Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]([Cl:9])([Cl:8])[Cl:7])=[O:3].[C:10]([C:14]1[CH:15]=[C:16]([NH2:34])[N:17]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][N:26]3[CH2:31][CH2:30][C:29]([F:33])([F:32])[CH2:28][CH2:27]3)[CH:20]=2)[N:18]=1)([CH3:13])([CH3:12])[CH3:11].CCN(C(C)C)C(C)C>C1COCC1>[Cl:7][C:6]([Cl:9])([Cl:8])[CH2:5][O:4][C:2](=[O:3])[NH:34][C:16]1[N:17]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][N:26]3[CH2:31][CH2:30][C:29]([F:33])([F:32])[CH2:28][CH2:27]3)[CH:20]=2)[N:18]=[C:14]([C:10]([CH3:12])([CH3:13])[CH3:11])[CH:15]=1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Reactant: CC(C)(C)c1cc(N)n(-c2cccc(CN3CCC(F)(F)CC3)c2)n1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)c1cc(NC(=O)OCC(Cl)(Cl)Cl)n(-c2cccc(CN3CCC(F)(F)CC3)c2)n1
Reaction time: 3 h
Yield: 72 %

Procedure:
2,2,2-Trichloroethyl chloroformate (0.077 mL, 0.57 mmol) was added to a solution of Intermediate 12c (200 mg, 0.57 mmol) and DIPEA (0.31 mL, 1.81 mmol) in THF (5 mL), and the mixture stirred for 3 h. The mixture was then partitioned between water (10 mL) and EtOAc (3×15 mL), and the combined organic extracts dried (Na2SO4). The solvent was evaporated and the residue triturated under pentane and filtered to give the title compound as a yellow solid (215 mg, 72%). LCMS (Method 1): Rt 2.89 min, m/z 523/525 [MH+]
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.[F:10][C:11]([F:21])([F:20])[C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=1)[CH2:15]Cl>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[C:5]([CH2:15][C:14]2[CH:17]=[CH:18][CH:19]=[C:12]([C:11]([F:10])([F:20])[F:21])[CH:13]=2)[CH:4]=1
Reactant: COc1ccc(O)cc1
Reactant: FC(F)(F)c1cccc(CCl)c1
Product: COc1ccc(O)c(Cc2cccc(C(F)(F)F)c2)c1

Procedure:
Alkylation of 4-methoxyphenol with 3-(trifluoromethyl)benzyl chloride according to the procedure described in J. Chem. Soc. 2431 (1958) gave 4-methoxy-2-(3′-(trifluoromethyl)benzyl)phenol. This material was converted to compound 67, mp 226.5-228° C., and compound 68, mp 188-190° C., byu the procedure similar to that in Example 18 method B.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:21][CH:22]1[CH2:27][CH2:26][N:25]([C:28]([C:30]2[CH:31]=[C:32]([CH:37]=[CH:38][CH:39]=2)[C:33]([O:35]C)=[O:34])=[O:29])[CH2:24][CH:23]1[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C@@H:9]([C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1)[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1COCC1.[OH-].[Na+].Cl>CO>[C:1]([O:5][C:6]([N:8]([CH2:21][CH:22]1[CH2:27][CH2:26][N:25]([C:28]([C:30]2[CH:31]=[C:32]([CH:37]=[CH:38][CH:39]=2)[C:33]([OH:35])=[O:34])=[O:29])[CH2:24][CH:23]1[C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1)[C@@H:9]([C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1)[CH3:10])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)c1cccc(C(=O)N2CCC(CN(C(=O)OC(C)(C)C)[C@H](C)c3cccc4ccccc34)C(c3ccccc3)C2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: C[C@H](c1cccc2ccccc12)N(CC1CCN(C(=O)c2cccc(C(=O)O)c2)CC1c1ccccc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 122 mg of the obtained methyl 3-{[4-({(tert-butoxycarbonyl)[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-3-phenylpiperidin-1-yl]carbonyl}benzoate were added 2.0 mL of THF, 1.0 mL of methanol, and 1.0 mL of a 1 M aqueous sodium hydroxide solution, followed by stirring at room temperature overnight. It was neutralized by addition of 1.1 mL of 1 M hydrochloric acid, and then extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and dried to obtain 3-{[4-({(tert-butoxycarbonyl)[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-3-phenylpiperidin-1-yl]carbonyl}benzoic acid as a crude product (colorless foamy substance, 121 mg).
Reaction SMILES: [CH3:1][C:2]([O:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][NH:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=2)=[CH:12][CH:11]=1)([CH3:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].Br[C:31]1[CH:36]=[CH:35][C:34]([Br:37])=[CH:33][N:32]=1.CCN(C(C)C)C(C)C>O1CCOCC1>[Br:37][C:34]1[CH:35]=[CH:36][C:31]([N:18]([CH2:19][C:20]2[CH:21]=[CH:22][C:23]([C:26]([F:27])([F:28])[F:29])=[CH:24][CH:25]=2)[CH2:17][CH2:16][C:13]2[CH:14]=[CH:15][C:10]([O:9][C:2]([CH3:1])([CH3:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4])=[CH:11][CH:12]=2)=[N:32][CH:33]=1
Reactant: Brc1ccc(Br)nc1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(CCNCc2ccc(C(F)(F)F)cc2)cc1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C(C)(C)Oc1ccc(CCN(Cc2ccc(C(F)(F)F)cc2)c2ccc(Br)cn2)cc1
Yield: 18.2 %

Procedure:
A solution of ethyl 2-methyl-2-[4-(2-{[4-(trifluoromethyl)benzyl]amino}ethyl)phenoxy]propanoate (3 g; 7.3 mmol) in 7 ml of dioxane was treated under nitrogen with 2,5-dibromopyridine (1.9 g; 8.1 mmol) and DIEA (1.4 ml; 8.1 mmol) and heated in a pressure tube for 2 days at 210C. Upon cooling, additional DIEA (1.4 ml) was added and heated 2 more days. Upon cooling, the reaction mixture was partitioned between ethyl acetate and 0.5N HCl. The organic phase was washed with 0.5N HCl and saturated brine, dried over sodium sulfate and concentrated. Purification by silica gel chromatography using an ethyl acetate-hexane gradient (5–60%) afforded the title compound (0.75 g; 18% yield).
Reaction SMILES: [CH:1]1([NH:8][C:9]2[O:10][CH2:11][C:12]3[CH:18]=[C:17]([NH2:19])[CH:16]=[CH:15][C:13]=3[N:14]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:20]1([S:26](Cl)(=[O:28])=[O:27])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH:1]1([NH:8][C:9]2[O:10][CH2:11][C:12]3[CH:18]=[C:17]([NH:19][S:26]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)(=[O:28])=[O:27])[CH:16]=[CH:15][C:13]=3[N:14]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Nc1ccc2c(c1)COC(NC1CCCCCC1)=N2
Product: O=S(=O)(Nc1ccc2c(c1)COC(NC1CCCCCC1)=N2)c1ccccc1
Yield: 5.5 %

Procedure:
Prepared from N2-cycloheptyl-4H-benzo[d][1,3]oxazine-2,6-diamine (example 92) (200 mg, 0.77 mmol) and benzenesulfonyl chloride (136 mg, 0.77 mmol) according to the procedure described for example 27. Obtained the title compound as a white foam (17 mg, 5.5%), MS (ISP) m/e=400.3 [(M+H)+].
Reaction SMILES: [BH4-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[C:11](=[O:22])[C:12]2[CH:13]=[CH:14][CH:15]=[C:16]3[C:21]=2[N:20]=[CH:19][CH:18]=[CH:17]3)=[CH:6][CH:5]=1.P([O-])(O)(O)=O.[Na+]>CO>[F:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:28])([CH3:27])[CH3:29])[CH:11]([OH:22])[C:12]2[CH:13]=[CH:14][CH:15]=[C:16]3[C:21]=2[N:20]=[CH:19][CH:18]=[CH:17]3)=[CH:6][CH:5]=1
Reactant: CC(C)(C)OC(=O)NC(C(=O)c1cccc2cccnc12)c1ccc(F)cc1
Agent: O=P([O-])(O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)NC(c1ccc(F)cc1)C(O)c1cccc2cccnc12
Temperature: 2.5 °C
Reaction time: 0.5 h
Yield: 87.6 %

Procedure:
tert-Butyl 4[1-(4-fluorophenyl)-2-hydroxy-2-quinolin-8-ylethyl]carbamate 0.314 g (8.3 mmol) of sodium borohydride was added in 4 portions to a solution of 3.16 g (8.3 mmol) of tert-butyl [1-(4-fluorophenyl)-2-oxo-2-quinolin-8-ylethyl]carbamate in 45 ml of methanol at 0-5° C. The reaction mixture was stirred at 0-5° C. for 0.5 h and then at room temperature for 0.5 h and subsequently poured into an aqueous sodium dihydrogen phosphate solution (80 g/l). Extraction twice with ethyl acetate was followed by drying on magnesium sulfate. Concentration resulted in 2.78 g of tert-butyl [1-(4-fluorophenyl)-2-hydroxy-2-quinolin-8-ylethyl]carbamate (diastereoisomer mixture: 80/20) as pale yellow powder (yield: 88%).
Reaction SMILES: NC(=O)[C@@H](N[C:6]1[CH:11]=[C:10]([C:12](=[O:14])[NH2:13])[N:9]=[C:8]([C:15]2[CH:16]=[CH:17][C:18]([O:25][C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)=[C:19]([CH:24]=2)[C:20](OC)=[O:21])[N:7]=1)C.[BH4-].[Na+]>C(O)C>[F:32][C:29]1[CH:30]=[CH:31][C:26]([O:25][C:18]2[CH:17]=[CH:16][C:15]([C:8]3[N:9]=[C:10]([C:12]([NH2:13])=[O:14])[CH:11]=[CH:6][N:7]=3)=[CH:24][C:19]=2[CH2:20][OH:21])=[CH:27][CH:28]=1
Reactant: COC(=O)c1cc(-c2nc(N[C@@H](C)C(N)=O)cc(C(N)=O)n2)ccc1Oc1ccc(F)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: NC(=O)c1ccnc(-c2ccc(Oc3ccc(F)cc3)c(CO)c2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 63.6 %

Procedure:
To a solution of (S)-methyl 5-(4-((1-amino-1-oxopropan-2-yl)amino)-6-carbamoylpyrimidin-2-yl)-2-(4-fluorophenoxy)benzoate (50 mg, 0.11 mmol) in ethyl alcohol (1 mL) at room temperature was added NaBH4 (21 mg, 0.55 mmol). The mixture was stirred at room temperature for 2 h and quenched with addition of MeOH. The mixture was poured onto silica gel and purified via chromatography with 0 to 20% MeOH in CH2CH2 to provide (S)-6-(1-amino-1-oxopropan-2-yl)amino)-2-(4-(4-fluorophenoxy)-3-(hydroxymethyl)phenyl)pyrimidine-4-carboxamide (30 mg, 0.07 mmol) as white solid. 1H NMR (400 MHz, DMSO-d6): 8.57 (1H, d, J=2 Hz), 8.27 (1H, dd, J=2.4, 8.8 Hz), 7.05-6.94 (5H, m), 6.70 (1H, d, J=8.4 Hz), 4.68 (2H, s), 4.50 (1H, s), 1.42 (3H, d, J=7.2 Hz). LC/MS: m/z=426 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7]([OH:13])=[C:8]([CH2:11][CH3:12])[CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15].[C:19](=O)([O-])[O-].[K+].[K+].IC>CN(C=O)C.CCOCC.O>[CH3:1][C:2]1[C:6]2[C:7]([O:13][CH3:19])=[C:8]([CH2:11][CH3:12])[CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: CCOC(=O)c1oc2ccc(CC)c(O)c2c1C
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOCC
Product: CCOC(=O)c1oc2ccc(CC)c(OC)c2c1C
Temperature: 25 °C
Reaction time: 14 h
Yield: 90.6 %

Procedure:
To a solution of 0.25 g (1.01 mmol) of ethyl 3-methyl-4-hydroxy-5-ethylbenzofuran-2-carboxylate in 3.0 mL of DMF was added 0.417 g (3 eq) of potassium carbonate and 0.63 mL (10 eq) of iodomethane and the reaction was stirred at room temperature for 14 h. The reaction was then diluted with ether and water. The organic layer was washed with water, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was chromatographed on silica gel eluting with ethyl acetate/hexanes (1:10) to provide 0.24 g of ethyl 3-methyl -4-methoxy-5-ethylbenzofuran-2-carboxylate.
Reaction SMILES: [C:1]([C:3]1[C:4]([CH3:29])([CH3:28])[O:5][C:6]2[C:11]([C:12]=1[C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1)=[CH:10][CH:9]=[C:8]([NH:20]C(=O)OC(C)(C)C)[CH:7]=2)#[N:2].Cl.O1CCOCC1>>[NH2:20][C:8]1[CH:7]=[C:6]2[C:11]([C:12]([C:13]3[CH:14]=[CH:15][C:16]([F:19])=[CH:17][CH:18]=3)=[C:3]([C:1]#[N:2])[C:4]([CH3:29])([CH3:28])[O:5]2)=[CH:10][CH:9]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc2c(c1)OC(C)(C)C(C#N)=C2c1ccc(F)cc1
Agent: Cl
Solvent: C1COCCO1
Product: CC1(C)Oc2cc(N)ccc2C(c2ccc(F)cc2)=C1C#N

Procedure:
The compound obtained in (3) described above (250 mg) and 4N hydrochloric acid-dioxane solution (5 mL) were treated in the same manner as Reference Example 5(5) to give the titled compound (148 mg) as a yellow powder.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8]C)=[CH:6][C:5]([N:10]2[C:14]([C:15]#[N:16])=[C:13]([C:17]#[N:18])[N:12]([CH3:19])[C:11]2=[O:20])=[C:4]([F:21])[CH:3]=1.ClC1C(OCC#C)=CC(N2C(C#N)=C(C#N)N(CCC)C2=O)=C(F)C=1.[Al+3].[Cl-].[Cl-].[Cl-]>C1C=CC=CC=1>[Cl:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([N:10]2[C:14]([C:15]#[N:16])=[C:13]([C:17]#[N:18])[N:12]([CH3:19])[C:11]2=[O:20])=[C:4]([F:21])[CH:3]=1
Reactant: COc1cc(-n2c(C#N)c(C#N)n(C)c2=O)c(F)cc1Cl
Agent: C#CCOc1cc(-n2c(C#N)c(C#N)n(CCC)c2=O)c(F)cc1Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: c1ccccc1
Product: Cn1c(C#N)c(C#N)n(-c2cc(O)c(Cl)cc2F)c1=O
Temperature: 25 °C

Procedure:
The product of Example 29, 1-(4-chloro-2-fluoro-5-methoxyphenyl)-4,5-dicyano-3-methyl-1,3-dihydro-2H-imidazol-2-one (VI) (2.7 g, 8.82 mmol) was stirred in 100 mL benzene. To this mixture was added AlCl3 (4.68 g, 35.3 mmol) and the mixture was heated to reflux for 15 minutes. The mixture was cooled to room temperature, poured onto water, and extracted three times with 100 mL ethyl acetate. The organic solution was washed with water and brine, dried over MgSO4, filtered, and evaporated. The crude product was purified by elution from a short silica gel column. Recrystallization with ethyl acetate/heptane gave 1.6 g of 1-(4-chloro-2-fluoro-5-hydroxyphenyl)-4,5-dicyano-3-methyl-1,3-dihydro-2H-imidazol-2-one (VIII) (m.p. 210°-12° C.).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([N:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1)=[O:9].[NH2:16][C:17]1[C:18]([C:39]#[N:40])=[N:19][C:20]([C:23]2[CH:28]=[CH:27][C:26](B3OC(C)(C)C(C)(C)O3)=[CH:25][C:24]=2[F:38])=[CH:21][N:22]=1>>[NH2:16][C:17]1[C:18]([C:39]#[N:40])=[N:19][C:20]([C:23]2[CH:28]=[CH:27][C:26]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=3[C:8]([N:10]3[CH2:15][CH2:14][O:13][CH2:12][CH2:11]3)=[O:9])=[CH:25][C:24]=2[F:38])=[CH:21][N:22]=1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)c(C#N)n3)c(F)c2)OC1(C)C
Reactant: O=C(c1ccccc1Br)N1CCOCC1
Product: N#Cc1nc(-c2ccc(-c3ccccc3C(=O)N3CCOCC3)cc2F)cnc1N

Procedure:
The title compound was prepared in a manner similar to that described in Example 88 using (2-bromophenyl)(morpholino)methanone and 3-amino-6-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrazine-2-carbonitrile. MS (ESI): mass calcd. for C22H18FN5O2, 403.14; m/z found, 404.1 [M+H]+. 1H NMR (500 MHz, CD3OD) δ 7.45 (d, J=2.1, 1H), 6.71 (m, 1H), 6.32-6.21 (m, 3H), 6.17-6.10 (m, 2H), 6.07 (dd, J=12.4, 1.8, 1H), 2.40-2.22 (m, 3H), 2.13-2.03 (m, 2H), 1.86-1.77 (m, 1H), 1.62-1.49 (m, 2H).
Reaction SMILES: [NH:1]([CH2:5][CH2:6][OH:7])[CH2:2][CH2:3][OH:4].CCN(CC)CC.[F:15][C:16]([F:23])([F:22])[C:17](OCC)=[O:18]>CO>[F:15][C:16]([F:23])([F:22])[C:17]([N:1]([CH2:5][CH2:6][OH:7])[CH2:2][CH2:3][OH:4])=[O:18]
Reactant: OCCNCCO
Reactant: CCOC(=O)C(F)(F)F
Solvent: CO
Solvent: CCN(CC)CC
Product: O=C(N(CCO)CCO)C(F)(F)F
Reaction time: 20 h

Procedure:
(Kamal, A.; et al J. Med. Chem. 2002, 45, 4679-4688) Diethanolamine (3.57 g, 34 mmol) was dissolved in methanol (20 mL) and treated with Et3N (4.7 mL, 34 mmol) and ethyl trifluoroacetate (4.90 g, 34 mmol) for 20 h at rt, followed by adding another 1 mL CF3COOEt. After another 20 h, removal of volatile solvents under high vacuum yielded N-trifluoroacetyl-diethanolamine compound 6 as light yellow oil, which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([N:12]3[CH:20]([CH2:21][C:22](=[O:28])[CH2:23][CH2:24][CH:25]([CH3:27])[CH3:26])[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[C:13]3=[O:29])=[N:9]2)=[CH:4][CH:3]=1.C[O:31]CCOC.O1CCCC1.[OH-].[K+]>O>[Cl:1][C:2]1[N:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([NH:12][CH:20]([C:19]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:13]([OH:31])=[O:29])[CH2:21][C:22](=[O:28])[CH2:23][CH2:24][CH:25]([CH3:26])[CH3:27])=[N:9]2)=[CH:4][CH:3]=1
Reactant: CC(C)CCC(=O)CC1c2ccccc2C(=O)N1c1ccc2ccc(Cl)nc2n1
Reactant: COCCOC
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)CCC(=O)CC(Nc1ccc2ccc(Cl)nc2n1)c1ccccc1C(=O)O
Temperature: 30 °C
Reaction time: 34 h
Yield: 85 %

Procedure:
To a reactor was charged racemic-2-(7-chloro-1,8-naphthyridin-2-yl)-3-(5-methyl-2-oxo-hexyl)-1-isoindolinone (170 kg), 1,2-dimethoxyethane (730 L), tetrahydrofuran (THF, 990 L). The slurry was heated to 30° C. and a solution of potassium hydroxide (140 Kg) in water (1730 L) was added. The slurry was stirred at 34° C. for 34 hours. The solution was cooled to 20° C. and the lower aqueous layer was removed and replaced with water (1000 L). The solution was adjusted to pH 9.0 with 4N hydrochloric acid. The solution was vacuum distilled at 30° C. to remove the THF. Water (550 L) was added and the pH of the reaction was adjusted to 11.5 with 2N potassium hydroxide. The solution was filtered to remove residual racemic-2-(7-chloro-1,8-naphthyridin-2-yl)-3-(5-methyl-2-oxo-hexyl)-1-isoindolinone. To the liquors was added methylene chloride (1200 L) and the pH was adjusted to 1.4 with 4N HCl. The aqueous layer was removed. The organic layer was washed with water (700 L) and the water was discarded. The organic layer was concentrated under vacuum and replaced with methanol (500 L). The slurry was cooled to 10° C., water was added (500 L), and the mixtrue was cooled to 0° C. The resulting precipitate was isolated by filtration and dried under vacuum at 50° C. to afford 150 kg (85%) of racemic-2-[1-(7-chloro-1,8-naphthyridin-2-ylamino)-6-methyl-3-oxo-heptyl]-benzoic acid as a white solid. DCl/MS: M+H+ at 426, 100%. M.P. 173-4° C. UV maxima at 236 nm, 268 nm, and 353 nm.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([CH:13]([CH3:15])[CH3:14])[C:11]=1[OH:12])[CH:7]=O)([CH3:3])[CH3:2].[S:16]([CH2:22][C:23]#[N:24])([CH2:19][C:20]#[N:21])(=[O:18])=[O:17]>C(O)C.N1CCCCC1>[C:20]([CH2:19][S:16](/[C:22](=[CH:7]/[C:6]1[CH:5]=[C:4]([CH:1]([CH3:3])[CH3:2])[C:11]([OH:12])=[C:10]([CH:13]([CH3:15])[CH3:14])[CH:9]=1)/[C:23]#[N:24])(=[O:18])=[O:17])#[N:21]
Reactant: CC(C)c1cc(C=O)cc(C(C)C)c1O
Reactant: N#CCS(=O)(=O)CC#N
Solvent: CCO
Solvent: C1CCNCC1
Product: CC(C)c1cc(/C=C(\C#N)S(=O)(=O)CC#N)cc(C(C)C)c1O

Procedure:
A mixture of 500 mg of 3,5-diisopropyl-4-hydroxybenzaldehyde and 700 mg of sulfonyl diacetonitrile in 6 ml of ethanol was refluxed with a few drops of piperidine for 4 hours. Ethanol was removed in a rotavap and the mixture worked up with ethyl acetate, diluted acid and brine. A portion of the crude was then purified by HPLC on a C-18 column to provide 50 mg of M27 along with 30 mg of M29.
Reaction SMILES: Br[C:2]1[C:3]2[C:8]([C:9]([Br:16])=[C:10]3[C:15]=1[CH:14]=[CH:13][CH:12]=[CH:11]3)=[CH:7][CH:6]=[CH:5][CH:4]=2.C([Li])CCC.[C:22]1([Si:28](Cl)([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>O1CCCC1>[Br:16][C:9]1[C:10]2[C:15]([C:2]([Si:28]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)=[C:3]3[C:8]=1[CH:7]=[CH:6][CH:5]=[CH:4]3)=[CH:14][CH:13]=[CH:12][CH:11]=2
Reactant: Cl[Si](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Brc1c2ccccc2c(Br)c2ccccc12
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Brc1c2ccccc2c([Si](c2ccccc2)(c2ccccc2)c2ccccc2)c2ccccc12
Reaction time: 0.5 h

Procedure:
In a nitrogen atmosphere, 12 g (35.7 mmol) of 9,10-dibromoanthracene, and 300 ml of tetrahydrofuran (THF) were added to a round-bottom flask. Next, 14.4 ml (35.7 mmol, 2.5M) of n-butyl lithium was added dropwise slowly into the round-bottom flask at −78° C. After mixing and reacting for 30 min, 12 g (40.7 mmol) triphenylsilyl chloride with 50 ml THF were added dropwise slowly into the round-bottom flask at −78° C. After reacting at room temperature for 24 hours, the resulting mixture was subjected to extraction with a mixed solvent (ethyl acetate:H2O), dried over anhydrous MgSO4, filtered, and condensed, then the crude product was purified by column chromatography (n-hexane/acetyl acetate=15/1), A 9.0 g of pure 9-bromo-10-triphenysilyl anthracene was collected.
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[NH:7][C@:8]([CH:26]=[O:27])([CH3:25])[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:13][CH:12]=1)([CH3:4])([CH3:3])[CH3:2].CC(=CC)C.Cl([O-])=[O:35].[Na+].Cl>C(O)(C)(C)C.OP([O-])(O)=O.[K+].CCOC(C)=O>[C:1]([O:5][C:6]([NH:7][C@:8]([CH3:25])([CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:13][CH:12]=1)[C:26]([OH:35])=[O:27])=[O:28])([CH3:2])([CH3:4])[CH3:3]
Reactant: CCCCCCCOc1ccc(CC[C@](C)(C=O)NC(=O)OC(C)(C)C)cc1
Reactant: [O-][Cl+][O-]
Agent: CC=C(C)C
Agent: Cl
Agent: O=P([O-])(O)O
Solvent: CC(C)(C)O
Solvent: CCOC(C)=O
Product: CCCCCCCOc1ccc(CC[C@@](C)(NC(=O)OC(C)(C)C)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of [(R)-1-formyl-3-(4-heptyloxy-phenyl)-1-methyl-propyl]-carbamic acid tert-butyl ester (103 mg, 0.26 mMol) in tert-butanol (1 ml) and 10% aqueous KH2PO4 (1 ml) is added 2-methyl-2-butene (0.66 ml, 5.27 mMol) and sodium chlorite (59 mg, 0.52 mMol). The mixture is stirred at RT for 1 hour. The reaction mixture is then poured onto a biphasic mixture of AcOEt and HCl (aqueous, 1M). The aqueous phase is extracted twice with AcOEt. The combined organic layers are washed with a small amount of NaHCO3 (saturated aqueous solution), dried (Na2SO4) and concentrated under reduced pressure. Column chromatography eluting with 5% MeOH in CH2Cl2 gives the title compound as a colourless oil.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][C:2]1=O.[C:12]1([Mg]Br)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(OCC)C>[C:12]1([C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:1]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C1CCc2ccccc2C1
Reactant: Br[Mg]c1ccccc1
Solvent: CCOCC
Product: c1ccc(-c2ccc3ccccc3c2)cc1
Temperature: 200 °C

Procedure:
A mixture of 14.6 g. of 2-tetralone, 20 g. of phenyl magnesium bromide, and 200 ml. of diethyl ether is stirred for 4 hours and then refluxed for one hour. The mixture is acidified with the addition of 200 ml. of 1 N hydrochloric acid, filtered, and extracted with diethyl ether. The extracts are combined, washed with water to neutrality, filtered, dried and evaporated; unchanged 2-tetralone is removed by distillation. The residue, containing 2-phenyl-3,4-dihydronaphthalene is mixed with 25 g. of 5 percent palladium-on-charcoal catalyst; the resulting mixture is heated to 200° C for 6 hours, cooled, diluted with 250 ml. of chloroform, filtered, and evaporated to give 2-phenylnaphthalene.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9](=[O:25])[NH:10][N:11]([CH:19]3[CH2:24][CH2:23][CH2:22][NH:21][CH2:20]3)[C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.Cl[C:27]1C=CC(C2C(=O)NN(C3CCNCC3)C=2C2C=CN=CC=2)=CC=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9](=[O:25])[NH:10][N:11]([CH:19]3[CH2:24][CH2:23][CH2:22][N:21]([CH3:27])[CH2:20]3)[C:12]=2[C:13]2[CH:14]=[CH:15][N:16]=[CH:17][CH:18]=2)=[CH:4][CH:3]=1
Reactant: O=c1[nH]n(C2CCNCC2)c(-c2ccncc2)c1-c1ccc(Cl)cc1
Reactant: O=c1[nH]n(C2CCCNC2)c(-c2ccncc2)c1-c1ccc(Cl)cc1
Product: CN1CCCC(n2[nH]c(=O)c(-c3ccc(Cl)cc3)c2-c2ccncc2)C1

Procedure:
The title compound was synthesized analogously by the method described in Example 10. 4-(4-Chlorophenyl)-1-piperidin-3-yl-5-pyridin-4-yl-1,2-dihydro-pyrazol-3-one, instead of 4-(4-chlorophenyl)-1-piperidin-4-yl-5-pyridin-4-yl-1,2-dihydro-pyrazol-3-one, was used. MS (ES+): 369.2 (M+H)+; (ES−): 367.1 (M−H)−.
Reaction SMILES: C[O:2][C:3]1[CH:12]=[C:11]([O:13]C)[CH:10]=[C:9]2[C:4]=1[C:5]([CH3:16])=[CH:6][C:7](=[O:15])[NH:8]2.[Cl-].[Al+3].[Cl-].[Cl-].C(Cl)(Cl)Cl.CO>ClC1C=CC=CC=1>[OH:2][C:3]1[CH:12]=[C:11]([OH:13])[CH:10]=[C:9]2[C:4]=1[C:5]([CH3:16])=[CH:6][C:7](=[O:15])[NH:8]2
Reactant: COc1cc(OC)c2c(C)cc(=O)[nH]c2c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: Clc1ccccc1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: Cc1cc(=O)[nH]c2cc(O)cc(O)c12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.2 %

Procedure:
To a stirred solution of compound 11 (12.5 g, 57.07 mmol) in chlorobenzene (100 mL), aluminium chloride (37 g, 285.3 mmol) was added in portions over a period of 10 min and heated at 100° C. overnight (TLC chloroform: methanol 9:1, Rf=0.2). The reaction mixture was then cooled to room temperature, poured on crushed ice (300 g) and stirred well for 30 min. The solid separated was filtered washed with water till neutral to pH. It was then washed with hexane (50 mL) and dried to give product 5,7-dihydroxy-4-methyl-1,2-dihydro-2-quinolinone (13, 10.5 g) in 96% yield as a dark brown solid. M.P. >300° C.