Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.CO[CH2:10][N:11]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:12][Si](C)(C)C.C([O:26][C:27](=[O:38])[C:28]#[C:29][C:30]1[CH:35]=[CH:34][C:33]([F:36])=[C:32]([F:37])[CH:31]=1)C.[OH-].[Na+]>C(Cl)Cl>[CH2:17]([N:11]1[CH2:10][C:29]([C:30]2[CH:35]=[CH:34][C:33]([F:36])=[C:32]([F:37])[CH:31]=2)=[C:28]([C:27]([OH:38])=[O:26])[CH2:12]1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CCOC(=O)C#Cc1ccc(F)c(F)c1
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)C1=C(c2ccc(F)c(F)c2)CN(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
At r.t., trifluoroacetic acid (0.11 ml, 1.34 mmol, 0.1 eq.) followed by N-(methoxymethyl)-N-(phenylmethyl)-N-(trimethylsilyl)methylamine (4.89 g, 20.2 mmol, 1.5 eq.) were added dropwise to a stirred solution of (3,4-difluoro-phenyl)-propynoic acid ethyl ester (2.83 g, 13.5 mmol) in CH2Cl2 (80 ml). The yellow solution was stirred at r.t. for 18 h. Trifluoroacetic acid (0.034 ml, 0.44 mmol, 0.033 eq.) and N-(methoxymethyl)-N-(phenylmethyl)-N-(trimethylsilyl) methylamine (1.66 g, 6.73 mmol, 0.5 eq.) were added, and the solution was stirred for 1 h. It was evaporated to dryness, and the residue was dissolved in dioxane (40 ml). An aqueous solution of NaOH (18.7 ml, 37.4 mmol, 2.8 eq.) was added. The resulting emulsion was stirred at r.t. for 18 h, and the low boiling organic solvent was removed under reduced pressure. Water (40 ml) was added, and the aqueous layer separated and washed twice with TBME (50 ml). The organic layers were washed with the same portion of water (15 ml). The combined aqueous layers were acidified by addition of aqueous 3M HCl (12.4 ml). The resulting suspension was stirred for 48 h at r.t. The white precipitate was filtered off, washed with water and ethanol and dried under high vacuum to yield 4.25 g (58%) of IIc as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:8][C:7]=1[CH3:15])[CH3:2].[H-].[Na+].ClS([N:23]=[C:24]=[O:25])(=O)=O>>[CH2:1]([O:3][C:4](=[O:16])[CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([C:24](=[O:25])[NH2:23])[C:7]=1[CH3:15])[CH3:2]
Reactant: CCOC(=O)Cc1c(C)[nH]c2ccccc12
Reactant: O=C=NS(=O)(=O)Cl
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)Cc1c(C)n(C(N)=O)c2ccccc12

Procedure:
The title compound was prepared in a similar manner as described in Scheme A8 Step A starting from (2-methyl-1H-indol-3-yl)-acetic acid ethyl ester [21909-49-9] (1.20 g, 5.52 mmol), NaH (60% in mineral oil, 331 mg, 8.28 mmol) and chlorosulfonylisocyanate (0.959 mL, 11.1 mmol). Purification by flash column chromatography on silica gel (EtOAc/c-hexane 1:4 to 1:1) afforded a yellowish solid. TLC, Rf (EtOAc/c-hexane 1:1)=0.31; MS: 261 [M+H]+; tR (HPLC conditions b) 3.54 min.
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[C:4]1[O:8][C:7]([CH:9]2[O:13][CH2:12][CH2:11][O:10]2)=[CH:6][CH:5]=1>C(OCC)(=O)C>[O:10]1[CH2:11][CH2:12][O:13][CH:9]1[C:7]1[O:8][C:4]([CH2:2][CH:3]=[O:1])=[CH:5][CH:6]=1
Reactant: c1cc(C2OCCO2)oc1C1CO1
Solvent: CCOC(C)=O
Product: O=CCc1ccc(C2OCCO2)o1
Temperature: 25 °C
Reaction time: 6.5 h
Yield: 69.8 %

Procedure:
The resulting 2-(5-oxiranyl-furan-2-yl)-[1,3]dioxolane (2.25 g) and silica gel (5.00 g) were suspended in ethyl acetate (40 mL), and the solution was stirred for 6.5 hours at room temperature. The reaction solution was filtered, then, the filtrate was evaporated in vacuo, and (5-[1,3]dioxolan-2-yl-furan-2-yl)-acetaldehyde (1.57 g) was obtained as a yellow oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[NH:8][C:9]1[N:13]2[N:14]=[C:15]([C:18]3[C:23]([F:24])=[CH:22][CH:21]=[CH:20][C:19]=3[F:25])[CH:16]=[CH:17][C:12]2=[CH:11][N:10]=1.ClC1C=CN=CC=1NC1N2N=C(C3C(F)=CC=CC=3F)C=CC2=CN=1.[NH2:51][C:52]1[CH:57]=[C:56](B(O)O)[CH:55]=[CH:54][N:53]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.CCOC(C)=O.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>[F:25][C:19]1[CH:20]=[CH:21][CH:22]=[C:23]([F:24])[C:18]=1[C:15]1[CH:16]=[CH:17][C:12]2[N:13]([C:9]([NH:8][C:3]3[CH:4]=[N:5][CH:6]=[CH:7][C:2]=3[C:56]3[CH:55]=[CH:54][N:53]=[C:52]([NH2:51])[CH:57]=3)=[N:10][CH:11]=2)[N:14]=1
Reactant: Fc1cccc(F)c1-c1ccc2cnc(Nc3cnccc3Br)n2n1
Reactant: Nc1cc(B(O)O)ccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Fc1cccc(F)c1-c1ccc2cnc(Nc3cnccc3Cl)n2n1
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: Nc1cc(-c2ccncc2Nc2ncc3ccc(-c4c(F)cccc4F)nn23)ccn1
Temperature: 130 °C
Yield: 17 %

Procedure:
A glass microwave reaction vessel was charged with a 1:1 mixture of N-(4-bromopyridin-3-yl)-2-(2,6-difluorophenyl)imidazo[1,5-b]pyridazin-7-amine and N-(4-chloropyridin-3-yl)-2-(2,6-difluorophenyl)imidazo[1,5-b]pyridazin-7-amine (Example 29, step 1, 85 mg), (2-aminopyridin-4-yl)boronic acid (44 mg, 0.31 mmol, CombiPhos Catalysis, Inc., Princeton, N.J.), Pd(PPh3)4 (12 mg, 10.6 μmol) and 2 M Na2CO3 (0.33 mL) in dioxane (1.5 mL). The reaction was stirred and heated in a microwave at 130° C. for 25 min. The mixture was diluted with EtOAc and water. The layers were separated and the aqueous layer was extracted with EtOAc (2×). The combined organic layers were dried over anh. Na2SO4, filtered and concentrated. The crude material was purified by prep HPLC method 4. The desired fractions were collected and concentrated. The residue was partitioned between 30 mL of EtOAc and 5 mL of 0.5 M NaOH. The organic solution was washed with brine (5 mL), dried over Na2SO4 and concentrated to afford N3′-(2-(2,6-difluorophenyl)imidazo[1,5-b]pyridazin-7-yl)-[4,4′-bipyridine]-2,3′-diamine (15 mg, 17% yield) as an orange solid. MS (ESI, pos. ion) m/z: 415.9 (M+1). 1H NMR (400 MHz, CDCl3) δ ppm 9.88 (s, 1 H), 8.34 (d, J=4.89 Hz, 1 H), 8.16 (d, J=5.09 Hz, 1 H), 7.75 (d, J=9.39 Hz, 1 H), 7.39 (m, 2 H), 7.34 (s, 1 H), 7.14 (d, J=4.89 Hz, 1 H), 7.05 (t, J=8.22 Hz, 2 H), 6.78-6.85 (m, 1 H), 6.63 (s, 1 H), 6.53 (dt, J=9.39, 1.76 Hz, 1 H), 4.55 (br., 2 H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([CH:13]([C:15]1[S:19][C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:17][C:16]=1[OH:26])[CH3:14])[CH:7]=[CH:6]2.Cl[CH2:28][O:29][CH:30]=[O:31]>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([CH:13]([C:15]1[S:19][C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:17][C:16]=1[O:26][C:30]([O:29][CH3:28])=[O:31])[CH3:14])[CH:7]=[CH:6]2
Reactant: COc1ccc2cc(C(C)c3sc(-c4ccccc4)nc3O)ccc2c1
Reactant: O=COCCl
Solvent: c1ccncc1
Product: COC(=O)Oc1nc(-c2ccccc2)sc1C(C)c1ccc2cc(OC)ccc2c1

Procedure:
The desired compound is prepared by treatment of the product of Example 5 with chloromethylformate and pyridine.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([C:15]2[CH:16]=[CH:17][C:18]3[C:19]4[CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25][CH2:24][C:20]=4[NH:21][C:22]=3[CH:23]=2)[C:11](=[O:35])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:36]>>[ClH:36].[ClH:36].[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([C:15]2[CH:16]=[CH:17][C:18]3[C:19]4[CH2:27][NH:26][CH2:25][CH2:24][C:20]=4[NH:21][C:22]=3[CH:23]=2)[C:11](=[O:35])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]c3cc(-n4ccc(OCc5ccccc5)cc4=O)ccc3c2C1
Agent: Cl
Product: O=c1cc(OCc2ccccc2)ccn1-c1ccc2c3c([nH]c2c1)CCNC3
Yield: 26 %

Procedure:
Prepared from tert-butyl 7-(4-(benzyloxy)-2-oxopyridin-1(2H)-yl)-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carboxylate (150 mg, 0.32 mmol) according to the procedure of Example 1 (step d). Purification by flash column chromatography (4 g ISCO column eluting with methylene chloride and a methanol/ammonia mixture (10:1); gradient 100% methylene chloride to 85% methylene chloride over 30 min) provided the free-base as a yellow solid. This was converted to the bis-HCl salt (2 N HCl Et2O in CH2Cl2) providing the title compound (36 mg, 26%) as a yellow solid: mp 240° C. dec.; 1H NMR (500 MHz, CD3OD) δ 7.65 (d, J=7.5 Hz, 1H), 7.57 (d, J=8.2 Hz, 1H), 7.47 (d, J=7.2 Hz, 2H), 7.42-7.36 (m, 4H), 7.03 (d, J=8.5 Hz, 1H), 6.39 (dd, J=7.6, 2.5 Hz, 1H), 6.21 (d, J=2.5 Hz, 1H), 5.21 (s, 2H), 4.47 (s, 2H), 3.64 (t, J=6.0 Hz, 2H), 3.20 (t, J=6.1 Hz, 2H); ESI MS m/z 372 [M+H]+; HPLC (Method A) 95.0% (AUC), tR=12.2 min.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=1)[C:11]1[CH2:10][CH2:9][C@@H:8]([NH:24][C:25]([CH:27]3[CH2:29][CH2:28]3)=[O:26])[CH2:7][C:6]2=1)#N.C(O)=[O:31]>[Al].[Ni].CO>[F:23][C:19]1[CH:18]=[C:17]([CH:22]=[CH:21][CH:20]=1)[CH2:16][N:12]1[C:11]2[CH2:10][CH2:9][C@@H:8]([NH:24][C:25]([CH:27]3[CH2:29][CH2:28]3)=[O:26])[CH2:7][C:6]=2[C:5]2[C:13]1=[CH:14][CH:15]=[C:3]([CH:1]=[O:31])[CH:4]=2
Reactant: N#Cc1ccc2c(c1)c1c(n2Cc2cccc(F)c2)CC[C@@H](NC(=O)C2CC2)C1
Reactant: O=CO
Agent: [Ni]
Agent: [Al]
Solvent: CO
Product: O=Cc1ccc2c(c1)c1c(n2Cc2cccc(F)c2)CC[C@@H](NC(=O)C2CC2)C1
Yield: 95 %

Procedure:
Combine (R)-cyclopropanecarboxylic acid[6-cyano-9-(3-fluorobenzyl)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]amide (Example 194) (3.70 g, 9.55 mmol) and nickel-aluminum catalyst (10.0 g) in 90% formic acid and heat at 90-100° C. for 18 h. Dilute with methanol, filter to remove catalyst, and concentrate the filtrate in vacuo. Neutralize the filtrate by addition of solid NaHCO3 after taking up in ethyl acetate/water. Dry the ethyl acetate portion over Na2SO4, filter, and evaporate to give 3.53 g (95%) of the title compound as a foam. MS (ES): n/z 391 (M+1); 1H NMR(DMSO-d6): δ 9.90 (s, 1H), 8.19 (d, 1H), 8.04 (s, 1H), 7.61 (d, 1H), 7.57 (d, 1H), 7.37 (dd, 1H), 7.15 (m, 1H), 6.81-6.92 (m, 2H), 5.44 (s, 2H), 4.08 (m, 1H), 3.03 (dd, 1H), 2.57-2.82 (m, 4H), 2.00 (m, 1H), 1.82 (m, 1H), 1.59 (m, 1H), 0.65 (m, 4H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:16](=[O:18])[CH3:17])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[CH:19]([S:22](Cl)(=[O:24])=[O:23])([CH3:21])[CH3:20]>C(Cl)Cl.N1C=CC=CC=1>[C:16]([C:4]1[CH:5]=[CH:6][C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:2]([NH:1][S:22]([CH:19]([CH3:21])[CH3:20])(=[O:24])=[O:23])[CH:3]=1)(=[O:18])[CH3:17]
Reactant: CC(C)S(=O)(=O)Cl
Reactant: CC(=O)c1ccc(OCc2ccccc2)c(N)c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)c1ccc(OCc2ccccc2)c(NS(=O)(=O)C(C)C)c1
Reaction time: 72 h
Yield: 29.9 %

Procedure:
To a stirred solution of 1-(3-amino-4-benzyloxy-phenyl)-ethanone (EP 0 659 737) (30 g, 125.0 mmol) in CH2Cl2 (500 mL) and pyridine (250 mL) was added dropwise isopropylsufonyl chloride (28.6, 200 mmol) at room temperature. The reaction was stirred for 3 days under nitrogen atmosphere. The mixture was diluted with CH2Cl2 (700 mL) and washed with 1N hydrochloric acid, water, dried over Na2SO4, and concentrated. The product was purified by flash silica gel chromatography eluting with ethyl acetate/hexanes to give the title compound as a white solid (13 g, 30%); 1H NMR (300 MHz, CDCl3) δ 1.35(d, J=6.9 Hz, 6 H), 2.56(s, 3 H), 3.25–3.45(m, 1 H), 5.18(s, 2 H), 6.75(brs, 1 H), 7.02 (d, J=8.6 Hz, 1 H), 7.30–7.50(m, 5 H), 7.70(dd, J=8.6, 2.1 Hz, 1 H), 8.18 (d, J=2.1 Hz, 1 H); MS (ES) m/z: 364.9 ((M+NH4)+, 100%; HRMS Calcd. for C18H22NO4S(MH+): 348.1264. Found: 348.1259.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[O:10][CH3:11].[F:12][C:13]([F:24])([F:23])[C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1.[F-].[K+]>C1(C)C=CC=CC=1.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>[CH3:11][O:10][C:3]1[CH:4]=[C:5]([C:6]#[N:7])[CH:8]=[CH:9][C:2]=1[C:17]1[CH:18]=[CH:19][C:14]([C:13]([F:24])([F:23])[F:12])=[CH:15][CH:16]=1
Reactant: COc1cc(C#N)ccc1Br
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [F-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: COc1cc(C#N)ccc1-c1ccc(C(F)(F)F)cc1
Yield: 94.8 %

Procedure:
A mixture of 4-bromo-3-methoxybenzonitrile (500 mg, 2.36 mmol), 4-(trifluoromethyl)phenyl boronic acid (671.9 mg, 3.54 mmol) and potassium fluoride (411 mg, 7.08 mmol) in toluene (11 mL) and water (3 mL) was purged with nitrogen. Pd(PPh3)4 (272.7 mg, 0.236 mmol) was added. The resulting mixture was heated at reflux overnight. The reaction mixture was washed with water (200 ml) and extracted with ethyl acetate (150 mL*4). The combined organic extracts were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give 2-methoxy-4′-(trifluoromethyl)biphenyl-4-carbonitrile (620 mg) as a colorless solid. 1HNMR (400 MHz, CDCl3) δ 7.68 (d, J=8.4 Hz, 2H), 7.60 (d, J=8.4 Hz, 2H), 7.36-7.40 (m, 2H), 7.22 (s, 1H), 3.87 (s, 3H).
Reaction SMILES: [ClH:1].[OH:2][NH:3][C:4]([C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH2:8][CH2:9][C:10]2=[N:15]O)=[NH:5].N[N:18]1[CH:22]=[C:21]([C:23]2[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=[CH:25][C:24]=2[O:31][CH3:32])[N:20]=[C:19]1[NH2:33]>C(O)(C)C>[ClH:1].[ClH:1].[OH:2][NH:3][C:4]([C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH2:8][CH2:9][C:10]2=[N:15][N:18]1[CH:22]=[C:21]([C:23]2[CH:28]=[C:27]([O:29][CH3:30])[CH:26]=[CH:25][C:24]=2[O:31][CH3:32])[N:20]=[C:19]1[NH2:33])=[NH:5]
Reactant: N=C(NO)c1cccc2c1CCC2=NO
Reactant: COc1ccc(OC)c(-c2cn(N)c(N)n2)c1
Agent: Cl
Solvent: CC(C)O
Product: COc1ccc(OC)c(-c2cn(N=C3CCc4c(C(=N)NO)cccc43)c(N)n2)c1
Temperature: 80 °C

Procedure:
0.6 ml of concentrated hydrochloric acid is added, with stirring, to a mixture of 0.41 g (0.002 mol) of 4-(N-hydroxyamidino)-2,3-dihydro-1H-inden-1-one oxime, 0.47 g (0.002 mol) of 1,2-diamino-4-(2,5-dimethoxyphenyl)-imidazole and 10 ml of isopropanol, and the reaction mixture is stirred at 80° C. for 3.hours. The reaction mixture is filtered while hot and the filtration product is washed with isopropanol and dried. In that manner there is obtained the title compound, m.p. >220° C., 1H-NMR (DMSO/D2 0): δ=8.23 (d, 1H); 7.75 (m, 2H); 7.61 (t, 1H); 7.17 (d, 1H); 7.07 (d, 1H); 6.93 (q, 1H); 3.82 (s, 3H), 3.71 (s, 3H); 3.25 (bs, 4H).
Reaction SMILES: [S:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1.[C:8]1(C)C=CC(S(O)(=O)=O)=C[CH:9]=1>C1(C)C=CC=CC=1>[CH:6]12[S:1][CH:2]([CH2:8][CH2:9]1)[CH2:3][C:4](=[O:7])[CH2:5]2
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O=C1CCSCC1
Solvent: Cc1ccccc1
Product: O=C1CC2CCC(C1)S2
Reaction time: 8 h
Yield: 5908.8 %

Procedure:
Tetrahydrothiopyran-4-one (19.1 g, 150 mmol), ethylene-1,2-diol (11.2 g. 180 mmol), toluene-p-sulfonic acid (0.5 g), and toluene (500 mL) was heated under reflux in a Dean-Stark apparatus for 1.5 h. The toluene was then removed by rotary evaporation, and the residue dissolved in ether and washed, first with 10% aqueous sodium hydroxide and then with water. The organic layer was dried (Na2SO4) and evaporated, and allowed to crystallize by standing in Et2O overnight, giving 24.4 g (93%) of the title compound.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[S:3]([O:6][C:7]1[CH:8]=[C:9]([C:13]23[CH2:20][CH2:19][C:16]([CH2:21][CH2:22][O:23][CH2:24][C:25]([O:27]C(C)(C)C)=[O:26])([CH2:17][CH2:18]2)[CH2:15][O:14]3)[CH:10]=[CH:11][CH:12]=1)(=[O:5])=[O:4].C(O)=O>C(Cl)Cl>[F:33][C:2]([F:1])([F:32])[S:3]([O:6][C:7]1[CH:8]=[C:9]([C:13]23[CH2:18][CH2:17][C:16]([CH2:21][CH2:22][O:23][CH2:24][C:25]([OH:27])=[O:26])([CH2:19][CH2:20]2)[CH2:15][O:14]3)[CH:10]=[CH:11][CH:12]=1)(=[O:4])=[O:5]
Reactant: CC(C)(C)OC(=O)COCCC12CCC(c3cccc(OS(=O)(=O)C(F)(F)F)c3)(CC1)OC2
Solvent: ClCCl
Solvent: O=CO
Product: O=C(O)COCCC12CCC(c3cccc(OS(=O)(=O)C(F)(F)F)c3)(CC1)OC2
Temperature: 25 °C
Reaction time: 18 h
Yield: 75.4 %

Procedure:
A mixture of tert-butyl 2-(2-(1-(3-(((trifluoromethyl)sulfonyl)oxy)phenyl)-2-oxabicyclo[2.2.2]octan-4-yl)ethoxy)acetate (28 mg, 0.057 mmol) and formic acid (0.022 mL, 0.57 mmol) in CH2Cl2 (0.5 mL) was stirred at rt for 18 h, then was concentrated in vacuo. The crude material was purified by preparative LC/MS (Column: Waters XBridge C18, 19×100 mm, 5-nm particles; Mobile Phase A: 5:95 MeCN:water with 0.1% TFA; Mobile Phase B: 95:5 MeCN:water with 0.1% TFA; Gradient: 40-80% B over 10 min, then a 5-min hold at 100% B; Flow rate: 20 mL/min) to give the title compound (19 mg, 0.043 mmol, 76% yield) as a clear oil. LCMS [M−H]+=437.0; 1H NMR (DMSO-d6) δ: 7.53-7.48 (m, 2H), 7.42 (d, J=2.7 Hz, 1H), 7.34 (dt, J=7.3, 2.3 Hz, 1H), 3.96 (s, 2H), 3.80 (s, 2H), 3.50 (t, J=6.7 Hz, 2H), 2.16-2.05 (m, 2H), 1.89-1.74 (m, 2H), 1.73-1.59 (m, 4H), 1.42 (t, J=6.8 Hz, 2H).
Reaction SMILES: C([O:3][C:4](=[O:20])[C@@H:5]([O:18][CH3:19])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]([OH:17])=O)=[CH:9][CH:8]=1)C.[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([CH:28]([NH2:35])[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:24][CH:23]=1.C(O[C@@H](CC1C=CC(O[C@@H](C(=O)NCCC2C=CC(OC3C=CC=CC=3)=CC=2)C)=CC=1)C(O)=O)C>>[Cl:21][C:22]1[CH:23]=[CH:24][C:25]([CH:28]([NH:35][C:15]([CH2:14][O:13][C:10]2[CH:9]=[CH:8][C:7]([CH2:6][C@H:5]([O:18][CH3:19])[C:4]([OH:3])=[O:20])=[CH:12][CH:11]=2)=[O:17])[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:26][CH:27]=1
Reactant: CCOC(=O)[C@H](Cc1ccc(OCC(=O)O)cc1)OC
Reactant: NC(c1ccccc1)c1ccc(Cl)cc1
Agent: CCO[C@@H](Cc1ccc(O[C@H](C)C(=O)NCCc2ccc(Oc3ccccc3)cc2)cc1)C(=O)O
Product: CO[C@@H](Cc1ccc(OCC(=O)NC(c2ccccc2)c2ccc(Cl)cc2)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-(4-carboxymethoxy-phenyl)-2-methoxy-propionic acid ethyl ester (PREPARATION 3, step 2) and C-(4-chloro-phenyl)-C-phenyl-methylamine via the same procedure used for the preparation of (2S,1R)-2-ethoxy-3-(4-{1-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionic acid (Example 1, step 3) to produce a yellow oil. MS (ES) for C25H24ClNO5 [M+H]+: 454.
Reaction SMILES: [Cl:1][C:2]1[N:7]2[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]2[N:5]=[C:4]([NH2:12])[CH:3]=1.[F:13][C:14]([F:25])([F:24])[C:15]1[CH:23]=[CH:22][C:18]([C:19](Cl)=[O:20])=[CH:17][N:16]=1.CN1C(=O)CCC1>O>[Cl:1][C:2]1[N:7]2[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]2[N:5]=[C:4]([NH:12][C:19](=[O:20])[C:18]2[CH:22]=[CH:23][C:15]([C:14]([F:25])([F:13])[F:24])=[N:16][CH:17]=2)[CH:3]=1
Reactant: Cc1cc2nc(N)cc(Cl)n2n1
Reactant: O=C(Cl)c1ccc(C(F)(F)F)nc1
Solvent: CN1CCCC1=O
Solvent: O
Product: Cc1cc2nc(NC(=O)c3ccc(C(F)(F)F)nc3)cc(Cl)n2n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a 20 ml scintillation vial was added 7-chloro-2-methylpyrazolo[1,5-a]pyrimidin-5-amine (1J, 237 mg, 1.30 mmol), 6-(trifluoromethyl)nicotinoyl chloride (328 mg, 1.57 mmol), and NMP (5 mL) and the reaction mixture was stirred at rt for 1 hr. The reaction mixture was then diluted with water, filtered, and the filter cake rinsed thoroughly with water. Drying with suction under a stream of dry nitrogen resulted in the desired product N-(7-chloro-2-methylpyrazolo[1,5-a]pyrimidin-5-yl)-6-(trifluoromethyl)nicotinamide (12A) as a pink solid. 1H NMR (DMSO-d6) δ: 11.87 (s, 1H), 9.29 (d, J=2.3 Hz, 1H), 8.62 (dd, J=8.0, 1.9 Hz, 1H), 8.11 (d, J=8.3 Hz, 1H), 8.04 (s, 1H), 6.51 (s, 1H), 2.46 (s, 3H); ESI-MS: m/z 356.1 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[C:3]([N:9]2C=NC=N2)=[N:4][C:5](=[O:8])[NH:6][CH:7]=1>N>[CH3:1][C:2]1[C:3]([NH2:9])=[N:4][C:5](=[O:8])[NH:6][CH:7]=1
Reactant: Cc1c[nH]c(=O)nc1-n1cncn1
Agent: N
Product: Cc1c[nH]c(=O)nc1N
Reaction time: 3 h
Yield: 97.2 %

Procedure:
1.06 g (6 mmol) of 5-methyl-4-(1,2,4-triazol-1-yl)-pyrimidin-2(1H)-one are dissolved in 30 ml of concentrated aqueous ammonia and stirred for 3 hours at reflux temperature. The cooled solution is evaporated to dryness, the residue is dissolved in hot water, the solution is cooled and three times the amount of acetone are added. The precipitate is filtered off by suction and is dried in vacuo. 0.73 g (97.3% of theory) of 5-methyl-cytosine is obtained as a colorless powder with melting point 271°-274° C.
Reaction SMILES: [CH:1]([C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].C(N(CC)CC)C.[Br:18][C:19]([CH3:26])([CH2:23][CH2:24][CH3:25])[C:20](Cl)=[O:21]>C1C=CC=CC=1>[Br:18][C:19]([CH3:26])([CH2:23][CH2:24][CH3:25])[C:20]([NH:8][C:7]1[CH:9]=[CH:10][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:5][CH:6]=1)=[O:21]
Reactant: CCCC(C)(Br)C(=O)Cl
Reactant: CC(C)c1ccc(N)cc1
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CCCC(C)(Br)C(=O)Nc1ccc(C(C)C)cc1
Yield: 65.3 %

Procedure:
410 mg (3.04 mmoles) of 4-isopropylaniline was dissolved in 10 ml of benzene, and 500 mg of triethylamine was added. With stirring under ice cooling, 800 mg (4.10 mmoles) of 2-bromo-2-methylvaleryl chloride was added dropwise. After the addition, the mixture was further stirred at room temperature for 1 hour. The crystals that precipitated were separated by filtration. The filtrate was concentrated, and the residue was recrystallized from benzene to give 620 mg of 2-bromo-2-methyl-4'-isopropylvaleranilide. m.p. 87.2°-88.2° C. IR νmaxcm-1 3300 and 1650. Yield 65.4%.
Reaction SMILES: [F:1][C:2]1[CH:41]=[CH:40][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][C:17]4[C:22](=[O:23])[N:21]5[CH2:24][CH2:25][CH2:26][CH:27]([O:28][CH2:29][CH2:30][CH2:31][NH:32]C(=O)C(C)(C)C)[C:20]5=[N:19][C:18]=4[CH3:39])[CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[NH2:32][CH2:31][CH2:30][CH2:29][O:28][CH:27]1[C:20]2=[N:19][C:18]([CH3:39])=[C:17]([CH2:16][CH2:15][N:12]3[CH2:11][CH2:10][CH:9]([C:6]4[C:5]5[CH:40]=[CH:41][C:2]([F:1])=[CH:3][C:4]=5[O:8][N:7]=4)[CH2:14][CH2:13]3)[C:22](=[O:23])[N:21]2[CH2:24][CH2:25][CH2:26]1
Reactant: Cc1nc2n(c(=O)c1CCN1CCC(c3noc4cc(F)ccc34)CC1)CCCC2OCCCNC(=O)C(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1nc2n(c(=O)c1CCN1CCC(c3noc4cc(F)ccc34)CC1)CCCC2OCCCN

Procedure:
A solution of N-(3-((3-(2-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperidin-1-yl)ethyl)-2-methyl-4-oxo-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-yl)oxy)propyl)pivalamide, prepared as described in Step A, (1.482 g, 2.54 mmol) in dichloromethane (10 mL) and trifluoroacetic acid (5 mL) was stirred for 1 h at room temperature. The reaction mixture was purified on a Porapak CX column to give the title compound which was used without further purification in the next step.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([NH:9][CH2:10][C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1)=[O:8].[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)=[CH:21][CH:20]=1>>[CH3:17][O:18][C:19]1[CH:20]=[CH:21][C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[N:31]2[CH2:36][CH2:35][N:34]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([NH:9][CH2:10][C:11]3[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=3)=[O:8])[CH2:33][CH2:32]2)=[CH:23][CH:24]=1
Reactant: COc1ccc(-c2ccccc2N2CCNCC2)cc1
Reactant: O=C(CCCCCBr)NCc1cccnc1
Product: COc1ccc(-c2ccccc2N2CCN(CCCCCC(=O)NCc3cccnc3)CC2)cc1

Procedure:
The title compound was prepared starting from 6-bromo-N-(3-pyridylmethyl)hexanamide and 1-[2-(4-methoxyphenyl)phenyl]piperazine following the procedure outlined for Example 21. 1H NMR (CDCl3): δ 1.35-1.42 (m, 2H), 1.53-1.63 (m, 2H), 1.68-1.78 (m, 2H), 2.28 (t, 2H, J=7.4 Hz), 2.42 (app. t, 2H), 2.65 (br s, 4H), 3.09 (br s, 4H), 3.80 (s, 3H), 4.45 (d, 2H, J=6.1 Hz), 6.12 (br t, 1H, D2O exchanged), 6.94 (d, 2H, J=8.8 Hz), 7.00 (d, 1H, J=8.0 Hz), 7.09-7.12 (m, 2H), 7.20-7.28 (m, 3H), 7.46 (d, 2H, J=8.8 Hz), 8.44 (m, 1H). GC-MS m/z 473 (M+1, 1), 472 (M+, 4), 379 (15), 282 (65), 226 (100), 210 (43), 196 (10).