Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]([C:29](=O)[C:30]1[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[CH:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([O:22]C(=O)C(C)(C)C)[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2].Cl[CH:39]([CH3:48])[C:40]([N:42]1[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]1)=O>>[CH2:1]([N:3]([CH2:29][C:30]1[CH:31]=[CH:32][C:33]([O:36][CH:39]([CH3:48])[CH2:40][N:42]2[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]2)=[CH:34][CH:35]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[CH:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([OH:22])[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2]
Reactant: CC(Cl)C(=O)N1CCCCC1
Reactant: CCN(C(=O)c1ccc(O)cc1)c1cc(OC)ccc1C1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Product: CCN(Cc1ccc(OC(C)CN2CCCCC2)cc1)c1cc(OC)ccc1C1CCc2cc(O)ccc2C1
Yield: 42.5 %

Procedure:
Synthesized from pivalic acid 6-{2-[ethyl(4-hydroxybenzoyl)amino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (29 mg) and 2-chloro-1-piperidin-1-ylpropan-1-one (20 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (13 mg) was obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([C:12]2[NH:16][C:15]([CH3:17])=[C:14]([CH3:18])[CH:13]=2)=[O:11])=[CH:4][CH:3]=1.Br[CH2:20][CH:21]=[CH2:22]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]([C:12]2[N:16]([CH2:22][CH:21]=[CH2:20])[C:15]([CH3:17])=[C:14]([CH3:18])[CH:13]=2)=[O:11])=[CH:6][CH:7]=1
Reactant: C=CCBr
Reactant: Cc1cc(C(=O)CCc2ccc(F)cc2)[nH]c1C
Product: C=CCn1c(C(=O)CCc2ccc(F)cc2)cc(C)c1C
Yield: 60.3 %

Procedure:
The title compound was prepared as a pale yellow oil in 60.3% yield in a similar procedure to that described in Referential Example 97 by using. -5-[3-(4-fluorphenyl)propionyl)-2,3-dimethylpyrrole and 3-bromo-1-propene.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:6]=[CH:5][C:4]=1[CH2:21][CH2:22][C:23]([OH:25])=O.Cl.C(N=C=NCCCN(C)C)C.[Cl:38][C:39]1[CH:48]=[CH:47][C:46]([NH2:49])=[CH:45][C:40]=1[C:41]([O:43][CH3:44])=[O:42].CN(C1C=CC=CN=1)C.Cl>C(N(CC)CC)C.CN(C)C=O>[Cl:38][C:39]1[CH:48]=[CH:47][C:46]([NH:49][C:23](=[O:25])[CH2:22][CH2:21][C:4]2[CH:5]=[CH:6][C:7]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:8][C:3]=2[O:2][CH3:1])=[CH:45][C:40]=1[C:41]([O:43][CH3:44])=[O:42]
Reactant: COC(=O)c1cc(N)ccc1Cl
Reactant: COc1cc(OCCCCCc2ccccc2)ccc1CCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)c1cc(NC(=O)CCc2ccc(OCCCCCc3ccccc3)cc2OC)ccc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.9 %

Procedure:
To a mixture of 3-[2-methoxy-4-(5-phenylpentyloxy)phenyl]propanoic acid (342 mg), 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide hydrochloride (288 mg), 1-hydroxybenzotriazole-1-hydrate (153 mg) and dimethylformamide (5 mL) was added methyl 2-chloro-5-aminobenzoate (265 mg) and triethylamine (0.7 mL). To the reaction mixture was added dimethylaminopyridine (50 mg). The reaction mixture was stirred at room temperature overnight. 1N hydrochloric acid was added to the reaction mixture, which was extracted with ethyl acetate. The extract was washed with saturated aqueous solution of sodium hydrogen carbonate and brine, dried over an anhydrous sodium sulfate and concentrated. The obtained residue was purified by column chromatography on silica gel (hexane:ethyl acetate=4:1) to give the title compound (300 mg) having the following physical data.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9](B3OC(C)(C)C(C)(C)O3)=[CH:10]2)=[CH:5][CH:4]=1.[Cl:22][C:23]1[CH:24]=[C:25]([CH2:29][N:30]2[CH:34]=[CH:33][N:32]=[C:31]2[CH3:35])[N:26]=[N:27][CH:28]=1>>[ClH:22].[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9]([C:23]3[CH:24]=[C:25]([CH2:29][N:30]4[CH:34]=[CH:33][N:32]=[C:31]4[CH3:35])[N:26]=[N:27][CH:28]=3)=[CH:10]2)=[CH:5][CH:4]=1
Reactant: Cc1nccn1Cc1cc(Cl)cnn1
Reactant: COc1ccc2ccc(B3OC(C)(C)C(C)(C)O3)cc2c1
Product: COc1ccc2ccc(-c3cnnc(Cn4ccnc4C)c3)cc2c1
Product: Cl

Procedure:
The title compound, MS: m/e 331.3 (M+H+), was prepared from 2-(7-methoxy-naphthalen-2-yl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane and 5-chloro-3-(2-methyl-imidazol-1-yl-methyl)-pyridazine.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:12]([O-:14])=[O:13])[C:5]2[N:9]=[C:8]([CH3:10])[NH:7][C:6]=2[CH:11]=1.Br[CH2:16][C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([N+:12]([O-:14])=[O:13])[C:5]2[N:9]=[C:8]([CH3:10])[N:7]([CH2:16][C:17]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH:20]=[CH:19][CH:18]=3)[C:6]=2[CH:11]=1
Reactant: Cc1nc2c([N+](=O)[O-])cc(Br)cc2[nH]1
Reactant: BrCc1cccc2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1nc2c([N+](=O)[O-])cc(Br)cc2n1Cc1cccc2ccccc12
Temperature: 80 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
A mixture of 6-bromo-2-methyl-4-nitro-1H-benzo[d]imidazole (prepared following the same procedure as Example 1) (3 g), 1-(bromomethyl)naphthalene (2.85 g) and K2CO3 (3.23 g) in DMF (100 mL) was stirred at 80° C. overnight. It was cooled to room temperature and filtered. The filtrate was then poured into water. It was then filtered to afford a solid and the solid was washed with water and then dried in-vacuo to afford the desired product (4.63 g, 100%). 1H NMR (300 MHz, DMSO-d6) δ ppm 2.54 (s, 3H), 6.16 (s, 2H), 6.32 (d, 1H, J=7.5 Hz), 7.33 (t, 1H, J=7.5 Hz), 7.61-7.72 (m, 2H), 7.87 (d, 1H, J=7.5 Hz), 8.01 (d, 1H, J=7.5 Hz), 8.14 (d, 1H, J=1.8 Hz), 8.19 (d, 1H, J=7.5 Hz), 8.28 (d, 1H, J=1.8 Hz); LC-MS: m/e=296 [M+1]+.
Reaction SMILES: [CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[C:17]([F:18])=[CH:16][C:13]([CH:14]=O)=[C:12]([NH:19][C@H:20]([C:22]4[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=4)[CH3:21])[N:11]=3)[CH:5]=2)[CH2:3][CH2:2]1.[NH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl>[CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[C:17]([F:18])=[CH:16][C:13]([CH2:14][N:29]4[CH2:34][CH2:33][O:32][CH2:31][CH2:30]4)=[C:12]([NH:19][C@H:20]([C:22]4[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=4)[CH3:21])[N:11]=3)[CH:5]=2)[CH2:3][CH2:2]1
Reactant: C[C@H](Nc1nc(Nc2cc(C3CC3)[nH]n2)c(F)cc1C=O)c1ccc(F)cc1
Reactant: C1COCCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: C[C@H](Nc1nc(Nc2cc(C3CC3)[nH]n2)c(F)cc1CN1CCOCC1)c1ccc(F)cc1
Reaction time: 48 h
Yield: 63.9 %

Procedure:
To a solution of (S)-6-(5-cyclopropyl-1H-pyrazol-3-ylamino)-5-fluoro-2-(1-(4-fluorophenyl)ethylamino)nicotinaldehyde (Example 73, 0.12 g, 0.31 mmol) in DCE (5 ml) was added morpholine (0.1 g, 1.14 mmol) and NaBH(OAc)3 (0.30 g, 1.5 mmol). The reaction was then stirred for 2 days, quenched with aq. Na2CO3 (10 ml), and extracted with DCM (2×20 ml). The combined organic fractions were dried over Na2SO4, filtered, and then concentrated. The resulting oil was purified by reverse-phase column chromatography (5-35% ACN) to give the title compound (0.09 g, 67%). 1H NMR (400 MHz, CD3OD) δ 7.41 (br s, 2H), 7.06-7.02 (m, 3H), 6.13 & 5.44 (s, 1H), 5.12 & 4.97 (s, 1H), 3.63 (br s, 4H), 3.42 (br s, 2H), 2.41 (br s, 4H), 1.87-1.82 (m, 1H), 1.54 (d, J=6.5 Hz, 3H), 0.96-0.90 (m, 2H), 0.65-0.64 (m, 2H). MS: Calcd.: 454. Found: [M+H]+ 455.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2([N:15]3[CH2:20][CH2:19][N:18]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH2:17][CH2:16]3)[CH2:13][CH2:12][CH:11]([CH3:14])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[C:34](Cl)(Cl)=[O:35].[NH2:38][C:39]1[CH:40]=[N:41][C:42]2[C:47]([CH:48]=1)=[CH:46][CH:45]=[CH:44][CH:43]=2>C(Cl)Cl>[CH3:14][CH:11]1[CH2:12][CH2:13][C:8]([C:4]2[CH:3]=[C:2]([NH:1][C:34]([NH:38][C:39]3[CH:40]=[N:41][C:42]4[C:47]([CH:48]=3)=[CH:46][CH:45]=[CH:44][CH:43]=4)=[O:35])[CH:7]=[CH:6][CH:5]=2)([N:15]2[CH2:16][CH2:17][N:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:19][CH2:20]2)[CH2:9][CH2:10]1
Reactant: Nc1cnc2ccccc2c1
Reactant: O=C(Cl)Cl
Reactant: CC1CCC(c2cccc(N)c2)(N2CCN(c3ccccc3)CC2)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1CCC(c2cccc(NC(=O)Nc3cnc4ccccc4c3)c2)(N2CCN(c3ccccc3)CC2)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 1-(3-aminophenyl)-1-(4-phenylpiperazin-1-yl)-4-methyl-cyclohexane (cis isomer, 90 mg, 0.258 mmol) and triethylamine (90 μL, 0.65 mmol) in dry CH2Cl2 (7 mL) was brought to 0° C. using an ice bath. Phosgene (1.93 M in toluene, 160 μL) was added dropwise and the resulting mixture was stirred at 0° C., under a dry N2 atmosphere, for 30 minutes. 3-aminoquinoline (45 mg, 0.310 mmol) was added as a solid and the reaction was allowed to come to room temperature. Upon completion of the reaction (disappearance of 3-aminoquinoline) the mixture was diluted with an equal volume of CH2Cl2, washed with H2O, dried (Na2SO4) and concentrated to give the crude urea. Silica gel chromatography yielded pure N-[3-[4-methyl-1-(4-phenyl-1-piperazinyl)cyclohexyl]phenyl]-N'-3-quinolinyl-urea (cis isomer) as an off-white solid. The HCl salt was prepared by adding excess saturated EtOAc/HCl solution to the free base in dry MeOH. Concentration of the homogeneous solution yielded a solid which was washed with EtOAc. mp=180-181° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH2:7])=[O:6].[F:11][C:12]([F:19])([F:18])[C:13]([F:17])([F:16])[CH:14]=O.[NH:20]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[N:22]=[N:21]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>>[N:20]1([CH:14]([NH:7][C:5](=[O:6])[C:4]2[CH:8]=[CH:9][CH:10]=[C:2]([Cl:1])[CH:3]=2)[C:13]([F:17])([F:16])[C:12]([F:19])([F:18])[F:11])[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[N:22]=[N:21]1
Reactant: O=CC(F)(F)C(F)(F)F
Reactant: c1ccc2[nH]nnc2c1
Reactant: NC(=O)c1cccc(Cl)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: O=C(NC(n1nnc2ccccc21)C(F)(F)C(F)(F)F)c1cccc(Cl)c1

Procedure:
3-Chlorobenzamide, pentafluoropropanal, benzotriazole, and p-toluenesulfonic acid were processed as described in Example 53A to provide the desired product.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:13][CH:14]=2)O1.C([O-])([O-])=O.[K+].[K+].Br[C:30]1[CH:35]=[C:34]([N+:36]([O-:38])=[O:37])[CH:33]=[CH:32][C:31]=1[O:39][CH3:40].O>CN(C=O)C>[CH3:40][O:39][C:31]1[CH:32]=[CH:33][C:34]([N+:36]([O-:38])=[O:37])=[CH:35][C:30]=1[C:9]1[CH2:10][CH2:11][N:12]([C:15]([O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:16])[CH2:13][CH:14]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: COc1ccc([N+](=O)[O-])cc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc([N+](=O)[O-])cc1C1=CCN(C(=O)OC(C)(C)C)CC1
Temperature: 80 °C
Yield: 45.2 %

Procedure:
To a 250-mL RB-flask containing tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-1(2H)-pyridinecarboxylate (3.09 g, 10.0 mmol), K2CO3 (4.14 g, 30.0 mmol) and PdCl2dppf (419 mg) was added a solution of 2-bromo-4-nitroanisole (2.30 g, 10 mmol) in DMF (10.0 mL) at room temperature under argon. The mixture was heated to 80° C. under argon overnight. After cooled to room temperature, water (500 mL) was added to the mixture. The aqueous layer was extracted with EtOAc (2×200 mL) and the combined organic extracts were dried over K2CO3, filtered and concentrated in vacuo. The crude material was purified on flash chromatography (20% EtOAc/hexane) to give tert-butyl 4-(2-methoxy-5-nitrophenyl)-3,6-dihydro-1(2H)-pyridinecarboxylate (1.51 g, 46%): ESMS m/e: 334.9 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][N:8]2[CH2:11][C:12]2[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.N1C=CC=CC=1.C(Cl)Cl.Cl[C:32]([O:34][CH:35]1[CH2:39][CH2:38][CH2:37][CH2:36]1)=[O:33].[C:40](OCC)(=[O:42])C>>[CH:35]1([O:34][C:32]([NH:1][C:2]2[CH:10]=[C:9]3[C:5]([CH:6]=[N:7][N:8]3[CH2:11][C:12]3[CH:21]=[CH:20][C:15]([C:16]([O:18][CH3:19])=[O:17])=[CH:14][C:13]=3[O:42][CH3:40])=[CH:4][CH:3]=2)=[O:33])[CH2:39][CH2:38][CH2:37][CH2:36]1
Reactant: CCOC(C)=O
Reactant: COC(=O)c1ccc(Cn2ncc3ccc(N)cc32)cc1
Reactant: O=C(Cl)OC1CCCC1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1ccc(Cn2ncc3ccc(NC(=O)OC4CCCC4)cc32)c(OC)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 73 %

Procedure:
To a mixture of indazole (L) (150 mg), pyridine (0.05 ml) and methylene chloride (2 ml), at -20° C., was added cyclopentyl chloroformate (0.07 ml). The reaction was warmed to 25° C. and stirred for 1 hour. The reaction mixture was added to ethyl acetate, and the ethyl acetate solution washed with saturated sodium carbonate, 1N HCl, and brine, and dried (MgSO4). Evaporation and trituration with diethyl ether gave methyl 4-[6-(cyclopentyloxycarbonyl)aminoindazol-1-ylmethyl]-3-methoxybenzoate (M) (148 mg, 73%) as a solid; mp 150.0°-151.0° C.
Reaction SMILES: COC[O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:20]([CH3:21])=[CH:19][C:18]3[C:17]([CH3:23])([CH3:22])[CH2:16][CH2:15][C:14]([CH3:25])([CH3:24])[C:13]=3[CH:12]=2)=[CH:7][C:6]=1[C:26](=[CH2:30])[C:27]([OH:29])=[O:28].CO.[CH2:33]1COCC1.S(=O)(=O)(O)O>O>[OH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:20]([CH3:21])=[CH:19][C:18]3[C:17]([CH3:23])([CH3:22])[CH2:16][CH2:15][C:14]([CH3:25])([CH3:24])[C:13]=3[CH:12]=2)=[CH:7][C:6]=1[C:26](=[CH2:30])[C:27]([O:29][CH3:33])=[O:28]
Reactant: C=C(C(=O)O)c1cc(-c2cc3c(cc2C)C(C)(C)CCC3(C)C)ccc1OCOC
Reactant: C1CCOC1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CO
Product: C=C(C(=O)OC)c1cc(-c2cc3c(cc2C)C(C)(C)CCC3(C)C)ccc1O
Temperature: 25 °C
Reaction time: 12 h

Procedure:
1.9 g (4.35 mmol) of 2-methoxymethoxy-5-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)phenylacrylic acid, 20 ml of methanol and 30 ml of THF are introduced into a round-bottomed flask. 2.8 ml of concentrated sulphuric acid are added and the mixture is stirred at room temperature for 12 hours. The reaction medium is poured into water and extracted with ethyl ether, and the organic phase is. separated out after settling has taken place, washed with water, dried over magnesium sulphate and evaporated. 1.63 g (95%) of methyl 2-hydroxy-5-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)phenylacrylate are collected.
Reaction SMILES: [NH:1]1[CH:8]=[C:7]([CH2:9][C:10]([OH:12])=O)[C:5](=[O:6])[NH:4][C:2]1=[O:3].CN1CCOCC1.[C:20]([CH:27]([NH2:36])[CH2:28][NH:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21].F[B-](F)(F)F.O=C1C2C=CC=CC=2N=NN1OC(N(C)C)=[N+](C)C>C(OCC)(=O)C.CN(C=O)C>[C:20]([CH:27]([NH2:36])[CH2:28][N:29]([C:10](=[O:12])[CH2:9][C:7]1[C:5](=[O:6])[NH:4][C:2](=[O:3])[NH:1][CH:8]=1)[CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21]
Reactant: O=C(O)Cc1c[nH]c(=O)[nH]c1=O
Reactant: CCOC(=O)CNCC(N)C(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2ccccc2c1=O)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Solvent: CCOC(C)=O
Product: CCOC(=O)CN(CC(N)C(=O)OC(C)(C)C)C(=O)Cc1c[nH]c(=O)[nH]c1=O
Temperature: 0 °C
Reaction time: 3 h

Procedure:
Uracil-5-ylacetic acid (34, 1.0 g, 5.9 mmol) was transferred to a round bottomed flask equipped with a septum through which a flow of nitrogen was applied. Dry DMF (10 ml) and N-methylmorpholine (1.9 ml, 17.6 mmol) were transferred to the flask and the mixture was cooled to 0° C. Ethyl N-(2-BOC-aminoethyl)glycinate (1.6 g, 6.5 mmol) and O-(3,4-dihydro-4-oxo-1,2,3-benzotriazin-3-yl)-N,N,N′,N′-tetramethyl uronium tetrafluoroborate (TDBTU, 2.5 g, 7.0 mmol) were added to the mixture. The reaction mixture was stirred for 3 hours at 0° C. and was then poured into ethyl acetate (300 ml). The resultant suspension was washed with saturated aqueous potassium hydrogen sulfate (2×50 ml), saturated aqueous sodium bicarbonate (2×50 ml) and with brine (1×50 ml). The organic phase was dried over magnesium sulfate, filtered and evaporated under reduced pressure. The residue was stirred overnight in dichloromethane (10 ml) and diethyl ether (40 ml). The resultant precipitate was isolated by filtration, washed once with diethyl ether and dried to give 1.13 g (48%) of the title compound as white crystals.
Reaction SMILES: [C:1]([C@@H:5]1[CH2:10][CH2:9][C@H:8]([NH:11][C:12]2[C:17](I)=[C:16]([CH2:19][CH3:20])[N:15]=[CH:14][N:13]=2)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[Cu][C:22]#[N:23]>O.ClCCl>[C:1]([C@@H:5]1[CH2:10][CH2:9][C@H:8]([NH:11][C:12]2[C:17]([C:22]#[N:23])=[C:16]([CH2:19][CH3:20])[N:15]=[CH:14][N:13]=2)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCc1ncnc(N[C@H]2CC[C@@H](C(C)(C)C)CC2)c1I
Reactant: N#C[Cu]
Solvent: O
Solvent: ClCCl
Product: CCc1ncnc(N[C@H]2CC[C@@H](C(C)(C)C)CC2)c1C#N

Procedure:
1.8 g (5 mmol) of 4-(cis-4-tert-butylcyclohexylamino)-6-ethyl-5-iodopyrimidine (Example 1) and 1.0 g of copper(I) cyanide were stirred at 200° C. for 30 minutes without solvent. After cooling, the mixture was taken up in water/dichloromethane, the organic phase was again extracted by stirring with aqueous ammonia solution, and the extract was dried and concentrated. The crude product was purified by chromatography on silica gel using petroleum ether/ethyl acetate (7:3), to give 750 mg (52.4% of theory) of a colorless oil which crystallized on standing.
Reaction SMILES: Cl[C:2]1[N:3]([CH3:19])[C:4](=[O:18])[C:5]2[C:10]([NH:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:9][NH:8][C:6]=2[N:7]=1.Cl.[NH2:21][C@@H:22]1[CH2:27][CH2:26][CH2:25][CH2:24][C@H:23]1[OH:28].CCN(C(C)C)C(C)C>CN(C=O)C>[OH:28][C@@H:23]1[CH2:24][CH2:25][CH2:26][CH2:27][C@H:22]1[NH:21][C:2]1[N:3]([CH3:19])[C:4](=[O:18])[C:5]2[C:10]([NH:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:9][NH:8][C:6]=2[N:7]=1
Reactant: Cn1c(Cl)nc2[nH]nc(Nc3ccccc3)c2c1=O
Reactant: N[C@@H]1CCCC[C@H]1O
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1c(N[C@@H]2CCCC[C@H]2O)nc2[nH]nc(Nc3ccccc3)c2c1=O
Yield: 64.7 %

Procedure:
A solution of 6-chloro-5-methyl-3-(phenylamino)-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one (75.8 mg, 0.275 mmol), trans-2-amino-cyclohexanol hydrochloride (83.4 mg, 0.55 mmol) and DIPEA (144 μL, 0.825 mmol) in DMF (3 mL) is heated at 110° C. overnight. The reaction mixture is evaporated to remove DMF under reduced pressure. The residue is then purified by chromatography to give 63.1 mg product (Yield: 64.7%). MS (ESI) m/z 355.0 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:26])=[C:8]2[CH:16]=[CH:15][N:14]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=3)[C:9]2=[C:10]([C:12]#[N:13])[N:11]=1)=[O:5])[CH3:2].[C:27](OC(=O)C)(=[O:29])[CH3:28]>C(N(CC)CC)C>[CH2:1]([O:3][C:4]([C:6]1[C:7]([O:26][C:27](=[O:29])[CH3:28])=[C:8]2[CH:16]=[CH:15][N:14]([CH2:17][C:18]3[CH:19]=[CH:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=3)[C:9]2=[C:10]([C:12]#[N:13])[N:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nc(C#N)c2c(ccn2Cc2ccc(OC)cc2)c1O
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1nc(C#N)c2c(ccn2Cc2ccc(OC)cc2)c1OC(C)=O

Procedure:
Prepared in analogy to that of Example 120(a) from 7-cyano-4-hydroxy-1-(4-methoxy-benzyl)-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester, acetic anhydride, and triethylamine. The title compound, ESI MS (m/z): 394 (M+H)+.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(N(CCCC)C2CCCCC2)CCCCC1.[O:33]=CCCCC(OC)=O.[C:42]([O:45][CH2:46][CH2:47][CH2:48][CH:49](N(C1CCCCC1)C1CCCCC1)[CH:50]([O:53][CH3:54])[O:51][CH3:52])(=O)C>>[CH2:9]([N:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH:49]([CH:50]([O:53][CH3:54])[O:51][CH3:52])[CH2:48][CH2:47][C:46]([O:45][CH3:42])=[O:33])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: c1ccc(CNCc2ccccc2)cc1
Reactant: COC(OC)C(CCCOC(C)=O)N(C1CCCCC1)C1CCCCC1
Reactant: COC(=O)CCCC=O
Agent: CCCCN(C1CCCCC1)C1CCCCC1
Product: COC(=O)CCC(C(OC)OC)N(Cc1ccccc1)Cc1ccccc1
Reaction time: 48 h
Yield: 67 %

Procedure:
The product was prepared by above general procedure and the same chemicals except employing dibenzylamine (1a′) (98 mg, 0.5 mmol), and methyl 5-oxopentanoate (2h′) (97 mg, 0.75 mmol). After 48 h, the crude product was purified by flash column chromatography (silica gel; ethyl acetate or diethyl ether/hexane=1:100) to afford the desired product 3h as a light yellowish oil (0.124g, 67% yield); Rf=0.54 (hexane:ethyl acetate=3:1); 1H NMR (CDCl3, 400 MHz) δ 7.33-7.27 (m, 8H), 7.25-7.19 (m, 2H), 4.44-4.42 (d, J=5.53 Hz, 1H), 3.82-3.63 (m, 4H), 3.55 (s, 3H), 3.363-3.359 (m, 6H), 2.78-2.73 (m, 1H), 2.53-2.26 (m, 2H), 1.86-1.70 (m, 2H) ppm; 13C NMR (CDCl3, 100 MHz) δ 174.2, 140.2 (C×2), 129.1 (CH×4), 128.1 (CH×4), 126.8 (CH2×2), 106.7, 56.6, 54.8, 54.2 (CH2×2), 53.6, 51.3, 31.1, 21.9 ppm; FTIR (neat): v=3017, 1454, 1215, 758, 494 cm−1; HRMS (ESI, m/z): calcd for C22H30NO4+ [M+H]+ 372.2175, found: 372.2178.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4](Cl)=[O:5].[NH2:7][C:8]1[C:17]([Cl:18])=[C:16]([Cl:19])[CH:15]=[C:14]2[C:9]=1[N:10]=[C:11]([O:22][CH3:23])[C:12]([O:20][CH3:21])=[N:13]2.N1C=CC=CC=1>ClCCl>[Cl:18][C:17]1[C:8]([NH:7][C:4](=[O:5])[CH2:3][O:2][CH3:1])=[C:9]2[C:14](=[CH:15][C:16]=1[Cl:19])[N:13]=[C:12]([O:20][CH3:21])[C:11]([O:22][CH3:23])=[N:10]2
Reactant: COCC(=O)Cl
Reactant: COc1nc2cc(Cl)c(Cl)c(N)c2nc1OC
Solvent: ClCCl
Solvent: c1ccncc1
Product: COCC(=O)Nc1c(Cl)c(Cl)cc2nc(OC)c(OC)nc12
Reaction time: 18 h
Yield: 88 %

Procedure:
Methoxyacetylchloride (27.3 ml, 32.4 g, 0.30 mol) was added to a stirred mixture of 5-amino-6,7-dichloro-2,3-dimethoxyquinoxaline (Preparation 2) (73.8 g, 0.27 mol) and pyridine (26.4 ml, 25.89, 0.33 mol) in dichloromethane (1.2 liters) at room temperature under nitrogen. After 18 hours standing at room temperature, the mixture was washed with 2M aqueous hydrochloric acid solution followed by brine, then dried (MgSO4) and concentrated under reduced pressure. The residue was triturated with methanol and filtered to give 6,7-dichloro-2,3-dimethoxy-5-methoxyacetamidoquinoxaline (82.09, 88%) as an off-white solid. mp 171-173° C.
Reaction SMILES: [CH:1]([C:4]1[C:9]([CH2:10][OH:11])=[C:8]([C:12]2[CH:17]=[CH:16][C:15]([CH2:18][CH3:19])=[CH:14][CH:13]=2)[C:7]([CH:20]=[CH:21][CH2:22][CH2:23][CH3:24])=[C:6]([CH:25]([CH3:27])[CH3:26])[N:5]=1)([CH3:3])[CH3:2]>C(OCC)(=O)C.CCCCCC>[CH:1]([C:4]1[C:9]([CH2:10][OH:11])=[C:8]([C:12]2[CH:13]=[CH:14][C:15]([CH2:18][CH3:19])=[CH:16][CH:17]=2)[C:7]([CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[C:6]([CH:25]([CH3:26])[CH3:27])[N:5]=1)([CH3:3])[CH3:2]
Reactant: CCCC=Cc1c(C(C)C)nc(C(C)C)c(CO)c1-c1ccc(CC)cc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCCCCc1c(C(C)C)nc(C(C)C)c(CO)c1-c1ccc(CC)cc1

Procedure:
The title compound was prepared from 2,6-diisopropyl-3-hydroxymethyl-4-(4ethylphenyl)5(pent-1-enyl)pyridine (Example 131) by the procedure described in Example 126. 1H NMR (300 MHz, CDCl3): δ 0.77 (t, J=7.0 Hz, 3 H), 1.0-1.40 (m, 22 H), 2.28 (m, 2 H), 2.73 (q, J=7.5 Hz, 2 H), 3.35 (m, 1 H), 3.45 (m, 1 H), 4.35 (s, 2 H), 7.10 (d, J=8.0 Hz, 2 H), 7.18-7.34 (d, J=8.0 Hz, 2 H). FAB-MS: calculated for C25H37NO 368; found 368 (M+H, 100%). Rf=0.31 (10% ethyl acetate/n-hexane). mp 87-88° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N+:18]([O-:20])=[O:19])=[C:6]([C:8]2[O:12][N:11]=[C:10]([C:13](OCC)=[O:14])[N:9]=2)[CH:7]=1.[BH4-].[Li+]>C(O)C>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N+:18]([O-:20])=[O:19])=[C:6]([C:8]2[O:12][N:11]=[C:10]([CH2:13][OH:14])[N:9]=2)[CH:7]=1
Reactant: CCOC(=O)c1noc(-c2cc(C)ccc2[N+](=O)[O-])n1
Agent: [BH4-]
Agent: [Li+]
Solvent: CCO
Product: Cc1ccc([N+](=O)[O-])c(-c2nc(CO)no2)c1
Reaction time: 1 h
Yield: 67.6 %

Procedure:
Ethyl 5-(5-methyl-2-nitro-phenyl)-1,2,4-oxadiazole-3-carboxylate (60 mg, 0.22 mmol) was dissolved in ethanol (3 mL) and treated with lithium borohydride (9 mg, 0.4 mmol) at room temperature. The mixture was stirred for 1 h then quenched with saturated ammonium chloride and extracted into dichloromethane. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo to provide (5-(5-methyl-2-nitrophenyl)-1,2,4-oxadiazol-3-yl)methanol (35 mg, 69% yield). LC/MS m/z 236.0 [M+H]+.