Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]([CH2:37][CH3:38])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[N:9]=[C:10]([C:27]2[CH:28]=[C:29]([CH:33]=[CH:34][C:35]=2[CH3:36])[C:30]([OH:32])=O)[C:11]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]3[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=3[F:26])[C:12]=2[N:13]=1)[CH3:2].CN(C(O[N:47]1N=N[C:49]2[CH:50]=CC=C[C:48]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N)CC>C1COCC1>[CH2:1]([N:3]([CH2:37][CH3:38])[CH2:4][CH2:5][CH2:6][NH:7][C:8]1[N:9]=[C:10]([C:27]2[CH:28]=[C:29]([CH:33]=[CH:34][C:35]=2[CH3:36])[C:30]([NH:47][CH2:48][CH2:49][CH3:50])=[O:32])[C:11]2[CH:17]=[CH:16][C:15](=[O:18])[N:14]([C:19]3[C:24]([F:25])=[CH:23][CH:22]=[CH:21][C:20]=3[F:26])[C:12]=2[N:13]=1)[CH3:2]
Reactant: CCN(CC)CCCNc1nc(-c2cc(C(=O)O)ccc2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCCN
Product: CCCNC(=O)c1ccc(C)c(-c2nc(NCCCN(CC)CC)nc3c2ccc(=O)n3-c2c(F)cccc2F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 38.4 %

Procedure:
To the compound 3-[2-{[3-(diethylamino)propyl]amino}-8-(2,6-difluorophenyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-4-methylbenzoic acid (40 mg, 0.074 mmol) in THF (2 mL) were added HBTU (30 mg, 0.079 mmol) and propylamine (0.031 mL, 0.37 mmol). The mixture was stirred at rt overnight. Solvent was removed by rotovap. Separation by HPLC with TFA, followed by neutralization with SPE amine cartridge afforded the title compound (16 mg, 37%). LC-MS m/z 563 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[O:13]C=[N:11][C:10]=2[C:14]([O:16][CH3:17])=[O:15])[CH:5]=[CH:6][C:7]=1[F:8].CCOCC>CO.Cl>[CH3:17][O:16][C:14](=[O:15])[CH:10]([NH2:11])[C:9]([C:4]1[CH:5]=[CH:6][C:7]([F:8])=[C:2]([F:1])[CH:3]=1)=[O:13]
Reactant: COC(=O)c1ncoc1-c1ccc(F)c(F)c1
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: COC(=O)C(N)C(=O)c1ccc(F)c(F)c1
Temperature: 50 °C
Yield: 104.4 %

Procedure:
To 5-(3,4-difluorophenyl)-4-methoxycarbonyloxazole (1.0 g, 4.18 mmol) in methanol (6 mL), 1N HCl (2 mL) was added and the mixture was heated at 50° C. for 2 hours. The reaction mixture was then concentrated to yield a syrup. Ether was added and the solution filtered to give 1.0 g (87%) of the product as a white solid: 1H-NMR (CDCl3) 3.74 (s, 3 H), 6.15 (s, 1H), 7.45-7.55 (m, 1H), 8.11-8.13 (m, 2H)
Reaction SMILES: [C:1](=[O:20])([O:18][CH3:19])[O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-])=O)[C:6]([Br:12])=[CH:5][C:4]=1[CH:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1>C(O)(=O)C.O.C(#N)C.CO.[Zn]>[C:1](=[O:20])([O:18][CH3:19])[O:2][C:3]1[CH:8]=[C:7]([NH2:9])[C:6]([Br:12])=[CH:5][C:4]=1[CH:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: COC(=O)Oc1cc([N+](=O)[O-])c(Br)cc1C1CCCC1
Agent: [Zn]
Solvent: CO
Solvent: CC(=O)O
Solvent: CC#N
Product: COC(=O)Oc1cc(N)c(Br)cc1C1CCCC1
Yield: 98.6 %

Procedure:
4-bromo-2-cyclopentyl-5-nitrophenyl methyl carbonate (211 mg, 0.61 mmol) was dissolved in a mixture of glacial acetic acid (3 mL) and water (1 mL). Additional acetic acid (1 mL) was added to facilitate stirring. Zn dust (401 mg, 6.13 mmol) was added at room temperature and the reaction stirred for 10 min. The reaction was diluted with acetonitrile (5 mL) and methanol (5 mL) and filtered. The solution was diluted with ethyl acetate, washed with 50% saturated aqueous NaHCO3 (2×20 mL) and brine, dried over Na2SO4, filtered, and dried down to provide 5-amino-4-bromo-2-cyclopentylphenyl methyl carbonate as a light orange solid (189 mg, 98% yield). LC/MS m/z 315.0 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:21])=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([C:12]1[CH:17]=[CH:16][C:15]([O:18]C)=[CH:14][CH:13]=1)=[CH:7][C:6]=2[Cl:20].B(Br)(Br)Br>>[Br:1][C:2]1[C:3]([OH:21])=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([C:12]1[CH:13]=[CH:14][C:15]([OH:18])=[CH:16][CH:17]=1)=[CH:7][C:6]=2[Cl:20]
Reactant: COc1ccc(-c2cc(Cl)c3cc(O)c(Br)cc3c2)cc1
Agent: BrB(Br)Br
Product: Oc1ccc(-c2cc(Cl)c3cc(O)c(Br)cc3c2)cc1

Procedure:
The title compound was prepared by reacting 3-bromo-8-chloro-6-(4-methoxyphenyl)-2-naphthol (0.24 g, 0.66 mmol) with boron tribromide (1.6 mL of 1N solution, 1.6 mmol) according to method D to yield 0.14 g (61%) of a yellow oil. The product was further purified by reverse phase preparative HPLC to yield the title compound as a white solid: mp 188-190° C.; 1H NMR (DMSO-d6): δ 6.88 (1H, d, J=8.60 Hz), 7.57 (1H, s), 7.71 (2H, d, J=8.61 Hz), 7.89 (1H, d, J=1.60 Hz), 8.02 (1H, s), 8.31 (1H, s), 9.67 (1H, s), 11.01 (1H, s); MS (ESI) m/z 347/349/351 (M−H)−.
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[N:11]([CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([OH:23])[CH:20]=[CH:19][C:16]=43)[CH:10]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].Br[CH2:25][C:26]([NH2:28])=[O:27].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O>[CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[C:16]4[CH:19]=[CH:20][C:21]([O:23][CH2:25][C:26]([NH2:28])=[O:27])=[CH:22][C:15]=4[O:14][CH2:13][CH2:12][N:11]3[CH:10]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(O)cc1OCC2
Reactant: NC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(OCC(N)=O)cc1OCC2
Temperature: 25 °C
Reaction time: 16 h
Yield: 63.7 %

Procedure:
To a solution of 2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-ol 490 (80 mg, 0.26 mmol) in DMF (3 mL) was added 2-bromoacetamide (53 mg, 0.39 mmol) and cesium carbonate (109 mg, 0.33 mmol). The reaction mixture stirred at RT for 16 h before being diluted with water. The mixture was extracted with ethyl acetate (3×10 mL) and the combined organic extracts, washed with brine, dried (MgSO4) and concentrated in vacuo. The residue was subjected to flash chromatography (SiO2, gradient 0-10% methanol in DCM) to yield 428 as a white solid (61 mg, 64%). LCMS: RT=6.70 min, [M+H]+=369; 1H NMR (400 MHz, d6-DMSO) 8.28 (1H, d, J=9.8 Hz), 7.85 (1H, s), 7.82 (1H, s), 7.51 (1H, s), 7.35 (1H, s), 6.76 (1H, dd, J=9.8, 2.7 Hz), 6.54 (1H, d, J=2.7 Hz), 5.85 (1H, sept, J=6.6 Hz), 4.49-4.39 (6H, m), 1.43 (6H, d, J=6.6 Hz).
Reaction SMILES: [C:1]1([C:7](=[N:14][CH:15]([CH2:21][CH2:22][CH2:23][CH2:24][B:25]2[O:29][C:28]([CH3:31])([CH3:30])[C:27]([CH3:33])([CH3:32])[O:26]2)[C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:34]1[CH2:38]OC[CH2:35]1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C(Br)C=C>C(OCC)(=O)C>[CH2:38]([C:15]([N:14]=[C:7]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)([CH2:21][CH2:22][CH2:23][CH2:24][B:25]1[O:26][C:27]([CH3:32])([CH3:33])[C:28]([CH3:31])([CH3:30])[O:29]1)[C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:34]=[CH2:35]
Reactant: C1CCOC1
Reactant: CCOC(=O)C(CCCCB1OC(C)(C)C(C)(C)O1)N=C(c1ccccc1)c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C=CCBr
Product: C=CCC(CCCCB1OC(C)(C)C(C)(C)O1)(N=C(c1ccccc1)c1ccccc1)C(=O)OCC
Temperature: -78 °C
Reaction time: 16 h
Yield: 59 %

Procedure:
A solution of ethyl 2-(diphenylmethyleneamino)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)hexanoate (2.79 g, 6.21 mmol) in freshly distilled (THF 15 mL, 0.4 M) was cooled to −78° C. and treated with lithium bis(trimethylsilyl)amide (6.8 mL, 1.0 M in THF). After stirring for 10 min allyl bromide (2.25 g, 18.6 mmol) was added the reaction was warmed to room temperature and stirred for 16 h. After being complete by TLC, the reaction mixture was cooled to 0° C., diluted with ethyl acetate and washed successively with saturated aqueous NaHCO3 and saturated aqueous NaCl, dried over MgSO4, filtered and concentrated. Purification by MPLC (1-20% ethyl acetate in heptane with 0.5% triethylamine over 6 CV) gave ethyl 2-allyl-2-(diphenylmethyleneamino)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)hexanoate as a colorless oil (1.81 g, 59%). Rf 0.52 (30% ethyl acetate in heptane); 1H NMR (CDCl3, 300 MHz) δ 7.58-7.53 (m, 2H), 7.39-7.22 (m, 6H), 7.16-7.12 (m, 2H), 5.89-5.74 (m, 1H), 5.07 (dd, J1=15.3 Hz, J2=2.1 Hz, 1H), 5.05 (dd, J1=8.7 Hz, J2=2.1 Hz, 1H), 3.70 (q, J=7.5 Hz, 1Hdiasterotopic), 3.69 (q, J=7.2 Hz, 1Hdiasterotopic), 2.70 (dd, J1=7.2 Hz, J2=1.2 Hz, 2H), 1.92-1.83 (m, 2H), 1.44-1.35 (m, 2H), 1.35-1.23 (m, 2H), 1.19 (s, 12H), 1.10 (t, J=7.2 Hz, 3H), 0.78 (t, J=6.6 Hz, 2H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][NH:11][C:10](=[O:14])[CH2:9]1)=O)(C)(C)C.[I-].[H-].[Na+].Br[CH2:19][C:20]1[CH:29]=[C:28]2[C:23]([C:24]([Cl:30])=[CH:25][N:26]=[N:27]2)=[CH:22][CH:21]=1>C1COCC1>[Cl:30][C:24]1[C:23]2[C:28](=[CH:29][C:20]([CH2:19][N:11]3[CH2:12][CH2:13][NH:8][CH2:9][C:10]3=[O:14])=[CH:21][CH:22]=2)[N:27]=[N:26][CH:25]=1
Reactant: Clc1cnnc2cc(CBr)ccc12
Reactant: CC(C)(C)OC(=O)N1CCNC(=O)C1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C1CNCCN1Cc1ccc2c(Cl)cnnc2c1
Temperature: 25 °C
Yield: 59.3 %

Procedure:
4-(t-Butyloxycarbonyl)-piperazin-2-one (0.6 g, 3.0 mmol), EXAMPLE 40, is dissolved in THF (80 mL), cooled in an ice bath and treated with tretrabutylammonium iodide (0.23 g, 0.62 mmol) and 60% sodium hydride (0.12 g, 3.0 mmol). The reaction mixture is stirred at ° C. for 40 minutes then treated dropwise with a solution of 7-bromomethyl-4-chlorocinnoline (10.7 g, 2.7 mmol), Example 15, in THF (20 mL). The resulting solution is warmed to ambient temperature over 2 hours. The solution is evaporated to dryness and the residue is taken up in ethyl acetate and 10% aqueous sodium bicarbonate solution. The organic layer is separated, washed with water, dried (sodium sulfate) and concentrated. The residue is chromatographed (ethyl acetate) to yield the title compound (0.6 g, 1.6 mmol). A portion of this material (0.21 g, 1.26 mmol) is dissolved in THF (˜4 mL) and treated with a saturated solution of HCl in ethyl acetate (50 mL) at room temperature for 2 hours. The solution is filtered and concentrated to a residue (0.14 g, 0.4 mmol). MS m/z: M+=275; 1H NMR (CD3OD, 300 MHz) δ9.15 (d, 1H), 8.5 (d, 1H), 8.25 (s, 1H), 8.15 (d, 1H), 8.0 (d, 1H), 5.0 (s, 2H), 4.1 (s, 2H), 3.7-3.8 (m, 2H), 3.6-3.7 (m, 2H).
Reaction SMILES: [OH-].[Li+].[Br:3][C:4]1[CH:5]=[C:6]([C:10]([NH:12][CH:13]2[CH2:18][CH2:17][N:16]([C:19]3[N:24]=[C:23]([Cl:25])[N:22]=[C:21]([C:26]([O:28]C)=[O:27])[CH:20]=3)[CH2:15][CH2:14]2)=[O:11])[NH:7][C:8]=1[CH3:9]>CO>[Br:3][C:4]1[CH:5]=[C:6]([C:10]([NH:12][CH:13]2[CH2:18][CH2:17][N:16]([C:19]3[N:24]=[C:23]([Cl:25])[N:22]=[C:21]([C:26]([OH:28])=[O:27])[CH:20]=3)[CH2:15][CH2:14]2)=[O:11])[NH:7][C:8]=1[CH3:9]
Reactant: COC(=O)c1cc(N2CCC(NC(=O)c3cc(Br)c(C)[nH]3)CC2)nc(Cl)n1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: Cc1[nH]c(C(=O)NC2CCN(c3cc(C(=O)O)nc(Cl)n3)CC2)cc1Br
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 86 %

Procedure:
Lithium hydroxide (2 M, 4 ml) was warmed to 40° C. and a solution of methyl 6-(4-{[(4-bromo-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}piperidin-1-yl)-2-chloropyrimidine-4-carboxylate (Example 73, 0.180 g, 0.394 mmol) in MeOH was added. The reaction was stirred at 40° C. for 30 mins. The MeOH was removed and the aqueous solution was cooled to 0° C. and it was acidified with 6 M HCl. The acidic solution was extracted with EtOAc, dried over MgSO4 and concentrated to give pink solid (0.15 g, 86%). An analytical sample was purified by reversed phase HPLC (acetonitrile/water (0.1% TFA), 20-95%).
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.[CH2:24]([N:26]([CH2:36][CH3:37])[CH2:27][CH2:28][NH:29][C:30]1[CH2:34][S:33][C:32](=[O:35])[N:31]=1)[CH3:25].CC(C)([O-])C.[K+]>C(O)C>[F:23][C:2]([F:1])([F:22])[C:3]1[CH:17]=[C:16]([C:18]([F:20])([F:21])[F:19])[CH:15]=[CH:14][C:4]=1[CH2:5][N:6]1[CH2:7][CH2:8][CH:9](/[CH:12]=[C:34]2/[C:30]([NH:29][CH2:28][CH2:27][N:26]([CH2:36][CH3:37])[CH2:24][CH3:25])=[N:31][C:32](=[O:35])[S:33]/2)[CH2:10][CH2:11]1
Reactant: O=CC1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Reactant: CCN(CC)CCNC1=NC(=O)SC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCO
Product: CCN(CC)CCNC1=NC(=O)S/C1=C\C1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Temperature: 80 °C
Reaction time: 0.33 h
Yield: 74.7 %

Procedure:
To a solution of 1-[2,4-bis(trifluoromethyl)benzyl]piperidine-4-carbaldehyde (6.64 g) and 4-{[2-(diethylamino)ethyl]amino}-1,3-thiazol-2(5H)-one (5.48 g) in ethanol (98 mL) was added potassium tert-butoxide (2.85 g). The reaction mixture was stirred at 80° C. for 20 min, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane). The solvent was evaporated under reduced pressure, the residue was dissolved in ethyl acetate, the solution was washed with water and 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 (NH, methanol/ethyl acetate) and further silica gel column chromatography (methanol/ethyl acetate) to give the title compound (7.84 g).
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[C:6]([Cl:9])[CH:5]=[CH:4][C:3]=1[C:10](=O)[CH2:11]Cl.[CH:14]1([Mg]Br)[CH2:16][CH2:15]1>C1(C)C=CC=CC=1>[Cl:9][C:6]1[C:7]([F:8])=[C:2]2[C:3]([CH:10]=[C:11]([CH:14]3[CH2:16][CH2:15]3)[NH:1]2)=[CH:4][CH:5]=1
Reactant: Br[Mg]C1CC1
Reactant: Nc1c(C(=O)CCl)ccc(Cl)c1F
Solvent: Cc1ccccc1
Product: Fc1c(Cl)ccc2cc(C3CC3)[nH]c12
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 63.4 %

Procedure:
To a stirred solution of compound 2 (4.5 g, 20.3 mmol) in toluene (50 mL) was added cyclopropyl magnesium bromide (0.5 M in THF; 102.0 mL, 50.9 mmol) at 0° C. under inert atmosphere. The reaction mixture was stirred at 0° C. for 15 min and then warmed to RT and stirring was continued for additional 1 h. After completion of the reaction (TLC), the reaction mixture was quenched with sat. NH4Cl solution (10 mL) and extracted with EtOAc (3×75 mL). The combined organic extracts were dried over Na2SO4, filtered and concentrated under reduced pressure to obtain the crude. The crude was purified (silica gel column chromatography; 1% EtOAc/Hexanes to afford compound 3 (2.7 g, 63%) as an off-white solid. 1H NMR (500 MHz, DMSO-d6): δ 11.55 (s, 1H), 7.18 (d, J=8.5 Hz, 1H), 6.97 (dd, J=8.5, 6.5 Hz, 1H), 6.16 (s, 1H), 2.03-1.99 (m, 1H), 0.99-0.96 (m, 2H), 0.83-0.80 (m, 2H); LC-MS (ESI): 91.6%; m/z 208.1 (M−H+); (column: X Select CSH C-18, 50×3.0 mm, 3.5 μm); RT 4.32 min; 5 mM NH4OAc: ACN; 0.8 mL/min).
Reaction SMILES: CO[CH2:3][N:4]([CH2:10][CH2:11][CH3:12])[CH2:5][Si](C)(C)C.[Br:13][C:14]1[CH:15]=[N:16][C:17]([CH:20]=[CH2:21])=[N:18][CH:19]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Br:13][C:14]1[CH:15]=[N:16][C:17]([CH:20]2[CH2:21][CH2:5][N:4]([CH2:10][CH2:11][CH3:12])[CH2:3]2)=[N:18][CH:19]=1
Reactant: CCCN(COC)C[Si](C)(C)C
Reactant: C=Cc1ncc(Br)cn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCN1CCC(c2ncc(Br)cn2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 35.3 %

Procedure:
Methoxymethyl-propyl-trimethylsilanylmethyl-amine (14.13 g, 74.61 mmol) in CH2Cl2 (4 ml) was added dropwise to a 0° C. cooled solution of 5-bromo-2-vinyl-pyrimidine (2 g, 10.80 mmol) and TFA (210 μl, 2.72 mmol) in CH2Cl2 (45 ml) over a period of 20 min. The reaction mixture was then stirred at room temperature for 2 h. The crude material was diluted with CH2Cl2, washed with saturated aqueous NaHCO3 and the organic layer was dried over Na2SO4 and evaporated. The residue was chromatographied on silica gel (CH2Cl2:methanol, 97:3) to afford the title compound (1.03 g, 34%) as a brown oil.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([N:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.Cl.[CH3:23][O:24][C:25](=[O:29])[CH2:26][NH:27][CH3:28].CCN(CC)CC>CN(C=O)C>[CH3:23][O:24][C:25](=[O:29])[CH2:26][N:27]([C:2]1[N:11]=[C:10]([N:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH3:13])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1)[CH3:28]
Reactant: COc1ccc(N(C)c2nc(Cl)nc3ccccc23)cc1
Reactant: CNCC(=O)OC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)CN(C)c1nc(N(C)c2ccc(OC)cc2)c2ccccc2n1
Temperature: 130 °C
Reaction time: 0.33 h

Procedure:
A mixture of (2-chloroquinazolin-4-yl)-(4-methoxyphenyl)-methylamine 0.335 g (1.0 mmol), sarcosine methyl ester hydrochloride 0.139 g (1.0 mmol) with Et3N 1.0 mL (10.0 mmol) in DMF 2 mL was stirred at 130° C. for 20 minutes under microwave irradiation. The crude mixture was directly charged to silica-gel, and purified by MPLC (SiO2, EtOAc 0˜100% in hexanes) to give the title compound, which was further purified by preparative HPLC for analytical use. 1H NMR (CD3OD, 400 MHz) δ 7.63-7.70 (m, 2H), 7.31 (d, J=9.0 Hz, 2H), 7.07-7.11 (m, 2H), 6.97-7.01 (m, 1H), 6.80 (d, J=8.4 Hz, 1H), 4.62 (s, 2H), 3.87 (s, 3H), 3.81 (s, 3H), 3.62 (s, 3H), 3.45 (s, 3H); HRMS (ES) m/z calcd for C20H22N4O3 (M+H) 367.1764, found 367.1772.
Reaction SMILES: [CH3:1][CH:2]([N:4]1[S:14](=[O:16])(=[O:15])[NH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:5]1=[O:6])[CH3:3].O.[NH3:18]>ClCCCl>[CH3:3][CH:2]([N:4]1[S:14](=[O:16])(=[O:15])[NH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:5]1=[O:6])[CH3:1].[NH4+:18]
Reactant: N
Agent: CC(C)N1C(=O)c2ccccc2NS1(=O)=O
Solvent: ClCCCl
Solvent: O
Product: [NH4+]

Procedure:
A solution of 24 g of bentazone (IIa) in 216 g of 1,2-dichloroethane was treated with stirring at 50°-60° C. with 34 g of ammonia water (5% strength solution of ammonia in water). After addition was complete, the aqueous phase was separated off at 50°-60° C. On cooling the aqueous phase, the bentazone-ammonium was deposited in crystalline form. The solid was separated off at 20° C. by filtration and freed from solvent residues under reduced pressure and at 50° C. 11.8 g of bentazone-ammonium (m.p. 180° C.) were obtained. By evaporating the water from the mother liquor under reduced pressure and at 50°-60° C., a further 13.7 g of bentazone-ammonium were obtained.
Reaction SMILES: [N:1]1([C:7]2[C:8]3[S:28][C:27]([CH2:29][N:30]4[CH2:35][CH2:34][N:33]([C:36]([CH3:41])([CH3:40])[C:37]([NH2:39])=[O:38])[CH2:32][CH2:31]4)=[CH:26][C:9]=3[N:10]=[C:11]([Sn](CCCC)(CCCC)CCCC)[N:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Br[C:43]1[C:48]([CH3:49])=[N:47][CH:46]=[C:45]2[NH:50][CH:51]=[CH:52][C:44]=12>O1CCOCC1.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.S1C=CC=C1C([O-])=O.[Cu+]>[CH3:40][C:36]([N:33]1[CH2:34][CH2:35][N:30]([CH2:29][C:27]2[S:28][C:8]3[C:7]([N:1]4[CH2:2][CH2:3][O:4][CH2:5][CH2:6]4)=[N:12][C:11]([C:43]4[C:48]([CH3:49])=[N:47][CH:46]=[C:45]5[NH:50][CH:51]=[CH:52][C:44]=45)=[N:10][C:9]=3[CH:26]=2)[CH2:31][CH2:32]1)([CH3:41])[C:37]([NH2:39])=[O:38]
Reactant: Cc1ncc2[nH]ccc2c1Br
Reactant: CCCC[Sn](CCCC)(CCCC)c1nc(N2CCOCC2)c2sc(CN3CCN(C(C)(C)C(N)=O)CC3)cc2n1
Agent: [Cu+]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])c1cccs1
Solvent: C1COCCO1
Product: Cc1ncc2[nH]ccc2c1-c1nc(N2CCOCC2)c2sc(CN3CCN(C(C)(C)C(N)=O)CC3)cc2n1
Temperature: 150 °C
Yield: 44.9 %

Procedure:
A mixture of 2-[4-(4-morpholin-4-yl-2-(tributylstannanyl)thieno[3,2-d]pyrimidin-6-ylmethyl)piperazin-1-yl]isobutyramide (72 mg, 0.10 mmol), 4-bromo-5-methyl-1H-pyrrolo[2,3-c]pyridine (22 mg, 0.10 mmol), Pd(PPh3)4 (12 mg, 10 mol %) and copper(I)-thiophene-2-carboxylate (4 mg, 20 mol %) in dioxane (1 mL) was purged with argon gas then heated at 150° C., for 20 min, in a microwave reactor. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge, the cartridge was washed with MeOH then the desired product eluted with 2 M NH3 in MeOH. The resulting residue was purified by column chromatography (Si—PCC, 0-20% MeOH in DCM) to give 153 as a pale yellow solid (24 mg, 43%). LCMS (Method E): RT=4.19 min, [M+H]+ 535.2. 1H NMR (400 MHz, CHCl3-d): δ 9.14 (s, 1 H), 8.73 (s, 1 H), 7.34-7.32 (m, 2 H), 7.11 (d, J=5.3 Hz, 1 H), 6.67-6.65 (m, 1 H), 5.30 (d, J=4.7 Hz, 1 H), 4.04 (t, J=4.7 Hz, 4 H), 3.87 (d, J=4.7 Hz, 4 H), 3.85 (s, 2 H), 2.76 (s, 3 H), 2.61 (m, 8 H), 1.28-1.22 (m, 6 H)
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH2:8])[N:3]=1.[C:9]([CH2:17][C:18](=O)[CH3:19])(=O)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.S(=O)(=O)(O)O.[OH-].[Na+]>O.C(O)(=O)C>[NH2:8][C:4]1[N:3]=[C:2]2[C:7]([C:18]([CH3:19])=[CH:17][C:9]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[N:1]2)=[CH:6][CH:5]=1
Reactant: Nc1cccc(N)n1
Reactant: CC(=O)CC(=O)c1ccccc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: Cc1cc(-c2ccccc2)nc2nc(N)ccc12
Reaction time: 24 h

Procedure:
2,6-Diaminopyridine (16.4 g., 0.15 mole), 24 g. of benzoylacetone, 75 ml. of acetic acid and 1.5 ml of 96% sulfuric acid was refluxed with stirring for 24 hours. The solution was poured slowly with stirring into 50 g. of sodium hydroxide in 250 ml. of water; the temperature was held 20°-30° by cooling. The tan solid was filtered, washed well with water and dried, 21.8 g. One recrystallization from 100 ml. of 95% ethanol gave 6.9 g. of coarse needles, m.p. 65°-190°; a second recrystallization from 50 ml. of ethanol furnished 2.1 g. (6) of the title compound, m.p. 253°-255°; 1H nmr (deuteriochloroform+DMSO-d6, 60 MHz): δ2.67 (s,3H, CH3), 6.20 (broad exchangeable s, 2H, NH2), 6.92 (d, 1H, H5, J=9 Hz), 7.58 (d,1H, H6), 7.50 (m,3H,meta and para protons on C6H5), 8.30 (m,2H, ortho protons on C6H5).
Reaction SMILES: [C:1]1([C:7](=[NH:9])[NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:11][C:12]([C:14]1[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=1)=O.C(=O)(O)[O-].[Na+].O>C1COCC1>[C:1]1([C:7]2[NH:9][CH:11]=[C:12]([C:14]3[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N=C(N)c1ccccc1
Reactant: N#Cc1ccc(C(=O)CBr)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1ccc(-c2c[nH]c(-c3ccccc3)n2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Benzenecarboximidamide (2.9 g, 24 mmol), 4-bromoacetylbenzonitrile (5 g, 22 mmol), and sodium bicarbonate (1.8 g, 22 mmol) were suspended in 70 mL of THF and 10 mL of water and heated at reflux overnight. The reaction mixture was cooled rt, and partially concentrated. An additional 10 mL of water was added, and the resulting suspension was stirred at 50-60° C. for 30 min. The mixture was cooled with an ice-water bath and the precipitate was collected by filtration, rinsed with two 10-mL portions of water, and air-dried. The solid material was stirred with 15 mL of EtOAc and 15 mL of hexanes, and was again collected by filtration, and dried to give 4-(2-phenyl-1H-imidazol-4-yl)benzonitrile. LCMS: min [M+1]=246.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][N:5]=[C:4]([CH3:12])[CH:3]=1.[Cl:13][C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[C:16]([F:23])[CH:15]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>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>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([C:2]2[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][N:5]=[C:4]([CH3:12])[CH:3]=2)=[C:16]([F:23])[CH:15]=1
Reactant: COC(=O)c1cnc(C)cc1Cl
Reactant: OB(O)c1ccc(Cl)cc1F
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: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1cnc(C)cc1-c1ccc(Cl)cc1F
Temperature: 80 °C
Yield: 43 %

Procedure:
To a solution of methyl 4-chloro-6-methylnicotinate (660 mg, 3.56 mmol) and (4-chloro-2-fluorophenyl)boronic acid (620 mg, 3.56 mmol) in 1,4-dioxane (20 mL) was added cesium carbonate (3.48 g, 10.67 mmol). The reaction mixture was degassed with argon over a period of 5 min. Pd(Ph3P)4 (205 mg, 0.178 mmol) was added to the reaction mixture and heated to 80° C. for 16 h. The mixture was cooled to room temperature, diluted with water, and extracted with ethyl acetate (100 mL). The organic phase was washed with brine (2×50 mL), dried over Na2SO4, and concentrated under reduced pressure. The residue obtained was purified by silica gel chromatography to afford methyl 4-(4-chloro-2-fluorophenyl)-6-methylnicotinate (500 mg, 1.53 mmol, 43% yield) as a yellow liquid. LC/MS (ESI) m/e 280.0 [(M+H)+, calcd for C14H12ClFNO2 279.6]; LC/MS retention time (method C): tR=1.87 min.