Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=1[C:11]#[N:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:17]([Mg]Br)[CH3:18].B(F)(F)F.CCOCC>C(OCC)C.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=1[C:11]1([NH2:12])[CH2:18][CH2:17]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#Cc1ccccc1OCc1ccccc1
Reactant: CC[Mg]Br
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: FB(F)F
Solvent: CCOCC
Product: NC1(c2ccccc2OCc2ccccc2)CC1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
Titanium(IV) isopropoxide (1.62 mL) was added to a stirred solution of 2-(benzyloxy)benzonitrile (1.05 g) in diethyl ether (25 mL) cooled to −78° C. under N2 followed by the dropwise addition of ethylmagnesium bromide (3.67 mL of a 3M solution in diethylether). The resulting mixture was stirred at −78° C. for 10 min and then warmed to rt over 1 h. Boron trifluoride diethyl etherate (1.27 mL) was added dropwise and the mixture was stirred for 1 h. The reaction was quenched with 1M HCl (30 mL). Diethyl ether (30 mL) was added and the organic layer separated. To the aqueous layer was added aqueous 10% NaOH (50 mL) and diethyl ether and this was filtered through celite to remove solids (which were washed with further diethyl ether). This mixture was extracted with diethyl ether (2×70 mL) and dichloromethane (70 mL). All the organic layers were combined, dried (Na2SO4) and the solvents removed in vacuo. The residue was dissolved in dichloromethane and loaded on to an 10 g SCX cartridge. The impurities were washed through with methanol (50 mL) and discarded. Elution with 7N methanolic ammonia (25 mL) and evaporation in vacuo gave the subtitle compound as a brown oil (0.625 g).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([S:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])[CH:5]=[CH:4][CH:3]=1.[F:15][C:16]([F:22])([F:21])[CH2:17][N:18]=[C:19]=S.C[N:24](C=O)C>>[F:15][C:16]([F:22])([F:21])[CH2:17][N:18]=[C:19]([NH2:24])[NH:1][C:2]1[N:7]=[C:6]([S:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])[CH:5]=[CH:4][CH:3]=1
Reactant: CN(C)C=O
Reactant: FC(F)(F)CN=C=S
Reactant: Nc1cccc(SCCCC(=O)O)n1
Product: NC(=NCC(F)(F)F)Nc1cccc(SCCCC(=O)O)n1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 4-(6-aminopyrid-2-ylthio)butyric acid (0.21 g.) DMF (3 ml.) and 2,2,2-trifluoroethylisothiocyanate (0.15 g.) was left at room temperature for 18 hours and then evaporated to dryness. A solution of the residue in methanolic ammonia was treated with yellow mercuric oxide (0.43 g.) and the mixture stirred at room temperature for 1 hour. The mixture was filtered and the filtrate evaporated to dryness and the residue treated with 2N aqueous NaOH (5 ml.) and then filtered. The filtrate was acidified with HOAc and the precipitate collected to give 4-[6-(2-[2,2,2-trifluoroethyl]guanidino)pyrid-2-ylthio]butyric acid (0.17 g.) which was used without further purification.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:9]1[CH:14]=[CH:13][C:12](C)=[CH:11][CH:10]=1.[C:16](OC(=O)C)(=O)C>C(O)(=O)C.ClCCl>[CH:16]([C:14]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1)=[CH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccncc1
Reactant: O=Cc1ccccc1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: CC(=O)O
Product: C(=Cc1ccccn1)c1ccccc1

Procedure:
A stirring solution of benzaldehyde (44.6 g) and 4-picoline (37.2 g) in acetic acid (24 g) and acetic anhydride (40.8 g) was refluxed for 18 hours. The resultant reaction mixture were cooled, diluted with dichloromethane (300 ml), washed with water and dilute aqueous alkali; and quenched with dilute hydrochloric acid. Precipitate of styrylpyridine hydrochloride (long golden needles) was separated by filtration, washed with methylenechloride, dried and poured into stirred solution of sodium carbonate in water. After 2 hours of stirring white-gray precipitate was filtered, washed with water and dried overnight at 60°-70° C. After recrystallization, 39.6 g. of styrylpyridine were obtained.
Reaction SMILES: [Br:1][CH2:2][CH:3]([C:5]1[S:6][CH:7]=[CH:8][CH:9]=1)[OH:4].[C:10]1(C)C=CC(S(O)(=O)=O)=CC=1>>[CH3:10][O:4][CH:3]([CH2:2][Br:1])[C:5]1[S:6][CH:7]=[CH:8][CH:9]=1
Reactant: OC(CBr)c1cccs1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Product: COC(CBr)c1cccs1

Procedure:
A solution of the halohydrin, α-(bromomethyl)-2-thiophenemethanol (10.0 g, 0.048 mole), described in Example 4, and p-toluenesulfonic acid (1.0 g) in 100 ml of the lower alkanol methanol, is heated at reflux for 5 hr. The mixture is concentrated and the concentrate extracted with ether. The ether extract is washed with water and brine, dried (MgSO4) and concentrated to yield a brown liquid which is purified by chromatography on silica gel to give α-(bromomethyl)-2-thiophenemethanol methyl ether; nmr (CDCl3) δ 3.36 (s, 3H), 3.58 (m, 2H), 4.68 (t, J = 6.5, 1H), 7.02 (m, 1H), 7.5 (m, 1H), 7.31 (m, lH).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[C:7]2[CH2:11][NH:12][CH3:13].CNCC1C2C=CC=CC=2N2CCCC=12.[NH2:29][C:30]1[N:35]=[CH:34][C:33](/[CH:36]=[CH:37]/[C:38]([OH:40])=O)=[CH:32][CH:31]=1.Cl.O=C1NC2N=CC(/C=C/C(O)=O)=CC=2CC1>>[NH2:29][C:30]1[N:35]=[CH:34][C:33](/[CH:36]=[CH:37]/[C:38]([N:12]([CH2:11][C:7]2[C:6]3[C:10](=[C:2]([F:1])[CH:3]=[CH:4][CH:5]=3)[NH:9][CH:8]=2)[CH3:13])=[O:40])=[CH:32][CH:31]=1
Reactant: Nc1ccc(/C=C/C(=O)O)cn1
Reactant: CNCc1c[nH]c2c(F)cccc12
Agent: CNCc1c2n(c3ccccc13)CCC2
Agent: Cl
Agent: O=C(O)/C=C/c1cnc2c(c1)CCC(=O)N2
Product: CN(Cc1c[nH]c2c(F)cccc12)C(=O)/C=C/c1ccc(N)nc1
Yield: 17.7 %

Procedure:
According to the procedure of Example 24, except substituting 7-fluoro-3-(methylaminomethyl)-1H-indole (0.31 g, 1.74 mmole) for the 2,3-dihydro-8-(methylaminomethyl)-1H-3a-azacyclopenta[a]indene, and substituting (E)-3-(6-amino-pyridin-3-yl)acrylic acid (0.285 g, 1.74 mmole) for the (E)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylic acid hydrochloride salt, the title compound (0.1 g, 18%) was prepared as a white powder: MS (ES) m/e 325 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][C:3]=1[CH2:4][O:5][CH2:6][CH2:7][CH2:8][CH2:9][OH:10].[CH3:16]C(C)([O-])C.[K+].CI>O1CCCC1>[CH3:16][O:10][CH2:9][CH2:8][CH2:7][CH2:6][O:5][CH2:4][C:3]1[CH:11]=[C:12]([Br:15])[CH:13]=[CH:14][C:2]=1[F:1]
Reactant: CC(C)(C)[O-]
Reactant: OCCCCOCc1cc(Br)ccc1F
Agent: [K+]
Solvent: CI
Solvent: C1CCOC1
Product: COCCCCOCc1cc(Br)ccc1F
Temperature: -78 °C

Procedure:
A solution of 4-(2-fluoro-5-bromobenzyloxy)butanol (897 mg, 3.24 mmol) in tetrahydrofuran (22 ml) was cooled to −40° C. and then treated with potassium t-butoxide (3.56 ml of a 1 M solution in tetrahydrofuran, 3.56 mmol). The resulting orange solution was stirred for thirty minutes, cooled to −78° C. and treated with methyl iodide (0.40 ml, 6.48 mmol). The reaction was warmed to 0° C. and stirred for 1.5 hours. The reaction mixture was then partitioned between methylene chloride and saturated sodium bicarbonate. The organic fraction was dried over sodium sulfate, and the solvents were removed in vacuo. The desired title intermediate was further purified by high performance liquid chromatography to yield 687 mg (73%) as a clear oil.
Reaction SMILES: [CH:1]([C:3]1[C:12]2[O:13][C:14]3([C:24]([CH3:26])([CH3:25])[C:23]4[C:18](=[CH:19][CH:20]=[C:21]([O:27][CH3:28])[CH:22]=4)[N:17]3[CH3:29])[CH:15]=[N:16][C:11]=2[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=1)=O.[C:30]([CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])#[N:31]>>[C:30]([C:32]([C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:1][C:3]1[C:12]2[O:13][C:14]3([C:24]([CH3:26])([CH3:25])[C:23]4[C:18](=[CH:19][CH:20]=[C:21]([O:27][CH3:28])[CH:22]=4)[N:17]3[CH3:29])[CH:15]=[N:16][C:11]=2[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=1)#[N:31]
Reactant: CCOC(=O)CC#N
Reactant: COc1ccc2c(c1)C(C)(C)C1(C=Nc3c(c(C=O)cc4ccccc34)O1)N2C
Product: CCOC(=O)C(C#N)=Cc1cc2ccccc2c2c1OC1(C=N2)N(C)c2ccc(OC)cc2C1(C)C

Procedure:
This compound is prepared according to the method employed for Example 10, from 0.39 g (1 mmol) of the compound of Example 2 and from 0.18 g (1.5 mmol) of ethyl cyanoacetate.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.CO[CH:12]1[CH2:16][CH2:15][CH:14](OC)O1>C1(C)C=CC=CC=1>[N:1]1([C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=2)[CH:12]=[CH:16][CH:15]=[CH:14]1
Reactant: COC1CCC(OC)O1
Reactant: N#Cc1ccc(N)cc1
Solvent: Cc1ccccc1
Product: N#Cc1ccc(-n2cccc2)cc1
Yield: 60.2 %

Procedure:
A mixture of 4-aminobenzonitrile (50 g., 0.42 mole), 2,5-dimethoxytetrahydrofuran (56 g., 0.42 mole) and 4 A molecular sieves (184 g) in toluene (560 ml) was heated under reflux for 24 hrs. The residue from evaporation was washed with pet. ether and then recrystallized from diisopropyl ether to yield 42.5 g (60%) of 4-(1-pyrrolyl)-benzonitrile, m.p. 104°-106° C.
Reaction SMILES: CC(C)([O:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][CH2:15]/[C:16](/[CH2:29][N:30]2[CH:34]=[CH:33][N:32]=[CH:31]2)=[CH:17]/[C:18]2[CH:28]=[CH:27][C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:20][CH:19]=2)=[CH:9][CH:8]=1)=[O:6])C.Cl.C(=O)([O-])O.[Na+]>C(O)(=O)C.O>[C:5]([C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][CH2:15]/[C:16](/[CH2:29][N:30]2[CH:34]=[CH:33][N:32]=[CH:31]2)=[CH:17]\[C:18]2[CH:19]=[CH:20][C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:27][CH:28]=2)=[CH:9][CH:8]=1)([OH:6])=[O:4]
Reactant: CCOC(=O)c1ccc(/C=C(/CCCc2ccc(C(=O)OC(C)(C)C)cc2)Cn2ccnc2)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)c1ccc(/C=C(\CCCc2ccc(C(=O)O)cc2)Cn2ccnc2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution containing ethyl 4-[5-[4-[(1,1-dimethylethoxy)carbonyl]phenyl]-2-(1H-imidazol-1-ylmethyl)-1E-pentenyl]benzoate (prepared as in Example 15; 3.5 g, 0.0074 mol) in acetic acid (45 ml) was treated with aqueous hydrochloric acid (5% of 35.4%). The solution was stirred at room temperature for three hours after which time the solution was basified with sodium hydrogen carbonate, diluted with water (500 ml) and extracted with dichloromethane (4×300 ml). The extracts were combined, dried over sodium sulphate, and the solvent was evaporated off under reduced pressure to yield a crude product. The crude product was purified by column chromatography (silica gel, 10% ethanol in chloroform) to yield ethyl 4-[5-(4-carboxyphenyl)-2-(1H-imidazol-1-ylmethyl)1E-pentenyl]benzoate as a colorless crystalline solid having a melting point of 167°-170° C. (chloroform/benzene) and the following structural characteristics:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([CH2:11]I)[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1)=[O:4].[C:13]([O-:16])(=[S:15])[CH3:14].[K+]>CN(C)C=O.O>[CH3:1][O:2][C:3]([C:5]1([CH2:11][S:15][C:13](=[O:16])[CH3:14])[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1)=[O:4]
Reactant: CC([O-])=S
Reactant: COC(=O)C1(CI)CCOCC1
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C1(CSC(C)=O)CCOCC1
Reaction time: 18 h
Yield: 97 %

Procedure:
4-Iodomethyltetrahydropyran-4-carboxylic acid methyl ester (3.05 g) was dissolved in N,N-dimethylformamide (20 ml) at room temperature and potassium thioacetate (1.47 g) added. The mixture was stirred for 18 hours then diluted with water (50 ml) and extracted with diethyl ether (4×25 ml). The combined organics were washed with saturated sodium bicarbonate solution (3×20 ml) and brine (20 ml), then dried (MgSO4), filtered and evaporated under reduced pressure to give the title compound as a yellow solid (2.42 g, 97%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[NH:12][CH:13]([CH:17]([CH3:19])[CH3:18])[C:14]([OH:16])=[O:15].[C:20]([C:28]1[N:33]=[C:32]([CH2:34]O)[CH:31]=[CH:30][CH:29]=1)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[NH:12][CH:13]([CH:17]([CH3:19])[CH3:18])[C:14]([O:16][CH2:34][C:32]1[CH:31]=[CH:30][CH:29]=[C:28]([C:20](=[O:27])[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:33]=1)=[O:15]
Reactant: CC(C)C(Nc1ccc(C(F)(F)F)cc1Cl)C(=O)O
Reactant: O=C(c1ccccc1)c1cccc(CO)n1
Product: CC(C)C(Nc1ccc(C(F)(F)F)cc1Cl)C(=O)OCc1cccc(C(=O)c2ccccc2)n1

Procedure:
Using the procedure of Example 1, the acid chloride of 2-(2-chloro-4-trifluoromethylphenylamino)-3-methylbutanoic acid is reacted with (6-benzoyl-2-pyridyl)methanol to yield (6-benzoyl-2-pyridyl)methyl 2-(2-chloro-4-trifluoromethylphenylamino)-3-methylbutanoate, MS m/e 490 (M+).
Reaction SMILES: [Br:1][C:2]([F:14])([F:13])[CH:3]([F:12])[CH2:4][CH2:5][S:6][C:7]1[S:8][CH:9]=[CH:10][N:11]=1.S(Cl)([Cl:18])(=O)=O.O>ClCCl>[Br:1][C:2]([F:13])([F:14])[CH:3]([F:12])[CH2:4][CH2:5][S:6][C:7]1[S:8][C:9]([Cl:18])=[CH:10][N:11]=1
Reactant: FC(CCSc1nccs1)C(F)(F)Br
Reactant: O=S(=O)(Cl)Cl
Solvent: ClCCl
Solvent: O
Product: FC(CCSc1ncc(Cl)s1)C(F)(F)Br

Procedure:
The compound from Step 1 (30.6 g) in dichloromethane (130 cm3) was treated at ambient temperature with sulfuryl chloride (9.6 cm3) in dichloromethane (30 cm3) over 1 hour with stirring under an atmosphere of nitrogen. The reaction was stirred for a further 1 hour, poured slowly into water (250 cm3) and stirred for 0.25 hours. The organic phase was separated, the aqueous phase extracted with dichloromethane (2×75 cm3), the combined organic phases washed with aqueous sodium hydrogen carbonate, brine and dried (MgSO4). The solvent was evaporated under reduced pressure and the residue fractionated by chromatography (silica; eluant 5% diethyl ether in hexane) to give 2-(4-bromo-3,4,4-trifluorobutylthio)-5-chlorothiazole (28.0 g); 1H NMR: δ 2.20-2.45 (2H,m); 3.25-3.50(2H,m); 4.70-5.0(1H,m); 7.45(1H,s); (oil).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10](=O)[CH3:11])=[CH:5][CH:4]=1.[N:13]1[CH:18]=[CH:17][N:16]=[CH:15][C:14]=1[NH:19][C:20]([NH2:22])=[S:21].CC1N=C(NC2C=NC=CN=2)SC=1C1C=CC(S(N)(=O)=O)=CC=1>>[CH3:11][C:10]1[N:22]=[C:20]([NH:19][C:14]2[CH:15]=[N:16][CH:17]=[CH:18][N:13]=2)[S:21][C:9]=1[C:6]1[CH:7]=[CH:8][C:3]([S:2][CH3:1])=[CH:4][CH:5]=1
Reactant: NC(=S)Nc1cnccn1
Reactant: CSc1ccc(CC(C)=O)cc1
Agent: Cc1nc(Nc2cnccn2)sc1-c1ccc(S(N)(=O)=O)cc1
Product: CSc1ccc(-c2sc(Nc3cnccn3)nc2C)cc1

Procedure:
Using 1-(4-methylsulfanyl-phenyl)-propan-2-one (27b) and pyrazin-2-yl-thiourea (1a) in an analogous procedure described for the preparation of 4-[4-methyl-2-(pyrazin-2-ylamino)-thiazol-5-yl]-benzenesulfonamide (Example 1b) affords the title compound.
Reaction SMILES: [C:1]1([C:7]#[C:8][CH2:9]O)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.[C:11]1([CH3:21])[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][CH:12]=1.[OH-].[K+]>>[S:17]([CH2:9][C:8]#[C:7][C:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1)([C:14]1[CH:15]=[CH:16][C:11]([CH3:21])=[CH:12][CH:13]=1)(=[O:19])=[O:18]
Reactant: OCC#CC1=CCCCC1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [K+]
Agent: [OH-]
Product: Cc1ccc(S(=O)(=O)CC#CC2=CCCCC2)cc1
Yield: 92 %

Procedure:
3-cyclohexenyl-2-propyn-1-ol (95)(3.04 g, 22.3 mmol), p-toluene sulfonyl chloride (4.04 g, 21.2 mmol) and potassium hydroxide (6.26 g, 112 mmol) were reacted using the above procedure to yield the product (5.66 g, 19.5 mmol, 91.8%) as a light yellow oil. 1H NMR (CDCl3): 7.79 (d, J=8.1 Hz, 2 H), 7.31 (d, J=8.1 Hz, 2 H), 5.97 (m, 1 H), 4.81 (s, 2 H), 2.42 (s, 3 H), 2.02 (m, 2 H), 1.92 (m, 2 H), 1.53 (m, 4 H). FAB LRMS (m/e): calcd. for (MH+)(C16H19O3S): 29 1, found 29 1.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH:10]2[CH2:12][CH2:11]2)=[CH:4][N:3]=1.[CH3:13][Si:14]([C:17]#[CH:18])([CH3:16])[CH3:15].C(N(CC)CC)C>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.[Cu]I.CN(C=O)C>[CH:10]1([CH2:9][O:8][C:5]2[CH:6]=[CH:7][C:2]([C:18]#[C:17][Si:14]([CH3:16])([CH3:15])[CH3:13])=[N:3][CH:4]=2)[CH2:12][CH2:11]1
Reactant: C#C[Si](C)(C)C
Reactant: Brc1ccc(OCC2CC2)cn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1ccc(OCC2CC2)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.8 %

Procedure:
A mixture of 2-bromo-5-(cyclopropylmethoxy)pyridine (1.145 g), bis(triphenylphosphine)palladium(II) dichloride (175 mg), copper(I) iodide (48 mg), trimethylsilylacetylene (737 mg), triethylamine (759 mg) and DMF (15 mL) was stirred at room temperature overnight under an argon atmosphere. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with ethyl acetate and water, and the mixture was filtered through celite. The aqueous layer was separated from the organic layer. The separated aqueous layer was extracted again with ethyl acetate. The combined organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound as a yellow oil (774 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH2:12][N:13]([CH3:15])[CH3:14])[CH:8]=2)[C:3]=1[CH2:16][C:17]([OH:19])=O.[NH3:20]>CN(C=O)C>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH2:12][N:13]([CH3:15])[CH3:14])[CH:8]=2)[C:3]=1[CH2:16][C:17]([NH2:20])=[O:19]
Reactant: N
Reactant: CN(C)Cc1ccc2c(CC(=O)O)c(Cl)ccc2c1
Solvent: CN(C)C=O
Product: CN(C)Cc1ccc2c(CC(N)=O)c(Cl)ccc2c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
(2-Chloro-6-dimethylaminomethyl-naphthalen-1-yl)-acetic acid (276 mg, 0.99 mmol) is dissolved under an atmosphere of argon in DMF (3 ml). 1,1-Carbonyl diimidazole (177 mg, 1.09 mmol) is added, and the clear solution is stirred at RT for 3 h. A conc. aqueous solution of ammonia (25%, 6 ml) is added, and stirring is continued for 10 minutes at RT. TLC analysis indicates complete consumption of starting material. The reaction mixture is poured on water. The aqueous layer is extracted with EtOAc, which is then washed with brine and dried over Na2SO4. After removal of solvent, the residue is found to be pure title compound, with no need of purification. 1H NMR (d6-DMSO, 400 MHz): δ 2.18 (s, 6H), 3.53 (s, 2H), 4.08 (s, 2H), 6.96-7.08 (br, 2H), 7.48-7.68 (m, 2H), 7.78-7.86 (m, 2H), 7.96-8.00 (d, J=10 Hz, 1H). ES+-MS: 277.3, 279.2 [M+H]+.
Reaction SMILES: [F:1][C:2]1([F:20])[C:15]([F:17])([F:16])[C:14]2[CH:13]=[C:12](Br)[CH:11]=[CH:10][C:9]=2[C:8]2[C:3]1=[CH:4][C:5](Br)=[CH:6][CH:7]=2.[CH2:21]([Mg]Br)[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26].Cl.[Na+].[Cl-]>C1COCC1>[F:1][C:2]1([F:20])[C:15]([F:17])([F:16])[C:14]2[CH:13]=[C:12]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH:11]=[CH:10][C:9]=2[C:8]2[C:3]1=[CH:4][C:5]([CH2:14][CH2:15][CH2:2][CH2:3][CH2:4][CH3:5])=[CH:6][CH:7]=2
Reactant: FC1(F)c2cc(Br)ccc2-c2ccc(Br)cc2C1(F)F
Reactant: CCCCCC[Mg]Br
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCCCc1ccc2c(c1)C(F)(F)C(F)(F)c1cc(CCCCCC)ccc1-2
Temperature: 0 °C
Reaction time: 4 h

Procedure:
4.1 g of 9,9,10,10-tetrafluoro-2,7-dibromo-9,10-dihydrophenanthrene are dissolved in 250 ml of THF and the solution is cooled to 0° C. 120 mg of 1,3-bis(diphenylphosphine)propanenickel(lI) chloride are added, and, at 0° C., 50 mmol of hexylmagnesium bromide in 100 ml of THF are added dropwise. Stirring is continued for 4 hours, and then for a further 18 hours at 50° C. The mixture is acidified with 1N HCl, the aqueous phase is saturated with NaCl and the phases are separated. The aqueous phase is subsequently subjected to extraction a number of times with tert-butyl methyl ether. The crude product is purified by chromatography on silica gel. This gives 3.45 g of 9,9,10,10-tetrafluoro-2,7-dihexyl-9,10-dihydrophenanthrene.
Reaction SMILES: [C:1]([NH:6][C:7]1[NH:8][C:9](=[O:34])[C:10]2[N:11]=[CH:12][N:13]([C:32]=2[N:33]=1)[C@@H:14]1[O:31][C@H:21]([CH2:22][O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])[C@@H:16]([O:17][CH2:18][S:19][CH3:20])[CH2:15]1)(=[O:5])[CH:2]([CH3:4])[CH3:3].[C:35]1([N:41]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[C:42](Cl)=[O:43])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.C(N(CC)C(C)C)(C)C>N1C=CC=CC=1>[C:1]([NH:6][C:7]1[N:8]=[C:9]([O:34][C:42](=[O:43])[N:41]([C:45]2[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=2)[C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:10]2[N:11]=[CH:12][N:13]([C:32]=2[N:33]=1)[C@@H:14]1[O:31][C@H:21]([CH2:22][O:23][Si:24]([C:27]([CH3:29])([CH3:28])[CH3:30])([CH3:25])[CH3:26])[C@@H:16]([O:17][CH2:18][S:19][CH3:20])[CH2:15]1)(=[O:5])[CH:2]([CH3:4])[CH3:3]
Reactant: CSCO[C@H]1C[C@H](n2cnc3c(=O)[nH]c(NC(=O)C(C)C)nc32)O[C@@H]1CO[Si](C)(C)C(C)(C)C
Reactant: O=C(Cl)N(c1ccccc1)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: c1ccncc1
Product: CSCO[C@H]1C[C@H](n2cnc3c(OC(=O)N(c4ccccc4)c4ccccc4)nc(NC(=O)C(C)C)nc32)O[C@@H]1CO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 80 %

Procedure:
To 1.0 g N2-isobutyryl-3′-O-(methylthiomethyl)-5′-O-(tert-butyldimethylsilyl)-2′-deoxyguanosine (11, 1.95 mmol) dissolved in 22 mL dry pyridine were added diphenylcarbamoyl chloride (0.677 g, 2.92 mmol) and 1.02 mL N,N-diisopropylethylamine, and stirred at room temperature for 3 h under nitrogen atmosphere. The reaction mixture became dark red during this time. The solvent was removed under high vacuum, and product was then purified by silica gel column chromatography using EtOAc:hex/1:1 to 7:3 as mobile phase. The product 12 was isolated as yellowish powder (1.09 g, ˜80% yield; Rf=0.7, EtOAc:hex (1:1)). HR-MS: Obs. m/z 707.3068 calcd. for C35H47O6N6SiS 707.3047 [M+H]+. 1H-NMR (CDCl3): δH 8.25 (s, 1H), 7.94 (brs, 1H), 7.47-7.37 (m, 10H), 6.42 (m, 1H), 4.75 (m, 2H), 4.71 (m, 1H), 4.18 (m, 1H), 3.88-3.70 (m, 2H), 2.80 (m, 1H), 2.60 (m, 1H), 2.19 (s, 3H), 1.30 (d, J=7.2 Hz, 6H), 0.93 (s, 9H) and 0.14 (s, 6H) ppm.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[C:9]([C:10](=[O:12])[CH:11]=1)=[CH:8][CH:7]=[CH:6][C:5]=2[CH:13]=O.[CH3:15][C:16](=O)[CH2:17][C:18](=[O:20])[CH3:19].[NH2:22]/[C:23](/[CH3:33])=[CH:24]\[C:25]([O:27][CH:28]1[CH2:32][CH2:31][CH2:30][CH2:29]1)=[O:26].C(O)(=O)C>CC(O)C>[C:18]([C:17]1[CH:13]([C:5]2[CH:6]=[CH:7][CH:8]=[C:9]3[C:4]=2[O:3][C:2]([CH3:1])=[CH:11][C:10]3=[O:12])[C:24]([C:25]([O:27][CH:28]2[CH2:32][CH2:31][CH2:30][CH2:29]2)=[O:26])=[C:23]([CH3:33])[NH:22][C:16]=1[CH3:15])(=[O:20])[CH3:19]
Reactant: Cc1cc(=O)c2cccc(C=O)c2o1
Reactant: CC(=O)CC(C)=O
Reactant: C/C(N)=C/C(=O)OC1CCCC1
Solvent: CC(C)O
Solvent: CC(=O)O
Product: CC(=O)C1=C(C)NC(C)=C(C(=O)OC2CCCC2)C1c1cccc2c(=O)cc(C)oc12

Procedure:
100 mg (0.53 mmol) of 2-methyl-4-oxo-4H-chromene-8-carbaldehyde are dissolved with 93.1 mg (0.93 mmol) of 2,4-pentanedione, 89.9 mg (0.53 mmol) of cyclopentyl 3-aminocrotonate and 31.9 mg (0.53 mmol) of acetic acid in 5 ml of 2-propanol and heated to reflux under argon for 10 h. The solvent is removed in vacuo, and the residue is purified by preparative HPLC. 84 mg (37.5% of theory) of the title compound are obtained as a yellow solid.
Reaction SMILES: [C:1]([CH2:3][C:4]([OH:6])=O)#[N:2].C(OC(=O)C)(=O)C.[C:14]1([NH:20][C:21]([NH2:23])=[O:22])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.CC(O)C>C(O)(=O)C>[C:1]([CH2:3][C:4]([NH:23][C:21]([NH:20][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:22])=[O:6])#[N:2]
Reactant: NC(=O)Nc1ccccc1
Reactant: N#CCC(=O)O
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Solvent: CC(C)O
Product: N#CCC(=O)NC(=O)Nc1ccccc1
Temperature: 95 °C
Reaction time: 1 h
Yield: 79.7 %

Procedure:
Cyanoacetic acid (28 g, 340 mmol) was taken in 20 ml acetic acid and 40 ml acetic anhydride (400 mmol), stirred at 50° C. until all cyanoacetic acid was solved. Phenyl urea (33.05 g, 247.5 mmol) was added and the mixture was stirred at 95° C. for 60 minute under LC-MS (Liquid Chromatography coupled with Mess Spectrometer) control of the reaction progress. After cooling down to room temperature, dilution with 20 ml 2-propanol and storing at 4° C. for 2 h, solids were separated by filtration, washed with cold 2-propanol and dried under high vacuum giving 40.06 g of white solids (82.6%).