Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.[O:35]1[CH2:40][CH2:39][N:38]([C:41]2[C:46]([NH2:47])=[CH:45][C:44]([N:48]3[CH2:53][CH2:52][O:51][CH2:50][CH2:49]3)=[CH:43][N:42]=2)[CH2:37][CH2:36]1.Cl[C:55]1[C:64]2[C:59](=[CH:60][C:61]([F:66])=[CH:62][C:63]=2[F:65])[N:58]=[C:57]([C:67]2[CH:68]=[N:69][C:70]([N:73]3[CH2:78][CH2:77][CH2:76][CH2:75][CH2:74]3)=[CH:71][CH:72]=2)[C:56]=1[CH3:79].CC(C)([O-])C.[Na+]>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]>[O:35]1[CH2:40][CH2:39][N:38]([C:41]2[C:46]([NH:47][C:55]3[C:64]4[C:59](=[CH:60][C:61]([F:66])=[CH:62][C:63]=4[F:65])[N:58]=[C:57]([C:67]4[CH:68]=[N:69][C:70]([N:73]5[CH2:74][CH2:75][CH2:76][CH2:77][CH2:78]5)=[CH:71][CH:72]=4)[C:56]=3[CH3:79])=[CH:45][C:44]([N:48]3[CH2:49][CH2:50][O:51][CH2:52][CH2:53]3)=[CH:43][N:42]=2)[CH2:37][CH2:36]1
Reactant: Cc1c(-c2ccc(N3CCCCC3)nc2)nc2cc(F)cc(F)c2c1Cl
Reactant: Nc1cc(N2CCOCC2)cnc1N1CCOCC1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: Cc1ccccc1
Product: Cc1c(-c2ccc(N3CCCCC3)nc2)nc2cc(F)cc(F)c2c1Nc1cc(N2CCOCC2)cnc1N1CCOCC1

Procedure:
The Buchwald coupled product was prepared according to Procedure S using dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (0.020 g, 0.043 mmol), 2,5-dimorpholinopyridin-3-amine (0.085 g, 0.32 mmol), 4-chloro-5,7-difluoro-3-methyl-2-(6-(piperidin-1-yl)pyridin-3-yl)quinoline (0.1 g, 0.268 mmol), Pd2dba3 (0.010 g, 0.011 mmol) and sodium tert-butoxide (0.064 g, 0.67 mmol) in toluene (2.7 mL) at 100° C. for 19 h. The crude product was purified by column chromatography on basic alumina (0 to 50% hexanes/EtOAc) to give the desired product N-(2,5-dimorpholinopyridin-3-yl)-5,7-difluoro-3-methyl-2-(6-(piperidin-1-yl)-pyridin-3-yl)quinolin-4-amine. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.44 (1H, dd, J=2.5, 0.4 Hz), 7.84 (1H, dd, J=8.9, 2.4 Hz), 7.74 (1H, d, J=6.3 Hz), 7.59 (1H, m), 7.55 (1H, d, J=2.7 Hz), 7.36-7.44 (1H, m), 6.94 (1H, d, J=9.0 Hz), 6.40 (1H, d, J=2.7 Hz), 3.78-3.59 (12H, m), 3.13 (2H, br. s.), 2.94-3.04 (4H, m), 2.84 (2H, br. s.), 2.13 (3H, s), 1.64 (2H, m), 1.57 (4H, m). Mass Spectrum (ESI) m/e=602.3 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]([C:14]3[CH:19]=[CH:18]C=CN=3)[N:12]=[C:11]([C:20]([OH:22])=[O:21])[CH:10]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.Cl.[Cl:24][C:25]1[CH:30]=C(NN)C=C[N:26]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]([C:14]3[CH:19]=[CH:18][N:26]=[C:25]([Cl:24])[CH:30]=3)[N:12]=[C:11]([C:20]([OH:22])=[O:21])[CH:10]=2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: O=C(O)c1cc(-c2cc(F)cc(Cl)c2)n(-c2ccccn2)n1
Reactant: NNc1ccnc(Cl)c1
Agent: Cl
Product: O=C(O)c1cc(-c2cc(F)cc(Cl)c2)n(-c2ccnc(Cl)c2)n1

Procedure:
807 mg (2.90 mmol) of the compound of Example 1A is reacted analogously to the synthesis of the compound of Example 20A with 574 mg (3.19 mmol) of 2-chloropyridin-4-yl-hydrazine hydrochloride. After hydrolysis, 248 mg (24% of theory) of the title compound is obtained.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([N+:10]([O-:12])=[O:11])=[CH:5][N:4]=1)#[N:2].[CH3:13][N:14]([CH:16]=O)[CH3:15]>>[C:1]([C:3]1[CH:8]=[C:7]([CH:9]=[CH:13][N:14]([CH3:16])[CH3:15])[C:6]([N+:10]([O-:12])=[O:11])=[CH:5][N:4]=1)#[N:2]
Reactant: Cc1cc(C#N)ncc1[N+](=O)[O-]
Reactant: CN(C)C=O
Product: CN(C)C=Cc1cc(C#N)ncc1[N+](=O)[O-]

Procedure:
A stirred solution of 2-cyano-4-methyl-5-nitropyridine (2.48 g, 15.2 mmol) in DMF (10 mL) and DMF-dimethylacetal (2.7 mL, 20 mmol) was heated to 90° C. for two h. The solution was cooled and evaporated in vacuo to give the title compound as a deep red solid:
Reaction SMILES: [Cl:1][CH2:2][C:3]([N:5]1[C@@H:13]([C:14]#[C:15][Si](C)(C)C)[CH2:12][CH2:11][C@H:6]1[C:7]([O:9]C)=[O:8])=[O:4].O[Li].O>CO.O>[Cl:1][CH2:2][C:3]([N:5]1[C@@H:13]([C:14]#[CH:15])[CH2:12][CH2:11][C@H:6]1[C:7]([OH:9])=[O:8])=[O:4]
Reactant: COC(=O)[C@@H]1CC[C@H](C#C[Si](C)(C)C)N1C(=O)CCl
Agent: [Li]O
Solvent: O
Solvent: CO
Product: C#C[C@H]1CC[C@@H](C(=O)O)N1C(=O)CCl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of methyl (5R)-1-(chloroacetyl)-5-((trimethylsilyl)ethynyl)-L-prolinate (3.69 g, 12.2 mmol) in MeOH (24 mL) and H2O (24 mL) at room temperature was added LiOH•H2O (0.8 g, 18 mmol). The reaction mixture was stirred at ambient temperature overnight and concentrated under reduced pressure. The residue was taken up in water and extracted with diethyl ether (2×). The aqueous layer was acidified to pH˜3 by adding 4% KHSO4 dropwise. The solution was extracted with ethyl acetate (3×). Combined ethyl acetate layers were washed with brine, dried (Na2SO4), filtered and concentrated under reduced pressure to provide the titled compound. MS (CI) m/z 216 (M+1)+.
Reaction SMILES: Cl.[NH2:2][OH:3].C(=O)([O-])[O-].[K+].[K+].[CH3:10][O:11][C:12]1[CH:17]=[C:16]([O:18][CH3:19])[N:15]=[C:14]([O:20][C:21]2[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=2[CH:23]=O)[N:13]=1>O.CO>[CH3:10][O:11][C:12]1[CH:17]=[C:16]([O:18][CH3:19])[N:15]=[C:14]([O:20][C:21]2[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=2[CH:23]=[N:2][OH:3])[N:13]=1
Reactant: NO
Reactant: COc1cc(OC)nc(Oc2ccccc2C=O)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: COc1cc(OC)nc(Oc2ccccc2C=NO)n1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 56 %

Procedure:
3.5 g of hydroxylamine hydrochloride were added to 100 ml of a 1:1 mixed solution of water and methanol containing 3.5 g of potassium carbonate at 0° C. The solution was stirred at 0° C. for 10 minutes. At 0° C., 13.0 g of 2-(4,6-dimethoxy-2-pyrimidinyloxy)benzaldehyde were added to the reaction mixture. The resulting mixture was stirred at room temperature for 1 hour and then warmed at 60° C. for 1 hour. After the reaction mixture was allowed to cool down, it was poured into water, followed by extraction with ethyl acetate. The organic layer was desired over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel chromatography (developer: n-hexane:ethyl acetate=5:1) to obtain 7.7 g of 2-(4,6-dimethoxy-2-pyrimidinyloxy)benzaldoxime.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[NH:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.Br[CH2:17][CH:18](F)[F:19]>>[F:19]/[CH:18]=[CH:17]/[N:13]1[CH:14]=[C:10]([C:9]#[C:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([CH3:1])[CH:7]=2)[N:11]=[C:12]1[CH3:15]
Reactant: FC(F)CBr
Reactant: Cc1cc(C#Cc2c[nH]c(C)n2)ccn1
Product: Cc1cc(C#Cc2cn(/C=C/F)c(C)n2)ccn1

Procedure:
The title compound, MS: m/e=242.3 (M+H+), was prepared in accordance with the general method of example 1 from 2-methyl-4-(2-methyl-1H-imidazol-4-ylethynyl)-pyridine and 2-bromo-1,1-difluoro ethane as a by-product.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][CH:6]=[CH:5][C:4]=1[C:11]1[C:12]2[N:13]([N:17]=[C:18]([NH:20][C:21]3[CH:26]=[CH:25][C:24]([CH:27]4[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]4)=[CH:23][CH:22]=3)[N:19]=2)[CH:14]=[CH:15][CH:16]=1.Cl[CH2:34][C:35]([N:37]([CH3:39])[CH3:38])=[O:36]>>[CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][CH:6]=[CH:5][C:4]=1[C:11]1[C:12]2[N:13]([N:17]=[C:18]([NH:20][C:21]3[CH:26]=[CH:25][C:24]([CH:27]4[CH2:32][CH2:31][N:30]([CH2:34][C:35]([N:37]([CH3:39])[CH3:38])=[O:36])[CH2:29][CH2:28]4)=[CH:23][CH:22]=3)[N:19]=2)[CH:14]=[CH:15][CH:16]=1
Reactant: COc1cccc(-c2cccn3nc(Nc4ccc(C5CCNCC5)cc4)nc23)c1OC
Reactant: CN(C)C(=O)CCl
Product: COc1cccc(-c2cccn3nc(Nc4ccc(C5CCN(CC(=O)N(C)C)CC5)cc4)nc23)c1OC

Procedure:
2-(4-{4-[8-(2,3-Dimethoxy-phenyl)-[1,2,4]-triazolo[1,5-a]pyridin-2-ylamino]-phenyl}-piperidin-1-yl)-N,N-dimethyl-acetamide was prepared from [8-(2,3-dimethoxy-phenyl)-[1,2,4]-triazolo[1,5-a]pyridin-2-yl]-(4-piperidin-4-yl-phenyl)-amine (0.188 g, 0.438 mmol) and 2-chloro-N,N-dimethyl-acetamide (0.067 mL, 0.656 mmol) in a manner analogous to Example 313 to give product (0.050 g, 22%). MP=222-223° C. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.54 (s, 1H), 8.77 (d, 1H), 7.52 (m, 3H), 7.10 (m, 6H), 3.87 (s, 3H), 3.59 (s, 3H), 3.15 (s, 2H), 3.05 (s, 3H), 2.90 (m, 2H), 2.80 (s, 3H), 2.40 (m, 1H), 2.12 (m, 2H), 1.65 (m, 4H). MS=515 (MH)+.
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][C:6]([O:9][C:10]([F:13])([F:12])[F:11])=[CH:5][CH:4]=1.[B:14](OC(C)C)([O:19]C(C)C)[O:15]C(C)C.Cl>C1COCC1.BrC1C=CC(OC(F)(F)F)=CC=1>[F:11][C:10]([F:13])([F:12])[O:9][C:6]1[CH:7]=[CH:8][C:3]([B:14]([OH:19])[OH:15])=[CH:4][CH:5]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: FC(F)(F)Oc1ccc(Br)cc1
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Product: OB(O)c1ccc(OC(F)(F)F)cc1
Temperature: 0 °C

Procedure:
A mixture of magnesium (3.25 g) in THF (25 mL) at room temperature was treated with several drops of 1-bromo-4-(trifluoromethoxy)benzene, stirred for several minutes, treated with THF (100 mL), treated with 1-bromo-4-(trifluoromethoxy)benzene (30.8 g), heated to reflux, stirred for 16 hours, treated with triisopropyl borate (34 mL) over 10 minutes, stirred for 1 hour, cooled to 0° C., treated with 6M HCl (50 mL), stirred for 45 minutes, and extracted with isopropyl acetate. The extract was washed with brine, filtered, and concentrated to provide 21.5 g of 4-(trifluoromethoxy)phenylboronic acid.
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[C:7]2[CH:8]=[CH:9][C:10]([C:12]([CH3:25])=[CH:13][C:14]3[CH:24]=[CH:23][C:17]([C:18]([O:20]CC)=[O:19])=[CH:16][CH:15]=3)=[CH:11][C:6]=2[S:5][CH2:4][CH2:3]1.[OH-].[K+].Cl>C(O)C.O>[CH3:1][C:2]1([CH3:26])[C:7]2[CH:8]=[CH:9][C:10]([C:12]([CH3:25])=[CH:13][C:14]3[CH:15]=[CH:16][C:17]([C:18]([OH:20])=[O:19])=[CH:23][CH:24]=3)=[CH:11][C:6]=2[S:5][CH2:4][CH2:3]1
Reactant: CCOC(=O)c1ccc(C=C(C)c2ccc3c(c2)SCCC3(C)C)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(=Cc1ccc(C(=O)O)cc1)c1ccc2c(c1)SCCC2(C)C
Temperature: 50 °C
Yield: 65 %

Procedure:
1 g of the thus-obtained ester was dissolved in 20 ml of ethanol and treated with a solution of 1.6 g of potassium hydroxide in 10 ml of water. After heating to 50° C. for 2 hours, the mixture was poured on to ice, acidified with 2N hydrochloric acid and extracted repeatedly with ethyl acetate. The crystalline residue obtained after evaporation was recrystallized from acetic acid. There was obtained 0.6 g of p-[2-(3,4-dihydro-4,4-dimethyl-2H-1 -benzothiopyran-7-yl)propenyl]benzoic acid, m.p. 255°-257° C.
Reaction SMILES: [CH3:1][S:2][C:3]1[N:4]=[CH:5][C:6]2[C:15](=[O:16])[N:14]([C:17]3[CH:18]=[C:19]([C:23]4[N:27]=[C:26]([C:28]([O:30]C)=O)[O:25][N:24]=4)[CH:20]=[CH:21][CH:22]=3)[CH2:13][C@H:12]3[N:8]([CH2:9][CH2:10][CH2:11]3)[C:7]=2[N:32]=1.[NH3:33].CO>CO>[CH3:1][S:2][C:3]1[N:4]=[CH:5][C:6]2[C:15](=[O:16])[N:14]([C:17]3[CH:18]=[C:19]([C:23]4[N:27]=[C:26]([C:28]([NH2:33])=[O:30])[O:25][N:24]=4)[CH:20]=[CH:21][CH:22]=3)[CH2:13][C@H:12]3[N:8]([CH2:9][CH2:10][CH2:11]3)[C:7]=2[N:32]=1
Reactant: COC(=O)c1nc(-c2cccc(N3C[C@@H]4CCCN4c4nc(SC)ncc4C3=O)c2)no1
Reactant: N
Solvent: CO
Product: CSc1ncc2c(n1)N1CCC[C@H]1CN(c1cccc(-c3noc(C(N)=O)n3)c1)C2=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 96.6 %

Procedure:
Methyl (S)-3-[3-(9-methylthio-6-oxo-2,3,3a,4-tetrahydro-1H,6H-5,8,10,10b-tetraazabenzo[e]azulen-5-yl)phenyl]-1,2,4-oxadiazole-5-carboxylate (320 mg, 0.71 mmol) obtained in Step 1 of Example 80 was dissolved in methanol (3.0 mL), and the mixture was stirred at room temperature for 3 hours after adding a 2.0 mol/L ammonia/methanol solution (3.50 mL, 7.07 mmol). The residue obtained by concentrating the mixture under reduced pressure was then purified by silica gel column chromatography to give (S)-3-[3-(9-methylthio-6-oxo-2,3,3a,4-tetrahydro-1H,6H-5,8,10,10b-tetraazabenzo[e]azulen-5-yl)phenyl]-1,2,4-oxadiazole-5-carboxamide (300 mg, 96%).
Reaction SMILES: [NH:1]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[C@H:2]([C:7]([OH:9])=[O:8])[C:3]([CH3:6])([CH3:5])[CH3:4].CCN=C=NCCCN(C)C.CCN(C(C)C)C(C)C.[CH2:37](O)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>ClCCl.CN(C1C=CN=CC=1)C>[CH2:37]([C@:2]([NH:1][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])([C:3]([CH3:6])([CH3:5])[CH3:4])[C:7]([OH:9])=[O:8])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)O)C(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@](Cc1ccccc1)(C(=O)O)C(C)(C)C
Temperature: 25 °C
Reaction time: 12 h
Yield: 93.5 %

Procedure:
Boc-Tle-OH (4.8 g, 22.3 mmol) was dissolved in dichloromethane (50 mL), and EDCI (4.3 g, 44.6 mmol), DMAP (0.6 g, 4.46 mmol), DIPEA (16 mL, 89.2 mmol), and benzyl alcohol (5 mL, 44.6 mmol) were added dropwise. The mixture was stirred at room temperature for 12 hours. The mixture was washed several times with an aqueous solution of 5% citric acid. The organic layer was dried over sodium sulfate, and filtered and distilled under reduced pressure to obtain the title compound as yellow oil (6.7 g, 99%).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][CH:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.[CH3:13][O:14][CH:15]([O:19][CH3:20])N(C)C>CO>[CH3:13][O:14][CH:15]([O:19][CH3:20])[N:10]1[CH2:11][CH2:12][CH:7]([CH2:6][C:2]2[NH:1][CH:5]=[CH:4][N:3]=2)[CH2:8][CH2:9]1
Reactant: COC(OC)N(C)C
Reactant: c1c[nH]c(CC2CCNCC2)n1
Solvent: CO
Product: COC(OC)N1CCC(Cc2ncc[nH]2)CC1

Procedure:
The free base of 4-(1H-imidazol-2-yl-methyl)piperidine (1.0 g, 0.006 M) and dimethylformamide dimethylacetal (15 ml) in methanol (20 ml) were heated at 90° C. for 8 hrs. The excess of dimethylformamide dimethylacetal was removed at the reduced pressure to give 4-(1H-imidazol-2-yl-methyl)piperidine carboxaldehyde dimethylacetal. To the mixture of 6-aminopenicillanic acid (1.16 g, 0.0054 M) and diisopropyl ethylamine (0.96 ml) in dry chloroform (20 ml) was added the solution (10 ml CHCl3 and 2 ml MeOH) of the above piperidine carboxaldehyde dimethylacetal at 0° C. The reaction was stirred at 0° C. for 1 hr. and then at room temperature for 3 hrs. After this period, the solvent was removed in vacuo and the residue dissolved in water (20 ml). The aqueous solution, washed with ethylacetate was acidified to pH 3 with dilute aqueous HCl and purified on Sephadex LH 20 columns to give [ 2S-(2alpha,5alpha,6beta)]-3,3-dimethyl-6-[[[4-(1H-imidazol-2-yl-methyl)-1-piperidinyl]methylene]amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid hydrochloride (0.84 g, 33%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1.C([N-][CH:22]([CH3:24])[CH3:23])(C)C.[Li+]>>[CH3:1][O:2][C:3](=[O:17])[C:4]1([CH2:8][C:9]2[CH:4]=[CH:5][CH:6]=[CH:24][C:22]=2[CH3:23])[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:14])([CH3:16])[CH3:15])=[O:11])[CH2:6][CH2:5]1
Reactant: COC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Product: COC(=O)C1(Cc2ccccc2C)CCN(C(=O)OC(C)(C)C)CC1

Procedure:
N-t-butoxycarbonyl isonipecotic acid methyl ester was transformed utilizing the alkylation procedure as described in Example 1, Step 3 substituting lithium diisopropylamide as the base to afford the product as a yellow syrup.
Reaction SMILES: O.[C:2]([O:8]CC)(=O)[CH2:3][C:4]([CH3:6])=[O:5].C1(C)C(C)=CC=CC=1.[NH2:19][C:20]1[CH:21]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:24][CH:25]=1>CCCCCC>[F:27][C:26]([F:28])([F:29])[C:22]1[CH:21]=[C:20]([CH:25]=[CH:24][CH:23]=1)[NH:19][C:2](=[O:8])[CH2:3][C:4]([CH3:6])=[O:5]
Reactant: CCOC(=O)CC(C)=O
Reactant: Nc1cccc(C(F)(F)F)c1
Solvent: CCCCCC
Solvent: O
Solvent: Cc1ccccc1C
Product: CC(=O)CC(=O)Nc1cccc(C(F)(F)F)c1
Reaction time: 4 h
Yield: 55.7 %

Procedure:
A two-liter reaction flask fitted with a magnetic stirrer, heating mantle, dropping funnel, thermometer, water-cooled condenser and Dean Stark trap was charged with 156.2 g (1.2 moles) of ethyl acetoacetate and 400 ml of xylene. The dropping funnel contained 161 g (1.0 mole) of 3-aminobenzotrifluoride and 320 ml xylene. The solution in the reaction pot was heated to 135° and the contents of the dropping funnel were added dropwise over a period of 3 hours. The low-boiling liquid which accumulated in the Dean Stark trap was periodically drained in order to maintain a reaction temperature of about 135°. After 4 hours, the reaction was judged to be completed and the reaction solution was cooled. There was added 650 ml of hexane. Cooling in an ice bath yielded a white crystalline precipitate. The product was collected on a vacuum filter and dried in an oven. There was obtained 136.6 g (55.7%) of 3'-trifluoromethylacetoacetanilide, m.p. 109°-10°. N.M.R. (CDCl3) ∂ 2.2 (CH3, keto), 3.5 (CH2), 7.2-7.9 (aromatic), 1.8 (CH3, enol).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:5]=1[CH3:11].[Br:13]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:5]=1[CH2:11][Br:13]
Reactant: COC(=O)c1cccc(Cl)c1C
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1cccc(Cl)c1CBr
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a suspension of 3-chloro-2-methylbenzoic acid methyl ester (5.62 g, 30.4 mmol), and N-bromosuccinimide (5.94 g, 33.4 mmol) in carbon tetrachloride (200 mL) was added benzoyl peroxide (800 mg, 3.30 mmol). The resulting suspension was immersed in an oil bath held at 85° C., and illuminated with a 300W halogen worklight. After stirring for 16 hours with heat and illumination the reaction mixture was allowed to cool to ambient temperature, filtered to remove the insoluble succinimide, and concentrated under reduced pressure to afford 2-bromomethyl-3-chlorobenzoic acid methyl ester as a yellow semi-solid. This crude material was carried on to the next step without purification.
Reaction SMILES: [C:1]([C:3]1([C:9](OC)=[O:10])[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1)#[N:2].CO.O.[BH4-].[Na+]>O1CCCC1.C(OCC)(=O)C>[C:1]([C:3]1([CH2:9][OH:10])[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1)#[N:2]
Reactant: COC(=O)C1(C#N)CCOCC1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CO
Product: N#CC1(CO)CCOCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65.1 %

Procedure:
Methyl 4-cyanotetrahydro-2H-pyran-4-carboxylate (2.93 g, 17.3 mmol) was dissolved in tetrahydrofuran (50 mL), methanol (10 mL) and water (5.0 mL). To this, sodium borohydride (1.31 g, 34.6 mmol) was added and the mixture was stirred at room temperature for 30 minutes. The reaction was stopped by addition of water to the reaction mixture, and extraction with ethyl acetate was performed, followed by washing with brine and drying over anhydrous sodium sulfate. The solvent was evaporated off under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate) to give 4-cyanotetrahydro-2H-pyran-4-ylmethanol (1.59 g, yield: 92%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([NH:12][C:13](=[O:20])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[S:11])[C:5](F)=[N:6][CH:7]=1.[OH-].[Na+]>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]2[N:9]=[C:10]([NH:12][C:13](=[O:20])[C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[S:11][C:5]2=[N:6][CH:7]=1
Reactant: O=C(NC(=S)Nc1cc(Br)cnc1F)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(Nc1nc2cc(Br)cnc2s1)c1ccccc1
Temperature: 60 °C
Yield: 94.2 %

Procedure:
To an ice-cold solution of N-(5-bromo-2-fluoropyridin-3-ylcarbamothioyl)benzamide II (1.80 g, 5.08 mmol) in THF (20.0 mL) was added a solution of NaOH (1.0 g, 22.0 mmol, dissolved in 10.0 mL H2O). The reaction mixture was then heated to 60° C. for 16 h. After the completion of the reaction (TLC monitoring), the reaction mixture was concentrated, added water and extracted with EtOAc (3×150 mL). The combined organics was washed with brine, dried (Na2SO4), filtered and concentrated under reduced pressure to obtain the desired product (1.60 g, 95%). 1H NMR (400 MHz, DMSO-d6): δ 7.42 (m, 3H), 7.82 (d, J=2.0 Hz, 1H), 8.14 (m, 2H) and 8.18 (d, J=2.0 Hz, 1H).
Reaction SMILES: [NH2:1][C:2](=[O:42])[CH2:3][C:4]1[C:5]([CH2:10][CH2:11][C:12]2[C:17]([C:18]([F:21])([F:20])[F:19])=[CH:16][N:15]=[C:14]([NH:22][C:23]3[CH:28]=[CH:27][C:26]([CH:29]4[CH2:34][CH2:33][CH2:32][N:31](C(OC(C)(C)C)=O)[CH2:30]4)=[CH:25][CH:24]=3)[N:13]=2)=[N:6][CH:7]=[CH:8][CH:9]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:31]1[CH2:32][CH2:33][CH2:34][CH:29]([C:26]2[CH:27]=[CH:28][C:23]([NH:22][C:14]3[N:13]=[C:12]([CH2:11][CH2:10][C:5]4[C:4]([CH2:3][C:2]([NH2:1])=[O:42])=[CH:9][CH:8]=[CH:7][N:6]=4)[C:17]([C:18]([F:20])([F:19])[F:21])=[CH:16][N:15]=3)=[CH:24][CH:25]=2)[CH2:30]1
Reactant: CC(C)(C)OC(=O)N1CCCC(c2ccc(Nc3ncc(C(F)(F)F)c(CCc4ncccc4CC(N)=O)n3)cc2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC(=O)Cc1cccnc1CCc1nc(Nc2ccc(C3CCCNC3)cc2)ncc1C(F)(F)F
Temperature: 25 °C
Reaction time: 17 h
Yield: 95.3 %

Procedure:
To a solution of tert-butyl 3-(4-((4-(2-(3-(2-amino-2-oxoethyl)pyridin-2-yl)ethyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperidine-1-carboxylate (I150) (23 mg, 0.039 mmol) in DCM (7 mL) was added TFA (1 mL). The resulting solution was stirred at room temperature for 17 hours then the volatiles were removed in vacuo. The residue was partitioned between ethyl acetate (50 mL) and a 2.0 M solution of NaOH (50 mL) then the organic layer was washed with water (50 mL), brine (50 mL) and dried over MgSO4 before being evaporated in vacuo to give the title compound (39) (18 mg, 94%) as a white solid; 1H NMR (400 MHz, d4-MeOH) δ 8.52 (s, 1H), 8.37 (dd, J=4.9, 1.6 Hz, 1H), 7.67 (dd, J=7.7, 1.6 Hz, 1H), 7.61 (d, J=8.6 Hz, 2H), 7.27-7.17 (m, 3H), 3.68 (s, 2H), 3.39-3.32 (m, 2H), 3.27 (d, J=8.7 Hz, 2H), 3.21-3.14 (m, 2H), 2.82-2.70 (m, 3H), 2.07-1.94 (m, 1H), 1.94-1.83 (m, 1H), 1.80-1.64 (m, 2H). LCMS Method C: rt 4.12 min, m/z=485.1 [M+H]+, 483.1 [M−H]−.
Reaction SMILES: Br[C:2]1[CH:31]=[CH:30][C:5]([C:6]([N:8]([CH2:22][CH2:23][CH2:24][CH:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)[C:9]2[CH:10]=[CH:11][C:12]3[C:17](=[O:18])[O:16][C:15]([CH3:20])([CH3:19])[O:14][C:13]=3[CH:21]=2)=[O:7])=[CH:4][CH:3]=1.[F:32][C:33]1[CH:38]=[CH:37][C:36]([C:39]#[CH:40])=[CH:35][CH:34]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>CN(C=O)C.CCOCC>[CH:25]1([CH2:24][CH2:23][CH2:22][N:8]([C:9]2[CH:10]=[CH:11][C:12]3[C:17](=[O:18])[O:16][C:15]([CH3:20])([CH3:19])[O:14][C:13]=3[CH:21]=2)[C:6](=[O:7])[C:5]2[CH:4]=[CH:3][C:2]([C:40]#[C:39][C:36]3[CH:37]=[CH:38][C:33]([F:32])=[CH:34][CH:35]=3)=[CH:31][CH:30]=2)[CH2:26][CH2:27][CH2:28][CH2:29]1
Reactant: CC1(C)OC(=O)c2ccc(N(CCCC3CCCC3)C(=O)c3ccc(Br)cc3)cc2O1
Reactant: C#Cc1ccc(F)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC1(C)OC(=O)c2ccc(N(CCCC3CCCC3)C(=O)c3ccc(C#Cc4ccc(F)cc4)cc3)cc2O1
Yield: 83.7 %

Procedure:
A solution of 4-bromo-N-(3-cyclopentylpropyl)-N-(2,2-dimethyl-4-oxo-4H-1,3-benzodioxin-7-yl)benzamide (355 mg, 0.73 mmol), 4-fluorophenylacetylene (Apollo, 96 mg, 0.80 mmol), bis(triphenylphosphine)palladium(I) chloride (26 mg, 0.04 mmol), triphenylphosphine (38 mg, 0.15 mmol) and cuprous(I) iodide (7 mg, 0.04 mmol) in DMF (3 mL) and TEA (1 mL) was heated under microwave conditions at 120° C. for 25 min. The reaction mixture was then diluted with Et2O and the precipitate obtained was filtered off. Filtrate was then washed with an aqueous solution of HCl (1N) and brine. The organic layer was dried over MgSO4 and the solvents were removed under reduced pressure. Purification by flash chromatography on silicagel (EtOAc/c-Hex (10/90 to 20/80)) gave 321 mg (84%) of the title compound. HPLC, Rt: 5.67 min (purity: 97.9%). 1H NMR (CDCl3) δ: 7.78 (d, J=8.3 Hz, 1H), 7.44 (m, 2H), 7.31 (AB, J=8.4, Δ=12 Hz, 4H), 7.01 (t, J=8.5 Hz, 2H), 6.75 (dd, J=8.3, 2.1 Hz, 1H), 6.58 (d, J=2.1 Hz, 1H), 3.91 (t, J=7.7 Hz, 2H), 1.40-1.71 (m, 15H), 1.34 (m, 2H), 1.03 (m, 2H).