Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH2:5][C:6]2([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[O:11][C:10](=[O:12])[N:9]([C:13]([C:16]3[N:17]=[N:18][N:19]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH:20]=3)([CH3:15])[CH3:14])[CH2:8][CH2:7]2)[CH2:4][O:3]1.O.OO.[O-]S([O-])(=S)=O.[Na+].[Na+]>C1COCC1>[OH:3][C:2]([CH3:4])([CH3:1])[CH2:5][C:6]1([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[O:11][C:10](=[O:12])[N:9]([C:13]([C:16]2[N:17]=[N:18][N:19]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:20]=2)([CH3:15])[CH3:14])[CH2:8][CH2:7]1
Reactant: CC1(CC2(c3ccccc3)CCN(C(C)(C)c3cn(-c4ccccc4)nn3)C(=O)O2)CO1
Agent: O=S([O-])([O-])=S
Agent: OO
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(O)CC1(c2ccccc2)CCN(C(C)(C)c2cn(-c3ccccc3)nn2)C(=O)O1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 32 %

Procedure:
A stirred solution of crude 6-((2-methyloxiran-2-yl)methyl)-6-phenyl-3-(2-(1-phenyl-1H-1,2,3-triazol-4-yl)propan-2-yl)-1,3-oxazinan-2-one (8.4 mg, 0.018 mmol) in dry THF (1 mL) was cooled in an ice bath and 1 M LiEt3BH in THF (0.1 mL, 0.1 mmol) was added. The mixture was stirred for 45 min in the ice bath. Water (1 mL) and 30% H2O2 (0.2 mL) were added. The mixture was stirred for 0.5 h and solid Na2S2O3 (˜200 mg) was added. The mixture was stirred for 0.5 h and applied to a 10-mL ChemElut cartridge. The cartridge was eluted with EtOAc (50 mL) and the eluate was concentrated to leave a residue which was purified by prep HPLC to afford the title compound (2.5 mg, 42% over 2 steps). LC-MS Method 1 tR=1.57 min, m/z=435.
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[C:5](=[O:6])[N:4]([CH:7]2[CH:14]3[CH2:15][C:10]4([C:17]([O:19][CH3:20])=[O:18])[CH2:11][CH:12]([CH2:16][CH:8]2[CH2:9]4)[CH2:13]3)[NH:3]1.[F:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27]Br)=[CH:25][CH:24]=1>>[F:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27][N:3]2[C:2]([CH3:21])([CH3:1])[C:5](=[O:6])[N:4]2[CH:7]2[CH:8]3[CH2:9][C:10]4([C:17]([O:19][CH3:20])=[O:18])[CH2:11][CH:12]([CH2:13][CH:14]2[CH2:15]4)[CH2:16]3)=[CH:25][CH:24]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: COC(=O)C12CC3CC(C1)C(N1NC(C)(C)C1=O)C(C3)C2
Product: COC(=O)C12CC3CC(C1)C(N1C(=O)C(C)(C)N1Cc1ccc(F)cc1)C(C3)C2

Procedure:
Methyl 4-(3,3-dimethyl-4-oxo-1,2-diazetidin-1-yl)adamantane-1-carboxylate and 4-fluorobenzyl bromide were used for a similar reaction and treatment as Process 6 of Example 1, and methyl 4-[2-(4-fluorobenzyl)-3,3-dimethyl-4-oxo-1,2-diazetidin-1-yl]adamantane-1-carboxylate was obtained as a colorless oil.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][C@@H:19]2[CH3:24])[C:5]2[CH2:10][N:9]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:8][C:6]=2[N:7]=1.[CH:25]1([NH:28][C:29]([NH:31][C:32]2[CH:37]=[CH:36][C:35](B3OC(C)(C)C(C)(C)O3)=[CH:34][CH:33]=2)=[O:30])[CH2:27][CH2:26]1>>[CH:25]1([NH:28][C:29](=[O:30])[NH:31][C:32]2[CH:33]=[CH:34][C:35]([C:2]3[N:3]=[C:4]([N:18]4[CH2:23][CH2:22][O:21][CH2:20][C@@H:19]4[CH3:24])[C:5]4[CH2:10][N:9]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:8][C:6]=4[N:7]=3)=[CH:36][CH:37]=2)[CH2:27][CH2:26]1
Reactant: CC1(C)OB(c2ccc(NC(=O)NC3CC3)cc2)OC1(C)C
Reactant: C[C@H]1COCCN1c1nc(Cl)nc2c1CN(C(=O)OC(C)(C)C)C2
Product: C[C@H]1COCCN1c1nc(-c2ccc(NC(=O)NC3CC3)cc2)nc2c1CN(C(=O)OC(C)(C)C)C2

Procedure:
(S)-tert-butyl 2-(4-(3-cyclopropylureido)phenyl)-4-(3-methylmorpholino)-5H-pyrrolo[3,4-d]pyrimidine-6(7H)-carboxylate was prepared by the method described for intermediate 5 using intermediate 1 and 1-cyclopropyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)urea as starting materials
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:12][N:13]3[CH2:18][C@@H:17]4[CH2:19][C@H:14]3[CH2:15][N:16]4[C:20]([CH3:24])([CH3:23])[CH2:21][OH:22])[N:8]2[CH3:11])=[C:4]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[N:3]=1.[CH2:31]([C:33]1[NH:37][C:36]2[CH:38]=[CH:39][CH:40]=[CH:41][C:35]=2[N:34]=1)[CH3:32].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.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]>[CH2:31]([C:33]1[N:34]([C:2]2[N:10]=[C:9]3[C:5]([N:6]=[C:7]([CH2:12][N:13]4[CH2:18][C@@H:17]5[CH2:19][C@H:14]4[CH2:15][N:16]5[C:20]([CH3:23])([CH3:24])[CH2:21][OH:22])[N:8]3[CH3:11])=[C:4]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[N:3]=2)[C:35]2[CH:41]=[CH:40][CH:39]=[CH:38][C:36]=2[N:37]=1)[CH3:32]
Reactant: CCc1nc2ccccc2[nH]1
Reactant: Cn1c(CN2C[C@@H]3C[C@H]2CN3C(C)(C)CO)nc2c(N3CCOCC3)nc(Cl)nc21
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CN(C)C=O
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3C[C@@H]4C[C@H]3CN4C(C)(C)CO)n(C)c2n1
Yield: 41.2 %

Procedure:
A mixture of 2-[(1S,4S)-5-(2-chloro-9-methyl-6-morpholin-4-yl-9H-purin-8-ylmethyl)-2,5-diazabicyclo[2.2.1]hept-2-yl]-2-methylpropan-1-ol (50 mg, 0.12 mmol), 2-ethyl-1H-benzoimidazole (20 mg, 0.14 mmol), Pd2dba3 (3 mg, 0.003 mmol), Xphos (6 mg, 0.012 mmol) and cesium carbonate (56 mg, 0.17 mmol) in DMF (1 mL) was purged with argon gas then subjected to microwave irradiation at 150° C. for 1 h. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge (10 g), which was washed with MeOH/DCM before the desired product was eluted with 2 M NH3 in MeOH/DCM. The product was collected and concentrated in vacuo. The resultant residue was purified by flash chromatography (Si—PPC, DCM:MeOH 100:0 to 95:5 to 90:10 to 80:20) to afford 521 as a tan solid (27 mg, 44%). LCMS (Method I): RT=2.50 min, M+H+=546. 1H NMR (CDCl3, 400 MHz) δ 8.01 (m, 1 H); 7.75 (m, 1 H); 7.28 (m, 2 H); 4.34 (m, 4 H); 4.02 (m, 2 H); 3.93-3.79 (m, 7 H); 3.49 (m, 2 H); 3.45-3.27 (m, 3 H); 2.89 (m, 2 H); 1.85 (s, 2 H); 1.64 (m, 3 H); 1.48-1.42 (m, 3 H) and 1.33-1.08 (m, 6 H)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:7]=[CH:6][S:5][CH:4]=1.[CH2:8](O)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]C.C1(C)C=CC=CC=1>C1(C)C=CC(S(O)(=O)=O)=CC=1.CO.C1(C)C=CC=CC=1>[CH2:1]([O:2][C:3]1[CH:7]=[CH:6][S:5][CH:4]=1)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: COc1ccsc1
Reactant: CCCCCCCCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: Cc1ccccc1
Product: CCCCCCCCCOc1ccsc1
Yield: 74.2 %

Procedure:
25 cm3 of 3-methoxythiophene (0.25 mole), 50 cm3 of 1-nonanol (0.28 mol) and 30 cm3 of toluene were heated to 120° C. together with 1 g of p-toluenesulfonic acid, and about 9.5 cm3 of a methanol/toluene mixture were distilled off over a period of 3 hours. The workup was carried out as described in Example 1. Fractionation through a 30 cm Vigreux column at 0.26 mbar gave 42 g of 3-n-nonyloxythiophene of boiling point 102° to 105° C., which corresponds to 74% of the theoretical yield. 1H-NMR and mass spectrum confirm the structure.
Reaction SMILES: O[CH2:2][CH2:3][O:4]/[N:5]=[C:6](/[C:8]1[N:13]=[C:12]2[N:14]([CH2:17][C:18]3[CH:19]=[C:20]4[C:25](=[CH:26][CH:27]=3)[N:24]=[CH:23][CH:22]=[CH:21]4)[N:15]=[N:16][C:11]2=[N:10][CH:9]=1)\[CH3:7].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:47]1(=[O:57])[C:55]2[C:50](=[CH:51][CH:52]=[CH:53][CH:54]=2)[C:49](=[O:56])[NH:48]1.N(/C(OC(C)C)=O)=N\C(OC(C)C)=O>C1COCC1>[N:24]1[C:25]2[C:20](=[CH:19][C:18]([CH2:17][N:14]3[C:12]4=[N:13][C:8](/[C:6](=[N:5]/[O:4][CH2:3][CH2:2][N:48]5[C:49](=[O:56])[C:50]6[C:55](=[CH:54][CH:53]=[CH:52][CH:51]=6)[C:47]5=[O:57])/[CH3:7])=[CH:9][N:10]=[C:11]4[N:16]=[N:15]3)=[CH:27][CH:26]=2)[CH:21]=[CH:22][CH:23]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: C/C(=N\OCCO)c1cnc2nnn(Cc3ccc4ncccc4c3)c2n1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C/C(=N\OCCN1C(=O)c2ccccc2C1=O)c1cnc2nnn(Cc3ccc4ncccc4c3)c2n1
Temperature: 25 °C
Reaction time: 48 h
Yield: 44.3 %

Procedure:
To a solution of (E)-1-(1-(quinolin-6-ylmethyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-6-yl)ethanone O-2-hydroxyethyl oxime (example 23) (200 mg, 0.55 mmol) in THF (10 mL) were added triphenylphosphine (144 mg, 0.55 mmol), isoindoline-1,3-dione (81 mg, 0.55 mmol) and (E)-diisopropyl diazene-1,2-dicarboxylate (111 mg, 0.55 mmol) sequentially. The mixture was stirred at rt for 48 h and concentrated in vacuo. The residue was purified by column chromatography to afford 120 mg (42%) of the title compound. 1H-NMR (400 MHz, DMSO-d6) δ ppm 8.90 (s, 1H), 8.89 (m, 1H), 8.35 (d, 1H), 8.02 (m, 2H), 7.81 (d, 1H), 7.71 (m, 2H), 7.63 (m, 2H), 7.52 (dd, 1H), 6.19 (s, 2H), 4.53 (t, 2H), 3.97 (t, 2H), 2.20 (s, 3H). LCMS (method B): [MH]+=493, tR=2.52 min.
Reaction SMILES: [CH3:1][N:2]([CH3:5])[CH:3]=O.N1C2[C:9](=[CH:10][C:11]([C:15]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([CH3:26])=[C:23]([F:25])[F:24])=[O:16])=[CH:12][CH:13]=2)[CH:8]=C1.CI.[H-].[Na+]>O>[CH3:1][N:2]1[C:5]2[C:9](=[CH:10][C:11]([C:15]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([CH3:26])=[C:23]([F:24])[F:25])=[O:16])=[CH:12][CH:13]=2)[CH:8]=[CH:3]1
Reactant: CN(C)C=O
Reactant: CC(CCCCOC(=O)c1ccc2[nH]ccc2c1)=C(F)F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CI
Product: CC(CCCCOC(=O)c1ccc2c(ccn2C)c1)=C(F)F
Reaction time: 1 h
Yield: 86 %

Procedure:
To 5 ml of N,N-dimethylformamide were dissolved 0.40 g (1.4 mmol) of 6,6-difluoro-5-methyl-5-hexenyl 1H-indole-5-carboxylate and 0.40 g (2.8 mmol) of methyl iodide, followed by the addition of 0.07 g (1.7 mmol) of sodium hydride at room temperature and stirring at the same temperature for 1 hour. The reaction liquid was then poured in water and extracted with diethyl ether. The organic layer was washed with water and a saturated saline solution in this order, followed by drying over anhydrous magnesium sulfate and concentration under reduced pressure. The residue was purified with silica gel column chromatography (ethyl acetate:hexane=1:5) to obtain 0.36 g (yield: 86%) of 6,6-difluoro-5-methyl-5-hexenyl 1-methyl-1H-indole-5-carboxylate.
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][C:7]2[S:11][C:10]([CH:12]3OCC[O:13]3)=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O.C(OCC)(=O)C.O>CO>[F:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][C:7]2[S:11][C:10]([CH:12]=[O:13])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1
Reactant: Fc1ccc(Cc2ccc(C3OCCO3)s2)cc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CCOC(C)=O
Solvent: CO
Solvent: O
Product: O=Cc1ccc(Cc2ccc(F)cc2)s1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-(5-(4-fluoro-benzyl)-thiophen-2-yl)-[1,3]dioxolane described in Preparation Example 36 (560 mg, 2.04 mmol) in methanol (20 mL) was added citric acid aqueous solution (20 mL), and the solution was stirred at room temperature for 30 minutes. Ethyl acetate and water were added to the reaction solution, which was then partitioned, the organic layer was washed with water twice, dried over anhydrous sodium sulfate, the solvent was evaporated in vacuo, and title compound (460 mg, 2.09 mmol) was obtained as a brown oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=O.Cl.[CH3:12][O:13][C:14](=[O:19])[C@H:15]([CH2:17][OH:18])[NH2:16].C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.CCN=C=NCCCN(C)C>CN(C=O)C.C(OCC)(=O)C>[CH3:12][O:13][C:14](=[O:19])[CH:15]([NH:16][C:5](=[O:7])[C:4]1[CH:8]=[CH:9][CH:10]=[C:2]([Cl:1])[CH:3]=1)[CH2:17][OH:18]
Reactant: O=C(O)c1cccc(Cl)c1
Reactant: COC(=O)[C@@H](N)CO
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: COC(=O)C(CO)NC(=O)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 87.6 %

Procedure:
To a mixture of 3-Chlorobenzoic acid (5.0 g, 31.9 mmol), serine methylester hydrochloride (6.1 g, 31.9 mmol) and HOBt (4.31 g, 31.9 mmol) in DMF (100 ml) was added N-methylmorpholine (NMM) (7.0 ml, 63.8 mmol) and EDCI (4.97 g, 31.9 mmol) at 0° C. The mixture was allowed to warm to room temperature and stirred for 18 h. The mixture was diluted with ethyl acetate (300 ml) and then washed with water (3×250 ml) followed by brine. The organic extract was dried over Na2SO4 (anhydrous) and then concentrated in vacuo giving 2-(3-Chloro-benzoylamino)-3-hydroxy-propionic acid methyl ester (7.2 g, 93%) of a pale yellow solid. 1H NMR (CDCl3) d (ppm): 7.78 (s, 1 H), 7.66 (d, 1 H), 7.45, (dd, 1 H), 7.34 (t, 1 H), 7.25 (br, d, 1H), 4.82 (m, 1 H), 4.08 (m, 2 H), 3.79 (s, 3 H), 3.19 (br, t, 1H).
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][CH:18]=[CH:17][C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH:13]=[C:14]([OH:16])[CH:15]=1)[C:9]([O:11][CH3:12])=[O:10].Br[CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:26]([O:25][C:23](=[O:24])[CH2:22][O:16][C:14]1[CH:13]=[C:8]([CH:7]=[C:6]([O:5][CH2:4][C:3]2[CH:17]=[CH:18][CH:19]=[CH:20][C:2]=2[F:1])[CH:15]=1)[C:9]([O:11][CH3:12])=[O:10])([CH3:29])([CH3:28])[CH3:27]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: COC(=O)c1cc(O)cc(OCc2ccccc2F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(OCC(=O)OC(C)(C)C)cc(OCc2ccccc2F)c1
Yield: 89.1 %

Procedure:
Methyl 3-(2-fluorobenzyloxy)-5-hydroxybenzoate (1.9 g, 1.0 eq., 6.9 mmole) was reacted with tert-butyl bromoacetate (1.6 g, 1.2 eq., 8.3 mmole) in the presence of potassium carbonate (2.4 g., 2.5 eq., 17.3 mmole) in dimethylformamide (5 mL) over 18 h. The product was partitioned between ethyl acetate and aqueous media. The combined organic extracts were dried over magnesium sulfate, filtered and evaporated to give 2.4 g (89% yield) of a yellow oil. The LC/MS was as expected with an (M+H+) of 391 calculated and found.
Reaction SMILES: [CH2:1]([N:3]([CH2:36][CH3:37])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[N:9]=[C:10]([C:27]2[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=2)[C:30](O)=[O:31])[C:11]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]3[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=3[F:26])[C:12]=2[N:13]=1)[CH3:2].[CH3:38][N:39](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.CN>CN(C=O)C.C1COCC1>[CH2:36]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[N:9]=[C:10]([C:27]2[CH:28]=[C:29]([CH:33]=[CH:34][CH:35]=2)[C:30]([NH:39][CH3:38])=[O:31])[C:11]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]3[C:20]([F:26])=[CH:21][CH:22]=[CH:23][C:24]=3[F:25])[C:12]=2[N:13]=1)[CH3:37]
Reactant: CCN(CC)CCCNc1nc(-c2cccc(C(=O)O)c2)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCN(CC)CCCNc1nc(-c2cccc(C(=O)NC)c2)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 30.7 %

Procedure:
To the compound 3-[2-{[3-(diethylamino)propyl]amino}-8-(2,6-difluorophenyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]benzoic acid (30 mg, 0.06 mmol) in DMF (0.5 mL) were added HBTU (27 mg, 0.072 mmol), triethylamine (16.9 uL, 0.12 mmol) and methylamine (45 uL, 0.09 mmol, 2M soln in THF). The mixture was stirred at rt overnight. Separation by HPLC with TFA, followed by neutralization with SPE amine cartridge afforded the title compound (9.6 mg, 31%). LC-MS m/z 521 (M+H)+.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[C:5]([NH2:10])[CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[C:11](OC(=O)C)(=[O:13])[CH3:12]>>[CH2:1]1[C:9]2[C:4](=[C:5]([NH:10][C:11](=[O:13])[CH3:12])[CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: Nc1cccc2c1CCC2
Reactant: CC(=O)OC(C)=O
Product: CC(=O)Nc1cccc2c1CCC2
Temperature: 70 °C
Reaction time: 16 h

Procedure:
226 mg (1.7 mmol) indan-4-ylamine are combined with 5 ml acetic anhydride. The suspension is stirred for 16 h at 70° C. The resulting solution is stirred into 40 ml distilled water, adjusted to pH 7 with sodium carbonate and extracted three times with 30 ml of ethyl acetate. Then the organic phase is dried with MgSO4, the solvent is eliminated in vacuo and the crude product is purified by chromatography. The carrier used is silica gel and the eluant used is a mixture of cyclohexane:ethyl acetate (70:30).
Reaction SMILES: Cl[C:2]1[C:11]2[N:12]=[CH:13][N:14]([CH2:15][CH2:16][CH:17]3[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]3)[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.[C:30]1([OH:36])[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.[OH-].[K+].[OH-].[Na+]>>[O:36]([C:2]1[C:11]2[N:12]=[CH:13][N:14]([CH2:15][CH2:16][CH:17]3[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]3)[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CCn2cnc3c(Cl)nc4ccccc4c32)CC1
Reactant: Oc1ccccc1
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Product: CC(C)(C)OC(=O)N1CCC(CCn2cnc3c(Oc4ccccc4)nc4ccccc4c32)CC1
Temperature: 120 °C
Reaction time: 7 h
Yield: 70.7 %

Procedure:
A mixture of 4.46 g of tert-butyl 4-[2-(4-chloro-1H-imidazo[4,5-c]quinolin-1-yl)ethyl]-1-piperidinecarboxylate, 10.1 g of phenol and 1.80 g of potassium hydroxide was stirred at 120° C. for 7 hours. The reaction mixture was adjusted to pH 10 with 10% aqueous sodium hydroxide solution, and extracted with ethyl acetate. The extract was washed successively with 10% aqueous sodium hydroxide solution and saturated brine, and dried, and then the solvent was evaporated to give a brown liquid. The resulting brown liquid was purified by silica gel column chromatography using ethyl acetate as an eluting solvent to give 3.59 g of a colorless solid. Recrystallization from a mixture of ethyl acetate and n-hexane gave colorless crystals having the melting point of from 130.5 to 132.5° C.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4](/[CH:7]=[CH:8]/[C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][CH:10]=2)=[N:5][N:6]=1.O1CCCC1>[C].[Pd].CO>[CH3:1][C:2]1[O:3][C:4]([CH2:7][CH2:8][C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)=[N:5][N:6]=1
Reactant: Cc1nnc(/C=C/c2ccc([N+](=O)[O-])cc2)o1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1nnc(CCc2ccc(N)cc2)o1
Temperature: 25 °C
Reaction time: 6 h
Yield: 102.8 %

Procedure:
To a mixture of 2-methyl-5-[(E)-2-(4-nitrophenyl)ethenyl]-1,3,4-oxadiazole (2.00 g), tetrahydrofuran (75 mL) and methanol (75 mL) was added palladium-carbon (Pd: 10%, 50% in water, 200 mg), and the mixture was stirred under a hydrogen atmosphere at room temperature for 6 hr. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give the title compound (1.807 g).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][C:11]=2[O:17][CH3:18])=[O:9])=[CH:6][N:5]=[C:4]([NH:19][CH:20]2[CH2:25][CH2:24][CH:23]([NH2:26])[CH2:22][CH2:21]2)[N:3]=1.[C:27](Cl)(=[O:29])[CH3:28]>>[NH2:1][C:2]1[C:7]([C:8](=[O:9])[C:10]2[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][C:11]=2[O:17][CH3:18])=[CH:6][N:5]=[C:4]([NH:19][CH:20]2[CH2:25][CH2:24][CH:23]([NH:26][C:27](=[O:29])[CH3:28])[CH2:22][CH2:21]2)[N:3]=1
Reactant: CC(=O)Cl
Reactant: COc1ccc(C)cc1C(=O)c1cnc(NC2CCC(N)CC2)nc1N
Product: COc1ccc(C)cc1C(=O)c1cnc(NC2CCC(NC(C)=O)CC2)nc1N

Procedure:
The similar procedure as described in Example 60 was used, starting from [4-amino-2-(4-amino-cyclohexylamino)-pyrimidin-5-yl]-(2-methoxy-5-methyl-phenyl)-methanone (Example 337) and acetyl chloride (Aldrich) to give N-[4-[4-amino-5-(2-methoxy-5-methyl-benzoyl)-pyrimidin-2-ylamino]-cyclohexyl]-acetamide. MS (M+H)+, 398.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[C:17]([F:18])=[CH:16][CH:15]=[CH:14][C:13]=1[C:19]1[N:24]=[CH:23][CH:22]=[CH:21][N:20]=1)=[O:11].F[C:26]1[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][N:27]=1>>[F:18][C:17]1[CH:16]=[CH:15][CH:14]=[C:13]([C:19]2[N:20]=[CH:21][CH:22]=[CH:23][N:24]=2)[C:12]=1[C:10]([N:4]1[CH2:5][CH2:6][CH2:7][C@@H:8]([CH3:9])[C@H:3]1[CH2:2][NH:1][C:26]1[CH:31]=[CH:30][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:28][N:27]=1)=[O:11]
Reactant: Fc1ccc(C(F)(F)F)cn1
Reactant: C[C@@H]1CCCN(C(=O)c2c(F)cccc2-c2ncccn2)[C@@H]1CN
Product: C[C@@H]1CCCN(C(=O)c2c(F)cccc2-c2ncccn2)[C@@H]1CNc1ccc(C(F)(F)F)cn1

Procedure:
The title compound was prepared following the same general protocol as described for Example A1 using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(6-fluoro-2-(pyrimidin-2-yl)phenyl)methanone and 2-fluoro-5-(trifluoromethyl)pyridine. ESI-MS (m/z): 474 [M+1]+. 1H NMR (500 MHz, DMSO-d6) δ 8.90-6.50 (m, 10H), 4.95-2.70 (m, 5H), 2.00-0.65 (m, 8H).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:12]=[C:11]2[C:7]([C:8](=[O:23])[N:9]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=3)[NH:10]2)=[CH:6][CH:5]=1.[CH3:24][Si:25]([CH2:28][CH2:29][O:30][CH2:31]Cl)([CH3:27])[CH3:26]>C1COCC1>[Br:3][C:4]1[CH:12]=[C:11]2[C:7]([C:8](=[O:23])[N:9]([C:13]3[CH:14]=[CH:15][C:16]([C:19]([F:20])([F:21])[F:22])=[CH:17][CH:18]=3)[N:10]2[CH2:31][O:30][CH2:29][CH2:28][Si:25]([CH3:27])([CH3:26])[CH3:24])=[CH:6][CH:5]=1
Reactant: O=c1c2ccc(Br)cc2[nH]n1-c1ccc(C(F)(F)F)cc1
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1c2cc(Br)ccc2c(=O)n1-c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A suspension of NaH in mineral oil (60%, 0.17 g, 0.0041 mol) was added portionwise to a solution of the product of Step 4 (1.3 g, 0.0035 mol) in dry THF (50 mL) at room temperature under N2. After 20 min, SEM chloride (0.68 g, 0.0041 mol) in THF (15 mL) was added and the resulting slurry stirred at room temperature overnight. The mixture was quenched with brine (10 mL) and extracted into ether (3×20 mL). The organic phase was washed with 1N HCl (10 mL), 2N NaOH (10 mL), brine (10 mL), dried (MgSO4) and concentrated to give crude product as an oil.
Reaction SMILES: O=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH:23]=[CH:22][CH:21]=[N:20]3)=[CH:15][CH:14]=2)[N:4]=[C:3]1[C:24]([O:26][CH2:27][CH3:28])=[O:25].COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:38]2)=CC=1>C1(C)C=CC=CC=1>[N:19]1([C:16]2[CH:15]=[CH:14][C:13]([CH2:12][N:5]3[C:6]4[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=4)[C:2](=[S:38])[C:3]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[N:4]3)=[CH:18][CH:17]=2)[CH:23]=[CH:22][CH:21]=[N:20]1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CCOC(=O)c1nn(Cc2ccc(-n3cccn3)cc2)c2ccccc2c1=O
Solvent: Cc1ccccc1
Product: CCOC(=O)c1nn(Cc2ccc(-n3cccn3)cc2)c2ccccc2c1=S
Temperature: 105 °C

Procedure:
Ethyl 4-oxo-1-{[4-(1H-pyrazol-1-yl)phenyl]methyl}-1,4-dihydrocinnoline-3-carboxylate (253 mg, 0.676 mmol) was suspended in toluene (3 mL) and treated with 2,4-bis-(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane 2,4-disulfide (Lawesson's Reagent, 164 mg, 0.405 mmol, 0.6 equiv). The mixture was heated at 105° C. for 1 hour, cooled to ambient temperature, and concentrated in vacuo. The residue was purified by silica gel chromatography (90:10 to 60:40; hexanes:ethyl acetate), providing the titled compound.
Reaction SMILES: [CH2:1]([NH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=2)[N:8]=[C:7](Cl)[N:6]=1)[CH:2]=[CH2:3].[C:19]([NH2:23])([CH3:22])([CH3:21])[CH3:20]>O>[CH2:1]([NH:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[CH:13]=2)[N:8]=[C:7]([NH:23][C:19]([CH3:22])([CH3:21])[CH3:20])[N:6]=1)[CH:2]=[CH2:3]
Reactant: C=CCNc1nc(Cl)nc2ccc([N+](=O)[O-])cc12
Reactant: CC(C)(C)N
Solvent: O
Product: C=CCNc1nc(NC(C)(C)C)nc2ccc([N+](=O)[O-])cc12
Yield: 93.7 %

Procedure:
At 80° C. were stirred 225 mg (0.85 mmol) of 4-allylamino-2-chloro-6-nitroquinazoline and 696 mg (9.52 mmol) of t-butylamine overnight. Water was added to the reaction mixture, followed by extraction with ethyl acetate, washing with brine and drying over anhydrous sodium sulfate. After the solvent was distilled off, the residue was purified by a silica gel column to give 240 mg (yield: 93.7%) of the title compound.