Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([CH:11]=O)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[CH3:13][C:14]([S:17]([NH2:19])=[O:18])([CH3:16])[CH3:15]>C1COCC1.C(OCC)(=O)C.[O-]CC.[Ti+4].[O-]CC.[O-]CC.[O-]CC>[O:4]1[C:5]2([CH2:6][CH2:7][CH:8](/[CH:11]=[N:19]/[S:17]([C:14]([CH3:16])([CH3:15])[CH3:13])=[O:18])[CH2:9][CH2:10]2)[O:1][CH2:2][CH2:3]1
Reactant: CC(C)(C)S(N)=O
Reactant: O=CC1CCC2(CC1)OCCO2
Agent: [Ti+4]
Agent: CC[O-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)S(=O)/N=C/C1CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 1,4-dioxaspiro[4.5]decane-8-carbaldehyde (6.68 g, 39.2 mmol, prepared as described in Pearson, et al. in J. Org. Chem. 1997, 62(16), 5284-5292), racemic 2-methylpropane-2-sulfinamide (3.50 g, 28.0 mmol), tech grade titanium (IV) ethoxide (14 mL, 67.5 mmol) were dissolved in dry THF (100 mL), placed under an argon atmosphere and stirred at ambient temperature for 16 hours. The next day the reaction mixture was diluted with ethyl acetate and poured onto rapidly stirred ice cold brine. The copious white precipitate was removed by filtration through celite and the organic layer removed. After drying over Na2SO4 and concentration the residue was purified by flash chromatography (silica gel, 0-100% ether/DCM) to afford the product.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([C:9]2[C:17]3[C:12](=[N:13][CH:14]=[CH:15][CH:16]=3)[O:11][N:10]=2)[CH:6]=[CH:7][CH:8]=1.B(Br)(Br)Br>ClCCCl>[O:11]1[C:12]2=[N:13][CH:14]=[CH:15][CH:16]=[C:17]2[C:9]([C:5]2[CH:4]=[C:3]([OH:2])[CH:8]=[CH:7][CH:6]=2)=[N:10]1
Reactant: COc1cccc(-c2noc3ncccc23)c1
Agent: BrB(Br)Br
Solvent: ClCCCl
Product: Oc1cccc(-c2noc3ncccc23)c1
Temperature: 50 °C
Reaction time: 8 h
Yield: 90.1 %

Procedure:
Combine 3-(3-methoxy-phenyl)-isoxazolo[5,4-b]pyridine (4.97 g, 21.97 mmol) and 1,2-dichloroethane (anhydrous, 50 mL), under a nitrogen atmosphere and cool (˜5° C.). Add a solution of boron tribromide (19.26 g, 77.89 mmol) in 1,2-dichloroethane (20 mL), dropwise and stir at 50° C. overnight. Cool (0° C.) the reaction mixture and quench with a solution of sodium hydrogen carbonate, dropwise. Pour the reaction mixture over a solution of dilute sodium hydrogen carbonate (˜300 mL) and stir for 1 hour. Filter and collect the solid. Extract the filtrate with chloroform, dry (Na2SO4), filter, evaporate, and combine with previously collected solid. Triturate with ether, filter and dry under vacuum to give the title compound as a white solid (4.2 g, 90% Yield). Microanalysis (C, H, N) is consistent with the final, desired compound. mp=175-178° C.
Reaction SMILES: [Na].[CH3:2][O:3][C:4](=[O:26])[CH2:5][N:6]1[C:14](=[O:15])[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:16][C:17]3[C:22]([CH3:23])=[CH:21][CH:20]=[CH:19][C:18]=3[CH3:24])[CH:12]=2)[C:7]1=[O:25].Cl.CCOC(C)=O.[CH2:34](O)[CH2:35][CH2:36]C>>[CH2:2]([O:3][C:4]([C:5]1[N:6]=[C:7]([OH:25])[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][C:11]([O:16][C:17]1[C:22]([CH3:23])=[CH:21][CH:20]=[CH:19][C:18]=1[CH3:24])=[CH:10][CH:9]=2)=[O:26])[CH2:34][CH2:35][CH3:36]
Reactant: COC(=O)CN1C(=O)c2ccc(Oc3c(C)cccc3C)cc2C1=O
Reactant: CCCCO
Agent: Cl
Agent: [Na]
Solvent: CCOC(C)=O
Product: CCCCOC(=O)c1nc(O)c2ccc(Oc3c(C)cccc3C)cc2c1O
Temperature: 70 °C
Reaction time: 3 h
Yield: 43 %

Procedure:
Sodium (1 eq) was dissolved in n-butanol (1.6 mL/mmol) with stirring at 70° C. Subsequently, the temperature was raised to 95° C. before a solution of [5-(2,6-Dimethyl-phenoxy)-1,3-dioxo-1,3-dihydro-isoindol-2-yl]-acetic acid methyl ester (0.5 eq) in hot n-butanol (2.3 mL/mmol) was added in one portion with stirring. Stirring was continued at 95° C. for 3 h before the mixture was concentrated in vacuo. To the residue was added 2 N hydrochloric acid (1.3 eq) and EtOAc (ca. 4-fold volume) and the mixture was stirred vigorously for 45 min. Subsequently, the solid component was sucked off, washed with water and dried in vacuo before it was suspended in EtOAc (ca. 20 mL/g) and the mixture was refluxed with stirring for 2 h. After cooling to ambient temperature the solid component was sucked off, washed with EtOAc and dried in vacuo to give the title compound as an off-white solid (yield: 43%); MS-(+)-ion: M+1=382.5
Reaction SMILES: [OH:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[OH:12])=[O:5].[CH3:17]S(C)=O.BrCBr.C(=O)([O-])[O-].[K+].[K+]>O.[OH-].[Na+]>[CH:13]1[C:3]2[C:4](=[O:5])[C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[O:12][CH2:17][O:1][C:2]=2[CH:16]=[CH:15][CH:14]=1
Reactant: CS(C)=O
Reactant: O=C(c1ccccc1O)c1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: BrCBr
Product: O=C1c2ccccc2OCOc2ccccc21
Reaction time: 1.5 h

Procedure:
A mixture of 21.4 g (100 mmol) of 2,2'-dihydroxybenzophenone, 150 mL of anhydrous dimethyl sulfoxide, 20.9 g (120 mmol) of dibromomethane, and 30.4 g of dry powdered potassium carbonate was prepared and was heated by means of an oil bath set at 75° C. and stirred. The temperature rose to 87° C. over a 15-min period and then dropped. After another 1.5 hours, the mixture was cooled, diluted with 250 mL of water and 100 mL of 1N aqueous sodium hydroxide. This mixture was extracted with ether (2×100 mL) and the combined ether extracts were washed with water (2×100 mL), dried over sodium sulfate, and concentrated by evaporation under reduced pressure to obtain 19.4 g of a light yellow, mostly solid residue. The residue was recrystallized from 50 mL of a 1:1 benzene/hexane mixture and washed with hexane to obtain, after drying at 75° C. under reduced pressure, 12.4 g (71 percent of theory) of the title compound as a white solid melting at 92.5°-94° C.
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[CH:12]1[CH2:15][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:13]1>CN.CO>[NH2:3][CH:12]1[CH2:13][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:15]1
Reactant: CC(C)(C)OC(=O)N1CC(N2C(=O)c3ccccc3C2=O)C1
Agent: CN
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC(N)C1

Procedure:
A solution of tert-butyl 3-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-1-azetidinecarboxylate (Preparation 77) in methylamine in methanol (2M) (10 ml) was stirred in a sealed tube at 55° C. for 3 hours. On cooling a precipitate formed and the reaction mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (100 ml) and washed with water (100 ml, containing (2M) hydrochloric acid (3 ml)) and water (50 ml, containing (2M) hydrochloric acid (2 ml)). The combined aqueous was basified with (2M) sodium hydroxide solution (20 ml) and extracted with ethyl acetate (3×75ml). The combined organic layers were dried over anhydrous magnesium sulphate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with a gradient system of 97.5:2.5:0.25 (dichloromethane:methanol:ammonia) gradually changing to 90:10:1 (dichloromethane:methanol:ammonia) to afford the title compound (935 mg) of approximately 90% purity, which was used in preparation without further purification.
Reaction SMILES: [OH:1][C@H:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[C@@H:4]([CH2:5][CH2:6][C@:7]3([CH3:31])[CH:16]2[CH2:15][CH2:14][C@H:13]2[C@@:8]3([CH3:30])[CH2:9][CH2:10][C@@:11]3([C:27]([OH:29])=[O:28])[CH2:23][CH2:22][C@@H:21]([C:24]([CH3:26])=[CH2:25])[C@@H:12]32)[C:3]1([CH3:33])[CH3:32].[N+](=[CH:36][Si](C)(C)C)=[N-]>CO.C1(C)C=CC=CC=1>[OH:1][C@H:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[C@@H:4]([CH2:5][CH2:6][C@:7]3([CH3:31])[CH:16]2[CH2:15][CH2:14][C@H:13]2[C@@:8]3([CH3:30])[CH2:9][CH2:10][C@@:11]3([C:27]([O:29][CH3:36])=[O:28])[CH2:23][CH2:22][C@@H:21]([C:24]([CH3:26])=[CH2:25])[C@@H:12]32)[C:3]1([CH3:33])[CH3:32]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: C=C(C)[C@@H]1CC[C@]2(C(=O)O)CC[C@]3(C)[C@H](CCC4[C@@]5(C)CC[C@H](O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Solvent: CO
Solvent: Cc1ccccc1
Product: C=C(C)[C@@H]1CC[C@]2(C(=O)OC)CC[C@]3(C)[C@H](CCC4[C@@]5(C)CC[C@H](O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 25 °C
Reaction time: 3 h
Yield: 97 %

Procedure:
To a solution of (1R,3aS,5aR,5bR,7aR,9S,11aR,13aR,13bR)-9-hydroxy-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysene-3a-carboxylic acid (1 g, 2.190 mmol) in MeOH (5 mL) and toluene (5.00 mL) was added (diazomethyl)trimethylsilane (1.642 mL, 3.28 mmol). The reaction mixture was stirred for 3 hours at room temperature. TLC indicated starting material was consumed and a new product was formed. The reaction mixture was concentrated under reduced pressure to give the desired product (1R,3aS,5aR,5bR,7aR,9S,11aR,13aR,13bR)-methyl 9-hydroxy-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)icosahydro-1H-cyclopenta[a]chrysene-3a-carboxylate as a white solid (1 g, 97%). 1H NMR (500 MHz, DMSO-D6) δ ppm 0.65 (s, 3H), 0.76 (s, 3H), 0.87 (d, J=12.67 Hz, 6H), 0.94 (s, 3H), 0.96-1.63 (m, 18H), 1.65 (s, 3H), 1.72-1.87 (m, 2H), 2.03-2.16 (m, 2H), 2.85-3.09 (m, 3H), 3.60 (s, 3H), 4.26 (d, J=4.58 Hz, 1H), 4.58 (s, 1H), 4.70 (d, J=1.83 Hz, 1H).
Reaction SMILES: C(N(CC)CC)C.CN(C)S([N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)(=O)=O.Cl[C:21]1[N:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][N:22]=1>C1COCC1>[N+:27]([C:24]1[CH:23]=[N:22][C:21]([CH:15]2[CH2:14][NH:13][CH2:18][CH2:17][NH:16]2)=[N:26][CH:25]=1)([O-:29])=[O:28]
Reactant: O=[N+]([O-])c1cnc(Cl)nc1
Reactant: CN(C)S(=O)(=O)N1CCNCC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cnc(C2CNCCN2)nc1

Procedure:
Triethylamine (7.2 mL, 51.8 mmol) was added to a solution of piperazine-1-sulfonic acid dimethyl amide (10 g, 51.8 mmol) dissolved in 400 mL of THF. 2-chloro-5-nitropyrimidine (7.7 g, 48.3 mmol) dissolved in 20 mL of THF was added to the stirred mixture. After 24 hours stirring at room temperature (RT), THF was removed under vacuum and 600 mL of CHCl3 was added to the residue. The CHCl3 layer was washed with 0.5 N HCl and brine, dried over Na2SO4, and filtered. Solvent evaporation gave 14.1 g (92%) of straw yellow solid 1-N,N′-dimethylsulfamoyl-4-(2-(5-nitropyrimidyl)piperazine. The structure was confirmed by 1H-NMR. 1H NMR (CDCl3) δ9.08 (s, 2H), 4.09 (appt, J=5.13 Hz, 4H), 3.35 (appt, J=5.13 Hz, 4H), 2.87 (s, 6H). Step 2: NH4Cl (1.43 g, 26.76 mmol) was added to a suspension of 1-N,N′-dimethylsulfamoyl-4-(2-(5-nitropyrimidyl)piperazine (14.1 g, 44.6 mmol) in a mixture of EtOH (175 mL) and H2O (48 mL), followed by iron powder (7.5 g, 133.9 mmol). After refluxing 1 hour, the reaction mixture was filtered and concentrated to give a brown solid which was dissolved in 800 mL of CHCl3, washed with NaHCO3 and brine, dried over Na2SO4, and filtered. Solvent evaporation gave a yellow solid which after CC with 100:1 CHCl3:MeOH gave 11.5 g (90%) of solid yellow 1-N,N′-dimethylsulfamoyl-4-(2-(5-nitro-pyrimidyl)-piperazine. The structure was confirmed by 1H-NMR and EI-MS. 1H NMR (CDCl3) δ7.98 (s, 2H), 3.76 (t, J=4.88 Hz, 4H), 3.30 (t, J=4.88 Hz, 4H), 2.86 (s, 6H); EI-MS (m/z) 286 (M+). Step 3: A suspension of 1-N,N′-dimethylsulfamoyl-4-(2-(5-nitro-pyrimidyl)-piperazine (5.76 g, 20.2 mmol) in 100 mL of 2 M H2SO4 was refluxed for 1.5 hours until the suspension became clear. After cooling to RT, the solution pH was adjusted to 6-7 with 10 N NaOH, and the cloudy mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, and filtered. Solvent evaporation gave a yellow solid, which was purified by CC using 1:1 EtOAc:hexane to yield 3.23 g (56%) of white solid JHX-2, mp 134-135° C. The structure was confirmed by 1H-NMR, 13C-NMR, ESI-MS and elemental analysis. 1H NMR (CDCl3) δ8.08 (s, 2H), 3.78 (appt, J=5.13 Hz, 4H), 3.29 (appt, J=5.13 Hz, 4H), 2.86 (s, 6H); 13C NMR (CDCl3) 156.9, 145.8, 143.5, 46.0, 44.3, 38.1; EI-MS (m/z) 287 (M+).
Reaction SMILES: COC1N=C([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][C:10]=2[N:15](C)[C:16](=O)C2C=C(C(F)(F)F)C=C(C(F)(F)F)C=2)C=CC=1.[F:33][C:34]1[C:39]([O:40][CH3:41])=[CH:38][CH:37]=[C:36]([F:42])[C:35]=1B(O)O>CCCCCC.CCOC(C)=O>[F:33][C:34]1[C:39]([O:40][CH3:41])=[CH:38][CH:37]=[C:36]([F:42])[C:35]=1[C:9]1[CH:14]=[CH:13][N:12]=[CH:11][C:10]=1[NH:15][CH3:16]
Reactant: COc1ccc(F)c(B(O)O)c1F
Reactant: COc1cccc(-c2ccncc2N(C)C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CNc1cnccc1-c1c(F)ccc(OC)c1F

Procedure:
The title compound was prepared in analogy to compound 284, intermediate, from (4-iodo-pyridin-3-yl)-methyl-amine (example 98, intermediate) and 2,6-difluoro-3-methoxyphenylboronic acid and using a gradient of n-hexane:EtOAc (70:30 to 60:40) for the chromatographic purification. Brown solid (75%). MS (ESI): m/z=251.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:17][CH2:16][C:11]3([O:15][CH2:14][CH2:13][O:12]3)[CH2:10][CH2:9]2)=[CH:4][C:3]=1[O:18][CH3:19].[Cl:20]N1C(=O)CCC1=O.O.[OH-].[Na+]>CC(O)=O>[Cl:20][C:6]1[CH:7]=[C:2]([Cl:1])[C:3]([O:18][CH3:19])=[CH:4][C:5]=1[N:8]1[CH2:9][CH2:10][C:11]2([O:15][CH2:14][CH2:13][O:12]2)[CH2:16][CH2:17]1
Reactant: O=C1CCC(=O)N1Cl
Reactant: COc1cc(N2CCC3(CC2)OCCO3)ccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: COc1cc(N2CCC3(CC2)OCCO3)c(Cl)cc1Cl
Temperature: 60 °C
Yield: 90.7 %

Procedure:
A mixture of 8-(4-chloro-3-methoxyphenyl)-1,4-dioxa-8-azaspiro[4.5]decane (1.67 g, 5.89 mmol, Example 13, step 1) and 1-chloropyrrolidine-2,5-dione (0.786 g, 5.89 mmol) in AcOH (15 mL) was heated at 60° C. overnight. The mixture was cooled and water was added. Upon completion of addition, the mixture was neutralized with 1N NaOH, extracted with EtOAc, dried (Na2SO4), and concentrated to give 8-(2,4-dichloro-5-methoxyphenyl)-1,4-dioxa-8-azaspiro[4.5]decane (1.7 g, 5.34 mmol, 91% yield) as a yellow oil.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([OH:12])=[O:11])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.C(=O)(O)[O-].[Na+].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN(C)C=O>[CH2:18]([O:11][C:10]([C:6]1[CH:5]=[C:4]2[C:9](=[CH:8][CH:7]=1)[NH:1][CH:2]=[CH:3]2)=[O:12])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: BrCc1ccccc1
Reactant: O=C(O)c1ccc2[nH]ccc2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)c1ccc2[nH]ccc2c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of indole-5-carboxylic acid (2.63 g, 16.34 mmol) in N,N-dimethylformamide (50 mL) was added sodium bicarbonate (8.24 g, 98.04 mmol) and benzyl bromide (11.66 mL, 98.04 mmol). The reaction was stirred for 48 hours at ambient temperature under nitrogen. The reaction was then partitioned between ethyl acetate and water. The organic layer was separated and the aqueous extracted with a further portion of ethyl acetate. The combined organic layers were dried (MgSO4) and evaporated in vacuo. The resultant crude product was purified by flash chromatography on SiO2, eluting with 20% ethyl acetate/hexane followed by 50% ethyl acetate/hexane to afford the title compound as an oil, 4.82 g, quantitative.
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][C:5]1([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][C:13]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:7][CH2:6]1.[C:38](OC(=O)C)(=[O:40])[CH3:39].C(=O)([O-])[O-].[K+].[K+].O>C(Cl)Cl>[C:32]1([C:5]2([CH2:4][NH:3][C:38](=[O:40])[CH3:39])[CH2:6][CH2:7][N:8]([CH2:11][CH2:12][C:13]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:9][CH2:10]2)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: CC(=O)OC(C)=O
Reactant: NCC1(c2ccccc2)CCN(CCC(c2ccccc2)(c2ccccc2)c2ccccc2)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: CC(=O)NCC1(c2ccccc2)CCN(CCC(c2ccccc2)(c2ccccc2)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 1 part of 4-aminomethyl-4-phenyl-1-(3,3,3-triphenylpropyl)piperidine dihydrochloride, 1 part by volume of acetic anhydride, 1 part of potassium carbonate, 10 parts by volume of water and 10 parts by volume of methylene chloride is stirred at room temperature for about 4 hours. The organic and aqueous layers are separated, the aqueous layer washed with methylene chloride and the methylene chloride fraction combined with the organic layer. The combined organic fraction is dried over potassium carbonate, the solvent evaporated and the residual colorless amorphous solid crystallized from a mixture of n-hexane and ether to afford N-([4-phenyl-1-(3,3,3-triphenylpropyl)piperidine-4-yl]methyl)acetamide melting at about 154-167° C. This compound is represented by the following structural formula ##STR14##
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:5]([C:7]([N:9]2[CH2:14][C@H:13]3[C@H:11]([CH2:12]3)[C@H:10]2[CH2:15][NH2:16])=[O:8])[N:6]=1.[CH3:24][N:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27]([C:34](O)=[O:35])=[CH:26]1>>[NH2:1][C:2]1[S:3][C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:5]([C:7]([N:9]2[CH2:14][C@H:13]3[C@H:11]([CH2:12]3)[C@H:10]2[CH2:15][NH:16][C:34]([C:27]2[C:28]3[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=3)[N:25]([CH3:24])[CH:26]=2)=[O:35])=[O:8])[N:6]=1
Reactant: NC[C@@H]1[C@H]2C[C@H]2CN1C(=O)c1nc(N)sc1-c1cccc(F)c1
Reactant: Cn1cc(C(=O)O)c2ccccc21
Product: Cn1cc(C(=O)NC[C@@H]2[C@H]3C[C@H]3CN2C(=O)c2nc(N)sc2-c2cccc(F)c2)c2ccccc21

Procedure:
prepared by reaction of [2-Amino-5-(3-fluoro-phenyl)-thiazol-4-yl]-((1S,2S,5R)-2-aminomethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-methanone with 1-Methyl-1H-indole-3-carboxylic acid. LC-MS (basic): tR=0.80 min; [M+H]+=490.1.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[Cl-:12].[Al+3].[Cl-].[Cl-]>ClC1C=CC=CC=1>[Cl:12][C:2]1[CH:10]=[CH:9][C:8]([C:4]([C:3]2[CH:7]=[CH:8][C:9]([CH3:11])=[CH:10][C:2]=2[Cl:1])=[O:5])=[CH:7][CH:3]=1
Reactant: [Cl-]
Reactant: Cc1ccc(C(=O)Cl)c(Cl)c1
Agent: [Al+3]
Solvent: Clc1ccccc1
Product: Cc1ccc(C(=O)c2ccc(Cl)cc2)c(Cl)c1
Temperature: 80 °C
Reaction time: 15 h
Yield: 152.8 %

Procedure:
A stirred 80° C. solution of 2-chloro-4-methylbenzoyl chloride (6.6 g, 39 mmol) in chlorobenzene (10 ml) was treated with aluminum chloride (5.14 g, 38.5 mmol) in portions over 15 minutes. The mixture was stirred 15 hours at 80° C., cooled, quenched by addition of ice and concentrated hydrochloric acid (5 ml), and extracted three times with diethyl ether. The combined extracts were washed with water and saturated aqueous sodium bicarbonate, dried over anhydrous magnesium sulfate, and evaporated under vacuum. The residue was chromatographed on a column of silica gel (250 g) eluted with 7:3 (v/v) n-hexane-dichloromethane to provide 7.9 g (76%) of 4-(4-chlorobenzoyl)-3-chlorotoluene, m.p. 58°-60.5° C.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[C:18]1[N:23]=[C:22]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[N:21]=[C:20]([N:30]2[C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=3[N:32]=[C:31]2[CH:39]([F:41])[F:40])[N:19]=1.O>CN(C)C=O.C(Cl)(Cl)Cl>[F:41][CH:39]([F:40])[C:31]1[N:30]([C:20]2[N:21]=[C:22]([N:24]3[CH2:25][CH2:26][O:27][CH2:28][CH2:29]3)[N:23]=[C:18]([O:1][C:2]3[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=3)[N:19]=2)[C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=2[N:32]=1
Reactant: FC(F)c1nc2ccccc2n1-c1nc(Cl)nc(N2CCOCC2)n1
Reactant: CC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)c1ccc(Oc2nc(N3CCOCC3)nc(-n3c(C(F)F)nc4ccccc43)n2)cc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 12 %

Procedure:
To a solution of 1-(4-hydroxyphenyl)ethanone (5.4 mg) in N,N-dimethylformamide (200 μL) were added potassium carbonate (6.9 mg) and a solution of 1-[4-chloro-6-(morpholin-4-yl)-1,3,5-triazin-2-yl]-2-(difluoromethyl)-1H-benzimidazole (9.2 mg) in N,N-dimethylformamide (300 μL), followed by stirring at 80° C. overnight. To the reaction solution were added water and chloroform at room temperature, followed by liquid-liquid phase separation, and the organic layer was evaporated under reduced pressure. The residue was purified by preparative HPLC to obtain 1-[4-({4-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-6-(morpholin-4-yl)-1,3,5-triazin-2-yl}oxy)phenyl]ethanone (1.4 mg).
Reaction SMILES: [BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].[CH:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23]1[CH:24]=[CH:25][C:26]([C:29]([NH:31][CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])=[O:30])=[N:27][CH:28]=1)=O.[C:39]1([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[CH:44]=[CH:43][C:42]([NH2:45])=[CH:41][CH:40]=1.CC(O)=O>CCOC(C)=O.C1COCC1>[C:39]1([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[CH:40]=[CH:41][C:42]([NH:45][CH2:15][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[C:23]2[CH:24]=[CH:25][C:26]([C:29]([NH:31][CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])=[O:30])=[N:27][CH:28]=2)=[CH:43][CH:44]=1
Reactant: CCOC(=O)CCNC(=O)c1ccc(-c2ccccc2C=O)cn1
Reactant: Nc1ccc(-c2ccccc2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCOC(=O)CCNC(=O)c1ccc(-c2ccccc2CNc2ccc(-c3ccccc3)cc2)cn1
Temperature: 40 °C

Procedure:
Solid NaBH(OAc)3 (214 mg, 1.0 mmol) was added to a THF solution of ethyl 3-(5-(2-formylphenyl)picolinamido)propanoate (220 mg, 0.7 mmol), [1,1′-biphenyl]-4-amine (171 mg, 1.0 mmol), and AcOH (0.04 mL, 0.7 mmol) and the resulting mixture was warmed to 40° C. After 18 h the resulting mixture diluted with EtOAc washed with water and brine, dried (Na2SO4), dry-packed onto silica gel and purified via column chromatography to yield the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[S:11][N:10]=[C:9]([NH2:12])[C:8]=2[CH:13]=1)([O-:3])=[O:2].[N:14]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH3:24])=[C:15]=[O:16]>>[CH3:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[CH2:17][NH:14][C:15]([NH:12][C:9]1[C:8]2[CH:13]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[CH:6][C:7]=2[S:11][N:10]=1)=[O:16]
Reactant: Cc1ccccc1CN=C=O
Reactant: Nc1nsc2ccc([N+](=O)[O-])cc12
Product: Cc1ccccc1CNC(=O)Nc1nsc2ccc([N+](=O)[O-])cc12

Procedure:
In analogy to example 6, 100 mg (0.51 mmol) of 5-nitrobenzo[d]isothiazol-3-ylamine were reacted with 90.4 mg (0.61 mmol) of 1-isocyanatomethyl-2-methylbenzene. Yield: 11 mg (6%), M+H+: 343.16.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6](=[O:30])[C@H:7]([CH2:20][C:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[NH:23][CH:22]=1)[N:8]([CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:10]O)([CH3:4])[CH3:3].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C(=O)N([Br:57])C(=O)C1>C(Cl)Cl>[CH3:1][C:2]([O:5][C:6](=[O:30])[C@H:7]([CH2:20][C:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[NH:23][CH:22]=1)[N:8]([CH2:9][CH2:10][Br:57])[CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])([CH3:4])[CH3:3]
Reactant: CC(C)(C)OC(=O)CN(CCO)[C@@H](Cc1c[nH]c2ccccc12)C(=O)OC(C)(C)C
Reactant: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)CN(CCBr)[C@@H](Cc1c[nH]c2ccccc12)C(=O)OC(C)(C)C
Temperature: 0 °C

Procedure:
To a solution of N-[2-(1,1-dimethylethoxy)-2-oxoethyl]-N-(2-hydroxyethyl)-L-tryptophan 1,1-dimethyl-ethyl ester (4.64 g; 11.09 mmol) in CH2Cl2 (44 mL; freshly distilled over CaH2) under an inert atmosphere, solid Ph3P (2.9 g; 11.09 mmol) was added. The solution was cooled to 0° C. and then solid NBS (1.97 g; 11.09 mmol) was portionwise added (45 min), waiting for complete dissolution after each addition. The reaction was monitored by TLC: