Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]1[C:7]([CH3:19])([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[N:15]=[N:16][NH:17][CH:18]=3)[CH:9]=2)[CH2:6][CH2:5][NH:4][CH2:3]1.[O:20]1[CH2:24][CH2:23][CH:22]([CH2:25][CH2:26][C:27](O)=O)[CH2:21]1.Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.C(=O)([O-])O.[Na+].[H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl-].[NH4+]>CN(C)C=O.O1CCCC1>[CH3:1][CH:2]1[C:7]([CH3:19])([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]3[N:15]=[N:16][NH:17][CH:18]=3)[CH:9]=2)[CH2:6][CH2:5][N:4]([CH2:27][CH2:26][CH2:25][CH:22]2[CH2:23][CH2:24][O:20][CH2:21]2)[CH2:3]1
Reactant: CC1CNCCC1(C)c1cccc(-c2c[nH]nn2)c1
Reactant: O=C(O)CCC1CCOC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: O
Product: CC1CN(CCCC2CCOC2)CCC1(C)c1cccc(-c2c[nH]nn2)c1
Temperature: 0 °C
Reaction time: 8 h
Yield: 25.6 %

Procedure:
To a solution of 3,4-dimethyl-4-(3-(1H-1,2,3-triazol-4-yl)phenyl)piperidine (Preparation 44, 45 mg, 0.18 mmol) in N,N-dimethylformamide (5 mL) was added 3-(tetrahydro-3-furanyl)propionic acid (Preparation 47, 28 mg, 0.19 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (44 mg, 0.23 mmol) and 1-hydroxybenzotriazole hydrate (24 mg, 0.18 mmol). The resultant mixture was heated to 80° C. and stirred overnight. The reaction mixture was cooled, poured onto saturated aqueous sodium hydrogencarbonate solution (100 mL) and extracted with ethyl acetate (3×20 mL). The combined organics were dried over MgSO4 and concentrated in vacuo to give an off-white gum. The product was dissolved in tetrahydrofuran (2 mL) and cooled to 0° C. The solution was treated dropwise with lithium aluminium hydride (1.0 M solution in THF, 0.35 mL, 0.35 mmol). The reaction was allowed to warm to room temperature and stirred overnight. The reaction mixture was treated with saturated ammonium chloride solution and the product extracted with ethyl acetate (3×10 mL). The combined organics were dried over Na2SO4 and the solvent removed in vacuo to give a white gum. The crude product was purified by reverse-phase high performance liquid chromatography (condition 1) to give the title compound as a clear oil (17 mg, 26%).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[O:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[CH2:25][OH:26].CCOC(/N=N/C(OCC)=O)=O.O[C:40]1[CH:48]=[CH:47][CH:46]=[C:45]2[C:41]=1[C:42](=[O:58])[N:43]([CH:50]1[CH2:55][CH2:54][C:53](=[O:56])[NH:52][C:51]1=[O:57])[C:44]2=[O:49]>C1COCC1.CO>[O:57]=[C:51]1[CH:50]([N:43]2[C:44](=[O:49])[C:45]3[C:41](=[CH:40][CH:48]=[CH:47][C:46]=3[O:26][CH2:25][C:21]3[O:20][CH:24]=[CH:23][CH:22]=3)[C:42]2=[O:58])[CH2:55][CH2:54][C:53](=[O:56])[NH:52]1
Reactant: O=C1CCC(N2C(=O)c3cccc(O)c3C2=O)C(=O)N1
Reactant: OCc1ccco1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CO
Product: O=C1CCC(N2C(=O)c3cccc(OCc4ccco4)c3C2=O)C(=O)N1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 43.7 %

Procedure:
To a solution of triphenylphosphine (630 mg, 2.4 mmol) and furan-2-yl-methanol (0.17 mL, 2.0 mmol) in THF (10 mL) was added a solution of DEAD (0.38 mL, 2.4 mmol) in THF (0.6 mL) at 0° C. After 5 min, 4-hydroxy-2-(2,6-dioxo(3-piperidyl))isoindoline-1,3-dione (550 mg, 2.0 mmol) was added to the mixture. The mixture was allowed to warm to room temperature and kept for 4 h. The solvent was removed in vacuo, and the residue was purified by column chromatography (Silca Gel) to give an oil. The oil was slurried in methanol (10 mL) for 3 h to give a suspension. The suspension was filtered and washed with methanol (20 mL) to give 2-(2,6-dioxo-piperidin-3-yl)-4-(furan-2-ylmethoxy)-isoindole-1,3-dione as a yellow solid (310 mg, 44% yield): mp, 184-186° C.; 1H NMR (DMSO-d6) δ 1.99-2.04 (m, 1H, CHH), 2.42-2.61 (m, 2H, CH2), 2.80-2.95 (m, 1H, CHH), 5.07 (dd, J=5, 13 Hz, 1H, NCH), 5.35 (s, 2H, CH2), 6.49 (dd, J=2, 3 Hz, 1H, Ar), 6.68 (d, J=8 Hz, 1H, Ar), 7.47 (d, J=7 Hz, 1H, Ar), 7.68-7.71 (m, 2H, Ar), 7.83 (t, J=8 Hz, 1H, Ar), 11.10 (s, 1H, NH); 13C NMR (DMSO-d6) δ 21.96, 30.93, 48.77, 62.55, 110.72, 111.38, 115.72, 116.64, 120.35, 133.35, 136.89, 143.99, 149.15, 155.12, 165.21, 166.73, 169.88, 172.76; Anal Calcd for C18H14N2O6+0.1H2O: C, 60.71; H, 4.02; N, 7.87; H2O, 0.51. Found: C, 60.47; H, 3.97; N, 7.73; H2O, 0.38.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([S:6](Cl)(=[O:8])=[O:7])[N:3]=[CH:2]1.[Cl:10][C:11]1[CH:18]=[CH:17][C:14]([NH:15][CH3:16])=[CH:13][CH:12]=1>>[Cl:10][C:11]1[CH:18]=[CH:17][C:14]([N:15]([CH3:16])[S:6]([C:4]2[N:3]=[CH:2][NH:1][CH:5]=2)(=[O:8])=[O:7])=[CH:13][CH:12]=1
Reactant: O=S(=O)(Cl)c1c[nH]cn1
Reactant: CNc1ccc(Cl)cc1
Product: CN(c1ccc(Cl)cc1)S(=O)(=O)c1c[nH]cn1

Procedure:
Imidazole-4-sulphonyl chloride was reacted with 4-chloro-N-methylaniline to give 4-[N-(4-chlorophenyl)-N-methylsulphamoyl]imidazole, m.p. 217°-9°. This was then treated with dimethylsulphamoyl chloride in a similar manner to that described in Example 1, to give 1-dimethylsulphamoyl-4-[N-(4-chlorophenyl)-N-methylsulphamoyl]imidazole, m.p. 131.5°-132°.
Reaction SMILES: C1C=NC2C(N=1)=CC1C3CNCC(C=1C=2)C3.[S:17]([C:21]1[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=1)([O-:20])(=[O:19])=[O:18].C1C=NC2C(N=1)=CC1C3CNCC(C=1C=2)C3>>[C:24]1([CH3:25])[CH:23]=[CH:22][C:21]([S:17]([OH:20])(=[O:18])=[O:19])=[CH:27][CH:26]=1
Reactant: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cnc2cc3c(cc2n1)C1CNCC3C1
Product: Cc1ccc(S(=O)(=O)O)cc1

Procedure:
Varenicline Tosylate can be prepared by combining Varenicline base, a solvent and p-Toluene sulfonic acid (p-TSA) to obtain a reaction mixture and precipitating Varenicline Tosylate from the reaction mixture. Preferably, the obtained Varenicline Tosylate is further recovered from the reaction mixture.
Reaction SMILES: S([O-])([O-])=O.[Na+].[Na+].C(=O)(O)[O-].[Na+].[C:12]1([CH3:22])[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=1.[Na].Cl[CH2:25]C(O)=O>O>[CH3:25][S:18]([C:15]1[CH:16]=[CH:17][C:12]([CH3:22])=[CH:13][CH:14]=1)(=[O:20])=[O:19]
Reactant: O=C(O)CCl
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C([O-])O
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Product: Cc1ccc(S(C)(=O)=O)cc1
Temperature: 15 °C
Reaction time: 8 h

Procedure:
176.4 g of sodium sulfite and 226 g of sodium bicarbonate were dissolved in 1800 ml of water and cooled down to 15° C. 244 g of p-toluenesulfonyl chloride were added at that temperature with thorough stirring. The mixture was additionally stirred for 3 hours at 15° C. and overnight at room temperature. It was then heated to 40° C. and a solution of 175 g of the sodium salt of chloroacetic acid in 400 ml of water was added. The reaction mixture was stirred under reflux for 24 hours. After cooling down to 5°-10° C. the precipitated product was filtered off with suction and dried at 50° C. under reduced pressure, leaving 192.5 g of 4-methylsulfonyltoluene (melting point 83°-86° C).
Reaction SMILES: N1C=CN=C1.[Br:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][OH:14])[N:8]=1.[Si:15](Cl)([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16]>C(Cl)Cl>[Br:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])[N:8]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCc1cccc(Br)n1
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCc1cccc(Br)n1
Reaction time: 8 h

Procedure:
Add imidazole (3.01 g, 44.19 mmol) to a solution of the product from Step 1 (5.54 g, 29.46 mmol) and t-butyldimethylsilyl chloride (4.97 g, 32.99 mmol) in CH2Cl2 (60 ml) at RT and stir overnight. Filter the reaction mixture and concentrate the filtrate. Purify the residue by chromatography to give the desired compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[C:19]4[C:23](=[CH:24][CH:25]=3)[NH:22][CH:21]=[CH:20]4)[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].[Br:26]Br>CN(C=O)C>[Br:26][C:20]1[C:19]2[C:23](=[CH:24][CH:25]=[C:17]([C:14]3[N:13]=[C:12]([C:4]4[CH:5]=[CH:6][C:7]([O:8][CH:9]([CH3:11])[CH3:10])=[C:2]([Cl:1])[CH:3]=4)[O:16][N:15]=3)[CH:18]=2)[NH:22][CH:21]=1
Reactant: CC(C)Oc1ccc(-c2nc(-c3ccc4[nH]ccc4c3)no2)cc1Cl
Reactant: BrBr
Solvent: CN(C)C=O
Product: CC(C)Oc1ccc(-c2nc(-c3ccc4[nH]cc(Br)c4c3)no2)cc1Cl
Reaction time: 0.25 h
Yield: 29.1 %

Procedure:
To 5-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indole (D5) (450 mg, 1.27 mmol) dissolved in DMF (12 ml) was added bromine (213 mg, 1.35 mmol) dropwise. Stirred for 15 minutes, evaporated off the DMF, added diethyl ether (70 ml) and washed with water (2×70 ml). Dried over MgSO4 and evaporated off the solvent. The residue was crystallised from diethyl ether/hexane to give 160 mg of the title compound as a white solid. δH (400 MHz, d6-DMSO) 1.37 (6H, d), 4.88 (1H, sept), 7.44 (1H, d), 7.59 (1H, dd), 7.72 (1H, d), 7.91 (1H, dd), 8.13-8.32 (3H, m). MS (ES) C19H1579BrClN3O2 requires 431; found 432 (MH+).
Reaction SMILES: C[O:2][C:3](=[O:34])[C@@H:4]([O:31][CH2:32][CH3:33])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]2[N:15]=[C:16]([C:20]3[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[C:22]([O:28][CH3:29])[CH:21]=3)[O:17][C:18]=2[CH3:19])=[CH:8][C:7]=1[CH3:30].[Li+].[OH-]>>[CH3:29][O:28][C:22]1[CH:21]=[C:20]([C:16]2[O:17][C:18]([CH3:19])=[C:14]([CH2:13][O:12][C:9]3[CH:10]=[CH:11][C:6]([CH2:5][C@H:4]([O:31][CH2:32][CH3:33])[C:3]([OH:34])=[O:2])=[C:7]([CH3:30])[CH:8]=3)[N:15]=2)[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=1
Reactant: CCO[C@@H](Cc1ccc(OCc2nc(-c3cc(OC)cc(OC)c3)oc2C)cc1C)C(=O)OC
Agent: [Li+]
Agent: [OH-]
Product: CCO[C@@H](Cc1ccc(OCc2nc(-c3cc(OC)cc(OC)c3)oc2C)cc1C)C(=O)O

Procedure:
In analogy to the procedure described in example 1 g], (S)-3-{4-[2-(3,5-dimethoxy-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2-methyl-phenyl}-2-ethoxy-propionic acid methyl ester was treated with LiOH to obtain (S)-3-{4-[2-(3,5-dimethoxy-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2-methyl-phenyl}-2-ethoxy-propionic acid as colorless solid.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:10]([Cl:11])=[CH:9][C:8]([C:12]([F:15])([F:14])[F:13])=[CH:7][N:6]=1)=[O:4].[C:16]1(=[O:26])[NH:20][C:19](=[O:21])[C:18]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:17]12.[K].O>CN(C)C=O.[I-].[K+]>[Cl:11][C:10]1[C:5]([C:3](=[O:4])[CH2:2][N:20]2[C:19](=[O:21])[C:18]3=[CH:22][CH:23]=[CH:24][CH:25]=[C:17]3[C:16]2=[O:26])=[N:6][CH:7]=[C:8]([C:12]([F:15])([F:14])[F:13])[CH:9]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: O=C(CBr)c1ncc(C(F)(F)F)cc1Cl
Agent: [I-]
Agent: [K+]
Agent: [K]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(CN1C(=O)c2ccccc2C1=O)c1ncc(C(F)(F)F)cc1Cl
Temperature: 85 °C
Reaction time: 1 h
Yield: 34.9 %

Procedure:
To 1.43 g of 2-bromo-1-[3-chloro-5-(trifluoromethyl)pyridin-2-yl]ethanone in 10 ml of N,N-dimethylformamide, 0.68 g of potassium phthalimide and 0.01 g of potassium iodide were added, and the mixture was stirred at 85° C. for 1 hour. After completion of the reaction, the reaction mixture was allowed to cool to room temperature, mixed with 10 ml of water and extracted with ethyl acetate (10 ml×3), the resulting organic layers were combined, washed with water and dried over saturated aqueous sodium chloride and then anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The resulting residue was purified by preparative medium pressure liquid chromatography (preparative medium pressure chromatograph: YFLC-Wprep manufactured by Yamazen Science, Inc.) using ethyl acetate-hexane (with a gradient of from 5:95 to 46:60) as the eluent to obtain 0.47 g of the desired product as a pale yellow resinous substance.
Reaction SMILES: [OH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[C:21]([C:22]([F:25])([F:24])[F:23])=[C:20]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[O:19][N:18]=3)[O:14][N:13]=2)=[CH:8][CH:7]=1)[C:3]([OH:5])=O.[NH2:32][CH2:33][C:34]([NH2:36])=[O:35].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>CN(C=O)C>[NH2:36][C:34](=[O:35])[CH2:33][NH:32][C:3](=[O:5])[CH:2]([OH:1])[C:6]1[CH:7]=[CH:8][C:9]([C:12]2[N:16]=[C:15]([C:17]3[C:21]([C:22]([F:24])([F:25])[F:23])=[C:20]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[O:19][N:18]=3)[O:14][N:13]=2)=[CH:10][CH:11]=1
Reactant: NCC(N)=O
Reactant: O=C(O)C(O)c1ccc(-c2noc(-c3noc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: NC(=O)CNC(=O)C(O)c1ccc(-c2noc(-c3noc(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reaction time: 1 h
Yield: 41.4 %

Procedure:
(R/S)-2-Hydroxy-2-(4-(5-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetic acid (Int-IX, 30 mg, 0.070 mmol), 2-aminoacetamide (7.73 mg, 0.104 mmol), HATU (34.4 mg, 0.090 mmol), and 4-methylmorpholine (28.1 mg, 0.278 mmol) were added to DMF (1 mL). It was stirred for 1 h and then was purified by prep HPLC (PHENOMENEX® Luna 5u 21.2×100 mm, gradient elution with Method 1—MeOH/water containing 0.1% trifluoroacetic acid as defined above, 0% B to 100% B over 10 min, 20 mL/min, 220 nM, product retention=11.5 min) to provide (R/S)-N-(2-amino-2-oxoethyl)-2-hydroxy-2-(4-(5-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamide (18 mg, 0.029 mmol, 42.2% yield): LCMS=488.1 [M+H]+; 1H NMR (400 MHz, methanol-d4) δ ppm 8.16 (2 H, d, J=7.48 Hz), 7.58-7.87 (7 H, m), 5.20 (1 H, s), 3.81-4.13 (2 H, m); HPLC peak RT=8.0 min (Method A).
Reaction SMILES: [O:1]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11][O:10][CH2:9][CH2:8][NH:7][CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[C:16](Cl)(=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18]>>[C:17]([C:16]([N:13]1[CH2:12][CH2:11][O:10][CH2:9][CH2:8][N:7]([C:16]([C:17]([CH3:20])([CH3:19])[CH3:18])=[O:21])[CH2:6][CH2:5][O:4][CH2:3][CH2:2][O:1][CH2:15][CH2:14]1)=[O:21])([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)C(=O)Cl
Reactant: C1COCCNCCOCCOCCN1
Product: CC(C)(C)C(=O)N1CCOCCOCCN(C(=O)C(C)(C)C)CCOCC1

Procedure:
Analogously to Example 2 from 1,4,10-trioxa-7,13-diazacyclopentadecane and pivalyl chloride.
Reaction SMILES: C(C1C2C=CC=CC=2C(=O)OC=1N[C@H](C1C=CC=CC=1)CC)(=O)C.C(OC(C)(C)C)(=O)NN.C(OC(=O)[NH:40][N:41]1[C:50]([CH3:51])=[C:49]([C:52](=[O:63])[NH:53][C@H:54]([C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)[CH2:55][CH3:56])[C:48]2[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=2)[C:42]1=[O:64])(C)(C)C.C(=O)=O>C(#N)C>[C:57]1([C@@H:54]([NH:53][C:52]([C:49]2[C:48]3[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=3)[C:42](=[O:64])[N:41]([NH2:40])[C:50]=2[CH3:51])=[O:63])[CH2:55][CH3:56])[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1
Reactant: CC[C@H](NC(=O)c1c(C)n(NC(=O)OC(C)(C)C)c(=O)c2ccccc12)c1ccccc1
Agent: CC(C)(C)OC(=O)NN
Agent: CC[C@H](Nc1oc(=O)c2ccccc2c1C(C)=O)c1ccccc1
Agent: O=C=O
Solvent: CC#N
Product: CC[C@H](NC(=O)c1c(C)n(N)c(=O)c2ccccc12)c1ccccc1
Temperature: 180 °C
Yield: 67.9 %

Procedure:
A solution of 4-acetyl-3-((S)-1-phenyl-propylamino)-2-benzopyran-1-one (4.330 g, 13.47 mmol) and tert-butyl carbazate (1.959 g, 14.82 mmol) in acetonitrile (20 mL) was heated under microwave irradiation at 140° C. for 30 min. LC-MS the formation of the intermediate [3-methyl-1-oxo-4-((S)-1-phenyl-propylcarbamoyl)-1H-isoquinolin-2-yl]-carbamic acid tert-butyl ester as a major component (tR=1.36, UV 60%, ELSD 95%.). Then it was heated under microwave irradiation at 180° C. for total of 30 min (caution: CO2 gas formation; the reaction mixture was cooled automatically three times then the excess CO2 was released by puncture before heating continued to keep the pressure below the maximum limit of 20 bar). After cooling, the excess CO2 was carefully removed by puncture with needle, then by gentle shaking, then with stirring, then under sonication (caution: very intensive gas evolution). White precipitate formed, which was filtered, washed with acetonitrile and water to give pure title compound (3.07 g; Yield=67.9%). LC-MS (m/z) 336.6 (MH+); tR=1.04. 1H NMR (250 MHz, 70° C., DMSO-d6, DMSO-d5=2.5 ppm): 0.96 (t, J=7.3 Hz, Me of Et), 1.7-1.96 (m, 2H, diastereotopic CH2 of Et), 2.38 (s, 3H, Me), 5.0 (q (unres. dt), J (d)=6.8, J (t)=8.1, 1H, CH—NH), 5.82 (br. s, 2H, NH2), 7.27 (tm, J (t)=6.7 Hz, J (m)=ca 1.5 Hz, 1H), 7.32-7.49 (m, 6H), 7.61 (t (unresolved tdd), J (t)=8.1 Hz, J (d)=1 Hz, J (d)<1 Hz, 1H), 8.25 (dd, J=8 Hz, J=0.8 Hz, 1H), 8.68 (br. d, J=8.1 Hz, 1H, NHCO).
Reaction SMILES: CC(OC([NH:8][CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH:12]1[C:24]([O:26]CC)=O)=O)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[C:24]1(=[O:26])[NH:8][CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH:12]12
Reactant: CCOC(=O)C1CN(C(=O)OC(C)(C)C)CCN1CCNC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1NCCN2CCNCC12
Reaction time: 2 h
Yield: 38.6 %

Procedure:
To a solution of 1-(1,1-dimethylethyl) 3-ethyl 4-[2-({[(1,1-dimethylethyl)oxy]carbonyl}amino)ethyl]-1,3-piperazinedicarboxylate (D77, 2.492 g, 6.21 mmol) in dichloromethane (30 mL) kept at 0° C. was added TFA (10 mL) dropwise. The solution was kept at 0° C. for 2 h, and then at room temperature for 6 h. The deprotected product was isolated by SCX and the resulting solution was evaporated at 50° C. to induce cyclization. The target product was purified by reverse phase chromatography (Oasis HLB 6 g×4 columns, eluted with water), obtaining 372 mg of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([O:9][CH3:10])[C:6](B(O)O)=[CH:5][N:4]=1.I[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].CO>CS(C)=O.ClCCl.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[CH3:1][O:2][C:3]1[N:8]=[C:7]([O:9][CH3:10])[C:6]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:5][N:4]=1
Reactant: Ic1ccccc1
Reactant: COc1ncc(B(O)O)c(OC)n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: CO
Solvent: ClCCl
Solvent: CS(C)=O
Product: COc1ncc(-c2ccccc2)c(OC)n1
Temperature: 25 °C
Reaction time: 10 h
Yield: 49.4 %

Procedure:
To 2,4-Dimethoxypyrimidine-5-boronic acid (200 mg, 10.6 mmol), Iodobenzene (326 mg, 1.60 mmol) and K3PO4 (900 mg, 4.24 mmol) in DMSO (5 mL, purged with Ar) was added 1,1′bis(diphenylphosphino)ferrocene palladium chloride, complex with dichloromethane (12 mg) and the reaction solution was heated to 60 C in a sealed tube. The solution was heated for 2 h, stirred at room temperature for 10 hr and filtered through celite. The solution was poured into sat. NaHCO3 to give a gray solid. This material was collected, dissolved in ethyl acetate, dried (Na2SO4). Flash chromatography 0 to 2% methanol in dichloromethane gave 2,4-Dimethoxy-5-phenyl-pyrimidine (171 mg, 75% yield). HPLC tr=5.62 min (83%), FIA m/e 217.2 (M+H), HNMR (500 MHz, CDCl3) 8.25 (1H, s), 7.45-7.29 (5H, m), 4.00 (3H, s), 3.98 (3H, s).
Reaction SMILES: [C:1]([N:4]1[CH2:12][CH2:11][CH:7]([C:8](Cl)=[O:9])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[Cl-].[Al+3].[Cl-].[Cl-].[CH3:17][O:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([O:25]C)[CH:20]=1>>[C:1]([N:4]1[CH2:12][CH2:11][CH:7]([C:8](=[O:9])[C:22]2[CH:23]=[CH:24][C:19]([O:18][CH3:17])=[CH:20][C:21]=2[OH:25])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: COc1cccc(OC)c1
Reactant: CC(=O)N1CCC(C(=O)Cl)CC1
Agent: [Al+3]
Agent: [Cl-]
Product: COc1ccc(C(=O)C2CCN(C(C)=O)CC2)c(O)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
16.5 g of 1-acetylisonipecotoyl chloride, Example 1(b) are slowly added to a stirring mixture of 60 ml of m-dimethoxybenzene and 20.0 g of aluminum chloride. Stirring is continued for 1 hour at ambient temperature and then for an additional 1 hour at about 100° C. The reaction mixture is allowed to cool to ambient temperature, poured into ice-water, and extracted with chloroform. The combined extracts are dried and the chloroform is removed leaving a yellow oil. The oil is triturated with hexane to effect a white solid which is collected and dried. Recrystallization from ethyl acetate yields colorless needles, mp 138°-140° C., 1-acetyl-4-(2-hydroxy-4-methoxybenzoyl)piperidine.
Reaction SMILES: [Cl:1][C:2]1[C:14]2[C:9](=[C:10]([CH3:16])[C:11]([CH3:15])=[CH:12][CH:13]=2)[N:8]=[C:4]([C:5](O)=[O:6])[CH:3]=1.[NH2:17][C:18]1[NH:22][N:21]=[N:20][N:19]=1>CN(C)C=O>[Cl:1][C:2]1[C:14]2[C:9](=[C:10]([CH3:16])[C:11]([CH3:15])=[CH:12][CH:13]=2)[N:8]=[C:4]([C:5]([NH:17][C:18]2[NH:22][N:21]=[N:20][N:19]=2)=[O:6])[CH:3]=1
Reactant: Cc1ccc2c(Cl)cc(C(=O)O)nc2c1C
Reactant: Nc1nnn[nH]1
Solvent: CN(C)C=O
Product: Cc1ccc2c(Cl)cc(C(=O)Nc3nnn[nH]3)nc2c1C
Temperature: 25 °C
Reaction time: 48 h

Procedure:
4-Chloro-7,8-dimethylquinaldic acid (1.72 g) and N,N'-carbonyldiimidazole (1.18 g) in dimethylformamide (15 ml) were stirred for 4 hours at room temperature. 5-Aminotetrazole (1.24 g) was added and the mixture was stirred for 2 days at room temperature. The solid was filtered off and dissolved in a mixture of dimethylformamide and dimethylaminoethanol and the solution was acidified with dilute hydrochloric acid. 4-Chloro-7,8-dimethyl-N(1H-tetrazol-5-yl)quinaldamide was collected, m.p. 262° (d).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:21])=[C:6]([C:8]2[C:9](=[O:20])[N:10]([CH3:19])[C:11]3[C:16]([CH:17]=2)=[CH:15][N:14]=[C:13](Cl)[CH:12]=3)[CH:7]=1.[C:22]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C[Al](C)C.Cl>O1CCOCC1.C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:21])=[C:6]([C:8]2[C:9](=[O:20])[N:10]([CH3:19])[C:11]3[C:16]([CH:17]=2)=[CH:15][N:14]=[C:13]([CH3:22])[CH:12]=3)[CH:7]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: Cc1ccc(N)cc1-c1cc2cnc(Cl)cc2n(C)c1=O
Agent: [Pd]
Agent: C[Al](C)C
Agent: Cl
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Product: Cc1cc2c(cn1)cc(-c1cc(N)ccc1C)c(=O)n2C
Temperature: 150 °C

Procedure:
To a solution of 3-(5-amino-2-methylphenyl)-7-chloro-1-methyl-1,6-naphthyridin-2-one 8 (0.53 mmol) in dioxane (3 mL) is added triphenylphosphine (0.08 mmol), Pd2(dba)3 (16 umol) and trimethylaluminum (0.8 mL of a 2.0 molar solution in toluene). The mixture is degassed for 10 minutes then the reaction vial sealed and heated via microwave for 10 minutes at 150° C. The reaction is cooled to rt and poured into 1M HCl (30 mL) and washed with EtOAc. The aqueous layer is made basic with 3M NaOH and extracted with EtOAc (3×20 mL). The combined organic layers are dried over magnesium sulfate, filtered and reduced to dryness. The crude yellow oil is purified by flash chromatography on silica with dichloromethane 3-5% MeOH as eluant to yield a yellow glassy solid 15. 1H NMR (400 MHz, CDCl3) δ 8.67 (s, 1H), 7.63 (s, 1H), 7.08 (s, 1H), 7.05 (d, J=8.4 Hz, 1H), 6.65 (dd, J=8.4, 2.4 Hz, 1H), 6.57 (d, J=2.4 Hz, 1H), 3.72 (s, 3H), 2.70 (s, 3H), 2.11 (s, 3H). MS (m/z) (M+1)+: 280.1.
Reaction SMILES: [NH2:1][C:2]1[C:14]([C:15]([OH:17])=O)=[C:5]2[N:6]=[C:7]([C:10]([F:13])([F:12])[F:11])[CH:8]=[CH:9][N:4]2[N:3]=1.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][N:23]=[CH:22][C:21]=1[NH2:26].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN1C(=O)CCC1>[NH2:1][C:2]1[C:14]([C:15]([NH:26][C:21]2[CH:22]=[N:23][CH:24]=[CH:25][C:20]=2[O:19][CH3:18])=[O:17])=[C:5]2[N:6]=[C:7]([C:10]([F:11])([F:12])[F:13])[CH:8]=[CH:9][N:4]2[N:3]=1
Reactant: Nc1nn2ccc(C(F)(F)F)nc2c1C(=O)O
Reactant: COc1ccncc1N
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccncc1NC(=O)c1c(N)nn2ccc(C(F)(F)F)nc12
Temperature: 100 °C
Reaction time: 2 h

Procedure:
2-Amino-5-(trifluoromethyl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid 5a (100 mg, 0.4063 mmol), 4-methoxypyridin-3-amine (50.44 mg, 0.4063 mmol) and DIPEA (52.51 mg, 70.77 μL, 0.4063 mmol) were dissolved in dry NMP (812.6 μL) in a microwave tube. TBTU (130.5 mg, 0.4063 mmol) was added in one portion and the resulting mixture was stirred at RT for ˜10 minutes and at 100° C. for ˜2 h under microwave conditions. The reaction mixture was allowed to cool to RT and filtered through a SCX-2 cartridge (5 g). The cartridge was washed with MeOH/DCM and eluted with 2M NH3 in MeOH (3×10 mL). The eluate was concentrated under reduced pressure. The residue was purified by column chromatography on silica (7.5% MeOH in DCM, ˜75 mL) to give the desired Compound I-O-1 as a bright yellow solid (87.9 mg, 61% Yield). LC-MS (M+H)+353.1; 1H NMR (500 MHz, DMSO-d6) δ 9.93 (s, 1H), 9.55 (s, 1H), 9.26 (dd, 1H), 8.24 (dd, 1H), 7.50-7.51 (d, 1H), 7.17-7.18 (d, 1H), 6.99 (s, 2H), 4.00 (s, 3H).