Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[NH:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[N:17]=[C:16]([CH3:21])[C:15]([C:22]([O:24]C(C)(C)C)=[O:23])=[C:14]2[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C(O)(C(F)(F)F)=O>[CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[NH:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[N:17]=[C:16]([CH3:21])[C:15]([C:22]([OH:24])=[O:23])=[C:14]2[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: Cc1nc2ccc(NC3Cc4ccccc4C3)cc2c(-c2ccccc2)c1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: Cc1nc2ccc(NC3Cc4ccccc4C3)cc2c(-c2ccccc2)c1C(=O)O
Yield: 89.1 %

Procedure:
A mixture of the product of Step 3 (1.4 g, 3.1 mmol), in anhydrous CF3COOH (3 ml) was stirred for 24 h at room temperature under N2, than evaporated to dryness under reduced pressure. The residue was dried in vacuo for 1 h and suspended in H2O (10 ml) and the pH of the mixture was adjusted to ˜8 with NH4OH. This was filtered and filtrate was partially evaporated under reduced pressure. The precipitate formed was filtered off, washed with H2O, small volume of EtOH, Et2O and dried in vacuo to give pure product as a deep yellow solid (1.09 g, 89%). 1H NMR (300 MHz, DMSO-d6) δ 7.69 (d, J=9.0 Hz, 1H), 7.3-7.5(m, 5H), 7.06-7.2(m, 5H), 6.42(m, 1H), 6.28(d, J=2.4 Hz, 1H), 3.93(m, 1H), 3.08(dd, J=7.0, 16 Hz, 2H), 2.72(dd, J=7.0, 16 Hz, 2H), 2.55(s, 3H). LCMS, >99%, m/z (%): 395 (M+·, 100).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:14]=[CH:13][C:9]3[O:10][CH2:11][O:12][C:8]=3[C:7]=2[C:15]2[C:16]3[NH:23][CH:22]=[C:21]([C:24](O)=[O:25])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:3][CH2:2]1.[C:27]([O:31][C:32](=[O:41])[NH:33][C@H:34]1[CH2:39][CH2:38][C@H:37]([NH2:40])[CH2:36][CH2:35]1)([CH3:30])([CH3:29])[CH3:28]>>[C:27]([O:31][C:32](=[O:41])[NH:33][C@H:34]1[CH2:35][CH2:36][C@H:37]([NH:40][C:24]([C:21]2[C:17]3[N:18]=[CH:19][N:20]=[C:15]([C:7]4[C:8]5[O:12][CH2:11][O:10][C:9]=5[CH:13]=[CH:14][C:6]=4[O:5][CH2:4][CH:1]4[CH2:3][CH2:2]4)[C:16]=3[NH:23][CH:22]=2)=[O:25])[CH2:38][CH2:39]1)([CH3:30])([CH3:28])[CH3:29]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](N)CC1
Reactant: O=C(O)c1c[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ncnc12
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](NC(=O)c2c[nH]c3c(-c4c(OCC5CC5)ccc5c4OCO5)ncnc23)CC1

Procedure:
Starting from 4-(5-cyclopropylmethoxy-1,3-benzodioxol-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example A67) and trans-(4-amino-cyclohexyl)-carbamic acid tert-butyl ester the title compound is obtained as colorless solid.
Reaction SMILES: O[Li].O.[Cl:4][C:5]1[CH:6]=[CH:7][N:8]2[CH2:13][CH2:12][N:11]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[N:19]([CH2:23][C:24]([O:26]C(C)(C)C)=[O:25])[CH:18]=[CH:17]4)[C:10](=[O:31])[C:9]=12>O.CO>[Cl:4][C:5]1[CH:6]=[CH:7][N:8]2[CH2:13][CH2:12][N:11]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[N:19]([CH2:23][C:24]([OH:26])=[O:25])[CH:18]=[CH:17]4)[C:10](=[O:31])[C:9]=12
Reactant: CC(C)(C)OC(=O)Cn1ccc2cc(N3CCn4ccc(Cl)c4C3=O)ccc21
Agent: [Li]O
Solvent: O
Solvent: CO
Product: O=C(O)Cn1ccc2cc(N3CCn4ccc(Cl)c4C3=O)ccc21
Temperature: 50 °C
Yield: 78 %

Procedure:
A solution of LiOH.H2O (4.0 equiv.) in water (5 ml) was added at 0° C. to a solution of tert-butyl 2-(5-(8-chloro-1-oxo-3,4-dihydropyrrolo[1,2-a]pyrazin-2(1H)-yl)-1H-indol-1-yl)acetate (1.5 mmol, 1.0 equiv.) in MeOH (20 ml), and the mixture was heated for 16 h at 50° C. The methanol was concentrated under reduced pressure, and the aqueous residue was diluted with water (20 ml) and extracted with ethyl acetate (2×15 ml). The aqueous phase was adjusted to pH 4 with 1 M HCl, the desired product precipitating in the form of a white solid. The solid was filtered out and dried. Yield: 78%
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:13]([OH:15])=O)[CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[NH2:16][CH2:17][CH2:18][CH2:19][N:20]1[CH2:25][CH2:24][CH:23]([C:26]2[CH:27]=[C:28]([NH:33][C:34](=[O:38])[CH:35]([CH3:37])[CH3:36])[CH:29]=[CH:30][C:31]=2[CH3:32])[CH2:22][CH2:21]1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:13]([NH:16][CH2:17][CH2:18][CH2:19][N:20]3[CH2:25][CH2:24][CH:23]([C:26]4[CH:27]=[C:28]([NH:33][C:34](=[O:38])[CH:35]([CH3:37])[CH3:36])[CH:29]=[CH:30][C:31]=4[CH3:32])[CH2:22][CH2:21]3)=[O:15])[CH2:9][CH2:10][CH2:11][CH2:12]2)=[CH:6][CH:7]=1
Reactant: O=C(O)C1(c2ccc(F)cc2)CCCC1
Reactant: Cc1ccc(NC(=O)C(C)C)cc1C1CCN(CCCN)CC1
Product: Cc1ccc(NC(=O)C(C)C)cc1C1CCN(CCCNC(=O)C2(c3ccc(F)cc3)CCCC2)CC1

Procedure:
Example 93 was prepared from 1-(4-fluorophenyl)cyclopentanecarboxylic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]-4-methylphenyl}-2-methylpropanamide according to the procedures described in Scheme 10: 1H NMR (400 MHz, CDCl3) δ 7.43–7.37 (m, 3H), 7.29–7.27 (m, 2H), 7.09 (d, 1H, J=8.4 Hz), 7.04–7.00 (m, 2H), 6.47 (br s, 1H), 3.29 (dd, 2H, J=5.6, 12.0 Hz), 2.94 (d, 2H, J=12.0 Hz), 2.66 (m, 1H), 2.54–2.48 (m, 3H), 2.33–2.30 (m, 2H), 2.29 (s, 3H), 2.03–1.95 (m, 4H), 1.84–1.60 (m, 10H), 1.26 (d, 6H, J=6.8 Hz); ESMS m/e: 508.3 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:5]=1[OH:11].[CH3:13][O:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19]Cl)=[CH:17][CH:16]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:5]=1[O:11][CH2:19][C:18]1[CH:21]=[CH:22][C:15]([O:14][CH3:13])=[CH:16][CH:17]=1
Reactant: COC(=O)c1cc(C)ccc1O
Reactant: COc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(C)ccc1OCc1ccc(OC)cc1
Temperature: 60 °C
Reaction time: 48 h

Procedure:
A mixture of 2-hydroxy-5-methylbenzoic acid methyl ester (4.98 g, 30 mmol), 4-methoxybenzyl chloride (4.69 g, 30 mmol) and K2CO3 (4.55 g, 33 mmol) in DMF (50 mL) is stirred at 60° C. for 48 h. The mixture is diluted with EtOAc and washed with 1N HCl and brine then the organic phase is dried over magnesium sulfate. The solvent is removed under reduced pressure and the residue is purified by column chromatography using a gradient of 0-100% EtOAc/hexane as eluent to give the title compound as a colorless oil.
Reaction SMILES: OO.C(O)(=[O:5])C.[C:7]([C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1)(=[O:9])[CH3:8].C([O-])([O-])=O.[K+].[K+]>CC(O)C>[C:7]([C:10]1[CH:11]=[N+:12]([O-:5])[CH:13]=[CH:14][CH:15]=1)(=[O:9])[CH3:8]
Reactant: CC(=O)c1cccnc1
Reactant: CC(=O)O
Agent: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: CC(C)O
Product: CC(=O)c1ccc[n+]([O-])c1
Temperature: 25 °C

Procedure:
Hydrogen peroxide (20.9 ml, 0.61453 moles, Baker) and acetic acid (125 ml, Baker) were combined and stirred at room temperature (RT). The 3-acetylpyridine (50 ml, 0.40984 moles, Aldrich), distilled prior to use (94° C., 2.00 mm Hg), was added and then, the reaction mixture was stirred overnight (O/N) at 95° C. Next, the reaction mixture was cooled to RT and then, neutralized with saturated K2CO3 (400 ml). Then, 5 g of KSO3 was added to destroy the remaining hydrogen peroxide. Next, methanol (750 ml) was added and the resultant cloudy solution was filtered. The filtrate was then evaporated to dryness using a rotary evaporator. The semi-solid was extracted repeatedly with hot CH2Cl2 (4×500 ml) and combined. Next, the solvent was removed leaving approximately 44 g of a crude, pale yellow solid. The crude solid was dissolved in hot 2-propanol (150 ml) and stirred until cool in an icebath. The white solid which precipitated was collected, washed with 2-propanol (100 ml) and dried in a vacuum dessicator O/N at 50° C. The air-dried weight was 41 g. HPLC analysis of the recrystallized sample (m.p. 146°-147° C.) showed a single principal peak 96% by area.
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3]=1I.[Li+].[Cl-].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C([O-])([O-])=O.[K+].[K+].[C:41]1([C:47]#[C:48][CH3:49])[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>CN(C=O)C.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:41]1([C:47]2[NH:1][C:2]3[C:3]([C:48]=2[CH3:49])=[CH:4][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:11][CH:12]=3)[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: CC#Cc1ccccc1
Reactant: CCOC(=O)c1ccc(N)c(I)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc2[nH]c(-c3ccccc3)c(C)c2c1
Temperature: 80 °C
Reaction time: 20 h
Yield: 57.2 %

Procedure:
Adapting the procedure of H.-C. Zhang (Tet. Lett. 1997, 38, 2439) ethyl 4-amino-3-iodobenzoate (from example 10, 0.500 g, 1.72 mmol) was dissolved in DMF (5 mL) and LiCl (0.073 g, 1.72 mmol, 1 equivalent), PPh3 (0.090 g, 0.34 mmol, 0.2 equivalent), K2CO3 (1.188 g, 8.6 mmol, 5 equivalents) and phenylpropyne (0.645 mL, 5.76 mmol, 3 equivalents) were added. The solution was degassed by purging with argon for 1 h and palladium acetate (0.039 g, 0.17 mmol, 0.1 equivalent) was added. The mixture was stirred at 80° C. under argon for 20 h. The reaction mixture was diluted with water (25 mL) and extracted with EtOAc (50 mL). The extract was washed with brine (3×25 mL) and dried (MgSO4). Concentration under reduced pressure and purification by flash chromatography with 10-15% EtOAc-hexane gave the desired 2-phenyl-3-methyl indole (0.275 g, least polar component) and the 3-phenyl-2-methyl isomer (0.109 g, more polar component).
Reaction SMILES: [C:1]([C:3]1[C:4]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:5]([C:17]([OH:19])=O)[S:6][C:7]=1[S:8][C:9]1[C:14]([Cl:15])=[CH:13][N:12]=[CH:11][C:10]=1[Cl:16])#[N:2].[CH3:26][N:27]1[CH2:32][CH2:31][CH:30]([NH2:33])[CH2:29][CH2:28]1>>[C:1]([C:3]1[C:4]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:5]([C:17]([NH:33][CH:30]2[CH2:31][CH2:32][N:27]([CH3:26])[CH2:28][CH2:29]2)=[O:19])[S:6][C:7]=1[S:8][C:9]1[C:14]([Cl:15])=[CH:13][N:12]=[CH:11][C:10]=1[Cl:16])#[N:2]
Reactant: CN1CCC(N)CC1
Reactant: N#Cc1c(Sc2c(Cl)cncc2Cl)sc(C(=O)O)c1-c1ccccc1
Product: CN1CCC(NC(=O)c2sc(Sc3c(Cl)cncc3Cl)c(C#N)c2-c2ccccc2)CC1

Procedure:
Prepared according to the procedure described for step A of example 44 from 4-cyano-5-((3,5-dichloropyridin-4-yl)thio)-3-phenylthiophene-2-carboxylic acid from above and 1-methylpiperidin-4-amine (0.11 g, 1.0 mmol). The title product was obtained as a white solid (29.5 mg, 6.0% yield). MS m/z: 503.04, 505.04 [M+H]+.
Reaction SMILES: C[O:2][C:3]1[CH:13]=[CH:12][C:6]2[N:7]=[C:8]([C:10]#[N:11])[S:9][C:5]=2[CH:4]=1.Cl.[NH+]1C=CC=CC=1>>[OH:2][C:3]1[CH:13]=[CH:12][C:6]2[N:7]=[C:8]([C:10]#[N:11])[S:9][C:5]=2[CH:4]=1
Reactant: COc1ccc2nc(C#N)sc2c1
Agent: Cl
Agent: c1cc[nH+]cc1
Product: N#Cc1nc2ccc(O)cc2s1
Temperature: 190 °C
Reaction time: 3 h
Yield: 45 %

Procedure:
A mixture of 6-methoxybenzo[d]thiazole-2-carbonitrile (1.0 g, 5.3 mmol) and dry pyridinium hydrochloride (11.3 g, 98.1 mmol) was stirred at 190° C. for 3 h. After the completion of reaction, it was cooled to room temperature to obtain a yellow solid. This solid was purified by flash chromatography (silica gel, methylene chloride/ethyl acetate=25/1) to afford 6-hydroxybenzo[d]thiazole-2-carbonitrile as a yellow solid (0.42 g, 45%). 1H-NMR (DMSO-d6, 300 MHz): δ 10.20 (s, 1H), 8.70 (m, 1H), 8.45 (m, 1H), 8.10 (m, 1H) ppm; MS (ESI): 177.1 (M+1).
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]2=[C:7](C(=O)C)[C:8]([CH3:10])=[N:9][N:4]2[CH:3]=1.[N:14]([O-])=O.[Na+].[OH-].[Na+]>Cl.[Zn]>[CH3:1][C:2]1[S:6][C:5]2=[C:7]([NH2:14])[C:8]([CH3:10])=[N:9][N:4]2[CH:3]=1
Reactant: O=N[O-]
Reactant: CC(=O)c1c(C)nn2cc(C)sc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Cc1cn2nc(C)c(N)c2s1
Temperature: 25 °C
Reaction time: 24 h
Yield: 54.3 %

Procedure:
A mixture of 1-(2,6-dimethylpyrazolo[5,1-b][1,3]thiazol-7-yl)ethanone (655 mg, 3.37 mmol) and a 5N aqueous solution of hydrochloric acid (14.2 mL) was cooled to 0° C., and an aqueous (1.0 mL) solution of sodium nitrite (465 mg, 6.74 mmol) was added. This reaction mixture was stirred at room temperature over one day and night. To the mixture was added a 5N aqueous solution of sodium hydroxide at 0° C. to make the solution basic, and produced blue solid was filtered and washed with a small amount of water. The obtained blue solid was dissolved in a 2N aqueous solution of hydrochloric acid (13.5 mL), zinc powder (220 mg, 3.37 mmol) was added to the mixture, and the mixture was stirred at room temperature for 15 minutes. To the mixture, zinc powder (220 mg, 3.37 mmol) was added again, and the mixture was stirred at room temperature for 1.5 hours. The insoluble matters were filtered off and then a 5N aqueous solution of sodium hydroxide was added to the filtrate at 0° C. to neutralize the mixture. A substance of interest was extracted with ethyl acetate, and the organic layer was washed with brine, and dried over magnesium sulfate. The mixture was filtered to yield a filtrate, the solvent was distilled off under reduced pressure, and the obtained solid was dried to obtain the title compound (306 mg, 1.83 mmol).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][O:22][CH:23]2[CH2:28]CCCO2)=[CH:15][CH:14]=1)[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].BrCCOCC>>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:13]1[CH:14]=[CH:15][C:16]([O:19][CH2:20][CH2:21][O:22][CH2:23][CH3:28])=[CH:17][CH:18]=1)[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)O)c1ccc(OCCOC2CCCCO2)cc1
Agent: CCOCCBr
Product: CCOCCOc1ccc([C@@H](NC(=O)OC(C)(C)C)C(=O)O)cc1

Procedure:
Prepared in a manner similar to that described in example 1 except that (i) 2-fluoro-4-iodoaniline was used in place of 4-bromoaniline in step 2, and (ii) (R)-tert-butoxycarbonylamino-[4-(2-ethoxy-ethoxy)-phenyl]-acetic acid was used in place of (R)-tert-butoxycarbonylamino-[4-methoxy-phenyl]-acetic acid in step 4. (R)-tert-Butoxycarbonylamino-[4-(2-ethoxy-ethoxy)-phenyl]-acetic acid was prepared as described in example 48 except that 1-bromo-2-ethoxyethane was used in place of 2-(2-bromo-ethoxy)-tetrahydropyran.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]1([CH2:16][C:17]#[N:18])[CH2:15][CH2:14][CH2:13][CH2:12]1.Cl.[Cl:20]C1C=CC(Cl)=CC=1C1(CC(N)=[NH:35])CCCC1>>[ClH:20].[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]1([CH2:16][C:17]([NH2:35])=[NH:18])[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: N=C(N)CC1(c2cc(Cl)ccc2Cl)CCCC1
Reactant: N#CCC1(c2ccc3ccccc3c2)CCCC1
Agent: Cl
Product: N=C(N)CC1(c2ccc3ccccc3c2)CCCC1

Procedure:
2-(1-Naphthalen-2-yl-cyclopentyl)-acetamidine hydrochloride (216) (5.0 g, crude) was synthesized as a white solid from (1-naphthalen-2-yl-cyclopentyl)-acetonitrile (215) (5.0 g, 21.27 mmol) following the procedure described for the HCl-salt of 2-[1-(2,5-dichlorophenyl)-cyclopentyl]-acetamidine hydrochloride (203).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][CH2:10][CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl.[CH3:24][O:25][NH2:26]>C(O)C>[CH3:24][O:25][N:26]=[C:8]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)[CH2:9][CH2:10][CH:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: CON
Reactant: O=C(CCC1CCCC1)c1ccc(Cl)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CON=C(CCC1CCCC1)c1ccc(Cl)cc1
Temperature: 25 °C
Yield: 60.6 %

Procedure:
To a solution of 1-(4-chloro-phenyl)-3-cyclopentyl-propan-1-one (1.12 g, 4.731 mmol) in ethanol (15 mL) was added potassium carbonate (1.962 g, 14.19 mmol) and methoxyamine hydrochloride (494 mg, 5.914 mmol). The reaction mixture was heated at reflux for 12 h. Upon cooling to room temperature, the reaction mixture was filtered, and the white solids were washed with diethyl ether. The filtrate was concentrated in vacuo, and the residue was partitioned between diethyl ether and water. The product was extracted with diethyl ether (2×30 mL). The organic layers were washed with brine and dried over anhydrous sodium sulfate. The solids were then filtered off, and the filtrate was concentrated in vacuo. Purification of the crude residue by flash chromatography (Biotage system, KP-Sil™ 32–63 μm, 60 Å silica gel) eluting with 1–2% ethyl acetate in hexanes yielded 1-(4-chloro-phenyl)-3-cyclopentyl-propan-1-one O-methyl-oxime (762 mg, 61%) as clear oil.
Reaction SMILES: [NH2:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([CH:9]([OH:34])[CH2:10][NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][CH2:21][C:22]2[CH:26]=[CH:25]OC=2C(N(CC)CC)=O)=[CH:4][C:3]=1[Cl:35].[H-].[Al+3].[Li+].[H-].[H-].[H-].[CH:42]1[CH:47]=CC=CC=1>CCOCC>[NH2:1][C:2]1[C:3]([Cl:35])=[CH:4][C:5]([CH:9]([CH2:10][NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][CH2:20][CH2:21][C:22]2[O:34][C:9]([CH2:10][N:11]([CH2:47][CH3:42])[CH2:12][CH3:13])=[CH:25][CH:26]=2)[OH:34])=[CH:6][C:7]=1[Cl:8]
Reactant: CCN(CC)C(=O)c1occc1CCCOCCCCCCNCC(O)c1cc(Cl)c(N)c(Cl)c1
Reactant: c1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: CCN(CC)Cc1ccc(CCCOCCCCCCNCC(O)c2cc(Cl)c(N)c(Cl)c2)o1
Reaction time: 24 h

Procedure:
A solution of 5-[3-[[6-[[2-(4-amino-3,5-dichlorophenyl)-2-hydroxyethyl]amino]hexyl]oxy]propyl -N,N-diethyl-2-furancarboxamide (0.83 g) in benzene (6 ml) was added dropwise over 10 min to a stirred suspension of lithium aluminium hydride (175 mg) in dry ether (15 ml) under nitrogen. The mixture was stirred under nitrogen at 22° for 24 h, then quenched sequentially with water (1 ml), 2N sodium hydroxide solution (1 ml) and water (2 ml). The mixture was filtered through hyflo and the solids washed with toluene-ether (1:1, 10 ml). The combined filtrate and washings were dried and evaporated in vacuo to an oil. Purification by FCC eluting with System C (93:5:2) afforded the title compound as a pale yellow oil (0.59 g), t.l.c. (System A 39:10:1) Rf 0.5.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([NH2:15])[N:10]=2)[CH:3]=1.[NH:16]1[CH2:21][CH2:20]OCC1.O.[Cl-].[Na+].O>C1COCC1>[NH2:15][C:11]1[N:10]=[C:9]([NH:8][C:4]2[CH:3]=[C:2]([NH:16][C:21]3[CH:20]=[CH:14][CH:13]=[CH:12][CH:11]=3)[N:7]=[CH:6][N:5]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: C1COCCN1
Reactant: Nc1cccc(Nc2cc(Cl)ncn2)n1
Agent: [Cl-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Nc1cccc(Nc2cc(Nc3ccccc3)ncn2)n1
Yield: 127.4 %

Procedure:
4-Fluoro-3-nitroaniline (1, 1 g, 1 equiv.) and morpholine (1.67 g, 3 equiv.) were dissolved in THF (10 mL). The reaction mixture was heated at reflux overnight. After cooling, water/brine (10 mL) was added, the mixture was agitated, and the layers were separated. The organic phase was dried over sodium sulfate, and the solvent was removed via rotary evaporation. The material was purified by flash chromatography using 0-40% gradient of heptane/EtOAc to give 800 mg of 3 as an orange-red solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[CH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.[N:21]([C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=1)=[C:22]=[O:23]>CN(C=O)C>[CH3:31][O:30][C:27]1[CH:28]=[CH:29][C:24]([NH:21][C:22]([N:18]2[CH2:19][CH2:20][CH:15]([C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][N:7]=3)[CH2:16][CH2:17]2)=[O:23])=[CH:25][CH:26]=1
Reactant: COc1ccc(N=C=O)cc1
Reactant: COc1cc2ncnc(C3CCNCC3)c2cc1OC
Solvent: CN(C)C=O
Product: COc1ccc(NC(=O)N2CCC(c3ncnc4cc(OC)c(OC)cc34)CC2)cc1
Yield: 55.7 %

Procedure:
To a solution of 6,7-dimethoxy-4-piperidin-4-yl-quinazoline (30 mg, 0.110 mmol), as prepared in Example 1d, in DMF (1 mL) was treated with 1-isocyanato-4-methoxy-benzene (24.5 mg, 0.164 mmol) at RT overnight. The reaction was then partitioned between EtOAc (10 mL) and H2O (10 mL). The organic phase was dried over Na2SO4 and concentrated in vacuo. Purification by prep tlc (1:9 MeOH/DCM) afforded the title compound as a yellow solid (25.9 mg, 56%). 1H NMR (300 MHz, CDCl3) δ 9.10 (s, 1H), 7.29 (m, 4H), 6.88 (m, 2H), 6.30 (br s, NH), 4.30-4.26 (m, 2H), 4.08 (s, 6H), 3.80 (s, 3H), 3.61 (m, 1H), 3.17 (m, 2H), 2.19-2.14 (m, 2H), 2.03-1.97 (m, 2H); LC/MS (ESI): calcd mass 422.2, found 423.3 [M+1]+.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[C:25]1([C:31]2[C:39]3[C:38]([N:40]4[CH2:45][CH2:44][CH2:43][CH:42]([C:46]([OH:48])=O)[CH2:41]4)=[N:37][CH:36]=[N:35][C:34]=3[S:33][CH:32]=2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(N(CC)CC)C.[O:56]1[CH2:61][CH2:60][N:59]([CH2:62][CH2:63][NH2:64])[CH2:58][CH2:57]1>C(#N)C>[O:56]1[CH2:61][CH2:60][N:59]([CH2:62][CH2:63][NH:64][C:46]([CH:42]2[CH2:43][CH2:44][CH2:45][N:40]([C:38]3[C:39]4[C:31]([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=5)=[CH:32][S:33][C:34]=4[N:35]=[CH:36][N:37]=3)[CH2:41]2)=[O:48])[CH2:58][CH2:57]1
Reactant: NCCN1CCOCC1
Reactant: O=C(O)C1CCCN(c2ncnc3scc(-c4ccccc4)c23)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=C(NCCN1CCOCC1)C1CCCN(c2ncnc3scc(-c4ccccc4)c23)C1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.23099 g, 0.58928 mmol) was added to a suspension of 1-(5-phenylthieno[2,3-d]pyrimidin-4-yl)piperidine-3-carboxylic acid (0.1 g, 0.29464 mmol) in acetonitrile (2 mL). Triethylamine (0.123 mL, 0.089443 g, 0.88391 mmol) and 2-morpholinoethanamine (0.0773 mL, 0.076718 g, 0.58928 mmol) were added and the mixture was stirred for 4 hr at room temperature. The solvent was evaporated and the residue was diluted with ethyl acetate (2 mL) and water (2 mL). The layers were separated and the aqueous was extracted with ethyl acetate (2×2 mL). The combined organic layers were washed with saturated aqueous sodium hydrogencarbonate (1×10 mL), dried (magnesium sulfate), filtered and evaporated to give a brown oil. Mass: 0.275 g. This was purified by prep HPLC (basic method 1). Fractions corresponding to the main peak were combined and evaporated to give a yellow oil. Yield=92 mg. LCMS [M+H]+=452; RT=2.89 min Other compounds prepared by Method K using the appropriate starting materials are listed in TABLE 1.
Reaction SMILES: Br[C:2]1[C:10]([F:11])=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH:5]([OH:12])[CH2:6]2.[C:13]1([C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[NH:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C([O-])([O-])=O.[Cs+].[Cs+]>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].C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:13]1([C:19](=[N:20][C:2]2[C:10]([F:11])=[CH:9][CH:8]=[C:7]3[C:3]=2[CH2:4][CH:5]([OH:12])[CH2:6]3)[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: OC1Cc2ccc(F)c(Br)c2C1
Reactant: N=C(c1ccccc1)c1ccccc1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: OC1Cc2ccc(F)c(N=C(c3ccccc3)c3ccccc3)c2C1
Temperature: 25 °C
Yield: 84.4 %

Procedure:
A solution of Example 25E (950 mg, 4.11 mmol), (R)-(+)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (154 mg, 0.247 mmol), Pd2(dba)3 (11 mg, 0.12 mmol), diphenylmethanimine (1.09 mL, 6.17 mmol) and Cs2CO3 (335 mg, 10.3 mmol) in toluene (20 mL) was heated at 85° C. for 16 hours. The mixture was cooled to ambient temperature, filtered through a layer of Celite, and washed with diethyl ether (60 mL). The filtrate was concentrated under reduced pressure and the resulting residue was purified by silica gel chromatography (gradient elution: 0-20% EtOAc/hexanes) to provide 4-(diphenylmethyleneamino)-5-fluoro-2,3-dihydro-1H-inden-2-ol (1.15 g, 3.47 mmol, 84%) which was used without further purification.