Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][C:3]([N:5]1[CH2:10][CH2:9][CH2:8][CH:7]([NH2:11])[CH2:6]1)=[O:4].C(O[CH:16]1[C:29]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[O:23][C:22]2[C:17]1=[CH:18][CH:19]=[CH:20][CH:21]=2)(=O)C>C1(C)C=CC=CC=1>[CH3:1][NH:2][C:3]([N:5]1[CH2:10][CH2:9][CH2:8][CH:7]([NH:11][CH:16]2[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:22]=3[O:23][C:24]3[C:29]2=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:6]1)=[O:4]
Reactant: CNC(=O)N1CCCC(N)C1
Reactant: CC(=O)OC1c2ccccc2Oc2ccccc21
Solvent: Cc1ccccc1
Product: CNC(=O)N1CCCC(NC2c3ccccc3Oc3ccccc32)C1

Procedure:
Reacting 1-(N-methylcarbamoyl)-3-aminopiperidine with 9-acetoxyxanthene in dry toluene by the procedure of Example 1 gives N-[1-(N-methylcarbamoyl)-3-piperidinyl]-9-xanthenylamine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([C:14]([OH:16])=O)[CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[N:17]1([NH2:23])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1>>[N:17]1([NH:23][C:14]([C:12]2[CH:11]=[CH:10][CH:9]=[C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[N:13]=2)=[O:16])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: O=C(O)c1cccc(-c2cccc(Cl)c2)n1
Reactant: NN1CCCCC1
Product: O=C(NN1CCCCC1)c1cccc(-c2cccc(Cl)c2)n1

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-(3-chlorophenyl)-2-pyridinecarboxylic acid (CAN 863704-38-5) and 1-piperidinamine (CAN 2213-43-6) as starting materials, MS (EI): m/e 316.0 [M+H]+.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[N:4]([C@H:12]2[CH2:17][CH2:16][C@@H:15]([N:18]3[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]3)[CH2:14][CH2:13]2)[N:3]=1.[CH:25]([C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1)=[O:26].C(=O)([O-])[O-].[Na+].[Na+].B([O-])[O-]>COCCOC.O>[NH2:11][C:9]1[N:8]=[CH:7][N:6]=[C:5]2[N:4]([C@H:12]3[CH2:17][CH2:16][C@@H:15]([N:18]4[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]4)[CH2:14][CH2:13]3)[N:3]=[C:2]([C:30]3[CH:31]=[CH:32][C:27]([CH:25]=[O:26])=[CH:28][CH:29]=3)[C:10]=12
Reactant: O=Cc1ccc(B(O)O)cc1
Reactant: CN1CCN([C@H]2CC[C@@H](n3nc(I)c4c(N)ncnc43)CC2)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [O-]B[O-]
Solvent: COCCOC
Solvent: O
Product: CN1CCN([C@H]2CC[C@@H](n3nc(-c4ccc(C=O)cc4)c4c(N)ncnc43)CC2)CC1
Temperature: 80 °C
Reaction time: 40 h
Yield: 44.2 %

Procedure:
A mixture of cis-3-iodo-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-ylamine (5.0 g, 11.33 mmol), 4-formylphenyl boronic acid (2.55 g, 16.98 mmol), palladium tetrakistriphenylphosphine (0.47 g, 0.4 mmol), and sodium carbonate (3.002 g, 28.32 mmol) in ethylene glycol dimethylether (170 mL) and water (30 mL) was heated at 80° C. for 18 h. Additional boronate (1.567 equiv.) and catalyst (0.0135 equiv.) were added and the reaction continued for a further 40 h. The reaction was cooled to ambient temperature and concentrated in vacuo. The residues were partitioned between ethyl acetate (300 mL) and water (200 mL). The resulting precipitate was collected by filtration and dried on the lyophiliser to afford cis-4-{4-Amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}benzaldehyde as a light brown solid (2.1 g, 43%); RP-HPLC 7.003 min, 98% purity (5% to 85% acetonitrile/0.1M aqueous ammonium acetate, buffered to pH 4.5, over 20 min at 1 mL/min; λ=254 nm; Deltapak C18, 300 Å, 5 μm, 150×3.9 mm column); 1H NMR (DMSO-d6, 400 MHz) δ 1.60 (2H, br t), 1.72 (2H, m), 2.06 (2H, m), 2.17 (3H, s), 2.27 (3H, m), 2.35-2.50 (6H, m), 3.39 (2H, m), 4.84 (1H, m), 7.88 (2H, d), 8.07 (2H, d), 8.26 (1H, s), and 10.11 (1H, s)
Reaction SMILES: C(C1C=CC(C2SC(C)=C(C(F)(F)F)C=2CO)=CC=1)C.OC1C=CC(CCC(OCC)=O)=C(C)C=1C.[CH2:37]([C:39]1[CH:44]=[CH:43][C:42]([C:45]2[S:46][C:47]([CH3:71])=[C:48]([C:67]([F:70])([F:69])[F:68])[C:49]=2[CH2:50][O:51][C:52]2[CH:57]=[CH:56][C:55]([CH2:58][CH2:59][C:60]([O:62]CC)=[O:61])=[C:54]([CH3:65])[C:53]=2[CH3:66])=[CH:41][CH:40]=1)[CH3:38]>>[CH2:37]([C:39]1[CH:40]=[CH:41][C:42]([C:45]2[S:46][C:47]([CH3:71])=[C:48]([C:67]([F:69])([F:68])[F:70])[C:49]=2[CH2:50][O:51][C:52]2[CH:57]=[CH:56][C:55]([CH2:58][CH2:59][C:60]([OH:62])=[O:61])=[C:54]([CH3:65])[C:53]=2[CH3:66])=[CH:43][CH:44]=1)[CH3:38]
Reactant: CCOC(=O)CCc1ccc(OCc2c(-c3ccc(CC)cc3)sc(C)c2C(F)(F)F)c(C)c1C
Agent: CCOC(=O)CCc1ccc(O)c(C)c1C
Agent: CCc1ccc(-c2sc(C)c(C(F)(F)F)c2CO)cc1
Product: CCc1ccc(-c2sc(C)c(C(F)(F)F)c2COc2ccc(CCC(=O)O)c(C)c2C)cc1

Procedure:
The title compound was prepared according to the procedure described in Example 220 by coupling of [2-(4-ethylphenyl)-5-methyl-4-(trifluoromethyl)thiophen-3-yl]methanol and ethyl 3-(4-hydroxy-2,3-dimethylphenyl)propanoate followed by hydrolysis of ethyl 3-(4-((2-(4-ethyl phenyl)-5-methyl-4-(trifluoromethyl)thiophen-3-yl)methoxy)-2,3-dimethylphenyl)propanoate to afford the desired product as an off-white solid. 1H NMR (300 MHz, CDCl3) δ: 7.43 (d, J=4.2 Hz, 2H), 7.24 (d, J=6.0 Hz, 2H), 6.97 (d, J=6.3 Hz, 2H), 6.67 (d, J=6.3 Hz, 2H), 4.86 (s, 2H), 2.97 (t, J=6.0 Hz, 2H), 2.61-2.73 (m, 7H) 2.23 (s, 3H), 2.18 (s, 3H), 1.27 (t, J=5.7 Hz, 2H). Mass spectrum (ESI, m/z): Calcd. for C26H27F3O3S, 475.2[M−H]. found 475.2.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)[CH2:3][N:4]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]1=[O:14].[Br:22][C:23]1[CH:32]=[CH:31][C:26]([C:27](OC)=[O:28])=[C:25]([CH2:33]Br)[CH:24]=1.C(N(CC)C(C)C)(C)C.C(O)CCC>>[Br:22][C:23]1[CH:24]=[C:25]2[C:26](=[CH:31][CH:32]=1)[C:27](=[O:28])[N:1]([C@@H:2]([CH2:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)[CH2:3][N:4]1[C:5](=[O:14])[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:12]1=[O:13])[CH2:33]2
Reactant: N[C@@H](CC1CCCCC1)CN1C(=O)c2ccccc2C1=O
Reactant: COC(=O)c1ccc(Br)cc1CBr
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: O=C1c2ccccc2C(=O)N1C[C@H](CC1CCCCC1)N1Cc2cc(Br)ccc2C1=O
Temperature: 140 °C
Reaction time: 2 h
Yield: 54 %

Procedure:
A mixture of 2-[(2S)-2-amino-3-cyclohexylpropyl]-1H-isoindole-1,3(2H)-dione (914.3 mg, 3.193 mmol), methyl 4-bromo-2-(bromomethyl)benzoate (960.0 mg, 3.117 mmol) and N,N-diisopropylethylamine (0.6 mL, 3 mmol) in 1-butanol (4 mL, 40 mmol) was stirred at 140° C. for 2 h under microwave irradiation. Direct purification by combi-flash chromatography afforded 810 mg (54% yield) of the desired product. LC-MS found: 481.1 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[S:10][C:5]2[CH2:6][O:7][CH2:8][CH2:9][C:4]=2[C:3]=1[C:11]#[N:12].C(N(CC)CC)C.[C:20]1([CH:26]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:27](Cl)=[O:28])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(Cl)Cl>[C:11]([C:3]1[C:4]2[CH2:9][CH2:8][O:7][CH2:6][C:5]=2[S:10][C:2]=1[NH:1][C:27](=[O:28])[CH:26]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)#[N:12]
Reactant: N#Cc1c(N)sc2c1CCOC2
Reactant: O=C(Cl)C(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: N#Cc1c(NC(=O)C(c2ccccc2)c2ccccc2)sc2c1CCOC2
Reaction time: 72 h
Yield: 37.3 %

Procedure:
To a stirred solution of 2-Amino-3-cyano-4,7-dihydro-5H-thieno[2,3-c]pyran (400 mg; 2.22 mmol) and triethylamine (0.93 mL; 6.66 mmol) in dry methylene chloride (10 mL) under nitrogen at room temperature was added diphenylacetyl chloride (768 mg; 3.33 mmol). After 72 h, the mixture was diluted with methylene chloride and washed with 1N HCl. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was triturated with cold diethyl ether and filtered to give 310 mg (37%) of N-(3-Cyano-4,7-dihydro-5H-thieno[2,3-c]pyran-2-yl)-2,2-diphenyl-acetamide as a white solid. ES-HRMS m/e calcd for C22H18N2O2S (M+H+) 375.1162, found 375.1165.
Reaction SMILES: Br[C:2]1[C:10]2[O:9][C:8]([C:11]3[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=3)=[N:7][C:6]=2[CH:5]=[C:4]([OH:18])[CH:3]=1.C[O-].[Na+].[C:22](OCC)(=[O:24])C>CN(C)C=O.Cl.[Cu]Br>[OH:17][C:14]1[CH:15]=[CH:16][C:11]([C:8]2[O:9][C:10]3[C:2]([O:24][CH3:22])=[CH:3][C:4]([OH:18])=[CH:5][C:6]=3[N:7]=2)=[CH:12][CH:13]=1
Reactant: Oc1ccc(-c2nc3cc(O)cc(Br)c3o2)cc1
Reactant: CCOC(C)=O
Agent: [Cu]Br
Agent: C[O-]
Agent: Cl
Solvent: CN(C)C=O
Product: COc1cc(O)cc2nc(-c3ccc(O)cc3)oc12
Temperature: 120 °C
Yield: 60 %

Procedure:
A mixture of 7-bromo-2-(4-hydroxyphenyl)-1,3-benzoxazol-5-ol (100 mg, 0.33 mmol), and copper(I) bromide (56 mg, 0.39 mmol) in anhydrous N,N dimethylformamide (1.5 mL) was stirred with freshly prepared sodium methoxide (15 wt % in methanol, 1 ml) and heated to 120° C. for 4 h. The mixture was cooled and diluted with HCl (1N, 5 ml). Isolation of the crude product with ethyl acetate followed by flash chromatography (40% -50% EtOAc/petroleum ether) gave the title compound as an off-white solid (50 mg, 60% yield, mp 225-228° C.); MS m/e 258 (M+H)+.
Reaction SMILES: Cl.[CH2:2]([NH:4][C:5]([C:7]1[S:33][C:10]2[N:11]=[C:12]([NH2:32])[N:13]=[C:14]([C:15]3[CH:20]=[C:19]([O:21][CH2:22][CH:23](OCC)OCC)[C:18]([Cl:30])=[CH:17][C:16]=3[Cl:31])[C:9]=2[CH:8]=1)=[O:6])[CH3:3].[NH:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1.ClCCl>[CH2:2]([NH:4][C:5]([C:7]1[S:33][C:10]2[N:11]=[C:12]([NH2:32])[N:13]=[C:14]([C:15]3[CH:20]=[C:19]([O:21][CH2:22][CH2:23][N:34]4[CH2:39][CH2:38][O:37][CH2:36][CH2:35]4)[C:18]([Cl:30])=[CH:17][C:16]=3[Cl:31])[C:9]=2[CH:8]=1)=[O:6])[CH3:3]
Reactant: CCNC(=O)c1cc2c(-c3cc(OCC(OCC)OCC)c(Cl)cc3Cl)nc(N)nc2s1
Reactant: C1COCCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCNC(=O)c1cc2c(-c3cc(OCCN4CCOCC4)c(Cl)cc3Cl)nc(N)nc2s1
Reaction time: 18 h

Procedure:
Hydrochloric acid was added to a solution of 2-Amino-4-(2,4-dichloro-5-(2,2-diethoxyethoxy)-phenyl)-thieno[2,3-d]pyrimidine-6-carboxylic acid ethyl amide in THF and the solution stirred for ˜18 hrs. Morpholine was added and the solution stirred, sodium triacetoxyborohydride was added and the resulting suspension stirred for ˜18 hrs. Dichloromethane was added and the mixture washed with aqueous ammonia (0.880), water and saturated aqueous sodium chloride solution. The solution was dried over anhydrous sodium sulphate and concentrated to a pale yellow solid. The crude product was purified by chromatography on silica eluting with mixtures of ethyl acetate and hexane.
Reaction SMILES: [Cl:1][C:2]1[C:3](F)=[C:4]([F:18])[CH:5]=[C:6]2[C:11]=1[N:10]([CH2:12][CH3:13])[CH:9]=[C:8]([C:14]([OH:16])=[O:15])[C:7]2=[O:17].C(OC([NH:27][C@H:28]1[C@@H:32]([CH3:33])[CH2:31][NH:30][CH2:29]1)=O)(C)(C)C.C1CCN2C(=NCCC2)CC1>C(#N)C>[NH2:27][C@H:28]1[C@@H:32]([CH3:33])[CH2:31][N:30]([C:3]2[C:2]([Cl:1])=[C:11]3[C:6]([C:7](=[O:17])[C:8]([C:14]([OH:16])=[O:15])=[CH:9][N:10]3[CH2:12][CH3:13])=[CH:5][C:4]=2[F:18])[CH2:29]1
Reactant: C[C@H]1CNC[C@H]1NC(=O)OC(C)(C)C
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(F)c(Cl)c21
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3C[C@@H](N)[C@@H](C)C3)c(Cl)c21
Yield: 31.3 %

Procedure:
A mixture of 8-chloro-1-ethyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (0.25 g), cis-3-t-butoxycarbonylamino-4-methylpyrrolidine (0.21 g), DBU (0.15 g) and anhydrous acetonitrile (4 ml) was refluxed for 2.5 hours. Then, the reacting mixture was treated as described in example 22 to give the title compound (0.1 g) as white powder, mp 222°-224° C. (decompd.).
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]([CH2:9]P(=O)(OCC)OCC)#[N:8].O=[CH:19][CH2:20][CH:21]1[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]1>O1CCCC1>[C:7]([CH:9]=[CH:19][CH2:20][CH:21]1[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]1)#[N:8]
Reactant: CC(C)(C)OC(=O)N1CCC(CC=O)CC1
Reactant: CCOP(=O)(CC#N)OCC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(CC=CC#N)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.3 %

Procedure:
To a solution of 1.0 M of potassium tert-butoxide in tetrahydrofuran (45.8 mL) at 0° C. was added dropwise a solution of diethyl cyanomethylphosphonate (7.77 mL, 0.0480 mol) in tetrahydrofuran (58.39 mL). The reaction was warmed to room temperature and then cooled at 0° C. again. To the reaction mixture was added a solution of tert-butyl 4-(2-oxoethyl)piperidine-1-carboxylate (9.91 g, 0.0436 mol) in tetrahydrofuran (11.7 mL). The reaction was allowed to warm up to room temperature and stirred at room temperature overnight. After being quenched with water, the mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried and evaporated to dryness. The crude mixture was purified on silica gel, eluting with 0 to 40% EtOAc in hexanes, to give the desired product (8.22 g, 75% in 2 steps). LCMS (M+Na) 273.0.
Reaction SMILES: C([O:5][C:6](=[O:38])[CH2:7][CH:8]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]2[CH:23]=[C:24]([C:28]3[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=3)[CH:25]=[CH:26][CH:27]=2)=[CH:16][CH:15]=1)[C:9]([N:11]([CH3:13])[CH3:12])=[O:10])(C)(C)C>ClCCl.C(O)(C(F)(F)F)=O>[F:35][C:34]([F:36])([F:37])[C:31]1[CH:30]=[CH:29][C:28]([C:24]2[CH:25]=[CH:26][CH:27]=[C:22]([CH2:21][O:20][C:17]3[CH:18]=[CH:19][C:14]([CH:8]([C:9]([N:11]([CH3:13])[CH3:12])=[O:10])[CH2:7][C:6]([OH:38])=[O:5])=[CH:15][CH:16]=3)[CH:23]=2)=[CH:33][CH:32]=1
Reactant: CN(C)C(=O)C(CC(=O)OC(C)(C)C)c1ccc(OCc2cccc(-c3ccc(C(F)(F)F)cc3)c2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(C)C(=O)C(CC(=O)O)c1ccc(OCc2cccc(-c3ccc(C(F)(F)F)cc3)c2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 70.7 %

Procedure:
Ester 50.4 (48 mg, 0.09 mmol) was dissolved in dichloromethane/TFA solution (3:1, 2 mL). The resulting mixture was stirred at room temperature for 2 h. The solvent removed under reduced pressure, and the product was purified on reserve phase HPLC to yield acid 50 (30 mg). MS ESI (pos.) m/e: 472 (M+H). 1H NMR (400 MHz) (CDCl3) δ 7.72 (4H, s); 7.67 (1H, s); 7.59-7.28 (3H, m); 7.2 (2H, d, J=8.6 Hz); 7.0 (2H, d, J=8.6 Hz); 5.13 (2H, s); 4.24-4.21 (1H, m); 3.20-3.13 (1H, m); 3.0 (3H, s); 2.95 (3H, s); 2.76-2.71 (1H, m).
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[S:12][CH:13]=[CH:14][C:15]=1[NH:16][C:17]1[C:18]2[CH:25]=[CH:24][NH:23][C:19]=2[N:20]=[CH:21][N:22]=1)=[O:10])C1C=CC=CC=1.[F:26][C:27]1[CH:35]=[CH:34][C:30]([CH2:31]CN)=[CH:29][CH:28]=1>>[F:26][C:27]1[CH:35]=[CH:34][C:30]([CH2:31][CH2:1][NH:8][C:9]([C:11]2[S:12][CH:13]=[CH:14][C:15]=2[NH:16][C:17]2[C:18]3[CH:25]=[CH:24][NH:23][C:19]=3[N:20]=[CH:21][N:22]=2)=[O:10])=[CH:29][CH:28]=1
Reactant: O=C(NCc1ccccc1)c1sccc1Nc1ncnc2[nH]ccc12
Reactant: NCCc1ccc(F)cc1
Product: O=C(NCCc1ccc(F)cc1)c1sccc1Nc1ncnc2[nH]ccc12
Yield: 14 %

Procedure:
The title compound was prepared in an analogous manner as 3-(7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-thiophene-2-carboxylic acid benzylamide using 4-fluorophenethylamine instead of benzylamine and obtained in 14% yield (HPLC: 92%, RT: 6.36 min). 1H NMR (DMSO-d6) 11.97 (br s, 1H), 11.37 (s, 1H), 8.47 (d, J=5.4 Hz, 1H), 8.38 (s, 1H), 8.31 (t, J=5.7 Hz, 1H), 7.75 (d, J=5.4 Hz, 1H), 7.37 (dd, J=3.4, 2.4 Hz, 1H), 7.32-7.26 (m, 2H), 7.16-7.08 (m, 2H), 6.45 (dd, J=3.6, 1.9 Hz, 1H), 3.49 (dd, J=14.3, 6.4 Hz, 2H), 2.86 (t, J=7.6 Hz, 2H); MS (m/z) 382 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[NH:6][CH:5]=[N:4][CH:3]=1.[H-].[Na+].Br[CH2:10][CH2:11][O:12][C:13]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CN(C=O)C.O>[Br:1][C:2]1[N:6]=[CH:5][N:4]([CH2:10][CH2:11][O:12][C:13]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:3]=1
Reactant: Brc1cnc[nH]1
Reactant: BrCCOC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Brc1cn(CCOC(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 69 %

Procedure:
To a solution of 5-bromo-1H-imidazole as prepared in part A (2.2 g, 15 mmol) in DMF (22 mL) at 0° C. was added NaH (658 mg, 60% dispersion, 2.42 mmol) in small portions. The resulting solution was allowed to warm to r.t. and then stirred for 1 hr. The solution was cooled to 0° C. and 1,1′,1″-[(2-bromoethoxy)methanetriyl]tribenzene (5.5 g, 15 mmol) in DMF (10 mL) was added drop-wise. The resulting solution was allowed to warm to r.t. where stirring continued until the reaction was judged complete by TLC (16 hr). The suspension was diluted with water and extracted with DCM (2×50 mL). The organics were dried (MgSO4), filtered, and concentrated to a solid that was recrystallized (EtOAc/Hex) to give 4.47 g of the title compound (69%).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2[O:13][C:12]([CH3:14])=[C:11]([CH:15]([NH:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]([NH:29][CH2:30][CH2:31][C:32]([O:34]CC)=[O:33])=[O:28])=[CH:23][CH:22]=3)[CH2:16][CH:17]([CH3:19])[CH3:18])[CH:10]=2)=[CH:5][CH:4]=1.O1CCCC1.[OH-].[Li+]>C(O)C>[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2[O:13][C:12]([CH3:14])=[C:11]([CH:15]([NH:20][C:21]3[CH:22]=[CH:23][C:24]([C:27]([NH:29][CH2:30][CH2:31][C:32]([OH:34])=[O:33])=[O:28])=[CH:25][CH:26]=3)[CH2:16][CH:17]([CH3:19])[CH3:18])[CH:10]=2)=[CH:5][CH:4]=1
Reactant: CCOC(=O)CCNC(=O)c1ccc(NC(CC(C)C)c2cc(-c3ccc(OC)nc3)oc2C)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: COc1ccc(-c2cc(C(CC(C)C)Nc3ccc(C(=O)NCCC(=O)O)cc3)c(C)o2)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 32 %

Procedure:
A mixture of 5-[4-(1-chloro-3-methylbutyl)-5-methylfuran-2-yl]-2-methoxypyridine (382 mg) obtained by the above-mentioned reaction, ethyl 3-{[(4-aminophenyl)carbonyl]amino}propanoate (378 mg), sodium carbonate (170 mg) and sodium iodide (240 mg) in N,N-dimethylacetamide (10 mL) was stirred overnight at 80° C. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (25% ethyl acetate/hexane to 65% ethyl acetate/hexane) to give ethyl 3-({[4-({1-[5-(6-methoxypyridin-3-yl)-2-methylfuran-3-yl]-3-methylbutyl}amino)phenyl]carbonyl}amino)propanoate. The obtained ethyl 3-({[4-({1-[5-(6-methoxypyridin-3-yl)-2-methylfuran-3-yl]-3-methylbutyl}amino)phenyl]carbonyl}amino)propanoate was dissolved in ethanol (2 mL) and tetrahydrofuran (2 mL) and 1N lithium hydroxide (0.9 mL) was added, and the mixture was stirred at room temperature for 1 hr. The solvent was evaporated under reduced pressure, water (10 mL) was added, and the mixture was neutralized with 1N hydrochloric acid under ice-cooling, and stirred for 1 hr. The resulting precipitate was collected by filtration and dried to give the title compound (191 mg, 32%).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([C:12](OCC)=[O:13])[S:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)=O.O.[Cl-].[Ca+2].[Cl-].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C(OCC)C>[OH:13][CH2:12][C:9]1[S:10][CH:11]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]=1
Reactant: CCOC(=O)c1nc(-c2ccccc2)cs1
Agent: O=C=O
Agent: [Al+3]
Agent: [Ca+2]
Solvent: O
Solvent: CCOCC
Product: OCc1nc(-c2ccccc2)cs1
Temperature: -40 °C
Reaction time: 2.5 h
Yield: 86.2 %

Procedure:
A solution of ethyl 4-phenylthiazole-2-carboxylate (Example 4B, 1.300 g, 5.57 mmol) in diethyl ether (60 mL) in a 500 mL flask under a nitrogen atmosphere was cooled to −40° C. (dry ice-water-calcium chloride bath) and treated with solid LiAlH4 (0.40 g, 10.54 mmol) added all at once. The mixture was stirred at −40° C. over 2.5 h. The reaction was quenched by dropwise addition of ethyl acetate (1 mL), water (0.4 mL) followed by 15% aqueous sodium hydroxide (0.4 mL) and water (1.2 mL). The bath was then removed and the mixture was stirred at room temperature for 50 min. The solid formed was filtered and washed with ether (50 mL). The combined filtrate and washing was washed with brine (20 mL) and dried over anhydrous magnesium sulfate. Evaporation gave a yellow oil which was purified by silica gel chromatography (2.5×8 cm, elution toluene-ethyl acetate 9:1, 8:2 to 7:3). The resulting light yellow oil (0.931 g) was then distilled in vacuo (bp: 105-110° C./0.1 torr, bulb to bulb, air bath temperature) to provide the title material (0.918 g, 86%) of a colorless syrup. LC (Method C): 1.672 min. HRMS (ESI) calcd for C10H10NOS [M+H]+ m/z 192.0478. found 192.0508. 1H NMR (CDCl3, 400 MHz) δ ppm: 2.90 (br t, 1H), 5.02 (d, J=4.30 Hz, 2H), 7.31-7.38 (m, 1H), 7.39-7.45 (m, 2H), 7.46 (d, J=0.8 Hz, 1H), 7.85-7.92 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([S:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(=[O:15])=[O:14])[CH:6]=[C:5]2[CH2:22]Br.[CH2:24]([N:26]([C@H:34]([CH2:37][NH:38][CH3:39])[CH2:35][OH:36])[C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])C.C(N(CC)C(C)C)(C)C>C1COCC1.O>[C:29]([O:28][C:27]([N:26]1[CH2:24][CH2:39][N:38]([CH2:22][C:5]2[C:4]3[C:9](=[CH:10][CH:11]=[C:2]([Br:1])[CH:3]=3)[C:8](=[O:12])[N:7]([S:13]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)(=[O:14])=[O:15])[CH:6]=2)[CH2:37][C@@H:34]1[CH2:35][OH:36])=[O:33])([CH3:30])([CH3:31])[CH3:32]
Reactant: O=c1c2ccc(Br)cc2c(CBr)cn1S(=O)(=O)c1ccccc1
Reactant: CCN(C(=O)OC(C)(C)C)[C@@H](CO)CNC
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCN(Cc2cn(S(=O)(=O)c3ccccc3)c(=O)c3ccc(Br)cc23)C[C@@H]1CO
Temperature: 50 °C
Reaction time: 1 h
Yield: 101.4 %

Procedure:
A solution of 6-bromo-4-(bromomethyl)-2-(phenylsulfonyl)isoquinolin-1(2H)-one (Example 11d, 1.75 g) in THF (20 mL) was treated with (R)-tert-butyl ethyl(1-hydroxy-3-(methylamino)propan-2-yl)carbamate (0.98 g) and N,N-diisopropylethylamine (0.80 mL) under nitrogen. The resulting solution was stirred at 50° C. for 1 h. The reaction mixture was diluted with water (300 mL), and extracted with ethyl acetate (250 mL×2). The combined organics were dried (MgSO4), filtered and evaporated. Triturated with diethyl ether/isohexane (1:1) afforded the subtitle compound (2.30 g) as a solid.
Reaction SMILES: [CH3:1][NH:2][CH3:3].Cl[C:5]1[CH:10]=[C:9]([Cl:11])[N:8]=[C:7]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:14][CH2:13]2)[N:6]=1.O>O1CCCC1>[Cl:11][C:9]1[CH:10]=[C:5]([N:2]([CH3:3])[CH3:1])[N:6]=[C:7]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:14][CH2:13]2)[N:8]=1
Reactant: CNC
Reactant: Clc1cc(Cl)nc(N2CCN(c3ccccc3)CC2)n1
Solvent: O
Solvent: C1CCOC1
Product: CN(C)c1cc(Cl)nc(N2CCN(c3ccccc3)CC2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70 %

Procedure:
The synthesis method shall be explained concretely following the order below. 50% dimethylamine aqueous solution (2.9 ml) was added to a solution of 4,6-dichloro-2-(4-phenylpiperazin-1-yl)pyrimidine (1.01 g, 3.26 mmol) in tetrahydrofuran (10 ml) solution, and this was agitated overnight at room temperature. Water was added and extraction was carried out 2 times with ethyl acetate. After washing the organic layer in saturated saline, drying was done with MgSO4, the solvent was distilled away under reduced pressure, and a 4-chloro-6-dimethylamino-2-(4-phenylpiperazin-1-yl)pyrimidine powder was obtained. This powder was used in the next reaction without separation and refinement. Morpholine (6.0 ml) was added to this powder, and this was agitated at 100 degrees Celsius overnight. After cooling, water was added and extraction was carried out 2 times with dichloromethane. The organic layer was washed with saturated saline, drying was done with MgSO4, and the solvent was distilled away under reduced pressure. The residue was washed with ether, and 810 mg (two step yield: 70%) of coarse crystals of 6-dimethylamino-4-morpholino-2-(4-phenylpiperazin-1-yl)pyrimidine was obtained. The melting point measurement result, the MS measurement result, and the NMR data for the obtained Compound 2 are shown below.