Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(C(C)C)CC)(C)C.[F:10][C:11]1([F:40])[CH2:16][C@@H:15]([C:17](O)=[O:18])[C@H:14]([C:20]2[C:24]([C:25]3[CH:30]=[CH:29][C:28]([S:31]([CH3:34])(=[O:33])=[O:32])=[CH:27][CH:26]=3)=[CH:23][N:22]([CH2:35][C:36]([F:39])([F:38])[F:37])[N:21]=2)[CH2:13][CH2:12]1.Cl.[NH2:42][C:43]1([C:46]#[N:47])[CH2:45][CH2:44]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[C:46]([C:43]1([NH:42][C:17]([C@@H:15]2[CH2:16][C:11]([F:10])([F:40])[CH2:12][CH2:13][C@H:14]2[C:20]2[C:24]([C:25]3[CH:26]=[CH:27][C:28]([S:31]([CH3:34])(=[O:32])=[O:33])=[CH:29][CH:30]=3)=[CH:23][N:22]([CH2:35][C:36]([F:39])([F:37])[F:38])[N:21]=2)=[O:18])[CH2:45][CH2:44]1)#[N:47]
Reactant: N#CC1(N)CC1
Reactant: CS(=O)(=O)c1ccc(-c2cn(CC(F)(F)F)nc2[C@@H]2CCC(F)(F)C[C@H]2C(=O)O)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc(-c2cn(CC(F)(F)F)nc2[C@@H]2CCC(F)(F)C[C@H]2C(=O)NC2(C#N)CC2)cc1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
Diisopropylethylamine (3.2 mL, 18 mmol) was added in one portion to a solution of (1R,2R)-5,5-difluoro-2-[4-[4-(methylsulfonyl)phenyl]-1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-yl]cyclohexanecarboxylic acid (1.69 g, 3.63 mmol), 1-aminocyclopropanecarbonitrile hydrochloride (1.16 g, 9.83 mmol) and HATU (1.72 g, 4.53 mmol) in DMF (10 mL) with stirring at rt for 2.5 h. The reaction vessel contents were then partitioned between ethyl acetate and water and the layers were separated. The aqueous phase was extracted with additional ethyl acetate and the combined organics were washed with 2 M HCl, 10% Na2CO3 and saturated NaCl aqueous solutions, followed by drying over Na2SO4. Concentration in vacuo and flash chromatography on silica gel eluting with 22.5/77.5 acetone/benzene provided the title compound as a colorless powder upon trituration with a mixture of hexanes and ether. 1H NMR (400 MHz, acetone d6) δ 8.03 (1H, s), 7.99 (2H, d, J= 8.5 Hz), 7.83 (1H, overlapped m), 7.81 (2H, d, J= 8.5 Hz), 5.05 (2H, q, J= 8.8 Hz), 3.36 (1H, m), 3.18 (3H, s), 3.12 (1H, m), 2.23 (1H, m), 2.15-1.95 (4H, m), 1.79 (1H, m), 1.37 (2H, m), 1.05 (1H, m), 0.81 (1H, m). MS: (+ESI) 531.0 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.CN(C)CCCN=C=NCC.[N:26]1([C:30]2[C:35]([C:36]#[N:37])=[C:34]([C:38]3[CH:43]=[CH:42][C:41]([O:44][CH2:45][CH2:46]O)=[CH:40][CH:39]=3)[C:33]([C:48]#[N:49])=[C:32]([S:50][CH2:51][C:52]3[N:53]=[C:54]([C:57]4[CH:62]=[CH:61][C:60]([Cl:63])=[CH:59][CH:58]=4)[S:55][CH:56]=3)[N:31]=2)[CH2:29][CH2:28][CH2:27]1>CN(C=O)C.ClCCl.CN(C)C1C=CN=CC=1>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][C:11]([O:13][CH2:46][CH2:45][O:44][C:41]1[CH:42]=[CH:43][C:38]([C:34]2[C:33]([C:48]#[N:49])=[C:32]([S:50][CH2:51][C:52]3[N:53]=[C:54]([C:57]4[CH:62]=[CH:61][C:60]([Cl:63])=[CH:59][CH:58]=4)[S:55][CH:56]=3)[N:31]=[C:30]([N:26]3[CH2:27][CH2:28][CH2:29]3)[C:35]=2[C:36]#[N:37])=[CH:39][CH:40]=1)=[O:12])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCC(=O)O
Reactant: N#Cc1c(SCc2csc(-c3ccc(Cl)cc3)n2)nc(N2CCC2)c(C#N)c1-c1ccc(OCCO)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCC(=O)OCCOc1ccc(-c2c(C#N)c(SCc3csc(-c4ccc(Cl)cc4)n3)nc(N3CCC3)c2C#N)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
101 mg (0.536 mmol) of N-(tert-butoxycarbonyl)-beta-alanine were initially charged in 2 ml of DMF/dichloromethane (1:1). 44.5 mg (0.232 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 10.9 mg (0.89 mmol) of 4-dimethylaminopyridine and 100 mg (0.179 mmol) of 2-(azetidin-1-yl)-6-({(2-(4-chlorophenyl)-1,3-thiazol-4-yl)methyl}sulfanyl)-4-(4-(2-hydroxyethoxy)phenyl)pyridine-3,5-dicarbonitrile (Example 8) were added, and the mixture was then stirred at RT overnight. The crude product was purified by preparative HPLC (acetonitrile/water+0.1% TFA). This gave 118 mg (90% of theory) of the target compound.
Reaction SMILES: O.[OH-].[Li+].[CH:4]1([O:9][C:10]([NH:12][C:13]2[CH:14]=[CH:15][C:16]3[O:21][CH2:20][CH2:19][N:18]([CH2:22][C:23]4[CH:32]=[CH:31][C:26]([C:27]([O:29]C)=[O:28])=[CH:25][C:24]=4[O:33][CH3:34])[C:17]=3[CH:35]=2)=[O:11])[CH2:8][CH2:7][CH2:6][CH2:5]1.Cl>CO.O>[CH:4]1([O:9][C:10]([NH:12][C:13]2[CH:14]=[CH:15][C:16]3[O:21][CH2:20][CH2:19][N:18]([CH2:22][C:23]4[CH:32]=[CH:31][C:26]([C:27]([OH:29])=[O:28])=[CH:25][C:24]=4[O:33][CH3:34])[C:17]=3[CH:35]=2)=[O:11])[CH2:5][CH2:6][CH2:7][CH2:8]1
Reactant: COC(=O)c1ccc(CN2CCOc3ccc(NC(=O)OC4CCCC4)cc32)c(OC)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1cc(C(=O)O)ccc1CN1CCOc2ccc(NC(=O)OC3CCCC3)cc21
Reaction time: 12 h
Yield: 67.4 %

Procedure:
Lithium hydroxide monohydrate (0.267 g.) was added as a solid to a stirred solution of methyl 4-[6-(cyclopentyloxycarbonyl)amino-2,3-dihydrobenz-1,4-oxazin-4-ylmethyl]-3-methoxybenzoate (0.7 g.) in methanol (15 ml.) and water (2 ml.). The mixture was stirred for 12 hours then diluted with water and acidified to pH 3.35 with 3M hydrochloric acid. The precipitate which formed was isolated by filtration, washed with water and crystallized from methanol to give the title compound as a solid (0.457 g., 67%), m.p. 221°-222° C.
Reaction SMILES: [Li].[Li]CCCC.C(NC(C)C)(C)C.[Br:14][C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=1[F:22].[C:23](=[O:25])=[O:24]>C1COCC1.C(=O)=O.CC(C)=O.CCOCC.Cl>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([Br:14])=[C:16]([F:22])[C:17]=1[C:23]([OH:25])=[O:24]
Reactant: Fc1cc(Cl)ccc1Br
Reactant: O=C=O
Agent: Cl
Agent: [Li]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)=O
Solvent: CC(C)NC(C)C
Product: O=C(O)c1c(Cl)ccc(Br)c1F
Temperature: -70 °C
Reaction time: 0.5 h

Procedure:
A solution of lithium diiosopropyl amide is generated by adding n-BuLi (360 mL of 2 M solution in THF) to diisopropylamine (73 g, 0.722 mol) in 500 mL of anhydrous THF while a reaction temperature of −60° C. is maintained by cooling in dry-ice acetone bath. After stirring for 30 minutes, 1-bromo-4-chloro-2-fluorobenzene (75 g, 0.36 mol) is added and stirring maintained at −70° C. for 2 hours. The cold solution is then transferred, via a cannula, under an inert atmosphere to a suspension of solid CO2 (100 g, excess) in anhydrous Et2O. The mixture is allowed to warm to room temperature with stirring and then the solvent removed by rotary evaporator. The residual solid is treated with 1 N HCl solution until pH=3.0 and the mixture is filtered. The white solid that is obtained is suspended in 1000 mL of 2 N HCl solution and stirred for an additional 1 hour. The suspension is filtered to collect a white solid which is air dried, suspended in 100 mL of hexanes and collected to give 2-chloro-5-bromo-6-fluorobenzoic acid.
Reaction SMILES: [OH:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1[NH2:4].[C:12]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[N:24]=[C:25]=[O:26])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[OH:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1[NH:4][C:25]([NH:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:26]
Reactant: Nc1ccc([N+](=O)[O-])cc1O
Reactant: O=C=Nc1ccccc1-c1ccccc1
Product: O=C(Nc1ccc([N+](=O)[O-])cc1O)Nc1ccccc1-c1ccccc1
Yield: 19.4 %

Procedure:
N-(2-Hydroxy-4-nitrophenyl)-N'-(2-phenylphenyl)urea was prepared from 2-hydroxy 4-nitro aniline (500 mg, 3.24 mmol) and 2-phenyl phenyl isocyanate (3.24 mmol) according to the procedure in General Method B. The product was purified by dilution with methylene chloride and precipitation with hexanes. Filtering afforded the title compound (0.22 g, 19%). EI-MS m/z 350 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][S:10]([C:13]1[N:23]=[C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[C:20](Cl)[N:15]2[N:14]=1)(=[O:12])=[O:11].C[O-].[Na+].[C:27](O)(=[O:29])C.CCOCC>CO.ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][S:10]([C:13]1[N:23]=[C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[C:20]([O:29][CH3:27])[N:15]2[N:14]=1)(=[O:12])=[O:11]
Reactant: CC(=O)O
Reactant: Cc1cc(Cl)n2nc(S(=O)(=O)Nc3c(Cl)cccc3Cl)nc2c1
Agent: C[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Solvent: CCOCC
Product: COc1cc(C)cc2nc(S(=O)(=O)Nc3c(Cl)cccc3Cl)nn12
Reaction time: 2 h

Procedure:
N-(2,6-Dichlorophenyl)-5-chloro-7-methyl[1,2,4]triazolo[1,5-a]pyridine-2-sulfonamide (3.0 g, 0.0077 mol) and 25 percent sodium methoxide in methanol (12 mL, 2.8 g, 0.050 mol) were combined in methanol (100 mL) and heated to reflux with stirring for 2 hours. The reaction mixture was cooled and acidified with acetic acid and the volatiles were removed by evaporation under reduced pressure. The residue obtained was diluted with dichloromethane and the mixture was washed with water. The organic solution phase was filtered and the filtrate was concentrated by evaporation under reduced pressure. The residue obtained was mixed with ether and filtered to recover the solids. The solids were dried to obtain 2.6 g (87 percent of theory) of the title compound as a white powder melting at 269°-270° C.(d).
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[CH2:3][NH:4][C:5]([C:7]1([CH2:20][CH2:21][CH2:22][CH2:23]Br)[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6].[N:27]1([C:34]2[S:35][C:36]3[CH:42]=[CH:41][CH:40]=[CH:39][C:37]=3[N:38]=2)[CH2:33][CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>>[F:1][C:2]([F:26])([F:25])[CH2:3][NH:4][C:5]([C:7]1([CH2:20][CH2:21][CH2:22][CH2:23][N:30]2[CH2:31][CH2:32][CH2:33][N:27]([C:34]3[S:35][C:36]4[CH:42]=[CH:41][CH:40]=[CH:39][C:37]=4[N:38]=3)[CH2:28][CH2:29]2)[C:19]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:13]2[C:8]1=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:6]
Reactant: O=C(NCC(F)(F)F)C1(CCCCBr)c2ccccc2-c2ccccc21
Reactant: c1ccc2sc(N3CCCNCC3)nc2c1
Product: O=C(NCC(F)(F)F)C1(CCCCN2CCCN(c3nc4ccccc4s3)CC2)c2ccccc2-c2ccccc21

Procedure:
Prepared analogously to Example 1 from 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid-(2,2,2-trifluoro-ethyl)-amide and 2-[1.4] diazepan-1-yl-benzothiazole.
Reaction SMILES: [N+:1]([C:4]1[O:8][C:7]([C:9](Cl)=[O:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH:12]([C:14]1[S:15][C:16]2[CH:22]=[C:21]([N+:23]([O-:25])=[O:24])[CH:20]=[CH:19][C:17]=2[N:18]=1)[NH2:13]>>[N+:23]([C:21]1[CH:20]=[CH:19][C:17]2[N:18]=[C:14]([NH:12][NH:13][C:9]([C:7]3[O:8][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=3)=[O:10])[S:15][C:16]=2[CH:22]=1)([O-:25])=[O:24]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])o1
Reactant: NNc1nc2ccc([N+](=O)[O-])cc2s1
Product: O=C(NNc1nc2ccc([N+](=O)[O-])cc2s1)c1ccc([N+](=O)[O-])o1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
The compound 4h was prepared according to above described method by using 5-nitro-2-furancarboxylic acid chloride (430 mg, 1.5 mmol) and 2-hydrazino-6-nitrobenzothiazole (290 mg, 1 mmol) which stirred for 1 h at 0° C. and stirring continued at 25° C. for 11 h (yield 283 mg, 87%).
Reaction SMILES: Br[C:2]1[C:3]([NH:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)=[N:4][C:5]([O:21][CH3:22])=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=2[O:19][CH3:20])[N:7]=1.[CH2:33](B(O)O)[CH3:34].C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.[OH-].[Na+].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>[CH2:33]([C:2]1[C:3]([NH:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)=[N:4][C:5]([O:21][CH3:22])=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=2[O:19][CH3:20])[N:7]=1)[CH3:34]
Reactant: CCB(O)O
Reactant: COc1ccc(CNc2nc(OC)c(-c3ccc(OC(F)(F)F)cc3OC)nc2Br)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: Cc1ccccc1
Product: CCc1nc(-c2ccc(OC(F)(F)F)cc2OC)c(OC)nc1NCc1ccc(OC)cc1
Temperature: 85 °C
Yield: 92.8 %

Procedure:
To a stirred solution of {3-bromo-6-methoxy-5-[2-methoxy-4-(trifluoromethoxy)phenyl]pyrazin-2-yl }[(4-methoxyphenyl)methyl]amine (514 mg, 1.0 mmol) and ethylboronic acid (219 mg, 3.0 mmol) in toluene (8 mL) is added tetrakis(triphenylphosphine)palladium(0) (50 mg) and potassium carbonate (2.0 M, 1.0 mL). The mixture is heated to 85° C. for 8 h, cooled to room temperature, diluted with 2.0 M sodium hydroxide and extracted twice with 1:1 hexane-ethyl ether. The combined extracts are dried (sodium sulfate), filtered and concentrated. The residue is purified by flash chromatography, eluting with 20% ether in hexanes to give {3-ethyl-6-methoxy-5-[2-methoxy-4-(trifluoromethoxy)phenyl]pyrazin-2-yl }[(4-methoxyphenyl)methyl]amine (430 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[CH3:9][O:10][C:11](=[O:24])[C:12]1[CH:17]=[C:16]([CH3:18])[C:15]([Br:19])=[C:14]([S:20](Cl)(=[O:22])=[O:21])[CH:13]=1.N1C=CC=CC=1>C(Cl)Cl>[CH3:9][O:10][C:11](=[O:24])[C:12]1[CH:17]=[C:16]([CH3:18])[C:15]([Br:19])=[C:14]([S:20](=[O:21])(=[O:22])[NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[OH:8])[CH:13]=1
Reactant: COC(=O)c1cc(C)c(Br)c(S(=O)(=O)Cl)c1
Reactant: Nc1ccccc1O
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1cc(C)c(Br)c(S(=O)(=O)Nc2ccccc2O)c1
Temperature: 10 °C
Reaction time: 8 h

Procedure:
A solution of 2-aminophenol (2.5 g, 22.9 mmol) in dry methylene chloride (10 mL) was added to a mixture of 4-bromo-3-chlorosulfonyl-5-methyl-benzoic acid methyl ester (7.18 g, 22.9 mmol) and dry pyridine (10 mL, 124.7 mmol) in methylene chloride (40 mL). The reaction mixture was stirred for 1 h at 10° C. and at room temperature overnight. It was concentrated, treated with 10% HCl (100 mL) and extracted with 1-butanol. The organic layer was washed with water, brine, dried, concentrated, treated with methanolic HCl (60 ml) and refluxed for 3 h. The reaction mixture was concentrated, treated with 10% aqueous sodium bicarbonate solution to alkaline pH and extracted using ethyl acetate. The organic layer was washed with water, brine, dried and purified, using flash chromatography (silica gel, 10% ethyl acetate/pet ether) to obtain the title compound. Yield: 2.2 g, (24%); 1H NMR (CDCl3): δ 2.4 (s, 3H, CH3), 3.9 (s, 3H, OCH3), 6.6 (t, 1H, Ar), 6.72 (t, 1H, Ar), 6.74 (d, 1H, Ar), 7.2 (d, 1H, Ar), 7.94 (s, 1H, OH), 7.96 (s, 1H, Ar), 8.5 (s, 1H, Ar); MS: m/e (EI+) 400 (M+1).
Reaction SMILES: II.[Mg].Br[CH2:5][CH3:6].[C:7]([C:10]1[CH:18]=[CH:17][C:13]2[O:14][CH2:15][O:16][C:12]=2[CH:11]=1)(=[O:9])[CH3:8].[Cl-].[NH4+]>O1CCCC1.O>[O:14]1[C:13]2[CH:17]=[CH:18][C:10]([C:7]([OH:9])([CH2:5][CH3:6])[CH3:8])=[CH:11][C:12]=2[O:16][CH2:15]1
Reactant: CCBr
Reactant: CC(=O)c1ccc2c(c1)OCO2
Agent: II
Agent: [Cl-]
Agent: [Mg]
Solvent: O
Solvent: C1CCOC1
Product: CCC(C)(O)c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 95.9 %

Procedure:
15 ml of tetrahydrofuran and a catalytic amount of iodine were added to 340 mg of magnesium ribbon to obtain a mixture. 1.59 g of bromoethane was gradually added to the mixture in a stream of nitrogen in such a way that the reaction system was mildly refluxed. The resulting mixture was heated under reflux for 30 minutes and cooled, followed by the addition of a solution of 2 g of 5-acetyl-1,3-benzodioxole in tetrahydrofuran. The obtained mixture was stirred at a room temperature for 20 minutes, followed by the addition of a saturated aqueous solution of ammonium chloride and water. The obtained mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of common salt, dried over anhydrous magnesium sulfate and filtered. The filtrate was distilled to remove the solvent. 2.27 g of the title compound was obtained as a crude oil.
Reaction SMILES: [CH3:1][Li].[CH3:3][C:4](=[CH:6][CH2:7][CH2:8][C:9](=[CH:11][CH:12]=[O:13])[CH3:10])[CH3:5]>O1CCCC1>[OH:13][CH:12]([CH3:1])[CH:11]=[C:9]([CH3:10])[CH2:8][CH2:7][CH:6]=[C:4]([CH3:3])[CH3:5]
Reactant: CC(C)=CCCC(C)=CC=O
Reactant: [Li]C
Solvent: C1CCOC1
Product: CC(C)=CCCC(C)=CC(C)O
Temperature: 30 °C

Procedure:
Methyl lithium in tetrahydrofuran (THF) (1.6 L, 1 M) was charged to a flame dried 3 L reaction flask equipped with a thermometer, a mechanical stirrer, condenser, and an addition funnel. Citral was added dropwise for over 2-2.5 hours. The reaction mixture was aged until the conversion rate was greater than 90%. The reaction mixture was cooled to lower than 30° C. and quenched by the slow addition of HCl (pH<5.10%). The aqueous phase was extracted three times with toluene (100 mL) and the extracts were added to the crude reaction mixture. The crude reaction mixture was then washed with saturated sodium bicarbonate (500 mL) followed by saturated salt solution and dried over anhydrous sodium sulphate. The crude reaction mixture was concentrated. The solvents were recovered via a rotary evaporator to provide 8-hydroxy-2,6-dimethyl-nona-2,6-diene.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[C:14]([CH3:22])[CH:13]=2)[N:3]=1.[Br:23][C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][CH:29]=1>>[Br:23][C:24]1[CH:29]=[C:28]([C:2]2[N:3]=[C:4]([C:12]3[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[C:14]([CH3:22])[CH:13]=3)[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:7]=2)[CH:27]=[CH:26][CH:25]=1
Reactant: OB(O)c1cccc(Br)c1
Reactant: Cc1cc(-c2cc(C(F)(F)F)nc(Cl)n2)ccc1C(F)(F)F
Product: Cc1cc(-c2cc(C(F)(F)F)nc(-c3cccc(Br)c3)n2)ccc1C(F)(F)F

Procedure:
The title compound was prepared from 2-chloro-6-(3-methyl-4-trifluoromethyl-phenyl)-4-trifluoromethyl-pyrimidine (example A.38) (0.68 g, 2.0 mmol) and commercially available 3-bromo-benzene-boronic acid (0.44 g, 2.20 mmol) according to the general procedure IVb. Obtained as a white solid (0.23 g, 25%). MS (EI) 462.1 [(M)+]; mp 102.5° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:23]=[CH:22][CH:21]=[CH:20][C:5]=1[O:6][C@@H:7]1[CH2:12][CH2:11][CH2:10][N:9](C(OC(C)(C)C)=O)[CH2:8]1)[CH3:2].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([O:3][C:4]1[CH:23]=[CH:22][CH:21]=[CH:20][C:5]=1[O:6][C@@H:7]1[CH2:12][CH2:11][CH2:10][NH:9][CH2:8]1)[CH3:2]
Reactant: CCOc1ccccc1O[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOc1ccccc1O[C@@H]1CCCNC1
Temperature: 22.5 °C
Reaction time: 4 h
Yield: 89.6 %

Procedure:
To a solution of tert-butyl (R)-3-(2-ethoxyphenoxy)piperidine-1-carboxylate (73 g, 227 mmol) in CH2Cl2 (300 mL) at 20-25° C. was added trifluoroacetic acid (150 mL). The reaction mixture was allowed to stir at 20-25° C. for 4 hours. The mixture was concentrated under reduced pressure, and the residue was dissolved in H2O (200 mL) and basified with saturated NaHCO3 solution (200 mL). The mixture was extracted with EtOAc (3 times with 200 mL). The organic extracts were dried over Na2SO4 and concentrated to afford (R)-3-(2-ethoxyphenoxy)piperidine (45 g, 89%). MS (ES+) 222.2 (M+H).
Reaction SMILES: C([Si](C)(C)[O:6][CH2:7][CH2:8][N:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([C:18]2[N:19]=[C:20]3[C:26]([C:27](=[O:32])[C:28]([CH3:31])([CH3:30])[CH3:29])=[CH:25][N:24](COCC[Si](C)(C)C)[C:21]3=[N:22][CH:23]=2)=[CH:10]1)(C)(C)C>CO>[OH:6][CH2:7][CH2:8][N:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([C:18]2[N:19]=[C:20]3[C:26]([C:27](=[O:32])[C:28]([CH3:30])([CH3:29])[CH3:31])=[CH:25][NH:24][C:21]3=[N:22][CH:23]=2)=[CH:10]1
Reactant: CC(C)(C)C(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3cn(CCO[Si](C)(C)C(C)(C)C)c4ccccc34)nc12
Solvent: CO
Product: CC(C)(C)C(=O)c1c[nH]c2ncc(-c3cn(CCO)c4ccccc34)nc12

Procedure:
1-{2-[1-(2-Hydroxy-ethyl)-1H-indol-3-yl]-5H-pyrrolo[2,3-b]pyrazin-7-yl}-2,2-dimethyl-propan-1-one was prepared following the same procedure but using 1-[2-{1-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-1H-indol-3-yl}-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-2,2-dimethyl-propan-1-one as starting material. The product was obtained in 67% by trituration in MeOH.
Reaction SMILES: [Br-].[C:2]([C:4]1[CH:5]=[N:6][N:7]([C:16]2[C:21]([Cl:22])=[CH:20][C:19]([C:23]([F:26])([F:25])[F:24])=[CH:18][N:17]=2)[C:8]=1[CH2:9][N+]1C=CC=CC=1)#[N:3].[CH3:27][N:28]([CH3:37])[C:29]1[CH:34]=[CH:33][C:32]([N:35]=[O:36])=[CH:31][CH:30]=1.C(=O)([O-])[O-].[K+].[K+]>C(O)C.O>[CH3:27][N:28]([CH3:37])[C:29]1[CH:34]=[CH:33][C:32]([N+:35]([O-:36])=[CH:9][C:8]2[N:7]([C:16]3[C:21]([Cl:22])=[CH:20][C:19]([C:23]([F:26])([F:25])[F:24])=[CH:18][N:17]=3)[N:6]=[CH:5][C:4]=2[C:2]#[N:3])=[CH:31][CH:30]=1
Reactant: N#Cc1cnn(-c2ncc(C(F)(F)F)cc2Cl)c1C[n+]1ccccc1
Reactant: CN(C)c1ccc(N=O)cc1
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CN(C)c1ccc([N+]([O-])=Cc2c(C#N)cnn2-c2ncc(C(F)(F)F)cc2Cl)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 87.4 %

Procedure:
To a stirred suspension of 9.0 grams (0.020 mole) of 1-[[4-cyano-1-(3-chloro-5-trifluoromethylpyridin-2-yl)-1H-pyrazol-5-yl]methyl]pyridinium bromide and 3.5 grams (0.023 mole) of N,N-dimethyl-4-nitrosoaniline in 95 mL of ethanol was added a solution of 16 grams (0.12 mole) of potassium carbonate in 59 mL of water. When the addition was complete, the reaction mixture was stirred at ambient temperature for four hours. After this time, the reaction mixture was filtered. The filter cake was washed in succession with water, ethanol, and diethyl ether, yielding 7.6 grams of N-[4-(dimethylamino)phenyl]-a-[4-cyano-1-(3-chloro-5-trifluoromethylpyridin-2-yl)-1H-pyrazol-5-yl]nitrone. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:9].[N+:10]([O-])([OH:12])=[O:11]>S(=O)(=O)(O)O>[Br:1][C:2]1[C:7]([CH3:8])=[C:6]([N+:10]([O-:12])=[O:11])[CH:5]=[CH:4][C:3]=1[CH3:9]
Reactant: Cc1cccc(C)c1Br
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: Cc1ccc([N+](=O)[O-])c(C)c1Br
Temperature: -10 °C
Reaction time: 1 h
Yield: 37 %

Procedure:
To a mixture of 2-bromo-1,3-dimethylbenzene (5.0 g, 27.03 mmol) in sulfuric acid (98%, 40 mL) at −10° C. was added dropwise a solution of nitric acid (68%, 2.74 g, 27.03 mmol) in sulfuric acid (98%, 10 mL). After the reaction was complete the mixture was stirred at −10° C. for 1 h. The reaction mixture was poured onto ice (200 g) the resulting solid filtered, washed with water, and dried in vacuo. The crude was purified by SiO2 chromatography eluting with petroleum ether/EtOAc (100:1) as eluting solvent to afford 2.3 g (37%) of 2-bromo-1,3-dimethyl-4-nitrobenzene as yellow solid (298): 1H NMR (500 MHz, DMSO-d6): δ 7.79 (d, J=8.5, 1H), 7.43 (d, J=8.5, 1H), 2.47 (s, 3H), 2.44 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)=[C:12]([CH3:24])[C:11]([C:25](O)=[O:26])=[N:10]1.B.CO>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:13]([C:14]2[CH:15]=[CH:16][C:17]([C:20]([F:23])([F:21])[F:22])=[CH:18][CH:19]=2)=[C:12]([CH3:24])[C:11]([CH2:25][OH:26])=[N:10]1
Reactant: Cc1c(C(=O)O)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(C(F)(F)F)cc1
Agent: B
Solvent: C1CCOC1
Solvent: CO
Product: Cc1c(CO)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(C(F)(F)F)cc1
Temperature: 25 °C

Procedure:
To a solution of 4.5 g of 1-(2,4-Dichloro-phenyl)-4-methyl-5-(4-trifluoromethyl-phenyl)-1H-pyrazole-3-carboxylic acid in 30 ml of THF, were added dropwise 43 ml of a 1M solution of borane in THF at room temperature. Then the reaction mixture was heated to reflux for 10 h. The reaction mixture was cooled to room temperature and 20 ml of methanol were carefully added. The solvents were removed under reduced pressure and the residue was dissolved in ethyl acetate. The organic layer was washed with 1 M hydrochloric acid, saturated sodium chloride solution and saturated sodium hydrogen carbonate solution. The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure. The product was obtained as a white solid and used without further purification. Yield: 4.3 g.