Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1([C:15]([N:17]2[CH2:24][CH2:23][CH2:22][C@H:18]2[C:19](O)=[O:20])=[O:16])[C:14]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2.[C:25]([O:29][C:30]([NH:32][CH2:33][C:34]1[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][C:35]=1[CH2:36][NH2:37])=[O:31])([CH3:28])([CH3:27])[CH3:26].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN1CCOCC1.CN(C)C=O>[OH:1][C:2]1([C:15]([N:17]2[CH2:24][CH2:23][CH2:22][C@H:18]2[C:19]([NH:37][CH2:36][C:35]2[CH:38]=[C:39]([Cl:42])[CH:40]=[CH:41][C:34]=2[CH2:33][NH:32][C:30]([O:29][C:25]([CH3:28])([CH3:26])[CH3:27])=[O:31])=[O:20])=[O:16])[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:8]=2[C:9]2[C:14]1=[CH:13][CH:12]=[CH:11][CH:10]=2
Reactant: O=C(O)[C@@H]1CCCN1C(=O)C1(O)c2ccccc2-c2ccccc21
Reactant: CC(C)(C)OC(=O)NCc1ccc(Cl)cc1CN
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCc1ccc(Cl)cc1CNC(=O)[C@@H]1CCCN1C(=O)C1(O)c2ccccc2-c2ccccc21

Procedure:
A solution of 9-hydroxy-9-fluorenylcarbonyl-L-proline (1.8 g, 5.6 mmol) from step 2 above, 2-tert-butoxycarbonylaminomethyl-5-chlorobenzylamine (1.8 g, 6.8 mmol), N-methylmorpholine (12 drops), and benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (3.0 g, 6.7 mmol) in N,N-dimethylformamide (25 mL) was stirred at ambient temperature for 24 hours, concentrated in vacuo, and purified on silica gel (ethyl acetate-hexane, 1:2) to give 1-((9-hydroxy-9H-fluoren-9-yl)carbonyl)-N-(2-tert-butyloxycarbonylaminomethyl-5-chlorobenzyl)-L-prolinamide. HPLC=99%, R.T.=3.69 min, method A; M+1=576.2.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([CH2:13][CH:14]=[CH2:15])[C:11]=1[OH:12])[O:8][C:7](=[O:16])[CH:6]=[CH:5]2.[C:17](O[Na])([CH3:19])=[O:18].C(OC(=O)C)(=O)C>O>[CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([CH2:13][CH:14]=[CH2:15])[C:11]=1[O:12][C:17](=[O:18])[CH3:19])[O:8][C:7](=[O:16])[CH:6]=[CH:5]2
Reactant: CC(=O)O[Na]
Reactant: C=CCc1c(O)c(C)cc2ccc(=O)oc12
Solvent: CC(=O)OC(C)=O
Solvent: O
Product: C=CCc1c(OC(C)=O)c(C)cc2ccc(=O)oc12
Yield: 129.2 %

Procedure:
In such a manner a mixture of 6-methyl-7-hydroxy-8-allylcoumarin (VII) (6.3 g), anhydrous AcONa (1.5 g) and acetic anhydride (40 ml) was refluxed for 1 h. The reaction mixture was gently diluted with water (40 ml), refluxed for 10 min and then poured into H2O (300 ml) yielding a precipitate, which was collected by filtration and washed several times with H2O. The dried product was crystallized from MeOH yielding 6-methyl-7-acetoxy-8-allylcoumarin (X) (6.1 g; m.p. 110°-11° C.). ##STR15##
Reaction SMILES: [N:1]1[C:10]2[N:9]3[CH2:11][CH2:12][O:13][CH2:14][CH:8]3[CH2:7][NH:6][C:5]=2[CH:4]=[N:3][C:2]=1[C:15]1[C:23]2[C:18](=[CH:19][C:20]([O:24][CH3:25])=[CH:21][CH:22]=2)[N:17](C(OC(C)(C)C)=O)[CH:16]=1.C(Cl)Cl.[C:36]([OH:42])([C:38]([F:41])([F:40])[F:39])=[O:37]>>[C:36]([OH:42])([C:38]([F:41])([F:40])[F:39])=[O:37].[CH3:25][O:24][C:20]1[CH:19]=[C:18]2[C:23]([C:15]([C:2]3[N:3]=[CH:4][C:5]4[NH:6][CH2:7][CH:8]5[CH2:14][O:13][CH2:12][CH2:11][N:9]5[C:10]=4[N:1]=3)=[CH:16][NH:17]2)=[CH:22][CH:21]=1
Reactant: COc1ccc2c(-c3ncc4c(n3)N3CCOCC3CN4)cn(C(=O)OC(C)(C)C)c2c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc2c(-c3ncc4c(n3)N3CCOCC3CN4)c[nH]c2c1
Yield: 35 %

Procedure:
A solution of tert-Butyl 3-(5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridin-2-yl)-6-methoxy-1H-indole-1-carboxylate (97 mg, 0.222 mmol) and CH2Cl2/TFA (1:1, 3 mL) was stirred at room temperature for 30 minutes. The reaction mixture was subsequently concentrated in vacuo and the crude product was purified by LC/MS using a gradient of 20-30% CH3CN (with 0.035% TFA) in H2O (with 0.05% TFA). The pure fractions were combined and lyophilized to give a TFA salt of the title compound as a pale yellow solid (26 mg, 35%). 1H NMR (400 MHz, DMSO-d6) δ 2.92-3.03 (m, 1H), 3.33-3.35 (m, 3H), 3.55-3.68 (m, 1H), 3.80 (s, 3H), 3.82-3.88 (m, 1H), 3.94-4.18 (m, 2H), 4.70-4.81 (m, 1H), 6.33-6.46 (br s, 1H), 6.82-6.93 (m, 1H), 6.97-7.08 (m, 1H), 7.36-7.50 (m, 1H), 8.07-8.22 (m, 2H), 11.77-11.94 (m, 1H). ESI-MS m/z [M+H]+ calc'd for C18H19N5O2S, 338.15. found 338.4.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8]O)=[N:6][CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:30]>C(Cl)Cl>[Br:30][CH2:8][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=1
Reactant: BrC(Br)(Br)Br
Reactant: OCc1ccc(Cl)cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Clc1ccc(CBr)nc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 16.8 %

Procedure:
To a 0° C. solution of (5-chloropyridin-2-yl)methanol Part D (10 mg, 0.070 mmol) and triphenylphosphine (32.9 mg, 0.125 mmol) in DCM (0.170 mL) was added a solution of carbon tetrabromide (31.4 mg, 0.095 mmol) in DCM (0.084 mL) dropwise. The mixture was stirred at RT for 2.0 h at which point the solvent was removed in vacuo and the crude product was subjected to flash chromatography (silica gel/DCM-EtOAc 100:0 to 0:100 gradient) to afford 2-(bromomethyl)-5-chloropyridine 16E (2.4 mg, 16.8% yield) as a light brown oil. LC-MS, [M+H]+208. 1H NMR (400 MHz, CDCl3) δ 8.47 (1H, d, J=2.2 Hz), 7.61 (1H, dd, J=8.4, 2.2 Hz), 7.33 (1H, d, J=8.4 Hz), 4.46 (2H, s). HPLC-Method 8; 2.42 min.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][S:9][CH2:10][CH2:11][C:12]([NH:14][NH2:15])=[O:13].[OH:16][C:17]1[C:34]2[CH2:33][C@@:32]([OH:39])([C:35](=O)[CH2:36][OH:37])[CH2:31][C@H:30]([O:40][C@@H:41]3[O:55][C@@H:54]([CH3:56])[C@H:44]4[O:45][C@H:46]5[N:51]([C@H:43]4[CH2:42]3)[CH2:50][CH2:49][O:48][C@@H:47]5[O:52][CH3:53])[C:29]=2[C:28]([OH:57])=[C:27]2[C:18]=1[C:19](=[O:61])[C:20]1[CH:21]=[CH:22][CH:23]=[C:24]([O:59][CH3:60])[C:25]=1[C:26]2=[O:58]>CO>[OH:37][CH2:36]/[C:35](=[N:15]\[NH:14][C:12](=[O:13])[CH2:11][CH2:10][S:9][S:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][N:2]=1)/[C@@:32]1([OH:39])[CH2:31][C@H:30]([O:40][C@@H:41]2[O:55][C@@H:54]([CH3:56])[C@H:44]3[O:45][C@H:46]4[N:51]([C@H:43]3[CH2:42]2)[CH2:50][CH2:49][O:48][C@@H:47]4[O:52][CH3:53])[C:29]2[C:34](=[C:17]([OH:16])[C:18]3[C:19](=[O:61])[C:20]4[C:25]([C:26](=[O:58])[C:27]=3[C:28]=2[OH:57])=[C:24]([O:59][CH3:60])[CH:23]=[CH:22][CH:21]=4)[CH2:33]1
Reactant: NNC(=O)CCSSc1ccccn1
Reactant: COc1cccc2c1C(=O)c1c(O)c3c(c(O)c1C2=O)C[C@@](O)(C(=O)CO)C[C@@H]3O[C@H]1C[C@H]2[C@H](O[C@@H]3[C@@H](OC)OCCN32)[C@H](C)O1
Agent: Cl
Solvent: CO
Product: COc1cccc2c1C(=O)c1c(O)c3c(c(O)c1C2=O)C[C@@](O)(/C(CO)=N/NC(=O)CCSSc1ccccn1)C[C@@H]3O[C@H]1C[C@H]2[C@H](O[C@@H]3[C@@H](OC)OCCN32)[C@H](C)O1
Temperature: 25 °C
Reaction time: 20 h
Yield: 27.1 %

Procedure:
A solution of 3-(2-pyridyldithio)propionic acid hydrazide HCl (41.5 mg, 0.156 mmol) in anhydrous methanol (5 ml) was added to (8S,10S)-6,8,11-trihydroxy-8-(hydroxyacetyl)-1-methoxy-10-{[(1S,3R,4aS,9S,9aR,10aS)-9-methoxy-1-methyloctahydro-1H-pyrano[4′,3′:4,5][1,3]oxazolo[2,3-c][1,4]oxazin-3-yl]oxy}-7,8,9,10-tetrahydrotetracene-5,12-dione [PNU-159682, compound IIA, prepared as reported in WO 9802446] (50 mg, 0.078 mmol). The solution was stirred in the dark at room temperature for 20 hours. The course of the reaction was followed by reverse-phase HPLC-MS. After this period the solvent was evaporated and the residue was purified by flash column chromatography (MeOH:CH2Cl2=0.2:9.8) on silica gel (230-400 mesh), affording 18 mg (yield 27%) of 53. MS (ESI): 853 [M+H]+. Retention time=5.52 min (method 2).
Reaction SMILES: CS(O[CH2:6][CH:7]1[S:11][C:10]([C:12]2[NH:13][C:14]3[C:19]([CH:20]=2)=[CH:18][CH:17]=[CH:16][C:15]=3[N:21]([CH3:31])[S:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=2)(=[O:24])=[O:23])=[N:9][CH2:8]1)(=O)=O.[NH:32]1[CH:36]=[CH:35][N:34]=[C:33]1[C:37]([O:39][CH2:40][CH3:41])=[O:38].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:31][N:21]([S:22]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1)(=[O:24])=[O:23])[C:15]1[CH:16]=[CH:17][CH:18]=[C:19]2[C:14]=1[NH:13][C:12]([C:10]1[S:11][CH:7]([CH2:6][N:32]3[CH:36]=[CH:35][N:34]=[C:33]3[C:37]([O:39][CH2:40][CH3:41])=[O:38])[CH2:8][N:9]=1)=[CH:20]2
Reactant: CCOC(=O)c1ncc[nH]1
Reactant: CN(c1cccc2cc(C3=NCC(COS(C)(=O)=O)S3)[nH]c12)S(=O)(=O)c1ccccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1nccn1CC1CN=C(c2cc3cccc(N(C)S(=O)(=O)c4ccccn4)c3[nH]2)S1
Temperature: 60 °C
Reaction time: 4.5 h
Yield: 83.2 %

Procedure:
A mixture of (2-{7-[methyl(pyridin-2-ylsulfonyl)amino]-1H-indol-2-yl}-4,5-dihydro-1,3-thiazol-5-yl)methyl methanesulfonate (250 mg), ethyl 1H-imidazole-2-carboxylate (146 mg), potassium carbonate (144 mg) and N,N-dimethylformamide (5 mL) was stirred at 60° C. for 4.5 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over magnesium sulfate, and filtrated, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=15:85-100:0) to give the title compound (227 mg, yield 83%) as a orange oil.
Reaction SMILES: Br.[F:2][C:3]1[CH:16]=[CH:15][C:6]2[N:7]([CH2:11][CH2:12][O:13][CH3:14])[C:8](=[NH:10])[S:9][C:5]=2[CH:4]=1.[Cl:17][C:18]1[CH:19]=[CH:20][C:21]([O:27][CH3:28])=[C:22]([CH:26]=1)[C:23](O)=[O:24]>>[Cl:17][C:18]1[CH:19]=[CH:20][C:21]([O:27][CH3:28])=[C:22]([CH:26]=1)[C:23](/[N:10]=[C:8]1\[S:9][C:5]2[CH:4]=[C:3]([F:2])[CH:16]=[CH:15][C:6]=2[N:7]\1[CH2:11][CH2:12][O:13][CH3:14])=[O:24]
Reactant: COCCn1c(=N)sc2cc(F)ccc21
Reactant: COc1ccc(Cl)cc1C(=O)O
Agent: Br
Product: COCCn1/c(=N/C(=O)c2cc(Cl)ccc2OC)sc2cc(F)ccc21

Procedure:
The product from Example 113A and 5-chloro-2-methoxybenzoic acid were processed using the methods described in Example 13 to afford the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 3.24 (s, 3H), 3.79 (t, J=5.3 Hz, 2H), 3.83 (s, 3H), 4.65 (t, J=5.3 Hz, 2H), 7.17 (d, J=9.2 Hz, 1H), 7.41 (td, J=9.1, 2.5 Hz, 1H), 7.52 (dd, J=8.8, 2.7 Hz, 1H), 7.78 (dd, J=9.0, 4.2 Hz, 1H), 7.83 (d, J=2.7 Hz, 1H), 7.89 (dd, J=8.5, 2.7 Hz, 1H); MS (ESI+) m/z 395 (M+H)+; Anal. Calculated for C18H16ClFN2O3S: C, 54.75; H, 4.08; N, 7.09. Found: C, 54.29; H, 3.94; N, 6.99.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[NH:10][C:11](=[O:13])[CH3:12].[N+:14]([O-])([O-:16])=[O:15].[K+]>C(O)(C(F)(F)F)=O.C(OCC)(=O)C>[CH3:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([N+:14]([O-:16])=[O:15])=[CH:4][C:3]=1[NH:10][C:11](=[O:13])[CH3:12]
Reactant: COc1ccc(NC(C)=O)c(C)c1
Reactant: O=[N+]([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: COc1cc(C)c(NC(C)=O)cc1[N+](=O)[O-]
Temperature: 0 °C
Yield: 46.3 %

Procedure:
N-[2-methyl-4-(methyloxy)phenyl]acetamide (1.95 g, 10.88 mmol) was dissolved in TFA (20 mL) and cooled to 0° C. in an ice bath. Potassium nitrate (1.210 g, 11.97 mmol) was added slowly. The reaction was monitored by tic and quenched by pouring into ice and diluting with EtOAc. A solution of saturated sodium bicarbonate was added until solution was a neutral pH. Organics were washed with water and saturated brine solution and dried over sodium sulfate. Solvents were removed under reduced pressure to afford a yellow solid. Efforts to dissolve the solid in ethyl acetate resulted in a suspension that was let sit for several hours. Hexanes were added and the solids filtered to afford N-[2-methyl-4-(methyloxy)-5-nitrophenyl]acetamide (1.13 g, 5.04 mmol) as yellow fluffy solid. The filtrate was purified via SiO2 chromatography to afford N-[2-methyl-4-(methyloxy)-5-nitrophenyl]acetamide (1.02 g, 4.55 mmol) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.00-2.11 (m, 3 H) 2.29 (s, 3 H) 3.90 (s, 3 H) 7.24 (s, H) 7.99 (s, 1 H) 9.42 (s, 1 H)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH2:18][CH2:17][C:12]3([O:16][CH2:15][CH2:14][O:13]3)[CH2:11][CH:10]=2)=[CH:5][CH:4]=1>CCO.[Pd]>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:18][CH2:17][C:12]3([O:16][CH2:15][CH2:14][O:13]3)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(C2=CCC3(CC2)OCCO3)cc1
Agent: [Pd]
Solvent: CCO
Product: COc1ccc(C2CCC3(CC2)OCCO3)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 8-(4-methoxyphenyl)-1,4-dioxaspiro[4.5]dec-7-ene (526.8 mg, 2.14 mmoL) in EtOH (20 mL) was added 10% Pd/C (50 mg). The reaction was put under an atmosphere of H2 (balloon) and stirred vigorously at room temperature. After 1.5 hours, the catalyst was removed by filtration. The filtrate was concentrated to afford 8-(4-methoxyphenyl)-1,4-dioxaspiro[4.5]decane. 1H NMR (500 MHz, CDCl3): δ 7.14-7.17 (m, 2H), 6.82-6.85 (m, 2H), 3.98 (s, 4H), 3.79 (s, 3H), 2.52 (m, 1H), 1.64-1.86 (m, 8H).
Reaction SMILES: [C:1]([BH3-])#[N:2].[Na+].[CH3:5][S:6][CH:7]1C(=O)[CH2:11][CH2:10][N:9]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:8]1.C([O-])(=O)C.[NH4+]>CO>[C:17]([O:16][C:14]([N:9]1[CH2:10][CH2:11][C@H:1]([NH2:2])[C@H:7]([S:6][CH3:5])[CH2:8]1)=[O:15])([CH3:18])([CH3:20])[CH3:19]
Reactant: [BH3-]C#N
Reactant: CSC1CN(C(=O)OC(C)(C)C)CCC1=O
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: CS[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1N

Procedure:
Sodium cyanoborohydride (344 mg, 5.48 mmol) was added to a solution of tert-butyl 3-(methylthio)-4-oxopiperidine-1-carboxylate (Intermediate 183, 1.07 g, 4.40 mmol), ammonium acetate (3.24 g, 42 mmol) and methanol (15 ml). The resultant mixture was stirred for 4 h. The reaction was quenched by addition of 1N HCl (3 ml). Aqueous sodium bicarbonate (saturated, 50 ml) was added slowly to the reaction mixture followed by extraction with ethyl acetate (3×75 ml). The combined organic phase was dried over sodium sulfate, filtered and concentrated under reduced pressure to yield the crude amine
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]([O:12][CH3:13])=[O:11])=[C:7]([CH3:14])[C:6]=2[CH:15]=1.[CH3:16][N:17](C)C=O>[C-]#N.[Zn+2].[C-]#N.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.O>[C:16]([C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]([O:12][CH3:13])=[O:11])=[C:7]([CH3:14])[C:6]=2[CH:15]=1)#[N:17]
Reactant: CN(C)C=O
Reactant: COC(=O)c1oc2ccc(Br)cc2c1C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: O
Product: COC(=O)c1oc2ccc(C#N)cc2c1C
Temperature: 80 °C
Reaction time: 8 h
Yield: 87 %

Procedure:
To a mixture of methyl 5-bromo-3-methyl-1-benzofuran-2-carboxylate (6.06 g) synthesized above, zinc cyanide (2.64 g) and N,N-dimethylformamide (60 mL) was added tetrakis(triphenylphosphine)palladium (0) (1.31 g), and the mixture was deaerated and stirred under argon atmosphere at 80° C. overnight. Water was added to quench the reaction, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was washed with diisopropyl ether to give the title object compound (4.20 g, 87%) as a pale-brown solid.
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C:9]1[C:14]([C:15]([C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=2[O:24][CH3:25])=[O:16])=[CH:13][N:12]=[C:11]([NH:26][CH:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[N:10]=1.[C:33](Cl)(=[O:36])[CH2:34][CH3:35]>>[NH2:8][C:9]1[C:14]([C:15](=[O:16])[C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=2[O:24][CH3:25])=[CH:13][N:12]=[C:11]([NH:26][CH:27]2[CH2:28][CH2:29][N:30]([C:33](=[O:36])[CH2:34][CH3:35])[CH2:31][CH2:32]2)[N:10]=1
Reactant: COc1ccc(F)cc1C(=O)c1cnc(NC2CCNCC2)nc1N
Reactant: CCC(=O)Cl
Solvent: O=C(O)C(F)(F)F
Product: CCC(=O)N1CCC(Nc2ncc(C(=O)c3cc(F)ccc3OC)c(N)n2)CC1

Procedure:
The same procedure as described in Example 60 was used, starting from [4-amino-2-(piperidin-4-ylamino)-pyrimidin-5-yl]-(5-fluoro-2-methoxy-phenyl)-methanone trifluoroacetic acid salt, Example 59, and propionyl chloride (Aldrich) to give 1-[4-[4-amino-5-(5-fluoro-2-methoxy-benzoyl)-pyrimidin-2-ylamino]-piperidin-1-yl]-propan-1-one. MS (M+H)+, 402.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[OH:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]2[CH2:19][CH2:18][N:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[N:16]=2)=[CH:10][CH:9]=1.Cl.[CH2:27]([N:29]([CH2:33][CH3:34])[CH2:30][CH2:31]Cl)[CH3:28].[C:35]([OH:42])(=[O:41])/[CH:36]=[CH:37]/[C:38]([OH:40])=[O:39]>CN(C)C=O.O.CCOCC>[C:35]([OH:42])(=[O:41])/[CH:36]=[CH:37]/[C:38]([OH:40])=[O:39].[CH2:27]([N:29]([CH2:33][CH3:34])[CH2:30][CH2:31][O:7][C:8]1[CH:9]=[CH:10][C:11]([NH:14][C:15]2[CH2:19][CH2:18][N:17]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[N:16]=2)=[CH:12][CH:13]=1)[CH3:28]
Reactant: Oc1ccc(NC2=NN(c3ccccc3)CC2)cc1
Reactant: CCN(CC)CCCl
Agent: Cl
Agent: O=C(O)/C=C/C(=O)O
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOCC
Product: CCN(CC)CCOc1ccc(NC2=NN(c3ccccc3)CC2)cc1
Yield: 315.3 %

Procedure:
Potassium carbonate (6.92 g), 4,5-dihydro-N-(4-hydroxyphenyl)-1-phenyl-1H-pyrazol-3-amine (4.22 g) and 2-diethylaminoethylchloride hydrochloride (2.95 g) in dimethylformamide (30 ml) were stirred together at room temperature for 25 hours. The reaction mixture was then diluted with water and extracted with ethyl acetate. The combined extracts were washed with water and dried. Solvent was removed to give an oil which was redissolved in ether and a solution of fumaric acid (0.33 g) in ether added to give a precipitate. This was collected and dried to give the title compound, (4.2 g) mp 54°-56° (dec).
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH2:10][N:11]3[CH2:15][CH2:14][CH2:13][CH2:12]3)=[N:7][C:6]=2[CH:16]=1.[C:17]([Si:19]([CH3:22])([CH3:21])[CH3:20])#[CH:18]>>[N:11]1([CH2:10][C:8]2[O:9][C:5]3[CH:4]=[CH:3][C:2]([C:18]#[C:17][Si:19]([CH3:22])([CH3:21])[CH3:20])=[CH:16][C:6]=3[N:7]=2)[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: Ic1ccc2oc(CN3CCCC3)nc2c1
Reactant: C#C[Si](C)(C)C
Product: C[Si](C)(C)C#Cc1ccc2oc(CN3CCCC3)nc2c1

Procedure:
Prepared analogously to Example 18b from 5-iodo-2-pyrrolidin-1-ylmethyl-benzoxazole and ethynyl-trimethyl-silane.
Reaction SMILES: [CH:1]([N:3]([CH2:16][C:17](=O)[CH3:18])[C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][C:5]=1[O:14][CH3:15])=O.C([O-])(=O)C.[NH4+:24].N.C(OCC)(=O)C>C(O)(=O)C>[CH3:15][O:14][C:5]1[CH:6]=[C:7]([CH:12]=[CH:13][C:4]=1[N:3]1[CH:16]=[C:17]([CH3:18])[N:24]=[CH:1]1)[C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)c1ccc(N(C=O)CC(C)=O)c(OC)c1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Agent: N
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: COC(=O)c1ccc(-n2cnc(C)c2)c(OC)c1
Temperature: 140 °C
Reaction time: 1 h
Yield: 62.4 %

Procedure:
A solution of methyl 4-[formyl-(2-oxopropyl)amino]-3-methoxybenzoate (118 g) and ammonium acetate (172 g) in acetic acid (255 mL) was heated and stirred at 140° C. for one hour. After the reaction was completed, the reaction solution was neutralized with aqueous ammonia under ice-cooling. Ethyl acetate was added to the reaction solution, and the organic layer was separated. The resulting organic layer was dried over anhydrous magnesium sulfate and then filtered on a silica gel pad, and the filtrate was concentrated under reduced pressure. tert-Butyl methyl ether and heptane were added to the residue, and the precipitated solid was collected by filtration and washed with a solution of 50% tert-butyl methyl ether in heptane. The resulting solid was air-dried overnight to obtain 68.4 g of the title compound. Further, the crystallization mother liquor was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate system) to obtain 22.3 g of the title compound.
Reaction SMILES: CCN=C=NCCCN(C)C.CS(C)=O.[CH3:16][O:17][C:18](=[O:34])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][N:25]1[C:30](=[O:31])[CH2:29][CH2:28][CH2:27][C@@H:26]1[CH2:32][OH:33].FC(F)(F)C([O-])=O.[NH+]1C=CC=CC=1>C1C=CC=CC=1>[CH3:16][O:17][C:18](=[O:34])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][N:25]1[C:30](=[O:31])[CH2:29][CH2:28][CH2:27][C@@H:26]1[CH:32]=[O:33]
Reactant: COC(=O)CCCCCCN1C(=O)CCC[C@@H]1CO
Agent: CCN=C=NCCCN(C)C
Agent: O=C([O-])C(F)(F)F
Agent: c1cc[nH+]cc1
Solvent: CS(C)=O
Solvent: c1ccccc1
Product: COC(=O)CCCCCCN1C(=O)CCC[C@@H]1C=O
Temperature: 0 °C
Reaction time: 3 h

Procedure:
EDCI (119 mg, 0.62 mmol) and DMSO (59 μL, 0.83 mmol) were added sequentially to a solution of 7-((R)-2-hydroxymethyl-6-oxo-piperidin-1-yl)-heptanoic acid methyl ester (56 mg, 0.21 mmol) in benzene (2.0 mL) at rt. The mixture was cooled to 0° C. and pyridinium trifluoroacetate (44 mg, 0.23 mmol) was added. The reaction was allowed to warm to rt and then was stirred at rt for 3 h. The solution was decanted from the oily residue and the residue was washed with benzene (3×2 mL). The combined benzene phases were concentrated in vacuo to afford crude 7-((R)-2-formyl-6-oxo-piperidin-1-yl)-heptanoic acid methyl ester that was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH3:13])[CH:8]=2)[N:3]=1.[C:14]([O:22][CH2:23][CH3:24])(=[O:21])[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:1][C:2]1[CH:11]=[C:10]([CH:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:14]([O:22][CH2:23][CH3:24])=[O:21])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH3:13])[CH:8]=2)[N:3]=1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: Cc1ccc2nc(Cl)cc(Cl)c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C(=O)OCC)c1cc(Cl)nc2ccc(C)cc12
Temperature: 70 °C
Reaction time: 3 h
Yield: 39.9 %

Procedure:
To a solution of 2,4-dichloro-6-methylquinoline (2.11 g, 10 mmol) and 1,3-diethyl propanedioate (2.64 g, 20 mmol) in N,N-dimethylformamide (40 mL) was added anhydrous potassium carbonate (2.8 g, 20 mmol). The mixture was stirred at 70° C. for 3 hours, then poured into ice/water (100 mL) and extracted with ethyl acetate (100 mL×3). The combined organic layers were washed with brine (150 mL×2), dried over sodium sulfate. The residue was purified by flash column chromatography on silica gel (eluting with 20-30% ethyl acetate in petroleum ether) to afford 1.34 g of the desired product (yield was 40%). MS obsd. (ESI+) [(M+H)+] 336.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]([CH2:29][CH:30]=O)[CH2:10][N:11]([CH3:28])[C:12]([C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=[C:16]([C:24]#[N:25])[C:15]=2[O:26][CH3:27])=[O:13])[CH:5]=[CH:6][C:7]=1[Cl:8].[NH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]([CH2:29][CH2:30][NH:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH2:10][N:11]([CH3:28])[C:12]([C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=[C:16]([C:24]#[N:25])[C:15]=2[O:26][CH3:27])=[O:13])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COc1c(C#N)cc2ccccc2c1C(=O)N(C)C[C@@H](CC=O)c1ccc(Cl)c(Cl)c1
Reactant: Nc1ccccc1
Product: COc1c(C#N)cc2ccccc2c1C(=O)N(C)C[C@@H](CCNc1ccccc1)c1ccc(Cl)c(Cl)c1

Procedure:
N-[(S)-2-(3,4-Dichlorophenyl)-4-oxobutyl]-N-methyl-2-methoxy-3-cyano-1-naphthamide was reacted with aniline under standard reductive amination conditions to give the title compound which was converted to the citrate salt. 1H NMR(300 MHz, DMSO-d6) δ8.64-8.61 (m), 8.07-7.98 (m), 7.79-7.55 (m), 7.51-7.47 (m), 7.37-7.32 (t), 7.08-7.00 (m), 6.53-6.49 (m), 6.31-6.28 (d), 4.60-4.50 (t), 4.07-3.96 (m), 3.92 (s), 3.90-3.78 (m), 3.86 (s), 3.45-3.11 (m), 3.00-2.88 (m), 2.79 (s), 2.73 (s), 2.68 (s), 2.56-2.44 (m), 2.03-1.88 (m); MS APCI, m/z=532 (M+).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)[N:3]=1.[CH3:18][O:19][C:20]1[CH:21]=[CH:22][C:23]([CH3:27])=[C:24]([CH:26]=1)[NH2:25]>>[CH3:18][O:19][C:20]1[CH:21]=[CH:22][C:23]([CH3:27])=[C:24]([CH:26]=1)[NH:25][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)[N:3]=1
Reactant: COc1ccc(C)c(N)c1
Reactant: FC(F)(F)c1cc(Cl)nc(-c2ccncc2)n1
Product: COc1ccc(C)c(Nc2cc(C(F)(F)F)nc(-c3ccncc3)n2)c1

Procedure:
The title compound was prepared from a mixture of 4-chloro-2-(4-pyridinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.193 mmol) and 5-methoxy-2-methylaniline (27 mg, 0.193 mmol) similar to Example 13 and isolated as a pink solid (23 mg, 33%). 1H NMR (CDCl3): 8.77 (d, J=5.7 Hz, 2H), 8.27 (d, J=5.7 Hz, 2H), 7.32 (s, 1H), 7.26 (d, J=9.0 Hz, 1H), 6.99 (s, 1H), 6.70 (s, 1H), 6.85 (dd, J=2.7, 8.4 Hz, 1H), 3.82 (s, 3H), 2.24 (s, 3H).