Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[CH2:11][C:9](=O)[C:8]2[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:2]1.O1CCCC1.[CH3:17][NH2:18]>C1(C)C=CC=CC=1.C(Cl)Cl.[Ti](Cl)(Cl)(Cl)Cl>[CH3:17][NH:18][C:9]1[C:8]2[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:2]=[CH:1][CH:11]=1
Reactant: CN
Reactant: O=C1CCCc2ccccc21
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CNc1cccc2ccccc12
Temperature: -40 °C
Reaction time: 16 h
Yield: 60 %

Procedure:
Into a solution of 10 g (68 mmol) of α-tetralone in 140 mL of toluene is added 200 mL (400 mmol) of a 2.0 M tetrahydrofuran solution of methylamine at -5° C. to 0° C. After the addition is complete, the reaction mixture is cooled to -40° C. and 34.6 mL (34.6 mmol) of a 1 M solution of titanium tetrachloride in methylene chloride is added over a 15 minute period. After this addition is complete, the reaction mixture is allowed to warm to ambient temperature. After stirring at ambient temperature for 16 hours, the reaction mixture is filtered and the filtrate is concentrated to a crude oil. The crude oil is then dissolved in 150 mL of xylene and 200 mg of 5% palladium on charcoal catalyst is added. The reaction mixture is then heated to reflux for 16 hours. The palladium catalyst is then removed by filtration and the filtrate is concentrated to give 9 g of a crude oil which is purified by flash chromatography (silica gel, 2.5% ethyl acetate in hexane) to give 6 g of an oil in 60% yield.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[CH3:10][CH:11]1[CH2:16][C:15](=[O:17])[O:14][C:13](=[O:18])[CH2:12]1>C1COCC1>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([NH:1][C:15](=[O:17])[CH2:16][CH:11]([CH3:10])[CH2:12][C:13]([OH:18])=[O:14])=[CH:3][CH:4]=1)#[N:7]
Reactant: N#Cc1ccc(N)cc1
Reactant: CC1CC(=O)OC(=O)C1
Solvent: C1CCOC1
Product: CC(CC(=O)O)CC(=O)Nc1ccc(C#N)cc1
Yield: 64.8 %

Procedure:
A solution of 4-aminobenzonitrile (4.61 g, 39.02 mmol) and 4-methyldihydro-2H-pyran-2,6(3H)-dione (5.0 g, 39.02 mmol) in THF (50 mL) was stirred at 90° C. for 14 hr. The reaction solution was concentrated, and the precipitate was washed with ethyl acetate to give 5-(4-cyanophenylamino)-3-methyl-5-oxopentanoic acid (6.23 g, 25.3 mmol, 64.8%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([CH:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)O)=[CH:7][CH:8]=2)[CH:3]=[N:2]1.C(Cl)Cl.[CH3:21][O:22][C:23]([O:27][Si](C)(C)C)=[C:24]([CH3:26])[CH3:25]>C1COCC1.Cl[Ti](Cl)(Cl)Cl>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([CH:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:24]([CH3:26])([CH3:25])[C:23]([O:22][CH3:21])=[O:27])=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: OC(c1ccccc1)c1ccc2[nH]ncc2c1
Reactant: COC(O[Si](C)(C)C)=C(C)C
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Solvent: C1CCOC1
Product: COC(=O)C(C)(C)C(c1ccccc1)c1ccc2[nH]ncc2c1
Reaction time: 12 h
Yield: 66.7 %

Procedure:
(1H-Indazol-5-yl)(phenyl)methanol (12.1 g, 54 mmol) was dissolved in 200 mL of dry THF and 200 mL of DCM and cooled to 0 C. Added 1-methoxy-2-methyl-1-(trimethylsiloxy)propene (43.6, 250 mmol) followed by dropwise addition of TiCl4 (60 mL of 1.0 M DCM solution, 60 mmol). After 12 h, the reaction was quenched with MeOH, poured into brine and extracted 2×DCM. The organic layers were dried over MgSO4, filtered, concentrated, and then chromatographed using 1:2 EtOAc/hexane to give 11.1 g (66% yield) of methyl 3-(1H-indazol-5-yl)-2,2-dimethyl-3-phenylpropanoate which was separated by chiral chromatography. MS found: (M+H)+=309.
Reaction SMILES: [C:1]([NH:9][C@H:10]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:11]([CH3:13])[CH3:12])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:20]>N1C=CC=CC=1>[C:1]([NH:9][C@H:10]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:11]([CH3:13])[CH3:12])(=[S:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: CCOC(=O)[C@@H](NC(=O)c1ccccc1)C(C)C
Solvent: c1ccncc1
Product: CCOC(=O)[C@@H](NC(=S)c1ccccc1)C(C)C
Yield: 45 %

Procedure:
Heat at reflux for 6 hours a solution of 0.025 mol (6.3 g) of ethyl N-benzoylvalinate obtained in Step B and 5.6 g of phosphorus pentasulphide in 120 ml of pyridine, and evaporate to dryness. Take up the residue in water and ethyl acetate. Wash the organic phase with a 2N hydrochloric acid solution, dry, filter and evaporate to dryness. The ethyl N-thiobenzoylvalinate obtained is purified by chromatography on a column of silica (eluant:ethyl acetate/hexane:25/75).
Reaction SMILES: [CH:1]1([C:5]2[N:9]3[CH:10]=[CH:11][N:12]=[C:13]([NH2:14])[C:8]3=[C:7](I)[N:6]=2)[CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[C:22]([O:26][C:27]([N:29]1[CH2:34][CH:33]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH2:31][CH2:30]1)=[O:28])([CH3:25])([CH3:24])[CH3:23]>COCCOC.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>[C:22]([O:26][C:27]([N:29]1[CH2:30][CH:31]=[C:32]([C:7]2[N:6]=[C:5]([CH:1]3[CH2:4][CH2:3][CH2:2]3)[N:9]3[CH:10]=[CH:11][N:12]=[C:13]([NH2:14])[C:8]=23)[CH2:33][CH2:34]1)=[O:28])([CH3:25])([CH3:23])[CH3:24]
Reactant: Nc1nccn2c(C3CCC3)nc(I)c12
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
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: COCCOC
Solvent: O
Product: CC(C)(C)OC(=O)N1CC=C(c2nc(C3CCC3)n3ccnc(N)c23)CC1
Temperature: 100 °C

Procedure:
To a stirred mixture of 3-cyclobutyl-1-iodoimidazo[1,5-a]pyrazin-8-amine (100.00 mg, 0.318 mmol), potassium carbonate (154.0 mg, 1.11 mmol) in DME (3.0 mL) and H2O (0.70 mL) was added 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (118.1 mg, 0.38 mmol). The solution was bubbled with nitrogen for 5 min. Then Pd(PPh3)4 (18 mg, 0.016 mmol) was added and the resulting mixture was refluxed at 100° C. for 30 min. The solvent was then removed under reduced pressure and the resulting residue was purified by a flash chromatography (2% MeOH in DCM). 1H NMR (400 MHz, MeOD) δ 1.53 (s, 9H), 1.95-2.07 (m, 1H), 2.14-2.28 (m, 1H), 2.44-2.54 (m, 4H), 2.62-2.71 (m, 2H), 3.73 (t, J=5.68 Hz, 2H), 3.87-3.98 (m, 1H), 4.12-421 (m, 2H), 5.94-6.00 (m, 1H), 6.96 (d, J=5.20 Hz, 1H), 7.33 (d, J=5.20 Hz, 1H). MS (ES+): m/z: 369.94, [MH+], HPLC: tR=2.33 min (OpenLynx, polar—5 min).
Reaction SMILES: [C:1]1([O:11][CH3:12])[C:2](=[CH:4][CH:5]=[C:6]([CH:10]=1)[CH2:7][CH:8]=[CH2:9])[OH:3].[CH:13]([O:15][CH2:16][CH2:17]Cl)=[CH2:14]>>[CH3:12][O:11][C:1]1[CH:10]=[C:6]([CH2:7][CH:8]=[CH2:9])[CH:5]=[CH:4][C:2]=1[O:3][CH2:17][CH2:16][O:15][CH:13]=[CH2:14]
Reactant: C=COCCCl
Reactant: C=CCc1ccc(O)c(OC)c1
Product: C=CCc1ccc(OCCOC=C)c(OC)c1

Procedure:
Eugenol (4-allyl-2-methoxyphenol) was reacted with 2-chloroethyl vinyl ether to produce o-methoxy-para-allyl-2-vinyloxyethoxy benzene (MAVB). 77 parts by weight of MAVB were dispersed in approximately 350 parts by weight toluene with 0.05 parts by weight of a platinum catalyst. 200 parts by weight of a 95 cps silicone copolymer fluid containing approximately 9.9% Si--H groups were added to the toluene solution. The reaction mixture was then refluxed overnight to where Si--H functionality was below about 1%. The toluene was stripped off under vacuum to yield a 300 cps fluid product.
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][CH:21]=[CH:20][C:3]=1[O:4][CH2:5][CH:6]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]2[C:13]([O:18]C)=[N:14][CH:15]=[CH:16][N:17]=2)[CH2:7]1.[C:24](=[O:27])([OH:26])[O-].[Na+].[C:29]([O:32]CC)(=[O:31])C>C(O)C.Cl.C(OCC)(=O)C>[C:29]([OH:32])(=[O:31])[C:24]([OH:26])=[O:27].[F:1][C:2]1[CH:23]=[CH:22][CH:21]=[CH:20][C:3]=1[O:4][CH2:5][CH:6]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]2[C:13](=[O:18])[NH:14][CH:15]=[CH:16][N:17]=2)[CH2:7]1
Reactant: O=C([O-])O
Reactant: CCOC(C)=O
Reactant: COc1nccnc1CN1CCC(COc2ccccc2F)C1
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: O=C(O)C(=O)O
Product: O=c1[nH]ccnc1CN1CCC(COc2ccccc2F)C1
Temperature: 60 °C
Reaction time: 8 h
Yield: 56 %

Procedure:
After dissolving 245 mg of 3-[3-(2-fluorophenoxymethyl)pyrrolidino]methyl-2-methoxypyrazine in 5 ml of ethanol, 15 ml of 4N hydrogen chloride/ethyl acetate was added, and the mixture was heated to reflux for 8 hours and then stirred overnight at 60° C. Aqueous sodium bicarbonate solution was added to the reaction solution and extraction was performed with ethyl acetate. The organic layer was washed with water and saturated brine in that order and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by NH silica gel column chromatography (solvent: ethyl acetate/methanol). This was dissolved in a small amount of ethanol, and then 47 mg of oxalic acid anhydrous and ethyl acetate were added and the precipitate was filtered out to obtain the title compound (171 mg, 56% yield).
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][CH:8]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=1)[C:9](=[O:14])N(OC)C)([CH3:4])([CH3:3])[CH3:2].[Br:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27](I)[CH:26]=1>>[C:1]([O:5][C:6](=[O:23])[NH:7][CH:8]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=1)[C:9]([C:27]1[CH:28]=[CH:29][CH:30]=[C:25]([Br:24])[CH:26]=1)=[O:14])([CH3:2])([CH3:3])[CH3:4]
Reactant: Brc1cccc(I)c1
Reactant: CON(C)C(=O)C(NC(=O)OC(C)(C)C)c1ccc(Cl)c(Cl)c1
Product: CC(C)(C)OC(=O)NC(C(=O)c1cccc(Br)c1)c1ccc(Cl)c(Cl)c1

Procedure:
The title compound was prepared from rac-[(3,4-dichloro-phenyl)-(methoxy-methyl-carbamoyl)-methyl]-carbamic acid tert-butyl ester (Intermediate 9) and 1-bromo-3-iodobenzene in analogy to Example 1a): MS (ISP): 460.1 (M+H)+ and 359.9 ((M-Boc)+H)+ (100%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.Cl[C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=1.C(N(CC)C(C)C)(C)C.C(O)(C)C>CN1CCCC1=O>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:15]3[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=3)[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: Oc1ccc(N2CCNCC2)cc1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Solvent: CN1CCCC1=O
Product: O=[N+]([O-])c1ccc(N2CCN(c3ccc(O)cc3)CC2)cc1

Procedure:
Under nitrogen, 420 g (2.36 mol) N-(4-Hydroxyphenyl)-piperazine, 520.6 g (3.30 mol) 1-chloro-4-nitrobenzene and 457.5 g (3.54 mol) N,N-Diisopropylethylamine (Hünig's Base) are suspended in 1260 ml N-Methylpyrrolidone and heated to 120°-125° C. The clear solution is stirred at 120°-125° C. and the reaction is followed by HPLC. After complete reaction (5-7 hours) the solution is cooled to 75°-80° C. and 6.3 liters of isopropanol are added over a period of about 30 minutes to the reaction mixture while keeping the temperature at 75°-80° C. (slight heating is necessary). Towards the end of the addition the product starts to precipitate (yellow crystals). The suspension is cooled to 20°-25° C. and stirred overnight at this temperature. Afterwards the suspension is cooled to −10° to −5° C. and stirred for 30 minutes. The product is filtered off, washed with 1.7 liters isopropanol, followed by 5×840 ml warm (35°-40° C.) water. The product is dried under vacuum at 50° C. (slight stream of nitrogen) to constant weight.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([O:13][CH3:14])[CH:7]=[C:8]([N+]([O-])=O)[CH:9]=1)([O-:3])=[O:2].[CH3:15][S:16][Si](C)(C)C.C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O.O.C(OCC)(=O)C>[CH3:14][O:13][C:6]1[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:9]=[C:8]([S:16][CH3:15])[CH:7]=1
Reactant: COc1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Reactant: CS[Si](C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: O
Product: COc1cc(SC)cc([N+](=O)[O-])c1
Temperature: 90 °C
Reaction time: 15 h
Yield: 28.6 %

Procedure:
To a solution of 3,5-dinitroanisole (5.0 g, 25.23 mmol) in dimethylsulfoxide (50 mL) were added methylthiotrimethylsilane (4.86 g, 40.37 mmol) and cesium carbonate (16.61 g, 50.46 mmol) at room temperature. The resulting dark green solution was stirred for 15 h at this temperature. Then, the reaction mixture was heated to 90° C. and the resulting brown mixture was stirred for another 5 h at which time TLC analysis of the mixture indicated the absence of starting material. The reaction mixture was cooled to room temperature and diluted with water (100 mL) and ethyl acetate (100 mL). The two layers were separated and the aqueous layer was extracted with ethyl acetate (50 mL). The combined extracts were washed with brine solution (150 mL) and dried over anhydrous magnesium sulfate. Filtration of the drying agent and the concentration of the solution under vacuum gave the crude residue which was purified by using an ISCO 120 column chromatography, eluting with 0-20% ethyl acetate in hexanes to obtain 1-methoxy-3-methylsulfanyl-5-nitro-benzene (1.44 g, 28.6%) as an yellow solid: EI(+)-HRMS m/e calcd for C8H9NO3S (M)+ 199.0303, found 199.0294.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[CH2:12][CH2:11][N:10]([CH2:13][C:14]2[NH:18][C:17]3[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=3[N:15]=2)[CH2:9][CH2:8]1.[N:23]1([C:28](Cl)=[O:29])[CH2:27][CH2:26][CH2:25][CH2:24]1.C(N(CC)CC)C>ClCCl>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[CH2:8][CH2:9][N:10]([CH2:13][C:14]2[N:15]([C:28]([N:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)=[O:29])[C:16]3[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=3[N:18]=2)[CH2:11][CH2:12]1
Reactant: O=C(Cl)N1CCCC1
Reactant: c1ccc(N2CCN(Cc3nc4ccccc4[nH]3)CC2)nc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(N1CCCC1)n1c(CN2CCN(c3ccccn3)CC2)nc2ccccc21
Temperature: 25 °C
Yield: 46.6 %

Procedure:
To a stirred solution of Example 1A (0.66 g, 2.2 mmol) in dichloromethane (7 mL) was added 1-pyrrolidinecarbonyl chloride (0.28 mL, 2.2 mmol) and triethylamine (0.625 mL, 4.5 mmol). The mixture was heated in a sealed vial for 17 hours, allowed to cool to room temperature, diluted dichloromethane, washed with 5% NaHCO3, dried and concentrated under reduced pressure. The residue was purified by flash column on SiO2 eluting with 20% hexanes/ethyl acetate to give 0.4 g (40%)of the title compound. mp 120-121° C. 1H NMR (CDCl3, 300 MHz) δ 1.79-2.10 (m, 4H), 2.70 (m, 4H), 3.13 (m, 1H), 3.35-3.78 (bm, 8H), 4.32 (m, 1H), 6.65 (m, 2H), 7.30 (m, 3H), 7.49 (m, 1H), 7.76 (m, 1H), 8.28 (m, 1H). MS (DCI/NH3) m/z 391 (M+H)+. Anal. Calcd for C22H26N6O. 1/2H2O: C, 66.14; H, 6.81; N, 21.04. Found: C, 66.22; H6.68; N21.11.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:9][CH2:10][CH2:11][NH:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[CH:7][CH:8]=1.Br[CH:21]([CH2:25]Br)[C:22]([NH2:24])=[O:23].C(N(CC)CC)C>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:9]2[CH2:10][CH2:11][N:12]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:21]([C:22]([NH2:24])=[O:23])[CH2:25]2)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(NCCNCc2ccccc2)c1
Reactant: NC(=O)C(Br)CBr
Solvent: CCN(CC)CC
Product: COc1cccc(N2CCN(Cc3ccccc3)C(C(N)=O)C2)c1

Procedure:
In a manner similar to Preparation 1, react N-(3-methoxyphenyl)-N'-(phenylmethyl)-1,2-ethanediamine (16 g, 63 mmol) with 2,3-dibromopropanamide (29 g, 126 mmol) and triethylamine (25 g, 0.25mol) to give the title compound.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7](/[CH:10]=[CH:11]/[C:12]([O:14]C)=[O:13])[CH:8]=2)[C:3](/[CH:16]=[CH:17]/[C:18]([O:20]C)=[O:19])=[CH:2]1.O.[OH-].[Li+].CO.Cl>O.O1CCCC1>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7](/[CH:10]=[CH:11]/[C:12]([OH:14])=[O:13])[CH:8]=2)[C:3](/[CH:16]=[CH:17]/[C:18]([OH:20])=[O:19])=[CH:2]1
Reactant: COC(=O)/C=C/c1ccc2c(/C=C/C(=O)OC)c[nH]c2c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)/C=C/c1ccc2c(/C=C/C(=O)O)c[nH]c2c1
Yield: 87.7 %

Procedure:
A mixture of dimethyl E,E-indole-3,6-diacrylate (1.1 g), lithium hydroxide monohydrate (1.29 g), methanol (25 ml), tetrahydrofuran (10 ml) and water (5 ml) was stirred and heated at 55°-60° for 7 hr under an atmosphere of nitrogen. The cooled mixture was diluted with water (30 ml) and acidified to pH 4 with 6M hydrochloride acid. The yellow precipitate was isolated by filtration, washed with water and dried under vacuum to give E,E-indole-3,6-diacrylic acid (0.87 g, 88%) as a solid; mp >360°; partial NMR (250 MHz, DMSO-d6): 6.33(d, J=16.0 Hz, 1H, olefinic H), 6.49(d, J=16.0 Hz, 1H, olefinic H), 11.94(br s, 1H, NH), 12.10(br s, 1H, COOH).
Reaction SMILES: [F:1][C:2]1([F:21])[CH2:5][N:4]([C:6]2[C:7]([O:15][CH2:16][C:17]([F:20])([F:19])[F:18])=[CH:8][C:9]([C:12](O)=[O:13])=[N:10][CH:11]=2)[CH2:3]1.[NH2:22][C:23]1([CH2:27][C:28]([NH2:30])=[O:29])[CH2:26][O:25][CH2:24]1>>[NH2:30][C:28](=[O:29])[CH2:27][C:23]1([NH:22][C:12]([C:9]2[CH:8]=[C:7]([O:15][CH2:16][C:17]([F:20])([F:19])[F:18])[C:6]([N:4]3[CH2:3][C:2]([F:1])([F:21])[CH2:5]3)=[CH:11][N:10]=2)=[O:13])[CH2:26][O:25][CH2:24]1
Reactant: NC(=O)CC1(N)COC1
Reactant: O=C(O)c1cc(OCC(F)(F)F)c(N2CC(F)(F)C2)cn1
Product: NC(=O)CC1(NC(=O)c2cc(OCC(F)(F)F)c(N3CC(F)(F)C3)cn2)COC1

Procedure:
The title compound was synthesized in analogy to Example 112e, using 5-(3,3-difluoroazetidin-1-yl)-4-(2,2,2-trifluoroethoxy)pyridine-2-carboxylic acid (Example 223b) and 2-(3-Amino-oxetan-3-yl)-acetamide (CAN 1417638-25-5) as starting material and isolated (42 mg, 31%); MS (ESI, m/z): 425.5 (M+H+).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][O:4][C:5](=[O:13])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C(OC([NH:21][CH2:22][C:23](=[O:29])[CH2:24][CH2:25][C:26]([OH:28])=[O:27])=O)(C)(C)C>>[ClH:1].[C:5]([O:4][CH:3]([O:28][C:26](=[O:27])[CH2:25][CH2:24][C:23](=[O:29])[CH2:22][NH2:21])[CH3:2])(=[O:13])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCC(=O)OCCCl
Reactant: CC(C)(C)OC(=O)NCC(=O)CCC(=O)O
Product: CCCCCCCC(=O)OC(C)OC(=O)CCC(=O)CN
Product: Cl

Procedure:
The compound was prepared as described in Procedures A and B above from 2-chloroethyloctanoate and 5-(tert-butoxycarbonylamino)-4-oxopentanoic acid. 1H-NMR (300 MHz, CDCl3) ppm δ 0.87 (t, J=7.20 Hz, 3H, CH2Me), 1.27 (m, 8H, (CH2)4CH2CH2CO2), 1.45 (d, J=5.40 Hz, 3H, OCH(CH3)O), 1.58 (sext, J=7.32 Hz, 2H, CH2CH2CH2CO2), 2.28 (t, J=7.30 Hz, 2H, CH2CH2CH2CO2), 2.66 (“t”, 2H, COCH2CH2CO2), 2.94 (“t”, 2H, COCH2CH2CO2), 4.28 (s, 2H, CH2NH2), 6.83 (q, J=5.60 Hz, 1H, OCHO).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([C:13]#[N:14])[C:10]=1[O:11][CH3:12])[C:5](O)=[O:6].C1(C)C=CC=CC=1.S(Cl)([Cl:24])=O>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([C:13]#[N:14])[C:10]=1[O:11][CH3:12])[C:5]([Cl:24])=[O:6]
Reactant: O=S(Cl)Cl
Reactant: COc1c(Cl)cc(C(=O)O)cc1C#N
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: COc1c(Cl)cc(C(=O)Cl)cc1C#N
Temperature: 60 °C
Reaction time: 16 h

Procedure:
To 3-chloro-5-cyano-4-methoxybenzoic acid (932 mg), toluene (9.3 mL), N,N-dimethylformamide (0.03 mL) and thionyl chloride (0.38 mL) were added, and the mixture was stirred at 60° C. for 16 hours. The solvent was distilled off under reduced pressure and then azeotroped with toluene to obtain the title compound (993 mg) as a brown solid.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][OH:6].N1C=CN=C1.[CH3:12][C:13]([Si:16](Cl)([CH3:18])[CH3:17])([CH3:15])[CH3:14]>C(Cl)Cl>[C:13]([Si:16]([O:6][CH2:5][CH2:4][CH2:3][CH2:2][Cl:1])([CH3:18])[CH3:17])([CH3:15])([CH3:14])[CH3:12]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCCCCCl
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCCCCCl
Temperature: 25 °C
Reaction time: 4 h
Yield: 50 %

Procedure:
Compound 7-a, 4-chloro-1-butanol, (CAS 928-51-8) (100 g, 920 mmol) was dissolved in CH2Cl2 (1000 mL) at room temperature. Imidazole (CAS 288-32-4) (81.5, 1200 mmol) and TBDMS-Cl (CAS 18162-48-6) (152 g, 1010 mmol) was added at 0° C. The mixture was stirred for 4 h at rt. The mixture was filtered off. The filtrate was washed with 10% aqueous HCl-solution and brine. After evaporation of the filtrate, we get the product 7-c as a clear oil (100 g, 50%).
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]1[CH2:10][C:9](=[O:11])[N:8]2[CH:12]([C:15]3[NH:16][C:17]([C:20]4[CH:25]=[CH:24][C:23](Br)=[CH:22][CH:21]=4)=[CH:18][N:19]=3)[CH2:13][CH2:14][CH:7]2[CH2:6]1)=[O:4].[CH3:27][O:28][C:29](=[O:62])[NH:30][CH:31]([C:35]([N:37]1[CH2:41][CH2:40][CH2:39][CH:38]1[C:42]1[NH:43][C:44]([C:47]2[CH:52]=[CH:51][C:50](B3OC(C)(C)C(C)(C)O3)=[CH:49][CH:48]=2)=[CH:45][N:46]=1)=[O:36])[CH:32]([CH3:34])[CH3:33].C(=O)([O-])[O-].[K+].[K+].COCCOC>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>[CH3:1][O:2][C:3]([N:5]1[CH2:10][C:9](=[O:11])[N:8]2[CH:12]([C:15]3[NH:16][C:17]([C:20]4[CH:25]=[CH:24][C:23]([C:50]5[CH:51]=[CH:52][C:47]([C:44]6[NH:43][C:42]([CH:38]7[CH2:39][CH2:40][CH2:41][N:37]7[C:35](=[O:36])[CH:31]([NH:30][C:29]([O:28][CH3:27])=[O:62])[CH:32]([CH3:34])[CH3:33])=[N:46][CH:45]=6)=[CH:48][CH:49]=5)=[CH:22][CH:21]=4)=[CH:18][N:19]=3)[CH2:13][CH2:14][CH:7]2[CH2:6]1)=[O:4]
Reactant: COC(=O)N1CC(=O)N2C(CCC2c2ncc(-c3ccc(Br)cc3)[nH]2)C1
Reactant: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)[nH]1)C(C)C
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: O
Solvent: COCCOC
Product: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc(-c3ccc(-c4cnc(C5CCC6CN(C(=O)OC)CC(=O)N65)[nH]4)cc3)cc2)[nH]1)C(C)C
Temperature: 120 °C
Yield: 16 %

Procedure:
A mixture of 6-[5-(4-bromo-phenyl)-1H-imidazol-2-yl]-4-oxo-hexahydro-pyrrolo[1,2-a]pyrazine-2-carboxylic acid methyl ester (65 mg, 0.15 mmol), [2-methyl-1-(2-{5-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-propyl]-carbamic acid methyl ester (77 mg, 0.15 mmol), tetrakis(triphenylphosphine)palladium(0) (18 mg, 0.015 mmol), potassium carbonate (42.8 mg, 0.31 mmol), 1,2-dimethoxyethane (4 mL) and water (1 mL) was heated in a microwave reactor at 120° C. for 20 minutes. The mixture was cooled and all volatiles were removed under reduced pressure. The resulting residue was taken up in dimethylformamide (2 mL) and subjected to reverse phase chromatography with an eluent of 0.1% TFA in water and 0.1% TFA in acetonitrile. The product-containing fractions were combined and the solvent was removed by lyophilization to provide 6-[5-(4′-{2-[1-(2-methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-biphenyl-4-yl)-1H-imidazol-2-yl]-4-oxo-hexahydro-pyrrolo[1,2-a]pyrazine-2-carboxylic acid methyl ester (16.8 mg, 0.024 mmol, 15%). C38H44BrN8O6 calculated 708.3 observed [M+1]+709.4; rt=1.39 min. 1H (DMSO-d6): δ=8.10 (s, 2H), 7.89 (m, 7H), 7.33 (d, J=9 Hz, 1H), 5.03 (t, J=7.8 Hz, 1H), 5.12 (m, 1H), 4.30 (m, 1H), 4.23 (m, 11-1), 4.11 (t, J=8.1 Hz, 1H), 3.99 (m, 2H), 3.83 (m, 1H), 3.67 (s, 3H), 3.54 (m, 3H), 2.90 (m, 1H), 2.41 (m, 1H), 2.18 (m, 2H), 2.01 (m, 4H), 1.67 (m, 1H), 0.82 (m, 6H).
Reaction SMILES: [Mg:1].[F:2][C:3]1[C:4]([F:12])=[C:5]([F:11])[C:6]([F:10])=[C:7]([F:9])[CH:8]=1.C([Br:16])(C)C>C1(C)C=CC=CC=1.C(OCC)C>[F:2][C:3]1[C:8]([Mg:1][Br:16])=[C:7]([F:9])[C:6]([F:10])=[C:5]([F:11])[C:4]=1[F:12]
Reactant: [Mg]
Reactant: Fc1cc(F)c(F)c(F)c1F
Reactant: CC(C)Br
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: Fc1c(F)c(F)c([Mg]Br)c(F)c1F

Procedure:
Air inside a reaction vessel of the same kind as the one used in Example 13 is displaced by a nitrogen gas in a satisfactory manner. Then, 2.650 g (0.109 mole) of magnesium, 17.469 g (0.104 mole) of pentafluorobenzene, and 10 ml of diethyl ether and 10 ml of toluene both serving as the solvent (e) (mixed solvent) are charged to the reaction vessel. Also, 14.185 g (0.109 mole) of isopropyl bromide is charged to the dropping funnel. Next, isopropyl bromide is dropped to the contents with stirring under a nitrogen gas atmosphere. After the completion of the dropping, the resulting reaction solution is subject to reaction for 2.5 hours at 69.0° C. with stirring. Consequently, pentafluorophenyl magnesium bromide is obtained in the form of a mixed solution of diethyl ether and toluene. A reaction yield of pentafluorophenyl magnesium bromide found in the same manner as Example 13 is 82.4 percent by mole.