Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3]([O:28][CH3:29])=[C:4]([CH:10]([NH:12][C:13]2[N:21]=[CH:20][N:19]=[C:18]3[C:14]=2[N:15]=[CH:16][N:17]3C2CCCCO2)[CH3:11])[CH:5]=[C:6]([Cl:9])[C:7]=1[F:8].CC1(C)C(C)(C)OB([C:38]2[CH2:39][CH2:40][N:41]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:42][CH:43]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>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.O1CCOCC1>[Cl:9][C:6]1[C:7]([F:8])=[C:2]([C:38]2[CH2:43][CH2:42][N:41]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:40][CH:39]=2)[C:3]([O:28][CH3:29])=[C:4]([CH:10]([NH:12][C:13]2[N:21]=[CH:20][N:19]=[C:18]3[C:14]=2[N:15]=[CH:16][NH:17]3)[CH3:11])[CH:5]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: COc1c(C(C)Nc2ncnc3c2ncn3C2CCCCO2)cc(Cl)c(F)c1Br
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
Product: COc1c(C(C)Nc2ncnc3[nH]cnc23)cc(Cl)c(F)c1C1=CCN(C(=O)OC(C)(C)C)CC1
Temperature: 90 °C
Yield: 55 %

Procedure:
Into a microwave vial was added N-[1-(3-bromo-5-chloro-4-fluoro-2-methoxyphenyl)ethyl]-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine (85 mg, 0.17 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (65 mg, 0.21 mmol, Aldrich #706531), sodium carbonate (420 μL, 0.44 mmol), 1,4-dioxane (1 mL) and tetrakis(triphenylphosphine)palladium(0) (12 mg, 0.010 mmol). The mixture was bubbled with nitrogen for 5 min and heated at 90° C. overnight. The mixture was diluted with water, extracted with EtOAc, dried over magnesium sulfate and concentrated. Purification on silica gel using 0-100% EtOAc in hexane gave the desired compound (47 mg, 46%). LCMS calculated for C29H37ClFN6O4 (M+H)+: m/z=586.3. found: 587.2.
Reaction SMILES: O.O.Cl[Sn]Cl.[CH3:6][O:7][C:8]1[CH:9]=[C:10]([C:16]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([N+:28]([O-])=O)[CH:21]=2)=[CH:17]C#N)[CH:11]=[C:12]([O:14][CH3:15])[CH:13]=1.[OH-].[Na+]>C(O)C.C(OCC)(=O)C>[CH3:6][O:7][C:8]1[CH:9]=[C:10]([C:16]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[C:22]([NH2:28])[CH:21]=2)=[CH2:17])[CH:11]=[C:12]([O:14][CH3:15])[CH:13]=1
Reactant: COc1cc(OC)cc(C(=CC#N)c2ccc(OC)c([N+](=O)[O-])c2)c1
Agent: Cl[Sn]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: CCOC(C)=O
Product: C=C(c1cc(OC)cc(OC)c1)c1ccc(OC)c(N)c1
Temperature: 70 °C
Yield: 63.2 %

Procedure:
SnCl2.2H2O (4.41 g, 19.54 mmol) was added to a stirred suspension of 3-(3,5-dimethoxy-phenyl)-3-(4-methoxy-3-nitro-phenyl)-acrylonitrile (1.12 g, 3.55 mmol) in ethanol (200 proof, 20 mL) and ethyl acetate (10 mL). The reaction mixture was heated at 70° C. for 1 h. The solution was cooled down to room temperature, poured into ice water (100 mL), and basified with 10 N NaOH (20 mL) to pH ˜12. The aqueous layer was extracted with ethyl acetate (5×35 mL). The combined organic layers were washed with water (60 mL), brine (50 mL) and dried (MgSO4). Removal of solvent and chromatography (Silica Gel) gave 5-[1-(3,5-dimethoxy-phenyl)-vinyl]-2-methoxy-phenylamine as a solid (0.64 g, 63% yield): mp, 93-95° C.; 1H NMR (CDCl3) δ 3.77-3.87 (2s+m, 11H, 3OCH3+NH2), 5.31-5.37 (dd, J=1.2, 13.1 Hz, 2H, CH2), 6.43-6.73 (m, 6H, Ar); 13C NMR (CDCl3) δ 55.36, 55.53, 99.77, 106.69, 109.92, 112.80, 1.14.92, 118.62, 134.13, 135.63, 144.19, 147.21, 149.86, 160.40; Anal. Calcd for C17H19NO3: C, 71.56; H, 6.71; N, 4.91. Found: C, 71.31; H, 6.76; N, 4.92.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][CH:27]=1)[O:5][C:6]1[S:10][C:9]([CH2:11][NH:12][C:13]([C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[N:21]=[CH:20][CH:19]=[CH:18]3)=[O:14])=[CH:8][CH:7]=1.C(OCC)(=O)C.O.[CH3:35][N:36](C)C=O>[C-]#N.[Zn+2].[C-]#N.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>[C:35]([C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][CH:27]=1)[O:5][C:6]1[S:10][C:9]([CH2:11][NH:12][C:13]([C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[N:21]=[CH:20][CH:19]=[CH:18]3)=[O:14])=[CH:8][CH:7]=1)#[N:36]
Reactant: O=C(NCc1ccc(Oc2cccc(Br)c2)s1)c1ccc2ncccc2c1
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: O
Solvent: CCOC(C)=O
Product: N#Cc1cccc(Oc2ccc(CNC(=O)c3ccc4ncccc4c3)s2)c1
Temperature: 100 °C
Reaction time: 1 h
Yield: 21 %

Procedure:
Next, to a solution of the mixture of quinoline-6-carboxylic acid (5-(3-bromophenoxy)-thiophene-2ylmethyl)-amide and debrominated compound (130 mg, 0.303 mmol) in N,N-dimethylformamide (5.0 mL) were added zinc cyanide (71 mg, 0.605 mmol) and tetrakis(triphenylphosphine)palladium(0) (70 mg, 0.061 mmol) under nitrogen atmosphere, the solution was stirred at 100° C. for 1 hour, and the solution was stirred at 140° C. for 3 hours. The reaction solution was allowed to room temperature, ethyl acetate and water were added to the reaction solution, which was then partitioned, the organic layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was evaporated, then, the residue was purified by NH silica gel column chromatography (hexane:ethyl acetate), and title compound (25 mg, 21%) was obtained as a colorless oil.
Reaction SMILES: Cl[C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[S:4][N:3]=1.O.[CH2:12]([NH2:15])[CH2:13][NH2:14]>>[S:4]1[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:2]([NH:14][CH2:13][CH2:12][NH2:15])=[N:3]1
Reactant: NCCN
Reactant: Clc1nsc2ccccc12
Solvent: O
Product: NCCNc1nsc2ccccc12
Temperature: 80 °C

Procedure:
Ethylenediamine (45 mL) was heated to 80° C. A room temperature solution of 3-chlorobenzo[d]isothiazole (12 g, 70.7 mmol) in ethylenediamine (5 mL) was added to the heated ethylenediamine dropwise. The resulting solution was heated at 80° C. for 3 h. The reaction mixture was cooled to room temperature and water (75 mL) was added. The aqueous mixture was extracted with ethyl acetate twice and the ethyl acetate layers were separated. The combined organic layers were dried over anhydrous sodium sulfate, filtered and the filtrate concentrated under reduced pressure to yield N1-(benzo[d]isothiazol-3-yl)ethane-1,2-diamine as a light yellow solid (8 g).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[C:15]([F:16])=[CH:14][C:13]([F:17])=[CH:12][N:11]=2)[CH:5]=[CH:4][N:3]=1.C([O-])(=[O:20])C.[NH4+]>C(O)=O>[F:16][C:15]1[C:10]([CH2:9][O:8][C:6]2[CH:5]=[CH:4][NH:3][C:2](=[O:20])[CH:7]=2)=[N:11][CH:12]=[C:13]([F:17])[CH:14]=1
Reactant: CC(=O)[O-]
Reactant: Fc1cnc(COc2ccnc(Cl)c2)c(F)c1
Agent: [NH4+]
Solvent: O=CO
Product: O=c1cc(OCc2ncc(F)cc2F)cc[nH]1
Yield: 63.8 %

Procedure:
2-((2-Chloropyridin-4-yloxy)methyl)-3,5-difluoropyridine (3.42 g, 13.3 mmol) and ammonium acetate (20.5 g, 267 mmol) were heated to 110° C. in formic acid (45 mL) for 5 days. The mixture was concentrated to remove most of the liquid and then adjusted to pH 8 with saturated NaHCO3 solution. The solid was filtered off to provide the title compound (2.02 g, 63%) as a white solid: ESI MS m/z 239 [M+H]+.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[N:9]=[C:10]3[N:14]([CH:15]=2)[C:13]([CH2:16][N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[CH:12][S:11]3)=[CH:6][CH:5]=[CH:4][N:3]=1.BrC1C(C2N=C3N(C=2)C(CN2CCOCC2)=CS3)=CC=CN=1.[CH3:45][O:46][C:47]1[CH:54]=[CH:53][C:50]([CH2:51][NH2:52])=[CH:49][CH:48]=1>C1(C)C=CC=CC=1>[CH3:45][O:46][C:47]1[CH:54]=[CH:53][C:50]([CH2:51][NH:52][C:2]2[C:7]([C:8]3[N:9]=[C:10]4[N:14]([CH:15]=3)[C:13]([CH2:16][N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:12][S:11]4)=[CH:6][CH:5]=[CH:4][N:3]=2)=[CH:49][CH:48]=1
Reactant: COc1ccc(CN)cc1
Reactant: Clc1ncccc1-c1cn2c(CN3CCOCC3)csc2n1
Agent: Brc1ncccc1-c1cn2c(CN3CCOCC3)csc2n1
Solvent: Cc1ccccc1
Product: COc1ccc(CNc2ncccc2-c2cn3c(CN4CCOCC4)csc3n2)cc1
Temperature: 25 °C

Procedure:
The 1:1 mixture of 6-(2-Chloro-pyridin-3-yl)-3-morpholin-4-ylmethyl-imidazo[2,1-b]thiazole and 6-(2-bromo-pyridin-3-yl)-3-morpholin-4-ylmethyl-imidazo[2,1-b]thiazole (600 mg) was mixed with 15 mL of toluene along with 0.47 mL of 4-methoxybenzylamine and stirred under reflux for 5 days. The reaction mixture was cooled to room temperature and partitioned between CH2Cl2 and brine. The organic layer was separated, dried (Na2SO4) and concentrated to afford the crude product. Purification by chromatography (Isco, gradient elution, CH2Cl2 to 95% CH2Cl2, 4% MeOH and 1% Et3N) afforded 200 mg of (4-methoxy-benzyl)-[3-(3-morpholin-4-ylmethyl-imidazo[2,1-b]thiazol-6-yl)-pyridin-2-yl]-amine.
Reaction SMILES: [OH:1][C:2]1[CH:19]=[CH:18][C:17]2[C@@H:16]3[C@H:7]([C@H:8]4[C@@:12]([CH2:14][CH2:15]3)([CH3:13])[C:11](=[O:20])[CH2:10][CH2:9]4)[CH2:6][CH2:5][C:4]=2[CH:3]=1.[Si:21](Cl)([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22].N1C=CN=C1.O>ClCCl>[Si:21]([O:1][C:2]1[CH:19]=[CH:18][C:17]2[C@@H:16]3[C@H:7]([C@H:8]4[C@@:12]([CH2:14][CH2:15]3)([CH3:13])[C:11](=[O:20])[CH2:10][CH2:9]4)[CH2:6][CH2:5][C:4]=2[CH:3]=1)([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C[C@]12CC[C@@H]3c4ccc(O)cc4CC[C@H]3[C@@H]1CCC2=O
Agent: c1c[nH]cn1
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)[Si](C)(C)Oc1ccc2c(c1)CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Temperature: 25 °C
Reaction time: 24 h
Yield: 95 %

Procedure:
To a solution of 3-hydroxy-estra-1,3,5(10)-triene-17-one (100 g, 0.370 mole) in 500 ml of dichloromethane was added tert-butyldimethylsilyl-chloride (58.3 g, 0.388 mole) and imidazole (26.4 g, 0.388 mole). The mixture was stirred for 24 hours at room temperature. Water (300 ml) was added and the organic layer was washed with 200 ml of water. After concentration the product was crystallized from a mixture of ethanol/diisopropyl ether, collected by filtration and dried. It weighed 145 g (95% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:17][CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([O:18][CH3:19])[CH:14]=3)[CH:9]2[CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[CH:23][CH:22]=2)=[CH:4][CH:3]=1.[C:35](Cl)(=[O:37])[CH3:36]>C(Cl)Cl>[C:35]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:17][CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([O:18][CH3:19])[CH:14]=3)[CH:9]2[CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH2:28][C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)=[CH:23][CH:22]=2)=[CH:4][CH:3]=1)(=[O:37])[CH3:36]
Reactant: CC(=O)Cl
Reactant: COc1ccc2c(c1)CCN(c1ccc(N)cc1)C2Cc1ccc(OCc2ccccc2)cc1
Solvent: ClCCl
Product: COc1ccc2c(c1)CCN(c1ccc(NC(C)=O)cc1)C2Cc1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 86.1 %

Procedure:
A solution of 2-(4-aminophenyl)-6-methoxy-1-[4-(phenylmethoxy)benzyl]-1,2,3,4-tetrahydroisoquinoline (0.205 g, 0.46 mmol) and TEA (0.060 g, 0.6 mmol) in 1 mL of CH2Cl2 at 0° C. was treated with acetyl chloride (0.043 g, 0.55 mmol). The reaction mixture was warmed to room temperature and stirred for 3 hours. The reaction was quenched by the addition of saturated aqueous NaHCO3 (0.5 mL). The organic layer was separated and the aqueous layer was extracted with CH2Cl2 (3×2 mL). The combined organic layer was dried over MgSO4 then concentrated. The crude product was purified by column chromatography to provide the title compound (0.195 g, 87% yield). ES-MS, (m/z) 493 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][CH:13]=1)[O:6][CH2:7][C:8]([OH:10])=O)#[N:2].CCN(C(C)C)C(C)C.[NH2:23][CH2:24][CH:25]([OH:37])[CH2:26][N:27]1[CH2:36][CH2:35][C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:28]1>C(Cl)Cl>[C:1]([C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][CH:13]=1)[O:6][CH2:7][C:8]([NH:23][CH2:24][CH:25]([OH:37])[CH2:26][N:27]1[CH2:36][CH2:35][C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:28]1)=[O:10])#[N:2]
Reactant: NCC(O)CN1CCc2ccccc2C1
Reactant: N#Cc1cccc(OCC(=O)O)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: N#Cc1cccc(OCC(=O)NCC(O)CN2CCc3ccccc3C2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 11.6 %

Procedure:
To a stirred mixture of 2-(3-cyanophenoxy) acetic acid (100 mg, 0.565 mmol) in DCM (5 mL) was added DIEA (109 mg, 0.85 mmol), 1-amino-3-(3,4-dihydroisoquinolin-2(1H)-yl)propan-2-ol (116 mg, 0.565 mmol) and BopCl (173 mg, 0.678 mmol). The resulting mixture was stirred at 25° C. for 16 hours until LCMS showed the completion of the reaction. The reaction mixture was quenched by addition of water (20 mL) then extracted with DCM (3×20 mL). The combined organic extracts were washed with brine (20 mL), dried over anhydrous Na2SO4 and concentrated. The residue was purified by prep-HPLC to afford the desired final product (24 mg, Yield 12%). 1H NMR (400 MHz, METHANOL-d4) δ 7.48 (dd, J1=J2=7.6 Hz, 1H), 7.37 (d, J=7.6 Hz, 1H), 7.25-7.21 (m, 2H), 7.13-7.03 (m, 4H), 4.60 (s, 2H), 4.04-4.00 (m, 1H), 3.71 (s, 2H), 3.44 (d, J=6.0 Hz, 2H), 2.93-2.80 (m, 4H), 2.62 (d, J=5.6 Hz, 2H). LCMS (m/z): 366.1 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[C:12]([NH:19][CH2:20][C:21](O)=[O:22])([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:9][O:8][C:6](=[O:7])[C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:21](=[O:22])[CH2:20][NH:19][C:12]([O:14][C:15]([CH3:17])([CH3:16])[CH3:18])=[O:13])=[CH:11][CH:10]=1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: COC(=O)c1ccc(N)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(NC(=O)CNC(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 98.3 %

Procedure:
Methyl 4-amino-benzoate (3.58 g, 23.70 mmol) and N-Boc glycine (4.15 g, 23.70 mmol) were stirred in DMF (50 mL) at room temperature. BOP (11.52 g, 26.07 mmol) was added followed by the addition of DIEA (6.18 mL, 35.55 mmol). The resulting mixture was stirred at rt for 1.5 h. It was quenched with sat'd NaHCO3 and EtOAc. The organic layer was washed with H2O, brine (3×), dried (MgSO4), and concentrated to dryness to give 4-(2-tert-butoxycarbonylamino-acetylamino)-benzoic acid methyl ester (7.18 g, yield: 98%). 1H NMR (CDCl3) δ 9.16 (s, br, 1H), 7.96 (d, J=8.4 Hz, 2H), 7.65 (d, J=8.4 Hz, 2H), 3.98 (s, 2H), 3.89 (s, 3H), 1.45 (s, 9H) ppm.
Reaction SMILES: [CH3:1][NH:2][C:3]1[N:8]=[C:7]([C:9]2[C:10]([O:15][C:16]3[CH:21]=[CH:20][C:19](B4OC(C)(C)C(C)(C)O4)=[CH:18][CH:17]=3)=[N:11][CH:12]=[CH:13][CH:14]=2)[CH:6]=[CH:5][N:4]=1.[OH:31]O.O>CCO.C(Cl)Cl>[CH3:1][NH:2][C:3]1[N:8]=[C:7]([C:9]2[C:10]([O:15][C:16]3[CH:21]=[CH:20][C:19]([OH:31])=[CH:18][CH:17]=3)=[N:11][CH:12]=[CH:13][CH:14]=2)[CH:6]=[CH:5][N:4]=1
Reactant: OO
Reactant: CNc1nccc(-c2cccnc2Oc2ccc(B3OC(C)(C)C(C)(C)O3)cc2)n1
Solvent: CCO
Solvent: ClCCl
Solvent: O
Product: CNc1nccc(-c2cccnc2Oc2ccc(O)cc2)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of N-methyl-4-(2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)pyridin-3-yl)pyrimidin-2-amine (0.414 g, 1.02 mmol) in 2 mL EtOH at 0° C. was added hydrogen peroxide, 30 wt. % solution in water (0.984 ml, 10.2 mmol). The reaction was allowed to warm to ambient temperature. After 1 h, the reaction was diluted with DCM, and the layers were separated. The aqueous layer was extracted with 5% MeOH/DCM. The combined organics were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography, (EtOAc/hexanes) to give 4-(3-(2-(methylamino)pyrimidin-4-yl)pyridin-2-yloxy)phenol as a white solid. MS m/z=295 [M+H]+. Calc'd for C16H14N4O2: 294.3.
Reaction SMILES: [C:1]([CH:3]=[C:4]([NH:15][C:16](=[O:20])OCC)[C:5]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][CH:6]=1)#[N:2].[F:21][C:22]([F:28])([F:27])[C:23]([NH:25][NH2:26])=O.C(OCC)(=O)C.O>CN1C(=O)CCC1>[F:21][C:22]([F:28])([F:27])[C:23]1[N:2]=[C:1]2[N:26]([C:16]([OH:20])=[N:15][C:4]([C:5]3[CH:6]=[CH:7][C:8]([C:11]([F:12])([F:13])[F:14])=[CH:9][CH:10]=3)=[CH:3]2)[N:25]=1
Reactant: CCOC(=O)NC(=CC#N)c1ccc(C(F)(F)F)cc1
Reactant: NNC(=O)C(F)(F)F
Solvent: O
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: Oc1nc(-c2ccc(C(F)(F)F)cc2)cc2nc(C(F)(F)F)nn12
Temperature: 160 °C
Reaction time: 4 h

Procedure:
2.42 g (8.5 mmol) of ethyl {2-cyano-1-[4-(trifluoromethyl)phenyl]ethenyl}carbamate (Example 129A) and 1.09 g (8.5 mmol) of 2,2,2-trifluoroacetohydrazide are dissolved in NMP (10 ml) and stirred in a flask with a calcium chloride drying tube at an oil-bath temperature of 160° C. for 4 h. The reaction mixture is cooled to RT and ethyl acetate (150 ml) and water (100 ml) are added. The organic phase is separated off, dried with magnesium sulphate and concentrated. The residue is stirred with diethyl ether (25 ml), and the solid is filtered off and dried. 0.67 g (23% of theory) of the product is obtained.
Reaction SMILES: [CH3:1][N:2]1[C:7]([NH2:8])=[N:6][C:4](=[O:5])[CH2:3]1.[Cl:9][C:10]1[S:11][CH:12]=[C:13]([N:15]=[C:16]=[O:17])[CH:14]=1.O>CN(C=O)C.C1(C)C=CC=CC=1>[Cl:9][C:10]1[S:11][CH:12]=[C:13]([NH:15][C:16]([N:8]=[C:7]2[NH:6][C:4](=[O:5])[CH2:3][N:2]2[CH3:1])=[O:17])[CH:14]=1
Reactant: O=C=Nc1csc(Cl)c1
Reactant: CN1CC(=O)N=C1N
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Solvent: O
Product: CN1CC(=O)NC1=NC(=O)Nc1csc(Cl)c1
Temperature: 80 °C
Yield: 30.6 %

Procedure:
To a stirred suspension of 2.5 g (22.5 mM) of creatinine in 30 ml of anhydrous DMF was added a solution of 2.87 g (18 mM) of 2-chloro-4-thienyl isocyanate in 20 mls toluene. The resulting mixture was heated at 80° C. for 3.5 hrs., cooled, and poured into a mixture of 250 ml of water and 50 ml toluene. The precipitate was collected and recrystallized from ethyl acetate to give 1.5 g of the above urea as a tan solid, m.p. 198°-200° C.
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[C:4]([NH:11][S:12]([C:15]2[C:16]3[N:17]=[CH:18][CH:19]=[N:20][C:21]=3[CH:22]=[CH:23][CH:24]=2)(=[O:14])=[O:13])[CH:3]=1.Cl.[Cl:26][C:27]1[CH:28]=[C:29]([CH:34]([CH3:37])[CH2:35][NH2:36])[CH:30]=[CH:31][C:32]=1[Cl:33]>>[Cl:26][C:27]1[CH:28]=[C:29]([CH:34]([CH3:37])[CH2:35][NH:36][C:6](=[O:7])[C:5]2[CH:9]=[CH:10][C:2]([I:1])=[CH:3][C:4]=2[NH:11][S:12]([C:15]2[C:16]3[N:17]=[CH:18][CH:19]=[N:20][C:21]=3[CH:22]=[CH:23][CH:24]=2)(=[O:13])=[O:14])[CH:30]=[CH:31][C:32]=1[Cl:33]
Reactant: CC(CN)c1ccc(Cl)c(Cl)c1
Reactant: O=C(O)c1ccc(I)cc1NS(=O)(=O)c1cccc2nccnc12
Agent: Cl
Product: CC(CNC(=O)c1ccc(I)cc1NS(=O)(=O)c1cccc2nccnc12)c1ccc(Cl)c(Cl)c1

Procedure:
The title compound was prepared from 4-iodo-2-(quinoxaline-5-sulfonylamino)-benzoic acid and (±)-2-(3,4-dichloro-phenyl)-propylamine hydrochloride as in EXAMPLE 1, Part C. HPLC: RT=10.97 min. MS (ESI+): mass calcd. for C24H19Cl2IN4O3S, 639.96; m/z found, 641/643 [M+H]+, m/z found, 663/665 [M+Na]+. 1H NMR (400 MHz, CDCl3): 11.07 (s, 1H), 9.03 (d, J=1.8, 1H), 8.95 (d, J=1.8, 1H), 8.56 (dd, J=7.4, 1.4, 1H), 8.33 (dd, J=8.5, 1.4, 1H), 8.05 (d, J=1.6, 1H), 7.91-7.87 (m, 1H), 7.39 (d, J=8.2, 1H), 7.28-7.24 (m, 2H), 7.02 (dd, J=8.3, 2.1, 1H), 6.75 (d, J=8.2, 1H), 5.81 (s, 1H), 3.68-3.61 (m, 1H), 3.31-3.24 (m, 1H), 3.00-2.95 (m, 1H), 1.29 (d, J=7.0, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH2:6][CH:5]([C:7]([O:9][CH3:10])=[O:8])[N:4]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[N:3]=1.O.[N+]([O-])([O-])=O.[Ce+4].[NH4+].[NH4+].[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O>O1CCCC1>[Cl:1][C:2]1[CH:6]=[C:5]([C:7]([O:9][CH3:10])=[O:8])[N:4]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[N:3]=1
Reactant: COC(=O)C1CC(Cl)=NN1c1cccnc1
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1cc(Cl)nn1-c1cccnc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 57.4 %

Procedure:
Methyl 3-chloro-1-(pyridine-3-yl)-4,5-dihydro-1H-pyrazole-5-carboxylate (2.63 g, 11.0 mmol) was stirred in tetrahydrofuran (50 mL) and water (50 mL) at 0° C. diammonium cerium (IV) nitrate (15.0 g, 27.4 mmol) was added in portions and the reaction was stirred at room temperature for 18 hours. thin layer chromatography analysis indicated that the starting material was consumed. The mixture was extracted with ethyl acetate (2×300 mL) and the organic layers were dried and concentrated. The residue was purified by flash column chromatography using 50-100% ethyl acetate/hexanes as eluent. The pure fractions were concentrated to provide the desired product as a yellow solid (1.50 g, 52%): mp 99-102° C.; 1H NMR (400 MHz, DMSO-d6) δ 9.00 (dd, J=2.5, 0.7 Hz, 1H), 8.83 (dd, J=5.2, 1.5 Hz, 1H), 8.35 (ddd, J=8.3, 2.5, 1.4 Hz, 1H), 7.83 (ddd, J=8.3, 5.2, 0.7 Hz, 1H), 7.35 (s, 1H), 3.78 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 158.34, 149.90, 146.89, 141.39, 136.09, 134.77, 133.30, 123.14, 112.01, 52.53; ESIMS m/z 238 ([M+H]+).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:17][CH2:16][C:15]3[C:10](=[CH:11][C:12]([C:18]#N)=[CH:13][CH:14]=3)[CH2:9]2)[CH:5]=[C:4]([N:20]2[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]2)[N:3]=1.[OH-:27].[Na+].Cl.[OH2:30]>>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:17][CH2:16][C:15]3[C:10](=[CH:11][C:12]([C:18]([OH:30])=[O:27])=[CH:13][CH:14]=3)[CH2:9]2)[CH:5]=[C:4]([N:20]2[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]2)[N:3]=1
Reactant: [OH-]
Reactant: O
Reactant: CN1CCN(c2cc(N3CCc4ccc(C#N)cc4C3)nc(N)n2)CC1
Agent: Cl
Agent: [Na+]
Product: CN1CCN(c2cc(N3CCc4ccc(C(=O)O)cc4C3)nc(N)n2)CC1
Temperature: 100 °C
Yield: 94.8 %

Procedure:
The mixture of 2-[2-amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-1,2,3,4-tetrahydroisoquinoline-7-carbonitrile (1 g, 2.86 mmol) and sodium hydroxide (801 mg, 20.0 mmol) in water (30 ml) was heated at 100° C. for 2 days. The reaction mixture was cooled to r.t., and acidified carefully to neutral with 6N HCl aqueous solution. The precipitate was filtered and washed with a little water, dried under vacuum to afford the desired compound (1 g, 94.8%). LCMS(M+H)+: m/z=369.1.
Reaction SMILES: C1(P(C2CCCCC2)C2C=[CH:12][CH:11]=[CH:10][C:9]=2[C:14]2[C:19]([O:20]C)=[CH:18][CH:17]=[CH:16][C:15]=2OC)CCCCC1.C([N:32](CC)CC)C.[CH3:37][C:38]1([CH3:45])[C:42]([CH3:44])([CH3:43])[O:41][BH:40][O:39]1>CC#N.CC#N.Cl[Pd]Cl>[CH:10]1([C:9]2[C:14]3[CH:15]=[CH:16][CH:17]=[C:18]([B:40]4[O:41][C:42]([CH3:44])([CH3:43])[C:38]([CH3:45])([CH3:37])[O:39]4)[C:19]=3[O:20][N:32]=2)[CH2:11][CH2:12]1
Reactant: CC1(C)OBOC1(C)C
Reactant: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Reactant: CCN(CC)CC
Agent: Cl[Pd]Cl
Solvent: CC#N
Product: CC1(C)OB(c2cccc3c(C4CC4)noc23)OC1(C)C
Temperature: 110 °C
Reaction time: 19 h

Procedure:
A vial was charged with bis(acetonitrile)palladium(II) chloride (1.090 mg, 4.20 μmol), dicyclohexyl(2′,6′-dimethoxybiphenyl-2-yl)phosphine (3.45 mg, 8.40 μmol), and Preparation 28D (0.050 g, 0.210 mmol). The vial was capped with a rubber septum and then evacuated and backfilled with N2 (this sequence was carried out a total of 2 times). Dioxane (0.126 mL) was added via syringe, through the septum, followed by the addition of triethylamine (0.088 mL, 0.630 mmol) and 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.046 mL, 0.315 mmol). The septum was then replaced with a Teflon screw valve, and the vial sealed. The reaction mixture was heated at 110° C. After 19 hr, the reaction mixture was allowed to cool to room temperature. The reaction mixture was filtered through a disposable fritted funnel and the filter cake washed with CH2Cl2. The filtrate was concentrated to afford the title compound as a brown residue (60 mg, 100%).