Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6](I)[C:5]([NH2:9])=[CH:4][CH:3]=1.[C:10]([O:14][CH2:15][CH3:16])(=[O:13])[CH:11]=[CH2:12].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C>C(#N)C>[CH2:15]([O:14][C:10](=[O:13])/[CH:11]=[CH:12]/[C:6]1[C:5]([NH2:9])=[CH:4][CH:3]=[C:2]([Br:1])[N:7]=1)[CH3:16]
Reactant: C=CC(=O)OCC
Reactant: Nc1ccc(Br)nc1I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOC(=O)/C=C/c1nc(Br)ccc1N
Temperature: 80 °C

Procedure:
15.5 g 6-Bromo-2-iodo-pyridin-3-ylamine, 5.9 ml ethyl acrylate, 2.72 g triphenylphosphine and 28.75 ml triethylamine were dissolved in 90 ml acetonitrile. An argon stream was bubbled through the reaction mixture for 10 minutes then 2.33 g palladium(II)acetate were added and the reaction mixture stirred at 80° C. The reaction mixture was filtered hot trough a pad of celite then the solvent was removed in vacuo. The residue was purified by chromatography on silica gel to obtain 10.2 g (E)-3-(3-Amino-6-bromo-pyridin-2-yl)-acrylic acid ethyl ester.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:13][C@@H:12]([C:14]([OH:16])=[O:15])[CH:11]=[CH:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:17](=O)([O-])[O-].[K+].[K+].CI>CN(C=O)C.CCOC(C)=O>[C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:13][C@@H:12]([C:14]([O:16][CH3:17])=[O:15])[CH:11]=[CH:10]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@@H]1C=C[C@H](C(=O)O)C1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: CCOC(C)=O
Product: COC(=O)[C@H]1C=C[C@@H](NC(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 103.6 %

Procedure:
To a solution of (1R,4S)-4-[(tert-butoxycarbonyl)amino]cyclopent-2-ene-1-carboxylic acid (10.0 g, 44 mmol) in DMF (25 mL) was added potassium carbonate (6.33 g, 45.8 mmol) followed by methyl iodide (4.0 mL, 64 mmol). After being stirred at room temperature overnight, the reaction mixture was diluted with EtOAc. The solution was washed with water four times and brine one time, dried (MgSO4) and concentrated. The residue was dried under high vacuum overnight to provide the title compound (11 g, 99%). MS calculated for C12H19NO4: (M+H)+ 242; found 142.1 (M-Boc+H)+. 1H NMR (CDCl3) δ 5.86 (m, 2H), 4.90 (m, 1H), 4.80 (m, 1H), 3.72 (s, 3H), 3.50 (m, 1H), 2.51 (m, 1H), 1.86 (m, 1H), 1.42 (s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[CH:11][C:12](=[O:21])[N:13]([CH2:15][C:16]([O:18]CC)=[O:17])[CH:14]=2)=[CH:5][CH:4]=1.[OH-].[Li+].Cl>O.CCO>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:10]=[CH:11][C:12](=[O:21])[N:13]([CH2:15][C:16]([OH:18])=[O:17])[CH:14]=2)=[CH:7][CH:8]=1
Reactant: CCOC(=O)Cn1cc(-c2ccc(OC)cc2)ccc1=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1ccc(-c2ccc(=O)n(CC(=O)O)c2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.7 %

Procedure:
According to Scheme 9 Step 2: To a solution of ethyl 2-(5-(4-methoxyphenyl)-2-oxopyridin-1(2H)-yl)acetate (1 eq, 3.38 mmol, 0.97 g) in water/EtOH (1:1, 20 mL) at 0° C. was added lithium hydroxide (10 eq, 33.8 mmol, 1.44 g). The reaction was then allowed to warm to room temperature and stirred for 2 hours. The reaction was then cooled to 0° C. and acidified with HCl 1M solution till pH=2. The resulting precipitate was filtered under reduced pressure to yield 2-(5-(4-methoxyphenyl)-2-oxopyridin-1(2H)-yl)acetic acid (2.56 mmol, 0.66 g, 76%) as a white solid.
Reaction SMILES: [C:1]1([CH3:8])[CH:6]=[CH:5][C:4]([SH:7])=[CH:3][CH:2]=1.[Br:9][C:10]1[CH:11]=[CH:12][C:13](F)=[C:14]([CH:17]=1)[CH:15]=[O:16]>[OH-].[Na+].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>[Br:9][C:10]1[CH:11]=[CH:12][C:13]([S:7][C:4]2[CH:5]=[CH:6][C:1]([CH3:8])=[CH:2][CH:3]=2)=[C:14]([CH:17]=1)[CH:15]=[O:16]
Reactant: O=Cc1cc(Br)ccc1F
Reactant: Cc1ccc(S)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Cc1ccc(Sc2ccc(Br)cc2C=O)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 74.9 %

Procedure:
p-Toluenethiol (0.12 g, 1.0 mmol) was dissolved in a 10% sodium hydroxide aqueous solution (1.7 mL), and tetrabutylammonium bromide (0.016 g, 0.05 mmol) was added thereto, followed by stirring at room temperature for 5 minutes. 5-Bromo-2-fluorobenzaldehyde (0.2 g, 1.0 mmol) dissolved in toluene (1.7 mL) was added thereto by dropping, followed by stirring at room temperature for 4 hours. After the conventional treatment, and was recrystallized and purified with ethanol and hexane, to give 5-bromo-2-[(4-methylphenyl)thio]benzaldehyde (0.23 g, 74.1%).
Reaction SMILES: [Li+].[OH-].O.[C:4]([NH:7][C@:8]1([CH:22]([CH2:24][CH3:25])[CH3:23])[CH2:12][CH2:11][N:10]([C@@H:13]([CH2:18][CH:19]=[CH2:20])[C:14]([O:16]C)=[O:15])[C:9]1=[O:21])(=[O:6])[CH3:5].Cl>C1COCC1>[C:4]([NH:7][C@:8]1([CH:22]([CH2:24][CH3:25])[CH3:23])[CH2:12][CH2:11][N:10]([C@@H:13]([CH2:18][CH:19]=[CH2:20])[C:14]([OH:16])=[O:15])[C:9]1=[O:21])(=[O:6])[CH3:5]
Reactant: C=CC[C@@H](C(=O)OC)N1CC[C@](NC(C)=O)(C(C)CC)C1=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: C=CC[C@@H](C(=O)O)N1CC[C@](NC(C)=O)(C(C)CC)C1=O
Reaction time: 72 h
Yield: 88.2 %

Procedure:
Step L (7): A solution of LiOH/H2O (2M, 28 mg in 0.50 mL) was added to the diastereomer B, (S)-methyl 2-((S)-3-acetamido-3-sec-butyl-2-oxopyrrolidin-1-yl)pent-4-enoate (122 mg, 0.39 mmol) from Step L (6) in THF (1.0 mL) at RT. The reaction was stirred for 3 days. The mixture was poured into 1N HCl and the aqueous layer was extracted with EtOAC. The combined organic layers were washed with brine, dried over NaSO4 and concentrated in vacuo to give 102 mg of the title compound as white solid. LC-MS (M+H)+=297.01.
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].[NH:10]([C:19]([O:21][CH2:22][CH:23]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:29]2[C:24]1=[CH:25][CH:26]=[CH:27][CH:28]=2)=[O:20])[C@H:11]([C:16](O)=[O:17])[C@H:12]([CH2:14][CH3:15])[CH3:13].C(N(C(C)C)CC)(C)C>CN(C)C=O>[NH:10]([C:19]([O:21][CH2:22][CH:23]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:29]2[C:24]1=[CH:25][CH:26]=[CH:27][CH:28]=2)=[O:20])[C@H:11]([C:16]([NH:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5])=[O:17])[C@H:12]([CH2:14][CH3:15])[CH3:13]
Reactant: CC[C@H](C)[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Reactant: CC(C)C[C@H](N)C(=O)O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC[C@H](C)[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)N[C@@H](CC(C)C)C(=O)O

Procedure:
Acylation of the Leu resin with Fmoc-Ile (1.42 g, 4 mmole) activated with O-(benzotriazol-1-yl),1,1,3,3,-tetramethyluronium hexafluorophosphate (HBTU) (1.52 g, 4 mmole) and diisopropylethylamine (1.4 ml, 8 mmole) in dimethylformamide (8 ml) for 30 minutes. After the reaction, the resin was washed five times (as above) with dimethylformamide to remove the excess reagents and dried. Only half of the Fmoc-Ile-Leu resin thus obtained was used in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:24]=[CH:23][C:18]([C:19](OC)=[O:20])=[CH:17][CH:16]=2)[N:10]=1.[F:25][C:26]1[CH:32]=[C:31]([CH3:33])[CH:30]=[CH:29][C:27]=1[NH2:28].C[Al](C)C>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:16]=[CH:17][C:18]([C:19]([NH:28][C:27]3[CH:29]=[CH:30][C:31]([CH3:33])=[CH:32][C:26]=3[F:25])=[O:20])=[CH:23][CH:24]=2)[N:10]=1
Reactant: COC(=O)c1ccc(-n2nc(-c3c(F)cccc3Cl)[nH]c2=O)cc1
Reactant: Cc1ccc(N)c(F)c1
Agent: C[Al](C)C
Product: Cc1ccc(NC(=O)c2ccc(-n3nc(-c4c(F)cccc4Cl)[nH]c3=O)cc2)c(F)c1
Yield: 44.6 %

Procedure:
The title compound was prepared according to the procedure described in Example-31, by using methyl 4-[3-(2-chloro-6-fluorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]benzoate (step-2 of Intermediate-9, 0.100 g, 0.28 mmol), 2-fluoro-4-methyl aniline (0.054 g, 0.43 mmol) and trimethyl aluminium (2M solution in toluene) (0.5 mL) to afford 0.055 g of desired product. 1HNMR (DMSO-d6): δ 2.30 (s, 3H), 7.00 (d, J=7.8 Hz, 1H), 7.11 (d, J=11.7 Hz, 1H), 7.39-7.48 (m, 2H), 7.51-7.58 (d, 1H), 7.65-7.72 (m, 1H), 8.07 (br s, 4H), 10.04 (br s, 1H), 12.73 (br s, 1H); MS (m/z): 439.13 [M−H]−.
Reaction SMILES: [CH3:1][N:2]1[CH:6]([C:7]([OH:9])=O)[CH2:5][N:4]([C:10]2[N:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][N:11]=2)[C:3]1=[O:20].C(N1CCOCC1)C.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[Cl:52][C:53]1[C:58]([C:59]([F:62])([F:61])[F:60])=[CH:57][CH:56]=[CH:55][C:54]=1[CH2:63][NH2:64]>ClCCl>[Cl:52][C:53]1[C:58]([C:59]([F:61])([F:62])[F:60])=[CH:57][CH:56]=[CH:55][C:54]=1[CH2:63][NH:64][C:7]([CH:6]1[CH2:5][N:4]([C:10]2[N:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][N:11]=2)[C:3](=[O:20])[N:2]1[CH3:1])=[O:9]
Reactant: NCc1cccc(C(F)(F)F)c1Cl
Reactant: CN1C(=O)N(c2nccc(C(F)(F)F)n2)CC1C(=O)O
Agent: CCN1CCOCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: CN1C(=O)N(c2nccc(C(F)(F)F)n2)CC1C(=O)NCc1cccc(C(F)(F)F)c1Cl
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 62.3 %

Procedure:
A mixture of crude 3-methyl-2-oxo-1-[4-(trifluoromethyl)-2-pyrimidinyl]-4-imidazolidinecarboxylic acid (10 ml of 0.05M solution in DCM, 0.5 mmol), N-ethylmorpholine (0.383 ml, 3.00 mmol), 1-hydroxybenzotriazole hydrate (92 mg, 0.600 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (115 mg, 0.600 mmol) was stirred at room temperature for 10 minutes. A solution of {[2-chloro-3-(trifluoromethyl)phenyl]methyl}amine (105 mg, 0.5 mmol) in dichloromethane (1 ml) was added and the reaction stirred at room temperature for 18 hours. The reaction mixture was diluted with dichloromethane and the solution was washed with saturated sodium hydrogen carbonate solution, water, aqueous citric acid, water and brine, dried and evaporated. The residue was purified by silica gel chromatography eluting with 0-10% methanol in dichloromethane. The residue was triturated with ether and the resulting solid was collected and dried to give N-{[2-chloro-3-(trifluoromethyl)phenyl]methyl}-3-methyl-2-oxo-1-[4-(trifluoromethyl)-2-pyrimidinyl]-4-imidazolidinecarboxamide (150 mg, 62%). LC/MS [M+H]+=482, retention time 2.81 minutes.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:12][N:13]3[CH2:18][CH2:17][C@@H:16]([N:19]([CH3:21])[CH3:20])[C@@H:15]([F:22])[CH2:14]3)[N:8]2[CH3:11])=[C:4]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[N:3]=1.[CH3:29][C:30]1[NH:34][C:33]2[CH:35]=[CH:36][CH:37]=[CH:38][C:32]=2[N:31]=1>>[F:22][C@@H:15]1[C@H:16]([N:19]([CH3:21])[CH3:20])[CH2:17][CH2:18][N:13]([CH2:12][C:7]2[N:8]([CH3:11])[C:9]3[C:5]([N:6]=2)=[C:4]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[N:3]=[C:2]([N:31]2[C:32]4[CH:38]=[CH:37][CH:36]=[CH:35][C:33]=4[N:34]=[C:30]2[CH3:29])[N:10]=3)[CH2:14]1
Reactant: Cc1nc2ccccc2[nH]1
Reactant: CN(C)[C@@H]1CCN(Cc2nc3c(N4CCOCC4)nc(Cl)nc3n2C)C[C@@H]1F
Product: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CC[C@@H](N(C)C)[C@@H](F)C3)n(C)c2n1

Procedure:
Following General Procedure I for Buchwald coupling, (3S,4R)-1-((2-chloro-9-methyl-6-morpholino-9H-purin-8-yl)methyl)-3-fluoro-N,N-dimethylpiperidin-4-amine and 2-methyl-1H-benzo[d]imidazole were reacted to give 181. LCMS m/z: 508.3 (MH+)
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([NH:9][NH2:10])=O.Cl[C:12]1[C:18]2=[CH:19][CH:20]=[CH:21][N:17]2[CH2:16][C:15]2[CH:22]=[CH:23][CH:24]=[CH:25][C:14]=2[N:13]=1>CN(C)C=O>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:13]2[C:14]3[CH:25]=[CH:24][CH:23]=[CH:22][C:15]=3[CH2:16][N:17]3[CH:21]=[CH:20][CH:19]=[C:18]3[C:12]2=[N:10][N:9]=1
Reactant: NNC(=O)c1ccccn1
Reactant: ClC1=Nc2ccccc2Cn2cccc21
Solvent: CN(C)C=O
Product: c1ccc(-c2nnc3n2-c2ccccc2Cn2cccc2-3)nc1

Procedure:
Into a suitable reactor are charged N,N-dimethylformamide (159 kg) and 2-pyridinecarboxylic acid hydrazide (25.2 kg) and the mixture is stirred 10-15 minuted at 20°-25° to give a solution. In a separate suitable reactor are charged N,N-dimethylformamide (97 kg) and 11-chloro-5H-pyrrolo-[2,1-c][1,4]benzodiazepine (34.4 kg). The mixture is stirred for 15-30 minutes at 20°-25° to give a solution. This solution is added over 2-3 hours to the preheated solution of 2-pyridinecarboxylic acid hydrazide in N,N-dimethylformamide at 48° to 52°. Once the addition is complete the reaction mixture is further stirred for 2-3 hours at 48° to 52°. The reaction mixture is then heated for 12-15 hours at 72°-75°. The mixture is then cooled to 15°-20° with stirring. The solid is filtered off and washed with N,N-dimethylformamide (28 L). The solid is then stirred in a 1:1 mixture of water and ethanol (140 L) for 30-60 minutes at 20°-25°. The pH is adjusted to about 7 using concentrated ammonium hydroxide solution. The reaction mixture is stirred for 30-60 minutes at 20°-25°. The solid is filtered off, washed with a mixture of ethanol and water (1:1, 50 L) and vacuum dried (60°-70°) to give the title compound as the free base, m.p. 255°-257°.
Reaction SMILES: [N:1]([C@@H:4]1[C@:8](C(=O)C)([OH:9])[C@@H:7]([CH:13](C(=O)C)[OH:14])[O:6][C@H:5]1[N:18]1[CH:25]=[CH:24][C:22](=O)[NH:21][C:19]1=[O:20])=[N+:2]=[N-:3].C(O)C.S(Cl)(Cl)=O.C[N:34](C)C=O>>[N:1]([C@@H:4]1[C@H:8]([OH:9])[C@@H:7]([CH2:13][OH:14])[O:6][C@H:5]1[N:18]1[CH:25]=[CH:24][C:22]([NH2:34])=[N:21][C:19]1=[O:20])=[N+:2]=[N-:3]
Reactant: CN(C)C=O
Reactant: CC(=O)C(O)[C@H]1O[C@@H](n2ccc(=O)[nH]c2=O)[C@H](N=[N+]=[N-])[C@@]1(O)C(C)=O
Solvent: O=S(Cl)Cl
Solvent: CCO
Product: [N-]=[N+]=N[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1n1ccc(N)nc1=O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
1 g. 2'-Azido-2'-desoxy-3',5'-diacetyl-uridine (see J. Hobbs, H. Sternbach, M. Sprinzl and F. Eckstein, Biochemistry, 12, 5138/1973) was mixed with 14 ml. ethanol-free chloroform and 0.14 ml. dimethyl formamide and then mixed with 2 ml. thionyl chloride. The reaction mixture was boiled under reflux, with the exclusion of moisture, for 6 hours. After cooling, the reaction mixture was evaporated in a vacuum and the residue treated with ammoniacal methanol (30 ml. dry methanol plus 30 ml. methanol saturated with ammonia). The solution was stirred for 2 days at ambient temperature and then left to stand for 2 days at 37° C. Thin layer chromatography (methanol/chloroform mixture (4/6 v/v) on silica gel plates, Herck 60 F 254) shows mainly a product with an Rf value of 0.62. The solution was evaporated, the residue applied to two plates coated with silica gel for preparative thin layer chromatography (Merck 60 F 254, 2 mm. layer thickness, 20×40 cm.) and developed with a chloroform/methanol mixture (6/4 v/v). The main bands were scraped off, the material was eluted with methanol and applied to an ion exchanger column (Dowex 1×2, OH, 1.7×21.5 cm.). After washing with water, the product was eluted with 30% aqueous methanol. The solution obtained was evaporated and the residue recrystallized from ethanol. 2'-Azido-2'-desoxycytidine was obtained in a yield of 12310 A270 units (1.32 mMol; 47% of theory). The product melts at 215° C.
Reaction SMILES: CC1(C)C[O:36][C:5]2([CH2:9][C@@H:8]([CH2:10][C@H:11]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=3)[C:12](N([C@H](C)[C@H](O)C3C=CC=CC=3)C)=[O:13])[CH2:7][CH2:6]2)OC1.S(=O)(=O)(O)[OH:40]>O1CCOCC1.O>[O:36]=[C:5]1[CH2:6][CH2:7][C@H:8]([CH2:10][C@H:11]([C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=2)[C:12]([OH:40])=[O:13])[CH2:9]1
Reactant: O=S(=O)(O)O
Reactant: C[C@H]([C@H](O)c1ccccc1)N(C)C(=O)[C@H](C[C@H]1CCC2(C1)OCC(C)(C)CO2)c1cccc(C(F)(F)F)c1
Solvent: O
Solvent: C1COCCO1
Product: O=C1CC[C@H](C[C@@H](C(=O)O)c2cccc(C(F)(F)F)c2)C1
Temperature: 110 °C
Yield: 73 %

Procedure:
A solution of (R)-3-((R)-8,8-dimethyl-6,10-dioxa-spiro[4.5]dec-2-yl)-N-((1R,2R)-2-hydroxy-1-methyl-2-phenyl-ethyl)-N-methyl-2-(3-trifluoromethyl-phenyl)-propionamide (250 mg, 0.47 mmol) in dioxane (2.5 mL) was treated with a 9 N aqueous sulfuric acid solution (1.5 mL). The resulting solution was then heated at 110° C. for 16 h. The reaction was then cooled and diluted with water (50 mL) and extracted with a chloroform/methanol solution (3:2, 2×25 mL) and then concentrated. The resulting residue was then dissolved in acetonitrile and concentrated with silica gel (2 g) and purified on Biotage Flash chromatography system (40S column, silica gel, 60% ethyl acetate/hexanes) to afford (R)-3-((R)-3-oxo-cyclopentyl)-2-(3-trifluoromethyl-phenyl)-propionic acid (102 mg, 73%) as a pale yellow oil: [α]22589=−86.1° (c=0.18, methanol); ES-HRMS m/e calcd for C15H15O3F3 (M+Na)+ 323.0865, observed 323.0865; 1H NMR (400 MHz, CDCl3) δ 1.55 (m, 1H, CH), 1.82-2.47 (m, 8H, 4×CH2), 3.73 (t, J=7.8 Hz, 1H, ArCHCO), 7.47-7.61 (m, 4H, Ar).
Reaction SMILES: [C:1]1([Li])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:8][C:9]1[CH:22]=[CH:21][C:20]2[C:19](=O)[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([Br:24])[CH:17]=3)[C:12](=O)[C:11]=2[CH:10]=1>CCOCC.CC(O)=O>[Br:8][C:9]1[CH:22]=[CH:21][C:20]2[C:11](=[C:12]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[C:13]3[C:18]([C:19]=2[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:17][C:16]([Br:24])=[CH:15][CH:14]=3)[CH:10]=1
Reactant: O=C1c2ccc(Br)cc2C(=O)c2ccc(Br)cc21
Reactant: [Li]c1ccccc1
Solvent: CC(=O)O
Solvent: CCOCC
Product: Brc1ccc2c(-c3ccccc3)c3cc(Br)ccc3c(-c3ccccc3)c2c1
Temperature: 130 °C
Reaction time: 24 h
Yield: 67.5 %

Procedure:
6 g of phenyl lithium was dissolved in Et2O, and the resulting solution was gradually added dropwise to a solution containing 5 g of 2,6-dibromoanthraquinone dissolved in Et2O. This reaction was carried out on a dry ice bath. Then, the temperature of the reaction material was elevated to room temperature, thereby obtaining white solids. The obtained solids were dissolved in 100 mL of AcOH, followed by addition of KI and NaH2PO2 and the resulting mixture was stirred at 130° C. for 24 hours. After the reaction was complete, the resulting material was filtered with addition of water. The filtrate was then recrystallized from MC and MeOH, thereby obtaining 4.5 g of 2,6-dibromo-9,10-diphenylanthracene.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][C:6]([CH3:12])=[CH:5][N:4]=1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[Br:31]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:31][CH2:12][C:6]1[CH:7]=[C:8]([N+:9]([O-:11])=[O:10])[C:3]([O:2][CH3:1])=[N:4][CH:5]=1
Reactant: COc1ncc(C)cc1[N+](=O)[O-]
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COc1ncc(CBr)cc1[N+](=O)[O-]
Yield: 67.2 %

Procedure:
To a well stirred solution of 2-methoxy-5-methyl-3-nitro-pyridine (8.4 g, 0.05 mol) in carbon tetrachloride (100 mL), benzoyl peroxide (3.5 g, 0.015 mol) and N-bromosuccinimide (17.8 g, 0.1 mol) were added. The reaction mixture was heated at reflux for 48 h under N2 atmosphere. After cooling, the mixture was evaporated. The residue was diluted with saturated aq. Na2CO3 (200 mL) and extracted (3×50 mL CH2Cl2). The combined extracts were washed with brine, dried on MgSO4, and filtered to yield an orange oil-like solid (8.3 g). Purification by chromatography over silica gel eluting with EtOAc/Petroleum ether (0:1 to 1:99 v/v) afforded product as a pale yellow solid. (4.1 g, 43%). 1H-NMR (CDCl3): δ 4.15 (s, 3H, OCH3), 4.51 (s, 2H, CH2), 8.34 (d, 1H, J=2.4 Hz, Py-H), 8.43 (d, 1H, J=2.0 Hz, Py-H); 13C-NMR (CDCl3): δ 27.72, 55, 17, 127.18, 133.66, 135.67, 151.40, 156.30.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][C:5]2[CH:6]([C:12]([NH2:14])=O)[CH2:7][CH2:8][CH2:9][C:10]=2[CH:11]=1>N1C=CC=CC=1>[C:12]([CH:6]1[C:5]2[N:4]=[CH:3][C:2]([CH3:1])=[CH:11][C:10]=2[CH2:9][CH2:8][CH2:7]1)#[N:14]
Reactant: Cc1cnc2c(c1)CCCC2C(N)=O
Solvent: c1ccncc1
Product: Cc1cnc2c(c1)CCCC2C#N
Reaction time: 3 h
Yield: 52.2 %

Procedure:
3-Methyl-5,6,7,8-tetrahydroquinoline-8-carboxamide (3.6 g.) in pyridine (54 ml.) was treated with P2Sl5 (7.56 g.) and the mixture heated at reflux with stirring for 3 hours. The solvent was removed under reduced pressure and the residue cooled in ice-water then made basic with 10% NaOH. The basic solution was extracted with chloroform (3 times) and the combined extracts extracted with 2NHCl (twice). The combined acid extracts were basified with solid sodium carbonate and extracted into chloroform (3 times). The combined chloroform extracts were washed with brine dried (MgSO4) and evaporated to give the title compound 1.7 g. This was converted to the hydrochloride by dissolving in ether and adding ethereal HCl. An oily residue was formed from which the supernatent liquid was decanted. The residue was triturated twice with dry ether and the remaining solid recrystallised from isopropyl alcohol giving the hydrochloride of the title compound m.p. 189° C. Analysis Found: C, 63,08; H, 6.26; N, 13.34%; C11H12N2HCl requires: C, 63,30; H, 6.28; N, 13.43%
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[O:3][C:4]1[CH:22]=[CH:21][C:7]([O:8][C:9]2[CH:20]=[CH:19][C:12]([O:13][CH:14]([CH3:18])[C:15](Cl)=[O:16])=[CH:11][CH:10]=2)=[CH:6][CH:5]=1.[CH3:25][NH2:26]>O1CCCC1>[CH3:25][NH:26][C:15](=[O:16])[CH:14]([O:13][C:12]1[CH:19]=[CH:20][C:9]([O:8][C:7]2[CH:21]=[CH:22][C:4]([O:3][C:2]([F:24])([F:23])[F:1])=[CH:5][CH:6]=2)=[CH:10][CH:11]=1)[CH3:18]
Reactant: CC(Oc1ccc(Oc2ccc(OC(F)(F)F)cc2)cc1)C(=O)Cl
Reactant: CN
Solvent: C1CCOC1
Product: CNC(=O)C(C)Oc1ccc(Oc2ccc(OC(F)(F)F)cc2)cc1

Procedure:
Into a solution of 3.61 g. (0.01 mole) of 2-[[4-[4-(trifluoromethoxy)phenoxy]phenoxy]]propanoyl chloride in 20 ml. of tetrahydrofuran (THF) is passed a stream of gaseous methylamine. When the reaction is over, the solvent is removed and the residue treated with methylene chloride. The methylene chloride solution is washed with water, dried, and the solvent removed, providing a residue of 2-[[4-[4-(trifluoromethoxy)phenoxy]phenoxy]]propanoic acid, N-methyl amide.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[S:10])=[CH:4][C:3]=1[O:11][CH3:12].[NH3:13]>CO>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH2:13])=[S:10])=[CH:4][C:3]=1[O:11][CH3:12]
Reactant: COc1cc(N=C=S)ccc1Br
Reactant: N
Solvent: CO
Product: COc1cc(NC(N)=S)ccc1Br
Temperature: 25 °C
Reaction time: 4 h
Yield: 100 %

Procedure:
Step P (2): To a solution of 1-bromo-4-isothiocyanato-2-methoxybenzene (0.46 g, 1.884 mmol) in methanol (5 mL) was added methanolic ammonia (2.0 M, 4.7). The resulting mixture was stirred at rt for 4 h. The crude mixture was concentrated in vacuo. The solid was dried under high vacuum to afford 0.49 g (100% yield) the titled compound as a white solid. LC-MS (M+H)+ 263.0. 1H NMR (400 MHz, methanol-d4) δ ppm 7.48 (d, J=8.31 Hz, 1 H) 7.21 (br. s., 1 H) 6.78 (dd, J=8.31, 2.27 Hz, 1 H) 3.85 (s, 3 H). The product was used for subsequent chemistry without purification.
Reaction SMILES: [F:1][C:2]([C:14]1[CH:19]=[CH:18][C:17]([NH2:20])=[C:16]([S:21][CH3:22])[CH:15]=1)([C:10]([F:13])([F:12])[F:11])[C:3]([F:9])([F:8])[C:4]([F:7])([F:6])[F:5].[Cl:23]N1C(=O)CCC1=O>C(#N)C>[Cl:23][C:18]1[CH:19]=[C:14]([C:2]([F:1])([C:10]([F:11])([F:12])[F:13])[C:3]([F:9])([F:8])[C:4]([F:7])([F:6])[F:5])[CH:15]=[C:16]([S:21][CH3:22])[C:17]=1[NH2:20]
Reactant: CSc1cc(C(F)(C(F)(F)F)C(F)(F)C(F)(F)F)ccc1N
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC#N
Product: CSc1cc(C(F)(C(F)(F)F)C(F)(F)C(F)(F)F)cc(Cl)c1N
Temperature: 25 °C
Reaction time: 16 h
Yield: 50.1 %

Procedure:
To a solution of 4-(1,2,2,3,3,3-hexafluoro-1-trifluoromethylpropyl)-2-methylthio-phenylamine (Example 3.1) (21.85 g, 61.16 mmol) in acetonitrile (170 ml) was added N-chlorosuccinimide (“NCS”) (8.578 g, 64.22 mmol). The reaction mixture was stirred at ambient temperature for 16 hours. The reaction mixture was concentrated and the residue partitioned between ethyl acetate (100 ml) and water (100 ml). The phases were separated and the aqueous phase was extracted twice with ethyl acetate. The combined organic extracts were dried over sodium sulfate and concentrated. The residue was purified by column chromatography on silica gel (eluent:cyclohexane/ethyl acetate 4:1) to give 2-chloro-4-(1,2,2,3,3,3-hexafluoro-1-trifluoromethylpropyl)-6-methylthiophenylamine (12.0 g, 50% yield). LC-MS (Method 2): RT=2.17, [M−H]−=392.