Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([O:9][C:10](=[O:14])[CH:11](Br)[CH3:12])[CH3:8].[C:15]1([C:25]2[N:30]=[N:29][N:28]=[C:27]([C:31]3[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][C:32]=3[OH:38])[C:26]=2[C:39]2[C:48]3[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=3)[CH:42]=[CH:41][CH:40]=2)[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][CH:16]=1>CN(C=O)C>[C:15]1([C:25]2[N:30]=[N:29][N:28]=[C:27]([C:31]3[CH:36]=[CH:35][C:34]([O:37][CH:11]([C:10]([O:9][CH2:7][CH3:8])=[O:14])[CH3:12])=[CH:33][C:32]=3[OH:38])[C:26]=2[C:39]2[C:48]3[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=3)[CH:42]=[CH:41][CH:40]=2)[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][CH:16]=1
Reactant: CCOC(=O)C(C)Br
Reactant: Oc1ccc(-c2nnnc(-c3cccc4ccccc34)c2-c2cccc3ccccc23)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)Oc1ccc(-c2nnnc(-c3cccc4ccccc34)c2-c2cccc3ccccc23)c(O)c1
Temperature: 125 °C

Procedure:
9.39 g of potassium carbonate and 9.02 g of 2-bromopropionic acid ethyl ester are added to a solution of 20.0 g of the product from Example A6 in 200 ml of DMF. The reaction mixture is heated at 125° C. for 3.5 h. The solid which precipitates is filtered off and washed with toluene. The combined organic phase is freed of solvent in vac. Chromatography of the residue on silica gel yields the product of melting point: 124–125° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[C:5]([CH:9]([CH2:14][CH2:15][CH3:16])[C:10]([O:12][CH3:13])=[O:11])=[C:4]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)[N:3]=1.[CH3:24][N:25]1[CH:29]=[C:28](B(O)O)[CH:27]=[N:26]1.C(N(CC)C(C)C)(C)C>COCCOC.O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:8][C:6]1[C:5]([CH:9]([CH2:14][CH2:15][CH3:16])[C:10]([O:12][CH3:13])=[O:11])=[C:4]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)[N:3]=[C:2]([C:28]2[CH:27]=[N:26][N:25]([CH3:24])[CH:29]=2)[N:7]=1
Reactant: Cn1cc(B(O)O)cn1
Reactant: CCCC(C(=O)OC)c1c(C)nc(Cl)nc1-c1ccc(C)cc1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: COCCOC
Product: CCCC(C(=O)OC)c1c(C)nc(-c2cnn(C)c2)nc1-c1ccc(C)cc1
Yield: 63 %

Procedure:
Methyl 2-(2-chloro-4-methyl-6-p-tolylpyrimidin-5-yl)pentanoate (100 mg; 0.300 mmol), 1-Methyl-1H-pyrazole-4-boronic acid, pinacol ester (188 mg; 0.901 mmol), tetrakis(triphenylphosphine) palladium(0) (34.7 mg; 0.030 mmol) were placed in a 5 mL reaction tube and dissolved in a mixture of degassed DME (1.50 mL) and water (0.5 mL). N,N-Diisopropylethylamine (0.185 mL; 1.202 mmol) was added, the tube was sealed and irradiated in a microwave oven at 130° C. for 1 h. The reaction mixture was partitioned between brine and dichloromethane, filtered over a phase separator filter (1PS) and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel using a linear gradient of ethylacetate (10-80%) in heptane to give 114 mg (63%) of the title compound as a colorless oil.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[N:13]=[C:12]([N:14]3[CH2:19][CH:18]4[CH2:20][CH:15]3[CH2:16][N:17]4[CH2:21][CH:22]([F:24])[F:23])[N:11]3[CH:25]=[CH:26][N:27]=[C:10]3[CH:9]=2)[CH:5]=[CH:4][N:3]=1.[CH3:28][C@H:29]([NH2:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC([O-])(C)C.[Na+]>C(Cl)Cl.CC([O-])=O.CC([O-])=O.[Pd+2].C1(C)C=CC=CC=1>[F:23][CH:22]([F:24])[CH2:21][N:17]1[CH2:16][C@@H:15]2[CH2:20][C@H:18]1[CH2:19][N:14]2[C:12]1[N:11]2[CH:25]=[CH:26][N:27]=[C:10]2[CH:9]=[C:8]([C:6]2([NH:36][C@H:29]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH3:28])[CH:5]=[CH:4][N:3]=[CH:2][CH2:7]2)[N:13]=1
Reactant: C[C@H](N)c1ccccc1
Reactant: FC(F)CN1CC2CC1CN2c1nc(-c2ccnc(Cl)c2)cc2nccn12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: C[C@H](NC1(c2cc3nccn3c(N3C[C@@H]4C[C@H]3CN4CC(F)F)n2)C=CN=CC1)c1ccccc1
Temperature: 90 °C
Reaction time: 3 h

Procedure:
To an RBF was added 7-(2-chloro-pyridin-4-yl)-5-[5-(2,2-difluoro-ethyl)-2,5-diaza-bicyclo[2.2.1]hept-2-yl]-imidazo[1,2-c]pyrimidine (40 mg, 0.10 mmol), 1 mL toluene, and (S)-α-methylbenzylamine (0.015 mL, 0.11 mmol). The mixture was degassed by bubbling nitrogen through solution for 1 h. After Pd(OAc)2 (2 mg, 0.01 mmol), rac-BINAP (6 mg, 0.01 mmol), and NaOtBu (0.20 mg, 0.21 mmol) were added, the mixture was warmed up to 90° C. and stirred for 3 h under nitrogen. The mixture was cooled down to ambient temperature, diluted with 50 mL DCM, washed with 20 mL sat. NaHCO3, and dried over anhydrous Na2SO4. After purification by preparatory TLC, the title compound was obtained. MS (ES+): 476 (M+H)+.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]([NH:6][C:7]([C:9]1[CH:10]=[C:11]([C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)[CH:12]=[C:13](N)[CH:14]=1)=[O:8])[CH3:5].N(OCCC(C)C)=O.[I:31]CI>>[CH3:1][O:2][CH2:3][CH:4]([NH:6][C:7]([C:9]1[CH:10]=[C:11]([C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)[CH:12]=[C:13]([I:31])[CH:14]=1)=[O:8])[CH3:5]
Reactant: ICI
Reactant: COCC(C)NC(=O)c1cc(N)cc(-c2ccc(C)cc2)c1
Agent: CC(C)CCON=O
Product: COCC(C)NC(=O)c1cc(I)cc(-c2ccc(C)cc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.4 %

Procedure:
A mixture of 5-amino-4′-methyl-biphenyl-3-carboxylic acid (2-methoxy-1-methyl-ethyl)-amide (5.3 g, 17.8 mmol), iso-amyl nitrite (13.5 ml, 88.9 mmol) and diiodomethane (8 ml, 106.7 mmol) was stirred at room temperature for 1 hour. The mixture was then heated to 65° C. and kept for 8 hours, LC/MS indicated that reaction completed. The reaction mixture was cooled to room temperature and the separation of iodobenzene from excess diiodomethane was effected by addition of the reaction mixture at room temperature to a stirred solution of piperidin-CH3CN (V/V=90 ml/90 ml). A vigorous exothermic reaction ensued. The excess volatile reagents were removed by rotary evaporation at 80° C. The residue was diluted with ethyl acetate, washed with 10% hydrochloric acid, water and brine. The organic layer was separated and dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash column chromatography (ethyl acetate/hexanes=10:1) to yield 5-iodo-4′-methyl-biphenyl-3-carboxylic acid (2-methoxy-1-methyl-ethyl)-amide as a yellow solid (5.2 g, 83.8%). MS (M+H)=410.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([C:9]2[N:10]=[C:11]([N:20]3[CH2:25][CH2:24][CH:23]([OH:26])[CH2:22][CH2:21]3)[C:12]3[CH2:17][S:16](=[O:19])(=[O:18])[CH2:15][C:13]=3[N:14]=2)=[C:4]([F:27])[CH:3]=1.Cl[C:29]([O:31][C:32]1[CH:37]=[CH:36][C:35]([N+:38]([O-:40])=[O:39])=[CH:34][CH:33]=1)=[O:30].N1C=CC=CC=1.[Cl-].[NH4+]>C(Cl)Cl>[C:29](=[O:30])([O:31][C:32]1[CH:33]=[CH:34][C:35]([N+:38]([O-:40])=[O:39])=[CH:36][CH:37]=1)[O:26][CH:23]1[CH2:24][CH2:25][N:20]([C:11]2[C:12]3[CH2:17][S:16](=[O:18])(=[O:19])[CH2:15][C:13]=3[N:14]=[C:9]([C:5]3[CH:6]=[C:7]([F:8])[C:2]([Cl:1])=[CH:3][C:4]=3[F:27])[N:10]=2)[CH2:21][CH2:22]1
Reactant: O=S1(=O)Cc2nc(-c3cc(F)c(Cl)cc3F)nc(N3CCC(O)CC3)c2C1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(Oc1ccc([N+](=O)[O-])cc1)OC1CCN(c2nc(-c3cc(F)c(Cl)cc3F)nc3c2CS(=O)(=O)C3)CC1
Temperature: 25 °C
Reaction time: 17 h
Yield: 112.1 %

Procedure:
A mixture of 571 mg of 1-[2-(4-chloro-2,5-difluorophenyl)-6,6-dioxido-5,7-dihydrothieno[3,4-d]pyrimidin-4-yl]piperidin-4-ol, 0.30 g of 4-nitrophenyl chloroformate, 0.12 ml of pyridine, and 10 ml of methylene chloride was stirred at ambient temperature for 17 hours. Saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted twice with chloroform. The organic phase was washed with brine, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure to yield 894 mg of 1-[2-(4-chloro-2,5-difluorophenyl)-6,6-dioxido-5,7-dihydrothieno[3,4-d]pyrimidin-4-yl]piperidin-4-yl 4-nitrophenyl carbonate as light yellow solid.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([N:8]=[C:9]([NH:11][C:12](=[O:19])[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:10]=2)[CH:7]=1.[O:20]1[C:24]2[CH:25]=[CH:26][C:27](B(O)O)=[CH:28][C:23]=2[CH2:22][CH2:21]1>>[O:20]1[C:24]2[CH:25]=[CH:26][C:27]([C:2]3[CH:3]=[CH:4][C:5]4[N:6]([N:8]=[C:9]([NH:11][C:12](=[O:19])[C:13]5[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=5)[N:10]=4)[CH:7]=3)=[CH:28][C:23]=2[CH2:22][CH2:21]1
Reactant: O=C(Nc1nc2ccc(Br)cn2n1)c1ccccc1
Reactant: OB(O)c1ccc2c(c1)CCO2
Product: O=C(Nc1nc2ccc(-c3ccc4c(c3)CCO4)cn2n1)c1ccccc1
Yield: 70 %

Procedure:
The title compound was prepared following procedure described for example 56 but starting from N-(6-bromo[1,2,4]triazolo[1,5-a]pyridin-2-yl)benzamide ((B5), 150 mg; 0.47 mmol; 1.0 eq.) and 2,3-dihydro-1-benzofuran-5-ylboronic acid (155 mg; 0.95 mmol; 2.0 eq.). Purification by flash chromatography on silica (EtOAc/c-Hex, gradient from 40:60 to 100:0) gave the title compound as a white solid (117.2 mg, 69%). HPLC, Rt: 3.18 min. (purity 84.6%). LC/MS, M+(ESI): 357.1, M−(ESI): 355.1.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[C:9]([CH3:13])[CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:14][O:15][C@H:16]1[CH2:21][CH2:20][CH2:19][C@@H:18]([O:22][CH2:23][CH2:24][O:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[B:32]2[O:36]C(C)(C)C(C)(C)[O:33]2)[CH2:17]1.Cl>C1COCC1>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[C:9]([CH3:13])[CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:14][O:15][C@H:16]1[CH2:21][CH2:20][CH2:19][C@@H:18]([O:22][CH2:23][CH2:24][O:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[B:32]([OH:33])[OH:36])[CH2:17]1
Reactant: Cc1cccc(-c2nc(CO[C@H]3CCC[C@@H](OCCOc4ccccc4B4OC(C)(C)C(C)(C)O4)C3)c(C)o2)c1
Agent: Cl
Solvent: C1CCOC1
Product: Cc1cccc(-c2nc(CO[C@H]3CCC[C@@H](OCCOc4ccccc4B(O)O)C3)c(C)o2)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Unpurified (1S,3R)-5-methyl-4-(3-{2-[2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenoxy]ethoxy}cyclohexyloxymethyl)-2-m-tolyloxazole is taken up in 6 ml of THF, and 0.75 ml of 1N HCl is added. After 3 h of stirring at room temperature, the solvent is evaporated and the residue is taken up in DMF then purified by RP-HPLC. This gives (1R,3S)-2-{2-[3-(5-methyl-2-m-tolyloxazol-4-ylmethoxy)cyclohexyloxy]ethoxy}phenylboronic acid as a colorless oil. 465.36 (C26H32BNO6), MS (ESI): 466 (M+H+).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:16]=[CH:15][C:10]3[O:11][CH2:12][CH2:13][NH:14][C:9]=3[CH:8]=2)[CH2:3][CH2:2]1.Cl[C:18]1[C:27]2[C:22](=[N:23][CH:24]=[CH:25][CH:26]=2)[N:21]=[C:20]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=2)[C:19]=1[CH3:34]>CC(C1C=C(C(C)C)C(C2C(P(C3CCCCC3)C3CCCCC3)=CC=CC=2)=C(C(C)C)C=1)C.C1C=[C-]C(CCN)=CC=1.Cl[Pd+].C1(C)C=CC=CC=1>[CH3:34][C:19]1[C:20]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=2)=[N:21][C:22]2[C:27]([C:18]=1[N:14]1[C:9]3[CH:8]=[C:7]([N:4]4[CH2:5][CH2:6][O:1][CH2:2][CH2:3]4)[CH:16]=[CH:15][C:10]=3[O:11][CH2:12][CH2:13]1)=[CH:26][CH:25]=[CH:24][N:23]=2
Reactant: Cc1c(-c2ccccn2)nc2ncccc2c1Cl
Reactant: c1cc2c(cc1N1CCOCC1)NCCO2
Agent: Cl[Pd+]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: NCCc1[c-]cccc1
Solvent: Cc1ccccc1
Product: Cc1c(-c2ccccn2)nc2ncccc2c1N1CCOc2ccc(N3CCOCC3)cc21

Procedure:
Prepared according to procedure Y by using 6-morpholino-3,4-dihydro-2H-benzo-[b][1,4]oxazine (68 mg, 0.31 mmol), 4-chloro-3-methyl-2-(pyridin-2-yl)-1,8-naphthyridine (79 mg, 0.31 mmol), XPhos precatalyst (23 mg, 0.031 mmol) in toluene (5 mL) for 2 h at 100° C. Purification by reverse phase HPLC (10 to 60% acetonitrile in water) gave 4-(3-methyl-2-(2-pyridinyl)-1,8-naphthyridin-4-yl)-6-(4-morpholinyl)-3,4-dihydro-2H-1,4-benzoxazine. 1H NMR (400 MHz, chloroform-d) δ ppm 9.10 (1H, dd, J=4.1, 2.0 Hz), 8.71 (1H, ddd, J=4.8, 1.9, 1.0 Hz), 8.16-8.24 (2H, m), 7.92 (1H, td, J=7.7, 1.8 Hz), 7.37-7.45 (2H, m), 6.89 (1H, d, J=8.8 Hz), 6.31 (1H, dd, J=8.8, 2.7 Hz), 5.60 (1H, d, J=2.7 Hz), 4.42-4.52 (2H, m), 3.80-3.87 (1H, m), 3.62-3.76 (5H, m), 2.68-2.80 (4H, m), 2.53 (3H, s). Mass Spectrum (ESI) m/e=440.0 (M+1).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[CH:22][CH:21]=2)[N:15]=1.[B:35](OC(C)C)([O:40]C(C)C)[O:36]C(C)C.Cl.[Cl-].[Na+]>O1CCCC1.CCCCCC>[F:13][C:14]1[C:19]([B:35]([OH:40])[OH:36])=[CH:18][CH:17]=[C:16]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[CH:22][CH:21]=2)[N:15]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: CCCCCCCCOc1ccc(-c2cccc(F)n2)cc1
Agent: Cl
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCCCCCCCOc1ccc(-c2ccc(B(O)O)c(F)n2)cc1
Temperature: -78 °C
Reaction time: 4 h
Yield: 78.5 %

Procedure:
8.00 ml (56.80 mmol) of diisopropylamine in 10 ml of tetrahydrofuran are stirred at 0° C. with 35.70 ml (56.80 mmol) of a 1.6-molar n-butyllithium solution in hexane for 1 hour. After cooling to -78° C., 8.56 g (28.40 mmol) of 2-fluoro-6-(4-octyloxyphenyl)pyridine (prepared as described in Example 2) in 1000 ml of tetrahydrofuran are added dropwise, and the mixture is stirred at -78° C. for 4 hours. 21.25 g (113.00 mmol) of triisopropyl borate are then added dropwise at -78° C., and the reaction mixture is stirred overnight, during which it warms to room temperature. After addition of 100 ml of 10% hydrochloric acid and stirring at room temperature for one hour, sodium chloride solution is added, the mixture is extracted with ether, the ether phase is washed with sodium chloride solution, dried over sodium sulfate, filtered and concentrated. Recrystallization from acetonitrile gives 7.70 g of 2-fluoro-6-(4-octyloxyphenyl)pyridine-3-boronic acid. ##STR29##
Reaction SMILES: [CH2:1]([Mg]Br)[CH3:2].[Cl:5][C:6]1[CH:7]=[CH:8][C:9]([CH:27]=[O:28])=[C:10]2[C:14]=1[N:13]=[C:12]1[N:15]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=3[Cl:26])[CH2:16][CH2:17][CH2:18][N:11]21>O1CCCC1>[Cl:5][C:6]1[C:14]2[N:13]=[C:12]3[N:15]([C:19]4[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=4[Cl:26])[CH2:16][CH2:17][CH2:18][N:11]3[C:10]=2[C:9]([CH:27]([OH:28])[CH2:1][CH3:2])=[CH:8][CH:7]=1
Reactant: O=Cc1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Reactant: CC[Mg]Br
Solvent: C1CCOC1
Product: CCC(O)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Temperature: 0 °C
Reaction time: 1 h
Yield: 92 %

Procedure:
Ethylmagnesium bromide (3.0 M solution in diethyl ether, 1.1 mL, 3.3 mmol) was added to a stirred solution of 9-chloro-1-(2,4-dichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole-6-carbaldehyde (1.00 g, 2.63 mmol) in tetrahydrofuran (13 mL) at 0° C., and the mixture was stirred at 0° C. for 1 hr. The reaction was quenched by aqueous saturated ammonium chloride, and the mixture was extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The residue was recrystallized from ethanol to give the title compound as a colorless crystal (992 mg, 2.42 mmol, 92%).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([C:9]2[CH:10]=[C:11]([OH:15])[CH:12]=[CH:13][CH:14]=2)[CH:6]=[C:5]([NH:16][CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)[N:4]=1.C([O-])([O-])=O.[Cs+].[Cs+].Br[C:34]([CH3:41])([CH3:40])[C:35]([O:37][CH2:38][CH3:39])=[O:36]>CN(C=O)C.O>[CH2:38]([O:37][C:35](=[O:36])[C:34]([O:15][C:11]1[CH:12]=[CH:13][CH:14]=[C:9]([C:7]2[CH:6]=[C:5]([NH:16][CH2:17][CH2:18][C:19]3[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=3)[N:4]=[C:3]([O:2][CH3:1])[N:8]=2)[CH:10]=1)([CH3:41])[CH3:40])[CH3:39]
Reactant: COc1ccc(CCNc2cc(-c3cccc(O)c3)nc(OC)n2)cc1
Reactant: CCOC(=O)C(C)(C)Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(C)(C)Oc1cccc(-c2cc(NCCc3ccc(OC)cc3)nc(OC)n2)c1
Temperature: 60 °C
Yield: 62 %

Procedure:
A mixture of 3-{2-methoxy-6-[2-(4-methoxy-phenyl)-ethylamino]-pyrimidin-4-yl}-phenol (400 mg, 1.14 mmol, Example 35(p)], Cs2CO3 (1.1 g, 3.41 mmol), and ethyl 2-bromo-2-methylpropionate (0.5 mL, 3.41 mmol) in N,N′-dimethylformamide (4 mL) is heated to 60° C. for 15 hours. The reaction mixture is diluted with water, and extracted with ethyl acetate. The extracts are dried over magnesium sulfate, filtered and concentrated. The residue is subjected to chromatography on silica gel eluting with 50% EtOAc in heptane to afford 2-(3-{2-methoxy-6-[2-(4-methoxy-phenyl)-ethylamino]-pyrimidin-4-yl}-phenoxy)-2-methyl-propionic acid ethyl ester [0.33 g, 62%, Example 22(a)]. LCMS: RT=2.95 minutes, MS: 466 (M+H). IC50=60 nM
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH2:11])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([NH2:9])=[O:8].Br[CH:13]([CH3:17])[C:14](=O)[CH3:15]>C1(=O)CCCCC1>[NH2:1][C:2]1[C:3]2[N:4]([C:13]([CH3:17])=[C:14]([CH3:15])[N:11]=2)[CH:5]=[C:6]([C:7]([NH2:9])=[O:8])[CH:10]=1
Reactant: NC(=O)c1cnc(N)c(N)c1
Reactant: CC(=O)C(C)Br
Solvent: O=C1CCCCC1
Product: Cc1nc2c(N)cc(C(N)=O)cn2c1C
Temperature: 20 °C
Reaction time: 2 h
Yield: 129.5 %

Procedure:
5,6-Diamino-nicotinamide (30.0 g; 0.183 mol; 1.0 equiv) was suspended in cyclohexanone (280 mL). 3-Bromo-2-butanone (24 mL; 0.22 mol; 1.2 equiv) was added and the mixture was heated for 4 h to 100° C. The reaction mixture was cooled to 20° C. and allowed to stir for another 2 h. The solid was filtered off, washed with TBME (200 mL) and dried to yield 48.4 g of the title compound. Yield: 78%.
Reaction SMILES: [Na].CO.[S:4]1[CH:8]=[CH:7][S:6][C:5]1=[C:9]([C:15](=[O:30])[N:16]([CH2:23][C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1)[CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])[C:10](OCC)=[O:11]>C1C=CC=CC=1>[N:26]1[CH:27]=[CH:28][CH:29]=[C:24]([CH2:23][N:16]2[C:15](=[O:30])[C:9](=[C:5]3[S:4][CH:8]=[CH:7][S:6]3)[C:10](=[O:11])[CH:18]([C:19]([O:21][CH3:22])=[O:20])[CH2:17]2)[CH:25]=1
Reactant: CCOC(=O)C(C(=O)N(CCC(=O)OC)Cc1cccnc1)=C1SC=CS1
Agent: [Na]
Solvent: CO
Solvent: c1ccccc1
Product: COC(=O)C1CN(Cc2cccnc2)C(=O)C(=C2SC=CS2)C1=O
Yield: 51 %

Procedure:
Sodium (156 mg) is added to methanol (5ml) and thereto is added a solution of ethyl 2-(1,3-dithiol-2-ylidene)-2-[N-(3-pyridylmethyl)-N-(methoxycarbonylethyl)carbamoyl]acetate (2.21 g) in benzene (35 ml). The mixture is refluxed for 3 hours, and distilled to remove the solvent. The residue is dissolved in ethyl acetate, and the solution is washed with water, dried and then distilled to remove the solvent. The residue is recrystallized from a mixture of ethyl acetate and n-hexane to give methyl 1-(3-pyridylmethyl)-5-(1,3-dithiol-2-ylidene)-4,6-dioxopiperidine-3-carboxylate (1.0 g, 51%) as pale yellow needles, m.p. 111°-114° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][CH2:14][OH:15])[CH2:11][O:10][C:9]1([CH3:17])[CH3:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C1COCC1.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[C:1]([O:5][C:6]([N:8]1[C@@H:12]([CH2:13][CH2:14][O:15][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:11][O:10][C:9]1([CH3:17])[CH3:16])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1[C@@H](CCO)COC1(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [H-]
Agent: [I-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1[C@@H](CCOCc2ccccc2)COC1(C)C
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 73 %

Procedure:
To a solution of (S)-4-(2-hydroxy-ethyl)-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (200 mg) in THF (5 ml) at room temperature were added sequentially tetrabutylammonium iodide (15 mg) and sodium hydride (35 mg, 60% dispersion in mineral oil). After stirring the mixture for 5 min at room temperature, benzyl bromide (0.10 ml) was added dropwise and stirring was continued for a further 16 h. The mixture was quenched by addition of saturated aq. ammonium chloride solution (3 ml), diluted with water, and extracted twice with diethyl ether. The combined organic phases were dried over sodium sulphate, filtered, and the filtrate was concentrated in vacuo. The residue was purified by column chromatography (SiO2; heptane/EtOAc) to yield (S)-4-(2-benzyloxy-ethyl)-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester as a colourless oil (199 mg, 73%); MS (ISP): 336.3 ([M+H]+).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][C:27]=1[OH:28])/[CH:5]=[CH:6]/[C:7]1[N:15]([CH3:16])[C:14]2[C:13](=[O:17])[N:12]([CH2:18][CH2:19][CH3:20])[C:11](=[O:21])[N:10]([CH2:22][CH2:23][CH3:24])[C:9]=2[N:8]=1.CI.[C:31](=O)([O-])[O-].[Li+].[Li+].O>CN(C)C=O>[OH:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][C:27]=1[O:28][CH3:31])/[CH:5]=[CH:6]/[C:7]1[N:15]([CH3:16])[C:14]2[C:13](=[O:17])[N:12]([CH2:18][CH2:19][CH3:20])[C:11](=[O:21])[N:10]([CH2:22][CH2:23][CH3:24])[C:9]=2[N:8]=1
Reactant: CCCn1c(=O)c2c(nc(/C=C/c3ccc(O)c(O)c3)n2C)n(CCC)c1=O
Reactant: O=C([O-])[O-]
Agent: [Li+]
Solvent: O
Solvent: CI
Solvent: CN(C)C=O
Product: CCCn1c(=O)c2c(nc(/C=C/c3ccc(OC)c(O)c3)n2C)n(CCC)c1=O
Temperature: 80 °C
Reaction time: 5 h
Yield: 31.3 %

Procedure:
Compound 53 (500 mg, 1.30 mmol) obtained in Reference Example 46 was dissolved in 10 ml of dimethylformamide. To the solution were added 0.40 ml (6.43 mmol) of methyl iodide and 400 mg (6.50 mmol) of lithium carbonate, and the mixture was stirred at 80° C. for 5 hours. Water was added thereto to dissolve lithium carbonate and deposited crystals were collected by filtration. The collected crude crystals were dissolved in chloroform, washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate, followed by evaporation under reduced pressure. The residue was purified by silica gel column chromatography (eluent:chloroform) to give 162 mg (yield 31%) of Compound 63 as yellow grains.
Reaction SMILES: [F-].[K+].[N+:3]([CH:6]([CH3:8])[CH3:7])([O-:5])=[O:4].[C:9]([O:13][CH3:14])(=[O:12])[CH:10]=[CH2:11]>C(O)C>[CH3:7][C:6]([N+:3]([O-:5])=[O:4])([CH3:8])[CH2:11][CH2:10][C:9]([O:13][CH3:14])=[O:12]
Reactant: CC(C)[N+](=O)[O-]
Reactant: C=CC(=O)OC
Agent: [F-]
Agent: [K+]
Solvent: CCO
Product: COC(=O)CCC(C)(C)[N+](=O)[O-]

Procedure:
A catalytic amount of potassium fluoride is added to 2-nitropropane and methyl acrylate, and the mixture is refluxed under heating in a suitable solvent such as ethanol and the like. The reaction mixture is concentrated (or evaporated) and extracted to give methyl 4-methyl-4-nitropentanoate (Bulletin of the Chemical Society of Japan 1966, 39 (11), 2549–2551). The obtained methyl 4-methyl-4-nitropentanoate can be isolated and/or purified by a conventional method, such as distillation, chromatography and the like, but generally, can be used in the next step without isolation and/or purification.