Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:6]2[C:7]3[C:16]([CH3:17])=[C:15]([C:18]([OH:20])=[O:19])[CH:14]=[C:13]([CH3:21])[C:8]=3[S:9](=[O:12])(=[O:11])[CH2:10][C:5]=2[CH:4]=[N:3]1.C(Cl)(=O)C(Cl)=O.[C:28]1(=O)[CH2:33][CH2:32][CH2:31][C:30](=[O:34])[CH2:29]1.C(N(CC)CC)C>CN(C)C=O.C(Cl)Cl>[CH3:1][N:2]1[C:6]2[C:7]3[C:16]([CH3:17])=[C:15]([C:18]([O:20][C:28]4[CH2:33][CH2:32][CH2:31][C:30](=[O:34])[CH:29]=4)=[O:19])[CH:14]=[C:13]([CH3:21])[C:8]=3[S:9](=[O:11])(=[O:12])[CH2:10][C:5]=2[CH:4]=[N:3]1
Reactant: Cc1cc(C(=O)O)c(C)c2c1S(=O)(=O)Cc1cnn(C)c1-2
Reactant: O=C1CCCC(=O)C1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1cc(C(=O)OC2=CC(=O)CCC2)c(C)c2c1S(=O)(=O)Cc1cnn(C)c1-2
Temperature: 0 °C
Reaction time: 72 h
Yield: 33 %

Procedure:
2.0 g (0.0065 mol) of the title compound of Step B, 1.71 mL (0.0196 mol) of oxalyl chloride (purchase from Janssen), and 2 drops of N,N-dimethylformamide were added to 50 mL of methylene chloride. The mixture was refluxed under nitrogen for 2 h and was then evaporated to dryness. 50 mL of methylene chloride was added to the residue and it was then evaporated to dryness. Another 50 mL of methylene chloride was added to the residue and the solution was cooled to about 0° C. 0.80 g (0.0071 mol) of 1,3-cyclohexanedione (purchased from Aldrich Chemical Company) was added followed by 2.8 mL (0.020 mol) of triethylamine, and the mixture was stirred for 3 days while warming to room temperature. The mixture was evaporated to dryness and the crude product was chromatographed over silica gel eluting with a mixture of ethyl acetate:hexane (6:4) to yield 0.86 g of the title compound of Step C as a solid melting at 196° C. (decomposed). 1H NMR (CDCl3): δ2.2(m,2H), 2.5 (m,2H), 2.64 (s,3H), 2.7 (m,2H), 2.8 (s,3H), 3.8 (s,3H), 4.3 and 4.4 (2d, 2H), 6.06 (s,1H), 7.65 (s,1H), 7.94 (s,1H).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=O.C1C[O:16][CH2:15][CH2:14]1>C(OCC)C.O.[Zn+2].[Br-].[Br-].[Cl-].[Cl-].[Zn+2]>[F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=[CH:14][CH:15]=[O:16]
Reactant: C1CCOC1
Reactant: O=Cc1ccccc1C(F)(F)F
Agent: [Br-]
Agent: [Cl-]
Agent: [Zn+2]
Solvent: O
Solvent: CCOCC
Product: O=CC=Cc1ccccc1C(F)(F)F
Temperature: 10 °C
Reaction time: 8 h

Procedure:
To a solution of 2-trifluoromethylbenzaldehyde (260 mg) in 5 mL THF was added 200 mg of ZnBr2. With stirring, 400 mg of α,α-bis(trimethylsilyl)-t-butylacetaldimine (7) was added, and stirring was continued overnight. The solution was cooled to 10° C., then hydrolyzed by the addition of a solution of ZnCl2 (200 mg) in diethyl ether/water (3 mL each), followed by stirring at room temperature for 1 h. The solids were removed by filtration through Celite and the filtrate extracted with diethyl ether (2×). The combined ether extracts were washed with water and brine, dried over magnesium sulfate, filtered and concentrated to provide the crude title compound as an oil. The product was purified via silica gel column chromatography to afford a white powder (130 mg): 1H NMR (CDCl3) δ 6.70 (dd, 1 H, J=9.6, 4.5 Hz), 7.55 (t, 1 H, J=4.5 Hz), 7.63 (t, 1 H, J=4.5 Hz), 7.76 (d, 2 H, J=4.8 Hz), 7.88 (br d, 1 H, J=9.6 Hz), 9.77 (d, 1 H, J=4.8 Hz).
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].Br[C:8]1[NH:12][C:11]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[N:10][N:9]=1.[F:20][CH:21]([F:46])[C@@:22]1([C:30]2[CH:35]=[C:34](B3OC(C)(C)C(C)(C)O3)[CH:33]=[CH:32][C:31]=2[F:45])[C@@H:28]2[C@@H:26]([CH2:27]2)[O:25][C:24]([NH2:29])=[N:23]1.O1CCOCC1>C(C1C(C(C)(C)C)=C([Pd]Cl)C=CC=1NC)(C)(C)C.O>[F:46][CH:21]([F:20])[C@@:22]1([C:30]2[CH:35]=[C:34]([C:8]3[NH:12][C:11]([C:13]4[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=4)=[N:10][N:9]=3)[CH:33]=[CH:32][C:31]=2[F:45])[C@@H:28]2[C@@H:26]([CH2:27]2)[O:25][C:24]([NH2:29])=[N:23]1
Reactant: CC1(C)OB(c2ccc(F)c([C@@]3(C(F)F)N=C(N)O[C@@H]4C[C@@H]43)c2)OC1(C)C
Reactant: Fc1ccc(-c2nnc(Br)[nH]2)cc1
Agent: CNc1ccc([Pd]Cl)c(C(C)(C)C)c1C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: NC1=N[C@@](c2cc(-c3nnc(-c4ccc(F)cc4)[nH]3)ccc2F)(C(F)F)[C@H]2C[C@H]2O1
Temperature: 120 °C

Procedure:
A glass microwave reaction vessel was charged with sodium carbonate (0.171 g, 1.609 mmol), 3-bromo-5-(4-fluorophenyl)-4H-1,2,4-triazole (0.078 g, 0.322 mmol, US20130184248 A1), (1R,5S,6R)-5-(difluoromethyl)-5-(2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2-oxa-4-azabicyclo[4.1.0]hept-3-en-3-amine, 1,4-dioxane (2.5 ml) and water (0.83 ml). The vessel was capped and the solution was degassed by bubbling nitrogen gas through the solution for 10 minutes. Next, 1,1-bis[(di-t-butyl-p-methylaminophenyl]palladium(II) chloride (0.023 g, 0.032 mmol) was added and the vessel was sealed. The reaction mixture was stirred and heated in a Initiator microwave reactor (Personal Chemistry, Biotage AB, Inc., Upssala, Sweden) at 120° C. for 20 minutes. The reaction was poured into water and the mixture was extracted with EtOAc. The combined organic extracts were washed with a 9:1 mixture of aqueous saturated ammonium chloride/ammonium hydroxide, saturated aqueous sodium chloride, and then stirred with activated carbon. The solution was filtered through a pad of celite and concentrated in vacuo to give the crude material. The crude material was purified by silica gel chromatography by eluting with 1:40 2M NH3.MeOH in CH2CL2, and then repurified by preparative TLC by eluting with 1:30 2M NH3.MeOH in CH2CL2 to provide the titled compound as a white solid after concentration with MeOH.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](O)([CH3:10])[CH3:9])=[C:4]([F:12])[CH:3]=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:9])[CH3:10])=[C:4]([F:12])[CH:3]=1
Reactant: CC(C)(O)c1ccc(Br)cc1F
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)c1ccc(Br)cc1F
Reaction time: 0.75 h
Yield: 80.1 %

Procedure:
To a solution of 2-(4-bromo-2-fluorophenyl)propan-2-ol (7.6 g, 32.8 mmol) dissolved in anhydrous CH2Cl2 (300 mL) at 25° C. was added triethylsilane (7.8 mL, 49.1 mmol), followed by trifluoroacetic acid (25 mL, 328 mmol). The resulting solution was stirred at that temperature for 45 min. The solvent was removed in vacuo and the residue was purified by flash column chromatography (0-10% EtOAc in hexanes) to give the desired product (5.7 g, 80% yield). 1H NMR (CDCl3, 400 MHz) δ: 1.23 (d, J=6.82 Hz, 3H), 3.15-3.22 (m, 1H), 7.11 (t, J=8.08 Hz, 1H), 7.17 (dd, J=9.85, 1.77 Hz, 1H), 7.22 (d, J=8.34 Hz, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:22]([CH2:29][CH2:30][CH3:31])[CH:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:5]([CH3:21])=[C:6]([CH:20]=1)[C:7]([NH:9][CH2:10][C:11]1[C:12](=[O:19])[NH:13][C:14]([CH3:18])=[CH:15][C:16]=1[CH3:17])=[O:8].CC1(C)C(C)(C)OB([C:40]2[CH:52]=[CH:51][C:43]([CH2:44][N:45]3[CH2:50][CH2:49][O:48][CH2:47][CH2:46]3)=[CH:42][CH:41]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:17][C:16]1[CH:15]=[C:14]([CH3:18])[NH:13][C:12](=[O:19])[C:11]=1[CH2:10][NH:9][C:7]([C:6]1[CH:20]=[C:2]([C:40]2[CH:41]=[CH:42][C:43]([CH2:44][N:45]3[CH2:50][CH2:49][O:48][CH2:47][CH2:46]3)=[CH:51][CH:52]=2)[CH:3]=[C:4]([N:22]([CH2:29][CH2:30][CH3:31])[CH:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:5]=1[CH3:21])=[O:8]
Reactant: CC1(C)OB(c2ccc(CN3CCOCC3)cc2)OC1(C)C
Reactant: CCCN(c1cc(Br)cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1C)C1CCOCC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CCCN(c1cc(-c2ccc(CN3CCOCC3)cc2)cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1C)C1CCOCC1
Temperature: 100 °C
Yield: 82.7 %

Procedure:
To a stirred solution of 5-bromo-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methyl-3-(propyl(tetrahydro-2H-pyran-4-yl)amino)benzamide (0.2 g, 0.412 mmol) and 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)morpholine (0.148 g, 0.488 mmol) in dioxane/water mixture (5 mL+1 mL), Na2CO3 (0.108 g, 1.01 mmol) was added and reaction mixture purged with argon for 15 min. Pd (PPh3)4 (0.048 g, 0.042 mmol) was then added and the reaction mixture again purged with argon for 10 min. The reaction mixture was heated at 100° C. for 2 h. The reaction mixture was diluted with water and extracted with 10% MeOH/DCM. The combined extracts were dried over Na2SO4 and solvent removed under reduced pressure to afford crude product which was purified by column chromatography over silica gel to afford the title compound (0.20 g, 83.68%). LCMS: 587.40 (M+1)+; HPLC: 98.68% (@254 nm) (Rt; 4.257; Method: Column: YMC ODS-A 150 mm×4.6 mm×5μ; Mobile Phase: A; 0.05% TFA in water/B; 0.05% TFA in acetonitrile; Inj. Vol: 10 μL, Col. Temp.: 30° C.; Flow rate: 1.4 mL/min.; Gradient: 5% B to 95% B in 8 min, Hold for 1.5 min, 9.51-12 min 5% B); 1H NMR (DMSO-d6, 400 MHz) δ 11.46 (s, 1H), 8.19 (t, 1H, J=4.8 Hz), 7.56 (d, 2H, J=8 Hz), 7.38 (t, 3H, J=8 Hz), 7.19 (s, 1H), 5.85 (s, 1H), 4.28 (d, 2H, J=4.4 Hz), 3.82-3.85 (m, 2H), 3.57 (m, 4H), 3.48 (s, 2H), 3.23 (t, 2H, J=10.8 Hz), 2.94-3.02 (m, 3H), 2.36 (bs, 4H), 2.24 (s, 3H), 2.20 (s, 3H), 2.10 (s, 3H), 1.56-1.65 (m, 4H), 1.20-1.25 (m, 2H), 0.76 (t, 3H, J=6.8 Hz).
Reaction SMILES: [OH:1]S([O-])=O.[Na+].[Cl:6][C:7]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][C:8]=1[CH:9]=[C:10]([CH3:13])[CH:11]=O.CC1[O:23][CH2:24][C:25](C)(C)N=1>C1(C)C=CC=CC=1>[Cl:6][C:7]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][C:8]=1[CH:9]=[C:10]([CH3:13])[CH:11]=[CH:25][C:24]([OH:1])=[O:23]
Reactant: O=S([O-])O
Reactant: CC(C=O)=Cc1cc([N+](=O)[O-])ccc1Cl
Reactant: CC1=NC(C)(C)CO1
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(C=CC(=O)O)=Cc1cc([N+](=O)[O-])ccc1Cl
Temperature: 100 °C

Procedure:
0.3 g of a 40 percent strength NaHSO3 solution is added to a mixture of 9 g of 2-chloro-5-nitro-α-methylcinnamaldehyde and 10.4 g of 2,4,4-trimethyloxazoline in 50 ml of toluene, and the mixture is refluxed for 10 hours. It is evaporated down, and 10 ml of water and 10 ml of concentrated HCl are added to the crude product of the structure ##STR23## Heating at 100° C. for 7 hours results in cleavage of the oxazoline ring. The crude product is filtered off under suction, washed with water and dried. Yield: 7.1 g (66%), mp. 178°-185° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:30])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:21]=[N:22][N:23]([CH3:25])[CH:24]=3)=[CH:16][C:15]=2[CH2:26][NH:27][CH2:28][CH3:29])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2].[CH2:31]([N:38]=[C:39]=[O:40])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[CH2:1]([O:3][C:4](=[O:30])[CH2:5][C:6]1[CH:7]=[C:8]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:21]=[N:22][N:23]([CH3:25])[CH:24]=3)=[CH:16][C:15]=2[CH2:26][N:27]([CH2:28][CH3:29])[C:39]([NH:38][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[O:40])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2]
Reactant: O=C=NCc1ccccc1
Reactant: CCNCc1cc(-c2cnn(C)c2)ccc1-c1cc(CC(=O)OCC)ccc1OC
Product: CCOC(=O)Cc1ccc(OC)c(-c2ccc(-c3cnn(C)c3)cc2CN(CC)C(=O)NCc2ccccc2)c1

Procedure:
Prepared according to the procedure described in Example 95, Step 2, using the following starting materials: [2′-ethylaminomethyl-6-methoxy-4′-(1-methyl-1H-pyrazol-4-yl)-biphenyl-3-yl]-acetic acid ethyl ester and benzyl isocyanate.
Reaction SMILES: [OH:1][C@H:2]([C:16]1[S:17][C:18]([C:21]2[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=2)=[CH:19][CH:20]=1)[C@@H:3]1[N:7]([CH3:8])[C:6](=[O:9])[CH2:5][C@@H:4]1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C1C=C(Cl)C=C(C(OO)=[O:35])C=1.C([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl>[OH:1][C@H:2]([C:16]1[S:17][C:18]([C:21]2[CH:22]=[N+:23]([O-:35])[CH:24]=[CH:25][CH:26]=2)=[CH:19][CH:20]=1)[C@@H:3]1[N:7]([CH3:8])[C:6](=[O:9])[CH2:5][C@@H:4]1[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: CN1C(=O)C[C@H](c2ccccc2)[C@@H]1[C@H](O)c1ccc(-c2cccnc2)s1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CN1C(=O)C[C@H](c2ccccc2)[C@@H]1[C@H](O)c1ccc(-c2ccc[n+]([O-])c2)s1
Reaction time: 0.67 h

Procedure:
To a solution of (4R,5R)-5-{(1S)-hydroxy[5-(3-pyridinyl)-2-thienyl]methyl}-1-methyl-4-phenyl-2-pyrrolidinone (Example 3b, 0.20 g, 0.55 mmol) in CHCl3 (10 mL) was added mCPBA (0.35 g, 1.4 mmol). The reaction mixture was stirred for 40 min, then was treated with a saturated NaHCO3 solution (10 mL). The organic layer was dried (Na2SO4) and was allowed to stand overnight. The white precipitate was filtered off, the filtrate was concentrated under reduced pressure. The crude product was triturated (Et2O/CH2Cl2) to give (4R,5R)-5-{(S)-hydroxy[5-(1-oxido-3-pyridinyl)-2-thienyl]methyl}-1-methyl-4-phenyl 2-pyrrolidinone: mp 138-140° C.; TLC (10% MeOH/CH2Cl2) Rf 0.20; ES-LRMS m/z 381 (MH+).
Reaction SMILES: [CH2:1]([OH:12])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]=[CH2:11].N1C=CC=CC=1.[Br:19][C:20]([CH3:25])([CH3:24])[C:21](Br)=[O:22]>O1CCCC1>[Br:19][C:20]([CH3:25])([CH3:24])[C:21]([O:12][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH:10]=[CH2:11])=[O:22]
Reactant: CC(C)(Br)C(=O)Br
Reactant: C=CCCCCCCCCCO
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: C=CCCCCCCCCCOC(=O)C(C)(C)Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 89 %

Procedure:
A similar synthetic scheme was conducted as followed.x To a solution of 4.257 g (25 mmol) of co-undecylenyl alcohol in 25 mL of dry tetrahydrofuran was added 2.1 mL of pyridine (26.5 mmol) by dropwise addition of 3.10 mL of 2-bromoisobutyryl bromide (25 mmol). The mixture was stirred at ambient temperature for 8 hours. The remaining THF was removed under reduced pressure followed by dilution with hexane (50 mL). The mixture was washed with 2 M HCl solution and twice with water (50 ml). The organic phase was dried over sodium sulfate and filtered. The solvent was removed from the filtrate under reduced pressure yielding a colorless oil (89%). 1H NMR (500 MHz, CDCl3) δ: 1.22-1.45 (br m, 12H); 1.62-1.75 (m, 2H); 1.94 (s 6H); 2.05 (q, 2H, J) 6 Hz); 4.17 (t, 2H, J=9 Hz); 4.9-5.05 (m, 2H); 5.72-5.9 (m, 1H) ppm.
Reaction SMILES: [C:1]([CH2:4][NH:5][C:6](=O)[C:7]1[CH:12]=[CH:11][CH:10]=[N:9][CH:8]=1)(=O)[CH3:2].P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:15].N.C>C1(C)C=CC=CC=1>[CH3:2][C:1]1[S:15][C:6]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)=[N:5][CH:4]=1
Reactant: CC(=O)CNC(=O)c1cccnc1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Agent: N
Solvent: Cc1ccccc1
Product: Cc1cnc(-c2cccnc2)s1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a solution of 8.0 g (0.045 mol) of 73 in 125 ml of toluene, 10 g (0.045 mol) of P4S10 was added. The suspension was refluxed for 4 h and left at room temperature overnight. The mixture was poured into ice water followed by basification with ammonia. The two-phase system was stirred with charcoal and filtered. The toluene phase was separated and the aqueous phase extracted with 2×100 ml of toluene. The combined organic phase were dried over MgSO4 and evaporated in vacuo leaving a heavy, yellow oil, 88. Yield: 2.3 g (0.013 mol), 29%).
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[C:10]([O:14][CH3:15])(=[O:13])[CH:11]=[CH2:12].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.CC(N(C)C)=O>[CH:6]([C:5]1[CH:8]=[CH:9][C:2](/[CH:12]=[CH:11]/[C:10]([O:14][CH3:15])=[O:13])=[CH:3][CH:4]=1)=[O:7]
Reactant: O=Cc1ccc(Br)cc1
Reactant: C=CC(=O)OC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: O
Solvent: CCN(CC)CC
Solvent: CC(=O)N(C)C
Product: COC(=O)/C=C/c1ccc(C=O)cc1
Temperature: 110 °C
Yield: 83 %

Procedure:
4-Bromobenzaldehyde (30 g, 162.15 mmol) and methyl acrylate (20.94 g, 243.22 mmol) were taken up in thoroughly degassed DMA (300 nil) and treated with tri-o-tolylphosphine (4.94 g. 16.21 mmol), palladium(II) acetate (1.820 g, 8.11 mmol) and triethylamine (45.2 ml, 324.29 mmol) and heated to 110° C. for 16 hours. The reaction appeared complete after this time. The reaction mixture was poured into water (4 L) and the resulting precipitate was filtered and dried. The solid was chromatographed on silica, eluting with 100% heptane to 30% EtOAc in heptane. Relevant fractions were combined and evaporated to dryness to afford a yellow solid product which was triturated with heptane, filtered and washed with cold heptane. The solid was dried to afford (E)-methyl 3-(4-formylphenyl)acrylate (25.6 g. 83%) as a yellow crystalline product. 1H NMR (400 MHz, DMSO, 30° C.) δ 3.75 (3H, s), 6.79 (1H, d), 7.72 (1H, d), 7.93 (4H, s), 10.03 (1H, s). No mass ion observed in LCMS.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]([C:11]2[N:12]=[C:13]([C:16](Cl)=[O:17])[S:14][CH:15]=2)=[C:8]([CH3:10])[N:9]=1)(=[O:3])[CH3:2].[NH2:19][C:20]1[CH:21]=[CH:22][C:23]2[C:28](=[O:29])[O:27][C:26]([CH3:31])([CH3:30])[O:25][C:24]=2[CH:32]=1.C(CC1SC=C(C2SC(NC(=O)C)=NC=2C)N=1)#N.C(N(CC)CC)C>C1COCC1.C(Cl)Cl>[C:1]([NH:4][C:5]1[S:6][C:7]([C:11]2[N:12]=[C:13]([C:16]([NH:19][C:20]3[CH:21]=[CH:22][C:23]4[C:28](=[O:29])[O:27][C:26]([CH3:30])([CH3:31])[O:25][C:24]=4[CH:32]=3)=[O:17])[S:14][CH:15]=2)=[C:8]([CH3:10])[N:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1nc(C)c(-c2csc(C(=O)Cl)n2)s1
Reactant: CC1(C)OC(=O)c2ccc(N)cc2O1
Agent: CC(=O)Nc1nc(C)c(-c2csc(CC#N)n2)s1
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Nc1nc(C)c(-c2csc(C(=O)Nc3ccc4c(c3)OC(C)(C)OC4=O)n2)s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2′-Acetylamino-4′-methyl-[4,5′]bithiazolyl-2-carbonyl chloride, prepared as in Step I of Example 13, described above, (200 mg, 0.66 mmol, 1 eq.), is dissolved in THF (8 ml) and DCM (4 ml). 7-Amino-2,2-dimethyl-4H-1,3-benzodioxine-4-one, Amine 3 prepared as described above, (128.0 mg; 0.66 mmol; 1 eq.) and triethylamine (0.19 ml; 1.33 mmol; 2 eq.) are added and the mixture is stirred overnight at rt. Solvents are evaporated and the crude product is purified by crystallization in MeOH. The resulting product is washed with MeOH and NaHCO3 (sat), affording 2′-(acetylamino)-N-(2,2-dimethyl-4-oxo-4H-1,3-benzodioxin-7-yl)-4′-methyl-4,5′-bi-1,3-thiazole-2 carboxamide as a beige solid (200 mg; 65%). 1H NMR (DMSO-d6, 300 MHz) δ 1.67 (s, 6H), 2.13 (s, 3H), 2.49 (s, 3H), 7.28 (m, 1H), 7.56 (s, 1H), 7.64 (br d, J=9 Hz, 1H), 7.75 (s, 1H), 11.65 (br s, 1H). M− (ESI): 457.08; M+ (ESI): 459.13. HPLC (method A), Rt: 3.86 min (purity: 97.7%).
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:17]#[N:18])=[CH:7][CH:6]=1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>O1CCCC1>[C:17]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[C:8]1[CH:7]=[CH:6][C:5]([CH2:4][NH2:1])=[CH:10][CH:9]=1)#[N:18]
Reactant: N#Cc1ccccc1-c1ccc(CN=[N+]=[N-])cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1ccccc1-c1ccc(CN)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 5.85 g (25 mmole) of 4-azidomethyl-2'-cyanobiphenyl (from Step A) in 50 ml of dry tetrahydrofuran was treated portionwise with 6.55 g (25 mmole) of triphenylphospine over 3-4 minutes. The solution was stirred at ambient temperature under N2, and gas evolution proceeded at a moderate rate. A mild exotherm occurred, and the solution was cooled in a water bath as necessary. After 2 hours, by which time gas evolution had ceased, 675 μl (37.5 mmole) of H2O was added, and stirring was continued at room temperature under N2. After 22 hours, the solution was concentrated in vacuo, and the residual oil was chromatographed on a column of silica gel (gradient elution with 2-10% methanol in CH2Cl2). The residue from evaporation of the pooled product fractions was partitioned between ether-CH2Cl2 and saturated Na2CO3 (aqueous). The organic phase was dried (Na2SO4), filtered, and concentrated in vacuo to yield the title compound as air-sensitive, nearly white crystals, mp 54°-55° C., homogeneous by TLC in 9:1 CH2Cl2 --MeOH; mass spectrum (FAB) m/e 209(M+1)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1.[ClH:10].[N:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]([Cl:19])=[O:18].C(OCC)C>O1CCCC1>[ClH:19].[ClH:10].[CH3:9][O:8][C:5]1[N:6]=[CH:7][C:2]([NH:1][C:17]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][N:11]=2)=[O:18])=[CH:3][CH:4]=1
Reactant: COc1ccc(N)cn1
Reactant: O=C(Cl)c1ccccn1
Agent: Cl
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1ccc(NC(=O)c2ccccn2)cn1
Yield: 73.8 %

Procedure:
5-Amino-2-methoxypyridine (4.40 g, 35.4 mmol), dissolved in a small amount of tetrahydrofuran, was added slowly to a stirred solution of pyridine-2-carbonyl chloride hydrochloride (7.12 g, 40.0 mmol) in tetrahydrofuran (75 mL). After stirring overnight at room temperature diethyl ether was added. The solids were isolated by suction, washed with diethyl ether and dried in a vacuum oven at 45° C., yielding the title compound (7.89 g, 75%).
Reaction SMILES: [C:1]([CH:5]1[C:10](=[O:11])[CH2:9][CH:8]([CH:12]2[CH2:17][CH:16]3[CH2:18][CH:14]([C:15]3([CH3:20])[CH3:19])[CH:13]2[CH3:21])[CH2:7][C:6]1=[O:22])(=O)[CH2:2][CH3:3].[Cl-].[CH2:24]([O:27][NH3+:28])[CH:25]=[CH2:26].C([O-])(=O)C.[Na+]>C(O)C>[CH2:24]([O:27][NH:28][C:1](=[C:5]1[C:10](=[O:11])[CH2:9][CH:8]([CH:12]2[CH2:17][CH:16]3[CH2:18][CH:14]([C:15]3([CH3:19])[CH3:20])[CH:13]2[CH3:21])[CH2:7][C:6]1=[O:22])[CH2:2][CH3:3])[CH:25]=[CH2:26]
Reactant: C=CCO[NH3+]
Reactant: CCC(=O)C1C(=O)CC(C2CC3CC(C2C)C3(C)C)CC1=O
Agent: CC(=O)[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Product: C=CCONC(CC)=C1C(=O)CC(C2CC3CC(C2C)C3(C)C)CC1=O
Yield: 91 %

Procedure:
7.5 parts by weight of 2-propionyl-5-(2,6,6-trimethylbicyclo[3.1.1]-hept-3-yl)-cyclohexane-1,3-dione, 2.9 parts per weight of allyloxyammonium chloride, 2.2 parts by weight of anhydrous sodium acetate and 80 of ethanol were stirred at room temperature for 12 hours, the solvent was distilled off under reduced pressure, the residue was stirred with 120 parts of water and 100 parts of methylene chloride, the organic phase was separated off, the aqueous phase was extracted with 50 parts of methylene chloride, and the combined organic phases were washed with water, dried over sodium sulfate and evaporated down under reduced pressure. 2-(1-allyloxyaminopropylidene)-5-(2,6,6-trimethylbicyclo[3.1.1]hept-3-yl)cyclohexane-1,3-dione was obtained in 91% yield as an oil (compound no. 2); nD33 : 1.5317.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[NH:12]1[C:16]2[CH:17]=[CH:18][C:19]([CH:21]=O)=[CH:20][C:15]=2[N:14]=[N:13]1.N1CCCCC1>CCO>[NH:12]1[C:16]2[CH:17]=[CH:18][C:19](/[CH:21]=[C:5]3/[C:6](=[O:11])[NH:7][C:8]4[C:4]/3=[CH:3][C:2]([NH2:1])=[CH:10][CH:9]=4)=[CH:20][C:15]=2[N:14]=[N:13]1
Reactant: Nc1ccc2c(c1)CC(=O)N2
Reactant: O=Cc1ccc2[nH]nnc2c1
Solvent: C1CCNCC1
Solvent: CCO
Product: Nc1ccc2c(c1)/C(=C\c1ccc3[nH]nnc3c1)C(=O)N2
Temperature: 90 °C
Yield: 20.4 %

Procedure:
A scintillation vial was charged with 5-aminoindolin-2-one (37 mg, 0.247 mmol), 1H-benzo[d][1,2,3]triazole-5-carbaldehyde (40 mg, 0.272 mmol), piperidine (2.5 uL, 0.025 mmol) and EtOH (2 mL). The reaction was then heated to 90° C. for 2 hrs. The EtOH was removed in vacuo and the residue loaded onto a silica gel column eluting with 92:8 CH2Cl2/MeOH to give 14 mg, 20% of a red solid. 1H NMR (400 MHz, d6-DMSO) δ 15.96 (bs, 1H), 10.15 (s, 1H), 8.21 (bs, 1H), 8.02 (bs, 1H), 7.73 (bs, 1H), 7.67 (s, 1H), 6.87 (s, 1H), 6.59-6.47 (m, 2H), 4.65 (bs, 2H); MS ESI 278.0 [M+H]+, calcd for [C15H11N5O+H]+ 278.10.