Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[Li]CCCC.CCCCCC.[CH2:25]1[O:27][CH2:26]1.CCOCC>C1COCC1>[CH:1]1[C:13]2[CH:12]([CH2:25][CH2:26][OH:27])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: C1CO1
Reactant: c1ccc2c(c1)Cc1ccccc1-2
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CCCCCC
Product: OCCC1c2ccccc2-c2ccccc21
Reaction time: 5 h

Procedure:
2-(9-Fluorenyl)ethanol was prepared from a solution of fluorene (116.35 g, 0.7 mmol) in 800 ml of dry THF at -20° C. which was added n-BuLi in hexane (0.7 mol) keeping the temperature below -10° C. To the clear solution was rapidly added 357 ml of 1.4M ethylene oxide in ether (0.5 mol) keeping the temperature below 5° C. The reaction mixture was stirred for 5 hours, then quenched with 50 ml of saturated ammonium chloride solution. The THF was removed at a rotary evaporator. The residue was partitioned between water and ethyl acetate. The organic layer was separated, dried with MgSO4 and concentrated in vacuo until crystallization began. The solution was allowed to stand overnight and the crystals were collected and dried (mp 97° C.) (85.5 g, (81%)).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH:17]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[C:18]([CH3:23])([CH3:22])[C:19]([OH:21])=O)=[CH:14][CH:15]=3)[CH:10]=[CH:9]2)=[CH:4][CH:3]=1.[NH2:30][C:31]1[S:32][CH:33]=[CH:34][N:35]=1.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH:17]([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)[C:18]([CH3:22])([CH3:23])[C:19]([NH:30][C:31]4[S:32][CH:33]=[CH:34][N:35]=4)=[O:21])=[CH:14][CH:15]=3)[CH:10]=[CH:9]2)=[CH:6][CH:7]=1
Reactant: CC(C)(C(=O)O)C(c1ccccc1)c1ccc2c(ccn2-c2ccc(F)cc2)c1
Reactant: Nc1nccs1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C(=O)Nc1nccs1)C(c1ccccc1)c1ccc2c(ccn2-c2ccc(F)cc2)c1
Temperature: 80 °C
Reaction time: 5 h
Yield: 22 %

Procedure:
To a stirred solution of 3-(1-(4-fluorophenyl)-1H-indol-5-yl)-2,2-dimethyl-3-phenylpropanoic acid (23 mg, 0.059 mmol), 2-aminothiazole (18 mg, 0.18 mmol), and diisopropylethylamine (0.03 mL, 0.18 mmol) in anhydrous DMF (0.3 mL) was added HATU (68 mg, 0.18 mmol) under argon. The reaction mixture was stirred at rt for 5 min and at 80° C. for 5 hr. Concentration and purification using reverse phase HPLC (YMC S5 20×100 mm, 10 min. run, solvent A: 10% MeOH: 90% H2O: 0.1% TFA, solvent B: 90% MeOH, 10% H2O, 0.1% TFA) gave 3-(1-(4-fluorophenyl)-1H-indol-5-yl)-2,2-dimethyl-3-phenyl-N-(thiazol-2-yl)propanamide (Example 110, 6 mg, 0.013 mmol, 22% yield) as a pink solid. MS found: (M+H)+=470. 1H-NMR (400 MHz, CDCl3) δ ppm 7.67 (1H, s) 7.32-7.43 (5H, m) 7.33 (1H, d, J=8.65 Hz) 7.22-7.28 (3H, m) 7.14-7.20 (4H, m) 6.94 (1H, d, J=3.56 Hz) 6.60 (1H, d, J=3.05 Hz) 4.59 (1H, s) 1.46 (6H, d, J=2.54 Hz).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[O:16][C:17]3[CH:23]=[C:22]([C:24]4[CH:25]([CH2:31][CH3:32])[CH2:26][C:27](=[O:30])[NH:28][N:29]=4)[CH:21]=[CH:20][C:18]=3[N:19]=2)=[CH:11][CH:10]=1)C1C=CC=CC=1.[H][H]>[Pd].CO>[CH2:31]([CH:25]1[C:24]([C:22]2[CH:21]=[CH:20][C:18]3[N:19]=[C:15]([C:12]4[CH:13]=[CH:14][C:9]([OH:8])=[CH:10][CH:11]=4)[O:16][C:17]=3[CH:23]=2)=[N:29][NH:28][C:27](=[O:30])[CH2:26]1)[CH3:32]
Reactant: CCC1CC(=O)NN=C1c1ccc2nc(-c3ccc(OCc4ccccc4)cc3)oc2c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CCC1CC(=O)NN=C1c1ccc2nc(-c3ccc(O)cc3)oc2c1

Procedure:
235 mg (552 μmol) 6-[2-(4-benzyloxy-phenyl)-benzoxazol-6-yl]-5-ethyl-4,5-dihydro-2H-pyridazin-3-one are hydrogenated together with 50 mg palladium on charcoal 10% and 50 ml of methanol at RT and 3.45 bar hydrogen pressure for 2.5 h, then the catalyst is filtered off and the filtrate is evaporated down completely i.V.
Reaction SMILES: C[O:2][C:3]1[C:11]2[CH:10]=[C:9]([C:12]3[O:13][C:14]([CH3:17])=[N:15][N:16]=3)[O:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.B(Br)(Br)Br>>[OH:2][C:3]1[C:11]2[CH:10]=[C:9]([C:12]3[O:13][C:14]([CH3:17])=[N:15][N:16]=3)[O:8][C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: COc1cccc2oc(-c3nnc(C)o3)cc12
Agent: BrB(Br)Br
Product: Cc1nnc(-c2cc3c(O)cccc3o2)o1
Yield: 54.1 %

Procedure:
By the reactions in the same manner as in Starting Material Synthesis Example 5 using 2-(4-methoxybenzo(b)furan-2-yl)-5-methyl-1,3,4-oxadiazole (6.5 g) and boron tribromide (27 ml), the title compound (3.3 g) was obtained as yellow crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:10]2[CH:22]([CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:21]3[C:12]([C:13]4[CH:14]=[CH:15][C:16]([C:28](O)=[O:29])=[N:17][C:18]=4[CH2:19][CH2:20]3)=[N:11]2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[CH2:31]([CH2:33][NH2:34])[OH:32].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>ClCCl.O.CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([N:10]2[CH:22]([CH:23]3[CH2:24][CH2:25][CH2:26][CH2:27]3)[CH:21]3[C:12]([C:13]4[CH:14]=[CH:15][C:16]([C:28]([NH:34][CH2:33][CH2:31][OH:32])=[O:29])=[N:17][C:18]=4[CH2:19][CH2:20]3)=[N:11]2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: N#Cc1ccc(N2N=C3c4ccc(C(=O)O)nc4CCC3C2C2CCCC2)cc1Cl
Reactant: NCCO
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccc(N2N=C3c4ccc(C(=O)NCCO)nc4CCC3C2C2CCCC2)cc1Cl
Temperature: 30 °C
Reaction time: 16 h
Yield: 19.2 %

Procedure:
In a dried reaction flask, the crude 2-(3-chloro-4-cyanophenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-pyrazolo[3,4-f]quinoline-7-carboxylic acid (0.4 g, about 0.9 mmol), ethanol amine (0.35 mL, 5.8 mmol), DIEA (0.68 mL, 3.93 mmol) and HATU (1.466 g, 3.856 mmol) were added to a mixed solvent of DMF (4.5 mL) and dichloromethane (4.5 mL). The reaction solution was stirred at room temperature for 4 days and at 30° C. for 16 hr. Water and dichloromethane were added. The mixture was extracted with dichloromethane. The combined organic phase was washed with water and saturated salt water, dried over anhydrous sodium sulfate, and concentrated at reduced pressure to produce a crude yellow solid, which was purified by preparative chromatography to obtain a purified product (80 mg) in 19.2% yield.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6](Cl)[C:5]([CH3:12])=[C:4]([CH3:13])[N:3]=1.C(N(CC)CC)C.[CH2:21](N)[CH:22]([CH3:24])[CH3:23].O>CN(C=O)C>[Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([CH2:21][CH:22]([CH3:24])[CH3:23])[C:5]([CH3:12])=[C:4]([CH3:13])[N:3]=1
Reactant: CC(C)CN
Reactant: Cc1nc(Cl)c([N+](=O)[O-])c(Cl)c1C
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1nc(Cl)c([N+](=O)[O-])c(CC(C)C)c1C

Procedure:
A modification of the method described in Part A of Example 4 was used to treat 2,4-dichloro-5,6-dimethyl-3-nitropyridine (Dellaria et al, U.S. Pat. No. 6,545,016, Example 7, Part A, 50.0 g, 0.194 mol) with triethylamine (47 mL, 0.34 mol) and isobutylamine (27 mL, 0.27 mol) in anhydrous DMF (500 mL). The work-up procedure was as follows. The reaction mixture was poured into hot water (1 L). The resulting mixture was extracted with chloroform (2×800 mL), and the combined extracts were dried over magnesium sulfate, filtered through a layer of CELITE filter agent, and concentrated under reduced pressure to provide 60.78 g of 2-chloro-5,6-dimethyl-4-(2-methylpropyl)-3-nitropyridine as a bright orange solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([S:11][CH2:12][C:13](=O)[CH3:14])[C:6]=1[F:16])[CH3:2].Cl.[Cl:19][C:20]1[C:21]([F:28])=[C:22]([NH:26]N)[CH:23]=[CH:24][CH:25]=1>>[CH2:1]([O:3][C:4](=[O:17])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([S:11][C:12]2[C:23]3[C:22](=[C:21]([F:28])[C:20]([Cl:19])=[CH:25][CH:24]=3)[NH:26][C:13]=2[CH3:14])[C:6]=1[F:16])[CH3:2]
Reactant: NNc1cccc(Cl)c1F
Reactant: CCOC(=O)c1cccc(SCC(C)=O)c1F
Agent: Cl
Product: CCOC(=O)c1cccc(Sc2c(C)[nH]c3c(F)c(Cl)ccc23)c1F

Procedure:
Prepared according to the procedure described in Example 2, Step 1, using the following starting materials: 2-Fluoro-3-(2-oxo-propylsulfanyl)-benzoic acid ethyl ester and (3-chloro-2-fluoro-phenyl) hydrazine hydrochloride
Reaction SMILES: C([Li])CCC.[O:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[CH:8]=[CH:7]1.[CH3:15][N:16]1[CH2:21][CH2:20][C:19](=[O:22])[CH:18]([CH3:23])[CH2:17]1>CCCCCC.C(OCC)C>[O:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[CH:8]=[C:7]1[C:19]1([OH:22])[CH2:20][CH2:21][N:16]([CH3:15])[CH2:17][CH:18]1[CH3:23]
Reactant: c1ccc2occc2c1
Reactant: CC1CN(C)CCC1=O
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: CC1CN(C)CCC1(O)c1cc2ccccc2o1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
50 ml of a bimolar solution of n-butyl lithium in hexane is added dropwise within 30 minutes, at a reaction temperature of -5°, to a solution of 11.8 g of benzofuran in 100 ml of diethyl ether. The solution is then stirred for a further hour at 0°. There is thereupon made within 15 minutes a dropwise addition of a solution of 1,3-dimethyl-4-piperidone in 50 ml of abs. diethyl ether. The reaction temperature is maintained at 0° by external cooling. The reaction solution is subsequently stirred for a further 15 hours at room temperature. It is then poured, with stirring, onto 200 g of ice, and the aqueous phase extracted three times with 500 ml of ethyl acetate each time. The combined organic extracts are dried over sodium sulphate, filtered, and concentrated by evaporation. The residue is dissolved in 500 ml of 2 N hydrochloric acid and the acid solution washed with ether. The aqueous solution is thereupon adjusted by addition of 10% sodium hydroxide solution to pH 12, and extracted with 1 liter of chloroform. The chloroform solution is dried with sodium sulphate, filtered off under suction, and concentrated by evaporation to obtain 4-(2-benzofuranyl)-1,3-dimethyl-4-piperidinol, which melts at 128°-130° after recrystallisation from hexane.
Reaction SMILES: C(OC([N:8]1[C@@H:12](/[CH:13]=[C:14](/[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)\[CH2:15][CH3:16])[CH2:11][O:10]C1(C)C)=O)(C)(C)C.Cl>>[NH2:8][C@@H:12](/[CH:13]=[C:14](/[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)\[CH2:15][CH3:16])[CH2:11][OH:10]
Reactant: CC/C(=C\[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C)c1ccccc1
Agent: Cl
Product: CC/C(=C\[C@H](N)CO)c1ccccc1

Procedure:
In analogy to example 162d (S)-2,2-dimethyl-4-((E)-2-phenyl-but-1-enyl)-oxazolidine-3-carboxylic acid tert-butyl ester was reacted with hydrogen chloride to give (E)-(S)-2-amino-4-phenyl-hex-3-en-1-ol. Yellow crystalline solid.
Reaction SMILES: [CH:1]([C:3]1[O:7][CH:6]=[C:5]([C:8]2[C:18]3[O:17][CH2:16][CH2:15][N:14]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:13][C:12]=3[CH:11]=[CH:10][CH:9]=2)[CH:4]=1)=O.O.NN.C(O)CO.[OH-].[K+]>O.CO>[CH3:1][C:3]1[O:7][CH:6]=[C:5]([C:8]2[C:18]3[O:17][CH2:16][CH2:15][N:14]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:13][C:12]=3[CH:11]=[CH:10][CH:9]=2)[CH:4]=1
Reactant: CC(C)(C)OC(=O)N1CCOc2c(cccc2-c2coc(C=O)c2)C1
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: OCCO
Solvent: CO
Product: Cc1cc(-c2cccc3c2OCCN(C(=O)OC(C)(C)C)C3)co1
Temperature: 70 °C
Reaction time: 0.17 h
Yield: 25 %

Procedure:
A mixture of tert-butyl 9-(5-formyl-3-furyl)-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (300 mg, 0.874 mmol), hydrazine monohydrate (0.100 ml, 2.06 mmol), ethylene glycol (6 ml) and methanol (4 ml) was stirred at 70° C. for 10 min. After cooling to room temperature, potassium hydroxide (147 mg, 2.62 mmol) was added, and the mixture was stirred at 100° C. for 1 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1) to give the desired product (72.0 mg, 25.0%) as an oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.[C:13]([N:21]=[C:22]([S-])[S-:23](C)[CH3:24])(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>ClCCl>[CH3:24][S:23][C:22]([N:10]1[CH2:9][CH2:8][N:7]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=2)[CH2:12][CH2:11]1)=[N:21][C:13](=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: C[S-](C)C([S-])=NC(=O)c1ccccc1
Reactant: c1ccc(N2CCNCC2)nc1
Solvent: ClCCl
Product: CSC(=NC(=O)c1ccccc1)N1CCN(c2ccccn2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 95.2 %

Procedure:
To a mixture of 1-(2-pyridyl)piperazine (10 ml, 64.37 mmol) in dichloromethane (200 ml) was added N-benzoyldimethyldithioimidocarbonate (14.64 g, 65.01 mmol) and the reaction mixture was stirred for 18 h at room temperature. The volatiles were evaporated in vacuo and the residue crystallised from a mixture of heptane/diethyl ether 9:1. The solid was filtered off, washed with a mixture of heptane/diethyl ether 1:1 and dried in vacuo affording 20.86 g of N-[methylsulfanyl-(4-(pyridin-2-yl)piperazin-1-yl)methylene]-benzamide as a solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([C:20]([F:23])([F:22])[F:21])[NH:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.Br[CH:25]([CH2:28]Br)[C:26]#[N:27].C(=O)([O-])[O-].[K+].[K+].C(N(CC)CC)C>CN(C=O)C>[F:19][C:16]1[CH:17]=[CH:18][C:13]([C:12]2[N:11]=[C:10]([C:20]([F:22])([F:21])[F:23])[N:9](/[CH:28]=[CH:25]/[C:26]#[N:27])[C:8]=2[C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)=[CH:14][CH:15]=1
Reactant: N#CC(Br)CBr
Reactant: Fc1ccc(-c2nc(C(F)(F)F)[nH]c2-c2ccc(F)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: N#C/C=C/n1c(C(F)(F)F)nc(-c2ccc(F)cc2)c1-c1ccc(F)cc1
Yield: 41.1 %

Procedure:
From 4,5-bis(4-fluorophenyl)-2-trifluoromethyl-1H-imidazole (3.045 g), 2,3-dibromopropionitrile (5.33 g), anhydrous potassium carbonate (3.1 g) and triethylamine (5.2 ml) in dry DMF (19 ml) by the process as described for the preparation of Intermediate (3 a) to afford a dark brown residue which was purified by FCC using gradient elution with System A (5-15% with 5% incremental increase of ethyl acetate per 500 ml eluant) to afford the title compound (1.449 g) as a white solid. νmax (CHBr3) 2229 cm-1 (C≡N).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]1[CH2:12][CH2:11][NH:10][C:9]1=[O:13].Br[C:15]1[CH:24]=[CH:23][C:18]2[O:19][CH2:20][CH2:21][O:22][C:17]=2[CH:16]=1.N[C@@H]1CCCC[C@H]1N.C(=O)([O-])[O-].[K+].[K+]>[Cu](I)I.O1CCOCC1>[O:19]1[C:18]2[CH:23]=[CH:24][C:15]([N:10]3[CH2:11][CH2:12][N:8]([C:3]4[CH:4]=[N:5][CH:6]=[CH:7][C:2]=4[CH3:1])[C:9]3=[O:13])=[CH:16][C:17]=2[O:22][CH2:21][CH2:20]1
Reactant: Cc1ccncc1N1CCNC1=O
Reactant: Brc1ccc2c(c1)OCCO2
Agent: I[Cu]I
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: Cc1ccncc1N1CCN(c2ccc3c(c2)OCCO3)C1=O
Yield: 42.1 %

Procedure:
Using the same reaction conditions as in Example 14, 1-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (I-14b: 150 mg, 0.84 mmol) was reacted with 6-bromo-2,3-dihydro-benzo[1,4]dioxine (180 mg, 0.84 mmol), 1,4-dioxane (10 mL), copper iodide (16 mg, 0.084 mmol), trans-1,2-diamino cyclohexane (28.8 mg, 0.25 mmol) and potassium carbonate (231 mg, 1.68 mmol) to afford the crude product. Purification by column chromatography on silica gel (1% MeOH in CHCl3) afforded 110 mg of the product (42.1% yield).
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2]([CH3:4])=[CH2:3].[CH3:7][CH:8]([CH2:10][CH2:11][CH2:12][C@H:13]([C@@H:15]1[C@:33]2([CH3:34])[C@H:18]([C@H:19]3[C@H:30]([CH2:31][CH2:32]2)[C@:28]2([CH3:29])[C:22]([CH2:23][C@H:24]([CH2:26][CH2:27]2)[OH:25])=[CH:21][CH2:20]3)[CH2:17][CH2:16]1)[CH3:14])[CH3:9].C(N(CC)CC)C>ClCCl>[CH3:14][C@@H:13]([C@@H:15]1[C@@:33]2([CH3:34])[CH2:32][CH2:31][C@@H:30]3[C@@:28]4([CH3:29])[CH2:27][CH2:26][C@H:24]([O:25][C:1]([C:2]([CH3:4])=[CH2:3])=[O:5])[CH2:23][C:22]4=[CH:21][CH2:20][C@H:19]3[C@@H:18]2[CH2:17][CH2:16]1)[CH2:12][CH2:11][CH2:10][CH:8]([CH3:7])[CH3:9]
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: C=C(C)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=C(C)C(=O)O[C@H]1CC[C@@]2(C)C(=CC[C@H]3[C@@H]4CC[C@H]([C@H](C)CCCC(C)C)[C@@]4(C)CC[C@@H]32)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 6 ml of methacryloyl chloride in 30 ml of dichloromethane is added dropwise to 20 g (51.72 mmol) of cholesterol and 8 ml of triethylamine in 170 ml of dichloromethane (abs.). The mixture is stirred overnight at room temperature. The solvent is distilled off under reduced pressure, and the residue is recrystallized three times from the ca. 400 ml of ethanol (95%). Drying is carried out at a pressure of 10−2 mbar for 24 h
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH:4]([C:9](=[O:18])[C:10]1[CH:15]=[CH:14][C:13]([Br:16])=[C:12]([F:17])[CH:11]=1)/[C:5](=[N:7]/C)/[CH3:6].Cl.NO>>[CH3:1][O:2][C:3]([C:4]1[C:5]([CH3:6])=[N:7][O:18][C:9]=1[C:10]1[CH:15]=[CH:14][C:13]([Br:16])=[C:12]([F:17])[CH:11]=1)=[O:19]
Reactant: C/N=C(\C)C(C(=O)OC)C(=O)c1ccc(Br)c(F)c1
Agent: Cl
Agent: NO
Product: COC(=O)c1c(C)noc1-c1ccc(Br)c(F)c1

Procedure:
Following the procedures described in Example 36: 4-bromo-3-fluorobenzoyl chloride and oxalyl chloride were reacted to provide 4-bromo-3-fluoro-benzoyl chloride, which was then reacted with 3-methylamino-but-2-enoic acid methyl ester to provide 2-(4-bromo-3-fluoro-benzoyl)-3-[(E)-methylimino]-butyric acid methyl ester. 2-(4-bromo-3-fluoro-benzoyl)-3-[(E)-methylimino]-butyric acid methyl ester and hydroxylamine hydrochloride were then reacted as described in Example 36, Step 3 to provide 5-(4-bromo-3-fluoro-phenyl)-3-methyl-isoxazole-4-carboxylic acid methyl ester, which was then hydrolyzed to 5-(4-bromo-3-fluoro-phenyl)-3-methyl-isoxazole-4-carboxylic acid as described in Example 36, Step 4. 5-(4-Bromo-3-fluoro-phenyl)-3-methyl-isoxazole-4-carboxylic acid and (R)-1-(2-chloro-phenyl)-ethanol were reacted to provide [5-(4-Bromo-3-fluoro-phenyl)-3-methyl-isoxazol-4-yl]-carbamic acid (R)-1-(2-chloro-phenyl)-ethyl ester as described in Example 36, Step 5.
Reaction SMILES: [C:1]([C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[C:6]([Cl:13])[C:5]=1[S:14]([NH2:17])(=[O:16])=[O:15])(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:24](Br)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.Cl>CN(C)C=O>[CH2:24]([NH:17][S:14]([C:5]1[C:6]([Cl:13])=[CH:7][CH:8]=[C:9]([N+:10]([O-:12])=[O:11])[C:4]=1[C:1](=[O:3])[CH3:2])(=[O:15])=[O:16])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CC(=O)c1c([N+](=O)[O-])ccc(Cl)c1S(N)(=O)=O
Reactant: BrCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)c1c([N+](=O)[O-])ccc(Cl)c1S(=O)(=O)NCc1ccccc1
Temperature: 75 °C
Yield: 44 %

Procedure:
A mixture of 2-acetyl-6-chloro-3-nitrobenzenesulfonamide (500 mg, 1.69 mmol), potassium carbonate (469 mg, 3.39 mmnol) and benzyl bromide (0.24 mL, 2.0 mmol) in 20 mL of N,N-dimethylformamide was heated to 75° C for 24 hours. The mixture was acidified with 1 N aq. HCl, then extracted with ethyl acetate. The solvent was concentrated to give the crude material. Column chromatography on silica gel, eluting with ethyl acetate/hexane/acetic acid (50/49/1, v/v/v), gave the desired product (274 mg, 42%). EI-MS (m/z) 383.3, 385.3 (M−).
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH:7]2[CH2:8][CH2:9][CH2:10][CH:6]2[CH2:5][N:4]1[C:11]([C:13]1[CH:18]=[C:17]([CH3:19])[CH:16]=[CH:15][C:14]=1[N:20]1[N:24]=[CH:23][CH:22]=[N:21]1)=[O:12].Cl[C:26]1[O:27][C:28]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][C:29]=2[N:30]=1>>[Cl:35][C:32]1[CH:33]=[CH:34][C:28]2[O:27][C:26]([NH:1][CH2:2][CH:3]3[CH:7]4[CH2:8][CH2:9][CH2:10][CH:6]4[CH2:5][N:4]3[C:11]([C:13]3[CH:18]=[C:17]([CH3:19])[CH:16]=[CH:15][C:14]=3[N:20]3[N:24]=[CH:23][CH:22]=[N:21]3)=[O:12])=[N:30][C:29]=2[CH:31]=1
Reactant: Cc1ccc(-n2nccn2)c(C(=O)N2CC3CCCC3C2CN)c1
Reactant: Clc1ccc2oc(Cl)nc2c1
Product: Cc1ccc(-n2nccn2)c(C(=O)N2CC3CCCC3C2CNc2nc3cc(Cl)ccc3o2)c1

Procedure:
The title compound was prepared following the same general protocol as described for Example A2 using (1-(aminomethyl)hexahydrocyclopenta[c]pyrrol-2(1H)-yl)(5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone and 2,5-dichlorobenzoxazole. MS (ESI) 477 (M+H).
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[O:7][C:6](=[O:8])[N:5]([C:9]2[CH:18]=[C:17]3[C:12]([CH:13]=[C:14]([CH:20](OCC)OCC)[NH:15][C:16]3=[O:19])=[CH:11][CH:10]=2)[CH2:4]1.[CH2:27]([NH:29][C:30]1[C:31]([NH2:36])=[CH:32][CH:33]=[CH:34][CH:35]=1)[CH3:28]>>[CH2:27]([N:29]1[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[N:36]=[C:20]1[C:14]1[NH:15][C:16](=[O:19])[C:17]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[C:9]([N:5]1[CH2:4][C@H:3]([CH2:2][OH:1])[O:7][C:6]1=[O:8])[CH:18]=2)[CH3:28]
Reactant: CCNc1ccccc1N
Reactant: CCOC(OCC)c1cc2ccc(N3C[C@H](CO)OC3=O)cc2c(=O)[nH]1
Product: CCn1c(-c2cc3ccc(N4C[C@H](CO)OC4=O)cc3c(=O)[nH]2)nc2ccccc21
Reaction time: 0.5 h
Yield: 74.2 %

Procedure:
Purified water (0.01 ml) and TFA (0.01 ml) were added to a dichloromethane solution that contained the 7-((R)-5-hydroxymethyl-2-oxooxazolidin-3-yl)-3-diethoxymethyl-2H-isoquinolin-1-one (3.3 mg, 0.009 mmol) prepared in step C. The obtained mixture was left at a room temperature for 30 minutes, and the reaction solution was concentrated. The obtained yellow solid and an ethanol solution that contained N-ethyl-1,2-benzenediamine (1.2 mg, 0.009 mmol), which was a known compound described in a publication (Leicester Polytech; Synthetic Communications, vol. 19(7-8), p. 1381, (1989)), were heated to reflux for 17 hours. Thereafter, the reaction solution was concentrated. The obtained residue was purified by preparative silica gel TLC (dichloromethane:methanol=20:1), so as to obtain 3-(1-ethyl-1H-benzoimidazol-2-yl)-7-((R)-5-hydroxymethyl-2-oxooxazolidin-3-yl)-2H-isoquinolin-1-one (2.7 mg, yield: 74%) in the form of a yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][OH:11])=[CH:4][CH:3]=1.[Cl:12][C:13]1[C:18]([F:19])=[CH:17][CH:16]=[C:15]([F:20])[C:14]=1O.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C(P(CCCC)CCCC)CCC>CCOCC.C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][CH2:10][O:11][C:14]2[C:13]([Cl:12])=[C:18]([F:19])[CH:17]=[CH:16][C:15]=2[F:20])=[CH:6][CH:7]=1
Reactant: OCCCc1ccc(Br)cc1
Reactant: Oc1c(F)ccc(F)c1Cl
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: Fc1ccc(F)c(OCCCc2ccc(Br)cc2)c1Cl
Temperature: 80 °C

Procedure:
3-(4-Bromophenyl)propan-1-ol from the previous step (1 eq.) and 2-chloro-3,6-difluorophenol (1 eq.) were taken up in freshly deoxygenated toluene (0.3 M). To this solution was then added 1,1′-(azodicarbonyl)-dipiperidine (1.2 eq.) and finally tributylphosphine (1.2 eq.). The resulting yellow solution was heated at 80° C. for 2 h. The reaction mixture was cooled to RT, diluted with ether, and washed with 1 N aq. NaOH. The aqueous wash was back extracted with ether and the combined organic extracts were dried over MgSO4. Filtration and concentration of the filtrate in vacuo afforded a yellow semi-solid. Purification of the crude product thus obtained by way of flash chromatography (SiO2, Hex→15:1 (v/v) Hex:EtOAc) afforded the title compound as a colorless oil.