Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[Mg][CH:3]([CH3:5])[CH3:4].[Cl:6][C:7]1[C:8]([C:13]#N)=[N:9][CH:10]=[CH:11][CH:12]=1.Cl.C1C[O:19]CC1>>[Cl:6][C:7]1[C:8]([C:13](=[O:19])[CH:3]([CH3:5])[CH3:4])=[N:9][CH:10]=[CH:11][CH:12]=1
Reactant: CC(C)[Mg]Cl
Reactant: C1CCOC1
Reactant: N#Cc1ncccc1Cl
Agent: Cl
Product: CC(C)C(=O)c1ncccc1Cl
Temperature: 0 °C
Reaction time: 2 h
Yield: 15 %

Procedure:
Chloro(isopropyl)magnesium in THF (35.0 mL, 0.070 mol) was added dropwise to a solution of chloro-2-pyridinecarbonitrile (5.01 g, 0.036 mol) in THF (100 mL) under nitrogen atmosphere at 0° C. It was kept at 0° C. for 2 hours after the addition was complete. The reaction mixture was poured into ice (100 g) and then acidified to pH=3 with an aqueous solution of hydrochloric acid (2.0 M, 100 mL). The product was then extracted with EtOAc (3×100 mL). The organics were combined, dried over sodium sulfate, filtered, and concentrated in vacuo. The resulting crude was purified by silica gel chromatography eluting with 3 to 10% EtOAc in heptane to yield the title compound as a yellow oil (1.98 g, 15% yield):
Reaction SMILES: Cl/[CH:2]=[CH:3]/[C:4](=[O:17])[CH2:5][CH2:6][CH2:7][CH2:8][CH:9]1[CH2:15][CH2:14][CH:13]2[CH2:16][CH:10]1[CH2:11][CH2:12]2.[I-:18].[Na+]>CC(C)=O>[I:18]/[CH:2]=[CH:3]/[C:4](=[O:17])[CH2:5][CH2:6][CH2:7][CH2:8][CH:9]1[CH2:15][CH2:14][CH:13]2[CH2:16][CH:10]1[CH2:11][CH2:12]2
Reactant: [I-]
Reactant: O=C(/C=C/Cl)CCCCC1CCC2CCC1C2
Agent: [Na+]
Solvent: CC(C)=O
Product: O=C(/C=C/I)CCCCC1CCC2CCC1C2
Yield: 84.4 %

Procedure:
A solution of 3.2 g (13 mmol) of 1-chloro-7-(bicyclo[3.2.1]oct-2-yl)-1E-hepten-3-one and 7.5 g (50 mmol) of sodium iodide in 25 ml of dry acetone (distilled from potassium carbonate) was refluxed for 18 hr under nitrogen. The solvent was removed in vacuo, and the residue was taken up in 50 ml of water and then extracted three times with 30 ml portions of ether. The combined ether extracts were washed with aqueous sodium thiosulfate, dried (MgSO4) and evaporated in vacuo to yield 3.8 g (88%) of 1-iodo-7-(bicyclo[3.2.1]oct-2-yl)-1E-hepten-3-one.
Reaction SMILES: [N+:1]([C:4]1[C:9]([N+:10]([O-])=O)=[CH:8][C:7]([OH:13])=[C:6]([O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][OH:20])[CH:5]=1)([O-:3])=[O:2].[CH3:21][O:22][CH2:23][CH2:24]N>O>[CH3:21][O:22][CH2:23][CH2:24][NH:10][C:9]1[C:4]([N+:1]([O-:3])=[O:2])=[CH:5][C:6]([O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][OH:20])=[C:7]([OH:13])[CH:8]=1
Reactant: O=[N+]([O-])c1cc(O)c(OCCOCCO)cc1[N+](=O)[O-]
Reactant: COCCN
Solvent: O
Product: COCCNc1cc(O)c(OCCOCCO)cc1[N+](=O)[O-]

Procedure:
A mixture prepared by adding 0.07 mol (20.2 g) of 4,5-dinitro-2-[β-(2-hydroxyethoxy)ethoxy]phenol, prepared according to Example 4, to 0.28 mol (21 g) of 2-methoxyethylamine and 15 ml of water is heated under reflux.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[NH:9][CH:8]=[CH:7][C:6]2=[S:15].Br[C:17]1[S:18][C:19]([N+:22]([O-:24])=[O:23])=[CH:20][N:21]=1.C(OCC)(=O)C.[OH-].[Na+]>CN(C)C=O.CCCCCC>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[S:15][C:17]1[S:18][C:19]([N+:22]([O-:24])=[O:23])=[CH:20][N:21]=1
Reactant: O=[N+]([O-])c1cnc(Br)s1
Reactant: COc1cc2[nH]ccc(=S)c2cc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COc1cc2nccc(Sc3ncc([N+](=O)[O-])s3)c2cc1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 48.7 %

Procedure:
After suspending 6,7-dimethoxy-1H-quinoline-4-thione (2.21 g, 10.0 mmol) in dimethylformamide (30 ml), 2-bromo-5-nitrothiazole (2.30 g, 11.0 mmol) was added at 0° C., and then the mixture was stirred at room temperature for 1 hour. The reaction solution was distributed between ethyl acetate and 1N aqueous sodium hydroxide, the organic layer was washed with water and saturated brine and dried over anhydrous magnesium sulfate, the drying agent was filtered off and the filtrate was distilled off under reduced pressure. The obtained crude product was subjected to silica gel column chromatography (eluent—ethyl acetate:hexane=3:1), and the fraction containing the target substance was concentrated, suspended in ethyl acetate and diluted with hexane, after which the crystals were filtered out, washed with hexane and then blow-dried to obtain the title compound (1.70 g, 4.87 mmol, 49%) as light yellow crystals.
Reaction SMILES: C(N(CC)C(C)C)(C)C.[CH2:10](Br)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[N+:18]([NH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1)([O-:20])=[O:19]>C(#N)C>[CH2:10]([N:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]1=[N:21][N+:18]([O-:20])=[O:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: BrCc1ccccc1
Reactant: O=[N+]([O-])Nc1ccccn1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])N=c1ccccn1Cc1ccccc1

Procedure:
20 ml (0.114 mole) of N,N-diisopropylethylamine and 12 ml (0.1 mole) of benzyl bromide are added to a suspension containing 14 g (0.1 mole) of 2-(nitroamino)pyridine [prepared according to J. Am. Chem. Soc. 77, 3154 (1955)] in 100 ml of acetonitrile, then the mixture is refluxed for 2.5 hours. The reaction mixture is cooled down then evaporated under reduced pressure, the residue is triturated with water, the suspension obtained is filtered and washed with a great volume of water. The filter cake is thoroughly sucked, then suspended in 50 ml of petroleum ether, filtered and washed again with petroleum ether to give 14.2 g (62%) of the named product, m.p.: 125°-126° C. (recrystallized from ethyl acetate).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:10]([CH2:18][CH3:19])=[N:11][C:12]([N+:15]([O-:17])=[O:16])=[CH:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.[CH3:20][N:21]1[CH:25]=[C:24](B2OC(C)(C)C(C)(C)O2)[CH:23]=[N:22]1.C([O-])([O-])=O.[K+].[K+].CCOC(C)=O>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:18]([C:10]1[C:9]([O:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([C:24]3[CH:23]=[N:22][N:21]([CH3:20])[CH:25]=3)[CH:7]=2)=[CH:14][CH:13]=[C:12]([N+:15]([O-:17])=[O:16])[N:11]=1)[CH3:19]
Reactant: CCc1nc([N+](=O)[O-])ccc1Oc1ccnc(Cl)c1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
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: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: CCc1nc([N+](=O)[O-])ccc1Oc1ccnc(-c2cnn(C)c2)c1
Temperature: 80 °C
Yield: 100 %

Procedure:
A mixture of Example A8 (1.10 g, 3.93 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.06 g, 5.11 mmol), K2CO3 (1.631 g, 11.80 mmol) and Pd(PPh3)4 (227 mg, 0.197 mmol) in dioxane (8 mL) and water (2 mL) was sparged with Ar and heated at 80° C. for 24 h. The mixture was cooled to RT, treated with EtOAc, washed with satd. NaHCO3, then brine, dried over Na2SO4 and concentrated to dryness to afford crude 2-ethyl-3-((2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yl)oxy)-6-nitropyridine (100% yield assumed) without further purification. MS (ESI) m/z: 326.1 (M+H+).
Reaction SMILES: Br[C:2]1[C:3]([CH2:8][C:9]#[N:10])=[N:4][CH:5]=[CH:6][CH:7]=1.[C:11]1(B(O)O)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C([O-])([O-])=O.[K+].[K+].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>C(O)C.C1(C)C=CC=CC=1>[C:11]1([C:2]2[C:3]([CH2:8][C:9]#[N:10])=[N:4][CH:5]=[CH:6][CH:7]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: OB(O)c1ccccc1
Reactant: N#CCc1ncccc1Br
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: N#CCc1ncccc1-c1ccccc1
Temperature: 110 °C
Yield: 94.4 %

Procedure:
To a stirred solution of (3-bromo-pyridin-2-yl)-acetonitrile (158) (1 g, 5.07 mmol) and phenyl boronic acid (928 mg g, 7.16 mmol) in a solvent mixture of toluene (25 mL) and ethanol (25 mL) was added K2CO3 (2.1 g, 15.23 mmol). The mixture was degassed by argon, X-Phos (484 mg, 1.01 mmol) and Pd(triphenyl phosphine)4 (586 mg g, 0.51 mmol) were added and the mixture was again degassed. The reaction mixture was refluxed (110° C.) for 4 h. Silica thin layer chromatography was performed (30% ethyl acetate in hexane, Rf=0.45). The catalyst was filtered off through a celite bed, washing with ethyl acetate (3×50 mL) was conducted, the mixture was concentrated, the crude product was purified by a CombiFlash column (eluted at 15% ethyl acetate in hexane) to get (3-phenyl-pyridin-2-yl)-acetonitrile (159) (930 mg, 94.34%) as a light yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)/[C:9](=[N:18]\O)/[C:10]2[CH:15]=[CH:14][N:13]=[C:12]([S:16][CH3:17])[N:11]=2)=[CH:4][CH:3]=1.C([O-])(=O)C.[NH4+:25].[CH:26](=O)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C(O)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:25]=[C:26]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[NH:18][C:9]=2[C:10]2[CH:15]=[CH:14][N:13]=[C:12]([S:16][CH3:17])[N:11]=2)=[CH:4][CH:3]=1
Reactant: [NH4+]
Reactant: CSc1nccc(/C(=N/O)C(=O)c2ccc(F)cc2)n1
Reactant: O=Cc1ccccc1
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Product: CSc1nccc(-c2[nH]c(-c3ccccc3)nc2-c2ccc(F)cc2)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 24.1 %

Procedure:
A mixture of (Z)-1-(4-fluorophenyl)-2-(hydroxyimino)-2-(2-(methylthio)pyrimidin-4-yl)ethanone (0.5 g), ammonium acetate (2.7 g) and benzaldehyde (0.2 g) in acetic acid (11 mL) are heated under reflux for 4 h, cooled to room temperature and the majority of the solvent evaporated. The residue is partitioned between ice-cold saturated aqueous sodium hydrogen carbonate and ethyl acetate. The layers are separated and the aqueous phase is extracted with ethyl acetate. The combined organic phases are dried over sodium sulfate, filtered and the solvent evaporated. The residue is dissolved in methanol (8 mL). This solution is treated with a solution of titanium (III) choride in hydrochloric acid (0.44 mL, 15 wt %, 20–30% hydrochloric acid), followed by stirring at room temperature for 3 h and solvent evaporation. The residue is partitioned between ice-cold saturated aqueous sodium hydrogen carbonate and ethyl acetate, then the layers are separated and the aqueous phase is extracted with ethyl acetate. The combined organic phases are dried over sodium sulfate, filtered, the solvent evaporated and the residue purified by chromatography to give the title compound, 75 (0.15 g).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH:9]=2)=[CH:4][CH:3]=1.[CH2:18]([Li])[CH2:19][CH2:20][CH3:21].[CH:23]1[C:36]2[C:35](=[O:37])[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:28](=[O:38])[C:27]=2[CH:26]=[CH:25][CH:24]=1.[Cl-].[NH4+]>CCCCCC.C1COCC1.C1(C)C=CC=CC=1>[CH:18]1[C:7]2[C:2](=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:21]=[CH:20][C:19]=1[C:8]1[CH:17]=[CH:16][C:15]([C:35]2([OH:37])[C:34]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[C:28]([C:2]3[CH:3]=[CH:4][C:5]([C:8]4[CH:9]=[CH:10][C:11]5[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=5)[CH:17]=4)=[CH:6][CH:7]=3)([OH:38])[C:27]3[C:36]2=[CH:23][CH:24]=[CH:25][CH:26]=3)=[CH:10][CH:9]=1
Reactant: Brc1ccc(-c2ccc3ccccc3c2)cc1
Reactant: [Li]CCCC
Reactant: O=C1c2ccccc2C(=O)c2ccccc21
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCCCCC
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: OC1(c2ccc(-c3ccc4ccccc4c3)cc2)c2ccccc2C(O)(c2ccc(-c3ccc4ccccc4c3)cc2)c2ccccc21
Temperature: -20 °C
Reaction time: 3 h
Yield: 89.5 %

Procedure:
Under an atmosphere of argon, 2-(4-bromophenyl)naphthalene (5.4 g, 19 mmole, 2.8 eq) was dissolved into a mixed solvent composed of anhydrous toluene (25 ml) and anhydrous THF (25 ml) and the resultant solution was cooled at −40° C. in a dry ice/methanol bath. To the cooled solution, a hexane solution of n-butyllithium (1.50 mole/liter, 14 ml, 21 mmole, 1.1 eq) was added and the resultant mixture was stirred at −20° C. for 1 hour. To the resultant solution, anthraquinone (1.4 g, 6.7 mmole) was added and the obtained mixture was stirred at −20° C. for 1 hour and at the room temperature for 3 hours and left standing for one night. To the obtained reaction mixture, a saturated aqueous solution of ammonium chloride (20 ml) was added. The formed solid was separated by filtration and washed with water, methanol and acetone and a white solid (3.7 g, 91%) was obtained.
Reaction SMILES: [CH2:1]([C:4]1[S:5][C:6]2[NH:7][CH:8]=[CH:9][C:10](=O)[C:11]=2[N:12]=1)[CH2:2][CH3:3].P(Cl)(Cl)([Cl:16])=O.[OH-].[Na+]>>[Cl:16][C:10]1[CH:9]=[CH:8][N:7]=[C:6]2[S:5][C:4]([CH2:1][CH2:2][CH3:3])=[N:12][C:11]=12
Reactant: CCCc1nc2c(=O)cc[nH]c2s1
Reactant: O=P(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Product: CCCc1nc2c(Cl)ccnc2s1
Yield: 89 %

Procedure:
The product of Example 5F (123 mg, 0.6332 mmol) and phosphorous oxychloride (2 mL) were refluxed for 1 hour under a nitrogen atmosphere. The solution was cooled in an ice bath, treated with ice, and the pH adjusted to 7 with 6N aqueous sodium hydroxide. Extracted with methylene chloride (3×50 mL) and dried the combined organic extracts over anhydrous sodium sulfate, filtered and concentrated under vacuum giving the title compound as a brown oil (120 mg, 0.564 mmol, 89%).
Reaction SMILES: [CH3:1][C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][C:3]=1[CH:11]([NH:20][C:21]1[CH:29]=[CH:28][C:24]([C:25](O)=[O:26])=[CH:23][CH:22]=1)[CH2:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[CH3:30][NH:31][CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35].O.ON1C2C=CC=CC=2N=N1.Cl>CN(C)C=O.C(N(CC)CC)C>[CH3:30][N:31]([C:25]([C:24]1[CH:28]=[CH:29][C:21]([NH:20][CH:11]([C:3]2[O:4][C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[C:2]=2[CH3:1])[CH2:12][O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:22][CH:23]=1)=[O:26])[CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35]
Reactant: Cc1c(C(COc2ccccc2)Nc2ccc(C(=O)O)cc2)oc2ccccc12
Reactant: CCOC(=O)CCNC
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCN(C)C(=O)c1ccc(NC(COc2ccccc2)c2oc3ccccc3c2C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.9 %

Procedure:
To a mixture of 4-{[1-(3-methyl-1-benzofuran-2-yl)-2-phenoxyethyl]amino}benzoic acid (100 mg) synthesized in Example A94(3), ethyl 3-(methylamino)propanoate (50.8 mg), 1-hydroxybenzotriazole monohydrate (59.3 mg), triethylamine (54 μL) and N,N-dimethylformamide (10 mL) 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (74.2 mg) was added, and the mixture was stirred overnight at room temperature. 1N Hydrochloric acid was added to quench the reaction, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (50% ethyl acetate/hexane) to give the title object compound (82.5 mg, 64%) as a yellow oil.
Reaction SMILES: [CH3:1][C@:2]12[C@@:19]3([CH3:20])[CH:10]([C@:11]4([CH3:31])[C@@H:16]([CH2:17][CH2:18]3)[C:15]([CH3:22])([CH3:21])[C:14](OS(C(F)(F)F)(=O)=O)=[CH:13][CH2:12]4)[CH2:9][CH2:8][C@@H:7]1[C@H:6]1[C@H:32]([C:35]([CH3:37])=[CH2:36])[CH2:33][CH2:34][C@:5]1(C(OCC1C=CC=CC=1)=O)[CH2:4][CH2:3]2.CC1(C)C(C)(C)OB(/[CH:56]=[CH:57]/[C:58]([O:60][CH2:61][CH3:62])=[O:59])O1.[C:64](=[O:67])([O-:66])[O-].[Na+].[Na+]>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>[CH2:61]([O:60][C:58](=[O:59])/[CH:57]=[CH:56]/[C:14]1[C:15]([CH3:22])([CH3:21])[C@H:16]2[C@:11]([CH3:31])([CH2:12][CH:13]=1)[CH:10]1[C@:19]([CH3:20])([C@@:2]3([CH3:1])[C@H:7]([CH2:8][CH2:9]1)[C@H:6]1[C@H:32]([C:35]([CH3:37])=[CH2:36])[CH2:33][CH2:34][C@:5]1([C:64]([O:66][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:67])[CH2:4][CH2:3]3)[CH2:18][CH2:17]2)[CH3:62]
Reactant: C=C(C)[C@@H]1CC[C@]2(C(=O)OCc3ccccc3)CC[C@]3(C)[C@H](CCC4[C@@]5(C)CC=C(OS(=O)(=O)C(F)(F)F)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)/C=C/B1OC(C)(C)C(C)(C)O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: C=C(C)[C@@H]1CC[C@]2(C(=O)OCc3ccccc3)CC[C@]3(C)[C@H](CCC4[C@@]5(C)CC=C(/C=C/C(=O)OCC)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 100 °C
Yield: 43 %

Procedure:
A mixture of (1R,3aS,5aR,5bR,7aR,11aR,13aR,13bR)-benzyl 5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-9-(trifluoromethylsulfonyloxy)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysene-3a-carboxylate, prepared as described in WO2011153315, (50 mg, 0.074 mmol), (E)-ethyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)acrylate (66.8 mg, 0.295 mmol), tetrakis(triphenylphosphine)palladium (8.54 mg, 0.0074 mmol) and sodium carbonate (39 mg, 0.369 mmol) in DME (1 mL) and water (1 mL) was heated to 100° C. for 1.5 hours. The reaction mixture was cooled to rt, extracted with ethyl acetate (3×5 mL). The extracts were combined, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude residue was purified by flash chromatography with 80-100% ethyl acetate/hexanes gradient to provide the title compound (20 mg, 43%). LCMS: m/e 627.55 (M+H)+, 3.60 min (method 6).
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[O:8][C:6](=[O:7])[CH2:5][C@@H:4]1[CH3:9].[S:10](Cl)([C:13]1[CH:19]=[CH:18][C:16]([CH3:17])=[CH:15][CH:14]=1)(=[O:12])=[O:11].Cl>N1C=CC=CC=1>[S:10]([C:13]1[CH:19]=[CH:18][C:16]([CH3:17])=[CH:15][CH:14]=1)([OH:1])(=[O:12])=[O:11].[CH3:9][C@@H:4]1[C@@H:3]([CH2:2][O:1][S:10]([C:13]2[CH:19]=[CH:18][C:16]([CH3:17])=[CH:15][CH:14]=2)(=[O:12])=[O:11])[O:8][C:6](=[O:7])[CH2:5]1
Reactant: C[C@H]1CC(=O)O[C@@H]1CO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)O)cc1
Product: Cc1ccc(S(=O)(=O)OC[C@H]2OC(=O)C[C@@H]2C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 106.6 %

Procedure:
In 60 ml of anhydrous pyridine, 7.9 g of (3S, 4S)-5-hydroxy-3-methylpentan-4-olide (60.8 mmol) obtained in step [B] were dissolved. To the resultant solution, 15.1 g of tosyl chloride (79.0 mmol) were added with cooling by ice. The obtained mixture was stirred at room temperature overnight. The reacted solution was poured into a diluted hydrochloric acid solution which had been cooled, and extracted with methylene chloride. The obtained extract was washed with water and a saturated sodium chloride aqueous solution, in this order, and dried with anhydrous magnesium sulfate. Next, the obtained solution was filtered, and the obtained filtrate was concentrated. The obtained residue was purified via silica gel column chromatography (n-hexane:ethyl acetate=5:1 to 1:2) to obtain 14.8 g of (3S,4S)-3-methyl-5-tosyloxypentan-4-olide (tosylate) (yield: 85.5%). This product exhibited the following physical properties:
Reaction SMILES: [CH3:1][CH:2]1[C:7]([C:8]2[CH:20]=[CH:19][C:11]([O:12][CH2:13][C:14]([O:16]CC)=O)=[CH:10][CH:9]=2)=[N:6][NH:5][C:4](=[O:21])[NH:3]1.[O:22]1[CH2:27][CH2:26][N:25]([CH2:28][CH2:29][NH2:30])[CH2:24][CH2:23]1>C(OCC)(=O)C>[O:22]1[CH2:27][CH2:26][N:25]([CH2:28][CH2:29][NH:30][C:14](=[O:16])[CH2:13][O:12][C:11]2[CH:10]=[CH:9][C:8]([C:7]3[CH:2]([CH3:1])[NH:3][C:4](=[O:21])[NH:5][N:6]=3)=[CH:20][CH:19]=2)[CH2:24][CH2:23]1
Reactant: CCOC(=O)COc1ccc(C2=NNC(=O)NC2C)cc1
Reactant: NCCN1CCOCC1
Solvent: CCOC(C)=O
Product: CC1NC(=O)NN=C1c1ccc(OCC(=O)NCCN2CCOCC2)cc1
Reaction time: 1 h
Yield: 69.8 %

Procedure:
0.4 g of ethyl α-[4-(2,3,4,5-tetrahydro-5-methyl-3-oxo-1,2,4-triazin-6-yl)phenoxy]acetate (prepared as described in Example 18) was mixed with 0.36 g of 2-morpholinoethylamine, and the mixture was stirred at 115° to 120° C. for 1 hour. The mixture was then cooled, and ethyl acetate was added. The crystals which precipitated were collected by filtration and washed with ethyl acetate to give a pale yellow powder. Recrystallization of this powder from ethyl acetate gave 0.36 g of the title compound as pale brown, fine crystals melting at 147°-149° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=3)[N:11]([C:20](Cl)=[O:21])[C:10]([C:23]3[C:24]([O:31][CH2:32][CH3:33])=[N:25][C:26]([S:29][CH3:30])=[N:27][CH:28]=3)=[N:9]2)=[CH:4][CH:3]=1.[N:34]1([C:40](=[O:48])[CH2:41][N:42]2[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]2)[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]2[C@@H:12]([C:13]3[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=3)[N:11]([C:20]([N:45]3[CH2:44][CH2:43][N:42]([CH2:41][C:40]([N:34]4[CH2:35][CH2:36][O:37][CH2:38][CH2:39]4)=[O:48])[CH2:47][CH2:46]3)=[O:21])[C:10]([C:23]3[C:24]([O:31][CH2:32][CH3:33])=[N:25][C:26]([S:29][CH3:30])=[N:27][CH:28]=3)=[N:9]2)=[CH:6][CH:7]=1
Reactant: O=C(CN1CCNCC1)N1CCOCC1
Reactant: CCOc1nc(SC)ncc1C1=NC(c2ccc(Cl)cc2)C(c2ccc(Cl)cc2)N1C(=O)Cl
Product: CCOc1nc(SC)ncc1C1=N[C@@H](c2ccc(Cl)cc2)[C@@H](c2ccc(Cl)cc2)N1C(=O)N1CCN(CC(=O)N2CCOCC2)CC1

Procedure:
cis-4-[4,5-Bis-(4-chloro-phenyl)-2-(4-ethoxy-2-methylsulfanyl-pyrimidin-5-yl)-4,5-dihydro-imidazole-1-carbonyl chloride (example 12) was reacted with 1-morpholin-4-yl-2-piperazin-1-yl-ethanone (Oakwood Products) to give cis-2-{4-[4,5-bis-(4-chloro-phenyl)-2-(4-ethoxy-2-methylsulfanyl-pyrimidin-5-yl)-4,5-dihydro-imidazole-1-carbonyl]-piperazin-1-yl}-1-morpholin-4-yl-ethanone in an analogous manner as described in example 1. HR-MS (ES, m/z) calculated for C33H38N7O4SCl2 [(M+H)+] 698.2078, observed 698.2078.
Reaction SMILES: [CH2:1]([N:5]([CH2:19][CH2:20][CH2:21][CH3:22])[S:6]([C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=1[Cl:18])C(Cl)=O)(=[O:8])=[O:7])[CH2:2][CH2:3][CH3:4].[N+](=C)=[N-].[ClH:26].C([O:29][CH2:30][CH3:31])C>COCCOCCOC>[CH2:1]([N:5]([CH2:19][CH2:20][CH2:21][CH3:22])[S:6]([C:9]1[CH:10]=[C:11]([C:30](=[O:29])[CH2:31][Cl:26])[CH:15]=[CH:16][C:17]=1[Cl:18])(=[O:7])=[O:8])[CH2:2][CH2:3][CH3:4]
Reactant: CCOCC
Reactant: CCCCN(CCCC)S(=O)(=O)c1cc(C(=O)Cl)ccc1Cl
Reactant: Cl
Agent: C=[N+]=[N-]
Solvent: COCCOCCOC
Product: CCCCN(CCCC)S(=O)(=O)c1cc(C(=O)CCl)ccc1Cl

Procedure:
18 g of the 3-di-n-butylsulfamoyl-4-chlorobenzoylchloride so obtained as an oil were reacted as prescribed in Example 70c) in diethyl ether with diazomethane and then with concentrated HCl in diethyleneglycol dimethyl ether and worked up, 3'-di-n-butylsulfamoyl-2,4'-dichlororacetophenone being obtained in the form of colorless crystals having a melting point of 71° C.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]4[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.B(O)(O)[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([NH2:33])=[O:32])[CH:26]=1>>[CH3:20][N:18]1[CH:19]=[C:15]([N:14]2[C:5]3[C:4]4[CH:3]=[C:2]([C:25]5[CH:26]=[C:27]([CH:28]=[CH:29][CH:30]=5)[C:31]([NH2:33])=[O:32])[CH:11]=[CH:10][C:9]=4[N:8]=[CH:7][C:6]=3[N:12]([CH3:23])[C:13]2=[O:22])[C:16]([CH3:21])=[N:17]1
Reactant: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Reactant: NC(=O)c1cccc(B(O)O)c1
Product: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(-c4cccc(C(N)=O)c4)cc3c21

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A, 40 mg, 0.106 mmol) and benzamide-3-boronic acid (ABCR, Karlsruhe, Germany, 21 mg, 0.129 mmol) to give the title compound as a white solid. (HPLC: tR 2.34 min (Method A); M+H=413 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 8.98 (s, 1H), 8.19-8.16 (m, 1H), 8.14-8.10 (m, 1H), 8.09-8.04 (m, 1H), 8.02-7.95 (m, 2H), 7.89-7.83 (m, 1H), 7.65-7.59 (m, 2H), 7.58-7.47 (m, 2H), 3.94 (s, 3H), 3.58 (s, 3H), 1.93 (s, 3H))