Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].[N+:2]([C:5]1[CH:14]=[C:13]2[C:8]([CH2:9][CH2:10][NH:11][CH2:12]2)=[CH:7][CH:6]=1)([O-:4])=[O:3].[OH-].[Na+].[CH2:17]1[O:19][CH2:18]1.Cl>C(O)C>[ClH:1].[OH:19][CH2:18][CH2:17][CH:12]1[C:13]2[C:8](=[CH:7][CH:6]=[C:5]([N+:2]([O-:4])=[O:3])[CH:14]=2)[CH2:9][CH2:10][NH:11]1
Reactant: C1CO1
Reactant: O=[N+]([O-])c1ccc2c(c1)CNCC2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=[N+]([O-])c1ccc2c(c1)C(CCO)NCC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 62 %

Procedure:
To a solution of 7-nitro-1,2,3,4-tetrahydroisoquinoline hydrochloride (5.01 g, 23.3 mmol) in ethanol (200 ml) at 0° C. in a pressure bottle was added 2.5 M sodium hydroxide solution (10 ml). This solution was stirred for 0.2 h before ethylene oxide (4.2 ml) was added and the bottle was capped and the solution was stirred overnight while slowly allowing it to warm to ambient temperature. The solvent was concentrated and the aqueous solution was extracted twice with dichloromethane. The combined and dried (magnesium sulfate) extracts were concentrated to give an oil. This oil was immediately dissolved in ethanol (125 ml) and hydrochloric acid in ethanol was added until a distinctly acidic solution was obtained. After cooling, the title compound was collected and isolated as an off-white solid (3.76 g, 62%), m.p. 213° C. (dec.).
Reaction SMILES: [CH2:1]([O:9][C:10]1[CH:17]=[CH:16][C:13]([CH:14]=O)=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[F:18][C:19]([F:29])([F:28])[C:20]1[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=1[CH2:22][NH2:23]>>[CH2:1]([O:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14][NH:23][CH2:22][C:21]2[CH:24]=[CH:25][CH:26]=[CH:27][C:20]=2[C:19]([F:18])([F:28])[F:29])=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: NCc1ccccc1C(F)(F)F
Reactant: CCCCCCCCOc1ccc(C=O)cc1
Product: CCCCCCCCOc1ccc(CNCc2ccccc2C(F)(F)F)cc1

Procedure:
The same procedure as employed in the preparation of Example 394 (step b) but using 4-(octyloxy)benzaldehyde and 2-(trifluoromethyl)benzylamine gave the title compound as an oil. HPLC (Condition A), Rt: 4.24 min (HPLC purity: 91.0%).
Reaction SMILES: C(N([CH2:6][C:7]1[CH:35]=[CH:34][C:10]2[C:11](=[O:33])[N:12]([C:14]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[O:13][C:9]=2[CH:8]=1)CC)C.C([Cl:41])(=O)OCC.C(Cl)Cl>CC(O)C>[Cl:41][CH2:6][C:7]1[CH:35]=[CH:34][C:10]2[C:11](=[O:33])[N:12]([C:14]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[O:13][C:9]=2[CH:8]=1
Reactant: CCOC(=O)Cl
Reactant: CCN(CC)Cc1ccc2c(=O)n(C(c3ccccc3)(c3ccccc3)c3ccccc3)oc2c1
Solvent: ClCCl
Solvent: CC(C)O
Product: O=c1c2ccc(CCl)cc2on1C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
20.0 g of 6-(diethylamino)methyl-2-triphenylmethyl-1,2-benzisoxazol-3(2H)-one and 5.1 mL of ethyl chlorocarbonate were added to 60 mL of methylene chloride. This was then stirred for 3 hours at room temperature, and 140 mL of 2-propanol was added dropwise into the reaction mixture over a period of 30 minutes. The result was stirred for 2 hours at 5-15° C. and solids were filtered to obtain 16.6 g of 6-(chloromethyl)-2-triphenylmethyl-1,2-benzisoxazol-3(2H)-one in the form of a pale yellowish-white solid.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]([OH:14])=[O:13].S(Cl)(Cl)=O.[CH3:19]O>>[Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]([O:14][CH3:19])=[O:13]
Reactant: CO
Reactant: O=C(O)c1cccc2c(Br)cccc12
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cccc2c(Br)cccc12
Yield: 98 %

Procedure:
5-Bromonapthoic acid (J Chem. Soc., 1950, 991) (5.13 g, 20 mmol) was added to a solution of thionyl chloride (10 ml) in methanol (200 ml). The mixture was stirred at reflux for 4 h, yielding a dark brown solution. On cooling, the title compound precipitated as a light brown solid, which was filtered off and dried, yielding 5.34 g material (98%).
Reaction SMILES: [CH2:1]([NH2:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C(N(CC)CC)C.[NH:17]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[C@H:18]([C:26](ON1C(=O)CCC1=O)=[O:27])[CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(OCC)(=O)C>[CH2:1]([NH:9][C:26](=[O:27])[C@H:18]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[NH:17][C:36]([O:38][C:39]([CH3:42])([CH3:40])[CH3:41])=[O:37])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCN
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)ON1C(=O)CCC1=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCCCCCCCNC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 20 h
Yield: 95.7 %

Procedure:
To a solution of 1-octylamine (0.9 g, 6.9 mmol) and triethylamine (0.7 g, 6.9 mmol) in ethyl acetate (80 ml) was added a solution of BOC-Phe-OSu (2.5 g, 6.9 mmol) in ethyl acetate (50 ml). The mixture was stirred at room temperature for 20 hours. The organic layer was washed with water, 10% sodium carbonate, water and brine and denied on MgSO4. Evaporation of the solvent in vacuo yielded MdL080 as a white powder (2.5 g, 6.6 mmol, 96%). 1H NMR (CDCl3): δ=7.26-7.14 (m, 5H), 5.59 (bp 1H), 5.02 (bp, 1H), 4.20 (m, 1H), 3.07 (m, 4H), 1.57-1.17 (m, 21H), 0.82 (t, 3H, 3J=6.8 Hz); 13C NMR (CDCl3): δ=170.98, 136.68, 129.19, 128.60, 126.76, 65.88, 39.34, 88.71, 31.66, 29.21, 29.07, 28.16, 26.64, 22.52, 13.97.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[C:19]([O:24][CH3:25])[CH:20]=3)[CH:15]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>O1CCCC1.C(OCC)(=O)C.[Pt]=O>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[C:19]([O:24][CH3:25])[CH:20]=3)[CH:15]=2)[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc2cc(C3=CCN(Cc4ccccc4)CC3)ccc2c1
Reactant: [H][H]
Agent: O=[Pt]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1ccc2cc(C3CCN(Cc4ccccc4)CC3)ccc2c1
Yield: 92.2 %

Procedure:
A mixture of 2.92 gm 1-benzyl-4-(6-methoxynaphth-2-yl)-1,2,3,6-tetrahydropyridine and 0.3 gm platinum oxide in 50 mL tetrahydrofuran and 50 mL ethyl acetate was hydrogenated at room temperature for 16 hours at an initial hydrogen pressure of 60 p.s.i. The reaction mixture was filtered and the filtrate concentrated under reduced pressure to provide 2.71 gm of the title compound as a white solid.
Reaction SMILES: Cl[CH2:2][N:3]1[CH:8]=[C:7]([Cl:9])[CH:6]=[N:5][C:4]1=[O:10].[CH3:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([SH:18])[CH:13]=1.C(N(CC)CC)C>>[C:12]1([CH3:11])[CH:17]=[CH:16][CH:15]=[C:14]([S:18][CH2:2][N:3]2[CH:8]=[C:7]([Cl:9])[CH:6]=[N:5][C:4]2=[O:10])[CH:13]=1
Reactant: O=c1ncc(Cl)cn1CCl
Reactant: Cc1cccc(S)c1
Solvent: CCN(CC)CC
Product: Cc1cccc(SCn2cc(Cl)cnc2=O)c1
Temperature: 40 °C
Reaction time: 0.33 h

Procedure:
1-Chloromethyl-5-chloropyrimidin-2-one (see Preparation 15) (1.0 mmol) was added to a mixture of m-thiocresol (1.0 mmol) and triethylamine (1.0 mmol). The mixture was stirred at room temperature for 20 mins and at 40° C. for 20 mins before the solvent was distilled off and the residue triturated with water, extracted into chloroform, dried (MgSO4) and evaporated. The residue was washed with cold acetone (1 ml). The insoluble product was identical with an authentic sample prepared as described in Example 14. Yield: 60 mg, 22%.
Reaction SMILES: [C:1]1([C:7](=[O:12])[C:8]([O:10][CH3:11])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:13]1([CH3:19])[CH:18]=[CH:17][CH:16]=CC=1>>[C:1]1([C:7]([CH:16]2[CH2:17][CH2:18][CH2:13][CH2:19]2)([OH:12])[C:8]([O:10][CH3:11])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cc1ccccc1
Reactant: COC(=O)C(=O)c1ccccc1
Product: COC(=O)C(O)(c1ccccc1)C1CCCC1
Yield: 76.9 %

Procedure:
Using the same method as described for (1) of example 3, raw materials at equal weight were added successively. The difference was using a reaction temperature of -10-6° C. during dropuise addition of the toluene solution of 82 g of methyl phenylglyoxylate to cyclopentadiene Grignard reagent. 90 g of methyl 2-phenyl-2-cyclopentyl-2-hydroxy-acetate was obtained in 76.9% yield, nD25 1.5203, boiling point 82-5° C./0.03 mmHg. Silicagel GF 254 thin layer plate; developer: 1,2-dichloroethane, ultraviolet 254 nm fluorescence localization, main spot: Rf=0.72, without impurity spot.
Reaction SMILES: [CH3:1][N:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH3:12])[CH:8]=2)[C:3]1=[O:13].[Br:14]Br>C(O)(=O)C>[Br:14][C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH3:12])[CH:8]=2)[C:3](=[O:13])[N:2]([CH3:1])[CH:11]=1
Reactant: BrBr
Reactant: Cc1ccc2c(=O)n(C)ccc2c1
Solvent: CC(=O)O
Product: Cc1ccc2c(=O)n(C)cc(Br)c2c1
Yield: 95.9 %

Procedure:
2,6-Dimethylisoquinolin-1-one (120.0 mg, 0.60 mmol) in acetic acid (4 mL) was treated with Br2 (96 mg, 0.6 mmol) in acetic acid (0.6 mL) at 0° C. in a manner similar to Example 72, step 2. Isolation, also in a similar manner, gave the title compound (145.0 mg, 82.9%) as a white yellow solid. 1H NMR (CDCl3, 400 MHz) δ 8.33 (d, J=8.0 Hz, 1H), 7.60 (s, 1H), 7.37 (d, J=8.0 Hz, 1H), 7.35 (s, 1H), 3.60 (s, 3H), 2.54 (s, 3H). LCMS: 252.1 (M+H)+
Reaction SMILES: [I:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[O:11][CH3:12].[NH4+].[Cl-]>CO.O.[Fe]>[I:1][C:2]1[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=1[O:11][CH3:12])[NH2:8]
Reactant: COc1ccc([N+](=O)[O-])cc1I
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CO
Product: COc1ccc(N)cc1I
Yield: 92.3 %

Procedure:
To 2-iodo-1-methoxy-4-nitrobenzene (485 mg, 1.74 mmol) suspended in methanol (6 mL) a solution of NH4Cl (465 mg, 8.69 mmol) in water (4.9 mL) and powdered Fe (290 mg, 5.192 mmol) were added and the mixture was heated to reflux for 3 h. The precipitate formed was filtered off and the filtrate was evaporated until the methanol was eliminated. After diluting with water and alkalinization with sodium carbonate the mixture was extracted with EtOAc (4×20 mL). The combined organic extracts were washed with brine (3×10 mL), water (10 mL), dried over sodium sulfate and the solvent was removed under vacuum. The crude dark oil was purified by flash chromatography on silica gel (hexane/EtOAc 1/1) to afford 400 mg of solid that was crystallized from n-pentane and diethyl ether to yield the title compound (363 mg, 83%).
Reaction SMILES: [CH3:1][C:2]1[C:3]2[CH2:11][CH2:10][O:9][C:4]=2[N:5]=[C:6]([NH2:8])[N:7]=1.N12CCN(CC1)CC2.[CH3:20][N:21]1[C:25]2[CH:26]=[CH:27][CH:28]=[C:29]([S:30]([N:33]=[C:34]=[O:35])(=[O:32])=[O:31])[C:24]=2[N:23]=[N:22]1>C(#N)C.O>[CH3:1][C:2]1[C:3]2[CH2:11][CH2:10][O:9][C:4]=2[N:5]=[C:6]([NH:8][C:34]([NH:33][S:30]([C:29]2[C:24]3[N:23]=[N:22][N:21]([CH3:20])[C:25]=3[CH:26]=[CH:27][CH:28]=2)(=[O:31])=[O:32])=[O:35])[N:7]=1
Reactant: Cn1nnc2c(S(=O)(=O)N=C=O)cccc21
Reactant: Cc1nc(N)nc2c1CCO2
Agent: C1CN2CCN1CC2
Solvent: O
Solvent: CC#N
Product: Cc1nc(NC(=O)NS(=O)(=O)c2cccc3c2nnn3C)nc2c1CCO2
Reaction time: 4 h

Procedure:
To a stirred solution of 5,6-dihydro-4-methylfuro(2,3-d)pyrimidin-2-amine (0.08 g) and 1,4-diazabicyclo[2,2,2]octane (catalytic amount) in acetonitrile (5 mL) was added 0.125M 1-methyl-1H-benzotriazole-4-sulfonylisocyanate in acetonitrile (4.0 mL) under a nitrogen atmosphere. After stirring for 4 hours, the reaction was diluted with water (20 mL) and the precipitate was filtered, washed with water and ether, and dried to give 0.09 g of the title compound as a white solid. m.p. 234°-240° C. with decomposition.
Reaction SMILES: B(Br)(Br)Br.ClCCl.C([O:15][C@@H:16]1[C@@H:20]([CH2:21][O:22]CC2C=CC=CC=2)[S:19][CH:18]([N:30]2[CH:37]=[CH:36][C:34]([NH2:35])=[N:33][C:31]2=[O:32])[C@H:17]1[F:38])C1C=CC=CC=1.CCCCCC>ClCCl>[F:38][C@H:17]1[C@H:16]([OH:15])[C@@H:20]([CH2:21][OH:22])[S:19][CH:18]1[N:30]1[CH:37]=[CH:36][C:34]([NH2:35])=[N:33][C:31]1=[O:32]
Reactant: Nc1ccn(C2S[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@@H]2F)c(=O)n1
Agent: BrB(Br)Br
Solvent: CCCCCC
Solvent: ClCCl
Product: Nc1ccn(C2S[C@H](CO)[C@@H](O)[C@@H]2F)c(=O)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.3 %

Procedure:
0.065 mL of a 1 mol/L boron tribromide-dichloromethane solution was added to a solution of 9.6 mg of 1-(3,5-bis-O-benzyl-2-deoxy-2-fluoro-4-thio-D-arabinofuranosyl)cytosine in 1 mL of dichloromethane under cooling on ice. While the temperature was gradually increased to room temperature, the obtained mixture was stirred for 2 hours. Thereafter, hexane was added to the reaction mixture, and a solid was then collected by filtration. The obtained solid was washed with toluene and ethyl acetate, so as to obtain 5.3 mg of 1-(2-deoxy-2-fluoro-4-thio-D-arabinofuranosyl)cytosine in the form of a white solid.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[O:22][CH2:23][CH:24]([CH3:26])C)[NH:13][C:12](=[O:27])[CH:11]=2)=[CH:6][C:3]=1[C:4]#[N:5].O.[NH2:29][NH2:30]>C(O)C>[NH2:5][C:4]1[C:3]2[C:2](=[CH:9][CH:8]=[C:7]([C:10]3[CH:15]=[C:14]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=4[O:22][CH2:23][CH2:24][CH3:26])[NH:13][C:12](=[O:27])[CH:11]=3)[CH:6]=2)[NH:30][N:29]=1
Reactant: NN
Reactant: CC(C)COc1ccccc1-c1cc(-c2ccc(F)c(C#N)c2)cc(=O)[nH]1
Solvent: CCO
Solvent: O
Product: CCCOc1ccccc1-c1cc(-c2ccc3[nH]nc(N)c3c2)cc(=O)[nH]1
Temperature: 100 °C

Procedure:
A mixture of 2-fluoro-5-(6-{2-[(2-methylpropyl)oxy]phenyl}-2-oxo-1,2-dihydropyridin-4-yl)benzonitrile (50 mg), and hydrazine hydrate (2 mL) in ethanol (10 mL)was heated to 100° C. for 3 h. The reaction mixture was concentrated and the product was purified by preparative HPLC (reverse-phase, acetonitrile/water with 0.01% ammonium acetate) to afford 4-(3-amino-1H-indazol-5-yl)-6-[2-(propyloxy)phenyl]pyridin-2(1H)-one (20 mg). 1H NMR (400 MHz, d4-CD3OD): δ 8.18 (s, 1H), 7.72 (d, 1H), 7.57 (d, 1H), 7.46 (t, 1H), 7.39 (d, 1H), 7.16-7.08 (m, 2H), 6.92 (d, 1H), 6.76 (s, 1H), 3.88 (d, 2H), 2.12-2.05 (m, 1H), 1.00 (d, 6H). MS (EI) for C22H22N4O2: 375 (MH±).
Reaction SMILES: [F:1][C:2]1[C:3]([C:9]([OH:11])=[O:10])=[N:4][CH:5]=[C:6]([F:8])[CH:7]=1.Cl.[CH3:13]O>O1CCOCC1>[CH3:13][O:10][C:9]([C:3]1[C:2]([F:1])=[CH:7][C:6]([F:8])=[CH:5][N:4]=1)=[O:11]
Reactant: CO
Reactant: O=C(O)c1ncc(F)cc1F
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)c1ncc(F)cc1F
Temperature: 60 °C
Yield: 86 %

Procedure:
3,5-Difluoropicolinic acid (1.40 g, 8.78 mmol) was dissolved in 30 mL MeOH and 0.5 mL 4.0 M HCl in 1,4-dioxane. The mixture was heated at 60° C. for 1.5 h and concentrated. Saturated aqueous NaHCO3 was added. The mixture was extracted with EtOAc, dried over Na2SO4, and concentrated to give a yellow solid (1.30 g, 86% yield). 1H NMR (400 MHz, CDCl3) δ 8.48 (d, J=2.27 Hz, 1 H) 7.28-7.47 (m, 1 H) 4.03 (s, 3 H); LCMS for C7H5F2NO2 m/z 174.00 (M+H+).
Reaction SMILES: C[O:2][C:3]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:7][CH2:6]1)=O.O.[NH2:19][NH2:20]>>[O:11]([C@H:8]1[CH2:9][CH2:10][C@H:5]([C:3]([NH:19][NH2:20])=[O:2])[CH2:6][CH2:7]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: NN
Reactant: COC(=O)[C@H]1CC[C@H](Oc2ccccc2)CC1
Solvent: O
Product: NNC(=O)[C@H]1CC[C@H](Oc2ccccc2)CC1
Temperature: 120 °C

Procedure:
A mixture of trans-4-phenoxy-cyclohexanecarboxylic acid methyl ester (1.07 g, 4.57 mmol) and hydrazine hydrate (0.22 g, 4.48 mmol) was heated at 120° C. for 4 h. After cooling to room temperature the reaction mixture was concentrated in vacuo to give the crude title compound as white solid in quantitative yield, which was used in the next step without further purification.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][C:6]=1[C:7]([OH:9])=O)([CH3:3])[CH3:2].[C:18]1([C:24]2[N:28]=[C:27]([N:29]3[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)[S:26][N:25]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH:1]([O:4][C:5]1[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][C:6]=1[C:7]([N:32]1[CH2:33][CH2:34][N:29]([C:27]2[S:26][N:25]=[C:24]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:28]=2)[CH2:30][CH2:31]1)=[O:9])([CH3:2])[CH3:3]
Reactant: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)O
Reactant: c1ccc(-c2nsc(N3CCNCC3)n2)cc1
Product: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCN(c2nc(-c3ccccc3)ns2)CC1
Yield: 69 %

Procedure:
Prepared in analogy to example 1 (b) from 2-isopropoxy-5-methanesulfonyl-benzoic acid (Example A1) and 3-phenyl-5-piperazino-1,2,4-thiadiazole. The crude material was purified by chromatography (SiO2, ethyl acetate/heptane) to yield the title compound as a white crystalline solid (yield 69%). MS (m/e): 487.3 (M+H+, 100%).
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[C:15]1[C:20]([C:21]([F:24])([F:23])[F:22])=[CH:19][CH:18]=[CH:17][N:16]=1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[C:10]([O:9][C:7]([N:1]1[CH2:6][CH2:5][N:4]([C:15]2[C:20]([C:21]([F:24])([F:23])[F:22])=[CH:19][CH:18]=[CH:17][N:16]=2)[CH2:3][CH2:2]1)=[O:8])([CH3:13])([CH3:12])[CH3:11]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: FC(F)(F)c1cccnc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(c2ncccc2C(F)(F)F)CC1
Yield: 33.9 %

Procedure:
tert-butyl piperazine-1-carboxylate (3.0 g, 16.11 mmol) and 2-chloro-3-trifluoromethyl pyridine (2.93 g, 16.11 mmol) charged to a microwave vial was added with diisopropylethylamine (7.05 mL, 40.28 mmol) and DMF (1.0 mL). The reaction mixture was subject to microwave irradiation at 160° C. for 30 minutes. The reaction mixture was partitioned between EtOAc and water, organic layer washed with brine and dried over Na2SO4. The crude product obtained by solvent evaporation was purified via flash column chromatography. 4-(3-trifluoromethyl-pyridin-2-yl)-piperazine-1-carboxylic acid tert-butyl ester was obtained in 33.9% yield (1.81 g) as light yellow oil.
Reaction SMILES: [N:1]1([C:7]2[C:8](=[O:25])[N:9]([CH2:13][CH2:14][O:15][C:16]3[CH:21]=[C:20]([F:22])[C:19]([F:23])=[CH:18][C:17]=3[F:24])[CH:10]=[CH:11][N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[ClH:26].N1(C2C(=O)N(CCOC3C=C(F)C(F)=CC=3F)C=CN=2)CCNCC1.Br[CH2:53][CH2:54][C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1>>[ClH:26].[C:55]1([CH2:54][CH2:53][N:4]2[CH2:5][CH2:6][N:1]([C:7]3[C:8](=[O:25])[N:9]([CH2:13][CH2:14][O:15][C:16]4[CH:21]=[C:20]([F:22])[C:19]([F:23])=[CH:18][C:17]=4[F:24])[CH:10]=[CH:11][N:12]=3)[CH2:2][CH2:3]2)[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1
Reactant: BrCCc1ccccc1
Reactant: O=c1c(N2CCNCC2)nccn1CCOc1cc(F)c(F)cc1F
Agent: Cl
Product: O=c1c(N2CCN(CCc3ccccc3)CC2)nccn1CCOc1cc(F)c(F)cc1F

Procedure:
The title compound was prepared according to the procedure of Example 60 starting from 3-(1-piperazinyl)-1-[2-(2,4,5-trifluorophenoxy)ethyl]-2(1H)-pyrazinone (0.71 g, 2.0 mmol; from the free base of Example 3) and (2-bromoethyl)benzene (0.41 g, 2.2 mmol). Yield: 0.20 g (20%). HPLC purity: 96%. HRMS calc for C24H25F3N4O2 (M)+ 458.1930, found 458.1928.
Reaction SMILES: Br[CH2:2][C:3](=O)[CH2:4][CH2:5][CH2:6][C:7]([O:9][CH3:10])=[O:8].[NH2:12][C:13]([NH2:15])=[S:14]>C(O)C.C(OCC)(=O)C>[NH2:12][CH:13]1[NH:15][C:3]([CH2:4][CH2:5][CH2:6][C:7]([O:9][CH3:10])=[O:8])=[CH:2][S:14]1
Reactant: NC(N)=S
Reactant: COC(=O)CCCC(=O)CBr
Solvent: CCOC(C)=O
Solvent: CCO
Product: COC(=O)CCCC1=CSC(N)N1
Temperature: 25 °C

Procedure:
Methyl 6-bromo-5-oxohexanoate and thiourea (1.2 eq) in ethanol (0.2M solution) were refluxed for 18 hrs. The reaction was cooled to room temperature, diluted with ethyl acetate, washed with water and brine. The organic layer was dried over sodium sulfate, concentrated in vacuo and the residue was purified by flash chromatography (100% ethyl acetate). EI-MS m/z 201 (M+H)+.
Reaction SMILES: I[CH2:2][C@@H:3]([CH3:16])[CH2:4][N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7][C:6]1=[O:15].[CH:17](=[C:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)[CH2:18][CH2:19][CH3:20]>CC#N>[CH:17](=[C:21]1[CH2:26][CH2:25][N:24]([CH2:2][C@@H:3]([CH3:16])[CH2:4][N:5]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH2:8][CH2:7][C:6]2=[O:15])[CH2:23][CH2:22]1)[CH2:18][CH2:19][CH3:20]
Reactant: C[C@H](CI)CN1C(=O)CCc2ccccc21
Reactant: CCCC=C1CCNCC1
Solvent: CC#N
Product: CCCC=C1CCN(C[C@@H](C)CN2C(=O)CCc3ccccc32)CC1
Reaction time: 20 h
Yield: 66.8 %

Procedure:
A 4 mL vial was charged with (S)-1-(3-iodo-2-methylpropyl)-3,4-dihydro-1H-quinolin-2-one (122LH18) (0.169 g, 0.51 mmol) and 4-butylidenepiperidine (0.200 g, 1.4 mmol) in MeCN (2 mL) and shaken at 40° for 20 h. The reaction mixture was quenched with water, basified with ammonium hydroxide, and the product extracted into EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated. The product was purified by flash CC (SiO2; n-heptane/EtOAc 4:1) to give the title compound (107LH53) (0.116 g, 67%). 1H NMR (CD3OD) δ 7.23-7.18 (m, 3H), 7.02-6.98 (m, 1H), 5.11 (t, J=7.4 Hz, 1H), 3.98 (d, J=6.8 Hz, 2H), 2.89-2.85 (m, 2H), 2.61-2.56 (m, 2H), 2.40-2.35 (m, 2H), 3.32-2.04 (m, 11H), 1.98-1.92 (m, 2H), 1.36-1.29 (m, 2H), 0.90-0.85 (m, 2 CH3); 13C NMR (CD3OD) δ 173.0, 140.3, 137.1, 129.1, 128.4, 128.4, 124.3, 123.7, 116.9, 64.6, 57.4, 56.6, 46.5, 37.0, 32.9, 30.2, 30.1, 29.1, 26.3, 24.2, 17.2, 14.1.
Reaction SMILES: [C:1]1(=[O:16])[N:5]([CH2:6][CH2:7][C:8]([OH:10])=O)[C:4](=[O:11])[C:3]2=[CH:12][CH:13]=[CH:14][CH:15]=[C:2]12.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:29][N:30]1[C:39]([OH:47])([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=2[Cl:46])[C:38]2[C:33](=[CH:34][CH:35]=[C:36]([Cl:48])[CH:37]=2)[N:32]=[CH:31]1>O1CCCC1>[Cl:48][C:36]1[CH:37]=[C:38]2[C:33](=[CH:34][CH:35]=1)[N:32]=[CH:31][N:30]([NH:29][C:8](=[O:10])[CH2:7][CH2:6][N:5]1[C:1](=[O:16])[C:2]3[C:3](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:4]1=[O:11])[C:39]2([OH:47])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=1[Cl:46]
Reactant: O=C(O)CCN1C(=O)c2ccccc2C1=O
Reactant: NN1C=Nc2ccc(Cl)cc2C1(O)c1ccccc1Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: O=C(CCN1C(=O)c2ccccc2C1=O)NN1C=Nc2ccc(Cl)cc2C1(O)c1ccccc1Cl
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To an ice cold solution of β-phthalimidopropionic acid (2.41 g., 0.011 mole) in dry tetrahydrofuran (20 ml.) is added 1,1'-carbonyldiimidazole (1.94 g., 0.011 mole) under nitrogen. The ice bath is removed and the reaction stirred for 11/2 hours before the bath is replaced and 3-amino-6-chloro-3,4-dihydro-4-hydroxy-4-(o-chlorophenyl)-quinazoline (3.22 g., 0.01 mole) in tetrahydrofuran (25 ml.) is added. The reaction is stirred for 18 hours at ambient temperature before the reaction is concentrated in vacuo. The residue is mixed with water, neutralized with sodium bicarbonate and extracted with methylene chloride. The extract is washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give N-[6-chloro-4-hydroxy-4-(o-chlorophenyl)-3(4H)-quinazolinyl]-1,3-dioxo-2-isoindolinepropionamide.
Reaction SMILES: [CH3:1][C:2]1[C:3]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[N:4][C:5]([CH3:9])=[C:6]([CH3:8])[CH:7]=1.[Br:16][C:17]1[CH:18]=[CH:19][C:20]([C:23](O)=[O:24])=[N:21][CH:22]=1>>[Br:16][C:17]1[CH:18]=[CH:19][C:20]([C:23]([N:13]2[CH2:12][CH2:11][N:10]([C:3]3[C:2]([CH3:1])=[CH:7][C:6]([CH3:8])=[C:5]([CH3:9])[N:4]=3)[CH2:15][CH2:14]2)=[O:24])=[N:21][CH:22]=1
Reactant: Cc1cc(C)c(N2CCNCC2)nc1C
Reactant: O=C(O)c1ccc(Br)cn1
Product: Cc1cc(C)c(N2CCN(C(=O)c3ccc(Br)cn3)CC2)nc1C
Yield: 63.3 %

Procedure:
Using 1-(3,5,6-trimethylpyridin-2-yl)piperazine (1.5 g) described in Preparation Example 92 and 5-bromo-2-picolinic acid (1.5 g) and by the reaction and treatment in the same manner as in Preparation Example 118, the title compound (1.8 g) was obtained