Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([NH:7][C:8]([N:10]=[N+:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH2:12]2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[BH4-].[Na+].Cl>C(O)C.O>[C:1]1([NH:7][C:8]([NH:10][N:11]2[CH2:12][CH:13]=[CH:14][CH2:15][CH2:16]2)=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(N=[N+]1C=CC=CC1)Nc1ccccc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: O=C(Nc1ccccc1)NN1CC=CCC1
Reaction time: 4 h

Procedure:
To a solution of N-(phenylcarbamoylimino)pyridinium ylide (0.64 g) in a mixture of ethanol (30 ml) and water (10 ml) was added sodium borohydride (0.20 g) at ambient temperature. After being stirred for 4 hours, the reaction mixture was acidified with 1N hydrochloric acid, concentrated to a volume of ca. 15 ml. The crystalline precipitate was collected, washed with water and dried in vacuo. The crude product was dissolved in ethyl acetate and extracted with 10% hydrochloric acid (20 ml). The extract was adjusted to pH 3 with aqueous sodium bicarbonate and extracted with ethyl acetate (30 ml). The organic layer was washed with aqueous sodium bicarbonate (10 ml), dried over magnesium sulfate and evaporated to give N-(phenylcarbamoylamino)-1,2,3,6-tetrahydropyridine (0.28 g), which was recrystallized from ethyl acetate to afford colorless needles (0.15 g). mp: 157°-159° C.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Br)=[CH:4][CH:3]=1.C(OP(OCC)OCC)C.[H-].[Na+].[Br:22][C:23]1[CH:30]=[CH:29][C:26]([CH:27]=O)=[CH:25][CH:24]=1>CN(C=O)C>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[CH:27][C:26]2[CH:29]=[CH:30][C:23]([Br:22])=[CH:24][CH:25]=2)=[CH:4][CH:3]=1
Reactant: BrCc1ccc(Br)cc1
Reactant: O=Cc1ccc(Br)cc1
Agent: CCOP(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Brc1ccc(C=Cc2ccc(Br)cc2)cc1
Temperature: 150 °C
Reaction time: 4 h
Yield: 65 %

Procedure:
47 g (0.188 mol) of 4-bromobenzylbromide and 37.5 g (0.224 mol) of check triethylphosphite were put into a 500 ml 3-neck round-bottom flask equipped with a stirrer, a thermometer and a reflux condenser under an argon atmosphere, and the resulting mixture was stirred at 150° C. for 4 hours. The temperature was dropped to room temperature, and 250 ml of anhydrous DMF was added. After an ice bath was installed, 11.28 g (0.282 mol) of sodium hydride (60%) was slowly added and the resultant was stirred for 30 minutes. After 33.7 g (0.182 mol) of 4-bromobenzaldehyde was slowly added, ice bath was removed, and then the reaction mixture was stirred at room temperature for 12 hours. The reaction mixture was poured into cold water to give solid. This solid was filtered, thoroughly washed with water and methanol, dried and then recrystallized, to obtain white crystal, which was sufficiently dried in a vacuum oven at 40° C. to give 40 g (yield: 63%) of the desired product, and its melting point was 212° C.–213° C.
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]3[CH:18]=[CH:17][C:14]([CH:15]=[O:16])=[CH:13][CH:12]=3)[N:10]=2)[CH:7]=1.C1(C)C=CC(S([CH2:28][N+:29]#[C-:30])(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+]>CO>[I:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([C:11]3[CH:18]=[CH:17][C:14]([C:15]4[O:16][CH:30]=[N:29][CH:28]=4)=[CH:13][CH:12]=3)[N:10]=2)[CH:7]=1
Reactant: O=Cc1ccc(-c2cn3cc(I)ccc3n2)cc1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: Ic1ccc2nc(-c3ccc(-c4cnco4)cc3)cn2c1
Yield: 45.9 %

Procedure:
4-(6-Iodoimidazo[1,2-a]pyridin-2-yl)benzaldehyde (647 mg) and p-toluenesulfonylmethyl isocyanide (454 mg) were dissolved in methanol (10 mL), and potassium carbonate (321 mg) was added to the solution at room temperature, followed by refluxing for 13 hours. The precipitated product was recovered through filtration and dried, to thereby yield the title compound (330 mg).
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([Cl:11])[CH:9]=2)[N:4]([CH3:12])[N:3]=1.[N:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1.C(Cl)Cl.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:11][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[N:4]([CH3:12])[N:3]=[C:2]2[C:16]1[CH:17]=[CH:18][N:13]=[CH:14][CH:15]=1
Reactant: Cn1nc(Br)c2cc(Cl)ccc21
Reactant: OB(O)c1ccncc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: ClCCl
Product: Cn1nc(-c2ccncc2)c2cc(Cl)ccc21
Temperature: 90 °C
Reaction time: 14 h

Procedure:
To a pressure flask was added 3-bromo-5-chloro-1-methyl-1H-indazole (0.737 g, 3 mmol), pyridine-4-boronic acid (0.996 g, 8.1 mmol), PdCl2(dppf).DCM (0.490 g, 0.6 mmol), and K3PO4 (3.184 g, 15 mmol). The flask was flushed with argon for 5 minutes, then dry DME (15 mL) was added and the flask sealed under argon. The reaction was then heated to 90° C. for 4 hours. Additional PdCl2(dppf).DCM (0.245 g, 0.3 mmol) and pyridine-4-boronic acid (0.370 g, 3 mmol) were added, and heating was continued for another 14 h at 90° C. After cooling to room temperature, the crude reaction was filtered over a plug of Celite, concentrated, dissolved in DCM, and purified by column chromatography (gradient 0 to 75% EtOAc/hexanes) to afford the product. 1H NMR (400 MHz, CDCl3) δ 8.73 (d, J=6.0 Hz, 2H), 8.02 (d, J=0.6 Hz, 1H), 7.87 (d, J=6.1 Hz, 2H), 7.53-7.32 (m, 2H), 4.15 (s, 3H).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[CH3:5][O:6][C:7](=[O:22])[C:8]([C@H:11]1[CH2:16][CH2:15][C@@H:14](OS(C)(=O)=O)[CH2:13][CH2:12]1)([CH3:10])[CH3:9]>CN(C)C=O.O>[CH3:5][O:6][C:7](=[O:22])[C:8]([C@H:11]1[CH2:12][CH2:13][C@H:14]([N:1]=[N+:2]=[N-:3])[CH2:15][CH2:16]1)([CH3:10])[CH3:9]
Reactant: [N-]=[N+]=[N-]
Reactant: COC(=O)C(C)(C)[C@H]1CC[C@@H](OS(C)(=O)=O)CC1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C(C)(C)[C@H]1CC[C@H](N=[N+]=[N-])CC1
Temperature: 100 °C

Procedure:
Sodium azide (0.761 g) is added to a solution of 0.898 g of cis-2-(4-methanesulfonyloxy-cyclohexyl)-2-methyl-propionic acid methyl ester in 7 ml of N,N-dimethylformamide. The reaction mixture is warmed to 100° C. for 16 hours. The mixture is cooled to room temperature, diluted with 20 ml of water and extracted with tert-butyl methyl ether (3×30 ml). The combined organic phases are washed with brine (20 ml), dried over sodium sulphate and concentrated by evaporation. The title compound is identified from the residue by means of flash chromatography (SiO2 60F) based on its Rf value.
Reaction SMILES: BrC1C(O)=C(C(CS(C2C=CC=C(Cl)C=2)(=O)=O)=CC=1)C(OC)=O.[C:24]1([S:30]([CH2:33][C:34]2[C:39]([C:40]([O:42][CH3:43])=[O:41])=[C:38]([O:44]C)[C:37]([CH2:46][CH3:47])=[CH:36][CH:35]=2)(=[O:32])=[O:31])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[C:24]1([S:30]([CH2:33][C:34]2[C:39]([C:40]([O:42][CH3:43])=[O:41])=[C:38]([OH:44])[C:37]([CH2:46][CH3:47])=[CH:36][CH:35]=2)(=[O:32])=[O:31])[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CCc1ccc(CS(=O)(=O)c2ccccc2)c(C(=O)OC)c1OC
Agent: COC(=O)c1c(CS(=O)(=O)c2cccc(Cl)c2)ccc(Br)c1O
Product: CCc1ccc(CS(=O)(=O)c2ccccc2)c(C(=O)OC)c1O

Procedure:
Prepared by proceeding in a similar manner to Intermediate 54, starting from methyl 6-(benzenesulphonylmethyl)-3-ethyl-2-methoxybenzoate (Intermediate 111).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([CH3:12])[C:5]([C:6]([O:8]C)=O)=[C:4]([I:13])[CH:3]=1.BrN1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C(N(CC)CC)C.[F:47][C:48]1([F:61])[CH2:53][CH2:52][CH:51]([N:54]2[CH2:59][CH2:58][CH:57]([NH2:60])[CH2:56][CH2:55]2)[CH2:50][CH2:49]1>C(OC)(=O)C(C)(C)C.ClCCl.ClCCl.C(O)C>[F:61][C:48]1([F:47])[CH2:53][CH2:52][CH:51]([N:54]2[CH2:55][CH2:56][CH:57]([N:60]3[CH2:12][C:10]4[C:5](=[C:4]([I:13])[CH:3]=[C:2]([Cl:1])[CH:11]=4)[C:6]3=[O:8])[CH2:58][CH2:59]2)[CH2:50][CH2:49]1
Reactant: NC1CCN(C2CCC(F)(F)CC2)CC1
Reactant: COC(=O)c1c(C)cc(Cl)cc1I
Agent: COC(=O)C(C)(C)C
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Agent: O=C1CCC(=O)N1Br
Solvent: CCO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1c2c(I)cc(Cl)cc2CN1C1CCN(C2CCC(F)(F)CC2)CC1
Temperature: 85 °C
Reaction time: 3 h
Yield: 46.9 %

Procedure:
To a solution of methyl 4-chloro-2-iodo-6-methylbenzoate (175 mg, 0.56 mmol) in methyl pivalate (1 mL), N-bromosuccinimide (120 mg, 0.67 mmol) and benzoylperoxide (14 mg, 0.06 mmol) were added. The reaction mixture was stirred at 85° C. under nitrogen atmosphere for 3 hours. Additional N-bromosuccinimide (60 mg) and benzoylperoxide (7 mg) were added and stirring continued for 1 hour. Crude was filtered on Gooch and washed with toluene. Volatiles were evaporated and the residue was dissolved in acetonitrile (2 mL). Triethylamine (0.28 mL, 2 mmol) and 1-(4,4-difluorocyclohexyl)-piperidin-4-ylamine (110 mg, 0.5 mmol) were added and the reaction mixture was stirred at 90° C. for 4 hours. Crude was diluted with dichloromethane and washed with 15% ammonium hydroxide. Organic phase was dried over sodium sulfate, filtered and evaporated. Column chromatography (dichloromethane/ethanol:97/3) afforded title compound (116 mg, 45% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]3[CH:15]=[N:16][N:17]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[C:11]=3[N:10]=[C:9]2[C:24]2[CH:29]=[CH:28][C:27](B3OC(C)(C)C(C)(C)O3)=[CH:26][CH:25]=2)=[CH:4][CH:3]=1.[NH2:39][C:40]1[CH:45]=[CH:44][C:43](Br)=[CH:42][N:41]=1.C([O-])([O-])=O.[Cs+].[Cs+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[NH2:39][C:40]1[N:41]=[CH:42][C:43]([C:27]2[CH:28]=[CH:29][C:24]([C:9]3[N:8]([C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=4)[C:13](=[O:14])[C:12]4[CH:15]=[N:16][N:17]([C:18]5[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=5)[C:11]=4[N:10]=3)=[CH:25][CH:26]=2)=[CH:44][CH:45]=1
Reactant: Nc1ccc(Br)cn1
Reactant: CC1(C)OB(c2ccc(-c3nc4c(cnn4-c4ccccc4)c(=O)n3-c3ccc(Cl)cc3)cc2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Product: Nc1ccc(-c2ccc(-c3nc4c(cnn4-c4ccccc4)c(=O)n3-c3ccc(Cl)cc3)cc2)cn1
Temperature: 100 °C
Yield: 52.2 %

Procedure:
A reaction tube charged with 5-(4-chloro-phenyl)-1-phenyl-6-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one (500.0 mg, 0.953 mmol), 2-amino-5-bromopyridine (247.3 mg, 1.43 mmol), Cs2CO3 (620.8 mg, 1.91 mmol), and Pd(dppf)2Cl2 (38.9 mg, 0.048 mmol) is purged with nitrogen. Anhydrous DMF (9.5 mL) is added via syringe. The reaction mixture is heated at 100° C. for overnight, cooled down to room temperature, then taken in H2O (100 mL) and ethyl acetate (50 mL). The insoluble solid is filtered off and the two layers of the filtrate are separated. The aqueous layer is extracted with ethyl acetate (2×50 mL). The combined organic phase is washed with brine, dried over MgSO4, concentrated, and purified by reverse phase HPLC to provide 6-[4-(6-amino-pyridin-3-yl)-phenyl]-5-(4-chloro-phenyl)-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one (244.2 mg, 52% yield) as a light yellow solid product; 1H NMR (CDCl3, 400 MHz) δ 8.33 (s, 1H), 8.28 (d, 1H), 8.16 (d, 2H), 7.66 (dd, 1H), 7.51 (t, 2H), 7.40 (m, 4H), 7.35 (m, 3H), 7.13 (d, 2H), 6.59 (d, 1H), 4.72 (br, 2H); HPLC-MS calculated for C28H19ClN6O (M+H+) 491.1. Found 491.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10]([C:12]([OH:14])=[O:13])=[CH:9][C:8](=O)[C:7]=2[CH:16]=1.[H][H]>[Pd].C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:11][CH:10]([C:12]([OH:14])=[O:13])[CH2:9][CH2:8][C:7]=2[CH:16]=1
Reactant: [H][H]
Reactant: COc1ccc2oc(C(=O)O)cc(=O)c2c1
Agent: [Pd]
Solvent: CC(=O)O
Product: COc1ccc2c(c1)CCC(C(=O)O)O2
Yield: 84.2 %

Procedure:
A mixture of 61 parts of 6-methoxy-4-oxo-4H-1-benzopyran-2-carboxylic acid and 500 parts of acetic acid was hydrogenated at normal pressure and at room temperature with 5 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated. The residue was stirred in petroleumether. The product was filtered off and dried in vacuo at about 65° C., yielding 49.1 parts (84.2%) of 3,4-dihydro-6-methoxy-2H-1-benzopyran-2-carboxylic acid; mp. 140° C. (intermediate 13).
Reaction SMILES: [CH3:1][CH:2]1[CH2:8][C:7]2[CH:9]=[C:10]3[O:15][CH2:14][O:13][C:11]3=[CH:12][C:6]=2[C:5]([C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=2)=[N:4][N:3]1[C:25](=[S:28])[NH:26][NH2:27].C(Cl)(Cl)Cl.[CH3:33][N:34]=[C:35]=[O:36]>>[CH3:1][CH:2]1[CH2:8][C:7]2[CH:9]=[C:10]3[O:15][CH2:14][O:13][C:11]3=[CH:12][C:6]=2[C:5]([C:16]2[CH:17]=[CH:18][C:19]([N+:22]([O-:24])=[O:23])=[CH:20][CH:21]=2)=[N:4][N:3]1[C:25]([NH:26][NH:27][C:35]([NH:34][CH3:33])=[O:36])=[S:28]
Reactant: CC1Cc2cc3c(cc2C(c2ccc([N+](=O)[O-])cc2)=NN1C(=S)NN)OCO3
Reactant: CN=C=O
Solvent: ClC(Cl)Cl
Product: CNC(=O)NNC(=S)N1N=C(c2ccc([N+](=O)[O-])cc2)c2cc3c(cc2CC1C)OCO3
Yield: 88 %

Procedure:
To a stirred solution of 0.40 g (1.0 mmol) of compound XVIII in 15 ml of chloroform 0.07 ml (1.2 mmol) of methyl isocyanate was added. After 1 h the reaction mixture was washed with sodium hydrogen carbonate solution and water and after concentration the obtained solid material was purified by refluxing in ethanol. The desired product was 0.36 g, yield: 88%. Mp.: 200° C.
Reaction SMILES: [Li]CCCC.Br[C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=1.[Sn:17](Cl)([CH2:26][CH2:27][CH2:28][CH3:29])([CH2:22][CH2:23][CH2:24][CH3:25])[CH2:18][CH2:19][CH2:20][CH3:21]>>[CH2:26]([Sn:17]([CH2:18][CH2:19][CH2:20][CH3:21])([CH2:22][CH2:23][CH2:24][CH3:25])[C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=1)[CH2:27][CH2:28][CH3:29]
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: Brc1ccc2ccccc2c1
Agent: [Li]CCCC
Product: CCCC[Sn](CCCC)(CCCC)c1ccc2ccccc2c1

Procedure:
2.5 M of n-BuLi (1.9 mL/hexane, 4.83 mmol) was added to 2-bromonaphthalene (1 g, 4.83 mmol/THF (20 mL)) and reacted at −78° C. for 40 minutes under a dry and anaerobic operation condition to form a solution. SnBu3Cl (1.5 mL, 5.31 mmol) was then added to the solution and reacted at −78° C. for 1 hour. After returning to room temperature, the solution was continuously reacted for 8 hours. After the reaction was completed, the solution was extracted by ether (30 mL) and deionized water (50 mL). An organic phase was collected. After removal of ether by a rotary concentrator, the organic phase was purified by reduced-pressure distillation to form a transparent pale yellow oily product (22, 1.68 g, 83%).
Reaction SMILES: CO[CH:3]=[C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7](=[O:14])[NH:6][C:5]1=[O:15].[N:16]1([CH2:21][CH2:22][C:23]2[CH:24]=[C:25]([NH2:29])[CH:26]=[CH:27][CH:28]=2)[CH2:20][CH2:19][CH2:18][CH2:17]1>CN(C)C=O>[N:16]1([CH2:21][CH2:22][C:23]2[CH:24]=[C:25]([NH:29]/[CH:3]=[C:4]3\[C:5](=[O:15])[NH:6][C:7](=[O:14])[C:8]4[C:13]\3=[CH:12][CH:11]=[CH:10][CH:9]=4)[CH:26]=[CH:27][CH:28]=2)[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: COC=C1C(=O)NC(=O)c2ccccc21
Reactant: Nc1cccc(CCN2CCCC2)c1
Solvent: CN(C)C=O
Product: O=C1NC(=O)c2ccccc2/C1=C/Nc1cccc(CCN2CCCC2)c1
Yield: 92.2 %

Procedure:
Prepared from a solution of 0.256 g (1.26 mmol) of 4-methoxymethylene-4H-isoquinoline-1,3-dione and 0.240 g (1.26 mmol) of 3-(2-pyrrolidin-1-yl-ethyl)-phenylamine in 4 mL of N,N-dimethylformamide (DMF) at 100° C. under N2 as described for example 21. After heating for 1 h, solvent is removed and the residue is filtered through Magnesol (20% MeOH in CHCl3). Solvent evaporation gave 0.420 g (92%) of a red glass: 1H NMR (DMSO-d6) δ 12.40 (d, 1H, J=9.0 Hz), 11.33 (s, 1H), 8.90 (d, 1H, J=9.0 Hz), 8.17 (d, 1H, J=6.0 Hz), 8.03 (d, 1H, J=6.0 Hz), 7.62 (m, 1H), 7.46 (s, 1H), 7.30 (m, 3H), 7.04 (d, 1H, J=6.0 Hz), 2.70 (m, 4H), 2.50 (m, 4H), 1.67 (m, 4H); HRMS (ESI) m/z calcd for C22H23N3O2 362.18631. found 362.18574 (M+H)−1; Analysis for C22H23N3O2.0.75H2O; Calcd: C, 70.46; H, 6.60; N, 11.21. Found: C, 70.83; 6.61; N, 11.24.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH2:8])[N:5]=[C:4]([N:9]([CH3:19])[C@H:10]([CH3:18])[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:3]=1.[F:20][C:21]1[CH:28]=[C:27](B2OC(C)(C)C(C)(C)O2)[CH:26]=[CH:25][C:22]=1[C:23]#[N:24].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.C1C=CC([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)=CC=1>[NH2:8][C:6]1[N:7]=[C:2]([C:27]2[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[C:21]([F:20])[CH:28]=2)[CH:3]=[C:4]([N:9]([CH3:19])[C@H:10]([CH3:18])[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:5]=1
Reactant: C[C@H](Cc1ccccc1)N(C)c1cc(Cl)nc(N)n1
Reactant: CC1(C)OB(c2ccc(C#N)c(F)c2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: C[C@H](Cc1ccccc1)N(C)c1cc(-c2ccc(C#N)c(F)c2)nc(N)n1
Temperature: 140 °C
Reaction time: 0.67 h
Yield: 80.1 %

Procedure:
To a mixture of 6-chloro-N4-methyl-N4-[(1R)-1-methyl-2-phenylethyl]-2,4-pyrimidinediamine (0.4 g, 1.45 mmol), 2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (0.46 g, 1.88 mmol) and Na2CO3 (0.38 g, 3.63 mmol) in 1,4-dioxane (6 mL) and water (3 mL) was added Pd(PPh3)4 (16 mg, 0.015 mmol), the reaction mixture was heated at 140° C. under microwave conditions with stirring for 40 minutes. The mixture was filtered and concentrated, and the resulting residue was purified by reverse phase chromatography using CH3CN in water from 45% to 55% (0.5% ammonium hydrogen carbonate in water) to afford the title compound (0.42 g) as a yellow solid. LC-MS (ES) m/z=362 [M+H]+.
Reaction SMILES: C([O:8][C:9]1[CH:36]=[CH:35][C:34]([CH2:37][CH2:38][N:39]2[CH2:44][CH2:43][N:42]([CH2:45][CH3:46])[CH2:41][CH2:40]2)=[CH:33][C:10]=1[C:11]([NH:13][C:14]1[CH:26]=[C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:24]=[CH:23][C:15]=1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[O:12])C1C=CC=CC=1>CO.C(OCC)(=O)C.[C].[Pd]>[CH2:45]([N:42]1[CH2:41][CH2:40][N:39]([CH2:38][CH2:37][C:34]2[CH:35]=[CH:36][C:9]([OH:8])=[C:10]([CH:33]=2)[C:11]([NH:13][C:14]2[CH:26]=[C:25]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH:24]=[CH:23][C:15]=2[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[O:12])[CH2:44][CH2:43]1)[CH3:46]
Reactant: CCN1CCN(CCc2ccc(OCc3ccccc3)c(C(=O)Nc3cc(-c4ccccc4)ccc3C(=O)OC(C)(C)C)c2)CC1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CCN1CCN(CCc2ccc(O)c(C(=O)Nc3cc(-c4ccccc4)ccc3C(=O)OC(C)(C)C)c2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88.7 %

Procedure:
To a solution mixture of the obtained tert-butyl 2-(2-(benzyloxy)-5-(2-(4-ethylpiperazin-1-yl)ethyl)benzamido)-4-phenylbenzoate (0.062 g) in methanol (1.5 mL) and ethyl acetate (1.5 mL), 10% palladium-carbon (0.062 g) was added, followed by stirring under a hydrogen atmosphere at room temperature for 2 hours and 30 minutes. The insoluble substance was removed by filtration, and the solvent was evaporated under reduced pressure to obtain 0.047 g of tert-butyl 2-(5-(2-(4-ethylpiperazin-1-yl)ethyl)-2-hydroxybenzamido)-4-phenylbenzoate.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:4]=1[CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([CH:12]=O)[CH2:8][CH2:7]1.[O:24]1[CH:28]=[CH:27][C:26]([CH2:29][NH:30][C:31]2[CH2:35][S:34][C:33](=[O:36])[N:32]=2)=[N:25]1.C([O-])(=O)C.[NH2+]1CCCCC1>CC(O)C>[F:1][C:2]([F:23])([F:22])[C:3]1[CH:17]=[C:16]([C:18]([F:19])([F:21])[F:20])[CH:15]=[CH:14][C:4]=1[CH2:5][N:6]1[CH2:11][CH2:10][CH:9](/[CH:12]=[C:35]2/[C:31]([NH:30][CH2:29][C:26]3[CH:27]=[CH:28][O:24][N:25]=3)=[N:32][C:33](=[O:36])[S:34]/2)[CH2:8][CH2:7]1
Reactant: O=C1N=C(NCc2ccon2)CS1
Reactant: O=CC1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Agent: C1CC[NH2+]CC1
Agent: CC(=O)[O-]
Solvent: CC(C)O
Product: O=C1N=C(NCc2ccon2)/C(=C/C2CCN(Cc3ccc(C(F)(F)F)cc3C(F)(F)F)CC2)S1
Temperature: 80 °C
Reaction time: 8 h
Yield: 71.9 %

Procedure:
To a solution of 1-[2,4-bis(trifluoromethyl)benzyl]piperidine-4-carbaldehyde (413 mg) in 2-propanol (5 mL) were added 4-[(isoxazol-3-ylmethyl)amino]thiazol-2(5H)-one (480 mg) and piperidinium acetate (90 mg). The reaction mixture was stirred at 80° C. overnight, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) and recrystallized from ethyl acetate/heptane to give the title compound (454 mg).
Reaction SMILES: CC1(C)C(C)(C)[O:5][B:4]([C:9]2[CH:13]=[CH:12][S:11][C:10]=2[CH3:14])[O:3]1.CC(C)=O>O>[CH3:14][C:10]1[S:11][CH:12]=[CH:13][C:9]=1[B:4]([OH:5])[OH:3]
Reactant: Cc1sccc1B1OC(C)(C)C(C)(C)O1
Solvent: O
Solvent: CC(C)=O
Product: Cc1sccc1B(O)O
Temperature: 25 °C
Reaction time: 24 h
Yield: 81 %

Procedure:
To a solution of 4,4,5,5-tetramethyl-2-(2-methyl-thiophen-3-yl)-[1,3,2]dioxaborolane (1.52 g, 6.78 mmol), acetone (15 mL) and water (15 mL) is added NaIO4 (2.90 g, 13.56 mmol). The solution is stirred at ambient temperature for 24 hours, then heated to a reflux for 24 hours. The solution is concentrated dissolved in EtOAc (1450 mL), washed with water (100 mL), dried over MgSO4, filtered and concentrated to furnish the title compound (0.75 g, 5.49 mmol, 78%). 1H NMR (CDCl3), δ 2.93 (s, 3H), 7.10 (d, J=5.3 Hz, 1H), 7.51 (d, 5.3 Hz, 1H).
Reaction SMILES: I[C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][C:3]=1[N+]([O-])=O>C(#N)C>[C:6]([NH2:8])(=[O:7])[C:5]1[CH:9]=[CH:10][CH:2]=[CH:3][CH:4]=1
Reactant: NC(=O)c1ccc(I)c([N+](=O)[O-])c1
Solvent: CC#N
Product: NC(=O)c1ccccc1
Reaction time: 0.5 h

Procedure:
Plasma samples were obtained from dog, rat and mouse studies, in which animals were administered 4-iodo-3-nitrobenzamide (BA). Plasma and tumor samples were prepared for HPLC injection by precipitating plasma (50 μl) with 3× volumes (150 μl) of acetonitrile. Tissue samples were prepared for HPLC injection by adding 1 μl of acetonitrile per mg of tissue, then homogenizing with an electric homogenizer. Following centrifugation, 150 μl of each supernatant was evaporated to dryness, reconstituted in 50 μl of 0.2% formic acid in water and analyzed by chromatography and mass spectrometry techniques (LC/MS/MS conditions). LC/MS/MS conditions are: HPLC (Shimadzu VP System); Mobile Phase: 0.2% formic acid in water (A) and 0.18% formic acid in methanol (B); Column: 1×50 mm Thermo BetaBasic C18 column; Injection volume: 25 μL; Gradient: 0-60% B in 30 minutes; Flow Rate: 100 μL/min; Mass Spectrometer: Applied Biosystems/MDS SCIEX Q-STAR; Interface: IonSpray split at 1/10; Parent Ion Scan: TOF Positive from 200-900 amu; Product Ion Scan: TOF Product Ion from 60-900 amu of most intense Ion in Parent Ion Scan; TOF calibration: Externally calibrated using Renin Substrate. Results of metabolite identification from dog and mouse plasma are depicted in Tables 1-3, as follows:
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][N:7]1[C:12]([CH3:13])=[C:11]([C:14]([OH:16])=[O:15])[CH:10]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-:25])=[O:24])[CH:18]=2)[C:9]([C:26]([O:28][CH3:29])=[O:27])=[C:8]1[CH3:30].C=C[C@@H]1[C@@H]2C[C@@H]([C@H](O)C3C=CN=C4C=CC=CC=34)N(CC2)C1>CCO>[CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][N:7]1[C:12]([CH3:13])=[C:11]([C:14]([OH:16])=[O:15])[C@@H:10]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-:25])=[O:24])[CH:18]=2)[C:9]([C:26]([O:28][CH3:29])=[O:27])=[C:8]1[CH3:30]
Reactant: COCCOCN1C(C)=C(C(=O)O)C(c2cccc([N+](=O)[O-])c2)C(C(=O)OC)=C1C
Agent: C=C[C@H]1CN2CC[C@H]1C[C@H]2[C@H](O)c1ccnc2ccccc12
Solvent: CCO
Product: COCCOCN1C(C)=C(C(=O)O)[C@@H](c2cccc([N+](=O)[O-])c2)C(C(=O)OC)=C1C
Reaction time: 8 h

Procedure:
The racemic N-protected mono-ester of formula 18 is then dissolved in a suitable lower alkanol solvent at about the solvent reflux temperature along with a suitable optically active base, and the resulting salt allowed to crystallize as the solution cools to provide the optically resolved salt of either the (R)-18 or (S)-18. (It is preferred to recrystallize the resulting optically active salt to obtain a higher degree of purity.) For example, (RS)-1-(2-methoxyethoxy)methyl-2,6-dimethyl-3-carbomethoxy-4-(3-nitrophenyl)-5-carboxy-1,4-dihydropyridine is dissolved in EtOH at reflux temperature along with one molar equivalent of cinchonidine, and the mixture allowed to stand at room temperature overnight. The resulting crystals are recrystallized twice from EtOH to yield the pure (R)-18 salt, (R)-1-(2-methoxyethoxy)methyl-2,6-dimethyl-3-carbomethoxy-4-(3-nitrophenyl)-5-carboxy-1,4-dihydropyridine.cinchonidine. (Scheme VI, Step 3)