Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si]([O:8][CH2:9][C:10]([C:12]1[N:29]([CH2:30][C@H:31]2[CH2:36][CH2:35][C@H:34]([CH3:37])[CH2:33][CH2:32]2)[C:15]2[C:16]([C:22]3[CH:23]=[N:24][CH:25]=[C:26]([Cl:28])[CH:27]=3)=[N:17][C:18]([C:20]#[N:21])=[CH:19][C:14]=2[N:13]=1)=[CH2:11])(C(C)(C)C)(C)C.[F-].[CH2:39]([N+](CCCC)(CCCC)CCCC)CCC.[H-].[Na+].CI>C1COCC1>[Cl:28][C:26]1[CH:27]=[C:22]([C:16]2[C:15]3[N:29]([CH2:30][C@H:31]4[CH2:36][CH2:35][C@H:34]([CH3:37])[CH2:33][CH2:32]4)[C:12]([C:10]([CH2:9][O:8][CH3:39])=[CH2:11])=[N:13][C:14]=3[CH:19]=[C:18]([C:20]#[N:21])[N:17]=2)[CH:23]=[N:24][CH:25]=1
Reactant: C=C(CO[Si](C)(C)C(C)(C)C)c1nc2cc(C#N)nc(-c3cncc(Cl)c3)c2n1C[C@H]1CC[C@H](C)CC1
Reactant: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Product: C=C(COC)c1nc2cc(C#N)nc(-c3cncc(Cl)c3)c2n1C[C@H]1CC[C@H](C)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Steps 5 & 6: A stirred solution of 2-(3-{[tert-butyl(dimethyl)silyl]oxy}prop-1-en-2-yl)-4-(5-chloropyridin-3-yl)-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile (1.2 g, 2.24 mmol) in THF (20 mL) was cooled to 0° C. Tetrabutylammonium fluoride (3.36 mL, 3.36 mmol, 1M solution in THF) was added dropwise over a period of 5 minutes, and the reaction mixture was warmed to room temperature and stirred for 1 h. The reaction mixture was quenched with water (10 mL) and extracted with ethyl acetate (15 mL). The organic phase was separated, washed with brine solution (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The crude 4-(5-chloropyridin-3-yl)-2-(3-hydroxyprop-1-en-2-yl)-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile (0.9 g, 2.14 mmol) was dissolved in dry THF (10 mL) and cooled to 0° C. NaH (0.123 g, 3.12 mmol, 60% in mineral oil) was added in several portions and stirred for 15 minutes. Methyl iodide (0.16 mL, 2.57 mmol) was added dropwise over a period of 5 minutes, and the reaction mixture was slowly warmed to room temperature and stirred for 1 h. The reaction mixture was quenched with ice and extracted with ethyl acetate (100 mL). The organic layer was separated, washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography using 15% ethyl acetate/petroleum ether as eluent to yield 4-(5-chloropyridin-3-yl)-2-(3-methoxyprop-1-en-2-yl)-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile. MS ES/APCI calcd. for C24H26ClN5O [M+H]+ 436. found 436
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:15][CH2:14][CH2:13][NH:12][C:11](=O)[CH2:10][N:9]1[S:17]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[O:26][C:27]([F:30])([F:29])[F:28])(=[O:19])=[O:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:40]2)=CC=1.C([O-])(O)=O.[Na+]>C1(C)C=CC=CC=1>[CH2:1]([C@@H:8]1[CH2:15][CH2:14][CH2:13][NH:12][C:11](=[S:40])[CH2:10][N:9]1[S:17]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[O:26][C:27]([F:30])([F:29])[F:28])(=[O:19])=[O:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: O=C1CN(S(=O)(=O)c2ccccc2OC(F)(F)F)[C@H](Cc2ccccc2)CCCN1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: O=S(=O)(c1ccccc1OC(F)(F)F)N1CC(=S)NCCC[C@H]1Cc1ccccc1
Temperature: 80 °C
Reaction time: 0.17 h
Yield: 94.8 %

Procedure:
A solution of compound 31m (500 mg, 1.13 mmol) in toluene (30 mL) was treated with 2,4-bis(4-methoxyphenyl)-1,3,2,4-dithiadiphosphetane 2,4-disulfide (Lawesson's reagent) (457 mg, 1.13 mmol), heated at 80° C. for 30 min, cooled to rt, treated with NaHCO3 (95 mg, 1.13 mmol) and stirred for 10 min. The mixture was extracted with EA three times and the combined organic layer was washed with brine and dried over anhydrous Na2SO4. After filtration, the filtrate was evaporated and the residue was purified by CC (hexane/EA=4:1) to give compound 31n (491 mg, 95% yield).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:3]=1[NH2:4].N([O-])=O.[Na+].[N-:14]=[N+:15]=[N-].[Na+].CC([O-])=O.[Na+]>Cl.O>[N:4]([C:3]1[CH:5]=[C:6]([F:9])[CH:7]=[CH:8][C:2]=1[Br:1])=[N+:14]=[N-:15]
Reactant: Nc1cc(F)ccc1Br
Reactant: [N-]=[N+]=[N-]
Agent: CC(=O)[O-]
Agent: Cl
Agent: O=N[O-]
Solvent: O
Product: [N-]=[N+]=Nc1cc(F)ccc1Br
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 96.2 %

Procedure:
2-Bromo-5-fluoro aniline (2.00 g, 10.53 mmol) was dissolved in concentrated HCl (10 mL) and water (10 mL) and cooled to 0° C. Aqueous NaNO2 solution (1.090 g, 15.8 mmol of NaNO2 in 10 mL of water) was added dropwise at such a rate that the temperature did not exceed 5° C. This mixture was stirred at 0° C. for 1.5 h. A solution of NaN3 (1.027 g, 15.8 mmol) and NaOAc (12.95 g, 158 mmol) in water (50 mL) was then added at 0–5° C. and the mixture was stirred for an additional 1 h at this temperature. The mixture was extracted with ethyl acetate and the combined extracts were washed with brine and dried over Na2SO4. The filtrate was concentrated to afford the title compound as a tan solid (2.188 g, 96%): 1H NMR (400 MHz, CDCl3): 7.53 (1H, dd, J=8.8, 5.6 Hz), 6.94 (1H, dd, J=8.8, 2.8 Hz), 6.79 (1H, ddd, J=8.8, 7.6, 2.8 Hz).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:12][C:13]([OH:15])=[O:14])[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10].[CH3:16]O>OS(O)(=O)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:12][C:13]([O:15][CH3:16])=[O:14])[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10]
Reactant: CO
Reactant: COc1cc(CC(=O)O)ccc1[N+](=O)[O-]
Agent: O=S(=O)(O)O
Product: COC(=O)Cc1ccc([N+](=O)[O-])c(OC)c1
Temperature: 25 °C
Yield: 92 %

Procedure:
A solution of 2-(3-methoxy-4-nitrophenyl)acetic acid (4.6 g, 21.78 mmol) and concentrated H2SO4 (2 drops) in methanol (200 mL) was heated to reflux for 3 hours. The mixture was allowed to cool to room temperature then the solvents were removed under reduced pressure. The residue was partitioned between water (100 mL) and EtOAc (100 mL), then the separated organic layer was washed with sodium bicarbonate solution (100 mL), brine (200 mL), dried (Na2SO4) and evaporated under reduced pressure to give the title compound (4.5 g, 92%) as a solid.
Reaction SMILES: [CH3:1][N:2]([CH3:32])[C:3]1[CH:8]=[C:7]([C:9]2[CH:10]=[N:11][N:12]([C:16]3[CH:31]=[CH:30][C:19]([C:20]([NH:22][CH2:23][CH:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)=[O:21])=[CH:18][N:17]=3)[C:13]=2[O:14]C)[CH:6]=[CH:5][N:4]=1.[Cl-].[Li+].CC(N(C)C)=O>CS(C)=O>[CH3:1][N:2]([CH3:32])[C:3]1[CH:8]=[C:7]([C:9]2[CH:10]=[N:11][N:12]([C:16]3[CH:31]=[CH:30][C:19]([C:20]([NH:22][CH2:23][CH:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)=[O:21])=[CH:18][N:17]=3)[C:13]=2[OH:14])[CH:6]=[CH:5][N:4]=1
Reactant: COc1c(-c2ccnc(N(C)C)c2)cnn1-c1ccc(C(=O)NCC2CCOCC2)cn1
Agent: [Cl-]
Agent: [Li+]
Solvent: CS(C)=O
Solvent: CC(=O)N(C)C
Product: CN(C)c1cc(-c2cnn(-c3ccc(C(=O)NCC4CCOCC4)cn3)c2O)ccn1
Temperature: 60 °C
Yield: 49.3 %

Procedure:
Combined 6-(4-(2-(dimethylamino)pyridin-4-yl)-5-methoxy-1H-pyrazol-1-yl)-N-((tetrahydro-2H-pyran-4-yl)methyl)nicotinamide from the above reaction and lithium chloride (42.7 mg, 1.008 mmol) and DMA (1 mL) and heated at 60° C. for 20 h. The reaction mixture was diluted with 0.2 mL DMSO and purified by prep HPLC (ammonium hydroxide conditions) to give the title compound (42 mg, 49.3% yield) as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.12-1.28 (m, 2 H) 1.56-1.67 (m, 2 H) 1.81 (ddt, J=14.9, 7.5, 3.8, 3.8 Hz, 1 H) 3.05 (s, 6 H) 3.17 (t, J=6.4 Hz, 2 H) 3.28 (td, J=11.6, 1.8 Hz, 2 H) 3.86 (dd, J=11.4, 2.5 Hz, 2 H) 7.07 (d, J=4.5 Hz, 1 H) 7.35 (br. s., 1 H) 7.67 (d, J=6.1 Hz, 1 H) 7.90 (s, 1 H) 8.10-8.19 (m, 1 H) 8.47-8.59 (m, 2 H) 8.80 (d, J=2.0 Hz, 1 H). MS m/z 423 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](Br)=[CH:4][CH:3]=1.[C:9]([O-])(=O)[CH3:10].[Na+]>[Pd].CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:9]=[CH2:10])=[CH:4][CH:3]=1
Reactant: Clc1ccc(Br)cc1
Reactant: CC(=O)[O-]
Agent: [Pd]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=Cc1ccc(Cl)cc1
Temperature: 130 °C
Reaction time: 6 h
Yield: 52.2 %

Procedure:
2 ml of the stock solution described in Example 23 are added to 18 ml of DMF. 9.77 g (50 mmols) of 4-chlorobromobenzene and 4.52 g (55 mmols) of anhydrous sodium acetate are then added. The reaction mixture is then placed under ethylene in a pressure apparatus and is stirred for 6 hours at 10 bar and 130° C. 3.62 g (26.1 mmols) of 4-chlorostyrene are obtained, corresponding to a yield of 52% of theory (conversion figure 5200; Pd content 0.01 mol %).
Reaction SMILES: [NH2:1][C:2]1[C:9](I)=[CH:8][C:5]([C:6]#[N:7])=[C:4]([Cl:11])[CH:3]=1.CCN(C(C)C)C(C)C.[C:21]([Si:23]([CH3:26])([CH3:25])[CH3:24])#[CH:22]>[Cu]I>[NH2:1][C:2]1[C:9]([C:22]#[C:21][Si:23]([CH3:26])([CH3:25])[CH3:24])=[CH:8][C:5]([C:6]#[N:7])=[C:4]([Cl:11])[CH:3]=1
Reactant: C#C[Si](C)(C)C
Reactant: N#Cc1cc(I)c(N)cc1Cl
Agent: [Cu]I
Solvent: CCN(C(C)C)C(C)C
Product: C[Si](C)(C)C#Cc1cc(C#N)c(Cl)cc1N
Temperature: 70 °C
Yield: 48.2 %

Procedure:
A round bottom bottle was charged with 236 (2.78 g, 0.01 mol), CuI (95 mg, 0.5 mmol), Pd(PPh3)Cl2 (200 mg, 0.5 mmol), DIPEA (3.87 g, 0.03 mol) and ethynyltrimethylsilane (2.94 g, 0.03 mol). The mixture was heated under nitrogen atmosphere at 70° C. overnight then cooled and partitioned between EtOAc (500 mL) and H2O (100 mL). The organic layer was concentrated to dryness in vacuo. The crude was purified by SiO2 chromatography eluting with 10% EtOAc/petroleum ether to afford 1.2 g (48%) of 4-amino-2-chloro-5-((trimethylsilyl)ethynyl)benzonitrile (238) as brown solid: MS (ESI) m/z=249.1 [M+1]+
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:16])[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:4]([F:17])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:25][CH2:26]Br>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:10]2([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:26][CH2:25]2)=[O:16])=[C:4]([F:17])[CH:3]=1
Reactant: CCOC(=O)CC(=O)Nc1ccc(Cl)cc1F
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1(C(=O)Nc2ccc(Cl)cc2F)CC1
Yield: 60.5 %

Procedure:
In a manner similar to the procedure described in Example B, 31.0 grams (119.0 mmol) of ethyl 3-[(4-chloro-2-fluorophenyl)amino]-3-oxopropanoate, 41.4 grams (300.0 mmol) of anhydrous potassium carbonate, 100 milliliters anhydrous dimethylformamide and 10.4 milliliters (120.0 mmol) of 1,2-dibromoethane were reacted for a period of 3 days to give 20.6 grams (72.0 mmol) of ethyl 1-(4-chloro-2-fluorophenylaminocarbonyl)cyclopropanecarboxylate as a colorless solid having a melting point of 94.0° C.-95.5° C. The total yield was 61 percent. NMR analysis of the product indicated the following:
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([Cl:12])[N:11]=1)[C:5]([O:7][CH3:8])=[O:6].[CH2:13]([Sn](CCCC)(CCCC)C=C)[CH2:14]CC>C1(C)C=CC=CC=1.C(OCC)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:8][O:7][C:5](=[O:6])[C:4]1[CH:3]=[C:2]([CH:13]=[CH2:14])[N:11]=[C:10]([Cl:12])[CH:9]=1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: COC(=O)c1cc(Cl)nc(Cl)c1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: C=Cc1cc(C(=O)OC)cc(Cl)n1
Temperature: 25 °C
Yield: 70 %

Procedure:
Add methyl 2,6-dichloro-isonicotinate (3.8 g, 18.4 mmol), tetrakis(triphenylphosphine)palladium (0) (1.15 g, 0.99 mmol), triphenyhlphosphine (524 mg, 2 mmol) in toluene (40 mL) to a previously nitrogen-filled sealed vessel. Flush the reactants with nitrogen again. Add tributyl(vinyl)tin (6.98 mL, 24.0 mmol) and heat the sealed mixture at 95° C. overnight. Cool to room temperature, dilute with diethyl ether and filter through a filtering agent. Wash the organic filtrate with saturated ammonium chloride, saturated sodium bicarbonate and saturated aqueous sodium chloride. Dry (magnesium sulfate), concentrate and purify (silica gel chromatography, eluting with 5:95 to 10:90 ethyl acetate:hexanes) to give the title compound (70%).
Reaction SMILES: [C:1]([O:13]C)(=O)[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[C:15]([C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][CH:27]=1)[C:24]([CH3:29])([CH3:28])[CH2:23][CH2:22][C:21]2([CH3:31])[CH3:30])(=[O:17])[CH3:16].[H-].[Na+].Cl>C1(C)C=CC=CC=1.C(COC)OC.O>[C:6]([C:5]1[CH:4]=[CH:3][C:2]([C:1](=[O:13])[CH2:16][C:15]([C:18]2[CH:27]=[CH:26][C:25]3[C:24]([CH3:29])([CH3:28])[CH2:23][CH2:22][C:21]([CH3:31])([CH3:30])[C:20]=3[CH:19]=2)=[O:17])=[CH:11][CH:10]=1)([O:8][CH3:9])=[O:7]
Reactant: CC(=O)c1ccc2c(c1)C(C)(C)CCC2(C)C
Reactant: COC(=O)c1ccc(C(=O)OC)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(C(=O)CC(=O)c2ccc3c(c2)C(C)(C)CCC3(C)C)cc1
Reaction time: 5 h
Yield: 56.3 %

Procedure:
A solution of 19.4 g (0.1 mole) of dimethyl terephthalate and 23 g (0.1 mole) of 6-acetyl-1,2,3,4-tetrahydro-1,1,4,4-tetramethylnaphthalene in a mixture of 80 ml of toluene and 20 ml of dimethoxyethane was added dropwise at 100° C. to a suspension of 6.3 g (0.15 mole) of sodium hydride in 21 ml of toluene under nitrogen. The reaction mixture was refluxed with stirring for 5 hours and then cooled, after which 50 ml of water were added and the mixture was acidified with semiconcentrated hydrochloric acid, poured onto 500 ml of water and extracted with chloroform. The product which had already precipitated was filtered off under suction, and the chloroform phase was dried over sodium sulfate and evaporated down. The residue and the crude product filtered off under suction beforehand were combined and were extracted several times with hot methanol. After the remaining crystals had been dried, 22.1 g of 1-(4-carbomethoxyphenyl)-3-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl- 2-naphthalenyl)-propane-1,3-dione of melting point 128° C. were obtained.
Reaction SMILES: [NH2:1][C@@H:2]([C:11]([OH:13])=[O:12])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.N[C@H](C(O)=O)CC1C=CC=CC=1.N[C@@H](C(O)=O)CC1C=CC=CC=1.O=C([C@H](CC1C=C(O)C(O)=CC=1)N)O.C1NC=NC=1C[C@@H](N)C(O)=O>>[NH2:1][C@H:2]([C:11]([OH:13])=[O:12])[CH2:3][C:4]1[CH:5]=[CH:6][C:7]([OH:10])=[CH:8][CH:9]=1
Reactant: N[C@H](Cc1ccc(O)cc1)C(=O)O
Agent: N[C@@H](Cc1ccc(O)c(O)c1)C(=O)O
Agent: N[C@@H](Cc1ccccc1)C(=O)O
Agent: N[C@H](Cc1c[nH]cn1)C(=O)O
Product: N[C@@H](Cc1ccc(O)cc1)C(=O)O

Procedure:
replace with: D-Tyr, Phe, D-Phe, L-Dopa, H is, D-His;
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][C:9]([C:11]([F:14])([F:13])[F:12])=[N:10][C:5]2=[N:4][CH:3]=1.[F:15][C:16]1[C:21]([C:22]2[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=2)=[C:20]([F:28])[CH:19]=[CH:18][C:17]=1B(O)O>>[F:28][C:20]1[C:21]([C:22]2[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=2)=[C:16]([F:15])[CH:17]=[CH:18][C:19]=1[C:2]1[N:6]2[CH:7]=[CH:8][C:9]([C:11]([F:14])([F:13])[F:12])=[N:10][C:5]2=[N:4][CH:3]=1
Reactant: OB(O)c1ccc(F)c(-c2cccnc2)c1F
Reactant: FC(F)(F)c1ccn2c(Br)cnc2n1
Product: Fc1ccc(-c2cnc3nc(C(F)(F)F)ccn23)c(F)c1-c1cccnc1

Procedure:
3-Bromo-7-trifluoromethylimidazo[1,2-α]pyrimidine was coupled with 2,4-difluoro-3-(pyridin-3-yl)benzeneboronic acid as described in Example 1 to give 3-[2,4-difluoro-3-(pyridin-3-yl)phenyl]-7-trifluoromethylimidazo[1,2-α]pyrimidine as an off-white solid. Bis-hydrochloride salt (from ethyl acetate/ethanol): δH (400 MHz, DMSO) 7.60-7.65 (2H, m), 7.90-7.96 (2H, m), 8.34 (1H, s), 8.47 (1H, d, J 8), 8.87 (1H, dd, J 5 and 1), 9.08 (1H, s), 9.32 (1H, dd, J 7 and 3).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[OH:7][C:8]1[CH:40]=[CH:39][C:11]2[O:12][C:13]([C:16]([N:18]3[CH2:23][CH2:22][N:21]([CH:24]([C:32]4[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=4)[C:25]4[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=4)[CH2:20][CH2:19]3)=O)=[CH:14][O:15][C:10]=2[CH:9]=1>C(OCC)C>[OH:7][C:8]1[CH:40]=[CH:39][C:11]2[O:12][C:13]([CH2:16][N:18]3[CH2:19][CH2:20][N:21]([CH:24]([C:32]4[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=4)[C:25]4[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=4)[CH2:22][CH2:23]3)=[CH:14][O:15][C:10]=2[CH:9]=1
Reactant: O=C(C1=COc2cc(O)ccc2O1)N1CCN(C(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: Oc1ccc2c(c1)OC=C(CN1CCN(C(c3ccc(F)cc3)c3ccc(F)cc3)CC1)O2
Yield: 85 %

Procedure:
Under a nitrogen atmosphere, heat at reflux for 3 hours, in the presence of 5 mmol of lithium aluminium hydride, a solution of 2 mmol of 6-hydroxy-2-{4-[bis-(4-fluorophenyl)methyl]piperazin-1-ylcarbonyl}-1,4-benzodioxin in 35 cm3 of diethyl ether. After cooling, hydrolysis, removal of the insoluble mineral compounds by filtration and drying over magnesium sulfate, the compound obtained is purified by chromatography on a column of silica (eluant:petroleum ether/ethyl acetate, 40:60). 6-Hydroxy-2-{4-[bis-(4-fluorophenyl)methyl]piperazin -1-ylmethyl}-1,4-benzodioxin is thereby obtained in a yield of 85%.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][O:11][C@H:10]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([CH:21]=[O:22])[CH:16]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+]>CO.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][O:11][C@H:10]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][OH:22])[CH:16]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCO[C@H](Cc2cccc(C=O)c2)C1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCO[C@H](Cc2cccc(CO)c2)C1

Procedure:
The solution of 0.48 g (1.6 mmol) (R)-2-(3-formyl-benzyl)-morpholine-4-carboxylic acid tert-butyl ester in 5 mL methanol was treated with 36 mg (0.95 mmol) sodium borohydride. After 2 h the reaction was diluted with ethyl acetate and extracted with 10% aqueous sodium bicarbonate solution and brine. The organic layer was dried over magnesium sulfate, filtered and evaporated. Chromatography of the remaining residue on silica gel with n-hexane:ethyl acetate (1:1 v/v) gave the desired compound in form of a colorless oil (87%).
Reaction SMILES: C([O:8][N:9]1[C:18](=[O:19])[C:17]2[C:12](=[CH:13][C:14]([N:21]3[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]3)=[C:15]([F:20])[CH:16]=2)[N:11]([CH2:28][CH3:29])[C:10]1=[O:30])C1C=CC=CC=1.[H][H]>C1COCC1.[Pd].[O-]S([O-])(=O)=O.[Ba+2]>[CH2:28]([N:11]1[C:12]2[C:17](=[CH:16][C:15]([F:20])=[C:14]([N:21]3[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]3)[CH:13]=2)[C:18](=[O:19])[N:9]([OH:8])[C:10]1=[O:30])[CH3:29]
Reactant: [H][H]
Reactant: CCn1c(=O)n(OCc2ccccc2)c(=O)c2cc(F)c(N3CCN(C)CC3)cc21
Agent: [Pd]
Agent: O=S(=O)([O-])[O-]
Agent: [Ba+2]
Solvent: C1CCOC1
Product: CCn1c(=O)n(O)c(=O)c2cc(F)c(N3CCN(C)CC3)cc21
Yield: 94 %

Procedure:
Five percent Pd/BaSO4 (110 mg) was added to a solution of 3-benzyloxy-1-ethyl-6-fluoro-7-(4-methylpiperazin-1-yl)-1H-quinazoline-2,4-dione (Example H, 0.14 g, 0.33 mmol) in 50 mL of THF. The mixture was shaken under 50 PSI of hydrogen for 60 hours, filtered, and concentrated to afford 0.1 g of the title compound as a solid, mp 132-134° C.
Reaction SMILES: [F: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.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH:22]([C:24]1[N:29]=[C:28]2[CH2:30][O:31][C:32](=O)[C:27]2=[CH:26][CH:25]=1)=[CH2:23].Cl>C1COCC1>[F: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=[C:32]1[C:27]2[C:28](=[N:29][C:24]([CH:22]=[CH2:23])=[CH:25][CH:26]=2)[CH2:30][O:31]1
Reactant: C=Cc1ccc2c(n1)COC2=O
Reactant: O=C1Cc2cc(F)ccc2N1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: C=Cc1ccc2c(n1)COC2=C1C(=O)Nc2ccc(F)cc21
Reaction time: 0.17 h
Yield: 23.8 %

Procedure:
A solution of 5-fluoro-1,3-dihydro-indol-2-one (1.13 g, 7.44 mmol) in THF (70 mL) is placed under an Argon atmosphere and cooled in an ice bath. A solution of lithium bis(trimethylsilyl)amide (14.9 mL of a 1.0 M solution in THF, 14.9 mmol) is added slowly at 0° C. and the resulting solution is stirred for 10 min. Solid 2-vinyl-7H-furo[3,4-b]pyridin-5-one (600 mg, 3.72 mmol) is added in one portion. The reaction mixture is stirred for 4.5 h and then poured into an aqueous 1N HCl solution (150 mL). The resulting mixture is stirred at room temperature for 70 h during which time a yellow solid precipitated from solution. The solid is collected by filtration and washed with aqueous 10% HCl solution, MeOH (3×5 mL) and Et2O (3×5 mL). The solid is dried under vacuum overnight to give the title compound (260 mg, 24%).
Reaction SMILES: C[O:2][C:3](=[O:30])[CH2:4][CH2:5][NH:6][C:7](=[O:29])[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([S:19][C:20]2[CH:25]=[C:24]([CH3:26])[C:23](Br)=[C:22]([CH3:28])[CH:21]=2)[CH2:15][CH:16]([CH3:18])[CH3:17])=[CH:10][CH:9]=1.[F:31][C:32]([F:43])([F:42])[C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1>>[CH3:28][C:22]1[CH:21]=[C:20]([S:19][CH:14]([C:11]2[CH:12]=[CH:13][C:8]([C:7]([NH:6][CH2:5][CH2:4][C:3]([OH:2])=[O:30])=[O:29])=[CH:9][CH:10]=2)[CH2:15][CH:16]([CH3:17])[CH3:18])[CH:25]=[C:24]([CH3:26])[C:23]=1[C:36]1[CH:37]=[CH:38][C:33]([C:32]([F:43])([F:42])[F:31])=[CH:34][CH:35]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: COC(=O)CCNC(=O)c1ccc(C(CC(C)C)Sc2cc(C)c(Br)c(C)c2)cc1
Product: Cc1cc(SC(CC(C)C)c2ccc(C(=O)NCCC(=O)O)cc2)cc(C)c1-c1ccc(C(F)(F)F)cc1

Procedure:
The title compound is prepared in a manner substantially similar to Example 358 starting from enantiomerically purified 3-{4-[1-(4-bromo-3,5-dimethyl-phenylsulfanyl)-3-methyl-butyl]-benzoylamino}-propionic acid methyl ester and 4-trifluoromethyl phenyl boronic acid. Isomer 1 MS: 542.2 [M−H]−; Isomer 2 MS: 542.2 [M−H]−.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[N:10]1[C:14](=[O:15])[CH:13](Br)[C:12]([NH:17][C:18](=[O:28])[C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-:27])=[O:26])[CH:20]=2)=[N:11]1.[NH:29]1[CH:33]=[CH:32][CH:31]=[N:30]1>C(#N)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[N:10]1[C:14](=[O:15])[CH:13]([C:33]2[CH:32]=[CH:31][NH:30][N:29]=2)[C:12]([NH:17][C:18](=[O:28])[C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-:27])=[O:26])[CH:20]=2)=[N:11]1
Reactant: c1cn[nH]c1
Reactant: O=C(NC1=NN(c2c(Cl)cc(Cl)cc2Cl)C(=O)C1Br)c1cccc([N+](=O)[O-])c1
Solvent: CC#N
Product: O=C(NC1=NN(c2c(Cl)cc(Cl)cc2Cl)C(=O)C1c1cc[nH]n1)c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Yield: 66.5 %

Procedure:
Next, 304 g (0.6 mol) of the 1-(2,4,6-trichlorophenyl)-3-(3-nitrobenzamido)-4-bromo-5-oxo-2pyrazoline and 163 g (2.4 mol) of pyrazole were mixed well and then heated to react for about 5 to 6 hours at 80° to 90° C in a stream of nitrogen gas. The mixture was then cooled to room temperature, 700 ml of acetonitrile was added, and the deposited crystals were thereafter filtered to obtain 197 g (66 %) of 1-(2,4,6-trichlorophenyl)-3-(3-nitrobenzamido)-4-pyrazolyl-5-oxo-2-pyrazoline.
Reaction SMILES: [C:1]1([C:7]2[N:8]([NH2:18])[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:19][C:20](=O)[C:21](=[O:23])[CH3:22].CN(C=O)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[C:12]1([C:9]2[N:8]([N:18]=[C:20]([CH3:19])[C:21](=[O:23])[CH3:22])[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[CH:11][CH:10]=2)[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: CC(=O)C(C)=O
Reactant: Nn1c(-c2ccccc2)ccc1-c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CC(=O)C(C)=Nn1c(-c2ccccc2)ccc1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A suspension of 2,5-Diphenyl-pyrrol-1-ylamine (1.91 g, 8.15 mmol) in toluene (5.45 mL) was treated with 2,3-butanedione (7.15 mL, 81.5 mmol), DMF (10.9 mL) and p-toluene sulfonic acid (10.9 mg). The resulting suspension was stirred under Ar at rt for 30 min, then heated to 70° C. in an oil bath. After 2.5 h, the solutions cooled to rt and concentrated in vacuo. The oily solid was dissolved in toluene and concentrated in vacuo to remove excess 2,3-butanedione. The residue was purified by flash chromatography (SiO2, 10% EtOAc/heptane) to afford 3-(2,5-Diphenyl-pyrrol-1-ylimino)-butan-2-one: 1H NMR (CDCl3, chemical shifts in ppm relative to TMS): 1.44 (s, 3H), 2.56 (s, 3H), 6.47 (s, 2H), 7.20-7.26 (m, 2H), 7.34 (t, 4H, J=8.0 Hz), 7.47 (d, 4H, J=8.0 Hz).