Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]1[N:12]=[CH:13][S:14][C:15]=1/[CH:16]=[CH:17]/[CH:18]([OH:24])[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])([O:3][CH3:4])=[O:2].[C:25](OC(=O)C)(=[O:27])[CH3:26]>N1C=CC=CC=1.O>[C:1]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]1[N:12]=[CH:13][S:14][C:15]=1/[CH:16]=[CH:17]/[CH:18]([O:24][C:25](=[O:27])[CH3:26])[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])([O:3][CH3:4])=[O:2]
Reactant: CCCCCC(O)/C=C/c1scnc1CCCCCCC(=O)OC
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: O
Product: CCCCCC(/C=C/c1scnc1CCCCCCC(=O)OC)OC(C)=O
Reaction time: 24 h

Procedure:
To the solution of 353 mg of 4-(6-carbomethoxyhexyl)-5-(3-hydroxy-1-trans-octenyl)-thiazole (Ic, R1 = H) in 4 ml of anhydrous pyridine, 1 ml of acetic anhydride was added. The reaction mixture was allowed to stand for 24 hours at room temperature, diluted with 50 ml of water and extracted with 3 × 15 ml of ethyl acetate. The ethyl acetate extract was washed with water, dried over sodium sulphate and evaporated under vacuum in vacuo. The obtained 390 mg of evaporation residue was purified by preparative thin layer chromatography, using a silica gel layer as adsorbent and a mixture of 40 % ethyl acetate and 60 % n-heptane as running solvent. Thus, 285 mg of 4-(6-carbomethoxyhexyl)-5-(3-acetoxy-1-trans-octenyl)-thiazole (Ie, R1 = H) of chromatographic purity were obtained.
Reaction SMILES: [CH:1]1([PH:7](=[S:14])[CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.P(Cl)(Cl)(Cl)(Cl)[Cl:16]>C1(C)C=CC=CC=1>[CH:1]1([P:7]([Cl:16])([CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[S:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: S=[PH](C1CCCCC1)C1CCCCC1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: S=P(Cl)(C1CCCCC1)C1CCCCC1
Reaction time: 4 h

Procedure:
A solution of 23 g (0.1 mol) dicyclohexylphosphine sulfide in 50 ml toluene was dropped into a suspension of 21 g (0.1 mol) PCl5 in 50 ml toluene. The reaction was exothermal and reached a maximum temperature of 35° C. After 4 hours, the low boilers were removed from the clear yellowish solution under vacuum. Yield: 24.3 g (91.5% of the theoretical). 31P-NMR: δ P=119.3 ppm.
Reaction SMILES: [C:1]([CH2:9][NH:10][CH2:11][C:12]1[CH:13]=[C:14]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][C@H:25]([NH:30][C:31]([CH3:41])=[CH:32][C:33](=[O:40])[C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:26]([O:28][CH3:29])=[O:27])=[CH:20][CH:19]=2)[CH:15]=[CH:16][CH:17]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.NC(CC1C=CC(C2C=CC=C(CNCC(=O)C3C=CC=CC=3)C=2)=CC=1)C(OC)=O>>[C:1]([CH2:9][NH:10][CH2:11][C:12]1[CH:13]=[C:14]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][CH:25]([NH:30][C:31]([CH3:41])=[CH:32][C:33](=[O:40])[C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:26]([O:28][CH3:29])=[O:27])=[CH:20][CH:19]=2)[CH:15]=[CH:16][CH:17]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)[C@H](Cc1ccc(-c2cccc(CNCC(=O)c3ccccc3)c2)cc1)NC(C)=CC(=O)c1ccccc1
Agent: COC(=O)C(N)Cc1ccc(-c2cccc(CNCC(=O)c3ccccc3)c2)cc1
Product: COC(=O)C(Cc1ccc(-c2cccc(CNCC(=O)c3ccccc3)c2)cc1)NC(C)=CC(=O)c1ccccc1
Yield: 66 %

Procedure:
In a manner similar to the preparation of the methyl (S)-3-{3′-[(benzoylmethylamino)methyl]biphenyl-4-yl}-2-(1-methyl-3-oxo-3-phenylpropenylamino)propionate (Example 31b), using 500 mg (1.24 mmol) of methyl 2-amino-3-{3′-[(benzoylmethylamino)methyl]biphenyl-4-yl}propionate, 450 mg of expected product is obtained with a 66% yield.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:9])/[CH:5]=[C:6](\[NH2:8])/[CH3:7])[CH3:2].N1C=CC=CC=1.[Cl:16][CH2:17][C:18](Cl)=[O:19].O>C1COCC1>[NH2:8]/[C:6](/[CH3:7])=[C:5](\[C:18](=[O:19])[CH2:17][Cl:16])/[C:4]([O:3][CH2:1][CH3:2])=[O:9]
Reactant: O=C(Cl)CCl
Reactant: CCOC(=O)/C=C(/C)N
Solvent: C1CCOC1
Solvent: c1ccncc1
Solvent: O
Product: CCOC(=O)/C(C(=O)CCl)=C(\C)N
Reaction time: 2 h

Procedure:
To a solution of ethyl-3-aminocrotonate (F-1) (64.6 g, 0.5 mol, 1.0 eq) and pyridine (44.5 mL, 0.55 mol, 1.1 eq) in THF (600 mL) at −20° C., 2-chloroacetyl chloride (59.3 g, 0.53 mol, 1.05 eq) is added dropwise within 1 h. The resulting mixture is stirred from −20° C. to RT for an additional 2 h and then it is poured into H2O (1200 mL). The mixture is extracted with ethyl acetate (3×1200 mL). The combined organic layer is washed with H2O (2×500 mL) and brine (500 mL), dried over anhydrous Na2SO4 and filtered. The filtrate is concentrated in vacuo to reduce the volume to about 200 mL. The residue is slurried in petroether (400 mL) at RT for 30 min. The solid is collected by filtration, rinsed with petroether (200 mL), and dried in vacuo to afford the product, (E)-ethyl 3-amino-2-(2-chloroacetyl)but-2-enoate (F-2).
Reaction SMILES: [C:1]([C:4]1[N:5]=[C:6]2[C:12]3[CH:13]=[C:14]([C:18]#[C:19][C:20]([OH:23])([CH3:22])[CH3:21])[C:15]([F:17])=[CH:16][C:11]=3[O:10][CH2:9][CH2:8][N:7]2[C:24]=1[C:25]([OH:27])=O)(=[O:3])[NH2:2].[N:28]1([CH2:33][CH2:34][NH2:35])[CH2:32][CH2:31][CH2:30][CH2:29]1>>[F:17][C:15]1[C:14]([C:18]#[C:19][C:20]([OH:23])([CH3:21])[CH3:22])=[CH:13][C:12]2[C:6]3[N:7]([C:24]([C:25]([NH:35][CH2:34][CH2:33][N:28]4[CH2:32][CH2:31][CH2:30][CH2:29]4)=[O:27])=[C:4]([C:1]([NH2:2])=[O:3])[N:5]=3)[CH2:8][CH2:9][O:10][C:11]=2[CH:16]=1
Reactant: NCCN1CCCC1
Reactant: CC(C)(O)C#Cc1cc2c(cc1F)OCCn1c-2nc(C(N)=O)c1C(=O)O
Product: CC(C)(O)C#Cc1cc2c(cc1F)OCCn1c-2nc(C(N)=O)c1C(=O)NCCN1CCCC1

Procedure:
2-carbamoyl-9-fluoro-10-(3-hydroxy-3-methyl-but-1-ynyl)-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-3-carboxylic acid (0.05 g) was reacted with 1-pyrrolidineethylamine similar to as described in Example 2 to afford 21.1 mg of 9-fluoro-10-(3-hydroxy-3-methyl-but-1-ynyl)-N3-(2-pyrrolidin-1-ylethyl)-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2,3-dicarboxamide following reverse phase hplc purification. MS (Q1) 470 (M)+. 1H NMR (400 MHz, DMSO) δ 11.20 (t, J=5.5 Hz, 1H), 8.61 (d, J=8.4 Hz, 1H), 8.42 (s, 1H), 7.90 (s, 1H), 7.03 (d, J=10.5 Hz, 1H), 5.47 (s, 1H), 5.02-4.84 (m, 2H), 4.64-4.43 (m, 2H), 3.65-3.49 (m, 2H), 3.16-2.81 (m, 6H), 1.95-1.79 (m, 4H), 1.49 (s, 6H).
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][C:21]=3[CH:22]=[O:23])[C@H:14]2[CH3:32])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH3:35][CH2:36][Mg+].[Br-]>C(OCC)C>[F:34][C:2]([F:1])([F:33])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:27]=[C:26]([C:28]([F:29])([F:30])[F:31])[CH:25]=[CH:24][C:21]=3[CH:22]([OH:23])[CH2:35][CH3:36])[C@H:14]2[CH3:32])[CH:6]=[C:7]([C:9]([F:11])([F:10])[F:12])[CH:8]=1
Reactant: CC[Mg+]
Reactant: C[C@H]1[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1cc(C(F)(F)F)ccc1C=O
Agent: [Br-]
Solvent: CCOCC
Product: CCC(O)c1ccc(C(F)(F)F)cc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Reaction time: 0.08 h

Procedure:
To a −78° C. solution of 2-({(4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-2-oxo-1,3-oxazolidin-3-yl}methyl)-4-(trifluoromethyl)benzaldehyde (230 mg, 0.461 mmol) in diethyl ether (5 mL) was added a solution of EtMgBr (230 μL, 0.691 mmol). The solution was stirred for 5 minutes, followed by a second addition of EtMgBr solution (230 μL, 0.691 mmol). After 5 minutes, the reaction was quenched with saturated NH4Cl solution (5 mL), diluted with EtOAc (60 mL), and washed with brine (30 mL). The organic layer was dried over Na2SO4, filtered, and concentrated. Purification of the residue by flash chromatography on silica gel (10 to 35% EtOAc/hexanes) afforded (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-(1-hydroxypropyl)-5-(trifluoromethyl)benzyl]-4-methyl-1,3-oxazolidin-2-one. Rf=0.14 (25% EtOAc/hexanes). LCMS=512.1 (M+1−18)+. 1H NMR (CDCl3, 500 MHz, diastereomers present) δ 7.89-7.45 (m, 6H), 5.69-6.65 (m, 1H), 5.04-4.91 (m, 1H), 4.27-4.18 (m, 1H), 4.03-3.93 (m, 1H), 2.87 (m, 1H), 1.89-1.66 (m, 2H), 1.00-0.93 (m, 3H), 0.79-0.75 (m, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[C:11]([CH:15]=[C:16]([C:18]([OH:21])([CH3:20])[CH3:19])[N:17]=1)[C:12]([OH:14])=O.[O-:22][N+:23]1[C:28]([C:29]([F:32])([F:31])[F:30])=[CH:27][CH:26]=[C:25]([C@H:33]([NH2:35])[CH3:34])[CH:24]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.FC(F)(F)C(O)=O>CN(C=O)C.O>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[C:11]([CH:15]=[C:16]([C:18]([OH:21])([CH3:20])[CH3:19])[N:17]=1)[C:12]([NH:35][C@@H:33]([C:25]1[CH:24]=[N+:23]([O-:22])[C:28]([C:29]([F:30])([F:31])[F:32])=[CH:27][CH:26]=1)[CH3:34])=[O:14]
Reactant: CC(C)(O)c1cc(C(=O)O)cc(-c2ccc(F)cc2F)n1
Reactant: C[C@@H](N)c1ccc(C(F)(F)F)[n+]([O-])c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: C[C@@H](NC(=O)c1cc(-c2ccc(F)cc2F)nc(C(C)(C)O)c1)c1ccc(C(F)(F)F)[n+]([O-])c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83.1 %

Procedure:
To a solution of 2-(2,4-difluorophenyl)-6-(1-hydroxy-1-methylethyl)isonicotinic acid (19.5 mg, 0.07 mmol) in DMF (0.67 mL) were added hydrochloride salt of (1R)-1-[1-oxido-6-(trifluoromethyl)pyridin-3-yl]ethanamine (24.2 mg, 0.10 mmol), HATU (0.5 M in DMA; 0.2 mL, 0.10 mmol) and diisopropylethylamine (46.5 uL, 0.27 mmol). The mixture was stirred at ambient temperature. After 30 min, small amount of water and trifluoroacetic acid were added and the mixture was purified by reverse phase chromatography (C-18, 95% water/acetonitrile→5% water/acetonitrile with 0.1% trifluoroacetic acid) gave the title compound (28 mg). HRMS 482.1462 (M+1). 1H NMR (400 MHz, CDCl3): δ 8.38 (s, 1H); 8.09-8.01 (m, 1H); 7.94 (s, 1H); 7.73 (s, 1H); 7.67 (d, J=8.3 Hz, 1H); 7.38 (d, J=8.3 Hz, 1H); 7.07-6.98 (m, 1H); 6.99-6.90 (m, 1H); 6.74 (d, J=6.9 Hz, 1H); 5.32-5.25 (m, 1H); 4.38 (s, 1H); 1.67 (d, J=7.1 Hz, 3H); 1.62 (s, 6H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14][CH:13]=1)[C:6]1[C:22](=[O:27])[O:23][C:24](=[O:26])[CH2:25][C:5]2=1.[NH:28]1[CH2:31][CH:30]([OH:32])[CH2:29]1>CCN(CC)CC>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14][CH:13]=1)[C:6]([C:22]([OH:23])=[O:27])=[C:5]2[CH2:25][C:24]([N:28]1[CH2:31][CH:30]([OH:32])[CH2:29]1)=[O:26]
Reactant: O=C1Cc2c(n(Cc3cccc4ccccc34)c3ccc(F)cc23)C(=O)O1
Reactant: OC1CNC1
Solvent: CCN(CC)CC
Product: O=C(O)c1c(CC(=O)N2CC(O)C2)c2cc(F)ccc2n1Cc1cccc2ccccc12

Procedure:
6-Fluoro-9-naphthalen-1-ylmethyl-4,9-dihydro-pyrano[3,4-b]indole-1,3-dione (from Example 68.1.) was ring opened with azetidin-3-ol and NEt3 at 22° C. to give the title compound as a white solid. MS: 431.3 ([M−H]−).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:14]([NH:16][CH2:17][C:18]2[C:19](=[O:26])[NH:20][C:21]([CH3:25])=[CH:22][C:23]=2[CH3:24])=[O:15])[C:5]2[CH:10]=[N:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:6]=2[N:7]=1.[NH2:27][CH2:28][CH2:29][NH:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=1>CN1C(=O)CCC1>[CH3:24][C:23]1[CH:22]=[C:21]([CH3:25])[NH:20][C:19](=[O:26])[C:18]=1[CH2:17][NH:16][C:14]([C:4]1[C:5]2[CH:10]=[N:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:6]=2[N:7]=[C:2]([NH:27][CH2:28][CH2:29][NH:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=2)[CH:3]=1)=[O:15]
Reactant: NCCNc1ccccn1
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Cl)nc3c2cnn3C(C)C)c(=O)[nH]1
Solvent: CN1CCCC1=O
Product: Cc1cc(C)c(CNC(=O)c2cc(NCCNc3ccccn3)nc3c2cnn3C(C)C)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
6-Chloro-N-[(4,6-dimethyl-2-oxo-1,2-dihydro-3-pyridinyl)methyl]-1-(1-methylethyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide (80 mg, 0.21 mmol) and (2-aminoethyl)-2-pyridinylamine (88 mg, 0.64 mmol) were suspended in 2 mL of NMP and irradiated (microwave) as follows: 180° C. for 30 min, 200° C. for 30 min, 220° C. for 30 min, 230° C. for 30 min and then 240° C. for 1 h. After cooling to room temperature, some of the solvent was removed in vacuo and the residue was purified by silica gel chromatography (eluent: DCM/MeOH/NH4OH, gradient 0 to 90:10:1). The collected solid was partitioned between water and EtOAc/toluene (1:1) and then extracted twice with DCM/isopropanol. The combined organic layers were washed with water, dried over MgSO4, filtered, and concentrated in vacuo to afford a dark brown oil. After drying under vacuum overnight, the residue was again purified by silica gel chromatography (eluent: DCM/MeOH/NH4OH (gradient 0 to 90:10:1). The collected solid was suspended in EtOH, sonicated, and filtered. The solid was further washed with EtOH/DCM, filtered, and dried in vacuum-oven for 2 days. The final product was collected as 47 mg (45%). LCMS E-S (M+H)=475.0 1H NMR (400 MHz, DMSO-d6) δ ppm 11.56 (br. s., 1H) 8.47 (t, J=5.05 Hz, 1H) 7.97 (dd, J=4.93, 1.14 Hz, 1H) 7.85 (s, 1H) 7.32-7.39 (m, 2H) 6.65 (s, 1H) 6.61 (t, J=5.43 Hz, 1H) 6.46-6.51 (m, 2H) 5.89 (s, 1H) 4.97 (quin, J=6.69 Hz, 1H) 4.32 (d, J=5.05 Hz, 2H) 3.49 (dt, J=15.28, 5.62 Hz, 4H) 2.21 (s, 3H) 2.13 (s, 3H) 1.44 (s, 3H) 1.43 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[F:14])[N:5]=[C:4]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:3]=1.CN(C)[CH:22]=[C:23]([F:26])[CH:24]=O.FC(F)(F)C(O)=O>O1CCOCC1>[F:26][C:23]1[CH:22]=[C:3]2[C:4]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[N:5][N:6]([CH2:7][C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[F:14])[C:2]2=[N:1][CH:24]=1
Reactant: CN(C)C=C(F)C=O
Reactant: CCOC(=O)c1cc(N)n(Cc2ccccc2F)n1
Solvent: O=C(O)C(F)(F)F
Solvent: C1COCCO1
Product: CCOC(=O)c1nn(Cc2ccccc2F)c2ncc(F)cc12
Reaction time: 72 h

Procedure:
13.487 g (51.228 mmol) of ethyl 5-amino-1-(2-fluorobenzyl)-1H-pyrazole-3-carboxylate (preparation described for example 20A in WO 00/06569) were initially charged in 300 ml of dioxane, and 6 g (51.228 mmol) of 3-(dimethylamino)-2-fluoroacrylaldehyde (preparation described in Justus Liebigs Annalen der Chemie 1970; 99-107) were added at RT. Subsequently, 4.736 ml (61.473 mmol) of trifluoroacetic acid were added and the mixture was heated to reflux while stirring for 3 days. After cooling, the mixture was concentrated under reduced pressure, and water and ethyl acetate were added to the residue. The phases were separated and the organic phase was washed twice with water. The combined aqueous phases were subsequently extracted twice with ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue (22 g) was subsequently purified by chromatography on silica gel (eluent: dichloromethane). This gave 5.67 g (35% of theory) of the title compound.
Reaction SMILES: [CH2:1]([CH:3]([O:6][C:7]1[CH:12]=[C:11]([CH3:13])[N:10]=[C:9]([O:14][C:15]2[C:20]([CH3:21])=[CH:19][C:18]([OH:22])=[CH:17][C:16]=2[CH3:23])[C:8]=1[CH3:24])[CH2:4][CH3:5])[CH3:2].[C:25]1(P(C2C=CC=CC=2)C2C=CC=CC=2)[CH:30]=CC=C[CH:26]=1.C(O)(C)C.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[CH2:1]([CH:3]([O:6][C:7]1[CH:12]=[C:11]([CH3:13])[N:10]=[C:9]([O:14][C:15]2[C:20]([CH3:21])=[CH:19][C:18]([O:22][CH:25]([CH3:30])[CH3:26])=[CH:17][C:16]=2[CH3:23])[C:8]=1[CH3:24])[CH2:4][CH3:5])[CH3:2]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: CCC(CC)Oc1cc(C)nc(Oc2c(C)cc(O)cc2C)c1C
Agent: CCOC(=O)N=NC(=O)OCC
Solvent: C1CCOC1
Solvent: CC(C)O
Product: CCC(CC)Oc1cc(C)nc(Oc2c(C)cc(OC(C)C)cc2C)c1C
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 58.1 %

Procedure:
To a solution of 4-[4-(1-ethyl-propoxy)-3,6-dimethyl-pyridin-2-yloxy]-3,5-dimethyl-phenol (58 mg, 0.176 mmol) in 3 ml of dry THF was added triphenylphosphine (70 mg, 0.264 mmol) and isopropanol (60 mg, 0.22 mmol). The resulting mixture was stirred at room temperature for 5 min, diethyl azodicarboxylate (46 mg, 0.264 mmol) was added. The mixture was stirred at room temperature overnight. An additional 20 mg of diethyl azodicarboxylate was added and the mixture was stirred for an additional 4 hours. The mixture was quenched with water and extracted with methylene chloride. The organic layer was dried and concentrated to give an oil. The oil residue was purified through silica gel column chromatography using 1:1 hexane:chloroform to 1:2 hexane: chloroform as eluent to give 38 mg (58%) of the title compound as a colorless oil. 1H NMR (CDCl3) δ6.60 (s, 2H), 6.28 (s, 1H), 4.50 (m, 1H), 4.18 (m, 1H), 2.20 (s, 3H), 2.19 (s, 3H), 2.079s,6H), 1.71 (m, 4H), 1.34 (d, 6H), 0.98 (t, 6H) ppm.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[CH2:8][CH2:7][CH2:6][O:5][C:4]2[C:9]([NH2:13])=[CH:10][CH:11]=[CH:12][C:3]1=2.Cl[C:16]1[N:21]=[C:20]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([N:29]3[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]3)=[CH:25][C:24]=2[O:36][CH3:37])[C:19]([Cl:38])=[CH:18][N:17]=1>>[Cl:38][C:19]1[C:20]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([N:29]3[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]3)=[CH:25][C:24]=2[O:36][CH3:37])=[N:21][C:16]([NH:13][C:9]2[C:4]3[O:5][CH2:6][CH2:7][CH2:8][C:2]([CH3:14])([CH3:1])[C:3]=3[CH:12]=[CH:11][CH:10]=2)=[N:17][CH:18]=1
Reactant: COc1cc(N2CCN(C)CC2)ccc1Nc1nc(Cl)ncc1Cl
Reactant: CC1(C)CCCOc2c(N)cccc21
Product: COc1cc(N2CCN(C)CC2)ccc1Nc1nc(Nc2cccc3c2OCCCC3(C)C)ncc1Cl

Procedure:
The title compound was prepared from 5,5-dimethyl-2,3,4,5-tetrahydro-benzo[b]oxepin-9-ylamine and (2,5-dichloro-pyrimidin-4-yl)-[2-methoxy-4-(4-methyl-piperazin-1-yl)-phenyl]-amine in the analogous manner to Example 179. Product was isolated as a tan solid (12 mg, 10%). LCMS (m/e) 523 (M+H); 1H NMR δ 8.28 (d, 1H, J=7.8 Hz), 8.21 (d, 1H, J=9.1 Hz), 8.03 (s, 1H), 7.74 (s, 1H), 7.48 (s, 1H), 6.89-6.97 (m, 2H), 6.58 (s, 2H), 4.01 (m, 2H), 3.90 (s, 3H), 3.22 (m, 4H), 2.61 (m, 4H), 2.38 (s, 3H), 2.07 (m, 2H), 1.69 (m, 2H), 1.39 (s, 6H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:8])[CH:5]=[N:6][CH:7]=1.C(N(C(C)C)CC)(C)C.[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=1)[C:23](Cl)=[O:24]>ClCCl.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([NH:8][C:23](=[O:24])[C:22]2[CH:26]=[CH:27][CH:28]=[C:20]([O:19][CH3:18])[CH:21]=2)[CH:5]=[N:6][CH:7]=1
Reactant: Nc1cncc(Br)c1
Reactant: COc1cccc(C(=O)Cl)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COc1cccc(C(=O)Nc2cncc(Br)c2)c1
Yield: 115.4 %

Procedure:
5-Bromopyridin-3-amine (1.5 g, 8.67 mmol) was dissolved in dichloromethane (40 ml). Diisopropylethylamine (1.81 ml, 10.39 mmol) first and then a solution of 3-methoxybenzoyl chloride (1.18 ml, 8.66 mmol) in dichloromethane (25 ml) were added. After 1 h at room temperature the reaction mixture was diluted with ethyl acetate and washed with water and brine, dried over sodium sulphate, filtered and evaporated under reduced pressure to give 3.07 g (89% yield) of the title compound. Purity 77%.
Reaction SMILES: [O:1]=[C:2]1[CH:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[S:5][C:4]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:22])([F:21])[F:20])=[N:3]1.[C:23]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])(=[O:26])[CH:24]=[CH2:25].C1CCN2C(=NCCC2)CC1>CCO>[C:28]([O:27][C:23](=[O:26])[CH2:24][CH2:25][C:6]1([C:7]([O:9][CH2:10][CH3:11])=[O:8])[S:5][C:4]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:22])([F:20])[F:21])=[N:3][C:2]1=[O:1])([CH3:31])([CH3:30])[CH3:29]
Reactant: C=CC(=O)OC(C)(C)C
Reactant: CCOC(=O)C1SC(Nc2ccccc2C(F)(F)F)=NC1=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCO
Product: CCOC(=O)C1(CCC(=O)OC(C)(C)C)SC(Nc2ccccc2C(F)(F)F)=NC1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The above compounds were prepared according to the procedure reported in the literature: see S. Muthusamy Synth. Commun. 2002, 32, 3247. To a stirred solution of ethyl 4-oxo-2-(2-(trifluoromethyl)phenylamino)-4,5-dihydrothiazole-5-carboxylate (1.1 g, 3.3 mol), tert-butyl acrylate (Aldrich, 2.5 mL, 16.5 mmol) in EtOH (10 mL) was added DBU (Aldrich, 0.25 mL, 1.6 mmol). The mixture was stirred at r.t. overnight and concentrated in vacuo. The crude product was purified by silica gel chromatography. MS: 461 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:14])[N:11]([CH3:13])[CH3:12])[CH:6]=[CH:7][CH:8]=1.I[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1.[H+].[B-](F)(F)(F)F>CC([O-])=O.[Ag+].CC([O-])=O.CC([O-])=O.[Pd+2].O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)=[C:5]([NH:9][C:10](=[O:14])[N:11]([CH3:13])[CH3:12])[CH:4]=1
Reactant: COc1ccc(I)cc1
Reactant: COc1cccc(NC(=O)N(C)C)c1
Agent: [Ag+]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: O
Product: COc1ccc(-c2ccc(OC)cc2NC(=O)N(C)C)cc1
Reaction time: 24 h
Yield: 67.9 %

Procedure:
3-(3-Methoxyphenyl)-1,1-dimethylurea (49 mg, 0.25 mmol), 1-iodo-4-methoxybenzene (117 mg, 0.50 mmol), AgOAc (0.5 mmol, 83 mg), and Pd(OAc)2 (0.025 mmol, 5.6 mg), were sequentially added under air to a reaction tube equipped with a stir bar and septum. An aliquot of TPGS-M-PEG-750/H2O (1.0 mL; 2.0% TPGS-M-PEG-750 by weight) solution, and 48 wt % aqueous HBF4 solution (1.25 mmol, 0.16 mL) were added by syringe and stirred vigorously for 24 h. After the reaction, the contents of the flask were quenched with NaHCO3 and extracted with EtOAc. The solution obtained was dried over anhydrous MgSO4 and concentrated by rotary evaporation. The residue was purified by flash chromatography eluting with 1:1 EtOAc/hexanes to afford the product (51 mg, 68%) as a white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]([N+]([O-])=O)[CH:10]=[C:6](C(O)=O)[C:5]=1[OH:16])([O-:3])=[O:2].C1C=CC2N(O)N=NC=2C=1.CC(C)N=C=NC(C)C>>[N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[CH:6][C:5]=1[OH:16])([O-:3])=[O:2]
Reactant: O=C(O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1O
Agent: CC(C)N=C=NC(C)C
Agent: On1nnc2ccccc21
Product: O=[N+]([O-])c1ccccc1O

Procedure:
This material was prepared from 3,5-dinitrosalicylic acid (1c) (1 g, 4.4 mmol), HOBt (1 g, 7.4 mmol), DIC (1,3-diisopropylcarodiimide, 1 mL, 6.4 mmol), and an amino polystyrene resin (1 g, 1.2 mmol) using a procedure similar to polystyrene resin (PS-2a).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=1.[CH2:12]([OH:15])[C:13]#[CH:14].C(N(CC)CC)C>C1(C)C=CC=CC=1.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.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:9][C:8]([F:11])([F:10])[C:5]1[CH:6]=[CH:7][C:2]([C:14]#[C:13][CH2:12][OH:15])=[CH:3][CH:4]=1
Reactant: C#CCO
Reactant: FC(F)(F)c1ccc(Br)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: OCC#Cc1ccc(C(F)(F)F)cc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 60 %

Procedure:
A mixture of 4-bromobenzotrifluoride (6.5 g, 28.89 mmol), propargyl alcohol (2.35 ml, 40.45 mmol), triethylamine (5.64 ml, 40.45 mmol), triphenylphosphine (230 mg, 0.87 mmol), cuprous iodide (110 mg, 0.58 mmol), and dichlorobis(triphenylphosphine)palladium (210 mg, 0.29 mmol) in toluene (100 ml) was stirred at 100° C. under a nitrogen atmosphere for 2 hours. The reaction mixture was allowed to return to room temperature and filtered through Celite. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methylene chloride/ethyl acetate =9/1) to afford 3-(4-trifluoromethylphenyl)-2-propyn-1-ol (3.47 g, yield 60%) as a pale brown oil.