Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:13]=[C:14]([Cl:27])[C:15]=1[O:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[C:19]([CH:24]([CH3:26])[CH3:25])[CH:18]=1)[CH:5]=[C:6]1[S:10][C:9](=[O:11])[NH:8][C:7]1=[O:12].[C:28](OCC)(=O)C.CO>[Pd]>[Cl:27][C:14]1[CH:13]=[C:4]([CH:3]=[C:2]([Cl:1])[C:15]=1[O:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:28])=[C:19]([CH:24]([CH3:25])[CH3:26])[CH:18]=1)[CH2:5][CH:6]1[S:10][C:9](=[O:11])[NH:8][C:7]1=[O:12]
Reactant: CC(C)c1cc(Oc2c(Cl)cc(C=C3SC(=O)NC3=O)cc2Cl)ccc1O
Reactant: CCOC(C)=O
Agent: [Pd]
Solvent: CO
Product: COc1ccc(Oc2c(Cl)cc(CC3SC(=O)NC3=O)cc2Cl)cc1C(C)C
Reaction time: 2 h

Procedure:
To a solution of the title compound from Step D (31 mg, 0.072 mmol) was dissolved in ethyl acetate/methanol (1 ml/1 ml) and placed in a hydrogenation bottle with 10% palladium on carbon (90 mg). The mixture was placed on Parr shaker for two hours under 50 p.s.i. of hydrogen, then filtered through diatomaceous earth, and the filter cake was washed with ethyl acetate/methanol. The combined filtrate was concentrated to give the title compound (26 mg) as a clear, viscous oil that was used in the next step without purification. MS (APCl−) Calc: 439.0, Found: 438.1 (M−1).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[CH:7][C:8]([NH:18][CH2:19][CH:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)=[C:9]([NH:11][C:12](=O)[C:13]([CH3:16])([CH3:15])[CH3:14])[CH:10]=1)(=[O:3])[CH3:2]>CC(O)=O>[C:13]([C:12]1[N:18]([CH2:19][CH:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[C:8]2[CH:7]=[CH:6][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[CH:10][C:9]=2[N:11]=1)([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(=O)Nc1ccc(NCC2CCOCC2)c(NC(=O)C(C)(C)C)c1
Solvent: CC(=O)O
Product: CC(=O)Nc1ccc2c(c1)nc(C(C)(C)C)n2CC1CCOCC1
Temperature: 120 °C

Procedure:
N-{5-(acetylamino)-2-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}-2,2-dimethylpropanamide (33.1 g, 95.3 mmol) was dissolved in AcOH (250 mL). The solution was heated at 120° C. for 8 h. Upon evaporation of the solvent, the residue was dissolved in EtOAc (500 mL), washed with 2N NaOH (3×50 mL), brine (50 mL) and dried over anhydrous Na2SO4. The crude product was recrystallized from EtOAc. Yield: 29.0 g (92%). 1H NMR (400 MHz, CHLOROFORM-D): δ 1.48-1.54 (m, 4 H), 1.56 (s, 9 H), 2.20 (s, 3 H), 2.24-2.35 (m, 1 H), 3.28-3.35 (m, 2 H), 3.96 (t, J=2.83 Hz, 1 H), 3.99 (t, J=3.03 Hz, 1 H), 4.19 (d, J=7.42 Hz, 2H), 7.27 (d, J=8.59 Hz, 1 H), 7.34 (br.s, 1 H), 7.57 (dd, J=8.79, 1.95 Hz, 1 H), 7.67 (d, J=1.95 Hz, 1 H); MS (ESI) (M+H)+=330.04.
Reaction SMILES: Br[CH2:2][CH2:3]Br.[CH2:5]([O:7][C:8](=[O:18])[C:9]1[CH:17]=[C:15]([OH:16])[C:13]([OH:14])=[C:11]([OH:12])[CH:10]=1)[CH3:6].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[CH2:5]([O:7][C:8]([C:9]1[CH:10]=[C:11]([OH:12])[C:13]2[O:14][CH2:3][CH2:2][O:16][C:15]=2[CH:17]=1)=[O:18])[CH3:6]
Reactant: CCOC(=O)c1cc(O)c(O)c(O)c1
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(O)c2c(c1)OCCO2
Temperature: 100 °C
Reaction time: 2 h

Procedure:
A solution of 0.2 ml of 1,2-dibromoethane in 4 ml of dimethylformamide is added dropwise, four times at 2 hour intervals, to a solution, stirred at 100° C., of 2 g of gallic acid ethyl ester and 6.5 g of caesium carbonate in 80 ml of dimethylformamide. After being stirred for a further 2 hours at 100° C. the reaction mixture is concentrated by evaporation and the residue is partitioned between diethyl ether and water. The organic phases are dried over sodium sulfate and concentrated by evaporation. The title compound is obtained from the residue by FC (50 g of silica gel, methylene chloride-methanol=8:2): Rf (methylene chloride/methanol=8:2)=0.39.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[CH3:9][NH:10][NH2:11]>C(OCC)(=O)C>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([N:10]([CH3:9])[NH2:11])=[N:3][CH:4]=1
Reactant: Brc1ccc(Br)nc1
Reactant: CNN
Solvent: CCOC(C)=O
Product: CN(N)c1ccc(Br)cn1
Temperature: 100 °C

Procedure:
A mixture of 2,5-dibromopyridine (500 mg) and methylhydrazine (1 mL) was heated at 100° C. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and washed with a saturated brine. The organic layer was dried over sodium sulfate and concentrated in vacuo. The resultant crude product was purified by column chromatography on silica gel (solvent; chloroform) and the eluted fraction was concentrated. The residue was dissolved in tert-butanol and lyophilized to give 5-bromo-2-(N-methylhydrazino)pyridine (460 mg) as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([CH2:27][CH2:28][CH2:29][C:30]([F:36])([F:35])[C:31]([F:34])([F:33])[F:32])(C(O)=O)[C:21]([OH:23])=[O:22])=[C:8]([C:37]1[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][CH:38]=1)[CH:7]=[CH:6]2.O>CS(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH:20]([CH2:27][CH2:28][CH2:29][C:30]([F:36])([F:35])[C:31]([F:34])([F:33])[F:32])[C:21]([OH:23])=[O:22])=[C:8]([C:37]1[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][CH:38]=1)[CH:7]=[CH:6]2
Reactant: COc1ccc(-c2ccc3cc(OC)ccc3c2CCCCCCCC(CCCC(F)(F)C(F)(F)F)(C(=O)O)C(=O)O)cc1
Solvent: CS(C)=O
Solvent: O
Product: COc1ccc(-c2ccc3cc(OC)ccc3c2CCCCCCCC(CCCC(F)(F)C(F)(F)F)C(=O)O)cc1
Temperature: 120 °C
Yield: 88.2 %

Procedure:
Next, the resulting 2-[7-[6-methoxy-2-(4-methoxyphenyl)napht-1-yl]heptyl]-2-(4,4,5,5,5-pentafluoropentyl)-malonic acid (1.0 g) was dissolved in dimethyl sulfoxide (10 ml) and the mixture was heated for 4 hours at 120° C. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride and dried over anhydrous sodium sulfate. After distilling off the solvent, the residue was purified by silica gel column chromatography (eluent: ethyl acetate/hexane=1/1) to give 9-[6-methoxy-2-(4-methoxyphenyl)naphth-1-yl]-2-(4,4,5,5,5-pentafluoropentyl)nonanoic acid (820 mg, Yield 94%).
Reaction SMILES: [C:1]([Si:5]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)Cl)([CH3:4])([CH3:3])[CH3:2].[F:19][C:20]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=1[OH:27].N1C=CN=C1>C(Cl)Cl>[C:1]([Si:5]([O:27][C:21]1[CH:22]=[CH:23][C:24]([F:26])=[CH:25][C:20]=1[F:19])([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: Oc1ccc(F)cc1F
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)[Si](Oc1ccc(F)cc1F)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 104.1 %

Procedure:
tert-Butydiphenylchlorosilane (76.8 g) was added over 30 min to a cooled (0° C.) solution of 2,4-difluorophenol (34.6 g) and imidazole (19.9 G) in CH2Cl2 (400 ml). The cooling bath was removed and the reaction mixture was stirred 2 h at rt before washing it with H2O (400 ml), 5% aq. NaHCO3 (300 ml) and brine. The aqueous layers were extracted with two more portions of CH2Cl2 (150 ml). The combined organic layers were dried (Na2SO4) and the solvent was evaporated to obtain 102 g (99%) of tert-butyl-(2,4-difluoro-phenoxy)-diphenyl-silane. Colorless liquid.
Reaction SMILES: [C:1]1([OH:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH2:12]([O:14][C:15](=[O:19])[C:16]#[C:17][CH3:18])[CH3:13].N12CCCN=C1CCCCC2>O1CCCC1>[CH2:12]([O:14][C:15](=[O:19])[CH:16]=[C:17]([O:11][C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1)[CH3:18])[CH3:13]
Reactant: CC#CC(=O)OCC
Reactant: Oc1cccc2ccccc12
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)C=C(C)Oc1cccc2ccccc12
Temperature: 130 °C
Reaction time: 8 h
Yield: 50.8 %

Procedure:
A mixture of naphthalen-1-ol (1.28 g, 8.91 mmol) and ethyl-2-butynoate (2.0 g, 17.8 mmol) in tetrahydrofuran (13.7 mL) was treated with 1,8-diazabicyclo[5.4.0]undec-7-ene (1.33 mL, 8.91 mmol). The reaction was then heated at 130° C. for 1.5 h. At this time, the reaction was cooled to 25° C. and was stirred at 25° C. overnight. At this time, the reaction was concentrated in vacuo. The residue was dissolved in dichloromethane (40 mL) and was washed with a 2N aqueous hydrochloric acid solution (1×100 mL), a 0.5N aqueous sodium hydroxide solution (1×100 mL) and a saturated aqueous sodium chloride solution (1×100 mL). The organics were then dried over sodium sulfate, filtered, rinsed with dichloromethane and concentrated in vacuo. Purification by Analogix flash chromatography (40 g, 5-10% ethyl acetate/hexanes) afforded 3-(naphthalen-1-yloxy)-but-2-enoic acid ethyl ester (1.16 g, 50%) as a clear oil: HR-ES-MS m/z calculated for C16H16O3 [M+H]+ 257.1172, observed 257.1172; 1H NMR (300 MHz, DMSO-d6), δ ppm 1.04 (t, J=7.1 Hz, 3H), 2.60 (s, 3H), 3.93 (q, J=7.1 Hz, 2H), 4.52 (s, 1H), 7.31 (d, J=7.2 Hz, 1H), 7.53-7.65 (m, 3H), 7.78-7.84 (m, 1H), 7.90 (d, J=8.2 Hz, 1H), 7.99-8.07 (m, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Br)=[CH:4][CH:3]=1.[CH:10]([CH:13]1[O:18][CH2:17][CH2:16][NH:15][CH2:14]1)([CH3:12])[CH3:11].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][N:15]2[CH2:16][CH2:17][O:18][CH:13]([CH:10]([CH3:12])[CH3:11])[CH2:14]2)=[CH:4][CH:3]=1
Reactant: BrCc1ccc(Br)cc1
Reactant: CC(C)C1CNCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)C1CN(Cc2ccc(Br)cc2)CCO1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The above compound could be made in the following manner: 1.5 eq. of 4-Bromobenzyl bromide and 1 eq. of 2-Isopropyl-morpholine in acetonitrile could be stirred at room temperature and 3 eq. of potassium carbonate could be added. The reaction could be stirred at room temperature overnight. The solution could be filtered through Celite and concentrated in vacuo to afford a brown solid. Purification could be done by flash chromatography to afford product.
Reaction SMILES: [F:1][C:2]([S:5]([C:8]1[CH:13]=[CH:12][C:11](Cl)=[CH:10][CH:9]=1)(=[O:7])=[O:6])([F:4])[F:3].[Cl:15][C:16]1[CH:17]=[C:18]([OH:23])[CH:19]=[CH:20][C:21]=1[Cl:22].C([O-])([O-])=O.[K+].[K+]>CS(C)=O>[F:1][C:2]([F:4])([F:3])[S:5]([C:8]1[CH:13]=[CH:12][C:11]([O:23][C:18]2[CH:19]=[CH:20][C:21]([Cl:22])=[C:16]([Cl:15])[CH:17]=2)=[CH:10][CH:9]=1)(=[O:7])=[O:6]
Reactant: Oc1ccc(Cl)c(Cl)c1
Reactant: O=S(=O)(c1ccc(Cl)cc1)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: O=S(=O)(c1ccc(Oc2ccc(Cl)c(Cl)c2)cc1)C(F)(F)F
Temperature: 125 °C
Yield: 86.3 %

Procedure:
To a solution of 4.7 g (0.0192 mole) of 4-chlorophenyl trifluoromethyl sulfone prepared according to known procedures (see E. A. Nodiff et al., J. Org. Chem., 25, 60 (1959)) and 4.7 g (0.0288 mole) of 3,4-dichlorophenol dissolved in 150 ml of DMSO was added 4.0 g (0.0288 mole) of K2CO3. The reaction mixture was heated at 125° C. for 3.5 hrs and the product recovered (6.15 g, 86.3% yield) as described in Example 18. Recrystallization from ethanol afforded purified 4-(4-((trifluoromethyl)sulfonyl)phenoxy)-1,2-dichlorobenzene, mp 77°-78° C.
Reaction SMILES: [Br:1][C:2]1[C:18]([CH3:19])=[C:17]([N+:20]([O-:22])=[O:21])[CH:16]=[C:15]([Br:23])[C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[C:7]([CH:12]([CH3:14])[CH3:13])[CH:6]=1.[C:24](O)(C(F)(F)F)=[O:25]>Cl>[Br:1][C:2]1[C:18]([CH3:19])=[C:17]([N+:20]([O-:22])=[O:21])[CH:16]=[C:15]([Br:23])[C:3]=1[O:4][C:5]1[CH:6]=[C:7]([CH:12]([CH3:14])[CH3:13])[C:8]([OH:11])=[C:9]([CH:10]=1)[CH:24]=[O:25]
Reactant: O=C(O)C(F)(F)F
Reactant: Cc1c([N+](=O)[O-])cc(Br)c(Oc2ccc(O)c(C(C)C)c2)c1Br
Agent: Cl
Product: Cc1c([N+](=O)[O-])cc(Br)c(Oc2cc(C=O)c(O)c(C(C)C)c2)c1Br
Temperature: 95 °C
Reaction time: 16 h
Yield: 79 %

Procedure:
Hexamethylentetramine (197 mg, 1.4 mmol) was added to a solution of compound 4-(2,6-dibromo-3-methyl-4-nitrophenoxy)-2-isopropylphenol of Part 8C (250 mg, 0.56 mmol) and TFA (5 mL). The resulting reaction mixture was stirred for 16 hours at 95° C. The reaction mixture was cooled to room temperature and 1N HCl (10 mL) was added. After another hour of stirring, the reaction mixture was extracted with EtOAc (3×30 mL), the combined organic phases washed by 1N HCl (15 mL), H2O (20 mL) and brine (20 mL). After drying over Na2SO4, concentration and filtration through a pad of silica, 210 mg (79%) of 5-(2,6-dibromo-3-methyl-4-nitrophenoxy)-2-hydroxy-3-isopropylbenzaldehyde was obtained as a light yellow solid.
Reaction SMILES: [O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]2[CH:13]=[N:14][C:15]([CH:16]=O)=[C:5]2[C@@H:4]2[CH2:18][CH2:19][CH2:20][N:3]12.Cl.[NH2:22][OH:23].O.O.O.O.O.O.O.O.O.O.C(=O)([O-])[O-].[Na+].[Na+]>O>[O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]2[CH:13]=[N:14][C:15]([CH:16]=[N:22][OH:23])=[C:5]2[C@@H:4]2[CH2:18][CH2:19][CH2:20][N:3]12
Reactant: O=Cc1ncn2c1[C@@H]1CCCN1C(=O)c1ccccc1-2
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=C1c2ccccc2-n2cnc(C=NO)c2[C@@H]2CCCN12
Temperature: 70 °C
Reaction time: 4 h

Procedure:
A suspension of 2.67 g (10 mmol) of (S)-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxaldehyde and 0.85 g (12.5 mmol) of hydroxylamine hydrochloride in 60 ml of water is treated dropwise at room temperature with a solution of 3.57 g (12.5 mmol) of sodium carbonate decahydrate in 10 ml of water. The mixture is stirred at 70° C. for 4 hours. After cooling, the separated material is filtered off under suction, washed with water and recrystallised directly from 50 ml of dimethylformamide. There is obtained (S)-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxaldehyde-1-oxime of melting point 285° C.
Reaction SMILES: [NH2:1][C:2]1([C:5]#[N:6])[CH2:4][CH2:3]1.[C:7](Cl)(=[O:23])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]>>[C:5]([C:2]1([NH:1][C:7](=[O:23])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[CH2:4][CH2:3]1)#[N:6]
Reactant: CCCCCCCCCCCCCCCC(=O)Cl
Reactant: N#CC1(N)CC1
Product: CCCCCCCCCCCCCCCC(=O)NC1(C#N)CC1
Yield: 77.4 %

Procedure:
General procedure F was used to couple 1.68 mmols of 1-amino-1-cyclopropanecarbonitrile to 2.184 mmols of palmitoyl chloride. After standard purification techniques, 1.3 mmols (77%) of the title product was recovered. 1H NMR (500 MHz, CDCl3) δ 5.95 (s, 1H), 2.16 (t, J=7.6, 2H), 1.65-1.59 (m, 2H), 1.58 (s, 1H), 1.57-1.53 (m, 2H), 1.39-1.15 (m, 28H), 0.88 (dd, J=6.0, 7.0, 3H). 13C NMR (126 MHz, CDCl3) δ 119.97, 36.08, 31.91, 29.64, 25.17, 22.68, 20.32, 16.85, 14.25.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7](=[O:11])[NH:8]2)=[CH:4][C:3]=1[F:12].N1CCCCC1.Cl[C:20]([CH:22]([O:24][C:25](=[O:27])[CH3:26])[CH3:23])=[O:21]>O1CCCC1>[F:12][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:2]=1[NH:1][C:20]([CH:22]([O:24][C:25](=[O:27])[CH3:26])[CH3:23])=[O:21])[NH:8][C:7](=[O:11])[CH2:6]2
Reactant: CC(=O)OC(C)C(=O)Cl
Reactant: Nc1cc2c(cc1F)CC(=O)N2
Solvent: C1CCNCC1
Solvent: C1CCOC1
Product: CC(=O)OC(C)C(=O)Nc1cc2c(cc1F)CC(=O)N2
Temperature: 25 °C
Yield: 110.6 %

Procedure:
5-Fluoro-6-amino-1,3-dihydro-indol-2-one 3d (450 mg, 2.71 mmol) was dissolved in 10 ml of tetrahydrofuran under stirring at room temperature. The mixture was cooled down to −45° C. in a dry ice-acetone bath and added with 364 μl of piperidine. A solution of acetic acid 1-chlorocarbonyl-ethyl ester (423 mg, 2.71 mmol) in 10 ml of tetrahydrofuran was added dropwise to the above reaction system. Upon completion of the addition, the ice-acetone bath was removed, and the reaction mixture was allowed to warm up to room temperature and stirred overnight. After thin lay chromatography showed the disappearance of starting materials, the reaction mixture was filtered. The filter cake was washed with water, and the resulting solid was dried to obtain the title compound acetic acid 1-(5-fluoro-2-oxo-2,3-dihydro-1H-indol-6-ylcarbamoyl)-ethyl ester 8a (840 mg) as a white solid to be used directly in the next step.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[C:4]([O:14][C:15]2[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][CH:16]=2)[C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([O:12][CH3:13])=[CH:7][CH:6]=2.[CH3:29][CH2:30][O:31][C:32]([CH:34](P(OCC)(OCC)=O)[CH3:35])=[O:33].[Li]CCCC>C1COCC1>[CH2:30]([O:31][C:32](=[O:33])[C:34]([CH3:35])=[CH:19][C:18]1[CH:17]=[CH:16][C:15]([O:14][C:4]2[C:5]3[C:10](=[CH:9][C:8]([O:12][CH3:13])=[CH:7][CH:6]=3)[CH:11]=[C:2]([CH3:1])[C:3]=2[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:22][CH:21]=1)[CH3:29]
Reactant: COc1ccc2c(Oc3ccc(C=O)cc3)c(-c3ccccc3)c(C)cc2c1
Reactant: CCOC(=O)C(C)P(=O)(OCC)OCC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC(=O)C(C)=Cc1ccc(Oc2c(-c3ccccc3)c(C)cc3cc(OC)ccc23)cc1
Yield: 77.5 %

Procedure:
As described above, 4-(6-Methoxy-3-methyl-2-phenyl-naphthalen-1-yloxy)-benzaldehyde (8) (0.21 g, 0.570 mmol), triethyl 2-phosphonopropionate (0.183 mL, 0.855 mmol), 1.6 M nBuLi (0.57 mL, 0.912 mmol) in dry THF (8 mL) afforded 0.2 g (78%) of the title compound (219) as oil. 1H NMR (400 MHz, d-CDCl3): δ 1.31 (t, J=7.1 Hz, 3H), 2.04 (s, 3H), 2.24 (s, 3H), 3.93 (s, 3H), 4.20-4.25 (m, 2H), 6.59 (d, J=8.8 Hz, 2H), 7.03-7.06 (m, 1H), 7.11-7.16 (m, 5H), 7.21-7.25 (m, 3H), 7.55 (d, J=9.7 Hz, 2H), 7.75 (d, J=9.1 Hz, 1H).
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:22])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8](B3OC(C)(C)C(C)(C)O3)[CH:7]=2)[CH2:3][CH2:2]1.Br[C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][CH:33]=1)[C:30](=[O:34])[N:29]([CH2:35][CH:36]1[CH2:38][CH2:37]1)[CH:28]=[C:27]2[C:39]([O:41][CH3:42])=[O:40].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C.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>[CH:1]1([NH:4][C:5]([C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([C:24]3[CH:25]=[C:26]4[C:31](=[CH:32][CH:33]=3)[C:30](=[O:34])[N:29]([CH2:35][CH:36]3[CH2:37][CH2:38]3)[CH:28]=[C:27]4[C:39]([O:41][CH3:42])=[O:40])[CH:7]=2)=[O:22])[CH2:2][CH2:3]1
Reactant: COC(=O)c1cn(CC2CC2)c(=O)c2ccc(Br)cc12
Reactant: Cc1ccc(C(=O)NC2CC2)cc1B1OC(C)(C)C(C)(C)O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1cn(CC2CC2)c(=O)c2ccc(-c3cc(C(=O)NC4CC4)ccc3C)cc12
Temperature: 80 °C

Procedure:
A mixture of N-cyclopropyl-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (4.24 g) [prepared as described in US2005020590], the product of step iii) (4.3 g), tetrakis(triphenylphosphine)palladium(0) (1.5 g) and potassium carbonate (3.54 g) in DMF (50 mL) was heated to 80° C. for 17 hours. The reaction mixture was diluted with ethyl acetate and washed with water and brine. The organics were dried over magnesium sulphate and evaporated. The crude product was purified (SiO2, 50 to 70% ethyl acetate in isohexane as eluent) to yield the sub-title compound (2.5 g).
Reaction SMILES: [Br:1][CH2:2][C:3](=[O:10])[C:4](C)(C)[CH2:5][CH:6]=[CH2:7].[C:11](O)(=O)CCCC=C>>[Br:1][CH2:2][C:3](=[O:10])[CH2:4][CH2:5][CH2:6][CH:7]=[CH2:11]
Reactant: C=CCCCC(=O)O
Reactant: C=CCC(C)(C)C(=O)CBr
Product: C=CCCCC(=O)CBr

Procedure:
The title compound was prepared according to the procedure described for Intermediate 4, using 5-hexenoic acid in place of 2,2-dimethylpent-4-enoic acid. 1H NMR (300 MHz, CDCl3) δ 5.77 (m, 1H), 5.05-4.98 (m, 2H), 3.87 (s, 2H), 2.66 (t, J 7.3, 2H), 2.89 (m, 2H), 2.09 (m, 2H).
Reaction SMILES: [N:1]1[C:8]([Cl:9])=[N:7][C:5]([Cl:6])=[N:4][C:2]=1Cl.[C:10]([Mg]Cl)([CH3:13])([CH3:12])[CH3:11].[NH4+].[Cl-]>C1COCC1.[Cu]I>[C:10]([C:2]1[N:4]=[C:5]([Cl:6])[N:7]=[C:8]([Cl:9])[N:1]=1)([CH3:13])([CH3:12])[CH3:11]
Reactant: CC(C)(C)[Mg]Cl
Reactant: Clc1nc(Cl)nc(Cl)n1
Agent: [Cu]I
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(C)c1nc(Cl)nc(Cl)n1
Temperature: -10 °C

Procedure:
Dissolved cyanuric chloride (4.2 g, 22.9 mmol) and CuI (0.22 g, 1.1 mmol) in anhydrous THF (12 mL) and cooled to −10° C. under N2. Added tert-butylmagnesium chloride (1.0M in THF, 25.4 mL) slowly over 20 min. Added saturated NH4Cl (5 mL) and warmed reaction to room temperature. Extracted mixture with CH2Cl2 (4×75 mL). Washed organic layer with water (35 mL) and saturated NaCl (35 mL) then dried (Na2SO4) and concentrated. Purified the product by filtration through a pad of silica gel eluting with CH2Cl2 to give the title compound (1.5 g) as a yellow oil.
Reaction SMILES: [CH3:1][N:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3](Cl)=[S:4].[CH3:12][NH:13][NH2:14]>CCOCC>[CH3:12][N:13]([C:3]([N:2]([CH3:1])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[S:4])[NH2:14]
Reactant: CN(C(=S)Cl)c1ccccc1
Reactant: CNN
Solvent: CCOCC
Product: CN(N)C(=S)N(C)c1ccccc1
Temperature: 25 °C
Yield: 83.4 %

Procedure:
To a solution of N-methyl-N-phenylthiocarbamyl chloride (79.6 g, 0.43 mole) in 250 ml dry ether, a solution of 39.5 g (0.86 mole) methylhydrazine in 100 ml of dry ether was added dropwise with stirring below 10° C. The reaction temperature was allowed to increase to room temperature and the mixture was filtered. The filtrate was evaporated to low volume and diluted with about 300 ml hexane. After stirring for a few hours the hexane layer was decanted. The hexane immiscible layer was reevaporated to remove organic solvents, giving the desired product, (70.0 g) as a thick orange liquid.
Reaction SMILES: [ClH:1].[C:2]([NH:5][C:6](=[NH:9])OC)(=[NH:4])[NH2:3].[CH2:10]([NH2:13])[CH:11]=[CH2:12]>C(O)C>[ClH:1].[CH2:10]([NH:13][C:6]([NH:5][C:2]([NH2:4])=[NH:3])=[NH:9])[CH:11]=[CH2:12]
Reactant: C=CCN
Reactant: COC(=N)NC(=N)N
Agent: Cl
Solvent: CCO
Product: C=CCNC(=N)NC(=N)N

Procedure:
Into 3 ml of ethanol were dissolved 5 g of guanyl-O-methylisourea hydrochloride and 3 ml of allylamine. The resulting solution was reacted at room temperature for 24 hours in a nitrogen stream. The reaction mixture was then filtered and the precipitates were washed with ethanol to give 3.14 g of allylbiguanide hydrochloride as needle like crystals (m.p.: 178°-179° C.).
Reaction SMILES: [CH2:1]([C:5]1[O:6][C:7]2[CH:13]=[CH:12][C:11]([NH:14][S:15]([CH3:18])(=[O:17])=[O:16])=[CH:10][C:8]=2[CH:9]=1)[CH2:2][CH2:3][CH3:4].[Li]CCCC.CCCCCC.[CH2:30]([N:34]([CH2:47][CH2:48][CH2:49][CH3:50])[CH2:35][CH2:36][CH2:37][O:38][C:39]1[CH:46]=[CH:45][C:42]([CH:43]=[O:44])=[CH:41][CH:40]=1)[CH2:31][CH2:32][CH3:33].[NH4+].[Cl-]>CCCCCC.C1COCC1>[CH2:1]([C:5]1[O:6][C:7]2[CH:13]=[CH:12][C:11]([NH:14][S:15]([CH3:18])(=[O:16])=[O:17])=[CH:10][C:8]=2[C:9]=1[CH:43]([C:42]1[CH:41]=[CH:40][C:39]([O:38][CH2:37][CH2:36][CH2:35][N:34]([CH2:47][CH2:48][CH2:49][CH3:50])[CH2:30][CH2:31][CH2:32][CH3:33])=[CH:46][CH:45]=1)[OH:44])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN(CCCC)CCCOc1ccc(C=O)cc1
Reactant: CCCCc1cc2cc(NS(C)(=O)=O)ccc2o1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCCc1oc2ccc(NS(C)(=O)=O)cc2c1C(O)c1ccc(OCCCN(CCCC)CCCC)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 40.1 %

Procedure:
2.67 g of N-(2-butyl-1-benzofuran-5-yl)methanesulfonamide (II) (0.01 mol, 1 eq) is dissolved in 35 mL of n-hexane and 7 mL of 2.5 M BuLi hexane solution is added in 30 min during which the temperature is kept at 20° C. The reaction mixture is stirred for 2 hours at room temperature and then it is added to the solution of 4.37 g of 4-(3-dibutylamino-propoxy)-benzaldehyde (V) (0.015 mol, 1.5 eq) in 80 mL of THF. The reaction mixture is stirred at room temperature for 2 hours and then 40 mL of NH4Cl solution is added. After 15 min of stirring, the product is extracted with 2×40 mL of diethyl ether. The organic phase is concentrated and the crude product is purified by column chromatography (spheric silica; eluent:toluene:MTBE:methanol=50:40:10) to obtain 2.24 g of compound (VI) (40%).