Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.Br[C:7]1[S:8][CH:9]=[CH:10][N:11]=1.[C:12]([C:15]1[S:16][CH:17]=[CH:18][N:19]=1)(=[O:14])[CH3:13].C(=O)([O-])O.[Na+]>C(OCC)C>[S:8]1[CH:9]=[CH:10][N:11]=[C:7]1[C:12]([C:15]1[S:16][CH:17]=[CH:18][N:19]=1)([OH:14])[CH3:13]
Reactant: CC(=O)c1nccs1
Reactant: Brc1nccs1
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCOCC
Product: CC(O)(c1nccs1)c1nccs1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
n-Butyllithium (2.5 M solution in hexanes, 17.3 ml) was added dropwise to a stirred solution of 2-bromothiazole (6.5 g) in anhydrous diethyl ether (40 ml) at -70° C. under an atmosphere of dry nitrogen. After 30 minutes, 2-acetylthiazole (5 g) in diethyl ether (10 ml) was added dropwise. After a further 1 hour, the mixture was allowed to warm to room temperature. After 1 hour, saturated aqueous sodium hydrogen carbonate solution was added and the organic phase was separated. Further processing in the usual fashion then gave the title compound. M.p. 146°-147° C. 13C Nmr (CDCl3) 31.4, 76.4, 120.3, 142.0 and 175.2 ppm. Found: C, 45.1; H, 3.5; N, 13.0. C8H8 N2OS2 requires C, 45.2; H, 3.8; N, 13.2%. Hydrochloride, m.p. 137°-140° C. (dec.). 13C Nmr (d6 -DMSO) 28.8, 75.4, 120.6, 142.0 and 176.0 ppm.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2([OH:14])[CH2:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1.[CH3:15]I>CN(C=O)C>[Br:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2([O:14][CH3:15])[CH2:13][CH2:12][CH2:11]2)=[CH:8][CH:9]=1
Reactant: OC1(c2ccc(Br)cc2)CCC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC1(c2ccc(Br)cc2)CCC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 74.5 %

Procedure:
To a suspension of NaH (24 mg, ˜55% dispersion in oil, 0.53 mmol) in DMF (2 ml) at 0° C. was added a solution of 1-(4-bromophenyl)-cyclobutanol (100 mg, 0.44 mmol) in DMF (2 ml). The mixture was stirred at 0° C. for 30 min and then methyl iodide (41 μl, 0.66 mmol) was added. The reaction mixture was then warmed up to rt and stirring was continued overnight. The mixture was quenched with water and extracted with ether. The organic phase was washed with water and brine, dried (MgSO4), filtered, and concentrated in vacuo to give a residue which was purified by flash column chromatography (1:9 ether:pentane) to give 1-bromo-4-(1-methoxycyclobutyl)-benzene (79 mg, 75%) as a colorless oil. 1H NMR (CDCl3, 300 MHz): δ 7.50 (d, J=8.5 Hz, 2H), 7.30 (d, J=8.5 Hz, 2H), 2.92 (s, 3H), 2.38-2.33 (m, 4H), 1.94 (m, 1H), 1.67 (m, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([CH2:8][CH2:9][NH:10]C(=O)OC(C)(C)C)=[N:6][CH:7]=1.FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>ClCCl>[Br:1][C:2]1[CH:3]=[N:4][C:5]([CH2:8][CH2:9][NH2:10])=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)NCCc1ncc(Br)cn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCCc1ncc(Br)cn1
Temperature: 25 °C
Reaction time: 7 h
Yield: 84.8 %

Procedure:
To a clear pale yellow mixture of the tert-butyl [2-(5-bromopyrimidin-2-yl)ethyl]carbamate (0.22 g, 0.7 mmol) in dichloromethane (2 ml) was added trifluoroacetic acid (10 equivs) and the mixture was left to stir at room temperature for 7 hrs and left to stand overnight. Saturated sodium bicarbonate solution was added until the effervescence stopped (to give a basic medium). The organic phase was collected, dried over MgSO4, and evaporated in vacuo after filtration, to yield to 0.12 g of 2-(5-bromopyrimidin-2-yl)ethanamine (80%) which is used directly without purification.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:8][CH2:7][CH2:6][CH2:5][C@@H:4]1C(O)=O.[N:12]([O-])=O.[Na+]>OS(O)(=O)=O>[NH2:12][C@H:4]1[CH2:5][CH2:6][CH2:7][CH2:8][C@H:3]1[CH2:2][OH:1]
Reactant: O=C(O)[C@H]1CCCC[C@H]1CO
Reactant: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: N[C@H]1CCCC[C@H]1CO
Temperature: 2.5 °C

Procedure:
The hydrazide of (1S,2R)-2-hydroxymethyl-1-cyclohexanecarboxylic acid (0.5 gram) is reacted with a solution of 0.5 grams of sodium nitrite in 10 ml of 5% H2SO4. The reaction mixture is maintained for 1 hour at 0-5° C., followed extraction of the reaction mixture with ethyl acetate, followed by basification of the resulting aqueous solution with NaOH, extraction with methyl t-butyl ether, drying of the extracts over MgSO4, filtration, and the removal of solvent by rotary evaporation. The product (1S,2R)-1-amino-2-(hydroxymethyl)cyclohexane is isolated as a light yellow oil.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([CH2:19][C:20]#[N:21])([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:10](=[O:22])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)(=O)C.CO.[Pt]=O>[NH2:21][CH2:20][CH2:19][C:11]1([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:12][CH2:13][N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:9][CH:10]1[OH:22]
Reactant: CCOC(=O)C1(CC#N)CCN(Cc2ccccc2)CC1=O
Agent: O=[Pt]
Solvent: CO
Solvent: CC(=O)O
Product: CCOC(=O)C1(CCN)CCN(Cc2ccccc2)CC1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into a 10000-mL 4-necked round-bottom flask was placed a solution of ethyl 1-benzyl-4-(cyanomethyl)-3-oxopiperidine-4-carboxylate (180 g, 599.30 mmol) in acetic acid/methanol (1:1, 5.4 L) and platinum oxide (27 g, 118.90 mmol). The flask was then flushed and charged with hydrogen and stirred overnight at room temperature. After filtration under nitrogen through CELITE®, the filtrate was concentrated under vacuum to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][C:5]([NH2:6])=[C:4]([O:12][CH3:13])[CH:3]=1.C(=O)([O-])O.[Na+].[C:19](Cl)(=[O:21])[CH3:20].O>O1CCCC1>[Cl:1][C:2]1[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][C:5]([NH:6][C:19](=[O:21])[CH3:20])=[C:4]([O:12][CH3:13])[CH:3]=1
Reactant: CC(=O)Cl
Reactant: COc1cc(Cl)c([N+](=O)[O-])cc1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(Cl)c([N+](=O)[O-])cc1NC(C)=O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a mixture of 4-chloro-2-methoxy-5-nitroaniline (0.3 g) and sodium hydrogen carbonate (0.37 g) in tetrahydrofuran (4.5 mL) was added acetyl chloride (0.12 mL), and the mixture was stirred at room temperature for 5 hours. The reaction mixture was poured into water, and the resulting mixture was extracted with ethyl acetate. The extract was washed with 1 mol/L hydrochloric acid, water and brine successively, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane−n-hexane/ethyl acetate=3/7) to give N-(4-chloro-2-methoxy-5-nitrophenyl)acetamide (0.24 g). This material was dissolved in N,N-dimethylformamide (5 mL). To the solution were added 2,3-difluoro-6-methoxybenzyl bromide (0.28 g) and sodium hydride (55%, 48 mg) under ice-cooling, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was poured into water, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was dissolved in tetrahydrofuran (4 mL). To the solution were added methanol (4 mL) and nickel(II) bromide (11 mg). To the mixture was added sodium borohydride (0.11 g) under ice-cooling, and the mixture was stirred at the same temperature for 30 minutes, and then stirred at room temperature for 30 minutes. To the reaction mixture was added a saturated aqueous sodium hydrogen carbonate solution, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane−n-hexane/ethyl acetate=3/7) to give the title compound (0.27 g).
Reaction SMILES: [C:1]([C:3]1[CH:19]=[CH:18][C:6]([O:7][C:8]2[CH:9]=[CH:10][C:11]3[B:15]([OH:16])[O:14][CH2:13][C:12]=3[CH:17]=2)=[CH:5][C:4]=1[OH:20])#[N:2].I[CH3:22].[H-].[Na+].Cl>CN(C)C=O.O>[C:1]([C:3]1[CH:19]=[CH:18][C:6]([O:7][C:8]2[CH:9]=[CH:10][C:11]3[B:15]([OH:16])[O:14][CH2:13][C:12]=3[CH:17]=2)=[CH:5][C:4]=1[O:20][CH3:22])#[N:2]
Reactant: N#Cc1ccc(Oc2ccc3c(c2)COB3O)cc1O
Reactant: CI
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(Oc2ccc3c(c2)COB3O)ccc1C#N
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.3 %

Procedure:
To a solution of 5-(4-cyano-3-hydroxyphenoxy)-1,3-dihydro-1-hydroxy-2,1-benzoxaborole (100 mg, 0.375 mmol) and iodomethane (0.070 mL. 1.1 mmol) in N,N-dimethylformamide (10 mL) was added sodium hydride (60% oil dispersion, 45 mg, 1.1 mmol) at 0° C. under nitrogen atmosphere, and the mixture was stirred at room temperature for 2 h. Water and 1 M HCl were added and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried on anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was treated with hexane/diisopropyl ether to give 5-(4-cyano-3-methoxyphenoxy)-1,3-dihydro-1-hydroxy-2,1-benzoxaborole (92 mg, 87%).
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[C:11]([C:16](=O)/[CH:17]=[CH:18]/[N:19](C)C)=[N:12][CH:13]=[CH:14][CH:15]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Cl.Cl.[F:25][C:26]([F:32])([F:31])[CH2:27][CH2:28][NH:29]N>CCO>[Si:1]([O:8][CH2:9][C:10]1[C:11]([C:16]2[N:29]([CH2:28][CH2:27][C:26]([F:32])([F:31])[F:25])[N:19]=[CH:18][CH:17]=2)=[N:12][CH:13]=[CH:14][CH:15]=1)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3]
Reactant: NNCCC(F)(F)F
Reactant: CN(C)/C=C/C(=O)c1ncccc1CO[Si](C)(C)C(C)(C)C
Agent: Cl
Solvent: CCO
Product: CC(C)(C)[Si](C)(C)OCc1cccnc1-c1ccnn1CCC(F)(F)F
Temperature: 80 °C
Yield: 76 %

Procedure:
To (E)-1-(3-((tert-butyldimethylsilyloxy)methyl)pyridin-2-yl)-3-(dimethylamino)prop-2-en-1-one (crude above, 1.73 g, 5.41 mmol, 1 eq.) in EtOH (10 mL) was added (3,3,3-trifluoropropyl)hydrazine dihydrochloride (1.30 g, crude above, 6.49 mmol, 1.2 eq.) at rt. The mixture was heated at 80° C. for 1 h, concentrated, and diluted with EtOAc (50 mL) and NaHCO3(sat) solution (10 mL). The layers were separated and aqueous layer was extracted with EtOAc three times. The combined organic layers were dried over Na2SO4, concentrated, and purified on silica gel using a mixture of EtOAc and hexanes as eluent to give 3-((tert-butyldimethylsilyloxy)methyl)-2-(1-(3,3,3-trifluoropropyl)-1H-pyrazol-5-yl)pyridine (1.58 g; 76% for 2 steps). 1H NMR (400 MHz, CDCl3) δ 8.53 (dd, J=4.7, 1.6 Hz, 1H), 7.96-7.88 (m, 1H), 7.51 (d, J=1.9 Hz, 1H), 7.29 (dd, J=7.9, 4.7 Hz, 1H), 6.34 (d, J=1.9 Hz, 1H), 4.62 (s, 2H), 4.45-4.33 (m, 2H), 2.82-2.61 (m, 2H), 0.85 (s, 8H), −0.00 (s, 5H). LRMS (M+H+) m/z 386.2.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:6][CH:5]=1)=[O:3].[Br:18]Br>CO>[CH2:11]([O:10][C:7]1[CH:8]=[CH:9][C:4]([C:2](=[O:3])[CH2:1][Br:18])=[CH:5][CH:6]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC(=O)c1ccc(OCc2ccccc2)cc1
Reactant: BrBr
Solvent: CO
Product: O=C(CBr)c1ccc(OCc2ccccc2)cc1
Reaction time: 0.17 h
Yield: 91 %

Procedure:
4-Benzyloxyacetophenone (56.57 g, 250 mmol) was dissoved in 1350 ml of methanol, with warming, and bromine (15.5 ml, 300 mmol) was added dropwise as a solution in 150 ml of methanol. After stirring for 3 hours the methanol was evaporated and the residue was suspended in 200 ml of 1 M hydrochloric acid and stirred for 10 minutes. The organic material was extracted into dichloromethane (1×500 ml, and 1×200 ml). The combined organic layers were washed with brine, dried over magnesium sulfate, and evaporated to an off-white solid, which was recrystalized from hot ethanol and water, to afford 69.39 g (91%) of 4-benzyloxyphenacylbromide. M.p. 85-88° C. MS(GC): m/z 306 (M+1). 1H-NMR (CDCl3, 200 MHz) δ: 4.39 (s, 2H); 5.13 (s, 2H); 7.03 (d, 2H); 7.32-7.46 (m, 5H); 7.98 (d, 2H).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[CH:9][C:10]([N:19]([CH:21]3[C:29]4[C:24](=[C:25]([O:30]COC)[CH:26]=[CH:27][CH:28]=4)[CH2:23][CH2:22]3)[CH3:20])=[N:11][C:12]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.C(=O)([O-])O.[Na+]>C(OCC)(=O)C.Cl>[C:1]1([C:7]2[N:8]=[CH:9][C:10]([N:19]([CH:21]3[C:29]4[C:24](=[C:25]([OH:30])[CH:26]=[CH:27][CH:28]=4)[CH2:23][CH2:22]3)[CH3:20])=[N:11][C:12]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COCOc1cccc2c1CCC2N(C)c1cnc(-c2ccccc2)c(-c2ccccc2)n1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: CN(c1cnc(-c2ccccc2)c(-c2ccccc2)n1)C1CCc2c(O)cccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 84.4 %

Procedure:
220 mg of 1-[N-(5,6-diphenylpyrazin-2-yl)-N-methylamino]-4-(methoxymethoxy)indane was dissolved in 2 ml of a 25% hydrogen chloride-ethyl acetate solution, followed by stirring at room temperature for 3 hours. After adding water, the reaction solution was neutralized with an aqueous saturated sodium hydrogen carbonate solution and then extracted with ethyl acetate. After drying over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 167 mg of the desired compound as a pale yellow oily substance.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[NH:7][C:6](=[O:8])[CH2:5][CH2:4]1.I[C:10]1[CH:15]=[CH:14][C:13]([C:16]([N:18]2[CH2:23][CH2:22][N:21]([C:24]3[C:29]([CH3:30])=[CH:28][C:27]([CH3:31])=[C:26]([CH3:32])[N:25]=3)[CH2:20][CH2:19]2)=[O:17])=[CH:12][CH:11]=1>>[OH:1][CH2:2][C@H:3]1[N:7]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([N:18]3[CH2:23][CH2:22][N:21]([C:24]4[C:29]([CH3:30])=[CH:28][C:27]([CH3:31])=[C:26]([CH3:32])[N:25]=4)[CH2:20][CH2:19]3)=[O:17])=[CH:12][CH:11]=2)[C:6](=[O:8])[CH2:5][CH2:4]1
Reactant: Cc1cc(C)c(N2CCN(C(=O)c3ccc(I)cc3)CC2)nc1C
Reactant: O=C1CC[C@@H](CO)N1
Product: Cc1cc(C)c(N2CCN(C(=O)c3ccc(N4C(=O)CC[C@H]4CO)cc3)CC2)nc1C

Procedure:
Using (S)-5-hydroxymethylpyrrolidin-2-one and (4-iodophenyl)[4-(3,5,6-trimethylpyridin-2-yl)piperazin-1-yl]methanone (871 mg) described in Preparation Example 120 and by the reaction and treatment in the same manner as in Example 1, the title compound (348 mg) was obtained.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[N:12]=[C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[N:10]=[C:9]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26](=[O:37])[NH:27][C:28]4[CH:36]=[CH:35][C:31]([C:32](O)=[O:33])=[CH:30][CH:29]=4)=[CH:21][CH:20]=3)[N:8]=2)[CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:71][N:72]([CH3:79])[CH:73]1[CH2:78][CH2:77][NH:76][CH2:75][CH2:74]1>CN1C(=O)CCC1>[CH3:71][N:72]([CH3:79])[CH:73]1[CH2:78][CH2:77][N:76]([C:32]([C:31]2[CH:35]=[CH:36][C:28]([NH:27][C:26]([NH:25][C:22]3[CH:21]=[CH:20][C:19]([C:9]4[N:10]=[C:11]([N:13]5[CH2:18][CH2:17][O:16][CH2:15][CH2:14]5)[N:12]=[C:7]([N:4]5[CH2:3][CH2:2][O:1][CH2:6][CH2:5]5)[N:8]=4)=[CH:24][CH:23]=3)=[O:37])=[CH:29][CH:30]=2)=[O:33])[CH2:75][CH2:74]1
Reactant: CN(C)C1CCNCC1
Reactant: O=C(Nc1ccc(C(=O)O)cc1)Nc1ccc(-c2nc(N3CCOCC3)nc(N3CCOCC3)n2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CN(C)C1CCN(C(=O)c2ccc(NC(=O)Nc3ccc(-c4nc(N5CCOCC5)nc(N5CCOCC5)n4)cc3)cc2)CC1
Yield: 50.2 %

Procedure:
To the solution of 4-(3-(4-(4,6-dimorpholino-1,3,5-triazin-2-yl)phenyl)ureido)benzoic acid (50 mg; 0.099 mmol), Hunig's base (103 μL, 0.594 mmol), HBTU (188 mg, 0.495 mmol) in 2 mL of NMP was reacted according to example 68 with N,N-dimethylpiperidin-4-amine (51 mg, 0.396 mmol). Evaporated the solvent and purified by HPLC to give the product (30.6 mg, 52% yield); MS (ESI) m/z=616.7
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10]([NH2:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[O:13][C:14]2[CH:19]=[CH:18][C:17]([O:20]CC3C=CC=CC=3)=[CH:16][CH:15]=2)[N:3]=1.[H][H]>[Pd].CN(C)C(=O)C>[NH2:1][C:2]1[N:11]=[C:10]([NH2:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[O:13][C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)[N:3]=1
Reactant: [H][H]
Reactant: Nc1nc(N)c2c(Oc3ccc(OCc4ccccc4)cc3)cccc2n1
Agent: [Pd]
Solvent: CC(=O)N(C)C
Product: Nc1nc(N)c2c(Oc3ccc(O)cc3)cccc2n1
Yield: 85.7 %

Procedure:
2,4-Diamino-5-(4-benzyloxyphenoxy)quinazoline (3.6 g, 10 mmol) was heated at 50-60° C. under 4 atmospheres of hydrogen gas in the presence of 0.36 g of 10% palladium on carbon in 80 mL of N,N-dimethylacetamide. After 4 hours the reaction mixture was filtered through silica gel in a fritted glass funnel, concentrated, dissolved in 50 mL of 2-propanol and allowed to crystallize at 4° C. The precipitate was collected by vacuum filtration, washed with 2-propanol and dried at 50° C. under vacuum to give 2.3 g (85.2% yield) of 2,4-diamino-5(4-hydroxyphenoxy)quinazoline, mp 330-341° C. (dec).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5]([N+:12]([O-])=O)=[CH:4][N:3]=1.[H][H]>[Pd].CO>[F:11][C:8]([F:9])([F:10])[C:7]1[CH:6]=[C:5]([NH2:12])[CH:4]=[N:3][CH:2]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1cnc(Cl)c(C(F)(F)F)c1
Agent: [Pd]
Solvent: CO
Product: Nc1cncc(C(F)(F)F)c1

Procedure:
A mixture of 2-chloro-5-nitro-3-trifluoromethyl-pyridine (30 mg, 0.13 mmol), 10% Pd/C (3 mg, 10% w/w), and MeOH (5 mL) is stirred under 1 atm of hydrogen for 3 h. The mixture is then filtered over Celite® and concentrated in vacuo to give the title compound as an oil. MS (ESI) m/z 162.9 (M+1).
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([C:9]([OH:11])=O)=[C:5]([CH2:7][CH3:8])[N:6]=1.C(Cl)([Cl:14])=O>C1(C)C=CC=CC=1>[CH3:1][C:2]1[S:3][C:4]([C:9]([Cl:14])=[O:11])=[C:5]([CH2:7][CH3:8])[N:6]=1
Reactant: O=C(Cl)Cl
Reactant: CCc1nc(C)sc1C(=O)O
Solvent: Cc1ccccc1
Product: CCc1nc(C)sc1C(=O)Cl

Procedure:
In a similar apparatus to Example 1, 8.6 g (0.05 mole) of 2-methyl-4-ethylthiazole-5carboxylic acid were suspended in 200 ml of toluene. Under heating and reflux, phosgene was blown at a rate of 340 ml/hr for 12 hours (0.18 mole). After completion of the reaction, the reaction mixture was filtered and the filtrate was concentrated to obtain 9.2 g of 2-methyl-4-ethylthiazole-5-carboxylic acid chloride. Its purity and yield were 96.0% and 96.6%, respectively. NMR (δCDCl 3/TMS, ppm): 1.25(3H,t,J=8Hz), 2.46(3H,s), 3.06(2H,q,J=8Hz).
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][CH2:21]Cl)=[CH:15][C:13]=3[CH:14]=2)[S:8][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[C:23]([C:25]1[C:33]2[C:28](=[CH:29][C:30]([CH3:34])=[CH:31][CH:32]=2)[NH:27][CH:26]=1)#[N:24].[OH-].[Na+].[Cl-]>O1CCCC1>[C:1]([C:5]1[N:6]=[C:7]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][CH2:21][N:27]4[C:28]5[C:33](=[CH:32][CH:31]=[C:30]([CH3:34])[CH:29]=5)[C:25]([C:23]#[N:24])=[CH:26]4)=[CH:15][C:13]=3[CH:14]=2)[S:8][CH:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc2c(C#N)c[nH]c2c1
Reactant: CC(C)(C)c1csc(-c2cc3cc(CCCCl)ccc3o2)n1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1ccc2c(C#N)cn(CCCc3ccc4oc(-c5nc(C(C)(C)C)cs5)cc4c3)c2c1
Temperature: 60 °C
Reaction time: 24 h
Yield: 42.5 %

Procedure:
A mixture of 4-tert-butyl-2-[5-(3-chloropropyl)-benzofuran-2-yl]thiazole (0.19 g), 3-cyano-6-methylindole (73 mg), sodium hydroxide (90 mg) and small amount of cetyl trymethylammonium chloride in tetrahydrofuran (1 ml) was stirred at 60° C. for 1 day. After the mixture was cooled to room temperature, the insolble mass was filtered off and the filtrate was concentrated under reduced pressure to give a syrup. The syrup was subjected to column chromatography on silica gel and eluted with a mixture of n-hexane and ethyl acetate. The fraction containing the objective compound were combined and concentrated under reduced pressure to give 4-tert-butyl-2-{5-[3-(3-cyano-6-methylindole-1-yl)propyl]-benzofuran-2-yl}thiazole (90 mg).
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:22])=[C:4]([C:18]([F:21])=[CH:19][CH:20]=1)[C:5]([C:7]1[C:15]2[C:10](=[N:11][CH:12]=[C:13]([C:16]#[N:17])[CH:14]=2)[NH:9][CH:8]=1)=[O:6].[F:23][C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=1[S:31](Cl)(=[O:33])=[O:32].Cl>O1CCCC1.N1C=CC=CC=1>[C:16]([C:13]1[CH:14]=[C:15]2[C:7]([C:5]([C:4]3[C:3]([F:22])=[C:2]([NH:1][S:31]([C:25]4[CH:26]=[C:27]([F:30])[CH:28]=[CH:29][C:24]=4[F:23])(=[O:33])=[O:32])[CH:20]=[CH:19][C:18]=3[F:21])=[O:6])=[CH:8][NH:9][C:10]2=[N:11][CH:12]=1)#[N:17]
Reactant: O=S(=O)(Cl)c1cc(F)ccc1F
Reactant: N#Cc1cnc2[nH]cc(C(=O)c3c(F)ccc(N)c3F)c2c1
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: N#Cc1cnc2[nH]cc(C(=O)c3c(F)ccc(NS(=O)(=O)c4cc(F)ccc4F)c3F)c2c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 66.1 %

Procedure:
To 3-(3-amino-2,6-difluoro-benzoyl)-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile (28, 100 mg, 0.335 mmol) in 2.7 mL of tetrahydrofuran, 0.24 mL of pyridine was added. 2,5-Difluoro-benzenesulfonyl chloride (29, 107 mg, 0.503 mmol) was added and the solution was stirred at room temperature for 48 hours. The reaction mixture was poured into 1 M aqueous hydrochloric acid and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under vacuum. The crude material was purified by silica gel column chromatography eluting with ethyl acetate and hexane. Appropriate fractions were combined and the solvent removed under reduced pressure to provide the desired compound (P-0004, 105 mg). MS(ESI)[M+H+]+=475.0.
Reaction SMILES: C[O:2][C:3](=O)[C@@H:4]([O:14][C:15]1[CH:38]=[CH:37][C:18]2[C:19]3[N:23]([CH2:24][CH2:25][O:26][C:17]=2[CH:16]=1)[CH:22]=[C:21]([C:27]1[N:28]([CH2:32][C:33]([F:36])([F:35])[F:34])[N:29]=[CH:30][N:31]=1)[N:20]=3)[CH2:5][O:6][Si:7]([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8].[NH3:40]>CO>[C:10]([Si:7]([CH3:9])([CH3:8])[O:6][CH2:5][C@H:4]([O:14][C:15]1[CH:38]=[CH:37][C:18]2[C:19]3[N:23]([CH2:24][CH2:25][O:26][C:17]=2[CH:16]=1)[CH:22]=[C:21]([C:27]1[N:28]([CH2:32][C:33]([F:34])([F:36])[F:35])[N:29]=[CH:30][N:31]=1)[N:20]=3)[C:3]([NH2:40])=[O:2])([CH3:11])([CH3:12])[CH3:13]
Reactant: N
Reactant: COC(=O)[C@H](CO[Si](C)(C)C(C)(C)C)Oc1ccc2c(c1)OCCn1cc(-c3ncnn3CC(F)(F)F)nc1-2
Solvent: CO
Product: CC(C)(C)[Si](C)(C)OC[C@H](Oc1ccc2c(c1)OCCn1cc(-c3ncnn3CC(F)(F)F)nc1-2)C(N)=O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
(S)-3-(tert-Butyl-dimethyl-silanyloxy)-2-{2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yloxy}-propionic acid methyl ester was dissolved in ammonia in methanol (7 N, 10 mL) and the reaction mixture stirred at RT for 48 hr. The reaction mixture was concentrated in vacuo and the resultant residue subjected to flash chromatography (SiO2, gradient 0-5% methanol in ethyl acetate) to give (S)-3-(tert-Butyl-dimethyl-silanyloxy)-2-{2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulen-8-yloxy}-propionamide as a yellow oil (101 mg, 49% over 2 steps). LCMS: RT=3.78 min, [M+H]+=553