Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[CH2:7][O:6][C:5]2[CH:8]=[CH:9][C:10]([C:12]([OH:14])=O)=[CH:11][C:4]=2[NH:3]1.[C:15]1([CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C.O>[C:15]1([CH:21]2[CH2:22][CH2:23][N:24]([C:12]([C:10]3[CH:9]=[CH:8][C:5]4[O:6][CH2:7][C:2](=[O:1])[NH:3][C:4]=4[CH:11]=3)=[O:14])[CH2:25][CH2:26]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C1COc2ccc(C(=O)O)cc2N1
Reactant: c1ccc(C2CCNCC2)cc1
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: O=C1COc2ccc(C(=O)N3CCC(c4ccccc4)CC3)cc2N1
Temperature: 23 °C
Reaction time: 4 h

Procedure:
To a solution of 104 (0.5 mmol) in DMF (4 mL) was added 4-phenylpiperidine (0.75 mmol), EDC (0.6 mmol), and HOBt (0.6 mmol) followed by Hunig's base (1.5 mmol). The solution was stirred at 23° C. for 4 h and then water (15 mL) was added. The resulting solid was isolated by filtration, washed with water and dried in vacuo to give a white solid: 1H NMR (DMSO-d6, 400 MHz): δ=10.81 (s, 1H), 7.24-7.32 (m, 5H), 7.20 (t, J=6.9 Hz, 1H), 7.01 (d, J=1.5 Hz, 1H), 6.98 (d, J=10.9 Hz, 3H), 4.62 (s, 2H), 3.90 (s, 0H), 3.33 (s, 0H), 2.81 (t, J=12.0 Hz, 1H), 1.73-1.85 (m, 2 H), 1.59 ppm (dd, J=12.5, 3.7 Hz, 2H). ESI-MS: m/z 337.2 (M+H)+.
Reaction SMILES: [F:1][C:2]1[C:3]([N:19]2[C:24](=[O:25])[CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[N:21]([CH3:30])[C:20]2=[O:31])=[CH:4][C:5]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17]C)[CH:12]=2)=[C:6]([C:8]#[N:9])[CH:7]=1.CO>C(Cl)(Cl)Cl.B(Br)(Br)Br>[C:8]([C:6]1[CH:7]=[C:2]([F:1])[C:3]([N:19]2[C:24](=[O:25])[CH:23]=[C:22]([C:26]([F:28])([F:29])[F:27])[N:21]([CH3:30])[C:20]2=[O:31])=[CH:4][C:5]=1[O:10][C:11]1[CH:12]=[C:13]([OH:17])[CH:14]=[CH:15][CH:16]=1)#[N:9]
Reactant: COc1cccc(Oc2cc(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)c(F)cc2C#N)c1
Agent: BrB(Br)Br
Solvent: CO
Solvent: ClC(Cl)Cl
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(Oc3cccc(O)c3)c(C#N)cc2F)c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 65.3 %

Procedure:
To a solution of 57 mg of 5-fluoro-2-(3-methoxyphenoxy)-4-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]cyanobenzene in 0.6 ml of chloroform, 48 μl of boron tribromide was added dropwise at 0° C. After the addition, the temperature of the reaction mixture was raised to room temperature and stirred for 1 hour. The mixture was cooled to 0° C. and 1 ml of methanol was added thereto. The solvent was removed under reduced pressure, the resultant was diluted with ethyl acetate, and then, saturated aqueous sodium bicarbonate solution was added thereto to be pH 4. The resultant was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography to obtain 36 mg of 3-{2-cyano-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}phenol.
Reaction SMILES: [CH2:1]([C@H:8]([NH:33][C:34](=[O:46])[C@@H:35]([N:39]1[CH2:44][CH2:43][CH2:42][NH:41][C:40]1=[O:45])[CH:36]([CH3:38])[CH3:37])[CH2:9][C@H:10]([OH:32])[C@@H:11]([NH:19][C:20](=[O:31])[CH2:21][O:22][C:23]1[C:28]([CH3:29])=[CH:27][CH:26]=[CH:25][C:24]=1[CH3:30])[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:47][S:48]([CH3:50])=O.C(OC(=O)C)(=O)C>C(O)(=O)C>[CH2:1]([C@H:8]([NH:33][C:34](=[O:46])[C@@H:35]([N:39]1[CH2:44][CH2:43][CH2:42][NH:41][C:40]1=[O:45])[CH:36]([CH3:38])[CH3:37])[CH2:9][C@H:10]([O:32][CH2:47][S:48][CH3:50])[C@@H:11]([NH:19][C:20](=[O:31])[CH2:21][O:22][C:23]1[C:24]([CH3:30])=[CH:25][CH:26]=[CH:27][C:28]=1[CH3:29])[CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1cccc(C)c1OCC(=O)N[C@@H](Cc1ccccc1)[C@@H](O)C[C@H](Cc1ccccc1)NC(=O)[C@H](C(C)C)N1CCCNC1=O
Reactant: CS(C)=O
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: CSCO[C@@H](C[C@H](Cc1ccccc1)NC(=O)[C@H](C(C)C)N1CCCNC1=O)[C@H](Cc1ccccc1)NC(=O)COc1c(C)cccc1C
Temperature: 25 °C
Reaction time: 48 h
Yield: 64 %

Procedure:
To a solution of the compound of Example 3 (3.0 g, 4.8 mmol), DMSO (18 mL), and acetic acid (3.6 mL) at room temperature was added acetic anhydride (23 mL), and the reaction was stirred for 48 hours at room temperature. The reaction was quenched with ice and 10% Na2CO3 was added to adjust the pH to 7. The mixture was extracted with ethyl acetate and washed with 10% Na2CO3 and brine. The organic was dried over Na2SO4, filtered and evaporated to give the crude product, which was chromatographed on silica gel eluting first with 25-100% ethyl acetate in dichloromethane to give the title compound (2.1 g, 64% yield).
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]([C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)([CH3:6])[CH3:5].[CH3:14][O:15][CH:16]([O:19][CH3:20])[CH2:17]Br.O>CN(C)C=O>[CH3:6][C:4]([C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:17][CH:16]([O:19][CH3:20])[O:15][CH3:14])=[CH:11][CH:12]=1)([CH3:3])[CH3:5]
Reactant: CC(C)(C)c1ccc(O)cc1
Reactant: COC(CBr)OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(COc1ccc(C(C)(C)C)cc1)OC
Reaction time: 0.17 h
Yield: 94.6 %

Procedure:
To a mixture of 5.33 g (0.133 mol.) of sodium hydride (60%) and 200 ml of anhydrous N,N-dimethylformamide, there was added dropwise a solution of 20.00 g (0.133 mol.) of 4-(1,1-dimethylethyl)phenol in 50 ml of anhydrous N,N-dimethylformamide with stirring at a temperature of from 5° C. to 10° C. for 10 minutes. Then the reaction mixture was stirred at the same temperature for 30 minutes. To the above mixture, there was added dropwise 24.75 g (0.146 mol.) of bromoacetoaldehyde dimethylacetal in 50 ml of anhydrous N,N-dimethylformamide with stirring at the same temperature for 30 minutes. The reaction mixture was then stirred at room temperature for 20 hours. After the reaction was completed, the reaction mixture was poured into water and extracted with ethyl acetate. Then the residue was washed three times with a saturated aqueous solution of ammonium chloride, dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel chromatography to give 30.00 g of 2-[4-(1,1-dimethylethyl)phenoxy]-1,1-dimethoxyethane as a light-yellowish oily substance (nD22.8 1.4911).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:40][CH3:41])=[C:17]([O:20][CH2:21][CH2:22][CH2:23][N:24]4[CH2:32][CH:31]5[CH:26]([CH2:27][N:28](C(OC(C)(C)C)=O)[CH2:29][CH2:30]5)[CH2:25]4)[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8].Cl>C(Cl)Cl.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:40][CH3:41])=[C:17]([O:20][CH2:21][CH2:22][CH2:23][N:24]4[CH2:32][CH:31]5[CH:26]([CH2:27][NH:28][CH2:29][CH2:30]5)[CH2:25]4)[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: COc1cc2ncnc(Nc3ccc(F)c(Cl)c3)c2cc1OCCCN1CC2CCN(C(=O)OC(C)(C)C)CC2C1
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COc1cc2ncnc(Nc3ccc(F)c(Cl)c3)c2cc1OCCCN1CC2CCNCC2C1
Yield: 90.5 %

Procedure:
To a solution of tert-butyl 2-(3-((4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)oxy) propyl)hexahydro-1H-pyrrolo[3,4-c]pyridine-5(6H)-carboxylate (0.40 g) in CH2Cl2 was added a solution of HCl in EtOAc (3 M, 10 mL). White solid was precipitated out after 2 h reaction. The resulted mixture was filtered and the residue was dried to give the title compound as a pale yellow solid (0.30 g, 80.00%), HPLC: 99.00%. The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 486.2 (M+1); 1H NMR (400 MHz, D2O) δ: 1.97-2.03 (m, 4H), 2.68-2.71 (m, 2H), 2.80-2.86 (m, 4H), 2.87-2.91 (m, 2H), 3.40-3.45 (m, 2H), 4.07-4.11 (m, 2H), 4.19 (s, 3H), 4.39-4.43 (m, 2H), 7.441 (s, 1H), 7.50 (t, J=8.6 Hz, 1H), 7.84 (s, 2H), 8.68 (t, J=4.6 Hz, 1H), 8.89 (s, 1H) ppm.
Reaction SMILES: Cl.[Si]([O:9][C@@H:10]([C@@H:12]1[C@@H:15]([C@@H:16]([CH3:35])[C:17]([C:19]2[S:23][C:22]3=[C:24]([C:27]([C:29]4[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=4)=[O:28])[N:25]=[CH:26][N:21]3[CH:20]=2)=[O:18])[N:14]([C:36]([C:56]([O:58][CH2:59][C:60]2[CH:65]=[CH:64][C:63]([N+:66]([O-:68])=[O:67])=[CH:62][CH:61]=2)=[O:57])=[P:37]([C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:13]1=[O:69])[CH3:11])(C(C)(C)C)(C)C.C(=O)(O)[O-].[Na+]>CO>[OH:9][C@@H:10]([C@@H:12]1[C@@H:15]([C@@H:16]([CH3:35])[C:17]([C:19]2[S:23][C:22]3=[C:24]([C:27]([C:29]4[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=4)=[O:28])[N:25]=[CH:26][N:21]3[CH:20]=2)=[O:18])[N:14]([C:36]([C:56]([O:58][CH2:59][C:60]2[CH:61]=[CH:62][C:63]([N+:66]([O-:68])=[O:67])=[CH:64][CH:65]=2)=[O:57])=[P:37]([C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[C:13]1=[O:69])[CH3:11]
Reactant: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)N(C(C(=O)OCc2ccc([N+](=O)[O-])cc2)=P(c2ccccc2)(c2ccccc2)c2ccccc2)[C@@H]1[C@@H](C)C(=O)c1cn2cnc(C(=O)c3cccnc3)c2s1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: C[C@@H](O)[C@H]1C(=O)N(C(C(=O)OCc2ccc([N+](=O)[O-])cc2)=P(c2ccccc2)(c2ccccc2)c2ccccc2)[C@@H]1[C@@H](C)C(=O)c1cn2cnc(C(=O)c3cccnc3)c2s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 73.5 %

Procedure:
A 5 N aqueous hydrochloric acid solution (1 ml) was added to a solution of 72.4 mg of (3S,4R)-3-[(1R)-1-(t-butyldimethylsilyloxy)ethyl]-4-{(1R)-1-methyl-2-[7-(pyridin-3-yl)carbonylimidazo[5,1-b]thiazol-2-yl]-2-oxoethyl}-1-[4-nitrobenzyloxycarbonyl(triphenylphosphoranylidene)-methyl]azetidin-2-one in 2 ml of methanol, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was neutralized with saturated aqueous sodium bicarbonate solution and was extracted with ethyl acetate. The organic layer was washed with saturated brine and was dried over anhydrous magnesium sulfate. The solvent was removed by evaporation, and the residue was purified by thin layer chromatography (developed with 10% methanol/methylene chloride) to give 46.9 mg of (3S,4R)-3-[(1R)-1-hydroxyethyl]-4-{(1R)-1-methyl-2-[7-(pyridin-3-yl)carbonylimidazo[5,1-b]thiazol-2-yl]-2-oxo ethyl}-1-[4-nitrobenzyloxycarbonyl(triphenyl phosphoranylidene)methyl]azetidin-2-one.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([O:10][CH3:11])[N:3]=1.[C:12](Cl)(=[O:20])[O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>O1CCCC1.CN(C)C1C=CN=CC=1>[CH3:9][O:8][C:6]1[CH:5]=[C:4]([O:10][CH3:11])[N:3]=[C:2]([NH:1][C:12](=[O:20])[O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:7]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: COc1cc(OC)nc(N)n1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: COc1cc(OC)nc(NC(=O)Oc2ccccc2)n1
Temperature: 25 °C
Reaction time: 17 h
Yield: 62.6 %

Procedure:
To a solution of 8.0 g of 2-amino-4,6-dimethoxypyrimidine in 50 ml of tetrahydrofuran are added 4.0 g of phenyl chlorocarbonate and 0.1 g of 4-dimethylaminopyridine, followed by stirring for 17 hours at room temperature. The mixture is allowed to stand overnight and filtered to remove insoluble product and the filtrate is purified by silica gel chromatography (eluent: dichloromethane) to give 4.4 g of the title compound. mp. 118°-119° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:13]=[CH:12][C:11](I)=[C:10]([C:15]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][C:25]4[CH:30]=[CH:29][N:28]=[C:27]5[CH:31]=[C:32]([C:34]6[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=6)[O:33][C:26]=45)=[CH:20][CH:19]=3)=[O:16])[C:9]2=[O:40])=[CH:4][CH:3]=1.[O-:41][CH2:42][CH3:43].[Na+]>>[C:34]1([C:32]2[O:33][C:26]3[C:27](=[N:28][CH:29]=[CH:30][C:25]=3[O:24][C:21]3[CH:22]=[CH:23][C:18]([NH:17][C:15]([C:10]4[C:9](=[O:40])[N:8]([C:5]5[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=5)[CH:13]=[CH:12][C:11]=4[O:41][CH2:42][CH3:43])=[O:16])=[CH:19][CH:20]=3)[CH:31]=2)[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: CC[O-]
Reactant: O=C(Nc1ccc(Oc2ccnc3cc(-c4ccccc4)oc23)cc1)c1c(I)ccn(-c2ccc(F)cc2)c1=O
Agent: [Na+]
Product: CCOc1ccn(-c2ccc(F)cc2)c(=O)c1C(=O)Nc1ccc(Oc2ccnc3cc(-c4ccccc4)oc23)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 101.8 %

Procedure:
To a dry 5 mL sealed tube with stirbar was added 1-(4-fluorophenyl)-4-iodo-2-oxo-N-{4-[(2-phenylfuro[3,2-b]pyridin-7-yl)oxy]phenyl}-1,2-dihydropyridine-3-carboxamide (46.30 mg; 0.07 mmol; 1.00 eq.) and the vial was sealed and flushed with N2. To the vial was added dry THF (1.00 ml) via syringe and then sodium ethoxide (0.04 ml; 0.09 mmol; 1.30 eq.) (21% solution in ethanol) was slowly added via syringe and the reaction mixture was stirred at room temperature for 1 h. The solution was concentrated, taken up in EtOAc and washed with sat. aq. NaHCO3. The organic layer was collected, extracting aqueous layer with EtOAc (3×). Combined organic layers were dried (Na2SO4) and concentrated on rotary evaporator to afford the title compound as a beige solid (40 mg, 100%). (HPLC (method F): 99%, RT: 6.08 min); 1H NMR (400 MHz, DMSO-d6) δ [ppm] 10.41 (s, 1H), 8.34 (d, J=5.5, 1H), 7.97-7.90 (m, 2H), 7.86 (d, J=7.8, 1H), 7.83-7.77 (m, 2H), 7.69 (s, 1H), 7.58-7.50 (m, 2H), 7.50-7.43 (m, 3H), 7.41-7.35 (m, 2H), 7.34-7.27 (m, 2H), 6.71 (d, J=5.5, 1H), 6.52 (d, J=7.9, 1H), 4.26 (q, J=7.0, 2H), 1.30 (t, J=7.0, 3H); MS (m/z) 562 [M+H]+, RT: 3.5 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:11]=[C:10]([CH2:19][CH2:20][CH:21]=O)[CH:9]=2)=[CH:4][CH:3]=1.[CH3:23][C:24]1[CH:25]=[C:26]([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[CH:27]=[CH:28][C:29]=1[CH3:30].CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:11]=[C:10]([CH2:19][CH2:20][CH2:21][N:34]3[CH2:35][CH2:36][N:31]([C:26]4[CH:27]=[CH:28][C:29]([CH3:30])=[C:24]([CH3:23])[CH:25]=4)[CH2:32][CH2:33]3)[CH:9]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(N2CCNCC2)cc1C
Reactant: O=CCCc1cc(-c2ccc(Cl)cc2)n(-c2ccccc2)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(N2CCN(CCCc3cc(-c4ccc(Cl)cc4)n(-c4ccccc4)n3)CC2)cc1C

Procedure:
99 mg (84%) of target compound was obtained by using a method same as in Example 1 by using 3-(5-(4-chlorophenyl)-1-phenyl-1H-pyrazol-3-yl)-propanal (70 mg, 0.225 mmol), 1-(3,4-dimethylphenyl)piperazine (61 mg, 0.225 mmol), DIPEA (0.059 mL, 0.338 mmol) and NaBH(OAc)3 (143 mg, 0.675 mmol).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][CH:9]2[CH2:14][CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10]2)[CH:3]=1.[Cl:22][C:23]1[CH:24]=[C:25]([CH:27]=[CH:28][C:29]=1[F:30])[NH2:26]>CCOC(C)=O>[Cl:22][C:23]1[CH:24]=[C:25]([NH:26][C:2]2[CH:3]=[C:4]([NH:8][CH:9]3[CH2:14][CH2:13][CH2:12][NH:11][CH2:10]3)[N:5]=[CH:6][N:7]=2)[CH:27]=[CH:28][C:29]=1[F:30]
Reactant: CC(C)(C)OC(=O)N1CCCC(Nc2cc(Cl)ncn2)C1
Reactant: Nc1ccc(F)c(Cl)c1
Solvent: CCOC(C)=O
Product: Fc1ccc(Nc2cc(NC3CCCNC3)ncn2)cc1Cl
Temperature: 140 °C
Reaction time: 1 h
Yield: 84.6 %

Procedure:
A mixture of tert-butyl 3-(6-chloropyrimidin-4-ylamino)piperidine-1-carboxylate (295 mg, 0.94 mmol) and 3-chloro-4-fluoroaniline (2.83 g, 19.4 mmol) was heated neat at 140° C. for 19 hours. Upon cooling, the melt was stirred in EtOAc and allowed to stand at room temperature for 1 hour. The precipitate was collected, washed with EtOAc and dried to give 256 mg (85%) of N4-(3-chloro-4-fluorophenyl)-N6-(piperidin-3-yl)pyrimidine-4,6-diamine, a grayish-violet amorphous solid. MS (APCI): (M+1)+=322.
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][CH:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9].[S].S>C(Cl)Cl.C1(C)C=CC=CC=1>[CH3:1][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CCOC(=O)C1=C(C)NC=CC1c1ccccc1
Agent: S
Agent: [S]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CCOC(=O)c1c(-c2ccccc2)ccnc1C
Temperature: 25 °C
Yield: 79.9 %

Procedure:
To a solution of 0.32 mol ethyl 1,4-dihydro-2-methyl-4-phenyl-3-pyridinecarboxylate in 50 ml of methylene chloride was added 16 g (0.5 mol) of sulfur. The temperature of the well-stirred dark solution was raised over a period of about 30 minutes to 170°-180° C. When the development of hydrogen sulfide had subsided, the reaction mixture was cooled to room temperature, taken up in toluene, and filtered through Celite filter aid. The filtrate was concentrate under vacuum and the residue chromatographed on silica gel, eluting with ethyl acetate/hexane to yield 61.7 g of ethyl 2-methyl-4-phenyl-3-pyridinecarboxylate.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:17])[CH:5]=[CH:6][C:7]=1[CH2:8][CH2:9][CH2:10][CH2:11][N:12]1[CH:16]=[CH:15][N:14]=[N:13]1.[H-].[Na+].Cl[CH2:21][C:22]1[CH:23]=[N:24][CH:25]=[C:26]([C:28]2[CH:33]=[CH:32][C:31]([O:34][C:35]([F:38])([F:37])[F:36])=[CH:30][CH:29]=2)[CH:27]=1.O>CN(C)C=O>[CH3:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[CH2:8][CH2:9][CH2:10][CH2:11][N:12]1[CH:16]=[CH:15][N:14]=[N:13]1)[O:17][CH2:21][C:22]1[CH:23]=[N:24][CH:25]=[C:26]([C:28]2[CH:29]=[CH:30][C:31]([O:34][C:35]([F:38])([F:36])[F:37])=[CH:32][CH:33]=2)[CH:27]=1
Reactant: Cc1cc(O)ccc1CCCCn1ccnn1
Reactant: FC(F)(F)Oc1ccc(-c2cncc(CCl)c2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(OCc2cncc(-c3ccc(OC(F)(F)F)cc3)c2)ccc1CCCCn1ccnn1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 72.5 %

Procedure:
A solution of 60 mg (0.26 mmol) 3-methyl-4-(4-[1,2,3]triazol-1-yl-butyl)phenol in 4.0 ml N,N-dimethylformamide was treated at 0° C. with 10 mg (0.26 mmol) of 60% sodium hydride and stirred at 0° C. for 30 min. Then 80 mg (0.26 mmol) 3-Chloromethyl-5-(4-trifluoromethoxy-phenyl)-pyridine were added and stirred continued at r.t. over night. After addition of 8 ml water, the precipitate was isolated, washed thoroughly with water, n-heptane and diisopropylether. The residue was dried at 40° C. to give 91 mg (72%) of the title compound as ochre powder.
Reaction SMILES: C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[C:20]1([C:26]2[N:27]=[C:28]([NH:31][C:32](=[O:37])[CH2:33][C:34]([OH:36])=O)[S:29][CH:30]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.CCN=C=NCCCN(C)C.Cl.Cl.[N:51]1([C:57]([C:59]2[CH:64]=[CH:63][CH:62]=[CH:61][C:60]=2[C:65]([F:68])([F:67])[F:66])=[O:58])[CH2:56][CH2:55][NH:54][CH2:53][CH2:52]1>CN(C=O)C.O>[O:36]=[C:34]([N:54]1[CH2:55][CH2:56][N:51]([C:57](=[O:58])[C:59]2[CH:64]=[CH:63][CH:62]=[CH:61][C:60]=2[C:65]([F:68])([F:66])[F:67])[CH2:52][CH2:53]1)[CH2:33][C:32]([NH:31][C:28]1[S:29][CH:30]=[C:26]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:27]=1)=[O:37]
Reactant: O=C(c1ccccc1C(F)(F)F)N1CCNCC1
Reactant: O=C(O)CC(=O)Nc1nc(-c2ccccc2)cs1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: O=C(CC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1)Nc1nc(-c2ccccc2)cs1
Temperature: 10 °C
Reaction time: 8 h
Yield: 14.4 %

Procedure:
HOBt (38 mg, 0.29 mmol) and DIEA (111 mg, 0.85 mmol) were added to a stirred solution of N-(4-phenyl-thiazol-2-yl)-malonamic acid (75 mg, 0.29 mmol) in DMF (1.5 mL). The reaction mixture was cooled to 10° C. and EDCI.HCl (66 mg, 0.34 mmol) followed by piperazin-1-yl-(2-trifluoromethyl-phenyl)-methanone hydrochloride (92 mg, 0.3 mmol) were added. The reaction mixture was stirred at room temperature overnight then diluted with water and the product extracted with ethyl acetate. The organic layer was washed with sodium bicarbonate and brine solution, dried over Na2SO4 and concentrated to afford 21 mg (13%) of 3-Oxo-N-(4-phenyl-thiazol-2-yl)-3-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-propionamide. LCMS: 503.13 (M+1)+, 97.4%, 1H NMR: (CDCl3): δ 7.85 (d, 2H), 7.74 (d, 1H), 7.6 (m, 2H), 7.4 (td, 2H), 7.33 (m, 2H), 7.15 (d, 1H), 4.02 (m, 2H), 3.7 (m, 4H), 3.52 (m, 2H), 3.24 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].CC1C=CC(S(O[CH2:33][CH:34]2[CH2:39][CH2:38][O:37][C:36]([CH3:41])([CH3:40])[CH2:35]2)(=O)=O)=CC=1.[H-].[Na+]>CN(C=O)C.CCOC(C)=O.C([O-])(O)=O.[Na+]>[Br:1][C:2]1[N:7]=[C:6]([N:8]([CH2:33][CH:34]2[CH2:39][CH2:38][O:37][C:36]([CH3:41])([CH3:40])[CH2:35]2)[C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:14])[CH3:13])[CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)Nc1cccc(Br)n1
Reactant: Cc1ccc(S(=O)(=O)OCC2CCOC(C)(C)C2)cc1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [H-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N(CC1CCOC(C)(C)C1)c1cccc(Br)n1
Temperature: 45 °C
Reaction time: 4 h

Procedure:
To a mixture of tert-butyl 6-bromopyridin-2-ylcarbamate (686 mg, 2.51 mmol), K2CO3 (347 mg, 2.51 mmol), (2,2-dimethyltetrahydro-2H-pyran-4-yl)methyl 4-methylbenzenesulfonate (750 mg, 2.51 mmol) in DMF (10 mL) was added carefully NaH (60 wt. %, 141 mg, 3.52 mmol) in portions [Caution: gas development!]. The resulting mixture was stirred at about 45° C. for 4 hr. The mixture was warmed to ambient temperature and was diluted with EtOAc (˜50 mL) and saturated aqueous NaHCO3. The organic layer was separated, washed with saturated aqueous NaHCO3 solution (1×), dried over Na2SO4, filtered off and concentrated in vacuo. The resulting residue was purified by column chromatography [SiO2, 40 g, 25 min, EtOAc/heptane=0/100 to 25/75 over 25 min] providing (R/S)-tert-butyl 6-bromopyridin-2-yl((2,2-dimethyltetrahydro-2H-pyran-4-yl)methyl)carbamate as highly viscous, colorless oil. Yield: 723 mg. LCMS (m/z): 344.9 {loss of tert Bu-group}/(399.0)[M+H]+; Retention time=1.22 min.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][N:27]=1)[C:5]([NH:7][C:8]1[S:9][C:10]2[C:16]([CH:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:15][CH:14]=[C:13]([O:23][CH3:24])[C:11]=2[N:12]=1)=[O:6].[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN1CCCC1=O>[CH3:24][O:23][C:13]1[C:11]2[N:12]=[C:8]([NH:7][C:5](=[O:6])[C:4]3[CH:25]=[CH:26][N:27]=[C:2]([N:28]4[CH2:33][CH2:32][O:31][CH2:30][CH2:29]4)[CH:3]=3)[S:9][C:10]=2[C:16]([CH:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[CH:15][CH:14]=1
Reactant: C1COCCN1
Reactant: COc1ccc(C2CCOCC2)c2sc(NC(=O)c3ccnc(Br)c3)nc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: COc1ccc(C2CCOCC2)c2sc(NC(=O)c3ccnc(N4CCOCC4)c3)nc12
Temperature: 140 °C
Yield: 44 %

Procedure:
A stirred suspension of 200 mg (0.45 mmol) 2-bromo-N-[4-methoxy-7-(tetrahydro-pyran-4-yl)-benzothiazol-2-yl]-isonicotinamide, 0.39 ml (4.46 mmol) morpholine and 291 mg (0.89 mmol) cesium carbonate in 5 ml N-methylpyrrolidone in a thick-walled glass pressure tube fitted with a teflon cap was heated at 140° C. for 24 h. The reaction mixture was then cooled to room temperature and poured onto water. The mixture was extracted three times with ethyl acetate, and the combined organic phases were washed with saturated brine, dried over sodium sulfate, and concentrated in vacuo. Flash chromatography (1/1 ethyl acetate/hexane) followed by trituration in ether and hexane afforded 90 mg (44%) N-[4-methoxy-7-(tetrahydro-pyran-4-yl)-benzothiazol-2-yl]-2-morpholin-4-yl-isonicotinamide as an off-white crystalline solid. ES-MS m/e (%): 477 (M+Na+, 13),455 (M+H+, 100).
Reaction SMILES: [CH2:1]([NH:6][C:7]([N:9]1[CH2:12][CH:11]([C:13]2[CH:18]=[CH:17][C:16]([O:19]CC3C=CC=CC=3)=[CH:15][C:14]=2[O:27]CC2C=CC=CC=2)[CH2:10]1)=[O:8])[CH2:2][CH2:3][CH2:4][CH3:5]>CO.[Pd]>[CH2:1]([NH:6][C:7]([N:9]1[CH2:12][CH:11]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][C:14]=2[OH:27])[CH2:10]1)=[O:8])[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCNC(=O)N1CC(c2ccc(OCc3ccccc3)cc2OCc2ccccc2)C1
Agent: [Pd]
Solvent: CO
Product: CCCCCNC(=O)N1CC(c2ccc(O)cc2O)C1
Reaction time: 6 h

Procedure:
In a 10 ml round-bottomed flask, 0.2 g of 3-(2,4-bis(benzyloxy)phenyl)azetidine-1-carboxylic acid pentylamide is dissolved in 6 ml of methanol in the presence of 0.1 g of palladium-on-charcoal at 10%. The reaction mixture is stirred for 6 hours under a hydrogen atmosphere. The reaction mixture is filtered and the residue is then chromatographed on silica gel (95/5 dichloromethane/methanol).