Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.C(O)C.COC[O:8][C:9]1[C:17]2[O:16][C:15]([CH3:19])([CH3:18])[C:14](=[O:20])[C:13]=2[C:12]([CH3:21])=[C:11]([N:22]2[CH2:27][CH2:26][N:25]([C:28]3[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=3)[CH2:24][CH2:23]2)[C:10]=1[CH3:36].O.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[OH:8][C:9]1[C:17]2[O:16][C:15]([CH3:18])([CH3:19])[C:14](=[O:20])[C:13]=2[C:12]([CH3:21])=[C:11]([N:22]2[CH2:27][CH2:26][N:25]([C:28]3[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=3)[CH2:24][CH2:23]2)[C:10]=1[CH3:36]
Reactant: COCOc1c(C)c(N2CCN(c3ccc(OC)cc3)CC2)c(C)c2c1OC(C)(C)C2=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccc(N2CCN(c3c(C)c(O)c4c(c3C)C(=O)C(C)(C)O4)CC2)cc1
Temperature: 25 °C
Yield: 87.3 %

Procedure:
Concentrated hydrochloric acid (0.1 mL) was added to a solution of ethanol (16 mL) containing 7-(methoxymethoxy)-5-[4-(4-methoxyphenyl)piperazin-1-yl]-2,2,4,6-tetramethyl-1-benzofuran-3(2H)-one (800 mg, 1.82 mmol) synthesized in Reference Example 72 and the mixture was stirred under heated reflux for 24 hours. After that, concentrated hydrochloric acid (0.1 mL) was further added thereto, and the mixture was stirred under heated reflux for 24 hours. The reaction solution was cooled to room temperature and poured into saturated sodium bicarbonate water, and extraction was performed using ethyl acetate. The extract was washed with saturated saline, and dried using anhydrous magnesium sulfate, followed by concentration under reduced pressure. The residue was crystallized using ethyl acetate and hexane to give 630 mg of the title compound (yield: 87%).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH3:8][N:9]1[C:15]2[CH:16]=[CH:17][C:18]([C:20]#[C:21][CH2:22][CH2:23][CH2:24][NH2:25])=[CH:19][C:14]=2[C:13](=[O:26])[N:12]([CH2:27][CH2:28][C:29]([OH:31])=[O:30])[CH2:11][C:10]1=[O:32].[C:33](S(O)(=O)=O)([NH2:35])=[NH:34]>C(=O)(O)[O-].[K+]>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH3:8][N:9]1[C:15]2[CH:16]=[CH:17][C:18]([C:20]#[C:21][CH2:22][CH2:23][CH2:24][NH:25][C:33]([NH2:35])=[NH:34])=[CH:19][C:14]=2[C:13](=[O:26])[N:12]([CH2:27][CH2:28][C:29]([OH:31])=[O:30])[CH2:11][C:10]1=[O:32]
Reactant: CN1C(=O)CN(CCC(=O)O)C(=O)c2cc(C#CCCCN)ccc21
Reactant: N=C(N)S(=O)(=O)O
Agent: O=C([O-])O
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Product: CN1C(=O)CN(CCC(=O)O)C(=O)c2cc(C#CCCCNC(=N)N)ccc21
Reaction time: 0.5 h
Yield: 3.6 %

Procedure:
To a magnetically stirred solution of 6 mgs of 1-methyl-4-(2-carboxyethyl)-7-(5-amino-1-pentynyl)-3,4-dihydro-1H-1,4-benzodiazepine-2,5-dione trifluoracetate (0.017 mol) in 1.0 mL 10% potassium bicarbonate was added 31.0 mgs of formamidine sulfonic acid (0.25 mmol). After 30 minutes, the reaction mixture was quenched with 0.5 mL acetic acid and concentrated in vacuo. The resulting residue was diluted with 2 mL water and purified by high pressure liquid chromatography, using a 1/2" C-18 reverse-phase column, eluting with a solvent gradient of 10:90 methanol (0.1% trifluoracetic acid)/water (0.1% trifluoracetic acid), time 0 to 10 min, to 50:50 methanol (0.1% trifluoracetic acid)/water (0.1% trifluoracetic acid), time 10 min to 40 min, flow=10 ml/min (Rt =36.8 min, un detection 254 nm) to yield 4.5 mgs (67%) 1-methyl-4-(2-carboxyethyl)-7-(5-guandino-1-pentynyl)-3,4-dihydro-1H-1, 4-benzodiazepine-2,5-dione trifluoracetate. HRMS (FAB) molecular ion m/z=386.1823 (cald. C19H24N5O4, 386.1829). 1H NMR (D2O) 7.60 (1H,d,4JHH, Ar-H o-CON), 7.51 (1H,dd, 4JHH =2 Hz, 3JHH =8 Hz, Ar-H p-CON), 7.20 (1H,d,3JHH =8 Hz, ArH m-CON), 4.05 (1H,d, 2JHH =14 Hz, NCHHCO), 3.92 (1H,m,NCHHCH2), 3.72 (1H,d,2 JHH =14 Hz, NCHHCO), 3.40 (1H,m,NCHHCH2), 3.23-3.15 (5H,NCH3H2NC(=NH2)NHCH2), 2.58 (2H,m, CH2 CO2), 2.38 (2H,t,3JHH =7 Hz, CjCCH2), 1.76 (2H,p,3JHH =7 Hz, CH2CH2CH2).
Reaction SMILES: CS(C)=O.[F:5][C:6]1[CH:15]=[C:14](F)[CH:13]=[CH:12][C:7]=1[C:8]([O:10][CH3:11])=[O:9].[NH:17]1[CH2:22][CH2:21][S:20][CH2:19][CH2:18]1.C(=O)([O-])[O-].[K+].[K+]>O>[F:5][C:6]1[CH:15]=[C:14]([N:17]2[CH2:22][CH2:21][S:20][CH2:19][CH2:18]2)[CH:13]=[CH:12][C:7]=1[C:8]([O:10][CH3:11])=[O:9]
Reactant: C1CSCCN1
Reactant: COC(=O)c1ccc(F)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: COC(=O)c1ccc(N2CCSCC2)cc1F
Temperature: 80 °C
Yield: 58 %

Procedure:
To a 30 ml dimethyl sulfoxide solution of 3.44 g (20 mmol) of methyl 2,4-difluorobenzoate, 1.9 ml (20 mmol) of thiomorpholine and 2.76 g (20 mmol) of potassium carbonate were added, and the mixture was stirred at 80° C. Then, the reaction mixture was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of sodium chloride. The washed system was dried over anhydrous sodium sulfate, and then the solvent was distilled off. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=5/1) to obtain 2.96 g (58%) of the captioned compound.
Reaction SMILES: [C:1]([Mg]Cl)([CH3:4])([CH3:3])[CH3:2].Cl[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH3:14].[CH2:15]1[CH2:19]OC[CH2:16]1>>[CH3:2][C:1]1[CH:4]=[CH:19][CH:15]=[CH:16][C:3]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH3:14]
Reactant: C1CCOC1
Reactant: CC(C)(C)[Mg]Cl
Reactant: Cc1ccccc1Cl
Product: Cc1ccccc1-c1ccccc1C

Procedure:
All of the following runs were made with 1 mmol NiBr2 and 24 mmol t-butylmagnesium chloride in THF at reflux for 16 hours. Protic ligands were converted to their magnesium salts by the addition of an equivalent amount of a Grignard reagent prior to addition of 2 -chlorotoluene.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=1.CC(C)([O-])C.[K+].[CH:15]1([CH2:18][OH:19])[CH2:17][CH2:16]1.CS(C)=O>O.CCOC(C)=O>[CH:15]1([CH2:18][O:19][C:2]2[N:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=2)[CH2:17][CH2:16]1
Reactant: Nc1cc(Cl)ncn1
Reactant: OCC1CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Solvent: CCOC(C)=O
Product: Nc1cc(OCC2CC2)ncn1
Temperature: 100 °C
Reaction time: 3 h
Yield: 74.1 %

Procedure:
A vial was charged with 6-chloropyrimidin-4-amine (0.200 g, 1.544 mmol), potassium tert-butoxide (0.381 g, 3.40 mmol), cyclopropylmethanol (0.223 g, 3.09 mmol), and dimethyl sulfoxide (3.09 ml). The vial was capped and the reaction was heated to 100° C. After 3 hour, the mixture was diluted with water and EtOAc. The layers were separated, and the aq. layer was extracted with EtOAc (2×). The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated. The residue was purified by chromatography on silica gel (40 g Redi-Sep Gold column, 0-50% of EtOAc/heptane to give 6-(cyclopropylmethoxy)pyrimidin-4-amine (0.189 g, 1.144 mmol, 74.1% yield) as a white solid. In/z (ESI) 166.2 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[CH2:3][C:4]1[NH:5][CH:6]=[C:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[N:8]=1.[CH3:16][Si:17]([CH2:20][CH2:21][O:22][CH2:23]Cl)([CH3:19])[CH3:18]>>[F:15][C:2]([F:1])([F:14])[CH2:3][C:4]1[N:5]([CH2:23][O:22][CH2:21][CH2:20][Si:17]([CH3:19])([CH3:18])[CH3:16])[CH:6]=[C:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[N:8]=1
Reactant: CCOC(=O)c1c[nH]c(CC(F)(F)F)n1
Reactant: C[Si](C)(C)CCOCCl
Product: CCOC(=O)c1cn(COCC[Si](C)(C)C)c(CC(F)(F)F)n1

Procedure:
The title compound was prepared using the procedure described in Example 52(b) starting from ethyl 2-(2,2,2-trifluoroethyl)-1H-imidazole-4-carboxylate (3.6 mmol, 0.8 g) and SEM-Cl (4.3 mmol, 0.8 ml). Yield 602 mg. 1H-NMR (400 MHz; CDCl3): δ 0.01 (s, 9H), 0.91 (t, 2H), 1.39 (t, 3H), 3.48 (t, 2H), 3.75 (q, 2H), 4.39 (q, 2H), 5.33 (s, 2H), 7.69 (s, 1H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][OH:10].[C:11]([Si:15]([CH3:35])([CH3:34])[O:16][Si:17]([CH:27]([CH2:30][CH:31]1[CH2:33][O:32]1)CC)([CH3:26])[O:18][Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20])([CH3:14])([CH3:13])[CH3:12].[CH2:36]([OH:38])[CH3:37]>>[O:18]([Si:17]([O:16][Si:15]([C:11]([CH3:12])([CH3:14])[CH3:13])([CH3:35])[CH3:34])([CH3:26])[CH2:27][CH2:30][CH2:31][O:32][CH2:33][CH:36]([OH:38])[CH2:37][NH:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][OH:10])[Si:19]([C:22]([CH3:25])([CH3:23])[CH3:24])([CH3:20])[CH3:21]
Reactant: CCO
Reactant: CCC(CC1CO1)[Si](C)(O[Si](C)(C)C(C)(C)C)O[Si](C)(C)C(C)(C)C
Reactant: NCCOCCOCCO
Product: CC(C)(C)[Si](C)(C)O[Si](C)(CCCOCC(O)CNCCOCCOCCO)O[Si](C)(C)C(C)(C)C
Temperature: 70 °C

Procedure:
2-(2-(2-Amino-ethoxy)-ethoxy)-ethanol (3.52 g) and ethanol (40 mL) were charged to a 100 mL RB flask equipped with a magnetic stirrer. The mixture was stirred and heated to 70° C. 1,5-Di(tert-butyl)-3-(oxiranylmethylpropyl)-1,1,3,5,5-Pentamethyltrisiloxane (2.0 g) mixed with ethanol (10 mL) was placed in an addition funnel and added dropwise to the flask. The mixture was stirred and maintained at 70° C. for an additional 4 hours. Reaction progress was monitored by NMR spectroscopy. Upon reaction completion, the ethanol was removed by rotary evaporation, and the mixture was distilled under vacuum to remove impurities and excess raw material.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([Cl:9])[CH:3]=1.O.Cl[C:12]([F:17])([F:16])C([O-])=O.[Na+].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:12]([F:17])[F:16])=[C:4]([Cl:9])[CH:3]=1
Reactant: Oc1ccc(Br)cc1Cl
Reactant: O=C([O-])C(F)(F)Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: FC(F)Oc1ccc(Br)cc1Cl
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 67.2 %

Procedure:
4-Bromo-2-chlorophenol (1.0 g, 4.8 mmol) was dissolved in DMF (35 mL) and water (5 mL) was added followed by sodium chloro(difluoro)acetate (2.0 g, 12 mmol) and cesium carbonate (3.1 g, 9.6 mmol). The mixture was stirred for 15 minutes at room temperature and then heated to 100° C. for 2 hours under nitrogen. The mixture was partitioned between water (50 mL) and TBME (50 mL). The organic phase was separated, washed brine, dried over sodium sulphate, filtered, and concentrated in vacuo. The resulting crude product was purified by silica gel chromatography eluting with 0 to 30% EtOAc in heptane to afford the title compound as colourless oil (0.83 g, 67%).
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1)=O.[OH-].[NH4+:12]>>[O:8]1[CH2:9][CH2:10][CH:5]([C:3]([NH2:12])=[O:2])[CH2:6][CH2:7]1
Reactant: [NH4+]
Reactant: COC(=O)C1CCOCC1
Agent: [OH-]
Product: NC(=O)C1CCOCC1

Procedure:
In a 5 L flask, charge methyltetrahydropyran-4-carboxylate (500 ml, 3.75 mol) and concentrated ammonium hydroxide (1.3 L) and stir the reaction at room temperature for 48 hours. Filter the reaction and dry the white solid in a vacuum oven at 60° C. overnight to obtained 36.33 g white solid of the title compound.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][N:12]3[C:16]4=[N:17][C:18]([C:21](=O)[CH3:22])=[CH:19][N:20]=[C:15]4[N:14]=[N:13]3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.Cl.[CH2:25]([O:27][NH2:28])[CH3:26]>>[CH2:25]([O:27]/[N:28]=[C:21](/[C:18]1[N:17]=[C:16]2[N:12]([CH2:11][C:7]3[CH:6]=[C:5]4[C:10](=[CH:9][CH:8]=3)[N:1]=[CH:2][CH:3]=[CH:4]4)[N:13]=[N:14][C:15]2=[N:20][CH:19]=1)\[CH3:22])[CH3:26]
Reactant: CC(=O)c1cnc2nnn(Cc3ccc4ncccc4c3)c2n1
Reactant: CCON
Agent: Cl
Product: CCO/N=C(\C)c1cnc2nnn(Cc3ccc4ncccc4c3)c2n1
Yield: 61 %

Procedure:
The title compound was prepared from 1-(1-(quinolin-6-ylmethyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-6-yl)ethanone (22.4) and O-ethylhydroxylamine hydrochloride in 61% yield using the same procedure as described in the synthesis of example 22. 1H-NMR (400 MHz, DMSO-d6), ppm 9.31 (s, 1H), 8.89 (m, 1H), 8.35 (d, 1H), 8.01 (m, 2H), 7.82 (d, 1H), 7.53 (dd, 1H), 6.20 (s, 2H), 4.34 (q, 2H), 2.32 (s, 3H), 1.24 (t, 3H). LCMS (method B): [MH]+=348, tR=2.59 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:29]=[CH:28][C:6]([CH2:7][N:8]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:10]=[C:9]2[CH2:19][O:20][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22])=[CH:5][CH:4]=1.[I:30]N1C(=O)CCC1=O>CC#N.CCOCC>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[C:12]([I:30])=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:10]=[C:9]2[CH2:19][O:20][Si:21]([C:24]([CH3:26])([CH3:25])[CH3:27])([CH3:22])[CH3:23])=[CH:28][CH:29]=1
Reactant: O=C1CCC(=O)N1I
Reactant: COc1ccc(Cn2cc(-c3ccccc3)nc2CO[Si](C)(C)C(C)(C)C)cc1
Solvent: CCOCC
Solvent: CC#N
Product: COc1ccc(Cn2c(CO[Si](C)(C)C(C)(C)C)nc(-c3ccccc3)c2I)cc1
Yield: 85 %

Procedure:
Treat a solution of 1-(4-methoxybenzyl)-2-tert-butyldimethylsilyloxymethyl-4-phenylimidazole (2.08 g, 5.09 mmol) in MeCN (25 mL) with N-iodosuccinimide (NIS) (1.35 g, 6.00 mmol) at room temperature for 24 hours. Dilute the mixture with Et2O (100 mL), wash with saturated NaHCO3 (25 mL), dry (Na2SO4), and concentrate in vacuo. Purify the residue by flash chromatography (SiO2, hexane/EtOAc 20:1→9:1) to provide 2.30 g (85% yield). MS (ES+): m/z 535 (M+H)+
Reaction SMILES: [NH2:1][CH:2]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=1)[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)[OH:4].[O:23]([C:30]1[CH:31]=[C:32]([CH:36]=[CH:37][CH:38]=1)[C:33](O)=[O:34])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>C(#N)C.O>[F:11][C:8]1[CH:9]=[CH:10][C:5]([CH:3]([OH:4])[CH:2]([NH:1][C:33](=[O:34])[C:32]2[CH:36]=[CH:37][CH:38]=[C:30]([O:23][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH:31]=2)[CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:20])[F:21])=[CH:15][CH:14]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)c1cccc(Oc2ccccc2)c1
Reactant: NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CC#N
Product: O=C(NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(F)cc1)c1cccc(Oc2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.3 %

Procedure:
To a solution of (1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-(4-(trifluoromethyl)phenyl)-1-propanol (400 mg, 1.28 mmol) in acetonitrile (20 ml) were added 3-phenoxybenzoic acid (274 mg, 1.28 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (368 mg, 1.92 mmol) and 1-hydroxy-1H-benzotriazole (196 mg, 1.28 mmol) and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (100 ml) and extracted with ethyl acetate (100 ml×2). The extract was washed successively with 1N hydrochloric acid, 1N aqueous sodium hydroxide solution and saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give the title compound (400 mg, 61%).
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:11]([N:12]2[CH2:24][CH2:23][N:15]3[C:16]4[CH2:17][CH2:18][CH2:19][CH2:20][C:21]=4[CH:22]=[C:14]3[C:13]2=[O:25])=[CH:10][C:9]([F:26])=[CH:8][C:7]=1[C:27]1[CH:32]=[C:31]([NH:33][C:34]2[CH:39]=[CH:38][C:37]([N:40]3[CH2:45][CH2:44][N:43]([CH3:46])[C@H:42]([CH3:47])[CH2:41]3)=[CH:36][N:35]=2)[C:30](=[O:48])[N:29]([CH3:49])[CH:28]=1)(=O)C.O[Li].O>CC(O)C.C1COCC1.O>[CH3:47][C@H:42]1[N:43]([CH3:46])[CH2:44][CH2:45][N:40]([C:37]2[CH:38]=[CH:39][C:34]([NH:33][C:31]3[C:30](=[O:48])[N:29]([CH3:49])[CH:28]=[C:27]([C:7]4[C:6]([CH2:5][OH:4])=[C:11]([N:12]5[CH2:24][CH2:23][N:15]6[C:16]7[CH2:17][CH2:18][CH2:19][CH2:20][C:21]=7[CH:22]=[C:14]6[C:13]5=[O:25])[CH:10]=[C:9]([F:26])[CH:8]=4)[CH:32]=3)=[N:35][CH:36]=2)[CH2:41]1
Reactant: CC(=O)OCc1c(-c2cc(Nc3ccc(N4CCN(C)[C@H](C)C4)cn3)c(=O)n(C)c2)cc(F)cc1N1CCn2c(cc3c2CCCC3)C1=O
Agent: [Li]O
Solvent: O
Solvent: CC(C)O
Solvent: C1CCOC1
Product: C[C@@H]1CN(c2ccc(Nc3cc(-c4cc(F)cc(N5CCn6c(cc7c6CCCC7)C5=O)c4CO)cn(C)c3=O)nc2)CCN1C
Temperature: 30 °C
Reaction time: 2 h
Yield: 26.4 %

Procedure:
A mixture of 108f (250 mg, 0.375 mmol) and LiOH.H2O (98 mg, 2.0 mmol) in iPrOH/THF (1:1, 3 mL) and H2O (1 mL) was stirred at 30° C. for 2 h. The mixture was evaporated in vacuo and the residue was extracted with EtOAc (10 mL×2). The combined EtOAc extract was concentrated under reduced pressure and the residue was purified with reverse-phase prep-HPLC to afford 108 (62 mg, 26%) as a white solid. LCMS: [M+H]+ 626. 1H NMR (500 MHz, CDCl3) δ 8.53 (s, 1H), 7.89 (d, J=2.5, 1H), 7.76 (s, 1H), 7.45 (d, J=2, 1H), 7.26 (s, 1H), 7.14-7.16 (m, 1H), 6.92-6.94 (m, 1H), 6.86 (s, 1H), 6.79 (d, J=9, 1H), 4.52-4.54 (m, 1H), 4.30-4.32 (m, 2H), 4.14-1.16 (m, 3H), 3.90-3.91 (m, 1H), 3.69 (s, 3H), 3.34-3.35 (m, 2H), 2.91-2.92 (m, 2H), 2.60-2.38 (m, 10H), 1.83-1.85 (m, 2H), 1.78-1.79 (m, 2H), 1.17 (s, 3H)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:22])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17](I)[CH:16]=1.[F:23][C:24]([F:35])([F:34])[C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][CH:30]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.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>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14]([C:15]1[CH:16]=[C:17]([C:28]2[CH:27]=[CH:26][C:25]([C:24]([F:35])([F:34])[F:23])=[CH:30][CH:29]=2)[CH:18]=[CH:19][CH:20]=1)=[O:22].[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14]([C:15]1[CH:16]=[C:17]([C:29]2[CH:28]=[CH:27][CH:26]=[C:25]([C:24]([F:35])([F:34])[F:23])[CH:30]=2)[CH:18]=[CH:19][CH:20]=1)=[O:22]
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1cccc(I)c1
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: [Na+]
Solvent: O
Solvent: COCCOC
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1cccc(-c2ccc(C(F)(F)F)cc2)c1
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1cccc(-c2cccc(C(F)(F)F)c2)c1
Yield: 41.1 %

Procedure:
N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4′-(trifluoromethyl)biphenyl-3-carboxamide was prepared according to method B with N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3-iodobenzamide (0.075 g; 0.176 mmol), 3-(trifluoromethyl)phenylboronic acid (0.035 g; 0.180 mmol), tetrakis(triphenylphosphine)palladium (0.010 g; 0.009 mmol), sodium carbonate (0.037 g; 0.353 mmol), in dimethoxyethane (3 mL) and water (1 mL), irradiated in a microwave oven at 130° C. for 15 minutes. Flash chromatography on silica gel (eluent 10 to 80% ethyl acetate in heptane) furnished 0.016 g (20%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-3′-(trifluoromethyl)biphenyl-3-carboxamide as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:10])[CH:9]=1)[CH2:5]O.P(Br)(Br)[Br:12]>C(Cl)Cl.CCOCC>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:10])[CH:9]=1)[CH2:5][Br:12]
Reactant: BrP(Br)Br
Reactant: OCc1cc(F)cc(Br)c1
Solvent: CCOCC
Solvent: ClCCl
Product: Fc1cc(Br)cc(CBr)c1
Reaction time: 3 h

Procedure:
To a solution of 3-Bromo-5-fluorobenzyl alcohol (2.3 g, 0.011 mole) in CH2Cl2 (15 mL) was added 12.4 mL of 1.0M PBr3 (3.33 g, 0.0123 mole) in CH2Cl2, stirred for 3 hr, diluted with ether (100 mL), washed with H2O (50 ml, 3×), dried over MgSO4, concentrated, and purified by column chromatography using 1:9 ethyl acetate/hexane as an eluant solvent system. 3-Bromo-5-fluorobenzyl bromide was obtained as a white crystalline material was obtained, mp 41-43° C. 1H NMR (DMSO-d6) δ4.69 (s, 2H), 7.52(d, 1H, J=1.76 Hz) 7.54(d, 1H, J=1.91 Hz), 7.56(s, 1H); MS(EI): M+. m/z 266; Anal. Calc. For C7H5Br2F: C, 31.38, H, 1.88. Found: C, 31.75, H, 1.78.
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH:10]3[C:22]4[NH:21][C:20]5[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=5)[C:14]=4[CH2:13][CH2:12][N:11]3[C:23](=[O:34])/[CH:24]=[CH:25]/[C:26]3[CH:31]=[CH:30][C:29]([CH:32]=O)=[CH:28][CH:27]=3)=[CH:4][C:3]=2[O:2]1.[CH3:35][NH2:36]>CO>[CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH:10]3[C:22]4[NH:21][C:20]5[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=5)[C:14]=4[CH2:13][CH2:12][N:11]3[C:23](=[O:34])/[CH:24]=[CH:25]/[C:26]3[CH:31]=[CH:30][C:29]([CH:32]=[N:36][CH3:35])=[CH:28][CH:27]=3)=[CH:4][C:3]=2[O:2]1
Reactant: O=Cc1ccc(/C=C/C(=O)N2CCc3c([nH]c4ccccc34)C2c2ccc3c(c2)OCO3)cc1
Reactant: CN
Solvent: CO
Product: CN=Cc1ccc(/C=C/C(=O)N2CCc3c([nH]c4ccccc34)C2c2ccc3c(c2)OCO3)cc1
Yield: 90 %

Procedure:
A stirred solution of Example 23 (0.5 g, 1.0 mmol) in MeOH was refluxed with methylamine (1.6 mL, 1.5 equiv. 33% in EtOH) for one hour. Evaporation in vacuo gave (E)-1-[1-(3,4-methylenedioxyphenyl)-1,3,4,9-tetrahydro-β-carbolin-2-yl]-3-(4-methyliminomethylphenyl)propene-1-one (0.46 g, 90%).
Reaction SMILES: [CH3:1][N:2]([CH3:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1.C1CCC(N=C=NC2CCCCC2)CC1.[CH3:28][S:29]([O:32][C:33]1[CH:38]=[CH:37][C:36]([C:39](=[NH:41])[NH2:40])=[CH:35][C:34]=1[C:42](=[O:49])[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)(=[O:31])=[O:30]>N1C=CC=CC=1>[CH3:28][S:29]([OH:32])(=[O:31])=[O:30].[CH3:1][N:2]([CH3:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7]([O:9][C:33]2[CH:38]=[CH:37][C:36]([C:39](=[NH:40])[NH2:41])=[CH:35][C:34]=2[C:42](=[O:49])[C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)=[O:8])=[CH:5][CH:4]=1
Reactant: CS(=O)(=O)Oc1ccc(C(=N)N)cc1C(=O)c1ccccc1
Reactant: CN(C)c1ccc(C(=O)O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: c1ccncc1
Product: CN(C)c1ccc(C(=O)Oc2ccc(C(=N)N)cc2C(=O)c2ccccc2)cc1
Product: CS(=O)(=O)O
Reaction time: 0.5 h
Yield: 24.8 %

Procedure:
In 50 ml of dried pyridine, was dissolved 1.65 g of 4-dimethylaminobenzoic acid followed by the addition of 3.1 g of DCC. After 30 minutes of stirring, 3.36 g of 4-amidino-2-benzoylphenol methanesulfonate was added to the mixture and the mixture was further stirred overnight. The reaction mixture was removed of the insolubles by filtration and recrystallized from ethanol to yield 1.2 g of 4-amidino-2-benzoylphenyl 4-dimethylaminobenzoate methanesulfonate.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1.C(N(CC)CC)C.[CH:17]1([C:20](Cl)=[O:21])[CH2:19][CH2:18]1>C(Cl)Cl>[CH:17]1([C:20]([N:1]2[C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N:3]=[N:2]2)=[O:21])[CH2:19][CH2:18]1
Reactant: c1ccc2[nH]nnc2c1
Reactant: O=C(Cl)C1CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(C1CC1)n1nnc2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 74.6 %

Procedure:
To a 0C solution of benzotriazole (5.05 g, 42.39 mmol) in CH2Cl2 (100 mL) was added dropwise triethylamine (9.0 ml, 64.57 mmol) followed by cyclopropyl carbonyl chloride (4.2 ml, 46.28 mmol). The mixture was stirred at rt for 1 h and then quenched with a solution of 2N aqueous HCl (75 ml). The organic phase was washed with 2 N HCl (2×75 mL) and water (100 ml), dried with MgSO4 and concentrated in vacuo. The solid residue was washed with hexenes, filtered and dried to yield 1-(cyclopropylcarbonyl)-1H-1,2,3-benzotriazole as a white solid (5.92 g, 75%).
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]([O:13][C:14](=[O:19])[NH:15][CH2:16][CH2:17][NH2:18])([CH3:12])([CH3:11])[CH3:10].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].ClCCl>ClCCCl>[C:9]([O:13][C:14](=[O:19])[NH:15][CH2:16][CH2:17][NH:18][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)([CH3:12])([CH3:10])[CH3:11]
Reactant: O=Cc1ccccc1
Reactant: CC(C)(C)OC(=O)NCCN
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCNCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 60.4 %

Procedure:
Benzaldehyde (3.3 ml, 32.4 mmol) was added to a stirred solution of tert-butyl-N-(2-aminoethyl)carbamate (5.19 g, 32.4 mmol) in 1,2-dichloroethane (50 ml). After stirring for 1 h sodium triacetoxyborohydride (10.3 g, 48.6 mmol) was added in two portions and the reaction mixture stirred at room temperature for a further 3 h. Dichloromethane (300 ml) was added and the mixture washed with 1N sodium hydroxide. The organic layer was dried (Na2SO4) and evaporated in vacuo. The residue was chromatographed on silica gel eluting with 50–100% ethyl acetate in hexane then 1–5% methanol in ethyl acetate to afford the title compound (4.9 g, 60%). Mass spectrum (AP+): Found 251 (MH+). C14H22N2O2 requires 250.