Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([CH3:33])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH2:20][CH2:21][C:22]([C:24]3[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=3)=O)[CH2:14][CH2:13]2)[CH:7]=1)=[O:4].Cl.[CH3:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[NH:42]N>>[CH3:1][CH:2]([CH3:33])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH2:20][C:21]3[C:38]4[C:37](=[C:36]([CH3:35])[CH:41]=[CH:40][CH:39]=4)[NH:42][C:22]=3[C:24]3[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=3)[CH2:14][CH2:13]2)[CH:7]=1)=[O:4]
Reactant: Cc1ccccc1NN
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)c3ccc([N+](=O)[O-])cc3)CC2)c1
Agent: Cl
Product: Cc1cccc2c(CCCN3CCC(c4cccc(NC(=O)C(C)C)c4)CC3)c(-c3ccc([N+](=O)[O-])cc3)[nH]c12

Procedure:
Prepared by Procedure E and Scheme M using 2-methyl-N-(3-{1-[5-(4-nitrophenyl)-5-oxopentyl]-4-piperidinyl}phenyl)propanamide and 1-(2-methylphenyl)hydrazine hydrochloride: ESMS m/e: 538.8 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][C:7]2[NH:8][C:9]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[N:23]=3)=[C:10]([C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][CH:21]=3)[N:18]=[CH:17][CH:16]=[N:15]4)[N:11]=2)=[CH:4][C:3]=1[N+:31]([O-])=O.O.NN>CO.[Ni]>[F:1][C:2]1[CH:30]=[CH:29][C:5]([CH2:6][C:7]2[NH:8][C:9]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[N:23]=3)=[C:10]([C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][CH:21]=3)[N:18]=[CH:17][CH:16]=[N:15]4)[N:11]=2)=[CH:4][C:3]=1[NH2:31]
Reactant: Cc1cccc(-c2[nH]c(Cc3ccc(F)c([N+](=O)[O-])c3)nc2-c2ccc3nccnc3c2)n1
Agent: [Ni]
Agent: NN
Solvent: O
Solvent: CO
Product: Cc1cccc(-c2[nH]c(Cc3ccc(F)c(N)c3)nc2-c2ccc3nccnc3c2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82 %

Procedure:
To a stirred solution of 6-(2-(4-fluoro-3-nitrobenzyl)-5-(6-methylpyridin-2-yl)-1H-imidazol-4-yl)quinoxaline (49.6 mg, 0.113 mmol, prepared according to the method described in US 2008/0319012 A1) in MeOH (5 mL) were added Raney Ni (0.1 mg, 10% w/w) and hydrazine monohydrate (0.027 mL, 0.563 mmol) and the mixture was stirred at room temperature for overnight. The reaction mixture was filtered through celite and the filtrate was concentrated under reduced pressure. The residue was purified by MPLC (MeOH:CH2Cl2=1:50 (v/v)) and on NH silica gel (MeOH:CH2Cl2=1:100 (v/v)) to afford the title compound (37.8 mg, 82%). (300 MHz, CDCl3) δ 1.99 (4H, m), 2.54 (3H, s), 3.23 (4H, t), 4.31 (2H, s), 6.37 (1H, dd), 6364 (1H, d), 6.95 (1H, d), 7.23-7.43 (5H, m), 7.98 (1H, dd), 8.08-8.17 (3H, m), 8.91 (1H, dd), 10.40 (1H, bs) MS (ESI) m/z 446 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](Br)[CH3:9])=[CH:4][CH:3]=1.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][C:13]=1[N+:19]([O-:21])=[O:20].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([O:18][C:15]2[CH:16]=[CH:17][C:12]([Cl:11])=[C:13]([N+:19]([O-:21])=[O:20])[CH:14]=2)[CH3:9])=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1cc(O)ccc1Cl
Reactant: CC(Br)c1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(Oc1ccc(Cl)c([N+](=O)[O-])c1)c1ccc(Br)cc1
Temperature: 25 °C
Yield: 92.2 %

Procedure:
The product from Example 44A (995 mg, 3.77 mmol) was reacted with 4-chloro-3-nitro-phenol (650 mg, 3.77 mmol) in 15 mL of DMF with K2CO3 (10.4 g, 3.77 mmol) at 80° C. for 3 h. Cooled to room temperature and diluted with water. Extracted with CH2Cl2, washed four times with water. Dried over Na2SO4, filtered and concentrated under vacuum giving the title compound (1.24 g, 92%).
Reaction SMILES: [OH-:1].[Li+].[C:3]1([CH2:9][CH2:10][CH2:11][CH2:12][C:13]2[CH:29]=[CH:28][C:16]([O:17][CH:18]3[CH2:22][CH:21]([C:23]([O:25]C)=[O:24])[NH:20][C:19]3=[O:27])=[CH:15][CH:14]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl>O.O1CCCC1>[C:3]1([CH2:9][CH2:10][CH2:11][CH2:12][C:13]2[CH:29]=[CH:28][C:16]([O:17][CH:18]([C:19]([OH:1])=[O:27])[CH2:22][C@@H:21]([C:23]([OH:25])=[O:24])[NH2:20])=[CH:15][CH:14]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: COC(=O)C1CC(Oc2ccc(CCCCc3ccccc3)cc2)C(=O)N1
Reactant: [OH-]
Agent: Cl
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: N[C@@H](CC(Oc1ccc(CCCCc2ccccc2)cc1)C(=O)O)C(=O)O
Temperature: 60 °C
Reaction time: 4 h
Yield: 28.3 %

Procedure:
A mixture of lithium hydroxide (0.072 g) in water (0.9 ml) and tetrahydrofuran (2.9 ml) was treated with methyl 3-[4-(4-phenylbutyl) phenoxy]-2-pyrrolidone-5-carboxylate (0.370 g), and heated to 60° C. After about 4.0 hours, the reaction mixture was allowed to cool to room temperature. After approximately 2.25 hours at room temperature, the reaction mixture was treated with 5N HCl (604 ml). The resulting biphasic solution was cooled to 5° C. for approximately 18 hours. The biphasic solution was treated with water (2 ml). The resulting milky solution was sonicated resulting in crystal formation. The crystals were collected by filtration, washed with 1:1 THF:water (10 ml), THF (10 ml), and water (10 ml). The crystals were then dried overnight in at vacuum oven at 60° C. to afford the title compound (106 mg).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:4][C:3]=1[F:16].[Li]CCCC.CN(C)[CH:24]=[O:25]>O1CCCC1>[CH2:9]([O:8][C:5]1[CH:6]=[CH:7][C:2]([CH:24]=[O:25])=[C:3]([F:16])[CH:4]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Fc1cc(OCc2ccccc2)ccc1Br
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=Cc1ccc(OCc2ccccc2)cc1F

Procedure:
In analogy to the procedure described in example 23 c], 1-bromo-2-fluoro-4-(phenylmethoxy)-benzene was treated with n-BuLi and N,N-dimethylformamide in dry tetrahydrofuran to yield 4-benzyloxy-2-fluoro-benzaldehyde as off-white crystals.
Reaction SMILES: [O:1]([C:9]1[C:10]([CH3:27])=[C:11]2[C:16](=[C:17]([CH3:20])[C:18]=1[CH3:19])[O:15][C:14]([CH3:26])([CH2:21][C:22](OC)=[O:23])[CH2:13][CH2:12]2)[Si:2]([C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:4])[CH3:3].[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+].S([O-])([O-])(=O)=O.[Mg+2]>C(OCC)C.O>[O:1]([C:9]1[C:10]([CH3:27])=[C:11]2[C:16](=[C:17]([CH3:20])[C:18]=1[CH3:19])[O:15][C:14]([CH2:21][CH2:22][OH:23])([CH3:26])[CH2:13][CH2:12]2)[Si:2]([C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:3])[CH3:4]
Reactant: COC(=O)CC1(C)CCc2c(C)c(O[Si](C)(C)C(C)(C)C)c(C)c(C)c2O1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: CCOCC
Product: Cc1c(C)c2c(c(C)c1O[Si](C)(C)C(C)(C)C)CCC(C)(CCO)O2
Reaction time: 1 h
Yield: 91.6 %

Procedure:
Under nitrogen, a solution of 11.35 g (28.91 mM) of methyl 6-tert-butyldimethylsiloxy-2,5,7,8-tetramethylchroman-2-acetate in diethyl ether (10 ml) was added to a suspension of 1.1 g (28.99 mM) of lithium aluminum hydride in diethyl ether (50 ml) at 0° C. and the mixture was stirred at the prevailing temperature for one hour. Then, water (1.1 ml), 15% aqueous solution of NaOH (1.1 ml), and water (1.1 ml) were added in that order and the mixture was stirred at room temperature for 30 minutes. To this mixture was added magnesium sulfate, and after the precipitate was filtered off, the solvent was distilled off under reduced pressure to provide a crude product. This crude product was purified by column chromatography (ethyl acetate-hexane: 20-30%) to provide the title compound as light-yellow oil (9.65 g, 92%).
Reaction SMILES: Cl.[F:2][C:3]1[CH:17]=[CH:16][C:6]2[C:7]([CH:10]3[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]3)=[N:8][O:9][C:5]=2[CH:4]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:25][CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([C:34](=[O:36])[CH3:35])=[CH:30][C:29]=1[O:37][CH3:38].CN(C)C=O>O>[F:2][C:3]1[CH:17]=[CH:16][C:6]2[C:7]([CH:10]3[CH2:11][CH2:12][N:13]([CH2:25][CH2:26][O:27][C:28]4[CH:33]=[CH:32][C:31]([C:34](=[O:36])[CH3:35])=[CH:30][C:29]=4[O:37][CH3:38])[CH2:14][CH2:15]3)=[N:8][O:9][C:5]=2[CH:4]=1
Reactant: COc1cc(C(C)=O)ccc1OCCCl
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(C(C)=O)ccc1OCCN1CCC(c2noc3cc(F)ccc23)CC1
Temperature: 90 °C
Yield: 89.7 %

Procedure:
A stirred mixture of 6-fluoro-3(4-piperidinyl)-1,2 benzisoxazole hydrochloride (5.1 g, 20 mmol), K2CO3 (5.2 g), 1-[4-(2-chloroethoxy)-3-methoxyphenyl]ethanone (5.0 g, 1022 mmol), and dimethylformamide (90 ml) was heated at 90° C. for 16 hours. The reaction was poured into water, and the aqueous mixture was extracted with ethyl acetate. The ethyl acetate was washed (water), dried (MgSO4), and concentrated to afford 7.4 g of a yellow solid. The solid was chromatographed on a Waters Prep LC 500 utilizing dichloromethane/methanol (4%) as eluent, and subsequent concentration of the appropriate fraction afforded 4.0 g of a yellow solid. The solid was recrystallized from ethyl alcohol to yield 3.1 g (38%) of 1-14-[2-14-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethoxy]-3-methoxyphenyl]ethanone, as slightly yellow flakes, m.p.=132°-134° C.
Reaction SMILES: [CH3:1][N:2]([CH3:9])[C@@H:3]1[CH2:7][NH:6][C@@H:5]([CH3:8])[CH2:4]1.[NH2:10][C:11]1[C:16]([N+:17]([O-:19])=[O:18])=[CH:15][CH:14]=[C:13](F)[CH:12]=1.CCN(CC)CC>CN1CCCC1=O.O>[CH3:1][N:2]([CH3:9])[C@@H:3]1[CH2:7][N:6]([C:13]2[CH:12]=[C:11]([NH2:10])[C:16]([N+:17]([O-:19])=[O:18])=[CH:15][CH:14]=2)[C@@H:5]([CH3:8])[CH2:4]1
Reactant: C[C@H]1C[C@H](N(C)C)CN1
Reactant: Nc1cc(F)ccc1[N+](=O)[O-]
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: C[C@H]1C[C@H](N(C)C)CN1c1ccc([N+](=O)[O-])c(N)c1
Temperature: 100 °C

Procedure:
(2S,4S)-4-dimethylamino-2-methylpyrrolidine (1.0 equivalent) and 1-amino-3-fluoro-6-nitrobenzene(1.2 equivalents) were dissolved in N-methylpyrrolidinone, and Et3N(5.0 equivalents) was added. The solution was heated for 5 hours at 100° C. The solution was then cooled and diluted with water. The aqueous layer was extracted with ethyl acetate. The organic layer was then washed twice with H2O, once with brine, dried over Na2SO4, filtered, and concentrated. The crude material was purified by column chromatography (1:1 ethyl acetate:hexane to 1:20 MeOH:ethyl acetate to 1:1 MeOH:ethyl acetate to give the title compound as a yellow gum. LC/MS (m/z) 265.2 (MH+), Rt 1.65 minutes.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[C:18](Cl)(=[O:26])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]>>[C:18]([NH:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1)(=[O:26])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CN1CCC(c2c[nH]c3ccc(N)nc23)CC1
Reactant: CCCCCCCC(=O)Cl
Product: CCCCCCCC(=O)Nc1ccc2[nH]cc(C3CCN(C)CC3)c2n1
Yield: 82.9 %

Procedure:
Beginning with 0.01 gm (0.044 mMol) 5-amino-3-(1-methylpiperidin-4-yl)pyrrolo[3,2-b]pyridine and 0.01 mL (0.057 mMol) octanoyl chloride, 0.013 gm (83%) of the title compound were prepared essentially by the procedure described in Example 7.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[F:5][C:6]1[CH:7]=[C:8]([OH:13])[CH:9]=[CH:10][C:11]=1[CH3:12]>ClCCl>[F:5][C:6]1[C:11]([CH3:12])=[CH:10][C:9]([N+:1]([O-:4])=[O:2])=[C:8]([OH:13])[CH:7]=1
Reactant: Cc1ccc(O)cc1F
Reactant: O=[N+]([O-])O
Solvent: ClCCl
Product: Cc1cc([N+](=O)[O-])c(O)cc1F
Reaction time: 0.5 h
Yield: 66.6 %

Procedure:
70% Nitric acid (0.759 mL, 8.42 mmol) was added dropwise to a solution of 3-fluoro-4-methylphenol (966 mg, 7.66 mmol) in dichloromethane (25 mL) at rt. The reaction was stirred for 30 min before being washed with water. The aqueous layer was extracted with dichloromethane (1×) and the combined organics were dried (Na2SO4) and concentrated by rotary evaporation to give a yellow/orange solid. The residue was purified via chromatography (silica, dichloromethane to 0.5% ammonia/9.5% methanol/90% dichloromethane) to give 5-fluoro-4-methyl-2-nitrophenol (D21, 873 mg, 67% yield) as a yellow solid.
Reaction SMILES: C([N:4]([C:13]1[CH:14]=[N:15][C:16]2[C:21]([CH:22]=1)=[CH:20][CH:19]=[C:18]([Cl:23])[CH:17]=2)[C:5]1[CH:10]=[CH:9][C:8]([O:11]C)=[CH:7][CH:6]=1)(=O)C.Br>C(O)(=O)C>[Cl:23][C:18]1[CH:17]=[C:16]2[C:21]([CH:22]=[C:13]([NH:4][C:5]3[CH:6]=[CH:7][C:8]([OH:11])=[CH:9][CH:10]=3)[CH:14]=[N:15]2)=[CH:20][CH:19]=1
Reactant: COc1ccc(N(C(C)=O)c2cnc3cc(Cl)ccc3c2)cc1
Agent: Br
Solvent: CC(=O)O
Product: Oc1ccc(Nc2cnc3cc(Cl)ccc3c2)cc1
Reaction time: 5 h

Procedure:
A mixture of 3-[N-acetyl-N-(4-methoxyphenyl)amino]-7-chloroquinoline (13.0 g), acetic acid (90 ml) and hydrobromic acid (48%, 90 ml) was heated under reflux with stirring for 5 hours. The solvent was evaporated under reduced pressure and the residue was partitioned between ethyl acetate and dilute aqueous sodium bicarbonate. The organic layer was separated, dried over magnesium sulphate and evaporated to give 4-[N-(7-chloroquinolin-3-yl)amino]phenol as a dark yellow solid (9 g, 85%, mp 218° C.
Reaction SMILES: Cl.CO.[Si]([O:11][CH:12]([CH3:43])[CH2:13][CH:14]([N:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:34]=[CH:33][N:32]=[C:31]([NH:35][CH:36]3[CH2:41][CH2:40][O:39][CH2:38][CH2:37]3)[N:30]=2)=[CH:25][C:24]1=[O:42])[C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([F:22])[CH:16]=1)(C(C)(C)C)(C)C.C([O-])(O)=O.[Na+]>CO>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([CH:14]([N:23]2[CH:28]=[CH:27][C:26]([C:29]3[CH:34]=[CH:33][N:32]=[C:31]([NH:35][CH:36]4[CH2:41][CH2:40][O:39][CH2:38][CH2:37]4)[N:30]=3)=[CH:25][C:24]2=[O:42])[CH2:13][CH:12]([OH:11])[CH3:43])=[CH:16][C:17]=1[F:22]
Reactant: CC(CC(c1ccc(Cl)c(F)c1)n1ccc(-c2ccnc(NC3CCOCC3)n2)cc1=O)O[Si](C)(C)C(C)(C)C
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: CC(O)CC(c1ccc(Cl)c(F)c1)n1ccc(-c2ccnc(NC3CCOCC3)n2)cc1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 49.4 %

Procedure:
HCl/methanol (3N, 1.0 mL) was added at 5° C. to a solution of 1-(3-(tert-butyldimethylsilyloxy)-1-(4-chloro-3-fluorophenyl)butyl)-4-(2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one (90.0 mg, 0.154 mmol) in methanol (3.0 mL). After being stirred at room temperature for 2 hours, the reaction mixture was adjusted to pH around 8-9 with saturated NaHCO3, extracted with dichloromethane, dried over Na2SO4 and concentrated. The residue was purified with prep-HPLC to afford 1-(1-(4-chloro-3-fluorophenyl)-3-hydroxybutyl)-4-(2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one (36 mg, 50% yield) as a solid. 1H NMR (500 MHz, (CD3)2SO) δ 10.92 (s, 1H), 8.41 (d, J=5.0 Hz, 1H), 7.95 (m, 1H), 7.58 (m, 1H), 7.46 (m, 1H), 7.30 (m, 1H), 7.23 (m, 1H), 7.10 (m, 1H), 7.07 (m, 1H), 6.87 (m, 1H), 6.14 (m, 1H), 4.70 (m, 1H), 3.97 (m, 1H), 3.89-3.87 (m, 2H), 3.41-3.33 (m, 2H), 2.47 (m, 1H), 2.06 (m, 1H), 1.86-1.84 (m, 2H), 1.56-1.52 (m, 2H), 1.12-1.09 (m, 3H); LCMS (ESI) m/z: 473.2 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[C:5]([CH2:20][C:21]([N:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1)=[O:22])([CH2:11][CH:12]=[CH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].OCC1(OC[C@@H](O)[C@@H](O)[C@H]1O)O>CCO.[Pd]>[CH2:9]([O:8][C:6](=[O:7])[C:5]([CH2:20][C:21]([N:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1)=[O:22])([CH2:11][CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:4]([O:3][CH2:1][CH3:2])=[O:29])[CH3:10]
Reactant: CCOC(=O)C(CC=Cc1ccccc1)(CC(=O)N1CCOCC1)C(=O)OCC
Agent: [Pd]
Agent: OCC1(O)OC[C@@H](O)[C@@H](O)[C@H]1O
Solvent: CCO
Product: CCOC(=O)C(CCCc1ccccc1)(CC(=O)N1CCOCC1)C(=O)OCC
Yield: 100.7 %

Procedure:
A solution of 2-(2-morpholin-4-yl-2-oxo-ethyl)-2-(3-phenyl-allyl)-malonic acid diethyl ester (257 mg, 0.637 mmol) in EtOH (15 ml) was hydrogenated over Pd/C at 55 Psi for 7.5 hrs. The catalyst filtered off over a pad of Celite and the filtrate evaporated under vacuum to give 2-(2-morpholin-4-yl-2-oxo-ethyl)-2-(3-phenyl-propyl)-malonic acid diethyl ester as a light yellow oil (260 mg); 1H NMR (CDCl3) 7.4–7.1 (m, 5H), 4.20 (q, J=7.1 Hz, 4H), 3.7–3.4 (m, 8H), 3.0 (s, 2H), 2.6 (t, J=7.6 Hz, 2H), 2.2 (m, 2H), 2.55 (m, 2H), 1.20 (t, J=7.1 Hz, 6H). MS: 406 (MH+).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:11]=[CH:10][C:9]([NH:12][CH:13]=O)=[CH:8][CH:7]=2)[N:3]=[CH:2]1.[H-].[H-].[H-].[H-].[Li+].[Al+3].C(OCC)C>O1CCCC1>[CH3:13][NH:12][C:9]1[CH:10]=[CH:11][C:6]([C:4]2[N:3]=[CH:2][NH:1][CH:5]=2)=[CH:7][CH:8]=1
Reactant: O=CNc1ccc(-c2c[nH]cn2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CNc1ccc(-c2c[nH]cn2)cc1

Procedure:
A suspension of N-[4-(imidazol-4-yl)-phenyl]-formamide (8 g) in anhydrous tetrahydrofuran (80 ml) was slowly added dropwise to a suspension of LiAlH4 (6.5 g) in anhydrous tetrahydrofuran. The reaction mixture was refluxed for 4 hours and cooled. Wet diethylether was added, and then the solution was evaporated to dryness. The residue was dissolved in water and ethylacetate. After working up the organic layer, 4.6 g of N-methyl-N-[4-(imidazol-4-yl)-phenyl]-amine, M.p. 75°-76° C., were obtained.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([O:8][C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15]C)=[O:14])=[CH:11][C:10]=2[C:19]([F:22])([F:21])[F:20])[CH2:4][CH2:3]1.[OH-].[Na+].Cl>C1COCC1.CO.O>[CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([O:8][C:9]2[CH:18]=[CH:17][C:12]([C:13]([OH:15])=[O:14])=[CH:11][C:10]=2[C:19]([F:20])([F:21])[F:22])[CH2:4][CH2:3]1
Reactant: COC(=O)c1ccc(OC2CCN(C)CC2)c(C(F)(F)F)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CN1CCC(Oc2ccc(C(=O)O)cc2C(F)(F)F)CC1
Temperature: 90 °C
Reaction time: 22 h
Yield: 80.1 %

Procedure:
Methyl 4-(1-methylpiperidine-4-yloxy)-3-(trifluoromethyl)benzoate (512 mg, 1.61 mmol) was dissolved in a mixture of THF (1.5 mL), MeOH (1.5 mL) and H2O (1.5 mL), and then NaOH (193 mg, 4.84 mmol) was added thereto. The reaction mixture was stirred at 90° C. for 22 hours and cooled to room temperature, and 1N HCl was added dropwise thereto to pH 4. The reaction mixture was concentrated, and a mixed solvent (DCM/MeOH=5/1) was added thereto. The remaining solid was filtered, and the filtrate was concentrated to obtain the title compound (391 mg, 80%) without further purification.
Reaction SMILES: [C:1]1([C:7]2[N:12]=[C:11](N)[CH:10]=[CH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClC1C=CN=C(C2C=CC=CC=2)N=1.N.C(N)(=N)C1C=CC=CC=1.C(CC([O-])=O)=[O:38].[Na+]>>[C:1]1([C:7]2[NH:12][C:11](=[O:38])[CH:10]=[CH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Nc1ccnc(-c2ccccc2)n1
Reactant: O=CCC(=O)[O-]
Agent: Clc1ccnc(-c2ccccc2)n1
Agent: N
Agent: N=C(N)c1ccccc1
Product: O=c1ccnc(-c2ccccc2)[nH]1

Procedure:
Ruhemann et al. [Chem. Ber. 30, 2022 (1897)] prepared 2-phenyl-4-pyrimidinamine by reacting 4-chloro-2-phenylpyrimidine with ammonia. The 4-chloro-2-phenylpyrimidine had been prepared in two steps by first reacting benzamidine with sodium formylacetate to produce 2-phenyl-4-pyrimidone and then reacting the latter with phosphorus oxychloride.
Reaction SMILES: C1([O:7][N:8]2[C:12](=[O:13])[C:11]3=[CH:14][CH:15]=[CH:16][CH:17]=[C:10]3[C:9]2=[O:18])CCCCC1.[Na].C(O)(=O)C1C(=CC=CC=1)C(O)=O.Cl.C1(=O)OC(=O)C2=CC=CC=C12>[OH-].[Na+]>[OH:7][N:8]1[C:9](=[O:18])[C:10]2=[CH:17][CH:16]=[CH:15][CH:14]=[C:11]2[C:12]1=[O:13]
Reactant: O=C1c2ccccc2C(=O)N1OC1CCCCC1
Agent: Cl
Agent: O=C(O)c1ccccc1C(=O)O
Agent: O=C1OC(=O)c2ccccc21
Product: O=C1c2ccccc2C(=O)N1O
Yield: 79.7 %

Procedure:
To a flask was added 50 mL of 1N sodium hydroxide aqueous solution, and powdery N-cyclohexyloxyphthalimide (4.9 g, 20 mmol) was slowly added thereto with stirring. The mixture was stirred at 97° C. for 5 hours to obtain an aqueous solution containing sodium salt of phthalic acid. To the aqueous solution was added diluted hydrochloric acid to convert into phthalic acid, and phthalic acid was recovered by condensation and filtration. To a flask were added the phthalic acid, 50 mL of pyridine and 0.05 g of sulfuric acid and stirred at 95° C. for 4 hours to obtain a mixture containing phthalic anhydride. Hydroxylamine hydrochloride NH2OH.HCl (2.8 g, 40 mmol) was added to the mixture, stirred at 50° C. for 3 hours to form N-hydroxyphthalimide (2.6 g, yield 81%).
Reaction SMILES: [Cl:1][CH:2]([CH2:6][O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3](Cl)=[O:4].C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:26]([O:33][C:34](=[O:37])[CH2:35][NH2:36])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(N(CC)CC)C.Cl>C(Cl)Cl.O>[CH2:8]([O:7][CH2:6][CH:2]([Cl:1])[C:3](=[O:4])[NH:36][CH2:35][C:34]([O:33][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:37])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: NCC(=O)OCc1ccccc1
Reactant: O=C(Cl)C(Cl)COCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(CNC(=O)C(Cl)COCc1ccccc1)OCc1ccccc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
76 g (326.1 mmol) of 2-chloro-3-(benzyloxy)-propionic acid chloride (produced according to Inorg. Chem. Vol. 31; 2422, 1992) is added in drops to 100 g (296.4 mmol) of glycine benzyl ester-p-toluenesulfonic acid salt and 33.0 g (326.1 mmol) of triethylamine in 400 ml of methylene chloride at 0° C., and it is stirred for 2 hours at this temperature. 500 ml of ice water is added, and the water phase is set at pH 2 with 10% aqueous hydrochloric acid. The organic phase is separated, washed once each with 300 ml of 5% aqueous hydrochloric acid, 300 ml of 5% aqueous soda solution and 400 ml of water. The organic phase is dried on magnesium sulfate and evaporated to dryness in a vacuum. The residue is chromatographed on silica gel (mobile solvent: methylene chloride/hexane/acetone=15/5/1).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([F:15])=[C:8]([N:10]([CH3:14])[C:11](=[O:13])[CH3:12])[CH:9]=1)(=[O:3])[CH3:2].C1(C)C=CC=CC=1>CCCCCCC>[CH3:8][N:10]([CH3:14])[CH:11]=[CH:2][C:1]([C:4]1[CH:5]=[CH:6][C:7]([F:15])=[C:8]([N:10]([CH3:14])[C:11](=[O:13])[CH3:12])[CH:9]=1)=[O:3]
Reactant: CC(=O)c1ccc(F)c(N(C)C(C)=O)c1
Solvent: CCCCCCC
Solvent: Cc1ccccc1
Product: CC(=O)N(C)c1cc(C(=O)C=CN(C)C)ccc1F
Temperature: 17.5 °C
Yield: 176.8 %

Procedure:
75.0 g (0.36 moles) of N-(5-acetyl-2-fluorophenyl)-N-methyl-acetamide (VI) were dissolved in 96.3 mL (86.4 g, 0.72 moles) of NNDMF-DMA. The resulting solution was refluxed for 8 hours. At the temperature of 80° C., 400 mL of toluene were added, and then, at the same temperature, 400 mL of n-heptane were slowly added. The resulting solution was slowly cooled to 15-20° C. The white-yellowish solid obtained by recrystallization was filtered off, washed with 263 mL of toluene:n-heptane (1:1), and then dried under vacuum at 40° C. A white-yellowish solid (84.1 g, 91.7% yield) with a melting point=131-132° C. was obtained.
Reaction SMILES: [N:1]([C:4]1[C:9]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:8][N:7]=[C:6]([C:16]2[C:24]3[C:19](=[N:20][CH:21]=[CH:22][CH:23]=3)[N:18]([CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[F:32])[N:17]=2)[N:5]=1)=[N+]=[N-].[H][H]>CN(C=O)C.[Pd]>[NH2:1][C:4]1[C:9]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:8][N:7]=[C:6]([C:16]2[C:24]3[C:19](=[N:20][CH:21]=[CH:22][CH:23]=3)[N:18]([CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[F:32])[N:17]=2)[N:5]=1
Reactant: [H][H]
Reactant: CCOC(=O)Cc1cnc(-c2nn(Cc3ccccc3F)c3ncccc23)nc1N=[N+]=[N-]
Agent: [Pd]
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1cnc(-c2nn(Cc3ccccc3F)c3ncccc23)nc1N

Procedure:
10.15 g (23.482 mmol) of the crude product from Example 18A were hydrogenated overnight in DMF (400 ml) using palladium on carbon (10%) at a hydrogen pressure of 1 atmosphere. The mixture was then filtered through Celite and concentrated. The residue was used without further purification for the next step.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:16]=[CH:15][CH:14]=[CH:13][C:8]=2[C:9]([O:11]C)=[O:10])=[N:3][CH:2]=1.[ClH:17]>C(O)(=O)C>[ClH:17].[N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:16]=[CH:15][CH:14]=[CH:13][C:8]=2[C:9]([OH:11])=[O:10])=[N:3][CH:2]=1
Reactant: COC(=O)c1ccccc1-c1ccncn1
Agent: Cl
Solvent: CC(=O)O
Product: O=C(O)c1ccccc1-c1ccncn1

Procedure:
A mixture of methyl 2-(pyrimidin-4-yl)benzoate (0.49 g), acetic acid (2.0 mL) and 6 N hydrochloric acid (10 mL) was heated under reflux for 5 hr. The solvent was evaporated under reduced pressure, and the obtained residue was washed with ethyl acetate to give the title compound (0.45 g).