Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)(C)C.C([O-])=O.[NH4+].Cl[C:10]1[N:11]=[C:12]([N:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)[C:13]2[N:19]=[C:18]([C:20]([O:22][CH3:23])=[O:21])[CH:17]=[C:16](Cl)[C:14]=2[N:15]=1>O.[Pd]>[N:25]1([C:12]2[C:13]3[N:19]=[C:18]([C:20]([O:22][CH3:23])=[O:21])[CH:17]=[CH:16][C:14]=3[N:15]=[CH:10][N:11]=2)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: COC(=O)c1cc(Cl)c2nc(Cl)nc(N3CCCCC3)c2n1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: O
Solvent: CC(C)O
Product: COC(=O)c1ccc2ncnc(N3CCCCC3)c2n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80.1 %

Procedure:
To a round-bottom flask were added palladium (540 mg; 0.51 mmol; 0.05 eq.) isopropanol (90 mL). Ar was bubbled in this mixture. A degazed ammonium formate solution in water (2.56 g, 40.6 mmol, 4 eq., in 4 mL of water) was added, followed by methyl 2,8-dichloro-4-(1-piperidinyl)pyrido[3,2-d]pyrimidine-6-carboxylate (Intermediate 1.4) (3.46 g; 10.5 mmol; 1 eq.) and degazed isopropanol (10 mL). After 30 min, a second batch of ammonium formate was added as solution in water (2.56 g, 40.6 mmol, 4 eq., in 4 mL of water). Finally, after additional 30 min, another 8 equivalents of ammonium formate in water were (5.12 g, 81.2 mmol, 8 eq., in 8 mL of water). The mixture was then stirred at rt. overnight and filtered through celite. The filtrate was evaporated. The crude product was dissolved in DCM and washed with water and brine. Organic phase was dried over magnesium sulfate, filtered and evaporated to give methyl 4-(1-piperidinyl)pyrido[3,2-d]pyrimidine-6-carboxylate (2.29 g; 83%) (Intermediate 1.5), as a yellow solid in 92.9% HPLC purity. This product was used in the next step without further purification.
Reaction SMILES: [CH2:1]([C@@H:8]([NH:22][C:23](=[O:32])[C:24]1[CH:29]=[C:28]([CH3:30])[CH:27]=[C:26](Br)[CH:25]=1)[C@H:9]([OH:21])[CH2:10][NH:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:33]1[CH:37]=[CH:36][CH:35]=[C:34]1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O.C(Cl)(Cl)Cl.C1(P([Pd](P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:1]([C@H:8]([NH:22][C:23](=[O:32])[C:24]1[CH:29]=[C:28]([CH3:30])[CH:27]=[C:26]([C:34]2[O:33][CH:37]=[CH:36][CH:35]=2)[CH:25]=1)[C@H:9]([OH:21])[CH2:10][NH:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH3:20])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cccc(CNC[C@@H](O)[C@@H](Cc2ccccc2)NC(=O)c2cc(C)cc(Br)c2)c1
Reactant: OB(O)c1ccco1
Agent: c1ccc([PH](c2ccccc2)(c2ccccc2)[Pd]([PH](c2ccccc2)(c2ccccc2)c2ccccc2)([PH](c2ccccc2)(c2ccccc2)c2ccccc2)[PH](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: COc1cccc(CNC[C@@H](O)[C@H](Cc2ccccc2)NC(=O)c2cc(C)cc(-c3ccco3)c2)c1
Temperature: 100 °C

Procedure:
N-{(1R,2R)-1-benzyl-2-hydroxy-3-[(3-methoxybenzyl)amino]propyl}-3-bromo-5-methylbenzamide (X, EXAMPLE 761, 295 mg, 0.59 mmol), 2-furanylboronic acid (133 mg, 1.19 mmol) and sodium carbonate (366 mg, 2.95 mmol) are combined in dimethylformamide (5 ml) and sparged under a flow of nitrogen for 15 minutes. Tetrakis(triphenylphosphino)palladium (136 mg, 0.12 mmol) is added and the mixture heated to 100 degrees C. overnight. The mixture is cooled to 20-25 degrees C., diluted with chloroform (50 ml) and extracted with water (3×100 ml). The organic phase is separated and washed with saturated sodium bicarbonate (2×100 ml) and saline (100 ml), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue is chouromatographed (silica gel; methanol/methylene chloride, 8/92) to give the title compound, MS [M+H]+=485.3.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1([C:13]#[N:14])[CH2:12][CH2:11][CH2:10]1.S(=O)(=O)(O)[OH:16].O>C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1([C:13]([NH2:14])=[O:16])[CH2:12][CH2:11][CH2:10]1
Reactant: O=S(=O)(O)O
Reactant: COc1ccccc1C1(C#N)CCC1
Solvent: CC(=O)O
Solvent: O
Product: COc1ccccc1C1(C(N)=O)CCC1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
To 1-(2-methoxyphenyl)cyclobutanecarbonitrile (4.29 g) was added sulfuric acid (20 mL, 95-98%)/water (20 mL) and the reaction warmed to 60° C. After 1 h the solution was warmed to 80° C. and heating was continued for 3 h. The reaction was cooled to room temperature and stirred for 16 h. Heating was resumed and after 1 h acetic acid (10 mL) was added. The temperature was increased to 90° C. and heating was continued for 1.75 h. The reaction was cooled to room temperature and then poured onto ˜300 ml of ice and extracted with ethyl acetate. The organic layer was dried (Na2SO4) and the solvent removed in vacuo to afford the subtitle product (4.19 g).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]([NH:11][CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][CH:17]([NH:20][CH3:21])[CH2:16][CH2:15]2)=[O:10])[CH:5]=[C:4]([CH3:22])[N:3]=1.[C:23]1([S:29](Cl)(=[O:31])=[O:30])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(Cl)Cl>[CH3:22][C:4]1[CH:5]=[C:6]([NH:8][C:9](=[O:10])[NH:11][CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][CH:17]([N:20]([CH3:21])[S:29]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)(=[O:31])=[O:30])[CH2:16][CH2:15]2)[CH:7]=[C:2]([CH3:1])[N:3]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CNC1CCN(CCNC(=O)Nc2cc(C)nc(C)c2)CC1
Solvent: ClCCl
Product: Cc1cc(NC(=O)NCCN2CCC(N(C)S(=O)(=O)c3ccccc3)CC2)cc(C)n1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a cooled (0° C.) mixture of 1-(2,6-dimethyl-pyridin-4-yl)-3-[2-(4-methylamino-piperidin-1-yl)-ethyl]-urea (Example E1., 0.3 mmol) and TEA (0.5 mL, 0.35 mmol) in CH2Cl2 (2 mL) is added a solution of benzenesulfonyl chloride (53.0 mg, 0.3 mmol) in CH2Cl2 (1 mL). The mixture is stirred at r.t. for 15 h and evaporated. the residue is purified by HPLC to provide the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([OH:9])[C:3]=1B(O)O.[CH2:13]([O:16][C:17]1([CH3:50])[CH2:22][CH2:21][N:20]([C:23]2[N:28]3[CH:29]=[C:30]([C:32]4[CH:37]=[CH:36][CH:35]=[C:34](Br)[CH:33]=4)[N:31]=[C:27]3[CH:26]=[C:25]([CH3:39])[C:24]=2[C@H:40]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])[C:41]([O:43][CH3:44])=[O:42])[CH2:19][CH2:18]1)[CH:14]=[CH2:15].C(OC1(C)CCN(C2N3C=C(C4C=C(C5C=C(C)C=CC=5O)C=CC=4)N=C3C=C(C)C=2[C@H](OC(C)(C)C)C(OC)=O)CC1)C=C>>[CH2:13]([O:16][C:17]1([CH3:50])[CH2:18][CH2:19][N:20]([C:23]2[N:28]3[CH:29]=[C:30]([C:32]4[CH:33]=[C:34]([C:3]5[C:4]([OH:9])=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=5[F:1])[CH:35]=[CH:36][CH:37]=4)[N:31]=[C:27]3[CH:26]=[C:25]([CH3:39])[C:24]=2[C@H:40]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])[C:41]([O:43][CH3:44])=[O:42])[CH2:21][CH2:22]1)[CH:14]=[CH2:15]
Reactant: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OC)c(C)cc3nc(-c4cccc(Br)c4)cn23)CC1
Reactant: Cc1cc(O)c(B(O)O)c(F)c1
Agent: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OC)c(C)cc3nc(-c4cccc(-c5cc(C)ccc5O)c4)cn23)CC1
Product: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OC)c(C)cc3nc(-c4cccc(-c5c(O)cc(C)cc5F)c4)cn23)CC1
Yield: 100 %

Procedure:
Prepared in 100% yield from (2-fluoro-6-hydroxy-4-methylphenyl)boronic acid and (S)-methyl 2-(5-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(3-bromophenyl)-7-methylimidazo[1,2-a]pyridin-6-yl)-2-(tert-butoxy)acetate following the procedure of (S)-methyl 2-(5-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(2′-hydroxy-5′-methyl-[1,1′-biphenyl]-3-yl)-7-methylimidazo[1,2-a]pyridin-6-yl)-2-(tert-butoxy)acetate. LCMS (ESI, M+1): 630.3.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[Cl:9])[NH2:5].Cl[C:11]1[N:16]=[C:15]([S:17][C:18]#[N:19])[C:14]([N+:20]([O-:22])=[O:21])=[CH:13][N:12]=1>C(O)C.C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:5][C:11]2[N:16]=[C:15]([S:17][C:18]#[N:19])[C:14]([N+:20]([O-:22])=[O:21])=[CH:13][N:12]=2)[CH:6]=[CH:7][C:8]=1[Cl:9]
Reactant: N#CSc1nc(Cl)ncc1[N+](=O)[O-]
Reactant: Nc1ccc(Cl)c(Cl)c1
Solvent: CCO
Solvent: Cc1ccccc1
Product: N#CSc1nc(Nc2ccc(Cl)c(Cl)c2)ncc1[N+](=O)[O-]
Reaction time: 16 h

Procedure:
2.47 g of 3,4-dichloroaniline in 12 ml ethanol are added to 3.00 g of 2-chloro-4-thiocyanato-5-nitro-pyrimidine in 40 ml toluene at ambient temperature. The mixture is stirred for another 16 hours, the solid is suction filtered, washed twice with 30 ml toluene and then once with 30 ml of ethanol and dried.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[OH:9])#[N:2].[Cl-].[NH4+].[N-:12]=[N+:13]=[N-:14].[Na+].Cl>CN(C)C=O>[NH:12]1[C:1]([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[OH:9])=[N:2][N:14]=[N:13]1
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1ccccc1O
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: Oc1ccccc1-c1nnn[nH]1
Temperature: 120 °C
Reaction time: 3 h

Procedure:
2-Cyanophenol (1.19 g), ammonium chloride (0.695 g), and sodium azide (0.845 g) were added to dimethylformamide (5 ml). The mixture was heated with stirring at 120° C. for 3 h. After cooling, it was poured into ice water and acidified with dilute hydrochloric acid. The resulting crystals were collected by filtration and dried to give the title compound.
Reaction SMILES: C([O:3][C:4](=[O:49])[CH2:5][N:6]([C:22](=[O:48])[CH2:23][N:24]1[CH:47]=[CH:46][C:28]([NH:29][C:30]([O:32][CH:33]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[O:31])=[N:27][C:25]1=[O:26])[CH2:7][CH2:8][NH:9][S:10]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N+:19]([O-:21])=[O:20])(=[O:12])=[O:11])C.[OH-].[Li+].Cl.[Cl-].[Na+]>C1COCC1.O>[CH:33]([O:32][C:30]([NH:29][C:28]1[CH:46]=[CH:47][N:24]([CH2:23][C:22]([N:6]([CH2:7][CH2:8][NH:9][S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[N+:19]([O-:21])=[O:20])(=[O:11])=[O:12])[CH2:5][C:4]([OH:49])=[O:3])=[O:48])[C:25](=[O:26])[N:27]=1)=[O:31])([C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1)[C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: CCOC(=O)CN(CCNS(=O)(=O)c1ccccc1[N+](=O)[O-])C(=O)Cn1ccc(NC(=O)OC(c2ccccc2)c2ccccc2)nc1=O
Agent: Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)CN(CCNS(=O)(=O)c1ccccc1[N+](=O)[O-])C(=O)Cn1ccc(NC(=O)OC(c2ccccc2)c2ccccc2)nc1=O
Reaction time: 1.5 h
Yield: 77.7 %

Procedure:
To a solution of N-{[4-N-(Benzhydryloxycarbonyl)-cytosin-1-yl]-acetyl}-N-[2-(2-nitro-benzenesulfonylamino)-ethyl]-glycine ethyl ester (1.91 g, 2.75 mmol) in THF (10 mL) was added a solution of lithium hydroxide (290 mg, 6.9 mmol) in water (9 mL) at 10° C. After stirring for 1.5 h, the reaction mixture was acidified to pH=3˜4 by adding 1 N HCl solution. The aqueous layer was saturated with sodium chloride and organic layer was separated. The aqueous layer was extracted with THF (15 mL×2). The combined organic layer was dried over sodium sulfate and filtered. The filtrate was concentrated and triturated with ethyl alcohol to precipitate solid. The precipitated solid was filtered off, washed with water, and dried in vacuo to give the tilted product as a white solid (1.42 g, 78%). 1H-NMR (500 MHz; DMSO-d6) δ 8.25˜7.80 (m, 5H), 7.50˜7.25 (m, 10H), 6.94 (d, 0.6H), 6.92 (d, 0.4H), 6.79 (1H, s), 4.78 (s, 1.2H), 4.60 (s, 0.8H), 4.22 (s, 0.8H), 3.94 (s, 1.2H), 3.50 (t, 1.2H), 3.35 (t, 0.8H), 3.24 (q, 1.2H), 3.02 (q, 0.8H).
Reaction SMILES: C([O:7][CH2:8][C:9]([F:15])([F:14])[S:10]([O-:13])(=[O:12])=[O:11])(=O)C(C)(C)C.[C:16]1([I+:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.CO.[OH-].[Na+].Cl>C(Cl)(Cl)Cl>[OH:7][CH2:8][C:9]([F:15])([F:14])[S:10]([O-:13])(=[O:12])=[O:11].[C:23]1([I+:22][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CC(C)(C)C(=O)OCC(F)(F)S(=O)(=O)[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: O=S(=O)([O-])C(F)(F)CO
Yield: 93.1 %

Procedure:
In 10 mL of chloroform, 7.32 g of a solid of diphenyliodonium 2-pivaloyloxy-1,1-difluoroethanesulfonate (purity: 90%, equivalent to 13.0 mmol) was dissolved by stirring. The resulting solution was admixed with 26 mL of methanol and 52 mg (1.30 mmol) of sodium hydroxide, and then, reacted at room temperature for 4 hours. To the thus-obtained reaction solution, 0.145 g (1.43 mmol) of concentrated hydrochloric acid was added. The reaction solution was subsequently subjected to concentration under reduced pressure. With this, 5.35 g of the target compound was obtained as a white solid (yield: 97%, purity: 90%).
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:15])[C:6]2[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][C:7]=2[OH:14])[CH2:3][CH2:2]1.[O:16]1[CH2:18][C@H:17]1[CH2:19]OS(C1C=CC=C([N+]([O-])=O)C=1)(=O)=O.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[CH:1]1([NH:4][C:5](=[O:15])[C:6]2[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][C:7]=2[O:14][CH2:19][C@@H:17]2[CH2:18][O:16]2)[CH2:2][CH2:3]1
Reactant: COc1ccc(C(=O)NC2CC2)c(O)c1
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)OC[C@@H]2CO2)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)NC2CC2)c(OC[C@@H]2CO2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 112.4 %

Procedure:
A mixture of N-cyclopropyl-2-hydroxy-4-methoxybenzamide (700 mg, 3.38 mmol), (2S)-oxiran-2-ylmethyl3-nitrobenzenesulfonate (876 mg, 3.38 mmol) and Cs2CO3 (1.31 g, 4.05 mmol) in DMF (12 mL) was stirred at room temperature overnight. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel flash chromatography (0-80% ethyl acetate in petroleum ether) to give the subtitled compound (1.0 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]2=[N:13][C:14](Cl)=[CH:15][CH:16]=[C:11]2[N:10]=[N:9]1.FC1C=CC=CC=1N.[OH-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)[OH:31]>CS(C)=O.O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]2=[N:13][C:14]([OH:31])=[CH:15][CH:16]=[C:11]2[N:10]=[N:9]1
Reactant: Fc1ccccc1-n1nnc2ccc(Cl)nc21
Reactant: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: Nc1ccccc1F
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: Oc1ccc2nnn(-c3ccccc3F)c2n1
Temperature: 100 °C
Reaction time: 3 h
Yield: 86 %

Procedure:
A solution of 3-(2-fluorophenyl)-5-chloro-1,2,3-triazolo[4,5-b]pyridine (1.01 g, 4.06 mmol; prepared following the procedure described in GB Patent No. 1268772 but using 2-fluoroaniline instead of aniline) and 2M sodium hydroxide (4 ml) in DMSO (15 ml) was stirred at 100° C. under nitrogen for 3 h. The mixture was cooled, diluted with water (250 ml) and neutralised with aqueous citric acid. After standing for 18 h, the brown precipitate was collected, dissolved in dichloromethane (100 ml), dried (Na2SO4), filtered and concentrated to give 3-(2-fluorophenyl)-5-hydroxy-1,2,3-triazolo[4,5-b]pyridine (0.80 g, 86%) as a brown solid. δH (360 MHz; d6-DMSO) 6.81 (1H, broad d, J=9), 7.50 (1H, dd, J=8 and 8), 7.60 (1H, dd, J=8 and 7), 7.68-7.72 (1H, m), 7.81 (1H, ddd, J=8, 8 and 2), 8.44 (1H, broad d, J=9) and 12.15 (1H, broad s); m/z (ES+) 231 (M+H+).
Reaction SMILES: [CH:1]1([C:4]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[N+:12]([O-])=O)=[O:5])[CH2:3][CH2:2]1.[H][H]>>[CH:1]1([C:4]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[NH2:12])=[O:5])[CH2:2][CH2:3]1
Reactant: [H][H]
Reactant: O=C(c1ccccc1[N+](=O)[O-])C1CC1
Product: Nc1ccccc1C(=O)C1CC1

Procedure:
Beneficially, the o-nitrophenyl cyclopropyl ketone may be reduced in the presence of hydrogen and a catalyst to give o-aminophenyl cyclopropyl ketone. The reaction is shown in Flow Diagram II. ##STR2##
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[CH:9]=[C:8]([C:10]3[C:15]([Cl:16])=[CH:14][N:13]=[C:12]([NH:17][CH2:18][CH2:19][CH2:20][N:21]4[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]4)[N:11]=3)[S:7][C:6]=2[CH:28]=1.[N:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[NH2:35].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C(#N)C>[Cl:16][C:15]1[C:10]([C:8]2[S:7][C:6]3[CH:28]=[C:2]([NH:35][C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][N:29]=4)[CH:3]=[CH:4][C:5]=3[CH:9]=2)=[N:11][C:12]([NH:17][CH2:18][CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]2)=[N:13][CH:14]=1
Reactant: CN1CCN(CCCNc2ncc(Cl)c(-c3cc4ccc(Br)cc4s3)n2)CC1
Reactant: Nc1ccccn1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CC#N
Product: CN1CCN(CCCNc2ncc(Cl)c(-c3cc4ccc(Nc5ccccn5)cc4s3)n2)CC1
Temperature: 150 °C
Yield: 32.3 %

Procedure:
A microwave tube is charged with [4-(6-bromobenzo[b]thiophen-2-yl)-5-chloropyrimidin-2-yl]-[3-(4-methylpiperazin-1-yl)-propyl]-amine (45 mg, 0.094 mmol), 2.5 equivalent of pyridin-2-amine (28 mg, 0.30 mmol), 2 mol % of tris(dibenzylideneacetone)dipalladium(0) (1.7 mg, 0.0020 mmol), 6 mol % of Xantphos (3.5 mg, 0.0060 mmol), 2.5 equivalent of cesium carbonate (77 mg, 0.24 mmol) and acetonitrile (2 mL). The reaction is sealed and heated under microwave condition at 150° C. for 15 minutes, cooled down, filtered and then evaporated to furnish a red oil. The crude material is subjected to reverse phase purification, eluting with 10-70% CH3CN/0.01 M NH4HCO3 in water using a C18 Xterra column, to give the title compound as a pale yellow solid (15 mg, 33% yield). ES+(m/z) 494 (35Cl) and 496 (37Cl) [M+H].
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl.[CH2:8]([N:11]([CH2:15][CH2:16][C:17]1[CH:18]=[CH:19][C:20]2[O:25][CH2:24][CH2:23][NH:22][C:21]=2[CH:26]=1)[CH2:12][CH2:13][CH3:14])[CH2:9][CH3:10].[Cl:27][CH2:28][C:29]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:32]=[CH:31][CH:30]=1.O>CN(C=O)C>[ClH:27].[CH2:8]([N:11]([CH2:15][CH2:16][C:17]1[CH:18]=[CH:19][C:20]2[O:25][CH2:24][CH2:23][N:22]([CH2:28][C:29]3[C:38]4[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=4)[CH:32]=[CH:31][CH:30]=3)[C:21]=2[CH:26]=1)[CH2:12][CH2:13][CH3:14])[CH2:9][CH3:10]
Reactant: CCCN(CCC)CCc1ccc2c(c1)NCCO2
Reactant: ClCc1cccc2ccccc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCN(CCC)CCc1ccc2c(c1)N(Cc1cccc3ccccc13)CCO2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Potassium carbonate (316 mg, 2.29 mmol) was added to a solution of 3,4-dihydro-6-[2-(N,N-dipropylamino)ethyl]-2H-1,4-benzoxazine hydrochloride (200 mg, 0.76 mmol) obtained in Example 134 and 1-chloromethyl naphthalene (400 mg, 2.29 mmol) in DMF (15 ml). After the reaction solution was stirred at room temperature for 2 hours, water was added to the reaction solution which was then extracted with ethyl acetate. The extract was washed with water, dried over anhydrous sodium sulfate and concentrated. The residues were purified by silica gel column chromatography (developing solvent; hexane:ethyl acetate=3:1), treated with 4 N hydrochloric acid in ethyl acetate and crystallized from acetone-pentane, whereby the title compound (80 mg) was obtained as crystals with a mp of 177 to 178° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][N:12]=[C:11](Cl)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:19][CH2:20][C@@H:21]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH3:22].P([O-])([O-])([O-])=O.[K+].[K+].[K+].C(#N)CC>O>[CH2:1]([O:8][C:9]1[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][N:12]=[C:11]([O:19][CH2:20][C@@H:21]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH3:22])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1cnc(Cl)nc1OCc1ccccc1
Reactant: C[C@@H](CO)NC(=O)OC(C)(C)C
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCC#N
Solvent: O
Product: C[C@@H](COc1ncc([N+](=O)[O-])c(OCc2ccccc2)n1)NC(=O)OC(C)(C)C
Temperature: 50 °C
Reaction time: 1 h
Yield: 16.7 %

Procedure:
A mixture of 4-(benzyloxy)-2-chloro-5-nitropyrimidine (670 mg), tert-butyl ((2S)-1-hydroxypropan-2-yl)carbamate (530 mg), potassium phosphate (642 mg) and propionitrile (10 mL) was stirred at 50° C. for 1 hr, and then at 100° C. for 5 hr. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The combined organic layer were washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (170 mg).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH3:11])=[C:6]([N+:12]([O-])=O)[CH:5]=1.Cl>[Pd].CO>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH3:11])=[C:6]([NH2:12])[CH:5]=1
Reactant: CNc1ccc(C(=O)OC)cc1[N+](=O)[O-]
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CNc1ccc(C(=O)OC)cc1N

Procedure:
71 g of 4-methylamino-3-nitro-benzoic acid-methyl ester (338 mmol) are hydrogenated in 1.41, of methanol and 67 ml of concentrated aqueous hydrochloric acid in the presence of 15 g of Pd/C (5%) at 2-5 bar, at room temperature. After filtering off the catalysts and distilling off the solvent under vacuum, the residue is dissolved in 200 ml of water, covered with ethyl acetate and basified with a 50% solution of potassium carbonate. The product is extracted in the organic phase, which is again washed with water and then dried over sodium sulphate. After removal of most of the solvent by distillation under vacuum, diethyl ether is added and it is cooled off. The resulting crystals are filtered off. Yield: 54 g (81%); MPt.: 215-220° C. (decomposition).
Reaction SMILES: FC(F)(F)C([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C@H:12]([OH:15])[CH2:13][CH3:14])=O.[ClH:18]>C(O)(C)C>[ClH:18].[NH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C@H:12]([OH:15])[CH2:13][CH3:14]
Reactant: CC[C@@H](O)c1ccccc1NC(=O)C(F)(F)F
Agent: Cl
Solvent: CC(C)O
Product: CC[C@@H](O)c1ccccc1N
Reaction time: 15 h
Yield: 74.9 %

Procedure:
(R)—N-trifluoroacetyl-2-amino phenyl propanol (11.8 g, 0.0477 mol) prepared as above was dissolved in 100 ml of isopropanol. At a controlled temperature of <10 with ice bath, 70 ml of concentrated hydrochloric acid was added dropwise. The temperature was slowly raised to 40, and a reaction was allowed to proceed for 15 hours. The solvent was removed by evaporation under reduced pressure (water bath temperature <60), and benzene (100 ml×2) was added to remove water by azeotropism. Ethanol (120 ml×2) was then added for the azeotropism. A white solid was obtained by evaporation till dry. The solid was recrystallized with ethanol, and dried, to produce 6.7 g of (R)-2-amino phenyl propanol hydrochloride. The yield was 74.9%.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][CH:8]([CH2:15][CH3:16])[CH:9]([OH:14])[CH2:10][N+:11]([O-:13])=[O:12])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:25][Si:26](Cl)([CH3:28])[CH3:27]>ClCCl>[C:1]([O:5][C:6](=[O:17])[NH:7][CH:8]([CH2:15][CH3:16])[CH:9]([O:14][Si:26]([CH3:28])([CH3:27])[CH3:25])[CH2:10][N+:11]([O-:13])=[O:12])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCC(NC(=O)OC(C)(C)C)C(O)C[N+](=O)[O-]
Reactant: C[Si](C)(C)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(NC(=O)OC(C)(C)C)C(C[N+](=O)[O-])O[Si](C)(C)C
Temperature: 25 °C
Reaction time: 24 h
Yield: 63.7 %

Procedure:
To a mixture of (1-ethyl-2-hydroxy-3-nitro-propyl)-carbamic acid tert-butyl ester (1.83 g, 7.37 mmol) and triethylamine (1.49 g, 14.75 mmol) in dry dichloromethane (25 mL) under N2 is added trimethylsilyl chloride (1.20 g, 11.05 mmol). The mixture is stirred at room temperature for 24 h, then diluted with 40 mL of dichloromethane and washed with water (40 mL). The organic layer is dried over magnesium sulfate and concentrated in vacuum. The residue is purified over 110 g silica gel, eluted with ethyl acetate: heptane (1:4) to afford (1-ethyl-3-nitro-2-trimethylsilanyloxy-propyl)-carbamic acid tert-butyl ester (1.505 g, 86%) as an oil.