Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5]2[CH:7]=[CH:8][C:9]([NH:11][C:12](=[O:16])[C:13]([OH:15])=O)=[CH:10][C:4]=2[S:3]1.[C:17]1([CH3:30])[CH:22]=[CH:21][C:20]([O:23][CH:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[CH:19][CH:18]=1>C(OCC)C>[O:15]=[C:13]([N:27]1[CH2:28][CH2:29][CH:24]([O:23][C:20]2[CH:21]=[CH:22][C:17]([CH3:30])=[CH:18][CH:19]=2)[CH2:25][CH2:26]1)[C:12]([NH:11][C:9]1[CH:8]=[CH:7][C:5]2[NH:6][C:2](=[O:1])[S:3][C:4]=2[CH:10]=1)=[O:16]
Reactant: O=C(O)C(=O)Nc1ccc2[nH]c(=O)sc2c1
Reactant: Cc1ccc(OC2CCNCC2)cc1
Solvent: CCOCC
Product: Cc1ccc(OC2CCN(C(=O)C(=O)Nc3ccc4[nH]c(=O)sc4c3)CC2)cc1

Procedure:
The title compound is prepared from N-(2-oxo-2,3-dihydro-benzothiazol-6-yl)-oxalamic acid (Example 61b) and 4-p-tolyloxy-piperidine according to the method described in Example 1c. Melting Point: 215-217° C. (diethylether)
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[C:9](=[O:14])[O:10][C:11](=[O:13])[NH:12][C:7]=2[CH:6]=[CH:5][CH:4]=1.[H-].[Na+].IC.O(C(C)C)[CH:20](C)C>CN(C)C=O>[CH3:1][O:2][C:3]1[C:8]2[C:9](=[O:14])[O:10][C:11](=[O:13])[N:12]([CH3:20])[C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: CC(C)OC(C)C
Reactant: COc1cccc2[nH]c(=O)oc(=O)c12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: COc1cccc2c1c(=O)oc(=O)n2C
Temperature: 0 °C
Reaction time: 8 h
Yield: 80.7 %

Procedure:
To a stirred and cooled (<10° C.) solution of 9.65 parts of 5-methoxy-2H-3,1-benzoxazine-2,4(1H)-dione in 54 parts of N,N-dimethylformamide were added portionwise 2.64 parts of a sodium hydride dispersion 50%. After stirring for 1 hour in an ice bath. 7.81 parts of iodomethane were added dropwise at <15° C. When the reaction mixture was solidified, 45 parts of N,N-dimethylformamide were added and a sodium hydride dispersion 50% was further added dropwise. Upon complete addition, stirring was continued overnight while the reaction mixture was allowed to reach room temperature. The reaction mixture was poured into ice water and 2,2'-oxybispropane was added. The precipitated product was filtered off, washed with water and dried, yielding 8.37 parts (80.7%) of 5-methoxy-1-methyl-2H-3,1-benzoxazine-2,4(1H)-dione; mp. 215.8° C. (interm. 2)
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([S:9][CH3:10])[N:3]=1.CO[CH:13](OC)[CH2:14]Br>O1CCOCC1.O>[Cl:8][C:6]1[N:5]=[C:4]([S:9][CH3:10])[N:3]2[CH:13]=[CH:14][N:1]=[C:2]2[CH:7]=1
Reactant: COC(CBr)OC
Reactant: CSc1nc(N)cc(Cl)n1
Solvent: O
Solvent: C1COCCO1
Product: CSc1nc(Cl)cc2nccn12

Procedure:
75 g (427 mmol) of 4-amino-6-chloro-2-(methylthio)pyrimidine are dissolved in 3000 ml of dioxane and 750 ml of water. 101.05 g (597.81 mmol) of bromoacetaldehyde dimethyl acetal are added, and the mixture is heated under reflux for 24 h. After the reaction is complete, the dioxane is removed in vacuo and the aqueous suspension is suspended in THF, filtered with suction and washed with some THF. Drying of the solid at 40° C. under high vacuum results in 56.5 g (66% of theory) of the product.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[CH:19]=[CH:18][S:17][C:16]=2[C:20]([O:22]C)=[O:21])(=[O:13])=[O:12])=[C:7]([CH:24]=[CH:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>O1CCCC1.CO>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[CH:19]=[CH:18][S:17][C:16]=2[C:20]([OH:22])=[O:21])(=[O:13])=[O:12])=[C:7]([CH:24]=[CH:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1sccc1NS(=O)(=O)c1ccc(C(C)(C)C)cc1C=Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)c1ccc(S(=O)(=O)Nc2ccsc2C(=O)O)c(C=Cc2ccccc2)c1
Temperature: 77.5 °C
Yield: 103.1 %

Procedure:
To a solution of 26 (60.0 mg; 0.13 mmol) in tetrahydrofuran (1 mL) and methanol (1 mL) was added aqueous sodium hydroxide (2 mL; 2M). The reaction mixture was heated at 75-80° C. for 6 hours, allowed to cool to room temperature and then concentrated under reduced pressure. The resulting residue was dissolved in chloroform (15 mL) and washed with aqueous hydrochloric acid (2×10 mL; 2N). The organic phase was dried over magnesium sulfate, filtered, and concentrated under reduced pressure to yield the title compound as a white solid (59.2 mg).
Reaction SMILES: [C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:10]([C:14]1[N:15]([CH2:27][CH2:28][CH2:29][NH2:30])[C:16]2[C:25]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[N:19]=[CH:18][C:17]=2[N:26]=1)[CH2:11][CH2:12][CH3:13]>ClCCl>[CH2:10]([C:14]1[N:15]([CH2:27][CH2:28][CH2:29][NH:30][C:8]([NH:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[O:9])[C:16]2[C:25]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[N:19]=[CH:18][C:17]=2[N:26]=1)[CH2:11][CH2:12][CH3:13]
Reactant: CCCCc1nc2cnc3ccccc3c2n1CCCN
Reactant: O=C=Nc1ccccc1
Solvent: ClCCl
Product: CCCCc1nc2cnc3ccccc3c2n1CCCNC(=O)Nc1ccccc1
Yield: 87.9 %

Procedure:
A solution of phenyl isocyanate (1.00 g, 7.79 mmol) in dichloromethane (10 mL) was added dropwise over 5 minutes with stirring to a solution of 3-(2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)propylamine (2.00 g, 7.08 mmol) in dichloromethane (50 mL). The resulting precipitate was isolated by filtration to provide 2.50 g of N-[3-(2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl]-N′-phenylurea.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH:12][C:13](=[O:15])[CH3:14])[S:5][C:6]=1[C:7]1[CH:11]=[CH:10][S:9][CH:8]=1.[Cl:16]N1C(=O)CCC1=O>C(#N)C>[Cl:16][C:8]1[S:9][CH:10]=[CH:11][C:7]=1[C:6]1[S:5][C:4]([NH:12][C:13](=[O:15])[CH3:14])=[N:3][C:2]=1[CH3:1]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC(=O)Nc1nc(C)c(-c2ccsc2)s1
Solvent: CC#N
Product: CC(=O)Nc1nc(C)c(-c2ccsc2Cl)s1
Temperature: 25 °C

Procedure:
N-[4-methyl-5-(3-thienyl)-1,3-thiazol-2-yl]acetamide, prepared as in Step I of Example 23 (600 mg; 2.52 mmol; 1 eq) is dissolved in ACN (20 ml) in presence of 100 μl of HClO4 at room temperature. A solution of N-chlorosuccinimide (369.8 mg; 2.77 mmol; 1.10 eq) in ACN (2 ml) is added slowly at room temperature over a period of one hour. Reaction mixture is stirred at room temperature for 1 night before being quenched with water (1 ml). It is then concentrated under vacuo and expected compound extracted with EtOAc, washed with NH4Cl saturated solution, water and dried over MgSO4. After evaporation of the solvents, ACN (5 ml) is added, affording after precipitation, the title compound as a solid (600 mg; 95%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[CH2:6][CH2:7][N:8]([CH3:12])[CH2:9][C:10]=2[CH:11]=1.S(=O)(=O)(O)O.[Br:18]Br.[OH-].[Na+]>C(O)(=O)C.O>[NH2:1][C:2]1[C:3]([Br:18])=[N:4][C:5]2[CH2:6][CH2:7][N:8]([CH3:12])[CH2:9][C:10]=2[CH:11]=1
Reactant: CN1CCc2ncc(N)cc2C1
Reactant: BrBr
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: CN1CCc2nc(Br)c(N)cc2C1
Reaction time: 0.42 h

Procedure:
D4 (978 mg, 6 mmol) was dissolved in acetic acid (10 ml) containing 2M sulphuric acid (2 ml). Bromine (0.31 ml, 6 mmol) was added dropwise with stirring over a period of approximately 25 min. After 2 h, the precipitated solid was removed by filtration and washed with ether to give a pale yellow solid which was dissolved in water. The solution was basified with 2M NaOH and extracted with ethyl acetate. The combined extracts were washed with brine, dried (MgSO4) and evaporation in vacuo gave the crude product as a pale yellow solid (444 mg). The above filtrate from the reaction mixture was concentrated by evaporation in vacuo, diluted with water and made basic with 2M sodium hydroxide. The mixture was extracted with dichloromethane and the extract dried (MgSO4) and evaporated to give a crude brown solid which was purified by chromatography on silica gel eluting with dichloromethane:methanol:aq. ammonia (0.880) (ratio 19:1:0.1). The title compound was obtained as a white solid (248 mg).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6](Cl)=[N:7][C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:11]([CH2:21][CH3:22])=[CH:10][C:9]=2[CH3:23])=[O:4].[CH2:25]([NH:27][CH3:28])[CH3:26]>>[CH2:21]([C:11]1[CH:12]=[C:13]2[C:8](=[C:9]([CH3:23])[CH:10]=1)[N:7]=[C:6]([N:27]([CH2:25][CH3:26])[CH3:28])[C:5]([C:3]([OH:2])=[O:4])=[C:14]2[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH3:22]
Reactant: CCNC
Reactant: CCc1cc(C)c2nc(Cl)c(C(=O)OC)c(-c3ccccc3)c2c1
Product: CCc1cc(C)c2nc(N(C)CC)c(C(=O)O)c(-c3ccccc3)c2c1

Procedure:
The title compound was prepared in analogy to example 54 step F from 2-chloro-6-ethyl-8-methyl-4-phenyl-quinoline-3-carboxylic acid methyl ester (prepared as described in example 54 step E) and ethyl-methyl-amine. Light brown solid. MS (ESI): 349.3 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4](=[CH2:16])[NH:5][C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7].[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:20])[CH3:19]>C(#N)C.CO>[C:6]([NH:5][CH:4]([CH2:16][N:28]1[CH2:27][CH2:26][N:25]([C:23]([O:22][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:24])[CH2:30][CH2:29]1)[C:3]([O:2][CH3:1])=[O:17])([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: C=C(NC(=O)OCc1ccccc1)C(=O)OC
Solvent: CC#N
Solvent: CO
Product: COC(=O)C(CN1CCN(C(=O)OC(C)(C)C)CC1)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To N-carbobenzyloxydehydroalanine methyl ester (2.0 g, 8.4 mmol) was added 4-tert-butoxycarbonylpiperazine (1.56 g, 1.0 eq), ferric chloride (0.220 g, 0.2 eq) in a 6:1 mixture of acetonitrile/methanol. The reaction mixture was stirred at room temperature for 2 days. The reaction mixture was evaporated under reduced pressure. EtOAc was added and the organic layer washed with a soldium sulfate solution. Upon removal of the solvent under reduced pressure, the crude material was purified by column chromatography (silica gel; CH2Cl2:MeOH 4:1) to afford the title compound.
Reaction SMILES: Cl[C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].Cl.[F:12][C:13]1([F:19])[CH2:18][CH2:17][CH2:16][NH:15][CH2:14]1.CCN(C(C)C)C(C)C>CCO>[F:12][C:13]1([F:19])[CH2:18][CH2:17][CH2:16][N:15]([C:2]2[N:6]([CH3:7])[N:5]=[CH:4][C:3]=2[N+:8]([O-:10])=[O:9])[CH2:14]1
Reactant: FC1(F)CCCNC1
Reactant: Cn1ncc([N+](=O)[O-])c1Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: Cn1ncc([N+](=O)[O-])c1N1CCCC(F)(F)C1
Temperature: 130 °C
Yield: 55.5 %

Procedure:
A mixture of 5-chloro-1-methyl-4-nitro-1H-pyrazole from Example 1 (0.1 g, 4.5 mmol), 3,3-difluoropiperidine hydrochloride (0.14 g, 0.93 mmol) and DIPEA (0.5 mL, 2.8 mmol) in EtOH (3 mL) was heated at 130° C. in a microwave for 1 hr. Additional DIPEA (0.5 mL, 2.8 mmol) and 3,3-difluoropiperidine hydrochloride (0.29 g, 1.8 mmol) were added and the mixture was heated at 130° C. in a microwave for 2 hr. The solvent was removed under reduced pressure and the crude product was purified via silica gel column chromatography (0-60% EtOAc/isohexane) to yield 3,3-difluoro-1-(1-methyl-4-nitro-1H-pyrazol-5-yl)piperidine as a yellow oil (127 mg, 83%). 1H NMR (400 MHz, CDCl3) δ 8.04 (s, 1H), 3.80 (s, 3H), 3.41-3.29 (m, 2H), 3.26-3.04 (m, 2H), 2.17-2.03 (m, 2H), 1.97-1.88 (m, 2H).
Reaction SMILES: O(CC(O)=O)C1C=CC=CC=1.[CH:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][C:13]=1[O:22][CH2:23][C:24](O)=O.[CH2:27]([NH:30][CH:31]1[CH2:40][CH2:39][C:38]2[C:33](=[CH:34][CH:35]=[CH:36][C:37]=2[O:41][CH3:42])[CH2:32]1)[CH2:28][CH3:29]>>[CH3:42][O:41][C:37]1[CH:36]=[CH:35][CH:34]=[C:33]2[C:38]=1[CH2:39][CH2:40][CH:31]([N:30]([CH2:24][CH2:23][O:22][C:13]1[CH:14]=[CH:15][C:16]3[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:12]=1)[CH2:27][CH2:28][CH3:29])[CH2:32]2
Reactant: CCCNC1CCc2c(cccc2OC)C1
Reactant: O=C(O)COc1ccc2ccccc2c1
Agent: O=C(O)COc1ccccc1
Product: CCCN(CCOc1ccc2ccccc2c1)C1CCc2c(cccc2OC)C1

Procedure:
In Example 29, phenoxyacetic acid was replaced with (2-naphthoxy)acetic acid and (-)-2-(N-n-propylamino)-5-methoxytetralin was replaced with (±)-2-(N-n-propylamino)-5-methoxytetralin. The resulting oil was subjected to flash chromatography (Silica: 8:2 pet ether/EtOAc) and the product showed characteristic peaks at: NMR (300 MHz, CDCl3) δ 7.8-6.6(m, 10H), 4.15(t, 2H), 3.8(S, 3H), 0.9(t, 3H).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:16]=2[C:17]([OH:19])=[O:18])(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:25]N1C(=O)CCC1=O>C(O)(=O)C>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([S:11]([NH:14][C:15]2[CH:23]=[C:22]([F:24])[C:21]([Cl:25])=[CH:20][C:16]=2[C:17]([OH:19])=[O:18])(=[O:13])=[O:12])=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Nc2cc(F)ccc2C(=O)O)cc1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC(=O)O
Product: CC(C)(C)c1ccc(S(=O)(=O)Nc2cc(F)c(Cl)cc2C(=O)O)cc1
Temperature: 80 °C
Reaction time: 7 h
Yield: 87.1 %

Procedure:
2-(4-tert-Butyl-benzenesulfonylamino)-4-fluoro-benzoic acid (23 g, 65.5 mmol) was added to 230 mL of stirring acetic acid in a 500 mL round bottom flask. N-chlorosuccinimide (17.5 g, 131 mmol) was then added and the mixture heated to 80° C. under a N2 atmosphere. The reaction was determined to be complete in seven hours according to LCMS analysis. The heat bath was subsequently removed and the reaction was quenched via the addition of 250 mL of a 50% solution of sodium metabisulfite. The mixture immediately formed a thick white slurry which was allowed to stir for approximately 15 minutes. Vacuum filtration of the slurry resulted in a white solid that was washed with a small amount of water and dried in vacuo to generate 22 g of 2-(4-tert-butyl-benzenesulfonylamino)-5-chloro-4-fluoro-benzoic acid (white solid, 87% yield): HPLC retention time=2.87 minutes; MS (ES) M+H expected 386.0, found 386.0.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=3)[N:10]=2)=[CH:4][C:5](F)=[N:6][CH:7]=1.[NH2:24][C@H:25]1[CH2:30][CH2:29][C@H:28]([CH2:31][NH:32]C(=O)OC(C)(C)C)[CH2:27][CH2:26]1.Cl.O1CCOCC1>CS(C)=O>[NH2:32][CH2:31][C@H:28]1[CH2:29][CH2:30][C@H:25]([NH:24][C:5]2[CH:4]=[C:3]([C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([O:15][CH2:16][C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=4)[N:10]=3)[C:2]([Cl:1])=[CH:7][N:6]=2)[CH2:26][CH2:27]1
Reactant: CC(C)(C)OC(=O)NC[C@H]1CC[C@H](N)CC1
Reactant: Fc1cccc(COc2cccc(-c3cc(F)ncc3Cl)n2)c1
Agent: Cl
Solvent: CS(C)=O
Solvent: C1COCCO1
Product: NC[C@H]1CC[C@H](Nc2cc(-c3cccc(OCc4cccc(F)c4)n3)c(Cl)cn2)CC1
Temperature: 102.5 °C
Reaction time: 40 h

Procedure:
To 5′-chloro-2′-fluoro-6-(3-fluorobenzyloxy)-2,4′-bipyridine (30 mg, 0.090 mmol) was added DMSO (0.8 ml), TEA (0.025 ml, 0.180 mmol), and tert-butyl (trans-4-aminocyclohexyl)methylcarbamate (41.2 mg, 0.180 mmol). The reaction mixture was flushed with argon and stirred at 100-105° C. for 40 hr. Formation of the intermediate product tert-butyl(trans-4-(5′-chloro-6-(3-fluorobenzyloxy)-2,4′-bipyridin-2′-yl-amino)cyclohexyl)methylcarbamate was indicated by LCMS. (LCMS (m/z): 541.4 (MH+), retention time=1.05 min.). The solvent DMSO was removed under reduce pressure. The Boc group was removed from the intermediate by adding 4M HCl in Dioxane (1.5 ml, 6.00 mmol), followed with stirring at ambient temperature for 90 minutes. The solvent was removed under reduced pressure. The crude product was dissolved in 1.0 ml of DMSO with 0.075 ml of water, filtered and purified by prep LC. After lyophilization, 28.3 mg of the title compound was obtained as a TFA salt. LCMS (m/z): 441.3 (MH+), retention time=0.76 min.; 1H NMR (300 MHz, METHANOL-d4, 25° C.) δ ppm 1.12-1.29 (m, 2 H) 1.29-1.47 (m, 2 H) 1.60-1.76 (m, J=14.76, 7.51, 3.66, 3.66 Hz, 1 H) 1.92 (d, J=12.60 Hz, 2 H) 2.16 (d, J=10.55 Hz, 2 H) 2.84 (d, J=6.74 Hz, 2 H) 3.58-3.71 (m, 1 H) 5.43 (s, 2 H) 6.92-6.99 (m, 2 H) 6.99-7.08 (m, 1 H) 7.18 (d, J=9.67 Hz, 1 H) 7.25 (d, J=7.62 Hz, 1 H) 7.30-7.42 (m, 2 H) 7.83 (t, J=7.77 Hz, 1 H) 8.01 (s, 1 H)
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.[C:11]1([C:17]#[CH:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(N(CC)CC)C.[Cl-].[NH4+]>CCOCC>[C:8]([C:5]1[CH:6]=[CH:7][C:2]([C:18]#[C:17][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:3][CH:4]=1)(=[O:10])[CH3:9]
Reactant: C#Cc1ccccc1
Reactant: CC(=O)c1ccc(Br)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CC(=O)c1ccc(C#Cc2ccccc2)cc1
Temperature: 90 °C
Yield: 95.3 %

Procedure:
Compound 5 (30 mg, 2 μmol Pd), 1-(4-bromo-phenyl)ethan-1-one (0.20 g, 1 mmol), phenylacetylene (0.16 g, 1.5 mmol), and triethylamine (3 mL) were sequentially added into a 15 mL septum-sealed test tube under protection of nitrogen. The mixture was then heated at 90° C. for 72 h. After it was cooled to the room temperature, 8 mL of anhydrous ether was added to precipitate compound 5. The mixture was centrifuged and the upper liquid layer was transferred via a syringe into a 20 mL round-bottom flask. Repeated the above precipitation procedure once. The combined liquid layer was concentrated under reduced pressure to give an oily residue. A saturated ammonium chloride solution (5 mL) was then added. The resulting mixture was extracted by ethyl acetate (10 mL×3), dried over anhydrous magnesium sulfate, filtrated, and concentrated to give a crude product. The crude product was further purified by column chromatography (silica gel, hexane/ethyl acetate=4/1) to give 0.21 g (98% yield) of 1-(4-acetylphenyl)-2-phenylethyne. 1H NMR (400 MHz, CDCl3) δ 2.57 (s, 3H), 7.33–7.35 (m, 3H), 7.52–7.54 (m, 2H), 7.58 (d, J=8.2 Hz, 2H), 7.91 (d, J=8.2 Hz, 2H) ppm.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][O:8][C:9](=[O:14])[CH2:10][CH2:11][CH2:12][NH2:13].[CH3:15][O:16][C:17](=[O:22])[C@H:18](Br)[CH2:19][CH3:20]>C(#N)C>[CH3:7][O:8][C:9](=[O:14])[CH2:10][CH2:11][CH2:12][NH:13][CH:18]([C:17]([O:16][CH3:15])=[O:22])[CH2:19][CH3:20]
Reactant: CC[C@@H](Br)C(=O)OC
Reactant: COC(=O)CCCN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCC(NCCCC(=O)OC)C(=O)OC
Temperature: 40 °C
Reaction time: 19 h
Yield: 98.6 %

Procedure:
To a mixture of potassium carbonate (19 g, 138 mmol, 5 equiv.) and methyl-4-aminobutyrate (IVc) (8.5 g, 55.3 mmol, 2 equiv.) in acetonitrile (70 ml, 14 vol.) is added methyl-(R)-2-bromobutyrate (IIf) (5 g, 27.6 mmol, 1 equiv.). The suspension is stirred at 40° C. for 19 hours. The mixture is then filtered and the cake is rinsed with 50 ml of acetonitrile. The filtrate is concentrated to dryness under reduced pressure and the residue is dissolved in isopropylactetate. The resulting organic layer is washed with 60 ml of water and is concentrated under vacuum to afford methyl-4-(1-methoxycarbonylpropylamino)butyrate (VIa) as a colourless oil (5.91 g, 27.2 mmol, 98%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:11]3[CH:12]=[CH:13][C:14]([F:16])=[CH:15][C:10]=3[N:9]=[C:8]2[C:17]([F:23])([F:22])[C:18]([F:21])([F:20])[F:19])[CH2:3][CH2:2]1.Br[CH2:25][CH2:26][CH2:27][S:28][C:29]1[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[F:22][C:17]([F:23])([C:8]1[N:7]([CH:4]2[CH2:5][CH2:6][N:1]([CH2:25][CH2:26][CH2:27][S:28][C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=3)[CH2:2][CH2:3]2)[C:11]2[CH:12]=[CH:13][C:14]([F:16])=[CH:15][C:10]=2[N:9]=1)[C:18]([F:21])([F:20])[F:19]
Reactant: Fc1ccc2c(c1)nc(C(F)(F)C(F)(F)F)n2C1CCNCC1
Reactant: Fc1ccc(SCCCBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Fc1ccc(SCCCN2CCC(n3c(C(F)(F)C(F)(F)F)nc4cc(F)ccc43)CC2)cc1
Yield: 8.6 %

Procedure:
3.9 g 1-(Piperidin-4-yl)-5-fluoro-2-pentafluoroethyl-1H-benzoimidazole, 4.4 g 1-(3-bromo-propylsulfanyl)-4-fluoro-benzene and 2 g K2CO3 were stirred in 50 ml DMF at 100° C. for 2 h. After cooling the mixture was poured into water and was extracted 2× with ethyl acetate. The organic layer was tracted 3× with water, dried and evaporated. The resulting oil was purified by flash chromatography with dichloromethane, the purified fractions were dissolved in acetone after evaporation of the solvent, and the solution was acidified with etherical HCl. After evaporation of the solvent the resulting crystals were filtered with diisopropyl ether. The crystals were dissolved in acetone again and evaporated to a volume of 2 ml. The product crystallized as hydrochloride to give 0.5 g product (mp. 208–209° C.).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([OH:9])=[C:4]([Cl:10])[N:3]=1.[CH3:11][O:12][C:13](=[O:19])[CH:14]([CH:16]1[CH2:18][CH2:17]1)O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1.O1CCOCC1>[CH3:11][O:12][C:13](=[O:19])[CH:14]([CH:16]1[CH2:18][CH2:17]1)[O:9][C:5]1[C:4]([Cl:10])=[N:3][C:2]([Cl:1])=[N:7][C:6]=1[Cl:8]
Reactant: COC(=O)C(O)C1CC1
Reactant: Oc1c(Cl)nc(Cl)nc1Cl
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: COC(=O)C(Oc1c(Cl)nc(Cl)nc1Cl)C1CC1
Reaction time: 6 h
Yield: 57.5 %

Procedure:
To a solution of 2,4,6-trichloro-pyrimidin-5-ol (250 mg, 1.25 mmol), cyclopropyl-hydroxy-acetic acid methyl ester (245 mg, 1.88 mmol) and triphenylphosphine (493 mg, 1.88 mmol) in THF (12 mL) was added DIAD (370 μL, 1.88 mmol) dropwise. The resultant suspension was stirred for 18 hours before the addition of dioxane (10 mL) and the reaction stirred for a further 6 hours. The heterogeneous mixture was concentrated in vacuo and the resultant residue was purified by column chromatography (SiO2, gradient 0-30% ethyl acetate in cyclohexane) affording Cyclopropyl-(2,4,6-trichloro-pyrimidin-5-yloxy)-acetic acid methyl ester as a white solid (224 mg, 32%). LCMS: RT=3.66 min, [M+H]+=311/313/315.
Reaction SMILES: [N:1]1([CH:6]2[CH:10]([OH:11])[CH2:9][NH:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:12][C:13]1[CH:14]=[CH:15][C:16](F)=[N:17][CH:18]=1.C(N(C(C)C)CC)(C)C>C(#N)C.C(=O)(O)[O-].[Na+]>[Br:12][C:13]1[CH:14]=[CH:15][C:16]([N:8]2[CH2:9][C@@H:10]([OH:11])[C@H:6]([N:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)[CH2:7]2)=[N:17][CH:18]=1
Reactant: OC1CNCC1N1CCCC1
Reactant: Fc1ccc(Br)cn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: O[C@@H]1CN(c2ccc(Br)cn2)C[C@H]1N1CCCC1
Yield: 67.6 %

Procedure:
Dissolve [1,3′]bipyrrolidinyl-4′-ol (452 mg, 2.89 mmol) in acetonitrile (10 mL) and add 5-bromo-2-fluoro-pyridine (764 mg, 4.34 mmol) and diisopropylethylamine (1.26 mL, 7.23 mmol). Reflux the mixture for 3 days. Dilute the mixture with saturated sodium bicarbonate and extract with dichloromethane (3×). Combine the organic fractions, dry over sodium sulfate, filter, and evaporate. Purify by silica gel chromatography, eluting with 0-7.5% methanol (2N NH3)/CH2Cl2 to give 610 mg (67%) of the title compound as a yellow foam. MS/ES m/z (79Br) 312.0 [M+H]+.
Reaction SMILES: [F:1][C:2]1[C:8]([C:9]([F:12])([F:11])[F:10])=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].C1C(=O)N([Br:20])C(=O)C1>CN(C=O)C.CCOCC>[Br:20][C:7]1[CH:6]=[CH:5][C:3]([NH2:4])=[C:2]([F:1])[C:8]=1[C:9]([F:10])([F:11])[F:12]
Reactant: Nc1cccc(C(F)(F)F)c1F
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: CCOCC
Product: Nc1ccc(Br)c(C(F)(F)F)c1F
Reaction time: 3 h

Procedure:
2-Fluoro-3-trifluoromethylaniline (28.8 g, 161 mmol) is dissolved in DMF (100 mL). A solution of NBS (28.6 g, 161 mmol) in DMF (100 mL) is added dropwise at room temperature. After 3 hours, the reaction is diluted with Et2O and washed with brine. The separated organic phase is dried (Na2SO4) and concentrated to give 4-bromo-2-fluoro-3-trifluoromethylaniline as an oil.