reactant: Cc1c(-c2ccccn2)nc2ccccc2c1Cl
Reactant: Nc1cc(N2CCOCC2)ccc1N1CCOCC1
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: C1COCCO1
Product: Cc1c(-c2ccccn2)nc2ccccc2c1Nc1cc(N2CCOCC2)ccc1N1CCOCC1

Procedure:
Prepared according to Procedure K, Method 2 using 4-chloro-3-methyl-2-(pyridin-2-yl)quinoline (77 mg, 302 μmol), 2,5-dimorpholinobenzenamine (80 mg, 302 μmol) and 4N hydrochloric acid solution in dioxane (7.6 μL, 30 μmol) in NMP (1 mL) to afford product as a colorless solid upon purification by reversed phase HPLC. 1H NMR (400 MHz, chloroform-d) δ ppm 8.58-8.72 (1H, m), 8.13 (1H, d, J=8.6 Hz), 7.74-7.90 (3H, m), 7.54-7.68 (1H, m), 7.39 (1H, td, J=7.6, 1.2 Hz), 7.25-7.35 (1H, m), 7.15 (1H, s), 7.02 (1H, d, J=8.6 Hz), 6.35 (1H, dd, J=8.6, 2.7 Hz), 5.95 (1H, d, J=2.7 Hz), 3.74-3.93 (4H, m), 3.52-3.72 (4H, m), 2.99 (4H, d, J=3.9 Hz), 2.72-2.89 (4H, m), 2.31 (3H, s). Mass Spectrum (ESI) m/e=482.2 (M+1).