Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[CH2:13][CH2:12][CH2:11][C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=3[C:8]=2[C:18]2[CH:23]=[CH:22][C:21](OS(C(F)(F)F)(=O)=O)=[CH:20][CH:19]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:32](#[N:35])[CH:33]=[CH2:34].C(N(CC)CC)C>CN(C=O)C.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>[C:1]1([C:7]2[CH2:13][CH2:12][CH2:11][C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=3[C:8]=2[C:18]2[CH:23]=[CH:22][C:21]([CH:34]=[CH:33][C:32]#[N:35])=[CH:20][CH:19]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C=CC#N
Reactant: O=S(=O)(Oc1ccc(C2=C(c3ccccc3)CCCc3ccccc32)cc1)C(F)(F)F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: N#CC=Cc1ccc(C2=C(c3ccccc3)CCCc3ccccc32)cc1
Temperature: 100 °C
Yield: 45.8 %

Procedure:
To a solution of the triflate (5b) (560 mg, 1.25 mmol) in DMF (6 mL) was added acrylonitrile (2.10 g, 39.6 mmol), triethylamine (2.90 g, 28.6 mmol), and bis(triphenyl-phosphine)palladium(II) chloride (700 mg, 1.0 mmol). The mixture was placed in a pressure bottle and heated at 100° C. for 4 days. The solvent was removed under reduced pressure and the residue was chromatographed (silica gel, 15% EtOAc/hexanes) to give the nitrile (5c) as a white solid (199 mg, 46%): 1H NMR (CDCl3) δ 7.30-7.13 (m, 11H), 6.94 (d, J=8.1 Hz, 2H), 6.82 (dd, J=7.3, 1.1 Hz, 1H), 5.75 (d, J=16.5 Hz, 1H), 2.81 (t, J=7.0 Hz, 2H), 2.40 (t, J=7.0 Hz, 2H), 2.19 (m, 2H).
Reaction SMILES: Cl.[C:2]1([NH:8][NH2:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:10][C:11]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:12]=1[C:13](Cl)=[O:14].O>N1C=CC=CC=1>[C:2]1([NH:8][NH:9][C:13](=[O:14])[C:12]2[CH:16]=[CH:17][C:18]([F:20])=[CH:19][C:11]=2[F:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NNc1ccccc1
Reactant: O=C(Cl)c1ccc(F)cc1F
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: O=C(NNc1ccccc1)c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 79 %

Procedure:
To a stirred mixture, under nitrogen, of 72.3 g of phenylhydrazine hydrochloride in 600 ml of pyridine, cooled in an ice bath, was added, dropwise, 97.1 g of 2,4-difluorobenzoyl chloride, such that the reaction temperature did not exceed 15° C. The reaction mixture was stirred at ambient temperature for about 16 hours. Dilution of the mixture with water formed a precipitate which was collected, dried, and recrystallized from ethyl acetate to yield 98 g (79%) of 2,4-difluorobenzoic acid, 2-phenylhydrazide. Subsequent recrystallization from ethyl acetate afforded the analytical sample, m.p. 171°-173° C.
Reaction SMILES: [CH3:1][C:2](=[CH:6][CH2:7][CH2:8][C:9]([CH3:31])=[CH:10][CH2:11][CH2:12][C:13]([CH3:30])=[CH:14][CH2:15][CH2:16][C:17]([CH3:29])=[CH:18][CH2:19][CH2:20][C:21]([CH3:28])=[CH:22][CH2:23][CH2:24][C:25](=[O:27])[CH3:26])[C:3](O)=O.[CH2:32]([NH2:34])[CH3:33].[C:35](Cl)(=[O:38])[CH2:36][CH3:37]>>[CH2:32]([N:34]([CH2:3][C:2]([CH3:1])=[CH:6][CH2:7][CH2:8][C:9]([CH3:31])=[CH:10][CH2:11][CH2:12][C:13]([CH3:30])=[CH:14][CH2:15][CH2:16][C:17]([CH3:29])=[CH:18][CH2:19][CH2:20][C:21]([CH3:28])=[CH:22][CH2:23][CH2:24][C:25](=[O:27])[CH3:26])[C:35](=[O:38])[CH2:36][CH3:37])[CH3:33]
Reactant: CCC(=O)Cl
Reactant: CCN
Reactant: CC(=O)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)C(=O)O
Product: CCC(=O)N(CC)CC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CCCC(C)=O

Procedure:
Starting materials: 2,6,10,14,18-pentamethyl-22-oxo-2,6,10,14,18-tricosapentaenoic acid; ethylamine (70% aqueous ethylamine solution); and propionyl chloride
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH2:28]([O:30][CH2:31][CH2:32]O)[CH3:29].B(F)(F)F.CCOCC>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:10]=[C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH2:29][CH2:28][O:30][CH2:31][CH3:32])=[O:5]
Reactant: CCOCCO
Reactant: CCCCCCCCCCCCCCCCNc1ccc(C(=O)O)c(F)c1
Agent: FB(F)F
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CCCCCCCCCCCCCCCCNc1ccc(C(=O)OCCOCC)c(F)c1
Reaction time: 120 h

Procedure:
A solution of 11.8 g of 2-fluoro-4-(hexadecylamino)-benzoic acid, 1.00 g. of 2-ethoxyethanol and 5.35 ml of boron trifluoride etherate in 200 ml of toluene is stirred under reflux for 48 hours. The solution is treated with an additional 5.35 ml of boron trifluoride etherate and refluxing is continued for 120 hours. Dilution with water and methylene chloride followed by filtration affords 2-ethoxyethyl 2-fluoro-4-(hexadecylamino)benzoate as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=O.[F:13][C:14]([F:23])([F:22])[C:15]1[CH:16]=[C:17]([CH:19]=[CH:20][CH:21]=1)[NH2:18].C(O)(=O)C>CO>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])/[C:5]/2=[N:18]\[C:17]1[CH:19]=[CH:20][CH:21]=[C:15]([C:14]([F:13])([F:22])[F:23])[CH:16]=1
Reactant: O=C1Nc2ccc(Br)cc2C1=O
Reactant: Nc1cccc(C(F)(F)F)c1
Solvent: CC(=O)O
Solvent: CO
Product: O=C1Nc2ccc(Br)cc2/C1=N/c1cccc(C(F)(F)F)c1
Temperature: 50 °C
Reaction time: 12 h
Yield: 392.3 %

Procedure:
A mixture of 5-bromo-1H-indole-2,3-dione (1.0 g, 0.442 mmol) and 3-trifluoromethylaniline (0.993 g, 6.2 mmol) in a solution of 1% acetic acid in methanol was stirred at 50° C. for 12 h. The crude product was concentrated in vacuo, giving the desired crude product (640 mg, 40%).
Reaction SMILES: [C:1]([O:10]C)(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[SH:4].[CH2:12]([N:19]([C:25]([C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([C:33]#[N:34])[N:28]=1)=[O:26])[C:20]([N:22]([CH3:24])[CH3:23])=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH2:12]([N:19]([C:25]([C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([C:33]2[S:4][C:3]3[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=3[C:1](=[O:10])[N:34]=2)[N:28]=1)=[O:26])[C:20]([N:22]([CH3:24])[CH3:23])=[O:21])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CN(C)C(=O)N(Cc1ccccc1)C(=O)c1cccc(C#N)n1
Reactant: COC(=O)c1ccccc1S
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CN(C)C(=O)N(Cc1ccccc1)C(=O)c1cccc(-c2nc(=O)c3ccccc3s2)n1
Yield: 91.7 %

Procedure:
A mixture of methyl thiosalicylate (1.8 g, 10.7 mmol), N-benzyl-N-[(6-cyano-2-pyridyl)carbonyl]-N′,N′-dimethylurea (1.6 g, 5.4 mmol), triethylamine (2.0 ml, 14 mmol) and toluene (4 ml) was refluxed for 8 hrs as described in Example 1. After cooling, the precipitated crystals were collected by filtration and recrystallized from hexane-chlorobenzene to give the titled compound (2.2 g, 93%) as crystals.
Reaction SMILES: S(O)(O)(=O)=O.[NH2:6][C:7]([NH2:9])=[NH:8].C(=O)([O-])[O-].[Na+].[Na+].[CH3:16][C:17](=O)[CH2:18][C:19](=O)[CH3:20]>O>[NH2:8][C:7]1[N:9]=[C:19]([CH3:20])[CH:18]=[C:17]([CH3:16])[N:6]=1
Reactant: N=C(N)N
Reactant: CC(=O)CC(C)=O
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: Cc1cc(C)nc(N)n1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
To a stirred solution containing 4.00 g (37.0 mmol) of guanidine sulfate and 8.40 g (79.3 mmol) of sodium carbonate in 25 mL of water were added 6.00 mL (58.1 mmol) of 2,4-pentanedione. The reaction mixture was stirred at 100° C. overnight. The reaction mixture was poured into 150 mL of water and then extracted with two 150-mL portions of dichloromethane. The combined organic phase was washed with 150 mL of brine, dried (MgSO4) and then concentrated under diminished pressure to afford the expected product as a colorless solid: yield 4.31 g (95%); mp 152-153° C.; silica gel TLC Rf 0.50 (9:1 dichloromethane-methanol); 1H NMR (CDCl3) δ 2.24 (s, 6H), 5.39 (br s, 2H) and 6.33 (s, 1H); 13C NMR (CDCl3) δ 23.7, 23.7, 110.5, 162.9, 162.9 and 167.7; mass spectrum (APCI), m/z 124.0869 (M+H)1 (C6H10N3 requires 124.0875).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([Si](C)(C)C)=[C:13]([F:21])[CH:12]=2)[N:8]=[C:7]([C:22]([O:24][CH3:25])=[O:23])[C:6]=1[Cl:26])(=[O:3])[CH3:2].[Br:27]Br.[O-]S([O-])=O.[Na+].[Na+]>ClCCl>[C:1]([NH:4][C:5]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([Br:27])=[C:13]([F:21])[CH:12]=2)[N:8]=[C:7]([C:22]([O:24][CH3:25])=[O:23])[C:6]=1[Cl:26])(=[O:3])[CH3:2]
Reactant: COC(=O)c1nc(-c2ccc([Si](C)(C)C)c(F)c2)cc(NC(C)=O)c1Cl
Reactant: BrBr
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)c1nc(-c2ccc(Br)c(F)c2)cc(NC(C)=O)c1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 98.7 %

Procedure:
To a 100-mL round bottom flask, equipped with a stir bar was added methyl 4-acetamido-3-chloro-6-(3-fluoro-4-(trimethylsilyl)phenyl)picolinate (433 mg, 1.11 mmol), dichloromethane (10 mL) and bromine (0.225 mL, 4.39 mmol). The reaction was allowed to stir at room temperature for 18 hrs. The reaction was then poured into 1 N Na2SO3 and extracted with ethyl acetate (3×50 mL). The combined organic layers were dried over anhydrous magnesium sulfate, filtered and concentrated. The resulting residue was purified by flash chromatography (0-50% EtOAc in Hexanes) to afford the title compound as a light tan solid (0.440 g, 100%): 1H NMR (400 MHz, DMSO-d6) δ 10.02 (s, 1H), 8.71 (s, 1H), 7.98-7.81 (m, 2H), 7.74 (dd, J=8.4, 2.1 Hz, 1H), 3.94 (s, 3H), 2.23 (s, 3H); 19F NMR (376 MHz, DMSO-d6) δ −107.44; ESIMS m/z 402 [(M+H)+].
Reaction SMILES: [C:1]([O:5][P:6]([CH:13]([OH:27])[C:14]1[CH:26]=[CH:25][C:17]([CH2:18][CH:19]([C:21]([O:23][CH3:24])=[O:22])[NH2:20])=[CH:16][CH:15]=1)([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.Cl[C:36]([O:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)=[O:37]>C1COCC1.CCOCC>[C:9]([O:8][P:6]([CH:13]([OH:27])[C:14]1[CH:26]=[CH:25][C:17]([CH2:18][CH:19]([C:21]([O:23][CH3:24])=[O:22])[NH:20][C:36]([O:38][CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)=[O:37])=[CH:16][CH:15]=1)([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])([CH3:10])([CH3:12])[CH3:11]
Reactant: COC(=O)C(N)Cc1ccc(C(O)P(=O)(OC(C)(C)C)OC(C)(C)C)cc1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)C(Cc1ccc(C(O)P(=O)(OC(C)(C)C)OC(C)(C)C)cc1)NC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 88.2 %

Procedure:
To a solution of 8 (876 mg, 2.18 mmol) in THF (22 mL) at 0° C. was added NEt3 1.22 mL, 8.74 mmol), followed by benzyl chloroformate (0.34 mL, 2.40 mmol) dropwise via syringe. The reaction was stirred at 0° C. for 0.5 hours, then diluted with Et2O (20 mL) and quenched by dropwise addition of brine (1 mL). Additional brine (20 mL) was added and the organic phase separated and combined with an Et2O extract (2×20 mL) of the residual brine. The combined Et2O was dried (MgSO4), filtered and solvent removed by rotary evaporation under reduced pressure to yield crude 9 (1.03 g, 88%). Silica gel chromatography [EtOAc/hexanes (4:3)] provided pure 9 (621 mg, 53%).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[C:13]3[CH2:19][C@@:18]([CH3:26])([CH:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)[O:17][C:14]3=[CH:15][N:16]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].Cl[C:28]1[N:33]=[CH:32][C:31]([CH2:34][CH3:35])=[CH:30][N:29]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[CH2:34]([C:31]1[CH:30]=[N:29][C:28]([N:23]2[CH2:24][CH2:25][CH:20]([C@@:18]3([CH3:26])[O:17][C:14]4=[CH:15][N:16]=[C:11]([C:8]5[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:6][CH:7]=5)[CH:12]=[C:13]4[CH2:19]3)[CH2:21][CH2:22]2)=[N:33][CH:32]=1)[CH3:35]
Reactant: CCc1cnc(Cl)nc1
Reactant: C[C@@]1(C2CCNCC2)Cc2cc(-c3ccc(S(C)(=O)=O)cc3)ncc2O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCc1cnc(N2CCC([C@]3(C)Cc4cc(-c5ccc(S(C)(=O)=O)cc5)ncc4O3)CC2)nc1

Procedure:
The title compound is prepared from (S)-5-(4-methanesulfonyl-phenyl)-2-methyl-2-piperidin-4-yl-2,3-dihydro-furo[2,3-c]pyridine (Intermediate 32; the configuration of the stereocenter is arbitrarily assigned) and 2-chloro-5-ethylpyrimidine in dimethylsulfoxide at 105° C. in the presence of potassium carbonate. LC (method 4): tR=1.09 min; Mass spectrum (ESI+): m/z=479 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:9]2[NH:14][C@@H:13]([CH:15]([OH:17])[CH3:16])[CH2:12][O:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[F:8].N1C=CC=CC=1.[C:24](Cl)(=[O:28])[C:25](Cl)=[O:26]>ClCCl.O>[F:1][C:2]1[CH:3]=[C:4]([C@@H:9]2[CH2:10][O:11][CH2:12][C@@H:13]3[C@H:15]([CH3:16])[O:17][C:24](=[O:28])[C:25](=[O:26])[N:14]23)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CC(O)[C@H]1COC[C@@H](c2ccc(F)c(F)c2)N1
Reactant: O=C(Cl)C(=O)Cl
Solvent: c1ccncc1
Solvent: O
Solvent: ClCCl
Product: C[C@@H]1OC(=O)C(=O)N2[C@@H]1COC[C@H]2c1ccc(F)c(F)c1

Procedure:
To a solution consisting of 1-[(3R,5R)-5-(3,4-difluorophenyl)morpholine-3-yl]ethanol (424 mg) and pyridine (2 mL) in dichloromethane (8 mL) was dropwise added oxalyl chloride (417 μL) while cooling with ice. The resultant solution was stirred at the same temperature for 30 minutes. The reaction solution was diluted with water, and the organic layer was partitioned. The organic layer was then dried over magnesium sulfate. Solvent was removed by distillation under reduced pressure, and the resulting residue was purified by silica gel column chromatography (heptane/ethyl acetate 9/1→1/4), to thereby obtain the titled compound (353 mg). The physical properties of the compound were as follows.
Reaction SMILES: ClC(Cl)(Cl)[CH2:3][CH:4](Cl)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.Cl.[C]=O.[CH:17]([OH:19])=[O:18]>>[C:17]([OH:19])(=[O:18])[CH:3]=[CH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: O=CO
Reactant: ClC(CC(Cl)(Cl)Cl)c1ccccc1
Agent: Cl
Agent: [C]=O
Product: O=C(O)C=Cc1ccccc1
Yield: 79 %

Procedure:
A mixture of 103.2 g of 1,1,1,3-tetrachloro-3-phenylpropane, 120 g of 85% formic acid and 17 g of Ostion KSC cation exchanger is refluxed at 100° to 105° C. for 7 h while hydrogen chloride and carbon monoxide is evolved. The cation exchanger is separated by filtration, the filtrate is cooled and the crystals precipitated are filtered off and washed with water to give 46.8 g of cinnamic acid in 79% chemical yield (melting point 127° to 133.5° C. and min. 97% purity).
Reaction SMILES: [Br:1][C:2]1[N:10]2[C:5]([C:6](Cl)=[N:7][C:8]([Cl:11])=[N:9]2)=[N:4][CH:3]=1.[CH3:13][O:14][C:15]1[CH:24]=[CH:23][C:18]([CH2:19][NH:20][CH2:21][CH3:22])=[CH:17][CH:16]=1>C1COCC1>[Br:1][C:2]1[N:10]2[C:5]([C:6]([N:20]([CH2:21][CH3:22])[CH2:19][C:18]3[CH:23]=[CH:24][C:15]([O:14][CH3:13])=[CH:16][CH:17]=3)=[N:7][C:8]([Cl:11])=[N:9]2)=[N:4][CH:3]=1
Reactant: CCNCc1ccc(OC)cc1
Reactant: Clc1nc(Cl)c2ncc(Br)n2n1
Solvent: C1CCOC1
Product: CCN(Cc1ccc(OC)cc1)c1nc(Cl)nn2c(Br)cnc12
Reaction time: 1 h
Yield: 106.8 %

Procedure:
(I10A): A solution of 7-bromo-2,4-dichloroimidazo[2,1-f][1,2,4]triazine (Intermediate I9F)(10 g, 37.3 mmol) in anhydrous THF (300 ml) was treated with N-(4-methoxybenzyl)ethanamine (8.01 ml, 46.7 mmol), resulting in the immediate precipitation of a solid. The reaction was stirred for 1 hour; the mixture was concentrated in vacuo. To the residue was added EtOAc (100 ml) and the mixture stirred 10 min. The salts were filtered off and the filtrate was washed with 0.5M citric acid, sat. NaHCO3, water and brine. The solution was dried over Na2SO4 and solvents removed to afford 7-bromo-2-chloro-N-ethyl-N-(4-methoxybenzyl)imidazo[2,1-f][1,2,4]triazin-4-amine (15.8 g).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][C:17]=1[OH:18])[C:5]([NH:7][CH:8]([CH2:12][CH2:13][CH3:14])[CH2:9][CH2:10][CH3:11])=[O:6].[CH3:19][O:20][C:21](OC)(OC)OC>>[CH2:9]([CH:8]([NH:7][C:5]([C:4]1[CH:15]=[CH:16][C:17]2[O:18][C:19]([O:20][CH3:21])=[N:1][C:2]=2[CH:3]=1)=[O:6])[CH2:12][CH2:13][CH3:14])[CH2:10][CH3:11]
Reactant: COC(OC)(OC)OC
Reactant: CCCC(CCC)NC(=O)c1ccc(O)c(N)c1
Product: CCCC(CCC)NC(=O)c1ccc2oc(OC)nc2c1
Yield: 60 %

Procedure:
Prepared in a similar manner to example 41 using 3-amino-4-hydroxy-N-(1-propylbutyl)benzamide (example 4aa) and tetramethylorthocarbonate. Yield: 60%. mp 137-138° C.; MS (M+H, 291.10).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:17])([CH3:16])[C:9]([NH:11][CH2:12][CH:13]([CH3:15])[CH3:14])=[O:10])=[CH:4][CH:3]=1.CCO.C([O-])([O-])=O.[K+].[K+].[O:27]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28]1>C1(C)C=CC=CC=1.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.O>[O:27]1[CH:31]=[CH:30][C:29]([C:2]2[CH:7]=[CH:6][C:5]([C:8]([CH3:17])([CH3:16])[C:9]([NH:11][CH2:12][CH:13]([CH3:15])[CH3:14])=[O:10])=[CH:4][CH:3]=2)=[CH:28]1
Reactant: CC(C)CNC(=O)C(C)(C)c1ccc(Br)cc1
Reactant: OB(O)c1ccoc1
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: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: CC(C)CNC(=O)C(C)(C)c1ccc(-c2ccoc2)cc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 36.9 %

Procedure:
2-(4-Bromophenyl)-N-isobutyl-2-methylpropanamide (Example 1a) (850 mg, 2,85 mmol) was dissolved in 30 ml of toluene, 6 ml of EtOH and 4.5 ml of water followed by 1.38 g (10 mmol) of K2CO3 and 560 mg (5 mmol) of 3-furanboronic acid. The suspension was degassed using argon stream and sonication (30 min). Then 1.16 g (1 mmol) of tetrakis(triphenylphosphine)palladium was added under argon and the mixture was stirred at 80° C. overnight. The solution was dried down on vacuum, diluted with EtOAc and extracted with water. The organic phase was dried over MgSO4 and evaporated on vacuum providing a crude product that was further purified using RP HPLC yielding 300 mg (41%) of the title compound as a white solid. 1H NMR (400 MHz, dDMSO): δ 0.74-0.75 (d 6H), 1.45 (s, 6H), 1.67-1.70 (m,1H), 2.83-2.86 (dd, 2H), 6.94-6.95 (dd, 1H), 7.30-7.32 (m, 3H), 7.54-7.57 (m, 2H), 7.72-7.73 (t, 1H), 8.15-8.16 (t, 1H). MS (M+H, 286).
Reaction SMILES: [CH:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7](O)=[O:8])=[CH:5][CH:4]=1)=[CH2:2].S(Cl)([Cl:14])=O.C(O)(=O)C1C=CC=CC=1>C(Cl)(Cl)Cl.[N+](C1C=CC=CC=1)([O-])=O>[CH:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([Cl:14])=[O:8])=[CH:5][CH:4]=1)=[CH2:2]
Reactant: C=Cc1ccc(C(=O)O)cc1
Reactant: O=S(Cl)Cl
Agent: O=C(O)c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: O=[N+]([O-])c1ccccc1
Product: C=Cc1ccc(C(=O)Cl)cc1
Temperature: 50 °C
Yield: 91 %

Procedure:
4-vinyl benzoyl chloride was synthesized from 4-vinyl benzoic acid (obtained from Trans World Chemicals). The 4-vinyl benzoic acid was dissolved in chloroform with a small (0.16 mole/mole 4-vinyl benzoic acid) amount of nitrobenzene added as an inhibitor to prevent cross-linking. A large excess of thionyl chloride (six times the moles of benzoic acid) was added dropwise while stirring and gently heating to 50° C. Once the thionyl chloride was completely added, and the solution was at a temperature of 50° C., it was allowed to stir for one hour. The solution was then distilled (rotary evaporator) to remove the bulk of the chloroform and unreacted thionyl chloride. The impure 4-vinylbenzoyl chloride was then vacuum distilled to further purify it. At <1 mm mercury the 4-vinylbenzoyl chloride distills at around 70° C. The composition of the product was checked by NMR and was confirmed to be 4-vinylbenzoyl chloride. The yield was 91%.
Reaction SMILES: [C:1]([O:7][CH2:8][CH2:9][CH2:10][N:11]1[C:19]2[C:14](=[CH:15][C:16]([CH2:23][C@H:24]([N:26](C(OC(C)(C)C)=O)[CH2:27][CH2:28][O:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[O:36][CH2:37][CH3:38])[CH3:25])=[CH:17][C:18]=2[C:20](=[O:22])[NH2:21])[CH:13]=[CH:12]1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].Cl.C(=O)(O)[O-].[Na+]>C(O)(C)C.O>[C:1]([O:7][CH2:8][CH2:9][CH2:10][N:11]1[C:19]2[C:14](=[CH:15][C:16]([CH2:23][C@H:24]([NH:26][CH2:27][CH2:28][O:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[O:36][CH2:37][CH3:38])[CH3:25])=[CH:17][C:18]=2[C:20](=[O:22])[NH2:21])[CH:13]=[CH:12]1)(=[O:6])[C:2]([CH3:4])([CH3:5])[CH3:3]
Reactant: CCOc1ccccc1OCCN(C(=O)OC(C)(C)C)[C@H](C)Cc1cc(C(N)=O)c2c(ccn2CCCOC(=O)C(C)(C)C)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)O
Product: CCOc1ccccc1OCCN[C@H](C)Cc1cc(C(N)=O)c2c(ccn2CCCOC(=O)C(C)(C)C)c1
Yield: 79.5 %

Procedure:
(R)-3-[5-[2-[N-(tert-Butoxycarbonyl)-N-[2-(2-ethoxy-phenoxy)ethyl]amino]propyl]-7-carbamoyl-1H-indol-1-yl]propyl pivalate (7.81 g) was dissolved in isopropanol (78 ml), and concentrated hydrochloric acid (39 ml) was added dropwise over a period of 10 minutes to the solution under ice-cooling with stirring. After the mixture was stirred for 4 hours at room temperature, the reaction mixture was adjusted to pH 8 by adding sodium bicarbonate powder under ice-cooling with stirring. The mixture was diluted with water (200 ml) and extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated aqueous sodium bicarbonate solution, water and brine subsequently, and dried over anhydrous sodium sulfate. The solvent was removed in vacuo, and the residue was purified by column chromatography on aminopropyl silica gel (eluent: ethyl acetate) and recrystallized from diethyl ether/hexane(2/1) to give (R)-3-[7-carbamoyl-5-[2-[[2-(2-ethoxyphenoxy)ethyl]amino]propyl]-1H-indol-1-yl]propyl pivalate (5.21 g) as colorless crystals.
Reaction SMILES: [C:1]([C:4]1[O:5][C:6]2[C:12]([CH2:13][CH3:14])=[CH:11][CH:10]=[CH:9][C:7]=2[CH:8]=1)(=[O:3])[CH3:2].[CH2:15](O)[CH2:16][OH:17].O>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:13]([C:12]1[C:6]2[O:5][C:4]([C:1]3([CH3:2])[O:17][CH2:16][CH2:15][O:3]3)=[CH:8][C:7]=2[CH:9]=[CH:10][CH:11]=1)[CH3:14]
Reactant: CCc1cccc2cc(C(C)=O)oc12
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCc1cccc2cc(C3(C)OCCO3)oc12
Yield: 78.8 %

Procedure:
A stirred mixture of 50 g of 2-acetyl-7-ethylbenzofuran, 3.0 g of paratoluenesulphonic acid and 45.0 g of ethyleneglycol in 1200 ml of toluene was heated under reflux for 12 hours with azeotropic removal of water. The cooled solution was washed successively with dilute sodium hydroxide solution, water and brine and then dried over anhydrous sodium sulphate. The sodium sulphate was filtered off and the filtrate evaporated to dryness. The residual yellow oil was distilled under nitrogen to give 48.6 g of 7-ethyl-2-(2-methyl-1,3-dioxolan-2-yl)benzofuran of boiling point 86°-88°C/0.05 mm Hg.
Reaction SMILES: O[CH:2]([C:17]1[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][CH2:25][CH:26]2[O:30][C:29](=[O:31])[NH:28][C:27]2=[O:32])=[CH:19][CH:18]=1)[CH2:3][CH2:4][C:5]1[N:6]=[C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[O:8][C:9]=1[CH3:10].C([SiH](CC)CC)C.FC(F)(F)C(O)=O.C(=O)([O-])O.[Na+]>O>[CH3:10][C:9]1[O:8][C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:6][C:5]=1[CH2:4][CH2:3][CH2:2][C:17]1[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][CH2:25][CH:26]2[O:30][C:29](=[O:31])[NH:28][C:27]2=[O:32])=[CH:19][CH:18]=1
Reactant: Cc1oc(-c2ccccc2)nc1CCC(O)c1ccc(CCCC2OC(=O)NC2=O)cc1
Agent: CC[SiH](CC)CC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: Cc1oc(-c2ccccc2)nc1CCCc1ccc(CCCC2OC(=O)NC2=O)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 81.6 %

Procedure:
A mixture of 5-[3-[4-[1-hydroxy-3-(5-methyl-2-phenyl-4-oxazolyl)propyl]phenyl]propyl]-2,4-oxazolidinedione (0.14 g), triethylsilane [(C2H5)3SiH] (0.075 g) and trifluoroacetic acid (2 ml) was stirred at room temperature for 3 hours. The reaction mixture was poured over water, neutralized with an aqueous solution of sodium hydrogen carbonate and then extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4) and then concentrated under reduced pressure; the residue was purified by silica gel column chromatography. From the fraction eluted with chloroform-methanol (100:3), 5-[3-[4-[3-(5-methyl-2-phenyl-4-oxazolyl)propyl]phenyl]propyl]-2,4-oxazolidinedione (0.11 g, 82%) was obtained, which was then recrystallized from ether-methanol to yield colorless needles having a melting point of 119°-120° C.