Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH3:9].[C:10]([O:16][CH2:17][CH3:18])(=[O:15])[CH2:11][CH2:12][CH:13]=[CH2:14].C(N(CC)CC)C.CC#N>C1COCC1>[CH3:9][O:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1/[CH:14]=[CH:13]/[CH2:12][CH2:11][C:10]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: C=CCCC(=O)OCC
Reactant: COc1ccccc1I
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOC(=O)CC/C=C/c1ccccc1OC
Temperature: 25 °C
Yield: 67.8 %

Procedure:
To a 200-mL RB-flask was added 2-iodoanisole (5.00 g, 21.4 mmol), ethyl 4-pentenoate (3.30 g, 25.6 mmol), tetrakis(triphenyl phosphine)palladium(0) (0.740 g, 0.600 mmol), triethylamine (6.00 mL, 42.7 mmol) and a mixture of CH3CN (45.0 mL) and THF (15.0 mL). The reaction mixture was refluxed for overnight and then cooled to room temperature. After solvents were removed in vacuo, the resulted dark brown residue was dissolved in 5% HCl (aq) and extracted with CH2Cl2 three times. The combined extracts were washed by saturated NaHCO3 solution, dried over MgSO4, concentrated in vacuo. The dark brown oil was purified by chromatography (silica gel, EtOAc/Hexanes 1:10) to afford the product as light yellow oil (3.40 g, 68%).
Reaction SMILES: FC(F)(F)C(O)=O.[N:8]1([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:24]=[C:23]([CH2:25][CH:26]([CH3:28])[CH3:27])[S:22][C:21]=3[C:29]([NH:31]C(C)(C)C)=[O:30])=[CH:16][CH:15]=2)[CH:12]=[CH:11][N:10]=[CH:9]1>C1(OC)C=CC=CC=1>[N:8]1([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:24]=[C:23]([CH2:25][CH:26]([CH3:27])[CH3:28])[S:22][C:21]=3[C:29]([NH2:31])=[O:30])=[CH:16][CH:15]=2)[CH:12]=[CH:11][N:10]=[CH:9]1
Reactant: CC(C)Cc1cc(-c2ccc(Cn3ccnc3)cc2)c(C(=O)NC(C)(C)C)s1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)Cc1cc(-c2ccc(Cn3ccnc3)cc2)c(C(N)=O)s1
Reaction time: 30 h
Yield: 82.7 %

Procedure:
Trifluoroacetic acid was added (2.5 mL) to 3-(4-imidazol-1-ylmethylphenyl)-5-iso-butyl-N-tert-butylthiophene,2-carboxamide (165 mg, 0.417 mmol, see step (d) above), and one drop (ca. 0.05 mL) of anisol was added to the reaction mixture. The mixture was stirred under a N2 atmosphere for 30 hours and then evaporated and co-evaporated with acetonitrile. The crude product was purified by column chromatography (CH2Cl2:MeOH (85:15)) to give the sub-title compound (117 mg, 0.345 mmol) in 73% yield.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:8]([NH2:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.CC([O-])(C)C.[Na+].O(CCCC)CCCC>>[CH2:8]([NH:15][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: NCc1ccccc1
Reactant: Clc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CCCCOCCCC
Product: c1ccc(CNc2ccccc2)cc1
Temperature: 85 °C
Yield: 89.8 %

Procedure:
Following general procedure D, a mixture of chlorobenzene (1.02 mL, 10 mmol), benzylamine (1.52 mL, 14 mmol), NaOt-Bu (1.15 g, 12 mmol), 10 (4 mg, 0.05 mol %), 1 (2.5 mg, 0.05 mol %), and Bu2O (3 mL) was heated to 85° C. for 1 h. The crude product was purified via the Biotage SP4 (silica-packed 25+M; 0-50% EtOAc/hexanes) to provide the title compound as a yellow oil (1.646 g, 90%). 1H NMR (300 MHz, CDCl3) δ: 7.69-7.61 (m, 5H), 7.53 (t, J=7.5 Hz, 2H), 7.09 (t, J=7.5 Hz, 1H), 6.92 (d, J=7.5 Hz, 2H), 4.57 (s, 2H), 4.22 (s, 1H) ppm. 13C NMR (75 MHz, CDCl3) δ: 148.8, 140.2, 129.9, 129.3, 128.1, 127.8, 118.1, 113.5, 48.7 ppm. IR (neat, cm−1): 3419, 3052, 3026, 2841, 1603, 1506, 1453, 1325, 750, 693. Anal. Calcd. for C13H13N: C, 85.21; H, 7.15. Found: C, 85.04; H, 7.15.
Reaction SMILES: P([O-])(OC1C=CC=CC=1)OC1C=CC=CC=1.[NH2:17][C:18]1[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[C:19]=1[C:20]([OH:22])=O.[C:28]([O:32][C:33]([NH:35][C@@H:36]([CH3:40])[C:37](O)=O)=[O:34])([CH3:31])([CH3:30])[CH3:29].[NH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>N1C=CC=CC=1.CCOC(C)=O>[Cl:27][C:23]1[CH:24]=[CH:25][CH:26]=[C:18]2[C:19]=1[C:20](=[O:22])[N:41]([C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[C:37]([C@@H:36]([NH:35][C:33](=[O:34])[O:32][C:28]([CH3:31])([CH3:30])[CH3:29])[CH3:40])=[N:17]2
Reactant: Nc1cccc(Cl)c1C(=O)O
Reactant: Nc1ccccc1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: [O-]P(Oc1ccccc1)Oc1ccccc1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: C[C@H](NC(=O)OC(C)(C)C)c1nc2cccc(Cl)c2c(=O)n1-c1ccccc1
Temperature: 40 °C
Reaction time: 2 h

Procedure:
Diphenyl phosphite (1.9 mL, 10 mmol) was added to a solution of 2-amino-6-chlorobenzoic acid (495 mg, 2.9 mmol) and (S)-2-(tert-butoxycarbonylamino)propanoic acid (710 mg, 3.77 mmol) in pyridine (3 mL). The reaction mixture was stirred at 40° C. for 2 hours. Aniline (274 mg, 3.48 mmol) was then added to the reaction mixture, which was then stirred at 55° C. for 12 hours. The reaction mixture was cooled to room temperature. This mixture was then diluted with EtOAc (50 mL), washed with 1N aqueous HCl (2×50 mL), brine (50 mL), and dried over sodium sulfate. The organics layer was filtered and concentrated in vacuuo to afford material which was purified by column chromatography on SiO2 eluting with EtOAc in hexanes (0-50%) to afford (S)-tert-butyl 1-(5-chloro-4-oxo-3-phenyl-3,4-dihydroquinazolin-2-yl)ethylcarbamate as a solid. ES/MS m/z=400.1 (M+H+).
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH:7]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:8]([OH:10])=[O:9])[C:5](=[S:18])[NH:4][CH2:3]1.[F:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[S:30][C:29]([CH:31]=O)=[CH:28][CH:27]=2)=[CH:22][CH:21]=1.NCCC(O)=O.CO.C(Cl)Cl>C(O)(=O)C>[F:19][C:20]1[CH:21]=[CH:22][C:23]([C:26]2[S:30][C:29]([CH:31]=[C:3]3[C:2](=[O:1])[N:6]([CH:7]([CH2:11][C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)[C:8]([OH:10])=[O:9])[C:5](=[S:18])[NH:4]3)=[CH:28][CH:27]=2)=[CH:24][CH:25]=1
Reactant: O=Cc1ccc(-c2ccc(F)cc2)s1
Reactant: O=C(O)C(Cc1ccccc1)N1C(=O)CNC1=S
Agent: NCCC(=O)O
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: CO
Product: O=C(O)C(Cc1ccccc1)N1C(=O)C(=Cc2ccc(-c3ccc(F)cc3)s2)NC1=S
Temperature: 170 °C

Procedure:
To a mixture of 2-(5-oxo-2-thioxoimidazolidin-1-yl)-3-phenylpropanoic acid (0.100g, 0.378 mmol) and 5-(4-fluorophenyl)thiophene-2-carbaldehyde (0.078 g, 0.378 mmol) in acetic acid 5 mL is added β-alanine (3.37 mg, 0.038 mmol) and heat to 170° C. for 30 min under microwave irradiation. The resulting reaction mixture is cooled down and the solvent is removed. The pure product (0.125 g, 0.276 mmol, red solid) is obtained by column chromatography using MeOH/DCM, 2-7% ration solvent system. 1H-NMR (CD3OD/300 MHz): 7.71 (m, 2H), 7.52 (d, J=4.5 Hz, 1H), 7.43 (d, J=4.5 Hz, 1H), 7.16 (m, 7H), 6.69 (s, 1H), 5.66 (dd, J=11.4, 5.1 Hz, 1H), 3.69 (dd, J=14.4, 11.7 Hz, 1H), 3.51 (dd, J=10.5, 5.1 Hz, 1H). MS (ES−, m/z): 451.4 (M−−1, 45.0).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[C:5]([N+:13]([O-:15])=[O:14])[CH:4]=1.B(Br)(Br)Br.CCOC(C)=O>C(Cl)(Cl)Cl>[N+:13]([C:5]1[CH:4]=[C:3]([OH:2])[CH:8]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:6]=1)([O-:15])=[O:14]
Reactant: COc1cc([N+](=O)[O-])cc(C(F)(F)F)c1
Agent: BrB(Br)Br
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1cc(O)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 42.7 %

Procedure:
To a solution of 1-Methoxy-3-nitro-5-trifluoromethyl-benzene (3.5 g, 15.83 mmol) in 20 ml of CHCl3 was added a solution of 1M boron tribromide (23.74 ml, 23.74 mmol) and the reaction was stirred at RT for 3 days resulting in conversion to product by TLC (20% EtOAc:Hexanes). The reaction was partitioned between CH2Cl2/1N NaOH and extracted. The aqueous phase was acidified with 1N HCl and again extracted with CH2Cl2. The organics were dried over sodium sulfate and stripped down in vacuo giving 3-Nitro-5-trifluoromethyl-phenol (1.4 g, 6.76 mmol) as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:13][OH:14])=[N:4][CH:5]=[CH:6][C:7]=1[N:8]([CH2:10][CH2:11]Cl)[CH3:9].[N+:15]([C:18]1[N:22]2[N:23]=[C:24]([SH:27])[CH:25]=[CH:26][C:21]2=[N:20][CH:19]=1)([O-:17])=[O:16].C1CCN2C(=NCCC2)CC1>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[C:3]([CH2:13][OH:14])=[N:4][CH:5]=[CH:6][C:7]=1[N:8]([CH3:9])[CH2:10][CH2:11][S:27][C:24]1[CH:25]=[CH:26][C:21]2[N:22]([C:18]([N+:15]([O-:17])=[O:16])=[CH:19][N:20]=2)[N:23]=1
Reactant: CN(CCCl)c1ccnc(CO)c1Cl
Reactant: O=[N+]([O-])c1cnc2ccc(S)nn12
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN(CCSc1ccc2ncc([N+](=O)[O-])n2n1)c1ccnc(CO)c1Cl
Temperature: 50 °C
Reaction time: 5 h
Yield: 71.2 %

Procedure:
0.33 g (1.28 mmol) of {3-chloro-4-[(2-chloro-ethyl)methylamino]pyridin-2-yl}methanol and 0.33 g (1.68 mmol) of 3-nitroimidazo[1,2-b]pyridazine-6-thiol are dissolved in 10 ml of anhydrous dimethylformamide under an argon atmosphere, and the solution is treated with 0.25 ml (1.53 mmol) of DBU and then stirred at 50° C for 5 h. It is then cooled to room temperature and diluted with ethyl acetate. The precipitate is filtered off, washed with ethyl acetate and diethyl ether and dried. 0.36 g (71%) of the title compound is isolated as a pale beige solid. M.p. 189-191° C.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[NH:6][C:7](=[O:23])[C:8]3([CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)[CH2:9][N:10]([CH:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)[C:11]=2[N:12]=1.[CH3:24]I.[H-].[Na+]>CN(C)C(=O)C.O.C(OCC)C>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[N:6]([CH3:24])[C:7](=[O:23])[C:8]3([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]3)[CH2:9][N:10]([CH:13]3[CH2:14][CH2:15][CH2:16][CH2:17]3)[C:11]=2[N:12]=1
Reactant: CI
Reactant: O=C1Nc2cnc(Cl)nc2N(C2CCCC2)CC12CCCCC2
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Solvent: CC(=O)N(C)C
Product: CN1C(=O)C2(CCCCC2)CN(C2CCCC2)c2nc(Cl)ncc21
Reaction time: 0.5 h
Yield: 73.8 %

Procedure:
2′-chloro-9′-cyclopentyl-8′,9′-dihydrospiro[cyclohexane-1,7′-pyrimido[5,4-b][1,4]diazepin]-6′(5′H)-one (Intermediate 256; 300 mg, 0.94 mmol) was dissolved in N,N-dimethylacetamide (10 mL) and methyl iodide (65 mL, 1.03 mmol) added followed by sodium hydride (41 mg of a 60% dispersion in mineral oil, 1.00 mmol). The reaction mixture was stirred for 30 minutes. A drop of water added was added and then the reaction mixture was diluted with water and extracted with ethyl acetate (×2). The combined organic extracts were dried (MgSO4) and concentrated and the residue purified by column chromatography (1% MeOH/DCM) to give a sticky white solid (Note 4) that was suspended in diethyl ether and filtered off to yield the title compound as a white crystalline solid (242 mg, 77%).
Reaction SMILES: [BH4-].[Na+].C(O)C.[N+:6]([CH:9]=[CH:10][C:11]1[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[C:13]([O:19][CH3:20])[CH:12]=1)([O-:8])=[O:7].C(O)(=O)C>O1CCOCC1>[N+:6]([CH2:9][CH2:10][C:11]1[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[C:13]([O:19][CH3:20])[CH:12]=1)([O-:8])=[O:7]
Reactant: COc1cc(C=C[N+](=O)[O-])cc(OC)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCO
Solvent: CC(=O)O
Product: COc1cc(CC[N+](=O)[O-])cc(OC)c1
Temperature: 0 °C
Yield: 53.5 %

Procedure:
To a well stirred suspension of sodium borohydride (5 g) in a mixture of dioxane (100 ml) and absolute ethanol (30 ml) was added dropwise a solution of 1-(2-nitroethenyl)-3,5-dimethoxybenzene (12.6 g) in dioxane (100 ml) over a 1 hour period. Following addition the mixture was stirred for an additionnal 45 minutes period. To the resulting suspension were added ice-water (120 ml) and 50% aqueous acetic acid (10 ml). Agitation was maintained for 1 hour and the clear solution was concentrated under reduced pressure. The residue was extracted with ethyl acetate/water, the organic layer was washed with saturated aqueous sodium chloride and dried over magnesium sulfate. Evaporation of solvents afforded the crude title compound (10.8 g). Trap to trap distillation under high vacuum (0.05 Millibars) at 180° C. yielded 1-(2-nitroethyl)-3,5-dimethoxybenzene as a colorless oil (6.8 g).
Reaction SMILES: [CH3:1][N:2]1[C:15]2[C:6]([CH:7]=[CH:8][C:9]3[NH:19][CH2:18][CH:17]=[C:11]4[NH:12][C:13](=[O:16])[C:14]=2[C:10]=34)=[C:5]([CH2:20][S:21]([CH3:24])(=[O:23])=[O:22])[CH:4]=[CH:3]1.[C:25](Cl)(=[O:28])[O:26][CH3:27].C(N(C(C)C)C(C)C)C.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C(=O)C.CO>[CH3:1][N:2]1[C:15]2[C:6]([CH:7]=[CH:8][C:9]3[N:19]([C:25]([O:26][CH3:27])=[O:28])[CH2:18][CH:17]=[C:11]4[NH:12][C:13](=[O:16])[C:14]=2[C:10]=34)=[C:5]([CH2:20][S:21]([CH3:24])(=[O:23])=[O:22])[CH:4]=[CH:3]1
Reactant: CN1C=CC(CS(C)(=O)=O)=c2ccc3c4c([nH]c(=O)c-4c21)=CCN3
Reactant: COC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)N1CC=c2[nH]c(=O)c3c4c(ccc1c2-3)=C(CS(C)(=O)=O)C=CN4C
Temperature: 25 °C
Reaction time: 8 h
Yield: 40.9 %

Procedure:
A mixture of Example 6a (0.0145 g, 0.042 mmol) in N,N-dimethylacetamide (0.5 mL) was treated sequentially with methyl carbonochloridate (0.016 mL, 0.211 mmol) and N-ethyl-N-isopropylpropan-2-amine (0.074 mL, 0.422 mmol) and stirred overnight at ambient temperature. The reaction mixture was then diluted with methanol (1.2 mL), treated with sodium carbonate (0.011 g, 0.105 mmol) and stirred at ambient temperature for 4 hours. The reaction mixture was partitioned between ethyl acetate and water and washed with saturated aqueous sodium chloride. The aqueous layers were combined and exhaustedly extracted with ethyl acetate. The combined organic layers were dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by reverse phase HPLC(C18, acetonitrile/water (0.1% TFA), 0-50%) to provide 0.0069 g (40.7%) of the title compound. 1H NMR (400 MHz, DMSO-d6) δ 10.51 (s, 1H), 7.76 (d, J=1.53 Hz, 1H), 7.69 (s, 1H), 7.29 (m, 1H), 7.23 (m, 1H), 6.79 (s, 1H), 5.00 (d, J=15.56 Hz, 1H), 4.44 (m, 2H), 4.12 (s, 3H), 3.94 (d, J=15.26 Hz, 1H), 3.50 (s, 3H), 2.93 (s, 3H). MS (ESI+) m/z 402.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[C:11]([CH:15]2[CH2:17][CH:16]2[NH:18]C(=O)OCC2C=CC=CC=2)[CH:12]=[N:13][CH:14]=1.B(Br)(Br)Br.[CH2:33]([S:35](Cl)(=[O:37])=[O:36])[CH3:34].[NH4+].[Cl-]>C(Cl)Cl.O>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[C:11]([CH:15]2[CH2:17][CH:16]2[NH:18][S:35]([CH2:33][CH3:34])(=[O:37])=[O:36])[CH:12]=[N:13][CH:14]=1
Reactant: CCS(=O)(=O)Cl
Reactant: O=C(NC1CC1c1cncc(-c2cccc(Cl)c2Cl)c1)OCc1ccccc1
Agent: BrB(Br)Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: O
Product: CCS(=O)(=O)NC1CC1c1cncc(-c2cccc(Cl)c2Cl)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 7.5 %

Procedure:
To a solution of benzyl 2-(5-(2,3-dichlorophenyl)pyridin-3-yl)cyclopropylcarbamate (94 mg, 0.227 mmol) in DCM (3 ml) was added BBr3 (0.682 ml, 0.682 mmol) at 0° C. This reaction mixture was stirred for 1 h at 0° C. The reaction was quenched by addition of saturated NaHCO3 solution, and the mixture was extracted with AcOEt. The extract was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was dissolved in pyridine (3.00 ml), and ethanesulfonyl chloride (0.086 ml, 0.910 mmol) was added to the solution. This reaction mixture was stirred at room temperature. After 1 h, saturated NH4Cl solution in water was added. The mixture was extracted with AcOEt. The extract was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash column (EtOAc/Heptane=0-50%, v/v) gave N-(2-(5-(2,3-dichlorophenyl)pyridin-3-yl)cyclopropyl)ethanesulfonamide (6.2 mg, 0.017 mmol, 7% yield). ESI-MS m/z: 371 [M+1]+. 1H NMR (CDCl3, 400 MHz) 1.31 (t, J=7.2 Hz, 3H), 1.38-1.43 (m, 2H), 2.35-2.38 (m, 1H), 2.86-2.91 (m, 1H), 3.14 (q, J=7.2 Hz, 2H), 7.41 (dd, J=7.6, 2.0 Hz, 1H), 7.47 (t, J=7.6 Hz, 1H), 7.57 (t, J=2.0 Hz, 1H), 7.65 (dd, J=7.6, 2.0 Hz, 1H), 8.46 (d, J=2.4 Hz, 1H), 8.53 (d, J=2.4 Hz, 1H).
Reaction SMILES: [O:1]1CCO[CH:2]1[C:6]1[CH:11]=[CH:10][C:9]([C:12]2(O)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[CH:8][CH:7]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(OCC)(=O)C.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[C:12]1([C:9]2[CH:8]=[CH:7][C:6]([CH:2]=[O:1])=[CH:11][CH:10]=2)[CH2:17][CH2:16][CH2:15][CH2:14][CH:13]=1
Reactant: OC1(c2ccc(C3OCCO3)cc2)CCCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: O=Cc1ccc(C2=CCCCC2)cc1
Temperature: 50 °C
Reaction time: 2 h
Yield: 13.9 %

Procedure:
1-(4-[1,3]Dioxolan-2-yl-phenyl)cyclohexanol (45 g) and p-toluenesulfonic acid (3.4 g) in 300 mL of toluene were refluxed for 3 hours under Dean-Stark conditions. After cooling, ethyl acetate and a saturated sodium hydrogen carbonate solution were added. The organic layer was washed twice with water, dried (magnesium sulphate), filtered and concentrated in vacuo. The residual oil was dissolved in glacial acetic acid (250 mL) and 1 M hydrochloric acid (25 mL) was added and the mixture was stirred at 50° C. for 2 hours. After cooling, the mixture was concentrated in vacuo. The residual oil was partitioned between ethyl acetate and water. The organic phase was washed three times with water, dried (magnesium sulphate), filtered and concentrated in vacuo. The residual oil was distilled in vacuo and the fraction boiling at 120-130° C. (0.2 mmHg) was collected to afford 4.7 g of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:12]([C:13]([OH:15])=[O:14])[O:11][C:10](=[O:16])[NH:9]2)[CH:5]=[CH:6][CH:7]=1.CO.[CH3:19][Si](C=[N+]=[N-])(C)C>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:12]([C:13]([O:15][CH3:19])=[O:14])[O:11][C:10](=[O:16])[NH:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: O=C1N[C@H](c2cccc(Br)c2)[C@@H](C(=O)O)O1
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)[C@H]1OC(=O)N[C@@H]1c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 82.9 %

Procedure:
To a solution of (4R,5S)-4-(3-bromophenyl)-2-oxooxazolidine-5-carboxylic acid (20 mg, 0.070 mmol) in tetrahydrofuran (2 mL)/methanol (0.500 mL) was added trimethylsilyldiazomethane (0.063 mL, 0.126 mmol) dropwise at 0° C. After 3 h, the reaction was allowed to warm to ambient temperature and stirred for an additional 15 h, at which time it was concentrated in vacuo to provide (4R,5S)-methyl 4-(3-bromophenyl)-2-oxooxazolidine-5-carboxylate (18.2 mg, 0.058 mmol, 82% yield). 1H NMR (500 MHz, DMSO-d6) δ ppm 3.78 (s, 3H) 4.98 (d, J=4.88 Hz, 1H) 5.01-5.04 (m, 1H) 7.37-7.45 (m, 2H) 7.56 (s, 1H) 7.57-7.61 (m, 1H) 8.60 (s, 1H). Mass spec.: 301.77 (MH)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:14][CH2:15][OH:16])[CH2:13][CH2:12][NH:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].CN1CCOCC1.[CH3:24][O:25][C:26]1[CH:34]=[CH:33][CH:32]=[CH:31][C:27]=1[C:28](Cl)=[O:29]>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:14][CH2:15][OH:16])[CH2:13][CH2:12][N:11]([C:28](=[O:29])[C:27]3[CH:31]=[CH:32][CH:33]=[CH:34][C:26]=3[O:25][CH3:24])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: OCCC1(c2ccc(Cl)c(Cl)c2)CCNC1
Reactant: COc1ccccc1C(=O)Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: COc1ccccc1C(=O)N1CCC(CCO)(c2ccc(Cl)c(Cl)c2)C1
Temperature: 0 °C
Reaction time: 4.5 h
Yield: 61.7 %

Procedure:
3-(3,4-Dichloro-phenyl)-3-(2-hydroxy-ethyl)-pyrrolidine, (218 mg, 0.83 mmol) was dissolved in dichloromethane at -78° C. and treated with 4-methylmorpholine (0.19 mL, 1.73 mmol, 2 eq.) and 2-methoxybenzoyl chloride (155 mg, 0.84 mmol, 1 eq.) in dichloromethane (3×1 mL). The solution was allowed to warm to 0° C. and stir for 4.5 hours. The solution was washed with 1N HCl and 5% sodium bicarbonate and the organic phase was dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue was chromatographed on silica gel (30 g) with a gradient of 50% ethyl acetate in hexane to 6% methanol in dichloromethane to give 202 mg (60%) of the title compound.
Reaction SMILES: CS(O[CH2:6][CH2:7][N:8]1[C:16]2[N:15]=[C:14]([NH2:17])[N:13]3[N:18]=[C:19]([C:21]4[O:22][CH:23]=[CH:24][CH:25]=4)[N:20]=[C:12]3[C:11]=2[CH:10]=[CH:9]1)(=O)=O.Cl.Cl.[F:28][C:29]1[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:30]=1[CH2:36][CH2:37][CH2:38][N:39]1[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1.CCN(C(C)C)C(C)C>CN(C=O)C>[F:28][C:29]1[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:30]=1[CH2:36][CH2:37][CH2:38][N:39]1[CH2:40][CH2:41][N:42]([CH2:6][CH2:7][N:8]2[C:16]3[N:15]=[C:14]([NH2:17])[N:13]4[N:18]=[C:19]([C:21]5[O:22][CH:23]=[CH:24][CH:25]=5)[N:20]=[C:12]4[C:11]=3[CH:10]=[CH:9]2)[CH2:43][CH2:44]1
Reactant: Fc1ccc(CCCN2CCNCC2)c(F)c1
Reactant: CS(=O)(=O)OCCn1ccc2c1nc(N)n1nc(-c3ccco3)nc21
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Nc1nc2c(ccn2CCN2CCN(CCCc3ccc(F)cc3F)CC2)c2nc(-c3ccco3)nn12
Temperature: 100 °C
Reaction time: 5 h

Procedure:
To a solution of the title D compound of Example 1, 2-{5-amino-2-(furan-2-yl)-7H-pyrrolo[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-7-yl}ethyl methanesulfonate (0.06 g, 0.165 mmol) in dry DMF (5 mL), the title A compound, 1-(3-(2,4-difluorophenyl)propyl)piperazine dihydrochloride (0.33 mmol) and 0.06 mL of DIEA are added, and the solution is stirred at 100° C. for 5 h. The reaction mixture is cooled to RT, and the solvent is removed under reduced pressure. The crude product is purified by flash chromatography using DCM/MeOH/NH4OH-95/5.0/0.5 as eluent to give 7-(2-(4-(3-(2,4-difluorophenyl)propyl)piperazin-1-yl)ethyl)-2-(furan-2-yl)-7H-pyrrolo[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5-amine: LC/MS (M+1=507.2). 1H NMR (DMSO-d6, 400 MHz) δ 1.66 (quintuplet, 2H, J=7.2 Hz), 2.24 (t, 2H, J=7.2 Hz), 2.32 (m, 4H), 2.45 (m, 4H), 2.58 (t, 2H, J=7.2 Hz), 2.67 (t, 2H, J=6.4 Hz), 4.22 (t, 2H, J=6.4 Hz), 6.58 (d, 1H, J=3.2 Hz), 6.71 (m, 1H), 6.99 (dt, 1H, J=8.4 Hz and 1.6 Hz), 7.14 (m, 2H), 7.18 (d, 1H, J=3.2 Hz), 7.32 (m, 1H), 7.48 (br s, 2H, NH2), 7.91 (s, 1H). Anal. calculated for (C26H28F2N8O): C, 61.65; H, 5.57; F, 7.50; N, 22.12; 0, 3.16. Found C, 61.38: H, 5.66; N, 22.07.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:44])=[C:6]([N:8]2[C:12](=[O:13])[N:11]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[S:27](=[O:39])(=[O:38])[NH:28][C:29](=[O:37])[C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=4[Cl:36])=[CH:17][CH:16]=3)[C:10]([CH2:40][CH2:41][CH2:42][CH3:43])=[N:9]2)[CH:7]=1.[CH2:45]([N:48]=[C:49]=[O:50])[CH2:46][CH3:47]>CN(C1C=CN=CC=1)C.N1C=CC=CC=1>[CH2:40]([C:10]1[N:11]([CH2:14][C:15]2[CH:16]=[CH:17][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[S:27](=[O:38])(=[O:39])[NH:28][C:29](=[O:37])[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[Cl:36])=[CH:19][CH:20]=2)[C:12](=[O:13])[N:8]([C:6]2[CH:7]=[C:2]([NH:1][C:49]([NH:48][CH2:45][CH2:46][CH3:47])=[O:50])[CH:3]=[CH:4][C:5]=2[Cl:44])[N:9]=1)[CH2:41][CH2:42][CH3:43]
Reactant: CCCCc1nn(-c2cc(N)ccc2Cl)c(=O)n1Cc1ccc(-c2ccccc2S(=O)(=O)NC(=O)c2ccccc2Cl)cc1
Reactant: CCCN=C=O
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CCCCc1nn(-c2cc(NC(=O)NCCC)ccc2Cl)c(=O)n1Cc1ccc(-c2ccccc2S(=O)(=O)NC(=O)c2ccccc2Cl)cc1
Yield: 60.1 %

Procedure:
At room temperature, under N2, a solution of 34 mg (0.052 mmole) of 2-(5-amino-2-chlorophenyl)-5-n-butyl-4-[[2'-[N-(2-chlorobenzoyl)sulfamoyl]biphenyl-4-yl]methyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (from Example 60), 6.4 mg (0.052 mmole) of DMAP, 23 mg (0.26 mmole) of propyl isocyanate, and 1 mL of pyridine was stirred overnight. After quenching with water, the organic material was extracted with EtOAc, washed with water and brine, and dried over sodium sulfate. The crude product obtained after filtration and removal of volatiles was flash chromatographed over silica gel (gradient elution with 0.5-5% MeOH/CH2Cl2) to give 23 mg (61%) of the desired compound as a white solid, mp >208° C. (gradual), homogeneous by TLC (9:1 MeOH/CH2Cl2), mass spectrum (FAB) m/e 773 (M+K)+.