Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][P:4]([C:9]1[CH:14]=[C:13]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][CH3:23])=[CH:18][CH:17]=2)[C:12]([O:24][CH3:25])=[CH:11][C:10]=1[O:26][CH3:27])(=[O:8])[O:5]CC)C.Br[Si](C)(C)C.CO>ClCCl>[CH3:27][O:26][C:10]1[CH:11]=[C:12]([O:24][CH3:25])[C:13]([CH2:15][C:16]2[CH:17]=[CH:18][C:19]([CH2:22][CH3:23])=[CH:20][CH:21]=2)=[CH:14][C:9]=1[P:4](=[O:3])([OH:8])[OH:5]
Reactant: CCOP(=O)(OCC)c1cc(Cc2ccc(CC)cc2)c(OC)cc1OC
Agent: C[Si](C)(C)Br
Solvent: CO
Solvent: ClCCl
Product: CCc1ccc(Cc2cc(P(=O)(O)O)c(OC)cc2OC)cc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 91 %

Procedure:
To a solution of [2,4-dimethoxy-5-(4-ethylbenzyl)phenyl]phosphonic acid diethylester (1.00 g) in dichloromethane (13.4 mL) was added bromotrimethylsilane (1.3 mL) at 0° C., and the reaction mixture was stirred for 17 hr at room temperature. Methanol (4.1 mL) was added to the reaction mixture, and the mixture was stirred for 10 min at room temperature. After evaporation, the residue was crystallized from ethyl acetate-n-hexane to give the title compound (0.78 g) as a colorless crystal.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]([CH2:23][CH2:24][CH2:25][C:26]2[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=2)[CH2:17][C:18]([O:20]CC)=[O:19])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[OH-].[Na+]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]([CH2:23][CH2:24][CH2:25][C:26]2[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=2)[CH2:17][C:18]([OH:20])=[O:19])(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: CCOC(=O)CC(CCCCNS(=O)(=O)c1ccc(Cl)cc1)CCCc1cccnc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)CC(CCCCNS(=O)(=O)c1ccc(Cl)cc1)CCCc1cccnc1

Procedure:
Hydrolysis of ethyl 7-(p-chlorophenylsulfonamido)-3-[3-(3-pyridyl)propyl]-heptanoate in 3 ml methanol with 5.2 ml (5.2 mmol) of 1N aqueous sodium hydroxide according to procedure described in the previous examples yields 7-(p-chlorophenylsulfonamido)-3-[3-(3-pyridyl)propyl]-heptanoic acid, m.p. 95°-97°.
Reaction SMILES: C([O:5][C:6](=[O:45])[C:7]([O:10]/[N:11]=[C:12](/[C:32]1[N:33]=[C:34]([NH:37]C(OC(C)(C)C)=O)[S:35][CH:36]=1)\[C:13]([NH:15][C@@H:16]1[C:19](=[O:20])[N:18]([S:21]([OH:24])(=[O:23])=[O:22])[C@@H:17]1[CH2:25][N:26]1[C:30]([CH3:31])=[N:29][N:28]=[N:27]1)=[O:14])([CH3:9])[CH3:8])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:37][C:34]1[S:35][CH:36]=[C:32](/[C:12](=[N:11]/[O:10][C:7]([CH3:9])([CH3:8])[C:6]([OH:45])=[O:5])/[C:13]([NH:15][C@@H:16]2[C:19](=[O:20])[N:18]([S:21]([OH:24])(=[O:22])=[O:23])[C@@H:17]2[CH2:25][N:26]2[C:30]([CH3:31])=[N:29][N:28]=[N:27]2)=[O:14])[N:33]=1
Reactant: Cc1nnnn1C[C@@H]1[C@H](NC(=O)/C(=N\OC(C)(C)C(=O)OC(C)(C)C)c2csc(NC(=O)OC(C)(C)C)n2)C(=O)N1S(=O)(=O)O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1nnnn1C[C@@H]1[C@H](NC(=O)/C(=N\OC(C)(C)C(=O)O)c2csc(N)n2)C(=O)N1S(=O)(=O)O
Yield: 12.4 %

Procedure:
Followed the general procedure for the acid mediated deprotection using (2R,3S)-3-((Z)-2-(((1-(tert-butoxy)-2-methyl-1-oxopropan-2-yl)oxy)imino)-2-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)acetamido)-2-((5-methyl-1H-tetrazol-1-yl)methyl)-4-oxoazetidine-1-sulfonic acid (151 mg, 0.224 mmol), DCM (2.24 mL) and TFA (1.04 mL, 13.45 mmol) for 2 h. The crude residue purified by reverse phase prep HPLC (XSelect CSH, 19×100 mm, 5 μm, C18 column; ACN-water with 0.1% formic acid modifier, 24 mL/min), affording the title compound (14.4 mg, 11%) as a white powder. LCMS: Rt=0.55 min, m/z=518.1 (M+1) Method 2m_acidic_polar; 1H NMR (400 MHz, D2O) δ 7.04 (s, 1H), 5.37 (d, J=5.5 Hz, 1H), 4.83-4.77 (m, 1H), 4.76-4.54 (m, 2H assumed; obscured by solvent), 2.48 (s, 3H), 1.35 (s, 3H), 1.33 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[C:4]([CH3:9])[C:3]=1[OH:10].[S-:11][C:12]#[N:13].[NH4+]>CO>[CH3:8][C:7]1[C:2]([CH3:1])=[C:3]([OH:10])[C:4]([CH3:9])=[CH:5][C:6]=1[S:11][C:12]#[N:13]
Reactant: Cc1ccc(C)c(O)c1C
Reactant: N#C[S-]
Agent: [NH4+]
Solvent: CO
Product: Cc1cc(SC#N)c(C)c(C)c1O
Temperature: 0 °C
Reaction time: 1 h
Yield: 96.5 %

Procedure:
2,3,6-trimethylphenol (1.6 g, 11.8 mmol) was disolved in 50 mL of anhydrous methanol which had been deoxygenated by bubbling with nitrogen. Ammonium thiocyanate (2.2 g, 28,9 mmol) was added to this solution which was then cooled to 0° C. and bubbled with chlorine gas. The initially colorless homogeneous solution becomes pink and then green with the formation of a white precipitate. The solution was stirred for 1 h at 0° C. and then for a further hour at 20° C. The dissolved chlorine was removed by bubbling with nitrogen and the precipitate removed by filtration. Evaporation of the filtrate under reduced pressure followed by drying under high vacuum (0.1 torr) yielded 2.20 g (97%) of 2,3,5-Trimethyl-4-hydroxyphenylthiocyanate in a form pure enough for the next step in the synthesis. An analytical sample was recrystallized from hexanes: white crystals, mp 100.3° C. 1H NMR (CDCl3) δ 7.2 (s, 1H), 5.0 (s, 1H) 2.4 (s, 3H), 2.2 (s, 6H).
Reaction SMILES: [CH2:1]([CH:7]1[CH2:11][O:10][C:9]([CH3:13])([CH3:12])[O:8]1)[CH2:2][CH2:3][CH2:4][CH:5]=[CH2:6].CC[O:16]CC>>[OH:16][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:1][CH:7]1[CH2:11][O:10][C:9]([CH3:13])([CH3:12])[O:8]1
Reactant: C=CCCCCC1COC(C)(C)O1
Reactant: CCOCC
Product: CC1(C)OCC(CCCCCCO)O1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Alkene ketal, 4(5-hexenyl)-2,2-dimethyl-1,3-dioxolane, (0.01 mole) was dissolved in ether (50 mL) in a flask equipped with dropping funnel, condenser and magnetic stirrer. A steady stream of dry nitrogen was bubbled through the solution. The dropping funnel was charged with borane methylsulfide (Aldrich Chemical Co., Milwaukee, Wis.) (5 mL) in ether (25 mL) and added dropwise to the alkene ketal solution over 30 mins. and the resulting mixture allowed to warm to room temperature and stirred for 3 hrs. Ethanol was then added to scavenge excess borane followed by sodium hydroxide (5 mL of 3 molar solution) and the resulting solution cooled in an ice bath before hydrogen peroxide (19 mL 30% solution) was added at such a rate that the reaction temperature did not exceed 35° C. After addition of the hydrogen peroxide was completed the reaction mixture was refluxed for 1 hr before it was poured over an ice/water (120 mL) mixture. The mixture was saturated with sodium chloride and extracted with ether. The extract was then dried over anhydrous sodium carbonate. The desired product (1.3 g) was obtained on evaporation of ether.
Reaction SMILES: C([NH:5][C:6]1[C:11]([C:12]2[N:16]([C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[C:19]([F:24])[C:18]=3[F:25])[N:15]=[N:14][N:13]=2)=[CH:10][CH:9]=[CH:8][N:7]=1)(C)(C)C.Cl.[OH-].[Na+]>CO>[F:25][C:18]1[C:19]([F:24])=[C:20]([CH3:23])[CH:21]=[CH:22][C:17]=1[N:16]1[C:12]([C:11]2[C:6]([NH2:5])=[N:7][CH:8]=[CH:9][CH:10]=2)=[N:13][N:14]=[N:15]1
Reactant: Cc1ccc(-n2nnnc2-c2cccnc2NC(C)(C)C)c(F)c1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1ccc(-n2nnnc2-c2cccnc2N)c(F)c1F
Temperature: 25 °C
Yield: 107.9 %

Procedure:
Compound 1072 (69 g) was taken into 210 mL of methanol and 420 mL of 6M HCl and refluxed for 18 hrs. The reaction was cooled to room temperature and the pH adjusted to 8 with 6M sodium hydroxide. The resulting white precipitate was collected by vacuum filtration, washed well with water, and dried at 55° C. under vacuum overnight to afford 3-(1-(2,3-difluoro-4-methylphenyl)-1H-tetrazol-5-yl)pyridin-2-amine (62.32 g).
Reaction SMILES: FC(F)(F)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:10]([CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)=[O:11].[F:20][C:21]([F:31])([F:30])[O:22]C1C=CC=CC=1N>>[F:20][C:21]([F:31])([F:30])[O:22][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:10]([CH:12]1[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]1)=[O:11]
Reactant: O=C(Nc1ccccc1C(F)(F)F)C1CCCCC1
Reactant: Nc1ccccc1OC(F)(F)F
Product: O=C(Nc1ccccc1OC(F)(F)F)C1CCCCC1
Yield: 100 %

Procedure:
This compound was prepared following the procedure described for compound 26A of example 26, except that 2-trifluoromethoxyaniline was used in place of 2-trifluoromethylaniline. Yield: 100%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:21])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N:15]1[CH:19]=[N:18][N:17]=[C:16]1[CH3:20].[CH2:22]=[O:23]>C1(C)C(C)=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:21])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N:15]1[C:16]([CH3:20])=[N:17][N:18]=[C:19]1[CH2:22][OH:23]
Reactant: Cc1nncn1-c1ccccc1C(=O)c1ccccc1Cl
Reactant: C=O
Solvent: Cc1ccccc1C
Product: Cc1nnc(CO)n1-c1ccccc1C(=O)c1ccccc1Cl
Temperature: 122 °C

Procedure:
In the manner given in Example 4, 2'-chloro-2-(3-methyl-4H-1,2,4-triazol-4-yl)benzophenone, paraformaldehyde and xylene are warmed under nitrogen to about 122° C. to give 2'-chloro-2-[3-(hydroxymethyl)-5-methyl-4H-1,2,4-triazol-4-yl]benzophenone.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[CH:19][CH:20]=[C:21]4[C:25]=3[N:24]([CH3:26])[CH:23]=[C:22]4[CH2:27][CH:28]=O)[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].[NH2:30][C:31]1([C:34]([OH:36])=[O:35])[CH2:33][CH2:32]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[CH:19][CH:20]=[C:21]4[C:25]=3[N:24]([CH3:26])[CH:23]=[C:22]4[CH2:27][CH2:28][NH:30][C:31]3([C:34]([OH:36])=[O:35])[CH2:33][CH2:32]3)[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:10])[CH3:11]
Reactant: CC(C)Oc1ccc(-c2nc(-c3cccc4c(CC=O)cn(C)c34)no2)cc1Cl
Reactant: NC1(C(=O)O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c(CCNC5(C(=O)O)CC5)cn(C)c34)no2)cc1Cl
Temperature: 20 °C
Reaction time: 3 h
Yield: 13.2 %

Procedure:
To a stirred solution of [7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1-methyl-1H-indol-3-yl]acetaldehyde (D88) (50 mg), 1-aminocyclopropanecarboxylic acid (25 mg) and acetic acid (0.1 mL) in DCM (10 mL) was added sodium triacetoxyborohydride (52 mg). The reaction was stirred at 20° C. for 3 h. The mixture was concentrated and the residue was partitioned between ethyl acetate (25 mL) and aqueous HCl (2 M, 25 mL). The organic phase was washed with water (25 mL) and brine (25 mL), dried over anhydrous sodium sulphate and evaporated to give the crude product, which was purified by Mass Directed Auto Prep to afford 1-({2-[7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1-methyl-1H-indol-3-yl]ethyl}amino)cyclopropanecarboxylic acid (E68) (8 mg, TFA salt). δH (DMSO-d6, 400 MHz): 1.36 (6H, d), 1.41 (4H, m), 3.06 (2H, t), 3.31 (2H, t), 3.65 (3H, s), 4.88 (1H, m), 7.22 (1H, t), 7.33 (1H, s), 7.46 (2H, m), 7.81 (1H, dd), 8.12 (1H, dd), 8.19 (1H, d). MS (ES): C26H27ClN4O4 requires 494; found 495.2 (M+H+).
Reaction SMILES: [CH3:1][CH:2]([C:8]([C:10]([F:13])([F:12])[F:11])=O)[C:3]([O:5][CH2:6][CH3:7])=[O:4].C([O-])(=O)C.[NH4+:18].C(O)C>O>[NH2:18]/[C:8](/[C:10]([F:13])([F:12])[F:11])=[C:2](/[CH3:1])\[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CCOC(=O)C(C)C(=O)C(F)(F)F
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CCO
Solvent: O
Product: CCOC(=O)/C(C)=C(\N)C(F)(F)F
Temperature: 25 °C
Yield: 88 %

Procedure:
Ethyl 2-methyl-4,4,4-trifluoroacetoacetate (10.2 g, 51 mmoles), ammonium acetate (11.9, 150 mmoles), ethanol (20 g), and water (1 g) were combined in a 100 mL round-bottom flask. The mixture was heated for 6 hr. at 70° C. The mixture was then cooled to room temperature and poured into water (50 mL). The aqueous mixture was extracted with ethyl acetate (approximately 40 mL) and the layers were separated. The ethyl acetate layer was dried over anhydrous magnesium sulfate and evaporated to give an 88% yield of ethyl 3-amino-2-methyl-4,4,4-trifluorocrotonate.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.C([Li])CCC.[C:15]1(=[O:19])[CH2:18][CH2:17][CH2:16]1>C1COCC1>[OH:19][C:15]1([C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=2)[CH2:18][CH2:17][CH2:16]1
Reactant: N#Cc1ccc(Br)cc1
Reactant: O=C1CCC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: N#Cc1ccc(C2(O)CCC2)cc1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 39.8 %

Procedure:
A 500 mL flask was charged with 10.8 g (59.4 mmol) 4-bromo-benzonitrile and 150 mL anhydrous THF. The solution was cooled to −78° C. and 26.1 mL (65.3 mmol) 2.5M n-butyl lithium was added dropwise. The reaction mixture was stirred at −78° C. for an additional 10 minutes, then 5.0 g (71.3 mmol) cyclobutanone was added dropwise. The reaction mixture was stirred for an additional 10 minutes at −78° C. then the bath was removed and the reaction stirred for an additional 1 hour. The material was poured into 300 mL water and extracted with ethyl acetate (3×100 mL). The combined organics were washed with water (2×100 mL), brine (1×100 mL), dried over Na2SO4 and concentrated to a light brown oil. The oil was chromatographed on a Biotage Flash 40S® silica column+SIM eluted with 10% ethyl acetate/90% hexanes to give 4.1 g of a light yellow oil.
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@H:13]([CH2:14][O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[CH2:12][C@@H:11]([NH:23][C:24]2[CH:29]=[C:28](Cl)[N:27]=[CH:26][N:25]=2)[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:31][O:32][C@H:33]1[CH2:41][C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[C@H:34]1[NH2:42].C([O-])([O-])=O.[Na+].[Na+]>>[Si:1]([O:8][C@@H:9]1[C@H:13]([CH2:14][O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[CH2:12][C@@H:11]([NH:23][C:24]2[CH:29]=[C:28]([NH:42][C@@H:34]3[C:35]4[C:40](=[CH:39][CH:38]=[CH:37][CH:36]=4)[CH2:41][C@@H:33]3[O:32][CH3:31])[N:27]=[CH:26][N:25]=2)[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CO[C@H]1Cc2ccccc2[C@H]1N
Reactant: CC(C)(C)[Si](C)(C)OC[C@@H]1C[C@@H](Nc2cc(Cl)ncn2)C[C@@H]1O[Si](C)(C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CO[C@H]1Cc2ccccc2[C@H]1Nc1cc(N[C@@H]2C[C@@H](CO[Si](C)(C)C(C)(C)C)[C@@H](O[Si](C)(C)C(C)(C)C)C2)ncn1
Temperature: 180 °C
Yield: 10.6 %

Procedure:
A mixture of N-[(1R,3S,4S)-3-{[tert-butyl(dimethyl)silyl]oxy}-4-({[tert-butyl(dimethyl)silyl]oxy}methyl)cyclopentyl]-6-chloropyrimidin-4-amine (0.114 g, 2.42 mmol), (1R,2S)-2-methoxyindan-1-amine (0.170 g, 1.04 mmol) and Na2CO3 (0.10 g, 0.97 mmol) was heated to 180° C. for 2 h in a sealed tube using an oil bath. The reaction was cooled and filtered. The filtrate was concentrated in vacuo. The residue was purified by flash chromatography (50 to 60% EtOAc/hexanes) to afford the title compound as a beige foam (0.066 g, 46%). LC/MS: Rt=2.20 min, ES+ 599 (Formic Acid).
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]2[C:6]3[CH2:7][CH2:8][CH2:9][NH:10][C:11]=3[CH2:12][CH2:13][C:4]=2[CH:3]=1.C(N(CC)CC)C.[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=1)[C:28](Cl)=[O:29]>C(Cl)Cl>[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=1)[C:28]([N:10]1[C:11]2[CH2:12][CH2:13][C:4]3[CH:3]=[C:2]([Cl:1])[CH:15]=[CH:14][C:5]=3[C:6]=2[CH2:7][CH2:8][CH2:9]1)=[O:29]
Reactant: Clc1ccc2c(c1)CCC1=C2CCCN1
Reactant: COc1cccc(C(=O)Cl)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cccc(C(=O)N2CCCC3=C2CCc2cc(Cl)ccc23)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
14.3 g (0.066 mol) of 8-chloro-1,2,3,4,5,6-hexahydrobenzo[f]quinoline were dissolved in 143 ml of methylene chloride, treated with 6.68 g (0.066 mol) of triethylamine and 11.3 g (0.066 mol) of m-methoxybenzoyl chloride in 60 ml of methylene chloride were added dropwise thereto at 0°. After stirring at room temperature for 1 hour the mixture was extracted with water, dried with magnesium sulphate and the solvent was distilled off in vacuo. Chromatography (silica gel, toluene-ethyl acetate, 19:1) and crystallization (methylene chloride-ether) gave 4-(m-methoxybenzoyl)-8-chloro-1,2,3,4,5,6-hexahydrobenzo[f]quinoline as white crystals of melting point 133°.
Reaction SMILES: C([O:3][C:4]([C:6]1[S:10][C:9]2[CH2:11][CH2:12][CH2:13][CH2:14][C:8]=2[C:7]=1[NH2:15])=O)C.Cl.Cl[C:18]([NH2:20])=[NH:19]>COCCOCCOC>[NH2:20][C:18]1[NH:15][C:7]2[C:8]3[CH2:14][CH2:13][CH2:12][CH2:11][C:9]=3[S:10][C:6]=2[C:4](=[O:3])[N:19]=1
Reactant: N=C(N)Cl
Reactant: CCOC(=O)c1sc2c(c1N)CCCC2
Agent: Cl
Solvent: COCCOCCOC
Product: Nc1nc(=O)c2sc3c(c2[nH]1)CCCC3
Temperature: 160 °C
Yield: 95.5 %

Procedure:
A 48 mL sealed tube was charged with 3-amino-4,5,6,7-tetrahydro-benzo[b]thiophene-2-carboxylic acid ethyl ester (2.8 g, 12.3 mmol), chloroformamidine hydrochloride (2.0 g, 17.2 mmol), and diethylene glycol dimethyl ether (24.6 mL). The tube was sealed and heated to 160° C. for 12 h with vigorous stirring. Filtration afforded the desired compound as a beige solid (2.6 g). MS: No signal. 1H NMR (400 MHz, d6-DMSO) δ ppm 2.84-2.73 (m, 2H), 2.58-2.51 (m, 2H), 1.89-1.70 (m, 4H).
Reaction SMILES: [CH3:1][O:2][CH:3]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1)[CH3:4].C(Cl)(=O)C(Cl)=O.[CH2:20]([O:28][C:29]1[CH:34]=[CH:33][C:32](O)=[CH:31][CH:30]=1)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].N1C=CC=CC=1>C1(C)C=CC=CC=1>[CH3:1][O:2][CH:3]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([O:11][C:32]2[CH:33]=[CH:34][C:29]([O:28][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[CH:30][CH:31]=2)=[O:10])=[CH:7][CH:6]=1)[CH3:4]
Reactant: CCCCCCCCOc1ccc(O)cc1
Reactant: COC(C)c1ccc(C(=O)O)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CCCCCCCCOc1ccc(OC(=O)c2ccc(C(C)OC)cc2)cc1
Reaction time: 1 h
Yield: 98.3 %

Procedure:
An acid chloride prepared from 1.80 g (10 mmol) of (-)-4-(1-methoxyethyl)benzoic acid and oxalyl chloride was added to a solution comprising 2.66 g (12 mmol) of 4-(octyloxy)phenol, 10 g of pyridine and 30 g of toluene at room temperature. The mixed solution was stirred at the same temperature for one hour and then at 40° C. -50° C. for 2 hours. The resulting reaction mixture was treated and purified according to Example 1 to obtain 3.78 g (98.5% yield) of (-)-4-(octyloxy)phenyl 4-(1-methoxyethyl)-benzoate. [α]D20 =-57.7° (c=1, CHCl3).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH2:8][CH2:9][CH3:10])[CH:5]=[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)[N:3]=1.[Cu][C:22]#[N:23].C(OCC)(=O)C.N>CN1CCCC1=O>[CH2:8]([C:6]1[CH:5]=[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)[N:3]=[C:2]([C:22]#[N:23])[N:7]=1)[CH2:9][CH3:10]
Reactant: N#C[Cu]
Reactant: CCCc1cc(-c2cccc(C(F)(F)F)c2)nc(Cl)n1
Agent: N
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: CCCc1cc(-c2cccc(C(F)(F)F)c2)nc(C#N)n1
Temperature: 200 °C
Yield: 8.5 %

Procedure:
To a solution of 2-chloro-4-propyl-6-(3-trifluoromethylphenyl)-pyrimidine (50 mg) in 1-methyl-2-pyrrolidinone (2 mL), was added copper(I) cyanide (60 mg). The suspension was heated in the microwave at 200° C. for 20 min, than poured into a mixture of ethyl acetate (10 mL) and ammonia solution (5 mL). The organic layer was separated, washed with water (10 mL), dried over sodium sulphate and evaporated at reduced pressure. Preparative HPLC afforded the title compound 4-propyl-6-(3-trifluoromethylphenyl)-pyrimidine-2-carbonitrile as a brown gum (4.1 mg).
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH2:9][CH:8]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:7][CH2:6]2.[I-].[Na+].C([N:23]1[CH:27]=[CH:26][N:25]=[CH:24]1)(=O)C.Cl>C(#N)C.C(O)C>[ClH:1].[NH:23]1[CH:27]=[CH:26][N:25]=[C:24]1[CH2:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH2:9][CH:8]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:7][CH2:6]2
Reactant: CC(=O)n1ccnc1
Reactant: CCOC(=O)C1CCc2cc(CCl)ccc2C1
Agent: Cl
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: CCO
Product: CCOC(=O)C1CCc2cc(Cc3ncc[nH]3)ccc2C1

Procedure:
The crude ethyl 6-(chloromethyl)-1,2,3,4-tetrahydro-2-naphthalenecarboxylate obtained in Referential Example 5 was dissolved in 100 ml of anhydrous acetonitrile and then 3.22 g of sodium iodide and 3.94 g of 1-acetylimidazole were added thereto. The resulting mixture was heated under reflux for 1.5 hours. The reaction mixture was concentrated in vacuo and 100 1 of mthanol as added to the residue. The mixture was stirred and concentrated in vacuo. Water was added to the residue. The mixture was neutralized by adding sodium bicarbonate and extracted with chloroform. The extract was washed with water, dried and then concentrated in vacuo. The residue was purified by silica gel column chromatography using a mixture of ethanol and chloroform (3:97 by volume) for elution to give an oily product. The product was suspended in ethanol, and an ethanolic solution of hydrogen chloride was added thereto. The mixture was concentrated to dryness in vacuo to give 4.8 g of ethyl 6-(1-imidazolylmethyl)-1,2,3,4-tetrahydro-2-naphthalenecarboxylate hydrochloride as colorless crystals with m.p. 170°-172 ° C.
Reaction SMILES: [OH-].[K+].[C:3]1([SH:9])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[C:11]1[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:12]=1[N+:21]([O-:23])=[O:22]>O.C(O)C.[Cu]>[N+:21]([C:12]1[CH:13]=[C:14]([C:17]([F:20])([F:19])[F:18])[CH:15]=[CH:16][C:11]=1[S:9][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)([O-:23])=[O:22]
Reactant: Sc1ccccc1
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1Cl
Agent: [Cu]
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=[N+]([O-])c1cc(C(F)(F)F)ccc1Sc1ccccc1
Reaction time: 0.5 h

Procedure:
A solution of 6.5 g of potassium hydroxide in 80 ml of water is treated under a nitrogen atmosphere at 50° C with 10.3 ml of thiophenol and the mixture is then stirred for 30 minutes. After the addition of 0.5 g of copper powder and 22.5 g of 4-chloro- 3-nitro-benzotrifluoride in 100 ml of ethanol, the mixture is heated under reflux for 48 hours. After filtration, the mixture is poured into water and extracted with ether. The ethereal phase is washed successively with aqueous sodium carbonate solution, water, aqueous sodium chloride solution, 2-N aqueous hydrochloric acid and water, dried, filtered and evaporated. There is obtained 3-nitro-4-(phenylthio)-benzotrifluoride as a red oil.
Reaction SMILES: [F:1][C:2]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:3]=1[O:4][C:5]1[CH:15]=[C:14]([CH:16]=O)[CH:13]=[CH:12][C:6]=1[NH:7][S:8]([CH3:11])(=[O:10])=[O:9].C1(P(=[CH:42][C:43](=[O:45])[CH3:44])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OCC)(=O)C>CS(C)=O>[F:1][C:2]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:3]=1[O:4][C:5]1[CH:15]=[C:14]([CH:16]=[CH:42][C:43](=[O:45])[CH3:44])[CH:13]=[CH:12][C:6]=1[NH:7][S:8]([CH3:11])(=[O:10])=[O:9]
Reactant: CS(=O)(=O)Nc1ccc(C=O)cc1Oc1ccc(F)cc1F
Reactant: CC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CC(=O)C=Cc1ccc(NS(C)(=O)=O)c(Oc2ccc(F)cc2F)c1
Temperature: 80 °C
Reaction time: 13 h
Yield: 38.7 %

Procedure:
A mixture of 2'-(2,4-difluorophenoxy)-4'-formylmethanesulfonanilide (2.3 g) and triphenylphosphoranylideneacetone (2.3 g) in dimethylsulfoxide (10 ml) was stirred for 13 hours at 80° C. After cooling of the mixture, ethyl acetate was added, and the resulting mixture was washed with water, then dried. The ethyl acetate layer was evaporated to dryness and the residue was purified by column chromatography on silica gel (80 g) eluting with a mixture of chloroform and methanol (200:1) and further recrystallized from ethanol to give pale yellow needles of 2'-(2,4-difluorophenoxy)-4'-(3-oxo-1-butenyl)methanesulfonanilide (1.0 g).