Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:7]([CH:8]=[O:9])=[CH:6][C:5]([O:10][CH3:11])=[N:4][CH:3]=1.Cl.Cl[CH2:14][C:15]1[C:20]([C:21]2[N:25]([CH:26]([CH3:28])[CH3:27])[N:24]=[CH:23][CH:22]=2)=[N:19][CH:18]=[CH:17][N:16]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH:26]([N:25]1[C:21]([C:20]2[C:15]([CH2:14][O:1][C:2]3[C:7]([CH:8]=[O:9])=[CH:6][C:5]([O:10][CH3:11])=[N:4][CH:3]=3)=[N:16][CH:17]=[CH:18][N:19]=2)=[CH:22][CH:23]=[N:24]1)([CH3:28])[CH3:27]
Reactant: COc1cc(C=O)c(O)cn1
Reactant: CC(C)n1nccc1-c1nccnc1CCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(C=O)c(OCc2nccnc2-c2ccnn2C(C)C)cn1
Temperature: 100 °C
Yield: 68 %

Procedure:
A mixture of 5-hydroxy-2-methoxyisonicotinaldehyde (110 mg, 0.60 mmol, 1.2 eq.), 2-(chloromethyl)-3-(1-isopropyl-1H-pyrazol-5-yl)pyrazine hydrochloride (crude above, 0.5 mmol, 1 eq.), and K2CO3 (207 mg, 1.50 mmol, 3 eq.) in DMF (15.0 mL) was heated at 100° C. for 30 min. The mixture was cooled, filtered, concentrated, and purified on silica gel using a mixture of EtOAc and hexanes as eluent to give 5-((3-(1-isopropyl-1H-pyrazol-5-yl)pyrazin-2-yl)methoxy)-2-methoxyisonicotinaldehyde (12.0 mg, 68%) as an off-white solid. 1H NMR (400 MHz, CDCl3) δ 10.31 (s, 1H), 8.73 (d, J=2.4 Hz, 1H), 8.65 (d, J=2.4 Hz, 1H), 8.05 (s, 1H), 7.61 (d, J=1.9 Hz, 1H), 7.06 (s, 1H), 6.49 (d, J=1.9 Hz, 1H), 5.32 (s, 2H), 4.68 (sep, J=6.6 Hz, 1H), 3.89 (s, 2H), 1.48 (d, J=6.6 Hz, 6H). LRMS (M+H+) ink 354.1.
Reaction SMILES: [C:1]([C:5]1[O:9][C:8]([CH3:10])=[C:7]([CH:11]([CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)[O:12][C:13]2[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][CH:14]=2)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:28][NH:29][CH2:30][CH2:31][C:32]([O:34]CC)=[O:33]>>[C:1]([C:5]1[O:9][C:8]([CH3:10])=[C:7]([CH:11]([CH:22]2[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]2)[O:12][C:13]2[CH:14]=[CH:15][C:16]([C:17]([N:29]([CH3:28])[CH2:30][CH2:31][C:32]([OH:34])=[O:33])=[O:18])=[CH:20][CH:21]=2)[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1oc(C(C)(C)C)cc1C(Oc1ccc(C(=O)O)cc1)C1CCCCC1
Reactant: CCOC(=O)CCNC
Product: Cc1oc(C(C)(C)C)cc1C(Oc1ccc(C(=O)N(C)CCC(=O)O)cc1)C1CCCCC1
Yield: 80.6 %

Procedure:
An operation similar to that in Example 1 (4) was performed using 4-[(5-tert-butyl-2-methyl-3-furyl)(cyclohexyl)methoxy]benzoic acid (111 mg) as well as ethyl 3-(methylamino)propanoate (47 mg) to give the title compound (110 mg, 81%) as an amorphous compound.
Reaction SMILES: C(OC([NH:8][CH2:9][C:10]([O:12][CH2:13][CH:14]([C:16]1[CH:17]=[N:18][C:19]([C:22]2[NH:23][C:24]([CH:27]([C:35]3[CH:40]=[CH:39][C:38]([S:41]([CH:44]4[CH2:46][CH2:45]4)(=[O:43])=[O:42])=[CH:37][CH:36]=3)[CH2:28][CH:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)=[CH:25][CH:26]=2)=[CH:20][CH:21]=1)[OH:15])=[O:11])=O)(C)(C)C.C(OCC)(=O)C.[ClH:53]>C(OCC)(=O)C.C(OCC)C>[ClH:53].[ClH:53].[NH2:8][CH2:9][C:10]([O:12][CH2:13][CH:14]([C:16]1[CH:17]=[N:18][C:19]([C:22]2[NH:23][C:24]([CH:27]([C:35]3[CH:40]=[CH:39][C:38]([S:41]([CH:44]4[CH2:46][CH2:45]4)(=[O:42])=[O:43])=[CH:37][CH:36]=3)[CH2:28][CH:29]3[CH2:30][CH2:31][O:32][CH2:33][CH2:34]3)=[CH:25][CH:26]=2)=[CH:20][CH:21]=1)[OH:15])=[O:11]
Reactant: CC(C)(C)OC(=O)NCC(=O)OCC(O)c1ccc(-c2ccc(C(CC3CCOCC3)c3ccc(S(=O)(=O)C4CC4)cc3)[nH]2)nc1
Agent: Cl
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: NCC(=O)OCC(O)c1ccc(-c2ccc(C(CC3CCOCC3)c3ccc(S(=O)(=O)C4CC4)cc3)[nH]2)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 41 %

Procedure:
To a solution of 2-[6-(5-{1-[4-(cyclopropylsulfonyl)phenyl]-2-(tetrahydro-2H-pyran-4-yl)ethyl}-1H-pyrrol-2-yl)pyridin-3-yl]-2-hydroxyethyl N-(tert-butoxycarbonyl)glycinate (245 mg) in ethyl acetate (5 mL) was added 4M hydrogen chloride-ethyl acetate solution (210 μL), and the mixture was stirred overnight at room temperature. The reaction mixture was diluted with diethyl ether, and the resulting precipitate was collected by filtration and dried to give the title compound (44.1 mg, yield 41%) as a pale-yellow solid. MS: 554 (MH+).
Reaction SMILES: [K+].[C:2]([O:8][CH2:9][CH3:10])(=[O:7])[CH2:3][C:4]([O-:6])=O.C(N(CC)CC)C.[Cl-].[Mg+2].[Cl-].[Br:21][C:22]1[CH:30]=[CH:29][C:25](C(Cl)=O)=[C:24]([Cl:31])[CH:23]=1>C(#N)C>[Br:21][C:22]1[CH:30]=[CH:29][C:25]([C:4](=[O:6])[CH2:3][C:2]([O:8][CH2:9][CH3:10])=[O:7])=[C:24]([Cl:31])[CH:23]=1
Reactant: O=C(Cl)c1ccc(Br)cc1Cl
Reactant: CCOC(=O)CC(=O)[O-]
Agent: [Cl-]
Agent: [K+]
Agent: [Mg+2]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOC(=O)CC(=O)c1ccc(Br)cc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.4 %

Procedure:
13bs) 6.8 g of monoethyl malonate potassium salt in 70 ml of acetonitrile were cooled to 10° under argon and treated with 5.3 ml of triethylamine and 4.8 g of magnesium chloride. The resulting thick suspension was stirred at room temperature for 2 hrs. Then, it was again cooled to 10° and 5 g of 4-bromo-2-chloro-benzoyl chloride were added dropwise thereto over 30 min. The mixture was stirred at room temperature for 15 hrs. and then concentrated. Extraction: twice with 100 ml of toluene, once with 100 ml of cold 1N HCl and twice with 100 ml of water. After drying and evaporation there were obtained 5.2 g (85%) of ethyl 3-(4-bromo-2-chlorophenyl)-3-oxo-propionate as a brown oil which crystallized in a refrigerator. M.p. 34° C.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([NH:17][C:18]3[CH:26]=[C:25]4[C:21]([CH:22]=[N:23][NH:24]4)=[CH:20][CH:19]=3)=[C:10]([C:15]#[N:16])[CH:11]=[N:12]2)=[CH:7][C:6]=1[O:27][CH3:28].[OH:29][CH:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1.[I-].[Na+]>COCCOC>[OH:29][CH:30]1[CH2:35][CH2:34][N:33]([CH2:2][CH2:3][O:4][C:5]2[CH:14]=[C:13]3[C:8]([C:9]([NH:17][C:18]4[CH:26]=[C:25]5[C:21]([CH:22]=[N:23][NH:24]5)=[CH:20][CH:19]=4)=[C:10]([C:15]#[N:16])[CH:11]=[N:12]3)=[CH:7][C:6]=2[O:27][CH3:28])[CH2:32][CH2:31]1
Reactant: COc1cc2c(Nc3ccc4cn[nH]c4c3)c(C#N)cnc2cc1OCCCl
Reactant: OC1CCNCC1
Agent: [I-]
Agent: [Na+]
Solvent: COCCOC
Product: COc1cc2c(Nc3ccc4cn[nH]c4c3)c(C#N)cnc2cc1OCCN1CCC(O)CC1
Temperature: 135 °C

Procedure:
Using an analogous procedure to that described in Example 157, 196.5 mg (0.5 mmol) of the 7-(2-chloro-ethoxy)-4-(1H-indazol-6-ylamino)-6-methoxy-quinoline-3-carbonitrile, 505.8 mg (5.0 mmol) of 4-hydroxypiperidine and 75.0 mg (0.5 mmol) of sodium iodide in 5 mL of DME was heated at 135° C. for 16 hr. The work up gave 97.9 mg (42.8%) of the product as a off white solid, m.p. 174° C. (dec.), mass (electrospray, m/e): M+H 459.0.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[C:6](=[O:10])[CH2:7][CH2:8][CH2:9][C:2]1=2.[Br:11]Br.[OH-].[Na+]>C(O)(=O)C.O>[Br:11][C:5]1[S:1][C:2]2[CH2:9][CH2:8][CH2:7][C:6](=[O:10])[C:3]=2[CH:4]=1
Reactant: O=C1CCCc2sccc21
Reactant: BrBr
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: O=C1CCCc2sc(Br)cc21
Temperature: 0 °C
Reaction time: 18 h
Yield: 92.2 %

Procedure:
6,7-Dihydro-4-Benzo[B]thiophenone (1.5 g, 9.86 mmol) was dissolved in acetic acid (10 mL) and water (10 mL). The mixture was cooled to 0° C. and bromine (0.51 mL, 9.86 mmol) was added drop-wise. After 20 min at 0° C. the reaction was warmed to room temperature and stirred for 18 hr. The reaction mixture was cooled in ice and then treated with 1 M aqueous sodium hydroxide solution until the mixture was basic. A precipitate formed which was collected by filtration, washed with water and dried in a vacuum oven at 50° C. to afford the title compound as a grey solid (2.1 g, 96%).
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[C:8]([O:10][CH2:11][CH2:12][C:13]2[N:14]=[C:15]([C:19]3[CH:24]=[CH:23][C:22]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[CH:21][CH:20]=3)[O:16][C:17]=2[CH3:18])[CH:7]=[CH:6][C:5]=1[OH:31])[CH2:2][CH3:3].Br[C:33]([CH3:40])([CH3:39])[C:34]([O:36][CH2:37][CH3:38])=[O:35].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH2:37]([O:36][C:34](=[O:35])[C:33]([O:31][C:5]1[CH:6]=[CH:7][C:8]([O:10][CH2:11][CH2:12][C:13]2[N:14]=[C:15]([C:19]3[CH:20]=[CH:21][C:22]([C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)=[CH:23][CH:24]=3)[O:16][C:17]=2[CH3:18])=[CH:9][C:4]=1[CH2:1][CH2:2][CH3:3])([CH3:40])[CH3:39])[CH3:38]
Reactant: CCCc1cc(OCCc2nc(-c3ccc(-c4ccccc4)cc3)oc2C)ccc1O
Reactant: CCOC(=O)C(C)(C)Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCCc1cc(OCCc2nc(-c3ccc(-c4ccccc4)cc3)oc2C)ccc1OC(C)(C)C(=O)OCC
Temperature: 55 °C

Procedure:
A mixture of 2-propyl-4-[2-(5-methyl-2-biphenyl-4-yl-oxazole-4-yl)ethoxy]phenol (0.90 mmol), ethyl 2-bromo-2-methylpropanoate (2.25 mmol) and cesium carbonate (0.45 g, 1.38 mmol) in anhydrous DMF (4 mL) was heated for 24 h at 55° C. The mixture was concentrated in vacuo, and the residue was partitioned between ethyl acetate (50 mL) and water (40 mL), washed with brine, dried (Na2SO4), and removed in vacuo to give a crude oil which was purified using radial chromatography eluting with 2% ethyl acetate/dichloromethane to give 2-{4-[2-(2-biphenyl-4-yl-5-methyloxazol-4-yl)ethoxy]-2-propylphenoxy}-2-methylpropionic acid ethyl ester, 1H NMR (400 MHz, CDCl3), δ 8.04 (d, J=8.3 Hz, 2H), 7.65 (dd, J=11.0, 8.1 Hz, 4H), 7.46 (t, J=7.6 Hz, 2H), 7.37 (t, J=7.3 Hz, 1H), 6.70 (d, J=2.9 Hz, 1H), 6.64-6.57 (m, 2H), 4.27-4.17 (m, 4H), 2.96 (t, J=6.8 Hz, 2H), 2.54 (t, J=7.1 Hz, 2H), 2.38 (s, 3H), 1.59 (quintet, 7.6 Hz, 2H), 1.53 (s, 6H), 1.26 (t, J=6.8 Hz, 3H), 0.93 (t, J=7.3 Hz, 3H), MS (ES) m/e 528 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][C:3]=1[I:10]>C(Cl)(Cl)Cl.[O-2].[O-2].[Mn+4]>[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[I:10]
Reactant: OCc1ccc(F)c(I)c1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: O=Cc1ccc(F)c(I)c1
Reaction time: 8 h
Yield: 29.2 %

Procedure:
The product from Example 8B (6.4 g, 26 mmol) in chloroform (300 mL) was treated with manganese dioxide (4.5 g, 50 mmol) and stirred overnight. Additional manganese dioxide (2.25 g) was added to the reaction mixture and stirred overnight. The slurry was filtered and the solvent evaporated. The crude product was purified by flash chromatography over silica gel (ethyl acetate/hexane 1:4) to provide 1.9 g of the title compound.
Reaction SMILES: [C:1]([C:3]([C:11]1[S:12][C:13]([C:16]#[N:17])=[CH:14][CH:15]=1)([CH:8]([CH3:10])[CH3:9])[CH2:4][CH2:5][CH2:6]I)#[N:2].[C:18]([C:20]1[N:25]=[C:24]([O:26][CH2:27][CH2:28][N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[CH:23]=[CH:22][CH:21]=1)#[N:19]>>[C:1]([C:3]([C:11]1[S:12][C:13]([C:16]#[N:17])=[CH:14][CH:15]=1)([CH:8]([CH3:10])[CH3:9])[CH2:4][CH2:5][CH2:6][N:32]1[CH2:33][CH2:34][N:29]([CH2:28][CH2:27][O:26][C:24]2[CH:23]=[CH:22][CH:21]=[C:20]([C:18]#[N:19])[N:25]=2)[CH2:30][CH2:31]1)#[N:2]
Reactant: N#Cc1cccc(OCCN2CCNCC2)n1
Reactant: CC(C)C(C#N)(CCCI)c1ccc(C#N)s1
Product: CC(C)C(C#N)(CCCN1CCN(CCOc2cccc(C#N)n2)CC1)c1ccc(C#N)s1

Procedure:
The title compound was synthesized in accordance with Example 75 from 4-cyano-4-(5-cyano-2-thienyl)-5-methylhexyl iodide and 1-[2-(6-cyano-2-pyridyloxy)ethyl]piperazine. The physico-chemical data of the compound was as below.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[O:8][CH:7]([CH3:14])[CH2:6]2)=[CH2:2].C1C=C(Cl)C=C(C(OO)=[O:23])C=1>C(Cl)Cl.O>[CH3:14][CH:7]1[CH2:6][C:5]2[C:10](=[CH:11][CH:12]=[C:3]([CH:1]3[CH2:2][O:23]3)[CH:4]=2)[C:9](=[O:13])[O:8]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=Cc1ccc2c(c1)CC(C)OC2=O
Solvent: O
Solvent: ClCCl
Product: CC1Cc2cc(C3CO3)ccc2C(=O)O1

Procedure:
A solution of 6-ethenyl-3-methyl-3,4-dihydro-1H-isochromen-1-one (1.69 g, 8.98 mmol) in DCM (60 mL) was treated with m-CPBA (3.10 g, 17.96 mmol) overnight at room temperature. The reaction was then diluted with water (50 mL) and DCM (50 mL). The organic layer was further washed successively with saturated aqueous sodium bicarbonate (30 mL), water (30 mL), and brine (30 mL). The organic layer was then dried over magnesium sulfate, filtered and concentrated. The residue was purified via MPLC (15-40% EtOAc/Hex) to give 3-methyl-6-(oxiran-2-yl)-3,4-dihydro-1H-isochromen-1-one.
Reaction SMILES: [F:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[N:20]=[C:14]2[CH:15]=[C:16]([NH2:19])[CH:17]=[CH:18][N:13]2[N:12]=1.[CH3:21][N:22]1[C:26]([C:27](O)=[O:28])=[C:25]([C:30]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)=[O:31])[CH:24]=[N:23]1>>[F:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[N:20]=[C:14]2[CH:15]=[C:16]([NH:19][C:27]([C:26]3[N:22]([CH3:21])[N:23]=[CH:24][C:25]=3[C:30]([N:32]3[CH2:33][CH2:34][O:35][CH2:36][CH2:37]3)=[O:31])=[O:28])[CH:17]=[CH:18][N:13]2[N:12]=1
Reactant: Nc1ccn2nc(-c3ccccc3OCCF)nc2c1
Reactant: Cn1ncc(C(=O)N2CCOCC2)c1C(=O)O
Product: Cn1ncc(C(=O)N2CCOCC2)c1C(=O)Nc1ccn2nc(-c3ccccc3OCCF)nc2c1

Procedure:
This compound was prepared in analogy to 2-methyl-2H-pyrazole-3,4-dicarboxylic acid 4-dimethylamide 3-({2-[2-(2-fluoro-ethoxy)-phenyl]-[1,2,4]triazolo[1,5-a]pyridin-7-yl}-amide) (Example 100) from 2-[2-(2-fluoro-ethoxy)-phenyl]-[1,2,4]triazolo[1,5-a]pyridin-7-ylamine 104 mg, 0.38 mmol) and 2-methyl-4-(morpholine-4-carbonyl)-2H-pyrazole-3-carboxylic acid (130 mg, 0.54 mmol). Yield: 76 mg (28%); off-white solid; LC-MS: m/z=494.4 (M+H+).
Reaction SMILES: [S:1]([OH:11])(=[O:10])([C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1)=O.[CH:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O>FC(F)(F)C(O)=O>[C:12]1([S:1]([C:3]2[CH:4]=[CH:5][C:6]([NH2:9])=[CH:7][CH:8]=2)(=[O:10])=[O:11])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Nc1ccc(S(=O)(=O)O)cc1
Reactant: c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: Nc1ccc(S(=O)(=O)c2ccccc2)cc1
Temperature: 100 °C

Procedure:
A mixture of sulfanilic acid (10 g, 0.52 mmol), benzene (4.7 g, 0.56 mmol) and trifluoroacetic anhydride (42 g) in trifluoroacetic acid (42 g) was heated to reflux for 3 days. The solvent was removed in vacuo and the residue taken up in 10% aqueous sodium hydroxide and heated to 100° C. for 15 minutes. The resulting white precipitate was filtered off, washed with water and dried to give [4-(phenylsulfonyl)phenyl]amine. 1H NMR (400 MHz, d6-DMSO) δ 7.83-7.81 (2H, m), 7.61-7.51 (5H, m), 6.62-6.58 (2H, m), 6.15 (2H, s).
Reaction SMILES: [CH2:1]([NH:8][C:9]1[C:10]2[S:18][CH:17]=[C:16]([C:19]#[CH:20])[C:11]=2[N:12]=[C:13](Cl)[N:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:21][CH2:22][C@@H:23]([OH:25])[CH3:24].C(OCC)(=O)C>O1CCOCC1>[CH2:1]([NH:8][C:9]1[C:10]2[S:18][CH:17]=[C:16]([C:19]#[CH:20])[C:11]=2[N:12]=[C:13]([NH:21][CH2:22][C@@H:23]([OH:25])[CH3:24])[N:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@H](O)CN
Reactant: C#Cc1csc2c(NCc3ccccc3)nc(Cl)nc12
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: C#Cc1csc2c(NCc3ccccc3)nc(NC[C@H](C)O)nc12
Temperature: 120 °C
Reaction time: 24 h
Yield: 52.3 %

Procedure:
N-Benzyl-2-chloro-7-ethynylthieno[3,2-d]pyrimidin-4-amine (30 mg, 0.096 mmol) was dissolved in anhydrous dioxane (0.5 mL) and (S)-1-aminopropan-2-ol (23 μL, 0.288 mmol) was added. The reaction mixture was stirred at 120° C. for 24 hours. After adding ethyl acetate (3 mL), the reaction mixture was washed with brine. After drying with MgSO4 and concentrating by filtration, purification by silica gel chromatography (ethyl acetate/hexane:1/3→1/1) yielded the target compound of Example 44 (17 mg, 50% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH:9]([C:13]1[S:14][CH:15]=[CH:16][C:17]=1[CH3:18])[N:10]([CH3:12])[CH3:11].[Br:19]N1C(=O)CCC1=O>CN(C)C=O>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:19])=[CH:4][C:3]=1[CH2:8][CH:9]([C:13]1[S:14][CH:15]=[CH:16][C:17]=1[CH3:18])[N:10]([CH3:11])[CH3:12]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccsc1C(Cc1ccccc1N)N(C)C
Solvent: CN(C)C=O
Product: Cc1ccsc1C(Cc1cc(Br)ccc1N)N(C)C
Yield: 28.1 %

Procedure:
To a solution of 6.0 g of 2-amino-N,N-dimethyl-α-(3-methyl-2-thienyl)benzeneethanamine in 30 ml of dimethylformamide, was added 5.32 g of N-bromosuccinimide in 30 ml of dimethylformamide, with stirring, and the mixture was stirred overnight at room temperature. The solution was concentrated, basified with 10% sodium hydroxide solution, and extracted with dichloromethane. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by preparative HPLC (Water's Associates Prep LC/System 500a, silica gel, eluted with methanol, flow rate of 200 ml/min, Gow Mac model 80-800 UV detector). The appropriate fractions were collected and concentrated. The residue was dissolved in 100 ml of diethylether and filtered. The filtrate was concentrated. The residue was triturated in hexane to give 2.2 g of product, mp 96°-98° C.
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[NH:6]1[CH2:9][CH:8]([N:10]2[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[Cl:25])=[N:17][C:16]3[C:11]2=[N:12][C:13]([CH3:34])=[N:14][C:15]=3[N:26]2[CH2:31][CH2:30][N:29]([CH2:32][CH3:33])[CH2:28][CH2:27]2)[CH2:7]1.N1C=CC=CC=1>ClCCl>[CH3:5][O:4][C:2]([N:6]1[CH2:7][CH:8]([N:10]2[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[Cl:25])=[N:17][C:16]3[C:11]2=[N:12][C:13]([CH3:34])=[N:14][C:15]=3[N:26]2[CH2:27][CH2:28][N:29]([CH2:32][CH3:33])[CH2:30][CH2:31]2)[CH2:9]1)=[O:3]
Reactant: COC(=O)Cl
Reactant: CCN1CCN(c2nc(C)nc3c2nc(-c2ccccc2Cl)n3C2CNC2)CC1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCN1CCN(c2nc(C)nc3c2nc(-c2ccccc2Cl)n3C2CN(C(=O)OC)C2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Add methyl chloroformate (0.0024 mol, 0.22 g, 2.5 equiv.) to a solution of 9-(azetidin-3-yl)-8-(2-chlorophenyl)-6-(4-ethylpiperazin-1-yl)-2-methyl-9H-purine (0.0009 mol, 0.4 g) and pyridine (2 mL) in dry dichloromethane (2 mL) at 0° C. and stir for 2 hours at room temperature. Quench the reaction mixture with saturated sodium bicarbonate solution and then extract with dichloromethane. Dry the organic layer over anhydrous sodium sulfate, filter and concentrate under reduced pressure to give the residue. Purify the residue by silica gel chromatography eluting with dichloromethane:methanol 98:2 to give the title compound as the freebase (0.155 g). MS (m/z): 470.63 (M+1).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([NH:9][S:10]([C:13]2[CH:22]=[C:21]3[C:16]([CH2:17][CH2:18][NH:19][CH2:20]3)=[CH:15][CH:14]=2)(=[O:12])=[O:11])[CH:6]=[CH:7][CH:8]=1.[CH2:23]([O:25][C:26](=[O:31])[CH2:27][CH2:28][CH2:29]Br)[CH3:24].C(N(CC)CC)C>C(#N)C>[CH2:23]([O:25][C:26](=[O:31])[CH2:27][CH2:28][CH2:29][N:19]1[CH2:18][CH2:17][C:16]2[C:21](=[CH:22][C:13]([S:10](=[O:12])(=[O:11])[NH:9][C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([Cl:2])[CH:4]=3)=[CH:14][CH:15]=2)[CH2:20]1)[CH3:24]
Reactant: CCOC(=O)CCCBr
Reactant: O=S(=O)(Nc1cccc(Cl)c1)c1ccc2c(c1)CNCC2
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOC(=O)CCCN1CCc2ccc(S(=O)(=O)Nc3cccc(Cl)c3)cc2C1
Yield: 16.9 %

Procedure:
A mixture of 7-(3-chlorophenylsulphamoyl)-1,2,3,4-tetrahydroisoquinoline hydrochloride (3.05 g, 8 mmol), ethyl-4-bromobutyrate (1.56 g), and triethylamine (0.81 g, 8 mmol) in acetonitrile (35 ml) was heated at 55°-60° for 4 hr. The mixture was filtered, the filtrate concentrated and chromatographed (silica gel, ether) to give ethyl-4-[7-(3-chlorophenylsulphamoyl)-1,2,3,4-tetrahydroisoquinolin-2-yl]butyrate (0.59 g, 17%) as an oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:14]([NH:16][C:17]([C:19]2[N:20]=[C:21](Cl)[O:22][CH:23]=2)=[O:18])[CH3:15])[CH:5]=[C:6]([F:13])[C:7]=1[NH:8][S:9]([CH3:12])(=[O:11])=[O:10].[CH:25]1([C:29]2[CH:30]=[C:31]([OH:35])[CH:32]=[CH:33][CH:34]=2)[CH2:28][CH2:27][CH2:26]1>>[F:1][C:2]1[CH:3]=[C:4]([CH:14]([NH:16][C:17]([C:19]2[N:20]=[C:21]([O:35][C:31]3[CH:32]=[CH:33][CH:34]=[C:29]([CH:25]4[CH2:28][CH2:27][CH2:26]4)[CH:30]=3)[O:22][CH:23]=2)=[O:18])[CH3:15])[CH:5]=[C:6]([F:13])[C:7]=1[NH:8][S:9]([CH3:12])(=[O:11])=[O:10]
Reactant: Oc1cccc(C2CCC2)c1
Reactant: CC(NC(=O)c1coc(Cl)n1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Product: CC(NC(=O)c1coc(Oc2cccc(C3CCC3)c2)n1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Yield: 98.6 %

Procedure:
2-Chloro-oxazole-4-carboxylic acid [1-(3,5-difluoro-4-methanesulfonylamino-phenyl)-ethyl]-amide (50 mg, 0.13 mmol) was reacted with 3-cyclobutyl-phenol (38.7 mg, 0.26 mmol) to give the title compound (63 mg, 98%) after purification by column chromatography (gradient 12% to 100% EtOAc in n-hexane).
Reaction SMILES: [CH2:1]([O:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]2[CH2:21][CH2:20][N:19]([C:22]3[CH:29]=[CH:28]C(C#N)=[CH:24][CH:23]=3)[CH2:18][CH2:17]2)=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].O.[C:31]([OH:34])(=[O:33])[CH3:32]>OS(O)(=O)=O>[CH2:1]([O:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]2[CH2:21][CH2:20][N:19]([C:22]3[CH:29]=[CH:28][C:32]([C:31]([OH:34])=[O:33])=[CH:24][CH:23]=3)[CH2:18][CH2:17]2)=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCOc1ccc(N2CCN(c3ccc(C#N)cc3)CC2)cc1
Reactant: CC(=O)O
Agent: O=S(=O)(O)O
Solvent: O
Product: CCCCCCCCOc1ccc(N2CCN(c3ccc(C(=O)O)cc3)CC2)cc1

Procedure:
A solution of 4-[4-(4-Octyloxyphenyl)piperazin-1-yl]benzonitrile (0.5 g) in 20% H2SO4 aqueous solution (30 ml) and acetic acid (20 ml) was refluxed for 9 hours. The reaction mixture was pulverized with water. The precipitate was collected by filtration, and added to a mixture of water, tetrahydrofuran and ethyl acetate, and adjusted to pH 2.5 with 1N NaOH aqueous solution. The organic layer was taken, and dried over magnesium sulfate. The magnesium sulfate was filtered off, and the filtrate was evaporated under reduced pressure to give 4-[4-(4-Octyloxyphenyl)piperazin-1-yl]benzoic acid (388 mg).
Reaction SMILES: P(Br)(Br)[Br:2].[CH2:5]([O:12][C:13]1[CH:18]=[CH:17][C:16]([I:19])=[CH:15][C:14]=1[CH2:20]O)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>C1(C)C=CC=CC=1>[CH2:5]([O:12][C:13]1[CH:18]=[CH:17][C:16]([I:19])=[CH:15][C:14]=1[CH2:20][Br:2])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: BrP(Br)Br
Reactant: OCc1cc(I)ccc1OCc1ccccc1
Solvent: Cc1ccccc1
Product: BrCc1cc(I)ccc1OCc1ccccc1
Temperature: 100 °C
Reaction time: 0.17 h

Procedure:
3.3 ml (35 mmol) of phosphorus tribromide are added dropwise to a solution of 35 g (103 mmol) of (2-benzyloxy-5-iodophenyl)methanol (Example 3A) in 350 ml of toluene at 40° C. The temperature of the reaction mixture is raised to 100° C. over the course of 15 min and the reaction mixture is stirred at this temperature for a further 10 min. After cooling, the two phases are separated. The organic phase is washed twice with distilled water and once with a saturated aqueous sodium chloride solution. The organic phase is dried over sodium sulfate and evaporated. The yield amounts to 41 g (99% of theory).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=O)[CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14])=[CH:5][CH:4]=1>C(O)C.C(O)(=O)C.[H][H].[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14])=[CH:7][CH:8]=1
Reactant: COc1ccc(C(=O)CCCC(=O)O)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCO
Product: COc1ccc(CCCCC(=O)O)cc1
Yield: 99.3 %

Procedure:
5-(4-methoxyphenyl)-5-oxopentanoic acid (8) (11.5 g) from the previous step was dissolved in ethyl alcohol (150 mL) and acetic acid (50 mL), 10% palladium-activated carbon (1.2 g) was added, then stirred overnight in hydrogen atmosphere at room temperature. After filtration and vacuum concentration, the above-identified compound was obtained as a colorless solid (10.7 g, yield 99%).
Reaction SMILES: [NH2:1][C@@H:2]([C:7]([OH:9])=[O:8])[C:3]([SH:6])([CH3:5])[CH3:4].[CH:10](=O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>O>[CH3:4][C:3]1([CH3:5])[S:6][CH:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[NH:1][C@H:2]1[C:7]([OH:9])=[O:8]
Reactant: O=Cc1ccccc1
Reactant: CC(C)(S)[C@@H](N)C(=O)O
Solvent: O
Product: CC1(C)SC(c2ccccc2)N[C@H]1C(=O)O
Reaction time: 0.5 h
Yield: 94.7 %

Procedure:
A 250 mL flask was charged with 20 mL of water and 2.0 g (13.4 mmol) of D-penicillamine. To the resulting colorless solution was added 1.4 g (13.3 mmol) of benzaldehyde dropwise over 2 minutes. The resulting suspension was stirred vigorously for 30 minutes and allowed to stand at room temperature overnight. The solids thus obtained were collected by filtration to yield 3.0 g (12.6 mmol) of the title thiazolidine.