Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][NH2:11])=[N:6][C:5]=1[NH:12][C:13]1[CH:18]=[CH:17][C:16]([Si:19]([CH3:22])([CH3:21])[CH3:20])=[CH:15][C:14]=1[F:23].[CH:25](O)=[O:26]>C(OC(=O)C)(=O)C>[CH3:1][O:2][C:3](=[O:24])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][NH:11][CH:25]=[O:26])=[N:6][C:5]=1[NH:12][C:13]1[CH:18]=[CH:17][C:16]([Si:19]([CH3:20])([CH3:22])[CH3:21])=[CH:15][C:14]=1[F:23]
Reactant: O=CO
Reactant: COC(=O)c1ccc(CN)nc1Nc1ccc([Si](C)(C)C)cc1F
Solvent: CC(=O)OC(C)=O
Product: COC(=O)c1ccc(CNC=O)nc1Nc1ccc([Si](C)(C)C)cc1F
Yield: 89 %

Procedure:
A solution of 6-aminomethyl-2-(2-fluoro-4-trimethylsilanyl-phenylamino)-nicotinic acid methyl ester (13.2 g, 38.2 mmol) in formic acid (200 mL) and acetic anhydride (40 mL) was stirred at ambient temperature for 1 hour. The reaction mixture was concentrated in vacuo and the residue azeotroped with toluene. The resultant residue was dissolved in dichloromethane and washed with a saturated aqueous solution of sodium, hydrogen carbonate, followed by brine. The organic phase was isolated, dried (Na2SO4), filtered and concentrated in vacuo to afford the title compound as a yellow solid (12.7 g, 89%). LCMS (method B): RT=4.17 min, M+H+=376.
Reaction SMILES: CCN(C(C)C)C(C)C.[CH3:10][O:11][C:12]1[C:20]2[O:19][C:18]([C:21]([OH:23])=O)=[CH:17][C:16]=2[CH:15]=[CH:14][CH:13]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[N:48]1[C:49]([C:57]2[CH:58]=[C:59]([NH2:63])[CH:60]=[CH:61][CH:62]=2)=[CH:50][N:51]2[CH:56]=[CH:55][CH:54]=[CH:53][C:52]=12>CN(C=O)C>[N:48]1[C:49]([C:57]2[CH:58]=[C:59]([NH:63][C:21]([C:18]3[O:19][C:20]4[C:12]([O:11][CH3:10])=[CH:13][CH:14]=[CH:15][C:16]=4[CH:17]=3)=[O:23])[CH:60]=[CH:61][CH:62]=2)=[CH:50][N:51]2[CH:56]=[CH:55][CH:54]=[CH:53][C:52]=12
Reactant: COc1cccc2cc(C(=O)O)oc12
Reactant: Nc1cccc(-c2cn3ccccc3n2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cccc2cc(C(=O)Nc3cccc(-c4cn5ccccc5n4)c3)oc12
Temperature: 25 °C

Procedure:
DIEA (49.9 μL, 0.29 mmol) was added to 7-Methoxy-benzofuran-2-carboxylic acid (50 mg, 0.26 mmol) and HATU (108.8 mg, 0.29 mmol) in 1 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 3-Imidazo[1,2-a]pyridin-2-yl-phenylamine (54.4 mg, 0.26 mmol) was added and allowed to react overnight when a solid precipitated out of solution. The resulting precipitate was filtered, dried under suction, and finally dried overnight in vacuo to give the final product: LCMS (ESI) m/z 384 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][CH:9]([NH2:12])[CH2:8][CH2:7]1)=[O:5])[CH3:2].F[C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=1[N+:21]([O-:23])=[O:22].C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O.O.C(OCC)(=O)C.[I-].[K+]>[F:20][C:18]1[CH:17]=[CH:16][C:15]([N+:21]([O-:23])=[O:22])=[C:14]([NH:12][CH:9]2[CH2:8][CH2:7][N:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:11][CH2:10]2)[CH:19]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Reactant: CCOC(=O)N1CCC(N)CC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)N1CCC(Nc2cc(F)ccc2[N+](=O)[O-])CC1
Temperature: 50 °C
Reaction time: 5 h
Yield: 86.2 %

Procedure:
Ethyl-4-amino-1-piperidine-carboxylate (11.9 g, 69 mmol) was added to a stirred suspension of 2,4-difluoronitrobenzene (10.0 g, 63 mmol), sodium carbonate (6.7 g, 63 mmol) and potassium iodide (0.1 g, 0.6 mmol) in dimethylformamide (100 mL). The mixture was heated to 50° C., stirred for 5 hours and then allowed to cool. The reaction mixture was diluted with water (130 mL) and ethyl acetate (200 mL). The organic phase was separated and the aqueous phase was extracted with ethyl acetate (2×200 mL). The organic extracts were combined, extracted with a 10% aqueous solution of citric acid (250 mL), dried over MgSO4 and evaporated under reduced pressure. The residue was purified by column chromatography on silica, eluting with ethyl acetate/hexane (1:2) to give the title compound (16.9 g, 86% yield) as a yellow solid. (Rf: 0.5 (ethyl acetate/hexane 7:8))
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([N:13](C(OC(C)(C)C)=O)[CH2:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=2[F:22])[CH2:10][CH:9]1[C:30](O)=[O:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[N:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1>>[CH2:1]([N:8]1[CH2:12][C@@H:11]([NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=2[F:22])[CH2:10][C@H:9]1[C:30]([N:43]1[CH2:44][CH2:45][N:40]([C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=2[F:33])[CH2:41][CH2:42]1)=[O:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Fc1ccccc1N1CCNCC1
Reactant: CC(C)(C)OC(=O)N(Cc1ccc(F)cc1F)C1CC(C(=O)O)N(Cc2ccccc2)C1
Product: O=C([C@@H]1C[C@H](NCc2ccc(F)cc2F)CN1Cc1ccccc1)N1CCN(c2ccccc2F)CC1
Yield: 9.9 %

Procedure:
As described for Example 1f, 1-benzyl-4-[tert-butoxycarbonyl-(2,4-difluoro-benzyl)-amino]-pyrrolidine-2-carboxylic acid (60.0 mg, 0.134 mmol) was converted, using 1-(2-fluoro-phenyl)-piperazine instead of 2-piperazin-1-yl-benzonitrile, to the title compound (6.8 mg, 9.9%) as light yellow oil. MS m/e=509.4 [M+H]+.
Reaction SMILES: Br[C:2]1[C:3]([NH:8][C:9]2[S:10][C:11]3[C:16]([N:17]=2)=[CH:15][CH:14]=[CH:13][N:12]=3)=[N:4][CH:5]=[CH:6][CH:7]=1.[SH:18][CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22].C(N(C(C)C)C(C)C)C.O1CCOCC1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.C(OCC)(=O)C>[N:17]1[C:16]2[C:11](=[N:12][CH:13]=[CH:14][CH:15]=2)[S:10][C:9]=1[NH:8][C:3]1[C:2]([S:18][CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: Brc1cccnc1Nc1nc2cccnc2s1
Reactant: COC(=O)CCS
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: COC(=O)CCSc1cccnc1Nc1nc2cccnc2s1
Temperature: 95 °C
Yield: 87.2 %

Procedure:
A mixture of N-(3-bromopyridin-2-yl)thiazolo[5,4-b]pyridin-2-amine (0.55 g, 1.79 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethyl-9H-xanthene (0.052 g, 0.090 mmol), Pd2dba3 (0.041 g, 0.045 mmol), methyl 3-mercaptopropanoate (0.21 mL, 1.88 mmol), N-ethyl-N-isopropylpropan-2-amine (0.62 mL, 3.60 mmol), and dioxane (40 mL) was heated to 95° C. under nitrogen. Cooled to ambient temperature and filtered the solids. Concentrated and purified by MPLC (Biotage) eluting with 1:1 hexane:ethyl acetate to afford the title compound (0.541 g, 87% yield) as a dark yellow oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:19])[O:10][CH:11]1[CH:16]2[CH2:17][CH2:18][N:13]([CH2:14][CH2:15]2)[CH2:12]1.[CH2:20]([C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][CH:27]=1)[CH3:21]>>[CH2:20]([C:22]1[CH:27]=[C:26]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[NH:8][C:9](=[O:19])[O:10][CH:11]2[CH:16]3[CH2:17][CH2:18][N:13]([CH2:14][CH2:15]3)[CH2:12]2)[CH:25]=[CH:24][CH:23]=1)[CH3:21]
Reactant: CCc1cccc(B(O)O)c1
Reactant: O=C(Nc1ccccc1Br)OC1CN2CCC1CC2
Product: CCc1cccc(-c2ccccc2NC(=O)OC2CN3CCC2CC3)c1
Yield: 86 %

Procedure:
Using general procedure E, quinuclidin-3-yl 2-bromophenylcarbamate, 3-ethylphenylboronic acid and [PdCl2(pddf)]CH2Cl2 gave the title compound as a white solid (120 mg, 86%). 1H NMR (500 MHz, CDCl3) δ 8.09 (br s, 1H), 7.41 (t, J=7.5 Hz, 1H), 7.36 (t, J=7.5 Hz, 1H), 7.26-7.18 (m, 4H), 7.14 (t, J=7.5 Hz, 1H), 6.71 (br s, 1H), 4.79 (m, 1H), 3.25 (m, 1H), 2.90-2.65 (m, 7H), 2.05 (m, 1H), 1.80-1.64 (m, 2H), 1.62-1.52 (m, 1H), 1.40-1.32 (m, 1H), 1.28 (t, J=7.5 Hz, 3H) ppm. 13C NMR (125 MHz, CDCl3) δ 153.4, 145.2, 138.1, 134.7, 131.8, 130.2, 129.1, 128.8, 128.4, 127.5, 126.6, 123.5, 120.1, 72.0, 55.3, 47.3, 46.4, 28.9, 25.3, 24.5, 19.4, 15.7 ppm. Purity: >95% LCMS (214 nm & 254 nm); retention time 1.55 min; (M+1) 351.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:13])=[C:4]([N+:10]([O-:12])=[O:11])[CH:5]=[C:6]([CH3:9])[C:7]=1Cl.[Cl:14][C:15]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:16]=1[OH:22].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>C(OCC)(=O)C.CCCCCC>[Cl:1][C:2]1[C:3]([CH3:13])=[C:4]([N+:10]([O-:12])=[O:11])[CH:5]=[C:6]([CH3:9])[C:7]=1[O:22][C:16]1[CH:17]=[CH:18][C:19]([Cl:21])=[CH:20][C:15]=1[Cl:14]
Reactant: Cc1cc([N+](=O)[O-])c(C)c(Cl)c1Cl
Reactant: Oc1ccc(Cl)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cc([N+](=O)[O-])c(C)c(Cl)c1Oc1ccc(Cl)cc1Cl
Temperature: 100 °C
Yield: 45.6 %

Procedure:
Into a 250 milliter three-necked round bottom reaction flask equipped with a magnetic stirrer and nitrogen inlet was charged 10.0 grams (45.44 mmol) of 3,4-dichloro-2,5-dimethylnitrobenzene, 7.95 grams (48.81 mmol) of 2,4-dichlorophenol, 9.41 grams (68.11 mmol) of potassium carbonate and 60 milliliters dimethylformamide. The reaction mixture was stirred and heated at a temperature of 100° C. for a period of 20 hours and then cooled to room temperature, filtered and concentrated under reduced pressure. The residue was diluted with methylene chloride and the organic layer was washed with 4% NaOH solution (2x) and brine, dried through Na2SO4 and concentrated under reduced pressure to afford the crude product as a dark brown, viscous liquid. The addition of hexane and ethyl acetate afforded a light brown solid which was subjected to Kugelrohr distillation (about 180° C. and about 0.1 mm mercury) to give pure 3-chloro-4-(2,4-dichlorophenoxy)-2,5-dimethylnitrobenzene (7.17 grams, 20.7 mmol, 45%) as a yellow solid having a melting point of 118° C.-121° C. NMR spectroscopic analysis indicated the following: H'-NMR (CDCl3) 7.76 (br S, 1H), 7.53 (d, J=2 Hz, 1H), 7.12 (d,d; 2.9 Hz; 1H), 6.34 (d, J=9 Hz, 1H), 2.45 (S, 3H), 2.24 (S, 3H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([CH2:6][C:7]#[N:8])=[CH:2]1.[C:9]1(=O)[CH2:13][CH2:12][CH2:11][CH2:10]1>>[C:9]1(=[C:6]([C:3]2[CH:4]=[CH:5][S:1][CH:2]=2)[C:7]#[N:8])[CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: N#CCc1ccsc1
Reactant: O=C1CCCC1
Product: N#CC(=C1CCCC1)c1ccsc1

Procedure:
The expected intermediate is obtained in the manner described in General Protocol A starting from 3-thienylacetonitrile and cyclopentanone.
Reaction SMILES: [N:1]#[C:2]Br.[NH2:4][C:5]1[CH:6]=[C:7]([C:13]2[N:18]=[C:17]3[N:19]([CH2:24][CH:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)[C:20](=[O:23])[CH2:21][NH:22][C:16]3=[N:15][CH:14]=2)[CH:8]=[C:9]([CH3:12])[C:10]=1[NH2:11]>CN(C)C=O.CO>[NH2:1][C:2]1[NH:4][C:5]2[CH:6]=[C:7]([C:13]3[N:18]=[C:17]4[N:19]([CH2:24][CH:25]5[CH2:30][CH2:29][O:28][CH2:27][CH2:26]5)[C:20](=[O:23])[CH2:21][NH:22][C:16]4=[N:15][CH:14]=3)[CH:8]=[C:9]([CH3:12])[C:10]=2[N:11]=1
Reactant: N#CBr
Reactant: Cc1cc(-c2cnc3c(n2)N(CC2CCOCC2)C(=O)CN3)cc(N)c1N
Solvent: CO
Solvent: CN(C)C=O
Product: Cc1cc(-c2cnc3c(n2)N(CC2CCOCC2)C(=O)CN3)cc2[nH]c(N)nc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 62.6 %

Procedure:
Cyanogen bromide (0.059 g, 0.556 mmol) in N,N-dimethylformamide (0.5 mL) was added to a stirred solution of 7-(3,4-diamino-5-methylphenyl)-1-((tetrahydro-2H-pyran-4-yl)methyl)-3,4-dihydropyrazino[2,3-b]pyrazin-2(1H)-one (0.195 g, 0.529 mmol) in N,N-dimethylformamide (3 mL) at 0° C. The resulting dark brown mixture was capped and stirred at room temperature for 16 h. The resulting mixture was diluted with methanol, filtered and purified using reverse-phase preparatory HPLC (5-50% acetonitrile+0.1% TFA in water+0.1% TFA, over 30 min). Fractions containing the desired product were combined and most of the solvent removed under reduced pressure. The residue was loaded onto a Strata X-C ion exchange column from Phenomenex. The column was washed successively with water, acetonitrile, methanol and 5% ammonium hydroxide in methanol. The product eluted with the 5% ammonium hydroxide in methanol eluent and was concentrated under reduced pressure and dried under high vacuum at 50° C. to give the desired product (0.130 g, 0.331 mmol, 62% yield) as an orange solid. 1H NMR (400 MHz, D2O and DMSO-d6) δ (ppm) 8.13 (s, 1H), 7.56 (s, 1H), 7.36 (s, 1H), 4.18 (s, 2H), 4.03 (d, J=6.64 Hz, 2H), 3.84-3.90 (m, 2H), 3.24 (t, J=11.32 Hz, 2H), 2.40 (s, 3H), 2.04-2.19 (m, 1H), 1.59 (d, J=12.10 Hz, 2H), 1.25-1.41 (m, 2H); MS (ESI) m/z 394.2 [M+1]+.
Reaction SMILES: [CH:1]([N:4]1[C:18]2[C:19]3[C:6]([CH2:7][C@@H:8]4[C@@H:13]([C:14]=3[CH:15]=[CH:16][CH:17]=2)[CH2:12][C@@H:11]([C:20]([O:22]C)=[O:21])[CH2:10][N:9]4C#N)=[CH:5]1)([CH3:3])[CH3:2].[OH-].[Na+].C(O)CO.O>C(O)(=O)C>[CH:1]([N:4]1[C:18]2[C:19]3[C:6]([CH2:7][C@@H:8]4[C@@H:13]([C:14]=3[CH:15]=[CH:16][CH:17]=2)[CH2:12][C@@H:11]([C:20]([OH:22])=[O:21])[CH2:10][NH:9]4)=[CH:5]1)([CH3:3])[CH3:2]
Reactant: COC(=O)[C@@H]1C[C@@H]2c3cccc4c3c(cn4C(C)C)C[C@H]2N(C#N)C1
Agent: [Na+]
Agent: [OH-]
Solvent: OCCO
Solvent: CC(=O)O
Solvent: O
Product: CC(C)n1cc2c3c(cccc31)[C@H]1C[C@@H](C(=O)O)CN[C@@H]1C2

Procedure:
A reaction mixture was prepared by combining 25 g of methyl 1-isopropyl-6-cyanoergoline-8β-carboxylate. 8.89 NaOH pellets and 250 ml of ethylene glycol. The reaction mixture was heated in the range 130°-40° C. for about 3 hours. 750 ml of water were added. The pH of the resulting solution was adjusted to about 5 with glacial acetic acid (30 mls.). Crystals began to form and the solution was chilled overnight. The crystals were separated by filtration and the filter cake washed with water; yield (after drying)=19.6 g of 1-isopropylergoline-8β-carboxylic acid, (97.3% pure by HPLC).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][NH2:11])[CH:6]=[CH:7][CH:8]=1.[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH2:22][C:23](Cl)=[O:24])[CH:17]=[CH:18][C:19]=1[O:20][CH3:21]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][NH:11][C:23](=[O:24])[CH2:22][C:16]2[CH:17]=[CH:18][C:19]([O:20][CH3:21])=[C:14]([O:13][CH3:12])[CH:15]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1ccc(CC(=O)Cl)cc1OC
Reactant: COc1cccc(CCN)c1
Product: COc1cccc(CCNC(=O)Cc2ccc(OC)c(OC)c2)c1

Procedure:
prepared by reaction of 3-methoxyphenylethylamine with 3,4-dimethoxyphenyl acetyl chloride.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH:13]([CH3:15])[CH3:14])=[C:11]([NH2:16])[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[CH3:17][C:18]1[N:19]([CH:27]([CH3:31])[C:28](O)=[O:29])[CH:20]=[C:21]([C:23]([F:26])([F:25])[F:24])[N:22]=1.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]([CH:13]([CH3:14])[CH3:15])=[C:11]([NH:16][C:28](=[O:29])[CH:27]([N:19]3[CH:20]=[C:21]([C:23]([F:24])([F:26])[F:25])[N:22]=[C:18]3[CH3:17])[CH3:31])[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: Cc1nc(C(F)(F)F)cn1C(C)C(=O)O
Reactant: CC(C)c1c(N)cnn1-c1ccc(F)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Cc1nc(C(F)(F)F)cn1C(C)C(=O)Nc1cnn(-c2ccc(F)cc2)c1C(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 24.3 %

Procedure:
To a solution of 1-(4-fluorophenyl)-5-isopropylpyrazol-4-amine (0.03 g, 0.14 mmol) in DMF (1.0 mL) was added 2-[2-methyl-4-(trifluoromethyl)imidazol-1-yl]propanoic acid (0.031 g, 0.14 mmol), followed by diisopropylethylamine (0.042 g, 0.32 mmol) and HATU (0.057 g, 0.15 mmol). After stirring at room temperature for 1 h, the reaction was diluted with water and the aqueous layer was extracted with ethyl acetate (2×5 mL). The combined organic layers were washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo. The resulting crude product was purified by reverse phase HPLC (C18 column, acetonitrile-H2O with 0.1% TFA as eluent) to give the title compound as a white solid (0.0145 g, 0.034 mmol, 25%). 1H NMR (400 MHz, CDCl3) δ 7.92 (d, J=0.6 Hz, 1H), 7.46 (q, J=1.2 Hz, 1H), 7.33-7.24 (m, 2H), 7.21-7.11 (m, 2H), 6.63 (s, 1H), 4.92 (q, J=7.3 Hz, 1H), 2.93 (m, 1H), 2.49 (s, 3H), 1.89 (d, J=7.3 Hz, 3H), 1.04 (dd, J=10.3, 7.2 Hz, 6H); MS: (ES) m/z calculated for C20H21F4N5O [M+H]+ 424.2, found 424.0.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:44])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([CH2:41][CH3:42])([C:22]3[CH:27]=[CH:26][C:25]([C:28]#[C:29][C:30]([OH:39])([C:35]([F:38])([F:37])[F:36])[C:31]([F:34])([F:33])[F:32])=[C:24]([CH3:40])[CH:23]=3)[CH2:20][CH3:21])=[CH:15][C:14]=2[CH3:43])=[CH:9][CH:8]=1.Cl>CO.O1CCCC1>[CH2:20]([C:19]([C:16]1[CH:17]=[CH:18][C:13]([C:10]2[CH:11]=[CH:12][C:7]([CH2:6][C:5]([OH:44])=[O:4])=[CH:8][CH:9]=2)=[C:14]([CH3:43])[CH:15]=1)([C:22]1[CH:27]=[CH:26][C:25]([C:28]#[C:29][C:30]([OH:39])([C:31]([F:33])([F:34])[F:32])[C:35]([F:37])([F:38])[F:36])=[C:24]([CH3:40])[CH:23]=1)[CH2:41][CH3:42])[CH3:21]
Reactant: CCC(CC)(c1ccc(C#CC(O)(C(F)(F)F)C(F)(F)F)c(C)c1)c1ccc(-c2ccc(CC(=O)OC)cc2)c(C)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCC(CC)(c1ccc(C#CC(O)(C(F)(F)F)C(F)(F)F)c(C)c1)c1ccc(-c2ccc(CC(=O)O)cc2)c(C)c1
Temperature: 60 °C
Reaction time: 1 h
Yield: 76.5 %

Procedure:
A 1 N sodium hydroxide aqueous solution (0.102 mL, 0.102 mmol) was added to a solution of (4′-{1-ethyl-1-[3-methyl-4-(4,4,4-trifluoro-3-hydroxy-3-trifluoromethyl-1-butynyl)-phenyl]-propyl}-2′-methyl-biphenyl-4-yl)acetic acid methyl ester (Example 45-(2); 20 mg, 0.034 mmol) in methanol-tetrahydrofuran (1:1, 2 mL), and the mixture was stirred at 60° C. for one hour. The reaction mixture was poured into 1 N hydrochloric acid aqueous solution, followed by extraction with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (chloroform:methanol=10:1) to give the target compound as a colorless oil (15 mg, 77%).
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH3:12][N:13]([CH3:27])[C:14](=[O:26])[CH2:15][CH:16]1[CH2:25][CH2:24][C:19]2(OCC[O:20]2)[CH2:18][CH2:17]1>CC(C)=O>[CH3:27][N:13]([CH3:12])[C:14](=[O:26])[CH2:15][CH:16]1[CH2:25][CH2:24][C:19](=[O:20])[CH2:18][CH2:17]1
Reactant: CN(C)C(=O)CC1CCC2(CC1)OCCO2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)=O
Product: CN(C)C(=O)CC1CCC(=O)CC1
Yield: 99.2 %

Procedure:
p-Toluenesulfonic acid (84 mg) is added to a solution of N,N-dimethyl-2-(1,4-dioxaspiro[4.5]decan-8-yl)acetamide (500 mg) in acetone (10 ml) and the mixture is heated under reflux for 3 hours. The solvent is removed under reduced pressure. The residue is dissolved in CH2Cl2 and washed with water. The organic layer is dried (Na2SO4) and filtered, and the solvent is removed under reduced pressure to give N,N-dimethyl-2-(4-oxocyclohexyl)acetamide (400 mg).
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH2:13]SC)=[C:4]([C:9]([F:12])([F:11])[F:10])[CH:5]=[CH:6][C:7]=1Cl.NC1C(CSC)=C(C(F)(F)F)C=CC=1Br.NC1C(CSC)=C(C(F)(F)F)C=CC=1I.NC1C(CSC)=C(C(F)(F)F)C=CC=1C.NC1C(SC)=C(C(F)(F)F)C=CC=1SCC.NC1C(CSC)=C(C(F)(F)F)C=CC=1SCCC.NC1C(CSC)=C(C(F)(F)F)C=CC=1SCCCC.NC1C(CSC)=C(C(F)(F)F)C=CC=1SCCCCCCC.NC1C(CSC)=C(C(F)(F)F)C=CC=1SCCCCCCCC>>[NH2:1][C:2]1[C:3]([CH3:13])=[C:4]([C:9]([F:10])([F:11])[F:12])[CH:5]=[CH:6][CH:7]=1
Reactant: CSCc1c(C(F)(F)F)ccc(Cl)c1N
Agent: CCCCCCCCSc1ccc(C(F)(F)F)c(CSC)c1N
Agent: CCCCCCCSc1ccc(C(F)(F)F)c(CSC)c1N
Agent: CCCCSc1ccc(C(F)(F)F)c(CSC)c1N
Product: Cc1c(N)cccc1C(F)(F)F

Procedure:
Similarly, the 3-amino-4-chloro-2-methylthiomethylbenzotrifluoride may be replaced with equivalent quantities of 3-amino-4-bromo-2-methylthiomethylbenzotrifluoride, 3-amino-4-iodo-2-methylthiomethylbenzotrifluoride, 3-amino-4-methyl-2-methylthiomethylbenzotrifluoride, 3-amino-4-ethylthio-2-methylthiobenzotrifluoride, 3-amino-4-n-propylthio-2-methylthiomethylbenzotrifluoride, 3-amino-4-n-butylthio-2-methylthiomethylbenzotrifluoride, 3-amino-4-heptylthio-2-methylthiomethylbenzotrifluoride, or 3-amino-4-octylthio-2-methylthiomethylbenzotrifluoride, and by following substantially the teachings of Step C of this example, there is produced 3-amino-2-methylbenzotrifluoride.
Reaction SMILES: [N:1]1([C:7]2[N:12]=[CH:11][NH:10][C:9](=[O:13])[CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH2:14]([C:17]1[CH:24]=[CH:23][CH:22]=[C:19]([CH:20]=O)[C:18]=1[OH:25])[CH:15]=[CH2:16]>>[CH2:14]([C:17]1[C:18]([OH:25])=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH2:20][N:4]1[CH2:5][CH2:6][N:1]([C:7]2[N:12]=[CH:11][NH:10][C:9](=[O:13])[CH:8]=2)[CH2:2][CH2:3]1)[CH:15]=[CH2:16]
Reactant: C=CCc1cccc(C=O)c1O
Reactant: O=c1cc(N2CCNCC2)nc[nH]1
Product: C=CCc1cccc(CN2CCN(c3cc(=O)[nH]cn3)CC2)c1O

Procedure:
6-[4-(3-Allyl-2-hydroxy-benzyl)-piperazin-1-yl]-3H -pyrimidin-4-one was prepared using Procedure B from 6-piperazin-1-yl-3H-pyrimidin-4-one (Intermediate 4) and 3-allylsalicylaldehyde (available from Aldrich). 1H NMR (400 MHz, CDCl3) δ 2.58-2.64 (m, 4H), 3.38 (s, 2H), 3.58-3.63 (m, 4H), 3.89 (s, 2H), 5.06-5.15 (m, 2H), 5.39 (s, 1H), 5.97-6.06 (m, 1H), 6.73-6.77 (m, 1H), 6.85-6.89 (m, 1H), 6.99-7.08 (m, 1H), 7.84 (s, 1H), 10.65 (br s, 1H), 12.31 (br s, 1H). Mass spectrum (ES) MH+=327.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([C:9]2[N:18]=[C:17](Cl)[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=2)[CH:3]=1.C(OC(N1CCCCC(N)C1)=O)(C)(C)C.[NH2:35][C@@H:36]1[CH2:40][N:39]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:38][C@H:37]1[C:48]([O:50][CH2:51][CH3:52])=[O:49]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([C:9]2[N:18]=[C:17]([NH:35][C@@H:36]3[CH2:40][N:39]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:38][C@H:37]3[C:48]([O:50][CH2:51][CH3:52])=[O:49])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=2)[CH:3]=1.[NH2:35][C@@H:36]1[CH2:40][N:39]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:38][C@H:37]1[C:48]([O:50][CH2:51][CH3:52])=[O:49]
Reactant: Oc1ccc(Br)cc1-c1nc(Cl)c2ccccc2n1
Agent: CC(C)(C)OC(=O)N1CCCCC(N)C1
Agent: CCOC(=O)[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]1N
Product: CCOC(=O)[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]1Nc1nc(-c2cc(Br)ccc2O)nc2ccccc12

Procedure:
The title compound was prepared using a method analogous to that described in Synthesis 52, replacing 4-chloro-2-(2-methoxyphenyl)quinazoline with 4-bromo-2-(4-chloroquinazolin-2-yl)phenol and tert-butyl-3-aminoazepane-1-carboxylate with (3R,4S)-1-tert-butyl 3-ethyl 4-aminopyrrolidine-1,3-dicarboxylate. (3R,4S)-1-tert-Butyl 3-ethyl 4-aminopyrrolidine-1,3-dicarboxylate was prepared as described in J. Am. Chem. Soc., 2006, 10638.
Reaction SMILES: CC([O-])(C)C.[K+].[C:7]([C:9]1[CH:17]=[C:16]2[C:12]([CH:13]=[CH:14][NH:15]2)=[CH:11][CH:10]=1)#[N:8].CC1C=CC=CC=1S(O[CH2:29][CH:30]1[CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:31]1)(=O)=O>O1CCCC1>[C:7]([C:9]1[CH:17]=[C:16]2[C:12]([CH:13]=[CH:14][N:15]2[CH2:29][CH:30]2[CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:39])([CH3:41])[CH3:40])=[O:36])[CH2:31]2)=[CH:11][CH:10]=1)#[N:8]
Reactant: Cc1ccccc1S(=O)(=O)OCC1CCN(C(=O)OC(C)(C)C)C1
Reactant: N#Cc1ccc2cc[nH]c2c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Cn2ccc3ccc(C#N)cc32)C1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
77 mmol of potassium tert-butylate are added to a solution of 70 mmol of 6-cyanoindole in 400 ml of tetrahydrofuran. After 10 minutes' stirring at room temperature, 70 mmol of tert-butyl 3-[(methylphenyl)sulphonyloxymethyl]-1-pyrrolidinecarboxylate in 60 ml of tetrahydrofuran are added. The reaction mixture is heated at reflux for 12 hours. After cooling and dilution with water, the solvent is removed by evaporation. The residue is extracted with dichloromethane and the organic phase is washed with water, dried and concentrated to yield the expected product.