Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCO[C:4]([CH:6]1[C:11](=O)[CH2:10][CH2:9][CH2:8][CH2:7]1)=[O:5].Cl.[Cl:14][CH2:15][C:16]([NH2:18])=[NH:17].C(N(CC)CC)C>CO>[Cl:14][CH2:15][C:16]1[NH:18][C:4](=[O:5])[C:6]2[CH2:7][CH2:8][CH2:9][CH2:10][C:11]=2[N:17]=1
Reactant: CCOC(=O)C1CCCCC1=O
Reactant: N=C(N)CCl
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: O=c1[nH]c(CCl)nc2c1CCCC2
Temperature: 25 °C
Reaction time: 60 h
Yield: 12.9 %

Procedure:
To a solution of ethyl 2-cyclohexanone-carboxylate (5.5 g, 32 mmol) in methanol was added chloroacetamidine hydrochloride (4.2 g, 32 mmol) and triethylamine (14 mL, 97 mmol). The mixture was stirred at ambient temperature for 60 h. It was then concentrated under reduced pressure and purified via flash column chromatography (ethyl acetate:hexane, 10:90 to 100:0) to provide product (0.82 g, 13% yield). 1H NMR (400 MHz, CD3OD) δ 4.40 (s, 2H), 2.61 (t, J=6.3 Hz, 2H), 2.45 (t, J=6.3 Hz, 2H), 1.68-1.87 (m, 4H). MS m/z 199.2 (M+1), retention time=0.94 min.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([NH:11][C:12](=[O:14])[CH3:13])[N:10]=2)[N:7]=1.[CH3:15][C:16]1[CH:21]=[CH:20][C:19]([S:22]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28](B3OC(C)(C)C(C)(C)O3)[CH:27]=2)(=[O:24])=[O:23])=[CH:18][CH:17]=1.C(=O)([O-])[O-].[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CN(C=O)C>[CH3:15][C:16]1[CH:17]=[CH:18][C:19]([S:22]([NH:25][C:26]2[CH:31]=[C:30]([C:2]3[CH:3]=[CH:4][C:5]4[N:6]([CH:8]=[C:9]([NH:11][C:12](=[O:14])[CH3:13])[N:10]=4)[N:7]=3)[CH:29]=[CH:28][CH:27]=2)(=[O:24])=[O:23])=[CH:20][CH:21]=1
Reactant: Cc1ccc(S(=O)(=O)Nc2cccc(B3OC(C)(C)C(C)(C)O3)c2)cc1
Reactant: CC(=O)Nc1cn2nc(Cl)ccc2n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)Nc1cn2nc(-c3cccc(NS(=O)(=O)c4ccc(C)cc4)c3)ccc2n1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
To a 10-mL, round-bottomed flask was added N-(6-chloroimidazo[1,2-b]pyridazin-2-yl)acetamide from Step 4 (0.060 g, 0.28 mmol), 4-methyl-N-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)benzenesulfonamide (0.19 g, 0.51 mmol, Aldrich, St. Louis, Mo.), DMF (3.0 mL), and aq. sodium carbonate (0.85 mL, 1.7 mmol, 2 M). The mixture was carefully evacuated and backfilled with N2. Bis(triphenylphosphine)palladium(II) chloride (20 mg, 0.028 mmol, Strem Chemical, Inc., Newburyport, Mass.) was added. Once again, the mixture was carefully evacuated and backfilled with N2. The mixture was stirred at 100° C. for 2 h and then allowed to cool to room temperature. The mixture was poured into water (75 mL) and extracted with EtOAc (3×75 mL). The combined extracts were washed with water (2×50 mL) and brine (50 mL) then dried (Na2SO4) and concentrated onto silica. Purification by silica gel chromatography (1 to 5% MeOH (2 M in NH3)/CH2Cl2) afforded the title compound as an off-white solid. MS (ESI positive ion) m/z: 422 (M+1). 1H NMR (400 MHz, DMSO-d6): δ ppm 10.92 (s, 1H), 10.44 (s, 1H), 8.26 (s, 1H), 8.05 (d, J=9.6 Hz, 1H), 7.77 (t, J=1.8 Hz, 1H), 7.67-7.71 (m, 3H), 7.61 (d, J=9.6 Hz, 1H), 7.40 (t, J=7.9 Hz, 1H), 7.35 (d, J=8.0 Hz, 2H), 7.19 (dd, J=8.0 Hz, 1.4 Hz, 1H), 2.32 (s, 3H), 2.11 (s, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][C:12]([C:13](OC)=[O:14])=[C:11]([OH:19])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH3:20]>C(O)C.CO>[OH:19][C:11]1[CH:10]=[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:18]=[CH:17][C:12]=1[C:13]([NH2:20])=[O:14]
Reactant: COC(=O)c1ccc(OCc2ccccc2)cc1O
Reactant: N
Solvent: CCO
Solvent: CO
Product: NC(=O)c1ccc(OCc2ccccc2)cc1O

Procedure:
A mixture of methyl 4-benzyloxy-2-hydroxybenzoate (20 g) and concentrated aqueous ammonia (30 mL) in ethanol (100 mL) is heated on the steam bath in a sealed pressure vessel overnight. The contents of the pressure vessel are dissolved in methanol and the solution is evaporated to dryness. The residue is subjected to flash chromatography, eluting first with dichloromethane to remove unreacted starting material, and then with a mixture of ethyl acetate and dichloromethane (3:7 v/v), to obtain 2-hydroxy-4-benzyloxybenzamide (4 g), in the form of a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[C:13]3[N:21]([CH2:22][CH2:23][CH2:24][CH2:25][NH:26]C(=O)OC(C)(C)C)[C:20]([CH2:34][O:35][CH2:36][CH3:37])=[N:19][C:14]=3[CH:15]=[N:16][C:17]=2[CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:38]>C(O)C>[ClH:38].[ClH:38].[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[C:13]3[N:21]([CH2:22][CH2:23][CH2:24][CH2:25][NH2:26])[C:20]([CH2:34][O:35][CH2:36][CH3:37])=[N:19][C:14]=3[CH:15]=[N:16][C:17]=2[CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOCc1nc2cnc3cc(OCc4ccccc4)ccc3c2n1CCCCNC(=O)OC(C)(C)C
Agent: Cl
Solvent: CCO
Product: CCOCc1nc2cnc3cc(OCc4ccccc4)ccc3c2n1CCCCN
Temperature: 25 °C

Procedure:
tert-Butyl [4-(7-benzyloxy-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]carbamate (21.0 g) was dissolved in ethanol (100 mL) and concentrated hydrochloric acid (13.0 mL). The reaction was heated at reflux for 1 hour and then cooled to ambient temperature. A tan precipitate formed. The solid was filtered and dried under vacuum for 16 hours to yield 12.1 g of 4-(7-benzyloxy-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)butylamine dihydrochloride as a beige solid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:10](=[O:12])[N:9]=[C:8]([C:13]3[CH:14]=[C:15]([S:23]([N:26]4[CH2:30][CH2:29][C@@H:28]([N:31]([CH3:33])[CH3:32])[CH2:27]4)(=[O:25])=[O:24])[CH:16]=[CH:17][C:18]=3[O:19][CH2:20][CH2:21][CH3:22])[NH:7][C:6]=2[C:5]2=[CH:34][N:35]([CH2:37][C:38]3[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[CH:40][CH:39]=3)[N:36]=[C:4]2[N:3]=1.[Cl:46][C:47]1[CH:48]=[C:49]([CH:52]=[CH:53][C:54]=1[O:55][CH3:56])[CH2:50][NH2:51].Cl.CCN(C(C)C)C(C)C>CCCCO>[CH3:32][N:31]([CH3:33])[C@@H:28]1[CH2:29][CH2:30][N:26]([S:23]([C:15]2[CH:16]=[CH:17][C:18]([O:19][CH2:20][CH2:21][CH3:22])=[C:13]([C:8]3[NH:7][C:6]4[C:5]5[C:4](=[N:36][N:35]([CH2:37][C:38]6[CH:39]=[CH:40][C:41]([O:44][CH3:45])=[CH:42][CH:43]=6)[CH:34]=5)[N:3]=[C:2]([NH:51][CH2:50][C:49]5[CH:52]=[CH:53][C:54]([O:55][CH3:56])=[C:47]([Cl:46])[CH:48]=5)[C:11]=4[C:10](=[O:12])[N:9]=3)[CH:14]=2)(=[O:25])=[O:24])[CH2:27]1
Reactant: COc1ccc(CN)cc1Cl
Reactant: CCCOc1ccc(S(=O)(=O)N2CC[C@@H](N(C)C)C2)cc1-c1nc(=O)c2c(Cl)nc3nn(Cc4ccc(OC)cc4)cc3c2[nH]1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: CCCOc1ccc(S(=O)(=O)N2CC[C@@H](N(C)C)C2)cc1-c1nc(=O)c2c(NCc3ccc(OC)c(Cl)c3)nc3nn(Cc4ccc(OC)cc4)cc3c2[nH]1

Procedure:
A mixture of (3R)-1-[[3-(5-Chloro-4,8-dihydro-8-[(4-methoxyphenyl)methyl]-4-oxo-1H-pyrazolo[4′,3′:5,6]pyrido[4,3-d]pyrimidin-2-yl)-4-propoxyphenyl]sulfonyl]-3-(dimethylamino)pyrrolidine (39 mg, 0.06 mmol), 3-chloro-4-methoxybenzylamine.HCl (25 mg, 0.12 mmol) and DIEA (78 mg, 0.6 mmol) in n-BuOH was heated at 125° C. under nitrogen for 4 h. The reaction mixture was concentrated and the residue was chromatographed (silica gel, 5% MeOH in DCM) to give the desired product (42.6 mg) as a yellow solid. LC: 4.36′ (Gradient 1); MH+: 787.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:9]([F:12])([F:11])[F:10])[C:5]([NH2:8])=[N:6][CH:7]=1.[F:13][C:14]([F:25])([F:24])[C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.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>[F:10][C:9]([F:12])([F:11])[C:4]1[C:5]([NH2:8])=[N:6][CH:7]=[C:2]([C:18]2[CH:19]=[CH:20][C:15]([C:14]([F:25])([F:24])[F:13])=[CH:16][CH:17]=2)[CH:3]=1
Reactant: Nc1ncc(Br)cc1C(F)(F)F
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
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: COCCOC
Product: Nc1ncc(-c2ccc(C(F)(F)F)cc2)cc1C(F)(F)F
Yield: 86.9 %

Procedure:
A mixture of 5-bromo-3-trifluoromethyl-pyridin-2-ylamine (11.5 g, 48 mmol) with 4-trifluormethylphenylboronic acid (9.97 g, 52 mmol), Pd(PPh3)4 (551 mg, 1 mol %) and 1M aq. Na2CO3 soln. (111 mL, 111 mmol) in DME (250 mL) at reflux for 1 h. Poured on icewater, extracted with EtOAc, dried over Na2SO4 and concentrated. Purified by column chromatography (heptane/AcOEt 2:1), then triturated the collected solids with heptane and a few drops of ether, ultrasound sonication for 10 min, filtrated and dried in to give the product as a white crystalline solid (12.77 g, 87%). MS (ISP) 307.2 [(M+H)+].
Reaction SMILES: [OH-].[Na+].[CH2:3]1[O:10][C:9]2[C:5](=[C:6]([Br:16])[S:7][C:8]=2[C:11]([O:13]CC)=[O:12])[O:4]1>CO>[CH2:3]1[O:10][C:9]2[C:5](=[C:6]([Br:16])[S:7][C:8]=2[C:11]([OH:13])=[O:12])[O:4]1
Reactant: CCOC(=O)c1sc(Br)c2c1OCO2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1sc(Br)c2c1OCO2
Reaction time: 2 h

Procedure:
NaOH (10%) and MeOH were mixed in the proportion 1:1 (80 mL) and added to 3,4-methylenedioxy-2-bromo-5-ethoxycarbonyl thiophene (1.91 g, 7.00 mmol (Example 77)), and the reaction mixture was heated to 60°-70° C. and kept there for 2h. After cooling, the reaction mixture was filtered and the MeOH of the filtrate was evaporated and water was added. Acidification with 10% HCl precipitated the free acid 3,4-methylenedioxy-2-bromo-5-carboxy thiophene, which was filtered and dried in a desiccator (P2O5), yielding 1.41 g (82%).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(N(C(C)C)CC)(C)C.[F:23][C:24]([F:35])([F:34])[C:25]1[CH:33]=[CH:32][CH:31]=[CH:30][C:26]=1[C:27](Cl)=[O:28]>ClCCl>[C:4]([O:3][C:1]([N:8]1[CH2:9][CH2:10][N:11]([C:27](=[O:28])[C:26]2[CH:30]=[CH:31][CH:32]=[CH:33][C:25]=2[C:24]([F:23])([F:34])[F:35])[CH2:12][CH2:13]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=C(Cl)c1ccccc1C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 0.02 h
Yield: 95 %

Procedure:
To a stirred solution of 1-Boc-piperazine (1.96 g, 10.5 mmol) and diisopropylethylamine (2.714 g, 21 mmol, 3.63 mL) in dichloromethane (50 mL) was added 2-trifluoromethylbenzoyl chloride (2.086 g, 10.0 mmol) dropwise. The resulting mixture was stirred at room temperature for 1 minutes and then quenched with water (25 mL). The organic phase was separated and washed with H2O, brine, dried over MgSO4 and then concentrated in vacuo to afford product 4-(2-trifluoromethylbenzoyl)-piperazine-1-carboxylic acid tert-butyl ester as pale yellow solid. Yield 95%, 3.575 g.
Reaction SMILES: [Li]CCCC.Br[C:7]1[CH:8]=[CH:9][C:10]([C:13]([F:16])([F:15])[F:14])=[N:11][CH:12]=1.[N+:17]([C:20]1[C:21]([CH:30]=[O:31])=[CH:22][CH:23]=[C:24]2[C:29]=1[N:28]=[CH:27][CH:26]=[CH:25]2)([O-:19])=[O:18]>C1COCC1>[N+:17]([C:20]1[C:21]([CH:30]([C:7]2[CH:12]=[N:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=2)[OH:31])=[CH:22][CH:23]=[C:24]2[C:29]=1[N:28]=[CH:27][CH:26]=[CH:25]2)([O-:19])=[O:18]
Reactant: FC(F)(F)c1ccc(Br)cn1
Reactant: O=Cc1ccc2cccnc2c1[N+](=O)[O-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=[N+]([O-])c1c(C(O)c2ccc(C(F)(F)F)nc2)ccc2cccnc12
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 22.7 %

Procedure:
n-BuLi (1.6M in hexane; 2.77 ml, 4.43 mmol) was added dropwise to a solution of 5-bromo-2-(trifluoromethyl)pyridine (1 g, 4.42 mmol) in THF (5 ml) at −78° C. The mixture was stirred at −78° C. for 30 min before 8-nitroquinoline-7-carbaldehyde (Intermediate 204) (0.89 g, 4.42 mmol) in THF (10 ml) was added and the mixture was stirred at −78° C. for 10 min. The mixture was quenched with sat. NH4Cl (5 ml) at −78° C. and allowed to warm to room temperature. The resulting mixture was extracted with EtOAc (50 ml, ×2), the organic phase was washed with brine (20 ml), dried (Na2SO4) and concentrated in vacuo. The crude residue was purified by column chromatography with heptane/EtOAc (50:50) as the eluent to give the title compound (350 mg, 23%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9](=[O:11])[CH3:10])[CH:5]=[N:6][C:7]=1[Cl:8].[CH3:12][Mg+].[Br-]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]([OH:11])([CH3:12])[CH3:10])[CH:5]=[N:6][C:7]=1[Cl:8]
Reactant: CC(=O)c1cnc(Cl)c(Cl)c1
Reactant: C[Mg+]
Agent: [Br-]
Product: CC(C)(O)c1cnc(Cl)c(Cl)c1

Procedure:
1-(5,6-Dichloro-pyridin-3-yl)-ethanone from step (a) above (300 mg, 1.58 mmol) reacted with MeMgBr (0.79 mL, 2.4 mmol, 3.0 M in ether, Aldrich) under the conditions of Example 154b to give the title compound. MS (ESI, pos. ion) m/z: 206 (M+1).
Reaction SMILES: [CH2:1]([N:5]([CH2:13][C:14](=[O:17])[CH:15]=[CH2:16])[C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9])[CH2:2]C=C>C(Cl)Cl>[O:17]=[C:14]1[CH2:13][N:5]([C:6]([O:7][C:8]([CH3:9])([CH3:10])[CH3:11])=[O:12])[CH2:1][CH2:2][CH:16]=[CH:15]1
Reactant: C=CCCN(CC(=O)C=C)C(=O)OC(C)(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC=CC(=O)C1
Temperature: 18 °C
Reaction time: 10 h
Yield: 64.1 %

Procedure:
To a mixture of tert-butyl N-but-3-enyl-N-(2-oxobut-3-enyl)carbamate (1.50 g, 6.27 mmol, 1.00 Eq) in DCM (250 mL), was added Zhan catalyst 1B (150.00 mg, 204.43 umol, 0.03 Eq) in one portion at 18° C. under N2. The mixture was stirred at 18° C. for 10 hr. TLC showed the reaction was completed. The mixture was concentrated in vacuum. The residue was purified by silica gel chromatography (PE/EA=30/1, 20/1) to afford tert-butyl 6-oxo-3,7-dihydro-2H-azepine-1-carboxylate (850.00 mg, 4.02 mmol, 64.17% yield) as yellow solid. 1H NMR (400 MHz, CHLOROFORM-d) 6.36-6.64 (m, 1H), 5.88-6.14 (m, 1H), 4.23-4.35 (m, 1H), 4.16 (s, 1H), 3.51-3.68 (m, 2H), 2.62-2.78 (m, 2H), 1.46 (d, J=17.32 Hz, 1H).
Reaction SMILES: [CH2:1]([N:4]([CH2:12][CH3:13])[S:5]([C:8]([F:11])([F:10])[F:9])(=[O:7])=[O:6])[CH:2]=[CH2:3].[CH2:14]([O:16][P:17]([O-:21])[O:18][CH2:19][CH3:20])[CH3:15]>>[CH2:12]([N:4]([CH2:1][CH2:2][CH2:3][P:17]([O:18][CH2:19][CH3:20])(=[O:21])[O:16][CH2:14][CH3:15])[S:5]([C:8]([F:11])([F:9])[F:10])(=[O:7])=[O:6])[CH3:13]
Reactant: C=CCN(CC)S(=O)(=O)C(F)(F)F
Reactant: CCOP([O-])OCC
Product: CCOP(=O)(CCCN(CC)S(=O)(=O)C(F)(F)F)OCC

Procedure:
Following the procedure of Example 1, N-allyl-N-ethyltrifluoromethanesulfonamide (b.p. 395° C. at 1.50-0.35 torr) was reacted with diethylphosphite to produce diethyl 3-(N-ethyltrifluoromethanesulfonamido)propanephosphonate (b.p. 147°-155° C. at 0.25 torr). Following the procedure of Example 2, this phosphonate was hydrolyzed to produce the corresponding phosphonic acid (m.p. 137.5°-139.5° C.).
Reaction SMILES: F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C.[Cl:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[CH:37]1[CH:41]=[C:40]([C:42]([OH:44])=O)[O:39][NH:38]1.[NH2:45][C:46]1[CH:47]=[CH:48][C:49]([Cl:64])=[C:50]([CH:63]=1)[C:51]([NH:53][C:54]1[CH:55]=[C:56]2[CH:62]=[CH:61][NH:60][C:57]2=[N:58][CH:59]=1)=[O:52]>CN(C=O)C>[Cl:64][C:49]1[CH:48]=[CH:47][C:46]([NH:45][C:42]([C:40]2[O:39][N:38]=[C:37]([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=3[Cl:30])[CH:41]=2)=[O:44])=[CH:63][C:50]=1[C:51](=[O:52])[NH:53][C:54]1[CH:55]=[C:56]2[CH:62]=[CH:61][NH:60][C:57]2=[N:58][CH:59]=1
Reactant: O=C(O)C1=CC(c2ccccc2Cl)NO1
Reactant: Nc1ccc(Cl)c(C(=O)Nc2cnc3[nH]ccc3c2)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(Cl)c(C(=O)Nc2cnc3[nH]ccc3c2)c1)c1cc(-c2ccccc2Cl)no1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 38.3 %

Procedure:
2-(1H-Benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TBTU) (0.084 g, 0.26 mmol) and triethylamine (50 μL, 0.35 mmol) were added to a solution of 3-(2-chloro-phenyl)-2,3-dihydro-isoxazole-5-carboxylic acid (0.058 g, 0.26 mmol) in DMF (1 ml) and the reaction stirred for 10 minutes at room temperature. 5-Amino-2-chloro-N-(1H-pyrrolo[2,3-b]pyridin-5-yl)-benzamide (0.050 g, 0.175 mmol) was added to the reaction mixture and stirred for a further 24 hours. The solvent was removed under reduced pressure then methanol (3 ml) and ammonium hydroxide (1 ml) were added to the residue and the mixture stirred for a further 3 hours. The solvent was removed under reduced pressure and the resultant solid triturated with acetonitrile:water (1:1, 5 ml). The solid was filtered to afford 3-(2-Chloro-phenyl)-isoxazole-5-carboxylic acid [4-chloro-3-(1H-pyrrolo[2,3-b]pyridin-5-ylcarbamoyl)-phenyl]-amide 0.033 g (37% yield)
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[C:16](=[O:20])[NH:15][N:14]=[CH:13]3)=[CH:4][CH:3]=1.Cl.[CH3:22][N:23]([CH3:27])[CH2:24][CH2:25][Cl:26]>>[ClH:26].[OH:1][C:2]1[CH:3]=[CH:4][C:5](/[CH:8]=[CH:9]/[C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[C:16](=[O:20])[N:15]([CH2:25][CH2:24][N:23]([CH3:27])[CH3:22])[N:14]=[CH:13]3)=[CH:6][CH:7]=1
Reactant: O=c1[nH]ncc2cc(/C=C/c3ccc(O)cc3)ccc12
Reactant: CN(C)CCCl
Agent: Cl
Product: CN(C)CCn1ncc2cc(/C=C/c3ccc(O)cc3)ccc2c1=O

Procedure:
Following the procedure of Example 15 above trans-6-[2-(4-hydroxyphenyl)ethenyl]-1(2H)phthalazinone (19.8 ) and 2-dimethylaminoethyl chloride hydrochloride (17.3 g) were reacted to give the 2-(2-dimethylaminoethyl)derivative as the hydrochloride (16 g), mp 283°-285° C.
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:10]=[C:9]([SH:11])[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[OH:16])([CH3:4])[CH3:3].[CH:17]([C:20]([CH:22]=[CH2:23])=[O:21])([CH3:19])[CH3:18].C(N(CC)CC)C>CO>[CH3:4][C:2]([C:5]1[CH:10]=[C:9]([S:11][CH2:23][CH2:22][C:20](=[O:21])[CH:17]([CH3:19])[CH3:18])[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[OH:16])([CH3:1])[CH3:3]
Reactant: C=CC(=O)C(C)C
Reactant: CC(C)(C)c1cc(S)cc(C(C)(C)C)c1O
Solvent: CO
Solvent: CCN(CC)CC
Product: CC(C)C(=O)CCSc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1

Procedure:
The thiol of Example 2 (4.76 g, 0.02 mole) was reacted with isopropylvinyl ketone (3.6 g) and triethylamine (3 ml) in methanol (50 ml) by the method of Example 3 to give the title compound, m.p. ca. 50-53° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[CH:6][C:5]2=O.[OH-].[Na+].P(Cl)(Cl)([Cl:17])=O>>[Cl:17][C:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([CH3:1])[CH:3]=2)[N:8]=[CH:7][CH:6]=1
Reactant: Cc1ccc2[nH]ccc(=O)c2c1
Reactant: O=P(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Product: Cc1ccc2nccc(Cl)c2c1
Temperature: 25 °C

Procedure:
6-Methyl-(1H)-quinolin-4-one (1.57 g, 9.7 mmol) in 20 mL phosphorus oxychloride is heated to 110° C. for 4 hours. The mixture is cooled to room temperature then diluted with ice water (˜200 mL) and the pH is adjusted to ca. 10 by the slow addition of 10 N NaOH. The aqueous solution is extracted with methylene chloride (4×250 mL) and the combined organic layers washed with brine, dried over Na2SO4, filtered and concentrated. The crude residue is filtered through silica gel with 33% EtOAc/hexanes to give the product (1.05 g, 5.9 mmol) as a yellow solid.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:10]=[C:11]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:12]=1[OH:13])[CH:8]=O)([CH3:4])([CH3:3])[CH3:2].[C:18]([CH2:20]C(O)=O)#[N:19].N1CCCCC1.Cl>N1C=CC=CC=1>[C:1]([C:5]1[CH:6]=[C:7]([CH:10]=[C:11]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:12]=1[OH:13])[CH:8]=[CH:20][C:18]#[N:19])([CH3:4])([CH3:3])[CH3:2]
Reactant: N#CCC(=O)O
Reactant: CC(C)(C)c1cc(C=O)cc(C(C)(C)C)c1O
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: CC(C)(C)c1cc(C=CC#N)cc(C(C)(C)C)c1O
Temperature: 25 °C

Procedure:
3,5-di tert.butyl-4-hydroxycinnamonitrile was prepared by heating a mixture of 85.5 grams of 3,5-di tert.butyl-4-hydroxybenzaldehyde, 62 grams of cyanoacetic acid, 360 milliliters of pyridine, and 18 milliliters of piperidine at 80° C. for 3 hours. The reaction mixture was cooled to room temperature and poured into a mixture of 200 milliliters of concentrated hydrochloric acid and 350 grams of ice. The sticky solid tht precipitated was separated and recrystallized from petroleum ether. The yield was 48.8 grams of product which melted at 109° to 113° C.
Reaction SMILES: COC1C=CC(C[N:8](CC2C=CC(OC)=CC=2)[C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]3[C:17]([NH:22][C:23]4[CH:24]=[CH:25][C:26]5[O:30][C:29]([CH3:31])=[N:28][C:27]=5[CH:32]=4)=[N:18][CH:19]=[CH:20][CH:21]=3)[N:10]=2)=CC=1>C(O)(C(F)(F)F)=O>[NH2:8][C:9]1[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]2[C:17]([NH:22][C:23]3[CH:24]=[CH:25][C:26]4[O:30][C:29]([CH3:31])=[N:28][C:27]=4[CH:32]=3)=[N:18][CH:19]=[CH:20][CH:21]=2)[N:10]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cccnc3Nc3ccc4oc(C)nc4c3)n2)cc1
Solvent: O=C(O)C(F)(F)F
Product: Cc1nc(N)nc(-c2cccnc2Nc2ccc3oc(C)nc3c2)n1
Yield: 1.6 %

Procedure:
A solution of N-(3-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)pyridin-2-yl)-2-methylbenzo[d]oxazol-5-amine (0.116 g, 0.202 mmol) in TFA (8.0 mL) (Aldrich) was heated at 80° C. overnight. The TFA was removed in vacuo. The crude product was dissolved in 4 mL of DMSO and was purified by reversed phase chromatography (Gilson; 10-90% CH3CN in water with TFA additive: 0.1% v/v in each solvent). The fractions were combined and the CH3CN was removed. DCM was added and the whole was washed with a saturated solution of NaHCO3 (1×), brine (1×), dried over MgSO4, filtered and concentrated. The compound and impurities had co-eluted. The material was purified by flash column chromatography using an ISCO Combiflash Companion (4 g column; 1-10% MeOH in DCM over 40 minutes). The compound and impurities co-eluted. The crude product was dissolved in 4 mL of DMSO. Purification by reversed phase chromatography (Gilson; 10-90% CH3CN in water with NH4OH additive: 0.1% v/v in each solvent) followed by drying in a Genevac Series II System gave N-(3-(4-amino-6-methyl-1,3,5-triazin-2-yl)pyridin-2-yl)-2-methylbenzo[d]oxazol-5-amine (1.079 mg, 3.24 μmol, 1.6% yield) as a yellow amorphous solid. 1H NMR (400 MHz, d6-DMSO) δ 12.04 (s, 1H); 8.79 (dd, J=7.7, 2.1 Hz, 1H); 8.37 (dd, J=4.7, 2.0 Hz, 1H); 8.33 (d, J=2.0 Hz, 1H); 7.86 (q, J=3.2 Hz, 1H); 7.70-7.77 (m, 1H); 7.62-7.68 (m, 1H); 7.54-7.60 (m, 1H); 6.91 (dd, J=7.8, 4.7 Hz, 1H); 2.60 (s, 3H); 2.45 (s, 4H). m/z (ESI, +ve ion) 334.1 (M+H)+.