Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(=[O:8])[O:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.S(=O)(=O)(O)O.[C:14](OCC)(=[O:16])C.CCCCCC>CO>[OH:16][CH2:14][CH2:5][CH2:4][CH2:3][CH2:2][C:1]([O:7][CH3:6])=[O:8]
Reactant: O=C1CCCCCO1
Reactant: CCOC(C)=O
Agent: O=S(=O)(O)O
Solvent: CCCCCC
Solvent: CO
Product: COC(=O)CCCCCO
Temperature: 25 °C
Reaction time: 48 h
Yield: 64 %

Procedure:
ε-Caprolactone (12.50 g, 109.51 mM) was dissolved in methanol (125 ml), and a sulfuric acid solution (1 ml, 0.01 mM) was slowly added thereto. The resulting mixture was stirred at room temperature for 2 days. After the completion of reaction, methanol was removed under reduced pressure, and then ice water was poured into the residue. The resulting mixture was extracted with ethyl ether. The organic layer was separated, washed with an aqueous saturated sodium bicarbonate solution and brine in order and concentrated under reduced pressure. The residue thus obtained was subjected to a silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/2) to obtain 10.18 g of the title compound (yield 64%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10](C(S)C(OCC)=O)=[S:11])=[CH:5][CH:4]=1.[NH:19]([C:21]([O:23][CH3:24])=[O:22])[NH2:20]>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][C:10]([NH:20][NH:19][C:21]([O:23][CH3:24])=[O:22])=[S:11])=[CH:7][CH:8]=1
Reactant: COC(=O)NN
Reactant: CCOC(=O)C(S)C(=S)Cc1ccc(OC)cc1
Solvent: ClCCl
Product: COC(=O)NNC(=S)Cc1ccc(OC)cc1

Procedure:
A mixture of 50 g of the above ester, 18.g. of methyl hydrazinocarboxylate and 300 ml of dichloromethane was refluxed for 2 hours, then washed twice with water, once with saturated sodium chloride and dried. The resulting oily residue was concentrated under high vacuum at 50° C. for 2 hours and the semi-solid crystallized from toluene-hexane, giving 36 g of the desired compound as ivory colored crystals, mp 94.5-95° C. Proton nuclear magnetic resonance (δ[ppm], CDCl3) 90MHz: 3.78 (s, 3H, OCH3); 3.80 (s, 3H, OCH3); 4.03 (s, 2H, CH2CS); [6.89 (d, 2H, J=8.2Hz) and 7.21 (d, 2H)(C6H4)]8.60 (bs, 1H, NH); 9.40 (bs, 1H, NH).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:35]=[CH:34][C:17]3[C:18]4[N:22]([CH2:23][CH2:24][O:25][C:16]=3[CH:15]=2)[CH:21]=[C:20]([C:26]2[N:27]([CH:31]([CH3:33])[CH3:32])[N:28]=[CH:29][N:30]=2)[N:19]=4)[CH2:10][CH2:9]1)=O)(C)(C)C.[C:36]([OH:42])([C:38]([F:41])([F:40])[F:39])=[O:37]>C(Cl)Cl>[F:39][C:38]([F:41])([F:40])[C:36]([OH:42])=[O:37].[CH:31]([N:27]1[C:26]([C:20]2[N:19]=[C:18]3[N:22]([CH2:23][CH2:24][O:25][C:16]4[CH:15]=[C:14]([CH:11]5[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]5)[CH:35]=[CH:34][C:17]=43)[CH:21]=2)=[N:30][CH:29]=[N:28]1)([CH3:33])[CH3:32]
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(C3CCN(C(=O)OC(C)(C)C)CC3)cc1OCC2
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(C3CCNCC3)cc1OCC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
To a solution of 4-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yl]-piperidine-1-carboxylic acid tert-butyl ester (1.2 g, 2.51 mmol) in DCM (12 mL) was added TFA (8 mL) and the reaction mixture stirred at RT for 1 h. The reaction mixture was concentrated in vacuo, the residue tirutrated in diethyl ether to give 2-(2-Isopropyl-2H-[1,2,4]triazol-3-yl)-8-piperidin-4-yl-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene trifluoroacetic acid salt as a grey solid (1.34 g, 100%). LCMS: RT=2.88 min, M+H+=379
Reaction SMILES: [CH3:1][Si:2]([C:5]#[CH:6])([CH3:4])[CH3:3].[Li]CCCC.[C:12]([SiH2:16][O:17][C:18]([CH3:27])([CH3:26])[CH:19]1[CH2:24][C:23](=[O:25])[CH2:22][CH2:21][O:20]1)([CH3:15])([CH3:14])[CH3:13]>C1COCC1>[C:12]([SiH2:16][O:17][C:18]([CH3:27])([CH3:26])[CH:19]1[CH2:24][C:23]([C:6]#[C:5][Si:2]([CH3:4])([CH3:3])[CH3:1])([OH:25])[CH2:22][CH2:21][O:20]1)([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)[SiH2]OC(C)(C)C1CC(=O)CCO1
Reactant: C#C[Si](C)(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)[SiH2]OC(C)(C)C1CC(O)(C#C[Si](C)(C)C)CCO1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84.3 %

Procedure:
A cold (−78 ° C.), stirred solution of (trimethylsilyl)acetylene (1.01 g, 10.3 mmol) in anhydrous THF (25 mL) was treated with nBuLi (4.12 mL in hexane, 10.3 mmol) under nitrogen. The colorless solution was stirred for 30 minutes and followed by the addition of 2-(tert-butyl-dimethyl-silanyloxymethyl)-tetrahydro-pyran-4-one (1.48 g, 6.06 mmol) in anhydrous THF (25 mL). The reaction was warmed up to room temperature, stirred for 2 hours, and quenched with water (30 mL). After removal of THF, the product was extracted with EtOAc (2×50 mL). The combined organic layer was washed with brine, dried over sodium sulfate, and concentrated to give 1.75 g (84%) of yellow oil: 1H NMR (CDCl3) δ 0.05 (s, 6H), 0.16 (s, 9H), 0.89 (s, 9H), 1.43 (m, 1H), 1.78 (td, 1H), 1.83 (d, 1H), 1.94 (d, 1H), 3.52-3.70 (m, 4H), 4.00 (m 1H).
Reaction SMILES: [C:1]([O:10]C)(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[SH:4].[F:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]2[CH2:24][CH2:23][N:22]([C:25]3[CH:26]=[C:27]([CH:30]=[CH:31][N:32]=3)[C:28]#[N:29])[CH2:21][CH2:20]2)=[CH:15][CH:14]=1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[F:12][C:13]1[CH:14]=[CH:15][C:16]([N:19]2[CH2:24][CH2:23][N:22]([C:25]3[CH:26]=[C:27]([C:28]4[S:4][C:3]5[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=5[C:1](=[O:10])[N:29]=4)[CH:30]=[CH:31][N:32]=3)[CH2:21][CH2:20]2)=[CH:17][CH:18]=1
Reactant: N#Cc1ccnc(N2CCN(c3ccc(F)cc3)CC2)c1
Reactant: COC(=O)c1ccccc1S
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=c1nc(-c2ccnc(N3CCN(c4ccc(F)cc4)CC3)c2)sc2ccccc12
Yield: 17.9 %

Procedure:
Methyl thiosalicylate (0.70 g, 4.2 mmol) and 2-[4-(4-fluorophenyl)-1-piperazinyl]isonicotinonitrile (0.69 g, 2.4 mmol) were dissolved in toluene (2.0 ml), and triethylamine (0.71 ml, 5.1 mmol) was added thereto. The reaction mixture was refluxed for 17 hrs and the precipitated crystals were collected by filtration. The filtrate was concentrated, subjected to a silica gel (50 g) column chromatography, eluted with hexane-ethyl acetate (2:1, v/v) to give crystals, which were combined with the previously obtained crystals and recrystallized from acetone-ethanol to give the titled compound (0.18 g, 17%) as white crystals.
Reaction SMILES: [H-].[Na+].[CH:3]1([C:9]2[NH:10][C:11](=[O:19])[C:12]([C:17]#[N:18])=[C:13]([S:15][CH3:16])[N:14]=2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.Br[CH2:21][C:22]([O:24][CH3:25])=[O:23]>O>[C:17]([C:12]1[C:11](=[O:19])[N:10]([CH2:21][C:22]([O:24][CH3:25])=[O:23])[C:9]([CH:3]2[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]2)=[N:14][C:13]=1[S:15][CH3:16])#[N:18]
Reactant: CSc1nc(C2CCCCC2)[nH]c(=O)c1C#N
Reactant: COC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: COC(=O)Cn1c(C2CCCCC2)nc(SC)c(C#N)c1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 99 %

Procedure:
To a cooled (0° C.), stirred suspension of NaH (50% dispersion in mineral oil, washed with hexane, 2.2 g, 0.047 (mol) in DME (350 mL) was added 2-cyclohexyl-1,6-dihydro-4-(methylthio)-6-oxo-5-pyrimidinecarbonitrile (9.5 g, 0.038 mol) in several portions. After 1 hour, methyl bromoacetate was added and the resulting solution was heated at 95°-100° C. for 2 days. The solution was cooled and water (300 mL) was added. The mixture was extracted with ethyl acetate and the combined extracts were washed with water, dried (MgSO4), and concentrated to give a beige powder (12.2 g, 99%) which was used without further purification.
Reaction SMILES: Cl[C:2]1[O:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[CH3:11][NH:12][CH2:13][CH2:14][OH:15]>O1CCCC1>[CH3:11][N:12]([CH2:13][CH2:14][OH:15])[C:2]1[O:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: Clc1nc2ccccc2o1
Reactant: CNCCO
Solvent: C1CCOC1
Product: CN(CCO)c1nc2ccccc2o1
Temperature: 25 °C

Procedure:
A solution of 2-chlorobenzoxazole (15.4 g) in dry tetrahydrofuran (50 ml) was added dropwise to an ice cooled solution of 2-methylaminoethanol (15.0 g) in dry tetrahydrofuran (100 ml) with stirring and protection from atmospheric moisture. The mixture was stirred at 0° C. for 1 hour, allowed to warm to room temperature and stirred for a further 2 hours. The solvent was removed under reduced pressure, the product was dissolved in ethyl acetate (200 ml) and washed with brine (2×150 ml). The organic layer was dried (MgSO4), filtered and the solvent evaporated. Chromatography of the residue on silica-gel in dichloromethane gave the title compound (mp 62°-3° C.) which was used in Preparation 3 without further purification.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[O:3][C:4]1[CH:5]=[C:6]([CH:15]=[CH:16][CH:17]=1)[O:7][CH2:8][CH2:9][C:10]([O:12]CC)=[O:11].[OH-].[Li+].Cl>C1COCC1.O>[F:1][C:2]([F:18])([F:19])[O:3][C:4]1[CH:5]=[C:6]([CH:15]=[CH:16][CH:17]=1)[O:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11]
Reactant: CCOC(=O)CCOc1cccc(OC(F)(F)F)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)CCOc1cccc(OC(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 105.2 %

Procedure:
To a solution of ethyl 3-(3-(trifluoromethoxy)phenoxy)propanoate (1.0 g, 3.42 mmol) in THF (8 mL) was added a solution of lithium hydroxide (164 mg, 6.83 mmol) in water (4 mL). The reaction was stirred at room temperature overnight. The reaction was neutralized with diluted HCl and extracted with ethyl acetate. The organic phase was washed with brine, dried over sodium sulfate, and concentrated to give 3-(3-(trifluoromethoxy)phenoxy)propanoic acid (0.9 g, 99.1% yield) as colorless oil which was used without purification.
Reaction SMILES: [CH2:1]([C:8]1[S:12][C:11]([NH:13][C:14](=[O:22])[C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)=[N:10][C:9]=1[C:23]1[CH:28]=[CH:27][C:26]([O:29]C)=[CH:25][CH:24]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>ClCCl>[CH2:1]([C:8]1[S:12][C:11]([NH:13][C:14](=[O:22])[C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)=[N:10][C:9]=1[C:23]1[CH:24]=[CH:25][C:26]([OH:29])=[CH:27][CH:28]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(-c2nc(NC(=O)c3ccc(F)cc3)sc2Cc2ccccc2)cc1
Solvent: ClCCl
Product: O=C(Nc1nc(-c2ccc(O)cc2)c(Cc2ccccc2)s1)c1ccc(F)cc1
Temperature: -10 °C
Reaction time: 1 h
Yield: 67.2 %

Procedure:
To a 100 ml three-necked flask were added 0.60 g (1.43 mmol) N-[5-benzyl-4-(4-methoxy-phenyl)-thiazol-2-yl]-4-fluoro-benzamide prepared in Example 4 and 15 ml dichloromethane, maintaining the temperature at lower than −10° C. in ice salt bath, and then added dropwise 1.7 ml of 1.763 mol/L BBR3 solution in dichloromethane. Upon the completion of addition, the resulting mixture was stirred at that temperature for 1 hour and then at room temperature for 1 hour, added 2 g ice, distilled under a reduced pressure to remove dichloromethane, and then added 20 ml ethyl acetate. The organic layer was separated, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated under a reduced pressure to give a crude product, which was recrystallized with ethyl acetate/petroleum ether to obtain a 0.39 product as a white solid in a yield of 67.2%, mp: 205-206 └. 1H-NMR (DMSO-d6, 400 MHz) δ: 4.22 (2H, s, CH2), 6.84 (2H, d, J=8.68 Hz, ArH), 7.23˜7.39 (7H, m, ArH), 7.47 (2H, d, J=8.68 Hz, ArH), 8.15 (2H, dd, 3JHH=9.00, 4JFH=5.64 Hz, ArH), 9.62 (1H, s, OH), 12.66 (1H, s, CONH); EI-MS m/e (%): 404.1 (M+, 100), 123.0 (70); HREI-MS Calcd. for C23H17FN2O2S: 404.0995. found: 404.0988.
Reaction SMILES: [CH3:1][C:2]([C:21]1[N:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=1)([C:6]1[CH:11]=[CH:10][C:9](B2OC(C)(C)C(C)(C)O2)=[CH:8][CH:7]=1)[CH:3]([CH3:5])[CH3:4].Cl[C:29]1[N:30]=[N:31][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:33][CH:34]=1.CC(C1C=CC(OCC2C=CC=CN=2)=CN=1)(C1C=CC(B2OC(C)(C)C(C)(C)O2)=CC=1)C(C)C.ClC1N=NC(Cl)=CC=1>>[CH3:1][C:2]([C:21]1[N:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=1)([C:6]1[CH:7]=[CH:8][C:9]([C:29]2[N:30]=[N:31][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:33][CH:34]=2)=[CH:10][CH:11]=1)[CH:3]([CH3:4])[CH3:5]
Reactant: CC(C)C(C)(c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)c1ccc(O)cn1
Reactant: FC(F)(F)c1ccc(Cl)nn1
Agent: CC(C)C(C)(c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)c1ccc(OCc2ccccn2)cn1
Agent: Clc1ccc(Cl)nn1
Product: CC(C)C(C)(c1ccc(-c2ccc(C(F)(F)F)nn2)cc1)c1ccc(O)cn1

Procedure:
Compound 8b was prepared from 8a following procedures similar to those described for preparing compound 5, substituting compound 8a and 3-chloro-6-trifluoromethylpyridazine for compound 5a and 3,6-dichloropyridazine, respectively. m/z (ES) 402 (MH)+)
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([C:14](=[N:25][NH2:26])[C:15]2[C:20](Cl)=[CH:19][N:18]=[C:17]3[NH:22][CH:23]=[CH:24][C:16]=23)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)([O-])C.[Na+].CO>CN1C(=O)CCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2CCCCC2)C2[C-](CCP(C(C)(C)C)C(C)(C)C)C=CC=2)CCCCC1.[CH-]1C=CC=C1.[Fe+2]>[CH2:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([C:14]2[C:15]3=[C:16]4[CH:24]=[CH:23][NH:22][C:17]4=[N:18][CH:19]=[C:20]3[NH:26][N:25]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NN=C(c1c(Cl)cnc2[nH]ccc12)C1CCCN(Cc2ccccc2)C1
Agent: [Fe+2]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CO
Solvent: CN1CCCC1=O
Product: c1ccc(CN2CCCC(c3n[nH]c4cnc5[nH]ccc5c34)C2)cc1
Temperature: 160 °C
Yield: 19 %

Procedure:
A mixture of 4-((1-benzylpiperidin-3-yl)(hydrazono)methyl)-5-chloro-1H-pyrrolo[2,3-b]pyridine (1.04 g, 2.84 mmol), sodium tert-butoxide (0.652 g, 6.78 mmol), palladium acetate (0.0064 g, 0.028 mmol) and (R)-1-[(S)-2-(dicyclohexylphosphino)ferrocenyl]ethyl-di-tert-butyl phosphine (0.016 g, 0.028 mmol) in NMP (10 mL) was heated in the microwave at about 160° C. for about 30 min. Additional palladium acetate (0.0064 g, 0.028 mmol) and (R)-1-[(S)-2-(dicyclohexylphosphino)ferrocenyl]ethyl-di-tert-butyl phosphine (0.016 g, 0.028 mmol) were added and the mixture was heated in a microwave at about 160° C. for about 15 min. Additional palladium acetate (0.003 g, 0.014 mmol) and (R)-1-[(−2-(dicyclohexylphosphino)ferrocenyl]ethyl-di-tert-butyl phosphine (0.008 g, 0.014 mmol) were added and the mixture was again heated at about 160° C. for about 8 min. The solvent was removed under reduced pressure and the residue was partitioned between water (25 mL) and EtOAc (25 mL). The organic phase was washed with brine (20 mL), dried over anhydrous MgSO4, decolorized with charcoal and filtered. The solvent was removed under reduced pressure and the residue purified by silica gel chromatography, eluting first with DCM (1 L), a mixture of 98:1:1 DCM:TEA:MeOH (1 L) and then with a mixture of 97:1:2 DCM:TEA:MeOH (1 L) to yield 1-(1-benzylpiperidin-3-yl)-3,6-dihydropyrazolo[4,3-d]pyrrolo[2,3-b]pyridine (0.18 g, 0.54 mmol, 19%) as a brown solid: LC/MS (Table 2, Method a) Rt=1.36 min; MS m/z: 332 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][CH:11]=[C:10]([CH2:16][C:17]3[CH:18]=[CH:19][C:20]([N:23]4[CH2:27][CH2:26][CH2:25][C@H:24]4[C:28](O)=[O:29])=[N:21][CH:22]=3)[C:9]=2[F:31])[CH:5]=[CH:6][CH:7]=1.C([N:35](C(C)C)CC)(C)C.C(OC(Cl)=O)C(C)C.[OH-].[NH4+]>C1COCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][CH:11]=[C:10]([CH2:16][C:17]3[CH:18]=[CH:19][C:20]([N:23]4[CH2:27][CH2:26][CH2:25][C@H:24]4[C:28]([NH2:35])=[O:29])=[N:21][CH:22]=3)[C:9]=2[F:31])[CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(Cc2ccc(N3CCC[C@H]3C(=O)O)nc2)c(F)c1-c1cccc(Cl)c1
Reactant: CCN(C(C)C)C(C)C
Agent: CC(C)COC(=O)Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(Cc2ccc(N3CCC[C@H]3C(N)=O)nc2)c(F)c1-c1cccc(Cl)c1
Temperature: 2.5 °C
Reaction time: 0.08 h

Procedure:
To a cooled (0-5° C.) and stirred solution of (S)-1-[5-(3′-chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-pyridin-2-yl]-pyrrolidine-2-carboxylic acid (I-143, 0.15 g, 0.34 mmol) in THF (2 mL) was added diisopropylethylamine (0.05 g, 0.37 mmol). The reaction mixture was stirred for 5 min, isobutylchloroformate (0.05 g, 0.37 mmol) was added, stirred at 0-5° C. for 45 min. Ammonium hydroxide (28%, 4.0 mL) was added, the reaction warmed to ambient temperature, stirred for 1.5 h. The reaction mixture was diluted with water (5 mL). The organic layer was separated, the aqueous layer was extracted with ethyl acetate (2×20 mL). The combined organic layers were dried with Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography using 5% methanol in dichloromethane followed by preparative thin layer chromatography using 5% methanol in dichloromethane to afford 0.074 g (49%) of P-612 as an off-white solid. 1H NMR (DMSO-d6, 400 MHz): 8.27 (d, J=2.4 Hz, 1H), 7.34-7.46 (m, 4H), 8.2 (d, J=8.8 Hz, 1H), 7.65 (dd, J=8.8, 2.4 Hz, 1H), 7.4-7.46 (m, 2H), 7.37 (br s, 1H), 7.26-7.38 (m, 2H), 6.94 (d, J=8.0 Hz, 1H), 3.92-3.98 (m 3H), 3.93 (s, 2H), 3.73 (s, 3H), 2.55 (t, J=8.4 Hz, 2H), 1.98-2.06 (m, 2H) ppm; MS (APCI+): 441.1 (M+1), LC-MS: 97.0%; HPLC 97.1% pure.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[F:12][C:13]([F:24])([F:23])[C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1.C(N(CC)CC)C>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.ClCCl>[F:12][C:13]([F:24])([F:23])[C:14]1[CH:19]=[CH:18][C:17]([O:1][C:2]2[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=2)=[CH:16][CH:15]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: COC(=O)c1ccc(O)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1ccc(Oc2ccc(C(F)(F)F)cc2)cc1
Reaction time: 48 h

Procedure:
A flask was charged with methyl 4-hydroxybenzoate (500 mg, 3.29 mmol), copper (II) acetate (895 mg, 4.93 mmol), 4-trifluoromethylphenylboronic acid (2.50 g, 13.15 mmol), and 4 angstrom molecular sieves (500 mg). Dichloromethane (33 mL) and triethylamine (1.83 mL, 13.15 mmol) were added, and the reaction mixture was stirred rapidly, open to air. After 48 h, the reaction mixture was filtered and concentrated in vacuo. Purification by flash chromatography on silica gel (0 to 10% EtOAc in hexanes, then 10 to 100% EtOAc in hexanes) provided the title compound: LCMS m/z 297.5 [M+H]+; 1H NMR (500 MHz, CDCl3) δ 8.07-8.05 (m, 2H), 7.63 (d, J=8.5 Hz, 2H), 7.12 (d, J=8.5 Hz, 2H), 7.06-7.04 (m, 2H), 3.92 (s, 3H).
Reaction SMILES: [CH3:1][CH:2]1[O:7][C:6]2[C:8]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:9][C:10]([CH:12]=O)=[CH:11][C:5]=2[NH:4][C:3]1=[O:20].[CH2:21]([NH:23][C:24](=[O:37])[C:25]1[CH:30]=[CH:29][C:28]([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)=[CH:27][CH:26]=1)[CH3:22]>>[CH2:21]([NH:23][C:24](=[O:37])[C:25]1[CH:26]=[CH:27][C:28]([N:31]2[CH2:32][CH2:33][N:34]([CH2:12][C:10]3[CH:9]=[C:8]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[C:6]4[O:7][CH:2]([CH3:1])[C:3](=[O:20])[NH:4][C:5]=4[CH:11]=3)[CH2:35][CH2:36]2)=[CH:29][CH:30]=1)[CH3:22]
Reactant: CCNC(=O)c1ccc(N2CCNCC2)cc1
Reactant: CC1Oc2c(cc(C=O)cc2-c2ccccc2)NC1=O
Product: CCNC(=O)c1ccc(N2CCN(Cc3cc4c(c(-c5ccccc5)c3)OC(C)C(=O)N4)CC2)cc1

Procedure:
Using 349A and N-ethyl-4-(piperazin-1-yl)benzamide 283 in the general procedure for reductive aminations, the title compound was obtained as a white solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 1.09 (t, J=7.20 Hz, 3H) 1.39 (d, J=6.82 Hz, 3H) 2.51-2.55 (m, 4H) 3.19-3.30 (m, 6H) 3.48 (s, 2H) 4.67 (q, J=6.57 Hz, 1H) 6.87-6.97 (m, 4H) 7.31-7.38 (m, 1H) 7.40-7.47 (m, 2H) 7.51-7.56 (m, 2H) 7.71 (d, J=8.84 Hz, 2H) 8.17 (t, J=5.68 Hz, 1H) 10.72 (br. s., 1H). ESI-MS: m/z 485.4 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:20]=[O:21])[C:6]2[O:10][C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)=[CH:8][C:7]=2[CH:19]=1.C[Si]([C:26]([F:29])([F:28])[F:27])(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-].Cl>C1COCC1>[F:27][C:26]([F:29])([F:28])[CH:20]([C:5]1[C:6]2[O:10][C:9]([C:11]3[CH:12]=[CH:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=3)=[CH:8][C:7]=2[CH:19]=[C:3]([O:2][CH3:1])[CH:4]=1)[OH:21]
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: COc1ccc(-c2cc3cc(OC)cc(C=O)c3o2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: C1CCOC1
Product: COc1ccc(-c2cc3cc(OC)cc(C(O)C(F)(F)F)c3o2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79.2 %

Procedure:
To a solution of 2 (1.2 g, 4.3 mmol) and Trimethylsilyltrifluoromethane (20 ml of 0.5M in THF, 10 mmol) in THF (20 ml) was added TBAF (10 ml of 1.0M in THF, 10 mmol) and the reaction was stirred at rt. After 30 min, the rextion was poured into 2N HCl and extracted with ether. The ether was dried, concentrated and the product was purified by column chromatography (eluent 10% EtOAc/Hex) to give 139 as a solid (1.2 g, 80%); Mp=120-122° C.; 1H NMR(CDCl3) δ 7.75 (d, 2 H, J=8.8 Hz), 7.15-6.95 (m, 4 H), 6.84 (s, 1 H), 5.59 (m, 1 H), 3.86 (s, 6 H); MS 353 (M+H)+
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]2[NH:17][C:16](=[O:18])[C:15]3[C:10](=[CH:11][C:12]([O:21][CH3:22])=[CH:13][C:14]=3[O:19][CH3:20])[N:9]=2)[CH:5]=[CH:4][C:3]=1[O:23][CH3:24].[CH:25]([N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1)([CH3:27])[CH3:26].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C([O-])([O-])=O.[Cs+].[Cs+]>ClCCl.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:25]([N:28]1[CH2:33][CH2:32][N:31]([C:2]2[N:7]=[C:6]([C:8]3[NH:17][C:16](=[O:18])[C:15]4[C:10](=[CH:11][C:12]([O:21][CH3:22])=[CH:13][C:14]=4[O:19][CH3:20])[N:9]=3)[CH:5]=[CH:4][C:3]=2[O:23][CH3:24])[CH2:30][CH2:29]1)([CH3:27])[CH3:26]
Reactant: COc1cc(OC)c2c(=O)[nH]c(-c3ccc(OC)c(Br)n3)nc2c1
Reactant: CC(C)N1CCNCC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Product: COc1cc(OC)c2c(=O)[nH]c(-c3ccc(OC)c(N4CCN(C(C)C)CC4)n3)nc2c1
Temperature: 100 °C
Yield: 25 %

Procedure:
To a mixture of 2-(6-bromo-5-methoxypyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one (0.196 g, 0.50 mmol), 1-isopropylpiperazine (0.077 g, 0.60 mmol), BINAP (0.062 g, 0.10 mmol), and Cs2CO3 (0.652 g, 2.0 mmol) in nitrogen saturated dioxane (10 mL) was added palladium(II) acetate (0.022 g, 0.10 mmol). The resulting mixture was heated at 100° C. for 3 h. After that time the reaction was cooled to rt, diluted with dichloromethane (100 mL) and washed with water (20 mL). The organic phase was dried over Na2SO4 and concentrated under reduced pressure. The product was purified by flash column chromatography (silica gel, 90:10:0.1 dichloromethane/methanol/ammonium hydroxide) to give 2-(6-(4-isopropylpiperazin-1-yl)-5-methoxypyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one (0.055 g, 25%) as a pale yellow solid: mp 208-210° C.; 1H NMR (400 MHz, CDCl3): δ 10.23 (br s, 1H), 8.08 (d, J=8.0 Hz, 1H), 7.17 (d, J=8.0 Hz, 1H), 6.79 (d, J=2.4 Hz, 1H), 6.45 (d, J=2.4 Hz, 1H), 3.98 (s, 3H), 3.95 (s, 3H), 3.93 (s, 3H), 3.56 (br s, 4H), 2.78 (br s, 5H), 1.15 (d, J=5.6 Hz, 6H); ESI MS m/z 440 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[N:8]=[C:9]([CH2:12][N:13]3[CH:17]=[CH:16][C:15]([NH2:18])=[N:14]3)[S:10][CH:11]=2)[O:6]CCO1.[CH3:19][N:20]([CH3:35])[C:21]1[CH:22]=[C:23]([C:27]2[O:31][CH:30]=[N:29][C:28]=2[C:32](O)=[O:33])[CH:24]=[CH:25][CH:26]=1>>[C:2]([C:7]1[N:8]=[C:9]([CH2:12][N:13]2[CH:17]=[CH:16][C:15]([NH:18][C:32]([C:28]3[N:29]=[CH:30][O:31][C:27]=3[C:23]3[CH:24]=[CH:25][CH:26]=[C:21]([N:20]([CH3:35])[CH3:19])[CH:22]=3)=[O:33])=[N:14]2)[S:10][CH:11]=1)(=[O:6])[CH3:1]
Reactant: CC1(c2csc(Cn3ccc(N)n3)n2)OCCO1
Reactant: CN(C)c1cccc(-c2ocnc2C(=O)O)c1
Product: CC(=O)c1csc(Cn2ccc(NC(=O)c3ncoc3-c3cccc(N(C)C)c3)n2)n1

Procedure:
Following general procedure B followed by C, starting from 1-[4-(2-methyl-[1,3]dioxolan-2-yl)-thiazol-2-ylmethyl]-1H-pyrazol-3-ylamine and 5-(3-dimethylamino-phenyl)-oxazole-4-carboxylic acid. LC-MS-conditions 05: tR=0.68 min; [M+H]+=437.04.