Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:6])[CH:4]=[CH2:5].[NH2:7][CH2:8][CH:9]1[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15]([F:19])[CH:16]=2)[O:11][CH2:10]1>CO>[F:19][C:15]1[CH:16]=[C:17]2[C:12](=[CH:13][CH:14]=1)[O:11][CH2:10][CH:9]([CH2:8][NH:7][CH2:5][CH2:4][C:3]([O:2][CH3:1])=[O:6])[CH2:18]2
Reactant: NCC1COc2ccc(F)cc2C1
Reactant: C=CC(=O)OC
Solvent: CO
Product: COC(=O)CCNCC1COc2ccc(F)cc2C1
Yield: 65 %

Procedure:
While stirring at a temperature of from 0° to 5°, a solution of 1.42 g (16.4 mmol) of acrylic acid methyl ester in 10 ml of methanol is added dropwise within a period of 15 minutes to a solution of 3.0 g (16.5 mmol) of 3-aminomethyl-6-fluoro-chroman in 80 ml of methanol. The reaction mixture is then stirred for 16 hours at from 0° to 5° and then concentrated by evaporation in vacuo. The oily residue is chromatographed on 250 g of silica gel (0.040-0.063 mm) with ethyl acetate as eluant, yielding 2.85 g of N-[(6-fluorochroman-3-yl)methyl]-N-(2-methoxycarbonylethyl)-amine in the form of a light-yellow oil. The N-[(6-fluorochroman-3-yl)methyl]-N-(2-methoxycarbonylethyl)-amine hydrochloride, prepared therefrom with hydrochloric acid in diethyl ether, crystallizes from acetone/diethyl ether and melts at 163°-165°. The N-[(6-fluorochroman-3-yl)methyl]-N-(2-methoxycarbonylethyl)-amine cyclamate, prepared from the crude base with N-cyclohexyl-sulfamic acid, crystallizes from acetone and melts at 155°-156°.
Reaction SMILES: [CH:1]([OH:3])=O.C(OC(=O)C)(=O)C.[CH:11]([C:14]1[CH:20]=[CH:19][CH:18]=[C:17]([CH:21]([CH3:23])[CH3:22])[C:15]=1[NH2:16])([CH3:13])[CH3:12]>ClCCl>[CH:1]([NH:16][C:15]1[C:17]([CH:21]([CH3:22])[CH3:23])=[CH:18][CH:19]=[CH:20][C:14]=1[CH:11]([CH3:13])[CH3:12])=[O:3]
Reactant: CC(C)c1cccc(C(C)C)c1N
Reactant: O=CO
Solvent: CC(=O)OC(C)=O
Solvent: ClCCl
Product: CC(C)c1cccc(C(C)C)c1NC=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of formic acid (14.361 g, 0.312 mol) and acetic anhydride (12.659 g, 0.124 mol) was stirred at room temperature for 1 h under an argon atmosphere. This mixture was added to a solution of 2,6-diisopropylaniline (17.729 g, 0.1 mol) in dry dichloromethane (60 ml) at such a rate that the temperature of the reaction mixture was kept between 5 and 10° C. The reaction was stirred at room temperature for 16 h and then refluxed for 4 h. The solvent was evaporated under reduced pressure, the residue was dissolved in CHCl3 (200 mL) and washed with a saturated aqueous NaHCO3 solution (3×200 mL), and water (200 mL). The organic layer was dried over Na2SO4 and the solvent was evaporated under reduced pressure. The remaining yellow solid was recrystallized from diethyl ether (500 mL) to afford N-formyl-2,6-diisopropylaniline 8e3 as a white solid (13.96 g, 68%). 1H NMR (CDCl3, 300 MHz): δ=8.47-8.01 (m, 1H, CHO), 7.36-7.18 (m, 3H), 6.79 (broad s, 1H, NH), 3.06-3.26 (m, 2H), 1.21 (d, J=7 Hz, 12H). 2 (a) Arduengo, A. J.; Goerlich, J. R.; Marshall, W. J. Liebigs Ann./Recueil 1997, 365-374. (b) J. Liebscher, Methoden der Organischen Chemie (Houben-Weyl) 4th ed. (Ed.: E. Schaumann), Georg Thieme Verlag, New York, 1994 Band E 8b, Heratrene III/Part 2, p. 48. (c) Hromatka, O. U.S. Pat. No. 2,160,867, 1939.3 Kamer, P. C. J.; Nolte, R. J. M.; Drenth, W. J. Am. Chem. Soc. 1988, 110, 6818-6825.
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].Br[C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][CH:12]=[CH:11]2.[Cl:17][C:18]1[CH:19]=[C:20](B(O)O)[CH:21]=[CH:22][CH:23]=1.CCO.O>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[Cl:17][C:18]1[CH:23]=[C:22]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[NH:13][CH:12]=[CH:11]3)[CH:21]=[CH:20][CH:19]=1
Reactant: OB(O)c1cccc(Cl)c1
Reactant: Brc1ccc2[nH]ccc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Clc1cccc(-c2ccc3[nH]ccc3c2)c1
Yield: 100.5 %

Procedure:
A stirred slurry of 4.23 g (40 mmol) Na2CO3, 1.84 g (9.4 mmol) 5-bromoindole, 1.88 g (10 mmol) 3-chlorophenylboronic acid, and 0.29 g (0.25 mmol) Pd(PPh3)4 in 50 mL 1:1 EtOH-water was heated to reflux for 2.5 hours. The reaction mixture was allowed to cool and was then poured into 400 mL water and extracted with EtOAc. The organic layer was separated, dried over MgSO4, and concentrated to afford 2.15 g crude 5-(3-chlorophenyl)indole as a tan solid.
Reaction SMILES: CS[C:3]1[NH:8][C:7](=[O:9])[C:6]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=2)=[N:5][N:4]=1.[CH3:19][C:20]1[NH:24][CH:23]=[N:22][C:21]=1[CH2:25][S:26][CH2:27][CH2:28][NH2:29]>>[CH3:19][C:20]1[NH:24][CH:23]=[N:22][C:21]=1[CH2:25][S:26][CH2:27][CH2:28][NH:29][C:3]1[NH:8][C:7](=[O:9])[C:6]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=2)=[N:5][N:4]=1
Reactant: COc1cccc(Cc2nnc(SC)[nH]c2=O)c1
Reactant: Cc1[nH]cnc1CSCCN
Product: COc1cccc(Cc2nnc(NCCSCc3nc[nH]c3C)[nH]c2=O)c1
Reaction time: 0.08 h
Yield: 41.4 %

Procedure:
3-Methylthio-6-(3-methoxybenzyl)-1,2,4-triazin-5-one (1.07 g) and 2-(5-methyl-4-imidazolylmethylthio)ethylamine (0.77 g) were heated together on an oil bath (160°-70°) for 3/4 hour. The solidified mass was broken up under methanol (ea 15 ml) and boiled for 5 minutes. After cooling the white solid was filtered off and recrystallised from dimethylformamide to give the title compound as a colourless solid (0.65 g) m.p. 203°-4°.
Reaction SMILES: [N:1]#[C:2][NH2:3].[Na].[CH3:5][C:6]1([CH3:21])[CH2:15][CH2:14][CH2:13][C:12]2[CH:11]=[C:10]([O:16][CH2:17][C@@H:18]3[CH2:20][O:19]3)[CH:9]=[CH:8][C:7]1=2>CO>[CH3:21][C:6]1([CH3:5])[CH2:15][CH2:14][CH2:13][C:12]2[CH:11]=[C:10]([O:16][CH2:17][CH:18]3[O:19][C:2]([NH2:3])=[N:1][CH2:20]3)[CH:9]=[CH:8][C:7]1=2
Reactant: N#CN
Reactant: CC1(C)CCCc2cc(OC[C@@H]3CO3)ccc21
Agent: [Na]
Solvent: CO
Product: CC1(C)CCCc2cc(OCC3CN=C(N)O3)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 46.1 %

Procedure:
To a vigorously stirred solution of sodium hydrogen cyanamide (0.52 g, 7.9 mmol) in methanol (20 mL) was added slowly (S)-2-(5,5-dimethyl-5,6,7,8-tetrahydro-naphthalen-2-yloxymethyl)-oxirane (1.8 g, 7.9 mmol). The reaction mixture was stirred at room temperature overnight after which it was concentrated. Anhydrous diethyl ether (100 mL) was added. The resulting white precipitate was filtered and the filtrate concentrated. The residue was purified by flash chromatography (silica, 7N NH3 in methanol/methylene chloride) to give 1.0 g (46%) of 5-(5,5-dimethyl-5,6,7,8-tetrahydro-naphthalen-2-yloxymethyl)-4,5-dihydro-oxazol-2-ylamine.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][O:22][C:23]1[C:28](=[O:29])[CH:27]=[C:26]([CH2:30]OS(C)(=O)=O)[O:25][CH:24]=1)=[CH:13][CH:12]=[C:11]([C:36]([F:39])([F:38])[F:37])[CH:10]=2)=[O:5])[CH3:2].[NH:40]1[CH2:45][CH2:44][O:43][CH2:42][CH2:41]1>ClCCl>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[O:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][O:22][C:23]1[C:28](=[O:29])[CH:27]=[C:26]([CH2:30][N:40]3[CH2:45][CH2:44][O:43][CH2:42][CH2:41]3)[O:25][CH:24]=1)=[CH:13][CH:12]=[C:11]([C:36]([F:39])([F:38])[F:37])[CH:10]=2)=[O:5])[CH3:2]
Reactant: C1COCCN1
Reactant: CCOC(=O)c1cnc2cc(C(F)(F)F)ccc2c1OCCCCCOc1coc(COS(C)(=O)=O)cc1=O
Solvent: ClCCl
Product: CCOC(=O)c1cnc2cc(C(F)(F)F)ccc2c1OCCCCCOc1coc(CN2CCOCC2)cc1=O
Temperature: 45 °C
Reaction time: 3 h

Procedure:
4-[5-(6-Methanesulfonyloxymethyl-4-oxo-4H-pyran-3-yloxy)-pentyloxy]-7-trifluoromethyl-quinoline-3-carboxylic acid ethyl ester 18 (123 mg, 0.214 mmol) was dissolved in dichloromethane (3 mL). Morpholine (47.3 μL, 0.537 mmol) was added via syringe. The mixture was stirred at 45° C. for 3 h. CH2Cl2 (50 ml) was added and the solution was washed with NaHCO3 10% (3×50 mL) and brine (3×50 mL). The organic layer was dried over MgSO4, filtered and evaporated. The crude product was purified by column chromatography on silica using as eluent CH2Cl2:MeOH=95:05. 4-[5-(6-Morpholin-4-ylmethyl-4-oxo-4H-pyran-3-yloxy)-pentyloxy]-7-trifluoromethyl-quinoline-3-carboxylic acid ethyl ester EHT 8935 was obtained (66 mg, 55%) as a colourless oil.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:20]Br.[C:22]([C:24]1[CH:25]=[C:26]([CH2:30][CH2:31][CH2:32]O)[CH:27]=[CH:28][CH:29]=1)#[N:23].C1C=CC=CC=1>C(#N)C>[Br:20][CH2:32][CH2:31][CH2:30][C:26]1[CH:25]=[C:24]([C:22]#[N:23])[CH:29]=[CH:28][CH:27]=1
Reactant: N#Cc1cccc(CCCO)c1
Reactant: BrBr
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Solvent: CC#N
Product: N#Cc1cccc(CCCBr)c1
Temperature: 25 °C
Yield: 101.1 %

Procedure:
To a mixture of 21.8 g (0.083 moles) of triphenyl phosphine stirred in 30 ml acetonitrile, 13.2 g (4.26 ml) bromine in 75 ml acetonitrile was added dropwise with stirring in an ice bath. After the addition was complete, the ice bath was removed and the mixture warmed to room temperature. Then a mixture of 12.1 g (0.075 mole) of 3-(3-cyanophenyl)-1-propanol (the product of step (b)) in 30 ml acetonitrile was added dropwise. The resulting mixture was allowed to warm to about 45°-50° C., was stirred overnight and then stripped. Benzene (50 ml) was added to the residue; the mixture was evaporated. Then, additional benzene (50 ml) was added. The mixture was stirred, and then filtered to remove the triphenyl phosphine. The liltrate was stripped to give an oil. The oil was chromatographed using a column containing 3.5 inches of 200 mesh silica gel (Merck) eluting with benzene, until TLC showed that no further product was eluted from the column. The eluates were pooled and stripped to give 17 g of an oil. The oil was distilled in a Kugelrohr apparatus, the fraction bpt. 102°-103° C. was collected to give 15.7 g of the above-identified product as an oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:46])=[C:4]([C@@H:8]2[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[NH:10][C@H:9]2[C:28]([NH:30][C:31]2[CH:43]=[CH:42][C:34]([C:35]([O:37][CH2:38][C:39]([OH:41])=[O:40])=[O:36])=[CH:33][C:32]=2[O:44][CH3:45])=[O:29])[CH:5]=[CH:6][CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH3:80][O:81][CH2:82][CH2:83][O:84][CH2:85][CH2:86][O:87][CH2:88][CH2:89]O>O1CCCC1>[CH3:80][O:81][CH2:82][CH2:83][O:84][CH2:85][CH2:86][O:87][CH2:88][CH2:89][O:40][C:39]([CH2:38][O:37][C:35](=[O:36])[C:34]1[CH:42]=[CH:43][C:31]([NH:30][C:28]([C@H:9]2[C@H:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=3[F:46])[C@:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[C@H:11]([CH2:23][C:24]([CH3:26])([CH3:27])[CH3:25])[NH:10]2)=[O:29])=[C:32]([O:44][CH3:45])[CH:33]=1)=[O:41]
Reactant: COCCOCCOCCO
Reactant: COc1cc(C(=O)OCC(=O)O)ccc1NC(=O)[C@@H]1N[C@@H](CC(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2F)[C@H]1c1cccc(Cl)c1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COCCOCCOCCOC(=O)COC(=O)c1ccc(NC(=O)[C@@H]2N[C@@H](CC(C)(C)C)[C@](C#N)(c3ccc(Cl)cc3F)[C@H]2c2cccc(Cl)c2F)c(OC)c1
Reaction time: 0.5 h
Yield: 35.7 %

Procedure:
In a 20 mL round-bottomed flask, 2-(4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoyloxy)acetic acid (Example 69, 150 mg, 222 μmol), HATU (84.6 mg, 222 μmol) and Hunig's base (86.2 mg, 117 μL, 667 μmol) were combined with dry tetrahydrofuran (1 mL) to give a light brown suspension at room temperature. It was stirred for 30 min and the solution became clear. Triethylene glycol monomethyl ether (76.9 mg, 73.4 μL, 445 μmol) was added drop wise to the mixture. After stirring at room temperature overnight, the reaction mixture was concentrated. The residue was reconstituted with ethyl acetate. It was washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was absorbed on small amount of silica gel and loaded on a 24 g pre-packed silica gel column. Eluting the column with ethyl acetate gave 4-{[(2R,3S,4R,5S)-4-(4-chloro-2-fluoro-phenyl)-3-(3-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-3-methoxy-benzoic acid 2-[2-(2-methoxy-ethoxy)-ethoxy]-ethoxycarbonylmethyl ester as an off-white solid (65 mg, 35% yield). LCMS (ES+) m/z calcd. for C40H46Cl2F2N3O9 [(M+H)+]: 820. found: 820.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[CH:7]2.[Br:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][CH:14]=1.Cl.CN(C)CCCN=C=NCC>CN(C)C1C=CN=CC=1.C(Cl)Cl>[Br:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([NH:1][C:2]2[CH:11]=[CH:10][CH:9]=[C:8]3[C:3]=2[CH:4]=[CH:5][N:6]=[CH:7]3)=[O:18])=[CH:15][CH:14]=1
Reactant: O=C(O)c1ccc(Br)cc1
Reactant: Nc1cccc2cnccc12
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: O=C(Nc1cccc2cnccc12)c1ccc(Br)cc1
Yield: 81.7 %

Procedure:
A solution of 5-aminoisoquinoline (800 mg, 5.54 mmol), 4-bromobenzoic acid (1.68 g, 8.3 mmol), (3-dimethylaminopropyl)-ethyl-carbodiimide hydrochloride (1.64 g, 8.3 mmol) and 4-dimethylaminopyridine (70 mg, 0.6 mmol) was stirred at room temperature overnight. The mixture was diluted with DCM, washed with saturated aqueous sodium bicarbonate solution and water, then dried over MgSO4 and concentrated in vacuo to give the crude product. Purification by flash column chromatography eluting with an EtOAc/40-60° C. pet. ether gradient gave the title compound as a white solid (1.48 g). 1H NMR (400 MHz, CDCl3) δ (ppm): 9.29 (br, 2H), 8.57 (d, 1H), 8.11 (d, 1H), 7.97, (d, 2H), 7.90 (d, 2H), 7.66 (m, 3H).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[O:5]=[C:6]([C:12]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=1)[CH2:7][CH2:8][C:9]([OH:11])=[O:10]>OS(O)(=O)=O>[CH3:18][C:15]1[CH:14]=[CH:13][C:12]([C:6](=[O:5])[CH2:7][CH2:8][C:9]([OH:11])=[O:10])=[CH:17][C:16]=1[N+:1]([O-:4])=[O:2]
Reactant: O=[N+]([O-])O
Reactant: Cc1ccc(C(=O)CCC(=O)O)cc1
Agent: O=S(=O)(O)O
Product: Cc1ccc(C(=O)CCC(=O)O)cc1[N+](=O)[O-]
Temperature: -5 °C
Reaction time: 2 h
Yield: 69 %

Procedure:
HNO3 (65%) (2300 mL) was cooled to about 0° C. Fuming HNO3 (5700 mL) was carefully added maintaining an internal temperature of less than 15° C. The solution was cooled to about −5° C. and H2SO4 (800 mL) was added maintaining an internal temperature of less than 5° C. After cooling to about −8° C., 4-oxo-4-(p-tolyl)butanoic acid (72) (4000 g, 20.8 mol) was added portionwise maintaining the temperature below about 0° C. After completion of addition the mixture was allowed to warm to about 15-17° C. The solution was poured onto crushed ice with stirring. After about 2 h at rt, the solid was collected by filtration washing with water (3×10 L) and then dried to afford 4-(4-methyl-3-nitrophenyl)-4-oxobutanoic acid (73) (3400 g, 69% yield). 1H NMR (300 MHz, DMSO): δ 8.46 (s, 1H), 8.20 (d, J=8.4 Hz, 1H), 7.64 (d, J=8.0 Hz, 1H), 3.25 (m, 2H), 2.62 (m, 2H), 2.60 (s, 3H).
Reaction SMILES: C1(O)C=CC=CC=1.[CH2:8]([C:17]1C=CC=C[C:18]=1O)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]CC.[OH:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]2([C:46]3[CH:51]=[CH:50][C:49]([OH:52])=[CH:48][CH:47]=3)[C:44]3[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=3)[C:38](=[O:45])[C:37]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]2=3)=[CH:27][CH:26]=1>>[OH:24][C:25]1[CH:26]=[CH:27][C:28]([C:31]2([C:46]3[CH:47]=[CH:48][C:49]([OH:52])=[CH:50][C:51]=3[CH2:18][CH2:17][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[C:32]3[C:37](=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:38](=[O:45])[C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][C:44]2=3)=[CH:29][CH:30]=1
Reactant: CCCCCCCCCc1ccccc1O
Reactant: O=C1c2ccccc2C(c2ccc(O)cc2)(c2ccc(O)cc2)c2ccccc21
Solvent: Oc1ccccc1
Product: CCCCCCCCCc1cc(O)ccc1C1(c2ccc(O)cc2)c2ccccc2C(=O)c2ccccc21

Procedure:
A 1:1 weight ratio of phenol and a 2-n-nonyl-phenol should be substituted for the phenol of Example 12 in this Example and the procedure of Example 12 should be followed in this Example to obtain the product herein.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([NH:12][C:13](=[O:15])[CH3:14])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.Cl.[CH3:17][CH:18]1[CH2:23][NH:22][CH2:21][CH:20]([CH3:24])[N:19]1[C:25]1[N:30]=[CH:29][CH:28]=[CH:27][N:26]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:24][CH:20]1[N:19]([C:25]2[N:26]=[CH:27][CH:28]=[CH:29][N:30]=2)[CH:18]([CH3:17])[CH2:23][N:22]([CH2:2][C:3]2[CH:8]=[CH:7][C:6]([C:9]3([NH:12][C:13](=[O:15])[CH3:14])[CH2:11][CH2:10]3)=[CH:5][CH:4]=2)[CH2:21]1
Reactant: CC1CNCC(C)N1c1ncccn1
Reactant: CC(=O)NC1(c2ccc(CCl)cc2)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)NC1(c2ccc(CN3CC(C)N(c4ncccn4)C(C)C3)cc2)CC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 647.6 %

Procedure:
N-[1-(4-Chloromethylphenyl)cyclopropyl]acetamide (22.3 mg) and 2-(2,6-dimethylpiperazin-1-yl)pyrimidine hydrochloride (265 mg) were dissolved in N,N-dimethylformamide (10 ml), potassium carbonate (415 mg) was added and the mixture was stirred at 80° C. for 8 hr. Water (20 mL) was added and the mixture was stirred, extracted with ethyl acetate, and dried over anhydrous sodium sulfate. The solvent was evaporated and the obtained residue was purified by column chromatography (Yamazen HI-FLASH™ COLUMN size 2 L, elution solvent: hexane/ethyl acetate) to give the title compound (245 mg).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[C:10]([CH2:21][OH:22])([CH3:20])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Br[C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][N:27]=1>CN(C=O)C>[CH2:1]([N:8]1[CH2:12][CH:11]([C:13]2[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=2)[C:10]([CH2:21][O:22][C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][N:27]=2)([CH3:20])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1(CO)CN(Cc2ccccc2)CC1c1ccc(Cl)cc1
Reactant: Clc1ccc(Br)nc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(COc2ccc(Cl)cn2)CN(Cc2ccccc2)CC1c1ccc(Cl)cc1
Temperature: 50 °C
Reaction time: 8 h
Yield: 71.9 %

Procedure:
To a stirred solution of [(3RS,4RS)-1-benzyl-4-(4-chloro-phenyl)-3-methyl-pyrrolidin-3-yl]-methanol (4.0 g, 12.7 mmol) in DMF (60 mL) at RT was added NaH (608 mg, 60%, 15.2 mmol). The reaction mixture was heated at 50° C. for 30 minutes, then cooled down to RT before 2-bromo-5-chloropyridine (3.66 g, 19.0 mmol) was added. The resulting brownish solution was stirred overnight at 60° C., then concentrated under high vacuum. The residues was taken up in EtOAc, and washed with water. The organic phase was dried over Na2SO4 and a purification by column chromatography gave 3.90 g (72%) of the title product as a viscous oil. ES-MS m/e: 427.2 (M+H+).
Reaction SMILES: C([N:8]1[CH:12]=[C:11]([C:13]2S[C:15]([C:19](O)=O)=[C:16](C)[N:17]=2)N=N1)C1C=CC=CC=1.[CH3:22][C:23]1[N:24]=[C:25]([C:31]2[N:32]=[N:33][N:34]([CH2:36][C:37]3[CH:42]=[CH:41][C:40]([C:43]([F:46])([F:45])[F:44])=[CH:39][CH:38]=3)[CH:35]=2)[S:26][C:27]=1[C:28](O)=[O:29].N1C=CC=C(CN)C=1>>[CH3:22][C:23]1[N:24]=[C:25]([C:31]2[N:32]=[N:33][N:34]([CH2:36][C:37]3[CH:38]=[CH:39][C:40]([C:43]([F:44])([F:46])[F:45])=[CH:41][CH:42]=3)[CH:35]=2)[S:26][C:27]=1[C:28]([NH:8][CH2:12][C:11]1[CH:13]=[N:17][CH:16]=[CH:15][CH:19]=1)=[O:29]
Reactant: Cc1nc(-c2cn(Cc3ccccc3)nn2)sc1C(=O)O
Reactant: Cc1nc(-c2cn(Cc3ccc(C(F)(F)F)cc3)nn2)sc1C(=O)O
Agent: NCc1cccnc1
Product: Cc1nc(-c2cn(Cc3ccc(C(F)(F)F)cc3)nn2)sc1C(=O)NCc1cccnc1
Yield: 65 %

Procedure:
Following the procedure as described in Example 4, making variations as necessary to replace 2-(1-benzyl-1H-1,2,3-triazol-4-yl)-4-methylthiazole-5-carboxylic acid with 4-methyl-2-(1-(4-(trifluoromethyl)benzyl)-1H-1,2,3-triazol-4-yl)thiazole-5-carboxylic acid to react with pyridin-3-ylmethanamine, the title compound was obtained as a white solid in 65% yield: mp 204-205° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, DMSO-d6) δ 8.94-8.83 (m, 2H), 8.52 (br s, 1H), 8.43 (br s, 1H), 7.78-7.66 (m, 3H), 7.58-7.51 (m, 2H), 7.38-7.29 (m, 1H), 5.77 (s, 2H), 4.45-4.39 (m, 2H), 2.57 (s, 3H); 13C NMR (75 MHz, DMSO-d6) δ 161.5, 157.9, 155.0, 149.3, 148.6, 142.3, 140.6, 135.7, 135.2, 129.3, 129.5, 126.3, 126.2, 125.3, 124.1, 123.9, 53.1, 41.1, 17.5; Ms (ES+) m/z 459.3 (M+1).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:5]2.[F:23][C:24]([F:36])([F:35])[O:25][C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1>>[CH2:11]([N:7]1[C:8]2[C:4](=[CH:3][C:2]([C:29]3[CH:28]=[CH:27][C:26]([O:25][C:24]([F:23])([F:35])[F:36])=[CH:31][CH:30]=3)=[CH:10][CH:9]=2)[CH:5]=[C:6]1[C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CCOC(=O)c1cc2cc(Br)ccc2n1Cc1ccccc1
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Product: CCOC(=O)c1cc2cc(-c3ccc(OC(F)(F)F)cc3)ccc2n1Cc1ccccc1

Procedure:
The title compound was prepared from ethyl 5-bromo-1-benzyl-1H-indole-2-carboxylate and 4-(trifluoromethoxy)phenylboronic acid in substantially the same manner, as described in Step 2 of Example 25. The product was obtained as an oil. Mass spectrum (ESI, [M+H]+) m/z 440. 1HNMR (400 MHz, DMSO-d6): δ 8.01 (s, 1H), 7.79 (d, 2H, J=8.86 Hz), 7.67 (d, 1H, J=8.85 Hz), 7.62 (dd, 1H, J=8.70 and 1.68 Hz), 7.44-7.42 (m, 2H), 7.28-7.20 (m, 3H), 7.04 (d, 2H, J=7.94 Hz), 5.88 (s, 2H), 4.28 (q, 2H), and 1.29 ppm (t, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([C:23]2[CH:28]=[CH:27][N:26]=[C:25]([NH:29][C:30](=[O:32])[CH3:31])[CH:24]=2)[S:12][C:13]=1[C:14]1[NH:15][CH:16]=[C:17]([C:19](F)(F)F)[N:18]=1.O.[OH-].[NH4+:35]>>[C:19]([C:17]1[N:18]=[C:14]([C:13]2[S:12][C:11]([C:23]3[CH:28]=[CH:27][N:26]=[C:25]([NH:29][C:30](=[O:32])[CH3:31])[CH:24]=3)=[N:10][C:9]=2[C:3]2[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=2[Cl:1])[NH:15][CH:16]=1)#[N:35]
Reactant: [NH4+]
Reactant: CC(=O)Nc1cc(-c2nc(-c3ccc(Cl)cc3Cl)c(-c3nc(C(F)(F)F)c[nH]3)s2)ccn1
Agent: [OH-]
Solvent: O
Product: CC(=O)Nc1cc(-c2nc(-c3ccc(Cl)cc3Cl)c(-c3nc(C#N)c[nH]3)s2)ccn1
Temperature: 60 °C
Reaction time: 6 h
Yield: 20 %

Procedure:
N-(4-{4-(2,4-dichlorophenyl)-5-[4-(trifluoromethyl)-1H-imidazol-2-yl]-1,3-thiazol-2-yl}pyridin-2-yl)acetamide (20 mg, 0.04 mmol) was taken up in 1 M of Ammonium hydroxide in water (2 mL, 3 mmol) and the mixture was stirred at 60° C. for 6 h. At that time, LCMS indicated complete conversion. Reaction mixture was evaporated under reduced pressure and was purified using preparative HPLC to give 0.004 g of the title compound (20%). LCMS: (FA) ES+ 455, 457. 1H NMR (400 MHz, d6-DMSO) 8.70 (s, 1H), 8.34 (dd, J=5.26, 0.71 Hz, 1H), 7.65 (dd, J=5.26, 1.60 Hz, 1H), 7.55-7.46 (m, 3H), 7.39 (dd, J=8.28, 2.06 Hz, 1H), 2.24 (s, 3H).