Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[C:29]5[O:28][CH2:27][O:26][C:25]=5[CH:24]=[CH:23][C:22]=4[O:30][CH2:31][CH:32]4[CH2:34][CH2:33]4)[C:15]=3[NH:14][C:13]=2[CH3:35])=[O:11])[CH2:5][CH2:4]1.Cl[C:37]([O:39][CH2:40][CH3:41])=[O:38]>>[CH:32]1([CH2:31][O:30][C:22]2[CH:23]=[CH:24][C:25]3[O:26][CH2:27][O:28][C:29]=3[C:21]=2[C:20]2[C:15]3[NH:14][C:13]([CH3:35])=[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@H:3]([NH:2][C:37](=[O:38])[O:39][CH2:40][CH3:41])[CH2:4][CH2:5]4)=[O:11])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:34][CH2:33]1
Reactant: Cc1[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ncnc2c1C(=O)N[C@H]1CC[C@H](N)CC1
Reactant: CCOC(=O)Cl
Agent: Cl
Product: CCOC(=O)N[C@H]1CC[C@H](NC(=O)c2c(C)[nH]c3c(-c4c(OCC5CC5)ccc5c4OCO5)ncnc23)CC1

Procedure:
Starting from N-(trans-4-aminocyclohexyl)-4-[5-(cyclopropylmethoxy)-1,3-benzodioxol-4-yl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f2) and commercially available ethyl chloroformate the title compound is obtained as colorless solid.
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[C:15](/[CH:17]=[CH:18]/[CH2:19][O:20][CH3:21])[CH:16]=1)[CH:12]=O)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH:22]1([NH2:25])[CH2:24][CH2:23]1.S([O-])([O-])(=O)=O.[Mg+2].[BH4-].[Na+]>C(Cl)Cl.CO>[Si:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[C:15](/[CH:17]=[CH:18]/[CH2:19][O:20][CH3:21])[CH:16]=1)[CH2:12][C:22]1([NH2:25])[CH2:24][CH2:23]1)([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:3])[CH3:2]
Reactant: NC1CC1
Reactant: COC/C=C/c1cc(C=O)cc(O[Si](C)(C)C(C)(C)C)c1
Agent: O=S(=O)([O-])[O-]
Agent: [BH4-]
Agent: [Mg+2]
Solvent: CO
Solvent: ClCCl
Product: COC/C=C/c1cc(CC2(N)CC2)cc(O[Si](C)(C)C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 3-{[tert-butyl(dimethyl)silyl]oxy}-5-[(1E)-3-methoxyprop-1-en-1-yl]benzaldehyde (1 eq.) from the previous step in DCM was added cyclopropanamine (2 eq.) and magnesium sulfate (1.5 eq.). The resulting suspension was stirred at rt for 12 h. The insolubles were removed via filtration. Concentration of the filtrate in vacuo afforded the crude imine as a yellow oil. This was then taken up in methanol (0.3 M), and sodium borohydride (1.5 eq.) was added portionwise at 0° C. over 5 min. The reaction mixture was slowly warmed to rt over 1 h and then stirred at rt for 2 h. The reaction was slowly quenched with saturated aqueous NaHCO3 solution, and the resulting mixture was extracted with ether. The combined organic extracts were washed with water, brine, dried over MgSO4, and concentrated in vacuo to afford the title compound as a golden, yellow oil.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[NH:13][C:14](=[O:26])[C:15]([NH:17][C:18]1[CH:23]=[C:22]([CH3:24])[CH:21]=[CH:20][C:19]=1[OH:25])=[O:16])([CH3:3])[CH3:2].[CH2:27]1[CH:32]2[CH2:33][C:34]3(O)[CH2:36][CH:30]([CH2:31]2)[CH2:29][CH:28]1[CH2:35]3.OS(O)(=O)=O.C(OCC)(=O)C>C(Cl)Cl>[CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[NH:13][C:14](=[O:26])[C:15]([NH:17][C:18]1[CH:23]=[C:22]([CH3:24])[CH:21]=[C:20]([C:28]23[CH2:29][CH:30]4[CH2:36][CH:34]([CH2:33][CH:32]([CH2:31]4)[CH2:27]2)[CH2:35]3)[C:19]=1[OH:25])=[O:16])([CH3:2])[CH3:3]
Reactant: OC12CC3CC(CC(C3)C1)C2
Reactant: Cc1ccc(O)c(NC(=O)C(=O)Nc2c(C(C)C)cccc2C(C)C)c1
Agent: O=S(=O)(O)O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cc1cc(NC(=O)C(=O)Nc2c(C(C)C)cccc2C(C)C)c(O)c(C23CC4CC(CC(C4)C2)C3)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 48.4 %

Procedure:
N-(2,6-Diisopropylphenyl)-N′-(2-hydroxy-5-methylphenyl)-oxalamide (5.59 g, 15.5 mmol, 1.0 eq), prepared according to the synthesis method described in Example 8, and 1-adamantol (2.83 g, 18.6 mmol, 1.2 eq) were dissolved in CH2Cl2 (150 ml), forming a suspension. To this suspension was then added concentrated H2SO4 (1 ml). After addition of the acid, the solids eventually went into solution. After stirring at room temperature for 24 hours, the TLC (9:1 hexanes:ethyl acetate, visualized by UV) showed that most of the starting material had gone to product. At this point, the solvent was removed under reduced pressure, and the resulting solids were redissolved in ethyl acetate (100 ml). The resulting solution was then washed with saturated NaHCO3 (3×50 ml, gas is evolved), and brine, then dried over MgSO4. The solvent was removed under reduced pressure, and the resulting solid was purified via column chromatography to give a product, light yellow solid (3.68 g, 7.5 mmol, 48%). 1H NMR (300 MHz, CDCl3) δ 9.51 (s, 1H), 8.77 (s, 1H), 7.84 (s, 1H), 7.37 (t, J=7.2 Hz 1H), 7.23 (d, J=7.5 Hz, 2H), 7.00 (d, J=2.1 Hz, 1H), 6.94 (d, J=1.8 Hz, 1H), 3.01 (septet, J=6.9, 2H), 2.29 (s, 3H), 2.18 (bs, 6H), 2.10 (bs, 3H), 1.80 (bs, 6H), 1.22 (d, J=6.9, 12H); 13C NMR (75 MHz, CDCl3) δ 158.3, 158.2, 146.2, 145.8, 140.6, 129.9, 129.2, 129.2, 126.8, 124.7, 123.8, 120.9, 40.7, 37.3, 37.1, 29.1, 29.0, 23.6, 20.8. Anal. Calcd for C31H40N2O3: C, 76.19; H, 8.25; N, 5.73. Found: C, 75.89; H, 8.42; N, 5.37.
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[F:28][C:29]1[CH:30]=[C:31](B(O)O)[CH:32]=[C:33]([C:35]([O:37][CH3:38])=[O:36])[CH:34]=1>>[F:28][C:29]1[CH:34]=[C:33]([CH:32]=[C:31]([C:2]2[C:3]([N:22]3[CH2:26][CH2:25][C@@H:24]([OH:27])[CH2:23]3)=[N:4][CH:5]=[C:6]([C:7](=[O:8])[NH:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][C:17]([F:19])([F:20])[F:18])=[CH:12][CH:11]=3)[CH:21]=2)[CH:30]=1)[C:35]([O:37][CH3:38])=[O:36]
Reactant: COC(=O)c1cc(F)cc(B(O)O)c1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC[C@@H](O)C2)c(Br)c1
Product: COC(=O)c1cc(F)cc(-c2cc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cnc2N2CC[C@@H](O)C2)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 35 using (R)-5-bromo-6-(3-hydroxypyrrolidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 35.1) and (3-fluoro-5-(methoxycarbonyl)phenyl)boronic acid to afford a white solid. UPLC-MS (Condition 3), tR=1.18 min, m/z=520.2 [M+H]+; 1H-NMR (400 MHz, DMSO-d6), δ ppm 1.67-1.75 (m, 1H) 1.77-1.89 (m, 1H) 2.81-2.90 (m, 1H) 3.13-3.27 (m, 2H) 3.33-3.45 (m, 1H) 3.88 (s, 3H) 4.13-4.20 (m, 1H) 4.82 (d, J=1.00 Hz, 1H) 7.33 (d, J=8.60 Hz, 2H) 7.54-7.63 (m, 1H) 7.65-7.73 (m, 1H) 7.74-7.79 (m, 1H) 7.84 (d, J=9.38 Hz, 2H) 8.03 (d, J=2.35 Hz, 1H) 8.75 (d, J=2.35 Hz, 1H) 10.17 (s, 1H).
Reaction SMILES: O[CH2:2][C@H:3]1[CH2:8][CH2:7][CH2:6][CH2:5][N:4]1[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]([CH3:19])[CH3:18])=[CH:13][CH:12]=1.C(N(CC)CC)C.CS([Cl:31])(=O)=O.C(=O)([O-])O.[Na+]>ClCCl>[Cl:31][C@@H:6]1[CH2:7][CH2:8][CH2:2][CH2:3][N:4]([CH2:9][CH2:10][C:11]2[CH:12]=[CH:13][C:14]([N:17]([CH3:18])[CH3:19])=[CH:15][CH:16]=2)[CH2:5]1
Reactant: CN(C)c1ccc(CCN2CCCC[C@@H]2CO)cc1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)c1ccc(CCN2CCCC[C@@H](Cl)C2)cc1
Reaction time: 14 h

Procedure:
(R)-2-Hydroxymethyl-1-(4-dimethylaminophenethyl)piperidine (452 mg, 1.72 mmol) was dissolved in 10 ml of dichloromethane. Triethylamine (226 mg, 2.26 mmol) and methanesulfonyl chloride (260 mg, 2.26 mmol) were added to the obtained solution under stirring under cooling on ice. They were stirred under cooling on ice for 1 hour and then at room temperature for 14 hours. The reaction liquid was distributed in dichloromethane and saturated aqueous sodium hydrogencarbonate solution. The organic layer was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure to obtain (R)-3-chloro-1-(4-dimethylaminophenethyl) homo-piperidine in the form of a light yellow oil (470 mg, 97%).
Reaction SMILES: Cl[C:2]1C(F)=C(C(F)=C[CH:9]=1)C=O.[Cl:12][C:13]1[C:14]([F:23])=[C:15]([C:18]([O:21][CH3:22])=[CH:19][CH:20]=1)[CH:16]=[O:17]>>[Cl:12][C:13]1[C:14]([F:23])=[C:15]([C:16](=[O:17])[CH:2]=[CH2:9])[C:18]([O:21][CH3:22])=[CH:19][CH:20]=1
Reactant: O=Cc1c(F)ccc(Cl)c1F
Reactant: COc1ccc(Cl)c(F)c1C=O
Product: C=CC(=O)c1c(OC)ccc(Cl)c1F

Procedure:
1-(3-Chloro-2-fluoro-6-methoxyphenyl)prop-2-en-1-one was prepared using a procedure analogous to intermediate 1 except that 3-chloro-2,6-difluorobenzaldehyde was replaced with 3-chloro-2-fluoro-6-methoxybenzaldehyde. 1H NMR (400 MHz, CHLOROFORM-d) δ 7.43-7.36 (m, 1H), 6.75-6.56 (m, 2H), 6.13-6.03 (m, 2H), 3.80 (s, 3H).
Reaction SMILES: [NH:1]([C:8]1[N:13]=[C:12]([CH3:14])[CH:11]=[C:10]([CH3:15])[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[Na].[N:19]#[C:20]Br>>[CH3:14][C:12]1[CH:11]=[C:10]([CH3:15])[N:9]=[C:8]([N:1]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:20]#[N:19])[N:13]=1
Reactant: N#CBr
Reactant: Cc1cc(C)nc(Nc2ccccc2)n1
Agent: [H-]
Agent: [Na+]
Agent: [Na]
Product: Cc1cc(C)nc(N(C#N)c2ccccc2)n1

Procedure:
2-Anilino-4,6-dimethylpyrimidine (3.98 g) was treated with sodium hydride in a similar manner to that described in Example 8. The resulting sodium salt was then treated with cyanogen bromide (2.12 g) and the mixture heated under reflux for 4 hours. The mixture was then filtered through silica gel and eluted with dichloromethane and the solution evaporated. The residue was recrystallised from ethyl acetate to give N-(4,6-dimethylpyrimidin-2-yl)-N-phenylcyanamide, m.p. 153°-4°. (Compound 94).
Reaction SMILES: [OH-].[Na+].[C:3]1([CH:9]2[C:13](=[O:14])[C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=3)=[C:11]([NH2:25])[O:10]2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.S(OC)(O[CH3:30])(=O)=O>O.C(Cl)Cl.[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1>[C:3]1([CH:9]2[C:13](=[O:14])[C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:22])([F:23])[F:24])[CH:16]=3)=[C:11]([NH:25][CH3:30])[O:10]2)[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: COS(=O)(=O)OC
Reactant: NC1=C(c2cccc(C(F)(F)F)c2)C(=O)C(c2ccccc2)O1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CNC1=C(c2cccc(C(F)(F)F)c2)C(=O)C(c2ccccc2)O1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In this example about 1 g of solid sodium hydroxide in 4.0 ml of water was added to a mixture of 3 g of 2-phenyl-3-oxo-4-(3-trifluoromethylphenyl)-5-amino-2,3-dihydrofuran in 50 ml of methylene chloride at room temperature followed by the addition of 1.19 g of dimethyl sulfate and 0.21 g of benzyltriethyl ammonium chloride. The resulting two-phase mixture was stirred at room temperature for about two hours and then washed three times with water, dried over magnesium sulfate and then concentrated by evaporation under vacuum. The residue was then purified by chromatography over silica gel eluting with mixtures of tetrahydrofuran and chloroform affording the title compound.
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH2:6]1)=O>CCOCC>[NH:7]1[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:14][CH:5]([CH2:3][OH:2])[CH2:6]1
Reactant: COC(=O)C1CNc2ccccc2C1
Solvent: CCOCC
Product: OCC1CNc2ccccc2C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of the 1,2,3,4-Tetrahydro-quinoline-3-carboxylic acid methyl ester (93 mg, 0.49 mmol) in 1.5 mL of Et2O at 0° C. under nitrogen was added LiA1H4 (1M in Et2O) dropwise with vigorous gas evolution and a white precipitate formation. After 30 min., the reaction was carefully quenched with 15% NaOH (3 mL) and 3 mL of Et2O was added and the mixture stirred rapidly at RT for 15 min. The layers were separated and the aqueous layer extracted (1×10 mL) with Et2O. The organics were combined, dried (MgSO4), filtered and concentrated to the alcohol (64 mg, 80%). 1H-NMR (400 MHz, CDCl3) δ6.97 (m, 2H), 6.62 (dd, 1H), 6.47 (d, 1H), 3.66 (m, 1H), 3.58 (m, 1H), 3.40 (m, 1H), 3.08 (m, 1H), 2.82 (m, 1H), 2.53 (m, 1H), 2.18 (m, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]([CH2:20][C:21]([C:23]2[O:24][CH:25]=[CH:26][CH:27]=2)=O)[CH2:10][C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[OH:19])=O)[CH:5]=[CH:6][C:7]=1[F:8].CC(O)=O.C[N:33](C)C=O>>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:20]=[C:21]([C:23]3[O:24][CH:25]=[CH:26][CH:27]=3)[N:33]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[OH:19])[CH:10]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=C(CC(CC(=O)c1ccccc1O)c1ccc(F)c(F)c1)c1ccco1
Reactant: CN(C)C=O
Solvent: CC(=O)O
Product: Oc1ccccc1-c1cc(-c2ccc(F)c(F)c2)cc(-c2ccco2)n1
Temperature: 100 °C

Procedure:
A mixture of 3-(3,4-difluorophenyl)-5-(furan-2-yl)-1-(2-hydroxyphenyl)-1,5-pentanedione on Wang resin (2.0 g, 1.76 mmol), NH4OAc (0.80 g), and AcOH (1.0 mL) in dimethylformamide (20 mL) was heated at 100° C. for 18 h. The resin was filtered, and washed with dimethylformamide (×2) and alternating MeOH and CH2Cl2 (×5), and dried under high vacuum overnight. The dried resin was treated with 50% TFA/CH2Cl2 (15 mL) for 1 h. After filtration of the reaction mixture, the filtrate was concentrated to dryness. The residue was repeatedly dissolved in CH2Cl2 (10 mL) and concentrated to remove traces of TFA. Purification by flash chromatography gave 2-[4-(3,4-difluoro-phenyl)-6-furan-2-yl-pyridin-2-yl]-phenol; mp 147-148° C.; 1H NMR (DMSO-d6) d 6.78 (m, 1 H), 6.98 (m, 2 H), 7.37 (m, 1 H), 7.43 (m, 1 H), 7.67 (m, 1 H), 8.00 (m, 2 H), 8.15 (d, J=1.3 Hz, 1 H), 8.31 (m, 2 H), 8.39 (d, J=1.3 Hz, 1 H), 14.26, (s, 1 H); IR (KBr) 1605 cm−1; MS [M+H]+ m/z=350. Anal. calcd for C21H13F2NO2: C, 72.20; H, 3.75; N, 4.01; Found: C, 71.94; H, 3.62; N, 3.74.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[N:17]=[C:16]([C:21]2[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=2)[N:15]=[C:14]3[NH:27][CH3:28])=[CH:7][CH:6]=1.C(N(CC)CC)C.[C:36](OC(=O)C)(=[O:38])[CH3:37].O>C(Cl)Cl>[CH3:28][NH:27][C:14]1[C:13]2[C:18](=[CH:19][CH:20]=[C:11]([C:8]3[CH:7]=[CH:6][C:5]([O:4][CH2:3][CH2:2][NH:1][C:36](=[O:38])[CH3:37])=[CH:10][CH:9]=3)[CH:12]=2)[N:17]=[C:16]([C:21]2[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=2)[N:15]=1
Reactant: CNc1nc(-c2cccnc2)nc2ccc(-c3ccc(OCCN)cc3)cc12
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CNc1nc(-c2cccnc2)nc2ccc(-c3ccc(OCCNC(C)=O)cc3)cc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 60.5 %

Procedure:
In a 50 mL round-bottomed flask was added 6-(4-(2-aminoethoxy)phenyl)-N-methyl-2-(pyridin-3-yl)quinazolin-4-amine (15.0 mg, 0.040 mmol) and triethylamine (0.017 ml, 0.121 mmol) in CH2Cl2 (5 mL) to give a yellow solution. Acetic anhydride (4.58 μl, 0.048 mmol) was added and the mixture was stirred for 2 h at room temperature. Water (10 mL) was added to the mixture and extracted with ethyl acetate (2×10 mL). The organic layers were combined and washed with brine (1×20 mL), dried over Mg2SO4, filtered and concentrated. The residue was purified by column chromatography on silica gel (eluted with CH2Cl2/MeOH 1:0 to 9:1). The product was converted to the HCl salt by addition of 4 M HCl-dioxane, then dissolved in a small amount of methanol, followed by ethyl acetate. The resulting solid was filtered and dried to give 10 mg of N-(2-(4-(4-(methylamino)-2-(pyridin-3-yl)quinazolin-6-yl)phenoxy)ethyl)acetamide as a HCl salt as a yellow solid in a 51% yield. LCMS m/z=414 (M+1) (Method C) (retention time=1.28 min). 1H NMR (300 MHz, DMSO) δ 10.26 (s, 1H), 9.62 (s, 1H), 9.06-8.90 (m, 2H), 8.81 (s, 1H), 8.34 (d, J=9.0 Hz, 1H), 8.17 (d, J=6.6 Hz, 2H), 7.86 (d, J=8.0 Hz, 3H), 7.13 (d, J=7.91 Hz, 2H), 4.06 (t, J=5.4 Hz, 2H), 3.52-3.38 (m, 2H), 3.30 (d, J=4.1 Hz, 3H), 1.84 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:10]([C:13]2[CH:14]=[C:15]3[C:21]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[O:28][CH3:29])=[CH:20][N:19]([S:30]([C:33]4[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][CH:34]=4)(=[O:32])=[O:31])[C:16]3=[N:17][CH:18]=2)=[CH:9][C:3]=1[C:4]([N:6]([CH3:8])[CH3:7])=[O:5].[C:40]([O-])(O)=[O:41].[Na+].C(Cl)(Cl)=O>C(Cl)Cl>[N:1]([C:2]1[CH:12]=[CH:11][C:10]([C:13]2[CH:14]=[C:15]3[C:21]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[O:28][CH3:29])=[CH:20][N:19]([S:30]([C:33]4[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][CH:34]=4)(=[O:31])=[O:32])[C:16]3=[N:17][CH:18]=2)=[CH:9][C:3]=1[C:4]([N:6]([CH3:7])[CH3:8])=[O:5])=[C:40]=[O:41]
Reactant: O=C([O-])O
Reactant: COc1ccccc1-c1cn(S(=O)(=O)c2ccc(C)cc2)c2ncc(-c3ccc(N)c(C(=O)N(C)C)c3)cc12
Agent: O=C(Cl)Cl
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccccc1-c1cn(S(=O)(=O)c2ccc(C)cc2)c2ncc(-c3ccc(N=C=O)c(C(=O)N(C)C)c3)cc12

Procedure:
Into a 50 mL round bottomed flask were added 2-amino-5-[3-(2-methoxy-phenyl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridin-5-yl]-N,N-dimethyl-benzamide (500 mg, 0.926 mmol), methylene chloride (10 mL) and sat'd NaHCO3(10 mL). The solution was cooled in an ice-water bath for 5 min then phosgene (2.5 mL, 20% w/w solution in toluene, Fluka) was added to the lower (organic) layer. The solution was stirred rapidly and the ice-bath was removed. The reaction mixture was stirred rapidly for 1 h, then the layers were separated and the aqueous phase was extracted 2× with methylene chloride. The combined organic fraction was treated with NaSO4, filtered and concentrated. The residue was triturated with anhydrous ether to give a light yellow/tan powder, which was used directly in the next step. Note: treatment of a small aliquot of the title compound with excess dimethylamine (2M, THF) followed by HPLC analysis provided evidence of isocyanate formation via transformation to the corresponding N,N-dimethyl urea; m/z=612.2 (M+H+).
Reaction SMILES: C1(O)CCCCC1.[C:8]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])(=[O:14])[CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]>>[C:8]([O:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)(=[O:14])[CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCCCCOC(=O)CCCCC
Solvent: OC1CCCCC1
Product: CCCCCC(=O)OC1CCCCC1
Yield: 95 %

Procedure:
Likewise, refluxing a toluene solution containing one equivalent of hexyl hexanoate, 2 equivalents of cyclohexanol and 1 mol % of the PNN complex 1 under argon atmosphere for 20 h resulted in 84% conversion of hexyl hexanoate as determined by GC analysis, with the exclusive formation of the ester cyclohexyl hexanoate in 83% yield (Table 30, entry 2). Notably, unlike the traditional transesterification methods, this reaction does not form an alcohol product; rather, an irreversible incorporation of both the acyl and alkoxo parts of the starting ester into the product ester takes place. While 2 equivalents of the alcohol with respect to the ester are sufficient, somewhat higher yields are obtained when 3 equivalents of alcohol were used. Thus, reaction of 3 equivalents of cyclohexanol with hexyl hexanoate resulted after 26 h in 96% conversion with 95% yield of cyclohexyl hexanoate, as observed by GC, and confirmed by GC-MS by comparison with an authentic sample (Table 30, entry 3). The pure product was isolated by evaporation of the solvent followed by passing through a basic alumina plug and analysis by NMR and GC-MS. Use of the PNP complexes 2 or 3 resulted after 20 h in 58% or 17% yield of cyclohexyl hexanoate, respectively. Studying the scope of this new reaction with regard to the secondary alcohol, reaction of hexyl hexanoate with cyclopentanol in the presence of 1 mol % 1 was carried out. After 26 h reflux in toluene, cyclopentyl hexanoate (70% yield) was formed, with 71% conversion of hexyl hexanoate (Table 30, entry 4). Similarly, upon reaction of hexyl hexanoate with excess of 1-phenylethanol, 50% conversion of hexyl hexanoate with the formation of 49% of the acylated product was observed (Table 30, entry 5). The lower conversion of the ester is a result of facile dehydrogenation of 1-phenylethanol to acetophenone (49%). Because of the expected easy dehydrogenation of the isopropyl alcohol to acetone, transesterification with this alcohol was performed in a closed vessel, to retard this dehydrogenation process. Thus, heating hexyl hexanoate with excess of isopropyl alcohol resulted after 19 h in 83% conversion of hexyl hexanoate with the formation of isopropyl hexanoate in 67% yield (entry 6). The reaction of hexyl hexanoate and 3-pentanol led to 91% conversion of the ester with formation of 3-pentyl hexanoate in 90% yield after 26 h reflux (entry 7).
Reaction SMILES: [Br:1]Br.[F:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:11](=[O:13])[CH3:12])=[CH:6][CH:5]=1.CCOCC>C(O)(=O)C>[Br:1][CH2:12][C:11](=[O:13])[CH:10]([C:7]1[CH:6]=[CH:5][C:4]([F:3])=[CH:9][CH:8]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: BrBr
Reactant: CC(=O)C(c1ccccc1)c1ccc(F)cc1
Solvent: CCOCC
Solvent: CC(=O)O
Product: O=C(CBr)C(c1ccccc1)c1ccc(F)cc1
Reaction time: 0.5 h

Procedure:
Bromine (14 85g.) in acetic acid (200 ml.) was added dropwise to a solution of 1-p-fluorophenyl-1-phenylpropan-2-one (20 1g.) in acetic acid (200 ml.) at 60° - 70°. After 30 minutes, the reaction mixture was poured on to ice. Isolation through ether in the usual manner gave crude 3-bromo-1-p-fluorophenyl-1-phenyl-propan-2-one (28g.) which was converted by the procedures described in Example 1 to 3-(N-Benzyl,N-methylamino)-1-p-fluorophenyl-1-phenyl-propan-2-ol (38%), m.p. 61° - 62°.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5](OCCCCCCC)=[C:6]([CH:32]=1)[C:7]([NH:9][C@@H:10]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][C:24](OC(F)(F)F)=[CH:23][CH:22]=2)=[CH:17][CH:16]=1)[C:11]([OH:13])=[O:12])=[O:8].[F:41][C:42]([F:53])([F:52])[C:43]1[CH:48]=[CH:47][C:46](B(O)O)=[CH:45][CH:44]=1>>[C:18]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:17]=[CH:16][C:15]([CH2:14][C@H:10]([NH:9][C:7]([C:6]2[CH:32]=[CH:2][C:3]([C:46]3[CH:47]=[CH:48][C:43]([C:42]([F:53])([F:52])[F:41])=[CH:44][CH:45]=3)=[CH:4][CH:5]=2)=[O:8])[C:11]([OH:13])=[O:12])=[CH:20][CH:19]=1
Reactant: CCCCCCCOc1ccc(Cl)cc1C(=O)N[C@@H](Cc1ccc(-c2ccc(OC(F)(F)F)cc2)cc1)C(=O)O
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Product: O=C(N[C@@H](Cc1ccc(-c2ccccc2)cc1)C(=O)O)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Yield: 87 %

Procedure:
3-Biphenyl-4-yl-(2S)-[(5-bromo-benzoylamino)-propionic acid (100 mg, 0.23 mmol) was reacted with 4-trifluoromethyl phenyl boronic acid (0.133 mg, 0.69 mmol) by following general procedure D yielding the title compound (98 mg) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:18][CH3:19])=[CH:5][C:6]2[S:10][C:9]([C:11]3[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=3)=[N:8][C:7]=2[CH:17]=1.[N+:20]([O-])([O-:22])=[O:21].[K+]>S(=O)(=O)(O)O>[CH3:1][O:2][C:3]1[C:4]([O:18][CH3:19])=[CH:5][C:6]2[S:10][C:9]([C:11]3[CH:12]=[CH:13][N:14]=[CH:15][CH:16]=3)=[N:8][C:7]=2[C:17]=1[N+:20]([O-:22])=[O:21]
Reactant: O=[N+]([O-])[O-]
Reactant: COc1cc2nc(-c3ccncc3)sc2cc1OC
Agent: O=S(=O)(O)O
Agent: [K+]
Product: COc1cc2sc(-c3ccncc3)nc2c([N+](=O)[O-])c1OC
Temperature: 0 °C

Procedure:
To a solution of 5,6-dimethoxy-2-pyridin-4-yl-benzothiazole (1.1 g) in sulfuric acid (10 ml) was added potassium nitrate (0.5 g). After 60 minutes in room temperature the mixture was poured into ice water and filtered. Recrystallization from acetone yielded the pure product.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:12])[N:3]=1.[NH2:13][C:14]1[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=1>>[CH3:12][C:4]1[N:3]=[C:2]([NH:13][C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1
Reactant: Nc1ccncc1
Reactant: Cc1nc(Cl)c2ccccc2n1
Product: Cc1nc(Nc2ccncc2)c2ccccc2n1

Procedure:
The title compound was prepared from 4-chloro-2-methyl-quinazoline and 4-amino-pyridine by a procedure similar to examples 100. 1H NMR (CDCl3): 8.58 (m, 1H), 7.79-7.93 (m, 5H), 7.70 (s, broad, 1H), 7.55 (ddd, J=1.2, 6.9, 8.1, 1H), 2.79 (s, 3H).