Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH2:1].[OH-:2].[Na+].[C:4]1([C:10]2[CH:11]=[CH:12][C:13]([C:16]#N)=[N:14][CH:15]=2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>C(O)C>[C:4]1([C:10]2[CH:11]=[CH:12][C:13]([C:16]([OH:2])=[O:1])=[N:14][CH:15]=2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O
Reactant: N#Cc1ccc(-c2ccccc2)cn1
Reactant: [OH-]
Agent: [Na+]
Solvent: CCO
Product: O=C(O)c1ccc(-c2ccccc2)cn1
Yield: 27 %

Procedure:
Water (1 mL) and NaOH (56 mg, 1.41 mmol) were added to a stirred solution of 5-phenyl-pyridine-2-carbonitrile (112 mg, 0.56 mmol) in ethanol at room temperature. The resulting mixture was heated at reflux temperature for 3 hours. The EtOH was evaporated, and the mixture was diluted with water (2 mL), acidified with citric acid solution and the product was extracted using EtOAc. The organic layer was washed with saturated brine solution, dried over Na2SO4 and concentrated under reduced pressure to afford 30 mg (27% yield) of 5-phenyl-pyridine-2-carboxylic acid.
Reaction SMILES: C([O:4][C:5]([C:7]1[N:8]=[CH:9][C:10]2[NH:11][C:12]3[C:17]([C:18]=2[C:19]=1[CH2:20][O:21][CH3:22])=[CH:16][C:15]([O:23][C:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26][N:25]=1)=[CH:14][CH:13]=3)=O)(C)C.C(N(CC)CC)C.Cl[Si](C)(C)C>C1(C)C=CC=CC=1>[C:24]1([O:23][C:15]2[CH:16]=[C:17]3[C:12](=[CH:13][CH:14]=2)[NH:11][C:10]2[CH:9]=[N:8][C:7]([CH:5]=[O:4])=[C:19]([CH2:20][O:21][CH3:22])[C:18]3=2)[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26][N:25]=1
Reactant: COCc1c(C(=O)OC(C)C)ncc2[nH]c3ccc(Oc4nccc5ccccc45)cc3c12
Agent: C[Si](C)(C)Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COCc1c(C=O)ncc2[nH]c3ccc(Oc4nccc5ccccc45)cc3c12
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 153.5 %

Procedure:
330 mg of 6-(1-isoquinolyloxy)-4-methoxymethyl-β-carboline-3-carboxylic acid isopropyl ester is mixed in 10 ml of toluene with 0.62 ml of triethylamine and 0.2 chlorotrimethylsilane and heated for 45 minutes to a bath temperature of 50°-60° C. After concentration by evaporation to about 6 ml, it is cooled to -78° C. under argon and 1.25 ml of a 1.2 molar diisobutyl aluminum hydride is instilled in hexane. After 30 minutes at -78° C., it is mixed with 3 ml of ethanol and 0.75 ml of 1N NaOH. It is mixed with ethyl acetate and very little water. The organic phase is separated and concentrated by evaporation without drying. The residue is mixed with hexane and yields 440 mg of 6-(1-isoquinolyloxy)-4-methoxymethyl-β-carboline-3-carbaldehyde. 254 mg of it is mixed in 2.5 ml of dimethylfuran with 67.5 mg of hydroxylamine hydrochloride and 69 mg of potassium hydroxide powder and allowed to stand for 16 hours at room temperature. The batch is poured on ice and the precipitate is suctioned off and rewashed with water. 133 mg of 6-(1-isoquinolyloxy-4-methoxymethyl-β-carboline-3-carbaldehyde oxime of melting point 215°-218° C. is obtained.
Reaction SMILES: [Br:1][C:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:10]=[C:11]([CH:16]=[CH:17][C:18]=2[CH3:19])[C:12]([O:14]C)=[O:13])[C:5]([CH3:20])=[N:4][C:3]=1[O:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=1[F:30].[OH-].[Na+].O1CCOCC1.FC(F)(F)C(O)=O>O>[Br:1][C:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:10]=[C:11]([CH:16]=[CH:17][C:18]=2[CH3:19])[C:12]([OH:14])=[O:13])[C:5]([CH3:20])=[N:4][C:3]=1[O:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=1[F:30]
Reactant: COC(=O)c1ccc(C)c(-n2c(C)nc(OCc3ccc(F)cc3F)c(Br)c2=O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: C1COCCO1
Solvent: O
Product: Cc1ccc(C(=O)O)cc1-n1c(C)nc(OCc2ccc(F)cc2F)c(Br)c1=O
Temperature: 55 °C
Reaction time: 0.5 h
Yield: 43.5 %

Procedure:
A mixture of methyl 3-[5-bromo-4-[(2,4-difluorobenzyl)oxy]-2-methyl-6-oxopyrimidin-1(6H)-yl]-4-methylbenzoate (0.40 g, 0.00084 mol, from Step 4), and 1.5 N NaOH (0.7 mL, 0.042 g, 0.001 mol) containing dioxane (0.5 mL) is stirred at 55° C. for 30 min. The resulting clear brown solution is cooled in an ice bath, diluted with water (3 mL), acidified with trifluoroacetic acid, and the product is purified by reverse-phase HPLC using 10-90% CH3CN/Water gradient (40 min) at a flow rate of 80 mL/min. The appropriate fractions (MH+, m/z=465) are combined and freeze-dried to afford the title compound (0.17 g, 44%) as a white powder: 1H NMR (CD3OD/400 MHz) δ 8.04 (d, 1H, J=1.6 Hz), 7.87 (d, 1H, J=1.6 Hz), 7.54 (m, 2H), 6.99 (m 2H), 5.56 (s, 2H), 2.15 (s, 3H), and 2.13 (s, 3H); ES-HRMS m/z 465.0256 (M+H calcd for C20H16N2O4F2Br requires 465.0256); 19F NMR (CD3OD/400 MHz) −111.89 (m) and −115.95 (m).
Reaction SMILES: [SH:1][C:2]1[N:3]([CH3:7])[CH:4]=[CH:5][N:6]=1.[H-].[Na+].CN(C)C=O.Cl[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:17]=1[N+:24]([O-:26])=[O:25]>C(O)(=O)C>[CH3:23][O:22][C:19]1[CH:20]=[CH:21][C:16]([S:1][C:2]2[N:3]([CH3:7])[CH:4]=[CH:5][N:6]=2)=[C:17]([N+:24]([O-:26])=[O:25])[CH:18]=1
Reactant: Cn1ccnc1S
Reactant: COc1ccc(Cl)c([N+](=O)[O-])c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: COc1ccc(Sc2nccn2C)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 37.7 %

Procedure:
To a mixture of 2-mercapto-1-methylimidazole (1.14 g, 10 mmoles), 0.6 of 60% sodium hydride in mineral oil and 20 ml of N,N-dimethylformamide was added 1.88 g (10 mmoles) of 4-chloro-3-nitroanisole. The mixture was stirred at room temperature for 0.5 hours and then heated at 90°-100° C. for 4 hours. After cooling in an icebath, 0.5 ml of acetic acid was added and the mixture was partitioned between dichloromethane and dilute sodium bicarbonate. The organics were concentrated on a steam bath to a small volume and the residue was chromatographed on silica gel using ethyl acetate as the eluent. The fractions containing the product were combined and concentrated to give 1.0 g (38%) of the product, mp 117°-120° C.).
Reaction SMILES: [CH:1]1([C:4](Cl)=[O:5])[CH2:3][CH2:2]1.[N:7]1([N:12]2[C:16](=[O:17])[C:15]3=[CH:18][CH:19]=[CH:20][CH:21]=[C:14]3[C:13]2=[O:22])[CH:11]=[CH:10][CH:9]=[CH:8]1>ClCCCl>[CH:1]1([C:4]([C:8]2[N:7]([N:12]3[C:16](=[O:17])[C:15]4=[CH:18][CH:19]=[CH:20][CH:21]=[C:14]4[C:13]3=[O:22])[CH:11]=[CH:10][CH:9]=2)=[O:5])[CH2:3][CH2:2]1
Reactant: O=C(Cl)C1CC1
Reactant: O=C1c2ccccc2C(=O)N1n1cccc1
Solvent: ClCCCl
Product: O=C(c1cccn1N1C(=O)c2ccccc2C1=O)C1CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Boron trifluoride-diethyl ether complex (10 g; 23.6×3 mM) was dissolved in 80 ml of 1,2-dichloroethane at 25° C., followed by adding dropwise cyclopropanecarbonyl chloride (7.4 g; 23.6×3 mM). After a suspension of N-(1H-pyrrol-1-yl)phthalimide (IX-1; 5 g; 23.6 mM) in 40 ml of 1,2-dichloroethane was added, the mixture was stirred at 25° C. for 18 hours. The reaction mixture was poured into ice-water and insoluble materials were removed by filtration. The 1,2-dichloroethane phase of the filtrate was separated and washed with a saturated saline solution, followed by drying with anhydrous sodium sulfate. After dried, it was concentrated and the resultant residue was purified with column chromatography on silica gel. White solid; m.p. 150°-2° C.; Yield 2.35 g (35.6%); HPLC purity 92% (254 nm) IR (KBr cm-1): 1803 1752 1647 1431 1398 1275 1236 1071 975 708 NMR(CDCl3, δ): 0.66~1.28(4H,m:cyclopropane ring CH2 --CH2) 2.16~2.5(1H,m:cyclopropane ring CH) 6.3(1H,dd,J=3,4 Hz:pyrrole ring C4) 6.9(1H,dd,J=2,3 Hz:pyrrole ring C3 or C5 ) 7.2(1H,dd,J=2,4 Hz:pyrrole ring C3 or C5 ) 7.5~8.0(4H,m:aromatic H)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]([CH2:13][CH:14]=[CH2:15])[C:10](O)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].O.ON1C2C=CC=CC=2N=N1.CN(C)CCCN=C=NCC.Cl.[CH3:39][NH:40][O:41][CH3:42].C(N(CC)CC)C>C(Cl)Cl>[CH3:42][O:41][N:40]([CH3:39])[C:10](=[O:11])[C@H:9]([C:4]1[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=1)[CH2:13][CH:14]=[CH2:15]
Reactant: CNOC
Reactant: C=CC[C@H](C(=O)O)c1ccc(Cl)c(Cl)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CC[C@H](C(=O)N(C)OC)c1ccc(Cl)c(Cl)c1
Temperature: 22 °C
Reaction time: 4 h
Yield: 88.6 %

Procedure:
A mixture of 306 mg (1.25 mmol) of (2S)-(3,4-dichlorophenyl)-4-pentenoic acid (prepared according to the procedure of Hale, J. J.; Finke, P. E.; MacCoss, M. Bioorganic & Medicinal Chemistry Letters 1993, 3, 319-322) and 202 mg (1.50 mmol) of 1-hydroxybenzotriazole hydrate in 10 mL of methylene chloride was cooled to 0° C. and treated with 287 mg (1.50 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide. The cooling bath was removed and after 45 min. a solution of 365 mg (3.75 mmol) of N,O-dimethyl-hydroxylamine hydrochloride and 522 μl (3.75 mmol) of triethylamine in 10 mL of methylene chloride was added via cannula. The mixture was then stirred at 22° C. for 4 hours and then quenched with 10 mL of water and diluted with 8 mL of methylene chloride. The layers were separated and the aqueous layer was extracted with methylene chloride (2×10 mL). The combined organic layers were washed with 10 mL of brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography on 75 g of silica gel using 1:9 v/v ethyl acetate/hexane as the eluant afforded 319 mg (89%) of the title compound as a clear oil.
Reaction SMILES: S[CH2:2][C:3]([OH:5])=O.C(C1C=C(C)C=C(C(C)(C)C)N=1)(C)(C)C.FC(F)(F)[S:23]([O-])(=O)=O.[F:29][C:30]([I+]C1C=CC=CC=1)([F:35])[C:31]([F:34])([F:33])[F:32]>C(Cl)Cl>[F:29][C:30]([CH2:2][C:3]([OH:5])=[S:23])([F:35])[C:31]([F:34])([F:33])[F:32]
Reactant: FC(F)(F)C(F)(F)[I+]c1ccccc1
Reactant: O=S(=O)([O-])C(F)(F)F
Reactant: O=C(O)CS
Agent: Cc1cc(C(C)(C)C)nc(C(C)(C)C)c1
Solvent: ClCCl
Product: OC(=S)CC(F)(F)C(F)(F)F
Temperature: 25 °C
Yield: 90 %

Procedure:
0.12 ml of mercaptoacetic acid and 350 ml of 2,6-di-tert-butyl-4-methylpyridine were added to 4 ml of methylene chloride and the mixture was stirred at room temperature. Then, 800 mg of pentafluoroethylphenyliodonium trifluoromethanesulfonate was added thereto and the mixture was allowed to react for 30 minutes at room temperature. The reaction mixture was subjected to column chromatography of silica gel and, after eluting iodobenzene with hexane, the product was eluted with diethyl ether. The diethyl ether was distilled off to obtain 319 mg (90% yield) of pentafluoroethylthioacetic acid as an oily substance. 19F-NMR (CCl3F internal standard in CDCl3): -83.98 ppm (t, JCF3,CF2 =3.5 Hz, CF3), -93.39 ppm (q, JCF3,CF2 =3.5 Hz, CF2)
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([CH:18]2[CH2:21][CH2:20][CH2:19]2)[NH:5][C:6]=1[C:7]1[CH:12]=[CH:11][N:10]=[C:9]([NH:13][CH2:14][CH:15]([NH2:17])[CH3:16])[N:8]=1.C([O-])(O)=O.[Na+].C1COCC1.Cl[C:33]([O:35][CH3:36])=[O:34]>C1COCC1.O>[Br:1][C:2]1[N:3]=[C:4]([CH:18]2[CH2:21][CH2:20][CH2:19]2)[NH:5][C:6]=1[C:7]1[CH:12]=[CH:11][N:10]=[C:9]([NH:13][CH2:14][C@@H:15]([NH:17][C:33](=[O:34])[O:35][CH3:36])[CH3:16])[N:8]=1
Reactant: COC(=O)Cl
Reactant: CC(N)CNc1nccc(-c2[nH]c(C3CCC3)nc2Br)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)N[C@@H](C)CNc1nccc(-c2[nH]c(C3CCC3)nc2Br)n1
Reaction time: 0.08 h
Yield: 108 %

Procedure:
A solution of S)—N1-(4-(4-bromo-2-cyclobutyl-1H-imidazol-5-yl)pyrimidin-2-yl)propane-1,2-diamine (0.25 g, 0.72 mmol) in THF-water (1:1, 8 mL) was cooled to 0° C. and then solid NaHCO3 (0.10 g, 1.2 mmol) was added with concomitant frothing. After 5 minutes, a THF solution of methyl chloroformate (0.1 M in THF, 4.3 mL, 0.43 mmol) was added dropwise to the mixture and the reaction was maintained overnight allowing the cooling bath to expire. LCMS indicate incomplete reaction and addition methyl chloroformate solution and NaHCO3 was added. After the reaction was deemed complete by LCMS, the reaction mixture was extracted with EtOAc. The organic phase was washed with brine and dried (Na2SO4), and concentrated to give (S)-methyl 1-(4-(4-bromo-2-cyclobutyl-1H-imidazol-5-yl)pyrimidin-2-ylamino)propan-2-ylcarbamate as a yellow solid (0.19 g): LCMS(m/z) 409.0 (MH+), tR=0.63 minute.
Reaction SMILES: [CH2:1]([O:3][CH:4]([C:11]#[C:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[O:5][CH2:6][CH2:7][CH2:8][CH2:9][OH:10])[CH3:2].[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=[O:26].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.O>CN(C=O)C>[CH2:1]([O:3][CH:4]([C:11]#[C:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[O:5][CH2:6][CH2:7][CH2:8][C:9]([OH:26])=[O:10])[CH3:2]
Reactant: CCCCCCCCCCCCC#CC(OCC)OCCCCO
Reactant: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCC#CC(OCC)OCCCC(=O)O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
1.2 g of the product from example 22 in 15 ml of dry DMF was added in portions to a solution of pyridinium dichromate (4.4 g) in 30 ml of dry DMF. The solution was stirred at room temperature for 24 hours, then poured into water (300 ml). The aqueous mixture was extracted several times with Et2O, the combined extracts were washed with water and dried over Na2SO4. The reaction mixture was purified by column chromatography (SiO2) (1% MeOH/CHCl3). The partially purified product (0.54 g) was further purified by preparative thin layer chromatography (SiO2) (2% MeOH/CHCl3). Yield: 0.35 g.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:37])[CH:4]([C:9]1[CH:10]=[C:11]([C:23]2[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[C:25]([C:33]([F:36])([F:35])[F:34])[CH:24]=2)[CH:12]=[C:13](OS(C(F)(F)F)(=O)=O)[CH:14]=1)[CH2:5][CH:6]([CH3:8])[CH3:7].[F:38][C:39]1[CH:40]=[C:41](B(O)O)[CH:42]=[CH:43][C:44]=1[Cl:45]>>[CH3:1][O:2][C:3](=[O:37])[CH:4]([C:9]1[CH:10]=[C:11]([C:23]2[CH:28]=[C:27]([C:29]([F:31])([F:30])[F:32])[CH:26]=[C:25]([C:33]([F:34])([F:35])[F:36])[CH:24]=2)[CH:12]=[C:13]([C:41]2[CH:42]=[CH:43][C:44]([Cl:45])=[C:39]([F:38])[CH:40]=2)[CH:14]=1)[CH2:5][CH:6]([CH3:8])[CH3:7]
Reactant: COC(=O)C(CC(C)C)c1cc(OS(=O)(=O)C(F)(F)F)cc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1
Reactant: OB(O)c1ccc(Cl)c(F)c1
Product: COC(=O)C(CC(C)C)c1cc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cc(-c2ccc(Cl)c(F)c2)c1
Yield: 65 %

Procedure:
The title compound was prepared in 65% yield from 4-methyl-2-(5-trifluoromethanesulfonyloxy-3′,5′-bis-trifluoromethyl-biphenyl-3-yl)-pentanoic acid methyl ester (prepared in Intermediate A) and 3-fluoro-4-chlorophenylboronic acid under the conditions described in Example 26, step (d).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([S:9]([CH3:12])(=O)=O)[N:3]=1.SC1[CH:19]=[CH:18][C:17]([NH:20][C:21]([CH:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)=[O:22])=[CH:16][CH:15]=1.C(N(CC)CC)C.O>C(#N)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([S:9][C:12]2[CH:19]=[CH:18][C:17]([NH:20][C:21]([CH:23]3[CH2:24][CH2:25][CH2:26][CH2:27]3)=[O:22])=[CH:16][CH:15]=2)[N:3]=1
Reactant: CS(=O)(=O)c1nc(Cl)cc(Cl)n1
Reactant: O=C(Nc1ccc(S)cc1)C1CCCC1
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: O
Product: O=C(Nc1ccc(Sc2nc(Cl)cc(Cl)n2)cc1)C1CCCC1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 58.4 %

Procedure:
A solution of 4,6-dichloro-2-(methylsulfonyl)pyrimidine (1.96 g, 8.69 mmol) and N-(4-mercaptophenyl)cyclopentanecarboxamide (2.06 g, 8.69 mmol) in acetonitrile (40 ml) was cooled to 0° C. Triethylamine (0.88 g, 8.69 mmol, 1.21 ml) was added dropwise and the solution stirred for 10 mins at 0° C. for 10 mins and then at room temperature for 2 hrs. Water (15 ml) was added and the suspension filtered, washing with water (30 ml), and then dried to give the title compound as a pale yellow solid (1.87 g, 49%). 1H NMR (DMSO-d6) 1.50-1.61 (2H, m), 1.65-1.78 (4H, m), 1.82-1.93 (2H, m), 2.76-1.82 (1H, m), 7.52 (2H, d), 1.70-1.75 (3H, m), 10.08 (1H, s). ES+ 368.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:15]Br>C1COCC1.CCOCC.C(OCC)(=O)C.[Cl-].[Al+3].[Cl-].[Cl-]>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11](=[O:14])[CH:12]([Br:15])[CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: BrBr
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: [Al+3]
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(=O)C(Br)C1
Reaction time: 24 h
Yield: 42.9 %

Procedure:
N-tert-Butoxycarbonyl-4-piperidone (5.67 g, 28.5 mol) is dissolved in a mixture of dry THF (50 ml) and dry ether (50 ml), and thereto is added anhydrous aluminum chloride (57 mg). To the mixture is gradually added dropwise bromine (1.47 ml, 28.5 mmol) at 0° C., and the mixture is allowed to stand at 5° C. for 24 hours. The resulting reaction solution is diluted with ethyl acetate, and the mixture is washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate, and the solvent is evaporated. The resulting residue is crystallized from ether to give N-tert-butoxycarbonyl-3-bromo-4-piperidone (3.40 g, yield; 43%) as pale yellow crystals.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:10])[CH3:9])[CH:5]=[CH:4][C:3]=1[C:11]1[CH:12]=[C:13]([C:22]#[N:23])[N:14]2[C:19](Cl)=[CH:18][C:17]([CH3:21])=[N:16][C:15]=12.[CH2:24]([CH:27]([NH2:31])[CH2:28][CH2:29][CH3:30])[CH2:25][CH3:26].C(N(CC)C(C)C)(C)C.C(=O)([O-])O.[Na+]>C(O)C>[Br:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:10])[CH3:9])[CH:5]=[CH:4][C:3]=1[C:11]1[CH:12]=[C:13]([C:22]#[N:23])[N:14]2[C:19]([NH:31][CH:27]([CH2:28][CH2:29][CH3:30])[CH2:24][CH2:25][CH3:26])=[CH:18][C:17]([CH3:21])=[N:16][C:15]=12
Reactant: CCCC(N)CCC
Reactant: Cc1cc(Cl)n2c(C#N)cc(-c3ccc(C(C)C)cc3Br)c2n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CCCC(CCC)Nc1cc(C)nc2c(-c3ccc(C(C)C)cc3Br)cc(C#N)n12
Temperature: 25 °C
Yield: 89 %

Procedure:
A mixture of 8-(2-bromo-4-isopropyl-phenyl)-4-chloro-2-methyl-pyrrolo[1,2-a]pyrimidine-6-carbonitrile (300 mg), 1-propyl-butylamine (267 mg), N,N-diisopropylethylamine (300 mg) in ethanol (1.0 mL) was heated at reflux overnight. The reaction mixture was cooled to room temperature, poured into a saturated aqueous sodium hydrogencarbonate, and then extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and purified by a silica gel column chromatography (silica gel: Wako Gel (C200), eluent: hexane/ethyl acetate=20:1) to give 8-(2-bromo-4-isopropyl-phenyl)-2-methyl-4-(1-propyl-butylamino)-pyrrolo[1,2-a]pyrimidine-6-carbonitrile (321 mg) as a pale brown solid.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12](O)=[O:13])=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:4]=1.[F:27][C:28]([F:40])([F:39])[S:29]([C:32]1[CH:33]=[C:34]([NH2:38])[CH:35]=[CH:36][CH:37]=1)(=[O:31])=[O:30]>>[F:40][C:28]([F:39])([F:27])[S:29]([C:32]1[CH:33]=[C:34]([NH:38][C:12]([C:11]2[CH:10]=[N:9][N:8]3[C:3]([C:2]([F:26])([F:25])[F:1])=[CH:4][C:5]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:22])[F:23])=[CH:17][CH:16]=4)=[N:6][C:7]=23)=[O:13])[CH:35]=[CH:36][CH:37]=1)(=[O:30])=[O:31]
Reactant: O=C(O)c1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: Nc1cccc(S(=O)(=O)C(F)(F)F)c1
Product: O=C(Nc1cccc(S(=O)(=O)C(F)(F)F)c1)c1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12

Procedure:
The title compound was prepared from 7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.2) and 3-trifluoromethanesulfonyl-phenylamine [commercially available] according to general procedure II. Yellow solid. MS (ISP) 583.3 [(M+H)+]; mp 207° C.
Reaction SMILES: [CH:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5]1)([CH3:3])[CH3:2].[C:13](Cl)(=[O:17])[C:14]([Cl:16])=[O:15].[N:19]1([CH2:25][CH2:26][CH2:27][NH2:28])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1.C(N(CC)CC)C>C(OCC)C.C1COCC1>[ClH:16].[CH:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([C:13](=[O:17])[C:14]([NH:28][CH2:27][CH2:26][CH2:25][N:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)=[O:15])=[CH:5]1)([CH3:3])[CH3:2]
Reactant: NCCCN1CCCCC1
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(C)n1ccc2ccccc21
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)n1cc(C(=O)C(=O)NCCCN2CCCCC2)c2ccccc21
Product: Cl
Temperature: 25 °C
Reaction time: 14 h
Yield: 14.3 %

Procedure:
The title compound was prepared according to general procedure B described in Scheme 1. A solution of N-isopropylindole (480 mg, 3 mmol) in diethylether (10 mL) was cooled to 0° C. and treated dropwise with oxalyl chloride (303 μL, 3.5 mmol). The reaction was gradually warmed to RT over a 3 h period affording a yellow precipitate. The reaction mixture was concentrated under reduced pressure and the resulting yellow solid was dissolved in DCM (15 mL), cooled to 0° C. and treated with a solution of 1-piperidinepropanamine (313 g, 2 mmol) and triethylamine (334 μL, 2.4 mmol) in THF (10 mL). The reaction mixture was allowed to warm to RT and stirred for 14 h. The reaction mixture was concentrated under reduced pressure and the crude material was purified on silica gel (Biotage, 0-30% MeOH/DCM) and then converted to the HCl salt to provide the title compound as a purple solid (112 mg, 100% yield). 1H NMR (400 MHz, CDCl3): δ 12.19 (NH+, br s, 1H), 9.02 (s, 1H), 8.44 (dd, 1H), 7.95 (br t, 1H), 7.44 (m, 1H), 7.33 (m, 2H), 4.71 (m, 1H), 3.54 (m, 4H), 3.00 (m, 2H), 2.59 (m, 2H), 2.29 (m, 4H), 1.9-1.7 (m, 3H), 1.61 (d, 6H) 1.39 (m, 1H); MS (ESI) m/z: Calculated for C21H29N3O2: 355.2. Found: 356.3 (M+H)+.
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:10][C:9]([CH2:11][CH2:12][CH3:13])=[N:8][C:7]=1[C:14]([OH:17])([CH3:16])[CH3:15])=[O:5])C.[C:18]1([C:24]([C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[N:25]2[C:29]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[C:36]3[CH:41]=[CH:40][C:39]([CH2:42]Br)=[CH:38][CH:37]=3)=[N:28][N:27]=[N:26]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(=O)([O-])[O-:57].[K+].[K+].C(#N)C>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.CC(C)=O>[OH2:3].[OH2:57].[OH:17][C:14]([C:7]1[N:8]=[C:9]([CH2:11][CH2:12][CH3:13])[N:10]([CH2:42][C:39]2[CH:38]=[CH:37][C:36]([C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=3[C:29]3[N:25]([C:24]([C:50]4[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=4)([C:44]4[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=4)[C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[N:26]=[N:27][N:28]=3)=[CH:41][CH:40]=2)[C:6]=1[C:4]([OH:3])=[O:5])([CH3:15])[CH3:16]
Reactant: BrCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: O=C([O-])[O-]
Reactant: CCCc1nc(C(C)(C)O)c(C(=O)OCC)[nH]1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CC#N
Product: CCCc1nc(C(C)(C)O)c(C(=O)O)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: O
Temperature: 35 °C
Reaction time: 3 h
Yield: 165.8 %

Procedure:
4-(1-Hydroxy-1-methylethyl)-2-propyl-1H-imidazole-5-carboxylic acid ethyl ester (100 g), N-(triphenylmethyl)-5-(4′-bromomethyl biphenyl-2-yl) tetrazole (250 g), potassium carbonate (170 g) & tetra butyl ammonium bromide (15 g) in acetone (2.5 L) were refluxed for 10-16 hours. Progress of reaction was monitor by HPLC. Reaction mass was cooled & filtered to remove the salts. Inorganic salts were washed with acetone (300 ml). Acetone from combine the filtrate & washings was distilled. The residue obtained was refluxed with acetonitrile (500 ml). The reaction mass was cooled, filtered & solid after filtration was dissolved in Isopropyl alcohol (1500 ml). Separately prepared solution of potassium hydroxide (180 g) in IPA (2000 ml) was added slowly to above solution at room temperature. Reaction mass was stir for 2-4 hrs at 30-40° C. Isopropyl alcohol was distilled under reduced pressure. Water (I 000 ml), sodium chloride (100 g) & ethyl acetate (2000 ml) was added to the residue. Separate the two layers & aqueous layer was extracted with ethyl acetate (3×1000 ml). Combined ethyl acetate layer was washed with sodium bicarbonate solution (2×2000 ml) & dried (Na2SO4). Distilled off ethyl acetate under reduced pressure completely. Add acetonitrile (2000 ml) was added to the residue. The reaction mass was cooled, filtered, washed with acetonitrile (500 ml) & dried to get 4-(1-hydroxy-1-methylethyl)-2-propyl-1-{4-[2-(trityltetrazol-5-yl)phenyl]phenyl}methylimidazole-5-carboxylic acid dihydrate (250 g).