Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][CH:3]=1.[Cl-].[Li+].C([Mg]Cl)(C)C.[CH3:16][CH:17]([CH3:21])[CH2:18][CH:19]=[O:20]>O1CCCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:19]([OH:20])[CH2:18][CH:17]([CH3:21])[CH3:16])=[CH:4][CH:3]=1
Reactant: CC(C)CC=O
Reactant: Brc1ccc(I)cc1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)CC(O)c1ccc(Br)cc1
Temperature: -40 °C
Reaction time: 0.5 h
Yield: 78.8 %

Procedure:
4-bromo-iodobenzene (1.42 g, 5.00 mmol) was dissolved in tetrahydrofuran (50 mL) and cooled to −40° C. A solution of isopropylmagnesium chloride lithium chloride (5 mL, 1.3 M in THF) was added dropwise over 5 minutes. The mixture was stirred at −40° C. for 30 minutes, then 3-methylbutanal (0.81 mL, 7.5 mmol) was added. The reaction was allowed to warm to room temperature and stir for 1 hour. The reaction was then quenched by addition of saturated ammonium chloride (10 mL) and water (40 mL). The mixture was diluted with ethyl acetate (50 mL), and the layers were separated. The organics were washed with water (50 mL) and brine (25 mL), dried over sodium sulfate, filtered and concentrated. Purification by column chromatography (0-50% ethyl acetate in heptane) gave (+/−)-1-(4-bromophenyl)-3-methylbutan-1-ol (958 mg, 79%) as a clear oil. 1H NMR (400 MHz, CDCl3, δ): 7.47-7.41 (m, 2H), 7.22-7.17 (m, 2H), 4.68 (dd, J=8.1, 5.4 Hz, 1H), 1.97 (br.s, 1H), 1.71-1.61 (m, 2H), 1.49-1.39 (m, 1H), 0.94-0.90 (m, 6H).
Reaction SMILES: [F:1][C:2]1([F:24])[CH2:7][CH2:6][CH:5]([CH2:8][NH:9][C:10]([C:12]2[C:13]3[CH:14]=[CH:15][C:16](Cl)=[N:17][C:18]=3[CH:19]=[CH:20][C:21]=2[Cl:22])=[O:11])[CH2:4][CH2:3]1.CC[N:27]([CH:31]([CH3:33])C)[CH:28]([CH3:30])C.N1CC[CH:36]([C@@H:39]([OH:41])C)C1>>[F:1][C:2]1([F:24])[CH2:7][CH2:6][CH:5]([CH2:8][NH:9][C:10]([C:12]2[C:13]3[CH:14]=[CH:15][C:16]([N:27]4[CH2:28][CH2:30][C@@H:33]([CH2:36][CH2:39][OH:41])[CH2:31]4)=[N:17][C:18]=3[CH:19]=[CH:20][C:21]=2[Cl:22])=[O:11])[CH2:4][CH2:3]1
Reactant: C[C@H](O)C1CCNC1
Reactant: O=C(NCC1CCC(F)(F)CC1)c1c(Cl)ccc2nc(Cl)ccc12
Reactant: CCN(C(C)C)C(C)C
Product: O=C(NCC1CCC(F)(F)CC1)c1c(Cl)ccc2nc(N3CC[C@@H](CCO)C3)ccc12

Procedure:
The title compound was synthesized according to the procedure described in example 1 using 2,6-dichloro-quinoline-5-carboxylic acid (4,4-difluoro-cyclohexylmethyl)-amide, DIPEA and (S)-pyrrolidin-3-ylethanol. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.71 (m, 1H), 7.75 (1H), 7.48 (2H), 6.96 (1H), 4.52 (1H), 3.79 (m, 1H), 3.66 (m, 1H), 3.49 (m, 2H), 3.34 (m, 1H), 3.23 (m, 2H), 3.09 (m, 1H), 2.44 (m, 1H), 2.12 (m, 1H), 2.06 (m, 2H), 1.85 (m, 2H), 1.77 (m, 2H), 1.60 (m, 4H), 1.27-1.30 (m, 2H). m/z: 452 [M+H]
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH2:4][CH:5]1[CH2:10][CH2:9][CH:8]([CH:11]=O)[CH2:7][CH2:6]1.[F:14][C:15]([F:51])([F:50])[C:16]1[CH:17]=[C:18]([CH:43]=[C:44]([C:46]([F:49])([F:48])[F:47])[CH:45]=1)[CH2:19][N:20]([C:37]1[O:41][N:40]=[C:39]([CH3:42])[CH:38]=1)[C@H:21]1[CH2:27][CH2:26][CH2:25][NH:24][C:23]2[CH:28]=[C:29]([C:33]([F:36])([F:35])[F:34])[C:30]([CH3:32])=[CH:31][C:22]1=2.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C.ClCCCl.C(Cl)Cl>[CH3:1][O:2][C:3](=[O:13])[CH2:4][CH:5]1[CH2:10][CH2:9][CH:8]([CH2:11][N:24]2[CH2:25][CH2:26][CH2:27][CH:21]([N:20]([CH2:19][C:18]3[CH:43]=[C:44]([C:46]([F:48])([F:49])[F:47])[CH:45]=[C:16]([C:15]([F:14])([F:50])[F:51])[CH:17]=3)[C:37]3[O:41][N:40]=[C:39]([CH3:42])[CH:38]=3)[C:22]3[CH:31]=[C:30]([CH3:32])[C:29]([C:33]([F:36])([F:34])[F:35])=[CH:28][C:23]2=3)[CH2:7][CH2:6]1
Reactant: COC(=O)CC1CCC(C=O)CC1
Reactant: Cc1cc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H]2CCCNc3cc(C(F)(F)F)c(C)cc32)on1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Solvent: ClCCl
Product: COC(=O)CC1CCC(CN2CCCC(N(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)c3cc(C)no3)c3cc(C)c(C(F)(F)F)cc32)CC1
Reaction time: 2 h
Yield: 83.1 %

Procedure:
Add (4-formyl-cyclohexyl)-acetic acid methyl ester (68 mg, 0.368 mmol) to a solution of (S)-(3,5-bis-trifluoromethyl-benzyl)-(3-methyl-isoxazol-5-yl)-(7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl)-amine (80 mg, 0.122 mmol) in acetic acid (0.5 mL) and 1,2-dichloroethane (5 mL) at room temperature under nitrogen and stir for 2 h. Add sodium triacetoxy borohydride (103 mg, 0.488 mmol) and stir for 3 h. Dilute the mixture with methylene chloride (30 mL) and wash with saturated aqueous sodium bicarbonate solution (2×10 mL). Extract the combined aqueous washes with methylene chloride (20 mL) and wash the combined organic extracts with brined (20 mL) and dry over anhydrous sodium sulfate. Remove the solvents under reduced pressure and purify the residue by column chromatography on silica gel, eluting with ethyl acetate/hexanes (1:2), to provide the title compound as a colorless semi-solid (73 mg, 85%). 1H NMR (CDCl3, 300 MHz) δ 0.72-2.34 (m, 21H), 2.60-2.65 (m, 1H), 2.82-2.90 (m, 1H), 3.00-3.10 (m, 2H), 3.89 (s, 3H), 4.60-4.89 (m, 3H), 5.12-5.18 (m, 1H), 6.89 (s, 1H), 7.15 (s, 1H), 7.68-7.71 (m, 3H), 7.82 (s, 1H); ESI MS m/z 720 [C35H38F9N3O3+H]+; HPLC 96.1%, tR 22.1 min.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9](=[O:11])[CH3:10].CO[CH:16](OC)[N:17]([CH3:19])[CH3:18]>>[CH3:16][N:17]([CH3:19])[CH:18]=[CH:10][C:9]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[C:2]([F:12])([F:13])[F:1])=[O:11]
Reactant: CC(=O)c1ccccc1C(F)(F)F
Reactant: COC(OC)N(C)C
Product: CN(C)C=CC(=O)c1ccccc1C(F)(F)F

Procedure:
A mixture of 35 g. of o-trifluoromethylacetophenone in 35 ml. of dimethylformamide dimethylacetal is refluxed for 8 hours under anhydrous conditions and then evaporated to a yellow oil. Bulb to bulb distillation gives the desired product as a thick yellow oil.
Reaction SMILES: [Cl:1][C:2]([Cl:7])=CC(Cl)C.C[Si](C)(C)[O:10][C:11]([O:16][CH2:17][CH3:18])=[CH:12][CH:13]([CH3:15])[CH3:14].[CH2:21](O)[C@H:22](O)[C@H:23]1OC(=O)C(O)=C1O>C(Cl)Cl.[Cl-].[Zn+2].[Cl-]>[Cl:1][C:2]([Cl:7])=[CH:14][CH:13]([CH3:15])[CH:12]([CH:22]([CH3:23])[CH3:21])[C:11]([O:16][CH2:17][CH3:18])=[O:10]
Reactant: CCOC(=CC(C)C)O[Si](C)(C)C
Reactant: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Reactant: CC(Cl)C=C(Cl)Cl
Agent: [Cl-]
Agent: [Zn+2]
Solvent: ClCCl
Product: CCOC(=O)C(C(C)C)C(C)C=C(Cl)Cl
Temperature: 25 °C
Reaction time: 67 h
Yield: 62 %

Procedure:
A 250 ml R.B. flask was equipped with a magnetic stirrer, reflux condenser, and N2 inlet tube. The glassware was dried thoroughly then charged with 23.91 g (0.15 mol) of 1,1,3-trichloro-1-butene, 30.36 g (0.15 mol) of 1-trimethylsilyloxy-1-ethoxy-3-methyl-1-butene, 100 ml of methylene chloride, and ~0.50 g of anhydrous zinc chloride. The reaction mixture was stirred at room temperature and monitored by infrared. The gradual disappearance of the ketene acetal C=C peak at 1675 cm-1 and the appearance of an ester C=O peak at 1720 cm-1 was observed. The reaction mixture after 67 hours showed only a c=O peak at 1720 cm-1 and no 1675 cm-1, and was diluted with 150 ml of methylene chloride, washed with 5×100 ml of 5% sodium bicarbonate solution, then 2×with 50 ml of water. The methylene chloride was dried (MgSO4), stripped, and the residue vacuum distilled through a vigreux column to give 23.41 g (62% yield) of the desired product, b.p. 64°-68° C./0.30 mm.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[CH2:10]([S:13]([O-:15])=[O:14])[CH2:11][CH3:12].[Na+].C(OCC)(=O)C>CS(C)=O.CCCCCC>[CH2:10]([S:13]([C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1)(=[O:15])=[O:14])[CH2:11][CH3:12]
Reactant: CCCS(=O)[O-]
Reactant: O=Cc1ccc(F)cc1
Agent: [Na+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCCS(=O)(=O)c1ccc(C=O)cc1
Temperature: 100 °C
Yield: 53.6 %

Procedure:
4-Fluorobenzaldehyde (3.03 mL, 28.2 mmol) and sodium n-propylsulphinate (4.03 g, 31.0 mmol, synthesised as described in J. Med. Chem. 1989, 32, 2436) were dissolved in dry DMSO and the resulting solution heated at 100° C. for 18 h. The mixture was allowed to cool and then poured onto approximately 50 g of ice. After the ice had melted, the product was extracted into ethyl acetate (×2). The combined organic extracts were dried (MgSO4) and concentrated. Chromatography on silica eluting with 20 to 40% ethyl acetate in hexane afforded the product as a white solid (3.21 g, 54% yield). 1H NMR (400 MHz, CDCl3) 1.02 (3H, t, J=7.5 Hz), 1.72-1.82 (2H, m), 3.10-3.14 (2H, m), 8.07-8.11 (4H, m), 10.14 (1H, s).
Reaction SMILES: Cl.[NH2:2][C:3]1[C:12]2[CH:11]=[C:10]([CH3:13])[S:9][C:8]=2[NH:7][C:6]2[CH:14]=[CH:15][C:16]([C:18]#[N:19])=[CH:17][C:5]=2[N:4]=1.[CH3:20][N:21]1[CH2:26][CH2:25]N[CH2:23][CH2:22]1>CS(C)=O.C1(C)C=CC=CC=1>[CH3:13][C:10]1[S:9][C:8]2[NH:7][C:6]3[CH:14]=[CH:15][C:16]([C:18]#[N:19])=[CH:17][C:5]=3[N:4]=[C:3]([N:2]3[CH2:25][CH2:26][N:21]([CH3:20])[CH2:22][CH2:23]3)[C:12]=2[CH:11]=1
Reactant: Cc1cc2c(s1)Nc1ccc(C#N)cc1N=C2N
Reactant: CN1CCNCC1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CS(C)=O
Product: Cc1cc2c(s1)Nc1ccc(C#N)cc1N=C2N1CCN(C)CC1
Temperature: 130 °C

Procedure:
To a solution of 10-amino-2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulene-7-carbonitrile hydrochloride, prepared as described in the previous step, (0.6 g) in DMSO (6 mL) and toluene (6 mL), was added 1-methylpiperazine (4 mL). The mixture was heated in a 130° C. oil bath for 17 hours. The solution was concentrated, diluted with ethyl acetate (50 mL), washed with water (20 mL) and brine (20 mL), and then concentrated. The solid was dissolved in dichloromethane (10 mL) and treated with saturated sodium bicarbonate solution. The title compound was collected as a light yellow precipitate, washed with water and dichloromethane, dried, and used in the next step without additional purification. LC-MS: m/z 338 (M+1). 1H NMR (CD3OD, 400 MHz): δ (ppm) 7.19-7.15 (m, 2H), 6.74 (d, 1H), 6.37 (s, 1H), 3.51 (m, 4H), 2.53 (m, 4H), 2.34 (s, 3H), 2.32 (s, 3H).
Reaction SMILES: [O:1]=[C:2]1[CH:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[CH:4][NH:3]1.C([O-])([O-])=O.[K+].[K+].C1[CH2:22][O:21][CH2:20][CH2:19]1.Br[CH2:24][CH2:25][O:26][CH3:27]>CN(C=O)C>[CH3:22][O:21][CH2:20][CH2:19][N:3]1[CH:4]=[CH:5][C:6]([C:8]([O:10][CH3:11])=[O:9])=[CH:7][C:2]1=[O:1].[CH3:27][O:26][CH2:25][CH2:24][O:1][C:2]1[CH:7]=[C:6]([CH:5]=[CH:4][N:3]=1)[C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)c1cc[nH]c(=O)c1
Reactant: C1CCOC1
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COCCOc1cc(C(=O)OC)ccn1
Product: COCCn1ccc(C(=O)OC)cc1=O
Yield: 44 %

Procedure:
Methyl 2-oxo-1H-pyridine-4-carboxylate (2.00 g, 13.1 mmol), K2CO3 (3.61 g, 26.1 mmol), THF (48 mL), DMF (38 mL) and 1-bromo-2-methoxy-ethane (3.63 g, 2.45 mL, 26.1 mmol) were combined and the mixture was stirred at 80° C. for 2d. The reaction was filtered using ethyl acetate and the solvent was evaporated under reduced pressure and the residue was purified by column chromatography on silica gel (0-100% ethyl acetate in hexane) to yield methyl 1-(2-methoxyethyl)-2-oxo-1,2-dihydropyridine-4-carboxylate[(1.22 g, 44%), ESI-MS m/z calc. 211.1, found 212.3 (M+1)+; Retention time: 0.57 minutes (3 min run); 1H NMR (400 MHz, DMSO) δ 8.35 (d, J=5.2 Hz, 1H), 7.41 (d, J=5.2 Hz, 1H), 7.21 (s, 1H), 4.47-4.36 (m, 2H), 3.89 (s, 3H), 3.71-3.64 (m, 2H), 3.30 (s, 3H)] and methyl 2-(2-methoxyethoxy)isonicotinate[(405 mg), ESI-MS m/z calc. 211.1, found 212.1 (M+1)+; Retention time: 1.04 minutes (3 min run); 1H NMR (400 MHz, DMSO) δ 7.75 (d, J=7.0 Hz, 1H), 6.86 (s, 1H), 6.55 (d, J=7.0 Hz, 1H), 4.09 (t, J=5.2 Hz, 2H), 3.85 (s, 3H), 3.58 (t, J=5.2 Hz, 2H), 3.23 (s, 3H)].
Reaction SMILES: Br[C:2]1[CH2:6][O:5][C:4](=[O:7])[CH:3]=1.CCN(C(C)C)C(C)C.[CH2:17]1[C:22]2([CH2:27][CH2:26][CH2:25][NH:24][CH2:23]2)[CH2:21][CH2:20][N:19]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:18]1>C1COCC1>[O:7]=[C:4]1[O:5][CH2:6][C:2]([N:24]2[CH2:25][CH2:26][CH2:27][C:22]3([CH2:17][CH2:18][N:19]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:20][CH2:21]3)[CH2:23]2)=[CH:3]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCCNC2)CC1
Reactant: O=C1C=C(Br)CO1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC2(CCCN(C3=CC(=O)OC3)C2)CC1
Temperature: 76 °C
Reaction time: 8 h

Procedure:
To commercially available 4-bromofuran-2(5H)-one (128 mg, 0.786 mmol) in THF (4 mL) was added Hunig's Base (275 μL, 1.57 mmol) and tert-butyl 3,8-diazaspiro[5,5]undecane-3-carboxylate (200 mg, 0.786 mmol). The reaction mixture was stirred at 76° C. overnight, concentrated and purified by column chromatography (0-10% MeOH in DCM) to afford the title compound. LCMS: [(M+1)]+=337
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][C:9]2=[N:12]O)=[CH:4][CH:3]=1.[C:14]1([N:20]2[C:24]3([CH2:29][CH2:28]N[CH2:26][CH2:25]3)[C:23](=[O:30])[NH:22][CH2:21]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[ClH:1].[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][CH:9]2[N:12]2[CH2:28][CH2:29][C:24]3([N:20]([C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=4)[CH2:21][NH:22][C:23]3=[O:30])[CH2:25][CH2:26]2)=[CH:4][CH:3]=1
Reactant: O=C1NCN(c2ccccc2)C12CCNCC2
Reactant: ON=C1CCCc2ccc(Cl)cc21
Product: Cl
Product: O=C1NCN(c2ccccc2)C12CCN(C1CCCc3ccc(Cl)cc31)CC2

Procedure:
The title compound, m.p.>250° C. and MS: m/e=396.2 (M+H+) was prepared in accordance with the general method of example 11 from 7-chloro-3,4-dihydro-1(2H)-naphthalenone oxime and 1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one.
Reaction SMILES: [Cl:1][CH2:2][C:3]([N:5]1[CH2:10][C:9]([CH3:11])=[C:8]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[N:7]2[N:19]=[CH:20][C:21]([C:22]#[N:23])=[C:6]12)=[O:4].C(=O)([O-])[O-].[Na+].[Na+].[CH3:30][O:31][C:32]1[CH:33]=[C:34]([CH:42]=[CH:43][CH:44]=1)[CH2:35][N:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1.[OH-].[Na+]>C1(C)C=CC=CC=1>[ClH:1].[ClH:1].[Cl:18][C:14]1[CH:13]=[C:12]([C:8]2[N:7]3[N:19]=[CH:20][C:21]([C:22]#[N:23])=[C:6]3[N:5]([C:3](=[O:4])[CH2:2][N:39]3[CH2:38][CH2:37][N:36]([CH2:35][C:34]4[CH:42]=[CH:43][CH:44]=[C:32]([O:31][CH3:30])[CH:33]=4)[CH2:41][CH2:40]3)[CH2:10][C:9]=2[CH3:11])[CH:17]=[CH:16][CH:15]=1
Reactant: CC1=C(c2cccc(Cl)c2)n2ncc(C#N)c2N(C(=O)CCl)C1
Reactant: COc1cccc(CN2CCNCC2)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: COc1cccc(CN2CCN(CC(=O)N3CC(C)=C(c4cccc(Cl)c4)n4ncc(C#N)c43)CC2)c1
Product: Cl
Reaction time: 18 h

Procedure:
A mixture of 2.7 g of 4-(chloroacetyl)-7-(3-chlorophenyl)-4,5-dihydro-6-methylpyrazolo[1,5-a]pyrimidine-3-carbonitrile, 920 mg of sodium carbonate and 1.7 g of 3-methoxybenzyl piperazine in 100 ml of toluene was stirred for 18 hours, then treated with 25 ml of 1N sodium hydroxide and shaken. The layers were separated and the alkaline layer extracted with chloroform. This extract and the toluene layer were combined, washed with water dried, filtered and concentrated. The residual oil was triturated in ether then concentrated and dissolved with heating in 25 ml of ethanol. A 10 ml portion of 2.44 N ethanolic hydrochloric acid and an excess of ether were added and the solid was collected. This solid was crystallized from hot acetonitrile giving 1.4 g of the desired product, mp 195°-197° C.
Reaction SMILES: [C:1]([C:3]1[N:4]=[C:5]([NH:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:6](=[O:22])[N:7]([C:9]2[CH:10]=[C:11]([CH:18]=[CH:19][C:20]=2[CH3:21])[C:12]([NH:14][CH:15]2[CH2:17][CH2:16]2)=[O:13])[CH:8]=1)#[N:2].N.[OH:32]O.O>CO>[CH:15]1([NH:14][C:12]([C:11]2[CH:18]=[CH:19][C:20]([CH3:21])=[C:9]([N:7]3[C:6](=[O:22])[C:5]([NH:23][CH2:24][C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)=[N:4][C:3]([C:1]([NH2:2])=[O:32])=[CH:8]3)[CH:10]=2)=[O:13])[CH2:16][CH2:17]1
Reactant: OO
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-n1cc(C#N)nc(NCc2ccccc2)c1=O
Agent: N
Solvent: O
Solvent: CO
Product: Cc1ccc(C(=O)NC2CC2)cc1-n1cc(C(N)=O)nc(NCc2ccccc2)c1=O
Reaction time: 12 h

Procedure:
To a stirred solution of 3-[5-cyano-2-oxo-3-[(phenylmethyl)amino]-1(2H)-pyrazinyl]-N-cyclopropyl-4-methyl-benzamide (Example 104, 100 mg) in methanol (1 mL) was added conc. ammonia solution (1 mL) followed by 30% hydrogen peroxide solution (1 mL). After 12 h, water was added and the mixture was extracted with dichloromethane. The pooled organics were washed with brine, dried (MgSO4), filtered and the solvent removed. Purification by preparative HPLC (Gemini column, 0.1% ammonia: acetonitrile eluent) afforded the title compound (31 mg).
Reaction SMILES: [CH3:1][C:2]([CH3:8])([CH3:7])[CH2:3][C:4](Cl)=[O:5].[Br:9][C:10]1[CH:15]=[CH:14][C:13](N)=[C:12]([C:17]([F:20])([F:19])[F:18])[CH:11]=1.O.C(#[N:24])C>>[Br:9][C:10]1[CH:15]=[CH:14][C:13]([CH:3]([C:2]([CH3:8])([CH3:7])[CH3:1])[C:4]([NH2:24])=[O:5])=[C:12]([C:17]([F:18])([F:19])[F:20])[CH:11]=1
Reactant: CC#N
Reactant: Nc1ccc(Br)cc1C(F)(F)F
Reactant: CC(C)(C)CC(=O)Cl
Solvent: O
Product: CC(C)(C)C(C(N)=O)c1ccc(Br)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 79 %

Procedure:
3,3-Dimethylbutanoyl chloride (617 mg, 0.64 mL, 4.6 mmol) was added to a solution of 4-Bromo-2-trifluoromethyl-phenylamine (1.0 g, 4.16 mmol) in acetonitrile (10 mL). The reaction mixture was stirred at room temperature overnight. Water was added to the mixture and the precipitate formed collected to give the title compound as a powder (1.1 g, 79% yield).
Reaction SMILES: Cl[C:2]1[C:11]2[N:10]=[C:9]([CH3:12])[CH:8]=[CH:7][C:6]=2[C:5](B(O)O)=[CH:4][N:3]=1.Br[C:17]1[N:21]([CH3:22])[CH:20]=[N:19][CH:18]=1.[NH2:23][C:24]1[N:25]=[C:26]([CH3:29])[S:27][CH:28]=1>>[CH3:12][C:9]1[CH:8]=[CH:7][C:6]2[C:11](=[C:2]([NH:23][C:24]3[N:25]=[C:26]([CH3:29])[S:27][CH:28]=3)[N:3]=[CH:4][C:5]=2[C:17]2[N:21]([CH3:22])[CH:20]=[N:19][CH:18]=2)[N:10]=1
Reactant: Cc1ccc2c(B(O)O)cnc(Cl)c2n1
Reactant: Cn1cncc1Br
Reactant: Cc1nc(N)cs1
Product: Cc1ccc2c(-c3cncn3C)cnc(Nc3csc(C)n3)c2n1

Procedure:
The title compound, MS: m/e=337.3 (M+H+), was prepared in accordance with the general method of example 15 step 1 and step 3 from 8-chloro-2-methyl-[1,7]naphthyridine-5-boronic acid (Example L), 5-bromo-1-methyl-1H-imidazole and 4-amino-2-methylthiazole (Example F).
Reaction SMILES: Cl[C:2]1[C:7]2[C:8]([CH3:16])=[N:9][C:10]3[N:11]([N:12]=[C:13]([CH3:15])[CH:14]=3)[C:6]=2[N:5]=[CH:4][C:3]=1[C:17]([O:19][CH2:20][CH3:21])=[O:18].[NH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>>[CH3:15][C:13]1[CH:14]=[C:10]2[N:9]=[C:8]([CH3:16])[C:7]3[C:2]([N:22]4[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]4)=[C:3]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:4]=[N:5][C:6]=3[N:11]2[N:12]=1
Reactant: C1CCNCC1
Reactant: CCOC(=O)c1cnc2c(c(C)nc3cc(C)nn32)c1Cl
Product: CCOC(=O)c1cnc2c(c(C)nc3cc(C)nn32)c1N1CCCCC1
Yield: 88 %

Procedure:
When 6-chloro-2,5-dimethylpyrazolo[1,5-a]pyrido[3,2-e]pyrimidine-7-carboxylic acid, ethyl ester of Example 1c is treated with piperidine according to the procedure of Example 1d, 2,5-dimethyl-6-(1-piperidinyl)-pyrazolo[1,5-a]pyrido[3,2-e]pyrimidine-7-carboxylic acid, ethyl ester is obtained, yield 88%, m.p. 161°-163° (ethyl acetate).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH:11]=[CH2:12].C([O-])(=[S:15])C.C(O)(=S)C>C1(C)C=CC=CC=1>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][SH:15]
Reactant: CC([O-])=S
Reactant: C=CCCCCCCCCCBr
Agent: CC(O)=S
Solvent: Cc1ccccc1
Product: SCCCCCCCCCCCBr
Temperature: 25 °C
Reaction time: 6 h

Procedure:
11-Bromo-1-undecanethiol was synthesized in two steps (see FIG. 11). First, 11-bromo-1-undecene (5.0 g) was converted to a thioacetate by reacting with AiBN (1.5 g) and thioacetic acid (10 mL) in toluene (50 mL). The reaction was run under Ar and refluxed for 2 h. The solution was washed with excess water and the toluene removed by rotary evaporation. The thioacetate was converted into a thiol by exposing the 11-bromo-1-undecanethioacetate to dry HCl. Acetyl chloride (6 mL) was added dropwise to dry methanol in an ice bath under Ar. The solution was allowed to warm to room temperature and the reaction progressed for approximately 6 h. Methylene chloride and water were added and the methylene chloride layer was washed several times with water. The solvent was removed by rotary evaporation.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[CH3:28][N:29]1[C:33]([C:34]([OH:36])=O)=[CH:32][C:31]([CH3:37])=[N:30]1.C(N(C(C)C)CC)(C)C.[CH3:47][O:48][C:49]1[CH:50]=[C:51]([NH:59][C:60]2[N:61]=[CH:62][C:63]3[CH2:69][NH:68][CH2:67][CH2:66][C:64]=3[N:65]=2)[CH:52]=[C:53]([O:57][CH3:58])[C:54]=1[O:55][CH3:56]>CN(C=O)C.CCOC(C)=O>[CH3:28][N:29]1[C:33]([C:34]([N:68]2[CH2:67][CH2:66][C:64]3[N:65]=[C:60]([NH:59][C:51]4[CH:50]=[C:49]([O:48][CH3:47])[C:54]([O:55][CH3:56])=[C:53]([O:57][CH3:58])[CH:52]=4)[N:61]=[CH:62][C:63]=3[CH2:69]2)=[O:36])=[CH:32][C:31]([CH3:37])=[N:30]1
Reactant: Cc1cc(C(=O)O)n(C)n1
Reactant: COc1cc(Nc2ncc3c(n2)CCNC3)cc(OC)c1OC
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cc(Nc2ncc3c(n2)CCN(C(=O)c2cc(C)nn2C)C3)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 52 %

Procedure:
A solution of (Benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (0.035 g, 0.079 mmol) in anhydrous DMF (2 mL) was treated sequentially with 1,3-dimethyl-1H-pyrazole-5-carboxylic acid (0.014 g, 0.103 mmol) and diisopropylethylamine (0.035 mL, 0.159 mmol). The reaction mixture was allowed to stir for 30 minutes at room temperature. After 30 minutes, N-(3,4,5-trimethoxyphenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-amine, Intermediate 1 (0.025 g, 0.079 mmol) was added to the reaction mixture. The reaction was allowed to stir for 3 hours at room temperature. The reaction mixture was then diluted with EtOAc and washed three times with brine. The combined aqueous layers were then washed twice with EtOAc. The organic layers were combined, dried over anhydrous Na2SO4(s), filtered and concentrated in vacuo. The crude product was then purified over silica using a MeOH/CHCl3 gradient affording the final product in 52% yield (0.018 g, 0.041 mmol).
Reaction SMILES: C[O:2][C:3](=[O:34])[CH2:4][NH:5][C:6]([C:8]1[S:9][C:10]([C:16]2[CH2:20][C:19]([C:25]3[CH:30]=[C:29]([Cl:31])[C:28]([F:32])=[C:27]([Cl:33])[CH:26]=3)([C:21]([F:24])([F:23])[F:22])[O:18][N:17]=2)=[C:11]2[CH2:15][CH2:14][CH2:13][C:12]=12)=[O:7].O[Li].O>C1COCC1.O>[Cl:31][C:29]1[CH:30]=[C:25]([C:19]2([C:21]([F:22])([F:24])[F:23])[O:18][N:17]=[C:16]([C:10]3[S:9][C:8]([C:6]([NH:5][CH2:4][C:3]([OH:34])=[O:2])=[O:7])=[C:12]4[CH2:13][CH2:14][CH2:15][C:11]=34)[CH2:20]2)[CH:26]=[C:27]([Cl:33])[C:28]=1[F:32]
Reactant: COC(=O)CNC(=O)c1sc(C2=NOC(c3cc(Cl)c(F)c(Cl)c3)(C(F)(F)F)C2)c2c1CCC2
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)CNC(=O)c1sc(C2=NOC(c3cc(Cl)c(F)c(Cl)c3)(C(F)(F)F)C2)c2c1CCC2

Procedure:
Stir a mixture of ({3-[5-(3,5-Dichloro-4-fluoro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-5,6-dihydro-4H-cyclopenta[c]thiophene-1-carbonyl}-amino)-acetic acid methyl ester (11 g, 18.6 mmol) and LiOH—H2O (1.56 g, 37.2 mmol) in THF (100 mL) and water (50 mL) at room temperature for overnight. After being checked with TLC, the solvent is removed under vacuum, dilute the residue with water (50 mL). Acidify the aqueous mixture with 2M HCl to pH=3, and extract the resultant mixture with EtOAc (100 mL×3), the combined organic layer is washed with brine, dried over anhydrous Na2SO4 and concentrated under vacuum, the residue is purified by silica gel chromatograph (PE:EtOAc 1:1) to afford ({3-[5-(3,5-Dichloro-4-fluoro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-5,6-dihydro-4H-cyclopenta[c]thiophene-1-carbonyl}-amino)-acetic acid as a white solid (10.2 g, 90.7% for two steps). MS (m/z): 525 (M+1).